A Comparative study of Ondansetron with Ondansetron and

Dexamethasone in prevention of post operative Nausea and Vomiting (PONV) in

Laparoscopic surgeries

By

Dr. Jayati Sinha

A dissertation Submitted to the Rajiv Gandhi University of Health Sciences in Partial fullfilment of University Regulations for the award of

M.D . Degree

IN

Anaesthesiology

2005

Guided by Dr. Rathna.N.,DA,MD,DNB,

Prof. and H.O.D

Department of Anaesthesiology and Critical care M.S. RAMAIAH MEDICAL COLLEGE

BANGALORE

I

DECLARATION

I, hereby declare that the entire work in this dissertation, entitled “ A Comparative

study of Ondansetron with Ondansetron and Dexamethasone in prevention of post

operative Nausea and Vomiting (PONV) in Laparoscopic surgeries”, has been

carried out by me, under the direct guidance and supervision of Dr. Rathna, MD, DA,

DNB, Prof. And H.O.D of Anaesthesiology and critical care, at M.S.Ramaiah Medical

College, Bangalore.

This dissertation or any part has not been submitted by me to any other

University for award of any degree or Diploma.

Place : Bangalore Dr. Jayati Sinha

Date : 21.2.2005

II

CERTIFICATE

This is to certify that Dr. Jayati Sinha has carried out the work presented in this

dissertation entitled “A Comparative study of Ondansetron with Ondansetron and

Dexamethasone in prevention of post operative Nausea and Vomiting (PONV) in

Laparoscopic surgeries”under my supervision and guidance in the department of

Anaesthesiology, M.S. Ramaiah Medical college, for the award of M.D.

Anaesthesiology, during the academic year 2003-2005

I certify that this study is a bonafide work of the candidate carried out in this

institution to the entire satisfaction of the Guide.

Professor & H.O.D Place : Bangalore Department of Anaesthesiology & Critical Care M.S. Ramaiah Medical College.

Date : Bangalore

III

CERTIFICATE This is to certify that this dissertation entitled “ A Comparative study of Ondansetron

with Ondansetron and Dexamethasone in prevention of post operative Nausea and

Vomiting (PONV) in Laparoscopic surgeries” has been prepared by Dr.Jayati Sinha in

the department of Anaesthesiology M.S. Ramaiah Medical College for the award of MD

Anaesthesiology, during the academic year 2003-2005

Place : Bangalore Dr. S. Kumar Principal and Dean Date : 21.2.2005 M.S. Ramaiah Medical College, Bangalore

IV

Copyright

Declaration by the Candidate

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka shall

have the rights to preserve, use and disseminate this dissertation / thesis in print or

eletronic format for academic / research purpose.

Date: 21.2.2005 Signature of the candidate

Place: Bangalore Name: Dr Jayati Sinha

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA

V

ACKNOWLEDGEMENT I am highly indebted and most grateful to Dr. Rathna.N. MD,DA, DNB, Professor and

Head of the Department of Anaesthesiology and Critical care, M.S. Ramaiah Medical

College, Bangalore, whose valuable guidance and constant encouragement enabled me to

complete this dissertation.

I Sincerely thank to my co-guide Dr. K R. Pai, Assistant Prof .in the department of

Anaesthesiology and critical care for his kind co-operation at every step of this study.

My special thanks to the principal M.S. Ramaiah Medical college, for permitting me to

study and report these cases.

I am indebted to all staffs , friends , colleagues of M.S. Ramaiah Medical college and my

family for their timely help and encouragement.

Last but not the least , I am grateful to all my patients without whose co-operation this

study would not have been possible.

Place: Bangalore Dr. Jayati Sinha Date: 21.2.2005

VI

LIST OF ABBREVIATIONS USED

1. ASA - American Society Of Anaesthesiologist

2. CO2 - Carbon di- oxide

3. DBP - Diastolic Blood Pressure

4. 5HT3 - 5-Hydroxytryptamine-3 Recepter

5. IV - Intravenous

6. IM - Intramuscular

7. INSUFL.Pr - Insufflation Pressure

8. PONV - Post Operative Nausea Vomiting

9. PR - Pulse Rate

10. SBP - Systolic Blood pressure

11. SpO2 - Oxygen Saturation By Pulse Oxymeter

12. TCO2 - Total Carbon di- oxide

VII

ABSTRACT

The high incidence of PONV in laproscopic surgeries is well documented. This study is

intended to compare the combinations of dexamethasone and ondansetron with

ondansetron alone in patients undergoing laparoscopic surgeries, with respect to nausea,

vomiting, pain, requirement of rescue analgesic and antiemetics, discharge time and side

effects. We studied 90 female patients requiring general anaesthesia for laparoscopic

surgeries, in a randomized clinical trial. 25 patients received 4mg ondansetron,

intravenously and another 25 patients received 4mg ondansetron and dexamethasone

8mg intravenously just after intubation , post operatively patients were assessed hourly

for 4 hours and then at 24hr for degree of nausea, vomiting, pain, post anaesthesia

discharge score and side effects. Vomiting occurring upto 2 hours was considered early

vomiting and from 2-24 hour as delayed vomiting.

Early nausea was lower in the combination group ( 20%) when compared to

monotherapy of ondansetron (60%) . Incidence of delayed vomiting was also less in

combination group (4 %) when compared to Ondansetron group (32%).

We conclude that the combination therapy of ondansetron and dexamethasone provides

adequate control of PONV, with delayed PONV being better controlled than early

PONV.

KEYWORDS :

Laparoscopy ; Nausea; Vomiting ;Early; Delayed; Ondansetron; Dexamethasone.

VIII

CONTENTS

SL. N0. PART – I Page

1. INTRODUCTION 1

2. AIM OF THE STUDY / OBJECTIVES 6

3. PHYSIOLOGY OF EMESIS 8

4. REVIEW OF LITERATURE 30

5. PHARMACOLOGY OF DRUGS 35

PART - II

6. MATERIALS AND METHODS 48

7. OBSERVATION AND RESULTS 54

8. DISCUSSION 73

9. CONCLUSION 77

10. SUMMARY 78

PART – III

11. BIBLIOGRAHY 79

12. ANNEXURES

PROTOCOL 84

IX

LIST OF TABLES

SI. NO. TABLES PAGES 1. Table 1 55 2. Table 2 56 3. Table 3 57 4. Table 4 58 5. Table 5 59 6. Table 6 61 7. Table 7 62 8. Table 8 64 9. Table 9. 65 10. Table 10 67 11. Table 11 68 12. Table 12 70 13. Table 13 71

X

LIST OF FIGURES SI. NO. FIGURES PAGES 1. FIG-1 11 2 FIG-2 12 3 FIG-3 27

XI

XII

CONCLUSION

We conclude that ondansetron and dexamethasone given intravenously just after

intubation is safe and more effective than intravenous ondansetron alone in early

nausea and delayed vomiting and long term prevention and post operative nausea and

vomiting in patients undergoing elective laparoscopic surgeries under general

anaesthesia.

77

78

SUMMARY

A randomized, open clinical trial was done to compare efficiency and safety of

ondansetron and combination of ondansetron and dexamethasone .

After institutional approval and written informed consent 50 patients between age

group of 20-45 years, coming for elective laparoscopic procedures under general

anaesthesia were selected . 25 patients were allocated randomly either ondansetron or

combination of (Ondasetron and Dexamethsone) group. The study drugs were injected

after intubation. Anaesthestic management was standardized. Vital parameters were

monitored intra-opertively and nausea, vomiting, pain , were monitored at hourly

interval for four hours and then at 24 hours interval . Need for rescue

analgesic,additional antiemetic and complication were also monitored. Patients were

given scores according to severity of sign and symptoms into mild, moderate and severe.

Statistical comparison were done for all the variables.

There were no difference in demographic data between 2 groups. Incidence and severity

of nausea and vomiting were less in the combination group. Single dose of

dexamethasone did not produce any significant side effects. Ondansetron is also

effective in controlling nausea and vomiting upto an extent, but the combination of

Ondansetron and Dexamethasone is more effective in early nausea and delayed

vomiting.Combination therapy when compare to monotherapy is more advantageous with

less need for rescue antiemetics. Use of dexamethasone is cost effective.

78

79

BIBLIOGRAPHY

1. Saeeda Islam, P.N. Jain, Post operative nausea and vomiting (PONV) : A review

article. Indian J. Anaesth 2004, 48(4): 253-58.

2. Thomas E.J.Healy, A practice of Anaesthesia- Wylie and Churchill- Davidson –

Seventh edition : 1030-1032.

3. P.L.R. Andrews, Physiology of nausea and vomiting. Br. J. Anaesth 1992;

69(S):2-19.

4. J. Lerman, Surgical and patient factors involved in post-operative nausea and

vomiting. Br. J. Anaesth. 1992; 69(S): 24-32.

5. Patricia A. Kapur, Editorial: The big “little problem”. Anesth Analg; 1991,73:

243-245.

6. J. Hirsch, Impact of post operative nausea and vomiting in the surgical setting.

Anaesthsia; 1994, 49(S): 30-33.

7. L. Lopez –oaondo, et al, Advances in antiemetic pharmacology – ESRA

refresher course., 2000 : 1-11.

8. D. Russel and G.N.C. Kenny , 5HT3 antagonist in post operative nausea and

vomiting . Br. J. Anaesth 1992 ; 69(S): 63-68.

9. M. Elhakim, Naglaa M Ali, Inas Rashed,Mostafa K. Riad,Mona Refat,

Dexamethasone reduces post operative vomiting and pain after pediatric

tonsillectomy. Can. J. Anesth 2003 : 50(4) : 392-397.

79

10. B. subramaniam, R. Madan,S. Sadhavisivam,Dexamethasone is a cost effective

alternative to ondansetron in preventing PONV after paediatric strabismus repair.

Br. J. Anaesth 2001; 86: 84-89

11.K. Korttila , The study of post operative nausea and vomiting . Br. J. Anaesth1992:

6.9(S): 20-23.P.L.R. Andrews, C.J.Davis, L. Maskell, The abdominal visceral

innervations and the emetic reflex : pathways ,pharmacology and plasticity . Can. J.

Physiol. Pharmacol. 1990;68: 325-345.

12. K. T. Bunce and M.B. Tyers , The role of 5HT in post operative nausea and

vomiting . Br. J. Anaesth. 1992; 69(S): 60-62.

13. W.S. Beattie, T.Lindblad,DN Buckley and JB Forrest, The incidence of post

operative nausea and vomiting in women undergoing laparoscopy is influenced by

the day of menstrual cycle. Can. J. Anesth 1991; 38: 298-302.

14. P.G. Rabey and G. Smith, Anaesthetic factors contributing to post operative

nausea and vomiting . Br. J. Anaesth. 1992; 69(S): 40-45.

15. G.N.C. Kenny , Risk factors for post operative nausea and vomiting. Anaesthesia

1994 ; 49(S): 6-10.

16. Alain Borgeat, Georgios Ekatodramis, Carlo A. Schenker, Post operative nausea

and vomiting in regional anaesthesia. Anesthesiolgy 2003; 98 : 530- 547.

17. Mehernoor F. Watcha , Paul F. White., Post operative nausea and vomiting , it’s

etiology , treatment and prevention. Anesthesiology 1992 ; 77: 162-184.

80

18. B.V.Wetchler, Post operative nausea and vomiting in day care surgery. Br. J.

Anaesth 1992; 69(S) : 33-39.

19. Colin Dollery , Therapeutic Drugs Vol.I, 2nd Edition, Churchill Livingstone1999;

D47-D50.

20. Goodman and Gilman’s, The pharmacological basis of therapeutics, 9th edition ;

249-262, 1459-1486.

21. Colin Dollery, 1999, Therapeutic Drug Vol.I, 2nd edition , Churchill

Livingstone1999; O21-O24.

22. Christine R. Culy, Nila Bhana,Greg L. Plosker, Ondansetron ; A review of its use

as an antiemetic in children . Paediatric drugs 2001; 3(6) : 441-479.

23. Willium L. Hasler; Nausea, Vomiting and indigestion, Harrison’s Medicine, 15th

edition; 236-238.

24. D. J. Rowbotham , Current management of post operative nausea and vomiting ,

Br. J. Anaesth. 1992 ; 69(S): 46-59.

25. V. Rajeeva,N. Bhardwaj,Y.K.Batra,L.K.Dhaliwal, Comparison of ondansetron

with ondansetron and dexamethsone in prevention of PONV in diagnostic

laparoscopy. Can. J. Anesth. 1999; 46(1): 40-44.

26. L. Lopez-olaondo, F.Carrascosa, F.J. Pueyo,P.Monedero,N.Busto,

A.Saez,Combination of ondansetron and dexamethason in the prophylaxis of post

operative nausea and vomiting. Br. J. anaesth 1996; 76(6): 835-840.

27. I. Henzi,Berhard Walder, MartinR. Tramer, Dexamethasone for the prevention of

post operative nausea and vomiting: a quantitative systematic review. Anesth.

Analg. 2000; 90(1): 186-194.

81

28. J.J. wang,S.T.Ho,H.S.Liu and C.M.HO, Prophylactic antiemetic effect of

dexamethasone in women undergoing ambulatory laporoscopic surgery. Br. J.

Anaesth. 2000; 84(4): 459-462.

29. R. Thomas, N.Jones, Prospective randomized, double blind comparative study of

dexamethasone, ondansetron, and ondansetron plus dexamethasone as

prophylactic antiemetic therapy in patients undergoing day care gynecological

surgery. Br. J. Anaesth 2001; 87(4): 588-592.

30. M. Elhakim,Madgy Nafie,Khalaf Mahmoud,Azza Atef, Dexamethasone 8mg. in

combination with ondansetron 4mg. appears to be the optimal dose for the

prevention of nausea and vomiting after laporoscopic cholecystectomy. Can. J.

Anesth 2002; 49(9): 922-926.

31. Y. Lee,Hsien-Yong Lai,Pei-Chin Lin,Shen-Jer Huang,Youh-Sheng Lin,

Dexamethasone prevents post operative nausea and vomiting more effectively in

women with motion sickness. Can. J. Anesth. 2003: 50(3): 232-237.

32. Ronald D. Miller, Miller’s Anaesthesia, sixth edition; 2708-2709.

33. J.J.Wang, ST Ho,YH Liu,SC LeeYC Liu, Dexamethasone reduces nausea and

vomiting after laparoscopic cholecystetomy. Br.J.anaesth 1999;83(5);772-775

82

34. Jos Leeser, and Harm lip, Prevention of postoperative nausea and vomiting using

ondansetrom a new selective 5HT3 receptor antagonist. Anesth.Analg

1991;72:751-755.

35. Vidar Aasboe, Johan C.Raeder andBjarne Groegaard, Betamethasone reduces

postoperative pain and nausea after ambulatory surgery. Anesth. Analg 1998;

87:319-323

36. J.J. Wang, TS Ho,CH Wong,JI Tzeng,HS Liu,IP Ger, Dexamethasone

prophylaxis of nausea and vomiting after epidural morphina for post ceasarean

analagesia. Br. J.Anesth 2001; 48(2): 185-190

83

PRTOCOL FOR STUDY A Comparative study of Ondansetron with Ondansetron and Dexamethasone in prevention of post operative Nausea and Vomiting (PONV) in Laparoscopic surgeries Name : Age: Sex I.P. no. Weight Surgery ASA grade. Premedication - Tab Diazepam 10mg H.S Inj. Atropin 0.6mg IM 1 Hr Before surgery Inj. Pethidine 0.5mg /kg IM Pre – operative Vital Signs - PR BP Type of Anaesthesia - GA with IPPV Time of Injection of study drug Just after Induction Inj. Ondansetron 4mg Inj. Ondansetron 4mg + Dexamethasone 8mg Intraoperative Monitoring Time (min)

PR (BPM)

S BP DBP SpO2(%)

ETCO2(mmHg)

Infl.Pr. (mmHg)

TCO2(L)

0 5 15 30 45 60 90 120

84

Duration of Surgery Duration of Anaesthesia Duration of CO2 insufflation Numerical score for Nausea 0 5 10 0 hr > 5 Severe Early 1hr = 5 Moderate 2hr < 5 Mild 3hr Delayed 4hr 24hr Vomiting Score 0 hr > 2 Severe Early 1hr = 2Moderate 2hr < 2 Mild 3hr Delayed 4hr 24hr Numerical Score for pain 0 5 10 0 hr > 5 Severe Early 1hr = 5Moderate 2hr < 5 Mild 3hr Delayed 4hr 24hr Discharge time – 0-1hr/1-2hr/2-3hr/3-4hr Rescue Analgesic needed - Yes/no Rescue Antiemetic needed - Yes/no Any other complications - Headache -Constipation -Flushing of face -Diarrhoea

85

86

INTRODUCTION

The most common and distressing symptoms following surgery and anaesthesia are pain,

nausea and vomiting. Pain causes suffering and draws first attention. Some times nausea

and vomiting maybe more distressing especially after minor and ambulatory surgery,

delaying the hospital discharge.1 But postoperative pain management has received much

more attention in past two decades than post operative nausea and vomiting. Incidence of

post operative nausea and vomiting is still very high inspite of few newer medication in

our armamentum.It is in the range of 20-30%.2 It has been seen that better antiemetic

effects are obtained with the combination of two drugs.

More than one and half century ago John Snow described phenomenon of nausea and

vomiting.3 His was the first extensive description of the phenomenon which was

published in 1948, within 18 months of introduction of anesthesia into Great Britain. He

observed that vomiting was more likely to occur in patients who have “eaten recently”.

In most cases the vomiting lasted only for a few minutes but in some it continued for

hours and even days. He suspected that movement shortly after operation may have

triggered the vomiting. Post operative treatment included WINE (which he considerd

more beneficial than smelling salts!) and Battleys solution of opium. During ether era,

reported incidence of PONV was as high as 75-80%. Seventy five years ago, Flagg4

suggested the PONV may result from causes other than anaesthetics. There are atleast

three kinds of vomiting , the first of which has been attributed to anaesthetics such as

1

ether, the second to reflex responses, and the last to opioids. Subsequent investigation

unfolded a spectrum of non anaesthetics factors in the pathogenesis of PONV.

There has been a general trend towards a decrease in the incidence and intensity of the

problem because of a change in Anaethesia practice from opioid and deep ether

anaesthesia to non opioid or supplemented opioids to lighter and non ether

anaesthesia,use of less emetic anaesthetic agents, improved pre and post operative

medication, refinement of operative techniques and identification of patient predictive

factors. However in spite of these advances, nausea and vomiting still occurs with

unacceptable frequency in association with surgery and anaesthesia. It has been described

as “a big little problem.”5Persistance nausea vomiting can have serious medical

consequences to the patient as well as financial implication in delayed discharge from the

hospital. Now a number of acceptable surgical procedures has increased in the field of

ambulatory anaesthesia, the need to find more effective alternatives to the options

available, has become more urgent. The potential cost saving by performing these

procedures on an ambulatory basis may be neglected by an unanticipated postoperative

admission for intractable nausea. In addition, although intractable nausea is distressing

possibly dehydrating and not easily manageable at home, the expense of a hospital stay is

disproportionate to the actual morbidity of nausea for most healthy outpatients.Thus the

therapy of last resort hospitalization is ultimately unsatisfactory for the patient, the

anaesthesiologist and the surgeon.

2

Even lesser degree of post operative nausea and vomiting are often perceived as failure of

therapy, rather than as an unavoidable consequences of the perioperative experience. In

most instances the later is in fact the case because of imperfect treatment options

available till date. When queried about previous anesthetic experiences many patients are

heard to lament about the distressing nausea after a prior procedure and begged to be

spared of that experience again6. During preoperative evaluation for subsequent

anesthetics such patients are often assured that the latest avaliable antiemetic medications

will be administered and that a nausea sparing anesthetic technique will be used.

However anesthesia provider cannot be sure that such a goal will be realized with the

antiemetic treatment alternatives now available.5 Previous pharmacological efforts to

diminish the incidence or reduce the risk of emesis have included administering

antihistaminics, anticholinergics, and dopamine antagonists. Physical maneuvers have

included imposing various “Nothing per os”5 regimens, preanaesthetic suctioning of

gastric contents, application of cricoid pressure, avoiding inflation of the stomach during

ventilation by mask and ingestion of antacid solutions. None of the above, alone or in

combination have been entirely successful in mitigating the distressing occurance of

emesis and its potential sequele.

Dexamethasone was first reported to be an effective antiemetic agent in patients

undergoing cancer chemotherapy in 19817. Since then randomized, placebo controlled

studies have shown that dexamethasone and other steroids are significantly better than

3

other agents (metoclopramide, prochlorperazine, droperidol, domperidone) in preventing

nausea and vomiting associated with chemotherapy.

The relative ineffectiveness and associated adverse effects of traditional antiemetic

agents led to a search of a newer and better antiemetic agent. A potential new entry into

the antiemetic pharmacopia in the year 1991 is ondansetron8, of the class of selective 5

hydroxytryptamine subtype 3 (5HT3) receptor antagonists which lack effects on

cholinergic adrenergic, dopaminergic or histaminergic receptors. Ondansetron is

structurally related to serotonine. 5HT3 receptors are located both peripherally (Vagal

nerve terminals)and centrally (Chemorecepter trigger zone). The antiematic property of

ondansetron maybe mediated peripherally, centrally or both. Ondansetron has little effect

on lower esophageal sphincter pressure, esophageal or gastric motility, or small bowel

transit time. By 5HT3 selectivity, the undersirable side effects of using antagonists of

dopaminergic, cholinergic or histaminergic receptors as antiemetic agents, such as

dysphoria, sedation and extrapyramidal symptoms, are avoided. It has been proved to be

extremely effective antiemetic in the group of patient receiving cytotoxic chemotherapy

with no significant side effects. The use of ondansetron has now become extended to the

management of PONV routinely. Extensive trails using oral and intravenous ondansetron

in various types of patients posted for various surgeries have confirmed the efficacy of

the drug with a less side effect profile. This has become the gold standard now against

which any future antiemetic drug must be judged.Since etiology of emesis is

4

multifactorial, optimal antiemetic effects are obtained with 5HT3 antagonist in

combination with steroids2

Dexamethasone has been reported to be effective in reducing PONV in combination with

ondansetron. A single dose of dexamethasone (4-8mgIV) is effective for PONV

prophylaxis (but not treatment) particularly when it is combined with other antiemetics.

There is no evidence that a single antiemetic at any dose can achieve more than 60-70%

prevention of nausea and vomiting.2 Therefore various combination of drugs are on trial

to get an optimal result. There are many causes of PONV and so antagonising only one

type of recepter is not sufficient in many patients.It is logical to give drugs which have

different mechanism of action. New evidence suggests that combination of antemetics

can act synergistically, even in pediatric cases9,10.

Nausea : is defined as subjectively unpleasant sensation associated with awareness of the

urge to vomit.It is usually felt in the back of throat and epigastrium and is accompained

by loss of gastric tone, duodenal contraction and reflex of the intestinal contents into the

stomach.

Retching : is defined as laboured, spasmodic, rhythmic contraction of the respiratory

muscle including the diaphragm, chest wall and abdominal wall muscle without the

expulsion of the gastric contents.

5

Vomiting or emesis: is the forceful expulsion of gastric contents from the mouth and is

brought about by the powerful sustained contraction of the abdominal muscles, descent in

the diaphragm and opening of the gastric cardia.

6

7

AIM OF THE STUDY/ OBJECTIVES

Incidence of post operative nausea and vomiting is high in patients undergoing

laproscopic surgeries under general anesthesia. Many drugs has been used to prevent

nausea and vomiting either alone or in different combinations. The aim of this study is to

compare the efficacy of combination of ondansetron and dexamethasone with

ondansetron alone in preventing PONV in laparoscopic surgeries under general

anesthesia,with respect to

Early vomiting

Delayed vomiting

Requirement of rescue antiemetic

Pain

Side effects

Discharge time

7

PHYSIOLOGY OF EMESIS

Nausea and vomiting are important defence mechanism of body against the ingesion

of toxins but exact mechanism of Nausea and vomiting are not known though the

problem exists for more than 150 years. This is a multifactorial and so very complex

process. Following factors explain why exact mechanism is difficult to elicit1.

Complexity of the problem - The variables are so many that it becomes

difficult to identify the mechanism to assess the effects of an intervention, as it

requires a considerable number of patients in well controlled trails.

Inadequate quantification of the phenomena - Through there have been a huge

number of clinical trails, the phenomena has been poorly quantified i.e. nausea,

retching, vomiting etc.

Inadequate anti emetic regimen - Although emesis is a common symptom of

disease, a side effect of many therapies (eg., cytotoxic chemotherapy, radiotherapy,

L-dopa) and a result of natural stimuli (e.g., motion sickness, pregnancy), the

physiology of the emetic mechanism has not been an area of particularly intense

research. If 5HT3 receptor antagonists are found as effective against PONV as

against anti-cancer therapy then this may help to identify the predominant

mechanisms involved.

Animal model – a lack of animal model to study the physiology and

pharmacology of the mechanism of PONV. Many species of rat and rabbit do not

vomit irrespective of stimulus. Though, monkeys and dogs respond to the same

range of emetic stimuli as man with cytotoxic drugs and radiation, they do not suffer

from pregnancy, motion sickness and post anesthetic emesis.

8

Three major components comprising the vomiting reflex have been identified3

I. Emetic detectors

II. Integrative mechanism

III. Motor output.

I. EMETIC DETECTORS

Abdominal visceral afferent - it forms the defence mechanism to ingested toxins. In

fact it represent second line of defence, first being vision, taste and smell. The vagus

is the major nerve involved in the detection of emetic stimuli. It contains 80-90 %

afferent fibers. Electrical stimulation of these can cause emesis within 20 seconds.

These can be divided into two types of receptors: -

Mechanoreceptors – They are located in the muscular wall of the gut and are

activated by both contraction and distension of the gut. Distension of the gastric

antrum (over eating) or proximal small intestine (obstruction) may induce emesis

through these receptors.

Chemo receptors – They are located in the mucosa of the upper gut. They

monitor several factors of the intraluminal environment. They respond to mucosal

stroking, acid, alkali, hypertonic solutions, temperature and irritants like Copper

Sulphate (CuSO4). The vomiting induced by the irritants are reduced or abolished

by vagotomy. It is seen that vomiting induced by intraluminal bacterial toxins such

as staphylococcal enterotoxin, can be abolished by vagotomy.

9

Area Postrema2,13 – This is a ‘v’ shaped, a few millimeter long structure located in

the caudal part of the 4th ventricle in the region of obex. It is one of the

circumventricular organs of the brain and is outside the BBB and the CSF fluid

barrier. It is therefore relatively permeable to polar molecules in the blood or CSF,

which makes it ideally suited for a general chemoreceptor function.

Wang and Borison3 demonstrated that several stimuli were detected by the cells of the

Area Postrema, termed as the chemoreceptor trigger zone for emesis, which in turn

activate the vomiting center. The Area Postrema is a highly vascularised area and the

vessels terminate in fenestrated capillaries surrounded by large perivascular spaces.

No effective BBB exists in these areas and thus CTZ can be activated by chemical

stimuli received through fluid as well as CSF. Area Postrema is present in animals

with or without emetic reflexes, which suggest that it has function other than emesis.

The Area Postrema of the brain is rich in dopamine, opioid, serotonin and 5HT

receptors. The nuclear tractus solitarius is rich in enkephalines and in histaminic and

muscarinic ,cholinegic receptors. These receptors may play an important role in the

transmission of impulses to the emetic centre. It has been speculated that blockade of

these receptors is an important mechanism of action of the currently used antiemetic

drugs.

10

Areas of the brain associated with nausea and vomiting

11

The chemoreceptor trigger zone and the emetic center withthe agonist and antagonist sites of action of variousanesthetic-related agents and stimuli.

12

Vestibular System – The vestibular labyrinthine system is essential for induction of

emesis by motion stimuli. Sudden movement of head should be avoided to minimize

any labyrinthine input to the vomiting center, particularly in patients who have been

relatively immobile for some time in recumbent posture. The labyrinthine input

should be borne in mind when moving patients in trolleys after surgery, as it may

induce emesis.

Higher influences: Inputs from limbic system can induce Nausea and Vomiting.

Emetic centre is also affected by visual centre and vestibular portion of eighth cranial

nerve.

Miscellaneous inputs: Nausea and Vomiting can be activated from several other

regions of the body. Unpleasant taste can induce nausea and retching. Stimulation of

pharyngeal afferents (via glossopharygeal nerve) and stimulation of tympanum (via

auricular branch of vagus also called Arnold’s nerve and Alderman’s nerve).

Ventricular cardiac afferents may induce Nausea &Vomiting as in association with

myocardial infarction.

II. Integrative Mechanism :

In organizing the vomiting reflex, motor components are mediated by both autonomic

and somatic nerves. All the motor pathways have non-emetic functions, e.g., the vagal

non-adrenergic, non-cholinergic innervations of the stomach mediates gastric

13

relaxation for the storage of food and the phrenic nerve contracts the diaphragm for

inspiration. It is a motor programme involving co-ordination between many

physiological systems and autonomic and somatic components of the nervous system.

These occur in brain stem. Degree of co-ordination is such that retrograde giant

contraction in the small intestine is not initiated until the proximal stomach has

relaxed and retching does not start until the giant contraction has reached the stomach.

The term vomiting centre has been used widely to describe the central emetic co-

coordinating mechanism. Vagal motor neurons supplying the gut and heart originate

in the dorsal motor vagal nucleus and nucleus ambiguous. The outputs of these are

coordinated mainly by the nucleus tractus solitarius with a smaller contribution by

parvicellular reticular formation.

III. Motor Outputs:

We can divide this or vomiting reflex into 3 phases-

Pre ejaculation phase –This phase is characterized by the sensation of nausea.

It is also called prodromal phase. There are cold sweating, cutaneous

vasoconstriction, pupillary dilatation (sympathetic nerve), salivation

(Parasympathetic nerve), tachycardia and reduction of gastric secretion.

Immediately before the onset of the ejaculation phase there is profound relaxation of

the proximal stomach mediated by vagal efferent nerves activating post ganglionic

neurones in the stomach wall. A retrograde giant contraction originates in the mid

small intestine and travels towards the stomach. The gastric relaxation serving to

confine orally ingested toxin to the stomach and the retrograde giant contraction

14

returning any contaminated gastric contents to the stomach ready for ejection. The

pre ejection phase is usually, but not invariably followed by the ejection phase.

Ejection phase: this phase comprises retching and vomiting with oral

expulsion of gut contents only occurring during vomiting. Both retching and

vomiting involve contraction of the somatic muscles of the abdomen and

diaphragm. During retching the abdominal muscles and the entire diaphragm

contract synchronously whereas during vomiting the periesophageal diaphragm

relaxes, presumably to facilitate passage of gastric contents into the oesophagus and

hence to outside. Thus the actual expulsion of gastric contents is caused by

compression of stomach by the descending diaphragm and the contracting

abdominal muscle under the influence of somatic motor neurons. During retching

and vomiting all animals adopt a characteristic posture presumably to optimize

compression of the stomach by the somatic muscle and to minimize strain on

muscle group and structures not involved in vomiting.

Sequence of events during vomiting is:

• Deep breath.

• Raising of the hyoid bone and the larynx to pull the cricoesophageal sphincter

to open.

• Closing of the glottis.

15

• Lifting of the soft palate to close the posterior nares. Then comes strong

downward contraction of the diaphragm along with simultaneous contraction

of the abdominal muscles.

Post ejection phase: consists of autonomic and visceral responses that return

the body to a quiescent phase, with or without residual nausea.

Consequences of Nausea and vomiting3

Effect of Nausea and Vomiting is not very simple. Sometimes it may be detrimental:

Physical consequences: retching and vomiting are fairly violent and intense

physical acts. It can even lead to esophageal tears, possibly resulting in hemorrhage

(Mallory-Weiss syndrome) and rupture of the esophagus, rib fracture, gastric

herniation, muscular strain and fatigue and rupture of cutaneous vessel in the upper

body. Vomiting may also cause wound dehiscence, intraocular bleeding and

bleeding of skin flaps, in the upper body after plastic surgery. Aspiration of vomitus

is another important problem in postoperative period. Increase in Intraocular and

Intracranial pressure can lead to complication in vulnerable group of patients.

Metabolic: Metabolic effects tend to occur when there is prolonged vomiting

and are unlikely to be a problem in PONV as it is usually of short duration but it can

lead to anorexia, dehydration, alkalaemia and electrolyte imbalance.

16

Psychological: Nausea is a very aversive stimulus. Psychological impact of

nausea and vomiting associated with anticancer chemotherapy and radiotherapy has

long been recognized. PONV is 3 times greater in patients who had previous

experience of PONV. This suggests that the sensitivity of the emetic reflux may be

altered by higher inputs, although the pathways involved are not defined. It suggests

that the sensitivity of an individual to particular emetic stimuli is contributed to by

their previous emetic history. This may account for the increased incidence of

nausea and vomiting after surgery, anticancer therapy with cytotoxic drugs and

pregnancy, in patients who are sensitive to motion stimuli.

Economical: These can lead to an unanticipated admission in day care surgery

leading to increase in cost. Long recovery room stay and extra cost of nursing care

is also added to overall cost.

FACTORS ASSOCIATED WITH POST OPERATIVE EMESIS

1. Non anesthetic related factors:

a. Patient related features :

Age – Incidents of emesis is higher in pediatric patients than in adults, it

increases with age to reach a peak incidence in the pre adolescent 11-14 year age

group.

17

Gender – frequency of emesis is more in female after puberty and before 60

years of age. It may be due to hormone-mediated factors.

Phase of menstrual cycle14: Emesis is highest if surgery is performed during

menses with highest incidence occurring on the 4th and 5th days of the menstrual

cycle.

Obesity – there is positive co-relation between body weight and postoperative

emesis. Adipose tissue act as a reservoir for inhaled anesthetic agents from which

they continue into the blood stream, even after their administration has been

discontinued.

History of motion sickness and previous Post Operative emesis: They have a

low threshold for vomiting and therefore associated with high incidence of PONV.

Anxiety – Preoperative anxiety, release of catecholamine can induce vomiting.

Excessive aerophagy can also be another cause.

Gastro paresis – Patients with delayed gastric emptying secondary to an

underlying disease (G.I. obstruction, chronic cholecystitis, neuromuscular disorder,

intrinsic neuropathies) may be at increased risk for emesis after surgery.

b. Operative procedures :

Emesis depends on types of operative procedures like-

OPTHALMIC SURGERY: Ocular, surgery is associated with a higher

incidence of PONV,it is higher with squint surgery than with non-squint ocular and

orbital surgery. Manipulation of and trauma to the squint corrected eye triggers the

oculoemetic reflex. The afferent pathway of this reflex has not been investigated.

18

Trigeminal afferents may be activated (as in oculocardiac reflex). In retinal

detachment surgery, there is increased incidence of emesis.

• EAR, NOSE AND THROAT SURGERY: Middle ear surgeries (activation of

vestibular afferent pathways or auricular branch of vagus nerve/Arnold’s nerve

supplying tympanum) are associated with a higher incidence of emesis.

Paediatric tonsillectomy is associated with up to 81% of vomiting (by mechanical

activation of glassopharyngeal afferents projecting into brain stem). The incidence

is higher when an orotracheal tube is used than when a nasotracheal tube is used,

probably because of the angle of impaction of tubes.

Emesis following nasal surgeries is secondary to pain or by stimulation (by

swallowed blood) of the gastric afferents or pharyngeal afferents.

• ABDOMINAL SURGERY: Intraabdominal surgeries are more emetic than

extra abdominal surgeries. Manipulations of gut results in vagal and splanchnic

afferent discharge. Kidney, bladder and uterine handling also activate these

afferents. Release of 5HT following manipulation of intestines cause direct

activation of afferents.

• GYNAECOLOGICAL SURGERY: Women are more sensitive to virtually all

emetic stimuli. Hormonal status maybe one of the chief factors. Relation of sex,

menstrual cycle to emesis is well known. Incidence of emesis is higher when

cervical dilatation and curettage is done than when curettage alone is performed.

Incidence is also reported to be higher when vagina packed in gynaecological

surgeries. Afferents are carried in hypogastric nerve and pelvic nerve from uterus,

19

broad ligament and vaginal cervix. They are sensitive to gentle probing and rubbing

in this region, to surgical manipulation, ischemic stimuli, Bradykinin and 5HT.

Other surgical procedures such as extra corporeal shockwave lithotripsy,

orchidopexy in children are associated with higher incidence of PONV.

c. Duration of surgery: The operative time also has an effect on the incidence of

postoperative emesis. During longer operations the patients may receive a large

number of potentially emetic anesthetic drugs. Therefore more frequent emesis has

been reported after longer operations.

II Anaesthetic related factors :

Pre operative fasting: Induction of anesthesia within 4-6 hrs of intake of food

is associated with higher incidence of PONV. It also depends on type of food,

concurrent drug effects, sympathetic stimulation, disease states etc.

Pre anesthetic medication : Atropine at dose of 0.6 mg I.M can delay gastric

emptying and hence contribute to PONV.

Analgesics: Opioids (morphine, pethidine, fentanyl) by an action on ‘mu’ receptor

in area postrema can induce emesis. In addition, morphine and pethidine can reduce

gastric emptying; increase sensitivity of emetic reflex to activation of labyrinthine.

Stimulation (PONV is increased in ambulatory patients given opioids) increases

release of 5HT from small intestine.

Intragastric tubes: - Passage of tubes and decompression of stomach is

associated with a lesser incidence of PONV. Continuous stimulation by a

nasogastric tube of nasopharynx may however cause persistence of nausea.

20

Gastric distension and suctioning : -Gastric distension from vigorous positive

pressure ventilation via a face mask will predispose a patient to vomiting in the Post

Operative period. This has been contributed to the increased incidence of emesis in

patients anaesthetized by less experienced trainees. However, gastric suctioning has

variable results in reducing emesis.

Anaesthetic techniques:

GENERAL ANAESTHESIA : the pharmacological and physical properties of general

anesthetics contribute to higher incidence of PONV.

EFFECT OF GENERAL ANAESTHESIA:

• Endocrine effects: release of peptide hormones (Angiotensin II, gastrin,

insulin etc.) can induce emesis via area postrema.

• Cardiovascular effects: Hypotension during anesthesia may induce large

sympathetic discharge (adrenaline) from adrenal medulla, which may then trigger

emesis by action on area postrema. Myocardial ischemia and tachycardia with

hypovolemia may activate vagal afferent mechanoreceptors in ventricles of heart

and induce nausea and vomiting.

• Gastro-intestinal effects of anesthetics: Inhalational agents in general produce

a reduction in lower oesophageal sphincter pressure and suppress gastro-intestinal

motility by vagal mechanisms centrally, including area postrema. There may also be

reduction in mesenteric perfusion, causing local release of agents like 5HT,

substance P, prostaglandines, etc. The 5HT may also be released by opioids,

adrenaline, mechanical stimulation of gut and initiate emesis.

21

• Effects on intra cranial pressure: Halothane, enflurane, isoflurane and

ketamine increase ICP whereas barbiturates lower the ICP. Rise in ICP may cause

headache, nausea, vomiting, and inhibition of gastric motility.

ANAESTHETIC FACTORS

Intubations: Stimulation of pharyngeal mechanoreceptor afferents leads to

emesis.

Anaesthetist15: Increased incidence of PONV was observed when an

inexperienced anaesthetist cause gastric inflation during mask ventilation.

Anaesthesia: A recumbent immobile patient on recovery may try to sit up or

move his head, stimulating a sudden vestibular discharge inducing nausea and

vomiting.

Anaesthetic drugs16: Opioids induces PONV the most. Induction agents like

Etomidate and Methohexital causes higher rate of PONV than Thiopentone and

Ketamine. Propofol is associated with a lower incidence of PONV compared to

Thiopentone.

Inhalational agents: Incidence of PONV is more with inhalation agents as

compared to intravenous agents. Use of Ether and Cyclopropane is associated with

high incidence of PONV compared to Halothane and Methoxyflurane as there is

increase circulating in circulating catecholamine. Alpha1 and Alpha2 receptor in

area postrema are involved in emesis. Anaesthetics may also suppress the antiemetic

centers and modulate release of neuro transmitters (5HT) at brain stem sites.

22

Sevoflurane, Enflurane, Desflurane are associated with less degree of

PONV.Nitrous Oxide has a significant role in PONV. The proposed mechanism for

induced emesis is its action on central opioid receptors. Changes in middle ear

pressure are less important. Secondary effect of Nitrous Oxide in distending the gut

may further stimulate the afferent receptors (gut volume can increase by 500 ml. /

hour with 75% of alvelor nitrous oxide concentration).

Neuro Muscular blocking agents: These do not contribute

significantly to PONV. Use of neostigmine as reversal agent is associated with a

higher incidence of PONV because of increased gastric motility stimulating vagal

afferent and direct activation of central cholinergic pathways via area postrema.

Balanced anaesthesia: Compared to the use of inhalation agents

or total intravenous anaesthesia (TIVA) the use of Nitrous Oxide-

opioid-relaxant technique is associated with a higher incidence of post

operative emesis.

Regional anesthesia17:

Emesis with central neuroaxial block is lower than general anesthesia but greater than

that of peripheral neural blocks because of associated sympathetic nervous system

blockade, which contributes to postural hypotension induced nausea and vomiting.

Epidural techniques are associated with excellent pain relief, but nausea and vomiting

and pruritus are frequent side effects.

23

Over all incidence of PONV with spinal anaesthesia is in the range of 13% to 42%.

Use of Procaine in addition phenylephrine or adrenaline are associated with higher

incidence of nausea.

Monitored anesthesia care18:

Many procedures can be performed using only local anesthetics and intravenous

sedation-analgesia techniques (e.g., cosmetic plastic surgery, cataract extractions,

breast biopsies, endoscopy, central line or vascular shunt placement). However, the

avoidance of general, spinal, and epidural anesthesia does not guarantee the absence

of emesis in the postoperative period. The incidence of emesis varies with the type of

operation and the sedative-analgesic medications. For example, antiemetic therapy

was required in 4-11% of patients undergoing extracorporeal shock-wave lithotripsy

with a sedative-analgesic infusion regimen. The incidence of nausea in these patients

was not significantly altered, regardless of whether one used a midazolam-alfentanil,

fentanyl-propofol or midazolam-ketamine technique. It would appear that emesis in

these patients is related to the extra corporeal shock-wave lithotripsy procedure and

not to the sedative-analgesic technique per se.

III Postoperative factor18:

Typically PONV last less than 24 hrs. more intense during first 4 hrs. Retching and

vomiting subside before the sensation of nausea. The postoperative factors involved in

triggering PONV are:

24

Drugs and anaesthetics: Peri-operative use of opioid can continue to have

emetogenic effect post operatively.

Rate of recovery also effects incidence of PONV as sedation itself suppresses the

emetic reflex. Hence, if recovery is rapid, emetic factors become dominant.

Pain: pain is often associated with nausea and may be followed by vomiting.

The mechanism of this nociceptor induced nausea is not clear. There may be effect on

central organizing mechanism, may be a reduction in threshold to emesis, tissue

trauma may release histamine, 5HT etc., both centrally and peripherally.

Dizziness: PONV is more in patients who feel dizzy. Postural hypotension in

postoperative period after a central neuraxis block may be an early sign of mild

unrecognized hypovolemia. When these patients try to stand up, they may feel dizzy

and nauseated. Perhaps as a result of decreased medullary blood flow to CTZ.

Elevated vagal tone in the postoperative period may exacerbate the dizziness and

nausea in these patients.

Ambulation: Sudden motion, change in position or even transport from post

operative recovery unit to the post surgical ward can precipitate nausea and vomiting

in patients who have received opioid compounds. The opioids sensitize the vestibular

system to motion induced nausea and vomiting. Afferent impulses from the vestibular

apparatus to CTZ may be responsible for emesis following ambulation in the post

operative period.

Prolonged disruption of gut function: Gut function is reduced specially after

abdominal surgery and delayed gastric emptying is the major factor contributing to

PONV.

25

Oral intake: The timing of oral intake after surgery can influence the incidence

of emesis in the postoperative period.

26

Pharmacological view of emetic stimuli

27

Prevention and treatment of Post Operative emesis

I. Pharmacological approach18

The vomiting center sends motor output from the dorsal nucleus of the vagus and

nucleus ambiguous to initiate the act of vomiting. Although this output is considered

the final common pathway of the emetic response, there is no single drug that can

block the pathway and thus serve as a universally effective antiemetic agent. The

vomiting center receives separate input from different types of receptors. Antagonism

of any one signal may alleviate emesis associated with the stimulation of that

receptor. However, no currently available drug will antagonize all receptor sites

involved in the emetic response.

Four major neurotransmitter systems appear to play important roles in mediating the

emetic response: dopaminergic, histaminic (H1), cholinergic ,muscarinic, and 5HT3.

As there are four different types of receptors, there are at least four sites of action of

the antiemetic drugs. Antiemetic agents may have actions at more than one receptor,

but they tend to have a more prominent action at one or two receptors. Hence, a

combination of drugs will probably have greater antiemetic action than a single drug.

Finally, sedation itself may also play a role of preventing vomiting.

28

II. Non pharmacological approach18

Non pharmacological techniques (eg., acupuncture and acupressure) have also been

evaluated for the prevention of post operative emesis with varying degrees of success.

Dundee et al. studied women undergoing minor

gynaecologic procedures after receiving an opioid and analgesic for pre anesthetic

medication. These investigators found the manual stimulation of the p-6 acupuncture

point (Neiguan) by a needle resulted in a significant reduction in postoperative

emesis. Similar results were obtained when low frequency electrical stimulation of the

p-6 point was performed. It is interesting that higher frequency electric stimulation

had no anti emetic activity. The efficacy of p-6 acupuncture as an antiemetic in

patients receiving chemotherapy is limited to approximately 6 hours. Application of

pressure every two hours to this acupuncture point was reported to produce an

antiemetic action for up to 24 hours. A commercially available elastic wristband with

plastic stud (Sea Band) was alleged to be an effective method of applying pressure to

the p-6 point and may possess some antiemetic activity. The future role of

acupuncture and acupressure in the prevention of postoperative vomiting is unclear.

29

REVIEW OF LITERATURE

The problem of Post Operative Nausea and Vomiting is more than 150 years old, but it

is always thought to be less of a problem. Before any specific antiemetic drugs became

available , various technique including olive oil and insulin glucose infusion were

reported to be effective in reducing incidence of Post Operative Nausea and Vomiting.

Robert Ferguson25 described the use of olive oil in 1912. The oil was administered by

mouth immediately after partial restoration of consciousness and he postulated that oil in

the stomach absorbed any ether that might be there. But effect of Atropine was

appreciated by Brown – Sequard as early as 1883 when he discovered that addition of

atropine to morphine prevents nausea and vomiting.

Recently , the 5HT3 antagonists such as Ondansetron have been proved effective in the

management of Post Operative Nausea and Vomiting and also in emesis induced by

cancer chemotherapy 7. These drugs act by being highly selective and potent antagonism

of 5HT3 receptor in the brain (Area postrema and nucleus tractus solitarius) and

peripherally in the gastrointestinal tract. Dexamethasone was first reported to be an

effective antiemetic agent in patients undergoing cancer chemotherapy in 1981.

30

Since then studies have shown that dexamethasone and other steroids are significantly

better than other agents. The mechanism of dexamethasone induced antiemetic activity is

not fully understood, but may involve central inhibition of prostaglandin synthesis.

Enhanced effect of combination of Ondansetron and Dexamethasone were shown in a

study done by Rajeva etal26, on patients undergoing diagnostic gynecological laparoscopy.

Two groups of patients who were comparable regarding age, weight, last

menstrual period (LMP), duration of procedure, were given only Ondansetron and

combination of Ondansetron and Dexamethasone . Nausea and pain were measured using

numerical analogue scale and vomiting were measured as mild, moderate and severe .

Overall incidence of nausea and vomiting were found to be lower in combination group.

Though pain score and discharge time were same in both the groups.

The combination therapy is most effective is also confirmed in day care surgical cases

done by Lopez et al,27. In this study incidence of background factors , factors related to

operations and anesthesia which can modify Post Operative Nausea and Vomiting were

similar in all the groups. The combination was proved useful in daycare cases because of

the absence of side effects and sedation. They also confirmed that Dexamethasone is

more cost effective than Ondansetron.

31

In a quantitative systemic review28 done on 1946 patients , it was concluded that best

prophylaxis of post operative nausea and vomiting currently available is achieved by

combining Dexamethasone with a 5HT3 receptor antagonist. Dexamethasone showed

antiemetic efficacy alone also, but there was evidence of synergistic effect when

dexamethsone was added to a 5HT3 receptor antagonist. Adverse effects were rarely

reported.

Prophylactic antiemetic effects of intravenous dexamethasone was evaluated in women

undergoing ambulatory laparoscopic tubal ligation29. 90 selected patients were randomly

allocated to receive either dexamethasone or saline as placebo. 34 percent of the patients

receiving dexamethasone reported nausea and vomiting within 24 hours compared to 73

percent of patients receiving saline. The aetiology of Post Operative Nausea and

Vomiting in patients undergoing laparoscopic tubal ligation is not fully understood. Risk

factors are residual Pneumoperitonium , intraoperative use of opoids, postoperative pain

and phase of menstrual cycle. All the factors were controlled in the study , therefore it is

likely that the difference in the incidence of Post Operative Nausea and vomiting

between groups are due to dexamethasone rather than any other variable . Therefore, it

can be safely concluded that pretreatment with dexamethasone reduces the incidence of

Post Operative Nausea and Vomiting significantly.

32

Ondansetron and Dexamethasone combination is superior for prevention of Post

Operative Nausea and Vomiting than each drug alone30. In a randomized trial of 177

women undergoing day care gynaecological surgeries, they concluded that failure of

prophylaxis was more frequent in patients who received dexamethasone alone. They also

found that Ondansetron and dexamethasone performed similarly , despite price difference

between these two drugs. Therefore use of dexamethasone is cost effective.

A study was conducted to determine the minimum effective dose of dexamethasone in

combination with ondansetron for prevention of Post Operative Nausea and Vomiting in

patients undergoing laparoscopic cholecystectomy31. 180 patients were allocated

randomly to different groups to receive either saline as placebo or ondansetron or the

combination of ondansetron and dexamethasone in different strengths. They were

evaluated for pain, nausea and vomiting, time to first demand of analgesia, total analgesic

consumption, duration of hospital stay and other side effects at different time intervals.

They concluded that dexamethasone 8 mg represents the most effective dose for

combination therapy along with 4mg Ondansetron. Dexamethasone has been shown to

decrease postoperative pain due to its strong anti- inflammatory action.

33

Antiemetic effect of dexamethasone was evaluated in women undergoing gynaecological

laparoscopy32. Effect of dexamethasone were compared with placebo (saline) for

prevention of nausea and vomiting. The episodes of nausea and vomiting were identified

by direct enquiry or when complaints were made by patients. The complete response for

patient with a history of motion sickness was 80.5% and 37.5% for dexamthasone and

saline respectively. It was also shown that dexamethasone was 45.3% more effective in

patients with motion sickness than in those without it. They concluded that

dexamethasone appear to be a cost-effective choice for the prevention of Post Operative

Nausea and Vomiting in patients with a history of motion sickness.

34

Ondansetron (hydrochloride)21,22

Ondansetron is a selective 5-hydroxytryptamine (5-HT3) receptor antagonist used in

the treatment of nausea and vomiting related to cancer chemotherapy and

radiotherapy, postoperative nausea and vomiting.

Structural formula and Chemistry:

C18H19N3O.HCl.2H2O

Molecular Weight (free base): 365.8(293.4)

pKa : 7.4

It is white to off white solid preparation by chemical synthesis. It is not present in any

compound preparations.

Pharmacology:

The 5-HT3 receptor belongs to the class of ligandgated ion channels.

Ondansetron is a highly selective 5-HT3 receptor antagonist, which inhibits nausea

and vomiting caused by cytotoxic agents and radiation. Its action is believed to be

35

mediated via antagonism of 5-hydroxytryptamine receptors located in the

chemoreceptor trigger zone in the area postrema of the brain and possibly on vagal

afferents in the upper gastrointestinal tract. Ondansetron also causes an increase in the

rate of gastric emptying. Ondansetron has no effect on normal behavior patterns in

animals even at high dosage. Ondansetron has a class III antiarrhythmic action.

Toxicology:

Serum transaminases rose by less than 50% in some rodents, but no long term liver

damage was seen. Small increases in aspartate aminotransferase and alanine

aminotransferase was also seen. No significant cardiovascular effects in the

anesthetized cat or the conscious dog or monkey. No teratogenic reproductive or

oncogenic effects have been identified.

Clinical pharmacology :

In normal subjects, ondansetron is well tolerated and mild symptoms such as

headache, abdominal pain and constipation occur infrequently. No effect was

demonstrable on the electrocardiogram, cardiac output, blood pressure and heart rate.

Ondansetron is an effective antiemetic in patients receiving chemotherapy and

radiotherapy and has been particularly useful in the control of vomiting in patients

receiving cisplatin.aHowever the gastric emptying rate appears to be increased only

when the basal rate of gastric emptying is slow. Constipation may therefore follow

the use of ondansetron. Ondansetron is not effective in the treatment of motion

sickness, compared to a standard therapy such as scopolamine. The commonest effect

is a mild headache, and dystonic reactions are much less likely than with agents such

as metoclopramide.

36

Pharmacokinetics:

High performance liquid chromatography after solid phase extraction is the method of

choice for determining the plasma concentration of ondansetron. Following oral

administration ondansetron is rapidly absorbed with a lag of approximately 30min

before absorption is measurable. Maximum concentration is usually achieved after1-

1.5h, a maximum plasma concentration of approximately 30 µgl being achieved after

a single dose of 8 mg. Oral bioavailability in healthy volunteers has been reported as

59%. Ondansetron plasma clearance averages 0.45l/h/kg.Intramuscular administration

of 4mg ondansetron in 2 ml aqueous solution achieved a maximum concentration of

24 µg/l after 5-10min. Bioavailability by this route is 87%. Ondansetron is

moderately highly bound (70-76%) to plasma proteins. It is rapidly distributed

throughout the body with a volume of distribution of 16.3 + 25.1. Ondansetron is

rapidly cleared from the body almost entirely by metabolism with less than 10% of an

intravenous dose being recovered unchanged in the urine. The main metabolites are

conjugates of 7-hydroxy or 8-hydroxyondansetron which appears to have little or no

pharmacological activity. In children the pharmacokinetics are similar to those in

adults when adjusted on a weight basis. The extent to which ondansetron is excreted

in breast milk or crosses the placenta is not known.

37

Metabolism

Onset of action (IV) – less than 30 minutes

Peak effect (IV) - Variable

Duration of action – ( IV) – 12-24 hour

The oral absorption of ondansetron is rapid. The renal clearance of the drug is

low, indicating that the major route of systemic clearance is by metabolism.It

is extensively metabolized in liver. The major route of metabolism is

glucuronide or sulfate conjugation. N-demethylation is a minor route of

metabolism. Less than 10% of the drug is excreted unchanged in urine.

Formulation:

Ondansetron is available as oral, intramuscular and intravenous preparations.

Oral Forms :

Tablets: Contain ondansetron hydrochloride equivalent to 4 mg or 8mg

ondansetron.

Parentral forms :

Injection: an aqueous solution of approximately pH 3.5 containing

ondansetron hydrochloride equivalent to ondansetron 2mg/ml.

Infusions available in multidose vials of 20 ml.

The tablet and injection should be stored between 20C and 300C, protected from light.

Ampoules should not be autoclaved.

38

THERAPEUTIC USE:

1. The control of nausea and vomiting associated with the treatment of cancer by

radiotherapy and chemotherapy.

2. The prevention and treatment of postoperative nausea and vomiting.

For emetogenic chemotherapy and radiotherapy a dose of 8 mg should be

administered intravenously immediately before treatment or 8 mg orally every 1-2h

before treatment followed by 8 mg orally every 12 hour if required. For the prevention of

postoperative nausea and vomiting 8mg ondansetron may be administered orally 1h prior

to anesthesia followed by two more 8mg doses at 8h intervals. Alternatively a single 4mg

intramuscular or intravenous dose at induction of anesthesia is effective. If nausea and

vomiting is established postoperatively a single intravenous/ intramuscular dose of 4mg

ondansetron is recommended.

Adverse reactions:

Headache (Commonest side effect)

Pruritus

Restlessness.

Constipation

Flushing or a sensation of warmth

39

High risk groups :

Neonate - Unlikely to be used in neonates because of its indications.

Children - Ondansetron is safe and effective when used in children at an intravenous

dose of 5mg/m2. The recommended dose for maintenance therapy is 4 mg orally

twice daily for 5 days.

Pregnant women -The safety of the drug in pregnancy has not been established and it

should not be used on pregnant women.

The elderly –Studies showed there is a tendency for plasma half-life to be increased,

5.0h compared with 3.2-3.7h for younger volunteers.

Liver disease - The clearance of ondansetron is significantlyredused and the serum

half life significantly prolonged in moderate to severe hepatic impairment and in such

patients a daily dose of not more than 8mg is recommended.

Drug interactions :

No interactions with other centrally acting drugs (Such as diazepam, alcohol or

morphine) or any interactions with concomitantly prescribed antiemetics have yet

been identified.

Useful interactions: The efficacy of ondansetron may be significantly enhanced by

the addition of a single intravenous dose of dexamethasone sodium phosphate (8-

20mg) prior to chemotherapy.

40

Dexamethasone19,20

Dexamethasone is one of the potent synthetic analogs of cortisol. Though commonly

identified with the standard suppression test of hypothalamic – pituitary – adrenal

function, its main clinical applications are as a steroidal anti-inflammatory agent, for the

prevention and treatment of cerebral edema, in shock and as an antiemetic agent in cancer

chemotherapy and postoperative nausea and vomiting. As a member of the glucocorticoid

family of drugs, its pharmacological and clinical features are represented well by those of

prednisolone.

Structural formula and chemistry

C22H29FO5

(11β, 16α)-9-Fluoro-11, 17, 21-trihydroxy-16-methylpregna-1, 4-diene-3, 20-dione

M olecular weight 392.5

It is white or almost white, odorless crystalline powder.

41

Pharmacology:

Dexamethasone is a highly potent and long-acting glucocorticoid with negligible sodium-

retaining properties. The major pharmacological actions of Dexamethasone can be

divided into three groups-

a. General effects on metabolism, water and electrolyte balance.

b. Negative feedback effect on the hypothalamus and pituitary.

c. Anti-inflammatory and immunosuppressive effect.

The clinical uses of dexamethasone are based mainly on its anti-inflammatory and

immunosuppressive properties and its effect on the HPA axis. Dexamethasone at low

doses (0.5-1 mg) suppresses cortisol secretion except in cases of Cushing’s syndrome,

and is used diagnostically for this purpose. The choice of dexamethasone for the

treatment of chronic inflammatory and autoimmune diseases is, as for other corticoids.

Pharmacokinetics:

The most convenient analytical method for measuring dexamethasone in blood is

radioimmunoassay. Dexamethasone is well absorbed when given orally. Peak plasma

levels are reached between 1 and 2 h after ingestion and show wide individual variations.

The systemic bioavailability of dexamethasone tablets shows wide variation, with a mean

value of 90%. Dexamethasone phosphate is hydrolyzed to dexamethasone in synovial

fluid much faster than Dexamethasone sulphate. The plasma half-life of dexamethasone

is shortened by simultaneous use of other drugs e.g.: rifampicin, phenobarbital, and

42

phenytoin and also possibly in chronic renal failure. Dexamethasone is bound (up to

77%) to plasma proteins mainly albumin.

Metabolism:

Dexamethasone metabolism in the liver is slow and rather limited. In humans, over 60%

of the administered dose is excreted in the urine within 24 h, largely as unconjugated

steroids. Ephedrine was reported to enhance the urinary excretion of dexamethasone.

Changes in the plasma half-life of dexamethasone may result from impairment and

acceleration of its metabolism in liver disease and chronic renal failure respectively.

Formulation -

It is available as parenteral, ophtalmic, topical, inhalational, or nasal preperations.

Oral forms -

Decadron tablets

Decadron elixir .

Parenteral form -

Decadron injection: is a clear, colorless solution of pH 7.0 to 8.5 containing

dexamethasone phosphate 4 mg/ ml. The strength is intended for intravenous,

intramuscular, intra articular or soft tissue injection.

Decadron shock pack injection containing dexamethasone 20mg/ml in 5ml vial,

equivalent to dexamethasone sodium phosphate 25 mg/ml.

. It is also available for parenteral use in combination with lidocaine hydrochloride.

DexamethasoneAcetatesuspension 8mg/ml or 16mg/mlforintraarticular/intramuscular

injection.

43

Other –

Nasal spray delivering 100µg dexamethasone phosphate per spray.

Various ophthalmic or optic preparations is also available.

INDICATIONS

1. Respiratory distress syndrome

2. Shock

3. Raised intracranial pressure

4. Suppression test of HPA axis function

5. Emesis in cancer chemotherapy

6. Post operative nausea and vomiting

Dexamethasone given at 10-30mg intravenous doses, improves the efficacy of antiemetic

drugs such as metoclopramide and diphenylhydramine used as an adjunct to cancer

chemotherapy. Such combination regimens can also lessen other side effects related to

cytotoxic drugs.

Other Uses :

In addition, dexamethasone may be used in most situations indicated for prednisolone

like -

7. Glucocorticoid replacement therapy

8. Diseases of the connective tissue

9. Asthma

10. Diseases of the liver and gastrointestinal tract

11. Renal diseases

12. Ocular diseases

44

13. Blood disorders and malignancies.

CONTRAINDICATIONS

Absolute contraindication –

Ocular herpes simplex

Relative contraindications –

1. Gastrointestinal ulcer

2. Acute or chronic infections

3. Osteoporosis

4. Pregnancy

5. Diabetes mellitus

6. Renal insufficiency

7. Hypertension

8. History of psychotic illness

9. Immediately before prophylactic immunization

Uses:

Primarily governed by its high potency as glucocorticoids.

Orally –0.02mg/kg

As with other corticosteroids, prolonged use of dexamethasone must be embarked upon

with caution, the objective is to gradually reduce the dose as soon as possible under

clinical supervision, either to zero or if essential, to maintenance dose preferably under 2

mg daily.

45

Intravenous dose 0.5 – 20 mg daily

large intravenous doses should be administered slowly to reduce the possibility of

cardiovascular collapse. The total daily intake of dexamethasone should not exceed 80

mg.

Children 0.03 to 0.09 mg/kg-1 body weight twice a day

Adverse reactions:

Patients on prolonged dexamethasone therapy are at risk of collapse or possible

deaths if their daily dose is not increased at times of severe physical stress, for

example injury, surgery or infections. Suppression of the HPA axis may persist for

many months after discontinuation of dexamethasone therapy.

Acute over dosage is unusual.

Growth retardation in children, osteoporosis and aseptic bone necrosis peptic

ulceration, ocular hypertension, subcapsular cataract, pancreatic disturbances and

myopathy.

Raised intraocular pressure, irreversible glaucoma and blindness.

Nocturia

Increased appetite, obesity, facial rounding, fragility of the skin

Nervousness, insomnia and euphoria to serious psychotic episodes.

Hyperglycemia and low renal threshold

Hyperlipidemia

Excretion of uric acid, calcium and phosphate.

46

High risk group

Mothers should avoid breast feeding.

Since dexamethasone is a long acting corticosteroid, growth inhibition may occur

inhildren or adolescents chronically receiving dexamethasone.

The evidence of the safety of use of dexamethasone in human pregnancy and its

possible connection with cleft palate and intrauterine growth retardation is

unclear.

In elderly the benefits of prolonged corticosteroid use have to be balanced against

side effects such as osteoporosis, diabetes, hypertension and loss of immunity.

Drug interaction-

Plasma half life of dexamethasone can be reduced by up to 50% by use of

Phenytoin and Phenobarbital.

Ephedrine enhances dexamethasone clearance from blood and urinary excretion

of its metabolites..

The gastrointestinal absorption and thus the bioavailability, of dexamethasone can

be decreased by concomitant magnesium trisilicate ingestion.

Glucocorticoids may increase the need for salicylates.

47

Materials and Methods Source of data

This study was undertaken at the M. S. Ramaiah Medical Teaching Hospital during the

year 2004-2005.

The study consisted of 50 adult female patients, posted for elective laparoscopic surgeries.

In this randomized , open clinical trial, we studied 50 ASA grade I and II patients of age

group 20-45 years undergoing elective laparoscopic surgeries under general anaesthesia.

Approval was taken from ethical committee and written informed consent was taken

from all patients. They were randomly divided into two groups eg Group A and Group B,

each consisting of 25 patients. Group I received 4mg. of Ondansetron intravenous (IV)

and group II received 4mg. Ondansetron and 8mg. Dexamethasone intravenous(IV),

soon after intubation .

Selection of patients

Inclusion Criteria

1. Patients of ASA grade I and II.

2. Patients between 20 to 45 years of age.

3. Patients weighing between 30 to 70 kgs.

48

Exclusion Criteria

1. Patients belonging to ASA grade III and IV.

2. Patients who are obese.

3. Pregnant women.

4. Patients with history of motion sickness.

5. Patients who have received antiemetic within 24 hrs. of surgery.

6. Patients on chronic steroid therapy.

7. Patients suffering from diabetes mellitus, intestinal obstruction and hiatus

hernia, renal and hepatic diseases.

Methods

Preoperative evaluation

Preoperative visit was conducted on the previous day of surgery. Detailed history

and present complaints were noted. General and systemic examination of cardio

vascular, respiratory and central nervous system were done. Routine laboratory

investigations like haemoglobin level, total count and differential count, routine

urine, blood urea nitrogen and serum creatinine, Bleeding and clotting time , ECG

were done.

49

Preoperative order

Patients were advised to remain nil orally after mid night and all of them received

tablet diazepam 10mg. orally in the night before surgery. Inj. pethidine 0.5mg./kg.

and atropine 0.6mg. intramascular(IM), one hour before surgery . Premedication

was satisfactory.

Anaesthesia

General anaesthesia with Intermittent positive pressure ventilation was given to

all patients.

Preoperative blood pressure and pulse rate were recorded in operation theatre

after connecting to the following monitors :

• Continuous electrocardiogram.

• Sphygmomanometer.

• Pulse oxymetry.

Intravenous cannulation with 18G catheter was established. After 3 minutes of

preoxygenation, anaesthesia was induced with 5mg./kg. thiopentone sodium and

relaxed with vecuronium 0.1mg./kg. and ventilated with O2 + N2O + halothane 1

mac for 3 minutes and then intubated with 7.5 size cuffed endotracheal tube and

ETCO2 monitor was connected. Anaesthesia was maintained with O2 and N2Oat

50:50% with halothane 0.5 mac to maintain HR and BP near preinduction values.

50

Inj. pethidine supplemented as needed. Ventilation was controlled. Muscle

paralysis was reversed at the end of surgery with 0.05 mg./kg. neostigmine and

0.02 mg./kg. atropine. Diclofenac sodium 75mg. Intramascular(IM) was given

before reversal of neuromuscular blockade for post operation pain.

Study drugs were injected Intravenous(IV) over a period of 30 seconds just after

intubation.

Monitoring

Intraoperative HR, BP, ETCO2 were monitored every 5 minutes in first hour and

then every 15 minutes. ECG was monitored continuously for any change of rate

and rhythm.

Duration of surgery and anaesthesia was noted. Patient was observed for 24 hours

post operatively. Nausea , vomiting, pain were recorded hourly for 4 hours and

then at the end of 24 hours. Discharge time from recovery room to ward was also

noted. Any other complications were also noted.

Assessment

The number of episodes of emesis and nausea were recorded. Repeated vomiting

within 1-2 minutes period was recorded as single emesis, the data were taken as

follows:

Nausea was measured using an 11 point visual numerical scale with

0 = No Nausea.

10 = Nausea as bad as can be.

51

A score of > 5 = Severe

5 = moderate

< 5 = minimal

Severe and moderate score were considered major nausea.

Vomiting

> 2 = Severe.

2 = Moderate.

< 2 = Mild.

Rescue antiemetic consisted of 0.15 mg./kg. metoclopramide IV and was given

for more than 2 episodes of vomiting.

Pain was measured on an 11 point visual numerical scale similar to that for

nausea.

> 5 = Severe

5 = moderate

< 5 = mild

Rescue analgesic consisted of 75 mg. diclofenac sodium IM, was given when

pain was more than 5 in the scale.

Discharge criterion from recovery room to ward was done on the basis of

Modified Aldrete Scoring system33.

52

Statistical Analysis

Incidence of nausea , vomiting ,pain, discharge scores , side effects and number

of patients needing rescue antiemetic and analgesic were compared using ‘Chi

Square’ test.

‘p-Value’ of <0.05 was considered significant.

p-Value of >0.05 was considered insignificant.

53

RESULTS AND OBSERVATIONS

DEMOGRAPHIC DATA (TABLE-III)

Fifty patients were randomized into 2 groups A & B of 25 patients each. The mean age

in group A was 28.96 + 5.2 as against 29.92 + 5.21 in group B (Table-I). This was

found to be statistically insignificant. (P>0.05)

The Mean weight of group A was 49.24 + 3.53 as against 49.4 + 3.7 in group B (Table-

II). this was statistically insignificant with a p value of more than 0.05.

DURATION OF SURGERY

The Mean duration of surgery was 62.4 + 27.5 minute in group A as against 63.6 + 28.04

minute in group B(Table -V). p value is insignificant.

TYPE OF SURGERY

In group A, out of total 25 patients, 11 underwent Diagnostic Laparoscopy, 9

Laproscopic Ligation, 3 Laparoscopic Appediectomy, one MTP with laparoscopic

Ligation and one Laparoscopic Cholecystectomy(Table-IV). This was comparable to

group B, where out of total 25 patients 11 underwent Diagnostic Laparoscopy, 7

Laparoscopic Ligation, one Laparoscopic Appendix, and three each MTP with

Laparoscopic Ligation and Laparoscopic Cholecystectomy.

54

TABLE I

Group -A Group B p value Significance AGE (Years) n % n %

20-30 18 72 12 4831-35 5 20 12 4836-40 1 4 1 441-45 1 4 0 0

>0.05 N.S.

AGE DISTRIBUTION

0

10

20

30

40

50

60

70

80

20-30 31-35 36-40 41-45

Group -AGroup -A %Group BGroup B %

PER

CEN

TAG

E

55

TABLE II

Group -A Group B p value Significance WEIGHT (Kgs) n % n %

40-45 7 28 7 2846-50 10 40 12 4850-55 7 28 5 2056-60 1 4 1 4

>0.05 N.S.

WEIGHT DISTRIBUTION

0

10

20

30

40

50

60

40-45 46-50 50-55 56-60

WEIGHT IN (Kgs)

Group -AGroup -A %Group BGroup B %

PER

CEN

TAG

E

56

TABLE III

VARIABLES Gr. A Gr. B p Value SIGNIFICANCE

AGE (MEAN + SD) 28.96 + 5.2 29.92 + 5.21 >0.05 NS

WEIGHT (MEAN + SD) 49.24 + 3.53 49.4 + 3.7 >0.05 NS

DURATION OF SURGERY (MEAN + SD) 62.4 + 27.5 63.6 + 28.04 >0.05 NS

DURATION OF ANAESTHESIA (MEAN + SD) 77.2 + 26.38 76.6 + 27.1 >0.05 NS

DURATION OF CO2 INSUFFLATION (MEAN + SD) 44.4 + 22.65 41.6 + 22.11 >0.05 NS

57

TABLE IV

Group -A Group B p VALUE SIGNIFICANCE TYPE OF SURGERY

n % n % Diagnostic Laparoscopy 11 44 11 44Laproscopic Ligation 9 36 7 28Laproscopic Appendix 3 12 1 4MTP + Lap.Ligation 1 4 3 12Laproscopic Cholecystecomy 1 4 3 12

>0.05 N.S.

TYPES OF SURGERY

0

5

10

15

20

25

30

35

40

45

50

Group -A Group B

Diagnostic Laparoscopy

Laproscopic Ligation

Laproscopic Appendix

MTP + Lap.Ligation

Laproscopic Cholecystecomy

PER

CEN

TAG

E

58

TABLE V

Group -A Group B p VALUE SIGNIFICANCE

DURATION OF SURGERY

(MIN) n % N % >0.05 NS 30-60 17 68 16 64 61-90 5 20 6 2491-120 3 12 3 12

DURATION OF SURGERY

0

10

20

30

40

50

60

70

80

30-60 61-90 91-120

Group -A

Group -A %

Group B

Group B %PER

CE

NTA

GE

59

DURATION OF ANAESHESIA

The Mean duration of anaesthesia was 77.2 + 26.38 minute in group A as against 76.6 +

27.1 minute in group B. The p value was not significant.

DURATION OF CO2 INSUFFLATION

The Mean duration of CO2 insufflation during the various procedure was 44.4 + 22.65

minute in group A compared to 41.6 + 22.11 minute in group B(Table-VI). The p value

was more than 0.05.

Hence the 2 groups were well randomized and statistically comparable in terms of age,

sex, weight, duration of surgery, anaesthesia and CO2 insufflation and type of surgical

procedures.

INTRAOPERATIVE DATA (TABLE-VII)

Heart rate and blood pressure were compared with student’s t test between two

groups.All the haemodynamic parameters like heart rate, diastolic and systolic blood

pressure were monitored every 5 minutes for the first hour and then every 15 minutes

next hour.

60

TABLE VI

Group -A GROUP B p VALUE SIGNIFICANCE

DURATION OF CO2

INSUFFLATION n % n % 20-60 22 88 22 8861-90 2 8 3 1291-100 1 4 0 0

>0.05 N.S.

DURATION OF CO2 INSUFFLATION

0

10

20

30

40

50

60

70

80

90

100

Group -A GROUP B

20-60

61-90

91-100

PER

CE

NTA

GE

61

TABLE VII

HEART RATE

020406080

100120140

0 5 15 30 45 60 90 120

TIME

GROUP AGROUP B

HEAR

T R

ATE

SYSTOLIC BLOOD PRESSURE

0

20

40

60

80

100

120

140

0 5 15 30 45 60 90 120

TIME

GROUP AGROUP BS

BP

DIASTOLIC BLOOD PRESSURE

78.478.678.8

7979.279.479.679.8

8080.2

0 5 15 30 45 60 90 120

TIME

GROUP AGROUP B

DB

P

62

HEART RATE

The mean heart rate was comparable between the 2 groups and the difference was not

significant. (p > 0.05).No patients of either group had bradycardia.

SYSTOLIC BLOOD PRESSURE

The mean systolic blood pressure in the 2 groups was comparable and the difference was

not significant. ( p > 0.05).There was no fall of systolic blood pressure intraoperatively in

both the groups

DIASTOLIC BLOOD PRESSURE

Mean diastolic blood pressure in the 2 groups were comparable and the difference was

statically insignificant .There was no fall in diastolic blood pressure.

POST OPERATIVE DATA

EARLY NAUSEA

Incidence of early nausea was statistically significant ( p < 0.05). Thirteen (52%)

patients of group A had mild nausea compared to 5 patients (20%) of group B (Table-

VIII) . Two patients of group A had moderate nausea compared to none in group B.

None of the patients in both groups had severe nausea.

63

TABLE VIII

EARLY NAUSEA DELAYED NAUSEA

GROUP

A GROUP

B p VALUE SIGNIFICANT

GROUP A

GROUP B

p VALUE SIGNIFICANT

n % n % n % n %

MILD 13 52 5 20 7 28 3 12

MODERATE 2 8 0 0 3 12 2 8

SEVERE 0 0 0 0 < 0.05 SIGNIFICANT 0 0 0 0 > 0.05 NS

NAUSEA

0

10

20

30

40

50

60

GROUP A GROUP B GROUP A GROUP B

EARLY NAUSEA DELAYED NAUSEA

MILDMODERATESEVERE

PER

CEN

TAG

E

64

TABLE IX

EARLY VOMITING DELAYED VOMITING

GROUP

A GROUP

B p VALUE SIGNIFICANT

GROUP A

GROUP B

p VALUE SIGNIFICANT

n % n % n % n % MILD 3 12 2 8 1 4 0 0 MODERATE 0 0 0 0 7 28 1 4 SEVERE 1 4 0 0 < 0.05 NS 0 0 0 0 <0.05 SIGNIFICANT

VOMITING

0

5

10

15

20

25

30

GROUP A GROUP B GROUP A GROUP B

EARLY VOMITING DELAYED VOMITING

MILDMODERATESEVEREP

ER

CE

NTA

GE

65

DELAYED NAUSEA

In group A 7 patients (28%) compared to 3 patients in group B (12%) had mild nausea.

3 patients (12%) had moderate nausea in group A compared to 2 patients (8%) in group

B. None of them had severe nausea (Table-VIII). The difference between the groups

were not significant (p > 0.05).

EARLY VOMITING

In group A 3 patients (12%) compared to 2 patients in group B (8%) had mild vomiting .

None of them had moderate vomiting. One patient (4%) in group A had severe

vomiting (Table-IX). Difference is not statistically significant.

DELAYED VOMITING

Incidence of delayed vomiting was statistically significant (p < 0.05). In group A one

patient (4%) had mild, 7 patient (28%) had moderate vomiting compared to only one

patient (4%) in group B who had mild vomiting and none had moderate vomiting. None

of them had severe vomiting in both the groups(Table-IX).

RESCUE ANTIEMETIC

Need for rescue antiemetic was not statistically significant (p > 0.05). 5 patients (20%) in

group A and 3 patients (12%) in group B needed rescue antiemetic (Table-XI).

66

TABLE X

EARLY PAIN DELAYED PAIN

GROUP

A GROUP

B p VALUE SIGNIFICANCE

GROUP A

GROUP B

p VALUE SIGNIFICANCE

n % n % n % n % MILD 15 60 16 64 4 16 3 12 MODERATE 5 20 4 16 1 4 0 0 SEVERE 5 20 5 20 > 0.05 NS 0 0 0 0 >0.05 NS

PAIN DISTRIBUTION

010203040506070

GROUP A GROUP B GROUP A GROUP B

EARLY PAIN DELAYED PAIN

MILDMODERATESEVERE

PE

RC

EN

TA

GE

67

TABLE XI

RESCUE ANTIEMETIC RESCUE ANALGESIC

GROUP

A GROUP

B p VALUE SIGNIFICANT

GROUP A

GROUP B

p VALUE SIGNIFICANT

n % n % n % n %

REQUIRED 5 20 3 12 6 24 5 20 NOT REQUIRED 20 20 22 88 >0.05 NS 19 76 20 80 >0.05 NS

RESCUE ANTIEMETIC & RESCUE ANALGESIC

0102030405060708090

100

GROUP A GROUP B GROUP A GROUP B

RESCUE ANTIEMETIC RESCUE ANALGESIC

REQUIREDNOT REQUIRED

PER

CEN

TAG

E

68

POST OPERATIVE PAIN

Both early and late post operative pain was not statistically significant in group A and

group B (Table-X).In group A 15 patients (60%) had mild pain compare to 16 patients

(64%) in group B.Five patients in group A (20%) had moderate pain compare to 4

patients (16%) in group B.Five patients (20%) had severe pain in both the groups.

RESCUE ANALGESIC

Need for rescue analgesic was not statistically significant (p > 0.05). 6 patients (245%)

in group A compared to 5 patients (20%) in group B needed rescue analgesic (Table-XI).

DISCHARGE TIME

Nineteen patients (76%) in group A compared to 20 patients (80%) in group B got

discharged with in one hour of surgery. Five patients(20%) in each group took 2

hours.One patient in group A got discharged in three hours (Table-XII). The difference is

not statistically significant.

69

TABLE XII

DISCHARGE TIME GROUP A GROUP B

n % n % 0-1 19 76 20 80 0-2 5 20 5 20 0-3 1 4 0 0 0-4 0 0 0 0

DISCHARGE TIME

0102030405060708090

0-1 0-2 0-3 0-4

DISCHARGE TIME (Hrs)

GROUP A

GROUP A

PER

CE

NTA

GE

70

TABLE XIII

SIDE EFFECTS GROUP A GROUP B p VALUE SIGNIFICANT

n % n % HEAD ACHE 2 8 2 8CONSTIPATION 0 0 0 0FLUSHING OF FACE 0 0 1 4DIARRHOEA 0 0 0 0 > 0.05 NS

SIDE EFFECTS

0

1

2

3

4

5

6

7

8

9

HEAD ACHE CONSTIPATION FLUSHING OF FACE DIARRHOEA

GROUP AGROUP B

PE

RC

EN

TAG

E

71

SIDE EFFECTS

2 patients (8%) in each group had mild headache. One patient in group B had flushing of

face for which no treatment was needed. None had diarrhoea or constipation (Table-

XIII). Difference were not statistically significant.

72

73

DISCUSSION

PONV is the most unpleasant experience for a patient undergoing anaesthesia and

surgery. It is a common sequel of general anaesthesia and unanticipated hospital

admission5 after day care surgery.

The aetiology of nausea &vomiting after laparoscopic surgeries are not fully understood.

34 Risk factors such as a long period of CO2 insufflation, intraoperative use of isoflurane,

fentanyl and glycopyrrolate, female sex and post operative use of opioids may contribute

to these episodes. Other factors 4,15 16 18,29 are intraoperative hypotension, manipulation

of abdominal visceras.27All these factors were avoided in our study.

Ondansetron , are selective 5HT3 receptors antagonist, has been shown to be effective in

the treatment and prevention of PONV in gynecological laparoscopy 35, laparoscopic

cholecystectomy 34, Since none of the available antiemetics , including ondansetron is

entirely effective in all the patients, the concept of combination therapy was introduced.

Although role of steroids as antiemetic was established in 1981 7, dexamethasone was

introduced later. The mechanism of action of corticosteroids is unknown but may be

related to inhibition of prostaglandin synthesis, decrease in 5HT3 level in CNS and by an

anti inflammatory action at operative site 31.

Different studies has been done to control PONV with various combination therapy.

In all these studies incidence of nausea has been very variable, probably related to

different types of and duration of surgery. In our study 60% patients of group A

73

showed early nausea and 40% of patients showed delayed nausea. Post operative

nausea was less in combination group which is comparable to the study of V. Rajeeva

et. al.26 Fewer patients in combination group had late nausea similar to finding of

Lopez etal 27, where only 12% of patients in combination group had delayed nausea

as compared with 38% in the ondansetron group.In group A 20 patients (80%) had

mild and 5 patients (20%) had moderate nausea compare to 8 patients(32%) in group

B who had mild and 10 patients (40%) who had moderate nausea.In both the groups,

none of the patients had severe nausea .

In our study incidence of early vomiting in ondansetron group is 16% and delayed

vomiting is 32%. This is comparable to V. Rajeeva at al 26 , who had 15% early

emesis and 35% delayed emesis after ondansetron. In the combination group it is

less, 8%(early vomiting) compared to 4% (late vomiting). This is also comparable to

the same study, but does not agree with lopez 27 et al where no patient vomited in

early period but 4% vomited by 24hr. In this study patients were undergoing major

gynecological surgery of longer duration than in our study, which may explain the

different results.In group A 4 patients (16%) had mild,7 patients (28%) had moderate

and one patient (4%) had severe vomiting.In group B, 2 patients (8%) had mild and

one patient (4%) had moderate vomiting.None of the patients had severe vomiting in

both the groups.

Delayed vomiting (4%) is less compared to early vomiting (8%) in combination

group. It is probable that the action of dexamethasone had not started by the time

74

surgery was completed. Corticosteroids interact with specific receptor proteins in

target tissues to regulate the expression of corticosteroid-responsive genes there by

changing the levels and array of proteins synthesized by the various target tissues.

As a consequence of the time required for the changes in gene expression and

protein synthesis, most effect of corticosteroids are not immediate 21.

A wide dose range of dexamethasone (2-16mg)31has been used in the management of

PONV and emesis related to chemotherapy and after pediatric9 and gynecocological

surgeries 29,30 . Dexamethasome 8mg was used most widely and found to be most

effective and was the reason behind our selection for the present study.

In our study postoperative pain scores were comparable in both the groups. Rescue

analgesic requirement was also not statistically different between the groups. As

dexamethasone has potent anti inflammatory 21, 31 effect, it may be beneficial 37 for

post operative pain. However in our study potent opioid (pethidine) was

administered as premedication and during intra operative period. Therefore, the

influence of dexamethasone on postoperative pain may have been masked.

All patients of group A and group B were haemodynamically stable throughout the

intraoperative period.

Five patients (20%) in group A required rescue antiemetics compared to only three

(12%) in group B.The difference was not significant.

75

Adverse effects related to a single dose of dexamethasone are extremely rare. Less

than 24 hour of dexamethasone therapy is considered safe and almost without

adverse effects9,28,29,32,34,38. In our study complication due to steroid was not

significant

Cost is an ever increasing concern in todays health care system. Dexamethasone is

relatively inexpensive drug compared to other antiemetics 30, 32.

76