1. Epidemiology and Incidence

Understanding who, where, and how often overdoses occur guides ICU planning and prevention strategies. The incidence and patterns of non-cardiovascular overdoses vary significantly by agent, geography, and patient population.

• Acetaminophen: Remains the leading cause of acute liver failure in North America, accounting for approximately 50,000 emergency department visits and over 500 deaths annually. A concerning trend is the rise of unintentional supratherapeutic ingestions in older adults and patients with polypharmacy.
• Salicylates: Lead to around 5,000 hospital admissions per year, with a fatality rate of 1–3% in severe cases. Overdose patterns are influenced by the availability of over-the-counter (OTC) aspirin versus combination cold preparations.
• Theophylline & Lithium: These agents cause fewer than 1,000 combined ICU admissions annually but are associated with high morbidity from seizures, arrhythmias, and profound neurotoxicity. The need for extracorporeal removal (dialysis) correlates with peak serum levels and patient comorbidities.
• Paraquat & Diquat: While rare in developed countries, these herbicides have a case-fatality rate exceeding 50% due to the rapid development of irreversible pulmonary fibrosis. Incidence is higher in agricultural and low-resource settings, often leading to prolonged and resource-intensive ICU stays.

Morbidity, Mortality & Resources

The ICU length of stay and overall resource utilization are driven by the specific toxin, the ingested dose, the timing of antidote administration, and the patient’s underlying comorbidities. Effective management requires a multidisciplinary team to optimize ventilation, hemodynamics, and toxin elimination strategies.

2. Pathophysiology of Toxicity by Agent

Mechanistic insights into how each toxin causes harm are fundamental to selecting appropriate monitoring parameters, anticipating clinical deterioration, and providing timely, targeted antidotal therapy.

3. Patient-Related Risk Factors

The clinical impact of an overdose is not solely determined by the toxin and dose; patient-specific factors like chronic diseases and physiologic extremes can dramatically alter toxin kinetics and lower toxicity thresholds.

Chronic Liver Disease

Patients with pre-existing liver disease have reduced Phase II metabolic capacity and lower baseline glutathione reserves. This makes them susceptible to severe hepatotoxicity at lower acetaminophen doses than healthy individuals. The Rumack-Matthew nomogram may underestimate their risk, and clinicians should consider initiating N-acetylcysteine (NAC) therapy early, even with borderline or “sub-toxic” levels.

Renal Dysfunction

Impaired renal function significantly prolongs the elimination half-lives of water-soluble toxins like salicylates and lithium, leading to delayed peak toxicity or recurrent toxicity after initial treatment. Lithium clearance can be halved in chronic kidney disease (CKD), necessitating daily level monitoring and aggressive dose adjustments.

Cardiopulmonary Comorbidities

Underlying lung disease (e.g., COPD, ILD) severely compromises a patient’s ability to tolerate the pulmonary injury from paraquat, accelerating the progression to profound hypoxemia. Similarly, heart failure worsens the fluid shifts and pulmonary edema seen in severe salicylate poisoning due to underlying cardiac dysfunction and the effects of metabolic acidosis on myocardial contractility.

Age Extremes

• Pediatrics: Children have a larger volume of distribution for water-soluble toxins. It is essential to use weight-based dosing and age-appropriate nomograms for accurate risk assessment.
• Geriatrics: Older adults exhibit decreased hepatic and renal clearance, are often on multiple medications (polypharmacy), and may have increased blood-brain barrier permeability. These factors combine to create a state of heightened susceptibility to neurotoxicity from many agents.

Co-ingestions & Polypharmacy

The presence of other substances can profoundly alter a toxin’s metabolism. Ethanol, for example, can induce CYP2E1, potentially worsening acetaminophen toxicity. CYP inhibitors (e.g., cimetidine, ciprofloxacin) or inducers (e.g., rifampin) can alter the clearance of drugs like theophylline. Multiple ingested agents can also create a confusing clinical picture (toxidrome), delaying specific diagnosis and antidotal therapy.

4. Social Determinants of Health

Socioeconomic, environmental, and cultural factors play a significant role in shaping overdose risk, the timing of clinical presentation, and ultimate patient outcomes. Addressing these determinants is a key component of public health and prevention strategies.

Medication Access and Availability

The widespread OTC availability of acetaminophen and aspirin contributes significantly to the high rate of both intentional and unintentional overdoses. In low- and middle-income countries (LMICs), the risk of paraquat exposure is heightened by the sale of counterfeit or poorly labeled herbicide products.

Health Literacy

Low health literacy is a major driver of unintentional dosing errors. Studies have shown that interventions like pictogram-based labeling and dedicated pharmacist counseling can reduce medication errors by approximately 30%.

Socioeconomic Status and Mental Health

Poverty, unemployment, and gaps in mental health services are strongly correlated with a higher incidence of intentional self-harm overdoses. Research has identified neighborhood deprivation as an independent predictor of overdose mortality, even after accounting for individual risk factors.

Language and Cultural Barriers

Limited English proficiency can create critical delays in identifying the ingested toxin and initiating time-sensitive treatment. The consistent use of professional medical interpreters and the development of culturally tailored educational materials are proven strategies to improve patient engagement and outcomes.

Strategies to Address Disparities

Effective overdose prevention requires a multi-pronged approach. This includes community outreach programs, the integration of mental and physical health services, and pharmacy-led harm reduction initiatives. On a broader scale, policy initiatives such as tighter regulations on certain OTC toxins and enhanced prescribing authority for pharmacists can have a substantial impact.