Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anaesthesia.1 Whereas it is controversial whether laparoscopy increases the incidence of PONV, laparoscopic gynaecological surgery is associated with an incidence of PONV of approximately 80%.2,3 In addition to female gender, increased intra-abdominal pressure during laparoscopic procedures can increase the risk of PONV.4 Patient-controlled analgesia (PCA) with opioids after surgery is also known to increase PONV.
A retrospective study in patients undergoing gynaecological surgery with fentanyl-based intravenous (IV) PCA showed that the incidence of PONV is still around 36% despite prophylaxis with a 5-HT3 receptor antagonist, indicating the need for multimodal or combination therapy.5 Aprepitant is a neurokinin-1 receptor antagonist that blocks the emetic effects of substance P at neurokinin-1 receptors in the gastrointestinal tract and central nervous system.6,7 Aprepitant has been used for the prevention of chemotherapy-induced nausea and vomiting.8 Recently, several studies have demonstrated that aprepitant is effective for preventing PONV.9–12
The aim of this randomised, double-blind controlled study was to investigate the prophylactic effect of combining aprepitant 80 mg with ondansetron on PONV in patients with fentanyl-based intravenous PCA after laparoscopic gynaecological surgery compared with ondansetron alone.
The study was approved by the institutional review board of Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; protocol number: 3-2012-0076; Chairperson Professor Bum-Kee Hong; date of approval June 2012; start of recruitment to the trial July 2012. The trial was registered at clinicaltrials.gov (NCT01897337): date of registration July 2013.
Adults of American Society of Anesthesiologists’ physical status 1 or 2 undergoing laparoscopic gynaecological surgery with planned intravenous PCA with fentanyl were enrolled after obtaining written informed consent. Exclusion criteria included patients with allergies to components of aprepitant; patients taking drugs that are known to interact with aprepitant including pimozide, terfenadine, astemizole, cisapride and warfarin; patients taking other antiemetics before surgery; hepatic dysfunction; or significant psychiatric disease or mental retardation.
For patients who met the inclusion criteria, written informed consent was obtained on the day before surgery. On the day of the surgery and prior to induction of anaesthesia, patients were assigned into one of two groups by a computer-based randomisation programme. The randomisation result was kept sealed in an envelope, and only a nurse who was not a part of the study was allowed to open the envelope and prepare the assigned drug. Based on the assigned group, patients received aprepitant 80 mg (aprepitant and ondansetron group) or placebo (ondansetron group) orally 1 h before anaesthesia. Anaesthesiologists in charge of patients were blinded to the assigned group of patients; however, if necessary, they were allowed to unblind and those patients were subsequently excluded from the study.
In all patients, glycopyrrolate 0.1 mg and midazolam 0.05 mg kg−1 were administered intravenously as premedication. When patients arrived at the operating room, standardised monitoring was initiated. Anaesthesia was then induced with propofol 2 mg kg−1 and remifentanil 0.3 to 0.5 μg kg−1 followed by rocuronium 0.8 mg kg−1 for muscle relaxation to facilitate tracheal intubation. Anaesthesia was maintained by administration of sevoflurane 1.5 to 2.5% and remifentanil 0.05 to 0.2 μg kg−1 min−1. About 20 min before the end of surgery, ondansetron 4 mg and fentanyl 1 μg kg−1 were administered. At the end of surgery, any residual neuromuscular blockade was reversed with glycopyrrolate 0.004 mg kg−1 and neostigmine 0.02 mg kg−1. An intravenous PCA consisting of fentanyl 15 μg kg−1, ondansetron 12 mg and 0.9% saline in a total volume of 100 ml was provided for 48 h after surgery at a basal rate of 2 ml h−1, bolus dose of 0.5 ml, and lockout time of 15 min. In the post-anaesthesia care unit (PACU), patients received fentanyl 1 μg kg−1 or metoclopramide 10 mg to reduce pain or nausea as requested or based on the intensity of pain or nausea according to an 11-point verbal numerical rating scale (VNRS, 0 to 10; 0 = no pain or nausea, 10 = worst pain or nausea imaginable) of 5 or higher. For patients who continued to suffer from nausea after intravenous administration of metoclopramide, PCA was stopped for 2 h and patients were monitored. After discharge from PACU, patients who suffered from nausea or pain were given metoclopramide or ramosetron and ketorolac intravenously as required. The numbers of administrations and doses of metoclopramide, ramosetron and ketorolac were recorded.
An independent nurse blinded to the patient group assessed VNRS for nausea at four time points (10 min after admission to the PACU, PACU discharge to 6 h, 6 to 24 h and 24 to 48 h after surgery in the ward). As we did not want to disturb patients when they were sleeping, assessments were made towards the end of each time period with time frames of 1 h for the first 6 h after PACU discharge and 6 h for the next two time periods.
The primary outcome of the study was complete response up to 48 h after surgery. Complete response was defined as no PONV and no rescue antiemetics. The incidences of retching/vomiting and nausea, the severity of nausea according to an 11-point VNRS and use of rescue antiemetics were recorded at each time point. In addition, any adverse events such as headache, dizziness or sedation [defined as a score of 3 or higher on the Ramsay Sedation Scale (1, anxious and restless or agitated, or both; 2, cooperative, tranquil and oriented; 3, responds to commands only; 4, exhibits a brisk response to loud auditory stimuli or a light glabellar tap; 5, exhibits a sluggish response to a loud auditory stimulus or a light glabellar tap; 6, does not respond)] delayed passage of flatus until more than 36 h postoperatively and pruritus were reported, and the use of rescue antiemetics and analgesic drugs was recorded. Patients were also asked to rate their intensity of pain using an 11-point VNRS.
All continuous variables were expressed as mean ± SD. All dichotomous variables were expressed as number (%). Comparisons between the two groups were made using the χ2 test, Fisher's exact test or Student's t-test, as appropriate. Kaplan–Meier curves were generated for time to first PONV during the first 48 h and the log-rank test was used to compare the two groups.
A retrospective study conducted previously at Gangnam Severance Hospital found that the incidence of PONV during the first 48 h after gynaecological surgery in patients treated with fentanyl-based intravenous PCA was 36% after a single administration of a 5-HT3 receptor antagonist such as ondansetron.5 Thus, the combination of ondansetron and aprepitant was assumed to be effective if there was a reduction in the incidence of PONV of at least 50%. With α = 0.05 and β = 0.8, 53 patients per group were required for the study. Anticipating a dropout rate of 15%, a total of 125 patients were enrolled in the study. SPSS 20.0 (SPSS Inc, Chicago, Illinois, USA) was used for statistical analysis and P < 0.05 was considered significant.
Of the 125 patients enrolled in the study, 118 received aprepitant or placebo and 110 completed the trial (Fig. 1).
There were no significant differences between the two groups in patient and operative characteristics (Table 1). Apfel's risk score and the duration of PACU stay (50 ± 19 min in the aprepitant and ondansetron group vs. 47 ± 16 min in the ondansetron only group; P = 0.276) were also similar in the two groups.
There was no statistical difference between the two groups in overall complete response during the first 48 h after surgery (33 vs. 16%, P = 0.05). However, the proportion of complete responses in the aprepitant and ondansetron group was higher in the PACU and up to 24 h after surgery (Table 2). There were no differences between the two groups in the incidence of retching or vomiting, severity of nausea or the use of rescue antiemetics (Table 2). The incidence of nausea was lower in the aprepitant and ondansetron group than the ondansetron group in the PACU and up to 24 h after surgery. The fentanyl doses in PCA, use of rescue analgesics with fentanyl in the PACU, the incidence of adverse events and VNRS scores for pain were similar in the two groups (Table 3).
During the first 48 h after surgery, the time to first PONV was delayed in the aprepitant and ondansetron group (P = 0.014) (Fig. 2).
The median value of Apfel's risk score in our study population was three, indicating that the predicted incidence of PONV was 61%.2 Such patients at high risk of PONV should be considered as excellent candidates for multimodal or combination therapy with different classes of antiemetics targeting different receptors. For instance, the combination of ondansetron, the standard for PONV prophylaxis, and aprepitant should be effective in preventing PONV because ondansetron blocks serotonin at 5-HT3 receptors, whereas aprepitant blocks substance P at neurokinin-1 receptors. Following the demonstration of the emetic action of substance P in the medullary emetic circuitry in ferrets,13 highly selective neurokinin-1 receptor antagonists that cross the blood–brain barrier have been developed, and aprepitant is the first neurokinin-1 receptor antagonist approved for use in the clinical setting as an antiemetic. In combination with other antiemetics, aprepitant is recommended for treatment and/or prevention of chemotherapy-induced nausea and vomiting.8 Several studies have reported the efficacy of neurokinin-1 receptor antagonists alone or combined with other antiemetics in preventing PONV.9–12,14–17
In our study, the effect of aprepitant on PONV lasted up to 24 h in combination with ondansetron. Studying aprepitant as a medication for monotherapy, previous trials on patients undergoing open abdominal surgery found that patients given either 40 or 125 mg of aprepitant were less likely to exhibit postoperative vomiting for 24 and 48 h after surgery than those given a single dose of ondansetron 4 mg.9,10 These results are consistent with the fact that aprepitant has a relatively longer half-life (9 to 12 h)18,19 and duration of action than ondansetron (5 to 6 h). Also, in a study of aprepitant as a medication for combination therapy with ondansetron,12 antiemesis lasted up to 48 h postoperatively which is longer than what we observed. Our study is different from previous studies in that ondansetron 12 mg in the PCA formulation was continuously infused for 48 h. This might have affected the overall incidence of PONV in both groups.
In this study, aprepitant delayed the time to first PONV and reduced the incidence of nausea in the PACU. These results are consistent with the previous study on laparoscopic procedures in which aprepitant was found to be more effective in acute PONV (postoperative 0 to 2 h).16
As the use of a drug depends heavily on its cost, it is important to consider the cost-effectiveness of drugs. A number of pharmacoeconomic analyses have reported that the increase in cost for PONV prophylaxis is compensated for by the decrease in potential costs needed to manage complications following vomiting or nausea; however, these results may not be applicable to all antiemetics or all geographical regions because of differences in healthcare systems, medical practice and associated costs.20–22 Thus, the cost of aprepitant should be comparable with the cost that patients are willing to pay for PONV treatment and prevention.23,24
In our study, combining aprepitant and ondansetron did not increase the incidence of adverse events such as headache, dizziness, sedation, delayed passage of flatus and pruritus. This finding is consistent with previous studies.9,10
There are potential limitations to this study. First, the sample size calculation was based on the incidence of PONV which is different from our primary endpoint of complete response based on PONV and use of rescue antiemetics. At the time of study conception, we could not find any study reporting the proportion of complete responses in a patient cohort similar to ours. A sample size of 55 in each group achieves 57% power to detect a 17% difference in the proportion of complete responses between the groups (33% in ondansetron and aprepitant group and 16% in ondansetron group, respectively). So, with a total sample size of 110, we obtain underpowered results. Second, the data were collected at any time towards the end of an assessment period. This is a significant limitation that affects the accuracy of the data because the incidence after the assessment can be missed during each assessment period. However, the effect on the results must have been small because the assessments were made towards the end of these periods, with a narrow time frame. Third, the 80 mg dose of aprepitant used in our study was higher than the Food and Drug Administration approved dose for PONV. From a previous study, Kakuta et al.16 suggested that aprepitant 80 mg can effectively reduce PONV and also hasten recovery after gynaecological laparoscopic surgery compared with placebo. In addition, only two formulations of 80 and 120 mg are available in our country.
In conclusion, this study showed that the addition of aprepitant 80 mg orally to ondansetron was superior to ondansetron alone in preventing early PONV with respect to a high incidence of complete response (no PONV and no rescue antiemetics) up to 24 h postoperatively and delayed time to first PONV in patients undergoing laparoscopic gynaecological surgery with fentanyl based intravenous PCA. However, combination prophylaxis with aprepitant and ondansetron failed to reach the predefined primary study outcome when compared with ondansetron alone. The addition of aprepitant to ondansetron did not increase clinically serious adverse effects.
Acknowledgements relating to this article
Assistance with the study: the authors thank Hanna Yoo, PhD, for expert statistical analysis.
Financial support and sponsorship: none.
Conflict of interest: none.
Presentation: preliminary data from this study were presented as a poster presentation at the European Society of Anaesthesiology (ESA) Euroanaesthesia meeting, 1 June 2013, Barcelona.
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