Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88

Effect on survival in patients with septic shock

Angel López, Jose Angel Lorente, Jay Steingrub, Jan Bakker, Angela McLuckie, Sheila Willatts, Michael Brockway, Antonio R Anzueto, Laurent Holzapfel, Desmond Breen, Michael S. Silverman, Jukka Takala, Jill Donaldson, Carl Arneson, Geraldine Grove, Steven Grossman, Robert Grover

Research output: Contribution to journalArticle

602 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)21-30
Number of pages10
JournalCritical Care Medicine
Volume32
Issue number1
StatePublished - Jan 2004
Externally publishedYes

Fingerprint

Septic Shock
Double-Blind Method
Nitric Oxide Synthase
Placebos
Survival
Clinical Trials Data Monitoring Committees
Australasia
Safety
Multiple Organ Failure
Mortality
South America
Incidence
Cardiovascular System
North America
South Africa
Pulmonary Hypertension
Pharmaceutical Preparations
Cardiac Output
Intensive Care Units
Cause of Death

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

López, A., Lorente, J. A., Steingrub, J., Bakker, J., McLuckie, A., Willatts, S., ... Grover, R. (2004). Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock. Critical Care Medicine, 32(1), 21-30.

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 journalArticle

López, A, Lorente, JA, Steingrub, J, Bakker, J, McLuckie, A, Willatts, S, Brockway, M, Anzueto, AR, Holzapfel, L, Breen, D, Silverman, MS, Takala, J, Donaldson, J, Arneson, C, Grove, G, Grossman, S & Grover, R 2004, 'Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock', Critical Care Medicine, vol. 32, no. 1, pp. 21-30.
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. / Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88 : Effect on survival in patients with septic shock. In: Critical Care Medicine. 2004 ; Vol. 32, No. 1. pp. 21-30.
@article{06064f47c564457da5a50709b104e535,
title = "Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock",
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.",
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",
author = "Angel L{\'o}pez and Lorente, {Jose Angel} and Jay Steingrub and Jan Bakker and Angela McLuckie and Sheila Willatts and Michael Brockway and Anzueto, {Antonio R} and Laurent Holzapfel and Desmond Breen and Silverman, {Michael S.} and Jukka Takala and Jill Donaldson and Carl Arneson and Geraldine Grove and Steven Grossman and Robert Grover",
year = "2004",
month = "1",
language = "English (US)",
volume = "32",
pages = "21--30",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

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 -