Authors: Calabrese A. et al.
Anesthesiology, October 20, 2025. DOI: 10.1097/ALN.0000000000005633
This comprehensive review explores how the renin–angiotensin system (RAS) influences the physiology and treatment of critically ill patients, addressing seven key questions relevant to intensivists. The RAS regulates vascular tone, fluid balance, and inflammation through two distinct pathways: the classical ACE/Ang II/AT1R axis (vasoconstrictive, pro-inflammatory) and the alternative ACE2/Ang-(1–7)/MasR axis (vasodilatory, anti-inflammatory, and organ-protective).
Exogenous angiotensin II (Ang II) has become an important adjunct therapy for catecholamine-resistant vasodilatory shock. In the ATHOS-3 trial, Ang II raised mean arterial pressure effectively, although mortality benefits were not established. Subgroup analyses suggest greatest benefit in patients with elevated plasma renin, prior ACE inhibitor use, or acute kidney injury requiring renal replacement therapy. Early Ang II use and patients with high disease severity may respond most favorably.
Beyond septic shock, Ang II shows potential in post–cardiac surgery vasoplegia, mechanical circulatory support, and liver transplantation, where RAS dysregulation is common. In respiratory failure (including ARDS and COVID-19), Ang II may improve oxygenation by enhancing ventilation–perfusion matching, though mechanisms remain uncertain.
Conversely, inhibition of the classical RAS—via ACE inhibitors or ARBs—remains valuable in chronic cardiovascular management and post–acute kidney injury recovery but is generally withheld during acute critical illness to avoid hypotension. Studies show resuming these agents after AKI improves long-term renal and cardiovascular outcomes.
The emerging frontier involves stimulating the alternative RAS pathway with agents such as Ang-(1–7), AT2R agonists (compound 21), or Mas receptor agonists (BIO101). Early preclinical and limited clinical data suggest anti-inflammatory and organ-protective effects, particularly in sepsis and COVID-19–related lung injury.
Unresolved issues include defining optimal timing, identifying biomarkers like plasma renin to guide therapy, clarifying genetic influences on RAS responsiveness, and understanding the role of DPP3 inhibition as a novel therapeutic target. Future patient-centered approaches may integrate individualized RAS modulation to optimize hemodynamics and organ protection in critical illness.
What You Should Know
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Angiotensin II effectively increases blood pressure in vasodilatory shock but shows uncertain mortality benefit.
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High plasma renin, ACE inhibitor use, or AKI may predict better Ang II response.
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The alternative RAS pathway represents a new therapeutic frontier for sepsis and respiratory failure.
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Restarting RAS inhibitors after AKI recovery appears beneficial for long-term outcomes.
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Genetic and enzymatic variability within the RAS may explain patient-specific treatment responses.
Thank you to Anesthesiology for publishing this detailed clinical focus review on RAS modulation in critical care.