1. First-Line Antidotes and Mechanistic Rationale

Rapid identification and targeted reversal of life-threatening syndromes is achieved through mechanism-based antidotes. Mastery of pharmacology, dosing, monitoring, and contraindications underpins safe administration and optimal outcomes.

2. Adjunctive Decontamination and Second-Line Therapies

Early decontamination and advanced therapies like lipid rescue can limit systemic toxin absorption and improve hemodynamics in refractory cases.

A. Activated Charcoal

Most effective within 1–2 hours of ingestion. Dose is 1 g/kg (max 50 g) orally or via NG tube. Multi-dose activated charcoal (MDAC) at 0.5 g/kg every 4 hours may be considered for drugs with enterohepatic circulation. It is contraindicated with an unprotected airway, caustic ingestion, or bowel obstruction.

B. Whole Bowel Irrigation (WBI)

Indicated for sustained-release formulations, iron, lithium, and body packers. Administer polyethylene glycol (PEG) solution at 1–2 L/h until rectal effluent is clear. Contraindicated in ileus, obstruction, or hemodynamic instability.

C. Intravenous Lipid Emulsion (ILE)

Acts as a “lipid sink” for lipophilic drug overdoses (e.g., local anesthetics, beta-blockers, calcium channel blockers) with cardiovascular collapse. A 20% lipid emulsion is given as a 1.5 mL/kg bolus, followed by an infusion. Monitor triglycerides and acid-base status.

3. Pharmacokinetic and Pharmacodynamic Adjustments in Critical Illness

Critical illness profoundly alters drug disposition, necessitating dose recalibration based on physiological changes rather than standard dosing.

• Increased Volume of Distribution (Vd): Capillary leak and aggressive fluid resuscitation increase the Vd for hydrophilic drugs. This may require higher loading doses to achieve therapeutic concentrations.
• Decreased Protein Binding: Hypoalbuminemia in sepsis or critical illness increases the free (active) fraction of highly protein-bound drugs, potentially increasing their effect and risk of toxicity.
• Impaired Hepatic Metabolism: Shock states reduce liver blood flow, impairing the clearance of high-extraction drugs. This often requires dose reduction or interval prolongation.

4. Dose Adjustments in Organ Dysfunction

Tailor dosing based on renal, hepatic, and extracorporeal support status to ensure efficacy while avoiding accumulation and toxicity.

5. Route of Administration and Delivery Device Selection

Choose routes to ensure rapid, predictable effect while minimizing risk.

• Intravenous (IV) Central: Preferred for vesicant or irritant solutions (e.g., high-dose benzodiazepine infusions) and when multiple simultaneous infusions are required.
• Intravenous (IV) Peripheral: Suitable for most bolus antidotes. Monitor the site carefully for signs of extravasation.
• Intramuscular (IM) / Intranasal (IN): Primarily for pre-hospital or community use of naloxone. Bioavailability is lower and more variable than IV.
• Endotracheal (ET): A last-resort route when IV/IO access is impossible. Requires 2–2.5 times the standard IV dose, diluted in sterile water.
• Enteral (PO / NG Tube): Used for agents like activated charcoal and cyproheptadine. Requires a protected airway in sedated patients.

6. Monitoring Plan for Pharmacotherapy Efficacy and Safety

A structured surveillance plan is critical to identify therapeutic success and emerging toxicity from antidote administration.

• Vital Signs: Monitor every 15 minutes during initial titration, then hourly once stable.
• Neurological/Sedation: Use validated scales (e.g., RASS) and continuous capnography for patients on sedative infusions.
• Laboratory: Regularly check electrolytes, renal/hepatic function panels, and creatine kinase (CK) for rhabdomyolysis. Obtain drug levels when available and clinically useful.
• Cardiovascular: Perform serial ECGs every 2–4 hours to monitor for QRS/QTc interval changes and arrhythmias, especially with agents like physostigmine.
• Point-of-Care Ultrasound (POCUS): Can be used to assess volume status and cardiac contractility, especially after large-volume therapies like WBI or ILE.

7. Pharmacoeconomic and Resource Utilization Considerations

Balancing cost, availability, and efficacy is a key component of toxicology stewardship.

• Low-Cost Agents: Activated charcoal and naloxone are inexpensive and widely available.
• High-Cost Agents: Dantrolene and intravenous lipid emulsion represent significant costs and should be used judiciously based on clear indications.
• Monitoring Costs: The need for continuous ECG, invasive monitoring, and frequent lab draws increases ICU workload and overall cost of care.
• Stewardship: Involving a regional poison center or a clinical toxicology consult service is crucial to optimize resource utilization and ensure evidence-based care.

8. Special Populations Considerations

Physiological differences in pregnancy, pediatrics, and geriatrics mandate careful therapeutic adjustments.

Pregnancy

Prioritize maternal stabilization, as it is the best way to ensure fetal well-being. Antidotes like naloxone and atropine have favorable safety profiles. Always involve obstetrics early in management.

Pediatrics

All dosing is weight-based (e.g., naloxone 0.01 mg/kg IV; activated charcoal 1 g/kg). Children have a higher volume of distribution and immature metabolic pathways, which can alter drug half-life.

Geriatrics

Start with reduced initial doses due to decreased clearance and increased sensitivity. Prefer agents with cleaner metabolic profiles (e.g., lorazepam over diazepam). Use smaller, more frequent increments of agents like physostigmine (e.g., 0.25 mg) to minimize the risk of bradycardia.