EFFECTS OF NITRIC-OXIDE SYNTHESIS INHIBITION IN HYPERDYNAMIC ENDOTOXEMIA

Objective: To investigate the effects of N omega-nitro-L-arginine meth yl ester, an inhibitor of nitric oxide synthesis, on hemodynamics, gas exchange and oxygen transport in an ovine model of hyperdynamic sepsi s. Design: Prospective, nonrandomized, controlled study, with repeated measurements. Setting: University research laboratory. Subjects:Twent y healthy adult sheep (weighing 20 to 45 kg) were divided into two gro ups of 12 treated sheep and eight control sheep and studied. Intervent ions: Twenty awake, chronically instrumented sheep received a continuo us infusion of endotoxin (10 ng/kg/min) over 48 hrs. Twenty-four hours after the start of the endotoxin infusion, 12 sheep (treatment group) received a bolus of the nitric oxide synthesis inhibitor N omega-nitr o-L-arginine methyl ester (25 mg/kg), while the other eight animals (c ontrol group) received the carrier (0.9% NaCl). Measurements and Main Results: Twenty-four hours after the start of the endotoxin infusion, both groups exhibited a hyperdynamic state with increased cardiac indi ces, decreased systemic vascular resistance indices, impaired oxygenat ion, and increased pulmonary shunt fractions. In both groups, oxygen d elivery was significantly increased, while oxygen consumption remained virtually unchanged, resulting in a decreased oxygen extraction ratio . In the control group, the significant alterations in systemic hemody namics, lung function and oxygen transport persisted for the remainder of the study. Administration of N omega-nitro-L-arginine methyl ester normalized cardiac index and systemic vascular resistance index, incr eased mean arterial blood pressure, and decreased heart rate. Although oxygen delivery significantly decreased after administration of N ome ga-nitro-L-arginine methyl ester, oxygen consumption did not change, r esulting in a normalization of oxygen extraction ratio. Despite a sign ificant reduction of pulmonary shunt fraction, oxygenation dig not imp rove. Pulmonary arterial pressure and pulmonary vascular resistance in dex showed a peak 2 hrs after administration of the nitric oxide synth esis inhibitor and then tended to decrease. In contrast, the effects o f N omega-nitro-L-arginine methyl ester on the systemic circulation pe rsisted for the remainder of the study. Conclusions: The data support the assumption that augmented nitric oxide production is a major cause of the hemodynamic alterations seen in hyperdynamic endotoxemia. Admi nistration of the nitric oxide synthesis inhibitor N omega-nitro-L-arg inine methyl ester normalized the endotoxin-induced hyperdynamic state , but did not impair oxygen consumption, indicating adequate tissue pe rfusion of metabolically active organs. Inhibition of nitric oxide syn thesis may be a therapeutic option in the treatment of hyperdynamic se ptic patients when conventional therapy fails to maintain a minimum of cardiovascular performance.