Epidemiology

Antihistamines are among the most frequently used medications in the United States.¹ Most of these drugs are available without a prescription. Although their efficacy is questionable, antihistamines are widely used for the symptomatic relief of cold and allergy symptoms. They are also found in nonprescription sleeping aids. Because of widespread access, these agents are commonly ingested intentionally, in suicide attempts, and unintentionally, particularly by children. Approximately 90,000 cases of antihistamine ingestions are reported to poison centers in the United States every year, and almost half of those involve children younger than 6 years.²

Pathophysiology

The antihistamines function as reversible competitive inhibitors of either H₁ or H₂ histamine receptors. Currently available antihistamines can be classified as first-generation, sedating H₁ receptor antagonists (e.g., diphenhydramine, hydroxyzine); second-generation, nonsedating H₁ receptor antagonists (e.g., loratadine, fexofenadine); or H₂ receptor antagonists. Antagonism of the H₁ receptors inhibits bronchoconstriction, vasoconstriction, and capillary permeability (the cause of edema and wheal), whereas H₂ receptor antagonism inhibits gastric acid secretion. In overdose, first-generation H₁ receptor antagonists may have some additional effects on other receptors and ion channels, particularly muscarinic-type cholinergic receptor inhibition, α-adrenergic receptor inhibition, and fast sodium channel blockade, whereas second-generation H₁ receptor blockers and H₂ receptor antagonists primarily cause sedation.

Presenting Signs and Symptoms

Patients typically present with some degree of altered mental status or suicidality. A history of ingestion or coingestions should be sought. Emergency medical personnel and family members, if available, may need to be questioned. Pill bottles, if present, may help clarify the history.

Although sedation is common with larger ingestions, signs of antimuscarinic toxicity may also be present (Box 157.1). In addition, patients may have mild hypotension or more worrisome wide complex dysrhythmia resulting from sodium channel–blocking effects of some antihistamines (e.g., diphenhydramine). Cardiovascular toxicity associated with some antihistamines is indistinguishable from that associated with cyclic antidepressants (Fig. 157.1).

Fig. 157.1 Recognizing the anticholinergic toxidrome.

ED, emergency department; IV, intravenous.

Differential Diagnosis and Medical Decision Making

The differential diagnosis of antihistamine toxicity is broad because many medications, street drugs, and disease processes can cause a presentation characterized by sedation or delirium, or both (Box 157.2). The emergency physician must consider nontoxicologic causes of altered mental status, such as infection and traumatic brain injury, and evaluate for these nontoxicologic conditions accordingly if the presence of the conditions cannot be excluded by other means. Computed tomography of the head and lumbar puncture may be warranted. In particular, patients presenting with antimuscarinic toxicity may be delirious, hyperthermic, and tachycardic, features that mimic infectious causes.

Bedside blood glucose measurements should be performed early in the course of management for individuals presenting with altered sensorium. An electrocardiogram should be obtained quickly to assess for conduction abnormalities, with particular attention paid to the QRS and QTc duration. Serum electrolyte concentrations should be measured to rule out metabolic abnormalities in patients who are confused or who exhibit evidence of cardiotoxicity. Laboratory evaluation of total creatinine kinase to evaluate for rhabdomyolysis may be indicated in acutely agitated patients. Serum acetaminophen levels should be measured in all patients with intentional overdose, because many cough and cold preparations combine antihistamines with antipyretics and analgesics. A urine immunoassay (standard urine drugs of abuse screen) may be considered to screen for recent exposure to opioids, benzodiazepines, or other drugs, although the clinical utility of this test is limited by frequent false-positive results. The emergency physician should recognize that a positive screening test result indicates only exposure to and not active toxicity of a compound. Qualitative testing for antihistamines is not useful and generally not readily available. Diphenhydramine may trigger a false-positive immunoassay result for tricyclic antidepressants or phencyclidine (PCP) on some urine drug immunoassays typically used in many hospitals.

Treatment

Prehospital treatment of the acutely poisoned patient should be based on providing supportive care and preventing complications such as injury from agitation or aspiration from decreased mental status.

Hospital treatment should also be focused on supportive care with assessment of airway, breathing, and circulation. Particular attention should be paid to controlling agitation and hydration (Table 157.1). Agitation should be treated with benzodiazepines in doses titrated to desired effect (e.g., lorazepam, 1 to 2 mg by intravenous [IV] push to effect). In addition to chemical restraint, physical restraint for patient and staff safety may be needed. Hydration should be addressed with 1- to 2-L boluses of 0.9% saline solution to ensure adequate urine output.

In patients who present within 1 hour of drug ingestion and who are alert and cooperative, activated charcoal (50 g or 1g/kg up to 50 g in children) should be considered. Data in humans are insufficient to support the use of activated charcoal beyond 1 hour.³

Hyperthermia should be managed with sedation and active, evaporative cooling (misting with water and applying direct fanning). Rarely, endotracheal intubation with neuromuscular paralysis may be necessary if hyperthermia or agitation fails to improve with less aggressive measures.

Physostigmine is a reversible acetylcholinesterase inhibitor that crosses the blood-brain barrier; it increases synaptic acetylcholine and may temporarily reverse antimuscarinic delirium. Peripheral signs may also be reversed. It may also be used therapeutically to control agitation.⁴ Physostigmine may have more value as a diagnostic tool by precluding the need for invasive tests (e.g., lumbar puncture) if complete reversal of delirium is achieved following administration.⁵ Beyond diagnostic use, the role of physostigmine in the treatment of most antimuscarinic poisonings with minor symptoms is debatable, and caution should be used if a possibility of tricyclic antidepressant ingestion exists.

Severe cardiac conduction abnormalities as evidenced by QRS prolongation should be treated with sodium bicarbonate (1 to 2 mEq/kg IV push) to overcome impaired sodium conduction. Hypotension is usually mild and should be treated with IV fluids. Refractory hypotension may also be treated with sodium bicarbonate and direct-acting alpha-agonists (norepinephrine, 2 to 12 mcg/min IV infusion).

As with all ingestions with significant toxicity, consultation with a medical toxicologist or a poison center should be considered.

Follow-Up, Next Steps in Care, and Patient Education

Patients with evidence of ongoing cardiovascular or neurologic toxicity should be admitted. Completely asymptomatic patients who have been observed for 6 hours after drug ingestion may be medically cleared for psychiatric evaluation or discharged, whichever is most appropriate.

Epidemiology

Dextromethorphan was approved by the U.S. Food and Drug Administration (FDA) as an over-the-counter antitussive in 1958. It is a common component of cold preparations, and its nonmedical use (abuse) appears to be increasing, especially among adolescents.⁶ Abuse of Coricidin (known on the streets as “Skittles”) and Robitussin (known as “DXM” and “robo”) has highlighted dextromethorphan’s abusive potential.

Pathophysiology

Dextromethorphan is the structural analogue of the opioid analgesic levorphanol that is devoid of analgesic properties but has antitussive properties resulting from agonism of σ-opioid receptors. In addition, dextromethorphan inhibits N-methyl-D-aspartate (NMDA)–glutamate receptors and alters dopaminergic and serotonergic neurotransmission. Associated psychoactive effects are attributed to the active metabolite dextrorphan. At very high doses, typical opioid toxicity may be seen.