DR. OLANREWAJU.N. AKANMU · A DISSERTATION REQUIRED IN PART FULFILLMENT OF THE AWARD OF FELLOWSHIP...
Transcript of DR. OLANREWAJU.N. AKANMU · A DISSERTATION REQUIRED IN PART FULFILLMENT OF THE AWARD OF FELLOWSHIP...
COMPARISON OF THE ANALGESIC EFFECT OF
INTRATHECAL FENTANYL
AND
MIDAZOLAM
A DISSERTATION REQUIRED IN PART FULFILLMENT OF
THE AWARD OF FELLOWSHIP IN ANAESTHESIA OF THE
NATIONAL POSTGRADUATE MEDICAL COLLEGE OF
NIGERIA (FMCA)
BY
DR. OLANREWAJU.N. AKANMU
M.B; Ch.B. (Ife) D.A.(U.I)
Department of Anaesthesia
University College Hospital,
Ibadan.
Nigeria.
ii
DECLARATION
I hereby declare that this work is original. It has not been presented to any
other examining body for fellowship award or any journal for publication
DR. OLANREWAJU NURUDEEN AKANMU
M.B;Ch.B(Ife) ,DA(Ibadan)
iii
CERTIFICATION
We certify that this study was carried out by Dr. O.N. AKANMU of the
Department of Anaesthesia, University College Hospital, Ibadan, Nigeria.
SUPERVISORS:
PROF. O.A.SOYANNWO DR P.T. SOTUNMBI DR.A.S. Lawani-Osunde
Consultant Anaesthetist Consultant Anaesthetist Consultant Anaesthetist
University College Hospital, University College Hospital, National Orthopaedic Hospital
Ibadan Ibadan Igbobi
………………… ……………………… ……………………..
SIGNATURE SIGNATURE SIGNATURE
……………… …..………… ………………
DATE DATE DATE
iv
DEDICATION
This work is dedicated to ALMIGHTY GOD for making this residency
programme a reality.
My wife, Funmilola and my son Oluwatomisin for their love and patience
throughout the residency programme.
v
ACKNOWLEDGEMENT
My profound gratitude and appreciation goes to the management of
University College Hospital, Ibadan, for giving me the opportunity and facilities
for the residency training programme. I also acknowledge the support and
encouragement of my colleagues in the Department of Anaesthesia, University
College Hospital, Ibadan throughout the period of my training.
I acknowledge the support of the members of staff of Anaesthesia
Department of the National Orthopaedic Hospital, (NOH) Igbobi, Lagos and
N.O.H management for their support throughout the period of this research.
My gratitude also goes to the Head of Department of Anaesthesia, U.C.H, Dr.
Arinola Sanusi who was always ready to proffer solutions to any problem I
encountered throughout the course of this study.
I am particularly grateful to my supervisors Prof O.A. Soyannwo, Dr P.T.
Sotunmbi and Dr A.S Lawani-Osunde for their CONSTANT unquantifiable
support and contribution throughout the course of this work.
I acknowledge with thanks, the contribution of other consultants in the
Department of Anaesthesia UCH; most especially Dr S.D. Amanor-Boadu whose
amiable leadership role has been a source of inspiration for me and for ensuring
that my training is sound as what obtains in the developed world. Also Dr. R.O.
Eyelade, Dr O.A.Oluwole and Dr. O. Akinyemi were good examples to follow.
I am greatly indebted to Mr. Tope. Alonge, Mr Ogunlade and Mr B.
Omololu for allowing me to study their patients and for being there for
vi
consultation. I am also grateful to all the resident doctors in orthopaedic surgery
unit at Ibadan and Igbobi for their cooperation throughout the period of this study.
My gratitude also goes to all the resident doctors in anaesthesia department for
their support throughout the period of this study.
I wish to thank the following people for their roles during the conduct of
this study: Mrs W. Yusuf and Dr A. Orimadegun for the statistical input. Miss
Oyindamola Olaifa for the translation of the consent form to Yoruba and Miss
Bukola Adeline for the typing of the project.
I am particularly grateful to the UCH and NOH theatre and recovery room
nurses for the assistance rendered in the care of the patients in the theatre and
recovery room. May Almighty God reward you all. (Amen).
vii
TABLE OF CONTENTS
Title Page i
Declaration ii
Certification iii
Dedication iv
Acknowledgment v
Table of Contents vii
List of Tables ix
List of Figures x
List of Appendices xi
List of Abbreviations xii
Summary xiii
CHAPTER ONE
Introduction 1
Aims and Objectives 3
CHAPTER TWO
Literature Review 5
CHAPTER THREE
Research Design 17
Research Methodology 20
CHAPTER FOUR
Results 26
CHAPTER FIVE
Discussion 42
Limitation of Study 49
Conclusion 49
Recommendation 50
Ethical considerations 51
Appendices 52
References 60
viii
LIST OF TABLES
PAGES
TABLE 1
Demographic Characteristics of the Patients. 29
TABLE II
Site of Surgery 31
TABLE III
Operative Condition of Patients 32
TABLE IV
Post-Operative Analgesia Data 33
TABLE V
Incidence of Hypotension 35
TABLE VI
Perioperative Undesirable Events. 39
ix
LIST OF FIGURES
PAGES
FIGURE 1
American Society of Anaesthesiologists(ASA) Status of the
Patients 30
FIGURE 2
Mean four hourly Pain Score in the first 24 hours Post-
operatively 34
FIGURE 3
Mean of Systolic Blood Pressure Changes Post Injection of
Study Drugs 36
FIGURE 4
Mean Arterial Blood Pressure Changes Post Injection of
Study Drugs. 37
FIGURE 5
Mean Heart Rate Changes Post Injection of Study Drugs. 38
FIGURE 6
Mean Respiratory Rate Changes in the Recovery Room 40
FIGURE 7
Mean Oxygen Saturation (SpO2) Changes in the Recovery
Room 41
x
LIST OF APPENDICES
PAGES
Appendix A
Patient informed Consent 52
Appendix B
Data collection form. 55
Appendix C
Ethical approval 59
xi
LIST OF ABBREVIATIONS
ASA: American Society of Anaesthesiologists
B: Bupivacaine Group
DAP: Diastolic Arterial Blood Pressure
FB: Fentanyl - Bupivacaine Group
FMCA: Fellow Medical College in Anaesthesia
GA: General Anaesthesia
HR: Heart Rate
IRB: Institution Review Board
MAP: Mean Arterial Pressure
MB: Midazolam – Bupivacaine Group
mg: milligramme
NIBP: None Invasive Blood Pressure
NOH: National Orthopaedic Hospital
ORIF: Open Reduction and Internal Fixation
PONV: Post Operative Nausea and Vomiting
RR: Respiratory Rate
SAB: Subarachnoid Block
SAP: Systolic Arterial Blood Pressure
SpO2: Oxygen saturation
UCH: University College Hospital
g: microgramme
xii
UI: University of Ibadan
VAS: Visual Analogue Scale
xiii
SUMMARY
The spinal route of analgesia has consolidated its place as a major modality
in the treatment of acute, chronic and cancer pain because the spinal cord
represents a principal target in the modulation of pain impulses from the periphery
as well as the brain. This makes it important in the management of pain. The use
of 0.5% heavy bupivacaine in combination with fentanyl or midazolam has been
reported to provide excellent and superior analgesia of longer duration during
surgical procedures.1,2 This combination has the added advantage of reduced side
effects in the perioperative period compared to when any of these drugs is used
singly as monotherapy.
This study is designed to determine the quality of analgesia provided by the
intrathecal administration of fentanyl 25µg or midazolam 2mg in combination
with 10mg of 0.5% heavy bupivacaine compared with single administration of
10mg 0.5% heavy bupivacaine alone as control in adult patients undergoing open
reduction and internal fixation of lower limb fractures. The total post operative
analgesic consumption of patients in 24 hours following surgery as well as the
incidence and severity of any undesirable effect were studied
The study groups comprise patients receiving intrathecal fentanyl 25µg
with 10mg 0.5% heavy bupivacaine(FB group) or midazolam 2mg with 10mg
0.5% heavy bupivacaine(MB group) for analgesia in adult patients undergoing
open reduction and internal fixation for lower limb fractures .The control group(B
group) were patients receiving neuraxial 10mg 0.5% heavy bupivacaine alone. A
total of fifty (50) patients, American Society of Anaesthesiologists (ASA) I and II
xiv
status requiring open reduction and internal fixation of lower limb fracture under
subarachnoid blocks were studied.
The mean duration of analgesia / neural blockade in the control group (B)
was 2.37(±0.30) hours; 4.73(±0.89) hours in the fentanyl – bupivacaine (FB)
group and 5.04(±0.99) hours in the midazolam – bupivacaine (MB) group. Two
patients (11.8%) in the fentanyl – bupivacaine( FB ) group had pruritus (p = 0.132)
while pruritus was absent in the other two groups. Two patients (11.8%) in the
fentanyl – bupivacaine (FB ) group, one patient in the control group (5.9%) and
none in the midazolam – bupivacaine ( MB ) group vomited (p = 0.364 )
It was found from this study that both intrathecal midazolam and fentanyl
potentiate the analgesic effect of 0.5% hyperbaric bupivacaine. Midazolam
bupivacaine combination however offers a better side effect profile than fentanyl –
bupivacaine
1
CHAPTER ONE
INTRODUCTION
More than a century after the first reported conduct of clinical neuraxial
blockade by Dr August Bier when he cocainized the spinal cord “to render large
parts of the body insensitive to pain for surgical purpose” our experience and
knowledge of spinal anaesthesia has increased greatly leading to new discovery
and development of new techniques. The use of intrathecal fentanyl and
midazolam has gained a wide acceptance among anaesthetists in order to improve
the quality of subarachnoid block. Intrathecal opioids added to local anaesthetics
for spinal anaesthesia was first introduced into clinical practice in 1979 with
intrathecal morphine as a forerunner3. Since then, neuraxial administration of other
opioids such as fentanyl, sufentanil and methadone with local anaesthetics has
been demonstrated to possess analgesic efficacy.3,4,5 Local anaesthetics
administered intrathecally with opioids was demonstrated to provide superior
analgesia of longer duration to that obtained with either drug alone and also
minimizes adverse effects of either of the drugs because of the reduced dose of
each drugs administered.
The profound segmental antinociception produced by neuraxial opioids in
doses much smaller than would be required for comparable antinociception if
administered systemically has made them very popular and effective in the
treatment of many pain states. The antinociception is also devoid of motor,
sensory and autonomic blockade so there is no paralysis or hypotension.
Furthermore is the availability of a specific opioid receptor antagonist, naloxone to
2
reverse their action when necessary. Side effects linked to intrathecal opioid
administration like pruritus, post-operative nausea and vomiting (PONV), urinary
retention and respiratory depression might retard their use in certain population of
patients4.
Intrathecal benzodiazepine was first suggested to possess `antinociceptive
properties by Haefely in 19756. It was not until a decade later that neuraxial
midazolam was demonstrated to have antinociceptive and analgesic efficacy in
animals and human studies7,8 by Goodchild et al, and Serrao J.M. and his co-
worker. Intrathecally administered midazolam attenuates post operative pain,
labour pain,cancer pain and chronic low back pain9. Furthermore neuraxial
midazolam administration lacks respiratory depressant effect, no post operative
nausea and vomiting (PONV}, no pruritus and decrease incidence of sedation
making it a more favorable agent in certain population of patients10. In addition to
intraoperative analgesia, effective pain control is crucial to the post operative
recovery of patients undergoing orthopaedic surgery, and optimization of post
operative analgesia improves the patient ability to participate in rehabilitation
session. Thus the assessment of the peri-operative analgesic effect and safety of
intrathecal midazolam was compared with intrathecal fentanyl in this study.
3
AIM OF STUDY
To compare the analgesic effect of intrathecal preservative-free fentanyl
and midazolam with 0.5% heavy bupivacaine in open reduction and internal
fixation of lower limb fracture under subarachnoid block.
OBJECTIVES
To compare quality of analgesia following administration of intrathecal
fentanyl and midazolam
To compare the side effect profile of the agents following administration of
the study drugs
To assess analgesic consumption in the first 24 hours in these patients.
HYPOTHESIS
Null Hypothesis: intrathecal midazolam provides better and long lasting
analgesia than intrathecal fentanyl
Alternate Hypothesis: intrathecal midazolam does not provide better and
long lasting analgesia than intrathecal fentanyl
4
JUSTIFICATION
The study is to determine whether intrathecally administered midazolam
compared with intrathecal fentanyl will provide excellent analgesia and better
side effect profile in patients undergoing open reduction and internal fixation of
lower limb fracture as was demonstrated previously in patients undergoing knee
arthroscopy. 10
There is limited anaesthetic personnel in Nigeria and this study will provide
an inexpensive, simple and readily available technique which can be employed to
provide excellent analgesia, early mobilization and rehabilitation of patients.
Furthermore elderly patients with high cardiovascular risk or other patients with
compromised cardiovascular and respiratory systems may benefit from this
technique and be able to have their surgical procedures with little or no adverse
effects. Also, the findings from the study will serve as local reference for other
investigators in future.
5
CHAPTER TWO
LITERATURE REVIEW
Subarachnoid block or spinal analgesia is the temporary neuraxial blockade
produced following administration of a local anesthetic agent singly or with other
spinal adjuvant into the cerebrospinal fluid.
The use of spinal analgesia for surgical procedures dates back to 1885, over
a century ago when August Bier performed the first successful clinical
subarachnoid block or spinal analgesia using intrathecal cocaine11. Adriani12and
his colleagues however established safe standardized technique that popularized
this method of analgesia. Furthermore, technological and pharmacological
research have improved the practice of subarachnoid block; bringing about
improved quality and duration of analgesia while reducing side effects to the
barest minimum.
Anaesthetists have placed drugs in the intrathecal space since the early days
of the specialty and even continuous infusion into intrathecal space first gained
acceptance in the 1980’s13 and had become common in the current practice of pain
medicine. The increase in utilization of intrathecal drug administration is
attributable to a better understanding of patient selection, advances in new drugs,
and improved ability to compound combinations of drugs and new drug
concentrations. Because drugs can be delivered directly into the spinal fluid, the
amount of drugs needed for equivalent analgesic effect is markedly reduced when
compared to oral, parenteral or epidural route and side effect profile is improved.
6
Subarachnoid block has enjoyed tremendous increase in popularity over the
past decade due to the financial motivation to decrease hospital cost, and
satisfaction for both patients and the anaesthetist. Furthermore, the technique is
associated with reduced intra-operative and post-operative intensity of care, as
well as decrease in recovery times, costs and side effects 14. There is also increased
post-operative alertness and increased mobility which facilitates rehabilitation
post-operatively as well as decreasing the risk of development of deep venous
thrombosis. There is potential economic saving and it is less expensive than
general anaesthesia 15.
Frequently, local anaesthetics are administered with opioids,
benzodiazepines and other analgesics or other sedative drugs in combination16.
One goal of using analgesics in combination is to achieve superior analgesia to
that obtained with one drug alone. A second goal of combining analgesics is to
significantly reduce the dose of each drug hence minimizing side effects.17,18
Combination of drugs should come close to achieving these goals when they act
synergistically to produce analgesia. Since pain control is the key to the post-
operative recovery of patients undergoing orthopaedic surgery, optimizing post-
operative analgesia improves the patients’ ability to participate in rehabilitation
session.
7
INTRATHECAL OPIOID
The use of intrathecal opioid was sequel to the discovery of highly specific
opioid receptors in the central nervous system (CNS) especially in the spinal cord
16 which brought a new enthusiasm for the possible realization of pure
antinociception without side effects. Increasing universal application of this
techniques in the 1980s, however resulted in a wide variety of clinically relevant
non – nociceptive side effects.3,4 Intrathecal opioids produced profound segmental
antinociception in doses much smaller than would be required for comparable
antinociception if administered systemically. Unlike the response to local
anaesthetic, there is no motor or autonomic blockade. Paralysis and hypotension
are also absent. Another critical advantage over local anesthetics is the availability
of specific opioid receptor antagonist naloxone.
Animal and human studies have demonstrated antinociceptive synergism
between intrathecal opioids and local anaesthetics during visceral and somatic
nociception18
Examples of opioids that can be given intrathecally are fentanyl, morphine,
methadone, sufentanil and alfentanil. Fentanyl a lipophilic opioid when
administered intrathecally has rapid onset of action and does not tend to migrate to
the fourth ventricle to cause delayed respiratory depression5. Its action is unlike
morphine which is hydrophilic, has slow onset of action, prolonged duration of
action and frequent delayed respiratory depression. Fentanyl is therefore a better
intra-operative analgesic and a safer alternative than morphine for the management
8
of early post –operative pain. Fentanyl acts by activating u- opioid receptor in the
human spinal cord.
Intrathecal opioids have the appeal of ease of administration at the time of
spinal local anaesthetic injection for surgical anesthesia. The side effects of
intrathecal opioids (fentanyl) might retard their use in certain groups of patients.3,4
These side effects could be in form of pruritus, post-operative nausea/vomiting
(PONV) and respiratory depression.
Possible risk of neurotoxicity entertained whenever any drug is
administered intrathecally has not been reported with intrathecal sufentanil a
congener of fentanyl in animal studies. There is no reported histological,
physiological or clinical evidence of neurotoxicity with preservative free spinal
fentanyl despite widespread clinical use of the drug19.
PHARMACO KINETICS OF INTRATHECAL OPIODS
Side effects of intrathecal opioids are caused by presence of the drug in
either cerebrospinal fluid or blood. Thus, side effects will be profoundly affected
by the pharmacokinetic behaviour. Intrathecal administration of opioids
immediately produces high cerebrospinal fluid concentrations of drugs that are
dose dependent19. Vascular re-absorption of opioids following intrathecal
administration does occur to some degree, but is clinically irrelevant 20. Fentanyl is
approximately 800 times as lipid soluble as morphine when administered
intrathecally, therefore morphine will exhibit slower onset and longer duration of
antinociception and a higher incidence of some side effects.
9
Fentanyl penetrates the spinal cord quickly, leaving little drugs to ascend
cephalad in the cerebrospinal fluid. Following lumbar intrathecal morphine
administration, appreciable cervical cerebrospinal fluid concentration occurs one
to five hours after injection while cervical cerebrospinal fluid concentration of
high lipophilic opioids similarly administered are minimal18. The underlying cause
of ascension of hydrophilic opioids is bulk flow of cerebrospinal fluid.
Cerebrospinal fluid ascends in a cephalad direction from the lumbar region
reaching the cisterna magna by 1 or 2 hours and the fourth and lateral ventricle by
3 to 6 hours Although coughing, sneezing or straining can affect movement of
cerebrospinal fluid, body posture does not .
Highly lipophilic opioids are removed from cerebrospinal fluid rapidly
secondary to vascular re-absorption and spinal cord penetration. In contrast,
hydrophilic opioids persist in the cerebrospinal fluid for prolonged period and may
depend on re-absorption through arachnoids granulation for elimination.
SIDE EFFECTS OF INTRATHECAL OPIOIDS
The four classic side effects of intrathecal/ spinal opioids are pruritus,
nausea, urinary retention and respiratory depression. Numerous other side effects
have been described and most are dose dependent. They are less common in
patients chronically exposed to either spinal or systemic opioids. Some side effects
are mediated via interaction with specific opioid receptors while others are not.
10
PRURITUS
The most common side effect of intrathecal opioids is pruritus. It may be
generalized but is more likely to be localized to the face, neck or upper thorax.
The incidence varies widely form 0 to 100%, and it is often elicited only after
direct questioning. Pruritus usually occurs within a few hours of injection and may
precede the onset of antinociception22
The pruritus induced by intrathecal opioid is likely due to cephalad
migration of the drug in cerebrospinal fluid and subsequent interaction with the
trigeminal nucleus in the medulla 23. The most common location of the pruritus is
in the facial area innervated by the trigeminal nerve. Altered central nervous
system(CNS) perception of pain may also play a role in pruritus induced by
intrathecal opioid .The trigeminal nucleus descends into the cervical region of the
spinal cord and becomes continuous with the substantia gelatinosa of the dorsal
horn. Opioid interaction in the substantia gelatinosa may thus initiate an “itch
reflex” through an indirect action of the trigeminal nucleus
Opioids can produce naloxone reversible pruritus without affecting plasma
concentration of histamine. Histamine release is not the underlying mechanism of
opioid induced pruritus. Interestingly, anti-histamines may be effective treatment
for pruritus likely secondary to their sedative effects.
Furthermore, rash following intrathecal opioid administration is very rare.
Pruritus also does not appear to be related to systemic absorption of opioid23.
11
RESPIRATORY DEPRESSION
The most dreaded side effect of intrathecal opioid is respiratory depression4
Only four months after initial utilization of intrathecal opioid in humans, life-
threatening respiratory depression was reported.24 Clinically important respiratory
depression has been reported following intrathecal fentanyl, morphine and
sufentanil.24, 25,26
It may occur within minutes of injection or may be delayed for hours. The
incidence requiring intervention is approximately 1% which is the same as
following administration of intravenous and intramuscular opioids.
Early respiratory depression occurs within two hours of injection of opioid.
This is likely to have resulted from systemic absorption of drug, since blood
concentration of opioid is proportional to the magnitude of respiratory
depression26. Cephalad migration in the cerebrospinal fluid however, may also
initiate early respiratory depression.
Delayed respiratory depression occurs more than two hours after injection
of opioid and is more common with administration of intrathecal morphine.
Continous infusion or repeated doses of a lipophilic opioid like fentanyl may also
initiate clinically relevant delayed respiratory depression. Cephalad migration of
opioid in the cerebrospinal fluid and subsequent interaction with opioid receptors
located in ventral medulla 25 is responsible for delayed respiratory depression.
Detection of respiratory depression induced by intrathecal opioid is
challenging, bradypnoea may or may not be present and hypercapnia may develop
despite a normal respiratory rate 25. Pulse oximeter may be valuable but must be
12
interpreted cautiously if supplemental oxygen is being administered. The most
reliable clinical sign appears to be depressed level of consciousness possibly
caused by hypercapnia5,27.
URINARY RETENTION
Incidence varies widely from 0 to 80% and occurs most often in young
male.3, 4, 23 Incidence is not dose related and is highest with intrathecal morphine.
The underlying mechanism is not related to systemic absorption of drug as it is
more common following spinal administration of opioids than after intramuscular
or intravenous administration of equivalent dose of opioid .
The underlying mechanism is likely related to interaction with opioid
receptors located in the sacral spinal cord. This interaction promotes inhibition of
sacral parasympathetic nervous system outflow which causes detrussor muscle
relaxation and an increase in maximal bladder capacity leading to urinary
retention. This effect could be reversed with naloxone.
NAUSEA AND VOMITING
The incidence of nausea and vomiting following intrathecal opioid is
approximately 30%. Although the underlying mechanism is not related to systemic
absorption of drugs, the incidence of nausea and vomiting following intravenous
opioid is the same. Nausea usually occurs within four hours of injection and
vomiting soon thereafter23. The incidence may or may not be dose related.
Nausea and vomiting induced by intrathecal opioid are likely the result of
cephalad migration of drug in the cerebrospinal fluid and subsequent interaction
13
with opioid receptors located in the area postrema. Sensitization of the vestibular
system to motion and decreased gastric emptying produced by opioids may also
play a role in nausea and vomiting induced by intrathecal opioids
INTRATHECAL MIDAZOLAM
The possibility that intrathecal benzodiazepines could influence a
nociceptive system was suggested in 1975, when Haefely et al6 demonstrated that
benzodiazepines interact with the gamma amino butyric acid {GABA} system.
This interaction was confirmed by Tallman et al, who showed that the binding of
benzodiazepine to its receptor is enhanced by GABA and that benzodiazepine by
also binding to GABA recognition sites, makes more free GABA available. It is
also known that an increase in the concentration of GABA in the central nervous
system by decreasing the degradation of GABA via inhibition of the enzyme
GABA transaminase or by administration of GABA reactor agonist like miscimol
enhances morphine analgesia28
Midazolam a water soluble benzodiazepine is analgesic in animal and
human studies after spinal but not systemic injection7,8,29 and since the early
1980’s, intrathecal midazolam has been reported to have antinociceptive action
and to be an effective analgesia agent in both animal and human subjects.
Midazolam appears to be effective as analgesic when given alone or when
combined with more traditional spinal analgesics.6,29 Spinally administered
midazolam attenuates post surgical pain and chronic low back pain7
Studies1,10,30 have revealed that intrathecal midazolam (1 or 2mg) prolonged
the post-operative analgesic effect of bupivacaine by approximately 2 to 4.5 hours.
14
The onset of first analgesic intake was delayed to 7 hours in orthopaedics patients
and decrease post-operative analgesic consumption was also observed in these
patients compared with control in the study.10,31 Van zundert30 and colleagues
have shown that the concentration and volume of subarachnoid injection do not
affect sensory block, motor block or duration of spinal anesthesia as long as the
dose of local anesthetic is constant, so the observed effect is attributed to the
injected midazolam.
In vitro autoradiography has shown that there is a high density of
benzodiazepine (GABA – A) receptors in lamina II of the dorsal horn in human
spinal cord, suggesting their possible role in pain modulation. Goodchild and
Serrao in 1987 reported that benzodiazepines might have analgesic effect at the
spinal cord level in animals8. Analgesic efficacy of intrathecal midazolam in
humans was demonstrated few years later. The selective opioid antagonist,
naltrindole suppresses the anti nociceptive effect of intrathecal midazolam,9, 32, 33
suggesting that intrathecal midazolam is involved in the release of an endogenous
opioid acting at the spinal δ – receptors. Cox and Collins also reported activation
of human k-opoid receptors following intrathecal administration of
midazolam34.The mechanism of its analgesic action is both indirect via
activation of benzodiazepine-GABA –A receptors in lamina II of the dorsal horn
of the spinal cord and directly via activation of δ and k(but not u) opioid receptors
in the central nervous system.
Possible neurotoxicity is the most serious risk of intrathecal midazolam as
with any agent given into the subarachnoid space. Animal studies have revealed
15
no damage to the spinal cord, nerve roots or meninges.35, 36 A single intrathecal
injection of 2mg midazolam did not cause any clinical neurological deficits but
produced significant anaglesia for two months in patients with chronic low back
pain7. Intrathecal midazolam was also effective after leg surgery without any side
effects 37. Several investigators have equally demonstrated the safety of neuraxial
administration of midazolam in humans7, 9, 10, 29-31, 36, 37.
In addition to the effectiveness of intrathecal midazolam against somatic
pain, an antinociceptive effect against visceral pain has been demonstrated in
rabbits subjected to intestinal distension 37 and in human after caesarean section 28
Intrathecal midazolam has been used in a continuous infusion in patients
with refractory neurogenic and musculo skeletal pain 36, 39.
Furthermore absence of post-operative nausea and vomiting (PONV),
pruritus, respiratory depression and sedation10 makes midazolam a more
favourable agent for intrathecal administration. This is particularly important in
patients with previous history of post operative nausea and vomiting (PONV) or
respiratory disease and the elderly for fear of post operative respiratory depression.
The advantages of intrathecal midazolam includes lack of respiratory
depressant effect, no nausea or vomiting, absence of pruritus and better
psychological acceptance by the patient, increased postoperative autonomy, easier
nursing care during and after the procedure, no delay in patient discharge, and
potentially reduced incidence of urinary retention while providing excellent
intraoperative analgesia that lasts longer in the post operative period.
16
Similarly, midazolam a water soluble benzodiazepine is more readily
available than opioids in our environment where supply of opioids is erratic and
highly restricted. The absence of side effects seen with intrathecal opioids during
administration of intrathecal midazolam is moving us closer to the possibility of
realization of the goal of pure antinociception without side effects.
17
CHAPTER THREE
RESEARCH DESIGN
PATIENTS AND METHODS
STUDY DESIGN
The study is a single blinded randomized controlled clinical trial in which
only the patients are blinded to the study drugs. Patients were randomized to either
control, fentanyl plus bupivacaine(FB) or midazolam plus bupivacaine(MB)
groups using table of random numbers
STUDY POPULATION
Patients aged eighteen years and above undergoing elective unilateral open
reduction and internal fixation of lower limb fracture under subarachnoid block
who are classified as American Society of Anaesthesiologists(ASA) I and II
status were studied.
SAMPLE SIZE
Sample size- The sample size was calculated using the formula
n = (Z+Z)2 x(p1q1)+(p2q 2
2
This is useful for independent samples with difference in proportions such
as sedation or quality of analgesia
n = sample size
Z =1.96 at 5%
18
Z= 1.28 at 90%
= type I error
= type II error
=p1 - p2, smallest clinically important difference to be detected
p=prevalence of undesirable effect in previous study,
q=1-p proportion
The prevalence of peri-operative sedation in previous study10 was used in
calculating the sample size.
Substituting,
Z + Z2 = 10.507
p1 =0.46
p2 =0.03
Therefore,
n =10.507 x 0.466 x 0.534 +0.033X0.967
0.4332
n =0.248844 +0.03191110.507
0.187489
n =0.280755 x10.507
0.187489
= 2.949893
0.187489
=15.73
Approximate sample size per group is 16
Sample size was increased by 10% to provide for attrition - 4.8
Approximately 5 patients; sum total of 53 patients.
19
SAMPLING PROCEDURE
This is a single-blind randomized study. The patients were randomly
divided into the following three equal groups according to the injected drugs using
the table of random numbers: a control group (B) that received 10mg of 0.5%
heavy bupivacaine, the MB group (midazolam + bupivacaine) received 10mg of
0.5% heavy bupivacaine plus 2mg of preservative-free midazolam hydrochloride
and the FB group (fentanyl + bupivacaine) that received 10mg of 0.5% heavy
bupivacaine plus 25g of preservative-free fentanyl.
EXCLUSION CRITERIA
Patients who refuse to be included in the study or are uncooperative:
Infection at the site of injection / sepsis
Coagulopathy / bleeding diasthesis
Severe hypovolaemia and increased intracranial pressure
Severe uncontrolled hypertension, or mitral stenosis
Pre-existing neurologic deficit
Patients with hypersensitivity to either midazolam or fentanyl
Complicated surgery that may be prolonged & result in major blood
loss.
Mute patient.
Patients with cardiorespiratory diseases
20
INCLUSION CRITERIA
Inclusion criteria
(a) Adult patients from 18 years and above scheduled for open reduction
and internal fixation of lower limb fracture(s).
(b) American Society of Anaesthesiologists physical status 1 and 2
(c) Consent given by patient.
CONSENT
An informed consent form was made available to all patients participating
in the study. The details of the procedure were explained to the patients in the
language they understand. (See appendix A for consent form sample)
METHODOLOGY
The approval of the hospital ethical committee was obtained to conduct this
single-blind randomized comparative study on adult patients undergoing unilateral
lower limb surgery. The orthopaedic department of the study centres were duly
informed before the commencement of the study and permission obtained to use
their patients. Patients were seen a day before surgery for pre-operative
assessment. All patients had routine work-up (Full Blood Count,
Urea/Electrolytes, Limbs and Chest X-ray) for surgery and if there was any
indication for special investigation, these were done. Patients were taught to use
the Visual Analogue Scale (VAS) preoperatively to assess pain and pain relief
after administration of post operative parenteral analgesic. In the theatre, the
21
patients were randomized into three groups; B (Bupivacaine group), MB
(Bupivacaine plus Midazolam) and FB (Bupivacaine plus Fentanyl)
The patients were preloaded with crystalloid at 10mls per kilogramme body
weight. Monitoring include non-invasive arterial blood pressure, heart rate and
pulse oximetry. The patients were in sitting position. Skin infiltration was
performed with plain lidocaine
In the sitting position, after establishing free flow of cerebrospinal fluid, the
B group received subarachnoid injection of 10mg of 0.5%. Hyperbaric
bupivacaine over about 20-30 seconds via 25G-Whitacre needle, with the needle
hole directed cranially. Patients in the MB group received 10mg of the same drug
(bupivacaine) plus 2mg of preservative-free midazolam injected over 20-30
seconds while the FB group received 10 mg of 0.5% hyperbaric bupivacaine
plus 25g of preservative-free fentanyl over 20-30 seconds. Patients were then
turned supine. Sensory and motor blocks were tested every five minutes after
intrathecal injection for the first fifteen minutes. Patients in each group were not
given supplementary oxygen, unless when oxygen saturation fell below 95% or
during hypotensive episodes. Patients that experienced inadequate analgesia
received supplementary analgesia of intravenous administration of fentanyl 2
µg/kg and the procedure was converted to general anaesthesia. Such patients were
however eliminated from the study
Hypotension, defined as systolic arterial pressure 30% less than baseline
value or less than 90mmHg, were treated with rapid infusion of crystalloid and
when this proved ineffective, slow infusion of 0.1mg epinephrine added to 500
22
mls of Ringers lactate was employed. Bradycardia was taken as heart rate less than
50 beats per minute, and was treated with iv atropine 0.5 –1.0mg.
MEASUREMENT
Data were collected by the investigator and collated using a data collection
form designed by the investigator with inputs from a statistician (See appendix B)
The non-invasive systolic, mean and diastolic blood pressure were
measured using automated oscillotonometry continuously every 5 minute.
Respiratory rate and oxygen saturation were also measured before spinal block
(baseline) and then continuously during the course of surgery.
The sensory and motor blockade were assessed every two minutes using
ethyl alcohol or ice cubes and Bromage scale23 respectively after administration of
spinal block every 5minutes for the first 15 minutes.
BROMAGE SCALE
0 - Full ability to flex the knee and foot.
1 – Ability to flex the knee, but inability to raise extended leg.
2 – Inability to flex the knee, but able to flex the foot.
3 –inability to move the legs or foot.
The quality of spinal anaesthesia was judged according to the need for
supplementary intravenous analgesics .Sedation was assessed using Ramsay
sedation score40 viz;
RAMSAY SEDATION SCORE
1- Patient is anxious and agitated
23
2- Patient is co-operative ,oriented and tranquil
3- Patient is drowsy but respond to command
4- Patient is asleep but with a brisk response to light glabellar tap or
loud auditory stimuli
5- Patient is asleep but with a sluggish response
6- Patient is asleep with no response.
Successful spinal block or analgesia was taken as surgical anaesthesia (loss
of temperature sensation T12 and complete motor block-Bromage 3) on the
operative side and non operated side.
Patient’s initial, age, gender, height, weight, American Society of
Anaesthesiologists ASA) status, indication and type of surgery, time of
establishment of subarachnoid block SAB) were obtained by the investigator.
Patients were monitored in the recovery room by qualified nursing staff who were
blinded to the study drugs for about forty five minutes to an hour before
transferring to the ward
Also time for first post operative analgesia was noted. Parenteral
pentazocine at a dose 0.5mg/kg weight was slowly administered intravenously
when patient’s pain intensity assessment using the visual analogue scale (VAS)
was ≥6.0 which connotes severe pain. The visual analogue scale consists of a
10cm line that ranges from ‘No pain’ to ‘Worst possible pain’. The patient or the
investigator then marks the point on the line to coincide with the reported level of
pain by the patient. The distance from ‘No pain’ to the point marked was then
measured and this gives a numerical score. Pain score at first pain medication &
24
number of analgesic doses requested in 24 hours were collected. Time interval
between the administration of intrathecal drug and the first post operative
analgesic dose was recorded
Undesirable events reported by patients were recorded, and include: incidence and
severity of PONV by a ‘four point’ verbal rating score 0 to 3 (where 0=none,
1=nausea, 2=vomited once and 3=repeated vomiting, pruritus (mild or
refractory), respiratory depression (through hourly monitoring of respiratory rate).
Protocol for the management of any undesirable effect intra and post
operatively were designed, and followed thus:
a. For respiratory rate of less than 8 breaths per min; incremental
intravenous dose of naloxone starting with 0.1mg plus oxygen
supplementation to fully reverse condition
b. For PONV Score 2-3; intravenous metoclopramide 10mg
c. For mild itching intravenous, chlorpheniramine 2 to 4mg or
Diphenydramine 12.5 to 25mg was to be given and for refractory
itching intravenous naloxone 0.1mg was to be administered.
d. For persistent urinary retention, catheterization was employed
STUDY SETTING
The study was conducted at the University College Hospital, Ibadan and
National Orthopaedic Hospital, Igbobi, Lagos.
PERIOD OF STUDY
The study was conducted over a six- month period.
25
FINANCIAL IMPLICATION
Patients only paid the required standard fee for anaesthesia and surgery.
DRUG
All the drugs used in this study; 0.5% heavy bupivacaine, atropine,
adrenaline or ephedrine, preservative free fentanyl and midazolam,
clopheniramine, naloxone, metoclopramide and pentazocine are all licensed for
clinical use in Nigeria.
STATISTICAL ANALYSIS
The data collected was entered into EPI Info version 6 and SPSS (Statistical
Package for the Social Sciences) 10. Data were presented using tables, graphs and
histogram.
Data description was by use of ranges, means and standard deviation. After
data editing and cleaning, statistical associations were determined using the chi-
square test for categorical variables and the ANOVA for continuous variables.
One way analysis of variance was performed (ANOVA) for normally distributed
data and non parametric tests were carried out for data that is not normally
distributed.
A p value less than 0.05 (<0.05) was considered statistically significant
26
CHAPTER FOUR
RESULTS
A total of 50 patients, American society of anaesthesiologist (ASA) I and
II status were studied out of 54 recruited for this study. The four excluded patients
had their subarachnoid block (SAB) converted to general anaesthesia (GA) due to
inadequate intraoperative analgesia
Patients were randomized into 3 groups (using table of random numbers) to either
receive:
(i) 0.5% heavy bupivacaine (AstraZeneca) 10 mg(2 mls) - B group
(ii) 25 micrograms of preservative-free fentanyl (Jansen) plus 10mg of 0.5%
heavy bupivacaine - FB group
(iii) 2mg of preservative free midazolam (Hoffman-La Roche, Basel
Switzerland) plus 10mg of 0.5% heavy bupivacaine – MB group.
The three study groups were comparable with respect to demographic
characteristics (Table1), American Society of Anesthesiologists (ASA) Status
(Figure 1), site of surgery (Table II), duration of surgery and other operative
conditions (Table III).
All the patients had adequate analgesia before surgical incision was made
with sensory block ≥ T12 level. The mean time to first post operative analgesic
dose in the fentanyl - bupivacaine (FB) and midazolam - bupivacaine (MB) groups
27
was significantly longer than the mean time in the control group B (P<0.001 ).
Midazolam appears to provide longer mean duration (5.04±0.99 hours) of
analgesia in the MB group than fentanyl in the FB group (4.73±0.89 hours)
clinically. There was no statistically significant difference in the mean duration of
analgesia between the FB and MB groups when compared to each other (Table
IV).
The mean dose of parenteral post operative analgesia (pentazocine) in 24
hours was higher in the B group, 148.1(±13.3) mg compared to FB group
108.8(±15.0) mg and MB group 105.0(±18.9) mg (Table IV). The frequency of
post operative analgesic administration in the first 24 hours was less in FB
3.6(±0.5) and MB 3.5(±0.6) groups than B group 4.9(±0.4) (Table IV).The
difference was statistically significant (p<0.001).However there was no significant
difference between FB and MB when compared with respect to frequency of post
operative analgesic administration in the first 24 hours
The mean Visual analogue scale (VAS) assessment of pain intensity at the
start of the first dose of parenteral post operative analgesic for the control group (B
group)was 7.0(±0.6),FB was 6.2(±1.3) and MB was 6.4(±1.3). There was no
statistically significant difference in the three groups (p=0.060).
The 4 hourly post operative pains score in 24 hours revealed that the FB
and MB groups had better pain relief (Figure 2) than the control group (B)
None of the patients in the control group (B) had significant hypotension whereas
one patient (5.9%) in FB and two patients (12.5%) in MB groups had hypotension
that required rapid infusion of crystalloid and epinephrine infusion (Table V)
28
Overall, the cardiovascular parameters were stable in all the three groups
through out the course of the open reduction and internal fixation (Figures 3 –
5).The mean arterial blood pressure (90-110mmHg) and mean pulse rate (82-
94b/min) were fairly constant though there were slight fluctuations in the mean
(125-145mmHg) systolic blood pressure in all the study groups.
One patient in the control group (5.9%) and none in the midazolam-
bupivacaine group (MB) had nausea and vomiting intra-operatively and post-
operatively compared to three (3) patients (17.7 %) in the fentanyl - bupivacaine
group (Table VI).
Level of sedation (Table VI) was noted to be higher in FB group as 3
patients (17.8 %) recorded Ramsay score 3 and 4 compared to 1 patient (6.3 %) in
the MB group. This was not statistically significant (p=0.456).
Pruritus was higher in the FB group (11.8%) compared to none in the other
two groups (Table VI). Urinary retention occurred in all three (3) groups to the
same extent in few of the studied patients with no statistically significant
difference (p=0.613) between them (Table VI).
None of the patients experienced apnoeic spells, bradypnoea or desaturation
intra operatively (Table VI). Figures 6 and 7 show normal respiratory rate (12-
16c/min) and oxygen saturation in all the patients in the recovery room. So there
was no respiratory depression post operatively in all the studied groups
29
Table I: Demographic Characteristics of the Patients
Control (B)
N=17
FB
N=17
MB
N=16
Gender (Male/Female) 10/7 10/7 7/9
Age in years (Mean ± SD) 47.8 (±16.9) 37.6 (±113.3) 46.2 (±17.1)
Weight in Kg (Mean ± SD) 79.0(±4.2) 66.7(±10.5) 72.8(±12.9)
30
0
2
4
6
8
10
12
Nu
mb
er
of
pa
tie
nts
B FB MB
Drugs given
Figure 1: American Society of Anaesthesiologists(ASA) of
the Patients in the Three Groups
ASA I
ASA II
31
Table II: Site of Open Reduction and Internal Fixation (ORIF) in the Study
Groups
Site of Surgery
B FB MB
N % N % n %
Femur and Hip
8 47.1 11 64.7 11 68.8
Ankle and
foot(ORIF/Arthrodesis)
5 29.4 3 17.6 4 25.0
Tibia(ORIF)
2 11.8 2 11.8 1 6.3
Knee(ORIF)
2 11.8 1 5.9 0.0 0.0
Total
17 100.0 17 100.0 16 100.0
32
Table III: Operative conditions. Results are presented as mean (±SD).
B
n= 17
FB
n=17
MB
n=16
P-value
Duration of surgery
Volume of fluid given
Blood loss
Blood Infused
107(10.4)
1975.68 ± 811.69
410.81 ± 500.16
108.11± 375.19
116(13.4)
1801.35± 622.33
515.68± 480.72
216.22 ± 433.66
109(16.8)
612.46+541880.
368.62+496.76
358.45+205.34
0.415
0.361
0.303
0.255
33
Table IV: Post operative Analgesia Data
Control (B)
N=17
FB
N=17
MB
N=16
F+ P
Time from SAB to first
analgesic dose in hours
(Mean±SD)
2.37(±0.30) 4.73(±0.89) 5.04(±0.99) 58.21 <0.001
Frequency of analgesia
24hrs post op
4.9(±0.4) 3.6(±0.5) 3.5(±0.6) 35.98 <0.001
Visual analogue scale at
first post op analgesia
dose
7.0(±0.6) 6.2(±1.3) 6.4(±1.3) 3.008 0.060
Total Dose of analgesic
given 24hrs post
op(Mean±SD)
148.1(±13.3) 108.8(±15.0) 105.0(±18.9)
+Analysis of variance (ANOVA) used to compare the groups
P is significant at <0.05
34
Figure 2: Mean 4 Hourly Pain Score in the first 24hours Post operatively
0
1
2
3
4
5
6
7
8
9
10
0 4 8 12 16 20 24
Time (Hours)
Pain
Sco
re
B FB MB
35
Table V: Frequency of hypotension Post Subarachnoid Block
Drug
Normal BP Hypotension
N % n %
B 17 100.0 0 0.0
FB 16 94.1 1 5.9
MB 14 87.5 2 12.5
FB vs MB - Yates’ corrected X2 = 0.001; p = 0.956
36
Figure 3: Mean of Systolic Blood Pressure Changes Post Injection of Study
Drugs
1 1 5
1 2 0
1 2 5
1 3 0
1 3 5
1 4 0
1 4 5
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5
T im e (m in u te s )
Blo
od
Pre
ss
ure
(m
mH
g)
B
F B
M B
37
Figure 4: The Mean Arterial Blood Pressure Changes Post
Injection of Study Drugs
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40 45
Time (minutes)
Blo
od
Pre
ss
ure
(m
mH
g)
B
FB
MB
38
Figure 5: Mean Heart Rate ChangesPost Injection of Study
Drugs
76
78
80
82
84
86
88
90
92
94
0 5 10 15 20 25 30 35 40 45
Time (minutes)
He
art
ra
te (
Be
at/
min
ute
)
B
FB
MB
39
Table VI: Perioperative Undesirable Events
Control (B)
N=17
FB
N=17
MB
N=16
X2 P
Pruritus, n(%) 0(0.0) 2(11.8) 0(0.0) 4.041 0.132
PONV n(%) 1(5.9) 3(17.7) 0(0.0) 2.023 0.364
Respiratory distress, n(%) 0(0.0) 0(0.0) 0(0.0) - -
Urinary retention, n(%) 1(5.9) 1(5.9) 1(5.9) 0.980 0.613
Allergy, n(%) 0(0.0) 0(0.0) 0(0.0) - -
Sedation, n(%) 0(0.0) 3(17.6) 1(6.3) 1.003 0.456
P is significant at <0.05
40
Figure 6:
Mean Respiratory Rate Changes in the Recovery Room
0
2
4
6
8
10
12
14
16
18
0 5 10 15 20 25 30 35 40 45
Time (minutes)
Resp
irato
ry r
ate
(B
reath
/min
ute
)
B
FB
MB
41
Figure 7: Mean Oxygen Saturation Changes in the Recovery
Room
97
97.5
98
98.5
99
99.5
0 5 10 15 20 25 30 35 40 45
Time (minutes)
Sa
O2
(%
)
B
FB
MB
42
CHAPTER FIVE
DISCUSSION
. Subarachnoid block because of its ability to cause profound muscle
relaxation, provide good analgesia and reduced blood loss has often been favoured
for procedures involving the lower extremities, especially orthopaedic and
urological procedures41. Furthermore addition of adjuncts like midazolam and
fentanyl to local anaesthetic like 0.5% bupivacaine at the time of subarachnoid
block has been proven to provide excellent and superior analgesia of longer
duration as well as reduced side effects.
The dose of 2mg of preservative- free midazolam and 25microgram of
preservative - free fentanyl were used as adjunct in the other two study groups
based on previous work 2,10,30 which described excellent analgesia of longer
duration at these doses with minimal effects. Van Zundert and colleagues30 in
response to critics that observed difference in block quality seen is due to different
volume of injected drugs have shown that the concentration and volume of
subarachnoid injection do not affect sensory block, motor block and duration of
spinal anaesthesia as long as the dose of local anaesthesic agent is constant as it
was in this study. So the observed effect is attributed to the injected drugs -
midazolam and fentanyl.
Sensory block during subarachnoid block was assessed by disappearance
of temperature discrimination using ethyl alcohol as has been used by previous
workers42. Other methods include use of ether drops, ice blocks and spray of
volatile mixture of dichloro fluoromethane and trichloromonofluoromethane43.
43
Compared with prinprick technique, the temperature discrimination test is more
accurate, less aggressive, easier to perform and easier to reproduce if performed by
different observers. Loss of temperature discrimination affects one or two
dermatomes higher than pinprick but its onset and regression closely parallel those
of the sensory block level assessed by pinprick.43 The motor block was assessed
using the modified Bromage score. This had been criticized as being only a
qualitative test and not quantitative44,45 like measuring isometric muscle force
which gives precise description and degree of motor blockade, however this test
was enough to assess motor blockade in this study. Successful spinal block or
surgical anaesthesia in this study was loss of temperature sensation > T12 and
complete motor block Bromage 3 on the lower limbs.
In this study 2mls (10mg) of 0.5% hyperbaric bupivacaine was used to
induce spinal analgesia in all the three groups as was used in previous studies7,46
to achieve higher satisfactory level block for analgesia for operations above the
knee and lower extremities. Hyperbaric 0.5% bupivacaine was favoured rather
than the isobaric to minimize the risk of excessive rostral spread and total spinal
anaesthesia following the use of isobaric bupivacaine.
This study revealed that the perioperative analgesic effect of bupivacaine
was potentiated by the action of intrathecal fentanyl and midazolam. The addition
of 25µg of fentanyl or 2mg midazolam to 10mg of 0.5% hyperbaric bupivacaine
lengthened the post-operative analgesic period. There is also statistically
significant difference in the duration of analgesia in FB & MB groups.
44
This was manifested by delayed onset of first analgesic intake to a mean of
5.04(±0.99) hours and 4.73(±0.89) hours in the MB and FB groups respectively. In
addition patients in the fentanyl and midazolam groups received less parenteral
pentazocine than the control group (Table I) in the first 24hours post operatively.
This result follows the pattern of result that had been reported in previous
studies.2,10,30 Abdelfatah10et al reported a potentiation of analgesic effect of 0.5%
hyperbaric bupivacaine by additional 3.15 hours and 3.35 hours following addition
of 25µg of preservative - free fentanyl and 2mg preservative - free midazolam in
their study. Kim30 et al reported prolonged analgesic effect of bupivacaine in the
patients having their surgery under subarachnoid block of up to seven hours when
midazolam was added compared to control whose analgesic effect was about three
hours.
The analgesic effect of fentanyl is due to stimulation of µ opioid receptor
that is abundant in the central nervous system. 1,4 Intrathecal midazolam acts on
GABA - A receptors of dorsal horn of spinal cord directly as well as indirectly
releasing endogenous opioid that act on κ and δ opioid receptors10,34. Post –
operative analgesic requirement of FB and MB groups was statistically less than
that of control group and this was similar to what Kim et al reported in their study.
Pentazocine though not an agonist at µ opioid receptor was used as post
operative analgesia because it was the only available narcotic available in Nigeria
at time this study was being conducted
Pain relief using the Visual Analogue Scale (VAS) was found to be better
in the FB and MB groups than the control group (Figure 7) in the first 24 hours.
45
Soyannwo et al 47 in their study showed that the VAS is an effective tool to assess
pain and pain relief in Nigeria. It also has significant positive relationship with
four/five point verbal rating scale. The VAS is a quick and easy method of scoring
pain and can be used at frequent intervals. It is sensitive to small changes, can be
used to measure pain intensity and pain relief and it is easy for the patient to use.
The disadvantages are that pain is only scored on a single dimension and the score
is influenced by the most prominent feature of the pain. Some patient groups like
the elderly or the visually impaired may also find it difficult to use, but such
patients were not included in this study.
All the patients in this study were prehydrated with 10mls/kg body weight
of crystalloid (e.g 0.9% Salines, Ringers lactate solution) prior to subarachnioid
block to prevent hypotension.48 Studies have concluded that volume loading is a
satisfactory method of preventing hypotension49,50 during subarachnoid
block(SAB). Although some authors have suggested that crystalloid preload was
of little use in the prevention of hypotension especially in the elderly and during
caesarean section. The hypotension is primarily due to blockade of preganglionic
sympathetic fibres resulting in decrease cardiac output.
Crystalloid was chosen in this study on account of ready availability, it is
non allergenic, cheap and supply at no extra cost to the patient in the perioperative
period. Hypotension has been variously defined as systolic arterial pressure less
than 100mHg or as greater than 20% or 30% decrease from baseline in systolic
blood pressure and changes in mean arterial pressure. Studies48,49 previously
supports the choice of systolic blood pressure less than 90mmHg or 30% decrease
46
from baseline systolic blood pressure as significant haemodynamic change and
this was what was used in this study. Significant hypotension was manifested by
5.9% of patients in the FB group and 12.5% of patients in the MB group. This is
not statistically significant (p=0.956) after Yates correction was factored into the
analysis. Hypotension was managed with rapid intravenous infusion of crystalloid
and or epinephrine. This was guided by some successes obtained with its use,
especially when ephedrine the closest of all the vasopressor to the “ideal
vasopressor” was not available.51,52 The ideal vasopressor is one that is capable of
reversing the adverse physiological changes in the sympathetic nervous system
without inducing its own adverse effects.
Other agents that have also been shown to be effective for treating
significant hypotension includes methoxamine, a pure peripheral vasoconstrictor
but which can cause reflex bradycardia. It is particularly useful in treating
hypotension associated with tachycardia. Phenylephrine, metaraminol and
dopamine can also be used.
Patient acceptance of subarachnoid block is often better when accompanied
by light sedation, however for methodological reasons, the patients were not
routinely sedated. The level of sedation peri-operatively was assessed using the
Ramsay sedation score which has been validated as an effective tool for assessing
level of sedation in anaesthesia and critical care.
Sedation was statistically significantly higher in the FB group than in the
control and MB group (p=0.04) a similar pattern to what was previously described
by Abdelfatah and his colleagues.10 This is rarely a significant problem with
47
moderate drug dosage. It results from the cephalad spread of the drug in the
cerebrospinal fluid to opioid receptors in the thalamus, limbic system and cerebral
cortex.
In comparison with previous studies54,55 bradycardia in this study was
defined as heart rate less than fifty (50) beats per minute. This value was thought
to be an appropriate endpoint of intervention because of the group of patients
involved (ASA 1 and 2) in this study. Other categories of patient may require
earlier intervention.
No patient in this study developed bradycardia as defined by the study
protocol( HR<50 beats/min). Carpenter et al54 identified low resting heart rate in
their study. Use of beta blocker, ASA physical status 1, peak block height and first
degree atrioventricular block were important factors in the development of
perioperative bradycardia during subarachnoid block. Elevated baseline heart rate
seen in the studied patients might have increased the threshold for the
development of bradycardia.
Bradypnoea, a respiratory rate of less than eight in one minute was
arbitrarily chosen as the cut-off for ventilatory or respiratory depression together
with loss of consciousness and fall in oxygen saturation based on the fact that
normal respiratory rate for adult is usually 12-16 per minute and that it is directly
related to minute ventilation. Direct measurement of the tidal volume and minute
volume using Wright’s spirometer would have given more objective assessment of
the respiratory system, this was however not available.
48
There was no bradypnoea, or dropping oxygen saturation value in any of
the studied patients (Figures 5 and 6). This seems to show that the level of the
block alone may not be an important factor in the development of desaturation /
respiratory depression during spinal analgesia. Other important factors are baseline
saturation and age of the patient. Manara et al 55 reported that subarachnoid block
(SAB) may be associated with decreasing level of oxygen saturation but will
usually be maintained around 94-95%, therefore it is logical that patients with
baseline oxygen saturation ( SP02) ≤ 96% may easily desaturate.
Intraoperative nausea/ retching and vomiting was found to be more in the
fentanyl bupivacaine group than in the midazolam bupivacaine and control groups.
No patient however vomited in the midazolam – bupivacaine group. This could be
due to cephalad migration of the opioid in the cerebrospinal fluid and subsequent
interaction with µ opioid receptors located in the area postrema. The incidence
(17.7%) in this present study appears lower than (40%) described previously.4,10
The patients were all relieved with intravenous administration of metoclopramide.
None of the patients vomited in the ward post operatively. Amanor-Boadu et al 56
in their study found that PONV was more common in the ward especially during
transfer / movement
Pruritus was also present in the FB group more than B and MB group
(Table IV) although this was not statistically significant (p= 0.132). Pruritus seen
is due to effect of intrathecal opioids .It appears to be localized to the face and
upper thorax in this study which is the classical location of opioid – induced
pruritus. It is due to the cephalad spread of the opioid in the cerebrospinal fluid to
49
the trigeminal nucleus in the medulla. It is important to note that none of the
patients who experienced pruritus required treatment as it was mild and was well
tolerated when patients were reassured. Furthermore pharmacological intervention
was not given for methodological reasons as antihistamines may likely sedate
patients and naloxone could reverse the opioid induced analgesia. Hamber 17 et al
described similar incidence in their study.
The vital signs in the first forty five minutes after subarachnoid block were
noted for this study so as to ensure that effects seen are directly related to the
spinal block and not due to haemorrhage.
LIMITATION
Double blinded study would have offered better result as it is more likely
to eliminate the slight investigator bias seen in single blinded study. A larger
sample size will ensure that inference can be confidently made
CONCLUSION
Intrathecal midazolam prolongs analgesic effect of 0.5% hyperbaric
bupivacaine more than intrathecal fentanyl but is not statistically significant.
Intrathecal midazolam provides a better side effect profile than intrathecal
fentanyl owing to its lack of nausea, pruritus and sedation. More excellent
analgesia is provided when adjunct is added to bupivacaine and there is associated
decrease post – operative analgesic requirement and better pain relief.
50
RECOMMENDATION
When patients with history of PONV, elderly cardio - respiratory diseases
present for ORIF or other lower limb surgery, intrathecal midazolam -bupivacaine
combination can be used to offer excellent analgesia of longer duration with
minimal side effect.
51
ETHICAL CONSIDERATIONS
1. Confidentiality of Data
Patients’ participation in this research is confidential. It is only the
investigator who has access to the patient’s identity and to the information
that can be associated with their identity. In the events of publication of this
research, no personal identity information will be disclosed.
2. The protocol of this study will be translated to patients own language for
better understanding and if there is a language barrier an interpreter will be
employed for the purpose.
3. Beneficence to the participants
The patients will not be required to pay for the study drugs. The outcome of
this study will help in providing better care (analgesia) for fracture patients
in future which will facilitate their recovery, mobilization and
rehabilitation.
4. Risk
Patient will not be exposed to any treatment not indicated. The patients will
not be exposed to any additional risk as a result of their participation in the
study.
52
APPENDIX A
PATIENT INFORMED CONSENT
Dear patient,
You are being asked to participate in a research/ study. In order to decide
whether or not you should agree to be part of this research study, you should
understand enough about the research to make an informed judgment.
This consent form gives detailed information about the study the
investigator will discuss with you. Once you understand the study, you will be
asked to sign this form if you wish to participate. The research study being
proposed to you is; comparison of the analgesic effect of intrathecal fentanyl and
midazolam in open reduction of lower limb fracture.
PURPOSE OF THE STUDY
The purpose of this study is to see if there are differences in the post
operative analgesic effect of the study drugs as well as their side effect profile.
DESCRIPTION OF THE RESEARCH PROCEDURES
The surgery you are about to undergo will be facilitated by provision of
spinal anaesthesia. This involves injecting a drug into the cerebrospinal fluid.
The injection is at the lower back, in the midline away from the spinal cord with
the patient sitting or lying down on one side. Few minutes after injection is given,
there is an experience of numbness in both lower limbs.
This signifies the onset of anaesthesia in the limbs. Only patients coming
for surgery of one of the lower limbs will take part in this study. For the purpose
53
of this study you will be allocated by chance either to the group that will have
anaesthesia only via injection of a single agent or combination of either of two
drugs. The blood pressure, heart rate, respiratory rate, time of spinal block, level
of sedation, duration/quality of analgesia and the percentage of oxygen in the
blood of the three groups will be recorded and compared.
STATEMENT OF CONFIDENTIALITY
Your participation in this research is confidential. Only the investigator
will have access to your identity and to information that can be associated with
your identity. In the event of publication of this research, no personally
identifying information will be disclosed.
BENEFITS
The result of this study will help in providing better care for patients like
you in future.
RISKS
You will not be exposed to any treatment that is not usually indicated for
your surgery. Taking part in this study will not expose you to any added risk.
FINANCIAL COST
There will be no additional charges to you for taking part in this study.
VOLUNTARY PARTICIPATION
The choice to enter or not to enter this study is yours. You are in a position
to make a decision if you understand what the doctor has explained and what you
54
have read about the research study. If you decide not to participate, all usual and
customary treatment will be made available without prejudice. You have the right
to withdraw at any time.
The UCH/UI ethical review committee, which is responsible for making
sure that research with patients is appropriate, has reviewed this study.
If you have any questions or need more information about the conduct of
this study, contact Dr. O. N. Akanmu, Dept. of Anaesthesia, UCH, 08023530389
I have read this consent form and the research study has been explained to my
satisfaction.
PERSON OBTAINING CONSENT
………………………… …….………………….
SIGNATURE DATE
PARTICIPANT
…………………………………… ………………….
THUMB PRINT/SIGNATURE DATE
INVESTIGATOR
…………………………… ………………….
SIGNATURE DATE
55
APPENDIX B
COMPARISON OF THE ANALGESIC EFFECT OF INTRATHECAL
FENTANYL AND MIDAZOLAM DURING OPEN REDUCTION OF
LOWER LIMB FRACTURE
DATA COLLECTION FORM
SECTION A: BIODATA
(i) Serial number in study –
(ii) Initial
(iii) Age –
(iv) Sex -
(v) Height (cm)-
(vi) Weight (kg -
(vii) ASA class -
(viii) Diagnosis -
(ix) Type of surgery -
SECTION B: REGIONAL BLOCK
(i) Injected drug ___________
(ii) Time of administration of intrathecal drug
(iii) Assessment of block before commencement of surgery
56
5
mins
10
mins
15
mins
Sensory
block level
Operative side (1)
Contralateral side (2)
Motor
(bromage
scale)
Operative side (1)
Contralateral side (2)
(iv). Quality of analgesia (Excellent / Good / Poor
Supplementary analgesia/sedation given (Yes / No)
If yes, indicate agent and dose given
If yes, indicate duration of block before analgesic
Pain Score at time of patients complain
Procedure converted to general anaesthesia (Yes /No)
(vi) Sedation(Yes/No Sedation
score(Ramsay)
(vii) Pruritus (Yes/No)
Quality (mild/refractory)
Intervention:
(viii Other undesirable ,intraoperative event(s: (nausea ,vomiting,……
………………………………………………………………………………
57
SECTION C: INTRAOPERATIVE MEASUREMENTS
Baseline (0) 5 10 15 20 25 30 35 40 45
SAP
MAP
DAP
HR
RR
SpO2
Key
SAP - Systolic arterial pressure
MAP - Mean arterial pressure
DAP - Diastolic arterial pressure
HR - Heart rate
RR - Respiratory rate
SpO2 - Arterial oxygen saturation.
Duration of Surgery (hours):
Estimated Blood Loss (mls):
Volume of Intra-operative Crystalloid (mls):
Volume of Blood Transfused (mls):
58
SECTION D: POST OPERATIVE DATA
POST-OPERATIVE MEASUREMENTS (RECOVERY ROOM)
Baseline (0) 5 10 15 20 25 30 35 40 45
SAP
MAP
DAP
HR
RR
SpO2
Key
SAP - Systolic arterial pressure
MAP - Mean arterial pressure
DAP - Diastolic arterial pressure
HR - Heart rate
RR - Respiratory rate
SpO2 - Arterial oxygen saturation
i. Duration of block before administration of analgesic post surgery
ii. Pain score before administration of first dose post operative analgesic
iii. 4hourly postoperative Pain score
First ………..
Second …………
Third …………
Fourth ………….
59
Fifth …………
Sixth …………
iv Analgesic Consumption in 24 hours : …….(mg
Postoperative Undesirable Effect
i. Pruritus (Yes/No)
Quality(mild/refractory)
Intervention
ii Post operative nausea and vomiting(PONV):Yes/No
PONV Score
Treatment /intervention
iii Respiratory Depression :Yes/No
Intervention
iv Urinary Retention :Yes/No
Intervention
v Allergy : Yes /No
Intervention/therapy
vi Sedation : Yes /No
Sedation score (Ramsay
vii Others(please specify):sensory /motor disturbance, bladder
dysfunction ,bowel dysfunction
60
REFERENCES
1. Rathmell JP, Lair TR, Nauman B. The role of Intrathecal Drugs in the
Treatment of Acute Pain. Anesth. Analg. 2005;101: S30–S43
2. Tucker AP, Mezzatesta J, Nadeson R. Intrathecal Midazolam II: Combination
with Intrathecal Fentanyl for Labor Pain. Anesth. Analg. 2004;98: 1521-27
3. Ben-David B, Solomon E, Levin H. Intrathecal fentanyl with small dose dilute
bupivacaine: better anaesthesia without prolonging recovery. Anesth Analg.
1997; 85: 560-5
4. Morgan M. The rational use of intrathecal and extradural opioids. Br. J.
Anaesth. 1989; 63: 165 –188.
5. Etches RC, Sandler AN, Daley MD. Respiratory depression and spinal
opioids. Can. J. Anaesth. 1989; 36: 165 – 185.
6. Haefely W, Kulscar A, Mahler H. Possible involvement of GABA in the
central action of benzodiazepines. In: Costa E, Greegard P (Eds).Mechanism
of action of benzodiazepines. New York: Raven Press, 1975; 131 –151.
7. Serrao JM, Marks RL, Morley SJ, Goodchild CS. Intrathecal midazolam for
the treatment of chronic mechanical low back pain: a controlled comparison
with epidural steroid. Pain 1992; 48: 5 – 12.
8. Goodchild CS, Serrao JM. Intrathecal midazolam in rat: evidence for spinally
mediated analgesia. Br. J. Anaesth. 1987; 59: 1563 –1570.
9. Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam: A
cohort study investigating safety. Anesth. Analg. 2004; 98:1512 -20.
10. Abdelfatah AM, Fawaz AA, Al –Azazi HM. The post operative analgesic
effect of intrathecal fentanyl versus midazolam in knee arthroscopy. Egy. J.
Anaesth. 2003;19: 173 –177.
11. Wulf HFW .The centennial of spinal anaesthesia. Anesthesiology 1998; 89:
500 – 508.
12. Gogarten W, Van Aken H. A century of regional analgesia in obstetrics. Anesth.
Analg 2000; 91: 773 – 775.
13. Freedman JM, Li DK, Drasner K. Transient Neurologic Symptoms after Spinal
Anaesthesia. Anesthesiology 1998; 89: 633-41
61
14. Parnas SM, McCarthy RJ, Bach BRJ, Corey ER, Hasson S, Werling MA et al.
A prospective evaluation of epidural versus general anaesthesia for outpatient
arthroscopy. Anesthesiology 1980; 73: A23.
15. Allen HW, Mulroy MF, Fundis K. Regional anaesthesia versus propofol
anaesthesia for outpatient hand surgery. Anesthesiology 1993; 79: A1.
16. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue.
Science 1973; 179: 1011 –1014.
17. Hamber EA, Viscomi CM. Intrathecal lipophilic opioids as adjuncts to
surgical spinal anaesthesia. Reg. Anesth Pain Med 1999; 24: 255-63 .
18. Ben-David B, DeMeo PJ, Lucyk C, Solosko D. A comparison of minidose of
lidocaine-fentanyl spinal anaesthesia and local anesthesia/propofol infusion
for outpatient knee arthroscopy. Anesth. Analg. 2001; 93: 319-25.
19. Ionescu TI, Taverne RHT, Houweling PL. Pharmacokinetic study of
extradural and intrathecal sufentanil anaesthesia for major surgery. Br. J.
Anaesth. 1991; 66: 458 – 464.
20. Max MB, Inturrisi CE, Kaiko RF, Grabinski PY, Li CH, Foley KM. Epidural
and intrathecal opiates: cerebrospinal fluid and plasma profiles in patients
with chronic cancer pain. Clin. Pharma. Therapy 1985; 38: 631 – 641.
21. D’Angelo R, Nelson K, Meister G. Dose response study of spinal fentanyl in
early labor. Anesthesiology 1998; SOAP: A17
62
22. Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates.
Pain 1988; 33:149 – 160.
23. Bromage PR, Camporesi EM, Durant PAC. Non respiratory side effects of
epidural morphine. Anesth. Analg. 1982; 61: 490 - 495.
24. Liolio A, Anderson FH. Selective spinal analgesia. Lancet 1979; 2: 351-353.
25. Palmer CM. Early respiratory depression following intrathecal fentanyl –
morphine combination. Anesthesiology 1991; 74: 1153 – 1155.
26. Whiting WC, Sandler AN, Lau LC, Chovaz PM, Slavchenko P, Daley D.
Analgesic and respiratory effects of epidural sufentanil in patients following
thoracotomy. Anesthesiology 1988; 69: 36 – 43.
27. Ready LB, Oden R, Chadwick HS, Benedetti C, Rooke GA, Caplan R, Wild
LM. Development of an anesthesiology-based post operative pain
management service. Anesthesiology 1988; 68: 100-106.
28. Tallman JF, Thomas JW, Gallager DW. GABAergic modulation of
benzodiazepines binding site sensitivity. Nature (London) 1978; 383 –385.
29. Valentine JM, Lyons G, Bellamy MC. The effect of intrathecal midazolam on
post operative pain. Eur. J. Anaesth. 1996; 13: 589 – 593.
30. Kim MH, Lee YM. Intrathecal midazolam increases the analgesic effect of
spinal blockade with bupivacaine in patients undergoing haemorrhoidectomy .
Br. J. Anaesth. 2001; 86: 77 – 79.
31. Faull RLM, Villigert JW. Benzodiazepine receptors in human spinal cord; a
detailed anatomical and pharmacological study. Neuroscience 1986; 17:791 –
802.
32. Goodchild CS, Guo Z, Musgreave A, Gent JP. Antinociception by intrathecal
midazolam involves endogenous neurotransmitters acting at spinal cord delta
opioid receptors. Br. J. Anaesth. 1996; 77: 758 – 763.
33. Cox RF, Collins MA. The effects of benzodiazepines on human opioid
receptor binding and function. Anesth. Analg. 2001; 93: 354 –358
34. Goodchild CS, Noble J. The effects of intrathecal midazolam on sympathetic
nervous system reflexes in man. Br. J. Clin. Pharmacology 1987; 23:279 –
285.
63
35. Serrao JM, Mackenzie JM, Goodchild CS, Gent JP. Intrathecal midazolam in
the rat: an investigation of possible neurotoxic effects. Eur. J. Anaesth. 1990;
7: 115 – 122
36. Johansen MJ, Gradert TL, Satterfield WC, Baze WB, Hildebrand K, Trissel
L et al. Safety and efficacy of continuous intrathecal midazolam infusion in
the sheep model. Anaesth. Analg . 2004; 98: 1528 – 35.
37. Nishiyama T, Odaka Y, Hirasaki A, Mikane T, Kobayashi O, Seto K.
Epidural midazolam with saline- optimal dose for post operative pain. Masui
1992;41: 49 – 54
38. Naguib M, Elhattab YS, El Gammal M, Seras M. Midazolam for caudal
analgesia in children. Can. J. Anaesth. 1995; 42: 758 – 764
39. Borg PA, Krijnen HJ. Longterm intrathecal administration of midazolam and
clonidine. Clin. J. Pain.1996; 12: 63 – 68.
40. Ramsay MAE, Savege TM, Simpson BRJ, Godwin R. Controlled-sedation
with alphaxolone-alphadolone. Br. Med. Journal 1974; 2: 656-59
41. Millar JM, Jago RH, Fawcett P. Spinal anaesthesia for transurethral
prostatectomy. Comparison of plain bupivacaine and hyperbaric lignocaine.
Br. J. Anaesth. 1986; 58: 862-867
42. Sakura S, Sakaguchi Y, Shinzawa M, Hara K. The assessment of dermatomal
level of surgical anaesthesia after spinal tetracaine. Anesth. Analg. 2000;
90:1406 – 10.
43. White JL, Stevens RA, Kao T. Differential sensory block: Spinal versus
epidural lidocaine (report of investigation) Can. J. Anaesth. 1998; 45:1049 –
53.
44. Pargger H, Hampl KF, Aeschbach A, Scheider MC. Combined effect of
patient variables on sensory block level after spinal with 0.5% plain
bupivacaine. Acta Anaesthesiologica Scandinavica. 1998; 42: 430 – 4.
45. Lanz E, Theiss D, Kellner G. Assessment of motor blockade during epidural
anaesthesia. Anesth. Analg. 1983; 62: 889 – 93.
46. Esmaoglu A, Boyeci A, Ersoy O, Guler G, Talo R . Unilateral spinal
anaesthesia with hyperbaric bupivacaine. Acta Anaesthesiologica
Scandinavica 1998; 42:1083 – 7.
64
47. Soyannwo OA ,Amanor – Boadu SD , Sanya AO, Gureje O . Pain assessment
in Nigerians – Visual Analogue Score and Verbal Rating Scale compared. W.
Afr. J. Medicine 2000; 19(4) :242 – 5
48. Casati A, Fanelli G, Berti M, Beccaria P. Cardiac performance during
unilateral lumbar spinal block after crystalloid preload. Can. J. Anaesth. 1997;
44(6): 623 – 28.
49. McCrae AF, Wildsmith JAW. Prevention and treatment of hypotension during
central neural block. Br. J. Anaesth. 1993; 70: 672 – 80.
50. Wenneberg E, Frid I, Haljamae H, Wenngren M. Comparison of Ringers
acetate with 3% dextran 70 for volume loading before extradural Caesarian
section. Br. J. Anaesth. 1990; 65: 654 – 60.
51. De Negri P, Borrelli F, Salvatore R, Visconti C, De Vivo P, Mastronardi P.
Spinal anaesthesia with clonidine and bupivacaine in young humans;
interactions and effect on cardiovascular system. Minerva Anaesthesiologica
1997; 63: 119 – 25.
52. Injala JK, Jaakkola PW, Pitkanen MT, Korkeilla JE. Restricted spinal
anaestheisa for ambulatory surgery: a pilot study. Eur. J. Anaesth. 1999; 16: 2
– 6.
53. Bromage PR. A comparison of the hydrochloride and carbonated salts of
lignocaine and prilocaine in epidural analgesia. Acta Anaesthesiologica
Scandinavica 1965; 16: 55 – 69.
54. Carpenter RL, Caplan RA, Brown DL, Stephenson C. Incidence and risk
factors for side effects of Spinal Anaesthesia. Anesthesiology 1991; 76(6):
906 – 12.
55. Manara AR, Smith DC, Nixon C. Sedation during spinal anaesthesia: a case
for the routine administration of oxygen. Br. J. Anaesth. 1989; 63; 343 – 46.
56. Amanor-Boadu SD, Soyannwo OA. Post operative nausea and vomiting in
Nigerians. E. Afr. Med. Journal 1998; 75(4): 243 – 45.