RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA

“CLINICAL SPECTRUM, FREQUENCY AND

SIGNIFICANCE OF MYOCARDIAL

DYSFUNCTION IN SEPSIS AND SEPTIC SHOCK”

BY

Dr. SHAHBAZ HASSAN M.B.B.S.

Dissertation submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

In Partial fulfilment

Of the requirements for the degree of

DOCTOR OF MEDICINE IN

EMERGENCY MEDICINE

Under the guidance of

Dr. SURENDRA E.M.

M.D PROFESSOR

DEPARTMENT OF EMERGENCY MEDICINE, J.J.M. MEDICAL COLLEGE,

DAVANGERE, KARNATAKA, INDIA– 577 004.

2019

vi

vii

viii

LIST OF ABBREVIATIONS USED

A Peak velocity of late mitral flow

CAD Coronary artery disease

DD Diastolic dysfunction

E Peak velocity of early mitral flow

ECG Electrocardiogram

ECHO Echocardiogram

EF% Ejection fraction

FiO2 Fraction of inspired oxygen

IVRT Isovolumic relaxation time

LV Left ventricle

LVIDd Left ventricular diameter in diastole

LVIDs Left ventricular diameter in systole

MAP Mean arterial pressure

PaO2 partial pressure of arterial oxygen

RV Right ventricle

SD Systolic dysfunction

SOFA Sequential Organ Failure Assessment

TAPSE Tricuspid Annular Plane Systolic Excursion

ix

LIST OF TABLES

TABLE NO

TABLES PAGE

1 Age distribution 59

2 Age-wise incidence of LV / RV dysfunction 60

3 Sex distribution 61

4 Sex-wise distribution of Dysfunction 61

5 Incidence of Cardiac Dysfunction 62

6 Incidence of various Myocardial Dysfunctions 62

7 Clinical and physiologic characteristics of Septic patients with

Normal Myocardial Function vs LV Systolic Dysfunction 64

8 Clinical and physiologic characteristics of Septic patients with

Normal Myocardial Function vs LV Diastolic Dysfunction 67

9 Clinical and physiologic characteristics of Septic patients with

Normal Myocardial Function vs RV Dysfunction 69

10 Severity of RV dysfunction 71

11 Physiologic and Echocardiographic markers in

survivors and non-survivors 72

12 Cardiac Function in Non-survivor group 74

13 Distribution of Cardiac dysfunction in Non-survivors(A & B) 75

14 Change in LV function in patients with cardiac dysfunction 77

15 Reversibility of Myocardial Dysfunction 78

x

LIST OF GRAPHS

GRAPH

NO GRAPHS PAGE

1 Age distribution 59

2 Sex-wise distribution of Dysfunction 61

3 Incidence of various Myocardial Dysfunctions 63

4 EF% in normal myocardial function vs LV systolic

dysfunction 65

5 Severity of LV systolic dysfunction 66

6

Clinical and physiologic characteristics of Septic patients

with Normal Myocardial Function vs LV Diastolic

Dysfunction

68

7 Clinical and physiologic characteristics of Septic patients

with Normal Myocardial Function vs RV Dysfunction 70

8 Severity of RV dysfunction 71

9 Physiologic and Echocardiographic markers in Survivors

and Non-survivors 73

10 Cardiac function in Non-survivors 74

11 Cardiac dysfunction in Non-survivors 76

12 Change in LV function in patients with cardiac dysfunction 77

13 Reversibility of Myocardial Dysfunction 78

xi

LIST OF FIGURES

FIG.

NO. LIST OF FIGURES PAGE

1 Pathogenesis of Sepsis 8

2 Cardiac Index and time in survivors and non-survivors 16

3 LVEF in survivors and non-survivors 17

4 End Diastolic Volumes in patients with Sepsis and Septic shock 18

5 Serial changes in RV ejection fraction and end diastolic volume

in septic shock patients 20

6 Coronary blood flow in normal subjects and septic shock

patients 21

7 Experimental study of myocardial cell shortening in septic shock

in rats 23

8 Transesophageal echocardiography in two patients–one with

cardiogenic shock and the other with septic shock 31

9 Transesophageal echo illustrating of RV dysfunction 33

10 End Diastolic size of left ventricle according to ejection fraction 33

xiii

ABSTRACT

TITLE:

“CLINICAL SPECTRUM, FREQUENCY, AND SIGNIFICANCE OF MYOCARDIAL

DYSFUNCTION IN SEVERE SEPSIS AND SEPTIC SHOCK”

BACKGROUND:

Myocardial dysfunction frequently accompanies severe sepsis and septic shock.

Whereas myocardial depression was previously considered a preterminal event, it is now

clear that cardiac dysfunction as evidenced by biventricular dilatation and reduced

ejection fraction is present in most patients with severe sepsis and septic shock.

Myocardial depression exists despite a fluid resuscitation-dependent hyperdynamic state

that typically persists in septic shock patients until death or recovery. Cardiac function

usually recovers within 7–10 days in survivors.

OBJECTIVE:

To determine the frequency and spectrum of myocardial dysfunction in

patients with severe sepsis and septic shock using transthoracic echocardiography

and to evaluate the impact of the myocardial dysfunction types on mortality. .

METHODOLOGY :

A prospective study was undertaken over 18 months period including a total of 100

patients irrespective of age and sex, TTE was performed on patients presenting to the

J.J.M medical college Emergency department who have developed Severe Sepsis and

Septic shock at/or within 24 hours of admission to ICU.

xiv

RESULTS :

The frequency of myocardial dysfunction in patients with severe sepsis or septic shock

was 61% (n61). Left ventricular diastolic dysfunction was present in 42 patients (42%),

LV systolic dysfunction in 29 (29%), and RV dysfunction in 27 (27%). There was

significant overlap. The 1 week mortality rate was 22%. There was no significant

difference in mortality between patients with normal myocardial function and those with

left, right, or any ventricular dysfunction

CONCLUSION :

Myocardial dysfunction is frequent in patients with severe sepsis or septic shock and

has a wide spectrum including LV diastolic, LV systolic, and RV dysfunction types.

Although evaluation for the presence and type of myocardial dysfunction is important for

tailoring specific therapy, its presence in patients with severe sepsis and septic shock was

not associated with increased 1 week mortality.

KEY WORDS : Myocardial Dysfunction; sepsis; septic shock; two dimensional

echocardiography

1

INTRODUCTION

Sepsis has been defined as the systemic inflammatory response to infection1.

An infectious stimulus (e.g. endotoxin or another microbiologic element) induces the

release of local and systemic inflammatory mediators, especially tumor necrosis

factor alpha (TNF-α) and IL-1β, from monocytes/ macrophages and other cells 2 .

These cytokines stimulate polymorphonuclear leukocytes, macrophages and

endothelial cells to release a number of downstream inflammatory mediators,

including platelet activating factor and nitric oxide (NO), further amplifying the

inflammatory response. Several anti- inflammatory mediators are also released as part

of this amplification cascade; namely, IL-10, transforming growth factor beta and IL-

1 receptor antagonist. The relative contribution of these cytokines will determine the

severity of the septic episode. If the inflammatory reaction is particularly intense,

homeostasis of the cardiovascular system will be disrupted, leading to septic shock.

One of the manifestations of cardiovascular dysfunction in septic shock is myocardial

depression.

Myocardial dysfunction in sepsis is one of the most complex organ failures to

characterise because of the dynamic adaptation of the cardiovascular system to the

disease process, host response, and resuscitation. The pathophysiology of this entity is

complex and multifactorial. Systemic, extracellular, and cellular mechanisms have

been described, including maldistribution of coronary blood flow, cytokine-induced

(tumour necrosis factor , interleukin 1, interleukin-6 neutrophil activation and

myocardial injury, complement (C5a)- triggered myocyte contractile failure, calcium

handling dysregulation, and cytopathic hypoxia due to mitochondrial dysfunction.3,4

2

OBJECTIVE

1) To determine the frequency and spectrum of myocardial dysfunction in

patients with severe sepsis and septic shock using trans-thoracic

echocardiography.

2) To evaluate the impact of the types of myocardial dysfunction on mortality.

3) To estimate the incidence of LV systolic dysfunction, LV diastolic

dysfunction and RV dysfunction.

3

REVIEW OF LITERATURE

DEFINITION:

Sepsis syndromes are a continuum, with specific definitions regularly updated

to include children5,6 . Although the definitions provide a conceptual and practical

framework for recognition of the systemic inflammatory response to infection,

definitions often are not sensitive or specific in the real world clinical setting. In

general, sepsis is defined as suspected or confirmed infection with evidence of

systemic inflammation (demonstrated either through evidence of the systemic immune

response syndrome or laboratory abnormalities), whereas severe sepsis is generally

defined as sepsis plus evidence of new organ dysfunction thought to be secondary to

tissue hypoperfusion. Septic shock exists when cardiovascular failure occurs,

evidenced as persistent hypotension or need for vasopressors despite adequate fluid

resuscitation; this latter category has a particularly poor prognosis.

Systemic Inflammatory Response Syndrome (SIRS) criteria:

1. Fever (temperature >38.3°C) or hypothermia (temperature <36°C)

2. Pulse rate (>90 beats/min or >2 SDs above the normal value for age)

3. Tachypnea (respiratory rate >20 breaths/min)

4. Leukocytosis (WBC >12,000 cells/μL) or leukopenia (WBC <4000 cells/μL),

or normal WBC with >10% immature forms

4

SEPSIS: Infection (documented or suspected), and some of the following:

1)General Parameters:

• Fever (temperature >38.3°C)

• Hypothermia (temperature <36°C)

• Pulse rate (>90 beats/min or >2 SDs above the normal value for age)

• Tachypnea

• Altered mental status

• Significant edema or positive fluid balance (>20 mL/kg during 24 h)

• Hyperglycemia (plasma glucose >140 milligrams/dL or 7.7 mmol/L) in the

absence of diabetes

2)Inflammatory Parameters:

• Leukocytosis (WBC >12,000 cells/μL)

• Leukopenia (WBC <4000 cells/μL)

• Normal WBC with >10% immature forms

• Plasma C-reactive protein (CRP) >2 SDs above the normal value

• Plasma procalcitonin >2 SDs above the normal value

5

3)Hemodynamic Parameters:

• Arterial hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or an SBP decrease

>40 mm Hg in adults or <2 SDs below normal for age)

4)Organ Dysfunction Parameters:

• Arterial hypoxemia (PaO2/FIO2 <300)

• Acute oliguria (urine output <0.5 mL/kg per hour for at least 2 h despite adequate

fluid resuscitation)

• Creatinine level increase >0.5 milligrams/dL

• Coagulation abnormalities (INR >1.5 or aPTT >60 s)

• Ileus (absent bowel sounds)

• Thrombocytopenia (platelet count <100,000 cells/μL)

• Hyperbilirubinemia (plasma total bilirubin >4 milligrams/dL)

5)Tissue Perfusion Parameters:

Hyperlactatemia (above upper limits of laboratory normal levels)

• Decreased capillary refill or mottling

6

SEVERE SEPSIS

• Sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following

thought to be due to infection)

• Sepsis-induced hypotension:

Lactate level above upper limits of laboratory normal levels

• Urine output <0.5 mL/kg per hour for atleast 2h despite adequate fluid

resuscitation

• Acute lung injury with PaO2/FIO2 <250 in the absence of pneumonia as infectious

source

• Acute lung injury with PaO2/FIO2 <200 in the absence of pneumonia as infectious

source

• Creatinine level >2.0 milligrams/dL Bilirubin level >2 milligrams/dL Platelet count

<100,000 cells/μL

• Coagulopathy (INR >1.5)

7

PATHOGENESIS:

In sepsis, the host immune response fails to control and/or overreacts to invasive

pathogens, leading to two critical events.7,8 The first event involves marked

abnormalities in the inflammatory response in the host. The host response typically

varies from a hyperinflammatory response in the early stages of sepsis, to a blunted

inflammatory response in the later stages of sepsis, which leads to an increased risk of

secondary hospital-acquired infections. The blunted inflammatory response results in

programmed death of key immune, epithelial, and endothelial cells, leading to tissue

injury and perpetuating multiorgan dysfunction.

The second event is an imbalance in procoagulant and anticoagulant functioning; in

the most extreme of situations, this results in the clinical syndrome of disseminated

intravascular coagulation. Disseminated intravascular coagulation results in micro-

and macrovascular clot formation, impaired microvascular tissue perfusion, and

thrombosis of small vessels. Notably, subclinical disseminated intravascular

coagulation is often lurking despite relatively normal basic laboratory findings, with

impaired microvascular perfusion (detectable in research settings) that is associated

with a worse prognosis.9 Continued microvascular ischemia likely contributes to

organ failure, as well as to the release of pro inflammatory intracellular contents,

which further stimulates the innate immune response and perpetuates the underlying

pathology.10 As these events progress, they intensify the inflammatory response and a

destructive cycle ensues. At this time, there are no specific therapies to remedy

microvascular dysfunction.

8

COMPLICATIONS OF SEPSIS:

While some presentations of severe sepsis are immediately clinically apparent,

sepsis can present in a subtle or occult manner, particularly early in the course. Given

that systemic inflammation produces physiologic changes, vital sign abnormalities—

notably fever, hypotension, and/or tachycardia— are a hint to sepsis, recognising that

many patients with these findings may have another cause. In ED patients with

undifferentiated hypotension, 40% will ultimately have an infectious cause of

symptoms.11

Fig 1- Pathogenesis of Sepsis

9

Although traditionally sepsis is categorised as an example of distributive

shock (peripheral vasodilation evidenced by warm extremities with a compensatory

increased cardiac output), this presentation does not accurately describe all patients

with sepsis. ED patients with sepsis are often volume depleted from decreased intake

and increased fluid losses (from emesis, diarrhea, or insensible losses associated with

fever and tachypnea). Intravascular volume depletion directly affects preload, cardiac

output, and ultimately peripheral perfusion. Further complicating matters is septic

cardiomyopathy, a reversible process characterised by impaired systolic function and

diastolic relaxation.12 Finally, the combination of intravascular volume depletion and

septic cardiomyopathy may manifest as ―cold shock,‖ impaired peripheral perfusion

and cool extremities.

1) PULMONARY INJURY:

Widespread inflammation secondary to sepsis commonly affects pulmonary

function even in the absence of pneumonia. Acute lung injury is common and may

result in acute respiratory distress syndrome, which is characterised by new lung

edema from increased alveolar and capillary permeability. Classification of acute

respiratory distress syndrome is based primarily on the degree of hypoxemia.13 The

three mutually exclusive categories are mild (PaO2 divided by fraction of inspired

oxygen [FIO2] of 200 to 300), moderate (PaO2/FIO2 of 100 to 200), and severe

(PaO2/ FIO2 <100), within 1 week of a clinical insult or change in respiratory status

coupled with new bilateral pulmonary infiltrates on chest radiographs not explained

by effusions, lung collapse, or nodules and not fully explained by heart failure or

volume overload. Clinically, severe refractory hypoxemia, noncompliant lungs noted

on mechanical ventilation, and a chest radiograph showing bilateral pulmonary

10

alveolar infiltrates suggest the diagnosis. Mortality increases from 27% to 45% with

increasing severity of acute respiratory distress syndrome.

2) RENAL INJURY:

The kidney is another common sepsis target; acute kidney injury can present

with azotemia, oliguria, or anuria. Factors increasing acute kidney injury risk include

pre-existing kidney dysfunction or vasculopathy, depth and duration of hypotension,

dehydration, and use of nephrotoxic substances (e.g., aminoglycoside antibiotics,

nonionic intravenous contrast). Renal ischemic injury from hypoperfusion is a major

factor in the pathogenesis of acute kidney injury in sepsis, although toxic products

resulting from neutrophil-endothelial interactions, endothelial damage by various

mediators, reperfusion injury, and microvascular thrombosis also contribute.

3) HEPATIC INJURY:

The most frequent hepatic abnormality is cholestatic jaundice, although it

occurs infrequently. Increased concentrations of transaminase, alkaline phosphatase

(one to three times the normal level), and bilirubin (usually not >10 milligrams/dL)

may be observed. Marked elevations of transaminases or bilirubin are less common

unless septic shock is present; if seen, consider a biliary source of infection. Smaller

elevations in liver function tests can result from intermittent or prolonged macro- or

micro- vascular hypoperfusion and ischemia or can be secondary to direct endotoxin,

cytokines, or immune complex damage. Red blood cell hemolysis from microvascular

coagulation can also rarely cause jaundice.

11

4) GI CHANGES:

The most common GI manifestation of sepsis is ileus, which may persist for

days after shock resolves. Major blood loss secondary to upper GI bleeding is rare in

septic patients. Minor GI blood loss within 24 hours of developing severe sepsis can

result from painless erosions in the mucosal layer of the stomach or duodenum.

5) HEMATOLOGIC CHANGES:

Multiple abnormalities are possible in the hematologic system in the setting of

sepsis, including neutropenia or neutrophilia, thrombocytopenia, or disseminated

intravascular coagulation.

Neutrophil:

Neutrophilic leukocytosis with a ―left shift‖ results from demargination and release of

newer granulocytes from the marrow storage pools. However, the presence of

excessive bands (the immature neutrophil) is neither sensitive nor specific for

infection.

Neutropenia occurs rarely and is associated with an increase in mortality; it results

from increased peripheral use of neutrophils, damage to neutrophils by bacterial by-

products, or depression of marrow granulocyte production by inflammatory

mediators. Functional neutropenia also creates a relative immunosuppression,

particularly later in patients‘ hospital course.

12

Erythrocytes:

Both red cell production and survival decrease during sepsis, but anemia is not

expected unless it existed prior to the infection, the infection is extremely prolonged,

or there is concomitant bleeding.

Thrombocyte:

Thrombocytopenia may arise as a consequence of disseminated intravascular

coagulation but is present in >30% of cases of sepsis even in the absence of overt

disseminated intravascular coagulation, and lower platelet levels are associated with

worse outcomes.14,15 Proposed mechanisms of thrombocytopenia include inhibition

of thrombopoiesis, increased platelet turnover (due to a consumptive coagulopathy),

increased endothelial adherence, and increased destruction secondary to immunologic

mechanisms.

Finally, fulminant disseminated intravascular coagulation where clinical clotting

and bleeding exist is rare but associated with a very poor prognosis.16 Occult

disseminated intravascular coagulation, with microvascular flow abnormalities,

subclinical increased activation of the coagulation system, and evidence of increased

fibrinogen split products in the absence of overt bleeding and clotting, is much more

common. The activation of the hemostatic (clotting) system is due primarily to the

activation of the extrinsic pathway of clotting. The fibrinolytic system is also

activated in sepsis and plays an important role in limiting fibrin deposition in the

microcirculation. The release of tissue plasminogen activator activates the fibrinolytic

system, at least initially in sepsis. As sepsis progresses, there is an increased release of

plasminogen activator inhibitor 1, which blocks plasmin generation and thus

13

contributes to fibrin deposition in the microcirculation and subsequent multiple-organ

failure. Laboratory studies suggesting the presence of disseminated intravascular

coagulation include thrombocytopenia, prolonged pro- thrombin and activated partial

thromboplastin values, decreased fibrinogen and antithrombin III levels, and increased

fibrin monomer, fibrin split products, and d-dimer levels.

6) METABOLIC CHANGES:

Sepsis induces multiple metabolic changes. Abnormalities in lactate

metabolism due to tissue hypoperfusion with resultant anaerobic metabolism as well

as increased aerobic production of lactate. Hyperglycemia is seen even in patients

without a history of diabetes; in this latter group, it is associated with a worse

prognosis, in contrast to less impact of glucose elevations in those with known

diabetes.17 Hypoglycemia with glucose levels as low as 10 to 20 milligrams/dL is

reported but uncommon, and may result due to depletion of hepatic glycogen and

inhibition of gluconeogenesis and/or adrenal insufficiency. Adrenal insufficiency can

occur, caused by hypoperfusion of the adrenal glands, adrenal or pituitary

hemorrhage, cytokine dysfunction of the adrenals, drug-induced hypermetabolism,

inhibition of steroidogenesis by chemotherapeutics (e.g. ketoconazole), and

desensitization of glucocorticoid responsiveness at the cellular level.

7 ) SKIN:

There are five potential cutaneous manifestations of sepsis: direct bacterial

involvement of the skin and underlying soft tissues (cellulitis, erysipelas, and

fasciitis); lesions from hematogenous seeding of the skin or the underlying tissue

(petechiae, pustules, cellulitis, ecthyma gangrenosum); lesions from hypotension

14

and/or disseminated intravascular coagulation (acrocyanosis and necrosis of

peripheral tissues); lesions from intravascular infections (microemboli and/or immune

complex vasculitis); and lesions caused by toxins (toxic shock syndrome).

CLINICAL MANIFESTATIONS OF SEPSIS ON THE CARDIOVASCULAR

SYSTEM

Historical perspectives:

Our understanding of the cardiovascular manifestations of septic shock has

evolved over the years, as new techniques to assess cardiovascular performance have

become available. Before the introduction of the pulmonary artery catheter (PAC),

two distinct cardiovascular clinical presentations of septic shock were described: a

high cardiac output (CO) state, associated with warm, dry skin and a bounding pulse

despite hypotension (warm shock); and a low CO state, associated with hypotension,

cold, clammy skin and a thready pulse (cold shock).18 Clowes et al. 19, in a 1966

study, described these two clinical pictures as different stages of septic shock: patients

were believed to initially experience a hyperdynamic phase (warm shock), and then to

either recover or progress to hypodynamic shock (cold shock) and death. This view

was reinforced by other clinical studies18,20 that correlated survival with high cardiac

index (CI). Only a few studies hinted at the relationship between volume status, the CI

and outcome 21,22. All these studies that supported the concept of terminal cold

shock suffered from the fact that they used central venous pressure (CVP) as the best

available estimate of left ventricular end-diastolic volume and adequacy of

resuscitation. Evidence accumulated over the past 40 years shows that CVP, as a

15

reflection of right ventricular preload, is a poor estimate of left ventricular preload in

critically ill patients, and particularly in sepsis.23

The introduction of the PAC (which could measure pulmonary artery wedge

pressure as a more accurate estimate of left ventricular preload) has allowed for better

definition of the cardiovascular dysfunction in septic shock and has improved volume

resuscitation. Several studies have shown that adequately resuscitated septic shock

patients consistently manifest a hyperdynamic circulatory state with high CO and low

systemic vascular resistance (SVR)24,25. In contrast to previous belief, this

hyperdynamic state usually persists until death in nonsurvivors26,27 (Fig. 2). Despite

the strong evidence characterising sepsis as a hyperdynamic state, studies that

examined myocardial performance still showed left ventricular dysfunction

(illustrated by decreased left ventricular stroke work index) in properly resuscitated

septic patients28. The depression in the Frank–Starling curve demonstrated in these

studies, however, could be explained by either a change in myocardial contractility or

compliance.

The development of portable radionuclide cineangiography and its application

to critically ill patients has further improved our understanding of cardiovascular

dysfunction in septic shock, by allowing differentiation between impaired contractility

and impaired compliance.

16

Fig 2 Cardiac Index and time in survivors and non-survivors

Left ventricular function

Parker et al.29 showed, using radionuclide cineangiography, that survivors of

septic shock demonstrated a decreased left ventricular ejection fraction (LVEF) and

an acutely dilated left ventricle, as evidenced by an increased left ventricular end-

diastolic volume index (LVEDVI) (Fig. 3). These parameters returned to normal over

7–10 days in survivors. Nonsurvivors maintained normal LVEF and LVEDVI

throughout the course of their illness until death. All patients in this study29 had

normal or elevated CI and low SVR, as measured by the PAC.

In 1988, Ognibene et al. compared left ventricular performance curves

(plotting left ventricular stroke work index versus LVEDVI of septic and non septic

17

critically ill patients (Fig. 4). They showed a flattening of the curve in septic shock

patients, with significantly smaller left ventricular stroke work index increments in

response to similar LVEDVI increments when compared with non septic critically ill

controls.30 Subsequent studies have confirmed the presence of significant left

ventricular systolic dysfunction in septic patients.31,32

Left ventricular diastolic function in septic shock is not as clearly defined. The

dilatation of the left ventricle29 and the lack of discordance between pulmonary artery

wedge pressure (PAWP) and left ventricular end-diastolic volume30 both argue

against significant diastolic dysfunction in sepsis. More recent studies using

echocardiography, however, have demonstrated slower left ventricular filling33 and

aberrant left ventricular relaxation34,35 in septic patients, suggesting that impaired

compliance may significantly contribute to myocardial depression in sepsis.

Fig 3 LVEF in survivors and non-survivors

18

Fig 4 End Diastolic Volumes in patients with Sepsis and septic shock

Right ventricular function

Low peripheral vascular resistance in sepsis leads to decreased left ventricular

afterload. However, the right ventricular afterload is frequently elevated due to

increased pulmonary vascular resistance from acute lung injury.36 These different

physiologic conditions mean that the right ventricle cannot be expected to behave like

the left ventricle in septic patients. Multiple studies have therefore specifically

examined right ventricular function in sepsis.

19

A number of studies have documented right ventricular systolic dysfunction in

volume-resuscitated septic patients, as evidenced by decreased right ventricular

ejection fraction (RVEF) and right ventricular dilation.37,38,39,40 Kimchi et al.37

and Parker et al.39also showed that right ventricular dysfunction occurred

independently of pulmonary vascular resistance and pulmonary artery pressure,

suggesting that increased right ventricular afterload could not be the dominant cause

of right ventricular depression in septic shock. Parker et al.39 further demonstrated a

close temporal parallel between right ventricular and left ventricular dysfunction in

sepsis. In their study, survivors experienced significant right ventricular dilation and

decreased RVEF and right ventricular stroke work index, all of which returned to

normal within 7–14 days (Fig. 5). Nonsurvivors had moderate right ventricular

dilation and a marginally decreased RVEF, neither of which improved throughout

their illness.

There is also evidence of right ventricular diastolic dysfunction in septic

patients. Kimchi et al37 noticed a lack of correlation between right atrial pressure and

right ventricular end-diastolic volume, suggesting altered right ventricular

compliance. Schneider et al.38 similarly identified a sub- group of patients who failed

to exhibit an increased right ventricular end-diastolic volume index in response to

volume loading, despite a rise in CVP. However, the relative contribution of systolic

and diastolic dysfunction to right ventricular depression in sepsis remains largely

unknown.

20

ETIOLOGY OF MYOCARDIAL DEPRESSION IN SEPTIC SHOCK

1)Myocardial hypoperfusion

The possibility of myocardial dysfunction in sepsis was originally proposed

and described in the 1960s. Its etiology, however, remained a mystery. For many

years, the leading theory was that sepsis was associated with a globally decreased

myocardial perfusion, leading to ischemic injury and myocardial depression. Two

studies disproved that view. Cunnion et al.45performed serial measurements of

coronary blood flow and metabolism using thermodilution coronary sinus catheters in

septic patients (Fig. 6). They found normal or elevated coronary blood flow in septic

patients compared with normal controls with comparable heart rates, and found no

difference in blood flow between patients who developed myocardial dysfunction and

Fig 5 Serial changes in RV ejection fraction and end diastolic volume in septic

shock patients

21

those who did not. There was no net myocardial lactate production. Dhainaut et al.46,

using the same technique, confirmed these findings.

Furthermore, studies on animal models of sepsis47 demonstrated that

myocardial oxygen metabolism and high-energy phosphates were preserved in septic

shock, neither of which is compatible with myocardial ischemia. However, Turner et

al.48 recently measured increased troponin I levels in patients with septic shock,

demonstrating some degree of myocardial cell injury in the course of septic shock. It

remains unclear from their study whether direct cardiac injury plays a role in sepsis-

induced myocardial dysfunction or is the result of other factors, including a

myocardial depressant substance (MDS) or exogenous catecholamine administration.

Fig 6 Coronary blood flow in normal subjects and septic shock patients

22

2) Circulatory depressant substances

Wiggers‘ landmark report49 in 1947 postulating the presence of a circulating

myocardial depressant factor in hemorrhagic shock provided the basis for the accepted

current theory of myocardial dysfunction in septic shock. The presence of a

myocardial depressant factor in sepsis was later confirmed experimentally by Lefer50

in the late 60s. Clinical studies performed at the same time associated death from

septic shock with a hypodynamic circulatory state marked by a decreased

CO.19.20,21 Although these earlier studies depended on the measurement of CVP to

assess preload, a factor now recognised as unreliable in the critically ill, Lefer‘s early

contributions furthered research into MDS in sepsis.50

The first study to actually show a link between septic shock- associated myocardial

depression in humans with the myocyte depressant effects of a patient‘s own septic

serum was carried out by Parrillo et al. in 1985.51 Serum from patients with septic

shock generated a significant concentration- dependent depression of in vitro myocyte

contractility (Fig. 7). The investigators were also able to demonstrate a strong

correlation between the timing and degree of septic shock-associated decrease in

LVEF in vivo and cardiac myocyte depression in vitro induced by exposure to serum

from the same patients.

23

Fig 7 Experimental study of myocardial cell shortening in septic shock in rats

Subsequent work focused on identifying the presence of a MDS. In a study of

34 patients with septic shock52, researchers noted high levels of myocardial

depressant activity that correlated with higher peak serum lactate, with increased

ventricular filling pressures and with increased LVEDVI. In addition, a trend towards

higher mortality was present in patients with high levels of myocardial depressant

activity compared with patients with lower or absent activity (36% versus 10%).52

These studies would argue in favor of a circulating substance rather than

hypoperfusion as the causative factor in septic shock-associated myocardial

depression.

3 ) Myocardial depression in sepsis: cytokines

Although the existence of MDS was demonstrated by the previous

studies59,60,61,62, the identity of the molecules remained in question. Potential

circulating inflammatory mediators that could cause septic myocardial depression

24

include the prostaglandin group, leukotrienes, platelet activating factor, histamine and

endorphins. However, the substance was found to be heat labile, soluble in water, and

its activity in filtration studies was present in the >10 kDa fraction62. Although full

molecular characterisation was not possible with the available data, the characteristics

were most consistent with either a polypeptide or protein. The list of potential

cytokine mediators of myocardial depression is exhaustive; however, TNF-α and IL-

1β play a central role and deserve further consideration.

TNF-α shares a similar biochemical profile with MDS, making it a plausible

mediator of the myocardial effects of sepsis and septic shock51,53,54.

Experimentally, increased levels of TNF-α produce fever, lactic acidosis,

disseminated intravascular coagulation, acute lung injury and death. The

cardiovascular effects are similar to clinical septic shock; namely, hypotension,

increased CO and low SVR55,56. Human volunteers given TNF-α infusions

demonstrate similar responses57,58.

A number of studies have shown that, when TNF-α is administered to human

and animal myocardial tissue in vitro or ex vivo, the result is a concentration-

dependent depression of contractility59,60,61,62. Furthermore, removal of TNF-α

from the serum of patients with septic shock partially eliminates its myocardial

depressant effect60. Although larger phase III clinical trials have shown no overall

survival benefit when anti- TNF-α monoclonal antibody has been administered to

patients with septic shock, left ventricular function did improve in this patient

group63.

25

IL-1β induces similar pathophysiologic responses to TNF-α. IL-1β is

increased in both human and animal models of sepsis and septic shock64. When

exposed to IL-1β, in vitro as well as ex vivo myocardial contractility is

depressed.62,65,66 Immuno absorption of IL-1β partially neutralizes cardiac myocyte

depressant activity of human septic serum.60 Administration of IL-1β antagonist

attenuates the hemodynamic and metabolic manifestations of septic shock.67,68 As

with TNF-α, overall mortality has not been improved in randomised trials with IL-

1β67,68

A number of studies have postulated that cytokine synergy plays a key role in

septic myocardial depression. When considering IL-1β and TNF-α independently,

substantially higher concentrations of each cytokine are required to depress

contractility in rat cardiac myocytes than when these two cytokines are combined.60

These findings have also been validated in ex vivo studies of isolated human atrial

trabeculae.69 The combination of TNF-α and IL-1β may cause myocyte depression at

concentrations 50–100 times lower than would be required if applied individually.

Such concentrations are well within those found in blood during human septic shock.

Available data supports a causative role for TNF-α and IL-1β acting synergistically in

septic myocardial depression.

4) Cellular mechanisms of septic myocardial depression

Depression of myocardial contractility by TNF-α, IL-1β and septic serum in

vitro occurs in two distinct time frames. The early phase of cardiac myocyte

depression occurs within minutes of exposure either to TNF-α, to IL-1β, to TNF-α and

IL-1β given together or to septic serum.60,61 In vivo canine studies also demonstrate

26

the ability of TNF-α to induce rapid myocardial depression.56,70 Furthermore, there

is a convincing relationship between the degree of in vitro early cardiac myocyte

depression produced by human septic serum and the decrease in LVEF from those

same patients during acute septic shock.51 Other studies also document a delayed

depressant effect of TNF-α, IL-1β and supernatants of activated macrophages on in

vitro myocardial tissue65,66,70,71. This effect begins hours after exposure and may

persist for days. This late phase of myocardial depression appears to occur by a

distinctly different biochemical pathway than the early depression, and may involve

de novo protein synthesis.

The generation of NO may be central to both early and late depression of

myocytes in in vitro and in vivo models of septic shock. The role of NO in cardiac

contractility is still under study. NO is produced by the conversion of L-arginine to L-

citrulline by the nitric oxide synthase, which exists in inducible nitric oxide synthase

(iNOS) and constitutive nitric oxide synthase (cNOS) forms. Studies support the role

of NO generated by cNOS in the physiologic regulation of cardiac

contractility72,73,74. In vitro studies of cardiac myocytes superperfused with either

NO, nitroprusside (NO donor) or the NO donor SIN-1 demonstrate reductions in

myocardial contractility.75 In human studies, nitroprusside infusion into coronary

arteries depresses intraventricular pressure while improving diastolic relaxation and

distensibility.76

In sepsis and septic shock, the pathophysiologic production of NO may

contribute to cardiovascular dysfunction. The initial process is thought to occur from

sequential NO and cGMP generation via cNOS activation rather than by de novo

synthesis of iNOS. This is consistent with the short time frame to the onset of

27

myocardial depression61,69,77. These studies cannot, however, account for the late-

onset of cytokine-driven myocardial depression discussed earlier. Further studies have

shown, in in vitro myocardial preparations, that the generation of iNOS, NO and

cGMP may be responsible for late onset myocardial depression.61,66,78,79

Studies thus suggest that NO-mediated depression of myocardial contractility

appears in two separate time frames by two distinct pathways. Prior to Kinugawa et

al.‘s study80, it might have been thought these mechanisms were mutually exclusive.

Kinugawa et al. demonstrated, using an avian cardiac myocyte model, a biphasic

response to IL-6 administration. IL-6 given in high concentration produced both early

(<30min) and late (24hours) cardiac myocyte depression, associated with a decrease

in intracellular calcium. Early depression could be blocked by pretreatment with a

calcium chelator, implicating that the calcium/calmodulin-dependent cNOS is

involved. However, late depression could not be blocked by the chelator, supporting

the role for the calcium/calmodulin-independent iNOS The study of Kinugawa et al.

clearly suggests that cytokines (or sepsis) can stimulate the heart to sequentially

produce NO by both cNOS and iNOS. The data would suggest that TNF-α, IL-1β and

possibly other cytokines involved in septic shock could mediate their cardiodepressant

effects by at least two distinct mechanisms. Early cardiodepressant activity may

involve both a NO-dependent but β-adrenoreceptor- independent mechanism and a

NO-independent defect of β-adrenoreceptor signal transduction.81 Late depression

involves an iNOS-dependent defect of β1-adrenergic signal transduction with further

addition of an undefined defect of myocardial contractility. While NO generation may

contribute to the cardiodepressant effects seen in sepsis, its precise role and the role of

other mechanisms underlying septic myocardial dysfunction continue to be defined.

28

Studies performed in humans have ruled out coronary hypoperfusion requiring

coronary intervention as a cause of LV systolic dysfunction in sepsis87,88. Of course,

patients with coronary disease may behave differently.

On the other hand, the role of cytokines has been strongly advocated in the

genesis of septic cardiomyopathy. In 1985, Parrillo et al. demonstrated in vitro that

myocardial cell shortening is reduced by exposure to the serum of septic patients89.

Later, the same team showed that the circulating factor responsible for this was tumor

necrosis factor a (TNF-a)90,91, even though later studies have implicated other

cytokines, such as interleukin-1b92. Kumar et al. suggested that the effect of

cytokines on cardiac myocytes results from an increase in intracellular cGMP and in

nitric oxide93. In addition, direct alteration in cellular respiration with mitochondrial

dysfunction also was advocated94, and, finally, Tavernier et al. suggested that

increased phosphorylation of troponin I was involved by reducing myofilament

response to Ca2+95.

29

SEPTIC CARDIOMYOPATHY:

Cardiomyopathy:

Cardiomyopathies constitute a group of diseases in which the dominant feature is

involvement of heart muscle itself. They are distinctive because they are not the result

of pericardial, hypertension, congenital, valvular or ischemic diseases.

Septic Cardiomyopathy:

Clinical, epidemiological, pathological data support the existence of a specific

cardiomyopathy associated with severe sepsis and septic shock.

For many years, septic cardiac dysfunction was largely underestimated because the

hemodynamic device used, i.e., the pulmonary artery catheter, was not appropriate for

establishing such a diagnosis. Development of new hemodynamic tools at the bedside,

such as echocardiography, allowed better characterisation of the septic

cardiomyopathy 86.

Clinical and Epidemiological Studies:

Reversible myocardial depression in patients with septic shock was first described in

1984 by Parker et al. using radionuclide cineangiography82. In a series of 20 patients,

they reported a 65% incidence of left ventricular (LV) systolic dysfunction, defined

by an ejection fraction <45% 82. In 1990, using transthoracic echocardiography,

Jardin et al. reported the same results 83.

30

Experimental Studies:

In a canine model simulating human septic shock, Natanson et al. demonstrated that

intrinsic LV performance was actually depressed in all animals and not corrected by

volume expansion 84

Finally, more recently, Barraud et al. confirmed the presence of severe depressed

intrinsic LV contractility using LV pressure/ volume loops in lipopolysaccharide-

treated rabbits 85. All of these studies, and many others not cited in this introduction,

demonstrate the reality of the impairment of intrinsic LV contractility in septic shock

Main characteristics of septic cardiomyopathy:

The first characteristic of septic cardiomyopathy is that it is acute and reversible,

providing the patient recovers. In 90 patients during a 5-year period, Jardin et al.

reported that LV ejection fraction is normalized in a few days96, as also reported

more recently by Bouhemad et al.97.

The second characteristic, which is crucial to full understanding, is that depressed LV

systolic function is associated with normal or low LV filling pressure, unlike the

―classic‖ pattern of cardiogenic shock where LV pressures are elevated (Figure 8).

This may explain why the pulmonary artery catheter has for many years under-

estimated the incidence of LV systolic dysfunction. Jardin et al. and Bouhemad et al.

reported an average pulmonary capillary wedge pressure close to 11 mmHg in

patients with decreased LV ejection fraction, which is not significantly different from

that found in patients with a preserved ejection fraction83,97. In the study by Parker

31

et al., the pulmonary capillary wedge pressure was 14 mmHg on average in patients

with LV ejection fraction <45%82.

Fig. 8 Transesophageal echocardiography in two patients–one with

cardiogenic shock (above) and the other with septic shock

(below).[In the patient with cardiogenic shock, the left ventricular short-

axis view demonstrated global hypokinesia of the left ventricle with

major dilatation. Pulsed Doppler at the mitral valve demonstrated a

restrictive pattern of the left ventricular inflow with a high E wave

velocity and a very low A wave velocity, highly suggestive of a high LV

filling pressure. Note also the thrombus in the left ventricle (arrow). In

the patient with septic shock, the short-axis view also demonstrated

global hypokinesia of the left ventricle, but without a major dilatation.

Note also the Doppler profile at the mitral valve, highly suggestive of

normal LV filling pressure.]

32

Two mechanisms may explain this absence of elevated LV pressures. The first relates

to the frequent association with right ventricular (RV) dysfunction. Vincent et al. in a

group of 93 patients with septic shock reported a decreased RV ejection fraction

compared with a ―control‖ group 98. Similar results were found by Kimchi et al. and

Parker et al. 99,100. Using transesophageal echocardiography, Antoine Vieillard-

Baron reported that almost 30% of patients have RV dilatation, which is highly

suggestive of significant RV dysfunction (Figure 9)101. RV dysfunction is related to

acute pulmonary hypertension, which is frequently associated in this situation because

of the acute lung injury, or depressed intrinsic contractility due to circulating

cytokines99. It protects the pulmonary circulation102 and avoids significant elevation

of LV pressures.

The second mechanism relates to LV compliance alteration, which usually occurs. In

their original work, Parker et al. suggested a huge increase in LV compliance; they

found a dilatation of the left ventricle of more than 100%82. This very impressive LV

―preload adaptation‖ was actually never confirmed and was probably explained in part

by technical errors related to the use of the pulmonary artery catheter. Most studies

using echocardiography only report a slight increase in LV size in patients with

decreased LV ejection fraction compared with patients with preserved ejection

fraction, suggesting a true but slight increase in LV compliance in these patients

(Figure 10)97,101,103. In 12 normal healthy volunteers, Suffredini et al.

demonstrated that injection of endotoxin induces a depression of LV systolic function

associated with a significant decrease in the ratio of pulmonary capillary wedge

pressure to LV end- diastolic volume index104. A limited but significant increase in

33

LV end-diastolic volume (+15%) was reported after volume loading with a pulmonary

capillary wedge pressure less augmented than in the control group104.

Fig. 9 Transesophageal echo illustrating of RV dysfunction[ Long-

axis view of the left ventricle by a transesophageal approach in a

patient ventilated for septic shock. At day 1 (panel A), the patient had

right ventricular dysfunction illustrated by major dilatation of the right

ventricle. At day 2 (panel B), this was corrected. RV, right ventricle;

LV, left ventricle]

34

ECHOCARDIOGRAPHY105,106,107,108,109

Echocardiology has come a long way since its invention and Hertz from

Sweden in the early 1950s. Today it is recognised as one of the most important bed

side diagnostic techniques available in cardiovascular medicine. The term

echocardiography refers to a group of test that utilise ultrasound to examine the heart

and record information in the form of echos i.e. reflected sonic waves. The upper limit

for audible sound is 20,000 cycles/second; or 20 kilo Hertz. The sonic frequency used

for echocardiography ranges from 1 to 10 millioncycles/second, or 1 to 10 megaHartz

(MHz). In adults the frequency ranges from 2.0 to 5.0 MHz, while in children from

3.5 to 10.0 MHz.

History:

In the eighteenth century, Lazzarro Spallanzani noted that bats, that were blind

were able to fly as well as bats that could see. The reason for this is that bats use echo

sounding for measuring distance. A similar mechanism is used by dolphins and

certain species of birds. High frequency sounds are generated, emitted, and reflected

back to the organism that in turn directs their motion. This principle was employed by

man in the 19th century to detect schools of fish and in worldwar I to detect

submarines.

In the early I940s, Firestone described the use of pulsed ultrasound techniques

for flaw detection in metals. His work served as a building block for the engineering

principles of the complex ultrasound equipment used in current medical diagnosis. In

the late 1940s and the early l950s, several Workers reported their experience using

pulsed reflected ultrasound to identify intracranial structures and localise cerebral

neoplasms, as well as assessing the integrity of other organs in the body.

35

In I953, Dr. Hertz examined the heart using a commercial ultrasonoscope.

Collaborating with Dr. Elder, they published a paper on the use of ultrasonic

reflectoscope for continuous recording of movements of heart walls. Their pioneering

efforts in echocardiography gave way to investigators like Reid, Wild, Feigenbaum,

Joyner to develop and advance echocardiography into a modern sophisticated,

diagnostic tool with no known hazard to the patient.

Source of Ultrasound:

Ultrasounds are generated by materials which have the property of Piezo

electric effect which is crystalline deformation secondary to electrical current or

mechanical vibration. The sound source of the transducer is a circular lead zirconate

titanate crystal which ranges from 6-13mm in diameter. The transducer is activated

about 3000 times per second to emit short duration pulses of ultrasound which is

directed into the organ to be studied and lasts for l msec. Reflected pulses return to the

transducer. The Piezo electric crystal has the ability not only to emit sound waves but

also to receive them and generate electrical potential. The transducer is placed along

the patient's left parasternal border .

Mechanism:

Following a two micro-second application of electric current the active

element expands and contracts initiating mechanical vibrations which are transmitted

as periodic oscillations through a coupling gel into the body. A portion of the energy

of the sound wave is reflected when it encounters a boundary between two materials

with different physical properties such as blood and endocardium. Echoes are

reflected sound waves.

36

If the target is small then sound waves are scattered. Such back scattering is the main

mechanism by which ultrasound returns from structures within the heart.

Types of Echocardiogram:

1) M-Mode: This provides an unidimensional time motion image of the cardiac

structures with great sensitivity.

2) Two dimensional: This provides a two dimensional image of the cardiac structures.

It can be either static or real time.

3) Doppler Echocardiography: Dopplers echocardiography utilises ultrasound to

record blood flow with in the cardiovascular system.

Advantages of Echocardiography:

The advantages of echocardiography are numerous. The examination is

painless and noninvasive. It is virtually harmless and it is less costly than other

sophisticated imaging techniques.

Limitations of Echocardiography:

1) Emphysema: In patients with emphysema adequate records cannot be obtained

as the echo window is poor.

2) Drop out Echoes: Some structures parallel to the ultrasound beam may not

reflect ultrasound well and may give a false impression of being absent e.g.

interatrial septum near fossa ovalis may give a false appearance of atrial septal

defect.

37

3) Lateral resolution: The lateral resolution i.e. the ability to distinguish two points

side by side is 4.5mm, which is much less than standard radiology ultrasound of

higher frequency gives better resolution but is absorbed by biological fluids and hence

is suitable only for infants and children.

4) Off-axis echoes: A strong reflecting target at the edge of the beam may give more

intense echoes than structural along its axis leading to errors in localisation of

intracardiac structures.

M-Mode Echocardiography:

The M-Mode echocardiography is used to obtain a record of the motion of

cardiac structures in a single direction. It is usually performed from the left

parasternal region. Usually three standard views of the heart taken, at the level

of the aorta and left atrium, at the level of anterior cusp of the mitral valve and across

the left ventricular cavity. M-Mode echocardiography provides accurate and

reproducible information about cardiac anatomy and function with no risk to the

patients (James B et al 1980). It provides an accurate assessment of LV mass that is

more sensitive and specific than the electrocardiogram for detecting LVH (Feichek N

et al I981)

DOPPLER ECHOCARDIOGRAPHY

M-Mode and two-dimensional echo essentially create ultrasonic images of the

heart. Doppler echocardiography utilizes ultrasound to record blood flow within the

cardiovascular system.

38

Principles of Doppler:

If the ultrasonic beam is reflected by stationary object, the transmitted frequency (Ft)

and the reflected frequency (Fr) are equal.

Fr= Ft.

However, if the target reflecting the ultrasonic energy is moving towards the

transducer the reflected frequency (Fr) is greater than the transmitted frequency (Fr is

more than Ft).

When the target is moving away from the transducer the reflected frequency is less

than the transmitted frequency (Fr is less than Ft).

The differences between the reflected and transmitted frequencies represent the

Doppler Shift or Doppler Frequency.

Doppler Shift or Frequency (Fd) = Fr - Ft

By knowing the Doppler frequency it is possible to calculate the velocity of the

moving target.

Doppler equation relating Doppler frequency (Fd), received frequency (Fr),

transmitted frequency (Ft) and the angle (0) between the direction of the moving

target and the path of the ultrasonic beam is as follows:

Fd = Fr-Ft

Fd - 2ft (V x Cos 0) / (C)

C = Velocity

V - Fd x CI 2Ft (Cos 0)

39

Continuous Wave Doppler:

There are two transducers, one of which continuously transmits ultrasonic

energy, and the other which continuously records the reflected ultrasonic signals. This

is the most useful method to record turbulent as well as laminar flow.

Pulsed Doppler:

Here only one transducer is needed. In addition, pulsed Doppler permits

creation of simultaneous M-Mode and two-dimensional images. Pulsed Doppler has

got limitations that it cannot be used to record blood flow with high frequency.

Laminar flow produces a Doppler signal consisting of fairly uniform

frequencies all moving in the same direction. If the blood flow is turbulent or

disturbed, multiple frequencies are recorded some of which maybe moving in the

opposite direction as depicted by signals below the base line. The Doppler recording

is a spectral display using fast Fourier analysis of the audible doppler signal. The

audio signals are helpful in interpreting the various types of flow and represents an

important aspect of the Doppler system Colour Doppler:

Colour doppler information from the cardio vascular system can also be

recorded in a spatially correct format superimposed on an M-mode or two-

dimensional echo. Doppler flow imaging is created by multiple Doppler gates that are

spatially corrected and display the moving blood within the two- dimensional or M-

mode recording. The direction of the blood is displayed in colours. With this

particular instrument blood moving towards the transducer is depicted in shades of

yellow and red, whereas blood moving away is in shades of blue. This method is

useful in detecting regurgitation.

40

Assessment of Diastolic Function Using Doppler:

Doppler flow pattern in the left ventricular inflow tract just beyond the mitral

valve superficially resembles an , M-mode tracing of the anterior mitral leaflet. There

is rapid inflow in the early diastole, decreased flow in the mid diastole and subsequent

increased in inflow with atrial systole.

Doppler echo has been used to evaluate left ventricular diastolic function. M-

mode techniques have been used to record the rate of relaxation of the left ventricular

cavity.

T.V. Strok et al and Nishimura R.A. et al demonstrated that Doppler

echocardiography is the primary non-invasive technique used for evaluating left

ventricular diastolic function in diabetes. Early diastolic flow is reduced and the

velocity following atrial contraction is increased in diabetes.

This phenomena has been quantitated in several ways. The simple technique is

to take a ratio of the peak velocity with early filling or 'E' point and the peak velocity

with atrial filling or 'A' point. Normally the velocity at the 'E" point is significantly

higher than at the 'A' point.

With reduced early left ventricular filling this ratio is reversed. With restrictive

ventricular filling the diastolic velocities may again reverse with a tall 'E' wave and

reduced 'A' wave. This is called as Pseudo normalisation.

41

EVALUATION OF DIASTOLIC DYSFUNCTION BY DOPPLER STUDY

The role of left ventricular diastolic function in health disease is still

incompletely understood and under appreciated by most primary care physicians and

many cardiologists. This is not surprising because diastole is a complex phenomenon

with many determinants that are difficult to individually study and has several phases

that encompass the relaxation and then filling of the ventricle. Physical examination,

ECG and chest radiographs are unreliable in making the diagnosis of LV diastolic

dysfunction in most individual and invasive measurement of cardiac pressures, rates

of LV relaxation and LV compliance are costly, clinically impracticable as they carry

increased risk, and require special catheter and software analysis program.110

This situation changed with development of echocardiography110. The non-

invasive evaluation of L V diastolic function has become increasingly important for

several reasons. First, abnormalities of diastolic filling are primarily, responsible for

the majority of symptoms observed in heart failure81

Diastole: One of the first attempt to explain ventricular filling was provided by Galen

in 100 BC who proposed that the heart is filled by dilation and right ventricle.

Centuries later in 1628 William Harvey recognised the heart was the central pump in

a circulatory system containing arteries and veins.

In a hypertrophic left ventricle were rapid filling phase was compromised due

to increased left ventricular diastolic pressure, atrial systole is the main force to ensure

left ventricular filling.And in such cases if a patient develops atrial fibrillation or

complete heart block, loss of atrial booster occurs and quick haemodynamic

deterioration takes place.

42

Determinants of Diastolic Function:

• Active relaxation

• Chamber stiffness

o Myocardium

1)Myocardial fibers

2)Extracellular components

o Wall thickness

o Left ventricular geometry

o Right ventricular left ventricular interaction

o Pericardial forces

• Mitral valve orifice

• Atrioventricular coupling

• Intrathoracic pressure.

Other conditions with diastolic dysfunction:

Hypertension

Hypertrophic cardiomyopathy

43

Ischemic heart disease

Restrictive heart disease

INDICES OF DIASTOLIC DYSFUNCTION:

Mitral flow velocities were recorded by Doppler from an apical four chamber view

with the sample volume placed near the tips of the mitral leaflet.

The following measurement were made:

1) Peak velocity of early mitral flow(E-Cms-1)

2) Peak velocity of late mitral flow (A-Cms-1)

3) E/A. ratio

4) Velocity time integral of the entire mitral curve (VTIM- cms-1)

5) Velocity time integral of the atrial curve (VTIA-cms·')

6) VTIA / VITM ratio

7) Pressure half - time (PHT - ms-1)

8) Isovolumic relaxation time (IVRT - ms-1)

The diastolic dysfunction (A/E ratio > I) is found in early stages indicating

reduced ventricular compliance. Abnormalities of systolic function parameter like EF,

fractional shortening occur later on. In I993 A.K. Das et al evaluated type I patients

and focused dysfunction in approximately 24% of patients in absence of any CAD.

44

The parameter which were most altered were E velocity, ElA ratio and peak filling

rate.

Clinical Application of Doppler to Assess Diastolic Dysfunction112

Doppler assessment of diastolic function has found a variety of applications in the

clinical setting. The usefulness of Doppler has been demonstrated or proposed for the

following.

1) To identify

2) To define mechanisms

3) To establish the etiology

4) To quantify the severity

5) To assess the prognosis of diastolic dysfunction.

45

Normal Values for Mitral Inflow Velocity Measurements in Subjects < 40 years

Old 111

Measurement* Mitral annulus Mitral valve tips

E 75 ± 12 cm/sec 86 ± 16 cm/sec

A 53± 10cm/ sec 56 ± 13 cm / sec

E/A 1.44 ± 0.4 1.6 ± 0.5

DT 199 ± 32 m I sec

AFF 0.27 ± 0.06

IVRT 69 ± 12 m I sec

* DT = Deceleration time; AFF = atrial filling fraction ; IVRT = isovolumic

relaxation time

Left ventricular filling patterns110:

1) Mitra/ flow velocity variables: LV filling patterns are assessed using PW Doppler

mitral flow velocity recordings and variables. Left ventricular isovolumic relaxation

time (IVRT) is the time interval from aortic valve closure to mitral valve opening.

Longer IVRT values (> I00ms) are associated with impaired LV relaxation and

normal filling pressures. This lengthening of the IVRT interval is the earliest change

seen with diastolic dysfunction, and is sensitive to slowing of the rate of LV

relaxation. A short LV IVRT indicates an earlier mitral valve opening and can be seen

in young normal individuals or patients with increased mean LA pressure. Peak E-

wave velocity reflects the early diastolic TMPG and the diastolic properties

46

previously discussed. Similarly, peak mitral A-wave velocity reflects the late diastolic

TMPG. The overall type of filling pattern is characterised by the mitral E to A wave

ratio. The mitral flow velocity at the start of atrial contraction, known as the E at A

velocity, is important to note because values > 20cm/s (usually caused by a faster

heart rate or first degree AV block) indicate partial fusion of early and late diastolic

filling, which increases A-wave velocity and duration, making the interpretation of E

to a ratio and A wave variables more difficult. Mitral deceleration time reflects LV

compliance in early diastole in patients with known heart disease and reduced (>

35%) LV ejection fraction and provides prognostic value in patients with various

cardiac diseases. The mitral A-wave duration and time velocity integral is affected by

multiple factors including heart rate, PR interval, the amount and duration of E-wave

filling, LV compliance in late diastole, and LA stroke volume.

2) Normal changes with ageing: Elastic recoil and rapid LV relaxation in adolescents

and young adults result in a predominance of early diastolic filling (E-wave) with

much less filling (10% to 15%) caused by atrial contraction. With normal ageing, LV

systolic function changes little but LV relaxation slows in most individuals. This

appears to be caused by an increase in systolic blood pressure and LV mass. The

result is reduced LV filling in early diastole and increased filling at atrial contraction.

In most individuals, the peak E and A wave velocities become approximately equal

during the seventh decade of life, with atrial filling contributing up to 35% to 40% of

LV diastolic stroke volume. In individuals with lower blood pressure and no increase

in LV mass, these age-related changes in filling are retarded and normal E-wave

predominance can occasionally be seen into the eighth decade of life.

47

3) Abnormal mitral filling pattern: In patients with cardiac diseases, three abnormal

LV filling patterns are recognised. The least abnormal and most common is termed

impaired relaxation, resulting from reduced filling in early diastole, a reduced mitral E

to A wave ratio, increased A-wave amplitude and filling caused by atrial contraction,

and often an S4 gallop. With disease progression, LV compliance becomes reduced

and LA pressure increases, which counteracts the impaired LV relaxation. The

increased early TMPG results in an LV filling pattern that appears normal but is

actualJy pseudonormal. This term indicates that despite the normal mitral E to A-

wave ratio, abnormalities of LV relaxation and LV compliance are present. Finally, in

patients with advanced disease and a severe decreased in LV compliance, high

pressures cause LV filling to become restrictive, with blood rapidly entering a slowly

relaxing ventricle in early diastole only to be abruptly decelerated, generating an S3

gallop. With a marked increase in early LV diastolic pressure the left atrium is dilated

and hypocontractile with additional filling at atrial contraction.

SYSTOLIC DYSFUNCTION:

Currently, the accepted definition of myocardial dysfunction in sepsis is based

solely on an LV ejection fraction (LVEF) of less than 45% to 50% in the absence of

cardiac disease that demonstrates reversibility on remission.113,114,115

Ejection Fraction

Definition:

―Ejection fraction represents the percent or fraction of left ventricular diastolic

volume that is ejected in a systole.this measurement is made by calculating the stroke

volume and dividing by diastolic volume.‖

48

If one uses two dimensional echocardiography to measure volumes, then

ejection fraction is a simple calculation.Some authors report the ―eyeball‖ estimate of

ejection fraction from the real time two dimensional echocardiogram without making

actual measurements.116,117

Any systolic index or function can be used to assess global function.Ejection

fraction uses volumes, although one can use linear dimensions to calculate fractional

shortening, which is diagnostic dimensional minus systolic dimension divided by

diastolic dimension.

One must be aware of the problems with echocardiographic calculations of the

volumes either with M mode or two dimensional technique.Evaluating left ventricular

systolic function with a combination of shortening a fractional area change is simpler,

introduces fewer magnified potential errors, and has a value in ventricles not

contracting symmetrically.It must be remembered, however, that all systolic area is

preload and after load dependent .118

M mode measurements has been used extensively for assessing left

ventricular performance.Circumferential shortening is a way of converting the

diameter into circumference and obtaining a systolic index.Introducing ejection time

provides a measurement of mean of circumferential shortening(Mean vcf).Some

investigators also use the excursion of the inter ventricular septum and posterior left

ventricular endocardium for assessing left ventricular function119 One may measure

the slope of the posterior ventricular wall motion(AEN/At).An other technique is to

divide the endocardial amplitude by the ejection time.This measurement can be

normalised fro left ventricular diastolic dimension with a formula of Ena/LVIDd =

49

ET.The amount and rate of left ventricular wall thickening have also been used as a

marker of function.120

M-mode echocardiography measurement of left ventricular performance

1. Left ventricular ejection fraction (EF%)

EF = LV diastolic volume - LV systolic volume x 100

LV diastolic volume

OR

EF = LV stroke volume x 100

LV diastolic volume

N: 55-85%

Doppler echocardiography can be used for determining global left ventricular

systolic function. The aortic Doppler velocity can be used to measure left ventricular

stroke volume. The aortic velocity time integral also can give an assessment of left

ventricular performance. 121 The initial half of the velocity time integral, up to the

peak velocity has been used to calculate ―Ejection Force‖. Some data indicate that the

rate or acceleration that blood leaves the left ventricle reflects the strength of left

ventricular contraction. The peak acceleration is the first derivative of the aortic flow

velocity, but it is difficult to measure. An easier calculation is the slope between the

onset of ejection and peak velocity, which is mean acceleration.

As with almost all global assessments, these Doppler measurements area again

preload and after load dependent122and are influenced by heart rate123

50

Another method of using Doppler echocardiography to assess left ventricular

systolic function is to examine Doppler flow in patients who have mitral regurgitation.

Doppler recording of mitral regurgitation and corresponding left –sided intracardiac

pressures. The rate with which the left ventricular pressure rises (dp/dt) is a measure

of left ventricular contractility. The rate of rise of left ventricular pressure will be

reflected by the rate that mitral regurgitant blood moves from the left ventricle into

the left atrium. A patient with mitral regurgitation in which the rate of rise of the

mitral regurgitation in which the rate of rise of the mitral regurgitant jet is rapid,

giving a dp/dt of 1800 mm Hg/sec. Another patient with mitral regurgitation and poor

left ventricle has a slower rise in the mitral regurgitate velocity, giving a dp/dt of 800

mm Hg/sec.

A relatively simple echocardiographic measurement for assessing global

systolic function is the mitral E-point septal separation. This measurement is usually

obtained from the M-mode echocardiogram. Normally, the distance between the E

point and the left side of the septum is less than 1 cm. Although this measurement is

simple, a reasonable rationale is behind it. As the left ventricle dilates, the septum

moves anteriorly. Mitral valve motion is influenced by the amount of blood flowing

through the mitral valve at the E point reflects the flow through the valve point

indicates reduced flow or stroke volume and anterior displacement of the septum

indicate increased diastolic volume, it is reasonable to expect an increase in the

distance between the mitral valve E point and the interventricular septum with a

decreased ejection fraction. There are, of course, inherent limitations. In a point with

intrinsic valve disease, such as mitral stenosis, the excursion of the mitral valve is not

a reliable indicator or flow through that orifice. In patients with aortic regurgitation,

the regurgitant jet may distort the excursion of the mitral valve. Furthermore, the

51

diastolic volume may be increased by segmental dilatation or aneurysm formation that

may not produce anterior displacement of the septum.

Investigators have also been using descent of the mitral annulus as an indicator

of global left ventricular function, it has been recognised for many years that the base

of the heart moves whereas the apex contributes little to the ejection of blood. In an

early observation, investigators used an M-mode tracing of annular motion to

calculate left ventricular stroke volume. The latest efforts involve the use of two-

dimensional echocardiography, whereby the extent of descent of the base of the

ventricle relates to global ventricular function.

3. Cardiac output:

It is the product of stroke volume and heart rate. Therefore, CO = SV x HR

Where Stroke volume, SV = LVEDV – LVESV

Normal value of CO is 4 to 8 litres per minute

4. E Point Septal Separation(EPSS):

It was measured by M-mode echocardiography as the the distance between the peak

downward motion of the interventricular septum and maximum upward

excursion of the mitral E point.

It can also be taken as the distance between the mitral valve and interventricular

septum at ‗E‘ point. Normal value of EPSS is 2 to 7 mm.

52

METHODOLOGY

Source of data:-

A total of 100 patients with sepsis and septic shock were randomly selected from

Bapuji hospital attached to J.J.M.Medical college Davangere between September

2016 - September 2018.

Sample size: 100 patients

Inclusion criteria:

1. All patients presenting to emergency department who meet criteria for new onset

sepsis as defined by American College of Chest Physicians/Society Critical Care

Medicine Consensus Conference124

. Severe Sepsis was defined as sepsis associated

with organ dysfunction, organ hypoperfusion or hypotension. Hypoperfusion

indicated by lactate level of 2.30mmol/L(institutional high normal value).Hypotension

defined as systolic pressure <90mmHg or decrease of 40mmHg below baseline.

Specific organ dysfunction was defined as Sequential Organ Failure

Assessment(SOFA) score of 2 or higher125 at the time of echocardiography and

Acute Physiology and Chronic Health Evaluation(APACHE 3) score was obtained on

the admission day.

2. Age above 18 years

3. Any sex

53

Exclusion criteria:

1. Patients with pre-existing congenital heart disease, valvular stenosis or clinically

significant valvular insufficiency, valvular prosthesis, and coronary artery disease

without recent echocardiography or known abnormalities on recent

echocardiography(within 6 months of enrolment)

2. Age less than 18years

3. Pregnancy

Method of collection of data :

An prospective study undertaken over 24 months period including a total of 100

patients, TTE will be performed on patients presenting to the J.J.M medical college

Emergency department who have developed Severe Sepsis and Septic shock at/or

within 24 hours of admission to ICU.

1) Myocardial dysfunction is classified as Left Ventricular(LV)systolic

dysfunction, LV diastolic dysfunction and Right ventricular (RV) dysfunction.

2) The frequency of myocardial dysfunction will be calculated, and demographic,

hemodynamic, and physiologic variables and mortality will be compared

between the myocardial dysfunction types and patients without myocardial

dysfunction.

Outcome measures:

The effect on the prognosis of patients presenting with sepsis and septic shock

developing myocardial dysfunction will be assessed by clinical examination,

54

Lab investigations and Transthoracic echocardiography.

Intervention:

1. Sepsis: antibiotics and eradication the foci of sepsis

2. Septic shock: resuscitation with fluids and inotropes with treatment of the sepsis.

3. Respiratory distress/ARDS: mechanical ventilation

4. Acute renal failure: hemodialysis

5. LV dysfunction: inotropic support

Investigations:

1. Complete blood count

2. Urine routine and micro analysis

3. LFT,APTT, PT-INR

4. RFT

5. Serum electrolytes

6. 2-D echocardiography

7. ECG

8. Chest X-ray

9. Cultures of blood,urine other secretions if required

55

10. Serum Brain Natreuretic Peptide(BNP) troponin I, when needed

11. Echocardiography

In Doppler echocardiography, following values will be studied.

A. E - Peak velocity of early mitral flow.

B. A - Peak velocity of late mitral flow.

C. E/A ratio.

D. IVRT - Isovolumic relaxation time.

E. TAPSE- Tricuspid annular plane systolic excursion.

F. LVIDd – Left ventricular diameter in diastole.

G. LVIDs - Left ventricular diameter in systole.

H. EF – Ejection fraction.

E/A ≤1 considered as diastolic dysfunction

EF% ≤ 50% considered as systolic dysfunction.

TAPSE <1.5 considered as RV dysfunction

Echocardiographic Evaluation and Definitions of Myocardial Dysfunction

Types:

Transthoracic echocardiography was performed in the ICU with a commercial

echocardiographic instrument ( GE Medical Systems). A comprehensive M-mode, 2-

dimensional, and Doppler echocardiographic study was performed in all patients from

56

the parasternal long-axis and short-axis views; apical 4-chamber, 2-chamber; and

subcostal views.

Left ventricular end-diastolic volume, LV end- systolic volume, and LVEF were

assessed using the modified Simpson method as recommended by the American

Society of Echocardiography.25 Measurements were taken during 3 cardiac cycles

and then averaged. Systolic dysfunction was defined as mild (LVEF, 41%-50%),

moderate (LVEF, 31%-40%), and severe (LVEF, 30%). Whenever suboptimal

endomyocardial border definition was encountered for volumetric assessment, M-

mode imaging and expert evaluation determined the final LVEF. Diastolic function

evaluation was performed in accordance with the American Society of

Echocardiography guidelines15. Mitral inflow pulsed wave Doppler measurement of

peak E and A waves, E/A ratio was obtained with the sample volume between mitral

leaflet tips during diastole. A multimodal approach was used to evaluate RV function,

which was graded as mild, moderate, or severe RV dysfunction. Tricuspid annular

plane systolic excursion doppler imaging was used in association with the relative

RV-to-LV size, motion of the RV wall, and expert evaluation. Patients were

categorised by myocardial dysfunction type and analysed against patients without any

myocardial dysfunction.

57

STATISTICAL ANALYSIS

Results are presented as Mean ± SD for continuous data and frequency as

number & percentages.

Unpaired t test was used to compare means of two groups and categorical data

was analysed by chi-square test. A P value of 0.05 or less was considered to be

statistically significant.

SPSS (version 17) software was used for analysis.

58

SAMPLE SIZE ESTIMATION

Evidence obtained from previous studies was used to estimate the sample size. It was

observed in the study that, overall, 64% of sepsis patients had myocardial

dysfunction. Assuming the same in the current study, sample size was estimated

taking a precision of 20%, desired confidence level of 95%.

The sample size was estimated by using the statistical formula:

N= (Z α)2

* p * q / d2

Where, N is the required sample size;

Zα is the standard normal deviate which is equal to 1.96 at 5% level of significance;

p is the weighted prevalence(60%);

q is equal to 100-p(100 - 60= 40%);

d is the allowable error 20%(20% of prevalence rate =12)

N= {1.96}2 p q / d

2

= {1.96}2 * 60 * 40/ (12)

2

=64

Evidence obtained from a prospective study by Pulido et al, was used to estimate the

sample size. It was observed in this study that overall, prevalence ranges between

42-70%.

Assuming the same in the current study, sample size was estimated taking a precision

of 20%, desired confidence level of 95%, the sample size was estimated to be 64 and

was rounded off to 80.

59

RESULTS

Table 1: Age distribution

Age groups (Yrs) No.of cases %

30 - 39 5 5

40 - 49 43 43

50 - 55 52 52

Total 100 100

0

15

30

45

60

30 - 39 40 - 49 50 - 55

5

43

52

No.o

f cases

Age groups(Yrs)

Graph 1: Age distribution

60

In the present study, out of 100 patients:

• 5 belong to age group of 30-39 years, out of which 1 has diastolic dysfunction

and 1 has systolic dysfunction.

• 43 belong to age group of 40-49 years, out of which 20 have diastolic

dysfunction and 12 have systolic dysfunction and 9 patients have RV

dysfunction.

• 52 belong to age group of 50-55 years, out of which 42 have diastolic

dysfunction, 29 have systolic dysfunction and 27 have RV dysfunction.

• Mean age of patient group being 48.5 ± 5.7 years and mean age of diastolic

dysfunction group is 48.7±4.4 years, systolic dysfunction is 49.5 ± 4.7 years

and RV dysfunction is 50.4 ± 3.6.

Table 2: Age-wise incidence of LV / RV dysfunction

Age groups

(Yrs) No.of cases

DD SD RV

positive negative positive negative positive negative

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

30 - 39 5 1(20.0) 4(80.0) 1(20.0) 4(80.0) 0(0.0) 5(100.0)

40 - 49 43 20(46.5) 23(53.5) 12(27.9) 31(72.1) 9(20.9) 34(79.1)

50 - 55 52 21(40.4) 31(46.5) 16(30.8) 36(69.2) 18(34.0) 34(65.4)

Total 100 42(42.0) 58(58.0) 29(29.0) 71(71.0) 27(27.0) 73(73.0)

Age significance X ² = 1.41, P = 0.49,NS X ² = 0.30, P = 0.86,NS X ² = 4.18, P = 0.12,NS

61

Table 3: Sex distribution

Sex No.of cases %

Male 64 64.0

Female 36 36.0

Total 100 100.0

Table 4: Sex-wise distribution of Dysfunction

Sex

LV Dysfunction RV Dysfunction

No % No %

Male 31 56.4 14 51.9

Female 24 43.6 13 48.1

Total 55 100.0 27 100.0

0

10

20

30

40

50

60

70

LV dysfunction RV dysfunction

56.4 51.9

43.6 48.1

% o

f cases

Graph 2: Sex-wise distribution of Dysfunction

Male

Female

62

In the present study, out of 100 patients :

• 64 were male out of which 31 have LV dysfunction and 14 have RV

dysfunction.

• 36 were female out of which 24 have LV dysfunction and 13 have RV

dysfunction.

Table 5: Incidence of Cardiac Dysfunction

Dysfunction No.of cases %

CardDysFn 61 61.0

NormalMyFn 39 39.0

Total 100 100.0

Table 6: Incidence of various Myocardial Dysfunctions

Dysfunction No.of cases %

Only DD 19 19.0

Only SD 3 3.0

Only RV 6 6.0

DD & SD 12 12.0

DD & RV 7 7.0

SD & RV 10 10.0

DD & SD & RV 4 4.0

Normal 39 39.0

Total 100 100.0

63

Graph 3: Incidence of various Myocardial Dysfunctions

Out of the 100 patients in our study:

61 patients had myocardial dysfunction, of which only LV DD was seen in 19,

only LV SD was seen in 3, only RV dysfunction was seen in 6.

12 patients had both LV systolic and diastolic dysfunction,7 patients had LV

diastolic and RV dysfunction and 10 patients had LV systolic and RV

dysfunction.

4 patients had LV systolic, LV diastolic dysfunction and RV dysfunction.

64

LV Systolic Dysfunction

Twenty-nine patients (29%) had LV systolic dysfunction. Three patients had isolated

LV systolic dysfunction, representing 3% of all patients.The mean EF% of patients

with systolic dysfunction was lower(40.1 ± 6.7 vs 58.9 ± 4.5;P< 0.001) compared

with the patient group with myocardial dysfunction. Upon comparing the clinical

characteristics of this group with patients with normal myocardial function,it was

Table 7: Clinical and physiologic characteristics of Septic patients with

Normal MF vs LV SD

Characteristic

Normal MF

(n = 39)

LV SD

(n = 29) t P

Age (Yrs) 48.5 ± 5.7 49.5 ± 4.7 0.82 0.42

Sex n(%)

M: 29(74%) M: 15(52%)

X ² = 3.73 0.05 F : 10(26%) F: 14(48.3%)

HTN, n(%) 26(67%) 29(100%) 11.95 0.001

SOFA 8.4 ± 5.7 8.9 ± 5.2 0.42 0.67

MAP 62.9 ± 3.8 60.5 ± 3.2 2.81 0.006

HR 122.5 ± 13.5 123.7 ± 14.8 0.32 0.75

M.Vent used, n(%) 9(23%) 22(76%) X 2

= 18.68 0.001

PaO2/FiO2 3.8 ± 1.3 2.9 ± 1.0 3.27 0.002

GHb% 7.2 ± 1.6 7.9 ± 2.0 1.55 0.13

Sr.Creatinine 1.68 ± 1.05 1.91 0.87 0.96 0.34

Lactate 2.9 ± 3.1 4.8 ± 4.3 2.10 0.04

Ph 7.4 ± 0.1 7.3 ± 0.2 1.92 0.06

HCT 44.7 ± 4.4 43.6 ± 4.4 1.02 0.31

VASOPRESSOR DAYS 4.1 ± 2.9 5.4 ± 1.8 2.00 0.05

WBC 16180 ± 6939 15824 ± 8665 0.19 0.85

LVIDd 4.3 ± 0.6 4.5 ± 0.5 1.61 0.11

LVIDs 2.95 ± 0.48 3.00 ± 0.51 0.35 0.73

E/A 1.27 ± 9.23 1.07 ± 0.22 3.61 0.001

EF% 58.9 ± 4.5 40.1 ± 6.7 14.27 0.001

65

noted that the LV systolic dysfunction group had a higher median (IQR) lactate level

(4.8 ± 4.3 vs 2.9 ± 3.1] mmol/L; P.04)and lower mean SD arterial blood pressure

(60.5 ± 3.2 vs 62.9 ± 3.8 mm Hg; P0.006)(Table 3). Both groups had similar numbers

of patients receiving vasoactive medications and homogeneous fluid administration,

but patients in the LV systolic dysfunction group had higher median (IQR) duration of

norepinephrine (5.4 ± 1.8 vs 4.1 ± 2.9 days; P0.05) (Table 3).This group had lower

PaO2/FiO2 ratio(2.9 ± 1.0 vs 3.8 ± 1.3;P0.002) and required mechanical

ventilation(76% vs 23%;P< 0.001) when compared to patients with normal

myocardial function.

0

10

20

30

40

50

60

Normal MF LVDD

58.9

40.1

EF

%

Graph 4: EF% in normal myocardial function vs LV

systolic dysfunction

66

Within the group of LV systolic dysfunction patients, 13 patients (44.8%) had mild,

13 (44.8%) had moderate, and 3 (10.3%) had severe LV systolic dysfunction.

0.0

10.0

20.0

30.0

40.0

50.0

Mild Moderate Severe

44.8 44.8

10.3 % o

f cases

Graph 5: Severity Of LV Systolic Dysfunction

67

LV Diastolic Dysfunction

Left ventricular diastolic dysfunction was present in 42 patients (42%). 19 patients

had isolated diastolic dysfunction, representing 19% of the entire cohort. Compared

Table 8: Clinical and physiologic characteristics of Septic patients with

Normal MF vs LV DD

Marker

Normal MF

(n = 39)

LV DD

(n = 42) t P

Age (Yrs) 48.5 ± 5.7 48.7±4.4 0.18 0.86

Sex, n(%)

M: 29(74%) M: 27(64%)

X ² = 0.96 0.33 F : 10(26%) F : 15(36%)

HTN, n(%) 26(67%) 34(81%) X 2

= 2.15 0.14

SOFA 8.4 ± 5.7 9.4 ± 5.8 0.84 0.41

MAP 62.9 ± 3.3 61.4 ± 4.1 1.71 0.09

HR 122.5 ± 13.5 126.4 ± 15.2 1.20 0.23

M.Vent used, n(%) 9(23%) 20(48%) X 2

= 5.30 0.02

PaO2/FiO2 3.8 ± 1.3 3.3 ± 1.2 1.86 0.07

GHb% 7.2 ± 1.6 8.3 ± 1.7 2.89 0.005

Sr.Creatinine 1.68 ± 1.05 1.61 ± 0.73 0.32 0.75

Lactate 2.9 ± 3.1 4.3 ± 4.0 1.82 0.07

Ph 7.4 ± 0.1 7.3 ± 0.1 1.29 0.20

HCT 44.7 ± 4.4 43.7 ± 3.0 1.22 0.23

VASOPRESSOR DAYS 4.1 ± 2.9 5.3 ± 2.5 1.63 0.11

WBC 16180 ± 6939 16077 ± 7723 0.06 0.95

LVIDd 4.25 ± 0.60 4.61 ± 0.61 2.68 0.009

LVIDs 2.95 ± 0.48 3.08 ± 0.56 1.10 0.28

E/A 1.27 ± 0.23 0.96 ± 0.09 7.67 0.001

EF% 58.9 ± 4.5 40.1± 6.2 4.03 0.001

68

with patients with normal myocardial function, patients with LV diastolic dysfunction

had lower ejection fraction(40.1± 6.2 vs 58.9 ± 4.5;P<0.001) and dilated LV(4.61 ±

0.61 vs 4.25 ±0.60;P.009) as shown in Table 2. Most physiologic characteristics were

similar between groups, including vasoactive medication use, norepinephrine dose

and fluid administered. However, hemoglobin concentration was lower in those with

normal myocardial function (7.2 ± 1.6 vs 8.3 ± 1.7 g/dL; P.005) (Table 2).

Among the patient groups, the mean E/A ratio was lower in patients with LV diastolic

dysfunction(0.96 ± 0.09 vs 1.27 ± 0.23;P.005)

1.27

7.2

4.25

0.96

8.3

4.61

0.0

2.3

4.5

6.8

9.0

E/A GHb% LVIDd

Me

an

va

lue

Graph 6: Clinical and physiologic characteristics of Septic

patients withNormal MF vs LV DD

Normal MF LVDD

69

Table 9: Clinical and physiologic characteristics of Septic patients with

Normal MF vs RV dysfunction

Characteristic

Normal MF

(n = 39)

RV dysfunction

(n = 27 ) t P

Age (Yrs) 48.5 ± 5.7 50.4 ± 3.6 1.61 0.11

Sex n(%)

M: 29(74%) M: 14(52%)

X ² = 3.56 0.06 F : 10(26%) F: 13(48%)

HTN, n(%) 26(67%) 23(85%) X 2

= 2.86 0.09

SOFA 8.4 ± 5.7 8.7 ± 5.3 0.27 0.79

MAP 62.9 ± 3.8 60.9 ± 3.6 2.19 0.03

HR 122.5 ± 13.5 123.9 ± 14.7 0.37 0.71

M.Vent used, n(%) 9(23%) 16(59) X 2

= 8.88 0.003

PaO2/FiO2 3.8 ± 1.3 3.1 ± 1.0 2.27 0.03

GHb% 7.2 ± 1.6 8.2 ± 2.0 2.33 0.02

Sr.Creatinine 1.68 ± 1.05 1.72 ± 0.77 0.15 0.88

Lactate 2.9 ± 3.1 4.0 ± 4.3 1.22 0.23

Ph 7.4 ± 0.1 7.3 ± 0.2 1.53 0.13

HCT 44.7 ± 4.4 45.1 ± 4.4 0.38 0.71

VASOPRESSOR DAYS 4.1 ± 2.9 5.4 ± 1.8 1.82 0.08

WBC 16180 ± 6939 14895 ± 8280 0.68 0.50

LVIDd 4.3 ± 0.6 4.5 ± 0.4 1.96 0.05

LVIDs 2.95 ± 0.48 3.11 ± 0.48 1.29 0.20

E/A 1.27 ± 0.23 1.16 ± 0.27 1.72 0.09

EF% 58.9 ± 4.8 49.8 ± 11.5 3.91 0.001

70

RV Dysfunction:

27 patients (27%) had evidence of RV dysfunction. 6 patients had isolated RV

dysfunction, representing 6% of all patients. The rest had concomitant LV diastolic

and/or systolic dysfunction (Figure 18). There was no statistically significant

difference in clinical or hemodynamic characteristics when this group was compared

with patients with normal myocardial function, except for lower ejection fraction(49.8

± 58.9 ± 4.8%; P<.001), lower mean arterial pressure(60.9 ± 3.6 vs 62.9 ± 3.8 mmHg;

P.03) and higher hemoglobin level (8.2 ± 2.0 vs 07.2 ± 1.6 gm%; P.02) in patients

with RV dysfunction. Mean LV diameter(4.5 ± 0.4 vs 4.3 ± 0.6cm; P.05) was also

higher in the RV dysfunction group compared with patients with normal myocardial

function.

2.95

7.2

3.8

3.11

8.2

3.1

0.0

2.3

4.5

6.8

9.0

LVIDs GHb% PaO2/FiO2

Mean

valu

e

Graph 7: Clinical and physiologic characteristics of Septic

patients with Normal MF vs RV dysfunction

Normal MF RVD

71

Within the group of patients with RV dysfunction, 15 (55.6%) had mild, 9 (33.3%)

had moderate, and 3 (11.1%) had severe RV dysfunction.

Mild 15

(55.6%)

Moderate 9

(33.3%)

Severe 2

(7.4%)

Normal 1

(3.7%)

Graph 8 : Severity of RV dysfunction

Table 10: Severity of RV dysfunction

TAPSE for RV No.of cases %

Mild 15 55.6

Moderate 9 33.3

Severe 3 11.1

Total 27 100.0

72

Table 11: Physiologic and Echocardiographic markers in

surviors and non-surviors

Marker Surviors(n = 78) Nonsurviors (n = 22) t P

Age (Yrs) 49.3±4.5 47.3±5.9 1.32 0.19

SOFA 6.0±2.1 18.3±2.5 23.51 0.001

MAP 63.3±2.3 56.5±3.3 10.89 0.001

GHb% 7.6±1.7 8.5±2.0 2.07 0.001

Lactate 1.86±1.42 9.65±2.52 18.83 0.001

PaO2/FiO2 3.72±1.10 2.43±0.68 5.20 0.001

Sr.Creatinine 1.41±0.68 2.57±0.90 6.55 0.001

HCT 44.2±3.9 44.8±4.2 0.57 0.56

Ph 7.4±0.1 7.2±0.1 12.36 0.001

WBC 15789±5646 15938±11792 0.08 0.93

VASOPRESSOR

DAYS 3.6±1.7 7.9±1.1 11.24 0.001

M.Vent used,

n(%) 18(23%) 22(100%)

X 2

=

42.31 0.001

LVIDd 4.45±0.56 4.39±0.62 0.41 0.68

LVIDs 3.04±0.54 3.05±0.42 0.13 0.90

E/A 1.13±0.25 1.14±0.23 0.13 0.90

EF% 53.9±9.7 51.9±11.4 0.82 0.41

HTN, n(%) 56(72%) 22(100%)

X 2

=

7.66 0.005

73

Non- survivors and Survivors:

In the present study, the patients who did not survive were 22 at the end of 1

week.When clinical and physiological characteristics of the survivors and non-

survivors were compared the non-survivor group had bigger SOFA score(18.3±2.5 vs

6.0±2.1;P<.05), higher lactate levels(9.65±2.52 vs 1.86±1.42 mmol/L;P<.05), higher

serum creatinine levels(2.57±0.90 vs 1.41±0.68 mg/dL;P<0.001) and higher levels of

hemoglobin(8.5±2.0 vs 7.6±1.7 gm%;P0.04).The non-survivors group had lower

mean arterial pressure(56.5±3.3 vs 63.3±2.3 mm Hg;P<.05), lower PaO2/FiO2

(2.43±0.68 vs 3.72±1.10;P>.05), more acidic Ph(7.2±0.1 vs 7.4±0.1;P<.05), and there

was no statistical difference in LV diameters, ejection fraction and E/A

ratio.However, the non-survivor required vasopressor support for longer

duration(7.9±1.1 vs 3.6±1.7;P<.05) and 100% the patients required mechanical

ventilation.

6

2

8

4

3

18

10 9

4

3

0

5

10

15

20

SOFA Lactate GHb% LVIDd LVIDs

Me

an

va

lue

Graph 9 :Physiologic and Echocardiographic markers in

Survivors and Non-survivors

Surviors NonSurvivors

74

Table 12: Cardiac Function in Non-survivor group

Dysfunction No.of cases Non survivors %

CardDysFn 61 14 23.0

NormalMyFn 39 8 20.5

Total 100 22 22.0

X² = 0.08, P = 0.77, ns

Among the group of non-survivors, it was observed that cardiac dysfunction was seen

in 14 patients and 8 patients had normal cardiac function.23% of the cardiac

dysfunction patients did not survive at the end of first week.

4.0

8.0

12.0

16.0

20.0

24.0

28.0

CardDysFn NormalMyFn Total

23.0

20.5 22.0

% o

f n

on

su

rviv

als

Graph 10: Cardiac Function in Non-survivor

group

75

Table 13A: Distribution of Cardiac dysfunction in Non-survivors

Dysfunction No.of cases Non survivors %

LV DD 42 11 26.2

LV SD 29 8 27.6

RVD 27 6 22.2

Normal 39 8 20.5

Table 13B: Distribution of Cardiac dysfunction in Non-survivors

Dysfunction No.of cases Non survivors %

Only DD 19 4 21.1

Only SD 3 0 0.0

Only RV 6 1 16.7

DD & SD 12 4 33.3

DD & RV 7 1 14.3

SD & RV 10 2 20.0

DD & SD & RV 4 2 50.0

Normal 39 8 20.5

Total 100 22 22.0

76

In the present study, among the non-survivor group it was noted that 4 patients had

only LV diastolic dysfunction, 1 patient had only RV dysfunction, 4 patients had LV

diastolic dysfunction and LV systolic dysfunction, 1 patient had LV diastolic

dysfunction and RV dysfunction, 2 patients had LV systolic dysfunction and RV

dysfunction and 2 patients had LV diastolic dysfunction, LV systolic dysfunction and

RV dysfunction; there was no patient with isolated LV systolic dysfunction.

0.0

5.0

10.0

15.0

20.0

25.0

30.0

LV DD LV SD RVD Normal

26.2 27.6

22.2 20.5

Graph 11: Cardiac dysfunction in Non-survivors

77

Table 14: Change in LV function in patients with cardiac dysfunction

LV function No.of cases %

NO IMPR 1 1.0

IMPR 9 9.0

SAME 32 70.0

NORMAL 19 20.0

Total 61 100.0

Out of the 61 patients of LV systolic dysfunction, LVEF in 19 patients had complete

normalisation of function, improved in 9, remained same in 32 and did not improve in

1 patient.

0

5

10

15

20

25

30

35

NO IMPR IMPR SAME NORMAL

1.0

9.0

32.0

19.0

% o

f cases

Graph 12 : Change in LV function in patients with

cardiac dysfunction

78

Table 15: Reversibility of Myocardial Dysfunction

Reversibility No.of cases %

Yes 28 45.9

No 33 54.1

Total 61 100.0

Out of 61 patients of LV systolic dysfunction, reversibility of cardiac function seen in

45.9% patients.

Yes

28

(45.9)%

No

33

(54.1%)

Graph 13: Reversibility of Myocardial

Dysfunction

79

DISCUSSION

We found that myocardial dysfunction is common in severe sepsis and septic

shock, affecting 61% of patients. With standard echocardiography, these

abnormalities can be further divided into LV dia- stolic (42% of all patients), LV

systolic (29%), and RV dysfunction (27%), which demonstrates the importance of

going beyond LVEF when categorising myocardial dysfunction in sepsis. There was

significant overlap between the different types, as well as a wide range of severity

within the groups (Figure 13).Survivors had larger and proportional LV end-diastolic

diameter (44.5mm±0.56 vs 44.39mm±0.62; P0.68) and non-survivors had larger LV

end-systolic diameter (30.4±0.54 vs 30.5±0.42 mm; P0.90) at the time of

presentation, with resultant mean LVEF being more in survivors(53.9%±9.7 vs

51.9%±11.4; P0.41). This observation of reversible compensatory LV dilatation has

been described previously,126, 127 suggesting that LV diameters and volumes could

be better markers of prognosis than LVEF. Arguably, this difference could be

secondary to discrepancies in resuscitation and loading conditions; patients having

less aggressive fluid resuscitation could demonstrate lower ventricular volumes,

which could translate to poorer prognosis. Nonetheless, we did not find significant

differences in fluid administration between survivors and nonsurvivors or between the

groups(Table 11).

Parker et al. suggested a huge increase in LV compliance; they found a dilatation of

the left ventricle of more than 100%82. Most studies using echocardiography only

report a slight increase in LV size in patients with decreased LV ejection fraction

compared with patients with preserved ejection fraction, suggesting a true but slight

increase in LV compliance in these patients.

80

LV Diastolic Dysfunction

Left ventricular diastolic dysfunction is frequent in severe sepsis and septic shock and

can complicate hemodynamic management because of a lower therapeutic index for

fluid resuscitation. We found that 42% of patients had diastolic dysfunction. Because

all patients with coronary artery disease had a recent echocardiogram showing normal

diastolic function, sepsis likely represents a significant stressor that can unmask

and/or precipitate diastolic heart failure. Moreover, because fluid resuscitation is the

back-bone of hemodynamic management in patients with sepsis, the presence of

diastolic dysfunction should alert the caregiver to have a more conservative approach

during resuscitation. Diastolic dysfunction should be considered a variant of

myocardial dysfunction in sepsis, given that a sizeable proportion of these patients

(19%) have preserved LVEF and RV function. The A/E ratio used in our study

showed that there was no statistical difference in A/E= (1.13±0.25 vs 1.14±0.23;

End-diastolic size of the left ventricle according to the ejection fraction

Decreased LVEF Preserved LVEF

Parker et al. [1] 20 patients, PAC LVEDV 159 ± 29 mL/m2 81 ± 9 mL/m

2 *

Jardin et al. [2] 21 patients, TTE LVEDV 76 ± 18 mL/m2 70 ± 20 mL/m

2

Jardin et al. [15] 90 patients, TTE LVEDV 80 ± 21 mL/m2 62 ± 15 mL/m

2 *

Vieillard-Baron et al. [25] 67 patients, TEE LVEDV 76 ± 24 mL/m2 68 ± 24 mL/m

2

Bouhemad et al. [16] 45 patients, TEE LVEDA 13 ± 3 cm2/m

2 11 ± 2 cm

2/m

2 *

81

P0.90) between survivors and non-survivors.

LV Systolic Dysfunction

Although often referred as the “classic” myocardial dysfunction in sepsis, isolated LV

systolic dysfunction was found in only 3% of our patients, and concomitant LV

diastolic and RV dysfunction was a more common scenario. As mentioned before,

LVEF was not statistically significant in survivors than in non-survivors(53.9±9.7 vs

51.9±11.4,P0.41) despite the greater LV diameters in survivors at the time of

presentation. These findings, along with the relatively high frequency of diastolic and

RV function abnormalities, beg the question of appropriateness of the current

definition of myocardial dysfunction in sepsis.

Parker et al.29 showed, using radionuclide cineangiography, that survivors of septic

shock demonstrated a decreased left ventricular ejection fraction (LVEF) and an

acutely dilated left ventricle, as evidenced by an increased left ventricular end-

diastolic volume index (LVEDVI) .The reported incidence of LV systolic dysfunction

varies significantly.

Our study also showed that LV contractility improved with patients recovering from

sepsis, as shown by improvement in LV ejection fraction, observed by repeat

transthoracic echocardiography, which was done either on discharge from ICU or on

day 5, similar results were also shown by Parker et al.29

82

RV Dysfunction

The adaptation of the RV to sepsis is complex, and the presence of positive pressure

ventilation complicates further its objective evaluation. Because of the known

sensitivity of the RV to changes in pulmonary vascular resistance induced by a variety

of factors, including mechanical ventilation, positive end-expiratory pressure,

hypoxemia, acidosis, and vasoactive medications, we compared these physiologic

parameters within all groups and found RV dysfunction had lower mean arterial

pressures and concurrently lower ejection fraction, also LV diameter were higher in

RV dysfunction group, all of these parameters being statistical significant when

compared with patients with normal myocardial function (Table 9).Although there

Incidence of LV systolic dysfunction in septic shock according to the time of evaluation

Time of study/admission

Incidence of LV systolic

dysfunction

Parker et al. [1] PAC + radionuclide

cineangiography Day 1 65%

Jardin et al. [2] TTE 0-6 hours 29%

Vieillard-Baron et al. [20] TEE 0-6 hours 18%

Vieillard-Baron et al. [25] TEE Day 1, 2, 3 60%

Bouhemad et al. [16] TEE ? 20%

Etchecopar-Chevreuil et al. [22]

TEE 12 hours 46%

PAC, pulmonary artery catheter; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography.

83

was no difference in early mortality, patients with RV dysfunction had lower ejection

fraction, longer duration of norepinephrine, and higher lactate levels compared with

patients with normal myocardial function, suggesting greater severity of illness.

Vincent et al. in a group of 93 patients with septic shock reported a decreased RV

ejection fraction compared with a “control” group 98. Similar results were found by

Kimchi et al. and Parker et al. 99,100. Using transesophageal echocardiography,

Antoine Vieillard-Baron reported that almost 30% of patients have RV dilatation,

which is highly suggestive of significant RV dysfunction.

Kimchi et al37 noticed a lack of correlation between right atrial pressure and right

ventricular end-diastolic volume, suggesting altered right ventricular compliance.

Schneider et al.38 similarly identified a sub- group of patients who failed to exhibit an

increased right ventricular end-diastolic volume index in response to volume loading,

despite a rise in CVP

84

LIMITATIONS:

Because of the dynamic nature of sepsis, variability in host response, and underlying

disease, as well as the complex interaction between the cardiovascular and respiratory

systems, the evaluation of myocardial dysfunction is limited to isolated “snapshots” in

time during the disease process and treatment. Furthermore, the variability in time

from initial presentation to echocardiogram, discrepancies in resuscitation, and

difference in vasoactive medication dose could alter echocardiographic measurements

and therefore the results. This could contribute to different echocardiographic results

in a single patient over time and variation in study results. Despite the current

challenges in critical care research, we had a somewhat homogeneous practice in

resuscitation during septic shock, and there was no difference in fluid administration.

Because of the variability in practice, we cannot ensure that patients were enrolled at

similar times during their disease process. Furthermore, our sample size was not large

enough to provide definite conclusions about mortality. Despite these limitations, this

study provides the general spectrum of myocardial dysfunction in severe sepsis and

septic shock. A more definitive larger trial is needed to confirm these findings and to

establish if indexed or non- indexed dimensions should be used in clinical context.

85

CONCLUSION

Myocardial dysfunction is frequent in patients with severe sepsis and septic

shock and presents in a wide spectrum including LV diastolic, LV systolic, and/or RV

dysfunction. Decreased LVEF as the sole criterion for diagnosis of myocardial

dysfunction in sepsis is inaccurate and misleading. Despite these findings,

echocardiography is a useful tool to diagnose and categorise the type of myocardial

dysfunction in sepsis and may aid in the management of these patients. Our findings

question the appropriateness of the current definitions of this entity and advocate for

the addition of these variants to more accurately describe cardiac dysfunction during

sepsis beyond LVEF because this marker lacks prognostic value.

86

Suggestions at the end of present study:

1. Echocardiography is simple non invasive, reproducible, cost effective and can

be carried out at all centers as bed side investigation.

2. It is a very valuable diagnostic tool in detecting myocardial dysfunction and

preventing catastrophic events.

3. Myocardial dysfunction is not limited to decreased LVEF alone, and LV

diastolic and RV dysfunction also should be looked for in patients with

severe sepsis.

4. Fluid resuscitation is the back-bone of hemodynamic management in patients

with sepsis, the presence of diastolic dysfunction should alert the

caregiver to have a more conservative approach during resuscitation.

5. Need for consideration of other factors like LV dilation as markers of

prognosis rather than LVEF alone.

87

SUMMARY

Myocardial dysfunction frequently accompanies severe sepsis and septic

shock. Whereas myocardial depression was previously considered a

preterminal event, it is now clear that cardiac dysfunction as evidenced by

biventricular dilatation and reduced ejection fraction is present in most

patients with severe sepsis and septic shock.

Myocardial depression exists despite a fluid resuscitation-dependent

hyperdynamic state that typically persists in septic shock patients until death

or recovery.

Myocardial dysfunction can be recognised in patients at much early stage by

doppler echocardiography which is simple, non- invasive, economical,

available at all centers and can even be done as a bed side investigation.

In our study, we have delineated the spectrum of myocardial dysfunction and

established the frequency with which dysfunction occurs as shown previously

by other studies.

Thus,with the use of bedside echocardiography for early detection of

myocardial dysfunction and appropriate guided resuscitation, catastrophic

events could be avoided.

88

BIBLIOGRAPHY

1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM,

Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of

innovative therapies in sepsis. Chest 1992, 101:1644-1655.

2. Van der Poll T, Van Deventer JH: Cytokines and anticytokines in the

pathogenesis of sepsis. Infect Dis Clin North Am 1999, 13:413-426.

3. Flierl MA, Rittirsch D, Huber-Lang MS, Sarma JV, Ward PA. Molecular events

in the cardiomyopathy of sepsis. Mol Med. 2008;14(5-6):327-336.

4. Hochstadt A, Meroz Y, Landesberg G. Myocardial dysfunction

in severe sepsis and septic shock: more questions than an-

swers? J Cardiothorac Vasc Anesth. 2011;25(3):526-535.

5. Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS

Interna- tional Sepsis Definitions Conference. Crit Care Med 31: 1250, 2003.

[PMID: 12682500]

6. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP: The

natural history of the systemic inflammatory response syndrome (SIRS). A

prospective study. JAMA 273: 117, 1995. [PMID: 7799491]

7. Angus DC, van der Poll T: Severe sepsis and septic shock. N Engl J Med 369:

840, 2013. [PMID: 23984731]

8. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J

Med 348: 138, 2003. [PMID: 12519925]

89

9. TrzeciakS,McCoyJV,DellingerRP,etal:Earlyincreasesinmicrocirculatoryperfusio

n during protocol-directed resuscitation are associated with reduced multi-organ

failure at 24 hours in patients with sepsis. Intensive Care Med 34: 2210, 2008.

[PMID: 18594793]

10. Zhang Q, Raoof M, Chen Y, et al: Circulating mitochondrial DAMPs cause

inflammatory responses to injury. Nature 464: 104, 2010. [PMID: 20203610]

11. Jones A, Tayal V, Sullivan D, Kline J: Randomized controlled trial of immediate

versus delayed goal-directed ultrasound to identify the cause of non traumatic

hypotension in emergency department patients. Crit Care Med 32: 1703, 2004.

[PMID: 15286547]

12. Romero-Bermejo FJ, Ruiz-Bailen M, Gil-Cebrian J, Huertos-Randchal MJ:

Sepsis- induced cardiomyopathy. Curr Cardiol Rev 7: 163, 2011. [PMID:

22758615]

13. The ARDS Definition Task Force: Acute respiratory distress syndrome: the

Berlin Definition. JAMA 307: 2526, 2012. [PMID: 22797452]

14. Sharma B, Sharma M, Majumder M, Steier W, Sangal A, Kalawar M:

Thrombocytopenia in septic shock patients: a prospective observational study of

incidence, risk factors and correlation with clinical outcome. Anaesth Intensive

Care 35: 874, 2007. [PMID: 18084977]

15. Vincent JL, Yagushi A, Pradier O: Platelet function in sepsis. Crit Care Med 30:

S313, 2002. [PMID: 12004253]

90

16. Schuetz P, Kennedy M, Lucas JM, et al: Initial management and outcomes of

patients with hyperglycemia and suspected sepsis in the non-critical care

inpatient setting. Am J Med 125: 670, 2012. [PMID: 22608986]

17. Annane D, Bellissant E, Bollaert PE, et al: Corticosteroids in the treatment of

severe sepsis and septic shock in adults: a systematic review. JAMA 301: 2362,

2009. [PMID: 19509383]

18. MacLean LD, Mulligan WG, McLean APH, Duff JH: Patterns of septic shock in

man: a detailed study of 56 patients. Ann Surg 1967, 166:543-562.

19. Clowes GHA, Vucinic M, Weidner MG. Circulatory and meta- bolic alterations

associated with survival or death in peritoni- tis. Ann Surg 1966, 163:844-866.

20. Nishijima H, Weil MH, Shubin H, Cavanilles J: Hemodynamic and metabolic

studies on shock associated with gram-negative bacteremia. Medicine

(Baltimore) 1973, 52:287-294.

21. Weil MH, Nishijima H. Cardiac output in bacterial shock. Am J Med 1978,

64:920-922.

22. Blain CM, Anderson TO, Pietras RJ, Gunnar RM: Immediate hemodynamic

effects of gram-negative vs gram-positive bac- teremia in man. Arch Intern Med

1970, 126:260-265.

23. Packman MI, Rackow EC: Optimum left heart filling pressure during fluid

resuscitation of patients with hypovolemic and septic shock. Crit Care Med

1983, 11:165-169.

91

24. Winslow EJ, Loeb HS, Rahimtoola SH, Kamath S, Gunnar RM: Hemodynamic

studies and results of therapy in 50 patients with bacteremic shock. Am J Med

1973, 54:421-432.

25. Krausz MM, Perel A, Eimerl D, Cotev S: Cardiopulmonary effects of volume

loading in patients with septic shock. Ann Surg 1977, 185:429-434.

26. Parker SM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE:

Serial cardiovascular variables in survivors and non-survivors of human septic

shock: heart rate as an early predictor of prognosis. Crit Care Med 1987, 15:923-

929.

27. Parker MM, Suffredini AF, Natanson C, Ognibene FP, Shelhamer JH, Parrillo

JE: Responses of left ventricular function in sur- vivors and non-survivors of

septic shock. J Crit Care 1989, 4:19-25.

28. Weisel RD, Vito L, Dennis RC, Hechtman HB: Myocardial depression during

sepsis. Am J Surg 1977, 133:512-521.

29. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson

C, Frederick TM, Damske BA, Parrillo JE: Profound but reversible myocardial

depression in patients with septic shock. Ann Intern Med 1984, 100:483-490.

30. Ognibene FP, Parker MM, Natanson C, Shelhamer JH, Parrillo JE:

Depressed left ventricular performance. Response to volume infusion in patients

with sepsis and septic shock. Chest 1988, 93:903-910.

92

31. Ellrodt AG, Riedinger MS, Kimchi A, Berman DS, Maddahi J, Swan HJC,

Murata GH: Left ventricular performance in septic shock: reversible segmental

and global abnormalities. Am Heart J 1985, 110:402-409.

32. Raper RF, Sibbald WJ, Driedger AA, Gerow K: Relative myocar- dial

depression in normotensive sepsis. J Crit Care 1989, 4:9- 18.

33. Jafri SM, Lavine S, Field BE, Thill-Baharozian MC, Carlson RW:

Left ventricular diastolic function in sepsis. Crit Care Med 1991, 18:709-714.

34. Munt B, Jue J, Gin K, Fenwick J, Tweeddale M: Diastolic filling in

human severe sepsis: an echocardiographic study. Crit Care

Med 1998, 26:1829-1833.

35. Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA: Left

ventricular systolic and diastolic function in septic shock.

Intensive Care Med 1997, 23:553-560.

36. Sibbald WJ, Paterson NAM, Holliday RL, Anderson RA, Lobb TR,

Duff JH: Pulmonary hypertension in sepsis: measurement by the pulmonary

artery diastolic-pulmonary wedge pressure gradient and the influence of passive

and active factors. Chest 1978, 73:583-591.

37. Kimchi A, Ellrodt GA, Berman DS, Murata GH, Riedinger MS, Swan HJC,

Murata GH: Right ventricular performance in septic shock: a combined

radionuclide and hemodynamic study. J Am Coll Cardiol 1984, 4:945-951.

38. Schneider AJ, Teule GJJ, Groenveld ABJ, Nauta J, Heidendal GAK, Thijs LG:

Biventricular performance during volume loading in patients with early septic

93

shock, with emphasis on the right ventricle: a combined hemodynamic and

radionu- clide study. Am Heart J 1988, 116:103-112.

39. Parker MM, McCarthy KE, Ognibene FP, Parrillo JE: Right ventricular

dysfunction and dilatation, similar to left ventricular changes, characterize the

cardiac depression of septic shock in humans. Chest 1990, 97:126-131.

40. Vincent JL, Reuse C, Frank N, Contempre B, Kahn RJ: Right ventricular

dysfunction in septic shock: assessment by measurements of right ventricular

ejection fraction using the thermodilution technique. Acta Anaesthesiol Scand

1989, 33: 34-38.

41. Baumgartner J, Vaney C, Perret C: An extreme form of hyper- dynamic

syndrome in septic shock. Intensive Care Med 1984, 10:245-249.

42. Groeneveld ABJ, Nauta JJ, Thijs L: Peripheral vascular resis- tance in septic

shock: its relation to outcome. Intensive Care Med 1988, 14:141-147.

43. Rhodes A, Lamb FJ, Malagon R, Newman PJ, Grounds M, Bennett D: A

prospective study of the use of a dobutamine stress test to identify outcome in

patients with sepsis, severe sepsis or septic shock. Crit Care Med 1999, 27:2361-

2366.

44. Schupp E, Kumar A, Bunnell E, Uretz E, Calvin J, Ali A, Parrillo JE: The

cardiovascular response to incremental doses of dobuta- mine in septic shock:

prediction of survival [abstract]. Crit Care Med 1994, 22:A109.

45. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE: The coronary

circulation in human septic shock. Circulation 1986, 73:637-644.

94

46. Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall'Ava- Santucci J,

Brunet F, Villemant D, Carli A, Raichvarg D: Coronary hemodynamics and

myocardial metabolism of lactate, free fatty acids, glucose and ketones in

patients with septic shock. Circulation 1987, 75:533-541.

47. Solomon MA, Correa R, Alexander HR, Koev LA, Cobb JP, Kim DK, Roberts

WC, Quezado ZMN, Schotz TD, Cunnion RE, Hoffman WD, Bacher J, Yatsiv I,

Danner RL, Banks SM, Ferrans VJ, Balaban RS, Natanson C: Myocardial energy

metabolism and morphology in a canine model of sepsis. Am J Physiol 1994,

266:H757-H768.

48. Turner A, Tsamitros M, Bellomo R: Myocardial cell injury in septic shock. Crit

Care Med 1999, 27:1775-1780.

49. Wiggers CJ: Myocardial depression in shock. A survey of car- diodynamic

studies. Am Heart J 1947, 33:633-650.

50. Lefer AM: Mechanisms of cardiodepression in endotoxin shock. Circ Shock

1979, 1(suppl):1-8

51. Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W: A

circulating myocardial depressant substance in humans with septic shock. Septic

shock patients with a reduced ejection fraction have a circulating factor that

depresses in vitro myocardial cell performance. J Clin Invest 1985, 76:1539-

1553.

52. Reilly JM, Cunnion RE, Burch-Whitman C, Parker MM, Shelhamer JH, Parrillo

JE: A circulating myocardial depressant substance is associated with cardiac

95

dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with

septic shock. Chest 1989, 95:1072-1080.

53. Cunnion RE, Parrillo JE: Myocardial dysfunction in sepsis. Recent insights.

Chest 1989, 95:941-945.

54. Seckinger P, Vey E, Turcatti G, Wingfield P, Dayer J: Tumor necrosis factor

inhibitor: purification, NH2-terminal amino acid sequence and evidence for anti-

inflammatory and immunomodulatory activities. Eur J Immunol 1990, 20:1167-

1174.

55. Eichacker PQ, Hoffman WD, Farese A, Banks SM, Kuo GC, MacVittie TJ,

Natanson C: TNF but not IL-1 in dogs causes lethal lung injury and multiple

organ dysfunction similar to human sepsis. J Appl Physiol 1991, 71:1979-1989.

56. Eichenholz PW, Eichacker PQ, Hoffman WD, Banks SM, Parrillo JE, Danner

RL, Natanson C: Tumor necrosis factor challenges in canines: patterns of

cardiovascular dysfunction. Am J Physiol 1992, 263:H668-H675.

57. van der Poll T, van Deventer SJ, Hack CE, Wolbink GJ, Aarden LA, Buller HR,

ten Cate H: Effects on leukocytes following injection of tumor necrosis factor

into healthy humans. Blood 1992, 79:693-698.

58. van der Poll T, Romjin JA, Endert E, Borm JJ, Buller HR, Sauerwein HP: Tumor

necrosis factor mimics the metabolic response to acute infection in healthy

humans. Am J Physiol 1991, 261:E457-E465.

96

59. Gu M, Bose R, Bose D, Yang J, Li X, Light RB, Mink S: Tumor necrosis factor-

alpha but not septic plasma depresses cardiac myofilament contraction. Can J

Anesth 1998, 45:280- 286.

60. Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE: Tumor necrosis factor-

alpha and interleukin1-beta are responsible for depression of in vitro myocardial

cell contractility induced by serum from humans with septic shock. J Exp Med

1996, 183:949-958.

61. Finkel MS, Oddis CV, Jacobs TD, Watkins SC, Hattler BG, Simmons RL:

Negative inotropic effects of cytokines mediated by nitric oxide. Science 1992,

257:387-389.

62. Weisensee D, Bereiter-Hahn J, Low-Friedrich I: Effects of cytokines on the

contractility of cultured cardiac myocytes. Int J Immunopharmacol 1993,

15:581-587.

63. Vincent JL, Bakker J, Marecaux G, Schandene L, Kahn RJ, Dupont E:

Administration of anti-TNF antibody improves left ventricu- lar function in

septic shock patients: results of a pilot study. Chest 1992, 101:810-815

64. Hesse DG, Tracey KJ, Fong Y, Manogue KR, Palladinao MA, Cerami A, Shines

GT, Lowry SF: Cytokine appearance in human endotoxemia and primate

bacteremia. Surg Gynecol Obstet 1988, 166:147-153.

65. Gulick T, Chung MK, Pieper SJ, Lange LG, Schreiner GF: IL-1 and TNF inhibit

cardiac myocyte adrenergic responsiveness. Proc Natl Acad Sci 1989, 86:6753-

6757.

97

66. Hosenpud JD, Campbell SM, Mendelson DJ: Interleukin-1 induced myocardial

depression in an isolated beating heart preparation. J Heart Transplant 1989,

8:460-464.

67. Fisher CJJr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ,

Rackow EC, Shapiro MJ, Greenman RL, Reines HD, Shelly MP, Thompson

BW, LaBreque JF, Catalano MA, Knaus WA, Saddoff JC: Recombinant human

IL-1 receptor antagonist in the treatment of patients with the sepsis syndrome:

results from a randomized, double blind placebo controlled trial. JAMA 1994,

271:1836-1843.

68. Fisher CJ, Jr., Slotner GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D,

Bloedow DC, Catalano MA: Initial evalua- tion of human recombinant IL-1

receptor antagonist in the treatment of the sepsis syndrome; a randomized, open-

label, placebo-controlled multicenter trial. Crit Care Med 1994, 22: 12-21.

69. Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A, Harken

AH: Tumor necrosis factor-α and interleukin-1β syner- gistically depress human

myocardial function. Crit Care Med 1999, 27:1309-1318.

70. Walley KR, Hebert PC, Wakai Y, Wilcox PG, Road JD, Cooper DJ: Decrease in

left ventricular contractility after tumor necro- sis factor-α in infusion in dogs. J

Appl Physiol 1994, 76:1060- 1067.

71. DeMeules JE, Pigula FA, Mueller M, Raymond SJ, Gamelli RL: Tumor necrosis

factor and cardiac function. J Trauma 1992, 32:686-692.

98

72. Hare JM, Keaney JF, Balligand JL, Loscalzo J, Smith TW, Colucci WS: Role of

nitric oxide in parasympathetic modulation of beta-adrenergic myocardial

contractility in normal dogs. J Clin Invest 1995, 95:360-366.

73. Sawyer DB, Colucci WS: Nitric oxide in the failing myocardium. Cardiol Clin

North Am 1998, 16:657-664.

74. Balligand JL, Kobzik L, Han X, Kaye DM, Belhassen L, O’Hara DS, Kelly RA,

Smith TW, Michel T: NO-dependent parasympathetic signalling is due to the

activation of constitutive endothelial (type III) nitric oxide synthase in cardiac

myocytes. J Biol Chem 1995, 270:14582-14586.

75. Brady AJ, Warren JB, Poole-Wilson PA, Williams TJ, Harding SE:

Nitric oxide attenuates cardiac myocyte contraction. Am J

Physiol 1993, 265:H176-H182.

76. Paulus WJ, Vantrimpont PJ, Shah AM: Acute effects of nitric

oxide on left ventricular relaxation and diastolic distensibility in humans.

Assessment by bicoronary sodium nitroprussside infusion. Circulation 1994,

89:2070-2078.

77. Kumar A, Brar R, Wang P, Dee L, Skorupa G, Khadour F, Schulz R, Parillo JE:

The role of nitric oxide and cyclic GMP in human septic serum-induced

depression of cardiac myocyte contractility. Am J Physiol 1999, 276:R265-R276.

78. Rozanski GJ, Witt RC: IL-1 inhibits beta-adrenergic control of the cardiac

calcium current: role of L-arginine/nitric oxide pathway. Am J Physiol 1994,

267:H1753-H1758.

99

79. Smith JA, Radomski MW, Schulz R, Moncada S, Lewis MJ:

Porcine ventricular endocardial cells in culture express the inducible form of

nitric oxide synthase. Br J Pharmacol 1993, 108:1107-1110.

80. Kinugawa K, Takahashi T, Kohmoto O, Yao A, Aoyagi T, Mono- mura S, Hirata

Y, Serizawa T: Nitric oxide-mediated effects of IL-6 on [Ca2+]i and cell

contraction in cultured chick ventricu- lar myocytes. Circ Res 1994, 75:285-295.

81. Kumar A, Krieger A, Symeoneides S, Kumar A, Parrillo JE:

Myocardial dysfunction in septic shock: Part II. Role of cytokines and nitric

oxide. J Cardiothorac Vasc Anesth 2001, 15:485-511

82. Parker M, Shelhamer J, Bacharach S, Green M, Natanson C, Frederick T,

Damske B, Parrillo J: Profound but reversible myocardial depression in patients

with septic shock. Ann Intern Med 1984, 100: 483-490.

83. Jardin F, Brun-Ney D, Auvert B, Beauchet A, Bourdarias JP: Sepsis-related

cardiogenic shock. Crit Care Med 1990, 18: 1055-1060.

84. Natanson C, Danner RL, Elin RJ, Hosseini JM, Peart KW, Banks SM, MacVittie

TJ, Walker RI, Parrillo JE: Role of endotoxemia in cardiovascular dysfunction

and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine

model of human septic shock. J Clin Invest 1989, 83: 243-251.

85. Barraud D, Faivre V, Damy T, Welschbillig S, Gayat E, Heymes C, Payen D,

Shah A, Mebazaa A: Levosimendan restores both systolic and diastolic cardiac

performance in lipopolysaccharide-treated rabbits: comparison with dobutamine

and milrinone. Crit Care Med 2007, 35: 1376-1382.

100

86. Vieillard-Baron A, Prin S, Chergui K, Dubourg O, Jardin F: Hemodynamic

instability in sepsis. Bedside assessment by Doppler echocardiography. Am J

Respir Crit Care Med 2003, 168: 1270-1276.

87. Cunnion RE, Schaer GK, Parker MM, Natanson C, Parrillo JE: The coronary

circulation in human septic shock. Circulation 1986, 73: 637-644.

88. Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall’Avasantucci J,

Brunet F, Villemant D, Carli A, Raichvarg D: Coronary hemodynamics and

myocardial metabolism of lactate, free fatty acids, glucose, and ketones in

patients with septic shock. Circulation 1987, 75: 533-541.

89. Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W: A

circulating myocardial depressant substance in humans with septic shock. Septic

shock patients with a reduced ejection fraction have a circulating factor that

depresses in vitro myocardial cell performance. J Clin Invest 1985, 76: 1539-

1553.

90. Natanson C, Eichenholz PW, Danner RL, Eichacker PQ, Hoffman WD,

Kuo GC, Banks SM, MacVittie TJ, Parrillo JE: Endotoxin and tumor necrosis

factor challenges in dogs stimulate the cardiovascular profile of human septic

shock. J Exp Med 1989, 169: 823-832.

91. Hollenberg SM, Cunnion RE, Lawrence M: Tumor necrosis factor depress

myocardial cell function: results using an in vitro assay of myocyte performance.

Clin Res 1989, 37: 528-534.

92. Kumar A, Thota V, Dee L, Olson J, Parrillo JE: Tumor necrosis factor-alpha and

interleukin-1 beta are responsible for depression of in-vitro myocardial cell

101

contractility induced by serum from human septic shock. J Exp Med 1996, 183:

949-958.

93. Kumar A, Brar R, Wang P, Dee L, Skorupa G, Khadour F, Schulz R, Parrillo JE:

Role of nitric oxide and cGMP in human septic serum-induced depression of

cardiac myocyte contractility. Am J Physiol 1999, 276: R265-R276.

94. Levy RJ, Piel DA, Acton PD: Evidence of myocardial hibernation in the septic

heart. Crit Care Med 2005, 33: 2752-2756.

95. Tavernier B, Li JM, El-Omar MM, Lanone S, Yang ZK, Trayer IP, Mebazaa A,

Shah AM: Cardiac contractility impairment associated with increased

phosphorylation of troponin I in endotoxemic rats. Faseb J 2001, 15: 294-296.

96. Jardin F, Fourme T, Page B, Loubières Y, Vieillard-Baron A, Beauchet A,

Bourdarias JP: Persistent preload defect in severe sepsis despite fluid loading: a

longitudinal echocardiographic study in patients with septic shock. Chest 1999,

116: 1354-1359.

97. Bouhemad B, Nicolas-Robin A, Arbelot C, Arthaud M, Féger F, Rouby JJ:

Acute left ventricular dilatation and shock-induced myocardial

dysfunction. Crit Care Med 2009, 37: 441-447.

98. Vincent JL, Reuse C, Frank N, Contempré B, Kahn RJ: Right ventricular

dysfunction in septic shock: assessment by measurements of right ventricular

ejection fraction using thermodilution technique. Acta Anaesthesiol Scand 1989,

33: 34-38.

102

99. Kimchi A, Ellrodt AG, Berman DS, Riedinger MS, Swan HJC, Murata GH:

Right ventricular performance in septic shock: A combined radionuclide

and hemodynamic study. J Am Coll Cardiol 1984, 4: 945-951.

100. Parker MM, McCarthy KE, Ognibene FP, Parrillo JE: Right ventricular

dysfunction and dilatation, similar to left ventricular changes, characterise the

cardiac depression of septic shock in humans. Chest 1990, 97: 126-131.

101. Vieillard-Baron A, Schmitt JM, Beauchet A, Augarde R, Prin S, Page B, Jardin

F: Early preload adaptation in septic shock? A transesophageal

echocardiographic study. Anesthesiology 2001, 94: 400-406.

102. Schneider AJ, Teule GJ, Groeneveld AB, Nauta J, Heidendal GA, Thijs LG:

Biventricular performance during volume loading in patients with early septic

shock, with emphasis on the right ventricle: a combined hemodynamic and

radionuclide study. Am Heart J 1988, 116: 103-112.

103. Etchecopar-Chevreuil C, François B, Clavel M, Pichon N, Gastinne H, Vignon

P: Cardiac morphological and functional changes during early septic shock: a

transesophageal echocardiographic study. Intensive Care Med 2008, 34: 250-

256.

104. Suffredini A, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA,

Parrillo JE: The cardiovascular response of normal humans to the administration

of endotoxin. N Engl J Med 1989, 321: 280-287.

105. Sam Kaddoura. Echo made easy. 1st edition. Churchill Livingstone 2003; 1-170.

106. Catherine MD. Textbook of clinical echocardiography. 3rd edition. International

edition. Elsevier Saunders 2004; 1-258.

103

107. Asmi MH, Walsh MJ. A practical guide to echocardiography. 1st edition.

Chapman and Hall Medical Pub 1995; 1-67.

108. Michael Henein. Clinical echocardiography from stable angina to ischaemic

cardiomyopathy. 1st edition. Springer Publication 2005; 1-50.

109. Braunwald's Heart disease, A textbook of cardiovascular medicine. Indian

edition. 7th edition. Zipes, Libby, Bonow, Braunwald (eds) 2005; 187-270.

110. Appleton Chistopher P. "Thfe echodoppler evaluation of left ventricular diastolic

function - a current prospective". In cardiology Clinic - Diastolic function and

dysfunction, Sander J. Kovascs, Philadelphia, W.B. Saunders Company, 2000,

600pp.

111. Quinones Miguel A. "Doppler assessment of left ventricular diastolic function".

Ch. 19 in Doppler echocardiography. Nanda Navin C, Philadelphia, Lea and

Febiger, 19th edition, 1993, 197pp.

112. Demaria Arathony N et al. 1991. "Doppler echocardiographic evaluation of

diastolic dysfunction". Circulation, 84: 288-295.

113. Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible

myocardial depression in patients with septic shock.

Ann Intern Med. 1984;100(4):483-490.

114. Vieillard-Baron A, Caille V, Charron C, Belliard G, Page B,

Jardin F. Actual incidence of global left ventricular hypokinesia

in adult septic shock. Crit Care Med. 2008;36(6):1701-1706.

104

115. Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med.

1993;328(20):1471-1477.

116. Amico AF, Lichtenberg GS. Superiority of visual versus computerised

echocardiographic estimation of radio nuclide LVEF. Am Heart J 1989;

118:1259.

117. Rich S, Sheikh A. Determination of left ventricular ejection fraction by visual

estimation during real time two dimensional echocardiography. Am Heart J

1982; 104:603.

118. Donnerstein RL. Llyod TR. After load dependence of echocardiographic LVEF

determination. Am J Cardio 1991; 67:901.

119. Antuono G Cipollarca. Analysis of L V wall motion by means of ultrasound G.

Ital Cardiol 1972; 2:234.

120. Brown DJ, Gibson DG. Study of LV wall thickness and dimension changes

using echocardiography. Br Heart J 1978; 40:162.

121. Boerboom CE, Sagar KB. Comparison of peak and modal aortic blood flow

velocities with invasive measures of LV performance.

122. Gardin JM. Doppler measurements of aortic blood flow velocity and

acceleration: load independent indexes of LV performance. Am J Cardio 1989;

64:935.

105

123. Harrison MR, Sulelett KL. Effort of heart rate on Doppler indexes of systolic

function in humans. J Am Coll Cardiol 1989; 14:929

124. American College of Chest Physicians/Society of Critical Care Medicine

Consensus Conference: definitions for sepsis and organ failure and guidelines for

the use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864-874.

125. Vincent JL, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess

the incidence of organ dysfunction/ failure in intensive care units: results of a

multicenter, prospective study: working group on ”sepsis-related problems” of

the European Society of Intensive Care Medicine. Crit Care Med.

1998;26(11):1793-1800.

126. Zanotti Cavazzoni SL, Guglielmi M, Parrillo JE, Walker T, Dellinger RP,

Hollenberg SM. Ventricular dilation is associated with improved cardiovascular

performance and survival in sepsis. Chest. 2010;138(4):848-855.

127. Bouhemad B, Nicolas-Robin A, Arbelot C, Arthaud M, Feger F, Rouby JJ. Acute

left ventricular dilatation and shock-induced myocardial dysfunction. Crit Care

Med. 2009;37(2):441-447.

106

J.J.M. MEDICAL COLLEGE, DAVANAGERE

DEPARTMENT OF EMERGENCY MEDICINE

INFORMED CONSENT

We, the undersigned guardians of ________________________________________

hereby give consent for the investigations carried upon our patient. We are satisfied with the

information given about this clinical study titled “CLINICAL SPECTRUM,

FREQUENCY AND SIGNIFICANCE OF MYOCARDIAL DYSFUNCTION IN

SEVERE SEPSIS AND SEPTIC SHOCK” conducted by Dr. SHAHBAZ HASSAN under

the guidance of Dr. SURENDRA .E.M M.D. Professor, Department of Emergency Medicine,

we have been informed and explained the risk involved and we hereby voluntarily and

unconditionally give consent without any fear or pressure, in mentally sound and conscious

state to participate in this study.

Date: Signature of Guardian

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107

Ethical Committee Clearance Letter

108

PROFORMA

CASE No. : Hospital :

Name : OP/IP No. :

Age :

Sex : Date of Admission:

Address : Date of Surgery:

Occupation : Date of Discharge:

History:

Presenting symptoms to know the primary focus of sepsis.

Time of onset of the symptoms.

Associated comorbidities like diabetes mellitus, hypertension,

immunocompromised states.

Previous history of congenital heart disease, valvular stenosis or

clinically significant valvular insufficiency, coronary artery disease and

its evaluation in the past.

GENERAL EXAMINATION :

Vitals:

Temperature:

Pulse rate:

Blood pressure:

Respiratory rate:

Pallor/Icterus/Cyanosis/Clubbing/Oedema/Lymphadenopathy

SYSTEMIC EXAMINATION:

CVS:

RS

P/A:

CNS:

109

LOCAL EXAMINATION:

Local focus of sepsis

Local signs:

1. Swelling

2. Edema

3. Warmth

4. Tenderness

5. Colour of the skin.

INVESTIGATIONS:

Complete blood picture

Urine routine and microanalysis

Blood,urine and pus(if present) cultures

Liver function tests

aPTT, PT, INR

Renal function test

Arterial blood gases

ECG

Chest X ray, Ultrasound abdomen and pelvis, if required

2-D Echocardiography:

1. Doppler study :

2. Peak Velocity of early mitral flow : (E – cms-1)

3. Peak Velocity of late mital flow : (A – cms-1)

4. A/E

5. LVIDd :

6. LVIDs :

7. TAPSE:

8. EF :

110

MANAGEMENT:

Immediate resuscitative measures using the ABCDE approach.

Fluid resuscitation on case of shock

Inotropic support when hypotension does not respond to fluid resuscitation.

Broad spectrum antibiotic coverage, until cultures are available.

Mechanical ventilation and Hemodialysis,if required.

Supportive and symptomatic treatment.

FOLLOW UP:

Duration of hospital stay

Progress notes and correspondence will be reviewed in all cases.

Outcome:

1. Recovered

2. Discharged against medical advice

3. Died

MASTER CHART

111

KEYWORDS TO MASTERCHART:

Sr. no – Serial number

F – Female

M – Male

’+’ – Present

‘-‘ – Absent

E – Peak Velocity of early mitral flow

A – Peak Velocity of late mital flow

LVIDd – Left ventricular diameter in diastole.

LVIDs – Left ventricular diameter in systole

RVIDd – Right ventricular diameter in diastole

EF% D1 – Ejection fraction on day 1

REV – Reversibility of Myocardial function

DD – Diastolic Dysfunction

SD – Systolic Dysfunction

TAPSE – Tricuspid Annular Plane Systolic Excursion

RVD – RV dysfunction

MyFn – Myocardial function

NE dose – Norepinephrine dose

MAP – Mean arterial pressure

SBP – systolic blood pressure

HR – heart rate

FiO2 – Fractional pressure of inspired oxygen

PaO2 – partial pressure of arterial oxygen

LAC – serum Lactate

VSP DAYS – Vasopressor days

M.VENT – Mechanical ventilator

S. CR – serum creatinine

HCT – Hematocrit

GHB% – Haemoglobin gm%

WBC – White blood cell count

SOFA – Sequential Organ Failure Assessment

MASTER CHART

112

sl.no NAME AGE SEX E A E/A LVIDd LVIDs RVIDd EF% D1 DD SD LV function REV TAPSE RVD MyFn OUTCOMEHYPOTEN

SIONNE dose MAP SBP HR PaO2 FiO2

PaO2/FiO

2Ph LAC VSP DAYS M. VENT S CR HCT GHB% WBC SOFA

1 SULOCHANAMMA 41 F 86 60 1.43 4.3 3.1 12 62.5 - - SAME - 1.3 + CardDysFn Survivor NO - 67 90 112 120 37 3.24 7.43 0.9 - - 1.1 47.2 9.2 16580 5

2 KENCHANAGOWDA 54 M 60 44 1.36 4.3 2.9 7 69.3 - - SAME - 1.4 + CardDysFn Survivor YES 0.05 58 77 132 110 29 3.79 7.28 1.2 3 - 1.6 45.2 8.6 21350 6

3 SHARANAPPA 53 M 83 76 1.09 4.4 3.2 11 61.5 - - SAME - 1.5 + CardDysFn Survivor YES 0.2 60 88 124 132 37 3.57 7.35 1.9 3 - 1.8 41.1 7 14560 3

4 PAMPATHI RAO 51 M 74 50 1.48 4.2 2.9 9 40 + + NO IMPR NO 1.4 + CardDysFn Nonsurvior YES 2 58 70 150 112 53 2.11 7.19 7 7 7 2.3 38 5.5 35890 15

5 SHIVAPPA 45 M 84 50 1.68 3.5 2.5 9 63 - - - - - - Norma1 Survivor NO - 68 90 132 121 29 4.17 7.38 3 - - 2.1 41.6 6 20780 8

6 PAKERAPPA 55 M 62 68 0.88 4.5 3 11 63.6 - - - - - - Norma1 Survivor NO - 69 88 124 112 21 5.33 7.42 1 - - 2.5 40.2 7.9 19870 7

7 SHEELA 53 F 62 62 0.97 4.4 3 10 52 + - NORMAL YES 1.2 + CardDysFn Survivor YES 1 61 84 142 121 45 2.69 7.32 2.3 5 4 1.8 47 10.8 14560 10

8 GOWRAMMA 55 F 58 62 0.94 4.2 3 11 63.6 + - SAME - 1.1 + CardDysFn Survivor YES - 70 90 122 108 21 5.14 7.37 1.1 - - 1.1 48 9.7 15670 7

9 NINGAMMA 51 F 60 60 1 4.3 2.6 10 61.9 - - - - - - Norma1 Survivor YES 0.5 64 88 112 123 29 4.24 7.38 1 2 - 1 44 6.9 13480 4

10 ABDUL RAHIM 53 M 79 63 1.25 4.6 2.1 11 60.2 - - - - - - Norma1 Survivor NO - 68 88 102 108 21 5.14 7.39 0.5 - - 0.9 43.2 7 14570 5

11 LALITHA 54 F 88 54 1.63 4.8 3.44 11 44 - + NORMAL YES 1 + CardDysFn Survivor YES 0.9 61 86 118 121 37 3.27 7.34 0.8 4 4 1.1 40.3 5.8 15670 9

12 KENCHAPPA 55 M 68 60 1.13 4.3 2.8 10 48 - + NORMAL YES 1.3 + CardDysFn Survivor YES 0.8 60 82 116 112 37 3.03 7.37 0.9 4 4 1.3 50.8 10 16980 11

13 PUNDALIKA RAO 48 M 63 64 0.98 4.6 2.4 10 30 + + IMPR YES - - CardDysFn Survivor YES 1.5 62 84 115 115 45 2.56 7.45 1.1 5 5 1.5 43.7 7 14320 12

14 GOWRAMMA 55 F 78 50 0.56 4.3 3.6 10 38 - + IMPR YES - - CardDysFn Survivor YES 0.7 64 86 114 121 29 4.17 7.36 1.1 4 - 1.4 41.4 6 13420 4

15 PAKIRAMMA 54 F 62 64 0.97 4.8 2.6 11 57.8 - - - - - - Norma1 Survivor YES - 68 90 113 126 21 6.00 7.39 0.6 - - 1 39.9 5.9 12560 4

16 PARVATAMMA 50 F 78 60 1.3 4.8 3.8 12 41 - + NORMAL YES 1.3 + CardDysFn Survivor YES 0.05 62 88 112 132 45 2.93 7.35 1.3 3 - 1.3 41.5 5.5 13650 5

17 THIMAPPA 51 M 90 64 1.41 4.31 2.9 9 48 - - - YES - - Norma1 Survivor YES 0.08 64 90 111 123 45 2.73 7.31 2 4 - 1.9 53.5 12 15870 5

18 THIRUKAPPA 47 M 80 53 1.51 5.9 3.5 10 65 - - - - - - Norma1 Survivor YES 0.02 65 90 110 126 21 6.00 7.37 0.9 1 - 1 45.8 9 14560 6

19 AJJAPPA 48 M 70 70 1 4.4 3.5 11 35 - + IMPR YES 1 + CardDysFn Nonsurvior YES 1.8 58 80 142 116 45 2.58 7.12 7.3 6 5 2.3 55.8 13 22450 18

20 SHANKARA NAIK 49 M 100 60 1.67 4.8 3.44 10 65 - - - - - - Norma1 Survivor YES 0.02 65 88 121 109 29 3.76 7.37 2 1 - 2.5 45.7 7.7 18670 4

21 PRABHAVATHI 40 F 88 80 1.1 4.8 3.5 11 61 - - - - - - Norma1 Survivor YES 0.04 64 88 111 126 29 4.34 7.46 1.1 2 - 3.7 40.3 5.8 13450 5

22 HANUMANTHAPPA 54 M 76 60 1.15 5 3.44 10 58 - - - - - - Norma1 Nonsurvior YES 2 56 78 148 88 53 1.66 7.2 8 7 7 5.4 41.8 5.9 21760 17

23 VENKATALAXMI 55 F 74 80 0.93 4.6 2.5 10 45 + + IMPR YES 1 + CardDysFn Nonsurvior YES 2 54 70 160 71 53 1.34 7.09 15 8 8 3.9 47.8 9.1 22670 16

24 NAGAMMA 54 F 68 66 1.13 4.31 2.6 9 61 - - - - - - Norma1 Survivor NO - 65 90 111 100 37 2.70 7.36 1 - - 1.2 51.6 10 3500 10

25 VIRUPAKSHAPPA 50 M 80 80 1 4.7 3.4 9 45 - + IMPR YES 1.3 + CardDysFn Survivor YES 0.9 61 82 121 112 37 3.03 7.31 4 5 4 2 52.7 9.6 2300 8

26 MALLIKARJUNAPPA 51 M 70 60 1 4.56 4.21 9 63 + - SAME - 1.4 + CardDysFn Survivor NO - 65 90 108 102 21 4.86 7.32 4 - - 0.9 42.2 6.2 1800 11

27 THIPPESWAMY 47 M 80 80 0.9 5.65 2.5 10 56 + + SAME - - - CardDysFn Survivor YES 0.02 64 88 121 125 21 5.95 7.34 2 1 - 2.9 40.6 7.4 3800 4

28 KARIYAMMA 48 F 70 70 1 4.56 4.3 10 41 - + IMPR YES - - CardDysFn Survivor YES 0.15 62 86 120 102 29 3.52 7.34 5 4 - 3.7 42.3 8 4500 5

29 SHARADAMMA 49 F 63 70 1.37 4.38 3.4 10 55 - - - - - - Norma1 Survivor NO - 65 90 110 112 21 5.33 7.2 1 - - 4.5 41.5 6.3 13870 6

30 BASAVARAJ 40 M 60 62 0.97 4.4 2.4 11 38.3 + + IMPR YES - - CardDysFn Nonsurvior YES 1.2 60 82 118 102 53 1.92 7.28 8 6 6 3.5 45 11 3000 17

31 RANGAPPA 54 M 74 54 1.12 4.2 3 9 63.6 - - - - - - Norma1 Survivor YES 0.02 64 88 120 123 29 4.24 7.3 5 1 - 2.7 39.8 5.9 13340 4

32 NAGAPPA 51 M 70 72 0.94 5.65 3 11 36 + + IMPR YES 0.9 + CardDysFn Survivor YES 0.8 62 84 124 112 37 3.03 7.32 4 5 2 2 40.1 9.1 12780 5

33 REVANAPPA 47 M 76 68 1.63 4.3 4.3 11 58 - - - - - - Norma1 Survivor NO - 65 90 120 108 21 5.14 7.28 3 - - 0.7 41.1 5.8 13980 6

MASTER CHART

113

34 KARIUN BAI 48 M 68 72 1 4.56 2.1 12 57 + - SAME - - - CardDysFn Survivor NO - 65 90 106 110 37 2.97 7.28 2 - - 1.7 42.4 7 14230 6

35 BABYA NAIK 49 M 88 54 0.94 4.8 3.5 10 40 + + NORMAL YES - - CardDysFn Survivor YES 0.9 63 84 104 99 45 2.20 7.26 5 6 4 1.5 48.9 10.3 14780 8

36 SEETHARAMARAJAN 40 M 70 70 1 5 3.5 11 30 + + NORMAL YES - - CardDysFn Nonsurvior YES 1.8 56 74 154 90 45 2.00 7.11 11 7 7 1.3 40.3 5.8 4120 15

37 VEERESH 54 M 68 72 0.92 4.2 3 10 25 + + NORMAL YES 1 + CardDysFn Survivor YES 1.4 62 84 112 128 45 2.84 7.23 4 7 7 1.6 47 10.1 13890 5

38 SHARADAMMA 55 F 70 70 1.32 4.31 2.6 11 36 - + IMPR YES - - CardDysFn Survivor YES 0.6 60 82 114 125 29 4.31 7.35 3 5 4 1.2 37.8 5.9 18990 3

39 BARMAVVA 53 F 68 74 0.94 4.56 3.4 10 41 + + NORMAL YES - - CardDysFn Survivor YES 0.7 64 86 113 112 37 3.03 7.37 1 4 2 1.3 41.2 7.3 19320 4

40 LAXMAMMA 49 F 74 56 1.17 4.38 2.4 10 43.5 - + NORMAL YES 1.3 + CardDysFn Survivor YES 0.8 62 84 115 126 37 3.41 7.38 1.1 5 - 1.4 40.1 6.5 20770 4

41 REVANNA 48 M 64 68 1.17 4.3 2.8 11 62.5 - - - - - - Norma1 Survivor NO - 63 86 116 112 21 5.33 7.42 1.3 - - 1.1 40.4 6.9 23780 5

42 KENCHAMMA 45 F 74 63 0.97 4.4 3 10 43 + + NORMAL YES - - CardDysFn Survivor YES 0.09 64 84 118 131 37 3.54 7.45 0.9 3 - 1.2 41.7 8.5 24670 6

43 ABDUL SAMEEL 48 M 70 60 1.31 4.2 3 11 63.6 - - - - - - Norma1 Survivor YES 0.05 64 86 123 124 21 5.90 7.42 1.1 1 - 1.2 45.9 9 20770 5

44 HONAMMA 45 F 63 70 1.23 4.4 3.2 11 39 - + NORMAL YES 1.3 + CardDysFn Survivor YES 0.4 62 84 121 102 37 2.76 7.44 2.3 5 2 1.5 41.5 7.5 19770 7

45 CHAMAN BEE 48 F 76 58 0.94 4.2 2.9 9 66 + - SAME - 1.4 + CardDysFn Survivor NO - 65 90 112 112 21 5.33 7.46 0.9 - - 1 43 8.3 13450 5

46 THIPAMMA 51 F 68 74 0.92 3.5 2.5 9 45 + + NORMAL YES - - CardDysFn Nonsurvior YES 1.8 54 70 142 90 45 2.00 7.2 13 8 8 2.3 43.8 9.1 31000 16

47 VIRUPAKSHAPPA 53 M 70 72 0.97 4.3 2.9 7 39 + + NORMAL YES - - CardDysFn Nonsurvior YES 1.8 52 70 147 81 45 1.80 7.12 9 9 9 2.8 42.8 8.2 25670 17

48 NAGAPPA 55 M 76 64 1.19 2.6 3.8 8 67.9 - - - - - - Norma1 Nonsurvior YES 2 60 80 164 100 37 2.70 7.23 8 8 8 1.8 40.7 5.7 2000 18

49 DODAPPA 38 M 64 70 0.91 3.4 2.4 1 40 + + NORMAL YES - - CardDysFn Survivor YES 0.5 63 82 123 108 37 2.92 7.25 4 6 2 1.1 42.7 8.2 18990 4

50 HAMNUMANTHAPPA 46 M 70 72 0.97 3.8 3 11 45 + + NORMAL YES - - CardDysFn Survivor YES 0.4 62 80 121 122 29 4.21 7.33 3 4 - 1.2 43.5 7 19870 3

51 PARAMESHWARAPPA 50 M 80 80 1 5.65 4.31 9 56 + - SAME - 1 + CardDysFn Survivor YES 0.09 60 78 111 112 21 5.33 7.36 2 4 - 1.4 46.8 9.6 13230 3

52 DURGAPPA 50 M 68 60 1.13 4.56 3.44 10 40 - + NORMAL YES 0.8 + CardDysFn Nonsurvior YES 1.8 58 78 99 100 45 2.22 6.9 15 9 9 3.6 48.9 10 3500 17

53 BASAPPA 46 M 74 80 0.93 4.7 2.6 10 55 + - SAME NO 0.9 + CardDysFn Nonsurvior YES 2 56 74 144 112 45 2.49 6.99 11 8 8 2.6 44.7 9.1 2300 22

54 GANGAMMA 49 F 76 66 1.15 4.31 2.5 11 35 - + NORMAL YES 1 + CardDysFn Survivor YES 1.5 60 86 120 112 45 2.49 7.51 1 6 5 1.4 41.5 5.7 3600 5

55 BAGYAMMA 47 F 70 80 0.88 456 3.44 10 61 + - SAME - 1.1 + CardDysFn Survivor NO - 65 90 132 102 29 3.52 7.48 1 - - 1 40.1 5.8 16890 4

56 MANNE NAIK 54 M 100 60 1.67 5 3.5 11 65 - - - - - - Norma1 Nonsurvior YES 2 50 68 134 97 45 2.16 7.28 6 7 2 1.8 42.6 7.7 17880 24

57 DYAYAMMA 50 F 70 70 1 4.8 3.5 10 50 + - SAME - - - CardDysFn Survivor NO - 65 90 131 112 37 3.03 7.47 2 - - 0.8 43.7 10.9 16870 10

58 NI NGAPPA 54 M 80 53 1.51 4.4 2.9 9 60 - - - - - - Norma1 Nonsurvior YES 1.8 56 78 142 121 37 3.27 7.11 11 8 8 1.9 43.8 9 3500 15

59 BIBIJAN 45 F 90 64 0.92 5.9 3.8 12 50 + - SAME - - - CardDysFn Nonsurvior YES 2 50 70 146 121 29 4.17 7.21 9 11 11 2 49 11 21980 21

60 SUMANGALAMMA 48 F 78 60 1.3 4.31 2.6 11 55 - - - - - - Norma1 Survivor YES 0.04 60 88 130 112 29 3.86 7.45 1.1 1 - 1 41 5.5 20890 6

61 JAGADEESHIAAH 54 M 62 64 0.97 4.8 3.6 10 57.8 + - SAME - - - CardDysFn Survivor YES 0.09 62 86 121 112 37 3.03 7.42 0.8 2 - 1 42.7 5.9 22340 8

62 BASAMMA 55 F 78 50 1.56 438 2.4 10 48 - + NORMAL YES 1.4 + CardDysFn Survivor YES 0.5 61 84 120 112 45 2.49 7.51 1.1 5 2 1.2 42.5 6 20760 7

63 THIPAMMA 52 F 63 64 0.98 4.3 2.6 11 35 + + NORMAL YES - - CardDysFn Survivor YES 0.6 62 82 132 102 53 1.92 7.43 6 6 4 1.6 41 5.9 17770 9

64 SASHIKANTHA 42 M 70 74 0.95 4.3 2.6 10 51 + - SAME - - - CardDysFn Nonsurvior YES 1.8 60 78 141 125 37 3.38 7.1 10 8 8 2 42.8 7 26540 20

65 PAMPAYHI ACHAR 51 M 70 34 0.83 5.9 2.8 12 61.3 + - SAME - - - CardDysFn Survivor YES 0.8 60 80 112 121 53 2.28 7.26 2 6 4 2.1 44.8 8.9 14560 4

66 SHAKUNTHALAMMA 55 F 64 63 0.94 4.8 2.8 11 60.2 + - SAME - - - CardDysFn Survivor NO - 65 90 131 112 21 5.33 7.42 1 - - 1 41.2 6.4 13670 5

67 YALAPPA 54 M 60 60 1 4.6 2.6 10 61.3 + - SAME - - - CardDysFn Survivor YES 0.03 64 86 112 112 29 3.86 7.47 1.3 1 - 1 41.2 6.9 12990 6

68 THIPESWAMY 49 M 58 62 0.94 4.2 3 11 63.6 + - SAME - - - CardDysFn Nonsurvior YES 2 58 78 148 110 37 2.97 7.19 11 8 8 2.1 42.3 9.5 3100 18

69 HIRABEE 45 F 62 62 1 4.4 3 10 68.3 + - SAME - - - CardDysFn Nonsurvior YES 2 56 74 158 110 37 2.97 7.21 9 7 7 2.3 43.6 10.8 1800 21

70 MAHAJAN 50 M 62 68 0.88 4.2 3 11 63.6 + - SAME - - - CardDysFn Survivor YES 0.3 60 84 125 111 45 2.47 7.46 1 4 - 1.3 43.7 7.9 14580 5

71 CHAMMA RAO 54 M 84 50 1.68 3.5 2.5 9 55 - - - - - - Norma1 Survivor NO - 65 90 114 111 21 5.29 7.45 0.9 - - 1 41.2 6 16790 6

72 LOKESHAPPA 53 M 74 50 1.48 4.2 2.9 9 60 - - - - - - Norma1 Survivor NO - 65 90 112 109 29 3.76 7.47 1.1 - - 0.9 41.1 5.5 18760 7

73 VERABASAPPA 51 M 70 76 0.92 4.4 3.2 11 61.5 + - SAME - - - CardDysFn Survivor NO - 65 90 109 112 21 5.33 7.43 0.8 - - 0.8 42.2 7 19680 8

74 HOLEPPANAVAR 52 M 60 44 1.36 4.3 2.9 7 54 - - - - - - Norma1 Survivor YES 0.05 62 86 123 112 29 3.86 7.42 0.7 2 - 1.1 43.2 8.6 14560 9

75 ERAMMA 50 F 86 60 1.43 4.3 3.1 12 62.5 - - - - - - Norma1 Nonsurvior YES 2 64 88 134 91 37 2.46 7.11 11 8 8 2.1 44.4 9.2 24560 19

76 SHIVARAMACHANDRAPPA 51 M 70 70 1 3.5 2.5 9 61 + - SAME - - - CardDysFn Survivor YES 0.09 64 88 121 100 45 2.22 7.4 3 4 - 1.2 41.1 6.2 16770 10

77 HANUMANTAPPA 46 M 63 70 0.9 5.65 4.3 9 55 + - SAME - - - CardDysFn Survivor YES 0.2 62 88 115 122 37 3.30 7.39 2 3 - 1.3 42.1 7.4 17890 9

78 SIRIYAPPA 45 M 60 62 0.97 4.56 3.4 10 61 + - SAME - - - CardDysFn Survivor NO - 65 90 114 108 21 5.14 7.49 1.2 - - 1 42.3 8 21350 8

79 HEMRAJU 50 M 74 54 1.37 4.38 2.4 10 62.5 - - - - - - Norma1 Survivor YES 0.3 64 88 124 102 37 2.76 7.33 6 4 - 1.2 48.6 6.3 18770 6

80 GIRIJAMMA 50 F 70 72 0.97 4.4 3 10 58 + - SAME - - - CardDysFn Survivor YES 0.3 62 84 124 123 37 3.32 7.35 4 3 - 1 44.8 11 17890 5

MASTER CHART

114

ANNEXURE-I

Recognition of postgraduate teacher as a guide

ANNEXURE-II

Confirmation for Registration of Subjects for Dissertation