A synthesis of the postulated sequence of events for development of the inappropriate response of the myocardium to a demand for increased cardiac index is schematically represented in Fig. 10. In sepsis, bacteremia and/or the release of endotoxin activate the macrophages which release a spectrum of mediators. Some of these mediators (and possibly also endotoxin itself) have a negative influence on myocardial contractile function either directly and/or through altering cellular calcium flux. This results in impaired myocardial function manifested initially by decreased stroke volume. Subsequently, stroke volume will be either partially or completely restored to normal through the action of circulating catecholamines, the concentration of which is markedly elevated due to the presence of endotoxin and/or macrophage-produced mediators. Endotoxin and/or these mediators also act on the SA node increasing its sensitivity to beta-adrenergic stimulation. This will result in elevated heart rates. The latter, combined with the restored stroke volume, will yield an increased cardiac index which is the hallmark of the hyperdynamic phase of sepsis. In the cecal ligation and puncture model of sepsis, where cardiac index is maintained at the original level, the partially restored stroke volume and the elevated heart rate will combine to maintain cardiac index. Although this mechanism of increasing cardiac index through tachycardia is not energy efficient, the myocardium is able to cope with these changes and also to maintain its high energy phosphate concentrations, since the utilization of the three major myocardial substrates (fatty acids, lactate and glucose) is not affected by sepsis. Although this putative sequence of events is consistent with the observed experimental findings, further work is needed to substantiate its applicability to the etiology of myocardial dysfunction in man during sepsis.