attenuation of the pressor response to...

ATTENUATION OF THE PRESSOR RESPONSE TO LARYNGOSCOPY

AND ENDOTRACHEAL INTUBATION: A COMPARISON OF

INTRAVENOUS ESMOLOL AND LIDOCAINE.

A DISSERTATION

BY

DR AMENAGHAWON ANDREA EHIOZE-OSIFO

MBBS (LAGOS), DA (BENIN)

SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENT

FOR THE AWARD OF THE FELLOWSHIP OF THE FACULTY OF

ANAESTHESIA, NATIONAL POSTGRADUATE MEDICAL

COLLEGE OF NIGERIA.

NOVEMBER, 2008.

DECLARATION

2

I, AMENAGHAWON ANDREA EHIOZE-OSIFO, here declare that the contents of

this dissertation are the results of work done by me at the Lagos University Teaching

Hospital, Lagos, Nigeria. The work has not been presented for any publication,

examination or fellowship award.

………………………………………………

Dr A.A. Ehioze-Osifo

CERTIFICATION

3

We certify that this work was carried out by Dr Amenaghawon Andrea Ehioze-Osifo

of the Department of Anaesthesia, Lagos University Teaching Hospital, under our

supervision.

Signature/ Date………………………………………………

Dr O.T Kushimo

Associate professor/Consultant Anaesthetist

Department of Anaesthesia

Lagos University Teaching Hospital

Signature/ Date……………………………………………….

Dr J.O Olatosi

Lecturer/Consultant Anaesthetist

Department of Anaesthesia

Lagos University Teaching Hospital

DEDICATION

This work is dedicated to my loving family for their support, understanding and prayers

which saw me through the residency training.

4

AKNOWLEDGEMENTS

I thank the Almighty God for his grace and mercy to start and conclude this work.

I am sincerely grateful to my supervisors Dr O.T Kushimo and Dr J.O. Olatosi for their

unstinted patience, encouragement and intellectual contributions to this book.

I seize this opportunity to express my appreciation to the other consultants in the

Department of Anaesthesia of the Lagos University Teaching Hospital for their

immense contribution to my training.

I also wish to thank the following people for the roles they played during the conduct

of this study. My fellow residents for their support and co-operation in collecting the

data for this study as well as Dr Oridota of the Community Health Department, for his

help with the statistical analysis of this study.

I appreciate the support and encouragement of my parents, brothers and in-laws who

have been very supportive during this period.

To my dear husband, Ehioze and our beloved sons, Obosa and Osasu, I wish to say

thank you for your perseverance, encouragement and support.

TABLE OF CONTENTS

5

1. TITLE i

2. TABLE OF CONTENTS ii

3. DECLARATION iii

4. CERTIFICATION iv

5. DEDICATION v

6. ACKNOWLEDGEMENTS vi

7. LIST OF ABBREVIATIONS vii

8. LIST OF TABLES viii

9. LIST OF FIGURES ix

10. LIST OF APPENDICES x

11. SUMMARY xi

12. INTRODUCTION 1

13. AIM AND OBJECTIVES 4

14. LITERATURE REVIEW 5

15. MATERIALS AND METHODS 20

16. RESULTS 24

17. TABLES 28

18. FIGURES 24

19. DISCUSSION 35

20. CONCLUSION 43

21. RECOMMENDATIONS 45

22. LIMITATIONS 46

23. REFERENCES 47

24. APPENDICES 60

LIST OF ABBREVIATIONS

ANOVA Analysis of Variance

ASA American Society of Anesthesiologists

BP Blood Pressure

CPB Cardiopulmonary bypass

6

DBP Diastolic Blood Pressure

ECG Electrocardiogram

Fig Figure

GA General Anaesthesia

g gram

HR Heart Rate

IV Intravenous

Kg Kilogram

LUTH Lagos University Teaching Hospital

MAP Mean Arterial Pressure

mg milligram

mgkg -1 milligram per kilogram body weight

MI Myocardial Infarction

ml millilitre

min minute

mmHg millimetres of mercury

RPP Rate Pressure Product

SBP Systolic Blood Pressure

SD Standard Deviation

SpO2 Arterial oxygen saturation

µg microgram

LIST OF TABLES

TABLE 1 - Demographic Data and Clinical Characteristics

Of Patients. 24

7

LIST OF FIGURES

FIGURE 1- Distribution of patients according to

Surgical Specialty. 23

FIGURE 2- Mean Heart Rate 25

FIGURE 3- Percentage Change From Baseline in Mean Heart Rate. 26

FIGURE 4- Mean Systolic Blood Pressure 27

FIGURE 5- Percentage Change from Baseline in Mean

Systolic Blood Pressure 28

FIGURE 6- Mean Diastolic Blood Pressure 29

FIGURE 7- Percentage Change from Baseline in Mean

Diastolic Pressure. 30

FIGURE 8- Mean Arterial Pressure 31

FIGURE 9- Percentage Change from Baseline in

Mean Arterial Pressure 32

FIGURE 10- Mean Rate Pressure Product 33

FIGURE 11- Percentage Change from Baseline in

Mean Rate Pressure Product 34

8

LIST OF APPENDICES

1. APPENDIX I- Patient Proforma

2. APPENDIX II- Patient Consent Form

3. APPENDIX III- Ethical Committee Approval

9

SUMMARY

Laryngoscopy and tracheal intubation often elicit a haemodynamic response which

could be deleterious in patients with cardiovascular and intracranial pathology.

Lidocaine and esmolol are two of several agents used by anaesthetists to attenuate this

response. Lidocaine is the agent commonly used by anaesthetists practicing in most

developing countries like Nigeria as it is cheap, while esmolol has been used in parts of

North America, Europe and Asia. The effect of esmolol on the pressor response is yet

to be evaluated in an African population. The aim of this study was to evaluate and

compare the effectiveness of these two drugs in attenuating the haemodynamic changes

which accompany laryngoscopy and endotracheal intubation in an adult Nigerian

population at the Lagos University Teaching Hospital (LUTH).

Ninety (90) ASA physical status class 1 and 2 adult patients undergoing elective

surgical procedures under general anaesthesia were included in this randomised, single-

blind, placebo controlled study. The effectiveness of 2mg.kg -1 of esmolol administered

two minutes before laryngoscopy was compared with intravenous lidocaine 1.5mg.kg -

1 given three minutes before laryngoscopy in attenuating the pressor response to

laryngoscopy and endotracheal intubation. The patients were randomly assigned by

blind balloting to one of three groups, Esmolol (E), Lidocaine (L), and Control(C).

Group E patients had 2mg.kg -1 of intravenous esmolol made up to 20mls, given two

minutes before laryngoscopy and intubation. Group L patients had 1.5mg.kg -1 of

lidocaine made up to 20mls, administered intravenously 3 minutes before laryngoscopy

and intubation, while those in the control group were given a placebo of 20mls of 0.9%

saline 3 minutes before laryngoscopy.

Anaesthesia was induced with 4mg.kg -1 of 2.5% thiopentone sodium and tracheal

intubation facilitated with 1.5mgkg-1 suxamethonium chloride in all three groups. Heart

10

rate (HR), systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean

Arterial Pressure (MAP) and Rate pressure product(RPP) were recorded as baseline,

immediate post-intubation, 1, 3, 5 and 10minutes after laryngoscopy and intubation.

Readings of HR, SBP, DBP, MAP and RPP were compared with baseline values and

among each group.

All patients showed post-intubation increases in haemodynamic variables but to

varying degrees. The mean heart rate increased by 19.1%, 25.7% and 41.4% in groups

E, L and C respectively. SBP increased by 13.3%, 21.6% and 26.9%, DBP by 16.2%,

34.5% and 46.1%, MAP by 12.2%, 19.1% and 30.2% and RPP by 28.1%, 45.8% and

78.7% in groups E, L and C respectively.

The post-intubation rise in heart rate (HR) was significantly less in both treatment

groups (p<0.05) compared to the control group, but more in the esmolol group. There

was also a significantly lower increase in SBP post-intubation in the esmolol group

(p<0.05), but not in the lidocaine group (p>0.05). The changes in DBP and MAP were

significantly less in both treatment groups compared to the control group. Both

treatment techniques showed significance in attenuating the post-intubation rise in RPP

(P<0.05) but this was more in the esmolol group.

These findings demonstrated that both drugs in the doses used in this study, attenuated

the pressor response to laryngoscopy and intubation to varying degrees. As observed in

similar studies conducted in non-African patients, intravenous esmolol was statistically

superior to intravenous lidocaine for attenuating the haemodynamic response to

laryngoscopy and intubation. There were no complications attributable to the use of

either drug recorded during the course of the study.

11

INTRODUCTION

Following the first direct vision examination of the human larynx by Albert Kirstein in

18951 and its subsequent modification to involve the insertion of intratracheal tubes by

Chevalier Jackson in 19131,2 laryngoscopy and tracheal intubation became an integral

component of airway management and general anaesthesia.

Physical and direct stimulation of the pharynx and larynx by the laryngoscope blade

and the placement of an endotracheal tube elicit a sympathetic nervous system response

12

with a reflex consisting of a transient increase in blood pressure and heart rate, as well

as the occurrence of cardiac dysrhythmias3. These haemodynamic changes were first

reported by Reid and Brace in 19404. King and colleagues5 described a similar

cardiovascular response to laryngoscopy and intubation in 1951. This reflex has been

termed the “pressor response” and has been attributed to the sudden release of plasma

catecholamines occurring as a consequence of laryngoscopy and endotracheal

intubation6. A 40-50% increase in mean arterial pressure and a 20% increase in heart

rate may occur if the duration of the stimulus is prolonged7. These haemodynamic

changes are greatest one minute after intubation and typically last for about 5-10

minutes before returning to baseline values8. A sudden decrease in blood pressure may

be observed as this response ends due to the rapid metabolism of released plasma

catecholamines6.

A transient haemodynamic change presents a low risk to healthy individuals. In fact,

some researchers have actually questioned the importance attached to the

phenomenon9-11. It is however of major clinical significance in patients with pre-

existing systemic hypertension, hypertensive heart disease, coronary artery disease,

eclampsia, aneurysmal vascular disease and head injury in whom such a change may

culminate in perioperative myocardial ischaemia or infarction, cardiac failure,

dysrhythmias, cerebrovascular accidents or secondary brain injury12.

With advances in medical care and public health, the number of elderly and high risk

patients presenting for elective surgeries has steadily increased. Of particular interest

are patients with hypertension and coronary artery disease (CAD). Anaesthetists often

encounter hypertensive patients scheduled for elective surgical procedures. Some of

these patients are not well controlled or have a background of cardiac, cerebral or renal

complications of hypertension. Perioperative hypertension is an important etiological

1

13

factor for myocardial ischaemia as a sequel to anaesthesia and surgery13. Recently

conducted studies have revealed a high prevalence of essential hypertension amongst

Nigerians and research has shown that optimal control of blood pressure is difficult to

achieve even with proper medication14-16. Despite the fact that diagnosis and treatment

of hypertension are easy, a good number of patients are either not diagnosed or not well

controlled. Hypertensive patients have been shown to exhibit an exaggerated

haemodynamic response to laryngoscopy and intubation, associated with a high

incidence of subendocardial ischaemia.17,18 This has been observed to occur even when

the patients’ blood pressure appears controlled with anti-hypertensive therapy19,20.

Also, under emergency conditions where there is insufficient time for optimisation of

the patients’ intercurrent medical problems, achieving optimal blood pressure control

may be difficult if not impossible.

The prevalence of coronary artery disease is steadily increasing in sub-Saharan Africa

due to trends in urbanisation, changes in life-style and acquisition of technology21

.Ischaemic heart disease previously considered rare now ranks 8th among the leading

causes of death in men and women in the region22,23. In these patients the tachycardia,

hypertension and increase in rate pressure product, concomitant with intubation

represent a serious risk and has been shown to result in perioperative myocardial

ischaemia and infarction22. Since the presence of coronary artery disease may not

always be diagnosed preoperatively, the prevention of these haemodynamic changes

and their adverse sequelae is necessary to reduce perioperative morbidity and mortality.

Several methods of preventing this response have been recommended24-28. These

include the use of alternative guiding devices such as the fibreoptic bronchoscope24,

light wand25 or airway management with the laryngeal mask airway (LMA)26,27.

Recently, the use of the McCoy laryngoscope has been found to reduce the severity of

14

these haemodynamic changes28. Various pharmacological agents have been

administered prior to laryngoscopy in an attempt to attenuate this reflex29-33. Of

particular interest is the use of intravenous lidocaine which is the agent commonly used

by anaesthetists practicing in this environment. The results of studies conducted on its

use in this respect have varied34,35. On the other hand, esmolol, an ultra-short acting

cardioselective beta- adrenergic blocker has been shown to provide more consistent and

reliable protection against the pressor response36. There is however a dearth of research

on its use in an African population.

This prospective study was undertaken to evaluate the effectiveness of these two agents,

namely- esmolol hydrochloride and lidocaine hydrochloride, in attenuating the

haemodynamic response to laryngoscopy and tracheal intubation, and to compare their

relative effectiveness in a Nigerian population.

15

AIM AND OBJECTIVES

AIM

To compare the effectiveness of intravenous lidocaine and esmolol in the prevention of

the haemodynamic response to laryngoscopy and endotracheal intubation in a Nigerian

population at the Lagos University Teaching Hospital.

OBJECTIVES

To evaluate the effect of an intravenous dose of lidocaine on the haemodynamic

response to laryngoscopy and intubation.

To evaluate the effect of an intravenous dose of esmolol on the haemodynamic

response to laryngoscopy and intubation.

To compare the effects of intravenous lidocaine and esmolol on the pressor response

to laryngoscopy and intubation.

To determine the occurrence of complications with the use of either agent.

16

LITERATURE REVIEW

A haemodynamic response of increased heart rate and blood pressure to manipulation

in the area of the larynx, by means of laryngoscopy and intubation was first reported

by Reid and Brace4. Subsequently, Forbes and Dally37 reported an average rise in mean

arterial pressure of 25mmHg following laryngoscopy and insertion of an endotracheal

tube in 22 patients in whom anaesthesia was induced with sodium thiopentone.

These haemodynamic changes have been interpreted as being the result of reflex

sympatho-adrenal stimulation. In a study conducted by Tomori and Widdicombe using

anaesthetised cats, they observed that mechanical stimulation of four areas of the upper

respiratory tract i.e. the nose, epipharynx, laryngopharynx and tracheobronchial tree

induced reflex cardiovascular responses associated with enhanced neuronal activity in

the cervical sympathetic efferent fibres38. These cardiovascular responses, tachycardia

and hypertension, as well as the enhanced neuronal activity were most pronounced

during stimulation of the epipharynx while those arising from the stimulation of the

tracheobronchial tree were least marked38.

Subsequent researchers have confirmed these findings. In a study of 24 patients

undergoing elective surgery under general anaesthesia, Shribman et al reported that

laryngoscopy alone increased blood pressure and that laryngoscopy and intubation

together increased both heart rate and blood pressure39. The study also demonstrated a

significant increase in serum catecholamine levels during laryngoscopy with or without

concomitant intubation. Similarly, Russel and colleagues40 demonstrated a significant

increase in mean arterial pressure and plasma norepinephrine levels following

endotracheal intubation suggesting a predominantly sympathetic response during

intubation. This elevation in blood pressure and heart rate was maximum when the

17

duration of laryngoscopy exceeded 30 seconds .The authors went on to recommend the

need for prophylaxis in high risk patients.

Some authors have questioned the notion that these cardiovascular reflexes are caused

solely by increased sympathetic and sympathoadrenal activity41,42. The efferent

sympathetic outflow to the heart is T1-T4, while that to the adrenal medulla is from T3-

L343,44. Wathill et al45 reported that the cardiovascular response to intubation is

abolished in patients undergoing thoracolumbar epidural anaesthesia. However, Dohi

et al42 observed that acute sympathectomy induced in part by cervical or lumbar

epidural block did not prevent haemodynamic responses to laryngoscopy and

intubation.

Anaesthesia literature contains several studies evaluating various pharmacological

agents used for attenuating these haemodynamic changes in adults. It has been

suggested that the ideal agent for obtunding the pressor response should have a rapid

onset of action, be safe, easily administered and have a relatively short duration of

action10. The following are the various drugs which have been utilised for blunting the

haemodynamic response to laryngoscopy and intubation:

Local anaesthetic agents

The efficacy of intravenous and topical oropharyngeal local anaesthetic agents for

attenuating the pressor response has been extensively studied29,34,46. The postulated

mechanism for inhibiting this sympathetic response is an increased threshold for airway

stimulation and central inhibition of sympathetic stimulation. Derbyshire and

colleagues47 investigated the use of topical anaesthesia of the upper airway using 160mg

of 4% lidocaine in adult patients. They concluded that it was an ineffective means of

ameliorating the pressor and catecholamine response to laryngoscopy and intubation.

18

Several researchers have recommended 1.5mgkg-1 of lidocaine given intravenously 3

minutes before laryngoscopy as optimal for attenuating the response 34,35,48 .

Durrani et al46 found intravenous chloroprocaine an excellent local anaesthetic for

blunting the sympathetic response. A bolus dose of 4.5mgkg-1 given 45 seconds before

laryngoscopy significantly diminished increases in blood pressure as well as plasma

catecholamine concentrations in response to intubation.

Opioids

Narcotics have been used for attenuating the haemodynamic as well as catecholamine

response to endotracheal intubation49,50. The analgesic effects of these agents suppress

the nociceptive stimulation caused by laryngoscopy and intubation. There is also a

centrally mediated decrease in sympathetic tone associated with their use49.

Fentanyl in doses ranging between 2µgkg-1 and 7µgkg-1 given 1 to 2 minutes before

laryngoscopy has been found to be effective in attenuating the increase in heart rate,

blood pressure and rate-pressure product following laryngoscopy and intubation51,52.

Crawford et al53 reported a significant reduction in post-intubation rise in heart rate,

systolic blood pressure and serum epinephrine concentration with the use of 40µgkg-1

of alfentanil. However, the doses of opioids required for attenuation of the pressor

response often result in hypotension, bradycardia, respiratory depression, skeletal

muscle rigidity and delayed recovery51,53.

Remifentanil, which has a rapid onset and short duration of action, has been used for

attenuation of the haemodynamic response. Maguire et al54 found that a bolus

intravenous dose of 0.5µgkg-1 remifentanil followed by a 0.1µgkg-1 min-1 infusion

administered just prior to laryngoscopy, was effective in controlling the response.

Beta adrenergic blockers

19

Selective beta-1 blockade produces a decrease in heart rate and myocardial contractility

whereas antagonism of the beta-2 receptor produces bronchial and vascular smooth

muscle constriction. Achola et al55 studied the use of intravenous practolol 10mg given

just before laryngoscopy for attenuation of the pressor response and concluded that it

lacked efficacy in this respect. The use of 10mg intravenous propranolol by McCamon

and colleagues was associated with excessive myocardial depression (hypotension and

bradycardia) and a duration of action which outlasted the transient haemodynamic

changes induced by laryngoscopy and intubation56. Of the various beta blockers used

for attenuation of the pressor response, esmolol, a beta-1 blocker with an ultra-short

duration of action has yielded the most reliable results.34,57

Vasodilators

Sodium nitroprusside and nitroglycerine have been evaluated for the attenuation of the

pressor response to laryngoscopy and intubation but their use requires continuous intra-

arterial monitoring. Mikawa et al30 reported that intravenous nitroglycerine 2.5µgkg-1

had no effect on the tachycardia but significantly reduced the mean arterial pressure

and rate-pressure product changes associated with tracheal intubation. Similarly,

Stoetling58 reported that rapid intravenous injection of sodium nitroprusside at a dose

of 1-2µgkg attenuated the blood pressure but not the heart rate changes following

laryngoscopy and intubation.

Calcium channel blockers

The commonly evaluated calcium channel blocking agents for attenuating the

haemodynamic response are verapamil, diltiazem and nicardipine59,60. Yaku et al61

found that intravenous verapamil given in a dose of 0.05mgkg-1 attenuated the increase

in mean arterial pressure and rate pressure product after tracheal intubation. Verapamil

failed to prevent the tachycardia despite its negative chronotropic effect. Similarly, both

20

nicardipine and verapamil at intravenous doses of 0.03mgkg-1 and 0.1mgkg-1

respectively failed to control the tachycardia despite being effective in attenuating the

increase in blood pressure associated with laryngoscopy and intubation62.

Volatile anaesthetic agents

Inhalational agents like halothane and enflurane in various concentrations have been

used during induction to increase depth of anaesthesia as well as control the

haemodynamic response63,64. High concentrations may prove detrimental in

cardiovascular compromised patients. Using halothane 2% with nitrous oxide in oxygen

for 2 minutes before laryngoscopy, Kautto et al observed a significant attenuation of

the pressor response63. However, a higher concentration of halothane produced

significant cardiac dysrhythmias. Bedford et al64 found 0.7% enflurane a more suitable

alternative to 2% halothane for attenuation of the pressor response to laryngoscopy and

intubation.

Intravenous induction agents

Agents used to induce anaesthesia have been shown to influence the pressor response

to laryngoscopy and tracheal intubation. Ebegue65 demonstrated that following

induction of anaesthesia with 4mgkg-1of sodium thiopentone, the administration of a

second dose of thiopentone (4mgkg-1) just before laryngoscopy significantly attenuated

the heart rate, systolic blood pressure and rate pressure product changes accompanying

laryngoscopy and intubation. Similarly, Amadasun66 reported that a repeat of an

induction dose of sodium thiopentone given just before laryngoscopy was statistically

superior to intravenous lidocaine for attenuation of the pressor response.

Sood and colleagues67 demonstrated that the administration of a repeat dose (25% of

the induction dose) of intravenous propofol just prior to laryngoscopy limits the

21

duration of the pressor response to one minute. However, 55.5% of their patients

complained of pain on injection of propofol.

Alpha 2-adrenoceptor antagonists

These agents interact with catecholaminergic neuronal system which modulates tonic

and phasic blood pressure control and reduce the release of norepinephrine from nerve

endings both centrally and peripherally. Ghignone68 showed that cardiovascular

responses following laryngoscopies of less than 30 seconds duration can be attenuated

with 5µg.kg -1oral clonidine given 45 minutes before laryngoscopy. Scheinin et al69

found that intravenous dexmedetomidine at a dose of 0.2-0.7µg.kg -1 attenuates the

stress-induced sympathoadrenal responses to laryngoscopy, intubation and surgery and

provides increased haemodynamic stability.

Miscellaneous

Other drugs that have been used to attenuate the haemodynamic response to

laryngoscopy and intubation are; labetalol, magnesium sulphate, gabapentin, captopril,

prostaglandin E1 and adenosine triphosphate.

Amar et al70 reported that labetalol, a non-selective α and β adrenergic blocker at a

dose of 0.5mgkg-1 significantly attenuated the rise in blood pressure and heart rate, but

did not prevent the rise in plasma catecholamines associated with laryngoscopy and

intubation. The use of larger doses of labetalol was associated with significant

hypotension.

Magnesium sulphate attenuates catecholamine output from adrenal medulla and

adrenergic nerve endings and this reduces the severity of the pressor response. Puri and

colleagues71 found intravenous magnesium sulphate 40mgkg-1 effective for attenuation

of the pressor response to laryngoscopy and intubation as well as producing less ST

segment changes in patients with coronary artery disease undergoing coronary artery

22

bypass grafting. In patients with gestational hypertension, magnesium was found to be

more effective than intravenous lidocaine in attenuating the pressor response72.

Fassoulaki and colleagues73 observed that oral gabapentin at a dose of 800-1600mg

given at 6 hourly intervals before surgery attenuated the pressor response but not the

tachycardia associated with laryngoscopy and endotracheal intubation. Sanir et al74

evaluated the effect of oral captopril on haemodynamic responses and reported that a

dose of 12.5mg administered 45minutes prior to induction of anaesthesia significantly

attenuated the hypertensive, but not the tachycardic response to tracheal intubation. In

a study by Mikawa and colleagues75, prostaglandin E1 given as an infusion at 0.6ugkg-

1 attenuated the hypertension during tracheal intubation but failed to blunt the

tachycardia. It also enhanced the increase in plasma noradrenaline concentration

following intubation. Adenosine, a potent vasodilator has been successfully used at a

dose of 0.05-0.1mgkg-1 to attenuate the haemodynamic response to laryngoscopy and

intubation76. Its onset of action is fast and its duration of action transient. Although it

has a negative chronotropic effect, like other vasodilators it fails to control the

tachycardia associated with the response

INTRAVENOUS LIDOCAINE HYDROCHLORIDE

Lidocaine is an amide –derived local anaesthetic and class IB anti-dysrhythmic agent77.

It has found clinical uses in local and regional anaesthesia, treatment of ventricular

dysrhythmias, and the attenuation of the haemodynamic response to laryngoscopy and

intubation. It acts by stabilising the neuronal membrane by inhibiting the sodium flux

required for the initiation and conduction of impulses78.

Its anti-pressor effect is believed to be via depression of laryngeal reflexes. It also

reduces thiopentone requirements by 13.3%.79,80

23

The use of intravenous lidocaine for the attenuation of the pressor response has been

extensively researched upon with different conclusions.

Abou-Madi et al35 compared 1.5mg.kg -1 of intravenous lidocaine given 3 minutes

before laryngoscopy with placebo in 30 patients; and found that the mean increase in

systolic blood pressure was 10.3% for patients pre-treated with lidocaine and 56% in

patients receiving placebo. The mean increase in heart rate was 16.8% in the lidocaine

group and 38.8% in the placebo group. Using a similar technique, Tam, Chung and

Campbell81 observed complete attenuation of the response when this dose of lidocaine

was administered 3 minutes before laryngoscopy. Splinter and Cevenko82 in a study of

150 geriatric patients, concluded that intravenous lidocaine given 4-4.5minutes before

intubation attenuated the pressor response. They however agreed with Tam et al81 that

in younger adults, the optimal time to administer intravenous lidocaine is 3 minutes

before laryngoscopy.

Lev and Rosen34 conducted a review of twenty-five studies pertaining to the use of

intravenous lidocaine for attenuation of the pressor response. Sixty per cent (60%) of

the studies reviewed demonstrated that lidocaine produced some benefit in attenuating

the cardiovascular response to intubation. A dose of 1.5mg.kg -1 administered

intravenously 3 minutes before intubation was recommended as optimal. None of the

studies documented any harmful effects of prophylactic lidocaine given preintubation.

Amadasun48 investigated the effectiveness of intravenous lidocaine in obtunding the

pressor response in a sample of Nigerian patients. In a randomised, controlled trial, a

total of 80 ASA class 1 and 2 patients were studied in two groups of 40 patients each.

Lidocaine was administered at a dose of 1.5mg.kg -1 three minutes before laryngoscopy

in the study group. He reported that intravenous lidocaine significantly attenuated the

24

post intubation rise in heart rate and rate-pressure products without significant effect on

blood pressure.

Miller and Warren83 in a study of 45 Chinese women could not demonstrate any

significant benefit of 1.5mg of lidocaine given intravenously 1, 2 or 3 minutes before

laryngoscopy. Prior to this, Laurito and colleagues84 administered a combination of

nebulized lidocaine 4mg.kg -1 and an intravenous dose 2mg.kg -1, and reported a lack

of effect on the cardiovascular response to laryngoscopy and intubation compared with

control. However, in their study they intubated their patients one minute after lidocaine

injection. They suggested the abandonment of the use of lidocaine prior to laryngoscopy

for the attenuation of the pressor response.

INTRAVENOUS ESMOLOL HYDROCHLORIDE

The use of beta adrenergic blockers for the attenuation of the pressor response was

pioneered by Prys-Roberts and colleagues in 197985. They studied the haemodynamic

sequelae to laryngoscopy and intubation in hypertensive patients and demonstrated a

significant attenuation of the pressor response in patients pre-treated with intravenous

or oral practolol. Subsequently, various workers have demonstrated the utility of beta

blockade in attenuation of the pressor response56, 86. Beta –adrenoceptor blockade

minimises the increase in heart rate and myocardial contractility (primary determinants

of oxygen consumption) by attenuating the positive chronotropic and inotropic effects

of increased adrenergic activity87. However, the use of beta-blocking agents for the

attenuation is not without risks. Potential negative sequelae related to beta- blockade

for attenuation include: excessive myocardial depression, bronchial constriction, and

the possibility that the duration of action of these agents may outlast the transient

haemodynamic changes induced by laryngoscopy and intubation.88

25

Esmolol, methyl-3-{4-3-[isopropyl amino] propoxy phenyl} propionate is a water

soluble, cardio-selective, ultra-short acting beta-adrenergic antagonist. It has been

shown to be effective in controlling both the heart rate and blood pressure responses to

intubation89.

Esmolol blocks the agonist effect of sympathetic neurotransmitters by competing for

beta 1 receptor sites. At therapeutic doses it lacks intrinsic sympathomimetic or

membrane stabilizing properties. Its anti-arrhythmic activity is due to blockade of

adrenergic stimulation of pacemaker potential. It is a class II antiarrhythmic agent90.

Esmolol undergoes rapid hydrolysis by esterases in red blood cells to a free acid

metabolite and methanol culminating in a short elimination half-life of 9.2 ±

2.0minutes. The short duration of action has led to its use in a number of situations

requiring beta receptor antagonism of limited duration e.g. treatment of

supraventricular dysrhythmias, perioperative hypertension and phaeochromocytoma64.

A total body clearance of 285 ml/min ensures a rapid offset of action and it is eliminated

via the kidneys almost entirely as its metabolite91. It achieves peak effect on heart rate

within one minute and on blood pressure within two minutes of intravenous injection92.

These unique pharmacokinetic and pharmacodynamic properties make esmolol suitable

for administration by either continuous infusion or bolus injection. It has been used in

different doses either as a bolus or in an infusion form to attenuate the haemodynamic

response to laryngoscopy and endotracheal intubation.

The first study conducted on the subject was published by Gold et al93 who found that

peak heart rates and systolic pressures following intubation after ketamine induction

were significantly attenuated by esmolol. Several researchers have established the

effectiveness of esmolol infusions in the prevention of haemodynamic alterations

following tracheal intubation. Ghaus et al94 reported that a bolus infusion of esmolol

26

administered at a dose of 300µg.kg-1.minute-1 for 4 minutes, followed by a maintenance

infusion of 200µg.kg-1.minute-1 for 12 minutes offered significant control of all the

haemodynamic variables. Figueredo and Fuentes95 conducted a meta-analysis of 38

randomised controlled trials on the effect of esmolol on the adrenergic stress response.

Eleven different regimens demonstrated effectiveness in the attenuation of heart rate

and blood pressure after laryngoscopy and intubation, the most effective of which was

a loading dose of 500µg.kg -1.minute-1 over 6 minutes followed by a continuous infusion

of 200-300µg.kg-1.minute-1 for 9 minutes.

Some authors have argued that while infusions are easy to set up, they require

additional equipment and time which may not be readily available96,97. In addition, the

dosing regimen and time required for preparation of an infusion may add a degree of

complexity to the induction process which is often unnecessary. Miller et al97 advocated

that since esmolol has a rapid onset and short duration of action, bolus injection might

be a simple and effective alternative to infusion in situations involving transient

hyperdynamic cardiovascular events such as laryngoscopy and intubation.

The use of bolus dosing of esmolol for the control of the pressor response to

laryngoscopy and intubation has produced different results.97-86 The optimal bolus dose

of esmolol required to attenuate the haemodynamic response to laryngoscopy and

endotracheal intubation has been a subject of debate .Various researchers have

administered esmolol as either fixed doses or on a weight basis. Tariq et al98 used

esmolol at a dose of 1mg/kg 2 minutes before laryngoscopy and concluded that it only

partially attenuated the haemodynamic response but did not abolish it completely.

Miller and Martineau99 demonstrated that bolus doses of esmolol, approximately

1.5mg.kg -1, administered to patients with known or suspected coronary artery diseases

2 minutes before laryngoscopy and intubation, could effectively control post induction

27

increases in heart rate. Hussein and Sultan100 evaluated the efficacy of esmolol at

2mg.kg -1 bolus given 2 minutes before intubation and reported an attenuation of the

increase in heart rate but not arterial pressure. However, following the administration

of an even larger dose of 4mg.kg -1 2 minutes before laryngoscopy in 100 elderly

patients scheduled for cataract surgery, Van den Berg and Honjol reported that esmolol

prevented the rise in heart rate and rate-pressure product only 101. Their findings were

similar to those of Cucchiara et al102 who concluded that although the increase in heart

rate and blood pressure associated with laryngoscopy and endotracheal intubation were

significantly lower when compared with placebo; the incidence of raised blood pressure

was about 60% even with large doses of esmolol.

Oxorn and Knox103 evaluated the effectiveness of esmolol administered in fixed doses

of 100mg and 200mg 90 seconds before laryngoscopy, in 48 patients undergoing

elective hysterectomy. They reported an attenuation of the rise in heart rate for 2.5

minutes following intubation after which it became indistinguishable from placebo. The

rise in blood pressure however, was not mitigated by either dose of esmolol when

compared with placebo. Rathore et al104 went further to compare three bolus doses of

esmolol for attenuation of the pressor response in 100 patients scheduled for elective

surgery under general anaesthesia. The patients were administered 50mg, 100mg or

150mg of esmolol 2 minutes before laryngoscopy and intubation. All the doses were

effective in blunting the pulse rate response but only the 150mg dose proved effective

in blunting the blood pressure response.

However, Bernstein105used similar doses of esmolol in a bolus fashion 2 minutes before

laryngoscopy and intubation, and found that hypertension and tachycardia were both

prevented following rapid sequence induction. He also reported a significantly lower

incidence of post-intubation ventricular tachyarrhythmias in the esmolol group. His

28

findings were attributed to a slightly larger dose of thiopentone (5mg.kg -1 versus

4.6mg.kg -1) given in closer proximity to the time of laryngoscopy and intubation than

was done by Oxorn and colleagues. There were no significant side effects attributable

to the use of esmolol in any of the studies.

ESMOLOL VERSUS LIDOCAINE

Helfman and colleagues106 compared the efficacies of intravenous esmolol and

lidocaine in attenuating the pressor response. In a double-blind, placebo-controlled trial

involving 80 patients undergoing non-cardiac surgery, they compared lidocaine 200mg,

fentanyl 200µg and esmolol 150mg, to determine which best prevented tachycardia and

hypertension due to tracheal intubation. Mean percentage increases in heart rate during

and after intubation were lowest in the esmolol group(12%) compared to the

lidocaine(51%), fentanyl (18%) and placebo(44%) groups; while the mean systolic

blood pressure increases were lowest in the fentanyl group(12%) compared to the

esmolol(19%) and lidocaine (20%) groups. Only esmolol provided consistent and

reliable protection against increases in both heart rate and blood pressure accompanying

laryngoscopy and intubation. Feng et al107 conducted a similar study but the test drugs

were administered on a weight basis as against the fixed doses used by Helfman and

colleagues. The incidence of tachycardia (heart rate more than 100/min) was 15% in

the esmolol group, significantly lower than the lidocaine (75%), fentanyl (55%) and

control (85%) groups. The incidence of hypertension (systolic blood pressure>

180mmHg) was also lower (20%) in the esmolol group compared to the lidocaine

(70%), fentanyl (40%) and control (80%) groups. They concluded that only esmolol

reliably offered protection against increases in both heart rate and systolic blood

pressure.

29

Questions have been raised with regards to the methodology deployed by these groups

of researchers which may have inadvertently introduced a bias in favour of esmolol108.

In both studies, laryngoscopy and intubation were performed 2 minutes after induction.

This might be expected to favour the effectiveness of esmolol which has a peak effect

on heart rate and blood pressure at 1 to 2 minutes as against that of lidocaine which is

at 2 to 3 minutes thus explaining why the principal benefits of lidocaine administered

within this time frame were not achieved.

Levitt and Dresden109 compared the effects of esmolol and lidocaine on the pressor

response during intubation of patients with intracranial hypertension following isolated

head trauma. Esmolol 2mg.kg -1 or lidocaine at 2mg.kg -1 was administered

intravenously just prior to intubation. The study did not reveal any significant difference

as neither drug effectively attenuated the haemodynamic response to intubation.

A few researchers have recommended the use of a combination of both drugs for

obtunding the pressor response to laryngoscopy and intubation. In a study conducted

by Kindler et al in 1996 110 , they compared esmolol, lidocaine and a combination of

both drugs administered 2 minutes prior to laryngoscopy. Esmolol 1 to 2 mg.kg -1 was

found to be reliably effective in attenuating the heart rate response to intubation while

the combination of esmolol 2mg.kg-1 and lidocaine 1.5mg.kg -1 attenuated both the heart

rate and blood pressure responses to intubation. Neither esmolol nor lidocaine

administered alone affected the blood pressure response. Bansal and Pawar111compared

the efficacy of two bolus doses of esmolol with or without lidocaine in 80 patients with

pregnancy induced hypertension scheduled to undergo lower segment caesarean

section. The patients were allocated to four groups of 20 patients each and were

administered esmolol 1mg.kg-1 alone, esmolol 2mg.kg-1 alone, esmolol 1mg.kg-1 and

lidocaine 1.5mg.kg-1, or esmolol 2mg.kg-1 and lidocaine 1.5mg.kg-1 2 minutes before

30

laryngoscopy and intubation. The combinations of esmolol and lidocaine were effective

in attenuating the adrenergic responses to laryngoscopy and intubation. There were no

adverse effects in the mothers or their babies.

MATERIALS AND METHODS

This was a prospective study conducted over a period of six months among adult

31

elective surgical patients at the Lagos University Teaching Hospital. The approval of

the Research and Ethics Committee of the hospital (Appendix III) and informed consent

(Appendix II) of each patient were obtained. Ninety (90) patients with the American

Society of Anesthesiologists (ASA) physical status 1 or 2, between the ages of 18 and

60 years were included in the study. There were 50 males and 40 females. Exclusion

criteria included: known allergies to beta-adrenergic antagonists or local anaesthetic

agents; compensatory tachycardia (anaemia, infection, and hypovolaemia); cardiac

diseases (heart block of any degree, myocardial infarction, congestive cardiac failure,

and cardiac dysrhythmias); bronchospastic disease and chronic obstructive airway

disease. Also excluded were those on cardioactive drugs, antihypertensive agents,

theophylline, beta-agonist, and ipatropium bromide or inhaled steroid therapy. All the

patients were seen in the ward at least a day before surgery for pre-operative

assessment. This entailed obtaining a history, conducting physical examination and

requesting relevant investigations. The patients were weighed and their weights were

documented in their case notes. Anaesthetic premedication was prescribed consisting

of 10mg oral diazepam given with a sip of water the night before surgery and one hour

before induction of anaesthesia. Preoperative fasting guidelines of 6 hours to solids and

2 hours to clear fluids were observed.

On arrival at the operating theatre, the patients who required endotracheal intubation

were randomly assigned by blind balloting to one of three groups, L (Lidocaine), E

(Esmolol) and C (Control).The anaesthetic drugs were drawn in appropriate doses and

an equipment check was performed. A multiparameter Siemens™ monitor incorporated

with a blood pressure cuff and pulse oximetry probe was attached to the patients.

Baseline heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP),

mean arterial pressure (MAP) and arterial oxygen saturation (SpO2) were obtained in

32

the supine position and recorded by an anaesthetist registrar (person A). Intravenous

access was established using a size 18G cannula and an infusion commenced with a

0.9% saline solution. Based on the designated study group, the drugs were drawn in

sterile unlabelled 20ml syringes and made up to equal volumes of 20mls with normal

saline by the primary researcher (person B). This was done in the preanaesthetic room

after which the drug was handed over to an anaesthetist registrar for administration to

the patient (person C). All test drugs were colourless.

The patients were pre-oxygenated for five minutes by the primary researcher. During

preoxygenation, the group L patients were given 1.5mg.kg -1 of Lidocaine

hydrochloride while the group E patients received 2mg.kg -1 Esmolol hydrochloride by

slow intravenous injection over 30 seconds. Patients in the control group(C) received

20mls of 0.9% saline solution. Following the administration of the test drugs, the

haemodynamic variables were measured and recorded (pre- induction values) by the

anaesthetist registrar (Person A) who was blinded to the designated agent.

Anaesthesia was then induced in all the groups with 5mg.kg-1 thiopentone sodium by

slow intravenous injection followed with 1.5mg.kg-1 suxamethonium chloride given

intravenously. Prior to and during the induction period, verbal contact was maintained

with the patients to detect any adverse reactions to the test drugs such as tinnitus,

circumoral numbness, pain at the injection site or tightness in the chest.

After adequate muscle relaxation as judged by jaw relaxation or disappearance of

fasciculations, laryngoscopy was undertaken by the primary researcher with a size 4

curved Macintosh blade at 3 minutes in the Lidocaine and Control groups and 2 minutes

in the Esmolol group, and then endotracheal intubation with an appropriate sized

polyvinyl chloride (PVC) tube was done in each case. Following successful passage of

the tracheal tube and immediately after removal of the laryngoscope, HR, SBP, DBP

33

and MAP were recorded from the automatic oscillometer while the Rate Pressure

Product (RPP) was calculated and recorded. Surgical stimulation as well as the

administration of analgesic supplements and muscle relaxants were avoided during the

study period i.e. start of induction to 10 minutes later. Anaesthesia was maintained with

an inspired halothane concentration of 1.5-1.8% in 100 per cent oxygen.

HR, SBP, DBP and MAP readings were obtained at 1, 3, 5 and 10 minutes after tracheal

intubation and at 10 minute intervals thereafter till the end of surgery.

The Rate Pressure Product (RPP) was calculated thus;

Rate Pressure Product = Heart Rate X Systolic Blood Pressure, and recorded.

The duration of laryngoscopy and intubation was determined by stop watch

measurement and recorded. This was taken as the time from oral passage of the

laryngoscope to successful placement of the endotracheal tube. Patients with difficult

and /or repeated laryngoscopy and /or intubation that lasted for over 30 seconds were

excluded from the study. Laryngoscopy was performed by the primary researcher in all

the patients.

The following parameters were defined for the study:1) Hypotension was defined as

SBP< 25% of baseline value or 90 mm Hg; 2) Hypertension was defined as SBP > 25%

of baseline value or 150mm Hg; 3) Tachycardia was defined as HR > 25% of baseline

value; 4) Bradycardia was defined as HR < 60 beats.min-1.

Data collected was entered into a proforma (Appendix I) and analysed with computer

analytical package Epi 6 info, version 6.4.

Data was reported as mean± SD and percentage changes. Repeated measures of

ANOVA were used to compare values for heart rate, systolic blood pressure, diastolic

blood pressure, mean arterial pressure and rate pressure product, to baseline values in

each group. Repeated measures of ANOVA were also used to compare the

34

haemodynamic variables between the three groups. Differences were deemed

significant at a p value<0.05.

Microsoft excel™ software was used for graphical presentation.

RESULTS

Patients were selected from the different surgical specialties. Patients presenting for

general surgical procedures constituted the largest number of 28 (31.1%), while the ear,

nose and throat (ENT) surgery patients were the least (2.2%). Figure 1 shows the

distribution of the sample population according to surgical specialty.

The demographic data was compared among the three groups. There was no significant

difference between the groups with respect to age, gender, weight, ASA score or

35

duration of laryngoscopy (Table 1).

A. HEART RATE

Compared with the baseline readings, the mean heart rate was increased after

laryngoscopy and tracheal intubation in all three groups as depicted in figure 2. This

was highest in the control group where laryngoscopy and intubation caused a rise in the

heart rate from a mean baseline value of 80.6 to 114.0, an increase of 41.4% which was

statistically significant (p=0.000). In the lidocaine group, the heart rate rose from 82.2

to 108.4, an increase of 25.7%. This was significantly less than the rise observed in the

control group (p=0.012). There was an initial decrease in heart rate after the

administration of esmolol which was significant (p=0.04) but this was followed by a

rise following laryngoscopy and intubation. In the esmolol group, mean heart rate

increased from 86.8 to 103.4, an insignificant increase of 19.1%. This differed

significantly from the control group (P=0.001) but not the lidocaine group (p=0.275).

At 1,3 and 5 minutes after laryngoscopy and endotracheal intubation, there was a

decrease in heart rate in all the three groups but the changes were not statistically

significant (P>0.05) and at 10 minutes post-intubation, this parameter closely

approached baseline values in the esmolol and lidocaine groups(figure 3)

B. MEAN SYSTOLIC BLOOD PRESSURE

Compared to the baseline values, the systolic blood pressure (SBP) increased in all three

groups following laryngoscopy and intubation (figure 4). The increase was highest in

the control group where it rose significantly from a mean baseline value of 128.7 to

163.3 (26.9%) post-intubation (p=0.002), and least in the esmolol group, which

increased from 135.1 to 153.1 (13.3%) (p=0.056). There was a significant difference

between the esmolol and control groups (p=0.002). In the lidocaine group there was a

36

significant rise in SBP of 21.6% post laryngoscopy and intubation, but this did not differ

significantly from the esmolol(p=0.066) or control(p=0.055) groups.

Systolic blood pressure gradually declined in all the three groups and decreased below

baseline values after 5 minutes in all the three groups. The decrease was significant in

both treatment groups (p=0.02) but not in the control group (p=0.062). Despite this

drop, systolic blood pressure remained above 110mmHg in all three groups. Figure 5

shows the mean systolic blood pressure changes in all three groups.

C. MEAN DIASTOLIC PRESSURE

The control group (C) and both study groups (L and E) all registered a rise in the mean

diastolic pressure (DBP) immediately after laryngoscopy and intubation. In the esmolol

group there was an initial insignificant fall in diastolic blood pressure following the

administration of the drug (p=0.506). The mean diastolic pressure in the control group

rose from 78.0mmHg to 114.0mmHg (46.1%) at laryngoscopy and intubation, whereas

in the lidocaine and esmolol groups, the values rose from 79.1 and 85.6 mmHg to 106.3

(34.5%) and 99.5mmHg (16.2%) respectively. The difference between both treatment

groups and the control group was significant following intubation but this was more

significant in the esmolol group (p=0.000) compared to the lidocaine group (P=0.001)

(figure 6)

By 5 minutes the mean diastolic blood pressure decreased below baseline values but

remained above 70mmHg in all three groups (figure7).

D. MEAN ARTERIAL PRESSURE

There was an initial decrease in mean arterial pressure (MAP) in the esmolol and

Lidocaine groups following the administration of the study drugs which was not

statistically significant (p=0.06 and p=0.08 respectively). This increased in all groups

37

following laryngoscopy and intubation. In the control group, there was a significant

30.2% increase from mean baseline value of 97.1 to 126.4(p=0.001). In the lidocaine

group, the mean baseline MAP of 109.3 rose to 130.2 post intubation, an increase of

19.1%. The increase was least in the esmolol group where it rose from 103.8 to 116.5

(12.2%). These changes were significantly less in both groups compared to the control

group, but more so in the esmolol group (p=0.000) than the lidocaine group (p=0.02).

(Figure 8). There was no significant difference between both treatment groups (p=0.08).

By 3 minutes post-intubation, there was a progressive decrease in MAP and by 5

minutes the values had dropped to less than the baseline values (figure 9). This drop

was most in the lidocaine group (19.5%) and least in the control group (10% ).

E. THE MEAN RATE PESSURE PRODUCT (RPP)

The mean rate pressure product values in the control group showed a significant

increase at intubation from 10381.3 to 18549.9 (78.7%) p=0.000. The values in the

lidocaine and esmolol groups also showed an increase from 11438.6, 12550.9 to

16681.4 (45.8%) and 16072.7 (28.1%) respectively (figure 10). The difference was

highly statististically significant compared to control group in both lidocaine and

esmolol groups following intubation, p=0.000 and p=0.000 respectively. At 3 minutes

post-intubation, a decrease in the mean rate pressure product below the baseline value

was observed in the esmolol group and was sustained till 10 minutes post intubation

(figure 11).

There were no complications attributable to the use of either study drug recorded during

the course of the study.

38

31%

29%22%

10%6% 2%

FIGURE 1. THE DISTRIBUTION OF PATIENTS ACCORDING TO SURGICAL SPECIALTY

General Surgery

Gynaecology

Urology

Orthopedics

Burns and Plastics

Ear, nose and throat

39

TABLE 1 DEMOGRAPHIC DATA AND CLINICAL CHARACTERISTICS

OF PATIENT

Control

n=30

Lidocaine

n=30

Esmolol

n=30

P value

Age/years

mean± SD

35.0±13.35 38.8±10.99 36.0±11.72 0.846

Weight/ kg

mean± SD

66.3±8.47 70.5±11.97 60.7±9.79 0.414

Gender ratio

(M:F)

16:14 15:15

18:12 0.302

ASA classification ratio

( I:II)

18:12 16:14 17:13 0.058

Duration of laryngoscopy and

Tracheal intubation/ seconds

(mean ± SD)

20.6±3.90 19.77±3.76 21.3±5.90 0.718

of 85

70

75

80

85

90

95

100

105

110

115

120

Ba

se

line

Imm

ed

po

st-

intu

ba

tion

3 M

in

10

Min

Me

an

He

art

Ra

te(b

ea

ts/m

inu

te)

Time

FIGURE 2. MEAN HEART RATE

Control

Esmolol

Lidocaine

of 85

FIGURE 3. PERCENTAGE CHANGE FROM BASELINE

IN MEAN HEART RATE

-20

-10

0

10

20

30

40

50

Baseline Pre-induction Immed post-

intubation

1 Min 2 Min 5 Min 10 Min

Time

% C

han

ge f

ro

m b

aseli

ne

Control

Esmolol

Lidocaine

of 85

100

110

120

130

140

150

160

170

Baselin

e

Pre-in

ductio

n

Imm

ed p

ost In

tubatio

n

1 M

in

3 M

in

5 M

in

10

Min

Mea

n S

yst

oli

c B

loo

d P

ress

ure

(m

mH

g)

Time

FIGURE 4. MEAN SYSTOLIC BLOOD PRESSURE

Control

Esmolol

Lidocaine

of 85

FIGURE 5. PERCENTAGE CHANGE FROM BASELINE IN MEAN SYSTOLIC BLOOD

PRESSURE

-20

-15

-10

-5

0

5

10

15

20

25

30

Baseline Pre-induction Immed post

Intubation


Time

% C

han

ge f

rom

baseli

ne

Control

Esmolol

Lidocaine

of 85

60

70

80

90

100

110

120

Baselin

e

Pre

-ind

uctio

n

Imm

ed

post

intu

batio

n

1 M

in

3 M

in

5 M

in

10

Min

Mean

Dia

sto

lic B

loo

d p

ressu

re (

mm

Hg

)

Time

FIGURE 6. MEAN DIASTOLIC BLOOD PRESSURE

Control

Esmolol

Lidocain

e

of 85

FIGURE 7. PERCENTAGE CHANGE IN MEAN DIASTOLIC

PRESSURE

-20

-10

0

10

20

30

40

50


intubation


Time

% c

han

ge i

n D

iasto

lic b

loo

d p

ressu

re

Control

Esmolol

Lidocaine

of 85

60

70

80

90

100

110

120

130

140

Ba

se

line

Pre

-ind

uctio

n

Imm

ed

po

st in

tub

atio

n

1 M

in

3 M

in

5 M

in

10

Min

Me

an

Art

eri

al

pre

ss

ure

(m

mH

g)

Time

FIGURE 8. MEAN ARTERIAL PRESSURE

Control

Esmolol

Lidocaine

of 85

FIGURE 9. PERCENTAGE CHANGE FROM BASELINE IN MEAN

ARTERIAL PRESSURE

-30

-20

-10

0

10

20

30

40


intubation


time

% c

han

ge f

rom

baseli

ne Control

Esmolol

Lidocaine

of 85

8000

10000

12000

14000

16000

18000

20000

Base

line

Pre

-ind

uctio

n

Imm

ed p

ost in

tuba

tion

1 M

in

3 M

in

5 M

in

10

Min

Mea

n R

ate

-p

res

su

re P

rod

uct

ch

an

ge

(mm

Hg

bea

ts.m

in-1

)

Time

FIGURE 10. MEAN RATE-PRESSURE PRODUCT

Control

Esmolol

Lidocaine

of 85

FIGURE 11. PERCENTAGE CHANGE FROM BASELINE IN MEAN RATE-

PRESSURE PRODUCT

-20

-10

0

10

20

30

40

50

60

70

80

90


intubation


Time

% C

han

ge f

rom

baseli

ne

Control

Esmolol

Lidocaine

of 85

DISCUSSION

Laryngoscopy and intubation are associated with a cardiovascular response of elevated

blood pressure and pulse rate as well as occasional dysrhythmias. Lidocaine and esmolol

are two drugs which have been used by anaesthetists in an attempt to attenuate this

response.

In this study, treatment with intravenous lidocaine three minutes before laryngoscopy and

intubation significantly attenuated the post-intubation increases in heart rate and rate

pressure product. A dose of 1.5mg.kg -1 was chosen based on work by Tam, Chung and

Campbell who observed complete attenuation of the response when this dose of lidocaine

(1.5mgkg-1) was given three minutes before laryngoscopy and intubation65. Similarly, a

review of 25 studies by Lev and Rosen on the preintubation use of lidocaine revealed that

a dose of 1.5mg.kg -1 given intravenously three minutes before intubation was optimal34.

In the present study, the heart rate increased by 25.7% in patients who received lidocaine

compared to the control value of 33.4%. This shows that lidocaine as used in this study

attenuates but does not abolish the post intubation rise in heart rate. This correlates with

of 85

the findings of Wilson et al112 who reported that irrespective of the timing of administration

of intravenous lidocaine, 2, 3 or 4 minutes before tracheal intubation, there was an increase

in heart rate of 21-26 % in all groups studied. In this study, intravenous lidocaine had an

insignificant effect on the systolic blood pressure; 21.6% rise compared to the control value

of 26.9%. The effects of intravenous lidocaine on diastolic blood pressure and mean arterial

pressure were also not significant.

of 85

Several authors have emphasized the importance of timing of administration of lidocaine

on its ability to attenuate the pressor response to laryngoscopy and endotracheal intubation.

Tam et al81 showed that when administered intravenously three minutes before intubation,

1.5mg.kg-1 lidocaine significantly attenuated haemodynamic changes secondary to

emergency intubation in patients with raised intracranial pressure following blunt head

injury. Wang et al113 reported that the values of systolic and diastolic pressures one minute

after intubation were significantly less in groups where 1.5mgkg-1 lidocaine was given

either 3 or 5 minutes before intubation.

In Miller and Warren’s study of a group of 45 Chinese women, intravenous lidocaine

1.5mg.kg-1 failed to attenuate the cardiovascular response to laryngoscopy and tracheal

intubation irrespective of the timing of administration i.e. 1, 2 or 3 minutes before

laryngoscopy83. In the same vein, Chraemmer-Jorgensen and colleagues114 reported a total

lack of effect of intravenous lidocaine given 2 minutes prior to laryngoscopy and

intubation, on the haemodynamic responses. Despite pre-treatment of their patients with

intravenous lidocaine, the rate- pressure products were observed to approach levels

considered potentially dangerous to patients with ischaemic heart disease. Differences in

study protocol, patient population, premedication, depth of anaesthesia, duration of

laryngoscopy and interval between lidocaine administration and laryngoscopy may

account for these apparently varied results among the different studies.

The pharmacokinetic properties of intravenous lidocaine may explain its ability to attenuate

the pressor response within a tightly specific time frame. Following intravenous injection,

the onset of action is between 45-90 seconds with a peak effect at 1-3 minutes77. Its

optimum effect on the haemodynamic response to laryngoscopy and intubation is most

of 85

likely exerted at about its peak effect. It also obtunds laryngeal reflexes and reduces

thiopentone requirement by 13.3%79,80. Abou-madi et al35 suggested other possible

mechanisms to explain the anti-pressor effects of lidocaine. These include a direct

myocardial depressant effect, a peripheral vasodilating effect and a possible effect on

synaptic transmission.

There were no complications recorded following the administration of intravenous

lidocaine in this study. However, in their study evaluating the haemodynamic response to

laryngoscopy and intubation in geriatric patients, Splinter and Cervenko reported that 34%

of their patients who were given intravenous lidocaine developed tinnitus82.

In this study, the administration of intravenous esmolol resulted in a 19.1% increase in

post-intubation heart rate compared to 41.4% in the control group and 25.7% in the

intravenous lidocaine group. The esmolol group showed a rise in systolic blood pressure

(13.3%) but this was significantly less than those observed in the lidocaine (21.6%) and

control (26.9%) groups. The response to the dose of esmolol used in this study was similar

to that obtained by Helfman et al106 who compared lidocaine and esmolol for attenuation

of the pressor response and reported mean percent increases in heart rate of 44% lidocaine,

51% placebo and 18% in esmolol group. Mean systolic blood pressure percent increases

were 20% in the lidocaine, 36% in the placebo and 19% in the esmolol groups. Only

esmolol provided consistent and reliable protection against increases in both heart rate and

systolic blood pressure accompanying laryngoscopy and intubation.

The rationale for the administration of esmolol as a bolus rather than as an infusion in this

study was twofold; the desire for a rapid onset and short duration of action in order to

promptly treat a transient haemodynamic event as well as the convenience of bolus

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administration compared with the preparation and administration of an infusion. A dose of

2mg.kg-1 administered two minutes prior to laryngoscopy and intubation was chosen for

this study based on results of several published trials evaluating the use of esmolol for

attenuation of the pressor response92,99,105. Sintetos et al92 recommended that esmolol be

given 2 minutes before intubation for effective results because its maximum effects on

heart rate and blood pressure occurred in the first and second minutes respectively.

At 5 minutes, both treatment groups showed significant decreases in mean SBP compared

to baseline which persisted even until 10 minutes after intubation. This could be attributed

to the rapid metabolism of released catecholamines, myocardial depressant effect of the

volatile agent (halothane) and the absence of surgical stimulation6,10,63. Although none of

the patients in the study had hypotension, by definition, the 14.5% and 13.8% mean

reduction in SBP observed in the esmolol and lidocaine groups respectively, suggest their

potential for hypotension especially in haemodynamically unstable patients.

The rate-pressure product (RPP) increased post intubation in all the groups. Esmolol

showed significantly greater effects than lidocaine in attenuating the post-intubation rise in

RPP. The rate-pressure product (a product of the systolic blood pressure and heart rate) is

a good index of myocardial oxygen consumption and a threshold of RPP has been

correlated with the onset of angina in patients with known coronary artery diseases or those

who have risk factors for coronary artery disease115. Increased blood pressure and heart

rate lead to elevated myocardial oxygen demand and the haemodynamic changes at

intubation may precipitate myocardial ischaemia and infarction. Tachycardia increases

myocardial oxygen demand, decreases diastolic filling time, and hence coronary blood

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flow. A moderate increase in heart rate (15%) has been shown to be accompanied by a 17%

decrease in coronary perfusion pressure116.

Raised blood pressure, on the other hand, increases both oxygen demand and supply and

thus has a less predictable effect on myocardial oxygen balance. Furthermore, the increase

in blood pressure accompanying laryngoscopy and intubation has been attributed to an

increase in cardiac output rather than increased systemic resistance117. Hence, by its

predominant attenuation of increases in heart rate, esmolol is more likely to optimize the

myocardial oxygen supply/demand relationship. Recommendations of maximum permitted

RPP range from 12,000 to 23,000 mmHg beats.minute-1 and values exceeding this are

commonly associated with myocardial ischaemia and angina118. The patient’s preoperative

level should however serve as a guide. Rao et al119 recommended that in the anaesthetic

management of patients with cardiac morbidity presenting for non-cardiac surgery, the

heart rate and systolic blood pressure and thus the RPP should not fluctuate beyond 20%

of the baseline value. Although RPP does not predict regional myocardial supply-demand

relationships, examination of the individual components (heart rate and systolic blood

pressure) is a useful guide in the management of ischaemic heart disease. Of the two

treatment techniques used in this study, esmolol was superior as it significantly attenuated

the heart rate, systolic blood pressure and rate-pressure product changes. However, the

28.06% rise in RPP recorded in the esmolol group still exceeds Rao's 20%

recommendation. This is however significantly superior to the 45.8% of the lidocaine

group and the 78.7% of the control group.

The transient decrease in RPP observed in the esmolol group following the administration

of the drug, correlate with those of Liu and colleagues who using esmolol to control

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haemodynamic responses associated with tracheal intubation, reported a decrease in RPP

prior to induction of anaesthesia120. As observed in the present study, Liu et al reported a

post intubation increase in RPP which was 50% less in the esmolol-treated patients

compared to the placebo group. However, Buffington121 was of the opinion that during

anaesthesia, myocardial ischaemia is poorly correlated with RPP. His advocacy of the

Pressure Rate Quotient (PRQ) as a more reliable index of myocardial ischaemia is disputed

by other workers.122

Apart from causing a transient decrease in heart rate and blood pressure following its

administration at induction, there were no adverse effects attributable to the use of esmolol

in this study. Miller et al97 showed that esmolol in doses of 1.5-3.0mg.kg -1 did not alter

stroke volume or depress left ventricular function in patients with preserved cardiac

function.

In this study, the adoption of different time intervals for administration of esmolol and

lidocaine i.e. 2 and 3 minutes respectively, may have introduced a possible source of bias

with respect to blinding. Review of available literature revealed that these doses and time

intervals were safe and produced consistent results with respect to attenuation of the pressor

response34,35,81,92. This bias was reduced by the use of an impartial observer (anaesthetist

registrar) who measured and recorded the haemodynamic data.

Thomson9 and Hung10 have questioned the clinical significance of the haemodynamic

responses associated with laryngoscopy and intubation and argue that the subject does not

deserve the attention it attracts. They are quick to point out that a transient increase in

arterial blood pressure and heart rate occurs in most of our daily activities and may not be

of any clinical importance. Hung10 argued that the interpretation of cardiovascular

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responses to anaesthetic drugs is difficult when a noxious intervention such as

laryngoscopic intubation introduces confounding variables such as magnitude and duration

of the noxious intervention as well as variables introduced by various medical conditions

such as cardiovascular diseases and diabetes mellitus. These he postulated, may explain

the inconsistent results reported in previous studies. In his experiment in which 21 healthy

volunteers were subjected to stress tests with continuous haemodynamic monitoring (intra-

arterial blood pressure and heart rate), he was able to demonstrate that haemodynamic

responses occur with normal daily activities and these responses are generally well

tolerated, provided they are short lived .

The clinical significance of the pressor response to laryngoscopy and intubation is most

important in the perioperative management of patients with cardiovascular diseases and

intracranial hypertension. Prys-Roberts et al17 found that hypertensive patients, whether

treated or untreated, are prone to much greater changes in arterial pressure (and thus RPP),

than normotensive patients of the same age group. They found that the excessive swings in

blood pressure observed in their patients, were accompanied by electrocardiograph (ECG)

evidence of myocardial ischaemia. In the hypertensive patient with normal left ventricular

function, the blood pressure falls at induction without a significant fall in heart rate; thus

maintaining left ventricular filling pressure and blood supply. Hence the incidence of

myocardial ischaemic changes in these patients is less than 6%. However, in the patient

with hypertensive heart disease and poor left ventricular function, the heart rate increases

following induction of anaesthesia, with a decrease in filling pressure and left ventricular

blood flow. The risk of ischaemic changes in these patients is almost as high as 33%103.

Urban et alix examined the relationship between several intraoperative haemodynamic

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variables, fixed cardiac risk factors, intraoperative myocardial ischaemia and postoperative

myocardial infarction (PMI) in a group of patients undergoing coronary by-pass graft

(CABG) surgery. They found that RPP > 12,000(beats.min-1.mmHg-1) was significantly

associated with pre-cardiopulmonary bypass (pre-CPB) myocardial ischaemia. In addition,

a pre-CPB electrocardiography ischaemia was significantly associated with a postoperative

myocardial infarction.

In an earlier editorial on the subject by Thomson9, several observations were made. He

noted that although researchers documented the haemodynamic changes accompanying

laryngoscopy and intubation, they gave no information on outcome. Thus, the influence of

their interventions on the incidence of perioperative cardiovascular morbidity and mortality

were unknown. Although he admitted that certain subgroups of patients (i.e. those with

symptomatic aortic aneurysm, recent myocardial infarction, cerebral aneurysm or

intracranial hypertension) required careful haemodynamic control during intubation of the

trachea, he noted that such patients were never included in the control group of studies

examining the efficacy of haemodynamic control during laryngoscopy and intubation. He

advocated that since myocardial infarction accompanying perioperative myocardial

ischaemia occurred between the second and fifth postoperative day, greater benefits will

be achieved if haemodynamic control is extended to cover the entire perioperative period,

rather than limited to two minutes following intubation9.

While making pertinent observations, Thompson appears to have ignored the ethical

aspects of such research. Withholding therapy from patients at risk in order to determine

outcome would raise a lot of questions with regards to ethics. Nonetheless, search of the

literature revealed a number of studies performed on patient populations at risk of

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developing perioperative complications such as the elderly, those with documented

coronary artery disease, vascular disease, hypertension, diabetes and obesity66,95,97. In these

studies, the duration of laryngoscopy and intubation was limited to 30 seconds to avoid

unduly endangering the patients in the control groups. Although the various researchers

did not advocate the routine use of these agents for all patients undergoing general

anaesthesia, they were recommended as useful adjuncts in patients at risk when it is

imperative to control haemodynamic responses to transient perioperative stimuli.

In this study, the unit costs of esmolol and lidocaine per patient were averagely N1, 700

($14.20) and N200 ($1.70) respectively which makes lidocaine more cost-effective to use

for attenuation of pressor responses to laryngoscopy and endotracheal intubationx. This is

particularly of significance in the face of dwindling health care resources and poor funding.

However, the use of more expensive drugs may be justified in susceptible groups of

patients if it will result in better perioperative management, reduced morbidity or an overall

reduction in length of hospital stay. Although esmolol is currently more expensive than

lidocaine, the observation in the past is that as patent rights expire, regularly used drugs

become cheaper and more readily available for use in Nigeria.

CONCLUSION

This study has confirmed that significant increases in haemodynamic variables accompany

laryngoscopy and endotracheal intubation following the widely utilized technique of

induction of anaesthesia with sodium thiopentone followed by suxamethonium for tracheal

intubation. These changes are maximal immediately after intubation, but return to baseline

values by 5 -10 minutes.

Neither drug deployed in this study completely abolished this response but it was

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attenuated to varying degrees. Intravenous lidocaine 1.5mg.kg-1 administered 3 minutes

before laryngoscopy significantly attenuated the heart rate and rate-pressure product

changes following laryngoscopy and intubation. Intravenous esmolol 2mg.kg -1 given 2

minutes prior to laryngoscopy was statistically superior to lidocaine as it significantly

attenuated all the cardiovascular changes. Comparing the results obtained in this study

with those conducted in Europe, North America and Asia in other patient groups,

intravenous esmolol had a significant effect in this African population as it significantly

attenuated every measured haemodynamic variable.

The use of these two agents in the doses deployed in this study was not associated with any

untoward effects.

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RECOMMENDATIONS

Based on the findings of this study, it is recommended that;

Greater efforts should be made by hospitals and relevant regulatory agencies to

make esmolol hydrochloride readily and cheaply available to anaesthetists

practicing in Nigeria for the control of periods of intense sympathetic stimulation

such as laryngoscopy and intubation. This would enhance perioperative patient

management and add on to the safety of anaesthetic practice.

Although not recommended for routine administration in all patients, esmolol is a

useful adjunct for use by anaesthetists involved in perioperative management of

patients with identifiable risk factors for coronary artery disease, hypertension or

hypertensive heart disease with preserved cardiac function as these patients are at

high risk for development of myocardial ischaemia and infarction following

laryngoscopy and intubation.

A dose of 2mgkg-1 esmolol administered 2 minutes before laryngoscopy is optimal

for attenuation of the pressor response.

The use of intravenous lidocaine at a dose of 1.5mgkg-1 given 3 minutes before

laryngoscopy should not be abandoned. However it should be reserved for use in

patients in whom beta blockers are contraindicated (reactive airway disease,

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diabetes mellitus, heart block, congestive cardiac failure and bradyarrhythmias i.e.

HR<60beats.minute-1) or where more effective agents are unavailable for use.

A combination of lower doses of esmolol and lidocaine may offer better control of

the pressor response in Nigerians and is worth evaluating in the future.

LIMITATIONS

This study had the following limitations.

1. All the patients received the same dose of oral diazepam premedication irrespective

of weight due to the available formulation of diazepam tablets. This may have

modified the observed pressor response as benzodiazepines are known to have a

moderating effect on intraoperative cardiovascular responses103.

2. Cardiac dysrhythmias and myocardial ischaemia are two well documented

consequences of the haemodynamic response to laryngoscopy4. Thus continuous

electrocardiogram (ECG) monitoring of leads II and V5 is highly desirable in a

study like this. The available continuous ECG monitors in this centre were

malfunctional at the time of data collection for this study.

3. Direct intra-arterial measurements which give continuous, beat-to-beat blood pressure

readings would have provided more precise information on the haemodynamic

changes and the effectiveness of the studied drugs in attenuating the pressor

response. Facilities for such monitoring are not available in this centre.

4. Several studies have established that the haemodynamic changes observed during

laryngoscopy and intubation are associated with corresponding increases in serum

adrenaline and noradrenaline levels 6,39,40 It would have been worth determining if

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any of the treatment techniques used in this study had an effect on the plasma

catecholamine levels. However, the unavailability of facilities for conducting such

biochemical assays in this centre as well as the cost implications of external analysis

precluded this.

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APPENDIX I

PROFORMA

ATTENUATION OF THE PRESSOR RESPONSE TO

LARYNGOSCOPY AND ENDOTRACHEAL INTUBATION: A

COMPARISION OF ESMOLOL AND LIDOCAINE

Name: Hospital No: Date:

Age: Sex: Weight:

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Height: Drug history: Diagnosis: Surgical

procedure: ASA score: Premedication:

Study Group : Group L ( )

Group E ( )

Group C ( )

Duration of laryngoscopy and intubation:

Parameters Baseline Pre-

Induction

Immediate

Post intubation Post Intubation

1 min 3mins 5mins 10mins

HR

SBP

DBP

MAP

RPP

HR = Heart rate, SBP = Systolic Blood Pressure, DBP = Diastolic Blood Pressure, MAP =

Mean Arterial Pressure, RPP = Rate Pressure Product.

Complications

Bradycardia

Bronchospasm

Hypotension

Tinnitus

Circumoral numbness

Pain on injection

Others (specify)

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APPENDIX II

PATIENT INFORMED CONSENT

TITLE OF THE STUDY: Attenuation of the pressor response to laryngoscopy and

endotracheal intubation: A Comparison of intravenous esmolol and lidocaine.

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INTRODUCTION

You are being approached because you are going to have elective surgery under general

anaesthesia. Laryngoscopy and endotracheal intubation are an integral component of

airway management during general anaesthesia. They have been shown to result in a rise

in heart rate, blood pressure and the occurrence of arrhythmias. This may have detrimental

effects in susceptible patients e.g. patients with ischaemic heart diseases, hypertension and

head injuries. Various drugs have been suggested to prevent these haemodynamic changes.

Esmolol and Lidocaine are two of such drugs.

PURPOSE AND DESCRIPTION OF STUDY

The aim of this study is to evaluate the effects of each drug and compare their effects in

preventing these haemodynamic changes. During the preoperative anaesthetic visit on the

ward, an anaesthetist will explain the study protocol, answer any questions you may have

and ask for a written informed consent.

In the operating theatre, according to our routine management, an intravenous infusion will

be set up in order to give you appropriate anaesthetic drugs. We will monitor your blood

pressure, heart rate and oxygen level as part of standard practice.

You will be assigned to one of three groups by balloting. The groups would be named

according to the study drug that will be used. The same drugs will be given to every patient

for induction of anaesthesia and maintenance of anaesthesia will be standard for every

patient.

POTENTIAL RISKS

Since the study drugs will be administered on a weight basis, with adequate consideration

given to maximum safe doses and contraindications to their use, the risk s involved in

participating in this study are minimal.

CONFIDENTIALITY

All information obtained during the study will be held in strict confidence

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CONSENT FORM

Signing this consent form does not wave your legal rights nor does it relieve the

investigators or this institution from legal and professional responsibilities.

CONSENT

I have had an opportunity to ask all necessary questions regarding the information of my

participation in this study and have received satisfactory answers. I understand that my

participation in this study is entirely voluntary. I, the undersigned, accept to participate

freely in this research project.

----------------------------------------------- ------------------------------

Patient’s name signature and date

----------------------------------------------- ------------------------------

Witness name signature and date

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ATTENUATION OF THE PRESSOR RESPONSE

TO LARYNGOSCOPY AND ENDOTRACHEAL INTUBATION: A

COMPARISON OF INTRAVENOUS ESMOLOL AND LIDOCAINE

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DR. A. A. EHIOZE-OSIFO

MBBS (Lagos) 1996, PGDA (Benin) 2001

DEPARTMENT OF ANAESTHESIA

LAGOS UNIVERSITY TEACHING HOSPITAL

IDI-ARABA, LAGOS.

1.

attenuation of the pressor response to...

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