Septic Myocardial Depression Research Articles

MYOCARDIAL DYSFUNCTION IN SEPTIC SHOCK

Over the last decade, it has become clear that myocardial depression, like vascular dysfunction, is typical of human septic shock. Human septic myocardial depression is characterized by reversible biventricular dilatation, decreased ejection fraction, and decreased response to fluid resuscitation and catecholamine stimulation (in the presence of overall hyperdynamic circulation). A circulating myocardial depressant substance, not myocardial hypoperfusion, is responsible for this phenomenon. This substance has been shown to represent low concentrations of TNF-alpha and IL-1 beta acting in synergy on the myocardium through mechanisms that include NO and cGMP generation. Despite major advances in our understanding of the hemodynamics and pathogenesis of cardiac dysfunction in sepsis, successful attempts to modulate these mechanisms to improve clinical outcomes in human trials have not been demonstrated to date. For the moment, the therapeutic approach to the patient with cardiac dysfunction in distributive or septic shock must be primarily aimed at reestablishing adequate organ perfusion and oxygen delivery by vigorous fluid resuscitation and vasopressor or inotropic support. In the long term, however, only continued research regarding the cellular mechanisms of organ dysfunction, including septic myocardial depression, will lead to successful therapeutic strategies. These strategies will likely involve direct manipulation of intracellular signaling processes that lead to organ dysfunction as manifested by septic myocardial dysfunction and septic shock.

Pathogenesis and management of septic shock

Summary In summary, the diagnosis of septic shock should prompt an aggressive diagnostic and therapeutic regimen. Infected fluid collections should be drained urgently, intravascular devices should be removed (if possible), and appropriate antimicrobial therapy should be initiated. Rapid administration of large volumes of fluid is routinely required. Initiation of mechanical ventilation should be considered early during resuscitation efforts. Careful supportive care may minimize occurrence of secondary sepsis caused by gut-derived bacteremia/endotoxemia, intravascular device infection, nosocomial pneumonia, or other sources. If aggressive volume resuscitation fails to achieve satisfactory perfusion indices or precipitates pulmonary edema/hypoxemic respiratory failure, then PAC placement should be considered. A trial of DB therapy to reverse any element of septic myocardial depression may be useful if perfusion is inadequate after appropriate volume resuscitation but should be initiated with caution, and drug effects should be monitored carefully at the bedside. If a vasoconstrictor agent is administered, a splanchnic and/or renal vasodilator (low-dose DA, FNP, DX, DB) probably should be added to offset regional hypoperfusion, although the benefit of this approach in septic shock is currently unproven. Whatever strategy is used for hemodynamic support, careful bedside serial assessments should gauge the effects of each intervention and guide subsequent therapeutic maneuvers. Septic shock is among the most urgent conditions treated by any physician, and there is no substitute for bedside management guided by an integrated synthesis of all available information.

Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum

Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This depression is associated with the presence of a circulating myocardial depressant substance with physical characteristics consistent with cytokines. The present study utilized an in vitro myocardial cell assay to examine the role of various human recombinant cytokines, including tumor necrosis factor (TNF)alpha and interleukin (IL)1beta, in depression of cardiac myocyte contractile function induced by serum from humans with septic shock. The extent and velocity of electrically paced rat cardiac myocytes in tissue culture was quantified by a closed loop video tracking system. Individually, TNF-alpha and IL-1beta each caused significant concentration-dependent depression of maximum extent and peak velocity of myocyte shortening in vitro. In combination, TNF-alpha and IL-1beta induced depression of myocardial cell contractility at substantially lower concentrations consistent with a synergistic effect. Using immunoabsorption, removal of both TNF-alpha and IL-1beta (but not either alone) from the serum of five patients with acute septic shock and marked reversible myocardial depression resulted in elimination of serum myocardial depressant activity. IL-2, -4, -6, -8, -10, and interferon gamma failed to cause significant cardiac myocyte depression over a wide range of concentrations. These data demonstrate that TNF-alpha and IL-1beta cause depression of myocardial cell contraction in vitro and suggest that these two cytokines act synergistically to cause sepsis-associated myocardial depression in humans.