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The primary objective of this study was to determine if 17\u03b1-ethinyl estradiol-3-sulfate (EE-3-SO<jats:sub>4<\/jats:sub>) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI\u2009+\u2009HS.\n<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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\u2009\u00b1\u200921.04\u00a0days old; 28.18\u2009\u00b1\u20092.72\u00a0kg) 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-SO<jats:sub>4<\/jats:sub> formulated in the vehicle at 5.0\u00a0mg\/mL (dosed at 0.2\u00a0mL\/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2\u00a0mL\/kg over 5\u00a0min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5\u00a0h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation).\n<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood\u2013brain barrier breach. The percentage of animals surviving to 295\u00a0min post-injury was significantly higher for the EE-3-SO<jats:sub>4<\/jats:sub> (28\/31; 90.3%) relative to Placebo (24\/33; 72.7%) cohort. EE-3-SO<jats:sub>4<\/jats:sub> 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-SO<jats:sub>4<\/jats:sub> group. Survival status was associated with biological sex (female\u2009&gt;\u2009male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO<jats:sub>4<\/jats:sub> or Placebo administration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>EE-3-SO<jats:sub>4<\/jats:sub> 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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13054-021-03844-7","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T09:02:29Z","timestamp":1639645349000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["17\u03b1-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"],"prefix":"10.1186","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2396-5609","authenticated-orcid":false,"given":"Andrew R.","family":"Mayer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Dodd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie G.","family":"Rannou-Latella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David D.","family":"Stephenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Dodd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M.","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carissa J.","family":"Mehos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cidney R.","family":"Robertson-Benta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharvani","family":"Pabbathi Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel E.","family":"Kinsler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan S.","family":"Vermillion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Gigliotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronik","family":"Sicard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik B.","family":"Erhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian A.","family":"Guedes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irshad H.","family":"Chaudry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"issue":"6 Suppl 5","key":"3844_CR1","doi-asserted-by":"publisher","first-page":"S431","DOI":"10.1097\/TA.0b013e3182755dcc","volume":"73","author":"BJ Eastridge","year":"2012","unstructured":"Eastridge BJ, Mabry RL, Seguin P, Cantrell J, Tops T, Uribe P, et al. 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