Experimental rat models of hemorrhagic shock: insights into controlled, uncontrolled, and trauma-associated protocols

Rat models of hemorrhagic shock (HS) are essential tools for investigating the pathophysiological mechanisms underlying trauma-induced hypovolemia and for evaluating therapeutic interventions. This review synthesizes established protocols across controlled (fixed-volume, fixed-pressure) and uncontrolled hemorrhage paradigms, as well as complex trauma HS models, including traumatic brain injury (TBI) combinations. Fixed-pressure models offer reproducibility by maintaining target mean arterial pressure (MAP) over extended durations, while fixed-volume approaches standardize blood loss relative to body weight, however their consistency may vary across animals due to physiological differences. On the other hand, uncontrolled hemorrhage models such as spleen or liver transection, tail amputation, and renal injury better replicate clinical pathophysiology, including unregulated bleeding and variable shock severity, but pose challenges to standardization. Combined trauma models, particularly TBI+HS, further enhance translational relevance by allowing investigation into compounded inflammation, coagulopathy, and neuro-ischemic damage. While controlled models offer precision for mechanistic studies, uncontrolled and complex models improve clinical applicability. Nevertheless, rat HS models are subject to several methodological limitations, including variability in anesthesia protocols, cannulation techniques, animal strains, and endpoint definitions. Finally, we outline future directions, including the standardization of hybrid models, optimization of resuscitation strategies, and incorporation of omics-based endpoints. This review aims to serve as a practical guide for the selection and design of rat hemorrhagic shock models in translational trauma research.