Role of nitric oxide in the hemodynamic changes of sepsis

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Abstract
Objective To study the role of nitric oxide in the hemodynamic changes of sepsis. Design Prospective, randomized, controlled, intervention study. Subjects Twenty-five sheep randomized to four groups: Group A (n = 8, nonseptic sheep) received NG-nitro L-arginine (20 mg/kg iv) followed 15 mins later by L-arginine (200 mg/kg iv); group B (n = 4, nonseptic sheep) received L-arginine followed 15 mins later by NG-nitro L-arginine; group C (n = 7, septic sheep) received NG-nitro L-arginine (20 mg/kg iv) alone; group D (n = 6, septic sheep) received L-arginine (200 mg/kg iv) followed by NG-nitro L-arginine (20 mg/kg iv). Interventions Sheep were anesthetized with pentobarbital, mechanically ventilated and monitored with a pulmonary artery catheter, a peripheral artery catheter, and a Millar catheter in the left ventricle. Sepsis was induced by the intravenous administration of live Escherichia coli (1.5 x 109 microorganisms/kg over 30 mins), which resulted in systemic hypotension, pulmonary hypertension, high cardiac output, and hyperlactatemia. Acetylcholine was administered before and after each intervention. Measurements and Main Results In nonseptic sheep (groups A and B) NG-nitro L-arginine induced an increase in mean blood pressure (BP), pulmonary arterial pressure, and systemic and pulmonary vascular resistances, accompanied by a decrease in cardiac index and the first derivative of left ventricular pressure. L-arginine administered to normal sheep induced systemic vasodilation. In the sepsis groups (groups C and D), the increases in BP and systemic vascular resistances induced by NG-nitro L-arginine were significant but less marked than in nonseptic sheep. Pretreatment of septic sheep with L-arginine totally abolished the NG-nitro L-arginine induced increases in systemic and pulmonary vascular resistances in this group. The administration of L-arginine in these animals induced both systemic and pulmonary vasodilation. Acetylcholine-mediated vasodilation was severely impaired in sepsis. In this condition, pretreatment with L-arginine improved the response to acetylcholine. Conclusions These data support the view that nitric oxide plays a significant role in modulating systemic and pulmonary vasomotor tone in normal and septic sheep. L-arginine produced systemic vasodilation in normal sheep, whereas both systemic and pulmonary vasodilation were observed in septic animals. The impaired response to an endothelium-dependent vasodilator in sepsis was improved by the previous administration of L-arginine. (Crit Care Med 1993; 21:759–767)

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