Fatal Diphenhydramine Overdose Resulting in Cardiac Arrest and Cerebral Edema

Introduction: Diphenhydramine is a first-generation H1-antihistamine commonly used for allergies, insomnia, and motion sickness. Due to its high lipophilicity, doses above 1 g can lead to sodium channel blockade, resulting in QRS widening, QT prolongation, seizures, and lethal arrhythmias. Its widespread availability makes it a common agent in intentional overdoses, due to its sedative and hallucinogenic effects in the CNS.


Description: A 22 year-old female presented to the ED following cardiac arrest after intentionally ingesting approximately 4.5 g of diphenhydramine. She underwent CPR, IV administration of lidocaine, amiodarone, and a sodium bicarbonate drip. Norepinephrine and vasopressin started for persistent hypotension. Lidocaine was ineffective, presumably due to competitive sequestration in the lipid phase, as lidocaine and diphenhydramine are both lipophilic agents. Lipid emulsion therapy was initiated aiming to mitigate cardiac toxicity. Seizure activity was managed with midazolam and levetiracetam. Physostigmine, the preferred agent for severe anticholinergic toxicity, was unavailable due to a national shortage. Neostigmine was considered but withheld due to QRS widening and increased risk of ventricular arrhythmias. Despite aggressive resuscitative efforts, she developed cerebral edema and brian death was subsequently confirmed.


Discussion: Diphenhydramine toxicity can rapidly evolve into a life-threatening condition requiring aggressive management. A key feature of severe toxicity is sodium channel blockade, leading to QRS widening and potential ventricular arrhythmias. IV sodium bicarbonate is first-line treatment, as serum alkalinization may reduce unbound diphenhydramine and improve cardiac conduction. Seizure control and close monitoring for progression to cerebral edema are vital. Although neostigmine may reverse anticholinergic delirium, its should be avoided in the setting of QRS widening due to the risk of inducing arrhythmias. Lipid emulsion therapy may provide benefit in severe cases, but its lipophilic nature can reduce the efficacy of other similarly lipophilic medications, such as lidocaine. This case highlights the lethality of diphenhydramine overdose, the complexity of its pharmacologic effects, and the importance of early and targeted interventions.