Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study.

OBJECTIVES: Inhibitors of nitric oxide synthesis have been suggested to be of value in the treatment of hypotension during sepsis. However, earlier clinical reports only describe the initial effects of these nitric oxide inhibitors. This study was designed to examine the effects of the prolonged inhibition of nitric oxide synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock.
DESIGN: Prospective, nonrandomized, clinical study.
SETTING: Medical-surgical intensive care unit in a university hospital. PATIENTS: Eleven consecutive patients with ongoing hyperdynamic septic shock that was unresponsive to fluid resuscitation and vasopressor therapy.
INTERVENTIONS: Measurements of hemodynamic, hematologic, and biochemical variables were made before, during, and after the start of a continuous intravenous infusion of 1 mg/kg/hr of L-NAME, an inhibitor of nitric oxide synthesis, for a period of 12 hrs.
MEASUREMENTS AND MAIN RESULTS: Continuous infusion of L-NAME resulted in a direct increase in mean arterial pressure from 65 +/- 3 (SEM) to 93 +/- 4 mm Hg and an increase in systemic vascular resistance from 426 +/- 54 to 700 +/- 75 dyne x sec/cm5, reaching a maximum at 0.5 hr. Pulmonary arterial pressure was increased from 31 +/- 2 to a maximum of 36 +/- 2 mm Hg at 1 hr, and pulmonary vascular resistance increased from 146 +/- 13 to a maximum of 210 +/- 23 dyne x sec/cm5 at 3 hrs. Paralleling these changes, cardiac output decreased from 10.8 +/- 0.8 to 8.7 +/- 0.7 L/min and oxygen delivery decreased from 1600 +/- 160 to 1370 +/- 130 mL/min (for all changes p < .05 as compared with the baseline value). Heart rate, cardiac filling pressures, oxygen consumption, urine production, arterial lactate concentration, and other biochemical parameters were not significantly changed by L-NAME administration (all p > .05). Arterial oxygenation was improved during L-NAME infusion, and the dosage of catecholamines could be reduced (both p< .05). Although sustained hemodynamic effects were seen, L-NAME was most effective during the early stages of administration, and the effect of L-NAME on blood pressure and vascular resistance tended to diminish throughout the continuous infusion of L-NAME. Seven of 11 patients ultimately died, with survival time ranging from 2 to 34 days.
CONCLUSIONS: Nitric oxide appears to play a role in cardiovascular derangements during human sepsis. The increased blood pressure and vascular resistance values are sustained during prolonged inhibition of nitric oxide synthesis with L-NAME in patients with severe septic shock, although the hemodynamic changes are most significant in the early stages of L-NAME infusion. The high mortality rate in these patients may suggest that L-NAME has only limited effects on outcome.