Effect of Intramuscular Adrenaline on Histamine-Induced Hypotension: A Randomised Placebo-Controlled Pilot Trial

Intramuscular adrenaline (epinephrine) is the first-line treatment for anaphylaxis. This recommendation is based purely on consensus, not randomised controlled trials. In humans, hypotension and shock strongly correlate with plasma histamine concentrations. The efficacy of intramuscular adrenaline in reversing histamine-induced hypotension remains unproven. This trial evaluated whether intramuscular adrenaline reverses histamine-induced shock.

We conducted an exploratory open-label trial and a confirmatory randomised, double-blind, placebo-controlled, crossover trial. Healthy volunteers received a 15-min continuous intravenous histamine infusion to induce hypotension. At 5 min, participants received either intramuscular adrenaline (300-500 μg) or placebo. A second adrenaline dose was administered if the mean arterial pressure (MAP) remained below 60 mmHg at 10 min. The primary endpoint was area under the effect curve for change in MAP.

During histamine-induced hypotension, intramuscular adrenaline failed to produce a pressor response and was indistinguishable from placebo in the majority of participants. Excluding two subjects who needed a simultaneous dose reduction of histamine, only 5 of 20 participants (25%; 95% CI 8.7%-49.1%) demonstrated a transient MAP recovery after a single dose. A second adrenaline dose administered to participants who did not reach a MAP > 60 mmHg also failed to reverse hypotension. The primary outcome in the confirmatory cohort, excluding two subjects with histamine dose adjustments, was not different between treatments (adrenaline-placebo: 7 mmHg·min, 95% CI -2 to 25; p = 0.06).

In this study of a limited number of healthy human subjects, intramuscular adrenaline injections did not provide a sustained response in severe histamine-mediated hypotension in a majority of recipients.

CTIS (2022-003591-16) and ISRCTN (Nr. 11335622; https://doi.org/10.1186/ISRCTN11335622).