i

COMPARATIVE TRIAL OF COMBINED METOCLOPRAMIDE AND

DEXAMETHASONE VERSUS DEXAMETHASONE IN POSTOPERATIVE

NAUSEA AND VOMITING IN GYNAECOLOGICAL SURGERY

A DISSERTATION SUBMITTED

BY

OREWOLE OLAYINKA TESLEEM

MBBS (Ibadan)

DEPARTMENT OF ANAESTHESIA

UNIVERSITY OF ILORIN TEACHING HOSPITAL,

ILORIN, NIGERIA.

TO

THE NATIONAL POST-GRADUATE MEDICAL COLLEGE OF NIGERIA IN

FULFILMENT OF THE REQUIREMENTS FOR THE AWARD OF THE

FELLOWSHIP OF THE MEDICAL COLLEGE IN ANAESTHESIA

(FMCA)

MAY 2011

ii

DECLARATION

This research work is hereby declared as original unless otherwise acknowledged. It

has never been presented to any other academic body or college for a Fellowship,

neither has it been submitted for presentation or publication.

..............................

Dr. O. T. Orewole

iii

CERTIFICATION

This is to certify that Dr O. Tesleem Orewole carried out this work titled “Comparative

trial of combined metoclopramide and dexamethasone versus dexamethasone in

postoperative nausea and vomiting in gynaecological surgery” at University of Ilorin

Teaching Hospital, Ilorin, Nigeria under our supervision.

................................

Dr. B.O. Bolaji

MBBS; FMCA

Senior Lecturer/Consultant

Department of Anaesthesia

University Of Ilorin Teaching Hospital

....................................

Dr. I.K. Kolawole

MBBS; FWACS

Lecturer/Consultant

Department of Anaesthesia

University Of Ilorin Teaching Hospital

iv

ACKNOWLEDGEMENT

I express my heartfelt gratitude to my supervisors, Dr. B.O. Bolaji and Dr. I.K. Kolawole

for their immense support and guidance throughout the period of conducting this research

work.

I equally appreciate all the efforts of other Consultants in the Department of

Anaesthesia, University of Ilorin Teaching Hospital, Ilorin, (UITH) for their invaluable

contributions to my residency training. I also thank all the other doctors who assisted me in

one way or the other in this study.

I appreciate the enabling environment provided by the UITH administration, the

Residency Training Committee and the administrative staff of Anaesthesia Department UITH

for my successful training.

My final appreciation goes to my wife and children for their cooperation and understanding

during the period of my residency training. Almighty God will abundantly reward you all.

Dr. O.T. Orewole.

v

TABLE OF CONTENTS

Title Page i

Declaration ii

Certification iii

Acknowledgement iv

Table of contents v

List of Tables vi

List of Figures vii

List of Abbreviations viii

SUMMARY 1

CHAPTER ONE

Introduction 3

Objectives of the Study 5

CHAPTER TWO

Literature Review 7

CHAPTER THREE

Patients and Methods 25

CHAPTER FOUR

Results 34

CHAPTER FIVE

Discussion 49

Conclusion and Recommendations 59

Limitations of the Study 60

REFERENCES 61

APPENDICES 74

vi

LIST OF TABLES

Tables

1. Patient Demographics

2. Types of Operation

3. Incidence of Postoperative Nausea and Vomiting (PONV) (0-24 h)

4. Incidence of Early and Late Postoperative Nausea and Vomiting

5. Incidence of PONV compared with Obesity and Age

6. Incidence of Pain in Study Groups

7. Incidence of PONV and Postoperative Pain in 24 hrs

8. Adverse Effects

vii

LIST OF FIGURES

1. Bar chart showing incidence of Nausea and Vomiting during the Postoperative

period of 24 hours- Figure 1

2. Bar chart showing the incidence of PONV during the postoperative period of

0-4 hours- Figure 2

3. Bar chart showing Incidence of PONV during the Post-operative period of 5-

24 hours.- Figure 3

viii

LIST OF ABBREVIATIONS

ASA - America Society of Anesthesiologists

ARR - Attributable Relative Risk

BP - Blood Pressure

BMI - Body Mass Index

BWt - Body weight

CTZ - Chemoreceptor Trigger Zone

DOA - Duration of Anaesthesia

DOS - Duration of Surgery

EC - Emetic centre

e.g. - Example Given

ECG - Electrocardiogram

ENT - Ear, Nose and Throat

h - hour

HA - Alternative Hypothesis

HR - Heart Rate

Ho - Null Hypothesis

ix

5-HT - 5-Hydroxytryptamine

IT - Incidence in the treatment group

IC - Incidence in the control group

i.v. - Intravenous

i.e. - That is

i.m. - Intramuscular

NS - Not Significant

n - Number

NK - Neurokinin

NNT - Number needed to treat

NRAs - Neurokinin Receptor Antagonists

NTS - Nucleus Tractus Solitarius

PACU - Post Anaesthesia Care Unit

PCV - Packed Cell Volume

PONV - Postoperative Nausea and vomiting

PR - Pulse Rate

RR - Respiratory Rate

RAs - Receptor Antagonists

x

SD - Standard Deviation

SPSS - Statistical Package for the Social Sciences

SaO2 - Oxygen Saturation

VAS - Visual Analogue Scale

Vs - Versus

Yr - Years

> - Greater than

< - Less than

≥ - Equal to or greater than

xi

SUMMARY

Background: Metoclopramide is a drug that has been used in the dose of 10 mg iv for

postoperative nausea and vomiting (PONV) prophylaxis for many years and has been

reported to be ineffective at this dose. That a higher dose of this drug, when used in

combination with 8 mg dexamethasone, is more effective when compared with 8 mg

dexamethasone only is worth validating and this study was designed to do so.

Objective : To compare the effectiveness of adding 50 mg metoclopramide (in two divided

doses) to 8 mg intravenous dose of dexamethasone versus 8 mg dexamethasone only as a

prophylactic anti-emetic in gynaecological surgery under spinal anaesthesia at University of

Ilorin Teaching Hospital, Ilorin.

Patients and methods: This was a prospective, controlled study in which seventy-four ASA

physical status 1 and 2 eligible gynaecological patients with 37 patients per group, were

randomly allocated to either the metoclopramide and dexamethasone group or the

dexamethasone only group for the purpose of this study. A simple random technique of

balloting was used for randomization of the study population. Every participant was

preloaded with one litre of normal saline. Spinal Anaesthesia was established with 3 ml of

0.5 percent hyperbaric bupivacaine and 25 µg of fentanyl. Both groups received 8 mg

dexamethasone iv immediately after induction of spinal anaesthesia. The test group

received 25 mg of metoclopramide iv after establishment of spinal anaesthesia and another

dose of 25 mg metoclopramide iv at the end of surgery while the control group received

normal saline at both times respectively.

xii

Data on PONV were collated for 24 hours postoperatively using a study pro-forma. Vital

signs such as pulse, SaO2 and BP as well as postoperative pain were monitored according to

the study protocol.

Results: During the 24-hour period of the study, patients in the metoclopramide group were

found to have a lower incidence of PONV (11% Vs 44%, p=0.003). This is statistically

significant. During the early postoperative period (0-4 h) and late period (5-24 h), the

incidence of PONV remained higher in the dexamethasone only group; (30.6% Vs 8.3%) and

(13.9% Vs 2.8%) respectively. The differences between the two groups were statistically

significant for 0-4 h (P = 0.02) but not significant for 5-24 h (P = 0.09).

Conclusion: Intravenous 50 mg metoclopramide in two divided doses added to 8 mg

dexamethasone is more effective than 8 mg dexamethasone only in reducing the incidence

of PONV in women undergoing gynaecological surgery under spinal anaesthesia.

CHAPTER ONE

xiii

INTRODUCTION

Although, many physicians continue to view postoperative nausea and vomiting (PONV) as a

minor complication that poses little problem, most patients view this complication as more

debilitating than the surgery itself.1 Patients often rate postoperative nausea and vomiting

as worse than postoperative pain.2, 3 Prevention of postoperative nausea and vomiting has

been found to improve satisfaction among patients who are likely to experience them.4 This

complication is not only unpleasant and aesthetically displeasing to patients and their care

givers but, when severe, is associated with electrolyte imbalance, dehydration, bleeding,

wound dehiscence and rarely, pulmonary aspiration of gastric contents.1

Most gynaecological surgeries are associated with high incidence of PONV.1 In Ibadan,

Nigeria, the incidence of post operative nausea and vomiting within twenty four hours of

surgery was 14.6% and 19.6%, respectively with female preponderance (66% of the patients

who vomited were females) (p < 0.05).5 At the University of Ilorin Teaching Hospital, the

incidence of PONV in gynaecological surgery was put at 30%.6

The efficacy of antiemetics is known to be improved by combining two or three

interventions.7,8 An example of such combination is dexamethasone and metoclopramide.8

Tzeng et al compared low-dose dexamethasone with metoclopramide and normal saline

and noticed that the total frequency of nausea and vomiting in the dexamethasone group

was significantly lower than the metoclopramide and saline groups.9

Jan Wallenborn et al also investigated the efficacy and safety of three doses of

metoclopramide (10 mg, 25 mg, and 50 mg) on the assumption that each patient would

receive basic antiemetic prophylaxis of 8 mg dexamethasone.8They found that 25 mg or 50

xiv

mg metoclopramide added to the basic intervention of 8 mg dexamethasone was effective,

safe, and cheap. Fifty milligrams metoclopramide was however found to be more effective

than 25 mg over 24 hours postoperatively. In their study the 50 mg was given as a single

dose intra-operatively but suggested that if given in divided doses of 25 mg intra-

operatively and 25 mg immediately after surgery it would be as effective and may further

reduce the side effect of this drug.

There is the need for a similar but modified study in this environment to verify this

research and determine if indeed dividing the 50 mg metoclopramide into two equal doses

will produce additive antiemetic effect with minimal adverse effects. This is because both

metoclopramide and dexamethasone are relatively cheap and readily available in our

environment.

THE OBJECTIVES OF THE STUDY

xv

GENERAL OBJECTIVE

The objective of the study was to find out if both 50 mg metoclopramide in two divided

doses and 8 mg dexamethasone would be more effective than 8 mg dexamethasone as

prophylactic antiemetic in patients undergoing gynaecological surgery.

SPECIFIC OBJECTIVES

1. To determine the efficacy of a combination of 50 mg metoclopramide (in two divided

doses) and 8 mg dexamethasone in the prevention of PONV in patients undergoing

gynaecological surgery.

2. To assess the side effects of metoclopramide and dexamethasone used in the study.

NULL-HYPOTHESIS

xvi

The incidence(IT) of PONV in patients given 50 mg metoclopramide in two divided dose and

8 mg dexamethasone intravenously is the same as for those given 8 mg dexamethasone

only .i.e. Ho: IT=IC

ALTERNATIVE HYPOTHESIS

The incidence rate of PONV in the treatment group is not equal to those in the control group

.i.e. HA: IT ≠ IC

Where IT = incidence in treatment group

IC = incidence in the control group

CHAPTER TWO

xvii

LITERATURE REVEIW

POSTOPERATIVE NAUSEA AND VOMITING

Postoperative nausea and vomiting (PONV) is a very distressing and unpleasant condition

regarded as one of the common causes of morbidity in postoperative patients.10

Identification of risk factors may lead to adoption of preventive measures to reduce the

morbidity in patients that are highly predisposed to PONV. Patients undergoing major

gynaecological surgery belong to this group of patients that are prone to developing

PONV.11

PHYSIOLOGY OF NAUSEA AND VOMITING

Nausea and vomiting ordinarily are important defence mechanisms against ingested toxins

but in the perioperative period, they are unpleasant, distressing and unacceptable to the

patient. Nausea is the subjective sensation of the need to vomit. It is the conscious

recognition of excitation of an area in the medulla that is associated with vomiting (emetic)

centre. Retching is said to occur when no stomach contents are expelled despite expulsive

muscular efforts while vomiting is the forced expulsion of upper gastrointestinal contents

through the mouth. Vomiting is mediated by a central coordinating “vomiting centre”,

which is located in the lateral reticular formation of the medulla, close to the fourth

ventricle.11 It is called the parvicellular reticular formation, or the emetic centre (EC), and it

receives inputs from the pharynx, gastro-intestinal tract, mediastinum, cerebellum,

brainstem centres, higher cortical centres (e.g. the visual, gustatory, olfactory & vestibular

centres), and the chemoreceptor trigger zone (CTZ).11

xviii

The CTZ is in the area postrema, on the lateral walls of the fourth ventricle near the

obex.1 Its activity is modified by a variety of receptors, including dopaminergic, histaminic,

muscarinic, serotonergic and opioid receptors.1,12,13 The CTZ is not protected by the blood-

brain barrier and can therefore be activated by chemical stimuli received through the

systemic circulation as well as the cerebrospinal fluid.1 Peripheral 5-HT3 receptors are also

present at the mucosal vagal afferents.14 All these receptors are thought to relay

transmission to the emetic centre. The EC receives this input, and initiates the vomiting

sequence, in a rather complex interplay of various systems.12 The cerebral cortex is

stimulated by smell and physiological stresses.1 Motion can stimulate the vestibular

apparatus, which may also stimulate the CTZ. The neurovegitative system is sensitive

principally to gastrointestinal stimulation and blocking of impulses from the CTZ does not

prevent vomiting due to irritative stimuli arising from the gastrointestinal stimulation.1

Emetic efferents are transmitted via cranial nerves V, VII, IX, X and XII to the gastrointestinal

tract and through the spinal nerves to the diaphragm muscles to cause the mechanical act

of vomiting. Motor changes during vomiting involve both respiratory and gastrointestinal

muscles. Before expulsion of the gastric contents, the glottis is closed, the diaphragm and

the muscles of the abdominal wall contract whereas the oesophagus contracts

longitudinally and the gastro-oesophageal sphincter zone relaxes. This motor act is

coordinated by brainstem structures.15

The areas in the CNS associated with balance, vasomotor activity, salivation, respiration

and bulbar control are located near, and have innervations to, the vomiting centre. The

close proximity of these areas to the vomiting centre corresponds to the physiological

xix

reactions often seen with PONV, such as salivation, increased swallowing, sweating, pallor,

tachypnoea, tachycardia, cardiac dysrhythmias and motion sickness.12

AETIOLOGY OF PONV

The aetiology of PONV is multifactorial in nature.16 These are related to the patient factors,

surgical procedure, and/or the anaesthetic technique used. The contribution of each factor

depends on the clinical situation.

PATIENT RELATED FACTORS

Age

Cohen et al showed that the incidence of vomiting is no doubt higher in paediatric age

groups when compared to adults.17Though relationship between age and emesis is not as

clear-cut as that between gender and PONV in the adult population. It is thought to be due

to unique paediatric characteristics like fear, pain, anxiety and peculiar surgical procedures

e.g. strabismus, adeno-tonsillectomies and testicular surgery.17 The risk of PONV ranges

from 5% (infants less than 12 months), 20% (children 1-5 years old) to about 34% in 6-10

years old before a plateau is reached.18 Elderly patients are less likely to experience PONV.

Sinclair et al reported that the incidence of PONV decreased after age 50 years. There is a

likelihood of decrease of PONV by 13% for each 10-year increase in age.11

xx

Gender

Probably the strongest risk factor for PONV identified is female gender from puberty on and

no study has contradicted this finding.19 Most workers on PONV have demonstrated a

higher incidence in adult female when compared to adult male patients.2, 5- 6 This gender

difference is not noted in the preadolescent age group or in geriatric, all these suggesting

female hormonal factor interplay.12

Ethnicity

Ethnicity has been proposed as a risk factor for the development of PONV.20, 21 A meta-

analysis of PONV after gynaecological surgery and studies involving laboratory-induced

motion sickness suggest that ethnicity (Dutch or English versus Scandinavian and Chinese or

Asian-American versus Caucasian- or African-American, respectively) could be a PONV risk

factor.20, 21 Recently, Reitze et al were able to demonstrate that black South African ethnicity

significantly reduces the incidence of PONV.22 They found that, despite that there were

more PONV risk factors in the African group (younger age, fewer smokers, less

intraoperative antiemetics, and more intraoperative morphine administration), the

incidence was still lower than that of the non-African group. The role of the hepatic P-450

cytochrome system and in particular the CYP1A2 and CYP2E1 isoenzymes has been

examined as a potential factor in the aetiology of PONV.23 It has been postulated that

volatile metabolism by the CYP2E1 poor metabolizer phenotype may be a risk factor for the

development of PONV. This allele has not been identified in black South Africans in the

province in which the South African study was conducted, possibly explaining the lower

xxi

incidence of PONV observed.24 Variations related to opioid sensitivity and metabolism may

offer additional explanations for these findings.25 Postoperative opioid administration was

identified as an independent risk factor in the non-African group but not in the African

group, further supporting this hypothesis.22

Anxiety

Impending surgery is often associated with anxiety and increased levels of endogenous

catecholamines. Catecholamine releasing anaesthetics like ether, cyclopropane and

ketamine are known to be highly emetic. Exogenous injection of adrenaline and nor-

adrenaline into 3rd and 4th ventricles results in vomiting whereas saline injection does not

and thus suggesting a role for catecholamines in vomiting.26 Swallowing of large amounts of

air involuntarily before surgery by anxious patients, causing gastric distension may lead to

PONV.27 Van den Bosch JE established that high levels of preoperative anxiety among adult

surgical inpatients are associated with PONV.28 Mirtazapine is a new antidepressant that

reduces anxiety by blocking 5-HT2 and 5-HT3 receptors. Premedication of patients with this

drug, 1 hr before surgery has been shown by Chin-Chuan et al to reduce postoperative

nausea and vomiting.29

Fasting status & dehydration

xxii

Abdominal vagal stimulation by food in the stomach and the central effects of anaesthetic

agents may increase emetic load and drive. The vagal stimulation caused by food is both by

its chemical composition and by volume. PONV risk is increased if anaesthesia is induced in a

patient with recently ingested food and in those with delayed gastric emptying for whatever

reasons.10 It has also been shown by Ali et al that correcting dehydration reduces

postoperative nausea and vomiting.30 In a study conducted by Rob Schuster et al, it was also

concluded that patients who did not experience PONV received a larger volume of

intravenous fluid at a faster rate than similar patients who complained of PONV.31

Body habitus

No study has demonstrated any direct relationship between BMI and the incidence of

PONV.32 However it has been observed that the incidence of PONV is higher in obese

patients i.e. when the body mass index (BMI) is greater than 30kg/m2.33

History of motion sickness and / or PONV and smoking

Individuals with history of motion sickness and / or PONV may have a well-developed reflex

arc sensitized by previous emetic stimuli, which predisposes them to vomiting.27 Sinclair et

al reported that smoking decreased the likelihood of PONV by 34%11. Apfel and co-

workers33as well as Hough and co-workers34 equally identified smoking as protective factor

against PONV in their studies. The mechanism of the antiemetic effect of nicotine is not

completely understood. Presumably nicotine inhibits serotonin 5-HT3 receptors which may

xxiii

affect nausea and vomiting.35 A stimulating effect on gastrointestinal motility could

influence symptoms of nausea and vomiting. Transdermal application of nicotine in healthy

non-smoking volunteers accelerates the motility of rectosigmoid colon.36

ANAESTHESIA RELATED FACTORS

Mask Ventilation

Mask ventilation, especially in the hand of an inexperienced anaesthetist, often results in

gastro-intestinal distension and possible stimulation of the afferent emetic pathway

especially leading to PONV.27

Premedication

Certain drugs used in premedication (anticholinergics and opioids) have been implicated in

the aetiology of PONV. Administration of opioids is also known to be associated with

increased incidence of PONV.12 Soyannwo et al also found use of pethidine and morphine to

be associated with nausea and vomiting (P< 0.05).8 The emetic actions of opioids are

multifactorial in nature. Opioid receptors (probably mu) present in the area postrema have

been implicated.12 Addition of atropine and hyoscine to opioids has been shown to reduce

postoperative vomiting.37

Clonidine can reduce PONV in children after strabismus repair.38

Inhalational Anaesthetic Agents

xxiv

Profound PONV has long been associated with the anaesthetic drugs like ether and

cyclopropane.27 It has been found that volatile anaesthetics are a main cause of early PONV

and no significant difference exists among halothane, enflurane and isoflurane with respect

to PONV.12,39 Recent study however established that incidence of PONV after paediatric

strabismus surgery using sevoflurane anaesthesia was relatively low and combining

remifentanyl with sevoflurane did not further increase the incidence.40 The use of nitrous

oxide has been associated with increases in the incidence of PONV.1

Intravenous Anaesthetic Agents

Propofol is associated with a lower incidence of postoperative nausea and vomiting when it

is used for induction of anaesthesia, compared with thiopentone.41The mechanism of

propofol for reducing PONV is unknown. Among intravenous agents etomidate and

ketamine are particularly associated with a high incidence of nausea and vomiting.42

Intraoperative Analgesia

Ketorolac has been reported to be as effective as morphine and fentanyl in the prevention

of postoperative pain following day case surgery and this and other non-steroidal anti-

inflammatory analgesics are associated with lower incidence of PONV.43

Muscle Relaxants

xxv

These agents have not been found to be emetogenic in anyway. Some authors reported no

significant difference in PONV between those who received a reversal agent and those who

did not.11,20

Regional Anaesthesia

The potential risk of PONV after regional technique is lower when compared to general

anaesthesia.12 Many studies investigating this time-honoured dictum in a controlled manner

mostly, but not unanimously, confirmed it.44-47 PONV after central neuraxial blockade is

greater than after peripheral nerve blocks.10 Several different mechanisms may play a role in

causing PONV in patients who receive regional anaesthesia.48 In a retrospective analysis,

Crocker and Vandam found that hypotension (systolic blood pressure< 80mmHg), a block

higher than the fifth thoracic segment, and the anaesthetic mixture (e.g. addition of

vasoconstrictors to the local anaesthetic) increased incidence of nausea and vomiting during

spinal anaesthesia.49 The prospective work of Carpenter et al 50in a similar setting confirmed

these findings. Nausea and vomiting are not among the cardinal signs and symptoms of

toxicity of the currently used local anaesthetics when infused systemically, although they

may occur in the context of general cerebral toxicity.51 Consequently, they are usually not

considered as emetogenic.48 The addition of other medications to local anaesthetics for

regional anaesthesia has become increasingly popular. When administered intrathecally,

hydrophilic substances (e.g., morphine) tend to remain in the cerebrospinal fluid for

prolonged periods of time and can move rostrally by diffusion or bulk movements of

cerebrospinal fluid, reaching the area of the chemoreceptor trigger zone.48 Morphine

concentrations in the medulla oblongata reach significant levels within 5-6 hr, as evidenced

by the onset of trigeminal analgesia.52 This time coincides with the peak time of nausea

xxvi

observed after spinal administration of morphine. Lipophilic opioids are taken up quickly

into the spinal cord. Nonetheless, about 10% of a dose of fentanyl administered in the

lumbar intrathecal space can be recovered in the cervical cerebrospinal fluid as early as 30

min after injection, demonstrating rapid ascension.53

Hypotension is a common occurrence during neuraxial anaesthesia. Low blood pressure

may lead to brain stem ischaemia, which is thought to activate the circulatory, respiratory,

and vomiting centres group in the medulla.54 Supplemental oxygen has been found to

relieve nausea in such circumstances.55 Other investigators have speculated that

hypotension rather leads to gut ischemia and the release of emetogenic substances (e.g.,

serotonin) from the intestines.56

Neuraxial anaesthesia also changes the function of the gastrointestinal tract.57

Sympathetic blockade by local anaesthetics creates unopposed vagal action, resulting in

gastrointestinal hyperactivity.48 The efficacy of vagolytic agents to relieve nausea during

spinal anaesthesia has been taken as evidence of the importance of this mechanism.55

SURGERY RELATED FACTORS

The indications, nature, and duration of surgery have effects on PONV. The following

conditions e.g. raised intracranial pressure, upper gastro-intestinal obstruction and

pregnancy may be associated with PONV.12 Surgeries such as plastic (breast augmentation),

ophthalmic (strabismus repair), ENT-dental, gynaecologic, laparoscopic (sterilization),

genitourinary, orthopaedic surgery (shoulder procedures), mastectomies and lumpectomies

are associated with increased incidence of PONV.11

The incidence and severity of PONV also increases with the duration of surgery.11, 27

xxvii

POSTOPERATIVE FACTORS

Pain especially visceral or pelvic pain is a common cause of postoperative nausea and

vomiting.10 Balanced analgesia using combinations of systemic opioids, regional nerve

blocks, local anaesthetics, and non-steroidal anti-inflammatory drugs can be used to

manage pain and reduce the incidence of opioid-related PONV.58, 59

Early oral intake following emergence from anaesthesia is usually associated with PONV

in some cases.10, 1 Early motion postoperatively including nursing procedures, ambulation,

and transfer on stretcher, wheelchair or vehicle can increase PONV, especially in patients

who have received opioids.2 Opioid sensitization of the vestibular apparatus has been

implicated.12

PREVENTION AND TREATMENT OF PONV

With escalating health care costs and availability of a myriad of antiemetic drugs in use

today, the anaesthetist’s choice of antiemetic drug depends not only on its efficacy and

safety profile, but also on its cost-effectiveness. Despite the availability of many drugs for

PONV, there is no single drug that can claim to be the miracle cure for this deceptively

simple problem. Combination drug therapy could be the answer since it is reasonable to

postulate that different pharmacological classes of drugs, with different mechanisms of

action, in combination should be more effective than single drugs alone in inhibiting the

complex emetic reflex.1

ANTIEMETIC DRUGS

xxviii

Drugs used to treat PONV include phenothiazines, anticholinergics (e.g. scopolamine),

benzamides (e.g. metoclopramide), butyrophenones (e.g. droperidol), histamine-receptor

antagonists (e.g. dimenhydrinate, diphenhydramine and cyclizine), dexamethasone, and

serotonin receptor antagonists (e.g. ondansetron, granisetron, tropisetron and dolasetron).

The neurokinin receptor antagonists (NRAs) represent another new class of antiemetics1.

Phenothiazines

The antiemetic effects of these drugs have been attributed to their ability to block receptors

in the CTZ, specifically dopaminergic receptors.12 Examples are chlorpromazine and

promethazine. The side effects of phenothiazines include significant lethargy and sedation

during recovery and extrapyramidal effects, ranging from restlessness to oculogyric crisis.60

Anticholinergics

Different cholinergic receptor sites are suggested to be present in the cerebral cortex and

pons and agents with specific activity at those receptors could form the basis for an anti-

emetic property.12 The vestibular apparatus of the inner ear and the nucleus of the tractus

solitarius are rich in muscarinic and histamine receptors. Scopolamine patch protects

against PONV after middle ear surgery and can reduce PONV in patients receiving epidural

morphine.16 Side effects include sedation, dry mouth and visual disturbances.

Butyrophenones

These are potent neuroleptic drugs with significant anti-emetic activity. The latter is due to

their antagonistic properties at the dopamine receptors.61 Droperidol is the only commonly

xxix

used butyrophenone for its antiemetic action. Side effects include sedation, drowsiness

(dose-dependent), dysphoria, restlessness and rarely extrapyramidal reactions. Children

may be more vulnerable to droperidol-related extrapyramidal symptoms.1

Histamine-Receptor Antagonists

H1 receptor antagonists are competitive antagonists of histamine by occupying H1 receptors

on effector cell membranes, thus preventing histamine binding and activity.1These drugs act

on the vomiting centre and the vestibular pathways. Examples include dimenhydrinate,

diphenhydramine and cyclizine. Sedation, dry mouth and occasional drowsiness are some of

their side effects.60

Serotonin Receptor Antagonists (SRA)

These drugs produce pure antagonism of the 5-HT3 receptor. 5-HT3 and 5-HT3 receptors are

present in both peripheral and central loci of the emetic pathways i.e. peripherally at vagal

afferents and centrally in the CTZ. The introduction of this class of drugs in the 90s

represents a major improvement in the pharmacotherapy of chemotherapy and radiation

therapy-induced nausea and vomiting. They have since proven to be highly effective in the

prevention and treatment of postoperative nausea and vomiting. They are not effective in

the treatment of motion induced nausea and vomiting.1 Ondansetron, the first 5-HT3

receptor antagonist to be introduced, is the most commonly used drug of this class. Others

include granisetron, tropisetron and dolasetron. The latest addition to this group of drugs is

palonosetron which was approved by the United States Drug and Food Administration (FDA)

in August 2008 for the treatment of postoperative nausea and vomiting.62

xxx

All serotonin antagonists, with the exception of palonosetron, are associated with

arrhythmias.63 For example, severe arrhythmias have been reported after dolasetron use in

Canada that has led to a strict black box warning through the Health Products and Food

Branch that dolasetron is contraindicated for any therapeutic use in children and

adolescents under 18 yr of age and for the prevention and treatment of PONV in adults.63

Benzamides

Metoclopramide is the most effective antiemetic of this class and has been used for more

than 40 years. It is a dopamine antagonist that is structurally similar to procainamide. Its

antiemetic effect results from antagonism of dopamine’s effects in the chemoreceptor

trigger zone. At high doses, it also antagonises 5-HT3 receptors.1 Additional antiemetic

effects are due to its dopaminergic and cholinergic actions on the gastrointestinal tract with

increases in lower oesophageal sphincter tone and facilitation of gastric emptying into the

small intestine.1 These latter effects reverse the gastric immobility and cephalad peristalsis

that accompany the vomiting reflex. Opioid-induced PONV can be treated with

metoclopramide because it reverses the gastric stasis induced by morphine.1 Side effects

include abdominal cramping, sedation, dizziness, and rarely dystonic extrapyramidal

reactions (oculogyric crises, opisthotonus, trismus, torticollis), and cardiac dysrhythmias.1

The dose of metoclopramide that is commonly used in clinical practice is 10 mg.8,9,64 A

systematic review showed that metoclopramide has no clinically relevant antiemetic effect

and does not show an increased risk of adverse effects in the doses used in daily clinical

practice.70 Studies have concluded that continued use of metoclopramide in the dose ranges

tested in many previous studies is inadequate.8,9,64 Higher doses of the drug have been

xxxi

effectively used for treatment of chemotherapy induced nausea and vomiting as well as

PONV prophylaxis.8

Dexamethasone

Dexamethasone has antiemetic effects that are reportedly comparable with conventional

antiemetic agents.65 Its anti-emetic efficacy is better when it is used in combination with

another antiemetic drug than when it is used as the sole agent.65 It is thought that

dexamethasone may exert its anti-emetic action through numerous glucocorticoid receptors

found in the nucleus of the solitary tract, the raphe nucleus and area postrema.66 All these

nuclei are known to have significant neuronal activity in the regulation of emetic reflex.12

Researchers have demonstrated the central antiemetic effects of dexamethasone in cats

and that this action is exerted through activation of the glucocorticoid receptors in the

bilateral nucleus tractus solitaries (NTS).67 The side effects of dexamethasone like other

steroids include delayed wound healing, wound dehiscence, and fluid retention which

presents especially during prolonged therapy. A single prophylactic dose of iv

dexamethasone 8 or 10 mg is antiemetic compared with placebo, without evidence of any

clinically relevant toxicity in otherwise healthy patients.68

The Newer Antiemetics

The neurokinin receptor antagonists (NRAs) represent another new class of antiemetics that

are under study at the moment.69,70 They are a novel class of medications that possesses

unique antidepressant, anxiolytic and antiemetic properties. These drugs demonstrate a

broader anti-emetic spectrum than 5HT3 receptor antagonist in animals.71 Examples of

drugs in this class are aprepitant and casopitant. NK1 receptors are abundant in the

xxxii

medullary areas where emetic inputs converge. Substance P, a member of the tachykinin

family of neuropeptides, is an important neurotransmitter in afferent pathways of emesis.72

Substance P may be released from enterochromaffin cells in the stomach and intestine (e.g.

postoperative trauma) or from sensory neurons (e.g. radiation, chemotherapeutic agents).72

Tachykinin peptide activity is tied to at least three G-protein–coupled receptor subtypes

found in the peripheral or central nervous tissue: neurokinin receptor subtype 1 (NK1), type

2 (NK2), and subtype 3 (NK3). The NK1 receptors are located in the area postrema and are

thought to play a particularly important role in emesis. However, NK1 receptor antagonists

(NK1 RAs) are thought to exert their mechanism of action on neurons in the “afferent relay

station” situated between the medial NTS and the central pattern generator for vomiting.72

The potential NK1 receptor blocking activity located deeper in the brain stem is thought to

prevent both acute and delayed emesis, whereas 5-HT3 RAs are largely effective only

against acute emesis,72 leading to considerable recent interest in the use of NK1 RAs for

prophylaxis of PONV.

Animal studies suggest that NK1 receptor antagonists have a wide spectrum of

antiemetic activity. It has been reported to be more effective than ondansetron for

prophylaxis against PONV after gynaecologic surgery and superior to placebo in the

treatment of established PONV.71,73 Animal studies had implicated substances P and

neurokinin, (NK1) receptors in the regulation of vomiting. The NRAs are responsive to

diverse emetic stimuli such as chemotherapeutic agents, X-irradiation, opioid, motion and

copper sulphate.

xxxiii

NON-PHARMACOLOGIC METHODS

Non-pharmacologic methods have also been studied for their efficacy in PONV prevention.

These include acupuncture, electro-acupuncture, transcutaneous electrical nerve

stimulation, acupoint stimulation, and acupressure.63,74 Supplemental oxygen has also been

shown to have a protective effect against PONV.1 The cost of newer antiemetic drugs and

their possible side effects have stimulated renewed interest and research in this area.63

PONV RISK ASSESSMENT AND TREATMENT

Several authors have attempted to quantify the relative impact of risk factors on PONV1 and

set up risk models for its prediction.2 Apfel and Koivuranta each independently developed

risk scores based mainly upon patient-related risk factors as the strongest predictors.75 The

four most important predictors of PONV included in their final simple risk score were female

gender, prior history of PONV or motion sickness, non-smoking, and the use of

postoperative opioids. If no or only one risk factor is present, the incidence of PONV may

vary between 10% and 21%. If at least two risk factors are present, the incidence may rise to

between 39% and 78%. It has been suggested that prophylactic antiemetic therapy be

considered for patients with at least two out of four risk factors.75, 76

PREVIOUS STUDIES OF PONV IN NIGERIA

In our environment Oduntan et al77 studied older anaesthetic agents such as ether,

cyclopropane and trichloroethylene and found an incidence of early PONV (0-3 hours) to be

5.1% and overall incidence of 10.4 – 15% in the series of surgical patients used.

xxxiv

Soyannwo et al in 1998 studied heterogeneous groups of patients undergoing diverse

surgical procedures.5 In the sub-group that had lower abdominal/pelvic surgery, incidence of

PONV was 11.5%, second only to those with head and neck surgery (14%). The study also

noted that PONV was highest in patients on opioid analgesics. This study however involved a

heterogeneous group of patients with different risk scores for PONV.75-76 In a study at the

University of Ilorin Teaching Hospital by Kolawole, the incidence of PONV in gynaecological

surgeries was put at 30%.6

PONV is one of the commonest complaints following anaesthesia, and its management

requires a multi-modal approach which can include the use of less emetogenic anaesthetic

techniques, balanced analgesia, appropriate intravenous hydration, the use of

pharmacotherapy and possibly non-pharmacologic methods.

CHAPTER THREE

PATIENTS AND METHODS

STUDY AREA

The study was conducted at the University of Ilorin Teaching Hospital, Ilorin (UITH).

ETHICAL APPROVAL AND INFORMED CONSENT

Ethical approval and consent for this study were obtained from the Ethical Review

Committee of the Hospital. Approval and informed consent of every participating patient

were obtained before recruitment of each patient was commenced.

xxxv

STUDY DESIGN

This was a prospective, randomised, controlled study of combined

metoclopramide+dexamethasone versus dexamethasone in the prevention of postoperative

nausea and vomiting.

Each eligible patient was randomly allocated to either metoclopramide+dexamethasone or

dexamethasone+normal saline groups (n=37 each) using a simple random technique of

balloting. The duration of the study was between June 2009 and May 2010.

SAMPLING TECHNIQUE

Study sample was obtained from a consecutive series of patients slated for elective

gynaecological surgery under spinal anaesthesia at the University of Ilorin Teaching Hospital

(UITH). A simple random technique of balloting was used.

SAMPLE SIZE DETERMINATION

In a previous study done by Kolawole, the incidence of PONV in gynaecological surgeries at

University of Ilorin Teaching hospital (UITH) was 30%.6

Using the Department of Anaesthesia records of surgical procedures done in a period of

four years between January 2002 and December 2005 at UITH, the estimated population of

xxxvi

elective gynaecological surgery was about 160 per annum and patients load for six months

was about 80. Patient load for six months was used but data collection was spread over one

year to give room for any logistics problems that might crop up during data collection.

The target population was less than 10,000. The formula: n = Z2pq/d2 was first used to

calculate the desired sample size (n) when the population is more than 10,000.78

n = the desired sample size when population is greater than 10,000

Z = the standard normal deviate, usually set at 1.96(or more simply at 2.0), which

corresponds to 95% confidence interval.

p = the proportion in the target population estimated to have a particular characteristic

(30% or 0.30).6

q = 1.0 – p

d = degree of accuracy desired (0.05)

n = (1.96)2(0.30)(0.70)/(0.05)2

=323

The sample size for this study was subsequently calculated using the formula78:

nf =n/1+ (n/N).

Where:

nf = the desired sample size when population is less than 10,000

n= the desired sample size when the population is more than 10,000=323

xxxvii

N = the estimate of the population size = 80

The sample size nf = 323/ {1+ (323/80)}

= 65

Minimum sample size of 65 patients was calculated

Using the attrition rate of 10%, 72 patients was calculated. Seventy-four patients divided

into two equal groups of 37 patients per group were eventually used for the study.

STUDY POPULATION

Seventy-four ASA physical status I and II female patients aged 18 years and above who were

scheduled for gynaecological surgery under spinal anaesthesia participated in this study

over a period of one year.

Exclusion Criteria

Patients with ASA classification higher than 2, those who were lactating, pregnant or who

had history of PONV, motion sickness or had received an anti-emetic or steroids within the

previous 24 hours were excluded from this study. Others with gastrointestinal diseases,

xxxviii

extrapyramidal disease, history of malignant hyperthermia, hepatic insufficiency,

pheochromocytoma, mechanical ileus, sickle cell disease, psychiatric illnesses and substance

abuse including smoking as well as patients on anticancer treatment were also excluded

from the study. Also excluded were patients who refused to participate in the study, those

who refused spinal anaesthesia, patients with coagulopathy or other bleeding diathesis,

patients with infection at the site of injection of intrathecal drugs, severe hypovolaemia,

increased intracranial pressure, severe aortic stenosis, severe mitral stenosis and those with

previous history of adverse reaction to dexamethasone, metoclopramide and bupivacaine.

STUDY PROTOCOL

PREOPERATIVE ASSESSMENT/ PREMEDICATION

Consented Patients aged 18 years and above and who were scheduled for gynaecological

surgery under spinal anaesthesia were recruited into the study during preoperative round

on the ward.

Each patient was reviewed a night before surgery by the investigator. Adequate history

including Bio data was taken. Previous medical history to exclude history of motion

sickness, previous PONV and other exclusion criteria was taken and thorough physical

examination was carried out. American Society of Anesthesiology (ASA) physical status

classification was determined. Height and the weight were also measured and recorded. The

xxxix

anaesthetic procedure as well as benefits and possible adverse effects of the study drugs,

anaesthetic drugs and that of the procedure were explained to the patients. Consent for

spinal anaesthesia and voluntary participation in the study was obtained from each patient.

Patients were fasted from midnight and 10 mg of oral diazepam prescribed for

premedication a night before and on the morning of surgery.

IN THE THEATRE

On arrival at operation suite, the patients were allowed to randomly pick a

ballot paper from a box containing seventy four (74) ballot papers. 37 papers

were labelled A for dexamethasone+Normal Saline (control group) and 37 were

labelled B for dexamethasone+metoclopramide combination (metoclopramide

or treatment group) in sealed envelopes. All safety anaesthetic precautions

were taken. Patients were connected to the multiparameter monitor and the

following vital signs were monitored noninvasively: arterial oxygen saturation,

blood pressure, and heart rate using the PM-800 Express patient monitor (S

Henzen Mindray Bio-medical Electronics Co.,Ltd). Intravenous access was

secured with 16G cannula and the drugs withdrawn appropriately.

Study medications were prepared in a double-blind fashion in identical 5 ml

syringes. A doctor in the Department of Anaesthesia prepared the drugs while

the investigator administered the medications. The observer was another

resident doctor who monitored the patient, measured and collated data on the

outcome variables (nausea, vomiting, time and vital signs).

Patients were preloaded with 1 litre of normal saline over 30 minutes after which they

were put in a sitting position for the spinal anaesthesia. The back of each patient was

xl

cleaned with antiseptic lotion and spirit and then draped. The appropriate lumbar inter-

space was located between L2 and L5 and the spinal anaesthesia was induced in each

patient using 3 ml of 0.5% hyperbaric bupivacaine and 25 µg of fentanyl. This was done

using size 26 G Quincke spinal needles. Both groups received 8 mg of iv dexamethasone

after induction of anaesthesia. The treatment group then received metoclopramide 25 mg iv

in a 5 ml syringe while the control group was given 5 ml 0.9% saline iv in identical 5 ml

syringe. The level of spinal block was tested for using sensation to light touch and cold

temperature. The maximum level of block was at the 5th thoracic spinal level.

Hypotension (defined as reduction in systolic blood pressure > 30 mmhg or diastolic

blood pressure >15 mmhg from base line) was treated with normal saline and where

necessary with iv ephedrine 3 mg boluses. Normal saline was used for intraoperative fluid

management and whole blood was administered whenever blood loss was more than

calculated allowable blood loss. At the closure of the skin, another 25 mg iv metoclopramide

in 5 ml syringe was given to the treatment group ( metoclopramide group) while the control

group received 5 ml 0.9% saline iv.

Patients breathed spontaneously room air supplemented with 100% oxygen by facemask

whenever SaO2 was < 95%. Patients pulse rate, blood pressure and arterial oxygen

saturation were monitored intraoperatively every 5 minutes using the PM-800 Express

patient monitor (S Henzen Mindray Biomedical Electronics Co., Ltd). At the end of surgery

patients were transferred to the recovery room where monitoring of patients continued for

1 hr. Patients were then transferred to the ward for further observation. Morphine 5 mg iv 4

hourly, diclofenac 75 mg im daily and paracetamol 600 mg 6 hourly iv were employed for

xli

postoperative pain management. Rescue anti-emetic ondansetron 4 mg iv bolus was

recommended for patients who vomited once or more.

Pain was assessed using the verbal rating scale (0 = no pain, 1 = mild pain, 2 = moderate

pain, 3 = severe pain, 4 = excruciating pain) at 15 minute intervals during patients stay in the

recovery room and at 4 hour, 12 hour, 16 hour and 24 hour in the ward by direct

questioning by a trained observer (another resident doctor) blinded to the study.

Breakthrough pain was controlled with additional doses of morphine titrated at 2 mg iv as

required. The total amount of morphine administered to each patient was recorded. Nausea

and vomiting were assessed immediately after surgery and at 30-min intervals in the

recovery room for 1 hour. In addition, nausea and vomiting were evaluated at 4 hour, 12

hour, 16 hour and 24 hour by direct questioning and by spontaneous complaint of the

patients. Nausea and vomiting were evaluated on a 3-point ordinal scale (0 = none, 1 =

nausea, and 2 = vomiting). No distinction was made between vomiting and retching (i.e., a

retching event was considered as a vomiting event).

The primary end point was a total effective antiemetic response (i.e., complete

response), defined as no PONV and no administration of rescue antiemetic medication for

24 hour postoperatively. Secondary end points included the proportion of patients who

experienced an episode of nausea, retching or vomiting, and the number of patients who

needed antiemetic rescue. The details of adverse effects throughout the study (0-24 hour

after anaesthesia) were assessed each time PONV was assessed.

A simplified risk score was calculated preoperatively for each patient.40,75 This predictive

score of PONV considers four predictors: female sex, history of PONV or motion sickness,

xlii

non-smoking and expected use of opioids; patients were assigned one point each for the

risk factors. In a cross-validation study, patients with a risk factor of 0 had a 10% risk for

PONV, those with a score of 1 had a risk of 21%; of 2, 39%, of 3, 61% and of 4, 79%40. All the

patients used in this study were female, non smoker and were expected to use opioids.

With the presence of 3 risk factors, the calculated risk for PONV was 61%.

SPECIAL DEFINITIONS

For the purpose of this study, and to ensure uniformity and standardization, duration of

anaesthesia was defined as the period between intrathecal injection of hyperbaric

bupivacaine and the time when the patient could feel pain at the surgical site. The duration

of surgery was taken as the period between skin incision and end of skin closure.

DATA COLLECTION

Nausea and vomiting and pain were assessed for 24 hrs starting from immediate

postoperative period, in the recovery room and in the ward.

Nausea and vomiting were evaluated on a 3 point ordinal scale (0-none; 1-nausea; 2-

vomiting and/or retching. No nausea, no vomiting and no anti-emetic medication in the first

24-hour post-operative period was defined as a successful end-point.

Pain intensity was assessed using verbal rating scale. An ordinal scale of 0-4 (0- no pain, 1-

mild pain, 2- moderate pain, 3- severe pain and 4- excruciating pain) was used.

xliii

STATISTICAL ANALYSIS

Data entry was done using the statistical package for the social sciences (SPSS 15.0 for

windows evaluation version. SPSS Inc.).Two-sample independent student’s t-test (2-tailed)

were used to analyse continuous patients’ variables like age, weight, duration of

anaesthesia/surgery, including their mean + SD (Standard Deviation). However, chi-squared

test or Fisher’s Exact test were used appropriately for discreet variables like symptoms of

PONV (nausea, vomiting). A p-value of less than 0.05 was considered significant.

CHAPTER FOUR

RESULTS

Seventy four patients (37 patients each in study and control groups) were recruited into the

study. However, two of them were disqualified because their spinal anaesthesia wore off

and anaesthesia was converted to general anaesthesia. Data obtained from seventy-two

patients were analysed.

From the analytic statistics of the patients’ characteristics (Table 1) it is apparent that

patients in both groups had comparable demographic and clinical profiles. Two-sample

independent student t-test confirms that continuous quantitative variables such as weight

(P = 0.108), body mass index (BMI) (P = 0.357), duration of anaesthesia (P = 0.507), duration

of surgery (P = 0.855) and total morphine consumption in 24 hours (P = 0.518) were not

statistically different between the two groups.

MAIN FINDINGS

xliv

During the first 24 h after anaesthesia, the percentage of patients with complete response

was 88.9% in the Metoclopramide Group (Dexamethasone+Metoclopramide) and 55.6% in

the Control Group (Dexamethasone+Normal Saline) (P = 0.002, Table 3). The incidence of

nausea, vomiting and the number of patients rescued in each group is also shown in Table 3.

The incidence of PONV (nausea and/or vomiting) in the Metoclopramide Group was 4

(11.1%) while it was 16 (44.4%) in the Control Group (P = 0.003). Similarly, 4 patients

(11.1%) in the Metoclopramide Group had nausea while 16 patients (44.4%) in the Control

Group had nausea (P = 0.003). No patient (0%) vomited in the Metoclopramide Group while

4 patients (11.1%) vomited in the Control Group (P = 0.57). This result showed that nausea

was the more common feature of PONV than vomiting in both groups in the first 24 hour.

Figures1 graphically illustrates the intra-group differences in outcomes during the total

study period (0-24 hour). Patients with complete response and less incidence of PONV are in

clear majority in the Metoclopramide Group.

The incidence of vomiting was lower in the Metoclopramide Group than the Control

Group for the same period of 0-24 h (0% Vs 11.11%). This was however not statistically

significant (P = 0.57).

During the early postoperative period (0-4 h) and late period (5-24 h) (Table 4 and

Figures 2 and 3), the incidence of PONV continued to be higher in the Control Group than

the Metoclopramide Group i.e. 30.6% Vs 8.3% and 13.9% Vs 2.8% respectively. The

difference was statistically significant for the period 0-4 hour (P = 0.02) while not significant

for the period 5-24 hour (P = 0.09). It is also noted that incidence of early PONV is higher

than late PONV in both groups.

xlv

Eleven patients (30.6%) had multiple episodes of nausea (greater than once) in the Control

Group while no patient had multiple episodes of nausea in the Metoclopramide Group (P =

0.003). One patient (2.8%) in the Control Group also had multiple episodes of vomiting

whereas no patient (0%) in the Metoclopramide Group had multiple episodes of vomiting (P

= 0.218) (Table 3).

The number of patients that required rescue antiemetic in the Metoclopramide Group was 1

(2.8%) while 5 patients (13.9%) required it in the Control Group. This was however not

statistically significant (P = 0.199). All the patients that required rescue antiemetic

responded favourably to one dose of the antiemetic used (4 mg ondansetron iv bolus).

OTHER FINDINGS

Table 5 shows the relationship between PONV and Age as well as that between PONV and

Obesity. The patients were categorized into those with age < 50 yr and age ≥ 50 yr. The

number of patients that were less than 50 yr was 51 while 21 patients were ≥ 50yr. The

incidence of PONV in age < 50 yr was 28% while the incidence in ≥ 50 yr category was 29%.

This was not statistically significant (P = 0.66).

Patients were also categorized into two groups based on the body mass index. There

were 53 patients with BMI < 30 and 19 patients with BMI ≥ 30. The incidence of PONV

among obese patients (BMI ≥ 30) was 15.8% while it was 20.8% among non obese patients.

This was however not statistically significant (P = 0.87).

Table 6 shows the incidence of pain in the two groups. The incidence of pain in the

Metoclopramide Group was 33.3% and 55.6% in the Control Group. The difference was not

statistically significant (P = 0.96).

xlvi

Table 7 shows relationship between PONV and Pain. Among patients who were free of

pain in the period 0-24 hour, 20% had PONV while 80% had no PONV. The difference was

also not statistically significant (P = 0.099). Only one patient reported severe pain and the

incidence of PONV in patients with severe pain was 100% (P = 0.278). This patient was in the

Control Group.

Adverse Effects

Table 8 shows the incidence of adverse effects in the study groups. The most frequent side

effects were hypotension, dizziness and drowsiness which were relatively mild. No

difference in the incidence of side effects was observed between the two groups.

xlvii

Table 1. Patient Demographics

Metoclopramide Group Control Group P- Values

Age (yr) 44 ± 9 41 ± 10 0.124

Weight (kg) 70 ± 17 64 ± 15 0.108

Height (cm) 163 ± 6 159 ± 5 0.026

BMI (kg/m2) 27 ± 6 25 ± 6 0.357

PCV (%) 35 ± 4 36 ± 4 0.978

Parity 3 ± 2 3 ± 2 0.529

ASA Score* 1 1 0.605

DOA (min) 158 ± 20 162 ± 37 0.507

DOS (min) 129 ± 23 130 ± 40 0.855

Morphine* (mg) 39 ± 5 40 ± 4 0.518

n = 36 in each group.

Morphine* = 24 hr morphine consumption

Values are mean ± SD in each group.

ASA score*- Mode values used

xlviii

Table 2. Types of Operation

Types of operation Metoclopramide Group n (%) Control Group n (%)

Abdominal hysterectomy 20 (55.6) 16 (44.4)

Vaginal hysterectomy 3 (8.3) 1 (2.8)

Myomectomy 11(30.6) 12 (33.3)

VVF* repair 0 (0) 1 (2.8)

Ovarian cystectomy 1 (2.8) 3 (8.3)

Tuboplasty 1 (2.8) 2 (5.5)

Manchester repair 0 (0) 1 (2.8)

n = 36 in each group.

P = 0.633

xlix

Table 3. Patients Having Complete Response, Nausea, Vomiting, or Rescue Antiemetic

Medication During The First 24 Hours After Anaesthesia

Metoclopramide Group n (%) Control Group n (%) P-Values

Complete response 32 (88.9) 20 (55.6) 0.002

Nausea+Vomiting 4 (11.1) 16 (44.4) 0.003

Nausea 4 (11.1) 16 (44.4) 0.003

Vomiting 0 (0) 4 (11.1) 0.57

Multiple Nausea 0 (0) 11 (30.6) 0.003

Multiple Vomiting 0 (0) 1 (2.8) 0.218

Rescue 1 (2.8) 5 (13.9) 0.199

n = 36 in each group.

l

Table 4. Incidence of Early and Late Postoperative Nausea and Vomiting

Metoclopramide Group n (%) Control Group n (%) P- values

Early PONV (0-4 hr)

Complete response 33 (91.7) 5 (69.4)

PONV 3 (8.3) 11(30.6) 0.02

Late PONV (5-24 hr)

Complete response 35 (97.2) 31 (86.1)

PONV 1 (2.8) 5 (13.9) 0.09

n = 36 in each group.

li

Table 5. Incidence of PONV compared with Obesity and Age

PONV (n) NO PONV (n)

Age

P = 0.66

Age < 50 yr 14 37

Age ≥ 50 yr 6 15

Obesity

P = 0.87

Obese (BMI ≥ 30) 3 16

Not Obese (BMI < 30) 11 42

lii

Table 6. Incidence of Pain in Study Groups

Metoclopramide Group n (%) Control Group n (%)

Pain 12 (33.3%) 20 (55.6%)

No Pain 24 (66.7%) 16 (44.4%)

n = 36 in each group

P = 0.96

liii

Table 7. Incidence of PONV and Postoperative Pain in 24 hrs

PONV n (%) NO PONV n (%) P-Values

No Pain 8(20%) 32(80%) 0.099

Mild Pain 9(36%) 16(64%) 0.256

Moderate Pain 2(33.3%) 4(66.7%) 0.537

Severe Pain 1(100%) 0(0%) 0.278

liv

Table 8. Adverse Effects

Metoclopramide Group (n) Control Group (n)

Any adverse effects 11 10

Mild Hypotension 8 8

Moderate Hypotension 1 0

Dizziness 1 1

Drowsiness 1 1

n = 36 in each group.

lv

lvi

lvii

NO PONV PONV

lviii

NO PONV PONV

lix

CHAPTER FIVE

DISCUSSION

Postoperative nausea and vomiting (PONV) is still the most troublesome event encountered

in the recovery room, despite advances in prevention and treatment.79 Furthermore, the

ongoing trend towards ambulatory procedures has increased the focus on PONV as its

occurrence may delay discharge or cause unanticipated hospital admission.80,81 PONV is a

very common morbidity after gynaecological procedures as reported by various studies in

the past.12, 82,83 In this study, a highly pro-emetic setting was inadvertently provided to test

the clinical efficacy of combination of two readily available, cheap and relatively safe anti-

emetics in our environment.

This study was designed as a prophylactic trial rather than a therapeutic one. Researchers

have suggested restricting prophylactic trials to high risk patients and/or procedures.84 This

is to prevent unnecessary exposures of patients to drugs and to prevent avoidable side

effects and/or adverse reactions. Gynaecological procedures rightly belong to this category.

Apfel simplified risk scores for the patients studied put the expected PONV risk at 61% (high

risk).75 This was because of the presence of three risk predictors of female gender, non-

smoking and use of postoperative opioid. The Apfel score consist of four predictors: female

gender, history of motion sickness or PONV, non-smoking, and the use of postoperative

opioids. If none, one, two, three, or four of these risk factors were present, the incidences of

PONV were 10%, 21%, 39%, 61% and 79% respectively.75 Although interventions in this

study were able to reduce the incidence of PONV in both the metoclopramide and the

lx

dexamethasone only groups to 11% and 44% respectively from the calculated Apfel score of

61% risk, none of the two interventions were able to totally abolish PONV.

It is obvious from the obtained results that the two groups involved patients with similar

and comparable demographic and clinical profile. Each of these characteristics has a p-value

> 0.05 (Table 1). These include number of patients in each group, age, weight, and BMI.

Others are duration of anaesthesia/surgery and total dose of morphine administered post

operatively. There were mild decreases in pulse rate and BP immediately after induction of

spinal anaesthesia. These were assumed to be due to the spinal anaesthesia. Administration

of normal saline was enough to correct the fall in BP. One patient in the dexamethasone

group required the use of iv ephedrine 3 mg bolus to correct the hypotension. It may

therefore be reasonable to say that the differences observed in the incidences of PONV

between the two groups were due to the study drugs each group was exposed to, and not

to any of the above variables, chance-finding or any other confounding variable.

In this study, the most noticeable finding is that combination of metoclopramide and

dexamethasone is more effective than dexamethasone alone in preventing PONV in

gynaecological surgery whether at 0-4 hour, 5-24 hour, or 0-24 hour period of the study

(Tables 3-4 and Figures 1-3). The difference in both groups was statistically significant

throughout the 24 hour. At 0-24 hour, the incidences of PONV were 44% and 11% in the

Control Group and Metoclopramide Group respectively (P = 0.003, Table 3). This is in

agreement with previous findings that combination therapy is better at preventing PONV in

high risk patients/procedures.1, 8, 70 The incidences of PONV in both groups (11% and 44% for

Metoclopramide Group and Control Group respectively) show that gynaecological

procedures are highly emetogenic.

lxi

During the early postoperative period 0-4 hour and late period (5-24 hour)(Table 4),

the incidence of PONV remained higher in the Control Group than the Metoclopramide

Group for the above two periods i.e 30.6% Vs 8.3% and 13.9% Vs 2.8% respectively. The

differences between the two groups was statistically significant for 0-4 hour (P = 0.02) but

not significant for 5-24 hour (P = 0.09). One of the set objectives of this study was to test

the hypothesis that 50 mg metoclopramide (in two divided doses) added to 8 mg

dexamethasone is effective for the prevention of postoperative nausea and vomiting. This

study reaffirmed the hypothesis (P = 0.002).

Metoclopramide has been used for almost 40 years to prevent PONV.69 The affinity for

doperminergic D2-receptors explains the antiemetic effect of metoclopramide.85 In adults,

the most often studied regimen to prevent PONV is 10 mg metoclopramide iv. There have

been conflicting reports on the efficacy of 10 mg metoclopramide in the prevention of

postoperative nausea and vomiting. In a meta analysis by Henzi et al, it has been shown that

this dose had no significant antinausea effect.69 This review by Henzi, et al involved 66

studies and 3260 patients who received 18 different regimens of metoclopramide and 3006

controls who received placebo or no treatment. There was no evidence of dose-

responsiveness with oral, im, intranasal or iv metoclopramide in children and adults. The

doses used in adults were 5-30 mg iv while 0.10-0.50 mgkg-1 were used in children. The best

documented regimen is 10 mg iv.69

High-dose metoclopramide has been used successfully as an antiemetic in highly

emetogenic chemotherapy (treatment with Cisplatin, for instance).86 Metoclopramide in

larger doses is said to have anti-5-HT receptor action.87 Knudsen et al also found

metoclopramide to be effective in counteracting emesis following spinal anaesthesia

lxii

supplemented with intrathecal morphine.88 This observation was confirmed by Pitkanem,

and co-workers.89

Studies have also been done comparing the efficacy of metoclopramide plus other drugs

combinations with other antiemetics. Eberhart et al compared dimenhydrinate (an

antihistaminic) and metoclopramide alone and in combination for prophylaxis of PONV.90

Metoclopramide in a dose 0.3 mgkg-1 was used for the study. Neither metoclopramide nor

dimenhydrinate alone reduced the incidence of PONV in male patients after endonasal

surgery. However, the combination of both drugs revealed a moderate additive effect:

PONV was reduced from 37.5% in the placebo group to 15.0%.90

Yoshitaka et al studied the effects of 8 mg dexamethasone on antiemetics in female

patients undergoing gynaecological surgery.91 The study demonstrated that incidence of

complete response, no PONV, and no administration of rescue antiemetic medication was

greater in patients who had received granisetron plus dexamethasone (96%) than in those

who had received droperidol (49%) or metoclopramide plus dexamethasone (51%) (P =

0.001).91

The doses of metoclopramide used in many previous studies are relatively low and

optimum dose of metoclopramide used in combination with another antiemetic (e.g.

dexamethasone) could be highly effective in the prophylaxis for postoperative nausea and

vomiting.

This hypothesis was put to test by Jan Wallenborn et al in their study.8 Jan Wallenborn et

al investigated the efficacy and safety of three doses of metoclopramide (10 mg, 25 mg, and

50 mg), on the assumption that each patient would receive basic antiemetic prophylaxis of 8

lxiii

mg dexamethasone. They found that 25 mg or 50 mg metoclopramide added to the basic

intervention of 8 mg dexamethasone was effective, safe, and cheap.8 50 mg

metoclopramide was however found to be more effective than 25 mg over 24 hours

postoperatively. In their study the whole 50 mg was given as a single dose intra-operatively

but in the present study, metoclopramide was given in two divided doses of 25 mg each at

the beginning and end of surgery respectively.

Another meta-analysis reported that 10 mg metoclopramide was clinically ineffective

and did not improve when combined with 8 mg dexamethasone.69 Larger dosages, however,

were as effective as ondansetron or droperidol when added to dexamethasone (odds ratios

around 0.5).7

Metoclopramide is a relatively safe drug. Jan Wallenborn et al recorded low incidence of

extrapyramidal symptoms while no incidence of extrapyramidal symptom was noted in this

study. This is probably due to larger sample size used in the previous study.8 It is also

possible that giving the drug in two divided doses rather than as a bolus prevented the

incidence of extrapyramidal effects in this study.

Jan Wallenborn et al found that metoclopramide also reduced the number of multiple

episodes of nausea and vomiting and the need for rescue drugs.8 Similarly in this study

Metoclopramide reduced the number of multiple episodes of nausea (0% in

Metoclopramide Group Vs 30.6% in the Control Group) and vomiting (0% in the

Metoclopramide group Vs 2.8% in the Control Group) and the need for rescue drug (2.8% in

the Metoclopramide Group Vs 13.9% in the Control Group) (Table 3). However, this was

only statistically significant for multiple episodes of nausea (P = 0.003) and not statistically

lxiv

significant for multiple episodes of vomiting (P = 0.218) and the need for rescue drug (P =

0.09).

There have been conflicting reports on the efficacy of dexamethasone in the prevention

of PONV. Several studies have found that dexamethasone is effective in prevention of

PONV.13,92,93 In these studies, the antiemetic effect of dexamethasone was reported to be

equal to or even better than that of serotonin subtype 3 (5-HT3) receptor antagonists such

as ondansetron and granisetron.92, 93 Dexamethasone also reduced the occurrence of

postoperative nausea and vomiting (PONV) in patients undergoing tonsillectomy,

thyroidectomy, cholecystectomy and hysterectomy.13, 14, 28 However in another study, Jann-

Inn Tzeng et al concluded that dexamethasone (8 mg) alone does not prevent PONV in

women undergoing dilatation and curettage.27 Dexamethasone was however found to

enhance the antiemetic effect of droperidol27. Although dexamethasone has been used in

the prophylaxis of chemotherapy related emesis in a wide dose range (8 – 32 mg), 92, 93 a

single fixed dose of 8 mg was most frequently used in the prevention against PONV.13, 14,

28This was the reason why a single fixed dose of dexamethasone of 8 mg was chosen in this

study.

Reviews dealing with PONV have discussed almost exclusively general anaesthesia and

largely ignored regional anaesthesia. This contrasted with the increasing popularity of

regional anaesthesia. A multitude of medications, such as synthetic opioids, α2-agonists, and

cholinesterase inhibitors, have been introduced in an attempt to enhance the action of local

anaesthetics. The decision about their usefulness will not only rely on their effects on nerve

blockade and pain relief, but also on their influence on side effects such as PONV.

lxv

Patients in this study had their surgery under spinal anaesthesia. Two patients whose

anaesthesia was converted to general anaesthesia were excluded from the study. Regional

anaesthesia has been reported to be less emetogenic than general anaesthesia.55-60

Intrathecal fentanyl was used for all patients in this study. It is possible that this could have

further increased the risk of PONV in the patients that were studied.71 Intrathecal morphine

is however more emetogenic than intrathecal fentanyl.5

Age

Twenty-one patients (29.2%) had age ≥ 50years while fifty-one patients (70.8%) had age <

50 years. In this study, age had no effects on the incidence of PONV (P = 0.66, Table 5). Jan

Wallenborn et al noticed that early postoperative nausea and vomiting was less frequent in

patients aged 50 or more but late episodes were more frequent, as were adverse reactions.8

There was no similar finding in this study. There was no difference in the incidence of PONV

between patients aged 50 or more and patients aged less than 50 years throughout 24

hours (Table 5). Soyannwo et al could not find significant relationship between age and

PONV in their study.5 Similarly, Berg Van den et al could not establish relationship between

age and postoperative vomiting in their study.32 Cohen et al17 showed that the incidence of

vomiting is no doubt higher in paediatric age groups when compared to adults. In a recent

study, Alesandro CS et al also found PONV to be significantly associated with younger age (P

= 0.034).94 All the patients in the present study were adults with age range of 21- 63 years

unlike some previous studies that included patients with younger age range and larger

population sample.94 Watcha and White concluded that the relationship between emesis

and age is not as clear as relationship between gender and postoperative nausea and

vomiting in adult population.12

lxvi

Obesity

Body mass index (BMI) had no effects on postoperative nausea and vomiting in this study (P

= 0.87). Obesity has actually been disproved as a patient-related PONV risk factor .95

Interestingly, the systematic review that did so found that the belief in increased body mass

index as a risk factor apparently largely stemmed from a “chain reaction” of 14 review

articles misquoting or misinterpreting 4 original studies.95

Postoperative pain

Postoperative pain after gynaecological surgery may precipitate or aggravate PONV.

Morphine, paracetamol and diclofenac were used for postoperative pain management in

this study to minimise the influence of pain on PONV. In the Metoclopramide Group, 12

(33.3%) patients had pain in the first 24 hour while 24(66.7%) were free of pain (Table 6). On

the other hand, 20 (55.6%) patients in the Control Group had pain during the 24 hour period

and 16 (44.4%) patients were free of pain. There was no statistically significant difference in

the incidence of pain between the two groups (P = 0.96). Therefore, pain could not have

been responsible for the higher incidence of PONV noticed in the Control Group.

Table 7 shows that among patients who experienced pain (mild, moderate and severe) and

those who did not, there was no statistically significant difference in the incidence of PONV.

In a similar vein, Stadler et al could not establish relationship between PONV and

postoperative pain.96Some studies have however established postoperative pain as risk

factor in PONV.12

More patients in the Control Group (55.6%) had pain within 24 hours postoperatively

compared with the Metoclopramide Group (33.3%) (P = 0.96, Table 6). Although the

lxvii

difference was not statistically significant, the observed result may be due to the analgesic

effect of metoclopramide that has been reported by some investigators.97,98 Ramaswamy et

al found that metoclopramide produced a significant analgesic effect when tested by both

acetic acid induced writhing and hot plate test.97 This effect was reduced by naloxone

suggesting opioid involvement. Furthermore, bromocriptine which inhibits the release of

prolactin attenuated the effect of metoclopramide indicating that this drug could act by

releasing prolactin.97 Lisander agreed that metoclopramide may enhance analgesic effect of

opioids and established that VAS-pain scores tended to be smaller in patients that had

metoclopramide compared with those that had no metoclopramide. He however could not

conclusively demonstrate clinically relevant analgesic effect of metoclopramide.98

Type of surgery

This study was conducted on patients undergoing major gynaecological surgery ranging

from total abdominal hysterectomy to Manchester repair (Table 2). There was relative even

distribution of types of surgery between the two study groups (P= 0.633). Some

investigators have established types of surgery as a risk factor in PONV.12 Whereas several

other studies have suggested that differences in the incidence of PONV are mainly due to

patient- or anesthesia-specific factors, regardless of the type of surgery.99 However in a

lxviii

more recent study, Ruiz et al found that the type of surgery, when categorized anatomically,

was associated with an increased frequency of early PACU antiemetic administration.100

Adverse events

The adverse effects seen during the study are shown in Table 8.The most frequently

reported side effects were dizziness and drowsiness which were relatively mild. No

difference in the incidence of adverse effects was observed among the groups. Only one

patient in the Metoclopramide Group had significant hypotension which responded to

intravenous administration of ephedrine 3 mg bolus and Normal Saline. No episode of

extrapyramidal symptom was recorded throughout the study period. No patient complained

of headache or vertigo in the both groups, although it might have been difficult to

differentiate headache caused by spinal anaesthesia from that due to metoclopramide had

there been an incidence in the Metoclopramide Group. In a review of several randomized

placebo-controlled studies by Henzi et al, they found no significant difference between

metoclopramide and placebo for adverse drug reactions such as extrapyramidal symptoms,

sedation and drowsiness, dizziness and vertigo, headaches.31Only one adult patient who had

received 20 mg metoclopramide was found to have extrapyramidal symptom while no

extrapyramidal symptom was found in children in their study.

There was no episode of intraoperative vomiting in both groups during the present study.

Conclusion and Recommendation

lxix

Patients at high risk of PONV should receive special considerations with respect to the

prophylactic use of antiemetic drugs. Due to different sites of action of antiemetic drugs, a

combination therapy using two antiemetics (acting at different sites) together with less

emetogenic anaesthetic procedure is more effective than monotherapy.12 A Combination of

8 mg dexamethasone and 50 mg metoclopramide in two divided doses given intravenously

is effective in the prevention of PONV and it is strongly recommended for patients with high

risk of developing PONV. It is found to be safe and cheap and this is in agreement with

previous study.8 It is recommended that 25 mg metoclopramide be given after induction of

anaesthesia and 25 mg at the closure of the skin.

Strengths and limitations

Metoclopramide has been reported to cause cardiac arrhythmias.101 Unavailability of ECG

machine which prevented the minute to minute monitoring of the cardiac effects of

metoclopramide is a weakness of this study.

The administration of metoclopramide immediately after induction made it impossible to

differentiate between hypotension caused by spinal anaesthesia and that of

metoclopramide.

lxx

The strength of this study was the fact that it was conducted using drugs that are readily

available, safe and cheap (metoclopramide and dexamethasone) in a highly pro-emetic

milieu. It was also conducted using spinal anaesthesia which is increasingly becoming a

popular anaesthetic procedure in our environment.

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APPENDIX 1

PROFORMA

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Study group : 8 mg Dexamethasone + Normal Saline ( ); 8 mg

Dexamethasone+ 50 mg metoclopramide in two divided doses ( ).

Serial No................

Hospital no................

Age:------------------------years

Weight---------------------kg

Height----------------------cm

Last menstrual period...........

Preoperative Medical Problems (I) HT, (II) DM, (III) others--

Co-morbidities controlled? YES or NO

Have you ever smoked/still smoking........yes/no

Current medications (i) Anti-HT (ii) Anti-D/M (iii) Others(specify)

Vital signs Onset of

procedure

End of

procedure

Time(q 15minutes)

1 2 3 4

RRc/min

SaO2

PR bpm

BP(mmHg)

Investigations:(i) PCV.........................(a) Normal (b) Low

ASA score: ASA I---, II,---III---

Verbal Rating Scale: No pain( 0), Mild pain( 1), Moderate pain(2 ), Severe

pain(3 ),Excruciating pain(4)

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Yoruba Version102: Kosi irora (0), Irora die(1), Irora ti oninilara (2), Irora ti

oga(3), Irora ti okoja ifarada (4)

PONV 3 point Ordinal scale: No nausea (0) nausea (1) vomiting (2).

TIME(POST OP) PONV SCORE PAIN SCORE

15 MINS

30 MINS

45 MINS

1 HR

4 HR

12 HR

16 HR

24 HR

Number of times patient felt nauseated:

Number of times patient vomited:

Duration of anaesthesia:

Type of surgery:

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Site of surgery:

Total Morphine consumption:

Ephedrine used: Yes ( ); No ( ). If yes what dose..............

Rescue Antiemetic: Yes( ); No( )

If yes, how many doses..........

Any Adverse reaction?

If yes, what type(s)..............?

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CONSENT FORM

Having been properly informed about this study on comparative trial of combined

metoclopramide and dexamethasone versus dexamethasone in postoperative

nausea and vomiting in gynaecological surgeries and that:

(1) The study is for a research purpose

(2) The information collected will be made confidential

(3) The study will be beneficial to mankind

(4) The drugs are free and safe

(5) The study is voluntary and you can withdraw from the study at any stage if so

desired,

I hereby give my consent to participate in the study.

………………… ……………………… ……………………

Initial of Participant Signature of the signature of the

Participant & date witness & date

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