3. INTRODUCTION
•
Understanding has evolved over decades - historically,
cardiovascular changes are hallmark of septic shock
•
Traditionally: “warm shock” vs “cold shock”: different
entities vs stages of same process
•
Under conditions of adequate volume resuscitation
reduced SVR increased cardiac index, and obscures
myocardial dysfunction
4.
5. Calvin JE, Driedger AA, Sibbald WJ. An assessment of
myocardial function in human sepsis utilizing ECG gated
cardiac scintigraphy. Chest. 1981; 80: 579–586
Parker MM, Shelhamer JH, Bacharach SL, et al: Profound
but reversible myocardial depression in patients with
septic shock. Ann Intern Med 1984; 100:483–490
Parker MM, McCarthy KE, Ognibene FP, et al: Right
ventricular dysfunction and dilatation, similar to left
ventricular changes, characterize the cardiac depression of
septic shock in humans. Chest 1990; 97:126–131
6. HOW WAS DYSFUNCTION DIAGNOSED?
•
Concept of depressed myocardial function despite increased
CO emerged from studies utilising ventriculography and
thermodilution (Parker et al)
•
Showed that LV dysfunction persisted despite a hyperdynamic
state and increased CI
•
Able to demonstrate significant depression of myocardial
function - impaired intrinsic myocardial performance, decreased
LVSWI
•
Changes reflected in right heart
7. WHAT ELSE?
•
Survivors more likely to have decreased ejection fractions with
increased EDVI
•
Non-survivors more likely to have preserved cardiac volumes
with less significant decreases in ejection fraction
•
Reversible changes 7-10 days
•
Diastolic dysfunction & right heart dysfunction not clear
8. THE RIGHT HEART
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Behaves differently:
•
LV afterload is decreased due to low SVR
•
RV afterload increased due to increased PVR
•
Number of studies have documented RV systolic dysfunction
independent of pulmonary vascular resistance
•
General consensus that RV dysfunction parallels LV dysfunction
in sepsis
9. AETIOLOGY
•
Multiple circulating factors suggested as culprits
•
Direct inhibitory effects on myocyte contractility
•
cytokines (TNF-alpha, IL1-B)
•
lysozyme c
•
endothelin 1
•
Nitric oxide: complex role
•
Mitochondrial dysfunction and apoptosis
•
Adrenergic receptor hypo-responsiveness
10. MECHANISMS
•
Circulatory and microvascular changes
•
volume depletion and vasodilatation
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Capillary leakage and microcirculatory changes
•
Autonomic dysregulation
•
Metabolic changes
•
Mitochondrial dysfunction and cell death
13. IS THERE A BENEFIT TO MYOCARDIAL
DEPRESSION?
•
Adaptive response? (Rudiger A., Singer M. 2007)
•
Reduces energy expenditure in a situation when energy
generation limited
•
Prevents activation of cell death pathways allowing for recovery
•
Pulido et al (2012) - Myocardial dysfunction - no effect
mortality 30 day or long term
14. PROGNOSIS OF MYOCARDIAL
DYSFUNCTION
•
Dobutamine stress test (Kumar, Parillo et al, 2007)
•
Biomarkers:
•
•
•
Elevation Troponin T and I correlate with presence left
ventricular systolic dysfunction
Increased levels of BNP also correlate with severe sepsis and
septic shock
So far…not clinically useful
15.
16. CONCLUSION
•
Cardiac dysfunction in sepsis characterised by:
•
decreased contractility
•
impaired ventricular response to fluid therapy
•
?ventricular dilatation
•
Complex pathophysiology: multiple circulating factors
•
Management: haemodynamic support and treatment of
infectious focus…& modulation of host response
Editor's Notes
How many develop cardiovascular dysfunction? Singer/Rudiger - echo decreased EF in as high a percentage as 50%. Blanco J, Muriel-Bombin A, Sagredo V, et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care 2008; 12:R158.
Parrillo JE, Parker MM, Natanson C, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113:227–242.
However, as early as the mid-1980s, significant reductions in both stroke volume and ejection fraction in septic patients were observed despite normal total cardiac output.11
Warm shock was characterized by fever, full bounding pulses, flushed skin, oliguria, and hypotension. Cold shock was associated with hypoten- sion, clammy skin, low volume pulses, and patients over- all appeared to be more severely ill. It is likely that many if not most of the patients described as having cold shock were inadequately volume resuscitated.
Studies by the same group showed that patients with severe sepsis and septic shock had impaired intrinsic myocardial performance as a function of an abnormal response in left ventricular stroke work index (LVSWI) to fluid infusion.
A provocative theory regarding the myocardial depression in sepsis suggests it may play a protective role in the heart similar to the phenomenon of hibernation in coronary ischemia [33,44]. This theory states that myocardial depression could represent a pro- tective adaptation by reducing cellular energy expendi- ture in the heart during a situation of decreased energy production resulting from mitochondrial dysfunction.
Early theories based on global myocardial ischaemia - but high coronary flow and decreased oxygen utilisation. Parrillo et al. [26] showed Although the existence of MDS was demonstrated by the pre- vious studies [36–39], the identity of the molecules remained in question. Potential circulating inflammatory mediators that could cause septic myocardial depression 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 fil- tration studies was present in the >10 kDa fraction [39]. Although full molecular characterization was not possible with the available data, the characteristics were most consistent with either a polypeptide or protein. The list of potential
myocardial depression in isolated myocytes exposed to serum obtained from septic patients with clinical manifestations of sepsis-induced myocardial dysfunction. TNF-a, IL-1b, and IL-6 as circulating causative factors of myocardial depression in sepsis. Lysozyme c has been shown to have cardiac depressant actions in animal models of sepsis [27]. Furthermore, competitive inhibition of lysozyme c in these animal models was protective and prevented sepsis-induced myocardial dysfunction. Early studies suggest a potential role for endothelin-1 (ET-1) in the development of sepsis-induced myocardial depression [28,29]. Effects of nitric oxide relevant to sepsis-induced myocardial dysfunction include vasodila- tion, depression of mitochondrial respiration, and further release of pro-inflammatory cytokines [30]. Current evidence suggests reductions in cytosolic calcium levels during sepsis lead to reduced contractility [33]. Calcium signaling and metabolism is linked to mitochondrial function, which is also altered in sepsis. The relationship of intramyocyte calcium homeostasis with alterations of nitric oxide in sepsis is still not fully understood.
Mitochondrial function is significantly impacted in sepsis and the degree of mitochondrial dysfunction is correlated with outcomes. It has been proposed that during sepsis, cardiac mitochondria pro- duce increased levels of nitric oxide and superoxide, which leads to inhibition of oxidative phosphorylation and decreased production of ATP [34]. This process leads to ‘cytopathic hypoxia’, inability of the cells to utilize oxygen and produce ATP, and has been postulated as a crucial step in the development of multiorgan failure in sepsis [36,37,38].TNF-α shares a similar biochemical profile with MDS, making it a plausible mediator of the myocardial effects of sepsis and septic shock [38,40,41]. Experimentally, increased levels of TNF-α produce fever, lactic acidosis, disseminated intravas- cular coagulation, acute lung injury and death. The cardiovas- cular effects are similar to clinical septic shock; namely, hypotension, increased CO and low SVR [42,43]. Human volunteers given TNF-α infusions demonstrate similar responses [44,45].
Tachycardia, a typical sepsis feature, is viewed as a response to cardiac underfill- ing, adrenergic stimulation, and fever. Sepsis-related tachycardia has several ad- verse effects on the heart, including re- stricted diastolic ventricular filling, in- creased oxygen requirements, and, potentially, a tachycardia-induced cardio- myopathy. Indeed, heart rate on presen- tation predicted survival in septic shock patients (66).
During sepsis, profound met- abolic changes are suggested by intracar- diomyocyte accumulation of lipids and glycogen in nonsurvivors (22) and in mice (68). Whereas sepsis is character- ized by hyperlactatemia, the hearts of septic patients show a net lactate extrac- tion between arterial and coronary sinus blood (54) and a diminished myocardial uptake of glucose, ketone bodies, and free fatty acids (55). In septic patients, oxygen consumption and resting metabolic rate are enhanced compared with normal me- tabolism (69). However, with the devel- opment of organ dysfunction and the progression of shock, both oxygen con- sumption and resting metabolic rate de- crease. This suggests that septic patients with established organ dysfunction or shock can tolerate lower values of oxygen delivery.
