Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients.

Despite efforts in prevention and intensive care, trauma and subsequent sepsis are still associated with a high mortality rate. Traumatic injury remains the main cause of death in people younger than 45 years and is thus a source of immense social and economic burden. In recent years, the knowledge concerning gender medicine has continuously increased. A number of studies have reported gender dimorphism in terms of response to trauma, shock and sepsis. However, the advantageous outcome following trauma-hemorrhage in females is not due only to sex. Rather, it is due to the prevailing hormonal milieu of the victim. In this respect, various experimental and clinical studies have demonstrated beneficial effects of estrogen for the central nervous system, the cardiopulmonary system, the liver, the kidneys, the immune system, and for the overall survival of the host. Nonetheless, there remains a gap between the bench and the bedside. This is most likely because clinical studies have not accounted for the estrus cycle. This review attempts to provide an overview of the current level of knowledge and highlights the most important organ systems responding to trauma, shock and sepsis. There continues to be a need for clinical studies on the prevailing hormonal milieu following trauma, shock and sepsis.

OBJECTIVE: 17α-ethynylestradiol-3-sulfate (EE-3-SO₄) is a highly water-soluble synthetic estrogen that has an extended half-life (∼ 10 hours) over that of naturally occurring estrogen (∼ 10 minutes). In this study, EE-3-SO₄ was evaluated in a lateral fluid percussion–induced traumatic brain injury (TBI) model in rats.METHODS: A total of 9 groups of Sprague-Dawley rats underwent craniectomy. Twenty-four hours later, lateral fluid percussion was applied to 6 groups of animals to induce TBI; the remaining 3 groups served as sham control groups. EE-3-SO₄ (1 mg/kg body weight in 0.4 ml/kg body weight) or saline (vehicle control) was injected intravenously 1 hour after TBI; saline was injected in all sham animals. One day after EE-3-SO₄/saline injection, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and partial brain oxygen pressure (PbtO₂) were measured in Groups 1–3 (2 TBI groups and 1 sham group), and brain edema, diffusion axonal injury, and cerebral glycolysis were assessed in Groups 4–6 using MRI T2 mapping, diffusion tensor imaging (DTI), and FDG-PET imaging, respectively. Four days after dosing, the open-field anxiety of animals was assessed in Groups 7–9 by measuring the duration that each animal spent in the center area of an open chamber during 4 minutes of monitoring.RESULTS: EE-3-SO₄ significantly lowered ICP while raising CPP and PbtO₂, compared with vehicle treatment in TBI-induced animals (p < 0.05). The mean size of cerebral edema of TBI animals treated with EE-3-SO₄ was 25 ± 3 mm³ (mean ± SE), which was significantly smaller than that of vehicle-treated animals (67 ± 6 mm³, p < 0.001). Also, EE-3-SO₄ treatment significantly increased the fractional anisotropy of the white matter in the ipsilateral side (p = 0.003) and cerebral glycolysis (p = 0.014). The mean duration that EE-3-SO₄-treated animals spent in the center area was 12 ± 2 seconds, which was significantly longer than that of vehicle-treated animals (4 ± 1 seconds; p = 0.008) but not different from that of sham animals (11 ± 3 seconds; p > 0.05).CONCLUSIONS: These data support the clinical use of EE-3-SO₄ for early TBI treatment.

Estrogen plays an important role as a neuroprotector in the central nervous system (CNS), directly interacting with neurons and regulating physiological properties of non-neuronal cells. Here we evaluated estrogen sulfate (E ₂ -SO ₄ ) for traumatic brain injury (TBI) using a Sprague–Dawley rat model. TBI was induced via lateral fluid percussion (LFP) at 24 h after craniectomy. E ₂ -SO ₄ (1 mg/kg BW in 1 mL/kg BW) or saline (served as control) was intravenously administered at 1 h after TBI ( n =5/group). Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and partial brain oxygen pressure (pbtO ₂ ) were measured for 2 h (from 23 to 25 h after E ₂ -SO ₄ injection). Brain edema and diffuse axonal injury (DAI) were assessed by diffusion tensor imaging (DTI), and cerebral glycolysis was measured by ¹⁸ F-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging, at 1 and 7 days after E ₂ -SO ₄ injection. E ₂ -SO ₄ significantly decreased ICP, while increasing CPP and pbtO ₂ ( p 0.05). These findings demonstrated the potential benefits of E ₂ -SO ₄ in TBI.

Gender is increasingly recognized as a key factor in trauma and sepsis. Multiple clinical and experimental studies on sepsis have shown a distinct advantage of females in the proestrus cycle to survive sepsis compared with age-matched males. In addition, estrogen treatment is beneficial in non-proestrus cycles and also in ovarectomized females. In this manuscript, the effects of gender and sex hormones in sepsis are summarized and potential gender-specific therapeutic strategies in women are evaluated. This review comprises current clinical studies on the effect of gender in sepsis and gives an overview on gender and sex hormone-related effects on immune cells and organ function. Based on clinical and experimental data, potential therapeutic targets are presented. Estrogens and estrogen-receptor agonists have been extensively shown to be beneficial in the setting of sepsis. Clinical data, however, do not clearly support their therapeutic use. This discrepancy appears to be mainly due to insufficient study design in clinical trials conducted up to now. Therefore, improved study protocols with exact analysis of the patients' hormonal status are needed to clarify the role of gender and sex hormones in trauma and sepsis.

Investigators continue to debate whether gender plays any role in patient outcome following injury/critical illness. We submit that age and hormonal milieu at the time of injury, rather than gender, are the critical factors influencing patient outcome under those conditions.