1. Clinical Examination and Toxidrome Phenotyping

Rapid bedside phenotyping uses clusters of vital‐sign patterns, skin and mucosal findings, pupil exam, bowel sounds and neuromuscular signs to distinguish major toxidromes and trigger early targeted therapy.

Anticholinergic (e.g., antihistamines, TCAs, antipsychotics)

• Delirium or agitation (“mad as a hatter”)
• Mydriasis, dry mucosa, flushed skin (“red as a beet, dry as a bone”)
• Tachycardia, urinary retention, decreased bowel sounds

Cholinergic (organophosphates, carbamates)

• Muscarinic: SLUDGE (salivation, lacrimation, urination, defecation, GI cramps, emesis), bronchorrhea, bronchospasm, bradycardia
• Nicotinic: Muscle fasciculations, weakness, paralysis, hypertension, tachycardia (early phase)

Sympathomimetic (cocaine, amphetamines)

• Agitation, diaphoresis, hyperthermia
• Mydriasis, hypertension, tachycardia

Opioid (morphine, fentanyl)

• CNS & respiratory depression
• Miosis (“pinpoint pupils”), hypotension

Sedative-hypnotic (benzodiazepines, barbiturates)

• Somnolence, ataxia, hypotonia
• Hypoventilation; pupils normal or mildly constricted

Serotonin Syndrome (SSRIs, MAOIs, tramadol, linezolid)

• Neuromuscular: Inducible/spontaneous clonus, hyperreflexia, tremor
• Autonomic: Fever, diaphoresis, tachycardia, hypertension
• Rapid onset (hours)

Neuroleptic Malignant Syndrome (dopamine antagonists)

• “Lead-pipe” rigidity, hyporeflexia
• Fever, autonomic instability (BP swings, tachycardia)
• Insidious onset over days

2. Laboratory and Diagnostic Testing

Targeted labs confirm clinical phenotypes, quantify severity and direct antidote dosing. Timing and specimen handling are critical to avoid false negatives.

3. Severity Scoring and Algorithmic Frameworks

Validated criteria and decision pathways improve risk stratification, ICU triage and resource allocation.

Hunter Serotonin Toxicity Criteria

Diagnosis requires exposure to a serotonergic agent plus one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Tremor plus hyperreflexia
• Hypertonia plus temperature >38°C plus ocular or inducible clonus

This tool has high specificity (~97%) for serotonin syndrome.

QRS Duration Algorithm in TCA Overdose

An algorithmic approach based on the QRS duration on ECG is critical for managing potential cardiotoxicity from tricyclic antidepressant overdose.

Other Frameworks

• Mixed Toxidromes: Weighted scoring systems that assess autonomic, muscarinic, neuromuscular, and ECG findings can help identify the predominant phenotype when polypharmacy complicates the clinical picture.
• ICU Admission Pathways: Standardized criteria for ICU admission include airway compromise, refractory hypotension, life-threatening arrhythmias, or severe hyperthermia. Early consultation with a poison control center or medical toxicologist is crucial.

4. Diagnostic Challenges and Pitfalls

Overlapping syndromes, altered exam conditions, and patient factors can obscure classic toxidrome patterns. It is essential to maintain a high index of suspicion.

Polypharmacy & Atypical Agents

Ingestion of multiple substances can create masked or confusing clinical phenotypes. Furthermore, patient tolerance to a substance may elevate the threshold dose required to produce classic signs.

Point‐of‐Care Testing Limitations

Standard urine drug screens are often immunoassays that can miss volatile agents (like toxic alcohols) and fail to detect novel psychoactive substances. Results should be interpreted with caution.

Sedated/Intubated Patients

A baseline neurologic impairment, sedation, or neuromuscular blockade precludes an accurate assessment of reflexes and clonus. Structured sedation vacations, when safe, can be invaluable for serial neurologic exams.

Pediatric Considerations

Children have unique physiology that alters toxidrome presentation. They have a lower baseline cholinesterase level, which can lead to false-low readings. Hypotension may be an early, rather than late, sign in anticholinergic poisoning. All antidote dosing and fluid resuscitation must be strictly weight-based.