Sepsis/InfectionMyocardial depression in sepsis: From pathogenesis to clinical manifestations and treatment☆
Introduction
Specific interventions for the treatment of severe sepsis and septic shock in critically ill patients remain evasive, despite broad consensus about basic pathophysiology (ie, initial inflammation/cytokine storm, and subsequent immunosuppression). The incidence and prevalence of complicated sepsis are increasing as the population ages [1] and as a result of recent advances in medicine (use of invasive procedures, immunosuppressive therapies, mechanical ventilation (MV), improved diagnostic techniques), which enable patients to survive longer than in the past. Mortality rates for patients with septic shock approach 50% [2].
The cardiovascular system plays a key role in the outcome of patients with sepsis, and numerous studies have demonstrated evidence of myocardial depression during septic syndromes over the last 50 years [3], [4]. Nevertheless, septic myocardial impairment remains a clinical enigma. The heart is only one part of the cardiovascular system, which is constantly changing in response to peripheral hemodynamic changes, such that it is difficult to distinguish between the direct cardiac effects of sepsis and the cardiac response to changes in preload, afterload, and neurohumoral activity that occur during sepsis (eg, as a result of exogenous catecholamines, sympathetic effects, nitric oxide [NO]) [5].
There is no universally accepted definition of septic myocardial depression, and although a reduced left ventricular ejection fraction (LVEF) is often used, septic cardiomyopathy can be defined as a global (systolic and diastolic) but reversible dysfunction of both the left and right sides of the heart [6]. In all experimental models of septic shock that used the load-independent parameter of left ventricular (LV) systolic function (ie, pressure/volume loops), LV contractile dysfunction (septic cardiomyopathy) was shown to be present [7]. However, the results and conclusions of experimental studies are difficult to apply to humans, and in the available literature, there is, therefore, a lack of consistency in the description and definition of septic cardiomyopathy. In addition, different definitions of sepsis are still used, patient selection and methods of evaluation are markedly heterogeneous, and older studies relied on radionuclide or pulmonary artery catheterization techniques, whereas tissue Doppler imaging (TDI) and perfusion echocardiography have only been used during the last decade [8], [9].
The purpose of this article is to review the pathogenesis and clinical manifestations of myocardial depression in sepsis, with a special focus on the underlying systemic and molecular alterations. We also discuss the most important diagnostic and therapeutic aspects, analyzing the scientific developments and new perspectives in this field.
Section snippets
Pathogenesis
The pathogenesis of myocardial depression in sepsis is the result of a complex interaction between genetic, molecular, metabolic, structural, autonomic, and hemodynamic alterations. As already stated, most studies have been performed in animals, and the results are not necessarily reproducible in the clinical setting. Some of the following assumptions are, therefore, still theoretical in humans.
Left and right ventricular dysfunction: double trouble
Defining septic myocardial dysfunction as a disorder defined by reduced LVEF during sepsis is too simplistic. Several experimental and human studies have shown a global impairment in cardiac function in sepsis. Thus, septic cardiomyopathy should be considered as a complex disorder, characterized by reversible left and right ventricular dysfunction [6], [7], [9], [82], [83].
Treatment
No specific treatment of septic myocardial depression exists, largely related to the fact that the heart is a “victim” rather than the “first actor” of the septic process. The Surviving Sepsis Campaign (SSC) guidelines [78] represent a good starting point for the treatment of sepsis and its complications, within limits of generalization. We concentrate here on the main therapeutic interventions aimed at hemodynamic stabilization and improvement of myocardial function, briefly mentioning other
Conclusions
Septic myocardial depression is a global (systolic and diastolic) dysfunction of both the left and right sides of the heart during septic states. The complex pathogenesis of septic myocardial depression involves a combination of hemodynamic, genetic, molecular, metabolic, and structural alterations. The PAC and echo-Doppler techniques have helped improve the diagnosis of this disorder. However, no specific treatment exists for septic myocardial depression. As a result, general sepsis management
References (148)
- et al.
Myocardial dysfunction in severe sepsis and septic shock: more questions than answers?
J Cardiothorac Vasc Anesth
(2011) - et al.
Endotoxin induced cardiac depression is associated with decreased cardiac dihydropyridine receptors in rabbits
J Mol Cell Cardiol
(1996) - et al.
Intracellular redistribution of dihydropyridine receptor in the rat heart during the progression of sepsis
J Surg Res
(2007) - et al.
Sepsis alters myocardial and plasma concentrations of endothelin and nitricoxide in rats
J Mol Cell Cardiol
(1997) - et al.
Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis induced myocardial dysfunction
Life Sci
(2007) - et al.
Administration of anti-TNF antibody improves left ventricular function in septic shock patients. Results of a pilot study
Chest
(1992) - et al.
Energetic myocardial metabolism and oxidative stress: let's make them our friends in the fight against heart failure
Biomed Pharmacother
(2010) - et al.
Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock
Lancet
(2003) - et al.
Disruption of sarcolemmal dystrophin and beta-dystroglycan may be a potential mechanism for myocardial dysfunction in severe sepsis
Lab Invest
(2010) - et al.
Cardiovascular determinants of the hemodynamic response to acute endotoxemia in the dog
J Crit Care
(1986)
Agonist-induced peroxynitrite production from endothelial cells
Arch Biochem Biophys
Serial blood lactate levels can predict the development of multiple organ failure following septic shock
Am J Surg
Noninvasive single-beat determination of left ventricular end-systolic elastance in humans
J Am Coll Cardiol
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
Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans
Chest
The effect of age on the development and outcome of adult sepsis
Crit Care Med
Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003
Crit Care Med
Profound but reversible myocardial depression in patients with septic shock
Ann Intern Med
The cardiovascular response of normal humans to the administration of endotoxin
N Engl J Med
Septic cardiomyopathy
Ann Intensive Care
Evaluation of left ventricular systolic function revisited in septic shock
Crit Care
Down but not out: myocardial depression in sepsis
Crit Care
Clinical management of the cardiovascular failure in sepsis
Curr Vasc Pharmacol
Sepsis-induced myocardial depression is associated with transcriptional changes in energy metabolism and contractile related genes: a physiological and gene expression based approach
Crit Care Med
Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs
Am J Physiol
Reduced L-type calcium current in ventricular myocytes from pigs with hyperdynamic septic shock
Crit Care Med
Electrophysiologic properties of isolated adult cardiomyocytes from septic rats
Circ Shock
The role of nitric oxide in sepsis: an overview
Acta Anaesthesiol Scand
Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock
Crit Care Med
Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes
Cardiovasc Res
Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure
Am J Physiol Regul Integr Comp Physiol
Mitochondrial nitric oxide synthase participates in septic shock myocardial depression by nitric oxide overproduction and mitochondrial permeability transition pore opening
Shock
Myocardial dysfunction in sepsis: a large, unsolved puzzle
Crit Care Res Pract
Efficacy and safety of monoclonal antibody to human tumor necrosis factor α in patients with sepsis syndrome: a randomized, controlled, double-blind, multicenter clinical trial
J Am Med Assoc
The role of IL-1 in the pathogenesis of heart disease
Arch Immunol Ther Exp
Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase
Crit Care Med
Treatment of myocardial dysfunction in sepsis: the toll-like receptor antagonist approach
Shock
Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis
Crit Care Med
The coronary circulation in human septic shock
Circulation
Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock
Cardiovasc Res
Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis
Shock
Relationship between thyroid function and ICU mortality: a prospective observation study
Crit Care
A network-based analysis of systemic inflammation in humans
Nature
Survival in critical illness is associated with early activation of mitochondrial biogenesis
Am J Respir Crit Care Med
Oxidative stress and mitochondrial dysfunction in sepsis
Br J Anaesth
The role of mitochondrial dysfunction in sepsis-induced multi-organ failure
Virulence
Induced hypothermia is protective in a rat model of pneumococcal pneumonia associated with increased adenosine triphosphate availability and turnover
Crit Care Med
Finally, activation of mitochondrial biogenesis by heme oxygenase-1–mediated NF-E2–related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis
Am J Respir Crit Care Med
The neuropathology of septic shock
Brain Pathol
Is myocardial adrenergic responsiveness depressed in human septic shock?
Intensive Care Med
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Conflicts of interest: Nothing to disclose.