Authors: Calabrese, Alberto et al.
Anesthesiology October 2025 | DOI: 10.1097/ALN.0000000000005633
This comprehensive narrative review examines the expanding role of renin–angiotensin system (RAS) modulation in critical care, focusing on both classical and alternative pathways. The authors explore how the dual RAS axes—one promoting vasoconstriction and inflammation, the other vasodilation and tissue protection—may be therapeutically targeted in circulatory and respiratory failure.
The review first outlines the physiologic foundation of RAS activity. The classical ACE/Ang II/AT1R pathway supports blood pressure and fluid balance but contributes to inflammation and fibrosis when overactivated. The counterregulatory ACE2/Ang-(1–7)/Mas receptor axis, by contrast, exerts vasodilatory, anti-inflammatory, and antifibrotic effects that may protect organs during systemic illness.
Clinical interest in RAS modulation has grown since the ATHOS-3 trial demonstrated that intravenous angiotensin II improved mean arterial pressure in catecholamine-refractory vasodilatory shock. Subsequent analyses identified subgroups—particularly patients with elevated plasma renin, prior ACE inhibitor exposure, or acute kidney injury—who appear most likely to benefit. Ang II may also support renal perfusion and shorten the duration of renal replacement therapy in these patients.
Beyond septic shock, potential applications include vasoplegia after cardiac surgery, liver and kidney transplantation, and ARDS. Although early data suggest possible benefits in oxygenation and hemodynamics, confirmatory trials are ongoing.
The authors also discuss the limited role of RAS inhibition in the acute phase of critical illness but note its importance during recovery, particularly after acute kidney injury, where restarting ACE inhibitors or ARBs can improve long-term renal and cardiovascular outcomes. Emerging interest in the alternative RAS pathway, through agents such as Ang-(1–7), Mas receptor agonists, and AT2R agonists, has produced mixed results in early human studies but remains a promising frontier for anti-inflammatory and organ-protective therapy.
The review concludes by emphasizing the challenges ahead: identifying genetic polymorphisms that influence RAS responsiveness, determining optimal timing for RAS-targeted therapies, and developing biomarkers like plasma renin concentration or DPP3 levels to guide individualized vasopressor selection. Future vasopressor therapy may integrate real-time RAS profiling to personalize hemodynamic management.
What You Should Know
RAS modulation represents an evolving paradigm in critical care. Angiotensin II can effectively restore vascular tone in vasodilatory shock, particularly in renin-elevated or ACE inhibitor–exposed patients. The alternative RAS pathway offers anti-inflammatory promise but requires further validation. Personalized, biomarker-guided RAS management may define the next era of vasopressor therapy.
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