What is the emergency management of a suspected first‑generation antihistamine overdose?

Emergency Management of First-Generation Antihistamine Overdose

Immediate stabilization with airway protection, benzodiazepines for seizures, and sodium bicarbonate for wide-complex dysrhythmias takes priority, while antihistamines themselves have no role in treating antihistamine toxicity. 1, 2

Immediate Resuscitation and Stabilization

Airway and Breathing Management

• Secure the airway immediately if the patient has altered mental status, active seizures, or respiratory depression, as first-generation antihistamines frequently cause CNS depression and loss of protective reflexes. 1, 2
• Provide supplemental oxygen and monitor oxygen saturation continuously, preparing for mechanical ventilation if respiratory failure develops. 1
• Preoxygenate adequately before intubation; if rapid sequence intubation is required, use midazolam 0.2 mg/kg IV after preoxygenation, allowing 2–3 minutes before administering a muscle relaxant. 1

Seizure Control

• Administer midazolam as the first-line agent for seizures: 0.2 mg/kg IM (maximum 6 mg per dose) or IV 0.05–0.10 mg/kg over 2–3 minutes (maximum single dose 5 mg), repeating every 10–15 minutes as needed. 1
• For refractory status epilepticus uncontrolled by standard benzodiazepine therapy, initiate a midazolam infusion with a loading dose of 0.15–0.20 mg/kg followed by continuous infusion starting at 1 mcg/kg/min, increasing by 1 mcg/kg/min increments every 15 minutes (maximum 5 mcg/kg/min) until seizures stop. 1
• Be prepared to provide respiratory support regardless of the route of benzodiazepine administration, as apnea risk increases when combined with other sedative effects of antihistamine toxicity. 1
• Critical pitfall: Do not administer flumazenil to reverse benzodiazepine-induced respiratory depression in this setting, as it will reverse anticonvulsant effects and may precipitate recurrent seizures. 1

Cardiac Dysrhythmia Management

• Obtain a 12-lead ECG immediately and initiate continuous cardiac monitoring, as first-generation antihistamines cause sodium channel blockade leading to QRS widening and ventricular dysrhythmias. 3, 2
• Administer sodium bicarbonate for wide-complex tachycardia or QRS prolongation (typically 1–2 mEq/kg IV bolus), as it reverses sodium channel blockade and is the specific antidote for antihistamine-induced cardiac toxicity. 2
• For refractory ventricular fibrillation or pulseless ventricular tachycardia despite standard advanced life support, consider extracorporeal cardiopulmonary resuscitation (ECPR) with veno-arterial ECMO if skills and equipment are available, as this has resulted in survival with good functional outcome in massive diphenhydramine overdose. 3
• Follow standard advanced life support guidelines including IV epinephrine 1 mg for cardiac arrest. 1

Gastrointestinal Decontamination

Pharmacobezoar Considerations

• Suspect pharmacobezoar formation in patients who develop biphasic clinical deterioration—initial stabilization followed by renewed toxicity hours later—as this indicates ongoing drug absorption from a gastric mass. 3
• Consider whole bowel irrigation or endoscopic removal of pharmacobezoars in consultation with toxicology and gastroenterology, particularly after massive ingestions (e.g., >800 tablets). 3
• Do not induce emesis, as altered mental status and seizure risk make aspiration highly likely. 4

Supportive Care and Monitoring

Hemodynamic Support

• Administer crystalloid fluid boluses (0.5–1 L rapid infusion, repeated as needed) for hypotension, as anticholinergic effects cause vasodilation. 1
• For persistent hypotension despite adequate fluid resuscitation, initiate vasopressor support with norepinephrine infusion (0.05–0.5 mcg/kg/min). 1

Observation Duration and Disposition

• Observe all patients with significant first-generation antihistamine overdose in a monitored setting for a minimum of 6 hours from symptom onset, as delayed toxicity from pharmacobezoars can occur. 1, 3
• Admit patients with Grade III reactions (severe hypotension, seizures, or dysrhythmias) or Grade IV reactions (cardiac arrest) to an intensive care unit for ongoing vasopressor requirements, mechanical ventilation, or ECMO support. 1
• Children who accidentally ingest doses approximately 3–4 times the normal therapeutic daily dose may be managed at home with observation, but larger ingestions require medical evaluation and monitoring for 2–3 hours minimum. 4

What NOT to Do

Contraindicated Interventions

• Never administer antihistamines (H1 or H2 blockers) to treat antihistamine overdose, as they provide no benefit and may worsen anticholinergic toxicity. 1
• Do not use naloxone, as opioid reversal is not relevant to antihistamine toxicity. 1
• Avoid flumazenil if benzodiazepines have been administered for seizure control, as reversal will precipitate recurrent seizures. 1

Common Pitfalls

• Do not assume clinical stability after initial resuscitation means the patient is out of danger; pharmacobezoars can cause delayed recurrence of life-threatening toxicity 7+ hours after ingestion. 3
• Do not discharge patients after brief observation if a large ingestion (>3–4 times therapeutic dose) has occurred, even if initially asymptomatic. 4
• Performance impairment and sedation from first-generation antihistamines can occur without subjective awareness of drowsiness, so objective assessment of mental status is essential. 1, 5

Special Populations

Pediatric Considerations

• First-generation antihistamine overdoses in children more commonly cause CNS excitation and seizures rather than pure sedation, requiring aggressive seizure management. 1, 4
• Serious adverse events are unusual following therapeutic-dose exposures, but life-threatening events have been described with overdoses. 4

Elderly Patients

• Older adults are at particularly high risk for severe anticholinergic toxicity, cognitive impairment, and cardiovascular complications from first-generation antihistamine overdose. 1, 6