What do you add to norepinephrine (Levophed) for septic shock when it is ineffective?

Vasopressor Management for Norepinephrine-Refractory Septic Shock

Add vasopressin at 0.03 units/minute to norepinephrine when target MAP of 65 mmHg cannot be achieved with norepinephrine alone. 1

First-Line Escalation Strategy

When norepinephrine fails to maintain adequate MAP despite appropriate fluid resuscitation (minimum 30 mL/kg crystalloid), the evidence-based escalation follows this protocol:

Add Vasopressin as Second-Line Agent

• Start vasopressin at 0.03 units/minute (range 0.01-0.03 units/min) to either raise MAP to target or decrease norepinephrine requirements 1, 2
• Vasopressin acts on different vascular receptors (V1) than norepinephrine's α1-adrenergic receptors, providing a complementary mechanism of action 3
• Never use vasopressin as monotherapy—it must always be added to norepinephrine, not used alone 1, 2
• Do not exceed 0.03-0.04 units/minute except as salvage therapy when all other vasopressors have failed, as higher doses cause cardiac, digital, and splanchnic ischemia 1, 2

Critical Timing Considerations

• Add vasopressin when norepinephrine requirements remain elevated, rather than waiting for extreme doses 1
• The Society of Critical Care Medicine recommends adding vasopressin before norepinephrine exceeds 15 mcg/min, as doses above this threshold are associated with mortality rates exceeding 80% 1, 4
• Early addition of a second agent with a different mechanism prevents the need for dangerously high catecholamine doses 4, 5

Alternative Second-Line Options

Epinephrine as Alternative Agent

• Add epinephrine at 0.05-2 mcg/kg/min IV when vasopressin is unavailable or additional support is needed beyond norepinephrine plus vasopressin 1, 6
• Epinephrine should be added as a third agent when norepinephrine exceeds moderate doses, rather than escalating vasopressin beyond 0.03-0.04 units/min 1
• Titrate in increments of 0.05-0.2 mcg/kg/min every 10-15 minutes to achieve desired MAP 6
• Warning: Epinephrine causes transient lactic acidosis through β2-adrenergic stimulation, which interferes with lactate clearance as a resuscitation endpoint 1
• Epinephrine increases risk of serious cardiac arrhythmias and myocardial oxygen consumption more than norepinephrine 1

Addressing Persistent Hypoperfusion

When to Add Dobutamine

• Add dobutamine (2.5-20 mcg/kg/min) if persistent hypoperfusion exists despite adequate MAP and vasopressor therapy, particularly when myocardial dysfunction is evident 1, 2, 7
• This addresses the perfusion problem rather than just the pressure problem 1
• Titrate to perfusion endpoints (lactate clearance, urine output, mental status) and discontinue if worsening hypotension or arrhythmias develop 7

Adjunctive Therapy for Refractory Shock

Corticosteroids

• Consider hydrocortisone 200 mg/day IV if hypotension remains refractory to vasopressors despite adequate fluid resuscitation 1, 7
• Taper when vasopressors are no longer required 7

Critical Monitoring Requirements

• Place arterial catheter for continuous blood pressure monitoring as soon as practical in all patients requiring vasopressors 1, 2
• Administer norepinephrine and other vasopressors through central venous access 1, 2, 7
• Monitor perfusion markers (lactate, urine output, mental status) rather than relying solely on blood pressure numbers 2

Agents to Absolutely Avoid

Dopamine

• Do not use dopamine except in highly selected patients with low risk of tachyarrhythmias or absolute/relative bradycardia 1, 2
• Dopamine is associated with higher mortality and more arrhythmias compared to norepinephrine 1, 2
• Never use low-dose dopamine for renal protection—this is strongly discouraged and has no benefit 1, 2

Phenylephrine

• Avoid phenylephrine except when norepinephrine causes serious arrhythmias, cardiac output is documented high with persistent hypotension, or as salvage therapy when all other agents have failed 1, 2
• Phenylephrine may raise blood pressure on the monitor while actually worsening tissue perfusion through excessive vasoconstriction 1

Common Pitfalls to Avoid

• Do not delay adding vasopressin while escalating norepinephrine to dangerously high doses—add vasopressin early when norepinephrine alone is insufficient 1, 3
• Do not escalate vasopressin beyond 0.03-0.04 units/min in routine practice; instead add epinephrine as a third agent 1
• Do not target supranormal blood pressure—excessive vasoconstriction compromises microcirculatory flow and tissue perfusion 1
• Monitor for signs of excessive vasoconstriction: digital ischemia, decreased urine output, rising lactate, or worsening organ dysfunction despite adequate MAP 1