COMPARATIVE STUDY OF THE EFFICACY OF ONDANSETRON VERSUS TRAMADOL IN THE PREVENTION OF POSTANAESTHESIA SHIVERING FOLLOWING ELECTIVE CAESAREAN SECTION UNDER SPINAL ANAESTHESIA
BY:
EJIRO, AKPOCHAFO BENJAMIN MBBS (Ibadan), D.A (Benin)
A DESERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL COLLEGE OF NIGERIA IN PART FULFILLMENT OF THE REQUIREMENT FOR THE FELLOWSHIP OF THE FACULTY OF ANAESTHESIA
NOVEMBER 2012
DECLARATION
I, Ejiro Akpochafo Benjamin, hereby declare that this study was conceived, designed and conducted by me at the University of Benin Teaching Hospital, Benin City, Nigeria. The development of the study concept, literature search, and conduct of the study, data collection/analysis and the preparation of the book were entirely done by me. No part of this book has been presented to any College for a Fellowship, nor has it been submitted for publication.
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Dr. Ejiro Akpochafo Benjamin
ii
CERTIFICATION
This is to certify that Dr. Ejiro Akpochafo Benjamin carried out this work titled “A comparative study of the efficacy of ondansetron versus tramadol in the prevention of postanaesthesia shivering following elective Caesarean section under spinal anaesthesia” at the University of Benin Teaching Hospital, Benin City, Nigeria, under our supervision.
………………….………………………………. Prof. (Mrs.) N.P Edomwonyi (FMCA, FWACS) Professor of Anaesthesia, University of Benin Teaching Hospital, Benin City.
…………………………………………………. HEAD OF DEPARTMENT Prof. C. O Imarengiaye (FWACS, FMCA) Professor of Anaesthesia and Head Department of Anaesthesia, University of Benin Teaching Hospital, Benin City.
iii
DEDICATION
This work is dedicated to God Almighty, my Maker and Creator, to the Lord Jesus Christ, my
Saviour and Shepherd and to the Holy Spirit, my Helper and Teacher, for divine guidance throughout this work.
Also to my precious wife, sweetheart and partner, Dianne for her encouragement and unwavering support. This work is also dedicated to my mentor, Dr T. Eresanara and to my father in the Lord, Dr O.S. Mosuro.
iv
ACKNOWLEDGEMENT
I must first of all thank God for his mercies upon my life and for making this work possible. I will like to express my sincere appreciation and gratitude to my supervisors, Prof. (Mrs.) N. P
Edomwonyi and Prof. C.O Imarengiaye for their encouragement, support and guidance throughout the course of this research work. I am also particularly grateful to Dr. T. Eresanara whose encouragement and profound support opened up this new window of opportunity to me.
My appreciation also goes to Dr. F.E Amadasun, for accepting me into the prestigious department of Anaesthesiology of the University of Benin Teaching Hospital, Edo State. I am also grateful to Dr. (Mrs.) O.P. Adudu, Dr. I.J. Isah, Dr. (Mrs.) I.T. Ekwere, Dr. S. Tudjegbe and Dr. K. Tobi all of the University of Benin Teaching Hospital for their various contributions to my training. Also, my gratitude goes to my colleagues who shared their knowledge and experiences with me.
I wish to sincerely acknowledge my father in the Lord, Pastor E.A. Adeboye whose prophecies and prayers contributed immensely to my success in life.
Finally, my eternal appreciation goes to my lovely and loving wife, my sweetheart for life whose encouragement, wise counsel, prayers and dedication to excellence helped me to succeed during my residency training.
v
TABLE OF CONTENTS Title Page i Declaration ii Certification iii Dedication iv Acknowledgement v Table of contents vi List of abbreviations vii Summary 1
CHAPTER ONE Introduction 4 Aim and Objectives 7
CHAPTER TWO Literature Review 8 Justification of the study 28
CHAPTER THREE Patients and Methods 29
CHAPTER FOUR Results 38
CHAPTER FIVE Discussion 61 Conclusion 75 Recommendation 76 Limitations of the Study 77
References 78 Appendix I: Ethical Approval 88 Appendix II: Consent Form 89 Appendix III: Questionnaire 91
vi
LIST OF ABBREVIATIONS
1. ASA ……………AMERICAN SOCIETY OF ANESTHESIOLOGISTS
2. BP………………BLOOD PRESSURE
3. BSAS …………..BEDSIDE SHIVERING ASSESSMENT SCALE
4. CI……………….CONFIDENCE INTERVAL
5. CSF ……………CEREBROSPINAL FLUID
6. ECG ……………ELECTROCARDIOGRAPHY
7. GA……………...GENERAL ANAESTHESIA
8. HR………………HOUR
9. HRS…………….HOURS
10. I.V ……………..INTRAVENOUS
11. ICU……………..INTENSIVE CARE UNIT
12. LSCS……………LOWER SEGMENT CAESAREAN SECTION
13. MIN…………....MINUTES
14. NNT…………….NUMBER NEEDED TO TREAT
15. o C ……………..DEGREE CELSIUS
16. PAS ……………POSTANAESTHESIA SHIVERING
17. PDPH ………….POST DURAL PUNCTURE HEADACHE
18. PIH……….……PREGNANCY INDUCED HYPERTENSION
19. PONV………….POSTOPERATIVE NAUSEA AND VOMITING
20. PR ……………...PULSE RATE
21. SAB ……………SUBARACHNOID BLOCK
22. SD………………STANDARD DEVIATION
23. SEC…………….SECONDS
vii
SUMMARY
Background:
One of the common complications of regional technique is shivering with an incidence of around 20-60%. Although shivering may have beneficial thermoregulatory effects, it places the patient under increased physiological stress. While patients find postanaesthesia shivering very uncomfortable, it causes artifacts in monitors and increases oxygen consumption, metabolic rate, heart rate, cardiac output and postoperative pain. This may lead to myocardial ischaemia, hypoxaemia, hypercarbia and lactic acidosis that could complicate recovery from anaesthesia.
Preventing postanaesthesia shivering may reduce morbidity and improve patient’s satisfaction.
Aim and Objectives:
This study compared the efficacy of ondansetron versus tramadol in the prevention of postanaesthesia shivering following elective Caesarean section under spinal anaesthesia.
Patients and Method:
This was a prospective, double-blind, randomized controlled trial of prophylactic intravenous ondansetron versus tramadol for the prevention of postanaesthesia shivering. ASA physical status 1 or 2 eligible patients, with singleton pregnancies, aged between 18 and 45 years who were scheduled for elective Caesarean section, were randomly allocated to 3 groups.
Each patient was premedicated with 10mg metoclopramide and 150mg ranitidine orally. In the theater, the patients were preloaded with 15ml/kg of normal saline at room temperature. Spinal anaesthesia was induced in the sitting position with 2.5ml of 0.5% hyperbaric bupivacaine.
Two minutes after spinal block and prior to surgical incision, the study drugs were administered to the patients. Group A received 4mg ondansetron, group B received 0.5mg/kg tramadol, while
viii the group C (control group) received normal saline. All study drugs were made up to 5ml and given intravenously. Intraoperatively, the heart rate, blood pressure, respiratory rate, ECG, core and skin temperatures were monitored and recorded for each.
The primary outcome variable which was the incidence of postanaesthesia shivering was observed from institution of SAB to discharge from the recovery room. Secondary outcome variables such as neonatal Apgar scores at 1min and 5min, hypotension, sedation, PONV, pain,
PDPH, and backache were also evaluated.
Results:
Ninety patients participated in the study. The incidence of shivering was 20.0% in the ondansetron group, 16.7% in the tramadol group and 53.3% in the saline group (p = 0.003).
This gives an overall incidence of shivering of 30%. The relative risk of developing shivering with saline compared to ondansetron is 2.65, with saline compared to tramadol is 3.12 and with ondansetron compared to tramadol is 1.18. The number needed to treat (NNT) is 2.9 for ondansetron and 2.7 for tramadol.
Eight parturient in the saline group had severe shivering compared to one in the ondansetron group and none in the tramadol group (p = 0.007). The core temperatures at 90min were significantly lower compared to baseline for ondansetron group (35.97 ± 0.41oC vs. 37.01 ±
0.25; p = 0.0001), for the tramadol group (36.28 ± 0.35oC vs. 37.13 ± 0.24oC, p = 0.0001) and for the saline group (36.12 ± 0.37oC vs. 37.00 ± 0.27oC, p = 0.0001).
Seven patients in the tramadol group had significant PONV compared to 1 patient in the ondansetron and 2 patients in the saline groups (p = 0.031). Time to first analgesic requirement was significantly longer in the ondansetron (87.83 ± 26.45min) and the tramadol groups (94.38
± 21.94min) compared to the saline group (62.44 ± 11.50min); p = 0.009. About 76.7% of the
ix patients in the ondansetron group were very satisfied with the prophylaxis of PAS compared to 70% of the patients in the tramadol group and 26.7% of the patients in the saline group (p =
0.001).
Conclusion:
The prophylactic use of i.v ondansetron 4mg was comparable to i.v tramadol 0.5mg/kg in protecting parturients against spinal anaesthesia-induced perioperative shivering than placebo.
Furthermore, ondansetron is superior to tramadol in protecting against PONV in parturients.
Ondansetron resulted in no side effects either to the parturient or to the neonate. It is suggested that ondansetron at a dose of 4mg may be considered for prophylaxis against PAS particularly in parturients undergoing Caesarean section under subarachnoid block.
x
CHAPTER ONE
INTRODUCTION
Spinal anaesthesia is a safe and popular anaesthetic technique for Caesarean section because of its rapid onset, the low dose of local anaesthetic used, its reliability, safety and the postoperative analgesia provided.i Imarengiaye et al,ii evaluated the trend of practice of regional anaesthesia for Caesarean section in the University of Benin Teaching Hospital,
Nigeria. During the 14-year period under review (January 1986 to December 1999), subarachnoid block accounted for 5.6% of all anaesthetic techniques. Further analysis shows that 18.1% of the regional blocks were done in the first half of the study period and 81.9% were carried out in the latter half of the study period. This demonstrated an increasing trend of regional technique for Caesarean section. However, anecdotal report shows that the trend of subarachnoid block for Caesarean section had increased to 78% by 2009.
Regional anaesthesia decreases the normal human core temperature by 0.5oC.iii The mechanism of action is by affecting the efficiency of the hypothalamic homoeostatic system. This results in perioperative hypothermia thereby triggering vasoconstriction and shivering above the level of block. This reduction in threshold is proportional to the number of spinal segments blocked, advanced age and high-level spinal blockade.iii
Perioperative hypothermia and postanaesthesia shivering (PAS) is one of the frequent, undesirable and unpleasant complications of regional anaesthesia. The incidence of shivering is up to 20-60% in parturients receiving spinal anaesthesia.iii This makes it one of the leading causes of discomfort in patients recovering from anaesthesia along with postoperative nausea and vomiting.iii,iv Apart from causing discomfort and exacerbating postoperative pain, PAS has been shown to increase metabolic activity up to 600% above basal level and oxygen
xi consumption as much as fivefold.v,vi It increases catecholamine release, cardiac output, heart rate, blood pressure and intra-ocular pressure. It also causes arterial hypoxia and has been shown to correlate with increased risk of myocardial ischaemia. Also, it commonly interferes with routine monitoring of blood pressure, ECG and oxygen saturation (pulse oximetry).vii
Prevention and treatment usually entails physical and pharmacological methods. Physical methods include actively rewarming the patient, administration of warm intravenous fluids, administration of humidified gases and warming of the operating room.
Pharmacologically, drugs such as pethidine, clonidine, tramadol, ketamine and ondansetron have been used.vii,8 Majority of the treatment modalities have their own respective drawbacks.
Though pethidine is the gold standard, its use has become limited in some hospitals due to unavailability.viii In addition, all opioids, including pethidine, have major side effects such as sedation, itching, respiratory depression and postoperative nausea and vomiting (PONV).
Other risk factors in this category of patients such as female gender, age and spinal anaesthesia will further increase the risk of PONV in the presence of opioids.ix Clonidine causes sedation while ketamine is known to cause hallucinations, delirium and sedation.x
Tramadol hydrochloride, a μ-opioid agonist, is a centrally–acting analgesic drug and is effective in the treatment of shivering after spinal anesthesia in parturients, through its modulatory effect on serotoninergic pathways which regulate body temperature.xi Though it has milder side effects than other μ receptor agonists, its sedative effect is undesirable as this may prevent early maternal-child bonding which is one of the advantages of spinal anaesthesia in this group of patients. It may also increase the risk of PONV in parturients which is more uncomfortable than shivering.ix
xii
Ondansetron, a 5HT-3 receptor antagonist, is primarily used to prevent emesis. Recently it has also been tried successfully for the prevention of shivering in a dose of up to 8mg intravenously without significant side effects.xii,xiii The drug is unique in that it can be used to treat PONV and shivering both of which are very distressful to the patient. Though more expensive, using a drug that can take care of two different common complications leads to fewer side effects and reduction in the cost of treatment. According to Roxanne,xiv other cheaper drugs such as pethidine or neostigmine have been used to decrease PAS but none has the excellent drug profile of ondansetron. In contrast to opioids, ondansetron lacks haemodynamic and central nervous system effects, making it extremely safe to administer in the recovery room.xii,xv This will therefore provide for easier postoperative monitoring.
To our knowledge, there are limited reports on the use of ondansetron for the management of postanaesthesia shivering following Caesarean section under spinal anaesthesia in the African region. This study, therefore, seeks to compare the efficacy of intravenous ondansetron 4mg versus i.v tramadol 0.5mg/kg in the prevention of postanaesthesia shivering following
Caesarean section under spinal anaesthesia during the intraoperative and the immediate postoperative period.
xiii
AIM AND OBJECTIVES
AIM:
To compare the efficacy of ondansetron versus tramadol in the prophylaxis of post- anaesthetic shivering (PAS) in the intraoperative and immediate postoperative period following
Caesarean section under spinal anaesthesia.
OBJECTIVES:
1. To compare the incidence and severity of PAS after spinal anaesthesia in parturients
pretreated with ondansetron, tramadol and placebo.
2. To determine the effect of ondansetron or tramadol on the core-peripheral temperature
difference in Caesarean patients undergoing spinal anaesthesia.
3. To compare the incidence and severity of side effects following the use of ondansetron
and tramadol for prevention of PAS in patients undergoing Caesarean section under
spinal anaesthesia.
4. To compare the incidence and severity of neonatal outcome using Apgar scores
following the use of ondansetron and tramadol for prevention of PAS in patients
undergoing Caesarean section under spinal anaesthesia.
5. To determine patients’ satisfaction with the prophylaxis of PAS following pretreatment
with ondansetron or tramadol.
xiv
CHAPTER TWO
LITERATURE REVIEW
Incidence of postanaesthetic shivering:
Postanaesthesia shivering (PAS) was first described over fifty years ago.x It has been observed both in normothermic and hypothermic postoperative patients.x Its incidence has been reported to vary from 20%-60% worldwide.iii The incidence of PAS varies between 36% and 65% in
USA,viii Europe,x Middle Eastxvi and Asia.xvii In the West African sub-region, two studies done by Edomwonyi et aliii,xviii from the University of Benin Teaching Hospital, Nigeria, reported an incidence of 29.8% intraoperatively and 40% postoperatively, as well as 23.5% in obese patients and 22.2% in non-obese patients among parturients. This high incidence is considered unacceptable as it shows that at least 1 in 5 patients will develop PAS following regional anaesthesia hence the need to evaluate the efficacy of ondansetron in preventing postanaesthesia shivering.
Physiopathology of shivering:
Shivering is defined as a readily detectable fasciculation or tremor of the face, jaw, trunk or extremities lasting longer than 15sec.xix It is an involuntary, rhythmic muscular activity that augments metabolic heat production up to 600% above basal level.v,xx
The human body maintains a core temperature of 36.6 ± 0.4ºC.xii When body temperature is lowered, the physiologic response is to prevent further heat loss through vasoconstriction.
When vasoconstriction is no longer effective, shivering occurs to counterbalance heat loss.
Humans are homoeothermic, that is, they have a pattern of temperature regulation in which the variation in core temperature is maintained within ±2°C in spite of much wider variations in ambient temperature.xxi Maintenance of homoeothermy requires both peripheral and central
xv receptor activities for monitoring body temperature changes continuously and activating specific responses.
Afferent thermal inputs originate from anatomically distinct cold and heat receptors, located predominantly in the skin, but also present centrally. Signals from cold receptors travel along
A-delta fibers while signals from heat receptors are conveyed by C fibers. Thermal inputs get integrated at the level of the spinal cord and its ability to sense and modulate thermal signals led to the development of currently accepted “multilevel concept of thermoregulation”.xxii
Subsequently, all afferent signals eventually arrive at the hypothalamus, the primary thermoregulatory control center in mammals. The anterior hypothalamus compares information coming from the peripheral tissues with a threshold value, the so-called “set- point”. Temperatures higher than this “set point” will trigger responses to cool the body, while temperatures lower than this set point will activate reflexes to warm the body.xx
In humans, the efferent responses to effect change in body heat content may be classified as behavioral and autonomic. Autonomic mechanisms involve control of cutaneous smooth muscle tone, shivering and non-shivering thermogenesis. The preoptic region of the anterior hypothalamus is the predominant autonomic thermoregulatory controller in mammals. Normal thermoregulatory shivering is elicited when the preoptic region of the hypothalamus is cooled.xxiii Much of the excitatory input to heat sensitive neurons comes from the hippocampus, which links the limbic system (emotion, memory and behaviour), to thermoregulatory responses.
Efferent shivering pathway arises and descends from the posterior hypothalamus. Adjacent to the centre in the posterior hypothalamus on which the impulses from cold receptors impinge, there is a motor centre for shivering.xxiv It is normally inhibited by impulses from the heat-
xvi sensitive area in the anterior hypothalamus, but when cold impulses exceed a certain rate, the motor centre for shivering becomes activated by “spillover” of signals and it sends impulses bilaterally into the spinal cord.xxv Initially, this increases the tone of skeletal muscles throughout the body, but when this muscle tone increases above a threshold level, shivering is observed.
Thermoregulatory shivering is “the last-resort defense” that is activated only when behavioral compensation and maximum arteriovenous vasoconstriction are insufficient to maintain core temperature.xxv These behavioral responses are often impaired under anaesthesia.
Thermoregulatory shivering is associated with cutaneous vasoconstriction in response to hypothermia. Non-shivering thermogenesis has an unknown aetiology and may be related to postoperative pain. It is the result of cellular metabolic processes that do not produce mechanical work; it has been demonstrated in human neonate..xxvi
Effect of regional anaesthesia on thermoregulation:
In homoeothermic species, a thermoregulatory system coordinates defenses against cold and heat to maintain internal body temperature within a narrow range, thus optimizing normal physiologic and metabolic functions. Both general and regional anaesthesia are known to affect the efficiency of this homoeostatic thermoregulatory system and may result in different degrees of perioperative hypothermia.xxvii
It has been shown that after central neuraxial blockade, the threshold for vasoconstriction and shivering is reduced by nearly 0.5°C.xxviii,xxix Various mechanisms such as decrease in core temperature and misinformation from receptors have been postulated to explain the shivering observed during spinal anaesthesia. Decreases in core temperature may be due to sympathetic blockade which results in peripheral vasodilatation, increased cutaneous blood flow, redistribution of body heat from the core to the periphery and subsequent increased heat loss
xvii via the skin.iii,v,xxv Patients given spinal anaesthesia cannot re-establish core temperature equilibrium, because peripheral vasoconstriction remains impaired. Shivering in these patients produces relatively little amount of heat because it is restricted to the small muscle mass cephalad to the block.v In contrast to general anaesthesia, where the heat produced by shivering is unchanged, heat produced by shivering during regional anaesthesia is reduced by approximately 60%.xix
After core-to-peripheral redistribution of body heat, the degree of subsequent hypothermia depends on the balance of cutaneous heat loss and rate of metabolic heat production. During neuraxial block, heat loss may be accelerated by reduced vasoconstriction caused by the block.
Hence heat loss continues unabated during spinal anaesthesia despite the activation of the effector mechanism above the level of the block causing further core hypothermia and shivering.
A fall in core temperature during spinal anaesthesia may also be due to a cold operating room, rapid infusion of intravenous fluids at room temperatures, differential inhibition of afferent thermoreceptor fibres within the spinal cord or direct effects of cold local anaesthetic solutions preserved at 4-8oC upon thermosensitive structures within the spinal cord.iii,xxx The combination of anesthesia-induced thermoregulatory impairment and exposure to a cold environment in the operating room makes most surgical patients who are not actively warmed become hypothermic.iii It has been shown that during the initial 30-45min after spinal anaesthesia induction, core temperature decreases rapidly to more than 1°C below the preoperative baseline value.xxxi Therefore, surgery might start with the patient already hypothermic. In evaluating the predictors of core hypothermia in 40 patients receiving spinal anaesthesia for radical retropubic prostatectomy, Frank et al,xxxi demonstrated that high-level spinal blockade is associated with a significant decrease of thermoregulatory threshold among
xviii others. They found a 0.15°C decrease of core temperature for each incremental rise in block level.
During general anaesthesia, body temperature usually decreases during the first 3-4hrs after induction due to redistribution of heat from the core to the periphery, until a new equilibrium is reached between heat production and heat loss.xxviii In central neuraxial block, time to new equilibrium is delayed due to inhibition of peripheral vasoconstriction, leading to further decreases in core temperature.xxix This effect continues until recovery of neuronal activity in the postoperative period further delaying the recovery of normothermia after surgery if the patient is not actively warmed. Therefore, patients are often discharged from the Post
Anaesthesia Care Unit (PACU) to the surgical ward with core temperatures still below the normal value.xxxii
Measurement of core temperature:
As shivering is mostly diagnosed clinically the role of body temperature remains unclear.
Previous studies have shown a relationship between peripheral temperature and postoperative shivering but not between core temperature and postoperative shivering.vii However, during the perioperative period, because of the rapid change in core temperature the relationship between the temperatures measured at various body sites may differ considerably.v Also measurement of the core temperature is important as hypothermia must be treated concurrently with shivering to prevent further cooling.vi
Core temperature is measured in the pulmonary artery, distal one-third of the oesophagus, nasopharynx, bladder, rectum and tympanic membrane. The ideal site for core temperature measurement is the pulmonary artery because in the heart, the blood from the viscera and the skin become mixed.xxxiii However, the pulmonary and oesophageal sites are considered
xix invasive and cannot be used for routine temperature measurement. Though highly accurate, the correct placement of the oesophageal devise is critical. Rectal temperatures fail to track rapid changes in core temperature because the rectum has no thermoreceptors, in addition to the insulating effect of its faecal content. The lag time may be up to one hour.xxxiv Urinary bladder core temperature changes better than rectal and is considered minimally invasive. However, it requires a urinary catheter with a thermistor tip to be inserted into the bladder. Moreover, the reading may be altered due to urinary volume or if the patient is receiving bladder irrigation.xxxiv
Tympanic temperatures are more effective in tracking changes in core temperature. The temperature of the tympanic membrane is also protected from the influence of ambient temperature and is unaffected by smoking, respiration, eating or drinking. However, its accuracy is affected by presence of wax in the ear, ear infection and correct placement of the device.xxxiv Complications such as perforation of the tympanic membrane may occur but this may be avoided by careful placement of the infrared thermometer.
Temperature monitoring must be accurate and consistent. Research has indicated that the accuracy of temperature reading is dependent on the operator, patient anatomy, and the instrument.xxxiii A recent survey found that infrared tympanic monitoring is the preferred route of temperature measurement perioperatively.v Recent studies on management of postanaesthetic shivering therefore measure core temperature using infrared thermometry with the Thermoscan.x,xiii,xxxv
Risk factors for post anaesthetic shivering:
Crossley,xxxvi did an audit of anaesthetic technique and observed that of the 2,595 patients admitted to the recovery room of a district hospital over a six month period, 6.3% shivered postoperatively. Logistic regression analysis done on these data showed that long duration of
xx surgery, male sex, anti-cholinergic premedication (e.g. atropine), spontaneous ventilation,
ASA physical status 3 and 4, general anaesthesia, and administration of blood were variables found to impact on the development of post-anaesthetic shivering. Older age and administration of propofol, alfentanil or morphine were found to be the most protective against post- anaesthetic shivering.
Eberhat et al,xxxvii similarly sought to identify risk factors for PAS after general anaesthesia in a prospective study of 1,340 patients. Potential risk factors for PAS were recorded from these patients. Stepwise multivariate analysis performed on these data and those obtained by
Crossley,xxxvi identified the three independent risk factors of PAS as younger age, low core temperature and level of block height in neuraxial anaesthesia. Young age is by far the most important risk factor for PAS accounting for more than 70% of the predictive power. It was not surprising because thermoregulatory responses to cold and heat are attenuated in older patients.xxxviii For instance, the shivering threshold during spinal anaesthesia is decreased by about 10C in the elderly.xxxix
Hypothermia that develops within the first hour after induction of neuraxial anaesthesia results primarily from core-to-peripheral redistribution of body heat.xxviii,xxix Shivering and vasoconstriction are each 80% controlled by core temperature and 20% by skin temperature.xl
It is thus reasonable to assume that hypothermia contributes to the development of post- anaesthetic shivering.xli
Grading of severity of shivering:
Grading of the severity of shivering is very important as it allows meaningful comparisons of interventions in this area. Different grading scales have commonly been employed. The first was introduced by Crossley and Mahajan,xlii to assess patients recovering from isoflurane
xxi anaesthesia. Shivering was graded as thus: 0-no shivering; 1-piloerection or peripheral vasoconstriction but no visible shivering; 2-muscular activity in one muscle group; 3-muscular activity in more than one muscle group but not generalized shivering; and 4-shivering involving the whole body.42 The major advantage of this grading scale is the inclusion of piloerection and peripheral vasoconstriction which are important compensatory physiological responses that are early warning signs of hypothermia. Interventions could be undertaken at this point before outright shivering occurs. Since grade 4 shivering is not expected from patients under spinal blockade, the scale may be adapted as follows: 0 = no shivering, 1 = mild shivering, 2 = moderate shivering and 3 = severe shivering. The adapted scale was used for this study.
Sesslerxliii introduced an alternative, more user-friendly, specific grading scale for shivering for neuraxial anaesthesia as follows: 0-no shivering; 1-shivering not interfering with monitoring or causing patient distress; and 2-shivering interfering with patient monitoring or causing patient distress. This scale is however too simplistic for this study design as shivering cannot be graded in terms of severity as mild, moderate or severe.
The Bedside Shivering Assessment Scale (BSAS) is an objective, simple and reliable tool for evaluating the metabolic stress of shivering. It was developed to monitor patients in the neuro- intensive care unit undergoing therapeutic temperature modulation.xliv Severity of shivering as measured by the BSAS is strongly associated with graded increases in systemic metabolism, hyper-metabolic index, oxygen consumption and carbon-dioxide production. The metabolic impact of shivering is proportional to its intensity and the affected muscle mass. By clinically assessing muscle involvement in the trunk and limbs, BSAS provides accurate representation of the metabolic impact of shivering. It is graded thus: 0-None: no shivering noted on palpation of the masseter muscle, neck, or chest wall; 1-Mild: shivering localized to the neck and/or thorax only; 2-Moderate: shivering involving gross movements of the upper extremities (in
xxii addition to the neck and thorax); 3-Severe: shivering involving gross movements of the trunk and lower extremities. The limitation in this scale is that it is developed for use in patients in neuro-ICU who are usually more critically ill and therefore unable to withstand the metabolic response to shivering. In parturients undergoing Caesarean section, discomfort arising from shivering is of more immediate concern. Furthermore, to regularly palpate female chest during surgery may be inconvenient especially when it is covered under drapes.
Another shivering scale is that used by Matthews and colleagues.xlv According to this scoring:
0 = no shivering, 1 = mild shivering of face or neck and ECG disturbances in the absence of voluntary activity of the arms, 2 = visible tremor involving more than 1 muscle group and 3 = gross muscular activity involving the entire body. This scale is more suitable for use in patients undergoing GA, patients under spinal are unable to experience whole body shivering. Also the definition of mild is not clear cut. Because the Crossley and Mahajan scale was validated by
Tsai and Chu, and has been used in similar studies,x,xxxv,xlvi it was adopted for this study.
Consequences of post-anaesthesia shivering:
Postanaesthesia shivering is very uncomfortable for patients. It is associated with a number of potentially deleterious sequelae such as increased oxygen consumption and an increase in metabolic rate by up to 600%. It causes significant aggravation of postoperative pain, increase in intracranial pressure and cardiopulmonary complications such as myocardial ischaemia.
Post-anaesthesia shivering also increases intra-ocular pressure and causes artifacts in monitors.v,xlvii It leads to catecholamine release and sympathetic stimulation. This increases cardiac output, heart rate and blood pressure and is detrimental to patients with low cardio- respiratory reserve.xlv Also, hypoxaemia, lactic acidosis, and hypercarbia may complicate recovery from anaesthesia, at a time when the patient is at risk of hypoxaemia from other causes. Preventing postanaesthesia shivering is therefore clearly desirable.v,vii
xxiii
Prevention and treatment of post-anaesthetic shivering:
Though not all patients who shiver are hypothermic, prevention of PAS mainly entails avoiding perioperative heat loss. Peri-operative heat loss occurs in three different phases. Phase 1 occurs in the first hour after induction of anaesthesia and is due mainly to internal redistribution of heat from the core to the periphery. Phase 2 occurs between 2-4 hours after anaesthesia and is due to heat loss via the skin and viscera. Phase 3 refers to a steady state where heat loss is equal to heat gain.
Body temperature is often not monitored in patients undergoing regional anaesthesia; therefore anaesthesiologists are usually unable to accurately estimate the hypothermic state of their patients.xlviii This makes significant, undetected hypothermia more likely and increases the chances of shivering occurring under regional anaesthetic technique. Numerous studies have evaluated the efficacy of a large variety of interventions that are thought to prevent shivering in normothermic or hypothermic surgical patients.xlix,l
Prevention of hypothermia can be achieved by a number of different techniques such as increasing the ambient temperature in theatre, using conventional or forced warm air blankets, using warmed intravenous and irrigation fluids and blood. Other useful techniques are cutaneous heat patch, water circulation blankets and use of humidified gases with the heat moisture exchanger (HME).iii,vi,xxv While these methods may continue to be employed, pharmacological agents are the most popular mode of prophylactic and therapeutic management of PAS.vii Drugs validated in clinical trials in both the treatment and prophylaxis of PAS includes Pethidine, Tramadol, Clonidine, Ondansetron and Ketamine.vii,li,lii
xxiv
Tramadol and post-anaesthetic shivering
Tramadol is a centrally-acting analgesic used for treatment of moderate to severe pain. It was developed in the late 1970s. It is an opioid that possesses weak agonist actions at the mu-opioid receptor, releases serotonin and inhibits the reuptake of nor-epinephrine.xv,xvi It is a synthetic analogue of the phenanthrene alkaloid codeine formulated as a pro-drug (it is converted to M-
I which is also known as O-desmethyl tramadol). The opioid agonistic effect of tramadol and its major metabolite are almost exclusively mediated by its action at the mu-receptor.
Tramadol is a combination of R- and L-enantiomers. Its clinical action is primarily mediated by inhibition of norepinephrine neuronal uptake by the L-enantiomer.liii However, the R- tramadol also inhibits 5-hydroxytryptamine (5-HT, serotonin) reuptake, facilitates its release and activates mu-opioid receptors.liii,liv Norepinephrine is a major mediator of central thermoregulatory control. The effects of 5-HT in thermoregulatory control are controversial. It causes hypothermia in humans which suggest that it inhibits thermoregulatory control thereby affecting shivering.lv,lvi Common adverse drug reactions of tramadol are nausea, vomiting, sweating and constipation. Drowsiness is less than for non-synthetic opioids. Respiratory depression is not clinically significant in normal doses. The probability of occurrence of various adverse effects of tramadol is as follows, any adverse effect (71%), drowsiness (17%), nausea (17%), dizziness (15%), constipation (11%), headache (7%), vomiting (6%), diarrhea
(5%), dry mouth (5%), fatigue (5%), indigestion (5%) and seizures (<1%).lvii
Ondansetron and post-anaesthetic shivering:
Ondansetron is a specific 5-HT3 receptor antagonist that inhibits serotonin receptors in GI tract or chemoreceptor trigger zone. Though primarily used to prevent emesis, it has been successfully tried for prevention of PAS with minimal side effects.x,xii,li The mechanism of action could be
xxv related to the inhibition of serotonin reuptake on the preoptic anterior hypothalamic region. 5-
HT3 receptors may also influence both heat production and heat loss pathways. The balance between the modulatory 5-HT3 and norepinephrine inputs may be responsible for the short and long term thermoregulation of shivering threshold.v Thus the 5-HT3 antagonists may be useful in preventing postanaesthesia shivering as shown in controlled trials enlisting about 150 patients and demonstrating comparable efficacy with pethidine.viii,xiii,li
The chemical name is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate.lviii Ondansetron hydrochloride dihydrate is a white to off-white powder that is soluble in water and normal saline. Plasma protein binding is about 76%. Its onset of action after intravenous dose is 5min, peaks by 15-
30min with a half-life of 3.5 to 5.5 hr. It is extensively metabolized in the liver and excreted in the urine. Gender-related differences such as slower clearance, smaller volume of distribution and higher bioavailability in women is not known to be clinically important.lix
Contraindications to the use of ondansetron include concomitant use with apomorphine and hypersensitivity to ondansetron. Drug interactions: Cytochrome P450 3A4 (CYP3A4) inducers
(e.g. phenytoin, carbamazepine, and rifampicin) may reduce the plasma levels of ondansetron, decreasing the antiemetic effect. Concomitant use with tramadol may reduce its analgesic activity. It is incompatible with alkaline solutions. It is stored between 20°C and 25°C.
Common adverse reactions include Headache (27%); drowsiness/sedation (20%); malaise/fatigue (13%); dizziness (7%); anxiety/agitation (6%); pruritus (5%); constipation
(9%); diarrhea (7%); urinary retention (5%); bradycardia (6%); hypotension (5%).
Hypersensitivity reactions include angioedema, shortness of breath, hypotension, laryngeal oedema, laryngospasm, shock and cardiopulmonary arrest. Ondansetron is been given during
xxvi pregnancy to control hyperemesis gravidarum. There is no evidence to suggest that it is teratogenic, and it seems to be less sedating than promethazine.59,60
Previous studies on post-anaesthetic shivering:
Chan and colleagues,l in a randomized, double-blind study investigated 36 obstetric patients who shivered during Caesarean section under regional anaesthesia and were randomized into three groups of tramadol 0.5mg/kg, tramadol 0.25mg/kg and normal saline (NS) 0.05 mls/kg.
Eighty percent of the patients in the tramadol 0.5mg/kg group and 92% in the tramadol
0.25mg/kg group had shivering controlled with no difference in response rates compared with
27% of the patients in the normal saline group (P < 0.001). There was no increased incidence of side effects such as pruritus, nausea and vomiting among the treatment groups. Fifty percent of the patients in the tramadol 0.5mg/kg group, 23% of the patients in tramadol 0.25mg/kg group and 18% of the patients in the normal saline group has severe PONV, but the difference was not statistically significant (P = 0.20). Forty-two percent of the patients in tramadol
0.5mg/kg group, 62% of the patients in tramadol 0.25mg/kg group and 64% of the patients in the normal saline group required ephedrine, but the differences were not significant (P = 0.50).
No patient in any group developed sedation or desaturation after injection of the study drug.
There was no significant difference in the Apgar scores between the treatment groups (P = NS).
There was no explanation as to why a lower dose of 0.25mg/kg was more effective than a higher dose of 0.5mg/kg. In addition, the incidence of PONV was one in two patients (50%) in the tramadol 0.5mg/kg which is unacceptably high. Furthermore, the focus of these authors was on response after treatment rather than the incidence of shivering, hence they did not control factors that might influence the incidence of shivering such as the dose of spinal or epidural morphine used and the temperature of drugs and intravenous fluids.
xxvii
Talakoub et al,lx in a prospective clinical trial randomized 73 ASA-I parturients who had
Caesarean section with established post-spinal shivering into tramadol 0.5mg/kg i.v group or pethidine 0.5mg/kg i.v group. There was no significant difference in the response rates between the tramadol and the pethidine groups (97.2% vs. 91.9%; P>0.3). The time from treatment to cessation of shivering was significantly faster in the tramadol group than the pethidine group
(2.54 ± 0.78 min vs. 5.03 ± 1.07min; P<0.001). While 77.8% (P<0.001) of patients had nausea and 19.4% (P<0.005) had vomiting in the tramadol group, none had nausea or vomiting in the pethidine group. More than half (55.6%) of the patients in the tramadol group had significantly higher incidence of somnolence as against none in the pethidine group (P<0.001). Though tramadol was found to be more effective in controlling post-spinal shivering, it however resulted in more frequent nausea, vomiting and sedation in comparison with pethidine. Most patients rate PONV as very distressful and, as such, is not desirable in obstetric patients.
Furthermore, sedation in obstetric patients may prevent early maternal-child bonding. For an average low dose of 33mg of tramadol to cause such significant side effects as reported by
Talakoub et al,lx is worrisome as this may limit its use in parturients.
Oranuch and coworkersxv compared the efficacy of nalbuphine, tramadol, ondansetron and placebo in the treatment of PAS after spinal anaesthesia for Caesarean delivery in 280 parturients who developed moderate to severe shivering. They were randomized into 4 groups of tramadol 0.5mg/kg, nalbuphine 0.05mg/kg, ondansetron 0.1mg/kg and normal saline 5ml i.v, respectively. Results showed that the treatment success rate (no or mild shivering) were
88%, 81%, 61% and 36 %, respectively (p < 0.001). Side effects such as pruritus, nausea and vomiting showed no significant difference among the 4 groups (P=0.789, 0.361, and 0.266 respectively). The study concluded that tramadol, nalbuphine and ondansetron were efficacious in the treatment of PAS after intrathecal morphine in Caesarean section patients with low
xxviii recurrence rates. Though Oranuch and colleaguesxv reported a low incidence of PONV among patients in the tramadol 0.5mg/kg group (2.4%), this contrasts with the high incidence reported by Chan et al,l (50%) and Talakoub et al,lx (77.8%) using the same treatment regime. The use of same amount of low dose spinal anaesthetics for all patients by Oranuch and colleagues, may have resulted in lower incidence of hypotension and hence lower risk of PONV. A review of the 3 studies above15,l,lx indicate that though tramadol is effective in treating PAS, this is masked by its unfavourable side effect profile and may diminish its usage in obstetric patients who are already at risk of PONV. Rather, ondansetron with its minimal side effects and anti- emetic property may be a better drug of choice. Furthermore, the studies under review were aimed at treating shivering but it is more clinically prudent to prevent shivering rather than engaging in its treatment.v,vi,vii
In other to compare the efficacy of clonidine vs. tramadol in the prevention of PAS, Velayudha and Sunillxi randomized 90 ASA 1 and 2 parturients, aged 18 - 35yrs, who shivered while undergoing Caesarean section under SAB. Group C received clonidine 50mcg while Group T received tramadol 50mg. Results showed significant differences in the response rate between clonidine and tramadol (95.56 % vs. 86.67%; p < 0.05). Time taken from the starting of treatment to cessation of shivering was significantly less with tramadol group (2.2 ± 0.41 vs.
3.17 ± 0.03; p < 0.05). Twelve patients in the tramadol group had nausea and vomiting compared to four in the clonidine group. Also, 8 patients in the tramadol group had sedation compared to 2 in the clonidine group. Though this study showed that tramadol was more effective than clonidine in treating PAS, its significantly higher incidence of PONV and sedation as reported in this study is not desirable in parturients. Also, giving all patients the same dose of tramadol (50mg) was a methodological flaw. The mean weight of the patients in the tramadol group was 63.62 ± 3.41kg which made the dose of tramadol less than the 1mg/kg claimed by Velayudha and Sunil.lxi
xxix
To find out if tramadol could prevent shivering, Javaherforoosh et al,xi randomized ninety parturients scheduled for elective Caesarean section under SAB to receive either tramadol
1mg/kg or normal saline. The study drugs were given at the end of surgery. Results showed that 86.6% of patients in the saline group developed shivering compared to 8.8% of patients in the tramadol group which was significant (P<0.001). There were no significant differences in the heart rate, systolic and diastolic blood pressure, oxygen saturation and body temperature in both groups. Nausea and vomiting had a similar incidence in both groups (30%) which were not clinically significant. Preventing shivering is the gold standard, but at what point should the prophylaxis be given? Giving prophylaxis towards the end of surgery as in this study does not take into account that shivering could occur immediately after spinal. Also, other causes of shivering such as patient exposure to cold environment or cold fluids might have come into play by this time.
Atashkhoyi and coworkersxvi investigated whether 1mg/kg tramadol i.v. administered immediately after SAB would reduce the incidence and severity of shivering in patients undergoing Caesarean section. Seventy patients were randomized into 2 groups of 35 each to receive tramadol 1mg/kg and saline respectively. They reported a significantly lower incidence of shivering in patients who received tramadol than those who received placebo (28.57% vs.
65.71%; p<0.0001). There was no significant difference in nausea and vomiting (P=0.35), sedation level (P=0.67) or Apgar scores (P=0.75 at 1 min; P = 0.22 at 5 min) among the two groups. This study revealed that pretreatment of parturients with tramadol up to 1mg/kg before delivery reduced the incidence of shivering and did not adversely affect neonatal outcome using
Apgar scores.
xxx
Tramadol has been shown not to adversely affect neonatal outcome. In the study carried out by
Chan and colleagues,50 neonates delivered by parturients who received tramadol 0.5mg/kg before delivery of the foetus had no significant difference in their Apgar scores compared with parturients who received same dose of tramadol after delivery (8.50 ± 1.29 vs. 8.75 ± 1.28,
P=NS at 1min; 9.75 ± 0.50 vs. 9.88 ± 0.35, P = NS at 5min). Tsai and Chu,xlvi in their study also found no significant difference in Apgar scores of newborns among parturients given tramadol 0.5mg/kg before or after delivery (7.8±0.6 vs. 8.0 ± 0.0 at 1min; 8.9 ± 0.3 vs. 9.0 ±
0.0 at 5min). In a related study, Atashkhoyi and co-workers16 found no significant difference in Apgar scores between parturients pretreated with tramadol 1mg/kg and parturients who received placebo (8.80±1.34 vs. 8.90 ± 1.15, P=0.75 at 1min; 9.2 ± 0.27 vs. 9.40 ± 0.46, P =
0.22 at 5min). From the studies under review, tramadol prophylaxis against shivering in parturients undergoing Caesarean section may be administered immediately after the spinal block as it has been demonstrated that neonatal outcome is not adversely affected.
The ability of ondansetron to prevent PONV is beneficial in contrast to opioids which increase the risk.x Nze, in a survey of PONV in Enugu, Nigeria reported an incidence of nausea and vomiting following gynaecological procedures over 24hrs of 52% and 25% respectively.lxii
Soyannwo et al, in their study on PONV in Nigerians found an incidence of nausea and vomiting of 41.6% and 19.6% respectively. Risk factors identified in their study included female gender and use of opioids.lxiii Olatosi et al, implicated ketamine as one of the risk factors in their study.lxiv All the three studies recommended the use of anti-emetic in the premedication of Nigerian women.lxii,lxiii,lxiv Ondansetron has been validated as a useful drug in the prevention of PONV.x,15,17 Pan and colleagues,lxv in a comparative study involving 48 parturients undergoing Caesarean section under epidural anaesthesia reported that ondansetron 8mg and haloperidol 0.625 mg significantly reduced PONV compared to placebo (6.3% vs.12.5% vs.
43.8% ; P < 0.02).
xxxi
Current pharmacologic modalities for management of shivering indicate that ondansetron 8mg is comparable to pethidine 0.5mg/kg which is the gold standard for control of postanaesthetic shivering.viii However, this dose of ondansetron has been reported to cause bradycardia in a patient requiring treatment with atropine.viii This may complicate the management of hypotension occurring as a result of spinal anaesthesia and the use of a lower dose of ondansetron need to be considered.x
A quantitative systematic review of randomized controlled trials of single-dose parenteral pharmacological interventions for the prevention of postoperative shivering was conducted by
Kranke and Colleagueslxvi. The study reported the efficacy and harm of pharmacological interventions for the prevention of postoperative shivering. Twenty seven (27) of the seventy two (72) studies evaluated met the criteria for the meta-analysis. The authors concluded that prophylaxis of postoperative shivering with simple pharmacological interventions is possible and clinically effective if the risk of developing postoperative shivering is high. With a quoted incidence of 20-60%, post-anaesthetic shivering following spinal anaesthesia for obstetric surgeries should be prevented with a drug like ondansetron whose favourable pharmacological profile and availability make it a good anti-shivering agent.
A review of the study carried out by Powell and Buggy,xiii indicate that the efficacy of ondansetron is dose dependent. Eighty-two patients, aged 18 to 60yr, scheduled for orthopaedic, general, or urologic surgery under general anaesthesia were randomized into 3 groups. Group O4 received 4 mg ondansetron i.v, Group O8 received 8mg ondansetron i.v, and
Group C received saline i.v, immediately before the induction of anesthesia. PAS occurred in
57% of patients in Group C compared with 33% in Group O4 (P = 0.13) and 15% in Group O8
(P = 0.003). Patients in Group O4 had an intermediate incidence (33%), not significantly different from either of the other groups. The study by Powell and Buggy,xiii was carried out in
xxxii patients undergoing various surgeries under GA. This study was designed to find out if a similar outcome would be observed in patients undergoing Caesarean section under SAB.
Most of the previous works on PAS were on therapeutic interventions using different drugs.
However, prophylactic administration of i.v drugs provides a better management option for a complication as distressing PAS.iv,v This may offer better patient satisfaction and reduction in morbidity associated with shivering especially in the parturients. Since the side effects profile of ondansetron is superior to other agents, it is imperative therefore to determine the effectiveness of low dose ondansetron versus tramadol in the prevention of PAS in women undergoing Caesarean section under SAB and estimate the associated side effects.
Previous studies in Nigeria:
There appears to be paucity of studies on the prophylactic treatment of PAS in Nigeria and the sub-Saharan region. The few available studies investigated its incidence as part of overall anaesthesia related complications. Edomwonyi et al,18 in a prospective study involving obstetric patients at the University of Benin Teaching Hospital, reported an incidence of 29.8% for PAS in the parturients. Sule and colleagueslxvii, conducted a prospective analysis involving
200 patients requiring anaesthesia for lower abdominal and lower limb surgery under subarachnoid block. Postanaesthesia shivering accounted for about 15% of the total number of complications observed which included nausea and vomiting, pain at injection site, post-dural puncture headache (PDPH) and hypotension. Kolawole and co-workerslxviii conducted a similar study on the efficacy and safety of subarachnoid block for lower abdominal and lower limb surgery. One hundred and ten patients (110) were studied over a period of two years and eight months for post-operative complications of which PAS accounted for 18%. Shivering was treated with only additional drape cover in this study.
xxxiii
These 3 studies18,67,68 were not designed to evaluate PAS as the primary outcome. Instead, the incidence reported were in cross-sectional studies and may underestimate the real clinical scenario. Nevertheless, the studies clearly demonstrated that PAS following central neuraxial block is not uncommon in Nigeria and deserves a closer attention. Furthermore, Kolawole and colleagues reported additional drape cover as the treatment given to the patients who shivered in their study. With the deleterious effects of post-anaesthetic shivering and the discomfort it causes to patients, use of additional drape cover alone may not be sufficient. Furthermore, pharmacological prophylaxis of PAS is the current trend been advocated.iv,v
This study seeks to evaluate the prophylactic anti-shivering profile of ondansetron in comparison with tramadol in patients undergoing Caesarean section under spinal anaesthesia intraoperatively and immediate postoperative period. Prophylactic i.v ondansetron given after the establishment of spinal anaesthesia for at-risk patients will not only provide a more desirable option but will add to our repository of knowledge.
xxxiv
JUSTIFICATION FOR THE STUDY
Post-anaesthesia shivering is a well recognized complication following regional anaesthesia technique. Apart from pain and nausea/vomiting, patients consider PAS quite distressful.
Various methods aimed at mitigating this problem underscore its relevance in clinical practice.
Drugs such as opioids, ketamine, and clonidine have been used but side effects such as sedation and PONV have limited their use in obstetrics. Ondansetron is a known anti-emetic drug. If prophylactic low dose i.v ondansetron is found useful in the prevention of postanaesthetic shivering, a drug that is effective, with minimal side effects and capable of preventing two important complications at once, thereby reducing cost would have been evaluated. This study was therefore aimed at comparing the efficacy of ondansetron 4mg versus tramadol 0.5mg/kg in the prevention of postanaesthesia shivering following elective Caesarean section under spinal anaesthesia
xxxv
CHAPTER THREE
PATIENTS AND METHOD
Study Design:
This was a prospective, randomized, double blind placebo controlled clinical trial of prophylactic intravenous ondansetron and tramadol for the prevention of post-anaesthesia shivering.
Setting:
The study was conducted at the University of Benin Teaching Hospital, Benin City, Nigeria.
The study population was recruited from patients scheduled for elective Caesarean section.
Inclusion criteria:
ASA I or II patients; patients with singleton term pregnancies; patients aged between 18 and
45 years and scheduled for elective Caesarean section. Only the patients who met the above criteria and gave consent to participate in the study were enrolled.
Exclusion criteria:
ASA III and IV patients; patients with known allergy to tramadol, ondansetron or bupivacaine; patients with history of any disease associated with shivering or pyrexia; patients with any contraindication to regional anaesthesia; patients with history of nausea or vomiting; patients with body temperature less than 36oC or more than 38oC and patients with failed, inadequate or high spinal anaesthesia who were converted to general anaesthesia.
xxxvi
Ethical Approval:
Ethical approval was obtained from the institution’s Research and Ethics Committee. All the patients scheduled for elective Caesarean section were approached during the preoperative visit to assess their eligibility for the study.
Informed consent:
All eligible patients were thereafter educated about the study and informed consent was obtained from each of the participants.
Randomization:
All eligible patients were randomly assigned into one of three groups. Group A (the ondansetron group), group B (the tramadol group) or group C (the saline/control group). A randomization schedule was prepared with sealed envelopes with patients allocated to one of the three study groups using computer generated codes (Stat Trek’s Random Number
Generator: StatTrek.com). Identical 5ml syringes were filled with either ondansetron, tramadol or saline each made up to 5ml. The patients and the administrator were both blinded to the content of the syringes. The attending anaesthetist assessed each patient for both the primary outcome (shivering) and for the side effects of the study medications.
Sample size estimation:
Sample size was calculated using the formula belowlxix n = [µ √∏ (1-∏) + v √∏null (1- ∏null) ]2
(∏ − ∏null ) 2
Where: n = required minimum sample size
xxxvii
∏ = proportion of interest (0.8)xiii
∏null = null hypothesis proportion (0.5)
µ = one sided percentage point of normal distribution corresponding to 100% - 90% (power) =
10% and µ = 1.28 v = percentage of the normal distribution corresponding to the required two sided, v = 1.96
Significance level = 5%.
n = [ 1.28 x √0.8(1-0.8) + (1.96 x √0.5(1- 0.5) ]2
(0.8 – 0.5)2
= [ 1.28 x √0.8(0.2) + (1.96 x √0.5 x 0.5) ]2
(0.3)2
= (0.51 + 0.9)2
0.32
= 1.4922
0.32
= 24.73
≈ 25
Giving a 10% attrition rate, a minimum of 30 patients will be recruited into each group making a total of 90 patients.
Intervention:
xxxviii
Preoperative assessment of all recruited patients was carried out by the researcher on the night before surgery and consent obtained. Patient’s age, weight, height, parity, educational status and gestational age were taken and recorded. Evaluation of the patient’s cardiovascular, respiratory and central nervous systems were done. The patients were classified using the ASA physical health status. Routine investigations like haemoglobin concentration, urinalysis, electrolyte and urea were done. Two units of blood were grouped and cross-matched for each patient. All Patients were fasted for at least 6-8 hours for solids and at least 2 hours for clear fluids before the operation.lxx,lxxi Each patient received ranitidine 150mg orally and metoclopramide 10mg orally, the night before and on the morning of the surgery.
In the theatre, the availability and functionality of the anaesthetic machine, endotracheal tubes, laryngoscopes, stilletes and suction machines were ascertained. Laryngeal mask airway, gum elastic bougie, face mask, and resuscitation drugs such as ephedrine, atropine and adrenaline were made available. Each patient had an Edan multiparameter monitor attached. Baseline vital signs including pulse rate, non invasive blood pressure (NIBP), oxygen saturation (SpO2), and electrocardiogram (ECG) were measured and recorded. Core temperature was measured using infrared ear thermometry with thermoscan (Thermoscan IRT 4020; Braun, Kronberg,
Germany). Skin temperature was measured with thermistor strapped to the forehead.xlviii
Ambient theatre temperature was kept at 25oCx,15,xlvi using Panasonic Air conditioner and confirmed with a temperature (thermistor) probe on the multiparameter monitor. Resuscitative drugs were drawn and appropriately labelled. Intravenous access was established with a 16G cannula. All patients were preloaded with 15ml/kg 0.9% saline kept at room temperature before establishment of spinal anaesthesia. All subsequent intravenous fluids were administered to the patients at room temperature.x,xvi
xxxix
A second anaesthetist who was not involved in the study prepared the study drugs. Each of the study drugs were withdrawn into 5ml syringes and coded A, B or C. Syringe A contained 4mg ondansetron (Setronon) diluted to 5ml, syringe B contained 0.5mg/kg tramadol (Tramadol) diluted to 5ml, while syringe C contained 5ml normal saline. Subarachnoid block was established in the sitting position. After skin preparation with 0.5% chlorhexidine and methylated spirit, each patient was draped with a sterile fenestrated drape. After locating the
L3-4 interspace, the overlying skin was then infiltrated with 2ml of 2% lidocaine. A 25G pencil point (Whitacre) spinal needle was inserted through the interspace and was gradually advanced towards the subarachnoid space. Upon reflux of cerebrospinal fluid (CSF), a hyperbaric solution of 0.5% bupivacaine 12.5mg (2.5ml) was instilled, the spinal needle was withdrawn and adhesive dressing was applied. The patients were slowly returned back to the supine position with head and shoulders supported on a pillow and with left uterine displacement. The vital signs were measured and recorded immediately after the spinal technique.
Two minutes after the spinal block and prior to surgical incision, the study drugs were administered intravenously by the researcher and shivering monitored by an observer both of whom were blinded to the study drugs. Following confirmation of spinal block by loss of sensory sensation to gentle pin prick up to a minimum level of T6, surgery was allowed to start.
Two consecutive assessments were made thereafter to ascertain maximum level of block height. Pulse rate, blood pressure, oxygen saturation, respiratory rate, core and body temperatures were recorded every 2min for the first 10min and thereafter every 5min till the end of surgery.
Intraoperatively, supplemental oxygen was administered to the patient via nasal prongs at
2L/min. Oxygen therapy was discontinued after the delivery of the foetus in the absence of complications such as hypotension, shivering and haemorrhage. Intravenous fluids for
xl maintenance were administered to the patients at 10mls/kg in the first one hour and 5mls/kg in the subsequent hours. Assessment of blood loss was done using the quantitative method
(number of soaked abdominal mops and amount of blood in suction bottle). Blood was transfused when the trigger point for transfusion was exceeded (blood loss of >20% of blood volume). Total amount of fluid administered and the total number of units of blood transfused were noted and recorded for each patient. Urine output was monitored via urethral catheterization to assess adequacy of fluid maintenance. Total urine output was recorded for all patients.
Following the delivery of the foetus, 5 units of intravenous oxytocin was given slowly. Another
35 units of oxytocin was added to 500ml of 5% glucose and was given by slow intravenous infusion. Neonatal outcome was assessed using Apgar score at 1 and 5min. A persistently low
Apgar score (below seven at 1 and 5 minutes) was considered an indicator of poor condition at birth.lxxii
Shivering, sedation, pain, nausea and vomiting were evaluated at 5 minutes interval during surgery and at 15 minutes interval postoperatively for 120 minutes. The onset time of shivering was noted and documented for each patient. Shivering was graded using a scale similar to that validated by Tsai and Chuxlvi (Grade 0: no shivering, Grade 1: piloerection or peripheral vasoconstriction but no visible shivering, Grade 2: muscular activity in only one muscle group,
Grade 3: muscular activity in more than one muscle group but not generalized and Grade 4: shivering involving the whole body). Grade 1 was considered as mild, grade 2 as moderate with grade 3 and 4 as severe shivering.
The levels of sedation of the patients were assessed using the Ramsaylxxiii sedation score: 1 - anxious, agitated and restless; 2 - oriented and cooperative, 3 - responds to command only; 4
- brisk response to loud voice and light glabellar tap; 5 - sluggish to no response to light
xli glabellar tap or loud auditory stimulus, 6: no response even to pain. Pain was assessed using a visual analogue score (VAS) (0=no pain, 10=worst imaginable pain). Pain was categorized as mild (1-3), moderate (4-6) and severe (7 and above).
The severity of PONV was assessed using the numeric scoring system for PONV (0=no nausea or vomiting; 1= nausea but no vomiting; 2=vomiting once; 3 = two or more episodes of vomiting).lxxiv For the purpose of this study, nausea was defined as the feeling of vomiting as reported by the patient; vomiting as the rhythmic movement of the anterior abdominal wall with ejection of gastric content as observed by the researcher; retching, which is the rhythmic movement of the anterior abdominal wall without ejection of gastric content, was considered as vomiting. The degree of patient’s satisfaction with prophylaxis of postanaesthesia shivering was assessed using the following scale; poor, satisfied, or very satisfied.lxxv
Peri-operatively, hypotension (defined as mild - blood pressure drop of < 20% of baseline; moderate - blood pressure drop of 20 - 30% of baseline; severe - blood pressure drop >30% of baselinexiii) was treated using intravenous fluid (0.9% saline) 20mls/kg alone or combined with bolus of intravenous ephedrine in aliquots of 3mg depending on the severity. Shivering of grade
3 or more was managed with intravenous pethidine 25mg. Nausea or vomiting was treated using intravenous metoclopramide 10mg. Intravenous pentazocine 30mg was used as rescue analgesia when pain score was ≥4. Patients who developed respiratory distress, or who had failed, inadequate or high spinal were converted to general anaesthesia and excluded from the study.
Postoperatively, vital signs, shivering score, pain score, level of sedation and PONV were assessed every 15min for a period of 120min and recorded. Urine output was also monitored during this period for adequacy of fluid management. Patients were followed up for 24hrs.
xlii
Complications like post-dural puncture headaches (PDPH), nausea and vomiting, backache, and difficulty in voiding were noted and managed accordingly.
Data collection:
Pre-coded and pre-tested structured-interview type questionnaires (Appendix II) were used perioperatively to obtain the socio-demographic and clinical information from the participants.
Shivering and side effect profile were recorded as follows:
The primary outcome was the proportion of patients in each group who had shivering in the perioperative period. Secondary outcome measures include the following: proportion of patients with a sedation score greater than 2; proportion of patients who required anti-emetic intra-operatively for nausea or vomiting; proportion of patients who experienced pain score ≥4 and required pain rescue; proportion of patients who had postoperative complications like
PDPH, backache and urinary retention; proportion of neonates who had Apgar score <7 at 1min and 5min; proportion of patients with intraoperative hypotension necessitating the administration of vasopressor (ephedrine); proportion of patients who were very satisfied with the prevention of PAS.
Statistical analysis:
Subjects from the 3 groups were stratified. Data entry and outcome variables were analyzed using the Statistical Package for Social Sciences (SPSS 16.0 - SPSS Inc., Chicago, IL, USA).
Data were presented as mean and standard deviation (SD), frequencies, proportions and trends.
Numerical variables such as age, weight, height, and duration of surgery between the 3 groups were analyzed using one-way analysis of variance (ANOVA) test. Post hoc comparisons were
xliii performed using Bonferroni correction of the significance level. Categorical data such as ASA, block height, shivering and sedation were analyzed using the Chi-square test with Pearson’s correction. The core and skin temperatures of shivering vs. non-shivering patients were compared using unpaired t-test. Paired t-test was used to compare the differences in patients’ blood pressure and core/skin temperatures at baseline and at 90min. All statistical tests were two-tailed.
P value <0.05 was considered statistically significant and formed the basis of accepting or rejecting the null hypothesis.
xliv
CHAPTER FOUR
RESULTS
Ninety patients participated in the study. Each group had 30 patients. Sixty-two (68.9%) were classified as ASA 1 patients while 28 (31.1%) were classified as ASA 2 patients.
Table 1 shows that the patients’ socio-demographic characteristics did not differ significantly in terms of age (p = 0.286, ANOVA), weight (p = 0.681, ANOVA), height (p = 0.745,
ANOVA), gestational age (p = 0.339, ANOVA), parity (p = 0.256, ANOVA) and ASA (p =
0.813, ANOVA).
Major indications for Caesarean section include previous scar (25%), transverse lie (19%) and
PIH (18%). Others were placenta praevia (7%), breech presentation (7%), maternal request
(7%), previous history of infertility (5%); foetal macrosomia (5%), intrauterine growth retardation (3.3%), elderly primipara (2.2%) and oligohydriamnios (1.1%). (Figure 1)
Table 2 shows baseline vital signs. The three groups did not differ with regards to pulse rate (p
= 0.778, ANOVA), systolic and diastolic blood pressure (p = 0.104 and 0.203, ANOVA), respiratory rate (p = 0.594, ANOVA), core and skin temperature (p = 0.054 and 0.179,
ANOVA), core-skin temperate gradient (p = 0.241, ANOVA) and oxygen saturation (p =
0.254, ANOVA).
xlv
Intraoperative clinical variables (Table 3) shows no significant difference between the 3 groups with regards to dose of tramadol (p = 0.681, ANOVA), block height (p = 0.831, Chi-square), time to extraction of foetus (p = 0.845, ANOVA), duration of surgery (p = 0.423, ANOVA), total intravenous fluid (p = 0.812, ANOVA), and estimated blood loss (p = 0.757, ANOVA).
However, time to first analgesic request differed significantly among the 3 groups (ondansetron
= 87.83 ± 26.45min, tramadol = 94.38 ± 21.94min, saline = 62.44 ± 11.50min; p = 0.009,
ANOVA). Further analysis showed no significant difference in time to first analgesic request between the patients in the ondansetron vs. the tramadol groups (p = 0.686, ANOVA). The difference was however very significant between the ondansetron vs. saline groups (p < 0.001,
ANOVA) and between the tramadol vs. saline groups (p < 0.001, ANOVA).
Neonatal outcome is shown in Table 4. Neonatal weight did not differ significantly between the 3 groups (p = 0.411, ANOVA). No neonate had Apgar score less than 7 in the study groups at 1min (p-value = 1.000, ANOVA) and at 5min (p = 1.000, ANOVA).
Shivering occurred in 6 (20.0%) patients in the ondansetron group, 5 (16.7%) patients in the tramadol group and 16 (53.3%) patients in the saline group (p = 0.003, Chi-square). The relative risk of developing shivering with saline compared to ondansetron is 2.65 (95% CI: 1.718 –
4.088; p < 0.0001, Chi-square with Fisher’s exact test), with saline compared to tramadol is
3.12 (95% CI: 1.947 – 4.993; p < 0.0001, Chi-square with Fisher’s exact) and with ondansetron compared to tramadol is 1.18 (95% CI: 0.656 to 2.110; p = 0.72, Chi-square with Fisher’s exact). The number needed to treat (NNT) for ondansetron is 2.9 and for tramadol is 2.7 (Table
5).
Eight (26.7%) patients in the saline group, 1(3.3%) patient in the ondansetron group and none
(0.0%) in the tramadol group experienced grade 3 shivering. This difference in the severity of
xlvi shivering was highly significant (p = 0.007, Chi-square). Severity of shivering was comparable between ondansetron and tramadol (p = 1.000, ANOVA), but differed significantly between ondansetron vs. saline (p-value = 0.003, ANOVA) and tramadol vs. saline (p-value = 0.001,
ANOVA).
The time to shivering for ondansetron (2.10 ± 4.58min), tramadol (1.85 ± 4.78min) and saline
(5.97 ± 6.97min) differed significantly between the 3 groups (p = 0.007, ANOVA). The time to shivering between ondansetron group and tramadol group was comparable (p = 1.000,
ANOVA), but the time to shivering between ondansetron vs. saline (p = 0.025, ANOVA) and tramadol vs. saline (p = 0.015, ANOVA) were statistically significant.
The temperature values at point of shivering are shown in Table 6. The difference in core temperature (p = 0.207, ANOVA), skin temperature (p = 0.513, ANOVA), and core-skin temperature gradient (p = 0.869, ANOVA) between the three groups at the time of shivering was not statistically significant.
Figure 2 shows the mean core temperature of shivering and non-shivering patients (36.60 ±
0.34oC vs. 36.76 ± 0.32oC; p = 0.745, unpaired t-test) and mean skin temperature of shivering and non-shivering patients (35.83 ± 0.36oC; 35.97 ± 0.39oC; p = 0.415, unpaired t-test).
Though, the patients who shivered had lower core temperatures and lower skin temperatures compared to non-shivering patients, this was not statistically significant.
Figure 3 shows the core and skin temperature trends among the 3 groups. The difference in the core temperatures at 90min between the 3 groups (ondansetron - 36.2oC, tramadol - 36.4 oC, saline - 36.0oC) was statistically significant (p = 0.049, ANOVA). The difference was not statistically significant between ondansetron vs. tramadol groups (p = 0.530, ANOVA) and between ondansetron vs. saline groups (p = 0.325) but the different was significant between
xlvii tramadol vs. saline groups (p = 0.011). The skin temperatures at 90min not differ significantly between the three groups: ondansetron - 35.3oC, tramadol - 35.6oC, saline - 35.4oC (p = 0.073,
ANOVA).
The core temperature trend from baseline (Figure 4) shows a comparable decrease in the 3 groups. By 15min there was a large drop in core temperature of 0.4oC, 0.4oC and 0.5oC for ondansetron, tramadol and saline groups respectively. Thereafter, the reduction was more gradual. At 30min it has dropped by 0.5oC, 0.6oC, and 0.7oC for ondansetron, tramadol and saline respectively; and at 90min by 0.8oC, 0.9oC and 1.1oC for ondansetron, tramadol and saline respectively. The core temperatures at 90min were significantly lower compared to baseline for ondansetron (35.97 ± 0.41oC vs. 37.01 ± 0.25; p = 0.0001, paired t-test), tramadol
(36.28 ± 0.35oC vs. 37.13 ± 0.24oC, p = 0.0001, paired t-test) and saline (36.12 ± 0.37oC vs.
37.00 ± 0.27oC, p = 0.0001, paired t-test).
Figure 5 shows that the patients in the ondansetron group experienced an increased core-skin temperature gradient from 0.8oC to 1.0oC in the first 30min and then stabilized. The tramadol group experienced an initial reduction from 0.9oC to 0.85oC in the first 15min and thereafter stabilized. The gradient in the saline group decreased from 0.8oC to 0.7oC over 30min before stabilizing. The core-skin temperature gradient at 90min was significantly different between the 3 groups (p = 0.0001, ANOVA). The gradient was comparable between the ondansetron vs. tramadol groups (p = 0.863, ANOVA), but differed significantly between ondansetron vs. saline groups (p = 0.0001, ANOVA) and between tramadol vs. saline groups (p = 0.0001,
ANOVA).
Figure 6 shows the trend of haemodynamic parameters. Systolic BP decreased significantly in all 3 groups in the first 10min of spinal anaesthesia. Ondansetron group decreased by 14mmHg
(p = 0.0001, paired t-test), the tramadol group decreased by 11mmHg (0.016, paired t-test) and
xlviii the saline group reduced by 10mmHg (0.0001, paired t-test). Thereafter, a gradual rise in the systolic BP was observed in all the 3 groups. The systolic BP did not differ significantly between the 3 groups at baseline (p = 0.104, ANOVA), at 10min (p = 0.465, ANOVA), at
60min (p = 0.652) or at 90min (p = 0.554, ANOVA). At 10min from baseline, the diastolic BP reduced by 13mmHg (p = 0.165, paired t-test), 10mmHg (p = 0.036, paired t-test) and 9mmHg
(p = 0.003, paired t-test) for ondansetron, tramadol and saline respectively. The diastolic BP did not differ between the 3 groups at baseline (p = 0.203, ANOVA), at 10min (p = 0.547,
ANOVA), at 60min (p = 0.716, ANOVA) or at 90min (p = 0.922, ANOVA). The pulse rate did not differ significantly between the 3 groups at baseline (p = 0.778, ANOVA), at 10min (p
= 0.086, ANOVA), at 60min (p = 0.057) or at 90min (p = 0.322, ANOVA). In addition, respiratory rate (p = 0.139, ANOVA) and oxygen saturation (p = 0.114, ANOVA) were not significantly different intraoperatively between the 3 groups (Figures 7 and 8).
Table 7 shows that the incidence of hypotension (p = 0.947, Chi-square test), pain (p = 0.664,
Chi-square test) and sedation (p = 0.600, Chi-square test) were not significantly different between the 3 groups. Eight (8.9%) out of the 26 (28.9%) hypotensive episodes observed had severe hypotension; 2 (2.3%) in the ondansetron group, 3 (3.3%) in the tramadol group and 3
(3.3%) in the saline group (p = 0.912, Chi-square). Hypotension was managed with intravenous bolus infusion of normal saline and 3mg aliquots of ephedrine depending on the severity.
Ondansetron and tramadol had one patient each with sedation score of 3, while the saline group had no patient with sedation score of 3 (p = 0.600, Chi-square). All other patients had sedation score of 2. Six (20.0%) patients in the ondansetron group, 5 (26.7%) patients in the tramadol group and 10 (33.3%) patients in the saline group had pain scores ≥4 and were given i.v pentazocine 30mg i.v for pain relief. The difference in pain scores was not statistically significant (p = 0.286, ANOVA).
xlix
Seven patients in the tramadol group, 2 patients in the saline group and 1 patient in the ondansetron group had PONV and were given i.v metoclopramide 10mg; the difference was significant (p = 0.031, Chi-square test). The relative risk of the patients in the tramadol group developing PONV compared to ondansetron is 7.67 (95% CI: 2.377 – 24.728; p = 0.0001, Chi- square test with Fisher’s exact) while for the saline group, the relative risk is 2.33 (95% CI:
0.621 – 8.771, P = 0.331, Chi-square test with Fisher’s exact).
Postoperative complications in the first 24hrs, as shown in Table 8, revealed no significant difference between the groups as regard PONV (p = 0.355, Chi-square test), PDPH (p = 0.160,
Chi-square test) and backache (p = 1.000, Chi-square test).
The degree of patient’s satisfaction with the prophylaxis of postanaesthesia shivering (Table 9) shows that 23 (76.7%) patients in the ondansetron group were very satisfied compared to 21
(70.0%) patients in the tramadol group and 8 (26.7%) patients in the saline group (p = 0.001,
Chi-square). Nine (30%) of the patients in the saline group were poorly satisfied with PAS prophylaxis compared to 3 (10%) in the ondansetron group and 2 (6.7%) in the saline group.
A strong inverse relationship existed between shivering and patients’ degree of satisfaction as shown by the Correlation coefficient (Pearson’s r) of -0.7030 (95% CI: -0.7945 to -0.5804, p
< 0.0001).
l
Table 1: Patients socio-demographic data
Ondansetron Tramadol Saline Parameter n = 30 n = 30 n = 30 p-value
Age (yrs) 31.33 ± 4.54 33.03 ± 5.34 31.33 ± 4.38 0.286
Weight (kg) 76.30 ± 13.41 77.60 ±12.45 79.40 ±15.21 0.681
Height (cm) 161.23 ± 4.90 161.72 ± 5.19 162.27±5.63 0.745
Gestational Age (wks) 38.03 ± 1.61 38.50 ±1.53 38.00 ± 1.23 0.339
Parity 0.256
Nulliparous 7 (23.3%) 7 (23.3%) 13 (43.3%)
Multiparous 23 (76.7%) 20 (66.7%) 17 (56.7%)
Grand multiparous 0 (0.00%) 3 (10.0%) 0 (0.00%)
ASA 1/2 20/10 22/8 20/10 0.813
li
Table 2: Preoperative baseline vital signs
Parameter Ondansetron Tramadol Saline n = 30 n = 30 n = 30 p-value
Mean + sd Mean + sd Mean + sd
Pulse Rate /min 94.23 ± 13.40 96.93 ± 14.78 95.27 ± 16.28 0.778
Systolic BP (mmHg) 134.30 ± 16.81 125.27 ± 17.60 130.04 ± 16.56 0.104
Diastolic BP (mmHg) 76.20 ± 14.87 69.80 ± 13.58 73.30 ± 12.80 0.203
Respiratory Rate (cpm) 20.90 ± 2.88 21.57 ± 2.60 21.17 ± 2.07 0.594
Core temperature (oC) 37.00 ± 0.27 37.15 ± 0.25 37.01 ± 0.25 0.054
Skin temperature (oC) 36.16 ± 0.36 36.30 ± 0.36 36.30 ± 0.28 0.179
Core/Skin temp difference (oC) 0.85 ± 0..33 0.89 ± 0.22 0.78 ± 0.21 0.241
SpO2(%) 98.10 ± 0.61 98.10 ± 0.71 98.33± 0.55 0.254
lii
Table 3: Intraoperative clinical characteristics
Ondansetron Tramadol Saline Parameter n = 30 n = 30 n = 30 p- value
Mean + sd Mean + sd Mean + sd
Dose of tramadol (mg/kg) 39.70 7.60 38.80 6.22 38.15 6.71 0. 681
Block height (T4/T5/T6, Mode) 17/8/5 (4) 18/6/6 (4) 14/9/7 (4) 0.831
Time to extraction (min) 11.99 ± 2.65 12.24 ± 2.95 11.77 ± 3.88 0.845
Total intravenous fluid (ml) 3526.67 725.37 3513.33 516.44 3610.00 623.31 0.812
Estimated blood loss (ml) 645.00 199.29 648.33 164.26 616.00 187.43 0.757
Duration of surgery (min) 66.07 ± 21.42 66.73 ± 22.81 60.33 ± 18.29 0.423
Time to 1st analgesic demand (min) 87.83 ± 26.45 94.38 ± 21.94 62.44 ± 11.50 0.009
liii
Table 4: Neonatal outcome
Ondansetron Tramadol Saline Parameter n = 30 n = 30 n = 30 p- value
Neonatal Weight (kg) 3.13 ± 0.418 3.13 ± 0.414 3.28 ± 0.696 0.411
Apgar scores 1 min (<7/≥7) 0/30(7-9) 0/30(7-9) 0/30(7-9) 1.000
5 min (<7/≥7) 0/30(7-9) 0/30(7-9) 0/30(7-9) 1.000
liv
Table 5: Incidence, severity and time to shivering
Ondansetron Tramadol Saline Parameter p-value n = 30 n = 30 n = 30
Shivering 0.003
No 24 (80.0%) 25 (83.3%) 14 (46.7%)
Yes 6 (20.0%) 5 (16.7%) 16 (53.3%)
Severity
Grade 1 2 (6.7%) 1 (3.3%) 3 (10.0%)
Grade 2 3 (10.0%) 4 (13.3%) 5 (16.7%)
Grade 3 1 (3.3%) 0 (0.0) 8(26.7%) 0.007
Time to shivering (min) 2.10 ± 4.58 1.85 ± 4.78 5.97 ± 6.97 0.007
lv
Table 6: Temperature values at shivering
Parameter ondansetron tramadol saline p-value n =30 n =30 n =30
Core temperature (oC) 36.57 ± 0.43 36.84 ± 0.24 36.53 ± 0.31 0.207
Skin temperature (oC) 35.80 ± 0.37 36.00 ± 0.16 35.79 ± 0 .40 0.513
Core-skin temperature difference (oC) 0.77 ± 0 .19 0.84 ± 0.25 0.73 ± 0.47 0.869
lvi
Table 7: Incidence of perioperative complications
Parameter Ondansetron Tramadol Saline p-value n = 30 n = 30 n = 30
Hypotension 8 (26.7%) 9 (30.0%) 9 (30.0%) 0.947
- mild/moderate/severe 4/2/2 4/2/3 3/3/3
PONV 1 (3.3%) 7 (23.3%) 2 (6.7%) 0.008
Pain 6 (20.0%) 8 (26.7%) 10 (30.0%) 0.664
Pain Score ≥4 6 (20%) 5 (16.7%) 10 (33.3%) 0.286
Sedation (2-3) 30 (100%) 30 (100%) 30 (100%) 1.000
Sedation score ≥4 0 0 0 1.000
Total = 83 (100%) 22 (26.5%) 30 (36.1%) 31 (37.4%) 0.721
lvii
Table 8: Incidence of postoperative complications in the first 24hrs
Parameter Ondansetron Tramadol Saline P value n = 30 n = 30 n = 30
PONV 0 (0.0%) 2 (6.6%) 1 (3.3%) 0.600
PDPH 1 (3.3%) 1(3.3%) 2 (6.7%) 0.770
Backache 3 (10.0%) 3 (10.0%) 3 (10.0%) 1.000
Total = 16 (100%) 4 (25.0%) 6 (37.5%) 6 (37.5%) 0.746
lviii
Table 9: Degree of patient’s satisfaction with PAS prophylaxis
Parameter Ondansetron Tramadol Saline p-value n = 30 n = 30 n = 30
Satisfaction 0.001
Poor 3(10.0%) 2 (6.7%) 9 (30.0%)
Satisfied 4(13.3%) 7 (23.3%) 13 (43.3%)
very satisfied 23 (76.7%) 21 (70.0%) 8 (26.7%)
lix
Figure 1: Indications for Caesarean section
others infertility 7% macrosomia 5% 5% previous scar maternal 25% request 7%
transverse lie 19% breech pih 7% 18%
placenta praevia 7%
lx
Figure 2: Core and skin temperatures of shivering and non-shivering patients
Non-shivering Shivering
36.8
36.6
36.4
36.2 36.76
oC 36.60 36
35.8 35.97 35.6 35.83
35.4
35.2 Mean core temperature Mean skin temperature
lxi
Figure 3: Trend of core and skin temperatures
lxii
ondansetron(core) tramadol(core) saline(core) ondansetron(skin) tramadol(skin) saline(skin)
37.5
37.2 C) o 37.0 37.1 core 36.5 36.3 36.4 36.2 36.0 36.0 skin Mean temperature (T Mean temperature 35.5 35.6 35.4 35.3 35.0
34.5
34.0 0 2 5 10 15 20 30 45 60 75 90
Time/min
Figure 4: Core temperature decrease from baseline
lxiii
ondansetron tramadol saline
Time (min)
0 15 30 45 60 75 90
0.0 C) o 0.2
0.4 0.4 0.4 0.5 0.5 0.6 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 Core temperature decrease ( temperature decrease Core 1.1 1.2
Figure 5: Trend of core - skin temperature gradient
lxiv
ondansetron tramadol saline
1.2
C) o 1.0
.8
.6
.4 skin temperature ( temperature gradient skin
- .2 Core Core .0 0 15 30 45 60 75 90
Time (min)
Figure 6: Trend of haemodynamic parameters
lxv
ondansetron(SBP) tramadol(SBP) saline(SBP) ondansetron(PR) tramadol(PR) saline(PR) ondansetron(DBP) tramadol(DBP) saline(DBP)
160
140 SBP 120
100 PR
80
60 DBP
40 Mean BP (mmHg) (mmHg) PR/min and Mean BP 20
0 0 2 5 10 15 20 30 45 60 75 90
Time (min)
lxvi
Figure 7: Trend of SpO2
ondansetron tramadol saline 99.0 98.8 98.6 98.4 98.2
SpO2(%) 98.0 97.8 97.6 0 2 5 10 15 20 30 45 60 75 90 Time (min)
lxvii
Figure 8: Trend of Respiratory rate
ondansetron tramadol saline
22 21.5 21 20.5 20 19.5
Respiratory Respiratory rate/min 19 0 2 5 10 15 20 30 45 60 75 90 Time (min)
lxviii
CHAPTER FIVE
DISCUSSION
This study shows that ondansetron and tramadol significantly reduce the incidence and severity of shivering compared to placebo. In comparison, ondansetron was superior to tramadol in prevention of postoperative nausea and vomiting. In addition to its antiemetic and anti- shivering properties, ondansetron also significantly prolonged the time to first analgesic requirement comparable to tramadol. Furthermore, core temperature was significantly reduced perioperatively in all patients studied, with patients who shivered having lower core temperature compared to non-shivering patients. The benefits of ondansetron were observed with acceptable side effects profile and high satisfaction rate.
The overall incidence of shivering in this study is 30%. This agrees with previous reports by
Edomwonyi et al,iii (29.8%) and Atashkhoyi et al,xvi (33.3%). However, in the study by
Edomwonyi et al,iii prophylactic intervention was not embarked upon as is the case in the index study. In contrast, a higher incidence of 47.8% was reported by Javaherforoosh et al.xi A lower room temperature of 21-23oC was used by Javaherforoosh et al,xi in their study with intravenous fluids administered at room temperature in a subtropical high pressure belt where maximum temperatures of 40 - 45ºC are common. This contrasted with the ambient temperature of 25oC used in the index study where a daytime maximum of 32ºC is more common. The use of higher ambient temperature coupled with infusion of relatively warmer intravenous fluids in the present study may have accounted for the lower incidence of shivering recorded. However, the worldwide incidence of shivering is usually quoted as 20 – 60%.iii
On the other hand, other authors have reported a lower incidence of shivering than that found in the present study. Sule and colleagueslxvii reported an incidence of 15%. This low incidence
lxix may have resulted from the fact that shivering was not their primary outcome of interest. It was rather observed as part of the overall postoperative complications in patients undergoing lower abdominal and lower limb surgery under SAB. Moreover, a retrospective study may likely fail to capture the total occurrence of shivering. This contrasts with the index study which is prospective in nature and has shivering as its primary outcome of interest. Furthermore, the present study was carried out in the obstetric patients where high incidence of shivering under
SAB has been reported by some authors.xi,xxxviii,l Therefore, the relatively higher incidence of shivering observed in the index study compared to that of Sule et allxvii, is not unexpected. In addition, pregnancy states are associated with a higher vascular sympathetic tone. As such, pharmacological sympathectomy is likely to cause a more profound vasodilatation, marked heat loss and attendant shivering.lxxvi The parturients in the index study lost 0.4 – 0.5oC of core temperature within 15min of SAB and this may explain why 1 in 3 parturients experienced shivering. Therefore, it is pertinent to consider obstetric patients for prophylaxis against PAS when undergoing Caesarean section under SAB.
In this study, more than half of the patients (53%) who did not receive prophylaxis developed shivering, while in those who received prophylaxis, shivering occurred in 20% (ondansetron) and 16.7% (tramadol) of patients. Several authors have also demonstrated similar shivering rate in the absence of prophylaxis.xvii,lxxvii,lxxviii,lxxix A complication of this magnitude with known dire consequences and such widespread occurrence poses a great burden on all care- givers. It places an enormous responsibility on the anaesthetic community to consider appropriate prophylactic measures against PAS. Pharmacological management has been advocated in addition to the use of physical methods.ix,xliii This study has shown that i.v ondansetron 4mg is effective in reducing the incidence and severity of PAS in parturients undergoing Caesarean section under spinal anaesthesia.
lxx
Conversely, some authors have reported lower incidences of shivering in placebo-treated obstetric patients in contrast to the findings in the present study.xvi,Error! Bookmark not defined.
Specifically, Oranuch et al,xv reported an incidence of 45.0%. They used 2.2ml of 0.5% heavy bupivacaine with 0.2mg of preservative-free morphine for SAB in all the patients unlike in the index study where SAB was achieved with 2.5ml of 0.5% hyperbaric bupivacaine. Opioid additives could not be used in the present study because of the non-availability of preservative- free opioids in our centre. Opioid additives are used to prolong the duration of analgesia while reducing the dose of the local anaesthetic agent used and therefore, the side effects. Intrathecal morphine has been reported to reduce the incidence of shivering.lxxx This may explain why a higher incidence of shivering was recorded in the present study.
Ondansetron was effective in reducing the incidence of PAS to about 1 in 5 patients compared to less than 1 in 2 patients achieved in the control group. In addition, the marked reduction in the severity of shivering in the population with ondansetron prophylaxis is also remarkable.
There is a plethora of evidence in the literature suggesting a lower incidence of PAS with ondansetron than that observed in this study. x,xvii,li Specifically, Kelsaka et al,li used 8mg of ondansetron as compared to 4mg used in the index study and reported an incidence of 8%. It may be too simplistic to assume that the difference in our observation is due to dosage alone, as the effect of ondansetron is known to be dose dependent. Moreover, Shakya et al,x and
Entezariasl et al,17 used similar doses but still got lower results (10 – 13.3%). However, the low incidence in Entezariasl et al,xvii may also be explained by the difference in technique as general anaesthesia was the preferred technique in their study. It has been shown that subarachnoid block reduces the threshold for vasoconstriction and shivering by only 0.5°C compared to about
1oC by general anaesthesia.xxv This means that patients shiver at a higher core temperature under subarachnoid block compared to general anaesthesia (35.5oC vs. 34.5oC).xliii Moreover,
lxxi there is less heat production with shivering during subarachnoid block compared to general anaesthesia.xliii Therefore, shivering has to be more intense for maximum gain to be achieved thereby increasing the incidence of shivering.
On the other hand, Shakya et al,x carried out their study in non-parturients who received diazepam premedication, a known anti-shivering agent. On the other hand, the index study involved parturients who were not premedicated with diazepam. It is against the protocol in our institution and elsewhere.lxxxi,lxxxii to use diazepam premedication for patients undergoing
Caesarean section as it may cause global hypotonia, heart rate variability and respiratory depression in the neonate.lxxxi In addition, Shakya et al,x achieved a median block height of T6 whereas the index study achieved a modal block height of T4 deemed necessary to avoid peritoneal irritation due to exteriorization of the uterus at delivery. It is known that the incidence of shivering is directly related to the number of spinal segment blocked.lxxxiii
Therefore, the higher level of block achieved in the present study may also account for the higher incidence of shivering observed.
The findings in this study indicate a 33 - 37% reduction in shivering rate in patients who received prophylaxis with ondansetron or tramadol. The implication of this finding is that there is a 2.65 to 3.12 fold risk of developing PAS in the absence of ondansetron or tramadol prophylaxis. Moreover, not only was shivering rate similar, but the NNT in patients who received ondansetron (2.9) was comparable to those who received tramadol (2.7). This means that for every 3 patients that received prophylaxis, one patient benefited who otherwise may not have benefited in the absence of chemo-prophylaxis. In addition, the significant reduction in the severity of shivering in the population with prophylaxis was remarkable and comparable between ondansetron and tramadol.
lxxii
The result from this study supports the well established efficacy of tramadol as an anti- shivering agent.xv That ondansetron has comparable efficacy to tramadol in the prophylaxis of
PAS as shown in this study deserves other comments. Besides the remarkable effects on PAS, ondansetron offers some protection against PONV as seen in this study. This advantage is rare with other commonly used chemo-prophylactic agents against PAS like nalbuphinexv, pethidinexvii, ketaminex and tramadol. Indeed, some of these troublesome side effects have limited the use of opioids and related analogues in the pharmacological management of PAS.
The low side effects exhibited by ondansetron, as seen in this study, makes it more attractive over tramadol for the prophylaxis of PAS in patients undergoing Caesarean section under SAB.
There are variable results concerning the efficacy of ondansetron in the management of
PAS.xiii,xv,xvii,li This has been attributed to the dose of ondansetron used. Specifically, Powell and Buggyxiii reported that 4mg ondansetron was not significantly different from saline in preventing shivering. The findings in the present study indicate otherwise. The primary objective of Powell and Buggy13 was to investigate the mechanism of PAS by evaluating the importance of 5-HT pathways using GA in non-parturients. This may have impacted on their methodology and sample size thus resulting in failure to detect any significant difference where it could have existed. On the other hand, the index study has the primary objective of evaluating the incidence of PAS in parturients undergoing Caesarean section under SAB. The difference in primary objectives and methodology in the two studies may account for the conflicting results observed.
Although ondansetron has been shown to compare favourably with tramadol in the prophylaxis of PAS in our study, we observed that tramadol fared marginally better. The shivering rate and the NNT were slightly higher for ondansetron-treated parturients compared to tramadol.
lxxiii
However, these differences were not significant. The marginal success of tramadol compared to ondansetron may be due to its relatively better performance in some key indices in our study.
The core and skin temperatures at the time of shivering were higher in the tramadol group compared to the ondansetron and saline groups. In addition, tramadol sustained higher core and skin temperatures throughout the perioperative period compared to ondansetron and saline.
This agrees with the findings reported by Atashkhoyi et al,16 where they found out that axillary temperatures of patients in the tramadol group were higher than in the saline group. Shivering is 20% related to skin temperature. The higher skin temperatures achieved by tramadol may probably be the mechanism of action by which it reduces the incidence and severity of shivering.
Furthermore, this study showed that patients who had tramadol prophylaxis had lesser heat loss within the first 30min compared to patients who received ondansetron and saline prophylaxis.
It has been suggested that heat loss with attendant core hypothermia is one of the causes of shivering. Eberhart et al,xxxvii identified low core temperature as one of the three risk factors that cause shivering. The patients who developed shivering had lower core and skin temperatures compared to non-shivering patients in the index study. Shivering and vasoconstriction are 80% controlled by core temperature and 20% by skin temperature.xl The ability of tramadol to reduce heat loss and thus maintain higher core and skin temperatures may explain why patients who received tramadol prophylaxis experienced less shivering compared to patients who received ondansetron prophylaxis.
The patients in this study shivered at a relatively higher core temperature than expected. The reason for this is not very distinct. It may be speculated that patients in the tropical climate tend to shiver at higher temperature because of up-regulation of thermogenic control mechanisms due to higher ambient temperatures. In addition, intense shivering is known to occur in some
lxxiv patients immediately after induction of spinal anaesthesia for Caesarean delivery – well before core temperature has had time to decrease.xliii The injection of refrigerated local anaesthetic fluid into the neuraxis has been implicated.
However, despite the prophylactic and other measures instituted to reduce heat loss, all the patients in this study experienced steady decline in core temperature in the perioperative period.
It is known that SAB causes progressive heat loss as patients cannot re-establish core temperature equilibrium because peripheral vasoconstriction remains impaired.xxix,lxxxiv The core temperature values at 90min were significantly lower compared to baseline in this study.
Other authors reported similar findings.x,xvi In addition, the fall in core temperatures in the index study may also be due to a cold operating room and rapid infusions of intravenous fluids at room temperatures. An ambient temperature of 25oC was used in this study where maximum temperatures are known to reach 32oC. When patients with normal core temperature of 37oC are anaesthetized and their skin exposed to cold operating theatre with ambient temperature of
25oC as in this study, they become hypothermic due to loss of heat from the skin to the environment by radiation, conduction and convection.xxv Furthermore, each patient received an average of 3-5 liters of fluids at room temperature. Cold intravenous infusions increase conductive heat losses, thereby contributing to reduction in core temperature.
The core-skin temperature gradient was not affected by ondansetron in this study. This is similar to that reported by Powell and Buggy.xiii The gradient was wider in the ondansetron group compared to the tramadol and saline group. The higher skin temperature observed in the tramadol group in this study may explain why the core-skin temperature gradient is narrower than in the ondansetron group. The difference in the mechanism of action of the two drugs may account for this. Central inhibitory mechanism involving serotoninergic pathways have been
lxxv suggested to be the mode of action of ondansetron. On the other hand, it is postulated that tramadol impairs peripheral compensatory vasoconstrictive mechanism. Why the patients in the saline group had the least core-skin temperature gradient in the present study is not clear.
However, shivering is known to increase skin temperature. Since more patients shivered in the saline group, the mean skin temperature is expected to be higher. This study revealed that the patients in the saline group achieved higher skin temperatures than patients in the ondansetron group. In the presence of falling core temperatures, this has the effect of narrowing the core- skin temperature gradient in the saline group.
It was observed in this study that the decrease in core and skin temperatures was more dramatic in the first 15min of spinal block. This is the critical period for the fixing and onset of spinal anaesthesia. It is possible that more rapid heat redistribution from core to periphery due to vasodilatation occurs at this time. This may have resulted in substantial heat loss from the skin below the level of block before the compensatory mechanism of vasoconstriction above the level of block is maximally activated. In addition, this study showed that all episodes of shivering occurred within 30minutes of SAB. Techanivate et al,lxxvii reported that shivering occurred within one hour in their study. The initial rapid heat loss may have accounted for shivering largely occurring within this period. Moreover, by 30min core temperature has significantly reduced compared to baseline in the index study. It is known that core temperature decreases to more than 1°C below baseline value during the initial 30-45 minutes after SAB while maximum core - peripheral heat redistribution takes place in the first hour.xxxi,lxxxv
Therefore surgery might start with the patient already hypothermic. Furthermore, almost all spinal-induced hypotension occurred during the first 30min of SAB in the index study. This was partly corrected with rapid infusion of fluid at room temperature, a factor associated with
lxxvi hypothermia. As a result, hypothermia and shivering thermogenesis is expected to occur more during this period.
The time to shivering was significantly shorter in the ondansetron and tramadol groups than in the saline group in this study. It is possible that ondansetron and tramadol prevented further shivering after their onset of action unlike the placebo which has no pharmacological action. It is suggested that for prophylactic measures to be effective, it should be instituted within the first 15min of SAB. In this study, prophylactic drugs were given within 2min after institution of SAB. This study showed, therefore, that the prophylactic use of ondansetron may effectively serve this purpose.
It was observed from this study that ondansetron is haemodynamically stable. The incidence and severity of hypotension did not differ significantly between the 3 groups. Most of the hypotensive episodes occurred in the initial 10min after SAB. Only 6.7% of patients required vasopressor (ephedrine) therapy in the ondansetron group. This is in keeping with previous findings.xiii,xvii However, Oranuch et al,xv reported bradycardia in one patient receiving 8mg ondansetron which was easily treated with atropine. Moreover, bradycardia may result from blockage of the cardiac accelerator cells (T1 – T4) due to high spinal block. No patient had bradycardia in this study. Thus, ondansetron has mild effects on the cardiovascular system. As a result of its haemodynamic stability ondansetron can be used during SAB in patients undergoing Caesarean section.
Ondansetron offers significant protection against PONV when compared to tramadol and placebo as observed from this study. Patients who received tramadol had a very high risk of developing PONV, as much as 7.7 times higher compared with ondansetron-treated patients and 2.3 times higher compared with placebo-treated patients. Several other studies have
lxxvii established that PONV is a common side effect of tramadol as a result of its opioid property.xvi,l,lx These side effects have limited its use, necessitating its avoidance in patients with high risk of PONV including parturients. Ondansetron, on the other hand is a known anti- emetic. This study has further revealed its ability to prevent PONV. This is an added advantage when employed for the management of shivering at a dose of 4mg/kg.
Other perioperative complication rates observed in this study were rather low. Mild sedation was experienced by two patients in this study. The patient who had sedation in the ondansetron group received pentazocin for pain relief. This shows that ondansetron has no sedative effects.
The low dose of tramadol used in this study may have resulted in the apparent lack of sedative effects observed. Sedation is not required in parturients undergoing Caesarean section as one of the advantages of SAB is early maternal-child bonding.
Patients who required pain rescue were comparable among the 3 groups from this study. Of the
21 patients who had pain rescue, majority requested for analgesia in the PACU. Time to first analgesic requirement was significantly shorter in patients who received saline compared to patients who received tramadol or ondansetron. Whereas, time to first analgesic request was longer in the tramadol group compared to the ondansetron group, this difference was not statistically significant. It is surprising that no difference was observed when a non-analgesic
(ondansetron) was compared with a known analgesic (tramadol) drug. In addition, patients who received ondansetron requested for analgesic much later than those who received placebo in this study. Whether ondansetron has analgesic effect is a subject of intense
lxxxvi,lxxxvii controversy. Serotonin (5-HT3) receptors have been localized on terminals of afferent fibres at the spinal levels, a novel subset of myelinated and unmyelinated nociceptors.lxxxviii
Ondansetron is likely to act by blockade of excitability of these afferent fibres thereby reducing nociception. This may account for the prolonged analgesic effect in the ondansetron-treated
lxxviii patients. McCleane et al,lxxxvi suggested that ondansetron may have an analgesic effect in neuropathic pain. In contrast, Derbent et al,lxxxvii could not demonstrate any difference in analgesic efficacy between ondansetron and saline in patients undergoing laminectomy. Nevertheless, the present study suggests that ondansetron may have analgesic effects comparable to tramadol in patients undergoing Caesarean section under SAB. This observation would benefit from further investigation with the analgesic quality of ondansetron as the primary outcome rather than as a secondary outcome as seen in this study.
The use of ondansetron or tramadol for prophylaxis against PAS prior to delivery of the foetus appeared safe. No neonate had Apgar scores < 7 at 1min and 5min in this study. This agrees with similar reports by other authors.xvi,Error! Bookmark not defined.,l In 1952, Virginia Apgarlxxxix proposed the Apgar score for evaluating the physical condition of the newborn. A score of 7 or higher indicates that the baby’s condition is good to excellent. Currently, measurement of umbilical-artery blood pH (UApH) is considered a more objective method of assessing the newborn.xc This is yet to become a routine practice in our obstetric services.
Postoperative complications in the first 24hrs did not differ significantly between the 3 groups in this study. Difficulty in voiding could not be ascertained as all the patients had urethral catheter in-situ in the first 24hrs according to hospital protocol. Only 4.4% of the study patients had PDPH. The use of 25G pencil-point (Whitacre) spinal needle in this study may account for this observation. This agrees with the findings of Vallejo et al,xci in which the authors, in a comparative study, reported a 3.5% incidence of PDPH with 25G Whitacre needles compared to 47% with 25G Quincke needles. The use of 25G Whitacre needles in this study may also explain why only 10% of patients complained of backache.
lxxix
Apart from shivering, a total perioperative complication rate of 99 was observed in this study,
83 in the intraoperative period and 16 in the postoperative period. There was no statistically significant difference between the 3 groups in terms of perioperative complications. However, there were fewer complications associated with the patients who received ondansetron compared to patients who received tramadol or placebo. The highest complication rate was observed with the placebo group. This study suggests that ondansetron does not adversely affect perioperative outcome.
The proportion of patients who were very satisfied with PAS prophylaxis was significantly higher among those who received ondansetron and tramadol compared to those who were given placebo in this study. More than three-quarters of the patients who received ondansetron were very satisfied in comparison to two-thirds of the patients who received tramadol. On the other hand, barely one-quarter of the patients who received saline were very satisfied with PAS prophylaxis. In addition, among the parturients who were poorly satisfied with PAS prophylaxis almost 50% of them received placebo. Moreover, a very strong negative correlation was observed between PAS and patients’ satisfaction as patients who did not shiver expressed better satisfaction with PAS prophylaxis compared to non-shivering patients.
Therefore, this study shows that majority of patients will rather receive prophylaxis against shivering. Furthermore, ondansetron prophylaxis would be a preferred choice compared to tramadol. It is suggested that ondansetron be considered for prophylaxis against PAS in patients undergoing Caesarean section under SAB.
Spinal anaesthesia was induced with 12.5mg (2.5ml) of 0.5% hyperbaric bupivacaine in all the patients in this study. Since the dose of local anaesthetic agent is one of the determinants of the level of spinal block and thus the degree of sympathectomy, the same dose was used for all participants to ensure uniformity. There was no significant difference in the level of sensory
lxxx block – modal block height was T4 in the 3 groups. Also, procedures that may likely last longer than the duration of spinal anaesthesia were carefully excluded from the study.
This study used tramadol as a comparator to ondansetron because of its ready availability and its well documented anti-shivering property. The contemporary gold standard anti-shivering drug in many literatures is pethidine.viii However, pethidine is associated with undesirable side effects such as PONV, sedation and respiratory depression. The non-availability of pethidine as a controlled drug has also limited its use.viii The addition of placebo group was necessitated by the need to determine the actual incidence of postanaesthesia shivering in our centre. Also, the use of placebo was justifiable as the modality of management of shivering in our centre has been majorly therapeutic in nature.
The gold standard for core temperature monitoring is the pulmonary artery.xxxiii However, this site is considered invasive for routine temperature measurements. Skin temperature monitoring with its limitations was the most commonly used method of temperature measurement in a survey conducted by Frank et al.xlviii In their survey of 60 anaesthesiologists, the preferred site for temperature monitoring during regional anaesthetic techniques was the forehead skin- surface (70%) or axillary (40%). Core monitoring sites were much less likely to be used. This is understandable as thermoscan is expensive and not readily available for routine use.
However, temperature measurements at peripheral sites are not without their limitations as core temperature may not be accurately tracked due to time lag and the cooling effect of the cold theatre environment. As a result, the measurement of tympanic temperatures using the thermoscan is more effective as it accurately tracks the core temperature. Thermoscan was used in this study to ensure a more accurate core temperature measurement.
lxxxi
Fluid was given at room temperature in this study. Warming intravenous fluids may mitigate the decrease in maternal temperature during elective Caesarean section under regional anaesthesia. Whether this significantly decreases the incidence of shivering is however, controversial. Workhoven,xcii reported that Caesarean candidates given room-temperature fluids shivered significantly compared to those given warm fluid. On the other hand, Goyal et al,xciii and Woolnough et al, xciv reported no significant difference in shivering between parturients subjected to either warm or cold fluids. Infusion of warm intravenous fluids results in a lesser reduction in core temperature and provides a significant temperature advantage.
However, this does not translate to prevention of postoperative shivering. In other to eliminate this as a confounding variable in this study, fluids were administered at room temperature of
25oC.
lxxxii
CONCLUSION
In conclusion, the prophylactic administration of 4mg ondansetron is comparable to low dose tramadol (0.5mg/kg) in producing significant anti-shivering effect in patients undergoing
Caesarean section under SAB. Ondansetron may be preferred to tramadol because of its anti- emetic property, haemodynamic stability, lack of significant side effects and better patient satisfaction associated with its use. Therefore, ondansetron at a dose of 4mg may be considered for prophylaxis of PAS particularly in patients undergoing Caesarean section under subarachnoid block.
lxxxiii
RECOMMENDATIONS
1. There is urgent need to develop a protocol for the prophylaxis of PAS in parturients
undergoing Caesarean section under subarachnoid block, considering the burden it
poses to the patients and the dissatisfaction associated with it.
2. When prophylaxis is considered, i.v ondansetron 4mg may be preferred considering its
efficacy, anti-emetic property and minimal side effect profile compared to tramadol.
3. It is suggested that ondansetron prophylaxis against PAS be administered immediately
after SAB and prior to surgical incision to take advantage of its onset of action.
4. The use of Thermoscan for measurement of core temperature in parturients undergoing
Caesarean section under SAB is advocated. This may help in detecting the occurrence
of hypothermia as early as possible.
5. Further research may be required to investigate whether ondansetron can prolong the
time to first analgesic request in the postoperative period using a larger population.
lxxxiv
LIMITATION/STRENGTH OF THE STUDY
Fentanyl would have been a better choice for pain rescue but its non-availability in our centre precluded its use.
This study shows that i.v ondansetron 4mg has remarkable anti-emetic and anti- shivering properties. This ability to prevent two major side effects experienced by the obstetric population during SAB expands our armamentarium in the quest to find the ideal pharmacological prophylactic therapy. Furthermore, its comparative efficacy to a proven anti- shivering and analgesic drug like tramadol places it as a foremost drug for the management of
PAS in patients undergoing Caesarean section under SAB. Finally, this study suggests that ondansetron has some analgesic property which may be beneficial in the management of patients undergoing Caesarean section under SAB.
lxxxv
REFERENCES:
i Morgan P. Spinal anaesthesia in obstetrics. Can J Anaesth 1995;42: 1145-63. ii Imarengiaye CO, Ande AB, Obiaya MO. Trends in Regional Anaesthesia for Caesarean
Section at University of Benin Teaching Hospital. Nig J Clin Practice 2001, 4: 15-18. iii Edomwonyi NP, Ekwere IT, Egbekun R, Idehen HO, Sadiq A. Anaesthesia Related
Complications in Obstetric patients. Afr J Anaesth Int C 2005; 6(2): 8-13 iv Alfonsi P. Postanaesthetic Shivering: Epidemiology, Pathophysiology, and Approaches to
Prevention and Management. Drugs 2001; 613(15): 2193-2205 v Bhattacharya P, Bhattacharya L, Jain R, Agarwal R. Post Anaesthesia Shivering. Indian J.
Anaesth 2003; 47(2): 88-93 vi Crossley AWA. Postoperative shivering: the influence of body temperature (Editorial). Br
Med J 1995; 311: 764 vii William E. Post-operative shivering, causes, prevention and treatment (Response to a ‘Letter to Editor’). Update In Anaesthesia 2002;15(Article 3): p6 viii Generali JA, Cada DJ. Ondansetron: Postanesthetic Shivering. Hospital Pharmacy 2009; 44
(8): 670–671 ix Jean-Denis R. Postoperative shivering. Anesthesiol Rounds 2004; 3(6):1-5 x Shakya B, Chaturvedi A, SahJ BP. Prophylactic Low Dose Ketamine and Ondansetron for
Prevention of Shivering During Spinal Anaesthesia. J Anaesth Clin Pharmacol 2010; 26(4):
465-469 xi Javaherforoosh F, Akhondzadeh R, Aein KB, Olapour A, Samimi M. Effects of Tramadol on shivering post spinal anesthesia in elective cesarean section. Pak J Med Sci 2009; 25(1): 12-
17.
lxxxvi
12 Xi L, Denise H.R. Pharmacological Management of Therapeutic Hypothermia-Induced
Shivering; Society of Critical Care Medicine; http://www.sccm.org/Publications/Critical
Connections/Archives/August2008/Pages/default.aspx. Accessed on 29/3/2011 at 12:25pm xiii Powell RM, Buggy DJ. Ondansetron Given Before Induction of Anaesthesia Reduces
Shivering After General Anaesthesia. Anesth Analg 2000;90:1423–7 xiv Zarmsky R. Ondansetron Given Before Induction of Anesthesia Reduces Shivering After
General Anaesthesia (Comment). Sur Anaesthesiol 2001;45(1): 29-29 xv Oranuch K, Decha T, Somrat C. Comparison of the efficacy of nalbuphine, tramadol, ondansetron and placebo in the treatment of postanaesthetic shivering after spinal anesthesia for cesarean delivery. Asian Biomed 2007; 1(2) 189-194 xvi Atashkhoyi S, Negargar S. Effect of tramadol for prevention of shivering after spinal anaesthesia for Caesarean section. Res J Biol Sci 2008; 3(12):1365-1369 xvii Entezariasl M, Isazadehfar K, Mohammadian A, Khoushbaten M. Comparing the effect of ondansetron and pethidine in the prevention of postoperative shivering after general anaesthesia. J Iran Soc Anaesth Int C 2008; 30(62):23-32 xviii Edomwonyi NP, Osaigbovo PE. Incidence of obesity in parturients scheduled for Caesarean section, intraoperative complications, management and outcome. East Afr Med J 2006; 83(4):
112-119 xix Aitkenhead AR, David JR, Graham S. Thermoregulation and anaesthesia In: Textbook of
Anaesthesia 4th Ed. Philadelphia, Churchill Livingstone, London, 2001:297-308 xx Gesbrecht GG, Sessler DI, Mekjavic IB, Bristow GW. Treatment of immersion hypothermia by direct body-body contact. J Appl Physiol 1994; 76:2373-2379 xxi Berti M, Fanelli G, Casati A, Aldeghen G, Lugani D et al. Hypothermia prevention and treatment. Anaesthesia 1998; 53 (Sppl.2): 46-47
lxxxvii
xxii Pehl U, Simon E, Schmid HA. Properties of spinal neuronal thermosensitivity in vivo and in vitro. Ann N Y Acad Sci 1997; 813: 138-145 xxiii Hammel HT, Hardy JD, Fusco MM. Thermoregulatory response to hypothalamus cooling in unanaesthesized dogs. Am J Physiology 1960;198:481-486 xxiv Asami T, Hori T, kiyohara T, Nakashima T. Convergence of thermal signals on the reticulospinal neurons in the midbrain, pons and medulla oblongata. Brain Res Bull 1988; 20:
581-596. xxv Buggy DJ and Crossley AWA. Thermoregulation, mild perioperative hypothermia and post-anaesthetic shivering. Br J Anaesth 2000; 84(5): 615-28 xxvi Dawkins MJR, Scopes JW. Non-shivering thermogenesis and brown adipose tissue in the human new-born infant. Nature 1965; 206; 201-202 xxvii Sessler D. Mild perioperative hypothermia. New Engl J Med 1997; 336: 1730-1737 xxviii Matsukawa T, Sessler D, Christensen R, Ozaki M, Shroeder M. Heat flow during epidural anaesthesia. Anesthesiology 1995; 83: 961-967 xxix Joris J, Ozaki M, Sessler D, Hardy AF, Lamy M, et al. Epidural anaesthesia impairs both central and peripheral thermoregulatory control during general anaesthesia. Anesthesiology
1994; 80: 268-277 xxx Walmsley AJ, Giesecke AH, Liptom JM. Contribution of external temperature to shivering during extradural anaesthesia. Br J Anaesth 1986;58:1130-1134 xxxi Frank SM, El-Rahmany HK, Cattaneo CG, Barns RA. Predictors of hypothermia during spinal anaesthesia. Anesthesiology 2000; 92: 1330-1334 xxxii Carli F, Kulkrni J, Webster I, McDonald A. Post surgery epidural blockade with local anaesthetic attenuates the catecholamine and thermogenic response to peri-operative hypothermia. Acta Anaesthesiol Scand 1995; 39: 1041-1047
lxxxviii
xxxiii Weiss M, Sitzer V, Clarke M. A comparison of temperature measurements using three ear thermometers. Appl Nurs Res 1998; 11: 158-166. xxxiv Knies C.R. Temperature Measurement in Acute Care: The Who, What, Where, When,
Why, and How? http://enw.org/Research-Thermometry.htm - accessed on 29/9/11 at 10:40am xxxv Talakoub R, Noori M.S. Tramadol versus pethidine in the treatment of shivering during spinal anesthesia in Caesarean section. J Iran Med Sci 2006; 11(3)151-155 xxxvi Crossley AW. Six months of shivering in a district General Hospital. Anaesthesia 1992;
47:845-848 xxxvii Eberhat LHJ, Doderiein f, Elsenhardt G, Kranke P, Sessler DI. Independent risk factors for post operative shivering. Anesth Analg 2005; 101:1849-1857 xxxviii De Witte, Sessler DI. Perioperative shivering: physiology and pharmacology.
Anesthesiology 2002; 96(2): 467-484 xxxix Vassiheff N, Rosencher n, Sessler DI, Conseiller C. Shivering threshold during spinal anaesthesia is reduced in elderly patients. Anesthesiology 1995; 83:1162-1166 xl Cheng C, Matsukawa T, Sessler DI, Ozaki M, Kurz A, et al. Increasing mean skin temperature linearly reduces the core-temperature thresholds for vasoconstriction and shivering in humans. Anesthesiology 1995; 82:11608 xli Sessler DI, Robinsten EH, Moayeri A. physiologic responses to mild perianaesthetic hypothermia in humans. Anesthesiology 1991; 75:594-610 xlii Crossley AWA, Mahajan RP. The intensity of post-operative shivering is unrelated to axillary temperature. Anaesthesia 1994; 49: 205-207 xliii Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology
2008; 109: 318-338
lxxxix
xliv Badjatia N, Strongilis E, Buitrago M, Gordon E, Prescutti R, et al. Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale.
Stroke 2008; 39: (12): 3242-3247 xlv Mathews S, Al Mulla, Varghese PK, Radin K, Mumtaz S. Post-anaesthetic shivering-a new look at Tramadol. Anaesthesia 2002; 57: 387-403. xlvi Tsai YC, Chu KS. A comparison of tramadol, amitriptyline, and meperidine for postepidural anaesthetic shivering in parturients. Anesth Analg 2001; 93: 1288–92
xlvii de Courcy JG. Artefactual “hypotension” from shivering (letter). Anaesthesia 1989; 44:
787-788 xlviii Frank SM, Nguyen J, Garcia C, Barnes RA. Temperature monitoring practices during regional anesthesia. Anesth Analg 1999; 88:373-377 xlix Aditi AD, Mamta GP, Swadia VN. Tramadol for control of shivering (comparison with pethidine). Indian J. Anaesth 2007; 51(1):28-31 l Chan AMH, Ng KFJ, Tony EWN, Jan GSK. Control of shivering under regional anaesthesia in obstetric patients with tramadol. Can J Anaesth 1999; 46(3):253-258 li Kelsaka E, Sibel B, Deniz K, Binnur S. Comparison of ondansetron and meperidine for prevention of shivering in patients undergoing spinal anesthesia. Reg Anesth Pain Med 2006;
31: 40-45. lii Wrench IJ, Singh P, Dennis AR, Mahajan RP, Crossely AW. The minimum effective dose of pethidine and doxapram in the treatment of post anaesthetic shivering. Anaesthesia 1997;
52: 32-36 liii Raffa RB, Friderichs E, Relmann W, Shank RP, Codd EE. Opioid and non-opioid components independently contribute to the mechanism of action of tramadol, an “atypical” opioid analgesic. J pharmacology Exp Ther 1992; 260:275-285
xc
liv Driessen B, Reiman W. Interaction of the central analgesic tramadol, with uptake and release of 5-HT in the rat brain in vitro. Br J Pharma 1992; 105:147-151 lv Leach KP, Poten B, Sohnle K, Schutte HM. Pharmacology of the Hypothermic response to
5-HT receptor activation in human. Eur J Clini Pharmacology 1990; 39:17-19 lvi Yu-chan T, Koung-shing C. A comparison of tramadol, amitryptiline and meperidine for post-epidural anaesthetic shivering in parturents. Anesth Analg 2001; 93:1288-1292. lvii Mullican WS, Lacy JR. Tramadol/acetaminophen combination and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial. Clin Ther 2001;
23 (9): 1429-1445 lviii Prescribing information: ZOFRAN® (ondansetron hydrochloride). GlaxoSmithKline 2011. http://us.gsk.com/products/assets/us_zofran_tablets.pdf; accessed on 13/6/12 at 1:18pm lix Drugs.com. Ondansetron Hydrochloride. http://www.drugs.com/ppa/ondansetron - hydrochloride. html; accessed on 13/6/12 at 12:56pm lx Talakoub R, Noori MS. Tramadol versus pethidine in the treatment of shivering during spinal anesthesia in Caesarean section. J Iran Med Sci 2006; 11(3)151-155 lxi Velayudha SR, Sunil C. clonidine versus tramadol for post spinal shivering during Caesarean section: A randomized double blind clinical study. J Obstet Anaesth Crit Car 2011; 1: 26-9 lxii Nze PUN. A survey of postoperative nausea and vomiting in Enugu, Nigeria. Orient Journal of Medicine 2005; 17(3): 11-16 lxiii Soyannwo O.A, Ajuwon A.J, Amanor-Boadu S.D, Ajao O.G. Post operative nausea and vomiting in Nigerians. East Afr Med J. 1998; 75(4):243-5. lxiv Olatosi JO, Kushimo OT, Okeke CI, Oriyomi OO. Post operative nausea and vomiting in adult Nigerians. Nig Q J Hosp Med. 2008; 18(4):227-30.
xci
lxv Pan PH, Moore CH. Intraoperative antiemetic efficacy of prophylactic ondansetron versus droperidol for Caesarean section patients under epidural anesthesia. Anesth Analg. 1996;
83(5):982-6. lxvi Kranke P, Loepold H, Eberhart, Norbert R, Martin R, Tramer. Single-dose parental pharmacological interventions for the prevention of postoperative shivering: a quantitative systematic review of randomized controlled trials. Anesth Analg 2004; 99:718-727 lxvii Sule AZ, Isamade ES, Ekwempu CC. Spinal anaesthesia for lower abdominal surgery: a review of 200 cases. Nig J Surg Res. 2005:226-230. lxviii Kolawole IK, Bolaji BO. Subarachnoid block for lower abdominal and lower limb surgery:
University of Ilorin teaching hospital experience. Nig J Med 2002; 11 (94): 153-155. lxix Betty RK, Jonathan ACS. “Calculation of required sample size”. Essentials of Medical
Statistics, 2nd Edition. Blackwell Science 2003: 413-428 lxx American Society of Anesthesiologists Task Force on Obstetric Anesthesia. Practice
Guidelines for Obstetric Anesthesia. An Updated Report by the American Society of
Anesthesiologists Task Force on Obstetric Anesthesia. Anesthesiology 2007; 106:843–63 lxxi Wong CA, Loffredi M, Ganchiff JN, Zhao J, Wang Z, Avram MJ. Gastric emptying of water in term pregnancy. Anesthesiology 2002; 96:1395–1400
lxxii Odd ED, Doyle P, Gunnell D, Lewis G, Whitelaw A, Rasmussen F. Risk of low Apgar score and socioeconomic position: a study of Swedish male births. Acta Paediatr 2008; 97(9):
1275–1280. lxxiii Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone
– alphadolone. Br Med J 1974; 2(5920):656-9 lxxiv Asharf MAS, Tarek A.H. The minimum effective intravenous dose of ondansetron for prevention of postoperative nausea and vomiting after adenotonsillectomy in dexamethasone pretreated children. Egypt J Hosp Med 2002; 8: 104-115
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lxxv Kohki N, Shinichiro Y, Yuki S, Motohiko I, Akiyoshi N. A comparison of spinal anaesthesia with small-dose lidocaine and general anaesthesia with fentanyl and propofol for ambulatory prostate biopsy procedures in elderly patients. J Clin Anaesth 2007; 19: 25-29 lxxvi Crowley LJ, Buggy DJ. Shivering and neuraxial anaesthesia. Reg Anesth Pain Med
2008; 33: 241-252. lxxvii Techanivate A, Rodanant O, Tachawattanawisal W, Somsiri T. Intrathecal fentanyl for prevention of shivering in Caesarean section. J Med Assoc Thai 2005 Sep; 88(9): 1214-21 lxxviii Bilotta F, Pietropaoli P, Sanita R, Liberatori G, Rosa G. Nefopam and Tramadol for the prevention of shivering during Neuraxial anaesthesia. Reg Anesth Pain Med 2002; 27: 380-84 lxxix Sagir O, Gulhas N, Toprak H, Yucel A, Begec Z, Ersoy O. Control of shivering during regional anaesthesia: prophylactic ketamine and granisetron. Acta Anaesthesiol Scand 2007;
51: 44-49 lxxx Hong JY, Lee IH. Comparison of the effects of intrathecal morphine and pethidine on shivering after Caesarean delivery under combined-spinal epidural anaesthesia. Anaesthesia
2005; 60(12): 1168–1172 lxxxi Drugs.com. Diazehttp://www.drugs.com/pam Pregnancy and Breastfeeding Warnings.
Error! Hyperlink reference not valid. at 12.45am lxxxii Collins C, Gurung A. Anaesthesia for Caesarean section. Update in Anaesthesia 1998; 9: 7-17 lxxxiii Leslie K, Sessler DI. Reduction in the shivering threshold is proportional to spinal block height. Anesthesiology 1996; 84:1327–31 lxxxiv Carli F, Kulkrni J, Webster I, McDonald A. Post surgery epidural blockade with local anaesthetic attenuates the catecholamine and thermogenic response to perioperative hypothermia. Acta Anaesthesiol Scand 1995; 39: 1041-1047 lxxxv Aitkenhead AR, David JR, Graham S. Thermoregulation and anaesthesia In: Textbook of
Anaesthesia 4th Ed. Philadelphia, Churchill Livingstone, London, 2001:297-308 xciii
lxxxvi McCleane GJ, Suzuki R, and Dickenson AH. Does a Single Intravenous Injection of the
5HT3 Receptor Antagonist Ondansetron Have an Analgesic Effect in Neuropathic Pain? A
Double-Blinded, Placebo-Controlled Cross-Over Study. Anesth Analg 2003;97:1474 –8 lxxxvii Derbent A , Uyar M , Demirag K , Uyer M , Kurtoglu E, Goktay A. Can antiemetics really relieve pain? Advances in therapy 2005; 22,(4):307-312 lxxxviii Zeitz KP, Guy N, Malmberg AB. The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J
Neurosci 2002;22:1010–9. lxxxix Apgar V. Proposal for new method of evaluation of newborn infant. Anesth Analg
1953;32:260-7. xc Casey BM, McIntire DD, Leveno KJ. The continuing value of the Apgar score for the assessment of newborn infants. N Engl J Med 2001;344:467-71. xci Vallejo MC, Mandell GL, Sabo DP, Ramanathan S. Postdural Puncture Headache: A
Randomized Comparison of Five Spinal Needles in Obstetric Patients. Anesth Analg
2000;91:916–20 xcii Workhoven MN. Intravenous fluid temperature, shivering, and the parturient. Anesth
Analg 1986; 65: 496-8 xciii Goyal P, Kundra S, Sharma S, Grewal A, Kaul TK, Singh MR. Efficacy of intravenous fluid warming for maintenance of core temperature during lower segment Caesarean section under spinal anesthesia. J Obstet Anaesth Crit Care 2011;1:73-7 xciv Woolnough M, Allam kJ, Hemingway C, Cox M, Yentis SM. Intra-operative fluid warming in elective Caesarean section: a blinded randomized controlled trial. Int J Obstet Anesth. 2009;
18(4):346-51
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APPENDIX 1
ETHICAL CLEARANCE
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APPENDIX II
CONSENT FORM
Dear Ma, PERMISSION TO INCLUDE YOU AS A SUBJECT IN THE RESEARCH:
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A COMPARATIVE STUDY OF THE EFFICACY OF ONDANSETRON VERSUS TRAMADOL IN THE PREVENTION OF POSTANAESTHESIA SHIVERING FOLLOWING ELECTIVE CAESAREAN SECTION UNDER SPINAL ANAESTHESIA.
I wish to obtain your consent for the above mentioned study. The research topic is a proposal submitted to the National Postgraduate Medical College of Nigeria in partial fulfillment of the award of the fellowship of the College.
You are being approached because you are going to have a Caesarean section under spinal anaesthesia. Postanaesthesia shivering is one of the known problems arising from spinal anaesthesia in which patients feel cold and begin to shake during or after surgery. It is known to be one of the most uncomfortable experience patients commonly have. This study is aimed at finding out if it can be prevented by the injection of one of the following drugs – ondansetron, tramadol or normal saline through the drip into your vein. The major side-effects of these drugs include excessive sleep, nausea and vomiting, itching and difficulty with urinating. The drug to be used for the spinal anaesthesia is heavy bupivacaine. The problems that can happen with the spinal anaesthesia may include the following: the drug may fail to work or may not last long enough, the drug may rise too high in the spinal cord and cause bad taste in the mouth, turning of the eyes, fainting, difficulty in breathing, low blood pressure and convulsion. Headache and backache may occur later after the operation. These side effects when observed or reported by you are treated immediately with full recovery.
The research involves three groups. Group one will receive intravenous ondansetron, group two will receive intravenous tramadol and group three will receive intravenous normal saline. Your participation will involve accepting to be part of one of the three groups by allowing one of the three treatment drugs above to be given to you. You will be involved only in one group. The study will begin from the night of your admission and will end 24 hours after your operation.
You are not forced to participate in this study. If you refuse to be involved in the study it will not in any way affect the proper care you are supposed to get. However, if you accept to participate, any information you give will be kept secret. You are free to withdraw from the study at any point in time and this will not affect the quality of care you will receive.
Pls be reassured that the study has been approved by the Ethics and Research Committee of the University of Benin Teaching Hospital.
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Pls, kindly sign below if you consent.
Thank you.
Dr EJIRO B.A. Snr Reg Department of Anaethesiology, UBTH. GSM number: 08052761213.
I hereby consent: ……………………...... …………………………………..
Name Signature & Date
Witnessed by: ……………………………… ……………………………………
Name Signature & Date
APPENDIX III
QUESTIONAIRE
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QUESTIONAIRE ON COMPARISON OF ONDANSETRON VERSUS TRAMADOL IN THE PREVENTION OF POSTANAESTHESIA SHIVERING FOLLOWING CAESAREAN SECTION UNDER SPINAL:
1. Initials…………………………………………… 2. Serial number…………………………………… 3. Group number………………………………….. 4. Hospital number…………………………………… 5. Age (yrs)…………… 5b. Weight (kg)…………… 5c. Height (cm)………… 6. Occupation……………………………….. 7. Educational status (Tick): 1o……….; 2o…..….. ; 3o……..… 8. ASA Status………… 8b Gestational Age……… Weeks. 8c. Parity………… 9. Previous surgery………………………….. 10. Indication for Caesarean section……………………………………….………….. 11. Baseline vital signs Pulse rate..……....bpm Blood Pressure…..………/…..…….mmHg Temperature: skin…………oC; core…..…… oC Respiratory rate ………..cpm SpO2…….…….% 12. Time of bupivacaine administration……………; Dose………../ml 13. Ondansetron dose……….……mg 14. Tramadol dose…………….mg 15. Saline dose………………………..ml 16. Time of study drug administration………………. 17. Level of block height……………………… 18. Time surgery commenced……………….. 19. Time shivering commenced…………………. 20. Time of extraction of baby……………… 21. Apgar Scores: 1min………..; 5min………… 22. Neonatal weight…………kg 23. Intraoperative Vital Signs: PR/BP/TEMP/SPO2/RR
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Time/min 0 2 4 6 8 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
PR/min
SBP(mmH g) DBP(mmH g) RR/min
T oC (Core)
T oC (Skin)
SPO2
24. Complication: Circle as appropriate. (i) Hypotension: Yes/No 25. Complications (Introperative): Score as appropriate Time/min 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 90
Shivering: Grade 0-4 Sedation: Score 1-6 Pain(VAS): Score 0-10 Nausea/Vomiting: Score 0-3
26. Time surgery ended……….…………. 27. Duration of surgery………………….. 28. Degree of patients satisfaction in relation to shivering: Poor/Satisfied/Very satisfied c
29. Postoperative: Time/min 0 15 30 45 60 75 90 105 120
PR/min
SBP(mmHg)
DBP(mmHg)
RR/min
T oC (Core)
T oC (Skin)
SPO2
Shivering (0-4)
Sedation (1-6)
Pain (0-10)
PONV (0-3)
30. Name and dose of rescue drug given: i. ……………………………………………………….………… ii. …………………………………………………………………. iii. ………………………………………………………………….
31. Postoperative complications within the first 24 hours: Circle as appropriate i. Postdural puncture headache: Yes/No ii. Nausea: Yes/No iii. Vomiting: Yes/No iv. Backache: Yes/No v. Difficulty in voiding: Yes/No ci
32. Patients GSM phone number (s): i. ……..………..……………………..………….……..…… ii. ………………..………………………………………..……
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