Diagnostic Assessment and Severity Classification for Non-Cardiovascular Overdoses

1. Clinical Presentation and Initial Evaluation

Rationale: Rapid, systematic assessment in acute overdose relies on a precise history, focused toxidrome recognition, and an understanding of symptom timing to direct appropriate diagnostics and therapy.

A. Comprehensive History: Dose, Timing, and Co-ingestions

The foundation of overdose management is a thorough history. Key elements include:

Substance and Formulation: Identify the specific agent(s), whether the formulation is immediate-release (IR) or extended-release (ER/SR), the estimated dose, route of exposure, and the exact time of ingestion.
Co-ingestants: Document any potential co-ingestants, particularly CNS depressants like alcohol or benzodiazepines, which can alter the clinical picture. Note chronic medications, as in cases of repeated supratherapeutic acetaminophen ingestion.
Patient Factors: Consider patient weight, especially in pediatric or low-BMI adult populations, as this can influence toxicity thresholds and nomogram interpretation.

B. Physical Examination: Vital Signs & Toxidrome Identification

A focused physical exam helps confirm suspected exposures and assess severity.

Vital Signs: Note abnormalities such as fever (anticholinergic, salicylate), hypotension or hypertension, and changes in respiratory rate (e.g., tachypnea in salicylate toxicity).
Mental Status: Use a standardized tool like the Glasgow Coma Scale (GCS) to objectively gauge the level of consciousness and determine the risk to the patient’s airway.
Toxidromes: Recognize classic patterns of signs and symptoms:
- Anticholinergic: Hyperthermia, mydriasis (dilated pupils), flushed skin, urinary retention, and delirium (“hot as a hare, blind as a bat, red as a beet, dry as a bone”).
- Cholinergic: Salivation, lacrimation, urination, defecation, GI distress, emesis (SLUDGE), along with miosis (constricted pupils) and bradycardia.
- Salicylate: Early tachypnea leading to respiratory alkalosis, followed by a mixed anion-gap metabolic acidosis, tinnitus, and hyperthermia.

Key Point: Prioritize a Focused Examination +

The physical examination should be driven by the patient’s history and presenting signs. Avoid exhaustive screening checklists that can delay critical interventions. Focus on vital signs, mental status, and key toxidrome features to rapidly build a differential diagnosis.

C. Symptom Timelines for Key Toxins

Understanding the expected onset of symptoms is crucial for risk stratification.

Acetaminophen: Often asymptomatic for the first 24 hours. Right upper quadrant (RUQ) pain and rising liver enzymes (AST/ALT) signal the onset of hepatic injury.
Salicylates: Respiratory alkalosis can appear almost immediately, transitioning to a mixed anion-gap metabolic acidosis over 12 to 24 hours.
Theophylline: Seizures and arrhythmias can occur within 1-2 hours for immediate-release products but may be delayed for 8-12 hours or more with sustained-release (SR) formulations.
Lithium: Symptoms progress from tremor to ataxia and eventually seizures. Peak effects occur at 4-6 hours for IR and 12-24 hours for extended-release (XR) products.
Paraquat: Oral ulcerations appear on day 1, followed by pulmonary edema on days 2-3, and irreversible pulmonary fibrosis from day 7 onward.

2. Laboratory and Imaging Modalities

Rationale: Targeted laboratory tests and selective imaging are used to confirm exposure, quantify the degree of toxicity, assess for end-organ dysfunction, and refine risk stratification.

A. Serum Drug Concentrations

Quantitative levels are essential for a few specific toxins where they directly guide therapy.

Toxicology Thresholds for Key Non-Cardiovascular Agents
Agent	Moderate Toxicity / Monitoring	Severe Toxicity / Action Threshold
Acetaminophen	Level drawn ≥4h post-ingestion	≥150 µg/mL at 4h: Initiate N-acetylcysteine (NAC) per Rumack-Matthew nomogram.
Salicylates	30–50 mg/dL (with mild alkalosis)	>50 mg/dL or pH < 7.35: Initiate urine alkalinization, consider hemodialysis.
Theophylline	>20 mg/L (arrhythmias)	>40 mg/L (seizures): Consider multi-dose activated charcoal, hemodialysis.
Lithium	1.5–2.5 mEq/L (tremor, GI upset)	>2.5 mEq/L (ataxia, seizures): Consider hemodialysis, especially with neurologic signs.
Paraquat	Any confirmed exposure	Plasma >2 µg/mL at 24h: Associated with extremely high mortality.

B. Acid–Base Assessment

An arterial blood gas (ABG) is critical in poisonings that disrupt metabolic balance.

ABG Analysis: Distinguishes between primary respiratory processes (e.g., salicylate-induced hyperventilation) and metabolic derangements.
Anion Gap: An elevated anion gap can reveal the presence of unmeasured acids, a hallmark of severe salicylate or paraquat toxicity.
Mixed Disorders: Always suspect a mixed acid-base disorder, such as the combined respiratory alkalosis and metabolic acidosis seen in salicylate poisoning.

C. Organ Function Panels

Monitoring for end-organ damage is a key component of management.

Liver Function Tests (LFTs): Serial AST and ALT measurements are essential for tracking the progression of liver injury in acetaminophen overdose.
Renal Function: BUN and creatinine monitor for nephrotoxicity and are crucial for assessing the clearance of renally-eliminated drugs like lithium and salicylates.
Coagulation Studies: An elevated INR or aPTT can signal the development of fulminant hepatic failure.

D. Imaging

Imaging is used selectively to identify specific complications.

Chest X-ray/CT: Essential for detecting paraquat-induced pulmonary edema or the later development of fibrosis.
ECG: An early ECG is vital to screen for QT prolongation or conduction delays that can occur with theophylline and salicylate overdoses or associated electrolyte shifts.

3. Severity Scoring and Classification Systems

Rationale: Combining validated scoring tools with sound clinical judgment is necessary for accurate risk assessment. Consultation with a poison control center is a critical step for managing complex cases.

A. The Rumack–Matthew Nomogram for Acetaminophen

This is the primary tool for assessing risk after an acute, single ingestion of acetaminophen. A serum level is plotted against the time since ingestion (between 4 and 24 hours).

Figure 1: Simplified Rumack-Matthew Nomogram. This tool plots serum acetaminophen concentration against time since a single, acute ingestion to determine the need for N-acetylcysteine (NAC) therapy. It is not valid for repeated, staggered, or extended-release ingestions.

B. Clinical Judgment and Poison Control Consultation

While nomograms are useful, they are not a substitute for clinical assessment. Standard severity scores often underperform compared to an experienced clinician’s gestalt. The decision to admit a patient to the ICU or administer an antidote should be based on a combination of mental status, hemodynamic stability, and laboratory trends. Broad, untargeted toxicology screens have limited utility and may yield misleading results; they should be avoided unless the result will definitively change management.

Clinical Pearl: The Value of Poison Control +

Early consultation with a regional poison control center is integral to diagnostic stewardship and optimal care. These experts provide invaluable guidance on rare exposures, complex toxidromes, indications for advanced elimination techniques like hemodialysis, and appropriate patient disposition. This collaboration frequently reduces unnecessary hospital admissions and ensures resources are used effectively.

4. Pharmacokinetic and Pharmacodynamic Considerations

Rationale: In overdose, standard pharmacokinetic principles are often disrupted. Diagnostic sampling schedules and the interpretation of results must be tailored to account for changes in drug absorption, distribution, and elimination.

A. Time to Peak and Delayed Absorption

Extended-release (ER/SR) or enteric-coated formulations can lead to dangerously delayed and prolonged absorption. For toxins like theophylline SR or lithium XR, peak serum concentrations may not occur for 8 to 24 hours. Serial drug levels are necessary to identify a rising concentration, and initial levels may be falsely reassuring.

B. Volume of Distribution and Protein Binding

In massive ingestions, normal physiological processes can become saturated. For highly protein-bound drugs like salicylates, saturation of binding sites increases the free (active) fraction of the drug, leading to disproportionately greater toxicity than the total serum level might suggest.

C. Impact of Organ Dysfunction on Elimination

Overdose-induced organ damage creates a vicious cycle. Acetaminophen-induced hepatic failure prolongs its own metabolism and that of other drugs. Similarly, salicylate- or lithium-induced renal failure dramatically delays clearance. In these scenarios, clinicians must consider earlier and more aggressive interventions, such as hemodialysis, even if serum levels have not yet reached traditional thresholds.

Key Point: Contextualize Lab Results +

Never interpret a drug level in isolation. Always adjust diagnostic timing and interpretive thresholds in the context of the formulation ingested (IR vs. ER), the time since ingestion, and the patient’s evolving organ function. A “non-toxic” level drawn too early can be dangerously misleading.

References

Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6):871–876.
Mégarbane B, Oberlin M, Alvarez J-C, et al. Management of pharmaceutical and recreational drug poisoning. Ann Intensive Care. 2020;10:157.
Larocque A, Dart RC, Mullins ME, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023;6(8):e2327739.
American College of Medical Toxicology. Guidance document: management priorities in salicylate toxicity. J Med Toxicol. 2015;11(2):149–152.

Lesson Objective