Mechanism of Epinephrine-Induced Lactate Elevation
Epinephrine increases lactate primarily through beta-2-adrenergic receptor stimulation in skeletal muscle, which activates glycogenolysis and glycolysis, producing lactate independent of tissue hypoxia or perfusion status. 1
Primary Mechanism: Beta-2-Adrenergic Stimulation
Epinephrine binds to beta-2-adrenergic receptors on skeletal muscle cells, triggering a cascade that activates glycogenolysis (breakdown of glycogen) and increases glycolytic flux. 1
Skeletal muscle lacks the enzyme glucose-6-phosphatase, which means glucose-6-phosphate generated from glycogen breakdown cannot be converted back to glucose and must proceed through glycolysis, ultimately producing lactate. 1
This lactate production occurs even in well-oxygenated tissue—hypoxia is not required for epinephrine to elevate lactate levels. 2
Dose-Dependent Effects
At lower infusion doses (<0.3 μg/kg/min), epinephrine predominantly produces beta-adrenergic effects with greater lactate production in peripheral tissues. 1
At higher doses (>0.3 μg/kg/min), alpha-adrenergic vasoconstriction becomes more prominent, though the metabolic lactate-producing effects persist throughout. 1
Additional Metabolic Mechanisms
Epinephrine increases Na+-K+-ATPase pump activity in skeletal muscle, which derives significant ATP from glycolysis rather than oxidative phosphorylation, further driving lactate production. 2
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." 3
Epinephrine mobilizes lactate and alanine from extrasplanchnic tissues (primarily skeletal muscle), which are then taken up by the liver for gluconeogenesis—this substrate mobilization contributes to sustained elevation in circulating lactate. 4
Hepatic Contribution
While the initial rise in glucose production from epinephrine is due to hepatic glycogenolysis, epinephrine subsequently stimulates hepatic gluconeogenesis by providing lactate and alanine as substrates. 4
The liver converts this mobilized lactate back to glucose through gluconeogenesis (the Cori cycle), but during epinephrine infusion, lactate production from muscle exceeds hepatic clearance capacity. 4
Clinical Distinction from Hypoperfusion
This epinephrine-induced lactate elevation is fundamentally different from lactate elevation due to tissue hypoxia—it represents accelerated aerobic glycolysis driven by beta-adrenergic stimulation, not anaerobic metabolism. 1, 5
Epinephrine can cause increased plasma lactate independent of changes in organ perfusion, making lactate a more difficult parameter to interpret in patients receiving epinephrine. 1
In comparative studies, epinephrine infusion produced a transient increase in serum lactate levels and decrease in arterial pH compared to norepinephrine, despite similar hemodynamic improvements. 1, 6
Time Course and Pharmacokinetics
The FDA label indicates epinephrine has rapid onset (<5 minutes) and short duration of action (offset within 20 minutes after stopping infusion), with an effective half-life of <5 minutes. 3
However, the metabolic effects on lactate production can persist as long as the infusion continues, with lactate levels typically peaking around 4 hours after starting epinephrine. 7
Important Clinical Caveat
When using epinephrine in clinical settings, particularly in septic shock or cardiogenic shock, clinicians must recognize that elevated lactate does not necessarily indicate worsening tissue perfusion—it may simply reflect the direct metabolic effects of the drug. 1, 6
Lactate-guided resuscitation strategies should account for this direct metabolic effect when interpreting lactate trends in patients receiving epinephrine. 1
The American College of Critical Care Medicine suggests that epinephrine may prevent the use of lactate clearance to guide resuscitation because elevated lactate does not necessarily indicate worsening tissue perfusion. 1