Endotoxin versus bacteremia: a comparison focusing on clinical relevance

All phenomena seen under ovine endotoxemia or bacteremia are typically observed in septic humans as well. The lethality (approximately 20%) in both sepsis models underlines the severity of the experimental sepsis in these models. As mentioned above, both models are ideal to objectify the effects of new therapeutic approaches for the treatment of sepsis, because they provide stable conditions. We tested the inhibition of nitric oxide synthase in both models: Nitric oxide is the main mediator of the vasodilation and the hyperdynamic circulation seen in sepsis. Since the restoration of the perfusion pressure is the major therapeutic goal to prevent further tissue damage (Chernow et al. 1990), the blockade of the nitric oxide synthase seems to be a logical approach for the treatment of hyperdynamic sepsis. Therefore, we tested the nitric oxide synthase inhibitor N(W)-nitro-L-arginine methyl ester (L-NAME) in the endotoxemic sheep model as well as in the bacteremic model. L-NAME reversed the hyperdynamic circulation of sepsis (Meyer et al.1992; Dehring et al.1993). The cardiac output was lowered back to baseline, and at the same time, the arterial pressure was elevated to baseline niveau, both resulting in a marked increase in systemic vascular resistance (figure 3). The pulmonary artery pressure showed only a slight increase, but due to the marked reduction in cardiac output the pulmonary vascular resistance increased significantly. The oxygen extraction was elevated to an extent, which prevented the oxygen consumption to fall, although the oxygen delivery dropped significantly because of the lowered cardiac output (figure 4). The intrapulmonary shunt was brought back to baseline (Meyer et al.1994a), allowing an improved pulmonary oxygen uptake. The renal function improved significantly after nitric oxide synthase inhibition in endotoxemia as well as in bacteremia (Hinder et al.1994; Lingnau et al.1994). Not only was the creatinine clearance elevated, but the urine output also increased, lowering the positive fluid balance. Another inhibitor of nitric oxide synthase N(W)-Mono-Methyl-L-Arginine (L-NMMA) was recently tested in these models as well. This drug is now already in clinical trials. The fact that the effects of these nitric oxide synthase inhibitors in septic humans are similar to the effects in the described experimental sepsis models proves the clinical relevance of the endotoxemic and the bacterimic sheep model.