When to Initiate Vasopressin in Septic Shock
Add vasopressin at 0.03 units/minute when norepinephrine reaches 0.25-0.50 mcg/kg/min (approximately 15-35 mcg/min in a 70 kg patient) and hypotension persists despite adequate fluid resuscitation. 1, 2
The Evidence-Based Threshold
The Society of Critical Care Medicine and Surviving Sepsis Campaign guidelines clearly recommend adding vasopressin rather than continuing to escalate norepinephrine once you reach this dose range. 1, 3 This recommendation is based on the concept of "decatecholaminization"—avoiding the cardiac and immunological adverse effects associated with high-dose norepinephrine. 3
The most recent and highest-quality evidence from the 2025 OVISS reinforcement learning study (JAMA) suggests even earlier initiation may be beneficial. 4 This study analyzed 10,217 patients across 227 US hospitals and found that:
- Vasopressin should be initiated earlier than current practice patterns (median 4 hours vs 5 hours from shock onset) 4
- At lower norepinephrine doses than clinicians typically use (median 0.20 mcg/kg/min vs 0.37 mcg/kg/min) 4
- This earlier initiation strategy was associated with reduced hospital mortality (adjusted OR 0.81,95% CI 0.73-0.91) 4
Practical Implementation Algorithm
Step 1: Ensure Prerequisites Are Met
- Minimum 30 mL/kg crystalloid fluid resuscitation completed 1
- Central venous access established 1
- Arterial line placed for continuous blood pressure monitoring 1
- Target MAP ≥65 mmHg not achieved with norepinephrine alone 1
Step 2: Initiate Vasopressin
- Start at 0.03 units/minute (fixed dose, not weight-based) 1, 2
- Never use vasopressin as monotherapy—it must be added to norepinephrine 1
- Do not titrate vasopressin; keep it at 0.03 units/minute 1
Step 3: Adjust Norepinephrine
Once vasopressin is running, you have two options: 2
- Raise MAP to target (if still below 65 mmHg), OR
- Decrease norepinephrine dosage while maintaining hemodynamic stability
Step 4: If Shock Remains Refractory
- Do NOT increase vasopressin above 0.03-0.04 units/minute 1, 5
- Higher doses cause cardiac, digital, and splanchnic ischemia without additional benefit 1, 5
- Instead, add epinephrine 0.05-2 mcg/kg/min as a third agent 1
- Consider dobutamine up to 20 mcg/kg/min if myocardial dysfunction is evident 1
Critical Nuances from the Literature
The VASST trial (2008) showed no overall mortality benefit with vasopressin versus norepinephrine (35.4% vs 39.3%, p=0.26). 6 However, in the prospectively defined subgroup with less severe septic shock (norepinephrine 5-14 mcg/min at randomization), vasopressin reduced 28-day mortality (26.5% vs 35.7%, p=0.05). 5, 6 This finding supports earlier rather than later vasopressin initiation.
The 2025 OVISS study reinforces this concept by demonstrating that machine learning algorithms recommend vasopressin initiation in 87% of patients versus the 31% who actually received it in clinical practice, and at substantially lower norepinephrine doses. 4
Common Pitfalls to Avoid
- Don't wait for "refractory shock": The traditional approach of waiting until norepinephrine exceeds 0.5 mcg/kg/min may be too conservative based on recent evidence 4
- Don't escalate vasopressin dose: Doses above 0.03-0.04 units/minute are reserved only for salvage therapy when all other options have failed 1, 5
- Don't use vasopressin alone: It must always be combined with norepinephrine 1
- Don't forget corticosteroids: The combination of vasopressin plus corticosteroids showed significant mortality reduction compared to norepinephrine plus corticosteroids (35% vs 44%, p=0.03) in VASST 5
The Bottom Line
While guidelines conservatively recommend adding vasopressin at norepinephrine doses of 0.25-0.50 mcg/kg/min, the most recent high-quality evidence suggests earlier initiation—potentially as soon as norepinephrine reaches 0.20 mcg/kg/min—may improve outcomes. 4 In practice, consider adding vasopressin when norepinephrine reaches 0.20-0.25 mcg/kg/min rather than waiting for higher doses. 4