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标题： Estrogens for the treatment of trauma and severe hemorrhage

讲者： Irshad H Chaudry

单位：美国阿拉巴马大学

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播放： 2581

论文摘要：

Trauma is the leading cause of death in persons between the ages of 1 and 44. The preponderance of trauma victims are young males; their mortality rate after trauma is not only higher compared to females but they are also more susceptible to subsequent sepsis. Our studies show that after the induction of sepsis in animals, even if the animals had undergone soft-tissue trauma-hemorrhage (T-H) and resuscitation first, the survival rate in proestrus (PE) females was significantly higher than in age-matched males. Ovariectomized (OVX) females, however, were extremely susceptible to sepsis after T-H as compared to PE females. Our clinical epidemiological studies also show the premenopausal females tolerate trauma better than age matched males. Thus, the prevailing hormonal milieu at the time of injury dictates whether the host is going to be susceptible to sepsis and mortality or tolerant to sepsis and mortality after trauma.

Administration of 17β-estradiol (E2) after major blood loss (60% of the circulating blood volume), maintained the rats in a state of permissive hypotension for 6 hr with no additional fluid administration. Survival in the E2-treated animals was significantly higher than in vehicle-treated animals. To examine if ethinyl estradiol-3-SO₄ (EE-3-SO₄) was also protective, rats were given a single dose of 1 mg/kg EE-3-SO₄ in 0.4 ml/kg of saline following controlled 60% hemorrhage. The survival rates in EE-3-SO₄-treated rats increased 6-fold even in the absence of resuscitation. Administration of a single dose of 1 mg/kg EE-3-SO₄ in 1 ml/kg of saline following severe hemorrhage also increased survival in 60% acutely-bled minipigs by 3.5-fold

In a lateral fluid percussion injury model of traumatic brain injury (TBI), E2 administration one hr. after TBI, markedly decreased edema formation and ICP at 24 hr after TBI. Brain metabolism (using fludoexoyglucose-PET/CT and diffusion tension imaging analysis) indicated that the relative % standard uptake values in E2-treated rats were significantly higher than in the vehicle-treated animals. To examine if EE-3-SO₄ was also protective following TBI, rats were given EE-3-SO₄ or vehicle 1 hr post-TBI. Animal activity was reduced after TBI more so that the EEs treated animals. The weight loss 3 days post-TBI was significantly less in the EE-treated group than in the vehicle-treated group.

This hormone (i.e., estrogens) should therefore be considered as a novel adjunct for preserving life when fluid resuscitation is not possible for an extended period of time after major blood loss. Furthermore, EE-3-SO₄ promotes recovery by increasing brain metabolism, resolving edema and improving physiologic parameters if administered 1 hr post-TBI. EE-3-SO₄ administration post-TBI improves physical activity, and decreases weight loss in animals. Estrogen therefore appears to be neuroprotective even after TBI. These results, together with similar findings in post-hemorrhage minipigs, support the use of EE-3-SO₄ for: 1) severe hemorrhage when standard resuscitation is not available or feasible, and 2) conditions in which prolonged transportation periods are required for definitive treatment of the injured. Thus, evaluation of the safety/efficacy of EE-3-SO₄ in humans encountering severe trauma is desirable.