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Impact of a prophylactic combination of dexamethasone–ondansetron on postoperative nausea and vomiting in obese adult patients undergoing laparoscopic sleeve gastrectomy during closed-loop propofol–remifentanil anaesthesia: A randomised double-blind placebo-controlled study

Bataille, Aurélien; Letourneulx, Jacques-Florian; Charmeau, Alain; Lemedioni, Pascale; Léger, Philippe; Chazot, Thierry; Le Guen, Morgan; Diemunsch, Pierre; Fischler, Marc; Liu, Ngai

European Journal of Anaesthesiology: December 2016 - Volume 33 - Issue 12 - p 898–905
doi: 10.1097/EJA.0000000000000427
Postoperative nausea and vomiting
Free

BACKGROUND In obese patients, the incidence of postoperative nausea and vomiting (PONV) following sleeve gastrectomy under titration of total intravenous anaesthesia (TIVA) and the relevance of risk factors to indicate prophylaxis is unknown.

OBJECTIVES The hypothesis was that after automated TIVA, prophylaxis reduces PONV following laparoscopic sleeve gastrectomy. Our objective was to determine the incidence of PONV and evaluate the efficacy of dexamethasone and ondansetron as prophylaxis when automated intravenous anaesthesia is employed.

DESIGN A randomised, placebo-controlled, single-centre, double-blinded study.

SETTING Secondary care centre in New Caledonia from June 2013 to January 2014.

PATIENTS A total of 122 patients were randomised and 117 (92 women) were included in the analysis (58 in the prophylaxis group and 59 in the placebo group). Eligibility criteria included at least two of the known risk factors for PONV: female sex, nonsmoking status, prior history of PONV or motion sickness and expected postoperative opioid analgesia. Exclusion criteria included disorders limiting the use of the bispectral index.

INTERVENTIONS All patients received propofol and remifentanil controlled by the same automated system during induction and maintenance of general anaesthesia. The controller modifies the calculated effect-site concentrations according to bispectral index values. Patients received either intravenous dexamethasone 4 mg after tracheal intubation and ondansetron 4 mg during skin closure, or placebo.

MAIN OUTCOME MEASURES The primary endpoint was the cumulative incidences of 24-h PONV and severe PONV (vomiting or nausea with a score of ≥4 on an 11-point verbal rating scale). Data are presented as percentage (95% confidence interval).

RESULTS PONV in the first 24 h occurred in 45 (34 to 60)% of patients who received prophylaxis and 54 (41 to 67)% in the placebo group (P = 0.35). The numbers of patients who suffered severe PONV [19 (10 to 32)% in the prophylaxis group vs. 20 (11 to 33)%, P = 1, in the placebo group] and who required rescue antiemetic drugs [55 (41 to 68) vs. 63 (49 to 75)%, P = 0.46] were similar between the groups.

CONCLUSION The combination of dexamethasone and ondansetron was not effective in preventing PONV or severe PONV in obese patients undergoing laparoscopic sleeve gastrectomy after TIVA.

TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT01876290.

From the Department of Anaesthesia, Hôpital Foch, and Université Versailles Saint-Quentin en Yvelines, Suresnes, France (AB, TC, MLG, MF, NL); Department of Anaesthesia (J-FL, AC, PL); Department of Surgery, Clinique de la Baie des Citrons, Nouméa, Nouvelle Calédonie (PL); Department of Anaesthesia, Hôpital Hautepierre, Strasbourg, and University of Strasbourg, France (PD); and Outcomes Research Consortium, Cleveland, Ohio, USA (NL)

Correspondence to Professor Marc Fischler, Department of Anaesthesiology, Hôpital Foch, 40 rue Worth, 92151 Suresnes, France Tel: +33 1 46 25 24 42; fax: +33 1 46 25 20 88; e-mail: m.fischler@hopital-foch.org

Published online 10 February 2016

This article is accompanied by the following Invited Commentary:

Eberhart LHJ, Kranke P. Postoperative nausea and vomiting: is everything now solved or still more questions than answers? Eur J Anaesthesiol 2016; 33:878–880.

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Introduction

Total intravenous anaesthesia (TIVA) using propofol is often used to reduce the risk of postoperative nausea and vomiting (PONV).1–3 Propofol has antiemetic properties at subhypnotic doses and can be used as rescue medication for PONV.4 Several studies have reported that tight control of depth of anaesthesia results in a decreased incidence of PONV in lean patients, related to the reduction of intraoperative drug consumption.5,6 We have developed a closed-loop controller allowing the automated titration of propofol and remifentanil guided solely by the bispectral index (BIS) during induction and maintenance of general anaesthesia.7 For obese patients, the titration of hypnotic agents using electrocortical activity as determined by the BIS improves the titration of anaesthesia8,9 and the doses of propofol and remifentanil administered by the automated controller provide satisfactory anaesthetic conditions without overdosing.10

In obese patients, the true incidence of PONV following laparoscopic sleeve gastrectomy (LSG) under TIVA guided by BIS is unknown. The clinical relevance of the PONV risk factors used to determine which patients need prophylactic antiemetic treatment is also unknown because the PONV risk factors were established under inhalational anaesthesia in lean patients.11

Our hypothesis was that prophylaxis reduces the incidence of PONV in obese patients undergoing LSG during TIVA guided by BIS. We therefore evaluated the efficacy of PONV prophylaxis in this setting. The objectives of this randomised placebo-controlled, double-blind study were to determine the incidences of overall and severe PONV after automated titration of propofol and remifentanil guided by BIS in the context of LSG in patients who had at least two PONV risk factors, and evaluate the efficacy of the combination of dexamethasone and ondansetron used as PONV prophylaxis in comparison with a placebo.

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Methods

The study was approved by a French Ethics Committee (Comité de Protection des Personnes Île de France VIII, Hôpital A. Paré, Boulogne Billancourt, France; Chairperson Dr Barthod, N°12 05 49; 15 May 2012). This study was registered at ClinicalTrials.gov (NCT01876290) and on EudraCT (ref: 2012-001486-32). Written informed consent was obtained during the preoperative visit performed by the investigators. Obese patients scheduled for elective LSG were enrolled at the private hospital of Clinique de la Baie des Citrons (Nouméa, New Caledonia). Eligibility criteria included patients aged between 18 and 75 years with American Society of Anesthesiologists’ physical status 1 to 3. We enrolled patients who had at least two of the following risk factors for developing PONV according to the simplified risk score from Apfel et al.11: female sex; nonsmoker; a prior history of PONV or motion sickness and expected to receive postoperative opioid analgesia. Exclusion criteria included pregnant or breast-feeding women; psychiatric illness (limiting the use of BIS); supraspinal neurological disorders; patients fitted with a pacemaker; symptomatic gastro-oesophageal reflux; contraindication to the use of dexamethasone, ondansetron, propofol, remifentanil or morphine and patients with expected difficult airway management or with planned awake fibreoptic intubation. The sequence of treatment with dexamethasone and ondansetron (DO group) or placebo (Placebo group) was determined in blocks of 10 (five DO and five Placebo group) using an internet-based randomisation system in a 1 : 1 ratio. The randomisation system gave the assignment to the pharmacy 1 h prior to induction of anaesthesia. The drugs or placebo were prepared in the pharmacy in a volume of 10 ml and were colourless and indistinguishable.

No sedative or anxiolytic premedication was used, but cimetidine 150 mg was administered preoperatively. Upon arrival in the operating theatre, a dedicated intravenous cannula was inserted and routine monitoring commenced, including temperature. Before induction of anaesthesia, a BIS electrode (Zipprep, Covidien, Dublin, Ireland) was positioned on the patient's forehead and connected to either an A-2000 XP (version 3.11) BIS monitor or a BIS M-Module (GE-Healthcare S/5, Helsinki, Finland). Before induction, the lungs were preoxygenated with a positive end-expiratory pressure of 10 cmH2O until an end-tidal oxygen concentration of more than 92% was obtained. All patients received propofol and remifentanil controlled by the same closed-loop automated system during induction and maintenance of general anaesthesia. The controller has a cascade structure including a dual proportional-integral-derivative algorithm that directs a target-controlled infusion system for the administration of propofol and remifentanil. The total body weight was entered into the target-controlled infusion systems, which used the pharmacokinetic models of Schnider et al.12 for propofol and of Minto et al.13 for remifentanil. The controller modifies the calculated effect-site concentrations according to BIS changes during surgery, on the assumption that small fluctuations of BIS are related to fluctuations in the intensity of noxious stimuli.14 The controller has been validated in obese patients in a prospective cohort comparison study.10 By continuous titration, the controller allows the tight control of adequate anaesthesia measured by BIS and avoids propofol and remifentanil overdosage related to the use of inadequate pharmacokinetic models.15,16 Details of the controller are provided in the appendices in the two previous randomised controlled studies.7,10 All investigators received a full day of training for the use of the automated controller at the Hôpital Foch, Suresnes, France, and were able to override the automated system if necessary, or to switch between automated and manual control. In both the groups, the investigator chose the initial propofol effect-site target concentration according to his/her clinical judgement and the controller fixed the first remifentanil effect-site target concentration.

Neuromuscular function at the adductor pollicis was monitored after loss of consciousness. After tracheal intubation, the lungs were mechanically ventilated with an inspired oxygen concentration of 40% (nitrogen 60%) and positive end-expiratory pressure of 5 cmH2O. All patients received atracurium to ensure muscle relaxation. Other than administration of the study drugs, each patient's management was based on current standards of care. No specific recommendations were given for the treatment of haemodynamic abnormalities.

Approximately 45 min before the anticipated end of surgery, intravenous analgesics (morphine 0.1 mg kg−1, proparacetamol 1 g and nefopam 20 mg) were given to provide postoperative pain relief. Intravenous ketoprofen was given at the discretion of the anaesthesiologist. In both the groups, the administration of propofol and remifentanil was stopped on completion of surgery. Neuromuscular blockade reversal agents (neostigmine with atropine) were administered when the train-of-four ratio was between 40 and 60% and the lungs were ventilated with 100% oxygen before tracheal extubation.

In both the groups, the induction phase was defined as the time from the start of propofol and remifentanil administration to BIS less than 60 for 30 s and the maintenance phase from this point to the end of propofol and remifentanil administration. Patients in the DO group received intravenous dexamethasone 4 mg after tracheal intubation and ondansetron 4 mg during skin closure. Patients in the Placebo group received two injections of 5 ml of 0.9% saline at the same times.

The primary outcome of the study was the overall incidence of PONV during the first 24 h, defined as any episode of vomiting or nausea.17 Nausea was measured using an 11-point verbal rating scale (VRS) running from 0 (no nausea) to 10 (the worst nausea imaginable). We defined severe PONV as nausea with a score of at least 4 on the VRS, or vomiting. PONV scores were recorded upon arrival in the postanaesthesia care unit (PACU), and at 1, 2, 4 and 24 h after admission to the PACU. During the postoperative period, all episodes of PONV within the 24 h after anaesthesia were recorded. Rescue medication of ondansetron 4 mg followed by droperidol 0.625 mg as necessary were administered to any patient who retched, vomited or experienced nausea from which they wanted relief, or when the VRS nausea score was at least 4.

Secondary outcomes included severe PONV defined as any vomiting and/or severe nausea (VRS ≥ 4) and the use of antiemetic rescue medication. The percentage of anaesthetic time during which anaesthesia was adequate [defined as BIS between 40 and 60 (BIS40–60)], deep anaesthesia (BIS<40), light anaesthesia (BIS>60) and excessive anaesthesia (defined as the occurrence of suppression ratio with suppression ratio >10% lasting at least 1 min) were recorded.18 The use of vasopressor or antihypertensive therapy was noted. Consumptions of propofol and remifentanil were recorded and the ideal body weight was calculated using the formula: 45.4 (49.9 if male) + 0.89 × (height in cm −152.4) kg.19

Pain was assessed on arrival in the PACU, and at 1, 2, 4 and 24 h after admission to the PACU. Pain intensity was measured using a simple 11-point VRS running from 0 (no pain) to 10 (unbearable pain), at rest and on mobilisation (asking the patient to cough). Recall of intraoperative events and awareness was evaluated by a standardised and validated questionnaire performed 24 h after surgery.20

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Statistical analysis

The primary outcome was PONV during the first 24 h. In the absence of PONV prophylaxis in patients with a simplified risk score more than 2 undergoing TIVA without nitrous oxide, the incidence of PONV has been reported as approximately 50%.21 Therefore, in obese patients, we expected that dexamethasone and ondansetron would decrease the incidence of severe PONV to 30% on the assumption that each antiemetic drug can decrease the incidence of PONV by 25%.1 Planned enrolment was for a minimum of 48 patients per group which would provide an 80% power for a two-sided error of 5% and, under the assumption that some would be excluded for various reasons, the intention was to randomise a total of 120 patients. Discrete binomial variables, expressed as numbers, frequencies, 95% confidence interval, calculated using the Wilson procedure with a correction for continuity, were compared using Fischer's exact test. Continuous variables were described as median and interquartile range and compared using nonparametric tests. Probability values less than 0.05 using two-tailed tests were considered statistically significant. To evaluate the efficacy of our intervention, we performed a per-protocol analysis, restricted to patients who did effectively receive the prophylaxis. Data analysis was performed using R Core Team 2014 (R Foundation for Statistical Computing, Vienna, Austria; htpp://http://www.R-project.org). Data from the BIS monitor were recorded every 5 s. Data were transmitted and analysed by Anesloop.org (htpps:/http://www.anesloop.org). Anesloop.org is a secure website dedicated to clinical trial research including the internet case report form, database storage, an internet-based randomisation system and the tools allowing analysis and calculation of BIS values and drug consumptions.

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Results

Among 130 obese patients who were approached, 122 were recruited between June 2013 and January 2014. Usable data were obtained from 58 patients in the DO group and 59 patients in the Placebo group (Fig. 1). Baseline characteristics and risk factors for PONV were similar between the two groups; median of BMI was greater than 40 kg m−2 in both the groups (Table 1). LSG was performed on all patients by the same surgeon (P.L.) and no conversion to laparotomy was required. Closed-loop anaesthesia was successfully provided for all patients. No episodes of hypoxaemia were recorded during induction. Propofol and remifentanil consumption, fluid loading, blood loss, use of vasopressor, postoperative body temperature, total morphine consumption, and the percentages of adequate, too deep or too light anaesthesia were similar between the two groups (Table 2).

Fig. 1

Fig. 1

Table 1

Table 1

Table 2

Table 2

The incidences of cumulative 24-h PONV in the DO and Placebo groups were 45 (32 to 59) and 54 (41 to 67)% (P = 0.5), respectively, and the incidences of severe PONV were 19 (10 to 32) and 20 (11 to 33)% (P = 1), respectively (Table 3).

Table 3

Table 3

No rescue medication was necessary for 45 (32 to 59)% of patients in the DO group and 37 (25 to 51)% in the Placebo group (Table 3). Overall and severe PONV stratified by the risk factors for PONV for the two groups are presented in Table 4. We aggregated the risk factors 3 and 4 for PONV because the number of cases of risk factor 4 was only four patients in each group (Table 4). The incidence of PONV increased with the number of PONV risk factors but the differences were not statically significant: P = 0.33 (risk factor = 2 vs. ≥3 for overall PONV) and P = 0.17 (risk factor = 2 vs. ≥3 for severe PONV). Pain evaluation was not different between groups except at 2 h after arrival in the PACU (Table 5). Median verbal rating scores were 0 at all times. No cases of awareness with recall were reported.

Table 4

Table 4

Table 5

Table 5

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Discussion

We report the incidence of overall and severe PONV in morbidly obese patients with moderate-to-high risk of PONV undergoing LSG. All obese patients received the same anaesthetic care with a reproducible method of intravenous anaesthesia titration and the same surgical procedure with the same surgeon. With this reproducible methodology, the incidences of overall PONV and severe PONV were similar with or without the prophylactic combination of dexamethasone and ondansetron (Table 4).

Obesity has become pandemic worldwide; the number of morbidly obese patients who require bariatric surgery is increasing. This surgical procedure is associated with morbidity and PONV represents a significant adverse event.22 In lean patients, PONV incidence is related to patient characteristics,11 the use of postoperative opioids,23 the method of anaesthesia,1 the use of PONV prophylaxis1,11,24 and probably to the type of procedure, such as laparoscopic surgery.25 Obese patients represent a particular population in this setting; PONV is more common after LSG than Roux-en-Y gastric bypass (59 vs. 19%).26

After bariatric surgery, PONV incidences have usually been reported for volatile anaesthesia, including PONV prophylaxis, and PONV risk factors have rarely been reported. However, two studies reported PONV during volatile anaesthesia without antiemetic prophylaxis. In 30 patients, including 13% who underwent LSG, the PONV rate was 67% with an incidence of vomiting of 20%.27 Another study reported that the PONV incidence was 79% in 19 patients undergoing laparoscopic bariatric procedures.28 However, patients with low risk factors for PONV or different laparoscopic bariatric procedures were included and probably the PONV was underestimated in these two studies.27,28 Another study21 reported that the incidence of PONV in obese patients with PONV risk factors of at least 2 who underwent LSG during volatile anaesthesia without nitrous oxide was between 57 and 70% of patients, with a different combination of antiemetic prophylaxis. In this trial, the patients were allocated to one of three groups of 30 patients who received ondansetron, a combination of dexamethasone–ondansetron or a combination of haloperidol–dexamethasone–ondansetron. Finally, the incidence of overall PONV varied between 23 and 60%, and the incidence of vomiting varied between 10 and 27% with three and one antiemetic prophylaxis, respectively. This study reported a high incidence of vomiting despite triple antiemetic prophylaxis.

Recently, a study of 60 obese patients with PONV risk factors of at least 2, who were anaesthetised using propofol guided by BIS, and who received triple antiemetic prophylaxis (dexamethasone, ondansetron and scopolamine), reported that the occurrence of nausea was 20% and vomiting was absent.26 Intraoperative opioids were omitted and replaced by a combination of dexmedetomidine–ketamine; LSG was performed in 22% of the cases. The current study confirms that LSG is an emotegenic procedure, probably related to the intense gastric stimulation causing the release of 5-hydroxytryptamine from the stomach enterochromaffin cells and explaining the lack of efficacy of conventional PONV prophylaxis. However, the incidence of PONV in our study was lower than in other studies in which volatile anaesthesia was administered without antiemetic prophylaxis.27,28 This incidence is relevant to determine the strategy of PONV prophylaxis during bariatric surgery.

One limitation of our study is that it lacks a volatile anaesthesia group and we have to place reliance on previous studies to compare incidences. Probably, avoiding the use of a volatile agent and using propofol during LSG would be similar to use of one or two antiemetic agents.21

There was a trend in the present study suggesting that the incidence of PONV increased in proportion to the number of risk factors (43 vs. 62%, PONV risk factor = 2 vs. ≥3) but the study was underpowered to demonstrate a difference between PONV risk factors. The simplified risk factors11 were validated in several thousand patients with a BMI of less than 40 kg m-2. In particular, the influence of each PONV risk factor needs to be compared with that of LSG for the prediction of PONV. The clinical relevance of PONV risk factors to stratify the risk of PONV in obese patients needs to be debated.

The strength of our study is that it was conducted with a minimum of bias relating to patients, surgery or the depth of anaesthesia. Automated TIVA guided by BIS was used and we were unable to demonstrate that our combination PONV prophylaxis was effective. The two drugs were correctly administered: dexamethasone after induction and ondansetron during wound closure.24 A possible explanation may relate to the dose range of dexamethasone or ondansetron. Dexamethasone has been previously administered at dose of 4 mg26 but more frequently the dose of dexamethasone has been 8 mg21,27,29 or 0.1 mg kg−1 of corrected body weight.28 Dexamethasone has a dose-dependent effect.30 A dose of 8 mg is more relevant in obese patients and appears well tolerated except in diabetic obese patients.31

In obese patients, ondansetron has previously been administered as antiemetic prophylaxis at doses of 426,29,32 or 8 mg.21,28 Ondansetron at doses of 4 or 8 mg is considered as low dose compared with 16 mg, which is the dose recommended for prophylaxis of chemotherapy-induced nausea and vomiting in lean patients.33 Knowledge of dose responsiveness, side-effects and optimal combinations of antiemetics is still limited in obese patients after TIVA. In the current study, the incidence of PONV in patients with two risk factors decreased nonsignificantly with the use of antiemetic prophylaxis (Table 4) but this study was underpowered for this subgroup analysis. Probably in the context of LSG under TIVA, the doses of dexamethasone and ondansetron need to be increased or another antiemetic needs to be added to decrease the incidence of overall and severe PONV. The true incidence of cumulative 24-h PONV after TIVA is difficult to determine in obese patients undergoing LSG. In one study of patients with a PONV risk factor of at least 2, who received intraoperative opioid administration, the overall incidence of PONV was above 50% without antiemetic prophylaxis. As the potential relative risk reduction of PONV associated with each antiemetic is about 26%,1 we can calculate for the current study that the PONV incidence would be 19% if the patients received triple antiemetic prophylaxis, on the hypothesis that the antiemetics were effective. Another study with triple prophylaxis and correct dose range is necessary to give a definitive conclusion.

In conclusion, the current study reports the incidences of overall and severe PONV after LSG under TIVA guided by BIS. Prophylaxis using dexamethasone 4 mg and ondensetron 4 mg was not effective in reducing the incidence of PONV in this setting. Optimal antiemetic dosage and combination therapies need to be established specifically for obese patients undergoing LSG under TIVA.

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Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: this work was supported by the Department of Anaesthesiology (Hôpital Foch, Suresnes, France), Vaincre la Mucoviscidose (Paris, France) and Alaris Medical (Hampshire, UK) who loaned the Asena GH infusion pumps for the study.

Conflicts of interest: Hôpital Foch, NL and TC are cofounders of MedSteer, a biomedical company aiming to promote research and development in closed-loop anaesthesia tools.

Presentation: preliminary data for this study were presented as an oral presentation at the American Society of Anesthesiologists, 2014, in New Orleans, Louisiana, USA.

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