What is the recommended use of vasopressin (antidiuretic hormone) in adult patients with septic shock who remain hypotensive despite fluid resuscitation and norepinephrine (Levophed) therapy?

Vasopressin in Septic Shock: Add at 0.03 units/minute When Norepinephrine Alone Fails to Maintain MAP ≥65 mmHg

Add vasopressin at 0.03 units/minute to norepinephrine when hypotension persists despite adequate fluid resuscitation (minimum 30 mL/kg crystalloid) and ongoing norepinephrine therapy, targeting a mean arterial pressure (MAP) of 65 mmHg. 1, 2, 3

Critical Pre-Vasopressin Requirements

Before initiating vasopressin, you must ensure:

• Norepinephrine is already running as first-line therapy – vasopressin should never be used as monotherapy or initial vasopressor 1, 2
• Adequate fluid resuscitation completed – minimum 30 mL/kg crystalloid in the first 3 hours 1, 2
• Arterial catheter placed for continuous blood pressure monitoring 1, 2
• Central venous access established for safe vasopressor administration 2

Vasopressin Dosing Protocol

The FDA-approved dosing for septic shock is 0.01 to 0.07 units/minute, but guidelines consistently recommend starting and maintaining at 0.03 units/minute. 1, 2, 3

Starting Dose

• Begin at 0.03 units/minute as a fixed dose – this is the standard recommendation from the Surviving Sepsis Campaign 1, 2
• Alternative conservative approach: start at 0.01 units/minute and titrate by 0.005 units/minute every 10-15 minutes up to 0.03 units/minute 2

Maximum Dose Ceiling

• Do not exceed 0.03-0.04 units/minute for routine use – higher doses are associated with cardiac, digital, and splanchnic ischemia 1, 2
• Doses above 0.04 units/minute should be reserved only for salvage therapy when all other vasopressors have failed 2

Evidence on Dose Comparison

Recent data shows no hemodynamic advantage to using 0.04 units/minute versus 0.03 units/minute – both achieve similar rates of hemodynamic response (50% vs. 53.1%, adjusted RR 1.06,95% CI 0.94-1.20) 4

Clinical Goals When Adding Vasopressin

Vasopressin serves two purposes when added to norepinephrine:

• Raise MAP to target of 65 mmHg when norepinephrine alone cannot achieve this 1, 2
• Decrease norepinephrine dosage while maintaining hemodynamic stability 1, 2

The Surviving Sepsis Campaign gives this a weak recommendation with moderate quality evidence, meaning either goal is acceptable 1

Mechanism and Rationale

Vasopressin works through V1 receptors on vascular smooth muscle, causing vasoconstriction through a different pathway than norepinephrine's alpha-adrenergic mechanism 3. This complementary action explains why it can restore blood pressure when catecholamines alone are insufficient 2, 5.

Vasopressin levels are relatively deficient during sepsis, making physiologic replacement particularly logical 6. The VASST trial demonstrated that while vasopressin didn't reduce overall 28-day mortality compared to norepinephrine escalation (35.4% vs. 39.3%, P=0.26), it showed benefit in less severe septic shock (26.5% vs. 35.7%, P=0.05) 7.

When to Add Vasopressin: Practical Thresholds

Add vasopressin when norepinephrine requirements remain elevated – specifically when norepinephrine reaches 0.1-0.2 mcg/kg/min (approximately 7-14 mcg/min in a 70 kg patient) without achieving target MAP 2, 8

The evidence supports adding vasopressin relatively early rather than escalating norepinephrine to very high doses, as norepinephrine doses ≥15 mcg/min are associated with significantly elevated mortality 2

Norepinephrine Tapering After Vasopressin Addition

Once vasopressin is added at 0.03 units/minute:

• Gradually reduce norepinephrine dose while maintaining MAP ≥65 mmHg 2
• Monitor continuously with arterial catheter for blood pressure, plus urine output, lactate clearance, mental status, and skin perfusion 2
• Specific tapering increments are not defined in guidelines, but gradual dose reduction is preferred over abrupt discontinuation 2

Third Vasopressor Options If Hypotension Persists

If MAP remains inadequate despite norepinephrine plus vasopressin 0.03 units/minute:

• Add epinephrine (0.05-2 mcg/kg/min) as the third vasopressor agent 1, 2
• Consider dobutamine (2.5-20 mcg/kg/min) if persistent hypoperfusion exists with evidence of myocardial dysfunction or low cardiac output 1, 2
• Do NOT increase vasopressin beyond 0.03-0.04 units/minute – escalate other agents instead 2

Renal Protection Benefit

Vasopressin may reduce the need for renal replacement therapy (RRT) – meta-analysis shows lower odds of RRT requirement with vasopressin versus norepinephrine alone (OR 0.68,95% CI 0.47-0.98) 9. This makes vasopressin particularly attractive in patients with acute kidney injury or other risk factors for renal failure requiring RRT 9.

Critical Monitoring Requirements

Monitor for vasopressin-related complications:

• Digital, coronary, and mesenteric ischemia – particularly at higher doses 2, 3
• Bradycardia – vasopressin can decrease heart rate 3
• Hyponatremia – due to V2 receptor-mediated antidiuretic effects 3
• Decreased cardiac output – vasopressin tends to reduce heart rate and cardiac output 3

Common Pitfalls to Avoid

• Never use vasopressin as initial monotherapy – it must be added to norepinephrine, not used alone 1, 2
• Never exceed 0.03-0.04 units/minute routinely – higher doses cause ischemic complications 2
• Never use dopamine for "renal protection" – this is strongly discouraged and provides no benefit 1, 2
• Don't delay vasopressin addition – adding it when norepinephrine reaches moderate doses (0.1-0.2 mcg/kg/min) is preferable to escalating norepinephrine to very high doses 2
• Don't rely on MAP alone – assess tissue perfusion using lactate clearance, urine output, mental status, and skin perfusion 2

Special Populations

Pregnancy: Vasopressin may induce uterine contractions – use with caution 3

Chronic hypertension: Consider higher MAP targets of 70-75 mmHg rather than the standard 65 mmHg 2

Elderly patients >75 years: Consider lower MAP targets of 60-65 mmHg, which may reduce mortality 8