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.

Presenting Signs and Symptoms

Some degree of altered mental status (sedation or agitation) is the most common presenting manifestation. This feature may impair the ability to obtain a reliable history from the patient, and emergency medical personnel or family may need to be questioned.

Along with altered mental status, dextromethorphan may cause gait disturbances known as “robo-walking.”⁷ Serotonin syndrome, which consists of a triad of central nervous system (CNS) dysfunction, neuromuscular dysfunction (clonus, hyperreflexia), and autonomic instability (tachycardia, mild hyperthermia), may also be noted in patients with toxicity.⁸

Differential Diagnosis and Medical Decision Making

The initial approach to patients with altered mental status includes ruling out potential emergency conditions such as trauma, CNS infection, and metabolic derangements. Other common CNS depressants, such as benzodiazepines, opioids, and ethanol, may also cause sedation. Recreational drugs of abuse with similar actions at the NMDA receptor, such as PCP and ketamine, may also cause dysphoria and psychoactive features. Antimuscarinic poisoning does not result from dextromethorphan poisoning but can occur from coingested antihistamines such as chlorpheniramine (as found in Coricidin).

Although structurally considered an opioid, dextromethorphan does not trigger the opiate screen on a standard urine immunoassay, but it may result in a false-positive result for PCP. Dextromethorphan is often formulated as a hydrobromide salt; ingestions of such a formulation may cause false elevations of chloride on an autoanalyzer test, although true toxicity from bromide is rare.

Emergency physicians should be mindful of potential coingestants because many cough and cold preparations frequently contain aspirin, acetaminophen, decongestants, and antihistamines. Acetaminophen levels should be routinely checked in poisoned patients.

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 be focused on supportive care with assessment of airway, breathing, and circulation. Attention should be paid to controlling agitation and hydration. Agitation should be treated with benzodiazepines in doses titrated to effect (IV lorazepam, 1 to 2 mg titrated to effect) (see Table 157.1). Reducing environmental stimuli may also be helpful. 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. Decontamination with activated charcoal may be considered in an alert, cooperative patient who presents within an hour of a possible ingestion. Supportive care is the treatment of choice. IV naloxone (1 to 2 mg) may be given for significant sedation, although reversal may not occur.⁹

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

Patients with evidence of ongoing neurologic toxicity should be admitted. Completely asymptomatic patients who have been observed for 6 hours after drug ingestion should be evaluated by a psychiatrist to determine whether admission is indicated.

Epidemiology

Over-the-counter decongestants rank among the top five most commonly used medications.¹ They are frequently present in multiple ingredient cough and cold products. Some are abused for their stimulatory effects or diverted for the production of methamphetamines. As with other over-the-counter medications, children are frequent victims of unintentional poisonings or dosing errors, and decongestant exposure in this population has been linked to adverse outcomes.²

Pathophysiology

Over-the-counter decongestants have their therapeutic effects primarily by stimulating α₁-adrenergic receptors and causing vasoconstriction and reducing edema in mucous membranes. They fall into two main classes. This first class is amphetamine-like substances (e.g., pseudoephedrine, ephedrine, phenylephrine), which cause release of catecholamines, and block their reuptake and breakdown and are taken orally. The other class is imidazoline decongestants (e.g., oxymetazoline, tetrahydrozoline, naphazoline), which directly stimulate α-adrenergic receptors on blood vessels and are applied topically.

Presenting Signs and Symptoms

The presenting signs and symptoms from the ingestion of over-the-counter decongestants will vary depending on the class ingested (see Table 157.1). Ingestion of an amphetamine-like decongestant typically presents signs and symptoms of sympathomimetic toxicity due to the increased stimulation of both α- and β-adrenergic receptors. This is typified by agitation, delirium, tachycardia, hypertension, hyperthermia, and mydriasis. Ingestion of imidazolines, which are meant for topical use, usually presents with sedation, bradycardia and hypertension early with subsequent hypotension. Respiratory depression, sedation, and miosis, mimicking opioid toxicity, have been described.¹⁰

Differential Diagnosis and Medical Decision Making

If the history of ingestion is not clear then the differential diagnosis for decongestant ingestions can be broad, especially considering the disparate presentations of the amphetamine-like and the imidazoline classes (see Table 157.1). Coingestions and nontoxicologic processes must be considered. Rhabdomyolysis and cardiac ischemia should be evaluated for in patients with significant toxicity.

Treatment

Standard prehospital care should be sufficient for decongestant-toxic patients, with particular attention paid to controlling agitation. Decontamination with activated charcoal is suitable for the alert patient with exposure in the previous hour. Agitation, tachycardia, and hypertension should be aggressively treated with benzodiazepines (IV lorazepam, 1 to 2 mg, or IV diazepam, 5 to 10 mg, titrated to effect). The physician must aggressively hydrate these patients to treat rhabdomyolysis. For refractory hypertension, an α-adrenergic antagonist (IV phentolamine, 5 mg) or a venous and arteriolar vasodilator (IV nitroprusside, 0.3 to 10 mcg/kg/min) should be given. In severe cases of CNS depression after imidazoline-type decongestant overdose, IV naloxone may be given (2 to 4 mg) but its effects are inconsistent, and endotracheal intubation may rarely be needed to support ventilation.¹¹

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

Symptoms of decongestant exposure, whether amphetamine-like or imidazoline, usually resolve within 8 hours or so. However, admission of symptomatic patients may be warranted. Depending on intent, psychiatry evaluation may be needed.

Epidemiology

Diarrhea remains an important and frequent health problem. Over-the-counter remedies are often sought by diarrhea sufferers, and many different over-the-counter agents are reported to be antidiarrheal. Loperamide (Imodium) is probably the best known of these agents. Diphenoxylate with atropine (Lomotil) is a prescription medication and frequently used interchangeably with loperamide.

Pathophysiology

Loperamide and diphenoxylate are synthetic analogues of meperidine used to treat diarrhea. Loperamide’s systemic absorption is restricted by its insolubility, and therapeutically only local µ-type opioid receptors in the gastrointestinal tract are affected, resulting in decreased intestinal motility. Diphenoxylate is combined with a small dose of atropine both to increase its antimotility effect and to discourage its abuse as an opioid (this combination is marketed as Lomotil). Diphenoxylate has a significantly worse adverse effect profile because it metabolizes to difenoxin, a compound with higher potency and a longer serum half-life.

Presenting Signs and Symptoms

Loperamide is generally well tolerated even in large ingestions, and drowsiness is the most common effect.¹² Diphenoxylate is significantly more toxic, and overdoses commonly manifest with some degree of opioid toxicity (e.g., CNS depression, respiratory depression, miosis, decreased bowel motility), with or without the antimuscarinic effects of the atropine (see Table 157.1).

Differential Diagnosis and Medical Decision Making

The differential diagnosis includes conditions that cause altered mental status and respiratory depression. No specific tests are available to order in evaluating these patients. Common urine drug screens do not detect either drug. Any diagnostic tests ordered should be geared toward the standard evaluation of the poisoned or altered patient and not these agents in particular.

Treatment and Disposition

Prehospital treatment should be oriented toward providing supportive care and preventing complications such as aspiration from decreased mental status. Prehospital administration of naloxone may be considered.

In general, loperamide has a high safety profile and has been associated with very few adverse events, even in overdose. However, diphenoxylate overdoses can cause significant symptoms, usually related to respiratory depression (see Table 157.1). Respiratory depression by can be recurrent or delayed, sometimes up to 24 hours after the ingestion, and children are particularly at risk.¹³ Decontamination with activated charcoal in the cooperative patient may be useful even beyond the 1 hour, given the impairment of gastrointestinal motility with these agents. IV naloxone (0.4 to 2.0 mg) is effective in reversing the respiratory depression and other signs of opioid toxicity, but CNS and respiratory depression may recur, and an IV naloxone infusion may be needed.¹³

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

Patients with loperamide ingestions can typically be observed for 6 hours and medically cleared for psychiatric evaluation if the ingestion was intentional or discharged if unintentional. Strong consideration should be given to admitting pediatric patients and patients with intentional and significant Lomotil ingestions because of the possibility of severe delayed or recurrent symptoms (e.g., respiratory depression).

Epidemiology

Any ingredient taken for the purpose of promoting health is considered a dietary supplement. Innumerable examples of dietary supplements exist, and a national surveyed showed that more than 15% of the U.S. population had used one or more in the previous week.¹⁴ Ginkgo, St. John’s wort, ginseng, echinacea, and synephrine are among the more commonly used dietary supplements (Table 157.2). Unlike with prescription drugs, proof of safety and proof of efficacy are not required for dietary supplements as long as the maker does not claim that the agent is a treatment for a particular disease. To be removed from the market, a dietary supplement must be proven unsafe. This situation occurred in 2006, when the FDA banned of ephedra over cardiovascular concerns.¹⁵

Table 157.2 Toxicities of Dietary Supplements

Epidemiology

Vitamins are frequently taken in supratherapeutic amounts. This is done typically under the premise of “more is better” or purportedly to treat or prevent conditions ranging from viral upper respiratory tract infections to Alzheimer dementia. Parents’ concern about their children’s eating patterns may result in vitamin oversupplementation.¹⁶ All these factors, added to the ready availability of vitamins, make vitamins prime targets for potential toxic exposures.¹⁷

Pathophysiology

Vitamins can be grouped into two main categories: water soluble and fat soluble. Toxicity may be caused by either group, though in general toxicity from water-soluble vitamins are rarer and less severe as they do not accumulate as fat-soluble vitamins do. Vitamin A and D, which are both fat soluble, have well described toxicity. Table 157.3 describes the normal function of the most common vitamins and their toxic effects.

Presenting Signs and Symptoms

The presenting signs and symptoms of hypervitaminosis depend on the offending vitamin.^16–19 Table 157.3 lists the toxic effects of the most clinically relevant vitamins.

Differential Diagnosis and Medical Decision Making

Because of the relative infrequency of severe toxicity from hypervitaminosis, the more common causes of such conditions as sensory neuropathies, increased intracranial pressure, and hypercalcemia must be explored first. The diagnosis of a vitamin overdose is most often made from a history of ingestion. In patients with vitamin A toxicity, elevations of aminotransferase, alkaline phosphatase, and bilirubin concentrations, as well as prothrombin time, are indicators of hepatic toxicity. Computed tomography of the head or lumbar puncture with measurement of the opening pressure should be performed to confirm increased intracranial pressure. Vitamin D toxicity can be demonstrated with elevated calcium and vitamin D levels. Because many vitamin preparations contain iron or fluoride, these agents must be considered and evaluated as possible coingestants.

Treatment

Typically, supportive care and cessation of the offending vitamin are sufficient to treat most vitamin toxicities. In the case of vitamin A toxicity, measures to reduce intracranial pressure may be warranted, and in the case of vitamin D toxicity, standard treatment for hypercalcemia (IV hydration and loop diuretics) should be employed (see Table 157.3).

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

Patients who are toxic from fat-soluble vitamin overdoses typically need admission because the effects of these agents may be prolonged. All patients should be educated on the risk of hypervitaminosis.