Surviving Blood Loss Without Fluid Resuscitation

Abstract

Patients with massive blood loss often die before delivery of definitive care, especially in austere environments. Strategies that can maintain life during evacuation and transport to higher levels of care may be lifesaving. We have previously shown that administration of histone deacetylase inhibitors (HDACI) enhance gene transcription through specific modifications of DNA-associated histone proteins. Furthermore, it protects against organ damage when given before hemorrhage. The current experiment was done to test whether administration of HDACI after lethal hemorrhage, without fluid resuscitation, would improve outcome by creating a pro-survival phenotype. Seventy-two male Wistar-Kyoto rats (n = 12 per group) were subjected to 60% blood volume loss for 1 hour (40% arterial bleed for 10 minutes and 20% venous bleed for 50 minutes). After hemorrhage, animals were randomized to receive one of two HDACI: (1) valproic acid (VPA, 300 mg/kg in 0.25 mL saline), or (2) suberoyanilide hydroxamic acid (SAHA, 7.5 mg/kg in 0.25 mL saline). Control groups included (3) no hemorrhage (Sham), (4) no resuscitation (NR), (5) 0.9% saline resuscitation, 3 times the volume of shed blood (NS), and (6) vehicle control, 0.25 mL 0.9% saline (VEH). Hemodynamic data were recorded continuously, and physiologic parameters were measured serially. Survival for 3 hours was the primary endpoint for this experiment. Nonresuscitated shock (NR group) was highly lethal and only 25% of the animals survived for 3 hours. Administration of HDACI after hemorrhage (without fluid resuscitation) significantly improved survival (75% and 83% in VPA and SAHA groups, respectively, p < 0.05 vs. NR). Survival was 40%, 100%, and 100% in the VEH, Sham, and NS resuscitation groups, respectively. This study demonstrates that post-shock administration of HDACI can significantly improve early survival in a highly lethal model of hemorrhagic shock, even in the absence of conventional fluid resuscitation. This approach may be especially relevant for austere environments where fluids are in limited supply, such as a battlefield.