|Ahead of print publication
Comparison of Palonosetron and Dexamethasone with Ondansetron and Dexamethasone to Prevent Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Cholecystectomy
Kumar Rajnikant1, Ishwar Bhukal2, Narender Kaloria3, Shiv Lal Soni2, Kamal Kajal2
1 Department of Anaesthesia, Cloud Nine Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Anaesthesiology and Critical Care, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
Department of Anaesthesiology and Critical Care, 3rd Floor, OPD Block, All India Institute of Medical Sciences, Jodhpur - 342 005, Rajasthan
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Laparoscopic cholecystectomy (LC) is associated with high risk of postoperative nausea and vomiting (PONV) if no prophylactic antiemetic is used. Aims: The study compared prophylactic palonosetron and dexamethasone with ondansetron and dexamethasone in patients undergoing LC. Setting and Design: This prospective, double-blinded, randomized, controlled study was conducted at a tertiary care center. Materials and Methods: The study was carried out in 86 patients who underwent LC. The patients were randomly assigned to following study groups: Group 1 who received palonosetron (0.75 mg) with dexamethasone (8 mg) and Group II who received ondansetron (4 mg) with dexamethasone (8 mg). Patients were observed for nausea with visual analog scale and vomiting episode during 48 h postoperative follow-up. Statistical Analysis Used: Data were analyzed as mean, standard deviation, percentage, and number. The following statistical tests were used: paired or unpaired t-test, Mann–Whitney test, Chi-square test, and repeated ANOVA test. Results: There was no statistically significant difference in heart rate, mean arterial pressure, and oxygen saturation from baseline. During 48 h follow-up, the incidence of nausea, vomiting, and PONV was higher in Group II, but the difference was not statistically significant. The total dose of rescue antiemetic was 2.14 ± 4.15 mg in Group I and 5.00 ± 8.62 mg in Group II patients (P = 0.058). Headache was present in three patients in Group I and two patients of Group II. Conclusion: The palonosetron with dexamethasone is comparable to ondansetron with dexamethasone in the prevention of PONV in patients undergoing LC.
Keywords: Laparoscopic cholecystectomy, ondansetron and dexamethasone, palonosetron, postoperative nausea and vomiting
|How to cite this URL:|
Rajnikant K, Bhukal I, Kaloria N, Soni SL, Kajal K. Comparison of Palonosetron and Dexamethasone with Ondansetron and Dexamethasone to Prevent Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Cholecystectomy. Anesth Essays Res [Epub ahead of print] [cited 2019 May 26]. Available from: http://www.aeronline.org/preprintarticle.asp?id=256043
| Introduction|| |
Postoperative nausea and vomiting (PONV) is common but distressing complaint following general anesthesia. The PONV incidence ranges between 20% and 30% in first 24 h, but its incidence can be as frequent as 63%–80% in the high-risk patients when no prophylactic antiemetic used such as laparoscopic cholecystectomy (LC).,,,, Vomiting episodes have several consequences such as gastric content aspiration, wound dehiscence, bleeding, fluid and electrolyte imbalance, and psychological distress.,
The 5-hydroxytryptamine 3 (5HT3) receptor antagonists are generally accepted as first-line drugs to prevent PONV. The mechanism of action of these drugs is antagonism of serotonin 5HT3 receptor in the chemoreceptor trigger zone and vagal afferents in the intestinal tract. Ondansetron and palonosetron are most widely used drugs from this group but later has a higher 5HT3 receptor affinity with a longer half-life (40 h). Dexamethasone is another class of drug which is a corticosteroid and has emerged as a potentially useful prophylaxis for patients at high risk of PONV with minimal side effects., However, the multimodal approach is described as the best way to decrease PONV, especially in high-risk cases. Studies have reported that the combination of dexamethasone with 5HT3 antagonists result in decrease incidence of PONV compared to 5HT3 antagonists alone.,, Hence, the study was planned to compare the efficacy of palonosetron and dexamethasone with ondansetron and dexamethasone in the prevention of PONV in patients undergoing LC.
| Materials and Methods|| |
This prospective, double-blind, randomized controlled study was conducted from August 2011 to October 2012 following approval from Institutional Ethical Committee (NK/695/MD). Eighty-six patients of the American Society of Anesthesiologists (ASA) Class I-II of either sex, aged 18–60 years underwent LC were included in the study after taking written informed consent. The patients who were allergic to study drug received antiemetic 24-h before surgery, gastroesophageal reflux disease, body mass index (BMI) >35 kg/m2, and pregnancy or menstruation, were excluded from the study.
Randomization, group allocation, and blinding
Patients were randomized into one of the two groups using a computer-generated list of random number chart and were allocated with sealed opaque envelope method to following two groups: In Group I (n = 43), patients received intravenous (i. v.) palonosetron (0.075 mg) with dexamethasone (8 mg), and in Group II (n = 43), ondansetron (4 mg) with dexamethasone (8 mg) was given. The sealed envelopes were opened 10 min before induction of anesthesia and all study drugs were diluted with 0.9% saline to get the final volume 5 ml in identical syringes by a person who was not involved in the study.
A detailed preoperative assessment was done in all the patients a day before surgery, and they were also explained about visual analog scale (VAS) for both nausea and pain. For nausea, it consists of a 10 cm unmarked linear scale where 0 = no nausea and 10 = worst possible nausea and for pain, it is 0 = no pain and 10 = worst possible pain. The risk of PONV was determined according to Apfel simplified risk scoring system. All patients were instructed for nil per oral according to ASA guidelines. Evidence-based routine investigations were done.
The similar anesthesia technique was followed in all the patients. Standard ASA monitoring such as electrocardiogram, pulse oximeter (SpO2), and noninvasive blood pressure (NIBP) was attached to the patients. Anesthesia was induced by propofol 2 mg/kg intravenous (i. v.) till loss of verbal command and fentanyl 2 μg/kg i. v. was given for intraoperative analgesia. Vecuronium 0.1 mg/kg i. v. was used to facilitate endotracheal intubation. After tracheal intubation, anesthesia was maintained with isoflurane and oxygen (O2)-nitrous oxide (N2O) mixture (40:60 ratio). A nasogastric tube was placed in the stomach to empty the contents which was removed after surgery.
The patient was mechanically ventilated to maintain end-tidal carbon dioxide (ETCO2) at 35–40 mm Hg by using Datex Ohmeda Avance Anesthesia work-station. LC was done with four ports using the American position (Surgeon stands left to the patient), and pneumoperitoneum was created with carbon dioxide (CO2) to an intra-abdominal pressure of 10–14 mm Hg. Intraoperatively, heart rate (HR), NIBP, SPO2, and ETCO2 were noted every 10 min until the end of the surgery. The total duration of surgery (from incision to port site skin closure), anesthesia (from induction to extubation of trachea), and duration of CO2 insufflation were noted. Before skin closure, the port site infiltration was done with 10–12 ml of 0.25% bupivacaine and diclofenac 75 mg i. v. was given for postoperative analgesia. Reversal of residual neuromuscular blockade was done with neostigmine 50 μg/kg and glycopyrrolate 10 μg/kg. The trachea was extubated once the patient fulfilled the extubation criteria.
In the postoperative period, the patients were observed for PONV during 48 h follow-up with 30 min interval in the first 6 h and then 12, 24, and 48 h. The hemodynamic parameters were also noted for the same time intervals. Rescue antiemetic metoclopramide 10 mg i. v. was given for VAS ≥4 score in nausea, vomiting episode and repeated if necessary. The time to receive the first rescue antiemetic and the total dose was also recorded. Complete response (CR) was also noted which is defined as no incidence of PONV during the 48 h observation period. The investigator also recorded any adverse effects related to drugs such as dizziness, headache, and arrhythmia.
The statistical analysis was done with Statistical Package for Social Sciences (version 14, SPSS, Chicago, IL and Statxat 3, Cytel Software, Cambridge, MA). Mean, and medians were calculated for all quantitative variables and for measures of dispersion (standard deviation and standard error). Kolmogorov–Smirnov tests were used to check the normality of data. Unpaired t-test was used for normally distributed mean data whereas Mann–Whitney test was applied for skewed data and scores. To see the difference between time-related variables, repeated measure ANOVA test was applied. Qualitative or categorical variables were described as frequencies and proportions. Chi-square or Fisher's exact test was used to compare proportions whichever was applicable. P ≤ 0.05 was considered statistically significant. The sample size has been calculated on the basis of a previous study, which showed the incidence of PONV was 70% in LC patients who were not received antiemetic prophylaxis. Presuming that after palonosetron and dexamethasone prophylaxis, there would be a 30% reduction in incidence, with power analysis 90% and α = 0.05, 38 patients in each group were required. Hence, 43 patients per group were enrolled to minimize the effect of data loss.
| Results|| |
Of 86 patients, the study protocol violation occurred in two patients where additional prophylactic antiemetic was given, and so both were excluded from the study [Consort Chart 1]. All demographic profile including age, weight, height, BMI, sex, ASA class, and Apfel score were well matched [Table 1]. The mean duration of surgery, anesthesia, duration of CO2 insufflation, and total i. v. fluid used intraoperatively were also comparable among both groups [Table 2]. The intraoperative hemodynamic parameter such as heart rate (HR), mean arterial pressure, oxygen saturation (SpO2), and ETCO2 were similar with no statistically significant difference between the groups [Figure 1], [Figure 2], [Figure 3], [Figure 4].
|Table 2: Duration of surgery, anaesthesia, carbon dioxide insufflation and total intravenous fluids|
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|Figure 1: The line diagram showing intraoperative heart rate in mean ± standard deviation which was comparable in both groups|
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|Figure 2: The line diagram showing intraoperative mean arterial pressure in mean ± standard deviation which was comparable in both groups|
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|Figure 3: The line diagram showing intraoperative oxygen saturation in mean ± standard deviation which was comparable in both groups|
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|Figure 4: The line diagram m showing intraoperative end tidal concentration of carbon dioxide heart rate in mean ± standard deviation which was comparable in both groups|
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During 6 h follow-up, CR was observed in 64.3% of patients in both groups which was statistically not significant (P = 1.00). The incidence of nausea and PONV was also the same in both groups (P = 1.00). The incidence of vomiting was more in Group II (11 patients) as compared to Group I (7 patients), but the difference was statistically not significant (P = 0.287) [Figure 5].
|Figure 5: The bar diagram of number of patients which experienced complete response, nausea, vomiting, and postoperative nausea and vomiting during 0–6 h|
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During 6–24 h period interval, 81% of patients in Group I and 76.2% of patients in Group II showed CR which was statistically not significant (P = 0.595). The incidence of vomiting was same in both groups (9.5% each), but nausea and overall incidence of PONV were higher in Group II in comparison to Group I, but the difference was statistically not significant (0.595) [Figure 6].
|Figure 6: The bar diagram of number of patients which experienced complete response, nausea, vomiting, and postoperative nausea and vomiting during 6–24 h|
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A follow-up was done for all day-care discharged (telephonic call) patients and in ward admitted patient 24–48 h. Only three patients in Group II and none in Group I reported nausea. No patient had vomited in either group. CR was observed in all the patients (100%) in Group I whereas 39 patients (92.9%) showed CR in Group II with no significant difference between the groups (P = 0.078). No incidence of PONV was noted in group I, but Group II had PONV in 3 patients (7.15%) [Figure 7].
|Figure 7: The bar diagram of number of patients which experienced complete response, nausea, vomiting, and postoperative nausea and vomiting during 24–48 h|
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During 48 h follow-up, 26 patients (61.9%) showed CR in Group I as compared to 25 patients (59.5%) in Group II which was not statistically significant (P = 0.823). Although the incidence of nausea, vomiting, and PONV was higher in Group II, this difference was not statistically significant [Figure 8].
|Figure 8: The bar diagram of number of patients which experienced complete response, nausea, vomiting, and postoperative nausea and vomiting during 0–48 h|
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Rescue antiemetic in the form of metoclopramide (10 mg) administered to patients who experienced moderate or severe nausea or vomiting. During 0–6 h, seven patients in Group I and 12 patients in Group II required rescue antiemetic therapy, but the difference was not statistically significant (P = 0.192). Between 6 and 24 h and 0–24 h, higher number of patients in Group II required rescue antiemetic than in Group I and the difference was statistically not significant (P = 0.746). Between 24 and 48 h, no patient required rescue antiemetic in Group I and in Group II one patient required rescue antiemetic. During overall 0–48 h period, 9 patients (21.4%) in Group I compared to 12 patients (28.6%) in Group II required rescue therapy and the difference between the groups was statistically not significant (P = 0.450).
The total dose of rescue antiemetic required between 0 and 48 h in Group I patients was 2.14 ± 4.15 mg compared to 5.00 ± 8.62 mg in Group II patients and the difference was statistically insignificant (P = 0.058). Diclofenac 75 mg was administered for postoperative pain when the VAS score >4. During 0–48 h, 24 patients in Group I and 19 patients in Group II required diclofenac and the difference between the groups was not significant (P = 0.275).
The only adverse effect reported was headache in 3 (7.1%) patients in Group I and 2 (4.8%) patients in Group II. No other adverse effect related to drugs used was observed in any patients in either of the groups.
| Discussion|| |
In this study, the incidence of PONV was 38.1% in Group I and 40.05% in Group II (P = 0.823) in 0–48 h time interval. In another study, the results were similar, but a slight higher incidence of PONV with the same drugs combination in patients underwent laparoscopic sleeve gastrectomy. The incidence of PONV was 54.6% in group PD in which patients received palonosetron (75 μg) and dexamethasone (0.1 mg/kg, max 8 mg) whereas 63.6% in group OD in which ondansetron (0.1 mg/kg, max 8 mg) and dexamethasone (0.1 mg/kg, max 8 mg) was given. However, Mendes et al. have reported 18.8% incidence of PONV in patients pretreated with ondansetron (0.1 mg/kg, max 8 mg) and dexamethasone (0.1 mg/kg, max 10 mg) in laparoscopic gastroplasties. In another study of laparoscopic surgery, Moussa and Oregancompared the incidence of PONV in patients treated with granisetron 1 mg, granisetron with droperidol 1.25 mg, and granisetron 1 mg with dexamethasone 8 mg and placebo in 0–24 h interval. Authors observed that only 20% of patients treated with granisetron plus dexamethasone had PONV in 24 h follow-up period. The incidence of PONV was lower as compared to our study, which could be explained that most of our study patients were females with inherently high emetogenic potential, the anesthesia was also maintained with a combination of N2O with isoflurane and smaller sample size.
Kovac et al. compared palonosetron with placebo in patients who had two or more risk factors of PONV. Authors found that the incidence of nausea was 50% in patients pretreated with palonosetron 0.075 mg as compared to placebo during 24 h follow-up. In this study, the incidence of nausea was higher which was probably due to more risk factor of PONV, and they have used palonosetron alone. In our study, 19% of patients in Group I and 28.6% in Group II, experienced vomiting during 0–48 h which is similar to that reported by Kovac et al. between 0 and 24 h (40%) and 0–72 h (44%) and Candiotti et al. 0–24 h (33%), 0–72 h (36%). None of our patients vomited between 24 and 48 h whereas Kovac et al. and Candiotti et al. reported emetic episodes in 4% and 9% patients between 24 and 72 h, respectively., This difference could be because of the use of opioids for postoperative analgesia in these studies. Our patients did not receive postoperative opioids for analgesia and analgesia was managed with diclofenac as on when required. The postoperative opioid use is associated with the development of late postoperative vomiting.
Although our observations did not show statistically significant difference in CR, but there was a better control of PONV in the palonosetron-dexamethasone group. This is because of the longer half-life of palonosetron compared to ondansetron. Our results are similar with the observation made by Park and Choin patients undergoing laparoscopic gynecological surgery, where number of patients with CR was significantly high in the palonosetron group versus ondansetron group. However, no previous studies are available in LC for comparison between Group I and Group II drugs.
The analgesic requirement in 0–48 h postoperative period in our study was not significantly different in between the groups (P = 0.113), but the total dose of diclofenac required between 0–48 h was higher in Group I than Group II. In a previous study, Fujii and Itakura found that the use of dexamethasone 8 mg resulted in decrease incidence of PONV as well as the need of analgesia after LC. Besides this, there was decrease pain score following dental surgery with the use of dexamethasone. However, Feo et al. observed that dexamethasone 8 mg was not superior to placebo in the control postoperative pain following LC. The mechanism of pain control by dexamethasone is not well known, but the possible explanation may be inhibition of prostaglandin synthesis caused by dexamethasone.
The prophylactic antiemetic administration timing is also very important in the prevention of PONV. In our study, the study drugs were administered before the induction of anesthesia. It is recommended that palonosetron or ondansetron should be administered 30 min before prophylaxis for cancer-induced nausea and vomiting and before the start of surgery for the prevention of PONV. The dexamethasone is also more effective if administered before the start of surgery. Therefore, in our study, drug combination was administered before induction of anesthesia.
There were few limitations of our study. First, the small sample size of the study. The second limitation of our study is not including a placebo (control) group due to high risk of PONV; it was not ethically right to withheld prophylactic antiemetic.
The PONV is very distressing and common complication following laparoscopic surgeries. The previously available literature is suggestive of lower incidence of PONV with the use of 5HT3 antagonists and dexamethasone combination which is in contrast to our study results, where the incidence was higher despite the use of best drug combination with optimal dosing. Our study could not find any statistically significant difference in the incidence of PONV between both groups. Hence, this study highlighted the need of further studies with few other drugs combination and with larger sample size to get any conclusive statement on optimal dosing to prevent PONV following laparoscopic surgeries.
| Conclusion|| |
Even though there is consistent better control of PONV in palonosetron-dexamethasone group, both palonosetron-dexamethasone and ondansetron-dexamethasone combinations are equally efficacious in the prevention of PONV in patients undergoing LC under general anesthesia.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2]