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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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