What is the next vasopressor to add after norepinephrine (Levophed) and vasopressin in a patient with persistent hypotension?

Third-Line Vasopressor After Norepinephrine and Vasopressin

Epinephrine is the recommended third vasopressor to add when hypotension persists despite norepinephrine and vasopressin at 0.03 units/minute. 1, 2

Algorithmic Approach to Escalating Vasopressor Therapy

First-Line: Norepinephrine

• Initiate norepinephrine as the first-choice vasopressor, targeting a mean arterial pressure (MAP) of 65 mmHg 1, 2
• Administer through central venous access with continuous arterial blood pressure monitoring 2, 3
• Titrate dose from 0.1-2 mcg/kg/min based on hemodynamic response 3

Second-Line: Add Vasopressin

• Add vasopressin at 0.03 units/minute when norepinephrine requirements reach 0.25-0.50 mcg/kg/min and target MAP is not achieved 2, 4
• Do not use vasopressin as monotherapy—it must be added to norepinephrine 2
• Maximum dose should not exceed 0.03-0.04 units/minute; higher doses are associated with cardiac, digital, and splanchnic ischemia 1, 2

Third-Line: Add Epinephrine

• When hypotension persists despite norepinephrine plus vasopressin at 0.03 units/minute, add epinephrine as the third vasopressor 1, 2
• Epinephrine provides both vasopressor and inotropic effects through combined alpha and beta-adrenergic stimulation 1
• FDA-approved dosing: 0.05-2 mcg/kg/min IV infusion 2

Alternative Consideration: Dobutamine for Low Cardiac Output

If persistent hypoperfusion exists despite adequate MAP and vasopressor therapy, consider adding dobutamine (up to 20 mcg/kg/min) rather than escalating vasopressors further 1, 2

• This approach is particularly important when myocardial dysfunction or low cardiac output is suspected 1
• Dobutamine is the first-choice inotrope for patients with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressure 1
• Cardiac output measurement is desirable when instituting pure vasopressors to guide therapy appropriately 1

Agents to Avoid as Third-Line Therapy

Phenylephrine

• Do not use phenylephrine except in highly specific circumstances: 2
  • When norepinephrine causes serious arrhythmias 2
  • When cardiac output is documented to be high with persistently low blood pressure 2
  • As salvage therapy when all other agents have failed 2
• Phenylephrine may raise blood pressure numbers while actually worsening tissue perfusion through excessive vasoconstriction without inotropic support 2

Dopamine

• Strongly avoid dopamine as it is associated with higher mortality and more arrhythmias compared to norepinephrine 1, 2
• Should only be considered in highly selected patients with low risk of tachyarrhythmias or absolute/relative bradycardia 2
• Do not use low-dose dopamine for renal protection—this has no benefit 1, 2

Critical Monitoring and Titration Principles

Hemodynamic Targets

• Target MAP ≥65 mmHg as the primary goal 2, 3
• Monitor markers of tissue perfusion beyond MAP: lactate clearance, urine output, mental status, and capillary refill 3
• Patients with chronic hypertension may require higher MAP targets 3

Monitoring Requirements

• Arterial catheter placement is recommended for all patients requiring vasopressors 1, 2
• Monitor blood pressure and heart rate every 5-15 minutes during initial titration 5, 3
• Cardiac output measurement is desirable when using pure vasopressors 1

Common Pitfalls to Avoid

Inadequate Fluid Resuscitation

• Ensure minimum 30 mL/kg crystalloid bolus before or concurrent with vasopressor initiation 3
• Vasoconstriction in hypovolemic patients causes severe organ hypoperfusion despite "normal" blood pressure 3

Excessive Vasopressin Dosing

• Never exceed 0.03-0.04 units/minute of vasopressin except as salvage therapy 1, 2
• Higher doses are associated with cardiac, digital, and splanchnic ischemia 1

Ignoring Cardiac Output

• Consider inotropic support (dobutamine) rather than adding more vasopressors if low cardiac output is suspected 1
• Escalating vasopressors in the setting of low cardiac output worsens tissue perfusion 1

Rebound Hypotension

• When terminating vasopressin, rebound hypotension occurs in approximately 9% of patients 4
• Vasopressin duration >24 hours is associated with lower risk of rebound hypotension 4

Patient-Specific Factors Affecting Vasopressor Response

Factors Associated with Poor Vasopressin Response

• Obesity (higher BMI) is negatively associated with vasopressin hemodynamic responsiveness 4
• Hyperlactatemia is negatively associated with vasopressin response 4
• Lower pH is associated with prolonged shock duration 4

Factors Associated with Better Vasopressin Response

• Norepinephrine infusion rate ≥0.30 mcg/kg/min shows positive odds of vasopressin response 4
• New-onset atrial fibrillation is less common in vasopressin responders (4% vs 14%) 4