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.

Predictive role of shock index in the early formation of cerebral infarction in patients with TBI and cerebral herniation

“…factors early after TBI can help to reduce the probability of PTCI occurrence and thus improve the prognosis of TBI patients. TBI patients are often associated with multiple injuries, and hypovolemic shock often already occurs before admission (9). SI is a commonly used assessment index for patients with acute trauma in clinical practice which can reflect the severity of trauma in patients (10).…”

Oxytocin and Related Peptide Hormones: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis

“…Besides peptides hormones like ghrelin, oxytocin and hCG, consideration should be giving to steroid hormones like estradiol and other steroid hormones (1,6,224,225).…”

Polynitroxylated PEGylated hemoglobin protects pig brain neocortical gray and white matter after traumatic brain injury and hemorrhagic shock

“…In most studies, they typically range in age from 4 days (neonatal model) ( 33 ), to 1 month (toddler model) ( 34 ), and to 35–45 kg (pre-pubertal juvenile model) ( 35 ); the latter are considered pediatric models. Because sexually mature adult domestic pigs are more difficult to accommodate logistically in most laboratories, minipig strains provide an alternative adult model ( 36 , 37 ), but their financial cost is considerably greater than domestic pigs. Here, we used 3-month-old juvenile pigs (approximately 30 kg) in our model of TBI + HS for testing the therapeutic efficacy of PNPH at doses of 10 or 20 ml/kg (300–600 ml for a 30-kg pig).…”