17α-ethynylestradiol-3-sulfate treatment of severe blood loss in rats

• Published in: The Journal of surgical research 2015-01, Vol.193 (1), p.355-360
• Main Authors: Hubbard, William, PhD, Keith, James, DVM, PhD, Berman, Jonathan, MD, PhD, Miller, Matthew, DVM, Scott, Charles, PhD, Peck, Carl, MD, Chaudry, Irshad H., PhD
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - metabolism; Blood Pressure - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Ethinyl Estradiol - analogs & derivatives; Ethinyl Estradiol - chemistry; Ethinyl Estradiol - pharmacology; Ethynylestradiol sulfate; Hemorrhage - blood; Hemorrhage - drug therapy; Hydrogen-Ion Concentration; Kaplan-Meier Estimate; Lactic Acid - blood; Male; Rat; Rats, Sprague-Dawley; Severe shock; Sodium Chloride - pharmacology; Surgery; Survival; Survival Rate; Trauma Severity Indices
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2014.06.047

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.