Rajiv Gandhi University of Health Sciences Karnataka s37

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

A RANDOMIZED DOUBLE-BLIND TRIAL OF PALONOSETRON COMPARED WITH ONDANSETRON IN PREVENTING POSTOPERATIVE NAUSEA AND VOMITING AFTER GYNAECOLOGICAL LAPAROSCOPIC SURGERY.

Dr. SOMASHEKAR P POST-GRADUATE STUDENT DEPARTMENT OF ANAESTHESIOLOGY K.V.G. MEDICAL COLLEGE AND HOSPITAL KURUNJIBHAG, SULLIA (D.K. DIST) KARNATAKA-574327

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE

ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1. NAME OF THE CANDIDATE AND DR. SOMASHEKAR P ADDRESS POST GRADUATE STUDENT DEPARTMENT OF ANESTHESIOLOGY K.V.G MEDICAL COLLEGE AND HOSPITAL KURUNJIBHAG SULLIA – 574327

2. NAME OF THE INSTITUTION K.V.G MEDICAL COLLEGE, SULLIA.

3. COURSE OF STUDY AND SUBJECT M.D. ANAESTHESIOLOGY

4. DATE OF ADMISSION TO COURSE 21/08/2012

5. TITLE OF TOPIC A RANDOMIZED DOUBLE-BLIND TRIAL OF PALONOSETRON COMPARED WITH ONDANSETRON IN PREVENTING POSTOPERATIVE NAUSEA AND VOMITING AFTER GYNAECOLOGICAL LAPAROSCOPIC SURGERY. 6. BRIEF RESUME OF THE INTENDED WORK. 6.1 Need for the study: Postoperative nausea and vomiting (PONV) is a common problem in the ambulatory surgery patient population, occurring in an estimated 35% of all patients1. PONV are distressing adverse effects of anesthesia and surgery, with a remarkably high incidence in women undergoing major gynaecological surgery2. Certain patient characteristics are associated with a higher risk of PONV: younger age, female gender, large body habitus, history of PONV or motion sickness, anxiety etc. Certain types of surgery are also known to predispose to PONV: head and neck procedures, intra- abdominal surgery, laparoscopic and gynaecologic procedures etc. Lastly, certain types of medications used in anesthesia are known to increase the incidence of PONV: opioids, reversal agents for neuromuscular blockade etc 1 Patient satisfaction with their ambulatory experience is closely tied with their ability to avoid nausea and vomiting after their surgery

The 5-HT3 receptor antagonists are selective serotonin inhibitors; competitively inhibit the binding of serotonin to 5-HT3 receptors. Their antiemetic effects are postulated to stem from blockade of 5-HT3 receptors located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. These drugs have little or no affinity for other serotonin receptors; for alpha or beta-adrenergic; for dopaminergic; or for histamine receptors.3 They are potent, rapidly absorbed and easily penetrate the blood-brain barrier; metabolized by the cytochrome P450-system with half-life varying from 3-10 hours.

Ondansetron, a selective blocking agent of the 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 high-risk outpatient surgical population. This drug, which was considered to represent the first universally effective antiemetic for postoperative nausea and vomiting, was later found to have less antinausea and more anti- vomiting efficacy 5

Palonosetron is a “second generation” 5‐hydroxytryptamin‐3 receptor antagonist

newly approved for the prevention of PONV since March 2008 and is characterized by high receptor binding affinity (pKi=10.45) and a prolonged mean elimination half‐life (40 hours) after intravenous administration. From this a superior effect in case of PONV has been deduced. The aim of this study is to analyse efficacy and safety of palonosetron by using a random effects model.6

In patients undergoing elective gynecological or abdominal laparoscopic surgery, a single 0.075 mg IV dose of palonosetron significantly improved the complete response (CR) rate, decreased nausea severity and reduced the interference with patients' postoperative functioning due to PONV. These benefits may distinguish palonosetron as unique among 5-

HT3 receptor antagonists and potentially address important needs such as protection against nausea in patients at risk for PONV. Although additional comparator studies are required, the recent Food and Drug Administration approval of palonosetron 0.075 mg for the prevention of PONV up to 24 hrs after surgery will give practitioners the opportunity to gain clinical experience with this new drug.7

Post-operative nausea and vomiting (PONV) is one of the most common complications following surgery. Particularly, in day-case surgery, it is one of the factors responsible for increasing the resources required for surgery. If managed poorly, PONV can frequently result in an overnight stay in hospital for what might otherwise have been a day-care procedure.. In multiple surveys, patients list the avoidance of nausea and vomiting as their number one concern when faced with surgery and anesthesia. In fact, this issue ranks ahead of such things as pain, death, myocardial infarction and stroke for patients. So, even though aggressive prevention and management of PONV might incur some additional costs, it is worth doing to insure patient satisfaction remains high.1 6.2 Review of the literature:

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 satisfaction8. In developing countries like India, per capita income is much lower and most of the patients avoid bearing expenses of the prolonged hospital stay. In contrast to that, the health infrastructure in our country is not organized uniformly to smoothly deliver the day care procedures. Consequently the international guidelines formulated for such outpatient procedures are not easy to implement completely in poor and developing nations as compared to countries of developed world. 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,9. 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 and metabolic derangement due to excessive emetic episodes are few of the adverse consequences of the PONV10. To compound the problems further, the lack of reliable and efficient transport, poor education level, lack of awareness, poorly developed referral system; underdeveloped communication systems, partially functioning primary healthcare services, and absence of community nursing have prevented the successful introduction of major surgical operations as day care surgery.

It is very difficult to predict the outcome in an individual patient as various other causes, besides the established risk factors, can influence the incidence of PONV. Various drugs regimens and antiemetic interventions have been tried from time-to-time for prevention of PONV but with a variable success rate. The present study will be carried out mainly to see the comparative efficacy of the new and much promising long-acting 5-HT3 antagonist palonosetron against ondansetron in day care surgery. The demographic profile of our patients was quite similar with majority of other research investigations and provided us the uniform platform to evenly compare the results obtained9,11 . Recently the premenstrual phase as a risk factor for PONV has been disapproved by many studies12. The duration of surgery and anesthesia, type of surgery, young female patients, increased postoperative opioid requirements, etc., are few of the extensively studied risk factors13,14. The mean duration of anesthesia and surgery will be almost comparable in both the groups with no significant statistical difference. A consultant of anesthesia and gynecology will be always present during the performance of these studies so as to confer uniformity to the study design as well to shorten the time of procedure which is quite similar to the profile of other researches13,14. The consumption of rescue antiemetics in our study will be significantly higher in the ondansetron group particularly in the first 24 hours which can be due to the weaning of antiemetic effect of IV ondansetron as the effect lasts for 4-5 hour.

The prophylaxis for PONV is always on the mind whenever patients are selected for the surgery on day care basis. The purpose of day care surgery itself gets defeated if any such discomfort is faced by the patient after discharge from the hospital. The premenstrual phases in younger females who undergo laparoscopic surgery under general anesthesia for ambulatory gynecological surgery are very important risk factors for PONV14.

The overall incidence of nausea and vomiting was significantly higher in the ondansetron group as 20% and 13.33% of the patients experienced the nausea and vomiting episodes as compared to 6.67% and 3.33% in the palonosetron group, respectively. There were some patients who had multiple episodes of nausea and vomiting especially in the first 24 hours in both the groups but for comparison sake we included only the number of patients and not the number of episodes. The values were significant in comparison during the 6-12-hour period which again goes in accordance with the shorter duration of action of ondansetron. Rescue antiemetics were used by these patients during every episode of nausea or vomiting. Our results in the first 24-hour period with palonosetron are quite comparable with many other studies but the comparative efficacy against ondansetron has not been demonstrated by any literary evidence and only placebo has been used for comparison in various clinical trials15,16,17,18,19.

On statistical analysis, the observed power of the study was estimated at 0.584. These results have proved the better effectiveness of long acting palonosetron in the control of PONV as compared to ondansetron, thus providing the patients with a smooth and uneventful postoperative convalescent period and a lesser need for rescue antiemetics. The 5-HT3 antagonists exerts their antiemetic action by blocking the binding of serotonin to 5-HT3 receptors in the gut and the CTZ of area postrema which has got projections to the vomiting centre of lateral reticular formation of medulla oblongata21,22. The side-effect profile of palonosetron seems to be more favorable as only 6.67% of patients experienced post-op headache in our study as compared 20% of such incidence in ondansetron group. The established incidence of headache with palonosetron has been cited at approximately 9-12% in the literature19. The other side effects like dizziness, anxiety, constipation and myalgia have presented a nonsignificant picture and have shown a slightly higher incidence of these side effects in ondansetron group which is statistically insignificant. Ondansetron was the first member of this group to be marketed22, and the recommended IV dose (6-8 mg) is most effective when administered just after the completion of surgery because of its short duration of effect. Its antiemetic effect is stronger than its antinausea effect23. Both ondansetron and palonosetron have similar antiemetic efficacy but dose of palonosetron is much less than ondansetron. Intravenous dose of 0.075 mg of palonosetron is equivalent to 6-8 mg of IV ondansetron24. Moreover ondansetron has a shorter half-life of 3-5 hours, whereas palonosetron has a half-life of approximately 40 hours, which makes it more effective in preventing nausea and vomiting for day care surgery25. Majority of our results particularly the ones related to the incidence of nausea and vomiting may have been due to the difference in the duration of these two drugs. How the efficacy of different 5-HT3 receptor antagonists vary is still unclear but most probably these differences may involve multiple factors such as intrinsic differences in 5- HT3 receptor blocking activity, 5- HT3 receptor affinity and binding stability, and differences in autocrine activity of serotonin released from enterochromaffin cells to act on 5-HT3 or 5- HT4 receptors on EC cells26.

6.3 Aims and Objectives of the study:

1) Comparing the effectiveness of Palanosetron 0.075mg iv against Ondansetron 8mg iv in prevention of PONV in patients undergoing gynaecological laproscopic surgeries.

2) To measure the severity of nausea, need for rescue medication, patient satisfaction and incidence of adverse effects. 7. MATERIALS AND METHODS.

7.1 Source of data collection: Women with the diagnosis of chronic pelvic inflammatory disease, ovarian cyst, fibroid of the uterus ,primary and secondary infertility for evaluation ,laproscopic tubal ligation in the age group 18 – 60 years who will be posted for elective gynecological laproscopic surgery in K V G Medical College Hospital.

7.2 Method of data collection:

1) After the approval by the Institutional Ethical Committee of the KVG Medical College and Hospital, Sullia, 90 patients aged between 18 to 60 years with ASA physical status I-III who will be scheduled for elective gynaecological laproscopic surgery , will be enrolled in this prospective double blind ,randomized comparative study with written informed consent. 2) Patients who will be selected for the study will be randomly allocated to 2 groups of 45 each by random number table, prepared by another anaesthetist not otherwise involved in the study. outside the operating room, namely: Group P : 0.075 mg Palanosetron with normal saline to a total volume of 4ml iv Group O: 8 mg ondansetron iv bolus 3) Before being shifted to operation room, IV line with 18G IV cannula in the dorsum of hand of the patient will be secured and the patient will be preloaded with 10ml/kg/hr ringer lactate half an hour before surgery. 4) In the operation room, patient will be monitored with standard anaesthetic monitoring techniques using non invasive blood pressure (NIBP), peripheral oxygen saturation

(SpO2) and electrocardiography evaluations .The baseline blood pressure, mean arterial

pressure, SpO2 and heart rate will be noted. Heart rate (HR), mean arterial blood pressure (MAP) and oxygen saturation will be monitored ,premedicated with Inj glycopyrrolate 0.2mg iv and Inj midazolam 1mg iv.

5) Patients are randomized to receive either palanosetron 0.075 mg iv or ondansetron 8 mg iv. No patient will receive preanaesthetic medication with antiemetic properties. 6) Palanosetron 0.075 mg is administered in single iv dose with saline solution added to bring the total volume to 4 ml immediately before induction of general anaesthesis to subjects in group P 7) Subjects in group O are given Ondansetron 8 mg bolus dose iv immediately before induction of general anaesthesia.

8) Anaesthesia is induced with propofol 2mg /kg and tracheal intubation done with vecuronium 0.1mg/kg and xylocard 1.5mg/kg. Anaesthesia is maintained with 50% nitrous oxide with oxygen and 0.6 to 2 % isoflurane.For intra operative pain control diclofenac aq iv 75 mg infusion or paracetamol infusion will be given.

9) At the completion of surgery patients will receive neostigmine 50µg/kg and glycopyrrolate 10µg/kg for removal of neuromuscular blockade 10) For post operative pain control diclofenac suppository or 100ml paracetamol infusion will be given. 11) The occurrence of nausea and vomiting and severity of nausea according to Visual analogue scale (VAS).VAS 0= no nausea, VAS 10= worst nausea and rescue antiemetic drug used are monitored immediately after the end of surgery at 0 to 2 hr, 2 to 6 hr, 6 to 24 hr post surgery. 12) An episode of VOMITING was defined as either vomiting (expulsion of stomach contents) or retching (an involuntary attempt to vomit but not productive of stomach contents). 13) Nausea is defined as as a subjectively unpleasant sensation associated with awareness of the urge to vomit. 14) Metoclopramide 10 mg iv is permitted as a rescue antiemetic when two episodes of PONV occurs or at VAS > 5 and the patients requests treatment. If metoclopramide treatment is ineffective ondansetron 4 mg iv is permitted. 15) A complete response is defined as the absence of PONV and no use of rescue antiemetics. 16) Details of any adverse effects including headache, dizziness, constipation and myalgia are recorded. Patients are also asked to rate their overall satisfaction on a 3 point scale as satisfied , neutral, dissatisfied 24 hrs after surgery completion. 17) The primary outcome measure of this study is the incidence of nausea and vomiting during the first 24 hrs after anaesthesia. Second outcome measures are the severity of nausea , need for rescue medication ,patients satisfaction and incidence of adverse effects.

Follow up YES Follow up period 24 hours in postoperative ward

Inclusion criteria: 1) Female Patients aged between 18 to 60 years. 2) ASA grade I-III 3) Elective gynaecological laproscopic surgeries

Exclusion criteria:

1) Patient refusal for procedure

2) Patients who have received antiemetics, steroids or psychoactive medications within

24 hrs of study initiation

3) Patients with vomiting or retching in the 24 hr preceding surgery.

4) Patients who had cancer chemotherapy within 4 wks.

5) Patients who received emetogenic radiation therapy within 8 wks before study entry 6) Patients with ongoing vomiting from gastrointestinal diseases Study design: It is a randomised double-blind prospective comparative study.

Study duration: January 2013 to May 2014

Sample size: . A sample size of 90 is required. We plan to conduct study on 90 women patients in the age group of 18-60 years attending OT complex of K.V.G Medical College Hospital for gynaelogical laproscopic surgeries from JAN 2013 to MAY2014 .

Analysis of data: 7.3 Does the study require any investigation\intervention to be conducted on patients\ humans\ animals? If so, please describe briefly: YES. This study will be conducted on the 90 patients undergoing laproscopic gynaelogical surgery under general anaesthesia with 0.075mg palonosetron with normal saline to a total volume of 4ml iv and 8mg of ondansetron iv bolus.

7.4 Has ethical clearance been obtained from your institution in case of 7.3? YES. Copy enclosed 8 REFERENCES.

1) Kim SI, Kim SC, Baek YH, Ok SY, .Kim SH: Comparison of ramosetron with ondansetron for prevention of postoperative nausea and vomiting in patients undergoing gynecological surgery. British J anaesth; 10.1093/bja/aep209.

2) Fujii Y, Saitoh Y, Tanaka H, Toyooka H: Comparison of ramosetron and granisetron for preventing postoperative nausea and vomiting after gynaecologic surgery. Anesth Analg

a. 1999;89:476–9.

3) Keane PW, Murray PF: Intravenous fluids in minor surgery- Their effect on recovery from anaesthesia. Anaesthesia. 1986;41:635-7.

4) NormaI.Cruz, Peter Portilla Rosendo E Vela ;Timing of ondansetron administration to prevent postoperative nausea and vomiting, PRHSJ Vol. 27 No. 1.

5) Sung YF, Wetchler BV, Duncalf D, Joslyn AF: A double-blind, placebo-controlled pilot study examining the effectiveness of intravenous ondansetron in the prevention of postoperative nausea and emesis. J Clin Anesth 1993;5:22-29.

6) Feng Yi Feng: Comparison of the Selective Serotonin 3 Antagonists Ramosetron and Granisetron in treating Acute Chemotherapy – Induced Emesis, Nausea and Anorexia: A single blind, Randomised, Crossover Study, Current Therapeutic research. 2000; 61(12):

7) Wilhelm SM, Dehoorne-Smith ML, Kale-Pradhan PB: Prevention of postoperative nausea and vomiting. The Annals of pharmacotherapy 2007;41:68-78

8) Boothe P, Finegan BA. Changing the admission process for elective surgery: an economic analysis. Can J Anaesth 1998;42:391-4

9) Myles PS, Williams DL, Hendrata M, Anderson H, Weeks AM. Patient satisfaction after anaesthesia and surgery: results of a prospective survey of 10,811 patients. Br J Anaesth 2000;84:6-10

10) Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg 2006;102:1884-98.

11) Apfel CC, Kranke P, Eberhart LH, Roos A, Roewer N. Comparison of predictive SIGNATURE OF CANDIDATE 9.

10. REMARKS OF THE GUIDE

Dr. GANAPATHI. P. MD Professor & HOD 11.1 NAME AND DESIGNATION OF Dept. of Anesthesiology GUIDE K.V.G. Medical College & Hospital Sullia (D.K. Dist)

11.2 SIGNATURE OF THE GUIDE

11.3 HEAD OF THE DEPARTMENT Dr. GANAPATHI. P. MD 11. Professor & Head Dept. of Anesthesiology K.V.G. Medical College & Hospital Sullia (D.K. Dist)

11.4 SIGNATURE OF THE HEAD OF THE DEPARTMENT

12.1 REMARKS OF THE PRINCIPAL: Topic can be taken up for study.

12.2 PRINCIPAL SIGNATURE INSTITUTIONAL ETHICAL COMMITTEE CLEARANCE

1 TITLE OF DISSERTATION A RANDOMIZED DOUBLE-BLIND TRIAL OF PALONOSETRON COMPARED WITH ONDANSETRON IN PREVENTING POSTOPERATIVE NAUSEA AND VOMITING AFTER GYNAECOLOGICAL LAPAROSCOPIC SURGERY.

2 NAME OF CANDIDATE Dr. SOMASHEKAR. P 3 NAME OF THE GUIDE Dr. GANAPATHI. P 4 APPROVED/NOT APPROVED

ETHICAL COMMITTEE

Sri KRISHNAMURTHY ,Chairperson ,Advocate, Sullia

Dr. SUBBANNAYYA KOTIGADDE,PROF. of MICROBIOLOGY

Dr. S. GOPAL RAO , PROF & HOD, GEN MEDICINE

Dr. MALLIKARJUN M , PROF & HOD, DERMATOLOGY

Dr. VIDYASHAMBHAVA PARE, ASSO.PROF. OF ANATOMY

Dr. UDAY KUMAR RAO , MEDICAL SUPERINTENDENT

Dr. H.R.SHIVAKUMAR , PROF & HOD OF CHEMISTRY DEPT

Dr. CHANDRASHEKAR DAMLE , SOCIAL SCIENTIST

PRINCIPAL K.V.G MEDICAL COLLEGE & HOSPITAL, SULLIA