Cough, Cold, and Allergy Preparation Toxicity 

Updated: Oct 07, 2019
Author: Laleh Gharahbaghian, MD, FACEP, FAAEM; Chief Editor: Stephen L Thornton, MD 

Overview

Practice Essentials

Cough and cold suppressant and allergy medicines are widely used and favored by medical professionals and parents alike. Because these medications are available over the counter (OTC) and are found in most households, they are frequently implicated in toxic ingestions, particularly in children. Although most of these incidents are unintentional, the number of intentional ingestions is growing, particularly for recreational use. Antihistamines and cough and cold preparations, respectively, rank sixth and fifteenth on the list of substance categories most frequently involved in human exposures in the United States.[1]

The 3 main components of most cough and cold medicines are antihistamines, decongestants, and antitussives. Allergy medications typically contain antihistamines, decongestants, or both. Toxicity caused by first-generation antihistamines is usually due to their anticholinergic rather than their antihistamine properties. While first-generation H1-receptor antagonists are responsible for the vast majority of antihistamine poisonings, the nonsedating H1-receptor antagonists also have been associated with serious toxicity.[2]

The most commonly used oral decongestants include pseudoephedrine and phenylephrine; a third agent, phenylpropanolamine, has been withdrawn from US market. These agents stimulate alpha-adrenergic receptors and cause a sympathomimetic response at toxic doses. The most common antitussive in OTC preparations is dextromethorphan. Many cold medications also contain acetaminophen. For more information on this topic, see Acetaminophen Toxicity.

Most poisonings are asymptomatic or mildly symptomatic and do not require specific therapy. However, the clinician may encounter severe intoxications that require prompt recognition and appropriate disposition. Involvement of the regional poison control center, as well as a medical toxicology consultant, if available, may aid in the treatment and follow-up care of these patients, and they should be contacted for all significant ingestions.

Signs and symptoms

Abnormal vital signs may include the following:

  • Hyperthermia
  • Tachypnea
  • Tachycardia
  • Hypertension

Otolaryngologic anticholinergic effects (typical with antihistamine toxicity) include the following:

  • Mydriasis
  • Nasal dryness and stuffiness
  • Eye dryness
  • Mouth and throat dryness

Cardiovascular findings may include the following:

  • Sinus tachycardia
  • Ventricular tachycardia
  • Torsade de pointes
  • Cardiogenic shock
  • Hypertension

Abnormal neurologic findings include the following:

  • Dizziness
  • Ataxia
  • Hyperexcitability
  • Somnolence
  • Seizures
  • Dystonia
  • Dyskinesia
  • Toxic psychosis (anxiety, agitation, hallucination)
  • Intracranial hemorrhage
  • Coma

Gastroenteritis (diarrhea, nausea, vomiting) can occur with the ethanolamine class of antihistamines. Urinary retention is a common anticholinergic adverse effect of the antihistamines. Rhabdomyolysis has been associated with doxylamine overdose, especially if the ingested dose is larger than 20 mg/kg.[3]

Symptoms of central anticholinergic syndrome include the following:

  • Disorientation
  • Agitation
  • Impairment of short-term memory
  • Nonsensical or incoherent speech
  • Meaningless motor activity that includes repetitive picking or grabbing
  • Visual hallucinations may be prominent

See Presentation for more detail.

Diagnosis

Ordering of drug screens should be decided in coordination with a regional toxicology center because most of these tests are costly and add little to a complete history with a known ingestion. Turn-around time for these tests often is very long; furthermore, screens are not sensitive or specific for many drugs.

An electrolyte panel and a complete blood count are recommended for all cases of possible toxicity. Studies in selected patients are as follows:

  • Plasma creatine kinase and myoglobin, if rhabdomyolysis is suspected secondary to antihistamine/decongestant combination that contains pseudoephedrine or phenylephrine
  • Blood cultures, if the patient is hyperthermic, seriously ill, or the diagnosis of anticholinergic poisoning is questionable
  • Chest radiography, if the patient has severe respiratory or CNS depression
  • Head CT scan, in patients with seizures or altered mental status
  • ECG, especially if tachycardia or bradycardia is present
  • Lumbar puncture, if patient has altered mental status or new-onset seizures in the setting of an unknown toxic exposure

See Workup for more detail.

Management

Emergency department care is as follows:

  • Perform bedside determinations of glucose for patients with altered levels of conscious and treat with intravenous dextrose, if appropriate
  • For hypotensive patients, administer a bolus of normal saline or lactated Ringer solution
  • Administer activated charcoal to patients who are cooperative, have a good gag reflex, and can take liquids by mouth safely

Acute dystonic reactions to antihistamines may be treated with oral or IV diazepam. Seizures can be treated with lorazepam. Physostigmine may be used for refractory seizures, when directed by a regional poison control center or a medical toxicologist

Serotonin syndrome must be managed by addressing each symptom individually. Hyperthermia should be managed by undressing the patient and enhancing evaporative heat loss by keeping the skin damp and using cooling fans. Muscle activity and agitation may be diminished with the use of diazepam.

Rhabdomyolysis

  • Ensure adequate hydration to maintain urine output at 2 mg/kg/h
  • Furosemide or mannitol may be needed to maintain diuresis
  • Consider using a solution of sodium bicarbonate and potassium chloride to alkalinize the urine to a pH of at least 7.5; monitor serum pH to avoid inducing severe alkalemia
  • Chart strict intake and output
  • Consult a nephrologist for oliguria or renal failure, and arrange hemodialysis for the anuric or severely acidotic patient

See Treatment and Medication for more detail.

Background

Despite the popularity of cough and cold medications, minimal data support their effectiveness. A Cochrane review found no good evidence for or against the effectiveness of OTC medicines in acute cough; in several pediatric studies, antitussives, antihistamines, antihistamine decongestants, and antitussive/bronchodilator combinations were no more effective than placebo.[4]

In 2006, the American College of Chest Physicians (ACCP) found that "literature regarding over-the-counter cough medications does not support the efficacy of such products in the pediatric age group."[5] In 2007, a US Food and Drug Administration (FDA) advisory committee recommended that the use of OTC cough and cold medications be prohibited in children younger than 6 years.[6, 7]

The FDA took action against unapproved prescription oral cough, cold, and allergy drug products due to concerns about risks, particularly the potential for medication errors because of confusing product names and inappropriate labeling of products for use in children aged 2 years or younger. From 2006-2011 the Unapproved Drugs Initiative led to the FDA removing 1,500 unapproved products.[8, 9]

Pathophysiology

The principal active ingredients in cough and cold medications are antihistamines, decongestants, and antitussives. Allergy medications typically contain antihistamines, decongestants, or both. Many cold medications also contain acetaminophen. For more information on this topic, see Acetaminophen Toxicity.

Antihistamines

Antihistamines comprise a broad class of pharmacologic agents that interact with four types of histamine receptors. H1-receptor antagonists are used for treatment of allergy and colds. These medicines include the first-generation, H1-receptor antagonists (eg, diphenhydramine), which are capable of producing significant central nervous system (CNS) effects; and the newer, second-generation, "nonsedating" H1 blockers (eg, loratadine).

H2-receptor antagonists (eg, cimetidine), work primarily on gastric mucosa, inhibiting gastric secretion. Newer, experimental antihistamines act on presynaptic H3 receptors and the recently discovered H4 receptors. Currently, no H3 or H4 receptor antagonists are commercially available, but several compounds, including conessine; diazepam amides; and diamine, dihydrobenzoxathin, biphenyl sulfonamide, and benzoquinoline derivatives, have been shown to interact with the H3 receptor.[10, 11, 12, 13, 14, 15]

Modulation of the H3 receptor may have various clinical effects on wakefulness, cognition, and hunger.[16] Phase IIb clinical trials for a wide range of disorders are already under way.[17, 18, 19, 20, 21, 22, 23, 24, 25, 26]

H4 receptors have been identified on cells of hematopoietic lineage (dendritic cells, mast cells, eosinophils, basophils, T cells, NK cells). Several ligands have been identified with affinity for this receptor. Modulation may have effects on nociception, inflammation, pruritus, and autoimmune disorders.[27, 28, 29] Phase II clinical trials involving antagonism of the H4 receptor for treatment of asthma, dermatitis, and rhinitis are under way.

The 6 structural classes of H1 antihistamines are as follows:

  • Alkylamines (eg, brompheniramine, chlorpheniramine, dexchlorpheniramine, pheniramine, triprolidine)
  • Ethanolamines (eg, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine)
  • Ethylenediamines (eg, pyrilamine, tripelennamine)
  • Phenothiazines (eg, methdilazine, promethazine, trimeprazine)
  • Piperidines (eg, cyproheptadine, fexofenadine, loratadine)
  • Piperazines (eg, cetirizine, cyclizine, hydroxyzine, levocetirizine, meclizine)

The most commonly used antihistamines in OTC preparations come from the alkylamine (eg, chlorpheniramine, brompheniramine) and ethanolamine (eg, diphenhydramine, clemastine) groups.

All H1 antagonists are reversible, competitive inhibitors of histamine receptors. Some of the first-generation H1-receptor blockers (eg, diphenhydramine, clemastine, promethazine) also have anticholinergic properties.

Histamine is not a major mediator of the common cold, and the benefits of antihistamines in relieving congestion appear to be secondary to their anticholinergic properties. Atropine, the prototype of anticholinergics, and other substances with anticholinergic properties competitively inhibit the muscarinic effect of acetylcholine by blocking its action in the autonomic ganglia and at the neuromuscular junctions of the voluntary muscle system. They affect the peripheral and central autonomic nervous systems.

The anticholinergic properties of antihistamine are also responsible for their toxicity. Anticholinergic toxicity may manifest as follows:

  • Sinus tachycardia
  • Dry skin and mucous membranes
  • Dilated pupils and blurred vision
  • Ileus
  • Urinary retention
  • Central nervous system depression or agitation
  • Hyperactivity or psychosis

H1-receptor blockers may disrupt cortical neurotransmission and block fast sodium channels. These effects can exacerbate sedation, but they also can result in seizure activity. Sodium channel blockade in the cardiac cells can cause conduction delays manifested by widening of the QRS interval and dysrhythmias.

Doxylamine has been associated with rhabdomyolysis. The mechanism of its toxicity is unknown, but doxylamine may have a direct toxic effect on muscle, possibly thorough injury to the sarcolemma.[30]

The first-generation antihistamine cyproheptadine is known to block serotonin receptors, as do the recently discovered compounds that have dual H3 antagonist and serotonin reuptake inhibition properties.[10] The phenothiazine class of antihistamines (eg, promethazine) has alpha-adrenergic blocking activity and may cause hypotension. H1 receptors have been found on sebocytes, and the use of H1 blockers in the management of acne may have a future role.[31]

Fexofenadine, loratadine, desloratadine, astemizole, cetirizine, and levocetirizine are peripherally selective H1-receptor antagonists. Desloratadine is the most potent of these.[32] They have a distinct clinical advantage because they bind much more selectively to peripheral H1 receptors and have a lower binding affinity for the cholinergic and alpha-adrenergic receptor sites than do other antihistamines.

This group of antihistamines is popular because specificity for the peripheral histamine receptor site eliminates many adverse effects, including CNS depression, blurred vision, dry mouth, and tachycardia. These medications are commonly used in the treatment of allergic rhinitis and chronic idiopathic urticaria.[33, 34]

Two nonsedating antihistamines, terfenadine and astemizole, are known to inhibit the potassium rectifier currents (HERG1K), which slows repolarization. This manifests clinically as prolongation of the QT interval and torsade de pointes (see the image below). For that reason, terfenadine and astemizole have been removed from the US market.

Terfenadine is the antihistamine most commonly ass Terfenadine is the antihistamine most commonly associated with torsade de pointes in both acute overdose and therapeutic administration.

Terfenadine has been replaced by fexofenadine, which is the pharmacologically active metabolite of terfenadine. Only one case has been reported in which a patient taking fexofenadine experienced QT prolongation progressing to ventricular tachycardia and degenerating into ventricular fibrillation.[35] However, this particular individual may have had additional risk factors that may have contributed to or caused that effect.[36, 37]

Levocetirizine, which is the L-enantiomer of cetirizine (cetirizine and levocetirizine are both metabolic derivatives of hydroxyzine) has not been associated with torsade de pointes in volunteer and animal studies. 

Diphenhydramine is known to prolong the QT interval. Previously, this effect was presumed to result from inhibition of the delayed potassium rectifier channel, but more recent studies showed that diphenhydramine has a relatively weak affinity for the HERG1K receptor.[38] Torsade de pointes has not been documented with diphenhydramine, most likely because its anticholinergic effect causes sinus tachycardia, which shortens repolarization.

In addition to differences in peripheral versus central binding, the propensity to cause sedation among the various antihistamines may be related to disease process (ie, atopic dermatitis versus allergic rhinitis), receptor internalization after binding, and the interaction of P-glycoprotein (a protein responsible for facilitating transport across various cell membranes and found in many tissues including the blood-brain barrier).[39, 40, 41]

Although the sedative properties of diphenhydramine have led to its use as a hypnotic, paradoxical excitation may occasionally occur. Paradoxical excitation in CYP2D6 ultrarapid metabolizers has been reported with diphenhydramine use.[42]

A new class of selective nonsedating H1 antagonists, the norpiperidine imidazoazepines, is currently in clinical trials. Current in vitro and in vivo safety studies show no increase in incidence of cardiac dysrhythmia. One such agent, bilastine, has demonstrated a favorable profile in animal models in preclinical trials.[43] In 2010, its use was authorized in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children older than 12 years.

Antihistamines are generally well absorbed after ingestion. Therapeutic effects begin within 15-30 minutes and are fully developed within 1 hour. They have varied peak plasma concentrations with a range of 1-5 hours. Antihistamines are capable of inducing the hepatic microsomal enzymes and may enhance their own rate of elimination in patients who use them long term. This phenomenon often is referred to as autoinduction of metabolism.

Decongestants

Decongestants are absorbed readily from the GI tract (except for phenylephrine, because of irregular absorption and first-pass metabolism by the liver) and attain a high concentration in the CNS. Peak plasma concentrations are achieved within 1-2 hours after oral administration. Toxic levels of pseudoephedrine have not been identified.

Pseudoephedrine, phenylephrine, and phenylpropanolamine cause direct presynaptic catecholamine release and may also block catecholamine reuptake and influence enzymes to slow catecholamine breakdown. Blood pressure elevation often is accompanied by a reflex bradycardia caused by the baroreceptors and results in postural hypotension.

Clinical manifestations of decongestant toxicity result from a direct effect on adrenergic receptors in muscles and glands and stimulation of the respiratory center and CNS, and include the following:

  • Bronchodilation
  • Hyperexcitability
  • Restlessness
  • Hallucinations
  • Seizures
  • Psychosis
  • Intracranial bleeding

One case report described cardiomyopathy and left ventricular dysfunction as a result of persistent tachycardia from pseudoephedrine use, with resolution upon its termination.[44]  However, a small study in India found no additional dysrhythmia risk from pseudoephedrine use in children with rhinitis.[45]

Phenylpropanolamine has often been implicated in cases of pediatric ingestion, with toxicity starting at 6-10 mg/kg. Toxic effects include seizure, cerebral vasculitis, and kidney failure.

A 2000 study found that phenylpropanolamine was an independent risk factor for hemorrhagic stroke in women aged 18-49 years. This resulted in the removal of phenylpropanolamine from the US OTC market.[46]  However, preparations containing this substance may still be in homes and in medications from foreign countries. All household medications should be checked for phenylpropanolamine, and those found to contain it should be discarded.

Antitussives

Dextromethorphan, the most common cough suppressant, is the methylated dextro-isomer of levorphanol, a codeine analog. See the image below.

Dextromethorphan. Dextromethorphan.

Dextromethorphan is a synthetic opioid that acts at opiate receptors in the CNS but does not have any of the other effects of typical opiates; it has no analgesic and minimal addictive properties. Dextromethorphan has shown agonist activity at the serotonergic transmission, inhibiting the reuptake of serotonin at synapses and causing potential serotonin syndrome, especially when used concomitantly with monoamine oxidase inhibitors (MAOIs).

In addition, dextromethorphan and its primary active metabolite, dextrorphan, which shows similar effects to other N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine (PCP), demonstrate anticonvulsant activity in animals by antagonizing the action of glutamate and are classified as a dissociative medication.

The usefulness of quantitative determination for dextromethorphan is unclear because no correlation exists between blood levels and clinical effects. However, qualitative determination in blood or urine can demonstrate the presence or absence of dextromethorphan. In a pharmacokinetic study, a peak serum concentration of 0.1-0.2 mg/mL was reached after a single 20-mg oral dose in healthy volunteers. Five percent of persons of European ethnicity lack the ability to metabolize the drug normally, leading to toxic levels with smaller doses.

In supra-therapeutic doses, dextromethorphan has psychoactive effects, and this has led to its recreational use in young persons.[47]  Effects of dextromethorphan megadoses (5-10 times the recommended dose) are similar to those of phencyclidine (PCP), and include ataxia, abnormal muscle movements, respiratory depression, and dissociative hallucinations. Dextromethorphan can cause false-positive results for PCP in urine toxicologic screening tests.

The half-life of dextromethorphan is short (typical intoxications last 6-8 h); the mainstay of treatment is supportive care. Naloxone has been used with intermittent success to reverse ataxia and respiratory depression.

Codeine is also thought to have antitussive effects and may be prescribed in combination with promethazine. This medication is not recommended for use in the pediatric population. Codeine is an opioid analgesic and is the most commonly ingested opioid, in toxic doses, by children younger than 6 years, as reported by the American Association of Poison Control Centers (AAPCC). Doses greater than 5 mg/kg are reported to produce respiratory and CNS depression.

Etiology

Unintentional exposures tend to occur in children younger than 6 years because they are eager to explore their environment and place objects into their mouths. Unintentional ingestion typically represents a smaller dose of the toxic substance, and the child presents to the emergency department soon after ingestion. Unfortunately, as many as 30% of children who experience one ingestion experience a repeat ingestion. In this age group, the possibility of child abuse or neglect should be explored.

Only 47% of reported adolescent ingestions are accidental, others are motivated by suicidal intention or recreational abuse. Both suicidal and recreational ingestion occur with increased frequency in the teenage population, and it may involve multiple substances at higher doses.

Dextromethorphan has been used as a recreational drug by adolescents. Deliberate ingestion of supra-therapeutic doses of dextromethorphan can lead to intoxication with symptoms of euphoria, bizarre behavior, hyperactivity, auditory hallucinations, visual hallucinations, and association of sounds with colors. Slang terms for dextromethorphan include CCC, triple C, DXM, dex, poor man's PCP, skittles, and robo; recreational use of high-dose dextromethorphan is known as robotripping.[47]

Chlorpheniramine is an OTC antihistamine that is usually used in adults. However, the abuse potential of this medication by adolescents has been recently reported. Its effects in deliberate megadosing for intoxication are similar to that of dextromethorphan.

Inappropriate use of antihistamines for upper respiratory infection symptoms and otitis media may unnecessarily expose children to the potential side effects of this class of medication. Furthermore, no study has shown a benefit in the management of these conditions with either antihistamines or decongestants.[48]

Epidemiology

The American Association of Poison Control Centers (AAPCC) reported that in the United States in 2017, antihistamines accounted for 76,152 single case exposures. The majority of exposures (42,435) were in children younger than 6 years. Diphenhydramine is the most common antihistamine exposure, accounting for 25% of cases. Cold and cough preparations accounted for 38,457 single case exposures, with 8,537 in children younger than 6 years.[1]  

The peak age for childhood poisoning ranges from 1-3 years. In children younger than 6 years, the vast majority of exposures are unintentional, whereas both suicidal and recreational ingestion occur with increased frequency in the teenage population and may involve multiple substances at higher doses. 

Data from the AAPCC's National Poison Data System showed that the annual rate of calls involving intentional abuse of dextromethorphan tripled from 2000 to 2006, then plateaued from 2006 to 2015. From 2006 to 2015, the rate in adolescents age 14-17 years decreased by 56.3%, from 143.8 to 80.9 calls per million population. The decrease corresponded to growing public health efforts to curtail the abuse of OTC products that contain dextromethorphan.[49]

Prognosis

The prognosis is affected by the presence of underlying medical conditions, co-ingestions, and the amount of drug ingested. The vast majority of patients recover with supportive care and observation.

Multisystem organ failure and death have resulted from severe antihistamine overdose. Among first-generation antihistamines, mortality from diphenhydramine occurs more than any other agent. In the United States, diphenhydramine is used more commonly than other antihistamines. It also is associated with more cardiotoxicity and a higher incidence of seizures than other first-generation antihistamines. Pheniramine, an antihistamine commonly used in Australia, also is associated with a relatively high incidence of seizures.

Morbidity and mortality differ based on the 2 categories of pediatric toxic ingestion: unintentional (children < 6 y) and intentional (adolescents aged 13-19 y). Of 34 fatalities in children younger than 6 years in 2017, none involved cold and cough preparations, and 3 involved antihistamines.[1]

Of 76,152 antihistamine exposures reported to US poison control centers in 2017, 6174 resulted in moderate-to-major toxicity with 21 deaths.[50] The vast majority of fatalities were associated with diphenhydramine.

First-generation H1-receptor antagonists, such as diphenhydramine, may be particularly dangerous because they may cause pronounced agitation and seizures, resulting occasionally in rhabdomyolysis and acidosis. Also, a quinidinelike sodium channel blocking effect, and at high doses, a potassium channel blocking effect (HERG1K), may cause delayed conduction (prolonged QRS) and repolarization (prolonged QT) and contribute to ventricular dysrhythmias.

From 1990-2005 the Civil Aerospace Medical Institute (CAMI) reported that antihistamines were found in 338 of 5383 pilot fatalities. It was felt that antihistamines were a factor in or the cause of 50 and 13 cases, respectively. The prevalence of antihistamine use among fatal crashes increased from 4% to 11% over this time span, indicating a worrisome trend that has led to protocols on allowed agents and abstinence time requirements.[51, 52]

Reports of delayed pulmonary edema from antihistamine overdose have been reported.[53] Famotidine has been shown to cause a significant increase in serum phosphate levels among hemodialysis patients taking calcium carbonate (even at the recommended dose of 10 mg/d).[54]

Patient Education

Patient education is an important part of pediatric toxicology. Half of children who ingested a poison do it again within a year. Review poison prevention techniques with parents.[55, 56, 57] Encourage poison proofing of the home and posting local poison control center telephone numbers by telephones throughout the home.

Review medication usage with caregivers. One study showed that only 30% of caregivers who administered acetaminophen were able to demonstrate both accurate measuring and correct dosage for their child.

Parents should be taught the following guidelines to prevent future ingestions:

  • Keep household cleaning products in high locked cabinets rather than under the sink. Safety latches should be place on all kitchen and bathroom cabinets and drawers that contain potentially hazardous substances.

  • Parents should lock all reachable medicine cabinets, always keep medications in their original (childproof) containers and dispose of unused prescriptions by flushing them down the toilet.

  • Medication should be considered "medicine," not a toy or candy. Medicine should never be referred to as candy and, if possible, not administered in front of other children. Parents, relatives, and friends also should childproof their homes.

In the past, parents were advised to have ipecac syrup available at home, to induce vomiting in case of poisoning. However, since 2004 the American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists have recommended that routine administration of ipecac at the site of ingestion or in the emergency department should definitely be avoided,[58] and the American Academy of Pediatrics currently recommends discarding bottles of ipecac syrup. However, the US Food and Drug Administration continues to permit over-the-counter sale of 1-oz bottles of ipecac syrup, with the warning that it is for use only under medical supervision in the emergency treatment of poisonings.[59]

In instances of recreational abuse, adolescents and their parents should be counseled on the dangers of addiction, as well as the health risks from dextromethorphan, especially in combination with pseudoephedrine, acetaminophen, and antihistamines.

In the 21st century, the use of cough and cold preparations has declined because of increased awareness of their potential toxicity.[60, 61]  However, proper labeling and health literacy remain growing issues.[62]

For patient education information, see Drugs and Medications, Drug Overdose and Poisoning, and Child-Proofing Basics.

 

Presentation

History

Eliciting the specific over-the-counter (OTC) medication ingested is important, because different preparations may contain different agents or combinations. For example, dextromethorphan is often present in combination with pseudoephedrine, antihistamines/anticholinergics, and acetaminophen.

Classification of antihistamines may proceed based on specific physiologic effect (eg, sedating vs nonsedating) or chemical structure (eg, alkylamine vs piperidine derivatives). Patients who ingest the newer nonsedating antihistamines may have fewer central anticholinergic symptoms than those who ingest any of the first-generation agents.

Consider classic or first-generation H1-antihistamine poisoning in any patient who presents with delirium, sedation, seizures, and anticholinergic symptoms. Agents include chlorpheniramine, hydroxyzine, and diphenhydramine.

Peak serum levels of diphenhydramine (DPH) are reached approximately 2–3 hours after ingestion, and elimination half‐life is approximately 4 hours. Symptoms are dose‐dependent. Severe symptoms (delirium/psychosis, seizures, and coma) can occur with ingestion of > 1.0 g DPH. The frequency of coma and seizures may increase with ingestion of > 1.5 g DPH, and electrocardiographic disturbances may occur with ingestion of > 3.0 g DPH. Serum DPH concentrations of > 5 μg/mL have been reported in fatalities.[63]

Nonsedating antihistamines differ from the other antihistamines in that they do not partition into the central nervous system (CNS), and they have long half-lives. The half-life of loratadine, for example, is typically 10 hours but may be more than doubled in overdose. Prolonged QT syndrome and cardiac arrhythmias rarely have been described with loratadine.

Alkylamine derivatives (eg, chlorpheniramine, brompheniramine, triprolidine) are among the most potent antihistamines. They produce more CNS stimulation and less drowsiness than other antihistamines. D-chlorpheniramine has been shown to suppress visuospatial cognition and visuomotor coordinating functions.[64]

Ethanolamine derivatives (eg, doxylamine, diphenhydramine, bromodiphenhydramine) have strong atropinelike activity; drowsiness is common. Adverse gastrointestinal effects are uncommon. Doxylamine can cause rhabdomyolysis and renal failure.

Seizures and cardiac conduction delays are common, especially in massive diphenhydramine ingestions. However, in an observational case series of acute, single ingestions of diphenhydramine in children under 6 years old, 99.6% of patients who reportedly ingested doses of less than 7.5 mg/kg did not develop serious clinical effects or require admission.[65]

Ethylenediamine derivatives (eg, pyrilamine, tripelennamine, antazoline) have weak CNS effects. Myoclonic jerks, hallucinations, and agitation were reported in a child with cutaneous tripelennamine exposure. Adverse GI effects are common. Tripelennamine has been used to enhance opioid effects and reduce itching associated with prescription narcotic use. The combination use of pentazocine (Talwin) with tripelennamine (blue tablets), commonly known as "T's and Blue's", reportedly produces a heroinlike effect.

Phenothiazine derivatives (eg, promethazine, trimeprazine, methdilazine) possess considerable anticholinergic activity and minimal GI adverse effects. Akathisia and dystonic reactions are common with phenothiazines.

Piperazine derivatives generally have a prolonged duration of action and low incidence of drowsiness. Specific examples include hydroxyzine, cetirizine, and meclizine.

Piperidine derivatives (eg, loratadine) are peripherally selective H1 antagonists with few GI adverse effects and a low incidence of drowsiness.

With regard to pharmacokinetics, all antihistamines are well absorbed following oral administration. Most achieve peak plasma concentrations within 3 hours with the onset of symptoms occurring between 30 minutes and 2 hours of ingestion. Duration of action ranges from 3 hours to more than 24 hours.

Physical Examination

Physical findings widely vary, depending on the agent or combination of agents ingested. In mixed ingestions, in elderly patients, or in very young patients, the physical findings may be variable and the clinical picture may not be clear.

If a single antihistamine agent has been ingested, a predominance of anticholinergic effects are demonstrated. The anticholinergic toxidrome consists of the following:

  • Agitation
  • Fever
  • Urinary retention
  • Dry, hot, flushed skin
  • Dilated pupils

The mnemonic, "dry as a bone, red as a beet, hot as a hare, mad as a hatter, and blind as a bat," summarizes this classic combination of central and peripheral anticholinergic effects. Other manifestations of toxicity, such as seizures, cardiac arrhythmias, and hypotension, are not uncommon and may be explained by mechanisms other than anticholinergic effects.

Although most cough and cold preparations are a combination of medications, a single toxidrome may not be present. The history is helpful to guide the expected physical examination findings; however, the history is often inaccurate.

The following physical examination findings are examples of what is possible, in addition to the common findings; however, the presentation of a patient with a toxic ingestion is not always straightforward. In general, the combined effects of the various classes of drugs in OTC preparations have been broken down into the following systems based on the approach in POISINDEX, the computer product database used by poison control centers.

Vital signs

Abnormal findings may include the following:

  • Hyperthermia
  • Tachypnea
  • Tachycardia
  • Hypertension

Hyperthermia has been reported with ingestion of both diphenhydramine and OTC antihistamine/decongestant combinations. In case reports of combination product exposure, findings are ascribed to the sympathomimetic component.

Head, ears, eyes, nose, and throat (HEENT)

Anticholinergic effects include the following:

  • Mydriasis
  • Nasal dryness and stuffiness
  • Eye dryness
  • Mouth and throat dryness

Dilated and minimally reactive pupils have been seen with antihistamine toxicity related to anticholinergic effects. Mydriasis and nystagmus may be observed with dextromethorphan ingestion.

Cardiovascular

The antihistamine and the sympathomimetic components of cold and allergy preparations can cause cardiac abnormalities that include arrhythmia (eg, atrioventricular [AV] block) and cardiac arrest.

Sinus tachycardia, ventricular tachycardia, torsade de pointes, cardiogenic shock, and hypertension have all been reported following overdose with antihistamines. Sinus tachycardia is the most common toxic cardiovascular effect from antihistamines with prominent anticholinergic properties.

Antihistamines with anticholinergic effects and the potential to block sodium channels include diphenhydramine, chlorpheniramine, pyrilamine, and certain phenothiazines. These drugs slow sodium conduction through cardiac sodium channels and result in decreased conduction and myocardial contractility. Rarely, myocardial pump failure occurs with large overdoses.

Ventricular tachycardias are less common but can occur at up to 4 times greater frequency in patients taking nonsedating antihistamines. Phenothiazines, diphenhydramine, and piperidine antihistamines are associated with prolongation of the QT interval, increasing the risk for ventricular tachyarrhythmias.

Torsades de pointes was principally associated with the piperidine antihistamines astemizole and terfenadine, which led to the removal of these drugs from the market in the United States. Other cardiac conduction disturbances, including atrioventricular dissociation and bundle-branch blocks, were reported in a 3-year-old girl who ingested 100 mg of astemizole.[66]

Respiratory

Findings include respiratory depression and adult respiratory distress syndrome. Pulmonary congestion was the most common finding on autopsy in a review of 76 reported deaths from diphenhydramine between 1946 and 2003.[67] This was presumably of cardiogenic origin due to cardiovascular collapse and ventricular failure, although the coincidence of myocardial toxicity is not reported.

Neurologic

Abnormal neurologic findings include the following:

  • Dizziness
  • Ataxia
  • Hyperexcitability
  • Somnolence
  • Seizures
  • Dystonia
  • Dyskinesia
  • Toxic psychosis (anxiety, agitation, hallucination)
  • Intracranial hemorrhage
  • Coma

Gastrointestinal and genitourinary

Gastroenteritis (diarrhea, nausea, vomiting) can occur with the ethanolamine class of antihistamines. Urinary retention is a common anticholinergic adverse effect of the antihistamines.

Rhabdomyolysis ( ie, decreased urinary output and increased creatinine phosphokinase) has been associated with doxylamine overdose, especially if the ingested dose is larger than 20 mg/kg.[3] It can result in acute kidney injury.[68]

Other

Findings may also include the following:

  • Hematologic effects, which are usually secondary to long-term use, include hemolytic anemia, thrombocytopenia, and agranulocytosis

  • Psychiatric effects include visual hallucinations in children receiving therapeutic doses of triprolidine (antihistamine/pseudoephedrine) combinations

  • Dermatologic effects include urticaria and hot, dry skin; rarely, fixed drug eruptions have been demonstrated with the use of cetirizine[69]

  • Potential changes in behavior of an infant exposed through breastfeeding include irritability, disturbed sleep patterns, and excessive crying.

Drug interactions between dextromethorphan and monoamine oxidase inhibitors (MAOIs) or serotonin reuptake inhibitors may result in a serotonin syndrome, which consists of the following:

  • Mental status changes (eg, agitation)
  • Myoclonus
  • Hyperreflexia
  • Diaphoresis
  • Shivering
  • Tremor
  • Diarrhea
  • Headache
  • Fever
  • Incoordination

Anticholinergic syndrome

Peripheral manifestations include dry mucous membranes and hot, dry, flushed skin. These result from inhibition of secretions from salivary glands, bronchioles, and sweat glands.

Vasodilation occurs in peripheral blood vessels, especially of the face and skin surfaces. Patients appear flushed and warm without sweat, despite agitation. The body temperature rises due to an inability to sweat and because of altered CNS thermoregulation.

Pupils are markedly dilated and vision is blurred with loss of accommodation. Lack of cholinergic stimuli alters peristalsis and may cause an intestinal ileus. Prolonged symptoms secondary to delayed drug absorption then may occur. Sinus tachycardia is one of the earliest signs of muscarinic receptor blockade. Urinary retention may contribute to the patient's agitation and placement of a Foley catheter may have a promptly calming effect.

The central anticholinergic syndrome normally occurs concomitantly with the peripheral signs of poisoning, although, occasionally, it has been reported to occur without evidence of peripheral signs. Symptoms include the following:

  • Disorientation
  • Agitation
  • Impairment of short-term memory
  • Nonsensical or incoherent speech
  • Meaningless motor activity that includes repetitive picking or grabbing
  • Visual hallucinations may be prominent

Central anticholinergic syndrome may be contrasted with pure psychosis, which is often accompanied by paranoia, auditory hallucinations, and, more commonly, an intact sensorium.

Agitation (physical or psychic perturbation) may complicate either anticholinergic delirium or psychosis and may be a reflection of underlying pain, drug withdrawal, or sympathomimetic overdose. Anticholinergic delirium has been misdiagnosed as meningoencephalitis, dementia, and sepsis.

Seizures

Seizures are not a common manifestation of antihistamine poisoning and are generally short-lived if they occur. However, large doses of diphenhydramine, pyrilamine, and hydroxyzine have resulted in prolonged or repeated seizure activity.

Researchers have suggested a natural anticonvulsant role of histamine because H1 receptors coalesce around epileptogenic foci in the brain and inhibit generalization of seizure activity. Antihistamines also are known to increase electroencephalographic (EEG) abnormalities and are suspected to produce seizures in patients with epilepsy.

Other CNS effects

In a review of 136 patients with diphenhydramine overdose, somnolence, lethargy, and coma were the most common findings, occurring in approximately 55% of reported overdoses.[70] Catatonic stupor was considered to be highly specific, occurring in 15% of patients. Acute extrapyramidal movement disorders, severe anxiety reactions, and toxic psychosis also have been reported.

In a report of chronic abuse, diphenhydramine resulted in withdrawal-like symptoms. A 34-year-old patient with schizophrenia had been ingesting approximately 800 mg of diphenhydramine twice daily for one month to achieve sedation and euphoria.

Diphenhydramine was tapered to 600 mg daily in divided doses over the first 3 days of hospitalization and then was reduced more slowly, with the last dose being administered on the ninth day of hospitalization. The patient developed recurrence of insomnia during the withdrawal period and increased daytime restlessness, irritability, and excessive blinking; extrapyramidal symptoms and psychosis were absent.[71]

 

DDx

Diagnostic Considerations

Other problems to be considered, in patients with altered mental status, include the following:

  • Trauma

  • Tumor

  • Intussusception

  • Shock

  • Alcohol or drug abuse

  • Epilepsy

  • Encephalopathy

  • Inborn errors of metabolism

  • Opiate toxicity

  • Uremia

  • Subdural or arachnoid hemorrhage

Conditions to consider in patients with psychosis include the following:

  • Psychiatric (eg, schizophrenia, mania)

  • Drug-induced (eg, amphetamines, hallucinogens)

  • Withdrawal states (eg, alcohol, barbiturates)

  • Cerebrovascular

  • Endocrine (eg, hyperthyroidism)

  • Hypoxia (eg, carbon monoxide toxicity, anemia)

  • Metabolic (eg, encephalopathy, uremia)

  • Neoplastic (eg, glioblastoma)

  • Pyogenic infections (eg, CNS abscess, sepsis)

  • Seizure disorder (eg, postictal psychosis, temporal lobe seizures, febrile seizures, drug-induced seizures)

  • Trauma

  • Viral infections (eg, encephalitis)

Differential Diagnoses

 

Workup

Approach Considerations

Emergency drug screens rarely aid clinical decisions because turn-around time often is very long; furthermore, screens are not sensitive or specific for many drugs, leading to either a missed diagnosis or a false diagnosis of systemic drug presence. In addition, a positive screen result is difficult to use as the explanation for a patient's presentation because cause and effect can be ascertained only from patient history. In the setting of an intentional overdose, the patient's history may be unreliable and unverifiable.

In general, drug screens are ordered when poisoning is suspected as the cause of an altered level of consciousness, unexplained seizures, or new onset of unusual behavior. Screening may be important when clinical history is lacking and the diagnosis is in question. Which drug screens to order should be decided in coordination with a regional toxicology center because most of these tests are costly and add little to a complete history with a known ingestion.

Drugs can be screened in blood or urine. Serum concentrations of over-the-counter (OTC) cough and cold preparations are not helpful, however. Most laboratories are not capable of testing for antihistamines, and pharmacokinetic studies have not been performed to establish therapeutic or toxic blood levels. However, a review of deaths from diphenhydramine monointoxication showed average lethal levels of diphenhydramine to be 19.5 mg/L in adults, 7.4 mg/L in children, and 1.53 mg/L in infants.[67]

Several antihistamine/decongestant combinations are also combined with salicylates or acetaminophen. In patients exposed to these combinations, blood levels should be measured for potential concurrent acetaminophen or salicylate toxicity.

An electrolyte panel and a complete blood count are recommended for all cases of possible toxicity. Uncommonly, agranulocytosis has been reported with chlorpheniramine and brompheniramine. A plasma creatine kinase level test may be helpful if rhabdomyolysis is suspected secondary to antihistamine/decongestant combination that contains pseudoephedrine or phenylephrine. The test result for myoglobin should be positive if rhabdomyolysis is present.

Obtain blood cultures to rule out sepsis if the patient is hyperthermic, seriously ill, or the diagnosis of anticholinergic poisoning is questionable.

Consider liver function tests in selected patients. Cholestatic jaundice was reported after prolonged treatment with cyproheptadine. Patients with moderate hepatic impairment experienced a greater increase in desloratadine exposure than those with normal LFTs even at the same dose.[72]

Imaging studies have limited indications. Chest radiography is useful if the patient has severe respiratory or CNS depression, in order to confirm or exclude pulmonary edema and adult respiratory distress syndrome. Computerized tomography (CT) scan of the head can be considered in any patient presenting with seizures or altered mental status. CT scan may not be necessary in patients with progressive improvement, supportive history, and a nonfocal neurologic examination.

An electrocardiogram (ECG) is indicated, especially if tachycardia or bradycardia is present. Antihistamines may cause a prolonged QTc or QRS complex and ST-T segment abnormalities. Cases of prolonged QTc and QRS intervals, with nonspecific ST and T wave changes, have been reported with antihistamine ingestions.

A lumbar puncture is helpful in excluding other causes (eg, infectious, autoimmune) of altered mental status or new-onset seizures in the setting of an unknown toxic exposure.

 

Treatment

Approach Considerations

Some states have laws mandating the reporting of child abuse, suspicion of child abuse, and neglect. If the history of ingestion is suspicious, reporting may be necessary.

Paramedics should follow set protocols for gastric decontamination, hypotension, and seizures; symptomatic patients should be transported rapidly with intravenous access and cardiac monitoring. Benzodiazepines may be used for agitation or seizures.

In the emergency department (ED), basic tenets of emergency care should dictate therapy. Perform bedside determinations of glucose for patients with altered levels of conscious and treat with intravenous dextrose, if appropriate. For hypotensive patients, administer 0.9% sodium chloride solution or lactated Ringer solution as boluses. Dopamine, or other cardiac pressor, may be titrated to achieve an acceptable blood pressure.

Administer activated charcoal to patients who are cooperative, have a good gag reflex, and can take liquids by mouth safely. Perform endotracheal intubation before instillation of activated charcoal for patients with significant CNS depression and an unprotected airway. The clinician should be aware that a severely toxic patient can experience seizures and aspirate charcoal.

Gastric emptying has not proven beneficial if the patient presents more than 1 hour postingestion, although case reports involving anticholinergic agents have demonstrated erratic absorption and repeated worsening of anticholinergic symptoms over 9 days. Ipecac syrup is not recommended in the ED because it may delay the administration of activated charcoal and seizures may occur at any time, with the possibility of aspiration. Repeated doses of activated charcoal may prevent continued absorption, but the development of ileus generally limits its use.

Anticholinergic-induced delirium ranges from mild confusion to severe agitation with associated hyperthermia and rhabdomyolysis. The use of chemical and physical restraints often is necessary to prevent patients from harming themselves or others. Controlling muscular activity is crucial in severely agitated patients, because agitation may exacerbate muscle injury, acidosis, rhabdomyolysis, and hyperthermia.

Although benzodiazepines often are considered first-line agents, physostigmine is safe and effective for the treatment of antihistamine-induced agitated delirium, provided that the electrocardiogram (ECG) does not demonstrate conduction disturbances (ie, PR and QRS prolongation). One study suggests that physostigmine is more effective and just as safe as benzodiazepines for controlling antihistamine-induced agitated delirium.[73] Physostigmine also reverses peripheral anticholinergic signs and symptoms.

Considering that patients with anticholinergic symptoms usually fare well with supportive therapy alone, physostigmine is indicated only in the following limited circumstances[73] :

  • Single-drug (anticholinergic) exposure
  • Pronounced hallucinations, delirium, or agitation (suggesting a CNS effect) unresponsive to benzodiazepines
  • Intractable seizures resistant to all other treatments
  • Absence of QRS prolongation on ECG

Always have atropine at bedside when using physostigmine in order to reverse excessive cholinergic activity (eg, bradycardia, salivation).

Treat antihistamine-induced seizures with benzodiazepines and barbiturates. Reserve physostigmine for refractory seizures. Although case reports suggest that physostigmine ends seizures, clinical experience is limited and no proof of its efficacy for seizure control exists.

Neuroleptic agents, such as haloperidol, have been used but have anticholinergic effects and may exacerbate hyperthermia or provoke a dystonic reaction. Their use should be discouraged.

Manage hyperthermia, especially when severe agitation is present, with neuromuscular paralysis, evaporative cooling, and ice-bath immersion if temperature is higher than 105°F (40.6°C). Use of dantrolene or bromocriptine is controversial.

Sinus tachycardia usually does not require treatment. Sedation with a benzodiazepine may be helpful when agitation is also present. Intravenous (IV) sodium bicarbonate improves widening of QRS that may result from antihistamines with sodium channel blocking properties (eg, diphenhydramine, pyrilamine). Provide support for patients with profound cardiovascular toxicity. In rare cases of refractory shock, placement of an intra-aortic balloon pump for several hours may bridge the patient through a period of cardiovascular collapse.

The American Association of Poison Control Centers has issued evidence-based consensus guidelines on the out-of-hospital management of diphenhydramine and dimenhydrinate poisoning.[71]

Emergency Department Management

Ensure the patient has adequate airway, breathing, and circulation. Place the patient on a cardiorespiratory monitor and obtain intravenous (IV) access if the patient appears ill or is symptomatic. Administer oxygen, naloxone, and glucose if an unexplained decreased level of consciousness is observed.

Obtain the patient's history through a relative or emergency medical services (EMS) personnel. Examine the patient, looking for an anticholinergic toxidrome. Obtain appropriate lab tests and an ECG. Perform cardiac monitoring on all symptomatic patients or as long as tachycardia, conduction delays, or prolonged QT intervals persist.

Consider decontamination with activated charcoal, if ingestion was recent and airway control is assured. Treat acute dystonic reactions with benzodiazepines.

Provide other supportive measures. Consider hospital admission if ingestion is significant or if the patient continues to be symptomatic. Contact the regional poison control center.

Gastrointestinal Decontamination

Activated charcoal is the first-line defense in GI decontamination and should be given to the patient if a significant ingestion has occurred within recent hours before presentation. Activated charcoal is most effective if administered within 1 hour of ingestion.

Complications of activated charcoal administration include emesis and aspiration; consequently, patients should be cooperative, have a good gag reflex, and be able to take liquids by mouth safely. Patients with significant CNS depression require endotracheal intubation to secure the airway before administration of activated charcoal.

The optimal dose of charcoal is not well established. Usual doses are as follows:

  • Adults and adolescents: 25-100 g in adults and adolescents
  • Children aged 1-12 years: 25-50 g
  • Infants younger than 1 year: 1 g/kg

Multiple doses of activated charcoal are not recommended because charcoal concretions may form leading to intestinal obstruction or ileus. Antihistamines may induce intestinal ileus causing delayed absorption of drug and delayed toxicity.

Other methods of decontamination

Controversial methods of decontamination include gastric lavage and ipecac syrup. Use of these agents should be on the advice of a poison center or toxicologist.

Ipecac and gastric lavage have fallen into disfavor, and cathartic therapy is not recommended, especially in children. Emesis is not usually recommended and is specifically contraindicated if a depressed gag reflex, CNS depression, ingestion of a corrosive substance, or high aspiration potential is noted.

Treatment of Dystonic Reactions

Dystonic reactions are treated with diphenhydramine in doses of 1 mg/kg IV every 2 minutes, with a maximum of 5 mg/kg/d, unless the dystonic reaction is thought to be caused by or involve antihistamine intoxication. Acute dystonic reactions to antihistamines may be treated with oral (PO) or IV diazepam. The dose is 0.1-0.3 mg/kg (slowly if IV) and as much as 10 mg in adults.

Treatment of Seizures

Seizures can be treated with lorazepam. The pediatric dose is 0.05-0.1 mg/kg, not to exceed 4 mg/dose; doses may be repeated every 10-15 minutes as needed. The adult dose is 4 mg, given by slow IV at 2 mg/min; if seizures persist after 10-15 minutes, administer 4 mg IV again. Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Case reports suggest that physostigmine may be effective for seizures refractory to benzodiazepines.

Treatment of Serotonin Syndrome

Serotonin syndrome must be managed by addressing each symptom individually. Hyperthermia should be managed by undressing the patient and enhancing evaporative heat loss by keeping the skin damp and using cooling fans. Muscle activity and agitation may be diminished with the use of diazepam.

Cyproheptadine is a nonspecific 5-hydroxytryptamine (5HT, serotonin) antagonist that has been shown to block development of serotonin syndrome in animals and is suggested as an antidote for serotonin syndrome in humans. It is available only as an oral preparation. Propranolol also has been used to some benefit as a 5HT1A receptor antagonist.

Treatment of Other Conditions

Cardiac arrhythmia can be managed with the appropriate cardiac medicine per advanced life support guidelines.[74] In diphenhydramine overdoses, bicarbonate may be helpful in treating QRS complex abnormalities and cardiac dysrhythmias. Treatment with bicarbonate in this overdose should be used in concert with poison center or medical toxicology consultation.

Successful use of intravenous lipid emulsion treatment for DPH overdose has been reported.[75]

Rhabdomyolysis is managed by ensuring adequate hydration to maintain urine output at 2 mg/kg/h. Furosemide or mannitol may be needed to maintain diuresis. Consider using a solution of sodium bicarbonate and potassium chloride to alkalinize the urine to a pH of at least 7.5. Monitor serum pH to avoid inducing severe alkalemia. Chart strict intake and output. Consult a nephrologist for oliguria or renal failure, and arrange hemodialysis for the anuric or severely acidotic patient.

Muscle rigidity and hyperactivity are secondary to sympathomimetic toxicity and can be controlled with neuromuscular paralysis.

Hyperthermia associated with sympathomimetics can be controlled with external evaporative cooling, removing the patient's clothes, and spraying with tepid water and fanning.

Use of Physostigmine

Use of physostigmine in antihistamine poisoning is extremely controversial, and it should not be given unless directed by a regional poison control center or in direct consultation with a medical toxicologist. Physostigmine, an anticholinesterase, may be indicated in the suspected anticholinergic poisoning for its therapeutic value.

Physostigmine is a tertiary amine that crosses the blood brain barrier and reverses both the central and the peripheral effects of anticholinergics. Reversal of anticholinergic signs and symptoms is not long-lasting because physostigmine has a relatively short duration of action (20-60 min). Indications are severe life-threatening complications, such as coma, hypotension with dysrhythmias unresponsive to other attempts at treatment, and intractable seizures.

Adolescent and adult trial dosages are 2 mg IV slowly every 5 minutes. To administer, dilute the dose of physostigmine in 10 mL of dextrose 5% in water (D5W) or in 10 mL of isotonic sodium chloride solution.

Hospital Admission

Patients with suspected cough, cold, or allergy preparation poisoning with persistent or significant hypertension, dysrhythmia, or CNS stimulation require admission for monitoring. For all intentional overdoses, a psychiatric evaluation is necessary. The decision to admit the patient to the intensive care unit should be based on the following:

  • Initial presentation
  • Comorbid diseases
  • Nature and number of the involved agents
  • Potential for delayed toxicity

Long-Term Monitoring

Most regional poison control centers have their own protocols on who may be observed at home; contact them if ingestion has occurred. As a general rule, patients who ingest less than 3 times the maximum daily dose can be observed at home.

If symptoms are present (other than mild somnolence) or ingestion is more than 4 times the maximum daily dose, the patient should be referred to a health care facility. The patient should be observed for 4-6 hours following ingestion of liquid and immediate-release solid preparations. Ingestion of sustained-release products may result in delayed onset of symptoms and may require longer periods of observation.

Patients who have ingested less than 10 mg/kg of dextromethorphan can be treated at home. If the patient has ingested a long-acting dextromethorphan preparation, refer the patient to a health care facility for evaluation.

If the ingestion was intentional, prompt psychiatric evaluation and admission is warranted. Additional counseling and social work involvement may be required for patients engaging in recreational abuse.

With children, further outpatient treatment should include teaching the patient's caretaker about medication storage and safety.

Consultations

The following consultations may be necessary:

  • Regional poison control center or a medical toxicologist as soon as possible
  • Intensivist for invasive monitoring and hemodynamic support in complicated cases
  • Nephrology service in the case of rhabdomyolysis and acute renal failure
  • Psychiatry for intentional overdoses
  • Neurology for neurologic complications

Prevention

Medications should be labeled and stored safety. Child-resistant closures should be applied to all medications and substances that can cause significant toxicity, such as cough and cold medications. Childproof safety caps and clear labeling have been shown to decrease toxic exposures in young children and elderly individuals. Elderly persons should not use anticholinergics as sleep aids.

 

Medication

Medication Summary

Most patients with toxicity from cold, cough, or allergy preparations have good outcomes with simple observation and meticulous attention to supportive care. Activated charcoal can reduce absorption of the medication in patients who present early after ingestion. Benzodiazepines can be used for control of anxiety, agitation, and seizures. Limit treatment with physostigmine to severe cases.

Antidotes, Other

Class Summary

GI decontamination with oral activated charcoal is selectively used in the emergency treatment of poisoning caused by some drugs and chemicals.

Activated charcoal (Actidose-Aqua, EZ-Char, Kerr Insta-Char)

Activated charcoal is used in emergency treatment for poisoning caused by drugs and chemicals. A network of pores adsorbs 100-1000 mg of drug per gram. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine.

Activated charcoal achieves its maximum effect when administered within 30 minutes after ingestion of a drug or toxin. However, decontamination with activated charcoal may be considered in any patient who presents within 4 hours after the ingestion. Repeated doses may help to lower systemic levels of ingested compounds, especially sustained-release preparations. Activated charcoal does not dissolve in water. Supply it as an aqueous mixture or in combination with a cathartic (usually sorbitol 70%).

Anxiolytics, Benzodiazepines

Class Summary

Diazepam is indicated for the control of anxiety and agitation.

Diazepam (Valium, Diastat)

Diazepam is indicated for treatment of acute dystonic reactions caused by antihistamines, as well as for muscle activity and agitation associated with serotonin syndrome. Diazepam depresses all levels of the CNS (eg, limbic system and reticular formation), possibly by increasing the activity of gamma-aminobutyric acid (GABA). It is a third-line agent for agitation or seizures because of its shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.

Lorazepam (Ativan)

A sedative hypnotic with short onset of effects and relatively long half-life, lorazepam is used to treat seizures. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including the limbic system and reticular formation. It is the drug of choice for seizure control because of a more prolonged anticonvulsant effects than diazepam or midazolam (4-6 h vs 1-3 h). It has an excellent safety profile, but the patient's blood pressure should be monitored after administration of this agent.

Midazolam

Midazolam is an alternative agent for termination of refractory status epilepticus. Compared with diazepam, midazolam has twice the affinity for benzodiazepine receptors; however, because it is water soluble, midazolam takes approximately 3 times longer than diazepam to achieve peak electroencephalographic effects. Thus, the clinician must wait 2-3 minutes to fully evaluate sedative effects before initiating a procedure or repeating the dose. This agent may be administered intramuscularly if vascular access cannot be obtained.

Clonazepam (Klonopin)

Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces the monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and the action of other inhibitory transmitters.

Anticholinergic Toxicity Antidotes

Class Summary

Acetylcholinesterase inhibitors are indicated to reverse central and peripheral toxicity of anticholinergic substances.

Physostigmine

Physostigmine is a reversible cholinesterase inhibitor that increases the concentration of acetylcholinesterase in the myoneural junction. It readily crosses the blood-brain barrier to produce desired CNS effects. This agent should not be given unless recommended by a regional poison control center or in direct consultation with a toxicologist.

Electrolyte Supplements, Parenteral

Class Summary

These agents alter the electrophysiologic mechanisms responsible for arrhythmia in patients with toxicity from cold, cough, or allergy medications.

Sodium Bicarbonate (Neut)

Intravenous sodium bicarbonate, 100 mEq over 5 minutes, followed by continuous infusion used for its alkalization properties to maintain a serum pH of 7.5-7.55, has reversed hypotension and resulted in narrowing of the QRS complex in isolated case reports. Sodium bicarbonate is the first-line agent for patients with prolongation of QRS interval after an overdose of an antihistamine with quinidinelike effects.

Magnesium sulfate

Magnesium acts as an antiarrhythmic agent and diminishes the frequency of premature ventricular contractions (PVCs), particularly those resulting from acute ischemia. Deficiency in this electrolyte can precipitate refractory ventricular fibrillation (VF) and is associated with sudden cardiac death. Magnesium sulfate is the first-line agent in the treatment of antihistamine-associated torsade de pointes.