Laparoscopic surgery and the female sex are both independent risk factors for postoperative nausea and vomiting (PONV).1,2 The incidence of PONV in laparoscopic gynaecological surgery is estimated to be as high as 56–92% resulting in unplanned hospital admissions.3–5
Palonosetron, a second generation serotonin (5HT3) receptor antagonist, has been extensively studied for the prevention of acute chemotherapy-induced vomiting 6–8 and recently has been approved for the prophylaxis of PONV. Its interaction at the 5HT3 receptor, through allosteric binding and positive cooperativity, results in a long elimination half-life of approximately 40 h.9 Studies comparing palonosetron with the first generation 5HT3 receptor blocker have demonstrated the superiority of palonosetron over ondansetron in prevention of PONV.10,11
Palonosetron is used in a fixed dose of 75 mcg for the prophylaxis of PONV. The use of such fixed doses can lead to underdosing or overdosing and thus either lack of efficacy or a high incidence of side-effects. In the literature, although there are a few trials evaluating bodyweight-adjusted doses of palonosetron,12,13 the role of weight-adjusted doses of palonosetron in laparoscopic surgery has not been investigated. The aim of our study was to determine the dose–response relationship for three doses of palonosetron (0.5, 1.0, or 1.5 mcg kg−1) in women undergoing laparoscopic gynaecological procedures and observe the effects over the first 72 postoperative hours. Earlier dose-ranging studies provided the rationale for the dose selection in the present trial.12,13
Material and methods
The study was conducted after being approved by the Institutional Ethics Review Committee (NK/987/res/2334). The trial was registered with the Clinical Trial Registry of India (CTRI/2014/09/004987). One hundred and forty patients, ASA physical status I or II, from 18 to 60 years old, undergoing laparoscopic gynaecological procedures on a day care basis were assessed for eligibility. Written informed consent was obtained from all patients.
Exclusion criteria included patients allergic to 5HT3 receptor antagonists, a BMI more than 30, menstruation, a history of gastrointestinal disease or motion sickness and those whose surgical procedure was converted to open laparotomy.
All the patients underwent a pre-anaesthetic check before surgery and were fasted according to our guidelines (2 h for clear fluid and 8 h for solids). Pre-medication, in the form of alprazolam 0.25 mg orally, was given the night before and on the day of surgery. One hundred and twenty patients were randomised into three groups using online randomisation software (http://www.randomisation.com). The allocation was concealed in opaque envelopes opened just before the start of anaesthesia. The patients (40 per group) were randomised to receive intravenous palonosetron at 0.5, 1.0 or 1.5 mcg kg−1 diluted to 4 ml with 0.9% normal saline. All the drugs were prepared in identical syringes by someone not involved in the study and were administered over 10 s before the induction of anaesthesia. Anaesthesia was induced with propofol 2 mg kg−1. Fentanyl intravenously 2 mcg kg−1 was given for intraoperative analgesia. Atracurium (0.5 mg kg−1 intravenously) was given to facilitate endotracheal intubation. Ventilation was mechanically controlled to maintain the end tidal carbon dioxide (CO2) between 4.7 and 6 kPa throughout surgery, measured by an anaesthesia gas analyser (Datex Ohmeda S5 Avance, Madison, Winconsin, USA). For surgery, the abdomen was insufflated with CO2 to maintain the intra-abdominal pressure between 10–16 mmHg. After induction of anaesthesia, a nasogastric tube was inserted and then, at the end of surgery after suctioning the gastric contents, it was removed before tracheal extubation. Before skin closure, the surgical port sites were infiltrated with 10 ml of 0.5% bupivacaine. Diclofenac (75 mg intravenously) was given for postoperative pain relief to all the patients.
The total duration of surgery, anaesthesia time, duration of CO2 insufflation and the total volume of intravenous fluid administered were noted. At the end of surgery, residual neuromuscular blockade was reversed with glycopyrrolate 10 mcg kg−1 and neostigmine 50 mcg kg−1 and the endotracheal tube was removed. In the postoperative recovery room, the haemodynamic variables along with postoperative complications such as shivering, hypotension, dizziness, constipation or any other adverse reaction to the drug were recorded by a blinded observer. After surgery, rescue medication was intravenous paracetamol (1 g) for pain and intravenous metoclopramide (10 mg) for more than two episodes of vomiting. These drugs were given at the discretion of the attending physician or nurse until the patient was discharged. The patients were discharged from the post-anaesthesia room when they were able to tolerate oral intake, void urine, and walk independently. They were prescribed oral diclofenac (75 mg, 8 hourly for pain relief) and oral metoclopramide (10 mg for nausea or more than two episodes of vomiting).
All episodes of nausea and vomiting were recorded for 72 h. After discharge, all patients were contacted by telephone at regular intervals for 72 h to record the episodes of nausea and vomiting as well as analgesic and antiemetic requirements. The primary outcome was the proportion of patients with a complete response (CR, i.e. patients who neither vomited nor required antiemetic rescue medication for nausea during the first 72 h after surgery). The secondary outcomes measured included the number of emetic episodes, the incidence of nausea, the need for rescue antiemetics and the analgesic requirement over 72 h.
Nausea was defined as a subjective unpleasant sensation associated with the urge to vomit, and vomiting was defined as the forceful expulsion of gastric contents from the mouth or retching (laboured, spasmodic contractions of respiratory muscles without expulsion of gastric content).14
The sample size was based on a preliminary study of 10 patients undergoing laparoscopic gynaecological procedures who were given intravenous palonosetron 0.5 mcg kg−1: four patients (40%) had a CR during the 72-h time frame. With respect to a CR, for an effect size of 0.3 with a two-sided P value of 0.05 and a power of 0.8, a minimum of 108 patients or 36 per dose group were required. To allow for possible dropouts, the aim was to recruit 40 patients in each group.
SPSS version 16 (SPSS, Chicago, Illinois, USA) was used for statistical analysis. Demographic data (continuous variables) in the three groups were expressed using measures of central location (mean, median) and measures of dispersion (SD). Normality of data was checked by measures of skewness and Kolmogorov Smirnov tests of normality. For normally distributed data means were compared using one-way analysis of variance. For skewed data, a Kruskal–Wallis test was applied. Qualitative or categorical variables were described as frequencies and proportions. Proportions were compared using χ2 square or Fisher's exact test. The dose-dependency effects of palonosetron were assessed using the χ2 trend test for proportions. P < 0.05 was considered significant.
A total of 140 patients were screened for eligibility. Twelve patients did not meet the inclusion criteria and eight patients refused consent. Thus, 120 patients were randomised into three groups. All 120 patients completed the trial and their data were analysed (Fig. 1). The demographic and intraoperative data of patients enrolled in the study are shown in Table 1. These data show that the groups were well matched with regards to age, weight, ASA status, type of surgery, duration of surgery, duration of CO2 insufflation and total intravenous fluid volumes.
The need for rescue analgesia and antiemetic medication for the three doses of palonosetron is shown in Table 1. There was a significant increase in the proportion of patients with a CR with increasing doses of palonosetron (37.5, 67.5, 75; P < 0.001) during the 72-h period (Fig. 2). A trend analysis revealed a slope of 38% (95% CI, 17 to 58) mcg−1 kg−1 of palonosetron. This was associated with a significant dose-dependent decrease in the proportion of patients with nausea (77.5 vs. 47.5 vs. 35%, P < 0.001) and vomiting (47.5 vs. 32.5 vs. 12.5%, P = 0.003).
The analgesic requirement was similar with all three doses of palonosetron. During the hospital stay (up to 6 h), significantly less rescue antiemetic was required with 1.5 mcg kg−1 compared with 0.5 mcg kg−1 of palonosetron. However, after discharge from hospital there was no significant difference in the consumption of rescue antiemetics between any of the three doses (Table 1).
Two patients who received 0.5 mcg kg−1 of palonosetron complained of headache whereas one patient who received 1.5 mcg kg−1 had dizziness.
The results of our study suggest that intravenous palonosetron demonstrates a dose-dependent effect in controlling postoperative nausea in patients undergoing laparoscopic gynaecological surgery for the first 72 h. The statistically significant decrease in nausea and vomiting episodes noted with increasing doses of palonosetron occurred without any increase in side-effects. Furthermore, the requirement of antiemetics decreased significantly with 1.5 mcg kg−1 during the 0–6 h interval. (i.e. the major effect was during the first 6 h).
In our study, an increase in the proportion of patients with a CR was observed with increasing doses of palonosetron: 37.5% patients treated with palonosetron 0.5 mcg kg−1 had a CR during the 72-h period, which was similar to the placebo group (36%) observed by Kovac et al.15 In the present study, 67.5 and 75% of the patients had a CR over the 72-h period with 1.0 mcg kg−1 and 1.5 mcg kg−1 palonosetron compared with 52% of the patients receiving 75 mcg of palonosetron for elective gynaecology in the trial conducted by Kovac et al.15 However, in this latter study,15 the patients had two additional risk factors for PONV and so more patients were likely to need antiemetics. In another study using 75 mcg palonosetron,16 only 39% of patients undergoing laparoscopic surgery did not require antiemetics over 72 h. The reason for the greater use of antiemetics in this study16 could be the inclusion of patients with a history of PONV, non-smokers, and use of opioids in the postoperative period, all of which are independent risk factors for PONV.
Another reason for the greater use of rescue antiemetics in the above trials15,16 could be underdosing of the antiemetic drug. In both these trials,15,16 the authors used fixed doses of palonosetron (75 mcg), irrespective of the body weight. Kovac et al.15 evaluated the effect of a fixed dose of palonosetron in a population with a wide weight range (45 to 120 kg). This represents a weight-based range of palonosetron ranging from 0.625 to 1.875 mcg kg−1. Thus, by using a fixed dose of palonosetron, this could have resulted in many patients receiving an inadequate dose of the drug, thereby leading to a relatively large proportion of patients having nausea or vomiting requiring additional antiemetic drugs.
In two studies using 75 mcg intravenously at induction of anaesthesia, Bala et al.17 reported 57 and 95% of patients to be antiemetic rescue free in the palonosetron group from 0 to 24 h and 24 to 48 h, respectively, whereas Bhatacharjee et al.18 found no emesis and no requirement of antiemetics in 90% of patients from 0 to 3 h, 3 to 24 h and 24 to 48 h. In the present trial, 67.5 and 75% of patients achieved a CR with 1 and 1.5 mcg kg−1 of palonosetron, respectively from 0 to 72 h. Although direct comparison of patients with a CR in the different time frames of our study with the former is not possible, the larger proportion of patients achieving rescue-free status in these trials could be because of the similar opioid-free postoperative analgesia used in those studies.17,18
In the general population devoid of any risk factors, the incidence of PONV in day care surgery is reported to be around 30 to 40%. However, this incidence rises to 70 to 80% in high-risk groups.19,20 In our study, both the laparoscopic nature of surgery and the female sex posed a higher risk for PONV. This latter fact justifies excluding a placebo group in our study protocol.
The mechanism of nausea and vomiting in patients undergoing laparoscopic surgery is multifactorial. Anxiety, pain, anaesthetic regime, pneumoperitoneum, type of surgery and the use of intraoperative and postoperative opioids have all been postulated as plausible factors in the genesis of PONV.20,21 In our study, in an attempt to minimise the variability of these factors across the groups, and thus prevent bias, our study involved only female patients undergoing laparoscopic gynaecological procedures and the anaesthesia protocol was standardized. Duration of anaesthesia and the duration of CO2 insufflation was comparable in all the three study groups. Pain and perioperative opioid use increase the risk of PONV. In our study, an attempt to eliminate these confounding factors was made by using wound site infiltration and intravenous diclofenac for postoperative analgesia as a substitute for opioids. Although an intraoperative opioid, in the form of intravenous fentanyl was given, the doses were comparable in all the three groups.
The majority of the studies demonstrating the efficacy of palonosetron for the prevention of PONV during the first 24 h after surgery have used 1 mcg kg−1 or a fixed dose of 75 mcg of palonosetron. However, in our study, a significant dose-dependent reduction in nausea continued beyond 24 h and up to 72 h with 1 and 1.5 mcg kg−1 of palonosetron. Thus from these results, it would seem that higher weight-adjusted doses of palonosetron may have a more prolonged action on PONV.
The mean weight of the patients in our study was 60 (range 59 to 61) kg compared with 73 (range 71 to 76) kg in the study by Kovac et al.15 As a result of the lower weight of the patients in our study, the average dose of palonosetron in the 1 mcg kg−1 group was 60 mcg, and thus was lower than in those earlier trials using a fixed dose of 75 mcg. However, in our study, using a weight-adjusted dose of palonosetron (1 and 1.5 mcg kg−1), the proportion of patients achieving a CR was higher than in the majority of the previous trials using a fixed dose of the drug.
Ideally, for a dose–response study, increasing doses should be used until a maximum plateau response occurs. This would have required a much larger sample size and our small study population is a major limitation of the study.
The current study produced results that were interesting in terms of the statistically significant 72-h trend of a decreasing incidence of PONV with increasing doses of palonosetron, but the actual effect sizes of the palonosetron doses could not be estimated because of the lack of a placebo group. In a dose–response pharmacodynamic study, a placebo group is useful to help estimate the lower constraint for the dose–response curve and thus establish a ’fundamental response rate.’ Without a placebo group, this latter could not be estimated. However, we feel that omitting the antiemetic in a patient group known to have a high incidence of PONV would have been unethical. The dose selection in our study was based on previous dose ranging trials.
In our study, the highest dose of 1.5 mcg kg−1 palonosetron was effective in preventing PONV in 75% of patients. However, larger studies with higher weight-adjusted doses of palonosetron are warranted in future to investigate if this 75% figure can be improved on.
In conclusion, we found that following gynaecological laparoscopic surgery, intravenous palonosetron, in doses of 0.5, 1.0 and 1.5 mcg kg−1 has dose-dependent antiemetic prophylactic effects for up to 72 h postoperatively.
Acknowledgements relating to this article
Assistance with the study: i would like to thank the EJA editorial board and in particular Dr M Columb, UK for help with statistical analyses.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: preliminary data for this study was presented as a poster presentation at the Research Society of Anaesthesiology and Clinical Pharmacology, 14–16 November 2014, Dehradun, India.
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