Standard doses of intramuscular adrenaline failed to reverse severe hypotension in most participants exposed to a controlled histamine challenge designed to mimic anaphylactic shock, according to results of the first randomized placebo-controlled study of its kind.

The findings raise questions about whether current emergency intramuscular adrenaline dosing strategies are sufficient to reverse the most severe cardiovascular manifestations of anaphylaxis. The investigators stressed, however, that the results should not be interpreted as a challenge to adrenaline’s status as first-line therapy.

“Our study addressed a question that has never previously been examined in a randomized controlled trial [RCT],” said Matthias Weiss-Tessbach, MD, PhD, Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. “Intramuscular adrenaline remains the recommended first-line treatment for anaphylaxis, but its ability to reverse severe hypotension caused by histamine, as in anaphylaxis, has largely been assumed rather than directly demonstrated,” he told Medscape Medical News.

Weiss-Tessbach presented the findings (L-FT05) at the European Academy of Allergy and Clinical Immunology (EAACI) 2026 Annual Congress. He won the session prize for the best abstract.

Addressing a Longstanding Evidence Gap

Intramuscular adrenaline is credited with reducing mortality when administered promptly for anaphylaxis. However, RCTs evaluating its effectiveness have traditionally been considered impractical and ethically impossible in patients experiencing genuine anaphylaxis.

To overcome this challenge, Weiss-Tessbach and colleagues developed a controlled human model using intravenous histamine infusion to reproduce the severe hypotension observed during grade 4 anaphylaxis. The model was informed by previous research showing that histamine concentrations seen during severe insect-sting anaphylaxis can produce profound cardiovascular collapse.

Randomized Crossover Trial

The single-center study at the Medical University of Vienna included 22 healthy volunteers who underwent a 15-minute intravenous histamine infusion, with doses up to 1 μg/kg/min, with continuous invasive arterial blood pressure monitoring. An initial open-label exploratory phase evaluated 300 μg intramuscular adrenaline, followed by a randomized, double-blind, placebo-controlled confirmatory phase assessing a 500-μg dose, consistent with adult dosing recommended in many contemporary anaphylaxis guidelines. Participants were randomized to receive intramuscular adrenaline or placebo.

Adrenaline doses ranged from 300 μg to 500 μg. A second dose was administered after 10 minutes if mean arterial pressure (MAP) remained below 60 mm Hg. Two participants required histamine dose reductions during the adrenaline period and were excluded from the primary analysis. Peak histamine concentrations reached 12.5 ng/mL, levels that were comparable with those reported in severe Hymenoptera sting anaphylaxis.

Limited Blood Pressure Recovery

The primary endpoint was restoration of MAP > 60 mm Hg. Only two of the 10 participants in the confirmatory cohort achieved a transient recovery of MAP > 60 mm Hg after receiving 500 μg intramuscular adrenaline.

When data from both the exploratory and confirmatory cohorts were pooled, only five of the 20 participants (25%; 95% CI, 8.7%-49.1%) achieved MAP > 60 mm Hg after a single adrenaline injection. Importantly, the effect was not sustained while histamine infusion continued even in those who initially responded.

A second adrenaline injection also failed to rescue most nonresponders. “Even when plasma adrenaline concentrations considered therapeutic by the FDA were achieved, most participants remained hypotensive,” Weiss-Tessbach said.

Peak plasma adrenaline concentrations reached approximately 399 pg/mL 5 minutes after injection, confirming adequate systemic absorption.

Implications for Clinical Practice

The findings suggest that histamine-driven vasodilation may be difficult to overcome with currently recommended intramuscular adrenaline doses alone. However, Weiss-Tessbach emphasized that the study model represents only one component of anaphylaxis pathophysiology. “Clinical anaphylaxis is much more complex,” he said.

Nevertheless, the results may help explain why some patients experiencing severe anaphylactic shock continue to deteriorate despite prompt administration of intramuscular adrenaline.

The findings also raise broader questions about optimal dosing, repeat administration strategies, and whether additional therapeutic approaches targeting histamine itself deserve further investigation.

Histamine Infusion Model

Commenting on the study, co-moderator, Pete Smith, MD, allergist at Queensland Allergy Services, Southport, Australia, said, “I was impressed both by the bravery of the volunteers who took part and by the researchers in conducting what is a very challenging study.”

“However, it is important to remember that clinical anaphylaxis is more complex than histamine alone,” Smith added. Multiple mediators are released during an anaphylactic reaction, and we know from everyday clinical practice that patients often improve after receiving adrenaline, he said.

“What the research does do is challenge us to think carefully about whether we are doing enough for patients with severe anaphylactic shock and whether additional therapeutic approaches may be needed in some situations.”

Also commenting was co-moderator, Håvard Ove Skjerven, MD, senior consultant in the Pediatric Department of Allergy and Pulmonary Diseases, Oslo University Hospital & University of Oslo, Norway, who likewise noted the bravery of the participants, but pointed out the limitations. “The negative result is interesting, but I don’t see that it has the potential to change practice. The number of patients is very small, and the histamine infusion setup cannot claim to fully mimic an anaphylactic shock.”

He added that a much larger, RCT on real anaphylactic patients must be conducted in order to challenge the use of intramuscular adrenaline. “However, all credit to the researchers for conducting a trial that at least introduces doubt about the effect of an obligatory treatment regime, and it should act as an inspiration to explore other possible medications against anaphylaxis.”

The study was conducted by investigators at the Medical University of Vienna. Weiss-Tessbach reported having no relevant disclosures in the conference presentation beyond institutional research support. Skjerven reported having no relevant conflicts of interest. Smith has previously reported receiving honoraria from AstraZeneca, GlaxoSmithKline, MEDA Pharmaceuticals, and Mundipharma.