The effect of intraoperative lidocaine versus esmolol infusion on postoperative analgesia in laparoscopic cholecystectomy: A randomized clinical trial

Abstract

Background

Acute pain after laparoscopic cholecystectomy (LC) is complex in nature, and therefore, opioids alone might not be sufficient to achieve quality analgesia.^{1 2} Besides,  use of  only opioids in perioperative settings are associated with undesirable effects.^3-6 In this regard, multimodal regimen (a combination of opioids and non-opioid drug)  is recommended for LC. It  provides superior analgesia and  improves quality of recovery after surgery.⁷

Several non-opioid agents  have been used for LC to  improve the postoperative analgesic profile. Among these, systemic lidocaine infusion is an extensively studied intervention due to its analgesic, anti-hyperalgesic and anti-inflammatory effects.⁸  Moreover, doses of IV lidocaine ≤ 3 mg. kg^-1. hr^-1 is considered safe and the technique  is feasible to use in perioperative setting.^8-10 Surprisingly,  a latest  cochrane systematic review  demonstrated  uncertaininty regarding the beneficial effects  of  IV perioperative lidocaine on postoperative pain outcomes.¹¹

In recent times, esmolol infusion has gained popularity as an alternative  adjunt due to its opioid sparing effects.^12-14 A current meta-analysis has revealed a significant reduction in perioperative opioid consumption with the use of intraoperative esmolol.¹⁵

Although both lidocaine and esmolol  are widely used for LC, studies comparing these agents are very few with conflicting results. Therefore, the primary objective of our study was to compare the effects of intraoperative lidocaine and esmolol infusion on postoperative opioid consumption and pain scores following LC.

Methods

This prospective, randomized, double-blinded, clinical trial was conducted at BP Koirala Institute of Health Sciences between January 2015 and April 2016. The study was approved by the Institutional Ethical Review Board (Ref: IERB 284/014) and the trial was registered prior to patient enrollment at clinicaltrials.gov (NCT02327923). The study was performed according to the Declaration of Helsinki and it adheres to the guidelines of the CONSORT statement.

Female patients aged 18 to 60 years of American society of Anesthesiologist physical status I and II scheduled for general anaesthesia for elective laparoscopic cholecystectomy were enrolled. Exclusion criteria included patients inability to comprehend pain assessment score or severe mental impairment, difficult intubation, pregnancy, morbid obesity, history of epilepsy and allergy to any drugs used in the study, current use of opioids or beta-adrenergic receptor antagonists, baseline heart rate < 50 beats/min, acute cholecystitis,  and chronic pain other than cholelithiasis.

Eligible participants were identified during the pre-anesthetic clinic visit. Informed written consent from the recruited patients was taken in the evening before surgery at the in-patient unit. During this visit, patients were also instructed about the use of the visual analogue scale (VAS, 0-10 cm) for pain where 0 was “no pain” and 10 was “worst pain”. Oral diazepam (5mg for ≤50 kg and 10 mg for > 50 kg) was given the night before and 2 h before surgery as premedication.

On the day of surgery at the preoperative holding area, patients were randomly assigned (allocation 1:1) into one of the two groups according to a computer generated random number table. Details of group assignment and case number were kept in a set of sealed opaque envelopes. The anesthesia staff opened the envelope and prepared drugs accordingly. Both the patient and the investigator observing the outcome were blinded to the patient group assignment.  The investigator did not enter the operating room, but was responsible for patient assessment and data collection in the postoperative period. The attending anesthesiologist was not involved in the data collection and analysis, and followed the standard general anesthesia protocol during the study.

On arrival to the operating room, standard monitoring was applied and baseline heart rate (HR), non-invasive blood pressure, peripheral oxygen saturation and bispectral index (BIS) value (BIS^® monitor; Covidien, Boulder, CO, USA) were recorded. General anesthesia was induced with IV fentanyl 1.5 µg/kg and propofol 2-2.5 mg/kg until the cessation of verbal response. Tracheal intubation was facilitated with vecuronium 0.1 mg/kg IV. The lungs were mechanically ventilated using the circle system with 50% mixture of oxygen with air to maintain end tidal carbon dioxide   between 35 to 45 mm Hg.

At induction, patients in the Lidocaine group received 1.5 mg/kg of lidocaine IV bolus followed by an infusion (Perfusor compact^®, B-Braun, Melsungen, Germany) at 1.5 mg/kg/hr. Patients in the Esmolol group received an IV bolus of esmolol (0.5mg/kg) at induction followed by an infusion  titrated between 5 and 15 µg/kg/min to maintain the HR within 25% of the baseline value. In both groups, paracetamol 1 g IV infusion was given over 15 min after the induction of anesthesia. Anesthesia was maintained with isoflurane targeting mean arterial pressure (MAP) within 20% of baseline, and BIS value between 50 and 60 in both groups. Neuromuscular blockade was maintained with supplemental doses of vecuronium IV after observing curare notch in the capnogram.

Hasson’s surgical technique was used. Each port site was infiltrated with 3 ml of 2% lidocaine before incision. Pneumoperitoneum was achieved with carbon dioxide maintaining the intra-abdominal pressure below 15 mmHg during the procedure. Episodes of intraoperative hypotension (MAP <65 mmHg) and bradycardia (HR <50 beats/min) were treated with IV ephedrine 5 mg and atropine 0.4 mg respectively.

No supplemental opioids were used during the surgery. All patients received IV ketorolac 30 mg after the removal of gall bladder.  At the end of surgery, the carbon dioxide remaining in the peritoneal cavity was expelled by slow abdominal decompression. Isoflurane was discontinued after the last skin suture, and the infusion of the study drug was stopped. Incision site was infiltrated with 10 ml of 0.25% bupivacaine. Residual neuromuscular block was reversed with IV neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. When the patients were conscious and had adequate muscle power, thorough oropharyngeal suctioning was done and endotracheal tube was removed. The patients were transferred to the PACU after they followed verbal commands.

Postoperative pain management included IV paracetamol 1 g and ketorolac 30 mg at 6 h and 8 h respectively.  VAS pain scores at rest and during movement were documented at the PACU (on arrival, 15 min, 30 min, 1 h) and  surgical in-patient-unit (2 h, 6 h, 12 h and 24 h) by the blinded investigator. If the VAS score for pain exceeded  >3 at rest, morphine 1 mg IV was administered in the PACU, and repeated every five min until the VAS score was ≤ 3, or if any adverse effects were noticed. These included increased sleepiness (Ramsay sedation scale (RSS) score > 3), respiratory depression (SpO₂ < 90% in room air or respiratory rate < 8/min). The patients were then transferred to the in-patient-unit after 1 h of stay in PACU. In the surgical unit, tramadol 50 mg IV was administered for VAS score for pain > 3.

 The primary outcome was the total morphine consumed in the first 24 h postoperatively. The tramadol used in surgical unit was converted to morphine equivalent using online calculator (http://clincalc.com/Opioids/). Secondary outcome measures included patient-reported VAS pain scores at rest and movement, postoperative nausea and vomiting (PONV) on four point scale¹⁶ (1 = no nausea, 2 = mild nausea, 3 = severe nausea, 4 = retching and/or vomiting), the 6-point RSS scores ¹⁷(1 = patient anxious and restless, 2 = cooperative and awake, 3 = responding to verbal commands, 4 = responding to mild stimulus, 5 = responding to deep stimulus, 6= no response). These parameters were noted in PACU and at 2, 6, 12 and 24 h in surgical unit. PONV grade 3 & 4 were treated with metoclopramide 10 mg IV. Time to first perception of pain and void, overall patient satisfaction from anesthesia at 24 h based on 5-point Likert scale (1= highly satisfied,  2 = satisfied, 3 = neutral, 4 = dissatisfied, 5 = highly dissatisfied), and occurrence of lidocaine  toxicity were also noted.  The patients were discharged from the hospital at 24 h after surgery.

The sample size was calculated based on non-inferiority trial, assuming that the 24 h morphine used postoperatively would not differ between lidocaine or esmolol treatment with the non-inferiority margin determined as 2 mg. A sample size of 78 patients (39 per arm) was required to achieve a power of 90%, a one-sided 95% confidence interval with assuming the standard deviation of 3. We finally enrolled 90 patients to allow for possible dropouts or protocol violators (https://www.sealedenvelope.com/power/continuous-noninferior/). 

The data collected was entered into excel software and analyzed on STATA version 13.0 (Stata Corporation, College Station, TX, USA). Normality of data was checked using histograms, Skewness-Kurtosis test and Shapiro-Wilk test. Normally distributed data were compared between the two groups using the unpaired Student t-test. Mann-Whitney U-tests were used for continuous non-normally distributed data and ordinal data.  For categorical variables, Chi-square test was applied.  Time to first perception of pain between the groups was plotted with Kaplan-Meier survival curves and compared with log-rank test. A p value < 0.05 was considered as statistically significant.

Results

Among 104 consecutive patients assessed for eligibility, 90 patients met the inclusion criteria and they were randomly assigned to lidocaine or esmolol group. Two patients in each group needed conversion to open cholecystectomy, and eventually 86 patients were included in the analysis (Fig. 1). Both the groups were comparable with respect to baseline demographic characteristics, duration of surgery and anesthesia time (Table 1).

In PACU, median morphine consumption was 1 (0-1.5) mg in lidocaine group and 1(0-1.5) mg in esmolol group (p =0.50). Similarly, in the surgical-unit, median tramadol needed was 0 (0-50) mg and 0 (0-50) mg in the lidocaine and esmolol groups, respectively (p= 0.65). There was no significant difference in postoperative total 24-h morphine consumption between the two groups (Fig. 2). The time until the first perception of pain in the two groups as revealed by survival curve analysis is shown in Figure 3. VAS scores (both at rest and movement) throughout the postoperative period were comparable in the lidocaine and esmolol groups (Fig. 4 & 5).

The number of patients with postoperative sedation scores was comparable except in the PACU where significantly higher scores were observed in lidocaine group (Table 2).  PONV score was not significantly different between the two groups (p >0.05).  Six patients (14%) in each group needed rescue anti-emetic. Systemic lidocaine did not significantly reduce the mean time to first void (2.60 ± 1.2 h in esmolol group vs 2.67 ± 1.1 h in lidocaine group, p=0.79).

An abdominal drain was inserted in one patient in lidocaine and in 2 patients in esmolol group.  Both groups of patient expressed similar level of satisfaction from anesthesia at 24h after surgery (p = 0.40). One patient in esmolol group manifested bronchospasm in PACU and it was managed successfully with salbutamol nebulization. No features of lidocaine toxicity were reported.

Discussion

This study demonstrated that both lidocaine and esmolol have a comparable analgesic effect when administered with multimodal analgesia for laparoscopic cholecystectomy. This is reflected by the postoperative opioid requirement and pain scores in the first 24 h of surgery with no significant difference detected. The time to first perception of pain was also not significantly different between the two groups. Level of sedation at the PACU was more in lidocaine group than in esmolol group, but was comparable at other observation points. There was no difference in other side effects, and patients of both groups expressed similar level of satisfaction.

Clinical studies investigating the effect of intraoperative IV lidocaine in comparison to esmolol on postoperative opioid and pain scores have shown conflicting results. Similar to our findings, Dogan  et al. found comparable postoperative opioid consumption in patients receiving IV lidocaine and esmolol infusions in the first 24 h after laparoscopic cholecystectomy.¹⁸ In contrast, Kavak Akelma and his colleagues found significantly less fentanyl requirement in patients receiving esmolol than those receiving lidocaine infusion, or placebo in the first 24 h of surgery.¹⁹ This difference might be due to the higher dose of esmolol (50 µg. kg^-1. min^-1), used in their patients compared to ours (esmolol infusion limited to 15 µg. kg^-1. min^-1).

A recent meta-analysis showed that intraoperative esmolol reduces perioperative opioid requirement compared to both remifentanil and non-remifentanil based controls.¹⁵ However, the difference in reduction in opioid consumption was limited to the PACU only. The study by Dogan et al.¹⁸ and Kavak et al.¹⁹ were not included in this meta-analysis, and perhaps inclusion of these studies might have influenced the treatment effects. Nevertheless, it is well understood that esmolol has an opioid-sparing role and most of the proposed mechanisms are related to indirect analgesic effects.  These includes blockade or modulation of central adrenergic activity on pain signaling,^{20 21} and enhancing the exposure of other analgesics by altering its pharmacokinetics.²²

Regarding the beneficial role of lidocaine infusion in perioperative setting the results are confusing. The report from a recent Cochrane based meta-analysis was inconclusive stating that lidocaine had no positive impact on postoperative outcomes.¹¹ Contrary to this; two other meta-analyses published recently which included only those RCTs comparing lidocaine with placebo in patients undergoing LC found significant reduction in pain related outcomes postoperatively in lidocaine group.^{23 24} Perhaps, the use of only placebo comparator in the above mentioned two meta-analyses might have influenced the results. Importantly, there are several reasons for inconsistent results with lidocaine infusion,¹¹ and therefore it is too early to draw a conclusion that perioperative lidocaine infusions are ineffective especially in laparoscopic abdominal surgery.

Early recovery is one of the relevant clinical outcomes after minimally invasive surgery. It is evident from the previous study that patients in esmolol group achieved early discharge criteria from the PACU as compared to lidocaine group.¹⁸ Similarly, patients receiving lidocaine had RSS scores higher than esmolol at 10 min post-extubation. When reported as primary outcome measure, perioperative lidocaine failed to reduce the discharge time after ambulatory surgery.²⁵ This is likely due to mild sedative effect of lidocaine and therefore, it could have prolonged the PACU stay. This is in concordance with our results. Patients in the lidocaine group had significantly higher sedation scores up to 1 hr after surgery compared to the esmolol group. Although, we did not compare the time to readiness to discharge from the PACU, use of esmolol has slight advantage over lidocaine in relation to discharge time. Moreover, the shorter elimination half-life of esmolol as compared to lidocaine might be beneficial in ambulatory surgery.^{26 27}   

There are several limitations in our study. First, only female patients were enrolled in the study considering the gender differences in pain perception and analgesic requirement. Therefore, the external validity of the study was limited and the results may not be generalizable. Secondly, there was no placebo control group to show either lidocaine or esmolol was superior to placebo. Thirdly, to preserve the double-blinding nature of the study design, we did not compare the intraoperative hemodynamic parameters. However, after the completion of the statistical analysis we retrieved patient files and found that one patient in esmolol group manifested bradycardia intraoperatively, and it responded to IV atropine and pneumoperitoneum decompression. Likewise, one patient in both groups received IV ephedrine 5 mg for hypotensive episode. Importantly, it is well established that infusions of lidocaine and esmolol at lower doses are safe with no significant alteration in hemodynamics.^{11 28} Finally, we did not assess the impact of these drugs on early discharge from hospital because at the time when we submitted the proposal to IRC, our patients undergoing LC were required to stay up to 24 h postoperatively. It would be interesting to explore with adequately powered future studies with regard to early discharge from the PACU, quality of recovery and length of hospital stay.

Discussion

In conclusion, esmolol infusion was equally effective as lidocaine infusion for postoperative opioid consumption and pain scores following laparoscopic cholecystectomy. More patients in lidocaine group were sedated in the early period after surgery than those receiving esmolol.

Conclusions

In conclusion, esmolol infusion was equally effective as lidocaine infusion for postoperative opioid consumption and pain scores following laparoscopic cholecystectomy. More patients in lidocaine group were sedated in the early period after surgery than those receiving esmolol.

Abbreviations

VAS: visual analogue scale

IV: Intravenous

CONSORT: Consolidated Standards of Reporting Trials

HR: Heart rate

BIS: Bispectral Index

MAP: Mean arterial pressure

PACU: Post anesthesia care unit

RSS: Ramsay sedation scale

PONV: Postoperative nausea vomiting

Declarations

• Ethics approval and consent to participate: Institutional Review Committee, BPKIHS, reference number: IERB 284/014. Written informed consent was obtained from parents.
• Consent for publication: Not applicable

• Availability of data and material: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

• Competing interests: The authors declare that they have no competing interests
• Funding: None
• Authors' contributions

Joshana Lal Bajracharya: This author helped in study design, patient recruitment, data collection and writing up of the first draft of the paper

Asish Subedi: This author helped in study design, patient recruitment, data collection, analysis and interpretation of data, manuscript revision and final draft

Krishna Pokharel: This author helped in study design, analysis and interpretation of data, manuscript revision and final approval

Balkrishna Bhattarai: This author helped in patient recruitment, data collection, manuscript first draft

• Acknowledgements: Not applicable

References

1. Bisgaard T. Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology 2006;104: 835–46
2. Joris J, Thiry E, Paris P, Weerts J, Lamy M. Pain after laparoscopic cholecystectomy: characteristics and effect of intraperitoneal bupivacaine. Anesth Analg 1995; 81: 379–84
3. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93: 409–17
4. Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid induced respiratory depression: a closed claims analysis. Anesthesiology 2015; 122: 659–65
5. Zhao SZ, Chung F, Hanna DB, Raymundo AL, Cheung RY, Chen C. Dose-response relationship between opioid use and adverse effects after ambulatory surgery. J Pain Symptom Manage 2004; 28: 35–46
6. White PF: The role of non-opioid analgesic techniques in the management of pain after ambulatory surgery. Anesth Analg 2002; 94: 577-85

7. Lau CS, Chamberlain RS. Enhanced recovery after surgery programs improve patient outcomes and recovery: a meta-analysis. World J Surg 2017; 41: 899–913
8. Marret E, Rolin M, Beaussier M, Bonnet F. Meta-analysis of intravenous lidocaine and postoperative recovery after abdominal surgery. Br J Surg 2008; 95: 1331–8
9. Sun Y, Li T, Wang N, Yun Y, Gan TJ. Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: A meta-analysis of randomized controlled trials. Dis Colon Rectum 2012; 55:1183–94
10. Kranke P, Jokinen J, Pace NL, et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery. Cochrane Database Syst Rev 2015; 7: CD009642
11. Weibel S, Jelting Y, Pace NL, et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database Syst Rev2018; 6: CD009642
12. Chia YY, Chan MH, Ko NH, Liu K. Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy. Br J Anaesth 2004; 93: 799–805
13. Coloma M, Chiu JW, White PF, Armbruster SC. The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-track outpatient gynecologic laparoscopic surgery. Anesth Analg 2001; 92: 352–7
14. White PF, Wang B, Tang J, Wender RH, Naruse R, Sloninsky A. The effect of intraoperative use of esmolol and nicardipine on recovery after ambulatory surgery. Anesth Analg 2003; 97: 1633–8
15. Gelineau AM, King MR, Ladha KS, Burns SM, Houle T, Anderson TA. Intraoperative Esmolol asan Adjunct for Perioperative Opioid and Postoperative Pain Reduction: A Systematic Review, Meta-analysis, and Meta-regression. Anesth Analg  2018; 126: 1035-1049
16. Sonner JM, Hynson JM, Clark O, Katz JA. Nausea and vomiting following thyroid and parathyroid surgery. J Clin Anesth1997; 9: 398-402
17. Ramsay MA, Savage TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2: 656 –9
18. Dogan SD, Ustun FE, Sener EB, et al. Effects of lidocaine and esmolol infusions on hemodynamic changes, analgesic requirement, and recovery in laparoscopic cholecystectomy operations. Braz J Anesthesiol 2016; 66: 145-50
19. Kavak Akelma F, Ergıl J, Özkan D, Akinci M, Özmen M, Gümüs H. A comparison of the effects of intraoperative esmolol and lidocaine infusions on postoperative analgesia. Anestezi Dergisi 2014; 22: 25–31
20. Pertovaara A. The noradrenergic pain regulation system: a potential target for pain therapy. Eur J Pharmacol 2013; 716: 2–7
21. Hagelüken A, Grünbaum L, Nürnberg B, Harhammer R, Schunack W, Seifert R. Lipophilic beta-adrenoceptor antagonists and local anesthetics are effective direct activators of G-proteins. Biochem Pharmacol 1994; 47: 1789–95
22. Avram J, Krejcie TC, Henthorn TK, Niemann CU. Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution. J Pharmacol Exp Ther 2004; 311: 617–24
23. Zhao JB, Li YL, Wang YM, et al. Intravenous lidocaine infusion for pain control after laparoscopic cholecystectomy: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018; 97: e9771
24. Li J, Wang G, Xu W, Ding M, Yu W. Efficacy of intravenous lidocaine on pain relief in patients undergoing laparoscopic cholecystectomy: A meta-analysis from randomized controlled trials. Int J Surg 2018; 50: 137-45
25. McKay A, Gottschalk A, Ploppa A, Durieux ME, Groves DS. Systemic lidocaine decreased the perioperative opioid analgesic requirements but failed to reduce discharge time after ambulatory surgery. Anesth Analg 2009; 109: 1805–8
26. Wiest D. Esmolol. A review of its therapeutic efficacy and pharmacokinetic characteristics. Clin Pharmacokinet 1995; 28: 190–202
27. Rowland M, Thomson PD, Guichard A, Melmon KL. Disposition kinetics of lidocaine in normal subjects. Ann N Y Acad Sci 1971; 179: 383-98
28. Yu SK, Tait G, Karkouti K, Wijeysundera D, McCluskey S, Beattie WS. The safety of perioperative esmolol: a systematic review and meta-analysis of randomized controlled trials. Anesth Analg 2011; 112: 267-81

Tables

Table 1: Comparison of demographic and baseline characteristics of patients

Values are in median (IQR), mean ± SD, number. Abbreviations: BMI, body mass index; ASA PS, American society of Anesthesiologist physical status

Table 2. Comparison of postoperative sedation score at various time points

Values are in number of patients with Ramsay sedation scale scores 1/2/3/4/5/6 (1= patient anxious and restless, 2= cooperative and awake, 3= responding to verbal commands, 4= responding to mild stimulus, 5= responding to deep stimulus, 6= no response)