Critical Care: Angiotensin II for Management of Refractory Shock

Annually, nearly 200,000 adults in the United States develop distributive shock.¹ Distributive shock is a result of inappropriate vasodilation that causes a pooling of blood in the vessels, leading to hypotension. It is the most common type of shock seen in emergency departments (EDs), making up more than half of all shock cases.² Most patients with distributive shock respond to fluids and vasoconstrictive medications—catecholamines (dopamine, epinephrine, norepinephrine) and vasopressin. Unfortunately, 6% of patients develop refractory vasodilatory shock, also called vasoplegic shock. Refractory or vasoplegic shock is characterized by abnormally low systemic vascular resistance and a diminished response to fluid resuscitation and catecholamines. This has an associated mortality rate as high as 92%.³  

Vasopressin is the only non-catecholamine vasopressor recommended by the American Heart Association (AHA) in cases of refractory shock. While effective, high doses carry the risk of adverse effects, including intestinal ischemia, renal failure, cardiac ischemia, digital ischemia, and hyponatremia.^4,5 Given these risks, other alternatives and adjuvants should continue to be explored. Angiotensin II, currently used for refractory vasoplegia in cardiac surgery, shows promise in serving as a powerful, adjunctive non-catecholamine agent for blood pressure support during vasoplegic shock. 

Angiotensin II 

Angiotensin II (Ang II) is a naturally occurring octapeptide that plays a central role in the renin-angiotensin-aldosterone system (RAAS), increasing blood pressure through vasoconstriction, aldosterone release, and other mechanisms.⁶ Multiple studies have found that Ang II is effective at increasing blood pressure in vasodilatory or refractory vasodilatory shock with additional benefits of reduced catecholamine exposure, lower myocardial toxicity, and better renal recovery.^5-9 

Currently, Ang II is primarily used to manage vasoplegic shock during cardiac surgery, where it has been shown to effectively increase blood pressure following cardiopulmonary bypass.⁹ In conjunction with vasopressin, it may offer valuable hemodynamic support in EDs for patients with vasodilatory shock who are unresponsive to catecholamines. 

The Benefits of Ang II 

Recent studies have increasingly highlighted the benefits of Ang II in the treatment of vasodilatory and refractory vasodilatory shock. The Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) trial, the first large-scale randomized controlled study of Ang II, demonstrated that the drug significantly increased mean arterial pressure (MAP) in patients with refractory vasodilatory shock, while also reducing norepinephrine requirements.⁷ Building on these findings, the Aramis study found that patients who received Ang II had a lower incidence of troponin elevation, suggesting a possible myocardial-sparing effect in shock states involving cardiac dysfunction. Additionally, patients receiving Ang II required significantly lower total catecholamine doses, translating to a potential reduction in myocardial toxicity. Ang II has also been associated with improved renal recovery in patients requiring continuous renal replacement therapy (CRRT) for vasodilatory shock.⁸ While CRRT is unlikely to be initiated in the ED, it is important to understand the trajectory of critically ill patients and how initiation of Ang II in the ED might have improved downstream renal outcomes. 

Beyond organ protection, Ang II has demonstrated reliable hemodynamic effects. Alamami et al. reported that Ang II produced significant increases in MAP and yielded comparable in-hospital mortality rates to conventional vasopressors.⁹ A review by Busse et al. further supports this: Ang II administration was associated with a 23.4% rise in MAP (from 63.3 mmHg to 78.1 mmHg), and a 125.2% increase in systolic blood pressure (from 56.9 mmHg to 128.2 mmHg). Improvements were seen across cardiogenic, septic, and mixed shock types, which are associated with greater illness severity and worse outcomes.^6,11 These findings demonstrate that Ang II could have a versatile role in the ED, not only as a vasopressor in vasodilatory shock, but also in select cases of profound circulatory collapse. 

Adverse Effects and Limitations 

While Ang II has demonstrated clinical benefit in refractory shock, it is not without potential adverse effects. In clinical trials, the most frequently reported complications were thromboembolic events (12.9%), including deep vein thrombosis (4.3%), thrombocytopenia (9.8%), and tachycardia (8.6%).¹¹ A separate analysis of ATHOS-3 participants found that 76% had elevated plasma renin levels (up to three times the upper limit of normal) correlating with a higher angiotensin I/II ratio.^7,12 Despite this, Ang II’s outcomes and rates of thromboembolic events remained comparable to those seen with conventional vasopressors.^9,11 Although Ang II does not have any absolute contraindications, clinicians should use caution in patients with ischemic conditions like acute coronary syndrome, mesenteric ischemia, or critical limb ischemia, where vasoconstriction may exacerbate the condition. It has also not been evaluated in pediatric populations, and there is limited information on its potential mutagenic, carcinogenic, or reproductive effects. Notably, the ATHOS-3 trial excluded patients with burns, acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, neutropenia (neutrophil count <1000), and those receiving high-dose glucocorticoids. Therefore, its safety and effectiveness in these groups requires more study and warrants caution in implementation.¹¹ 

Overall, Ang II is an underutilized drug with potent effects in the management of catecholamine-refractory vasodilatory shock that warrants consideration for implementation in EDs. With its established ability to raise blood pressure, lessen catecholamine burden, and reduce myocardial toxicity, it may be a valuable addition when standard therapy is ineffective. Given its growing body of evidence and unique mechanism of action, Ang II deserves greater consideration as an adjunctive therapy in refractory vasodilatory shock. Emergency physicians should advocate for more research, broader access, familiarity, and protocol-driven use of Ang II to better support hemodynamic stability in the most critically ill patients. 

Key Points 

• Ang II is a catecholamine-independent vasopressor that works via the RAAS. 

• Ang II effectively increases blood pressure, reduces catecholamine requirements, and has been associated with lower troponin levels and improved renal recovery in patients with vasodilatory and refractory vasodilatory shock. 

• Despite growing clinical evidence, Ang II remains underutilized in emergency medicine and should be more routinely considered alongside vasopressin in managing refractory vasodilatory shock. 

References 

1. Bonanno FG. Clinical pathology of the shock syndromes. J Emerg Trauma Shock. 2011 Apr;4(2):233-243. 
2. Stampfl M, DeBlieux P. A clinical review of vasopressors in emergency medicine. J Emerg Med. 2024;67(1):e31-e41. 
3. Alam A, Sovic W, Gill J, et al. Angiotensin II: A review of current literature. J Cardiothorac Vasc Anesth. 2022 Apr;36(4):1180-1187. 
4. Melchers M, de Smet V, Rooijakkers C, et al. Hemodynamic effects of adjunct arginine vasopressin to norepinephrine in septic shock: insights from a prospective multicenter registry study. Annals of Intensive Care. 2025 Apr;15(1):1-14. 
5. Kunkes JH, Baker WL, Hammond JA, Gluck J. Vasopressin therapy in cardiac surgery. J Cardiac Surgery. 2019;34(1):20-27. 
6. Busse LW, McCurdy MT, Ali O, Hall A, Chen H, Ostermann M. The effect of angiotensin II on blood pressure in patients with circulatory shock: A structured review of the literature. Critical Care. 2017 Dec;21(1). 
7. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017 Aug 3;377(5):419-430. 
8. See EJ, Clapham C, Liu J, et al. A pilot study of angiotensin II as primary vasopressor in critically ill adults with vasodilatory hypotension: The ARAMIS study. Shock. 2023 May 1;59(5):691-696. 
9. Alamami A, Rahhal A, Alqudah B, et al. Clinical outcomes of angiotensin II therapy in vasoplegic shock: A systematic review and meta-analysis. Life. 2024 Aug;14(9):1085.  
10. Jentzer JC, Berg DD, Chonde MD, et al. Mixed cardiogenic-vasodilatory shock: Current insights and future directions. JACC: Advances. 2024 Dec 5;4(1):101432. 
11. Patel P, Sanghavi DK, Morris DL, Kahwaji CI. Angiotensin II. Handbook of hormones: Comparative endocrinology for basic and clinical research. Published online 2023 May 26:258,e29B-2-260,e29B-4.