Palonosetron and palonosetron plus dexamethasone to prevent postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: A prospective, randomized, double-blind comparative study

Abstract

Background:

Laparoscopic cholecystectomy (LC) is associated with a high risk of postoperative nausea and vomiting (PONV). Palonosetron is a newer 5HT3 receptor antagonist, which is routinely used in our institution to prevent PONV in patients scheduled for LC, under general anesthesia (GA). We formulated this study to find out whether the palonosetron and dexamethasone combination will be a better choice than palonosetron alone in the prevention of PONV.

Materials and Methods:

Sixty American Society of Anesthesiologists (ASA) physical status I and II patients, scheduled for LC under GA, were randomized to receive either palonosetron or a combination of palonosetron and dexamethasone. The number of complete responders (no emesis, no requirement of rescue anti-emetic medication) and the four-point nausea score was recorded at 2, 6, 24, 48 h postoperatively and the data was analyzed statistically.

Results:

The number of complete responders, as well as the nausea score, did not vary significantly (P=0.718) between the two groups over the 48-h postoperative period.

Conclusions:

The palonosetron and dexamethasone combination was not more effective than palonosetron alone in the prevention of PONV, in patients undergoing LC under GA.

INTRODUCTION

Laparoscopic cholecystectomy (LC) is one of the most commonly performed procedures in general surgery. It is the most preferred procedure for symptomatic cholelithiasis, because of less morbidity and mortality associated with it. The advantages of LC may be counteracted by a high incidence of distressing side-effects like postoperative nausea and vomiting (PONV). PONV is more undesirable than pain[1] and can lead to delay in recovery, wound dehiscence and prolonged hospitalization.[2] Creation of pneumo-peritoneum is an essential part of laparoscopy, leading to stretching of mechano receptors, increased serotonin (5HT) synthesis and PONV.

5HT3 receptor antagonists (5HT3RA) have a definite role in the prevention of PONV. 5HT3 receptors are found in the gut and in areas of the central nervous system (CNS), being abundant in the chemoreceptor trigger zone (CTZ) of the area postrema,[3] which has projections to the vomiting center located in the lateral reticular formation of the medulla oblongata. Peripheral 5HT3 receptors are located in vagal nerve terminals, which are linked to the vomiting center via the nucleus tractus solitarius.[4] Competitive antagonism with 5HT3RA at these sites, and probably others, can block initiation of the vomiting reflex, caused by emetogenic stimuli.

Palonosetron is a newer 5HT3RA, recently introduced in clinical usage, with reduced need for repeat dosage. Palonosetron is a single stereoisomer isoquinoline based on a fused tricyclic ring system attached to a quinuclidine moiety. A single dose is widely distributed in the tissues (mean ± SD volume of distribution 8.3 ± 2.4 L/kg), moderately bound to plasma proteins (62%) and has a long terminal half-life of approximately 40 h.[5]

Dexamethasone causes better control of late PONV probably by inhibiting prostaglandin synthesis, decreasing 5HT levels in the nervous system, and anti-inflammatory action at the operative site.[6] Moreover, a single dose of dexamethasone is not associated with any significant side-effects.[7]

A meta-analysis concluded that the best prophylaxis of PONV is by combining dexamethasone with a selective 5HT3RA.[8] Previous studies have shown that dexamethasone when added to 5HT3 antagonist ondansetron, increases its efficacy.[9] In this research work, we wanted to study whether a combination of palonosetron and dexamethasone would be more effective than palonosetron alone in the prevention of PONV, in patients undergoing LC under general anesthesia (GA).

MATERIALS AND METHODS

After obtaining institutional approval and informed consent from participating patients, we studied 60 American Society of Anesthesiologists (ASA) physical Status I and II patients, aged 18 to 60 years, weighing 40-70 kg, scheduled for elective laparoscopic surgery under GA. The study was a prospective, randomized, double-blind one.

Patients who were pregnant or menstruating, with gastrointestinal or renal disease, who received cancer chemotherapy within past four weeks, emetogenic radiotherapy within past eight weeks, who had experienced nausea, vomiting or taken anti-emetic medication within 24 h before surgery, were excluded from the study.

The patients were randomly (computer-generated numbers inserted into opaque envelope) allocated to two groups P and PD. Group P patients received 0.075 mg palonosetron and Group PD received a combination of 0.075 mg palonosetron with 8 mg dexamethasone. One of the authors, who took no further part in the study, prepared the study drugs in identical syringes, containing either 0.075 mg palonosetron or 0.075 mg palonosetron and 8 mg dexamethasone (total volume of 5 ml made with normal saline). The study drugs were known to be compatible when mixed and administered just before induction of anesthesia.

A consultant anesthesiologist who performed general anesthesia and used the study drug, was unaware of the type of study drug used and did not participate in the study. A standard institutional protocol for general anesthesia was followed in all the patients. All patients were advised overnight fasting and were premedicated with tablet midazolam 7.5 mg, 2 h before surgery, injection (Inj) ranitidine 50 mg and glycopyrolate 0.2 mg, and fentanyl 2 mcg/kg given by intravenous (IV) route, before start of the anesthetic procedure. Monitoring of pulse, non-invasive blood pressure, electrocardiography ECG, oxygen saturation, and end-tidal carbon dioxide (ET CO2) was done. The study drugs were administered slow IV, just before induction of anesthesia. The patients were pre-oxygenated with oxygen for 3 min, induction done with IV thiopentone 5 mg/kg, followed by IV rocuronium 0.6 mg/kg and direct laryngoscopy with intubation by endo-tracheal tube of appropriate size. Oro-gastric tube was introduced after endo-tracheal intubation and suction through tube was done. Maintenance of anesthesia was done with 33% oxygen with nitrous oxide with 0.5-1.5% isoflurane and 8 liters of total gas flow. Inj rocuronium was repeated at 25% of the initial dose and Inj fentanyl 1 mcg/kg at 30-min interval. Ventilation was done to maintain ET CO2 at 30-35 mm Hg. Intra-abdominal pressure was maintained below 15 mm Hg. Inj tramadol 100 mg IV and diclofenac 75 mg intramuscular (IM) was given to all patients, 30 min before the end of surgery and diclofenac repeated eight-hourly. At end of the operation, residual neuromuscular blockade was antagonized with Inj neostigmine 0.05 mg/kg with glycopyrolate (0.2 mg for each 1 mg of neostigmine). Extubation was done after suction of the oropharynx and adequate recovery from GA, judged on a clinical basis. Patient was sent to post anaesthesia care unit (PACU) and oxygen administered at 3 l/min. There was provision of rescue analgesic in the form of IV paracetamol 1 g (100 ml).

Patients were asked about nausea, vomiting, retching and any side-effects, at 2, 6, 24, 48 h by an investigator. The investigator and the patients were blinded to the study drug used. The severity of PONV was measured on a four-point (0-3) scoring system. PONV score 0 = no nausea and no retching; 1 = complaining of sickness and retching; 2 = vomiting one or two time in 30 min; 3 = vomiting more than two times in 30 min.[10] Nausea was defined as the subjectively unpleasant sensation associated with awareness of the urge to vomit, retching was defined as the labored, spastic, rhythmic contraction of the respiratory muscles without the expulsion of the gastric contents, and vomiting was defined as the forceful expulsion of gastric contents from the mouth. The number of complete responders was recorded. Complete response is defined as no nausea, vomiting or retching and no need of rescue anti-emetic medicines within postoperative 48 h. If vomiting occurred or PONV score was 2 or more, IV ondansetron 4 mg was given as rescue anti-emetic. Any need for rescue drug and side-effects like headache, dizziness and drowsiness were noted. Data was analyzed using graph-pad software using Chi square test and t test where appropriate. Results were expressed in mean±SD. A P value<0.05 was considered as statistically significant.

RESULTS

The groups P and PD were comparable in respect of age, sex, weight, ASA physical status and duration of surgery [Table 1].

Table 1.

Demographic profile, duration of surgery and ASA physical status

The number of complete responders (no vomiting, no rescue anti-emetics) was 25/30 (83.33%) in Group P and 24/30 (86.66%) in Group PD over the time period of 48 h and the difference was not statistically significant (P=0.718) [Table 2].

Table 2.

Complete responders and nausea score over the time periods

The four-point nausea score (0-3) recorded over the time period 0-2, 2-6, 6-24, 24-48 h did not differ significantly (P=0.718) between the two groups. Only five patients (16.66%) in Group P and four patients (13.33%) in Group PD experienced nausea and retching (Score 1). None of the patients had any vomiting episodes [Table 2]. There was provision of rescue anti-emetic but none of the patients required it.

The hemodynamic parameters, oxygen saturation, ECG changes were recorded intra-operatively and no significant difference between the groups was recorded. No incidence of hypotension was noted in any of patients in the postoperative 48-h period.

The patients were observed for side-effects during the 48-h postoperative period. None of the patients had any clinically serious side-effects; one patient in Group PD reported slight dizziness, which was insignificant and not of much clinical concern.

DISCUSSION

Laparoscopic cholecystectomy is associated with a high incidence of PONV ranging from 53-72%.[11] PONV is an unpleasant sensation which is associated with poor patient satisfaction.[12] PONV is multi-factorial, the important factors being patient age, sex, smoking habits, duration and type of surgery, pain, opioid requirements, inhalation agents used, use of nitrous oxide, and inadequate intravenous fluid therapy.[13,14]

Anesthetic agents initiate the vomiting reflex by stimulating the central 5HT3 receptors on the chemoreceptor trigger zone (CTZ). The relation between pneumoperitoneum and PONV is not exactly known. The abdominal insufflation during LC increases the abdominal pressure with subsequent dilatation of intestinal loops which could influence the secretion of 5HT.[15] The mucosal enterochromaffin cells of the intestinal tract contain approximately 90% of 5HT present in the body.[16]

Palonosetron is a “second-generation” 5HT3RA, reported to be superior to the “first-generation” 5HT3RAs, because it binds at the allosteric site of 5HT3 receptor and this binding may prevent attachment of 5HT at the orthosteric site of the receptor, explaining its long-lasting effects.[17] Palonosetron is not simply a competitive antagonist at the 5HT3 receptor. Its high affinity is accompanied by high selectivity for 5HT3 receptors. The metabolism of palonosetron is primarily in the liver, by the Cytochrome P450 enzyme system, with CYP2D6 being the predominant isoenzyme. Following initial rapid distribution, IV palonosetron undergoes a slow elimination phase, primarily handled by the kidney.[18]

Dexamethasone, a long-acting glucocorticoid with some mineralocorticoid effects, has been reported as an effective anti-emetic in cancer chemotherapy patients[19] and has been found to have a prophylactic effect on PONV in adults undergoing laparoscopic surgery.[20] It has a low cost and a prolonged biological half-life of 36 to 48 h. Dexamethasone appears to have an excellent side-effect profile after a single dose, although its effects on immune function, and the potential for adverse outcomes such as wound infection, have not been studied.

A study by Song et al., demonstrated that combined dexamethasone and ondansetron is more effective in reducing severe nausea and vomiting than ondansetron alone in patients receiving fentanyl-based intravenous patient-controlled analgesia.[21] Rusch et al., found that addition of dexamethasone to different anti-emetics significantly decreases the incidence of PONV.[22] Bisgaard et al., observed that preoperative dexamethasone compared to placebo, reduces the incidence of PONV in patients undergoing LC and recommended its routine use in LC.[23] Maemondo et al., in their study of the combination of palonosetron and dexamethasone to prevent chemotherapy-induced nausea and vomiting found this combination to be very effective.[24] We therefore formulated our study to find out whether the combination of palonosetron and dexamethasone is more beneficial than palonosetron to prevent PONV. As PONV is a common occurrence after LC under GA, we believed it would be unethical to include a placebo group. Our selections of drug dosages are based on previous research works that demonstrated that these doses are effective. Our study results show that the number of complete responders and the nausea score in the periods 2, 6, 24 and 48 h postoperative, in the two groups P and PD, did not differ significantly (P=0.718). Blitz et al., in their study of 118 patients undergoing laparoscopic surgery, randomized to receive a combination of 8 mg dexamethasone plus 0.075 mg palonosetron, and 0.075 mg palonosetron alone found no significant difference in the incidence of PONV between the groups.[25] Our study results are in accordance with their study.

CONCLUSION

A combination of palonosetron and dexamethasone does not decrease the incidence of PONV compared to palonosetron alone. We recommend not to add dexamethasone to palonosetron as it will further increase the cost, expose the patient to the risk of added side-effects, without any extra benefit, in patients undergoing LC under GA.