Interventional Vitamin C: A Strategy for Attenuation of Coagulopathy and Inflammation in a Swine Polytrauma Model

AbstractBACKGROUNDCoagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the pro-inflammatory and pro-coagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of polytrauma and hemorrhage.METHODSMale Sinclair swine (n = 24; mean body weight 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiological monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500mL of hydroxyethyl starch, and randomized to receive either intravenous saline (NS), low dose VitC (50mg/kg; LO), or high dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours post-resuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung.RESULTSCompared to VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue pro-inflammatory mediators (IL-1β, IL-8, TNFα), PAI-1, and TF. There were no statistically significant differences between treatment groups on MAP or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours.CONCLUSIONSAlthough correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the pro-inflammatory/pro-coagulant response that contributes to multiple organ failure following acute severe polytrauma.LEVEL OF EVIDENCEPreclinical (animal-based)STUDY TYPEProspective randomized controlled blinded trial BACKGROUND Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the pro-inflammatory and pro-coagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of polytrauma and hemorrhage. METHODS Male Sinclair swine (n = 24; mean body weight 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiological monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500mL of hydroxyethyl starch, and randomized to receive either intravenous saline (NS), low dose VitC (50mg/kg; LO), or high dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours post-resuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung. RESULTS Compared to VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue pro-inflammatory mediators (IL-1β, IL-8, TNFα), PAI-1, and TF. There were no statistically significant differences between treatment groups on MAP or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours. CONCLUSIONS Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the pro-inflammatory/pro-coagulant response that contributes to multiple organ failure following acute severe polytrauma. LEVEL OF EVIDENCE Preclinical (animal-based) STUDY TYPE Prospective randomized controlled blinded trial CORRESPONDING AUTHOR: Dr. P. S. Reynolds, PhD, Department of Anesthesiology, University of Florida, Gainesville FL, USA. email: PReynolds@anest.ufl.edu; FAX: 01.352.392.7029 CONFLICTS OF INTEREST AND SOURCES OF FUNDING: This research was supported by United States Department of Defense USAMRMC Contract Number W81XWH-15-2-0064 to R. Natarajan. Sponsor had no role in study design, data collection, analysis and interpretation; in the writing of the report; and in the decision to submit the article for publication. The authors declare that they have no competing interests. PREVIOUS PRESENTATIONS OR PUBLICATIONS: Summary findings from this study were presented as an oral presentation at the 2017 Military Health System Research Symposium (MHSRS), August 27, 2017, in Kissimmee, FL © 2018 Lippincott Williams & Wilkins, Inc.

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