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.
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.


METHODS
Multicenter, open-label, uncontrolled, dose range finding study.


METHODS
Ten intensive care units in Europe and the United States.


METHODS
Thirty-two patients with septic shock diagnosed within <24 hrs.


METHODS
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.


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.
Grover
R
R
International Department of Cardiovascular/Critical Care Medicine Clinical Research, Glaxo Wellcome Research and Development, Greenford, UK.
Zaccardelli
D
D
Colice
G
G
Guntupalli
K
K
Watson
D
D
Vincent
J L
JL
D000328:Adult; D000368:Aged; D001784:Blood Gas Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D016019:Survival Analysis; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000627:therapeutic use
D014662:Vasoconstrictor Agents; D019001:Nitric Oxide Synthase