An open-label dose escalation study of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group
Grover, R; Zaccardelli, D; Colice, G; Guntupalli, K; Watson, D; Vincent, JL
OBJECTIVE: To assess the effects of the nitric oxide synthase inhibitor, 546C88, in patients with septic shock and to evaluate the range of dose rates that sustain mean arterial pressure (MAP) of > or =70 mmHg.
DESIGN: Multicenter, open-label, uncontrolled, dose range finding study.
SETTING: Ten intensive care units in Europe and the United States.
PATIENTS: Thirty-two patients with septic shock diagnosed within <24 hrs.
INTERVENTIONS: Patients received a fixed dose rate of 546C88 at either 1(n = 6), 2.5 (n = 6), 5 (n = 4), 10 (n = 5), or 20 mg/kg/hr (n = 11) by intravenous infusion for up to 8 hrs. Conventional vasoactive therapy was restricted to norepinephrine and/or dobutamine. During 546C88 therapy, MAP was to be maintained between 70 and 90 mm Hg, while attempting to withdraw any concurrent norepinephrine.
MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamics, blood gases, and plasma nitrate were assessed. Infusion of 546C88 (1-20 mg/kg/hr) for up to 8 hrs enabled a 60 to 80% reduction of the norepinephrine dose rate in all cohorts, while MAP was sustained at >70 mm Hg. There was an increase in vascular tone and a decrease in cardiac index within the 1st hr of therapy. Systemic vascular resistance returned toward baseline with reduction of concomitant administration of norepinephrine. The decline in oxygen delivery was associated with an increase in extraction and, therefore, the maintenance of oxygen consumption. There was a sustained reduction of venous admixture within the 1st hr of therapy. 546C88 was not associated with any major or dose-dependent adverse effect on pulmonary, hepatic, or renal function.
CONCLUSIONS: Treatment with the nitric oxide synthase inhibitor, 546C88, can restore the balance of vasomotor tone, thereby, maintaining blood pressure and reducing or eliminating the requirement for norepinephrine therapy in patients with septic shock. Infusion of 546C88 (1-20 mg/kg/hr) appears to have a satisfactory overall safety profile.