What is the next step if norepinephrine (norepi) is not sufficient to maintain adequate blood pressure in the absence of vasopressin?

Vasopressor Escalation When Norepinephrine Alone is Insufficient (Without Vasopressin)

Add epinephrine as your second-line vasopressor when norepinephrine alone fails to achieve target MAP of 65 mmHg, starting at 0.05-2 mcg/kg/min and titrating to hemodynamic response. 1, 2

Escalation Algorithm

Step 1: Optimize Norepinephrine First

• Ensure norepinephrine is being administered through central venous access with continuous arterial blood pressure monitoring 1, 3
• Titrate norepinephrine up to maximum effective doses (typically 0.05-0.5 mcg/kg/min) before adding a second agent 3
• Confirm adequate fluid resuscitation has been completed (minimum 30 mL/kg crystalloid in first 3 hours) 1

Step 2: Add Epinephrine as Second-Line Agent

• Initiate epinephrine at 0.05 mcg/kg/min and titrate up to 2 mcg/kg/min to achieve MAP ≥65 mmHg 1, 2
• Prepare epinephrine by diluting 1 mg in 1,000 mL of 5% dextrose solution (1 mcg/mL concentration) 2
• Adjust dosing every 10-15 minutes in increments of 0.05-0.2 mcg/kg/min until target MAP is achieved 2
• This recommendation is supported by the Society of Critical Care Medicine and American College of Critical Care Medicine as an alternative when vasopressin is unavailable 1

Step 3: Consider Dobutamine for Persistent Hypoperfusion

• If signs of inadequate tissue perfusion persist despite achieving MAP target (elevated lactate, decreased urine output, altered mental status), add dobutamine up to 20 mcg/kg/min 1, 3
• This addresses potential myocardial dysfunction that may be contributing to shock despite adequate blood pressure 1, 4
• Dobutamine provides inotropic support without further increasing vasoconstriction 4

Critical Monitoring Requirements

Hemodynamic Parameters

• Maintain continuous arterial blood pressure monitoring via arterial catheter 1, 3
• Target MAP of 65 mmHg for most patients; consider 70-80 mmHg only in patients with chronic hypertension 3

Tissue Perfusion Markers

• Monitor lactate clearance, urine output (>0.5 mL/kg/hr), mental status, capillary refill time, and skin temperature 1, 3
• These markers are more important than blood pressure numbers alone for assessing adequacy of resuscitation 4

Adverse Effects to Watch

• Tachycardia and tachyarrhythmias (epinephrine has potent β1-adrenergic effects) 5
• Hyperglycemia and hyperlactatemia (epinephrine increases glycogenolysis and lactate production) 5
• Digital ischemia or signs of excessive vasoconstriction 1

Agents to Avoid

Dopamine

• Do not use dopamine as a second-line agent—it is associated with higher mortality and more arrhythmias compared to norepinephrine 1
• Dopamine should only be considered in highly selected patients with absolute or relative bradycardia and low risk of tachyarrhythmias 1
• The Society of Critical Care Medicine strongly discourages dopamine use for renal protection, as it provides no benefit 1

Phenylephrine

• Avoid phenylephrine except in specific circumstances: norepinephrine-induced serious arrhythmias, documented high cardiac output with persistent hypotension, or salvage therapy when all other agents have failed 1
• Phenylephrine is a pure α1-agonist that may raise blood pressure numbers while actually compromising microcirculatory flow and tissue perfusion 1

Alternative Considerations

Corticosteroids for Refractory Shock

• Consider adding low-dose corticosteroids (hydrocortisone 200 mg/day IV as continuous infusion or divided doses) for shock reversal if hypotension remains refractory to vasopressors 6, 1
• This recommendation comes from the Surviving Sepsis Campaign guidelines 6

Weaning Strategy Once Stabilized

• After achieving hemodynamic stability, wean epinephrine incrementally over 12-24 hours by decreasing doses every 30 minutes 2
• Wean norepinephrine gradually by 0.05 mcg/kg/min every 15-30 minutes while monitoring MAP 3
• If MAP falls below target during weaning, reinstate the previous effective dose 3

Key Evidence Considerations

The recommendation for epinephrine as second-line therapy is based on high-quality guideline evidence from the Society of Critical Care Medicine and American College of Critical Care Medicine 1. While the VANISH trial 7 and other research 8 primarily compared vasopressin to norepinephrine, these studies support the general principle that when norepinephrine alone is insufficient, adding a second vasopressor is appropriate. The FDA-approved dosing for epinephrine in septic shock provides clear practical guidance for implementation 2.

The critical pitfall to avoid is using phenylephrine or dopamine as second-line agents, as both have inferior safety profiles and may worsen outcomes despite raising blood pressure numbers 1.