Evidence Base Practice an RUA on Nutrition and liver Disease.

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Cochrane Database of Systematic Reviews

Nutritional support for liver disease (Review)

Koretz RL, Avenell A, Lipman TO

Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. Cochrane Database of Systematic Reviews 2012, Issue 5. Art. No.: CD008344. DOI: 10.1002/14651858.CD008344.pub2.

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Nutritional support for liver disease (Review)

https://doi.org/10.1002%2F14651858.CD008344.pub2

https://www.cochranelibrary.com

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T A B L E O F C O N T E N T S HEADER......................................................................................................................................................................................................... 1 ABSTRACT..................................................................................................................................................................................................... 1 PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2 BACKGROUND.............................................................................................................................................................................................. 4 OBJECTIVES.................................................................................................................................................................................................. 4 METHODS..................................................................................................................................................................................................... 5 RESULTS........................................................................................................................................................................................................ 9

Figure 1.................................................................................................................................................................................................. 10 Figure 2.................................................................................................................................................................................................. 11 Figure 3.................................................................................................................................................................................................. 20

DISCUSSION.................................................................................................................................................................................................. 21 AUTHORS' CONCLUSIONS........................................................................................................................................................................... 22 ACKNOWLEDGEMENTS................................................................................................................................................................................ 22 REFERENCES................................................................................................................................................................................................ 23 CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 42 DATA AND ANALYSES.................................................................................................................................................................................... 94

Analysis 1.1. Comparison 1 Mortality, Outcome 1 All studies............................................................................................................ 97 Analysis 1.2. Comparison 1 Mortality, Outcome 2 Parenteral nutrition............................................................................................. 97 Analysis 1.3. Comparison 1 Mortality, Outcome 3 Enteral nutrition.................................................................................................. 98 Analysis 1.4. Comparison 1 Mortality, Outcome 4 Supplements....................................................................................................... 99 Analysis 1.5. Comparison 1 Mortality, Outcome 5 Medical trials....................................................................................................... 99 Analysis 1.6. Comparison 1 Mortality, Outcome 6 Surgical trials....................................................................................................... 100 Analysis 1.7. Comparison 1 Mortality, Outcome 7 Alcoholic hepatitis............................................................................................... 101 Analysis 1.8. Comparison 1 Mortality, Outcome 8 Cirrhosis............................................................................................................... 102 Analysis 1.9. Comparison 1 Mortality, Outcome 9 HCC...................................................................................................................... 103 Analysis 1.10. Comparison 1 Mortality, Outcome 10 Abstracts excluded.......................................................................................... 103 Analysis 1.11. Comparison 1 Mortality, Outcome 11 Surgical trials without transplant patients.................................................... 105 Analysis 1.12. Comparison 1 Mortality, Outcome 12 Intent to treat - best-case scenario for intervention...................................... 105 Analysis 1.13. Comparison 1 Mortality, Outcome 13 Intent to treat - worst-case scenario for intervention.................................... 107 Analysis 2.1. Comparison 2 Appearance of ascites, Outcome 1 All studies....................................................................................... 111 Analysis 2.2. Comparison 2 Appearance of ascites, Outcome 2 Parenteral nutrition....................................................................... 111 Analysis 2.4. Comparison 2 Appearance of ascites, Outcome 4 Supplements.................................................................................. 112 Analysis 2.5. Comparison 2 Appearance of ascites, Outcome 5 Medical trials.................................................................................. 112 Analysis 2.6. Comparison 2 Appearance of ascites, Outcome 6 Surgical trials................................................................................. 113 Analysis 2.7. Comparison 2 Appearance of ascites, Outcome 7 Alcoholic hepatitis......................................................................... 113 Analysis 2.8. Comparison 2 Appearance of ascites, Outcome 8 Cirrhosis......................................................................................... 114 Analysis 2.9. Comparison 2 Appearance of ascites, Outcome 9 HCC................................................................................................. 115 Analysis 2.10. Comparison 2 Appearance of ascites, Outcome 10 Abstracts excluded..................................................................... 115 Analysis 2.11. Comparison 2 Appearance of ascites, Outcome 11 Surgical trials without transplant.............................................. 117 Analysis 2.12. Comparison 2 Appearance of ascites, Outcome 12 Intent to treat - best-case scenario for intervention................. 117 Analysis 2.13. Comparison 2 Appearance of ascites, Outcome 13 Intent to treat - worst-case scenario for intervention............... 118 Analysis 3.1. Comparison 3 Resolution of ascites, Outcome 1 All studies......................................................................................... 123 Analysis 3.2. Comparison 3 Resolution of ascites, Outcome 2 Parenteral nutrition......................................................................... 123 Analysis 3.3. Comparison 3 Resolution of ascites, Outcome 3 Enteral nutrition.............................................................................. 124 Analysis 3.4. Comparison 3 Resolution of ascites, Outcome 4 Supplements.................................................................................... 124 Analysis 3.5. Comparison 3 Resolution of ascites, Outcome 5 Medical trials.................................................................................... 125 Analysis 3.7. Comparison 3 Resolution of ascites, Outcome 7 Alcoholic hepatitis........................................................................... 125 Analysis 3.8. Comparison 3 Resolution of ascites, Outcome 8 Cirrhosis........................................................................................... 126 Analysis 3.10. Comparison 3 Resolution of ascites, Outcome 10 Abstracts excluded....................................................................... 127 Analysis 3.12. Comparison 3 Resolution of ascites, Outcome 12 Intent to treat - best-case scenario for intervention - no changes made because all patients with ascites reported...............................................................................................................................

128

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Analysis 3.13. Comparison 3 Resolution of ascites, Outcome 13 Intent to treat - worst case scenario for intervention - no changes made because all patients with ascites reported...............................................................................................................................

129

Analysis 4.1. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 1 All studies......................................................... 133 Analysis 4.2. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 2 Parenteral nutrition.......................................... 133 Analysis 4.3. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 3 Enteral nutrition (all medical).......................... 134 Analysis 4.4. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 4 Supplements.................................................... 134 Analysis 4.5. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 5 Medical trials.................................................... 135 Analysis 4.6. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 6 Surgical trials.................................................... 136 Analysis 4.7. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 7 Alcoholic hepatitis............................................ 136 Analysis 4.8. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 8 Cirrhosis............................................................ 137 Analysis 4.9. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 9 HCC................................................................... 138 Analysis 4.10. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 10 Abstracts excluded....................................... 138 Analysis 4.11. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 11 Surgical trials without transplant patients (no trials with transplant patients)......................................................................................................................................................

140

Analysis 4.12. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 12 Intent to treat - best-case scenario for intervention...........................................................................................................................................................................................

140

Analysis 4.13. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 13 Intent to treat - worst-case scenario for intervention...........................................................................................................................................................................................

141

Analysis 5.1. Comparison 5 Appearance of encephalopathy - all studies, Outcome 1 All studies.................................................... 148 Analysis 5.2. Comparison 5 Appearance of encephalopathy - all studies, Outcome 2 Parenteral nutrition - all trials.................... 150 Analysis 5.3. Comparison 5 Appearance of encephalopathy - all studies, Outcome 3 Parenteral nutrition - medical trials........... 150 Analysis 5.4. Comparison 5 Appearance of encephalopathy - all studies, Outcome 4 Parenteral nutrition - surgical trials............ 151 Analysis 5.5. Comparison 5 Appearance of encephalopathy - all studies, Outcome 5 Enteral nutrition - all studies...................... 151 Analysis 5.6. Comparison 5 Appearance of encephalopathy - all studies, Outcome 6 Enteral nutrition - medical trials................. 152 Analysis 5.8. Comparison 5 Appearance of encephalopathy - all studies, Outcome 8 Supplements............................................... 153 Analysis 5.9. Comparison 5 Appearance of encephalopathy - all studies, Outcome 9 Medical trials all trials................................. 154 Analysis 5.10. Comparison 5 Appearance of encephalopathy - all studies, Outcome 10 Medical trials - standard amino acids....... 155 Analysis 5.11. Comparison 5 Appearance of encephalopathy - all studies, Outcome 11 Medical trials - BCAAs.............................. 156 Analysis 5.12. Comparison 5 Appearance of encephalopathy - all studies, Outcome 12 Surgical trials - all studies....................... 157 Analysis 5.14. Comparison 5 Appearance of encephalopathy - all studies, Outcome 14 Surgical trials - BCAAs............................. 157 Analysis 5.15. Comparison 5 Appearance of encephalopathy - all studies, Outcome 15 Alcoholic hepatitis - all studies............... 158 Analysis 5.16. Comparison 5 Appearance of encephalopathy - all studies, Outcome 16 Alcoholic hepatitis - standard amino acids.......................................................................................................................................................................................................

159

Analysis 5.17. Comparison 5 Appearance of encephalopathy - all studies, Outcome 17 Alcoholic hepatitis - BCAA....................... 160 Analysis 5.18. Comparison 5 Appearance of encephalopathy - all studies, Outcome 18 Cirrhosis - all studies............................... 160 Analysis 5.19. Comparison 5 Appearance of encephalopathy - all studies, Outcome 19 Cirrhosis - standard amino acids............ 161 Analysis 5.20. Comparison 5 Appearance of encephalopathy - all studies, Outcome 20 Cirrhosis - BCAAs..................................... 162 Analysis 5.21. Comparison 5 Appearance of encephalopathy - all studies, Outcome 21 HCC - all studies...................................... 163 Analysis 5.23. Comparison 5 Appearance of encephalopathy - all studies, Outcome 23 HCC - BCAAs............................................ 163 Analysis 5.24. Comparison 5 Appearance of encephalopathy - all studies, Outcome 24 Abstracts excluded.................................. 164 Analysis 5.25. Comparison 5 Appearance of encephalopathy - all studies, Outcome 25 Surgical trials - transplant trials eliminated..............................................................................................................................................................................................

167

Analysis 5.26. Comparison 5 Appearance of encephalopathy - all studies, Outcome 26 ITT - Parenteral nutrition - best-case scenario..................................................................................................................................................................................................

167

Analysis 5.27. Comparison 5 Appearance of encephalopathy - all studies, Outcome 27 ITT - Parenteral nutrition - worst-case scenario..................................................................................................................................................................................................

168

Analysis 5.28. Comparison 5 Appearance of encephalopathy - all studies, Outcome 28 ITT - Enteral nutrition - best-case scenario..................................................................................................................................................................................................

169

Analysis 5.29. Comparison 5 Appearance of encephalopathy - all studies, Outcome 29 ITT - Enteral nutrition - worst-case scenario..................................................................................................................................................................................................

170

Analysis 5.30. Comparison 5 Appearance of encephalopathy - all studies, Outcome 30 ITT- Supplements - best-case scenario...... 170 Analysis 5.31. Comparison 5 Appearance of encephalopathy - all studies, Outcome 31 ITT - Supplements - worst-case scenario.... 172 Analysis 6.1. Comparison 6 Resolution of encephalopathy, Outcome 1 All trials............................................................................. 181 Analysis 6.2. Comparison 6 Resolution of encephalopathy, Outcome 2 Parenteral nutrition (all medical trials)............................ 181

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Analysis 6.3. Comparison 6 Resolution of encephalopathy, Outcome 3 Enteral nutrition (all medical trials)................................. 182 Analysis 6.4. Comparison 6 Resolution of encephalopathy, Outcome 4 Supplements (all medical trials)...................................... 182 Analysis 6.5. Comparison 6 Resolution of encephalopathy, Outcome 5 Medical trials - all trials.................................................... 183 Analysis 6.6. Comparison 6 Resolution of encephalopathy, Outcome 6 Medical trials - standard amino acids.............................. 184 Analysis 6.7. Comparison 6 Resolution of encephalopathy, Outcome 7 Medical trials - BCAAs....................................................... 185 Analysis 6.11. Comparison 6 Resolution of encephalopathy, Outcome 11 Alcoholic hepatitis - all trials........................................ 185 Analysis 6.12. Comparison 6 Resolution of encephalopathy, Outcome 12 Alcoholic hepatitis - standard amino acids.................. 186 Analysis 6.13. Comparison 6 Resolution of encephalopathy, Outcome 13 Alcoholic hepatitis - BCAAs.......................................... 187 Analysis 6.14. Comparison 6 Resolution of encephalopathy, Outcome 14 Cirrhosis - all................................................................. 187 Analysis 6.16. Comparison 6 Resolution of encephalopathy, Outcome 16 Cirrhosis - BCAAs.......................................................... 188 Analysis 6.20. Comparison 6 Resolution of encephalopathy, Outcome 20 Abstracts excluded - all trials....................................... 188 Analysis 6.21. Comparison 6 Resolution of encephalopathy, Outcome 21 Abstracts excluded - standard amino acids................. 189 Analysis 6.22. Comparison 6 Resolution of encephalopathy, Outcome 22 Abstracts excluded - BCAAs.......................................... 190 Analysis 6.24. Comparison 6 Resolution of encephalopathy, Outcome 24 ITT - All trials - best-case scenario - no changes made because all patients reported..............................................................................................................................................................

191

Analysis 6.25. Comparison 6 Resolution of encephalopathy, Outcome 25 ITT - Parenteral nutrition trials - best-case scenario - no changes made because all patients reported...............................................................................................................................

191

Analysis 6.26. Comparison 6 Resolution of encephalopathy, Outcome 26 ITT - Enteral trials - best-case scenario - no changes made because all patients reported....................................................................................................................................................

192

Analysis 6.27. Comparison 6 Resolution of encephalopathy, Outcome 27 ITT - Supplements trials - best-case scenario - no changes made because all patients reported.....................................................................................................................................

193

Analysis 6.28. Comparison 6 Resolution of encephalopathy, Outcome 28 ITT - All trials - worst-case scenario - no changes made because all patients reported..............................................................................................................................................................

193

Analysis 6.29. Comparison 6 Resolution of encephalopathy, Outcome 29 ITT - Parenteral nutrition trials - worst-case scenario - no changes made because all patients reported.............................................................................................................................

194

Analysis 6.30. Comparison 6 Resolution of encephalopathy, Outcome 30 ITT - Enteral nutrition trials - worst-case scenario - no changes made because all patients reported.....................................................................................................................................

195

Analysis 6.31. Comparison 6 Resolution of encephalopathy, Outcome 31 ITT - Supplement trials - worst-case scenario - no changes made because all patients reported.....................................................................................................................................

195

Analysis 7.1. Comparison 7 infections, Outcome 1 All studies........................................................................................................... 198 Analysis 7.2. Comparison 7 infections, Outcome 2 Trials with total numbers (Meng) excluded...................................................... 198 Analysis 7.3. Comparison 7 infections, Outcome 3 Parenteral nutrition........................................................................................... 199 Analysis 7.4. Comparison 7 infections, Outcome 4 Enteral nutrition................................................................................................ 199 Analysis 7.5. Comparison 7 infections, Outcome 5 Supplements...................................................................................................... 200 Analysis 7.6. Comparison 7 infections, Outcome 6 Medical trials...................................................................................................... 201 Analysis 7.7. Comparison 7 infections, Outcome 7 Surgical trials..................................................................................................... 201 Analysis 7.8. Comparison 7 infections, Outcome 8 Alcoholic hepatitis............................................................................................. 201 Analysis 7.9. Comparison 7 infections, Outcome 9 Cirrhosis............................................................................................................. 202 Analysis 7.10. Comparison 7 infections, Outcome 10 HCC................................................................................................................. 202 Analysis 7.11. Comparison 7 infections, Outcome 11 Abstracts excluded......................................................................................... 203 Analysis 7.12. Comparison 7 infections, Outcome 12 Abstracts excluded......................................................................................... 203 Analysis 7.13. Comparison 7 infections, Outcome 13 Surgical trials excluding transplants............................................................. 204 Analysis 7.14. Comparison 7 infections, Outcome 14 Parenteral nutrition - best-case scenario...................................................... 205 Analysis 7.15. Comparison 7 infections, Outcome 15 Parenteral nutrition - worst-case scenario.................................................... 205 Analysis 7.16. Comparison 7 infections, Outcome 16 Enteral nutrition - best-case scenario........................................................... 206 Analysis 7.17. Comparison 7 infections, Outcome 17 Enteral nutrition - worst-case scenario......................................................... 206 Analysis 7.18. Comparison 7 infections, Outcome 18 Supplements - best-case scenario................................................................ 207 Analysis 7.19. Comparison 7 infections, Outcome 19 Supplements - worst-case scenario.............................................................. 208 Analysis 8.1. Comparison 8 Serum bilirubin, Outcome 1 All studies................................................................................................. 212 Analysis 8.2. Comparison 8 Serum bilirubin, Outcome 2 Parenteral nutrition................................................................................. 212 Analysis 8.3. Comparison 8 Serum bilirubin, Outcome 3 Enteral nutrition (all medical trials)........................................................ 213 Analysis 8.4. Comparison 8 Serum bilirubin, Outcome 4 Supplements............................................................................................ 213 Analysis 8.5. Comparison 8 Serum bilirubin, Outcome 5 Medical trials............................................................................................ 213

iii

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Analysis 8.6. Comparison 8 Serum bilirubin, Outcome 6 Surgical trials........................................................................................... 214 Analysis 8.7. Comparison 8 Serum bilirubin, Outcome 7 Alcoholic hepatitis................................................................................... 215 Analysis 8.8. Comparison 8 Serum bilirubin, Outcome 8 Cirrhosis................................................................................................... 215 Analysis 8.10. Comparison 8 Serum bilirubin, Outcome 10 Abstracts excluded............................................................................... 216 Analysis 9.1. Comparison 9 Duration of hospitalisation, Outcome 1 All studies............................................................................... 217 Analysis 9.2. Comparison 9 Duration of hospitalisation, Outcome 2 Enteral nutrition - medical versus surgical trials.................. 218 Analysis 9.3. Comparison 9 Duration of hospitalisation, Outcome 3 Cirrhosis................................................................................. 218 Analysis 9.4. Comparison 9 Duration of hospitalisation, Outcome 4 Surgery................................................................................... 219 Analysis 10.1. Comparison 10 Duration of stay in ICU, Outcome 1 All studies (all surgery [transplantation])................................. 220 Analysis 11.1. Comparison 11 Postoperative total complications, Outcome 1 All studies............................................................... 221 Analysis 11.2. Comparison 11 Postoperative total complications, Outcome 2 All studies except those with total complications not patients...........................................................................................................................................................................................

222

Analysis 11.3. Comparison 11 Postoperative total complications, Outcome 3 HCC......................................................................... 223 Analysis 12.1. Comparison 12 Postoperative intra-abdominal complications, Outcome 1 All studies............................................ 224 Analysis 12.2. Comparison 12 Postoperative intra-abdominal complications, Outcome 2 HCC...................................................... 224 Analysis 13.1. Comparison 13 Postoperative pneumonia, Outcome 1 All studies............................................................................ 225 Analysis 13.2. Comparison 13 Postoperative pneumonia, Outcome 2 HCC...................................................................................... 226 Analysis 14.1. Comparison 14 Postoperative wound infections, Outcome 1 All studies................................................................... 227 Analysis 14.2. Comparison 14 Postoperative wound infections, Outcome 2 HCC............................................................................. 228 Analysis 15.1. Comparison 15 Nitrogen balance, Outcome 1 All studies (all medical)..................................................................... 229 Analysis 15.2. Comparison 15 Nitrogen balance, Outcome 2 Cirrhosis............................................................................................. 229 Analysis 16.1. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 1 All studies.................................................... 233 Analysis 16.2. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 2 Parenteral nutrition..................................... 234 Analysis 16.3. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 3 Enteral nutrition.......................................... 234 Analysis 16.4. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 4 Supplements............................................... 235 Analysis 16.5. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 5 Medical trials............................................... 236 Analysis 16.6. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 6 Surgical trials............................................... 237 Analysis 16.7. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 7 Alcoholic hepatitis....................................... 238 Analysis 16.8. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 8 Cirrhosis....................................................... 238 Analysis 16.9. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 9 HCC.............................................................. 239 Analysis 16.10. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 10 Abstracts excluded................................... 240 Analysis 16.11. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 11 Surgical trials without transplant patients..................................................................................................................................................................................................

241

Analysis 16.12. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention...........................................................................................................................................................................................

242

Analysis 16.13. Comparison 16 Mortality - absolute risk diHerence (ARD), Outcome 13 Intent to treat - worst-case scenario for intervention...........................................................................................................................................................................................

243

Analysis 17.1. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 1 All studies................................ 248 Analysis 17.2. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 2 Parenteral nutrition................ 249 Analysis 17.4. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 4 Supplements........................... 249 Analysis 17.5. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 5 Medical trials........................... 250 Analysis 17.6. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 6 Surgical trials.......................... 250 Analysis 17.7. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 7 Alcoholic hepatitis.................. 251 Analysis 17.8. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 8 Cirrhosis.................................. 252 Analysis 17.9. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 9 HCC......................................... 252 Analysis 17.10. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 10 Abstracts excluded.............. 253 Analysis 17.11. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 11 Surgical trials without transplant..............................................................................................................................................................................................

254

Analysis 17.12. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention......................................................................................................................................................................

255

Analysis 17.13. Comparison 17 Appearance of ascites - absolute risk diHerence (ARD), Outcome 13 Intent to treat - worst-case scenario for intervention......................................................................................................................................................................

256

Analysis 18.1. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 1 All studies................................. 260

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Analysis 18.2. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 2 Parenteral nutrition.................. 261 Analysis 18.3. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 3 Enteral nutrition....................... 261 Analysis 18.4. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 4 Supplements............................ 262 Analysis 18.5. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 5 Medical trials............................ 262 Analysis 18.7. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 7 Alcoholic hepatitis.................... 263 Analysis 18.8. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 8 Cirrhosis.................................... 263 Analysis 18.10. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 10 Abstracts excluded................ 264 Analysis 18.12. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention - no changes made.....................................................................................................................................

265

Analysis 18.13. Comparison 18 Resolution of ascites - absolute risk diHerence (ARD), Outcome 13 Intent to treat - worst-case scenario for intervention - no changes made.....................................................................................................................................

266

Analysis 19.1. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 1 All studies....... 271 Analysis 19.2. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 2 Parenteral nutrition.................................................................................................................................................................................................

271

Analysis 19.3. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 3 Enteral nutrition (all medical)...........................................................................................................................................................................................

272

Analysis 19.4. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 4 Supplements.... 272 Analysis 19.5. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 5 Medical trials.... 273 Analysis 19.6. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 6 Surgical trials.... 274 Analysis 19.7. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 7 Alcoholic hepatitis.................................................................................................................................................................................................

274

Analysis 19.8. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 8 Cirrhosis......... 275 Analysis 19.9. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 9 HCC................ 276 Analysis 19.10. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 10 Abstracts excluded.................................................................................................................................................................................................

276

Analysis 19.11. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 11 Surgical trials without transplant patients (no trials with transplant patients).......................................................................................................

277

Analysis 19.12. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention...................................................................................................................................................

278

Analysis 19.13. Comparison 19 Appearance gastrointestinal bleeding - absolute risk diHerence (ARD), Outcome 13 Intent-to- treat - worst-case scenario for intervention........................................................................................................................................

279

Analysis 20.1. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 1 All studies................ 286 Analysis 20.2. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 2 Parenteral nutrition - all trials................................................................................................................................................................................................

288

Analysis 20.3. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 3 Parenteral nutrition - medical trials......................................................................................................................................................................................

288

Analysis 20.4. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 4 Parenteral nutrition - surgical trials.......................................................................................................................................................................................

289

Analysis 20.5. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 5 Enteral nutrition - all studies....................................................................................................................................................................................................

290

Analysis 20.6. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 6 Enteral nutrition - medical trials.........................................................................................................................................................................................

290

Analysis 20.8. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 8 Supplements........... 291 Analysis 20.9. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 9 Medical trials all trials.......................................................................................................................................................................................................

293

Analysis 20.10. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 10 Medical trials - standard amino acids...........................................................................................................................................................................

294

Analysis 20.11. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 11 Medical trials - BCAAs.....................................................................................................................................................................................................

294

Analysis 20.12. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 12 Surgical trials - all studies....................................................................................................................................................................................................

295

Analysis 20.14. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 14 Surgical trials - BCAAs.....................................................................................................................................................................................................

296

Analysis 20.15. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 15 Alcoholic hepatitis - all studies............................................................................................................................................................................................

297

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Analysis 20.16. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 16 Alcoholic hepatitis - standard amino acids.........................................................................................................................................................................

297

Analysis 20.17. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 17 Alcoholic hepatitis - BCAA....................................................................................................................................................................................................

298

Analysis 20.18. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 18 Cirrhosis - all studies....................................................................................................................................................................................................

299

Analysis 20.19. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 19 Cirrhosis - standard amino acids...........................................................................................................................................................................................

300

Analysis 20.20. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 20 Cirrhosis - BCAAs..... 300 Analysis 20.21. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 21 HCC - all studies...... 301 Analysis 20.23. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 23 HCC - BCAAs......... 302 Analysis 20.24. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 24 Abstracts excluded.................................................................................................................................................................................................

302

Analysis 20.25. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 25 Surgical trials - transplant trials eliminated..................................................................................................................................................................

305

Analysis 20.26. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 26 ITT - Parenteral nutrition - best-case scenario for intervention...................................................................................................................................

306

Analysis 20.27. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 27 ITT - Parenteral nutrition - worst-case scenario for intervention.................................................................................................................................

307

Analysis 20.28. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 28 ITT - Enteral nutrition - best-case scenario for intervention...................................................................................................................................

308

Analysis 20.29. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 29 ITT - Enteral nutrition - worst-case scenario for intervention.................................................................................................................................

308

Analysis 20.30. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 30 ITT- Supplements - best-case scenario for intervention...................................................................................................................................................

309

Analysis 20.31. Comparison 20 Appearance of encephalopathy - absolute risk diHerence (ARD), Outcome 31 ITT - Supplements - worst-case scenario for intervention.................................................................................................................................................

310

Analysis 21.1. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 1 All trials...................... 319 Analysis 21.2. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 2 Parenteral nutrition (all medical trials).................................................................................................................................................................................

320

Analysis 21.3. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 3 Enteral nutrition (all medical trials)........................................................................................................................................................................................

321

Analysis 21.4. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 4 Supplements (all medical trials)........................................................................................................................................................................................

321

Analysis 21.5. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 5 Medical trials - all trials.......................................................................................................................................................................................................

322

Analysis 21.6. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 6 Medical trials - standard amino acids...........................................................................................................................................................................................

323

Analysis 21.7. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 7 Medical trials - BCAAs.... 323 Analysis 21.11. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 11 Alcoholic hepatitis - all trials................................................................................................................................................................................................

324

Analysis 21.12. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 12 Alcoholic hepatitis - standard amino acids.........................................................................................................................................................................

325

Analysis 21.13. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 13 Alcoholic hepatitis - BCAAs...................................................................................................................................................................................................

325

Analysis 21.14. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 14 Cirrhosis - all.......... 326 Analysis 21.16. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 16 Cirrhosis - BCAAs...... 327 Analysis 21.20. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 20 Abstracts excluded - all trials................................................................................................................................................................................................

327

Analysis 21.21. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 21 Abstracts excluded - standard amino acids.........................................................................................................................................................................

328

Analysis 21.22. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 22 Abstracts excluded - BCAAs...................................................................................................................................................................................................

329

Analysis 21.24. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 24 ITT - All trials - best case scenario - no changes made because all patients reported......................................................................................................

329

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Analysis 21.25. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 25 ITT - Parenteral nutrition trials - best-case scenario - no changes made because all patients reported...................................................................

330

Analysis 21.26. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 26 ITT - Enteral nutrition trials - best-case scenario - no changes made because all patients reported..................................................................................

331

Analysis 21.27. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 27 ITT - Supplement trials - best-case scenario - no changes made because all patients reported..................................................................................

331

Analysis 21.28. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 28 ITT - All trials - worst- case scenario - no changes made because all patients reported......................................................................................................

332

Analysis 21.29. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 29 ITT - Parenteral nutrition trials - worst-case scenario - no changes made because all patients reported.................................................................

333

Analysis 21.30. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 30 ITT - Enteral nutrition trials - worst-case scenario - no changes made because all patients reported................................................................................

333

Analysis 21.31. Comparison 21 Resolution of encephalopathy - absolute risk diHerence (ARD), Outcome 31 ITT - Supplement trials - worst-case scenario - no changes made because all patients reported................................................................................

334

Analysis 22.1. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 1 All studies................................................... 336 Analysis 22.2. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 2 Trials with total numbers (Meng) excluded.... 337 Analysis 22.3. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 3 Parenteral nutrition................................... 337 Analysis 22.4. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 4 Enteral nutrition......................................... 338 Analysis 22.5. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 5 Supplements.............................................. 339 Analysis 22.6. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 6 Medical trials.............................................. 339 Analysis 22.7. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 7 Surgical trials............................................. 340 Analysis 22.8. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 8 Alcoholic hepatitis..................................... 340 Analysis 22.9. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 9 Cirrhosis..................................................... 340 Analysis 22.10. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 10 HCC......................................................... 341 Analysis 22.11. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 11 Abstracts excluded................................. 342 Analysis 22.12. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 12 Abstracts excluded................................. 342 Analysis 22.13. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 13 Surgical trials excluding transplants....... 343 Analysis 22.14. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 14 Parenteral nutrition - best-case scenario..................................................................................................................................................................................................

343

Analysis 22.15. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 15 Parenteral nutrition - worst-case scenario..................................................................................................................................................................................................

344

Analysis 22.16. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 16 Enteral nutrition - best-case scenario...... 344 Analysis 22.17. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 17 Enteral nutrition - worst-case scenario..... 345 Analysis 22.18. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 18 Supplements - best-case scenario......... 346 Analysis 22.19. Comparison 22 Infections - absolute risk diHerence (ARD), Outcome 19 Supplements - worst-case scenario........ 346 Analysis 23.1. Comparison 23 Serum albumin, Outcome 1 Parenteral nutrition.............................................................................. 347 Analysis 23.2. Comparison 23 Serum albumin, Outcome 2 Enteral nutrition................................................................................... 348 Analysis 23.3. Comparison 23 Serum albumin, Outcome 3 Supplements........................................................................................ 348

ADDITIONAL TABLES.................................................................................................................................................................................... 349 APPENDICES................................................................................................................................................................................................. 350 CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 352 DECLARATIONS OF INTEREST..................................................................................................................................................................... 352 SOURCES OF SUPPORT............................................................................................................................................................................... 352 DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 352 INDEX TERMS............................................................................................................................................................................................... 353

vii

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[Intervention Review]

Nutritional support for liver disease

Ronald L Koretz1, Alison Avenell2, Timothy O Lipman3

1Granada Hills, CA, USA. 2Health Services Research Unit, Health Sciences Building, University of Aberdeen, Aberdeen, UK. 3GI-Hepatology- Nutrition Section, Department of Veterans AHairs Medical Center, Washington, DC, USA

Contact address: Ronald L Koretz, 16847 Colven Road, Granada Hills, CA, CA 91344, USA. [email protected], [email protected].

Editorial group: Cochrane Hepato-Biliary Group Publication status and date: New, published in Issue 5, 2012.

Citation: Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. Cochrane Database of Systematic Reviews 2012, Issue 5. Art. No.: CD008344. DOI: 10.1002/14651858.CD008344.pub2.

A B S T R A C T

Background

Weight loss and muscle wasting are commonly found in patients with end-stage liver disease. Since there is an association between mal- nutrition and poor clinical outcome, such patients (or those at risk of becoming malnourished) are often given parenteral nutrition, enteral nutrition, or oral nutritional supplements. These interventions have costs and adverse effects, so it is important to prove that their use results in improved morbidity or mortality, or both.

Objectives

To assess the beneficial and harmful effects of parenteral nutrition, enteral nutrition, and oral nutritional supplements on the mortality and morbidity of patients with underlying liver disease.

Search methods

The following computerised databases were searched: the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Cen- tral Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and Science Citation Index Expanded (January 2012). In addition, reference lists of identified trials and review articles and Clinicaltrials.gov were searched. Trials identified in a previous systematic handsearch of Index Medicus were also considered. Handsearches of a number of medical journals, including abstracts from annual meetings, were done. Experts in the field and manufacturers of nutrient formulations were contacted for potential references.

Selection criteria

Randomised clinical trials (parallel or cross-over design) comparing groups of patients with any underlying liver disease who received, or did not receive, enteral or parenteral nutrition or oral nutritional supplements were identified without restriction on date, language, or publication status. Six categories of trials were separately considered: medical or surgical patients receiving parenteral nutrition, enteral nutrition, or supplements.

Data collection and analysis

The following data were sought in each report: date of publication; geographical location; inclusion and exclusion criteria; the type of nutritional support and constitution of the nutrient formulation; duration of treatment; any nutrition provided to the controls; other in- terventions provided to the patients; number, sex, age of the study participants; hospital or outpatient status; underlying liver disease; risks of bias (sequence generation, allocation concealment, blinding, incomplete outcome reporting, intention-to-treat analysis, selec- tive outcome reporting, others (vested interests, baseline imbalance, early stopping)); mortality; hepatic morbidity (development or res- olution of ascites or hepatic encephalopathy, occurrence of gastrointestinal bleeding); quality of life scores; adverse events; infections; lengths of stay in the hospital or intensive care unit; costs; serum bilirubin; postoperative complications (surgical trials only); and nutri- tional outcomes (nitrogen balance, anthropometric measurements, body weight). The primary outcomes of this review were mortality, hepatic morbidity, quality of life, and adverse events. Data were extracted in duplicate; differences were resolved by consensus.

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https://doi.org/10.1002%2F14651858.CD008344.pub2

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Data for each outcome were combined in a meta-analysis (RevMan 5.1). Estimates were reported using risk ratios or mean differences, along with the 95% confidence intervals (CI). Both fixed-effect and random-effects models were employed; fixed-effect models were re- ported unless one model, but not the other, found a significant difference (in which case both were reported). Heterogeneity was assessed by the Chi2 test and I2 statistic. Subgroup analyses were planned to assess specific liver diseases (alcoholic hepatitis, cirrhosis, hepato- cellular carcinoma), acute or chronic liver diseases, and trials employing standard or branched-chain amino acid formulations (for the hepatic encephalopathy outcomes). Sensitivity analyses were planned to compare trials at low and high risk of bias and trials reported as full papers. The following exploratory analyses were undertaken: 1) medical and surgical trials were combined for each nutritional in- tervention; 2) intention-to-treat analyses in which missing dichotomous data were imputed as best- and worst-case scenarios; 3) all trials were combined to assess mortality; 4) effects were estimated by absolute risk reductions.

Main results

Thirty-seven trials were identified; only one was at low risk of bias. Most of the analyses failed to find any significant differences. The significant findings that were found were the following: 1) icteric medical patients receiving parenteral nutrition had a reduced serum bilirubin (mean difference (MD) -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) and better nitrogen balance (MD 3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day, 1 trial); 2) surgical patients receiving parenteral nutrition had a reduced incidence of postoperative ascites only in the fixed-effect model (RR 0.65, 95% CI 0.48 to 0.87, 2 trials, I2 = 70%) and one trial demonstrated a reduction in postoperative complications, especially infections (pneumonia in particular); 3) enteral nutrition may have improved nitrogen balance in medical patients (although a combination of the three trials was not possible); 4) one surgical trial of enteral nutrition found a reduction in postoperative complications; and 5) oral nutritional supplements had several effects in medical patients (reduced occurrence of ascites (RR 0.57, 95% CI 0.37 to 0.88, 3 trials), possibly (significant differences only seen in the fixed-effect model) reduced rates of infection (RR 0.49, 95% CI 0.24 to 0.99, 3 trials, I2 = 14%), and improved resolution of hepatic encephalopathy (RR 3.75, 95% CI 1.15 to 12.18, 2 trials, I2 = 79%). While there was no overall effect of the supplements on mortality in medical patients, the one low risk of bias trial found an increased risk of death in the recipients of the supplements. Three trials of supplements in surgical patients failed to show any significant differences. No new information was derived from the various subgroup or sensitivity analyses. The exploratory analyses were also unrevealing except for a logical conundrum. There was no difference in mortality when all of the trials were combined, but the trials of parenteral nutrition found that those recipients had better survival (RR 0.53, 95% CI 0.29 to 0.98, 10 trials). Either the former observation represents a type II error or the latter one a type I error.

Authors' conclusions

The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demon- strated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.

P L A I N L A N G U A G E S U M M A R Y

Nutritional support for patients with liver disease

Patients with liver diseases, especially decompensated cirrhosis, commonly have weight loss and muscle wasting. It is known that such patients have poorer clinical outcomes than patients with similar diagnoses but without such weight loss or muscle wasting. If the problem is just deprivation of nutrients, it would be expected that the provision of some type of nutrition should result in better outcomes. Nutri- ents in addition to food, or in place of food when food is not taken in sufficient amounts, can be provided in a manner whereby the patient voluntarily consumes them by drinking various nutrient formulations. Nutrients can also be provided in an involuntary manner; tubes can be placed in the vein (parenteral nutrition) or intestinal tract (enteral nutrition) and nutrient solutions infused through them. All of these nutritional interventions have associated economic costs and also can produce a variety of complications (including vomiting, diarrhoea, and altered metabolic functions (for example, high blood sugar)). Thus, it is important to determine if such nutritional interventions (that is, the provision of nutrients in some manner other than just as food) do result in improvements in clinical outcomes. Since the best way to make such a determination is to undertake randomised trials, in which patients are assigned by chance to receive, or not receive, one or another of these treatments, this systematic review was undertaken to identify and summarise this information. Randomised trials com- paring patients with liver diseases who were assigned to receive parenteral nutrition, enteral nutrition, or oral nutritional supplements to similar patients assigned not to receive any nutritional intervention were collected. The three nutritional interventions were considered separately. In addition, within each category of nutritional intervention, patients with medical conditions were compared separately from patients with surgical conditions. Thus there were six primary analyses, medical patients receiving or not receiving parenteral nutrition, surgical patients receiving or not receiving parenteral nutrition, medical patients receiving or not receiving enteral nutrition, surgical pa- tients receiving or not receiving enteral nutrition, medical patients receiving or not receiving supplements by mouth, and surgical patients receiving or not receiving supplements by mouth. The outcomes of interest were mortality, hepatic morbidity (ascites, gastrointestinal bleeding, encephalopathy), quality of life, adverse events, infections, cost, duration of hospitalisation, jaundice, postoperative complica- tions (only for the surgical trials), and nutritional outcomes (for example, body weight). A total of 37 randomised trials were identified. All but one had a high risk of systematic error (bias, that is overestimation of benefits and underestimation of harms). When the data were combined, most of the analyses failed to demonstrate a difference. There were some significant differences observed. These were that 1) parenteral nutrition reduced serum bilirubin more rapidly and improved one type of nutritional outcome (nitrogen balance) in med-

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ical patients with jaundice, and may have reduced some postoperative complications; 2) enteral nutrition may have improved nitrogen balance in medical patients, and reduced postoperative complications in surgical patients; and 3) supplements reduced the occurrence of ascites and also may have decreased the number of infections. Furthermore, the receipt of supplements (especially ones containing branched-chain amino acids) may have been helpful in the treatment of patients with hepatic encephalopathy. No significant effects were seen from the use of supplements in surgical patients. None of these observed benefits can be said to be definitively present because of the presence of methodologic flaws in the trials, which may have produced an overestimation of the observed effect. Moreover, due to too few patients included in the trials with two few outcome measures, both spurious significant findings and spurious insignificant findings cannot be excluded. The data are not strong enough to justify a recommendation to use these nutritional interventions routinely. We need well-designed and well-conducted randomised trials to prove that such therapy is indeed efficacious.

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B A C K G R O U N D

In 1936, Studley observed that patients undergoing surgery for pep- tic ulcer disease who had lost more than 20% of their body weight had a significantly higher postoperative mortality than patients with less profound weight loss (Studley 1936). Since then, a num- ber of other observational studies have demonstrated an associa- tion between malnutrition and a poor outcome in a variety of dis- ease states (Buzby 1980; Reinhardt 1980; Baker 1982) including liver disease (Nielsen 1993; Italian Multicentre Cooperative Project 1994; Alvares-da-Silva 2005; Norman 2006; Sanchez 2006). Furthermore, any person who is deprived of nutrients for a long enough period of time (usually weeks) will develop morbidity, and ultimately die, from malnutrition (Keys 1962). Based on this latter observation, as well as an assumption that the association between malnutrition and outcome was causative, recommendations to provide protein and calories to malnourished patients with liver disease, particular- ly cirrhosis, have been promulgated (Kondrup 1997; Alberino 2001; Tajika 2001).

The development of parenteral nutrition in the 1960s allowed clin- icians to infuse high density nutrient formulations intravenously to patients who, for various reasons, were not eating sufficient amounts of nutrients to maintain body weight (Rhoads 1981). The advent of this technology led to the wide-spread implementation of parenteral nutrition. In 1971, a narrative review of this interven- tion claimed that the adverse course of a wide variety of disease states would be influenced favourably by the provision of these ad- ditional nutrients (Dudrick 1971). This enthusiasm was transferred to enteral nutrition when it became clear that patients with intact gastrointestinal function could have calorie-dense nutrient formu- lations infused through tubes located in the stomach or small in- testine.

Neither parenteral nutrition nor enteral nutrition should be con- fused with eating. These nutritional interventions require the placement of tubes (in the venous system or gastrointestinal tract) through which the liquid formulations of nutrients can be in- fused. The formulations are prepared in areas that look more like laboratories or pharmacies than kitchens. Furthermore, the nutri- ent provision does not require any active effort by the recipient. To make a distinction with regard to this latter point, other liquid (or powders to which water is added) formulations containing calories and source(s) of nitrogen have been tested and marketed as nutri- ent supplements that are consumed orally; these require the vo- litional actions of the patient (that is, the patient has to swallow them) in order for the contents to be assimilated in the body.

Since association should not be confused with causation, and since it is well established that individuals can tolerate a few weeks of nu- trient deprivation without adverse consequences (Keys 1962), one cannot assume that these various techniques (parenteral nutrition, enteral nutrition, or oral supplements) are effective therapeutic in- terventions. Since they all have associated potential harms (includ- ing cost), efficacy needs to be demonstrated in randomised clinical trials comparing the use of the intervention to a control group that is not receiving any nutritional intervention.

Furthermore, the perspective regarding what causes 'malnutrition' has been broadened (Jensen 2010) to consider the role of the un- derlying disease. It is now being recognised that weight loss is not just a matter of poor nutrient intake. Rather, underlying inflamma- tory processes may produce various chemical substances (for ex-

ample, cytokines) that impair protein synthesis and increase pro- tein degradation. In such situations, it would not necessarily be ex- pected that simply providing exogenous nutrients would improve clinical outcomes. In fact, it might even be possible that such nu- trient provision simply further stokes the catabolic fires. This more recent perspective further emphasises the need for establishing proof of efficacy with randomised trials.

A systematic review published in 2001 (Koretz 2001) assessed the utility of parenteral nutrition versus no nutritional therapy in a wide variety of disease states. The available evidence at that time indi- cated that parenteral nutrition was not, in general, beneficial. In fact, when all of the trials were considered together, the use of par- enteral nutrition resulted in more infectious complications. Eight of the randomised clinical trials addressed patients with liver disease; parenteral nutrition was not found to have any significant effect on morbidity or mortality when those trials were considered together (Koretz 2001).

A subsequent systematic review assessed the utility of enteral nu- trition and oral supplements (Koretz 2007). When various subgroup combinations of all of these trials were considered, some benefits were teased out. With regard to liver disease, five trials of oral sup- plements did not find that this intervention significantly improved morbidity or mortality in general (Koretz 2007). Five other trials failed to show that enteral nutrition had any impact on morbidi- ty (Koretz 2007). However, when the three enteral nutrition trials that reported mortality were combined in a meta-analysis, a signif- icant benefit was observed (Koretz 2007). Unfortunately, all of the observed effects were confounded by the fact that they were only seen in trials with high risks of bias (Koretz 2007).

It has been claimed that the parenteral infusion or enteral deliv- ery of special nutrient formulations that are rich in branched-chain amino acids (BCAA) are helpful in patients with liver disease, espe- cially in the treatment of hepatic encephalopathy. The postulated mechanism has been that the encephalopathy is due to an excess of aromatic amino acids in the central nervous system and that BCAA can compete for uptake in the brain thereby restoring a more nor- mal balance (Fischer 1971; Morgan 1990). A previous Cochrane re- view (Als-Nielsen 2003) described an improvement in hepatic en- cephalopathy associated with the use of BCAA, but the effect was only seen in trials with high risks of bias.

Other than these two somewhat dated systematic reviews (Koretz 2001; Koretz 2007) and a Cochrane protocol designed to assess nu- tritional interventions in patients with liver transplantation (Langer 2009), no systematic reviews of the nutritional interventions of par- enteral nutrition, enteral nutrition, or oral supplements in liver dis- ease are available. It is the purpose of this systematic review to ad- dress the question of whether or not any of these nutritional in- terventions favourably impact on the morbidity or mortality of pa- tients with liver disease other than those who have undergone liver transplantation.

O B J E C T I V E S

We assessed the beneficial and harmful effects of parenteral nutri- tion, enteral nutrition, and oral nutritional supplements (liquid for- mulations containing at least a source of nitrogen and non-nitrogen calories) on the mortality and morbidity of patients with underly- ing liver disease.

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M E T H O D S

Criteria for considering studies for this review

Types of studies

We included randomised clinical trials of parallel or cross-over de- sign evaluating the effect of enteral or parenteral nutrition or mul- ticomponent oral supplements for patients with liver disease. For cross-over trials we only planned to use the data from the first peri- od (although no such trials were identified). For trials with multifac- torial designs, we planned on only using the groups receiving the nutritional intervention and the group receiving no intervention, if possible. If not, we compared all patients receiving the nutritional intervention to all patients not receiving this intervention. We did not apply any restrictions on date of publication, language of pub- lication, or publication status (published or unpublished work). For trials published in a language other than English, we planned to ob- tain a translation done by a person who was fluent in both English and the language of the paper. If a full translation was not available but there was an English abstract, the trial was treated as one that was available only in abstract form.

Types of participants

Patients of any age, sex, and ethnic group with any underlying acute or chronic liver disease and who were treated as inpatients or out- patients were considered.

There were two general categories of patients, medical and surgi- cal. Since there is a planned systematic review of nutritional inter- ventions in liver transplantation (Langer 2009), in general trials in transplanted patients were not included in this review. The excep- tions to this rule were trials that provided perioperative nutrition- al support in patients undergoing liver transplantation, since this is analogous to perioperative trials for other types of surgery in pa- tients with liver disease. In such trials, only clinical events in the im- mediate post-transplant course (the hospitalisation for the trans- plant or the first 30 postoperative days, or both) were considered as outcomes. (If the trial enrolled patients on a transplant list but did not follow them through the transplant surgery, that trial was considered to be a medical trial in patients with cirrhosis.) The sur- gical and medical trials were assessed separately. Thus, there were six planned primary analyses, namely each of the three nutritional interventions in medical patients, and each of the three in surgical patients.

Alcoholic hepatitis was defined in whatever manner the original investigators chose, but a necessary component of that definition was that there was a history of recent alcohol use (within the pre- ceding two weeks).

Types of interventions

We included trials that compared parenteral or enteral nutrition or oral nutritional supplements (as defined in the following para- graphs) to placebo or no treatment. The intervention had to be provided for at least five days; we assumed that nutritional sup- port would not have an effect if it was given for a shorter period of time. Trials that compared different types of nutritional interven- tions but did not include a group receiving placebo or no interven- tion were excluded.

Parenteral nutrition was defined as the receipt of intravenous flu- ids containing a source of nitrogen (as amino acids or protein hy-

drolysate) and some quantity of non-protein calories (as fat or car- bohydrate), which were greater than the intravenous calories giv- en to the control group. The intravenous infusion of only a source of nitrogen (without additional calories) was not considered to be parenteral nutrition. In a previous systematic review of parenter- al nutrition, a distinction was made between full parenteral nutri- tion and 'protein-sparing therapy' or hypocaloric parenteral nutri- tion (Koretz 2001). These two forms of parenteral nutrition differed with regard to the amount of calories that were provided. In this re- view, this distinction was disregarded.

Enteral nutrition was defined as the intestinal infusion (through a tube) of a liquid formulation containing at least a source of nitrogen (as amino acids, protein hydrolysates, or intact protein) and some quantity of non-protein calories (as fat or carbohydrate) such that the planned total (intravenous fluids and enteral nutrition) caloric intake was greater than the intravenous calories given to the con- trol group. The site of infusion could be the stomach or small intes- tine.

Oral nutritional supplements were defined as liquid formulations containing a source of nitrogen (as amino acids, protein hy- drolysates, or intact protein) and a non-protein source of calories (as fat or carbohydrate). These formulations could be commercially available or specifically manufactured or developed by the inves- tigators. Powdered formulations that were mixed with water prior to ingestion were acceptable. Trials of supplements that consisted only of additional food or of vitamins or minerals, or both, were ex- cluded.

Control patients received no nutrient intake beyond that contained in ad libitum feedings or 5% (or in the case of neonatal trials, 10%) dextrose intravenously, or both, as maintenance fluid. If cross-over to a nutritional intervention was designed to occur in a parallel group trial, and in fact was done in at least one patient before at least five days, the trial was excluded. (Since the question is the use or non-use of nutritional support, we assumed that a period of at least five days of no support would provide a minimum time for the effects of the nutrient deprivation to become manifest.)

Trials that included more than one nutritional intervention were in- cluded provided that there was also a group that received place- bo or no intervention; each intervention was compared to the no- treatment group. However, trials that compared different types of nutritional interventions but did not include a group receiving placebo or no intervention were excluded.

If the treatment group received more than one nutritional inter- vention (for example, some patients received enteral nutrition and others received oral supplements), we classified the trial according to the intervention that the majority of patients in the treatment group received. (No such trials were identified.)

Cointerventions were acceptable as long as they were provided in the same manner to both arms of the trial.

Types of outcome measures

Primary outcomes

1. Mortality. 2. Hepatic morbidity (appearance or failure of resolution of as- cites, appearance of gastrointestinal bleeding, appearance or failure of resolution of hepatic encephalopathy).

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3. Health-related quality of life as assessed by the original investi- gators.

4. Adverse events.

Depending on the availability of data, we attempted to classify ad- verse events as serious or non-serious. Serious adverse events were defined as any untoward medical occurrence that was life threaten- ing; resulted in death, or persistent or significant disability; or any medical event which may have jeopardised the patient or required intervention to prevent it (ICH-GCP 1997). All other adverse events (that is, any medical occurrence not necessarily having a causal re- lationship with the treatment but did, however, cause a dose reduc- tion or discontinuation of the treatment were considered as non- serious.

Secondary outcomes

1. Serum bilirubin as a manifestation of jaundice; only trials in which the average baseline bilirubin level in the participants was at least 3 mg% (51.3 µmol/l) were employed.

2. Infection. 3. Postoperative surgical complications (for the surgical trials on- ly) (if the surgical trial involved patients without cirrhosis, the outcomes of liver failure (ascites, variceal bleeding, and en- cephalopathy) would not be expected to be reported):• total;• intra-abdominal;• pneumonia;• wound problems.

4. Duration of hospitalisation (including duration of stay in an in- tensive care unit for critically ill patients).

5. Costs or other economic outcomes, or both, as assessed by the original investigators.

6. Nutritional variables (body weight, anthropometrics (triceps skinfold thickness, midarm muscle circumference, midarm cir- cumference), nitrogen balance).

Search methods for identification of studies

We searched the Cochrane Hepato-Biliary Group Controlled Tri- als Register (Gluud 2011), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). The search strate- gies (designed at the protocol stage) are available in Appendix 1 with the time span for the searches. As it was expected that thou- sands of potential titles would be identified, RK did the preliminary review of all of the titles. One of the other authors (AA) was given a sample of 500 titles to also check. If it was discovered that RK had missed any pertinent references, the remaining citations were then to be searched in duplicate; however, no new trials were identified in this second review. We also searched the reference lists of identi- fied trials and review articles for additional publications of interest.

In addition, RK has already conducted a handsearch of a num- ber of medical subject headings (alimentation; branched chain amino acids; dietary disorders; enteral nutrition; enterosto- my; fat emulsion; food, formulated; gastrostomy; hyperalimenta- tion; hypocaloric alimentation; hypocaloric nutrition; intragastric feeding; intragastric feeds; intragastric nutrition; nutrition; nutri- tion diseases; nutrition disorders; nutrition supplement; parenteral nutrition; percutaneous endoscopic gastrostomy; peripheral par- enteral nutrition; permissive underfeeding; post-pyloric feeding;

post-pyloric nutrition; protein hydrolysate; supplemental feeding; supplemental feeds; total parenteral nutrition) in Index Medicus from 1960 until it ceased publication in 2000.

RK conducted hand searches of several medical journals (includ- ing published abstracts of meetings of the American Society of Par- enteral and Enteral Nutrition, the European Society of Parenteral and Enteral Nutrition, the American Gastroenterological Associa- tion, and the American Association for the Study of Liver Diseases) from 1965 to the present (January 2012). These journals included Annals of Internal Medicine, Clinical Nutrition, Gastroenterology, Hepatology, Journal of Parenteral and Enteral Nutrition, Lancet, and The New England Journal of Medicine.

We contacted experts in the field, including scientific societies for nutritional support, and asked whether they have been involved in, or were aware of, any further trials (recent or ongoing) on the ef- fects of parenteral nutrition, enteral nutrition, or supplements for patients with liver disease. We have also tried to identify unpub- lished studies by contacting manufacturers of nutritional support formulations that have been sold for use in liver disease. (The reg- istered products identified were Hepatic-Aid II™ (Hormel Health- labs), NutriHep™ (Nestle USA), HepatAmine™ (B. Braun Medical), and Aminoleban™ (Otsuka); three companies were contacted via email through the contact mechanism available on the company website (Nestle, B. Braum, Otsuka), and the fourth was contact- ed via an email address available on that website (Hormel Health- labs).)

Finally, we searched Clinicaltrials.gov in an effort to identify unpub- lished trials (Appendix 1).

We had planned to modify the search strategies if required as the review progressed, but this was not necessary.

Data collection and analysis

Selection of studies

RK assessed the retrieved references for eligibility in the manner described above. The excluded studies and the reasons for their ex- clusion are listed in the Characteristics of excluded studies table. Trials deemed to be eligible for inclusion were reviewed by a sec- ond individual (either AA or TL).

Data extraction and management

We extracted data on source (the geographical region where the trial was conducted, the year of publication); type of nutritional in- tervention (parenteral nutrition, enteral nutrition, oral nutritional supplement); inclusion and exclusion criteria; description of partic- ipants (number, sex distribution, age distribution, surgical or med- ical, underlying liver disease: acute (hepatitis (viral, alcoholic in ab- sence of cirrhosis, drug-induced, other), obstructive jaundice, oth- er), chronic (cirrhosis with etiology (viral, alcoholic, autoimmune, drug-induced, metabolic, other), hepatitis (alcoholic with cirrhosis, viral, other)), or acute-on-chronic); presence or absence of hepat- ic decompensation (ascites, encephalopathy, variceal bleeding); and setting (inpatient or outpatient); interventions and co-inter- ventions; outcomes; factors assessing risk of bias (see next section); and sample size calculation using a data extraction sheet.

For each of the groups of trials, we reported total number of pa- tients randomised and the demographic features of sex and age; for these latter two estimations, we used whatever data were avail-

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able. We assumed that when these features were not reported for the dropouts in a particular trial they were comparable to the fea- tures of those reported. We also assumed that when the sex distri- bution or age was not reported for a particular trial the averages reported for the remaining trials were representative of the missing data. Medians were used as means if the means were not reported and the averages were calculated on a weighted basis rather than calculating a simple average from the average age or percentage male in each trial.

Assessment of risk of bias in included studies

Two investigators (RK and either AA or TL) independently assessed the methodological quality of the trials without masking the trial names. These assessments followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Hig- gins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2011). Due to the risk of biased overestimation of intervention ef- fects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), we looked at the influence of methodological quality of the trials on the re- sults by evaluating the reported randomisation and follow-up pro- cedures in each trial. If information was not available in the pub- lished trial, we attempted to contact authors of the publications in order to assess the trials correctly; the details of these contact at- tempts are summarised in the descriptions of each included trial. We assessed generation of the allocation sequence, allocation con- cealment, blinding, incomplete outcome data, intention-to-treat analysis, selective outcome reporting, and other biases (baseline imbalance, early stopping, and vested interest bias) using the fol- lowing criteria.

Generation of the allocation sequence• Low risk, sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are ade- quate if performed by an independent adjudicator.• Unclear risk, the trial was described as randomised but the method of sequence generation was not specified.• High risk, the sequence generation method is not, or may not be, random. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate patients, are inade- quate and were excluded for the assessment of benefits but not for the assessment of harms.

Allocation concealment• Low risk, allocation was controlled by a central and independent randomisation unit; sequentially numbered, opaque and sealed envelopes, or similar; so that intervention allocations could not have been foreseen in advance of, or during, enrolment.• Unclear risk, the trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in ad- vance of or during enrolment.• High risk, if the allocation sequence was known to the investi- gators who assigned participants or if the study was quasi-ran- domised. Quasi-randomised studies were excluded for the as- sessment of benefits but not for the assessment of harms.

Blinding• Low risk, the trial was described as double blind and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.• Unclear risk, the trial was described as double blind but the method of blinding was not described, so that knowledge of al- location was possible during the trial.• High risk, the trial was not double blind, so that the allocation was known during the trial.

Incomplete outcome data• Low risk, the numbers and reasons for dropouts and with- drawals in all intervention groups were described, or if it was specified that there were no dropouts or withdrawals.• Unclear risk, the report gave the impression that there had been no dropouts or withdrawals but this was not specifically stated.• High risk, the number or reasons for dropouts and withdrawals were not described.

Intention-to-treat analysis• Low risk, all patients randomised into the trial were accounted for in the analyses or, if not, it was possible from the available data to perform such analyses.• Unclear risk, the report gave the impression that all of the pa- tients were included in the analyses but the actual numbers were not available.• High risk, not all of the patients were accounted for in the analy- ses and it was not possible to redo the analyses from the data provided.

Selective outcome reporting• Low risk, predefined, or clinically relevant and reasonably ex- pected outcomes were reported on. For these trials, there should be data regarding mortality and at least one element of hepatic (or, for the surgical trials in patients without cirrhosis, postoperative) morbidity.• Unclear risk, not all predefined or clinically relevant and reason- ably expected outcomes (mortality and at least one element of hepatic or postoperative morbidity) were reported on or were not reported fully, or it was unclear whether data on these out- comes were recorded or not.• High risk, one or more of the clinically relevant and reasonably expected outcomes (mortality and at least one element of he- patic morbidity) were not reported on; data on these outcomes should have been likely to have been recorded.

Potential vested interest biases (of investigators or sponsors, or both)• Low risk, the trial was not sponsored (in part or in whole) by fun- ders who would have an apparent interest in the outcome and the trial was conducted by investigators without previous work in the same area that might have produced a vested interest in them.• Unclear risk, identity of sponsors or prior work of investigators was not available.• High risk, trial sponsored by funders with potential vested inter- est or the trial conducted by investigators with previous publi- cations that would suggest vested interest, or both.

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Definition of low and high risk of bias

It was expected that few, if any, of the identified trials would be blinded. If blinding was not assessed as being adequate, trials with lower risk of bias were to be defined as those with the following fea- tures.

1. Low risk assessment of generation of allocation sequence. 2. Low risk assessment of allocation concealment. 3. Low risk assessment of handling of incomplete outcome data. 4. Low risk assessment of intention-to-treat analysis. 5. Low risk assessment of selective outcome reporting. 6. Low risk assessment of vested interest bias.

If a trial was adequately blinded, it was to be considered to be at lower risk of bias if the following features were present.

All other trials were considered to be at high risk of bias.

Measures of treatment e<ect

Most of the primary outcomes (mortality, appearance or failure of resolution of ascites, appearance of gastrointestinal bleeding, ap- pearance or failure of resolution of hepatic encephalopathy, ad- verse events) are dichotomous and were assessed as present or absent. Two of the secondary outcomes (infections, postoperative complications) were also similarly assessed. The continuous data (duration of hospitalisation or duration of stay in an intensive care unit for critically ill patients, nutritional outcomes (body weight, anthropometrics, nitrogen balance), and economic parameters) were treated as continuous variables and were assessed as means and standard deviations. Health-related quality of life (defined by the investigators of the individual trials) was also expected to be presented as scales representing continuous variables. The end-of- study serum bilirubin was used with the assumption that the value at the beginning of the trial was the same in both groups.

If the report did not describe the number of patients with a partic- ular outcome, but only the total number of outcomes, it was as- sumed that each outcome occurred in an individual patient.

If the report did not specify the number of patients who newly developed one of the prespecified outcomes (that is, ascites, en- cephalopathy, infections, or the postoperative complications) or which of the patients had one of these conditions at the beginning of the trial and failed to resolve it but only noted the numbers of patients with these outcomes at the beginning and the end of the study, it was assumed that the difference between the numbers represented the number who failed to resolve it (if there were more outcomes at the beginning than at the end) or developed it (if the number at the end was greater than the number at the beginning). (For example, if the report only stated that there were five patients with ascites at the beginning and one at the end, it was assumed that four of the five had the ascites resolve and one did not.)

Unit of analysis issues

Health-related quality of life measurements were expected to vary from trial to trial and it was planned to perform the analysis af- ter standardisation. However, the data that were presented em- ployed a large number of scales, often without any explanation regarding what a normal value was nor whether a high number was favourable or unfavourable, so these data were presented only qualitatively.

Dealing with missing data

See section on exploratory analyses (Sensitivity analysis)

Assessment of heterogeneity

Heterogeneity was explored by the Chi2 test, with significance set at P < 0.10, and with the I2 statistic. The value of I2 is considered to represent the amount of heterogeneity that is present in a meta- analysis (Higgins 2002); values < 30% were defined as representing limited heterogeneity.

Assessment of reporting biases

We planned to use a funnel plot to explore bias (Egger 1997; Macaskill 2001) and the linear regression approach described by Egger et al to determine the funnel plot asymmetry (Egger 1997). However, with the exception of the medical trials of supplements, no category had a sufficient number of trials (at least 10) to make such an analysis worthwhile.

Data synthesis

We conducted primary analyses in the following six categories of comparisons.

Parenteral nutrition versus placebo or no intervention• Medical patients• Surgical patients Enteral nutrition versus placebo or no intervention• Medical patients• Surgical patients Oral supplements versus placebo or no intervention• Medical patients• Surgical patients We performed meta-analyses of these categories according to the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2011). We used the software package Review Manager 5 (RevMan 2011). For dichotomous variables, we calculated the risk ratio (RR) (previous- ly known as the 'relative risk') with 95% confidence interval (CI). For continuous variables, we calculated the mean difference (MD) with 95% CI. We used both a random-effects model (DerSimonian 1986) and a fixed-effect model (DeMets 1987). In the case of discrepancy between the two models we reported both results; otherwise we only reported the results from the fixed-effect model.

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses.

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• Low risk of bias trials and high risk of bias trials as separate analyses.• Trials of acute and trials of chronic liver disease as separate analyses (for the purposes of these analyses, alcoholic hepati- tis and hepatocellular carcinoma were considered to be chronic liver disease).• Patients with cirrhosis of any aetiology.• Trials of alcoholic hepatitis.• Trials in patients with hepatocellular carcinoma.• Publication status (only trials reported as full papers).• Trials of branched-chain amino acids and trials of standard amino acids in patients with hepatic encephalopathy as sepa- rate analyses.• Surgical trials excluding the liver transplant ones.

Sensitivity analysis

We planned to perform the following exploratory analyses.

• Combining the surgical and medical trials for each intervention.• Intention-to-treat analysis employing worst-best case (assum- ing the worst outcome for all patients with missing data in the treatment group and best outcome for all patients with miss- ing data in the control group) and best-worst case (assuming best outcome for all patients with missing data in the treatment group and worst outcome for all patients with missing data in the control group) scenarios. (These analyses provide the maxi- mum extremes in effect estimates.)• Using the absolute risk difference (ARD) as a measure of treat- ment effect.• Combining all of the trials for an assessment of mortality.• Because of the finding of a beneficial effect of enteral nutrition on mortality without any demonstrable effect on morbidity in a previous systematic review of enteral nutrition (Koretz 2007), we employed trial sequential analysis to evaluate if significant differences in the primary outcomes could be due to random er- ror (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009).

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of exclud- ed studies.

Results of the search

Initially, we identified 15,033 references from the computer search- es performed through January 2012. Most of these were duplicates or clearly irrelevant. We reviewed 322 citations in more detail; these were reports from 224 separate randomised trials and non-ran- domised or observational studies, review articles, and editorials. A total of 181 of these 224 studies and other publications did not meet the inclusion criteria and the 254 associated references were excluded; these are all listed in the table entitled Characteristics of excluded studies. Nine other studies (10 publications) were pub- lished in journals that were not readily available, in languages that required translation, failed to completely explain how the control groups were treated, or did not provide quantitative data (Fink 1978; Leweling 1980; Caballera Rovira 1987; Hartung 1989; Zhu- ming 2001; Khlynov 2009; Macias-Rosales 2010; Chen 2011; Korena-

ga 2011); these are listed in the Characteristics of studies awaiting classification. The remaining 34 trials, reported in 58 publications, were eligible for this review. Finally, a search of the records of RK identified an additional three eligible trials (Guy 1995; Sievert 1999; Schuetz 2006) that were reported in abstract format only. The de- tails of the 37 eligible trials are presented in the table entitled Char- acteristics of included studies and Table 1.

A search of clinicaltrials.gov identified 224 titles but most of them were not relevant to this topic. Seven potential (registered but un- published) trials (Córdoba; Mao; Pirlich; Seguin; Soriano; Tayek; Van Erpecum) were identified; three of these were clearly not go- ing to be eligible and are also listed in the Characteristics of exclud- ed studies (Córdoba; Soriano; Tayek) and the others (Mao; Pirlich; Seguin; Van Erpecum) are listed in Characteristics of ongoing stud- ies.

Five of the 37 eligible trials (Calvey 1985; Reilly 1990; Hasse 1997; Sievert 1999; Qiu 2009) included more than one treatment group. In four of them, one treatment group was given standard amino acid formulations and the second treatment group was given branched- chain amino acid formulations (Calvey 1985; Reilly 1990; Hasse 1997; Sievert 1999). In the fiKh, one treatment group was given a standard amino acid formulation and a second treatment group was given a formulation enriched with glutamine (Qiu 2009). For most of the analyses, the two treatment groups were combined; in the subgroup analyses that assessed the different amino acid for- mulations, only the appropriate treatment group was included and compared with the common control group. One of these trials (Reil- ly 1990) provided continuous data for each group separately; in or- der to accommodate this in the RevMan software, the mean value was calculated for both groups and the smaller standard deviation was used (Reilly 1990).

Two trials were designed to include two separate interventions and the patients were separately randomised to each one (Bonkovsky 1991; Hendry 2010). In the former (Bonkovsky 1991), patients were also randomised to receiving or not receiving oxandrolone; data were provided for all four groups and only the data from those receiving the parenteral nutrition and those not receiving either intervention were used. The latter report (Hendry 2010) also ran- domised the patients to the receipt or non-receipt of postoperative laxatives; the data were only reported for the combined groups, so all of the patients who received the supplements were compared with all of the patients not receiving the supplements (regardless of whether or not laxatives were also received).

Included studies

See 'References to studies' (Included studies).

Excluded studies

See 'References to studies' (Excluded studies).

Risk of bias in included studies

One unblinded trial of supplements in medical patients did meet the other six criteria and was judged to be at lower risk of bias af- ter we received more information from the investigator (Kobashi 2006). All of the remaining trials were assessed as being at high risk of bias and were judged to be inadequate or unclear in at least two of the six domains. These risks are summarised in Figure 1 and Fig- ure 2.

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Figure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 2. (Continued)

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Figure 2. (Continued)

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Allocation

Only nine trials (Naveau 1986; Achord 1987; Humbert 1988; Bonkovsky 1991; Meng 1999; Kobashi 2006; Nakaya 2007; Norman 2008; Hendry 2010) described an adequate method for generat- ing the randomisation sequence. The employed methods includ- ed random number tables, blind drawing of cards, and computer generation. Only seven trials provided information to suggest that the allocation sequence was adequately concealed (Naveau 1986; Achord 1987; Poon 2004; Kobashi 2006; Nakaya 2007; Norman 2008; Hendry 2010); the techniques included serially numbered, sealed, opaque envelopes; central registration; and blind drawing of a card at the time of randomisation.

Blinding

Only two of the trials (Simko 1983; Sievert 1999) even mentioned potential blinding in the details of the methodology. In these two trials of supplements (Simko 1983; Sievert 1999) the 'placebo' was not described.

Incomplete outcome data

All but 10 of the trials (Simon 1988; Hayashi 1991; Kearns 1992; Guy 1995; Hasse 1997; Sievert 1999; Zheng 2003; Schuetz 2006; Nor- man 2008; Hendry 2010) accounted for dropouts. In 10 of the re- maining 27 trials, there were no dropouts (Calvey 1985; Puglionisi 1985; Cabre 1990; Reilly 1990; Bonkovsky 1991; DeLedinghen 1997; Kobashi 2006; Qiu 2009; Takeshita 2009; Ichikawa 2010). Thus, in spite of adequate reporting of dropouts, intention-to-treat analysis could only be done in the 10 trials in which there were no dropouts (Calvey 1985; Puglionisi 1985; Cabre 1990; Reilly 1990; Bonkovsky 1991; DeLedinghen 1997; Kobashi 2006; Qiu 2009; Takeshita 2009; Ichikawa 2010) or in one trial where, in spite of dropouts being described, an intention-to-treat analysis was reported (Humbert 1988).

Selective reporting

Most of the trials reported mortality and one or more variables of morbidity. Eight trials (Simko 1983; Hayashi 1991; Guy 1995; Hasse 1995; Hasse 1997; Sievert 1999; Tangkijvanich 2000; Mikagi 2011) did not report mortality and three (Reilly 1990; Qiu 2009; Takeshi- ta 2009) provided mortality but not morbidity data. While one trial did not explicitly report mortality, quality of life data were present- ed for all of the patients at the end of the eight-week follow-up, in- ferring that there were no deaths (Ichikawa 2010). Finally, two tri- als were assessed as inadequate in this category because the meth- ods sections explicitly described outcomes to be assessed and for which no quantitative or qualitative data were reported (Takeshita 2009; Ishikawa 2010).

Other potential sources of bias

Baseline imbalance was absent in most of the trials. Baseline dif- ferences between the treated and control groups were present in four trials (Simko 1983; Fan 1994; Kobashi 2006; Takeshita 2009). Baseline characteristics were not reported in two trials (Hasse 1997; Schuetz 2006); both of these trials were reported only as abstracts.

Most of the investigators did not provide information to suggest that a sample size was predetermined, so it was not possible to be sure whether or not that trial was stopped prematurely. One tri- al was stopped early because the investigator leK the institution (Norman 2008). Five trials did describe predetermined sample sizes

(Naveau 1986; Kearns 1992; Fan 1994; Poon 2004; Hendry 2010); one of these was stopped after an unplanned interval analysis (Kearns 1992).

Most of the reports did not indicate how the trial was funded. Indus- try provided at least partial funding for six (Simko 1983; Cabre 1990; Bonkovsky 1991; Kearns 1992; Hasse 1995; Meng 1999) and three of the trials were funded by governmental or educational agen- cies (Calvey 1985; Bunout 1989; Hirsch 1993). One other trial was performed by investigators who had previously published a paper showing an association between malnutrition and a poor clinical outcome (LeCornu 2000).

E<ects of interventions

Parenteral nutrition

Medical disorders

Four trials compared parenteral nutrition with no parenteral nutri- tion (Naveau 1986; Achord 1987; Simon 1988; Bonkovsky 1991) (170 patients, 59% male, average age 46 years). All of these trials were conducted in patients hospitalised with various forms of alcoholic liver disease.

All four trials reported mortality data (Naveau 1986; Achord 1987; Simon 1988; Bonkovsky 1991). When the data were combined, par- enteral nutrition had no demonstrable effect. No effect was ob- served with regard to the appearance (Achord 1987; Simon 1988) or resolution (Naveau 1986; Achord 1987; Simon 1988) of ascites. No effect was demonstrated on the appearance (Naveau 1986; Achord 1987; Simon 1988) or resolution (Achord 1987; Simon 1988) of he- patic encephalopathy; all of these trials employed standard amino acid formulations. None of the trials reported data for gastrointesti- nal bleeding.

Adverse events, thrombophlebitis with or without sepsis in partic- ular, were noted in occasional patients in the parenteral nutrition arms but no comparable data were available concerning the occur- rence of similar complications in the control groups (Naveau 1986; Achord 1987; Simon 1988; Bonkovsky 1991). No quality of life data were available.

Only one trial (Naveau 1986) provided information regarding in- fections. There were four such events in the recipients of the par- enteral nutrition versus none in the control group, a difference that was not statistically significant. Parenteral nutrition was associated with a larger reduction in the serum bilirubin (MD -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) (Naveau 1986; Achord 1987; Si- mon 1988). No data were available regarding duration of hospital- isation or cost.

One trial (Bonkovsky 1991) did provide data regarding nitrogen bal- ance; it was significantly better in the recipients of the parenteral nutrition (MD 3.60 g/day, 95% CI 0.86 grams/day to 6.34 g/day). Oth- er nutritional outcomes that were assessed were reported in differ- ent ways and could not be combined in a meta-analysis; no differ- ences were seen with regard to body weight (Bonkovsky 1991) or anthropometric measurements (Naveau 1986; Bonkovsky 1991).

Surgical disorders

Five trials assessed the use of parenteral nutrition in patients with liver disease undergoing surgery (Puglionisi 1985; Reilly 1990; Fan 1994; Zheng 2003; Qiu 2009) (333 patients, 68% male, average age

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52 years). The surgical procedures were resection of hepatocellu- lar carcinoma (Fan 1994), portocaval shunt (Puglionisi 1985), liver transplantation (Reilly 1990; Qiu 2009), and various hepatobiliary procedures in patients with cirrhosis (Zheng 2003).

Parenteral nutrition did not have a significant effect on mortality (Puglionisi 1985; Reilly 1990; Fan 1994; Zheng 2003; Qiu 2009). The fixed-effect model analysis of two trials (Fan 1994; Zheng 2003) sug- gested that ascites was less likely to occur postoperatively in the re- cipients of the parenteral nutrition (RR 0.65, 95% CI 0.48 to 0.87) but there was statistical heterogeneity in these trials (I2 = 70%) and the significant difference was not seen in the random-effects model (RR 0.67, 95% CI 0.39 to 1.15). There was no significant difference in the incidence of postoperative encephalopathy in two trials, both em- ploying branched-chain amino acid formulations (Puglionisi 1985; Fan 1994). Patients with pre-existent ascites or encephalopathy were not enrolled into the surgical trials. Only one trial reported da- ta regarding gastrointestinal bleeding (Fan 1994) or jaundice (Qiu 2009); parenteral nutrition was not shown to affect either outcome.

No data were available concerning adverse events or quality of life.

One trial reported data regarding infections (Fan 1994); there were fewer in the group receiving the parenteral nutrition (RR 0.47, 95% CI 0.25 to 0.88). Parenteral nutrition had no effect on the serum bilirubin (Reilly 1990; Zheng 2003). Postoperative complications were only reported in one trial (Fan 1994); parenteral nutrition was associated with an improvement in total complications and pneu- monia but not in intra-abdominal complications or wound infec- tions. Duration of hospitalisation (including days in the intensive care unit) and cost were reported in one trial (Reilly 1990); no dif- ferences were seen.

Nutritional variables were reported in two trials (Fan 1994; Zheng 2003). Body weight loss or gain was improved by parenteral nutri- tion (Fan 1994; Zheng 2003) as was nitrogen balance (reported as 'accumulated nitrogen equilibrium' and thus not entered into the meta-analysis) (Zheng 2003). Anthropometric variables were im- proved in one (Zheng 2003) but not the other (Fan 1994) trial.

Enteral nutrition

Medical disorders

Seven trials assessed the role of enteral nutrition in various med- ical conditions (Calvey 1985; Cabre 1990; Kearns 1992; Guy 1995; DeLedinghen 1997; Schuetz 2006; Norman 2008) (279 patients, 59% male, average age 51 years). The underlying medical conditions in- cluded malnourished cirrhosis (Cabre 1990), alcoholic liver disease (Calvey 1985; Kearns 1992), stabilised variceal bleeding (DeLed- inghen 1997); patients awaiting liver transplantation (Guy 1995); and decompensated cirrhosis with (Schuetz 2006) or without (Nor- man 2008) associated hepatic encephalopathy. All seven trials were conducted in hospitalised patients.

Enteral nutrition did not have any significant impact on mortality (Calvey 1985; Cabre 1990; Kearns 1992; DeLedinghen 1997; Norman 2008). Only one trial reported any data regarding ascites (Cabre 1990); there was no difference in the incidence of ascites resolution. Four trials (Calvey 1985; Kearns 1992; Guy 1995; Schuetz 2006) re- ported data on the appearance and two trials (Calvey 1985; Kearns 1992) reported data on the resolution of hepatic encephalopa- thy; no significant differences were observed regardless of whether standard (Calvey 1985; Kearns 1992; Guy 1995; Schuetz 2006) or

branched-chain amino acid (Calvey 1985) formulations were em- ployed. (The hepatic encephalopathy that was present as an in- clusion criterion in one of these trials (Schuetz 2006) was subclini- cal; no frank episodes of encephalopathy developed in any patients during the trial.) Four trials failed to find any effect of the enteral nu- trition on the subsequent development of gastrointestinal bleed- ing (Calvey 1985; Cabre 1990; DeLedinghen 1997; Norman 2008). Likewise, two trials (Kearns 1992; Norman 2008) failed to show that enteral nutrition had any effect on the serum bilirubin levels in icteric patients.

Only one trial reported adverse events (Kearns 1992). No significant differences were seen in the occurrence of renal insufficiency or di- arrhoea. On average, the nasoduodenal tube had to be replaced three times in the recipients of the enteral nutrition over the course of the 28-day trial.

No data were available regarding quality of life.

No significant effect was observed on the rate of infection (Calvey 1985; Cabre 1990; DeLedinghen 1997; Norman 2008) or duration of hospitalisation (Cabre 1990; Kearns 1992; DeLedinghen 1997); one of these trials was not included in the meta-analysis (Kearns 1992) because the standard deviation or standard error was not provided. No cost data were available.

Nitrogen balance was reported differently in three trials (Calvey 1985; Kearns 1992; DeLedinghen 1997). It was significantly better in the recipients of enteral nutrition in one trial (Kearns 1992) but there was no difference between the groups in another (DeLed- inghen 1997); the third trial (Calvey 1985) did not report any statis- tical analysis but the median balance was higher in the recipients of the branched-chain amino acid formulation (+2.3 g/day) than in those who received a standard amino acid formulation (+0.4 g/ day) or in the controls (+0.3 g/day). There was a significantly higher weight loss in the control group in one trial (Kearns 1992) but no difference in the body mass index in another (DeLedinghen 1997). There was no apparent effect of the enteral nutrition on anthro- pometric measurements (Calvey 1985; Cabre 1990; Kearns 1992; DeLedinghen 1997).

Surgical disorders

Only two trials assessed the use of enteral nutrition in liver dis- ease, one in patients with obstructive jaundice (Foschi 1986) and the other in patients in the immediate postoperative period after liver transplantation (Hasse 1995) (110 patients, 62% male, average age 60 years).

The enteral nutrition did not have any significant impact on mor- tality (Foschi 1986). No data were available to assess the outcomes of the appearance or resolution of ascites or hepatic encephalopa- thy, gastrointestinal bleeding, quality of life, or serum bilirubin (al- though the intraoperative biliary drainage that was performed in all patients in one trial (Foschi 1986) would have confounded such an analysis).

With regard to adverse events, only one trial (Hasse 1995) stated that there were no significant differences between the two groups with regard to organ rejection or rehospitalisation.

There was no significant effect of the enteral nutrition on the rate of infection (Foschi 1986; Hasse 1995), the duration of hospitalisation (including length of stay in the intensive care unit) (Hasse 1995), or

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cost (Hasse 1995). There was a significant reduction in total postop- erative complications in the one trial that provided such data (Fos- chi 1986) (RR 0.38, 95% CI 0.16 to 0.91) but not in any of the specific ones (intra-abdominal complications, pneumonia, or wound infec- tions) (Foschi 1986). Furthermore, these data were limited by the fact that four patients dropped out of the treatment group of the trial for reasons related to factors of illness (including two who had complications of biliary drainage).

With regard to nutritional outcomes, no significant differences were seen for weight (Foschi 1986), triceps skinfold thickness (Fos- chi 1986), or nitrogen balance (Hasse 1995).

It must be appreciated that the available data were limited.

Oral nutritional supplements

Medical disorders

Fourteen trials compared the use of oral nutritional supplements versus no supplements in patients with liver disease (Simko 1983; Humbert 1988; Bunout 1989; Hayashi 1991; Hirsch 1993; Hasse 1997; San-In Group 1997; Sievert 1999; Tangkijvanich 2000; Poon 2004; Kobashi 2006; Nakaya 2007; Takeshita 2009; Ichikawa 2010) (987 patients, 74% male, average age 66 years). The underlying dis- ease states included alcoholic liver disease (Hirsch 1993), compen- sated cirrhosis (Ichikawa 2010), malnourished patients with cirrho- sis (Bunout 1989; Hasse 1997; Sievert 1999), patients with cirrhosis and hepatic encephalopathy (Simko 1983; Hayashi 1991), decom- pensated cirrhosis (Humbert 1988; Tangkijvanich 2000; Nakaya 2007), and patients with hepatocellular carcinoma and cirrhosis without any other criteria (Kobashi 2006) or who had recently undergone an attempted curative resection (San-In Group 1997) or who were receiving transarterial chemoembolisation for unre- sectable disease (Poon 2004; Takeshita 2009). All but three of these trials (Bunout 1989; Hayashi 1991; Takeshita 2009) were conducted in outpatients.

Nine trials (including the one trial in which no mortality was in- ferred (Ichikawa 2010)) reported data regarding mortality (Hum- bert 1988; Bunout 1989; Hirsch 1993; San-In Group 1997; Poon 2004; Kobashi 2006; Nakaya 2007; Takeshita 2009; Ichikawa 2010); no sig- nificant difference was seen when all of the trials were considered (RR 1.08, 95% CI 0.87 to 1.33, I2 = 35%) but mortality was significant- ly higher in the recipients of the oral supplements in the one low risk of bias trial (RR 1.37, 95% CI 1.03 to 1.72) (Kobashi 2006).

Twelve trials provided data regarding the appearance of hepatic encephalopathy (Simko 1983; Humbert 1988; Bunout 1989; Hayashi 1991; Hirsch 1993; Hasse 1997; Sievert 1999; Tangkijvanich 2000; Poon 2004; Kobashi 2006; Nakaya 2007; Ichikawa 2010). No sig- nificant differences were present when all of the trials were com- bined or when the trials that employed standard or branched- chain amino acids were considered separately. (Two of these tri- als (Hasse 1997; Sievert 1999) included three study groups, with two of them receiving one or the other solution.) Only two trials as- sessed the utility of supplements in resolving hepatic encephalopa- thy; one trial employed a standard amino acid-based formulation (Bunout 1989) and the other a branched-chain amino acid formu- lation (Hayashi 1991). Again, remembering that an RR > 1.0 favours the intervention group, there was an improved resolution when both trials were combined with the fixed-effect model (RR 3.75, 95% CI 1.15 to 12.18) but not with the random-effects model (RR 2.04, 95% CI 0.06 to 75.19). The I2 was 79% and the P value for the Chi2

test was 0.03 when these trials were combined. This effect was not seen in the trial of standard amino acids (RR 0.29, 95% CI 0.02 to 4.29) but was present in the trial of the branched-chain amino acid formulation (RR 11.30, 95% CI 1.62 to 78.95).

While two trials did not find any significant effect of the supple- ments on the resolution of ascites (Hayashi 1991; Nakaya 2007), four trials indicated that there was a reduced incidence regarding the appearance of ascites (RR 0.58, 95% CI 0.38 to 0.87) (Hirsch 1993; Poon 2004; Kobashi 2006; Nakaya 2007). There was no hetero- geneity in this analysis and the estimated effect was comparable with the fixed-effect and random-effects models. An external peer reviewer asked us to assess the effect of supplements on serum albumin levels in these medical trials. A meta-analysis of nine tri- als that provided end-of-trial serum albumin levels (Humbert 1988; Bunout 1989; Hayashi 1991; Hirsch 1993; San-In Group 1997; Tangk- ijvanich 2000; Nakaya 2007; Takeshita 2009; Ichikawa 2010) indicat- ed that, if anything, it was slightly better in the control group (MD -0.09 g%, 95% CI -0.18 to 0.00). When only the four trials that provid- ed the ascites data were considered with regard to the effect of the supplements on serum albumin, two failed to see any differences (Hirsch 1993; Nakaya 2007), one did not provide any data (Kobashi 2006), and one that could not be included in the meta-analysis be- cause the standard deviation or standard error was not reported found significant improvements at three, six, and nine months but not at the end of the trial (12 months) (Poon 2004).

Five trials reported data regarding the subsequent development of gastrointestinal bleeding (Hirsch 1993; Tangkijvanich 2000; Poon 2004; Kobashi 2006; Nakaya 2007); no significant differences were seen. The serum bilirubin was not affected by the supplements in two trials (Bunout 1989; Hirsch 1993).

Three trials reported no significant difference in various quality of life scores (Functional Assessment of Cancer Therapy (Poon 2004); Karnofsky score (Hayashi 1991); SF-36 questionnaire (Nakaya 2007)). A fourth trial (Kobashi 2006) stated that there was a better improvement in three domains of the SF-36 questionnaire in the re- cipients of the supplement, a branched-chain amino acid formula- tion. A fiKh trial (San-In Group 1997) found that more controls had a deterioration of the performance status score over the course of the trial. Finally, one trial found that the Epworth Sleepiness Score improved as a consequence of the ingestion of a branched-chain amino acid supplement at night (Ichikawa 2010).

Adverse events were reported in a variety of different ways in six tri- als (Hayashi 1991; San-In Group 1997; Sievert 1999; Tangkijvanich 2000; Poon 2004; Nakaya 2007). Hayashi et al observed no differ- ences in serious events, defined as the need for an additional in- tervention or the cessation of the experimental therapy (Hayashi 1991). On the other hand, 5/41 patients receiving supplements and 14/43 controls were readmitted for complications of chemoemboli- sation in the trial by Poon et al (Poon 2004); this difference was significant. Nakaya et al noted five serious adverse events, four in the 19 recipients of the supplements (one fatal cerebral bleed, one bone fracture, and two increased ascites) and one in the 19 con- trols (worsening encephalopathy) (Nakaya 2007). Minor gastroin- testinal adverse events (diarrhoea, vomiting, abdominal pain or distension, loss of appetite) were reported as consequences of the supplements (without any comparable data for the control groups) in two trials (San-In Group 1997; Tangkijvanich 2000). The incidence of diarrhoea, vomiting, or abdominal pain was not significantly dif-

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ferent from what was observed in the control group in two trials (Sievert 1999; Nakaya 2007).

The incidence of subsequent infection was lower in the patients treated with supplements (RR 0.49, 95% CI 0.24 to 0.99, 4 trials) (Hirsch 1993; Sievert 1999; Poon 2004; Nakaya 2007) when the fixed- effect model was used (I2 = 14%, P = 0.28) but not when the ran- dom-effects model was employed (RR 0.49, 95% CI 0.20 to 1.23). In addition, one trial only reported the number of episodes of spon- taneous bacterial peritonitis (Tangkijvanich 2000); none was seen in either group. No difference was seen with regard to the length of hospitalisation in the single trial that reported such data (Bunout 1989). In two trials conducted in outpatients (Poon 2004; Ichikawa 2010), no differences were seen with regard to the length of time they spent in the hospital receiving transarterial chemoembolisa- tion in one (Poon 2004) and no patients required hospitalisation in the other (Ichikawa 2010). One trial did not provide any numeri- cal data (Takeshita 2009) but the investigators stated that no differ- ence was observed with regard to the duration of hospitalisation. No cost data were available.

One trial provided data regarding nitrogen balance (Nakaya 2007); it was more positive in the experimental group but the differ- ence did not quite achieve significance (weighted mean difference (WMD) 1.54 g/day, 95% CI -0.01 g/day to 3.09 g/day). Body weight was again reported in a variety of ways; most of the trials did not find any significant differences (Simko 1983; Bunout 1989; Hayashi 1991; Hirsch 1993; San-In Group 1997; Sievert 1999; Tangkijvanich 2000; Poon 2004; Takeshita 2009; Ichikawa 2010). One trial noted that the patients in the treated, but not those in the control, group gained weight (Nakaya 2007). Only one trial reported a significant improvement in any anthropometric measurement (triceps skin- fold thickness (Simko 1983)); other trials failed to find any effect of the supplements on triceps skinfold thickness (Humbert 1988; Bunout 1989; Hirsch 1993; Poon 2004), midarm muscle circumfer- ence (Simko 1983; Humbert 1988; Tangkijvanich 2000), midarm cir- cumference (Bunout 1989; Hirsch 1993; Poon 2004), or anthropo- metrics generically (Hasse 1997).

Surgical disorders

Five trials compared the use of oral nutritional supplements with no supplements in surgical patients (Meng 1999; LeCornu 2000; Hendry 2010; Ishikawa 2010; Mikagi 2011) (271 patients, 68% male, average age 57 years). One assessed malnourished patients with cirrhosis who were undergoing liver transplantation (LeCornu 2000) and the other four included patients who were scheduled to have resections of hepatocellular carcinomas (Meng 1999) or a va- riety of benign and malignant lesions (Hendry 2010; Ishikawa 2010; Mikagi 2011).

No significant differences in mortality were seen when four trials were combined (Meng 1999; LeCornu 2000; Hendry 2010; Ishikawa 2010). Two trials failed to see any hepatic encephalopathy appear in either group (Meng 1999; Ishikawa 2010). No data were available regarding the appearance of ascites or the resolution of ascites or encephalopathy. One trial reported no difference in gastrointesti- nal bleeding (Meng 1999). It should be remembered, however, that three of these trials assessed patients who did not necessarily have underlying cirrhosis (Hendry 2010; Ishikawa 2010; Mikagi 2011).

No significant difference in the occurrence of infection was seen in three trials (Meng 1999; Ishikawa 2010; Mikagi 2011). No signif-

icant differences were found with regard to any of the postopera- tive complications in four trials (Meng 1999; Hendry 2010; Ishikawa 2010; Mikagi 2011). The fiKh trial did not present any numerical data but stated that there were no differences in postoperative compli- cations (LeCornu 2000). Serum bilirubin was not different between the two groups in one trial (LeCornu 2000) (given the confounding factor of a new liver) but was improved more in the recipients of the supplements in another (Meng 1999). One trial reported a shorter duration of stay in the hospital in the treated group (Meng 1999) but there was no such difference in three others (LeCornu 2000; Hendry 2010; Mikagi 2011). The data were not reported in a manner that permitted meta-analysis. One trial did not find any differences in the lengths of stay in the intensive care unit (LeCornu 2000). No cost or quality of life data were identified.

There was limited information regarding adverse events. No dif- ferences between the groups were seen with respect to rejection episodes (LeCornu 2000). A second report simply stated that no sig- nificant adverse events regarding the supplement were seen (Meng 1999). Finally, three out of 25 patients initially randomised to sup- plements, but none to a control group, were subsequently exclud- ed for "side effects" (Mikagi 2011). No data regarding quality of life were available.

No significant differences were seen with regard to some nutrition- al outcomes. These included weight (Meng 1999; Hendry 2010), tri- ceps skinfold thickness (Meng 1999; LeCornu 2000), midarm mus- cle circumference, or midarm circumference (Meng 1999; LeCornu 2000). No data were provided regarding nitrogen balance.

Again, it should be appreciated that these data were limited by both the low numbers of trials and the methodologic problems (high risks of bias) in the trials.

Summary of significant findings in these primary analyses

Parenteral nutrition resulted in reduction in the serum bilirubin lev- els and better nitrogen balance in medical patients. In surgical pa- tients, the fixed-effect model (but not the random-effects model) estimated that it reduced the appearance of ascites after surgery. In one trial, this nutritional intervention reduced postoperative com- plications, especially infections (pneumonia in particular).

Enteral nutrition may have resulted in better nitrogen balance in medical patients. In one trial of surgical patients, there were fewer postoperative complications in the recipients of the enteral nutri- tion.

Oral nutritional supplements reduced the occurrence of ascites in medical patients. Analyses employing the fixed-effect model sug- gested that the treated medical patients had fewer infections and better improvement of pre-existent hepatic encephalopathy (espe- cially when a branched-chain amino formulation was employed) but these benefits were not seen in the random-effects model. In five trials of supplements in surgical patients, no benefits were ob- served.

Subgroup and sensitivity analyses

E'ect of risk of bias assessments

Since only one of the trials Kobashi 2006 was at low risk of bias, these analyses could not be performed. However, as noted, the mortality was higher in the recipients of the oral nutritional supple- ment in that trial. On the other hand, three quality of life measures

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were improved in the treated arm and there was a trend (RR 0.60, 95% CI 0.35 to 1.05) for there to be less appearance of ascites in that trial.

Acute compared to chronic liver disease

The patients in each of the trials had some type of underlying liver disease. Even though a surgical intervention could be viewed as an acute event, the underlying liver disease was still a chronic one. As such, these analyses were not performed.

Alcoholic hepatitis

Three trials of parenteral nutrition (Achord 1987; Simon 1988; Bonkovsky 1991), two of enteral nutrition (Calvey 1985; Kearns 1992), and two of oral nutritional supplements (Bunout 1989; Hirsch 1993) were conducted in patients with alcoholic hepatitis. In all of these trials, there were only a few significant differences.

In two trials of parenteral nutrition (Achord 1987; Simon 1988), the intervention resulted in a lower serum bilirubin level (MD -6.41 mg %, 95% CI -9.41 mg% to -3.40 mg%). Nitrogen balance was also significantly better in patients with alcoholic hepatitis (Bonkovsky 1991) who received parenteral nutrition (MD +3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day).

Enteral nutrition did not have any demonstrable effect on mor- tality, the occurrence of gastrointestinal bleeding, the appearance or resolution of hepatic encephalopathy, infection rates, or serum bilirubin. However, only one or two trials contributed data for each of these analyses.

Likewise, there were only a limited number of trials of supplements. No effect was demonstrated from this intervention with regard to mortality, appearance of ascites, occurrence of gastrointestinal bleeding, the appearance or resolution of hepatic encephalopathy, serum bilirubin, or length of stay in the hospital. One trial report- ed infection rates (Hirsch 1993); this outcome was significantly re- duced in the recipients of the supplement.

Cirrhosis

Two trials of parenteral nutrition (Puglionisi 1985; Naveau 1986), five of enteral nutrition (Cabre 1990; Guy 1995; DeLedinghen 1997; Schuetz 2006; Norman 2008), and nine of oral nutritional supple- ments (Simko 1983; Humbert 1988; Hayashi 1991; Hirsch 1993; Has- se 1997; Sievert 1999; Tangkijvanich 2000; Nakaya 2007; Ichikawa 2010) assessed patients with cirrhosis, including two trials that ad- dressed the use of enteral nutrition (Guy 1995) or supplements (Hasse 1997) in patients undergoing liver transplantations.

Parenteral nutrition did not appear to affect mortality in the two trials (Puglionisi 1985; Naveau 1986). Only one trial provided any further information (Naveau 1986). No significant differences were seen with regard to the appearance of hepatic encephalopathy or infections. However, there was a significant reduction in the serum bilirubin level (-1.6 mg%, 95% CI -2.74 mg% to -0.46 mg%). On the other hand, the recipients of the parenteral nutrition were less like- ly to resolve their pre-existent ascites (RR 0.57, 95% CI 0.37 to 0.88). (In this analysis a RR < 1.0 favoured the control group.)

Enteral nutrition was not shown to have any significant effect on mortality, the resolution of ascites, the occurrence of gastrointesti- nal bleeding, the appearance of encephalopathy, subsequent in- fections, serum bilirubin, duration of hospitalisation, or nitrogen

balance. Supplements also did not appear to have any impact on mortality, the appearance or resolution of ascites, occurrence of gastrointestinal bleeding, appearance of encephalopathy, infec- tions, or bilirubin levels. One trial of a branched-chain amino acid supplement (Hayashi 1991) did find a significant improvement in the resolution of encephalopathy (RR 11.30, 95% CI 1.62 to 78.95).

Supplements may have improved nitrogen balance in one trial (Nakaya 2007) although the 95% CI just crossed the line of equiva- lence (+1.54 g/day, 95% CI -0.01 g/day to + 3.09 g/day). When this trial was combined with the single trial of enteral nutrition that al- so reported this outcome (DeLedinghen 1997) the nutritional inter- ventions had an effect (+1.53 g/day, 95% CI +0.06 g/day to +2.99 g/ day).

Hepatocellular carcinoma

One trial of parenteral nutrition (Fan 1994) and five of supplements (San-In Group 1997; Meng 1999; Poon 2004; Kobashi 2006; Takeshi- ta 2009) included patients with hepatocellular carcinoma. Two of the trials assessed the effect of immediate postoperative parenter- al nutrition (Fan 1994) or an enteral supplement (Meng 1999) af- ter undergoing attempted curative resection. Another trial com- pared the use of an oral nutritional supplement to no specific nu- tritional therapy in patients who had undergone such surgery two weeks earlier (San-In Group 1997). The other three trials evaluat- ed patients who still had known cancer (Poon 2004; Kobashi 2006; Takeshita 2009); in two of these trials, the patients were receiving transarterial chemoembolisation (Poon 2004; Takeshita 2009).

Whether all of the trials were considered together or as one trial of parenteral nutrition and five of supplements, there was no signifi- cant beneficial effect of the intervention(s) on mortality. In fact, the only low risk of bias trial (Kobashi 2006) reported increased mor- tality in those receiving supplements. For the remainder of the out- comes, data were only available for one or two trials. With this lim- itation, no significant differences were seen with regard to the oc- currence of encephalopathy or gastrointestinal bleeding. Ascites was significantly less likely to occur with the use of supplements (Poon 2004; Kobashi 2006) (RR 0.53, 95% CI 0.32 to 0.87). Infections were less common in the parenteral nutrition trial (Fan 1994) (RR 0.47, 95% CI 0.25 to 0.86) but not in one of the supplement trials (Poon 2004). As noted earlier, there were also fewer total postoper- ative complications as well as less pneumonia in the recipients of parenteral nutrition in that trial (Fan 1994). The use of supplements resulted in significantly fewer total postoperative complications in the other surgical trial (Meng 1999) (RR 0.71, 95% CI 0.62 to 0.97).

Publication status

When only the trials published as full papers were considered, no significant differences were seen in most of the outcomes. As re- ported above, two trials of parenteral nutrition (Fan 1994; Zheng 2003) and two trials of supplements (Hirsch 1993; Poon 2004) found a significant reduction in the appearance of ascites when the fixed- effect (but not when the random-effects) model was employed. As also noted earlier, resolution of hepatic encephalopathy was more common when two trials of supplements in medical patients (Bunout 1989; Hayashi 1991) were combined with a fixed-effect model.

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Branched-chain versus standard amino acid formulations for hepatic encephalopathy

These results have been discussed previously. None of the trials, separately or in various combinations, found any significant dif- ferences with either standard or branched-chain amino acid for- mulations in preventing encephalopathy; and only one trial using a branched-chain amino acid supplement (Hayashi 1991) showed that any of these nutritional interventions were better than no ther- apy in resolving pre-existent hepatic encephalopathy.

Surgical trials excluding liver transplantation

Because of the ongoing systematic review of nutritional interven- tions in liver transplantation (Langer 2009), an analysis was under- taken to assess only the trials that did not include patients during the perioperative phase of liver transplantation. Largely driven by the findings of one trial (Fan 1994), parenteral nutrition was associ- ated with less postoperative ascites and fewer postoperative com- plications, especially infections (pneumonia in particular). One of the remaining surgical trials (assessing enteral nutrition) also iden- tified fewer total postoperative complications in the recipients of enteral nutrition (Foschi 1986).

Exploratory analyses

Combining medical and surgical trials for each intervention

Most of these analyses did not find any significant differences. Not surprisingly, given the previous observations, parenteral nutrition was associated with a significant reduction in the serum bilirubin levels (-2.52 mg%, 95% CI -3.45 mg% to -1.60 mg%). Also as previ- ously noted, the fixed-effect model indicated that both parenter- al nutrition and supplements resulted in a lower incidence of as- cites but the significant difference was lost when the random-ef- fects model was used in the parenteral nutrition analysis. (There were no surgical trials in the analysis of the supplement trials.)

Parenteral nutrition was associated with a significant reduction in mortality in the fixed-effect model (RR 0.53, 95% CI 0.29 to 0.98) but not in the random-effects model (RR 0.55, 95% CI 0.29 to 1.01). The tests for heterogeneity did not suggest that there was an issue with heterogeneity (P = 0.96, I2 = 0%) although there clearly were substantial differences in the various trials. Nine trials provided da- ta for this analysis (Puglionisi 1985; Naveau 1986; Achord 1987; Si- mon 1988; Reilly 1990; Bonkovsky 1991; Fan 1994; Zheng 2003; Qiu 2009) but over one-third of the weight in both analyses was from the single surgical trial that reported the most impressive postop- erative morbidity outcomes. Two of the trials did not contain any deaths; when the estimate was calculated using the absolute risk difference (ARD), the 95% CI in the fixed-effect model touched the line of equivalence (ARD -0.05, 95% CI -0.11 to 0.00). We undertook a trial sequential analysis, assuming that the mortality was 10% in the controls; even using the optimistic assumption that parenter- al nutrition could reduce that incidence by half the Z-curve did not cross the boundary limits (Figure 3).

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Figure 3. Trial sequential analysis for parenteral nutrition trials that reported mortality; assumed mortality rate in controls = 10% and RR - 0.50.

Best-worst and worst-best case scenario intention-to-treat analyses

One way to test the robustness of a significant finding with regard to dropouts in the trials is to see if the finding persists under extreme conditions. In this case, intention-to-treat analyses were conduct- ed so that all of the missing patients were included. In the truly best-worst case scenario (for the intervention) all of the dropouts in the treated arm were considered to have a successful outcome and all of the controls were given an adverse one. A truly worst-best case scenario was the opposite, namely the missing treatment arm patients were assigned a bad outcome and the missing controls a good one. The dichotomous data (mortality, hepatic morbidity, rates of infection) were reanalysed under these two hypotheses.

Although 21 trials described dropouts, not all of them could be used in these analyses. Five trials (Naveau 1986; Bunout 1989; Hayashi 1991; Hendry 2010; Ishikawa 2010) stated that dropouts did oc- cur but did not specify how many were lost in each experimen- tal group. In four trials (Achord 1987; Simon 1988; LeCornu 2000; Nakaya 2007) the dichotomous data for hepatic morbidities were not provided in a manner that was suitable for use in these analy- ses (for example, data only reported for subgroups). One other trial (Kearns 1992) did have dropouts from the trial but it was not clear if

those dropouts did or did not have some clinical data provided be- fore exiting from the trial. Fourteen trials (Simko 1983; Foschi 1986; Achord 1987 (mortality data only); Hirsch 1993; Fan 1994; Guy 1995; Hasse 1995; Hasse 1997; San-In Group 1997; Meng 1999; Tangkij- vanich 2000; Poon 2004; Norman 2008; Mikagi 2011) provided suffi- cient information to be included in some or all of these analyses.

In the analyses, all of the significant differences in the dichotomous variables were either observations from a single trial or were only seen in the fixed-effect model. None of them persisted in both ex- tremes of the intention-to-treat analyses.

Outcomes expressed as absolute risk di'erences

One of the limitations of the risk ratio (RR) calculation is that trials with no events cannot be included in the analyses. This is not the case for ARD calculations. For this reason, all of the analyses were redone using the ARD as the measure of the effect.

With regard to parenteral nutrition, mortality was possibly im- proved in five surgical trials; a borderline effect (confidence inter- val included but did not overlap the line of equivalence) was seen with the fixed-effect model (ARD -0.06, 95% CI -0.12 to 0.00) but not with the random-effects model (ARD -0.03, 95% CI -0.08 to +0.02).

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(The tests for statistical heterogeneity indicated a P value of 0.47 and an I2 = 0%.) As was the case when the mortality rates in all of the parenteral nutrition trials were considered, the Fan trial (Fan 1994) accounted for about 40% of the weight in the fixed-effect model. The finding of a reduced postoperative incidence of ascites in the surgical trials persisted. In the only trial of parenteral nutrition in medical patients that provided data (Naveau 1986) there was an in- creased rate of infection in the recipients of the therapy (ARD +0.20, 95% CI +0.01 to +0.39).

The only new finding in the trials of enteral nutrition related to the rates of postoperative infections. These were significantly better in the recipients of the treatment (ARD -0.18, 95% CI -0.35 to -0.01).

The observations regarding the reduced incidences of ascites and infections in the trials of supplements in the medical patients were seen again. In two small trials assessing oral nutritional supple- ments in medical patients (Hayashi 1991; Nakaya 2007), the recipi- ents of the supplements were less likely to resolve pre-existent as- cites (ARD 0.40, 95% CI 0.08 to 0.71).

Mortality when all trials were combined

Mortality data were available in 27 of the 35 trials. When these were all combined, no significant difference was observed (RR 0.91, 95% CI 0.76 to 1.09).

Funnel plot analyses

Funnel plot analyses were only conducted if there were at least 10 trials; it was only possible to assess the effect of supplements on mortality and the appearance of hepatic encephalopathy in the medical patients. No asymmetry was apparent.

D I S C U S S I O N

'Malnutrition' is commonly encountered in patients with liver dis- ease, especially those with end-stage processes. As a consequence, efforts have been expended to supply nutrients with the intent of improving the nutritional status. This problem has been blamed on a variety of underlying processes, including poor caloric and other nutrient intake, problems with the assimilation and absorption of ingested nutrients, and abnormalities in metabolism. While the first two processes might be fixed with the provision of nutrients, the third is more a result of the disease itself. If the issue is abnormal metabolism, there would be no reason to believe that the simple addition of more fuel or other nutrients will alter anything. In fact, if the abnormal metabolism is bad for the patient, providing more nutrients might make the problem worse.

The best way to prove that any intervention is useful is to compare its use to non-use in patients who have been randomised to one or the other group. It was the intent of this review to summarise the trials that have addressed this question. The data to date have cer- tainly not unequivocally shown that the interventions are useful.

Summary of main results

A total of 37 randomised trials of parenteral nutrition, enteral nutri- tion, or oral nutritional supplements compared with no nutritional intervention was identified. Because of the high risks of bias of al- most all of the trials, significant findings of benefit have to be con- sidered as being potentially overestimated. Even with this limita- tion, there were only a few areas where the treatments were found to have benefit. The benefits were typically limited to the findings

from a single trial or the result of combining data with the fixed-ef- fect model. The benefits that were identified were the following.

Parenteral nutrition produced a more rapid reduction in serum bilirubin and also improved nitrogen balance in icteric patients with medical liver diseases. (In a previously published analysis of all of the trials of artificial (parenteral or enteral) nutrition, the im- provement of some nutritional parameters, body weight, and nitro- gen balance in particular was commonly accomplished, but these effects did not translate into improvements in clinical outcomes (Koretz 2005). In postoperative liver patients, parenteral nutrition may have reduced postoperative untoward events (ascites and in- fection, particularly pneumonia). The significant reduction in post- operative ascites was only seen in the fixed-effect model and there was substantial heterogeneity (I2 = 70%) in the two trials identified. The reduction in other postoperative complications was only seen in one trial.

Enteral nutrition may have improved nitrogen balance and body weight in medical patients although these findings were not consis- tently found. While one surgical trial suggested that enteral nutri- tion had a favourable impact on postoperative complications (Fos- chi 1986), dropouts appeared to be a confounding factor. A pre- vious systematic review of enteral nutrition in surgical trials also found such an effect, but it was only demonstrated in trials with high risks of bias (Koretz 2007).

Over half of the trials (19/37) assessed the use of oral nutrition- al supplements. The use of these agents appeared to reduce the incidence of ascites. Four (Hirsch 1993; Sievert 1999; Poon 2004; Nakaya 2007) and two (Bunout 1989; Hayashi 1991) trials found a reduction in infections and improvement in pre-existent en- cephalopathy, respectively, but the significant differences were on- ly found in the fixed-effect model (I2 = 21% in the former, and 79% in the latter analysis). The improvement in hepatic encephalopa- thy was associated with the usage of branched-chain amino acids. Some (but not all) of the trials in medical patients suggested that there may have been an improvement in quality of life scores (al- though the lack of blinding will always compromise endeavours to study such an outcome). On the other hand, the single trial with a lower risk of bias indicated that mortality was increased with the use of a supplement.

The subgroup and sensitivity analyses did not provide any addi- tional insight. The effect of the nutritional interventions in the three predefined liver diseases (alcoholic hepatitis, cirrhosis, hepatocel- lular carcinoma) largely paralleled the findings of these nutrition- al interventions in all liver diseases. Employing only full papers did not provide any further insights. A comparison of the trials at high versus lower risks of bias could not be done.

The exploratory analyses did make one additional observation, namely that parenteral nutrition resulted in improved mortality. When all of the trials were combined, no significant differences were seen. These two observations create a logical paradox; either the analysis of the parenteral nutrition represents a type I error or the analysis of all of the trials contain a type II error.

Overall completeness and applicability of evidence

Since trials assessing nutritional interventions in general have been systematically collected by one of the authors (RK) for over three decades, it is unlikely that a substantial number of relevant publi-

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cations have not been identified. Thus, at this time, the findings of this systematic review challenge the practice of widely employing these nutritional interventions. This inability to identify clear ben- efits from nutritional interventions is consistent with the proposal that the malnutrition observed in many patients with liver disease is actually due to fundamental problems with metabolism, not to simple nutrient deprivation. This concept of viewing malnutrition as being more than simple nutrient deficiency is now being adopt- ed by nutrition support societies (Jensen 2010).

Quality of the evidence

All but one of the trials were at high risk of bias. Since such trials tend to overestimate therapeutic efficacy, the actual effect may be even less advantageous to patients than what was observed.

Potential biases in the review process

As noted, for many of the outcomes the data were derived from a relatively small number of trials, and type I and type II errors (either for benefit or harm) may be present. The high risk of bias in almost all of the individual trials does challenge the reliability of the esti- mates, especially of the few benefits that were observed.

Agreements and disagreements with other studies or reviews

While no other formal systematic review of the effect of these inter- ventions in liver disease in general was identified, the results are consistent with what has been observed about these interventions in other disease states (Koretz 2001; Koretz 2007).

A U T H O R S ' C O N C L U S I O N S

Implications for practice

There are no compelling data to justify the use of artificial nutrition (parenteral or enteral nutrition) or oral nutritional supplements as a component of a treatment program for patients with liver disease. Since these interventions do have defined economic costs (and less well-defined but real adverse effects), the available evidence does not support the routine use of either form of artificial nutrition, or marketed oral nutritional supplements, in patients with liver dis- ease.

Implications for research

There is, at this time, no compelling evidence to support the use of these interventions. Thus, parenteral or enteral nutrition, or com- mercial nutritional supplements, should only be employed within the context of well-designed and executed randomised clinical tri- als. Given the absence of strong supportive data to date, these tri- als need to include a control group that does not receive the thera- py. Furthermore, it is apparent that any potential benefit from such treatment is not going to be dramatic, so trials need to be powered adequately to see important but less dramatic differences. Given the dissociation between the effect of nutritional interventions on so-called 'nutritional outcomes' (for example, nitrogen balance), future clinical trials have to use true clinical outcomes (mortality, hepatic morbidity, quality of life, or costs) rather than unvalidated nutritional surrogates.

A C K N O W L E D G E M E N T S

We appreciate the contributions of the peer reviewers, Ove Schaf- falitzky de Muckadell in Denmark, Esteban Mezey in the United States, Yutaka Nakaya in Japan, and Bruno Caramelli in Brazil. We acknowledge the assistance of the contact editor, Christian Glu- ud, in Denmark. We also thank Sarah Klingenberg for the perfor- mance of the literature searches and Dimitrinka Nikolova for tech- nical assistance. We must also express our appreciation to the in- vestigators who took the time to respond to our questions about their trials, namely Drs Roger Williams (for Calvey 1985), Esteban Mezey (for Diehl 1985), Charles Miller (for Guy 1995), Janet Has- se, Haruhiko Kobashi, Kate Le Cornu, Enrico DiCera (for Puglion- isi 1985), Supeecha Wittayalertpanya (for Tangkijvanich 2000) and Yatuka Nakaya. Finally, we acknowledge the efforts of Todd Jones who endeavoured to identify trials on behalf of B. Braun Medical.

Protocol

Peer Reviewers: Ove Schaffalitzky de Muckadell, Denmark; Bruno Caramelli, Brazil. Contact Editor: Christian Gluud, Denmark.

Review

Peer Reviewers: Esteban Mezey, USA; Yutaka Nakaya, Japan. Contact Editor: Christian Gluud, Denmark.

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R E F E R E N C E S References to studies included in this review Achord 1987 {published data only (unpublished sought but not used)} Achord JL. A prospective randomized clinical trial of peripheral amino acid-glucose supplementation in acute alcoholic hepatitis. American Journal of Gastroenterology 1987;82(9):871-5.

Bonkovsky 1991 {published data only (unpublished sought but not used)} Bonkovsky H, Fiellin D, Smith G, Slaker D, Simon D, Galambos J. Treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone: a randomized controlled trial I short-term eHects on liver function [AASLD abstract]. Hepatology 1990;12(4):870.

Bonkovsky H, Jafri I, Singh R, Cotsonis G, Slaker D. Treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone: a randomized controlled trial II EHects on nitrogen metabolism [AASLD abstract]. Hepatology 1990;12(4):978.

* Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone I Short-term eHects on liver function. American Journal of Gastroenterology 1991;86(9):1200-8.

Bonkovsky HL, Singh RH, Jafri IH, Fiellin DA, Smith GS, Simon D, et al. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone II Short-term eHects on nitrogen metabolism, metabolic balance, and nutrition. American Journal of Gastroenterology 1991;86(9):1209-18.

Bunout 1989 {published data only (unpublished sought but not used)} Bunout D, Aicardi V, Hirsch S, Petermann M, Kelly M, Silva G, et al. Nutritional support in hospitalized patients with alcoholic liver disease. European Journal of Clinical Nutrition 1989;43(9):615-21.

Cabre 1990 {published data only (unpublished sought but not used)} Abad-Lacruz A, Cabre E, Gonzalez-Huix F, Esteve M, Xiol X, Acero D, et al. Total enteral nutrition (TEN) as a new approach influencing the clinical outcome and mortality in liver cirrhosis (LC) [AASLD abstract]. Hepatology 1988;8(5):1413.

Cabre E, Abad A, Glez-Huix F, Esteve M, Xiol X, Acero D, et al. Total enteral nutrition as a new approach influencing the clinical outcome and mortality in liver cirrhosis [abstract]. Journal of Parenteral and Enteral Nutrition 1989;13 Suppl(1):10.

Cabre E, Gonzales-Huix F, Abad-Lacruz A, Esteve M, Xiol X, Acero D, et al. EHect of total enteral nutrition (TEN) on the clinical outcome of hospitalized cirrhotics with severe protein- energy malnutrition (PEM) [abstract]. Clinical Nephrology 1988;7 Special Suppl:34.

* Cabre E, Gonzalez Huix F, Abad Lacruz A, Esteve M, Acero D, Fernandez Banares F, et al. EHect of total enteral nutrition

on the short-term outcome of severely malnourished cirrhotics A randomized controlled trial. Gastroenterology 1990;98(3):715-20.

Calvey 1985 {published data only (unpublished sought but not used)} * Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. Journal of Hepatology 1985;1(2):141-51.

Calvey H, Davis M, Williams R. Prospective study of nasogastric feeding via East Grinstead (Reg.trademark) or Viomedex (Reg.trademark) tubes compared with oral dietary supplementation in patients with cirrhosis. Clinical Nutrition 1984;3(2):63-6.

Williams R, Calvey H, Davis M. Controlled trial of nutritional supplementation in acute alcoholic hepatitis. In: Holm E, Kasper H editor(s). Metabolism and nutrition in liver disease. Lancaster, England: MTP Press, Ltd., 1985:361-8.

DeLedinghen 1997 {published data only (unpublished sought but not used)} De Ledinghen V, Mannant PR, Beau P, Borderie C, Oui B, Silvain C, et al. EHects of early enteral nutrition in cirrhotics patients aKer bleeding from esophageal varices: a randomized controlled study (Abstract). Gastroenterology 1996;110(4):A13.

* de Ledinghen V, Beau P, Mannant PR, Borderie C, Ripault MP, Silvain C, et al. Early feeding or enteral nutrition in patients with cirrhosis aKer bleeding from esophageal varices? A randomized controlled study. Digestive Diseases and Sciences 1997;42(3):536-41.

de Ledinghen V, Mannant PR, Beau P, Borderie C, Ripault MP, Silvain C, et al. EHect of enteral nutrition immediately aKer digestive hemorrhage in cirrhotics: A randomised controlled study (abstract) [EHets de la nutrition enterale au decours immediat de l`hemorragie digestive du cirrhotique: Etude controlee randomisee (abstract)]. Gastroenterologie Clinique et Biologique 1996;20 Suppl:A120.

Fan 1994 {published data only (unpublished sought but not used)} Fan ST, Lo CM, Lai EC, Chu KM, Liu CL, Wong J. Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. New England Journal of Medicine 1994;331(23):1547-52.

Foschi 1986 {published data only (unpublished sought but not used)} Foschi D, Cavagna G, Callioni F, Morandi E, Rovati V. Hyperalimentation of jaundiced patients on percutaneous transhepatic biliary drainage. British Journal of Surgery 1986;73(9):716-9.

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Guy 1995 {published and unpublished data} Guy S, Tanzer-Torres G, Palese M, Sheiner P, Mor E, Emre S, et al. Does nasoenteral nutritional support reduce mortality aKer liver transplant? (Abstract). Hepatology 1995;22:144A.

Hasse 1995 {published data only (unpublished sought but not used)} Hasse JM, Blue LS, Liepa GU, Goldstein RM, Jennings LW, Mor E, et al. Early enteral nutrition support in patients undergoing liver transplantation. Journal of Parenteral and Enteral Nutrition 1995;19(6):437-43.

Hasse 1997 {published and unpublished data} Hasse J, Crippin J, Blue L, Huang K, DiCecco S, Francisco- Ziller N, et al. Does nutrition supplementation benefit liver transplant candidates with a history of encephalopathy? (Abstract). Journal of Parenteral and Enteral Nutrition 1997;21(1):S16.

Hayashi 1991 {published and unpublished data} * Hayashi S, Aoyagi Y, Fujiwara K, Oka H, Oda T. A randomized controlled trial of branched-chain amino acid (BCAA)-enriched elemental diet (ED-H) for hepatic encephalopathy [abstract]. Journal of Gastroenterology and Hepatology 1991;6(2):191.

Hayashi S, Aoyagi Y, Oka H, Oda T. A randomized controlled study of an elementary diet (ED-H) in cirrhotics with hepatic encephalopathy. Unpublished data.

Hendry 2010 {published data only} Hendry PO, Van Dam RM, Bukkems SFFW, McKeovm DW, Parks RW, Preston T, et al. Randomized clinical trial of laxatives and oral nutritional supplements within an enhanced recovery aKer surgery protocol following liver resection. British Journal of Surgery 2010;97(8):1198-206.

Hirsch 1993 {published data only (unpublished sought but not used)} Hirsch S, Bunout D, de la Maza P, Iturriaga H, Petermann M, Icazar G, et al. Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis. Journal of Parenteral and Enteral Nutrition 1993;17(2):119-24.

Humbert 1988 {published data only (unpublished sought but not used)} Humbert P, Pintó A, Johnston S, Fábrega C, Planas R, Boix J, et al. EHect of oral administration of branched-chain amino acids for the treatment of nutrition disturbances and for the prophylaxis of encephalopathy in cirrhotic patients [Efecto de la administración oral de aminoácidos ramificados en el tratamiento de los trastornos nutricionales y en la prevención de la encefalopatía de pacientes cirróticos.]. Gastroenterología y Hepatología 1989;12(1):9-13.

Ichikawa 2010 {published data only (unpublished sought but not used)} Ichikawa T, Naota T, Miyaaki H, Miuma S, Isomoto H, Takeshima F, et al. EHect of an oral branched chain amino acid- enriched snack in cirrhotic patients with sleep disturbance. Hepatology Research 2010;40(10 (Oct)):971-8.

Ishikawa 2010 {published data only (unpublished sought but not used)} * Ishikawa Y, Yoshida H, Mamada Y, Taniai N, Matsumoto S, Bando K, et al. Prospective randomized controlled study of short-term perioperative oral nutrition with branched chain amino acids in patients undergoing liver surgery. Hepatogastroenterology 2010;57:583-90.

Ishikawa Y, Yoshida H, Weiner J, Tajiri T. Prospective randomized controlled study of short-term perioperative enteral nutrition support with branched chain amino acids in liver surgery (Abstract). Gastroenterology 2009;136 Suppl 1:176.

Kearns 1992 {published data only (unpublished sought but not used)} Kearns PJ, Young H, Garcia G, Blaschke T, O'Hanlon G, Rinki M, et al. Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102(1):200-5.

Kobashi 2006 {published and unpublished data} Kobashi H, Morimoto Y, Ito T, Shimoe T, Makino Y, Araki Y, et al. EHects of supplementation with a branched-chain amino acid- enriched preparation on event-free survival and quality of life in cirrhotic patients with hepatocellular carcinoma. A multicenter, randomized controlled trial (Abstract) . Gastroenterology 2006;130:A497.

LeCornu 2000 {published data only (unpublished sought but not used)} LeCornu KA, McKiernan FJ, Kapadia SA, Neuberger JM. A prospective randomized study of preoperative nutritional supplementation in patients awaiting elective orthotopic liver transplantation. Transplantation 2000;69(7):1364-9.

Meng 1999 {published data only (unpublished sought but not used)} Meng WC, Leung KL, Ho RL, Leung TW, Lau WY. Prospective randomized control study on the eHect of branched-chain amino acids in patients with liver resection for hepatocellular carcinoma. Australian and New Zealand Journal of Surgery 1999;69(11):811-5.

Mikagi 2011 {published data only} Mikagi K, Kawahara R, Kinoshita H, Aoyagi S. EHect of preoperative immunonutrition in patients undergoing hepatectomy; a randomized controlled trial. Kurume Medical Journal 2011;58(1):1-8.

Nakaya 2007 {published and unpublished data} * Nakaya Y, Ikita K, Suzuki K, Moriwaki H, Kato A, Miwa Y, et al. BCAA-enriched snack improves nutritional state of cirrhosis. . Nutrition 2007;23:113-20.

Nakaya Y, Okita K, Kato A, Miwa Y, Suzuki K, Moriwaki H. Randomized trial of branched chain amino acid rich supplement against carbohydrate-rich snacks as a late evening snack in patients with liver cirrhosis (Abstract). Hepatology 2005;42 Suppl 1(4):699A-700A.

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Naveau 1986 {published data only (unpublished sought but not used)} Naveau S, Pelletier G, Poynard T, Attali P, Poitrine A. BuHet C, et al. A randomised Clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients. Hepatology 1986;6(2):270-4.

Norman 2008 {published and unpublished data} Norman K, Kirchner H, Friedrich U, Lochs H, Ockenga J, Pirlich M. Enteral nutrition improves functional parameters in patients with advanced liver cirrhosis (Abstract) [Enterale Ernahrung verbessert funktionale Parameter in Patienten mit fortgeschrittener Leberzirrhose]. Zeitschri1 fur Gastroenterologie 2005;43(8):913.

* Norman K, Smoliner C, Stobacus N, Schuetz T, Lochs H, Ockenga, et al. Early enteral nutrition improves functional parameters in liver cirrhosis (Abstract). Gastroenterology 2008;134 Suppl 1:A563.

Pirlich M, Norman K, Lochs H. Malnutrition in liver cirrhosis: impact of protein rich oral diet. Zeitschri1 fur Gastroenterologie 2006;44(4):344-5. [MEDLINE: 16625465]

Poon 2004 {published data only (unpublished sought but not used)} Poon RT, Yu WC, Fan ST, Wong J. Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Alimentary Pharmacology and Therapeutics 2004;19(7):779-88.

Puglionisi 1985 {published data only (unpublished sought but not used)} * Ceriati F, Cavicchioni C, Marino IR, De Luca G, Puglionisi A. Management of hepatic encephalopathy in cirrhotic patients aKer derivative surgery [Trattamento dell'encefalopatia epatica nei pazienti cirrotici sottoposti ad intervento chirurgico derivativo]. Acta Medica Romana 1985;23(1):69-76.

Puglionisi A, Ceriati F, Marino IR, Cavicchioni C, De Luca G, Roncone A, et al . Prophylaxis of hepatic encephalopathy aKer porta-caval anastomosis using branched chain amino acid mixtures. In: Capacaccio L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:345-50.

Qiu 2009 {published data only (unpublished sought but not used)} Qiu Y, Zhu X, Wang W, Xu Q, Ding Y. Nutrition support with glutamine dipeptide in patients undergoing liver transplantation. Transplantation Proceedings 2009;41:4232-7.

Reilly 1990 {published data only (unpublished sought but not used)} * Reilly J, Mehta R, Teperman L, Cemaj S, Tzakis A, Yanaga K, et al. Nutritional support aKer liver transplantation: a randomized prospective study. Journal of Parenteral and Enteral Nutrition 1990;14(4):386-91.

Reilly J, Yanaga K, Tzakis A, Teperman L, Mehta R, Rezak A, et al. A randomized prospective study of nutritional support

aKer liver transplant (Abstract). Journal Parenteral and Enteral Nutrition 1989;13:8S.

San-In Group 1997 {published data only (unpublished sought but not used)} Heys SD. Long-term oral administration of branched chain amino acids aKer curative resection of hepatocellular carcinoma: a prospective randomized trial (Letter). British Journal of Surgery 1998;85(3):423.

Mann DV. Long-term oral administration of branched chain amino acids aKer curative resection of hepatocellular carcinoma: a prospective randomized trial (Letter). British Journal of Surgery 1998;85(6):875.

Nagasue N. Long-term oral administration of branched chain amino acids aKer curative resection of hepatocellular carcinoma: a prospective randomized trial - reply. British Journal of Surgery 1998;85(3):423-4.

* San-in Group of Liver Surgery. Long-term oral administration of branched chain amino acids aKer curative resection of hepatocellular carcinoma: a prospective randomized trial. British Journal of Surgery 1997;84(11):1525-31.

Schuetz 2006 {published data only (unpublished sought but not used)} Schuetz T, Norman K, Friedrich-Pagels U, Ockenga J, Luu TN, Lochs H, et al. Tube feeding does not aHect subclinical hepatic encephalopathy in patients with liver cirrhosis (Abstract) . Gastroenterology 2006;130:A326.

Sievert 1999 {published and unpublished data} Stevert W, Gibson PR, Colman JC, Kronborg I, Crawford DH, Keogh J, et al. Energy and amino acid supplements in malnourished patients with cirrhosis: a randomised controlled trial (Abstract) . Hepatology 1999;30:434A.

Simko 1983 {published data only (unpublished sought but not used)} Simko V. Long-term tolerance of a special amino acid oral formula in patients with advanced liver disease. Nutrition Reports International 1983;27(4):765-73.

Simon 1988 {published data only (unpublished sought but not used)} Galambos JT, Simon D. Peripheral hyperalimentation (Ppn) in moderate and severe alcoholic hepatitis (Ah) - a randomized controlled-study (abstract). Alcohol and Alcoholism 1988;23(3):A25.

* Simon D, Galambos JT. A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis. Journal of Hepatology 1988;7(2):200-7.

Simon D, Galambos JT. Peripheral hyperalimentation (Ppn) in moderate and severe alcoholic hepatitis (Ah): a randomized controlled study (Abstract). Hepatology 1986;6(5):1163.

Simon D, Galambos JT. Peripheral hyperalimentation (Ppn) in severe alcoholic hepatitis (Ah) - a blinded randomized controlled study - preliminary data (abstract). Digestive Diseases and Sciences 1986;31(10):S216.

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Simon DM, Galambos JT. Peripheral hyperalimentation (Ppn) in moderate and severe alcoholic hepatitis (Ah) a randomized controlled study (abstract). American Journal of Gastroenterology 1987;82(9):979.

Takeshita 2009 {published data only (unpublished sought but not used)} Takeshita S, Ichikawa T, Nakao K, Miyaaki H, Shibata H, Matsuzaki T, et al. A snack enriched with oral branched-chain amino acids prevents a fall in albumin in patients with liver cirrhosis undergoing chemoembolization for hepatocellular carcinoma. Nutrition Research 2009;29:89-93.

Tangkijvanich 2000 {published data only (unpublished sought but not used)} Tangkijvanich P, Mahachai V, Wittayalertpanya S, Ariyawongsopon V, Isarasena S. Short-term eHects of branched- chain amino acids on liver function tests in cirrhotic patients. The Southeast Asian Journal of Tropical Medicine and Public Health 2000;31(1):152-7.

Zheng 2003 {published data only (unpublished sought but not used)} * Hu Q-G, Zheng Q-C. The influence of enteral nutrition in postoperative patients with poor liver function. World Journal of Gastroenterology 2003;9(4):843-6.

Zheng Q, Hu Q. The influence of enteral nutrition on gut barrier in the post-operative patients with damaged hepatic function. Journal of Tongji Medical University 2001;21(4):323-5.

References to studies excluded from this review Abad Lacruz 1990 {published data only} Abad Lacruz A, Gonzalez Huix F, Esteve M, Fernandez Banares F, Cabre E, Boix J, et al. Liver function tests (LFT) derangement in patients with active inflammatory bowel disease (IBD) on either ten or TPN A prospective, randomized study (Abstract). Clinical Nutrition 1988;7 Special Suppl:60.

* Abad Lacruz A, Gonzalez Huix F, Esteve M, Fernandez Banares F, Cabre E, Boix J, et al. Liver function tests abnormalities in patients with inflammatory bowel disease receiving artificial nutrition: a prospective randomized study of total enteral nutrition vs total parenteral nutrition. Journal of Parenteral and Enteral Nutrition 1990;14(6):618-21.

Adams 2011 {published data only} Adams L, Zhu K, Kerr D, Devine A, Solah V.A, Binns C, et al. The eHect of whey protein supplementation on hepatic steatosis: Results from a randomized placebo controlled trial in postmenopausal women (abstract). Hepatology 2011;54 Suppl 1:1146A.

Akoglu 2008 {published data only} Akoglu B, Schrott M, Bolouri H, JaHari A, Kutschera E, Caspary WF, et al. The folic acid metabolite L-5- methyltetrahydrofolate eHectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo-controlled study. European Journal of Clinical Nutrition 2008;62(6):796-801.

Al Mardini 2006 {published data only} Al Mardini H, Douglass A, Record CA. Amino acid challenge in patients with cirrhosis and control subjects: ammonia, plasma amino acid and EEG changes. Metabolic Brain Disease 2006;21(1):1-10.

Alvarez 2004 {published data only} Alvarez MA, Cabre E, Lorenzo-Zuniga V, Montoliu S, Planas R, Gassull MA. Combining steroids with enteral nutrition: a better therapeutic strategy for severe alcoholic hepatitis? Results of a pilot study. European Journal of Gastroenterology and Hepatology 2004;16(12):1375-80.

Andreone 2001 {published data only} Andreone P, Fiorino S, Cursaro C, Gramenzi A, Margotti M, Di Giammarino L, et al. Vitamin E as treatment for chronic hepatitis B: Results of a randomized controlled pilot trial. Antiviral Research 2001;49(2):75-81.

Awad 2010 {published data only} Awad S, Constantin-Teodosiu D, Constantin D, Rowlands BJ, Fearon KCH, Macdonald IA, et al. Cellular mechanisms underlying the protective eHects of preoperative feeding. Annals of Surgery 2010;252:247-53.

Badalamenti 1995 {published data only} Badalamenti S, Salerno F, Lorenzano E, Paone G, Como G, Finazzi S, et al. Renal eHects of dietary supplementation with fish oil in cyclosporine- treated liver transplant recipients. Hepatology 1995;22(6):1695-701.

Baldermann 1988 {published data only} * Baldermann H, Wicklmayr M, Rett K, Banholzer P, Dietze G, Mehnert H. Changes in ultrasonic findings in the liver in relation to parenteral nutrition with long chain triglyceride and medium chain triglyceride/long chain triglyceride lipid solutions [Untersuchungen zur Veranderung des Sonographiebefundes der Leber unter parenteraler Ernahrung mit LCT-bzw MCT/LCT Lipidlosungen ]. Infusionstherapie 1988;15(4):140-3.

Baldermann H, Wicklmayr M, Rett K, Banholzer P, Dietze G, Mehnert H. Changes of hepatic morphology during parenteral nutrition with lipid emulsions containing LCT or MCT/LCT quantified by ultrasound. Journal of Parenteral and Enteral Nutrition 1991;15(6):601-3.

Barle 1997 {published data only} Barle H, Nyberg B, Andersson K, Essen P, McNurlan MA, Wernerman J, et al. The eHects of short-term parenteral nutrition on human liver protein and amino acid metabolism during laparoscopic surgery. Journal of Parenteral and Enteral Nutrition 1997;21(6):330-5.

Bartels 2004 {published data only} Bartels M, Biesalski HK, Engelhart K, Sendlhofer G, Rehak P, Nagel E. Pilot study on the eHect of parenteral vitamin E on ischemia and reperfusion induced liver injury: a double blind, randomized, placebo-controlled trial. Clinical Nutrition 2004;23(6):1360-70.

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Bernardi 1981 {published data only} Bernardi R. Liver, protein metabolism, branched chain amino acids [Fegato, metabolismo proteico, aminoacidi a catena ramificata]. La Clinica Terapeutica 1981;99:653-75.

Bianchi 1993 {published data only} Bianchi G.P, Marchesini G, Fabbri A, Rondelli A, Bugianesi E, Zoli M, et al. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. Journal of Internal Medicine 1993;233(5):385-92.

Bories 1994 {published data only} Bories PN, Campillo B. One-month regular oral nutrition in alcoholic cirrhotic-patients - changes of nutritional-status, hepatic-function and serum-lipid pattern. British Journal of Nutrition 1994;72(6):937-46.

Brans 1987 {published data only} Brans YW, Ritter DA, Kenny JD, Andrew DS, Dutton EB, Carrillo DW. Influence of intravenous fat emulsion on serum bilirubin in very low birthweight neonates. Archives of Disease in Childhood 1987;62(2):156-60.

Bresci 1993 {published data only} Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: A long-term treatment. European Journal of Medicine 1993;2(7):414-6.

Buchmiller 1993 {published data only} Buchmiller CE, Kleiman-Wexler RL, Ephgrave KS, Booth B, Hensley CE. Liver dysfunction and energy source: results of a randomized clinical trial. Journal of Parenteral and Enteral Nutrition 1993;17(4):301-6.

Cabre 2000 {published data only} Cabre E. Outcome of severe alcoholic hepatitis (SAH) treated with steroids (STE) or total enteral nutrition (TEN) (Abstract). Journal of Hepatology 2000;32(2):32.

Cabre E. Short and long-term outcome in severe alcoholic hepatitis (SAH) treated with steroids or total enteral nutrition (TEN) (Abstract). Hepatology 1999;30(4):405A.

Cabre E. Short and long-term outcome in severe alcoholic hepatitis (SAH) treated with steroids or total enteral nutrition (TEN). A multicentric randomized controlled trial (Abstract). Hepatology 1999;30(4):979.

Cabre E. Treatment of severe alcoholic hepatitis with steroids or total enteral nutrition: Interim results of a prospective, randomized, multicentric trial. Gastroenterology 1998;114(4):G3562.

Cabre E. Treatment of severe alcoholic hepatitis with steroids or total enteral nutrition: interim results of a prospective, randomized, multicentric trial (Abstract). Clinical Nephrology 1998;17 Suppl 1:18.

* Cabre E, Rodriguez Iglesias P, Caballeria J, Quer JC, Sanchez Lombrana JL, Pares A, et al. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or

enteral nutrition: a multicenter randomized trial. Hepatology 2000;32(1):36-42.

Cabre E, Rodriguez-Iglesias P, Caballeria J, Quer JC, Sanchez- Lombrana JL, Pares A, et al. Short- and long-term outcome of sever alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial [abstract]. European Journal of Gastroenterology and Hepatology 2000;12(8):963-6.

Cabre E, Spanish Group for the Study of Alcoholic Hepatitis. Steroids vs enteral nutrition in severe alcoholic hepatitis Interim results of a prospective, randomized, multicentric trial (Abstract). Journal of Hepatology 1998;28 Suppl 1(1):129.

Gassull M, Cabre E. Short and long-term outcome in severe alcoholic hepatitis (SAH) treated with steroids or total enteral nutrition (TEN). A multicentric randomized controlled trial by the Spanish Group for the study of Alcoholic Hepatitis. Journal of Parenteral and Enteral Nutrition 2000;24(1):S5.

Campo 1997 {published data only} Campo G, Amodio P, Caregaro L, Sacerdoti D, Bolognesi M, Burlina A, et al. EHect of a dietary integration with BCAA or casein on nutritional state and lower limb amino acid exchange in cirrhosis. Advances in Hepatic Encephalopathy and Metabolism in Liver Disease. Great Britain: Ipswich Book Company Ltd., 1997:149-55.

Cao 2007 {published data only} Cao J, Luo SM, Liang L, Lai J. EHects of parenteral nutrition without and with growth hormone on growth hormone/insulin- like growth factor-1 axis aKer hepatectomy in hepatocellular carcinoma with liver cirrhosis. Journal of Parenteral and Enteral Nutrition 2007;31(6):496-501.

Cerra 1983 {published data only} Cerra FB, Cheung NK, Fischer JE, Kaplowitz N, SchiH ER, Dienstag JL, et al. A multicenter trial of branched chain enriched amino acid infusion (F080) in hepatic encephalopathy (HE) (Abstract). Hepatology 1982;2(5):699.

* Cerra FB, McMillen M, Angelico R, Cline B, Lyons J, Faulkenbach L, et al. Cirrhosis, encephalopathy, and improved results with metabolic support. Surgery 1983;94(4):612-9.

Cerra 1985 {published data only} * Cerra FB, Cheung NK, Fischer JE, Kaplowitz N, SchiH ER, Dienstag JL, et al. Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind, controlled trial. Journal of Parenteral and Enteral Nutrition 1985;9(3):288-95.

Cowan GS Jr. Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double- blind, controlled trial (Letter). Journal of Parenteral and Enteral Nutrition 1986;10:247.

Cerwenka 1998 {published data only} Cerwenka H, Bacher H, Werkgartner G, El-Shabrawi A, Quehenberger F, Hauser H, et al. Antioxidant treatment during liver resection for alleviation of ischemia-reperfusion injury. Hepato-Gastroenterology 1998;45(21):777-82.

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Chelarescu 2003 {published data only} Chelarescu O, Chelarescu D, Rusu M, Stratan I. Parenteral vs enteral nutrition in acute liver failure (Abstract). Journal of Hepatology 2003;38 Suppl 2:192.

Chin 1992 {published data only} Chin SE, Shepherd RW, Thomas BJ, Cleghorn GJ, Patrick MK, Wilcox JA, et al. Nutritional support in children with end-stage liver disease: a randomized crossover trial of a branched-chain amino acid supplement. American Journal of Clinical Nutrition 1992;56(1):158-63.

Christie 1985 {published data only} Christie ML, Sack DM, Horst D, Lenger S, Pomposelli J. Enriched branched-chain amino acid formula versus a casein based supplement in the treatment of cirrhosis (Abstract). Journal of Parenteral and Enteral Nutrition 1984;8:91.

* Christie ML, Sack DM, Pomposelli J, Horst D. Enriched branched-chain amino acid formula versus a casein-based supplement in the treatment of cirrhosis. Journal of Parenteral and Enteral Nutrition 1985;9(6):671-8.

Clarke 2004 {published data only} Clarke S, Bernal W, Rees G, Wendon J. Immunonutrition in critically ill patients with liver disease: a prospective randomised double-blind controlled trial. Hepatology 2004;40 Suppl 1:500A.

Conti 1971 {published data only} Conti F, Natangelo R, Cattani F, Mandelli V. Controlled clinical trial of liver-protective agents [La sperimentazione clinica controllata degli epatoprotettori]. La Clinica Terapeutica 1971;59(2):155-65.

Córdoba {unpublished data only} Córdobo J. EHects of proteins in patients with cirrhosis and prior hepatic encephalopathy. ClinicalTrials.gov 2009. [Other (ClinicalTrials.gov): NCT00955500]

Córdoba 2004 {published data only} Cordoba J, Sanpedro F, Lopez-Hellin Sabin P, Planas M, Esteban R, Guardia J. A low-protein diet does not improve the outcome of acute hepatic encephalopathy. Results of a pilot study using enteral nutrition (Abstract). Hepatology 2001;34(4):187A.

* Córdoba J, López-Hellín J, Planas M, Sabín P, Sanpedro F, Castro F, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. Journal of Hepatology 2004;41(1):38-43.

Cortez Pinto 1990 {published data only} Cortez Pinto H, Cravo M, Saraiva A, Camilo ME, Moura MC. Parenteral nutrition in cirrhosis (Abstract). Journal of Hepatology 1990;10 Suppl 1:19.

Cunha 2004 {published data only} Cunha L, Nono MH, Guibert AL, Nidegger D, Beau P, Beauchant M. EHects of prolonged oral nutritional support

in malnourished cirrhotic patients: Results of a pilot study. Gastroenterologie Clinique Et Biologique 2004;28(1):36-9.

De Antoni 1984 {published data only} De Antoni E, Grilli P, Orsi E. . EHicacy of TPN in cirrhotic patients with bleeding esophageal varices. Italian Journal of Surgical Sciences 1984;14(3):253-5.

De-Fang 2011 {published data only} De-Fang Z, Ke Z, Ren L, Li-Jun Z. Clinical observation of enteral immunonutrition in patients undergoing liver transplantation. Journal of Clinical Rehabilitative Tissue Engineering Research 2011;15(31):5873-8.

de la Maza 1995 {published data only} de la Maza MP, Petermann M, Bunout D, Hirsch S. EHects of long- term vitamin E supplementation in alcoholic cirrhotics. Journal of the American College of Nutrition 1995;14(2):192-6.

de Luis 2010 {published data only} de Luis DA, Aller R, Izaola O, Gonzalez Sagrado M, Conde RTI. EHect of two diHerent hypocaloric diets in transaminases and insulin resistance in nonalcoholic fatty liver disease and obese patients. Nutricion Hospitalaria 2010;25(5):730-5.

Di Cecco 1997 {published data only} Di Cecco SR, Francisco-Ziller NM, Porayko MK, Crippin JS, Blue LS, Huang KS, et al. Does pretransplant oral nutrition supplementation aHect post-transplant clinical outcomes? (Abstract). Hepatology 1997;26(4 (Pt 2)):500A.

Diehl 1985 {published and unpublished data} Diehl AM, Boitnott JK, Herlong HF, Potter JJ, Van Duyn MA, Chandler E, et al. EHect of parenteral amino acid supplementation in alcoholic hepatitis. Hepatology 1985;5(1):57-63.

Dionigi 1984 {published data only} Dionigi P, Holdsworth JD, Clague MB, James OF, Wright PD. Body protein synthesis and breakdown in chronic liver disease. The eHect of diHerent amino acid solutions (Abstract). Clinical Nutrition 1984;2 Special Suppl:O.81.

Egberts 1981 {published data only} * Egberts E-H, Hamster W, Jurgens P, Schumacher H, Fondalinski G, Reinhard U, et al. EHect of branched chain amino acids on latent portal-systemic encephalopathy. In: Walser M, Williamson JR editor(s). Metabolism and Clinical Implications of Branched Chain Amino and Ketoacids. Amsterdam: Elsevier North Holland, 1981:453-63.

Hamster W, Egberts EH, Hamster H. Treatment with branched- chain amino acids and eHect on psycho-physical capacity functions in latent porto-systemic encephalopathy [Behandlung mit verzweigtkettigen aminosauren und ihre auswirkung auf psychophysische leistungsfunktionen bel latenter portosystemischer enzephalopathie]. Arzneimittelforschung 1982;32:901-2.

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Egberts 1985 {published data only} Egberts EH, Hamster W, Schomerus H, Jürgens P. EHect of branched chain amino acids on latent porto-systemic- encephalopathy (PSE) (Abstract). Journal of Parenteral and Enteral Nutrition 1981;5:354.

Egberts EH, Schomeerus H, Hamster W, Jürgens P. EHective treatment of latens porto-systemic encephalopathy with oral branched chain amino acids. In: Capocaccia L, Fischer JE, Rossi- Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. Plenum Press, New York, 1984:351-7.

* Egberts EH, Schomerus H, Hamster W, Jurgens P. Branched chain amino acids in the treatment of latent portosystemic encephalopathy A double-blind placebo-controlled crossover study. Gastroenterology 1985;88(4):887-95.

Egberts EH, Schomerus H, Hamster W, Jurgens P. Branched- chain amino acids in the treatment of latent porto-systemic encephalopathy A placebo-controlled double-blind cross-over study [Verzweigtkettige Aminosauren bei der Behandlung der latenten portosystemischen Enzephalopathie Eine placebokontrollierte Doppelblind-Cross-over-Studie ]. Zeitschri1 für Ernährungswissenscha1 1986;25(1):9-28.

Egberts 1988 {published data only} Egberts E-H, Plauth M, Hamster W, Torok M, Brand O, Furst P. Long-term double-blind crossover study on the treatment of latent portosystemic encephalopathy (PSE) with branched chain amino acids (BCAA) (Abstract). Clinical Nutrition 1988;76 Suppl:31.

Eriksson 1982 {published data only} * Eriksson LS, Persson A, Wahren J. Branched-chain amino acids in the treatment of chronic hepatic encephalopathy. Gut 1982;23(10):801-6.

Eriksson LS, Persson A, Wahren J. Failure of oral branched- chain amino acids to improve chronic hepatic encephalopathy (Abstract). Journal of Parenteral and Enteral Nutrition 1981;5:355.

Ferenci 1981 {published data only} Ferenci P, Dragosics B, Wewalka F. Oral administration of branched chain amino acids (BCAA) and keto acids (BCKA) in patients with liver cirrhosis (LC). In: Walser M, Williamson JR editor(s). Metabolism and Clinical Implications of Branched Chain Amino and Ketoacids. Amsterdam: Elsevier North Holland, 1981:507-12.

Fiaccadori 1984 {published data only} * Fiaccadori F, Ghinelli F, Pedretti G, Pelosi G, Sacchini D, Zeneroli ML, et al. Branched chain amino acid enriched solutions in the treatment of hepatic encephalopathy: a controlled trial. In: Capocaccia L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic encephalopathy in chronic liver failure. Plenum Press, New York, 1984:323-33.

Fiaccadori F, Ghinelli F, Pedretti G, Pelosi G, Sacchini D, Zeneroli ML, et al. Branched-chain enriched amino acid solutions in the treatment of hepatic encephalopathy: A

controlled trial (Abstract). Italian Journal of Gastroenterology 1985;17:5-10.

Fiaccadori F, Ghinelli F, Pelosi G, Sacchini D, Vaona GL, Zeneroli ML, et al. Selective amino acid solutions in hepatic encephalopathy (a preliminary report). La Ricerca in Clinica e in Laboratorio 1980;10:411-22.

Fiaccadori 1988 {published data only} * Fiaccadori F, Elia GF, LehndorH H, Merli M, Pedretti G, Riggio O, et al. The EHect of dietary supplementation with branched- chain amino acids (BCAAs)vs casein in patients with chronic recurrent portal systemic encephalopathy: a controlled trial. In: Soeters PB, Wilson JHP, Meijer AJ, Holm E editor(s). Advances in Ammonia Metabolism and Hepatic Encephalopathy. Amsterdam: Elsevier Science Publishers B.V., 1988:489-97.

Fiaccadori F, LehndorH H, Merli M, Pedretti G, Perinotto P, Riggio O, et al. BCAA oral dietary supplementation vs casein in chronic recurrent HE A controlled trial (Abstract). Journal of Hepatology 1987;4 Suppl 1:16.

Freeman 1983 {published data only} Freeman JG, Bassendine M, Heath P, James OFW, Record CO. Double blind trial of branched chain amino acid infusions in cases of hepatic encephalopathy (Abstract). Gut 1983;24(5):A503.

Fukushima 2003 {published data only} Fukushima H, Miwa Y, Ida E, Kuriyama S, Toda K, Shimomura Y, et al. Nocturnal branched-chain amino acid administration improves protein metabolism in patients with liver cirrhosis: comparison with daytime administration. Journal Parenteral Enteral Nutrition 2003;27(5):315-22. [MEDLINE: 12971730]

Galloway 1987 {published data only} Galloway JR, Hooks MA, Millikan WJ, HendersonJM, Towns M, Kutner MH, et al. The nutritional eHects of F080 versus standard intravenous hyperalimentation in malnourished cirrhotics with subclinical encephalopathy (Abstract). Journal of Parenteral and Enteral Nutrition 1987;13 Suppl 1:8.

Gavazzl 1999 {published data only} Gavazzl C, Bozzetti F, Crippa F, Mariani L, Antonini R. Impact of diHerent energy substrates on liver metastases metabolism (Abstract). Clinical Nutrition 1999;18 Suppl 1:50.

Glynn 1988 {published data only} * Glynn MJ, Powell Tuck J, Reaveley DA, Murray Lyon IM. High lipid parenteral nutrition improves portosystemic encephalopathy. Journal of Parenteral and Enteral Nutrition 1988;12(5):457-61.

Glynn MJ, Powell-Tuck J, Reaveley D, Murray-Lyon IM. High lipid parenteral feeds raise plasma branched chain amino acid concentrations - a possible therapeutic approach to portasystemic encephalopathy? (Abstract). Gut 1985;26(5):A569.

Glynn MJ, Powell-Tuck J, Reaveley DA, Murray-Lyon IM. High lipid parenteral feeds raise plasma branched chain amino acid concentrations - a possible therapeutic approach

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to portasystemic encephalopathy?. Clinical Nephrology 1986;5:109-12.

Grungrei< 1993 {published data only} GrungreiH K, Kleine FD, Musil HE, Diete U, Franke D, Klauck S, et al. Valine enriched branched-chain amino acids in the treatment of hepatic encephalopathy [Valin und Verzweigtkettige Aminosauren in der Behandlung der Hepatischen Enzephalopathie]. Zeitschri1 für Gastroenterologie 1993;31(4):235-41.

Grungrei< 2001 {published data only} GrungreiH K, Lambert-Baumann J. EHicacy of L-ornithin-L- aspartate-granules in chronic liver diseases [Wirksamkeit von L-ornithin-L-aspartat-granulat bei chronischen lebererkrankungen]. Medizinische Welt 2001;52(7-8):219-26.

Guarnieri 1982 {published data only} * Guarnieri GF, Toigo G, Pozzato G, Faccini L, Giuntini D, Situlin R, et al. Long-term oral supplementation of chronic liver disease patients with branched-chain amino acids and/or energy (Abstract). Clinical Nutrition 1982;1 Special Suppl:54.

Guarnieri GF, Toigo G, Situlin R, Pozzato G, Faccini L, et al. Muscle biopsy studies on malnutrition in patients with liver cirrhosis. In: Capocaccia L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:193-208.

Guarnieri 1984 {published data only} Guarnieri GF, Chiesa L, Toigo G, Pozzato G, Lucchesi A, Sasso F, et al. Short-term treatment of chronic recurrent hepatic encephalopathy with enteral administration of a mixture rich in branched-chain amino acids and energy [Trattamento a breve termine dell'encefalopatia epatica cronica ricorrente con somministrazione enterale di una miscela ricca in aminoacidi ramificati ed energia]. Giornale di Clinica Medica 1984;65(2):79-85.

Habu 2003 {published data only} Habu D, Nishiguchi S. EHect of oral supplementation with branched-chain amino acid granules on serum albumin level in the early stage of cirrhosis (Abstract). Journal of Parenteral and Enteral Nutrition 2003;27(1):37-8.

* Habu D, Nishiguchi S, Nakatani S, Kawamura E, Lee C, Enomoto M, et al. EHect of oral supplementation with branched- chain amino acid granules on serum albumin level in the early stage of cirrhosis: a randomized pilot trial. Hepatology Research 2003;25(3):312-8.

Habu 2009 {published data only} Habu D, Nishiguchi S, Nakatani S, Lee C, Enomoto M, Tamori A, et al. Comparison of the eHect of BCAA granules on between decompensated and compensated cirrhosis. Hepato- gastroenterology 2009;56(96):1719-23.

Haji 2008 {published data only} Haji S, Shinzaki W, Satoi S, Ohlyanagi H. Immunonutrition with high-dose EPA and arginine induces immunological preconditioning on TH1/TH2 balance in major hepatic resection

for liver malignancy (Abstract). Clinical Nutrition 2008;Suppl 1:64.

Hayaishi 2011 {published data only} Hayaishi S, Chung H, Kudo M, Ishikawa G, Takita M, Ueda T, et al. Oral Branched-Chain Amino Acid Granules Reduce the Incidence of Hepatocellular Carcinoma and Improve Event- Free Survival in Patients With Liver Cirrhosis. Digestive Diseases 2011;29(3):326-32.

Hayashi 2007 {published data only} Hayashi M, Ikezawa K, Ono A, Okabayashi S, Hayashi Y, Shimizu S, et al. Evaluation of the eHects of combination therapy with branched-chain amino acid and zinc supplements on nitrogen metabolism in liver cirrhosis. Hepatology Research 2007;37(8):615-9.

Herlong 1980 {published data only} Herlong HF, Maddrey WC, Walser M. The use of ornithine salts of branched-chain ketoacids in portal-systemic encephalopathy. Annals of Internal Medicine 1980;93(4):545-50.

Hernandez-Guerra 2006 {published data only} Hernandez-Guerra M, Garcia-Pagan JC, Turnes J, Bellot P, Deulofeu R, Abraldes JG, et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology 2006;43(3):485-91.

Holdsworth 1984 {published data only} Holdsworth JD, Dionigi P, Clague MB, James OFW, Wright PD. Body protein metabolism and plasma amino acids in cirrhosis of the liver The eHect of varying the branched chain amino acid content of intravenous amino acid solutions. Clinical Nutrition 1984;3:153-62.

Holm 1981 {published data only} Holm E, Langhans W, Meisinger E, Hiltmann W-D, Gastreiger P. BCAA-enriched diets for oral treatment of patients with liver cirrhosis: a controlled study of biochemical variables, psychometric performance, and the EEG (Abstract). Journal of Parenteral and Enteral Nutrition 1981;5:354.

Holm 1984 {published data only} Holm E, Tschepe A, Staedt U, Leweling H, Striebel JP. Concentrations of energy yielding substrates and metabolites in the postabsorptive state and during parenteral nutrition (lipid systems) in patients with liver cirrhosis (Abstract). Clinical Nutrition 1984;2(Spec Suppl):O.66.

Holm 2000 {published data only} Holm E, Hess Y, Leweling H, Barth H-O, Hagmüller E. Ornithine aspartate (OA) promotes amino acid (AA) retention in the peripheral tissues of patients with liver cirrhosis A double-blind randomized crossover study (Abstract). Journal of Parenteral and Enteral Nutrition 2000;15(1):368.

Horst 1984 {published data only} Horst D, Grace N, Conn HO, SchiH E, Schenker S, Viteri A, et al. A double-blind randomized comparison of dietary protein and an oral branched chain amino acid (BCAA) solution in cirrhotic

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patients with chronic portal-systemic encephalopathy (PSE) (Abstract). Hepatology 1982;2(1):184.

Horst D, Grace N, Conn HO, SchiH E, Schenker S, Viteri A, et al. A double-blind randomized comparison of dietary protein and oral branched chain amino acid (BCAA) supplement in cirrhotic patients with chronic portal-systemic encephalopathy (PSE) (Abstract). Hepatology 1981;1:518.

* Horst D, Grace ND, Conn HO, SchiH E, Schenker S, Viteri A, et al. Comparison of dietary protein with an oral, branched chain- enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 1984;4(2):279-87.

Huisman 2011 {published data only} Huisman E, Van Hoek B, Van Soest H, Van Nieuwkerk KC, Arends J, Siersema PD, et al. Preventive versus "on-Demand" nutritional support to maintain nutritional state and quality of life during antiviral therapy for hepatitis C: A randomized controlled trial. Hepatology 2011;54 Suppl 1:851A.

Hwang 1988 {published data only} Hwang SJ, Chan CY, Wu JC, Lee SD, Huan YS, Tsai YT. A randomized controlled trial for the evaluation of the eHicacy of branched chain amino acid-enriched amino acid solution in the treatment of patients with hepatic encephalopathy. Chinese Journal of Gastroenterology 1988;5:185-92.

Ichida 1995 {published data only} Ichida T, Shibasaki K, Muto Y, Satoh S, Watanabe A, Ichida F. Clinical-study of an enteral branched-chain amino-acid solution in decompensated liver-cirrhosis with hepatic-encephalopathy. Nutrition 1995;11(2):238-44.

Ikegami 2012 {published data only} Ikegami T, Shirabe K, Yoshiya S, Yoshizumi T, Ninomiya M, Uchiyama H, et al. Bacterial sepsis aKer living donor liver transplantation: the impact of early enteral nutrition. Journal of the American College of Surgeons 2012;214:288-95.

Ilan 2000 {published data only} Ilan Y, Sobol T, Sasson O, Ashur Y, Berry EM. A balanced 5:1 carbohydrate:protein diet: a new method for supplementing protein to patients with chronic liver disease. Journal of Gastroenterology and Hepatology 2000;15(12):1436-41.

Itou 2009 {published data only} Itou M, Kawaguchi T, Taniguchi E, Shiraishi S, Ibi R, Mutou M, et al. Heating improves poor compliance with branched chain amino acid-rich supplementation in patients with liver cirrhosis: a before-aKer pilot study. Molecular Medicine Reports 2009;2(6):983-7.

Itou 2011 {published data only} Itou M, Kawaguchi T, Taniguchi E, Oriishi T, Suetsugu T, Hano R, et al. Supplementation before endoscopic therapy for esophageal varices reduces mental stress in patients with liver cirrhosis. Hepato-Gastroenterology 2011;58(107-108):814-8.

Jentschura 1996 {published data only} Jentschura D, Storz LW, Rumstadt B, Winkler M. Hepatic encephalopathy following porto-systemic shunt. Langenbecks Archiv Fur Chirurgie 1996;381(5):283-8.

Jiang 2001 {published data only} Jiang ZM, Gu ZY, Chen FL, Wang XR, Li ZJ, Xu Y, et al. The role of immune enhanced enteral nutrition on plasma amino acid, gut permeability and clinical outcome (a randomized, double blind, controlled, multi-center clinical trail with 120 cases). Acta Academiae Medicinae Sinicae 2001;23(5):515-8.

Jiang 2007 {published data only} Jiang H, Li B, Yan L-N, Lu S-C, Wen T-F, Zhao J-C, et al. EHect of intravenous glutamine-dipeptide fortified enteral nutrition on clinical outcomes in patients aKer liver transplantation: a prospective randomized controlled study. Chinese Jouirnal of Clinical Nutrition 2007;15(1):21-5.

Jonung 1987 {published data only} Jonung T, Jeppsson B, Aslund U, Nair BM. A comparison between meat and vegan protein diet in patients with mild chronic hepatic encephalopathy. Clinical Nutrition 1987;6(3):169-74.

Kaido 2010 {published data only} Kaido T, Mori A, Ogura Y, Hata K, Yoshizawa A, Iida T, et al. Impact of enteral nutrition using a new immuno-modulating diet aKer liver transplantation. Hepato-Gastroenterology 2010;57(104):1522-5.

Kakumitsu 1998 {published data only} Kakumitsu S, Shijo H, Yokoyama M, Kim T, Akiyoshi N, Ota K, et al. EHects of L-arginine on the systemic, mesenteric, and hepatic circulation in patients with cirrhosis. Hepatology 1998;27(2):377-82.

Kanematsu 1988 {published data only} * Kanematsu T, Koyanagi N, Matsumata T, Kitano S, Takenaka K, Sugimachi K. Lack of preventive eHect of branched-chain amino acid solution on postoperative hepatic encephalopathy in patients with cirrhosis: a randomized, prospective trial. Surgery 1988;104(3):482-8.

Kanematsu Takashi, et al. Is branched chain amino acid infusion eHective in prevention of postoperative hepatic failure in patients with hepatic cirrhosis?: a prospective, randomized study [Kankohen Shorei no Jutsugo Kanfuzen Yobo ni Bunkisa Aminosan (BCAA) Yueki wa Yuko ka?: Prostective, Randomized Study]. Rinsho to Kenkyu (The Japanese Journal of Clinical and Experimental Medicine) 1988;65(3):897.

Katsumi 2005 {published data only} Katsumi N, Kawamura N, Yamaguchi Y, Sato Y, Morozumi K, Nakajima H, et al. EHect of oral branched chain amino acid- rich nutrient administered during endoscopic injection sclerotherapy of cirrhotic patients. Hepatology Research 2005;32(3):158-62.

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Kawaguchi 2008 {published data only} Kawaguchi T, Taniguchi E, Itou M, Mutou M, Ibi R, Shiraishi S, et al. Supplement improves nutrition and stresses caused by examination-associated fasting in patients with liver cirrhosis. Hepatology Research 2008;38(12):1178-85.

Kawamura 2009 {published data only} Kawamura E, Habu D, Iwai S, Morikawa H, Enomoto M, Tamori A, et al. A randomized pilot trial of oral branched-chain amino acids in early liver cirrhosis. Journal of Hepatology 2008;48 Suppl 2:116-7.

* Kawamura E, Habu D, Morikawa H, Enomoto EM, Kawabe J, Tammori A, et al. A randomized pilot trial of oral branched- chain amino acids in early cirrhosis: validation using prognostic markers for pre-liver transplant status. Liver Transplantation 2009;15(7):790-7. [MEDLINE: 19562716]

Keshavarzian 1984 {published data only} Keshavarzian A, Meek J, Sutton C, Emery VM, Hughes EA, Hodgson HJ. Dietary protein supplementation from vegetable sources in the management of chronic portal systemic encephalopathy. American Journal of Gastroenterology 1984;79(12):945-9.

Kircheis 1997 {published data only} * Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Gortelmeyer R, et al. Therapeutic eHicacy of L-ornithine-L- aspartate infusions in patients with cirrhosis and hepatic encephalopathy: Results of a placebo-controlled, double-blind study. Hepatology 1997;25(6):1351-60.

Stauch S, Kircheis G, Adler G, Beckh K, Ditschuneit H, Gortelmeyer R, et al. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: Results of a placebo- controlled double-blind study. Journal of Hepatology 1998;28(5):856-64.

Kobayashi 2008 {published data only} Kobayashi M, Ikeda K, Arase Y, Suzuki Y, Suzuki F, Akuta N, et al. Inhibitory eHect of branched-chain amino acid granules on progression of compensated liver cirrhosis due to hepatitis C virus. Journal of Gastroenterology 2008;43(1):63-70.

Krasno< 2006 {published data only} KrasnoH JB, Vintro AQ, Ascher NL, Bass NM, Paul SM, Dodd MJ, et al. A randomized trial of exercise and dietary counselling aKer liver transplantation. American Journal of Transplantation 2006;6(8):1896-905.

Kuroda 2010 {published data only} Kuroda H, Ushio A, Miyamoto Y, Sawara K, Iokawa K, Kasai K, et al. EHects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: a one-year prospective trial. Journal of Gastroenterology and Hepatology 2010;25:1550-5.

Kuse 1990 {published data only} * Kuse ER, Kemnitz J, Kotzerke J, Wassmann R, Gubernatis G, Ringe B, et al. Fat emulsions in parenteral nutrition aKer liver

transplantation: The recovery of the allograKs RES function and histological observations. Clinical Nutrition 1990;9(6):331-6.

Kuse ER, Kotzerke J, Ringe B, Wassmann R, Gubernatis G, Pichlmayr I. Fat emulsions in parenteral feeding following liver transplantation I EHect on the recovery of RES function in the transplant [Fettemulsionen in der parenteralen Ernahrung nach Lebertransplantation I Einfluss auf die Erholung der RES- Funktion im Transplantat]. Annales Chirurgiae et Gynaecologiae 1990;25(6):428-31.

Kuse ER, Nordmann S, Kemnitz J, Gubernatis G, Kotzerke J. MCT/LCT-fat emulsions in the parenteral nutrition of patients aKer liver transplantation. Influence on the recovery of the RES function and the level of liver cell fatty degeneration [MCT/LCT-Fettemulsionen in der parenteralen Ernahrung des lebertransplantierten Patienten. Einfluss auf die Erholung der RES-Funktion und den Grad der Leberzellverfettung.]. Zeitschri1 fur Gastroenterologie 1989;27(1):40.

Kuse 2002 {published data only} * Kuse ER, Kotzerke J, Muller S, Nashan B, Luck R, Jaeger K. Hepatic reticuloendotherlial function during parenteral nutrition including an MCT/LCT or LCT emulsion aKer liver transplantation ? a double-blind study. Transplantation International 2002;15:272-7.

Müller S, Kotzerke J, Behrend M, Liebau P, Wu A, Kuse ER. Double-blind study on hepatic RES-function aKer hepatic transplantation under parenteral nutrition with an MCT- or LCT-lipid-emulsion [Doppelblind-Studie zur hepatischen RES-Funktion nach Lebertransplantation unter parenteraler Ernährung mit einer MCT- oder LCT-Fettemulsion]. Wiener Klinische Wochenschri1 1995;107 Suppl 198:13-4.

Labadie 1994 {published data only} Labadie M, Arnaud J, Enkaoua W, Zarski JP, Tricot F, Vaysse J, et al. EHect of zinc supplementation in alcoholic cirrhosis. A double blind, randomized study. Trace Elements in Medicine 1994;11(1):23-8.

LaTerre 2007 {unpublished data only} Laterre P-F, Fleury Y. Safety and tolerance on lipids of parenteral and enteral nutrition in critically ill patients with liver failure. ClinicalTrials.gov NCT00522730.

Leon 2009 {published data only} Leon CDG. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: A randomized 12-month trial. Nutrition in Clinical Practice 2009;24(1):104-6.

Les 2011 {published data only} * Les I, Doval E, Garcia-Martinez R, Planas M, Cardenas G, Gomez P, et al. EHects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: A randomized study. American Journal of Gastroenterology 2011;106:1081-8.

Les I, Planas M, Cardenas G, Flavia M, Vergara M, Soriano G, et al. EHects of the proteins of the diet in patients with cirrhosis

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and a prior episode of hepatic encephalopathy. A long-term randomized study. Hepatology 2009;50 Suppl(4):313A.

Luntz 2005 {published data only} Luntz SP, Unnebrink K, Seibert-Grafe M, Bunzendahl H, Kraus TW, Buchler MW, et al. HEGPOL: Randomized, placebo controlled, multicenter, double-blind clinical trial to investigate hepatoprotective eHects of glycine in the postoperative phase of liver transplantation [ISRCTN69350312]. BMC Surgery 2005;5:18.

Mager 2006 {published data only} * Mager DR, Wykes LJ, Roberts EA, Ball RO, Pencharz PB. Branched-chain amino acid needs in children with mild-to- moderate chronic cholestatic liver disease. Journal of Nutrition 2006;136(1):133-9.

Mager DR, Wykes LJ, Roberts EA, Ball RO, Pencharz PB. EHect of orthotopic liver transplantation (OLT) on branched-chain amino acid requirement. Pediatric Research 2006;59(6):829-34.

Makay 2007 {published data only} Makay B, Duman N, Ozer E, Kumral A, Yesilirmak D, Ozkan H. Randomized, controlled trial of early intravenous nutrition for prevention of neonatal jaundice in term and near-term neonates. Journal of Pediatric Gastroenterology and Nutrition 2007;44(3):354-8.

Malaguarnera 2009 {published data only} Malaguarnera M, Risino C, Cammalleri L, Malaguanera L, Astuto M, Vecchio I, et al. Branched chain amino acids supplemented with l-acetylcarnitine versus BCAA treatment in hepatic coma: a randomized and controlled double blind study. European Journal of Gastroenterology and Hepatology 2009;21(7):762-70. [MEDLINE: 19357525]

Mangiante 2002 {published data only} * Mangiante G, Rossi L, Carluccio S, Marchiori L, Colucci G, Ciola M, et al. Influence of enteral nutrition on cytokine response in resective liver surgery [Influenza della nutrizione enterale sulla risposta citochinica in chirurgia resettiva epatica]. Chirurgia Italiana 2002;54(5):613-9.

Mangiante GL. Influence of enteral nutrition on cytokines response in resective liver surgery for HCC. International Journal of Cancer 2002;Suppl 13:235.

Manguso 2005 {published data only} Manguso F, D'Ambra G, Menchise A, Sollazzo R, D'Agostino L. EHects of an appropriate oral diet on the nutritional status of patients with HCV-related liver cirrhosis: a prospective study. Clinical Nutrition 2005;24(5):751-9.

Marchesini 1980 {published data only} Marchesini G, Zoll M, Dondi C, Cecchini L, Angiolini A, Bianchi F, et al. Prevalence of subclinical hepatic encephalopathy in cirrhotics and relationship to plasma amino acid imbalance. Digestive Diseases and Sciences 1980;25(10):763-8.

Marchesini 1990 {published data only} Bianchi GP, Marchesini G, Zoli M, Abbiati R, Ferrario E, Fabbri A, et al. Oral BCAA supplementation in cirrhosis with chronic

encephalopathy: eHects on prolactin and estradiol levels. Hepatogastroenterology 1992;39(5):443-6.

Bianchi GP, Marchesini G, Zoli M, Bellati G, Colombo A, Ideol G, et al. Oral BCAA supplementation in patients with liver cirrhosis Preliminary results of a randomized double multicentre study (Abstract). Italian Journal of Gastroenterology 1987;19:120.

Marchesini G, Bianchi GP, Zoli M, Bellati G, Colombo A, Ideo G, et al. A randomized double-blind study of oral BCAA in patients with cirrhosis (Abstract). Journal of Hepatology 1987;5 Suppl 1:43.

* Marchesini G, Dioguardi F.S, Bianchi G.P, Zoli M, Bellati G, RoHi L, et al. Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. Journal of Hepatology 1990;11(1):92-101.

Marchesini G, Dioguardi FS, Bianchi GP, Zoli M, Bellati G, RoHi L, et al. A randomized double-blind study of oral BCAA in patients with cirrhosis (Abstract). Journal of Hepatology 1990;10 Suppl 1:15.

Marchesini 2003 {published data only} Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched- chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 2003;124(7):1792-801.

Marchini 1983 {published data only} Marchini JS, Vannucchi H, Dutra de Oliveira JE. EHect of two carbohydrate :lipid ratios of diets enterally fed to chronic alcoholics. Human Nutrition: Clinical Nutrition 1983;37C:329-37.

Marra 1998 {published data only} Marra F, Riccardi D, Melani L, Spadoni S, Galli C, Fabrizio P, et al. EHects of supplementation with unsaturated fatty acids on plasma and membrane lipid composition and platelet function in patients with cirrhosis and defective aggregation. Journal of Hepatology 1998;28(4):654-61.

McGhee 1983 {published data only} McGhee A, Henderson JM, Millikan WJ Jr, Bleier JC, Vogel R, Kassouny M, et al. Comparison of the eHects of Hepatic-Aid and a Casein modular diet on encephalopathy, plasma amino acids, and nitrogen balance in cirrhotic patients. Annals of Surgery 1983;197(3):288-93.

Mendenhall 1985 {published data only} Mendenhall C, Bongiovanni G, Goldberg S, et al. VA cooperative study on alcoholic hepatitis III: Changes in protein-calorie malnutrition associated with 30 days of hospitalization with and without enteral nutritional therapy. Journal of Parenteral & Enteral Nutrition 1985;9(5):590-6.

Mendenhall 1993 {published data only} * Mendenhall CL, Moritz TE, Roselle GA, Morgan TR, Nemchausky BA, Tamburro CH, et al. A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans AHairs cooperative study. Hepatology 1993;17(4):564-76.

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Mendenhall CL, Moritz TE, Roselle GA, Morgan TR, Nemchausky BA, Tamburro CH, et al. Protein-energy malnutrition in severe alcoholic hepatitis - diagnosis and response to treatment. Journal of Parenteral and Enteral Nutrition 1995;19(4):258-65.

Morgan TR, Moritz TE, Mendenhall CL, Haas R. Protein consumption and hepatic encephalopathy in alcoholic hepatitis VA Cooperative Study Group #275. Journal of the American College of Nutrition 1995;14(2):152-8.

Mezey 1991 {published data only} Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. EHect of parenteral amino-acid supplementation on short- term and long-term outcomes in severe alcoholic hepatitis - a randomized controlled trial. Hepatology 1991;14(6):1090-6.

Michel 1985 {published data only} * Michel H, Bories P, Aubin JP, Pomier-Layrargues G, Bauret P, Bellet-Herman H. Treatment of acute hepatic encephalopathy in cirrhotics with a branched-chain amino acids enriched versus a conventional amino acids mixture. A controlled study of 70 patients. Liver 1985;5(5):282-9.

Michel H, Bories P, Nalet B, Mourrut C, Pierrugues R. Exclusive parenteral nutrition (EPN) in denutritive alcoholic cirrhotics (Abstract). Journal of Hepatology 1985;1 Suppl 2:290.

Michel H, Pomier-Layrargues G, Duhamel O, Lacombe B, Cuilleet G, Bellet-Hermann H. Intravenous infusion of ordinary and modified amino-acid solutions in the management of hepatic encephalopathy (controlled study, 30 patients) (AASLDabstract). Gastroenterology 1980;79:1038.

Michel H, Pomier-Layrargues G, Qubin JP, Bories P, Mirouze D, Bellet-Herman H. Treatment of hepatic encephalopathy by infusion of a modified amino acid solution: results of a controlled study in 47 cirrhotic patients. In: Capocaccia L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:301-10.

Pomier-Layrargues G, Duhamel O, Lacombe B, Cuilleret G, Bellet H, Michel H. Intravenous infusion of ordinary and modified amino-acid solutions in the management of hepatic encephalopathy. Liver 1981;1:140.

Mochizuki 2000 {published data only} Mochizuki H, Togo S, Tanaka K, Endo I, Shimada H. Early enteral nutrition aKer hepatectomy to prevent postoperative infection. Hepatogastroenterology 2000;47:1407-10.

Moreno 2010 {published data only} Moreno C, Langlet P, Hittelet A, Evrard S, Lasser L, Colle I, et al. Enteral nutrition with or without n-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized, multicenter, controlled trial (Abstract). Journal of Hepatology 2009;50 Suppl 1:366.

* Moreno C, Langlet P, Hittelet A, Lasser L, Degre D, Evrard S, et al. Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial. Journal of Hepatology 2010;53:1117-22.

Morioka 1983 {published data only} Morioka S, Kanai K, Kako M, Nakajima T, Yoshimi T, Masaka M, et al. EHects of branched chain amino acid infusion on glucose metabolism in cirrhotic patients with encephalopathy. Gastroenterologia Japonica 1983;18(6):553-9.

Muto 1984 {published data only} Muto Y, Yoshida T. EHect of oral supplementation with branched-chain amino acid granules on improvement of protein nutrition in decompensated liver cirrhosis: a cross- over controlled study. In: Ogoshi S, Ikada A editor(s). Parenteral and Enteral Hyperalimentation. Amsterdam: Elsevier Science Publishers, 1984:280-92.

Muto 1991 {published data only} Muto Y, Yoshida T, Sato SI, Watanabe A, Okabe K. EHect of branched-chain amino acid granule (BSAA-G) on improvement in protein malnutrition in patients with liver cirrhosis: a multicentre double-blind trial (Abstract). Journal of Gastroenterology and Hepatology 1991;6(3):312.

Muto 2005 {published data only} Moriwaki H, Muto Y, Sato S, Watanabe A, Suzuki K, Kato A, et al. Oral supplementation with branched chain amino acids reduces the incidence of liver failure in lean cirrhotic patients and prevents liver cancer in overweight/obese cirrhotics (Abstract). Hepatology 2006;44 Suppl 1(4):216A.

* Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. EHects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clinical Gastroenterology and Hepatology 2005;3(7):705-13.

Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. Long-term survival study (LOTUS) of branched-chain amino acid (BCAA) granules improves event-free survival in patients with advanced liver cirrhosis (Abstract). Hepatology 2004;40 Suppl 4(4):511A.

Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatology Research 2006;35(3):204-14.

Nagayama 1989 {published data only} Nagayama M, Takai T, Okuno M, Umeyama K. Fat emulsion in surgical patients with liver disorders. The Journal of Surgical Research 1989;47(1):59-64.

Nasrallah 1980 {published data only} Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2(8207):1276-7.

Ndraha 2011 {published data only} Ndraha S, Hasan I, Simadibrata M. The eHect of L-ornithine L- aspartate and branch chain amino acids on encephalopathy and nutritional status in liver cirrhosis with malnutrition. Acta Medica Indonesiana 2011;43(1):18-22.

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Nickkholgh 2007 {published data only} Nickkholgh A, Schneider H, Encke J, Buchler MW, Schmidt J, Schemmer P. PROUD: EHects of peroperative long-term immunonutritin in patients listed for liver transplantation. Trials 2007;8:20.

Nielsen 1995 {published data only} Nielsen K, Kondrup J, Martinsen L, Dossing H, Larsson B, Stilling B, et al. Long-term oral refeeding of patients with cirrhosis of the liver. British Journal of Nutrition 1995;74(4):557-67.

Nishiguchi 2004 {published data only} Nishiguchi S, Habu D. EHect of oral supplementation with branched-chain amino acid granules in the early stage of cirrhosis. Hepatology Research 2004;30 Suppl:36-41.

Nishizaki 1996 {published data only} Nishizaki T, Takenaka K, Yanaga K, Shimada M, Shirabe K, Matsumata T, et al. Nutritional support aKer hepatic resection: a randomized prospective study. Hepatogastroenterology 1996;43(9):608-13.

Nordenstrom 1995 {published data only} Nordenstrom J, Johansson U, Thorne A, Hagenfeldt L. Metabolism of long-chain triglycerides (LCT) vs structured triglycerides (STG) in chronic liver failure (Abstract). Clinical Nutrition 1995;14 Suppl 2:59.

O'Keefe 1987 {published data only} O'Keefe SJ, Ogden J, Dicker J. Enteral and parenteral branched chain amino acid-supplemented nutritional support in patients with encephalopathy due to alcoholic liver disease. Journal of Parenteral and Enteral Nutrition 1987;11(5):447-53.

Okabayashi 2008 {published data only} Okabayashi T, Nishimori I, Sugimoto T, Iwasaki S, Akisawa N, Maeda H, et al. The benefit of the supplementation of perioperative branched-chain amino acids in patients with surgical management for hepatocellular carcinoma: a preliminary study. Digestive Diseases and Sciences 2008;53(1):204-9.

* Okabayashi T, Nishimori I, Sugimoto T, Maeda H, Dabanaka K, Onishi S, et al. EHects of branched-chain amino acids-enriched nutrient support for patients undergoing liver resection for hepatocellular carcinoma. Journal of Gastroenterology and Hepatology 2008;23(12):1869-73.

Okabayashi 2010 {published data only} Okabayashi T, Iyoki M, Sugimoto T, Kobayashi M, Hanazaki K. Oral supplementation with carbohydrate- and branched-chain amino acid-enriched nutrients improves postoperative quality of life in patients undergoing hepatic resection. Amino Acids 2011;40:1213-20.

* Okabayashi T, Nishimori I, Yamashita K, Sugimoto T, Namikawa T, Maeda H, et al. Preoperative oral supplementation with carbohydrate and branched-chain amino acid-enriched nutrient improves insulin resistance in patients undergoing

a hepatectomy: a randomized clinical trial using an artificial pancreas. Amino Acids 2010;38:901-7. [MEDLINE: 20852905]

Okita 1985 {published data only} Okita M, Watanabe A, Nagashima H. A branched-chain amino acid-supplemented diet in the treatment of liver cirrhosis. Current Therapeutic Research 1984;35(1):83-92.

* Okita M, Watanabe A, Nagashima H. Nutritional treatment of liver cirrhosis by branched-chain amino acid-enriched nutrient mixture. Journal of Nutrition Science and Vitaminology 1985;31(3):291-303.

Okuno 1985 {published data only} Okuno M, Nagayama M, Takai T, Rai A, Nakao S, Kamino K, et al. Postoperative total parenteral nutrition in patients with liver disorders. Journal of Surgical Research 1985;39(2):93-102.

Olde Damink 2007 {published data only} Olde Damink SWM, Jalan R, Deutz NEP, Dejong CHC, Redhead DN, Hynd P, et al. Isoleucine infusion during "simulated" upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients. Hepatology 2007;45(3):560-8.

Panella 1987 {published data only} Panella C, Guglielmi FW, Laddaga L, Rocco VP, Marcone I, Polimeno L, et al. Improvement of nitrogen balance in cirrhotic patients aKer oral BCAA (Abstract). Journal of Hepatology 1987;5 Suppl 1:50.

Pierrugus {published data only} Pierrugues R, Bauret P, Michel H. Continous enteral nutrition (CEN) in denutritive alcoholic cirrhotics (randomized trial) (Abstract). Journal of Hepatology 1985;1 Suppl 2:308.

Plank 2005 {published data only} Plank LD, McCall JL, Gane EJ, Rafique M, Gillanders LK, McIlroy K, Munn SR. Pre- and postoperative immunonutrition in patients undergoing liver transplantation: a pilot study of safety and eHicacy. Clinical Nutrition 2005;24(2):288-96.

Plank 2008 {published data only} Plank LD, Gane EJ, Peng S, Muthu C, Mathur S, Gillanders L, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12- month trial. Hepatology 2008;48(2):557-66.

Plauth 1993 {published data only} Plauth M, Egberts EH, Hamster W, Török M, Müller P, Brand O, et al. Long-term treatment with branched-chain amino acids (BCA) improves the portosystemic encephalopathy (PSE) in ambulant patients Results of a double blind, placebo controlled crossover study (Abstract) [Langzeitbehandlung mit verzweigtkettingen aminosauren verbessert die portosystemische enzephalopathie (PSE) ambulanter patienten Ergebnisse einer dobbelt-blinden plazebo-kontrollerten crossover studie]. Klinische Wochenschri1 1992;69 Suppl 28:126.

* Plauth M, Egberts EH, Hamster W, Török M, Müller PH, Brand O, et al. Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids. A double-

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blind placebo-controlled crossover study. Journal of Hepatology 1993;17(3):308-14.

Protheroe 1996 {published data only} Protheroe S, Jones R, Kelly DA. Evaluation of the role of branched chain amino acids in the treatment of protein malnutrition in infants with liver disease (Abstract). Gut 1995;37 Suppl 2:A30.

* Protheroe S, McNurlan M, Garlick P, Golden M, Booth I, Kelly D. Faillure to suppress protein breakdown contributes towards malnutrition in infants with liver disease (Abstract). Hepatology 1996;24(4 (Pt 2)):141A.

Puglionisi 1984 {published data only} Puglionisi A, Ceriati F, Marino IR, Cavicchioni C, De Luca G, Roncone A, et al. Prophylaxis of hepatic encephalopathy aKer porta-caval anastomosis using branched chain amino acid mixtures. In: Capocaccia L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:345-50.

Rakette 1981 {published data only} Rakette S, Fischer M, Reimann H-J, von Sommoggy S. EHects of special amino acid solutions in patients with liver cirrhosis and hepatic encephalopathy. In: Walser M, Williamson JR editor(s). Metabolism and Clinical Implications of Branched Chain Amino and Ketoacids. Amsterdam: Elsevier North Holland, 1981:419-25.

Rayes 2005 {published data only} Rayes N, Hansen S, Boucsein K, Seehofer D, Muller AR, Bengmark S, et al. Enteral nutrition containing lactobacillus versus selective gut decontamination aKer liver transplantation [Laktobazillenhaltige enterale Ernahrung versus SDD nach Lebertransplantation]. Zeitschri1 fur Gastroenterologie 2002;40(2):119.

Rayes N, Hansen S, Muller AR, StaHa G, Bechstein WO, Neuhaus P. SBD versus fibre containing enteral nutrition plus Lactobacillus or placebo to prevent bacterial infections aKer liver transplantation. Transplantation 1999;67(7):747.

Rayes N, Seehofer D, Hansen S, Boucsein K, Muller AR, Serke S, et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 2002;74(1):123-7.

Rayes N, Seehofer D, Theruvath T, Langrehr JM, Muller AR, Bengmark S, et al. Impact of early enteral nutrition with a combination of pre- and probiotics in patients following liver transplantation on the incidence of postoperative bacterial infections - a randomised, double-blind trial. Liver Transplantation 2003;9(6):305.

* Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, et al. Supply of pre- and probiotics reduces bacterial infection rates aKer liver transplantation--a randomized, double-blind trial. American Journal of Transplantation 2005;5(1):125-30.

Riederer 1980 {published data only} Riederer P, Jellinger K, Kleinberger G, Weiser M. Oral and parenteral nutrition with L-valine: mode of action. Nutrition and Metabolism 1980;24:209-17.

Rifai 2006 {published data only} Rifai K, Ockenga J, Manns MP, BischoH SC. Repreated administration of a vitamin preparation containing glycocholic acid in patients with hepatobiliary disease. Alimentary Pharmacology and Therapeutics 2006;23(9):`337-45.

Riggio 1984 {published data only} Riggio O, Canbgiano C, Cascino A, Merli M, Stortoni M, Rossi Fanelli F, et al. Long term dietary supplement with branched chain amino acids: a new approach in the prevention of hepatic encephalopathy: results of a controlled study in cirrhotics with porto-caval anastomosis. In: Capocaccia L, Fischer JE, Rossi- Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:183-92.

Rocchi 1985 {published data only} * Rocchi E, Cassanelli M, Gibertini P, Pietrangelo A, Casalgrandi G, Ventura E. Standard or branched-chain amino acid infusions as short-term nutritional support in liver cirrhosis?. Journal of Parenteral and Enteral Nutrition 1985;9(4):447-51.

Rocchi E, Cassanelli M, Gibertini P, Pietrangelo A, Trenti T, Ventura E. Nutritional eHects of branched chain amino acid alone and enriched parenteral solutions in liver cirrhosis (Abstract). Clinical Nutrition 1984;2 Special Suppl:O.65.

Rocchi E, Gibertini P, Casanelli M, Pietrangelo A, Ventura E. Plasma amino acids and nitrogen balance in response to short term branched amino acid parenteral nutrition in liver cirrhosis. Medecine and Chirurgie Digestives 1984;13:185-92.

Rossi Fanelli 1986 {published data only} * Rossi Fanelli F, Cangiano C, Capocaccia L, Cascino A, Ceci F, Muscaritoli M, et al. Use of branched chain amino acids for treating hepatic encephalopathy: clinical experiences. Gut 1986;27 Suppl 1:111-5.

Rossi Fanelli F, Cangiano C, Cascino A, Merli M, Riggio O, Stortoni M, et al. Branched-chain amino acids in the treatment of severe hepatic encephalopathy. In: Capocaccia L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:335-44.

Rossi Fanelli F, Riggio O, Cangiano C, Cascino A, DeConciliis D, Merli M, et al. Branched-chain amino acids vs lactulose in the treatment of hepatic coma: a controlled study. Digestive Diseases and Sciences 1982;27:929-35.

Sakaida 2004 {published data only} Sakaida I, Tsuchiya M, Okamoto M, Terai S, Okita K. The eHect of a late evening snack in patients with liver cirrhosis (Abstract). Hepatology 2004;40:632A.

Sato 2005 {published data only} Sato S, Watanabe A, Muto Y, Suzuki K, Kato A, Moriwaki H, et al. Clinical comparison of branched-chain amino acid (l-Leucine,

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l-Isoleucine, l-Valine) granules and oral nutrition for hepatic insuHiciency in patients with decompensated liver cirrhosis (LIV-EN study). Hepatology Research 2005;31(4):232-40.

Schafer 1981 {published data only} Schafer VK, Winther MB, Ukida M, Leweling H, Reiter HJ, Bode JC. Influence of an orally administered protein mixture enriched in branched chain amino acids on the chronic hepatic encephalopathy (CHE) of patients with liver cirrhosis. Zeitschri1 Gastroenterologie 1981;19:356-62.

Shirabe 1997 {published data only} Shirabe K, Matsumata T, Shimada M, Takenaka K, Kawahara N, Yamamoto K, et al. A comparison of parenteral hyperalimentation and early enteral feeding regarding systemic immunity aKer major hepatic resection-- the results of a randomized prospective study. Hepatogastroenterology 1997;44(13):205-9.

Shirabe 2011 {published data only} Shirabe K, Yoshimatsu M, Motomura T, Takeishi K, Toshima T, Muto J, et al. Beneficial eHects of supplementation with branched-chain amino acids on postoperative bacteremia in living donor liver transplant recipients. Liver Transplantation 2011;17(9):1073-80.

Sieg 1983 {published data only} Sieg A, Walker S, Czygan P, Gärtner U, Lanzinger-Rossnagel G, Stiehl A, et al. Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. A double blind crossover trial. Zeitschri1 für Gastroenterologie 1983;21(11):644-50.

Soriano {unpublished data only} Soriano G. Study of the benefit of exercise and aminoacid supplements in cirrhotic patients. ClinicalTrials.gov NCT01060813.

Strauss 1986 {published data only} * Strauss E, Dos Santos WR, Da Silva EC, Lacet CM, Capacci Mde LL, Bernardini AP. Treatment of hepatic encephalopathy: A randomized clinical trial comparing a branched chain enriched amino acid solution to oral neomycin. Nutritional Support Services 1986;6(7):18-21.

Strauss E, Santos WR, Cartapatti da Silva E, Lacet CM, Capacci MLL, Bernardini AP. A randomized controlled clinical trial for the evaluation of the eHicacy of a enriched branched- chain amino-acid solution compared to neomycin in hepatic encephalopathy (Abstract). Hepatology 1983;3(5):862.

Striebel 1979 {published data only} Striebel JP, Holm E, Lutz H, Storz LW. Parenteral nutrition and coma therapy with amino acids in hepatic failure. Journal of Parenteral and Enteral Nutrition 1979;3(4):240-6.

Sugawara 2011 {published data only} Sugawara G, Ebata T, Yokoyama Y, Igami T, Takahashi Y, Nagino M. Perioperative nutritional support for biliary cancer surgery. HPB 2011;13 Suppl 3:226.

Suzuki 2004 {published data only} Suzuki K, Kato A, Iwai M. Branched-chain amino acid treatment in patients with liver cirrhosis. Hepatology Research 2004;30 Suppl:25-9.

Swart 1981 {published data only} Swart GR, Frenkel M, van den Berg JWO. Minimum protein requirements in advanced liver disease: a metabolic ward study of the eHects of oral branched chain amino acids . In: Walser M, Williamson JR editor(s). Metabolism and Clinical Implications of Branched Chain Amino and Ketoacids. Amsterdam: Elsevier North Holland, 1981:427-32.

Swart 1989 {published data only} Swart GR, Zillikens MC, Van Vuure JK, Van den Berg JWO. EHect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver. BMJ (Clinical Research Ed.) 1989;299(6709):1202-3.

Tai 2011 {published data only} Tai M-LS, Razlan H, Goh K-L, Taib SHM, Huzaini ATM, Rampal S, et al. Short-term nasogastric feeding for hospitalised Asian patients with liver cirrhosis. Hepatology International 2011;5(1):356.

Tai MLS, Mahadeva S. Short term feeding for Asian patients with liver cirrhosis. ClinicalTrials.gov NCT 01165073.

* Tai MLS, Razlan H, Goh K-L, Mohd Taib SH, Huzaini AHM, Rampal S, et al. Short term nasogastric versus oral feeding in hospitalised patients with advanced cirrhosis: A randomised trial. e-SPEN 2011;6(6):e242-e247.

Tang 2007 {published data only} Tang Z-F, Ling Y-B, Hao Z, Lin N, Xu R-Y. EHects of glutamine and recombinant human growth hormone on intestinal mucosal barrier in postoperative portal hypertension patients. Chinese Journal of Clinical Nutrition 2006;14(5):296-9.

* Tang ZF, Ling YB, Lin N, Hao Z, Xu RY. Glutamine and recombinant human growth hormone protect intestinal barrier function following portal hypertension surgery. World Journal of Gastroenterology 2007;13(15):2223-8.

Tayek {unpublished data only} Tayek JA. Treatment of alcoholic hepatitis with arginine. ClinicalTrials.gov NCT00200746.

Togo 2005 {published data only} Togo S, Tanaka K, Morioka D, Sugita M, Ueda M, Miura Y, et al. Usefulness of granular BCAA aKer hepatectomy for liver cancer complicated with liver cirrhosis. Nutrition 2005;21(4):480-6.

Tomiya 2002 {published data only} Tomiya T, Inoue Y, Yamaoka M, Hayashi S, Yanase M, Arai M, et al. Branched-chain amino acids may stimulate protein production by hepatocytes through the induction of hepatocyte growth factor synthesis by hepatic stellate cells (Abstract). Hepatology 2002;36(4 (Pt 2)):320A.

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Tschepe 1985 {published data only} Tschepe A, Holm E, Leweling H, Staedt U, Weber K. Oral administration of branched chain amino acids (BCAA) in patients with liver cirrhosis. A double-blind, randomized crossover study (Abstract). Clinical Nutrition 1985;4 Special Suppl:40.

Tsuchiya 2007 {published data only} Tsuchiya K, Asahina Y, Hirayama I, Sato M, Tanaka T, Komatsu N, et al. Oral supplementation with branched-chain amino acids improves survival and recurrence-free survival aKer successful treatment of hepatocellular carcinoma in patients with cirrhosis: A prospective study. Hepatology 2007;46 Suppl 1(4):401A-2A.

Uribe 1982 {published data only} Uribe M, Márquez MA, Garcia Ramos G, Ramos-Uribe MH, Vargas F, Villalobos A, et al. Treatment of chronic portal-- systemic encephalopathy with vegetable and animal protein diets. A controlled crossover study. Digestive Diseases and Sciences 1982;27(12):1109-16.

Valdivieso 1989 {published data only} Valdivieso A, Morales H, Maiz A, Vial S. EHect of intravenous branched chain-enriched amino acids (BCAA)on renal function in patients with chronic liver disease (CLD). Kidney International 1989;35:475.

Vilar-Gomez 2009 {published data only} Vilar Gomez E, Rodriguez De Miranda A, Gra Oramas B, Arus Soler E, Llanio Navarro R, Calzadilla Bertot L, et al. Clinical trial: A nutritional supplement Viusid, in combination with diet and exercise, in patients with nonalcoholic fatty liver disease. Alimentary Pharmacology and Therapeutics 2009;30(10):999-1009.

Vilstrup 1990 {published data only} Gluud C, Dejgaard A, Hardt F, Kristensen, Kohler O, Melgaard B, et al. Preliminary treatment results with balanced amino acid infusion to patients with hepatic encephalopathy (Abstract). Scandinavian Journal of Gastroenterology 1983;18 Suppl 86:19.

Hardt F, Dejgard A, Gluud C, Kristensen M, Kohler O, Melgaard B, et al. The eHect of branched chain enriched amino acid nutrition on the outcome of acute hepatic coma in cirrhosis. The Copenhagen Coma Group (Abstract). Clinical Nutrition 1985;4 Special Suppl:43.

* Vilstrup H, Gluud C, Hardt F, Kristensen M, Køhler O, Melgaard B, et al. Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis. Journal of Hepatology 1990;10(3):291-6.

Vilstrup H, Gluud C, Hardt F, Kristensen M, Melgaard B, Køhler O, et al. Branced chain enriched amino acid nutrition does not change the outcome of hepatic coma in patients with cirrhosis of the liver (Abstract). Journal of Hepatology 1985;1 Suppl 2:347.

Wahren 1983 {published data only} * Wahren J, Denis J, Desurmont P, Eriksson LS, EscoHier JM, GauthierAP, et al. Is intravenous administration of branched chain amino acids eHective in the treatment of hepatic encephalopathy? A multicenter study. Hepatology 1983;3(4):475-80.

Wahren JH, Gauthier H, Michel P, Opolon H. Influence of branched-chain amino acid administration on hepatic encephalopathy- A multicenter study (Abstract). Journal of Parenteral and Enteral Nutrition 1981;5:355.

Walker 1982 {published data only} Walker S, Gotz R, Czygan P, Stiehl A, Lanzinger G, Sieg A, et al. Oral keto analogs of branched-chain amino acids in hyperammonemia in patients with cirrhosis of the liver A double-blind crossover study. Digestion 1982;24(2):105-11.

Wang 2011 {published data only} Wang Y-L, Cao J-Y, Wu L-Q, Liu J-X. EHects of -3 fatty acids on inflammatory reaction and immunologic function of patients aKer hepatectomy. Chinese Journal of Clinical Nutrition 2011;19(3):162-6.

Watanabe 1983 {published data only} Watanabe A, Shiota T, Okita M, Nagashima H. EHect of a branched chain amino acid-enriched nutritional product on the pathophysiology of the liver and nutritional state of patients with liver cirrhosis. Acta Medica Okayama 1983;37(4):321-33.

Watanabe 1995 {published data only} Watanabe A, Kuwabara Y, Hioki O, Yago K, Kugu K, Akira M. Tentative diet for liver failure containing well-polished rice. Nutrition 1995;11(4):355-9.

Weber 1990 {published data only} Weber FL, Bagby BS, Licate L, Kelsen SG. EHects of branched- chain amino acids on nitrogen metabolism in patients with cirrhosis. Hepatology 1990;11(6):942-50.

Wicks 1994 {published data only} Wicks C, Somasundaram S, Bjarnason I, Menzies IS, Routley D, Potter D, et al. Comparison of enteral feeding and total parenteral nutrition aKer liver transplantation. Lancet 1994;344(8926):837-40.

Yamamoto 2005 {published data only} Yamamoto M, Iwasa M, Matsumura K, Nakagawa Y, Fujita N, Kobayashi Y, et al. Improvement of regional cerebral blood flow aKer oral intake of branched-chain amino acids in patients with cirrhosis. World Journal of Gastroenterology 2005;11(43):6792-9.

Yamana-Okumuru 2010 {published data only} Yamanaka-Okumura H, Nakamura T, Miyake H, Takeuchi H, Katayama T, Morine Y, et al. EHect of long-term late-evening snack on health-related quality of life in cirrhotic patients. Hepatology Research 2010;40(5):470-6.

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Yang 2011 {published data only} Yang J, Zhang J-X, Zheng Q-C. Olive oil-based lipid emulsion for parenteral nutrition in patients aKer hepatectomy. Chinese Journal of Clinical Nutrition 2011;19(2):79-83.

Yoshiji 2011 {published data only} Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Aihara Y, Yamazaki M, et al. Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: A randomized control trial. Oncology Reports 2011;26(6):1547-53.

Yu 2007 {published data only} Yu L-X, Liu Y-H, Shen Z-Y, Kang M-N. Prospective study of eHect of recombinant human growth hormone on nutritional status and immune function in early postoperative stage of liver transplantation. Chinese Critical Care Medicine 2007;19(7):390-3.

Zhang 2003 {published data only} Zhang T, Jia JD, Zhang FK, Wang BE. The eHect of oral branched amino acid for cirrhotic patient with low serum protein. Chinese Journal of Clinical Hepatology 2003;19(2):84-5.

Zhang 2005 {published data only} Zhang K, Sun WB, Wang HF, Li ZW, Zhang XD, Wang HB, et al. Early enteral and parenteral nutritional support in patients with cirrhotic portal hypertension aKer pericardial devascularization. Hepatobiliary & Pancreatic Diseases International 2005;4(1):55-9.

Zheng EN {published data only} Zheng Q, Hu Q. The influence of enteral nutrition on gut barrier in the post-operative patients with damaged hepatic function. Journal of Tongji Medical University 2001;21(4):323-5.

Zhuang 2003 {published data only} Zhuang W, Wu X, Lü R, Xu H, Cao J. Pre-operation application of recombinant human growth hormone for liver cirrhosis with portal hypertension and hypoproteinemia. Sichuan da Xue Xue Bao. Yi Xue Ban (Journal of Sichuan University. Medical science edition) 2003;34(1):109-11.

References to studies awaiting assessment Caballera Rovira 1987 {published data only} Caballeria Rovira E, Arago Lopez JV, Ubeda Masso RM, Vidal Clemente JL, Sanchis Closa A. Treatment of hepatic encephalopathy with oral branched chain amino acids [Tratamiento de la encefalopatia hepatica con aminoacidos de cadena ramificada (BCAA) por via oral: I. Encefalopatia hepatica aguda]. Revista Española de Enfermedades Digestivas 1987;72(2):116-22.

Chen 2011 {published data only} Chen Q. EHects of early enteral nutrition on acute inflammatory response syndrome aKer the operations for obstructive jaundice. Hepatology International 2011;5(1):415.

Fink 1978 {published data only} Fink M, Mader R, Brauer HTI. Controlled double- blind study on the eHectiveness and tolerability of a

combination therapy in chronic alcoholic liver diseases [Kontrollierte Doppelblind-Studie auf EHektivitat und Vertraglichkeit einer Kombinationstherapie bei chronischen alkoholischen Lebererkrankungen]. Fortschritte der Medizin 1978;96(28):1428-32.

Hartung 1989 {published data only} Hartung H-D. Aminoacid prevents hepatic encephalopathy [Aminosauren verhindern hepatische Enzephalopathie]. Fortschritte der Medizin 1989;107:56.

Khlynov 2009 {published data only} Khlynov IB, Chikunova MV, Lisovskaia TV. EHectiveness of nutritional support for the liver-cell deficiency in the liver cirrhosis. Experimental and Clinical Gastroenterology 2009;2:39-43. [MEDLINE: PMID: 19552020]

Korenaga 2011 {published data only} Korenaga M, Korenaga K, Nishina S, Tomiyama Y, Hino K. Oral branched-chain amino acid supplementation reduces oxidative stress and interacts with iron metabolism in patients with hepatitis C virus-related advanced liver fibrosis - A pilot study (abstract). Hepatology 2011;54 Suppl 1:513A.

Leweling 1980 {published data only} * Leweling H, KnauH HG, Nitschke J, Paquet KJ. EHect of parenteral amino acid administration on the brain function and the serum aminogram of patients with liver cirrhosis [Beeingflussung von zerebralem Funktionszustand und Serumaminogramm von Patienten mit Leberzirrhose durch parenterale Aminosaurenzufuhr]. Infusionstherapie und Klinische Ernahrung 1980;7:88-94. [MEDLINE: 6776054]

Schafer K, Winther MB, Ukida M, Leweling H, Reiter HJ, Bode JC. Influence of an orally administered protein mixture enriched in branched chain amino acids on the chronic hepatic encephalopathy (CHE) of patients with liver cirrhosis. Zeitschri1 fur Gastroenterologie 1981;19(7):356-62. [MEDLINE: 7293293]

Macias-Rosales 2010 {published data only} Macias-Rosales R, Larrosa-Haro A. EHicacy of enteral vs. oral nutrition with a medium-chain triglyceride formula to prevent malnutrition and growth impairment in infants with biliary atresia. Journal Pediatric Gastroenterology and Nutrition 2011;51 Suppl 2:E22-3.

Zhu-ming 2001 {published data only} Zhu-ming J, Zhuo-yun G, Fu-lai C, Xiu-rong W, Ze-jian L, Yuan X, et al. The role of immune enhanced enteral nutrition on plasma amino acid, gut permeability and clinical outcome (A randomized, double blind, controlled, multi-center clinical trial with 120 cases). Acta Academiae Medicinae Sinicae 2001;23(5):515-8.

References to ongoing studies Mao {unpublished data only} Mao Y. A clinical study to evaluate the clinical outcomes of hepatectomy with nutritional risk aKer preoperative nutritional support. ClinicalTrials.gov NCT01292330.

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Pirlich {unpublished data only} Pirlich M. Enteral nutrition in liver cirrhosis. ClinicalTrials.gov NCT00168961.

Seguin {unpublished data only} Seguin P, Boudjema K, Malledant Y, Bellissant E. EHect of a perioperative oral nutritional supplementation on patients undergoing hepatic surgery for liver cancer (IMPACT). ClinicalTrials.gov NCT00151671.

Van Erpecum {unpublished data only} van Erpecum KJ. Nutritional support during antiviral therapy for hepatitis C. ClinicalTrials.gov NCT00841243.

Additional references Alberino 2001 Alberino F, Gatta A, Amodio P, Merkel C, Di Pascoli L, Boggo G, et al. Nutrition and survival in patients with liver cirrhosis. Nutrition 2001;17:445-50.

Als-Nielsen 2003 Als-Nielsen B, Koretz RL, Gluud LL, Gluud C. Branched- chain amino acids for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2003, Issue 1. [DOI: 10.1002/14651858.CD001939]

Alvares-da-Silva 2005 Alvares-da-Silva MR, Reverbel da Silveira T. Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic patients. Nutrition 2005;21:113-7.

Baker 1982 Baker JP, Detsky AS, Wesson DE, Wolman SL, Stewart S, Whitewall J, et al. Nutritional assessment. A comparison of clinical judgment and objective measurements. New England Journal of Medicine 1982;306:969-72.

Brok 2008 Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insuHicient information size and potentially false positive results in many meta-analyses. Journal of Clinical Epidemiology 2008;61(8):763-9.

Brok 2009 Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive - Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. International Journal of Epidemiology 2009;38(1):287-98.

Buzby 1980 Buzby GP, Mullen JL, Matthews DC, Hobbs CL, Rosato EF. Prognostic nutritional index in gastrointestinal surgery. American Journal of Surgery 1980;139:160-7.

DeMets 1987 DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341-50.

DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177-88.

Dudrick 1971 Dudrick SJ, Ruberg RL. Principles and practices of parenteral nutrition. Gastroenterology 1971;61:901-10.

Egger 1997 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta- analysis detected by a simple, graphical test. BMJ (Clinical Research Ed) 1997;315(7109):629-34.

Fischer 1971 Fischer JE, Baldessarini RJ. False neurotransmitters and hepatic failure. Lancet 1971;2:75-9. [MEDLINE: 71235553]

Gluud 2011 Gluud C, Nikolova D, Klingenberg SL, Alexakis N, Als-Nielsen B, Colli A, et al. Cochrane Hepato-Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2011, Issue 11. Art. No.: LIVER.

Higgins 2002 Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539-58.

Higgins 2011 Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Colloboration, 2011. Available from www.cochrane-handbook.org.

ICH-GCP 1997 International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice1997 CFR & ICH Guidelines. Vol. 1, PA 19063-2043, USA: Barnett International/PAREXEL, 1997.

Italian Multicentre Cooperative Project 1994 Italian Multicentre Cooperative Project on Nutrition in Liver Cirrhosis. Nutritional status in cirrhosis. Journal of Hepatology 1994;21:317-25.

Jensen 2010 Jensen GL, Mirtallo J, Compher C, Dhaliwal R, Forbes A, Figueredo Grijalba R, et al. Adult starvation and disease-related malnutrition. A proposal for etiology-based diagnosis in the clinical practice setting from the International Consensus Guideline Committee. JPEN. Journal of Parenteral and Enteral Nutrition 2010; Vol. 34, issue 2:156-9.

https://doi.org/10.1002%2F14651858.CD001939

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Keys 1962 Keys A. Caloric deficiency and starvation. In: JolliHe N editor(s). Clinical Nutrition. 2nd Edition. New York: Harper and Brothers, 1962:122-36.

Kjaergard 2001 Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135:982-9.

Kondrup 1997 Kondrup J, Muller MJ. Energy and protein requirements of patients with chronic liver disease. Journal of Hepatology 1997;27:239-47.

Koretz 2001 Koretz RL, Lipman TO, Klein S. AGA technical review - parenteral nutrition. Gastroenterology 2001;121:970-1001.

Koretz 2005 Koretz RL. Death, morbidity, and economics are the only end-points for trials. Proceedings of the Nutrition Society 2005;64:277-84.

Koretz 2007 Koretz RL, Avenell A, Lipman TO, Braunschweig C, Milne AC. Does enteral nutrition aHect outcome: a systematic review of the randomized trials. American Journal of Gastroenterology 2007;102:412-29.

Langer 2009 Langer G, Großmann K, Saal S, Grothues D, Wienke A. Nutritional interventions for liver-transplanted patients. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD007605]

Macaskill 2001 Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Statistics in Medicine 2001;20(4):641-54.

Moher 1998 Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials aHect estimates of intervention eHicacy reported in meta-analyses?. Lancet 1998;352:609-13.

Morgan 1990 Morgan MY. Branched chain amino acids in the management of chronic liver disease. Facts and fantasies. Journal of Hepatology 1990;11(2):133-41. [MEDLINE: 91072916]

Nielsen 1993 Nielsen K, Kondrup J, Martinsen C, Stilling B, Wikman B. Nutritional assessment and adequacy of dietary intake in hospitalized patients with alcoholic cirrhosis. British Journal of Nutrition 1993;69:665-79.

Norman 2006 Norman K, Kirchner H, Lochs H, Pirlich M. Malnutrition aHects quality of life in gastroenterology patients. World Journal of Gastroenterology 2006;12(21):3380-5.

Reinhardt 1980 Reinhardt GF, Myscofski JW, Wilkens DB, Dobrin PB, Mangan JE, Stannard RT. Incidence and mortality of hypoalbuminemic patients in hospitalized veterans. JPEN. Journal of Parenteral and Enteral Nutrition 1980;4:357-9.

RevMan 2011 [Computer program] The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.

Rhoads 1981 Rhoads JE, Vars HM, Dudrick SJ. The development of intravenous hyperalimentation. The Surgical Clinics of North America 1981;61:429-35.

Royle 2003 Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591-603.

Sanchez 2006 Sanchez AJ, Aranda-Michel J. Nutrition for the liver transplant patient. Liver Transplantation 2006;12:1310-6.

Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment eHects in controlled trials. JAMA 1995;273:408-12.

Studley 1936 Studley HO. Percentage of weight loss. A basic indicator of surgical risk in patients with chronic peptic ulcer. JAMA 1936;106:458-60.

Tajika 2001 Tajika M, Kato M, Mohri H, Miwa Y, Kato T, Ohnishi H, et al. Prognostic value of energy metabolism in patients with viral liver cirrhosis. Nutrition 2002;18(3):229-34.

Thorlund 2009 Thorlund K, Devereaux PJ, Wetterslev J, Gyuatt G, Ioannidis JPA, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses?. International Journal of Epidemiology 2009;38(1):276-86.

Wetterslev 2008 Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of Clinical Epidemiology 2008;61:64-75.

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* Indicates the major publication for the study

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Methods Randomised trial comparing parenteral nutrition to no parenteral nutrition in hospitalized patients with alcoholic hepatitis. Geographical location: Jackson, Mississippi, USA. Paper published 1987.

Participants Inclusion criteria: alcoholic hepatitis. Exclusion criteria: none cited. 40 hospitalized patients randomised, but demographics only available for the 28 who completed trial (23 male/5 female, mean age 46/51 in treatment/control groups).

Interventions Intervention group received parenteral nutrition (21.25 g amino acids, 430 kcal/liter, 2 liters/day) + con- ventional diet; Controls received conventional diet (2675 kcal, 100 gm protein, 119 gm fat, 295 gm carbohydrates with salt restriction as needed). Duration therapy at least 21 days.

Outcomes Mortality, appearance/resolution ascites, appearance/resolution hepatic encephalopathy, serum bilirubin (estimated from Figure 1A). One patient in parenteral nutrition group noted to have throm- bophlebitis, but data regarding adverse events did not appear to have been systematically obtained.

Category of study Parenteral nutrition/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Patients in parenteral nutrition group also given 10 mg cortisol/1000 IU heparin/d for thrombophlebitis prophylaxis; it was decided that these agents were not likely to impact on the clinical course. Re- quest for further information sent to Dr Achord via US mail on September 12, 2011. (Address = James L Achord, MD, Emeritus Professor at University of Mississippi, University of Mississippi, P.O. Box 1848, Uni- versity, MS 38677), but the letter returned as undeliverable.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk Blind drawing of coded cards at time of assignment.

Allocation concealment (selection bias)

Low risk Blind drawing of coded cards at time of assignment.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk 7 dropouts in treatment group and 5 dropouts in control group all accounted for.

Achord 1987

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Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Funder of trial not reported.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No imbalance identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Achord 1987 (Continued)

Methods Randomised trial comparing parenteral nutrition to no parenteral nutrition in hospitalized patients with alcoholic hepatitis. Geographical location Atlanta, Georgia, USA. Paper published 1991.

Participants Inclusion criteria: 1) Prolonged alcohol intake (100 g/d for at least 5 days/week for at least 1 year); 2) AST < 500, AST/ALT >1.5, albumin < 3.0 gm%, bilirubin > 5 mg%, PT > 6 sec over control; 3) Alcohol ces- sation within last 5-14 days). Exclusion criteria: Recent bleeding (within 2 days), severe ascites, severe hepatic encephalopathy, cre- atinine > 2 mg%, sepsis, acute pancreatitis, hemodynamic instability (systolic blood pressure < 80 mm Hg or fluctuating > 20 mm Hg), advanced pulmonary disease (pO2 < 50/pCO2 > 50 mm Hg), diabetes mellitus, active cancer. 21 patients (11 male/10 female, mean age 43).

Interventions Intervention group received intravenous formulation (35 gm amino acids (Aminosyn II, Abbott), 5% dextrose, minerals, 500 units heparin, 5 mg hydrocortisone/liter), 2 liters/day + daily diet; Controls received daily diet (30 kcal/kg/d, 1 g protein/kg/d). Duration therapy 21 days.

Outcomes Mortality, serum bilirubin body weight and nitrogen balance (estimated from figures); triceps skinfold thickness and midarm circumference assessed but not reported numerically. One case each of throm- bophlebitis and hyponatraemia reported in parenteral nutrition group, but data regarding adverse events did not appear to have been systematically obtained.

Category of study Parenteral nutrition/Medical.

Sample size calculation None reported if done.

Full paper or abstract only Full paper.

Notes Treatment group got 1000 units heparin and 10 mg hydrocortisone per day for thrombophlebitis pro- phylaxis; it was decided that these agents were not likely to impact on any outcomes. There were two other trial groups that received oxandrolone with or without parenteral nutrition, but, because of the use of this agent, these groups not considered in the analysis. Request for further information made by e-mail on September 11, 2011 that failed (address = [email protected]) and then by US mail on September 12, 2011 (Address = Herbert L Bonkovsky, MD, Division of Digestive Disease & Nutri- tion, The Liver-Biliary-Pancreatic Center, University of Massachusetts Medical School, 55 Lake Ave., North Worcester, MA 01655). The letter was returned with a note on envelope that Dr Bonkovsky was no longer there.

Risk of bias

Bias Authors' judgement Support for judgement

Bonkovsky 1991

http://mailto:[email protected]

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Random sequence genera- tion (selection bias)

Low risk Random number table, no blocks.

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk No dropouts.

Selective reporting (re- porting bias)

Low risk Bilirubin reported and this accepted as hepatic morbidity.

Other bias High risk Partial funding by Miles Laboratory.

Intent to treat analysis Low risk Performed.

Baseline imbalance? Low risk No imbalance identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Bonkovsky 1991 (Continued)

Methods Randomised trial comparing supplements to no supplements in hospitalized patients with alcoholic liver disease. Geographical location Santiago, Chile. Paper published 1989.

Participants Inclusion criteria: Excessive alcohol ingestion for at least 2 years, 2 or more signs of liver failure (jaun- dice, hepatic encephalopathy, ascites, hepatomegaly, collateral circulation, edema) who had not been in hospital > 3 days. Exclusion criteria: Contraindication for oral or enteral feeding, current upper gastrointestinal bleeding, grade IV hepatic encephalopathy, extrahepatic major organ (cardiac, pulmonary, renal) failure. 40 pa- tients (no details regarding sex, mean age 49).

Interventions Intervention group received nutritional supplement (casein, maltodextrin, MCT, sunflower oil) to in- crease intake to 50 kcal/kg and 1.5 gms protein/kg per day; Controls received standard diet containing 35 kcal/kg and 0.8 gm protein/kg per day. All patients re- ceived bed rest, sodium restriction prn, vitamins. Duration therapy 3 to 4 weeks.

Outcomes Mortality, appearance/resolution hepatic encephalopathy, duration hospitalization, bilirubin.

Category of study Supplement/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Request for further information sent via e-mail on September 18, 2011 ([email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bunout 1989

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Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomly assigned".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Four dropouts accounted for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Funder of trial not reported.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No imbalance identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Bunout 1989 (Continued)

Methods Randomised trial comparing enteral nutrition to no enteral nutrition in hospitalized malnourished pa- tients with cirrhosis. Geographical location: Barcelona and Girona, Spain. Paper published 1990.

Participants Inclusion criteria: Patients with cirrhosis who were malnourished (at least 1 of 3 [triceps skinfold thick- ness, mid-arm muscle circumference, albumin] below 5th percentile of healthy persons). Exclusion criteria: Hepatocellular carcinoma, current upper gastrointestinal bleeding. 35 hospitalized patients (23 male/5 female, mean age 51).

Interventions Intervention group received enteral nutrition through nasogastric tube (2115 kcal [38 gm fat {including MCTs}, carbohydrate [367 gm as maltodextrin], 71 gm protein/day [UNIASA, Granada, Spain] with no change in protein intake for hepatic encephalopathy);

Control group given oral diet (18-2400 kcal, 70-100 gm protein daily [decreased to 40-60 gm for hepatic encephalopathy]) + intravenous dextrose (5-20%) as needed. Duration therapy planned to be 3 weeks.

Outcomes Mortality, resolution ascites, gastrointestinal bleeding, infections, duration hospitalization, triceps skinfold thickness, midarm muscle circumference.

Category of study Enteral nutrition/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Child's Pugh score also reported, but this was not one of the planned outcomes to assess. E-mail re- quest for further information sent to Drs Cabre and Gassul on September 15, 2011 (ecabre.germans-

Cabre 1990

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[email protected] and [email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were randomised".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk No dropouts.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias High risk Funded by industry.

Intent to treat analysis Low risk No dropouts.

Baseline imbalance? Low risk No imbalance identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Cabre 1990 (Continued)

Methods Randomised trial comparing artificial (majority receiving enteral) nutrition (branched chain or stan- dard amino acid formulation) to no enteral nutrition in patients hospitalized with alcoholic hepatitis. Geographical location: London, England. Paper published 1985.

Participants Inclusion criteria: Patients with alcoholic hepatitis (clinical and biochemical evidence of hepatocellular damage, alcohol intake > 80 gm for several years and up to present, poor uptake tracer on liver scan, no evidence active hepatitis A or B serologically. Exclusion criteria: Hepatocellular carcinoma, hypotensive (usually from current upper gastrointestinal bleeding). 64 hospitalized patients (31 male/33 female, mean age 49).

Interventions Intervention group received enteral nutrition through nasogastric tube (either branched chain amino acid formulation [described in Calvey 1985 - BCAA] or standard amino acid formulation [described in Calvey 1985 - SAA] + oral diet given to controls); Control group given oral diet (18-2400 kcal, 70-100 gm protein daily [decreased to 40-60 gm for hepatic encephalopathy]) + intravenous dextrose (5-20%) as needed. Duration therapy planned to be 3 weeks.

Outcomes Mortality, gastrointestinal bleeding, appearance/resolution of hepatic encephalopathy, infections, ni- trogen balance (in subgroup without renal insufficiency. Triceps skinfold thickness and midarm muscle circumference reported only as showing "no difference".

Category of study Enteral nutrition/Medical.

Calvey 1985

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Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Enteral nutrition (or supplements) changed to parenteral nutrition if gastrointestinal bleeding or oth- er gastrointestinal problems prevented enteral delivery of nutrients. Days of observation reported, but not clear if this equivalent to duration of hospitalization. E-mail request for more information sent to Dr Williams (since we were not able to identify address for Dr Calvey) on September 15, 2011 ([email protected]). Response from Dr Williams received on September 19, 2011; Dr Calvey died several years ago and no data available except what is in paper.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomly allocated".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Assumption made that only the reported patients were randomised.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Low risk Funded by Joint Research Committee of King's College Hospital and Medical School.

Intent to treat analysis Low risk No dropouts.

Baseline imbalance? Low risk No imbalance identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Calvey 1985 (Continued)

Methods Randomised trial comparing enteral nutrition to no enteral nutrition in patients hospitalized with variceal bleeding associated with cirrhosis. Geographical location: Poitiers, France. Paper published 1997.

Participants Inclusion criteria: Patients admitted for active variceal bleeding which had been stabilized associated with cirrhosis. Exclusion criteria: Hepatocellular carcinoma, hepatorenal syndrome, severe hepatic en- cephalopathy, age > 80 years. 22 hospitalized patients (17 male/5 female, mean age 56).

Interventions Intervention group received enteral nutrition through nasogastric tube (commercial formulation [Dri- pac Sondalis, Sopharga, France] with 1665 kcal and 71 gm protein/day until second sclerotherapy) + standard feeding;

DeLedinghen 1997

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Control group given oral diet (nothing by mouth X 3 days, low-Na milk on day 4, mixed warm low-Na di- et on day 5, 1800 kcal low Na diet from day 6 on). Mean duration of therapy 8.5 days.

Outcomes Mortality, gastrointestinal bleeding, infections, duration of hospitalization, bilirubin, body weight, tri- ceps skinfold thickness, midarm muscle circumference, nitrogen balance.

Category of study Enteral nutrition/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Request for information sent via e-mail on September 16, 2011 ([email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomly assigned patients".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk No dropouts.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Fund source not reported.

Intent to treat analysis Low risk No dropouts.

Baseline imbalance? Low risk No imbalance identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

DeLedinghen 1997 (Continued)

Methods Randomised trial comparing parenteral nutrition to no parenteral nutrition in patients hospitalized for resection of hepatocellular carcinoma. Geographical location Hong Kong. Study published 1994.

Participants Inclusion criteria: Potentially resectable hepatocellular carcinoma. Exclusion criteria: None cited. 150 patients initially randomised, but 26 dropped out because metastatic disease found at time of surgery, leaving 124 patients (109 men/15 women, median age 54).

Interventions Intervention group received parenteral nutrition (35% branched-chain amino acids [1.5 gm/kg], intra- venous dextrose and lipid [30 kcal/kg], vitamins, minerals/day) provided for 12 hours at night for 7 days

Fan 1994

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preoperatively and for 7 days postoperatively as continuous infusion with 1.75 liter/d fluid restriction; Controls received usual diet preoperatively, 5% dextrose in normal saline postoperatively. Both groups received cefotaxime at time of anesthesia, normal diet preoperatively, and 25 gm intravenous albumin X 5d postop Duration 14 days.

Outcomes Mortality, appearance ascites/gastrointestinal bleeding/encephalopathy, infections, median dura- tion hospitalization, postoperative complications (total/intra-abdominal/pneumonia/wound), median body weights, median triceps skinfold thickness, median midarm circumference. Adverse event record- ed for parenteral nutrition group, but no evidence that similar complications were sought in control arm. Bilirubin only reported as "no difference".

Category of study Parenteral nutrition/surgical (hepatocellular carcinoma resection).

Sample size calculation Planned to reduce mortality by 50% and needed 60 patients per group.

Full paper or abstract only Full paper.

Notes E-mail sent to Dr Fan on September 13, 2011 ([email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomly assigned".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk 11 dropouts in parenteral nutrition group and 15 in control group for metastat- ic disease (all accounted for).

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk More patients in parenteral nutrition group retained > 10% indocyanine green at 15 minutes (difference in baseline characteristics); funding source not re- ported.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? High risk Parenteral nutrition patients may have been less ill.

Early stopping? Low risk Achieved planned number.

Fan 1994 (Continued)

Methods Randomised trial comparing artificial nutrition (most receiving enteral nutrition) to no artificial nutri- tion in patients hospitalized for surgery for obstructive jaundice. Geographical location Milan, Italy. Study published 1986.

Foschi 1986

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Participants Inclusion criteria: Patients with obstructive jaundice with bilirubin > 200 micromol/l who were eligible for surgery with preoperative transhepatic biliary drainage. Exclusion criteria: None cited. 60 patients (39 men/21 women, mean age 64) described, but there were 4 other dropouts.

Interventions Intervention group received preoperative enteral nutrition through nasogastric tube (commercial for- mulation [Precision BR] with 10% peptides, 0.8% lipid, 81.9% carbohydrate); some patients received parenteral nutrition (50% dextrose and 8.5% AA [Freamine III]); a "few" enteral nutrition recipients re- ceived amino acids through nasogastric tube volume was 2-3 liters/day. Controls received standard di- et. Duration at least 12 days (mean 20 days). All patients received biliary decompression preoperative- ly.

Outcomes Mortality, infections, postoperative total/intra-abdominal/pneumonia/wound complications. Body weight and triceps skinfold thickness noted not to be different, but no numerical data.

Category of study Enteral nutrition/surgery.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes E-mail request for more information sent to Dr Foschi on September 17, 2011 ([email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomly divided".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Four dropouts accounted for.

Selective reporting (re- porting bias)

Low risk Molrtality and morbidity outcomes reported.

Other bias Unclear risk Funding source not identified.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No difference in per protocol group of 60 patients.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Foschi 1986 (Continued)

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Methods Randomised trial comparing enteral nutrition to no enteral nutrition in patients hospitalized awaiting liver transplant. Geographical location: New York, New York, USA. Abstract published 1995.

Participants Inclusion criteria: Hospitalized patients awaiting liver transplantation > 18 years. Exclusion criteria: Hospitalized in ICU, grade 4 hepatic encephalopathy, infections precluding transplantation. 42 hospi- talized patients (no data regarding sex or age; 10 dropped out).

Interventions Intervention group received enteral nutrition through nasogastric tube (Commercial formulation [Im- pact®]) + unrestricted oral diet prior to transplant; Control group given unrestricted oral diet. Mean du- ration of therapy at least 5 days (excluded if fewer days).

Outcomes Hepatic encephalopathy.

Category of study Enteral nutrition/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Abstract.

Notes Randomised patients who received transplant within 5 days were excluded from analysis. Data ob- tained from author at poster. Request for further information sent via US mail on September 16, 2011 to senior author, Dr Miller, as Dr Guy could not be located. (Charles Miller, MD, Transplantation Center, Director, Cleveland Clinic Main Campus, Mail Code A80, 9500 Euclid Avenue, Cleveland, OH 44195). Dr Miller responded on September 24, 2011; he had no information but suggested that we try to contact Dr Steve Guy at Hahneman. A search for a Dr Stephen Guy turned up the following address: Stephen Guy, MD, Drexel Transplant Associates, 216 N. Broad Street, Feinstein Building, 5th Floor, Philadelphia, PA 19102 and letter sent to him on September 26, 2011. No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "prospective randomised trial".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

High risk 10 dropouts (unknown how many from each group nor reasons for all of them, although at least some probably had transplant within 5 days of randomisa- tion).

Selective reporting (re- porting bias)

High risk No mortality data provided.

Other bias Unclear risk Funding source not identified.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk Although no numbers were presented, poster stated that there were no differ- ences.

Guy 1995

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Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Guy 1995 (Continued)

Methods Randomised trial comparing postoperative enteral nutrition to no enteral nutrition in patients under- going liver transplant. Geographical location Dallas, Texas, USA. Study published 1995.

Participants Inclusion criteria: Liver transplant individuals who had required continuous medical care (not neces- sarily in hospital) and were status 2 who then underwent transplant (randomised after transplant). Ex- clusion criteria: Requirement for hemodialysis, performance of choledochojejunostomy. 31 patients (17 men/14 women, mean age 51); an additional 19 dropouts also randomised.

Interventions Intervention group received preoperative enteral nutrition through nasojejunal tube (commercial for- mulation [Reabilin HN)] beginning at 20 cc/hr and advancing to 40 cc/hr); Control group received stan- dard progression of diet from clears to solids; those who were begun on artificial nutrition were to be dropped from trial. Planned duration 12 days.

Outcomes Infections, duration hospitalization/intensive care unit, cost, nitrogen balance. No numerical data, but stated no differences in rejections or rehospitalizations.

Category of study Enteral nutrition/surgery (liver transplant).

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes E-mail request for more information sent to Dr Hasse on September 17, 2011 (jm.hasse@bay- lorhealth.edu). Dr Hasse did acknowledge receipt of the request, but has not yet (March 20, 2012) pro- vided further data.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients randomised at time of transplant".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

Low risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk All 19 dropouts (38% of those randomised) accounted for.

Selective reporting (re- porting bias)

High risk No mortality data provided.

Other bias Unclear risk Partial funding by industry.

Intent to treat analysis High risk Could not be done.

Hasse 1995

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Baseline imbalance? Low risk No differences in per protocol groups.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Hasse 1995 (Continued)

Methods Randomised trial comparing supplements (standard or branched chain amino acids) to no supple- ments in outpatients awaiting liver transplant. Geographical location Dallas, Texas, USA. Paper pub- lished 1997.

Participants Inclusion criteria: Malnourished outpatient cirrhotic patients with history of encephalopathy awaiting liver transplantation. Exclusion criteria: None cited. 36 patients (no details regarding sex, age).

Interventions Intervention group received commercial nutritional supplement (Ensure® or Hepatic-Aid® [0.5 gm/kg/d protein and non-protein calories]); Controls received standard diet. Duration therapy 64-143 days.

Outcomes Appearance hepatic encephalopathy. Text indicates no difference in triceps skinfold thickness, midarm circumference, midarm muscle circumference, but no numerical data.

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Abstract.

Notes Information regarding dropouts and hepatic encephalopathy admissions obtained from author at poster. E-mail request for more information sent to Dr Hasse on September 17, 2011 (jm.hasse@bay- lorhealth.edu). See above note regarding response.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were randomised 2:2:1".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk Large number dropouts for variety of reasons.

Selective reporting (re- porting bias)

High risk No mortality data.

Other bias Unclear risk Funder of trial not reported.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Unclear risk No data in abstract.

Hasse 1997

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Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Hasse 1997 (Continued)

Methods Randomised trial comparing supplements (standard or branched chain amino acids) to no supple- ments in patients hospitalized with cirrhosis and hepatic encephalopathy. Geographical location Tokyo, Japan. Paper published 1991.

Participants Inclusion criteria: Hospitalized patient with cirrhosis (documented clinically and histologically) and Grade I or II encephalopathy or abnormal psychometric testing or abnormal sleeping pattern. Exclusion criteria: <15 years of age, gastrointestinalI bleeding, hepato-renal syndrome, recent/current cancer treatment, recent/current sclerotherapy for varices, women who were pregnant or thought to be. 67 patients (44 men/21 women [2 other dropouts], age in both groups < 39 to >70).

Interventions Intervention group received nutritional supplement (elemental diet [300 kcal, 11.2 gm amino acid {5.45 grams BCAA]/80} gm pack]), 2 packs/day orally or via tube + oral diet (1400 kcal/40 gm protein per day); Controls received oral diet (2000 kcal, 60 gm protein). Aminoleban EN®, and intravenous amino acids prohibited in general, but Aminoleban® PO/intravenous albumin prn; lactulose, antibiotics, other con- comitant drugs used in fixed doses. Duration therapy 21 days.

Outcomes Resolution ascites, appearance/resolution hepatic encephalopathy, Karnofsky score, serious/non-seri- ous adverse events, bilirubin, body weight (only in patients without ascites).

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full report (manuscript of PhD thesis or submitted paper).

Notes Information from trial came from a thesis that RLK received years ago as well as abstract; no address found for Dr Hayashi, so no information request could be sent.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "envelope method".

Allocation concealment (selection bias)

Unclear risk "envelop method" (no other details).

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

High risk 2 patients dropped out for being "in appropriate" but unknown from which group.

Selective reporting (re- porting bias)

Unclear risk No mortality data.

Other bias Unclear risk Funder of trial not reported.

Hayashi 1991

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Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Hayashi 1991 (Continued)

Methods Randomised trial comparing carbohydrate drink the evening before surgery and 30 days postoperative oral supplements to regular eating in patients undergoing hepatic resections for liver tumors.

Geographical location Scotland and the Netherlands. Paper published 2010.

Participants Inclusion criteria: Resectable benign or malignant liver tumor, age 18-80, BMI 18-30 scheduled for surgery between July 2006 and June 2008.

Exclusion criteria: Pre-existing conditions limiting mobility, underlying cirrhosis, history of liver resec- tion, need for bile duct excision, need for central or extended hepatectomy.

Interventions Intervention group received 400 ml commercial loading drink (Nutricia Preop®) 10 PM/4AM preop; 400 ml commerical supplement (Nutricia Fortisip®) bid postop (for one month).

Control group received regular diet.

Outcomes Primary outcome was time to passage of stool; secondary outcomes included mortality, postoperative complications. duration of hospitalization, rehospitalizations, and reoperations

Category of study Supplements/Surgical.

Sample size calculation Yes, but powered to see difference in time of appearance of stool.

Full paper or abstract only Full paper.

Notes Trial had factorial design in which patients also randomised to receiving or not receiving laxative (mag- nesium oxide) during hospitalization; data in paper presented only for combination groups (supple- ments versus no supplements and laxative versus no laxative). E-mail request for further information sent to Dr Hendry on 2/17/12 at [email protected]., but no further information has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk Block randomisation with random number table.

Allocation concealment (selection bias)

Low risk Sealed opaque envelopes (not noted if serially numbered, but accepted as ad- equate concealment of allocation).

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

High risk 6/74 patients dropped out of trial by investigators because the planned resec- tion could not be accomplished and palliative surgery done instead; no indica- tion how many from each group. However, given the block design and the fact

Hendry 2010

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that 30 treated versus 38 control patients were compared, it is likely that most, or even all, came from treatment arm (which may have resulted in the removal of higher risk patients).

Selective reporting (re- porting bias)

Low risk Mortality and morbidity reported, but data presented for individuals who also did, or did not, receive laxatives postoperatively.

Other bias Unclear risk Unclear funder although commercial company provided the nutrient solu- tions.

Intent to treat analysis High risk Unknown from which arm each dropout came, so intent to treat analysis could not be done.

Baseline imbalance? Low risk No differences in baseline characteristics of the per protocol arms.

Early stopping? Low risk Sample size calculation indicated need for 14 patients for each of the four arms, and more than that reported.

Hendry 2010 (Continued)

Methods Randomised trial comparing supplements (standard or branched-chain amino acids) to no supple- ments in outpatients with alcoholic liver disease. Geographical location Santiago, Chile. Paper published 1993.

Participants Inclusion criteria: At least 5 years alcohol consumption (> 150 gm/day), clinical evidence of alcoholic liv- er disease (2 or more of: jaundice, hepatic encephalopathy, ascites, edema, spiders, collateral circula- tion, bleeding disorder, varices), residence in Santiago. Exclusion criteria: HBsAg+, significant renal/pulmonary/cardiac disease, diabetes mellitus, malignancy. 65 patients (42 men/9 women (14 other dropouts), mean age 48).

Interventions Intervention group received nutritional supplement (commercial casein-based supplement (1 liter/day) - 34 gm protein, 1000 kcal/day [ADN®, Laboratorios Davis, Santiago, Chile]) + diet; Controls received 1 placebo tablet + diet. Duration therapy 12 months.

Outcomes Mortality, appearance ascites/hepatic encephalopathy/gastrointestinal bleeding, infections, bilirubin, body weight, triceps skinfold thickness, midarm circumference.

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Request for more information sent via e-mail on September 18, 2011 ([email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were assigned randomly".

Allocation concealment (selection bias)

Unclear risk No details.

Hirsch 1993

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Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Six dropouts in treatment group and eight in control group accounted for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Low risk Funded by Chilean government.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences in per protocol group.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Hirsch 1993 (Continued)

Methods Randomised trial comparing supplements (branched-chain amino acids) to no supplements in outpa- tients with cirrhosis. Geographical location Barcelona, Spain. Paper published 1988.

Participants Inclusion criteria: Cirrhosis (almost all of the patients were Childs B or C). Exclusion criteria: None cited. 49 patients (31 men/18 women , mean age 54).

Interventions Intervention group received nutritional supplement (branched-chain amino acid-enriched amino acid supplement [65 gm/d in 300 cc water {2224 kcal, 19.6 gm amino acids with 40% as branched chain- amino acids}]; Controls did not receive supplement. All participants received 80-90-gm protein diet, standard treat- ment for complications. Duration therapy six months.

Outcomes Mortality, appearance hepatic encephalopathy, bilirubin, triceps skinfold thickness, midarm muscle circumference.

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full report.

Notes Number of episodes of hepatic encephalopathy were total; for purposes of meta-analysis, assumed one per patient. Article in Spanish. Unable to find any contact address or e-mail for Dr Humbert, so no re- quest sent for further information.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk Table of random numbers.

Humbert 1988

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Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Two and four dropouts in treatment and control groups accounted for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Funder not reported.

Intent to treat analysis Low risk Although dropouts noted, denominators in paper were all randomised pa- tients.

Baseline imbalance? Low risk No differences identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Humbert 1988 (Continued)

Methods Randomised trial comparing the use of a late-evening snack of a branched-chain amino acid-enriched supplement to no supplement in cirrhotic patients.

Participants 21 patients (12 treatment, 9 controls) with compensated cirrhosis (documented by laboratory data and imaging). Exclusion criteria - hepatocellular carcinoma, overt encephalopathy, chronic renal failure, use of BCAA supplements, alcohol use, or albumin infusions.

Interventions Experimental group received a commercial supplement (Aminoleban EN - 13.5 gm protein [enriched with BCAAs] and 210 kcal energy in 50 gm pack) ingested at night for 8 weeks. The control group did not receive any nutrition therapy but consumed food (rice ball containing 210 kcal energy and 9 gm pro- tein) as nocturnal snack.

Outcomes Sleepiness (assessed by Epworth Sleepiness Scale), symptoms (assessed by cirrhosis symptom score), development encephalopathy, mortality (inferred), need for hospitalization, serum bilirubin, BMI.

Category of study Supplements/Medical.

Sample size calculation None reported.

Full paper or abstract only Full paper.

Notes Request for further information sent via e-mail on September 18, 2011 ([email protected] and [email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk "After balancing both groups for sex, age, Child-{ugh score (CPS), cirrhotic symptom score (CSS) and albumin level, patients were randomised…"

Ichikawa 2010

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Allocation concealment (selection bias)

Unclear risk No information provided indicating if or how allocation was concealed.

Blinding (performance bias and detection bias) All outcomes

High risk No blinding performed.

Incomplete outcome data (attrition bias) All outcomes

Low risk No dropouts.

Selective reporting (re- porting bias)

Low risk Mortality and onset encephalopathy (morbidity) reported or inferred (data presented for 8 week evaluation on 21 patients, suggesting that there were no deaths).

Other bias Unclear risk Unclear funding; authors had published other paper employing this prepara- tion (Takeshita 2009 below).

Intent to treat analysis Low risk No dropouts.

Baseline imbalance? Low risk No difference in variety of baseline characteristics.

Early stopping? Unclear risk No sample size calculation provided and not clear why trial included 21 pa- tients.

Ichikawa 2010 (Continued)

Methods Randomised trial comparing preoperative branched-chain amino acid-enriched supplements to usual diet in patients subsequently undergoing partial hepatectomy for the resection of benign or malignant tumours.

Participants Patients with benign or malignant tumours.

Interventions Intervention group received a commercial supplement (Aminoleban EN) twice daily for two weeks pre- operatively and for 1 to 7 days postoperatively; the control group only consumed normal diet.

Outcomes Mortality, duration of operation/hospitalization, intraoperative blood loss, postoperative complica- tions including "clinical and biologic signs of hepatic dysfunction".

Category of study Supplements/Surgical.

Sample size calculation None reported if done.

Full paper or abstract only Full paper.

Notes 14 patients excluded form analysis because of reasons that became apparent at the time of surgery; since the trial began 2 weeks earlier, these had to be excluded after randomisation (although that fact was not explicitly stated in the paper). Trial presented at Digestive Disease Week 2009 where addition- al information was available. Request for further information sent to Drs Ishikawa and Tajiri via e-mail ([email protected] and [email protected]) on September 19, 2011. No response has been re- ceived as of March 20, 2012.

Risk of bias

Ishikawa 2010

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Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Patients "randomly assigned", but no further details.

Allocation concealment (selection bias)

Unclear risk At time of presentation of paper at national meeting, stated that sealed en- velopes employed, but unclear if opaque and serially numbered.

Blinding (performance bias and detection bias) All outcomes

High risk No placebo solution employed.

Incomplete outcome data (attrition bias) All outcomes

Low risk Reasons for exclusion stated, but large number of dropouts (14 of original 38).

Selective reporting (re- porting bias)

High risk Explicitly stated in Methods section that lengths of stay data would be collect- ed, but this outcome was not reported quantitatively or qualitatively.

Other bias Unclear risk Funder not reported.

Intent to treat analysis High risk 14 participants unaccounted for.

Baseline imbalance? Low risk There were no differences in the remaining 24 patients with regard to baseline features.

Early stopping? Unclear risk No sample size calculation reported and there was no explanation as to why the trial was stopped when it was.

Ishikawa 2010 (Continued)

Methods Randomised trial comparing enteral nutrition to no enteral nutrition in patients hospitalised with alco- holic liver disease. Geographical location: San Jose, California, USA. Paper published 1992.

Participants Inclusion criteria: Clinical diagnosis of alcoholic liver disease, bilirubin > 51 micromol/l, one of the fol- lowing: albumin < 3gm%, PT > 4 secs above control, ascites on examination. Exclusion criteria: None cited. 31 hospitalized patients (21 male/10 female, mean age 44).

Interventions Intervention group received enteral nutrition through nasoduodenal tube (commercial formulation [Isocal HCN, Mead Johnson] with 167 kj/kg, 1.5 gm/kg protein/day) + regular diet. Control group given regular diet. Duration of therapy 28 days.

Outcomes Mortality, appearance/resolution hepatic encephalopathy, bilirubin, serious/non-serious adverse events, body weight, nitrogen balance. Appearance/resolution of ascites and gastrointestinal bleeding noted to be comparable, but no numerical data. Anmthrometic measurements noted not to be differ- ent, but no numerical data. Duration hospitalization provided as mean, but no standard deviation or standard error.

Category of study Enteral nutrition/Medical.

Sample size calculation Planned to enrol 25 patients in each arm, but did not achieve those numbers.

Full paper or abstract only Full paper.

Kearns 1992

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Notes 31 patients described and 6 dropouts; unclear if original randomisation included 37, or if only 25 com- pleted trial; for purposes of analysis, assumed 31 patients reported. Morlality data estimated from Ka- plan-Meier curve. Request for further information sent via e-mail on September 16, 2011 (pj.kearn- [email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomly assigned".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

High risk Six dropouts (3 from each group, but unclear reasons).

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias High risk Partial funding by industry.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences identified.

Early stopping? High risk Stopped after 31 patients completed trial without any preplanned intention to do so.

Kearns 1992 (Continued)

Methods Randomised trial comparing supplements (branched chain amino acids) to no supplements in outpa- tients with cirrhosis and hepatocellular carcinoma. Geographical location Japan. Paper published 2006

Participants Inclusion criteria: Cirrhotic patients with hepatocellular carcinoma. Exclusion criteria: None cited. 233 patients (159 men/74 women, mean age 69).

Interventions Intervention group received nutritional supplement (Commercial supplement [Amionleban® - 40.5 gm protein (18.3 gm BCAA), 630 kcal/day); Controls did not receive supplement. Duration therapy three years.

Outcomes Mortality, appearance hepatic encephalopathy. Quality of life information collected but not presented in usable format.

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Kobashi 2006

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Full paper or abstract only Abstract.

Notes Data for mortality and hepatic encephalopathy obtained at poster presentation by RK; numbers of he- patic encephalopathy episodes presented as total, and, for purposes of meta-analysis, assumed to be one per patient. Request for further information sent via e-mail to Dr Kobashi on September 19, 2011 ([email protected]); email address failed. Letter via US mail sent same day (Depart- ment of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry, and Pharmaceu- tical Sciences, Okayama University, Okayama, Japan). Response received via e-mail (kobashi0584@g- mail.com) informing us 1) that randomisation performed with computer software by study center, 2) that, while no formal mechanism in place to provide concealment of allocation, the assignment was accomplished by fax from the study center, 3) that a sample size was calculated (but no number pro- vided), 4) that there were no significant differences between the 2 groups as for age, sex, viral markers (HBV or HCV), serum ammonia, total bilirubin, prothrombin-time, BTR, ascites, or Child-Pugh class, but serum albumin was significantly lower and encephalopathy significantly higher in the BCAA group, and 5) that the trial was not funded (unclear what he meant, but possibly by industry). He also informed us that both ascites and encephalopathy were present in 31 patients at the beginning of the trial and new- ly occurred in 54 but that he did not have any data regarding how many had resolution of either dur- ing the trial, that 9 patients developed bleeding during the trial, that the serum bilirubin levels in the treated/control arms was 1.29 (0.77 SD)/1.15 (0.078 SD), there were no infections, that quality of life da- ta were obtained (and he sent a spread sheet with numerical scores but no standard deviations), and that no data were obtained regarding costs, lengths of stay, nutritional outcomes, or adverse events. An email was sent back to Dr Kobashi on October 14, 2011, inquiring about the exact sample size calcu- lation, the numbers in each group who had new ascites and encephalopathy, how many in each arm bled, and whether the bilirubin values were baseline or end of study values. On October 17, Dr Kobashi replied with data regarding ascites (16/100 versus 27 [+ 1 pleural effusion]/102 developed it, 3/19 ver- sus 7/12 with ascites deteriorated, but no information provided regarding numbers with ascites who improved), encephalopathy (12/108 versus 16/113 developed it, and no apparent worsening in the 11/1 individuals who had it at the beginning, but no data regarding improvement in this small group of patients), and bleeding (7 [4 varices, 2 without endoscopy, 1 biliary]/5 [2 varices, 3 gastric ulcers] had bleeding, but the 2 without endoscopy and 1 with biliary bleeding were excluded). Also informed us that trial was not funded. While the mortality data was noted on the poster to be not significant, the analyses indicated that the 95% confidence interval did not overlap the line of equivalence; a subse- quent e-mail was sent to him and he responded that the numbers that RK had copied were correct. Dr Kobashi also informed us that the trial has not been published in full paper form to date for the follow- ing reason: "Sorry to say we have not yet published the full paper of this study. I have some difficulties in the authorship, and the priority for the full authorship of this study belongs to another person (my colleague)." He indicated that this other investigator has some reason not to publish it in a full paper.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk See comment in notes.

Allocation concealment (selection bias)

Low risk See comment in notes.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Outcomes of all 233 patients at point in time reported.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Kobashi 2006 (Continued)

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Other bias Low risk See comment in notes re: funding.

Intent to treat analysis Low risk All patients accounted for.

Baseline imbalance? High risk No data provided in abstract; data from email indicated that most character- istics similar, but BCAA group had lower albumin and more encephalopathy (suggesting that there was an imbalance in the degree of illness between the two groups).

Early stopping? Unclear risk Information from author indicated that he estimated need for 150 to 200 pa- tients per group, but statistician did do sample size calculation. However, do not know what the exact number was and < 150 in each arm.

Kobashi 2006 (Continued)

Methods Randomised trial comparing branched chain amino acid supplement to no supplement in malnour- ished outpatients with cirrhosis who were awaiting liver transplant at time of entry and who subse- quently received a transplant. Geographical location: Birmingham, UK. Paper published 2000.

Participants Inclusion criteria: Adult patients with end-stage liver disease on liver transplantation and waiting as outpatients, mid-arm muscle circumference < 25 percentile. Exclusion criteria: midarm muscle circumference > 25th percentile, fulminant/subacute liver failure (need for urgent transplantation), malignant disease, fluid restriction (< 500 ml/d), regrafts, multiple or- gan failure, celiac disease. 82 patients (60 male/22 female [1 patient in each of the treatment and con- trol groups subsequently dropped out], median age 51).

Interventions Intervention group received 500 cc daily of a specially prepared supplement (20 gm protein, 33.5 gm fat, minerals, 750 kcal/day) + usual diet; Control group received the usual diet. Duration of therapy un- til transplantation (median 77 days in treatment group, 45 days in control group). All patients received postoperative immunosuppression.

Outcomes Mortality, bilirubin, triceps skinfold thickness, midarm muscle circumference, midarm circumference. Methods section described all of the postoperative information that was to be collected (infections, du- ration of stay in intensive care unit/hospital, postoperative total complications) but the only mention of it was a terse statement that there were no differences; mild rejection in 14/39 versus 10/32 and se- vere rejection in 15/39 versus 16/32.

Category of study Supplements/Surgery.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Request for further information sent to Dr LeCornu via email ([email protected]) on Septem- ber 19, 2011. Subsequent responses in October 4, 2011, provided details about sample size calculation, concealment of allocation, and funding, as well as some outcome data (LOS in hospital and ICU); an- other response on October 28, 2011, indicated that further information was not available.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomisation to either the intervention group or control group".

LeCornu 2000

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Allocation concealment (selection bias)

Unclear risk Sealed envelopes selected by someone other than trial coordinator (but not stated re: opaque, numbered, or if person associated with investigators).

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk One dropout in each arm accounted for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported (mostly qualitatively).

Other bias High risk Authors have prior publication showing association between malnutrition and poor outcome in transplant patients; industry supplied product.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences in per protocol groups.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

LeCornu 2000 (Continued)

Methods Randomised trial comparing the use of postoperative branched chain amino acid supplement to no supplement in patients who underwent surgery for an attempted curative resection for hepatocellular carcinoma. Geographical location: Hong Kong. Paper published 1999.

Participants Inclusion criteria: Patients with cirrhosis undergoing attempted curative resection of hepatocellular carcinoma. Exclusion criteria: Palliative resection, benign nodular hyperplasia, adenoma. 44 patients (37 male/7 female [4 other dropouts], median age 52).

Interventions Intervention group received branched chain amino acid supplement (Aminoleban EN®) - 3 packs/day (? 50 gm packs); Control group received isocaloric, isonitrogenous diet. Duration of therapy 12 weeks.

Outcomes Mortality, appearance gastrointestinal bleeding/hepatic encephalopathy, infections, duration hos- pitalization postoperative total complications (total number, not number of patients with complica- tions)/intra-abdominal complications/wound infections/pneumonia/major complications (not prede- fined outcome). Paper indicates that serum bilirubin better in treatment group, but no usable numeri- cal data. Paper indicated that there were no differences in body weight, triceps skinfold thickness, mi- darm circumference, but no numerical data.

Category of study Supplements/Surgery.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Request for further information sent to Drs Meng and Lau via e-mail ([email protected] and [email protected]) on September 19, 2011. No response has been received as of March 20, 2012.

Risk of bias

Meng 1999

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Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk Computer-generated sequence.

Allocation concealment (selection bias)

Unclear risk Closed envelopes, but not stated if opaque, serially numbered.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Four dropouts from treatment group, 2 dropouts from control group account- ed for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias High risk Funded by industry.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences in per protocol groups.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Meng 1999 (Continued)

Methods Randomised trial comparing use of preoperative supplements to standard care.

Geographical location Japan. Paper published in 2011.

Participants Inclusion criteria: Patients undergoing segmentectomy or more extensive hepatectomy not including biliary tract reconstruction for liver tumors (HCC, cholangiocellular carcinoma, metastatic liver cancer, carcinoid) between 2/05 and 12/08

Exclusion criteria: Marked renal dysfunction (creatinine clear < 30 ml/min), severe diabetes (requiring insulin), chemoradiotherapy within past month, inability to take oral nutrition.

Interventions Intervention group received 750 cc/day commercial supplement (Impact®, Ajinomoto Pharm, Tokyo) + 1/2 daily diet.

Control group received regular diet.

Outcomes Primary outcomes appeared to be surrogate measures of inflammatory status (WBC count, interleukin 6 levels), "nutrition" (albumin, prealbumin), liver "function" (ALT, AST levels), and fatty acid metabolism (eicosopentaenoic acid level). Other outcomes reported included postoperative complications (includ- ing infections), duration of stay.

Category of study Supplements/Surgical.

Sample size calculation Not reported.

Full paper or abstract only Full paper.

Mikagi 2011

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Notes Concern about randomisation - see comment below. E-mail sent requesting further information about trial sent to Dr Mikagi on 2/17/12 at [email protected]. No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states that patients were randomised. However, according to the patient flow sheet, 41 patients were initially randomised, 26 to the supplement arm and 15 to the controls, and there were 15 dropouts (12 from the supplement arm).

Allocation concealment (selection bias)

Unclear risk Not reported.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Since reasons for all dropouts were provided (12 dropouts from supplement arm [8 change of treatment, 3 side effects, 1 withdrew consent], 3 from con- trol arm [2 change of treatment, 1 withdrew consent], our criteria for low risk met. However, the disproportionate number from supplement, especially for change in treatment or side effects, could have introduced bias.

Selective reporting (re- porting bias)

High risk No mortality data reported.

Other bias Unclear risk Unclear funder.

Intent to treat analysis High risk 15/41 patients dropped out and no intent-to-treat analysis reported.

Baseline imbalance? Low risk No baseline differences in the per protocol groups.

Early stopping? Unclear risk No sample size provided and not clear why trial was stopped when it was.

Mikagi 2011 (Continued)

Methods Randomised trial comparing supplements (branched chain amino acids) to no supplements in outpa- tients with cirrhosis secondary to hepatitis C. Geographical location Japan. Paper published 2005.

Participants Inclusion criteria: Cirrhosis, anti-HCV+, albumin < 3.5 gm%. Exclusion criteria: Overt hepatic encephalopathy, uncontrolled variceal bleeding, refractory ascites, re- nal impairment, prior history poor compliance, hepatocellular carcinoma with overt disease, positive alpha-fetoprotein, diabetes mellitus on medications, intravenous albumin use. 48 patients (28 men/10 women [10 other dropouts], mean age 68).

Interventions Intervention group received nutritional supplement (Commercial branched chain amino acid supple- ment [Amionleban EN® - 13.5 gm protein, 3.5 gm fat, trace minerals and vitamins] 210 kcal/day); Controls received food (9 gm protein, 5 gm fat, 210 kcal/day). Duration therapy 3 months.

Nakaya 2007

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Outcomes Mortality, bilirubin, body weight. Quality of life reported, but not in usable format. Triceps skinfold thickness, midarm muscle circumference, midarm circumference measured but not reported; nitrogen balance change only reported as significant for treatment group but not for control group.

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Request for further information sent via e-mail on September 19, 2011 ([email protected] ma-u.ac.jp); e-mail address failed. Letter sent via US mail on same day (Yutaka Nakaya, MD, Depart- ment of Nutrition and Metabolism, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan). Letter dated Novenber 15, 2011 received indicating that the generation of the randomisation scheme was adequate (computer generated based on stratification for "important parameters"), concealment of allocation was adequate (central computer), no sample size calculation was performed and no explanation provided as to why trial was stopped when it was, funding was not obtained and trial conducted by interested investigators. Ascites developed in 1/16 treatment versus 1/15 controls and resolved in 2/3 versus 0/4. Hepatic encephalopathy developed in 0/19 versus 1/19; no patient was encephalopathic at the beginning of the trial. There were no episodes of GI bleeding or infections. 8 different quality of life scores were provided; there were no apparent differences. Data re- garding costs and lengths of stay were not collected. There were 5/19 versus 2/19 adverse events in the two arms (in addition to nonsevere ones (fever in one versus nausea in one), there were 4 [death from cerebral bleed, bone fracture, and 2 worsening of ascites] versus 1 [worse encephalopathy] serious ad- verse events). The weights in the two groups at the beginning/end of the trial were 18.6 (9.0) versus 56.6 (7.7)/59.4 (9.6 SD) versus 57.1 (7.7). The arm muscle circumferences at the beginning/end of the trial were 241.3 (39.6) versus 239.7 (32.5)/244.4 (33.7) versus 243.2 (31.8). Triceps skinfold thicknesses at the beginning/end of the trial were 11.7 (4.4) versus 12.6 (4.5)/12.6 (4.5) versus 13.4 (4.5). New e-mail ad- dress also provided ([email protected]).

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk Computer generated with stratifications for "important parameters" (informa- tion from investigator).

Allocation concealment (selection bias)

Low risk Central randomisation and assignment (information from investigator).

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Six dropouts in treatment group, 4 dropouts in control group all accounted for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk No external funding; trial conducted by interested investigators. (information from investigator). No sample size calculation (see below).

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences identified.

Nakaya 2007 (Continued)

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Early stopping? Unclear risk No sample size calculation was performed (information from investigator) and unknown why stopped.

Nakaya 2007 (Continued)

Methods Randomised trial comparing parenteral nutrition to no parenteral nutrition in hospitalized patients with alcoholic cirrhosis. Geographical location Bicetre, France. Study published 1986.

Participants Inclusion criteria: Alcoholic cirrhosis on biopsy or, if not possible, at least 2 our of 5 clinical character- istics (firm liver, ascites, hepatic encephalopathy, splenomegaly, varices at endoscopy) AND bilirubin > 5mg%. Exclusion criteria: Hepatocellular carcinoma, creatinine > 2mg%, sodium < 130 meq/l, sep- ticemia, spontaneous bacterial peritonitis, gastrointestinal bleeding within 3 days, hepatic coma. 40 patients (25 men/15 women, mean age 52).

Interventions Intervention group received intravenous formulation (20 kcal/kg glucose, 20 kcal/kg lipid, 0.2 gm nitro- gen/kg, minerals, vitamins) + oral diet; Controls received oral diet (40 kcal/kg, 0.2 gm nitrogen/kg). Duration therapy 28 days. Patients in both groups received neomycin for encephalopathy.

Outcomes Mortality, ascites resolution, development of encephalopathy, infections (sepsis), serum bilirubin, triceps skinfold thickness, midarm muscle circumference. The only adverse effects noted were four episodes of sepsis in patients receiving parenteral nutrition; no apparent attempt to look for such events in all of the patients in the trial.

Category of study Parenteral nutrition/Medical.

Sample size calculation Sample size based on previously reported trial (Nasrallah 1980).

Full paper or abstract only Full paper.

Notes Attempt made to follow patients for 2 years; decision made to confine analysis to in-hospital peri- od. Request for further information sent to Dr Naveau via e-mail on September 11, 2011 (Address = [email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk Computer-generated.

Allocation concealment (selection bias)

Low risk Serially numbered, opaque, sealed envelopes.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Three dropouts in treatment group and 2 in control group accounted for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Naveau 1986

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Other bias Unclear risk Unclear funder.

Intent to treat analysis High risk All information on dropouts not available, although in-hospital mortality re- ported.

Baseline imbalance? Low risk No differences identified.

Early stopping? Low risk Achieved planned number.

Naveau 1986 (Continued)

Methods Randomised trial comparing enteral nutrition to no enteral nutrition in patients hospitalised with de- compensated cirrhosis. Geographical location: Germany. Paper published 2008.

Participants Inclusion criteria: Clinical diagnosis of alcoholic liver disease, bilirubin > 51 micromol/l, one of the fol- lowing: albumin < 3gm%, PT > 4secs above control, ascites on examination. Exclusion criteria: None cited. 63 hospitalized patients (40 male/23 female, age not provided).

Interventions Intervention group received enteral nutrition through nasogastric tube (only detail was "high protein formulation"); Control group given standard diet. Duration of therapy 14 days.

Outcomes Mortality, gastrointestinal bleeding, infections, bilirubin.

Category of study Enteral nutrition/Medical.

Sample size calculation Not performed (information obtained from author at poster).

Full paper or abstract only Abstract.

Notes Much of the information obtained via discussion with author who was present at poster where study presented (Digestive Disease Week, 2008) Trial from same group as Schuetz 2006, but appears to be dif- ferent trial. On September 17, 2011, emails sent to Drs Norman and Pirlich ([email protected]

and [email protected]) requesting information about both Norman and Schuetz trials. (Email for Dr Pirlich failed.) No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Low risk Computer generated (information obtained at poster from author).

Allocation concealment (selection bias)

Low risk Central phone (information obtained at poster from author).

Blinding (performance bias and detection bias) All outcomes

High risk Information obtained at poster.

Incomplete outcome data (attrition bias) All outcomes

High risk Dropouts had to have occurred, as percentages at poster did not produce whole numbers.

Norman 2008

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Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Funding source not reported; trial stopped because primary investigator leK institution (information obtained at poster).

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk Although no numerical data, abstract stated that there were no differences.

Early stopping? High risk Trial stopped early because principal investigator leK institution. (Information obtained at poster.)

Norman 2008 (Continued)

Methods Randomised trial comparing supplements to no supplements in outpatients with newly diagnosed he- patocellular carcinoma. Geographical location: Hong Kong. Paper published 2004.

Participants Inclusion criteria: Newly diagnosed unresectable hepatocellular carcinoma eligible for transarterial chemoembolisation, no extrahepatic metastases, no vascular complications (hepatic artery throm- bosis, main protal vein thrombosis, arteriovenous shunting), no hepatic encephalopathy, no refracto- ry ascites, no variceal bleed within 3 months, bilirubin < 50 micromol/l, albumin > 2.5 gm%, Karnofsky score > 50. Exclusion criteria: Previous treatment for hepatocellular carcinoma, tumor rupture. 88 pa- tients (78 male/6 female [4 additional dropouts], median age of per protocol population 59).

Interventions Intervention group received branched chain amino acid supplement (Aminoleban EN®) - 27 gm protein (13 gm amino acids, 13 gm peptide, 1 gm casein), 420 kcal (62.1 gm dextran, 7 gm rice oil), various min- erals and vitamins/day); Control group received no supplement. All patients received transarterial chemoembolization (cis- platin/Lipiodol emulsion). Duration of therapy up to one year.

Outcomes Mortality, appearance ascites/gastrointestinal bleeding/hepatic encephalopathy, infections, quality of life score, bilirubin, body weight, triceps skinfold thickness, midarm circumference. Adverse events not reported by group. Number of readmissions to hospitalization later in study, but these were likely relat- ed to underlying disease and not to supplement therapy (so data not used).

Category of study Supplement/Medical.

Sample size calculation Calculated need for 44 patients per arm and achieved that number.

Full paper or abstract only Full report.

Notes Although longer term mortality also reported, decided to use mortality that occurred by one month af- ter transarterial chemoembolization therapy. Request for further information sent to Dr Poon (poont- [email protected] or [email protected]) with copy to Dr Fan ([email protected]) via e-mail on September 19, 2011. No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were randomised".

Poon 2004

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Allocation concealment (selection bias)

Low risk Consecutively numbered sealed envelopes. Not mentioned whether opaque or not, but we assume so.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk Three dropouts in treatment group and 1 in control group adequately account- ed for.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Funder of trial not reported.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences identified.

Early stopping? Low risk Achieved planned number.

Poon 2004 (Continued)

Methods Randomised trial comparing parenteral nutrition to no parenteral nutrition in patients hospitalised for elective portocaval shunt. Geographical location Rome, Italy. Study published 1995.

Participants Inclusion criteria: Elective porto-caval shunt surgery for variceal bleeding. Exclusion criteria: None cited. 20 patients (13 men/7 women, mean age 55).

Interventions Intervention group received parenteral nutrition (40 gm/l branched chain amino acids X 3 days, then 80 gm/l standard amino acids X 4 days; 16% dextrose [unspecified dose]) postoperatively; Controls received 6% dextrose intravenously. Duration 7 days.

Outcomes Mortality, appearance encephalopathy.

Category of study Parenteral nutrition/Surgical (Portocaval shunt).

Sample size calculation None reported if done.

Full paper or abstract only Full paper.

Notes No address or location found for Dr Puglionisi; e-mail sent to one of co-authors (Dr Di Cera - enrico@s- lu.edu) on September 13, 2011. On September 17, 2011, Dr DiCera replied that he was only a medical student at the time and had no information to supply. E-mail returned to him asking if there was any- one else we could contact on September 17, 2011. Response received on September 18 indicated that Dr DiCera was no longer in Italy and that Dr Puglionisi died 20 years ago.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "20 patients divided into 2 random groups of 10".

Puglionisi 1985

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Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk No dropouts.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Funding source not reported.

Intent to treat analysis Low risk No dropouts.

Baseline imbalance? Low risk No differences identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Puglionisi 1985 (Continued)

Methods Randomised trial comparing two different parenteral nutrition solutions (a standard one and one con- taining glutamine) to a control group receiving no nutritional interventions in patients undergoing liver transplantation.

Participants Patients undergoing liver transplantation.

Interventions One interventional group received standard parenteral nutrition (1 gm/kg amino acids as a commercial BCAA solution, 104.5 kJ/kg [dextrose and MCT/LCT combination 20% solution in a 2:1 ratio of carbohy- drate to fat]) and a second intervention group receiving an isocaloric, isonitrogenous solution contain- ing glutamine. Treatment was provided for 7 days postoperatively. The control arm received only standard intravenous fluids (5% dextrose and minerals).

Outcomes Mortality (both short term and long term), duration of hospitalization, a variety of lab tests (including parameters of the Prognostic Nutritional Index).

Category of study Parenteral nutrition, Surgical.

Sample size calculation None reported.

Full paper or abstract only Full paper.

Notes For purposes of this analysis, the short-term mortality was employed (since this was a surgical trial and the therapy was all done during that hospitalization). Both treatment groups were combined and com- pared to the control arm. For bilirubin outcome, we used the calculated mean of two treatment groups and the lower standard deviation (since no significant difference between the two groups) and com- pared to the control group. Attempt to send e-mails to both Dr Qiu ([email protected] and [email protected]) and Dr Ding ([email protected]) on September 13/14, 2011 failed; both returned. Letter sent to Dr Ding on September 14, 2011 (Dr Yitao Ding, Department of Hepatobil- iary Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Zhongshang Road 321, Nanjing 210008, China). No response has been received as of March 20, 2012.

Qiu 2009

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Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only stated that the patients were "randomly assigned".

Allocation concealment (selection bias)

Unclear risk No details provided.

Blinding (performance bias and detection bias) All outcomes

Unclear risk No placebo intravenous solution provided, although it was stated that the two treatment arms could not be distinguished.

Incomplete outcome data (attrition bias) All outcomes

Low risk No apparent dropouts (One patient excluded for graK dysfunction, but it was assumed that that was the reason for the liver transplantation that was re- sponsible for the patient being considered for the trial.)

Selective reporting (re- porting bias)

High risk No hepatic or postoperative morbidity data provided.

Other bias Unclear risk Funding source not disclosed.

Intent to treat analysis Low risk No dropouts.

Baseline imbalance? Low risk No differences in the baseline features.

Early stopping? Unclear risk No explanation provided regarding why the trial was stopped when it was.

Qiu 2009 (Continued)

Methods Randomised trial comparing two different parenteral nutrition solutions (standard or branched-chain amino acids) to no parenteral nutrition in patients hospitalized for liver transplant. Geographical location Pittsburgh, Pennsylvania, USA. Study published 1999.

Participants Inclusion criteria: Immediately postoperative after successful liver transplantation. Exclusion criteria: None cited. 28 patients (13 men/15 women, mean age 49).

Interventions Intervention group received parenteral nutrition (1.5 gm/d standard or branched chain amino acids, 35 kcal/kg/d [carbohydrate and lipid]); Controls received standard dextrose solutions intravenously. Duration 7 days. All patients received cy- closporine and steroids.

Outcomes Mortality, serum bilirubin, duration intensive care unit and total hospitalization, cost, nitrogen balance

Category of study Parenteral nutrition/Surgical (liver transplant).

Sample size calculation None reported if done.

Full paper or abstract only Full paper.

Notes For bilirubin outcome, we used the calculated mean of two treatment groups and the lower stan- dard deviation (since no significant difference between the two groups) and compared to the control group. Unable to find address or location for Dr Reilly; e-mail sent to coauthor, Dr Leonard Makowka ([email protected]) on September 13 failed; letter then sent by US mail (Leonard Makowka, M.D.,

Reilly 1990

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ITF Global Partners. 181 Hudson Street, PH, New York, NY 10013). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomised".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk No dropouts.

Selective reporting (re- porting bias)

High risk Serum bilirubin not useful, as patients had liver transplant as confounding fac- tor; no postoperative morbidity reported, so no morbidity data at all reported.

Other bias Unclear risk Funding source not reported.

Intent to treat analysis Low risk No dropouts.

Baseline imbalance? Low risk No differences identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Reilly 1990 (Continued)

Methods Randomised trial comparing supplements to no supplements in outpatients who had had an attempt- ed curative resection for hepatocellular carcinoma 2 to 3 weeks earlier. Geographical location: Izumo, Japan. Paper published 1997.

Participants Inclusion criteria: Patients 2 to 3 weeks after attempted curative resection for HCC. Exclusion criteria: None cited. 150 patients (109 male/23 female [18 additional dropouts], median age of per protocol population 50 to 70).

Outcomes Mortality, bilirubin, body weight. Outcomes of ascites and encephalopathy reported as percentages, but not clear what denominators were, so the data could not be used in the meta-analyses.

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

San-In Group 1997

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Notes No e-mail address available for corresponding author (Dr N Nagasue); letters sent to two different addresses that were found (N Nagasue, MD, Department of Digestive and General Surgery, Shimane University School of Medicine, Izumo 693-8501, Japan and N Nagasue, MD, Department of Surgery, Kawasaki Hospital, Higashiyama-cho 3-3-1, Hyogo-ku, Kobe, Hyogo 652-0042, Japan) on September 19, 2011. Latter letter returned as being undeliverable and not able to forward. No other response received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were randomised".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Eight dropouts in treatment group, 10 dropouts in control group all adequate- ly accounted for.

Incomplete outcome data (attrition bias) All outcomes

Low risk All dropouts accounted for.

Selective reporting (re- porting bias)

Low risk Outcomes of ascites and encephalopathy reported as percentages, but not clear what denominators were. Thus, while the data could not be used in the meta-analyses, the outcomes were reported.

Other bias Unclear risk Funder of trial not reported.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

San-In Group 1997 (Continued)

Methods Randomised trial comparing enteral nutrition to no enteral nutrition in patients hospitalized with cir- rhosis and encephalopathy. Geographical location: Germany. Paper published 2006.

Participants Inclusion criteria: Hospitalized patients with cirrhosis and hepatic encephalopathy. Exclusion criteria: None cited. 22 hospitalised patients (16 male/6 female, mean age 60).

Interventions Intervention group received enteral nutrition through nasogastric tube (only detail was "high protein formulation"); Control group given standard diet. Duration of therapy 14 days.

Outcomes Appearance of hepatic encephalopathy.

Category of study Enteral nutrition/Medical.

Sample size calculation Not reported if performed.

Schuetz 2006

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Full paper or abstract only Abstract.

Notes Trial from same group as Norman 2008, but appears to be different trial. Abstract states no change in encephalopathy and all patients appeared to have subclinical encephalopathy at beginning, so as- sumed no frank encephalopathy developed. On September 17, 2011, e-mails sent to Drs Norman and Pirlich ([email protected] and [email protected]) requesting information about both Norman and Schuetz trials. (E-mail for Dr Pirlich failed.) No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were randomly assigned".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk 22 patients presented, but unclear if they were the only ones randomised.

Selective reporting (re- porting bias)

High risk No mortality data.

Other bias Unclear risk Funding source not reported.

Intent to treat analysis Unclear risk 22 patients reported but unknown if other patients enrolled in trial.

Baseline imbalance? Unclear risk Only Childs-Pugh scores at baseline presented.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Schuetz 2006 (Continued)

Methods Randomised trial comparing supplements (standard or branched-chain amino acids) to "placebo" in malnourished outpatients with cirrhosis. Geographical location: Melbourne, Australia. Abstract pub- lished 1999.

Participants Inclusion criteria: Malnourished cirrhotic patients expected to survive for 4 months. Exclusion criteria: None cited. 95 patients (80 male/15 female, no data regarding age) in three groups, but no information about sex distribution in each of those groups.

Interventions Intervention group received standard amino acid supplement (40 gm protein [20% BCAA] 400 kcal, vita- mins, minerals/day) or branched chain amino acid supplement (40 gm protein [45% BCAA], 400 kcal, vi- tamins, minerals/day); Control group received placebo (only vitamins and minerals). Duration of thera- py 4 months.

Outcomes Appearance hepatic encephalopathy, infections, non-serious adverse events, body weight. Quality of life data allegedly collected, but not reported.

Sievert 1999

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Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Abstract.

Notes In meta-analyses, data treated as if intent to treat (all patients counted in denominator). Data regard- ing appearance hepatic encephalopathy, infections, non-serious adverse events obtained from poster at meeting of AASLD in 1999. Request for further information sent via e-mail to Drs Sievert and Strauss ([email protected] and [email protected]) on September 19, 2011.No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were randomised".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

Unclear risk No description of placebo.

Incomplete outcome data (attrition bias) All outcomes

High risk 7 dropouts from trial, but no information regarding which group or reason.

Selective reporting (re- porting bias)

High risk No mortality data and quality of life not reported (even though it was planned to be collected).

Other bias Unclear risk Funding source not reported.

Intent to treat analysis Unclear risk Not clear if data from all patients or just those who completed trial.

Baseline imbalance? Low risk Although no data presented in abstract, it is stated that there were no differ- ences.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Sievert 1999 (Continued)

Methods Randomised trial comparing supplements to "placebo" in outpatients who had chronic (alcoholic) liver disease with past history of encephalopathy but were currently no worse that Grade I. Geographical lo- cation: Cincinatti, Ohio, USA. Paper published 1983.

Participants Inclusion criteria: Biopsy-proven chronic liver disease (all alcoholic, either cirrhosis or alcoholic hepati- tis) with past history of hepatic encephalopathy but currently no worse than Grade 1. Exclusion criteria: None cited. 15 patients (5 male/5 female [5 additional dropouts], median age of per protocol population 51).

Interventions Intervention group received branched-chain amino acid supplement (Hepatic-Aid®) containing in- creased amounts branched-chain amino acids/decreased amounts aromatic amino acids, sucrose, maltodextrins (69.9%) and fat (19/7%) to tolerance or total supplement intake of 60 gm protein;

Simko 1983

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Control group received placebo. Duration of therapy 3 months.

Outcomes Appearance hepatic encephalopathy, bilirubin, body weight, triceps skinfold thickness, midarm muscle circumference.

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Disproportionate number randomised to treatment group with no explanation. We assumed no hepatic encephalopathy since serum ammonia and trailmaking did not deteriorate in either group. On Google, found address for Vlado Simko (VA NY Harbor Healthcare System, 800 Poly Place, Brooklyn, NY 11209) and report of paper published by a Dr Vlado Simko from the GI unit at the University of Cincinnati in same time period when paper written; letter sent to him on September 19, 2011. No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "all patients were randomly assigned".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

Unclear risk No description of placebo.

Incomplete outcome data (attrition bias) All outcomes

Low risk 5 dropouts accounted for; 4 were in treatment group and one in control group (unknown which reason caused dropout in the control group, however).

Selective reporting (re- porting bias)

High risk No mortality data.

Other bias High risk Five control patients older than 5 treatment patients; partial funding by indus- try.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? High risk Controls older than treated patients (at least in those that completed the trial).

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Simko 1983 (Continued)

Methods Randomised trial comparing parenteral nutrition to no parenteral nutrition in hospitalized patients with alcoholic hepatitis. Geographical location Atlanta, Georgia. Study published 1988.

Participants Inclusion criteria: >80 gm alcohol intake for at least 2 years, right hepatic lobe enlargement, severe al- coholic hep (bilirubin >5 mg% and either primary hepatic encephalopathy or prothrombin time at least

Simon 1988

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5 sec > control) or moderate alcoholic hepatitis (albumin < 2.9gm% and one of the three criteria for severe hepatitis), and either biopsy-proven alcoholic hepatitis or, if no biopsy possible, AST <350 IU/l, AST/ALT >2, and actively consuming alcohol at time of admission. Exclusion criteria: Acute pancreatitis, insulin-dependent diabetes mellitus, positive test for hepatitis B surface antigen, malignancy, hypotension, congestive heart failure, sepsis, severe chronic obstruc- tive pulmonary disease, recent severe trauma or surgery. 34 patients in the full paper, but 69 in a subse- quent abstract (age and sex only available for 22 patients in the original paper (7 men/15 women, mean age 41).

Interventions Intervention group received intravenous formulation (35 gm AA, 5% dextrose, minerals, MVI/liter, 2 liters/day, 0.5 liter 10% lipid solution/day) and oral intake offered to control patients; Controls received oral diet (2400 kcal and 100 gm protein) and 1 can Ensure with each meal, 1 mg folic acid/day, multivitamins. Duration therapy 28 days.

Outcomes Mortality (in abstract with 69 patients), appearance/resolution of ascites or hepatic encephalopathy (only for severe subgroup), bilirubin (only for severe subgroup).

Category of study Parenteral nutrition/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes A couple of the numbers in the abstract describing the 69 patients were inconsistent with the original paper, and the data from the larger group were accepted.

Address and location not identified for Dr Simon; letter sent to Dr Galambos (John T Galambos, MD, 95 Collier Road, Suite 4075, Atlanta, Georgia 30309) on September 12, 2011. No response has been re- ceived as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomised".

Allocation concealment (selection bias)

Unclear risk Sealed envelope noted, but not mentioned if opaque and/or serially num- bered.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk Two dropouts in trial reported in full paper; one from each group in those with moderate alcoholic hepatitis, but not stated which reason for which group. No information regarding subsequent report of 69 patients provided as abstract.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Other bias Unclear risk Funding source not reported.

Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences identified.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Simon 1988 (Continued)

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Methods Randomised trial comparing the use of a late-evening snack of a branched-chain amino acid-enriched supplement to no supplement in patients undergoing transarterial chemoembolization for hepatocel- lular carcinoma.

Participants Patients undergoing transarterial chemoembolisation for hepatocellular carcinoma.

Interventions Experimental group received a commercial supplement (Aminoleban EN - 878.64 kJ energy in 50 gram pack) ingested at night (10 PM) beginning one day before the procedure and lasting for two weeks af- terward. The control group did not receive any nutrition therapy.

Outcomes Mortality, duration of hospitalization (for the chemoembolization procedure), lab tests, adverse events, body mass index.

Category of study Supplements/Medical.

Sample size calculation None reported.

Full paper or abstract only Full paper.

Notes Request for further information sent via e-mail on September 18, 2011 ([email protected] and [email protected]). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk "patients were randomly placed into 2 groups".

Allocation concealment (selection bias)

Unclear risk No details provided.

Blinding (performance bias and detection bias) All outcomes

High risk No placebo solution provided.

Incomplete outcome data (attrition bias) All outcomes

Low risk No dropouts.

Selective reporting (re- porting bias)

High risk Although explicitly stated to be a secondary outcome, no hepatocellular carci- noma recurrence rates provided. No morbidity data reported.

Other bias Unclear risk Differences in white and red blood cell, platelet counts and total serum choles- terol between the two groups; funding not reported.

Intent to treat analysis Low risk All patients accounted for.

Baseline imbalance? High risk Controls had more abnormal hemograms and other laboratory tests.

Early stopping? Unclear risk No sample size calculation presented and no explanation regarding why trial stopped when it was.

Takeshita 2009

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Methods Randomised trial comparing branched chain amino acid supplement to no supplement in outpatients with cirrhosis. Geographical location: Bangkok, Thailand. Abstract published 2000.

Participants Inclusion criteria: Patients with cirrhosis documented by biopsy and/or "clear cut evidence"; no current hepatic encephalopathy, gastrointestinal bleeding, uncontrolled ascites, spontaneous bacterial peri- tonitis, hepatocellular carcinoma. Exclusion criteria: Diabetes mellitus, renal failure, severe cardiopulmonary disease. 30 patients (22 male/8 female [1 other dropout], mean age 53).

Interventions Intervention group received branched-chain amino acid supplement (Aminoleban EN®) containing 150 gm protein plus 40 gm protein/2000 kcal diet; Control group received standard 80 gram protein/2000 kcal diet. Duration of therapy 4 weeks.

Outcomes Appearance gastrointestinal bleeding/hepatic encephalopathy, bilirubin, body weight, midarm mus- cle circumference. Probably no mortality but not explicitly stated. Data regarding infections limited to episodes of spontaneous bacterial peritonitis, but this probably did not include all infections and not used in meta-analysis. Data regarding duration of stay in hospital/intensive care unit collected but not specifically reported; data regarding septic morbidity, six-month survival (after transplant), major non- infectious complications all supposed to be collected similarly not specifically reported (other than noting no difference).

Category of study Supplements/Medical.

Sample size calculation Not reported if done.

Full paper or abstract only Full paper.

Notes Request for further information sent to senior author (Dr. Willayalertpanya) via e-mail (wsupeech@pio- neer.chula.ac.th) on September 19, 2011. E-mail address failed and letter sent on September 26, 2011 to Assoc Prof Supeecha Wittayalertpanya, Department of Pharmacology, Faculty of Medicine, Chula- longkorn University, Bangkok 10330, Thailand. Response 10/16/11 stated that Dr Tangkijvanich was contacted but that he had no recollection of any details about trial.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "patients were randomised".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk One dropout from treatment group accounted for.

Selective reporting (re- porting bias)

High risk No mortality data. Other data that were supposed to be collected were not available (see note in Outcomes above.)

Other bias Unclear risk Funder of trial not reported. Company acknowledged for supplying supple- ments, but this alone not sufficient to judge this parameter as inadequate.

Tangkijvanich 2000

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Intent to treat analysis High risk Could not be done.

Baseline imbalance? Low risk No differences in per protocol groups.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Tangkijvanich 2000 (Continued)

Methods Randomised trial comparing parenteral nutrition to no parenteral nutrition in patients with chronic liv- er disease hospitalized for surgery. Geographical location Wuhan, China. Study published 2003.

Participants Inclusion criteria: Patients with chronic liver damage (Childs B or C, need for at least 7 days nutritional support postoperatively. Exclusion criteria: Presence of factors that affect metabolism other than those related to underlying disease. 70 patients (no sex or age data provided).

Interventions Intervention group received parenteral nutrition (30 kcal/kg [carbohydrate and lipid], 0.16 gm/kg nitro- gen per day for at least 7 days postoperatively); Controls received no nutritional support. Duration > 7 days.

Outcomes Mortality, appearance ascites, bilirubin, weight, midarm circumference, nitrogen balance.

Category of study Parenteral nutrition/Surgical (postoperative).

Sample size calculation None reported if done.

Full paper or abstract only Full paper.

Notes E-mail sent to Dr Hu on September 14, 2011 ([email protected]) after one sent to Dr Zheng on September 13, 2011 ([email protected]) failed; the former failed as well. Letter sent to Dr Hu by US mail on September 14, 2011 (Dr Qing-Gang Hu, Department of Surgery, Xiehe Hospital, Tongji Med- ical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China). No response has been received as of March 20, 2012.

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- tion (selection bias)

Unclear risk Only states "randomly assigned".

Allocation concealment (selection bias)

Unclear risk No details.

Blinding (performance bias and detection bias) All outcomes

High risk Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk Numbers somewhat disparate in paper.

Selective reporting (re- porting bias)

Low risk Mortality and morbidity outcomes reported.

Zheng 2003

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Other bias Unclear risk Funding source not reported.

Intent to treat analysis Unclear risk Somewhat disparate numbers reported in paper.

Baseline imbalance? Low risk Superficially adequate.

Early stopping? Unclear risk No sample size calculation and unknown why stopped.

Zheng 2003 (Continued)

gm = gram. ckal = (EU) kilocalories; (U.S) calories. cc = cum cibo (with food). HCC = hepatocellular carcinoma. Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Abad Lacruz 1990 Randomized trial comparing enteral to parenteral nutrition; no untreated control group.

Adams 2011 Only a protein supplement was assessed (not a complete supplement).

Akoglu 2008 Randomized trial assessing folic acid.

Al Mardini 2006 Not randomized trial.

Alvarez 2004 BCAA solution compared to casein; no complete nutritional formula.

Andreone 2001 Randomized trial assessing vitamin E.

Awad 2010 Randomized trial comparing an Incomplete formulation immediately post op (for only 2 doses on days 0 and 1).

Badalamenti 1995 Randomized trial comparing fish oil to standard oil.

Baldermann 1988 Randomized trial comparing two parenteral formulations with different lipid constituents.

Barle 1997 Randomized trial in patients undergoing cholecystectomy (no liver disease) who only received 8 hours of parenteral nutrition; no clinical outcomes reported.

Bartels 2004 Randomized trial comparing vitamin E to placebo; no complete nutrient formulation.

Bernardi 1981 Review article.

Bianchi 1993 Randomized trial comparing animal to vegetable protein; no artificial nutrition formulation.

Bories 1994 Not randomized trial; no control group.

Brans 1987 Randomized trial comparing different doses of lipid.

Bresci 1993 Randomized trial comparing zinc to no zinc.

Buchmiller 1993 Randomized trial comparing two different parenteral nutrition formulations; no untreated control group.

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Study Reason for exclusion

Cabre 2000 Randomized trial comparing enteral nutrition to steroids in patients with alcoholic hepatitis; no un- treated control group.

Campo 1997 Randomized trial comparing oral BCAAs to oral casein (no artificial nutrition); no clinical data.

Cao 2007 Randomized trial comparing growth hormone to no growth hormone; both groups received par- enteral nutrition.

Cerra 1983 Randomized trial comparing BCAA solution to neomycin; both groups received parenteral nutri- tion.

Cerra 1985 Randomized trial comparing BCAA solution to neomycin; both groups received parenteral nutri- tion.

Cerwenka 1998 Randomized trial comparing antioxidants.

Chelarescu 2003 Randomized trial comparing enteral to parenteral nutrition.

Chin 1992 Randomized crossover trial comparing BCAA and standard amino acid solution.

Christie 1985 Randomized trial comparing BCAAs to casein; both arms received artifical nutrition.

Clarke 2004 Two different enteral nutrition formulas compared; no untreated group.

Conti 1971 Not randomized trial.

Cortez Pinto 1990 No indication that trial was randomized.

Cunha 2004 Uncontrolled observational study.

Córdoba Comparison of branched-chain amino acids versus maltodextrin added to meals; no nutrition sup- port to either group.

Córdoba 2004 Randomized trial comparing low protein to standard protein diet.

De Antoni 1984 No evidence that trial was randomized.

de la Maza 1995 Randomized trial comparing vitamin E to placebo.

de Luis 2010 Randomized trial comparing two different diets in patients with fatty liver disease.

De-Fang 2011 Both arms received enteral nutrition.

Di Cecco 1997 Randomized trial comparing BCAA solution to casein.

Diehl 1985 Controls received same intravenous infusion as treated group except no amino acids, so trial actu- ally only compared the use of an infused amino acid formulation.

Dionigi 1984 Randomized trial comparing different amino acid solutions; all patients received parenteral nutri- tion.

Egberts 1981 Randomized trial comparing two different parenteral nutrition formulations; no untreated group.

Egberts 1985 Randomized trial comparing BCAAs to casein; neither treatment group received artificial nutrition.

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Study Reason for exclusion

Egberts 1988 Randomized trial of BCAA solution; no artificial nutrition provided.

Eriksson 1982 Randomized trial comparing BCAAs to placebo; neither treatment group received artificial nutri- tion.

Ferenci 1981 Randomized trial comparing BCAAs to keto acids; no artificial nutrition.

Fiaccadori 1984 Randomized trial BCAA vs lactulose; both arms received hypertonic glucose.

Fiaccadori 1988 Randomized trial oral BCAAs versus casein; neither group received artificial nutrition.

Freeman 1983 Randomized trial BCAA vs no BCAA; neither treatment group received artificial nutrition.

Fukushima 2003 Nocturnal branched-chain ingestion compared to daytime ingestion; no nutrition support program and no untreated control group.

Galloway 1987 Randomized trial comparing two different parenteral nutrition formulations; no untreated control group.

Gavazzl 1999 Not a controlled trial.

Glynn 1988 Randomized trial comparing lipid to no lipid; all patients received parenteral nutrition.

Grungreiff 1993 Randomized trial comparing BCAAs versus BCAAs and valine; no untreated control patients.

Grungreiff 2001 Randomized trial of l-ornithine l-aspartate for encephalopathy.

Guarnieri 1982 Randomized trial comparing BCAA-rich amino acid solution to equicaloric glucose (1120 calories).

Guarnieri 1984 Supplements containing BCAAs compared to lactulose in patients with encephalopathy; no true untreated control group.

Habu 2003 BCAAs compared to no treatment; no artificial nutrition provided to any patients.

Habu 2009 Only branched-chain amino acids assessed; no complete formulation employed.

Haji 2008 No clinical outcomes reported.

Hayaishi 2011 Retrospective study (not randomized).

Hayashi 2007 BCAAs with or without zinc compared; no artificial nutrition provided to any patients.

Herlong 1980 Randomized trial comparing BCAAs to ornithine salts of BCAAs; no artificial nutrition provided to either group.

Hernandez-Guerra 2006 Trial compared ascorbic acid to no ascorbic acid; no artificial nutrition provided.

Holdsworth 1984 Different BCAA solutions in 10% dextrose compared to 10% dextrose in patients receiving enteral nutrition; no clinical data.

Holm 1981 Randomized trial comparing two different amino acid supplements; no artificial nutrition provided.

Holm 1984 Study in healthy people; no control group.

Holm 2000 No clinical data.

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Study Reason for exclusion

Horst 1984 Randomized trial comparing BCAA supplements to increasing protein intake; no true control group given 'standard' diet.

Huisman 2011 Most of the patients in the 'preventive' group only received dietary advice.

Hwang 1988 Randomized trial assessing BCAA solution with 10% dextrose, but only 500 cc provided daily; no group received artificial nutrition.

Ichida 1995 Not randomized trial.

Ikegami 2012 Not a randomized trial.

Ilan 2000 Trial compared different diets; no artificial nutrition provided.

Itou 2009 Not randomized trial.

Itou 2011 Supplements only provided on evening before procedure.

Jentschura 1996 Not randomized trial.

Jiang 2001 Randomized trial comparing standard to specialized.

Jiang 2007 Two parenteral nutrition formulations compared; no true control group.

Jonung 1987 Trial compared animal to vegetable protein; no artificial nutrition provided to either group.

Kaido 2010 Not randomized trial.

Kakumitsu 1998 Randomized trial comparing arginine infusion to no arginine infusion; no artificial nutrition provid- ed.

Kanematsu 1988 Randomized trial comparing BCAA-based to standard amino acid-based parenteral nutrition; no untreated control group.

Katsumi 2005 Three different supplements compared; no untreated control group.

Kawaguchi 2008 Trial only assessed one dose of supplement prior to endoscopy.

Kawamura 2009 BCAAs compared to no amino acids; no artificial nutrition provided to either group.

Keshavarzian 1984 Trial comparing two different protein diets; no artificial nutrition provided to either group.

Kircheis 1997 Trial comparing l-ornithine l-aspartate to no such treatment; no artificial nutrition provided to ei- ther group.

Kobayashi 2008 BCAA granules compared to no treatment; no artificial nutrition provided to either group.

Krasnoff 2006 Randomized trial of dietary counseling and exercise; no artificial nutrition provided to any patients.

Kuroda 2010 Trial not randomized; patients chose the group into which they were placed.

Kuse 1990 Randomized trial of the use of different lipids in patients receiving parenteral nutrition; no untreat- ed control group.

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Study Reason for exclusion

Kuse 2002 Randomized trial comparing two different parenteral nutrition formulations; no untreated control group.

Labadie 1994 Randomized trial comparing zinc to no zinc; no artificial nutrition provided to either group.

LaTerre 2007 Parenteral nutrition compared to enteral nutrition; no untreated control group.

Leon 2009 Editorial commentary.

Les 2011 Randomized trial comparing BCAA compound to maltodextrin; supplement incomplete.

Luntz 2005 Randomized trial comparing glycine to no glycine after liver transplantation.

Mager 2006 Trial comparing different doses of BCAAs.

Makay 2007 Randomized trial comparing early to delayed parenteral nutrition; no untreated control group.

Malaguarnera 2009 All patients received branched chain amino acids, but no calories (no artificial nutrition); patients randomized to receiving or not receiving l-acetycarnitine.

Mangiante 2002 Randomized trial comparing parenteral to enteral nutrition.

Manguso 2005 Randomized trial comparing two different diets; no artificial nutrition provided to any patients.

Marchesini 1980 Not randomized trial.

Marchesini 1990 Trial comparing BCAA to protein; no artificial nutrition provided to either group.

Marchesini 2003 Randomized trial comparing BCAAs to placebo; no artificial nutrition provided to either group.

Marchini 1983 Randomized trial comparing two different intragastric formulations to controls who received solid food; the patients were chronic alcoholics, but most of them did not have liver disease.

Marra 1998 Randomized trial comparing two different fatty acids.

McGhee 1983 Randomized trial comparing two different supplements; no untreated control group.

Mendenhall 1985 Not randomized trial.

Mendenhall 1993 Randomized trial comparing supplement plus oxandrolone to placebo; treated group received more than just supplements.

Mezey 1991 Controls received same intravenous infusion as treated group except no amino acids, so trial actu- ally only compared the use of an infused amino acid formulation.

Michel 1985 Randomized trial comparing two different parenteral nutrition formulations; no untreated control group.

Mochizuki 2000 Retrospective study.

Moreno 2010 Both groups received enteral nutrition; variable changed was receipt or non-receipt of n-acetycys- teine.

Morioka 1983 No clinical data; unclear if randomized or not.

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Study Reason for exclusion

Muto 1984 Randomized trial comparing BCAA supplements; no artificial nutrition provided.

Muto 1991 Trial compared BCAAs to diet; no artificial nutrition provided to either group.

Muto 2005 Randomized trial assessing BCAAs alone; neither group received artificial nutrition.

Nagayama 1989 Randomized trial comparing lipid-based to carbohydrate-based parenteral nutrition; no untreated control group.

Nasrallah 1980 Randomized trial comparing solution containing amino acids and other nutrients to a solultion containing the other nutrients (only compared amino acid solution).

Ndraha 2011 Randomized trial comparing l-ornithine l-aspartate to no treatment in patients with hepatic en- cephalopathy.

Nickkholgh 2007 Although trial only in protocol stage, is ineligible because both arms received oral supplements; no true control group.

Nielsen 1995 Uncontrolled study.

Nishiguchi 2004 Randomized trial BCAA granules versus no granules; no artificial nutrition provided to patients.

Nishizaki 1996 Patients in both arms received intravenous amino acids.

Nordenstrom 1995 Two different lipid formulations compared; no clinical outcomes.

O'Keefe 1987 Trial compared enteral and parenteral nutrition; no untreated control group.

Okabayashi 2008 Not randomized; retrospective analysis.

Okabayashi 2010 Patients in both arms received parenteral nutrition postoperatively.

Okita 1985 Comparison of different diets; no artificial nutrition provided; non-randomized crossover random- ized.

Okuno 1985 Trial comparing two different parenteral nutrition formulations; no untreated group.

Olde Damink 2007 Trial comparing isoleucine to no isoleucine; artificial nutrition not provided to either group.

Panella 1987 BCAA compared to casein; no artificial nutrition provided to either group.

Pierrugus Some control patients received parenteral nutrition.

Plank 2005 Not randomized.

Plank 2008 Randomized trial comparing daytime to nocturnal supplements; no untreated control group.

Plauth 1993 Randomized crossover trial assessing BCAAs only; no artificial nutrition provided.

Protheroe 1996 Two different feeding formulations compared.

Puglionisi 1984 Only branched chain amino acids infused (no nutrition support program).

Rakette 1981 No evidence that trial randomized.

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Study Reason for exclusion

Rayes 2005 Trial comparing different formulations; all patients received enteral nutrition.

Riederer 1980 No clinical data provided; unclear if trial randomized.

Rifai 2006 All patients received parenteral nutrition; randomization to bile acid or not.

Riggio 1984 Trial comparing BCAAs to lactulose; no artificial nutrition provided.

Rocchi 1985 Trial comparing two different amino acid formulations; all patients received hypertonic glucose.

Rossi Fanelli 1986 BCAA-based parenteral nutrition compared to lactulose; no untreated control group.

Sakaida 2004 Randomized trial of two different BCAA-based supplements; no untreated control group.

Sato 2005 Randomized trial comparing Aminoleben® to BCAAs alone; no untreated control arm.

Schafer 1981 Randomized trial comparing BCAA to other diets; no artificial nutrition provided.

Shirabe 1997 Trial comparing enteral to parenteral nutrition; no untreated control group.

Shirabe 2011 Not randomized trial, but retrospective study.

Sieg 1983 Crossover trial BCAAs versus placebo; no artificial nutrition provided to patients.

Soriano No nutrition support; all patients received branched-chain amino acids and randomized to exercise or no exercise.

Strauss 1986 BCAA-based parenteral nutrition compared to neomycin; no untreated control group.

Striebel 1979 No evidence that trial randomized.

Sugawara 2011 Not randomized trial.

Suzuki 2004 Review article.

Swart 1981 Randomized trial comparing different amino acid preparations; no artificial nutrition provided.

Swart 1989 Randomized crossover trial of three meals versus 4 to6 meals; no artificial nutrition provided.

Tai 2011 Enteral nutrition compared to group that received supplements; no true control group.

Tang 2007 Trial assessing glutamine and/or growth hormone; all patients received parenteral nutrition.

Tayek Trial identified on Clionical Trials.gov; is in process, but is only assessing utility of arginine.

Togo 2005 Randomized trial of BCAAs versus no BCAAs; no artificial nutrition provided.

Tomiya 2002 Trial comparing BCAAs to increased protein in diet; no artificial nutrition provided and no clinical data.

Tschepe 1985 Randomized crossover trial of BCAAs versus protein; no artificial nutrition provided.

Tsuchiya 2007 Trial comparing BCAAs with diet compared to equicaloric/equinitrogenous diet; no artificial nutri- tion provided and trial may not have been randomized.

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Study Reason for exclusion

Uribe 1982 Crossover trial comparing animal and vegetable protein; no artificial nutrition provided.

Valdivieso 1989 BCAA-based versus standard amino acid-based parenteral nutrition; no untreated control group and no clinical outcomes reported.

Vilar-Gomez 2009 Randomized trial comparing 'supplement' containing amino acids, vitamins, and minerals to no supplement; supplement was not complete.

Vilstrup 1990 BCAA-based parenteral nutrition compared to hypertonic glucose; no untreated control group.

Wahren 1983 Randomized trial comparing BCAAs to glucose; all patients received intravenous glucose and lipid, so no true untreated control group.

Walker 1982 Randomized crossover trial comparing keto-analogs of BCAAs versus placebo; no artificial nutrition provided.

Wang 2011 Two different parenteral nutrition formulations compared; no untreated control group.

Watanabe 1983 Non-randomized crossover trial.

Watanabe 1995 Trial comparing different forms of rice; no artificial nutrition provided.

Weber 1990 Trial comparing two different amino acid solutions; unclear if randomized and no clinical out- comes reported.

Wicks 1994 Trial comparing enteral to parenteral nutrition; all patients received artificial nutrition.

Yamamoto 2005 Trial comparing BCAAs to placebo; no artificial nutrition provided.

Yamana-Okumuru 2010 Randomized trial comparing an additional amount of food at night to no treatment.

Yang 2011 Randomized trial comparing two different parenteral nutrition formulations; no untreated control group.

Yoshiji 2011 Only branched-chain amino acids were assessed; no complete nutritional formulation employed.

Yu 2007 Randomized trial comparing growth hormone to no growth hormone; all patients received artificial nutrition.

Zhang 2003 Two different amino acid preparations compared; no clinical outcomes reported.

Zhang 2005 Randomized trial comparing enteral to parenteral nutrition.

Zheng EN Some of the enteral nutrition patients received parenteral nutrition.

Zhuang 2003 Randomized trial comparing growth hormone to no growth hormone; all patients received par- enteral nutrition.

BCAA = branched chain amino acid Characteristics of studies awaiting assessment [ordered by study ID]

Methods

Caballera Rovira 1987

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Participants

Interventions

Outcomes

Notes Paper published in Spanish, and information in English abstract inadequate to use, as could not even determine if the trial is randomised. Requires translation.

Caballera Rovira 1987 (Continued)

Methods

Participants

Interventions

Outcomes

Notes Study presented at conference in Bangkok, and only information was citation identified in EM- BASE search; no quantitative data.

Chen 2011

Methods

Participants

Interventions

Outcomes

Notes Paper published in German and need translation.

Fink 1978

Methods

Participants

Interventions

Outcomes

Notes Abstract or very short paper published in German; no English abstract and need transla- tion.

Hartung 1989

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Methods

Participants

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Outcomes

Notes Paper published in Russian and information in English abstract inadequate for inclusion. Re- quires translation.

Khlynov 2009

Methods

Participants

Interventions

Outcomes

Notes No clinical data provided in abstract nor was it clear how the branched-chain amino acids were formulated or delivered

Korenaga 2011

Methods

Participants

Interventions

Outcomes

Notes Paper published in German and information in brief English abstract inadequate for inclusion; un- clear if even randomised. Requires translation.

Leweling 1980

Methods

Participants

Interventions

Outcomes

Notes Only abstract available and unclear how control group treated; no quantitative data.

Macias-Rosales 2010

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Methods

Participants

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Notes Paper published in Chinese and information in English abstract largely described biochemical outcomes; needs translation.

Zhu-ming 2001

Characteristics of ongoing studies [ordered by study ID]

Trial name or title

Methods

Participants

Interventions

Outcomes

Starting date

Contact information

Notes Trial identified on ClinicalTrials.gov; no apparent pub- lication yet.

Mao

Trial name or title

Methods

Participants

Interventions

Outcomes

Starting date

Contact information

Notes Trial identified on ClinicalTrials.gov; no apparent pub- lication yet.

Pirlich

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Trial name or title

Methods

Participants

Interventions

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Starting date

Contact information

Notes Trial identified on ClinicalTrials.gov; no apparent pub- lication yet.

Seguin

Trial name or title

Methods

Participants

Interventions

Outcomes

Starting date

Contact information

Notes Trial identified on ClinicalTrials.gov; no apparent pub- lication yet.

Van Erpecum

D A T A A N D A N A L Y S E S Comparison 1. Mortality

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 28 1668 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.75, 1.08]

2 Parenteral nutrition 9 465 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.29, 0.98]

2.1 Medical trials 4 158 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.28, 1.62]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

2.2 Surgical trials 5 307 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.18, 1.02]

3 Enteral nutrition 6 275 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.47, 1.20]

3.1 Medical trials 5 215 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.50, 1.33]

3.2 Surgical trials 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.03, 2.41]

4 Supplements 13 928 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.84, 1.27]

4.1 Medical trials 9 710 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.87, 1.33]

4.2 Surgical trials 4 218 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.25, 1.65]

5 Medical trials 18 1083 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.82, 1.20]

5.1 Parenteral nutrition 4 158 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.28, 1.62]

5.2 Enteral nutrition 5 215 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.50, 1.33]

5.3 Supplements 9 710 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.87, 1.33]

6 Surgical trials 10 585 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.27, 0.89]

6.1 Parenteral nutrition 5 307 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.18, 1.02]

6.2 Enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.03, 2.41]

6.3 Supplements 4 218 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.25, 1.65]

7 Alcoholic hepatitis 7 300 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.50, 1.21]

7.1 Parenteral nutrition 3 118 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.25, 1.62]

7.2 Enteral nutrition 2 95 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.61, 1.99]

7.3 Supplements 2 87 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.18, 1.23]

8 Cirrhosis 9 349 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.28, 0.97]

8.1 Parenteral nutrition 2 60 Risk Ratio (M-H, Fixed, 95% CI) 0.6 [0.08, 4.27]

8.2 Enteral nutrition 3 120 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.19, 1.18]

8.3 Supplements 4 169 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.22, 1.39]

9 HCC 6 673 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.93, 1.42]

9.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.19, 1.47]

9.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

9.3 Supplements 5 549 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.98, 1.52]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

10 Abstracts excluded 25 1348 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.57, 0.92]

10.1 Medical trials - parenteral nutrition 4 158 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.28, 1.62]

10.2 Surgical trials - parenteral nutrition 5 307 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.18, 1.02]

10.3 Medical trials - enteral nutrition 4 152 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.51, 1.38]

10.4 Surgical trials - enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.03, 2.41]

10.5 Medical trials - supplements 8 477 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.60, 1.12]

10.6 Surgical trials - supplements 3 194 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.25, 1.65]

11 Surgical trials without transplant pa- tients

7 410 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.30, 1.20]

11.1 Parenteral nutrition 3 214 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.18, 1.17]

11.2 Enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.03, 2.41]

11.3 Supplements 3 136 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.37, 5.98]

12 Intent to treat - best-case scenario for intervention

24 1539 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.61, 0.86]

12.1 Medical trials - parenteral nutrition 4 170 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.19, 0.96]

12.2 Surgical trials - parenteral nutrition 4 268 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.10, 0.49]

12.3 Medical trials - enteral nutrition 5 215 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.50, 1.33]

12.4 Surgical trials - enteral nutrition 1 64 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.03, 2.12]

12.5 Medical trials - supplements 8 690 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.74, 1.12]

12.6 Surgical trials - supplements 2 132 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.23, 1.52]

13 Intent to treat - worst-case scenario for intervention

24 1539 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.99, 1.40]

13.1 Medical trials - parenteral nutrition 4 170 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.56, 2.50]

13.2 Surgical trials - parenteral nutrition 4 268 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.63, 2.25]

13.3 Medical trials - enteral nutrition 5 215 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.50, 1.33]

13.4 Surgical trials - enteral nutrition 1 64 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [0.37, 4.23]

13.5 Medical trials - supplements 8 690 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [1.03, 1.56]

13.6 Surgical trials - supplements 2 132 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.50, 2.96]

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Analysis 1.1. Comparison 1 Mortality, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Achord 1987 1/14 3/14 1.84% 0.33[0.04,2.83]

Bonkovsky 1991 0/9 0/12 Not estimable

Bunout 1989 2/17 5/19 2.89% 0.45[0.1,2.01]

Cabre 1990 2/16 9/19 5.04% 0.26[0.07,1.05]

Calvey 1985 16/42 7/22 5.63% 1.2[0.58,2.47]

DeLedinghen 1997 3/12 2/10 1.34% 1.25[0.26,6.07]

Fan 1994 5/64 9/60 5.69% 0.52[0.19,1.47]

Foschi 1986 1/28 4/32 2.29% 0.29[0.03,2.41]

Hendry 2010 0/30 2/38 1.36% 0.25[0.01,5.05]

Hirsch 1993 3/26 6/25 3.75% 0.48[0.13,1.72]

Humbert 1988 2/27 4/22 2.7% 0.41[0.08,2.02]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Kearns 1992 5/16 5/15 3.16% 0.94[0.34,2.6]

Kobashi 2006 63/119 44/114 27.54% 1.37[1.03,1.83]

LeCornu 2000 2/42 7/40 4.39% 0.27[0.06,1.23]

Meng 1999 4/21 1/23 0.58% 4.38[0.53,36.13]

Nakaya 2007 1/25 0/23 0.32% 2.77[0.12,64.76]

Naveau 1986 1/20 1/20 0.61% 1[0.07,14.9]

Norman 2008 1/31 2/32 1.21% 0.52[0.05,5.41]

Poon 2004 0/41 3/43 2.09% 0.15[0.01,2.81]

Puglionisi 1985 0/10 1/10 0.92% 0.33[0.02,7.32]

Qiu 2009 0/44 0/21 Not estimable

Reilly 1990 1/18 2/10 1.58% 0.28[0.03,2.7]

San-In Group 1997 34/67 32/65 19.91% 1.03[0.73,1.45]

Simon 1988 5/33 7/36 4.1% 0.78[0.27,2.22]

Takeshita 2009 0/28 0/28 Not estimable

Zheng 2003 0/40 1/30 1.05% 0.25[0.01,5.98]

Total (95% CI) 863 805 100% 0.9[0.75,1.08]

Total events: 152 (Treatment), 157 (Control)

Heterogeneity: Tau2=0; Chi2=27.9, df=22(P=0.18); I2=21.15%

Test for overall effect: Z=1.11(P=0.27)

Favors treatment 2000.005 100.1 1 Favors control

Analysis 1.2. Comparison 1 Mortality, Outcome 2 Parenteral nutrition.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.2.1 Medical trials

Achord 1987 1/14 3/14 11.64% 0.33[0.04,2.83]

Bonkovsky 1991 0/9 0/12 Not estimable

Naveau 1986 1/20 1/20 3.88% 1[0.07,14.9]

Simon 1988 5/33 7/36 25.99% 0.78[0.27,2.22]

Subtotal (95% CI) 76 82 41.51% 0.67[0.28,1.62]

Total events: 7 (Treatment), 11 (Control)

Favors treatment 1000.01 100.1 1 Favors control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=0.57, df=2(P=0.75); I2=0%

Test for overall effect: Z=0.88(P=0.38)

1.2.2 Surgical trials

Fan 1994 5/64 9/60 36.06% 0.52[0.19,1.47]

Puglionisi 1985 0/10 1/10 5.82% 0.33[0.02,7.32]

Qiu 2009 0/44 0/21 Not estimable

Reilly 1990 1/18 2/10 9.98% 0.28[0.03,2.7]

Zheng 2003 0/40 1/30 6.63% 0.25[0.01,5.98]

Subtotal (95% CI) 176 131 58.49% 0.43[0.18,1.02]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=0.41, df=3(P=0.94); I2=0%

Test for overall effect: Z=1.92(P=0.05)

Total (95% CI) 252 213 100% 0.53[0.29,0.98]

Total events: 13 (Treatment), 24 (Control)

Heterogeneity: Tau2=0; Chi2=1.52, df=6(P=0.96); I2=0%

Test for overall effect: Z=2.03(P=0.04)

Test for subgroup differences: Chi2=0.52, df=1 (P=0.47), I2=0%

Favors treatment 1000.01 100.1 1 Favors control

Analysis 1.3. Comparison 1 Mortality, Outcome 3 Enteral nutrition.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.3.1 Medical trials

Cabre 1990 2/16 9/19 27.01% 0.26[0.07,1.05]

Calvey 1985 16/42 7/22 30.16% 1.2[0.58,2.47]

DeLedinghen 1997 3/12 2/10 7.16% 1.25[0.26,6.07]

Kearns 1992 5/16 5/15 16.94% 0.94[0.34,2.6]

Norman 2008 1/31 2/32 6.46% 0.52[0.05,5.41]

Subtotal (95% CI) 117 98 87.74% 0.81[0.5,1.33]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=4.15, df=4(P=0.39); I2=3.7%

Test for overall effect: Z=0.83(P=0.41)

1.3.2 Surgical trials

Foschi 1986 1/28 4/32 12.26% 0.29[0.03,2.41]

Subtotal (95% CI) 28 32 12.26% 0.29[0.03,2.41]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.15(P=0.25)

Total (95% CI) 145 130 100% 0.75[0.47,1.2]

Total events: 28 (Treatment), 29 (Control)

Heterogeneity: Tau2=0; Chi2=5.28, df=5(P=0.38); I2=5.33%

Test for overall effect: Z=1.19(P=0.23)

Test for subgroup differences: Chi2=0.88, df=1 (P=0.35), I2=0%

Favors treatment 10000.001 100.1 1 Favors control

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Analysis 1.4. Comparison 1 Mortality, Outcome 4 Supplements.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.4.1 Medical trials

Bunout 1989 2/17 5/19 4.42% 0.45[0.1,2.01]

Hirsch 1993 3/26 6/25 5.72% 0.48[0.13,1.72]

Humbert 1988 2/27 4/22 4.12% 0.41[0.08,2.02]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 63/119 44/114 42.02% 1.37[1.03,1.83]

Nakaya 2007 1/25 0/23 0.49% 2.77[0.12,64.76]

Poon 2004 0/41 3/43 3.2% 0.15[0.01,2.81]

San-In Group 1997 34/67 32/65 30.37% 1.03[0.73,1.45]

Takeshita 2009 0/28 0/28 Not estimable

Subtotal (95% CI) 362 348 90.33% 1.08[0.87,1.33]

Total events: 105 (Treatment), 94 (Control)

Heterogeneity: Tau2=0; Chi2=9.16, df=6(P=0.16); I2=34.5%

Test for overall effect: Z=0.68(P=0.5)

1.4.2 Surgical trials

Hendry 2010 0/30 2/38 2.07% 0.25[0.01,5.05]

Ishikawa 2010 0/11 0/13 Not estimable

LeCornu 2000 2/42 7/40 6.7% 0.27[0.06,1.23]

Meng 1999 4/21 1/23 0.89% 4.38[0.53,36.13]

Subtotal (95% CI) 104 114 9.67% 0.65[0.25,1.65]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=2(P=0.09); I2=58.34%

Test for overall effect: Z=0.91(P=0.36)

Total (95% CI) 466 462 100% 1.03[0.84,1.27]

Total events: 111 (Treatment), 104 (Control)

Heterogeneity: Tau2=0; Chi2=15.3, df=9(P=0.08); I2=41.19%

Test for overall effect: Z=0.32(P=0.75)

Test for subgroup differences: Chi2=1.07, df=1 (P=0.3), I2=6.95%

Favors treatment 10000.001 100.1 1 Favors control

Analysis 1.5. Comparison 1 Mortality, Outcome 5 Medical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.5.1 Parenteral nutrition

Achord 1987 1/14 3/14 2.24% 0.33[0.04,2.83]

Bonkovsky 1991 0/9 0/12 Not estimable

Naveau 1986 1/20 1/20 0.75% 1[0.07,14.9]

Simon 1988 5/33 7/36 5% 0.78[0.27,2.22]

Subtotal (95% CI) 76 82 7.98% 0.67[0.28,1.62]

Total events: 7 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.57, df=2(P=0.75); I2=0%

Test for overall effect: Z=0.88(P=0.38)

Favors treatment 10000.001 100.1 1 Favors control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.5.2 Enteral nutrition

Cabre 1990 2/16 9/19 6.14% 0.26[0.07,1.05]

Calvey 1985 16/42 7/22 6.85% 1.2[0.58,2.47]

DeLedinghen 1997 3/12 2/10 1.63% 1.25[0.26,6.07]

Kearns 1992 5/16 5/15 3.85% 0.94[0.34,2.6]

Norman 2008 1/31 2/32 1.47% 0.52[0.05,5.41]

Subtotal (95% CI) 117 98 19.94% 0.81[0.5,1.33]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=4.15, df=4(P=0.39); I2=3.7%

Test for overall effect: Z=0.83(P=0.41)

1.5.3 Supplements

Bunout 1989 2/17 5/19 3.52% 0.45[0.1,2.01]

Hirsch 1993 3/26 6/25 4.56% 0.48[0.13,1.72]

Humbert 1988 2/27 4/22 3.29% 0.41[0.08,2.02]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 63/119 44/114 33.53% 1.37[1.03,1.83]

Nakaya 2007 1/25 0/23 0.39% 2.77[0.12,64.76]

Poon 2004 0/41 3/43 2.55% 0.15[0.01,2.81]

San-In Group 1997 34/67 32/65 24.24% 1.03[0.73,1.45]

Takeshita 2009 0/28 0/28 Not estimable

Subtotal (95% CI) 362 348 72.08% 1.08[0.87,1.33]

Total events: 105 (Treatment), 94 (Control)

Heterogeneity: Tau2=0; Chi2=9.16, df=6(P=0.16); I2=34.5%

Test for overall effect: Z=0.68(P=0.5)

Total (95% CI) 555 528 100% 0.99[0.82,1.2]

Total events: 139 (Treatment), 130 (Control)

Heterogeneity: Tau2=0; Chi2=15.86, df=14(P=0.32); I2=11.75%

Test for overall effect: Z=0.09(P=0.93)

Test for subgroup differences: Chi2=1.91, df=1 (P=0.39), I2=0%

Favors treatment 10000.001 100.1 1 Favors control

Analysis 1.6. Comparison 1 Mortality, Outcome 6 Surgical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.6.1 Parenteral nutrition

Fan 1994 5/64 9/60 31.88% 0.52[0.19,1.47]

Puglionisi 1985 0/10 1/10 5.15% 0.33[0.02,7.32]

Qiu 2009 0/44 0/21 Not estimable

Reilly 1990 1/18 2/10 8.82% 0.28[0.03,2.7]

Zheng 2003 0/40 1/30 5.86% 0.25[0.01,5.98]

Subtotal (95% CI) 176 131 51.71% 0.43[0.18,1.02]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=0.41, df=3(P=0.94); I2=0%

Test for overall effect: Z=1.92(P=0.05)

1.6.2 Enteral nutrition

Favors treatment 10000.001 100.1 1 Favors control

100

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Foschi 1986 1/28 4/32 12.81% 0.29[0.03,2.41]

Subtotal (95% CI) 28 32 12.81% 0.29[0.03,2.41]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.15(P=0.25)

1.6.3 Supplements

Hendry 2010 0/30 2/38 7.6% 0.25[0.01,5.05]

Ishikawa 2010 0/11 0/13 Not estimable

LeCornu 2000 2/42 7/40 24.61% 0.27[0.06,1.23]

Meng 1999 4/21 1/23 3.28% 4.38[0.53,36.13]

Subtotal (95% CI) 104 114 35.48% 0.65[0.25,1.65]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=2(P=0.09); I2=58.34%

Test for overall effect: Z=0.91(P=0.36)

Total (95% CI) 308 277 100% 0.49[0.27,0.89]

Total events: 13 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=5.64, df=7(P=0.58); I2=0%

Test for overall effect: Z=2.33(P=0.02)

Test for subgroup differences: Chi2=0.67, df=1 (P=0.71), I2=0%

Favors treatment 10000.001 100.1 1 Favors control

Analysis 1.7. Comparison 1 Mortality, Outcome 7 Alcoholic hepatitis.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.7.1 Parenteral nutrition

Achord 1987 1/14 3/14 8.6% 0.33[0.04,2.83]

Bonkovsky 1991 0/9 0/12 Not estimable

Simon 1988 5/33 7/36 19.19% 0.78[0.27,2.22]

Subtotal (95% CI) 56 62 27.79% 0.64[0.25,1.62]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=0.49, df=1(P=0.48); I2=0%

Test for overall effect: Z=0.94(P=0.35)

1.7.2 Enteral nutrition

Calvey 1985 16/42 7/22 26.34% 1.2[0.58,2.47]

Kearns 1992 5/16 5/15 14.8% 0.94[0.34,2.6]

Subtotal (95% CI) 58 37 41.13% 1.1[0.61,1.99]

Total events: 21 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.7); I2=0%

Test for overall effect: Z=0.33(P=0.74)

1.7.3 Supplements

Bunout 1989 2/17 5/19 13.54% 0.45[0.1,2.01]

Hirsch 1993 3/26 6/25 17.54% 0.48[0.13,1.72]

Subtotal (95% CI) 43 44 31.07% 0.47[0.18,1.23]

Total events: 5 (Treatment), 11 (Control)

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.94); I2=0%

Test for overall effect: Z=1.54(P=0.12)

Total (95% CI) 157 143 100% 0.78[0.5,1.21]

Total events: 32 (Treatment), 33 (Control)

Heterogeneity: Tau2=0; Chi2=3.17, df=5(P=0.67); I2=0%

Test for overall effect: Z=1.13(P=0.26)

Test for subgroup differences: Chi2=2.55, df=1 (P=0.28), I2=21.48%

Favors treatment 10000.001 100.1 1 Favors control

Analysis 1.8. Comparison 1 Mortality, Outcome 8 Cirrhosis.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.8.1 Parenteral nutrition

Naveau 1986 1/20 1/20 3.86% 1[0.07,14.9]

Puglionisi 1985 0/10 1/10 5.79% 0.33[0.02,7.32]

Subtotal (95% CI) 30 30 9.64% 0.6[0.08,4.27]

Total events: 1 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=0.28, df=1(P=0.6); I2=0%

Test for overall effect: Z=0.51(P=0.61)

1.8.2 Enteral nutrition

Cabre 1990 2/16 9/19 31.74% 0.26[0.07,1.05]

DeLedinghen 1997 3/12 2/10 8.42% 1.25[0.26,6.07]

Norman 2008 1/31 2/32 7.59% 0.52[0.05,5.41]

Subtotal (95% CI) 59 61 47.75% 0.48[0.19,1.18]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=2.14, df=2(P=0.34); I2=6.44%

Test for overall effect: Z=1.6(P=0.11)

1.8.3 Supplements

Hirsch 1993 3/26 6/25 23.6% 0.48[0.13,1.72]

Humbert 1988 2/27 4/22 17% 0.41[0.08,2.02]

Ichikawa 2010 0/12 0/9 Not estimable

Nakaya 2007 1/25 0/23 2.01% 2.77[0.12,64.76]

Subtotal (95% CI) 90 79 42.61% 0.56[0.22,1.39]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=1.19, df=2(P=0.55); I2=0%

Test for overall effect: Z=1.25(P=0.21)

Total (95% CI) 179 170 100% 0.52[0.28,0.97]

Total events: 13 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=3.6, df=7(P=0.82); I2=0%

Test for overall effect: Z=2.07(P=0.04)

Test for subgroup differences: Chi2=0.08, df=1 (P=0.96), I2=0%

Favors treatment 10000.001 100.1 1 Favors control

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Analysis 1.9. Comparison 1 Mortality, Outcome 9 HCC.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.9.1 Parenteral nutrition

Fan 1994 5/64 9/60 10.2% 0.52[0.19,1.47]

Subtotal (95% CI) 64 60 10.2% 0.52[0.19,1.47]

Total events: 5 (Treatment), 9 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.24(P=0.22)

1.9.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

1.9.3 Supplements

Kobashi 2006 63/119 44/114 49.34% 1.37[1.03,1.83]

Meng 1999 4/21 1/23 1.05% 4.38[0.53,36.13]

Poon 2004 0/41 3/43 3.75% 0.15[0.01,2.81]

San-In Group 1997 34/67 32/65 35.66% 1.03[0.73,1.45]

Takeshita 2009 0/28 0/28 Not estimable

Subtotal (95% CI) 276 273 89.8% 1.22[0.98,1.52]

Total events: 101 (Treatment), 80 (Control)

Heterogeneity: Tau2=0; Chi2=4.95, df=3(P=0.18); I2=39.43%

Test for overall effect: Z=1.79(P=0.07)

Total (95% CI) 340 333 100% 1.15[0.93,1.42]

Total events: 106 (Treatment), 89 (Control)

Heterogeneity: Tau2=0; Chi2=7.5, df=4(P=0.11); I2=46.66%

Test for overall effect: Z=1.27(P=0.2)

Test for subgroup differences: Chi2=2.49, df=1 (P=0.11), I2=59.84%

Favors treatment 10000.001 100.1 1 Favors control

Analysis 1.10. Comparison 1 Mortality, Outcome 10 Abstracts excluded.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.10.1 Medical trials - parenteral nutrition

Achord 1987 1/14 3/14 2.58% 0.33[0.04,2.83]

Bonkovsky 1991 0/9 0/12 Not estimable

Naveau 1986 1/20 1/20 0.86% 1[0.07,14.9]

Simon 1988 5/33 7/36 5.76% 0.78[0.27,2.22]

Subtotal (95% CI) 76 82 9.2% 0.67[0.28,1.62]

Total events: 7 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.57, df=2(P=0.75); I2=0%

Test for overall effect: Z=0.88(P=0.38)

1.10.2 Surgical trials - parenteral nutrition

Fan 1994 5/64 9/60 7.99% 0.52[0.19,1.47]

Puglionisi 1985 0/10 1/10 1.29% 0.33[0.02,7.32]

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Qiu 2009 0/44 0/21 Not estimable

Reilly 1990 1/18 2/10 2.21% 0.28[0.03,2.7]

Zheng 2003 0/40 1/30 1.47% 0.25[0.01,5.98]

Subtotal (95% CI) 176 131 12.96% 0.43[0.18,1.02]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=0.41, df=3(P=0.94); I2=0%

Test for overall effect: Z=1.92(P=0.05)

1.10.3 Medical trials - enteral nutrition

Cabre 1990 2/16 9/19 7.08% 0.26[0.07,1.05]

Calvey 1985 16/42 7/22 7.9% 1.2[0.58,2.47]

DeLedinghen 1997 3/12 2/10 1.88% 1.25[0.26,6.07]

Kearns 1992 5/16 5/15 4.44% 0.94[0.34,2.6]

Subtotal (95% CI) 86 66 21.29% 0.84[0.51,1.38]

Total events: 26 (Treatment), 23 (Control)

Heterogeneity: Tau2=0; Chi2=3.92, df=3(P=0.27); I2=23.49%

Test for overall effect: Z=0.7(P=0.49)

1.10.4 Surgical trials - enteral nutrition

Foschi 1986 1/28 4/32 3.21% 0.29[0.03,2.41]

Subtotal (95% CI) 28 32 3.21% 0.29[0.03,2.41]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.15(P=0.25)

1.10.5 Medical trials - supplements

Bunout 1989 2/17 5/19 4.06% 0.45[0.1,2.01]

Hirsch 1993 3/26 6/25 5.26% 0.48[0.13,1.72]

Humbert 1988 2/27 4/22 3.79% 0.41[0.08,2.02]

Ichikawa 2010 0/12 0/9 Not estimable

Nakaya 2007 1/25 0/23 0.45% 2.77[0.12,64.76]

Poon 2004 0/41 3/43 2.94% 0.15[0.01,2.81]

San-In Group 1997 34/67 32/65 27.94% 1.03[0.73,1.45]

Takeshita 2009 0/28 0/28 Not estimable

Subtotal (95% CI) 243 234 44.44% 0.82[0.6,1.12]

Total events: 42 (Treatment), 50 (Control)

Heterogeneity: Tau2=0; Chi2=5.64, df=5(P=0.34); I2=11.34%

Test for overall effect: Z=1.23(P=0.22)

1.10.6 Surgical trials - supplements

Hendry 2010 0/30 2/38 1.9% 0.25[0.01,5.05]

LeCornu 2000 2/42 7/40 6.17% 0.27[0.06,1.23]

Meng 1999 4/21 1/23 0.82% 4.38[0.53,36.13]

Subtotal (95% CI) 93 101 8.89% 0.65[0.25,1.65]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=2(P=0.09); I2=58.34%

Test for overall effect: Z=0.91(P=0.36)

Total (95% CI) 702 646 100% 0.73[0.57,0.92]

Total events: 88 (Treatment), 111 (Control)

Heterogeneity: Tau2=0; Chi2=19.7, df=20(P=0.48); I2=0%

Test for overall effect: Z=2.62(P=0.01)

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for subgroup differences: Chi2=3.02, df=1 (P=0.7), I2=0%

Favors treatment 10000.001 100.1 1 Favors control

Analysis 1.11. Comparison 1 Mortality, Outcome 11 Surgical trials without transplant patients.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.11.1 Parenteral nutrition

Fan 1994 5/64 9/60 47.89% 0.52[0.19,1.47]

Puglionisi 1985 0/10 1/10 7.73% 0.33[0.02,7.32]

Zheng 2003 0/40 1/30 8.81% 0.25[0.01,5.98]

Subtotal (95% CI) 114 100 64.42% 0.46[0.18,1.17]

Total events: 5 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.24, df=2(P=0.89); I2=0%

Test for overall effect: Z=1.63(P=0.1)

1.11.2 Enteral nutrition

Foschi 1986 1/28 4/32 19.24% 0.29[0.03,2.41]

Subtotal (95% CI) 28 32 19.24% 0.29[0.03,2.41]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.15(P=0.25)

1.11.3 Supplements

Hendry 2010 0/30 2/38 11.41% 0.25[0.01,5.05]

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 4/21 1/23 4.92% 4.38[0.53,36.13]

Subtotal (95% CI) 62 74 16.33% 1.5[0.37,5.98]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=2.35, df=1(P=0.13); I2=57.5%

Test for overall effect: Z=0.57(P=0.57)

Total (95% CI) 204 206 100% 0.6[0.3,1.2]

Total events: 10 (Treatment), 18 (Control)

Heterogeneity: Tau2=0; Chi2=4.69, df=5(P=0.45); I2=0%

Test for overall effect: Z=1.45(P=0.15)

Test for subgroup differences: Chi2=2.44, df=1 (P=0.3), I2=17.89%

Favours experimental 1000.01 100.1 1 Favours control

Analysis 1.12. Comparison 1 Mortality, Outcome 12 Intent to treat - best-case scenario for intervention.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.12.1 Medical trials - parenteral nutrition

Achord 1987 1/19 10/21 4.69% 0.11[0.02,0.78]

Bonkovsky 1991 0/9 0/12 Not estimable

Naveau 1986 1/20 1/20 0.49% 1[0.07,14.9]

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Simon 1988 5/33 7/36 3.3% 0.78[0.27,2.22]

Subtotal (95% CI) 81 89 8.48% 0.42[0.19,0.96]

Total events: 7 (Treatment), 18 (Control)

Heterogeneity: Tau2=0; Chi2=3.5, df=2(P=0.17); I2=42.92%

Test for overall effect: Z=2.06(P=0.04)

1.12.2 Surgical trials - parenteral nutrition

Fan 1994 5/75 24/75 11.84% 0.21[0.08,0.52]

Puglionisi 1985 0/10 1/10 0.74% 0.33[0.02,7.32]

Reilly 1990 1/18 2/10 1.27% 0.28[0.03,2.7]

Zheng 2003 0/40 1/30 0.84% 0.25[0.01,5.98]

Subtotal (95% CI) 143 125 14.69% 0.22[0.1,0.49]

Total events: 6 (Treatment), 28 (Control)

Heterogeneity: Tau2=0; Chi2=0.13, df=3(P=0.99); I2=0%

Test for overall effect: Z=3.73(P=0)

1.12.3 Medical trials - enteral nutrition

Cabre 1990 2/16 9/19 4.06% 0.26[0.07,1.05]

Calvey 1985 16/42 7/22 4.53% 1.2[0.58,2.47]

DeLedinghen 1997 3/12 2/10 1.08% 1.25[0.26,6.07]

Kearns 1992 5/16 5/15 2.55% 0.94[0.34,2.6]

Norman 2008 1/31 2/32 0.97% 0.52[0.05,5.41]

Subtotal (95% CI) 117 98 13.18% 0.81[0.5,1.33]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=4.15, df=4(P=0.39); I2=3.7%

Test for overall effect: Z=0.83(P=0.41)

1.12.4 Surgical trials - enteral nutrition

Foschi 1986 1/32 4/32 1.97% 0.25[0.03,2.12]

Subtotal (95% CI) 32 32 1.97% 0.25[0.03,2.12]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.27(P=0.2)

1.12.5 Medical trials - supplements

Bunout 1989 2/17 5/19 2.33% 0.45[0.1,2.01]

Hirsch 1993 3/32 14/33 6.8% 0.22[0.07,0.7]

Humbert 1988 2/27 4/22 2.17% 0.41[0.08,2.02]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 63/119 44/114 22.17% 1.37[1.03,1.83]

Nakaya 2007 1/25 0/23 0.26% 2.77[0.12,64.76]

Poon 2004 0/44 4/44 2.22% 0.11[0.01,2]

San-In Group 1997 34/75 42/75 20.71% 0.81[0.59,1.11]

Subtotal (95% CI) 351 339 56.66% 0.91[0.74,1.12]

Total events: 105 (Treatment), 113 (Control)

Heterogeneity: Tau2=0; Chi2=18.55, df=6(P=0.01); I2=67.65%

Test for overall effect: Z=0.91(P=0.36)

1.12.6 Surgical trials - supplements

LeCornu 2000 2/42 7/40 3.54% 0.27[0.06,1.23]

Meng 1999 4/25 3/25 1.48% 1.33[0.33,5.36]

Subtotal (95% CI) 67 65 5.02% 0.59[0.23,1.52]

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=2.33, df=1(P=0.13); I2=57.16%

Test for overall effect: Z=1.1(P=0.27)

Total (95% CI) 791 748 100% 0.73[0.61,0.86]

Total events: 152 (Treatment), 198 (Control)

Heterogeneity: Tau2=0; Chi2=46.9, df=21(P=0); I2=55.22%

Test for overall effect: Z=3.58(P=0)

Test for subgroup differences: Chi2=15.47, df=1 (P=0.01), I2=67.68%

Favours experimental 1000.01 100.1 1 Favours control

Analysis 1.13. Comparison 1 Mortality, Outcome 13 Intent to treat - worst-case scenario for intervention.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.13.1 Medical trials - parenteral nutrition

Achord 1987 6/19 3/21 1.78% 2.21[0.64,7.63]

Bonkovsky 1991 0/9 0/12 Not estimable

Naveau 1986 1/20 1/20 0.63% 1[0.07,14.9]

Simon 1988 5/33 7/36 4.19% 0.78[0.27,2.22]

Subtotal (95% CI) 81 89 6.6% 1.19[0.56,2.5]

Total events: 12 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=1.6, df=2(P=0.45); I2=0%

Test for overall effect: Z=0.45(P=0.65)

1.13.2 Surgical trials - parenteral nutrition

Fan 1994 16/75 9/75 5.63% 1.78[0.84,3.77]

Puglionisi 1985 0/10 1/10 0.94% 0.33[0.02,7.32]

Reilly 1990 1/18 2/10 1.61% 0.28[0.03,2.7]

Zheng 2003 0/40 1/30 1.07% 0.25[0.01,5.98]

Subtotal (95% CI) 143 125 9.25% 1.19[0.63,2.25]

Total events: 17 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=4.24, df=3(P=0.24); I2=29.28%

Test for overall effect: Z=0.55(P=0.58)

1.13.3 Medical trials - enteral nutrition

Cabre 1990 2/16 9/19 5.15% 0.26[0.07,1.05]

Calvey 1985 16/42 7/22 5.75% 1.2[0.58,2.47]

DeLedinghen 1997 3/12 2/10 1.37% 1.25[0.26,6.07]

Kearns 1992 5/16 5/15 3.23% 0.94[0.34,2.6]

Norman 2008 1/31 2/32 1.23% 0.52[0.05,5.41]

Subtotal (95% CI) 117 98 16.73% 0.81[0.5,1.33]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=4.15, df=4(P=0.39); I2=3.7%

Test for overall effect: Z=0.83(P=0.41)

1.13.4 Surgical trials - enteral nutrition

Foschi 1986 5/32 4/32 2.5% 1.25[0.37,4.23]

Subtotal (95% CI) 32 32 2.5% 1.25[0.37,4.23]

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 5 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.36(P=0.72)

1.13.5 Medical trials - supplements

Bunout 1989 2/17 5/19 2.96% 0.45[0.1,2.01]

Hirsch 1993 9/32 6/33 3.7% 1.55[0.62,3.85]

Humbert 1988 2/27 4/22 2.76% 0.41[0.08,2.02]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 63/119 44/114 28.14% 1.37[1.03,1.83]

Nakaya 2007 1/25 0/23 0.33% 2.77[0.12,64.76]

Poon 2004 3/44 3/44 1.88% 1[0.21,4.69]

San-In Group 1997 42/75 32/75 20.03% 1.31[0.94,1.83]

Subtotal (95% CI) 351 339 59.79% 1.27[1.03,1.56]

Total events: 122 (Treatment), 94 (Control)

Heterogeneity: Tau2=0; Chi2=4.62, df=6(P=0.59); I2=0%

Test for overall effect: Z=2.26(P=0.02)

1.13.6 Surgical trials - supplements

LeCornu 2000 2/42 7/40 4.49% 0.27[0.06,1.23]

Meng 1999 8/25 1/25 0.63% 8[1.08,59.32]

Subtotal (95% CI) 67 65 5.12% 1.22[0.5,2.96]

Total events: 10 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=7.17, df=1(P=0.01); I2=86.06%

Test for overall effect: Z=0.44(P=0.66)

Total (95% CI) 791 748 100% 1.18[0.99,1.4]

Total events: 193 (Treatment), 155 (Control)

Heterogeneity: Tau2=0; Chi2=23.64, df=21(P=0.31); I2=11.16%

Test for overall effect: Z=1.84(P=0.07)

Test for subgroup differences: Chi2=2.7, df=1 (P=0.75), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

Comparison 2. Appearance of ascites

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 8 582 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.47, 0.77]

2 Parenteral nutrition 4 214 Risk Ratio (M-H, Random, 95% CI)

0.65 [0.39, 1.08]

2.1 Medical trials 2 26 Risk Ratio (M-H, Random, 95% CI)

0.23 [0.01, 3.97]

2.2 Surgical trials 2 188 Risk Ratio (M-H, Random, 95% CI)

0.67 [0.39, 1.15]

3 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

3.1 Medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

3.2 Surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Supplements 4 368 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.38, 0.87]

4.1 Medical trials 4 368 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.38, 0.87]

4.2 Surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

5 Medical trials 6 394 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.37, 0.84]

5.1 Parenteral nutrition 2 26 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 3.97]

5.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

5.3 Supplements 4 368 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.38, 0.87]

6 Surgical trials 2 188 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.48, 0.87]

6.1 Parenteral nutrition 2 188 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.48, 0.87]

6.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

6.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

7 Alcoholic hepatitis 3 77 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.31, 1.26]

7.1 Parenteral nutrition 2 26 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 3.97]

7.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

7.3 Supplements 1 51 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.34, 1.45]

8 Cirrhosis 2 82 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.36, 1.46]

8.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

8.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

8.3 Supplements 2 82 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.36, 1.46]

9 HCC 2 286 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.32, 0.87]

9.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

9.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

9.3 Supplements 2 286 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.32, 0.87]

10 Abstracts excluded 7 380 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.46, 0.79]

10.1 Parenteral nutrition - medical trials 2 26 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 3.97]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

10.2 Parenteral nutrition - surgical trials 2 188 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.48, 0.87]

10.3 Enteral nutrition - medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

10.4 Enteral nutrition = surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

10.5 Supplements - medical trials 3 166 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.29, 1.00]

10.6 Supplements - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

11 Surgical trials without transplant 2 188 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.48, 0.87]

11.1 Parenteral nutrition 2 188 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.48, 0.87]

11.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

11.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

12 Intent to treat - best-case scenario for in- tervention

8 626 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.39, 0.64]

12.1 Parenteral nutrition - medical trials 2 26 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 3.97]

12.2 Parenteral nutrition - surgical trials 2 214 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.39, 0.70]

12.3 Enteral nutrition - medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

12.4 Enteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

12.5 Supplements - medical trials 4 386 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.33, 0.73]

12.6 Supplements - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13 Intent to treat - worst-case scenario for intervention

8 626 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.65, 1.02]

13.1 Parenteral nutrition - medical trials 2 26 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 3.97]

13.2 Parenteral nutrition - surgical trials 2 214 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.66, 1.15]

13.3 Enteral nutrition - medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.4 Enteral nutrition = surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.5 Supplements - medical trials 4 386 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.53, 1.11]

13.6 Supplements - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

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Analysis 2.1. Comparison 2 Appearance of ascites, Outcome 1 All studies.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Achord 1987 0/9 0/6 Not estimable

Fan 1994 16/64 30/60 29.45% 0.5[0.31,0.82]

Hirsch 1993 8/26 11/25 10.67% 0.7[0.34,1.45]

Kobashi 2006 16/100 27/102 25.43% 0.6[0.35,1.05]

Nakaya 2007 1/16 1/15 0.98% 0.94[0.06,13.68]

Poon 2004 3/41 10/43 9.28% 0.31[0.09,1.06]

Simon 1988 0/5 2/6 2.19% 0.23[0.01,3.97]

Zheng 2003 23/37 20/27 21.99% 0.84[0.6,1.17]

Total (95% CI) 298 284 100% 0.6[0.47,0.77]

Total events: 67 (Experimental), 101 (Control)

Heterogeneity: Tau2=0; Chi2=6.04, df=6(P=0.42); I2=0.7%

Test for overall effect: Z=4(P<0.0001)

Favours experimental 1000.01 100.1 1 Favours control

Analysis 2.2. Comparison 2 Appearance of ascites, Outcome 2 Parenteral nutrition.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

2.2.1 Medical trials

Achord 1987 0/9 0/6 Not estimable

Simon 1988 0/5 2/6 3.12% 0.23[0.01,3.97]

Subtotal (95% CI) 14 12 3.12% 0.23[0.01,3.97]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.01(P=0.31)

2.2.2 Surgical trials

Fan 1994 16/64 30/60 42.65% 0.5[0.31,0.82]

Zheng 2003 23/37 20/27 54.24% 0.84[0.6,1.17]

Subtotal (95% CI) 101 87 96.88% 0.67[0.39,1.15]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0.11; Chi2=3.38, df=1(P=0.07); I2=70.37%

Test for overall effect: Z=1.46(P=0.14)

Total (95% CI) 115 99 100% 0.65[0.39,1.08]

Total events: 39 (Experimental), 52 (Control)

Heterogeneity: Tau2=0.1; Chi2=4.14, df=2(P=0.13); I2=51.7%

Test for overall effect: Z=1.67(P=0.09)

Test for subgroup differences: Chi2=0.51, df=1 (P=0.48), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

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Analysis 2.4. Comparison 2 Appearance of ascites, Outcome 4 Supplements.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.4.1 Medical trials

Hirsch 1993 8/26 11/25 23.01% 0.7[0.34,1.45]

Kobashi 2006 16/100 27/102 54.84% 0.6[0.35,1.05]

Nakaya 2007 1/16 1/15 2.12% 0.94[0.06,13.68]

Poon 2004 3/41 10/43 20.03% 0.31[0.09,1.06]

Subtotal (95% CI) 183 185 100% 0.58[0.38,0.87]

Total events: 28 (Experimental), 49 (Control)

Heterogeneity: Tau2=0; Chi2=1.38, df=3(P=0.71); I2=0%

Test for overall effect: Z=2.64(P=0.01)

2.4.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 183 185 100% 0.58[0.38,0.87]

Total events: 28 (Experimental), 49 (Control)

Heterogeneity: Tau2=0; Chi2=1.38, df=3(P=0.71); I2=0%

Test for overall effect: Z=2.64(P=0.01)

Test for subgroup differences: Not applicable

Favours experimental 2000.005 100.1 1 Favours control

Analysis 2.5. Comparison 2 Appearance of ascites, Outcome 5 Medical trials.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.5.1 Parenteral nutrition

Achord 1987 0/9 0/6 Not estimable

Simon 1988 0/5 2/6 4.52% 0.23[0.01,3.97]

Subtotal (95% CI) 14 12 4.52% 0.23[0.01,3.97]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.01(P=0.31)

2.5.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.5.3 Supplements

Hirsch 1993 8/26 11/25 21.97% 0.7[0.34,1.45]

Kobashi 2006 16/100 27/102 52.37% 0.6[0.35,1.05]

Nakaya 2007 1/16 1/15 2.02% 0.94[0.06,13.68]

Poon 2004 3/41 10/43 19.12% 0.31[0.09,1.06]

Subtotal (95% CI) 183 185 95.48% 0.58[0.38,0.87]

Total events: 28 (Experimental), 49 (Control)

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=1.38, df=3(P=0.71); I2=0%

Test for overall effect: Z=2.64(P=0.01)

Total (95% CI) 197 197 100% 0.56[0.37,0.84]

Total events: 28 (Experimental), 51 (Control)

Heterogeneity: Tau2=0; Chi2=1.8, df=4(P=0.77); I2=0%

Test for overall effect: Z=2.8(P=0.01)

Test for subgroup differences: Chi2=0.38, df=1 (P=0.54), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

Analysis 2.6. Comparison 2 Appearance of ascites, Outcome 6 Surgical trials.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.6.1 Parenteral nutrition

Fan 1994 16/64 30/60 57.25% 0.5[0.31,0.82]

Zheng 2003 23/37 20/27 42.75% 0.84[0.6,1.17]

Subtotal (95% CI) 101 87 100% 0.65[0.48,0.87]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=3.38, df=1(P=0.07); I2=70.37%

Test for overall effect: Z=2.88(P=0)

2.6.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.6.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 101 87 100% 0.65[0.48,0.87]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=3.38, df=1(P=0.07); I2=70.37%

Test for overall effect: Z=2.88(P=0)

Test for subgroup differences: Chi2=0, df=1 (P<0.0001), I2=100%

Favours experimental 50.2 20.5 1 Favours control

Analysis 2.7. Comparison 2 Appearance of ascites, Outcome 7 Alcoholic hepatitis.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.7.1 Parenteral nutrition

Achord 1987 0/9 0/6 Not estimable

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Simon 1988 0/5 2/6 17.06% 0.23[0.01,3.97]

Subtotal (95% CI) 14 12 17.06% 0.23[0.01,3.97]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.01(P=0.31)

2.7.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.7.3 Supplements

Hirsch 1993 8/26 11/25 82.94% 0.7[0.34,1.45]

Subtotal (95% CI) 26 25 82.94% 0.7[0.34,1.45]

Total events: 8 (Experimental), 11 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.96(P=0.33)

Total (95% CI) 40 37 100% 0.62[0.31,1.26]

Total events: 8 (Experimental), 13 (Control)

Heterogeneity: Tau2=0; Chi2=0.56, df=1(P=0.45); I2=0%

Test for overall effect: Z=1.33(P=0.18)

Test for subgroup differences: Chi2=0.54, df=1 (P=0.46), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

Analysis 2.8. Comparison 2 Appearance of ascites, Outcome 8 Cirrhosis.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.8.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.8.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.8.3 Supplements

Hirsch 1993 8/26 11/25 91.57% 0.7[0.34,1.45]

Nakaya 2007 1/16 1/15 8.43% 0.94[0.06,13.68]

Subtotal (95% CI) 42 40 100% 0.72[0.36,1.46]

Total events: 9 (Experimental), 12 (Control)

Heterogeneity: Tau2=0; Chi2=0.04, df=1(P=0.84); I2=0%

Test for overall effect: Z=0.92(P=0.36)

Favours experimental 500.02 100.1 1 Favours control

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Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 42 40 100% 0.72[0.36,1.46]

Total events: 9 (Experimental), 12 (Control)

Heterogeneity: Tau2=0; Chi2=0.04, df=1(P=0.84); I2=0%

Test for overall effect: Z=0.92(P=0.36)

Test for subgroup differences: Not applicable

Favours experimental 500.02 100.1 1 Favours control

Analysis 2.9. Comparison 2 Appearance of ascites, Outcome 9 HCC.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.9.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.9.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.9.3 Supplements

Kobashi 2006 16/100 27/102 73.25% 0.6[0.35,1.05]

Poon 2004 3/41 10/43 26.75% 0.31[0.09,1.06]

Subtotal (95% CI) 141 145 100% 0.53[0.32,0.87]

Total events: 19 (Experimental), 37 (Control)

Heterogeneity: Tau2=0; Chi2=0.93, df=1(P=0.34); I2=0%

Test for overall effect: Z=2.5(P=0.01)

Total (95% CI) 141 145 100% 0.53[0.32,0.87]

Total events: 19 (Experimental), 37 (Control)

Heterogeneity: Tau2=0; Chi2=0.93, df=1(P=0.34); I2=0%

Test for overall effect: Z=2.5(P=0.01)

Test for subgroup differences: Not applicable

Favours experimental 500.02 100.1 1 Favours control

Analysis 2.10. Comparison 2 Appearance of ascites, Outcome 10 Abstracts excluded.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.10.1 Parenteral nutrition - medical trials

Achord 1987 0/9 0/6 Not estimable

Simon 1988 0/5 2/6 2.94% 0.23[0.01,3.97]

Subtotal (95% CI) 14 12 2.94% 0.23[0.01,3.97]

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.01(P=0.31)

2.10.2 Parenteral nutrition - surgical trials

Fan 1994 16/64 30/60 39.49% 0.5[0.31,0.82]

Zheng 2003 23/37 20/27 29.49% 0.84[0.6,1.17]

Subtotal (95% CI) 101 87 68.99% 0.65[0.48,0.87]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=3.38, df=1(P=0.07); I2=70.37%

Test for overall effect: Z=2.88(P=0)

2.10.3 Enteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.10.4 Enteral nutrition = surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.10.5 Supplements - medical trials

Hirsch 1993 8/26 11/25 14.3% 0.7[0.34,1.45]

Nakaya 2007 1/16 1/15 1.32% 0.94[0.06,13.68]

Poon 2004 3/41 10/43 12.45% 0.31[0.09,1.06]

Subtotal (95% CI) 83 83 28.07% 0.54[0.29,1]

Total events: 12 (Experimental), 22 (Control)

Heterogeneity: Tau2=0; Chi2=1.41, df=2(P=0.5); I2=0%

Test for overall effect: Z=1.97(P=0.05)

2.10.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 198 182 100% 0.6[0.46,0.79]

Total events: 51 (Experimental), 74 (Control)

Heterogeneity: Tau2=0; Chi2=6.05, df=5(P=0.3); I2=17.34%

Test for overall effect: Z=3.63(P=0)

Test for subgroup differences: Chi2=0.72, df=1 (P=0.7), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

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Analysis 2.11. Comparison 2 Appearance of ascites, Outcome 11 Surgical trials without transplant.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.11.1 Parenteral nutrition

Fan 1994 16/64 30/60 57.25% 0.5[0.31,0.82]

Zheng 2003 23/37 20/27 42.75% 0.84[0.6,1.17]

Subtotal (95% CI) 101 87 100% 0.65[0.48,0.87]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=3.38, df=1(P=0.07); I2=70.37%

Test for overall effect: Z=2.88(P=0)

2.11.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.11.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 101 87 100% 0.65[0.48,0.87]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=3.38, df=1(P=0.07); I2=70.37%

Test for overall effect: Z=2.88(P=0)

Test for subgroup differences: Chi2=0, df=1 (P<0.0001), I2=100%

Favours experimental 100.1 50.2 20.5 1 Favours control

Analysis 2.12. Comparison 2 Appearance of ascites, Outcome 12 Intent to treat - best-case scenario for intervention.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.12.1 Parenteral nutrition - medical trials

Achord 1987 0/9 0/6 Not estimable

Simon 1988 0/5 2/6 1.8% 0.23[0.01,3.97]

Subtotal (95% CI) 14 12 1.8% 0.23[0.01,3.97]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.01(P=0.31)

2.12.2 Parenteral nutrition - surgical trials

Fan 1994 16/75 45/75 35.18% 0.36[0.22,0.57]

Zheng 2003 23/37 20/27 18.08% 0.84[0.6,1.17]

Subtotal (95% CI) 112 102 53.26% 0.52[0.39,0.7]

Total events: 39 (Experimental), 65 (Control)

Heterogeneity: Tau2=0; Chi2=10.29, df=1(P=0); I2=90.28%

Test for overall effect: Z=4.33(P<0.0001)

2.12.3 Enteral nutrition - medical trials

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.12.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.12.5 Supplements - medical trials

Hirsch 1993 8/32 19/33 14.63% 0.43[0.22,0.85]

Kobashi 2006 16/100 27/102 20.9% 0.6[0.35,1.05]

Nakaya 2007 1/16 1/15 0.81% 0.94[0.06,13.68]

Poon 2004 3/44 11/44 8.6% 0.27[0.08,0.91]

Subtotal (95% CI) 192 194 44.93% 0.49[0.33,0.73]

Total events: 28 (Experimental), 58 (Control)

Heterogeneity: Tau2=0; Chi2=1.81, df=3(P=0.61); I2=0%

Test for overall effect: Z=3.51(P=0)

2.12.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 318 308 100% 0.5[0.39,0.64]

Total events: 67 (Experimental), 125 (Control)

Heterogeneity: Tau2=0; Chi2=13.12, df=6(P=0.04); I2=54.26%

Test for overall effect: Z=5.61(P<0.0001)

Test for subgroup differences: Chi2=0.34, df=1 (P=0.84), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

Analysis 2.13. Comparison 2 Appearance of ascites, Outcome 13 Intent to treat - worst-case scenario for intervention.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

2.13.1 Parenteral nutrition - medical trials

Achord 1987 0/9 0/6 Not estimable

Simon 1988 0/5 2/6 2.22% 0.23[0.01,3.97]

Subtotal (95% CI) 14 12 2.22% 0.23[0.01,3.97]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.01(P=0.31)

2.13.2 Parenteral nutrition - surgical trials

Fan 1994 27/75 30/75 28.84% 0.9[0.6,1.36]

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Zheng 2003 23/37 20/27 22.23% 0.84[0.6,1.17]

Subtotal (95% CI) 112 102 51.07% 0.87[0.66,1.15]

Total events: 50 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=0.08, df=1(P=0.78); I2=0%

Test for overall effect: Z=0.96(P=0.34)

2.13.3 Enteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.13.4 Enteral nutrition = surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

2.13.5 Supplements - medical trials

Hirsch 1993 14/32 11/33 10.41% 1.31[0.7,2.45]

Kobashi 2006 16/100 27/102 25.7% 0.6[0.35,1.05]

Nakaya 2007 1/16 1/15 0.99% 0.94[0.06,13.68]

Poon 2004 6/44 10/44 9.61% 0.6[0.24,1.51]

Subtotal (95% CI) 192 194 46.71% 0.77[0.53,1.11]

Total events: 37 (Experimental), 49 (Control)

Heterogeneity: Tau2=0; Chi2=3.86, df=3(P=0.28); I2=22.36%

Test for overall effect: Z=1.39(P=0.16)

2.13.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 318 308 100% 0.81[0.65,1.02]

Total events: 87 (Experimental), 101 (Control)

Heterogeneity: Tau2=0; Chi2=4.84, df=6(P=0.56); I2=0%

Test for overall effect: Z=1.83(P=0.07)

Test for subgroup differences: Chi2=1.07, df=1 (P=0.59), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

Comparison 3. Resolution of ascites

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 6 131 Risk Ratio (M-H, Fixed, 95% CI)

0.91 [0.66, 1.27]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

2 Parenteral nutrition 3 73 Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.48, 1.05]

2.1 Medical trials 3 73 Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.48, 1.05]

2.2 Surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Enteral nutrition 1 29 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.46, 1.62]

3.1 Medical trials 1 29 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.46, 1.62]

3.2 Surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Supplements 2 29 Risk Ratio (M-H, Fixed, 95% CI)

4.16 [0.87, 19.84]

4.1 Medical trials 2 29 Risk Ratio (M-H, Fixed, 95% CI)

4.16 [0.87, 19.84]

4.2 Surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Medical trials 6 131 Risk Ratio (M-H, Fixed, 95% CI)

0.91 [0.66, 1.27]

5.1 Parenteral nutrition 3 73 Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.48, 1.05]

5.2 Enteral nutrition 1 29 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.46, 1.62]

5.3 Supplements 2 29 Risk Ratio (M-H, Fixed, 95% CI)

4.16 [0.87, 19.84]

6 Surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Alcoholic hepatitis 2 40 Risk Ratio (M-H, Fixed, 95% CI)

1.01 [0.46, 2.19]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

7.1 Parenteral nutrition 2 40 Risk Ratio (M-H, Fixed, 95% CI)

1.01 [0.46, 2.19]

7.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Cirrhosis 4 91 Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.62, 1.27]

8.1 Parenteral nutrition 1 33 Risk Ratio (M-H, Fixed, 95% CI)

0.57 [0.37, 0.88]

8.2 Enteral nutrition 1 29 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.46, 1.62]

8.3 Supplements 2 29 Risk Ratio (M-H, Fixed, 95% CI)

4.16 [0.87, 19.84]

9 HCC 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10 Abstracts excluded 6 131 Risk Ratio (M-H, Fixed, 95% CI)

0.91 [0.66, 1.27]

10.1 Parenteral nutrition - medical trials 3 73 Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.48, 1.05]

10.2 Parenteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.3 Enteral nutrition - medical trials 1 29 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.46, 1.62]

10.4 Enteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.5 Supplements - medical trials 2 29 Risk Ratio (M-H, Fixed, 95% CI)

4.16 [0.87, 19.84]

10.6 Supplements - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

11 Surgical trials without transplant 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12 Intent to treat - best-case scenario for in- tervention - no changes made because all pa- tients with ascites reported

6 131 Risk Ratio (M-H, Fixed, 95% CI)

0.91 [0.66, 1.27]

12.1 Parenteral nutrition - medical trials 3 73 Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.48, 1.05]

12.2 Parenteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.3 Enteral nutrition - medical trials 1 29 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.46, 1.62]

12.4 Enteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.5 Supplements - medical trials 2 29 Risk Ratio (M-H, Fixed, 95% CI)

4.16 [0.87, 19.84]

12.6 Supplements - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13 Intent to treat - worst case scenario for in- tervention - no changes made because all pa- tients with ascites reported

6 131 Risk Ratio (M-H, Fixed, 95% CI)

0.91 [0.66, 1.27]

13.1 Parenteral nutrition - medical trials 3 73 Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.48, 1.05]

13.2 Parenteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.3 Enteral nutrition - medical trials 1 29 Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.46, 1.62]

13.4 Enteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.5 Supplements - medical trials 2 29 Risk Ratio (M-H, Fixed, 95% CI)

4.16 [0.87, 19.84]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

13.6 Supplements - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 3.1. Comparison 3 Resolution of ascites, Outcome 1 All studies.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Achord 1987 3/5 3/8 6.56% 1.6[0.51,5.03]

Cabre 1990 7/13 10/16 25.49% 0.86[0.46,1.62]

Hayashi 1991 6/14 1/8 3.62% 3.43[0.5,23.63]

Nakaya 2007 2/3 0/4 1.26% 6.25[0.4,96.5]

Naveau 1986 9/16 17/17 48.33% 0.57[0.37,0.88]

Simon 1988 4/14 5/13 14.74% 0.74[0.25,2.18]

Total (95% CI) 65 66 100% 0.91[0.66,1.27]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=9.28, df=5(P=0.1); I2=46.14%

Test for overall effect: Z=0.53(P=0.6)

Favours control 2000.005 100.1 1 Favours experimental

Analysis 3.2. Comparison 3 Resolution of ascites, Outcome 2 Parenteral nutrition.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.2.1 Medical trials

Achord 1987 3/5 3/8 9.42% 1.6[0.51,5.03]

Naveau 1986 9/16 17/17 69.41% 0.57[0.37,0.88]

Simon 1988 4/14 5/13 21.17% 0.74[0.25,2.18]

Subtotal (95% CI) 35 38 100% 0.71[0.48,1.05]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=2.85, df=2(P=0.24); I2=29.89%

Test for overall effect: Z=1.74(P=0.08)

3.2.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 35 38 100% 0.71[0.48,1.05]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=2.85, df=2(P=0.24); I2=29.89%

Test for overall effect: Z=1.74(P=0.08)

Test for subgroup differences: Not applicable

Favours control 1000.01 100.1 1 Favours experimental

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Analysis 3.3. Comparison 3 Resolution of ascites, Outcome 3 Enteral nutrition.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.3.1 Medical trials

Cabre 1990 7/13 10/16 100% 0.86[0.46,1.62]

Subtotal (95% CI) 13 16 100% 0.86[0.46,1.62]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.46(P=0.64)

3.3.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 13 16 100% 0.86[0.46,1.62]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.46(P=0.64)

Test for subgroup differences: Not applicable

Favours control 200.05 50.2 1 Favours experimental

Analysis 3.4. Comparison 3 Resolution of ascites, Outcome 4 Supplements.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.4.1 Medical trials

Hayashi 1991 6/14 1/8 74.12% 3.43[0.5,23.63]

Nakaya 2007 2/3 0/4 25.88% 6.25[0.4,96.5]

Subtotal (95% CI) 17 12 100% 4.16[0.87,19.84]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%

Test for overall effect: Z=1.79(P=0.07)

3.4.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 17 12 100% 4.16[0.87,19.84]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%

Test for overall effect: Z=1.79(P=0.07)

Test for subgroup differences: Chi2=0, df=1 (P<0.0001), I2=100%

Favours control 1000.01 100.1 1 Favours experimental

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Analysis 3.5. Comparison 3 Resolution of ascites, Outcome 5 Medical trials.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.5.1 Parenteral nutrition

Achord 1987 3/5 3/8 6.56% 1.6[0.51,5.03]

Naveau 1986 9/16 17/17 48.33% 0.57[0.37,0.88]

Simon 1988 4/14 5/13 14.74% 0.74[0.25,2.18]

Subtotal (95% CI) 35 38 69.63% 0.71[0.48,1.05]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=2.85, df=2(P=0.24); I2=29.89%

Test for overall effect: Z=1.74(P=0.08)

3.5.2 Enteral nutrition

Cabre 1990 7/13 10/16 25.49% 0.86[0.46,1.62]

Subtotal (95% CI) 13 16 25.49% 0.86[0.46,1.62]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.46(P=0.64)

3.5.3 Supplements

Hayashi 1991 6/14 1/8 3.62% 3.43[0.5,23.63]

Nakaya 2007 2/3 0/4 1.26% 6.25[0.4,96.5]

Subtotal (95% CI) 17 12 4.88% 4.16[0.87,19.84]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%

Test for overall effect: Z=1.79(P=0.07)

Total (95% CI) 65 66 100% 0.91[0.66,1.27]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=9.28, df=5(P=0.1); I2=46.14%

Test for overall effect: Z=0.53(P=0.6)

Test for subgroup differences: Chi2=4.71, df=1 (P=0.09), I2=57.53%

Favours control 1000.01 100.1 1 Favours experimental

Analysis 3.7. Comparison 3 Resolution of ascites, Outcome 7 Alcoholic hepatitis.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.7.1 Parenteral nutrition

Achord 1987 3/5 3/8 30.8% 1.6[0.51,5.03]

Simon 1988 4/14 5/13 69.2% 0.74[0.25,2.18]

Subtotal (95% CI) 19 21 100% 1.01[0.46,2.19]

Total events: 7 (Experimental), 8 (Control)

Heterogeneity: Tau2=0; Chi2=0.93, df=1(P=0.33); I2=0%

Test for overall effect: Z=0.02(P=0.99)

3.7.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours control 500.02 100.1 1 Favours experimental

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Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.7.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 19 21 100% 1.01[0.46,2.19]

Total events: 7 (Experimental), 8 (Control)

Heterogeneity: Tau2=0; Chi2=0.93, df=1(P=0.33); I2=0%

Test for overall effect: Z=0.02(P=0.99)

Test for subgroup differences: Not applicable

Favours control 500.02 100.1 1 Favours experimental

Analysis 3.8. Comparison 3 Resolution of ascites, Outcome 8 Cirrhosis.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.8.1 Parenteral nutrition

Naveau 1986 9/16 17/17 61.41% 0.57[0.37,0.88]

Subtotal (95% CI) 16 17 61.41% 0.57[0.37,0.88]

Total events: 9 (Experimental), 17 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.53(P=0.01)

3.8.2 Enteral nutrition

Cabre 1990 7/13 10/16 32.39% 0.86[0.46,1.62]

Subtotal (95% CI) 13 16 32.39% 0.86[0.46,1.62]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.46(P=0.64)

3.8.3 Supplements

Hayashi 1991 6/14 1/8 4.6% 3.43[0.5,23.63]

Nakaya 2007 2/3 0/4 1.61% 6.25[0.4,96.5]

Subtotal (95% CI) 17 12 6.2% 4.16[0.87,19.84]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%

Test for overall effect: Z=1.79(P=0.07)

Total (95% CI) 46 45 100% 0.89[0.62,1.27]

Total events: 24 (Experimental), 28 (Control)

Heterogeneity: Tau2=0; Chi2=7.81, df=3(P=0.05); I2=61.6%

Test for overall effect: Z=0.64(P=0.53)

Test for subgroup differences: Chi2=6.2, df=1 (P=0.04), I2=67.77%

Favours control 1000.01 100.1 1 Favours experimental

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Analysis 3.10. Comparison 3 Resolution of ascites, Outcome 10 Abstracts excluded.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.10.1 Parenteral nutrition - medical trials

Achord 1987 3/5 3/8 6.56% 1.6[0.51,5.03]

Naveau 1986 9/16 17/17 48.33% 0.57[0.37,0.88]

Simon 1988 4/14 5/13 14.74% 0.74[0.25,2.18]

Subtotal (95% CI) 35 38 69.63% 0.71[0.48,1.05]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=2.85, df=2(P=0.24); I2=29.89%

Test for overall effect: Z=1.74(P=0.08)

3.10.2 Parenteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

3.10.3 Enteral nutrition - medical trials

Cabre 1990 7/13 10/16 25.49% 0.86[0.46,1.62]

Subtotal (95% CI) 13 16 25.49% 0.86[0.46,1.62]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.46(P=0.64)

3.10.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

3.10.5 Supplements - medical trials

Hayashi 1991 6/14 1/8 3.62% 3.43[0.5,23.63]

Nakaya 2007 2/3 0/4 1.26% 6.25[0.4,96.5]

Subtotal (95% CI) 17 12 4.88% 4.16[0.87,19.84]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%

Test for overall effect: Z=1.79(P=0.07)

3.10.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 65 66 100% 0.91[0.66,1.27]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=9.28, df=5(P=0.1); I2=46.14%

Test for overall effect: Z=0.53(P=0.6)

Test for subgroup differences: Chi2=4.71, df=1 (P=0.09), I2=57.53%

Favours control 1000.01 100.1 1 Favours experimental

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Analysis 3.12. Comparison 3 Resolution of ascites, Outcome 12 Intent to treat - best-case scenario for intervention - no changes made because all patients with ascites reported.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.12.1 Parenteral nutrition - medical trials

Achord 1987 3/5 3/8 6.56% 1.6[0.51,5.03]

Naveau 1986 9/16 17/17 48.33% 0.57[0.37,0.88]

Simon 1988 4/14 5/13 14.74% 0.74[0.25,2.18]

Subtotal (95% CI) 35 38 69.63% 0.71[0.48,1.05]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=2.85, df=2(P=0.24); I2=29.89%

Test for overall effect: Z=1.74(P=0.08)

3.12.2 Parenteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

3.12.3 Enteral nutrition - medical trials

Cabre 1990 7/13 10/16 25.49% 0.86[0.46,1.62]

Subtotal (95% CI) 13 16 25.49% 0.86[0.46,1.62]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.46(P=0.64)

3.12.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

3.12.5 Supplements - medical trials

Hayashi 1991 6/14 1/8 3.62% 3.43[0.5,23.63]

Nakaya 2007 2/3 0/4 1.26% 6.25[0.4,96.5]

Subtotal (95% CI) 17 12 4.88% 4.16[0.87,19.84]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%

Test for overall effect: Z=1.79(P=0.07)

3.12.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 65 66 100% 0.91[0.66,1.27]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=9.28, df=5(P=0.1); I2=46.14%

Test for overall effect: Z=0.53(P=0.6)

Test for subgroup differences: Chi2=4.71, df=1 (P=0.09), I2=57.53%

Favours control 1000.01 100.1 1 Favours experimental

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Analysis 3.13. Comparison 3 Resolution of ascites, Outcome 13 Intent to treat - worst case scenario for intervention - no changes made because all patients with ascites reported.

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

3.13.1 Parenteral nutrition - medical trials

Achord 1987 3/5 3/8 6.56% 1.6[0.51,5.03]

Naveau 1986 9/16 17/17 48.33% 0.57[0.37,0.88]

Simon 1988 4/14 5/13 14.74% 0.74[0.25,2.18]

Subtotal (95% CI) 35 38 69.63% 0.71[0.48,1.05]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=2.85, df=2(P=0.24); I2=29.89%

Test for overall effect: Z=1.74(P=0.08)

3.13.2 Parenteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

3.13.3 Enteral nutrition - medical trials

Cabre 1990 7/13 10/16 25.49% 0.86[0.46,1.62]

Subtotal (95% CI) 13 16 25.49% 0.86[0.46,1.62]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.46(P=0.64)

3.13.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

3.13.5 Supplements - medical trials

Hayashi 1991 6/14 1/8 3.62% 3.43[0.5,23.63]

Nakaya 2007 2/3 0/4 1.26% 6.25[0.4,96.5]

Subtotal (95% CI) 17 12 4.88% 4.16[0.87,19.84]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%

Test for overall effect: Z=1.79(P=0.07)

3.13.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 65 66 100% 0.91[0.66,1.27]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=9.28, df=5(P=0.1); I2=46.14%

Test for overall effect: Z=0.53(P=0.6)

Test for subgroup differences: Chi2=4.71, df=1 (P=0.09), I2=57.53%

Favours control 1000.01 100.1 1 Favours experimental

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Comparison 4. Appearance of gastrointestinal bleeding

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 11 783 Risk Ratio (M-H, Fixed, 95% CI)

1.29 [0.85, 1.96]

2 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI)

2.82 [0.12, 67.80]

2.1 Medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Surgical trials 1 124 Risk Ratio (M-H, Fixed, 95% CI)

2.82 [0.12, 67.80]

3 Enteral nutrition (all medical) 4 180 Risk Ratio (M-H, Fixed, 95% CI)

1.50 [0.78, 2.86]

3.1 Medical trials 4 180 Risk Ratio (M-H, Fixed, 95% CI)

1.50 [0.78, 2.86]

3.2 Surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Supplements 6 479 Risk Ratio (M-H, Fixed, 95% CI)

1.08 [0.62, 1.89]

4.1 Medical trials 5 435 Risk Ratio (M-H, Fixed, 95% CI)

1.08 [0.61, 1.91]

4.2 Surgical trials 1 44 Risk Ratio (M-H, Fixed, 95% CI)

1.10 [0.07, 16.43]

5 Medical trials 9 615 Risk Ratio (M-H, Fixed, 95% CI)

1.27 [0.82, 1.94]

5.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Enteral nutrition 4 180 Risk Ratio (M-H, Fixed, 95% CI)

1.50 [0.78, 2.86]

5.3 Supplements 5 435 Risk Ratio (M-H, Fixed, 95% CI)

1.08 [0.61, 1.91]

6 Surgical trials 2 168 Risk Ratio (M-H, Fixed, 95% CI)

1.70 [0.23, 12.73]

6.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI)

2.82 [0.12, 67.80]

6.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

130

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

6.3 Supplements 1 44 Risk Ratio (M-H, Fixed, 95% CI)

1.10 [0.07, 16.43]

7 Alcoholic hepatitis 1 64 Risk Ratio (M-H, Fixed, 95% CI)

2.88 [0.70, 11.87]

7.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Enteral nutrition 1 64 Risk Ratio (M-H, Fixed, 95% CI)

2.88 [0.70, 11.87]

7.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Cirrhosis 6 234 Risk Ratio (M-H, Fixed, 95% CI)

1.01 [0.62, 1.67]

8.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Enteral nutrition 3 116 Risk Ratio (M-H, Fixed, 95% CI)

1.16 [0.55, 2.43]

8.3 Supplements 3 118 Risk Ratio (M-H, Fixed, 95% CI)

0.87 [0.45, 1.69]

9 HCC 2 317 Risk Ratio (M-H, Fixed, 95% CI)

1.50 [0.53, 4.26]

9.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Eneral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 2 317 Risk Ratio (M-H, Fixed, 95% CI)

1.50 [0.53, 4.26]

10 Abstracts excluded 9 491 Risk Ratio (M-H, Fixed, 95% CI)

1.27 [0.76, 2.13]

10.1 Parenteral nutrition - medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.2 Parenteral nutrition - surgical trials 1 124 Risk Ratio (M-H, Fixed, 95% CI)

2.82 [0.12, 67.80]

10.3 Enteral nutrition - medical trials 3 121 Risk Ratio (M-H, Fixed, 95% CI)

1.67 [0.68, 4.10]

10.4 Enteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

131

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

10.5 Supplements - medical trials 4 202 Risk Ratio (M-H, Fixed, 95% CI)

0.97 [0.51, 1.84]

10.6 Supplements - surgical trials 1 44 Risk Ratio (M-H, Fixed, 95% CI)

1.10 [0.07, 16.43]

11 Surgical trials without transplant patients (no trials with transplant patients)

2 168 Risk Ratio (M-H, Fixed, 95% CI)

1.70 [0.23, 12.73]

11.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI)

2.82 [0.12, 67.80]

11.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.3 Supplements 1 44 Risk Ratio (M-H, Fixed, 95% CI)

1.10 [0.07, 16.43]

12 Intent to treat - best-case scenario for in- tervention

11 838 Risk Ratio (M-H, Fixed, 95% CI)

0.67 [0.47, 0.97]

12.1 Parenteral nutrition - medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.2 Parenteral nutrition - surgical trials 1 150 Risk Ratio (M-H, Fixed, 95% CI)

0.07 [0.01, 0.49]

12.3 Enteral nutrition - medical trials 4 184 Risk Ratio (M-H, Fixed, 95% CI)

1.26 [0.69, 2.30]

12.4 Enteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.5 Supplements - medical trials 5 454 Risk Ratio (M-H, Fixed, 95% CI)

0.70 [0.42, 1.16]

12.6 Supplements - surgical trials 1 50 Risk Ratio (M-H, Fixed, 95% CI)

0.33 [0.04, 2.99]

13 Intent to treat - worst-case scenario for intervention

11 838 Risk Ratio (M-H, Fixed, 95% CI)

2.14 [1.46, 3.15]

13.1 Parenteral nutrition - medical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.2 Parenteral nutrition - surgical trials 1 150 Risk Ratio (M-H, Fixed, 95% CI)

25.0 [1.51, 414.73]

13.3 Enteral nutrition - medical trials 4 184 Risk Ratio (M-H, Fixed, 95% CI)

1.61 [0.85, 3.07]

13.4 Enteral nutrition - surgical trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

132

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

13.5 Supplements - medical trials 5 454 Risk Ratio (M-H, Fixed, 95% CI)

1.72 [1.02, 2.88]

13.6 Supplements - surgical trials 1 50 Risk Ratio (M-H, Fixed, 95% CI)

5.0 [0.63, 39.79]

Analysis 4.1. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 1/16 4/19 11.52% 0.3[0.04,2.4]

Calvey 1985 11/42 2/22 8.27% 2.88[0.7,11.87]

DeLedinghen 1997 4/12 1/10 3.44% 3.33[0.44,25.23]

Fan 1994 1/64 0/60 1.62% 2.82[0.12,67.8]

Hirsch 1993 10/26 11/25 35.32% 0.87[0.45,1.69]

Kobashi 2006 7/119 5/114 16.08% 1.34[0.44,4.1]

Meng 1999 1/21 1/23 3.01% 1.1[0.07,16.43]

Nakaya 2007 0/19 0/19 Not estimable

Norman 2008 8/30 6/29 19.21% 1.29[0.51,3.26]

Poon 2004 1/41 0/43 1.54% 3.14[0.13,75.02]

Tangkijvanich 2000 0/14 0/15 Not estimable

Total (95% CI) 404 379 100% 1.29[0.85,1.96]

Total events: 44 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=5.87, df=8(P=0.66); I2=0%

Test for overall effect: Z=1.17(P=0.24)

Favours treatment 2000.005 100.1 1 Favours control

Analysis 4.2. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 2 Parenteral nutrition.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.2.1 Medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.2.2 Surgical trials

Fan 1994 1/64 0/60 100% 2.82[0.12,67.8]

Subtotal (95% CI) 64 60 100% 2.82[0.12,67.8]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.64(P=0.52)

Favours treatment 2000.005 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 64 60 100% 2.82[0.12,67.8]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.64(P=0.52)

Test for subgroup differences: Not applicable

Favours treatment 2000.005 100.1 1 Favours control

Analysis 4.3. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 3 Enteral nutrition (all medical).

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.3.1 Medical trials

Cabre 1990 1/16 4/19 27.14% 0.3[0.04,2.4]

Calvey 1985 11/42 2/22 19.48% 2.88[0.7,11.87]

DeLedinghen 1997 4/12 1/10 8.1% 3.33[0.44,25.23]

Norman 2008 8/30 6/29 45.28% 1.29[0.51,3.26]

Subtotal (95% CI) 100 80 100% 1.5[0.78,2.86]

Total events: 24 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=3.83, df=3(P=0.28); I2=21.65%

Test for overall effect: Z=1.21(P=0.22)

4.3.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 100 80 100% 1.5[0.78,2.86]

Total events: 24 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=3.83, df=3(P=0.28); I2=21.65%

Test for overall effect: Z=1.21(P=0.22)

Test for subgroup differences: Not applicable

Favours treatment 500.02 100.1 1 Favours control

Analysis 4.4. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 4 Supplements.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.4.1 Medical trials

Hirsch 1993 10/26 11/25 63.13% 0.87[0.45,1.69]

Kobashi 2006 7/119 5/114 28.75% 1.34[0.44,4.1]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 1/41 0/43 2.75% 3.14[0.13,75.02]

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 219 216 94.63% 1.08[0.61,1.91]

Total events: 18 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=0.98, df=2(P=0.61); I2=0%

Favours treatment 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Z=0.27(P=0.79)

4.4.2 Surgical trials

Meng 1999 1/21 1/23 5.37% 1.1[0.07,16.43]

Subtotal (95% CI) 21 23 5.37% 1.1[0.07,16.43]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 240 239 100% 1.08[0.62,1.89]

Total events: 19 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.98, df=3(P=0.81); I2=0%

Test for overall effect: Z=0.28(P=0.78)

Test for subgroup differences: Chi2=0, df=1 (P=0.99), I2=0%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 4.5. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 5 Medical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.5.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.5.2 Enteral nutrition

Cabre 1990 1/16 4/19 12.08% 0.3[0.04,2.4]

Calvey 1985 11/42 2/22 8.67% 2.88[0.7,11.87]

DeLedinghen 1997 4/12 1/10 3.6% 3.33[0.44,25.23]

Norman 2008 8/30 6/29 20.15% 1.29[0.51,3.26]

Subtotal (95% CI) 100 80 44.49% 1.5[0.78,2.86]

Total events: 24 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=3.83, df=3(P=0.28); I2=21.65%

Test for overall effect: Z=1.21(P=0.22)

4.5.3 Supplements

Hirsch 1993 10/26 11/25 37.03% 0.87[0.45,1.69]

Kobashi 2006 7/119 5/114 16.86% 1.34[0.44,4.1]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 1/41 0/43 1.61% 3.14[0.13,75.02]

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 219 216 55.51% 1.08[0.61,1.91]

Total events: 18 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=0.98, df=2(P=0.61); I2=0%

Test for overall effect: Z=0.27(P=0.79)

Total (95% CI) 319 296 100% 1.27[0.82,1.94]

Total events: 42 (Treatment), 29 (Control)

Favours treatment 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=5.58, df=6(P=0.47); I2=0%

Test for overall effect: Z=1.08(P=0.28)

Test for subgroup differences: Chi2=0.54, df=1 (P=0.46), I2=0%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 4.6. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 6 Surgical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.6.1 Parenteral nutrition

Fan 1994 1/64 0/60 35.08% 2.82[0.12,67.8]

Subtotal (95% CI) 64 60 35.08% 2.82[0.12,67.8]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.64(P=0.52)

4.6.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.6.3 Supplements

Meng 1999 1/21 1/23 64.92% 1.1[0.07,16.43]

Subtotal (95% CI) 21 23 64.92% 1.1[0.07,16.43]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 85 83 100% 1.7[0.23,12.73]

Total events: 2 (Treatment), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.2, df=1(P=0.66); I2=0%

Test for overall effect: Z=0.52(P=0.61)

Test for subgroup differences: Chi2=0.2, df=1 (P=0.66), I2=0%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 4.7. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 7 Alcoholic hepatitis.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.7.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.7.2 Enteral nutrition

Favours treatment 200.05 50.2 1 Favours control

136

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Calvey 1985 11/42 2/22 100% 2.88[0.7,11.87]

Subtotal (95% CI) 42 22 100% 2.88[0.7,11.87]

Total events: 11 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.47(P=0.14)

4.7.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 42 22 100% 2.88[0.7,11.87]

Total events: 11 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.47(P=0.14)

Test for subgroup differences: Not applicable

Favours treatment 200.05 50.2 1 Favours control

Analysis 4.8. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 8 Cirrhosis.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.8.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.8.2 Enteral nutrition

Cabre 1990 1/16 4/19 16.57% 0.3[0.04,2.4]

DeLedinghen 1997 4/12 1/10 4.94% 3.33[0.44,25.23]

Norman 2008 8/30 6/29 27.65% 1.29[0.51,3.26]

Subtotal (95% CI) 58 58 49.17% 1.16[0.55,2.43]

Total events: 13 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=2.73, df=2(P=0.26); I2=26.76%

Test for overall effect: Z=0.39(P=0.69)

4.8.3 Supplements

Hirsch 1993 10/26 11/25 50.83% 0.87[0.45,1.69]

Nakaya 2007 0/19 0/19 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 59 59 50.83% 0.87[0.45,1.69]

Total events: 10 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Test for overall effect: Z=0.4(P=0.69)

Total (95% CI) 117 117 100% 1.01[0.62,1.67]

Total events: 23 (Treatment), 22 (Control)

Favours treatment 500.02 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=3.11, df=3(P=0.37); I2=3.55%

Test for overall effect: Z=0.06(P=0.95)

Test for subgroup differences: Chi2=0.31, df=1 (P=0.58), I2=0%

Favours treatment 500.02 100.1 1 Favours control

Analysis 4.9. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 9 HCC.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.9.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.9.2 Eneral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.9.3 Supplements

Kobashi 2006 7/119 5/114 91.27% 1.34[0.44,4.1]

Poon 2004 1/41 0/43 8.73% 3.14[0.13,75.02]

Subtotal (95% CI) 160 157 100% 1.5[0.53,4.26]

Total events: 8 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.25, df=1(P=0.62); I2=0%

Test for overall effect: Z=0.76(P=0.45)

Total (95% CI) 160 157 100% 1.5[0.53,4.26]

Total events: 8 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.25, df=1(P=0.62); I2=0%

Test for overall effect: Z=0.76(P=0.45)

Test for subgroup differences: Chi2=0, df=1 (P<0.0001), I2=100%

Favours treatment 2000.005 100.1 1 Favours control

Analysis 4.10. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 10 Abstracts excluded.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.10.1 Parenteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.10.2 Parenteral nutrition - surgical trials

Favours treatment 2000.005 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 1/64 0/60 2.51% 2.82[0.12,67.8]

Subtotal (95% CI) 64 60 2.51% 2.82[0.12,67.8]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.64(P=0.52)

4.10.3 Enteral nutrition - medical trials

Cabre 1990 1/16 4/19 17.8% 0.3[0.04,2.4]

Calvey 1985 11/42 2/22 12.78% 2.88[0.7,11.87]

DeLedinghen 1997 4/12 1/10 5.31% 3.33[0.44,25.23]

Subtotal (95% CI) 70 51 35.88% 1.67[0.68,4.1]

Total events: 16 (Treatment), 7 (Control)

Heterogeneity: Tau2=0; Chi2=3.65, df=2(P=0.16); I2=45.17%

Test for overall effect: Z=1.11(P=0.27)

4.10.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.10.5 Supplements - medical trials

Hirsch 1993 10/26 11/25 54.58% 0.87[0.45,1.69]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 1/41 0/43 2.38% 3.14[0.13,75.02]

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 100 102 56.96% 0.97[0.51,1.84]

Total events: 11 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.62, df=1(P=0.43); I2=0%

Test for overall effect: Z=0.1(P=0.92)

4.10.6 Supplements - surgical trials

Meng 1999 1/21 1/23 4.65% 1.1[0.07,16.43]

Subtotal (95% CI) 21 23 4.65% 1.1[0.07,16.43]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 255 236 100% 1.27[0.76,2.13]

Total events: 29 (Treatment), 19 (Control)

Heterogeneity: Tau2=0; Chi2=5.83, df=6(P=0.44); I2=0%

Test for overall effect: Z=0.91(P=0.36)

Test for subgroup differences: Chi2=1.21, df=1 (P=0.75), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

139

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Analysis 4.11. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 11 Surgical trials without transplant patients (no trials with transplant patients).

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.11.1 Parenteral nutrition

Fan 1994 1/64 0/60 35.08% 2.82[0.12,67.8]

Subtotal (95% CI) 64 60 35.08% 2.82[0.12,67.8]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.64(P=0.52)

4.11.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.11.3 Supplements

Meng 1999 1/21 1/23 64.92% 1.1[0.07,16.43]

Subtotal (95% CI) 21 23 64.92% 1.1[0.07,16.43]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 85 83 100% 1.7[0.23,12.73]

Total events: 2 (Treatment), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.2, df=1(P=0.66); I2=0%

Test for overall effect: Z=0.52(P=0.61)

Test for subgroup differences: Chi2=0.2, df=1 (P=0.66), I2=0%

Favours experimental 2000.005 100.1 1 Favours control

Analysis 4.12. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 12 Intent to treat - best-case scenario for intervention.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.12.1 Parenteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.12.2 Parenteral nutrition - surgical trials

Fan 1994 1/75 15/75 24.98% 0.07[0.01,0.49]

Subtotal (95% CI) 75 75 24.98% 0.07[0.01,0.49]

Total events: 1 (Treatment), 15 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.66(P=0.01)

4.12.3 Enteral nutrition - medical trials

Cabre 1990 1/16 4/19 6.09% 0.3[0.04,2.4]

Favours experimental 2000.005 100.1 1 Favours control

140

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Calvey 1985 11/42 2/22 4.37% 2.88[0.7,11.87]

DeLedinghen 1997 4/12 1/10 1.82% 3.33[0.44,25.23]

Norman 2008 8/31 9/32 14.75% 0.92[0.41,2.07]

Subtotal (95% CI) 101 83 27.03% 1.26[0.69,2.3]

Total events: 24 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=4.62, df=3(P=0.2); I2=35.07%

Test for overall effect: Z=0.74(P=0.46)

4.12.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.12.5 Supplements - medical trials

Hirsch 1993 10/32 19/33 31.16% 0.54[0.3,0.98]

Kobashi 2006 7/119 5/114 8.51% 1.34[0.44,4.1]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 1/44 2/44 3.33% 0.5[0.05,5.32]

Tangkijvanich 2000 0/15 0/15 Not estimable

Subtotal (95% CI) 229 225 42.99% 0.7[0.42,1.16]

Total events: 18 (Treatment), 26 (Control)

Heterogeneity: Tau2=0; Chi2=2.08, df=2(P=0.35); I2=3.81%

Test for overall effect: Z=1.38(P=0.17)

4.12.6 Supplements - surgical trials

Meng 1999 1/25 3/25 5% 0.33[0.04,2.99]

Subtotal (95% CI) 25 25 5% 0.33[0.04,2.99]

Total events: 1 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.98(P=0.33)

Total (95% CI) 430 408 100% 0.67[0.47,0.97]

Total events: 44 (Treatment), 60 (Control)

Heterogeneity: Tau2=0; Chi2=15.16, df=8(P=0.06); I2=47.24%

Test for overall effect: Z=2.15(P=0.03)

Test for subgroup differences: Chi2=8.97, df=1 (P=0.03), I2=66.56%

Favours experimental 2000.005 100.1 1 Favours control

Analysis 4.13. Comparison 4 Appearance of gastrointestinal bleeding, Outcome 13 Intent to treat - worst-case scenario for intervention.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.13.1 Parenteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours experimental 5000.002 100.1 1 Favours control

141

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

4.13.2 Parenteral nutrition - surgical trials

Fan 1994 12/75 0/75 1.58% 25[1.51,414.73]

Subtotal (95% CI) 75 75 1.58% 25[1.51,414.73]

Total events: 12 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.25(P=0.02)

4.13.3 Enteral nutrition - medical trials

Cabre 1990 1/16 4/19 11.53% 0.3[0.04,2.4]

Calvey 1985 11/42 2/22 8.28% 2.88[0.7,11.87]

DeLedinghen 1997 4/12 1/10 3.44% 3.33[0.44,25.23]

Norman 2008 9/31 6/32 18.62% 1.55[0.62,3.84]

Subtotal (95% CI) 101 83 41.86% 1.61[0.85,3.07]

Total events: 25 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=3.67, df=3(P=0.3); I2=18.28%

Test for overall effect: Z=1.46(P=0.14)

4.13.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

4.13.5 Supplements - medical trials

Hirsch 1993 16/32 11/33 34.15% 1.5[0.83,2.72]

Kobashi 2006 7/119 5/114 16.1% 1.34[0.44,4.1]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 4/44 0/44 1.58% 9[0.5,162.33]

Tangkijvanich 2000 1/15 0/15 1.58% 3[0.13,68.26]

Subtotal (95% CI) 229 225 53.41% 1.72[1.02,2.88]

Total events: 28 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=1.77, df=3(P=0.62); I2=0%

Test for overall effect: Z=2.05(P=0.04)

4.13.6 Supplements - surgical trials

Meng 1999 5/25 1/25 3.15% 5[0.63,39.79]

Subtotal (95% CI) 25 25 3.15% 5[0.63,39.79]

Total events: 5 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.52(P=0.13)

Total (95% CI) 430 408 100% 2.14[1.46,3.15]

Total events: 70 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=10.92, df=9(P=0.28); I2=17.61%

Test for overall effect: Z=3.88(P=0)

Test for subgroup differences: Chi2=4.43, df=1 (P=0.22), I2=32.35%

Favours experimental 5000.002 100.1 1 Favours control

142

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Comparison 5. Appearance of encephalopathy - all studies

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 23 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 All trials 23 1062 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.65, 1.08]

1.2 Standard amino acids 11 339 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.50, 1.48]

1.3 BCAAs 15 772 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.63, 1.09]

2 Parenteral nutrition - all trials 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

2.1 All trials 5 231 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.21, 1.25]

2.2 Standard amino acids 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

2.3 BCAAs 2 144 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

3 Parenteral nutrition - medical trials 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

3.1 All trials 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

3.2 Standard amino acids 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

3.3 BCAAs 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Parenteral nutrition - surgical trials 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

4.1 All trials 2 144 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

4.2 Standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

4.3 BCAAs 2 144 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

5 Enteral nutrition - all studies 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

5.1 Standard amino acids 4 91 Risk Ratio (M-H, Fixed, 95% CI) 1.73 [0.67, 4.45]

5.2 BCAAs 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

6 Enteral nutrition - medical trials 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

6.1 All studies 4 102 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.52, 3.44]

6.2 Standard amino acids 4 91 Risk Ratio (M-H, Fixed, 95% CI) 1.73 [0.67, 4.45]

6.3 BCAAs 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

7 Enteral nutrition - surgical trials 0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

7.1 All trials 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

7.2 Standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

143

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

7.3 BCAAs 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

8 Supplements 14 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

8.1 All trials 14 734 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.61, 1.05]

8.2 Standard amino acids -medical trials 4 170 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.31, 1.57]

8.3 BCAAs - medical trials 10 536 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.60, 1.05]

8.4 All supplements - medical 12 666 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.61, 1.05]

8.5 All surgical 2 68 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

9 Medical trials all trials 19 846 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.66, 1.11]

9.1 Parenteral nutrition 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

9.2 Enteral nutrition 4 102 Risk Ratio (M-H, Fixed, 95% CI) 1.85 [0.75, 4.56]

9.3 Supplements 12 657 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.61, 1.06]

10 Medical trials - standard amino acids 11 339 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.50, 1.48]

10.1 Parenteral nutrition 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

10.2 Enteral nutrition 4 91 Risk Ratio (M-H, Fixed, 95% CI) 1.73 [0.67, 4.45]

10.3 Supplements 4 161 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.32, 1.67]

11 Medical trials - BCAAs 11 560 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.64, 1.12]

11.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

11.2 Enteral nutrition 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

11.3 Supplements 10 536 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.60, 1.05]

12 Surgical trials - all studies 4 212 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

12.1 Parenteral nutrition 2 144 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

12.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

12.3 Supplements 2 68 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13 Surgical trials - standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

144

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

14 Surgical trials - BCAAs 4 212 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

14.1 Parenteral nutrition 2 144 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

14.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

14.3 Supplements 2 68 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

15 Alcoholic hepatitis - all studies 6 172 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.53, 2.68]

15.1 Parenteral nutrition 2 47 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 3.52]

15.2 Enteral nutrition 2 48 Risk Ratio (M-H, Fixed, 95% CI) 1.95 [0.57, 6.69]

15.3 Supplements 2 77 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.32, 4.56]

16 Alcoholic hepatitis - standard amino acids

6 161 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.45, 2.50]

16.1 Parenteral nutrition 2 47 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 3.52]

16.2 Enteral nutrition 2 37 Risk Ratio (M-H, Fixed, 95% CI) 1.75 [0.45, 6.70]

16.3 Supplements 2 77 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.32, 4.56]

17 Alcoholic hepatitis - BCAA 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

17.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

17.2 Enteral nutrition 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

17.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

18 Cirrhosis - all studies 12 420 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.64, 1.08]

18.1 Parenteral nutrition 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.5 [0.10, 2.43]

18.2 Enteral nutrition 2 54 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.46, 6.44]

18.3 Supplements 9 326 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.62, 1.04]

19 Cirrhosis - standard amino acids 6 229 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.53, 1.72]

19.1 Parenteral nutrition 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.5 [0.10, 2.43]

19.2 Enteral nutrition 2 54 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.46, 6.44]

19.3 Supplements 3 135 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.44, 1.97]

20 Cirrhosis - BCAAs 8 231 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.63, 1.04]

20.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

145

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

20.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

20.3 Supplementss 8 231 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.63, 1.04]

21 HCC - all studies 2 305 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.38, 1.48]

21.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

21.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

21.3 Supplements 2 305 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.38, 1.48]

22 HCC - standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

22.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

22.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

22.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

23 HCC - BCAAs 2 305 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.38, 1.48]

23.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

23.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

23.3 Supplements 2 305 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.38, 1.48]

24 Abstracts excluded 18 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

24.1 All trials 18 659 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.64, 1.13]

24.2 Standard amino acids 7 201 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.42, 1.86]

24.3 BCAAs 12 471 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.67, 1.16]

24.4 Parenteral nutrition all 5 231 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.21, 1.25]

24.5 Parenteral nutrition - SAAs 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

24.6 Parenteral nutrition - BCAAs 2 144 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.21, 2.12]

24.7 Enteral nutrition all 2 48 Risk Ratio (M-H, Fixed, 95% CI) 1.95 [0.57, 6.69]

24.8 Enteral nutrition - SAAs 2 37 Risk Ratio (M-H, Fixed, 95% CI) 1.75 [0.45, 6.70]

24.9 Enteral nutrition - BCAAs 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

24.10 Supplements all 11 380 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.68, 1.13]

24.11 Supplements - SAAs 2 77 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.32, 4.56]

24.12 Supplements - BCAAs 9 303 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.68, 1.03]

146

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

25 Surgical trials - transplant trials elim- inated

3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

25.1 All trials 3 192 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.25, 3.58]

25.2 Standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

25.3 BCAAs 3 192 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.25, 3.58]

26 ITT - Parenteral nutrition - best-case scenario

5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

26.1 All trials 5 257 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.11, 0.55]

26.2 Standard amino acids 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

26.3 BCAAs 2 170 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.08, 0.55]

27 ITT - Parenteral nutrition - worst-case scenario

5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

27.1 All trials 5 257 Risk Ratio (M-H, Fixed, 95% CI) 1.37 [0.70, 2.71]

27.2 Standard amino acids 3 87 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.48]

27.3 BCAAs 2 170 Risk Ratio (M-H, Fixed, 95% CI) 2.38 [0.99, 5.73]

28 ITT - Enteral nutrition - best-case sce- nario

4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

28.1 All trials 4 112 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.53, 2.74]

28.2 Standard amino acids 4 101 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.45, 2.52]

28.3 BCAAs 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

29 ITT - Enteral nutrition - worst-case scenario

4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

29.1 All trials 4 112 Risk Ratio (M-H, Fixed, 95% CI) 2.77 [1.23, 6.26]

29.2 Standard amino acids 4 101 Risk Ratio (M-H, Fixed, 95% CI) 2.78 [1.19, 6.48]

29.3 BCAAs 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [0.53, 10.55]

30 ITT- Supplements - best-case sce- nario

14 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

30.1 All trials 14 782 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.47, 0.79]

30.2 Standard amino acids -medical tri- als

4 191 Risk Ratio (M-H, Fixed, 95% CI) 0.36 [0.18, 0.72]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

30.3 BCAAs - medical trials 10 559 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.52, 0.90]

30.4 All supplements - medical 12 707 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.48, 0.81]

30.5 All surgical 2 74 Risk Ratio (M-H, Fixed, 95% CI) 0.2 [0.01, 3.97]

31 ITT - Supplements - worst-case sce- nario

14 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

31.1 All trials 14 781 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.90, 1.54]

31.2 Standard amino acids -medical tri- als

4 191 Risk Ratio (M-H, Fixed, 95% CI) 1.57 [0.79, 3.13]

31.3 BCAAs - medical trials 10 559 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.78, 1.35]

31.4 All supplements - medical 12 707 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.85, 1.45]

31.5 All surgical 2 74 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.51, 158.85]

Analysis 5.1. Comparison 5 Appearance of encephalopathy - all studies, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.1.1 All trials

Achord 1987 0/12 0/10 Not estimable

Bunout 1989 1/14 0/12 0.72% 2.6[0.12,58.48]

Calvey 1985 7/21 2/13 3.31% 2.17[0.53,8.88]

Fan 1994 4/64 4/60 5.53% 0.94[0.25,3.58]

Guy 1995 4/14 3/18 3.51% 1.71[0.46,6.44]

Hasse 1997 5/23 3/6 6.37% 0.43[0.14,1.32]

Hayashi 1991 0/2 0/6 Not estimable

Hirsch 1993 3/26 3/25 4.1% 0.96[0.21,4.32]

Humbert 1988 24/27 22/22 33.08% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Kearns 1992 1/6 1/8 1.15% 1.33[0.1,17.28]

Kobashi 2006 12/108 16/113 20.94% 0.78[0.39,1.58]

Meng 1999 0/21 0/23 Not estimable

Nakaya 2007 0/19 1/19 2.01% 0.33[0.01,7.7]

Naveau 1986 2/20 4/20 5.36% 0.5[0.1,2.43]

Poon 2004 0/41 1/43 1.96% 0.35[0.01,8.34]

Puglionisi 1985 0/10 2/10 3.35% 0.2[0.01,3.7]

Schuetz 2006 0/11 0/11 Not estimable

Sievert 1999 4/61 3/34 5.16% 0.74[0.18,3.13]

Simko 1983 0/7 0/3 Not estimable

Simon 1988 0/13 2/12 3.47% 0.19[0.01,3.52]

Tangkijvanich 2000 0/14 0/15 Not estimable

Favours treatment 2000.005 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 557 505 100% 0.84[0.65,1.08]

Total events: 67 (Treatment), 67 (Control)

Heterogeneity: Tau2=0; Chi2=8.65, df=14(P=0.85); I2=0%

Test for overall effect: Z=1.36(P=0.17)

5.1.2 Standard amino acids

Achord 1987 0/12 0/10 Not estimable

Bunout 1989 1/14 0/12 2.39% 2.6[0.12,58.48]

Calvey 1985 3/10 2/13 7.76% 1.95[0.4,9.54]

Guy 1995 4/14 3/18 11.71% 1.71[0.46,6.44]

Hasse 1997 4/14 3/6 18.73% 0.57[0.18,1.81]

Hirsch 1993 3/26 3/25 13.64% 0.96[0.21,4.32]

Kearns 1992 1/6 1/8 3.82% 1.33[0.1,17.28]

Naveau 1986 2/20 4/20 17.84% 0.5[0.1,2.43]

Schuetz 2006 0/11 0/11 Not estimable

Sievert 1999 1/30 3/34 12.54% 0.38[0.04,3.44]

Simon 1988 0/13 2/12 11.56% 0.19[0.01,3.52]

Subtotal (95% CI) 170 169 100% 0.86[0.5,1.48]

Total events: 19 (Treatment), 21 (Control)

Heterogeneity: Tau2=0; Chi2=5.19, df=8(P=0.74); I2=0%

Test for overall effect: Z=0.54(P=0.59)

5.1.3 BCAAs

Calvey 1985 4/11 2/13 3.15% 2.36[0.53,10.55]

Fan 1994 4/64 4/60 7.09% 0.94[0.25,3.58]

Hasse 1997 1/9 3/6 6.18% 0.22[0.03,1.66]

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 42.43% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Kobashi 2006 12/108 16/113 26.85% 0.78[0.39,1.58]

Meng 1999 0/21 0/23 Not estimable

Nakaya 2007 0/19 1/19 2.58% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 2.52% 0.35[0.01,8.34]

Puglionisi 1985 0/10 2/10 4.29% 0.2[0.01,3.7]

Sievert 1999 3/31 3/34 4.91% 1.1[0.24,5.04]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 387 385 100% 0.82[0.63,1.09]

Total events: 48 (Treatment), 54 (Control)

Heterogeneity: Tau2=0; Chi2=6.32, df=8(P=0.61); I2=0%

Test for overall effect: Z=1.37(P=0.17)

Test for subgroup differences: Chi2=0.02, df=1 (P=0.99), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

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Analysis 5.2. Comparison 5 Appearance of encephalopathy - all studies, Outcome 2 Parenteral nutrition - all trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.2.1 All trials

Achord 1987 0/12 0/10 Not estimable

Fan 1994 4/64 4/60 31.23% 0.94[0.25,3.58]

Naveau 1986 2/20 4/20 30.25% 0.5[0.1,2.43]

Puglionisi 1985 0/10 2/10 18.91% 0.2[0.01,3.7]

Simon 1988 0/13 2/12 19.61% 0.19[0.01,3.52]

Subtotal (95% CI) 119 112 100% 0.52[0.21,1.25]

Total events: 6 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.63, df=3(P=0.65); I2=0%

Test for overall effect: Z=1.46(P=0.14)

5.2.2 Standard amino acids

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 60.67% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 39.33% 0.19[0.01,3.52]

Subtotal (95% CI) 45 42 100% 0.38[0.1,1.48]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.2.3 BCAAs

Fan 1994 4/64 4/60 62.29% 0.94[0.25,3.58]

Puglionisi 1985 0/10 2/10 37.71% 0.2[0.01,3.7]

Subtotal (95% CI) 74 70 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

Test for subgroup differences: Chi2=0.37, df=1 (P=0.83), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

Analysis 5.3. Comparison 5 Appearance of encephalopathy - all studies, Outcome 3 Parenteral nutrition - medical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.3.1 All trials

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 60.67% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 39.33% 0.19[0.01,3.52]

Subtotal (95% CI) 45 42 100% 0.38[0.1,1.48]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.3.2 Standard amino acids

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 60.67% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 39.33% 0.19[0.01,3.52]

Favours experimental 2000.005 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 45 42 100% 0.38[0.1,1.48]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.3.3 BCAAs

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Not applicable

Favours experimental 2000.005 100.1 1 Favours control

Analysis 5.4. Comparison 5 Appearance of encephalopathy - all studies, Outcome 4 Parenteral nutrition - surgical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.4.1 All trials

Fan 1994 4/64 4/60 62.29% 0.94[0.25,3.58]

Puglionisi 1985 0/10 2/10 37.71% 0.2[0.01,3.7]

Subtotal (95% CI) 74 70 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

5.4.2 Standard amino acids

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.4.3 BCAAs

Fan 1994 4/64 4/60 62.29% 0.94[0.25,3.58]

Puglionisi 1985 0/10 2/10 37.71% 0.2[0.01,3.7]

Subtotal (95% CI) 74 70 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

Test for subgroup differences: Not applicable

Favours experimental 2000.005 100.1 1 Favours control

Analysis 5.5. Comparison 5 Appearance of encephalopathy - all studies, Outcome 5 Enteral nutrition - all studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.5.1 Standard amino acids

Favours treatment 500.02 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Calvey 1985 3/10 2/13 33.31% 1.95[0.4,9.54]

Guy 1995 4/14 3/18 50.28% 1.71[0.46,6.44]

Kearns 1992 1/6 1/8 16.42% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 41 50 100% 1.73[0.67,4.45]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.06, df=2(P=0.97); I2=0%

Test for overall effect: Z=1.14(P=0.25)

5.5.2 BCAAs

Calvey 1985 4/11 2/13 100% 2.36[0.53,10.55]

Subtotal (95% CI) 11 13 100% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

Test for subgroup differences: Chi2=0.12, df=1 (P=0.73), I2=0%

Favours treatment 500.02 100.1 1 Favours control

Analysis 5.6. Comparison 5 Appearance of encephalopathy - all studies, Outcome 6 Enteral nutrition - medical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.6.1 All studies

Calvey 1985 3/21 2/13 41.5% 0.93[0.18,4.84]

Guy 1995 4/14 3/18 44.1% 1.71[0.46,6.44]

Kearns 1992 1/6 1/8 14.4% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 52 50 100% 1.33[0.52,3.44]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.32, df=2(P=0.85); I2=0%

Test for overall effect: Z=0.59(P=0.55)

5.6.2 Standard amino acids

Calvey 1985 3/10 2/13 33.31% 1.95[0.4,9.54]

Guy 1995 4/14 3/18 50.28% 1.71[0.46,6.44]

Kearns 1992 1/6 1/8 16.42% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 41 50 100% 1.73[0.67,4.45]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.06, df=2(P=0.97); I2=0%

Test for overall effect: Z=1.14(P=0.25)

5.6.3 BCAAs

Calvey 1985 4/11 2/13 100% 2.36[0.53,10.55]

Subtotal (95% CI) 11 13 100% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

Test for subgroup differences: Chi2=0.42, df=1 (P=0.81), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

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Analysis 5.8. Comparison 5 Appearance of encephalopathy - all studies, Outcome 8 Supplements.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.8.1 All trials

Bunout 1989 1/14 0/12 0.96% 2.6[0.12,58.48]

Hasse 1997 5/23 3/6 8.54% 0.43[0.14,1.32]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/26 3/25 5.49% 0.96[0.21,4.32]

Humbert 1988 24/27 22/22 44.35% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Kobashi 2006 12/108 16/113 28.08% 0.78[0.39,1.58]

Meng 1999 0/21 0/23 Not estimable

Nakaya 2007 0/19 1/19 2.69% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 2.63% 0.35[0.01,8.34]

Sievert 1999 4/70 3/34 7.25% 0.65[0.15,2.73]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 395 339 100% 0.8[0.61,1.05]

Total events: 49 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=4.58, df=7(P=0.71); I2=0%

Test for overall effect: Z=1.63(P=0.1)

5.8.2 Standard amino acids -medical trials

Bunout 1989 1/14 0/12 4.87% 2.6[0.12,58.48]

Hasse 1997 4/14 3/6 38.18% 0.57[0.18,1.81]

Hirsch 1993 3/26 3/25 27.81% 0.96[0.21,4.32]

Sievert 1999 1/39 3/34 29.14% 0.29[0.03,2.66]

Subtotal (95% CI) 93 77 100% 0.7[0.31,1.57]

Total events: 9 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=1.58, df=3(P=0.66); I2=0%

Test for overall effect: Z=0.87(P=0.38)

5.8.3 BCAAs - medical trials

Hasse 1997 1/9 3/6 7.23% 0.22[0.03,1.66]

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 49.64% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 12/108 16/113 31.42% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 3.01% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 2.94% 0.35[0.01,8.34]

Sievert 1999 3/31 3/34 5.75% 1.1[0.24,5.04]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 270 266 100% 0.79[0.6,1.05]

Total events: 40 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=4.79, df=5(P=0.44); I2=0%

Test for overall effect: Z=1.64(P=0.1)

5.8.4 All supplements - medical

Bunout 1989 1/14 0/12 0.96% 2.6[0.12,58.48]

Favours treatment 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hasse 1997 5/23 3/6 8.54% 0.43[0.14,1.32]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/26 3/25 5.49% 0.96[0.21,4.32]

Humbert 1988 24/27 22/22 44.35% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 12/108 16/113 28.08% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 2.69% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 2.63% 0.35[0.01,8.34]

Sievert 1999 4/70 3/34 7.25% 0.65[0.15,2.73]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 363 303 100% 0.8[0.61,1.05]

Total events: 49 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=4.58, df=7(P=0.71); I2=0%

Test for overall effect: Z=1.63(P=0.1)

5.8.5 All surgical

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Subtotal (95% CI) 32 36 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Chi2=0.1, df=1 (P=0.99), I2=0%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.9. Comparison 5 Appearance of encephalopathy - all studies, Outcome 9 Medical trials all trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.9.1 Parenteral nutrition

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 5.88% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 3.81% 0.19[0.01,3.52]

Subtotal (95% CI) 45 42 9.69% 0.38[0.1,1.48]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.9.2 Enteral nutrition

Calvey 1985 7/21 2/13 3.63% 2.17[0.53,8.88]

Guy 1995 4/14 3/18 3.86% 1.71[0.46,6.44]

Kearns 1992 1/6 1/8 1.26% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 52 50 8.75% 1.85[0.75,4.56]

Total events: 12 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.12, df=2(P=0.94); I2=0%

Test for overall effect: Z=1.33(P=0.18)

Favours treatment 1000.01 100.1 1 Favours control

154

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.9.3 Supplements

Bunout 1989 1/14 0/12 0.79% 2.6[0.12,58.48]

Hasse 1997 5/23 3/6 6.99% 0.43[0.14,1.32]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/26 3/25 4.49% 0.96[0.21,4.32]

Humbert 1988 24/27 22/22 36.3% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 12/108 16/113 22.98% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 2.2% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 2.15% 0.35[0.01,8.34]

Sievert 1999 4/61 3/34 5.66% 0.74[0.18,3.13]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 354 303 81.57% 0.8[0.61,1.06]

Total events: 49 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=4.22, df=7(P=0.75); I2=0%

Test for overall effect: Z=1.57(P=0.12)

Total (95% CI) 451 395 100% 0.85[0.66,1.11]

Total events: 63 (Treatment), 61 (Control)

Heterogeneity: Tau2=0; Chi2=7.35, df=12(P=0.83); I2=0%

Test for overall effect: Z=1.19(P=0.24)

Test for subgroup differences: Chi2=4.33, df=1 (P=0.11), I2=53.85%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.10. Comparison 5 Appearance of encephalopathy - all studies, Outcome 10 Medical trials - standard amino acids.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.10.1 Parenteral nutrition

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 17.84% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 11.56% 0.19[0.01,3.52]

Subtotal (95% CI) 45 42 29.4% 0.38[0.1,1.48]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.10.2 Enteral nutrition

Calvey 1985 3/10 2/13 7.76% 1.95[0.4,9.54]

Guy 1995 4/14 3/18 11.71% 1.71[0.46,6.44]

Kearns 1992 1/6 1/8 3.82% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 41 50 23.29% 1.73[0.67,4.45]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.06, df=2(P=0.97); I2=0%

Test for overall effect: Z=1.14(P=0.25)

Favours treatment 1000.01 100.1 1 Favours control

155

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.10.3 Supplements

Bunout 1989 1/14 0/12 2.39% 2.6[0.12,58.48]

Hasse 1997 4/14 3/6 18.73% 0.57[0.18,1.81]

Hirsch 1993 3/26 3/25 13.64% 0.96[0.21,4.32]

Sievert 1999 1/30 3/34 12.54% 0.38[0.04,3.44]

Subtotal (95% CI) 84 77 47.31% 0.74[0.32,1.67]

Total events: 9 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=1.29, df=3(P=0.73); I2=0%

Test for overall effect: Z=0.74(P=0.46)

Total (95% CI) 170 169 100% 0.86[0.5,1.48]

Total events: 19 (Treatment), 21 (Control)

Heterogeneity: Tau2=0; Chi2=5.19, df=8(P=0.74); I2=0%

Test for overall effect: Z=0.54(P=0.59)

Test for subgroup differences: Chi2=3.63, df=1 (P=0.16), I2=44.88%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.11. Comparison 5 Appearance of encephalopathy - all studies, Outcome 11 Medical trials - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.11.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.11.2 Enteral nutrition

Calvey 1985 4/11 2/13 3.55% 2.36[0.53,10.55]

Subtotal (95% CI) 11 13 3.55% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

5.11.3 Supplements

Hasse 1997 1/9 3/6 6.98% 0.22[0.03,1.66]

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 47.88% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 12/108 16/113 30.3% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 2.91% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 2.84% 0.35[0.01,8.34]

Sievert 1999 3/31 3/34 5.55% 1.1[0.24,5.04]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 270 266 96.45% 0.79[0.6,1.05]

Total events: 40 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=4.79, df=5(P=0.44); I2=0%

Test for overall effect: Z=1.64(P=0.1)

Favours treatment 1000.01 100.1 1 Favours control

156

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 281 279 100% 0.85[0.64,1.12]

Total events: 44 (Treatment), 48 (Control)

Heterogeneity: Tau2=0; Chi2=4.81, df=6(P=0.57); I2=0%

Test for overall effect: Z=1.19(P=0.24)

Test for subgroup differences: Chi2=1.99, df=1 (P=0.16), I2=49.82%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.12. Comparison 5 Appearance of encephalopathy - all studies, Outcome 12 Surgical trials - all studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.12.1 Parenteral nutrition

Fan 1994 4/64 4/60 62.29% 0.94[0.25,3.58]

Puglionisi 1985 0/10 2/10 37.71% 0.2[0.01,3.7]

Subtotal (95% CI) 74 70 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

5.12.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.12.3 Supplements

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Subtotal (95% CI) 32 36 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 106 106 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

Test for subgroup differences: Not applicable

Favours treatment 2000.005 100.1 1 Favours control

Analysis 5.14. Comparison 5 Appearance of encephalopathy - all studies, Outcome 14 Surgical trials - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.14.1 Parenteral nutrition

Fan 1994 4/64 4/60 62.29% 0.94[0.25,3.58]

Favours treatment 2000.005 100.1 1 Favours control

157

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Puglionisi 1985 0/10 2/10 37.71% 0.2[0.01,3.7]

Subtotal (95% CI) 74 70 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

5.14.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.14.3 Supplements

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Subtotal (95% CI) 32 36 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 106 106 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

Test for subgroup differences: Not applicable

Favours treatment 2000.005 100.1 1 Favours control

Analysis 5.15. Comparison 5 Appearance of encephalopathy - all studies, Outcome 15 Alcoholic hepatitis - all studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.15.1 Parenteral nutrition

Achord 1987 0/12 0/10 Not estimable

Simon 1988 0/13 2/12 27.25% 0.19[0.01,3.52]

Subtotal (95% CI) 25 22 27.25% 0.19[0.01,3.52]

Total events: 0 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.12(P=0.26)

5.15.2 Enteral nutrition

Calvey 1985 7/21 2/13 25.97% 2.17[0.53,8.88]

Kearns 1992 1/6 1/8 9.01% 1.33[0.1,17.28]

Subtotal (95% CI) 27 21 34.97% 1.95[0.57,6.69]

Total events: 8 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.11, df=1(P=0.74); I2=0%

Test for overall effect: Z=1.06(P=0.29)

5.15.3 Supplements

Favours experimental 2000.005 100.1 1 Favours control

158

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Bunout 1989 1/14 0/12 5.63% 2.6[0.12,58.48]

Hirsch 1993 3/26 3/25 32.15% 0.96[0.21,4.32]

Subtotal (95% CI) 40 37 37.78% 1.21[0.32,4.56]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.32, df=1(P=0.57); I2=0%

Test for overall effect: Z=0.28(P=0.78)

Total (95% CI) 92 80 100% 1.19[0.53,2.68]

Total events: 12 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=2.55, df=4(P=0.64); I2=0%

Test for overall effect: Z=0.42(P=0.68)

Test for subgroup differences: Chi2=2.11, df=1 (P=0.35), I2=5.34%

Favours experimental 2000.005 100.1 1 Favours control

Analysis 5.16. Comparison 5 Appearance of encephalopathy - all studies, Outcome 16 Alcoholic hepatitis - standard amino acids.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.16.1 Parenteral nutrition

Achord 1987 0/12 0/10 Not estimable

Simon 1988 0/13 2/12 29.52% 0.19[0.01,3.52]

Subtotal (95% CI) 25 22 29.52% 0.19[0.01,3.52]

Total events: 0 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.12(P=0.26)

5.16.2 Enteral nutrition

Calvey 1985 3/10 2/13 19.8% 1.95[0.4,9.54]

Kearns 1992 1/6 1/8 9.76% 1.33[0.1,17.28]

Subtotal (95% CI) 16 21 29.56% 1.75[0.45,6.7]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.06, df=1(P=0.8); I2=0%

Test for overall effect: Z=0.81(P=0.42)

5.16.3 Supplements

Bunout 1989 1/14 0/12 6.1% 2.6[0.12,58.48]

Hirsch 1993 3/26 3/25 34.83% 0.96[0.21,4.32]

Subtotal (95% CI) 40 37 40.92% 1.21[0.32,4.56]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.32, df=1(P=0.57); I2=0%

Test for overall effect: Z=0.28(P=0.78)

Total (95% CI) 81 80 100% 1.06[0.45,2.5]

Total events: 8 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=2.28, df=4(P=0.69); I2=0%

Test for overall effect: Z=0.14(P=0.89)

Test for subgroup differences: Chi2=1.85, df=1 (P=0.4), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

159

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Analysis 5.17. Comparison 5 Appearance of encephalopathy - all studies, Outcome 17 Alcoholic hepatitis - BCAA.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.17.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.17.2 Enteral nutrition

Calvey 1985 4/11 2/13 100% 2.36[0.53,10.55]

Subtotal (95% CI) 11 13 100% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

5.17.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 11 13 100% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

Test for subgroup differences: Not applicable

Favours treatment 500.02 100.1 1 Favours control

Analysis 5.18. Comparison 5 Appearance of encephalopathy - all studies, Outcome 18 Cirrhosis - all studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.18.1 Parenteral nutrition

Naveau 1986 2/20 4/20 8.99% 0.5[0.1,2.43]

Subtotal (95% CI) 20 20 8.99% 0.5[0.1,2.43]

Total events: 2 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.86(P=0.39)

5.18.2 Enteral nutrition

Guy 1995 4/14 3/18 5.9% 1.71[0.46,6.44]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 25 29 5.9% 1.71[0.46,6.44]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.8(P=0.42)

5.18.3 Supplements

Favours treatment 1000.01 100.1 1 Favours control

160

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hasse 1997 5/23 3/6 10.69% 0.43[0.14,1.32]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/26 3/25 6.87% 0.96[0.21,4.32]

Humbert 1988 24/27 22/22 55.52% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Nakaya 2007 0/19 1/19 3.37% 0.33[0.01,7.7]

Sievert 1999 4/61 3/34 8.66% 0.74[0.18,3.13]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 191 135 85.11% 0.8[0.62,1.04]

Total events: 36 (Treatment), 32 (Control)

Heterogeneity: Tau2=0; Chi2=3.39, df=4(P=0.49); I2=0%

Test for overall effect: Z=1.67(P=0.1)

Total (95% CI) 236 184 100% 0.83[0.64,1.08]

Total events: 42 (Treatment), 39 (Control)

Heterogeneity: Tau2=0; Chi2=4.13, df=6(P=0.66); I2=0%

Test for overall effect: Z=1.37(P=0.17)

Test for subgroup differences: Chi2=1.59, df=1 (P=0.45), I2=0%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.19. Comparison 5 Appearance of encephalopathy - all studies, Outcome 19 Cirrhosis - standard amino acids.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.19.1 Parenteral nutrition

Naveau 1986 2/20 4/20 23.96% 0.5[0.1,2.43]

Subtotal (95% CI) 20 20 23.96% 0.5[0.1,2.43]

Total events: 2 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.86(P=0.39)

5.19.2 Enteral nutrition

Guy 1995 4/14 3/18 15.72% 1.71[0.46,6.44]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 25 29 15.72% 1.71[0.46,6.44]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.8(P=0.42)

5.19.3 Supplements

Hasse 1997 9/14 3/6 25.16% 1.29[0.53,3.13]

Hirsch 1993 3/26 3/25 18.32% 0.96[0.21,4.32]

Sievert 1999 1/30 3/34 16.85% 0.38[0.04,3.44]

Subtotal (95% CI) 70 65 60.32% 0.93[0.44,1.97]

Total events: 13 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=1.14, df=2(P=0.57); I2=0%

Test for overall effect: Z=0.18(P=0.86)

Favours treatment 500.02 100.1 1 Favours control

161

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 115 114 100% 0.95[0.53,1.72]

Total events: 19 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=2.51, df=4(P=0.64); I2=0%

Test for overall effect: Z=0.16(P=0.87)

Test for subgroup differences: Chi2=1.4, df=1 (P=0.5), I2=0%

Favours treatment 500.02 100.1 1 Favours control

Analysis 5.20. Comparison 5 Appearance of encephalopathy - all studies, Outcome 20 Cirrhosis - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.20.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.20.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.20.3 Supplementss

Hasse 1997 1/9 3/6 11.02% 0.22[0.03,1.66]

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 75.63% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Nakaya 2007 0/19 1/19 4.59% 0.33[0.01,7.7]

Sievert 1999 3/31 3/34 8.76% 1.1[0.24,5.04]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 121 110 100% 0.81[0.63,1.04]

Total events: 28 (Treatment), 29 (Control)

Heterogeneity: Tau2=0; Chi2=3.58, df=3(P=0.31); I2=16.16%

Test for overall effect: Z=1.65(P=0.1)

Total (95% CI) 121 110 100% 0.81[0.63,1.04]

Total events: 28 (Treatment), 29 (Control)

Heterogeneity: Tau2=0; Chi2=3.58, df=3(P=0.31); I2=16.16%

Test for overall effect: Z=1.65(P=0.1)

Test for subgroup differences: Not applicable

Favours treatment 1000.01 100.1 1 Favours control

162

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Analysis 5.21. Comparison 5 Appearance of encephalopathy - all studies, Outcome 21 HCC - all studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.21.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.21.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.21.3 Supplements

Kobashi 2006 12/108 16/113 91.43% 0.78[0.39,1.58]

Poon 2004 0/41 1/43 8.57% 0.35[0.01,8.34]

Subtotal (95% CI) 149 156 100% 0.75[0.38,1.48]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.24, df=1(P=0.62); I2=0%

Test for overall effect: Z=0.84(P=0.4)

Total (95% CI) 149 156 100% 0.75[0.38,1.48]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.24, df=1(P=0.62); I2=0%

Test for overall effect: Z=0.84(P=0.4)

Test for subgroup differences: Not applicable

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.23. Comparison 5 Appearance of encephalopathy - all studies, Outcome 23 HCC - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.23.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.23.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.23.3 Supplements

Kobashi 2006 12/108 16/113 91.43% 0.78[0.39,1.58]

Poon 2004 0/41 1/43 8.57% 0.35[0.01,8.34]

Subtotal (95% CI) 149 156 100% 0.75[0.38,1.48]

Total events: 12 (Treatment), 17 (Control)

Favours treatment 1000.01 100.1 1 Favours control

163

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=0.24, df=1(P=0.62); I2=0%

Test for overall effect: Z=0.84(P=0.4)

Total (95% CI) 149 156 100% 0.75[0.38,1.48]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.24, df=1(P=0.62); I2=0%

Test for overall effect: Z=0.84(P=0.4)

Test for subgroup differences: Not applicable

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.24. Comparison 5 Appearance of encephalopathy - all studies, Outcome 24 Abstracts excluded.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.24.1 All trials

Achord 1987 0/12 0/10 Not estimable

Bunout 1989 1/14 0/12 1.12% 2.6[0.12,58.48]

Calvey 1985 7/21 2/13 5.17% 2.17[0.53,8.88]

Fan 1994 4/64 4/60 8.64% 0.94[0.25,3.58]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/26 3/25 6.4% 0.96[0.21,4.32]

Humbert 1988 24/27 22/22 51.67% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Kearns 1992 1/6 1/8 1.79% 1.33[0.1,17.28]

Meng 1999 0/21 0/23 Not estimable

Nakaya 2007 0/19 1/19 3.14% 0.33[0.01,7.7]

Naveau 1986 2/20 4/20 8.37% 0.5[0.1,2.43]

Poon 2004 0/41 1/43 3.06% 0.35[0.01,8.34]

Puglionisi 1985 0/10 2/10 5.23% 0.2[0.01,3.7]

Simko 1983 0/7 0/3 Not estimable

Simon 1988 0/13 2/12 5.42% 0.19[0.01,3.52]

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 340 319 100% 0.85[0.64,1.13]

Total events: 42 (Treatment), 42 (Control)

Heterogeneity: Tau2=0; Chi2=5.77, df=10(P=0.83); I2=0%

Test for overall effect: Z=1.09(P=0.27)

5.24.2 Standard amino acids

Achord 1987 0/12 0/10 Not estimable

Bunout 1989 1/14 0/12 4.19% 2.6[0.12,58.48]

Calvey 1985 3/10 2/13 13.6% 1.95[0.4,9.54]

Hirsch 1993 3/26 3/25 23.93% 0.96[0.21,4.32]

Kearns 1992 1/6 1/8 6.71% 1.33[0.1,17.28]

Naveau 1986 2/20 4/20 31.29% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 20.28% 0.19[0.01,3.52]

Subtotal (95% CI) 101 100 100% 0.89[0.42,1.86]

Total events: 10 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=3.1, df=5(P=0.68); I2=0%

Favours treatment 2000.005 100.1 1 Favours control

164

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Z=0.31(P=0.75)

5.24.3 BCAAs

Calvey 1985 4/11 2/13 5.07% 2.36[0.53,10.55]

Fan 1994 4/64 4/60 11.43% 0.94[0.25,3.58]

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 68.37% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Nakaya 2007 0/19 1/19 4.15% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 4.05% 0.35[0.01,8.34]

Puglionisi 1985 0/10 2/10 6.92% 0.2[0.01,3.7]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 239 232 100% 0.88[0.67,1.16]

Total events: 32 (Treatment), 32 (Control)

Heterogeneity: Tau2=0; Chi2=3.41, df=5(P=0.64); I2=0%

Test for overall effect: Z=0.92(P=0.36)

5.24.4 Parenteral nutrition all

Achord 1987 0/12 0/10 Not estimable

Fan 1994 4/64 4/60 31.23% 0.94[0.25,3.58]

Naveau 1986 2/20 4/20 30.25% 0.5[0.1,2.43]

Puglionisi 1985 0/10 2/10 18.91% 0.2[0.01,3.7]

Simon 1988 0/13 2/12 19.61% 0.19[0.01,3.52]

Subtotal (95% CI) 119 112 100% 0.52[0.21,1.25]

Total events: 6 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.63, df=3(P=0.65); I2=0%

Test for overall effect: Z=1.46(P=0.14)

5.24.5 Parenteral nutrition - SAAs

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 60.67% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 39.33% 0.19[0.01,3.52]

Subtotal (95% CI) 45 42 100% 0.38[0.1,1.48]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.24.6 Parenteral nutrition - BCAAs

Fan 1994 4/64 4/60 62.29% 0.94[0.25,3.58]

Puglionisi 1985 0/10 2/10 37.71% 0.2[0.01,3.7]

Subtotal (95% CI) 74 70 100% 0.66[0.21,2.12]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=1(P=0.34); I2=0%

Test for overall effect: Z=0.7(P=0.48)

5.24.7 Enteral nutrition all

Calvey 1985 7/21 2/13 74.24% 2.17[0.53,8.88]

Kearns 1992 1/6 1/8 25.76% 1.33[0.1,17.28]

Subtotal (95% CI) 27 21 100% 1.95[0.57,6.69]

Favours treatment 2000.005 100.1 1 Favours control

165

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 8 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.11, df=1(P=0.74); I2=0%

Test for overall effect: Z=1.06(P=0.29)

5.24.8 Enteral nutrition - SAAs

Calvey 1985 3/10 2/13 66.99% 1.95[0.4,9.54]

Kearns 1992 1/6 1/8 33.01% 1.33[0.1,17.28]

Subtotal (95% CI) 16 21 100% 1.75[0.45,6.7]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.06, df=1(P=0.8); I2=0%

Test for overall effect: Z=0.81(P=0.42)

5.24.9 Enteral nutrition - BCAAs

Calvey 1985 4/11 2/13 100% 2.36[0.53,10.55]

Subtotal (95% CI) 11 13 100% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

5.24.10 Supplements all

Bunout 1989 1/14 0/12 1.71% 2.6[0.12,58.48]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/26 3/25 9.78% 0.96[0.21,4.32]

Humbert 1988 24/27 22/22 79.02% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Nakaya 2007 0/19 1/19 4.8% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 4.69% 0.35[0.01,8.34]

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 194 186 100% 0.88[0.68,1.13]

Total events: 28 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=4(P=0.87); I2=0%

Test for overall effect: Z=1.01(P=0.31)

5.24.11 Supplements - SAAs

Bunout 1989 1/14 0/12 14.9% 2.6[0.12,58.48]

Hirsch 1993 3/26 3/25 85.1% 0.96[0.21,4.32]

Subtotal (95% CI) 40 37 100% 1.21[0.32,4.56]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.32, df=1(P=0.57); I2=0%

Test for overall effect: Z=0.28(P=0.78)

5.24.12 Supplements - BCAAs

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 89.28% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Nakaya 2007 0/19 1/19 5.42% 0.33[0.01,7.7]

Poon 2004 0/41 1/43 5.29% 0.35[0.01,8.34]

Favours treatment 2000.005 100.1 1 Favours control

166

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Simko 1983 0/7 0/3 Not estimable

Tangkijvanich 2000 0/14 0/15 Not estimable

Subtotal (95% CI) 154 149 100% 0.84[0.68,1.03]

Total events: 24 (Treatment), 24 (Control)

Heterogeneity: Tau2=0; Chi2=1.39, df=2(P=0.5); I2=0%

Test for overall effect: Z=1.7(P=0.09)

Test for subgroup differences: Chi2=7.78, df=1 (P=0.73), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

Analysis 5.25. Comparison 5 Appearance of encephalopathy - all studies, Outcome 25 Surgical trials - transplant trials eliminated.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.25.1 All trials

Fan 1994 4/64 4/60 100% 0.94[0.25,3.58]

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Subtotal (95% CI) 96 96 100% 0.94[0.25,3.58]

Total events: 4 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.09(P=0.92)

5.25.2 Standard amino acids

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

5.25.3 BCAAs

Fan 1994 4/64 4/60 100% 0.94[0.25,3.58]

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/21 0/23 Not estimable

Subtotal (95% CI) 96 96 100% 0.94[0.25,3.58]

Total events: 4 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.09(P=0.92)

Test for subgroup differences: Not applicable

Favours treatment 100.1 50.2 20.5 1 Favours control

Analysis 5.26. Comparison 5 Appearance of encephalopathy - all studies, Outcome 26 ITT - Parenteral nutrition - best-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.26.1 All trials

Achord 1987 0/12 0/10 Not estimable

Favours treatment 2000.005 100.1 1 Favours control

167

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 4/75 19/75 67.63% 0.21[0.08,0.59]

Naveau 1986 2/20 4/20 14.24% 0.5[0.1,2.43]

Puglionisi 1985 0/10 2/10 8.9% 0.2[0.01,3.7]

Simon 1988 0/13 2/12 9.23% 0.19[0.01,3.52]

Subtotal (95% CI) 130 127 100% 0.25[0.11,0.55]

Total events: 6 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=3(P=0.82); I2=0%

Test for overall effect: Z=3.46(P=0)

5.26.2 Standard amino acids

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 60.67% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 39.33% 0.19[0.01,3.52]

Subtotal (95% CI) 45 42 100% 0.38[0.1,1.48]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.26.3 BCAAs

Fan 1994 4/75 19/75 88.37% 0.21[0.08,0.59]

Puglionisi 1985 0/10 2/10 11.63% 0.2[0.01,3.7]

Subtotal (95% CI) 85 85 100% 0.21[0.08,0.55]

Total events: 4 (Treatment), 21 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.97); I2=0%

Test for overall effect: Z=3.16(P=0)

Test for subgroup differences: Chi2=0.47, df=1 (P=0.79), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

Analysis 5.27. Comparison 5 Appearance of encephalopathy - all studies, Outcome 27 ITT - Parenteral nutrition - worst-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.27.1 All trials

Achord 1987 0/12 0/10 Not estimable

Fan 1994 15/75 4/75 30.55% 3.75[1.31,10.78]

Naveau 1986 2/20 4/20 30.55% 0.5[0.1,2.43]

Puglionisi 1985 0/10 2/10 19.09% 0.2[0.01,3.7]

Simon 1988 0/13 2/12 19.8% 0.19[0.01,3.52]

Subtotal (95% CI) 130 127 100% 1.37[0.7,2.71]

Total events: 17 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=8.5, df=3(P=0.04); I2=64.71%

Test for overall effect: Z=0.92(P=0.36)

5.27.2 Standard amino acids

Achord 1987 0/12 0/10 Not estimable

Naveau 1986 2/20 4/20 60.67% 0.5[0.1,2.43]

Simon 1988 0/13 2/12 39.33% 0.19[0.01,3.52]

Subtotal (95% CI) 45 42 100% 0.38[0.1,1.48]

Favours treatment 1000.01 100.1 1 Favours control

168

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.4(P=0.16)

5.27.3 BCAAs

Fan 1994 15/75 4/75 61.54% 3.75[1.31,10.78]

Puglionisi 1985 0/10 2/10 38.46% 0.2[0.01,3.7]

Subtotal (95% CI) 85 85 100% 2.38[0.99,5.73]

Total events: 15 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=3.48, df=1(P=0.06); I2=71.23%

Test for overall effect: Z=1.94(P=0.05)

Test for subgroup differences: Chi2=4.94, df=1 (P=0.08), I2=59.52%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 5.28. Comparison 5 Appearance of encephalopathy - all studies, Outcome 28 ITT - Enteral nutrition - best-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.28.1 All trials

Calvey 1985 7/21 2/13 28.84% 2.17[0.53,8.88]

Guy 1995 4/22 5/20 61.15% 0.73[0.23,2.34]

Kearns 1992 1/6 1/8 10.01% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 60 52 100% 1.2[0.53,2.74]

Total events: 12 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=1.39, df=2(P=0.5); I2=0%

Test for overall effect: Z=0.44(P=0.66)

5.28.2 Standard amino acids

Calvey 1985 3/10 2/13 22.2% 1.95[0.4,9.54]

Guy 1995 4/22 5/20 66.86% 0.73[0.23,2.34]

Kearns 1992 1/6 1/8 10.94% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 49 52 100% 1.07[0.45,2.52]

Total events: 8 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=1, df=2(P=0.61); I2=0%

Test for overall effect: Z=0.14(P=0.89)

5.28.3 BCAAs

Calvey 1985 4/11 2/13 100% 2.36[0.53,10.55]

Subtotal (95% CI) 11 13 100% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

Test for subgroup differences: Chi2=0.84, df=1 (P=0.66), I2=0%

Favours treatment 200.05 50.2 1 Favours control

169

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Analysis 5.29. Comparison 5 Appearance of encephalopathy - all studies, Outcome 29 ITT - Enteral nutrition - worst-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.29.1 All trials

Calvey 1985 7/21 2/13 38.18% 2.17[0.53,8.88]

Guy 1995 12/22 3/20 48.57% 3.64[1.2,11.04]

Kearns 1992 1/6 1/8 13.25% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 60 52 100% 2.77[1.23,6.26]

Total events: 20 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.66, df=2(P=0.72); I2=0%

Test for overall effect: Z=2.45(P=0.01)

5.29.2 Standard amino acids

Calvey 1985 3/10 2/13 30.3% 1.95[0.4,9.54]

Guy 1995 12/22 3/20 54.76% 3.64[1.2,11.04]

Kearns 1992 1/6 1/8 14.94% 1.33[0.1,17.28]

Schuetz 2006 0/11 0/11 Not estimable

Subtotal (95% CI) 49 52 100% 2.78[1.19,6.48]

Total events: 16 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.73, df=2(P=0.69); I2=0%

Test for overall effect: Z=2.37(P=0.02)

5.29.3 BCAAs

Calvey 1985 4/11 2/13 100% 2.36[0.53,10.55]

Subtotal (95% CI) 11 13 100% 2.36[0.53,10.55]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.13(P=0.26)

Test for subgroup differences: Chi2=0.04, df=1 (P=0.98), I2=0%

Favours treatment 500.02 100.1 1 Favours control

Analysis 5.30. Comparison 5 Appearance of encephalopathy - all studies, Outcome 30 ITT- Supplements - best-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.30.1 All trials

Bunout 1989 1/14 0/12 0.72% 2.6[0.12,58.48]

Hasse 1997 5/37 6/9 13.04% 0.2[0.08,0.52]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/32 11/33 14.63% 0.28[0.09,0.92]

Humbert 1988 24/27 22/22 33.37% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Kobashi 2006 12/108 16/113 21.12% 0.78[0.39,1.58]

Meng 1999 0/25 2/25 3.38% 0.2[0.01,3.97]

Nakaya 2007 0/19 1/19 2.03% 0.33[0.01,7.7]

Poon 2004 0/44 2/44 3.38% 0.2[0.01,4.05]

Sievert 1999 4/71 3/34 5.48% 0.64[0.15,2.7]

Favours treatment 2000.005 100.1 1 Favours control

170

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Simko 1983 0/11 1/4 2.86% 0.14[0.01,2.86]

Tangkijvanich 2000 0/15 0/15 Not estimable

Subtotal (95% CI) 428 354 100% 0.61[0.47,0.79]

Total events: 49 (Treatment), 64 (Control)

Heterogeneity: Tau2=0; Chi2=34.6, df=9(P<0.0001); I2=73.99%

Test for overall effect: Z=3.66(P=0)

5.30.2 Standard amino acids -medical trials

Bunout 1989 1/14 0/12 2.37% 2.6[0.12,58.48]

Hasse 1997 4/18 6/9 35.44% 0.33[0.13,0.89]

Hirsch 1993 3/32 11/33 47.98% 0.28[0.09,0.92]

Sievert 1999 1/39 3/34 14.2% 0.29[0.03,2.66]

Subtotal (95% CI) 103 88 100% 0.36[0.18,0.72]

Total events: 9 (Treatment), 20 (Control)

Heterogeneity: Tau2=0; Chi2=1.77, df=3(P=0.62); I2=0%

Test for overall effect: Z=2.9(P=0)

5.30.3 BCAAs - medical trials

Hasse 1997 1/19 6/9 14.17% 0.08[0.01,0.56]

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 42.99% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 12/108 16/113 27.21% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 2.61% 0.33[0.01,7.7]

Poon 2004 0/44 2/44 4.35% 0.2[0.01,4.05]

Sievert 1999 3/31 3/34 4.98% 1.1[0.24,5.04]

Simko 1983 0/11 1/4 3.69% 0.14[0.01,2.86]

Tangkijvanich 2000 0/15 0/15 Not estimable

Subtotal (95% CI) 288 271 100% 0.69[0.52,0.9]

Total events: 40 (Treatment), 51 (Control)

Heterogeneity: Tau2=0; Chi2=18.64, df=6(P=0); I2=67.8%

Test for overall effect: Z=2.67(P=0.01)

5.30.4 All supplements - medical

Bunout 1989 1/14 0/12 0.75% 2.6[0.12,58.48]

Hasse 1997 5/37 6/9 13.5% 0.2[0.08,0.52]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 3/32 11/33 15.14% 0.28[0.09,0.92]

Humbert 1988 24/27 22/22 34.54% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 12/108 16/113 21.87% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 2.1% 0.33[0.01,7.7]

Poon 2004 0/44 2/44 3.5% 0.2[0.01,4.05]

Sievert 1999 4/70 3/34 5.65% 0.65[0.15,2.73]

Simko 1983 0/11 1/4 2.96% 0.14[0.01,2.86]

Tangkijvanich 2000 0/15 0/15 Not estimable

Subtotal (95% CI) 391 316 100% 0.62[0.48,0.81]

Total events: 49 (Treatment), 62 (Control)

Heterogeneity: Tau2=0; Chi2=31.41, df=8(P=0); I2=74.53%

Test for overall effect: Z=3.49(P=0)

5.30.5 All surgical

Favours treatment 2000.005 100.1 1 Favours control

171

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 0/25 2/25 100% 0.2[0.01,3.97]

Subtotal (95% CI) 36 38 100% 0.2[0.01,3.97]

Total events: 0 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.06(P=0.29)

Test for subgroup differences: Chi2=3.52, df=1 (P=0.48), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

Analysis 5.31. Comparison 5 Appearance of encephalopathy - all studies, Outcome 31 ITT - Supplements - worst-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

5.31.1 All trials

Bunout 1989 1/14 0/12 0.94% 2.6[0.12,58.48]

Hasse 1997 19/37 3/9 8.48% 1.54[0.58,4.09]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 9/32 3/33 5.19% 3.09[0.92,10.4]

Humbert 1988 24/27 22/22 43.42% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Ishikawa 2010 0/11 0/13 Not estimable

Kobashi 2006 12/108 16/113 27.48% 0.78[0.39,1.58]

Meng 1999 4/25 0/25 0.88% 9[0.51,158.85]

Nakaya 2007 0/19 1/19 2.64% 0.33[0.01,7.7]

Poon 2004 3/44 1/44 1.76% 3[0.32,27.74]

Sievert 1999 4/70 3/34 7.1% 0.65[0.15,2.73]

Simko 1983 4/11 0/4 1.24% 3.75[0.24,57.45]

Tangkijvanich 2000 1/15 0/15 0.88% 3[0.13,68.26]

Subtotal (95% CI) 427 354 100% 1.18[0.9,1.54]

Total events: 81 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=21.77, df=10(P=0.02); I2=54.07%

Test for overall effect: Z=1.21(P=0.23)

5.31.2 Standard amino acids -medical trials

Bunout 1989 1/14 0/12 5.01% 2.6[0.12,58.48]

Hasse 1997 8/18 3/9 37.4% 1.33[0.46,3.84]

Hirsch 1993 9/32 3/33 27.62% 3.09[0.92,10.4]

Sievert 1999 1/39 3/34 29.97% 0.29[0.03,2.66]

Subtotal (95% CI) 103 88 100% 1.57[0.79,3.13]

Total events: 19 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=3.62, df=3(P=0.31); I2=17.13%

Test for overall effect: Z=1.28(P=0.2)

5.31.3 BCAAs - medical trials

Hasse 1997 11/19 3/9 7.99% 1.74[0.64,4.72]

Hayashi 1991 0/2 0/2 Not estimable

Humbert 1988 24/27 22/22 48.46% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Favours treatment 5000.002 100.1 1 Favours control

172

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Kobashi 2006 12/108 16/113 30.67% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 2.94% 0.33[0.01,7.7]

Poon 2004 3/44 1/44 1.96% 3[0.32,27.74]

Sievert 1999 3/31 3/34 5.61% 1.1[0.24,5.04]

Simko 1983 4/11 0/4 1.38% 3.75[0.24,57.45]

Tangkijvanich 2000 1/15 0/15 0.98% 3[0.13,68.26]

Subtotal (95% CI) 288 271 100% 1.02[0.78,1.35]

Total events: 58 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=7.38, df=7(P=0.39); I2=5.11%

Test for overall effect: Z=0.17(P=0.86)

5.31.4 All supplements - medical

Bunout 1989 1/14 0/12 0.95% 2.6[0.12,58.48]

Hasse 1997 19/37 3/9 8.56% 1.54[0.58,4.09]

Hayashi 1991 0/2 0/2 Not estimable

Hirsch 1993 9/32 3/33 5.24% 3.09[0.92,10.4]

Humbert 1988 24/27 22/22 43.8% 0.89[0.77,1.04]

Ichikawa 2010 0/12 0/9 Not estimable

Kobashi 2006 12/108 16/113 27.73% 0.78[0.39,1.58]

Nakaya 2007 0/19 1/19 2.66% 0.33[0.01,7.7]

Poon 2004 3/44 1/44 1.77% 3[0.32,27.74]

Sievert 1999 4/70 3/34 7.16% 0.65[0.15,2.73]

Simko 1983 4/11 0/4 1.25% 3.75[0.24,57.45]

Tangkijvanich 2000 1/15 0/15 0.89% 3[0.13,68.26]

Subtotal (95% CI) 391 316 100% 1.11[0.85,1.45]

Total events: 77 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=15.1, df=9(P=0.09); I2=40.4%

Test for overall effect: Z=0.76(P=0.45)

5.31.5 All surgical

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 4/25 0/25 100% 9[0.51,158.85]

Subtotal (95% CI) 36 38 100% 9[0.51,158.85]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.5(P=0.13)

Test for subgroup differences: Chi2=3.49, df=1 (P=0.48), I2=0%

Favours treatment 5000.002 100.1 1 Favours control

Comparison 6. Resolution of encephalopathy

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All trials 6 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

1.1 All studies 6 119 Risk Ratio (M-H, Fixed, 95% CI)

2.10 [1.18, 3.72]

173

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1.2 Standard amino acids 5 66 Risk Ratio (M-H, Fixed, 95% CI)

1.13 [0.62, 2.07]

1.3 BCAA's 2 62 Risk Ratio (M-H, Fixed, 95% CI)

7.48 [1.87, 29.94]

2 Parenteral nutrition (all medical trials) 2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

2.1 All trials 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

2.2 Standard amino acids 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

2.3 BCAA's 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Enteral nutrition (all medical trials) 2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

3.1 All trials 2 47 Risk Ratio (M-H, Fixed, 95% CI)

1.57 [0.59, 4.13]

3.2 Standard amino acids 2 37 Risk Ratio (M-H, Fixed, 95% CI)

1.28 [0.48, 3.39]

3.3 BCAA's 1 19 Risk Ratio (M-H, Fixed, 95% CI)

3.6 [0.49, 26.54]

4 Supplements (all medical trials) 2 Risk Ratio (M-H, Random, 95% CI)

Subtotals only

4.1 All trials 2 53 Risk Ratio (M-H, Random, 95% CI)

2.04 [0.06, 75.19]

4.2 Standard amino acids 1 10 Risk Ratio (M-H, Random, 95% CI)

0.29 [0.02, 4.29]

4.3 BCAA's 1 43 Risk Ratio (M-H, Random, 95% CI)

11.30 [1.62, 78.95]

5 Medical trials - all trials 6 119 Risk Ratio (M-H, Fixed, 95% CI)

2.10 [1.18, 3.72]

5.1 Parenteral nutrition 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

5.2 Enteral nutrition 2 47 Risk Ratio (M-H, Fixed, 95% CI)

1.57 [0.59, 4.13]

5.3 Supplements 2 53 Risk Ratio (M-H, Fixed, 95% CI)

3.75 [1.15, 12.18]

174

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

6 Medical trials - standard amino acids 5 66 Risk Ratio (M-H, Fixed, 95% CI)

1.13 [0.62, 2.07]

6.1 Parenteral nutrition 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

6.2 Enteral nutrition 2 37 Risk Ratio (M-H, Fixed, 95% CI)

1.28 [0.48, 3.39]

6.3 Supplements 1 10 Risk Ratio (M-H, Fixed, 95% CI)

0.29 [0.02, 4.29]

7 Medical trials - BCAAs 2 62 Risk Ratio (M-H, Fixed, 95% CI)

7.48 [1.87, 29.94]

7.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Enteral nutrition 1 19 Risk Ratio (M-H, Fixed, 95% CI)

3.6 [0.49, 26.54]

7.3 Supplements 1 43 Risk Ratio (M-H, Fixed, 95% CI)

11.30 [1.62, 78.95]

8 Surgical trials - all trials 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.1 Pareneral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9 Surgical trials - standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.1 Pareneral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10 Surgical trials - BCAAs 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.1 Pareneral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

175

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

10.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11 Alcoholic hepatitis - all trials 5 76 Risk Ratio (M-H, Fixed, 95% CI)

1.26 [0.68, 2.31]

11.1 Parenteral nutrition 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

11.2 Enteral nutrition 2 47 Risk Ratio (M-H, Fixed, 95% CI)

1.57 [0.59, 4.13]

11.3 Supplements 1 10 Risk Ratio (M-H, Fixed, 95% CI)

0.29 [0.02, 4.29]

12 Alcoholic hepatitis - standard amino acids

5 66 Risk Ratio (M-H, Fixed, 95% CI)

1.13 [0.62, 2.07]

12.1 Parenteral nutrition 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

12.2 Enteral nutrition 2 37 Risk Ratio (M-H, Fixed, 95% CI)

1.28 [0.48, 3.39]

12.3 Supplements 1 10 Risk Ratio (M-H, Fixed, 95% CI)

0.29 [0.02, 4.29]

13 Alcoholic hepatitis - BCAAs 1 19 Risk Ratio (M-H, Fixed, 95% CI)

3.6 [0.49, 26.54]

13.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.2 Enteral nutrition 1 19 Risk Ratio (M-H, Fixed, 95% CI)

3.6 [0.49, 26.54]

13.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

14 Cirrhosis - all 1 43 Risk Ratio (M-H, Fixed, 95% CI)

11.30 [1.62, 78.95]

14.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

14.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

14.3 Supplements 1 43 Risk Ratio (M-H, Fixed, 95% CI)

11.30 [1.62, 78.95]

176

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

15 Cirrhosis - standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

15.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

15.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

15.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

16 Cirrhosis - BCAAs 1 43 Risk Ratio (M-H, Fixed, 95% CI)

11.30 [1.62, 78.95]

16.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

16.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

16.3 Supplements 1 43 Risk Ratio (M-H, Fixed, 95% CI)

11.30 [1.62, 78.95]

17 HCC - all studies 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

17.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

17.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

17.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18 HCC - standard amino acids 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

19 HCC - BCAAs 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

19.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

177

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

19.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

19.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

20 Abstracts excluded - all trials 6 119 Risk Ratio (M-H, Fixed, 95% CI)

2.10 [1.18, 3.72]

20.1 Parenteral nutrition 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

20.2 Enteral nutrition 2 47 Risk Ratio (M-H, Fixed, 95% CI)

1.57 [0.59, 4.13]

20.3 Supplements 2 53 Risk Ratio (M-H, Fixed, 95% CI)

3.75 [1.15, 12.18]

21 Abstracts excluded - standard amino acids

5 66 Risk Ratio (M-H, Fixed, 95% CI)

1.13 [0.62, 2.07]

21.1 Parenteral nutrition 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

21.2 Enteral nutrition 2 37 Risk Ratio (M-H, Fixed, 95% CI)

1.28 [0.48, 3.39]

21.3 Supplements 1 10 Risk Ratio (M-H, Fixed, 95% CI)

0.29 [0.02, 4.29]

22 Abstracts excluded - BCAAs 3 72 Risk Ratio (M-H, Random, 95% CI)

2.75 [0.40, 19.10]

22.1 Parenteral nutrition 0 0 Risk Ratio (M-H, Random, 95% CI)

0.0 [0.0, 0.0]

22.2 Enteral nutrition 1 19 Risk Ratio (M-H, Random, 95% CI)

3.60 [0.49, 26.54]

22.3 Supplements 2 53 Risk Ratio (M-H, Random, 95% CI)

2.04 [0.06, 75.19]

23 Surgical trials (transplant patients re- moved) - all trials

0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

23.1 Pareneral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

23.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

23.3 Supplements 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

178

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

24 ITT - All trials - best-case scenario - no changes made because all patients reported

6 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

24.1 All studies 6 119 Risk Ratio (M-H, Fixed, 95% CI)

2.10 [1.18, 3.72]

24.2 Standard amino acids 5 66 Risk Ratio (M-H, Fixed, 95% CI)

1.13 [0.62, 2.07]

24.3 BCAA's 2 62 Risk Ratio (M-H, Fixed, 95% CI)

7.48 [1.87, 29.94]

25 ITT - Parenteral nutrition trials - best-case scenario - no changes made because all pa- tients reported

2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

25.1 All studies 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

25.2 Standard amino acids 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

25.3 BCAA's 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

26 ITT - Enteral trials - best-case scenario - no changes made because all patients re- ported

2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

26.1 All studies 2 47 Risk Ratio (M-H, Fixed, 95% CI)

1.57 [0.59, 4.13]

26.2 Standard amino acids 2 37 Risk Ratio (M-H, Fixed, 95% CI)

1.28 [0.48, 3.39]

26.3 BCAA's 1 19 Risk Ratio (M-H, Fixed, 95% CI)

3.6 [0.49, 26.54]

27 ITT - Supplements trials - best-case sce- nario - no changes made because all pa- tients reported

2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

27.1 All studies 2 53 Risk Ratio (M-H, Fixed, 95% CI)

3.75 [1.15, 12.18]

27.2 Standard amino acids 1 10 Risk Ratio (M-H, Fixed, 95% CI)

0.29 [0.02, 4.29]

27.3 BCAA's 1 43 Risk Ratio (M-H, Fixed, 95% CI)

11.30 [1.62, 78.95]

28 ITT - All trials - worst-case scenario - no changes made because all patients reported

6 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

179

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

28.1 All studies 6 119 Risk Ratio (M-H, Fixed, 95% CI)

2.10 [1.18, 3.72]

28.2 Standard amino acids 5 66 Risk Ratio (M-H, Fixed, 95% CI)

1.13 [0.62, 2.07]

28.3 BCAA's 2 62 Risk Ratio (M-H, Fixed, 95% CI)

7.48 [1.87, 29.94]

29 ITT - Parenteral nutrition trials - worst- case scenario - no changes made because all patients reported

2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

29.1 All studies 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

29.2 Standard amino acids 2 19 Risk Ratio (M-H, Fixed, 95% CI)

1.42 [0.66, 3.07]

29.3 BCAA's 0 0 Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

30 ITT - Enteral nutrition trials - worst-case scenario - no changes made because all pa- tients reported

2 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

30.1 All studies 2 47 Risk Ratio (M-H, Fixed, 95% CI)

1.57 [0.59, 4.13]

30.2 Standard amino acids 2 37 Risk Ratio (M-H, Fixed, 95% CI)

1.28 [0.48, 3.39]

30.3 BCAA's 1 19 Risk Ratio (M-H, Fixed, 95% CI)

3.6 [0.49, 26.54]

31 ITT - Supplement trials - worst-case sce- nario - no changes made because all pa- tients reported

3 Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

31.1 All studies 2 53 Risk Ratio (M-H, Fixed, 95% CI)

3.75 [1.15, 12.18]

31.2 Standard amino acids 2 23 Risk Ratio (M-H, Fixed, 95% CI)

0.93 [0.28, 3.09]

31.3 BCAA's 1 43 Risk Ratio (M-H, Fixed, 95% CI)

11.30 [1.62, 78.95]

180

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Analysis 6.1. Comparison 6 Resolution of encephalopathy, Outcome 1 All trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.1.1 All studies

Achord 1987 2/2 3/4 20.5% 1.19[0.55,2.56]

Bunout 1989 0/3 3/7 18.22% 0.29[0.02,4.29]

Calvey 1985 6/21 1/9 10.93% 2.57[0.36,18.4]

Hayashi 1991 13/23 1/20 8.36% 11.3[1.62,78.95]

Kearns 1992 5/10 3/7 27.57% 1.17[0.41,3.36]

Simon 1988 3/6 2/7 14.42% 1.75[0.42,7.23]

Subtotal (95% CI) 65 54 100% 2.1[1.18,3.72]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=8.35, df=5(P=0.14); I2=40.12%

Test for overall effect: Z=2.53(P=0.01)

6.1.2 Standard amino acids

Achord 1987 2/2 3/4 22.96% 1.19[0.55,2.56]

Bunout 1989 0/3 3/7 20.41% 0.29[0.02,4.29]

Calvey 1985 2/11 1/9 9.62% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 30.87% 1.17[0.41,3.36]

Simon 1988 3/6 2/7 16.15% 1.75[0.42,7.23]

Subtotal (95% CI) 32 34 100% 1.13[0.62,2.07]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.48, df=4(P=0.83); I2=0%

Test for overall effect: Z=0.4(P=0.69)

6.1.3 BCAA's

Calvey 1985 4/10 1/9 49.6% 3.6[0.49,26.54]

Hayashi 1991 13/23 1/20 50.4% 11.3[1.62,78.95]

Subtotal (95% CI) 33 29 100% 7.48[1.87,29.94]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=0.69, df=1(P=0.41); I2=0%

Test for overall effect: Z=2.85(P=0)

Test for subgroup differences: Chi2=6.58, df=1 (P=0.04), I2=69.6%

Favours control 1000.01 100.1 1 Favours treatment

Analysis 6.2. Comparison 6 Resolution of encephalopathy, Outcome 2 Parenteral nutrition (all medical trials).

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.2.1 All trials

Achord 1987 2/2 3/4 58.71% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 41.29% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 100% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.2.2 Standard amino acids

Achord 1987 2/2 3/4 58.71% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 41.29% 1.75[0.42,7.23]

Favours control 100.1 50.2 20.5 1 Favours treatment

181

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 8 11 100% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.2.3 BCAA's

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Not applicable

Favours control 100.1 50.2 20.5 1 Favours treatment

Analysis 6.3. Comparison 6 Resolution of encephalopathy, Outcome 3 Enteral nutrition (all medical trials).

Study or subgroup Tretment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.3.1 All trials

Calvey 1985 6/21 1/9 28.4% 2.57[0.36,18.4]

Kearns 1992 5/10 3/7 71.6% 1.17[0.41,3.36]

Subtotal (95% CI) 31 16 100% 1.57[0.59,4.13]

Total events: 11 (Tretment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.54, df=1(P=0.46); I2=0%

Test for overall effect: Z=0.91(P=0.36)

6.3.2 Standard amino acids

Calvey 1985 2/11 1/9 23.76% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 76.24% 1.17[0.41,3.36]

Subtotal (95% CI) 21 16 100% 1.28[0.48,3.39]

Total events: 7 (Tretment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.08, df=1(P=0.78); I2=0%

Test for overall effect: Z=0.49(P=0.62)

6.3.3 BCAA's

Calvey 1985 4/10 1/9 100% 3.6[0.49,26.54]

Subtotal (95% CI) 10 9 100% 3.6[0.49,26.54]

Total events: 4 (Tretment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

Test for subgroup differences: Chi2=0.83, df=1 (P=0.66), I2=0%

Favours control 500.02 100.1 1 Favours treatment

Analysis 6.4. Comparison 6 Resolution of encephalopathy, Outcome 4 Supplements (all medical trials).

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

6.4.1 All trials

Favours control 5000.002 100.1 1 Favours treatment

182

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Bunout 1989 0/3 3/7 46.6% 0.29[0.02,4.29]

Hayashi 1991 13/23 1/20 53.4% 11.3[1.62,78.95]

Subtotal (95% CI) 26 27 100% 2.04[0.06,75.19]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=5.36; Chi2=4.71, df=1(P=0.03); I2=78.75%

Test for overall effect: Z=0.39(P=0.7)

6.4.2 Standard amino acids

Bunout 1989 0/3 3/7 100% 0.29[0.02,4.29]

Subtotal (95% CI) 3 7 100% 0.29[0.02,4.29]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.91(P=0.36)

6.4.3 BCAA's

Hayashi 1991 13/23 1/20 100% 11.3[1.62,78.95]

Subtotal (95% CI) 23 20 100% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Test for subgroup differences: Chi2=4.73, df=1 (P=0.09), I2=57.69%

Favours control 5000.002 100.1 1 Favours treatment

Analysis 6.5. Comparison 6 Resolution of encephalopathy, Outcome 5 Medical trials - all trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.5.1 Parenteral nutrition

Achord 1987 2/2 3/4 20.5% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 14.42% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 34.92% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.5.2 Enteral nutrition

Calvey 1985 6/21 1/9 10.93% 2.57[0.36,18.4]

Kearns 1992 5/10 3/7 27.57% 1.17[0.41,3.36]

Subtotal (95% CI) 31 16 38.5% 1.57[0.59,4.13]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.54, df=1(P=0.46); I2=0%

Test for overall effect: Z=0.91(P=0.36)

6.5.3 Supplements

Bunout 1989 0/3 3/7 18.22% 0.29[0.02,4.29]

Hayashi 1991 13/23 1/20 8.36% 11.3[1.62,78.95]

Subtotal (95% CI) 26 27 26.58% 3.75[1.15,12.18]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=4.71, df=1(P=0.03); I2=78.75%

Favours control 2000.005 100.1 1 Favours treatment

183

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Z=2.2(P=0.03)

Total (95% CI) 65 54 100% 2.1[1.18,3.72]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=8.35, df=5(P=0.14); I2=40.12%

Test for overall effect: Z=2.53(P=0.01)

Test for subgroup differences: Chi2=1.93, df=1 (P=0.38), I2=0%

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.6. Comparison 6 Resolution of encephalopathy, Outcome 6 Medical trials - standard amino acids.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.6.1 Parenteral nutrition

Achord 1987 2/2 3/4 22.96% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 16.15% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 39.1% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.6.2 Enteral nutrition

Calvey 1985 2/11 1/9 9.62% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 30.87% 1.17[0.41,3.36]

Subtotal (95% CI) 21 16 40.49% 1.28[0.48,3.39]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.08, df=1(P=0.78); I2=0%

Test for overall effect: Z=0.49(P=0.62)

6.6.3 Supplements

Bunout 1989 0/3 3/7 20.41% 0.29[0.02,4.29]

Subtotal (95% CI) 3 7 20.41% 0.29[0.02,4.29]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.91(P=0.36)

Total (95% CI) 32 34 100% 1.13[0.62,2.07]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.48, df=4(P=0.83); I2=0%

Test for overall effect: Z=0.4(P=0.69)

Test for subgroup differences: Chi2=1.25, df=1 (P=0.54), I2=0%

Favours control 1000.01 100.1 1 Favours treatment

184

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Analysis 6.7. Comparison 6 Resolution of encephalopathy, Outcome 7 Medical trials - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.7.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

6.7.2 Enteral nutrition

Calvey 1985 4/10 1/9 49.6% 3.6[0.49,26.54]

Subtotal (95% CI) 10 9 49.6% 3.6[0.49,26.54]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

6.7.3 Supplements

Hayashi 1991 13/23 1/20 50.4% 11.3[1.62,78.95]

Subtotal (95% CI) 23 20 50.4% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Total (95% CI) 33 29 100% 7.48[1.87,29.94]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=0.69, df=1(P=0.41); I2=0%

Test for overall effect: Z=2.85(P=0)

Test for subgroup differences: Chi2=0.65, df=1 (P=0.42), I2=0%

Favours control 1000.01 100.1 1 Favours treatment

Analysis 6.11. Comparison 6 Resolution of encephalopathy, Outcome 11 Alcoholic hepatitis - all trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.11.1 Parenteral nutrition

Achord 1987 2/2 3/4 22.37% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 15.73% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 38.1% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.11.2 Enteral nutrition

Calvey 1985 6/21 1/9 11.93% 2.57[0.36,18.4]

Kearns 1992 5/10 3/7 30.08% 1.17[0.41,3.36]

Subtotal (95% CI) 31 16 42.01% 1.57[0.59,4.13]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.54, df=1(P=0.46); I2=0%

Test for overall effect: Z=0.91(P=0.36)

6.11.3 Supplements

Favours control 2000.005 100.1 1 Favours treatment

185

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Bunout 1989 0/3 3/7 19.89% 0.29[0.02,4.29]

Subtotal (95% CI) 3 7 19.89% 0.29[0.02,4.29]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.91(P=0.36)

Total (95% CI) 42 34 100% 1.26[0.68,2.31]

Total events: 16 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.9, df=4(P=0.75); I2=0%

Test for overall effect: Z=0.74(P=0.46)

Test for subgroup differences: Chi2=1.37, df=1 (P=0.5), I2=0%

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.12. Comparison 6 Resolution of encephalopathy, Outcome 12 Alcoholic hepatitis - standard amino acids.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.12.1 Parenteral nutrition

Achord 1987 2/2 3/4 22.96% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 16.15% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 39.1% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.12.2 Enteral nutrition

Calvey 1985 2/11 1/9 9.62% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 30.87% 1.17[0.41,3.36]

Subtotal (95% CI) 21 16 40.49% 1.28[0.48,3.39]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.08, df=1(P=0.78); I2=0%

Test for overall effect: Z=0.49(P=0.62)

6.12.3 Supplements

Bunout 1989 0/3 3/7 20.41% 0.29[0.02,4.29]

Subtotal (95% CI) 3 7 20.41% 0.29[0.02,4.29]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.91(P=0.36)

Total (95% CI) 32 34 100% 1.13[0.62,2.07]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.48, df=4(P=0.83); I2=0%

Test for overall effect: Z=0.4(P=0.69)

Test for subgroup differences: Chi2=1.25, df=1 (P=0.54), I2=0%

Favours control 2000.005 100.1 1 Favours treatment

186

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Analysis 6.13. Comparison 6 Resolution of encephalopathy, Outcome 13 Alcoholic hepatitis - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.13.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

6.13.2 Enteral nutrition

Calvey 1985 4/10 1/9 100% 3.6[0.49,26.54]

Subtotal (95% CI) 10 9 100% 3.6[0.49,26.54]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

6.13.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 10 9 100% 3.6[0.49,26.54]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

Test for subgroup differences: Not applicable

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.14. Comparison 6 Resolution of encephalopathy, Outcome 14 Cirrhosis - all.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.14.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

6.14.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

6.14.3 Supplements

Hayashi 1991 13/23 1/20 100% 11.3[1.62,78.95]

Subtotal (95% CI) 23 20 100% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Favours control 2000.005 100.1 1 Favours treatment

187

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 23 20 100% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Test for subgroup differences: Not applicable

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.16. Comparison 6 Resolution of encephalopathy, Outcome 16 Cirrhosis - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.16.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

6.16.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

6.16.3 Supplements

Hayashi 1991 13/23 1/20 100% 11.3[1.62,78.95]

Subtotal (95% CI) 23 20 100% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Total (95% CI) 23 20 100% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Test for subgroup differences: Not applicable

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.20. Comparison 6 Resolution of encephalopathy, Outcome 20 Abstracts excluded - all trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.20.1 Parenteral nutrition

Achord 1987 2/2 3/4 20.5% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 14.42% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 34.92% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Favours control 2000.005 100.1 1 Favours treatment

188

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.20.2 Enteral nutrition

Calvey 1985 6/21 1/9 10.93% 2.57[0.36,18.4]

Kearns 1992 5/10 3/7 27.57% 1.17[0.41,3.36]

Subtotal (95% CI) 31 16 38.5% 1.57[0.59,4.13]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.54, df=1(P=0.46); I2=0%

Test for overall effect: Z=0.91(P=0.36)

6.20.3 Supplements

Bunout 1989 0/3 3/7 18.22% 0.29[0.02,4.29]

Hayashi 1991 13/23 1/20 8.36% 11.3[1.62,78.95]

Subtotal (95% CI) 26 27 26.58% 3.75[1.15,12.18]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=4.71, df=1(P=0.03); I2=78.75%

Test for overall effect: Z=2.2(P=0.03)

Total (95% CI) 65 54 100% 2.1[1.18,3.72]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=8.35, df=5(P=0.14); I2=40.12%

Test for overall effect: Z=2.53(P=0.01)

Test for subgroup differences: Chi2=1.93, df=1 (P=0.38), I2=0%

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.21. Comparison 6 Resolution of encephalopathy, Outcome 21 Abstracts excluded - standard amino acids.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.21.1 Parenteral nutrition

Achord 1987 2/2 3/4 22.96% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 16.15% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 39.1% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.21.2 Enteral nutrition

Calvey 1985 2/11 1/9 9.62% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 30.87% 1.17[0.41,3.36]

Subtotal (95% CI) 21 16 40.49% 1.28[0.48,3.39]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.08, df=1(P=0.78); I2=0%

Test for overall effect: Z=0.49(P=0.62)

6.21.3 Supplements

Bunout 1989 0/3 3/7 20.41% 0.29[0.02,4.29]

Subtotal (95% CI) 3 7 20.41% 0.29[0.02,4.29]

Favours control 2000.005 100.1 1 Favours treatment

189

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.91(P=0.36)

Total (95% CI) 32 34 100% 1.13[0.62,2.07]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.48, df=4(P=0.83); I2=0%

Test for overall effect: Z=0.4(P=0.69)

Test for subgroup differences: Chi2=1.25, df=1 (P=0.54), I2=0%

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.22. Comparison 6 Resolution of encephalopathy, Outcome 22 Abstracts excluded - BCAAs.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

6.22.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

6.22.2 Enteral nutrition

Calvey 1985 4/10 1/9 36% 3.6[0.49,26.54]

Subtotal (95% CI) 10 9 36% 3.6[0.49,26.54]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

6.22.3 Supplements

Bunout 1989 0/3 3/7 27.26% 0.29[0.02,4.29]

Hayashi 1991 13/23 1/20 36.75% 11.3[1.62,78.95]

Subtotal (95% CI) 26 27 64% 2.04[0.06,75.19]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=5.36; Chi2=4.71, df=1(P=0.03); I2=78.75%

Test for overall effect: Z=0.39(P=0.7)

Total (95% CI) 36 36 100% 2.75[0.4,19.1]

Total events: 17 (Treatment), 5 (Control)

Heterogeneity: Tau2=1.68; Chi2=4.7, df=2(P=0.1); I2=57.48%

Test for overall effect: Z=1.02(P=0.31)

Test for subgroup differences: Chi2=0.07, df=1 (P=0.79), I2=0%

Favours control 2000.005 100.1 1 Favours treatment

190

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Analysis 6.24. Comparison 6 Resolution of encephalopathy, Outcome 24 ITT - All trials - best-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.24.1 All studies

Achord 1987 2/2 3/4 20.5% 1.19[0.55,2.56]

Bunout 1989 0/3 3/7 18.22% 0.29[0.02,4.29]

Calvey 1985 6/21 1/9 10.93% 2.57[0.36,18.4]

Hayashi 1991 13/23 1/20 8.36% 11.3[1.62,78.95]

Kearns 1992 5/10 3/7 27.57% 1.17[0.41,3.36]

Simon 1988 3/6 2/7 14.42% 1.75[0.42,7.23]

Subtotal (95% CI) 65 54 100% 2.1[1.18,3.72]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=8.35, df=5(P=0.14); I2=40.12%

Test for overall effect: Z=2.53(P=0.01)

6.24.2 Standard amino acids

Achord 1987 2/2 3/4 22.96% 1.19[0.55,2.56]

Bunout 1989 0/3 3/7 20.41% 0.29[0.02,4.29]

Calvey 1985 2/11 1/9 9.62% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 30.87% 1.17[0.41,3.36]

Simon 1988 3/6 2/7 16.15% 1.75[0.42,7.23]

Subtotal (95% CI) 32 34 100% 1.13[0.62,2.07]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.48, df=4(P=0.83); I2=0%

Test for overall effect: Z=0.4(P=0.69)

6.24.3 BCAA's

Calvey 1985 4/10 1/9 49.6% 3.6[0.49,26.54]

Hayashi 1991 13/23 1/20 50.4% 11.3[1.62,78.95]

Subtotal (95% CI) 33 29 100% 7.48[1.87,29.94]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=0.69, df=1(P=0.41); I2=0%

Test for overall effect: Z=2.85(P=0)

Test for subgroup differences: Chi2=6.58, df=1 (P=0.04), I2=69.6%

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.25. Comparison 6 Resolution of encephalopathy, Outcome 25 ITT - Parenteral nutrition trials - best-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.25.1 All studies

Achord 1987 2/2 3/4 58.71% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 41.29% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 100% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.25.2 Standard amino acids

Favours control 200.05 50.2 1 Favours treatment

191

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Achord 1987 2/2 3/4 58.71% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 41.29% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 100% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.25.3 BCAA's

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Not applicable

Favours control 200.05 50.2 1 Favours treatment

Analysis 6.26. Comparison 6 Resolution of encephalopathy, Outcome 26 ITT - Enteral trials - best-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.26.1 All studies

Calvey 1985 6/21 1/9 28.4% 2.57[0.36,18.4]

Kearns 1992 5/10 3/7 71.6% 1.17[0.41,3.36]

Subtotal (95% CI) 31 16 100% 1.57[0.59,4.13]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.54, df=1(P=0.46); I2=0%

Test for overall effect: Z=0.91(P=0.36)

6.26.2 Standard amino acids

Calvey 1985 2/11 1/9 23.76% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 76.24% 1.17[0.41,3.36]

Subtotal (95% CI) 21 16 100% 1.28[0.48,3.39]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.08, df=1(P=0.78); I2=0%

Test for overall effect: Z=0.49(P=0.62)

6.26.3 BCAA's

Calvey 1985 4/10 1/9 100% 3.6[0.49,26.54]

Subtotal (95% CI) 10 9 100% 3.6[0.49,26.54]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

Test for subgroup differences: Chi2=0.83, df=1 (P=0.66), I2=0%

Favours control 500.02 100.1 1 Favours treatment

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Analysis 6.27. Comparison 6 Resolution of encephalopathy, Outcome 27 ITT - Supplements trials - best-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.27.1 All studies

Bunout 1989 0/3 3/7 68.56% 0.29[0.02,4.29]

Hayashi 1991 13/23 1/20 31.44% 11.3[1.62,78.95]

Subtotal (95% CI) 26 27 100% 3.75[1.15,12.18]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=4.71, df=1(P=0.03); I2=78.75%

Test for overall effect: Z=2.2(P=0.03)

6.27.2 Standard amino acids

Bunout 1989 0/3 3/7 100% 0.29[0.02,4.29]

Subtotal (95% CI) 3 7 100% 0.29[0.02,4.29]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.91(P=0.36)

6.27.3 BCAA's

Hayashi 1991 13/23 1/20 100% 11.3[1.62,78.95]

Subtotal (95% CI) 23 20 100% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Test for subgroup differences: Chi2=4.7, df=1 (P=0.1), I2=57.4%

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.28. Comparison 6 Resolution of encephalopathy, Outcome 28 ITT - All trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.28.1 All studies

Achord 1987 2/2 3/4 20.5% 1.19[0.55,2.56]

Bunout 1989 0/3 3/7 18.22% 0.29[0.02,4.29]

Calvey 1985 6/21 1/9 10.93% 2.57[0.36,18.4]

Hayashi 1991 13/23 1/20 8.36% 11.3[1.62,78.95]

Kearns 1992 5/10 3/7 27.57% 1.17[0.41,3.36]

Simon 1988 3/6 2/7 14.42% 1.75[0.42,7.23]

Subtotal (95% CI) 65 54 100% 2.1[1.18,3.72]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=8.35, df=5(P=0.14); I2=40.12%

Test for overall effect: Z=2.53(P=0.01)

6.28.2 Standard amino acids

Achord 1987 2/2 3/4 22.96% 1.19[0.55,2.56]

Bunout 1989 0/3 3/7 20.41% 0.29[0.02,4.29]

Calvey 1985 2/11 1/9 9.62% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 30.87% 1.17[0.41,3.36]

Simon 1988 3/6 2/7 16.15% 1.75[0.42,7.23]

Favours control 2000.005 100.1 1 Favours treatment

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 32 34 100% 1.13[0.62,2.07]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=1.48, df=4(P=0.83); I2=0%

Test for overall effect: Z=0.4(P=0.69)

6.28.3 BCAA's

Calvey 1985 4/10 1/9 49.6% 3.6[0.49,26.54]

Hayashi 1991 13/23 1/20 50.4% 11.3[1.62,78.95]

Subtotal (95% CI) 33 29 100% 7.48[1.87,29.94]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=0.69, df=1(P=0.41); I2=0%

Test for overall effect: Z=2.85(P=0)

Test for subgroup differences: Chi2=6.58, df=1 (P=0.04), I2=69.6%

Favours control 2000.005 100.1 1 Favours treatment

Analysis 6.29. Comparison 6 Resolution of encephalopathy, Outcome 29 ITT - Parenteral nutrition trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.29.1 All studies

Achord 1987 2/2 3/4 58.71% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 41.29% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 100% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.29.2 Standard amino acids

Achord 1987 2/2 3/4 58.71% 1.19[0.55,2.56]

Simon 1988 3/6 2/7 41.29% 1.75[0.42,7.23]

Subtotal (95% CI) 8 11 100% 1.42[0.66,3.07]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.29, df=1(P=0.59); I2=0%

Test for overall effect: Z=0.9(P=0.37)

6.29.3 BCAA's

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Not applicable

Favours control 500.02 100.1 1 Favours treatment

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Analysis 6.30. Comparison 6 Resolution of encephalopathy, Outcome 30 ITT - Enteral nutrition trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.30.1 All studies

Calvey 1985 6/21 1/9 28.4% 2.57[0.36,18.4]

Kearns 1992 5/10 3/7 71.6% 1.17[0.41,3.36]

Subtotal (95% CI) 31 16 100% 1.57[0.59,4.13]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.54, df=1(P=0.46); I2=0%

Test for overall effect: Z=0.91(P=0.36)

6.30.2 Standard amino acids

Calvey 1985 2/11 1/9 23.76% 1.64[0.18,15.26]

Kearns 1992 5/10 3/7 76.24% 1.17[0.41,3.36]

Subtotal (95% CI) 21 16 100% 1.28[0.48,3.39]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.08, df=1(P=0.78); I2=0%

Test for overall effect: Z=0.49(P=0.62)

6.30.3 BCAA's

Calvey 1985 4/10 1/9 100% 3.6[0.49,26.54]

Subtotal (95% CI) 10 9 100% 3.6[0.49,26.54]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

Test for subgroup differences: Chi2=0.83, df=1 (P=0.66), I2=0%

Favours control 1000.01 100.1 1 Favours treatment

Analysis 6.31. Comparison 6 Resolution of encephalopathy, Outcome 31 ITT - Supplement trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

6.31.1 All studies

Bunout 1989 0/3 3/7 68.56% 0.29[0.02,4.29]

Hayashi 1991 13/23 1/20 31.44% 11.3[1.62,78.95]

Subtotal (95% CI) 26 27 100% 3.75[1.15,12.18]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=4.71, df=1(P=0.03); I2=78.75%

Test for overall effect: Z=2.2(P=0.03)

6.31.2 Standard amino acids

Bunout 1989 0/3 3/7 55.83% 0.29[0.02,4.29]

Simon 1988 3/6 2/7 44.17% 1.75[0.42,7.23]

Subtotal (95% CI) 9 14 100% 0.93[0.28,3.09]

Total events: 3 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=1.49, df=1(P=0.22); I2=32.83%

Test for overall effect: Z=0.11(P=0.91)

6.31.3 BCAA's

Favours control 2000.005 100.1 1 Favours treatment

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hayashi 1991 13/23 1/20 100% 11.3[1.62,78.95]

Subtotal (95% CI) 23 20 100% 11.3[1.62,78.95]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.45(P=0.01)

Test for subgroup differences: Chi2=5.37, df=1 (P=0.07), I2=62.74%

Favours control 2000.005 100.1 1 Favours treatment

Comparison 7. infections

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 15 793 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.57, 0.91]

2 Trials with total numbers (Meng) ex- cluded

14 749 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.54, 0.90]

3 Parenteral nutrition 2 164 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.37, 1.16]

3.1 Medical trials 1 40 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.52, 156.91]

3.2 Surgical trials 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.25, 0.88]

4 Enteral nutrition 6 267 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.59, 1.09]

4.1 Medical trials 4 176 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.67, 1.30]

4.2 Surgical trials 2 91 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.22, 1.05]

5 Supplements 7 362 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.39, 1.03]

5.1 Medical trials 4 268 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.24, 0.99]

5.2 Surgical trials 3 94 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.44, 1.67]

6 Medical trials 9 484 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.63, 1.15]

7 Surgical trials 6 309 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.39, 0.85]

8 Alcoholic hepatitis 2 115 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.28, 1.13]

9 Cirrhosis 7 336 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.62, 1.17]

9.1 Parenteral nutrition 1 40 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.52, 156.91]

9.2 Enteral nutrition 3 112 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.66, 1.31]

9.3 Supplements 3 184 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.24, 1.03]

10 HCC 2 208 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.25, 0.86]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

10.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.25, 0.88]

10.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

10.3 Supplements 1 84 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.01, 8.34]

11 Abstracts excluded 14 738 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.52, 0.93]

12 Abstracts excluded 14 738 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.52, 0.93]

12.1 Parenteral nutrition 2 164 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.37, 1.16]

12.2 Enteral nutrition 5 212 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.50, 1.24]

12.3 Supplements 7 362 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.39, 1.03]

13 Surgical trials excluding trans- plants

5 278 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.39, 0.90]

14 Parenteral nutrition - best-case scenario

2 190 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.24, 0.70]

14.1 Medical trials 1 40 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.52, 156.91]

14.2 Surgical trials 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.16, 0.54]

15 Parenteral nutrition - worst-case scenario

2 190 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.73, 1.90]

15.1 Medical trials 1 40 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.52, 156.91]

15.2 Surgical trials 1 150 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.61, 1.64]

16 Enteral nutrition - best-case sce- nario

6 298 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.46, 0.84]

16.1 Medical trials 4 184 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.60, 1.16]

16.2 Surgical trials 2 114 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.13, 0.60]

17 Enteral nutrition - worst-case sce- nario

6 298 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.85, 1.46]

17.1 Medical trials 4 184 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.76, 1.41]

17.2 Surgical trials 2 114 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.78, 2.16]

18 Supplements - best-case scenario 7 401 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.24, 0.62]

18.1 Medical trials 4 286 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.17, 0.67]

18.2 Surgical trials 3 115 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.23, 0.84]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

19 Supplements - worst-case scenario 7 401 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.77, 1.73]

19.1 Medical trials 4 286 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.55, 1.71]

19.2 Surgical trials 3 115 Risk Ratio (M-H, Fixed, 95% CI) 1.42 [0.79, 2.55]

Analysis 7.1. Comparison 7 infections, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 5.95% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 7.33% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 1.02% 1.67[0.18,15.8]

Fan 1994 11/64 22/60 21.13% 0.47[0.25,0.88]

Foschi 1986 4/28 9/32 7.82% 0.51[0.18,1.47]

Hasse 1995 3/14 8/17 6.72% 0.46[0.15,1.4]

Hirsch 1993 2/26 9/25 8.54% 0.21[0.05,0.89]

Ishikawa 2010 2/11 3/13 2.56% 0.79[0.16,3.9]

Meng 1999 8/21 9/23 7.99% 0.97[0.46,2.05]

Mikagi 2011 0/13 1/13 1.4% 0.33[0.01,7.5]

Nakaya 2007 0/19 0/19 Not estimable

Naveau 1986 4/20 0/20 0.47% 9[0.52,156.91]

Norman 2008 16/26 22/29 19.35% 0.81[0.56,1.17]

Poon 2004 0/41 1/43 1.36% 0.35[0.01,8.34]

Sievert 1999 10/61 7/34 8.36% 0.8[0.33,1.9]

Total (95% CI) 414 379 100% 0.72[0.57,0.91]

Total events: 80 (Treatment), 105 (Control)

Heterogeneity: Tau2=0; Chi2=12.58, df=13(P=0.48); I2=0%

Test for overall effect: Z=2.71(P=0.01)

Favours treatment 2000.005 100.1 1 Favours control

Analysis 7.2. Comparison 7 infections, Outcome 2 Trials with total numbers (Meng) excluded.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 6.47% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 7.96% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 1.1% 1.67[0.18,15.8]

Fan 1994 11/64 22/60 22.97% 0.47[0.25,0.88]

Foschi 1986 4/28 9/32 8.49% 0.51[0.18,1.47]

Hasse 1995 3/14 8/17 7.31% 0.46[0.15,1.4]

Hirsch 1993 2/26 9/25 9.28% 0.21[0.05,0.89]

Ishikawa 2010 2/11 3/13 2.78% 0.79[0.16,3.9]

Mikagi 2011 0/13 1/13 1.52% 0.33[0.01,7.5]

Favours treatment 2000.005 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Nakaya 2007 0/19 0/19 Not estimable

Naveau 1986 4/20 0/20 0.51% 9[0.52,156.91]

Norman 2008 16/26 22/29 21.04% 0.81[0.56,1.17]

Poon 2004 0/41 1/43 1.48% 0.35[0.01,8.34]

Sievert 1999 10/61 7/34 9.09% 0.8[0.33,1.9]

Total (95% CI) 393 356 100% 0.7[0.54,0.9]

Total events: 72 (Treatment), 96 (Control)

Heterogeneity: Tau2=0; Chi2=12.07, df=12(P=0.44); I2=0.55%

Test for overall effect: Z=2.81(P=0)

Favours treatment 2000.005 100.1 1 Favours control

Analysis 7.3. Comparison 7 infections, Outcome 3 Parenteral nutrition.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.3.1 Medical trials

Naveau 1986 4/20 0/20 2.15% 9[0.52,156.91]

Subtotal (95% CI) 20 20 2.15% 9[0.52,156.91]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.51(P=0.13)

7.3.2 Surgical trials

Fan 1994 11/64 22/60 97.85% 0.47[0.25,0.88]

Subtotal (95% CI) 64 60 97.85% 0.47[0.25,0.88]

Total events: 11 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Test for overall effect: Z=2.35(P=0.02)

Total (95% CI) 84 80 100% 0.65[0.37,1.16]

Total events: 15 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=4.29, df=1(P=0.04); I2=76.68%

Test for overall effect: Z=1.46(P=0.14)

Test for subgroup differences: Chi2=3.91, df=1 (P=0.05), I2=74.45%

Favours treatment 10000.001 100.1 1 Favours control

Analysis 7.4. Comparison 7 infections, Outcome 4 Enteral nutrition.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.4.1 Medical trials

Cabre 1990 7/16 7/19 12.36% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 15.21% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 2.11% 1.67[0.18,15.8]

Norman 2008 16/26 22/29 40.16% 0.81[0.56,1.17]

Subtotal (95% CI) 96 80 69.83% 0.94[0.67,1.3]

Favours treatment 200.05 50.2 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 36 (Treatment), 36 (Control)

Heterogeneity: Tau2=0; Chi2=1.17, df=3(P=0.76); I2=0%

Test for overall effect: Z=0.39(P=0.69)

7.4.2 Surgical trials

Foschi 1986 4/28 9/32 16.22% 0.51[0.18,1.47]

Hasse 1995 3/14 8/17 13.95% 0.46[0.15,1.4]

Subtotal (95% CI) 42 49 30.17% 0.48[0.22,1.05]

Total events: 7 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.02, df=1(P=0.89); I2=0%

Test for overall effect: Z=1.84(P=0.07)

Total (95% CI) 138 129 100% 0.8[0.59,1.09]

Total events: 43 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=3.18, df=5(P=0.67); I2=0%

Test for overall effect: Z=1.43(P=0.15)

Test for subgroup differences: Chi2=2.38, df=1 (P=0.12), I2=57.94%

Favours treatment 200.05 50.2 1 Favours control

Analysis 7.5. Comparison 7 infections, Outcome 5 Supplements.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.5.1 Medical trials

Hirsch 1993 2/26 9/25 28.26% 0.21[0.05,0.89]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 0/41 1/43 4.51% 0.35[0.01,8.34]

Sievert 1999 10/61 7/34 27.68% 0.8[0.33,1.9]

Subtotal (95% CI) 147 121 60.46% 0.49[0.24,0.99]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=2.53, df=2(P=0.28); I2=20.99%

Test for overall effect: Z=1.99(P=0.05)

7.5.2 Surgical trials

Ishikawa 2010 2/11 3/13 8.47% 0.79[0.16,3.9]

Meng 1999 8/21 9/23 26.46% 0.97[0.46,2.05]

Mikagi 2011 0/13 1/13 4.62% 0.33[0.01,7.5]

Subtotal (95% CI) 45 49 39.54% 0.86[0.44,1.67]

Total events: 10 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=0.47, df=2(P=0.79); I2=0%

Test for overall effect: Z=0.45(P=0.65)

Total (95% CI) 192 170 100% 0.64[0.39,1.03]

Total events: 22 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=4.11, df=5(P=0.53); I2=0%

Test for overall effect: Z=1.84(P=0.07)

Test for subgroup differences: Chi2=1.29, df=1 (P=0.26), I2=22.55%

Favours treatment 1000.01 100.1 1 Favours control

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Analysis 7.6. Comparison 7 infections, Outcome 6 Medical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 11.37% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 13.99% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 1.94% 1.67[0.18,15.8]

Hirsch 1993 2/26 9/25 16.3% 0.21[0.05,0.89]

Nakaya 2007 0/19 0/19 Not estimable

Naveau 1986 4/20 0/20 0.89% 9[0.52,156.91]

Norman 2008 16/26 22/29 36.95% 0.81[0.56,1.17]

Poon 2004 0/41 1/43 2.6% 0.35[0.01,8.34]

Sievert 1999 10/61 7/34 15.97% 0.8[0.33,1.9]

Total (95% CI) 263 221 100% 0.85[0.63,1.15]

Total events: 52 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=7.66, df=7(P=0.36); I2=8.67%

Test for overall effect: Z=1.04(P=0.3)

Favours treatment 2000.005 100.1 1 Favours control

Analysis 7.7. Comparison 7 infections, Outcome 7 Surgical trials.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 11/64 22/60 44.38% 0.47[0.25,0.88]

Foschi 1986 4/28 9/32 16.41% 0.51[0.18,1.47]

Hasse 1995 3/14 8/17 14.12% 0.46[0.15,1.4]

Ishikawa 2010 2/11 3/13 5.37% 0.79[0.16,3.9]

Meng 1999 8/21 9/23 16.79% 0.97[0.46,2.05]

Mikagi 2011 0/13 1/13 2.93% 0.33[0.01,7.5]

Total (95% CI) 151 158 100% 0.57[0.39,0.85]

Total events: 28 (Treatment), 52 (Control)

Heterogeneity: Tau2=0; Chi2=2.81, df=5(P=0.73); I2=0%

Test for overall effect: Z=2.8(P=0.01)

Favours treatment 1000.01 100.1 1 Favours control

Analysis 7.8. Comparison 7 infections, Outcome 8 Alcoholic hepatitis.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Calvey 1985 11/42 6/22 46.18% 0.96[0.41,2.25]

Hirsch 1993 2/26 9/25 53.82% 0.21[0.05,0.89]

Total (95% CI) 68 47 100% 0.56[0.28,1.13]

Total events: 13 (Treatment), 15 (Control)

Heterogeneity: Tau2=0; Chi2=3.29, df=1(P=0.07); I2=69.63%

Test for overall effect: Z=1.63(P=0.1)

Favours treatment 500.02 100.1 1 Favours control

201

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Analysis 7.9. Comparison 7 infections, Outcome 9 Cirrhosis.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.9.1 Parenteral nutrition

Naveau 1986 4/20 0/20 1.06% 9[0.52,156.91]

Subtotal (95% CI) 20 20 1.06% 9[0.52,156.91]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.51(P=0.13)

7.9.2 Enteral nutrition

Cabre 1990 7/16 7/19 13.63% 1.19[0.53,2.67]

DeLedinghen 1997 2/12 1/10 2.32% 1.67[0.18,15.8]

Norman 2008 16/26 22/29 44.3% 0.81[0.56,1.17]

Subtotal (95% CI) 54 58 60.25% 0.93[0.66,1.31]

Total events: 25 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=1.14, df=2(P=0.57); I2=0%

Test for overall effect: Z=0.42(P=0.68)

7.9.3 Supplements

Hirsch 1993 2/26 9/25 19.54% 0.21[0.05,0.89]

Nakaya 2007 0/19 0/19 Not estimable

Sievert 1999 10/61 7/34 19.14% 0.8[0.33,1.9]

Subtotal (95% CI) 106 78 38.69% 0.5[0.24,1.03]

Total events: 12 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=2.45, df=1(P=0.12); I2=59.18%

Test for overall effect: Z=1.88(P=0.06)

Total (95% CI) 180 156 100% 0.85[0.62,1.17]

Total events: 41 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=7.28, df=5(P=0.2); I2=31.33%

Test for overall effect: Z=0.99(P=0.32)

Test for subgroup differences: Chi2=4.94, df=1 (P=0.08), I2=59.49%

Favours experimental 2000.005 100.1 1 Favours control

Analysis 7.10. Comparison 7 infections, Outcome 10 HCC.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.10.1 Parenteral nutrition

Fan 1994 11/64 22/60 93.94% 0.47[0.25,0.88]

Subtotal (95% CI) 64 60 93.94% 0.47[0.25,0.88]

Total events: 11 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Test for overall effect: Z=2.35(P=0.02)

7.10.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Favours experimental 1000.01 100.1 1 Favours control

202

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Not applicable

Test for overall effect: Not applicable

7.10.3 Supplements

Poon 2004 0/41 1/43 6.06% 0.35[0.01,8.34]

Subtotal (95% CI) 41 43 6.06% 0.35[0.01,8.34]

Total events: 0 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.65(P=0.52)

Total (95% CI) 105 103 100% 0.46[0.25,0.86]

Total events: 11 (Treatment), 23 (Control)

Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.86); I2=0%

Test for overall effect: Z=2.44(P=0.01)

Test for subgroup differences: Chi2=0.03, df=1 (P=0.86), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

Analysis 7.11. Comparison 7 infections, Outcome 11 Abstracts excluded.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 7.38% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 9.09% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 1.26% 1.67[0.18,15.8]

Fan 1994 11/64 22/60 26.2% 0.47[0.25,0.88]

Foschi 1986 4/28 9/32 9.69% 0.51[0.18,1.47]

Hasse 1995 3/14 8/17 8.34% 0.46[0.15,1.4]

Hirsch 1993 2/26 9/25 10.59% 0.21[0.05,0.89]

Ishikawa 2010 2/11 3/13 3.17% 0.79[0.16,3.9]

Meng 1999 8/21 9/23 9.91% 0.97[0.46,2.05]

Mikagi 2011 0/13 1/13 1.73% 0.33[0.01,7.5]

Nakaya 2007 0/19 0/19 Not estimable

Naveau 1986 4/20 0/20 0.58% 9[0.52,156.91]

Poon 2004 0/41 1/43 1.69% 0.35[0.01,8.34]

Sievert 1999 10/61 7/34 10.37% 0.8[0.33,1.9]

Total (95% CI) 388 350 100% 0.7[0.52,0.93]

Total events: 64 (Treatment), 83 (Control)

Heterogeneity: Tau2=0; Chi2=12.18, df=12(P=0.43); I2=1.44%

Test for overall effect: Z=2.49(P=0.01)

Favours treatment 5000.002 100.1 1 Favours control

Analysis 7.12. Comparison 7 infections, Outcome 12 Abstracts excluded.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.12.1 Parenteral nutrition

Favours experimental 5000.002 100.1 1 Favours control

203

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 11/64 22/60 26.2% 0.47[0.25,0.88]

Naveau 1986 4/20 0/20 0.58% 9[0.52,156.91]

Subtotal (95% CI) 84 80 26.78% 0.65[0.37,1.16]

Total events: 15 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=4.29, df=1(P=0.04); I2=76.68%

Test for overall effect: Z=1.46(P=0.14)

7.12.2 Enteral nutrition

Cabre 1990 7/16 7/19 7.38% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 9.09% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 1.26% 1.67[0.18,15.8]

Foschi 1986 4/28 9/32 9.69% 0.51[0.18,1.47]

Hasse 1995 3/14 8/17 8.34% 0.46[0.15,1.4]

Subtotal (95% CI) 112 100 35.76% 0.79[0.5,1.24]

Total events: 27 (Treatment), 31 (Control)

Heterogeneity: Tau2=0; Chi2=3.18, df=4(P=0.53); I2=0%

Test for overall effect: Z=1.01(P=0.31)

7.12.3 Supplements

Hirsch 1993 2/26 9/25 10.59% 0.21[0.05,0.89]

Ishikawa 2010 2/11 3/13 3.17% 0.79[0.16,3.9]

Meng 1999 8/21 9/23 9.91% 0.97[0.46,2.05]

Mikagi 2011 0/13 1/13 1.73% 0.33[0.01,7.5]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 0/41 1/43 1.69% 0.35[0.01,8.34]

Sievert 1999 10/61 7/34 10.37% 0.8[0.33,1.9]

Subtotal (95% CI) 192 170 37.46% 0.64[0.39,1.03]

Total events: 22 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=4.11, df=5(P=0.53); I2=0%

Test for overall effect: Z=1.84(P=0.07)

Total (95% CI) 388 350 100% 0.7[0.52,0.93]

Total events: 64 (Treatment), 83 (Control)

Heterogeneity: Tau2=0; Chi2=12.18, df=12(P=0.43); I2=1.44%

Test for overall effect: Z=2.49(P=0.01)

Test for subgroup differences: Chi2=0.49, df=1 (P=0.78), I2=0%

Favours experimental 5000.002 100.1 1 Favours control

Analysis 7.13. Comparison 7 infections, Outcome 13 Surgical trials excluding transplants.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 11/64 22/60 51.67% 0.47[0.25,0.88]

Foschi 1986 4/28 9/32 19.11% 0.51[0.18,1.47]

Ishikawa 2010 2/11 3/13 6.26% 0.79[0.16,3.9]

Meng 1999 8/21 9/23 19.55% 0.97[0.46,2.05]

Mikagi 2011 0/13 1/13 3.41% 0.33[0.01,7.5]

Total (95% CI) 137 141 100% 0.59[0.39,0.9]

Favours treatment 1000.01 100.1 1 Favours control

204

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 25 (Treatment), 44 (Control)

Heterogeneity: Tau2=0; Chi2=2.57, df=4(P=0.63); I2=0%

Test for overall effect: Z=2.47(P=0.01)

Favours treatment 1000.01 100.1 1 Favours control

Analysis 7.14. Comparison 7 infections, Outcome 14 Parenteral nutrition - best-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.14.1 Medical trials

Naveau 1986 4/20 0/20 1.33% 9[0.52,156.91]

Subtotal (95% CI) 20 20 1.33% 9[0.52,156.91]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.51(P=0.13)

7.14.2 Surgical trials

Fan 1994 11/75 37/75 98.67% 0.3[0.16,0.54]

Subtotal (95% CI) 75 75 98.67% 0.3[0.16,0.54]

Total events: 11 (Treatment), 37 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.02(P<0.0001)

Total (95% CI) 95 95 100% 0.41[0.24,0.7]

Total events: 15 (Treatment), 37 (Control)

Heterogeneity: Tau2=0; Chi2=5.65, df=1(P=0.02); I2=82.31%

Test for overall effect: Z=3.29(P=0)

Test for subgroup differences: Chi2=5.24, df=1 (P=0.02), I2=80.93%

Favours treatment 5000.002 100.1 1 Favours control

Analysis 7.15. Comparison 7 infections, Outcome 15 Parenteral nutrition - worst-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.15.1 Medical trials

Naveau 1986 4/20 0/20 2.22% 9[0.52,156.91]

Subtotal (95% CI) 20 20 2.22% 9[0.52,156.91]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.51(P=0.13)

7.15.2 Surgical trials

Fan 1994 22/75 22/75 97.78% 1[0.61,1.64]

Subtotal (95% CI) 75 75 97.78% 1[0.61,1.64]

Total events: 22 (Treatment), 22 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours treatment 5000.002 100.1 1 Favours control

205

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 95 95 100% 1.18[0.73,1.9]

Total events: 26 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=2.36, df=1(P=0.12); I2=57.65%

Test for overall effect: Z=0.67(P=0.5)

Test for subgroup differences: Chi2=2.2, df=1 (P=0.14), I2=54.61%

Favours treatment 5000.002 100.1 1 Favours control

Analysis 7.16. Comparison 7 infections, Outcome 16 Enteral nutrition - best-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.16.1 Medical trials

Cabre 1990 7/16 7/19 9.85% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 12.12% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 1.68% 1.67[0.18,15.8]

Norman 2008 16/31 25/32 37.87% 0.66[0.45,0.97]

Subtotal (95% CI) 101 83 61.52% 0.83[0.6,1.16]

Total events: 36 (Treatment), 39 (Control)

Heterogeneity: Tau2=0; Chi2=2.58, df=3(P=0.46); I2=0%

Test for overall effect: Z=1.1(P=0.27)

7.16.2 Surgical trials

Foschi 1986 4/32 9/32 13.85% 0.44[0.15,1.3]

Hasse 1995 3/25 16/25 24.63% 0.19[0.06,0.56]

Subtotal (95% CI) 57 57 38.48% 0.28[0.13,0.6]

Total events: 7 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=1.22, df=1(P=0.27); I2=18.3%

Test for overall effect: Z=3.31(P=0)

Total (95% CI) 158 140 100% 0.62[0.46,0.84]

Total events: 43 (Treatment), 64 (Control)

Heterogeneity: Tau2=0; Chi2=9.25, df=5(P=0.1); I2=45.93%

Test for overall effect: Z=3.07(P=0)

Test for subgroup differences: Chi2=6.71, df=1 (P=0.01), I2=85.11%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 7.17. Comparison 7 infections, Outcome 17 Enteral nutrition - worst-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.17.1 Medical trials

Cabre 1990 7/16 7/19 11.85% 1.19[0.53,2.67]

Calvey 1985 11/42 6/22 14.58% 0.96[0.41,2.25]

DeLedinghen 1997 2/12 1/10 2.02% 1.67[0.18,15.8]

Norman 2008 21/31 22/32 40.08% 0.99[0.7,1.38]

Subtotal (95% CI) 101 83 68.53% 1.04[0.76,1.41]

Favours treatment 1000.01 100.1 1 Favours control

206

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 41 (Treatment), 36 (Control)

Heterogeneity: Tau2=0; Chi2=0.39, df=3(P=0.94); I2=0%

Test for overall effect: Z=0.22(P=0.83)

7.17.2 Surgical trials

Foschi 1986 8/32 9/32 16.66% 0.89[0.39,2.01]

Hasse 1995 14/25 8/25 14.81% 1.75[0.9,3.42]

Subtotal (95% CI) 57 57 31.47% 1.29[0.78,2.16]

Total events: 22 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=1.59, df=1(P=0.21); I2=37.3%

Test for overall effect: Z=0.99(P=0.32)

Total (95% CI) 158 140 100% 1.12[0.85,1.46]

Total events: 63 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=2.83, df=5(P=0.73); I2=0%

Test for overall effect: Z=0.8(P=0.42)

Test for subgroup differences: Chi2=0.53, df=1 (P=0.47), I2=0%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 7.18. Comparison 7 infections, Outcome 18 Supplements - best-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.18.1 Medical trials

Hirsch 1993 2/32 17/33 31.79% 0.12[0.03,0.48]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 0/44 2/44 4.75% 0.2[0.01,4.05]

Sievert 1999 10/61 7/34 17.07% 0.8[0.33,1.9]

Subtotal (95% CI) 156 130 53.61% 0.34[0.17,0.67]

Total events: 12 (Treatment), 26 (Control)

Heterogeneity: Tau2=0; Chi2=5.89, df=2(P=0.05); I2=66.06%

Test for overall effect: Z=3.1(P=0)

7.18.2 Surgical trials

Ishikawa 2010 2/11 3/13 5.22% 0.79[0.16,3.9]

Meng 1999 8/25 11/25 20.89% 0.73[0.35,1.5]

Mikagi 2011 0/16 13/25 20.27% 0.06[0,0.89]

Subtotal (95% CI) 52 63 46.39% 0.44[0.23,0.84]

Total events: 10 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=4.48, df=2(P=0.11); I2=55.34%

Test for overall effect: Z=2.48(P=0.01)

Total (95% CI) 208 193 100% 0.39[0.24,0.62]

Total events: 22 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=11.04, df=5(P=0.05); I2=54.72%

Test for overall effect: Z=3.97(P<0.0001)

Test for subgroup differences: Chi2=0.28, df=1 (P=0.6), I2=0%

Favours treatment 5000.002 100.1 1 Favours control

207

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Analysis 7.19. Comparison 7 infections, Outcome 19 Supplements - worst-case scenario.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

7.19.1 Medical trials

Hirsch 1993 8/32 9/33 28.24% 0.92[0.4,2.08]

Nakaya 2007 0/19 0/19 Not estimable

Poon 2004 3/44 1/44 3.19% 3[0.32,27.74]

Sievert 1999 10/61 7/34 28.65% 0.8[0.33,1.9]

Subtotal (95% CI) 156 130 60.07% 0.97[0.55,1.71]

Total events: 21 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=1.21, df=2(P=0.55); I2=0%

Test for overall effect: Z=0.11(P=0.92)

7.19.2 Surgical trials

Ishikawa 2010 2/11 3/13 8.76% 0.79[0.16,3.9]

Meng 1999 12/25 9/25 28.68% 1.33[0.69,2.59]

Mikagi 2011 3/16 1/25 2.49% 4.69[0.53,41.24]

Subtotal (95% CI) 52 63 39.93% 1.42[0.79,2.55]

Total events: 17 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=1.72, df=2(P=0.42); I2=0%

Test for overall effect: Z=1.18(P=0.24)

Total (95% CI) 208 193 100% 1.15[0.77,1.73]

Total events: 38 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=3.71, df=5(P=0.59); I2=0%

Test for overall effect: Z=0.67(P=0.5)

Test for subgroup differences: Chi2=0.85, df=1 (P=0.36), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

Comparison 8. Serum bilirubin

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 10 450 Mean Difference (IV, Fixed, 95% CI)

-1.91 [-2.72, -1.11]

2 Parenteral nutrition 6 269 Mean Difference (IV, Fixed, 95% CI)

-2.52 [-3.45, -1.60]

2.1 Medical trials 3 106 Mean Difference (IV, Fixed, 95% CI)

-2.86 [-3.82, -1.89]

2.2 Surgical trials 3 163 Mean Difference (IV, Fixed, 95% CI)

1.32 [-1.95, 4.59]

3 Enteral nutrition (all medical trials) 2 94 Mean Difference (IV, Fixed, 95% CI)

-0.17 [-2.63, 2.29]

3.1 Medical trials 2 94 Mean Difference (IV, Fixed, 95% CI)

-0.17 [-2.63, 2.29]

208

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

3.2 Surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Supplements 2 87 Mean Difference (IV, Fixed, 95% CI)

0.24 [-2.03, 2.51]

4.1 Medical trials 2 87 Mean Difference (IV, Fixed, 95% CI)

0.24 [-2.03, 2.51]

4.2 Surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Medical trials 7 287 Mean Difference (IV, Fixed, 95% CI)

-2.13 [-2.96, -1.30]

5.1 Parenteral nutrition 3 106 Mean Difference (IV, Fixed, 95% CI)

-2.86 [-3.82, -1.89]

5.2 Enteral nutrition 2 94 Mean Difference (IV, Fixed, 95% CI)

-0.17 [-2.63, 2.29]

5.3 Supplements 2 87 Mean Difference (IV, Fixed, 95% CI)

0.24 [-2.03, 2.51]

6 Surgical trials 3 163 Mean Difference (IV, Fixed, 95% CI)

1.32 [-1.95, 4.59]

6.1 Parenteral nutrition 3 163 Mean Difference (IV, Fixed, 95% CI)

1.32 [-1.95, 4.59]

6.2 Enteral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 Supplements 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Alcoholic hepatitis 5 184 Mean Difference (IV, Random, 95% CI)

-3.51 [-7.20, 0.18]

7.1 Parenteral nutrition 2 66 Mean Difference (IV, Random, 95% CI)

-6.41 [-9.41, -3.40]

7.2 Enteral nutrition 1 31 Mean Difference (IV, Random, 95% CI)

-5.90 [-17.54, 5.74]

7.3 Supplements 2 87 Mean Difference (IV, Random, 95% CI)

0.24 [-2.03, 2.51]

8 Cirrhosis 3 154 Mean Difference (IV, Fixed, 95% CI)

-1.10 [-2.08, -0.12]

8.1 Parenteral nutrition 1 40 Mean Difference (IV, Fixed, 95% CI)

-1.60 [-2.74, -0.46]

209

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

8.2 Enteral nutrition 1 63 Mean Difference (IV, Fixed, 95% CI)

0.10 [-2.42, 2.62]

8.3 Supplements 1 51 Mean Difference (IV, Fixed, 95% CI)

0.60 [-2.33, 3.53]

9 HCC 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.1 Pareneral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Enteral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

10 Abstracts excluded 9 387 Mean Difference (IV, Fixed, 95% CI)

-2.15 [-3.01, -1.30]

10.1 Parenteral nutrition 6 269 Mean Difference (IV, Fixed, 95% CI)

-2.52 [-3.45, -1.60]

10.2 Enteral nutrition 1 31 Mean Difference (IV, Fixed, 95% CI)

-5.90 [-17.54, 5.74]

10.3 Supplements 2 87 Mean Difference (IV, Fixed, 95% CI)

0.24 [-2.03, 2.51]

11 Intent to treat - best-case scenario for intervention (cannot do analyses for con- tinuous variables)

0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.1 Parenteral nutrition - medical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.2 Parenteral nutrition - surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.3 Enteral nutrition - medical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.4 Enteral nutrition - surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.5 Supplements - medical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.6 Supplements - surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

210

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

12 Intent to treat - worst-case scenario for intervention (cannot do analyses for con- tinuous variables)

0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.1 Parenteral nutrition - medical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.2 Parenteral nutrition - surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.3 Enteral nutrition - medical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.4 Enteral nutrition - surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.5 Supplements - medical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.6 Supplements - surgical trials 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

13 Alcoholic liver disease 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.1 Parenteral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.2 Enteral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.3 Supplements 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

14 Non-alcoholic liver disease 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

14.1 Parenteral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

14.2 Enteral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

14.3 Supplements 0 0 Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

211

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Analysis 8.1. Comparison 8 Serum bilirubin, Outcome 1 All studies.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Achord 1987 14 3 (1) 14 8.5 (3.5) 17.95% -5.5[-7.41,-3.59]

Bunout 1989 17 3.8 (4.9) 19 4.1 (6.1) 5.04% -0.3[-3.9,3.3]

Hirsch 1993 26 2.1 (6.1) 25 1.5 (4.5) 7.58% 0.6[-2.33,3.53]

Kearns 1992 16 2.7 (9.2) 15 8.6 (21.2) 0.48% -5.9[-17.54,5.74]

Naveau 1986 20 2.5 (1.4) 20 4.1 (2.2) 49.98% -1.6[-2.74,-0.46]

Norman 2008 31 5.2 (4.9) 32 5.1 (5.3) 10.28% 0.1[-2.42,2.62]

Qiu 2009 44 3.8 (14) 21 3.1 (9.4) 1.96% 0.7[-5.07,6.47]

Reilly 1990 18 5.5 (5.7) 10 2.5 (7.9) 2.11% 3[-2.56,8.56]

Simon 1988 19 4.7 (3) 19 13.7 (11) 2.48% -9[-14.13,-3.87]

Zheng 2003 40 2.7 (12) 30 2.4 (11.5) 2.12% 0.3[-5.25,5.85]

Total *** 245 205 100% -1.91[-2.72,-1.11]

Heterogeneity: Tau2=0; Chi2=32.12, df=9(P=0); I2=71.98%

Test for overall effect: Z=4.65(P<0.0001)

Favours treatment 4020-40 -20 0 Favours control

Analysis 8.2. Comparison 8 Serum bilirubin, Outcome 2 Parenteral nutrition.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

8.2.1 Medical trials

Achord 1987 14 3 (1) 14 8.5 (3.5) 23.47% -5.5[-7.41,-3.59]

Naveau 1986 20 2.5 (1.4) 20 4.1 (2.2) 65.32% -1.6[-2.74,-0.46]

Simon 1988 19 4.7 (3) 19 13.7 (11) 3.25% -9[-14.13,-3.87]

Subtotal *** 53 53 92.03% -2.86[-3.82,-1.89]

Heterogeneity: Tau2=0; Chi2=17.54, df=2(P=0); I2=88.6%

Test for overall effect: Z=5.81(P<0.0001)

8.2.2 Surgical trials

Qiu 2009 44 3.8 (14) 21 3.1 (9.4) 2.56% 0.7[-5.07,6.47]

Reilly 1990 18 5.5 (6.3) 10 2.5 (7.9) 2.63% 3[-2.7,8.7]

Zheng 2003 40 2.7 (12) 30 2.4 (11.5) 2.77% 0.3[-5.25,5.85]

Subtotal *** 102 61 7.97% 1.32[-1.95,4.59]

Heterogeneity: Tau2=0; Chi2=0.51, df=2(P=0.78); I2=0%

Test for overall effect: Z=0.79(P=0.43)

Total *** 155 114 100% -2.52[-3.45,-1.6]

Heterogeneity: Tau2=0; Chi2=23.81, df=5(P=0); I2=79%

Test for overall effect: Z=5.35(P<0.0001)

Test for subgroup differences: Chi2=5.76, df=1 (P=0.02), I2=82.62%

Favours treatment 2010-20 -10 0 Favours control

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Analysis 8.3. Comparison 8 Serum bilirubin, Outcome 3 Enteral nutrition (all medical trials).

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

8.3.1 Medical trials

Kearns 1992 16 2.7 (9.2) 15 8.6 (21.2) 4.48% -5.9[-17.54,5.74]

Norman 2008 31 5.2 (4.9) 32 5.1 (5.3) 95.52% 0.1[-2.42,2.62]

Subtotal *** 47 47 100% -0.17[-2.63,2.29]

Heterogeneity: Tau2=0; Chi2=0.98, df=1(P=0.32); I2=0%

Test for overall effect: Z=0.13(P=0.89)

8.3.2 Surgical trials

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total *** 47 47 100% -0.17[-2.63,2.29]

Heterogeneity: Tau2=0; Chi2=0.98, df=1(P=0.32); I2=0%

Test for overall effect: Z=0.13(P=0.89)

Test for subgroup differences: Not applicable

Favours treatment 2010-20 -10 0 Favours control

Analysis 8.4. Comparison 8 Serum bilirubin, Outcome 4 Supplements.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

8.4.1 Medical trials

Bunout 1989 17 3.8 (4.9) 19 4.1 (6.1) 39.94% -0.3[-3.9,3.3]

Hirsch 1993 26 2.1 (6.1) 25 1.5 (4.5) 60.06% 0.6[-2.33,3.53]

Subtotal *** 43 44 100% 0.24[-2.03,2.51]

Heterogeneity: Tau2=0; Chi2=0.14, df=1(P=0.7); I2=0%

Test for overall effect: Z=0.21(P=0.84)

8.4.2 Surgical trials

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total *** 43 44 100% 0.24[-2.03,2.51]

Heterogeneity: Tau2=0; Chi2=0.14, df=1(P=0.7); I2=0%

Test for overall effect: Z=0.21(P=0.84)

Test for subgroup differences: Not applicable

Favours treatment 105-10 -5 0 Favours control

Analysis 8.5. Comparison 8 Serum bilirubin, Outcome 5 Medical trials.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

8.5.1 Parenteral nutrition

Favours treatment 2010-20 -10 0 Favours control

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Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Achord 1987 14 3 (1) 14 8.5 (3.5) 19.14% -5.5[-7.41,-3.59]

Naveau 1986 20 2.5 (1.4) 20 4.1 (2.2) 53.28% -1.6[-2.74,-0.46]

Simon 1988 19 4.7 (3) 19 13.7 (11) 2.65% -9[-14.13,-3.87]

Subtotal *** 53 53 75.07% -2.86[-3.82,-1.89]

Heterogeneity: Tau2=0; Chi2=17.54, df=2(P=0); I2=88.6%

Test for overall effect: Z=5.81(P<0.0001)

8.5.2 Enteral nutrition

Kearns 1992 16 2.7 (9.2) 15 8.6 (21.2) 0.51% -5.9[-17.54,5.74]

Norman 2008 31 5.2 (4.9) 32 5.1 (5.3) 10.96% 0.1[-2.42,2.62]

Subtotal *** 47 47 11.48% -0.17[-2.63,2.29]

Heterogeneity: Tau2=0; Chi2=0.98, df=1(P=0.32); I2=0%

Test for overall effect: Z=0.13(P=0.89)

8.5.3 Supplements

Bunout 1989 17 3.8 (4.9) 19 4.1 (6.1) 5.37% -0.3[-3.9,3.3]

Hirsch 1993 26 2.1 (6.1) 25 1.5 (4.5) 8.08% 0.6[-2.33,3.53]

Subtotal *** 43 44 13.46% 0.24[-2.03,2.51]

Heterogeneity: Tau2=0; Chi2=0.14, df=1(P=0.7); I2=0%

Test for overall effect: Z=0.21(P=0.84)

Total *** 143 144 100% -2.13[-2.96,-1.3]

Heterogeneity: Tau2=0; Chi2=27.46, df=6(P=0); I2=78.15%

Test for overall effect: Z=5.01(P<0.0001)

Test for subgroup differences: Chi2=8.79, df=1 (P=0.01), I2=77.25%

Favours treatment 2010-20 -10 0 Favours control

Analysis 8.6. Comparison 8 Serum bilirubin, Outcome 6 Surgical trials.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

8.6.1 Parenteral nutrition

Qiu 2009 44 3.8 (14) 21 3.1 (9.4) 32.18% 0.7[-5.07,6.47]

Reilly 1990 18 5.5 (6.3) 10 2.5 (7.9) 33.01% 3[-2.7,8.7]

Zheng 2003 40 2.7 (12) 30 2.4 (11.5) 34.81% 0.3[-5.25,5.85]

Subtotal *** 102 61 100% 1.32[-1.95,4.59]

Heterogeneity: Tau2=0; Chi2=0.51, df=2(P=0.78); I2=0%

Test for overall effect: Z=0.79(P=0.43)

8.6.2 Enteral nutrition

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

8.6.3 Supplements

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours treatment 105-10 -5 0 Favours control

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Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Total *** 102 61 100% 1.32[-1.95,4.59]

Heterogeneity: Tau2=0; Chi2=0.51, df=2(P=0.78); I2=0%

Test for overall effect: Z=0.79(P=0.43)

Test for subgroup differences: Not applicable

Favours treatment 105-10 -5 0 Favours control

Analysis 8.7. Comparison 8 Serum bilirubin, Outcome 7 Alcoholic hepatitis.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI

8.7.1 Parenteral nutrition

Achord 1987 14 3 (1) 14 8.5 (3.5) 26.85% -5.5[-7.41,-3.59]

Simon 1988 19 4.7 (3) 19 13.7 (11) 18.56% -9[-14.13,-3.87]

Subtotal *** 33 33 45.41% -6.41[-9.41,-3.4]

Heterogeneity: Tau2=2.23; Chi2=1.57, df=1(P=0.21); I2=36.42%

Test for overall effect: Z=4.18(P<0.0001)

8.7.2 Enteral nutrition

Kearns 1992 16 2.7 (9.2) 15 8.6 (21.2) 7.46% -5.9[-17.54,5.74]

Subtotal *** 16 15 7.46% -5.9[-17.54,5.74]

Heterogeneity: Not applicable

Test for overall effect: Z=0.99(P=0.32)

8.7.3 Supplements

Bunout 1989 17 3.8 (4.9) 19 4.1 (6.1) 22.68% -0.3[-3.9,3.3]

Hirsch 1993 26 2.1 (6.1) 25 1.5 (4.5) 24.45% 0.6[-2.33,3.53]

Subtotal *** 43 44 47.13% 0.24[-2.03,2.51]

Heterogeneity: Tau2=0; Chi2=0.14, df=1(P=0.7); I2=0%

Test for overall effect: Z=0.21(P=0.84)

Total *** 92 92 100% -3.51[-7.2,0.18]

Heterogeneity: Tau2=12.25; Chi2=19.33, df=4(P=0); I2=79.3%

Test for overall effect: Z=1.86(P=0.06)

Test for subgroup differences: Chi2=12.33, df=1 (P=0), I2=83.78%

Favours treatment 2010-20 -10 0 Favours control

Analysis 8.8. Comparison 8 Serum bilirubin, Outcome 8 Cirrhosis.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

8.8.1 Parenteral nutrition

Naveau 1986 20 2.5 (1.4) 20 4.1 (2.2) 73.67% -1.6[-2.74,-0.46]

Subtotal *** 20 20 73.67% -1.6[-2.74,-0.46]

Heterogeneity: Not applicable

Test for overall effect: Z=2.74(P=0.01)

8.8.2 Enteral nutrition

Favours treatment 105-10 -5 0 Favours control

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Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Norman 2008 31 5.2 (4.9) 32 5.1 (5.3) 15.16% 0.1[-2.42,2.62]

Subtotal *** 31 32 15.16% 0.1[-2.42,2.62]

Heterogeneity: Not applicable

Test for overall effect: Z=0.08(P=0.94)

8.8.3 Supplements

Hirsch 1993 26 2.1 (6.1) 25 1.5 (4.5) 11.18% 0.6[-2.33,3.53]

Subtotal *** 26 25 11.18% 0.6[-2.33,3.53]

Heterogeneity: Not applicable

Test for overall effect: Z=0.4(P=0.69)

Total *** 77 77 100% -1.1[-2.08,-0.12]

Heterogeneity: Tau2=0; Chi2=2.9, df=2(P=0.24); I2=30.95%

Test for overall effect: Z=2.19(P=0.03)

Test for subgroup differences: Chi2=2.9, df=1 (P=0.24), I2=30.95%

Favours treatment 105-10 -5 0 Favours control

Analysis 8.10. Comparison 8 Serum bilirubin, Outcome 10 Abstracts excluded.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

8.10.1 Parenteral nutrition

Achord 1987 14 3 (1) 14 8.5 (3.5) 20.03% -5.5[-7.41,-3.59]

Naveau 1986 20 2.5 (1.4) 20 4.1 (2.2) 55.77% -1.6[-2.74,-0.46]

Qiu 2009 44 3.8 (14) 21 3.1 (9.4) 2.19% 0.7[-5.07,6.47]

Reilly 1990 18 5.5 (6.3) 10 2.5 (7.9) 2.25% 3[-2.7,8.7]

Simon 1988 19 4.7 (3) 19 13.7 (11) 2.77% -9[-14.13,-3.87]

Zheng 2003 40 2.7 (12) 30 2.4 (11.5) 2.37% 0.3[-5.25,5.85]

Subtotal *** 155 114 85.38% -2.52[-3.45,-1.6]

Heterogeneity: Tau2=0; Chi2=23.81, df=5(P=0); I2=79%

Test for overall effect: Z=5.35(P<0.0001)

8.10.2 Enteral nutrition

Kearns 1992 16 2.7 (9.2) 15 8.6 (21.2) 0.54% -5.9[-17.54,5.74]

Subtotal *** 16 15 0.54% -5.9[-17.54,5.74]

Heterogeneity: Not applicable

Test for overall effect: Z=0.99(P=0.32)

8.10.3 Supplements

Bunout 1989 17 3.8 (4.9) 19 4.1 (6.1) 5.63% -0.3[-3.9,3.3]

Hirsch 1993 26 2.1 (6.1) 25 1.5 (4.5) 8.46% 0.6[-2.33,3.53]

Subtotal *** 43 44 14.09% 0.24[-2.03,2.51]

Heterogeneity: Tau2=0; Chi2=0.14, df=1(P=0.7); I2=0%

Test for overall effect: Z=0.21(P=0.84)

Total *** 214 173 100% -2.15[-3.01,-1.3]

Heterogeneity: Tau2=0; Chi2=29.22, df=8(P=0); I2=72.62%

Test for overall effect: Z=4.94(P<0.0001)

Test for subgroup differences: Chi2=5.27, df=1 (P=0.07), I2=62.05%

Favours treatment 2010-20 -10 0 Favours control

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Comparison 9. Duration of hospitalisation

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 5 152 Mean Difference (IV, Fixed, 95% CI) -0.16 [-3.50, 3.17]

1.1 Parenteral nutrition (surgical tri- al)

1 28 Mean Difference (IV, Fixed, 95% CI) 7.20 [-9.29, 23.69]

1.2 Enteral nutrition 3 88 Mean Difference (IV, Fixed, 95% CI) 0.62 [-3.02, 4.27]

1.3 Supplements (medical trial) 1 36 Mean Difference (IV, Fixed, 95% CI) -8.0 [-17.54, 1.54]

2 Enteral nutrition - medical versus surgical trials

3 88 Mean Difference (IV, Fixed, 95% CI) 0.62 [-3.02, 4.27]

2.1 Medical trials 2 57 Mean Difference (IV, Fixed, 95% CI) 1.08 [-2.65, 4.80]

2.2 Surgical trials 1 31 Mean Difference (IV, Fixed, 95% CI) -9.8 [-27.66, 8.06]

3 Cirrhosis 2 57 Mean Difference (IV, Fixed, 95% CI) 1.08 [-2.65, 4.80]

3.1 Parenteral nutrition 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

3.2 Enteral nutrition 2 57 Mean Difference (IV, Fixed, 95% CI) 1.08 [-2.65, 4.80]

3.3 Supplements 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Surgery 2 59 Mean Difference (IV, Fixed, 95% CI) -0.62 [-12.74, 11.49]

4.1 Parenteral nutrition 1 28 Mean Difference (IV, Fixed, 95% CI) 7.20 [-9.29, 23.69]

4.2 Enteral nutrition 1 31 Mean Difference (IV, Fixed, 95% CI) -9.8 [-27.66, 8.06]

4.3 Supplements 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

Analysis 9.1. Comparison 9 Duration of hospitalisation, Outcome 1 All studies.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

9.1.1 Parenteral nutrition (surgical trial)

Reilly 1990 18 54.4 (25) 10 47.2 (19) 4.09% 7.2[-9.29,23.69]

Subtotal *** 18 10 4.09% 7.2[-9.29,23.69]

Heterogeneity: Not applicable

Test for overall effect: Z=0.86(P=0.39)

9.1.2 Enteral nutrition

Cabre 1990 16 23.2 (15.9) 19 25.3 (13.6) 11.35% -2.1[-12,7.8]

DeLedinghen 1997 12 14.5 (4.1) 10 12.9 (5.3) 68.83% 1.6[-2.42,5.62]

Favours treatment 5025-50 -25 0 Favours control

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Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Hasse 1995 14 17.3 (5.4) 17 27.1 (37.1) 3.49% -9.8[-27.66,8.06]

Subtotal *** 42 46 83.67% 0.62[-3.02,4.27]

Heterogeneity: Tau2=0; Chi2=1.83, df=2(P=0.4); I2=0%

Test for overall effect: Z=0.33(P=0.74)

9.1.3 Supplements (medical trial)

Bunout 1989 17 20 (12) 19 28 (17) 12.24% -8[-17.54,1.54]

Subtotal *** 17 19 12.24% -8[-17.54,1.54]

Heterogeneity: Not applicable

Test for overall effect: Z=1.64(P=0.1)

Total *** 77 75 100% -0.16[-3.5,3.17]

Heterogeneity: Tau2=0; Chi2=5.36, df=4(P=0.25); I2=25.41%

Test for overall effect: Z=0.1(P=0.92)

Test for subgroup differences: Chi2=3.54, df=1 (P=0.17), I2=43.46%

Favours treatment 5025-50 -25 0 Favours control

Analysis 9.2. Comparison 9 Duration of hospitalisation, Outcome 2 Enteral nutrition - medical versus surgical trials.

Study or subgroup Experimental Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

9.2.1 Medical trials

Cabre 1990 16 23.2 (15.9) 19 25.3 (13.6) 13.56% -2.1[-12,7.8]

DeLedinghen 1997 12 14.5 (4.1) 10 12.9 (5.3) 82.27% 1.6[-2.42,5.62]

Subtotal *** 28 29 95.83% 1.08[-2.65,4.8]

Heterogeneity: Tau2=0; Chi2=0.46, df=1(P=0.5); I2=0%

Test for overall effect: Z=0.57(P=0.57)

9.2.2 Surgical trials

Hasse 1995 14 17.3 (5.4) 17 27.1 (37.1) 4.17% -9.8[-27.66,8.06]

Subtotal *** 14 17 4.17% -9.8[-27.66,8.06]

Heterogeneity: Not applicable

Test for overall effect: Z=1.08(P=0.28)

Total *** 42 46 100% 0.62[-3.02,4.27]

Heterogeneity: Tau2=0; Chi2=1.83, df=2(P=0.4); I2=0%

Test for overall effect: Z=0.33(P=0.74)

Test for subgroup differences: Chi2=1.37, df=1 (P=0.24), I2=26.74%

Favours experimental 5025-50 -25 0 Favours control

Analysis 9.3. Comparison 9 Duration of hospitalisation, Outcome 3 Cirrhosis.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

9.3.1 Parenteral nutrition

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Favours treatment 2010-20 -10 0 Favours control

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Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Test for overall effect: Not applicable

9.3.2 Enteral nutrition

Cabre 1990 16 23.2 (15.9) 19 25.3 (13.6) 14.15% -2.1[-12,7.8]

DeLedinghen 1997 12 14.5 (4.1) 10 12.9 (5.3) 85.85% 1.6[-2.42,5.62]

Subtotal *** 28 29 100% 1.08[-2.65,4.8]

Heterogeneity: Tau2=0; Chi2=0.46, df=1(P=0.5); I2=0%

Test for overall effect: Z=0.57(P=0.57)

9.3.3 Supplements

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total *** 28 29 100% 1.08[-2.65,4.8]

Heterogeneity: Tau2=0; Chi2=0.46, df=1(P=0.5); I2=0%

Test for overall effect: Z=0.57(P=0.57)

Test for subgroup differences: Not applicable

Favours treatment 2010-20 -10 0 Favours control

Analysis 9.4. Comparison 9 Duration of hospitalisation, Outcome 4 Surgery.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

9.4.1 Parenteral nutrition

Reilly 1990 18 54.4 (25) 10 47.2 (19) 53.97% 7.2[-9.29,23.69]

Subtotal *** 18 10 53.97% 7.2[-9.29,23.69]

Heterogeneity: Not applicable

Test for overall effect: Z=0.86(P=0.39)

9.4.2 Enteral nutrition

Hasse 1995 14 17.3 (5.4) 17 27.1 (37.1) 46.03% -9.8[-27.66,8.06]

Subtotal *** 14 17 46.03% -9.8[-27.66,8.06]

Heterogeneity: Not applicable

Test for overall effect: Z=1.08(P=0.28)

9.4.3 Supplements

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total *** 32 27 100% -0.62[-12.74,11.49]

Heterogeneity: Tau2=0; Chi2=1.88, df=1(P=0.17); I2=46.76%

Test for overall effect: Z=0.1(P=0.92)

Test for subgroup differences: Chi2=1.88, df=1 (P=0.17), I2=46.76%

Favours treatment 5025-50 -25 0 Favours control

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Comparison 10. Duration of stay in ICU

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies (all surgery [transplanta- tion])

2 59 Mean Difference (IV, Fixed, 95% CI) 0.38 [-0.53, 1.30]

1.1 Parenteral nutrition 1 28 Mean Difference (IV, Fixed, 95% CI) -2.3 [-6.80, 2.20]

1.2 Enteral nutrition 1 31 Mean Difference (IV, Fixed, 95% CI) 0.5 [-0.44, 1.44]

1.3 Supplements 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

Analysis 10.1. Comparison 10 Duration of stay in ICU, Outcome 1 All studies (all surgery [transplantation]).

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

10.1.1 Parenteral nutrition

Reilly 1990 18 3.7 (3) 10 6 (6.9) 4.15% -2.3[-6.8,2.2]

Subtotal *** 18 10 4.15% -2.3[-6.8,2.2]

Heterogeneity: Not applicable

Test for overall effect: Z=1(P=0.32)

10.1.2 Enteral nutrition

Hasse 1995 14 2.4 (1.7) 17 1.9 (0.6) 95.85% 0.5[-0.44,1.44]

Subtotal *** 14 17 95.85% 0.5[-0.44,1.44]

Heterogeneity: Not applicable

Test for overall effect: Z=1.05(P=0.29)

10.1.3 Supplements

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total *** 32 27 100% 0.38[-0.53,1.3]

Heterogeneity: Tau2=0; Chi2=1.43, df=1(P=0.23); I2=29.99%

Test for overall effect: Z=0.82(P=0.41)

Test for subgroup differences: Chi2=1.43, df=1 (P=0.23), I2=29.99%

Favours treatment 105-10 -5 0 Favours control

Comparison 11. Postoperative total complications

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 6 346 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.55, 0.86]

1.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.42, 0.94]

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1.2 Enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.16, 0.91]

1.3 Supplements 4 162 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.66, 1.10]

2 All studies except those with total complications not patients

5 302 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.41, 0.80]

2.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.42, 0.94]

2.2 Enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.16, 0.91]

2.3 Supplements 3 118 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.31, 1.31]

3 HCC 2 168 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.62, 0.97]

3.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.42, 0.94]

3.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

3.3 Supplements 1 44 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.92, 1.09]

Analysis 11.1. Comparison 11 Postoperative total complications, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

11.1.1 Parenteral nutrition

Fan 1994 22/64 33/60 39.61% 0.63[0.42,0.94]

Subtotal (95% CI) 64 60 39.61% 0.63[0.42,0.94]

Total events: 22 (Treatment), 33 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.25(P=0.02)

11.1.2 Enteral nutrition

Foschi 1986 5/28 15/32 16.28% 0.38[0.16,0.91]

Subtotal (95% CI) 28 32 16.28% 0.38[0.16,0.91]

Total events: 5 (Treatment), 15 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.16(P=0.03)

11.1.3 Supplements

Hendry 2010 6/30 11/38 11.29% 0.69[0.29,1.65]

Ishikawa 2010 2/11 3/13 3.2% 0.79[0.16,3.9]

Meng 1999 21/21 23/23 26.14% 1[0.92,1.09]

Mikagi 2011 1/13 3/13 3.49% 0.33[0.04,2.8]

Subtotal (95% CI) 75 87 44.11% 0.85[0.66,1.1]

Total events: 30 (Treatment), 40 (Control)

Heterogeneity: Tau2=0; Chi2=14.02, df=3(P=0); I2=78.61%

Test for overall effect: Z=1.21(P=0.23)

Favours treatment 500.02 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 167 179 100% 0.69[0.55,0.86]

Total events: 57 (Treatment), 88 (Control)

Heterogeneity: Tau2=0; Chi2=75.61, df=5(P<0.0001); I2=93.39%

Test for overall effect: Z=3.26(P=0)

Test for subgroup differences: Chi2=4.01, df=1 (P=0.13), I2=50.11%

Favours treatment 500.02 100.1 1 Favours control

Analysis 11.2. Comparison 11 Postoperative total complications, Outcome 2 All studies except those with total complications not patients.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

11.2.1 Parenteral nutrition

Fan 1994 22/64 33/60 53.63% 0.63[0.42,0.94]

Subtotal (95% CI) 64 60 53.63% 0.63[0.42,0.94]

Total events: 22 (Treatment), 33 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.25(P=0.02)

11.2.2 Enteral nutrition

Foschi 1986 5/28 15/32 22.04% 0.38[0.16,0.91]

Subtotal (95% CI) 28 32 22.04% 0.38[0.16,0.91]

Total events: 5 (Treatment), 15 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.16(P=0.03)

11.2.3 Supplements

Hendry 2010 6/30 11/38 15.28% 0.69[0.29,1.65]

Ishikawa 2010 2/11 3/13 4.33% 0.79[0.16,3.9]

Mikagi 2011 1/13 3/13 4.72% 0.33[0.04,2.8]

Subtotal (95% CI) 54 64 24.33% 0.64[0.31,1.31]

Total events: 9 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.46, df=2(P=0.8); I2=0%

Test for overall effect: Z=1.23(P=0.22)

Total (95% CI) 146 156 100% 0.57[0.41,0.8]

Total events: 36 (Treatment), 65 (Control)

Heterogeneity: Tau2=0; Chi2=1.58, df=4(P=0.81); I2=0%

Test for overall effect: Z=3.26(P=0)

Test for subgroup differences: Chi2=1.08, df=1 (P=0.58), I2=0%

Favours treatment 500.02 100.1 1 Favours control

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Analysis 11.3. Comparison 11 Postoperative total complications, Outcome 3 HCC.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

11.3.1 Parenteral nutrition

Fan 1994 22/64 33/60 60.25% 0.63[0.42,0.94]

Subtotal (95% CI) 64 60 60.25% 0.63[0.42,0.94]

Total events: 22 (Treatment), 33 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.25(P=0.02)

11.3.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

11.3.3 Supplements

Meng 1999 21/21 23/23 39.75% 1[0.92,1.09]

Subtotal (95% CI) 21 23 39.75% 1[0.92,1.09]

Total events: 21 (Treatment), 23 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 85 83 100% 0.77[0.62,0.97]

Total events: 43 (Treatment), 56 (Control)

Heterogeneity: Tau2=0; Chi2=34.79, df=1(P<0.0001); I2=97.13%

Test for overall effect: Z=2.23(P=0.03)

Test for subgroup differences: Chi2=4.86, df=1 (P=0.03), I2=79.44%

Favours experimental 1000.01 100.1 1 Favours control

Comparison 12. Postoperative intra-abdominal complications

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 4 252 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.42, 1.31]

1.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.52, 1.97]

1.2 Enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.10, 2.17]

1.3 Supplements 2 68 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.05, 1.74]

2 HCC 2 168 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.45, 1.58]

2.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.52, 1.97]

2.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

2.3 Supplements 1 44 Risk Ratio (M-H, Fixed, 95% CI) 0.27 [0.03, 2.26]

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Analysis 12.1. Comparison 12 Postoperative intra-abdominal complications, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

12.1.1 Parenteral nutrition

Fan 1994 14/64 13/60 57.62% 1.01[0.52,1.97]

Subtotal (95% CI) 64 60 57.62% 1.01[0.52,1.97]

Total events: 14 (Treatment), 13 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.03(P=0.98)

12.1.2 Enteral nutrition

Foschi 1986 2/28 5/32 20.04% 0.46[0.1,2.17]

Subtotal (95% CI) 28 32 20.04% 0.46[0.1,2.17]

Total events: 2 (Treatment), 5 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.98(P=0.33)

12.1.3 Supplements

Ishikawa 2010 0/11 1/13 5.95% 0.39[0.02,8.69]

Meng 1999 1/21 4/23 16.39% 0.27[0.03,2.26]

Subtotal (95% CI) 32 36 22.34% 0.3[0.05,1.74]

Total events: 1 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.85); I2=0%

Test for overall effect: Z=1.34(P=0.18)

Total (95% CI) 124 128 100% 0.74[0.42,1.31]

Total events: 17 (Treatment), 23 (Control)

Heterogeneity: Tau2=0; Chi2=2.21, df=3(P=0.53); I2=0%

Test for overall effect: Z=1.03(P=0.3)

Test for subgroup differences: Chi2=2.14, df=1 (P=0.34), I2=6.72%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 12.2. Comparison 12 Postoperative intra-abdominal complications, Outcome 2 HCC.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

12.2.1 Parenteral nutrition

Fan 1994 14/64 13/60 77.85% 1.01[0.52,1.97]

Subtotal (95% CI) 64 60 77.85% 1.01[0.52,1.97]

Total events: 14 (Treatment), 13 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.03(P=0.98)

12.2.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours experimental 2000.005 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

12.2.3 Supplements

Meng 1999 1/21 4/23 22.15% 0.27[0.03,2.26]

Subtotal (95% CI) 21 23 22.15% 0.27[0.03,2.26]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.2(P=0.23)

Total (95% CI) 85 83 100% 0.85[0.45,1.58]

Total events: 15 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=1.37, df=1(P=0.24); I2=26.83%

Test for overall effect: Z=0.52(P=0.6)

Test for subgroup differences: Chi2=1.34, df=1 (P=0.25), I2=25.12%

Favours experimental 2000.005 100.1 1 Favours control

Comparison 13. Postoperative pneumonia

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 4 252 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.15, 0.79]

1.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.12, 0.81]

1.2 Enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.02, 8.95]

1.3 Supplements 2 68 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.05, 5.61]

2 HCC 2 168 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.14, 0.81]

2.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.12, 0.81]

2.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

2.3 Supplements 1 44 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.05, 5.61]

Analysis 13.1. Comparison 13 Postoperative pneumonia, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

13.1.1 Parenteral nutrition

Fan 1994 5/64 15/60 82.38% 0.31[0.12,0.81]

Subtotal (95% CI) 64 60 82.38% 0.31[0.12,0.81]

Total events: 5 (Treatment), 15 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.4(P=0.02)

Favours treatment 2000.005 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

13.1.2 Enteral nutrition

Foschi 1986 0/28 1/32 7.47% 0.38[0.02,8.95]

Subtotal (95% CI) 28 32 7.47% 0.38[0.02,8.95]

Total events: 0 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.6(P=0.55)

13.1.3 Supplements

Ishikawa 2010 0/11 0/13 Not estimable

Meng 1999 1/21 2/23 10.16% 0.55[0.05,5.61]

Subtotal (95% CI) 32 36 10.16% 0.55[0.05,5.61]

Total events: 1 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.51(P=0.61)

Total (95% CI) 124 128 100% 0.34[0.15,0.79]

Total events: 6 (Treatment), 18 (Control)

Heterogeneity: Tau2=0; Chi2=0.2, df=2(P=0.91); I2=0%

Test for overall effect: Z=2.5(P=0.01)

Test for subgroup differences: Chi2=0.2, df=1 (P=0.91), I2=0%

Favours treatment 2000.005 100.1 1 Favours control

Analysis 13.2. Comparison 13 Postoperative pneumonia, Outcome 2 HCC.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

13.2.1 Parenteral nutrition

Fan 1994 5/64 15/60 89.02% 0.31[0.12,0.81]

Subtotal (95% CI) 64 60 89.02% 0.31[0.12,0.81]

Total events: 5 (Treatment), 15 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.4(P=0.02)

13.2.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

13.2.3 Supplements

Meng 1999 1/21 2/23 10.98% 0.55[0.05,5.61]

Subtotal (95% CI) 21 23 10.98% 0.55[0.05,5.61]

Total events: 1 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.51(P=0.61)

Total (95% CI) 85 83 100% 0.34[0.14,0.81]

Total events: 6 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.19, df=1(P=0.66); I2=0%

Favours experimental 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Z=2.43(P=0.02)

Test for subgroup differences: Chi2=0.19, df=1 (P=0.66), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

Comparison 14. Postoperative wound infections

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 4 252 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.31, 1.29]

1.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.19, 2.11]

1.2 Enteral nutrition 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.10, 2.17]

1.3 Supplements 2 68 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.26, 2.29]

2 HCC 2 168 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.32, 1.71]

2.1 Parenteral nutrition 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.19, 2.11]

2.2 Enteral nutrition 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

2.3 Supplements 1 44 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.27, 2.83]

Analysis 14.1. Comparison 14 Postoperative wound infections, Outcome 1 All studies.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

14.1.1 Parenteral nutrition

Fan 1994 4/64 6/60 36.4% 0.63[0.19,2.11]

Subtotal (95% CI) 64 60 36.4% 0.63[0.19,2.11]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.76(P=0.45)

14.1.2 Enteral nutrition

Foschi 1986 2/28 5/32 27.42% 0.46[0.1,2.17]

Subtotal (95% CI) 28 32 27.42% 0.46[0.1,2.17]

Total events: 2 (Treatment), 5 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.98(P=0.33)

14.1.3 Supplements

Ishikawa 2010 0/11 1/13 8.14% 0.39[0.02,8.69]

Meng 1999 4/21 5/23 28.05% 0.88[0.27,2.83]

Favours treatment 1000.01 100.1 1 Favours control

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Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 32 36 36.18% 0.77[0.26,2.29]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.23, df=1(P=0.63); I2=0%

Test for overall effect: Z=0.48(P=0.63)

Total (95% CI) 124 128 100% 0.63[0.31,1.29]

Total events: 10 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.56, df=3(P=0.91); I2=0%

Test for overall effect: Z=1.26(P=0.21)

Test for subgroup differences: Chi2=0.29, df=1 (P=0.87), I2=0%

Favours treatment 1000.01 100.1 1 Favours control

Analysis 14.2. Comparison 14 Postoperative wound infections, Outcome 2 HCC.

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

14.2.1 Parenteral nutrition

Fan 1994 4/64 6/60 56.48% 0.63[0.19,2.11]

Subtotal (95% CI) 64 60 56.48% 0.63[0.19,2.11]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.76(P=0.45)

14.2.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

14.2.3 Supplements

Meng 1999 4/21 5/23 43.52% 0.88[0.27,2.83]

Subtotal (95% CI) 21 23 43.52% 0.88[0.27,2.83]

Total events: 4 (Treatment), 5 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.22(P=0.83)

Total (95% CI) 85 83 100% 0.73[0.32,1.71]

Total events: 8 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.69); I2=0%

Test for overall effect: Z=0.72(P=0.47)

Test for subgroup differences: Chi2=0.15, df=1 (P=0.7), I2=0%

Favours experimental 1000.01 100.1 1 Favours control

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Comparison 15. Nitrogen balance

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies (all medical) 3 81 Mean Difference (IV, Fixed, 95% CI) 1.99 [0.69, 3.28]

1.1 Parenteral nutrition 1 21 Mean Difference (IV, Fixed, 95% CI) 3.60 [0.86, 6.34]

1.2 Enteral nutrition 1 22 Mean Difference (IV, Fixed, 95% CI) 1.40 [-3.16, 5.96]

1.3 Supplements 1 38 Mean Difference (IV, Fixed, 95% CI) 1.54 [-0.01, 3.09]

2 Cirrhosis 2 60 Mean Difference (IV, Random, 95% CI) 1.53 [0.06, 2.99]

Analysis 15.1. Comparison 15 Nitrogen balance, Outcome 1 All studies (all medical).

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

15.1.1 Parenteral nutrition

Bonkovsky 1991 9 6.8 (2.1) 12 3.2 (4.2) 22.22% 3.6[0.86,6.34]

Subtotal *** 9 12 22.22% 3.6[0.86,6.34]

Heterogeneity: Not applicable

Test for overall effect: Z=2.57(P=0.01)

15.1.2 Enteral nutrition

DeLedinghen 1997 12 5.3 (5.8) 10 3.9 (5.1) 8.06% 1.4[-3.16,5.96]

Subtotal *** 12 10 8.06% 1.4[-3.16,5.96]

Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Test for overall effect: Z=0.6(P=0.55)

15.1.3 Supplements

Nakaya 2007 19 1.5 (1.9) 19 0 (2.9) 69.73% 1.54[-0.01,3.09]

Subtotal *** 19 19 69.73% 1.54[-0.01,3.09]

Heterogeneity: Not applicable

Test for overall effect: Z=1.95(P=0.05)

Total *** 40 41 100% 1.99[0.69,3.28]

Heterogeneity: Tau2=0; Chi2=1.71, df=2(P=0.43); I2=0%

Test for overall effect: Z=3.01(P=0)

Test for subgroup differences: Chi2=1.71, df=1 (P=0.43), I2=0%

Favours control 105-10 -5 0 Favours treatment

Analysis 15.2. Comparison 15 Nitrogen balance, Outcome 2 Cirrhosis.

Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI

DeLedinghen 1997 12 5.3 (5.8) 10 3.9 (5.1) 10.36% 1.4[-3.16,5.96]

Nakaya 2007 19 1.5 (1.9) 19 0 (2.9) 89.64% 1.54[-0.01,3.09]

Favours experimental 10050-100 -50 0 Favours control

229

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Study or subgroup Treatment Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI

Total *** 31 29 100% 1.53[0.06,2.99]

Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.95); I2=0%

Test for overall effect: Z=2.04(P=0.04)

Favours experimental 10050-100 -50 0 Favours control

Comparison 16. Mortality - absolute risk di<erence (ARD)

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 28 1668 Risk Difference (M-H, Fixed, 95% CI)

-0.02 [-0.05, 0.01]

2 Parenteral nutrition 9 465 Risk Difference (M-H, Random, 95% CI)

-0.03 [-0.07, 0.01]

2.1 Medical trials 4 158 Risk Difference (M-H, Random, 95% CI)

-0.03 [-0.11, 0.06]

2.2 Surgical trials 5 307 Risk Difference (M-H, Random, 95% CI)

-0.03 [-0.08, 0.02]

3 Enteral nutrition 6 275 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.15, 0.03]

3.1 Medical trials 5 215 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.15, 0.06]

3.2 Surgical trials 1 60 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.22, 0.04]

4 Supplements 13 928 Risk Difference (M-H, Random, 95% CI)

-0.02 [-0.06, 0.03]

4.1 Medical trials 9 710 Risk Difference (M-H, Random, 95% CI)

-0.01 [-0.07, 0.05]

4.2 Surgical trials 4 218 Risk Difference (M-H, Random, 95% CI)

-0.03 [-0.12, 0.07]

5 Medical trials 18 1083 Risk Difference (M-H, Fixed, 95% CI)

-0.00 [-0.05, 0.04]

5.1 Parenteral nutrition 4 158 Risk Difference (M-H, Fixed, 95% CI)

-0.04 [-0.14, 0.06]

5.2 Enteral nutrition 5 215 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.15, 0.06]

5.3 Supplements 9 710 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.04, 0.08]

230

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

6 Surgical trials 10 585 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.10, -0.01]

6.1 Parenteral nutrition 5 307 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.12, 0.00]

6.2 Enteral nutrition 1 60 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.22, 0.04]

6.3 Supplements 4 218 Risk Difference (M-H, Fixed, 95% CI)

-0.03 [-0.11, 0.04]

7 Alcoholic hepatitis 7 300 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.14, 0.04]

7.1 Parenteral nutrition 3 118 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.18, 0.07]

7.2 Enteral nutrition 2 95 Risk Difference (M-H, Fixed, 95% CI)

0.03 [-0.16, 0.23]

7.3 Supplements 2 87 Risk Difference (M-H, Fixed, 95% CI)

-0.13 [-0.29, 0.03]

8 Cirrhosis 9 349 Risk Difference (M-H, Fixed, 95% CI)

-0.07 [-0.13, -0.01]

8.1 Parenteral nutrition 2 60 Risk Difference (M-H, Fixed, 95% CI)

-0.03 [-0.16, 0.09]

8.2 Enteral nutrition 3 120 Risk Difference (M-H, Fixed, 95% CI)

-0.11 [-0.22, 0.01]

8.3 Supplements 4 169 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.15, 0.03]

9 HCC 6 673 Risk Difference (M-H, Fixed, 95% CI)

0.04 [-0.02, 0.10]

9.1 Parenteral Nutrition 1 124 Risk Difference (M-H, Fixed, 95% CI)

-0.07 [-0.18, 0.04]

9.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 5 549 Risk Difference (M-H, Fixed, 95% CI)

0.07 [-0.01, 0.14]

10 Abstracts excluded 25 1348 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.08, -0.01]

10.1 Medical trials - parenteral nutri- tion

4 158 Risk Difference (M-H, Fixed, 95% CI)

-0.04 [-0.14, 0.06]

231

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

10.2 Surgical trials - parenteral nutri- tion

5 307 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.12, 0.00]

10.3 Medical trials - enteral nutrition 4 152 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.20, 0.09]

10.4 Surgical trials - enteral nutrition 1 60 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.22, 0.04]

10.5 Medical trials - supplements 8 477 Risk Difference (M-H, Fixed, 95% CI)

-0.04 [-0.10, 0.02]

10.6 Surgical trials - supplements 3 194 Risk Difference (M-H, Fixed, 95% CI)

-0.04 [-0.12, 0.04]

11 Surgical trials without transplant patients

7 410 Risk Difference (M-H, Fixed, 95% CI)

-0.04 [-0.09, 0.01]

11.1 Parenteral nutrition 3 214 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.14, 0.01]

11.2 Enteral nutrition 1 60 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.22, 0.04]

11.3 Supplements 3 136 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.06, 0.10]

12 Intent to treat - best-case scenario for intervention

24 1539 Risk Difference (M-H, Fixed, 95% CI)

-0.07 [-0.11, -0.03]

12.1 Medical trials - Parenteral nutri- tion

4 170 Risk Difference (M-H, Fixed, 95% CI)

-0.12 [-0.22, -0.02]

12.2 Surgical trials - Parenteral nutri- tion

4 268 Risk Difference (M-H, Fixed, 95% CI)

-0.17 [-0.25, -0.10]

12.3 Medical trials - Enteral nutrition 5 215 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.15, 0.06]

12.4 Surgical trials - enteral nutrition 1 64 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.22, 0.04]

12.5 Medical trials - Supplements 8 690 Risk Difference (M-H, Fixed, 95% CI)

-0.03 [-0.09, 0.03]

12.6 Surgical trials - Supplements 2 132 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.17, 0.05]

13 Intent to treat - worst-case scenario for intervention

24 1539 Risk Difference (M-H, Fixed, 95% CI)

0.04 [-0.00, 0.08]

13.1 Medical trials - Parenteral nutri- tion

4 170 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.08, 0.13]

232

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

13.2 Surgical trials - Parenteral nutri- tion

4 268 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.06, 0.10]

13.3 Medical trials - Enteral nutrition 5 215 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.15, 0.06]

13.4 Surgical trials - Enteral nutrition 1 64 Risk Difference (M-H, Fixed, 95% CI)

0.03 [-0.14, 0.20]

13.5 Medical trials - Supplements 8 690 Risk Difference (M-H, Fixed, 95% CI)

0.07 [0.01, 0.14]

13.6 Surgical trials - Supplements 2 132 Risk Difference (M-H, Fixed, 95% CI)

0.03 [-0.09, 0.14]

Analysis 16.1. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 1 All studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Achord 1987 1/14 3/14 1.7% -0.14[-0.4,0.11]

Bonkovsky 1991 0/9 0/12 1.25% 0[-0.17,0.17]

Bunout 1989 2/17 5/19 2.18% -0.15[-0.4,0.1]

Cabre 1990 2/16 9/19 2.11% -0.35[-0.63,-0.07]

Calvey 1985 16/42 7/22 3.51% 0.06[-0.18,0.31]

DeLedinghen 1997 3/12 2/10 1.33% 0.05[-0.3,0.4]

Fan 1994 5/64 9/60 7.53% -0.07[-0.18,0.04]

Foschi 1986 1/28 4/32 3.63% -0.09[-0.22,0.04]

Hendry 2010 0/30 2/38 4.07% -0.05[-0.14,0.04]

Hirsch 1993 3/26 6/25 3.1% -0.12[-0.33,0.08]

Humbert 1988 2/27 4/22 2.95% -0.11[-0.3,0.08]

Ichikawa 2010 0/12 0/9 1.25% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 1.45% 0[-0.15,0.15]

Kearns 1992 5/16 5/15 1.88% -0.02[-0.35,0.31]

Kobashi 2006 63/119 44/114 14.15% 0.14[0.02,0.27]

LeCornu 2000 2/42 7/40 4.98% -0.13[-0.26,0.01]

Meng 1999 4/21 1/23 2.67% 0.15[-0.04,0.33]

Nakaya 2007 1/25 0/23 2.91% 0.04[-0.07,0.15]

Naveau 1986 1/20 1/20 2.43% 0[-0.14,0.14]

Norman 2008 1/31 2/32 3.83% -0.03[-0.13,0.07]

Poon 2004 0/41 3/43 5.1% -0.07[-0.16,0.02]

Puglionisi 1985 0/10 1/10 1.22% -0.1[-0.34,0.14]

Qiu 2009 0/44 0/21 3.45% 0[-0.07,0.07]

Reilly 1990 1/18 2/10 1.56% -0.14[-0.41,0.13]

San-In Group 1997 34/67 32/65 8.02% 0.02[-0.16,0.19]

Simon 1988 5/33 7/36 4.18% -0.04[-0.22,0.14]

Takeshita 2009 0/28 0/28 3.4% 0[-0.07,0.07]

Zheng 2003 0/40 1/30 4.17% -0.03[-0.12,0.05]

Favors treatment 10.5-1 -0.5 0 Favors control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 863 805 100% -0.02[-0.05,0.01]

Total events: 152 (Treatment), 157 (Control)

Heterogeneity: Tau2=0; Chi2=29.05, df=27(P=0.36); I2=7.05%

Test for overall effect: Z=1.12(P=0.26)

Favors treatment 10.5-1 -0.5 0 Favors control

Analysis 16.2. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 2 Parenteral nutrition.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

16.2.1 Medical trials

Achord 1987 1/14 3/14 2.58% -0.14[-0.4,0.11]

Bonkovsky 1991 0/9 0/12 5.7% 0[-0.17,0.17]

Naveau 1986 1/20 1/20 9.11% 0[-0.14,0.14]

Simon 1988 5/33 7/36 5.25% -0.04[-0.22,0.14]

Subtotal (95% CI) 76 82 22.63% -0.03[-0.11,0.06]

Total events: 7 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=1.25, df=3(P=0.74); I2=0%

Test for overall effect: Z=0.6(P=0.55)

16.2.2 Surgical trials

Fan 1994 5/64 9/60 13.31% -0.07[-0.18,0.04]

Puglionisi 1985 0/10 1/10 2.95% -0.1[-0.34,0.14]

Qiu 2009 0/44 0/21 34.51% 0[-0.07,0.07]

Reilly 1990 1/18 2/10 2.29% -0.14[-0.41,0.13]

Zheng 2003 0/40 1/30 24.32% -0.03[-0.12,0.05]

Subtotal (95% CI) 176 131 77.37% -0.03[-0.08,0.02]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=3.53, df=4(P=0.47); I2=0%

Test for overall effect: Z=1.31(P=0.19)

Total (95% CI) 252 213 100% -0.03[-0.07,0.01]

Total events: 13 (Treatment), 24 (Control)

Heterogeneity: Tau2=0; Chi2=4.59, df=8(P=0.8); I2=0%

Test for overall effect: Z=1.44(P=0.15)

Test for subgroup differences: Chi2=0.01, df=1 (P=0.92), I2=0%

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

Analysis 16.3. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 3 Enteral nutrition.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.3.1 Medical trials

Cabre 1990 2/16 9/19 12.96% -0.35[-0.63,-0.07]

Calvey 1985 16/42 7/22 21.55% 0.06[-0.18,0.31]

DeLedinghen 1997 3/12 2/10 8.14% 0.05[-0.3,0.4]

Kearns 1992 5/16 5/15 11.56% -0.02[-0.35,0.31]

Favors treatment 10.5-1 -0.5 0 Favors control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Norman 2008 1/31 2/32 23.5% -0.03[-0.13,0.07]

Subtotal (95% CI) 117 98 77.71% -0.05[-0.15,0.06]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=5.76, df=4(P=0.22); I2=30.59%

Test for overall effect: Z=0.88(P=0.38)

16.3.2 Surgical trials

Foschi 1986 1/28 4/32 22.29% -0.09[-0.22,0.04]

Subtotal (95% CI) 28 32 22.29% -0.09[-0.22,0.04]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.31(P=0.19)

Total (95% CI) 145 130 100% -0.06[-0.15,0.03]

Total events: 28 (Treatment), 29 (Control)

Heterogeneity: Tau2=0; Chi2=6.07, df=5(P=0.3); I2=17.69%

Test for overall effect: Z=1.27(P=0.21)

Test for subgroup differences: Chi2=0.23, df=1 (P=0.63), I2=0%

Favors treatment 10.5-1 -0.5 0 Favors control

Analysis 16.4. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 4 Supplements.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

16.4.1 Medical trials

Bunout 1989 2/17 5/19 3.02% -0.15[-0.4,0.1]

Hirsch 1993 3/26 6/25 4.12% -0.12[-0.33,0.08]

Humbert 1988 2/27 4/22 4.78% -0.11[-0.3,0.08]

Ichikawa 2010 0/12 0/9 5.57% 0[-0.17,0.17]

Kobashi 2006 63/119 44/114 8.33% 0.14[0.02,0.27]

Nakaya 2007 1/25 0/23 10.15% 0.04[-0.07,0.15]

Poon 2004 0/41 3/43 12.32% -0.07[-0.16,0.02]

San-In Group 1997 34/67 32/65 5.58% 0.02[-0.16,0.19]

Takeshita 2009 0/28 0/28 14.78% 0[-0.07,0.07]

Subtotal (95% CI) 362 348 68.62% -0.01[-0.07,0.05]

Total events: 105 (Treatment), 94 (Control)

Heterogeneity: Tau2=0; Chi2=13.72, df=8(P=0.09); I2=41.7%

Test for overall effect: Z=0.32(P=0.75)

16.4.2 Surgical trials

Hendry 2010 0/30 2/38 12.04% -0.05[-0.14,0.04]

Ishikawa 2010 0/11 0/13 6.75% 0[-0.15,0.15]

LeCornu 2000 2/42 7/40 7.75% -0.13[-0.26,0.01]

Meng 1999 4/21 1/23 4.84% 0.15[-0.04,0.33]

Subtotal (95% CI) 104 114 31.38% -0.03[-0.12,0.07]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=5.8, df=3(P=0.12); I2=48.32%

Test for overall effect: Z=0.55(P=0.58)

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

235

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Total (95% CI) 466 462 100% -0.02[-0.06,0.03]

Total events: 111 (Treatment), 104 (Control)

Heterogeneity: Tau2=0; Chi2=20.16, df=12(P=0.06); I2=40.47%

Test for overall effect: Z=0.65(P=0.52)

Test for subgroup differences: Chi2=0.09, df=1 (P=0.77), I2=0%

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

Analysis 16.5. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 5 Medical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.5.1 Parenteral nutrition

Achord 1987 1/14 3/14 2.61% -0.14[-0.4,0.11]

Bonkovsky 1991 0/9 0/12 1.91% 0[-0.17,0.17]

Naveau 1986 1/20 1/20 3.72% 0[-0.14,0.14]

Simon 1988 5/33 7/36 6.41% -0.04[-0.22,0.14]

Subtotal (95% CI) 76 82 14.65% -0.04[-0.14,0.06]

Total events: 7 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=1.25, df=3(P=0.74); I2=0%

Test for overall effect: Z=0.87(P=0.38)

16.5.2 Enteral nutrition

Cabre 1990 2/16 9/19 3.23% -0.35[-0.63,-0.07]

Calvey 1985 16/42 7/22 5.38% 0.06[-0.18,0.31]

DeLedinghen 1997 3/12 2/10 2.03% 0.05[-0.3,0.4]

Kearns 1992 5/16 5/15 2.88% -0.02[-0.35,0.31]

Norman 2008 1/31 2/32 5.86% -0.03[-0.13,0.07]

Subtotal (95% CI) 117 98 19.38% -0.05[-0.15,0.06]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=5.76, df=4(P=0.22); I2=30.59%

Test for overall effect: Z=0.88(P=0.38)

16.5.3 Supplements

Bunout 1989 2/17 5/19 3.34% -0.15[-0.4,0.1]

Hirsch 1993 3/26 6/25 4.75% -0.12[-0.33,0.08]

Humbert 1988 2/27 4/22 4.51% -0.11[-0.3,0.08]

Ichikawa 2010 0/12 0/9 1.91% 0[-0.17,0.17]

Kobashi 2006 63/119 44/114 21.68% 0.14[0.02,0.27]

Nakaya 2007 1/25 0/23 4.46% 0.04[-0.07,0.15]

Poon 2004 0/41 3/43 7.81% -0.07[-0.16,0.02]

San-In Group 1997 34/67 32/65 12.28% 0.02[-0.16,0.19]

Takeshita 2009 0/28 0/28 5.21% 0[-0.07,0.07]

Subtotal (95% CI) 362 348 65.96% 0.02[-0.04,0.08]

Total events: 105 (Treatment), 94 (Control)

Heterogeneity: Tau2=0; Chi2=13.72, df=8(P=0.09); I2=41.7%

Test for overall effect: Z=0.68(P=0.49)

Total (95% CI) 555 528 100% -0[-0.05,0.04]

Total events: 139 (Treatment), 130 (Control)

Favors treatment 10.5-1 -0.5 0 Favors control

236

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=19.93, df=17(P=0.28); I2=14.71%

Test for overall effect: Z=0.09(P=0.93)

Test for subgroup differences: Chi2=1.93, df=1 (P=0.38), I2=0%

Favors treatment 10.5-1 -0.5 0 Favors control

Analysis 16.6. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 6 Surgical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.6.1 Parenteral nutrition

Fan 1994 5/64 9/60 21.67% -0.07[-0.18,0.04]

Puglionisi 1985 0/10 1/10 3.5% -0.1[-0.34,0.14]

Qiu 2009 0/44 0/21 9.95% 0[-0.07,0.07]

Reilly 1990 1/18 2/10 4.5% -0.14[-0.41,0.13]

Zheng 2003 0/40 1/30 12% -0.03[-0.12,0.05]

Subtotal (95% CI) 176 131 51.62% -0.06[-0.12,0]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=3.53, df=4(P=0.47); I2=0%

Test for overall effect: Z=1.86(P=0.06)

16.6.2 Enteral nutrition

Foschi 1986 1/28 4/32 10.45% -0.09[-0.22,0.04]

Subtotal (95% CI) 28 32 10.45% -0.09[-0.22,0.04]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.31(P=0.19)

16.6.3 Supplements

Hendry 2010 0/30 2/38 11.73% -0.05[-0.14,0.04]

Ishikawa 2010 0/11 0/13 4.17% 0[-0.15,0.15]

LeCornu 2000 2/42 7/40 14.34% -0.13[-0.26,0.01]

Meng 1999 4/21 1/23 7.68% 0.15[-0.04,0.33]

Subtotal (95% CI) 104 114 37.93% -0.03[-0.11,0.04]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=5.8, df=3(P=0.12); I2=48.32%

Test for overall effect: Z=0.95(P=0.34)

Total (95% CI) 308 277 100% -0.05[-0.1,-0.01]

Total events: 13 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=9.39, df=9(P=0.4); I2=4.19%

Test for overall effect: Z=2.34(P=0.02)

Test for subgroup differences: Chi2=0.55, df=1 (P=0.76), I2=0%

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

237

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Analysis 16.7. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 7 Alcoholic hepatitis.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.7.1 Parenteral nutrition

Achord 1987 1/14 3/14 9.56% -0.14[-0.4,0.11]

Bonkovsky 1991 0/9 0/12 7.02% 0[-0.17,0.17]

Simon 1988 5/33 7/36 23.5% -0.04[-0.22,0.14]

Subtotal (95% CI) 56 62 40.08% -0.06[-0.18,0.07]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=0.91, df=2(P=0.63); I2=0%

Test for overall effect: Z=0.93(P=0.35)

16.7.2 Enteral nutrition

Calvey 1985 16/42 7/22 19.71% 0.06[-0.18,0.31]

Kearns 1992 5/16 5/15 10.57% -0.02[-0.35,0.31]

Subtotal (95% CI) 58 37 30.28% 0.03[-0.16,0.23]

Total events: 21 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=0.16, df=1(P=0.69); I2=0%

Test for overall effect: Z=0.34(P=0.74)

16.7.3 Supplements

Bunout 1989 2/17 5/19 12.25% -0.15[-0.4,0.1]

Hirsch 1993 3/26 6/25 17.4% -0.12[-0.33,0.08]

Subtotal (95% CI) 43 44 29.65% -0.13[-0.29,0.03]

Total events: 5 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.02, df=1(P=0.9); I2=0%

Test for overall effect: Z=1.63(P=0.1)

Total (95% CI) 157 143 100% -0.05[-0.14,0.04]

Total events: 32 (Treatment), 33 (Control)

Heterogeneity: Tau2=0; Chi2=2.75, df=6(P=0.84); I2=0%

Test for overall effect: Z=1.14(P=0.25)

Test for subgroup differences: Chi2=1.68, df=1 (P=0.43), I2=0%

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

Analysis 16.8. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 8 Cirrhosis.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.8.1 Parenteral nutrition

Naveau 1986 1/20 1/20 11.51% 0[-0.14,0.14]

Puglionisi 1985 0/10 1/10 5.76% -0.1[-0.34,0.14]

Subtotal (95% CI) 30 30 17.27% -0.03[-0.16,0.09]

Total events: 1 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=0.54, df=1(P=0.46); I2=0%

Test for overall effect: Z=0.52(P=0.6)

16.8.2 Enteral nutrition

Cabre 1990 2/16 9/19 10% -0.35[-0.63,-0.07]

DeLedinghen 1997 3/12 2/10 6.28% 0.05[-0.3,0.4]

Norman 2008 1/31 2/32 18.12% -0.03[-0.13,0.07]

Favors treatment 10.5-1 -0.5 0 Favors control

238

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 59 61 34.4% -0.11[-0.22,0.01]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=5.83, df=2(P=0.05); I2=65.68%

Test for overall effect: Z=1.82(P=0.07)

16.8.3 Supplements

Hirsch 1993 3/26 6/25 14.67% -0.12[-0.33,0.08]

Humbert 1988 2/27 4/22 13.95% -0.11[-0.3,0.08]

Ichikawa 2010 0/12 0/9 5.92% 0[-0.17,0.17]

Nakaya 2007 1/25 0/23 13.79% 0.04[-0.07,0.15]

Subtotal (95% CI) 90 79 48.33% -0.06[-0.15,0.03]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=4.34, df=3(P=0.23); I2=30.9%

Test for overall effect: Z=1.22(P=0.22)

Total (95% CI) 179 170 100% -0.07[-0.13,-0.01]

Total events: 13 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=11.26, df=8(P=0.19); I2=28.94%

Test for overall effect: Z=2.18(P=0.03)

Test for subgroup differences: Chi2=0.8, df=1 (P=0.67), I2=0%

Favors treatment 10.5-1 -0.5 0 Favors control

Analysis 16.9. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 9 HCC.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.9.1 Parenteral Nutrition

Fan 1994 5/64 9/60 18.42% -0.07[-0.18,0.04]

Subtotal (95% CI) 64 60 18.42% -0.07[-0.18,0.04]

Total events: 5 (Treatment), 9 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.26(P=0.21)

16.9.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

16.9.3 Supplements

Kobashi 2006 63/119 44/114 34.63% 0.14[0.02,0.27]

Meng 1999 4/21 1/23 6.53% 0.15[-0.04,0.33]

Poon 2004 0/41 3/43 12.48% -0.07[-0.16,0.02]

San-In Group 1997 34/67 32/65 19.62% 0.02[-0.16,0.19]

Takeshita 2009 0/28 0/28 8.33% 0[-0.07,0.07]

Subtotal (95% CI) 276 273 81.58% 0.07[-0.01,0.14]

Total events: 101 (Treatment), 80 (Control)

Heterogeneity: Tau2=0; Chi2=15.62, df=4(P=0); I2=74.4%

Test for overall effect: Z=1.81(P=0.07)

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

239

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total (95% CI) 340 333 100% 0.04[-0.02,0.1]

Total events: 106 (Treatment), 89 (Control)

Heterogeneity: Tau2=0; Chi2=15.37, df=5(P=0.01); I2=67.47%

Test for overall effect: Z=1.29(P=0.2)

Test for subgroup differences: Chi2=4.15, df=1 (P=0.04), I2=75.88%

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

Analysis 16.10. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 10 Abstracts excluded.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.10.1 Medical trials - parenteral nutrition

Achord 1987 1/14 3/14 2.11% -0.14[-0.4,0.11]

Bonkovsky 1991 0/9 0/12 1.55% 0[-0.17,0.17]

Naveau 1986 1/20 1/20 3.02% 0[-0.14,0.14]

Simon 1988 5/33 7/36 5.19% -0.04[-0.22,0.14]

Subtotal (95% CI) 76 82 11.87% -0.04[-0.14,0.06]

Total events: 7 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=1.25, df=3(P=0.74); I2=0%

Test for overall effect: Z=0.87(P=0.38)

16.10.2 Surgical trials - parenteral nutrition

Fan 1994 5/64 9/60 9.34% -0.07[-0.18,0.04]

Puglionisi 1985 0/10 1/10 1.51% -0.1[-0.34,0.14]

Qiu 2009 0/44 0/21 4.29% 0[-0.07,0.07]

Reilly 1990 1/18 2/10 1.94% -0.14[-0.41,0.13]

Zheng 2003 0/40 1/30 5.17% -0.03[-0.12,0.05]

Subtotal (95% CI) 176 131 22.25% -0.06[-0.12,0]

Total events: 6 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=3.53, df=4(P=0.47); I2=0%

Test for overall effect: Z=1.86(P=0.06)

16.10.3 Medical trials - enteral nutrition

Cabre 1990 2/16 9/19 2.62% -0.35[-0.63,-0.07]

Calvey 1985 16/42 7/22 4.35% 0.06[-0.18,0.31]

DeLedinghen 1997 3/12 2/10 1.65% 0.05[-0.3,0.4]

Kearns 1992 5/16 5/15 2.34% -0.02[-0.35,0.31]

Subtotal (95% CI) 86 66 10.95% -0.06[-0.2,0.09]

Total events: 26 (Treatment), 23 (Control)

Heterogeneity: Tau2=0; Chi2=5.61, df=3(P=0.13); I2=46.49%

Test for overall effect: Z=0.74(P=0.46)

16.10.4 Surgical trials - enteral nutrition

Foschi 1986 1/28 4/32 4.5% -0.09[-0.22,0.04]

Subtotal (95% CI) 28 32 4.5% -0.09[-0.22,0.04]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.31(P=0.19)

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

240

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.10.5 Medical trials - supplements

Bunout 1989 2/17 5/19 2.71% -0.15[-0.4,0.1]

Hirsch 1993 3/26 6/25 3.84% -0.12[-0.33,0.08]

Humbert 1988 2/27 4/22 3.66% -0.11[-0.3,0.08]

Ichikawa 2010 0/12 0/9 1.55% 0[-0.17,0.17]

Nakaya 2007 1/25 0/23 3.61% 0.04[-0.07,0.15]

Poon 2004 0/41 3/43 6.33% -0.07[-0.16,0.02]

San-In Group 1997 34/67 32/65 9.95% 0.02[-0.16,0.19]

Takeshita 2009 0/28 0/28 4.22% 0[-0.07,0.07]

Subtotal (95% CI) 243 234 35.88% -0.04[-0.1,0.02]

Total events: 42 (Treatment), 50 (Control)

Heterogeneity: Tau2=0; Chi2=6.38, df=7(P=0.5); I2=0%

Test for overall effect: Z=1.23(P=0.22)

16.10.6 Surgical trials - supplements

Hendry 2010 0/30 2/38 5.06% -0.05[-0.14,0.04]

LeCornu 2000 2/42 7/40 6.18% -0.13[-0.26,0.01]

Meng 1999 4/21 1/23 3.31% 0.15[-0.04,0.33]

Subtotal (95% CI) 93 101 14.55% -0.04[-0.12,0.04]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=5.54, df=2(P=0.06); I2=63.88%

Test for overall effect: Z=0.98(P=0.33)

Total (95% CI) 702 646 100% -0.05[-0.08,-0.01]

Total events: 88 (Treatment), 111 (Control)

Heterogeneity: Tau2=0; Chi2=22.81, df=24(P=0.53); I2=0%

Test for overall effect: Z=2.65(P=0.01)

Test for subgroup differences: Chi2=0.59, df=1 (P=0.99), I2=0%

Favors treatment 0.50.25-0.5 -0.25 0 Favors control

Analysis 16.11. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 11 Surgical trials without transplant patients.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.11.1 Parenteral nutrition

Fan 1994 5/64 9/60 30.44% -0.07[-0.18,0.04]

Puglionisi 1985 0/10 1/10 4.91% -0.1[-0.34,0.14]

Zheng 2003 0/40 1/30 16.85% -0.03[-0.12,0.05]

Subtotal (95% CI) 114 100 52.2% -0.06[-0.14,0.01]

Total events: 5 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.59, df=2(P=0.74); I2=0%

Test for overall effect: Z=1.63(P=0.1)

16.11.2 Enteral nutrition

Foschi 1986 1/28 4/32 14.68% -0.09[-0.22,0.04]

Subtotal (95% CI) 28 32 14.68% -0.09[-0.22,0.04]

Total events: 1 (Treatment), 4 (Control)

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

241

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Not applicable

Test for overall effect: Z=1.31(P=0.19)

16.11.3 Supplements

Hendry 2010 0/30 2/38 16.48% -0.05[-0.14,0.04]

Ishikawa 2010 0/11 0/13 5.86% 0[-0.15,0.15]

Meng 1999 4/21 1/23 10.79% 0.15[-0.04,0.33]

Subtotal (95% CI) 62 74 33.12% 0.02[-0.06,0.1]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=4.49, df=2(P=0.11); I2=55.48%

Test for overall effect: Z=0.52(P=0.6)

Total (95% CI) 204 206 100% -0.04[-0.09,0.01]

Total events: 10 (Treatment), 18 (Control)

Heterogeneity: Tau2=0; Chi2=5.29, df=6(P=0.51); I2=0%

Test for overall effect: Z=1.46(P=0.14)

Test for subgroup differences: Chi2=3, df=1 (P=0.22), I2=33.31%

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

Analysis 16.12. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.12.1 Medical trials - Parenteral nutrition

Achord 1987 1/19 10/21 2.61% -0.42[-0.66,-0.19]

Bonkovsky 1991 0/9 0/12 1.35% 0[-0.17,0.17]

Naveau 1986 1/20 1/20 2.62% 0[-0.14,0.14]

Simon 1988 5/33 7/36 4.51% -0.04[-0.22,0.14]

Subtotal (95% CI) 81 89 11.09% -0.12[-0.22,-0.02]

Total events: 7 (Treatment), 18 (Control)

Heterogeneity: Tau2=0; Chi2=11.84, df=3(P=0.01); I2=74.67%

Test for overall effect: Z=2.31(P=0.02)

16.12.2 Surgical trials - Parenteral nutrition

Fan 1994 5/75 24/75 9.83% -0.25[-0.37,-0.13]

Puglionisi 1985 0/10 1/10 1.31% -0.1[-0.34,0.14]

Reilly 1990 1/18 2/10 1.68% -0.14[-0.41,0.13]

Zheng 2003 0/40 1/30 4.49% -0.03[-0.12,0.05]

Subtotal (95% CI) 143 125 17.31% -0.17[-0.25,-0.1]

Total events: 6 (Treatment), 28 (Control)

Heterogeneity: Tau2=0; Chi2=13.24, df=3(P=0); I2=77.33%

Test for overall effect: Z=4.34(P<0.0001)

16.12.3 Medical trials - Enteral nutrition

Cabre 1990 2/16 9/19 2.28% -0.35[-0.63,-0.07]

Calvey 1985 16/42 7/22 3.78% 0.06[-0.18,0.31]

DeLedinghen 1997 3/12 2/10 1.43% 0.05[-0.3,0.4]

Kearns 1992 5/16 5/15 2.03% -0.02[-0.35,0.31]

Favours experimental 10.5-1 -0.5 0 Favours control

242

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Norman 2008 1/31 2/32 4.13% -0.03[-0.13,0.07]

Subtotal (95% CI) 117 98 13.64% -0.05[-0.15,0.06]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=5.76, df=4(P=0.22); I2=30.59%

Test for overall effect: Z=0.88(P=0.38)

16.12.4 Surgical trials - enteral nutrition

Foschi 1986 1/32 4/32 4.19% -0.09[-0.22,0.04]

Subtotal (95% CI) 32 32 4.19% -0.09[-0.22,0.04]

Total events: 1 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.42(P=0.16)

16.12.5 Medical trials - Supplements

Bunout 1989 2/17 5/19 2.35% -0.15[-0.4,0.1]

Hirsch 1993 3/32 14/33 4.26% -0.33[-0.53,-0.13]

Humbert 1988 2/27 4/22 3.18% -0.11[-0.3,0.08]

Ichikawa 2010 0/12 0/9 1.35% 0[-0.17,0.17]

Kobashi 2006 63/119 44/114 15.26% 0.14[0.02,0.27]

Nakaya 2007 1/25 0/23 3.14% 0.04[-0.07,0.15]

Poon 2004 0/44 4/44 5.76% -0.09[-0.18,0]

San-In Group 1997 34/75 42/75 9.83% -0.11[-0.27,0.05]

Subtotal (95% CI) 351 339 45.12% -0.03[-0.09,0.03]

Total events: 105 (Treatment), 113 (Control)

Heterogeneity: Tau2=0; Chi2=21.99, df=7(P=0); I2=68.17%

Test for overall effect: Z=0.93(P=0.35)

16.12.6 Surgical trials - Supplements

LeCornu 2000 2/42 7/40 5.37% -0.13[-0.26,0.01]

Meng 1999 4/25 3/25 3.28% 0.04[-0.15,0.23]

Subtotal (95% CI) 67 65 8.64% -0.06[-0.17,0.05]

Total events: 6 (Treatment), 10 (Control)

Heterogeneity: Tau2=0; Chi2=1.98, df=1(P=0.16); I2=49.59%

Test for overall effect: Z=1.13(P=0.26)

Total (95% CI) 791 748 100% -0.07[-0.11,-0.03]

Total events: 152 (Treatment), 198 (Control)

Heterogeneity: Tau2=0; Chi2=52.21, df=23(P=0); I2=55.95%

Test for overall effect: Z=3.74(P=0)

Test for subgroup differences: Chi2=8.89, df=1 (P=0.11), I2=43.79%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 16.13. Comparison 16 Mortality - absolute risk di<erence (ARD), Outcome 13 Intent to treat - worst-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

16.13.1 Medical trials - Parenteral nutrition

Achord 1987 6/19 3/21 2.61% 0.17[-0.08,0.43]

Favours experimental 10.5-1 -0.5 0 Favours control

243

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Bonkovsky 1991 0/9 0/12 1.35% 0[-0.17,0.17]

Naveau 1986 1/20 1/20 2.62% 0[-0.14,0.14]

Simon 1988 5/33 7/36 4.51% -0.04[-0.22,0.14]

Subtotal (95% CI) 81 89 11.09% 0.02[-0.08,0.13]

Total events: 12 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=2.02, df=3(P=0.57); I2=0%

Test for overall effect: Z=0.45(P=0.66)

16.13.2 Surgical trials - Parenteral nutrition

Fan 1994 16/75 9/75 9.83% 0.09[-0.03,0.21]

Puglionisi 1985 0/10 1/10 1.31% -0.1[-0.34,0.14]

Reilly 1990 1/18 2/10 1.68% -0.14[-0.41,0.13]

Zheng 2003 0/40 1/30 4.49% -0.03[-0.12,0.05]

Subtotal (95% CI) 143 125 17.31% 0.02[-0.06,0.1]

Total events: 17 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=5.64, df=3(P=0.13); I2=46.79%

Test for overall effect: Z=0.57(P=0.57)

16.13.3 Medical trials - Enteral nutrition

Cabre 1990 2/16 9/19 2.28% -0.35[-0.63,-0.07]

Calvey 1985 16/42 7/22 3.78% 0.06[-0.18,0.31]

DeLedinghen 1997 3/12 2/10 1.43% 0.05[-0.3,0.4]

Kearns 1992 5/16 5/15 2.03% -0.02[-0.35,0.31]

Norman 2008 1/31 2/32 4.13% -0.03[-0.13,0.07]

Subtotal (95% CI) 117 98 13.64% -0.05[-0.15,0.06]

Total events: 27 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=5.76, df=4(P=0.22); I2=30.59%

Test for overall effect: Z=0.88(P=0.38)

16.13.4 Surgical trials - Enteral nutrition

Foschi 1986 5/32 4/32 4.19% 0.03[-0.14,0.2]

Subtotal (95% CI) 32 32 4.19% 0.03[-0.14,0.2]

Total events: 5 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.36(P=0.72)

16.13.5 Medical trials - Supplements

Bunout 1989 2/17 5/19 2.35% -0.15[-0.4,0.1]

Hirsch 1993 9/32 6/33 4.26% 0.1[-0.1,0.3]

Humbert 1988 2/27 4/22 3.18% -0.11[-0.3,0.08]

Ichikawa 2010 0/12 0/9 1.35% 0[-0.17,0.17]

Kobashi 2006 63/119 44/114 15.26% 0.14[0.02,0.27]

Nakaya 2007 1/25 0/23 3.14% 0.04[-0.07,0.15]

Poon 2004 3/44 3/44 5.76% 0[-0.11,0.11]

San-In Group 1997 42/75 32/75 9.83% 0.13[-0.03,0.29]

Subtotal (95% CI) 351 339 45.12% 0.07[0.01,0.14]

Total events: 122 (Treatment), 94 (Control)

Heterogeneity: Tau2=0; Chi2=11.33, df=7(P=0.13); I2=38.19%

Test for overall effect: Z=2.31(P=0.02)

16.13.6 Surgical trials - Supplements

LeCornu 2000 2/42 7/40 5.37% -0.13[-0.26,0.01]

Favours experimental 10.5-1 -0.5 0 Favours control

244

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Meng 1999 8/25 1/25 3.28% 0.28[0.08,0.48]

Subtotal (95% CI) 67 65 8.64% 0.03[-0.09,0.14]

Total events: 10 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=11.33, df=1(P=0); I2=91.18%

Test for overall effect: Z=0.47(P=0.64)

Total (95% CI) 791 748 100% 0.04[-0,0.08]

Total events: 193 (Treatment), 155 (Control)

Heterogeneity: Tau2=0; Chi2=39.24, df=23(P=0.02); I2=41.39%

Test for overall effect: Z=1.9(P=0.06)

Test for subgroup differences: Chi2=3.96, df=1 (P=0.56), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Comparison 17. Appearance of ascites - absolute risk di<erence (ARD)

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 8 582 Risk Difference (M-H, Fixed, 95% CI)

-0.14 [-0.21, -0.08]

2 Parenteral nutrition 4 214 Risk Difference (M-H, Random, 95% CI)

-0.16 [-0.30, -0.03]

2.1 Medical trials 2 26 Risk Difference (M-H, Random, 95% CI)

-0.13 [-0.48, 0.22]

2.2 Surgical trials 2 188 Risk Difference (M-H, Random, 95% CI)

-0.20 [-0.34, -0.07]

3 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.1 Medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Supplements 4 368 Risk Difference (M-H, Fixed, 95% CI)

-0.11 [-0.19, -0.03]

4.1 Medical trials 4 368 Risk Difference (M-H, Fixed, 95% CI)

-0.11 [-0.19, -0.03]

4.2 Surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Medical trials 6 394 Risk Difference (M-H, Fixed, 95% CI)

-0.11 [-0.19, -0.04]

245

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

5.1 Parenteral nutrition 2 26 Risk Difference (M-H, Fixed, 95% CI)

-0.14 [-0.41, 0.12]

5.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.3 Supplements 4 368 Risk Difference (M-H, Fixed, 95% CI)

-0.11 [-0.19, -0.03]

6 Surgical trials 2 188 Risk Difference (M-H, Fixed, 95% CI)

-0.21 [-0.34, -0.07]

6.1 Parenteral nutrition 2 188 Risk Difference (M-H, Fixed, 95% CI)

-0.21 [-0.34, -0.07]

6.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Alcoholic hepatitis 3 77 Risk Difference (M-H, Fixed, 95% CI)

-0.14 [-0.33, 0.06]

7.1 Parenteral nutrition 2 26 Risk Difference (M-H, Fixed, 95% CI)

-0.14 [-0.41, 0.12]

7.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 Supplements 1 51 Risk Difference (M-H, Fixed, 95% CI)

-0.13 [-0.40, 0.13]

8 Cirrhosis 2 82 Risk Difference (M-H, Fixed, 95% CI)

-0.08 [-0.26, 0.09]

8.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.3 Supplements 2 82 Risk Difference (M-H, Fixed, 95% CI)

-0.08 [-0.26, 0.09]

9 HCC 2 286 Risk Difference (M-H, Fixed, 95% CI)

-0.12 [-0.21, -0.03]

9.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

246

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

9.3 Supplements 2 286 Risk Difference (M-H, Fixed, 95% CI)

-0.12 [-0.21, -0.03]

10 Abstracts excluded 7 380 Risk Difference (M-H, Fixed, 95% CI)

-0.17 [-0.25, -0.08]

10.1 Parenteral nutrition - medical trials 2 26 Risk Difference (M-H, Fixed, 95% CI)

-0.14 [-0.41, 0.12]

10.2 Parenteral nutrition - surgical trials 2 188 Risk Difference (M-H, Fixed, 95% CI)

-0.21 [-0.34, -0.07]

10.3 Enteral nutrition - medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.4 Enteral nutrition = surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.5 Supplements - medical trials 3 166 Risk Difference (M-H, Fixed, 95% CI)

-0.12 [-0.24, -0.01]

10.6 Supplements - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11 Surgical trials without transplant 2 188 Risk Difference (M-H, Fixed, 95% CI)

-0.21 [-0.34, -0.07]

11.1 Parenteral nutrition 2 188 Risk Difference (M-H, Fixed, 95% CI)

-0.21 [-0.34, -0.07]

11.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12 Intent to treat - best-case scenario for intervention

8 626 Risk Difference (M-H, Fixed, 95% CI)

-0.20 [-0.27, -0.14]

12.1 Parenteral nutrition - medical trials 2 26 Risk Difference (M-H, Fixed, 95% CI)

-0.14 [-0.41, 0.12]

12.2 Parenteral nutrition - surgical trials 2 214 Risk Difference (M-H, Fixed, 95% CI)

-0.31 [-0.43, -0.19]

12.3 Enteral nutrition - medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.4 Enteral nutrition - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.5 Supplements - medical trials 4 386 Risk Difference (M-H, Fixed, 95% CI)

-0.15 [-0.23, -0.07]

247

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

12.6 Supplements - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13 Intent to treat - worst-case scenario for intervention

8 626 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.13, 0.00]

13.1 Parenteral nutrition - medical trials 2 26 Risk Difference (M-H, Fixed, 95% CI)

-0.14 [-0.41, 0.12]

13.2 Parenteral nutrition - surgical trials 2 214 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.19, 0.07]

13.3 Enteral nutrition - medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.4 Enteral nutrition = surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.5 Supplements - medical trials 4 386 Risk Difference (M-H, Fixed, 95% CI)

-0.06 [-0.14, 0.02]

13.6 Supplements - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 17.1. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 1 All studies.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Achord 1987 0/9 0/6 2.48% 0[-0.23,0.23]

Fan 1994 16/64 30/60 21.38% -0.25[-0.42,-0.08]

Hirsch 1993 8/26 11/25 8.8% -0.13[-0.4,0.13]

Kobashi 2006 16/100 27/102 34.85% -0.1[-0.22,0.01]

Nakaya 2007 1/16 1/15 5.34% -0[-0.18,0.17]

Poon 2004 3/41 10/43 14.49% -0.16[-0.31,-0.01]

Simon 1988 0/5 2/6 1.88% -0.33[-0.75,0.08]

Zheng 2003 23/37 20/27 10.77% -0.12[-0.35,0.11]

Total (95% CI) 298 284 100% -0.14[-0.21,-0.08]

Total events: 67 (Experimental), 101 (Control)

Heterogeneity: Tau2=0; Chi2=6.9, df=7(P=0.44); I2=0%

Test for overall effect: Z=4.17(P<0.0001)

Favours experimental 10.5-1 -0.5 0 Favours control

248

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Analysis 17.2. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 2 Parenteral nutrition.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

17.2.1 Medical trials

Achord 1987 0/9 0/6 24.91% 0[-0.23,0.23]

Simon 1988 0/5 2/6 9.44% -0.33[-0.75,0.08]

Subtotal (95% CI) 14 12 34.35% -0.13[-0.48,0.22]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Tau2=0.04; Chi2=2.24, df=1(P=0.13); I2=55.38%

Test for overall effect: Z=0.72(P=0.47)

17.2.2 Surgical trials

Fan 1994 16/64 30/60 39.72% -0.25[-0.42,-0.08]

Zheng 2003 23/37 20/27 25.93% -0.12[-0.35,0.11]

Subtotal (95% CI) 101 87 65.65% -0.2[-0.34,-0.07]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=0.83, df=1(P=0.36); I2=0%

Test for overall effect: Z=3(P=0)

Total (95% CI) 115 99 100% -0.16[-0.3,-0.03]

Total events: 39 (Experimental), 52 (Control)

Heterogeneity: Tau2=0; Chi2=4.01, df=3(P=0.26); I2=25.26%

Test for overall effect: Z=2.34(P=0.02)

Test for subgroup differences: Chi2=0.16, df=1 (P=0.69), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 17.4. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 4 Supplements.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.4.1 Medical trials

Hirsch 1993 8/26 11/25 13.86% -0.13[-0.4,0.13]

Kobashi 2006 16/100 27/102 54.9% -0.1[-0.22,0.01]

Nakaya 2007 1/16 1/15 8.42% -0[-0.18,0.17]

Poon 2004 3/41 10/43 22.82% -0.16[-0.31,-0.01]

Subtotal (95% CI) 183 185 100% -0.11[-0.19,-0.03]

Total events: 28 (Experimental), 49 (Control)

Heterogeneity: Tau2=0; Chi2=1.92, df=3(P=0.59); I2=0%

Test for overall effect: Z=2.74(P=0.01)

17.4.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 183 185 100% -0.11[-0.19,-0.03]

Total events: 28 (Experimental), 49 (Control)

Heterogeneity: Tau2=0; Chi2=1.92, df=3(P=0.59); I2=0%

Test for overall effect: Z=2.74(P=0.01)

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

249

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for subgroup differences: Not applicable

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

Analysis 17.5. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 5 Medical trials.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.5.1 Parenteral nutrition

Achord 1987 0/9 0/6 3.66% 0[-0.23,0.23]

Simon 1988 0/5 2/6 2.77% -0.33[-0.75,0.08]

Subtotal (95% CI) 14 12 6.44% -0.14[-0.41,0.12]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Tau2=0; Chi2=2.24, df=1(P=0.13); I2=55.38%

Test for overall effect: Z=1.07(P=0.28)

17.5.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.5.3 Supplements

Hirsch 1993 8/26 11/25 12.97% -0.13[-0.4,0.13]

Kobashi 2006 16/100 27/102 51.37% -0.1[-0.22,0.01]

Nakaya 2007 1/16 1/15 7.88% -0[-0.18,0.17]

Poon 2004 3/41 10/43 21.35% -0.16[-0.31,-0.01]

Subtotal (95% CI) 183 185 93.56% -0.11[-0.19,-0.03]

Total events: 28 (Experimental), 49 (Control)

Heterogeneity: Tau2=0; Chi2=1.92, df=3(P=0.59); I2=0%

Test for overall effect: Z=2.74(P=0.01)

Total (95% CI) 197 197 100% -0.11[-0.19,-0.04]

Total events: 28 (Experimental), 51 (Control)

Heterogeneity: Tau2=0; Chi2=3.93, df=5(P=0.56); I2=0%

Test for overall effect: Z=2.91(P=0)

Test for subgroup differences: Chi2=0.05, df=1 (P=0.82), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 17.6. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 6 Surgical trials.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.6.1 Parenteral nutrition

Fan 1994 16/64 30/60 66.49% -0.25[-0.42,-0.08]

Zheng 2003 23/37 20/27 33.51% -0.12[-0.35,0.11]

Subtotal (95% CI) 101 87 100% -0.21[-0.34,-0.07]

Total events: 39 (Experimental), 50 (Control)

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

250

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=0.83, df=1(P=0.36); I2=0%

Test for overall effect: Z=3.02(P=0)

17.6.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.6.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 101 87 100% -0.21[-0.34,-0.07]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=0.83, df=1(P=0.36); I2=0%

Test for overall effect: Z=3.02(P=0)

Test for subgroup differences: Not applicable

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

Analysis 17.7. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 7 Alcoholic hepatitis.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.7.1 Parenteral nutrition

Achord 1987 0/9 0/6 18.88% 0[-0.23,0.23]

Simon 1988 0/5 2/6 14.3% -0.33[-0.75,0.08]

Subtotal (95% CI) 14 12 33.18% -0.14[-0.41,0.12]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Tau2=0; Chi2=2.24, df=1(P=0.13); I2=55.38%

Test for overall effect: Z=1.07(P=0.28)

17.7.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.7.3 Supplements

Hirsch 1993 8/26 11/25 66.82% -0.13[-0.4,0.13]

Subtotal (95% CI) 26 25 66.82% -0.13[-0.4,0.13]

Total events: 8 (Experimental), 11 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.98(P=0.32)

Total (95% CI) 40 37 100% -0.14[-0.33,0.06]

Total events: 8 (Experimental), 13 (Control)

Favours experimental 10.5-1 -0.5 0 Favours control

251

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=2.16, df=2(P=0.34); I2=7.28%

Test for overall effect: Z=1.36(P=0.17)

Test for subgroup differences: Chi2=0, df=1 (P=0.95), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 17.8. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 8 Cirrhosis.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.8.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.8.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.8.3 Supplements

Hirsch 1993 8/26 11/25 62.21% -0.13[-0.4,0.13]

Nakaya 2007 1/16 1/15 37.79% -0[-0.18,0.17]

Subtotal (95% CI) 42 40 100% -0.08[-0.26,0.09]

Total events: 9 (Experimental), 12 (Control)

Heterogeneity: Tau2=0; Chi2=0.94, df=1(P=0.33); I2=0%

Test for overall effect: Z=0.93(P=0.35)

Total (95% CI) 42 40 100% -0.08[-0.26,0.09]

Total events: 9 (Experimental), 12 (Control)

Heterogeneity: Tau2=0; Chi2=0.94, df=1(P=0.33); I2=0%

Test for overall effect: Z=0.93(P=0.35)

Test for subgroup differences: Not applicable

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

Analysis 17.9. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 9 HCC.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.9.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.9.2 Enteral nutrition

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

252

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.9.3 Supplements

Kobashi 2006 16/100 27/102 70.64% -0.1[-0.22,0.01]

Poon 2004 3/41 10/43 29.36% -0.16[-0.31,-0.01]

Subtotal (95% CI) 141 145 100% -0.12[-0.21,-0.03]

Total events: 19 (Experimental), 37 (Control)

Heterogeneity: Tau2=0; Chi2=0.34, df=1(P=0.56); I2=0%

Test for overall effect: Z=2.62(P=0.01)

Total (95% CI) 141 145 100% -0.12[-0.21,-0.03]

Total events: 19 (Experimental), 37 (Control)

Heterogeneity: Tau2=0; Chi2=0.34, df=1(P=0.56); I2=0%

Test for overall effect: Z=2.62(P=0.01)

Test for subgroup differences: Not applicable

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

Analysis 17.10. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 10 Abstracts excluded.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.10.1 Parenteral nutrition - medical trials

Achord 1987 0/9 0/6 3.81% 0[-0.23,0.23]

Simon 1988 0/5 2/6 2.89% -0.33[-0.75,0.08]

Subtotal (95% CI) 14 12 6.7% -0.14[-0.41,0.12]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Tau2=0; Chi2=2.24, df=1(P=0.13); I2=55.38%

Test for overall effect: Z=1.07(P=0.28)

17.10.2 Parenteral nutrition - surgical trials

Fan 1994 16/64 30/60 32.81% -0.25[-0.42,-0.08]

Zheng 2003 23/37 20/27 16.54% -0.12[-0.35,0.11]

Subtotal (95% CI) 101 87 49.35% -0.21[-0.34,-0.07]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=0.83, df=1(P=0.36); I2=0%

Test for overall effect: Z=3.02(P=0)

17.10.3 Enteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.10.4 Enteral nutrition = surgical trials

Subtotal (95% CI) 0 0 Not estimable

Favours experimental 10.5-1 -0.5 0 Favours control

253

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.10.5 Supplements - medical trials

Hirsch 1993 8/26 11/25 13.5% -0.13[-0.4,0.13]

Nakaya 2007 1/16 1/15 8.2% -0[-0.18,0.17]

Poon 2004 3/41 10/43 22.24% -0.16[-0.31,-0.01]

Subtotal (95% CI) 83 83 43.95% -0.12[-0.24,-0.01]

Total events: 12 (Experimental), 22 (Control)

Heterogeneity: Tau2=0; Chi2=2.03, df=2(P=0.36); I2=1.28%

Test for overall effect: Z=2.07(P=0.04)

17.10.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 198 182 100% -0.17[-0.25,-0.08]

Total events: 51 (Experimental), 74 (Control)

Heterogeneity: Tau2=0; Chi2=7.09, df=6(P=0.31); I2=15.35%

Test for overall effect: Z=3.8(P=0)

Test for subgroup differences: Chi2=0.88, df=1 (P=0.64), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 17.11. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 11 Surgical trials without transplant.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.11.1 Parenteral nutrition

Fan 1994 16/64 30/60 66.49% -0.25[-0.42,-0.08]

Zheng 2003 23/37 20/27 33.51% -0.12[-0.35,0.11]

Subtotal (95% CI) 101 87 100% -0.21[-0.34,-0.07]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=0.83, df=1(P=0.36); I2=0%

Test for overall effect: Z=3.02(P=0)

17.11.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.11.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

254

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Not applicable

Total (95% CI) 101 87 100% -0.21[-0.34,-0.07]

Total events: 39 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=0.83, df=1(P=0.36); I2=0%

Test for overall effect: Z=3.02(P=0)

Test for subgroup differences: Not applicable

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

Analysis 17.12. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.12.1 Parenteral nutrition - medical trials

Achord 1987 0/9 0/6 2.31% 0[-0.23,0.23]

Simon 1988 0/5 2/6 1.75% -0.33[-0.75,0.08]

Subtotal (95% CI) 14 12 4.06% -0.14[-0.41,0.12]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Tau2=0; Chi2=2.24, df=1(P=0.13); I2=55.38%

Test for overall effect: Z=1.07(P=0.28)

17.12.2 Parenteral nutrition - surgical trials

Fan 1994 16/75 45/75 24.05% -0.39[-0.53,-0.24]

Zheng 2003 23/37 20/27 10.01% -0.12[-0.35,0.11]

Subtotal (95% CI) 112 102 34.06% -0.31[-0.43,-0.19]

Total events: 39 (Experimental), 65 (Control)

Heterogeneity: Tau2=0; Chi2=3.79, df=1(P=0.05); I2=73.59%

Test for overall effect: Z=4.95(P<0.0001)

17.12.3 Enteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.12.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.12.5 Supplements - medical trials

Hirsch 1993 8/32 19/33 10.42% -0.33[-0.55,-0.1]

Kobashi 2006 16/100 27/102 32.39% -0.1[-0.22,0.01]

Nakaya 2007 1/16 1/15 4.97% -0[-0.18,0.17]

Poon 2004 3/44 11/44 14.11% -0.18[-0.33,-0.03]

Subtotal (95% CI) 192 194 61.88% -0.15[-0.23,-0.07]

Total events: 28 (Experimental), 58 (Control)

Favours experimental 10.5-1 -0.5 0 Favours control

255

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=5.9, df=3(P=0.12); I2=49.17%

Test for overall effect: Z=3.77(P=0)

17.12.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 318 308 100% -0.2[-0.27,-0.14]

Total events: 67 (Experimental), 125 (Control)

Heterogeneity: Tau2=0; Chi2=19.35, df=7(P=0.01); I2=63.82%

Test for overall effect: Z=6.17(P<0.0001)

Test for subgroup differences: Chi2=4.62, df=1 (P=0.1), I2=56.71%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 17.13. Comparison 17 Appearance of ascites - absolute risk di<erence (ARD), Outcome 13 Intent to treat - worst-case scenario for intervention.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.13.1 Parenteral nutrition - medical trials

Achord 1987 0/9 0/6 2.31% 0[-0.23,0.23]

Simon 1988 0/5 2/6 1.75% -0.33[-0.75,0.08]

Subtotal (95% CI) 14 12 4.06% -0.14[-0.41,0.12]

Total events: 0 (Experimental), 2 (Control)

Heterogeneity: Tau2=0; Chi2=2.24, df=1(P=0.13); I2=55.38%

Test for overall effect: Z=1.07(P=0.28)

17.13.2 Parenteral nutrition - surgical trials

Fan 1994 27/75 30/75 24.05% -0.04[-0.2,0.12]

Zheng 2003 23/37 20/27 10.01% -0.12[-0.35,0.11]

Subtotal (95% CI) 112 102 34.06% -0.06[-0.19,0.07]

Total events: 50 (Experimental), 50 (Control)

Heterogeneity: Tau2=0; Chi2=0.32, df=1(P=0.57); I2=0%

Test for overall effect: Z=0.97(P=0.33)

17.13.3 Enteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

17.13.4 Enteral nutrition = surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours experimental 10.5-1 -0.5 0 Favours control

256

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

17.13.5 Supplements - medical trials

Hirsch 1993 14/32 11/33 10.42% 0.1[-0.13,0.34]

Kobashi 2006 16/100 27/102 32.39% -0.1[-0.22,0.01]

Nakaya 2007 1/16 1/15 4.97% -0[-0.18,0.17]

Poon 2004 6/44 10/44 14.11% -0.09[-0.25,0.07]

Subtotal (95% CI) 192 194 61.88% -0.06[-0.14,0.02]

Total events: 37 (Experimental), 49 (Control)

Heterogeneity: Tau2=0; Chi2=3.03, df=3(P=0.39); I2=0.88%

Test for overall effect: Z=1.42(P=0.16)

17.13.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 318 308 100% -0.06[-0.13,0]

Total events: 87 (Experimental), 101 (Control)

Heterogeneity: Tau2=0; Chi2=5.23, df=7(P=0.63); I2=0%

Test for overall effect: Z=1.85(P=0.06)

Test for subgroup differences: Chi2=0.37, df=1 (P=0.83), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Comparison 18. Resolution of ascites - absolute risk di<erence (ARD)

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 6 131 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.20, 0.11]

2 Parenteral nutrition 3 73 Risk Difference (M-H, Fixed, 95% CI)

-0.20 [-0.40, 0.00]

2.1 Medical trials 3 73 Risk Difference (M-H, Fixed, 95% CI)

-0.20 [-0.40, 0.00]

2.2 Surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Enteral nutrition 1 29 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.45, 0.27]

3.1 Medical trials 1 29 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.45, 0.27]

3.2 Surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Supplements 2 29 Risk Difference (M-H, Fixed, 95% CI)

0.40 [0.08, 0.71]

257

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

4.1 Medical trials 2 29 Risk Difference (M-H, Fixed, 95% CI)

0.40 [0.08, 0.71]

4.2 Surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Medical trials 6 131 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.20, 0.11]

5.1 Parenteral nutrition 3 73 Risk Difference (M-H, Fixed, 95% CI)

-0.20 [-0.40, 0.00]

5.2 Enteral nutrition 1 29 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.45, 0.27]

5.3 Supplements 2 29 Risk Difference (M-H, Fixed, 95% CI)

0.40 [0.08, 0.71]

6 Surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Alcoholic hepatitis 2 40 Risk Difference (M-H, Fixed, 95% CI)

0.00 [-0.29, 0.30]

7.1 Parenteral nutrition 2 40 Risk Difference (M-H, Fixed, 95% CI)

0.00 [-0.29, 0.30]

7.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Cirrhosis 4 91 Risk Difference (M-H, Fixed, 95% CI)

-0.07 [-0.25, 0.11]

8.1 Parenteral nutrition 1 33 Risk Difference (M-H, Fixed, 95% CI)

-0.44 [-0.69, -0.19]

8.2 Enteral nutrition 1 29 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.45, 0.27]

8.3 Supplements 2 29 Risk Difference (M-H, Fixed, 95% CI)

0.40 [0.08, 0.71]

258

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

9 HCC 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10 Abstracts excluded 6 131 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.20, 0.11]

10.1 Parenteral nutrition - medical trials 3 73 Risk Difference (M-H, Fixed, 95% CI)

-0.20 [-0.40, 0.00]

10.2 Parenteral nutrition - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.3 Enteral nutrition - medical trials 1 29 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.45, 0.27]

10.4 Enteral nutrition = surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.5 Supplements - medical trials 2 29 Risk Difference (M-H, Fixed, 95% CI)

0.40 [0.08, 0.71]

10.6 Supplements - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11 Surgical trials without transplant 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12 Intent to treat - best-case scenario for intervention - no changes made

6 131 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.20, 0.11]

12.1 Parenteral nutrition - medical trials 3 73 Risk Difference (M-H, Fixed, 95% CI)

-0.20 [-0.40, 0.00]

12.2 Parenteral nutrition - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

259

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

12.3 Enteral nutrition - medical trials 1 29 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.45, 0.27]

12.4 Enteral nutrition = surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.5 Supplements - medical trials 2 29 Risk Difference (M-H, Fixed, 95% CI)

0.40 [0.08, 0.71]

12.6 Supplements - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13 Intent to treat - worst-case scenario for intervention - no changes made

6 131 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.20, 0.11]

13.1 Parenteral nutrition - medical trials 3 73 Risk Difference (M-H, Fixed, 95% CI)

-0.20 [-0.40, 0.00]

13.2 Parenteral nutrition - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.3 Enteral nutrition - medical trials 1 29 Risk Difference (M-H, Fixed, 95% CI)

-0.09 [-0.45, 0.27]

13.4 Enteral nutrition = surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.5 Supplements - medical trials 2 29 Risk Difference (M-H, Fixed, 95% CI)

0.40 [0.08, 0.71]

13.6 Supplements - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 18.1. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 1 All studies.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Achord 1987 3/5 3/8 9.6% 0.22[-0.32,0.77]

Cabre 1990 7/13 10/16 22.39% -0.09[-0.45,0.27]

Hayashi 1991 6/14 1/8 15.89% 0.3[-0.04,0.65]

Nakaya 2007 2/3 0/4 5.35% 0.67[0.12,1.21]

Naveau 1986 9/16 17/17 25.73% -0.44[-0.69,-0.19]

Simon 1988 4/14 5/13 21.04% -0.1[-0.45,0.26]

Total (95% CI) 65 66 100% -0.05[-0.2,0.11]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=21.21, df=5(P=0); I2=76.42%

Test for overall effect: Z=0.6(P=0.55)

Favours control 10.5-1 -0.5 0 Favours experimental

260

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Analysis 18.2. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 2 Parenteral nutrition.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.2.1 Medical trials

Achord 1987 3/5 3/8 17.04% 0.22[-0.32,0.77]

Naveau 1986 9/16 17/17 45.64% -0.44[-0.69,-0.19]

Simon 1988 4/14 5/13 37.32% -0.1[-0.45,0.26]

Subtotal (95% CI) 35 38 100% -0.2[-0.4,0]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=6.2, df=2(P=0.05); I2=67.72%

Test for overall effect: Z=1.93(P=0.05)

18.2.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 35 38 100% -0.2[-0.4,0]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=6.2, df=2(P=0.05); I2=67.72%

Test for overall effect: Z=1.93(P=0.05)

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours experimental

Analysis 18.3. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 3 Enteral nutrition.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.3.1 Medical trials

Cabre 1990 7/13 10/16 100% -0.09[-0.45,0.27]

Subtotal (95% CI) 13 16 100% -0.09[-0.45,0.27]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.47(P=0.64)

18.3.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 13 16 100% -0.09[-0.45,0.27]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.47(P=0.64)

Test for subgroup differences: Not applicable

Favours control 10050-100 -50 0 Favours experimental

261

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Analysis 18.4. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 4 Supplements.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.4.1 Medical trials

Hayashi 1991 6/14 1/8 74.81% 0.3[-0.04,0.65]

Nakaya 2007 2/3 0/4 25.19% 0.67[0.12,1.21]

Subtotal (95% CI) 17 12 100% 0.4[0.08,0.71]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.81%

Test for overall effect: Z=2.47(P=0.01)

18.4.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 17 12 100% 0.4[0.08,0.71]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.81%

Test for overall effect: Z=2.47(P=0.01)

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours experimental

Analysis 18.5. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 5 Medical trials.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.5.1 Parenteral nutrition

Achord 1987 3/5 3/8 9.6% 0.22[-0.32,0.77]

Naveau 1986 9/16 17/17 25.73% -0.44[-0.69,-0.19]

Simon 1988 4/14 5/13 21.04% -0.1[-0.45,0.26]

Subtotal (95% CI) 35 38 56.37% -0.2[-0.4,0]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=6.2, df=2(P=0.05); I2=67.72%

Test for overall effect: Z=1.93(P=0.05)

18.5.2 Enteral nutrition

Cabre 1990 7/13 10/16 22.39% -0.09[-0.45,0.27]

Subtotal (95% CI) 13 16 22.39% -0.09[-0.45,0.27]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.47(P=0.64)

18.5.3 Supplements

Hayashi 1991 6/14 1/8 15.89% 0.3[-0.04,0.65]

Nakaya 2007 2/3 0/4 5.35% 0.67[0.12,1.21]

Subtotal (95% CI) 17 12 21.24% 0.4[0.08,0.71]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.81%

Favours control 10.5-1 -0.5 0 Favours experimental

262

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Z=2.47(P=0.01)

Total (95% CI) 65 66 100% -0.05[-0.2,0.11]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=21.21, df=5(P=0); I2=76.42%

Test for overall effect: Z=0.6(P=0.55)

Test for subgroup differences: Chi2=9.82, df=1 (P=0.01), I2=79.64%

Favours control 10.5-1 -0.5 0 Favours experimental

Analysis 18.7. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 7 Alcoholic hepatitis.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.7.1 Parenteral nutrition

Achord 1987 3/5 3/8 31.34% 0.22[-0.32,0.77]

Simon 1988 4/14 5/13 68.66% -0.1[-0.45,0.26]

Subtotal (95% CI) 19 21 100% 0[-0.29,0.3]

Total events: 7 (Experimental), 8 (Control)

Heterogeneity: Tau2=0; Chi2=0.95, df=1(P=0.33); I2=0%

Test for overall effect: Z=0.02(P=0.99)

18.7.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

18.7.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 19 21 100% 0[-0.29,0.3]

Total events: 7 (Experimental), 8 (Control)

Heterogeneity: Tau2=0; Chi2=0.95, df=1(P=0.33); I2=0%

Test for overall effect: Z=0.02(P=0.99)

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours experimental

Analysis 18.8. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 8 Cirrhosis.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.8.1 Parenteral nutrition

Naveau 1986 9/16 17/17 37.09% -0.44[-0.69,-0.19]

Subtotal (95% CI) 16 17 37.09% -0.44[-0.69,-0.19]

Favours control 10.5-1 -0.5 0 Favours experimental

263

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 9 (Experimental), 17 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=3.46(P=0)

18.8.2 Enteral nutrition

Cabre 1990 7/13 10/16 32.28% -0.09[-0.45,0.27]

Subtotal (95% CI) 13 16 32.28% -0.09[-0.45,0.27]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.47(P=0.64)

18.8.3 Supplements

Hayashi 1991 6/14 1/8 22.91% 0.3[-0.04,0.65]

Nakaya 2007 2/3 0/4 7.72% 0.67[0.12,1.21]

Subtotal (95% CI) 17 12 30.63% 0.4[0.08,0.71]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.81%

Test for overall effect: Z=2.47(P=0.01)

Total (95% CI) 46 45 100% -0.07[-0.25,0.11]

Total events: 24 (Experimental), 28 (Control)

Heterogeneity: Tau2=0; Chi2=20.01, df=3(P=0); I2=85.01%

Test for overall effect: Z=0.76(P=0.45)

Test for subgroup differences: Chi2=16.68, df=1 (P=0), I2=88.01%

Favours control 10.5-1 -0.5 0 Favours experimental

Analysis 18.10. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 10 Abstracts excluded.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.10.1 Parenteral nutrition - medical trials

Achord 1987 3/5 3/8 9.6% 0.22[-0.32,0.77]

Naveau 1986 9/16 17/17 25.73% -0.44[-0.69,-0.19]

Simon 1988 4/14 5/13 21.04% -0.1[-0.45,0.26]

Subtotal (95% CI) 35 38 56.37% -0.2[-0.4,0]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=6.2, df=2(P=0.05); I2=67.72%

Test for overall effect: Z=1.93(P=0.05)

18.10.2 Parenteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

18.10.3 Enteral nutrition - medical trials

Cabre 1990 7/13 10/16 22.39% -0.09[-0.45,0.27]

Subtotal (95% CI) 13 16 22.39% -0.09[-0.45,0.27]

Favours control 10.5-1 -0.5 0 Favours experimental

264

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.47(P=0.64)

18.10.4 Enteral nutrition = surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

18.10.5 Supplements - medical trials

Hayashi 1991 6/14 1/8 15.89% 0.3[-0.04,0.65]

Nakaya 2007 2/3 0/4 5.35% 0.67[0.12,1.21]

Subtotal (95% CI) 17 12 21.24% 0.4[0.08,0.71]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.81%

Test for overall effect: Z=2.47(P=0.01)

18.10.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 65 66 100% -0.05[-0.2,0.11]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=21.21, df=5(P=0); I2=76.42%

Test for overall effect: Z=0.6(P=0.55)

Test for subgroup differences: Chi2=9.82, df=1 (P=0.01), I2=79.64%

Favours control 10.5-1 -0.5 0 Favours experimental

Analysis 18.12. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention - no changes made.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.12.1 Parenteral nutrition - medical trials

Achord 1987 3/5 3/8 9.6% 0.22[-0.32,0.77]

Naveau 1986 9/16 17/17 25.73% -0.44[-0.69,-0.19]

Simon 1988 4/14 5/13 21.04% -0.1[-0.45,0.26]

Subtotal (95% CI) 35 38 56.37% -0.2[-0.4,0]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=6.2, df=2(P=0.05); I2=67.72%

Test for overall effect: Z=1.93(P=0.05)

18.12.2 Parenteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Favours control 10.5-1 -0.5 0 Favours experimental

265

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Not applicable

18.12.3 Enteral nutrition - medical trials

Cabre 1990 7/13 10/16 22.39% -0.09[-0.45,0.27]

Subtotal (95% CI) 13 16 22.39% -0.09[-0.45,0.27]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.47(P=0.64)

18.12.4 Enteral nutrition = surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

18.12.5 Supplements - medical trials

Hayashi 1991 6/14 1/8 15.89% 0.3[-0.04,0.65]

Nakaya 2007 2/3 0/4 5.35% 0.67[0.12,1.21]

Subtotal (95% CI) 17 12 21.24% 0.4[0.08,0.71]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.81%

Test for overall effect: Z=2.47(P=0.01)

18.12.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 65 66 100% -0.05[-0.2,0.11]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=21.21, df=5(P=0); I2=76.42%

Test for overall effect: Z=0.6(P=0.55)

Test for subgroup differences: Chi2=9.82, df=1 (P=0.01), I2=79.64%

Favours control 10.5-1 -0.5 0 Favours experimental

Analysis 18.13. Comparison 18 Resolution of ascites - absolute risk di<erence (ARD), Outcome 13 Intent to treat - worst-case scenario for intervention - no changes made.

Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.13.1 Parenteral nutrition - medical trials

Achord 1987 3/5 3/8 9.6% 0.22[-0.32,0.77]

Naveau 1986 9/16 17/17 25.73% -0.44[-0.69,-0.19]

Simon 1988 4/14 5/13 21.04% -0.1[-0.45,0.26]

Subtotal (95% CI) 35 38 56.37% -0.2[-0.4,0]

Total events: 16 (Experimental), 25 (Control)

Heterogeneity: Tau2=0; Chi2=6.2, df=2(P=0.05); I2=67.72%

Test for overall effect: Z=1.93(P=0.05)

Favours control 10.5-1 -0.5 0 Favours experimental

266

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Study or subgroup Experimental Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

18.13.2 Parenteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

18.13.3 Enteral nutrition - medical trials

Cabre 1990 7/13 10/16 22.39% -0.09[-0.45,0.27]

Subtotal (95% CI) 13 16 22.39% -0.09[-0.45,0.27]

Total events: 7 (Experimental), 10 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.47(P=0.64)

18.13.4 Enteral nutrition = surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

18.13.5 Supplements - medical trials

Hayashi 1991 6/14 1/8 15.89% 0.3[-0.04,0.65]

Nakaya 2007 2/3 0/4 5.35% 0.67[0.12,1.21]

Subtotal (95% CI) 17 12 21.24% 0.4[0.08,0.71]

Total events: 8 (Experimental), 1 (Control)

Heterogeneity: Tau2=0; Chi2=1.23, df=1(P=0.27); I2=18.81%

Test for overall effect: Z=2.47(P=0.01)

18.13.6 Supplements - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Experimental), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 65 66 100% -0.05[-0.2,0.11]

Total events: 31 (Experimental), 36 (Control)

Heterogeneity: Tau2=0; Chi2=21.21, df=5(P=0); I2=76.42%

Test for overall effect: Z=0.6(P=0.55)

Test for subgroup differences: Chi2=9.82, df=1 (P=0.01), I2=79.64%

Favours control 10.5-1 -0.5 0 Favours experimental

Comparison 19. Appearance gastrointestinal bleeding - absolute risk di<erence (ARD)

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 11 783 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.01, 0.06]

267

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

2 Parenteral nutrition 1 124 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.03, 0.06]

2.1 Medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Surgical trials 1 124 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.03, 0.06]

3 Enteral nutrition (all medical) 4 180 Risk Difference (M-H, Fixed, 95% CI)

0.08 [-0.04, 0.19]

3.1 Medical trials 4 180 Risk Difference (M-H, Fixed, 95% CI)

0.08 [-0.04, 0.19]

3.2 Surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Supplements 6 479 Risk Difference (M-H, Fixed, 95% CI)

0.01 [-0.04, 0.05]

4.1 Medical trials 5 435 Risk Difference (M-H, Fixed, 95% CI)

0.01 [-0.04, 0.05]

4.2 Surgical trials 1 44 Risk Difference (M-H, Fixed, 95% CI)

0.00 [-0.12, 0.13]

5 Medical trials 9 615 Risk Difference (M-H, Fixed, 95% CI)

0.03 [-0.02, 0.07]

5.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Enteral nutrition 4 180 Risk Difference (M-H, Fixed, 95% CI)

0.08 [-0.04, 0.19]

5.3 Supplements 5 435 Risk Difference (M-H, Fixed, 95% CI)

0.01 [-0.04, 0.05]

6 Surgical trials 2 168 Risk Difference (M-H, Fixed, 95% CI)

0.01 [-0.03, 0.06]

6.1 Parenteral nutrition 1 124 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.03, 0.06]

6.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 Supplements 1 44 Risk Difference (M-H, Fixed, 95% CI)

0.00 [-0.12, 0.13]

7 Alcoholic hepatitis 1 64 Risk Difference (M-H, Fixed, 95% CI)

0.17 [-0.01, 0.35]

268

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

7.1 Parenteral Nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Enteral nutrition 1 64 Risk Difference (M-H, Fixed, 95% CI)

0.17 [-0.01, 0.35]

7.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Cirrhosis 6 234 Risk Difference (M-H, Fixed, 95% CI)

0.00 [-0.09, 0.10]

8.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Enteral nutrition 3 116 Risk Difference (M-H, Fixed, 95% CI)

0.03 [-0.11, 0.17]

8.3 Supplements 3 118 Risk Difference (M-H, Fixed, 95% CI)

-0.02 [-0.15, 0.10]

9 HCC 2 317 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.03, 0.06]

9.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Eneral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 2 317 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.03, 0.06]

10 Abstracts excluded 9 491 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.02, 0.07]

10.1 Parenteral nutrition - medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.2 Parenteral nutrition - surgical trials 1 124 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.03, 0.06]

10.3 Enteral nutrition - medical trials 3 121 Risk Difference (M-H, Fixed, 95% CI)

0.09 [-0.04, 0.21]

10.4 Enteral nutrition - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.5 Supplements - medical trials 4 202 Risk Difference (M-H, Fixed, 95% CI)

-0.00 [-0.08, 0.07]

10.6 Supplements - surgical trials 1 44 Risk Difference (M-H, Fixed, 95% CI)

0.00 [-0.12, 0.13]

269

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

11 Surgical trials without transplant pa- tients (no trials with transplant patients)

2 168 Risk Difference (M-H, Fixed, 95% CI)

0.01 [-0.03, 0.06]

11.1 Parenteral nutrition 1 124 Risk Difference (M-H, Fixed, 95% CI)

0.02 [-0.03, 0.06]

11.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11.3 Supplements 1 44 Risk Difference (M-H, Fixed, 95% CI)

0.00 [-0.12, 0.13]

12 Intent to treat - best-case scenario for intervention

11 838 Risk Difference (M-H, Fixed, 95% CI)

-0.05 [-0.09, -0.01]

12.1 Parenteral nutrition - medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.2 Parenteral nutrition - surgical trials 1 150 Risk Difference (M-H, Fixed, 95% CI)

-0.19 [-0.28, -0.09]

12.3 Enteral nutrition - medical trials 4 184 Risk Difference (M-H, Fixed, 95% CI)

0.05 [-0.07, 0.16]

12.4 Enteral nutrition - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12.5 Supplements - medical trials 5 454 Risk Difference (M-H, Fixed, 95% CI)

-0.03 [-0.08, 0.01]

12.6 Supplements - surgical trials 1 50 Risk Difference (M-H, Fixed, 95% CI)

-0.08 [-0.23, 0.07]

13 Intent-to-treat - worst-case scenario for intervention

11 838 Risk Difference (M-H, Fixed, 95% CI)

0.09 [0.05, 0.13]

13.1 Parenteral nutrition - medical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.2 Parenteral nutrition - surgical trials 1 150 Risk Difference (M-H, Fixed, 95% CI)

0.16 [0.07, 0.25]

13.3 Enteral nutrition - medical trials 4 184 Risk Difference (M-H, Fixed, 95% CI)

0.09 [-0.02, 0.20]

13.4 Enteral nutrition - surgical trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.5 Supplements - medical trials 5 454 Risk Difference (M-H, Fixed, 95% CI)

0.05 [0.00, 0.10]

13.6 Supplements - surgical trials 1 50 Risk Difference (M-H, Fixed, 95% CI)

0.16 [-0.01, 0.33]

270

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Analysis 19.1. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 1 All studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 1/16 4/19 4.48% -0.15[-0.37,0.07]

Calvey 1985 11/42 2/22 7.44% 0.17[-0.01,0.35]

DeLedinghen 1997 4/12 1/10 2.81% 0.23[-0.09,0.56]

Fan 1994 1/64 0/60 15.97% 0.02[-0.03,0.06]

Hirsch 1993 10/26 11/25 6.57% -0.06[-0.33,0.21]

Kobashi 2006 7/119 5/114 30.02% 0.01[-0.04,0.07]

Meng 1999 1/21 1/23 5.66% 0[-0.12,0.13]

Nakaya 2007 0/19 0/19 4.9% 0[-0.1,0.1]

Norman 2008 8/30 6/29 7.6% 0.06[-0.16,0.28]

Poon 2004 1/41 0/43 10.82% 0.02[-0.04,0.09]

Tangkijvanich 2000 0/14 0/15 3.73% 0[-0.12,0.12]

Total (95% CI) 404 379 100% 0.02[-0.01,0.06]

Total events: 44 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=7.68, df=10(P=0.66); I2=0%

Test for overall effect: Z=1.22(P=0.22)

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 19.2. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 2 Parenteral nutrition.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.2.1 Medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.2.2 Surgical trials

Fan 1994 1/64 0/60 100% 0.02[-0.03,0.06]

Subtotal (95% CI) 64 60 100% 0.02[-0.03,0.06]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.71(P=0.48)

Total (95% CI) 64 60 100% 0.02[-0.03,0.06]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.71(P=0.48)

Test for subgroup differences: Not applicable

Favours treatment 0.20.1-0.2 -0.1 0 Favours control

271

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Analysis 19.3. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 3 Enteral nutrition (all medical).

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.3.1 Medical trials

Cabre 1990 1/16 4/19 20.05% -0.15[-0.37,0.07]

Calvey 1985 11/42 2/22 33.32% 0.17[-0.01,0.35]

DeLedinghen 1997 4/12 1/10 12.59% 0.23[-0.09,0.56]

Norman 2008 8/30 6/29 34.04% 0.06[-0.16,0.28]

Subtotal (95% CI) 100 80 100% 0.08[-0.04,0.19]

Total events: 24 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=6.05, df=3(P=0.11); I2=50.41%

Test for overall effect: Z=1.35(P=0.18)

19.3.2 Surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 100 80 100% 0.08[-0.04,0.19]

Total events: 24 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=6.05, df=3(P=0.11); I2=50.41%

Test for overall effect: Z=1.35(P=0.18)

Test for subgroup differences: Not applicable

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 19.4. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 4 Supplements.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.4.1 Medical trials

Hirsch 1993 10/26 11/25 10.65% -0.06[-0.33,0.21]

Kobashi 2006 7/119 5/114 48.65% 0.01[-0.04,0.07]

Nakaya 2007 0/19 0/19 7.94% 0[-0.1,0.1]

Poon 2004 1/41 0/43 17.54% 0.02[-0.04,0.09]

Tangkijvanich 2000 0/14 0/15 6.05% 0[-0.12,0.12]

Subtotal (95% CI) 219 216 90.83% 0.01[-0.04,0.05]

Total events: 18 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=0.62, df=4(P=0.96); I2=0%

Test for overall effect: Z=0.26(P=0.8)

19.4.2 Surgical trials

Meng 1999 1/21 1/23 9.17% 0[-0.12,0.13]

Subtotal (95% CI) 21 23 9.17% 0[-0.12,0.13]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 240 239 100% 0.01[-0.04,0.05]

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

272

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 19 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.63, df=5(P=0.99); I2=0%

Test for overall effect: Z=0.27(P=0.79)

Test for subgroup differences: Chi2=0, df=1 (P=0.98), I2=0%

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

Analysis 19.5. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 5 Medical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.5.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.5.2 Enteral nutrition

Cabre 1990 1/16 4/19 5.71% -0.15[-0.37,0.07]

Calvey 1985 11/42 2/22 9.5% 0.17[-0.01,0.35]

DeLedinghen 1997 4/12 1/10 3.59% 0.23[-0.09,0.56]

Norman 2008 8/30 6/29 9.7% 0.06[-0.16,0.28]

Subtotal (95% CI) 100 80 28.5% 0.08[-0.04,0.19]

Total events: 24 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=6.05, df=3(P=0.11); I2=50.41%

Test for overall effect: Z=1.35(P=0.18)

19.5.3 Supplements

Hirsch 1993 10/26 11/25 8.38% -0.06[-0.33,0.21]

Kobashi 2006 7/119 5/114 38.3% 0.01[-0.04,0.07]

Nakaya 2007 0/19 0/19 6.25% 0[-0.1,0.1]

Poon 2004 1/41 0/43 13.81% 0.02[-0.04,0.09]

Tangkijvanich 2000 0/14 0/15 4.76% 0[-0.12,0.12]

Subtotal (95% CI) 219 216 71.5% 0.01[-0.04,0.05]

Total events: 18 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=0.62, df=4(P=0.96); I2=0%

Test for overall effect: Z=0.26(P=0.8)

Total (95% CI) 319 296 100% 0.03[-0.02,0.07]

Total events: 42 (Treatment), 29 (Control)

Heterogeneity: Tau2=0; Chi2=7.57, df=8(P=0.48); I2=0%

Test for overall effect: Z=1.11(P=0.27)

Test for subgroup differences: Chi2=1.3, df=1 (P=0.25), I2=23.05%

Favours treatment 10.5-1 -0.5 0 Favours control

273

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Analysis 19.6. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 6 Surgical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.6.1 Parenteral nutrition

Fan 1994 1/64 0/60 73.83% 0.02[-0.03,0.06]

Subtotal (95% CI) 64 60 73.83% 0.02[-0.03,0.06]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.71(P=0.48)

19.6.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.6.3 Supplements

Meng 1999 1/21 1/23 26.17% 0[-0.12,0.13]

Subtotal (95% CI) 21 23 26.17% 0[-0.12,0.13]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 85 83 100% 0.01[-0.03,0.06]

Total events: 2 (Treatment), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.04, df=1(P=0.85); I2=0%

Test for overall effect: Z=0.54(P=0.59)

Test for subgroup differences: Chi2=0.03, df=1 (P=0.86), I2=0%

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

Analysis 19.7. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 7 Alcoholic hepatitis.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.7.1 Parenteral Nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.7.2 Enteral nutrition

Calvey 1985 11/42 2/22 100% 0.17[-0.01,0.35]

Subtotal (95% CI) 42 22 100% 0.17[-0.01,0.35]

Total events: 11 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.87(P=0.06)

19.7.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

274

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 42 22 100% 0.17[-0.01,0.35]

Total events: 11 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.87(P=0.06)

Test for subgroup differences: Not applicable

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

Analysis 19.8. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 8 Cirrhosis.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.8.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.8.2 Enteral nutrition

Cabre 1990 1/16 4/19 14.88% -0.15[-0.37,0.07]

DeLedinghen 1997 4/12 1/10 9.34% 0.23[-0.09,0.56]

Norman 2008 8/30 6/29 25.26% 0.06[-0.16,0.28]

Subtotal (95% CI) 58 58 49.49% 0.03[-0.11,0.17]

Total events: 13 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=4.13, df=2(P=0.13); I2=51.57%

Test for overall effect: Z=0.41(P=0.68)

19.8.3 Supplements

Hirsch 1993 10/26 11/25 21.83% -0.06[-0.33,0.21]

Nakaya 2007 0/19 0/19 16.27% 0[-0.1,0.1]

Tangkijvanich 2000 0/14 0/15 12.41% 0[-0.12,0.12]

Subtotal (95% CI) 59 59 50.51% -0.02[-0.15,0.1]

Total events: 10 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.43, df=2(P=0.81); I2=0%

Test for overall effect: Z=0.37(P=0.71)

Total (95% CI) 117 117 100% 0[-0.09,0.1]

Total events: 23 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=4.21, df=5(P=0.52); I2=0%

Test for overall effect: Z=0.06(P=0.95)

Test for subgroup differences: Chi2=0.31, df=1 (P=0.58), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

275

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Analysis 19.9. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 9 HCC.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.9.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.9.2 Eneral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.9.3 Supplements

Kobashi 2006 7/119 5/114 73.5% 0.01[-0.04,0.07]

Poon 2004 1/41 0/43 26.5% 0.02[-0.04,0.09]

Subtotal (95% CI) 160 157 100% 0.02[-0.03,0.06]

Total events: 8 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.05, df=1(P=0.82); I2=0%

Test for overall effect: Z=0.76(P=0.45)

Total (95% CI) 160 157 100% 0.02[-0.03,0.06]

Total events: 8 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.05, df=1(P=0.82); I2=0%

Test for overall effect: Z=0.76(P=0.45)

Test for subgroup differences: Not applicable

Favours treatment 0.20.1-0.2 -0.1 0 Favours control

Analysis 19.10. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 10 Abstracts excluded.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.10.1 Parenteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.10.2 Parenteral nutrition - surgical trials

Fan 1994 1/64 0/60 25.59% 0.02[-0.03,0.06]

Subtotal (95% CI) 64 60 25.59% 0.02[-0.03,0.06]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.71(P=0.48)

19.10.3 Enteral nutrition - medical trials

Cabre 1990 1/16 4/19 7.18% -0.15[-0.37,0.07]

Favours treatment 10.5-1 -0.5 0 Favours control

276

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Calvey 1985 11/42 2/22 11.93% 0.17[-0.01,0.35]

DeLedinghen 1997 4/12 1/10 4.51% 0.23[-0.09,0.56]

Subtotal (95% CI) 70 51 23.62% 0.09[-0.04,0.21]

Total events: 16 (Treatment), 7 (Control)

Heterogeneity: Tau2=0; Chi2=6.07, df=2(P=0.05); I2=67.03%

Test for overall effect: Z=1.31(P=0.19)

19.10.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.10.5 Supplements - medical trials

Hirsch 1993 10/26 11/25 10.53% -0.06[-0.33,0.21]

Nakaya 2007 0/19 0/19 7.85% 0[-0.1,0.1]

Poon 2004 1/41 0/43 17.35% 0.02[-0.04,0.09]

Tangkijvanich 2000 0/14 0/15 5.98% 0[-0.12,0.12]

Subtotal (95% CI) 100 102 41.72% -0[-0.08,0.07]

Total events: 11 (Treatment), 11 (Control)

Heterogeneity: Tau2=0; Chi2=0.89, df=3(P=0.83); I2=0%

Test for overall effect: Z=0.1(P=0.92)

19.10.6 Supplements - surgical trials

Meng 1999 1/21 1/23 9.07% 0[-0.12,0.13]

Subtotal (95% CI) 21 23 9.07% 0[-0.12,0.13]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 255 236 100% 0.02[-0.02,0.07]

Total events: 29 (Treatment), 19 (Control)

Heterogeneity: Tau2=0; Chi2=7.47, df=8(P=0.49); I2=0%

Test for overall effect: Z=0.96(P=0.34)

Test for subgroup differences: Chi2=1.42, df=1 (P=0.7), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 19.11. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 11 Surgical trials without transplant patients (no trials with transplant patients).

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.11.1 Parenteral nutrition

Fan 1994 1/64 0/60 73.83% 0.02[-0.03,0.06]

Subtotal (95% CI) 64 60 73.83% 0.02[-0.03,0.06]

Total events: 1 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.71(P=0.48)

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

277

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.11.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.11.3 Supplements

Meng 1999 1/21 1/23 26.17% 0[-0.12,0.13]

Subtotal (95% CI) 21 23 26.17% 0[-0.12,0.13]

Total events: 1 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.07(P=0.95)

Total (95% CI) 85 83 100% 0.01[-0.03,0.06]

Total events: 2 (Treatment), 1 (Control)

Heterogeneity: Tau2=0; Chi2=0.04, df=1(P=0.85); I2=0%

Test for overall effect: Z=0.54(P=0.59)

Test for subgroup differences: Chi2=0.03, df=1 (P=0.86), I2=0%

Favours experimental 0.50.25-0.5 -0.25 0 Favours control

Analysis 19.12. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 12 Intent to treat - best-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.12.1 Parenteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.12.2 Parenteral nutrition - surgical trials

Fan 1994 1/75 15/75 18.05% -0.19[-0.28,-0.09]

Subtotal (95% CI) 75 75 18.05% -0.19[-0.28,-0.09]

Total events: 1 (Treatment), 15 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=3.88(P=0)

19.12.3 Enteral nutrition - medical trials

Cabre 1990 1/16 4/19 4.18% -0.15[-0.37,0.07]

Calvey 1985 11/42 2/22 6.95% 0.17[-0.01,0.35]

DeLedinghen 1997 4/12 1/10 2.62% 0.23[-0.09,0.56]

Norman 2008 8/31 9/32 7.58% -0.02[-0.24,0.2]

Subtotal (95% CI) 101 83 21.33% 0.05[-0.07,0.16]

Total events: 24 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=6.56, df=3(P=0.09); I2=54.27%

Test for overall effect: Z=0.81(P=0.42)

19.12.4 Enteral nutrition - surgical trials

Favours experimental 10.5-1 -0.5 0 Favours control

278

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.12.5 Supplements - medical trials

Hirsch 1993 10/32 19/33 7.82% -0.26[-0.5,-0.03]

Kobashi 2006 7/119 5/114 28.02% 0.01[-0.04,0.07]

Nakaya 2007 0/19 0/19 4.57% 0[-0.1,0.1]

Poon 2004 1/44 2/44 10.59% -0.02[-0.1,0.05]

Tangkijvanich 2000 0/15 0/15 3.61% 0[-0.12,0.12]

Subtotal (95% CI) 229 225 54.61% -0.03[-0.08,0.01]

Total events: 18 (Treatment), 26 (Control)

Heterogeneity: Tau2=0; Chi2=7.53, df=4(P=0.11); I2=46.87%

Test for overall effect: Z=1.4(P=0.16)

19.12.6 Supplements - surgical trials

Meng 1999 1/25 3/25 6.02% -0.08[-0.23,0.07]

Subtotal (95% CI) 25 25 6.02% -0.08[-0.23,0.07]

Total events: 1 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.05(P=0.29)

Total (95% CI) 430 408 100% -0.05[-0.09,-0.01]

Total events: 44 (Treatment), 60 (Control)

Heterogeneity: Tau2=0; Chi2=27.89, df=10(P=0); I2=64.14%

Test for overall effect: Z=2.28(P=0.02)

Test for subgroup differences: Chi2=11.43, df=1 (P=0.01), I2=73.74%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 19.13. Comparison 19 Appearance gastrointestinal bleeding - absolute risk di<erence (ARD), Outcome 13 Intent-to-treat - worst-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

19.13.1 Parenteral nutrition - medical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.13.2 Parenteral nutrition - surgical trials

Fan 1994 12/75 0/75 18.05% 0.16[0.07,0.25]

Subtotal (95% CI) 75 75 18.05% 0.16[0.07,0.25]

Total events: 12 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=3.68(P=0)

19.13.3 Enteral nutrition - medical trials

Favours experimental 10.5-1 -0.5 0 Favours control

279

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 1/16 4/19 4.18% -0.15[-0.37,0.07]

Calvey 1985 11/42 2/22 6.95% 0.17[-0.01,0.35]

DeLedinghen 1997 4/12 1/10 2.62% 0.23[-0.09,0.56]

Norman 2008 9/31 6/32 7.58% 0.1[-0.11,0.31]

Subtotal (95% CI) 101 83 21.33% 0.09[-0.02,0.2]

Total events: 25 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=6.12, df=3(P=0.11); I2=51.02%

Test for overall effect: Z=1.62(P=0.11)

19.13.4 Enteral nutrition - surgical trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

19.13.5 Supplements - medical trials

Hirsch 1993 16/32 11/33 7.82% 0.17[-0.07,0.4]

Kobashi 2006 7/119 5/114 28.02% 0.01[-0.04,0.07]

Nakaya 2007 0/19 0/19 4.57% 0[-0.1,0.1]

Poon 2004 4/44 0/44 10.59% 0.09[-0,0.18]

Tangkijvanich 2000 1/15 0/15 3.61% 0.07[-0.1,0.23]

Subtotal (95% CI) 229 225 54.61% 0.05[0,0.1]

Total events: 28 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=4.49, df=4(P=0.34); I2=10.93%

Test for overall effect: Z=2.08(P=0.04)

19.13.6 Supplements - surgical trials

Meng 1999 5/25 1/25 6.02% 0.16[-0.01,0.33]

Subtotal (95% CI) 25 25 6.02% 0.16[-0.01,0.33]

Total events: 5 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.8(P=0.07)

Total (95% CI) 430 408 100% 0.09[0.05,0.13]

Total events: 70 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=19.47, df=10(P=0.03); I2=48.63%

Test for overall effect: Z=4.19(P<0.0001)

Test for subgroup differences: Chi2=5.18, df=1 (P=0.16), I2=42.12%

Favours experimental 10.5-1 -0.5 0 Favours control

Comparison 20. Appearance of encephalopathy - absolute risk di<erence (ARD)

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 23 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

1.1 All trials 23 1062 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.06, 0.01]

1.2 Standard amino acids 11 339 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.09, 0.05]

280

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1.3 BCAAs 15 772 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.07, 0.01]

2 Parenteral nutrition - all trials 5 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

2.1 All trials 5 231 Risk Difference (M-H, Fixed, 95% CI) -0.05 [-0.13, 0.02]

2.2 Standard amino acids 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

2.3 BCAAs 2 144 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.12, 0.05]

3 Parenteral nutrition - medical trials 3 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

3.1 All trials 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

3.2 Standard amino acids 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

3.3 BCAAs 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Parenteral nutrition - surgical trials 2 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

4.1 A;ll trials 2 144 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.12, 0.05]

4.2 Standard amino acids 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

4.3 BCAAs 2 144 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.12, 0.05]

5 Enteral nutrition - all studies 4 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

5.1 All trials 4 102 Risk Difference (M-H, Fixed, 95% CI) 0.10 [-0.04, 0.25]

5.2 Standard amino acids 4 91 Risk Difference (M-H, Fixed, 95% CI) 0.08 [-0.07, 0.24]

5.3 BCAAs 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

6 Enteral nutrition - medical trials 4 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

6.1 All studies 4 102 Risk Difference (M-H, Fixed, 95% CI) 0.04 [-0.10, 0.18]

6.2 Standard amino acids 4 91 Risk Difference (M-H, Fixed, 95% CI) 0.08 [-0.07, 0.24]

6.3 BCAAs 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

7 Enteral nutrition - surgical trials 0 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

7.1 All trials 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

7.2 Standard amino acids 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

7.3 BCAAs 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

8 Supplements 14 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

8.1 All trials 14 734 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.07, 0.01]

281

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

8.2 Standard amino acids -medical trials

4 170 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.13, 0.05]

8.3 BCAAs - medical trials 10 536 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.09, 0.01]

8.4 All supplements - medical 12 666 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.08, 0.01]

8.5 All surgical 2 68 Risk Difference (M-H, Fixed, 95% CI) 0.0 [-0.08, 0.08]

9 Medical trials all trials 19 846 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.07, 0.02]

9.1 Parenteral nutrition 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

9.2 Enteral nutrition 4 102 Risk Difference (M-H, Fixed, 95% CI) 0.10 [-0.04, 0.25]

9.3 Supplements 12 657 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.08, 0.01]

10 Medical trials - standard amino acids

11 339 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.09, 0.05]

10.1 Parenteral nutrition 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

10.2 Enteral nutrition 4 91 Risk Difference (M-H, Fixed, 95% CI) 0.08 [-0.07, 0.24]

10.3 Supplements 4 161 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.13, 0.06]

11 Medical trials - BCAAs 11 560 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.08, 0.02]

11.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

11.2 Enteral nutrition 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

11.3 Supplements 10 536 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.09, 0.01]

12 Surgical trials - all studies 4 212 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.09, 0.04]

12.1 Parenteral nutrition 2 144 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.12, 0.05]

12.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

12.3 Supplements 2 68 Risk Difference (M-H, Fixed, 95% CI) 0.0 [-0.08, 0.08]

13 Surgical trials - standard amino acids

0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

14 Surgical trials - BCAAs 4 212 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.09, 0.04]

282

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

14.1 Parenteral nutrition 2 144 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.12, 0.05]

14.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

14.3 Supplements 2 68 Risk Difference (M-H, Fixed, 95% CI) 0.0 [-0.08, 0.08]

15 Alcoholic hepatitis - all studies 6 172 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.07, 0.12]

15.1 Parenteral nutrition 2 47 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.25, 0.07]

15.2 Enteral nutrition 2 48 Risk Difference (M-H, Fixed, 95% CI) 0.14 [-0.09, 0.37]

15.3 Supplements 2 77 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.11, 0.16]

16 Alcoholic hepatitis - standard amino acids

6 161 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.09, 0.11]

16.1 Parenteral nutrition 2 47 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.25, 0.07]

16.2 Enteral nutrition 2 37 Risk Difference (M-H, Fixed, 95% CI) 0.11 [-0.15, 0.36]

16.3 Supplements 2 77 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.11, 0.16]

17 Alcoholic hepatitis - BCAA 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

17.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

17.2 Enteral nutrition 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

17.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

18 Cirrhosis - all studies 12 420 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.10, 0.02]

18.1 Parenteral nutrition 1 40 Risk Difference (M-H, Fixed, 95% CI) -0.1 [-0.32, 0.12]

18.2 Enteral nutrition 2 54 Risk Difference (M-H, Fixed, 95% CI) 0.07 [-0.12, 0.26]

18.3 Supplements 9 326 Risk Difference (M-H, Fixed, 95% CI) -0.05 [-0.11, 0.01]

19 Cirrhosis - standard amino acids 6 229 Risk Difference (M-H, Fixed, 95% CI) -0.01 [-0.09, 0.08]

19.1 Parenteral nutrition 1 40 Risk Difference (M-H, Fixed, 95% CI) -0.1 [-0.32, 0.12]

19.2 Enteral nutrition 2 54 Risk Difference (M-H, Fixed, 95% CI) 0.07 [-0.12, 0.26]

19.3 Supplements 3 135 Risk Difference (M-H, Fixed, 95% CI) -0.01 [-0.12, 0.10]

20 Cirrhosis - BCAAs 8 231 Risk Difference (M-H, Fixed, 95% CI) -0.05 [-0.13, 0.02]

20.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

20.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

283

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

20.3 Supplementss 8 231 Risk Difference (M-H, Fixed, 95% CI) -0.05 [-0.13, 0.02]

21 HCC - all studies 2 305 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.09, 0.04]

21.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

21.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

21.3 Supplements 2 305 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.09, 0.04]

22 HCC - standard amino acids 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

22.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

22.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

22.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

23 HCC - BCAAs 2 305 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.09, 0.04]

23.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

23.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

23.3 Supplements 2 305 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.09, 0.04]

24 Abstracts excluded 18 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

24.1 All trials 18 659 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.06, 0.02]

24.2 Standard amino acids 7 201 Risk Difference (M-H, Fixed, 95% CI) -0.01 [-0.10, 0.08]

24.3 BCAAs 12 471 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.06, 0.02]

24.4 Parenteral nutrition all 5 231 Risk Difference (M-H, Fixed, 95% CI) -0.05 [-0.13, 0.02]

24.5 Parenteral nutrition SAAs 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

24.6 Parenteral nutrition BCAAs 2 144 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.12, 0.05]

24.7 Enteral nutrition all 2 48 Risk Difference (M-H, Fixed, 95% CI) 0.14 [-0.09, 0.37]

24.8 Enteral nutrition SAAs 2 37 Risk Difference (M-H, Fixed, 95% CI) 0.11 [-0.15, 0.36]

24.9 Enteral nutrition BCAAs 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

24.10 Supplements all 11 380 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.07, 0.03]

24.11 Supplements - SAAs 2 77 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.11, 0.16]

24.12 Supplements - BCAAs 9 303 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.08, 0.02]

284

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

25 Surgical trials - transplant trials eliminated

3 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

25.1 All trials 3 192 Risk Difference (M-H, Fixed, 95% CI) -0.00 [-0.07, 0.06]

25.2 Standard amino acids 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

25.3 BCAAs 3 192 Risk Difference (M-H, Fixed, 95% CI) -0.00 [-0.07, 0.06]

26 ITT - Parenteral nutrition - best- case scenario for intervention

5 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

26.1 All trials 5 257 Risk Difference (M-H, Fixed, 95% CI) -0.16 [-0.25, -0.08]

26.2 Standard amino acids 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

26.3 BCAAs 2 170 Risk Difference (M-H, Fixed, 95% CI) -0.2 [-0.30, -0.10]

27 ITT - Parenteral nutrition - worst- case scenario for intervention

5 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

27.1 All trials 5 257 Risk Difference (M-H, Fixed, 95% CI) 0.04 [-0.04, 0.12]

27.2 Standard amino acids 3 87 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.23, 0.04]

27.3 BCAAs 2 170 Risk Difference (M-H, Fixed, 95% CI) 0.11 [0.01, 0.20]

28 ITT - Enteral nutrition - best-case scenario for intervention

4 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

28.1 All trials 4 112 Risk Difference (M-H, Fixed, 95% CI) 0.03 [-0.11, 0.17]

28.2 Standard amino acids 4 101 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.13, 0.16]

28.3 BCAAs 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

29 ITT - Enteral nutrition - worst-case scenario for intervention

4 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

29.1 Standard amino acids 4 112 Risk Difference (M-H, Fixed, 95% CI) 0.21 [0.07, 0.35]

29.2 BCAAs 1 24 Risk Difference (M-H, Fixed, 95% CI) 0.21 [-0.14, 0.56]

29.3 All trials 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

30 ITT- Supplements - best-case sce- nario for intervention

14 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

30.1 All trials 14 782 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.12, -0.03]

30.2 Standard amino acids -medical trials

4 191 Risk Difference (M-H, Fixed, 95% CI) -0.15 [-0.25, -0.06]

285

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

30.3 BCAAs - medical trials 10 559 Risk Difference (M-H, Fixed, 95% CI) -0.06 [-0.11, -0.02]

30.4 All supplements - medical 12 707 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.12, -0.03]

30.5 All surgical 2 74 Risk Difference (M-H, Fixed, 95% CI) -0.05 [-0.16, 0.05]

31 ITT - Supplements - worst-case scenario for intervention

14 Risk Difference (M-H, Fixed, 95% CI) Subtotals only

31.1 All trials 14 781 Risk Difference (M-H, Fixed, 95% CI) 0.03 [-0.02, 0.07]

31.2 Standard amino acids -medical trials

4 191 Risk Difference (M-H, Fixed, 95% CI) 0.07 [-0.03, 0.16]

31.3 BCAAs - medical trials 10 559 Risk Difference (M-H, Fixed, 95% CI) 0.00 [-0.05, 0.05]

31.4 All supplements - medical 12 707 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.03, 0.07]

31.5 All surgical 2 74 Risk Difference (M-H, Fixed, 95% CI) 0.11 [-0.01, 0.23]

Analysis 20.1. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 1 All studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.1.1 All trials

Achord 1987 0/12 0/10 2.11% 0[-0.16,0.16]

Bunout 1989 1/14 0/12 2.49% 0.07[-0.11,0.26]

Calvey 1985 7/21 2/13 3.1% 0.18[-0.1,0.46]

Fan 1994 4/64 4/60 11.95% -0[-0.09,0.08]

Guy 1995 4/14 3/18 3.04% 0.12[-0.17,0.41]

Hasse 1997 5/23 3/6 1.84% -0.28[-0.72,0.15]

Hayashi 1991 0/2 0/6 0.58% 0[-0.46,0.46]

Hirsch 1993 3/26 3/25 4.92% -0[-0.18,0.17]

Humbert 1988 24/27 22/22 4.68% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 1.99% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 2.3% 0[-0.15,0.15]

Kearns 1992 1/6 1/8 1.32% 0.04[-0.33,0.42]

Kobashi 2006 12/108 16/113 21.32% -0.03[-0.12,0.06]

Meng 1999 0/21 0/23 4.24% 0[-0.08,0.08]

Nakaya 2007 0/19 1/19 3.67% -0.05[-0.19,0.08]

Naveau 1986 2/20 4/20 3.86% -0.1[-0.32,0.12]

Poon 2004 0/41 1/43 8.1% -0.02[-0.09,0.04]

Puglionisi 1985 0/10 2/10 1.93% -0.2[-0.48,0.08]

Schuetz 2006 0/11 0/11 2.12% 0[-0.16,0.16]

Sievert 1999 4/61 3/34 8.43% -0.02[-0.14,0.09]

Simko 1983 0/7 0/3 0.81% 0[-0.36,0.36]

Simon 1988 0/13 2/12 2.41% -0.17[-0.4,0.07]

Favours treatment 10.5-1 -0.5 0 Favours control

286

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Tangkijvanich 2000 0/14 0/15 2.8% 0[-0.12,0.12]

Subtotal (95% CI) 557 505 100% -0.02[-0.06,0.01]

Total events: 67 (Treatment), 67 (Control)

Heterogeneity: Tau2=0; Chi2=11.69, df=22(P=0.96); I2=0%

Test for overall effect: Z=1.31(P=0.19)

20.1.2 Standard amino acids

Achord 1987 0/12 0/10 6.53% 0[-0.16,0.16]

Bunout 1989 1/14 0/12 7.74% 0.07[-0.11,0.26]

Calvey 1985 3/10 2/13 6.77% 0.15[-0.2,0.49]

Guy 1995 4/14 3/18 9.43% 0.12[-0.17,0.41]

Hasse 1997 4/14 3/6 5.03% -0.21[-0.68,0.25]

Hirsch 1993 3/26 3/25 15.26% -0[-0.18,0.17]

Kearns 1992 1/6 1/8 4.11% 0.04[-0.33,0.42]

Naveau 1986 2/20 4/20 11.98% -0.1[-0.32,0.12]

Schuetz 2006 0/11 0/11 6.59% 0[-0.16,0.16]

Sievert 1999 1/30 3/34 19.09% -0.05[-0.17,0.06]

Simon 1988 0/13 2/12 7.47% -0.17[-0.4,0.07]

Subtotal (95% CI) 170 169 100% -0.02[-0.09,0.05]

Total events: 19 (Treatment), 21 (Control)

Heterogeneity: Tau2=0; Chi2=5.98, df=10(P=0.82); I2=0%

Test for overall effect: Z=0.51(P=0.61)

20.1.3 BCAAs

Calvey 1985 4/11 2/13 3.1% 0.21[-0.14,0.56]

Fan 1994 4/64 4/60 16.13% -0[-0.09,0.08]

Hasse 1997 1/9 3/6 1.88% -0.39[-0.84,0.06]

Hayashi 1991 0/2 0/2 0.52% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 6.31% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 2.68% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 3.1% 0[-0.15,0.15]

Kobashi 2006 12/108 16/113 28.76% -0.03[-0.12,0.06]

Meng 1999 0/21 0/23 5.72% 0[-0.08,0.08]

Nakaya 2007 0/19 1/19 4.95% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 10.93% -0.02[-0.09,0.04]

Puglionisi 1985 0/10 2/10 2.6% -0.2[-0.48,0.08]

Sievert 1999 3/31 3/34 8.45% 0.01[-0.13,0.15]

Simko 1983 0/7 0/3 1.09% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 3.77% 0[-0.12,0.12]

Subtotal (95% CI) 387 385 100% -0.03[-0.07,0.01]

Total events: 48 (Treatment), 54 (Control)

Heterogeneity: Tau2=0; Chi2=8.75, df=14(P=0.85); I2=0%

Test for overall effect: Z=1.34(P=0.18)

Test for subgroup differences: Chi2=0.05, df=1 (P=0.98), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

287

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Analysis 20.2. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 2 Parenteral nutrition - all trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.2.1 All trials

Achord 1987 0/12 0/10 9.46% 0[-0.16,0.16]

Fan 1994 4/64 4/60 53.71% -0[-0.09,0.08]

Naveau 1986 2/20 4/20 17.34% -0.1[-0.32,0.12]

Puglionisi 1985 0/10 2/10 8.67% -0.2[-0.48,0.08]

Simon 1988 0/13 2/12 10.82% -0.17[-0.4,0.07]

Subtotal (95% CI) 119 112 100% -0.05[-0.13,0.02]

Total events: 6 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=3.85, df=4(P=0.43); I2=0%

Test for overall effect: Z=1.47(P=0.14)

20.2.2 Standard amino acids

Achord 1987 0/12 0/10 25.14% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 46.09% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 28.76% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 100% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.2.3 BCAAs

Fan 1994 4/64 4/60 86.1% -0[-0.09,0.08]

Puglionisi 1985 0/10 2/10 13.9% -0.2[-0.48,0.08]

Subtotal (95% CI) 74 70 100% -0.03[-0.12,0.05]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.81, df=1(P=0.18); I2=44.67%

Test for overall effect: Z=0.72(P=0.47)

Test for subgroup differences: Chi2=0.62, df=1 (P=0.74), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.3. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 3 Parenteral nutrition - medical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.3.1 All trials

Achord 1987 0/12 0/10 25.14% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 46.09% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 28.76% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 100% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.3.2 Standard amino acids

Achord 1987 0/12 0/10 25.14% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 46.09% -0.1[-0.32,0.12]

Favours experimental 10.5-1 -0.5 0 Favours control

288

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Simon 1988 0/13 2/12 28.76% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 100% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.3.3 BCAAs

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Chi2=0, df=1 (P=1), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 20.4. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 4 Parenteral nutrition - surgical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.4.1 A;ll trials

Fan 1994 4/64 4/60 86.1% -0[-0.09,0.08]

Puglionisi 1985 0/10 2/10 13.9% -0.2[-0.48,0.08]

Subtotal (95% CI) 74 70 100% -0.03[-0.12,0.05]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.81, df=1(P=0.18); I2=44.67%

Test for overall effect: Z=0.72(P=0.47)

20.4.2 Standard amino acids

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.4.3 BCAAs

Fan 1994 4/64 4/60 86.1% -0[-0.09,0.08]

Puglionisi 1985 0/10 2/10 13.9% -0.2[-0.48,0.08]

Subtotal (95% CI) 74 70 100% -0.03[-0.12,0.05]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.81, df=1(P=0.18); I2=44.67%

Test for overall effect: Z=0.72(P=0.47)

Test for subgroup differences: Not applicable

Favours experimental 10.5-1 -0.5 0 Favours control

289

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Analysis 20.5. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 5 Enteral nutrition - all studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.5.1 All trials

Calvey 1985 7/21 2/13 32.33% 0.18[-0.1,0.46]

Guy 1995 4/14 3/18 31.71% 0.12[-0.17,0.41]

Kearns 1992 1/6 1/8 13.81% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 22.15% 0[-0.16,0.16]

Subtotal (95% CI) 52 50 100% 0.1[-0.04,0.25]

Total events: 12 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.96, df=3(P=0.58); I2=0%

Test for overall effect: Z=1.37(P=0.17)

20.5.2 Standard amino acids

Calvey 1985 3/10 2/13 25.17% 0.15[-0.2,0.49]

Guy 1995 4/14 3/18 35.07% 0.12[-0.17,0.41]

Kearns 1992 1/6 1/8 15.27% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 24.49% 0[-0.16,0.16]

Subtotal (95% CI) 41 50 100% 0.08[-0.07,0.24]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.31, df=3(P=0.73); I2=0%

Test for overall effect: Z=1.09(P=0.27)

20.5.3 BCAAs

Calvey 1985 4/11 2/13 100% 0.21[-0.14,0.56]

Subtotal (95% CI) 11 13 100% 0.21[-0.14,0.56]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

Test for subgroup differences: Chi2=0.42, df=1 (P=0.81), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.6. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 6 Enteral nutrition - medical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.6.1 All studies

Calvey 1985 3/21 2/13 32.33% -0.01[-0.26,0.24]

Guy 1995 4/14 3/18 31.71% 0.12[-0.17,0.41]

Kearns 1992 1/6 1/8 13.81% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 22.15% 0[-0.16,0.16]

Subtotal (95% CI) 52 50 100% 0.04[-0.1,0.18]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=0.68, df=3(P=0.88); I2=0%

Test for overall effect: Z=0.57(P=0.57)

20.6.2 Standard amino acids

Calvey 1985 3/10 2/13 25.17% 0.15[-0.2,0.49]

Guy 1995 4/14 3/18 35.07% 0.12[-0.17,0.41]

Favours experimental 10.5-1 -0.5 0 Favours control

290

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Kearns 1992 1/6 1/8 15.27% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 24.49% 0[-0.16,0.16]

Subtotal (95% CI) 41 50 100% 0.08[-0.07,0.24]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.31, df=3(P=0.73); I2=0%

Test for overall effect: Z=1.09(P=0.27)

20.6.3 BCAAs

Calvey 1985 4/11 2/13 100% 0.21[-0.14,0.56]

Subtotal (95% CI) 11 13 100% 0.21[-0.14,0.56]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

Test for subgroup differences: Chi2=0.84, df=1 (P=0.66), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 20.8. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 8 Supplements.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.8.1 All trials

Bunout 1989 1/14 0/12 3.65% 0.07[-0.11,0.26]

Hasse 1997 5/23 3/6 2.69% -0.28[-0.72,0.15]

Hayashi 1991 0/2 0/2 0.56% 0[-0.6,0.6]

Hirsch 1993 3/26 3/25 7.2% -0[-0.18,0.17]

Humbert 1988 24/27 22/22 6.84% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 2.9% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 3.36% 0[-0.15,0.15]

Kobashi 2006 12/108 16/113 31.18% -0.03[-0.12,0.06]

Meng 1999 0/21 0/23 6.2% 0[-0.08,0.08]

Nakaya 2007 0/19 1/19 5.36% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 11.85% -0.02[-0.09,0.04]

Sievert 1999 4/70 3/34 12.92% -0.03[-0.14,0.08]

Simko 1983 0/7 0/3 1.19% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 4.09% 0[-0.12,0.12]

Subtotal (95% CI) 395 339 100% -0.03[-0.07,0.01]

Total events: 49 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=5.2, df=13(P=0.97); I2=0%

Test for overall effect: Z=1.53(P=0.13)

20.8.2 Standard amino acids -medical trials

Bunout 1989 1/14 0/12 15.54% 0.07[-0.11,0.26]

Hasse 1997 4/14 3/6 10.1% -0.21[-0.68,0.25]

Hirsch 1993 3/26 3/25 30.66% -0[-0.18,0.17]

Sievert 1999 1/39 3/34 43.69% -0.06[-0.17,0.04]

Subtotal (95% CI) 93 77 100% -0.04[-0.13,0.05]

Total events: 9 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=2.26, df=3(P=0.52); I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

291

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for overall effect: Z=0.85(P=0.4)

20.8.3 BCAAs - medical trials

Hasse 1997 1/9 3/6 2.7% -0.39[-0.84,0.06]

Hayashi 1991 0/2 0/2 0.75% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 9.11% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.86% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 41.48% -0.03[-0.12,0.06]

Nakaya 2007 0/19 1/19 7.14% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 15.76% -0.02[-0.09,0.04]

Sievert 1999 3/31 3/34 12.18% 0.01[-0.13,0.15]

Simko 1983 0/7 0/3 1.58% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 5.44% 0[-0.12,0.12]

Subtotal (95% CI) 270 266 100% -0.04[-0.09,0.01]

Total events: 40 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=4.82, df=9(P=0.85); I2=0%

Test for overall effect: Z=1.61(P=0.11)

20.8.4 All supplements - medical

Bunout 1989 1/14 0/12 4.03% 0.07[-0.11,0.26]

Hasse 1997 5/23 3/6 2.97% -0.28[-0.72,0.15]

Hayashi 1991 0/2 0/2 0.62% 0[-0.6,0.6]

Hirsch 1993 3/26 3/25 7.96% -0[-0.18,0.17]

Humbert 1988 24/27 22/22 7.57% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.21% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 34.48% -0.03[-0.12,0.06]

Nakaya 2007 0/19 1/19 5.93% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 13.1% -0.02[-0.09,0.04]

Sievert 1999 4/70 3/34 14.29% -0.03[-0.14,0.08]

Simko 1983 0/7 0/3 1.31% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 4.52% 0[-0.12,0.12]

Subtotal (95% CI) 363 303 100% -0.04[-0.08,0.01]

Total events: 49 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=4.59, df=11(P=0.95); I2=0%

Test for overall effect: Z=1.56(P=0.12)

20.8.5 All surgical

Ishikawa 2010 0/11 0/13 35.18% 0[-0.15,0.15]

Meng 1999 0/21 0/23 64.82% 0[-0.08,0.08]

Subtotal (95% CI) 32 36 100% 0[-0.08,0.08]

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Not applicable

Test for subgroup differences: Chi2=0.75, df=1 (P=0.95), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

292

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Analysis 20.9. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 9 Medical trials all trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.9.1 Parenteral nutrition

Achord 1987 0/12 0/10 2.65% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 4.86% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 3.03% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 10.55% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.9.2 Enteral nutrition

Calvey 1985 7/21 2/13 3.9% 0.18[-0.1,0.46]

Guy 1995 4/14 3/18 3.83% 0.12[-0.17,0.41]

Kearns 1992 1/6 1/8 1.67% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 2.67% 0[-0.16,0.16]

Subtotal (95% CI) 52 50 12.08% 0.1[-0.04,0.25]

Total events: 12 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.96, df=3(P=0.58); I2=0%

Test for overall effect: Z=1.37(P=0.17)

20.9.3 Supplements

Bunout 1989 1/14 0/12 3.14% 0.07[-0.11,0.26]

Hasse 1997 5/23 3/6 2.31% -0.28[-0.72,0.15]

Hayashi 1991 0/2 0/2 0.49% 0[-0.6,0.6]

Hirsch 1993 3/26 3/25 6.2% -0[-0.18,0.17]

Humbert 1988 24/27 22/22 5.89% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 2.5% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 26.85% -0.03[-0.12,0.06]

Nakaya 2007 0/19 1/19 4.62% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 10.21% -0.02[-0.09,0.04]

Sievert 1999 4/61 3/34 10.62% -0.02[-0.14,0.09]

Simko 1983 0/7 0/3 1.02% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 3.52% 0[-0.12,0.12]

Subtotal (95% CI) 354 303 77.37% -0.03[-0.08,0.01]

Total events: 49 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=4.58, df=11(P=0.95); I2=0%

Test for overall effect: Z=1.5(P=0.13)

Total (95% CI) 451 395 100% -0.02[-0.07,0.02]

Total events: 63 (Treatment), 61 (Control)

Heterogeneity: Tau2=0; Chi2=9.54, df=18(P=0.95); I2=0%

Test for overall effect: Z=1.15(P=0.25)

Test for subgroup differences: Chi2=4.09, df=1 (P=0.13), I2=51.07%

Favours treatment 10.5-1 -0.5 0 Favours control

293

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Analysis 20.10. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 10 Medical trials - standard amino acids.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.10.1 Parenteral nutrition

Achord 1987 0/12 0/10 6.53% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 11.98% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 7.47% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 25.98% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.10.2 Enteral nutrition

Calvey 1985 3/10 2/13 6.77% 0.15[-0.2,0.49]

Guy 1995 4/14 3/18 9.43% 0.12[-0.17,0.41]

Kearns 1992 1/6 1/8 4.11% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 6.59% 0[-0.16,0.16]

Subtotal (95% CI) 41 50 26.89% 0.08[-0.07,0.24]

Total events: 8 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.31, df=3(P=0.73); I2=0%

Test for overall effect: Z=1.09(P=0.27)

20.10.3 Supplements

Bunout 1989 1/14 0/12 7.74% 0.07[-0.11,0.26]

Hasse 1997 4/14 3/6 5.03% -0.21[-0.68,0.25]

Hirsch 1993 3/26 3/25 15.26% -0[-0.18,0.17]

Sievert 1999 1/30 3/34 19.09% -0.05[-0.17,0.06]

Subtotal (95% CI) 84 77 47.12% -0.03[-0.13,0.06]

Total events: 9 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=2.08, df=3(P=0.56); I2=0%

Test for overall effect: Z=0.72(P=0.47)

Total (95% CI) 170 169 100% -0.02[-0.09,0.05]

Total events: 19 (Treatment), 21 (Control)

Heterogeneity: Tau2=0; Chi2=5.98, df=10(P=0.82); I2=0%

Test for overall effect: Z=0.51(P=0.61)

Test for subgroup differences: Chi2=3.08, df=1 (P=0.21), I2=35.17%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.11. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 11 Medical trials - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.11.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours treatment 10.5-1 -0.5 0 Favours control

294

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.11.2 Enteral nutrition

Calvey 1985 4/11 2/13 4.28% 0.21[-0.14,0.56]

Subtotal (95% CI) 11 13 4.28% 0.21[-0.14,0.56]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

20.11.3 Supplements

Hasse 1997 1/9 3/6 2.59% -0.39[-0.84,0.06]

Hayashi 1991 0/2 0/2 0.72% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 8.72% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.7% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 39.7% -0.03[-0.12,0.06]

Nakaya 2007 0/19 1/19 6.83% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 15.09% -0.02[-0.09,0.04]

Sievert 1999 3/31 3/34 11.66% 0.01[-0.13,0.15]

Simko 1983 0/7 0/3 1.51% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 5.21% 0[-0.12,0.12]

Subtotal (95% CI) 270 266 95.72% -0.04[-0.09,0.01]

Total events: 40 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=4.82, df=9(P=0.85); I2=0%

Test for overall effect: Z=1.61(P=0.11)

Total (95% CI) 281 279 100% -0.03[-0.08,0.02]

Total events: 44 (Treatment), 48 (Control)

Heterogeneity: Tau2=0; Chi2=6.47, df=10(P=0.77); I2=0%

Test for overall effect: Z=1.17(P=0.24)

Test for subgroup differences: Chi2=1.97, df=1 (P=0.16), I2=49.12%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.12. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 12 Surgical trials - all studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.12.1 Parenteral nutrition

Fan 1994 4/64 4/60 58.54% -0[-0.09,0.08]

Puglionisi 1985 0/10 2/10 9.45% -0.2[-0.48,0.08]

Subtotal (95% CI) 74 70 67.99% -0.03[-0.12,0.05]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.81, df=1(P=0.18); I2=44.67%

Test for overall effect: Z=0.72(P=0.47)

20.12.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours treatment 10.5-1 -0.5 0 Favours control

295

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.12.3 Supplements

Ishikawa 2010 0/11 0/13 11.26% 0[-0.15,0.15]

Meng 1999 0/21 0/23 20.75% 0[-0.08,0.08]

Subtotal (95% CI) 32 36 32.01% 0[-0.08,0.08]

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Not applicable

Total (95% CI) 106 106 100% -0.02[-0.09,0.04]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=2.08, df=3(P=0.56); I2=0%

Test for overall effect: Z=0.66(P=0.51)

Test for subgroup differences: Chi2=0.27, df=1 (P=0.6), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.14. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 14 Surgical trials - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.14.1 Parenteral nutrition

Fan 1994 4/64 4/60 58.54% -0[-0.09,0.08]

Puglionisi 1985 0/10 2/10 9.45% -0.2[-0.48,0.08]

Subtotal (95% CI) 74 70 67.99% -0.03[-0.12,0.05]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.81, df=1(P=0.18); I2=44.67%

Test for overall effect: Z=0.72(P=0.47)

20.14.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.14.3 Supplements

Ishikawa 2010 0/11 0/13 11.26% 0[-0.15,0.15]

Meng 1999 0/21 0/23 20.75% 0[-0.08,0.08]

Subtotal (95% CI) 32 36 32.01% 0[-0.08,0.08]

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Not applicable

Total (95% CI) 106 106 100% -0.02[-0.09,0.04]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=2.08, df=3(P=0.56); I2=0%

Test for overall effect: Z=0.66(P=0.51)

Test for subgroup differences: Chi2=0.27, df=1 (P=0.6), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

296

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Analysis 20.15. Comparison 20 Appearance of encephalopathy - absolute

risk di<erence (ARD), Outcome 15 Alcoholic hepatitis - all studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.15.1 Parenteral nutrition

Achord 1987 0/12 0/10 12.88% 0[-0.16,0.16]

Simon 1988 0/13 2/12 14.73% -0.17[-0.4,0.07]

Subtotal (95% CI) 25 22 27.61% -0.09[-0.25,0.07]

Total events: 0 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=1.58, df=1(P=0.21); I2=36.88%

Test for overall effect: Z=1.1(P=0.27)

20.15.2 Enteral nutrition

Calvey 1985 7/21 2/13 18.96% 0.18[-0.1,0.46]

Kearns 1992 1/6 1/8 8.09% 0.04[-0.33,0.42]

Subtotal (95% CI) 27 21 27.05% 0.14[-0.09,0.37]

Total events: 8 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.34, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.19(P=0.23)

20.15.3 Supplements

Bunout 1989 1/14 0/12 15.25% 0.07[-0.11,0.26]

Hirsch 1993 3/26 3/25 30.09% -0[-0.18,0.17]

Subtotal (95% CI) 40 37 45.34% 0.02[-0.11,0.16]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.37, df=1(P=0.54); I2=0%

Test for overall effect: Z=0.3(P=0.76)

Total (95% CI) 92 80 100% 0.02[-0.07,0.12]

Total events: 12 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=4.12, df=5(P=0.53); I2=0%

Test for overall effect: Z=0.45(P=0.65)

Test for subgroup differences: Chi2=2.72, df=1 (P=0.26), I2=26.53%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 20.16. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 16 Alcoholic hepatitis - standard amino acids.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.16.1 Parenteral nutrition

Achord 1987 0/12 0/10 13.64% 0[-0.16,0.16]

Simon 1988 0/13 2/12 15.61% -0.17[-0.4,0.07]

Subtotal (95% CI) 25 22 29.25% -0.09[-0.25,0.07]

Total events: 0 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=1.58, df=1(P=0.21); I2=36.88%

Test for overall effect: Z=1.1(P=0.27)

20.16.2 Enteral nutrition

Calvey 1985 3/10 2/13 14.14% 0.15[-0.2,0.49]

Favours treatment 10.5-1 -0.5 0 Favours control

297

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Kearns 1992 1/6 1/8 8.58% 0.04[-0.33,0.42]

Subtotal (95% CI) 16 21 22.71% 0.11[-0.15,0.36]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.17, df=1(P=0.68); I2=0%

Test for overall effect: Z=0.81(P=0.42)

20.16.3 Supplements

Bunout 1989 1/14 0/12 16.16% 0.07[-0.11,0.26]

Hirsch 1993 3/26 3/25 31.88% -0[-0.18,0.17]

Subtotal (95% CI) 40 37 48.04% 0.02[-0.11,0.16]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.37, df=1(P=0.54); I2=0%

Test for overall effect: Z=0.3(P=0.76)

Total (95% CI) 81 80 100% 0.01[-0.09,0.11]

Total events: 8 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=3.25, df=5(P=0.66); I2=0%

Test for overall effect: Z=0.16(P=0.87)

Test for subgroup differences: Chi2=1.94, df=1 (P=0.38), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.17. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 17 Alcoholic hepatitis - BCAA.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.17.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.17.2 Enteral nutrition

Calvey 1985 4/11 2/13 100% 0.21[-0.14,0.56]

Subtotal (95% CI) 11 13 100% 0.21[-0.14,0.56]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

20.17.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 11 13 100% 0.21[-0.14,0.56]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

Favours treatment 10.5-1 -0.5 0 Favours control

298

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Test for subgroup differences: Not applicable

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.18. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 18 Cirrhosis - all studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.18.1 Parenteral nutrition

Naveau 1986 2/20 4/20 10.02% -0.1[-0.32,0.12]

Subtotal (95% CI) 20 20 10.02% -0.1[-0.32,0.12]

Total events: 2 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.89(P=0.37)

20.18.2 Enteral nutrition

Guy 1995 4/14 3/18 7.89% 0.12[-0.17,0.41]

Schuetz 2006 0/11 0/11 5.51% 0[-0.16,0.16]

Subtotal (95% CI) 25 29 13.4% 0.07[-0.12,0.26]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.85, df=1(P=0.36); I2=0%

Test for overall effect: Z=0.74(P=0.46)

20.18.3 Supplements

Hasse 1997 5/23 3/6 4.77% -0.28[-0.72,0.15]

Hayashi 1991 0/2 0/2 1% 0[-0.6,0.6]

Hirsch 1993 3/26 3/25 12.77% -0[-0.18,0.17]

Humbert 1988 24/27 22/22 12.14% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 5.15% 0[-0.17,0.17]

Nakaya 2007 0/19 1/19 9.52% -0.05[-0.19,0.08]

Sievert 1999 4/61 3/34 21.87% -0.02[-0.14,0.09]

Simko 1983 0/7 0/3 2.1% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 7.25% 0[-0.12,0.12]

Subtotal (95% CI) 191 135 76.58% -0.05[-0.11,0.01]

Total events: 36 (Treatment), 32 (Control)

Heterogeneity: Tau2=0; Chi2=3.37, df=8(P=0.91); I2=0%

Test for overall effect: Z=1.5(P=0.13)

Total (95% CI) 236 184 100% -0.04[-0.1,0.02]

Total events: 42 (Treatment), 39 (Control)

Heterogeneity: Tau2=0; Chi2=4.82, df=11(P=0.94); I2=0%

Test for overall effect: Z=1.26(P=0.21)

Test for subgroup differences: Chi2=1.7, df=1 (P=0.43), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

299

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Analysis 20.19. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 19 Cirrhosis - standard amino acids.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.19.1 Parenteral nutrition

Naveau 1986 2/20 4/20 17.78% -0.1[-0.32,0.12]

Subtotal (95% CI) 20 20 17.78% -0.1[-0.32,0.12]

Total events: 2 (Treatment), 4 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.89(P=0.37)

20.19.2 Enteral nutrition

Guy 1995 4/14 3/18 14% 0.12[-0.17,0.41]

Schuetz 2006 0/11 0/11 9.78% 0[-0.16,0.16]

Subtotal (95% CI) 25 29 23.77% 0.07[-0.12,0.26]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.85, df=1(P=0.36); I2=0%

Test for overall effect: Z=0.74(P=0.46)

20.19.3 Supplements

Hasse 1997 9/14 3/6 7.47% 0.14[-0.33,0.62]

Hirsch 1993 3/26 3/25 22.65% -0[-0.18,0.17]

Sievert 1999 1/30 3/34 28.33% -0.05[-0.17,0.06]

Subtotal (95% CI) 70 65 58.45% -0.01[-0.12,0.1]

Total events: 13 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=0.99, df=2(P=0.61); I2=0%

Test for overall effect: Z=0.19(P=0.85)

Total (95% CI) 115 114 100% -0.01[-0.09,0.08]

Total events: 19 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=2.47, df=5(P=0.78); I2=0%

Test for overall effect: Z=0.16(P=0.87)

Test for subgroup differences: Chi2=1.35, df=1 (P=0.51), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.20. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 20 Cirrhosis - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.20.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.20.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Favours treatment 10.5-1 -0.5 0 Favours control

300

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.20.3 Supplementss

Hasse 1997 1/9 3/6 6.32% -0.39[-0.84,0.06]

Hayashi 1991 0/2 0/2 1.76% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 21.3% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 9.03% 0[-0.17,0.17]

Nakaya 2007 0/19 1/19 16.69% -0.05[-0.19,0.08]

Sievert 1999 3/31 3/34 28.49% 0.01[-0.13,0.15]

Simko 1983 0/7 0/3 3.69% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 12.72% 0[-0.12,0.12]

Subtotal (95% CI) 121 110 100% -0.05[-0.13,0.02]

Total events: 28 (Treatment), 29 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=7(P=0.68); I2=0%

Test for overall effect: Z=1.51(P=0.13)

Total (95% CI) 121 110 100% -0.05[-0.13,0.02]

Total events: 28 (Treatment), 29 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=7(P=0.68); I2=0%

Test for overall effect: Z=1.51(P=0.13)

Test for subgroup differences: Not applicable

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.21. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 21 HCC - all studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.21.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.21.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.21.3 Supplements

Kobashi 2006 12/108 16/113 72.46% -0.03[-0.12,0.06]

Poon 2004 0/41 1/43 27.54% -0.02[-0.09,0.04]

Subtotal (95% CI) 149 156 100% -0.03[-0.09,0.04]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.87); I2=0%

Test for overall effect: Z=0.85(P=0.4)

Total (95% CI) 149 156 100% -0.03[-0.09,0.04]

Total events: 12 (Treatment), 17 (Control)

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

301

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.87); I2=0%

Test for overall effect: Z=0.85(P=0.4)

Test for subgroup differences: Not applicable

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

Analysis 20.23. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 23 HCC - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.23.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.23.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.23.3 Supplements

Kobashi 2006 12/108 16/113 72.46% -0.03[-0.12,0.06]

Poon 2004 0/41 1/43 27.54% -0.02[-0.09,0.04]

Subtotal (95% CI) 149 156 100% -0.03[-0.09,0.04]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.87); I2=0%

Test for overall effect: Z=0.85(P=0.4)

Total (95% CI) 149 156 100% -0.03[-0.09,0.04]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.87); I2=0%

Test for overall effect: Z=0.85(P=0.4)

Test for subgroup differences: Not applicable

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

Analysis 20.24. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 24 Abstracts excluded.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.24.1 All trials

Achord 1987 0/12 0/10 3.34% 0[-0.16,0.16]

Bunout 1989 1/14 0/12 3.96% 0.07[-0.11,0.26]

Calvey 1985 7/21 2/13 4.92% 0.18[-0.1,0.46]

Fan 1994 4/64 4/60 18.96% -0[-0.09,0.08]

Favours treatment 10.5-1 -0.5 0 Favours control

302

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hayashi 1991 0/2 0/2 0.61% 0[-0.6,0.6]

Hirsch 1993 3/26 3/25 7.8% -0[-0.18,0.17]

Humbert 1988 24/27 22/22 7.42% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.15% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 3.65% 0[-0.15,0.15]

Kearns 1992 1/6 1/8 2.1% 0.04[-0.33,0.42]

Meng 1999 0/21 0/23 6.72% 0[-0.08,0.08]

Nakaya 2007 0/19 1/19 5.82% -0.05[-0.19,0.08]

Naveau 1986 2/20 4/20 6.12% -0.1[-0.32,0.12]

Poon 2004 0/41 1/43 12.85% -0.02[-0.09,0.04]

Puglionisi 1985 0/10 2/10 3.06% -0.2[-0.48,0.08]

Simko 1983 0/7 0/3 1.29% 0[-0.36,0.36]

Simon 1988 0/13 2/12 3.82% -0.17[-0.4,0.07]

Tangkijvanich 2000 0/14 0/15 4.43% 0[-0.12,0.12]

Subtotal (95% CI) 340 319 100% -0.02[-0.06,0.02]

Total events: 42 (Treatment), 42 (Control)

Heterogeneity: Tau2=0; Chi2=9.25, df=17(P=0.93); I2=0%

Test for overall effect: Z=1.05(P=0.29)

20.24.2 Standard amino acids

Achord 1987 0/12 0/10 10.91% 0[-0.16,0.16]

Bunout 1989 1/14 0/12 12.93% 0.07[-0.11,0.26]

Calvey 1985 3/10 2/13 11.31% 0.15[-0.2,0.49]

Hirsch 1993 3/26 3/25 25.5% -0[-0.18,0.17]

Kearns 1992 1/6 1/8 6.86% 0.04[-0.33,0.42]

Naveau 1986 2/20 4/20 20.01% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 12.48% -0.17[-0.4,0.07]

Subtotal (95% CI) 101 100 100% -0.01[-0.1,0.08]

Total events: 10 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=3.98, df=6(P=0.68); I2=0%

Test for overall effect: Z=0.29(P=0.77)

20.24.3 BCAAs

Calvey 1985 4/11 2/13 5.09% 0.21[-0.14,0.56]

Fan 1994 4/64 4/60 26.48% -0[-0.09,0.08]

Hayashi 1991 0/2 0/2 0.86% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 10.36% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 4.4% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 5.09% 0[-0.15,0.15]

Meng 1999 0/21 0/23 9.39% 0[-0.08,0.08]

Nakaya 2007 0/19 1/19 8.12% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 17.95% -0.02[-0.09,0.04]

Puglionisi 1985 0/10 2/10 4.28% -0.2[-0.48,0.08]

Simko 1983 0/7 0/3 1.8% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 6.19% 0[-0.12,0.12]

Subtotal (95% CI) 239 232 100% -0.02[-0.06,0.02]

Total events: 32 (Treatment), 32 (Control)

Heterogeneity: Tau2=0; Chi2=5.87, df=11(P=0.88); I2=0%

Test for overall effect: Z=0.85(P=0.39)

20.24.4 Parenteral nutrition all

Achord 1987 0/12 0/10 9.46% 0[-0.16,0.16]

Favours treatment 10.5-1 -0.5 0 Favours control

303

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 4/64 4/60 53.71% -0[-0.09,0.08]

Naveau 1986 2/20 4/20 17.34% -0.1[-0.32,0.12]

Puglionisi 1985 0/10 2/10 8.67% -0.2[-0.48,0.08]

Simon 1988 0/13 2/12 10.82% -0.17[-0.4,0.07]

Subtotal (95% CI) 119 112 100% -0.05[-0.13,0.02]

Total events: 6 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=3.85, df=4(P=0.43); I2=0%

Test for overall effect: Z=1.47(P=0.14)

20.24.5 Parenteral nutrition SAAs

Achord 1987 0/12 0/10 25.14% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 46.09% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 28.76% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 100% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.24.6 Parenteral nutrition BCAAs

Fan 1994 4/64 4/60 86.1% -0[-0.09,0.08]

Puglionisi 1985 0/10 2/10 13.9% -0.2[-0.48,0.08]

Subtotal (95% CI) 74 70 100% -0.03[-0.12,0.05]

Total events: 4 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.81, df=1(P=0.18); I2=44.67%

Test for overall effect: Z=0.72(P=0.47)

20.24.7 Enteral nutrition all

Calvey 1985 7/21 2/13 70.08% 0.18[-0.1,0.46]

Kearns 1992 1/6 1/8 29.92% 0.04[-0.33,0.42]

Subtotal (95% CI) 27 21 100% 0.14[-0.09,0.37]

Total events: 8 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.34, df=1(P=0.56); I2=0%

Test for overall effect: Z=1.19(P=0.23)

20.24.8 Enteral nutrition SAAs

Calvey 1985 3/10 2/13 62.24% 0.15[-0.2,0.49]

Kearns 1992 1/6 1/8 37.76% 0.04[-0.33,0.42]

Subtotal (95% CI) 16 21 100% 0.11[-0.15,0.36]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.17, df=1(P=0.68); I2=0%

Test for overall effect: Z=0.81(P=0.42)

20.24.9 Enteral nutrition BCAAs

Calvey 1985 4/11 2/13 100% 0.21[-0.14,0.56]

Subtotal (95% CI) 11 13 100% 0.21[-0.14,0.56]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

20.24.10 Supplements all

Bunout 1989 1/14 0/12 6.86% 0.07[-0.11,0.26]

Hayashi 1991 0/2 0/2 1.06% 0[-0.6,0.6]

Favours treatment 10.5-1 -0.5 0 Favours control

304

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hirsch 1993 3/26 3/25 13.52% -0[-0.18,0.17]

Humbert 1988 24/27 22/22 12.86% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 5.46% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 6.32% 0[-0.15,0.15]

Meng 1999 0/21 0/23 11.65% 0[-0.08,0.08]

Nakaya 2007 0/19 1/19 10.08% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 22.27% -0.02[-0.09,0.04]

Simko 1983 0/7 0/3 2.23% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 7.68% 0[-0.12,0.12]

Subtotal (95% CI) 194 186 100% -0.02[-0.07,0.03]

Total events: 28 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=3.39, df=10(P=0.97); I2=0%

Test for overall effect: Z=0.87(P=0.38)

20.24.11 Supplements - SAAs

Bunout 1989 1/14 0/12 33.64% 0.07[-0.11,0.26]

Hirsch 1993 3/26 3/25 66.36% -0[-0.18,0.17]

Subtotal (95% CI) 40 37 100% 0.02[-0.11,0.16]

Total events: 4 (Treatment), 3 (Control)

Heterogeneity: Tau2=0; Chi2=0.37, df=1(P=0.54); I2=0%

Test for overall effect: Z=0.3(P=0.76)

20.24.12 Supplements - BCAAs

Hayashi 1991 0/2 0/2 1.33% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 16.16% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 6.85% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 7.94% 0[-0.15,0.15]

Meng 1999 0/21 0/23 14.63% 0[-0.08,0.08]

Nakaya 2007 0/19 1/19 12.66% -0.05[-0.19,0.08]

Poon 2004 0/41 1/43 27.97% -0.02[-0.09,0.04]

Simko 1983 0/7 0/3 2.8% 0[-0.36,0.36]

Tangkijvanich 2000 0/14 0/15 9.65% 0[-0.12,0.12]

Subtotal (95% CI) 154 149 100% -0.03[-0.08,0.02]

Total events: 24 (Treatment), 24 (Control)

Heterogeneity: Tau2=0; Chi2=2.58, df=8(P=0.96); I2=0%

Test for overall effect: Z=1.32(P=0.19)

Test for subgroup differences: Chi2=7.16, df=1 (P=0.79), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.25. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 25 Surgical trials - transplant trials eliminated.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.25.1 All trials

Fan 1994 4/64 4/60 64.65% -0[-0.09,0.08]

Ishikawa 2010 0/11 0/13 12.44% 0[-0.15,0.15]

Meng 1999 0/21 0/23 22.92% 0[-0.08,0.08]

Subtotal (95% CI) 96 96 100% -0[-0.07,0.06]

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

305

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 4 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=2(P=1); I2=0%

Test for overall effect: Z=0.08(P=0.93)

20.25.2 Standard amino acids

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

20.25.3 BCAAs

Fan 1994 4/64 4/60 64.65% -0[-0.09,0.08]

Ishikawa 2010 0/11 0/13 12.44% 0[-0.15,0.15]

Meng 1999 0/21 0/23 22.92% 0[-0.08,0.08]

Subtotal (95% CI) 96 96 100% -0[-0.07,0.06]

Total events: 4 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=2(P=1); I2=0%

Test for overall effect: Z=0.08(P=0.93)

Test for subgroup differences: Not applicable

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

Analysis 20.26. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 26 ITT - Parenteral nutrition - best-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.26.1 All trials

Achord 1987 0/12 0/10 8.5% 0[-0.16,0.16]

Fan 1994 4/75 19/75 58.42% -0.2[-0.31,-0.09]

Naveau 1986 2/20 4/20 15.58% -0.1[-0.32,0.12]

Puglionisi 1985 0/10 2/10 7.79% -0.2[-0.48,0.08]

Simon 1988 0/13 2/12 9.72% -0.17[-0.4,0.07]

Subtotal (95% CI) 130 127 100% -0.16[-0.25,-0.08]

Total events: 6 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=4.77, df=4(P=0.31); I2=16.08%

Test for overall effect: Z=3.92(P<0.0001)

20.26.2 Standard amino acids

Achord 1987 0/12 0/10 25.14% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 46.09% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 28.76% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 100% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.26.3 BCAAs

Fan 1994 4/75 19/75 88.24% -0.2[-0.31,-0.09]

Puglionisi 1985 0/10 2/10 11.76% -0.2[-0.48,0.08]

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

306

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 85 85 100% -0.2[-0.3,-0.1]

Total events: 4 (Treatment), 21 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Z=3.77(P=0)

Test for subgroup differences: Chi2=1.53, df=1 (P=0.47), I2=0%

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

Analysis 20.27. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 27 ITT - Parenteral nutrition - worst-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.27.1 All trials

Achord 1987 0/12 0/10 8.5% 0[-0.16,0.16]

Fan 1994 15/75 4/75 58.42% 0.15[0.04,0.25]

Naveau 1986 2/20 4/20 15.58% -0.1[-0.32,0.12]

Puglionisi 1985 0/10 2/10 7.79% -0.2[-0.48,0.08]

Simon 1988 0/13 2/12 9.72% -0.17[-0.4,0.07]

Subtotal (95% CI) 130 127 100% 0.04[-0.04,0.12]

Total events: 17 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=11.7, df=4(P=0.02); I2=65.81%

Test for overall effect: Z=0.95(P=0.34)

20.27.2 Standard amino acids

Achord 1987 0/12 0/10 25.14% 0[-0.16,0.16]

Naveau 1986 2/20 4/20 46.09% -0.1[-0.32,0.12]

Simon 1988 0/13 2/12 28.76% -0.17[-0.4,0.07]

Subtotal (95% CI) 45 42 100% -0.09[-0.23,0.04]

Total events: 2 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=1.67, df=2(P=0.43); I2=0%

Test for overall effect: Z=1.39(P=0.16)

20.27.3 BCAAs

Fan 1994 15/75 4/75 88.24% 0.15[0.04,0.25]

Puglionisi 1985 0/10 2/10 11.76% -0.2[-0.48,0.08]

Subtotal (95% CI) 85 85 100% 0.11[0.01,0.2]

Total events: 15 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=5.29, df=1(P=0.02); I2=81.1%

Test for overall effect: Z=2.11(P=0.03)

Test for subgroup differences: Chi2=5.65, df=1 (P=0.06), I2=64.61%

Favours treatment 0.50.25-0.5 -0.25 0 Favours control

307

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Analysis 20.28. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 28 ITT - Enteral nutrition - best-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.28.1 All trials

Calvey 1985 7/21 2/13 29.27% 0.18[-0.1,0.46]

Guy 1995 4/22 5/20 38.19% -0.07[-0.32,0.18]

Kearns 1992 1/6 1/8 12.5% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 20.05% 0[-0.16,0.16]

Subtotal (95% CI) 60 52 100% 0.03[-0.11,0.17]

Total events: 12 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=1.83, df=3(P=0.61); I2=0%

Test for overall effect: Z=0.45(P=0.65)

20.28.2 Standard amino acids

Calvey 1985 3/10 2/13 22.56% 0.15[-0.2,0.49]

Guy 1995 4/22 5/20 41.81% -0.07[-0.32,0.18]

Kearns 1992 1/6 1/8 13.68% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 21.95% 0[-0.16,0.16]

Subtotal (95% CI) 49 52 100% 0.01[-0.13,0.16]

Total events: 8 (Treatment), 8 (Control)

Heterogeneity: Tau2=0; Chi2=1.02, df=3(P=0.8); I2=0%

Test for overall effect: Z=0.14(P=0.89)

20.28.3 BCAAs

Calvey 1985 4/11 2/13 100% 0.21[-0.14,0.56]

Subtotal (95% CI) 11 13 100% 0.21[-0.14,0.56]

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

Test for subgroup differences: Chi2=1.1, df=1 (P=0.58), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.29. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 29 ITT - Enteral nutrition - worst-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.29.1 Standard amino acids

Calvey 1985 7/21 2/13 29.27% 0.18[-0.1,0.46]

Guy 1995 12/22 3/20 38.19% 0.4[0.14,0.66]

Kearns 1992 1/6 1/8 12.5% 0.04[-0.33,0.42]

Schuetz 2006 0/11 0/11 20.05% 0[-0.16,0.16]

Subtotal (95% CI) 60 52 100% 0.21[0.07,0.35]

Total events: 20 (Treatment), 6 (Control)

Heterogeneity: Tau2=0; Chi2=9.32, df=3(P=0.03); I2=67.82%

Test for overall effect: Z=2.89(P=0)

20.29.2 BCAAs

Calvey 1985 4/11 2/13 100% 0.21[-0.14,0.56]

Subtotal (95% CI) 11 13 100% 0.21[-0.14,0.56]

Favours treatment 10.5-1 -0.5 0 Favours control

308

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Total events: 4 (Treatment), 2 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.19(P=0.23)

20.29.3 All trials

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Chi2=0, df=1 (P=1), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.30. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 30 ITT- Supplements - best-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.30.1 All trials

Bunout 1989 1/14 0/12 3.46% 0.07[-0.11,0.26]

Hasse 1997 5/37 6/9 3.88% -0.53[-0.86,-0.2]

Hayashi 1991 0/2 0/2 0.54% 0[-0.6,0.6]

Hirsch 1993 3/32 11/33 8.7% -0.24[-0.43,-0.05]

Humbert 1988 24/27 22/22 6.49% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 2.75% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 3.19% 0[-0.15,0.15]

Kobashi 2006 12/108 16/113 29.56% -0.03[-0.12,0.06]

Meng 1999 0/25 2/25 6.69% -0.08[-0.21,0.05]

Nakaya 2007 0/19 1/19 5.09% -0.05[-0.19,0.08]

Poon 2004 0/44 2/44 11.78% -0.05[-0.12,0.03]

Sievert 1999 4/71 3/34 12.31% -0.03[-0.14,0.08]

Simko 1983 0/11 1/4 1.57% -0.25[-0.67,0.17]

Tangkijvanich 2000 0/15 0/15 4.01% 0[-0.12,0.12]

Subtotal (95% CI) 428 354 100% -0.08[-0.12,-0.03]

Total events: 49 (Treatment), 64 (Control)

Heterogeneity: Tau2=0; Chi2=19.54, df=13(P=0.11); I2=33.48%

Test for overall effect: Z=3.54(P=0)

20.30.2 Standard amino acids -medical trials

Bunout 1989 1/14 0/12 13.79% 0.07[-0.11,0.26]

Hasse 1997 4/18 6/9 12.8% -0.44[-0.81,-0.08]

Hirsch 1993 3/32 11/33 34.66% -0.24[-0.43,-0.05]

Sievert 1999 1/39 3/34 38.75% -0.06[-0.17,0.04]

Subtotal (95% CI) 103 88 100% -0.15[-0.25,-0.06]

Total events: 9 (Treatment), 20 (Control)

Heterogeneity: Tau2=0; Chi2=11.79, df=3(P=0.01); I2=74.56%

Test for overall effect: Z=3.19(P=0)

20.30.3 BCAAs - medical trials

Hasse 1997 1/19 6/9 4.43% -0.61[-0.94,-0.29]

Favours treatment 10.5-1 -0.5 0 Favours control

309

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hayashi 1991 0/2 0/2 0.73% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 8.8% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.73% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 40.09% -0.03[-0.12,0.06]

Nakaya 2007 0/19 1/19 6.9% -0.05[-0.19,0.08]

Poon 2004 0/44 2/44 15.97% -0.05[-0.12,0.03]

Sievert 1999 3/31 3/34 11.77% 0.01[-0.13,0.15]

Simko 1983 0/11 1/4 2.13% -0.25[-0.67,0.17]

Tangkijvanich 2000 0/15 0/15 5.44% 0[-0.12,0.12]

Subtotal (95% CI) 288 271 100% -0.06[-0.11,-0.02]

Total events: 40 (Treatment), 51 (Control)

Heterogeneity: Tau2=0; Chi2=15.85, df=9(P=0.07); I2=43.21%

Test for overall effect: Z=2.6(P=0.01)

20.30.4 All supplements - medical

Bunout 1989 1/14 0/12 3.84% 0.07[-0.11,0.26]

Hasse 1997 5/37 6/9 4.3% -0.53[-0.86,-0.2]

Hayashi 1991 0/2 0/2 0.59% 0[-0.6,0.6]

Hirsch 1993 3/32 11/33 9.66% -0.24[-0.43,-0.05]

Humbert 1988 24/27 22/22 7.2% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.06% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 32.82% -0.03[-0.12,0.06]

Nakaya 2007 0/19 1/19 5.65% -0.05[-0.19,0.08]

Poon 2004 0/44 2/44 13.08% -0.05[-0.12,0.03]

Sievert 1999 4/70 3/34 13.6% -0.03[-0.14,0.08]

Simko 1983 0/11 1/4 1.74% -0.25[-0.67,0.17]

Tangkijvanich 2000 0/15 0/15 4.46% 0[-0.12,0.12]

Subtotal (95% CI) 391 316 100% -0.08[-0.12,-0.03]

Total events: 49 (Treatment), 62 (Control)

Heterogeneity: Tau2=0; Chi2=18.88, df=11(P=0.06); I2=41.74%

Test for overall effect: Z=3.39(P=0)

20.30.5 All surgical

Ishikawa 2010 0/11 0/13 32.28% 0[-0.15,0.15]

Meng 1999 0/25 2/25 67.72% -0.08[-0.21,0.05]

Subtotal (95% CI) 36 38 100% -0.05[-0.16,0.05]

Total events: 0 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=0.67, df=1(P=0.41); I2=0%

Test for overall effect: Z=1.04(P=0.3)

Test for subgroup differences: Chi2=3.01, df=1 (P=0.56), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 20.31. Comparison 20 Appearance of encephalopathy - absolute risk di<erence (ARD), Outcome 31 ITT - Supplements - worst-case scenario for intervention.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

20.31.1 All trials

Bunout 1989 1/14 0/12 3.46% 0.07[-0.11,0.26]

Favours treatment 10.5-1 -0.5 0 Favours control

310

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hasse 1997 19/37 3/9 3.88% 0.18[-0.17,0.53]

Hayashi 1991 0/2 0/2 0.54% 0[-0.6,0.6]

Hirsch 1993 9/32 3/33 8.7% 0.19[0.01,0.37]

Humbert 1988 24/27 22/22 6.49% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 2.75% 0[-0.17,0.17]

Ishikawa 2010 0/11 0/13 3.19% 0[-0.15,0.15]

Kobashi 2006 12/108 16/113 29.58% -0.03[-0.12,0.06]

Meng 1999 4/25 0/25 6.69% 0.16[0.01,0.31]

Nakaya 2007 0/19 1/19 5.09% -0.05[-0.19,0.08]

Poon 2004 3/44 1/44 11.78% 0.05[-0.04,0.13]

Sievert 1999 4/70 3/34 12.26% -0.03[-0.14,0.08]

Simko 1983 4/11 0/4 1.57% 0.36[-0.02,0.74]

Tangkijvanich 2000 1/15 0/15 4.02% 0.07[-0.1,0.23]

Subtotal (95% CI) 427 354 100% 0.03[-0.02,0.07]

Total events: 81 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=18.56, df=13(P=0.14); I2=29.95%

Test for overall effect: Z=1.26(P=0.21)

20.31.2 Standard amino acids -medical trials

Bunout 1989 1/14 0/12 13.79% 0.07[-0.11,0.26]

Hasse 1997 8/18 3/9 12.8% 0.11[-0.27,0.5]

Hirsch 1993 9/32 3/33 34.66% 0.19[0.01,0.37]

Sievert 1999 1/39 3/34 38.75% -0.06[-0.17,0.04]

Subtotal (95% CI) 103 88 100% 0.07[-0.03,0.16]

Total events: 19 (Treatment), 9 (Control)

Heterogeneity: Tau2=0; Chi2=7.3, df=3(P=0.06); I2=58.89%

Test for overall effect: Z=1.36(P=0.17)

20.31.3 BCAAs - medical trials

Hasse 1997 11/19 3/9 4.43% 0.25[-0.13,0.63]

Hayashi 1991 0/2 0/2 0.73% 0[-0.6,0.6]

Humbert 1988 24/27 22/22 8.8% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.73% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 40.09% -0.03[-0.12,0.06]

Nakaya 2007 0/19 1/19 6.9% -0.05[-0.19,0.08]

Poon 2004 3/44 1/44 15.97% 0.05[-0.04,0.13]

Sievert 1999 3/31 3/34 11.77% 0.01[-0.13,0.15]

Simko 1983 4/11 0/4 2.13% 0.36[-0.02,0.74]

Tangkijvanich 2000 1/15 0/15 5.44% 0.07[-0.1,0.23]

Subtotal (95% CI) 288 271 100% 0[-0.05,0.05]

Total events: 58 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=10.47, df=9(P=0.31); I2=14.07%

Test for overall effect: Z=0.19(P=0.85)

20.31.4 All supplements - medical

Bunout 1989 1/14 0/12 3.84% 0.07[-0.11,0.26]

Hasse 1997 19/37 3/9 4.3% 0.18[-0.17,0.53]

Hayashi 1991 0/2 0/2 0.59% 0[-0.6,0.6]

Hirsch 1993 9/32 3/33 9.66% 0.19[0.01,0.37]

Humbert 1988 24/27 22/22 7.2% -0.11[-0.25,0.03]

Ichikawa 2010 0/12 0/9 3.06% 0[-0.17,0.17]

Kobashi 2006 12/108 16/113 32.82% -0.03[-0.12,0.06]

Favours treatment 10.5-1 -0.5 0 Favours control

311

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Nakaya 2007 0/19 1/19 5.65% -0.05[-0.19,0.08]

Poon 2004 3/44 1/44 13.08% 0.05[-0.04,0.13]

Sievert 1999 4/70 3/34 13.6% -0.03[-0.14,0.08]

Simko 1983 4/11 0/4 1.74% 0.36[-0.02,0.74]

Tangkijvanich 2000 1/15 0/15 4.46% 0.07[-0.1,0.23]

Subtotal (95% CI) 391 316 100% 0.02[-0.03,0.07]

Total events: 77 (Treatment), 49 (Control)

Heterogeneity: Tau2=0; Chi2=14.98, df=11(P=0.18); I2=26.57%

Test for overall effect: Z=0.8(P=0.42)

20.31.5 All surgical

Ishikawa 2010 0/11 0/13 32.28% 0[-0.15,0.15]

Meng 1999 4/25 0/25 67.72% 0.16[0.01,0.31]

Subtotal (95% CI) 36 38 100% 0.11[-0.01,0.23]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Tau2=0; Chi2=2.46, df=1(P=0.12); I2=59.3%

Test for overall effect: Z=1.76(P=0.08)

Test for subgroup differences: Chi2=3.24, df=1 (P=0.52), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Comparison 21. Resolution of encephalopathy - absolute risk di<erence (ARD)

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All trials 6 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

1.1 All studies 6 119 Risk Difference (M-H, Fixed, 95% CI)

0.25 [0.10, 0.41]

1.2 Standard amino acids 5 66 Risk Difference (M-H, Fixed, 95% CI)

0.05 [-0.17, 0.27]

1.3 BCAA's 2 62 Risk Difference (M-H, Fixed, 95% CI)

0.45 [0.25, 0.64]

2 Parenteral nutrition (all medical trials) 2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

2.1 All trials 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

2.2 Standard amino acids 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

2.3 BCAA's 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Enteral nutrition (all medical trials) 2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

312

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

3.1 All trials 2 47 Risk Difference (M-H, Fixed, 95% CI)

0.13 [-0.12, 0.39]

3.2 Standard amino acids 2 37 Risk Difference (M-H, Fixed, 95% CI)

0.07 [-0.20, 0.35]

3.3 BCAA's 1 19 Risk Difference (M-H, Fixed, 95% CI)

0.29 [-0.08, 0.66]

4 Supplements (all medical trials) 2 Risk Difference (M-H, Random, 95% CI)

Subtotals only

4.1 All trials 2 53 Risk Difference (M-H, Random, 95% CI)

0.07 [-0.86, 0.99]

4.2 Standard amino acids 1 10 Risk Difference (M-H, Random, 95% CI)

-0.43 [-0.90, 0.04]

4.3 BCAA's 1 43 Risk Difference (M-H, Random, 95% CI)

0.52 [0.29, 0.74]

5 Medical trials - all trials 6 119 Risk Difference (M-H, Fixed, 95% CI)

0.25 [0.10, 0.41]

5.1 Parenteral nutrition 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

5.2 Enteral nutrition 2 47 Risk Difference (M-H, Fixed, 95% CI)

0.13 [-0.12, 0.39]

5.3 Supplements 2 53 Risk Difference (M-H, Fixed, 95% CI)

0.36 [0.15, 0.57]

6 Medical trials - standard amino acids 5 66 Risk Difference (M-H, Fixed, 95% CI)

0.05 [-0.17, 0.27]

6.1 Parenteral nutrition 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

6.2 Enteral nutrition 2 37 Risk Difference (M-H, Fixed, 95% CI)

0.07 [-0.20, 0.35]

6.3 Supplements 1 10 Risk Difference (M-H, Fixed, 95% CI)

-0.43 [-0.90, 0.04]

7 Medical trials - BCAAs 2 62 Risk Difference (M-H, Fixed, 95% CI)

0.45 [0.25, 0.64]

7.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Enteral nutrition 1 19 Risk Difference (M-H, Fixed, 95% CI)

0.29 [-0.08, 0.66]

313

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

7.3 Supplements 1 43 Risk Difference (M-H, Fixed, 95% CI)

0.52 [0.29, 0.74]

8 Surgical trials - all trials 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.1 Pareneral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9 Surgical trials - standard amino acids 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.1 Pareneral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10 Surgical trials - BCAAs 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.1 Pareneral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11 Alcoholic hepatitis - all trials 5 76 Risk Difference (M-H, Fixed, 95% CI)

0.09 [-0.12, 0.30]

11.1 Parenteral nutrition 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

11.2 Enteral nutrition 2 47 Risk Difference (M-H, Fixed, 95% CI)

0.13 [-0.12, 0.39]

11.3 Supplements 1 10 Risk Difference (M-H, Fixed, 95% CI)

-0.43 [-0.90, 0.04]

12 Alcoholic hepatitis - standard amino acids

5 66 Risk Difference (M-H, Fixed, 95% CI)

0.05 [-0.17, 0.27]

314

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

12.1 Parenteral nutrition 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

12.2 Enteral nutrition 2 37 Risk Difference (M-H, Fixed, 95% CI)

0.07 [-0.20, 0.35]

12.3 Supplements 1 10 Risk Difference (M-H, Fixed, 95% CI)

-0.43 [-0.90, 0.04]

13 Alcoholic hepatitis - BCAAs 1 19 Risk Difference (M-H, Fixed, 95% CI)

0.29 [-0.08, 0.66]

13.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.2 Enteral nutrition 1 19 Risk Difference (M-H, Fixed, 95% CI)

0.29 [-0.08, 0.66]

13.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

14 Cirrhosis - all 1 43 Risk Difference (M-H, Fixed, 95% CI)

0.52 [0.29, 0.74]

14.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

14.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

14.3 Supplements 1 43 Risk Difference (M-H, Fixed, 95% CI)

0.52 [0.29, 0.74]

15 Cirrhosis - standard amino acids 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

15.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

15.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

15.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

16 Cirrhosis - BCAAs 1 43 Risk Difference (M-H, Fixed, 95% CI)

0.52 [0.29, 0.74]

16.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

16.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

315

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

16.3 Supplements 1 43 Risk Difference (M-H, Fixed, 95% CI)

0.52 [0.29, 0.74]

17 HCC - all studies 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

17.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

17.2 Enteral nutritionBCAA's 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

17.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18 HCC - standard amino acids 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18.2 Enteral nutritionBCAA's 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

18.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

19 HCC - BCAAs 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

19.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

19.2 Enteral nutrition BCAA's 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

19.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

20 Abstracts excluded - all trials 6 119 Risk Difference (M-H, Fixed, 95% CI)

0.25 [0.10, 0.41]

20.1 Parenteral nutrition 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

20.2 Enteral nutrition 2 47 Risk Difference (M-H, Fixed, 95% CI)

0.13 [-0.12, 0.39]

20.3 Supplements 2 53 Risk Difference (M-H, Fixed, 95% CI)

0.36 [0.15, 0.57]

21 Abstracts excluded - standard amino acids

5 66 Risk Difference (M-H, Fixed, 95% CI)

0.05 [-0.17, 0.27]

316

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

21.1 Parenteral nutrition 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

21.2 Enteral nutrition 2 37 Risk Difference (M-H, Fixed, 95% CI)

0.07 [-0.20, 0.35]

21.3 Supplements 1 10 Risk Difference (M-H, Fixed, 95% CI)

-0.43 [-0.90, 0.04]

22 Abstracts excluded - BCAAs 3 72 Risk Difference (M-H, Random, 95% CI)

0.16 [-0.34, 0.66]

22.1 Parenteral nutrition 0 0 Risk Difference (M-H, Random, 95% CI)

0.0 [0.0, 0.0]

22.2 Enteral nutrition 1 19 Risk Difference (M-H, Random, 95% CI)

0.29 [-0.08, 0.66]

22.3 Supplements 2 53 Risk Difference (M-H, Random, 95% CI)

0.07 [-0.86, 0.99]

23 Surgical trials (transplant patients re- moved) - all trials

0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

23.1 Parenteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

23.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

23.3 Supplements 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

24 ITT - All trials - best case scenario - no changes made because all patients re- ported

6 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

24.1 All studies 6 119 Risk Difference (M-H, Fixed, 95% CI)

0.25 [0.10, 0.41]

24.2 Standard amino acids 5 66 Risk Difference (M-H, Fixed, 95% CI)

0.05 [-0.17, 0.27]

24.3 BCAA's 2 62 Risk Difference (M-H, Fixed, 95% CI)

0.45 [0.25, 0.64]

25 ITT - Parenteral nutrition trials - best- case scenario - no changes made because all patients reported

2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

25.1 All studies 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

317

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

25.2 Standard amino acids 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

25.3 BCAA's 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

26 ITT - Enteral nutrition trials - best-case scenario - no changes made because all patients reported

2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

26.1 All studies 2 47 Risk Difference (M-H, Fixed, 95% CI)

0.13 [-0.12, 0.39]

26.2 Standard amino acids 2 37 Risk Difference (M-H, Fixed, 95% CI)

0.07 [-0.20, 0.35]

26.3 BCAA's 1 19 Risk Difference (M-H, Fixed, 95% CI)

0.29 [-0.08, 0.66]

27 ITT - Supplement trials - best-case sce- nario - no changes made because all pa- tients reported

2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

27.1 All studies 2 53 Risk Difference (M-H, Fixed, 95% CI)

0.36 [0.15, 0.57]

27.2 Standard amino acids 1 10 Risk Difference (M-H, Fixed, 95% CI)

-0.43 [-0.90, 0.04]

27.3 BCAA's 1 43 Risk Difference (M-H, Fixed, 95% CI)

0.52 [0.29, 0.74]

28 ITT - All trials - worst-case scenario - no changes made because all patients re- ported

6 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

28.1 All studies 6 119 Risk Difference (M-H, Fixed, 95% CI)

0.25 [0.10, 0.41]

28.2 Standard amino acids 5 66 Risk Difference (M-H, Fixed, 95% CI)

0.05 [-0.17, 0.27]

28.3 BCAA's 2 62 Risk Difference (M-H, Fixed, 95% CI)

0.45 [0.25, 0.64]

29 ITT - Parenteral nutrition trials - worst- case scenario - no changes made because all patients reported

2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

29.1 All studies 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

29.2 Standard amino acids 2 19 Risk Difference (M-H, Fixed, 95% CI)

0.22 [-0.22, 0.66]

318

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Cochrane Database of Systematic Reviews

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

29.3 BCAA's 0 0 Risk Difference (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

30 ITT - Enteral nutrition trials - worst- case scenario - no changes made because all patients reported

2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

30.1 All studies 2 47 Risk Difference (M-H, Fixed, 95% CI)

0.13 [-0.12, 0.39]

30.2 Standard amino acids 2 37 Risk Difference (M-H, Fixed, 95% CI)

0.07 [-0.20, 0.35]

30.3 BCAA's 1 19 Risk Difference (M-H, Fixed, 95% CI)

0.29 [-0.08, 0.66]

31 ITT - Supplement trials - worst-case scenario - no changes made because all patients reported

2 Risk Difference (M-H, Fixed, 95% CI)

Subtotals only

31.1 All studies 2 53 Risk Difference (M-H, Fixed, 95% CI)

0.36 [0.15, 0.57]

31.2 Standard amino acids 1 10 Risk Difference (M-H, Fixed, 95% CI)

-0.43 [-0.90, 0.04]

31.3 BCAA's 1 43 Risk Difference (M-H, Fixed, 95% CI)

0.52 [0.29, 0.74]

Analysis 21.1. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 1 All trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.1.1 All studies

Achord 1987 2/2 3/4 4.8% 0.25[-0.33,0.83]

Bunout 1989 0/3 3/7 7.56% -0.43[-0.9,0.04]

Calvey 1985 6/21 1/9 22.68% 0.17[-0.11,0.46]

Hayashi 1991 13/23 1/20 38.51% 0.52[0.29,0.74]

Kearns 1992 5/10 3/7 14.82% 0.07[-0.41,0.55]

Simon 1988 3/6 2/7 11.63% 0.21[-0.31,0.74]

Subtotal (95% CI) 65 54 100% 0.25[0.1,0.41]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=14.13, df=5(P=0.01); I2=64.61%

Test for overall effect: Z=3.21(P=0)

21.1.2 Standard amino acids

Achord 1987 2/2 3/4 8.48% 0.25[-0.33,0.83]

Bunout 1989 0/3 3/7 13.35% -0.43[-0.9,0.04]

Calvey 1985 2/11 1/9 31.47% 0.07[-0.24,0.38]

Favours control 10.5-1 -0.5 0 Favours treatment

319

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Kearns 1992 5/10 3/7 26.17% 0.07[-0.41,0.55]

Simon 1988 3/6 2/7 20.54% 0.21[-0.31,0.74]

Subtotal (95% CI) 32 34 100% 0.05[-0.17,0.27]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=4(P=0.31); I2=16.59%

Test for overall effect: Z=0.44(P=0.66)

21.1.3 BCAA's

Calvey 1985 4/10 1/9 30.69% 0.29[-0.08,0.66]

Hayashi 1991 13/23 1/20 69.31% 0.52[0.29,0.74]

Subtotal (95% CI) 33 29 100% 0.45[0.25,0.64]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=1.07, df=1(P=0.3); I2=6.81%

Test for overall effect: Z=4.56(P<0.0001)

Test for subgroup differences: Chi2=7.19, df=1 (P=0.03), I2=72.18%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.2. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 2 Parenteral nutrition (all medical trials).

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.2.1 All trials

Achord 1987 2/2 3/4 29.21% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 70.79% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 100% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.2.2 Standard amino acids

Achord 1987 2/2 3/4 29.21% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 70.79% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 100% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.2.3 BCAA's

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours treatment

320

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Analysis 21.3. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 3 Enteral nutrition (all medical trials).

Study or subgroup Tretment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.3.1 All trials

Calvey 1985 6/21 1/9 60.47% 0.17[-0.11,0.46]

Kearns 1992 5/10 3/7 39.53% 0.07[-0.41,0.55]

Subtotal (95% CI) 31 16 100% 0.13[-0.12,0.39]

Total events: 11 (Tretment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.7); I2=0%

Test for overall effect: Z=1.03(P=0.3)

21.3.2 Standard amino acids

Calvey 1985 2/11 1/9 54.59% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 45.41% 0.07[-0.41,0.55]

Subtotal (95% CI) 21 16 100% 0.07[-0.2,0.35]

Total events: 7 (Tretment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Z=0.51(P=0.61)

21.3.3 BCAA's

Calvey 1985 4/10 1/9 100% 0.29[-0.08,0.66]

Subtotal (95% CI) 10 9 100% 0.29[-0.08,0.66]

Total events: 4 (Tretment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.54(P=0.12)

Test for subgroup differences: Chi2=0.88, df=1 (P=0.65), I2=0%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.4. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 4 Supplements (all medical trials).

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

21.4.1 All trials

Bunout 1989 0/3 3/7 47.48% -0.43[-0.9,0.04]

Hayashi 1991 13/23 1/20 52.52% 0.52[0.29,0.74]

Subtotal (95% CI) 26 27 100% 0.07[-0.86,0.99]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0.41; Chi2=12.55, df=1(P=0); I2=92.03%

Test for overall effect: Z=0.14(P=0.89)

21.4.2 Standard amino acids

Bunout 1989 0/3 3/7 100% -0.43[-0.9,0.04]

Subtotal (95% CI) 3 7 100% -0.43[-0.9,0.04]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.78(P=0.08)

21.4.3 BCAA's

Hayashi 1991 13/23 1/20 100% 0.52[0.29,0.74]

Favours control 10.5-1 -0.5 0 Favours treatment

321

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

Subtotal (95% CI) 23 20 100% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Test for subgroup differences: Chi2=12.84, df=1 (P=0), I2=84.42%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.5. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 5 Medical trials - all trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.5.1 Parenteral nutrition

Achord 1987 2/2 3/4 4.8% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 11.63% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 16.43% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.5.2 Enteral nutrition

Calvey 1985 6/21 1/9 22.68% 0.17[-0.11,0.46]

Kearns 1992 5/10 3/7 14.82% 0.07[-0.41,0.55]

Subtotal (95% CI) 31 16 37.5% 0.13[-0.12,0.39]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.7); I2=0%

Test for overall effect: Z=1.03(P=0.3)

21.5.3 Supplements

Bunout 1989 0/3 3/7 7.56% -0.43[-0.9,0.04]

Hayashi 1991 13/23 1/20 38.51% 0.52[0.29,0.74]

Subtotal (95% CI) 26 27 46.07% 0.36[0.15,0.57]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=12.55, df=1(P=0); I2=92.03%

Test for overall effect: Z=3.34(P=0)

Total (95% CI) 65 54 100% 0.25[0.1,0.41]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=14.13, df=5(P=0.01); I2=64.61%

Test for overall effect: Z=3.21(P=0)

Test for subgroup differences: Chi2=1.83, df=1 (P=0.4), I2=0%

Favours control 10.5-1 -0.5 0 Favours treatment

322

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Analysis 21.6. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 6 Medical trials - standard amino acids.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.6.1 Parenteral nutrition

Achord 1987 2/2 3/4 8.48% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 20.54% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 29.01% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.6.2 Enteral nutrition

Calvey 1985 2/11 1/9 31.47% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 26.17% 0.07[-0.41,0.55]

Subtotal (95% CI) 21 16 57.64% 0.07[-0.2,0.35]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Z=0.51(P=0.61)

21.6.3 Supplements

Bunout 1989 0/3 3/7 13.35% -0.43[-0.9,0.04]

Subtotal (95% CI) 3 7 13.35% -0.43[-0.9,0.04]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.78(P=0.08)

Total (95% CI) 32 34 100% 0.05[-0.17,0.27]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=4(P=0.31); I2=16.59%

Test for overall effect: Z=0.44(P=0.66)

Test for subgroup differences: Chi2=4.41, df=1 (P=0.11), I2=54.69%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.7. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 7 Medical trials - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.7.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

21.7.2 Enteral nutrition

Calvey 1985 4/10 1/9 30.69% 0.29[-0.08,0.66]

Subtotal (95% CI) 10 9 30.69% 0.29[-0.08,0.66]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.54(P=0.12)

Favours control 10.5-1 -0.5 0 Favours treatment

323

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.7.3 Supplements

Hayashi 1991 13/23 1/20 69.31% 0.52[0.29,0.74]

Subtotal (95% CI) 23 20 69.31% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Total (95% CI) 33 29 100% 0.45[0.25,0.64]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=1.07, df=1(P=0.3); I2=6.81%

Test for overall effect: Z=4.56(P<0.0001)

Test for subgroup differences: Chi2=1.07, df=1 (P=0.3), I2=6.23%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.11. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 11 Alcoholic hepatitis - all trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.11.1 Parenteral nutrition

Achord 1987 2/2 3/4 7.81% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 18.91% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 26.72% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.11.2 Enteral nutrition

Calvey 1985 6/21 1/9 36.88% 0.17[-0.11,0.46]

Kearns 1992 5/10 3/7 24.11% 0.07[-0.41,0.55]

Subtotal (95% CI) 31 16 60.99% 0.13[-0.12,0.39]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.7); I2=0%

Test for overall effect: Z=1.03(P=0.3)

21.11.3 Supplements

Bunout 1989 0/3 3/7 12.29% -0.43[-0.9,0.04]

Subtotal (95% CI) 3 7 12.29% -0.43[-0.9,0.04]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.78(P=0.08)

Total (95% CI) 42 34 100% 0.09[-0.12,0.3]

Total events: 16 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=5.48, df=4(P=0.24); I2=27.07%

Test for overall effect: Z=0.84(P=0.4)

Test for subgroup differences: Chi2=4.96, df=1 (P=0.08), I2=59.69%

Favours control 10.5-1 -0.5 0 Favours treatment

324

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Analysis 21.12. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 12 Alcoholic hepatitis - standard amino acids.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.12.1 Parenteral nutrition

Achord 1987 2/2 3/4 8.48% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 20.54% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 29.01% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.12.2 Enteral nutrition

Calvey 1985 2/11 1/9 31.47% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 26.17% 0.07[-0.41,0.55]

Subtotal (95% CI) 21 16 57.64% 0.07[-0.2,0.35]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Z=0.51(P=0.61)

21.12.3 Supplements

Bunout 1989 0/3 3/7 13.35% -0.43[-0.9,0.04]

Subtotal (95% CI) 3 7 13.35% -0.43[-0.9,0.04]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.78(P=0.08)

Total (95% CI) 32 34 100% 0.05[-0.17,0.27]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=4(P=0.31); I2=16.59%

Test for overall effect: Z=0.44(P=0.66)

Test for subgroup differences: Chi2=4.41, df=1 (P=0.11), I2=54.69%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.13. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 13 Alcoholic hepatitis - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.13.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

21.13.2 Enteral nutrition

Calvey 1985 4/10 1/9 100% 0.29[-0.08,0.66]

Subtotal (95% CI) 10 9 100% 0.29[-0.08,0.66]

Total events: 4 (Treatment), 1 (Control)

Favours control 10.5-1 -0.5 0 Favours treatment

325

Cochrane Library

Trusted evidence. Informed decisions. Better health.

Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Heterogeneity: Not applicable

Test for overall effect: Z=1.54(P=0.12)

21.13.3 Supplements

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 10 9 100% 0.29[-0.08,0.66]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.54(P=0.12)

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.14. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 14 Cirrhosis - all.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.14.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

21.14.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

21.14.3 Supplements

Hayashi 1991 13/23 1/20 100% 0.52[0.29,0.74]

Subtotal (95% CI) 23 20 100% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Total (95% CI) 23 20 100% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours treatment

326

Cochrane Library

Trusted evidence. Informed decisions. Better health.

Cochrane Database of Systematic Reviews

Analysis 21.16. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 16 Cirrhosis - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.16.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

21.16.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

21.16.3 Supplements

Hayashi 1991 13/23 1/20 100% 0.52[0.29,0.74]

Subtotal (95% CI) 23 20 100% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Total (95% CI) 23 20 100% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.20. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 20 Abstracts excluded - all trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.20.1 Parenteral nutrition

Achord 1987 2/2 3/4 4.8% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 11.63% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 16.43% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.20.2 Enteral nutrition

Calvey 1985 6/21 1/9 22.68% 0.17[-0.11,0.46]

Kearns 1992 5/10 3/7 14.82% 0.07[-0.41,0.55]

Subtotal (95% CI) 31 16 37.5% 0.13[-0.12,0.39]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.7); I2=0%

Test for overall effect: Z=1.03(P=0.3)

Favours control 10.5-1 -0.5 0 Favours treatment

327

Cochrane Library

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.20.3 Supplements

Bunout 1989 0/3 3/7 7.56% -0.43[-0.9,0.04]

Hayashi 1991 13/23 1/20 38.51% 0.52[0.29,0.74]

Subtotal (95% CI) 26 27 46.07% 0.36[0.15,0.57]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=12.55, df=1(P=0); I2=92.03%

Test for overall effect: Z=3.34(P=0)

Total (95% CI) 65 54 100% 0.25[0.1,0.41]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=14.13, df=5(P=0.01); I2=64.61%

Test for overall effect: Z=3.21(P=0)

Test for subgroup differences: Chi2=1.83, df=1 (P=0.4), I2=0%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.21. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 21 Abstracts excluded - standard amino acids.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.21.1 Parenteral nutrition

Achord 1987 2/2 3/4 8.48% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 20.54% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 29.01% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.21.2 Enteral nutrition

Calvey 1985 2/11 1/9 31.47% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 26.17% 0.07[-0.41,0.55]

Subtotal (95% CI) 21 16 57.64% 0.07[-0.2,0.35]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Z=0.51(P=0.61)

21.21.3 Supplements

Bunout 1989 0/3 3/7 13.35% -0.43[-0.9,0.04]

Subtotal (95% CI) 3 7 13.35% -0.43[-0.9,0.04]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.78(P=0.08)

Total (95% CI) 32 34 100% 0.05[-0.17,0.27]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=4(P=0.31); I2=16.59%

Test for overall effect: Z=0.44(P=0.66)

Test for subgroup differences: Chi2=4.41, df=1 (P=0.11), I2=54.69%

Favours control 10.5-1 -0.5 0 Favours treatment

328

Cochrane Library

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Cochrane Database of Systematic Reviews

Analysis 21.22. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 22 Abstracts excluded - BCAAs.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

21.22.1 Parenteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

21.22.2 Enteral nutrition

Calvey 1985 4/10 1/9 33.11% 0.29[-0.08,0.66]

Subtotal (95% CI) 10 9 33.11% 0.29[-0.08,0.66]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.54(P=0.12)

21.22.3 Supplements

Bunout 1989 0/3 3/7 29.63% -0.43[-0.9,0.04]

Hayashi 1991 13/23 1/20 37.25% 0.52[0.29,0.74]

Subtotal (95% CI) 26 27 66.89% 0.07[-0.86,0.99]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0.41; Chi2=12.55, df=1(P=0); I2=92.03%

Test for overall effect: Z=0.14(P=0.89)

Total (95% CI) 36 36 100% 0.16[-0.34,0.66]

Total events: 17 (Treatment), 5 (Control)

Heterogeneity: Tau2=0.16; Chi2=12.59, df=2(P=0); I2=84.12%

Test for overall effect: Z=0.63(P=0.53)

Test for subgroup differences: Chi2=0.19, df=1 (P=0.66), I2=0%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.24. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 24 ITT - All trials - best case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.24.1 All studies

Achord 1987 2/2 3/4 4.8% 0.25[-0.33,0.83]

Bunout 1989 0/3 3/7 7.56% -0.43[-0.9,0.04]

Calvey 1985 6/21 1/9 22.68% 0.17[-0.11,0.46]

Hayashi 1991 13/23 1/20 38.51% 0.52[0.29,0.74]

Kearns 1992 5/10 3/7 14.82% 0.07[-0.41,0.55]

Simon 1988 3/6 2/7 11.63% 0.21[-0.31,0.74]

Subtotal (95% CI) 65 54 100% 0.25[0.1,0.41]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=14.13, df=5(P=0.01); I2=64.61%

Test for overall effect: Z=3.21(P=0)

Favours control 10.5-1 -0.5 0 Favours treatment

329

Cochrane Library

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.24.2 Standard amino acids

Achord 1987 2/2 3/4 8.48% 0.25[-0.33,0.83]

Bunout 1989 0/3 3/7 13.35% -0.43[-0.9,0.04]

Calvey 1985 2/11 1/9 31.47% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 26.17% 0.07[-0.41,0.55]

Simon 1988 3/6 2/7 20.54% 0.21[-0.31,0.74]

Subtotal (95% CI) 32 34 100% 0.05[-0.17,0.27]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=4(P=0.31); I2=16.59%

Test for overall effect: Z=0.44(P=0.66)

21.24.3 BCAA's

Calvey 1985 4/10 1/9 30.69% 0.29[-0.08,0.66]

Hayashi 1991 13/23 1/20 69.31% 0.52[0.29,0.74]

Subtotal (95% CI) 33 29 100% 0.45[0.25,0.64]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=1.07, df=1(P=0.3); I2=6.81%

Test for overall effect: Z=4.56(P<0.0001)

Test for subgroup differences: Chi2=7.19, df=1 (P=0.03), I2=72.18%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.25. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 25 ITT - Parenteral nutrition trials - best-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.25.1 All studies

Achord 1987 2/2 3/4 29.21% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 70.79% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 100% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.25.2 Standard amino acids

Achord 1987 2/2 3/4 29.21% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 70.79% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 100% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.25.3 BCAA's

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours treatment

330

Cochrane Library

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Analysis 21.26. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 26 ITT - Enteral nutrition trials - best-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.26.1 All studies

Calvey 1985 6/21 1/9 60.47% 0.17[-0.11,0.46]

Kearns 1992 5/10 3/7 39.53% 0.07[-0.41,0.55]

Subtotal (95% CI) 31 16 100% 0.13[-0.12,0.39]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.7); I2=0%

Test for overall effect: Z=1.03(P=0.3)

21.26.2 Standard amino acids

Calvey 1985 2/11 1/9 54.59% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 45.41% 0.07[-0.41,0.55]

Subtotal (95% CI) 21 16 100% 0.07[-0.2,0.35]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Z=0.51(P=0.61)

21.26.3 BCAA's

Calvey 1985 4/10 1/9 100% 0.29[-0.08,0.66]

Subtotal (95% CI) 10 9 100% 0.29[-0.08,0.66]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.54(P=0.12)

Test for subgroup differences: Chi2=0.88, df=1 (P=0.65), I2=0%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.27. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 27 ITT - Supplement trials - best-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.27.1 All studies

Bunout 1989 0/3 3/7 16.41% -0.43[-0.9,0.04]

Hayashi 1991 13/23 1/20 83.59% 0.52[0.29,0.74]

Subtotal (95% CI) 26 27 100% 0.36[0.15,0.57]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=12.55, df=1(P=0); I2=92.03%

Test for overall effect: Z=3.34(P=0)

21.27.2 Standard amino acids

Bunout 1989 0/3 3/7 100% -0.43[-0.9,0.04]

Subtotal (95% CI) 3 7 100% -0.43[-0.9,0.04]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.78(P=0.08)

Favours control 10.5-1 -0.5 0 Favours treatment

331

Cochrane Library

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.27.3 BCAA's

Hayashi 1991 13/23 1/20 100% 0.52[0.29,0.74]

Subtotal (95% CI) 23 20 100% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Test for subgroup differences: Chi2=12.53, df=1 (P=0), I2=84.04%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.28. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 28 ITT - All trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.28.1 All studies

Achord 1987 2/2 3/4 4.8% 0.25[-0.33,0.83]

Bunout 1989 0/3 3/7 7.56% -0.43[-0.9,0.04]

Calvey 1985 6/21 1/9 22.68% 0.17[-0.11,0.46]

Hayashi 1991 13/23 1/20 38.51% 0.52[0.29,0.74]

Kearns 1992 5/10 3/7 14.82% 0.07[-0.41,0.55]

Simon 1988 3/6 2/7 11.63% 0.21[-0.31,0.74]

Subtotal (95% CI) 65 54 100% 0.25[0.1,0.41]

Total events: 29 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=14.13, df=5(P=0.01); I2=64.61%

Test for overall effect: Z=3.21(P=0)

21.28.2 Standard amino acids

Achord 1987 2/2 3/4 8.48% 0.25[-0.33,0.83]

Bunout 1989 0/3 3/7 13.35% -0.43[-0.9,0.04]

Calvey 1985 2/11 1/9 31.47% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 26.17% 0.07[-0.41,0.55]

Simon 1988 3/6 2/7 20.54% 0.21[-0.31,0.74]

Subtotal (95% CI) 32 34 100% 0.05[-0.17,0.27]

Total events: 12 (Treatment), 12 (Control)

Heterogeneity: Tau2=0; Chi2=4.8, df=4(P=0.31); I2=16.59%

Test for overall effect: Z=0.44(P=0.66)

21.28.3 BCAA's

Calvey 1985 4/10 1/9 30.69% 0.29[-0.08,0.66]

Hayashi 1991 13/23 1/20 69.31% 0.52[0.29,0.74]

Subtotal (95% CI) 33 29 100% 0.45[0.25,0.64]

Total events: 17 (Treatment), 2 (Control)

Heterogeneity: Tau2=0; Chi2=1.07, df=1(P=0.3); I2=6.81%

Test for overall effect: Z=4.56(P<0.0001)

Test for subgroup differences: Chi2=7.19, df=1 (P=0.03), I2=72.18%

Favours control 10.5-1 -0.5 0 Favours treatment

332

Cochrane Library

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Cochrane Database of Systematic Reviews

Analysis 21.29. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 29 ITT - Parenteral nutrition trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.29.1 All studies

Achord 1987 2/2 3/4 29.21% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 70.79% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 100% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.29.2 Standard amino acids

Achord 1987 2/2 3/4 29.21% 0.25[-0.33,0.83]

Simon 1988 3/6 2/7 70.79% 0.21[-0.31,0.74]

Subtotal (95% CI) 8 11 100% 0.22[-0.22,0.66]

Total events: 5 (Treatment), 5 (Control)

Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.93); I2=0%

Test for overall effect: Z=1(P=0.32)

21.29.3 BCAA's

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Test for subgroup differences: Not applicable

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.30. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 30 ITT - Enteral nutrition trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.30.1 All studies

Calvey 1985 6/21 1/9 60.47% 0.17[-0.11,0.46]

Kearns 1992 5/10 3/7 39.53% 0.07[-0.41,0.55]

Subtotal (95% CI) 31 16 100% 0.13[-0.12,0.39]

Total events: 11 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0.15, df=1(P=0.7); I2=0%

Test for overall effect: Z=1.03(P=0.3)

21.30.2 Standard amino acids

Calvey 1985 2/11 1/9 54.59% 0.07[-0.24,0.38]

Kearns 1992 5/10 3/7 45.41% 0.07[-0.41,0.55]

Subtotal (95% CI) 21 16 100% 0.07[-0.2,0.35]

Total events: 7 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

Test for overall effect: Z=0.51(P=0.61)

21.30.3 BCAA's

Calvey 1985 4/10 1/9 100% 0.29[-0.08,0.66]

Favours control 10.5-1 -0.5 0 Favours treatment

333

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Cochrane Database of Systematic Reviews

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 10 9 100% 0.29[-0.08,0.66]

Total events: 4 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.54(P=0.12)

Test for subgroup differences: Chi2=0.88, df=1 (P=0.65), I2=0%

Favours control 10.5-1 -0.5 0 Favours treatment

Analysis 21.31. Comparison 21 Resolution of encephalopathy - absolute risk di<erence (ARD), Outcome 31 ITT - Supplement trials - worst-case scenario - no changes made because all patients reported.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

21.31.1 All studies

Bunout 1989 0/3 3/7 16.41% -0.43[-0.9,0.04]

Hayashi 1991 13/23 1/20 83.59% 0.52[0.29,0.74]

Subtotal (95% CI) 26 27 100% 0.36[0.15,0.57]

Total events: 13 (Treatment), 4 (Control)

Heterogeneity: Tau2=0; Chi2=12.55, df=1(P=0); I2=92.03%

Test for overall effect: Z=3.34(P=0)

21.31.2 Standard amino acids

Bunout 1989 0/3 3/7 100% -0.43[-0.9,0.04]

Subtotal (95% CI) 3 7 100% -0.43[-0.9,0.04]

Total events: 0 (Treatment), 3 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=1.78(P=0.08)

21.31.3 BCAA's

Hayashi 1991 13/23 1/20 100% 0.52[0.29,0.74]

Subtotal (95% CI) 23 20 100% 0.52[0.29,0.74]

Total events: 13 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.51(P<0.0001)

Test for subgroup differences: Chi2=12.53, df=1 (P=0), I2=84.04%

Favours control 10.5-1 -0.5 0 Favours treatment

Comparison 22. Infections - absolute risk di<erence (ARD)

Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

1 All studies 15 793 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.13, -0.02]

2 Trials with total numbers (Meng) excluded

14 749 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.14, -0.03]

3 Parenteral nutrition 2 164 Risk Difference (M-H, Fixed, 95% CI) -0.10 [-0.22, 0.03]

334

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

3.1 Medical trials 1 40 Risk Difference (M-H, Fixed, 95% CI) 0.2 [0.01, 0.39]

3.2 Surgical trials 1 124 Risk Difference (M-H, Fixed, 95% CI) -0.19 [-0.35, -0.04]

4 Enteral nutrition 6 267 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.19, 0.03]

4.1 Medical trials 4 176 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.16, 0.11]

4.2 Surgical trials 2 91 Risk Difference (M-H, Fixed, 95% CI) -0.18 [-0.35, -0.01]

5 Supplements 7 362 Risk Difference (M-H, Fixed, 95% CI) -0.07 [-0.14, 0.00]

5.1 Medical trials 4 268 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.15, -0.00]

5.2 Surgical trials 3 94 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.21, 0.13]

6 Medical trials 9 484 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.10, 0.03]

7 Surgical trials 6 309 Risk Difference (M-H, Fixed, 95% CI) -0.14 [-0.24, -0.05]

8 Alcoholic hepatitis 2 115 Risk Difference (M-H, Fixed, 95% CI) -0.14 [-0.30, 0.02]

9 Cirrhosis 7 336 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.13, 0.04]

9.1 Parenteral nutrition 1 40 Risk Difference (M-H, Fixed, 95% CI) 0.2 [0.01, 0.39]

9.2 Enteral nutrition 3 112 Risk Difference (M-H, Fixed, 95% CI) -0.04 [-0.20, 0.13]

9.3 Supplements 3 184 Risk Difference (M-H, Fixed, 95% CI) -0.10 [-0.21, 0.00]

10 HCC 2 208 Risk Difference (M-H, Fixed, 95% CI) -0.13 [-0.22, -0.03]

10.1 Parenteral nutrition 1 124 Risk Difference (M-H, Fixed, 95% CI) -0.19 [-0.35, -0.04]

10.2 Enteral nutrition 0 0 Risk Difference (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

10.3 Supplements 1 84 Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.09, 0.04]

11 Abstracts excluded 14 738 Risk Difference (M-H, Fixed, 95% CI) -0.07 [-0.13, -0.02]

12 Abstracts excluded 14 738 Risk Difference (M-H, Fixed, 95% CI) -0.07 [-0.13, -0.02]

12.1 Parenteral nutrition 2 164 Risk Difference (M-H, Fixed, 95% CI) -0.10 [-0.22, 0.03]

12.2 Enteral nutrition 5 212 Risk Difference (M-H, Fixed, 95% CI) -0.06 [-0.18, 0.05]

12.3 Supplements 7 362 Risk Difference (M-H, Fixed, 95% CI) -0.07 [-0.14, 0.00]

13 Surgical trials excluding trans- plants

5 278 Risk Difference (M-H, Fixed, 95% CI) -0.13 [-0.23, -0.03]

14 Parenteral nutrition - best-case scenario

2 190 Risk Difference (M-H, Fixed, 95% CI) -0.23 [-0.35, -0.11]

335

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Outcome or subgroup title No. of studies

No. of partici- pants

Statistical method Effect size

14.1 Medical trials 1 40 Risk Difference (M-H, Fixed, 95% CI) 0.2 [0.01, 0.39]

14.2 Surgical trials 1 150 Risk Difference (M-H, Fixed, 95% CI) -0.35 [-0.49, -0.21]

15 Parenteral nutrition - worst- case scenario

2 190 Risk Difference (M-H, Fixed, 95% CI) 0.04 [-0.08, 0.16]

15.1 Medical trials 1 40 Risk Difference (M-H, Fixed, 95% CI) 0.2 [0.01, 0.39]

15.2 Surgical trials 1 150 Risk Difference (M-H, Fixed, 95% CI) 0.0 [-0.15, 0.15]

16 Enteral nutrition - best-case scenario

6 298 Risk Difference (M-H, Fixed, 95% CI) -0.17 [-0.27, -0.07]

16.1 Medical trials 4 184 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.21, 0.06]

16.2 Surgical trials 2 114 Risk Difference (M-H, Fixed, 95% CI) -0.32 [-0.46, -0.17]

17 Enteral nutrition - worst-case scenario

6 298 Risk Difference (M-H, Fixed, 95% CI) 0.04 [-0.06, 0.15]

17.1 Medical trials 4 184 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.12, 0.15]

17.2 Surgical trials 2 114 Risk Difference (M-H, Fixed, 95% CI) 0.09 [-0.08, 0.26]

18 Supplements - best-case sce- nario

7 401 Risk Difference (M-H, Fixed, 95% CI) -0.16 [-0.23, -0.10]

18.1 Medical trials 4 286 Risk Difference (M-H, Fixed, 95% CI) -0.13 [-0.21, -0.06]

18.2 Surgical trials 3 115 Risk Difference (M-H, Fixed, 95% CI) -0.24 [-0.40, -0.09]

19 Supplements - worst-case sce- nario

7 401 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.05, 0.10]

19.1 Medical trials 4 286 Risk Difference (M-H, Fixed, 95% CI) -0.00 [-0.08, 0.07]

19.2 Surgical trials 3 115 Risk Difference (M-H, Fixed, 95% CI) 0.09 [-0.06, 0.25]

Analysis 22.1. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 1 All studies.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 4.47% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 7.43% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 2.81% 0.07[-0.21,0.35]

Fan 1994 11/64 22/60 15.93% -0.19[-0.35,-0.04]

Foschi 1986 4/28 9/32 7.68% -0.14[-0.34,0.06]

Hasse 1995 3/14 8/17 3.95% -0.26[-0.58,0.06]

Favours treatment 10.5-1 -0.5 0 Favours control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Hirsch 1993 2/26 9/25 6.56% -0.28[-0.5,-0.07]

Ishikawa 2010 2/11 3/13 3.07% -0.05[-0.37,0.27]

Meng 1999 8/21 9/23 5.65% -0.01[-0.3,0.28]

Mikagi 2011 0/13 1/13 3.34% -0.08[-0.27,0.11]

Nakaya 2007 0/19 0/19 4.89% 0[-0.1,0.1]

Naveau 1986 4/20 0/20 5.14% 0.2[0.01,0.39]

Norman 2008 16/26 22/29 7.05% -0.14[-0.39,0.1]

Poon 2004 0/41 1/43 10.8% -0.02[-0.09,0.04]

Sievert 1999 10/61 7/34 11.23% -0.04[-0.21,0.12]

Total (95% CI) 414 379 100% -0.08[-0.13,-0.02]

Total events: 80 (Treatment), 105 (Control)

Heterogeneity: Tau2=0; Chi2=23.99, df=14(P=0.05); I2=41.64%

Test for overall effect: Z=2.8(P=0.01)

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.2. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 2 Trials with total numbers (Meng) excluded.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 4.74% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 7.87% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 2.97% 0.07[-0.21,0.35]

Fan 1994 11/64 22/60 16.89% -0.19[-0.35,-0.04]

Foschi 1986 4/28 9/32 8.14% -0.14[-0.34,0.06]

Hasse 1995 3/14 8/17 4.19% -0.26[-0.58,0.06]

Hirsch 1993 2/26 9/25 6.95% -0.28[-0.5,-0.07]

Ishikawa 2010 2/11 3/13 3.25% -0.05[-0.37,0.27]

Mikagi 2011 0/13 1/13 3.54% -0.08[-0.27,0.11]

Nakaya 2007 0/19 0/19 5.18% 0[-0.1,0.1]

Naveau 1986 4/20 0/20 5.45% 0.2[0.01,0.39]

Norman 2008 16/26 22/29 7.48% -0.14[-0.39,0.1]

Poon 2004 0/41 1/43 11.44% -0.02[-0.09,0.04]

Sievert 1999 10/61 7/34 11.9% -0.04[-0.21,0.12]

Total (95% CI) 393 356 100% -0.08[-0.14,-0.03]

Total events: 72 (Treatment), 96 (Control)

Heterogeneity: Tau2=0; Chi2=24.51, df=13(P=0.03); I2=46.96%

Test for overall effect: Z=2.91(P=0)

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.3. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 3 Parenteral nutrition.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.3.1 Medical trials

Favours treatment 10.5-1 -0.5 0 Favours control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Naveau 1986 4/20 0/20 24.41% 0.2[0.01,0.39]

Subtotal (95% CI) 20 20 24.41% 0.2[0.01,0.39]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.09(P=0.04)

22.3.2 Surgical trials

Fan 1994 11/64 22/60 75.59% -0.19[-0.35,-0.04]

Subtotal (95% CI) 64 60 75.59% -0.19[-0.35,-0.04]

Total events: 11 (Treatment), 22 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.5(P=0.01)

Total (95% CI) 84 80 100% -0.1[-0.22,0.03]

Total events: 15 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=11.28, df=1(P=0); I2=91.14%

Test for overall effect: Z=1.54(P=0.12)

Test for subgroup differences: Chi2=10.24, df=1 (P=0), I2=90.24%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.4. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 4 Enteral nutrition.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.4.1 Medical trials

Cabre 1990 7/16 7/19 13.38% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 22.25% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 8.4% 0.07[-0.21,0.35]

Norman 2008 16/26 22/29 21.12% -0.14[-0.39,0.1]

Subtotal (95% CI) 96 80 65.16% -0.03[-0.16,0.11]

Total events: 36 (Treatment), 36 (Control)

Heterogeneity: Tau2=0; Chi2=1.66, df=3(P=0.65); I2=0%

Test for overall effect: Z=0.4(P=0.69)

22.4.2 Surgical trials

Foschi 1986 4/28 9/32 23.01% -0.14[-0.34,0.06]

Hasse 1995 3/14 8/17 11.83% -0.26[-0.58,0.06]

Subtotal (95% CI) 42 49 34.84% -0.18[-0.35,-0.01]

Total events: 7 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=0.38, df=1(P=0.54); I2=0%

Test for overall effect: Z=2.03(P=0.04)

Total (95% CI) 138 129 100% -0.08[-0.19,0.03]

Total events: 43 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=3.94, df=5(P=0.56); I2=0%

Test for overall effect: Z=1.47(P=0.14)

Test for subgroup differences: Chi2=1.83, df=1 (P=0.18), I2=45.44%

Favours treatment 10.5-1 -0.5 0 Favours control

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Analysis 22.5. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 5 Supplements.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.5.1 Medical trials

Hirsch 1993 2/26 9/25 14.4% -0.28[-0.5,-0.07]

Nakaya 2007 0/19 0/19 10.73% 0[-0.1,0.1]

Poon 2004 0/41 1/43 23.72% -0.02[-0.09,0.04]

Sievert 1999 10/61 7/34 24.67% -0.04[-0.21,0.12]

Subtotal (95% CI) 147 121 73.52% -0.08[-0.15,-0]

Total events: 12 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=8.97, df=3(P=0.03); I2=66.57%

Test for overall effect: Z=2.04(P=0.04)

22.5.2 Surgical trials

Ishikawa 2010 2/11 3/13 6.73% -0.05[-0.37,0.27]

Meng 1999 8/21 9/23 12.4% -0.01[-0.3,0.28]

Mikagi 2011 0/13 1/13 7.34% -0.08[-0.27,0.11]

Subtotal (95% CI) 45 49 26.48% -0.04[-0.21,0.13]

Total events: 10 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=0.2, df=2(P=0.91); I2=0%

Test for overall effect: Z=0.45(P=0.65)

Total (95% CI) 192 170 100% -0.07[-0.14,0]

Total events: 22 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=7.85, df=6(P=0.25); I2=23.61%

Test for overall effect: Z=1.87(P=0.06)

Test for subgroup differences: Chi2=0.17, df=1 (P=0.68), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.6. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 6 Medical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 7.4% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 12.3% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 4.65% 0.07[-0.21,0.35]

Hirsch 1993 2/26 9/25 10.86% -0.28[-0.5,-0.07]

Nakaya 2007 0/19 0/19 8.1% 0[-0.1,0.1]

Naveau 1986 4/20 0/20 8.52% 0.2[0.01,0.39]

Norman 2008 16/26 22/29 11.68% -0.14[-0.39,0.1]

Poon 2004 0/41 1/43 17.88% -0.02[-0.09,0.04]

Sievert 1999 10/61 7/34 18.6% -0.04[-0.21,0.12]

Total (95% CI) 263 221 100% -0.04[-0.1,0.03]

Total events: 52 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=13.58, df=8(P=0.09); I2=41.09%

Test for overall effect: Z=1.06(P=0.29)

Favours treatment 10.5-1 -0.5 0 Favours control

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Analysis 22.7. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 7 Surgical trials.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 11/64 22/60 40.21% -0.19[-0.35,-0.04]

Foschi 1986 4/28 9/32 19.39% -0.14[-0.34,0.06]

Hasse 1995 3/14 8/17 9.97% -0.26[-0.58,0.06]

Ishikawa 2010 2/11 3/13 7.74% -0.05[-0.37,0.27]

Meng 1999 8/21 9/23 14.25% -0.01[-0.3,0.28]

Mikagi 2011 0/13 1/13 8.44% -0.08[-0.27,0.11]

Total (95% CI) 151 158 100% -0.14[-0.24,-0.05]

Total events: 28 (Treatment), 52 (Control)

Heterogeneity: Tau2=0; Chi2=2.53, df=5(P=0.77); I2=0%

Test for overall effect: Z=2.95(P=0)

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.8. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 8 Alcoholic hepatitis.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Calvey 1985 11/42 6/22 53.11% -0.01[-0.24,0.22]

Hirsch 1993 2/26 9/25 46.89% -0.28[-0.5,-0.07]

Total (95% CI) 68 47 100% -0.14[-0.3,0.02]

Total events: 13 (Treatment), 15 (Control)

Heterogeneity: Tau2=0; Chi2=2.95, df=1(P=0.09); I2=66.06%

Test for overall effect: Z=1.72(P=0.09)

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.9. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 9 Cirrhosis.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.9.1 Parenteral nutrition

Naveau 1986 4/20 0/20 12.21% 0.2[0.01,0.39]

Subtotal (95% CI) 20 20 12.21% 0.2[0.01,0.39]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.09(P=0.04)

22.9.2 Enteral nutrition

Cabre 1990 7/16 7/19 10.6% 0.07[-0.26,0.39]

DeLedinghen 1997 2/12 1/10 6.66% 0.07[-0.21,0.35]

Norman 2008 16/26 22/29 16.73% -0.14[-0.39,0.1]

Subtotal (95% CI) 54 58 33.99% -0.04[-0.2,0.13]

Total events: 25 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=1.66, df=2(P=0.44); I2=0%

Test for overall effect: Z=0.42(P=0.67)

Favours experimental 10.5-1 -0.5 0 Favours control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.9.3 Supplements

Hirsch 1993 2/26 9/25 15.56% -0.28[-0.5,-0.07]

Nakaya 2007 0/19 0/19 11.6% 0[-0.1,0.1]

Sievert 1999 10/61 7/34 26.65% -0.04[-0.21,0.12]

Subtotal (95% CI) 106 78 53.8% -0.1[-0.21,0]

Total events: 12 (Treatment), 16 (Control)

Heterogeneity: Tau2=0; Chi2=7.57, df=2(P=0.02); I2=73.58%

Test for overall effect: Z=1.92(P=0.05)

Total (95% CI) 180 156 100% -0.04[-0.13,0.04]

Total events: 41 (Treatment), 46 (Control)

Heterogeneity: Tau2=0; Chi2=13.75, df=6(P=0.03); I2=56.35%

Test for overall effect: Z=1.01(P=0.31)

Test for subgroup differences: Chi2=7.65, df=1 (P=0.02), I2=73.85%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 22.10. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 10 HCC.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.10.1 Parenteral nutrition

Fan 1994 11/64 22/60 59.6% -0.19[-0.35,-0.04]

Subtotal (95% CI) 64 60 59.6% -0.19[-0.35,-0.04]

Total events: 11 (Treatment), 22 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.5(P=0.01)

22.10.2 Enteral nutrition

Subtotal (95% CI) 0 0 Not estimable

Total events: 0 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

22.10.3 Supplements

Poon 2004 0/41 1/43 40.4% -0.02[-0.09,0.04]

Subtotal (95% CI) 41 43 40.4% -0.02[-0.09,0.04]

Total events: 0 (Treatment), 1 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=0.73(P=0.47)

Total (95% CI) 105 103 100% -0.13[-0.22,-0.03]

Total events: 11 (Treatment), 23 (Control)

Heterogeneity: Tau2=0; Chi2=10.95, df=1(P=0); I2=90.87%

Test for overall effect: Z=2.59(P=0.01)

Test for subgroup differences: Chi2=4.13, df=1 (P=0.04), I2=75.79%

Favours experimental 10.5-1 -0.5 0 Favours control

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Analysis 22.11. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 11 Abstracts excluded.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Cabre 1990 7/16 7/19 4.81% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 7.99% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 3.02% 0.07[-0.21,0.35]

Fan 1994 11/64 22/60 17.14% -0.19[-0.35,-0.04]

Foschi 1986 4/28 9/32 8.27% -0.14[-0.34,0.06]

Hasse 1995 3/14 8/17 4.25% -0.26[-0.58,0.06]

Hirsch 1993 2/26 9/25 7.05% -0.28[-0.5,-0.07]

Ishikawa 2010 2/11 3/13 3.3% -0.05[-0.37,0.27]

Meng 1999 8/21 9/23 6.08% -0.01[-0.3,0.28]

Mikagi 2011 0/13 1/13 3.6% -0.08[-0.27,0.11]

Nakaya 2007 0/19 0/19 5.26% 0[-0.1,0.1]

Naveau 1986 4/20 0/20 5.54% 0.2[0.01,0.39]

Poon 2004 0/41 1/43 11.62% -0.02[-0.09,0.04]

Sievert 1999 10/61 7/34 12.08% -0.04[-0.21,0.12]

Total (95% CI) 388 350 100% -0.07[-0.13,-0.02]

Total events: 64 (Treatment), 83 (Control)

Heterogeneity: Tau2=0; Chi2=22.84, df=13(P=0.04); I2=43.09%

Test for overall effect: Z=2.57(P=0.01)

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.12. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 12 Abstracts excluded.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.12.1 Parenteral nutrition

Fan 1994 11/64 22/60 17.14% -0.19[-0.35,-0.04]

Naveau 1986 4/20 0/20 5.54% 0.2[0.01,0.39]

Subtotal (95% CI) 84 80 22.68% -0.1[-0.22,0.03]

Total events: 15 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=11.28, df=1(P=0); I2=91.14%

Test for overall effect: Z=1.54(P=0.12)

22.12.2 Enteral nutrition

Cabre 1990 7/16 7/19 4.81% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 7.99% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 3.02% 0.07[-0.21,0.35]

Foschi 1986 4/28 9/32 8.27% -0.14[-0.34,0.06]

Hasse 1995 3/14 8/17 4.25% -0.26[-0.58,0.06]

Subtotal (95% CI) 112 100 28.33% -0.06[-0.18,0.05]

Total events: 27 (Treatment), 31 (Control)

Heterogeneity: Tau2=0; Chi2=3.58, df=4(P=0.47); I2=0%

Test for overall effect: Z=1.05(P=0.29)

22.12.3 Supplements

Hirsch 1993 2/26 9/25 7.05% -0.28[-0.5,-0.07]

Ishikawa 2010 2/11 3/13 3.3% -0.05[-0.37,0.27]

Meng 1999 8/21 9/23 6.08% -0.01[-0.3,0.28]

Favours experimental 10.5-1 -0.5 0 Favours control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Mikagi 2011 0/13 1/13 3.6% -0.08[-0.27,0.11]

Nakaya 2007 0/19 0/19 5.26% 0[-0.1,0.1]

Poon 2004 0/41 1/43 11.62% -0.02[-0.09,0.04]

Sievert 1999 10/61 7/34 12.08% -0.04[-0.21,0.12]

Subtotal (95% CI) 192 170 48.99% -0.07[-0.14,0]

Total events: 22 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=7.85, df=6(P=0.25); I2=23.61%

Test for overall effect: Z=1.87(P=0.06)

Total (95% CI) 388 350 100% -0.07[-0.13,-0.02]

Total events: 64 (Treatment), 83 (Control)

Heterogeneity: Tau2=0; Chi2=22.84, df=13(P=0.04); I2=43.09%

Test for overall effect: Z=2.57(P=0.01)

Test for subgroup differences: Chi2=0.21, df=1 (P=0.9), I2=0%

Favours experimental 10.5-1 -0.5 0 Favours control

Analysis 22.13. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 13 Surgical trials excluding transplants.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Fan 1994 11/64 22/60 44.66% -0.19[-0.35,-0.04]

Foschi 1986 4/28 9/32 21.54% -0.14[-0.34,0.06]

Ishikawa 2010 2/11 3/13 8.59% -0.05[-0.37,0.27]

Meng 1999 8/21 9/23 15.83% -0.01[-0.3,0.28]

Mikagi 2011 0/13 1/13 9.37% -0.08[-0.27,0.11]

Total (95% CI) 137 141 100% -0.13[-0.23,-0.03]

Total events: 25 (Treatment), 44 (Control)

Heterogeneity: Tau2=0; Chi2=1.9, df=4(P=0.75); I2=0%

Test for overall effect: Z=2.57(P=0.01)

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.14. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 14 Parenteral nutrition - best-case scenario.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.14.1 Medical trials

Naveau 1986 4/20 0/20 21.05% 0.2[0.01,0.39]

Subtotal (95% CI) 20 20 21.05% 0.2[0.01,0.39]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.09(P=0.04)

22.14.2 Surgical trials

Fan 1994 11/75 37/75 78.95% -0.35[-0.49,-0.21]

Favours treatment 10.5-1 -0.5 0 Favours control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 75 75 78.95% -0.35[-0.49,-0.21]

Total events: 11 (Treatment), 37 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=4.9(P<0.0001)

Total (95% CI) 95 95 100% -0.23[-0.35,-0.11]

Total events: 15 (Treatment), 37 (Control)

Heterogeneity: Tau2=0; Chi2=23.06, df=1(P<0.0001); I2=95.66%

Test for overall effect: Z=3.88(P=0)

Test for subgroup differences: Chi2=21.16, df=1 (P<0.0001), I2=95.27%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.15. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 15 Parenteral nutrition - worst-case scenario.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.15.1 Medical trials

Naveau 1986 4/20 0/20 21.05% 0.2[0.01,0.39]

Subtotal (95% CI) 20 20 21.05% 0.2[0.01,0.39]

Total events: 4 (Treatment), 0 (Control)

Heterogeneity: Not applicable

Test for overall effect: Z=2.09(P=0.04)

22.15.2 Surgical trials

Fan 1994 22/75 22/75 78.95% 0[-0.15,0.15]

Subtotal (95% CI) 75 75 78.95% 0[-0.15,0.15]

Total events: 22 (Treatment), 22 (Control)

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total (95% CI) 95 95 100% 0.04[-0.08,0.16]

Total events: 26 (Treatment), 22 (Control)

Heterogeneity: Tau2=0; Chi2=3.05, df=1(P=0.08); I2=67.25%

Test for overall effect: Z=0.67(P=0.5)

Test for subgroup differences: Chi2=2.73, df=1 (P=0.1), I2=63.37%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.16. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 16 Enteral nutrition - best-case scenario.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.16.1 Medical trials

Cabre 1990 7/16 7/19 11.93% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 19.83% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 7.49% 0.07[-0.21,0.35]

Favours treatment 10.5-1 -0.5 0 Favours control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Norman 2008 16/31 25/32 21.62% -0.27[-0.49,-0.04]

Subtotal (95% CI) 101 83 60.86% -0.08[-0.21,0.06]

Total events: 36 (Treatment), 39 (Control)

Heterogeneity: Tau2=0; Chi2=4.73, df=3(P=0.19); I2=36.61%

Test for overall effect: Z=1.13(P=0.26)

22.16.2 Surgical trials

Foschi 1986 4/32 9/32 21.97% -0.16[-0.35,0.04]

Hasse 1995 3/25 16/25 17.16% -0.52[-0.75,-0.29]

Subtotal (95% CI) 57 57 39.14% -0.32[-0.46,-0.17]

Total events: 7 (Treatment), 25 (Control)

Heterogeneity: Tau2=0; Chi2=5.72, df=1(P=0.02); I2=82.51%

Test for overall effect: Z=4.2(P<0.0001)

Total (95% CI) 158 140 100% -0.17[-0.27,-0.07]

Total events: 43 (Treatment), 64 (Control)

Heterogeneity: Tau2=0; Chi2=16.46, df=5(P=0.01); I2=69.63%

Test for overall effect: Z=3.37(P=0)

Test for subgroup differences: Chi2=5.66, df=1 (P=0.02), I2=82.33%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.17. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 17 Enteral nutrition - worst-case scenario.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.17.1 Medical trials

Cabre 1990 7/16 7/19 11.93% 0.07[-0.26,0.39]

Calvey 1985 11/42 6/22 19.83% -0.01[-0.24,0.22]

DeLedinghen 1997 2/12 1/10 7.49% 0.07[-0.21,0.35]

Norman 2008 21/31 22/32 21.62% -0.01[-0.24,0.22]

Subtotal (95% CI) 101 83 60.86% 0.01[-0.12,0.15]

Total events: 41 (Treatment), 36 (Control)

Heterogeneity: Tau2=0; Chi2=0.33, df=3(P=0.95); I2=0%

Test for overall effect: Z=0.22(P=0.83)

22.17.2 Surgical trials

Foschi 1986 8/32 9/32 21.97% -0.03[-0.25,0.19]

Hasse 1995 14/25 8/25 17.16% 0.24[-0.03,0.51]

Subtotal (95% CI) 57 57 39.14% 0.09[-0.08,0.26]

Total events: 22 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=2.41, df=1(P=0.12); I2=58.54%

Test for overall effect: Z=1.02(P=0.31)

Total (95% CI) 158 140 100% 0.04[-0.06,0.15]

Total events: 63 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=3.01, df=5(P=0.7); I2=0%

Test for overall effect: Z=0.81(P=0.42)

Test for subgroup differences: Chi2=0.45, df=1 (P=0.5), I2=0%

Favours treatment 10.5-1 -0.5 0 Favours control

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Analysis 22.18. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 18 Supplements - best-case scenario.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.18.1 Medical trials

Hirsch 1993 2/32 17/33 16.61% -0.45[-0.64,-0.26]

Nakaya 2007 0/19 0/19 9.71% 0[-0.1,0.1]

Poon 2004 0/44 2/44 22.5% -0.05[-0.12,0.03]

Sievert 1999 10/61 7/34 22.32% -0.04[-0.21,0.12]

Subtotal (95% CI) 156 130 71.15% -0.13[-0.21,-0.06]

Total events: 12 (Treatment), 26 (Control)

Heterogeneity: Tau2=0; Chi2=24.78, df=3(P<0.0001); I2=87.89%

Test for overall effect: Z=3.55(P=0)

22.18.2 Surgical trials

Ishikawa 2010 2/11 3/13 6.09% -0.05[-0.37,0.27]

Meng 1999 8/25 11/25 12.78% -0.12[-0.39,0.15]

Mikagi 2011 0/16 13/25 9.98% -0.52[-0.73,-0.31]

Subtotal (95% CI) 52 63 28.85% -0.24[-0.4,-0.09]

Total events: 10 (Treatment), 27 (Control)

Heterogeneity: Tau2=0; Chi2=9, df=2(P=0.01); I2=77.77%

Test for overall effect: Z=3.05(P=0)

Total (95% CI) 208 193 100% -0.16[-0.23,-0.1]

Total events: 22 (Treatment), 53 (Control)

Heterogeneity: Tau2=0; Chi2=44.03, df=6(P<0.0001); I2=86.37%

Test for overall effect: Z=4.69(P<0.0001)

Test for subgroup differences: Chi2=1.56, df=1 (P=0.21), I2=35.99%

Favours treatment 10.5-1 -0.5 0 Favours control

Analysis 22.19. Comparison 22 Infections - absolute risk di<erence (ARD), Outcome 19 Supplements - worst-case scenario.

Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

22.19.1 Medical trials

Hirsch 1993 8/32 9/33 16.61% -0.02[-0.24,0.19]

Nakaya 2007 0/19 0/19 9.71% 0[-0.1,0.1]

Poon 2004 3/44 1/44 22.5% 0.05[-0.04,0.13]

Sievert 1999 10/61 7/34 22.32% -0.04[-0.21,0.12]

Subtotal (95% CI) 156 130 71.15% -0[-0.08,0.07]

Total events: 21 (Treatment), 17 (Control)

Heterogeneity: Tau2=0; Chi2=1.5, df=3(P=0.68); I2=0%

Test for overall effect: Z=0.1(P=0.92)

22.19.2 Surgical trials

Ishikawa 2010 2/11 3/13 6.09% -0.05[-0.37,0.27]

Meng 1999 12/25 9/25 12.78% 0.12[-0.15,0.39]

Mikagi 2011 3/16 1/25 9.98% 0.15[-0.06,0.35]

Favours treatment 10.5-1 -0.5 0 Favours control

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Study or subgroup Treatment Control Risk Difference Weight Risk Difference n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Subtotal (95% CI) 52 63 28.85% 0.09[-0.06,0.25]

Total events: 17 (Treatment), 13 (Control)

Heterogeneity: Tau2=0; Chi2=1.05, df=2(P=0.59); I2=0%

Test for overall effect: Z=1.18(P=0.24)

Total (95% CI) 208 193 100% 0.02[-0.05,0.1]

Total events: 38 (Treatment), 30 (Control)

Heterogeneity: Tau2=0; Chi2=3.33, df=6(P=0.77); I2=0%

Test for overall effect: Z=0.66(P=0.51)

Test for subgroup differences: Chi2=1.22, df=1 (P=0.27), I2=17.73%

Favours treatment 10.5-1 -0.5 0 Favours control

Comparison 23. Serum albumin

Outcome or subgroup title

No. of studies

No. of partici- pants

Statistical method Effect size

1 Parenteral nutrition 5 230 Mean Difference (IV, Fixed, 95% CI) -0.09 [-0.30, 0.12]

1.1 Medical 3 95 Mean Difference (IV, Fixed, 95% CI) -0.11 [-0.34, 0.11]

1.2 Surgical 2 135 Mean Difference (IV, Fixed, 95% CI) 0.16 [-0.51, 0.83]

2 Enteral nutrition 4 151 Mean Difference (IV, Fixed, 95% CI) 0.03 [-0.17, 0.23]

2.1 Medical 4 151 Mean Difference (IV, Fixed, 95% CI) 0.03 [-0.17, 0.23]

2.2 Surgical 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

3 Supplements 9 477 Mean Difference (IV, Fixed, 95% CI) -0.09 [-0.18, 0.00]

3.1 Medical 9 477 Mean Difference (IV, Fixed, 95% CI) -0.09 [-0.18, 0.00]

3.2 Surgical 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

Analysis 23.1. Comparison 23 Serum albumin, Outcome 1 Parenteral nutrition.

Study or subgroup Experimental Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

23.1.1 Medical

Achord 1987 14 3.3 (0.8) 14 3.1 (0.8) 14.48% 0.2[-0.36,0.76]

Naveau 1986 20 2.9 (0.4) 20 3.4 (0.6) 44.75% -0.5[-0.82,-0.18]

Simon 1988 12 3 (0.6) 15 2.7 (0.4) 30.71% 0.3[-0.08,0.68]

Subtotal *** 46 49 89.94% -0.11[-0.34,0.11]

Heterogeneity: Tau2=0; Chi2=11.48, df=2(P=0); I2=82.58%

Test for overall effect: Z=1(P=0.32)

Favours control 21-2 -1 0 Favours experimental

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Study or subgroup Experimental Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

23.1.2 Surgical

Qiu 2009 44 3.5 (1.7) 21 3.3 (1.3) 7.64% 0.12[-0.64,0.89]

Zheng 2003 40 3.2 (3.2) 30 2.9 (2.6) 2.42% 0.27[-1.09,1.63]

Subtotal *** 84 51 10.06% 0.16[-0.51,0.83]

Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.85); I2=0%

Test for overall effect: Z=0.47(P=0.64)

Total *** 130 100 100% -0.09[-0.3,0.12]

Heterogeneity: Tau2=0; Chi2=12.1, df=4(P=0.02); I2=66.93%

Test for overall effect: Z=0.8(P=0.42)

Test for subgroup differences: Chi2=0.58, df=1 (P=0.45), I2=0%

Favours control 21-2 -1 0 Favours experimental

Analysis 23.2. Comparison 23 Serum albumin, Outcome 2 Enteral nutrition.

Study or subgroup Experimental Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

23.2.1 Medical

Cabre 1990 16 2.9 (0.5) 19 2.6 (0.7) 26.64% 0.35[-0.04,0.74]

DeLedinghen 1997 12 2.9 (1.4) 10 2.7 (1.6) 2.55% 0.14[-1.11,1.39]

Kearns 1992 16 2.9 (0.8) 15 3 (1.2) 8.04% -0.1[-0.81,0.61]

Norman 2008 31 2.8 (0.6) 32 2.9 (0.4) 62.76% -0.1[-0.35,0.15]

Subtotal *** 75 76 100% 0.03[-0.17,0.23]

Heterogeneity: Tau2=0; Chi2=3.79, df=3(P=0.28); I2=20.89%

Test for overall effect: Z=0.25(P=0.8)

23.2.2 Surgical

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total *** 75 76 100% 0.03[-0.17,0.23]

Heterogeneity: Tau2=0; Chi2=3.79, df=3(P=0.28); I2=20.89%

Test for overall effect: Z=0.25(P=0.8)

Test for subgroup differences: Not applicable

Favours experimental 42-4 -2 0 Favours control

Analysis 23.3. Comparison 23 Serum albumin, Outcome 3 Supplements.

Study or subgroup Experimental Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

23.3.1 Medical

Bunout 1989 17 2.2 (0.6) 19 2.3 (0.3) 8.13% -0.02[-0.35,0.31]

Hayashi 1991 34 3 (0.6) 31 3.1 (0.7) 8.45% -0.13[-0.45,0.19]

Hirsch 1993 26 3.8 (3.1) 25 3.8 (2) 0.43% 0[-1.41,1.41]

Humbert 1988 27 2.8 (0.5) 22 3.2 (0.6) 8.65% -0.33[-0.65,-0.01]

Ichikawa 2010 12 3.5 (0.7) 9 3.4 (0.7) 2.32% 0.09[-0.52,0.7]

Favours control 21-2 -1 0 Favours intervention

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Study or subgroup Experimental Control Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI

Nakaya 2007 19 3.2 (0.4) 19 3 (0.4) 13.36% 0.2[-0.05,0.45]

San-In Group 1997 67 4 (0.5) 65 4 (0.5) 35.08% 0[-0.16,0.16]

Takeshita 2009 28 3.2 (0.5) 28 3.5 (0.3) 21.19% -0.35[-0.55,-0.15]

Tangkijvanich 2000 14 3.7 (0.8) 15 3.9 (0.8) 2.39% -0.23[-0.83,0.37]

Subtotal *** 244 233 100% -0.09[-0.18,0]

Heterogeneity: Tau2=0; Chi2=15.63, df=8(P=0.05); I2=48.82%

Test for overall effect: Z=1.94(P=0.05)

23.3.2 Surgical

Subtotal *** 0 0 Not estimable

Heterogeneity: Not applicable

Test for overall effect: Not applicable

Total *** 244 233 100% -0.09[-0.18,0]

Heterogeneity: Tau2=0; Chi2=15.63, df=8(P=0.05); I2=48.82%

Test for overall effect: Z=1.94(P=0.05)

Test for subgroup differences: Not applicable

Favours control 21-2 -1 0 Favours intervention

A D D I T I O N A L T A B L E S

Catego- ry of nu- tritional support

Category of patient

Number trials

Publi- cation status (full pa- pers/ab- stracts)

Disease states Total num- ber pa- tients (range)

Parenteral nutrition

Medical 4 4/0 Alcoholic hepatitis, alcoholic cirrhosis. 170 (21 to 69)

Surgical 5 5/0 Resectable hepatocellular carcinoma, portocaval shunt, liver transplantation, various surgeries in patients with cirrhosis.

333 (20 to 150)

Enteral nutrition

Medical 7 4/3 Malnourished cirrhotics, alcoholic hepatitis, alcoholic liver dis- ease, stabilized variceal bleeding, awaiting transplantation in hospital, decompensated cirrhosis.

279 (22 to 64)

Surgical 2 2/0 Obstructive jaundice, liver transplantation. 114 (50, 64)

Supple- ments

Medical 14 11/3 Cirrhosis (+ malnutrition, encephalopathy, other evidence of decompensation), alcoholic hepatitis, hepatocellular carcino- ma (unresectable or postoperative resection).

1003 (15 to 233)

Surgical 5 5/0 Resection of hepatocellular carcinoma or a variety of benign and malignant liver tumours, liver transplantation.

285 (38 to 82)

Table 1. Details of included studies

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A P P E N D I C E S

Appendix 1. Search strategies

Database Span of Search Search strategy

Cochrane Hepa- to-Biliary Group Controlled Trials Register

January 18, 2012 (alimentation OR 'branched chain amino acids' OR BCAA OR 'Dietary disorder*' OR 'Enter- al nutrition' OR Enterostom* OR 'Fat emulsion' or 'formulated food*' OR Gastrostom* OR Hyperalimentation* OR 'Hypocaloric alimentation*' OR 'Hypocaloric nutrition' OR 'Intra- gastric feed*' OR 'Intragastric nutrition' OR Nutrition OR 'Nutrition diseases' OR 'Nutrition disorders' OR 'Nutrition supplement*' OR 'Parenteral nutrition' OR 'Percutaneous endo- scopic gastrostom*' OR 'Peripheral parenteral nutrition' OR 'Permissive underfeeding' OR 'Post-pyloric feeding' OR 'Post-pyloric nutrition' OR 'Protein hydrolysate' OR 'Supplemen- tal feed*' OR 'Total parenteral nutrition') AND ('Alcoholic liver disease*' OR Ascites OR Cir- rhosis OR 'Esophageal varic*' OR Hepat* OR Liver OR Varic*)

Cochrane Cen- tral Register of Controlled Trials (CENTRAL) in The Cochrane Library

Issue 4, 2011 #1 MeSH descriptor Feeding Methods explode all trees #2 MeSH descriptor Nutrition Therapy explode all trees #3 MeSH descriptor Enterostomy explode all trees #4 MeSH descriptor Fat Emulsions, Intravenous explode all trees #5 MeSH descriptor Food, Formulated explode all trees #6 MeSH descriptor Gastrostomy explode all trees #7 MeSH descriptor Nutrition Disorders explode all trees #8 MeSH descriptor Protein Hydrolysates explode all trees #9 alimentation OR branched chain amino acids OR BCAA OR Dietary disorder* OR Enter- al nutrition OR Enterostom* OR Fat emulsion or formulated food* OR Gastrostom* OR Hy- peralimentation* OR Hypocaloric alimentation* OR Hypocaloric nutrition OR Intragas- tric feed* OR Intragastric nutrition OR Nutrition OR Nutrition diseases OR Nutrition disor- ders OR Nutrition supplement* OR Parenteral nutrition OR Percutaneous endoscopic gas- trostom* OR Peripheral parenteral nutrition OR Permissive underfeeding OR Post-pyloric feeding OR Post-pyloric nutrition OR Protein hydrolysate OR Supplemental feed* OR Total parenteral nutrition #10 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9) #11 MeSH descriptor Liver Diseases explode all trees #12 MeSH descriptor Fibrosisexplode all trees #13 MeSH descriptor Ascitesexplode all trees #14 MeSH descriptor Liver Transplantation explode all trees #15 MeSH descriptor Varicose Veins explode all trees #16 Alcoholic liver disease* OR Ascites OR Cirrhosis OR Esophageal varic* OR Hepat* OR Liver OR Varic* #17 (#11 OR #12 OR #13 OR #14 OR #15 OR #16) #18 (#10 AND #17)

MEDLINE (Ovid SP)

1948 to January 18, 2012

1. exp Feeding Methods/ 2. exp Nutrition Therapy/ 3. exp Enterostomy/ 4. exp Fat Emulsions, Intravenous/ 5. exp Food, Formulated/ 6. exp Gastrostomy/ 7. exp Nutrition Disorders/ 8. exp Protein Hydrolysates/ 9. (alimentation or branched chain amino acids or BCAA or Dietary disorder$ or Enteral nutrition or Enterostom$ or Fat emulsion or formulated food$ or Gastrostom$ or Hyperal- imentation$ or Hypocaloric alimentation$ or Hypocaloric nutrition or Intragastric feed$ or Intragastric nutrition or Nutrition or Nutrition diseases or Nutrition disorders or Nutri- tion supplement$ or Parenteral nutrition or Percutaneous endoscopic gastrostom$ or Pe- ripheral parenteral nutrition or Permissive underfeeding or Post-pyloric feeding or Post- pyloric nutrition or Protein hydrolysate or Supplemental feed$ or Total parenteral nu-

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trition).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 10. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 11. exp Liver Diseases/ 12. exp Fibrosis/ 13. exp Ascites/ 14. exp Liver Transplantation/ 15. exp Varicose Veins/ 16. (Alcoholic liver disease$ or Ascites or Cirrhosis or Esophageal varic$ or Hepat$ or Liver or Varic$).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 17. 11 or 16 or 13 or 12 or 15 or 14 18. 10 and 17 19. (random$ or blind$ or placebo$ or meta-analysis).mp. [mp=title, original title, ab- stract, name of substance word, subject heading word] 20. 18 and 19

EMBASE (Ovid SP) From 1980 to Jan- uary 18, 2012

1. exp Diet Therapy/ 2. exp Artificial Feeding/ 3. exp Enterostomy/ 4. exp Lipid Emulsion/ 5. exp Gastrostomy/ 6. exp Nutrition/ 7. exp Nutritional Disorder/ 8. exp Diet Supplementation/ 9. exp Percutaneous Endoscopic Gastrostomy/ 10. exp Protein Hydrolysate/ 11. (alimentation or branched chain amino acids or BCAA or Dietary disorder$ or Enteral nutrition or Enterostom$ or Fat emulsion or formulated food$ or Gastrostom$ or Hyperal- imentation$ or Hypocaloric alimentation$ or Hypocaloric nutrition or Intragastric feed$ or Intragastric nutrition or Nutrition or Nutrition diseases or Nutrition disorders or Nutri- tion supplement$ or Parenteral nutrition or Percutaneous endoscopic gastrostom$ or Pe- ripheral parenteral nutrition or Permissive underfeeding or Post-pyloric feeding or Post- pyloric nutrition or Protein hydrolysate or Supplemental feed$ or Total parenteral nutri- tion).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 12. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 13. exp Liver Disease/ 14. exp Ascites/ 15. exp Esophagus Varices/ 16. exp Hepatic Encephalopathy/ 17. exp Liver Cancer/ 18. exp Liver Failure/ 19. exp Liver Transplantation/ 20. exp Liver/ 21. (Alcoholic liver disease$ or Ascites or Cirrhosis or Esophageal varic$ or Hepat$ or Liv- er or Varic$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 22. 21 or 17 or 20 or 15 or 14 or 18 or 13 or 16 or 19 23. 22 and 12 24. (random$ or blind$ or placebo$ or meta-analysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug man- ufacturer name] 25. 24 and 23

Science Cita- tion Index Ex- panded (http:// portal.isiknowl- edge.com/por-

From 1900 to Jan- uary 18, 2012

# 4 (#3 AND #2 AND #1) # 3 TS=(random* OR blind* OR placebo* OR meta-analysis) # 2 TS=('Alcoholic liver disease*' OR Ascites OR Cirrhosis OR 'Esophageal varic*' OR He- pat* OR Liver OR Varic*)

(Continued)

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tal.cgi?DestAp- p=WOS&Func=Frame)

# 1TS=(alimentation OR 'branched chain amino acids' OR BCAA OR 'Dietary disorder*' OR 'Enteral nutrition' OR Enterostom* OR 'Fat emulsion' or 'formulated food*' OR Gastros- tom* OR Hyperalimentation* OR 'Hypocaloric alimentation*' OR 'Hypocaloric nutrition' OR 'Intragastric feed*' OR 'Intragastric nutrition' OR Nutrition OR 'Nutrition diseases' OR 'Nutrition disorders' OR 'Nutrition supplement*' OR 'Parenteral nutrition' OR 'Percuta- neous endoscopic gastrostom*' OR 'Peripheral parenteral nutrition' OR 'Permissive un- derfeeding' OR 'Post-pyloric feeding' OR 'Post-pyloric nutrition' OR 'Protein hydrolysate' OR 'Supplemental feed*' OR 'Total parenteral nutrition')

Clinicaltrials.gov November 14, 2011

'Liver disease" AND 'Nutrition'

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C O N T R I B U T I O N S O F A U T H O R S

RK designed the review and wrote the protocol; RK was involved in screening the computer searches to identify pertinent articles, deciding on the eligibility of each trial identified, abstracting the data from each eligible trial, entering the data into RevMan, and writing the report. AA assisted in the writing of the protocol and was involved in screening the computer searches for identifying pertinent articles, deciding on the eligibility of each trial, abstracting the data, and writing the report. TL was involved in deciding on the eligibility of each trial identified, abstracting the data, and writing the report.

D E C L A R A T I O N S O F I N T E R E S T

Neither RK, AA, or TL have any real or potential conflict of interest with any party (commercial or third party payers). There was no external or internal funding source that sponsored this review.

S O U R C E S O F S U P P O R T

Internal sources• No sources of support supplied External sources• None, Not specified. D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

1. Emma Metcalfe was unable to participate as author and her name was dropped from the review.

2. Because over 8000 titles were initially identified, RK alone reviewed all of the titles. A sample of 500 were sent to AA, who did not identify any trials that were not also identified by RK. It was therefore assumed that the RK review was adequate and RK alone subsequently reviewed all of the titles from subsequent literature searches.

3. Jaundice, as defined by a serum bilirubin > 3 mg%, was added as a secondary outcome and was considered as representing a manifes- tation of hepatic morbidity.

4. When not specified in the paper, alcoholic hepatitis was defined as a history of recent alcohol usage in a patient who presented with decompensated (one or more of jaundice, variceal bleeding, ascites, encephalopathy, coagulopathy) liver disease.

5. The subgroup and sensitivity analyses were only performed for the outcomes for which meta-analyses were available.

6. The results were reported from the fixed-effect model unless one, but not the other, model found a significant difference, in which case the results of both models were reported.

7. It was initially intended to assess individual disease states, including 'alcoholic liver disease' and 'non-alcoholic liver disease'. However, each category contained patients with a variety of different diagnoses. As the intent of the analysis was to assess particular diseases, these two analyses were not done. However, a separate category, namely patients with cirrhosis, was added.

8. At the Cochrane Colloquium in Keystone, Colorado, in 2010, a policy was adopted that baseline imbalance and early stopping no longer be routinely considered in the assessment of the risk of bias of trials. These two domains were eliminated from among those considered in assessing risk of bias, although the information, already collected, was retained in the description of each trial.

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9. In accordance with Cochrane Hepato-Biliary Group policy, the primary outcomes were changed to mortality, morbidity, quality of life, and adverse events; the other outcomes became secondary ones.

10. Because immediate postoperative nutritional support in surgical trials in non-transplanted patients was to be considered, any trials assessing perioperative (including immediate postoperative) nutritional interventions were included. The word 'preoperative' in the pro- tocol was changed to 'perioperative'.

11. At the request of an external reviewer, the serum albumin was also assessed . However, since this was a post hoc analysis of a continuous outcome in one specific application and done by request, we did not include albumin as another secondary outcome in the systematic review as a whole. Furthermore, we did not view the serum albumin as a marker of nutrition since it is influenced by the underlying liver disease as well as by circulating cytokines.

12. Because two trials with factorial designs were identified, it was decided to use only the data from the groups receiving the nutritional intervention and the group receiving neither intervention if possible; but, if the data were only available from the combined groups, to use those instead.

13. Because surgical trials in patients without cirrhosis would not be expected to observe postoperative ascites or encephalopathy, it was decided to add postoperative complications as the primary morbidity outcome in such situations.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Ascites [prevention & control]; Enteral Nutrition [*methods]; Hepatic Encephalopathy [therapy]; Infection; Liver Diseases [*therapy]; Parenteral Nutrition [*methods]; Postoperative Complications [prevention & control]; Randomized Controlled Trials as Topic

MeSH check words

Humans

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