10.1 Acute Poisoning & Toxidromes
Key Takeaways
- Paracetamol (acetaminophen) hepatotoxicity is driven by N-acetyl-p-benzoquinone imine (NAPQI) accumulation when glutathione stores fall below 30%; N-acetylcysteine (NAC) is virtually 100% protective against severe liver injury if administered within 8 hours of ingestion.
- The King's College Hospital Criteria for paracetamol-induced acute liver failure indicate emergency liver transplantation referral if arterial pH < 7.30 after fluid resuscitation OR if all three of prothrombin time > 100 seconds (INR > 6.5), serum creatinine > 300 µmol/L, and grade III/IV hepatic encephalopathy are present.
- Salicylate toxicity produces a mixed respiratory alkalosis (direct respiratory center stimulation) and severe metabolic acidosis (uncoupling of oxidative phosphorylation); urinary alkalinisation with intravenous sodium bicarbonate to achieve a urine pH of 7.50–7.55 enhances renal clearance.
- Toxidrome recognition allows rapid syndromic identification prior to laboratory confirmation: anticholinergic ("mad as a hatter, blind as a bat"), cholinergic ("SLUDGEM"), opioid (miosis, respiratory depression, coma), and sympathomimetic (hyperthermia, mydriasis, diaphoresis).
10.1 Acute Poisoning & Toxidromes
General Principles & Emergency Decontamination
The initial approach to acute poisoning in adult medicine requires immediate clinical stabilization adhering to structured Resuscitation A-B-C-D-E principles before pursuing toxin identification. Protecting the airway is paramount, particularly in obtunded patients with a Glasgow Coma Scale (GCS) score $\le 8$ or those who have ingested central nervous system (CNS) depressants, hydrocarbon solvents, or corrosive agents. Early consultation with national poisons information services (such as TOXBASE in the UK and Ireland) provides authoritative, evidence-based guidance regarding toxic doses, kinetic profiles, and specific antidote protocols.
Decontamination strategies must be applied judiciously. Single-dose activated charcoal ($1\text{ g/kg}$ up to $50\text{ g}$) adsorbs many small organic molecules but is clinically beneficial only when administered within 1 hour of ingesting an adsorbable substance. Charcoal is ineffective for heavy metals (lead, iron, lithium), alcohols (ethanol, ethylene glycol, methanol), corrosive acids/alkalis, cyanides, and essential ions (potassium, sodium). Gastric lavage and syrup of ipecac are obsolete in contemporary toxicology due to significant risks of pulmonary aspiration, oesophageal perforation, and lack of proven clinical benefit. Whole bowel irrigation using polyethylene glycol solution ($1-2\text{ L/hour}$) is reserved for sustained-release preparations, massive iron overdoses, or body packers carrying illicit drug packets.
Recognition of Classic Toxidromes
A toxidrome is a constellation of clinical signs and symptoms characteristic of a specific class of toxin. Rapid recognition allows syndromic diagnosis and empirical treatment prior to receiving laboratory blood toxicological screens.
| Toxidrome | Mental Status | Pupil Size | Vital Signs | Skin & Secretions | Classic Etiologies |
|---|---|---|---|---|---|
| Anticholinergic | Delirium, agitation, hallucinations | Mydriasis (dilated) | Tachycardia, hyperthermia, hypertension | Dry, flushed skin, dry mucous membranes | Atropine, diphenhydramine, hyoscine, tricyclic antidepressants |
| Cholinergic | Confusion, coma, seizures | Miosis (constricted) | Bradycardia, hypotension, tachypnoea | Diaphoresis, lacrimation, salivation, bronchorrhoea (SLUDGEM) | Organophosphate insecticides, nerve agents, carbamates |
| Sympathomimetic | Agitation, paranoia, hyperalertness | Mydriasis (dilated) | Tachycardia, severe hypertension, hyperthermia | Diaphoresis (profuse sweating), piloerection | Cocaine, amphetamines, MDMA, methamphetamine, ephedrine |
| Opioid | CNS depression, coma | Miosis (pinpoint) | Hypoventilation/bradypnoea, bradycardia, hypotension | Normal or cool skin, hypothermia | Morphine, methadone, oxycodone, fentanyl, heroin |
| Sedative-Hypnotic | Stupor, coma, ataxia | Normal or variable | Hypoventilation, hypotension, bradycardia | Dry skin, hypothermia | Benzodiazepines, z-drugs, barbiturates, ethanol |
Clinical Exam Pearl: The physical examination of the skin reliably differentiates sympathomimetic from anticholinergic toxidromes. Patients with sympathomimetic toxicity present with profuse diaphoresis ("soaking wet"), whereas anticholinergic toxicity produces dry axillae and anhidrotic, warm skin ("dry as a bone").
Paracetamol Toxicity & Acute Liver Failure
Paracetamol (acetaminophen) is the most common agent involved in deliberate self-poisoning. Toxic doses ($> 75-150\text{ mg/kg}$ or $> 12\text{ g}$ in an adult) saturate hepatic phase II glucuronidation and sulfation pathways. Excess drug is shunted to Cytochrome P450 (CYP2E1), generating N-acetyl-p-benzoquinone imine (NAPQI), a highly reactive toxic metabolite. When hepatic glutathione reserves fall below 30%, NAPQI covalently binds to hepatocyte proteins, inducing acute centrilobular hepatic necrosis.
Timing of Paracetamol Levels & Nomogram Interpretation
- $< 4$ Hours Post-Ingestion: Serum levels are uninterpretable due to incomplete absorption. Administer activated charcoal if within 1 hour.
- $4-8$ Hours Post-Ingestion: Measure serum paracetamol concentration at exactly 4 hours. Compare against the single treatment line ($100\text{ mg/L}$ at 4 hours, declining to $15\text{ mg/L}$ at 15 hours). If above the line, commence N-acetylcysteine (NAC) immediately.
- $> 8$ Hours Post-Ingestion: Start NAC infusion immediately without waiting for lab results. Discontinue later if the level falls below the treatment line and LFTs/INR are normal.
NAC restores hepatic glutathione stores. When administered within 8 hours of acute ingestion, NAC provides near $100%$ protection against severe hepatotoxicity. Modern practice utilizes a simplified 2-bag infusion protocol ($150\text{ mg/kg}$ over 2 hours, followed by $200\text{ mg/kg}$ over 10 hours) to reduce anaphylactoid adverse reactions (flushing, pruritus, bronchospasm). If an anaphylactoid reaction occurs, temporarily pause the infusion, administer chlorphenamine, and resume NAC at a reduced rate once symptoms resolve.
King's College Hospital Criteria for Acute Liver Failure
Patients developing severe liver injury require urgent discussion with a liver transplant unit.
| Category | Criteria for Emergency Liver Transplantation |
|---|---|
| Paracetamol-Induced ALF | Arterial pH $< 7.30$ (or lactate $> 3.0\text{ mmol/L}$) after fluid resuscitation,<br>OR all three of the following within 24 hours:<br>1. Prothrombin time $> 100\text{ seconds}$ (INR $> 6.5$)<br>2. Serum creatinine $> 300\text{ }\mu\text{mol/L}$ ($> 3.4\text{ mg/dL}$)<br>3. Grade III or IV hepatic encephalopathy |
| Non-Paracetamol ALF | Prothrombin time $> 100\text{ seconds}$ (INR $> 6.5$),<br>OR any three of the following five parameters:<br>1. Age $< 10$ or $> 40$ years<br>2. Etiology: non-A/non-B hepatitis, halothane, idiosyncratic drug reaction<br>3. Duration of jaundice before encephalopathy $> 7\text{ days}$<br>4. Prothrombin time $> 50\text{ seconds}$ (INR $> 3.5$)<br>5. Serum bilirubin $> 300\text{ }\mu\text{mol/L}$ |
Salicylate & Tricyclic Antidepressant Overdose
Salicylate Toxicity (Aspirin)
Salicylates directly stimulate the medullary respiratory center, causing hyperventilation and respiratory alkalosis. Concurrently, salicylates uncouple oxidative phosphorylation, inhibiting the Krebs cycle and accumulating lactate, pyruvate, and acetoacetate, generating a severe high anion gap metabolic acidosis. Clinical features include tinnitus, vertigo, vomiting, hyperpyrexia, sweating, and confusion.
Management involves aggressive resuscitation, correction of hypokalaemia, and urinary alkalinisation. Infusing $1.26%$ or $8.4%$ sodium bicarbonate to achieve a urine pH of $7.50-7.55$ ion-traps salicylate ($\text{Salicylate}^-$) in the renal tubules, accelerating urinary elimination. Extracorporeal haemodialysis is indicated for serum salicylate levels $> 500\text{ mg/L}$ ($3.6\text{ mmol/L}$) in acute overdose, severe metabolic acidosis ($\text{pH} < 7.20$), acute kidney injury, pulmonary oedema, or central nervous system impairment.
Tricyclic Antidepressant (TCA) Overdose
TCAs (amitriptyline, dosulepin) induce toxicity via four mechanisms: central anticholinergic blockade, peripheral alpha-1 adrenergic blockade (hypotension), cardiac fast sodium channel blockade (QRS prolongation), and inhibition of reuptake of monoamines. ECG changes dictate mortality risk:
- QRS duration $> 120\text{ ms}$: Predicts increased risk of seizures.
- QRS duration $> 160\text{ ms}$: Predicts high risk of ventricular arrhythmias (ventricular tachycardia/fibrillation).
- Terminal $40\text{ ms}$ QRS axis shift: Prominent R wave in lead aVR ($> 3\text{ mm}$).
First-line therapy for TCA-induced cardiac toxicity (QRS widening or hypotension) is intravenous sodium bicarbonate 8.4% ($1-2\text{ mmol/kg}$ boluses). Sodium bicarbonate increases extracellular sodium concentration to compete with fast sodium channel blockade and induces serum alkalinisation ($\text{target pH } 7.45-7.55$), which increases protein binding of the drug and decreases the active free serum concentration. Antiarrhythmics such as amiodarone, procainamide, and flecainide are strictly contraindicated.
Antidote Summary & Enhanced Elimination
Specific antidotes play vital roles in critical toxicological resuscitation:
| Poison / Drug Class | Specific Antidote / Specific Agent | Clinical Mechanism of Action |
|---|---|---|
| Opioids | Naloxone | Competitive opioid receptor antagonist ($0.4-2.0\text{ mg}$ IV/IM) |
| Organophosphates | Atropine + Pralidoxime | Atropine blocks muscarinic receptors; pralidoxime reactivates acetylcholinesterase |
| Toxic Alcohols (Methanol / Ethylene Glycol) | Fomepizole (or Ethanol) | Competitive inhibitor of alcohol dehydrogenase (ADH), preventing toxic acid production |
| Digoxin | Digoxin-specific Fab antibodies | Binds free serum digoxin, reversing $\text{Na}^+/\text{K}^+$-ATPase pump inhibition |
| Beta-blockers / Calcium Channel Blockers | High-dose Insulin Euglycaemic Therapy (HIET) + Calcium Chloride | HIET ($1\text{ unit/kg}$ bolus + $1\text{ unit/kg/hr}$) provides ionotropic energy substrate to myocytes |
| Local Anaesthetic Toxicity (LAST) | Intravenous Lipid Emulsion (Intralipid 20%) | Acts as a "lipid sink" extracting lipophilic local anaesthetics from target cardiac/brain tissue |
Haemodialysis effectively removes toxins characterized by low molecular weight ($< 500\text{ Da}$), low volume of distribution ($< 1\text{ L/kg}$), low plasma protein binding, and high water solubility. The toxicological mnemonic VISTAA outlines classic dialyzable toxins: Valproate, Isopropanol, Salicylates, Theophylline, Alcohol/Methanol/Ethylene glycol, and Lithium.
A 24-year-old man presents 6 hours after ingesting 25 grams of paracetamol in a suicide attempt. Arterial blood gas on admission reveals pH 7.38, pCO2 4.2 kPa, pO2 12.5 kPa, HCO3- 22 mmol/L. Serum paracetamol concentration drawn at 6 hours post-ingestion is 140 mg/L (well above the treatment line). Liver function tests are currently within normal limits. Which of the following is the most appropriate immediate intervention?
A 45-year-old woman is brought to the emergency department after an intentional ingestion of an unknown medication. She is agitated and confused. Examination reveals a heart rate of 135 bpm, blood pressure of 145/90 mmHg, dilated pupils (7 mm bilaterally) that are minimally reactive, temperature of 38.6°C, dry axillae, and absent bowel sounds. Which toxidrome does this clinical presentation best represent?
A 19-year-old woman presents 4 hours after ingesting an overdose of amitriptyline. Her GCS is 11, blood pressure is 88/52 mmHg, and heart rate is 128 bpm. An ECG demonstrates sinus tachycardia with a QRS duration of 168 ms and a prominent R wave in lead aVR. What is the most appropriate immediate medical treatment to reverse the cardiac toxicity?