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Excerpt
The mechanisms underlying sepsis-induced myocardial dysfunction remain unclear, despite a plethora of data implicating several molecular mechanisms. The preponderance of evidence suggests that myocardial ischemia is not an important mechanism (10, 11); rather, myocardial dysfunction appears related to transferable myocardial depressant factors in serum, including tumor necrosis factor (TNF)-α and interleukin-1 (2, 12, 13). The hypothesis that TNF-α is an important myocardial depressant factor has been fortified by several studies documenting the negative inotropic effects of TNF (7, 9, 14), as well as by data demonstrating that TNF is produced locally in the myocardium, where it is both necessary and sufficient to cause myocardial dysfunction and severe cardiac failure (15–17).
Because even clinically severe myocardial dysfunction is transient and likely related to serum mediators, it has been assumed that myocyte cytotoxicity and/or myocyte necrosis were unimportant in the pathogenesis of this syndrome. However, recent studies on septic adults (18, 19), burn-injured adults (20), and the current study by Dr. Thiru and colleagues (21) in this issue of Critical Care Medicine force us to reexamine this assumption.
Dr. Thiru and colleagues (21) at St. Mary’s examined myocyte necrosis in a large cohort of children with severe meningococcal sepsis, and determined that 24% of patients at admission and 62% of patients within 48 hrs had significant elevations of cTnI. Moreover, the cTnI levels correlated with Pediatric Risk of Mortality mortality predictions, myocardial dysfunction by echocardiography, and need for inotropic support. The investigators conclude that myocardial dysfunction in children with meningococcemia is associated with myocyte death—a very straightforward mechanism to explain myocardial dysfunction.
There are several methodologic issues that should be considered. First, it is possible that the findings of Dr. Thiru and colleagues (21) are only applicable to meningococcal sepsis, which is associated with a much higher incidence and degree of histologic myocarditis than nonmeningococcal sepsis, and therefore may be unrepresentative (22). However, the recent study by Turner et al. (18) suggests that some degree of myocyte necrosis may be involved in adult, nonmeningococcal sepsis as well. Secondly, it is impossible to exclude myocardial ischemia in the cohort of children with severe meningococcal sepsis, irrespective of their blood pressure. Disseminated microemboli are common in meningococcal sepsis (23, 24), and the presence of such microemboli in the coronary circulation could account for the transient elevations in cTnI. It is unfortunate that the authors provide no postmortem pathologic correlation, which might further elucidate the mechanism of cTnI elevation. Nevertheless, ischemia and micro-infarctions seem relatively unlikely given the high incidence of cTnI elevations (62%) and the relative stability and favorable outcome of patients (5% mortality) in the study by Dr. Thiru and colleagues (21). In addition, assessment of cardiac function by a load-dependent index (ejection fraction) is problematic given the extreme variations in preload and afterload that occur during the early treatment of meningococcemia. Noninvasive ejection phase indices and wall stress analyses might better determine the actual state of left ventricular systolic mechanics (5).
