Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.
OBJECTIVE
To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28.


METHODS
Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study.


METHODS
A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia.


METHODS
A total of 797 patients with septic shock diagnosed for <24 hrs.


METHODS
Patients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL.kg(-1).hr(-1) (2.5 mg.kg(-1).hr(-1) 546C88) and titrated up to a maximum rate of 0.4 mL.kg(-1).hr(-1) to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors.


RESULTS
Hemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p <.001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group.


CONCLUSIONS
In this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.
López
Angel
A
Hospital Infanta Cristinam, Badajoz, Spain.
Lorente
Jose Angel
JA
Steingrub
Jay
J
Bakker
Jan
J
McLuckie
Angela
A
Willatts
Sheila
S
Brockway
Michael
M
Anzueto
Antonio
A
Holzapfel
Laurent
L
Breen
Desmond
D
Silverman
Michael S
MS
Takala
Jukka
J
Donaldson
Jill
J
Arneson
Carl
C
Grove
Geraldine
G
Grossman
Steven
S
Grover
Robert
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002423:Cause of Death; D003422:Critical Care / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000401:mortality; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality*; D016019:Survival Analysis; D016896:Treatment Outcome; D019323:omega-N-Methylarginine / Q000008:administration & dosage* / Q000009:adverse effects
D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase