Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.

Tissue Po(2) (tPo(2)) reflects the balance between local O(2) supply and demand and, thus, could be a useful monitoring modality. However, the consistency and amplitude of the tPo(2) response in different organs during different cardiorespiratory insults is unknown. Therefore, we investigated the effects of endotoxemia, hemorrhage, and hypoxemia on tPo(2) measured in deep and peripheral organ beds. We compared arterial pressure, blood gas and lactate levels, descending aortic and renal blood flow, and tPo(2) in skeletal muscle, bladder epithelium, liver, and renal cortex during 1) LPS infusion (10 mg/kg), 2) sequential removal of 10% of circulating blood volume, and 3) reductions in inspired O(2) concentration in an anesthetized Wistar rat model with values measured in sham-operated animals. Different patterns were seen in each of the shock states, with condition-specific variations in the degree of acidemia, lactatemia, and tissue O(2) responses between organs. Endotoxemia resulted in a rise in bladder tPo(2) and an early fall in liver tPo(2) but no significant change in muscle and renal cortical tPo(2). Progressive hemorrhage, however, produced proportional declines in liver, muscle, and bladder tPo(2), but renal cortical tPo(2) was maintained until profound blood loss had occurred. By contrast, progressive hypoxemia resulted in proportional decreases in tPo(2) in all organ beds. This study highlights the heterogeneity of responses in different organ beds during different shock states that are likely related to local changes in O(2) supply and utilization. Whole body monitoring is not generally reflective of these changes.

Hypoxaemia and hyperoxaemia both compromised haemodynamics and biochemical markers of organ perfusion during severe, progressive haemorrhage. This may carry implications for resuscitation practice.

The insufflation of oxygen at 1 litre kg-1 min-1 via two endobronchial catheters (called continuous flow ventilation (CFV)) maintained a normal PaCO2 and a constant PaO2 in anaesthetized paralysed dogs and in five out of seven cats. In two cats with a high carbon dioxide production, CFV failed to maintain carbon dioxide homeostasis since gas flows greater than 1 litre kg-1 min-1 caused thoracic distension and a decrease in arterial pressure. In five patients, endobronchial insufflation of oxygen 0.5 litre kg-1 min-1 caused approximately a 30% decrease in the increase in PaCO2 compared with apnoeic oxygenation (P less than 0.05) during a period of 6 min. CFV at 1 litre kg-1 min-1 can be used for physiological measurement without respiratory movement while maintaining blood-gas homeostasis in dogs and in cats with a normal carbon dioxide production. Ethical constraints have so far prevented the investigation of the effects of comparable gas flows in man.