PONV in Ambulatory surgery: A comparison between Ramosetron and Ondansetron: a prospective, double-blinded, and randomized controlled study.

BACKGROUND: postoperative nausea and vomiting (PONV) frequently hampers implementation of ambulatory surgery in spite of so many antiemetic drugs and regimens. AIMS: the study was carried out to compare the efficacy of Ramosetron and Ondansetron in preventing PONV after ambulatory surgery. SETTING AND
DESIGN: it was a prospective, double blinded, and randomized controlled study.
METHODS: 124 adult patients of either sex, aged 25-55, of ASA physical status I and II, scheduled for day care surgery, were randomly allocated into Group A [(n=62) receiving (IV) Ondansetron (4 mg)] and Group B [(n=62) receiving IV Ramosetron (0.3 mg)] prior to the induction of general anesthesia in a double-blind manner. Episodes of PONV were noted at 0.5, 1, 2, 4 h, 6, 12, and 18 h postoperatively. STATISTICAL ANALYSIS AND
RESULTS: statistically significant difference between Groups A and B (P <0.05) was found showing that Ramosetron was superior to Ondansetron as antiemetic both regarding frequency and severity.
CONCLUSION: it was evident that preoperative prophylactic administration of single dose IV Ramosetron (0.3 mg) has better efficacy than single dose IV Ondansetron (4 mg) in reducing the episodes of PONV over 18 h postoperatively in patients undergoing day-care surgery under general anesthesia.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Postoperative nausea and vomiting (PONV), one of the most common and distressing adverse events experienced by patients after an anesthesia and surgery[12] may prolong recovery, delay patient discharge, and increase hospitalization costs.[12] Prevention and treatment of PONV help in accelerating postoperative recovery and increase patient satisfaction.[34] PONV is not uncommon after general surgery with incidence of 20-30%.[56] PONV causes 0.17% unanticipated admission to the hospital following ambulatory surgery.[7]

Numerous studies have investigated the prevention and treatment of PONV for patients scheduled to undergo day-care surgeries by a variety of antiemetics including anticholinergics,[89] antihistamines,[10] promethazine,[11] butyrophenones such as haloperidol[12] and droperidol.[13] However, these agents may cause undesirable adverse effects such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrapyramidal signs.[14] 5-HT3 antagonists prevent serotonin from binding to 5-HT3 receptors on the ends of the vagus nerve's afferent branches, which send signals directly to the vomiting center in the medulla oblongata and in the chemoreceptor trigger zone of the brain.[15] By preventing activation of these receptors, 5-HT3 antagonists interrupt one of the pathways leading to vomiting.[15] Ondansetron, the most commonly used prophylactic 5-HT3 antagonist, was found to be more effective than traditional antiemetics, such as droperidol and metoclopramide, in reducing the incidence of PONV.[161718] Ramosetron, a new 5-HT3 receptor antagonist, has higher potency and prolonged activity than previously developed 5-HT3 antagonists as an antiemetic after chemotherapy,[1920] gynecological surgery,[21] laparoscopic surgery,[22] middle ear like day-care surgeries.[23]

The aim and objective of this study was to compare the antiemetic efficacy of these two drugs in the first 18 h postoperative period of a day-care surgery. The severity of PONV was recorded using VAS with choice options ranging from 0 (no nausea) to 10 (worst possible nausea).

METHODS

After obtaining permission from institutional ethics committee, written informed consent was taken. Total 124 adult patients were randomly allocated to two equal groups (n = 62 in each group) using computer generated random number list. Group A comprised patients who received single dose IV Ondansetron (4 mg) and group B comprised those who received single dose IV Ramosetron (0.3 mg).

Exclusion criteria

Patient refusal, any known allergy or contraindication to any of the two drugs, pregnancy, lactation and children, subjects who vomited or received antiemetics within 24 h before surgery, hepatic, renal or cardiopulmonary abnormality, alcoholism, diabetes, significant gastrointestinal disorders (for example peptic ulcer disease or gastro esophageal reflux disease) and motion sickness were excluded. As we were dealing with day-care surgery patients having no assistance in home and dwelling at more than 10 km from our institution were also excluded from our study.

In preoperative assessment, patients were enquired about heartburn, belching, and abdominal discomfort, h/o motion sickness, any antiemetic treatment received, h/o previous exposure to anesthesia and h/o PONV. The patients were enquired about any history of drug allergy, previous operations or prolonged drug treatment. General examination, systemic examinations, and assessment of the airway were done. Preoperative fasting of minimum 6 h was ensured before operation in all day-care cases. All patients received premedication of tablet diazepam 5 mg orally the night before surgery as per preanesthetic check up direction to allay anxiety, apprehension, and for sound sleep. The patients also received tablet ranitidine 150 mg in the previous night and in the morning of operation with sips of water.

The patients were preoxygenated with 100% oxygen for a period of 5 min. Injection fentanyl (2 μg/kg) and glycopyrrolate (0.01 mg/kg) were given intravenously 3 min before induction of anesthesia. All the patients were induced with IV injection of Thiopentone Sodium 2.5% (5 mg/kg) titrated till the loss of eyelash reflex. After that, atracurium (0.5 mg/kg) was given to facilitate laryngoscopy and intubation. Controlled ventilation was maintained with 33% oxygen in 67% nitrous oxide using Boyle's apparatus. Laryngoscopy, intubation, and cuff inflation were completed within 15 s in all cases. Muscle relaxation was maintained with intermittent intravenous atracurium (0.2 mg/kg) as and when required. Intraoperatively, the pulse rate, respiratory rate, arterial oxygen saturation, ECG, capnography, systolic, and diastolic pressure were monitored continuously. Ventilation was controlled manually and adjusted to maintain the End tidal CO2 pressure (ET CO2) between 35-45 mmHg. Laparoscopic surgeries were performed under video guidance and involved four punctures of the abdomen and abdomen insufflated with carbon dioxide through a veress needle to a maximum intra-abdominal pressure of 14 mmHg. At the completion of surgery, residual neuromuscular blockade was antagonized at TOF ratio more than 0.7 with neostigmine 0.05 mg/kg and atropine 0.02 mg/kg intravenously and patient was extubated in conscious condition. All the patients received tramadol 2 mg/kg IV 20 min before the end of surgery. The patients were then sent to the postoperative recovery unit. Postoperative analgesia was provided with injection diclofenac 50 mg intramuscularly. All patients received moist oxygen supplementation (3 l/min) for 2 h and standard minimum monitoring systems were used. All the patients were on intravenous drip and did not have any oral fluid during the study period of 12 h.

Throughout the 18 h of postoperative period, all the parameters were recorded on 0.5, 1, 2, 4, 6, 12, 18 h. All episodes of nausea, retching, vomiting, and rescue antiemetic provided were recorded by using score of Bellville and co-workers,[24] being the primary assessment parameter. Severity of PONV was observed by VAS scoring (0 represent ‘no nausea’ and 10 represents ‘worst possible nausea’) at same interval in the postoperative period. The time to first administration of rescue antiemetic and the total dose of rescue antiemetic were also recorded. If the patient experienced emetic episodes, retching or requested for treatment, rescue antiemetic was given with IV Metoclopramide (10 mg) slowly.

Statistical analysis

The raw data were entered into Microsoft excel spread sheet and analyzed by appropriate statistical software SPSS® statistical package version 18.0 (SPSS Inc., Chicago, IL, USA). Normally distributed numerical variables were compared between groups by independent sample t test. Chi square test, Officers exact test, and Fischer's exact test were used to compare categorical variables between groups. All analysis was two tailed and P < 0.05 was considered statistically significant.

RESULTS AND ANALYSIS

There were no statistically significant differences between the two groups in terms of demographic characteristics of the patients namely age, sex, and body weight, ASA status, duration of anesthesia and surgery [Table 1]. Table 2 shows that types of surgical procedures were almost similar in both the groups and had no statistical significance. From Table 3 it is clear that at 0.5 h and 18th hour episodes of PONV are not significantly different among the two groups but other readings show Ramosetron has controlled PONV more significantly than Ondansetron. Postoperative mean VAS scoring (in 18 h postoperative period) for the severity of PONV between the two study groups at same time intervals [Table 3] showed that at fourth and sixth postoperative hour period there was statistically significant difference between Groups A and B (P < 0.05), showing that severity of PONV is more in case of Ondansetron than Ramosetron.

Table 1

Comparison of demographic data between the two study groups

Table 2

Ambulatory surgical procedures for randomized patient groups

Table 3

Comparing the postoperative mean PONV episodes (in 12 h postoperative period) between the two study groups at succeeding time intervals

Again during the 18 h postoperative study period, the comparison of mean pulse rate, respiratory rate, systolic, and diastolic blood pressure showed that there was no clinically significant difference between the groups.

DISCUSSION

Day care surgery has proven over the years as the best method to reduce the burden on the health care resources as well as achievement of extreme patient satisfaction.[25] In developing countries like India, most of the patients avoid bearing expenses of prolonged hospital stay. At the same time the infrastructure in our country is not organized uniformly to smoothly deliver the day-care procedures. In the present day scenario, PONV still remains a big headache and nuisance for the surgeons and anesthesiologists as well as an irritating discomfort for the patients almost equal in intensity to pain.[26] The delayed convalescence, hospital readmission, delayed return to work of ambulatory patients; postoperative surgical morbidities such as pulmonary aspiration, wound dehiscence, bleeding from the wound, dehydration, electrolyte disturbances, and metabolic derangement due to excessive emetic episodes are few of the adverse consequences of the PONV.[27]

Various drugs regimens and antiemetic interventions have been tried from time-to-time for the prevention of PONV but with a variable success rate. This study was carried out mainly to see the comparative efficacy of the new and much promising long acting 5-HT3 antagonist Ramosetron against Ondansetron in day-care surgery.

The demographic profile, between two groups, which was statistically insignificant (P > 0.05) of our patients was quite similar with other research investigations and provided us the uniform platform to evenly compare the results obtained. A study conducted by Fujii et al.[28] in a total of 100 patients yielded similar results. The mean duration of anesthesia and surgery were almost comparable in both the groups with no significant statistical difference [Table 1].

From Table 2 it is quite evident that types of surgical procedures were almost similar in both the groups and had no statistical significance.

The incidence of PONV is very less in both the groups [Table 3] within first half hour and is not statistically significant (P > 0.05) but with passage of time Ondansetron treated A group shows signs of PONV. In all the readings 1-12 h group A (Ondansetron) patients suffered a significantly high (P < 0.05) amount of PONV in comparison with group B (Ramosetron). Again at 18th hour PONV episodes become comparable among two groups. Our results in the first 18-hour period with Ramosetron are quite comparable with many other studies[21293031] but comparison in a day-care setting has not been demonstrated by any literary evidence.

The postoperative mean VAS scoring (in 24 h postoperative period) between the two study groups at succeeding time intervals was compared that showed no significant difference between two groups at 0.5th, 1st, 2nd, 12th, 18th h but at 4th and 6th h statistically significant difference found between Groups A and B (P < 0.05) [Table 4] suggesting that the severity of PONV was more after second hour in the case of Ondansetron than Ramosetron.

Table 4

Comparing the postoperative mean VAS Scoring (in 12 h postoperative period) for severity of PONV between the two study groups at succeeding time intervals

Analysis of the primary outcome variable (need for rescue antiemetic metoclopramide 10 mg slow IV; Table 5) indicated that 72.58% (45 of 62) of patients receiving Ondansetron required rescue antiemetic therapy, compared with 8.06% (5 of 62) of patients receiving Ramosetron that is undoubtedly statistically significant (P < 0.05). Although the Ramosetron group was superior, both groups had a good number of patients who experienced PONV even after day-care surgeries. There were some patients who had multiple episodes of nausea and vomiting especially in the first 18 h in both the groups but for comparison sake we included only the number of episodes and not the number of patients.

Table 5

Comparison of rescue antiemetic (Metoclopramide) use frequency between the study groups

Similar study was conducted by Choi et al.[30] in 94 female nonsmoker patients (aged 18-65 years), randomly allocated into either Ondansetron group (group O, n = 47) or the Ramosetron group (group R, n = 47) after lumbar spine surgery. They concluded that Ramosetron was superior to Ondansetron in terms of preventing vomiting and reducing the severity of nausea related to Fentanyl-based IV PCA. Hahm et al.[31] compared the prophylactic antiemetic efficacy of Ramosetron and Ondansetron in patients at high-risk for PONV after total knee replacement. The incidence of nausea between 2 and 24 h and the severity of nausea between 2 and 48 h were less in the Ramosetron group. Kim et al.[32] studied the comparison of Ramosetron with Ondansetron for the prevention of postoperative nausea and vomiting in patients undergoing gynecological surgery. The incidence of vomiting was lower in both the Ramosetron (17%) and the Ondansetron (20%) groups than in the placebo group (44%) during the first 24 h after surgery (P < 0.05). The VAS score for nausea was also lower in the Ramosetron and Ondansetron groups compared with the placebo group. They concluded that Ramosetron 0.3 mg IV was as effective as Ondansetron 8 mg IV in decreasing the incidence of PONV and reducing nausea severity in female patients during the first 24 h after gynecological surgery.

We conclude from the study that Ramosetron is a very effective, safe antiemetic in the prevention of PONV and preoperative prophylactic administration of single dose IV Ramosetron (0.3 mg) has better efficacy than single dose IV Ondansetron (4 mg) in reducing the incidence of PONV over first 18-h postoperative period, in patients undergoing ambulatory surgery under general anesthesia. A control group was not included in our study because we regarded it as unethical to withhold prophylaxis in these patients for PONV particularly when being posted for ambulatory surgery. Another limitation is that we compared Ramosetron and Ondansetron based on the known optimal doses without knowledge of their equipotent doses. The manufacturer's recommended doses of Ramosetron and Ondansetron are 0.3 and 4 mg intravenous, respectively, and were chosen for this study. However, a larger study with large sample size needs to be conducted to establish the author's point of view with solidarity. The study being conducted in a developing country, the authors could not measure some of the biochemical parameters of nausea and vomiting like C reactive protein, urea, aldehydes, and ketones. Another limitation of the study was the failure to obtain information after 18-h period.