Epinephrine (Adrenaline) Increases Lactate More Than Norepinephrine
Epinephrine is significantly more likely to increase lactate levels compared to norepinephrine, primarily through β2-adrenergic receptor stimulation of skeletal muscle glycolysis rather than tissue hypoxia. 1
Mechanism of Lactate Production
Epinephrine causes aerobic lactate production through β2-adrenergic receptor activation in skeletal muscle, which stimulates glycogenolysis and glycolysis, leading to increased lactate production independent of tissue perfusion 1. This occurs because skeletal muscle lacks glucose-6-phosphatase, preventing complete glucose metabolism and resulting in lactate accumulation 2.
In contrast, norepinephrine has predominantly α-adrenergic effects with minimal β2-receptor stimulation, making it far less likely to trigger this metabolic lactate production 3.
Clinical Evidence
Direct Comparative Studies
In septic shock patients, epinephrine infusion caused lactate levels to increase from 3.1 to 5.9 mmol/L after 6 hours, while norepinephrine-dobutamine decreased lactate from 3.1 to 2.7 mmol/L 4. The lactate/pyruvate ratio also increased significantly with epinephrine (from 15.5 to 21) but remained stable with norepinephrine-dobutamine 4.
In cardiogenic shock, epinephrine similarly increased lactate levels after 6 hours while norepinephrine-dobutamine decreased them 5. Importantly, animal studies confirmed that epinephrine-induced hyperlactatemia occurs without cellular hypoxia, demonstrating this is a metabolic rather than ischemic phenomenon 6.
Dose-Dependent Effects
At lower doses (<0.3 μg/kg/min), epinephrine predominantly produces β-adrenergic effects with greater lactate production 1. Even at higher doses where α-adrenergic vasoconstriction becomes more prominent, the metabolic effects persist 1.
Clinical Implications
Impact on Resuscitation Monitoring
Epinephrine may prevent the use of lactate clearance to guide resuscitation because elevated lactate does not necessarily indicate worsening tissue perfusion 7, 3. This is a critical pitfall when managing patients on epinephrine—rising lactate may reflect the drug's metabolic effects rather than inadequate resuscitation 1.
Guideline Recommendations
Major guidelines recommend norepinephrine as first-line therapy for septic shock, with epinephrine as the first alternative when norepinephrine is unavailable or ineffective 3. Despite the lactate-elevating effects, randomized trials found no mortality difference between the two agents (RR 0.96; 95% CI 0.77-1.21) 7, 3.
Splanchnic Perfusion Concerns
Epinephrine transiently worsens gastric mucosal perfusion (decreased pHi and increased PCO2 gap) compared to norepinephrine-dobutamine 4, 5. However, these effects typically normalize within 24 hours 4.
Common Pitfalls
- Do not interpret rising lactate as treatment failure in patients receiving epinephrine—this may represent aerobic lactate production rather than tissue hypoxia 1, 6
- Epinephrine causes more arrhythmias and higher heart rates than norepinephrine, making it less predictable in critically ill patients 5
- The lactate increase with epinephrine is transient, typically returning to baseline within 24 hours even with continued infusion 4