Emergency & Toxicology

Anticholinergic toxidrome: recognition and management

Clinical Overview and When to Suspect Anticholinergic Toxidrome

— Hyperthermia, anhidrosis, flushing, mydriasis with blurred vision, delirium, urinary retention

— Antihistamines (diphenhydramine, doxylamine, hydroxyzine) — most frequent in adolescent intentional ingestions

— TCAs (amitriptyline, nortriptyline) — anticholinergic + Na-channel + α-blockade

— Antipsychotics (olanzapine, quetiapine, low-potency typicals like chlorpromazine)

— Antiparkinsonian agents (benztropine, trihexyphenidyl)

— Antispasmodics (oxybutynin, dicyclomine, hyoscyamine), scopolamine patches

— Plants: Datura stramonium (jimsonweed), Atropa belladonna, Brugmansia (angel's trumpet)

— Cyclobenzaprine, atropine, ipratropium overdoses

— Adolescent or young adult with agitated delirium after OTC sleep aid or "robotripping"-style polypharmacy

— Elderly patient on multiple drugs with new confusion (Beers list culprits)

— Recreational ingestion of jimsonweed seeds/tea

— Sleep-aid or motion-sickness patch overuse in pediatrics

Board pearl: The single most discriminating feature separating anticholinergic from sympathomimetic toxidrome is dry skin and mucous membranes. Both produce mydriasis, tachycardia, hyperthermia, and agitation — but sympathomimetics are diaphoretic, anticholinergics are bone-dry. If the axilla is dry, think anticholinergic.

Definition: Syndrome from antagonism of muscarinic acetylcholine receptors (central and peripheral), producing a recognizable constellation: "hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter, full as a flask"

Common culprits to suspect in the ED:

High-suspicion clinical scenarios:

Why it matters on Step 3: Recognizing the toxidrome saves the workup — diagnosis is clinical, not laboratory-based, and early physostigmine in pure cases can reverse delirium and avoid unnecessary intubation, CT, and LP

Presentation Patterns and Key History

— Onset 30–60 min after ingestion (oral); delayed and prolonged with diphenhydramine and TCAs due to slowed GI motility and large volumes of distribution

— Symptoms may persist 24–72 hours, especially with long-acting agents or transdermal scopolamine

— Exact product, dose, time, co-ingestants (alcohol, opioids, acetaminophen — always check APAP level)

— OTC products: "PM" formulations, motion-sickness, sleep aids, cold preparations

— Herbal/recreational: jimsonweed tea, "deliriant" trips, datura seeds

— Psychiatric history and access to TCAs or antipsychotics

— Pediatric exposure: grandparent's pillbox, transdermal patch ingestion or chewing

— Mumbling, picking at clothes or air ("woolgathering"), grabbing at unseen objects

— Severe thirst with inability to swallow (dry mouth)

— Inability to urinate, abdominal distension

— Visual blurring, photophobia, "can't read my phone"

— Frank visual or tactile hallucinations, often non-threatening Lilliputian figures

— TCA ingestion → seizures, wide QRS, hypotension within 2 hours

— Massive diphenhydramine (>7.5 g) → Na-channel blockade mimicking TCA

— Co-ingestion with anticholinergic + serotonergic agent → overlapping pictures

— Hyperthermia >40°C, rigidity → consider concurrent NMS or serotonin syndrome

Step 3 management: In any undifferentiated agitated delirium, bedside fingerstick glucose, core temp, EKG, and a focused medication reconciliation are the first four actions before committing to a head CT or LP — they often clinch an anticholinergic diagnosis and redirect care.

Classic temporal course:

History elements to elicit (often from family/EMS — patient is delirious):

Symptom patterns patients/families report:

Red-flag history pointing to severe toxicity:

Pediatric pitfall: Toddlers exposed to scopolamine patches or eye drops can present with isolated fixed dilated pupil and altered mental status, mimicking herniation — always ask about patches on the caregiver

Physical Exam Findings and Hemodynamic Assessment

— Tachycardia (sinus, often 110–140) — the most consistent finding; absence argues against the diagnosis

— Hyperthermia from impaired sweating; can reach 40–41°C, especially with exertion or restraints

— Hypertension mild; severe hypotension suggests TCA (α-blockade) or coingestant

— Tachypnea from agitation or acidosis (TCA)

— Mydriasis, sluggishly reactive; blurred vision from cycloplegia

— Dry mucous membranes, dry tongue, hoarse voice

— Flushed facial skin ("atropine flush") from cutaneous vasodilation compensating for impaired sweat-based heat loss

— Agitated delirium with mumbling speech, picking at clothes, conversing with absent persons

— Myoclonus, tremor, choreoathetoid movements

— Seizures (especially diphenhydramine, TCA, antipsychotics)

— Coma in severe cases; no focal deficits — focality should redirect workup

— Regular tachycardia

— Listen for normal S1/S2 — new murmurs suggest alternative

— EKG is part of the exam in suspected toxidrome: QRS >100 ms or QTc prolongation flags sodium-channel or potassium-channel blockade

— Anticholinergic: dry, flushed, mydriasis, hyperthermia, normal/↑BP, ileus, urinary retention

— Sympathomimetic: diaphoretic, mydriasis, hyperthermia, ↑BP, hyperactive bowels

— Cholinergic (organophosphate): SLUDGE/DUMBELS, miosis, wet

— Opioid: miosis, bradypnea, hyporeflexia

— Sedative-hypnotic: normal pupils, hypotonia, depressed respirations

Key distinction: A patient with "agitated delirium and tachycardia" who is diaphoretic is sympathomimetic until proven otherwise; bone-dry is anticholinergic. This single physical finding redirects the antidote pathway (benzodiazepines vs. physostigmine consideration).

Vital signs:

HEENT:

Skin: Dry axillae and palms — the pathognomonic exam maneuver

Abdomen: Distended bladder (palpable), decreased/absent bowel sounds, ileus

Neuro/psych:

Cardiac exam and EKG-driven assessment:

Bedside differentiation grid:

Diagnostic Workup — Initial Labs, Imaging, ECG

— Fingerstick glucose at bedside (rule out hypoglycemia masquerading as delirium)

— Acetaminophen and salicylate levels — mandatory in any intentional ingestion, even when story doesn't include them

— Ethanol level

— Basic metabolic panel — anion gap, K⁺, renal function

— CK — rhabdomyolysis from agitation/hyperthermia/restraints

— Lactate — elevated with seizures or shock

— Urine pregnancy test in women of reproductive age

— Urinalysis — concentrated urine from retention; myoglobinuria

— VBG — acid-base status; metabolic acidosis with TCA

— QRS >100 ms → consider Na-channel blockade (TCA, massive diphenhydramine) → sodium bicarbonate 1–2 mEq/kg bolus

— Terminal R wave in aVR >3 mm or R/S ratio in aVR >0.7 → TCA toxicity

— QTc prolongation → torsades risk; correct K⁺/Mg²⁺

— Sinus tachycardia is expected; new arrhythmias suggest severe toxicity

— Head CT if focal deficits, trauma, persistent coma without clear toxidrome, or failure to improve

— CXR if aspiration suspected (vomiting, decreased consciousness)

— Bladder ultrasound to confirm retention before catheterization

— Will not detect diphenhydramine, TCAs reliably (some immunoassays cross-react), datura, scopolamine

— TCA immunoassay can be falsely positive (carbamazepine, cyclobenzaprine, diphenhydramine, quetiapine) and falsely negative; treat based on EKG and clinical findings, not the screen

Board pearl: A wide-QRS tachycardia in an agitated delirious patient = TCA or diphenhydramine toxicity until proven otherwise. Give sodium bicarbonate before chasing other diagnoses; do not give physostigmine when QRS is wide — it can precipitate asystole.

The diagnosis is clinical — labs serve to identify coingestants, complications, and mimics, not to "confirm" the toxidrome

Universal initial workup in suspected overdose:

EKG — obtain immediately and repeat:

Imaging:

Urine drug screen — low yield:

Diagnostic Workup — Advanced or Confirmatory Studies

— TCA levels are not real-time actionable; treatment is based on EKG and exam

— Digoxin, lithium, valproate, phenytoin, carbamazepine levels if those coingestants suspected

— Acetaminophen at 4 hours post-ingestion to plot on Rumack-Matthew nomogram (mandatory)

— Reserve for patients with fever and altered mental status when toxidrome is unclear or fails to improve with supportive care

— Anticholinergic delirium should resolve as drug clears; persistent CNS dysfunction → reconsider encephalitis, meningitis, NCSE

— Consider non-convulsive status epilepticus in patient who fails to improve or has subtle twitching

— TCA, diphenhydramine, and bupropion overdoses are well-documented seizure triggers

— Indicated when hypotension persists despite fluids — assess for cardiogenic shock from TCA-induced myocardial depression or coingestant (e.g., beta-blocker, CCB)

— Confirm urinary retention (>300 mL) to justify Foley placement and explain agitation

— Assess gastric distension; bedside US can identify pill bezoars rarely

— In selected patients with pure anticholinergic delirium, normal QRS, no TCA, and no asthma/bowel obstruction/heart block, a small dose of physostigmine 1–2 mg IV over 5 min can be both diagnostic and therapeutic

— Rapid resolution of delirium (within minutes) confirms the toxidrome and avoids further workup (CT, LP)

Step 3 management: Persistent delirium >24 hours despite supportive care should trigger reassessment — order head CT, LP, EEG, repeat tox panel, and consult toxicology. Don't anchor on the initial diagnosis when the trajectory is wrong.

Targeted serum drug levels (when available and clinically relevant):

Cerebrospinal fluid (LP):

EEG:

Echocardiography:

Bladder scan / point-of-care ultrasound:

Diagnostic challenge — physostigmine trial:

Coingestant screening philosophy: Always assume polypharmacy in intentional overdose; check APAP, salicylate, ethanol, EKG as the non-negotiable quartet

Risk Stratification and First-Line Management Logic

— Airway: Intubate if GCS <8, inability to protect airway, severe hyperthermia requiring paralysis for cooling, or seizures

— Breathing: Supplemental O₂, monitor for aspiration

— Circulation: Two large-bore IVs, continuous cardiac monitoring, IV crystalloid

— Low risk: Isolated diphenhydramine <1 g, normal EKG, mild agitation → observe 6 hours

— Moderate risk: Agitated delirium, hyperthermia <39°C, normal QRS → supportive ± physostigmine

— High risk: TCA ingestion, QRS >100 ms, seizures, dysrhythmia, hyperthermia >39.5°C, hemodynamic instability → ICU, sodium bicarbonate, aggressive cooling

— Activated charcoal 1 g/kg within 1–2 hours of ingestion if airway protected and no contraindication

— Anticholinergic drugs delay gastric emptying → window for charcoal may be extended (consider up to 4 hours for massive ingestions), individualized with toxicology input

— No gastric lavage routinely; no ipecac

— Multi-dose charcoal not standard for this class

— Agitation: Benzodiazepines (lorazepam 1–2 mg IV, midazolam 2–5 mg IV) — first-line for safety, can be escalated; avoid antipsychotics (anticholinergic, lower seizure threshold, QT)

— Hyperthermia: Active external cooling (evaporative, ice packs to groin/axilla, cooled IVF) targeting <39°C; antipyretics don't work (no fever set-point change)

— Seizures: Benzodiazepines first; phenobarbital second; avoid phenytoin (Na-channel blockade additive in TCA)

— Urinary retention: Foley catheter

— Wide QRS: Sodium bicarbonate

CCS pearl: Order set for suspected anticholinergic overdose — continuous cardiac monitor, IV access ×2, NS bolus, EKG, fingerstick glucose, APAP/salicylate/ethanol levels, BMP, CK, UA, hCG, activated charcoal (if appropriate), lorazepam PRN agitation, Foley catheter, toxicology consult. Reassess every 2 hours.

ABCs and decontamination first:

Risk stratification by ingestion:

GI decontamination:

Symptom-targeted control:

Pharmacotherapy — First-Line Drug Regimen

— Lorazepam 1–2 mg IV q10–15 min titrated to calm, arousable state

— Midazolam 2–5 mg IV for rapid onset; diazepam 5–10 mg IV for longer duration

— Targets agitation, hyperthermia (by reducing motor activity), and seizures

— No ceiling — escalate aggressively before reaching for sedating adjuncts

— Indications: QRS >100 ms, ventricular dysrhythmia, hypotension from TCA or massive diphenhydramine

— Dose: 1–2 mEq/kg IV bolus, repeat until QRS narrows; follow with infusion (150 mEq in D5W 1 L at 250 mL/h)

— Goal serum pH 7.50–7.55; monitor K⁺ (hypokalemia common)

— Tertiary amine carbamate that crosses BBB, reversibly inhibits acetylcholinesterase

— Indications: Severe agitated delirium or peripheral toxicity from a pure anticholinergic agent (antihistamine, scopolamine, datura, atropine) when benzodiazepines fail or to avoid intubation

— Dose: 1–2 mg IV over 5 minutes, may repeat once in 10–20 min

— Contraindications (absolute): TCA ingestion, QRS >100 ms, AV block, asthma/COPD active bronchospasm, bowel/bladder obstruction, peripheral vascular disease

— Have atropine at bedside (half the physostigmine dose) for cholinergic crisis

— Effects last 30–60 min; delirium may recur — re-dose or transition to supportive care

— Crystalloid 10–20 mL/kg bolus for hypotension; reassess

— Persistent hypotension after Na-bicarb in TCA → norepinephrine (direct α-agonist preferred over dopamine)

— Antipsychotics (haloperidol, droperidol) — anticholinergic, QT, seizure-lowering, impair thermoregulation

— Physostigmine in TCA — bradyasystole risk

— Flumazenil — never in mixed overdose; can precipitate seizures

Board pearl: Physostigmine outperforms benzodiazepines in restoring normal mentation and reducing intubations in pure anticholinergic delirium — but the magic phrase to memorize is "normal QRS, no TCA" before you order it.

Benzodiazepines — the universal first-line:

Sodium bicarbonate — for sodium-channel blockade:

Physostigmine — the antidote (selected cases):

IV fluids:

Avoid:

Expanded Pharmacology and Specific Agents

— Onset 3–8 min IV, peak 5 min, duration 30–60 min

— Adverse effects: bradycardia, bronchospasm, salivation, lacrimation, diarrhea, seizures (rapid push), vomiting

— Push slowly over 5 min to minimize cholinergic surge

— Reversal: atropine 0.5–1 mg IV if cholinergic toxicity emerges

— Pregnancy category C — generally considered safe when clearly indicated

— Consider in refractory cardiovascular collapse from lipophilic anticholinergics (TCA, diphenhydramine) failing bicarb and pressors

— Dose: 1.5 mL/kg bolus, then 0.25 mL/kg/min infusion

— Toxicology consult before use

— Lidocaine is the preferred antiarrhythmic for refractory ventricular dysrhythmias (class IB, dissociates rapidly from Na channels)

— Avoid class IA (procainamide, quinidine), IC (flecainide), III (amiodarone has Na-channel effects) — worsen blockade

— Norepinephrine first-line for TCA-related hypotension (direct α-agonist counters α-blockade)

— Avoid dopamine (depletes catecholamines, indirect action blunted)

— Diphenhydramine massive OD: Na-channel blockade, seizures, rhabdo — treat like TCA

— Quetiapine: Profound sedation, tachycardia, hypotension, mild QTc; usually doesn't need physostigmine

— Jimsonweed: Prolonged delirium 24–48 h from slowly absorbed alkaloids (atropine, scopolamine, hyoscyamine)

Step 3 management: In TCA overdose with seizures and wide QRS: benzodiazepine, sodium bicarbonate bolus + infusion, intubation if needed, norepinephrine for hypotension, lidocaine for ventricular dysrhythmia, lipid emulsion if refractory — and do NOT give physostigmine.

Physostigmine — practical pharmacology:

Why not neostigmine? Quaternary amine — doesn't cross BBB; useful only for peripheral effects (e.g., ileus) and not delirium

Sodium bicarbonate mechanism: Increases extracellular Na⁺ (overcomes channel blockade) and alkalinization decreases drug binding to fast Na channels; both effects narrow QRS

Lipid emulsion therapy (Intralipid 20%):

Hypertonic saline: Adjunct or alternative to bicarbonate when sodium overload becomes problematic

Antiarrhythmic choices in TCA toxicity:

Vasopressors:

Specific agents — pearls:

Special Populations — Elderly and Renal/Hepatic Impairment

— Reduced cholinergic reserve and baseline cognitive impairment amplify central effects

— Beers Criteria flags first-generation antihistamines, TCAs, oxybutynin, benztropine, antispasmodics, scopolamine, and many antipsychotics as potentially inappropriate

— Polypharmacy anticholinergic burden (ACB score ≥3) is associated with delirium, falls, dementia progression, and mortality

— Often present as isolated delirium without dramatic peripheral signs (atrophic skin masks flushing, baseline xerostomia)

— Misdiagnosed as UTI, dementia exacerbation, or stroke

— Tachycardia may be blunted by beta-blocker use

— Urinary retention can precipitate acute kidney injury

— Diphenhydramine for sleep in hospitalized patients (avoid)

— Oxybutynin for urge incontinence → switch to mirabegron (β3 agonist, non-anticholinergic) or selective M3 agents (darifenacin, solifenacin — less CNS penetration)

— Promethazine for nausea, dimenhydrinate for vertigo

— Combination cold preparations

— Many anticholinergic drugs and metabolites accumulate in CKD (e.g., cetirizine, ranitidine historically, oxybutynin metabolite)

— Reduce dosing, monitor for prolonged effects

— Hemodialysis is not effective for most lipophilic anticholinergics (large Vd, high protein binding) — exception: lithium and salicylate coingestants

— TCAs, antipsychotics, diphenhydramine all undergo hepatic metabolism (CYP2D6, CYP3A4)

— Duration of toxicity prolonged; titrate antidotes cautiously

— Watch for hypoglycemia, coagulopathy with severe liver disease compounding presentation

Step 3 management: For any older adult with new delirium, perform a medication review for anticholinergic burden as part of the workup — discontinue offending agents, treat retention/constipation, and arrange follow-up to consolidate the medication list (deprescribing visit within 1–2 weeks of discharge).

The elderly are uniquely vulnerable:

Clinical presentation differences in elderly:

Common iatrogenic triggers in older adults:

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, and Psychiatric

— Anticholinergic overdose in pregnancy treated the same way as non-pregnant patients — maternal stabilization is fetal stabilization

— Physostigmine category C — use when indicated for severe toxicity; benefits outweigh theoretical risks

— Sodium bicarbonate safe and indicated for wide-QRS TCA toxicity

— Fetal monitoring after 24 weeks; OB consultation

— Activated charcoal safe; lavage avoided

— Postpartum: screen for depression/suicidality given intentional overdose context

— Toddlers ingest diphenhydramine, jimsonweed seeds, scopolamine patches, ophthalmic mydriatics; adolescents abuse for hallucinogenic effects

— Pediatric presentation: hyperthermia, mydriasis, seizures, hallucinations; fixed dilated pupil from ocular agent contamination can mimic herniation

— Physostigmine pediatric dose: 0.02 mg/kg IV (max 0.5 mg) over 5 min, may repeat

— Benzodiazepines: lorazepam 0.05–0.1 mg/kg IV

— Sodium bicarbonate: 1–2 mEq/kg as in adults

— Aggressive cooling — children develop hyperthermia faster

— Mandatory child protective services involvement for accessibility/neglect concerns; suicide screening in adolescents

— Intentional ingestions require medical clearance first, then psychiatric evaluation before discharge

— Document suicide risk assessment, means restriction counseling, lethal means counseling for caregivers

— TCA prescribing in suicidal patients = high lethality (low therapeutic index); transition to safer alternatives (SSRI, SNRI) at follow-up

— Avoid co-prescribing multiple anticholinergic drugs in psychiatric patients on antipsychotics

Board pearl: A toddler with isolated unilateral fixed dilated pupil and otherwise normal exam — think topical anticholinergic contamination (scopolamine patch, eye drops, plant sap rubbed in eye) before ordering head CT for herniation.

Pregnancy:

Pediatrics:

Psychiatric patients:

Recreational deliriant ingestion (jimsonweed/datura) often in adolescents — counsel on toxicity, persistent visual symptoms 24–48 h, and risk of repeat use

Complications and Adverse Outcomes

— Core temp >40°C → rhabdomyolysis, AKI, DIC, hepatic injury, multi-organ failure

— Cooling must be aggressive and early; mortality rises with duration of hyperthermia

— From agitation, restraints, hyperthermia, seizures

— Monitor CK serially; aggressive IV crystalloid to maintain UOP 1–2 mL/kg/h

— Watch for hyperkalemia, hyperphosphatemia, hypocalcemia

— Diphenhydramine, TCA, bupropion (often coingested), antihistamines in massive dose

— Status epilepticus risk; benzodiazepines first-line

— Non-convulsive status if delirium fails to clear → EEG

— Wide-complex tachycardia, ventricular fibrillation, asystole (TCA, massive diphenhydramine)

— Hypotension from α-blockade and myocardial depression

— Torsades from QTc prolongation (especially with concurrent hypokalemia, hypomagnesemia)

— Decreased LOC + vomiting; ileus increases volume of gastric contents available to aspirate

— CXR, supportive care, antibiotics only if superimposed bacterial pneumonia develops

— Physostigmine-induced cholinergic crisis: bradycardia, bronchospasm, seizures (especially if given in TCA toxicity)

— Antipsychotics given for agitation worsening anticholinergic burden, QT

— Restraint-related injury

— Persistent cognitive impairment in elderly after delirium episode (months)

— Psychological sequelae after frightening hallucinations, especially adolescents after datura

Key distinction: Anticholinergic hyperthermia has no fever set-point change — antipyretics (acetaminophen) are useless; physical cooling and treating the toxidrome is the only effective intervention. Compare to infection, where antipyretics work because the hypothalamic set-point is elevated.

Hyperthermia and end-organ injury:

Rhabdomyolysis:

Seizures:

Cardiovascular complications:

Aspiration pneumonitis:

Acute urinary retention → bladder injury, AKI: Decompress with Foley

Bowel ischemia / perforation: Rare; severe ileus with prolonged distension

Anoxic brain injury: From prolonged seizures, hyperthermia, or cardiac arrest

Compartment syndrome: From prolonged immobility, restraints, or rhabdomyolysis

Iatrogenic complications:

Long-term sequelae:

When to Escalate Care — ICU, Consult, Inpatient Triage

— Hemodynamic instability, vasopressor requirement

— Wide QRS, dysrhythmia, persistent EKG abnormalities

— Seizures or status epilepticus

— Core temp >39.5°C or requiring active cooling

— Intubation for airway protection

— Continuous physostigmine re-dosing requirement

— Severe agitation requiring high-dose sedation

— TCA ingestion of significant amount, regardless of initial presentation (delayed deterioration risk)

— Persistent tachycardia or mild EKG changes

— Moderate delirium requiring monitoring

— Significant ingestion with potential for delayed peak (e.g., extended-release formulations, large diphenhydramine OD)

— Resolving toxidrome but unable to tolerate POs, persistent retention, ongoing observation needs

— Psychiatric hold pending bed availability

— Asymptomatic after small ingestion, normal EKG, normal exam, accidental

— Adolescent recreational with full resolution and reliable disposition

— Medical toxicology / Poison Control (1-800-222-1222) — call early for any non-trivial ingestion

— Cardiology for refractory dysrhythmia or wide QRS

— Psychiatry for all intentional ingestions before discharge

— Social work for pediatric exposures, polypharmacy elderly, psychiatric patients

— Pharmacy for medication reconciliation in elderly delirium

— Hospitals without toxicology, ICU, or pediatric capability should stabilize and transfer

— Stabilize airway, give bicarbonate if indicated, start vasopressors, then transfer

CCS pearl: Disposition decisions in toxidromes hinge on trajectory over 4–6 hours of observation, not the initial presentation. Order serial EKGs every 2 h, vital signs every 30 min initially, neuro checks every hour. Document medical clearance before psychiatric handoff in intentional ingestions.

ICU admission criteria:

Step-down / telemetry admission:

Floor admission:

ED observation (6–8 h) and discharge:

Consultations:

Transfer considerations:

Key Differentials — Other Toxidromes

— Cocaine, methamphetamine, MDMA, synthetic cathinones, pseudoephedrine

— Shares: mydriasis, tachycardia, hypertension, hyperthermia, agitation

— Distinguishes: diaphoresis, hyperactive bowel sounds, normal-to-moist mucous membranes

— Management diverges: benzodiazepines yes; physostigmine contraindicated

— SSRIs, SNRIs, MAOIs, tramadol, linezolid, triptans, dextromethorphan, MDMA

— Shares: hyperthermia, altered mentation, tachycardia

— Distinguishes: clonus (especially lower extremity), hyperreflexia, diaphoresis, GI hyperactivity

— Management: cyproheptadine, cooling, benzodiazepines

— Antipsychotic exposure (typical > atypical); dopamine antagonism

— Distinguishes: "lead-pipe" rigidity, bradykinesia, autonomic instability, very elevated CK, slow onset over days

— Management: dantrolene, bromocriptine, withdraw offending drug

— Volatile anesthetics, succinylcholine; genetic predisposition

— Rigidity, hypercarbia, hyperthermia intraoperatively → dantrolene

— Organophosphates, carbamates, nerve agents

— Opposite picture: SLUDGE (salivation, lacrimation, urination, defecation, GI cramping, emesis), DUMBELS, miosis, bronchorrhea, bradycardia

— Treatment: atropine, pralidoxime

— Benzodiazepines, barbiturates, alcohol, GHB

— Hyporeflexia, normal/small pupils, respiratory depression — opposite mental state

— Miosis, bradypnea, hyporeflexia, CNS depression — naloxone reverses

— LSD, psilocybin, ketamine — hallucinations with insight, sympathomimetic features, no anticholinergic peripheral signs

Key distinction: The axilla check is the single fastest toxidrome triage. Dry + agitated = anticholinergic. Wet + agitated = sympathomimetic or serotonergic. Wet + miotic + bradypneic = cholinergic. Dry + miotic + bradypneic = opioid.

Sympathomimetic toxidrome:

Serotonin syndrome:

Neuroleptic malignant syndrome:

Malignant hyperthermia:

Cholinergic toxidrome:

Sedative-hypnotic toxidrome:

Opioid toxidrome:

Hallucinogen toxidrome:

Key Differentials — Non-Toxicologic Causes

— Sepsis with delirium — fever, leukocytosis, hypotension, identifiable source; lactate elevated, procalcitonin may help

— Meningitis/encephalitis — headache, photophobia, neck stiffness; LP if persistent or unclear

— HSV encephalitis — temporal lobe focality on imaging, CSF lymphocytic pleocytosis

— UTI in elderly — common precipitant of delirium without classic anticholinergic exam

— Hypoglycemia — fingerstick glucose at bedside; classic mimic

— Hyperthyroid storm — tachycardia, hyperthermia, tremor, GI hyperactivity, weight loss, goiter, diaphoresis

— DKA — Kussmaul respirations, fruity breath, dehydration, hyperglycemia, anion gap acidosis

— Hyponatremia, hypernatremia, uremia, hepatic encephalopathy — labs distinguish

— Wernicke encephalopathy — ophthalmoplegia, ataxia, confusion in malnourished/alcoholic

— Status epilepticus / postictal state — EEG

— Stroke with agitation — focal deficits, CT/MRI

— Subarachnoid hemorrhage — thunderclap headache, meningismus

— Autoimmune encephalitis (anti-NMDA receptor) — young woman, psychiatric features, dyskinesias, autonomic instability, may mimic anticholinergic delirium for days

— Alcohol/benzodiazepine withdrawal — diaphoresis, tremor, seizures, hallucinations (often visual), tachycardia, hypertension; diaphoretic differentiates

— Delirium tremens 48–96 h after last drink

— Heat stroke (exertional or non-exertional) — context, diaphoresis often impaired in classic heat stroke, similar to anticholinergic; differentiated by exposure history

— Acute psychosis, mania — usually no autonomic instability or pupillary findings

Step 3 management: When the toxidrome doesn't fit cleanly, expand the workup: head CT, LP, EEG, ammonia, TSH, B12/thiamine, urine for autoimmune panels in young patients with prolonged delirium. Don't anchor; reassess at 4 and 12 hours.

Infectious:

Metabolic/endocrine:

Neurologic:

Withdrawal syndromes:

Environmental:

Psychiatric:

Secondary Prevention, Discharge Planning, Long-Term Plan

— Resolution of toxidrome with stable vitals ≥6 h

— Normal EKG (or return to baseline)

— Tolerating PO, voiding spontaneously

— Cleared by psychiatry if intentional

— Reliable disposition and follow-up

— Identify and discontinue contributory anticholinergic medications

— Calculate Anticholinergic Burden (ACB) score in elderly; target reduction

— Substitute lower-risk alternatives:

— Diphenhydramine for sleep → trazodone, melatonin, sleep hygiene

— Oxybutynin for OAB → mirabegron, behavioral therapy

— TCAs for depression → SSRI/SNRI

— Hydroxyzine for anxiety → buspirone, SSRI, CBT

— Promethazine for nausea → ondansetron

— Read OTC labels; avoid "PM" combinations

— Avoid combining sleep aids with alcohol, opioids, benzodiazepines

— Safe storage in homes with children, adolescents, cognitively impaired adults

— Adolescents: explicit counseling on jimsonweed/diphenhydramine abuse risks

— Lethal means restriction — remove TCAs, large pill stockpiles; lock medications

— Establish outpatient psychiatric follow-up within 7 days of discharge (joint commission/zero suicide framework)

— Safety plan documented; 988 Suicide & Crisis Lifeline; warm handoff when possible

— Consider switching from TCA to safer antidepressant

— Poison Control number visible in home

— Childproof caps, locked cabinets, patch disposal counseling

— Schedule deprescribing visit with PCP within 1–2 weeks

— Update problem list, medication list, communicate to pharmacy

— Consider Medicare Annual Wellness Visit, comprehensive medication review

Board pearl: Step 3 commonly tests deprescribing: an elderly patient with delirium on oxybutynin, diphenhydramine, and amitriptyline — the next best step is discontinuing the anticholinergic burden, not adding a new medication.

Discharge criteria after anticholinergic toxicity:

Medication reconciliation — the single highest-yield discharge intervention:

Patient and caregiver counseling:

Secondary prevention for intentional ingestions:

For accidental pediatric exposures:

Polypharmacy elderly:

Follow-Up, Monitoring Parameters, Rehab and Counseling

— Intentional ingestion: Psychiatry within 7 days; PCP within 1–2 weeks

— Accidental elderly delirium: PCP within 1 week for medication review; cognitive reassessment at 4–6 weeks (delirium can unmask dementia)

— Pediatric accidental exposure: Pediatrician within 1–2 weeks; safety/social work check

— Adolescent recreational: PCP and behavioral health within 1–2 weeks

— EKG follow-up if QTc prolongation occurred — repeat in 1–2 weeks, especially if remaining on QT-prolonging medications

— Renal function if rhabdomyolysis occurred (BMP at 1 week)

— Cognitive assessment in elderly (MoCA) at 4–6 weeks

— Liver function if hepatotoxicity from coingested APAP

— Post-ICU syndrome counseling for prolonged ICU stays

— Physical therapy if rhabdomyolysis with significant deconditioning

— Cognitive rehab for persistent post-delirium cognitive impairment in elderly

— Adolescents: substance use counseling, motivational interviewing, school-based resources, harm reduction

— Elderly/caregivers: Beers list education, recognizing medication side effects, pill organizer use, single-pharmacy practice

— Mental health patients: medication adherence with safer agents, recognition of overdose risk, means restriction conversation with family

— Warning signs and triggers

— Internal coping strategies

— Social contacts for distraction

— Professional resources (therapist, crisis line)

— Lethal means restriction

— 30-day readmission for overdose is a tracked metric

— Suicide prevention follow-up rate within 7 days (CMS, JCAHO)

— Comprehensive medication review for elderly

Step 3 management: After medical clearance of an intentional anticholinergic overdose, the next best step before discharge is documenting psychiatric evaluation, safety planning, lethal means restriction, and a confirmed outpatient follow-up appointment within 7 days — not simply discharging "after medical stability."

Timeline of follow-up after discharge:

Monitoring parameters after discharge:

Rehabilitation considerations:

Counseling content:

Documented safety plan elements (intentional overdoses):

Quality measures:

Ethical, Legal, and Patient Safety Considerations

— Patients refusing care while still intoxicated lack capacity — hold under emergency exception, restraint only if necessary for safety

— Reassess capacity once toxicity clears

— Document capacity assessment clearly (understanding, appreciation, reasoning, expression of choice)

— Involuntary psychiatric hold (state-dependent — e.g., 5150 in CA, "9-hour hold" elsewhere) for suicidal patients refusing voluntary admission

— Activated charcoal in an awake but borderline-encephalopathic patient: if patient refuses and has capacity, do not force; if no capacity and risk justifies, proceed under emergency doctrine — document

— Physostigmine: explain risks (cholinergic crisis, seizures) — but in severe delirium, surrogate or implied consent applies

— Pediatric exposures suggesting neglect or improper storage → CPS report

— Elder abuse/neglect (caregiver-administered overdose, polypharmacy mismanagement) → Adult Protective Services

— Suspected intentional harm by another → law enforcement

— Boarding psychiatric patients in the ED — continue medical monitoring, EKG, vitals; do not assume "medically cleared" means "no further monitoring needed"

— Handoff to inpatient psychiatry: written and verbal handoff of medications, EKG, allergies, social history, suicide risk

— Discharge prescriptions: avoid large quantities of any single agent; limit TCA scripts to 1-week supply for suicidal patients

— Adolescent intentional overdose: most states require parental notification for safety; balance with adolescent confidentiality preferences for follow-up substance use treatment (state-specific consent laws)

— Hospital formulary review: minimize diphenhydramine PRN orders for hospitalized older adults (delirium prevention bundle)

— Pharmacy alerts for anticholinergic burden in elderly

— Root cause analysis for inpatient medication-induced delirium

Board pearl: A suicidal patient who regains capacity during ED stay and demands to leave still requires psychiatric evaluation before discharge — high-risk patients can be held under state law on the basis of imminent danger to self even with intact capacity at the moment of evaluation.

Capacity assessment in intentional overdose:

Informed consent edge case:

Mandatory reporting:

Transition-of-care safety:

Confidentiality:

Patient safety / systems:

High-Yield Associations and Rapid-Fire Clinical Facts

Key distinction: Don't confuse "antimuscarinic" overdose treatment (physostigmine) with "anticholinesterase poisoning" treatment (atropine + pralidoxime) — they are mechanistic opposites.

Mnemonic: "Hot, dry, red, blind, mad, full" — hyperthermia, anhidrosis, flushing, mydriasis, delirium, retention/ileus

Pathognomonic exam: Dry axilla in agitated tachycardic delirious patient

TCA EKG triad: Sinus tachycardia, QRS widening >100 ms, terminal R wave in aVR >3 mm

Jimsonweed = Datura stramonium = atropine, hyoscyamine, scopolamine; "gardener's mydriasis" from touching plant and rubbing eyes

"Mad as a hatter" historically refers to mercury, not anticholinergic — but mnemonic stuck

Physostigmine "no-go" criteria: TCA, wide QRS, AV block, asthma, bowel/bladder obstruction

Atropine = tertiary amine, crosses BBB → causes anticholinergic delirium

Glycopyrrolate = quaternary amine, does NOT cross BBB → preferred when CNS effects undesirable (e.g., preoperative drying)

Scopolamine patch = transdermal, prolonged release, common in toddlers and post-op nausea; prolonged toxidrome

Diphenhydramine massive OD behaves like TCA (Na-channel blockade) → wide QRS, seizures

Antimuscarinic ≠ antinicotinic — toxidrome is muscarinic; nicotinic agents (e.g., succinylcholine) don't produce this syndrome

Heat stroke and anticholinergic toxicity share impaired sweating — combined exertion + anticholinergic = lethal hyperthermia

First-line antiarrhythmic for TCA VT: lidocaine; avoid IA, IC, III

Sodium bicarbonate target pH 7.50–7.55

Norepinephrine preferred over dopamine for TCA hypotension

Beers Criteria drugs to avoid in elderly: diphenhydramine, oxybutynin, TCAs, benztropine, hyoscyamine

ACB score ≥3 = high anticholinergic burden, increased delirium and dementia risk

Mirabegron = β3 agonist alternative to anticholinergic OAB agents

Cyproheptadine = antidote for serotonin syndrome (also has anticholinergic properties — sedating)

Carbamate (physostigmine, neostigmine) vs organophosphate anticholinesterases: carbamates reversible, OPs irreversible (need pralidoxime)

Board Question Stem Patterns

— 17-year-old after argument, found agitated, mumbling, dry mouth, dilated pupils, T 38.9°C, HR 130, BP 140/90, dry axillae, distended bladder, EKG sinus tach with QRS 92 ms

— Next steps: IV access, EKG, glucose, APAP/salicylate/ethanol, lorazepam, bladder catheter, charcoal if early, consider physostigmine, psychiatry consult

— 30-year-old depressed patient with seizures, BP 80/50, QRS 140 ms, R wave in aVR 4 mm

— Best next step: Sodium bicarbonate 1–2 mEq/kg IV bolus, intubate if seizing, norepinephrine for hypotension, lidocaine if VT, NOT physostigmine

— 82-year-old on oxybutynin, amitriptyline, diphenhydramine PRN sleep; new confusion, dry mucous membranes, urinary retention

— Best next step: Discontinue anticholinergic medications, treat retention, identify alternatives (mirabegron, SSRI, melatonin)

— Two teenagers brewed "tea" in field, brought in agitated with visual hallucinations, mydriasis 24 hours later

— Best next step: Supportive care, benzodiazepines, consider physostigmine; expect prolonged 24–48 h course

— Toddler with new unilateral fixed dilated pupil, otherwise normal

— Best next step: Examine for transdermal patch (scopolamine on caregiver), check for ocular contamination, avoid unnecessary head CT

— Agitated tachycardic mydriatic patient — diaphoresis present → sympathomimetic (cocaine, meth) → benzodiazepines, NOT physostigmine

— Suicidal patient medically cleared after diphenhydramine OD — next step: psychiatric evaluation, safety plan, lethal means restriction, follow-up within 7 days

— Question lists physostigmine for TCA overdose as a distractor — recognize this as the wrong answer (bradyasystole risk)

Step 3 management: The most commonly tested decision points are (1) recognizing wide QRS → sodium bicarbonate, (2) avoiding physostigmine when TCA suspected, (3) deprescribing anticholinergics in elderly with delirium, (4) ensuring psychiatric follow-up within 7 days after intentional overdose.

Classic Step 3 stem #1 — Adolescent diphenhydramine OD:

Classic stem #2 — TCA overdose:

Classic stem #3 — Elderly delirium with polypharmacy:

Classic stem #4 — Jimsonweed in teens:

Classic stem #5 — Pediatric patch ingestion:

Classic stem #6 — Sympathomimetic vs anticholinergic differentiation:

Classic stem #7 — Post-discharge planning:

Classic stem #8 — Wrong antidote:

One-Line Recap

Anticholinergic toxidrome is a clinical diagnosis — "hot, dry, red, blind, mad, full" — managed with supportive care, benzodiazepines, and physostigmine in pure cases (never with TCAs or wide QRS), and sodium bicarbonate when Na-channel blockade is present.

Board pearl: When in doubt — check the axilla, check the EKG, check the medication list — these three actions resolve most exam vignettes and most real-world cases.

Recognition: Dry axilla + mydriasis + tachycardia + hyperthermia + delirium + urinary retention; distinguishes from sympathomimetic by anhidrosis and from cholinergic by mydriasis and dryness. Always check fingerstick glucose, EKG, core temp, and medication list before committing to a diagnosis.

Acute management: ABCs, IV access, monitor, EKG, glucose, APAP/salicylate/ethanol levels, activated charcoal if early and airway protected, benzodiazepines for agitation/seizures/hyperthermia control, active external cooling (no antipyretics), Foley for retention, sodium bicarbonate (1–2 mEq/kg) if QRS >100 ms, physostigmine (1–2 mg IV) for pure anticholinergic delirium with normal QRS, no TCA, no asthma, no obstruction.

Disposition and prevention: ICU for wide QRS, dysrhythmia, seizures, hyperthermia, hemodynamic instability, or TCA ingestion. Always involve toxicology/poison control and psychiatry for intentional ingestions; document safety plan and arrange follow-up within 7 days. In elderly delirium, the highest-yield intervention is deprescribing anticholinergic medications (Beers list, ACB score), substituting safer alternatives (mirabegron, trazodone, SSRI, ondansetron), and scheduling a medication reconciliation visit.

Tested traps: Giving physostigmine to TCA overdose (asystole), using class IA/IC/III antiarrhythmics in TCA VT (worsens blockade — use lidocaine), confusing sympathomimetic (diaphoretic) with anticholinergic (dry), missing transdermal scopolamine in pediatric mydriasis, and discharging suicidal patients without psychiatric clearance after "medical stability."