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January 1994

The Metabolic Effects of Platelet-Activating Factor Antagonism in Endotoxemic Man

Author Affiliations

From the Laboratory of Surgical Metabolism, Department of Surgery (Drs Thompson, Van Zee, Oldenburg, Rogy, Moldawer, and Lowry and Mss Coyle and Trousdale), and the Division of Urology (Dr Felsen), The New York Hospital—Cornell University Medical College, New York.

Arch Surg. 1994;129(1):72-79. doi:10.1001/archsurg.1994.01420250084011

Objective:  To determine if the inflammatory phospholipid platelet-activating factor (PAF) participated in the symptomatologic, metabolic, and counterregulatory hormonal responses of human endotoxemia.

Design:  In a double-blind, placebo-controlled study, five subjects received 10 mg of the PAF antagonist Ro 24-4736 orally, while five control subjects received a placebo. Eighteen hours later, all subjects were administered 4 ng/kg of endotoxin (lipopolysaccharide) intravenously.

Setting:  The Clinical Research Center of The New York Hospital—Cornell Medical Center.

Participants:  Healthy male volunteers.

Main Outcome Measures:  Repeated measurements of vital signs, symptoms, cytokine and hormone levels, resting energy expenditure, platelet aggregation, and bleeding times were performed during a 24-hour period.

Results:  Subjects who were pretreated with the PAF antagonist experienced fewer symptoms, including rigors at 1 hour (P<.05) and myalgias at 1 through 4 hours (P<.05) after administration of lipopolysaccharide. This was in concert with a diminished peak cortisol level (668±107 vs 959± 159 nmol/L in controls; P<.05), epinephrine secretion (1057±165 vs 2029±431 nmol/L in controls; P<.05), and almost complete inhibition of PAF-induced platelet aggregation ex vivo.

Conclusions:  These findings in the face of unaltered circulating cytokines tumor necrosis factor α, interleukin 1β, and interleukin 6, as well as the tumor necrosis factor receptor-I s, suggest that PAF may influence some endotoxin-induced, counterregulatory hormonal responses and symptoms through cytokine-independent mechanisms. This study further supports the role of PAF antagonists as an adjunct to cytokine blockade in the treatment of gram-negative sepsis.(Arch Surg. 1994;129:72-79)