A STUDY OF INTRAVENOUS DEXAMETHASONE AS AN ADJUVANT FOR POSTOPERATIVE CONTROL FOLLOWING HERNIOTOMY

BY

DR MARYROSE OMOKHUKPON OSAZUWA

DEPARTMENT OF ANAESTHESIA UNIVERSITY OF BENIN TEACHING HOSPITAL BENIN CITY

A DISSERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL COLLEGE OF NIGERIA IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE AWARD OF THE FELLOWSHIP OF THE COLLEGE IN ANAESTHESIA

NOVEMBER 2012

1

DECLARATION

It is hereby declared that this work is original unless otherwise acknowledged. The work has not been presented to any other College for a Fellowship, nor has it been submitted elsewhere for publication.

______

Osazuwa, Maryrose Omokhukpon

2

CERTIFICATION

The study reported in this dissertation was carried out by the author under our supervision. We also supervised the writing of this dissertation.

Signature: ______

Name of Supervisor: Professor (Mrs) N. P. Edomwonyi

Status of Supervisor: Professor/Consultant Anaesthesiologist

Year of Qualification: ______

Signature: ______

Name of Supervisor: Dr F. E. Amadasun

Status of Supervisor: Associate Professor/Consultant Anaesthesiologist

Year of Qualification: ______

3

DEDICATION

I dedicate this book to the memory of my father, Sir Samuel Eghikpevhokan Agboifo

KSG; KSM; OON, who brought me up in the fear of God, ensured my medical education and taught me to love and respect every person.

I also dedicate this book to:

 My mother, my pillar of strength and love, Lady Jacinta Uhunamen Agboifo

 My ever supportive and caring husband, my inspiration, Dr Henry Osamwonyi

Osazuwa

 My children, my number one fans: Annabelle Osayemwenre, Samuel

Osamudiamen and Isabelle Osasumwen.

4

ACKNOWLEDGEMENTS

The conception and completion of this work was made possible due to various influences. First of all, I thank God Almighty, my creator, my protector, my all.

I want to acknowledge in a special way, my supervisors, Professor N.P. Edomwonyi and Dr F.E. Amadasun for accepting to supervise this work, for their immense contribution to it and for being excellent teachers.

I also want to thank my other teachers in the Department of Anaesthesia,

UNIBEN/UBTH: Professor C.O. Imarengiaye, Dr O.P. Adudu, Dr I.I. Ekwere, Dr I.J.

Isa, Dr S. Tudjegbe, Dr D.D. Akpoduado, Dr H. Idehen, Dr K. Tobi and Dr T. Isesele.

May God bless them all for always being accessible and enthusiastic in their assistance.

I thank all residents of the Department of Anaesthesia UBTH, for their patience and solidarity.

At this juncture, I must make mention of my family. I thank my father, for everything good about me. My mother for always being there for me, and now for my children.

My husband for championing me every step of the way, my brother Thomas Agboifo, who bought me my first medical examination equipment as a student, my sisters

Pauline, Sarah, Lilian, Linda, Patricia, Bernadette and my children. May God bless them all.

Finally, my very special thanks go to all past and present teachers of anaesthesia in

Nigeria (like Professor Mathias Obiaya who started the Department of Anaesthesia in the University of Benin Teaching Hospital). I thank each and every one of them, for all their contribution to this great specialty. God bless them all.

5

TABLE OF CONTENT

Title Page ...... i

Declaration ...... ii

Certification ...... iii

Dedication ...... iv

Acknowledgements ...... v

Table of Content ...... vi

List of Tables...... viii

List of Figures ...... viii

List of Abbreviations ...... ix

Summary ...... 1

CHAPTER ONE

Introduction ...... 4

CHAPTER TWO

Aim and Objectives ...... 7

CHAPTER THREE

Literature Review ...... 8

CHAPTER FOUR

Methodology ...... 19

6

CHAPTER FIVE

Results ...... 28

CHAPTER SIX

Discussion ...... 46

Study Limitations ...... 55

Relevance of Study ...... 56

Conclusion ...... 57

Recommendation ...... 58

REFERENCES ...... 59

Appendix I. Ethics committee approval…...... 71

Appendix II. Parent/Guardian informed consent form...... 72

Appendix III. Data Collection form...... 73

7

LIST OF TABLES

I. Socio-demographic characteristics of patients

II. Preoperative vital signs, haemoglobin concentration

III. Intraoperative vital signs, duration of surgery

IV. Number of subjects on 8-point and 10-point MOPS scale

V. Median pain scores of patients on 8-point MOPS scale

VI. Median pain scores of patients on 10-point MOPS scale

VII. Proportion of subjects with low MOPS scores

VIII. Time to first requirement, total consumption

IX. Perioperative adverse events

X. Parental/guardian satisfaction with postoperative pain relief

LIST OF FIGURES

1. Intraoperative heart rate, blood pressure

2. Proportion of patients with low MOPS scores

3. Adverse events profile

4. Parental/guardian satisfaction with postoperative pain relief

8

LIST OF ABBREVIATIONS

ASA - American Society of Anesthesiologists cm - Centimetre g - Gram

Hb - Haemoglobin concentration hr - Hour

IM - Intramuscular

IV - Intravenous kg - Kilogram

L - Litre m - Metre mg - milligram ml - Millilitre min - minute mmHg - millimetres of mercury n - Number in each group

MOPS - Modified Objective

SD - Standard Deviation

SpO2 - Arterial oxygen saturation

SPSS® - Statistical Package for the Social Sciences vs. - Versus

9

SUMMARY

Pain management following paediatric surgeries has evolved over the years; nevertheless, there is still room for improvement. Herniotomy is a short procedure which can be done as day-case surgery, however in our centre, patients are admitted overnight after herniotomy partly for effective . Pain after day-case surgery impairs the resumption of activities of daily living. Effective postoperative analgesia is therefore essential for herniotomy to be practiced as day-case surgery.

Dexamethasone possesses potent anti-inflammatory and anti-emetic properties; it can reduce postoperative pain and improve patient well-being, with resultant early ambulation, early feeding, and reduced need for overnight hospital stay. It may therefore be a useful analgesic adjuvant. It was hypothesized therefore, that the use of intravenous dexamethasone and intravenous will provide better postoperative pain control following herniotomy, compared to intravenous tramadol alone.

This is a prospective, randomized, double-blind and placebo-controlled study. It was carried out at the University of Benin Teaching Hospital, Benin City. Following

Institutional Research and Ethics Committee approval, a total of 74 patients were recruited, drawn from paediatric patients scheduled for unilateral herniotomy. All patients received standardized general anaesthesia. Patients were randomized into two groups. Group 1 received IV tramadol 1mg/kg and 5ml of IV normal saline while

Group 2 received IV tramadol 1mg/kg and IV dexamethasone 0.5mg/kg diluted to 5ml,

5-10 minutes before skin incision. Postoperative pain assessment was done using the

Modified Objective Pain Scale (MOPS). Data analysis was done using SPSS®

10

(Statistical Package for the Social Sciences) version 18. Level of significance was set at p < 0.05.

There was no statistically significant difference in the socio-demographic characteristics between the two groups. The baseline and intraoperative vital signs of heart rate, blood pressure, SpO2 were also comparable in both groups.

The time from study drug administration to first analgesic requirement was significantly longer in the dexamethasone/tramadol group (472.79 ± 218.42min) compared to the tramadol/saline group (347.35 ± 273.64min) (p = 0.033). Furthermore, postoperative paracetamol consumption was significantly higher in the tramadol/saline group

(535.15 ± 313.10) than in the dexamethasone/tramadol group (336.00 ± 288.05) (p =

0.004).

The proportion of patients with low MOPS scores was higher in the dexamethasone/tramadol group than in the tramadol/saline group at most study time points. However this was not statistically significant at any study time point.

The perioperative adverse events in group 1 and group 2 were bradycardia (18.92% vs. 16.22%), laryngospasm (8.11% vs. 10.81%) and fever (24.32% vs. 10.81%).

Parental/guardian satisfaction with pain relief was similar in both groups. Most of the parents/guardians in group 1 (62.16%) and group 2 (64.86%) reported satisfaction with pain management to be good (p = 0.809).

This study shows that intravenous dexamethasone as an adjuvant is useful in the management of post-herniotomy pain. The addition of intravenous dexamethasone to tramadol prolonged time to first analgesic requirement and decreased total analgesic

11 consumption in the first 24 hours following herniotomy, with minimal side effects and good parental/guardian satisfaction.

Intravenous dexamethasone therefore has a role to play in the management of post- herniotomy pain and could be used as an analgesic adjuvant for pain management following herniotomy.

12

CHAPTER ONE

INTRODUCTION

Pain is defined by the International Association for the Study of Pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”.1 Historically, children have been under-treated for pain and for painful procedures, because of the wrong notion that they neither suffer nor feel pain, nor respond to or remember painful experiences to the same degree that adults do.2

Under-treatment of post-operative pain, even in children and new-borns may trigger biochemical and physiologic stress responses and cause impairments in pulmonary, cardiovascular, neuroendocrinal, gastrointestinal, immunological, and metabolic functions; these can be prevented or attenuated by appropriate analgesic therapy.3

Finley et al have reported that many so called “minor” surgeries can cause significant pain in children.4 It has been suggested therefore that post-operative pain treatment must be included in the anaesthetic plan even before induction of anaesthesia, adopting the idea of ‘managing pain before it occurs’.5

Herniotomy is the repair of inguinal hernia in children and it is the most common operation for children worldwide.6 It is usually a day-case surgery in developed countries and in some centres in Nigeria.7 In our centre, patients stay overnight postoperatively after herniotomy partly for effective pain management. Post-operative pain is the commonest complication of inguinal herniotomy.7 Part of this pain arises from local inflammatory response to surgical incision. Mediators of inflammation, like bradykinin and serotonin, may directly activate peripheral nociceptors, other mediators

13 such as prostaglandins, are known to sensitize nociceptors to inflammatory mediators.8 Anti-inflammatory agents therefore, may be beneficial in the management of postoperative pain.

Different methods have been used for managing post-herniotomy pain with different results. One of these methods is incisional infiltration with bupivacaine which has been used by Kushimo et al with good outcome.9 Previous studies have also demonstrated that caudal analgesia is effective for post-herniotomy pain management.10,11 Caudal block however requires expertise which may not always be available, it may also fail.

Moreover a review by Cyna and Middleton comparing the effects of caudal analgesia with other forms of postoperative analgesia following circumcision in boys, found no difference between caudal and parenteral analgesia in the need for rescue analgesia.12 They also observed a significant incidence of temporary leg weakness following caudal block (two trials, 107 boys).12 Caudal block may therefore not be ideal for day case herniotomy as it may result in postoperative hospitalization and overnight stay of patients. Other modalities for pain control are still very relevant following herniotomy.

Dexamethasone is a synthetic glucocorticoid with a powerful anti-inflammatory effect.

When administered pre- or intra-operatively, it has been shown to reduce post- operative pain, and improve patient well-being, with resultant early ambulation, early feeding, and reduced need for overnight hospital stay. 13-15

Tramadol is a synthetic analgesic indicated for treatment of moderate to severe pain.16 The purpose of this study was to assess if adding intravenous (IV) dexamethasone preoperatively to IV tramadol in patients undergoing herniotomy, will

14 result in better pain control in the post-operative period. This may ultimately contribute to the practice of herniotomy as day case surgery in our centre.

15

CHAPTER TWO

AIM

To examine the effects of preoperative single-dose intravenous dexamethasone and tramadol versus intravenous tramadol and saline, on post-operative pain after herniotomy.

OBJECTIVES

1. To evaluate the additive analgesic effect of dexamethasone to tramadol in postoperative pain management of herniotomy.

2. To determine the time of first analgesic requirement in the postoperative period after preoperative administration of tramadol and dexamethasone versus tramadol and saline.

3. To determine the total analgesic requirement within twenty-four hours postoperatively after preoperative administration of tramadol and dexamethasone versus tramadol and saline.

4. To determine the incidence of side effects, if any, from the perioperative use of single dose dexamethasone and tramadol versus tramadol and saline in children.

5. To determine other beneficial effects of dexamethasone in the postoperative period such as anti-emetic effect.

6. To assess parental/patient satisfaction following the use of dexamethasone and tramadol versus tramadol and saline for postoperative pain relief following herniotomy.

16

CHAPTER THREE

LITERATURE REVIEW

Herniotomy is the repair of inguinal hernia in children.17 It is a common paediatric surgical procedure in the University of Benin Teaching Hospital, Benin City; it is also the most common operation for children worldwide.6 For herniotomy to be successful as day-case surgery, good postoperative analgesia is important as inadequate postoperative pain management may result in re-hospitalization. Faponle and Usang have advised that pain following day-case surgery should be prevented with a wider use of drugs.18 However, the availability of potent analgesic labelled for children is limited.19 Non-steroidal anti-inflammatory drugs (NSAIDs) have restricted approval for use in children and may cause bleeding tendency, renal impairment and aggravate asthma. on the other hand, carry the risk of respiratory depression.19

Tissue injury from surgery causes acute inflammation, this inflammation is known to play a significant role in the genesis of surgical pain.20 Some inflammatory mediators are released upon surgical damage to cells while others are synthesized during the events that follow. The release of these inflammatory mediators leads to within the zone of tissue injury from activation and sensitization of peripheral nociceptors, and reduction of their activation threshold.8

Glucocorticoids exert powerful anti-inflammatory effects by inhibiting the activation of

nuclear factor-kB (NF-kB), a transcription factor which plays a key role in the

inflammatory response. Glucocorticoids also inhibit phospholipase A2, causing a

17 reduction in the release of arachidonic acid from tissue phospholipids and consequently a decrease in the formation of inflammatory mediators such as prostaglandins, leukotrienes and other eicosanoids.21

Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones.22 It has 25-50 times the potency of hydrocortisone and is 16 times as potent as prednisolone.22 Like all glucocorticoids, dexamethasone acts on the glucocorticoid receptor resulting in the decreased release of bradykinin, tumour necrosis factor, interleukin-1, interleukin-2 and interleukin-6 and decreased production of prostaglandins.23 Dexamethasone also causes decreased transmission of impulses in nociceptive C fibres by increasing the activity of inhibitory potassium channels.24 It undergoes hepatic metabolism (both glucuronidation and sulfation) to produce inactive metabolites, with 65% of it excreted in urine within 24 hours, and less than 3% unchanged.25

The potential risks of perioperative use of dexamethasone include gastrointestinal bleeding, hyperglycaemia, impaired wound healing and increased susceptibility to infection.26,27 However previous studies have revealed that the risk of side effects from single dose dexamethasone is negligible.26-28

A single preoperative dose of dexamethasone has gained widespread acceptance as an effective preventive treatment for postoperative nausea and vomiting.29 Recently though, single doses of dexamethasone have been reported to improve analgesia after various surgical procedures, including tonsillectomy, lower limb orthopaedic procedures, laparoscopic cholecystectomy, breast and spine surgeries.14,15,26

Dexamethasone potentiates analgesia due to its prolonged suppressive effect on the inflammatory response with duration of action of about 48 to 72 hours26; it also blocks

18 transmission in C pain fibres.30 The analgesic effect of dexamethasone is better demonstrated on preoperative rather than intraoperative administration of the drug.27

When used in combination with routine , dexamethasone has been shown to reduce postoperative pain, facilitate early discharge and reduce postoperative analgesic requirements.13-15

Various studies have demonstrated that dexamethasone improves postoperative analgesia in children. In a study by Hong et al, children aged 1-5 years undergoing day-case orchidopexy, received either dexamethasone 0.5 mg/kg or the same volume of saline intravenously; a caudal anaesthetic block was then performed using 1.5 ml/kg of ropivacaine 0.15% in all patients.13 It was found that the addition of dexamethasone to caudal block provided superior analgesia compared with caudal block alone as evidenced by the following: the patients who required for rescue analgesia in the post-anaesthesia care unit were fewer in the dexamethasone group compared with the control group(7.9% versus 38.5%); The patients who received acetaminophen

(paracetamol) after discharge were also less in the dexamethasone group compared with the control group (23.7% versus 64.1%).13 The time to first administration of oral acetaminophen post-surgery was significantly longer in the dexamethasone group

(646 versus 430 minutes). Furthermore, postoperative pain scores were lower in the dexamethasone group.13 Orchidopexy and herniotomy are both inguinal surgeries, thus the proposed study may be expected to yield comparable results with that of Hong et al.

In another study, Kaan and colleagues evaluated the effect of preoperative 0.5 mg/kg

IV dexamethasone on postoperative early oral intake, pain and vomiting in patients undergoing adenotonsillectomy.14 Sixty two children aged 4-12 years who underwent

19 tonsillectomy with or without adenoidectomy, were randomly assigned to receive single dose of 0.5 mg/kg intravenous dexamethasone or placebo preoperatively.

Intraoperative analgesia was achieved with fentanyl 1µg/kg and postoperative pain assessment was done using a 5-point “Faces” scale.14 When compared with placebo, the patients who received preoperative dexamethasone had significantly less pain scores during the first 6 hours postoperatively (p<0.05) and had earlier discharge time

(p<0.05). The investigators concluded that the use of preoperative dexamethasone significantly reduces early post-tonsillectomy pain, improves oral intake and facilitates meeting the discharge criteria without any significant side effects.14 It remains to be seen if the effect of dexamethasone on post-herniotomy pain will parallel its effect on post-tonsillectomy pain.

Different doses of dexamethasone have been evaluated for postoperative pain management in children. Al-Shehri compared the effect of dexamethasone in two different doses of 0.5mg/kg and 1mg/kg in children undergoing tonsillectomy with or without adenoidectomy.31 One hundred and fifty children aged 2 to 6 years were allocated randomly into three equal groups. Children received either IV dexamethasone 0.5mg/kg with maximum total dose of 8mg (group D1), or dexamethasone 1mg/kg with maximal total dose of 16 mg (group D2) or 2 ml normal saline, with induction of anaesthesia.31 Rectal paracetamol 30 mg/kg was given to all children on arrival to recovery room and continued 6 hourly for 24 hours postoperatively. The overall incidence of postoperative vomiting episodes was less in the two dexamethasone groups compared to the saline group (D1 22%, D2 18%, saline 46%). Also, the time to first oral intake was shorter in the dexamethasone groups. Satisfaction scores were better in the dexamethasone groups compared to saline group P<0.05. The Visual Analogue Scale (VAS) pain scores were significantly

20 less in the two dexamethasone groups at 2, 4 and 6 hours postoperatively.31 There was no significant difference between the two dexamethasone groups in all measured parameters, indicating that IV dexamethasone 0.5 mg/kg was as effective as dexamethasone 1 mg/kg in reducing the incidence of postoperative vomiting, time to first oral intake, and postoperative pain; with increased parent satisfaction among children undergoing tonsillectomy by electrodissection.31 Thus the dose of 0.5mg/kg of IV dexamethasone in the present study was expected to achieve effective postoperative analgesia.

Prolonged anti-inflammatory and adjuvant analgesic effects of dexamethasone were demonstrated in a double-blind, placebo-controlled study by Bisgaard et al15. Eighty- eight adult patients were randomized to receive 8 mg intravenous dexamethasone or placebo, 90 minutes before laparoscopic cholecystectomy.15 All patients received similar standardized anaesthesia, surgery and multimodal analgesic treatment.

Assays were done on venous blood samples to measure C-reactive protein level

(CRP). Dexamethasone significantly reduced postoperative levels of CRP (P = 0.01), fatigue (P = 0.01), overall pain, and incisional pain during the first 24 postoperative hours (P < 0.05) and total requirements of opioids (P < 0.05).15 In addition, cumulated overall and visceral pain scores during the first postoperative week were significantly reduced (P < 0.05). Dexamethasone also reduced nausea and vomiting on the day of operation (P < 0.05). Resumption of recreational activities was significantly faster in the dexamethasone group versus placebo group (median 1 day versus 2 days) (P <

0.05).15 The authors therefore recommended preoperative dexamethasone for routine use in laparoscopic cholecystectomy.

21

C-reactive protein is an acute-phase reactant during inflammation. The study by

Bisgaard et al underscores the anti-inflammatory role of dexamethasone and its analgesic effect even on visceral pain.

Kardash and colleagues also found out that a single, preoperative IV dose of dexamethasone 40 mg had a prolonged suppressive effect on the inflammatory response and decreased dynamic pain, 24 hours after total hip arthroplasty in adults

(P < 0.0001).26 The study was a randomized, double-blind, placebo-controlled study on fifty consecutive patients undergoing elective, unilateral, primary total hip arthroplasty under spinal anaesthesia with propofol sedation.26

However, some other studies did not demonstrate any analgesic effect of dexamethasone. For example, Liu et al studied the effect of preoperative administration of IV dexamethasone 10mg on postoperative pain in sixty women undergoing general anaesthesia for major gynaecological surgery.20 Dexamethasone

10mg or saline was administered IV in a double-blind manner during the induction of anaesthesia. Postoperative pain relief was provided with bolus doses of IV using a patient-controlled analgesia (PCA) device.20 Patients were assessed for incidence of vomiting, sedation score, pain using the verbal pain rating score (VPRS), time to first morphine demand and morphine consumption at 4, 8, 12 and 24 hours after surgery. There was a consistent reduction in morphine requirements in the dexamethasone group, but this was not statistically significant (p=0.053). There was also no significant difference in VPRS between the groups. The authors concluded that the influence of dexamethasone on postoperative pain was minimal.20 According to the authors of the above study, different postoperative pain intensities among the

22 sample population may be responsible for the results obtained. Also, the dose of 10 mg dexamethasone may not have been sufficient for adult patients.

In all the studies mentioned above, it is of note that there were no recorded side effects from the use of single dose of dexamethasone for postoperative pain.

Intravenous dexamethasone will be used in combination with intravenous tramadol in this study. Tramadol is one of the readily available analgesics used for postoperative pain management in our centre. It is a synthetic opioid introduced in Germany in 1971.

Tramadol is a phenylpiperidine analogue of with 10% the potency of morphine. It is used in the treatment of moderate to severe pain and its effect on respiration is minimal.16 The dose for children is 1-2 mg/kg. Side effects from its use may include nausea and vomiting.16 It is considered a safe and effective drug for postoperative analgesia in children.32

A study by Khosravi et al compared the use of intravenous tramadol versus ilioinguinal and iliohypogastric nerve blocks for control of post-herniotomy pain in children aged

2–7 years.32 Sixty patients were randomly allocated to two groups of thirty. One group received intravenous tramadol 1.5 mg/kg before induction of general anaesthesia and the other had ilioinguinal and iliohypogastric nerve block with 0.5% bupivacaine (0.25 ml/kg) before skin incision.32 At 1, 4 and 24 hours after surgery the two groups had identical pain scores. At 2 hours and 3 hours after surgery the tramadol group experienced significantly less pain (P < 0.05). 36.7% of the patients who received tramadol did not require a rescue analgesic after their operation. The tramadol group of patients were found to have more episodes of nausea and vomiting (P < 0.05).32

23

Thus this study by Khosravi et al shows that tramadol has been used for post- herniotomy pain management with some success.

Nevertheless, a synergistic action has been demonstrated between dexamethasone and tramadol and their combination could therefore be further beneficial in the management of postoperative pain.33

Pain assessment in children

In children, because of the varying capabilities of communication, age-appropriate pain assessment tools are needed to facilitate accurate assessment. The three major modalities for pain assessment are: self-reports, behavioural observation, and monitoring of physiological parameters.34 Self-report measures are considered a gold standard, because pain is primarily a subjective experience.35 Unfortunately, self- report is possible only in children with sufficient cognitive and communicative abilities.36

Some common pain assessment tools in children include the Wong-Baker FACES pain rating scale, Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS), the

Faces Legs Activity Cry Consolability (FLACC) scale, the Objective Pain Scale (OPS) and the OUCHER scale.37-40 Others are Hester’s Poker chip tool (Pieces of Hurt tool),

Faces scale of Bieri et al, Faces scale of Kutner and LePage, Eland’s Colour scale,

Smiley Analogue Scale, Work Graphic Scale of Tesler et al, Directly observed behaviors, Toddler preschool post-operative pain scale and Ten item post-operative pain score.36 The and Numerical Rating Scale are also used in older children.36

24

The Wong-Baker FACES scale requires self-report; in this scale, there are drawings of 6 faces and the child is asked to choose the face that best depicts his or her own pain.37 Face 0 implies doesn’t hurt at all, face 2- hurts just a little bit, face 4- hurts a little more, face- 6 hurts even more, face 8- hurts a whole lot and face 10- hurts as much as you can imagine. The Wong-Baker FACES scale is recommended for children who are 3 years and above. Another self-report pain scale is the OUCHER scale, which is ethnically based.38 It consists of two scales: a 0-100 numerical scale for older children and a six-picture photographic scale for younger children. There are currently five versions of the Oucher: Caucasian, African-American, Hispanic, First

Nations and Asian. Each version has been tested primarily with children in the ethnic group depicted in the photographs. It is for use in children aged 3 to12 years.

Other methods available for self-report in children are Poker chip tool, Faces scale of

Bieri et al, Faces scale of Kutner and LePage, Eland’s Colour scale, Smiley Analogue

Scale, and Work Graphic Scale of Tesler et al.36 The Visual analogue scale and

Numerical Rating scale are self-report tools used in children aged 7-8years and above.36

The pain assessment tools which require behavioural observation include the

Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) and the FLACC scale.

The CHEOPS has six parameters of cry, facial, child verbal, torso, touch, legs. Scores are assigned to each parameter; the sum of the scores gives the CHEOPS pain score.39 A total score of 4 to 13 is assignable. It is for use in young children, under five years old. The FLACC scale has five parameters -faces, legs, activity, cry,

25 consolability; a score of 0 to 2 is given to each parameter.40 It is for use in children aged 2-7 years.

Other behavioural pain scales are Directly observed behaviors, Toddler preschool post-operative pain scale, Ten item post-operative pain score, and CRIES scale.36

The Objective Pain Scale (OPS) was developed by Hannallah et al.41 The OPS assesses blood pressure, crying, movement, agitation and pain complaints. In children who cannot self-report, the fifth parameter of pain complaints is excluded.

A modification of the Objective Pain Scale by Pappas and colleagues will be used to assess pain in this study; Pappas and colleagues used this modification to assess pain in children aged 6 months to 6 years42; they substituted heart rate for blood pressure measurement because of difficulty in interpreting blood pressure readings in an agitated, moving child.42 In this study also, heart rate will be substituted for blood pressure. The maximum score for the modified Objective Pain Scale (like the OPS) is

10 or 8 (for children too young to complain of pain) while the minimum is 0. The higher the score, the greater the degree of pain.

The reason for choosing the OPS (modified) in this study is because it incorporates self-report, behavioural observation and a physiological parameter. Thus it is hoped to provide more objective pain assessment than when a single modality is employed.

Another reason for choosing the OPS is that it can be used in a wide age range of children from 8months to thirteen years, unlike most pain scales.

There is currently a paucity of reports in the literature on dexamethasone and post- herniotomy pain. Most studies in children which have evaluated the effect of

26 dexamethasone on postoperative pain, involved ear nose and throat (ENT) or dental surgeries. Hence this study seeks to determine the effect of intravenous dexamethasone in combination with tramadol on post-herniotomy pain in children.

CHAPTER FOUR

METHODOLOGY

27

Study design:

This is a prospective, randomized, double-blind and placebo-controlled study.

Setting:

The study was carried out at the University of Benin Teaching Hospital (UBTH), Benin

City, a tertiary healthcare facility situated in Edo state, Nigeria which provides specialized care for a large proportion of patients in Edo, Delta, and neighbouring states.

Study population:

The study population was drawn from paediatric patients scheduled for unilateral herniotomy.

Sample size estimation:

The sample size was determined using the following formula by Joseph and Reinhold based on proportion43:

2 n = (p1 x (1- p1 ) + p2 x (1- p2 ) ) x z h2 Where n is the sample size for each group

p1 is the probability of tramadol relieving post-herniotomy pain

p2 is the probability of tramadol and dexamethasone relieving post-herniotomy pain

z, the critical value corresponding to a confidence level of 95% (1.96)

h, half the estimated difference between groups.

28

The probability p1 of tramadol relieving post-herniotomy pain in this study is estimated to be 37%. This is derived from a study done by Khosravi et al in which they compared the use of intravenous tramadol versus ilioinguinal and iliohypogastric nerve blocks for control of post-herniotomy pain in children aged 2–7 years; and it was found that

36.7%of the patients who received tramadol did not require a rescue analgesic for 24 hours after their operation. 32

The probability p2 of tramadol and dexamethasone relieving post-herniotomy pain in this study was estimated to be 80% from a study by Hong et al13.

The estimated difference between the two groups in this study is 43% and thus h is

0.215

n = (0.37 x (1-0.37) + 0.80 x (1- 0.80) ) x 1.962 0.2152 =32.67

Value substitution evaluates to a sample size of 33 subjects for each group. Allowing for a 10% loss to protocol violation, a total of 74 patients, 37 in each group, were therefore entered for this study.

Inclusion criteria:

 ASA I or II children aged between 1 and 6 years scheduled for elective

unilateral herniotomy.

 Patients with written informed consent of parents/guardians.

29

Exclusion criteria:

 Parent’s or guardian’s refusal

 Bilateral herniotomy

 Repeat herniotomy

 Febrile patients

 Patients allergic to or with known idiosyncratic reaction to tramadol or

dexamethasone

 Patients with congenital abnormalities

 Presence of medical such as seizure disorders

 Renal or hepatic disease

 Patients with blood dyscrasias/coagulopathy

 Patients on concomitant steroid use

Informed consent and Randomization:

Ethical clearance was obtained from the Ethics and Research Committee of the

University of Benin Teaching Hospital. Eligible patients were identified during the preoperative evaluation and the study explained to the parents or responsible guardian. Written consent was obtained from those willing for their child/ward to be

30 included. Parents/guardians were informed of their right to withdraw their children from the study at any time, if they wished to, and still receive standard care for herniotomy.

Randomization of patients was achieved by blind balloting. Equal number of pieces of paper on which group 1 or group 2 was written were placed in a large opaque envelope. For each child, a parent/guardian was asked to pick one, after thoroughly shaking the envelope, thus randomizing the patients into group 1 or group 2. Group 1 received IV tramadol 1mg/kg and 5ml of IV normal saline via 2 different syringes.

Group 2 received IV tramadol 1mg/kg and IV dexamethasone 0.5mg/kg diluted to 5ml using 2 different syringes.

Study Design

A preoperative review was done for each patient to design anaesthetic plan and to identify those who met the inclusion criteria. This included taking a detailed history and carrying out a general examination. The respiratory, cardiovascular and central nervous systems were specifically examined. All patients were weighed. Haemoglobin concentration and urinalysis were done for every patient. An American Society of

Anesthesiologists (ASA) physical health status score was assigned to each child. All children were kept nil per oral after midnight for solids, breast milk was allowed till 4 am, while clear fluids were permitted until 2 hours before anticipated time of surgery.

Each patient received syrup 0.5 mg/kg as premedication on the morning of surgery.

On arrival in theatre, a DASH 4000 multi-parameter monitor (manufactured by GE

Medical System Information Technology International, Wisconsin USA) was attached

31 to the patient and baseline respiratory rate, heart rate, blood pressure and oxygen saturation of haemoglobin were obtained and recorded. A precordial stethoscope was also attached to the patient. Monitoring continued throughout the period of anaesthesia and surgery and in the Post Anaesthesia Care Unit (PACU).

Induction of anaesthesia was carried out using a stepwise increase of halothane in

100% oxygen via a face mask of appropriate size using the Jackson-Rees modification of the Ayre’s T-piece. Intravenous access was secured using 20 or 22Gauge cannula.

A laryngeal mask airway (LMA) of appropriate size (size 2 or 2½) was inserted at adequate depth of anaesthesia.

Anaesthesia was maintained with halothane at concentrations between 0.5 -1.5% in

100% oxygen via the LMA, with the patient breathing spontaneously. Group 1 patients received IV tramadol 1mg/kg and 5ml of IV normal saline via 2 different syringes, while

Group 2 patients received IV tramadol 1mg/kg and IV dexamethasone 0.5mg/kg

(diluted to 5ml) using 2 different syringes, 5-10 minutes before skin incision. The study drugs were prepared by an anaesthetist and administered by another anaesthetist (the investigator) who was blinded to the option of drug combination administered. Vital signs were taken and recorded every 5 minutes. Fluid maintenance was achieved with

4.3% dextrose in 0.18% saline. Intraoperative complications were noted and managed. Bradycardia which was defined as a heart rate below 80 beats per minute44 was managed by continuing the administration of 100% oxygen and reducing the concentration of halothane with or without administration of intravenous atropine 0.01 mg/kg; while laryngospasm was managed by increasing depth of anaesthesia and positive pressure ventilation. At the end of surgery, the oropharynx was suctioned and halothane was discontinued, LMA was removed and 100% oxygen was administered for five to ten minutes via a face-mask. In the recovery room, the investigator (who

32 remained blinded to the study drugs administered) carried out pain assessment. After transfer to the ward, the investigator also performed pain assessment in the ward. All pain assessment was done using the Modified Objective Pain Scale.

MODIFIED OBJECTIVE PAIN SCALE (MOPS)42

Parameter Finding Points Heart rate Increase < 20% of preoperative heart 0 rate

Increase 20-30% of preoperative 1 heart rate

Increase > 30% of preoperative heart 2 rate Crying Not crying 0

Responds to age appropriate 1 nurturing

Does not respond to nurturing 2

Movements Relaxed 0

Moving about in bed constantly 1

Thrashing (moving wildly) 2

Rigid (stiff) 2 Agitation Asleep or calm 0

Can be comforted to lessen the 1 agitation (mild)

Cannot be comforted (hysterical) 2

Complaints of pain Asleep 0

States no pain 0

Cannot localize pain 1

Localizes pain 2

33

Postoperative pain scores were assessed every 15 minutes for the first hour, hourly for the next 3 hours, then 12 hours and 24 hours after surgery.

The 10-point MOPS scale was used to assess pain in patients who could self-report

(children older than 2 years), while the 8-point MOPS scale was used in patients who could not self-report (children ≤ 2 years). MOPS scores below 5 on the 10-point scale and below 4 on the 8-point scale were regarded as low pain scores (mild or no pain).

Scores exceeding 5 points on the 10-point scale or exceeding 4 points on the 8-point scale, were treated in PACU using IV paracetamol 15mg/kg and in the ward using oral paracetamol at a dose of 15mg/kg. Postoperatively, fever defined as a temperature of

38oC and above45 on axillary temperature measurement, was noted and managed with oral paracetamol 15mg/kg and tepid sponging in the ward.

Measurement of outcomes:

Primary outcome: a) Proportion of subjects scoring either less than 5 points (if self- reporting) or less than 4 points (if not self-reporting) on the Modified Objective Pain

Scale, 24 hours postoperatively.

Secondary outcomes: a) Time of first analgesic requirement (Time of administration of study drugs to first analgesic requirement). b) Total analgesic requirement within 24 hours postoperatively. c) Incidence of side effects: nausea/retching/ vomiting, bradycardia, laryngospasm, fever.

34 d) Parental or guardian satisfaction with analgesia as assessed with a 5 point Likert scale as follows: Excellent, Very good, Good, Poor, Very poor.

Socio-demographic data and perioperative events were recorded using a data collection form. Pain scores at each measurement interval, time of first analgesic requirement, the total dose of paracetamol administered in 24 hours and side effects were recorded.

Data analysis:

Data analysis was done using SPSS® (Statistical Package for the Social Sciences) version 18. The parametric data were summarized as means and standard deviations, and categorical data presented as counts or frequencies.

Continuous data such as weight, height, haemoglobin concentration, heart rate, blood pressure, duration of surgery, time to first analgesic requirement and analgesic consumption were analysed using the unpaired Student’s t-test. Categorical data such as male/female ratio, number of subjects on the 8-point or 10-point MOPS scale and proportion of subjects with low MOPS scores were analysed using the chi square test or Fischer’s exact test where applicable. Level of significance was set at p value of <

0.05.

35

CHAPTER FIVE RESULTS

Seventy-four ASA I children aged between 1 to 6 years were enrolled in this study.

None of the patients was lost to protocol violation. Thus, data from 74 patients (37 in each group) were analysed.

Table I shows the socio-demographic characteristics of the patients. The mean ages of patients in group 1 (tramadol and saline) and group 2 (dexamethasone and tramadol) were 2.54 ± 1.84 and 3.27 ± 1.73 years respectively (p = 0.086, t-test). There was no statistically significant difference between the groups with regard to weight (p

= 0.389) and height (p = 0.315). The male: female ratio was 35:2 in each group and all the patients were ASA I.

36

The preoperative haemoglobin concentration was 11.03 ± 1.25 g/dL in group 1 and

11.07 ± 1.01 g/dL in group 2 (p = 0.887, t-test). The preoperative heart rate, blood pressure, respiratory rate and arterial oxygen saturation (SpO2) were also comparable between both groups (Table II).

The mean duration of surgery was 46.89 ± 29.65 and 44.05 ± 18.41minutes in groups

1 and 2 respectively (p = 0.623). Intraoperative vital signs were also similar in both groups (Table III). There was initial rise in heart rate and blood pressure in both groups as shown in Figure 1.

The 8-point MOPS scale was used in 25 (67.57%) patients in group 1 and 19 (51.35%) patients in group 2. While the 10-point MOPS scale was used in 12 (32.43%) and 18

(48.65%) patients in groups 1 and 2 respectively (p = 0.237). (Table IV).

Table V shows the median pain scores of patients on the 8-point MOPS scale.

Generally, the patients in the tramadol/saline group had higher median pain scores than patients in the dexamethasone/tramadol group at the study time points. However both groups had low median pain scores and there was no significant difference in median pain scores between both groups.

The median pain scores for patients in the tramadol/saline group and the dexamethasone/tramadol group were similar and also low for patients on the 10-point scale as outlined in Table VI. This indicates that more patients in both groups had low pain scores than high pain scores postoperatively.

Figure 2 shows that the proportion of patients with low MOPS scores was higher in the dexamethasone/tramadol group than in the tramadol/saline group at most study time

37 points. This difference in proportion was statistically significant at 6 hours after surgery

(p = 0.002) (Table VII).

The time to first analgesic requirement was significantly longer in group 2 (472.79 ±

218.42 min) compared to group 1 (347.35 ± 273.64 min) (p = 0.033). Therefore, patients in the tramadol/saline group required postoperative analgesic earlier than patients in the dexamethasone/tramadol group. Postoperative paracetamol consumption was significantly higher in group 1 (535.15 ± 313.10 mg) than in group 2

(336.00 ± 288.05 mg) (p = 0.004). Thus, patients who received tramadol and saline consumed more postoperative analgesic than patients who received dexamethasone and tramadol. (Table VIII).

In the post anaesthesia care unit, 4 (10.81%) patients in group 1 (tramadol/saline group) required analgesic, while none in group 2 (dexamethasone/tramadol group) required analgesic.

Four (10.81%) patients in the dexamethasone/tramadol group versus 1 (2.70%) patient in the tramadol/saline group, did not require analgesic within the 24 hour study period.

The perioperative adverse events in group 1 and group 2 were bradycardia (18.92% vs. 16.22%), laryngospasm (8.11% vs. 10.81%) and fever (24.32% vs. 10.81%) as illustrated in Figure 3.

Table IX shows the adverse events within each group at induction, the intraoperative period and postoperatively. At induction, 7 (18.92%) patients in group 1 and 4

(10.81%) patients in group 2 had bradycardia, while 3 (8.11%) patients had laryngospasm in group 1. Intraoperatively, 2 (5.41%) patients had bradycardia in group

38

2 and 3 (8.11%) patients had laryngospasm also in group 2. Postoperatively, 1 (2.70%) patient in group 2 had laryngospasm. Fever was observed in 9 (24.32%) patients in group 1 and 4 (10.81%) patients in group 2 within 24hr after surgery.

Bradycardia was managed by administering 100% oxygen and reducing the concentration of halothane with or without administration of intravenous atropine 0.01 mg/kg. Laryngospasm was managed by increasing depth of anaesthesia and positive pressure ventilation via the Jackson-Rees modification of the Ayre’s T-piece. Fever was managed with oral paracetamol 15mg/kg and tepid sponging.

Table IX shows parental/guardian satisfaction with postoperative analgesia. Most of the parents/guardians in groups 1 (62.16%) and 2 (64.86%) reported satisfaction with pain management to be good. No assessment of poor or very poor was reported by the parents/guardians.

39

TABLES

Table I: Socio-demographic characteristics of patients

Parameter Tramadol and Tramadol and P value Level of saline dexamethasone significance

n =37 n = 37

Mean ± SD Mean ± SD

Age (years) 2.54 ± 1.84 3.27 ± 1.73 0.086 NS

Weight (kg) 13.21 ± 4.06 14.22 ± 5.81 0.389 NS

Height (cm) 89.00 ± 18.91 93.16 ± 16.36 0.315 NS

n (%) n (%)

Male 35 (94.59) 35 (94.59)

Female 2 (5.41) 2 (5.41) 1.000 NS

ASA I 37 (100) 37 (100)

NS – Not Significant

40

Table II: Preoperative vital signs

Parameter Tramadol and Tramadol and P value Level of saline dexamethasone significance

Mean ± SD Mean ± SD

Heart rate 113.51 ± 23.41 108.22 ± 15.97 0.259 NS (beats per minute)

Systolic blood 104.50 ± 12.10 100.00 ± 11.20 0.101 NS pressure (mmHg)

Diastolic blood 55.00 ± 11.50 58.25 ± 10.28 0.204 NS pressure (mmHg)

Respiratory rate 28.38 ± 5.25 27.84 ± 3.98 0.619 NS (cycles/minute)

SpO2* (%) 100 (99-100) 100 (99-100) 0.529 NS

NS – Not Significant

*Reported as median (interquartile range)

41

Table III: Intraoperative vital signs, duration of surgery

Parameter Tramadol and Tramadol and P value Level of saline dexamethasone significance

Mean ± SD Mean ± SD

Heart rate 122.35 ± 6.37 120.08 ± 5.27 0.099 NS (beats/minute)

Systolic blood 100.92 ± 11.36 98.841 ± 10.47 0.416 NS pressure (mmHg)

Diastolic blood 62.26 ± 9.27 60.93 ± 8.65 0.526 NS pressure (mmHg)

SpO2* (%) 100 (100-100) 100 (100-100) 1.000 NS

Duration of 46.89 ± 29.65 44.05 ± 18.41 0.623 NS surgery (minutes)

NS – Not Significant

*Reported as median (interquartile range)

42

Table IV: Number of subjects on 8-point and 10-point MOPS scale

Parameter Tramadol and Tramadol and P value Level of saline dexamethasone significance

n (%) n (%)

8 point 25 (67.57) 19 (51.35)

10 point 12 (32.43) 18 (48.65) 0.237 NS

NS – Not Significant

43

Table V: Median pain scores of patients on 8-point MOPS scale

Time Tramadol and saline Tramadol and P value Level of dexamethasone significance

Median (IQR) Median (IQR)

0min 0 (0-0) 0 (0-0) 0.684 NS

15min 0 (0-2) 0 (0-0) 0.262 NS

30min 0 (0-2) 0 (0-0) 0.262 NS

45min 1 (0-1) 0 (0-1) 0.862 NS

60min 1 (0-2) 0 (0-0) 0.170 NS

2hr 0 (0-3) 0 (0-0) 0.262 NS

3hr 2 (0-3) 0 (0-0) 0.379 NS

4hr 1 (0-1) 0 (0-0) 0.521 NS

44

12hr 0 (0-1) 0 (0-0) 0.379 NS

24hr 0 (0-0) 0 (0-0) 1.000 NS

IQR - Interquartile range

NS – Not Significant

Table VI: Median pain scores of patients on 10-point MOPS scale

Time Tramadol and saline Tramadol and P value Level of dexamethasone significance

Median (IQR) Median (IQR)

0min 0 (0-1) 0 (0-1) 0.395 NS

15min 0 (0-4) 0 (0-2) 0.261 NS

30min 0 (0-7) 0 (0-2) 0.654 NS

45min 0 (0-2) 0 (0-2) 0.438 NS

60min 0 (0-1) 0 (0-0) 0.268 NS

2hr 0 (0-2) 0 (0-2) 0.668 NS

3hr 0 (0-1) 0 (0-0) 0.160 NS

45

4hr 0 (0-2) 0 (0-2) 0.899 NS

12hr 0 (0-1) 0 (0-0) 0.478 NS

24hr 0 (0-2) 0 (0-0) 0.909 NS

IQR - Interquartile range

NS – Not Significant

Table VII: Proportion of subjects with low MOPS scores

Time Tramadol and Tramadol and P value Level of saline dexamethasone significance

n = 37 n = 37

0min 33/4 35/2 0.674 NS

15min 28/9 33/4 0.221 NS

30min 30/7 33/4 0.515 NS

45min 35/2 36/1 1.000 NS

60min 37/0 37/0 - -

46

2hr 37/0 37/0 - -

3hr 37/0 37/0 - -

4hr 35/2 37/0 0.493 NS

6hr 28/9 37/0 0.002 S

12hr 35/2 36/1 1.000 NS

24hr 37/0 37/0 - -

NS – Not Significant

S - Significant

Table VIII: Time to first analgesic requirement, total paracetamol consumption.

Parameter Tramadol and Tramadol and P value Level of saline dexamethasone significance

Mean ± SD Mean ± SD

Time to first analgesic 347.35 ± 273.64 472.79 ± 218.42 0.033 S requirement (minutes)

47

Paracetamol consumption 535.15 ± 313.10 336.00 ± 288.05 0.004 S (mg)

S- Significant

Table IX: Perioperative adverse events

Adverse event Tramadol Tramadol and Total and saline dexamethasone

n (%) n (%) n (%)

At induction

Bradycardia 7 (18.92) 4 (10.81) 11 (14.87)

48

Laryngospasm 3 (8.11) 0 (0.00) 3 (4.05)

Intraoperative

Bradycardia 0 (0.00) 2 (5.41) 2 (2.70)

Laryngospasm 0 (0.00) 3 (8.11) 3 (4.05)

Postoperative

Laryngospasm 0 (0.00) 1 (2.70) 1 (1.35)

Fever 9 (24.32) 4 (10.81) 13 (17.57)

Table X: Parental or guardian satisfaction with postoperative pain relief

Parameter Tramadol and Tramadol and P value Level of saline dexamethasone significance

49

n (%) n (%)

Excellent 7 (18.92) 6 (16.22) 0.760 NS

Very good 7 (18.92) 7 (18.92) 1.000 NS

Good 23 (62.16) 24 (64.86) 0.809 NS

Poor 0 (0.00) 0 (0.00) - -

Very poor 0 (0.00) 0 (0.00) - -

NS- Not Significant

FIGURES

50

Time

Figure 1: Intraoperative heart rate, blood pressure

51

40

35

30

25

20 Tramadol and saline

Number of patients of Number 15 Tramadol and dexamethasone 10

5

0 0min 15min 30min 45min 60min 2hr 3hr 4hr 6hr* 12hr 24hr Time

Figure 2: Proportion of patients with low MOPS scores

52

30

25

20

Tramadol and saline 15 Tramadol and

Percentage (%) Percentage dexamethasone 10

5

0 Laryngospasm Bradycardia Fever Adverse events

Figure 3: Adverse events profile

53

70

60

50

40

Tramadol and saline 30

Tramadol and 20

dexamethasone Percentage of parents/guardians (%) parents/guardians of Percentage 10

0 Excellent Very good Good Poor Very poor Satisfaction with pain relief

Figure 4: Parental/guardian satisfaction with postoperative pain relief

54

CHAPTER SIX

DISCUSSION

This study shows that the addition of intravenous dexamethasone to tramadol prolonged the time to first analgesic requirement and decreased total analgesic consumption in the first 24 hours following herniotomy, with minimal side effects and good parental/guardian satisfaction. The implication of these findings is that dexamethasone is a useful analgesic adjuvant in the management of post-herniotomy pain.

Dexamethasone significantly prolonged the time to first analgesic requirement, indicating that 0.5 mg/kg of intravenous dexamethasone contributed significantly to postoperative analgesia and increased the period of effective analgesia. Hong et al in a similar study also observed a longer time to first analgesic requirement when 0.5 mg/kg of intravenous dexamethasone was administered before paediatric orchidopexy.13 In the study by Hong et al, the time to first analgesic was 640 min in the dexamethasone group while in the present study it was 473 min. The longer time to first analgesic in the study by Hong et al (compared to this study) may be attributed to caudal block which they performed in all the patients. (Caudal analgesia has been shown to prolong analgesia up to 554 min after surgery).46

Elhakim and colleagues have also reported that the time to first dose of postoperative analgesic was longer in the dexamethasone group following tonsillectomy in children.47 However, the time to first analgesic requirement in the study by Elhakim

55 and colleagues was 88 minutes.47 The shorter duration in their study compared to this study may be attributed to their use of fentanyl which is a short acting drug, for intraoperative analgesia; while in the present study tramadol was used for intraoperative analgesia. Tramadol has a duration of action of 3-6hr48; hence the patients in this study had residual analgesia from the intraoperative period which was significantly prolonged by dexamethasone.

On the other hand, Tan and co-workers failed to demonstrate any difference in the time to first analgesic between the dexamethasone group and saline group after inguinal herniorrhaphy in male adults.49 This may be due to the dose of 10mg dexamethasone they used in all the patients which may have been inadequate considering their weight, unlike in this study where 0.5 mg/kg dexamethasone was administered. Liu et al also could not demonstrate significant difference in time to first postoperative morphine demand when 10 mg of dexamethasone was administered before gynaecological surgery.20 The lack of significance in the study by Liu et al may also be attributed to the fixed dose of 10 mg dexamethasone administered to all patients in their study as opposed to 0.5 mg/kg used in the present study. The dose of

10 mg dexamethasone was also probably inadequate for their adult patients.

Moreover, even with the inadequate dose, Liu et al observed a consistent reduction in postoperative morphine requirements in the dexamethasone group.20 It is plausible therefore that using a dose of 0.5 mg/kg dexamethasone in their study may have prolonged the time to first analgesic requirement as observed in this study. However, a dose of 0.5 mg/kg dexamethasone in adults may not be safe as this will involve large doses of dexamethasone with resultant adverse effects and consequences.

The paracetamol consumption after surgery was significantly higher in the tramadol/saline group compared to the dexamethasone/tramadol group. This

56 indicates that dexamethasone effectively reduced postoperative analgesic requirement and provided better postoperative analgesia. Similarly, Hong et al recorded significantly lower postoperative analgesic consumption when dexamethasone was administered before orchidopexy.13 Elhakim and colleagues also observed significantly less postoperative analgesic consumption in the dexamethasone group compared to the placebo group after tonsillectomy in children.47

Other authors have also demonstrated reduced postoperative analgesic consumption following preoperative administration of intravenous dexamethasone.15,50,51

Vosdoganis and co-workers however did not observe significant difference in analgesic consumption between the dexamethasone and placebo groups after tonsillectomy in children.52 This lack of significant difference in analgesic consumption reported by Vosdoganis and co-workers, may be due to the small sample size (forty- one) in their study; a larger sample size may have yielded significant difference in analgesic consumption. It may also be due to the rectal paracetamol and IV which were administered intraoperatively to all the patients. These drugs may have influenced postoperative analgesia.

In this study, none of the patients in the dexamethasone/tramadol group required rescue analgesic in the post-anaesthesia care unit (PACU) unlike in the tramadol/saline group. This suggests that dexamethasone effectively prolonged the duration of analgesia. In similar fashion, Hong et al found out that patients who received rescue fentanyl in PACU were significantly less in the dexamethasone group.13 This finding underscores the usefulness of intravenous dexamethasone in day-case surgeries.

In this study, patients who did not require any analgesic in the 24hr study period were more in the dexamethasone/tramadol group compared to the tramadol/saline group.

57

While this finding did not achieve statistical significance, it is however worthy of note and emphasizes the analgesic property of intravenous dexamethasone.

The median pain scores ranged from 0 to 2 in both study groups, indicating that low pain scores were observed more often than high pain scores in both groups. This is further highlighted by the greater proportion of patients in both groups who had low pain scores compared to those who had high pain scores at each study time point.

However, the proportion of patients with low pain scores was higher in the dexamethasone/tramadol group than the tramadol/saline group at most study time points; this was statistically significant 6 hours postoperatively. A likely explanation for the lack of statistical significance in the early postoperative period is residual analgesia from tramadol which was administered to all patients. This explanation is strengthened by the mean time to analgesic requirement in the tramadol/saline group which was noted to be almost 6 hours and conforms with the duration of action of tramadol. In addition, the lack of significance in proportion of patients with low pain scores between the groups at 12 hours and 24 hours post-surgery may be attributed to the use of paracetamol in both groups.

Giannoni et al also reported no difference in postoperative pain scores when IV dexamethasone was administered before tonsillectomy in children.53 However, the lack of difference in pain scores between the dexamethasone and placebo groups in their study may be due to the oral and the peritonsillar injection of ropivacaine and administered to all patients preoperatively; this may have influenced postoperative pain scores. Moreover, the authors observed a trend towards less analgesic consumption in the dexamethasone group postoperatively. Coloma et al also reported no significant difference in pain scores between the dexamethasone and placebo groups when IV dexamethasone was administered before anorectal

58 surgeries.54 Nevertheless, their inability to demonstrate significant difference in pain scores may be attributed to local infiltration of the operative site with bupivacaine containing adrenaline in both groups; this may have prolonged analgesia well into the postoperative period. In addition, though Vosdoganis and co-workers also reported no difference in pain scores between the dexamethasone and placebo groups, it was noted that pain scores were low and pain control was satisfactory in both groups.52

Conversely, Elhakim et al reported significantly lower postoperative pain scores at 30 min, 12 hr and 24 hr when IV dexamethasone 0.5 mg/kg was administered before paediatric surgery.47 This significant difference in pain scores between the dexamethasone and placebo groups was probably easier to detect by their use of a short-acting analgesic (fentanyl) in the intraoperative period; unlike in this study where a longer acting intraoperative analgesic was used. Furthermore, the larger sample size of 120 in the study by Elhakim et al may also have helped to detect significant differences in pain scores.

Bisgaard and colleagues also recorded significantly lower postoperative pain scores in the dexamethasone group compared to the placebo group when dexamethasone was administered before laparoscopic cholecystectomy.15 This outcome in their study may be due to the administration of dexamethasone 90 minutes before surgery, thus the anti-inflammatory effect of dexamethasone was probably well established before surgical incision. Other authors have also reported significantly lower postoperative pain scores following preoperative administration of intravenous dexamethasone.

13,14,26,31

The male/female ratio was high in both groups, this suggests that more male children present for herniotomy than female. Inguinal hernia has been reported to be more

59 common in males with a male/female ratio between 3:1 and 10:1.55,56 This therefore explains the high male/female ratio seen in this study. All the patients in this study were ASA I. This also is not surprising as patients who present for elective herniotomy are usually normal healthy patients.57

Parental/guardian satisfaction was similar in both groups. This may be due to the similarity in proportion of patients with low postoperative pain scores; moreover this proportion was high in both groups. However, patient satisfaction with pain relief has been revealed to be an unreliable indicator of effective pain relief.58 It has been argued that factors such as level of care and affection from care-givers, patient (parental) expectations and culture may affect response from the patient (parent) regarding satisfaction with pain relief.58,59 Therefore, parental/guardian satisfaction with pain relief which was assessed in this study may have been influenced by other variables.

The adverse events recorded in this study were bradycardia, laryngospasm and fever.

Children have a high vagal tone and thus parasympathetic stimulation in this age group may lead to bradycardia.60,61 Bradycardia may also occur from halothane use, hypoxaemia, suxamethonium, laryngoscopy and intubation during light anaesthesia and also from surgical stimulation.60,62 In the present study, bradycardia occurred at induction and in the intraoperative period. However, 85% of the total cases of bradycardia occurred at induction. This is in agreement with another study in children which also revealed that most cases of bradycardia (60%) occurred at induction.44 The major causes of perioperative bradycardia in paediatric patients have been found to be anaesthesia-related factors.44 In this study, inhalational induction using halothane may therefore be a likely cause of the bradycardia observed at induction.

60

Bradycardia in this study was managed by administering 100% oxygen and reducing the concentration of halothane with or without administration of intravenous atropine

0.01mg/kg. This is in line with the management of perioperative bradycardia in children which involves immediate cessation of stimulus and treatment with oxygen and atropine.61

Laryngospasm is another complication of paediatric anaesthesia and it is more likely to occur in the presence of respiratory tract infection.63 However none of the patients in this study had respiratory tract infection preoperatively. Other causes of laryngospasm include laryngoscopy during light plane of anaesthesia, secretions or blood or foreign body around the larynx during light anaesthesia, tracheal extubation during light anaesthesia and use of isoflurane for induction of anaesthesia.63 The use of laryngeal mask airway (LMA) has also been implicated as one of the causes of laryngospasm.64 Therefore the use of LMA in this study may have contributed to the incidence of laryngospasm.

Laryngospasm was managed in this study by increasing depth of anaesthesia and positive pressure ventilation. Other methods of managing laryngospasm are IV suxamethonium, spray, emergency cricothyrotomy or tracheostomy.63 The methods used for managing this reflex depend on the severity.

In the present study, the number of patients who had fever postoperatively were more than double in the tramadol/saline group compared to the dexamethasone/tramadol group. Hence dexamethasone may have helped to reduce the incidence of fever in this study. Moreover, corticosteroids have been shown to inhibit the release of pyrogenic cytokines.65 Yared and co-workers have also reported less incidence of

61 postoperative fever after preoperative dexamethasone administration.66 Fever was observed in 17.57% of the patients in this study which is in agreement with the published incidence of postoperative fever (14-91%).67 Early postoperative fever is more often due to the inflammatory response to surgical trauma than infection and may be self-limiting.68 Dexamethasone was therefore useful in preventing post- operative fever in this study.

Common causes of postoperative fever include infection (such as pneumonia, urinary tract infection, surgical site infection), malaria and blood transfusion.68-70 Other causes are drug reactions and rarely, malignant hyperthermia.68,71 The fever observed in this study occurred within 24 hours after surgery which suggests that the fever was not due to infection. Malaria has been shown to be an important cause of postoperative fever in our environment70; hence some of these patients may have had malaria.

However, none of the patients in this study was febrile prior to surgery. It may be surmised that the inflammatory response to surgery most likely played an important role in the fever observed in this study.

Axillary technique of temperature measurement was used in this study to ensure co- operation of all the patients. Also, axillary temperature measurement is recommended as a screening technique for fever in the age group of children who were recruited in this study.45

No incidence of nausea/retching/vomiting was recorded in this study (even though nausea and vomiting are side effects of tramadol). This may be attributed to promethazine which was administered as premedication to all the patients. Therefore any anti-emetic effect of dexamethasone was difficult to establish in this study.

However, dexamethasone is widely known for its anti-emetic effect. It has been

62 suggested to provide effect via central inhibition of prostaglandin synthesis, decrease in serotonin turnover in the central nervous system and serotonin inhibition in the gut. 13,20 Other mechanisms postulated are release of endorphins and changes in the permeability of the blood cerebrospinal fluid barrier to serum proteins. 13,20

This study was carried out in herniotomy patients. Previous studies which have examined the effect of dexamethasone on postoperative pain in children have been mostly otorhinolaryngological or dental surgeries. This may be because of the marked inflammation associated with otorhinolaryngological and dental surgeries. However, this study has further illustrated that dexamethasone as an adjuvant in postoperative pain management is also pertinent in herniotomy patients.

STUDY LIMITATIONS

Pain assessment can be subjective and non-specific even when using validated pain scores, especially in children. For example, heart rate and crying which were some of the parameters for assessing pain in this study, may have been affected by other factors apart from pain, such as hunger, unfamiliar surroundings and absence of a parent.

63

Self-report of pain is regarded as the gold standard in pain assessment; however this could not be used in all the children in this study because of their different communication capabilities.

64

RELEVANCE OF THE STUDY

Postoperative pain management in children is still a problem in many centres in

Nigeria and indeed worldwide. Any treatment modality that will lead to superior quality of postoperative analgesia is thus a welcome development. Dexamethasone is cheap, readily available and is associated with minimal side effects following single-dose administration.

This study has highlighted some of the benefits of dexamethasone in postoperative analgesia, specifically in children. The use of dexamethasone resulted in better pain control, less analgesic consumption, less incidence of fever and good parental satisfaction. The findings in this study will help to improve the practice of herniotomy as day-case surgery when dexamethasone is employed in the management of post- herniotomy pain. The consequent lack of overnight stay following herniotomy will result in reduced expenses for the patient and increased turn-over for the hospital.

Dexamethasone also offers the advantage of reduced need for strong opioids (with consequent reduction in their associated side effects), as it provides a viable alternative for good quality analgesia when used as an adjuvant with tramadol.

65

CONCLUSION

This study shows that intravenous dexamethasone as an adjuvant is useful in the management of post-herniotomy pain. The addition of intravenous dexamethasone to tramadol prolonged the time to first analgesic requirement and decreased total analgesic consumption in the first 24 hours following herniotomy, with minimal side effects and good parental/guardian satisfaction.

Intravenous dexamethasone therefore has a role to play in the management of post- herniotomy pain and could be used as an analgesic adjuvant for pain management following herniotomy.

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RECOMMENDATION

It is advised that preoperative administration of intravenous dexamethasone 0.5mg/kg should be incorporated in the management of post-herniotomy pain. This will help to enhance (and promote) the practice of herniotomy as day case surgery due to improved pain management.

Dexamethasone should also be included in pain management during other day case surgeries as its use may lead to improved analgesia and therefore better patient care.

It is also recommended that the use of dexamethasone for postoperative pain management in other paediatric surgeries should be studied.

In addition, the timing of dexamethasone for postoperative pain management in children needs to be further evaluated in order to achieve the maximum analgesic effect from its administration.

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APPENDIX I

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80

APPENDIX II

PARENT/GUARDIAN INFORMED CONSENT

Title of the study: A Study of Intravenous Dexamethasone as an Adjuvant for Postoperative Pain Control following Herniotomy

It is important you read and understand the explanation of the procedure your child/ward will undergo before agreeing to participate in this study. This information describes the purpose, procedure, precaution, risks and benefits associated with this study. The informed consent process enables you to make an informed decision based on a clear understanding of the risks and benefits associated with this study. Please ask the doctor of this study to explain any word(s) that may not be clear to you. Make sure all questions have been answered to your satisfaction before signing this document.

Introduction: Your child/ward is going to undergo a surgical procedure known as herniotomy. Pain relief is required for this procedure. Pain relief can be provided by injecting a drug called Tramadol into your child/ward’s vein. Additional pain relief may/may not be provided by also injecting a drug called dexamethasone into a vein.

Procedure: Your child/ward will be randomly assigned to one of two groups: group I receiving tramadol 1mg/kg and normal saline, group II receiving tramadol 1mg/kg and dexamethasone 0.5mg/kg. After the procedure and recovery from anaesthesia, presence of pain will be determined using a modified version of a scoring system known as the Objective Pain Scale. Pain if present, will be treated using paracetamol.

Potential risks: Your child/ward may experience post-surgery nausea and vomiting from use of tramadol, this is hoped to be prevented by dexamethasone. Delayed wound healing and infection may result from use of dexamethasone, this is very unlikely with the single-shot dose employed in this study.

Benefits: Your child/ward may get additional pain relief from the use of intravenous dexamethasone. Also, information from this study will help improve pain management following herniotomy.

Compensation: You will not receive any form of financial compensation from participating in this study.

Confidentiality: Your child/ward will not be identified by name during the analysis of the data. The results of the investigation may be published in a scientific journal without identifying subjects by name.

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Voluntary Participation: Please understand that your participation in this study is voluntary. You may terminate your participation at any time if you wish, and withdrawal from the study will not jeopardize your child/ward’s right to obtain appropriate medical therapy.

Answers to questions: You are welcome to ask questions now or any time during the study. Please contact Dr Maryrose Osazuwa if any questions, on 08023524913.

Consent: I understand that my participation in this study is voluntary. I understand that I may terminate my participation at any time, and withdrawal from the study will not jeopardize the right of my child/ward to obtain appropriate medical therapy.

______

Name and signature (or thumbprint) of parent/guardian Date

______

Name and signature of investigator Date

______

Name and signature of witness Date

APPENDIX III

DATA COLLECTION FORM

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A STUDY OF INTRAVENOUS DEXAMETHASONE AS AN ADJUVANT FOR POSTOPERATIVE PAIN CONTROL FOLLOWING HERNIOTOMY

Name: Date:

Age (months and years): Hospital number:

Sex: Phone number:

Weight (kg): Height (cm):

ASA physical status:

Baseline parameters:

Heart rate: Blood pressure: systolic- diastolic-

Respiratory rate: SpO2: Hb concentration:

Intraoperative parameters:

Time of administration of study drugs: Time of skin incision:

Heart rate(b/min) Blood SpO2 (%) pressure(mmHg) Baseline 2 minutes 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes Time surgery ended:

Duration of surgery (minutes):

Intraoperative complications:

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Postoperative pain assessment.

Modified Objective Pain Scale (MOPS)

Heart rate Crying Movements Agitation Pain Total complaints

0min 15min

30min 45min

60min 2hr 3hr

4hr 12hr 24hr

Note: The MOPS scores minimum of 0, it scores a maximum of 8 for patients who cannot self-report and 10 for patients who can self-report. For each of the parameters, the scoring system is as follows:

Heart rate: 0 If increase < 20% of baseline

1 If increase between 20-30% of baseline

2 If increase > 30% of baseline

Crying: 0 If not crying

1 Responds to age appropriate nurturing

2 Does not respond to appropriate nurturing

Movement: 0 If relaxed

1 If restless, constantly moving in bed

2 If thrashing about wildly

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2 If rigid (stiff)

Agitation: 0 If asleep or calm

1 If can be comforted to lessen the agitation (mild)

2 If cannot be comforted

Pain complaints: 0 - Asleep

0 - No pain

1 - Pain cannot be localized

2 - Pain can be localized

Time of first administration of paracetamol:

Time from administration of study drugs to first administration of paracetamol (minutes):

Total dose of paracetamol received 24 hours post-surgery (mg):

Parent/Guardian satisfaction with pain relief:

Excellent □ Very good □ Good □ Poor □ Very poor □

Adverse incidents

At induction Intraoperative Postoperative

Bradycardia Bradycardia Nausea/retching/vomiting

Hypotension Hypotension Bradycardia

Tachycardia Tachycardia Tachycardia

Respiratory depression Respiratory depression Respiratory depression

Laryngeal spasm Laryngeal spasm Laryngeal spasm

Apnoea Apnoea Apnoea

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