Therapeutic aspects of oxygen utilisation.

Total body oxygen consumption 0702) is a measure of global aerobic metabolism and it has been suggested that an inability to consume oxygen is the best early predictor of organ failure1. V02 is however, dependent on metabolic demands, which may vary widely in critically ill patients and there has therefore been considerable interest in using the relationship between oxygen delivery (DO21 and V02 as a means of evaluating the adequacy of tissue oxygenation. A number of studies have demonstrated that in apparently stable critically ill patients, in contrast to normal physiology, V02 increases when DO2 is augmented and falls in response to reductions in D022,3. Characteristically this phenomenon, termed supply dependency, is associated with increased oxygen demand, a diminished ability of the tissues to alter oxygen extraction in response to a change in DO2 and the presence of raised lactate levels. The demonstration of supply dependency has been regarded as indi4 rect evidence of occult tissue oxygen debt and associated with a high mortality. In contrast, in some recent studies although an oxygen flux test was not specifically performed, the ability to increase VO2 when DO2 was enhanced was associated with survival, whereas in those in whom V02 was unresponsive to increases in DO2 had persistently elevated lactate concentrations and an extremely poor prognosis5.6. Studies investigating the relationship between DO2 and V02 are complicated by many factors including; mathematical coupling7; the spontaneous fluduations in V02 and DO2 in apparently stable critically ill patients8; and the effect of catecholamines on oxidative metabolism which can lead to increases in V029. Recent work has even suggested that the critical level of oxygen delivery is much lower than that previously reported in normal humans and perhaps surprisingly is not altered by sepsislO. The uncertainty surrounding supply dependency and the knowledge that the critical level of oxygen delivery may not be altered by sepsis undermines the basis for goal directed therapy in critically ill patients. It is now clear that outcome of this group of patients is worsened when aggressive treatment with inotropes is directed towards attaining supranormal levels of both oxygen delivery and consumption. It is also understood that it is the ability to attain a hypermetabolic state with elevated levels of cardiac index, D02, and V02 that is associated with a good outcome. Administration of very small doses of endotoxin to normal human volunteers produces a significant increase in both DO2 and VO2l1. Patients with uncomplicated sepsis have a greater capacity to extract oxygen (and consequently a higher V02) despite a lower cardiac index and DO2 than more severely ill patients with sepsis syndrome12. Hypermetabolism therefore appears to be an important component of a successful host response particularly in sepsis. In rats made septic by caecal ligation and puncture, those who survived remained hypermetabolic, whilst preterminal animals were hypometab~lic'~. It is perhaps not surprising, therefore, that impaired oxygen utilisation, as reflected by significantly falling oxygen extraction, has been shown to be associated with non survival5, an observation that is consistent with a study that has shown a relationship between low oxygen extraction and death in paediatric septic shock14. In patients with sepsis syndrome and septic shock, cardiac index and DO2 increased in survivors and nonsurvivors, however in nonsurvivors this was offset by a fall in oxygen extraction which prevented or limited any rise in V026. Survivors were characterised by a significant increase in DO2 but as oxygen extraction was maintained, this was accompanied by a significant increase in V02. Importantly, aggressive inotropic support administered to boost DO2 simply appeared to exacerbate the fall in oxygen extraction in nonsurvivors6. These results are consistent with previous work demonstrating that low V02 is associated with a poor outcome15; increased V02 is characteristic of survivors16 and an early inability to increase V02 to survivor levels in trauma patients can predict the subsequent development of multiple organ failure 1 .