Shock/Sepsis/Trauma/Critical CareDecay-accelerating factor limits hemorrhage-instigated tissue injury and improves resuscitation clinical parameters
Introduction
Hemorrhage is responsible for 50% of combat field deaths [1]. In an analysis of in-hospital deaths at a modern combat support hospital, Martin et al. found that deaths with high preventability scores (mean > 54) were primarily related to delays in hemorrhage control during the transportation (47%) or resuscitation phase (43%) [2]. A significant number of trauma victims that survive the initial hemorrhage subsequently die of some form of systemic inflammatory response due to complications of ischemia and/or reperfusion injury, ultimately leading to multiple organ dysfunction syndrome or acute respiratory distress syndrome [3], [4]. This associated mortality secondary to hemorrhagic shock occurs despite seemingly acceptable medical therapy and surgical intervention [5]. Maintenance of tissue oxygenation with adequate fluid resuscitation is believed to be one of the critical elements in the management of hemorrhagic patients. However, the most effective resuscitation strategies remain controversial. Pope et al. demonstrated that conventional resuscitation strategies, such as intravenous administration of crystalloids and colloids, can exacerbate cell injury caused by hemorrhagic shock [6]. Therefore, strategies aimed at reducing or eliminating the need for resuscitation fluid infusion have been identified as a major requirement for both military and civilian emergency medicine [6].
Late morbidity and mortality following hemorrhage is an outcome of a vicious cycle involving the activation of multiple inflammatory pathways, including the complement and coagulation systems. We and others have reported that complement activation is critical in the pathogenesis of ischemia/reperfusion-instigated intestinal injury and hemorrhage-induced intestinal damage and inflammation in mice [7], [8], [9]. Both local and systemic complement activation are part of a common inflammatory cascade in the pathogenesis of tissue damage and organ dysfunction in the early phase after trauma [10], [11]. Complement system activation in patients has been observed immediately after trauma and its activity correlates to the severity of the injury and complications [12].
Complement inhibition has been shown to be a promising therapeutic strategy in intestinal ischemia/reperfusion in mice and hemorrhagic shock in rats and swine [9], [13], [14]. Decay-accelerating factor (CD55/DAF) is a complement membrane protein that decays C3/5 convertases in both the classical and alternative pathways and prevents the assembly of the C3/5 convertases, thus blocking the formation of the generation of C3a and C5a and the formation of the membrane attack complex [15]. We have previously demonstrated that DAF treatment attenuates tissue damage and lowers tissue complement activation and deposition in hemorrhaged swine [16]. In this study, we evaluated the ability of DAF to reduce or eliminate Hextend fluid resuscitation requirements in swine subjected to controlled severe hemorrhage.
Section snippets
Materials and methods
After Institutional Animal Care and Use Committee approval, adolescent male swine underwent controlled isobaric arterial hemorrhage with target mean arterial pressure of 35 mm Hg for 20 min followed by a bolus of DAF with or without Hextend infusion (Hospira, Lake Forest, IL), a plasma expander. All animals were cared for according to the Animal Welfare Act, the Animal Welfare Regulations, and the principles of the Guide for the Care and Use of Laboratory Animals.
DAF prolongs Hextend fluid–achieved resuscitation of swine subjected to hemorrhage
Animals were subjected to controlled bleeding to a MAP target fixed at 35 mm Hg for 20 min followed by bolus intravenous injection of saline or DAF (5, 25, 50 μg/kg), as outlined in Figure 1. This procedure was not lethal during the 200-min posthemorrhage observation period. The administration of Hextend resuscitation fluid alone resulted in a 27% survival rate (three out of 11 animals survived the observation period) (Fig. 2). The average time to death for Hextend fluid–resuscitated animals
Discussion
The present study was designed to investigate the therapeutic potential of complement inhibition in a resuscitated porcine model of controlled hemorrhage. Complement activation has been an important contributor to the pathophysiology of hemorrhagic shock. Complement activation significantly contributes to the mechanisms of systemic and local postinjury complications, such as ischemia/reperfusion injury, sepsis, and multiple organ failure [7], [22]. As an ongoing effort to learn more about the
Acknowledgment
The authors would like to thank Ms Shawn L. Dalle Lucca for the invaluable contributions in the editing and formatting of this manuscript.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
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