Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial.
OBJECTIVE
Platelet-activating factor (PAF) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome. One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase (PAF-AH). Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients, the present study was conducted to determine whether treatment with recombinant human PAF-AH (rPAF-AH, Pafase) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality.


METHODS
A prospective, randomized, double-blind, placebo-controlled, multicenter trial.


METHODS
Thirty-three medical and surgical intensive care units located in the United States.


METHODS
A total of 127 patients with severe sepsis, but without established acute respiratory distress syndrome, were enrolled in the study. Randomization occurred within 12 hrs of the onset of severe sepsis. Patients then received 1.0 mg/kg rPAF-AH (n = 45), 5.0 mg/kg rPAF-AH (n = 39), or placebo (n = 43) administered intravenously, once daily, for five consecutive days.


RESULTS
Demographic and baseline clinical characteristics of the three treatment groups were similar, except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH. There were no treatment-related deaths, and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients. There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups. However, 28-day all-cause mortality was 21% in the 1.0 mg/kg rPAF-AH group, 28% in the 5.0 mg/kg rPAF-AH group, and 44% in the placebo group (overall chi-square p =.07; 1.0 mg/kg rPAF-AH vs. placebo, p =.03). A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group (p =.11).


CONCLUSIONS
The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis.
Schuster
Daniel P
DP
Washington University School of Medicine, St. Louis, MO, USA.
Metzler
Michael
M
Opal
Steven
S
Lowry
Stephen
S
Balk
Robert
R
Abraham
Edward
E
Levy
Howard
H
Slotman
Gus
G
Coyne
Eileen
E
Souza
Sonia
S
Pribble
John
J
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000494:pharmacology / Q000627:therapeutic use*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D015995:Prevalence; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011994:Recombinant Proteins; D012128:Respiratory Distress Syndrome / Q000453:epidemiology / Q000517:prevention & control*; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D014481:United States / Q000453:epidemiology
D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase