The past four decades have seen the mortality of sepsis increase from 0.5 to 7 per 100,000 episodes with the occurrence of severe sepsis in for example the United States today being estimated at 750,000 cases per year, resulting in 215,000 deaths annually. The majority of these sepsis patients die of hypotension unresponsive to therapy and of systemic cardiovascular failure. One of the manifestations of cardiovascular dysfunction in septic shock is myocardial depression and despite much research its cause and treatment is largely unknown. This insight into the nature of septic cardiomyopathy was achieved in the early eighties with the key note publication from the group of Parrillo who identified the presence of sepsis-induced cardiac dysfunction in patients with septic shock using portable radionuclide cardiac imaging and simultaneous thermodilution cardiac output measurements. They identified that following the onset of septic shock patients had a depression of left ventricular ejection fraction (1). Several mechanisms have been proposed as underlying this depressed contractility associated with septic myocardiopathy. One such mechanism has been regional myocardial ischemia and hypoxemia due to a failure in myocardial autoregulatory needed to match regional oxygen need by the myocytes by adequate microcirculatory delivery. The inflammatory mediators associated with sepsis and especially increased nitric oxide are thought to underlie this aspect of cardio-(micro)vascular dysfunction (2). Such abnormalities have been shown to give rise to weak microcirculatory units becoming hypoxemic (3), emphasizing the defect in the distributive capacity of the microvasculature to provide adequate oxygen to the organs. It is this microcirculatory failure which is thought to define the pathogenesis of sepsis leading to multi organ failure (4). Microcirculatory failure in otherwise well resuscitated systemic hemodynamic parameters results in the functional shunting of the microcirculation. It is this functional shunting which has made the clinical management of sepsis so difficult because impaired microculatory function can occur in the presence of a normal or even elevated cardiac output hiding as it where the actual defect from conventional monitoring of systemic hemodynamic variables such as blood pressure, stroke volume and cardiac output. Such abnormal microcirculation with the presence of shunting pathways can be observed clinically by the use of bedside intravital microscopic introduced by us to observe the microcirculation during surgery and intensive care (e.g. 5, 6). Clinically, microcirculatory shunting manifests itself as a deficit in the ability of tissues to extract oxygen from macroscopically delivered oxygen resulting in microcirculatory hypoxemia in the presence high venous oxygen pressures.

Besides the (micro) vascular dysfunction described above, cellular and sub cellular pathologies have been show to be present especially in experimental studies. These pathogenic mechanisms include electrophysiological dysfunction due to abnormal ion channel activity resulting in action potential shortening and depressed functioning of gap junctions between cardiomyocytes resulting inefficient electrical conduction (7,8). Also a defect in intracellular calcium handeling has been found to results in depressed actin myosin contraction in septic cardiomyocytes (9). Mitochondrial depression has often been speculated to be associated with many of the oxygen transport abnormalities such as oxygen extraction deficit, seen in sepsis (10). This involves the idea that despite adequate oxygen delivery to the parenchymal cells, the mitochondria are unable to utilize oxygen adequately by oxidative phosphrylation to produce ATP needed for cellular energy requirements. Although not in heart, but in skeletal muscle, clinical studies studying mitochondrial bioenergetics from muscle biopsies have indeed shown depressed mitochondrial function to exist in septic patients, a condition associated with increased mortality (11). Whether this actually occurs in vivo and to what extent this phenomena contributes to the pathogensis of sepsis should be measureable if mitochondrial oxygen pressures could be reliably measured in vivo, a feat which to date had not been accomplished. Recently, we were successful in accomplishing this holy grail in myocardial bioenergetics by our identification of the oxygen-dependent optical properties of the endogenous mitochondrial molecule, protoporphyrin IX by which it became possible to quantitatively measure mitochondrial pO2 in vivo by use of delayed decay of fluorescence measurements (12). After validation in single cells we showed that the technique worked in vivo and allowed us the first time quantitative measurements of mitochondrial pO2 in liver and heart (13,14). Application in experimental models of sepsis has given new and startling insights into the mitochondrial origin of possible mechanisms of oxygen extraction deficit in the septic myocardium.

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