What are the treatment options for neurologic effects of diphenhydramine (Benadryl) toxicity?

Treatment of Neurologic Effects of Diphenhydramine Toxicity

Immediate Management of Life-Threatening Neurologic Manifestations

For seizures or severe agitation from diphenhydramine toxicity, administer benzodiazepines immediately as first-line therapy. 1, 2, 3

Seizure Management

• Benzodiazepines are the definitive treatment for diphenhydramine-induced seizures, which occur in approximately 11.6% of all diphenhydramine overdoses 1, 2, 4
• Diazepam is first-line, with midazolam as an alternative 1
• EMS personnel may administer benzodiazepines if authorized by medical direction 3
• Seizures are the most common severe neurologic outcome and require immediate intervention 4

Altered Mental Status and Anticholinergic Delirium

Diphenhydramine toxicity produces central anticholinergic syndrome characterized by anxiety, delirium, disorientation, hallucinations, hyperactivity, and potentially coma. 5

Clinical Presentation

• Central toxic effects include anxiety, delirium, disorientation, hallucinations, hyperactivity, and seizures 5
• Severe poisoning may produce coma and medullary paralysis 5
• Toxic psychosis with bizarre behavior and hallucinations is well-documented 6
• Patients may present with staring spells, inconsolable crying, or loss of consciousness 3

Physostigmine Considerations

• Physostigmine should be reserved for administration in a hospital setting only 3
• Physostigmine is a reversible anticholinesterase that crosses the blood-brain barrier and can reverse both central and peripheral anticholinergic effects 5
• Dramatic reversal of anticholinergic symptoms can occur within minutes of intravenous administration 5
• Duration of action is relatively short (45-60 minutes), potentially requiring repeat dosing 5
• Physostigmine should NOT be administered in the prehospital setting 3

Cardiac Sodium Channel Blockade Management

Diphenhydramine is classified as a sodium channel blocker and requires sodium bicarbonate for life-threatening cardiotoxicity. 1, 2

Sodium Bicarbonate Administration

• For QRS prolongation (>120 ms) or wide-complex dysrhythmias, administer sodium bicarbonate 1-2 mEq/kg IV bolus 2, 1
• The 2023 American Heart Association guidelines recommend sodium bicarbonate as reasonable treatment for life-threatening cardiotoxicity from sodium channel blockers including diphenhydramine 1
• QRS prolongation is strongly associated with severe outcomes and requires immediate intervention 4
• EMS personnel may administer sodium bicarbonate if QRS widening (>0.10 msec) is present and authorized by medical direction 3

High-Risk Indicators

• Acidemia (pH <7.2), QRS prolongation (>120 ms), and elevated anion gap (>20) are most strongly associated with severe outcomes 4
• Wide complex tachycardia can occur due to sodium channel blockade and represents life-threatening toxicity 7, 8
• These electrocardiographic changes typically precede ventricular dysrhythmias 1

Refractory Cases and Advanced Therapies

Intravenous Lipid Emulsion (IFE)

• For cardiovascular collapse refractory to sodium bicarbonate, consider intravenous fat emulsion therapy 7, 8
• IFE is proposed as adjunctive therapy due to diphenhydramine's lipophilicity (octanol/water partition coefficient of 3.3) 7
• Case reports demonstrate rapid improvement in wide complex tachycardia and cardiovascular collapse after IFE administration when other therapies failed 7, 8
• IFE showed temporal association with improvement in QRS duration in refractory cases 8

Extracorporeal Support

• For refractory cardiac arrest, extracorporeal life support such as VA-ECMO is reasonable 1
• This represents the most aggressive intervention for sodium channel blocker poisoning unresponsive to other measures 1

Supportive Care and Monitoring

Cardiovascular Support

• Administer IV fluids for volume resuscitation 2
• For hypotension unresponsive to fluids, administer vasopressors such as dopamine or vasopressin 2
• Monitor vital signs continuously, including blood pressure for hypotension and respiratory rate for depression 9, 2

Airway Management

• Stop any ongoing diphenhydramine administration immediately 2
• Assess and maintain airway, breathing, and circulation 2
• Administer supplemental oxygen as needed 2
• Consider intubation for severe cases with loss of consciousness or respiratory depression 3

Triage and Referral Criteria

Emergency Department Referral Required

• Any patient with moderate to severe symptoms including agitation, staring spells, inconsolable crying, hallucinations, abnormal muscle movements, loss of consciousness, seizures, or respiratory depression 3
• All patients with suicidal intent, intentional abuse, or suspected malicious intent 3
• Children <6 years ingesting ≥7.5 mg/kg diphenhydramine 3
• Patients ≥6 years ingesting ≥7.5 mg/kg or 300 mg (whichever is less) 3

Home Observation Acceptable

• Asymptomatic patients with <4 hours elapsed since ingestion and sub-toxic doses can be observed at home 3
• If >4 hours have elapsed since ingestion and patient remains asymptomatic, emergency department referral is not recommended 3
• Follow-up call should be made at approximately 4 hours post-ingestion 3

Critical Pitfalls to Avoid

• Do NOT induce emesis following oral diphenhydramine exposure due to potential for rapid loss of consciousness or seizures 3
• Do NOT administer activated charcoal en route to emergency department due to seizure and altered mental status risk 3
• Do NOT use neuromuscular blockers metabolized by cholinesterase (succinylcholine, mivacurium) in anticholinergic toxicity 1, 2
• Self-harm ingestions and male patients are more commonly associated with intubation requirements 4
• Children 0-12 years are less likely to require intubation compared to teens and adults 4