What are the risks and guidelines for using adrenaline (epinephrine) and noradrenaline (norepinephrine) simultaneously?

Simultaneous Use of Adrenaline and Noradrenaline

Adrenaline (epinephrine) and noradrenaline (norepinephrine) should not be used simultaneously as first-line therapy—norepinephrine is the mandatory first-line vasopressor, and epinephrine should only be added as a second or third-line agent when norepinephrine plus vasopressin fail to achieve target mean arterial pressure. 1, 2

Evidence-Based Escalation Algorithm

First-Line Therapy

• Initiate norepinephrine as the sole initial vasopressor, targeting a MAP of 65 mmHg, administered through central venous access with continuous arterial blood pressure monitoring 1, 3
• Norepinephrine is superior to other vasopressors due to lower mortality rates and significantly fewer arrhythmias (ventricular arrhythmias RR 0.35; 95% CI 0.19-0.66) 4, 3

When to Add Second-Line Agents

• Add vasopressin 0.03 units/minute when norepinephrine reaches 0.25-0.5 mcg/kg/min (approximately 15-35 mcg/min in a 70kg patient), rather than continuing to escalate norepinephrine alone 1, 2
• Never exceed vasopressin 0.03-0.04 units/minute for routine use—higher doses cause cardiac, digital, and splanchnic ischemia 1, 2

When to Add Epinephrine (Third-Line)

• Add epinephrine 0.1-0.5 mcg/kg/min only when the combination of norepinephrine plus vasopressin fails to achieve target MAP 1, 2
• Epinephrine should be the first alternative to norepinephrine when vasopressin is unavailable, but randomized trials show no mortality difference between norepinephrine and epinephrine monotherapy (RR 0.96; 95% CI 0.77-1.21) 4, 3

Critical Risks of Simultaneous Use

Metabolic and Cardiac Complications

• Epinephrine causes transient lactic acidosis through β2-adrenergic stimulation of skeletal muscle, which interferes with lactate clearance as a resuscitation endpoint 4, 3, 5
• Epinephrine significantly increases heart rate and arrhythmia risk compared to norepinephrine alone—in one study, epinephrine caused new arrhythmias in 3 patients and prompted withdrawal in 18/139 (12.9%) patients due to metabolic effects 6, 5
• When combined with norepinephrine, the additive sympathomimetic effects increase the risk of serious cardiac arrhythmias, particularly in patients receiving cardiac glycosides, digitalis, or antiarrhythmics 7

Splanchnic Perfusion Concerns

• Epinephrine increases the tonometered PCO2 gap (indicating inadequate splanchnic perfusion) while norepinephrine decreases it 5
• Epinephrine increases myocardial oxygen consumption more than norepinephrine, making it less safe in patients with potential cardiac ischemia 5, 8

Drug Interaction Warnings (FDA Label)

• The FDA explicitly warns that epinephrine should be administered cautiously to patients taking other sympathomimetic agents (including norepinephrine) due to additive effects 7
• Patients receiving both agents require careful observation for cardiac arrhythmias, particularly if also receiving cardiac glycosides, digitalis, diuretics, quinidine, or other antiarrhythmics 7

Practical Implementation

Monitoring Requirements

• Place an arterial catheter immediately in all patients requiring vasopressors 1, 2
• Monitor continuously for: tachycardia, new arrhythmias, rising lactate despite adequate MAP, digital ischemia, decreased urine output, and worsening organ dysfunction 1

Dosing Thresholds That Mandate Escalation

• Norepinephrine >0.5 mcg/kg/min is associated with mortality rates exceeding 80-96%—add vasopressin before reaching this threshold 2
• If norepinephrine exceeds 1 mcg/kg/min despite vasopressin, add epinephrine rather than further escalating norepinephrine 2

Alternative to Epinephrine Addition

• Consider adding dobutamine (up to 20 mcg/kg/min) instead of epinephrine if persistent hypoperfusion exists with evidence of myocardial dysfunction, as the combination of norepinephrine-dobutamine is safer than epinephrine alone 1, 5, 9
• Norepinephrine-dobutamine combination improves gastric mucosal perfusion better than epinephrine and avoids the lactic acidosis and arrhythmias associated with epinephrine 5, 9

Common Pitfalls to Avoid

• Never use epinephrine and norepinephrine together as initial therapy—this violates guideline recommendations and increases arrhythmia risk without mortality benefit 1, 3, 7
• Never skip vasopressin—adding epinephrine before trying vasopressin is inappropriate escalation 1, 2
• Never exceed vasopressin 0.04 units/minute to accommodate higher epinephrine doses—this causes ischemic complications 1, 2
• Do not use lactate clearance to guide resuscitation when epinephrine is running, as it artificially elevates lactate through β2-adrenergic effects 4, 3
• Avoid in patients on halogenated anesthetics—the combination of epinephrine with norepinephrine in the presence of halothane or similar agents dramatically increases arrhythmia risk 7

Emerging Pediatric Evidence

• Recent 2025 data suggests norepinephrine may be superior to epinephrine as first-line therapy even in pediatric septic shock, with epinephrine associated with greater 30-day mortality (3.7% vs 0%; risk difference 3.7%; 95% CI 0.2%-7.2%) 10
• This contradicts older pediatric data showing epinephrine superiority and reinforces the adult guideline approach of norepinephrine-first strategy 10