Does epinephrine (adrenaline) cause higher serum lactate levels compared with other vasopressors?

Does Epinephrine Cause Increased Lactate Compared to Other Pressors?

Yes, epinephrine causes significantly higher serum lactate levels compared to other vasopressors, particularly norepinephrine, through β2-adrenergic-mediated skeletal muscle glycogenolysis rather than tissue hypoperfusion—this is a transient, non-clinically harmful metabolic effect but can confound resuscitation monitoring.

Mechanism of Epinephrine-Induced Hyperlactatemia

Epinephrine's β-adrenergic stimulation activates glycogenolysis in skeletal muscle, which lacks glucose-6-phosphatase, leading to lactate production rather than glucose release 1. The FDA label confirms that epinephrine "increases glycogenolysis, reduces glucose uptake by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia and increased blood lactic acid" 2.

This is fundamentally different from shock-related hyperlactatemia—it reflects metabolic reprogramming, not inadequate tissue perfusion 3.

Clinical Evidence: Epinephrine vs. Other Vasopressors

Epinephrine vs. Norepinephrine

The most robust comparative data shows:

• Epinephrine causes transient lactate elevation: Compared to norepinephrine, epinephrine infusion produces a "transient, non-clinically relevant increase in serum lactate levels and decrease in arterial pH" 1

• Magnitude of effect: In severe infections, adrenaline increased plasma lactate by a mean of 3.2 mmol/L with pH falling by 0.052 units, while dopamine actually decreased lactate by 1.0 mmol/L 4. The geometric mean lactate increment per unit adrenaline dose was 8.2 mmol/L per μg/kg/min 4

• Clinical significance: In one randomized crossover study of 23 critically ill patients, 84% had to terminate epinephrine infusion before reaching maximum dose due to lactic acidosis, versus none with dopamine 4

Post-Cardiac Surgery Data

After cardiopulmonary bypass, 6 of 19 patients (32%) receiving epinephrine developed lactic acidosis versus 0 of 17 receiving norepinephrine 5. This occurred despite:

• Higher cardiac index with epinephrine (p < 0.03)
• Higher mixed venous PO₂ (p = 0.04)
• Increased lower limb blood flow and femoral venous oxygen saturation

This confirms the lactate rise is NOT from tissue hypoperfusion 5.

Critical Clinical Pitfall: Misinterpreting Lactate During Epinephrine Use

The major danger is mistaking epinephrine-induced metabolic lactate elevation for inadequate resuscitation, leading to:

1. Overresuscitation: Clinicians may inappropriately escalate fluids or other interventions when lactate remains elevated on epinephrine
2. Delayed recognition of true shock: The β-mediated lactate obscures the utility of lactate as a perfusion marker
3. Premature discontinuation: Some may stop epinephrine unnecessarily when it's providing needed hemodynamic support

Guideline-Based Recommendations

Current ICM guidelines position epinephrine as:

• Second-line agent: Use when persistent hypotension occurs with myocardial depression despite norepinephrine, either adding dobutamine to norepinephrine OR using epinephrine as a single agent 1
• Not first-line: Norepinephrine remains the recommended initial vasopressor after fluid resuscitation 1

The 2025 ESICM guidelines acknowledge that "lactate does not increase solely because of poor tissue perfusion" and emphasize integrating multiple perfusion markers rather than relying on lactate alone 6, 1.

Practical Algorithm for Lactate Interpretation on Epinephrine

When lactate rises or remains elevated on epinephrine:

1. Assess timing: Is this within 6-12 hours of initiation? (Flow-dependent phase vs. metabolic phase 3)

2. Check other perfusion markers:

   • Capillary refill time (CRT)
   • Central venous oxygen saturation (ScvO₂)
   • Veno-arterial PCO₂ difference
   • Urine output
   • Skin mottling/temperature 6

3. If other perfusion markers are normal: The lactate elevation is likely β-mediated and does NOT require escalation of resuscitation

4. If other perfusion markers are abnormal: True tissue hypoperfusion exists—consider switching from epinephrine to norepinephrine plus dobutamine rather than adding more epinephrine 1

5. At moderate doses (NE-equivalent 0.3-0.5 μg/kg/min) with lactate >2 mmol/L: Consider this a higher-risk state requiring closer monitoring, though this is exploratory 7

Comparative Safety Profile

Norepinephrine demonstrates superior outcomes:

• Meta-analysis of 32 trials (3,544 patients) showed norepinephrine reduced all-cause mortality versus dopamine (RR 0.89,95% CI 0.81-0.98), with absolute risk reduction of 11% and NNT of 9 8
• Lower risk of major adverse events and cardiac arrhythmias with norepinephrine 8
• No mortality benefit demonstrated for epinephrine over norepinephrine 8

Epinephrine carries higher arrhythmia risk: approximately 15% versus 2-15% with norepinephrine 1.

Bottom Line for Clinical Practice

Use norepinephrine as first-line vasopressor 1. When epinephrine is necessary for refractory shock with myocardial depression, recognize that lactate elevation is expected and does NOT automatically indicate worsening shock. Integrate capillary refill time, ScvO₂, and PCO₂ gap to guide resuscitation rather than chasing lactate normalization 6, 3. The ANDROMEDA-SHOCK trial validated that CRT-guided resuscitation improved outcomes compared to lactate-guided therapy, highlighting the risk of overintervention when relying solely on lactate 3.