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Comparative evaluation of the effects of Etomidate versus

conventional induction techniques on hemodynamic stability

during induction in patients with impaired left ventricular

function undergoing cardiac surgery.

A Thesis submitted to the Tamil Nadu Dr. M.G.R Medical University

in partial fulfillment of the degree

M.D ANAESTHESIA.

By

Dr .J. Felinda Angelin

Christian Medical College and Hospital, Vellore,

Tamil Nadu, 632004 – India.

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CERTIFICATE

This is to certify that the dissertation entitled “Comparative evaluation of the

effects of Etomidate versus conventional induction techniques on

hemodynamic stability during induction in patients with impaired left

ventricular function undergoing cardiac surgery” is a bonafide work of Dr.

J.FELINDA ANGELIN in partial fulfillment of the requirements for the M.D.

Anaesthesiology (Branch X) degree examination of the Tamil Nadu Dr.M.G.R

Medical University, Chennai, to be held in April 2017.

Dr. ANNA PULIMOOD

Principal,

Christian Medical College,

Vellore

SIGNATURE OF THE GUIDE SIGNATURE OF THE H.O.D Dr.RAJ SAHAJANANDAN Dr. SAJAN PHILIP GEORGE Professor Professor and Head Department of Anaesthesiology Department of Anaesthesiology Christian Medical College Christian Medical College Vellore-632004 Vellore- 632004

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DECLARATION

 

I hereby declare that this dissertation titled “Comparative evaluation of the

effects of Etomidate versus conventional induction techniques on

hemodynamic stability during induction in patients with impaired left

ventricular function undergoing cardiac surgery”was prepared by me in

partial fulfilment of the regulations for the award of the degree of M.D

ANAESTHESIA of the Tamil Nadu Dr. M.G.R Medical University,

Chennai. This has not formed the basis for the award of any degree to me

before and I have not submitted this to any other university previously.

J. Felinda Angelin

Vellore

 

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ACKNOWLEDGEMENTS

First and foremost, I thank God the Almighty for enabling me to do this thesis.

I would like to express my sincere gratitude to my guide Dr. Raj Sahajanandan

for his constant support and encouragement, with his patience and immense

knowledge without whom this study might not have been possible. I would like

to thank Dr.Sajan Philip George, the Head of the Department of

Anaesthesiology for his continual encouragement. I would also thank

Dr.Vinayak Shukla, the Head of the Department of Cardiothoracic Intensive

Care Unit to conduct this study. I thank Dr. Varsha A.V and Dr.Gladdy

George, my co-guide, for their involvement in this study and Mr.Bijesh Yadav

for all the help in analyzing the data.

I also thank all my colleagues, seniors and juniors, for helping me in filling the

proforma and our Anaesthesia technicians who helped a lot in collecting the

data.

TTURNITINN ORIGINNALITY

RE

REPORT

EPORT

T – ANTIPPLAGIAR

5

RISM

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CONTENTS

TITLE PAGE NO

1) Introduction 7

2) Aims and objectives 10

3) Review of literature 11

4) Materials and Methods 66

5) Analysis and results 74

6) Discussion 89

7) Conclusions 94

8) Bibliography 95

9) Annexures 130

Proforma

Consent form

Information sheet

Data sheet

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INTRODUCTION

Coronary artery disease is prevalent worldwide, and many in India are

also affected due to the increasing sedentary lifestyle and high prevalence of

diabetes and hypertension...

In patients with coronary artery disease, induction of anesthesia is

challenging because the circulatory system cannot tolerate depression. The

main aim should be to avoid hypotension, minimize the stress response to

laryngoscopy and to maintain the balance between myocardial oxygen supply

and demand. This challenge is exaggerated when you are dealing with a patient

whose left ventricular function is impaired. Avoidance of hypotension is

crucial as it is associated with increased morbidity and mortality. Induction of

anesthesia is associated with loss of sympathetic tone, and myocardial

depression. Hypotension has been defined as a decrease in mean arterial

pressure (MAP) less than 60 mm Hg or a decrease of > 40% from the base line.

An episode of hypotension lasting for more than 1.5 minutes is shown to be

associated with a 13.3 % increase in hospital stay and 8.6% increase in death.

Intraoperative hypotension has been shown to be associated with myocardial

ischemia as evidenced by elevated troponin T levels(1).Intraoperative

hypotension is associated with the occurrence of myocardial ischemia as

evidenced by elevated Troponin levels. Given the high risk of poor outcomes

due to post induction hypotension, an ideal induction agent should be the one

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which produces minimal changes from baseline hemodynamic variables and

suppresses the stress response to intubation.

Normally laryngoscopy and intubation produce hypertension and tachycardia

or rarely bradycardia as result of autonomic stimulation which can jeopardize

the balance between myocardial supply and demand. Suppression/ minimizing

this response is an important aspect of anesthesia induction.

However our search for an ideal agent is still far from reality.

Various intravenous drugs are used for induction of anesthesia in these

patients, the common ones are thiopentone, propofol, ketamine, etomidate and

midazolam. We have to select an anesthetic that has the balance between

prevention of hypotension and avoiding a surgical stress response. Etomidate

has a stable cardiovascular profile and is considered by many as an ideal

induction agent in patients with significant coronary artery disease and left

ventricular dysfunction. Use of Etomidate is associated with adrenal

suppression even after single dose. Cortisol which is a stress hormone, is also

involved in maintaining the vascular tone, gets suppressed by etomidate. So,

there can be increasing requirement of vasopressors postoperatively and may

lead to poorer outcome in patients with sepsis. However the evidence is

conflicting.

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Midazolam is another induction agent with good cardiovascular stability and is

effective in suppressing the stress response to laryngoscopy and intubation.

However, combining midazolam with fentanyl may result in hemodynamic

instability.

We propose a study to compare etomidate and midazolam for induction

of anesthesia in patients with impaired left ventricular function undergoing

coronary artery bypass graft. We will compare the effects of these drugs on

hemodynamic stability and the ability to prevent intubation response. We will

also study whether the use of etomidate results in significant adrenal

suppression and general outcomes.

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AIMS AND OBJECTIVES

Primary aim:

1. To compare the effects of Etomidate and Midazolam on hemodynamic

stability during induction of anesthesia in patients with impaired left ventricular

undergoing Coronary artery bypass grafting.

2. To compare their efficacy in minimizing hemodynamic response to

intubation.

Secondary aim:

To measure serum cortisol levels in both group of patients to see if there is

any adrenal suppression with a single dose of etomidate used during induction.

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REVIEW OF LITERATURE

Global burden

Coronary artery disease is a leading cause of death and disability in

developed countries. Over the age of 35, one third or more of the mortality is

due to ischemic heart disease. The prevalence of coronary artery disease

worldwide is 70%. There are so many risk factors which promote coronary

artery disease like smoking, dyslipidemia, diabetes, and hypertension.

In 2010 the American Heart Association, Heart Disease and Stroke

Statistics(NHANES) in an update has reported that IHD prevalence to be 17.6

million .Among them myocardial infarction(MI) prevalence was 8.5 million

and the prevalence of angina pectoriswas 10.2 million (2).In both sexes there

was a progressive increase in the prevalence. Since 1990 there was a 41%

increase of deaths due to cardiovascular disease, that is 17.3 million deaths

worldwide.(3) The age-standardized death rate has decreased by 22 percent in

the same period.

During 1988-1994 and 1999-2004 time periods, in age group of 35-54

years, prevalence of MI was compared against sexin a NHANES data

2009report. It was found that men had a greater prevalence than women in both

the time period (2.5 in men versus 0.7 in women, and 2.2 in men versus 1.0 in

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women) and there was a declining trend in men and increasing trend in

women.(3)

INCIDENCE

In the original Framingham study,for an individual aged more than 40

yearsin a cohort of 44 years of follow up, the lifetime risk to develop CHD is

49 percent in men and 32 percent in women (4–6).The risk was found to be 35

percent in menand 24 percent in women, in individuals nearing 70 years. The

incidence of coronary events increases with age, in women MI presents later by

about 10 years. Women lag behind men in incidence by 20 years in the

incidence of MI and sudden death.

The incidence at ages 65-94years compared to ages 35-64 years, more

than doubles in men and triples in women (7–9).The annual incidence rate was

found to be 12 per 1000 in men below 65 years of age, this was more than the

rate of all the other atherosclerotic cardiovascular events combined (7 per

1000); in women, it equals the rate of the other events (5 per 1000). After 65

years of age, the leading health problem among the elderly is coronary artery

disease. Of the atherosclerotic cardiovascular events in men, coronary events

form 33 to 65 percent and 28 to 58 percent in women. Below 75 years of age in

women, coronary disease presents more often as angina pectoris than MI.

(5,6).Having said that, 80% angina in women is more often uncomplicated

whereas 66% of angina in men often occurs after a MI.At all ages in men,

myocardial infarction occurs, among them 20 % have pre-existing long-

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standing angina. If the MI is silent or unrecognized, the percentage is even

lower (5,6).

An analysis from the (NHANES) I Epidemiologic Follow-up study

compared two cohorts of subjects, from 1971 to 1982 (10,869 patients) and

from 1982 to 1992 (9774 patients)(10) . In the yearly follow up per 10,000

persons, the incidence of CHD decreased from 133 to 114 cases. There was an

overall large decline in cardiovascular disease (from 294 to 225 cases per

10,000 persons per year). In Olmsted County, Minnesota,a report from the

Mayo Clinic examined the incidence of CHD over time (11). During the

interval from 1988 to 1998, there was a decrease from 57 to 50 cases per

10,000 persons in the age-adjusted incidence of any new coronary diseaselike

MI, sudden death, unstable angina, or angiographically diagnosed CHD

(relative risk 0.91, 95% CI 0.82-1.01).

In 2014 in a study done by World Health Organization, it was found

that over 4 million annual deaths are due to cardiovascular disease, from data

collected from 49 countries in Europe and northern Asia(10).

• In India, the prevalence of ischemic heart disease could not be fully

explained by traditional risk factors (12).

• In China, due to higher cholesterol levels, there have been an increase in

CHD mortality in Beijing.

• Due to a higher prevalence of physical inactivity, obesity and smoking in

Latin America,the vascular disease rates are comparatively higher than the

United States.(13).

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There has been a relative increase in non-ST elevation MI (NSTEMI) in

relation to ST elevation MI with time (14–16) . For example, a report from the

National Registry of Myocardial Infarction 1 to 5 reviewed over 2.5 million

MIs between 1990 and 2006(14) and found that the proportion of MIs due to

NSTEMI increased from 19 percent in 1994 to 59 percent in 2006. This change

in proportion was associated with an absolute decrease in the incidence of

STEMI and either a rise (using MI defined either CK-MB or troponin criteria)

or no change (using MI defined using only CM-MB criteria) in the rate of

NSTEMI.(13)

INDIAN BURDEN OF DISEASE

India is going through a phase where the communicable disease is

decreasing, and the non -communicable diseases are on the rise. This has led to

a dual burden. There has been a disturbing increase over the few years in the

prevalence of cardiovascular disease in India and South-east Asia. In India, the

prevalence over the past 40 years has increased 4-fold. In a study done from

across the country ,the prevalence was found to be 7-13% in urban(17,18) and

2-7% in rural(19,20) regions .In Chennai the deaths due to cardiovascular

causes was highest at 38.6% .Cardiovascular deaths were highest in Chennai

38.6% as reported by Gajalakshmi et al (21) .

The Global Burden of Diseases Study has reported thatduring 1990 the

disability-adjusted life years lost due to CHD in India was 5.6 million in men

and 4.5 million in women; it is expected to rise to 14.4 million in men and 7.7

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million in women respectivelyby 2020.(22) Risk factors of CAD like

dyslipidemia, central obesity, hypertension,diabetes, physical inactivity and

smoking has beenalarmingly increasingwhich explains the overpowering

disease burden. Over the past two decades, there has been rapid urbanization

and lifestyle change.Previous studies which were done in migrant Indians were

misinterpreted that they are genetically preordained to develop the disease and

that conventional risk factors do not contribute to the CHD prevalence among

Indians(23).The high prevalence and occurrence of CHD prematurely cannot

be attributed to the conventional risk factors.

 

However, the large INTERHEART study an international study

recruiting 30,000 people from 52 countries, found that most of the CHD

burden was due to conventional risk factors.(24) It also recruited a large

number of Indians. The aim was to establish the risk factors associated with

myocardial infarction .The influence of factors like nationality, sex and age on

the prevalence was studied. The secondary aim was to find the overall

population attributable risk and in various subgroups. The influence of obesity,

physical inactivity, alcohol consumption was studied. It was seen that at the age

of 40 or younger, the first attack of MI was seen in the Middle East and Africa

and South Asia with an incidence of 12.6, 10.9, and 9.7

respectively.Psychosocial factors, abdominal obesity, diabetes, hypertension,

dietary patterns and waist-hip ratio were the next most important risk factors in

men and women.

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There are over 32 million diabetics in India. In 2025it may reach 57.2

million.(25)In 2000 it was reported that the prevalence of type2 diabetes in

urban Indian adults has increased from less than 3.0% in 1970 to about 12.0%

in 2000(26).In a survey done by ICMR the prevalence of diabetes was 3.8% in

rural areas and 11.8% in urban areas. In 2025, the count of hypertensives will

rise from 118 million in 2000 to 214 million.(27)

Globalization due to increasing connectivity among countries,

increased trade and finances, acceptance to ideashave contributed to the disease

burden. In the last decade, the prevalence and production of tobacco products

has increased by more than double in the developing world compared to 36%

reduction in the developed world.

Among the 1.1 billion smokers worldwide, India accommodates 182 million. In

tobacco production and consumption, India is the third largest country in the

world, in both tobacco production and consumption.(28) The production of

tobacco products have increased markedly in the developing countries.Except

the poorest countries, all other countries have replaced the traditional diet rich

in fruit and vegetables by a diet rich in calories provided by animal fats and

low in complex carbohydrates. Such changes will in general lead to increased

rates of many non-communicable diseases, although not necessarily stroke

rates.

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HISTORY OF CARDIAC SURGERY

In 1801,Francisco Romero ,in 1810 Dominique Jean Larrey,in

1891,Henry Dalton and in 1893,Daniel Hale Williams were the first ones to

operate on the pericardium. On 4 September 1895, in Rikshospitalet Kristiania,

the first surgery on the heart was performed by a Norwegian surgeon Axel

Cappelen . On September 7, 1896, Dr. Ludwig Rehn of Frankfurt, Germany, by

repairing a stab wound to the right ventricle did the first successful surgery on

the heart. After World War II, cardiac surgery changed significantly .In 1948,

four surgeons independently did work on mitral valve repair. In 1947, Thomas

Holmes Sellors operated on a Fallot's tetralogy in Middlesex hospital. Dr.

Wilfred G. Bigelow found out that a motionless and bloodless field made the

repair of intracardiac pathologies easier. Correction of congenital heart disease

was done by Dr. C. Walton Lillehei and Dr. F. John Lewis at the University of

Minnesota on September 2, 1952.In 1956 Dr. John Carter Callaghan performed

a number of firsts in heart surgery, including the first documented open-heart

surgery in Canada. The first successful use of extracorporeal circulation by

means of an oxygenator was reported by Dr. John Heysham Gibbon at

Jefferson Medical School in Philadelphia in 1953.

Coronary Artery disease

Coronary artery disease is most commonly defined as more than 50%

luminal stenosis of any epicardial coronary artery. It is most commonly due to

atheromatous plaque. Coronary artery disease manifests as stable angina, acute

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coronary syndrome, congestive heart failure, silent ischemia and sudden

cardiac death.

Acute coronary syndrome ranges from unstable angina to STEMI. It

results from acute thrombosis of coronary artery at the site of atheromatous

plaque rupture or ulceration.

SYNTAX is the most important trial of CABG and PCI .Report of the

final 5 year follow up by Friedrich Mohr et al is as follows:

There was a significant difference in Major adverse cardiac and

cerebrovascular events (MACCE) .It was 26·9% in the CABG group versus

37·3% in the PCI group (p<0·0001).

The incidence of cardiac death was 5·3% vs9·0% with p=0·003,

myocardial infarction was 3·8% vs9·7% with p<0·0001, and repeat

revascularisation 13·7% vs. 25·9% with p<0·0001.There was no significant

difference in all-cause death (11·4%vs13·9%; p=0·10) or stroke (3·7% vs2·4%:

p=0·09)(29)

CABG SURGERY

In 1910 A. Carrel attempted the first CABG in animals. In1954,

G. Murray used the internal mammary artery (IMA) as a graft in CABG. R.

Goetz performed the first reported CABG using the IMA in humans .He used

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the suture less technique in 1960. The technique of sutured bypass grafting was

introduced in 1964 by V. Kolessov. From 1962 to 1967, saphenous vein was

used as autogenous graftsin CABG. By 1990s Off-pump coronary artery

bypass came into existence. This was done without cardiopulmonary bypass.

The goal is to revascularize the area of myocardium that was perfused

previously by coronary arteries with a stenosis of more than 50%.A durable

conduit is needed for this purpose.

A systemic inflammatory response is triggered in patients undergoing

cardiothoracic surgery with cardiopulmonary bypass (CPB) as a result of the

combination of surgical trauma, activation of blood components in the

extracorporeal circuit, ischemia/reperfusion injury, and endotoxin release(30–

33)There is evidence for activation of all the body’s major host defensive

pathways, including complement, coagulation, kinins, fibrinolysis, leukocytes,

platelets, and inflammatory cytokines (33–42). This broad wave of systemic

activation has been linked to adverse clinical outcomes ranging from mild

adverse effects (fever or diffuse tissue edema), to moderate adverse effects

(pathological hemodynamic instability or coagulopathy), to severe

complications (acute organ injury requiring mechanical support), and even

mortality (43–45).The sympathetic nervous system stimulates the

cardiovascular system. This causes catecholamine levels to increase leading to

tachycardia and hypertension, which can cause myocardial ischemia and

infarction(46–48).Short lived effects can have dire consequences on the

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coronary circulation of high-risk patients causing morbidity and

mortality.(49,50).

A best available summary of the evidence suggests that the use of

OPCAB may reduce myocardial injury (troponin and CKMB), but this could

not be linked in an obligate relationship with inflammatory suppression.(51)

There were eight RCTs on approaches to minimize the surface area of the

extracorporeal circuit, and three of these eight achieved clinical benefit. There

were 14 RCTs examining different biocompatible surface coatings of which six

indicated a clinical benefit. Heparin was the most widely studied biocompatible

coating plus one paper was a direct comparison of two different types of

heparin-coated circuits. Poly-2-methoxyethylacrylate and amphophilic

silicone–caprolactone oligomer were also studied as surface coatings. There

were eight RCTs studying leukocyte depletion, seven of which used the same

arterial line leuko-depleting filter. Two of these eight studies were assigned a

clinical benefit. There were 13 RCTs and one Cochrane database review (52)on

steroid interventions. Among the 13 RCTs, three were assigned a clinical

benefit. Five RCTs investigated the use of complement inhibitors, three of

which found a clinical benefit. There was one RCT and one meta-analysis for

aspirin given preoperatively, and neither study was able to demonstrate a

clinical benefit.

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There were three RCTs examining different methods to deliver nitric

oxide (NO) to patients perioperatively: all demonstrated clinical benefit. There

were three RCTs examining administration of neutrophil elastase inhibitors

were adjudged clinically beneficial. There were two RCTs studying propofol

anesthesia. Both studies demonstrated a clinical outcome improvement. There

were two RCTs from the same research group on the bronchodilator

aminophylline. Both of these small studies (n = 30) demonstrated a clinical

benefit. There were two RCTs on sevoflurane anesthesia, only one of which

demonstrated an improvement in a clinical outcome. There was one RCT on

intensive insulin therapy using the Portland Protocol(53) in patients with no

history of diabetes. This well-designed study (n = 100) showed a clinical

benefit with significantly shortened intensive care unit stay and myocardial

protection. There was one RCT on fluvastatin administered for 3 weeks up to

the day of surgery; this study demonstrated clinical benefit. There was one

RCT on propionyl L-carnitine administration in a diabetic cohort,

whichassigned a clinical benefit for this intervention. There were three RCTs

on ultrafiltration using three different ultrafiltration techniques. However, none

of the trials recorded a significant depletion of inflammatory biomarkers and

none achieved a clinical benefit. There were no indications of negative patient

outcomes.

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Induction of anesthesia

Propofol, Etomidate, barbiturate, acts on γ-aminobutyric acid type A

receptors. A state of sedation is induced with a small dose of propofol,

barbiturate, and etomidate (54).When the drug is given, it causes

excitation.(55).At that time there are random movements, mumbled speech,

and euphoria. It is accompanied by an increase in beta activity on EEG.(13 to

25 Hz)(55–58).This state is called paradoxical because the drug causes

excitation instead of unconsciousness.

As the induction agent is given over 10-15 seconds, respiration becomes jerky,

bag and mask ventilation is started to support breathing. Simultaneously,the

patient becomes unresponsive,and muscle tone is lost. Further on, when the

anesthesiologist asks the patient to follow the finger, eye movements stop, and

nystagmus may occur and there is increased blinking. Oculocephalic and

eyelash reflex, corneal reflex is also lost(83) However, pupillary reflex remains

intact.(84). There can be fluctuations in blood pressure, while tachycardia

occurs. Opioid or benzodiazepines are given to suppress the tachycardia,

vasopressors are given to maintain blood pressure.

Problems during induction

There is no standard definition of intraoperative hypotension, as a result

it is difficult to assess the incidence across various studies. Hypotension mostly

occurs between start of induction and starting of surgery. Various parameters

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have been analyzed such as baseline variation, a decrease in systolic arterial

pressure or mean arterial pressure (MAP) under a set-point, combination of

parameters, period of hypotension, and vasopressor requirement or fluid

requirement.(61)It was found that hypotension occurs in 5-99% of patients

during anesthesia (Bijker et al) (61).There have been no clear definitions of the

threshold and duration of hypotensive episodes which can lead to

complications. 20% or more Systolic arterial pressure decrease is defined as

perioperative hypotension .In their study, Reich et al showed that hypotension

occurred more often 5–10 minutesafter induction rather than the initial 0–5

minute period(62).A decrease in MAP more than 40% or <70 mmHg, or <60

mmHg is defined as hypotension.The incidence of hypotension was 7.7% in

ASA I–II, 12.6% in ASA III–V patients respectively. Various predictors of

hypotension included: ASA III-V, MAP <70 mmHg, age ≥50 years, high dose

fentanyl and propofol use at induction .Many studies have indicated that

cardiac complications result from hemodynamic instability during surgery.

Acute intraoperative hypertension alone is not known to cause complications.

A MAP decrease of 40% or <50 mmHg MAP intraoperatively are associated

with coronary events in high-risk patients.(63). After a noncardiac surgery

,episodes of MAP <55mm Hg which are short lived can cause acute kidney

injury and myocardial ischemia.(64)The blood pressure threshold and duration

which can be associated witha perioperative stroke is not established

yet.(65)Hypotension at the time of surgery,is the most frequent causative

factor related to mortality in anesthesia.(66)

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Stress response to intubation

Laryngoscopy and endotracheal intubation forma major part of general

anesthesia for cardiac surgery (67). Laryngoscopy and orotracheal intubation

are potent stimuli, which can provoke hemodynamic response like hypertension

and tachycardia which can lead to myocardial ischemia, ventricular arrhythmia,

left ventricular failure and cerebral hemorrhage. The mechanism of these

responses is explained by somatovisceral reflexes. During laryngoscopy,

stimulation of proprioceptors at the base of the tongue, induces impulse

dependent increase in blood pressure, heart rate, and catecholamine surges.

Repeated orotracheal intubation elicits augmented hemodynamic and

epinephrine responses and some vagal inhibition of the heart. These incidences

are harmful in such a group of patients like coronary artery disease, cardiac

arrhythmias, cardiomyopathy, congestive heart failure, hypertension and

geriatric population. To suppress the stress response to laryngoscopy and

intubation various drugs like barbiturates, calcium channel blockers,

vasodilators, beta blockers, and opioids have been tried at regular intervals.

Hence there is a need to attenuate hemodynamic responses to laryngoscopy and

surgery without undue hypotension.

In 1940, Reid and Brace,first described a hemodynamic response to

laryngoscopy and intubation(68).It leads to an average increase in blood

pressure by 40-50% and 20% increase in heart rate (69).The increase in blood

pressure and heart rate is usually transient and variable, but can be

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unpredictable and life-threatening if left unaddressed. For most patients, the

hemodynamic response to the stress of laryngoscopy and endotracheal

intubation does not present a problem(70).However, cardiac patients respond to

anesthetic induction and endotracheal intubation with an increase of blood

pressure and heart rate and are more prone to develop hemodynamic instability

(71). The delicate balance between myocardial oxygen demand and supply is

altered due to hemodynamic changes caused due to intubation .This may

precipitate myocardial ischemia in patients with coronary artery disease (129).

Laryngoscopy itself is one of the most invasive stimuli during endotracheal

intubation (70,72). Many anesthesiologists agree that a skilled anesthesiologist

applies only a small force to the patient’s larynx when using a laryngoscope

and that reducing the force on the larynx might prevent excessive

hyperdynamic responses to endotracheal intubation (73–75).After seconds of

direct laryngoscopy, hemodynamic changes occur, leading to further increase

in heart rate and blood pressure with passage of the tracheal tube.The first is

the response to laryngoscopy and the second is the response to endotracheal

intubation. The component which is responsible for the hyperdynamic response

is not known. Singh et al., while doing a study on different induction agents in

Coronary artery disease, showed that stress response on intubation was most

obviouswhen etomidate was the induction agentin patients with coronary artery

disease while midazolam was most effective in preventing intubation

stress(76). Hemodynamic changes were lesser when intubation was done with

the Airtraq, when compared to the Macintosh laryngoscope (77,78). Thus,

26  

many studies have focussed on stress response to endotracheal intubation, high

doses of opioids, α2-adrenergic receptor agonists, β-adrenergic blocking drugs

or other antihypertensive drugs and a number of drugs have been used to

suppress the hemodynamic response(48,49,79–89)

A wide variety of pharmacological agents were used to attenuate the

hemodynamic responses to laryngoscopy and endotracheal intubation like

lignocaine,(90),fentanyl(91),alfentanil,(92),remifentanil,(143)nifedipine,(93)

beta-blockers,(94) gabapentin,(95)magnesium sulfate,(96) verapamil,

nicardipine, diltiazem(97)with varying results. Previous studies(97–101)have

also documented that nitroglycerin does not attenuate the rise in heart rate after

intubation, which can be attributed to reflex tachycardia produced by

vasodilation. The principal advantage of using nitroglycerin is that, while a

desirable and transient hypotension is achieved, cardiac output is not likely to

decrease. Preload reduction and accompanying decrease in ventricular end-

diastolic pressure(98), reduces myocardial oxygen demand and increases

endocardial perfusion by dilating the coronary vessels. NTG may increase the

coronary blood flow and oxygen delivery to the myocardium. Because of its

predominantly venodilatory action, it seems to be the best choice in patients

with low cardiac output and moderately elevated resistance.(102)

Myocardial oxygen consumption or demand (as measured by the

pressure-rate product, tension-time index, and stroke-work index) is decreased

27  

by both the arterial and venous effects of nitroglycerin resulting in a more

favorable supply-demand ratio(98).Esmolol given IV in a dose of 1 mg kg-1

before intubation suppressed the stressor response due to intubation (Bostana

and Eroglu (2012)(103). Lidocaine has been a popular agent for attenuating

circulatory responses. Lidocaine causes depression of cardiovascular system

and vasodilation of the peripheral vasculature (104).The airway reflexes due to

tracheal irritationare attenuated .Its analgesic and antiarrhythmic action have

been fully made use of in cardiac anesthesia.The effects have been shown to be

beneficial in some(105) while other studies indicated that there is no effect

when it is given 1-3 minutes before the time of laryngoscopy

(106,107).Lidocaine in a dose of 1.5 mg/kg and esmolol in a dose of 2 mg/kg

were effective in attenuating the response to laryngoscopy and intubation.

There were no harmful effects reported.Tachycardia and hypertension are

known to contribute to myocardial infarction perioperatively and is an

important factor leading to morbidity and mortality(108).Hence it can be

concluded that the quest for ideal induction agent is still elusive.

Hemodynamic goals in CABG

After induction and intubation, there is hypotension and there is intense

surgical stimulus like skin incision and sternotomy that produces hypertension,

tachycardia. Themain aim during anesthesia is suppression of sympathetic

responses to laryngoscopy, intubation. Steps of surgery like skin incision,

splitting of sternum, and spreading which can cause massive response should

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be avoided. Anesthetic drugs cause vasodilation and depression of

cardiovascular system, leading to hypotension which has to be prevented.One

induction agent is not favorable for every CABG patient, and anesthesia has to

be tailored for each individual to achieve stability in hemodynamics.(109,110)

Since many years, there have been several anesthetic techniques used

with their own adverse cardiac effects, inhalational agents at increased doses

causing depression of cardiac system, absence of myocardial depression with

increased doses of opioids, isoflurane causing coronary vasodilatation leading

to steal phenomenon. Another concern is interactions due to pre-op

medications, beta blockers causing cardiovascular depression, hypotension due

to ACE inhibitors or ARB(111–113). The underlying principle is that oxygen

supply and demand ratio should not be altered to avoid injury to myocardium.

Now- a days surgical management is moving on to accelerated recovery

protocols or fast track management (114,115). Efforts are on to improve the

final outcome and to decrease costs which lead to decreased duration of in-

hospital stay(114,115).

High-dose opioids with benzodiazepines have been used since the 1970s

and 1980s.Eventually volatile anesthetics became more popular, due to their

protective effect on the myocardium. However, inhalational agents are not

29  

better when compared to intravenous agents in terms of advantage in the rate of

mortality.Hence, opioids have been given a secondary role (116,117).

Patients can be optimized by 1)preoperative assessment done

carefully,risk factor modification2) all medications should be handled properly

in the preoperative period (3) monitoring cardiovascular system carefully,

inserting a central venous line4) amnesia, analgesia, and muscle relaxation is

induced 5) a smooth progress to the immediate postoperative period. The goal

is to extubate early, mobilize the patient, and discharge early.

During CPB, changes in hemodynamics or hormonal changes which can

cause ischemia of the myocardium or have a harmful effect on metabolism of

the myocardium should be prevented. Appropriate management and careful

monitoring is required. Close interaction between the surgeon, anesthesiologist,

is needed particularly when the heart, great vessels are being manipulated.

Anesthetic goals in patients with LV dysfunction

In patients with LV dysfunction, in order to increase blood pressure and

cardiac output, various mechanisms are activated. To increase the circulating

blood volume several neurohumoral pathways are activated. The sympathetics

cause an increasein heart rate and myocardial contractility, vasoconstriction of

the arteriolar system in splanchnic vascular system, and stimulation of the

juxtaglomerular apparatus of the kidney to secrete renin. Activation of the

Renin–angiotensin systemcausesvasoconstriction of the arteriolar system,

30  

retention of water and sodium, and release of aldosterone. Aldosterone increase

leads to sodium and water retention. Additionally, vasopressin released from

the hypothalamus due to baroreceptor and osmotic stimuli, cause water

reabsorption from the renal collecting duct. Eventually these mechanisms, even

though they are beneficial, aggravate ischemia, dysrhythmia, cause endothelial

dysfunction, promote cardiac remodeling and are toxic to myocytes.

Any deterioration in the structure or function in the filling of left

ventricle, or systolic ejection results in heart failure .Changes in hemodynamics

and drugs used in anesthesia can have a harmful effect on the diastolic function

of the left ventricle.

Arrhythmia and myocardial ischemia affect diastolic time. Any

preexisting dysfunction in diastole is decompensated. Diastolic time is

shortened by tachycardia and left ventricular filling is impaired. Hypo- or

hyper-kalaemia, anaemia, or hypovolemia cause rhythm disturbances.

Tachycardia can be prevented by beta-blockers or calcium-channel blockers

andleft ventricular filling is improved(118,119).

Myocardial relaxation is slowed significantly when there is myocardial

ischemia or sudden volume loading or positionchanges. Myocardial ischemia

may cause rhythm changes which can precipitate diastolic dysfunction of the

left ventricle. Myocardial ischemia is the imbalance between myocardial blood

supply and demand. It can be multifactorial in cardiac surgery. It can happen

31  

due to native coronary artery disease, hypotension at the time of induction,

inadequate myocardial protection, inadequate surgical correction (poor target

vessels, poor conduits) graft kinking and graft thrombosis.

Thus, when dealing withsuspected diastolic heart failure, prevention of

ischemic episodes should be the main stay of management. Beta-blockers are

the best drugs known,to decrease oxygen consumption of the myocardium. The

mortality due to coronary events overall has been decreased by use of beta-

blockers perioperatively.(120,121). It is not known whether this line of

management is still suitable for diastolic heart failure. There have been less

studies on the effect of intravenous agents on diastolic properties, however, the

effect of volatile agents has been extensively studied.Left ventricular diastolic

function is not affected by inhalational agents like sevoflurane and desflurane,

as well as opioids or muscle relaxants.

LV DYSFUNCTION AND ANESTHESIA

Persons with a healthy heart have good cardiac function .However,

patients with LV dysfunction have limited cardiac reserve. Since most of the

anesthetics that we use routinely are associated with cardiovascular depression

the anesthesiologist is placed in a very challenging situation.

Anesthetics depress the sympathetics and these patients rely on the

sympathetic system to maintain a good cardiac output. The anesthetics can

32  

cause myocardial depression directly or can indirectly affect the cardiovascular

control mechanisms. Initially it was thought that LV diastolic dysfunction was

primarily due to systolic dysfunction, but now it is being seen that diastolic

dysfunction alone can affect the overall performance of the heart.

In a healthy heart, cardiac output is affected by changes in preload,

however in patients with LV dysfunction, it is very sensitive to changes in

afterload. Hence arterial vasodilation can improve cardiac output. After

anesthetic induction, venodilation occurs leading to decreased cardiac output.

In the absence of a coronary intervention, data suggests that before a non-

cardiac surgery,≥60 days should elapse after a MI. MI which has occurred in

the last 6 months before a non cardiac surgery is defined as recent MI. It was

alsoan independent risk factor for stroke perioperatively, this was linked with

8-times increase in the mortality rate perioperatively(122).Given the fact that

adults more often are affected with diseases like coronary artery disease,

stroke,and diabetes mellitus, age plays a major role(123). When they come for

noncardiac surgery, risk of MACE increases overall. Another important risk

factor for stroke in perioperative period is age more than 62 years (125).There

was a higher incidence of acute ischemic stroke ,among older adult patients

(those >65 years of age) than those ≤65 years of age undergoing noncardiac

surgery (124). Complications in the postoperative period was higher in those

who had poor cognition, and who had to rely on others for activities of daily

33  

living. Hence, the duration of hospital stay increased(126).A history of stroke is

a risk factor to develop MACE perioperatively.(122)

DRUGS USED FOR ANESTHESIA INDUCTION

FENTANYL

It was invented by Paul Janssen (1926–2003) (127–130)It is a

derivativeof phenylpyperidine. It is 100 times more potent than morphine. It is

an agonist at the mu receptor. It has great analgesic properties, and till it causes

unconsciousness, producesincrease in analgesia depending on the dose given.

Along with fentanyl,other agonists are hydromorphone morphine, and

oxymorphone. Compared with nalbuphine, an agonist at the kappa receptor, it

has greater effects on analgesia. (Morgan et al., 1999). The ED50 was 0.08 and

95% limits were 0.045to 0.142 mg/kg(131).The LD50 in humans is unknown

.After injecting, fentanyl quickly enters into theCSF.The Tmaxwas 2.5-10

minutes.(Hug & Murphy, 1979) and the Tmax in brain was 10-20 min (Ainslie

et al., 1979). The concentrations of fentanyl were found to be equal to that of

plasma, later it was lower than the concentration in plasma. (Hug & Murphy,

1979). Concentrations in brain decreased slowly than that of plasma. In a study

by Ainslie et al in 1979, it was found that in a duration of 30 min-2 hrs during

the study, the concentrations in brain exceeded plasma concentrations. Due to

its lipophilic properties, great amounts of the drug are found in the

brain.Metabolism and excretion of H-fentanyl occurred in urine and feces,

following IV and subcutaneous injection (132) (Ohtsuka et al., 2001).After a

34  

single injection of H-fentanyl,4% of the drug and 36% of the overall dose was

found in 6 hour urine collection (132)(Murphy et al., 1979).Cytochrome P450

is responsible for metabolism. It is dealkylated to nor fentanyl (Feierman,

1996; Feierman & Lasker, 1996; Labroo et al., 1997). Other metabolites were

despropionylfentanyl and hydroxyfentanyl.

The duration of analgesia lasts for 30 minutes. There was minimal

depression of cerebral cortex.The alterations in respiration are long lasting than

the effect of analgesia.At doses in therapeutic range, there was no significant

cardiovascular effects. Fentanyl binds to human plasma proteins and rapidly

distributes with sequestration in fat. Metabolism occurs in the liver and

excretion through the kidney. Elimination half-life ranges from 6 - 32 h. After

intravenous injection the effect starts quickly, and it takes 7 to 8 mins after

intramuscular dose. After IV injection, it peaks in 5 to 15 min. Duration of the

analgesic effect lasts for 1 to 2 hrs on intramuscular administration.In contrast

to morphine,the onset is fast and duration of action is short.

With other opioids and CNS depressants it acts synergistically.

Tolerance develops with repeated use. This leads to increase in the minimal

effective dose. Over a few days, physical dependence develops. Side effects are

nausea, vomiting, bradycardia, depression of respiration and chest wall rigidity

(133–135).

35  

They act synergistically with anesthetics and reduce dose requirement of

anesthetic agents. It does not cause myocardial depression, so it is invaluable in

LV dysfunction. It has definite cardio protective actions like antiarrhythmic

activity especially in ischemic reperfusion injury. Due to its action on δ- and κ-

opioid receptors there is prolongation of the cardiac action potential

duration.(136)Remifentanil and fentanyl both induce preconditioning of the

myocardium, even though their action at δ- and κ-opioid receptors are weak.

Reducing the dose of anesthetic drugs is often the safest way to induce patients

with LV dysfunction. Large doses of fentanyl as the only anesthetic have the

advantage of stable hemodynamics ,there is lack of direct depression on the

myocardium, withno release of histamine and stress response to surgery is

suppressed(137).There are no changes in the contractility of myocardium.

After large doses of fentanyl, hemodynamic variables remained unchanged.

Fentanyl may depress cardiac conduction by direct membrane

actions.(138).During induction in patients undergoing CABG, QT interval was

found to be prolonged. Conductance in coronary circulation is regulated by

arterial baroreceptors. This is increased by low fentanyl concentration in

plasma, but it is suppressed with high fentanyl plasma

concentrations(139).Studies in dogs showed a direct peripheral vessel smooth

muscle relaxation(140) .Its antiarrhythmic potential, anti-ischemic action and

action on opioid receptors was demonstrated in rabbits, (141)

36  

In mitral valve surgery, Fentanyl was used as the only anesthetic in

doses of 50-100 pg/kg. (STANLEX & WEBSTER 1978) and CABG (LUKN et

al. 1979). Thehemodynamic stability was good as there is lack of myocardial

depressant effect. Fentanyl in dose of 50-70 pg/kg caused deep surgical

anesthesia, as seen in EEG, no awareness was being reported. (SEBEL et al.

1981)

To achieve stability in hemodynamics, opioids in high dose and

anesthetic agents in a low dose were used to suppress the response to surgery

(Ruggeri et al., 2011).It did not cause depression of the myocardium (Howie et

al., 2001; Rauf et al., 2005 and Steinlechner et al., 2007). However, opioids in

increasing doses do not suppress the surgical stress response, the plane of

anesthesia has to be modified (Howie et al., 2001).

In the myocardium, metabolism of phosphates was blocked in a study by

VAN DEK VUSSE et al. (I 979) whenischemia was caused in dogs, and

showed that it could be explained by the negative chronotropic effect of

fentanyl.When high doses of fentanyl are used, metabolic and hormonal

changes were decreased.During gynaecological surgery, there was a decrease

in metabolic and hormonal changes as demonstrated by HALL et al. (1978).In

the stage before bypass, it diminishes the endocrine and hyperglycemic

response to surgical stimuli. During bypass, there was significant increase in

catecholamines (SEBEL et al. 1981b). Similar study was done by STANLEY

37  

et al. (1980).Stress response was higher when fentanyl was given in a low dose,

with associated coagulopathy, and required more transfusion. Fentanyl at high

doses were favorable in preventing stress response.There was better analgesia

post operatively, when dexmedetomidine was added to fentanyl at low doses

vs. low dose fentanyl, in preventing response to stress(142).It may cause

prolongation of recovery due to respiratory depression, as it gets accumulated.

(Lison et al., 2007).In cardiac patients with high risk, Remifentanil has been

used successfully (Lehmann et al., 1999). Recovery was rapid when

remifentanil infusion was given for a long time (Ruggeri et al., 2011).

Midazolam at a dose of 0.075 mg/kg or 0.15 mg/kg IValong with high-

dose fentanyl caused decrease in the mean arterial pressure by 24-32% from the

baseline rapidly. Minor to moderate decreases in mean arterial pressure was

observed when midazolam was used as the sole induction agent (143–

145)along with low doses of fentanyl (144)in cardiac patients; peripheral

vascular resistance decreases caused by the midazolam causing drop in BP

(144).When high doses of midazolam more than 1 mg/kg are given, it

hasnegative inotropic effects on the myocardium (146).Since the combination

of midazolam and fentanyl caused significant hypotension, a loading dose of 3-

5 mcg/kg was given during induction in our study, as hypotension is

detrimental to patients with left ventricular dysfunction. When fentanyl is used

as the sole anesthetic, the disadvantages are failure to prevent sympathetic

38  

stress response, unpredictable amnestic effects leading to recall, and

postoperative ventilatory depression.(147–149).

Fentanyl is available as transmucosal and transdermal forms. Intrathecal

fentanyl in labor can produce good analgesia. Side effects include bradycardia,

seizure-like activity, in head injury patients is associated with increase in

ICP.(137)

PROPOFOL

It was developed at Imperial Industries in UKwhen the effect of phenol

derivatives to cause sedation in animal models was discovered. In January

1973,its properties as an anesthetic agent were discovered(150,151). The

chemical name is 2, 6- diisopropylphenol and the weight of a molecule is

178.27.At a pH of 6-8.5, the octanol and water partition coefficient is 6761 .At

a pKa of 11,the formulation is in anoil-in-water emulsion, which is white, as it

is not soluble in water. All fat soluble anesthetic agents can be delivered,

bacteria proliferate easily in that media.After contamination, there is risk of

sepsis .It acts on GABA receptors(152).This was first observed by Collins et.

al. in 1988 (153).The strong point of propofol is its fast onset and fast offset

due to it’s short, context-sensitive half time. The onset of action is dose

dependent 9-51 seconds, the peak effect is seen at 90-100 seconds. The initial

t1/2 is 1-8 minutes, terminal t ½ is 4-7 hrs. Adose of 2 - 2.5 mg/kg

causessystolic BP to drop by 25% -40% (154). Mean and diastolic blood

pressure also falls which is due to vasodilation of the arterial system. There is

39  

reduced vascular tone.It may also affect myocardial contractility and autonomic

control of cardiac output (155).There is decrease in systemic vascular

resistance in arteries and veins, so preload and afterload are reduced.The

pulmonary arterial and capillary wedge pressure decrease in cases of valvular

heart disease (156).The effect is more in hypovolemic patients and in the

elderly.

It causes decrease in systemic blood pressure, decrease in sympathetic

tone of vasculature, and decrease in SVR, with no effect on myocardial

contractility.(157,158).This explains the cardiovascular depression, revealed as

a reduction in arterial blood pressure .Calcium is taken up into thesarcoplasm

which explains the negative inotropy. At usual doses, the effect on myocardium

is not significant.Propofol concentrations in blood decreased slower than

thiopentone as the tissue and blood distribution coefficient was higher(5.94).

There is negative inotropic effect depending on dose.It causes decrease

in preload of LV,afterload and stiffness of regional chambers, causes LV filling

to be impaired.

It protects the myocardium against injury by ischemia and reperfusion.

It inhibits KATP channels at 5-15 times high concentrations at that of clinically

used concentrations.

40  

It has a free-radical scavenging property similar to vitamin E as the

structure is similar. Free oxygen radicals are scavenged,decreases disulfide

bonds in proteins. In organelles it prevents lipid peroxidation caused by

oxidative stress.(159–161)Due to its antioxidant and free radical scavenging

nature, it protects the myocardium, which was demonstrated in experiments.

Propofol causes significant cerebral vasoconstriction according to the dose

given. It causes cerebral blood flow to decrease, oxygen demand is decreased

and any pre-existing cerebral edema is enhanced(162,163). It has no effect on

cerebral auto regulation and cerebrovascular reactivity to CO2 (164).It causes

rise or fall in ICP,causing cerebral perfusion pressure to decrease(165)The

induction dose of propofol of 1 - 3 mg/ kg .Apnea occurs in a few minutes. The

apnea duration and its occurrence is affected by the speed and dose of injection

and any premedicant given (166).

It is the drug of choice when rapid and complete awakening is desired. It

is used in TIVA (total intravenous anaesthesia) .It is used as continuous

infusion for sedation in ICU. Other favorable effects are its antiemetic effects,

antipruritic, and anticonvulsant actions. It also attenuates bronchoconstriction.

It decreases ICP in patients with normal or raised ICP. Unfavorable effects are

pain on injection, apnea, and hypotension. When propofol is given for 48 hours

or longer at a rate of 4 mg/kg/hr, propofol infusion syndrome may occur.

41  

THIOPENTONE

It is a barbiturate, supplied as a hygroscopic pale yellow powder.It is

insoluble in water.It is available as a carbonate salt to maintain the alkaline pH.

Even though it is 80% protein bound it is taken up into brain rapidly within 30

secs due to itslipophilic nature and non-ionised fraction of 60% which is high.

Ampoules containsodium thiopental (500 mg)in nitrogen atmosphere with 6%

sodium carbonate. When 20ml of water is added, 2.5% solution (25mg/ml) is

formed. It has a pH of 10.8. The solution is alkaline and kept for 48 hrs safely,it

is also bacteriostatic. GABA action is enhanced, whereas it blocks the synaptic

action of glutamate and acetyl choline. The onset of action is 10-30 secs, t1/2 is

4.6-8.5 minutes, peak effect is 30 secs, and duration of action is 10-30 minutes.

In the barbiturate ring, the sulphur at C2 is replaced by oxygen atom. It

has a fast onset of action and terminal half-life is reduced from 30 ± 50 h to 10

± 15 h, due to its chemical structure(Chan et al.,1985) It should be termed as

RS-, (+/-).It is a racemate as equal concentrations of (+)-R- and (7)-S-

enantiomers are present. In mice it was found that the hypnotic potential of S-

thiopentoneis more than R-thiopentone (Christensen & Lee 1973; Haley &

Gidley1976) (Market al., 1977)

In volume depleted patients, or those who have low serum albumin, or

when non-ionized fraction is increasesas in metabolic acidosis, at a particular

dose, concentrations in the brain and heart achieved were higher .There is risk

42  

of cardiacdepression . When a single dose given as bolus, it is distributed

quickly to tissues with high perfusion and low volume like brain and spinal

cord .It then redistributes to lean muscle tissue, then theeffect of the induction

dose ends. (202)

There was minimal depression of arterial pressure at 10, 15, 20 minutes

(p<0.05).There were significant increases in cardiac output at 2, 5 minutes.

(p<0.01), there was decrease in total peripheral resistance at 2 and 5 minutes.

With thiopental, heart rate changes were also significant at 2minutes (p<0.001),

5minutes (p<0.01),and at 10 and 15 minutes (p<0.05).There was a decrease in

stroke volume at 2 minutes (p<0.01) and 5 minutes (p<0.05).The peripheral

leg blood flow increased significantly at 2 and 5 minutes.(167)

It causes depression of the myocardium, due to medullary centre

inhibition, causing mean arterial pressure (MAP) to decrease.The outflow of

sympathetics decreases, causing capacitance vessels to dilate. Baroreceptors

cause reflex sympathetic stimulation, elevation in heart rate occurs due to

baroreceptor-mediated sympathetic reflex stimulation of the heart when BP or

cardiac output decreases. These effects are seen clearly in hypovolemic

patients, those on beta-blockers, and valvular heart disease and cardiac

tamponade. It causes ventilatory centre in the medulla to get depressed and

hypoxic and hypercapnic response decreases. It causes spasm of larynx or

bronchi as airway reflexes are not suppressed fully. It has

43  

antanalgesicproperties. Cerebral metabolic oxygen consumption rate (CMRO2)

decreases, cerebral blood flow and intracranial pressure also decrease. In EEG

increased doses, cause burst suppressionwhich may prevent ischemia of focal

areas.(168)

It is used as a premedicant and in the induction of anesthesia. Prompt

onset, and smooth induction are the benefits. In normovolemic patients it

causes transient decrease in BP that is compensated by tachycardia. It causes

dose-dependent depression of medullary ventilatory centres. It stimulates an

increase in enzyme induction which may result in altered drug interactions.

Intra-arterial injection causes intense vasoconstriction. It is also associated with

allergic reactions.

The effects of thiopentone on eight patients who had CAD and normal

ejection fraction were studied by Reiz et al. Thiopentone decreases myocardial

oxygen consumption ,caused a decrease in arterial pressure, SVR and

SVI.(169)

KETAMINE

Ketamine is a phencyclidine derivative that produces dissociative

anesthesia. It is soluble in water,has a pKa of7.5.This enables it to be non-

irritant drug in any route of administration.(170–175).

44  

It is 10 times more lipophilic than thiopentone and therefore can cross

the blood brain barrier. Due to rapid redistribution, ketamine has fast onset and

offset, which is similar in action to thiobarbiturates. It is a noncompetitive

NMDA antagonist. The onset of sedation was 45 seconds with intravenous

injection in a dose of 2 mg/kg, and after i.m injection (3 mg/kg) was 4 minutes.

The time for recovery was 18 mins with IV and 25 mins with IM

injection.(203) After intravenous injection, half-life of distribution was

24.1seconds, half-life of redistribution was 4.68 minutes, and half-life due to

elimination was 2.17hours (176). Peak effect is seen within one minute of

intravenous injection. Liver is where biotransformation occurs. However, one

of the most important path way involves cytochromep450enzyme system

causes N-demethylation of ketamine to nor ketamine.

The induction dose is 1-2 mg/kg intravenously. It produces analgesia,

induces significant ( 33%) increase in heart rate, mean arterial pressure

(+28%)(177)and epinephrine levels, there is centrally mediated sympathetic

nervous stimulation.

There is uptake of catecholamines in the neurons, stimulation of the

central sympathetic system.These effects are in contrast to the negative

inotropy on the myocardium. In a healthy individual, increase in arterial blood

pressure, heart rate, and cardiac output occurs.

45  

In the absence of good myocardial function and sympathetic reserve,

hypotension may occur due to myocardial depression.

Coronary blood flow may not be enough to meet the increased oxygen

demands due to sympathetic stimulation.

In the presence of increased β-adrenergic stimulation, the failing heart

cannot increase the contractility when given ketamine.(178). In such patients,

there is decrease in cardiac performance and cardiovascular instability occurs.

In the presence of adrenoceptor blockade, the negative inotropic effects may be

unmasked.(179) Ketamine is a chiral compound, and until recently was only

available as the racemic mixture.

The advantages of S (+)-ketamine at lower concentrations, is that it

causes hypnosis and analgesia, agitated behavior and emergence delirium are

less. This isomer depresses the myocardium to a lesser extent than its

racemate.(180)The R (–) isomer, blocks ischemic preconditioning of the

myocardium, S (+)-ketamine does not have this action. (181)In contrast,

however, Hanouz et al (207) demonstrated that both isomerscauses

preconditioning of the myocardium. The mechanism involvedis that Potassium

ATP channels are activated, and α- , β- receptorsare stimulated. It has some

anticonvulsant activity due to its action on NMDA-receptors. Ketamine is both

anticonvulsant and neuroprotective as shown by recent studies(182–184)

46  

It is unique in the sense that, it induces intense analgesia at sub

anesthetic doses (0.2-0.5mg/kg), and causes prompt induction of anesthesia at

higher doses. Analgesia can be produced in labor without neonatal depression.

Due to its rapid onset of action, it has been used as an intramuscular injection

drug in mentally challenged patients. In acutely hypovolemic patients,

induction with ketamine is often done. However, it can be drastic in critically

ill patients where catecholamine stores are depleted. In asthma patients it is

useful, as it causes bronchodilation.

It causes emergence delirium. It causes sustained increase in ICP in

patients with intracranial pathology. It inhibits platelet aggregation.

MIDAZOLAM

It is an imidobenzodiazepine derivative. It can be used as a premedicant,

sedative and an induction agent. It has a fused imidazole ring, which is

responsible for the basic nature, stability of an aqueous solution and for its

rapid metabolism. The pKa of midazolam is 6.15.The onset of action is about 2

minutes. The distribution half-life is 6-15 minutes, elimination half-life is 1.7-

3.5 hrs. Peak effect is 30-80 minutes, duration of action is 1-4 hours.

There is no irritation after IV injection. It becomes highly lipophilic at

physiologic pH. It is one of the most lipid soluble of the benzodiazepines.

47  

There is rapid entry of midazolam into the brain tissue.96-97% is bound to

plasma proteins. GABA chloride channels are opened causing

hyperpolarization.

Pharmacodynamics

It causes anxiolysis, hypnosis, muscle relaxation and amnesia. It also

has anticonvulsant action. It has affinity for glycine receptors in the brain, it

increases the glycine inhibitory neurotransmitter, and thus it exerts anxiolytic

effect. It has a high affinity for benzodiazepine receptor about 2 times that of

diazepam and GABA accumulation occurs. GABA is accumulated because

GABAreuptake is inhibited. Hypnosis is explained by the excess GABA at

neuronal synapses.

It was found that the midazolam dose when used together with fentanyl

was significantly lower than that in the other 2 groups, indicating that fentanyl

enhanced the degree of sedation, and our results are similar to those of

others.(185,186)

It is effective in minimizing stress response to intubation

With a dose of 0.15 mg/kg it caused anesthesia while 0.5 mg/kg caused

sedation. The induction dose is 0.05-0.15 mg/kg. Sedation dose is 0.5-1 mg

which is repeated at intervals. An ideal induction agent is one which induces

sleep in one arm-brain circulation time. Onset and duration of action varies.

48  

Hence, it has a delayed onset of action which has the risk of over dosage.Due

to its nonirritant and short acting nature, sedative doses of 0.05 mg/kg have

been used during cardiac catheterization (122).For CABG ,midazolam at low

doses when combined (0.075 -0.15mg/kg)with fentanyl at high doses,75pg/kg

causes systolic BP to drop by 29 to 33%,diastolic BP to drop by 30 to 31%.The

stroke index decreases by 25 to 30%.Theleft and right ventricular stroke work

index decrease by 42 to 46% and 48 to 61 % respectively.This can be explained

due to increasedpooling of the venous system (124).The elimination is slowed

with a half-life of 281 mins,after perfusion of the extracorporeal system. As the

overall peripheral resistance decreases, it causes a significant reduction (2.2%)

in the mean blood pressure. There is minimal cardiovascular and respiratory

effects, there is smooth transition to inhalation anesthesiaafter sub anesthetic

doses. There is almost total absence of excitatory effects.Patient acceptance is

good, making it a goodalternative to thiopental. The amnesic effectis more than

double its respiratory depression properties (144). Generally, when compared

with thiopentone, respiratory depression was less (144,148).

It causes decrease in CMRO2 and cerebral blood flow similar to

thiopentone and propofol. It is a potent anticonvulsant used for treating status

epilepticus. It causes dose dependent decrease in ventilation by decreasing

hypoxic drive. Studies done have shown it may have a role in prevention of

post op nausea and vomiting.(187).The most important side effect is respiratory

depression.

49  

The agents used during induction commonly in cardiac patients are

diazepam and flunitrazepam because the effects on the cardiovascular system

are minimal (Coleman et al in 1973; Cote, Gueret and Bourassa in 1974;

Stanley et al.in 1976; Clarke and Lyons in1977; Tarnow et al.in1979;

McCammon, Hilgenberg and Stoelting in1980)

In CAD patients 0.2 mg/kg of midazolam caused the MAP to decrease

from 92-80 mm of Hg 5 mins after induction. Midazolam in a dose of 0.2

mg/kg was used and its effect on five CAD-patients who had low cardiac

output, increased SVR and high filling pressures of the left ventricle was

studied by Reves, Samuelson and Lewis in 1979.It caused a significant

decrease of systemic vascular resistance (SVR). Thereby it allowed a

significant improvement in pump function and a decrease in the increased left

ventricular filling pressure. However midazolam did not prevent the intubation

stress response.

Dose in elderly:In elderly, doses of 300 mcg/kg can be given over a time of

20-30 seconds initially; after 2 to 3 minutes, the effect of sedation is assessed

and adjustments in dose are made. The dose used in Left ventricular

dysfunction patients was 0.15-0.2 mg/kg(9)

50  

Metabolism:

Midazolam is metabolized by hydroxylation through hepatic

microsomal enzymes .The fused imidazole ring is oxidized by the liver rapidly,

1-hydroxy midazolam is the main metabolite, and 4-hydroxy midazolam are

formedin small amounts. These are excreted in urine in the form of glucoronide

conjugates.

Its rapid onset of action is explained by its high lipophilicity,

equilibration between plasma and CSF occurs very rapidly. Due to rapid

clearance and elimination it has a short duration of action.

The first phase of metabolism is due to the drug distribution. The second

elimination phase is due to biotransformation. 50% blood flow in liver causes

midazolam to get cleared fully. Distribution is wide andrapid elimination

occurs. In elderly, volume of distribution is increased. Volume of distribution is

larger in women than men.

CLINICAL USES

It produces sleep and amnesia but no analgesic effect. The induction

dose is 0.1-0.4 mg/kg. A dose of 0.2 mg/kg can be given safely in high risk

patients.2 studies were done, White used 0.3mg/kg and induced anesthesia in

30-60 sec.(188) Finucaine gave the same amount in 4 incremental doses and

took 4.9 minutes to induce(189).The elderly require a lower dose of

midazolam.ASA 3 and 4 patients require less dose 0.15-0.2 mg/kg.Age >55

and ASA >3 patients require 20% less dose than young ,fit patients.

51  

In patientsin pediatric age group, who had very low cardiac index,

Fentanyl has a fast onset and changes in hemodynamics were minimal.

However, when given along withbenzodiazepines it can cause circulatory

depression and requires volume expansion, and in some cases inotropic

support.(190–193)Heart rate, BP and cardiac index were depressed, by fentanyl

and midazolam combination in a study done by Revines et al (222). In children

undergoing CABG, dexmedetomidine and fentanyl was compared with

midazolam and fentanyl, was compared .The effect on cardiac output in both

the arms could not be determined, even in the presence of similar SvO2 at the

recording moments(194).At one hour before surgical stimulus, HR and systolic

blood pressure were reduced in both groups to a significant extent. However,

midazolam recorded a significant response to surgical stressand required

increased supplementation with isoflurane. With the use of

Dexmedetomidine,analgesic effects was potentiated (195). The changes in

hemodynamics were similar in both the arms.

Massaut et al. studied the effect in hemodynamics due to midazolam on

eight anesthetized patients with CAD. Heart rate decreased by 9%, mean

arterial pressure by 17%, CI by 9%, and SVR by 12%. They showed the effects

on endocardial viability to be of benefit, and recommended the use of

midazolam as an adjuvant to fentanyl anesthesia especially in patients with

CAD.(169)

52  

In chronic renal failure, anesthesia is induced more rapidly as there is

more unbound drug to CNS receptors. Males are more sensitive to midazolam

than females.

Side effects:

There is no nausea and vomiting. Since it is water soluble, there is low

incidence of venous irritation and thrombophlebitis.

ETOMIDATE

It is not chemically related to any other drug. It contains an imidazole

compound which is carboxylated. In 1965, it was first reported as one of the

aryl alkyl imidazole-5-carboxylate esters .It was synthesized by Janssen

Pharmaceuticals .During animal studies, the hypnotic action was observed. It

has anti-fungal action. At physiologic pH it was lipid soluble, and at an acidic

pH, it is soluble in water which is due to the imidazole compound. The original

formulation included 35% propylene glycol which caused pain during

injection. This was changed later to a fat emulsion. Myoclonus incidence is the

same in both. Oral preparation has a higher blood concentration than

intravenous preparation. Doenicke et al. have shown that the pain during

injection was due to propylene glycol, a solubilizer.Pain and thrombophlebitis

can be avoided, by using a lipid- emulsion formulation. Original preparation

had high incidence of anaphylaxis which was avoided after they changed the

preservative.

53  

Mechanism of action:

There are several isomers of which the anesthetic effect is seen in the

R+ isomer. It acts on the GABA receptor at specific sites and increases the

affinity of GABA to these receptors.

Pharmacokinetics:

Onset of action is 30–60 seconds. Peak effect is seen at 1 minute.

Duration of action is 3–5 minutes; the induction dose is 0.2-0.6 mg/kg. Volume

of distribution is large hence there is considerable tissue uptake. After IV

injection, in a time period of 1 minute, it reaches the peak effect due to rapid

penetration into the brain. About 76% of the drug is bound to albumin

independent of the drug concentration.

Metabolism:

The ethyl ester side chain is hydrolysed to carboxylic acid ester,

resulting in a pharmacologically inactive compound. Hepatic enzymes and

plasma esterases mediate this reaction.About 85% is seen as the carboxylic acid

metabolite in urine and 10-13% as this metabolite in bile.

Cardiopulmonary bypass:

There is an initial decrease of 34% in plasma etomidate concentration,

later it decrease to 11% of the prebypass value, there is a further decrease with

rewarming.

54  

Clinical uses:

In an unstable cardiovascular system etomidate is the drug of choice.

Induction dose is 0.2-0.4 mg/kg. The onset of unconsciousness starts within

one arm to brain circulation time. There is alteration in the balance between

inhibitory and excitatory influences on the thalamocortical tract, hence

involuntary myoclonic movements occur. By giving opioid before, this can be

avoided. Awakening is more rapid compared with other barbiturates, there is

no hangover effect. It does not have analgesic properties. After giving

etomidate the return of psychomotor function is said to be intermediate to

methohexital and thiopentone. It may also decrease the duration of seizures, it

can be used as an alternate drug to propofol and thiopentone.

EFFECTS ON SYSTEMS

CNS:

CMRO2 (cerebral oxygen consumption rate) decreases by 35 to 45%, and

cerebral blood flow is decreased due to vasoconstriction of cerebral vessels.

Hence it decreases intracranial pressure. The pattern produced in EEG is

similar to thiopentone, the frequency of excitatory spikes is more with

etomidate.

55  

Cardiovascular system:

Unlike other induction agents ,it has fast onset and a safe cardiovascular

profile, and hence causes less significant fall in blood pressure (196–

198).The 30- day mortality and cardiovascular morbidity is increased with the

use of etomidate, although hypotension during induction is prevented which

can cause less perfusion of coronaries, arrhythmia, and cardiac arrest. There is

also prolonged hospital stay.(199)

It has structural similarities to α2B agonists and results in

vasoconstriction. This explains its hemodynamic stability. A patient with

cardiovascular disease depends on the sympathetic tone for maintaining the

blood pressure, systemic vascular resistance (SVR), and cardiac output.

Etomidate by its action on α2B receptors negates the need for treatment of post

induction hypotension and is considered as an ideal induction agent in patients

with cardiovascular compromise.(200)

The change in heart rate, cardiac output orstroke volume is minimal.

There is no effect on the sympathetic nervous system or on the function of the

baroreceptor. During induction it causes more hypertension and tachycardia

than with the use of propofol. The myocardial oxygen supply to demand ratio is

well maintained(177).Hence in acutely hypovolemic patients if etomidate is

given, it can cause sudden hypotension due to parallel changes in SVR and

56  

MAP. The only change which was observed was a 10% increase in heart rate,

(201)hence etomidate is considered to have a stable hemodynamic profile.

RESPIRATORY SYSTEM:

There is decrease in tidal volume with a compensatory increase in

respiratory rate.

It may stimulate ventilation independently, hence it is useful when

spontaneous ventilation is needed.

Musculoskeletal

Myoclonus occurs in 50-80% of the patients receiving etomidate. Giving

fentanyl or benzodiazepine may reduce the occurrence of myoclonus. Giese et

al. (202) reported that premedication with 100 µg fentanyl significantly

decreased the rate of etomidate-induced myoclonus; however, it introduced the

risk of respiratory depression. The mechanism of myoclonus is explained by

disinhibition of subcortical structures that normally suppress extrapyramidal

motor activity.

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58  

patients in etomidate group who developed adrenal suppression received higher

doses and longer duration of inotropic support postoperatively. The duration of

adrenal suppression can last between 12–72 hours. The inflammatory response

is stimulated after cardiac surgery, during bypass surgery, level of

catecholamine and stress hormones are elevated (205).Cortisol and

corticosterone which are endogenous cytokines have a role in the maintaining

the vascular tone and nitric oxide production is inhibited. Since it acts

synchronously with epinephrine and norepinephrine in maintaining BP,these

hormones are impaired due to etomidate. During the postoperative period.there

is an increased vasopressors requirement (205)

In critically ill who have adrenal suppression CORTICUS trial showed

that exogenous hydrocortisone did not improve the survival.(200)

The cortisol suppressioncaused by a single dose of etomidate is always limited

to 24 hours,there is no threat of prolonged adrenocortical suppression. In this

study the cortisol levels returned to normal levels at twenty-four hours post

induction.(206). The benefit of minimal cardiac suppression is weighed against

causing adrenocortical suppression and longer hospital stay. The risk for 30-

day mortality, cardiovascular morbidity, and prolonged hospital stay were

increased.(207)

RCT done showed that one group was assigned toreceive etomidate0.3

mg/kg (n=328) the other group ketamine 2 mg/kg (n=327) for induction. It was

found that adrenal insufficiency was significantly more in the etomidate group

than in the ketamine group.(208)

59  

The ideal induction agent

The ideal induction agent obtunds the intubation stress response and also

maintains hemodynamic stability. The properties of an ideal induction agent

are as follows:

Physical properties

• It should be water soluble & stable in solution and stable on exposure to

light.

• It should have a long shelf life with no pain on intravenous injection.

• It should be painful when injected into an artery and non-irritant when

injected subcutaneously. There should be a low incidence of

thrombophlebitis and it should be cheap.

Pharmacokinetic properties

It should have a rapid onset in one arm-brain circulation time, rapid

redistribution to vessel rich tissue. It should have rapid clearance and

metabolism with no active metabolites.

Pharmacodynamic properties

• It should have a high therapeutic ratio (ratio of toxic dose: minimally

effective dose) with minimal cardiovascular and respiratory effects.

• There should be no histamine release/hypersensitivity reactions, no emetic

effects.

• There should be no involuntary movements and no emergence nightmares.

60  

• There should be no hang over effect, no adrenocortical suppression.

• It should be safe to use in porphyria.

Patients with impaired left ventricular function are at a high risk for any

cardiac surgery. Etomidate is well known to have a stable cardiovascular

profile. Other conventional techniques like using high dose fentanyl or

midazolam with fentanyl normal dose have also been used during induction. A

RCT done in AIIMS compared four induction agents: etomidate, propofol,

thiopentone and midazolam. The hemodynamic variables were comparable in

all the four groups. Etomidate was not that effective while midazolam was the

most effective in preventing stress response to intubationamong the induction

agents.Among the four groups, there was a comparable decrease in

hemodynamic parameters.This can be explained by the hypothesis that during

induction sympathetic stimulation is lost, it cannot be attributed to anesthetic

induction agents(169)Etomidate was the most cardio stable drug, its effect on

adrenal suppression was not studied.

Hemodynamic effects of various intravenous induction agents in patients

with normal LV function

The magnitude of hypotension is directly proportional to the plasma

concentration of the induction agent. The concentration depends on many

factors like age, sex, dose and body weight, cardiac output and infusion rate.

There is no agreement on the minimum dose of propofol and the method of

61  

administeringwhich minimizes hypotension risk. The dose of etomidate utilized

by various studies ranges from 0.2 to 0.45 mg/kg. The doses at the higher end

of the spectrum (0.4 mg/kg) for etomidate may cause direct myocardial

depression(209).The exact induction dose of etomidate for maintaining

hemodynamic stability has not been zeroed upon as yet. The magnitude of

variations in SBP, DBP and MAP from baseline was greater when propofol

was used as an induction agent versus etomidate in comparable doses. The

mechanisms of arterial hypotension following IV anesthetic induction are

multifactorial. There is no effect on the sympathetic nervous system, or the

function of baroreceptors, this explains the safe cardiovascular profile.

(209,210)It has the ability to bind and stimulate alpha-2B adrenergic peripheral

receptors causing vasoconstriction.(211). Decrease in systemic blood pressure

after a bolus injection of propofol is dependent on both vasodilation with

reduced preload and afterload and myocardial depression (negative inotropic

action).(209,212–214).It was demonstrated that ketamine, used as the

anesthetic induction agent during high-dose remi fentanil administration, might

prevent cardiovascular depression. The choice of ketamine as the induction

agent during high-dose remifentanil administration might be a safer alternative

to propofol in patients in whom cardio-vascular depression needs to be

avoided.(215)

Thiopentone, causes an increase in heart rate(216,217) but in

infantsthere was no change at lower doses (217,218) and in the elderly there

62  

was a decrease in heart rate (219)Direct effects on the myocardium explains the

cardiac depression by propofol or thiopentone(220,221).It has indirect action

on the neuronal system(222).Many studies have reported depression of

myocardium in a dose-related manner(220,221,223).There are a very few

studies on the comparison of depressive effect on the myocardium by

thiopentone versus propofol during induction.(216–218)After induction with

thiopentone, there was fractional shortening which decreased by 14%, there

was no change with propofol. Gauss et al (243), Mulier et al (244) found that

propofol group had significant cardiac depression than equal doses of

thiopentone given as a single bolus. Left ventricular volume was measured

using Trans esophageal echocardiographyintraoperatively.

Glissen et al. (224)studied the effects of propofol, thiopentone and

etomidate .At clinical concentrations, etomidate did not have any effect on

contractility of myocardium. Thiopental ,however had a significant negative

inotropic effect .Haris et al. (225)studied thiopental in a dose of 4 mg /kg,

etomidate in a dose of 0.3 mg /kg and propofol in a dose of 2.5 mg /kg along

with 2 µg/ kg fentanyl in tracheal intubation. In the propofol group, there was a

decrease in SAP, in the group which received only thiopentone and etomidate

after intubation, SAP was found to be increased. Vohra et al. compared the

stress response to intubation with thiopentone in a dose of 5 mg/kg, and

propofol 3 mg/kg along with fentanyl 1.5mcg/kg. (226).The cardiac outputwere

measured using thoracic impedance in order to evaluate the hemodynamic

63  

responses to intubation. There was no significant difference in the heart rate

after induction, but in both groups there was a statistically significant increase

in heart rate after intubation (p<0.01). After induction and intubation there was

a significant decrease in cardiac output.

Pandey et al, did a study (227) comparing the effects of etomidate and

propofol on hemodynamics and serum cortisol in patients undergoing CABG

with normal left ventricular function. It was demonstrated that compared with

propofol,etomidate offers hemodynamic stabilityduring induction of anesthesia.

Studies done on patients with LV dysfunction

In a study done in AIIMS which compared induction agents in patients

with coronary artery disease and left ventricular dysfunction, in all four groups,

the hemodynamic response was similar. Variable changes in systemic vascular

resistance was noted at induction and intubation, however the stroke volume

variation and central venous pressure showed no significant changes.

Inpreventing the stress response to intubation, midazolam was most effective,

as evidenced by increase in heart rate by 4%, (p=0.12), MAP decreased by

1%(p=0.77).In the etomidate group, it was the least effective in preventing

stress response. Heart rate(P = 0.001) and mean arterial pressure (P = 0.001)

increasedat 1 minute after intubation. All the four induction agents were

suitable andcan be used for induction in patients with coronary artery disease

and left ventricular dysfunction, though cardiac index decreased by 30 to 40 %

64  

.In such patients with left ventricular dysfunction, experience ofclinician along

with knowledge of the interactions (concomitant opioid use andpremedication)

is needed to achieve hemodynamic stability.

Etomidate which is used during anesthetic induction during cardiac

surgery which includes CABG ,has the least side effects on respiratory and

cardiovascular functions, release of histamine was minimal, especially in

patients withcardiac compromise(228).However, several studies suggest an

association between etomidate administration, adrenal insufficiency and

increased mortality in patients undergoing cardiac surgery (229,230).Etomidate

reversibly inhibits 11-beta-hydroxylase, an important enzyme in steroid

production in adrenal cortex, which can lead to primary adrenal

suppression(231).Etomidate blunts the HPA axis responses. HPA axis is

activated as a body’s mechanism for adapting to illness and stress, which forms

a component in maintaining the homeostasis of cells and organs.(229)

Morel et al., (256) did a study comparing propofol or etomidate use

during induction,the requirement of norepinephrine use during first 48 hours

after cardiac surgery, the results showthat with a single bolus of etomidate the

HPA axis response was blunted lasting more than 24 hours, however

requirement of vasopressors were not increased. They concluded that due to its

significant inhibition of the HPA axis, etomidate should be used carefully in

cardiac patients with high risk.

Another study found no difference in hemodynamic variable such as

SAP, DAP, MAP and HR after induction of anesthesia and intubation with

65  

etomidate versus ketamine-thiopental sodium combination between two

groups. Due to these results we can consider the combination of ketamine and

thiopental for anesthetic induction in CABG surgery patients with low EF

(232)

66  

MATERIALS AND METHODS

STUDY SETTING:

The study was conducted in the cardiothoracic operating theaters and

cardiothoracic intensive care units in Christian Medical College Hospital,

Vellore.

Study population:

49 consenting patients between 14-75 years who underwent cardiac

surgeries during the 6 month study period in Christian Medical College

Hospital, Vellore.

Inclusion criteria

Patients who were scheduled for coronary artery bypass grafting who

have ejection fraction between 30- 45% were approached and those who were

willing to participate were included in the study

Exclusion criteria

• associated valvular heart disease,

• congestive cardiac failure

• on mechanical ventilation

• severe systemic non-cardiac disease

• known adrenal insufficiency

• on chronic steroid use

67  

Study period

It was conducted over a period of 6 months between January to

September 2016.

Sample size

A RCT done in AIIMS compared four induction agents etomidate,

propofol, thiopentone and midazolam. The hemodynamic response was

comparable in all four groups. Hemodynamic parameters were recorded

starting from induction at 1 minute intervals till 7 minutes after intubation.

Baseline Mean arterial pressure and every minute after induction the MAP was

recorded. The MAP after 3-minute induction in the etomidate group was 75.3

and MAP in the midazolam group was 68.7.

With expected mean BP 75.3 (SD 10.7) in etomidate group and mean

BP 68.7 (SD 9.2) in the midazolam group the minimum required sample for the

study is 36 in each arm.

68  

Two means- Hypothesis testing for two means

Standard deviation in group

I 11.7 11.7 10.7 10.7 7.1 7.1

Standard deviation in group

II 16.2 16.2 9.2 9.2 11.1 11.1

Mean difference 14 14 6.6 6.6 8 8

Effect size 1.003584229 1.003584 0.663317 0.663317 0.879121 0.879121

Alpha error (%) 5 5 5 5 5 5

Power (1- beta) % 80 90 80 90 80 90

1 or 2 sided 2 2 2 2 2 2

Required sample size per

group 16 21 36 48 21 29

The sample size calculation using the Mean BP after 3 minute induction

and standard deviation in each group was 72 using power of 80 and I have

chosen the sample size as 72 with 36 in each arm.

Selection of study patient:

Prior permission was obtained from the institutional review board and

the ethics committee to conduct the study. Patients who were electively

planned for cardiac surgery and with a low ejection fraction were given the

patient information sheet in the OPD. The primary investigator visited them the

day before surgery and explained about the study .Patients who gave consent

and fulfilled the inclusion criteria were included in the study and were allocated

into either of the group, by random allocation.

69  

Methodology

49 patients with moderate to severe left ventricular dysfunction, ejection

fraction 30-45% were randomly assigned to two groups after informed consent.

Patients who were scheduled for elective CABG were only included in the

study. Exclusion criteria were patients with persistent arrhythmias,associated

valvular heart disease, congestive cardiac failure, emergency surgery, on

mechanical ventilation,known adrenal insufficiency, renal disease, history of

steroid use in the preceding six months, and those with severe systemic non-

cardiac disease, other than diabetes and hypertension. Patients with critical left

main coronary disease and severe left ventricular dysfunction (Ejection fraction

(EF) <30%) were also excluded from the study. On the day of surgery patients

were premedicated with lorazepam 2 mg orally two hours prior to the

procedure. Base line monitoring was established with pulse-oximetry, invasive

blood pressure, and five lead ECG. Baseline heart rate (HR), systolic BP,

Diastolic BP, Mean BP and ST segment at 0 (Before induction) were

documented. Patients were randomized to the groups with computer based

random allocation as sealed envelopes. The consultant anesthetist who

anesthetize the patient used a drug according to the randomization. The

variables like HR, SBP, MAP, DBP, ST segment, PPV were analyzed and

documented at 1 minute after induction, 1 minute after intubation, 3 minutes

after intubation and 5 minutes after intubation. Any rise or fall within 20% of

base line or a MAP < 60 mmHg is considered significant. As we are

70  

monitoring this continuously we will treat it aggressively if the values go

beyond 20%.

Hypotension will be treated with Phenylephrine, ephedrine or

noradrenaline infusion and hypertensive response will be treated with addition

of fentanyl/ sevoflurane (toincrease the depth of anesthesia).

Baseline data like Heart rate, ST segment analysis in lead II and V5,

Systolic Diastolic and Mean arterial pressure and pulse pressure variation

(PPV) were measured. The patients were preoxygenated and received either

etomidate or midazolam over a period of 60-90 seconds. Fentanyl a dose up to

3-5 mcg/kg was given during induction in both groups. Titrated doses of

Etomidate (0.2-0.3 mg/kg) was given over 60-90 seconds in group A patients.

Titrated doses of Midazolam (0.05-0.1 mg/kg) was given over 60-90 seconds in

group B patients. Sevoflurane was used to induce and maintain 1MAC end

tidal anesthetic agent concentration. Rocuronium (1mg/kg) will be used as the

muscle relaxant to facilitate tracheal intubation. The patients were ventilated by

bag and mask with oxygen and sevoflurane 2%. Heart rate, ST, systolic,

diastolic and mean arterial pressure, and PPV were recorded before induction

of anesthesia, every minute after induction till intubation, one, three, and five

minutes after intubation. The first sample for serum cortisol levels was

measured at 8:00 AM on the day of surgery, the second sample after protamine

reversal (during C-sample) and the last sample at an interval of 24 hours after

71  

the first sample (the next day 8:00 am). Hemodynamic variables were also

measured at the times stated above. The range for serum cortisol at 8:00 AM is

5-25 microgram/dl. The study aims to see whether etomidate causes cortisol

suppression. The data was analyzed to determine which drug is more

hemodynamically stable during cardiac induction and intubation. Secondary

outcomes like ICU days, Hospital days and any morbidity and mortality were

also analyzed.

72  

Detailed Diagrammatic Algorithm of the study

[Type a quote from the document or the summary of an interesting point. 

You can position the text box anywhere in the document. Use the Drawing Tools tab to change the formatting of the pull quote text 

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Patients  who are electively planned forCABG based on inclusion and exclusion criteria 

Preoperative informed consent 

Baseline hemodynamic parameters  are recorded 

Patient will receive either etomidate or midazolam during induction  (by double blinding) 

Hemodynamic variables  will be measured at one  minute intervals from induction till five minutes post intubation 

Comparison of hemodynamic response after intubation 

Data analysed to determine which drug is hemodynamically stable 

73  

Methods

The agent used in cardiac surgery induction will be etomidate or other

conventional techniques like fentanyl and midazolam. Both the groups were

compared for their hemodynamic variables. The data was analysed to

determine which drug is more hemodynamically stable.

ii. Key Criteria

a. Inclusion Criteria: Patients who were electively planned for coronary

artery bypass grafting who have ejection fraction between 30- 45% will

be included in the study.

b. Exclusion Criteria: Patients with associated valvular heart disease,

congestive cardiac failure, on mechanical ventilation, severe systemic

non-cardiac disease and known adrenal insufficiency will be excluded

from the study.

iii. Method of randomization: Random blocks will be generated and the

patient will be allocated to either arm by randomly allocating based on the

blocks.

iv. Method of allocation concealment: The allocation is concealed using

sealed envelope technique.

v. Blinding and masking: The investigator who collects the data will be

blinded to the drug. The anesthesia sheets will be marked as either drug A

or B.

74  

ANALYSIS RESULTS Baseline characteristics expressed as mean +/-SD Etomidate n=22 Midazolam n=27 P value

Age 61.36+/-9 56.37+/-9.3 0.06

Sex Male 22 26

Female 0 1

Weight 63.86+/-8.49 65.04+/-9.0 0.36

Height 161.90+/-4.6 163.15+/-7.5 0.5

EF 42.38+/-2.9 41.6+/-3.6 0.42

Drug treatment (%)

Beta blockers 95.5 100 0.45

CCB 0 3.7 1.0

ACEI 36.4 22.2 0.35

ARB 13.6 14.8 1.0

Diabetes (%) 46.4 53.6 1.0

Hypertension (%) 47.8 52.2 0.78

Induction dose 0.2 mg/kg 0.04 mg/kg

The baseline characters were comparable in both the groups.

This

P val

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ws the age diistribution aamong the ppatients.

75

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76

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Phen

Nora

The

the M

group

modynamic

uirement

edrine(mg)

nylephrine(m

adrenaline(m

requiremen

Midazolam

ps.

stability a

of Phenyl

mcg)

mcg)

nt of Pheny

group. Th

t induction

ephrine/E

E

1

1

4

ylephrine, E

here was no

n

Ephedrine/

Etomidate

0.29

17.65

4.0

Ephedrine a

o significan

/Noradren

Midazol

12.44

160.0

17.8

and Noradre

nt differenc

naline

lam P v

0.1

0.2

0.1

enaline was

ce between

79

value

17

27

11

s more in

n the two

Stres

Hem

ss response

modynamic r

e to intubat

response to

tion

intubation was compaarable betwween the gro

80

oups

81  

Serum cortisol level

Serum cortisol values

It can be seen that first sample at induction, in both the groups it is

within normal values, but the baseline values were higher in the etomidate

group. (The baseline was comparable. P=0.46) Etomidate causes suppression of

cortisol values, hence after weaning from CPB, the C sample shows a decline

in Etomidate group ,not in the midazolam group.(p value=0.001) The third

sample value is higher in the etomidate than midazolam group. The value is

reaching near normal in the midazolam group.

At induction C sample 24 hrs after first sample

Etomidate 17.22 10.16 29.84

Midazolam 15.73 17.21 25.8

17.22

10.16

29.84

15.7317.21

25.8

0

5

10

15

20

25

30

35

mcg per dl

Serum Cortisol

Etomidate Midazolam

CK –

CKM

– MB level

MB values p

ls

post –op shoow a declin

ning trend inn both the ggroups.

82

Vaso

p=0.2

VIS w

Iono

(mcg

Vaso

Vaso

henc

mida

oactive inot

21

was calcula

otrope scor

g/kg/min) +

oactive Ion

opressin dos

Though

e requiring

azolam grou

trope score

ated using t

re (IS)= D

+100x Adren

notrope sco

se (units/kg

there were

vasopresso

up has recor

e

he followin

Dopamine

naline dose

ore= IS+ 10

g/min) +100

e concerns

ors postoper

rded a high

ng over 24 h

dose (mcg

(mcg/kg/m

0x Milrinon

0x Noradren

over adren

ratively, the

her ionotrop

hours:

g/kg/min)

min)

ne dose (mc

naline dose

nal suppres

e above bar

e score.

+Dobutam

g/kg/min) +

(mcg/kg/m

ssion by et

r diagram sh

83

ine dose

+10000 x

min)

tomidate,

hows that

Num

p=0.0 Num

p=0.2

mber of ICU

02

mber of hos

25

U days

spital days

84

Ther

decre

41.4%

basel

re was a n

eases, the P

% of patie

line)

negative co

PPV was fou

ents had PP

orrelation

und to be ri

PV> 12 an

seen betwe

ising.

nd hypotens

een EF an

sion (>20%

nd PPV.As

% drop in

85

s the EF

BP from

38.3%

the o

% of patien

other group

nts (among

(36.5%), in

second cas

n evaluating

ses) had hyp

g the role of

potension w

f NPO statu

which was s

us in hypote

86

similar in

ension.

The a

Ther

with

above graph

re were no

the use of e

hs show the

reported in

etomidate.

e relation be

ncidents of

etween ST

pain on inj

changes an

jection, phl

nd hypotens

ebitis or m

87

ion.

myoclonus

88  

Incidence of significant hypotension

Etomidate(n=22) Midazolam(n=27)

Number of cases 7 (31.8%) 14 (51.85%)

p=0.88

The number of patients who had MAP less than 60 at any point of time

during induction among the two groups were compared. 51.85% patients in the

midazolam developed significant hypotension compared to only 31.8% in the

etomidate group. (p value between the 2 groups=0.88)

89  

DISCUSSION

49 patients were assigned to two groupsEtomidate or Midazolam, based

on random allocation. Baseline demographic characteristics were comparable

between the two groups. The study was conducted in patients with mild to

moderate LV dysfunction. However the mean EF was 42.38+/-2.9 vs. 41.6+/-

3.6 in the etomidate and midazolam groups respectively, which qualifies as

mild LV dysfunction.

Etomidate was more hemodynamically stable as seen by the serial MAP values

which were consistently not less than 20% of baseline in the etomidate group.

There was significant difference in the MAP value 1 minute after intubation.

Our results were comparable to studies which have shown etomidate tohave a

safe cardiovascular profile by Gooding et al., Sun (1991), Yunqi et al., Hosten

et al., and Pandey et al. The number of patients who had MAP less than 60 at

any point of time during induction among the two groups was compared.

51.85% patients in the midazolam developed significant hypotension compared

to only 31.8% in the etomidate group. (p value=0.88). However we didn’t

measure the duration of significant hypotension (MAP <60 mmHg) which is a

drawback of the study. Any blood pressure less than 20% of the baseline was

treated with pressors and if needed noradrenaline. The patients in the

midazolam group received more ephedrine, phenylephrine and noradrenaline.

Even though the difference is not statistically significant,it indirectly indicates

the increased incidence of hypotension in the midazolam group.

90  

In patients who are to undergo CABG, using fentanyl in high doses is an

established technique in anesthesia.(148,233,234). The advantage is that there

is minimal disturbances in hemodynamics, even in patients with poor left

ventricular function. (149).But fentanyl in high doses is not sufficient to blunt

the stress response by intubation and additional sedation is required to cause

amnesia(235,236). However, a combination of midazolam and fentanyl are

known to result in significant hypotension. In the era of fast tracking, the use of

high dose fentanyl is almost obsolete as it can result in delayed extubations. We

decided to use 0.05 -0.1 mg/kg of midazolam, but most consultants who gave

anesthesia erred on the side of caution and the average dose of midazolam

administered was 0.04 mg/kg. 43% of patients were more than 60 year old and

the anesthetist would have accounted for the age for dose reduction.

Hemodynamic response to intubation were comparable between the

groups. Both groups suppressed the laryngoscopic response to intubations

effectively. Our findings are in contrast to Singh etal who found that

midazolam was more effective than etomidate in prevention of hemodynamic

response to intubation. We agree with him in his hypothesis that most of the

hemodynamic changes are attributable to the loss of sympathetic stimulation on

induction rather than to anesthetic drugs per se.

91  

It can be seen that the first sample of serum cortisol at induction, in both

the groups is within normal values, but the baseline values were higher in the

etomidate group. (The baseline was comparable. P=0.46) The C sample shows

a decline in serum cortisol level in Etomidate group but not in the midazolam

group. (p value=0.001). However the values are within normal limits. The third

sample value is higher in the etomidate than midazolam group.

In both the groups, third sample 24 hour value were higher as compared

to baseline values. Hence it can be seen that the adrenal suppression caused by

Etomidate did not last more than 24 hours. Also the clinical significance of this

suppression is not clear. Our results are comparable to Zurick et al who showed

that Etomidate caused suppression of serum cortisol levelsafter even a single

dose, leading to cortisol reduction lasting up to twenty-four hours (206).

The inotrope score ICU stay and hospital stay were less in etomidate

group compared to midazolam group. The ICU stay in the etomidate group was

found to be significantly less in the etomidate group. Our results are in contrast

to CORTICUS trial and other trials done in ICU patients and septic patients

(230) showing an increased inotropic requirement, morbidity and mortality in

etomidate group. However our population is different. We agree with A.M

Zurick etal who concluded that the cortisol suppression caused by a single dose

of etomidate is mostly limited to 24 hour period (206), there is no threat of

prolonged adrenocortical suppression. Our data is in agreement with Morel.et

92  

al who concluded that a single bolus of etomidate causes the hypothalamic–

pituitary–adrenal axis response to be blunted for more than 24 h in patients

who are to undergo elective cardiac surgery, but this was not associated with an

increase in requirement ofvasopressors(229). However our sample size is not

complete to reach a conclusion. Our results contrasted with Iribarren et al who

found that the use of etomidate in elective CABG cases was associated with

relative adrenal insufficiency and increasing requirement of vasopressors

postoperatively.(230). Our study showed a reduced inotropic requirement and

ICU stay in etomidate group. Our results contrasted Iribarren who did a study

in 120 cardiac patients and found that a single dose of etomidate resulted in 12

-72 hours of adrenal suppression.

In our study there were no reported incidents of pain on injection,

phlebitis or myoclonus with the use of Etomidate. None of the patients

developed stroke, renal failure, and myocardial injury .There were 2 cases of

mortality during the study period.

We couldn’t find any significant ST segment changes during induction

or intubation.

We could not derive any meaningful association between PPV and

hypotension. This is partly because we did not fulfill the prerequisite for

measuring PPV that the patient should be mechanically ventilated.

93  

LIMITATIONS OF THE STUDY

We did not complete the required sample size. So the study is

underpowered to reach any conclusions.

Duration of hypotension was not documented.

We didn’t analyze the multivariate predictors of hypotension as we

didn’t complete the sample size.

We didn’t use a pulmonary artery catheter which would have showed us

the changes in cardiac output, stroke volume and systemic vascular resistance.

Even though these data would have added to the value of the study we didn’t

find a favorable risk benefit ratio as most of our patients had only mild LV

dysfunction.

94  

Conclusion

1. Etomidate offered significantly better hemodynamic stability compared

to midazolam for induction of anesthesia in coronary artery disease

patients with mild left ventricular dysfunction.

2. Etomidate was comparable to midazolam in suppressing hemodynamic

response to intubation in the study population.

3. Even though etomidate suppressed the immediate stress response to

surgery, the serum cortisol levels were within normal limits and reached

a comparable value by 24 hours. Also the inotrope score, ICU stay and

hospital stay were better in etomidate group indicating that the adrenal

suppression is not clinically significant.

95  

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