Bridging bench to bedside: mechanistic elucidation and clinical translation of vasopressin and its analogues for hemorrhagic shock resuscitation

Hemorrhagic shock remains a leading cause of preventable mortality in civilian and military trauma, despite advances in trauma systems and resuscitation strategies. Vasopressor therapy for early resuscitation is controversial, as conventional catecholamine agents are limited by adverse effects on organ perfusion and uncertain net benefit during active bleeding. Vasopressin and its analogues (notably terlipressin) have emerged as potential alternatives, with unique non-adrenergic pharmacology that enables rapid hemodynamic restoration, reduced transfusion requirements, and organ protection-properties supported by recent molecular and translational research. However, clinical adoption is hindered by critical knowledge gaps, inconsistent trial outcomes, unresolved questions around patient selection and optimal dosing, practical barriers including regulatory approval and cost, and persistent safety concerns such as potential splanchnic hypoperfusion. This review comprehensively synthesizes the pharmacological profiles, cellular and molecular mechanisms, and preclinical/clinical evidence for vasopressin and its analogues in hemorrhagic shock resuscitation. It critically addresses current controversies, methodological limitations of existing research, and key uncertainties in clinical application-including the risks of intestinal ischemia and the challenges of formulary access for terlipressin in the US. We also highlight the ongoing CAVALIER trial (NCT05958342), a pivotal multicenter randomized study investigating early vasopressin use, and outline specific, actionable directions for mechanistic research and precision clinical trials to address unmet needs. By consolidating multidisciplinary evidence in an unbiased framework, this review clarifies the evolving role of vasopressin-based therapies and aims to inform evidence-based, individualized resuscitation strategies to improve outcomes in this high-risk population.