Platelet-activating factor receptor antagonist BN 52021 in... : Critical Care Medicine (original) (raw)

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Dhainaut, Jean-Francois A. MD, PhD; Tenaillon, Alain MD; Le Tulzo, Yves MD; Schlemmer, Benoit MD; Solet, Jean-Pierre MD; Wolff, Michel MD; Holzapfel, Laurent MD; Zeni, Fabrice MD; Dreyfuss, Didier MD; Mira, Jean-Paul MD; de Vathaire, Florent PhD; Guinot, Philippe MD, PhD the BN 52021 Sepsis Study Group

From the Medical Intensive Care Units of Cochin Port-Royal University Hospital, Paris, France (Drs. Dhainaut and Mira); L. Michel University Hospital, Evry, France (Dr. Tenaillon); Pontchaillou University Hospital, Rennes, France (Dr. Le Tulzo); Saint Louis University Hospital, Paris, France (Dr. Schlemmer); V. Dupouy Hospital, Argenteuil, France (Dr. Solet); Bichat University Hospital, Clichy, France (Dr. Wolff); Bourg en Bresse Hospital, Bourg en Bresse, France (Dr. Holzapfel); Bellevue University Hospital, Clermont Ferrand, France (Dr. Zeni); L. Mourier Hospital, Colombes, France (Dr. Dreyfuss); the Department of Biostatistics (INSERM U351), G. Roussy Institut, Villejuif, France (Dr. de Vathaire); and the Research and Development Division, H. Beaufour-Ipsen Institut, Paris, France (Dr. Guinot).

This study was supported, in part, by H. Beaufour-Ipsen Institut.

*The BN 52021 Sepsis Study Group was composed of the following groups.

Participating Centers: Bourg en Bresse Hospital, Bourg en Bresse, France (L. Holzapfel, MD, D. Demingeon, MD, B. Piralla MD); Bellevue University Hospital, Clermont Ferrand, France (F. Zeni, MD; J.C. Bertrand, MD; P. Gery, MD); L. Mourier University Hospital, Colombes, France (D. Dreyfuss, MD, L. Mier, MD, K. Djedaïni, MD); Saint Louis University Hospital, Paris, France (B. Schlemmer, MD, E. Deland, MD, G. Leuleu, MD); Cochin Port-Royal University Hospital, Paris, France (J.F.A. Dhainaut, MD, PhD [Principal Investigator], J.P. Mira, MD, F. Brunet, MD); L. Michel University Hospital, Evry, France (A. Tenaillon, MD [Co-Principal Investigator], R. Boiteau, MD, T. Lherm, MD); Pontchaillou University Hospital, Rennes, France (Y. Letulzo, MD, I. Jouanic-Martinez, MD, P. Seguin, MD); E. Herriot University Hospital, Lyon, France (J. Motin, J.M. Vedrinne, MD); Sainte Marguerite University Hospital, Marseille, France (Claude Martin, MD, F. Gouin, MD); V. Dupouy University Hospital, Argenteuil, France (J.P. Sollet, MD, G. Bleichner, MD); Bichat University Hospital, Clichy, France (J. Chastre, MD, S. Calvat, MD); Bicetre University Hospital, Kremlin-Bicètre, France (P. Auzepy, MD, C. Richard, MD); Hôtel Dieu University Hospital, Nantes, France (D. Villers, MD, E. Bironneau, MD); A. Calmette University Hospital—A-Lille, France (A. Durocher, MD, F. Saulnier, MD); La Croix Rousse University Hospital, Lyon, France (M. Sirodot, MD, J.M. Dubois, MD); R. Poincaré University Hospital, Garches, France (P. Gajdos, MD, B. Clerc, MD); G. Roussy Institut, Villejuif, France (G. Nitenberg, MD, M. Garrouste, MD); Hautepierre University Hospital, Strasbourg, France (J.D. Tempe, MD, F. Schneider, MD; A. Calmette University Hospital—Lille-B, France (A. Rime, MD, H Mehdaoui, MD); Caen University Hospital, Caen, France (P. Charbonneau, MD, E. Gallet, MD); Limoges University Hospital, Limoges, France (H. Gastinne, MD, P. Vignon, MD).

Independent Department of Biostatistics: G. Roussy Institut, Villejuif, France (Florent de Vathaire, PhD).

Institut Beaufour-Ipsen Research and Development, Paris, France: Jean M. Chrétien, MD, Marie Laurence Gourlay, MD, Véronique Lavergne, MD, Philippe Guinot, PhD, Jérome Marsais, MS.

Clinical Evaluation Committee: Jean-François A. Dhainaut, MD, PhD, Alain Tenaillon, MD, Yves Letulzo, MD, Benoit Schlemmer, MD, Jean-Pierre Solet, MD, Michel Wolff, MD.

Address requests for reprints to: Dr. Jean-François A. Dhainaut, Medical ICU, Cochin Port-Royal University Hospital, 27 rue du Faubourg Saint Jacques, 75679 Paris Cedex 14, France.

Abstract

Objective:

To evaluate the safety and efficacy of a natural platelet-activating factor receptor antagonist, BN 52021 (Ginkgolide B), in the treatment of patients with sepsis syndrome.

Design:

Prospective, randomized, placebocontrolled, double-blind, phase III, multicenter clinical trial.

Setting:

Twenty-one academic medical center intensive care units in France.

Patients:

Two hundred sixty-two patients with sepsis syndrome who received standard supportive care and antimicrobial therapy, in addition to the administration of platelet-activating factor receptor antagonist or placebo.

Interventions:

Patients received either a 120-mg dose of platelet-activating factor receptor antagonist intravenously every 12 hrs over a 4-day period or placebo.

Main Outcome Measurements:

All patients were evaluated for 28-day, all-cause mortality.

Results:

The 28-day mortality rate was 51% for the placebo group and 42% for the platelet-activating factor receptor antagonist group ( p = .17). However, the efficacy of platelet-activating factor receptor antagonist was significantly greater in patients with Gram-negative sepsis (test for interaction, p = .03). In a separate analysis of patients with and without Gram-negative sepsis, the 28-day mortality rate was 57% for the patients receiving placebo (30 deaths of 53 patients) and 33% for patients receiving platelet-activating factor receptor antagonist (22 deaths of 67 patients; p = .01). Platelet-activating factor receptor antagonist also significantly ( p = .01) reduced the mortality rate among patients with Gram-negative sepsis who were in shock at entry into the study (mortality rate was 65% for placebo vs. 37% for platelet-activating factor receptor antagonist) and among patients >60 yrs of age (mortality rate was 74% for placebo vs. 31% for platelet-activating factor receptor antagonist). A Cox proportional-hazards model identified five independent prognostic factors: a) adequacy of antibiotic therapy; b) severity of illness; c) renal failure; d) hematologic failure; and e) hepatic failure at study entry. When the Gram-negative sepsis population was stratified by age and these five prognostic factors were controlled for, the relative risk of death of the platelet-activating factor receptor antagonist group was 0.61 (0.34 to 1.08, 95% confidence interval; p = .09). This risk corresponds with an adjusted reduction in mortality rate of 39% for patients receiving plateletactivating factor receptor antagonist. No differences in mortality rates were found between the placebo and the platelet-activating factor receptor antagonist groups in the absence of Gram-negative sepsis. There were no differences in adverse events between the placebo and the treated groups.

Conclusion:

The studied platelet-activating factor receptor antagonist (BN 52021) seems to be a safe and promising treatment for patients with severe Gram-negative sepsis. (Crit Care Med 1994; 22:1720–1728)