When to add epinephrine (epi) drip to a patient on a norepinephrine (levophed) infusion for refractory hypotension?

When to Add Epinephrine to Norepinephrine for Refractory Hypotension

Add epinephrine infusion when norepinephrine reaches 0.25 mcg/kg/min (approximately 15-20 mcg/min in a 70 kg adult) and hypotension persists despite adequate fluid resuscitation (minimum 30 mL/kg crystalloid bolus). 1

Initial Management Before Adding Epinephrine

Before escalating to epinephrine, ensure the following have been addressed:

• Adequate fluid resuscitation: Administer at least 30 mL/kg crystalloid bolus before or concurrent with vasopressor initiation 1, 2
• Norepinephrine optimization: Start norepinephrine at 0.1-0.5 mcg/kg/min and titrate to achieve mean arterial pressure (MAP) ≥65 mmHg 1, 2
• Central venous access: Strongly preferred to minimize extravasation risk and tissue necrosis 1, 2
• Arterial catheter placement: Place as soon as practical for continuous blood pressure monitoring 1

Specific Threshold for Adding Epinephrine

The critical decision point occurs when norepinephrine reaches 0.25 mcg/kg/min and MAP remains <65 mmHg despite adequate volume resuscitation. 1 At this threshold, you have two evidence-based options:

Option 1: Add Vasopressin First (Preferred in Most Cases)

• Add vasopressin 0.03-0.04 units/min as second-line therapy rather than continuing to escalate norepinephrine alone 1, 3
• Vasopressin acts on different vascular receptors (V1) than α1-adrenergic receptors and addresses the relative vasopressin deficiency that occurs in sepsis 3
• Do not increase vasopressin above 0.03-0.04 units/min; reserve higher doses for salvage therapy only 1

Option 2: Add Epinephrine (Alternative Approach)

• Add epinephrine 0.1-0.5 mcg/kg/min when norepinephrine reaches 0.25 mcg/kg/min and hypotension persists 1
• Start at the lower end of the dosing range (0.05-0.1 mcg/kg/min) and titrate based on hemodynamic response 4

Clinical Context: When to Favor Epinephrine Over Vasopressin

Epinephrine should be prioritized in specific clinical scenarios:

• Low cardiac output shock: When there is evidence of inadequate cardiac contractility by echocardiogram or clinical assessment (cold extremities, prolonged capillary refill >3 seconds, decreased pulse pressure) 4
• Pediatric septic shock: Children with fluid-refractory shock predominantly have low cardiac output, making epinephrine a more appropriate choice than in adults 4
• Persistent hypoperfusion despite adequate MAP: When tissue perfusion markers remain abnormal (lactate >2 mmol/L, urine output <0.5 mL/kg/h, altered mental status) despite achieving MAP ≥65 mmHg with norepinephrine alone 1

Important Caveats and Pitfalls

Avoid Epinephrine in Cardiogenic Shock

• In cardiogenic shock after acute myocardial infarction, norepinephrine is superior to epinephrine. A randomized trial showed epinephrine was associated with a significantly higher incidence of refractory shock (37% vs. 7%, p=0.008) compared to norepinephrine 5
• Epinephrine increases heart rate, cardiac double product, and lactic acidosis more than norepinephrine in this population 5

Metabolic Effects of Epinephrine

• Epinephrine increases plasma lactate concentrations independent of tissue perfusion through stimulation of gluconeogenesis (Cori cycle), making lactate more difficult to interpret 4
• Epinephrine stimulates glycogenolysis and inhibits insulin action, leading to hyperglycemia 4
• Monitor blood glucose closely and expect lactate elevation that may not reflect worsening tissue perfusion 4

Splanchnic Perfusion Concerns

• At lower doses (<0.3 mcg/kg/min), epinephrine has greater β2-adrenergic effects causing peripheral vasodilation, which may redirect blood flow away from splanchnic circulation 4
• This effect may transiently reduce gastric intramucosal pH, though clinical significance in children is unclear 4

Dosing and Administration of Epinephrine

• Starting dose: 0.05-0.1 mcg/kg/min (3.5-7 mcg/min in a 70 kg adult) 4, 1
• Titration: Increase in increments of 0.03-0.05 mcg/kg/min every 10-15 minutes based on hemodynamic response 4
• Maximum dose: 0.3 mcg/kg/min for most patients, though higher doses up to 0.5 mcg/kg/min may be necessary in refractory cases 4, 1
• Route: Administer via central venous catheter when possible; peripheral IV or intraosseous access acceptable in emergencies while obtaining central access 4, 1

Alternative Strategy: Escalating Norepinephrine

Increasing norepinephrine dose further beyond 0.25 mcg/kg/min cannot be discouraged and may be appropriate in certain situations. 3 Recent literature suggests that early and aggressive norepinephrine administration may be beneficial because:

• Profound and durable hypotension is an independent factor of increased mortality 3
• Early norepinephrine increases cardiac output and improves microcirculation 3
• It avoids fluid overload from excessive crystalloid administration 3

However, when norepinephrine exceeds 0.25 mcg/kg/min, adding a second agent (vasopressin or epinephrine) is generally preferred over continuing to escalate norepinephrine alone 1, 6, 3

Monitoring After Adding Epinephrine

• Hemodynamic parameters: Monitor blood pressure and heart rate every 5-15 minutes during initial titration 1
• Tissue perfusion markers: Assess lactate clearance, urine output >0.5 mL/kg/h, mental status, capillary refill, and skin temperature 1
• Cardiac function: Consider echocardiography to assess contractility and guide inotropic therapy 4
• Adverse effects: Watch for excessive tachycardia (HR >120 bpm), arrhythmias, myocardial ischemia, and hyperglycemia 4, 5

Refractory Shock: Beyond Epinephrine

If hypotension persists despite norepinephrine plus epinephrine (or vasopressin):

• Add dobutamine: Up to 20 mcg/kg/min if persistent hypoperfusion exists despite adequate vasopressors, particularly with evidence of myocardial dysfunction 1
• Consider hydrocortisone: 200 mg/day in divided doses or continuous infusion for severe refractory shock 6
• Novel agents: Synthetic human angiotensin II can increase blood pressure and reduce catecholamine requirements in refractory vasodilatory shock 6
• Avoid phenylephrine: Not recommended as first-line therapy; may raise blood pressure while worsening tissue perfusion 1