Optimal dose of adrenaline auto‐injector for children and young people at risk of anaphylaxis: A phase IV randomized controlled crossover study

• Published in: Allergy (Copenhagen) Vol. 78; no. 7; pp. 1997 - 2006
• Main Authors: Patel, Nandinee, Isaacs, Emily, Duca, Bettina, Nagaratnam, Nanthagopan, Donovan, Jackie, Fontanella, Sara, Turner, Paul J.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.07.2023
• Subjects: Adolescent; adrenaline; Adult; Anaphylaxis; Anaphylaxis - drug therapy; at-risk population; auto‐injector; cardiac output; Child; Cross-Over Studies; Epinephrine; Epinephrine - therapeutic use; Female; health services; Heart rate; Humans; Injection; Injections, Intramuscular; intramuscular injection; Male; males; Pharmacodynamics; risk; Self Administration; Single-Blind Method; stroke volume; syringes; ultrasonics; anaphylaxis; epinephrine; adrenaline; auto-injector; stroke volume
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15675

Background Guidelines recommend intramuscular injection of 500 μg adrenaline (epinephrine) for anaphylaxis in teenagers and adults; however, most autoinjectors deliver a maximum 300 μg dose. We evaluated plasma adrenaline levels and cardiovascular parameters (including cardiac output) following self‐injection with 300 μg or 500 μg adrenaline in teenagers at risk of anaphylaxis. Methods Subjects were recruited to a randomized, single‐blind two period crossover trial. Participants received all 3 injections (Emerade® 500 μg, Emerade® 300 μg, Epipen® 0.3 mg) on 2 separate visits (allocated in a randomized block design), at least 28 days apart. Intramuscular injection was confirmed by ultrasound, and heart rate/stroke volume assessed using continuous monitoring. The trial was registered at Clinicaltrials.gov (NCT03366298). Results Twelve participants (58% male, median 15.4 years) participated; all completed the study. 500 μg injection resulted in a higher and more prolonged peak concentration (p = 0.01) and greater Area‐Under‐Curve for plasma adrenaline (p < 0.05) compared to 300 μg, with no difference in adverse events. Adrenaline caused a significant increase in heart rate irrespective of dose and device. Unexpectedly, 300 μg adrenaline resulted in a significant increase in stroke volume when delivered with Emerade®, but a negative inotropic effect with Epipen® (p < 0.05). Conclusions These data support a 500 μg dose of adrenaline to treat anaphylaxis in individuals >40 kg in the community. The contrasting effects on stroke volume between Epipen® and Emerade®, despite similar peak plasma adrenaline levels, are unexpected. There is an urgent need to better understand differences in pharmacodynamics following adrenaline administration by autoinjector. In the meantime, we recommend adrenaline injection by needle/syringe in the healthcare setting in individuals with anaphylaxis refractory to initial treatment. This crossover study assesses the pharmacokinetics/pharmacodynamics of self‐injection with 300 μg or 500 μg adrenaline in food‐allergic teenagers at risk of anaphylaxis. Our findings challenge the assumption that optimal cardiovascular effects are associated with the adrenaline autoinjector causing the fastest and highest peak in plasma adrenaline. These data justify the global availability of adrenaline autoinjectors which deliver 500 μg adrenaline for use in adolescents and adults over 40 kg.Abbreviations: IM, intramuscular; min, minutes