Intramuscular (IM) injection of epinephrine in adults: What is the optimal interval between doses?

In first-aid treatment of anaphylaxis, the recommended interval between epinephrine injections ranges from 5–30 minutes. We hypothesized that epinephrine's pharmacologic effects might differ depending on the dose interval. In a randomized, blinded, placebo-controlled, two-way crossover study, healthy men received three IM injections in the lateral thigh on each of two different study days ≥ one week apart. Two injections were epinephrine 0.3 mg from an EpiPen® (Epi) and one injection was 0.9% NaCl. The order of the injections, given at 0, 15 and 30 minutes, was either: Epi/Epi/NaCl, or Epi/NaCl/Epi. Plasma epinephrine concentrations, heart rate, blood pressure, and adverse effects were monitored at 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 60, 75, 90, 105, 120, 150, and 180 minutes. Pharmacokinetic parameters were compared using the Student's t-test. 8 men (26 ± SEM 2 years, 77 ± 3 kg) completed the study. When the Epi injections were separated by 15 minutes, the time of maximum plasma concentration (t max) after the first dose was 10 ± SEM1.6 minutes and the t max after the second dose was 16.3 ± 3.5 minutes. When the epinephrine injections were separated by 30 minutes, the t max after the first dose was 16.9 ± 2.8 minutes and the t max after the second dose was 15.6 ± 3.3 minutes. The t max, heart rate, and blood pressure (p>0.05), and adverse effects did not differ significantly between the two treatment regimens. There were no significant differences in t max or safety parameters when the epinephrine injection was repeated at 15 compared to 30 minutes.