17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial.

Abstract

BACKGROUND:

Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS.

METHODS:

All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation).

RESULTS:

A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood-brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration.

CONCLUSIONS:

EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

• 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: Critical care (London, England) (Crit Care) Vol. 25 Issue 1 Pg. 428 (12 16 2021) ISSN: 1466-609X [Electronic] England
• PMID: 34915927 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• estradiol-3-sulfate
• Estradiol

Topics

• Animals
• Brain Injuries, Traumatic (complications, drug therapy)
• Disease Models, Animal
• Estradiol (analogs & derivatives)
• Female
• Hemodynamics
• Male
• Neuroinflammatory Diseases
• Resuscitation
• Shock, Hemorrhagic (drug therapy)
• Swine