Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock.

Abstract

BACKGROUND:

We have shown that therapy directed at polymorphonuclear neutrophil (PMN) CD18 receptors attenuates sequelae associated with a post-trauma endotoxin (lipopolysaccharide [LPS]) challenge. Platelet activating factor (PAF) stimulates PMNs by CD18-independent pathways, and WEB-2086, a PAF receptor antagonist, blunts septic symptoms in many experimental models. This study tested the hypothesis that the blockade of non-CD18 dependent PMN adherence attenuates trauma- and LPS-evoked pulmonary dysfunction.

METHODS:

We performed three experiments. First, anesthetized swine were subjected to hind-limb trauma and 30% hemorrhage. After 1 hour animals were resuscitated with shed blood, lactated Ringer's solution (LRS), and WEB-2086 (10 mg/kg/hr) or vehicle. After a 72-hour recovery period, LPS was administered. LPS was then administered without an earlier episode of traumatic shock to animals treated with WEB-2086 or vehicle. Finally, PAF was infused before and after trauma and a dose response curve was obtained.

RESULTS:

Surprisingly, PAF blockade increased mortality after trauma (5 of 11 WEB-2086 animals versus 1 of 9 vehicle animals; p = 0.15) and depressed cardiac index and O2 delivery at 72 hours (p < 0.05). After LPS administration WEB-2086 treated pigs were unable to manifest the hyperdynamic circulatory compensation seen in the vehicle pigs. In the absence of traumatic shock, WEB-2086 was associated with reduced mortality (four of five WEB-2086 treated pigs versus two of five vehicle pigs survived 5 hours; p = 0.07) and improved arterial PO2 (p = 0.05) and base excess (p = 0.04) 60 minutes after LPS administration. The dose response curve for PAF infusion on the cardiac index was altered after trauma compared with the nontraumatized state.

CONCLUSIONS:

Because WEB-2086 had unexpected and fundamentally opposite properties before and after trauma, PAF may have a previously undescribed homeostatic role in the compensatory response to injury. These results also suggest that blockade of endogenous inflammatory mediators can have a positive or negative action, depending on the timing of administration and the preexisting condition.

• Authors: M J Schurr, T C Fabian, M A Croce, S A Geraci, K G Proctor
• Journal: Surgery (Surgery) Vol. 121 Issue 5 Pg. 493-500 (May 1997) ISSN: 0039-6060 [Print] United States
• PMID: 9142146 (Publication Type: Journal Article)

Chemical References

• Azepines
• Lipopolysaccharides
• Platelet Activating Factor
• Platelet Aggregation Inhibitors
• Triazoles
• WEB 2086

Topics

• Animals
• Azepines (pharmacology)
• Blood Gas Analysis
• Fluid Therapy
• Hemodynamics (drug effects)
• Lipopolysaccharides (pharmacology)
• Platelet Activating Factor (antagonists & inhibitors, pharmacology)
• Platelet Aggregation Inhibitors (pharmacology)
• Resuscitation
• Shock, Traumatic (blood, immunology, physiopathology, therapy)
• Swine
• Triazoles (pharmacology)