What is the role of angiotensin 2 in treating patients with vasodilatory shock?

Angiotensin II for Vasodilatory Shock

Angiotensin II is an effective second-line vasopressor for patients with vasodilatory shock who remain hypotensive despite high-dose norepinephrine, demonstrating superior blood pressure response compared to placebo and offering norepinephrine-sparing effects. 1

First-Line Management Remains Norepinephrine

• Norepinephrine is the established first-line vasopressor for vasodilatory shock and should be initiated after adequate fluid resuscitation, targeting a mean arterial pressure of at least 65 mmHg 2
• Catecholamines remain the most commonly used vasoactive agents in intensive care, with norepinephrine being first-line therapy in most clinical conditions 2

When to Consider Angiotensin II

Add angiotensin II when norepinephrine requirements exceed 0.2 μg/kg/min (or equivalent doses of other vasopressors) and the patient remains hypotensive despite adequate fluid resuscitation. 1

Evidence for Efficacy

• The landmark ATHOS-3 trial demonstrated that 69.9% of patients receiving angiotensin II achieved the primary endpoint (MAP increase ≥10 mmHg or MAP ≥75 mmHg without increasing background vasopressors) compared to only 23.4% receiving placebo (odds ratio 7.95, P<0.001) 1
• Angiotensin II improved cardiovascular Sequential Organ Failure Assessment scores more than placebo at 48 hours (-1.75 vs -1.28, P=0.01) 1
• The mechanism involves stimulation of NADH/NADPH membrane-bound oxidase with subsequent oxygen production by vascular smooth muscles, acting synergistically with norepinephrine 2

Patients Who Benefit Most

Prioritize angiotensin II in patients with higher severity of illness and relative deficiency of intrinsic angiotensin II, as these subgroups showed improved mortality rates. 3

Additional populations showing benefit include:

• Patients with acute kidney injury 4
• Those with high APACHE II scores 4
• Patients requiring cardiac surgery 4

Positioning in the Vasopressor Algorithm

The treatment sequence should follow this hierarchy:

1. First-line: Norepinephrine after adequate fluid resuscitation 2
2. Second-line options when norepinephrine exceeds 0.2-0.5 μg/kg/min:
   • Vasopressin (≤0.03-0.04 units/min) 2
   • Angiotensin II (particularly if vasopressin already initiated or contraindicated) 1
3. Third-line: Epinephrine if MAP targets still not achieved 5

Rationale for Angiotensin II as Second-Line

• Angiotensin II acts through catecholamine-independent mechanisms, making it effective when alpha-adrenergic receptors are down-regulated in septic shock 2
• It provides norepinephrine-sparing effects, which is clinically valuable given that high catecholamine levels and excessive vasoconstriction are associated with increased mortality 2
• Unlike vasopressin, angiotensin II has no chronotropic or inotropic properties, avoiding additional cardiac stress 6

Safety Profile

• Serious adverse events occurred in 60.7% of angiotensin II patients versus 67.1% in placebo, demonstrating comparable safety 1
• A systematic review confirmed infrequent adverse reactions with angiotensin II 3
• The 28-day mortality showed a trend toward benefit (46% vs 54%, hazard ratio 0.78) though not statistically significant in the overall population 1

Critical Caveats

Do not use angiotensin II as monotherapy—it must be combined with norepinephrine or other background vasopressors, as the ATHOS-3 trial specifically studied it as add-on therapy in patients already receiving high-dose conventional vasopressors 1

Avoid excessive vasoconstriction—titrate vasopressors to optimize perfusion pressure and organ function (urine output, creatinine clearance) rather than simply maximizing blood pressure, as studies with nonselective NO synthase inhibitors showed increased mortality when used solely to increase blood pressure through excessive vasoconstriction 2

Monitor closely—invasive arterial line monitoring is mandatory when using any vasopressor, and cardiac output monitoring should be considered to ensure adequate tissue perfusion despite improved blood pressure 7

Practical Implementation

• Angiotensin II was FDA-approved in 2017 and EU-approved in 2019 specifically for vasodilatory shock 6
• It represents a noncatecholamine option that should be integrated into a multimodal approach rather than following a one-size-fits-all strategy 3
• The drug is particularly useful owing to its norepinephrine-sparing effects in patients with refractory hypotension 2