PICO

RESEARCH ARTICLE Open Access

Retrospective case-control non-inferiority analysis of intravenous lidocaine in a colorectal surgery enhanced recovery program Bhiken I. Naik1,2*, Siny Tsang3, Anne Knisely1, Sandeep Yerra1 and Marcel E. Durieux1,2

Abstract

Background: Enhanced recovery after surgery (ERAS) programs typically utilizes multi-modal analgesia to reduce perioperative opioid consumption. Systemic lidocaine is used in several of these ERAS algorithms and has been shown to reduce opioid use after colorectal surgery. However it is unclear how much the other components of an ERAS protocol contribute to the final outcome. Using a noninferiority analysis we sought to assess the role of perioperative lidocaine in an ERAS program for colorectal surgery, using pain and opioid consumption as outcomes.

Methods: We conducted a retrospective review of patients who had received intravenous lidocaine perioperatively during colorectal surgery. We matched them with patients who were managed using a multi-component ERAS protocol, which included perioperative lidocaine. We tested a joint hypothesis of noninferiority of lidocaine infusion to ERAS protocol in postoperative pain scores and opioid consumption. We assigned a noninferiority margin of 1 point (on an 11-point numerical rating scale) difference in pain and a ratio [mean (lidocaine) / mean (ERAS)] of 1.2 in opioid consumption, respectively.

Results: Fifty-two patients in the lidocaine group were matched with patients in the ERAS group. With regards to opioid consumption, in the overall [1.68 (1.43–1.98)] [odds ratio (95% confidence interval)] analysis and on postoperative day (POD) 1 [2.38 (1.74–3.31)] lidocaine alone was inferior to multi-modal analgesia. On POD 2 and beyond, although the mean odds ratio for opioid consumption was 1.43 [1.43 (1.17–1.73)], the lower limit extended beyond the pre-defined cut-off of 1.2, rendering the outcome inconclusive. For pain scores lidocaine is non-inferior to ERAS [-0.17 (-1.08–0.74)] on POD 2 and beyond. Pain scores on POD 1 and in the overall cohort were inconclusive based on the noninferiority analysis.

Conclusions: The addition of a multi-component ERAS protocol to intravenous lidocaine incrementally reduces opioid consumption, most evident on POD 1. For pain scores the data is inconclusive on POD 1, however on POD 2 and beyond lidocaine alone is non-inferior to an ERAS program with lidocaine. Opioid-related complications, including return of bowel function, were not different between the groups despite reduced opioid use in the ERAS group.

Keywords: Lidocaine, Enhanced Recovery After Surgery, Colorectal Surgery, Opioid Consumption, Pain Scores

* Correspondence: [email protected] 1Department of Anesthesiology, University of Virginia, Charlottesville, VA, USA 2Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA Full list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Naik et al. BMC Anesthesiology (2017) 17:16 DOI 10.1186/s12871-017-0306-6

Background Enhanced Recovery After Surgery (ERAS) protocols are evidence-based algorithms first described by Kehlet almost two decades ago [1] ERAS protocols have im- proved patient satisfaction and outcomes with a concomi- tant reduction in perioperative opioid use [2, 3]. Enhanced recovery protocols typically utilize multi-

modal analgesia to reduce perioperative opioid use. Whereas the benefits of multi-modal analgesic approaches are well demonstrated, it is less clear which components are essential and which have little effect on outcome. As each component adds some degree of work, cost and potential risk, it is important to define how each compo- nent contributes to pain management. Intravenous lidocaine has gained increasing popularity

over the last decade [4–6]. Systemic lidocaine has anal- gesic, anti-hyperalgesic and anti-inflammatory properties, making it a virtually ideal agent for pain management dur- ing the perioperative period [7]. The short- and long-term benefits of lidocaine have been demonstrated across a variety of surgical procedures including colorectal, breast and spine surgery [6, 8, 9]. Several meta-analyses have reported that intravenous lidocaine during abdominal surgery decreases postoperative pain severity, reduces opioid consumption and nausea and vomiting, improves gastrointestinal function and shortens length of hospital stay [4, 5]. Using a noninferiority analysis we recently reported that after major abdominal surgery patients who received intravenous lidocaine had clinically similar pain scores on postoperative day (POD) 2 and beyond com- pared with patients receiving epidural analgesia [10]. Given these effects, it can be hypothesized that intra-

venous lidocaine provides the majority of the analgesic benefits of any ERAS protocol, even if the protocol contains many additional interventions. If so, those other components could be eliminated without affecting out- come, which would likely reduce cost and improves safety. At our institution we utilized perioperative lido- caine with opioid-based analgesia for colorectal surgery, and then implemented an ERAS program that included perioperative lidocaine but added multi-modal analgesia, opioid restriction and fluid and activity interventions. This practice change allowed a comparison between the two approaches as to pain scores, opioid consumption and side effects. We hypothesized that in colorectal surgery perioperative

systemic lidocaine with opioid analgesia is non-inferior to a full ERAS protocol with regards to the endpoints of postoperative pain scores and opioid consumption.

Methods This study was initially performed as a quality improve- ment project with approval from our local departmental quality improvement committee. Subsequent approval for

publication of the data was obtained from the Univer- sity of Virginia institutional review board (HSR #10712) and the need to obtain consent was waived. The study period was from January 2013 to June 2015 and in- cluded all patients who underwent colorectal surgery. The two cohorts identified were patients who received perioperative lidocaine with opioid-based postoperative analgesia (LIDO group) and those who were part of an ERAS program that included multi-modal analgesia and perioperative lidocaine, as well as restriction of intravenous fluids and encouragement of oral fluid intake and ambulation (ERAS group). Patients were matched by age (within 5 years), gender and chronic opioid use (>1 month). As described in our previous study, we assigned a non-

inferiority margin of 1-point (on an 11-point numerical rating scale) difference in pain and a ratio [mean (LIDO) / mean (ERAS)] of 1.2 in opioid consumption [10, 11]. Noninferiority is established when the lower bound of the 95% confidence interval (CI) does not cross the inferiority margin, whereas the comparison is rendered inconclusive if the lower bound 95% CI does cross the inferiority margin [12]. We wished to know if lidocaine alone was no less effective than an ERAS program; therefore a non- inferiority analysis, as opposed to a superiority analysis was conducted. The primary outcome was patient-reported pain

scores at rest and opioid consumption for the first four postoperative days or discharge if earlier. Secondary outcomes include hypotension (defined by any blood pressure requiring adjusting/holding the pain regimen, additional fluid administration or administration of inotropes/vasopressors), patient-reported nausea and documented vomiting, pruritus, urinary retention re- quiring catheterization, duration of indwelling urinary catheterization, time to first ambulation, time to first bowel movement and duration of hospital stay. The re- gional anesthesia team monitored the lidocaine infusion and collected data on patient satisfaction and mental status.

Anesthetic and analgesic regimen The anesthetic regimen in both groups included general anesthesia with endotracheal intubation. The typical induc- tion agent was propofol with muscle relaxation achieved with either succinylcholine or rocuronium. Anesthesia was maintained with either sevoflurane or desflurane. If rever- sal of neuromuscular blockade was required, neostigmine and glycopyrrolate were administered.

LIDO group In the LIDO group, intraoperative opioid administration was at the discretion of the anesthesiology provider. A lidocaine infusion was started following induction of

Naik et al. BMC Anesthesiology (2017) 17:16 Page 2 of 10

general anesthesia at a rate of 2–3 mg/min, based on previous reported dosing regimens [13, 14]. Prior to transfer to the recovery room the infusion was decreased to 0.5–1 mg/min. The infusion was continued between 0.5 and 1 mg/min for 2–5 days postoperatively. Postoperatively, hydromorphone patient-controlled

analgesia (PCA) was commenced at a dose of 0.1 to 0.2 mg hydromorphone per bolus, and opioid-tolerant patients received 0.3 to 0.4 mg hydromorphone per bolus; both groups had an 8-min lockout. Patients who did not receive a PCA were given 0.5 to 1.0 mg intravenous hydromorphone every hour as needed. Acetaminophen was administered intravenously ini- tially with a total dose that did not exceed 4 gram/day. Acetaminophen was changed to an oral formulation when oral intake resumed. Oxycodone was started when oral intake permitted to facilitate transitioning off the PCA. At this time the lidocaine infusion was typically discontinued.

ERAS group In the ERAS group, prior to surgery, patients received an oral regimen of celecoxib 200 mg (not given to pa- tient with coronary artery disease), acetaminophen 975 mg and gabapentin 600 mg (Table 1). The components of the intraoperative multi-modal

analgesia included: (1) Prior to induction of anesthesia, a single intrathecal dose of preservative free morphine (100 mcg), (2) ketamine 0.5 mg/kg IV at induction followed by an infusion at 0.6 mg/kg/h (stopped 45-min before closure for laparoscopic cases and decreased to 0.3 mg/kg/h in open cases until completion of the case

(3) magnesium 30 mg/kg intravenously at induction, (4) dexamethasone 4 mg at induction (Table 1). An intravenous lidocaine infusion was commenced as in

the LIDO group for the perioperative period. Intraopera- tive intravenous opioid administration was only adminis- tered following approval of the attending anesthesiologist. Postoperatively 1 g intravenous acetaminophen was

administered every 6 h after initial dose and every 6 h subsequently. Oral oxycodone 5 mg, 10 mg and 15 mg every 4 h as required for mild, moderate and severe pain respectively was prescribed. No PCA was utilized. Cele- coxib 100 mg was administered twice daily in patients without coronary artery disease.

Data collection and synthesis Perioperative data was collected from the anesthesia infor- mation system and electronic health record. All opioids used during the intraoperative and postoperative period were converted to morphine equivalents for analysis [15]. Intrathecal morphine was converted to oral morphine by a ratio of 1: 100. A 11-point visual analog scale (VAS) was used to rate postoperative pain. Hypotension was defined as any blood pressure that required administration of fluids, inotropes, or vasopressors or withholding pain medication. Postoperative nausea was identified as any pa- tient requiring treatment. Time to ambulation, first bowel movement or passage of flatus, removal of indwelling urinary catheter and discharge from hospital were calcu- lated from the time the patient left the operating room. Patient satisfaction was measured using a binary variable (yes/no). Patients were asked regularly about peri-oral numbness/tingling, dizziness, tinnitus, diplopia, seizures, arrhythmia, extremity numbness and muscle twitching to

Table 1 Perioperative analgesia regimen in the standard therapy-perioperative lidocaine and enhanced recovery multi-modal analgesia-perioperative lidocaine group

Perioperative Analgesia Regimen

Standard Therapy-Perioperative Lidocaine ER Multi-Modal Analgesia-Perioperative Lidocaine

Preoperative 1. None 1. Celecoxib 200 mg POc

2. Acetaminophen 975 mg PO 3. Gabapentin 600 mg PO

Intraoperative 1. Intravenous lidocaine 2–3 mg/min 2. Intravenous Opioidsa

3. Intravenous Ketaminea

1. Intravenous lidocaine 2–3 mg/min 2. Single intrathecal dose of preservative free morphine (100 μg) 3. Ketamine 0.5 mg/kg IV at induction followed by an infusion at 0.6 mg/kg/h (stopped 45-min before closure for laparoscopic cases and decreased to 0.3 mg/kg/h in open cases until completion of the case

4. Magnesium 30 mg/kg intravenously at induction 5. Dexamethasone 4 mg at induction 6. Intravenous opioidsb

Postoperatively 1. Intravenous lidocaine 0.5–1 mg/min 2. Hydromorphone PCA and oral oxycodone 3. Acetaminophen

1. Intravenous lidocaine 0.5–1 mg/min 2. Celecoxib 100 mg twice daily 3. No opioid PCA 4. Oral oxycodone 5. Acetaminophen

PO-per oral, μg-microgram, mg-milligram aDiscretion of anesthesiology provider. bAfter approval of attending anesthesiologist.cNot administered to patients with coronary artery disease

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assess for lidocaine toxicity, as is standard for our practice. Postoperative mental status was assessed using the follow- ing scale: awake/alert, confused, somnolent, arouses with simulation, difficult to arouse, or unresponsive.

Power analysis As we did not foresee the use of the data for the current study at the time of data collection, an a priori power analysis was not conducted. The size of the con- fidence interval provides an indication of the likelihood of the real effect size being zero or very small. For our non-inferiority study, the upper limit of the confidence interval is an estimation of the maximum effect size supported by the current data. We feel it is inappropriate to perform post-hoc power

calculations in this setting, because the calculated power (i.e., “observed” power obtained from the model estimates) is a function of the p-values of the model estimates, meaning that post-hoc power analysis does not provide additional information to the results [16]. In addition, when there is a non-significant finding (such as the ones in the current study), a higher post- hoc power provides stronger evidence against the null hypothesis [17].

Statistical analysis Normality of data was established using the Shapiro- Wilk test. Normally distributed data are reported as mean and SD while non-normally distributed data are reported as median and 25th-75th interquartile range. The two primary outcomes (postoperative pain and

opioid consumption) were assessed postoperatively in the recovery room, and every 12 h for up to 4 days. Mixed- effects models were used to examine the changes in the primary outcomes over time, taking into account the within-individual correlations between assessments. The mixed-effects model found to be best fit the

changes in the overall postoperative pain scores is:

Y ij ¼ β0 þ β1x1ij þ β2x2ij þ bi0 þ bi1z1ij þ εij

where Yij is the postoperative pain score for observation j in patient i; x1ij refers to the linear time (number of days), and x2ij refers to the analgesia group (ERAS vs. LIDO) fixed effects for observation j in patient i; β0 is the random intercept for patient i, z1ij is the random slope for time; and εij is the error for observation j in patient i. This model indicates that the change in post- operative pain scores follows a linear trend over time, with between-patient heterogeneity in initial postopera- tive pain scores (in recovery room) and the rate of changes in pain scores across time. The same model was fitted to the changes in postoperative pain scores POD1 only, and POD2 to POD4.

The mixed-effects model found to be best fit the changes in the overall postoperative morphine consump- tion is:

Y ij ¼ β0 þ β1x1ij þ β2x2ij þ β3x3ij þ bi0 þ bi1z1ij þ εij

where Yij is the postoperative morphine consumption for observation j in patient i; x1ij refers to the linear time (number of days), x2ij refers to the quadratic (non-linear) time, and x3ij refers to the analgesia group (ERAS vs. LIDO) fixed effects for observation j in patient i; β0 is the random intercept for patient i, z1ij is the random slope for time; and εij is the error for observation j in pa- tient i. This model indicates that the change in morphine consumption follows a non-linear trend over time, with between-patient heterogeneity in initial postoperative pain scores (in recovery room) and the rate of changes in pain scores across time. The same model was fitted to the changes in postoperative morphine consumption POD1 only. However, the model without the quadratic time fixed effects was fitted to the changes in postoperative mor- phine consumption on POD2 to POD4, meaning that the changes in postoperative morphine consumption POD2 to POD4 follows a linear trend over time. Fisher’s exact test or Mann-Whitney U test was used

to compare the incidences of each secondary outcome. All statistical analyses were conducted using the statis- tical program R version 3.2 (R Core Team (2015). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/).

Results Fifty-two patients in the LIDO group were matched with 52 patients in the ERAS group. Perioperative vari- ables are shown in Table 2. No significant differences in demographic and preoperative opioid consumption were noted. Total intraoperative opioid use was similar between the groups (LIDO: 18.8 [10.6-27.5] mg vs. ERAS: 15 [7.50–25] mg, p = 0.14), however significantly more intravenous opioids were administered in the lidocaine group while there was more intrathecal opioid use in the ERAS group. This was primarily related to the ERAS protocol limiting intravenous administration of opioids. All patients in the ERAS group received oral acetaminophen, gabapentin and celecoxib prior to sur- gery. No patient in the standard group received oral acetaminophen, gabapentin and celecoxib prior to sur- gery. Total lidocaine dose was higher in the LIDO group (LIDO: 2888 [2188-4322] mg versus ERAS: 1557 [959-1992] mg, p = 0.0001), primarily due to the earlier discharge in the ERAS group. An additional supple- mentary file titled ‘Database’ reports the raw data in more detail [see Additional file 1].

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Primary outcome As previously described, the non-inferiority margin for pain was defined a priori as a 1-point difference between the two groups. Mean pain scores are represented in Fig. 1. Our data demonstrate that for the overall study period the upper limit 95% confidence interval extends beyond the 1-point difference (Table 3, Fig. 3), indicating one can not conclude from the data that lidocaine is inferior to ERAS group. The pain score for POD 1 is similar, with the mean difference and 95% confidence interval 1.16 (0.15–2.18); thus, although the difference falls within the non-inferiority range, the upper limit CI extends beyond the 1-point difference (Table 3, Fig. 3a). For POD 2 and beyond lidocaine is non-inferior to ERAS [-0.17 (-1.08–0.74)]. For opioid consumption, the non-inferiority limit was

defined a priori as a ratio of mean lidocaine / mean ERAS of 1.2. Mean opioid use (morphine equivalents) is demon- strated in Fig. 2. In the overall and POD 1 group lidocaine was inferior to ERAS for opioid consumption (Table 3, Fig. 3b). For POD 2 and beyond, although the mean ratio was 1.43, the lower limit extended beyond the pre-defined cut-off, rendering the outcome inconclusive.

Secondary outcome Secondary outcomes are listed in Table 4. There was no difference noted in the incidence of hypotension and

nausea/vomiting between the groups. There was an in- creased incidence of pruritus present on POD 2 in the LIDO group, however this was not evident on POD 3 and 4. In the LIDO group a higher percentage of patients with either confusion, somnolence, difficulty with arousal or unresponsive was evident on POD 2 (LIDO: 11.54% vs. ERAS: 0%, p = 0.03). Time to ambulation, duration of bladder catheterization

and duration of hospital stay were significantly reduced in the ERAS group (Table 4). No difference in the time to first bowel movement was noted between the groups. Total postoperative lidocaine dose was significantly higher in LIDO group.

Discussion Our study demonstrates incremental benefit of adding the components of a full ERAS protocol (including multi-modal analgesics) to perioperative lidocaine for reducing opioid requirements after colorectal surgery. The opioid-sparing effects are most evident on POD 1 and extend into POD 2 and beyond even though it does not reach the statistical significance level defined a prior. Although pain scores tended to be higher in the

LIDO group, the non-inferiority analysis is inconclusive on POD 1 and in the overall cohort. However, pain scores demonstrate noninferiority in the standard care- perioperative lidocaine group on POD 2 and beyond. It

Table 2 Perioperative data in the standard therapy-perioperative lidocaine and enhanced recovery multi-modal analgesia- perioperative lidocaine group

Standard Therapy-Perioperative Lidocaine

ER Multi-Modal Analgesia-Perioperative Lidocaine

P-value

Preoperative

Age (years)a 52.8 (14.6) 53.5 (13) 0.79

Gender (% men)b 50 50 1

BMI (kg/m2)c 26.11 [22.9-29.8] 26.7 [23.6-31] 0.47

Chronic pain (%)b 44 44 1

Preoperative morphine equivalent (mg)c 0 [0-23.3] 0 [0-10] 0.17

Intraoperative

Laparoscopic Procedures n (%) 12 (23%) 27 (52%) 0.004

Total Intraoperative morphine equivalent (mg)c 18.8 [10.6-27.5] 15 [7.50-25] 0.14

Intrathecal Morphine (mg) 0 [0-0] 0.15 [0.1-0.25] 0.0001

Intravenous Fentanyl (μg) 150 [100-250] 0 [0-0] 0.0001

Intravenous Hydromorphone (mg) 1 [0.4-2] 0 [0-0] 0.0001

Ketamine (mg) 0 [0-60.7] 102 [63.8-150.2] 0.0001

Magnesium (mg) 0 [0-0] 2000 [2000-2500] 0.0001

Lidocaine (mg) 494 [379-615] 592 [388-900] 0.13

Postoperative

Lidocaine (mg) 2888 [2188-4322] 1557 [959-1992] 0.0001 aPresented as mean (SD), P value from simple t test bPresented as frequency, P value from χ2 or Fisher exact test cPresented as median and (IQR), P value from Mann-Whitney U test

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Fig. 1 Mean and standard error of postoperative NRS pain scores. NRS: Numerical Rating Scale, ERAS: Enhanced Recovery After Surgery

Table 3 Difference in NRS pain scores and opioid consumption

Difference in NRS Pain Scores and Opioid Consumption

Difference in NRS Pain Scores

Standard Therapy-Perioperative Lidocaine

ER Multi-Modal Analgesia-Perioperative Lidocaine

Mean Difference (ST − ER) (95% CI)

Δ p-value

Overall 4.7 (2) 4.5 (2) 0.43 (-0.46-1.31) 1 0.1

4.5 [3.0, 6.0] 4.7 [2.7, 6.0]

Day 1 5.23 (2.12) 4.17 (2.10) 1.16 (0.15-2.18) 1 0.62

5.11 [3.65, 6.76] 4.02 [2.60, 5.88]

Day 2 and beyond 4.44 (2.06) 4.70 (2.04) -0.17 (-1.08-0.74) 1 0.006

4.49 [2.66, 6.00] 4.77 [3.40, 6.22]

Difference in Opioid Consumption

Standard Therapy-Perioperative Lidocaine

ER Multi-Modal Analgesia-Perioperative Lidocaine

Mean ST/Mean ER Opioid Consumption (95% CI)

Overall 52.54 (64.45) 31.22 (36.62) 1.68 (1.43-1.98) 1.2 <0.0001

30.20 [17.32, 54.94] 22.91 [9.77, 40.39]

Day 1 43.77 (54.02) 18.43 (28.83) 2.38 (1.74-3.31) 1.2 <0.0001

25.18 [13.93, 46.54] 9.95 [1.95, 23.78]

Day 2 and beyond 57.03 (72.42) 39.93 (40.58) 1.43 (1.17-1.73) 1.2 0.8

27.46 [16.15, 71.43] 28.42 [15.98, 47.68]

Data presented as mean (SD) and median [IQR]

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Fig. 2 Mean and standard error of opioid (morphine equivalent) consumption. ERAS: Enhanced Recovery After Surgery

Fig. 3 Noninferiority margins for pain scores (a) and opioid consumption (b). Squares represent the mean and the whiskers represent the 95% confidence interval. ERAS: Enhanced Recovery After Surgery

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is important to note these findings were present despite there being significantly more open (and presumably more painful) procedures in the LIDO group (23% vs. 52%, p = 0.004). The reduced time to ambulation, duration of urinary

catheterization and hospital stay noted in the ERAS group are related to standardized goals for early ambula- tion and removal of urinary catheters.

ERAS programs are designed to reduce opioid con- sumption, opioid-related complications (nausea, ileus, etc.) and to encourage early mobilization. It is import- ant to note that the early ambulation noted in the ERAS group (ERAS: 20 [13.50, 25.75] hrs vs. LIDO: 44.5 [22, 65.5] hrs) potentially may have contributed to increase pain and opioid consumption, which was obvi- ated by intraoperative multi-modal analgesia (Table 1).

Table 4 Secondary outcomes

Standard Therapy-Perioperative Lidocaine ER Multi-Modal Analgesia-Perioperative Lidocaine P value

Hypotensiona

POD 1 0 (52); 0% 1 (52); 1.92% 1

POD 2 0 (52); 0% 0 (49); 0% -

POD 3 0 (40); 0% 0 (10); 0% -

POD 4 1 (23); 4.35% 0 (5); 0% 1

Nausea and Vomitinga

POD 1 11 (52); 21.15% 6 (52); 11.54% 0.29

POD 2 16 (52); 30.77% 7 (49); 14.29% 0.06

POD 3 9 (40); 22.50% 5 (10); 50% 0.12

POD 4 8 (23); 34.78% 2 (5); 40% 1

Pruritisa

POD 1 5 (52); 9.62% 2 (52); 0.04% 0.44

POD 2 13 (52); 25% 2 (49); 4.08% 0.004

POD 3 6 (40); 15% 1 (10); 10% 1

POD 4 2 (23); 8.70% 0 (5); 0% 1

Mental status: not awake or alerta

POD 1 4 (52); 7.69% 2 (52); 0.04% 0.68

POD 2 6 (52); 11.54% 0 (49); 0% 0.03

POD 3 3 (40); 7.50% 0 (10); 0% 1

POD 4 0 (23); 0% 0 (5); 0% -

Urinary retentiona

POD 1 1 (52); 1.92% 6 (52); 0.12% 0.11

POD 2 1 (52); 1.92% 3 (49); 6.12% 0.35

POD 3 31 (40); 77.50% 6 (10); 60% 0.42

POD 4 0 (22); 0% 1 (5); 20% 0.19

Patient Satisfaction: yesa

POD 1 34 (52); 65.38% 38 (52); 73.08% 0.52

POD 2 42 (52); 80.77% 40 (49); 81.63% 1

POD 3 31 (40); 77.50% 6 (10); 60% 0.42

POD 4 19 (23); 82.61% 1 (5); 20% 0.01

Time to ambulation (hr)bc 44.50 [22, 65.50] 20 [13.50, 25.75] < .001

Duration of urine catheter (hr)bc 43.50 [25.75, 67.50] 27 [20, 42] 0.006

Time to bowel movement (hr)bc 40 [18, 71.50] 41.25 [28.38, 51] 0.63

Duration hospital stay (hr)bc 146 [96.75, 288] 72.25 [66.75, 114.12] < .001 aPresented as frequency, P value from χ2 or Fisher exact tests bPresented as median and (IQR), P value from Mann-Whitney U test cAll these measurements calculated from the time the patient left the operating room

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Based on our results the addition of this multi-modal analgesic regimen to perioperative lidocaine is associated with a reduction in opioid consumption most evident on POD 1, but interestingly not with a decrease in opioid- related side effects. The combination of intraoperative intrathecal mor-

phine, ketamine and magnesium likely contributed to the significant reduction in opioid requirements noted on POD 1 (LIDO: 25.18 [13.93, 46.54] mg vs. ERAS: 9.95 [1.95, 23.78] mg). This effect is less striking on POD 2 and beyond (LIDO: 27.46 [16.15, 71.43] mg vs. ERAS: 28.42 [15.98, 47.68] mg) and probably reflects the waning effect of neuraxial morphine and N-methyl-D- aspartate (NMDA) antagonist. A single dose of intrathecal morphine prior to surgery

reduces postoperative enteral and parenteral opioid re- quirements after abdominal surgery. The duration of opioid-sparing depends on the type of opioid and the dose administered. Reported benefits of a single dose of intrathecal morphine are evident up to 24 h after admin- istration [18, 19]. These findings are consistent with our data, which demonstrates significant opioid sparing ef- fect in the ERAS group on POD 1. Complications of intrathecal morphine such as pruritus, respiratory de- pression and nausea/vomiting are not evident in our study, with no clinically significant morbidity noted in the group that received intrathecal morphine (Table 4). Furthermore, alterations in mental status, which would be a surrogate marker of significant respiratory depres- sion, were not different between the groups (LIDO: 7.69% vs. ERAS: 0.04%, p = 0.11] on POD 1. The inclusion of ketamine also likely played a role in

reducing postoperative opioid use. In abdominal surgery sub-anesthetic doses of ketamine modulate opioid- induced hyperalgesia via the NMDA receptor reducing postoperative pain and opioid consumption [20, 21]. The anti-nociceptive benefits of low-dose ketamine are evi- dent up to 24 h after surgery. Anti-nociceptive effects mediated via NMDA antagonism are more pronounced when a second NMDA antagonist is added to ketamine. Magnesium, an endogenous voltage-dependent NMDA receptor-channel blocker, demonstrates synergism with ketamine. In a rat model of acute nociception, the com- bination of magnesium and ketamine was more effective in reducing pain than either drug alone [22, 23]. Although our data demonstrates reduction in opioid use

in the ERAS group, opioid-related complications were not significantly different between the two groups. Somewhat surprisingly, return of bowel function, a major side effect of opioids, was not different (LIDO: 40 [18, 71.50] h vs. ERAS 41.3[28.38, 51] h, p = 0.63) between the two groups. The opioid consumption and pain scores profile re-

ported here are similar to findings presented in our pre- vious study comparing lidocaine to epidural analgesia

for major abdominal surgery [10]. In that study intraven- ous lidocaine was inferior to epidural for opioid con- sumption (overall, POD 1 and POD 2 beyond) with pain scores demonstrating non-inferiority on POD 2 and beyond. There are several limitations of this study. In the

LIDO group no pre-defined algorithm for opioid ad- ministration was utilized with opioid administration solely determined by the clinical team managing the pa- tient. This variability may have influenced our results. We had a small study size, which reduces the chance of detecting a true effect or reduces the likelihood that a statistically significant result reflects a true effect. This was a single-center study investigating an institutional specific ERAS program, therefore our results may not be translatable to other institutions using different ERAS programs. Finally this was retrospective chart review and the possibility of misclassification bias or incorrectly coded data in the electronic medical record cannot be excluded. As reported in our previous study, there are no stan-

dardized criteria for non-inferiority analysis [10]. We uti- lized a noninferiority margin of 1-point (on an 11-point numerical rating scale) difference in pain and a ratio [mean (lidocaine)/ mean (ERAS)] of 1.2 in opioid con- sumption for consistent reporting between our studies. Changing the noninferiority margin can potentially alter the outcomes of our results. Finally, we acknowledge the limitation of the lack of an a priori power analysis in the current study; however, power analysis for future studies can be performed with the current data.

Conclusions In conclusion, our data suggest that ERAS protocols that include intraoperative intrathecal opioids and non- opioid analgesics have a distinct opioid-sparing effect within the first 24 h compared to lidocaine alone. We suggest that a combination of intraoperative protoco- lized pain management with postoperative continuation of intravenous lidocaine has distinct benefits on pain scores and opioid use for colorectal surgery.

Additional file

Additional file 1: Database. Raw, de-identified data in an excel spreadsheet. (XLSX 93 kb)

Abbreviations CI: Confidence interval; ERAS: Enhanced Recovery After Surgery; LIDO group: Perioperative lidocaine with opioid-based postoperative analgesia; NMDA: N-methyl-D-aspartate; PCA: Patient-controlled analgesia; POD: Postoperative day; VAS: Visual analog scale

Acknowledgements None.

Naik et al. BMC Anesthesiology (2017) 17:16 Page 9 of 10

Funding No funding was involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials The datasets used and/or analysed during the current study available in the Additional File Section.

Authors’ contributions BIN: Conception and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the version to be published and agree to be accountable for all aspects of the work. ST: analysis and interpretation of data, drafting the manuscript, final approval of the version to be published and agree to be accountable for all aspects of the work. AK: acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the version to be published and agree to be accountable for all aspects of the work. SY: acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the version to be published and agree to be accountable for all aspects of the work. MED: Conception and design, acquisition of data, analysis and interpretation of data, drafting the manuscript, final approval of the version to be published and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.

Competing interests The authors declare that they have no competing interests.

Consent for publication Not applicable.

Ethics approval and consent to participate The study was approved by the University of Virginia’s Institutional Review Board (HSR #10712) and the need for consent was waived.

Author details 1Department of Anesthesiology, University of Virginia, Charlottesville, VA, USA. 2Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA. 3Department of Epidemiology, Columbia University, New York, NY, USA.

Received: 20 October 2016 Accepted: 19 January 2017

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