1
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
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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
8
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.
9
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
12
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).
14
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
15
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.
16
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
18
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.
21
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
23
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
25
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
28
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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204).Patient
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57
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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
box.]
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
chart show
lue =0.42
ws the age diistribution aamong the ppatients.
75
Out o
Out o
of 23 patien
of 28 patien
nts with hyp
nts with dia
pertension 1
abetes 13 rec
11 received
ceived drug
d drug A, 12
g A, 15 rece
2 received d
eived drug B
76
drug B
B
Hem
MAP
1 min
1 min
3 min
5 min
Mida
respo
modynamic
P baseline
n after indu
n after intub
n after intub
n after intub
This show
azolam, hyp
onse to intu
response (
uction
bation
bation
bation
ws that Eto
potension is
ubation was
(MAP) to in
Etomidat
102.
93.
87.
90.
83
midate is m
s more in th
similar bet
nduction a
te Midaz
.91
.77
.23
.14
3.5
more hemod
he midazola
tween the g
and intubat
zolam P
97.15
91.63
74.26
83.78
85.22
dynamically
am group. H
roups.
tion
P value
0.24
0.70
0.02
0.35
0.78
y stable than
Hemodynam
77
n
mic
Hem
HR b
1 min
1 min
3 min
5 min
Both
is no
modynamic
baseline
n after indu
n after intub
n after intub
n after intub
h Etomidate
o significant
response (
uction
bation
bation
bation
e and Midaz
t difference
(HR) to ind
zolam cause
between th
duction and
Etomida
73.7
72.3
76.6
78.2
73.0
e a rise in h
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d intubatio
ate Mida
73
32
68
27
05
heart rate af
ups (p=0.83
on
azolam P
77.48
76.74
75.44
79.26
77.15
fter intubati
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78
P value
0.24
0.22
0.78
0.83
0.36
ion, there
Hem
Req
Ephe
Phen
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The
the M
group
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edrine(mg)
nylephrine(m
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Midazolam
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of Phenyl
mcg)
mcg)
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Ephedrine/
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Ephedrine a
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/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
Bibliography
1. Arne O. Budde, MD, and Berend Mets, MB, PhD. Pro: Etomidate Is the
Ideal Induction Agent for a Cardiac Anesthetic Arne O. Budde, MD,
and Berend Mets, MB, PhD. PhDJournal Cardiothorac Vasc Anesth.
Vol 27, No 1 (February), 2013:
2. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone
G, et al. Executive summary: heart disease and stroke statistics--2010
update: a report from the American Heart Association. Circulation. 2010
Feb 23;121(7):948–54.
3. Towfighi A, Zheng L, Ovbiagele B. Sex-specific trends in midlife
coronary heart disease risk and prevalence. Arch Intern Med. 2009 Oct
26;169(19):1762–6.
4. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and
coronary heart disease. The Framingham Study. Ann Intern Med. 1978
Aug;89(2):157–61.
5. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and
mortality in the sexes: a 26-year follow-up of the Framingham
population. Am Heart J. 1986 Feb;111(2):383–90.
6. Kannel WB. Prevalence and clinical aspects of unrecognized myocardial
infarction and sudden unexpected death. Circulation. 1987 Mar;75(3 Pt
2):II4-5.
7. Ceyhan D, Tanrıverdi B, Bilir A. Comparison of the effects of
sevoflurane and isoflurane on myocardial protection in coronary bypass
96
surgery. Anadolu Kardiyol Derg AKD Anatol J Cardiol. 2011
May;11(3):257–62.
8. Straarup TS, Hausenloy DJ, Rolighed Larsen JK. Cardiac troponins and
volatile anaesthetics in coronary artery bypass graft surgery: A
systematic review, meta-analysis and trial sequential analysis. Eur J
Anaesthesiol. 2016 Jun;33(6):396–407.
9. Kling D, Laubenthal H, Börner U, Boldt J, Hempelmann G.
[Comparative hemodynamic study of anesthesia induction with propofol
(Diprivan), thiopental, methohexital, etomidate and midazolam in
patients with coronary disease]. Anaesthesist. 1987 Oct;36(10):541–7.
10. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular
disease in Europe 2014: epidemiological update. Eur Heart J. 2014 Nov
7;35(42):2950–9.
11. Arciero TJ, Jacobsen SJ, Reeder GS, Frye RL, Weston SA, Killian JM,
et al. Temporal trends in the incidence of coronary disease. Am J Med.
2004 Aug 15;117(4):228–33.
12. Goyal A, Yusuf S. The burden of cardiovascular disease in the Indian
subcontinent. Indian J Med Res. 2006 Sep;124(3):235–44.
13. Rodríguez T, Malvezzi M, Chatenoud L, Bosetti C, Levi F, Negri E, et
al. Trends in mortality from coronary heart and cerebrovascular diseases
in the Americas: 1970-2000. Heart Br Card Soc. 2006 Apr;92(4):453–
60.
97
14. Furman MI, Dauerman HL, Goldberg RJ, Yarzebski J, Lessard D, Gore
JM. Twenty-two year (1975 to 1997) trends in the incidence, in-hospital
and long-term case fatality rates from initial Q-wave and non-Q-wave
myocardial infarction: a multi-hospital, community-wide perspective. J
Am Coll Cardiol. 2001 May;37(6):1571–80.
15. Roger VL, Weston SA, Gerber Y, Killian JM, Dunlay SM, Jaffe AS, et
al. Trends in incidence, severity, and outcome of hospitalized
myocardial infarction. Circulation. 2010 Feb 23;121(7):863–9.
16. Rogers WJ, Frederick PD, Stoehr E, Canto JG, Ornato JP, Gibson CM,
et al. Trends in presenting characteristics and hospital mortality among
patients with ST elevation and non-ST elevation myocardial infarction
in the National Registry of Myocardial Infarction from 1990 to 2006.
Am Heart J. 2008 Dec;156(6):1026–34.
17. S.S M. . R, Deepa. Prevalence of coronary artery disease and its
relationship to lipids in a selected population in South India. J Am Coll
Cardiol 200138682–687. (2001):682–7.
18. Kamili M.A., Dar I.H., Ali G. Prevalence of coronary heart disease in
Kashmiris. Indian Heart J 20076144–49 PubMed.
19. AshotraS GA., Bharadwaj A. Feasibility and training of multipurpose
workers in detection, prevention and control of coronary artery disease
in apple-belt of Shimla hills. South Asian J Prev Cardiol. 2002;6:17–22.
98
20. Kumar R., Singh M.C., Ahlawat S.K. Urbanization and coronary heart
disease: a study of urban–rural differences in northern India. Indian
Heart J 2006. 2006;58:126–30.
21. Gajalakshmi V., Peto R., Kanaka S. Verbal autopsy of 48000 adult
deaths attributable to medical causes in Chennai, India. BMC Public
Health. 2002;2:7.
22. Ezzati M., Lopez A.D., Rodgers A. World Health Organisation; Geneva:
2004. Comparative Quantification of Health Risks. Global and Regional
Burden of Disease Attributable to Major Risk Factors.
23. Prevalence of coronary artery disease in Asian Indians. Am J Cardiol.
1992;70:945–9.
24. Yusuf S., Hawken S., Ounpuu S.,. The INTERHEART Study
Investigators Effect of potentially modifiable risk factors associated with
myocardial infarction in 52 countries (the INTERHEART Study): case
control study. Lancet Lond Engl. 2004;364:937–52.
25. King H., Aubert R.E., Herman W.H. Global burden of diabetes, 1995–
2025: prevalence, numerical estimates, and projections. Diabetes Care.
1998(21):1414–31.
26. Ramachandran A. Epidemiology of diabetes in India—three decades of
research. J Assoc Physicians India. 2005;53: :34–8.
27. Reddy K.S., Shah B., Varghese C. Responding to the challenge of
chronic diseases in India. Lancet 2005. 366:1744–9.
99
28. Beaglehole R., Yach D. Globalization and the prevention and control of
non-communicable diseases: the neglected chronic diseases of adults.
Lancet 2003362. 362:903–908.
29. Mohr FW, Morice M-C, Kappetein AP, et al. Coronary artery bypass
graft surgery versus percutaneous coronary intervention in patients with
three-vessel disease and left main coronary disease: 5-year follow-up of
the randomised, clinical SYNTAX trial. Lancet 2013; 381: 629–38.
30. Rastan AJ, Bittner HB, Gummert JF, et al. On-pump beating heart
versus off-pump coronary artery bypass surgery—Evidence of pump-
induced myocardial injury. Eur J Cardiothorac Surg. 2005;27:1057–
1064.
31. Nesher N, Frolkis I, Vardi M, et al. Higher levels of serum cytokines
and myocardial tissue markers during on-pump versus off-pump
coronary artery bypass surgery. J Card Surg. 2006;21:395–402.
32. Serrano CV Jr, Souza JA, Lopes NH, et al. Reduced expression of
systemic proinflammatory and myocardial biomarkers after off-pump
versus on-pump coronary artery bypass surgery: A prospective
randomized study. J Crit Care. 2010;25:305–312.
33. Tsai CS, Tsai YT, Lin CY, et al. Expression of thrombomodulin on
monocytes is associated with early outcomes in patients with coronary
artery bypass graft surgery. Shock. 2010;34:31–39.
100
34. Sahlman A, Ahonen J, Nemlander A, et al. Myocardial metabolism on
off-pump surgery; a randomized study of 50 cases. Scand Cardiovasc J.
2003;37:211–215.
35. Wan IY, Arifi AA, Wan S, et al. Beating heart revascularization with or
without cardiopulmonary bypass: Evaluation of inflammatory response
in a prospective randomized study. J Thorac Cardiovasc Surg. 2004;
127:1624–1631.
36. Velissaris T, Tang AT, Murray M, et al. A prospective randomized
study to evaluate stress response during beating-heart and conventional
coronary revascularization. Ann Thorac Surg. 2004;78:506–512.
37. Quaniers JM, Leruth J, Albert A, Limet RR, Defraigne JO. Comparison
of inflammatory responses after off-pump and on-pump coronary
surgery using surface modifying additives circuit. Ann Thorac Surg.
2006;81:1683–1690.
38. Paulitsch FS, Schneider D, Sobel BE, et al. Hemostatic changes and
clinical sequelae after on-pump compared with off-pump coronary
artery bypass surgery: A prospective randomized study. Coron Artery
Dis. 2009;20:100–105.
39. Formica F, Broccolo F, Martino A, et al. Myocardial revascularization
with miniaturized extracorporeal circulation versus off pump:
Evaluation of systemic and myocardial inflammatory response in a
prospective randomized study. J Thorac Cardiovasc Surg.
2009;137:1206–1212.
101
40. Sun JC, Whitlock R, Cheng J, et al. The effect of pre-operative aspirin
on bleeding, transfusion, myocardial infarction, and mortality in
coronary artery bypass surgery: A systematic review of randomized and
observational studies. Eur Heart J. 2008;29:1057–1071.
41. Akowuah E, Shrivastava V, Jamnadas B, et al. Comparison of two
strategies for the management of antiplatelet therapy during urgent
surgery. Ann Thorac Surg. 2005;80:149–152.
42. Berkan O, Katrancioglu N, Ozker E, Ozerdem G, Bakici Z,Yilmaz MB.
Reduced P-selectin in hearts pretreated with fluvastatin: A novel benefit
for patients undergoing open heart surgery. Thorac Cardiovasc Surg.
2009;57:91–95.
43. Meyns B, Autschbach R, Boning A, et al. Coronary artery bypass
grafting supported with intracardiac microaxial pumps versus
normothermic cardiopulmonary bypass: A prospective randomized trial.
Eur J Cardiothorac Surg. 2002;22:112–117.
44. Stassano P, Di TL, Monaco M, et al. Left heart pump-assisted
myocardial revascularization favorably affects neutrophil apoptosis.
World J Surg. 2010;34:652–657.
45. Stassano P, Di TL, Monaco M, et al. Myocardial revascularization by
left ventricular assisted beating heart is associated with reduced
systemic inflammatory response. Ann Thorac Surg. 2009;87:46–52.
46. Frank SM, Beattie C, Christopherson R. Epidural versus general
anesthesia, ambient operating room temperature, and patient age as
102
predictors of inadvertent hypothermia. Anesthesiology. 1992;77:252–
257.
47. Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces the
risk of postoperative myocardial ischemia in patients with cardial risk
factors. Can J Anaesth. 1993;40:532–541.
48. Howie MB, Hiestand DC, Jopling MW, Romanelli VA, Kelly WB,
McSweeney TD. Effect of oral clonidine premedication on anesthetic
requirement, hormonal response, hemodynamics, and recovery in
coronary artery bypass graft surgery patients. J Clin Anesth.
1996;8:263–272.
49. Edwards ND, Alford AM, Dobson PMS, Peacock JE, Reilly CS.
Myocardial ischemia during tracheal intubation and extubation. Br J
Anaesth. 1994;73:537–539.
50. Choyce A, Avidan MS, Harvey A, Patel C, Timberlake C,Sarang K,
Tilbrook L. The cardiovascular response to insertion of the intubating
laryngeal mask airway. Anaesthesia. 2002;57:330–333.
51. Landis RC, Brown JR, Fitzgerald D, Likosky DS, Shore-Lesserson L,
Baker RA, et al. Attenuating the Systemic Inflammatory Response to
Adult Cardiopulmonary Bypass: A Critical Review of the Evidence
Base. J Extra Corpor Technol. 2014 Sep;46(3):197–211.
52. Svenmarker S, Haggmark S, Jansson E, et al. Use of heparin-bonded
circuits in cardiopulmonary bypass improves clinical outcome. Scand
Cardiovasc J. 2002;36:241–246.
103
53. de Vroege R van Oeveren W, van Klarenbosch J, et al. The impact of
heparin-coated cardiopulmonary bypass circuits on pulmonary function
and the release of inflammatory mediators. Anesth Analg.
2004;98:1586–1594,.
54. Davis MH, Coleman MR, Absalom AR, et al. Dissociating speech
perception and comprehension at reduced levels of awareness. Proc Natl
Acad Sci U S A. 2007;104:16032–7.
55. Bevan JC, Veall GR, Macnab AJ, Ries CR, Marsland C. Midazolam
premedication delays recovery after propofol without modifying
involuntary movements. Anesth Analg. 1997;85:50–4.
56. Gibbs FA, Gibbs LE, Lennox WG. Effects on the electroencephalogram
of certain drugs which influence nervous activity. Arch Intern Med.
1937;60:154–66.
57. Kiersey DK, Bickford RG, Faulconer A., Jr Electro-encephalographic
patterns produced by thiopental sodium during surgical operations;
description and classification. Br J Anaesth. 1951;23:141–52.
58. McCarthy MM, Brown EN, Kopell N. Potential network mechanisms
mediating electroencephalographic beta rhythm changes during
propofol-induced paradoxical excitation. J Neurosci. 2008;28:13488–
504.
59. Coté CJ, Goudsouzian NG, Liu LM, Dedrick DF, Rosow CE. The dose
response of intravenous thiopental for the induction of general
anesthesia in unpremedicated children. Anesthesiology.1981;55:703–5.
104
60. Gray AT, Krejci ST, Larson MD. Neuromuscular blocking drugs do not
alter the pupillary light reflex of anesthetized humans. Arch Neurol.
1997;54:579–84.
61. Bijker JB, van Klei WA, Kappen TH, van Wolfswinkel L, Moons KG,
Kalkman CJ. Incidence of intraoperative hypotension as a function of
the chosen definition: literature definitions applied to a retrospective
cohort using automated data collection. Anesthesiology.
2007;107(2):213–220.
62. Reich DL, Hossain S, Krol M, et al. Predictors of hypotensionafter
induction of general anesthesia. Anesth Analg. 2005;101(3):622–628.
63. Kheterpal S, O’Reilly M, Englesbe MJ, et al. Preoperative and
intraoperative predictors of cardiac adverse events after general,
vascular, and urological surgery. Anesthesiology. 2009;110(1):58–66.
64. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between
intraoperative mean arterial pressure and clinical outcomes after
noncardiac surgery: toward an empirical definition of hypotension.
Anesthesiology. 2013;119(3):507–515.
65. Bijker JB, Gelb AW. Review article: the role of hypotension in
perioperative stroke. Can J Anaesth. 2013;60(2):159–167.
66. Lienhart A, Auroy Y, Péquignot F, et al. Survey of anesthesia-related
mortality in France. Anesthesiology. 2006;105(6):1087–1097.
67. Muralidhar K, Hema CN, Sanjay B, Keshava M, Murugesan C.
Haemodynamic response to endotracheal intubation in coronary artery
105
disease: Direct versus video laryngoscopy. Indian J Anaesth. 2011 May-
Jun;55(3):260–265.
68. Reid LC, Brace DE. Irritation of the respiratory tract and its reflex effect
upon heart. Surg Gynaecol Obstet. 1940;70:157–62S.
69. Bruder N, Ortega D, Granthil C. Consequences and prevention methods
of hemodynamic changes during laryngoscopy and intratracheal
intubation. Ann Fr Anesth Reanim. 1992;11:57–71.
70. Kovak AL. Controlling the hemodynamic response to laryngoscopy and
enfotracheal intubation. J Clin Anesth. 1996 Feb;8(1):63–79.
71. Schälte G, Scheid U, Rex S, Coburn M, Fiedler B, Rossaint R, Zoremba
N. The use of the Airtraq®optical laryngoscope for routine tracheal
intubation in high-risk cardiosurgical patients. BMC Res Notes.
2011;4:425.
72. Adachi YU, Satomoto M, Higuchi H, Watanabe K. Fentanyl attenuates
the hemodynamic response to endotracheal intubation more than the
response to laryngoscopy. Anesth Analg. 2002 Jul;95(1):233–237.
73. Bishop MJ, Harrington RM, Tencer AF. Force applied during tracheal
intubation. Anesth Analg. 1992;74:411–414.
74. Bucx MJ, Snijders CJ, Van Geel RT, et al. Forces acting on the
maxillary incisor teeth during laryngoscopy using the Macintosh
laryngoscope. Anaesthesia. 1994;49:1064–1070.
106
75. Tong JL, Ashworth DR, Smith JE. Cardiovascular responses following
laryngoscope assisted, fibreoptic orotracheal intubation. Anaesthesia.
2005;60:754–758.
76. Singh R, Choudhury M, Kapoor PM, Kiran U. A randomized trial of
anesthetic induction agents in patients with coronary artery disease and
left ventricular dysfunction. Ann Card Anaesth. 2010;13(3):217–223.
77. Ndoko SK, Amathieu R, Tual L, Polliand C, Kamoun W, El Housseini
L, Champault G, Dhonneur G. Tracheal intubation of morbidly obese
patients: a randomized trial comparing performance of Macintosh and
AirtraqTM laryngoscopes. British Journal of Anaesthesia.
2008;100(2):263–268.
78. Gaszyński T, Gaszyński W. A comparison of the optical AirTraq and
the standard Macintosh laryngoscope for endotracheal intubation in
obese patients. Anestezjol Intens Ter. 2009;41:145–148.
79. Flacke JW, Bloor BC, Flacke WE. Reduced narcotic requirement by
clonidine with improved hemodynamic and adrenergic stability in
patients undergoing coronary bypass surgery. Anesthesiology.
1987;67:11–19.
80. Helbo-Hansen S, Fletcher R, Lundberg D. Clonidine and the sympatico-
adrenal response to coronary artery bypass surgery.Acta Anaesthesiol
Scand. 1986;30:235–242.
107
81. Ghignone M, Quintin L, Duke PC. Effects of clonidine on narcotic
requirements and hemodynamic response during induction of fentanyl
anesthesia and endotracheal intubation. Anesthesiology. 1986;64:36–42.
82. Segal IS, Jarvis DJ, Duncan SR. Clinical efficacy of oral-transdermal
clonidine combinations during the perioperative period. Anesthesiology.
1991;74:220–225.
83. Quinton L, Roudot F, Roux C. Effect of clonidine on the circulation and
vasoactive hormones after aortic surgery. Br J Anaesth. 1991;66:108–
115.
84. Engelman E, Lipszyc M, Gilbart E. Effects of clonidine on anesthetic
drug requirements and hemodynamic response during aortic surgery.
Anesthesiology. 1989;71:178–187.
85. Dorman BH, Zucker JR, Verrier ED, Gartman DM, Slachman FN.
Clonidine improves perioperative myocardial ischemia, reduces
anesthetic requirement, and alters hemodynamic parameters in patients
undergoing coranary arterie bypass surgery. J Cardiothorac Vasc
Anesth. 1993;7:386–395.
86. Dorman T, Clarkson K, Rosenfeld B, Shanholtz C, Lipsett PA, Breslow
MJ. Effects of clonidine on prolonged postoperative sympathetic
response. Critical Care Medicine. 1997;25:1147–1152.
87. Boussofara M, Bracco D, Ravussin P. Comparison of the effects of
clonidine and hydroxyzine on haemodynamic and catecholamine
108
reactions to microlaryngoscopy. European Journal of Anaestehsiology.
2001;18:75–78.
88. Nishikawa T, Taguchi M, Kimura T, Taguchi N, Sato Y, Dai M. Effects
of clonidine premedication upon hemodynamic changes associated with
laryngoscopy and tracheal intubation. Masui. 1991;40:1083–1088.
89. Chadha R, Padmanabhan V, Joseph A, Mohandas K. Oral clonidine
pretreatment for heamodynamic stability during craniotomy. Anaesth
Intensive Care. 1992;20:341–344.
90. Kim WY, Lee YS, Ok SJ, Chang MS, Kim JH, Park YC, et al.
Lidocaine does not prevent bispectral index increases in response to
endotracheal intubation. Anesth Analg. 2006;102:156–9.
91. Dahlgren N, Messeter K. Treatment of stress response to laryngoscopy
and intubation with fentanyl. Anaesthesia. 1981;36:1022–6.
92. Habib AS, Parker JL, Maguire AM, Rowbotham DJ, Thompson
JPEffects of remifentanil and alfentanil on the cardiovascular responses
to induction of anaesthesia and tracheal intubation in the elderly. Br J
Anaesth. 2002;88:430–3.
93. Kumar N, Batra YK, Bala I, Gopalan S. Nifedipine attenuates the
hypertensive response to tracheal intubation in pregnancy-induced
hypertension. Can J Anaesth. 1993;40:329–33.
94. Ogurlu UB, Erdal MC, Aydin ON. Effects of esmolol, lidocaine and
fentanyl on haemodynamic responses to endotracheal intubation:A
comparative study. Clin Drug Investig. 2007;27:269–77.
109
95. Kumari I, Pathania VS. A prospective randomised double blind placebo
controlled trial of oral gabapentin in attenuation of haemodynamic
responses during laryngoscopy &tracheal intubation. J Anaesth Clin
Pharmacol. 2009;25:439–43.
96. Ashton WB, James MF, Janicki P, Uys PC. Attenuation of the pressor
response to tracheal intubation by magnesium sulphate with and without
alfentanil in hypertensive proteinuric patients undergoingcaesarean
section. Br J Anaesth. 1991;67:741–7.
97. Kim HJ, Jun JH, Yoo HK, Kim KS, Choi WJ, Cho YH. The effects of
remifentanyl, lidocaine, nicardipine and nitroglycerine on hemodynamic
changes during tracheal intubation. Korean J Anesthesiol. 2008;54:614–
8.
98. Mikawa K, Hasegawa M, Suzuki T, Maekawa N, Kaetsu H, Goto R, et
al. Attenuation of hypertensive response to tracheal intubation with
nitroglycerin. J Clin Anesth. 1992;4:367–71.
99. Hemodynamic Effects of Nitroglycerin in Acute Myocardial Infarction
Decrease in Ventricular Preload at the Expense of Cardiac Output. [Last
accessed on 2015 Feb 24];Williams D O, AMSTERDAM E A, MASON
D T, M.D. Circulation. 1975 Mar;Volume 51.
100. Dich-Nielsen J, Hole P, Lang-Jensen T, Owen-Falkenberg A, Skovsted
P. The effect of intranasally administered nitroglycerin on the blood
pressure response to laryngoscopy and intubation in patients undergoing
110
coronary artery by-pass surgery. Acta Anaesthesiol Scand. 1986;30:23–
7.
101. Grover VK, Sharma S, Mahajan RP, Singh H. Intranasal nitroglycerine
attenuates pressor response to tracheal intubation in beta-blocker treated
hypertensive patients. Anaesthesia. 1987;42:884–7.
102. Nishina K, Mikawa K, Maekawa N, Obara H. Attenuation of
cardiovascular responses to tracheal extubation with diltiazem. Anesth
Analg. 1995;80:1217–22.
103. Bostana H, Eroglu A. Comparison of the clinical efficacies of fentanyl,
esmolol and lidocaine in preventing the hemodynamic responses to
endotracheal intubation and extubation. J Curr Surg. 2012;2:24–8.
104. Abou-Madi M, Keszler H, Yacoub JM. Cardiovascular reactions to
laryngoscopy and tracheal intubation following small and large
intravenous dose of lidocaine. Can J Anaesth. 1977;24:12–9.
105. Pandey CK, Raza M, Ranjan R. Intravenous lidocaine suppresses
fentanyl-induced coughing: A double-blind, prospective, randomized
placebo-controlled study. Anesth Analg. 2004;99:1696–8.
106. Miller CD, Warren SJ. Intravenous lignocaine fails to attenuate the
cardiovascular response to laryngoscopy and tracheal intubationBr J
Anaesth. 1990;65:216–9.
107. Jolliffe CT, Leece EA, Adams V, Marlin DJ. Effect of intravenous
lidocaine on heart rate, systolic arterial blood pressure and cough
111
responses to endotracheal intubation in propofol-anaesthetized dogs. Vet
Anaesth Analg. 2007;34:322–30.
108. Savio KH, Tait G, Karkouti K, Wijeysundera D, McCluskey S, Beattie
WS. The safety of perioperative esmolol: A systematic review and meta-
analysis of randomized controlled trials. Anesth Analg. 2011;112:267–
81.
109. Moffitt EA, Tarhan S, Lundborg RO. Anesthesia for cardiac surgery:
principles and practice. Anesthesiology. 1968;29:1181–205.
110. Bondy RJ, Wynands JE. Anesthesia induction and maintenance
strategies. In: Estafanous FG, Barash FG, Reves JG, editors. Cardiac
Anesthesia: Principles and Clinical Practice. Philadelphia, USA:
Lippincott company; 1994. p. 221.
111. Lowenstein E., Hallowell P., Levine F.H., et al; Cardiovascular
response to large doses of intravenous morphine in man. N Engl J Med.
1969;281:1389-1393.
112. Reiz S., Balfors E., Sorensen M.B., et al; Isoflurane—a powerful
coronary vasodilator in patients with coronary artery disease.
Anesthesiology. 1983;59:91-97.
113. Slogoff S., Keats A.S., Ott E.; Preoperative propranolol therapy and
aortocoronary bypass operation. JAMA. 1978;240:1487-1490.
114. Myles P.S., Daly D.J., Djaiani G., et al; A systematic review of the
safety and effectiveness of fast-track cardiac anesthesia. Anesthesiology.
2003;99:982-987.
112
115. London M.J., Shroyer A.L., Grover F.L.; Fast tracking into the new
millennium: an evolving paradigm. Anesthesiology. 1999;91:911-915.
116. Frassdorf J., De Hert S., Schlack W.; Anaesthesia and myocardial
ischaemia/reperfusion injury. Br J Anaesth. 2009;103:89-98.
117. Tanaka K., Ludwig L.M., Kersten J.R., et al; Mechanisms of
cardioprotection by volatile anesthetics. Anesthesiology. 2004;100:707-
721.
118. Aronow WS, Ahn C, Kronzon I Effect of propranolol versus no
propranolol on total mortality plus nonfatal myocardial infarction in
older patients with prior myocardial infarction, congestive heart failure,
and left ventricular ejection fraction > or = 40% treated with diuretics
plus angiotensin-converting enzyme inhibitors. Am J Cardiol
1997;80:207-9.
119. Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R Usefulness of
verapamil for congestive heart failure associated with abnormal left
ventricular diastolic filling and normal left ventricular systolic
performance. Am J Cardiol 1990;66:981-6.
120. Mangano DT, Layug EL, Wallace A, Tateo IEffect of atenolol on
mortality and cardiovascular morbidity after noncardiac surgery.
Multicenter Study of Perioperative Ischemia Research Group. N Engl J
Med 1996;335:1713-20.
113
121. Wallace A, Layug B, Tateo I, et al Prophylactic atenolol reduces
postoperative myocardial ischemia. McSPI Research Group.
Anesthesiology 1998;88:7-17.
122. Lentine K.L., Costa S.P., Weir M.R., et al; Cardiac disease evaluation
and management among kidney and liver transplantation candidates: a
scientific statement from the American Heart Association and the
American College of Cardiology Foundation. J Am Coll Cardiol.
2012;60:434-480.
123. Mashour G.A., Shanks A.M., Kheterpal S.; Perioperative stroke and
associated mortality after noncardiac, nonneurologic surgery.
Anesthesiology. 2011;114:1289-1296.
124. Schoenborn C.A., Heyman K.M.; Health characteristics of adults aged
55 years and over: United States, 2004–2007. Natl Health Stat Report.
2009:1-31.
125. Livhits M., Gibbons M.M., de V.C., et al; Coronary revascularization
after myocardial infarction can reduce risks of noncardiac surgery. J Am
Coll Surg. 2011;212:1018-1026.
126. Bateman B.T., Schumacher H.C., Wang S., et al; Perioperative acute
ischemic stroke in noncardiac and nonvascular surgery: incidence, risk
factors, and outcomes. Anesthesiology. 2009;110:231-238.
127. Galemmo RA, Jr, Janssens FE, Lewi PJ, et al. In Memoriam: Dr Paul AJ
Janssen (1926-003) J. Med. Chem. 2005;48(6):1686.
114
128. Black J. A personal perspective on Dr Paul Janssen. J. Med. Chem.
2005;48(6):1687–1688.
129. Van Gestel S, Schuermans V. Thirty-three years of drug discovery and
research with Dr Paul Janssen. Drug Dev. Res. 1986;8(1-4):
130. Stanley TH, Egan TD, Van Aken H. A tribute to Dr Paul AJ Janssen:
entrepreneur extraordinaire, innovative scientist, and significant
contributor to anesthesiology. Anesth. Analgesia.
131. Gardocki JF, Yelnosky J. Some of the pharmacologic actions of fentanyl
citrate and droperidol. Toxicol. Appl. Pharmacol. 1964;6(1):48–62.
132. Ainslie, S.G., Eisele, J.H. Jr & Corkill, G. (1979) Fentanyl
concentrations in brain and serum during respiratory acid – base changes
in the dog. Anesthesiology, 51, 293–297.
133. Planas E. Fentanyl pharmacological characteristics. Dolor.
2000;15(1):7–12.
134. Barutell C, Ribera MV, Martinez P, et al. Fentanyl. Dolor.
2004;19(2):98–104.
135. Andrews CJH, Prys-Roberts C. Fentanyl - a review. Clin. Anaesthesiol.
1983;1(1):97–122.
136. Xiao G-S, Zhou J-J, Wang G-Y, et al: In vitro electrophysiologic effects
of morphine in rabbit ventricular myocytes. Anesthesiology 103:280-
286, 2005.
137. Stoelting’s Pharmacology and Physiology in Anesthetic practice.
138. Weber G et al Acta Anesthesiol Scand 39:1071,1995.
115
139. Moore PG et al�:Clin Exp Pharmacol Physiol 27:1028,2000.
140. White DA et al�:Anesth Analg 71:29,1990.
141. Lessa MA ,Tibirica E:Anesth Analg 103:815,2006.
142. Naguib AN, Tobias JD, Hall MW, Cismowski MJ, Miao Y, Barry N, et
al. The Role of Different Anesthetic Techniques in Altering the Stress
Response During Cardiac Surgery in Children: A Prospective, Double-
Blinded, and Randomized Study. Pediatr Crit Care Med J Soc Crit Care
Med World Fed Pediatr Intensive Crit Care Soc [Internet]. 2013 Jun
[cited 2016 Oct 1];14(5). Available from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885862/
143. Samuelsson P N, Reves J G, Kouchoukos N T, Smith L R, Dole K M.
Hemodynamic responses to anesthetic induction with midazolam or
diazepam in patients with ischemic heart diseasc. Anesth Analg 1981:
60: 802-809.
144. Massaut J, d’Hollander A, Barvais L, Dubois-Primo J. Haemo- dynamic
effects of midazolam in the anaesthetized patient with coronary artery
disease. Acta Anaesthesia1 &and 1983: 27: 299-302.
145. Schulte-Sasse U, Hess W, Tarnow J. Haemodynamic responscs to
induction of anaesthesia using midazolam in cardiac surgical patients.
Br 3 Anaesth 1982: 54: 1053-1057.
146. Pieri L, Schaffner R, Scherschlicht P. Pharmacology of midazo- lam.
Arzneimittel Forsch 1981: 31: 2180-2201. 20.
116
147. Hilgenberg JC.Intraoperative awareness during high dose fentanyl-
oxygen anesthesia Anesthesiology 1981;54(4):341-343.
148. Sprigge J S, Wynands J E, Whalley D C et al. Fentanyl infusion
anesthesia for aortocoronary bypass surgery: plasma levels and
hemodynamic responses. Aneslh Analg 1982: 12: 972-978.
149. WynandsJ E, Wong P, Whalley D G? Sprigge J S, Townsend G E, Patel
Y C:. Oxygen-fentanyl anesthesia in patients with poor left ventricular
function: hemodynamics and plasma Fcntanyl concentrations. Anesth
Analg 1983: 62: 476-482.
150. Thompson KA, Goodale DB. The recent development of propofol
(DIPRIVAN) Intensive care medicine. 2000;26(Suppl 4):S400–4.
151. James R, Glen JB. Synthesis, biological evaluation, and preliminary
structure-activity considerations of a series of alkylphenols as
intravenous anesthetic agents. Journal of medicinal chemistry.
1980;23(12):1350–7.
152. Sanna E, Mascia MP, Klein RL, Whiting PJ, Biggio G, Harris RA.
Actions of the general anesthetic propofol on recombinant human
GABAA receptors: influence of receptor subunits. The Journal of
pharmacology and experimental therapeutics. 1995; 274(1):353–.
153. Collins GG. Effects of the anaesthetic 2,6-diisopropylphenol on synaptic
transmission in the rat olfactory cortex slice. British journal of
pharmacology. 1988; 95(3):939–.
117
154. Reves, JG.; Glass, P.; Lubarsky, DA. Miller’s Anesthesia. 7. Churchill
Livingstone; Philadelphia: 2010. Intravenous Anesthestics.
155. Robinson BJ, Ebert TJ, OBrien TJ, Colinco MD, Muzi M. Mechanisms
whereby propofol mediates peripheral vasodilation in humans -
Sympathoinhibition or direct vascular relaxation? Anesthesiology.
1997; 86(1):64–7.
156. Vuyk, J.; Sitsen, E.; Reekers, M. Miller’s. 8. Elsevier; Philadelphia:
2014. Intravenous anesthest.
157. Gelissen HP, Epema AH, Henning RH, et al: Inotropic effects of
propofol, thiopental, midazolam, etomidate, and ketamine on isolated
human atrial muscle. Anesthesiology 84:397-403, 1996.
158. Zheng D, Upton RN, Martinez AM: The contribution of the coronary
concentrations of propofol to its cardiovascular effects in anesthetized
sheep. Anesth Analg 96:1589-1597, 2003.
159. Eriksson O, Pollesello P, Saris N-EL. Inhibition of lipid peroxidation in
isolated rat liver mitochondria by the general anaesthetic propofol.
Biochem Pharmacol 44:391-393, 1992.
160. Murphy PG, Myers DS, Davies MJ, et al: The antioxidant potential of
propofol (2,6- diisopropylphenol). Br J Anaesth 68:613-618, 1992.
161. Kahraman S, Demiryurek AT: Propofol is a peroxynitrite scavenger.
Anesth Analg 84:1127-1229, 1997.
118
162. Szabo EZ, Luginbuehl I, Bissonnette B. Impact of anesthetic agents on
cerebrovascular physiology in children. Paediatric anaesthesia. 2009;
19(2):108–.
163. Karsli C, Luginbuehl I, Farrar M, Bissonnette B. Propofol decreases
cerebral blood flow velocity in anesthetized children. Canadian journal
of anaesthesia = Journal canadien d’anesthesie. 2002; 49(8):830–4.
164. Matta BF, Lam AM, Strebel S, Mayberg TS. Cerebral pressure
autoregulation and carbon dioxide reactivity during propofol-induced
EEG suppression. Br J Anaesth. 1995; 74(2):159–.
165. Noterman J, Berre J, Vandesteene A, Brotchi J. [Monitoring of
intracranial pressure during the postoperative period of aneurysms].
Neuro-Chirurgie. 1988; 34(3):161.
166. Dahan A, Nieuwenhuijs DJ, Olofsen E. Influence of propofol on the
control of breathing. Advances in experimental medicine and biology.
2003; 523:81–92.
167. Rubin A, Allen GD, Everett GB. Induction of general anesthesia with
diazepam or thiopental: A comparison of the cardiorespiratory effects.
Anesth Prog. 1978;25(2):39–44.
168. untitled - bjaceaccp.mkt039.full.pdf [Internet]. [cited 2016 Oct 1].
Available from:
http://ceaccp.oxfordjournals.org/content/early/2013/09/19/bjaceaccp.mk
t039.full.pdf
119
169. Raveen Singh, Minati Choudhury, Poonam Malhotra Kapoor, Usha
Kiran. A randomized trial of anesthetic induction agents in patients with
coronary artery disease and left ventricular dysfunction. KiranAnnals
Card Anaesth � Vol 133 � Sep-Dec-2010.
170. Cotsen MR,Donaldson JS,UejimaT, MorelloFP.Ef-ficacy of ketamine
hydrochloride sedation in children for in-terventional radiologic
procedures.Am J Roentgenol. 1997;169:1019-1022.
171. Lu DP,Lu GP,Reed JFR.Safety,efficacy,and acceptance of intramuscular
sedation:assessment of 900 dental cases.Cmpendium
1994;15:1348,1350,1352,1362.
172. AldersonPJ,Lerman J.Oral premedication for paediatric ambulatroy
anesthesia:a comparison of midazolam and ketamine.Can J
Anaesth.1994;41:221-226.
173. Louon A,Reddy VG.Nasal midazolam and ketamine for paediatric
sedation during computerised tomography Acta Anaesthesiol
Scand.1994;38:259-261.
174. Abrams R,Morrison JE,Villasenor A,Hencmann D,Da Fonseca
M,Mueller W.Safety and effectiveness of intra nasal administration of
sedative medications(ketamine,midaolam,sufentanil)for urgent brief
pediatric dental procedures Anesth Prog 1993;40:63-66.
175. LokkenP,BakstadOJ,Fonnelop E et al.Conscious sedation by rectal
administration of midazolam or midazolam plus ketamine as alternatives
120
to general anesthesia for dental treatment of uncooperative children
Scand J Dent Res 1994;102:274-280.
176. Domino EF,Domino SE,Smith RE.Ketamine kinetics in unmedicated
and diazepam premedicated subjects Clin Phaacol Ther 1984;36:645-
653.
177. Miller’s Anaesthesia 8th edition,Miller,Eriksson,Fleisher,.
178. Sprung J, Schuetz S, Stewart RW, et al: Effects of ketamine on the
contractility of failing and nonfailing human heart muscles in vitro.
Anesthesiology 88:1202-1210, 1998.
179. Hanouz J-L, Persehaye E, Zhu L, et al: The inotropic and lusitropic
effects of ketamine in isolated human atrial myocardium: The effect of
adrenoceptor blockade. Anesth Analg 99:1689-1695, 2004.
180. Kunst G, Martin E, Graf B, et al: Actions of ketamine and its isomers on
contractility and calcium transients in human myocardium.
Anesthesiology 90:1363-1371, 1999.
181. Mullenheim J, Rulands R, Wietschorke T, et al: Late preconditioning is
blocked by racemic ketamine, but not by S(+)-ketamine. Anesth Analg
93:265-270, 2001.
182. Sagratella S. NMDAantagonists: antiepileptic-neuro-protective drugs
with diversified neuropharmacological pro-files. Pharmacol Res.
1995;32:1-13.
121
183. Church J,ZemanS, Lodge D. The neuroprotective action of ketamine and
MK-801 after transient cerebral ische-mia in rats.Anesthesiology.
1988;69:702-709.
184. Pfenninger E,HimmelseherS. Neuroprotection by ketamine at the
cellular level:Review[in German].Anaesthesist. 1997;46(suppl1):47-54.
185. Parworth LP, Frost DE, Zuniga JR, et al: Propofol and fentanyl
compared with midazolam and fentanyl during third molar surgery. J
Oral Maxillofac Surg 56:447, 1998.
186. Moore PA, Crout RJ, Jackson DL, et al: Tramadol hydrochloride:
Analgesic efficacy compared with codeine, aspirin with co- deine and
placebo after dental extraction. J Clin Pharmacol 38:554, 1998.
187. Jung JS et al�:Otolaryngol Head Neck Surg 137:753,2007.
188. White PF. Comparative evaluation of intravenous agents for rapid
sequence induction-thiopentone,ketamine,midazolam. Anesthesiol
571982. :279–84.
189. Finucaine BT Judelman J Braswell R. comparison of thiopentone and
midazolam for induction of anesthesia:influence of diazepam
premedication. Can Anaesth Soc J 29 1982. :227–30.
190. Rivenes SM, Lewin MB, Stayer SA et al. - Cardiovascular effects of
sevoflurane, isoflurane, halothane, and fentanyl-midazolan in children
with congenital heart disease: an echocardiographic study of myocardial
contractility and hemodynamics. Anesthesiology 2001;94:223-229.
122
191. Gruber EM, Laussen PC, Costa A et al. - Stress response in infants
undergoing cardiac surgery: a randomized study of fentanyl bolus,
fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg,
2001;92:882-890.
192. Pirat A, Akpek E, Arslan G - Intrathecal versus IV fentanyl in pediatric
cardiac anesthesia. Anesth Analg 2002;95:1207-1214.
193. Ickeringill M Shehabi Y, Adamson H et al. - Dexmedetomidine infusion
without loading dose in surgical patients requiring mechanical
ventilation: haemodynamic effects and efficacy. Anaesth Intensive Care
2004;32:741-745.
194. Klamt JG, Vicente WV de A, Garcia LV, Ferreira CA. Hemodynamic
effects of the combination of dexmedetomidine-fentanyl versus
midazolam-fentanyl in children undergoing cardiac surgery with
cardiopulmonary bypass. Rev Bras Anestesiol. 2010 Aug;60(4):356–62.
195. Gerlach AT, Dasta JF - Dexmedetomidine: an update review. Ann
Pharmacother, 2007;41:245-252.
196. P. J. Zed, R. B. Abu-Laban and D. W. Harrison, “Intubating Conditions
and Hemodynamic Effects of Etomidate for Rapid Sequence Intubation
in the Emergency Department: An Observational Cohort Study,”
Academic Emergency Medicine, Vol. 13, No. 4, 2006, pp. 378-383.
197. P. E. Sokolove, D. D. Price and P. Okada, “The Safety of Etomidate for
Emergency Rapid Sequence Intubation of Pediatric Patients,” Pediatric
Emergency Care, Vol. 16, No. 1, 2000, pp. 18-21. doi.
123
198. C. M. Hohl, C. H. Kelly-Smith, T. C. Yeung, D. D. Sweet, M. M.
Doyle-Waters and M. Schulzer, “The Effect of a Bolus Dose of
Etomidate on Cortisol Levels, Mortality, and Health Services
Utilization: A Systematic Review,” Annals of Emergency Medicine,
Vol. 56, No. 2, 2010, pp. 105-113.
199. Anesthetic Induction with Etomidate, Rather than Propofol, Is
Associated with Increased 30-Day Mortality and Cardiovascular
Morbidity After Noncardiac Surgery Ryu Komatsu, MD,* Jing You,
MS,†‡ Edward J. Mascha, PhD,†‡ Daniel I. Sessler, MD,‡ Yusuke
Kasuya, MD,§ and Alparslan Turan, MD‡.
200. Flynn G, Shehabi Y. Pro/con debate: Is etomidate safe in
hemodynamically unstable critically ill patients? Crit Care 2012 16227.
201. John gooding Guenter Corssen. Effect of Etomidate on the
Cardiovascular System. Anesth Analg 56 717-7191977.
202. Giese JL, Stockham RJ, Stanley TH, et al. Etomidate versus thiopental
for induction of anesthesia. Anesth Analg. 1985;64:871–76. [.
203. R. L. Wagner, P. F. White, P. B. Kan, M. H. Rosenthal and D. Feldman,.
“Inhibition of Adrenal Steroidogenesis by the Anesthetic Etomidate,.” N
Engl J Med Vol 310 No 22 1984. :pp. 1415–21.
204. I. M. Ledingham and I. Watt,. Influence of Sedation in Critically Ill
Multiple Trauma Patients,”. Lancet Vol. 321, No. 8336, 1983,:1270.
124
205. Anita K. Malhotra, MD. Con: Etomidate—The Ideal Induction Agent
for a Cardiac Anesthetic? J Cardiothorac Vasc Anesth Vol 27 No 1 Febr
2013.
206. A. M. Zurick, H. Sigurdsson, L. S. Koehler, et al. , “Magnitude and
Time Course of Perioperative Adrenal Suppression with Single Dose
Etomidate in Male Adult Cardiac Surgical Patients,.” Anesthesiol Vol
65 No 3A 1986 P A248.
207. Ryu Komatsu, MD,* Jing You, MS,†‡ Edward J. Mascha, PhD,†‡
Daniel I. Sessler, MD,‡ Yusuke Kasuya, MD,§ and Alparslan Turan,
MD‡. Anesthetic Induction with Etomidate, Rather than Propofol, Is
Associated with Increased 30-Day Mortality and Cardiovascular
Morbidity After Noncardiac Surgery. December 2013 • Volume 117 •
Number 6.
208. The use of etomidate as an induction agent in patients undergoing
cardiac surgery Pro Con Hong Liu.
209. Miller RD, Reves JG, Glass PS, Lubarsky DA, McEvoy MD. 6th ed.
Vol. 10. Philadelphia: Elsevier Churchill Livingstone; 2009. Intravenous
non opioid anaesthetics; Miller’s Anaesthesia; pp. 318–61.
210. Sarkar M, Laussen PC, Zurakowski D, Shukla A, Kussman B, Odegard
KC. Hemodynamic responses to etomidate on induction of anesthesia in
pediatric patients. Anesth Analg. 2005;101:645–50.
125
211. Creagh O, Torres H, Rodríguez N, Gatica SR. Alpha-2B adrenergic
receptor mediated hemodynamic profile of etomidate. P R Health Sci J.
2010;29:91–5.
212. Saricaoglu F, Uzun S, Arun O, Arun F, Aypar U. A clinical comparison
of etomidate-lipuro, propofol and admixture at induction. Saudi J
Anaesth. 2011;5:62–6.
213. Weisenberg M, Sessler DI, Tavdi M, Gleb M, Ezri T, Dalton JE, et al.
Dose-dependent hemodynamic effects of propofol induction following
brotizolam premedication in hypertensive patients taking angiotensin-
converting enzyme inhibitors. J Clin Anesth. 2010;22:190–5.
214. Larsen JR, Torp P, Norrild K, Sloth E. Propofol reduces tissue-Doppler
markers of left ventricle function: A transthoracic echocardiographic
study. Br J Anaesth. 2007;98:183–8.
215. Takuro Sanuki, , Yu Ozaki, , Shinji Kurata, , Toshihiro Watanabe, ,
Kensuke Kiriishi, , Mizuki Tachi, et al. Comparison of the
hemodynamic effects of propofol and ketamine as anesthetic induction
agents during high-dose remifentanil administration: a single-center
retrospective comparative study.
216. Gauss A, Heinrich H, Wilder-Smith OH. Echocardiographic assessment
of the haemodynamic effects of propofol: a comparison with etomidate
and thiopentone. Anaesthesia. 1991;46:99–105.
217. Mulier JP, Wouters PF, Van Aken H, Vermaut G, Vandermeersch E.
Cardiodynamic effects of propofol in comparison with thiopental:
126
assessment with a transesophageal echocardiographic approach. Anesth
Analg. 1991;72:28–35.
218. Wodey E, Chonow L, Beneux X, Azzis O, Bansard JY, Ecoffey C.
Haemodynamic effects of propofol vs thiopental in infants: an
echocardiographic study. Br J Anaesth. 1999;82:516–520.
219. Sørensen MK, Dolven TL, Rasmussen LS. Onset time and
haemodynamic response after thiopental vs. propofol in the elderly: a
randomized trial. Acta Anaesthesiol Scand. 2011;55:429–434.
220. Park WK, Lynch C., 3rd Propofol and thiopental depression of
myocardial contractility. A comparative study of mechanical and
electrophysiologic effects in isolated guinea pig ventricular muscle.
Anesth Analg. 1992;74:395–405.
221. Chen WH, Lee CY, Hung KC, Yeh FC, Tseng CC, Shiau JM. The direct
cardiac effect of propofol on intact isolated rabbit heart. Acta
Anaesthesiol Taiwan. 2006;44:19–23.
222. Russo H, Bressolle F. Pharmacodynamics and pharmacokinetics of
thiopental. Clin Pharmacokinet. 1998;35:95–134.
223. Komai H, Rusy BF. Differences in the myocardial depressant action of
thiopental and halothane. Anesth Analg. 1984;63:313–318.
224. Gelissen HP, Epema AH, Henning RH. Inotropic effects of propo- fol,
thiopental, midazolam, etomidate, and ketamine on isolated hu- man
atrial muscle. Anesthesiology 1996; 84: 397-403.
127
225. Harris E, Murray AM, Anderson JM, Grounds RM, Morgan M. Ef- fects
of thiopentone, etomidate and propofol on the haemodynamic
response to tracheal intubation. Anaesthesia 2007; 43: 32-6. [.
226. Vohra A, Thomas AN, Harper NJ, Pollard BJ. Non-invasive
measurement of cardiac output during induction of anaesthesia and
tracheal intubation: thiopentone and propofol compared. Br J Anaesth
1991; 67: 64-8.
227. Pandey AK, Makhija N, Chauhan S, Das S, Kiran U, Bisoi AK, et al.
The Effects of Etomidate and Propofol Induction on Hemodynamic and
Endocrine Response in Patients Undergoing Coronary Artery Bypass
Graft Surgery on Cardiopulmonary Bypass. World Journal of
Cardiovascular Surgery. 2012;2:48–53.
228. Guo-hua Z, Li S. Peri-intubation hemodynamic changes during low dose
fentanyl, remifentanil and sufentanil combined with etomidate for
anesthetic induction. Chinese Medical Journal. 2009;122:2330–34.
229. Morel J, Salard M, Castelain C, Bayon MC, Lambert P, Vola M,
Auboyer C, Molliex S. Haemodynamic consequences of etomidate
administration in elective cardiac surgery: a randomized double-blinded
study. Br J Anaesth. 2011;107:503–09.
230. Iribarren JL, Jiménez JJ, Hernández D, Lorenzo L, Brouard M, Milena
A, et al. Relative adrenal insufficiency and hemodynamic status in
cardiopulmonary bypass surgery patients. A prospective cohort study. J
Cardiothorac Surg. 2010;5:26.
128
231. Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition
of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med.
1984;310:1415–21.
232. Habibi MR, Baradari AG, Soleimani A, Emami Zeydi A, Nia HS,
Habibi A, et al. Hemodynamic responses to etomidate versus ketamine-
thiopental sodium combination for anesthetic induction in coronary
artery bypass graft surgery patients with low ejection fraction: a double-
blind, randomized, clinical trial. J Clin Diagn Res JCDR. 2014
Oct;8(10):GC01-05.
233. Lunn J K, Stanley T H, EiseleJ,Wehster L, Woodward A. High-dose
fentanyl anesthesia for coronary artery surgery: plas- ma fentanyl
concentrations and influence of nitrous oxide on cardiovascular
responses. Anesth Analg 1979: 58: 390-395.
234. Quintin L, Whalley D G, Wynands J E, Morin J E, Burke J. High-dose
fentanyl anaesthesia with oxygen for aorto-coronary bypass surgery.
Can Anaesfh Soc 3 1981: 28: 314-320.
235. Waller J L, Hug C C, Nagle G MCraver J M. Hemodynamic changes
during fentanyl-oxygen anesthesia for aorto-coronary bypass
operation. Anesthesin/o,g 1981: 55: 212-217.
236. Zurick A M, Urzua J, Yared J-P, Estafanous F G. Comparison or
hemodynamic and hormonal effects of large single-dose fentanyl
anesthesia and halothane lnitrous oxide anesthesia for coronary
surgery. Anesth Analg 1982: 61: 521-526.
129
237. Haemodynamic consequences of etomidate administration in elective
cardiac surgery: a randomized double-blinded study J. Morel1*, M.
Salard1, C. Castelain1, M. C. Bayon1, P. Lambert1, M. Vola2, C.
Auboyer1 and S. Molliex1.
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ANNEXURES