What is the antidote for diphenhydramine (Benadryl) toxicity?

Diphenhydramine Toxicity Management

There is no specific antidote for diphenhydramine toxicity—treatment is entirely supportive with targeted interventions for specific complications including sodium bicarbonate for QRS widening, benzodiazepines for seizures, and aggressive airway management. 1

Primary Management Approach

The cornerstone of diphenhydramine toxicity management is supportive care with symptom-directed therapy, as no reversal agent exists for this anticholinergic and sodium channel-blocking toxin. 1, 2

Immediate Stabilization

• Establish and maintain airway patency with bag-mask ventilation or endotracheal intubation for patients with CNS depression and loss of protective airway reflexes. 3
• Avoid succinylcholine and mivacurium for intubation as these neuromuscular blockers are metabolized by cholinesterase and are contraindicated in anticholinergic toxicity. 3, 4
• Provide supplemental oxygen and support ventilation as needed. 3
• Establish IV access and administer fluids for volume resuscitation. 3
• Initiate continuous cardiac monitoring for dysrhythmias, particularly QRS widening. 3, 1

Specific Interventions by Complication

Cardiac Toxicity (Sodium Channel Blockade)

For QRS prolongation >100 ms or wide-complex dysrhythmias, administer sodium bicarbonate 1-2 mEq/kg IV bolus immediately. 3, 1 This is the most critical intervention for diphenhydramine's sodium channel blocking effects, which can cause life-threatening arrhythmias. 5, 6

• Monitor ECG closely for intraventricular conduction delay and terminal rightward axis deviation in lead aVR. 3
• QRS prolongation is strongly associated with severe outcomes including seizures and cardiovascular collapse. 6
• For hypotension unresponsive to IV fluids, administer vasopressors such as dopamine or vasopressin. 3

Neurological Complications

For seizures or severe agitation, administer benzodiazepines (diazepam first-line or midazolam) immediately. 3, 4, 1 Seizures occurred in 11.6% of diphenhydramine overdoses in one large registry study. 6

• Benzodiazepines may be administered by EMS personnel if authorized by medical direction. 1
• Physostigmine should be reserved for administration in a hospital setting only, not in the prehospital environment. 1

Metabolic Derangements

Monitor for and address:

• Acidemia (pH <7.2), which is strongly associated with severe outcomes. 6
• Elevated anion gap (>20), another predictor of severe toxicity. 6
• These metabolic abnormalities warrant aggressive supportive care and consideration of ICU-level monitoring. 6

Dose-Dependent Risk Stratification

Understanding toxic dose thresholds guides disposition decisions:

• Moderate symptoms (agitation, confusion, hallucinations, ECG disturbances) occur above 0.3 g (300 mg) ingested. 2
• Severe symptoms (delirium, seizures, coma) occur above 1.0 g ingested. 2
• Children <6 years: Refer to ED if ingestion ≥7.5 mg/kg. 1
• Patients ≥6 years: Refer to ED if ingestion ≥7.5 mg/kg or 300 mg (whichever is less). 1

Critical Pitfalls to Avoid

• Do not induce emesis following oral exposures due to potential for rapid loss of consciousness or seizures. 1
• Do not administer activated charcoal en route to the emergency department for the same reason. 1
• Do not delay sodium bicarbonate when QRS widening is present—this is the immediate life-saving intervention for cardiac toxicity. 3, 1
• Consider co-ingestions, as mixed overdoses are common and may complicate management. 3

Observation and Disposition

• If no symptoms and >4 hours have elapsed since ingestion, referral to ED is not necessary. 1
• Patients with suicidal intent, intentional abuse, or malicious intent should always be referred to an emergency department. 1
• For symptomatic patients, contact poison control (1-800-222-1222 in the US) for expert guidance. 3, 4
• Monitor for at least 48-72 hours in hospitalized patients as delayed complications can occur. 4

Emerging Therapies

Intravenous fat emulsion (IFE) has been reported as a potential rescue therapy for refractory diphenhydramine toxicity with cardiovascular collapse, given diphenhydramine's lipophilicity (octanol/water partition coefficient of 3.3). 5 However, this remains an experimental adjunctive therapy reserved for cases refractory to standard interventions including sodium bicarbonate and benzodiazepines. 5