Tonsillectomy, with or without surgical removal of the adenoids, remains one of the most common surgical procedures performed in children worldwide. Postoperative vomiting (POV) is a known complication of this procedure, with an incidence of at least 70% when no anti-emetic prophylaxis is used.1
Several pharmacological interventions to prevent POV have been studied. Many of the anti-emetic drugs available are costly and do not completely eliminate POV.2 Furthermore, side effects such as agitation, extrapyramidal symptoms, bleeding and cardiac rhythm disturbances have been reported, reducing their cost-effectiveness.3
There is some evidence suggesting that the use of an intravenous lidocaine infusion in patients undergoing abdominal surgery could provide better postoperative pain control with less postoperative nausea and vomiting. This effect has been attributed to an increase in intestinal motility and/or a reduction in postoperative pain and opioid use.4 Other studies suggest that the reduction is not related to an opioid-sparing effect.5 Scarce evidence exists for the use of lidocaine infusion in children. There is only one study available; it showed no benefit in patients undergoing tonsillectomies, and was clearly underpowered.6
Our hypothesis is that a lidocaine infusion could prevent POV in children who underwent tonsillectomy under general anaesthesia.
The purpose of this study was to evaluate the effectiveness of an intravenous lidocaine infusion used as an adjuvant to general anaesthesia, in preventing nausea and vomiting in children undergoing tonsillectomies, with or without adenoidectomy.
We designed a double-blind, single-centre, parallel-group, randomised, controlled clinical trial (ClinicalTrials.gov Identifier: NCT01986309).
The current study was approved by the Institutional Review Board of the School of Medicine of the Pontificia Universidad Católica de Chile (CEI 12-132, 1 July 2012). Written, informed, parental consent and child assent (if applicable) were obtained from all participants. Children aged 2 to 12 years, ASA I or II, scheduled for elective tonsillectomy, with or without surgical removal of the adenoids under general anaesthesia, were studied. Subjects fulfilling the trial entry criteria were approached before surgery by a research member not involved in the clinical care.
We excluded patients with a history of intellectual impairment, obesity, diabetes mellitus, use of any psychoactive and/or anti-emetic drugs within the 24 h prior to surgery, known congenital conduction disorders, gastro-oesophageal reflux, history of liver or renal insufficiency, seizures and a known allergy to the study drug.
Subjects were randomised to receive: intravenous lidocaine [1.5 mg kg−1 bolus administered over 5 min followed by an infusion (2 mg kg−1 h−1)] that was continued until the end of the surgical procedure (Lidocaine group), or an identical volume and rate of 0.9% saline (Saline group). A randomisation sequence was generated using the website Randomization.com with a 1 : 1 allocation ratio, using randomly permuted blocks of 2, 4 and 6.
To maintain blindness of the study, an anaesthetist, not involved in the anaesthesia care or study evaluation, prepared lidocaine and 0.9% saline in 20 ml syringes based on the randomisation list.
During the entire study period, investigators performing the intra-operative and postoperative assessments, medical staff (nurse, anaesthetist and surgeon), subjects and parents/guardians were unaware of the group allocation.
The minimum fasting time prior to surgery was 4 h, and no premedication was used. In the operating room, standard monitoring was applied [electrocardiogram, pulse oximetry and noninvasive arterial blood pressure (BP)] before induction of general anaesthesia with 8% inspired sevoflurane in 100% oxygen by face mask. Once intravenous access was attained, fentanyl (4 μg kg−1), dexamethasone (0.15 mg kg−1) and mivacurium (0.16 mg kg−1) were given. At this time, the intravenous lidocaine (bolus dose followed by infusion using a 5 mg ml−1 concentration) or a similar volume placebo infusion using a syringe infusion pump (Pilot Anesthesia 2; Fresenius Vial S.A., Brezins, France) were administered according to group allocation. Endotracheal intubation was performed using a Ring Adair Elwyn oral tube, and anaesthesia maintained with sevoflurane 2% in a mixture of nitrous oxide 50% and oxygen 50%. Fentanyl (1 μg kg−1 bolus) was given to maintain BP and heart rate to within 20% of baseline. All subjects received intravenous acetaminophen (7.5 mg kg−1 for those less than 2 years of age and 15 mg kg−1, up to 750 mg, if ≥2 years)7 during the intra-operative phase, followed by oral acetaminophen in the phase II postanaesthesia care unit (PACU), continued every 6 h afterwards. All subjects received 25 to 30 ml kg−1 of Ringer's lactate solution during anaesthesia.8
The surgical techniques used in tonsillectomies and adenoidectomies were standardised for all cases.8
At the end of the surgical procedure, the lidocaine or placebo infusion was stopped. Then, a 1-ml venous blood sample was drawn to measure the plasma lidocaine concentration. Muscle relaxation was reversed with atropine 20 μg kg−1 and neostigmine 50 μg kg−1 if needed, after evaluating residual muscular blockade using a neuromuscular monitor (TOF-Watch; Organon, Dublin, Ireland). The criteria used for reversal were to achieve normalised train of four and Double burst stimulation tests. An orogastric tube was used to suction the stomach. All patients were extubated awake in the operating room when able to open their eyes, and then transported to the PACU. The time to extubation, defined as time from end of surgery to tracheal extubation, was recorded.
After extubation, each vomiting or retching event was documented by one of the investigators and a rescue anti-emetic was given (intravenous ondansetron 0.15 mg kg−1 or intravenous droperidol 0.015 mg kg−1) as previously described.8 Only retching and vomiting episodes were recorded, as nausea is difficult to assess in children. Continuous cardiac monitoring via telemetry was maintained during their PACU stay.
The Watcha scale9 (1 to 4 points) was used to assess emergence delirium. Pain was assessed using the children and infants postoperative pain scale (CHIPPS; 0 to 10 points) or the visual analogue scale (VAS; 0 = no pain, 10 = worst possible pain). The CHIPPS scale was used when the child was less than 6 years old or unable to understand the visual pain scale. Pain scores and emergence delirium were quantified on admission to the PACU, and then repeated every 15 min for the first 2 h after surgery. When the reported CHIPPS or VAS score was at least 4 and/or Watcha at least 3, intravenous fentanyl (0.5 μg kg−1 dose−1) was administered.
Oral intake was restarted in PACU as soon as requested. Children were transferred to the ward when the modified Aldrete score was at least 9. Based on the surgeons’ preference, all children stayed at the hospital overnight. A telephone call was made 24 h after surgery to assess the presence of retching or vomiting. We also quantified the worst pain score after discharge using the CHIPPS scale or a verbal scale of 0 to 10, as previously described by Elgueta el al.8
Our primary outcome was defined as the presence of at least one episode of vomiting (forcible ejection of stomach contents through the mouth), retching (unproductive effort to vomit) or both in the first 24 h postoperatively (POV). Secondary outcomes included plasma concentrations of lidocaine and postoperative pain.
Within 2 h of collection, all blood samples were centrifuged and then stored in a cryotube at −20 °C until analysis.
Plasma concentrations of lidocaine were measured as previously described by Barat et al.10 and O’Neal and Poklis11 The limit of quantification for the assay was 0.1 μg ml−1 and the coefficient of variation was 7.5%.
Based on the study by Elgueta et al.8 who reported an incidence of POV of 62%, 43 subjects per arm were regarded as necessary to test a difference in proportions of at least 30% with a power of 0.8 and an α level of 0.05. A total of 46 patients per arm were enrolled to allow for potential dropouts.
Between-group comparisons were performed using Student's t test or Wilcoxon rank-sum test, based on the results of the Shapiro–Wilk test. We used χ2 test and Fisher's exact test for inferences on proportions. Postoperative pain scores were analysed using rank-based repeated measures analysis of variance.
The primary outcome was tested using univariate logistic regression. Multivariable logistic regression was later used to adjust the primary outcome estimate for potential confounders.12–14 To avoid the potential risk of over-fitting the model, a total of two confounding variables were included in the final model (sex and ASA physical status). Calibration of the final model was evaluated using the Hosmer–Lemeshow goodness-of-fit test.
Mean ± SD, median [interquartile range] or odds ratio (OR) [95% confidence interval (CI)] were used as descriptive statistics. A two-sided P value of less than 0.05 was considered significant. We used STATA/SE v12.1 (StataCorp LP, College Station, Texas, USA) for the analyses. We followed the intention-to-treat (ITT) principle.
We enrolled 92 children. All received their assigned study treatment. One child randomised to the Saline group had all data missing (Fig. 1). Subject characteristics were comparable between groups (Table 1). Patients in the Lidocaine group had a longer time to extubation [10.3 (4.2) vs. 7.5 (3.3) min, P < 0.001] (Table 1). Postoperative pain scores were similar between groups (Table 2). No neuromuscular blocker reversal was required in either group.
In the Lidocaine group, a total of 2.9 (0.38) mg kg−1 of lidocaine was administrated. The median lidocaine plasma concentration was 3.94 μg ml−1 (range: 0.87 to 4.88).
In the Lidocaine group, 28 of 46 patients (60.8%) experienced at least one episode of retching, vomiting or both during the first 24-h postoperative period, compared with 37 of 45 patients (82.2%) in the Saline group [difference in proportions 21.3% (95% CI, 2.8 to 38.8), P = 0.024], which represent an unadjusted OR of 0.33 (95% CI, 0.13 to 0.88).
The ITT analysis showed that when we assumed that the patient in the Saline group lost to follow-up did not have POV, the difference in proportions decreased to 19.6% (95% CI, 0.9 to 37.2), with an unadjusted OR of 0.38 (95% CI, 0.15 to 0.97, P = 0.044). Thus, the odds of having POV were 62% less likely in those patients who received lidocaine compared with patients in the Saline group.
The results of the multivariable logistic regression are presented in Table 3. After adjusting for sex12 and ASA physical status (univariable analysis P = 0.130), the odds of POV the first 24-h postoperative period were 71% less likely in the Lidocaine group than in the Saline group (OR 0.29, 95% CI, 0.10 to 0.80; P = 0.017).
The results of this double-blind, randomised clinical trial show that a lidocaine infusion given as an adjuvant drug to children undergoing tonsillectomy under general anaesthesia reduces the risk of POV compared with placebo treatment.
The underlying mechanism of postoperative nausea and/or vomiting (PONV) has not been completely elucidated. The ‘central pattern generator’ for vomiting includes key structures within the lateral reticular formation of the medulla oblongata. This area receives multiple sensory inputs from the heart, abdominal viscera, vestibular system, brain stem area postrema (chemoreceptor trigger zone) and higher brain centres.15 Neurotransmitter receptors involved in the mediation of signals leading to nausea and/or vomiting include dopaminergic (D2), histaminergic (H1), cholinergic, serotonergic (5-HT316) and neurokinin NK1 systems.17
Noxious stimuli (such as surgery) can induce PONV through different mechanisms, such as pain, neurotransmitter release (serotonin, dopamine), head positioning (through vestibular nerve stimulation) and opioid use.18
Multiple mechanisms of action for local anaesthetics have been described. Primarily, lidocaine binds to voltage-gated sodium (Na+) channels preventing the flow of Na+ ions through the channel pore.19 Blockade of muscarinic, nicotinic and dopaminergic receptors, enhancement of gamma-aminobutyric acid-inergic pathways, inhibition of opiate receptors and anti-inflammatory properties have also been reported.20
There is also evidence that local anaesthetics may inhibit the release of substance P,16,21 a potent NK1 agonist. Lidocaine may exert its anti-emetic properties through one or several of these mechanisms.
In a recent meta-analysis by Weibel et al.,20 an intravenous infusion of lidocaine was associated with a lower risk of developing nausea [45/218 patients in the Lidocaine group vs. 66/222 in the control group, relative risk (RR) 0.82 (95% CI, 0.70 to 0.97)], but the risk of vomiting was no different between groups [RR 0.49 (95% CI, 0.16 to 1.48)]. As this meta-analysis only included studies performed in adult patients, extrapolations to children should be done with caution.
A systematic review and meta-analysis performed by Kranke et al.5 suggested that one of the possible explanations of fewer episodes of POV among patients receiving lidocaine was its opioid-sparing effect. We did not find a difference in terms of opioid consumption during the intra-operative or postoperative period. This absence of difference, however, could be explained as the study is not powered to find differences in terms of pain outcomes, as sample size calculation was based on POV.
Although patients in the Lidocaine group had a longer time to extubation (2.5 min) that was statistically significant, we think that this difference is not clinically relevant. Furthermore, any potential sedative effect of intravenous lidocaine did not affect the incidence of emergence delirium.
No clinical evidence of local anaesthetic systemic toxicity, including arrhythmias, was seen in any of the participants. All measured lidocaine plasma levels were below the toxicity threshold of 5 μg ml−1,22 suggesting that this technique could be a safe alternative for prevention of POV. The dose scheme utilised in this study is similar to other protocols previously described, using lidocaine either as anti-arrhythmic drug23 or as an adjunct to general anaesthesia to reduce opioid consumption.5 It is possible that lower lidocaine levels could be also effective in POV prevention. Further studies are warranted to determine a minimum effective concentration to obtain this effect.
Our study has several limitations. The evaluation of pain and nausea in children is difficult to assess. We used validated scales to measure these outcomes, but lack of precision in determining symptoms in young children may have limited our results.
Another limitation is the use of telephone contact with parents to evaluate children 24 h after surgery. This may have introduced over-reporting of symptoms in some parents.
Lastly, although we found a statistically significant decrease in the incidence of POV of 21.3% (ITT analysis = 19.6%) in the Lidocaine group, this was less than the 30% level we chose to use for our power analysis. However, a 30% decrease was within our calculated 95% CI, (upper limit of the ITT 95% CI, 37.2%).
Tonsillectomy is common in paediatric patients, and POV is a common problem for this type of surgery. The efficacy of lidocaine, absence of clinical toxicity in the dose scheme used, low cost and availability make it an attractive drug to use as an adjuvant with general anaesthesia.
In conclusion, an intravenous lidocaine infusion for prophylaxis of nausea and vomiting after tonsillectomy, in children under 12 years old, is feasible and effective. Care must be taken not to exceed toxic doses. Although our results suggest that the use of lidocaine may be administered safely in children they are not conclusive. Further larger studies adequately designed to evaluate safety, tolerability and toxicity must be conducted to address these issues.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: this study was supported by a Research Fund, Dirección de Investigación y Doctorado (DIDEMUC), Escuela de Medicina, Pontificia Universidad Católica de Chile.
Conflicts of interests: none.
Presentation: presented at the 2014 Euroanaesthesia Meeting (Stockholm, Sweden).
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