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A Randomized Trial of 1% vs 2% Lignocaine by the Spray-as-You-Go Technique for Topical Anesthesia During Flexible Bronchoscopy Harpreet Kaur , MSc ; Sahajal Dhooria , MD , DM ; Ashutosh N. Aggarwal , MD , DM , FCCP ; Dheeraj Gupta , MD , DM , FCCP ; Digambar Behera , MD , FCCP ; and Ritesh Agarwal , MD , DM , FCCP

BACKGROUND: Th e optimal concentration of lignocaine to be used during fl exible bronchos- copy (FB) remains unknown. Th is randomized controlled trial compared the effi cacy and safety of 1% and 2% lignocaine solution for topical anesthesia during FB. METHODS: Consecutive patients were randomized to receive either 1% or 2% lignocaine solu- tion through the bronchoscope by the “spray-as-you-go” technique. Th e primary outcome of the study was the assessment of cough by the operator and the patient using the visual analog scale (VAS) and pain assessment using the faces pain rating scale. Th e secondary outcomes included total lignocaine dose, oxygenation status, adverse reactions related to lignocaine, and others. RESULTS: Five hundred patients were randomized (median age, 51 years; 71% men) 1:1 to either group. Th e median operator VAS score for cough was signifi cantly higher (25 vs 21, P 5 .015) in the 1% group; however, the patient VAS score was not significantly different (32 vs 27, P 5 .065). Th e pain rating was similar between the two groups. Th e median cumulative dose of lignocaine was signifi cantly higher in the 2% group (397 mg vs 312 mg, P 5 .0001; 7.1 mg/kg vs 5.7 mg/kg, P 5 .0001). About 28% of patients in the 2% group exceeded the maxi- mum recommended dose ( . 8.2 mg/kg) of lignocaine. No adverse event related to lignocaine overdose was seen in either group. CONCLUSIONS: One percent lignocaine was found to be as eff ective as 2% solution for topical anesthesia during FB, albeit at a signifi cantly lower dose as the latter. Th us, 1% lignocaine should be the preferred concentration for topical anesthesia during FB. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01955824; URL: www.clinicaltrials.gov CHEST 2015; 148 ( 3 ): 739 - 745

[ Original Research Pulmonary Procedures ]

Manuscript received January 5, 2015; revision accepted March 2, 2015; originally published Online First March 26, 2015. ABBREVIATIONS: EBB 5 endobronchial biopsy; FB 5 flexible bron- choscopy; RCT 5 randomized controlled trial; TBLB 5 transbronchial lung biopsy; TBNA 5 transbronchial needle aspiration; VAS 5 visual analog scale AFFILIATIONS: From the Department of Pulmonary Medicine, Post- graduate Institute of Medical Education and Research, Chandigarh, India. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

CORRESPONDENCE TO: Ritesh Agarwal, MD, DM, FCCP, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh-160012, India; e-mail: agarwal. [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.15-0022

740 Original Research [ 1 4 8 # 3 C H E S T S E P T E M B E R 2 0 1 5 ]

Flexible bronchoscopy (FB) is a widely used procedure for the diagnosis and treatment of a variety of broncho- pulmonary disorders because of patient comfort, low rate of complications, and lack of requirement of general anesthesia. 1 Most patients tolerate the procedure well although cough is reported to be an extremely distressing symptom. 2 It is likely that the acceptance of bronchoscopy would be signifi cantly improved with control of cough. A combination of midazolam and hydrocodone has been shown to signifi cantly reduce cough during FB, especially when invasive diagnostic procedures are performed. 3 However, in several centers including ours, due to logistics, sedation is not routinely used during basic diagnostic bronchoscopy; procedures such as BAL, endobronchial biopsy (EBB), and transbronchial lung biopsy (TBLB) are performed under topical anesthesia.

Lignocaine is the most common local anesthetic used during FB because of its quick onset, short duration of action, and lesser toxicity compared with other agents. 4 Th e use of topical lignocaine during FB has been shown to improve patient’s tolerance and satisfaction of

the procedure. 5,6 Furthermore, it has been demonstrated that nebulized lignocaine can reduce the need for sup- plemental topical anesthesia, administered as injection through the bronchoscope. 7,8 Th e optimal concentration of lignocaine as topical anesthesia, however, remains speculative, and 1% and 2% concentrations of lignocaine solutions are commonly used. The British Thoracic Society guidelines recommend the use of 1% lignocaine while the American College of Chest Physicians (CHEST) consensus statement endorses a wide range of lignocaine concentrations (1%-10%) that have been found to be eff ective without advocating any particular value. 9,10

Th ere is little data on the effi cacy of lower concentra- tions (1%-2%) of lignocaine. 11 It is important that the superiority of a particular concentration be ascertained, as eff ectiveness of lower concentrations would allow the use of higher volumes with lesser chances of complica- tions. In this randomized controlled trial (RCT), we report the effi cacy and safety of 1% vs 2% lignocaine for topical anesthesia in patients undergoing FB.

Materials and Methods Setting Th is was an investigator-initiated, single-center, randomized double- blind trial conducted in the bronchoscopy suite of this institute between May and November 2014. The study protocol was approved by the Ethics Review Committee (Ref. No. NK/1473/Res/687), and written informed consent was obtained from all the patients. As a protocol in our bronchoscopy suite, patients undergoing BAL, EBB, and TBLB are not routinely sedated, and bronchoscopy is performed under topical anesthesia. Patients undergoing other procedures such as conventional transbronchial needle aspiration (TBNA), endobronchial ultrasonography- guided TBNA, and other interventions are routinely sedated with mid- azolam and pentazocine.

Patients Patients were eligible for inclusion into the study if they met all of the following criteria: (1) indication for fl exible bronchoscopy, (2) age group of 12 to 90 years, and (3) hemodynamic stability (defi ned as systolic BP . 100 mm Hg and , 180 mm Hg). Patients with any of the following were excluded: (1) pregnancy, (2) hypoxemia (oxygen saturation [by pulse oximetry] , 92% with F io 2 of 0.3), (3) patients undergoing TBNA and other interventions, and (4) failure to provide informed consent.

Randomization Patients were randomized in 1:1 ratio to receive either 1% or 2% ligno- caine solution. Th e randomization sequence was computer-generated, and the assignments were placed in sealed opaque envelopes. Both the patient and the bronchoscopist were blinded to the concentration of lignocaine solution used for the procedure.

Study Protocol Demographic profi le including age, sex, height, weight, smoking history, BMI, and the type of procedure performed (airway inspection, BAL, EBB, TBLB) was recorded for all patients. Patients in both the groups were prepared in a similar fashion except for the concentration of lig- nocaine used. All patients were kept fasting overnight. The patients

were nebulized with 2.5 mL of 4% lignocaine (Lox, 42.7 mg/mL; Neon Laboratories Ltd) for 15 min prior to the procedure. Lignocaine spray (10%, Lox, 100 mg/mL; Neon Laboratories Ltd) was sprayed twice (10 mg/puff ) over the oropharynx. Approximately 5 mL of lignocaine gel (2%; Neon Laboratories Ltd), equivalent to 100 mg of lignocaine, was administered in the nasal cavity prior to the introduction of the broncho- scope. Patients thereaft er received 2-mL aliquots of 1% or 2% lignocaine solution (Wocaine; Wockhardt) delivered through the bronchoscope using the ‘‘spray-as-you-go’’ technique. Four aliquots of 2 mL of ligno- caine were administered: one each at the vocal cord, tracheal carina, and in the right and left main bronchus. Extra lignocaine aliquots were given as a ‘‘rescue’’ treatment to suppress cough, at the discretion of the oper- ator. Th e sum of the standard dose (2.5 mL of 4% nebulized lignocaine [106.75 mg] plus 5 mL of 2% lignocaine gel [100 mg] plus two puff s of 10% lignocaine spray [20 mg] plus 8 mL of 1% [85.2 mg] or 2% [170.4 mg] lignocaine) and rescue dose made up the total dose of lignocaine used. Patients were monitored for any adverse eff ects related to lignocaine use (like arrhythmia, involuntary movements, convulsions, anaphylaxis, and bronchospasm). Heart rate, respiratory rate, BP, and oxy gen satu- ration (by pulse oximetry) were monitored throughout the procedure.

Th e bronchoscopist was asked to assess the intensity of the patient’s cough during FB using a visual analog scale (VAS) immediately aft er the procedure. The VAS for cough was rated on a horizontal line, 100 mm in length anchored by “No cough” at one end and “Worst cough” at the other. 12 Once stable, the patients recorded their quantum of cough and pain using the VAS and the faces pain rating scale, respec- tively. Th e faces pain rating scale consists of six faces with brief word instructions provided with the scale representing increasing intensity of pain on an ordinal scale from 0 to 5. 13

Study Outcomes Th e primary outcome of the study was patient comfort during the pro- cedure measured by the intensity of cough rated on a VAS by both the operator and the patient and the pain assessment by the patient using the faces pain rating scale. The secondary outcomes included total lignocaine dose; changes in respiratory rate, heart rate and BP, and

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oxygenation status following the procedure; and adverse reactions related to lignocaine (arrhythmia, involuntary movements, convul- sions, anaphylaxis, and bronchospasm).

Statistical Analysis Statistical analysis was performed using the commercial statistical pack- age SPSS for MS-Windows, version 22 (IBM Corporation). P , .05

was considered as statistically significant. Data are presented in a descriptive fashion as number with percentage or median with interquar- tile range. x 2 (or the Fisher exact test) was used to analyze categorical variables and the Mann-Whitney U test was used for comparing the numerical data. The change in variables before, during, and after the procedure was analyzed with multiple repeated measure analysis of variance.

Results During the study period, 500 consecutive patients (250 in each group, 70.6% men) with a median (interquartile range) age of 51 years (40-60) were included in the study ( Fig 1 ). Th e baseline characteristics including the demographic characteristics, physiologic parameters, and the type of bronchoscopic procedures performed were similar in the two groups ( Table 1 ). Heart rate, respiratory rate, and BP increased aft er the procedure as compared with baseline in both the study groups. However, the change was not significantly different between the two groups ( Table 2 ).

Th e median operator VAS score for cough was signifi - cantly higher in the 1% group (1% group: 25 vs 2% group: 21; P 5 .015); however, the median patient VAS score for cough was similar between the two groups ( Table 3 ). Th e faces pain rating score was similar in the two groups ( Table 3 ). Th e median total dose of lignocaine used was

signifi cantly higher in the 2% group (2% group: 397 mg vs 1% group: 312 mg; P 5 .0001). Similarly, the ligno- caine dose adjusted for body weight was also signifi - cantly higher in the 2% group ( Table 3 ). Th e number of patients with total administered dose . 8.2 mg/kg lig- nocaine was also signifi cantly higher in the 2% group ( Table 3 ). Heart rate, respiratory rate, and BP aft er the procedure were similar in the two groups. No adverse events related to lignocaine such as bronchospasm, arrhythmias, involuntary movements, or convulsions were observed in any patient.

Discussion Th e result of this large RCT demonstrates that 1% and 2% concentrations of lignocaine solution are equally eff ective in anesthetizing the airway. Th e bronchoscopist- reported VAS scores for cough were higher in the 1% lignocaine group; the diff erence although statistically significant is unlikely to be clinically relevant as the

Figure 1 – CONSORT diagram demonstrating the fl ow of participants in the study. EBUS 5 endobronchial ultrasonography; TBNA 5 trans- bronchial needle aspiration.

742 Original Research [ 1 4 8 # 3 C H E S T S E P T E M B E R 2 0 1 5 ]

median diff erence of VAS score was merely four points on a scale ranging from 0 to 100. Moreover, the diff er- ence was not signifi cant in the patients’ own assessment of their cough in the two groups. Th e pain rating was also not diff erent in the two groups. Th e cumulative dose in the 1% arm was signifi cantly lower compared with the other group. Thus, 1% lignocaine could achieve topical anesthesia during bronchoscopy as eff ec- tively as 2% but at a much lower dose compared with 2% lignocaine.

Most guidelines currently recommend performance of FB under IV sedation. 9,10 However, in our center, due to high patient load and lower doctor-to-patient ratio, basic diagnostic procedures such as BAL, EBB, and TBLB are performed under topical anesthesia without any IV sedation. Although sedation should be used wherever possible, 3,14 local anesthesia can be achieved within 2 min of endotracheal lignocaine application, which blunts the cough refl ex eff ectively, 15 allowing for safe and comfortable performance of FB. 16

TABLE 1 ] Baseline Characteristics of the Study Population Characteristics 1% Lignocaine (n 5 250) 2% Lignocaine (n 5 250) Total (N 5 500) P Value

Demographic variables

Male, No. (%) 177 (70.4) 176 (70.8) 353 (70.6) .890

Age, y 50 (40-60) 52 (38-61) 51 (40-60) .710

Height, cm 165 (157-170) 165 (155-170) 165 (156-170) .873

Weight, kg 55 (49-64) 56 (48-65) 55 (49-65) .595

BMI, kg/m 2 20.5 (18-23) 20.9 (18-24) 20.8 (18-24) .540

Current smokers, No. (%) 106 (42.3) 104 (41.8) 210 (42) .926

Physiologic parameters

Heart rate, beats/min 98 (87-111) 98 (86-111) 98 (86-111) .804

Respiratory rate, breaths/min 20 (18-22) 20 (18-22) 20 (18-22) .340

Oxygen saturation, % 97 (95-98) 97 (95-98) 97 (95-98) .349

Systolic BP, mm Hg 120 (110-135) 122 (112-137) 121 (112-136) .136

Diastolic BP, mm Hg 76 (69-83) 76 (70-84) 76 (70-83) .662

Procedures performed, No. (%)

BAL 86 (34.4) 82 (32.8) 168 (33.6) .753

Endobronchial biopsy 90 (36) 86 (34.4) 176 (35.2) .758

Transbronchial lung biopsy 67 (26.8) 59 (23.6) 126 (25.2) .440

Airway inspection only 70 (28) 73 (29.2) 143 (28.6) .724

All values are expressed as median with interquartile range, unless otherwise stated.

TABLE 2 ] Serial Physiologic Parameters Measured Before, During, and After FB in the Two Groups

Parameters

1% Lignocaine 2% Lignocaine

Baseline During After Baseline During After

Heart rate, beats/min 99.0 (18.4) 113.4 (20.7) a 110.9 (18.8) b 98.6 (17.9) 112.4 (19.9) a 107.8 (17.9) b

Respiratory rate, breaths/min

19.9 (3.5) … 22.5 (3.3) b 20.2 (3.6) … 22.4 (3.3) b

Systolic BP, mm Hg 122.5 (17.8) … 124.5 (16.1) b 125.1 (16.6) … 126.6 (15.5) b

Diastolic BP, mm Hg 75.5 (10.9) … 76.1 (10.1) 76.4 (10.2) … 76.5 (9.8)

Oxygen saturation, % 96.2 (3.2) 96.7 (3.2) 96.3 (2.5) 96.5 (2.8) 96.5 (2.9) 96.3 (2.7)

All values are mean (SD) unless otherwise stated. P , .05 was taken as signifi cant. The diff erences between the means was analyzed using multiple repeated measure analysis of variance with Bonferroni adjustment for multiple comparisons; the within-groups factor was time (baseline, during, and after), and the between-groups factor was the lignocaine groups (1% vs 2%). FB 5 fl exible bronchoscopy. a Value during procedure signifi cantly diff erent from that at baseline within the groups. b Value after procedure signifi cantly diff erent from that at baseline within the groups.

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Few studies have evaluated the effective lignocaine concentration for topical anesthesia during FB ( Table 4 ). 11,17-19 Of the four, one has been published only as an abstract while three are peer reviewed. 19 Of the three peer-reviewed studies, only a single study was performed in the bronchoscopy suite, while the other two studies were conducted in the operating suite and are, thus, diff erent from the routine practice in the bronchoscopy suite. Th e results of these studies suggest that 2% is as effi cacious as 4% solution while 1% is as eff ective at 2% lignocaine. Th e limitation of these studies apart from diff ering methodologies is the small sample size. Th e results of our study supplement these studies and confi rm that 1% lignocaine solution is as efficacious as 2% but has the added advantage of effectiveness at signifi cantly lower cumulative dose.

Th ese fi ndings are important for routine practice as there are reported cases of death from presumed ligno- caine toxicity after FB. 20,21 In fact, 28% of patients in the 2% lignocaine arm of our study exceeded the dose of . 8.2 mg/kg, recommended as the maximum dose by the British Th oracic Society. 22 In another study, the anesthetists used doses of up to 14.8 mg/kg lignocaine by a spray-as-you-go method in a study involving volunteer subjects undergoing awake fi ber-optic intuba- tion; some volunteers were reported to have experi- enced involuntary movements, symptoms that may precede convulsions, which is a sign of lignocaine toxicity. 23 Th e pharmacokinetics of topical lignocaine during FB are complex and can be influenced by several factors, including the duration and frequency of suctioning. 24 This means that the plasma levels

TABLE 3 ] Primary and Secondary Outcomes of the Study Outcomes 1% Lignocaine (n 5 250) 2% Lignocaine (n 5 250) P Value

Primary

VAS score (cough) for operator 25 (12-51) 21 (9-38) .015

VAS score (cough) for patient 32 (11-60) 27 (10-50) .065

Faces pain rating scale 0 (0-2) 0 (0-2) .883

Secondary

Total dose of lignocaine, mg 312 (312-312) 397 (397-397) .0001

Lignocaine dose, mg/kg 5.7 (5.0-6.5) 7.1 (6.1-8.3) .0001

No. of patients with dose . 8.2 mg/kg, No. (%) 12 (4.8) 70 (28) .0001

Heart rate after procedure, beats/min 111 (98-123) 108 (96-118) .054

Respiratory rate after procedure, breaths/min 22 (20-24) 22 (20-24) .493

Systolic BP after procedure, mm Hg 122 (112-132) 126 (116-134) .075

All values in median (interquartile range), unless mentioned. VAS 5 visual analog scale.

TABLE 4 ] Studies Evaluating Different Lignocaine Concentrations for Topical Anesthesia During FB

Study/Year Nature of the

Study No. of

Patients Concentration of

Lignocaine End Points Outcome

Mainland et al 17 /2001

Double-blind RCT 96 1% (n 5 31) vs 1.5% (n 5 16) vs 2%

(n 5 48)

Nature and duration of cough; requirement of

additional supplements

All concentrations and dosages equally

eff ective

Hasmoni et al 11 /2008

Double-blind RCT 61 1% (n 5 32) vs 2% (n 5 29)

Cough frequency with digital voice recorder;

bronchoscopists overall satisfaction

No diff erence between the two groups

Xue et al 18 /2009

Double-blind RCT 52 2% (n 5 26) vs 4% (n 5 26)

Faces pain rating scale, 4-point cough severity

scale, 3-point tracheal intubation scale

No diff erence between the two groups

Bansal et al 19 /2011

Double-blind RCT 52 1% (n 5 26) vs 2% (n 5 26)

VAS, cough severity, and frequency score

No diff erence between the two groups

RCT 5 randomized controlled trial. See Table 2 and 3 legends for expansion of other abbreviations.

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achieved in an individual patient are often unpre- dictable. 25-29 However, the propensity would increase with increasing doses of lignocaine used. By using 1% lignocaine, the risk of potential toxicity would be lower although it is still essential to carefully monitor the amount of lignocaine administered during FB. Another important benefit of a lower concentration would be the usage in patients with renal and hepatic dysfunction, as well as in patients with airway infl am- mation and pediatric age group, as the dose would be minimized.

Finally, our study is not without limitations. Th ere were several factors in our study that could aff ect the out- comes. Th ese were multiple operators (consultants, fellows), variable duration of bronchoscopy, wide range of indications, and concomitant procedures. However,

they were equally distributed between the two groups. Th e other limitation could be the lack of widespread generalization of our results given the fact that IV seda- tion was not used while a vast majority of bronchosco- pists use sedation. However, lack of sedation can also be regarded as a major strength of the study as it allowed a clear assessment of the cough severity by the patient in contrast to the previous study where the patients were sedated. 11 Th e other obvious strength of the study is the large sample size.

In conclusion, the results of this study suggest that 1% lignocaine is similar in effi cacy to 2% lignocaine for top- ical anesthesia during FB, at signifi cantly lower doses of lignocaine. Hence, 1% lignocaine should be the preferred concentration for topical anesthesia of the larynx and the tracheobronchial tree during FB.

Acknowledgments Author contributions: R. A. is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. H. K. contributed to data collection as well as drafting of the manuscript; S. D. and A. N. A. contributed to patient management, data collection, and revision of the manuscript for intellectual content; D. G. and D. B. contributed to patient management and revision of the manuscript; and R. A. conceived the idea and contributed to patient management as well as draft ing and revision of the manuscript for intellectual content. Financial/nonfi nancial disclosures: Th e authors have reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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