General Principles of Toxidromes

A toxidrome is a group of clinical signs and symptoms associated with a toxic ingestion or exposure. There are 5 traditional toxidromes: anticholinergic, cholinergic, opioid, sympathomimetic, and sedative-hypnotic. Toxidromes often arise from ingestion of overdose amounts, accumulation of medications with resultant elevated serum levels, adverse drug reactions, or interactions between 2 or more medications. Rapid recognition of a toxidrome can help determine the specific poison or class of toxin that was ingested. On presentation of a suspected toxidrome, appropriate airway, breathing, and circulation assessment is initiated. Decontamination is performed, and the patient is stabilized. Diagnosis is accomplished with clinical findings based on medication and exposure history, vital signs, mental status, and physical examination. Testing generally includes toxicology and drug levels, electrolytes, and ECG. Management consists of supportive care and antidote administration if indicated.

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Overview

Definition

A toxidrome describes a group of signs, symptoms, and/or characteristic effects associated with exposure to a particular substance or class of substances.

Epidemiology

  • In the United States:
    • By 2008, poisonings surpassed motor vehicle collisions as the leading cause of injury-related death.
    • In 2017: 
      • > 70,000 drug overdose-related deaths 
      • 68% involving opioid(s)
  • Most cases involving children < 6 years old involved non-intentional ingestion, whereas most fatalities in adults were suicidal attempts.
  • Suicidal poisoning varies by region:
    • Suicide cases are prevalent in the United Kingdom and Scandinavian nations.
    • Generally fewer cases in Eastern Europe and Central and South America

Approach to the poisoned patient

  • Initial evaluation:
    • Utilize the airway, breathing, and circulation (ABC) assessment to secure the airway and begin resuscitation of the patient.
    • Vital signs, Glasgow Coma Scale, pulse oximetry
    • ECG and continuous cardiac monitoring
    • Capillary glucose measurement
  • Additional examination:
    • Pupil size
    • Characteristic odors
    • Skin findings
    • Neuromuscular abnormalities
  • Assess for occult trauma.
  • If a toxidrome is suspected:
    • Decontamination (e.g., GI, skin, eye)
    • Utilize an antidote if needed (e.g., naloxone administration in suspected opioid toxicity can prevent intubation).
    • Patients are most commonly poisoned by oral ingestion, but other routes have to be considered:
      • Inhalation
      • Insufflation
      • Cutaneous
      • Mucous membrane exposure
      • Injection
    • Attempt to obtain information about exposure or ingestion: 
      • Check pill bottles, confirming dosing and amount left.
      • Ask about supplements and recent environmental exposure(s).
      • Check for drug-related equipment or a medical alert bracelet.
    • Utilize your local toxicology center for information.

Testing

Tests depend on the clinical situation and should not delay initiation of supportive care. These include but are not limited to:

  • Drug levels (e.g., acetaminophen, salicylates)
  • Toxicology screen: 
    • Some substances are not detected.
    • A number of substances also give false-positive results.
  • Electrolyte, renal, and hepatic panel
  • Serum osmolality, ketones, creatine kinase, lactate, lipase
  • Blood gas, co-oximetry (for carbon monoxide poisoning)
  • Pregnancy test in all women of childbearing age
  • Radiologic imaging (evaluate radiopaque toxins, drug packets, and other possible effects, including pulmonary edema)

Anticholinergic Toxicity

Etiology

  • Drugs: 
    • Antihistamines (diphenhydramine, hydroxyzine)
    • Tricyclic antidepressants (TCA) (e.g., amitriptyline)
    • Antimuscarinic for overactive bladder (oxybutynin)
    • Belladonna alkaloids (atropine, scopolamine)
    • Muscle relaxant (cyclobenzaprine)
    • Cyclopentolate (eye drops)
    • Antipsychotics (chlorpromazine, quetiapine, olanzapine)
  • Plants: 
    • Deadly nightshade or belladonna
    • Jimson weed
Atropa belladonna

Berries of Atropa belladonna

Image: “Berries of Atropa belladonna” by Intensive Care Unit, Mother and Child Hospital, University Hospital Hassan II, Fes, Morrocco. License: CC BY 2.0

Pathophysiology

  • Inhibition of muscarinic cholinergic neurotransmission → blocking acetylcholine from binding to receptors
  • Muscarinic receptors are located on:
    • Smooth muscle in the GI tract, bladder, bronchi, heart
    • Salivary glands
    • Sweat glands
    • Ciliary body of the eye
    • CNS

Clinical presentation and diagnosis

Signs and symptoms:

  • “Red as a beet”: cutaneous vasodilation
  • “Dry as a bone”: anhidrosis or inhibition of sweat glands, dry axilla and groin, dry mouth (can cause a muffled voice)
  • “Hot as a hare”: lack of sweating and ↑ stimulation causes hyperthermia
  • “Blind as a bat”: mydriasis or blurry vision due to inability to constrict pupils and accommodate (blown pupils)
  • “Mad as a hatter”: central muscarinic blockade → delirium, hallucinations, psychosis, seizures, skin picking
  • “Full as a flask”: urinary retention because detrusor muscle and urethral sphincter unable to relax
  • Other:
    • Tachycardia: earliest and most reliable sign of anticholinergic toxicity
    • Decreased or absent bowel sounds

Diagnostic approach:

Suspect in patients with above features.

Management

  • ABC assessment
  • Decontamination:
    • Poisoning usually by ingestion
    • In patients with intact mental status, administer activated charcoal (AC).
  • Supportive care: IV fluids, cooling, sedation, intubation
  • Cardiotoxicity:
    • Arrhythmias or long QT interval on ECG (e.g., TCA ingestion): Administer sodium bicarbonate or urinary alkalinization.
    • Tachycardia: supportive care, as this eventually resolves
  • Agitation and seizures: Give benzodiazepines.
  • Antidotal therapy: physostigmine 
    • Inhibits acetylcholinesterase (AChE) reversibly, thus increasing acetylcholine
    • Used in severe anticholinergic toxicity (patient is agitated and delirious)
    • 0.5–2 mg IV push slowly over 5 minutes

Cholinergic Toxicity

Etiology

  • Pesticides resulting in field workers exposed (dermal, inhalation) to sprayed chemicals
  • Organophosphates: 
    • Cause inhibition of AChE enzyme irreversibly
    • Malathion, parathion, fenthion
  • Carbamates:
    • Cause transient inhibition of AChE enzyme
    • Aldicarb, methomyl
  • Donepezil: used in Alzheimer therapy
  • Reversal of neuromuscular blockade (neostigmine, pyridostigmine, edrophonium)

Pathophysiology

  • Inhibition or binding of AChE causes ↑ levels of acetylcholine in synaptic clefts
  • Symptoms arise from areas where receptors are found:
    • Primary effect is on the RBC AChE.
    • Smooth muscle in the GI tract
    • Bronchi
    • Heart
    • Salivary and sweat glands
    • Ciliary body of the eye

Clinical presentation and diagnosis

Signs and symptoms:

  • Dominant features:
    • Miosis, lacrimation, salivation
    • Bradycardia
    • Bronchorrhea, bronchospasm
    • Urination, emesis, and diarrhea
    • Diaphoresis 
  • CNS: 
    • CNS depression or coma
    • Seizure 
    • Neuropathy
  • Cardiac toxicity (aside from bradycardia):
    • Heart blocks 
    • QT interval prolongation 
    • Myocardial ischemia

Diagnostic approach:

  • Take note of medication and occupational/exposure history.
  • Presenting symptoms
  • Some organophosphorus agents have a distinct petroleum- or garlic-like odor.

Management

  • ABC assessment
  • Decontamination:
    • Removal of clothes, irrigation or washing of exposed areas
    • AC (within an hour of ingestion)
  • Supportive care: 
    • IV fluids
    • Intubation (avoid succinylcholine because succinylcholine is metabolized by AChE)
  • Seizures: Give benzodiazepines.
  • Antidotal therapy:
    • Atropine: 
      • Binds to muscarinic receptors, temporarily blocking them and reducing cholinergic effect(s)
      • Dosing titrated to clearance of respiratory secretions and cessation of bronchoconstriction
    • Pralidoxime (2PAM): 
      • Effective in both muscarinic and nicotinic effects
      • Reactivates AChE but has a transient inhibition effect on the enzyme, so should be given in conjunction with atropine

Mnemonic

SLUDGE BBB” (muscarinic effects):

  • Salivation
  • Lacrimation (crying—key feature)
  • Urination
  • Defecation (diarrhea)
  • GI cramping (distress)
  • Emesis
  • Bronchospasm
  • Bronchorrhea
  • Bradycardia

“DUMBELS” (muscarinic effects):

  • Defecation
  • Urination
  • Miosis,
  • Bronchorrhea/Bronchospasm/Bradycardia
  • Emesis
  • Lacrimation
  • Salivation 

“MTWRF” (nicotinic effects):

  • Muscle cramps and Mydriasis
  • Tachycardia
  • Weakness/paralysis
  • Twitching
  • Fasciculations

Opioid Toxicity

Etiology

  • Natural opiate derivatives: opium, codeine, morphine
  • Semi-synthetic opiate derivatives: heroin, oxycodone, hydromorphone, hydrocodone
  • Synthetic opiate derivatives: buprenorphine, fentanyl, methadone, meperidine

Pathophysiology

  • Stimulation of 3 receptors:
    • Mu 
    • Kappa 
    • Sigma 
  • Receptors are found throughout the central and peripheral nervous system, producing multiple effects:
    • Analgesia: Nociceptive information is inhibited at multiple points in the nervous system, preventing transmission to the brain.
    • Euphoria: ↑ dopamine release from the mesolimbic system
    • Anxiolysis: noradrenergic effect in locus ceruleus

Clinical presentation and diagnosis

Features:

  • Respiratory:
    • Bradypnea (respiratory rate usually < 12/min is the best predictor of opioid toxicity)
    • Capnography: ↑ end-tidal carbon dioxide (ETCO₂) indicating respiratory depression/poor ventilation
  • Bradycardia
  • Hypotension
  • CNS depression, coma
  • Seizures (can be from meperidine, tramadol)
  • Pinpoint or constricted pupils
  • QT interval prolongation (methadone)
  • Noncardiogenic pulmonary edema (heroin)
  • Bowel obstruction or decreased bowel sounds

Diagnostic approach:

  • History, medication(s), and presenting features
  • Patients may be hiding drugs:
    • With consent, perform vaginal and/or rectal exam.
    • Imaging as indicated
  • Examine for track marks, skin infections (from injection sites).
  • Check for medication patches.
  • Immediately check glucose (hypoglycemia can present similarly).

Management

  • ABC assessment
  • Supportive measures, focusing on respiratory support
  • Naloxone (narcan):
    •  0.4 to 2 mg IV, and up to 10 mg, every 3 minutes
    • Can be given nasally, subcutaneously, or intramuscularly if IV access is delayed
    • Naloxone infusion if the patient continually needs more naloxone pushes
    • Withdrawal possible in opioid-dependent individuals
  • GI decontamination: generally not indicated, as opioid-intoxicated patients are at risk of aspiration

Related videos

Sympathomimetic

Etiology

  • Amphetamines (ephedrine)
  • Bath salts (mephedrone)
  • Cocaine
  • Ecstasy (3,4-methylenedioxy-N-methylamphetamine (MDMA))
  • α1-adrenergic agonists or decongestants (phenylephrine, phenylpropanolamine)

Pathophysiology

Sympathetic nervous stimulation by:

  • ↑ Circulating levels of catecholamines (epinephrine, norepinephrine, and dopamine) 
  • Reducing catecholamine reuptake at the preganglionic synapse
  • Some lead to serotonin release.

Clinical presentation and diagnosis

Features (signs of sympathetic excess):

  • Diaphoresis
  • Hyperthermia (can lead to rhabdomyolysis, brain injury, acidosis, and disseminated intravascular coagulation)
  • Tachycardia
  • Hypertension
  • Agitation/psychosis
  • Seizures
  • Dilated pupils (but will react to light)

Common causes of death:

  • Arrhythmia
  • Hyperthermia 
  • Intracerebral hemorrhage

Diagnosis:

  • History and clinical features
  • Injection of a substance can show skin changes (infection/cellulitis).
  • Historical details often accompanied by other substances (e.g., alcohol, cannabis)

Management

  • Initial approach:
    • ABC assessment
    • Avoid ketamine in intubation (due to dissociative effects).
    • Supportive care: IV fluids, cooling
  • Medication(s):
    • Benzodiazepines for hypertension, hyperthermia, seizures, and agitation
    • Nitroprusside or phentolamine for hypertension, especially if refractory to sedatives
    • Avoid succinylcholine (potential for hyperkalemia).
    • Avoid pure beta blockers (paradoxical ↑ BP elevation due to unopposed alpha stimulation).
    • In general, antipyretics are not effective for hyperthermia, as there is hypothalamic dysregulation.

Sedative-Hypnotic

Etiology

  • Barbiturates
  • Benzodiazepines
  • Chloral hydrate
  • Gamma-hydroxybutyrate (GHB)
  • Anticonvulsants
  • Muscle relaxants (baclofen, carisoprodol, cyclobenzaprine)

Pathophysiology

  • CNS depressants: typically ↑ gamma-aminobutyric acid (GABA) neurotransmission
  • Benzodiazepines: enhance the effect of GABA at the GABAA receptor

Clinical presentation and diagnosis

  • Effects secondary to depression of CNS, cardiovascular and respiratory centers: 
    • Hypothermia
    • Bradypnea
    • Bradycardia
    • Hypotension
    • Lethargy/coma
  • Isolated benzodiazepine overdose usually has CNS depression with stable vital signs (“coma with normal vitals”).
  • Diagnosis by history, especially medication intake

Management

  • ABC
  • Supportive care, especially respiratory support
  • Flumazenil: benzodiazepine antagonist
    • Should not be used routinely
    • Can induce seizures (from withdrawal) in chronic benzodiazepine users 
  • Dialysis (utilized in some severe poisonings such as carbamazepine)

Toxidrome Comparison

  • As patients present with possible multiple drug or substance intake, isolating the offending toxin is difficult.
  • Knowledge of the toxidromes helps determine the diagnosis and the appropriate management.
  • Signs and symptoms associated with the different toxins are generally grouped into findings in the following:
    • Vital signs
    • Eyes
    • Skin
    • Secretions
    • Mental status
Table: Toxidrome comparative chart
SympathomimeticAnticholinergicCholinergicSedative-hypnoticOpioids
Heart rate/blood pressure↑↑↑↑↓↓
Respiratory rate– or ↓↓↓
Temperature↑↑
EyesMydriasisMydriasisMiosisMiosis
Skin/secretionsDiaphoreticDryCopiously wetNormal
Mental statusAgitatedAgitatedSomnolentSomnolent-comaSomnolent-coma

Differential Diagnosis

  • Acetaminophen overdose: a major cause of overdose and liver injury. The medication is found in combination with other drugs (e.g., opioids), so overdose effects can occur concurrently with another toxidromes. Symptoms of overdose can be nonspecific in the first 24 hours (vomiting, diaphoresis, lethargy). Within 72–96 hours, evidence of hepatotoxicity (mental status changes such as confusion, abnormal liver enzymes, jaundice, bleeding) is present. N-acetylcysteine is the antidote and is given to patients with significant risk of hepatotoxicity.
  • Serotonin syndrome (serotonin toxicity): potentially life-threatening condition usually caused by use of selective serotonin reuptake inhibitors (e.g., citalopram, sertraline). Effects are from increased serotonergic activity. Most cases present within 24 hours of initiating or changing a drug. Typical features in these patients include tachycardia, hyperthermia, dilated pupils, dry mucous membranes, vomiting, diarrhea, rigidity, shivering, hyperreflexia, and myoclonus. Management involves discontinuation of the drug and supportive care.
  • Neuroleptic malignant syndrome: a medical emergency that stems from intake of antipsychotic agents. Features include dysautonomia, altered mental status, rigidity, and fever. Symptoms usually occur within 2 weeks of intake, but association with the drug is idiosyncratic. Withdrawal of medication and supportive care are part of the management.
  • Alcohol intoxication: acute intoxication generally occurs from binge drinking or intake of ≥ 5 alcoholic drinks on a single occasion. Patients can present with hypotension and tachycardia (partly from vasodilation and volume loss) accompanied by slurred speech, nystagmus, unsteady gait, memory impairment, stupor, or coma. Diagnosis is by serum alcohol level determination. Treatment is primarily supportive.

References

  1. Arnold, T, & Ryan, M. (2021) Acute amphetamine and synthetic cathinone (“bath salt”) intoxication. UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/acute-amphetamine-and-synthetic-cathinone-bath-salt-intoxication
  2. Bird, S. (2020). Organophosphate and carbamate poisoning. UpToDate. Retrieved March 12, 2021, from https://www.uptodate.com/contents/organophosphate-and-carbamate-poisoning
  3. Cunta, J. (2020). Poisoning. Emedicine. Retrieved March 24, 2021, from https://www.emedicinehealth.com/poisoning/article_em.htm
  4. Goldman, R, & Wylie, B. (2020). Occupational and environmental risks to reproduction in females: Specific exposures and impact. UpToDate. Retrieved March 10, 2021, from https://www.uptodate.com/contents/occupational-and-environmental-risks-to-reproduction-in-females-specific-exposures-and-impact
  5. Greller, H, & Gupta, A. (2021) Benzodiazepine poisoning and withdrawal. UpToDate. Retrieved June 12, 2021, from https://www.uptodate.com/contents/benzodiazepine-poisoning-and-withdrawal
  6. Katz, L. (2020). Organophosphate toxicity treatment & management. Emedicine. Retrieved March 22, 2021, from https://emedicine.medscape.com/article/167726-treatment
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