An initial dose of 0.3 mg intramuscular (IM) epinephrine was tied to a greater escalation of care than a dose of 0.5 mg in patients with anaphylaxis, a retrospective single-center study found.

The lower dose was associated with the need for an additional epinephrine dose, epinephrine infusion, or intubation compared with the higher dose, according to Caroline A. Jackson, PharmD, an ICU pharmacist in the Department of Pharmaceutical Services at Vanderbilt University Hospital in Nashville, Tennessee.

These findings support the World Allergy Organization (WAO) weight-based recommendation for adult patients experiencing anaphylaxis, the authors wrote in The American Journal of Emergency Medicine.

While the WAO recommends 0.5 mg IM epinephrine for all patients weighing at least 50 kg, a 0.3-mg dose was also commonly used at Vanderbilt University Hospital during the study period, Jackson told Medscape Medical News. Because there were limited data on the topic of differing doses of epinephrine, “our team decided to conduct a retrospective analysis to further investigate the potential efficacy and safety differences of these dosing regimens,” she said.

Although epinephrine has been linked to cardiotoxicities, including fatal arrhythmias and myocardial infarction, these are most commonly associated with intravenous boluses, the authors noted.

Study Details

Chart review in the Vanderbilt health network identified 338 patients meeting inclusion criteria, of whom 254 patients were in the 0.3 mg group and 84 were in the 0.5 mg group.

Patients were treated for anaphylaxis from January 1, 2018, to November 17, 2024. Baseline characteristics between groups were similar. Included patients had a median age of 44 years (IQR, 29-57), were predominantly female (61%), and had a median weight of 82 kg.

The primary reason for hospital admission was anaphylaxis in 73% of patients. The remaining 27% were already in the emergency department or hospital during the initial anaphylaxis episode. The most common initial symptoms were urticaria (78%), shortness of breath (57%), facial or mouth swelling (38%), and nausea or vomiting (23%).

The primary composite outcome was defined by the occurrence of any of the following events within 6 hours of the initial dose of IM epinephrine deemed to indicate progression: an additional dose of IM epinephrine, an epinephrine infusion, or intubation as a result of anaphylaxis progression.

In addition to individual components of the composite outcome, secondary outcomes included the resolution of symptoms after the initial dose and length of stay in the emergency department. Safety outcomes occurring within 6 hours of dosing included a change in peak heart rate and systolic blood pressure greater than 200 mm Hg, ischemic changes on an ECG, and atrial or ventricular arrhythmia, as well as elevated troponin levels within 12 hours of dosing.

The primary composite outcome was significantly more common in the lower-dose group — 30% vs 7% (P < .001) — primarily driven by the 0.3 mg group receiving additional doses of epinephrine. The most common treatment escalation in the entire cohort was an additional dose, occurring in 23% of patients overall, followed by epinephrine infusion in 6% and intubation in 2%.

Multivariate logistic regression confirmed an initial dose of 0.5 mg epinephrine was independently associated with a lower incidence of the primary outcome.

Jackson noted that the lower dose was more commonly used in the Vanderbilt health system during the study period. “But our institution currently carries vials of epinephrine rather than epinephrine autoinjector pens, which allow providers the option to order either 0.3 mg or 0.5 mg to be prepared for IM injection at the bedside.”

Her group called for larger, prospective studies to confirm the finding that an initial IM dose of 0.5 mg appears to lead to less escalation of care and to determine the impact of either dose on safety outcomes.

“While our analysis found a correlation between the higher dose and a lower risk of escalating care — primarily driven by the need for additional doses of epinephrine — our study was not designed to prove causation, nor was it powered to detect differences in safety outcomes between groups,” Jackson said. Therefore, safety outcomes remain an area that has not yet been addressed in either prospective or retrospective analyses.

Offering a nonparticipant’s perspective on the study, allergist David B.K. Golden, MD, an associate professor of medicine at Johns Hopkins University in Baltimore, said that despite its limitations, this report provides important evidence of the efficacy of epinephrine and the relative safety and efficacy of the 0.5-mg dose in adults.

“The report does not include how or why the decision was made in each individual case to give either 0.3 or 0.5 mg, but it was not a randomized trial,” he told Medscape Medical News. “The option to give a second dose was probably considered more readily when the first dose was 0.3 mg. Still, the need for IV epi [intravenous epinephrine] or intubation was also higher when the first dose was 0.3 mg.”

Determining the optimal dosing of epinephrine would probably require a prospective randomized trial that controls for age, body size, severity, and time since the onset of reaction, among other variables, Golden said.

“There are so many unanswered questions about optimal epinephrine dosing and pharmacokinetic profiles, and it is exceedingly difficult to study severe anaphylactic reactions.” Clinicians should keep in mind that the recommended initial dose is up to 0.5 mg, which may be considered on a case-by-case basis when manual dose adjustment is available.

In other comments, Richard F. Lavi, MD, an allergist based in Twinsburg, Ohio, believes that US allergists likely default to 0.3 mg because of familiarity with autoinjector dosing and lack of safety data for the 0.5-mg dosing.

“Anecdotally, I believe 0.5 mg is more effective, and I have limited experience to agree with the findings of this study supporting that belief. I think we should be using 0.5-mg IM dosing for healthy teens and adults experiencing anaphylaxis,” Lavi said. “The downside is we don’t have safety data, and this study does not provide it either.”

Questions remaining for optimal dosing include injection site, depth of needle in all body sizes and types, possible monitoring with higher IM doses, and adjustments to the monitoring timing, said Lavi.

This study received no specific funding. The authors had no competing interests to declare. Golden reported consulting and speaker activities for several private-sector companies unrelated to his comments. Lavi had no competing interests to disclose.