Why is angiotensin 2 (angiotensin II) not universally included in sepsis guidelines for critically ill adult patients with sepsis or septic shock?

Why Angiotensin II Is Not Universally Included in Sepsis Guidelines

Angiotensin II remains absent from most sepsis guidelines because it was only FDA-approved in 2017 for vasodilatory shock, after the major guideline publications, and subsequent real-world evidence has failed to demonstrate mortality benefit or superior hemodynamic response compared to traditional catecholamine-based vasopressor strategies.

Historical Context and Timing Issues

The major international sepsis guidelines were developed and published before angiotensin II became available as a therapeutic option:

• The Surviving Sepsis Campaign guidelines from 2012 and 2016 established norepinephrine as the first-choice vasopressor for maintaining MAP ≥65 mmHg in septic shock, with vasopressin as a second-line agent 1, 2
• These guidelines were based on decades of evidence supporting catecholamine-based resuscitation protocols, including the landmark Rivers EGDT study and subsequent multicenter trials 1
• Angiotensin II (Giapreza) received FDA approval only in 2017, years after these foundational guidelines were established 3, 4

Evidence Quality and Clinical Outcomes

The available evidence for angiotensin II has significant limitations that prevent its inclusion in standard sepsis protocols:

Real-World Effectiveness Data

A 2022 propensity-weighted analysis of 147 patients receiving third-line vasopressors showed no mortality benefit with angiotensin II compared to other vasopressor options 5. Key findings included:

• After propensity score weighting, mortality trended higher in the angiotensin II group (86.0% vs 71.0%, p = 0.16), though not statistically significant 5
• Only 37.5% of angiotensin II patients achieved MAP >65 mmHg at 3 hours, compared to 45.1% with alternative vasopressors (relative risk = 1.07,95% CI 0.6-1.93; p = 0.81) 5
• Patients receiving angiotensin II required significantly more concurrent vasopressor agents (45.9% needed ≥5 agents vs 12.5% in the non-angiotensin II group, p < 0.01) 5
• SOFA score was the only variable associated with mortality, not the choice of vasopressor agent 5

Limited Clinical Trial Data

The evidence base consists primarily of the ATHOS-3 trial and small observational studies, which is insufficient to change established guideline recommendations 6, 3:

• Very few clinical data support angiotensin II administration in septic shock, with most evidence coming from experimental rather than clinical studies 6
• Critical questions remain unanswered regarding optimal dosing, timing, comparison with standard vasopressors, and effects on microcirculation 6
• Longer trials with extended follow-up are needed to address unanswered questions about effects on lungs, brain, microcirculation, inflammation, and venous thromboembolism risk 3

Established Guideline Recommendations Remain Superior

Current sepsis guidelines provide a clear, evidence-based vasopressor algorithm that has proven effective:

First-Line Strategy

• Norepinephrine is the first-choice vasopressor to maintain MAP ≥65 mmHg if hypotension persists despite adequate fluid resuscitation (30 mL/kg crystalloids) 1, 2
• This recommendation is supported by multiple high-quality studies and systematic reviews 1, 2

Second-Line Options

• Vasopressin can be added to norepinephrine to raise MAP or decrease norepinephrine dosage 1, 2
• Epinephrine may be added when additional agents are needed 2

Hemodynamic Targets

• Target MAP ≥65 mmHg as the primary hemodynamic endpoint 1, 2
• Monitor clinical indicators of tissue perfusion including capillary refill, skin mottling, peripheral pulses, mental status, and urine output >0.5 mL/kg/hour 2

Pathophysiological Considerations

Paradoxically, endogenous angiotensin II levels are often low in septic shock patients, and low levels predict both shock development and mortality 7. However, this does not necessarily mean exogenous replacement improves outcomes:

• Angiotensin II levels were significantly lower in septic shock and non-survivors 7
• Angiotensin II receptor-2 (AT-2) levels were lower in septic shock compared to controls 7
• While angiotensin II and AT-2 levels had high sensitivity (95%, 82%) and specificity (100%, 87%) for predicting shock, this predictive value does not translate to therapeutic benefit from exogenous administration 7

Practical Implementation Barriers

Even if future evidence supports angiotensin II, significant barriers exist for guideline inclusion:

• Guidelines must be applicable across diverse resource settings, and angiotensin II is expensive and not widely available, particularly in low- and middle-income countries where sepsis burden is highest 1
• Current guidelines already struggle with applicability in resource-constrained settings, with 8/10 guidelines having significant deficits in this domain 1
• The complexity of adding another vasopressor to algorithms must be justified by clear mortality or morbidity benefits, which current evidence does not demonstrate 5

Critical Pitfalls in Current Practice

When managing refractory septic shock without angiotensin II:

• Do not delay initiation of norepinephrine when MAP remains <65 mmHg despite adequate fluid resuscitation—this prolongs tissue hypoperfusion and increases mortality 2
• Ensure adequate initial fluid resuscitation with 30 mL/kg crystalloids—this is a minimum, not a maximum, and some patients require up to 200 mL/kg 2
• Avoid excessive catecholamine doses that cause ischemia and arrhythmias—consider adding vasopressin as a second-line agent before escalating norepinephrine to extreme doses 1, 2, 6
• Monitor for end-organ perfusion using lactate clearance, urine output, and clinical markers rather than relying solely on MAP targets 2

Future Directions

The renin-angiotensin-aldosterone system dysregulation in sepsis is complex and likely contributes to organ failure, but therapeutic modulation with exogenous angiotensin II requires substantially more evidence before guideline inclusion 4. A multinational expert panel has proposed that further research should focus on patient selection criteria, optimal timing, and specific clinical scenarios where angiotensin II might provide benefit over standard therapy 4.

Until high-quality randomized controlled trials demonstrate clear mortality or morbidity benefits, angiotensin II will remain a niche agent for highly refractory cases rather than a guideline-recommended component of standard septic shock management 5, 6, 3, 4.