Modeling Acute Traumatic Hemorrhagic Shock Injury: Challenges and Guidelines for Preclinical Studies

Trauma is responsible for a large proportion of the world's burden of disease, and is by far the biggest killer of young adults. Hemorrhage is the leading cause of preventable death and its effects are directly correlated with the incidence multi-organ failure in survivors. Trauma research is challenging due to patient heterogeneity, limited randomized controlled trials, and in vitro studies that fail to mimic the systemic injury response. Preclinical research remains essential for mechanistic and therapeutic discovery. Yet modeling the multifaceted nature of traumatic injury poses important experimental and welfare challenges associated with the onset of injury and prehospital and intra-operative care, the limited inter-species validation of coagulation profiles, the use of anesthesia/analgesia, and its impact on the systemic response to trauma; and the challenge of sustaining intensive care in recovery models. Proper model selection depends on the purpose of a given model and the criteria by which the experimental readouts will be clinically relevant. Such complexity warrants further refinement of experimental methodology and outcome measures to improve its clinical efficacy, while ensuring animal well-being. We review the experimental methodologies currently used for modeling traumatic hemorrhagic shock and addressing their impact on clinical translation. The aim of the review is to improve transparency and form a consensus when reporting methodology in trauma modeling.