• Jan Bakker, Robert Grover, Angela McLuckie, Laurent Holzapfel, Jan Andersson, Robert Lodato, David Watson, Steven Grossman, Jill Donaldson, Jukka Takala, and Glaxo Wellcome International Septic Shock Study Group.
• Department of Intensive Care, Gelre Lukas Hospital, Apeldoorn, The Netherlands.
• Crit. Care Med. 2004 Jan 1;32(1):1-12.

ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure > or =70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period.DesignMulticentered, randomized, placebo-controlled, safety and efficacy study.SettingForty-eight intensive care units in Europe, North America, and Australia.PatientsA total of 312 patients with septic shock diagnosed within 24 hr before randomization.InterventionsPatients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s).Measurements And Main ResultsRequirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p =.004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups.ConclusionsIn this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

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