A clinical framework for phenotype-guided angiotensin II therapy: rethinking RAAS dysregulation and angiotensin II deficiency in vasodilatory shock

Abstract Background Vasodilatory shock is a heterogeneous syndrome characterized by dysregulated vascular signaling pathways contributing to microvascular injury, circulatory failure, and increased morbidity and mortality risk. Despite recent advances, contemporary vasopressor strategies remain mostly empiric without accounting for pathophysiologic heterogeneity. More specifically, renin–angiotensin–aldosterone system (RAAS) dysregulation during critical illness may result in a relative angiotensin II (ATII) deficiency state and represents patients more likely to benefit from targeted ATII therapy. This narrative review aims to characterize enriched vasodilatory shock phenotypes associated with RAAS dysregulation and relative ATII deficiency as well as to propose a pragmatic clinical and functional phenotype-guided framework for targeted ATII utilization. Main body Critical illness may disrupt RAAS homeostasis through systemic inflammation, organ-specific injury, procedure-related exposures, and RAAS-modulating medications. Growing evidence suggests several vasodilatory shock clinical phenotypes, including severe acute kidney injury, cardiac surgery-associated vasoplegia, kidney transplantation, acute respiratory distress syndrome, and recent exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, may be associated with RAAS dysregulation and relative ATII deficiency through distinct underlying mechanisms. Among several of these clinical phenotypes, administration of ATII demonstrated rapid restoration of mean arterial pressure and vasopressor-sparing effects with signals of improved clinical outcomes observed in selected populations. However, responsiveness may be attenuated following recent angiotensin receptor blocker exposure. More recently, the Angiotensin II Initial Mean Arterial Pressure Response Index of Treatment Effect (AIMRITE) study introduced a complementary functional phenotyping approach based on early hemodynamic responsiveness following ATII therapy initiation. Conclusions Clinical phenotypes associated with RAAS dysregulation may represent an enriched vasodilatory shock population for targeted ATII therapy. Integration of clinical phenotype recognition with early functional assessment of treatment responsiveness offers a pragmatic, individualized framework for vasopressor selection and stewardship. Further investigation is warranted to validate phenotype-guided ATII strategies and evaluate the impact on patient-centered outcomes.