Abstract
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. Design: Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. Setting: A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. Patients: A total of 797 patients with septic shock diagnosed for <24 hrs. Interventions: 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. Measurements and Main 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 21-30 |
| Number of pages | 10 |
| Journal | Critical Care Medicine |
| Volume | 32 |
| Issue number | 1 |
| State | Published - Jan 2004 |
| Externally published | Yes |
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Keywords
- Dobutamine
- Dopamine
- Human
- N-methyl-L-arginine hydrochloride
- Nitrate
- Nitric oxide
- Nitric oxide synthase inhibitor
- Norepinephrine
- Placebo-controlled study
- Resolution of shock
- Septic shock
- Severe sepsis
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine
Cite this
Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88 : Effect on survival in patients with septic shock. / López, Angel; Lorente, Jose Angel; Steingrub, Jay; Bakker, Jan; McLuckie, Angela; Willatts, Sheila; Brockway, Michael; Anzueto, Antonio R; Holzapfel, Laurent; Breen, Desmond; Silverman, Michael S.; Takala, Jukka; Donaldson, Jill; Arneson, Carl; Grove, Geraldine; Grossman, Steven; Grover, Robert.
In: Critical Care Medicine, Vol. 32, No. 1, 01.2004, p. 21-30.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88
T2 - Effect on survival in patients with septic shock
AU - López, Angel
AU - Lorente, Jose Angel
AU - Steingrub, Jay
AU - Bakker, Jan
AU - McLuckie, Angela
AU - Willatts, Sheila
AU - Brockway, Michael
AU - Anzueto, Antonio R
AU - Holzapfel, Laurent
AU - Breen, Desmond
AU - Silverman, Michael S.
AU - Takala, Jukka
AU - Donaldson, Jill
AU - Arneson, Carl
AU - Grove, Geraldine
AU - Grossman, Steven
AU - Grover, Robert
PY - 2004/1
Y1 - 2004/1
N2 - 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. Design: Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. Setting: A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. Patients: A total of 797 patients with septic shock diagnosed for <24 hrs. Interventions: 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. Measurements and Main 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.
AB - 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. Design: Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. Setting: A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. Patients: A total of 797 patients with septic shock diagnosed for <24 hrs. Interventions: 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. Measurements and Main 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.
KW - Dobutamine
KW - Dopamine
KW - Human
KW - N-methyl-L-arginine hydrochloride
KW - Nitrate
KW - Nitric oxide
KW - Nitric oxide synthase inhibitor
KW - Norepinephrine
KW - Placebo-controlled study
KW - Resolution of shock
KW - Septic shock
KW - Severe sepsis
UR - http://www.scopus.com/inward/record.url?scp=4444273012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4444273012&partnerID=8YFLogxK
M3 - Article
VL - 32
SP - 21
EP - 30
JO - Critical Care Medicine
JF - Critical Care Medicine
SN - 0090-3493
IS - 1
ER -