Incidence of nausea is about 1/3rd patient while vomiting is about 2/3rd patients in LSCS patients in which carboprost was given intramuscularly. Carboprost stimulates the gravid uterine myometrial contractions similar to labour contractions at the end of a full term pregnancy. Postpartum, the resultant myometrial contaction provide hemostasis at the site of placentation. Carboprost also stimulates the smooth muscles of gastrointestinal tract. This activity may produce vomiting diarrhea or both that is common when carboprost is used to terminate pregnancy and for use postpartum following normal labour or LSCS.1 Over the years, numerous approaches have been used in management of PONV. Robert Ferfguson described the use of olive oil in 1912; he postulated that oil in the stomach absorbed any ether that may be present there. The effect of atropine was appreciated by Brown -Sequard as early as 1883 when he wrote "in the very great majority of cases, the addition of a certain amount of atropine to morphine prevents the nausea and vomiting occuring with morphine alone " 2 Phenothiazines were synthesized originally in the late 19th century. In the late 1930s, Promethazine was found to have antiemetic property. Charpentier synthesized Chlorpromazine in 1949, but sedation and hypotension were limiting side-effects. 2 The traditional antiemetics include Anticholinergics (Scopolamine); Dopamine receptor antagonists which include the Phenothiazines (Promethazine), Benzamides (Metoclopramide) and Butyrophenone (Droperidol) and Benzodiazepines (Midazolam). The non-traditional antiemetics include Ephedrine, Propofol and Corticosteroids.3 The newest class of antiemetics used for prevention and treatment of PONV are serotonin (5-HT3) receptor antagonist - Ondansetron, Granisetron, Tropisetron, Palonosetron, Ramosetron and Dolasetron. These antiemetics do not have adverse effects of older traitional antiemetics. 3 Ondansetron, a selective blocking agent of serotonin 5-HT3(5-hydroxytrptamine type3) receptor type, is a highly effective antiemetic that has been used successfully for both the prophylaxis and treatment of PONV in the surgical outpatient population . This drug, which was considered to represent the universally effective antiemetic for post-operaive nausea and vomiting, was later found to have less antinausea and more anti-emetic efficacy. 4 Ramosetron is a potent and selective serotonin 5-HT3 receptor antagonist. It is effective for the treatment of nausea and vomiting induced by anticancer drugs.5 Ramosetron has more potent and longer acting properties against cisplatin-induced emesis than granisetron.6 It exhibits a higher affinity for the receptors with slower dissociation, resulting in a longer duration of action.7 In our study, we have compared intravenous Ramosetron 0.3mg versus ondansetron 4mg as a premedication in LSCS patients with usage of carboprost IM under spinal anesthesia in terms of prevention of nausea and vomiting intaoperative and postoperatively.

This Prospective, Comparative study was conducted among Patients scheduled for LSCS with use of carboprost IM under spinal anaesthesia in Bapuji Hospital, Chigateri General Hospital, Women and Child Health Hospital attached to JJM Medical College, Davangere. Duration of study was Two years, the study was covered over a period from October 2019- September 2021 Sample size: 110 patients. Sample Size Estimation8 Z (1-α/2) + Z 2 [P1 (100-P1) + P2 (100-P2) Sample Size : n= (P1 – P2)2 n = Sample Size n = [1.96+0.84]2 [56 (100-56) + 80 (100-80) (56-80)2 n = 7.84 [ 56 (44) + 89 (20) ] (24)2 n = 7.84 [2464 + 1600] 576 n = 31,861.76 = 55.31 576 n = 55. (The sample size were taken as 55 in each group.) Inclusion Criteria: • Age between 18 to 35 years • A patient who fits into American Society of Anaesthesiologists (ASA) physical status criteria II scheduled for LSCS. • Patients who are willing and able to give informed written consent. Exclusion criteria: • Patient refusal. • Age more than 35 years or less than 18 years. • ASA physical status III or IV. • Patients allergic to local anaesthetics. • Patients on anti coagulants or known coagulation disorder. • Patients with asthma, hepatic disorder • Local infection at the site of proposed puncture for spinal anaesthesia. • Plan of study: Pre anaesthetic check up was done on previous day of surgery with detailed medical history, general physical examination, systemic examination, airway assessment and spine examination was done for all patients. Patient’s weight and height were recorded. Routine investigations like blood grouping, complete haemogram, routine urine examination with urine albumin, sugar, microscopy and other relevant investigations were done. Baseline vital parameters were recorded. All patients were kept nil orally for 6-8 hours. Premedication were administered with tablet Ranitidine on previous night. Written and informed consent was taken from patients/ guardian prior to scheduled operation and the procedure of spinal anaesthesia was explained in detail to the patient. Patients were divided randomly into two groups: • Group R - Receiving inj. Ramosetron 0.3mg IV. • Group O- Receiving inj. Ondansetron 4mg IV. On the day of surgery, patient were shifted onto operation table and intravenous access established on the forearm with 18G intravenous cannula and randomly allocate into two groups ; group R and group O.inj ramosetron 0.3mg and inj ondansetron 4mg IV were given respectively and Lactated Ringer’s solution 10ml/kg was infused before the block to prevent intraoperative hypotension followed by nausea and vomiting. Baseline hemodynamic parameters like heart rate (HR), noninvasive blood pressure (NIBP), electrocardiogram (ECG) and oxygen saturation (SpO2) was recorded. Patients in sitting or left lateral position, under aseptic precautions subarachnoid block was performed by midline approach using 23G Quincke Babcock spinal needle L3-L4 intervertebral space and 2ml of 0.5% (H) Bupivacaine was given into subarachnoid space .Inj Carboprost 250µg IM was given after extraction of the baby. Patients were observed intraoperatively and postoperatively for 24 hours for any episodes of nausea , vomiting and were evaluated on a PONV score, 0- No nausea or vomiting. 1- Episode of nausea. 2- Episode of vomiting. Rescue antiemetic injection metoclopramide 10 mg iv was given if the patient had PONV score of 2 and was recorded. All the patients were observed for any other side effects if present and were treated accordingly. Statistical analysis: Categorical data was represented in the form of frequency. Association between variables were assessed with Chi Square Test. Quantitative data was represented as mean & Standard deviation. Comparison of variables has been done with Unpaired t test. A P value of <0.05 was considered statistically significant. Data was analyzed with IBM SPSS Version 22 for windows.

The average age of patients in ramosetron group was 25.07years with the standard deviation of 4.04, whereas it was 25.27years with the standard deviation of 4.08 in Ondansetron group. This distribution of sample in both group was found to be statistically insignificant. (p value =0.80). The mean body weight of patients in Ramosetron group was 62.67 kilogram (kg) with the standard deviation of 8.00 and in Ondansteron group was 64.49kg with standard deviation of 8.03 (p>0.05). The mean body height of patients in Ramosetron group was 154.05centimeter(cm)with the standard deviation of 7.08 and in Ondansteron group was 153.11cm with standard deviation of 6.81 (p>0.05). Weight and height in both group was found to be statistically insignificant. The mean duration of surgery in Ramosetron group was 51.80 minutes with the standard deviation of 10.16 and in Ondansetron group was 51.55minutes with the standard deviation of 11.00(p>0.05). Incidence Of Nausea: Occurance of nausea in post-operative follow up among study participant in Ramosetron group with duration of 0-3hrs were 5 patients, no patient had nausea in the duration of 3-6hrs, only one patient had nausea during 6-12hrs, 2 patient had nausea in duration of 12-24hrs. In the Ondansetron group 12 patient had nausea in 0-3hrs, one patient had nausea in 3-6hrs. one patient had nausea in 6-12hrs and 2patient had nausea in 12-24hrs. These results were found to be statistically insignificant (p>0.05). Table 1 : Incidence of nausea in two group of patient studied. Nausea Group-R Group-O Chi Square/Fisher's Exact Test 0-3HRS 5 12 0.06, NS 3-6HRS 0 1 0.315, NS 6-12HRS 1 1 1.00, NS 12-24HRS 2 2 1.00, NS NS=Not Sig Incidence Of Retching Occurance of retching in two groups in post-operative period. During the 0-3hrs both in Ramosetron and Ondansetron 2 patients had retching. From both the groups none of the patients had retching from 3-6 hrs. 6- 12hrs no patient had retching in ramosetron group , one patient from ondansetron group had retching . In 12-24hrs duration no retching was present in ramosetron group and only one patient had retching from ondansetron group. These results were found to be statistically insignificant(p>0.05). Table 2 : Incidence of retching in two group of patients studied. Retching Group-R Group-O Chi Square/Fisher's Exact Test 0-3HRS 2 2 1.00, NS 3-6HRS 0 0 6-12HRS 0 1 0.315, NS 12-24HRS 0 1 0.315, NS NS=Not Sig Incidence Of Vomiting: During the 0-3hrs 1 patients of ramosetron and 2 patients of ondansetron had vomiting. None of patient had vomiting in duration of 3-6hrs in both the groups. In 6-12hrs duration, 2 patients of ramosetron and 1 patient of ondansetron group had vomiting. 1 patient of ramosetron and 3 patient of ondansetron groups had vomiting in the duration of 12-24hrs. These results were found to be statistically insignificant(p>0.05). Table 3 : Incidence of vomiting in two groups of patients studied. Vomiting Group-R Group-O Chi Square/Fisher's Exact Test 0-3 Hrs 1 2 0.558, NS 3-6 Hrs 0 0 6-12 Hrs 2 1 0.547, NS 12-24 Hrs 1 3 0.308, NS NS=Not Sig Incidence Of Rescue Antiemetics Required. The rescue antiemetics used was Metoclopramide 10mg I.V During 0-3hrs 2 patients of ramosetron group and 2 patients of ondansetron group needed rescue antiemetic. In duration of 6-12hrs none of the patients from ramosetron group needed rescue antiemetic and 1 patient of ondansetron needed rescue antiemetics. None of patient in ramosetron group and 3 patients in ondansetron group needed rescue antiemetic in the duration of 12-24hrs. (p>0.05) Table 4: Incidence of rescue antiemetics in two group of patients studied. Rescue Antiemitic used Group-R Group-O Chi Square/Fisher's Exact Test 0-3HRS 2 2 1.0, NS 3-6HRS 0 0 6-12HRS 0 1 0.315, NS 12-24HRS 0 1 0.315, NS NS=Not Sig Incidence Of Complete Response Complete response defined as the absence of nausea, retching or vomiting and no need of rescue antiemetic during the 24hrs observation period. The incidence of complete responders in Ramosetron group was 42 patients (76%) and in Ondansetron group it was 31patients( 56%). Complete response is significantly more in ramosetron with p<0.05. Table 5: Distribution of complete response in two group of patients studied. Complete Response Group-R Group-O Yes 42 (76) 31 (56) No 13 (24) 24 (44) Total 55 55 Chi Square Test P<0.023, Sig Incidence Of Adverse Reaction In Ramosetron group, 2 patients complained of headache and 3 patient complained of dizziness. In Ondansetron group 3 patients complained of headache and 2 complained of dizziness. (p>0.05) Table 6 : Distribution of adverse reactions in two group of patients studied. Adverse Reaction Group-R Group-O Headache 2 (3.6) 3 (5.4) Dizziness 3 (5.4) 2 (3.6) Nil 50 (91) 50 (91) Total 55 55 Chi Square Test P<0.819, Not Sig Overall Incidence Of Nausea, Retching, Vomiting And Rescue Antiemetic: In Ramosetron group, 7 patients (12.7%) had nausea, 1 retching and 6 patients had vomitting. Whereas in ondansetron group 16 patients had nausea, 4 patient retching and 4 patient had vomiting. Table 7: Overall incidence of nausea, retching, vomiting and rescue antiemetic in two group of patients studied. Total PONV Score Group-R Group-O N % N % No Nausea / Vomiting 41 74.5 29 52.7 Nausea 7 12.7 16 29.1 Retching 1 1.8 4 7.3 Vomiting 6 10.9 6 10.9 Total 55 100 55 100

The most commonly used, 5-HT3 receptor antagonist is Ondansetron. Ondansetron, a selective blocking agent of serotonin 5-HT3 (5-hydroxytryptamine type 3) receptor type, is a highly effective antiemetic that has been used successfully for both the prophylaxis and treatment of PONV in the surgical outpatient population. This drug, which was considered to represent the first universally effective antiemetic for post-operative nausea and vomiting, was later found to have less antinausea and more antiemetic efficacy.4 Ramosetron is a potent and selective serotonin 5-HT3 receptor antagonist. Ramosetron is effective for the treatment of nausea and vomiting induced by anti-cancer drugs.5 Ramosetron has more potent and longer acting properties against Cisplatin-induced emesis than granisetron.6 It exhibits a higher affinity for the receptors with a slower dissociation, resulting in a longer duration of action.7 Recommended dose of Ondansetron for PONV prophylaxis is 4 mg. In Our Study, the dosage selection of Ondansetron (4 mg, iv) was based on the previous studies done by McKenzie R et al9, in 1993, Raphacl JH and Norton AC in 1993 prophylactic Ondansetron- meta analysis by Figueredo and Canosa in 1998, Dershwitz M. et al in 1998, and Chidambaram A et al2 in 2010. Ching-Liang lo, et al10 demonstrated Ramosetron effectiveness in the dose of 0.3 mg in the control of CINV caused by Cisplatin and non-cisplatin patients with a good safety profile. S. L Kim, et al11 have shown Ramosetron 0.3 mg to be effective in decreasing the incidence of PONV and reducing severity of nausea during the first 24 hours after gynaecological surgeries. The dosage of 0.3 mg Ramosetron was adequate in controlling PONV following laparoscopic cholecystectomy (Maulana M Ansari, et al11) and in total thyroidectomy in females (Dong Chul Lee, et al).12 Metoclopramide (10 mg i.v) was chosen as the rescue antiemetic based on previous studies done by Naguib M et al13 in 1996, Chidambaram A et al2 in 2010. Therefore we chose Ramosetron in the dose of 0.3 mg IV, Ondansetron 4 mg IV, and Metoclopramide 10 mg IV for our study. In our study we decided to administer the study just before the spinal anaesthesia as premedication on the basis of previous studies done by Kuldip C. Gupta, Nandita Mehta, Kulbhushan Malhotra et al.14 The onset of action of an intravenous dose of Ondansetron occurs in less than 30 minutes but for time taken for the peak effect to manifest is variable. The duration of action is 12 to 24 hours, The onset of the antiemetic action of Ramosetron occurs within approximately 30 minules after a single intravenous administration, with a duration of action of more than 24 hours.15 Hence intravenous administration of both the drugs just before the procedure, is supposed to provide sufficient postoperative antiemetic effect. In our study postoperative assessment of nausea, retching and vomiting at 0-3hours, 3-6 hours, 6-12 hours and 12 -24 hour intervals in both the Ondansetron, Ramosetron groups were found to be statistically insignificant (p> 0.05), which is comparable to studies done by Maulana M Ansari et al16 in 2015 who compared Ramosetron and Ondansetron for control of postoperative nausea and vomiting following laparoscopic cholecystectomy. However, in the 0-3 hour post-operative period,while incidence of nausea and retching were similar in both the groups, 2 patients had vomiting in Ondansetron group while 3 patient had vomiting in Ramosetron group. This is statistically not significant and is in accordance with the results found by Sarbari Swaika et al in 2011.17 During the 0-3 hr postoperative period, 2 patients in the Ondansetron group needed rescue antiemetic, whereas 2 patient needed it in the Ramosetron group. This is statistically insignificant and the result is in accordance with studies done by S I Kim et al11 and Maulana M Ansari.16 In 12-24 hour 1 patient in the Ramosetron group needed rescue antiemetic whereas 3 patient in ondansetron group. These are statistically not significant. With regard to adverse effects, both the drugs were relatively well tolerated. In Ondansetron group 3 patients complained of headache and 2 patient complained of dizziness, whereas in Ramosetron group 2 patients complained of headache and 3 patients complained of dizziness. The side eftects of both the groups were comparable in accordance with the study done by Sameer Denai in 2015.18 In our study, the complete response occurred in 31 patients (56%) in Ondansetron group whereas it was 42(76%) patients in Ramosetron group. This is in accordance with studies done by Kuldip C Gupta et al in 2014.14 The most frequently reported adverse events of 5HT3 receptor antagonists are dizziness and headache,9 adverse events observed in our study were similar in both the groups. We did not address the issues of economy and surrogate variables like hospital discharge times, expenses incurred towards treating established PONV and sequelae of PONV and can be considered as the shortcomings in this study.

Ramosetron at an intravenous dose of 0.3 mg is safe and well-tolerated and more effective in controlling the incidence of vomiting and need for rescue antiemetic, and increasing the incidence of complete response in the first 24 hour post-operative period, than 4 mg intravenous Ondansetron when used for antiemetic prophylaxis after carboprost in LSCS in patients under spinal anaesthesia. Benefits of Ramosetron like high receptor specificity, high potency, and longer duration of action, make it a valuable alternative to Ondansetron.

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