Anticholinergic Syndrome (Anticholinergic Toxicity)

Definition and EtiologyTop

Acute anticholinergic syndrome refers to signs and symptoms caused by the inhibition of the effect of acetylcholine on muscarinic receptors.

Causes:

1) Belladonna alkaloids (atropine, scopolamine, hyoscine, hyoscyamine); jimson weed (Datura stramonium), nightshade plant (Atropa belladonna), henbane (Hyoscyamus niger).

2) Antihistamines and antihistamine sleep aids (diphenhydramine, dimenhydrinate, doxylamine).

3) Cholinolytic drugs used in the treatment of Parkinson disease (biperiden, benztropine [INN benzatropine]).

4) Tricyclic antidepressants (TCAs) (eg, amitriptyline, imipramine, clomipramine).

5) Antipsychotics (eg, olanzapine, clozapine).

6) Phenothiazines (eg, chlorpromazine, prochlorperazine, promethazine, thioridazine).

7) Eye drops (eg, cyclopentolate).

8) Illicit drugs (eg, heroin, which is often mixed with scopolamine).

Clinical Features and DiagnosisTop

Diagnosis is based on signs and symptoms:

1) Central nervous system manifestations:

a) Hallucinations; “Alice in Wonderland” hallucinations where people or objects appear larger or smaller.

b) Confusion, delirium.

c) Psychosis with paranoid delusions.

d) Psychomotor agitation with jerky myoclonic or choreoathetotic movements (this can lead to rhabdomyolysis).

e) Coma.

f) Seizures (pure antimuscarinic agents do not cause seizures but other properties of drugs such as TCAs or antihistamines can have this effect).

2) Peripheral manifestations:

a) Mydriasis leading to blurry vision.

b) Vasodilation, diffuse erythema.

c) Warm dry skin and dry mucosae.

d) Hyperthermia.

e) Tachycardia.

f) Adynamic ileus.

g) Urinary retention.

Diagnostic Tests

For some anticholinergic medications (particularly TCAs) blood level measurements are possible. However, studies neither showed a good correlation with the severity of the toxicity, nor predict the clinical outcome.

While the presence of many nonprescription anticholinergic agents can be confirmed with comprehensive toxicology panels, routine hospital urine toxicology assays will not be useful.

Other diagnostic workup can include electrolytes, creatinine, blood glucose, blood gas analysis, creatine kinase, oximetry, and electrocardiography (ECG) or cardiac monitoring.

Diagnosis may be confirmed by resolution or improvement of symptoms during a slow (over 2-5 minutes) IV injection of 0.5 to 1 mg of physostigmine salicylate, a carbamate that reversibly inhibits acetylcholinesterase. Contraindications to physostigmine use: see Antidotes, below.

Differential Diagnosis

Psychiatric disorders, poisoning with sympathomimetics (presence of sweating and mydriasis with reaction to light is unlikely with anticholinergics) or hallucinogenic substances, alcohol withdrawal syndrome (including delirium tremens), serotonin syndrome, neuroleptic malignant syndrome.

TreatmentTop

1. Decontamination can be attempted with oral activated charcoal (AC). Because anticholinergic drugs impair gastric emptying and gut motility, AC may still be useful in delayed (>1 hour from ingestion) presentations. There is no role for hemodialysis or hemoperfusion.

2. Physical or pharmacologic (high-dose sedatives) restraints are sometimes necessary to decrease the risks of injury, rhabdomyolysis, and hyperthermia. In exceptional cases patients may need endotracheal intubation and mechanical ventilation. Also see Approach to the Agitated Patient.

3. In severe poisoning monitor cardiac function, blood pressure, and urine output (to monitor for urinary retention). Watch for hyperthermia, coma, and rhabdomyolysis.

4. Antidote: In patients with agitated delirium use IV physostigmine salicylate 0.5 to 1 mg over 2 to 5 minutes; the dose may be repeated every 10 to 15 minutes up to a total dose of 2 mg.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational data and risk of bias, and increased due to effect size. Boley SP, Olives TD, Bangh SA, Fahrner S, Cole JB. Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center. Clin Toxicol (Phila). 2019 Jan;57(1):50-55. doi: 10.1080/15563650.2018.1485154. Epub 2018 Jun 29. PMID: 29956570. Wang GS, Baker K, Ng P, et al. A randomized trial comparing physostigmine vs lorazepam for treatment of antimuscarinic (anticholinergic) toxidrome. Clin Toxicol (Phila). 2021 Aug;59(8):698-704. doi: 10.1080/15563650.2020.1854281. Epub 2020 Dec 9. PMID: 33295809. For patients requiring additional doses, discussion with a medical toxicologist is recommended. The drug is rarely used due to adverse effects (bradycardia and heart block) and is contraindicated in patients with seizure disorders, serious TCA overdose, or any patient with anticholinergic toxicity and a prolonged QRS complex on ECG. Caution should be used when considering physostigmine for patients with atrioventricular (AV) conduction disorders, parkinsonian syndrome, recent succinylcholine use, bronchospastic disease, and severe peripheral vascular disease. Patients must be in a setting with cardiac and respiratory monitoring and tools for resuscitation available. Atropine may be given to reverse any excessive muscarinic stimulation from physostigmine.

5. IV diazepam 10 mg in repeated doses every 3 to 5 minutes can be used for agitation if physostigmine cannot be used or is ineffective. Do not use phenothiazines or butyrophenones.

6. In the case of TCA-induced anticholinergic syndrome (caused by the TCA effect on muscarinic receptors), the effect of the drug through other mechanisms may cause widening of the QRS complex. In such patients a sodium bicarbonate injection followed by a continuous infusion should be administered. Our pattern is to give sodium bicarbonate until the QRS is normalized, pH is 7.5, or serum sodium levels are >150 mmol/L. The usual dose starts with 50 to 150 mmol (1-3 ampoules) and then is followed by 150 mmol of sodium bicarbonate in 1000 mL of 5% glucose (dextrose) at a rate of ~200 mL/h.