Angiotensin II in Catecholamine-Refractory Shock: A Systematic Review and Exploratory Analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) Trial.

Vasodilatory shock that does not respond to high-dose catecholamine vasopressors remains a life-threatening condition and is characterized by severe hypotension and high mortality. Angiotensin II, a non-catecholamine vasopressor that activates angiotensin type 1 receptors, has emerged as a potential therapeutic agent for restoring vascular tone in this setting. This systematic review aimed to evaluate the efficacy, safety, and hemodynamic effects of intravenous angiotensin II in adult patients with vasodilatory shock unresponsive to catecholamines, with a focus on data from the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) randomized trial and related studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a systematic search was performed to identify randomized controlled trials and protocol-based investigations involving angiotensin II administration in adult patients with catecholamine-refractory vasodilatory shock. Eligible studies included the ATHOS-3 randomized trial, a renal-focused post hoc analysis, and the DARK-Sepsis protocol. Extracted outcomes included the proportion of patients achieving target mean arterial pressure, changes in catecholamine dose requirements, incidence of renal replacement therapy, and adverse event profiles. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Three studies involving a total of 321 patients were included. In the ATHOS-3 trial, angiotensin II significantly increased mean arterial pressure within 30 minutes. The proportion of patients achieving the target pressure threshold was 69.9% in the angiotensin II group versus 23.4% in the placebo group (P < 0.001). Angiotensin II administration was associated with a reduction in concurrent catecholamine use and a lower rate of renal replacement therapy initiation (19.0% versus 32.4%; P = 0.015). The overall incidence of adverse events, including thromboembolic and ischemic complications, did not differ significantly between groups. Exploratory findings indicated a greater therapeutic response in patients with elevated baseline plasma renin levels. All studies included were rated as low risk of bias. Angiotensin II appears to be a safe and effective adjunct to conventional vasopressor therapy in catecholamine-refractory vasodilatory shock, offering rapid hemodynamic improvement and potential organ protection. The observed reduction in renal replacement therapy initiation and the enhanced response in renin-elevated subgroups warrant further investigation in biomarker-guided clinical trials.