Anticholinergic Toxicity

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Anticholinergic Toxicity 

Synopsis

Urgent Action

  • Immediately obtain ECG and place all patients on continuous cardiac monitoring
    • Administer sodium bicarbonate to patients with prolonged QRS interval to avoid increased risk of arrhythmia associated with ingestion of certain medications that cause both anticholinergic toxicity and sodium channel blockade (eg, tricyclic antidepressants, diphenhydramine)
    • Administer sodium bicarbonate to patients presenting with nonsinus arrhythmia in association with an anticholinergic toxidrome
  • Perform gastrointestinal decontamination with activated charcoal administration for patients presenting within 1 hour of ingestion
  • Treat prolonged seizures and agitation aggressively with physostigmine and/or benzodiazepines in consultation with a medical toxicologist
  • Treat hyperthermia aggressively with passive and active cooling measures while treating factors that aggravate hyperthermia (eg, seizures, agitation)

Key Points

  • Acute anticholinergic toxicity results from consumption of products containing anticholinergic properties in supratherapeutic doses
  • Chronic toxicity can occur as a result of repeated therapeutic dosing, ingestion of multiple medications with anticholinergic properties, and with therapeutic dosing in susceptible individuals
  • Many substances and medications possess anticholinergic properties including belladonna alkaloids, botanicals (eg, jimson weed, psychoactive mushrooms), antihistamines, tricyclic antidepressants, antipsychotics, antiparkinsonian agents, and muscle relaxants
  • Acute toxicity is characterized by sinus tachycardia, mydriasis, dry mucous membranes and axillae, flushed skin, alterations in mental status (eg, agitated delirium), and hyperthermia
  • Chronic toxicity more commonly presents with subtle alterations in mental status (eg, worsening confusion, disorientation, delirium) in individuals taking Parkinson, tricyclic antidepressant, or antipsychotic medications
  • Diagnosis of acute anticholinergic or sedating antihistamine poisoning is based on clinical presentation, primarily physical examination
  • Obtain ECG in all individuals presenting with symptoms to assess for interval prolongation (eg, QRS, PR, QTc) associated with some agents that can cause sodium channel blockade (eg, tricyclic antidepressants, antihistamines, phenothiazines)
  • Assess patients for rhabdomyolysis using creatine kinase levels and urinalysis if they are at high risk (eg, severe agitation, seizure, hyperthermia, coma)
  • Management for acute toxicity may involve
    • Gastrointestinal decontamination
    • Symptomatic care for agitation, hyperthermia, and seizures
    • Supportive care to prevent rhabdomyolysis
    • Sodium bicarbonate for evidence of myocardial sodium channel blockade
    • Antidote (physostigmine) therapy in select patients with absence of contraindications
  • Majority of patients with anticholinergic poisoning have a good outcome with supportive care; patients who develop hyperthermia are at increased risk for poor outcome
  • Patient education to prevent exploratory ingestion and unintentional toxicity is key to prevention

Pitfalls

  • Failure to consider chronic toxicity in older individuals with preexisting brain injury and in psychiatric patients can lead to increased morbidity; patients with chronic poisoning often present with primarily central nervous system manifestations of toxicity 
  • Can mistake symptoms for anticholinergic withdrawal or adrenergic toxicity
  • Use of physostigmine remains somewhat controversial; consult medical toxicologist or poison control center staff member for appropriate treatment of anticholinergic toxicity before repeated administration of benzodiazepines to prevent unnecessary complications
  • Carefully titrating physostigmine and allowing an appropriate time interval to observe for clinical response can lead to decreased repeated dosing that may lead to unnecessary adverse effects (eg, precipitation of cholinergic symptoms)
  • Ensure safety precautions are in place before administering physostigmine (eg, review of ECG, atropine at bedside, ongoing continuous cardiac monitoring)
  • Duration of physostigmine effects is short; need for repeated dosing is common
  • Avoid using antipsychotics to treat hallucinations and agitation as these medications may further contribute to anticholinergic toxidrome and lower seizure threshold
  • Avoid using phenytoin to treat seizures owing to lack of efficacy and association with cardiotoxicity in patients with anticholinergic toxicity
  • Closely monitor infants who are given mydriatic eye drops to treat transient apnea and bradycardia because systemic absorption is common
  • Anticholinergics may delay gastric motility, leading to delayed absorption; monitor asymptomatic or mildly symptomatic patients after exposure for a minimum of 6 hours
  • Anticholinergic toxicity results from intentional or unintentional consumption of products containing anticholinergic properties in supratherapeutic doses due to drug interactions; in susceptible individuals and sometimes in healthy individuals, toxicity can occur with therapeutic doses 
    • Common medications that have anticholinergic properties 
      • Prescription and OTC antihistamines
      • Cyclic antidepressants
      • Antipsychotics
      • Antiparkinsonian agents
      • Muscle relaxants
      • Antispasmodics
    • Botanicals that have anticholinergic properties include certain plants and fungi, including foods (eg, lupine beans) and topical wipes or creams 
  • Toxicity is characterized by a constellation of clinical manifestations including: 
    • Alterations in mental status (eg, confusion, disorientation, hallucinations, delirium, agitation); agitated delirium is the classic alteration in mental status associated with significant central nervous system toxicity
    • Sinus tachycardia
    • Mydriasis
    • Dry mucous membranes and axillae
    • Dry flushed skin
    • Urinary retention and decreased gastric motility
    • Seizures (up to 2.5% of patients) 
    • Hyperthermia
  • Acute anticholinergic toxicity is not uncommon
    • Suspect acute anticholinergic toxicity in any patient with unexplained symptoms such as altered mental status, sinus tachycardia, dry mucous membranes and skin, and/or dilated pupils

Classification

  • Classification based on chronicity
    • Acute
      • Intentional or unintentional overdose
    • Chronic
      • Often a result of supratherapeutic dose or ingestion of multiple medications with anticholinergic properties
      • Can be an adverse effect of therapeutic dosing with certain medications (eg, OTC sleep aids or antihistamines, antiparkinsonian medications, antipsychotics, tricyclic antidepressants, transdermal scopolamine)

Clinical Presentation

History

  • Medication and exposure history
    • Often no exposure history is available or patient does not recall taking causative agent 
      • Consider the diagnosis in any patient with agitated delirium and/or elements of anticholinergic toxidrome
    • Patient may or may not describe overdose after acute exposure
      • Patients are often less forthcoming after intentional abuse or overdose
        • Recreational consumption of jimson weed or psychoactive mushrooms
        • Suicide attempt
        • Abuse of OTC or prescription medications with anticholinergic properties 
      • Recent use of scopolamine patch during travel 
      • Use of anticholinergic eye drops in an infant or young child
      • Polypharmacy
        • Patients often are unaware of additive effect when taking multiple (including OTC) medications with similar ingredients 
      • Use of topical diphenhydramine on a child, especially if combined with oral diphenhydramine 
    • History suggestive of unintentional exposure
      • Recent farm work, particularly during harvest, owing to incidental growth of jimson weed in crop fields
      • Illicit drugs adulterated with anticholinergics (eg, heroin mixed with scopolamine)
      • Recent victims of rape and/or robbery, during which they were drugged with anticholinergic alkaloids 
        • Victims can be found without clothing and with no memory of the incident
      • Ingestion of plants, particularly by children or after misidentification of plant as edible
      • Consumption of tea or other herbal preparation 
      • Polypharmacy
      • Unable to recall last dose or uses agent as needed
    • Chronic use of anticholinergic medications
      • Past medical history may include Parkinson disease or a psychiatric disorder
      • Polypharmacy
        • History may indicate recent dosage increase or recent addition of a new anticholinergic medication, including OTC medication
        • Medical condition may have changed (eg, renal or hepatic dysfunction may have developed)
  • Presentation is variable
    • Symptoms often are evident between 1 and 4 hours after acute ingestion; severity and duration of manifestations are highly variable 
    • Most present with some but not all manifestations that are associated with the toxidrome 
      • Tricyclic antidepressant ingestion often presents with mild anticholinergic symptoms followed by rapid mental status depression
    • Chronic toxicity tends to present with predominantly central nervous system effects and often lacks peripheral effects associated with toxicity 
      • Often occurs in older or psychiatric patients with chronic toxicity caused by medication to treat underlying illness
  • Symptoms may include:
    • Classic anticholinergic toxidrome
      • Mnemonic: red as a beet, blind as a bat, hot as a hare, dry as a bone, and mad as a hatter
        • Flushed skin
        • Blurred vision and photophobia from mydriasis
        • Elevated body temperature
        • Dry skin from anhidrosis
        • Mental status changes
          • Alert with confusion, disorientation, agitation, and mumbled speech
          • Visual hallucinations are common (eg, picking or grasping at inanimate objects)
          • Mental status depression may be present 
      • Other common symptoms
        • Urinary retention
          • May contribute to agitation
        • Palpitations from tachycardia
        • Seizure
          • Typically short-lived, self-resolving, and generalized tonic-clonic in nature
          • More common in children 
          • Prolonged or repeated seizures are more commonly associated with coingestion (eg, with large dose of tricyclic antidepressant or diphenhydramine) 
        • Myoclonic jerking
          • At times, difficult to differentiate from seizure activity
    • Symptoms and signs of anticholinergic toxicity.Peripheral (muscarinic blockade)Central anticholinergic syndromeTachycardiaConfusionDry, flushed skinDisorientationDry mucous membranesLoss of short-term memoryMydriasisAtaxiaHyperpyrexiaPsychomotor agitationUrinary retentionPicking and grasping movementsDecreased bowel soundsExtrapyramidal reactionsHypertensionVisual/auditory hallucinationsHypotension (late finding)Frank psychosisComaSeizuresRespiratory failureCardiovascular collapse
    • Citation:
  • From Kirk MA et al: Anticholinergics and antihistamines. In: Shannon MW et al, eds: Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose. 4th ed. WB Saunders; 2007:721-34, Box 39-2.

Physical examination

  • Dry flushed skin
  • Mydriasis
    • Characterized by minimally reactive or nonreactive pupils
  • Hyperthermia
  • Dry mucous membranes and axillae
    • Most useful finding to differentiate between anticholinergic and sympathomimetic toxidromes
    • Occurs in up to 75% of patients with toxicity 
  • Mental status changes
    • Central effects often persist longer than peripheral effects; therefore, some patients present with primarily central effects after peripheral effects have waned 
    • Mental status changes are variable and can include:
      • Confusion and disorientation
      • Agitation, restlessness, and motor hyperactivity
      • Hallucinations
        • Visual or auditory
        • Picking at self, objects, or air 
      • Delirium
        • Agitated delirium: classic presentation of central anticholinergic toxicity 
          • Characterized by fluctuating course of a combination of the following:
            • Disorganized thoughts with rambling, irrelevant, or incoherent speech
            • Inability to maintain attention
            • Mental status changes ranging from decreased level of consciousness to psychomotor agitation
            • Sensory misperceptions
            • Impaired memory
            • Disorientation to person, place, and/or time
      • Other signs can include ataxia, slurred or mumbled speech, choreoathetosis, myoclonus, and tremor 
      • Coma as a result of massive ingestion 
  • Sometimes a palpable bladder due to urinary retention
  • Tachycardia
    • Occurs in up to 68% of patients with toxicity 
    • Often the earliest sign of toxicity 
    • May not develop in very young and old patients without a high resting vagal tone 
  • Hypertension or hypotension (late finding) 
  • Decreased or absent bowel sounds

Causes

  • Common sources of exposure
    • Orally ingested medications and botanicals with anticholinergic properties 
      • Numerous classes of pharmaceuticals possess anticholinergic properties including:
        • Belladonna alkaloids and representative synthetic congeners 
          • Common examples include atropine, glycopyrrolate, hyoscyamine, and scopolamine 
        • Antihistamines (H₁ antagonists)
          • First-generation antihistamines (eg, diphenhydramine, dimenhydrinate, hydroxyzine, chlorphenamine, cyproheptadine)
            • Penetrate the blood-brain barrier well, resulting in central anticholinergic and antihistaminergic effects (ie, sedation)
            • Are nonspecific in their actions and often cause marked anticholinergic effects 
          • Antihistamines have numerous other potential mechanisms for toxicity, such as: 
            • Sodium channel antagonism
            • α₁-Adrenergic antagonism
            • Serotonin receptor antagonism
            • Potassium channel antagonism
          • Some antihistamines cause a lower seizure threshold
        • Cyclic antidepressants and drugs related to tricyclic antidepressants
          • Common examples include clomipramine, imipramine, desipramine, amitriptyline, and nortriptyline
          • Multiple mechanisms for potential toxicity
            • Primary toxic effects are secondary to sodium channel blockade, biogenic amine reuptake inhibition (eg, serotonin, norepinephrine, dopamine), and antimuscarinic properties
            • Additional toxic effects are secondary to potassium channel blockade, α₁-adrenergic antagonism, γ-aminobutyric acid antagonism, and antihistaminergic properties
            • Some tricyclic antidepressants lead to a lower seizure threshold by numerous mechanisms including potent H₁ receptor antagonism 
          • Common examples of drugs related to tricyclic antidepressants include cyclobenzaprine and carbamazepine
        • Antipsychotics
          • Phenothiazines (eg, promethazine, chlorpromazine, prochlorperazine, mesoridazine, thioridazine)
            • Exhibit significant α₁-adrenergic antagonism; therefore, can result in hypotension 
            • Lower seizure threshold and may cause cardiac sodium channel blockade 
          • Butyrophenones (eg, haloperidol)
        • Antiparkinsonian agents (eg, benztropine, trihexyphenidyl) 
          • Synthetic congeners of atropine used as second line antiparkinsonian agents and to counteract extrapyramidal adverse effects of neuroleptics
        • Muscle relaxants and antispasmodics
          • Common examples include dicyclomine, cyclobenzaprine, and oxybutynin 
          • Chemical structure sometimes resembles tricyclic antidepressants. When patient overdoses on muscle relaxants or antispasmodics, symptoms can be similar to cyclic antidepressant overdose
      • Plants and fungi with anticholinergic properties
        • Plants
          • Contain anticholinergic alkaloids (eg, solanine, atropine [a racemic mixture of D-hyoscyamine and L-hyoscyamine], and scopolamine [L-hyoscine])
          • Many plants have anticholinergic properties, including:
            • Atropa belladonna (deadly nightshade)
            • Datura stramonium (jimson weed)
            • Datura inoxia (downy thorn apple)
            • Mandragora officinarum (mandrake)
            • Hyoscyamus niger (henbane)
            • Brugmansia arborea (angel trumpet)
        • Fungi
          • Some species of fungi such as Inocybe species, Clitocybe species, and to a lesser extent Amanita species
          • Contain psychoactive compounds such as ibotenic acid and muscimol
    • Topical medications
      • Scopolamine cutaneous patch is most common cause
        • Accidental contact with eyes can occur after touching the scopolamine patch; result is unilateral or bilateral fixed dilated pupils without focal neurologic changes 
      • Application of dilator eye drops (eg, homatropine, cyclopentolate, tropicamide) 
    • Inhaled or insufflated substances
      • Adulterated cocaine or heroin
      • Herbal products (smoking or other consumption) 
    • IV administration of pharmaceuticals or adulterated illicit drugs
      • Adulterated cocaine or heroin
      • Anticholinergic alkaloids (eg, atropine)
    • Some agents with anticholinergic properties.ClassExamplesPlants and mushroomsAtropa belladonna (deadly nightshade)Datura stramonium (jimson weed)Mandragora officinarum (mandrake)Hyoscyamine niger (henbane)Amanita muscaria (fly agaric)AntihistaminesChlorpheniramine (Chlor-Trimeton)Dimenhydrinate (Dramamine)Diphenhydramine (Benadryl)Hydroxyzine (Atarax, Vistaril)Meclizine (Antivert)Belladonna alkaloids and related synthetic compoundsAtropineScopolamine (Transderm Scop)Glycopyrrolate (Robinul)Hyoscyamine (Levbid, Levsin)AntipsychoticsChlorpromazine (Thorazine)Clozapine (Clozaril)Olanzapine (Zyprexa)Quetiapine (Seroquel)Thioridazine (Mellaril)AntispasmodicsDicyclomine (Bentyl)Oxybutynin (Ditropan)Tolterodine (Detrol)Solifenacin (Vesicare)OTC sleep aidsDiphenhydramine (Benadryl)Doxylamine (Unisom)Cyclic antidepressantsAmitriptyline (Elavil)Clomipramine (Anafranil)Doxepin (Sinequan)Imipramine (Tofranil)Nortriptyline (Pamelor)Antiparkinsonian agentsAmantadine (Symmetrel)Benztropine (Cogentin)Trihexyphenidyl (Artane)Local mydriaticsCyclopentolate (Cyclogyl)Homatropine (Isopto Homatropine)Muscle relaxantsCyclobenzaprine (Flexeril)Orphenadrine (Norflex)Tizanidine (Zanaflex)Respiratory agentsAclidinium (Tudorza Pressair)Ipratropium (Atrovent)Tiotropium (Spiriva)OthersCarbamazepine (Tegretol)Cyproheptadine (Periactin)
    • Citation: Data from Kirk MA et al: Anticholinergics and antihistamines. In: Shannon MW et al, eds: Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose. 4th ed. WB Saunders; 2007:721-34, Box 39-1; and PL Detail-Document #271206: Drugs with Anticholinergic Activity. Pharmacist’s Letter/Prescriber’s Letter website. December 2011. https://pharmacist.therapeuticresearch.com
  • Pharmacology
    • Mechanism of action
      • Anticholinergic compounds block the action of acetylcholine by competitive antagonism at muscarinic receptor sites; this leads to decreased acetylcholine effects at central and peripheral muscarinic receptors
        • Receptor blockade and clinical effects are usually dose-dependent 
          • In general, progression of peripheral effects are as follows:
            • Smaller doses cause a decrease in sweat, bronchial secretions, and saliva (might not cause noticeable symptoms)
            • Larger doses cause mydriasis, cycloplegia, and increased heart rate
            • Even larger doses cause urinary retention and ileus
          • Central nervous system effects are somewhat dose-dependent
            • Stimulation often occurs first; with increasing doses, central nervous system depression may follow initial central nervous system stimulation 
            • Degree of central effects (eg, acute psychosis or delirium) depends on substance’s ability to penetrate blood-brain barrier
        • Hyperthermia
          • Results primarily from:
            • Impaired heat dissipation secondary to peripheral blockade of exocrine sweat glands results in anhidrosis
            • Increased muscle activity (eg, restlessness, agitation, seizures) secondary to central blockade greatly increases heat production
    • Absorption
      • Anticholinergic agents decrease gut motility; may result in delayed, erratic, and prolonged absorption in overdose 
      • Absorption from gastrointestinal tract is variable between different compounds
      • Ingestion of plant seeds can result in delayed absorption 
    • Distribution
      • Degree of central anticholinergic activity is related to ability of a medication to cross the blood-brain barrier; for example:
        • All first-generation antihistamines readily cross the blood-brain barrier and have central effects (eg, diphenhydramine causes drowsiness)
        • Second-generation antihistamines are unable to cross the blood-brain barrier and lack central effects (eg, loratadine does not cause drowsiness) 
    • Onset/duration
      • Acute overdose usually results in onset of toxicity within 2 hours 
        • Seizures most commonly occur within the first few hours and represent severe toxicity
        • Decreased gut motility may cause delayed onset
      • Toxicity can last from hours to several days, depending on severity of overdose and substance ingested

Risk factors and/or associations

Age
  • Infants, especially premature infants, are at risk for systemic toxicity after they are given anticholinergics (including eye drops) 
Other risk factors/associations
  • At higher risk for chronic toxicity
    • People taking multiple anticholinergic medications for various medical conditions (eg, Parkinson disease, psychiatric disorders, overactive bladder, muscle spasms, motion sickness, seasonal allergies) 
  • At higher risk for central effects of toxicity
    • Older and very young people
    • People with preexisting brain injury 
    • Those with exaggerated antimuscarinic responses at therapeutic doses 

Diagnostic Procedures

  • Anticholinergic toxicity diagnosis algorithm.

Primary diagnostic tools

  • Diagnosis of acute anticholinergic or sedating antihistamine poisoning primarily is based on physical examination at clinical presentation 
    • History of ingestion or multiple medications with anticholinergic properties may be elicited; most patients present without clear history of exposure 
    • Physical findings consistent with the anticholinergic syndrome include hypertension, tachycardia, mydriasis, altered mental status, myoclonic jerking, and hyperthermia 
      • Salient findings that are key to differentiating anticholinergic syndrome from sympathomimetic syndrome and anticholinergic withdrawal include: 
        • Anticholinergic syndrome: dry mucous membranes, decreased bowel sounds, urinary retention, dry flushed skin, and hallucinations
        • Sympathomimetic syndrome: moist mucous membranes, normal bowel sounds, absence of urinary retention, diaphoretic skin, and euphoria or psychomotor agitation
        • Anticholinergic withdrawal: bradycardia, headaches, nausea, abdominal cramps, sweating, confusion, and dizziness
  • Obtain ECG in all patients presenting with concerns for anticholinergic toxicity 
    • ECG often demonstrates sinus tachycardia alone
    • Carefully assess for PR, QTc, and QRS interval prolongation
      • Use of physostigmine in individuals with evidence of conduction delay remains controversial; seek expert advice
      • Interval prolongation may represent evidence of sodium channel blockade that occurs with some antihistamines, tricyclic antidepressants, and phenothiazines 
        • Safety of physostigmine in the setting of tricyclic antidepressant toxicity is difficult to predict 
        • If QRS interval is greater than 120 milliseconds, use of physostigmine is not recommended 
  • Assess for rhabdomyolysis
    • Patients with severe agitation (eg, making excessive movements, thrashing, requiring restraints), seizure, hyperthermia, and coma are at high risk for developing rhabdomyolysis 
    • Rhabdomyolysis
    • Obtain creatine phosphokinase level and perform urinalysis with microscopy for patients at risk
  • Consider diagnostic trial of physostigmine in consultation with a medical toxicologist when contraindications are lacking and diagnosis is uncertain 
    • Complete reversal of delirium, hallucinations, and agitation may help exclude alternate diagnosis and avoid additional ancillary testing such as head CT and lumbar puncture 
  • Obtain other routine screening tests in patients with suspected intentional overdose, including: 
    • Acetaminophen level
    • Pregnancy screening in females of childbearing age
    • Blood glucose in patients with mental status depression
  • Additional testing to exclude alternate cause may be required based on presentation, including: 
    • Head CT: significant, persistent, and altered mental status
      • Performed to exclude diagnoses such as central nervous system catastrophe, space-occupying lesion, and/or increased intracranial pressure
    • Lumbar puncture: hyperthermia and persistent altered mental status
      • Performed to investigate for central nervous system infectious process if patient has persistent fever or neck stiffness
    • Renal function tests and electrolyte levels: suspected rhabdomyolysis
    • Cardiac enzyme levels: chest pain
  • Diagnosis of chronic poisoning is difficult owing to often subtle manifestations 
    • Relies on a high degree of clinical suspicion in patients on maintenance medications that may cause symptomatology
      • Maintain a high degree of suspicion in older patients taking multiple medications and in psychiatric patients 
      • Diagnosis can be delayed owing to attributing dementia or deterioration in mental status to underlying comorbidity 
    • Withdrawal of offending medication resulting in resolution of symptoms confirms diagnosis 

Laboratory

  • Drug screening
    • Not often helpful
      • Agents that produce anticholinergic toxicity usually are not included in routine urine drug screen 
      • Comprehensive qualitative testing (eg, gas chromatography–mass spectrometry) and quantitative assays are not readily available
    • Toxicology screens often are more useful for identifying:
      • Unsuspected coingestions (eg, serum acetaminophen concentration)
  • Urinalysis with urine microscopy
    • Presence of myoglobinuria is a sign of rhabdomyolysis
      • When dipstick result is positive for blood (ie, heme positive) and significant RBCs are absent on urine microscopy, myoglobinuria is present
      • When dipstick result is negative for blood (ie, heme negative), myoglobinuria is excluded
  • Creatine phosphokinase
    • Elevated creatine kinase level is the most sensitive indicator of myocyte injury
    • Creatine phosphokinase level more than 5 times the reference range is evidence of rhabdomyolysis 

Imaging

  • Can be used to rule out neurological conditions (eg, stroke, abscess), especially if there are focal signs

Functional testing

  • ECG
    • Most common finding is sinus tachycardia alone
    • Findings suggestive of tricyclic antidepressant toxicity include:
      • Intraventricular conduction delay is characteristic
      • Prominent R wave in lead aVR, an S wave in leads I and aVL, and a QRS interval duration of more than 100 milliseconds 
        • Prominent R wave is defined as more than 3 mm in R wave or R/S ratio of more than 0.7
      • Ventricular tachycardia and fibrillation can occur
      • Note: PR, QRS, and QT interval prolongation can occur even at therapeutic dosing
    • Findings consistent with diphenhydramine toxicity include:
      • Presence of repolarization abnormalities (eg, nonspecific ST-T changes, QT prolongation) 
      • Torsades de pointes is rare 

Procedures

  • Diagnostic tool intended to be used in select patients in consultation with a medical toxicologist or poison control center staff member
  • When diagnosis is indeterminate and contraindications are lacking, diagnostic trial of physostigmine sometimes is used in an attempt to reverse anticholinergic toxidrome 
    • Physostigmine use may help positive responders (ie, those who clear delirium) avoid need for head CT 
    • Physostigmine use may diminish rate of lumbar puncture required for certain patients during evaluation process in positive responders (ie, clearing of delirium)
  • Physostigmine is a reversible inhibitor of acetylcholinesterase. Its use results in a rise in acetylcholine level and cholinergic effects at nicotinic and muscarinic acetylcholine receptors 
  • ECG to exclude significant PR, QRS, or QTc interval prolongation is suggested before administration of physostigmine 
  • Continuous cardiac monitoring and atropine available at bedside is recommended during physostigmine administration 
  • Limited reported dose range of physostigmine used for diagnostic trial ranges from 0.5 to 2 mg (mean 1.3 mg) 
    • Considerable individual variability exists in dose required to reverse anticholinergic toxicity; total maximum accumulative dose of 4 mg is sufficient to elicit improvement for most patients
  • Suspected anticholinergic toxidrome to confirm anticholinergic toxicity as cause for symptomatology 
  • Use of physostigmine in patients with evidence of conduction delay remains controversial; seek expert advice if: 
    • QRS interval prolongation is greater than 120 milliseconds 
    • There is bradycardia or atrioventricular block
  • Use of physostigmine in patients with known or suspected tricyclic antidepressant ingestion is controversial 
    • Safety of physostigmine in the setting of tricyclic antidepressant toxicity is difficult to predict; physostigmine may worsen conduction disturbances 
  • Seizures related to ingestion or history of seizure disorder
  • Asthma, severe cardiovascular disease, diabetes, parkinsonism, mechanical obstruction of intestinal or urinary tract, vagotonic states, or gangrene 
  • Patients receiving a depolarizing neuromuscular-blocking drug
  • Precipitation of cholinergic syndrome, including increased secretions with possible airway compromise, bronchospasm, nausea, vomiting, or diarrhea 
    • Particularly common in patients with no or minimal anticholinergic toxicity after ingestion of a low dose of anticholinergic 
  • Seizure can result from lowering of seizure threshold
    • Related to rate of administration; according to most experts, seizure is rare if dose is given slowly (around 1 mg/minute)
  • Bradycardia or heart block in patients without anticholinergic toxicity; rare occurrence of asystole in patients severely poisoned with tricyclic antidepressants 
    • Related to rate of administration; according to most experts, it is rare if dose is given slowly (more than 1 mg/minute)
  • Complete reversal of delirium, hallucinations, and/or agitation increases likelihood of diagnosis and helps exclude alternate diagnoses
  • Positive clinical response is expected in 83% to 100% of patients affected by anticholinergic delirium 
  • Effects of physostigmine are relatively short-lived (about 22 minutes) 

Differential Diagnosis

Most common

  • Adrenergic toxicity (sympathomimetic toxicity)
    • Caused by cocaine, amphetamines, and other stimulants
    • Similar features include mydriasis, tachycardia, hyperpyrexia, mental status changes, hallucinations, confusion, disorientation, and seizures
    • Differentiating features include diaphoresis, moist mucous membranes, lack of urinary retention, bowel sounds within reference range, and hallucinations that are typically characterized as paranoid and associated with violent behavior
    • Differentiate by clinical presentation, ingestion history, and toxicology drug screen; diagnostic trial of physostigmine will not improve symptoms if patient has adrenergic toxicity
    • Definitively diagnosed by comprehensive toxicologic screening
  • Alcohol and benzodiazepine withdrawal
    • Prolonged heavy alcohol, benzodiazepine, or other sedative-hypnotic use can result in withdrawal symptoms after cessation or decreased consumption
    • Withdrawal symptoms begin a few hours after cessation or decreased consumption and evolve over 3 to 5 days 
      • Common primary symptoms of withdrawal include tremors, nausea, vomiting, and insomnia
    • Similar features include sympathomimetic hyperactivity (eg, tachycardia, hypertension) along with disorientation, delirium, agitation, seizures, and hallucinations
    • Differentiating features include diaphoresis, bowel sounds within reference range, and lack of urinary retention in patients experiencing withdrawal
    • Differentiate and diagnose by clinical presentation and clinical course
  • Phencyclidine toxicity
    • Similar features include tachycardia, mental status changes, agitation, hallucinations, confusion, disorientation, and seizures
    • Differentiating features include diaphoresis, moist mucous membranes, marked nystagmus, bowel sounds within reference range, lack of urinary retention, and miosis
    • Differentiate by clinical presentation, history of ingestion, and toxicology drug screen; diagnostic trial of physostigmine will not improve symptoms if patient has phencyclidine toxicity
    • Definitively diagnose by comprehensive toxicology screening
  • Serotonin syndrome
    • Caused by excess central nervous system serotonergic antagonism from therapeutic drug use, intentional poisoning, or inadvertent interactions between drugs
    • Most commonly occurs within 12 hours of a new 2-drug combination (eg, MAOI and tricyclic antidepressant)
    • Similar features include agitation and hyperthermia
    • Differentiating features include diaphoresis, rigidity and clonus, primarily lower extremity tremor, and significant akathisia
    • Diagnosis is clinical and supported by resolution of symptoms after removing offending drugs; diagnostic trial of physostigmine will not improve symptoms if patient has serotonin syndrome
  • Heat stroke
    • Similar features include hyperthermia, tachycardia, mental status changes, confusion, disorientation, and dry hot skin
    • Differentiating features include bowel sounds and pupils within reference range and lack of urinary retention
    • Differentiate and definitively diagnose by history and clinical presentation
  • Psychiatric illness
    • Similar features include mental status changes, hallucinations, confusion, and disorientation
    • Differentiating features include moist mucous membranes, bowel sounds and pupils within reference range, lack of urinary retention, and lack of hyperthermia
    • Differentiate by lack of anticholinergic toxidrome and slower onset of mental status changes
    • Definitively diagnose with formal psychiatric evaluation and symptoms compatible with DSM-5 criteria 
  • Sepsis
    • Similar features include tachycardia, fever, mental status changes, disorientation, and confusion
    • Differentiating features may include abnormal WBC count and elevated C-reactive protein
    • Differentiate by clinical presentation and, potentially, by imaging of suspected infection site
    • Definitively diagnose by positive cultures in blood, urine, or other bodily fluid
  • Anticholinergic withdrawal 
    • Can develop after stopping anticholinergic drugs, and may present with symptoms similar to those of toxicity
    • Dizziness
    • Bradycardia
    • Headaches
    • Nausea, abdominal cramps
    • Sweating
    • Confusion
    • Withdrawal is characterized by bradycardia and lack of pupil constriction, which can help differentiate from toxicity

Treatment Goals 

  • Reduce patient’s risk of harm to self or others secondary to alterations in mental status with reversal (physostigmine) or symptomatic treatment (benzodiazepine)
  • Stabilize patients who have hemodynamic changes and/or respiratory depression
  • Address cardiac conduction abnormalities that may be present with certain drugs that cause anticholinergic toxicity by using sodium bicarbonate to reverse sodium channel blockade
  • Reduce risk of rhabdomyolysis by aggressively controlling seizures, hyperthermia, and agitation
  • Reduce risk of acute renal failure in patients who develop rhabdomyolysis with appropriate hydration and maintenance of urine output

Admission criteria

Symptoms that persist for more than 6 hours 

Moderate to severe symptoms, including: 

  • Central nervous system findings such as significantly altered mental status and/or seizures
  • QRS, QT interval prolongation, and/or nonsinus arrhythmias
  • Hyperthermia
Criteria for ICU admission
  • Delirium, dysrhythmias, seizures, or coma
  • Patients requiring repeated physostigmine treatment or physostigmine drip

Recommendations for specialist referral

  • Consult medical toxicologist and/or local poison center staff member regarding any suspected anticholinergic toxicity for assistance with diagnosis and treatment
  • Consult psychiatrist regarding any patient who intentionally ingested a toxic amount of anticholinergics or antihistamines for diagnostic and treatment recommendations

Treatment Options

Focus initial management on supporting airway, breathing, and circulation

  • Protect airway and support breathing
  • Administer IV bolus if dehydration or hypotension is present
  • Use continuous cardiac monitoring and pulse oximetry for all patients

Overview of immediate management 

  • Address any life-threatening manifestations of anticholinergic toxicity; this may involve gastrointestinal decontamination, symptomatic and supportive care, and antidote (physostigmine) therapy in select patients
    • Administer activated charcoal when indicated in consultation with poison control center or medical toxicologist 
    • Aggressive management of agitation is indicated to prevent development or worsening hyperthermia, trauma, and rhabdomyolysis
      • Aggressive management of hyperthermia is paramount to prevent rhabdomyolysis and potential associated sequelae (eg, disseminated intravascular coagulation, renal failure, multisystem organ failure, death)
    • Aggressive treatment of prolonged seizures is indicated to diminish risk of rhabdomyolysis and central nervous system injury
    • Treat prolonged QRS interval caused by sodium channel blockade with sodium bicarbonate administration to prevent ventricular arrhythmia
    • Manage arrhythmia with immediate sodium bicarbonate administration; manage specific arrhythmia in accordance with established guidelines (eg, magnesium sulfate for torsades de pointes)
    • Treat with IV fluid to maintain adequate hydration status and ensure adequate urine output to diminish risk of rhabdomyolysis-related renal damage
    • Consider antidote (physostigmine) to treat significant toxicity (eg, delirium, agitation, hyperthermia) when there are no contraindications
  • Mild to moderate signs of toxicity can be managed with symptomatic care alone 
    • Early consultation with a medical toxicologist and poison control center staff member can help develop treatment strategy and avoid potentially harmful treatment
    • Individualized treatment strategies are often required owing to the myriad of substances that can result in anticholinergic toxicity

Decontamination

  • Gastrointestinal decontamination with single-dose activated charcoal
    • Indications include patients presenting within 1 hour of ingestion of a potentially toxic quantity of anticholinergic compound 
      • Greatest benefit from activated charcoal occurs when it is administered within 1 hour of ingestion; effectiveness decreases over time 
    • Contraindications include active vomiting, bowel obstruction or ileus, depressed mental status, and unprotected airway
    • Charcoal administration is standard of care despite lack of evidence of significant clinical benefits 
  • External decontamination
    • Remove anticholinergic patches (eg, scopolamine, oxybutynin) and other topical preparations (eg, diphenhydramine cream or lotion) by washing skin

Administer specific antidote when indicated in the absence of contraindications

  • Physostigmine
    • This antidote is a short-acting, reversible inhibitor of acetylcholinesterase, which breaks down acetylcholine 
    • Use is controversial; not recommended for routine use for all cases of anticholinergic toxicity because of potential adverse effects 
      • Many toxicologists support use to treat anticholinergic toxidrome 
      • Limited current data supports use given lack of contraindications; physostigmine is considered relatively safe and effective in reversing anticholinergic toxidrome 
      • Physostigmine may be preferred over benzodiazepines to treat agitation and delirium owing to increased efficacy and decreased risk of significant sedation requiring intubation. Rapid reversal of symptoms with physostigmine use may decrease risk of rhabdomyolysis 
      • Physostigmine controls agitation in up to 87% and reverses delirium in up to 96% of patients with pure anticholinergic poisoning 
    • Consider administration in consultation with a medical toxicologist or poison control center staff member when both central and peripheral toxicity findings are present 
    • Indicated for anticholinergic symptoms (peripheral and central) if there are no contraindications. Common treatment indications include:
      • Severe agitation caused by anticholinergic agents other than tricyclic antidepressants 
      • Delirium caused by anticholinergic agents other than tricyclic antidepressants 
      • Tachycardia with hemodynamic instability 
      • Severe hyperthermia with impaired sweating 
    • Relative contraindications include: 
      • ECG findings
        • Use of physostigmine in individuals with evidence of conduction delay remains controversial; seek expert advice
          • Wide QRS complex (QRS greater than 120 milliseconds)
        • Bradycardia or presence of atrioventricular block
        • Only consider physostigmine after any cardiovascular toxicity has resolved
      • Overdose with any agent that is not primarily anticholinergic (eg, tricyclic antidepressants) 
        • Use is controversial in tricyclic antidepressant overdose
          • Safety of physostigmine in setting of tricyclic antidepressant toxicity is difficult to predict
          • May help with antimuscarinic effects but will not reverse serotonergic effects or α-adrenergic blockade
          • May aggravate conduction disturbances in tricyclic antidepressant overdose
          • ECG findings suggestive of tricyclic antidepressant toxicity include prominent R wave in lead AvR, an S wave in leads I and AvL, and a QRS interval duration of greater than 100 milliseconds 
      • Seizures
        • Related to ingestion or history of seizure disorder
      • History significant for parkinsonism, diabetes, gangrene, asthma, severe cardiovascular disease, peripheral vascular disease, mechanical obstruction of intestine or urogenital tract, or vagotonic states. Also, patients receiving depolarizing neuromuscular blockers (ie, succinylcholine) 
    • Precautions before administration
      • Review ECG for contraindications 
      • Ensure that patient is on a continuous cardiac monitor with secure IV access
      • Ensure that IV atropine is available at bedside to treat significant cholinergic toxicity if it develops
    • Onset/duration
      • Typical onset is within minutes (average 11 minutes)
      • Duration of action is typically about 1 hour
        • Repeated dosing is often required owing to longer action of most ingested medications associated with toxicity
    • Monitor closely for adverse effects of administration
      • Cholinergic toxidrome (eg, bronchospasm, bronchorrhea, vomiting, diarrhea) can result from excess physostigmine administration
      • Seizures can result from rapid administration or from excess physostigmine administration; reported in up to 2.5% of patients 
      • Bradycardia and heart block are very rarely reported 
      • Asystole and death has occurred in individuals with massive tricyclic antidepressant ingestions; however, risk for cardiac death is extremely low in patients with QRS duration within reference range

Symptomatic care

  • Cardiovascular toxicity
    • Sinus tachycardia
      • Most common toxic cardiovascular effect from anticholinergic poisoning; rarely requires intervention
    • QRS prolongation and dysrhythmias
      • Many drugs with anticholinergic effects cause cardiac conduction delays and subsequent dysrhythmias from fast sodium channel blockade (type 1a activity)
      • Treat sodium channel blockade with IV sodium bicarbonate 
        • Improves impaired conduction from fast sodium channel blockers such as cyclic antidepressants, diphenhydramine, and orphenadrine
      • Clinical indications for sodium bicarbonate include:
        • QRS prolongation greater than 100 milliseconds
        • Hypotension due to tricyclic antidepressant overdose
      • Monitoring of QRS interval, potassium, and pH is indicated during and after administration
      • Goals of therapy are narrowing of QRS interval, improvement in hypotension, and normalization of ECG changes
  • Central nervous system toxicity
    • Agitation
      • Benzodiazepines can be used to treat agitation
        • Indications include:
          • Risk of patient causing harm to self or others
            • Caution: escalating doses of benzodiazepines as primary treatment of severe delirium can lead to increased need for intubation and disinhibited delirium 
          • To facilitate diagnosis and treatment of underlying condition(s)
        • After administration, monitor closely for signs of excessive sedation and respiratory depression
        • Benzodiazepines alone control agitation in up to 24% of patients and have no effect on delirium in those with pure anticholinergic poisoning 
      • For severe agitation, consider physostigmine in consultation with a medical toxicologist
      • Assess and treat urinary retention
        • May contribute to agitation if not appropriately addressed 
      • Avoid antipsychotics (eg, phenothiazines, butyrophenones); most antipsychotics have anticholinergic properties and lower seizure threshold 
      • Avoid prolonged physical restraints
        • Brief period of restraint use may be necessary before definitive treatment
        • Prolonged use of restraints may place patient at higher risk of developing rhabdomyolysis
      • Paralysis with intubation and mechanical ventilation may be required if other measures fail or if clinical indicators dictate (eg, refractory shock, mental status depression) 
    • Seizures
      • Often short-lived, requiring no specific treatment unless prolonged 
      • First line treatment: benzodiazepines 
        • Preferred benzodiazepines are intramuscular midazolam, IV lorazepam, or IV diazepam 
        • Use intramuscular dosing of lorazepam or midazolam or rectal dosing of diazepam if IV access is initially unobtainable 
        • Note: do not use IV diazepam in neonates because there is sodium benzoate and benzoic acid in the injection
      • Second line treatment is barbiturates or propofol if benzodiazepines are ineffective 
      • Phenytoin is contraindicated; evidence suggests that phenytoin is ineffective at terminating drug-induced seizures and may add to cardiovascular toxicity
  • Hyperthermia
    • Treat factors that exacerbate hyperthermia (eg, seizures, agitation)
    • Mild to moderate hyperthermia
      • Begin passive cooling measures for temperatures exceeding 38 °C 
      • Strategies may include:
        • Evaporative cooling measures such as cool mist and fan 
        • Ice packs applied over major arteries in axillae and groin 
    • Severe hyperthermia with temperatures exceeding 41 °C
      • Begin aggressive active cooling measures because severe hyperthermia is associated with poor outcomes
      • Strategies are often institution-dependent and may include:
        • Cooling mattresses 
        • Convection-immersion devices that cool by rapidly circulating water from a perforated top sheet to an underblanket 
        • Neuromuscular paralysis with mechanical ventilation may be required for recalcitrant hyperthermia 
    • Monitor core temperature with a rectal or bladder thermocouple; maintain euvolemic state with adequate fluid replacement 
    • Anticipate development of rhabdomyolysis and potentially disseminated intravascular coagulation, renal failure, hepatic failure, and hyperkalemia 
    • Discontinue cooling measures once patient has reached 38 °C 
    • Avoid antipyretics (eg, NSAIDs, acetaminophen) because drug-induced hyperthermia does not respond to them 
  • Chronic toxicity
    • Management involves refining medication profile
      • First, decrease dose of offending medication and eliminate or reduce dose of other medications that have anticholinergic adverse effects
      • Second, change medication to one with a lesser anticholinergic profile

Drug therapy 

  • Charcoal
    • Activated Charcoal Oral suspension; Children: 1 to 2 g/kg/dose or 25 to 50 g/dose PO as a single dose.
    • Activated Charcoal Oral suspension; Adults and Adolescents: 50 g as a single dose; not recommended for multiple dosage regimens.
  • Benzodiazepines
    • Agitation
      • Lorazepam
        • Lorazepam Solution for injection; Children and Adolescents: 0.05 to 0.1 mg/kg/dose IV every 30 to 60 minutes as needed (Max: 2 mg).
        • Lorazepam Solution for injection; Adults: 2 mg IV every 30 to 60 minutes as needed.
      • Diazepam
        • Multiple doses may be required to achieve optimum clinical effect
        • Diazepam Solution for injection; Adults: Titrated doses of up to 10 mg IV every 5 to 10 minutes until agitation is controlled.
    • Seizures
      • Lorazepam
        • Note: IV route is preferred. However, if IV port is not available, intramuscular route may be used. 
        • Lorazepam Solution for injection; Infants†, Children†, and Adolescents†: 0.05 to 0.1 mg/kg IV or IM (Max: 4 mg) as a single dose; may repeat once in 5 to 15 minutes if needed.
        • Lorazepam Solution for injection; Adults: 4 mg IV at a rate of 2 mg/minute; may give a second dose in 10 to 15 minutes if needed. Experience is limited with further doses.
      • Diazepam
        • Intravenous
          • Diazepam Solution for injection; Infants and Children 1 month to 4 years: 0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV; may repeat once in 5 minutes if needed. Alternately, 0.2 to 0.5 mg IV every 2 to 5 minutes PRN. Max: 5 mg. May repeat in 2 to 4 hours, if needed
          • Diazepam Solution for injection; Children and Adolescents 5 to 17 years: 0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV; may repeat once in 5 minutes if needed. Alternately, 1 mg IV every 2 to 5 minutes PRN. Max: 10 mg. May repeat in 2 to 4 hours, if needed
          • Diazepam Solution for injection; Adults: 0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV; may repeat once in 5 minutes if needed. Alternately, 5 to 10 mg IV every 10 to 15 minutes PRN. Max: 30 mg. May repeat in 2 to 4 hours, if needed.
        • Rectal
          • Diazepam Rectal gel; Children 2 to 5 years: 0.5 mg/kg/dose (Max: 20 mg/dose) PR once.
          • Diazepam Rectal gel; Children 6 to 11 years: 0.3 mg/kg/dose (Max: 20 mg/dose) PR once.
          • Diazepam Rectal gel; Children and Adolescents 12 to 17 years: 0.2 mg/kg/dose (Max: 20 mg/dose) PR once.
          • Diazepam Rectal gel; Adults: 0.2 to 0.5 mg/kg/dose (Max: 20 mg/dose) PR once.
      • Midazolam
        • Midazolam Hydrochloride Solution for injection; Infants, Children, and Adolescents weighing 13 to 40 kg: 5 mg IM once. 
        • Midazolam solution for injection; Adults and Adolescents weighing more than 40 kg: 10 mg IM once. 
      • Barbiturates
        • Phenobarbital Sodium Solution for injection; Infants, Children, and Adolescents: 15 to 20 mg/kg IV load over 10 to 15 minutes (Max: 1,000 mg/dose). Additional 5 to 10 mg/kg doses may be given at 15- to 30-minute intervals for refractory seizures (Max total dose: 40 mg/kg). Initiate maintenance dose 12 to 24 hours after load.
        • Phenobarbital Sodium Solution for injection; Adults: Initially, a loading dose of 15 to 18 mg/kg IV. In the absence of mechanical ventilation, a dose of 10 mg/kg IV should be administered initially and followed by an additional 5 mg/kg IV approximately 30 to 60 minutes after the first dose. An additional 5 mg/kg may be given for refractory seizures. The usual max total loading dose is 25 to 30 mg/kg. Initiate maintenance dose 12 to 24 hours after the loading dose (see maintenance dosage regimens listed for seizures).
  • General anesthetic
    • Propofol
      • Propofol Emulsion for injection; Adults: Definitive dosage not established; 1 to 2 mg/kg IV loading dose, then 2 to 10 mg/kg/hour continuous IV infusion has been recommended to induce anesthesia in patients with refractory status epilepticus
  • Physostigmine
    • Bolus
      • Use of physostigmine is typically reserved for patients with severe agitation, tachycardia with hemodynamic instability, and severe hyperthermia with impaired sweating 
      • Of note, manufacturer’s labeling states physostigmine may be given intramuscularly. In cases of anticholinergic toxicity, IV use is recommended at a slow controlled rate
      • Limited evidence suggests lower dosing range (0.5-1 mg in adults and 0.01-0.02 mg in children) with a titrated dose in 10- to 15-minute increments before redosing is safest method of administration; slower administration of dose may also reduce risk of adverse effects; response is often noted several minutes after administration 
      • Physostigmine Salicylate Solution for injection; Children: 0.02 mg/kg (range, 0.01 to 0.03 mg/kg up to 0.5 mg) slow IV over 5 minutes (Max rate: 0.5 mg/minute IV); may repeat at 5- to 10-minute intervals as needed until total dose of 2 mg
      • Physostigmine Salicylate Solution for injection; Adults: 0.5 to 2 mg slow IV over 5 minutes (Max: 1 mg/minute IV). May repeat every 10 to 30 minutes as needed until total dose of 2 to 4 mg. 
  • Sodium bicarbonate
    • Bolus
      • Sodium Bicarbonate Solution for injection; Adults, Adolescents, and Children younger than 2 years: 1 to 2 mEq/kg IV over 1 to 2 minutes
      • May repeat every 3 to 5 minutes until the QRS interval narrows and hypotension improves or a blood pH of 7.5 to 7.55 has been achieved
    • Infusion
      • Sodium bicarbonate solution for injection; Adults, Adolescents, and Children: 150 mEq in 1 L 5% dextrose in water (D5W), run at twice maintenance rate
      • Do not initiate infusion if sodium bicarbonate bolus(es) fail to narrow QRS interval or improve hypotension

Nondrug and supportive care

General supportive measures include:

  • Rhabdomyolysis
    • Treat seizures and agitation with benzodiazepines
      • Excessive movement and agitation can contribute to or worsen rhabdomyolysis
    • Establish and maintain a normothermic core temperature below 38 °C 
      • Hyperthermia can contribute to development of rhabdomyolysis
    • Maintain adequate urine output with IV fluids
      • Titrate fluids to maintain a goal urine output 1 to 3 mL/kg/hour
  • Urinary retention treatment
    • Assess with bedside ultrasonography before catheterization to document retention and after catheterization to assess for postvoid residual
    • Treat with urinary catheter placement
  • Nonpharmacologic delirium management
    • Provide frequent patient orientation and explanation
    • Attempt to maintain a low stimulus environment

Avoid certain agents

  • Avoid antipsychotics (eg, phenothiazines, butyrophenones)
    • Most antipsychotics have anticholinergic properties, lower seizure threshold, and potential to worsen or precipitate hyperthermia 
  • Phenytoin is contraindicated
    • Evidence suggests that phenytoin is ineffective at terminating drug-induced seizures and may precipitate or worsen cardiovascular toxicity
  • Avoid prolonged physical restraints
    • Prolonged physical restraints may increase risk of rhabdomyolysis
  • Several antiarrhythmic medications are contraindicated in patients who have ingested tricyclic antidepressants
    • Class Ia, class Ic, and class III antiarrhythmics are contraindicated

Monitoring

  • Monitoring during and after physostigmine administration
    • Continuous cardiac monitoring
    • ECG before administration to assess for safety of administration (ie, exclude interval prolongation)
    • Observe for adverse effects of administration including:
      • Findings associated with cholinergic toxicity (eg, bronchospasm, bradycardia, emesis, miosis, diaphoresis, muscle weakness, bronchorrhea, urination, diarrhea, lacrimation, salivation, sweating)
        • Administer atropine if severe cholinergic toxicity; dose of atropine is one-half the dose of physostigmine given 
      • Findings associated with excessive nicotinic stimulation
        • Seizures
          • Generally self-limited 
          • Proconvulsant adverse effect of central nicotinic receptor stimulation 
            • Excessive nicotinic stimulation precipitates seizures and facilitates generalization of seizures from coingestants
        • Neuromuscular weakness 
      • Bradycardia and heart block are very rarely reported; asystole has occurred in individuals with massive tricyclic antidepressant ingestions
    • Observe clinically for recurrence of anticholinergic symptoms (eg, delirium, agitation)
      • Many patients require repeat dosing of physostigmine, often about 1 hour after last dose 
  • Monitoring of patients treated with benzodiazepines
    • Carefully monitor for excessive sedation and respiratory depression
  • Monitoring of patients at high risk for developing rhabdomyolysis (eg, severe agitation, seizure, hyperthermia, coma)
    • Obtain serial creatine phosphokinase and urinalysis with microscopy to monitor for occult blood (ie, positive for blood on dipstick without significant RBCs on microscopy) 
    • Monitor renal function and electrolyte levels in patients who develop findings consistent with rhabdomyolysis
    • Monitor urine output and maintain goal urine output of 1 to 3 mL/kg/hour 
    • Monitor core temperature with a rectal or bladder thermocouple 
  • Monitoring of patients who require sodium bicarbonate treatment of interval prolongation associated with sodium channel blockade
    • Monitor QRS interval with serial ECG and continuous cardiac monitoring
    • Monitor potassium
      • Hypokalemia may exacerbate QT prolongation
    • Monitor pH
      • Target pH should not exceed 7.55
  • Monitoring in emergency department after ingestion of anticholinergic substance or preparation
    • All patients not requiring admission (eg, alert with mild symptoms) require observation for at least 6 hours after ingestion 
      • Patients with absent bowel sounds or significant coingestants with delayed toxicity may require longer observation 
      • Ingestion of plant seeds require longer observation (at least 8 hours) because of delayed absorption 
    • Clinical criteria for safe discharge include:
      • Vital signs and mental status are at baseline
      • ECG is at baseline without any toxicity-related abnormalities
      • Other manifestations of toxicity are resolving
      • Psychiatric clearance and follow-up plan in place for any patient thought to have intentional ingestion
      • Social clearance for older individuals and children to ensure safety of living environment

Complications

  • Severe acute anticholinergic toxicity can be associated with the following: 
    • Hyperthermia
      • Can contribute to development of rhabdomyolysis and multiorgan dysfunction
    • Seizures
      • Can contribute to development of rhabdomyolysis
    • Coma
      • Can develop as a result of massive anticholinergic ingestion
      • More commonly develops in the setting of multiple ingestions secondary to effects of coingestants
    • Rhabdomyolysis
      • Patients at increased risk are those with agitation, seizures, and hyperthermia
      • May lead to acute renal failure, hyperkalemia, disseminated intravascular coagulation, liver failure, multiorgan failure, and potentially death
    • Arrhythmias
      • Can develop in association with electrolyte abnormalities associated with rhabdomyolysis and certain ingestions (eg, antihistamines, tricyclic antidepressants) and in individuals with underlying cardiac disorders coupled with stress of anticholinergic-related tachycardia
    • Ileus
      • As a result of direct anticholinergic toxicity leading to decreased gastrointestinal motility
    • Death
      • Can occur without adequate treatment and can occur with massive ingestion
      • Most often caused by cardiac arrhythmia and frequently associated with refractory seizures 
      • Can occur from trauma or drowning caused by anticholinergic-related perceptual distortion 
      • Can occur as a result of fatal hyperthermia, particularly in an ineffectively treated agitated or seizing patient 

Prognosis

  • Majority of patients with anticholinergic poisoning have a good outcome with supportive care
    • Poisoning from preparations with only anticholinergic effects rarely results in death if there is adequate supportive care 
    • Timeframe for symptom resolution is variable; delirium may last for days after acute ingestion 
  • Patients who develop hyperthermia are at increased risk for poor outcome
    • Severe hyperthermia (higher than 41 °C) is associated with poor outcome without aggressive treatment 
    • Critical hyperthermia (higher than 41.6 °C-42 °C) is associated with a significant increase in mortality 

Screening and Prevention

Prevention

  • Patient education is key to prevention
    • Prevent exploratory ingestion in children
      • Keep medications out of reach of children and in child-resistant containers
    • Prevent unintentional toxicity in children
      • Avoid administering cough and cold medicines to young children, especially those younger than 4 to 6 years
      • Avoid administering antihistamines to children to treat upper respiratory infections
    • Prevent toxicity in patients receiving medications with potential for anticholinergic toxicity
      • Encourage patients to strictly adhere to dosing instructions
      • Remind patients to wash hands after applying topical or ophthalmic medications, including topical patches
      • Document and review all patient medications, including prescription, OTC, and herbal preparations and supplements

References

Velez LI: Anticholinergics. In: Marx JA et al, eds: Rosen’s Emergency Medicine: Concepts and Clinical Practice. 8th ed. Elsevier; 2014:1970-74.e1

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