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. 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). 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. 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.

中文翻译：

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17α-Ethinyl estradiol-3-sulfate 可提高合并创伤性脑损伤和失血性休克的大型动物模型的存活率和血流动力学功能：一项随机对照试验

创伤性脑损伤 (TBI) 和导致失血性休克 (HS) 的严重失血是导致创伤性死亡的主要原因，尤其是在标准疗法不易获得的院前环境中同时发生时。本研究的主要目的是确定 17α-乙炔雌二醇-3-硫酸盐 (EE-3-SO4) 在 TBI + HS 后相对于安慰剂是否能增加存活率、促进更快的心血管恢复或赋予神经保护作用。在研究开始之前，所有方法均已获得所需监管机构的批准。在这项完全随机、双盲的临床前研究中，使用了 80 头（50% 雌性）性成熟（190.64 ± 21.04 天；28.18 ± 2.72 kg）的尤卡坦猪。68 只动物接受了封闭式加速 TBI，然后去除了大约 40% 的循环血量。然后通过连续泵（0.2 mL/kg，5 分钟内）静脉内给予动物以 5.0 mg/mL（以 0.2 mL/kg 给药）或安慰剂（0.45% 氯化钠溶液）配制在载体中的 EE-3-SO4。将 12 头猪作为未受伤的 Shams 包括在内，以进一步表征模型病理学并复制先前的发现。在没有任何其他救生措施（例如，机械通气、液体复苏）的情况下，对所有动物进行长达 5 小时的监测。安慰剂治疗与 Sham 动物的比较表明存在酸中毒、动脉压降低、心率增加、弥漫性轴突损伤和血脑屏障破坏的证据。相对于安慰剂组（24/33；72.7%），EE-3-SO4（28/31；90.3%）的动物在受伤后存活至 295 分钟的百分比显着更高。EE-3-SO4 在给药后也能更快地恢复脉压，但在休克指数方面没有任何好处。神经炎症和血脑破裂的主要血液测量结果也无效，而弥漫性轴索损伤的二次测量表明 EE-3-SO4 组更快地恢复到基线。生存状态与生理性别相关（女性 > 男性），以及与 EE-3-SO4 或安慰剂给药无关的酸中毒和神经损伤增加的证据。在没有标准疗法的情况下，EE-3-SO4 在院前环境（农村和军事）中的多发性损伤后可有效促进生存和更快地恢复心血管稳态。针对其他机制（增加止血、携氧能力、