Comparative study of the effects of intravenous palonosetron versus

ondansetron and dexamethasone for prevention of postoperative

nausea and vomiting (PONV) after laparoscopic cholecystectomy: A

prospective randomized control study.

A  dissertation  submitted  to  The  Tamil  Nadu  Dr.  MGR  Medical  University  

in  part  fulfillment  of  the  degree  MD  ANAESTHESIA  

By  

 

Dr.  Karen  Lynn  Lee  

Christian  Medical  College  and  Hospital  –  Vellore  

Tamil  Nadu  –  632004    

 

2

CERTIFICATE  

This is to certify that the dissertation titled “Comparative study of the effects of

intravenous palonosetron versus ondansetron and dexamethasone for prevention of

postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy: A

prospective randomized control study” is the bonafide work of Dr. Karen Lynn Lee

in partial fulfillment of the requirements for the M.D Anaesthesia (final)

examinations of The Tamil Nadu Dr. M.G.R medical university to be conducted in

April 2017.

 

Signature:  

 

 

 

Dr. Anna B. Pulimood,

Principal,

Christian Medical College,

Vellore

Dr. Sajan Phillip George,

Head of Department,

Anaesthesia,

Christian Medical College,

Vellore

Dr. Raj Sahajanandan,

Guide,

Department of Anaesthesia,

Christian Medical College,

Vellore

 

 

 

 

3

DECLARATION  

I hereby declare that this dissertation titled “Comparative study of the effects of

intravenous palonosetron versus ondansetron and dexamethasone for prevention of

postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy: A

prospective randomized control study” was prepared by me in partial fulfillment of the

regulations for the award of the degree of M.D Anaesthesia of The Tamil Nadu Dr. M.G.R

medical university, Chennai. This has not formed the basis for the award of any degree to

me before and I have not submitted this to any other university previously.

 

 

 

 

 

 

 

Vellore                 Dr.  Karen  Lynn  Lee    

 

 

 

4

ACKNOWLEDGEMENTS  

I acknowledge God, for all guidance, mercies and support.

Dr. Raj Sahajanadan for all that he has taught me and for mentoring me.

Dr. Sajan Philip George for being supportive throughout the course.

I acknowledge all my teachers, for making this study and this course a reality.

I also thank my family for being a constant source of support and encouragement.

Finally and most importantly, I would like to express my gratitude to all the patients for

their participation.

 

 

 

 

 

 

 

 

 

 

 

5

TURNITIN  REPORT  

 

 

 

 

 

 

 

 

 

                               

6

CONTENTS  INTRODUCTION  ....................................................................................................................................  7  

AIMS  AND  OBJECTIVES  .....................................................................................................................  10  

REVIEW  OF  LITERATURE  .................................................................................................................  13  

DEFINITION  ...................................................................................................................................................  14  

CAUSES OF NAUSEA AND VOMITING  ...............................................................................................  21  

POSTOPERATIVE NAUSEA AND VOMITING  ..................................................................................  25  

MANAGEMENT  OF  POSTOPERATIVE  NAUSEA  AND  VOMITING  .....................................................  32  

METHODS  ..............................................................................................................................................  51  

RESULTS  ................................................................................................................................................  59  

DISCUSSION  ..........................................................................................................................................  81  

LIMITATIONS  .......................................................................................................................................  85  

CONCLUSION  ........................................................................................................................................  86  

BIBLIOGRAPHY  ...................................................................................................................................  88  

ANNEXURES  ..........................................................................................................................................  94  

Annexure  –  1  :  Pro  forma  ............................................................................................................................  94  

Annexure  –  2:  Patient  Information  Sheet  .............................................................................................  96  

Annexure  –  3:  Consent  Form  .....................................................................................................................  98  

Annexure  –  4:  Ethics  committee  approval  ...........................................................................................  99  

Annexure  –  5:  Data  sheet  .........................................................................................................................  102  

7

         

 

               

INTRODUCTION                                            

8

INTRODUCTION

Following the inception of General anaesthesia in the first half of the nineteenth century

the phenomenon of postoperative nausea and vomiting (PONV) has challenged

postoperative care. John Snow in the 1840s recognized and pioneered the management of

this entity.(1)Despite the advances in surgical technique and anaesthetic technique the

incidence of PONV has remained high. The incidence of PONV has been higher for

certain procedures such as laparoscopic cholecystectomies and gynaecological

surgeries.(2) Unresolved PONV may result in prolonged post anesthesia care unit stay

and unanticipated hospital re-admission that result in a significant increase in overall

health care cost.(3) PONV is influenced by numerous factors, which may be patient

related, surgery related, and anesthesia related factors. Different antiemetics, a

combination of the same and even acupuncture has been in use to treat this distressing

problem. Guidelines have been published in order to better define and manage this

condition. The 2014 guidelines published by Gan et al. include risk scoring systems for

PONV; recommendations on new antiemetics; changes in recommendations from

previous guidelines based on new published information on efficacy and risk of

antiemetic drugs; recommendation on a new antiemetic combination strategy and a

multimodal prevention approach to prevent PONV and implementation of PONV

prevention and treatment strategies in the clinical setting.(4)

9

A wide variety of prophylactic antiemetic regimens have been used for the prevention of

PONV. Many of the traditional antiemetics produce undesirable side effects and have

limited efficacy. Therefore, the search for more ideal compounds has continued.

Ondansetron is considered as the “gold standard” of treatment when compared with the

other antiemetics. The combination of ondansetron with dexamethasone has been found

to be highly effective in the reduction of PONV.(5)(6) However, ondansetron has to be

administered thrice daily when used alone and the addition of dexamethasone may be

deleterious in diabetics as this may hamper optimum glycemic control. Palonosetron, a

newer 5-hydroxytryptamine 3 (5-HT3) receptor antagonist that has recently been

introduced and has a longer half-life and a better safety profile when compared to the

older generation of 5-HT3 receptor antagonists such as ondansetron.(7) There is limited

literature comparing the efficacy of palonosetron with ondansetron and dexamethasone,

especially when comparing laparoscopic operations.

Our study was designed to assess and compare the efficacy of two drug regimens,

palonosetron and ondansetron with dexamethasone in patients undergoing laparoscopic

cholecystectomy. A prospective randomized trial comparing the above-mentioned drugs

was therefore constructed. The primary outcome that was studied was to compare the

incidence of PONV between the two arms. Secondary objectives such as need for rescue

antiemetic, dosage time of administering the same and the complications if any were

studied.

10

AIMS  AND  OBJECTIVES  

11

Aim of the study

To compare the efficacy of palonosetron vs. a combination of dexamethasone and

ondansetron in preventing postoperative nausea and vomiting in patients undergoing

laparoscopic cholecystectomy.

12

Primary objectives

To compare the efficacy of a single dose palonosetron vs. a combination of ondansetron and

dexamethasone for the prevention of postoperative nausea and vomiting after laparoscopic

cholecystectomy.

Secondary Objective

1. To study the requirement for rescue anti-emetic medications

2. To observe the side effects of the drugs administered, if any.

13

       

REVIEW  OF  LITERATURE  

14

DEFINITION

Vomiting is defined as the expulsion of contents of the gastrointestinal tract through the

oral cavity. This forceful expulsion of gastrointestinal contents is the end product of

contraction of the upper gastrointestinal musculature and synchronous contraction of the

muscles of the thoracoabdominal wall. This must be differentiated from regurgitation,

which is generally used to define a condition where the passage of stomach contents into

the mouth is in a passive manner. The term retching can be described as the presence of

only the forceful muscular events present in vomiting without the actual expulsion of

gastric contents. Nausea is described as a painless unpleasant feeling that vomiting is

imminent(8)(9). This is a subjective sensation and the patient that feels nauseated may

not actually retch or vomit. Vomiting may actually ease the sensation of nausea. This is

differentiated from dyspepsia, which presents as epigastric burning pain, bloating or

discomfort. Nausea may be present along with dyspepsia however they are two distinct

events(10).

The vomiting reflex consists of two phases. The first phase is known as the pre-ejection

phase that is characterized by a feeling of nausea. This is associated with sweating,

salivation, pupillary dilation and tachycardia and the parasympathetic as well as

sympathetic nerves mediate it. The second phase is known as the ejection phase that is

comprised of the process of retching followed by expulsion of gastric contents(1).

15

The complex mechanisms present in nausea include the CNS, the endocrine system, the

autonomic nervous system, psychological states, and gastric dysrhythmias.

The medulla oblongata houses the vomiting center, which is comprised of the nucleus

tractus solitaries and the reticular formation. Activation of this center causes motor

efferents to descend to the upper gastro intestinal tract within cranial nerves V, VII, IX, X

and XII, to the lower gastro intestinal tract via the vagal and sympathetic nerves and to

the diaphragm and abdominal muscles via the spinal nerves.

Noxious stimuli arising from higher centers of the cortex and thalamus, viscera,

chemoreceptor trigger zone and vestibular system activate this pathway and result in

nausea and vomiting. The stimuli from the viscera and chemoreceptor trigger zone are

mediated by dopamine - serotonin and from the vestibular system are mediated by

histamine – acetylcholine. The current recommended pharmacological treatment for

vomiting and nausea is based on the ability of the drug to block these receptor sites(11).

16

DA2 – dopamine NK1 – Neurokinin, substance P mu/kappa – Opioids

Cortex Thalamus

[Anxiety, Pain]

Gastro Intestinal

Tract [5-HT3]

Vestibular [H1, M1]

VOMITING CENTER

[H1, M1, NK1, 5-HT3]

CHEMORECEPTOR TRIGGER ZONE

[DA2, NK1, mu, kappa]

H1 – histamine M1 – acetylcholine 5-HT3 – serotonin

Fig 1: Pathway of vomiting

17

The Central Nervous system

Although the neurocircuitry in the process of vomiting has been better illustrated, the

central mechanism that results in nausea is yet to be clearly explained(12). Autonomic

responses such as sweating or salivation may be seen during nausea or vomiting. These

are brought about by the medulla oblongata. The chemoreceptor trigger zone (CTRZ) is

found between the floor of the IV ventricle and the medulla oblongata. This receptor,

unlike other centers in the brain is not shielded by the blood-brain barrier. This implies

that due to lack of the surrounding glial cells, emetic irritants directly permeate the

endothelium of its capillaries irrespective of the size of the molecule or its lipid

solubility. They then relay information to the nucleus tractus solitarius. Afferent fibers

from the gastro intestinal tract are carried by the vagus nerve. They detect the gastric

contents as well as the gastric tone, which is also projected to the nucleus tractus

solitarius. From the nucleus tractus solitarius the neurons carry impulses to a central

pattern generator that coordinates the many actions that result in vomiting(13).

Several studies have suggested the involvement of the cerebral cortex in the pathway of

nausea(14)(15). Napadow et al in 2013 used the functional MRI to study healthy human

adults and inferred that regions of the brain that are involved in cognitive function and

emotions such as the medial part of the prefrontal cortex and the pre-genual anterior

cingulate cortex and are correlated with an increased heart rate during nausea(15). This

suggests the importance of emotional and cognitive centers in mediating the

parasympathetic to sympathetic shift seen in nausea.

18

The Autonomic Nervous system

The physiological changes seen before vomiting such as pallor, tachycardia, increased

blood pressure, cutaneous vasoconstriction, sweating and decreased gastrointestinal

motility are directed by the autonomic nervous system. Afferent signals arise from vagal

inputs that are a result of chemical or mechanical stimuli(16). Many studies now show

that an increased perception of nausea is seen with increased sympathetic and decreased

parasympathetic modulation(17)(18). This explains the presence of the symptoms

mentioned earlier. Therefore autonomic outflows as well as the CNS network that

controls it may in fact determine the overall intensity of nausea that is perceived.

Understanding these in detail could have therapeutic importance.

The Endocrine System

Research has been done on the role of various hormones in the pathogenesis of nausea

and vomiting. Many studies suggest that vasopressin plays a significant role is this.

During emetogenic situations it has been noted that vasopressin secretion is increased.

This shows clearly that rise in vasopressin levels occur before vomiting and not as a

response to hyperosmolarity or volume depletion that occurs after emesis(19). Although

various studies have shown that the severity of nausea and the levels of serum

vasopressin are related, the relationship of cause and effect is not clear yet(20)(21). Apart

from Vasopressin, Corticotropin releasing factor has been recognized as a brain – gut

19

mediator in the functioning of the foregut. It stimulates the inhibitory motor nerves that

are present in the dorsal motor nucleus of the vagal nerve and causes delayed gastric

emptying along with nausea(22).

Gastric dysrhythmias

The myoelectrical activity of the stomach can be measured by various techniques, as it is

a neuromuscular organ. A balance of the enteric nervous system, the autonomic nervous

system, the intrinsic activity of the stomach, smooth muscles and hormone levels result in

normal gastric myoelectrical activity(19). Many studies have demonstrated the

relationship between nausea and the onset of gastric dysrhythmias in pregnant women,

those with motion sickness and also in drug induced nausea(23). However it is unclear if

activation of sympathetics occurs before the onset of dysrhythmias or vice versa.

Interventions and medications that cause gastric myoelectric activity to normalize have

been shown to decrease nausea(18,23).

20

PATHOGENESIS OF NAUSEA – in summary

Cerebral cortex and limbic system – providing cognitive and emotional input

Cerebellar and Vestibular signals from motion induced nausea

Area prostema recognizes the presence of emetic agents in blood

Nucleus Tractus Solitarius receives afferent information from various parts of the body including the Vagus

Increase in Vasopressin level Autonomic nervous system response

Gastric Dysrhythmias

Nausea

Vagus mediated

CENTRAL

PERIPHERAL

21

CAUSES OF NAUSEA AND VOMITING MEDICATIONS AND TOXIC ETIOLOGIES(24)

Cancer chemotherapy Antibiotics/antivirals

Mild -fluorouracil, vinblastine, tamoxifen Erythromycin

Moderate - etoposide, methotrexate, cytarabine Tetracycline

Severe - cisplatinum, dacarbazine Sulfonamides

Analgesics Antituberculous drugs

Aspirin Acyclovir

Nonsteroidal antiinflammatory drugs Gastrointestinal medications

Antigout drugs Sulfasalazine

Cardiovascular medications Azathioprine

Digoxin CNS active drugs

Antihypertensives Narcotics

Antiarrhythmics Antiparkinsonian drugs

Calcium channel antagonists Anticonvulsants

Beta blockers Antiasthmatics

Diuretics Theophylline

Hormonal preparations/therapies Radiation therapy

Oral anti diabetics Ethanol abuse

Oral contraceptives Hypervitaminosis

22

INFECTIOUS CAUSES

Gastroenteritis Nongastrointestinal infections

Viral Otitis media

Bacterial

DISORDERS OF THE GUT AND PERITONEUM

Mechanical obstruction Organic gastrointestinal disorders

Gastric outlet obstruction Pancreatic adenocarcinoma

Small bowel obstruction Inflammatory intraperitoneal disease

Functional gastrointestinal disorders Peptic ulcer disease

Gastroparesis Cholecystitis

Chronic intestinal pseudo-obstruction Pancreatitis

Nonulcer dyspepsia Hepatitis

Irritable bowel syndrome Crohn disease

Mesenteric ischemia

Retroperitoneal fibrosis

Mucosal metastases

23

CNS CAUSES

Migraine Psychiatric disease

Increased intracranial pressure Psychogenic vomiting

Malignancy Anxiety disorders

Hemorrhage Depression

Infarction Pain

Abscess Anorexia nervosa

Meningitis Bulimia nervosa

Congenital malformation Labyrinthine disorders

Hydrocephalus Motion sickness

Pseudotumor cerebri Labyrinthitis

Seizure disorders Tumors

Demyelinating disorders Ménière disease

Emotional responses Cranial radiation

24

ENDOCRINOLOGIC AND METABOLIC CAUSES

Pregnancy

Other endocrine and metabolic

Uremia

Diabetic ketoacidosis

Hyperparathyroidism

Hypoparathyroidism

Hyperthyroidism

Addison's disease

Acute intermittent porphyria

MISCELLANEOUS CAUSES

Postoperative nausea and vomiting

Cyclic vomiting syndrome

Cardiac disease

Myocardial infarction

Heart failure

Radiofrequency ablation of the liver

Starvation

25

POSTOPERATIVE NAUSEA AND VOMITING

Nausea and vomiting are one of the most common complaints that follow surgery under

general anaesthesia. It has been described as “the big little problem” that complicates

postoperative recovery(25). 18 months after the introduction of chloroform to

anaesthesia, Sir John Snow in 1848 was the first to extensively describe the phenomenon

of PONV(1). Older inhalational anaesthetics such as chloroform and ether were used

before the 1960s; the incidence of postoperative vomiting at that time was as high as

60%(26). Advances in the field of anaesthesia with better techniques as well as the

development of newer anti-emetics and shorter acting anaesthetic drugs has decreased the

overall incidence of PONV in the first 24hours to around 30%(27)(28). However high

risk patients have an incidence of up to 80% following surgery(29). Therefore nausea and

vomiting that follows surgery is known to be multifactorial as it includes anaesthetic

factors, surgical factors as well as individual patient risk factors(30)(31).

Preoperative surveys often rate PONV as the outcome that patients would like to avoid

the most and are often willing to pay, up to even 100$ in order to avoid this unpleasant

complication(32). In Netherlands a survey done showed 22.7% of patients expressed fear

of postoperative nausea(33). Vomiting following surgery can result in dehydration and

electrolyte imbalance. Surgical wound dehiscence, esophageal tear, esophageal rupture,

aspiration of vomitus, and other complications that are associated with retching and

vomiting following surgery may be rare but can result in delay in discharge from the

26

postoperative care unit, cause an increase unanticipated hospital admission in out-patients

and also significantly increase overall costs of health care(3)(34).

There are numerous anti-emetic drugs that are available in the market today that have

been proven to be safe. However there is no drug that is available that does not have side

effects. These side effects can be mild, for example headache may occur with

ondansetron or can even be severe, for example QT prolongation that is also seen with

ondansetron. Therefore it is important to identify those individuals who are at risk of

developing nausea and vomiting after surgery and reduce it with appropriate anti-emetic

prophylaxis without the unnecessary risk of side effects of medications(29).

The etiology of postoperative nausea and vomiting is often multifactorial. These factors

can be classified under the following -

1. Patient factors

2. Intraoperative factors

a. Anaesthetic factors

b. Surgical factors

3. Postoperative factors

27

Patient Factors

Gender:

The female gender has been consistently noted as the strongest risk factor for developing

postoperative nausea and vomiting. Women in the reproductive age group are three time

more likely to suffer from PONV than men thereby suggesting the involvement of

hormones(28)(2).

Smoking Status:

Non-smokers have double the risk of developing PONV. Although the protective

mechanism is unknown, it has been suggested that cytochrome P450 enzyme is induced

by the polycyclic aromatic hydrocarbons found in cigarette smoke. This increases the

metabolism of the emetogenic anaesthetic agents(35).

History of PONV or motion sickness:

Patients who suffer from motion sickness, past history of nausea or vomiting following

surgery or both are 2-3 times more likely to develop PONV(36).

Age:

Although clinically not very significant, it has been found that in adults there is decrease

in the incidence of postoperative nausea and vomiting with increasing age of the patient.

However in children above the age of 3 it is noted that there is and increased risk of

vomiting in the postoperative period when compared to children under the age of 3.(29)

28

Delayed gastric emptying:

Those patients with diabetes mellitus, pregnancy, hypothyroidism, intra abdominal

pathologies such as pyloric stenosis, and increased intra cranial tension that have delay in

gastric emptying are also at the risk of developing PONV.

Obesity:

Although several studies have suggested that an increased BMI may predispose the

patient to develop nausea and vomiting after surgery, a systematic review done in 2001

showed no correlation.(37)

Anesthesia Factors

Inhalational agents:

The use of volatile anaesthetic agents during surgery has the highest risk of developing

PONV (38). Newer volatile agents such as halothane, sevoflurane and desflurane have a

lower incidence of nausea and vomiting in the postoperative period when compared to

the older agents such as ether and cyclopropane. Nitrous oxide when used has also been

known to cause PONV. A meta-analysis done in 2010, suggested that by avoiding nitrous

oxide, the overall risk of PONV is reduced, this has been noted especially in women(39).

However it is less of an effect than previously believed.

29

Opioid use:

The use of opioids in the intraoperative and the postoperative period also increases the

risk of developing postoperative nausea and vomiting, in a dose dependent manner.

Opioids reduce the muscle tone and the peristaltic activity, causing delayed gastric

emptying and inducing gastric distension. This triggers the vomiting reflex.

Duration of Anesthesia:

The duration of surgery and thereby anaesthesia can also predict the risk of developing

nausea and vomiting in the postoperative period. The duration of exposure to emetogenic

stimuli such as intraoperative opioids and volatile anaesthetics is also increased with

prolonged duration of surgery.

Neostigmine:

Due to insufficient evidence it is not possible to conclude whether the dose of

neostigmine causes an increase in the risk of nausea and vomiting following surgery.

Method of Anesthesia:

Some studies have suggested that an increased duration of facemask ventilation may

increase the risk of PONV. However the data available is conflicting.

30

Surgical factors Whether the type of surgery has an impact on the risk of developing of postoperative

nausea and vomiting still remains controversial. There are some studies that have shown

that ophthalmological, otological, cholecystectomies, gynaecological and thyroid

surgeries increase the risk of postoperative nausea and vomiting. (40)(41)(2). There is a

very high incidence of vomiting after intra abdominal surgeries like gall bladder and

intestinal surgeries, ear surgeries, head and neck surgeries, ovum retrieval procedures,

laminectomies, mitral valve replacements and kidney procedures. Intra abdominal

surgeries are more emetic than extra abdominal surgeries irrespective of the patient

gender. Stimulation of the mechanoreceptors and the release of 5hydroxy tryptamine

(5HT) from the enterochromaffin cells of intestine have been implicated. Laparoscopic

surgeries in particular have a higher incidence of postoperative nausea and vomiting. The

incidence of PONV following laparoscopic cholecystectomies varied from 50 to

70%.(42) In laparoscopic gynecology surgery up to 80% of patients developed nausea

and vomiting postoperatively.(43)Post operative nausea and vomiting is one of the main

complaints after laparoscopic surgeries including gall bladder surgeries and is the most

important factor determining the length of hospital stay after ambulatory anesthesia. The

etiology of nausea and vomiting after laparoscopic cholecystectomy is not fully

understood. Risk factors such as long periods of co2 insufflations, gall bladder surgery,

intraoperative use of isoflurane, fentanyl, glycopyrrolate, female sex, phase of menstrual

cycle, and postoperative use of PCA morphine may contribute to these episodes.

31

Postoperative Factors

Early intake of food, postoperative pain, early ambulation and dizziness are said to be

associated with increased incidence of nausea and vomiting.

Although various factors seem to determine the incidence of developing post operative

nausea and vomiting, the data available is sometimes conflicting or of no clinical

relevance. As per the consensus guidelines from 2014, the risk factors were classified

based on the level of evidence as well as the clinical implication. (4)

RISK FACTORS FOR PONV – IN ADULTS EVIDENCE RISKFACTORS

POSITIVE OVERALL

Female sex (B1) History of PONV or motion sickness (B1) Nonsmoking (B1) Younger age (B1) General versus regional anesthesia (A1) Use of volatile anesthetics and nitrous oxide (A1) Postoperative opioids (A1) Duration of anesthesia (B1) Type of surgery (cholecystectomy, laparoscopic, gynecological) (B1)

CONFLICTING

ASA physical status& BMI (B1) Menstrual cycle (B1) Level of anesthetist’s experience (B1) Muscle relaxant antagonists (A2)

DISPROVEN OR OF LIMITED RELEVANCE

Anxiety (B1) Nasogastric tube (A1) Supplemental oxygen (A1) Perioperative fasting (A2) Migraine (B1)

32

MANAGEMENT OF POSTOPERATIVE NAUSEA AND VOMITING The goal of prophylaxis is to decrease the incidence of nausea and vomiting that follows

surgery and thereby reduce the distress caused as well as the cost of health care. There

are several guidelines that have been published on the management of postoperative

nausea and vomiting. As per the most recent guidelines published in 2014, by Gan et al,

the first step in management is to identify the patient’s risk of developing PONV. As

discussed earlier, various risk factors are said to influence the incidence of developing

PONV. However not all play a significant role as the data available is sometimes

conflicting or of limited clinical relevance. In adults, the patient specific risk factors that

were identified include a younger age, the female sex, and a past history of PONV or

motion sickness and non-smoking status.

As seen with all drugs that are available, antiemetics also carry some risk of adverse

effects that may occur. Therefore it is important to objectively assess the individual’s risk

of developing postoperative nausea or vomiting and thereby decide on the need for

antiemetic prophylaxis. Therefore it is essential to objectively assess the baseline risk for

developing PONV by using a validated risk score. Although there are certain risk factors

for PONV that have strong evidence, no single predictor is used to clinically decide on

the need for antiemetic prophylaxis.(44) There are 2 risk scores that are commonly used

in adults, the Apfel score and Koivuranta score.(45)

The risk of developing nausea and vomiting postoperatively may be objectively assessed

using risk scores, however they are known to have a sensitivity and sensitivity between

65% and 70%. Also, it is important to make a decision for antiemetic prophylaxis based

33

on the implications of vomiting in certain clinical scenarios such as oesophageal or

gastric surgeries, increased intracranial pressures or in patients after facial surgeries with

wired jaws.

Koivuranta et al. developed a scoring system that consisted of 5 predictors of PONV –

Female sex, non-smoking status, history of motion sickness or PONV in the past, the use

of opioids postoperatively and the duration of surgery more than 60 minutes. It is an

additive score and the incidence of postoperative nausea and vomiting is 17%, 18%, 42%,

54%, 74% and 87% if 0, 1, 2, 3, 4 or 5 risk factors are present (28).

Fig. 2: Koivuranta score

Risk  Factors   Points  

Female Gender 1

Non-Smoker 1

History of Motion Sickness or PONV 1

Postoperative opioids 1

Surgery more than 60 minutes 1

Sum= 0 … 5

17%   18%  

42%  54%  

74%  87%  

0%  

20%  

40%  

60%  

80%  

100%  

0   1   2   3   4   5  

PONV  -­‐  Risk    

#  of  Risk  Factors  

34

Subsequently Apfel et al developed a simplified scoring system that reduced the number

risk factors in the scoring system from five to four, based on the data from Koivuranta et

al. as well as their own previous data. As per the Apfel simplified score, 4 risk factors

were taken into consideration for the prediction of PONV. Nonsmoking status, the female

sex, history of motion sickness/ PONV and the use of postoperative opioids are included

in this score. The presence of 0, 1, 2, 3 or 4 risk factors implies that the risk of PONV is

10%, 20%, 40%, 60% or 80% respectively.

Fig. 3: Apfel Score

35

In children, postoperative vomiting (POV) can be predicted using a simple score

described by Eberhart et al., which identifies 4 risk factors of developing POV – age of

the child more than 3 years; duration of surgery more than 30 minutes; history of

vomiting after surgery in the patient, sibling or parent; and strabismus surgery. The risk

of postoperative vomiting was 9%, 10%, 30%, 55% and 70% with a risk score of 0, 1, 2,

3 or 4.

Fig. 4: Eberhart Score

36

As per the 2014 guidelines, patients were categorized as “low”, “medium” or “high” risk

based on their Apfel scores of 0 – 1, 2 – 3 and 4 respectively. Depending on which

category the patient belonged to, antiemetic prophylaxis as well as anaesthetic

management guidelines were suggested to prevent the occurrence of PONV.

It is also important to minimize the baseline risk factors for developing PONV. Strategies

that were suggested include the preference of regional anaesthesia over general

anaesthesia. The incidence of developing PONV after regional anaesthesia was almost 9

times less than after general anaesthesia. When it was necessary to give general

anaesthesia, induction and maintenance of anaesthesia with propofol decreased the

incidence of nausea and vomiting in the early postoperative period. According to the

IMPACT study, which evaluated 6 strategies to reduce postoperative nausea and

vomiting, it was found that total intravenous anaesthesia (TIVA) with propofol reduced

the risk of PONV by 25% (46). Reducing the dose of intraoperative as well as

postoperative opioids by using alternative methods of pain relief decrease the risk of

PONV as well as hyperalgesia (27)(47) . Another simple strategy suggested was adequate

hydration, which has also shown to decrease PONV (48).

There are 3 main classes of antiemetic drugs that are widely used in the prevention of

nausea and vomiting (49)(50). These are serotonin antagonists, corticosteroids and

dopamine antagonists, which have a similar efficacy and cause a 25% decrease in the

relative risk of developing PONV. They have different mechanisms of action, therefore

when use together they have an additive effect.

37

5-­‐Hydroxytryptamine  (5-­‐HT3)  Receptor  Antagonists Radioligand binding studies have demonstrated a high density of 5HT3 receptors in areas

known to be involved in the emetic reflex, including vagal afferent terminals in gastric

mucosa, the brainstem dorsovagal nucleus, the nucleus tractus solitarius and the area

postrema. It is possible that anesthetic agents may stimulate neurons within the area

postrema and activate the vomiting reflex via 5 HT mediated pathway. Anesthetics can

disrupt mucosal enterochromaffin cells and induce the release of paracrine transmitters,

including 5HT, resulting in afferent vagal firing and this initiate the vomiting reflex.

Gastrointestinal distension caused by diffusion of nitrous oxide, laparotomy and

manipulation of gastro intestinal tract, can activate vagal afferents via mucosal 5HT

release.

5HT3 antagonists belong to the class of antiemetics that act by blocking the 5HT3

receptor. The pathway involved in emesis consists of several sites, at which the 5HT3

receptors are present, such as the vagal afferents, the nucleus tractus solitarius and also

the area postrema. These drugs prevent the binding of serotonin to the 5HT3 receptor and

thereby suppress nausea and vomiting. Based on their chemical structure they may be

classified further into 3 classes. (51)

• Carbazole derivatives:

• Indole derivatives

• Indazole derivative

38

Fig.5: Chemical structure of 5HT3 antagonists

Carbazole derivatives:

Ondansetron belongs to this class of 5HT3 receptor antagonist. It is one of the most

researched amongst its class of drugs and is often considered as the “gold standard” of

antiemetics. Ondansetron is a selective antagonist at the 5HT3 receptor and is the first

drug in the class of 5HT3 antagonist to be introduced for the clinical management of

vomiting associated with chemotherapy and radiotherapy. Ondansetron has been in

Name Structure

Ondansetron

Granisetron

Dolasetron

Ramosetron

Palonosetron

39

clinical development for the prevention and treatment of PONV since 1988. The initial

literature recommended dose is 0.1 to 0.15 mg/kg and effective blood levels are attained

30-60 minutes after administration. The elimination half-life of ondansetron is

approximately 3.5-4 hours in adults. Due to its relatively short half-life it may be relevant

to administer the drug intraoperatively towards the end of the surgical procedure,

especially those surgeries of more than 2 hours duration. Large multicenter studies have

demonstrated that intravenously administered ondansetron 4 mg is effective in preventing

and treating established PONV. This is confirmed in the 2014 consensus guidelines in the

management of PONV by Gan etal The recommended intravenous dose of ondansetron is

4mg, usually at the end of surgery(4).

Farhat etal compared 4 mg ondansetron with 10 mg metoclopramide for prevention of

PONV after laparoscopic cholecystectomy and found that prophylactic ondansetron was

more effective with fewer side effects. Hemley compared ondansetron with droperidol

and metoclopramide for laparoscopic cholecystectomy under propofol TIVA and found

that PONV in the ondansetron group was significantly less in the 1 -4 hours, but similar

in the rest of the 24 hours.

The adverse effects that are seen with the use of ondansetron include headache, diarrhea

or constipation, dry mouth, and even QT prolongation.

Indole derivatives:

Dolansetron has shown to effectively prevent PONV at a dose of 12.5mg given

intravenously(51). Due to concerns regarding QT interval prolongation and torsade de

pointes, in certain countries it is not available for use (52).

40

Indazole derivatives

Granisetron was found be as effective in the treatment of nausea and vomiting when

compared to the other first generation 5HT3 receptor blockers. The dose needed was 0.3

to 3mg given intravenously. When compared to 8mg of dexamethasone, a 3mg dose of

IV granisetron was found to be equally effective but when used as a combination it was

found to be better than using each drug alone.(53)

Ramosetron has a higher affinity for the 5HT3 receptors than the older drugs in this class.

The antiemetic property of this drug is present for more than 2 days. At a dose of 0.3mg

IV, it is effective in preventing nausea and vomiting in patients that are on patient

controlled analgesia (PCA) with fentanyl. It is available only in certain South East Asian

countries. (54)

Palonosetron is the newest of this class of drugs and it belongs to the second-generation

5HT3 receptor blockers. This drug has a significantly longer half-life of up to 40hours,

which is 4 – 5 times longer than that of ondansetron, granisetron or dolasetron. It is also

more potent and has and increased binding affinity to the 5HT3receptors. Palonosetron is

usually given at the beginning of surgery. The most effective dose for intravenous

palonosetron was found to be 0.075mg given intravenously (55). Palonosetron was also

found to have a better safety profile as studies have shown that it does not cause QT

prolongation (56)(57).

41

5HT3 receptor antagonists are usually well tolerated. Minor side effects of these

medications include mild headaches seen in 15 to 20% of patient population or

constipation that occurs in 5 – 10% of the population. Electrocardiogram interval

changes, QT prolongation is seen in the first – generation 5HT3 receptor antagonists.

Corticosteroids

In 1980 methyl prednisolone was first reported to be an effective antiemetic in

chemotherapy patients. Since 1981, dexamethasone has been reported to be more

effective than metoclopramide in controlling chemotherapy induced nausea and vomiting

and was preferred by the patients’ treated. The antiemetic effect of dexamethasone was

reported to be equal or better than the 5HT3 receptor antagonists such as ondansetron and

granisetron. Dexamethasone has also been reported to effective in reducing the incidence

of postoperative nausea and vomiting (PONV) in paediatric patients undergoing

strabismus repair, tonsillectomy, adenoidectomy, thyroidectomy, cholecystectomy, and

women undergoing major gynecological surgery.

The mechanism of action of dexamethasone is not well understood, but central

inhibition of prostaglandin synthesis, and decrease in 5HT turnover in the central nervous

system or changes in the permeability of blood CSF barrier to serum proteins may be

involved. Corticosteroids may reduce levels of 5HT, (5hydroxytryptophan) in neural

tissue by depleting its precursor tryptophan. Also, the anti-inflammatory properties of

corticosteroids may prevent the release of serotonin in the gut. It causes release of

42

endorphins; this results in mood elevation, a feeling of well-being and also an appetite. It

may potentiate the main effect of other antiemetics by sensitizing the pharmacological

receptor. Dexamethasone has a biological half life of 36-72 hours, so delayed emesis

following chemotherapy is better controlled with dexamethasone compared with classic

antiemetics. Dexamethasone, when administered immediately before the induction of

anesthesia, provided an effective decreases in nausea and vomiting throughout the first 24

hours of the postoperative period. On the contrary, when dexamethasone was given at the

end of anesthesia, it did not provide an effective antiemetic effect during the immediate

postoperative period of 0-2 hours. Since more than 50% of the patients experienced

nausea and vomiting in this early postoperative period it is very essential that a

prophylactic antiemetic should be effective during this period. It was suggested that the

onset time of dexamethasone’s antiemetic effect might be approximately two hours. It

was concluded that the prophylactic administration of dexamethasone immediately before

the induction of anesthesia was more effective than at the end of anesthesia for

preventing PONV. A wide range of dose of dexamethasone (8-32mg) has been used in

the prophylaxis of emesis related to chemotherapy and after pediatric and gynecological

surgery. Liu and his colleagues have suggested a dose of 0.15 mg/kg of dexamethasone

up to a maximum dose of 10mg for prevention of postoperative nausea and vomiting. The

minimum effective dose of dexamethasone for the prevention of PONV was suggested to

be 2.5mg in a recent study. Adverse effects related to a single dose of dexamethasone are

extremely rare. However single dose intravenous dexamethasone has been implicated in

the etiology of perineal irritation.

43

Dexamethasone when given as a prophylactic dose of 4mg intravenously is seen to

effectively decrease nausea and vomiting following surgery (58)(59)(60). It is

preferentially given after the induction of anaesthesia than at the end of surgery. A 4mg

dose of dexamethasone IV is considered to be as efficacious as a 4mg IV dose of

ondansetron or 1.25mg IV dose of droperidol.

Apart from addressing the problem of postoperative nausea and vomiting, dexamethasone

also has a dose dependent effect on the quality of recovery. De Oliveira et al. compared a

dose of 0.1mg/kg of dexamethasone with 0.05mg/kg and showed that with a higher dose

there was less opioid requirement, less nausea, sore throat and muscle pain and thereby

decreasing the time for discharge readiness(60).

The data available on the safety of using dexamethasone in the perioperative period is

inconclusive. They may have other detrimental or beneficial effects on patient recovery.

Therefore most of the available literature suggests the use of a single dose of

dexamethasone in the perioperative period as this does not seem to increase the risks of

wound infection(61)(60). An editorial published in 2013 has suggested that a single 4 to

8mg dose of dexamethasone was considered safe after considering the risks as well as the

benefits(62). Recent studies have shown an increase in the levels of blood glucoses after

an 8mg dose of dexamethasone. Therefore it is best avoided in labile diabetic patients.

Wang, Ho and Liu evaluated the antiemetic effect of dexamethasone 8 mg in prevention

of postoperative nausea and vomiting in 90 ASA l or ll patients, aged 30-55years, and

undergoing general anesthesia for elective laparoscopic cholecystectomy in a randomized

44

double blind study. They concluded that dexamethasone was effective in the prevention

of nausea and vomiting after laparoscopic cholecystectomy.(63)

Bianchin etal had similar results when he compared placebo vs 8 mg dexamethasone

for prevention of PONV after laparoscopic cholecystectomy.

Dopamine Antagonists

Drugs belonging to this class, which exhibit antiemetic properties act on the D2

receptors. They are often used as rescue antiemetics. They may be classified into three-

• Phenothyazines (e.g. Promethazine)

• Butyrophenones (e.g. Droperidol)

• Benzamides (e.g. Metoclopromide)

Other  Antiemetics  

Neurokinin – 1 (NK-1) receptor antagonist

Aprepitant was found to have a greater antiemetic effect when compared with

ondansetron. When used in combination with dexamethasone it was also found to be

more effective in decreasing postoperative vomiting than the combination of ondansetron

in a study done on patients undergoing craniotomy (64).

The current guidelines do not support the use of antiemetics in all patients that

undergo surgery. It is necessary to determine the risk of developing nausea and vomiting

postoperatively, based on which antiemetic prophylaxis is decided. An algorithm

suggested in the 2014 consensus guidelines for the management of postoperative nausea

and vomiting is as follows (4)–

45

Consensus Guidelines for the Management of PONV

January 2014 Volume 118 Number 1 www.anesthesia-analgesia.org 91

(5-HT3) receptor antagonists (ondansetron, dolasetron, granisetron, tropisetron, ramosetron, and palonosetron), neurokinin-1 (NK-1) receptor antagonists (aprepitant, casopitant, and rolapitant), corticosteroids (dexametha-sone and methylprednisolone), butyrophenones (droperi-dol and haloperidol), antihistamines (dimenhydrinate and meclizine), and anticholinergics (transdermal scopolamine [TDS]). While PONV prevention is recommended in a sub-set of patients, current evidence does not support giving

prophylactic antiemetics to all patients who undergo surgi-cal procedures. However, with more inexpensive generics becoming available, properly conducted cost-effectiveness (C/E) studies need to be done to support the more uni-versal use of prophylactic antiemetics. Ondansetron 4 mg, droperidol 1.25 mg, and dexamethasone 4 mg were equally effective, and each independently reduced PONV risk by approximately 25%.47 The recommended doses and timing of these drugs are listed in Table 3. Recommendations given

Adult Risk Factors Children Risk FactorsPatient Related Environmental Surgery > 30 minHistory of PONV/motion sickness Postop opioids Age > 3 yearsFemale gender Emetogenic surgery Strabismus surgeryNon-smoker (type and duration) History of POV/relative with PONV

Cost-effectiveness

Consider

LowWait and See

High>2 Interventions/

Multimodal Approach

Dexa-methasone

5-HT3 antagonist

NonPharmacological:

Acupuncture

ScopolaminePerphenazine Dimen-

hydrinate

Propofol subhypnotic dose infusion or

Propofol in PACU (rescue only)

NK-1 receptor antagonists

Droperidol†Haloperidol

Regional Anesthesia

Propofol Anesthesia

Portfolio ofprophylaxis

and treatmentstrategies

Treatment Options• If prophylaxis fails or was not received: use

antiemetic from different class than prophylactic drug

• Readminister only if >6 hours after PACU; • Do not readminister dexamethasone or

scopolamine

† Use droperidol in children only if other therapy has failed and patient is being admitted to hospital;Haloperidol for adults only

Patient preferencesFear of PONVFrequency of PONV causing headaches/migraine

Reducing baseline risksAvoidance/minimization of:Nitrous oxideVolatile anestheticsPost-op opioids

Medium

Pick 1 or 2 Interventions

Patient risk

Figure 4. Algorithm for management of postoperative nausea and vomiting. PONV = postoperative nausea and vomiting.

46

Ondansetron is generally considered as the gold standard in treating PONV (4). The

efficacy of ondansetron in reducing PONV was proven with different anaesthetic agents

as well (65). Since the early 1990s large randomized controlled studies and multi

centered studies have established the efficacy of 4mg of IV ondansetron in treating and

preventing PONV. Eight mg of ondansetron has also been proven to also reduce the

incidence of PONV in high-risk patients such as those with prior PONV history.

However a metaanalysis done by Tramer et al highlighted some of the limitations of

monotherapy for the management of PONV. Fifty-three trials studied proved the efficacy

of ondansetron in reducing PONV was 20% at best. Therefore although ondansetron was

the treating drug of choice newer drugs or combined therapy with other drugs needed to

be explored (66).

With this in mind, literature emerged about the use of combination therapy of

ondansetron and dexamethasone for PONV prophylaxis and treatment. Many studies

have shown the superiority of ondansetron plus dexamethasone.

Dexamethasone as monotherapy has been proven to be inferior to the combination of

ondansetron and dexamethasone. In a study published in 2008 by Bano et al, one hundred

patients undergoing laparoscopic cholecystectomy were randomly allocated either to

ondansetron alone or ondansetron plus dexamethasone. The authors concluded that

combination of ondansetron plus dexamethasone was better than dexamethasone alone in

preventing postoperative nausea and vomiting. A recent metaanalysis done in 2015

included 7 trials, it concluded that it was safe to use dexamethasone as an alternative to

ondansetron as prophylaxis for PONV as they were both found to be equally effective. .

47

Dexamethasone was found to have more effect than ondansetron in the late postoperative

period (63). Combination antiemetic therapy has been seen to have better results in the

prevention of PONV than using a single drug. Ondansetron has been compared with a

combination of ondansetron and dexamethasone. Song et al outlined the superiority of the

above-mentioned combination over ondansetron alone in a randomized control trial

involving one hundred and thirty patients who received patient controlled analgesia with

fentanyl. Four milligrams of ondansetron was administered to all patients undergoing

thoracoscopic surgery and 12 mg was administered as boluses through patient controlled

analgesic devices, the trial arm received 8 mg dexamethasone whereas the comparator

arm did not receive dexamethasone. The combination of ondansetron with

dexamethasone was reported to be better in preventing and treating PONV over a 48-hour

period (5). This was also confirmed by Ahsan et al in an RCT published in 2014. One

hundred patients that underwent laparoscopic cholecystectomy were randomly assigned

to receive ondansetron or ondansetron plus dexamethasone. The authors observed that

the combination of dexamethasone and ondansetron was superior to ondansetron alone

(6).Kumar et al compared a combination of ondansetron plus dexamethasone (4mg plus

8mg) vs either drug alone in the same dose and placebo in patients undergoing

laparoscopic cholecystectomy and found that the incidence was 85% in the placebo group

30% in dexamethasone group, 35% in ondansetron group and only 10% in the

combination group which was statistically significant.(67)

The current literature supporting the use of palonosetron is robust. Chun et al in a

randomized controlled trial involving over two hundred ASA I and II patients compared

48

the efficacy of palonosetron with a placebo undergoing various surgeries. This double-

blinded placebo controlled study divided patients into two arms, in one arm 0.075 mg of

palonosetron was given and in the second arm normal saline was used. At 72 hours post

operatively various parameters were assessed and the authors found PONV reduced

significantly in the arm where palonosetron was used, 33% versus 47% at 0-24 hours and

6% versus 11% at 24 -72 hours. The study also proved that severity and intensity of

nausea in the initial 24 hour period following the operation was reduced in the group that

palonosetron was administered, however this difference although clinically significant

did not show statistical significance (P value - 0.08) This has been corroborated by

various other RCTs. Kovac et al in a study published in 2008 demonstrated the efficacy

of palonosetron versus placebo in a randomized controlled trial involving over five

hundred patients undergoing either gynaecological or breast surgery. Patients were

randomly allocated to one of four groups – placebo vs. 0.025 mg of palonosetron vs.

0.050 mg palonosetron vs. 0.075 mg palonosetron. The primary end point analyzed was

the ability to prevent vomiting with various doses. They concluded that a dose of

0.075mg was required for prevention of PONV(55).

Various studies have compared the efficacy of palonosetron versus ondansetron. Park et

al in 2014 published a randomized controlled trial comparing the efficacy of 0.075 mg of

palonosetron and 8 mg of ondansetron in patients undergoing gynaecological surgery. A

total of ninety patients were randomly allotted to either of the two arms. The incidence

of PONV and the severity of nausea were assessed using a visual analogue score. The

49

study results confirmed that the incidence of PONV was significantly lower in the arm

where palonosetron was given (42.2 percent versus 66.7 percentage). The severity of

nausea as assessed by the visual analogue score was statistically equal between the two

arms. The study suggested that palonosetron was better than ondansetron in preventing

nausea and vomiting in the postoperative period (68).

The efficacy of a single dose palonosetron versus ondansetron was also studied by Kim et

al. This study from Korea, randomly allotted one hundred patients to receive

palonosetron as a single IV bolus of 0.075 mg versus ondansetron which was

administered as a bolus dose of 8 mg intravenously following which 16 mg was added to

the IV – PCA. The study revealed that a bolus of ondansetron followed by an infusion

was equal in efficacy to a single dose of palonosetron in the prevention of PONV after

laparoscopic gynaecological surgery (69). In a study done by Bhattacharjee et al,

palonosetron or granisetron was administered as PONV prophylaxis in patients

undergoing laparoscopic cholecystectomy. It was found that palonosetron was more

effective in the prevention of PONV in the 24 to 48 hour postoperative period rather than

the first 24 hours.(70)Laha etal compared palonosetron with ondansetron for prevention

of PONV after laparoscopic cholecystectomy and found that both drugs are comparable.

This result was against the pharmacokinetic (t1/2 and receptor affinity) and expected

pharmacodymamic effect of palonosetron. Researchers have compared palonosetron vs.

palonosetron plus dexamethasone in various surgical populations and found that a

combination of palonosetron plus dexamethasone is superior.(71) However the 2014

50

consensus guidelines do not suggest the combination of palonosetron and

dexamethasone, as both the drugs are long acting (24 hours) and it doesn’t offer any

additional advantage.

The use of dexamethasone alone as PONV prophylaxis was also studied in patients

undergoing laparoscopic cholecystectomies. Bianchin et al in 2007 published an RCT

done on 80 patients that received either 8mh of dexamethasone or normal saline as

placebo. The study showed that there was significant decrease in the incidence of PONV

in the dexamethasone group with no side effects noted. (72)

The literature comparing palonosetron versus a combination of ondansetron and

dexamethasone in laparoscopic surgery is sparse; therefore we have conducted a

randomized controlled trial comparing these two regimens.  

51

     

METHODS  

 

 

 

 

 

 

 

 

52

Design: A prospective blinded randomized controlled trial was designed.

There were two arms in the study:

The patients were randomly allotted to either the ‘palonosetron group’ or ‘ondansetron

plus dexamethasone group’.

Randomized groups -

Intervention:  Palonosetron 0.075 mg IV  

Comparator  Agent:  Dexamethasone 4 mg IV with Ondansetron 4mg IV  

Inclusion and exclusion criteria

Inclusion Criteria:

-ASA grade I/II patients within the age group of 18 to 60 years scheduled to undergo

laparoscopic cholecystectomy, under general anaesthesia.

Exclusion Criteria:

-Pregnant and lactating patients

-Patient with hypersensitivity to palonosetron, dexamethasone or ondansetron

-Patients with history of motion sickness

-Patients on steroid therapy, antiemetics or on treatment with other medication known to

produce nausea and vomiting.

53

Recruitment:

All patients who consented for the study and fulfilled the inclusion criteria were recruited

by the principal investigator for the study.

Institutional review board clearance and ethics committee approval was obtained before

the start of the study.

Method of randomization:

The patients were be randomized to one of two groups by a computer generated random

assignment.

Method of allocation concealment:

Sequentially numbered, sealed, opaque envelopes opened in the operation theatre after

the patient is anaesthetized.

Blinding and masking:

A double blinded study was conducted. The participant and outcome assessors were

blinded to treatment allocation. The anesthetist after administering the drug documents as

either study drug A (palonosetron) or drug B (ondansetron plus dexamethasone). Even

though ondansetron can be repeated after 6 hours according to recommendations we did

not do it to keep the study blinded and as there is no role of giving ondansetron to

patients who have received palonosetron.

54

Allocation concealment opaque envelope

Intervention arm Comparator arm

Postoperative assessment for complaints of nausea or vomiting for 0-2 hours, 2-6 hours and 6-24 hours

Palonosetron 0.075 mg IV after induction of General Anaesthesia

Group A

Dexamethasone 4 mg IV after induction of General Anesthesia

+ Ondansetron 4mg IV 30 minutes

prior to extubation Group B

Inclusion criteria met -- >PISgiven- Consent and recruitment

Randomization - block randomization 2 or 4 or 6

In case of nausea or vomiting Rescue antiemetics* are to be given and documented

*Promethazine 6.25 to 12.5 mg IV If it persists ondansetron 0.1mg/kg will be given with intension to treat

Diagrammatic algorithm of the study

55

Sample size:

Sample size calculated was 77 patients in each arm of the study. With expected

difference in PONV % as 20% between the two arms, the minimum required samples

needed for this study is 77 in each arm. The sample size was calculated using the

following formula (Non-inferiority - Two Groups - Parallel - Two propotions - Equal

Allocation).

56

Proportion in the standard treatment 0.5

Proportion in the new treatment 0.5

Observed/Expected difference in proportions 0

Non-inferiority margin 0.2

Power (1- beta) % 80

Alpha Error % 5

Required sample size in each group 77

Statistical Analyses:

Statistical methods used for the primary outcome; include description of methods to

estimate the strength of the effect (e.g.: Odds ratios, relative risks, etc.).

The comparison of the post-operative nausea and vomiting (primary outcome) were done

using a chi-square test. The bootstrap 95% confidence interval was used to calculate the

difference of proportions between the two methods. Risk estimates were calculated with

95% confidence interval.

All patients were explained about the study after giving them the information sheet

(Annexure 2).

Informed consent (Annexure 3) was taken.

Those who did not give consent were not recruited in the study.

57

After informed consent, the details required as per the pro forma (Annexure 1) were

collected.

They were all followed up during their stay in hospital.

67 patients were randomized into one of the 2 arms

Six patients had to be excluded due to logistical reasons such as lost randomization

envelope and rescheduled surgeries.

Of the remaining 61 patients in the study, 2 were converted to open surgeries and 4 had

protocol violation. Therefore55 patients were analyzed, 27 in the ‘palonosetron’ arm and

28 in the ‘ondansetron with dexamethasone’ arm.

Phase of trial: Phase 3

Duration of trial: 1 year

The study had no provision for interim analysis or premature stoppage

58

 

 

   

 

 

 

 

 

 

 

 

 

 

 

 

 

*Grp  1  =  Palonosetron        Grp  2  =  Ondansetron  with  dexamethasone  

Lost to follow-up (n= 0) Lost to follow-up (n=0)

Follow-­‐Up  

Analysed (n=27)

Analysed (n=28)

Analysis  

Excluded (n=6) (n=2)envelope was misplaced due to

logistical reasons and n = 4 excluded as surgeries were

rescheduled}

Randomized (n=61)

Enrollment  

Assessed for eligibility (n=67))

Allocation  

Allocated to intervention (Grp 1*) (n=30) ♦ Received allocated intervention (n= 30) ♦ Protocol violation (n = 3)

Allocated to intervention (Grp 2*) (n=31) ♦ Received allocated intervention (n= 28) ♦ Did not receive allocated intervention (n= 3)

♦ Protocol violation (n = 1) • Converted to open cholecystectomy

(n=2)

59

 

   

RESULTS  

60

 

CATEGORICAL  VARIABLES:  

Sex distribution: Out of the total of 55 patients, 10 were male and 45 were females.

 

 

 

 

 

 

 

 

9  

18  

1  

27  

0  

5  

10  

15  

20  

25  

30  

Male     Female  

Grp  1(P)  

Grp  2(O+D)  

Fig. 6 showing sex distribution in both groups

61

SEX DISTRIBUTION BETWEEN THE TWO ARMS:

In the intervention (Palonosetron) group 9 patients were males and 18 patients were

females.

In the comparator (Ondansetron + Dexamethasone) group, 1 were males and 27 were

females

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

62

AGE  DISTRIBUTION:  

The  mean  age  of  patients  undergoing  laparoscopic  cholecystectomy  was  44.7  

years      

 

AGE  DISTRIBUTION:  

The  mean  age  between  the  two  arms  was  comparable.  

 

 

 

    N   Mean   Std.  Deviation   Std.  Error  Mean  

 

Palonosetron   27   46.08   16.2   2.29  

Dexamethasone  +  Ondansetron   28   43.28   15.38   2.29  

 

 

 

 

 

Table 1 shows the mean ages in the two arms along with the standard deviation

63

 

BODY MAS DISTRIBUTION:

The mean body mass index of patients having laparoscopic cholecystectomy was 20.4

kg/m2

BODY MASS INDEX DISTRIBUTION:

The body mass index in both groups was comparable.

N Mean Std. Deviation Std. Error Mean

Palonosetron 27 26.7 3.95 0.61

Dexamethasone + Ondansetron 28 28.1 4.22 0.71

Table 2 shows the mean BMI in the two arms along with the standard deviation

64

DISTRIBUTION BETWEEN TWO ARMS ACCORDING TO THE PRESENCE OF

COMORBID ILLNESSES

The following comorbidities were analyzed to ascertain the baseline characteristics in

both groups

1. Diabetes mellitus

 

 

 

(P=  0.16)  

 

 

3  

24  

5  

23  

0  

5  

10  

15  

20  

25  

30  

Diabetes  mellitus   No  diabetes  mellitus  

Grp1  P  

Grp  2  O+D  

Fig. 7 showing distribution of diabetes mellitus among the two arms.

65

2. Hypertension

 

 

 

 

(P=  0.9)  

 

 

 

 

 

 

 

4  

23  

5  

23  

0  

5  

10  

15  

20  

25  

Hypertension   No  hypertension  

Palonosetron  

Ondansetron+Dexamethasone  

Fig. 8 showing distribution of hypertension between the two arms.

66

3. Smoking

 

 

 

 

P=0.093  

 

 

 

 

 

 

 

3  

24  

1  

27  

0  

5  

10  

15  

20  

25  

30  

Smoker   Non  smoker  

Palonosetron  

Dexamethasone  +  Ondansetron  

Fig. 9 showing distribution of smoking between the two arms.

67

4. COPD or Asthma

 

 

 

 

 

 

 

 

 

 

 

 

1  

26  

2  

26  

0  

5  

10  

15  

20  

25  

30  

COPD   No  COPD  

Palonosetron  

Ondansetron  +  dexamethasone  

Fig.10 showing distribution of COPD or asthma between the two arms.

68

5. Hypothyroidism

 

 

 

 

 

 

 

The  baseline  characteristics  between  the  two  groups  were  comparable.  

 

 

 

 

3  

24  

1  

27  

0  

5  

10  

15  

20  

25  

30  

Hypothyroidism   No  hypothyroidism  

Palonosetron  

Ondansetron+Dexamethasone  

Fig.11 showing distribution of hypothyroidism between the two arms.

69

The Apfel score comparison between the two groups

Palonosetron  group  

Score   n(%)  

1   3(11.1%)  

2   6  (22.2%)  

3   16  (59.3%)  

4   2  (7.4%)  

 

Ondansetron  +  dexamethasone  group  

Score    n(%)  

1   4(7.3%)  

2   7(12.7%)  

3   20(69.1%)  

4   4(10.9%)  

 

 

 

 

70

 

 

 

 

 

We did not analyze the relationship between Apfel score and the incidence of PONV.

Since the data collection is not complete, our numbers are not big enough for a

meaningful interpretation.

 

3  

1  

6  

1  

16  

22  

2  

4  

0  

5  

10  

15  

20  

25  

Palonosetron   Ondansetron+Dexamethasone  

Num

ber  of  patients  

1  

2  

3  

4  

Fig.12 showing distribution of patients based onApfel score in the two groups

71

Nausea over a period of 24 hours

Nausea Palonosetron Dexamethasone+Ondansetron p value

n(%) n(%)

Yes 7(29) 10(42) 0.365

No 17(71) 14(58)

The above graph shows if a patient had nausea at any given point in time.

 

Fig.13 showing occurrence of nausea in the two arms

29  

42  

71  

58  

0  

10  

20  

30  

40  

50  

60  

70  

80  

Palonosetron   Dexamethasone+Ondansetron  

Percentage  of  cases  

Yes  

No  

72

The occurrence of nausea at intervals of 0-2, 2 -6 and 6 – 24 hours  

Palonosetron Dexamethasone+Ondansetron p value

n n

0-2hrs 0 5 0.182

2-6hrs 4 5

6-24hrs 4 5

   

               

0  

4   4  5  

5   5  

0  

1  

2  

3  

4  

5  

6  

7  

8  

9  

10  

0-­‐2hrs   2-­‐6hrs   6-­‐24hrs  

Ondansetron+Dexamethasone  

Palonosetron  

Fig.14 showing occurrence of nausea in the two arms at three time intervals

73

Vomiting over a period of 24 hours    

Vomiting Palonosetron Dexamethasone+Ondansetron

p value n(%) n(%)

Yes 6(22.2) 10(35.7) 0.525

No 21(77.8) 18(64.3)

 

       

Fig.15 showing occurrence of vomiting in the two arms

22.2  

35.7  

77.8  

64.3  

0  

10  

20  

30  

40  

50  

60  

70  

80  

90  

Palonosetron   Ondansetron+Dexamethasone  

%  of  Cases  

Vomiting  

No  Vomiting  

74

The occurrence of vomiting at intervals of 0-2, 2 -6 and 6 – 24 hours  

Palonosetron Dexamethasone+Ondansetron

p value n n

0-2hrs 1 0

0.2854 2-6hrs 3 3

6-12hrs 3 8

   

                     

1  

3   3  0  

3  

8  

0  

2  

4  

6  

8  

10  

12  

0-­‐2hrs   2-­‐6hrs   6-­‐24hrs  

Num

ber  of  patients  

  Ondansetron+Dexamethasone  

Palonosetron  

Fig.16 showing occurrence of vomiting in the two arms at three time intervals

75

Occurrence of nausea in relation to opioid use  

     

     

   

38.70%  

29.40%  

36.60%  

28.60%  

0.00%  

5.00%  

10.00%  

15.00%  

20.00%  

25.00%  

30.00%  

35.00%  

40.00%  

45.00%  

NAUSEA  %  

Title  

FENTANYL  <=2.5mg/kg  

FENTANYL  >2.5mg/kg  

MORPHINE  <=.1mg/kg  

MORPHINE  >.1mg/kg  

NAUSEA N(%) P VALUE

FENTANYL

.519 <=2.5mg/kg 12 (38.7%)

>2.5mg/kg 5(29.4%)

MORPHINE

>.999 <=.1mg/kg 15 (36.6%)

>.1mg/kg 2 (28.6%)

Fig.17 showing occurrence of nausea in relation to the dose of opioid used

76

The occurrence of vomiting in relation to opioid use  

VOMITING N (%) P VALUE

FENTANYL

>.999 <=2.5mg/kg 9 (29%)

>2.5mg/kg 5 (29.4%)

MORPHINE

>.999 <=.1mg/kg 12 (29.3%)

>.1mg/kg 2 (28.6%)

 

       With increasing intra operative opioid dose no increase was seen in the incidence of

vomiting postoperatively in both groups.

29%  

29.40%  29.30%  

28.60%  

28%  

28%  

29%  

29%  

29%  

29%  

29%  

30%  

VOMITING  %  

Percentgae  of  cases  

FENTANYL  <=2.5mg/kg  

FENTANYL  >2.5mg/kg  

MORPHINE  <=.1mg/kg  

MORPHINE  >.1mg/kg  

Fig.18 showing occurrence of vomiting in relation to the dose of opioid used

77

Table 3: Correlation between Pain and Nausea at three time intervals 0 to 2hrs, 2 to 6 hrs

and 6 to 24 hrs.

Time intervals n Correlation Coefficient p value

0 to 2 54 .279 .041

2 to 6 55 .126 .361

6 to 24 55 .241 .076

The Spearman’s Rank correlation coefficient was calculated here. The Pain and Nausea is

correlated at 0 to 2hrs. The graphical representation is given below:

There was weak correlation that was noted between nausea and pain at 0 to 2 hours and 6 to 24 hour time period.

78

Table 4: Correlation between Pain and Vomiting at three time intervals 0 to 2hrs, 2 to hrs

and 6 to 24 hrs.

Time intervals n Correlation Coefficient p value

0 to 2 54 0.077 .582

2 to 6 55 -0.003 .980

6 to 24 55 -0.060 .663

 

The above table shows that no correlation was found on the incidence of vomiting and

the severity of pain at various time points.

79

RESULTS As depicted by the consort diagram twenty-seven patients were randomized to the

palonosetron arm and 28 patients were randomized to ondansetron and dexamethasone

arm after the protocol violators were excluded.

Of the fifty-five patients, ten were male and forty-five were female. The mean age of

patients assessed was 44.7 years.

The baseline demographics between the two groups were identical except for uneven

gender distribution between the two groups (figure 6).

The distribution of patients based on comorbid illnesses such as diabetes mellitus,

hypertension, COPD, smoking history and hypothyroidism were comparable.

The primary objective studied was to compare the efficacy of palonosetron versus

ondansetron and dexamethasone in preventing PONV. There was no significant

difference between the two groups studied(6 patients in the palonosetron arm versus 8 in

the arm which received dexamethasone with ondansetron)(0.525).

This was studied across different time periods 0-2 hours, 2-6 and 6 – 24 hours. However

the results found were almost similar and there was no statistical significance in the

outcomes for nausea (p = 0.182) or vomiting (p = 0.2854).

80

The analysis also showed that the occurrence of nausea and vomiting was not

significantly affected by the amount of fentanyl (nausea p = 0.519 and vomiting p>0.999)

and morphine (nausea p >.0.999 and vomiting p= >0.99) used intraoperatively.

The correlation between pain represented by VAS and nausea as well as vomiting was

studied. Weak correlation between pain and nausea was noticed at 0 to 2 hours and 6 to

24 hours. There was no correlation between pain and vomiting that was noted.

81

DISCUSSION   The problem of postoperative nausea and vomiting has troubled surgeon and anaesthetist

alike since the advent of general anaesthesia in the early 1800s. With the advent of

modern anaesthetic agents such as sevoflurane and desflurane; newer surgical techniques

such as laparoscopy and robotic surgery and newer antiemetics, this wheel unfortunately

needs to be re-invented and the question re-answered.

As more centers push towards doing laparoscopic cholecystectomy as a day care

procedure with a same day discharge system the use of a efficacious anti-emetic agent

may well answer most of the above mentioned questions.

Ondansetron has generally been considered as the gold standard in preventing and

managing PONV. The addition of dexamethasone has further enhanced the efficacy of

ondansetron. This has been recommended as a treatment recommendation in patients with

moderately high risk of PONV.(4) Palonosetron because of the long t ½ has been

suggested as the alternative choice by the consensus guideline published in 2014. We

wanted to compare a combination of ondansetron plus dexamethasone vs single dose IV

palonosetron for prevention of PONV after laparoscopic cholecystectomy.

The patients with history of motion sickness are thought to have a well-developed reflex

arc for vomiting and are more prone to develop PONV. Therefore they were excluded.

Safety of drugs under study is not clearly established in pregnancy and lactation. Hence

these patients were also excluded. The patients who received antiemetics or drugs with

82

emetic effects, 48 hours before surgery were also excluded, as they would have interfered

with the actions of the study drugs. Patients with known hypersensitivity to palonosetron,

ondansetron or dexamethasone and in whom the surgical procedure was converted to

open cholecystectomy were also excluded due to obvious reasons. All the patients

underwent laparoscopic cholecystectomy by the same team of anesthetists and surgeons.

The anesthetic procedure, except for the test drug, was similar in all the three groups.

Our study was not designed to find out the incidence of PONV after laparoscopic

cholecystectomy. We thought it was unethical to have a placebo arm as the side effect of

PONV is quite distressing and the established guidance clearly recommends prophylactic

anti emetic therapy.(73)

Even though a wide variety of doses of study drugs have been described in literature and

various dose finding studies suggesting the optimal doses as 0.15 mg/kg of

dexamethasone, 0.1 mg/kg of ondansetron and 0.075 mg of palonosetron, we followed

the 2014 consensus guideline for PONV and used 4 mg ondansetron, 4 mg

dexamethasone and 0.075mg of palonosetron.

The baseline demographic data were comparable except for these distribution. The

percentage of females was more in the ondansetron with dexamethasone group. This may

be explained by the fact that this is an interim analysis of the data and may equalize once

the sample size is reached.

83

Our study has shown that the incidence of PONV between the two drugs regimens is

similar during the 1st 24 hours with no statistical difference. The use of rescue antiemetic

was also similar between the two groups. There was no adverse event or drug side effect

documented in either group. The sub group analysis shows similar incidence at 0-2 hours,

2-6 hours and 6-24 hours confirming that the faster onset of iv ondansetron combined

with the longer duration of action of dexamethasone offers similar duration of anti emetic

action of palonosetron.

Our results show good agreement with the consensus guidelines that palonosetron is an

alternative to ondansetron and dexamethasone. The fact that palonosetron can be

administered as a single dose during the surgery and that it can be administered to

patients with endocrine abnormalities such as diabetes (dexamethasone may impair

glycemic control) is an added benefit. It is also known to have a better safety profile than

ondansetron as QT prolongation is not seen with this newer drug.

Palonosetron is available as a 5ml solution with 0.25mg per ml and it costs

Rs.119.Ondansetron costs Rs.8.55 for a 4mg vial and dexamethasone costs Rs.5.23 for

8mg vial. The cost of palonosetron is more than a single dose of ondansetron, which has

recently come out of the patency rules and has become cheap. However it probably

worthwhile due to its better safety profile (no QT prolongation). Even though our study

was not designed to find out the incidence of hyperglycemia and the requirement of

insulin therapy/ risk of wound infection resulting in additional costs it is well proven as a

84

complication of dexamethasone. This indirect effect may be an added financial burden to

the patient.

The analysis also showed weak correlation between PONV and pain. However as

laparoscopic cholecystectomies are usually not very painful procedures it may not be

possible to show accurate correlation as well

The BMI of patients in our study is lower than most western populations so we could not

find a correlation between obesity and PONV.

Two patients in the palonosetron group and 4 patients in the ondansetron plus

dexamethasone group had Apfel score of 4 which indicated high risk of PONV and the

anesthetists should have adopted total intravenous anesthesia with propofol as per the

recommendation of 2014 consensus guidelines. We agree with the statement in the

recommendation that a major problem is the lack of compliance among anesthetists to

follow the PONV guidelines.

In our study we could not find any association between PONV and the dose of opioids.

Similarly we could not find the association between PONV and postoperative pain.

85

LIMITATIONS  

As this is a postgraduate dissertation and the study had to be done within a fixed time

frame of one year, the target sample size was not reached. The sample size that was

targeted prior to the start of the study was 77 patients in each arm. This number was not

reached.

Deviation from protocol was another challenge due to pre-existing bias towards

ondansetron from surgeon and anesthetist alike. Six patients were excluded from

analysis as there was significant protocol violation. Protocol violation were for the

following reasons – unwilling to give promethazine as rescue anti-emetic by the

surgeon(1), the consultant anaesthetist preferring to use succinylcholine over rocuronium

for anticipated difficult airway(1), conversion of laparoscopic cholecystectomies to open

procedures (2) and surgical registrar accidentally writing round the clock ondansetron

orders in the ward(2).

Blood glucose levels as well as delay in wound healing were not studied to see if

dexamethasone had any negative effect on these.

We did not document the incidence of wound infection in the study groups.

None of the patients in study groups developed life-threatening arrhythmia. However we

didn’t do an ECG routinely and looked for long QT prolongation

86

CONCLUSION  

The aim of constructing a RCT and doing this study was to assess the efficacy of

palonosetron a combination of ondansetron and dexamethasone. Even though we could

not complete the study, the results from the analysis of 55 patients suggest that

palonosetron is as efficacious as ondansetron and dexamethasone in preventing post

operative nausea and vomiting. The single pre-induction dosing schedule without the

need of repeating post operatively and better safety profile makes it a cost effective

proposition in patients undergoing laparoscopic cholecystectomy.

87

Future direction and scope for further research

The study will be continued in the department of anesthesia of Christian Medical College

till sample size will be reached.

The single center RCT confers a certain bias, which needs to be mitigated through a well

constructed multi-centered RCT.

88

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63. Habib AS, Keifer JC, Borel CO, White WD, Gan TJ. A comparison of the combination of aprepitant and dexamethasone versus the combination of ondansetron and dexamethasone for the prevention of postoperative nausea and vomiting in patients undergoing craniotomy. AnesthAnalg. 2011 Apr;112(4):813–8.

64. Zhang D, Shen Z, You J, Zhu X, Tang Q-F. Effect of ondansetron in preventing postoperative nausea and vomiting under different conditions of general anesthesia: A preliminary, randomized, controlled study. Ups J Med Sci. 2013 May;118(2):87–90.

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65. Tramèr MR, Moore RA, Reynolds DJ, McQuay HJ. A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting. BMJ. 1997 Apr 12;314(7087):1088–92.

66. Wang X-X, Zhou Q, Pan D-B, Deng H-W, Zhou A-G, Huang F-R, et al. Dexamethasone versus ondansetron in the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic surgery: a meta-analysis of randomized controlled trials. BMC Anesthesiol [Internet]. 2015 Aug 15 [cited 2016 Aug 16];15. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536735/

67. Park SK, Cho EJ. A randomized, double-blind trial of palonosetron compared with ondansetron in preventing postoperative nausea and vomiting after gynaecological laparoscopic surgery. J Int Med Res. 2011;39(2):399–407.

68. Kim YY, Moon SY, Song DU, Lee KH, Song JW, Kwon YE. Comparison of palonosetron with ondansetron in prevention of postoperative nausea and vomiting in patients receiving intravenous patient-controlled analgesia after gynecological laparoscopic surgery. Korean J Anesthesiol. 2013 Feb;64(2):122–6.

69. Bianchin A, De Luca A, Caminiti A. Postoperative vomiting reduction after laparoscopic cholecystectomy with single dose of dexamethasone. Minerva Anestesiol. 2007 Jun;73(6):343–6.

70. Aspinall RL, Goodman NW. Denial of effective treatment and poor quality of clinical information in placebo controlled trials of ondansetron for postoperative nausea and vomiting: a review of published trials. BMJ. 1995 Sep 30;311(7009):844–6.

                           

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ANNEXURES  Annexure  –  1  :  Pro  forma  Pro forma

Department of Anesthesia

Christian Medical College and Hospital

Serial no: Name: Age : Sex: Hospital No.: Weight(in Kg): Height(in cm): Body mass index(wt/ht2): ASA I / II / III / IV Comorbidities – Diabetes Mellitus / Hypertension / COPD / Asthma / Others- History of -

- Smoking Y / N - PONV Y / N - Motion sickness Y / N

Pre operative fasting (in hours): Apfel Score - Intraoperative: Duration of General anaesthesia: (in minutes) Duration of Surgery: (in minutes) Use of Nitrous: Y / N Anesthesia ( MAC) Fentanyl dose- ___mcg Morphine dose- ___mg Reversal Dose: Neostigmine - __mg Glycopyrolate - __mg Anesthetist experience (in years) - Post operative: Opioid used (mg/kg) Post operative: 0 to 2 hours Nausea Retching Vomiting Pain score VAS score - Yes / No Episodes - 1/ 2 / > 2 /

None VAS

Rescue anti emetic used –

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2 to 6 hours Nausea Retching Vomiting Pain score VAS score - Yes / No Episodes - 1/ 2 / > 2 /

None VAS

Rescue anti emetic used – 6 to 24 hours Nausea Retching Vomiting Pain score VAS score - Yes / No Episodes - 1/ 2 / > 2 /

None VAS

Rescue anti emetic used - Overall satisfaction - unsatisfied/ neutral/ fully satisfied

Visual Analogue Score  

 

 

 

 

 

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Annexure  –  2:  Patient  Information  Sheet   Christian Medical College, Vellore Department of Anaesthesia Comparative study of the effects of intravenous palonosetronversus ondansetron and dexamethasone for prevention of postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy: a prospective randomized controlled study Information sheet You are invited to be part of a study to improve the current knowledge regarding the role of anti-emetics during the operation. This study will help other patients who later come to hospital for the same operation. By agreeing to be a part of this study, you will contribute to scientific knowledge. The information collected from you will include

1. History – This includes details regarding your general health and the disease for which you are undergoing the operation.

2. Clinical examination – Besides the regular doctors rounds, the primary investigator will examine you regularly.

You will be examined post operatively by the primary investigator in the ward and data will be collected and analysed.

Whether you accept or decline to be a part of this study will not affect your further treatment at this hospital Although you may not directly benefit by enrolling in the study, you will be contributing to scientific knowledge. You are scheduled to undergo laparoscopic cholecystectomy under general anaesthesia. Considering the type of surgery anesthesia and your risk factors you have a moderate high risk of suffering from nausea and vomiting at the end of surgery. The current recommendations of therapy involves a combination of two drugs dexamethasone and ondansetron. The former has side effects such as bleeding, infection and cause high blood sugars. However it offers protection from nauea and vomiting for 24 hours. The later offers good prophylaxis with side effects like head ache, constipation and rarely arrhythmia. An alternate option will be a drug called palonosetron which has a slightly better safety profile than ondansetron and a long duration of action of 24 to 48hrs. By being a part of the study you will be randomly allotted into two groups. In one group, patients will receive inj. Palenosetron and in the second group patients will receive inj. Ondansetron + dexamethasone. Both of these regimens are well studied and are routinely used during the operation to prevent post operative nausea and vomiting. The operative technique and all other anaesthetic approaches will be similar. If you develop nausea or vomiting at any time you will be treated with droperidol/ promethazine as a rescue medication according to the standard guidelines. We wished to study this in detail and are therefore conducting a scientific study.

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All details including personal data, assessment of the doctor during and after the operation will be kept confidential. We aim to include about 60 people from this hospital in this study in the next one years. Participation in this study is purely voluntary, and you can withdraw from the study at any time and that refusal to participate will not involve any penalty or loss of benefits to which you are otherwise entitled.                                                  

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Annexure  –  3:  Consent  Form   Informed consent form to participate in a clinical trial

Consent to take part in a clinical trial

Study Title: Comparative study of the effects of intravenous palonosetronversus ondansetron and dexamethasone for prevention of postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy: a prospective randomized controlled study Study Number: Participant’s name: Date of Birth / Age (in years): I_____________________________________________________________ ___________, son/daughter of ___________________________________ (Please tick boxes) Declare that I have read the information sheet provide to me regarding this study and have clarified any doubts that I had. [ ] I also understand that my participation in this study is entirely voluntary and that I am free to withdraw permission to continue to participate at any time without affecting my usual treatment or my legal rights [ ] I also understand that neither I, nor my doctors, will will know which anti-emetic I will receive(palonosetron or ondansetron + dexamethasone)[ ] I understand that I will receive free treatment for any study related injury or adverse event but I will not receive and other financial compensation [ ] I understand that the study staff and institutional ethics committee members will not need my permission to look at my health records even if I withdraw from the trial. I agree to this access [ ] I understand that my identity will not be revealed in any information released to third parties or published [ ] I agree to pay for any investigation routinely warranted for my treatment [ ] I voluntarily agree to take part in this study [ ] Name: Signature: Date: Name of witness: Relation to participant: Date: Name and Signature of the Doctor  

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Annexure  –  4:  Ethics  committee  approval  

 

 

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101

                           

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Annexure  –  5:  Data  sheet  

 

sno group age sex wt ht BMI ASA DiabetesMellitusHypertensionHypothyroidCOPD_AsthmaSmoking PONV MotionSicknessFasting_hrs Apfel_ScoreDuration_of_GA_mins

Duration_of_surgery_mins

1 2 23 1 66 166 24 2 2 2 2 2 2 2 2 14 2 220 1902 1 37 2 38 162 22.1 1 2 2 2 2 2 1 2 12 4 105 803 1 23 2 64 155 26.6 2 2 2 2 1 2 2 2 3 210 1654 25 1 38 2 74 160 28.9 2 2 2 1 2 2 2 2 9 3 165 1406 2 31 2 44 142 21.8 1 2 2 2 2 2 2 2 12 3 195 1507 18 29 110 2 61 2 67 148 30.6 2 1 1 2 2 2 2 2 12 3 300 27011 2 50 2 59 161 32.8 1 2 2 2 2 2 2 2 7.5 3 60 4512 113 1 48 2 55 153 23.5 2 2 1 2 2 2 2 2 7 3 180 15014 1 48 1 81 179 25.3 2 1 2 2 2 1 2 2 18 1 120 10015 2 44 2 65 158 26 2 1 1 2 2 2 2 2 3 120 10016 2 26 2 55 148 25.1 1 2 2 2 2 2 2 2 4 317 2 43 2 43 159 17 1 2 2 2 2 2 2 2 10 318 2 42 2 65 156 26.7 1 2 2 2 2 2 2 2 3 105 7519 1 41 2 53 154 22.3 1 2 2 2 2 2 2 2 18.5 3 105 9020 1 45 2 87 150 38.7 2 2 2 1 2 2 2 2 8.5 3 160 14021 2 57 2 65 148 29.7 2 1 1 2 2 2 2 2 3 120 12022 1 44 1 60 170 20.8 1 2 2 2 2 2 2 2 13.5 2 90 9023 1 24 2 55 152 23.8 1 2 2 2 2 2 2 2 14 3 120 12024 2 47 2 55 145 26.2 1 2 2 2 2 2 2 2 3 255 21025 2 39 2 58 151 25.4 1 2 2 2 2 2 2 1 4 180 15026 1 38 2 50 153 21.4 1 2 2 2 2 2 2 2 15 3 210 17527 2 2 57 145 27.1 1 2 2 2 2 2 2 2 14 3 190 16528 1 38 2 74 162 28.2 1 2 2 2 2 2 2 2 8 3 190 17029 2 38 2 69 152 29.9 1 2 2 2 2 2 2 2 9 3 240 19530 1 50 1 70 175 22.9 2 2 1 2 2 2 2 2 3 140 12031 1 42 1 55 170 19 1 2 2 2 2 1 2 2 16.5 2 110 6032 2 21 2 85 162 32.4 1 2 2 2 2 2 1 1 9 4 150 12033 1 48 2 75 149 33.8 2 1 1 2 2 2 2 2 19.5 3 220 17034 2 26 2 75 167 26.9 1 2 2 2 2 2 2 2 12 3 190 16035 1 41 2 58 153 24.8 1 2 2 2 2 2 1 2 4 90 7036 2 39 2 70 155 29.1 1 2 2 2 2 2 2 2 3 75 6037 2 48 2 52 153 22.2 1 2 2 2 2 2 2 2 9.5 3 187 14538 1 36 2 65 163 24.5 1 2 2 2 2 2 2 2 10.5 3 180 15039 1 47 2 63 146 29.6 1 2 2 2 2 2 2 2 12.75 3 135 10540 2 42 2 59 150 26.2 1 2 2 2 2 2 2 2 10 3 120 7541 1 51 1 75 173 25.1 1 2 2 2 2 2 2 1 17 2 110 9042 1 31 1 84 171 28.7 1 2 2 2 2 2 2 2 13 2 240 21043 2 56 2 65 155 27.1 2 1 1 1 2 2 2 2 3 80 11044 2 44 2 65 155 27.1 2 2 1 2 2 2 2 2 14 3 120 9045 1 28 1 60 170 20.5 2 2 2 2 2 2 2 2 11 2 135 9046 1 51 1 90 175 29.4 2 1 2 2 2 1 2 2 15 1 130 10047 2 36 2 60 154 25.3 1 2 2 2 2 2 2 2 348 2 44 2 75 155 31.2 2 1 2 2 2 2 2 2 11 3 200 17049 1 35 2 38 158 15.2 1 2 2 2 2 2 2 2 19 3 180 14550 2 32 2 80 160 31.3 2 2 2 2 1 2 2 2 9 3 165 14051 1 50 2 44 152 19 2 2 1 2 2 2 2 2 3 125 10052 2 50 2 62 148 28.3 1 2 2 2 2 2 2 2 14 3 190 15053 2 45 1 74 157 30 1 2 2 2 2 1 2 2 10 154 1 46 2 76 151 33.3 2 2 2 1 2 2 2 2 10 3 130 11555 156 2 41 2 36 139 18.6 1 2 2 2 2 2 2 2 11 3 240 22057 2 21 2 54 158 21.6 1 2 2 2 1 2 2 2 10 2 150 10558 1 23 2 50 156 20.5 1 2 2 2 2 2 2 2 17 3 120 9059 1 58 1 45 145 21.4 1 2 2 2 2 2 2 2 9.5 1 270 23060 1 29 2 70 168 24.8 2 2 2 2 2 2 2 2 12.5 2 120 10061 2 37 2 50 147 23.1 2 2 2 2 2 2 2 1 10.5 4 235 19062 263 2 35 2 53 154 22.3 1 2 2 2 2 2 1 2 11 4 180 150

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Nitrous MAC FentanylFentany_mcg_per_kg Morphine

Morphine_mg_per_kg NeostigmineGlycopyrolateExperiecne_yrsPostop_opioidsNausea_t1_VASRetching_t1Vomiting_t1Pain_t1_VASRescue_med_t1Nausea_t2_VAS

2 1 140 2.121212121 5 0.0757575762 0.9 160 4.210526316 6 0.157894737 2.5 0.4 1 2 0 2 4 6 2 02 1 120 1.875 0 2.5 0.4 2 0 2 4 0 2 1

2 1 180 2.432432432 6 0.081081081 3 0.6 2 2 0 2 4 3 2 02 1 100 2.272727273 4 0.090909091 2.5 0.4 1 0 2 4 0 2 0

#DIV/0!2 1 120 1.791044776 9 0.134328358 2.5 0.4 7 2 0 2 4 0 2 02 1.5 200 3.389830508 4 0.06779661 2.5 1.2 2 0 1 4 0 1 0

2 1 100 1.818181818 6 0.109090909 2.5 0.4 1 2 0 2 4 0 2 02 0.8 200 2.469135802 7 0.086419753 2.5 0.4 1 2 0 2 4 0 2 02 0.9 200 3.076923077 6.5 0.1 2.5 0.4 2 2 0 2 4 3 2 02 0.9 0 5.5 0.1 2.5 0.4 2 1 0 2 4 0 2 82 1 140 3.255813953 0 0 2 0.3 17 1 0 2 4 0 2 02 0.9 120 1.846153846 0 2.5 0.4 1 2 2 2 4 3 2 02 1 160 3.018867925 6 0.113207547 2.5 0.4 18 2 0 2 4 0 2 02 1 200 2.298850575 5 0.057471264 3.5 0.6 18 1 0 2 4 0 2 02 0.9 200 3.076923077 8 0.123076923 2.5 0.4 1 0 2 4 0 2 02 0.8 120 2 5 0.083333333 2.5 0.4 2 0 2 4 0 2 02 0.9 200 3.636363636 6 0.109090909 2.5 0.4 9 2 0 2 4 0 2 32 1 260 4.727272727 5 0.090909091 2.5 0.4 2 0 2 4 0 2 22 1 150 2.586206897 5 0.086206897 2.5 0.4 2 0 2 4 0 2 32 1 175 3.5 5 0.1 2.5 0.4 6 2 0 2 2 0 1 12 1 150 2.631578947 6 0.105263158 2.5 0.4 2 0 2 4 0 2 02 0.9 100 1.351351351 4 0.054054054 2.5 0.4 12 2 0 2 4 0 2 02 0.9 170 2.463768116 4 0.057971014 2.5 0.4 2 0 2 4 0 2 02 1 150 2.142857143 5 0.071428571 2.5 0.4 2 0 2 4 0 2 02 1 140 2.545454545 5 0.090909091 2.5 0.4 2 0 2 4 0 2 02 0.9 200 2.352941176 7 0.082352941 2.5 0.4 1 7 1 4 2 2 02 1 150 2 5 0.066666667 2.5 0.4 6 1 0 2 4 0 2 12 1 150 2 0 0 2.5 0.4 3 2 0 2 4 2 2 02 1 120 2.068965517 4 0.068965517 2 0.4 2 0 2 4 0 2 02 1 140 2 0 2.5 0.4 6 2 5 1 4 6 2 62 1 100 1.923076923 4.5 0.086538462 2.5 0.4 1 0 2 4 0 2 02 1 100 1.538461538 5 0.076923077 2.5 0.4 4 2 0 2 4 0 2 02 1 100 1.587301587 5 0.079365079 2.5 0.4 4 2 0 2 4 0 2 02 0.9 100 1.694915254 4 0.06779661 3 0.5 5 1 0 2 4 4 2 02 0.7 100 1.333333333 3 0.04 2.5 0.4 15 2 0 2 4 0 2 02 1 150 1.785714286 7 0.083333333 2.5 0.4 2 2 0 2 4 0 2 02 0.9 150 2.307692308 5 0.076923077 2.5 0.4 2 0 2 4 0 2 02 1 150 2.307692308 0 0 3.5 0.5 1 2 0 2 4 0 2 02 1 100 1.666666667 0 0 2.5 0.4 1 2 0 2 4 0 2 02 0.9 100 1.111111111 5 0.055555556 2.5 0.4 8 2 0 2 4 0 2 0

0 0 2 0 2 4 0 2 02 0.9 130 1.733333333 4 0.053333333 2.5 0.4 8 2 0 2 4 0 2 02 1 120 3.157894737 0 2 0.4 8 2 0 2 4 2 2 02 0.8 200 2.5 8 0.1 2.5 0.4 26 2 0 2 4 2 2 32 0.8 130 2.954545455 3 0.068181818 2.5 0.4 1.5 2 0 2 4 2 2 02 1 140 2.258064516 4 0.064516129 2.5 0.4 2 0 2 4 2 2 02 0.8 160 2.162162162 0 2.5 0.4 0 2 4 0 2 02 0.8 140 1.842105263 4 0.052631579 2.5 0.4 2 2 0 2 4 2 0

#DIV/0! #DIV/0!2 1 100 2.777777778 3 0.083333333 2 0.4 6 2 0 2 4 2 2 02 1 150 2.777777778 0 2.5 0.4 5 2 0 2 4 0 2 02 1 100 2 5 0.1 2.5 0.4 1 0 2 4 0 2 02 0.9 100 2.222222222 4 0.088888889 2.5 0.4 10 1 0 2 4 0 2 02 0.9 100 1.428571429 5 0.071428571 2.5 0.4 2 2 0 2 4 0 2 02 0.9 140 2.8 4 0.08 2.5 0.4 3 2 6 2 4 0 1 0

2 0.9 140 2.641509434 5 0.094339623 2.5 0.4 2 7 2 4 0 1 0

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Retching_t2 Vomit_t2 Pain_t2_VASRescu_t2 Nausea_t3_VASRetching_t3 Vomit_t3 Pain_t3_VASRescu_t3 Satisfaction

2 4 7 2 0 1 4 4 1 20 1 1 2 0 2 4 1 2

2 4 1 2 0 2 4 0 22 4 1 2 0 2 4 4 2

2 4 3 2 0 2 4 0 2 32 4 0 2 0 2 1 0 1 3

2 4 0 2 2 2 4 2 2 32 4 0 2 0 2 4 1 2 32 4 2 2 0 2 4 2 21 2 2 1 0 2 1 3 12 4 2 2 0 2 4 0 2 32 4 4 2 0 2 1 2 2 32 4 2 2 0 2 4 2 2 32 4 4 2 0 2 4 3 2 32 4 2 2 0 1 3 3 1 22 4 2 2 2 2 1 2 2 32 2 2 1 0 2 4 2 2 22 4 2 2 0 2 4 3 2 31 1 3 1 0 2 4 3 2 22 4 2 2 0 2 4 2 2 32 4 2 2 0 2 4 2 22 4 0 2 0 2 4 2 2 32 4 3 2 0 2 4 2 22 4 2 2 0 2 4 1 2 32 4 0 2 0 1 1 2 22 4 2 2 8 2 4 4 22 1 2 2 1 2 1 3 1 22 4 2 2 0 2 4 2 2 32 4 3 2 0 2 4 2 2 32 4 6 2 6 2 4 6 2 22 4 2 2 0 2 2 2 22 4 0 2 0 2 4 0 2 32 4 1 2 0 2 4 2 22 4 2 2 3 1 1 2 1 22 4 3 2 0 2 4 2 2 32 4 1 2 0 2 4 1 2 32 4 3 2 3 2 1 2 1 32 4 0 2 0 2 4 0 2 32 4 2 2 0 2 4 8 2 32 4 2 2 2 1 4 2 2 22 4 2 2 0 2 4 3 2 32 4 2 2 3 1 2 3 1 12 4 2 2 0 2 4 2 2 31 2 0 1 0 2 4 2 2 32 4 2 2 0 2 4 1 2 32 4 2 4 0 2 4 2 2 32 4 1 2 0 2 4 2 2 32 4 2 2 0 2 4 2 2 3

2 4 2 2 0 2 4 2 2 32 4 0 2 0 2 4 2 0 22 4 1 2 0 2 4 4 2 32 4 0 2 0 2 4 5 2 32 4 1 2 0 2 4 2 2 32 4 2 2 0 2 4 3 2 3

2 4 0 2 0 2 4 2 2 3

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