William Hubbard1, James Keith2, Jonathan Berman3, Matthew Miller4, Charles Scott3, Carl Peck5, Irshad H Chaudry6. 1. Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama. 2. Keith Pharmacology Research Group, LLC, Andover, Massachusetts. 3. Fast-Track Drugs and Biologics LLC, North Potomac, Maryland. 4. Texas A&M Institute for Preclinical Studies, Texas A&M University, College Station, Texas. 5. NDA Partners LLC, Falls Church, Virginia. 6. Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: ichaudry@uabmc.edu.
Abstract
BACKGROUND: From 2001-2011, >80% of potentially survivable United States battlefield deaths were due to severe hemorrhage. We subjected male rats to acute severe blood loss, administered a single dose of 17α-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and measured survival and also mean arterial pressures (MAP). METHODS: After controlled removal of 60% circulating blood volume (10-11 mL) over approximately 45 min, rats received EE-3-SO4 at 0 (vehicle controls), 0.1, 0.3, 1.0, or 3.0 mg/kg in 40 μL/100 g BW saline intravenously. MAP was recorded for 40 min after drug administration and survival was recorded for 6 h. RESULTS: The dose response curve was bell shaped with optimum survival at 1 mg/kg EE-3-SO4. Median survival times of rats receiving 1 mg/kg (360 min) were approximately 6 times that of the control group (57 min): P = 0.0001. The number of animals alive at 6 h was 16 of 20 (80%) in the 1 mg/kg group versus 0 of 20 (0%) in the control group. Early increases in MAP correlated with longer survival times. CONCLUSIONS: Administration of a single dose of 1 mg/kg EE-3-SO4 in 0.4 mL/kg of saline after controlled severe hemorrhage increased survival in rats by 6-fold. Partial recovery of blood pressure values correlated with longer survival time. These results, coupled with similar findings in a companion study in minipigs, support the further product development of EE-3-SO4 for: (1) severe hemorrhage when standard resuscitative fluids are not available, and (2) situations in which prolonged transportation periods are required for definitive treatment of the injured.
BACKGROUND: From 2001-2011, >80% of potentially survivable United States battlefield deaths were due to severe hemorrhage. We subjected male rats to acute severe blood loss, administered a single dose of 17α-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and measured survival and also mean arterial pressures (MAP). METHODS: After controlled removal of 60% circulating blood volume (10-11 mL) over approximately 45 min, rats received EE-3-SO4 at 0 (vehicle controls), 0.1, 0.3, 1.0, or 3.0 mg/kg in 40 μL/100 g BW saline intravenously. MAP was recorded for 40 min after drug administration and survival was recorded for 6 h. RESULTS: The dose response curve was bell shaped with optimum survival at 1 mg/kg EE-3-SO4. Median survival times of rats receiving 1 mg/kg (360 min) were approximately 6 times that of the control group (57 min): P = 0.0001. The number of animals alive at 6 h was 16 of 20 (80%) in the 1 mg/kg group versus 0 of 20 (0%) in the control group. Early increases in MAP correlated with longer survival times. CONCLUSIONS: Administration of a single dose of 1 mg/kg EE-3-SO4 in 0.4 mL/kg of saline after controlled severe hemorrhage increased survival in rats by 6-fold. Partial recovery of blood pressure values correlated with longer survival time. These results, coupled with similar findings in a companion study in minipigs, support the further product development of EE-3-SO4 for: (1) severe hemorrhage when standard resuscitative fluids are not available, and (2) situations in which prolonged transportation periods are required for definitive treatment of the injured.
Authors: Andrew R Mayer; Andrew B Dodd; Julie G Rannou-Latella; David D Stephenson; Rebecca J Dodd; Josef M Ling; Carissa J Mehos; Cidney R Robertson-Benta; Sharvani Pabbathi Reddy; Rachel E Kinsler; Meghan S Vermillion; Andrew P Gigliotti; Veronik Sicard; Amy L Lloyd; Erik B Erhardt; Jessica M Gill; Chen Lai; Vivian A Guedes; Irshad H Chaudry Journal: Crit Care Date: 2021-12-16 Impact factor: 9.097