A comparison of prophylactic antiemetic therapy with palonosetron and dexamethasone as single-agents or in combination in adult patients undergoing laparoscopic surgery

A randomized trial

Abstract

Background: 

The incidence of postoperative nausea and vomiting (PONV) is quite high after laparoscopic surgeries. This study endeavors to compare the efficacy of the combination of palonosetron and dexamethasone with that of either drug alone in the prevention of PONV in patients undergoing laparoscopic surgeries.

Methods: 

This randomized, parallel-group trial was done on ninety adults of American Society of Anesthesiologists Grade I and II patients aged 18–60 years undergoing laparoscopic surgeries under general anesthesia. The patients were randomly divided into three groups of thirty patients each. Group P (n = 30) received palonosetron 0.075 mg intravenously (iv), Group D (n = 30) received dexamethasone 8 mg iv and Group P + D (n = 30) received palonosetron 0.075 mg and dexamethasone 8 mg iv. The primary outcome was incidence of PONV in 24 h, and the secondary outcome was a number of rescue antiemetics required. To compare the proportions in the groups, unpaired t-test, Mann–Whitney U-test, Chi-square test, or Fisher's exact test was applied.

Results: 

We found that the overall incidence of PONV was 46.7% in Group P, 50% in Group D, and 43.3% in Group P + D during the first 24 h. Rescue antiemetic was required in 27% of the patients in Group P and Group D compared to 23% of the patients in Group P + D and twice in 3% of the patients in Group P, 7% of the patients in Group D, and none in Group P + D which were not significant.

Conclusions: 

The combination therapy of palonosetron plus dexamethasone did not significantly reduce the incidence of PONV when compared with either drug alone.

INTRODUCTION

Postoperative nausea and vomiting (PONV) can be such an unpleasant experience that patients often rate it worse than postoperative pain.[¹] PONV remains a continuing problem with an average incidence of 20%–30%.[²] The incidence is quite high after laparoscopic surgeries like gallbladder surgeries[³⁴] as a creation of pneumoperitoneum which lead to stretching of mechanoreceptors. PONV is generally short-lasting but repeated nausea, vomiting or retching may result in more serious and undesirable consequences such as dehydration, electrolyte imbalance, tension on suture lines, venous hypertension, increased bleeding under skin flaps, and delayed discharge of the patient.[⁵⁶] A number of factors influence the occurrence of PONV which includes patient factors (age, sex, obesity, anxiety, history of motion sickness, migraine, or previous PONV and gastroparesis), operative procedures, anesthetic techniques (drugs for general anesthesia, regional anesthesia, and monitored anesthesia care), and postoperative factors (pain, dizziness, ambulation, oral intake, and opioids).[⁷]

Palonosetron is unique from other 5-HT3 receptor antagonists by its unique chemical structure, greater binding affinity (pKi = 10.45), and substantially longer half-life (40 h).[⁸] The findings demonstrate that palonosetron has an allosteric binding and confers a long-lasting functional effect which inhibits serotonin-mediated Ca2 + influx. Dexamethasone was first reported to be an effective antiemetic agent in patients who underwent cancer chemotherapy in 1981.[⁹] Recent studies suggest that the addition of dexamethasone as part of a multimodal approach can decrease PONV in high-risk patient populations.[¹⁰¹¹] None of the available antiemetics is entirely effective in all patients, perhaps because there is no single stimulus for PONV.

This study endeavors to compare the efficacy of the combination of palonosetron and dexamethasone with that of either drug alone in the prevention of PONV in patients undergoing laparoscopic surgeries.

METHODS

Following institutional ethics committee approval, a randomized parallel-group trial was conducted from January 2012 to June 2013. The study was registered retroactively with Clinical Trials Registry - India, and the manuscript adheres to the CONSORT 2010 statement. The project was performed in adherence with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Ninety adults of American Society of Anesthesiologists (ASA) physical Status I or II patients of either sex in the age group of 18–60 years who underwent elective abdominal laparoscopic surgeries under general anesthesia were enrolled in the study after getting written and informed consent. Pregnant or lactating females, with a history of the central nervous system or neuromuscular disease, ASA physical status grade > II, morbidly obese patients, with hepatic, renal, or cardiorespiratory disease, with gastroesophageal reflux and history of drug or alcohol abuse, with known hypersensitivity to either palonosetron or dexamethasone, previous history of PONV or motion sickness, and patients receiving chemotherapy or radiotherapy were excluded from the study.

A detailed history was elicited including the history of any major illness or disease in the past, and a general physical and systemic examination of each patient was performed to exclude any major medical disorder. All routine biochemical, hematological, and radiological investigations were done as per our hospital protocol. All patients were shown the Visual Analog Scale (VAS) and were apprised about the same during a preoperative visit 1 day before the surgery. The patients were asked to restrict oral intake at least 6 h before surgery.

The patients were randomly divided into three groups of thirty patients each by one independent anesthesiologist as per computer-generated random numbers with a sealed envelope method to ensure concealment of allocation sequence. The anesthesiologist, who has not participated in the study, prepared the drug. The principal investigator was blinded to the drug, observed, and recorded the parameters of the study. Hence, both principle investigator and patients were blinded to medication. Group P (n = 30) received palonosetron 0.075 mg intravenously (iv), Group D (n = 30) received dexamethasone 8 mg iv, and Group P + D (n = 30) received palonosetron 0.075 mg and dexamethasone 8 mg iv. Drugs were administered immediately after endotracheal intubation.

Every effort was made to standardize the anesthetic technique. Preanesthetic medication consisting of oral alprazolam 0.5 mg was given to all patients on the night before surgery. On arrival to the operating room, following placement of standard monitors comprising 5-lead electrocardiogram (ECG), noninvasive automatic blood pressure (NIBP) monitor and pulse oximeter were applied to all the patients. Baseline heart rate (HR), blood pressure, respiratory rate (RR), and oxygen saturation (SpO₂) were recorded. A suitable peripheral vein was secured in all the patients before the induction of anesthesia. Patients were given midazolam 1 mg iv as premedication. Before the induction of anesthesia, patients were preoxygenated with 100% oxygen. Induction was accomplished with injection propofol 2 mg/kg body weight (wt) and fentanyl 2 mcg/kg body wt. After giving vecuronium bromide 0.1 mg/kg body wt iv and ventilating the patient with O₂ and air (50:50) for 3 min, intubation was facilitated with a cuffed oral endotracheal tube of appropriate size for airway management. A forced-air warmer was applied once the patient was anesthetized. Immediately after induction, the selected antiemetic drug was administered iv depending on the group. Anesthesia was maintained by isoflurane with air and oxygen (50:50) with controlled mechanical ventilation by Drager Fabius GS Premium to keep end-tidal CO₂(EtCO₂) between 30 and 35 mmHg. All patients received paracetamol 1 g iv intraoperatively. A nasogastric tube was inserted after induction of anesthesia for baseline emptying of the stomach of air and gastric contents, and the same was removed soon after. Muscle relaxation was continued with maintenance doses of vecuronium. Intraoperative analgesia was supplemented with additional doses of injection fentanyl 0.5–1 μg/kg body wt, if blood pressure and HR rose by 20% from the baseline, after excluding other causes of tachycardia and hypertension. The abdomen was insufflated with carbon dioxide, with an intra-abdominal pressure of 10–16 mmHg. Standard monitoring comprising pulse rate, blood pressure, ECG, SpO₂, EtCO₂, temperature, and neuromuscular monitoring were carried out throughout the surgical procedure. At the end of the surgery, the anesthetic was discontinued after the withdrawal of laparoscope from the abdominal cavity, and after the last skin suture was placed, nitrous oxide was discontinued. Before closure, each laparoscopy port was infiltrated with 5 ml of 0.25% bupivacaine for postoperative analgesia. Residual neuromuscular blockade was reversed with injection neostigmine (0.05 mg/kg) and injection glycopyrrolate (0.01 mg/kg), and the trachea was extubated. Postoperatively, the following parameters were recorded at 0, l, 2, 4, 8, and 24 h in all the patients: HR, NIBP and RR, the incidence of nausea and vomiting, and VAS score. Pain intensity scores were obtained with VAS test. Pain was categorized as “severe” if VAS > 7, “moderate” if VAS 3–7, and “mild” if VAS < 3.[¹²] PONV was evaluated on a three-point ordinal scale[¹³] (0 – none, 1 – nausea, and 2 – vomiting). Nausea was defined as an unpleasant sensation with an awareness of the urge to vomit, whereas vomiting was defined as vomiting (expulsion of gastric contents forcefully from the mouth) or retching (without expulsion of gastric contents but labored, spasmodic, rhythmic contractions of the respiratory muscles).[²] No distinction was made between retching and vomiting. The highest score during the study was determined as a category to which a patient was allocated. Thus, the patients who experienced both nausea and vomiting at one point of time were included in the vomiting category. Rescue antiemetic in the form of injection metoclopramide 10 mg iv was given if the patient vomited more than once or demanded treatment. Patients receiving a further dose of rescue antiemetic after a time period greater than its duration of action, i.e., 8 h for metoclopramide, were also included. The number of complete responders was also recorded. Complete response was defined as no nausea, vomiting, or retching and no need of rescuing antiemetic medicines within postoperative 24 h. Patients complaining of postoperative pain received injection diclofenac sodium 75 mg im whenever VAS score was >3. Patients requiring further pain relief received injection tramadol 50 mg iv. The total amount of metoclopramide, diclofenac, and paracetamol consumed was recorded. Side effects, if any, were observed and recorded.

Sample size (SS) calculation was based on 30% difference in the PONV incidence rate among the three groups. At minimum 80% power of the study and 95% confidence interval (CI 0.16), calculated sample size of each of the group came out to be 30.

Statistical analysis was done by the SPSS program for Windows, version 17.0 (SPSS-17, IBM, Chicago, USA). Continuous variables are presented as mean ± standard deviation or median (interquartile range) if the data were skewed, and categorical variables are presented as absolute numbers and percentages. Data were checked for normality before statistical analysis. Normally distributed continuous variables were compared using the unpaired t-test, whereas the Mann–Whitney U-test was used for those variables that were not normally distributed. Categorical variables were analyzed using either the Chi-square test or Fisher's exact test. P < 0.05 was considered statistically significant.

RESULTS

In the present study, a total of 90 patients met the inclusion criteria, 30 in each group, and no patient was lost to follow-up [Figure 1]. All the patients were demographically comparable with respect to age, sex, weight, ASA physical status, and duration of surgery [Table 1] and found no statistical difference between the groups.

Figure 1: Consort flow diagram

Table 1: Demographic characteristics of study groups

Immediately after shifting the patient to the postanesthesia care unit, the incidence of PONV observed was 40%, 46.7%, and 20% in the P, D, and P + D groups, respectively (P > 0.05). After 1 h postoperatively, the percentage of patients who had PONV was 36.7%, 46.7%, and 13.3% in the P, D, and P + D groups, respectively (P = 0.054). After 2 h postoperatively, no one complained of PONV in the PD group, however, 33.3% in Group P and 26.7% in Group D (P = 0.040). The difference in the incidence of PONV score was statistically significant between Groups P and P + D (P = 0.011) and between Groups D and P + D (P = 0.038). The difference was statistically not significant between Groups P and D (P = 0.598). After 4 h postoperatively, the incidence of PONV was 10%, 3.3%, and 16.7% in the P, D, and P + D groups, respectively (P = 0.227). However, no episodes of vomiting were recorded across all the three groups. After 8 h postoperatively, the percentage of patients who had PONV was 10% in Group P compared to 13.3% in Group D and 16.7% in Group P + D (P = 0.688). However, no episodes of vomiting were reported in Groups P and D. The incidence of PONV was 3.3% in Group P as compared to 10% in Group D and Group P + D. The percentage of patients who had vomiting was 3.3% in Group P + D compared to none in Groups P and D after 24 h postoperatively (P = 0.542) [Table 2].

Table 2: Incidence of postoperative nausea and vomiting in the study groups

On the evaluation of nausea and vomiting separately, we observed that the incidence of nausea in Group P was the same up to 2 h; then, it started decreasing; in Group D, incidence decreases up to 4 h; and in Group P + D, it was unpredictable [Figure 2]. However, no patient reported any incidence of vomiting after the 2^nd h till 24^th h postoperatively in Group P and Group D in our study [Figure 3].

Figure 2: Comparison of incidence of nausea between P, D, and P + D groups

Figure 3: Comparison of incidence of vomiting between P, D, and P + D groups

The overall incidence of PONV was 46.7% in Group P, 50% in Group D, and 43.3% in Group P + D during the first 24 h. Rescue antiemetic was required in 27% of the patients in Group P and Group D compared to 23% of the patients in Group P + D and twice in 3% of the patients in Group P, 7% of the patients in Group D, and none in Group P + D. Hence, the requirement was more in the D > P > P + D groups which were not significant [Table 2]. VAS scores were comparable in the different groups at different hours of observations which were not significant [Figure 4].

Figure 4: Comparison of the Visual Analog Scale between P, D, and P + D groups

DISCUSSION

In spite of the advances in anesthesia and surgery over the last few decades, PONV still occurs with significant frequency and is often regarded as the worst part of patients’ surgical experience.[²] It continues to be the “big little problem” for surgical patients. Studies carried out in the previous years have identified a high incidence of PONV after laparoscopic surgeries, the proportion varying between 53% and 72%.[³⁴¹³]

A wide range of antiemetics are available, but 5-HT3 receptor antagonists are proven to be the most effective among them. The previous study reported that palonosetron 0.075 mg significantly reduced PONV in the first 24 h after anesthesia compared with 0.025 mg and 0.050 mg doses of the same drug.[¹⁴] The minimum effective antiemetic dose of dexamethasone is 2.5 mg,[¹⁵] and the most commonly used dose in adults is 8 mg.[¹³] We also used palonosetron and dexamethasone in similar doses, i.e., 0.075 mg and 8 mg iv, respectively. Ascertain risk factors may interfere with the interpretation of study data; we tried to control these within the study design. The anesthetic procedure, except for the test drug, was similar in all the three groups. An attempt was made to tranquil the patients by administering injection midazolam as premedication. Although it is difficult to assess the level of patient's preoperative anxiety, most of them appeared outwardly calm. The role of smoking as a confounding factor was removed as none of the patients across all the three groups smoked. Therefore, we believe that the difference in the incidence of PONV can be attributed to the study drugs. Although there have been reports of perineal irritation[¹⁶¹⁷] even after a single dose of dexamethasone, no such observations were seen in our study.

We found that the overall incidence of PONV was 46.7% in Group P, 50% in Group D, and 43.3% in Group P + D during the first 24 h. These seemingly large and unflattering numbers may be a result of the inclusion of even the mildest form of nausea under category 1. Nevertheless, our results are still consistent with the previously conducted studies in patients undergoing laparoscopic cholecystectomy.[³⁴] In view of these findings, The study on high-risk patients undergoing elective laparoscopic or major plastic surgery observed that the incidence of any nausea (mild, moderate, and severe) and PONV as a whole was 64% and 50%, respectively, in patients receiving two antiemetics.[¹⁸] The overall higher incidence of PONV observed in our study could also be attributable to various factors such as female sex, nonsmoking population, CO2 insufflation, and use of tramadol.

Overall, complete response rates were 53.3% in Group P, 50% in Group D, and 56.7% in Group P + D. Although Group P + D had a better complete response rate than the other two groups, the difference was not statistically significant over the 24-h observation period. It was reported that palonosetron alone and a combination of palonosetron–dexamethasone were equally effective in the prevention of PONV; however, dexamethasone alone was least effective among the three groups.[¹⁹²⁰] The combination of palonosetron–dexamethasone was more effective as compared to only palonosetron for reducing PONV after laparoscopic cholecystectomy.[²¹] However, in our study, we observed that the combination of palonosetron–dexamethasone did not significantly reduce the incidence of PONV when compared with either drug alone. We also found that neither dexamethasone nor palonosetron affected the severity of pain or postoperative analgesic consumption. The study on the effect of dexamethasone on postoperative emesis and pain found similar results.[²²] Although VAS scores were reported to be better in the group receiving combination therapy, this difference was not statistically significant. The results of the present study are comparable with previous studies done.[²³²⁴] Palonosetron and dexamethasone combination was compared to palonosetron alone, and the number of complete responders and the PONV score in the two groups did not differ significantly over the study period.[²⁵] Our findings are in accordance with this study. For prevention of postoperative and postdischarge nausea and vomiting in high-risk patients showed that complete response was not different between the treatment groups for any time intervals, however, the combination group showed a trend toward greater satisfaction, especially in the “nausea domain,” and the combination therapy of palonosetron plus dexamethasone did not reduce the incidence of PONV when compared with palonosetron alone.[²⁶] Our results corroborate this finding. A previous study concluded that there were no differences between palonosetron monotherapy and combination therapy in patients with high emetogenic risk.[²⁷] Our results are also consistent with this study.

Our study demonstrated a significant difference between the palonosetron/dexamethasone combination and either drug alone in the 2-h period. However, this difference failed to maintain significance overall, i.e., in the 0–24-h period. This may be as a result of underpowering of our study for the size of the actual difference observed, and failure to demonstrate significance overall (0–24 h) may be because of some other reasons. It could be argued that our baseline prevalence for PONV was too high in the absence of a placebo group. Another reason for the statistically insignificant difference over 24 h could be the lacunae in the three-point scoring system that we used for assessing PONV. It does not differentiate between the various episodes of nausea based on its severity; hence, a patient reporting nausea even once during 24-h observation period is also included. It also does not take into account the number of PONV episodes during a particular period of observation. In addition, we may have reduced the likelihood of a significant result by our decision to include all types of laparoscopic surgeries and not limiting ourselves to any one specific procedure like laparoscopic cholecystectomy.

As nausea and vomiting are distressing to the patient and increase the risk of delayed discharge from the hospital, we recommend that antiemetic prophylaxis should be given to patients undergoing laparoscopic surgeries. We also suggest that the combination therapy of palonosetron and dexamethasone should only be reserved for patients who are at extremely high risk of developing PONV after laparoscopic surgeries. The multimodal approach to PONV has been advocated with a good understanding of the pathophysiology of PONV which involves different sets of receptors, antiemetics as combination therapy acting through different pathways and appear to be the better choice.[²⁷²⁸²⁹] There is a current need for a definitive study to expand this database as the real benefit to patients will be realized only if effective prophylactic combinations of drugs make PONV a rare occurrence.

CONCLUSIONS

The incidence of PONV after laparoscopic surgeries is very high. Both prophylactic intravenous palonosetron (0.075 mg) and dexamethasone (8 mg) are safe and effective in reducing the incidence of PONV for 24 h after surgery. The combination therapy of palonosetron plus dexamethasone did not significantly reduce the incidence of PONV when compared with either drug alone. The combination therapy with intravenous palonosetron and dexamethasone should only be reserved for patients who are at extremely high risk of developing PONV after laparoscopic surgeries. There is a current requirement for a definitive study to additionally look at combination therapy of palonosetron and dexamethasone in preventing PONV after laparoscopic surgeries as the real benefit to patients may be acknowledged whether these combinations make PONV a rare occurrence.

Research quality and ethics statement

This study was approved by the Institutional Review Board / Ethics Committee at Batra Hospital & Medical Research Centre (Approval # 2011/20; Approval date 24/11/2011). The study was registered retroactively with Clinical Trials Registry - India (Approval # CTRI/2016/07/007108; Approval date July 20, 2016). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the CONSORT 2010 statement, during the conduct of this research project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.