Objectiveor=to70 mmHg.DesignMulticenter, open-label, uncontrolled, dose range finding study.SettingTen intensive care units in Europe and the United States.PatientsThirty-two patients with septic shock diagnosed within <24 hrs.InterventionsPatients 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 noreplnephrine 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 Results70 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.ConclusionsTreatment 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. (Crit Care Med 1999; 27:913-922)