1.4 Clinical Toxicology & Acute Poisoning

Clinical Toxicology & Acute Poisoning

Acute poisoning and intentional overdoses account for substantial emergency department admissions in the United Kingdom. Clinical management is guided by the National Poisons Information Service (NPIS) via TOXBASE, the British National Formulary (BNF), and NICE clinical guidelines. The cornerstone of toxicology management is aggressive ABCDE supportive care followed by targeted antidotal therapy.

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Paracetamol (Acetaminophen) Overdose

Paracetamol is the most common agent taken in deliberate self-harm in the UK. Understanding its metabolism and time-sensitive antidotal therapy is essential for preventing acute liver failure.

Pathophysiology of Hepatotoxicity

At therapeutic doses, >90% of paracetamol is metabolized by hepatic glucuronidation and sulfation into non-toxic conjugates. A minor fraction (~5–10%) is metabolized by cytochrome CYP2E1 to the highly reactive, electrophilic, and hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is normally detoxified by conjugation with endogenous hepatic glutathione into harmless mercapturic acid conjugates.

In overdose, normal sulfation and glucuronidation pathways become saturated. Excess paracetamol is shunted to CYP2E1, producing massive quantities of NAPQI. Once hepatic glutathione stores are depleted to <30% of normal, un-conjugated NAPQI binds covalently to intracellular hepatocyte proteins and mitochondrial structures, causing acute centrilobular hepatic necrosis and fulminant liver failure.

                    [ Paracetamol Ingestion ]
                               │
        ┌──────────────────────┴──────────────────────┐
        ▼                                             ▼
  [ Glucuronidation & Sulfation ]            [ CYP2E1 Oxidation ]
  (Major pathways: saturated in OD)                   │
        │                                             ▼
  [ Non-Toxic Metabolites ]                        [ NAPQI ] (Toxic)
                                                      │
                            ┌─────────────────────────┴─────────────────────────┐
                            ▼                                                   ▼
              [ Normal / Low Ingestion ]                               [ Severe Overdose ]
              + Glutathione Conjugation                                Glutathione Depleted (<30%)
                            │                                                   │
                            ▼                                                   ▼
              [ Non-Toxic Mercapturate ]                              [ Covalent Protein Binding ]
                                                                      [ Centrilobular Necrosis ]
                                                                      [ Acute Liver Failure ]

The UK Paracetamol Treatment Nomogram & Timings

• Single Acute Ingestion < 4 Hours: Paracetamol absorption is ongoing. Blood paracetamol concentration drawn before 4 hours cannot be interpreted on the nomogram. Measure serum paracetamol, ALT, creatinine, and INR at 4 hours post-ingestion.
• Single Acute Ingestion 4 to 8 Hours: Draw blood paracetamol concentration immediately. Await the result and compare to the single UK treatment line (starting at 100 mg/L at 4 hours). If on or above the line, start IV N-acetylcysteine (NAC).
• Presentation > 8 Hours Post-Ingestion: The efficacy of NAC decreases with delay, particularly beyond 8 hours. Commence IV NAC immediately without waiting for laboratory results. If the subsequent level is below the line and ALT/INR are normal, NAC may be discontinued.
• Staggered Overdose (taken over >1 hour): The nomogram cannot be used. Commence IV NAC immediately regardless of time elapsed.

Simplified SNAP Regimen (12-Hour Protocol)

The Scottish and Newcastle Acetylcysteine Protocol (SNAP) is now used by many UK hospitals (follow the local protocol and TOXBASE; the licensed 21-hour three-bag regimen is still used elsewhere), delivering the total therapeutic dose of 300 mg/kg over 12 hours instead of 21 hours:

• Total Dose: 300 mg/kg over 12 hours.
• End of Infusion Testing: Check ALT, INR, creatinine, and paracetamol level 2 hours before the second infusion finishes (at 10 hours). If ALT is normal, INR ≤1.3, and paracetamol is undetectable, stop NAC. Continue infusion (at 20 mg/kg/hour) if ALT is rising, INR >1.3, or paracetamol remains detectable.
• Anaphylactoid Reactions: Non-IgE mediated histamine release (flushing, pruritus, wheeze) occurs in ~10–15% of patients, usually during the first infusion. Manage by temporarily stopping the infusion, giving an antihistamine ± salbutamol, and restarting once symptoms settle (per local protocol); these reactions are not true allergy and are not a reason to withhold acetylcysteine.

King's College Hospital Criteria for Acute Liver Failure

In paracetamol-induced acute liver failure, the King's College Hospital Criteria determine when emergency referral for super-urgent orthotopic liver transplantation is indicated:

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Opioid Toxicity & Naloxone Titration

• Clinical Triad: CNS depression (coma), respiratory depression (bradypnoea <8–10 breaths/min), and pinpoint pupils (miosis).
• Antidote: Naloxone is a competitive opioid mu-receptor antagonist.
• Titration Goal: The objective of naloxone therapy is adequate spontaneous respiratory ventilation (respiratory rate >10–12 breaths/min), not complete restoration of consciousness. Abrupt reversal precipitates acute opioid withdrawal, severe agitation, vomiting, and non-cardiogenic pulmonary oedema.
• Dosing (BNF, opioid overdose): Give 400 micrograms IV, then 800 micrograms for up to two doses at 1-minute intervals if there is no response, then 2 mg (4 mg may be needed in seriously poisoned patients); if there is still no response, reconsider the diagnosis. When respiratory depression must be reversed without precipitating withdrawal or pain (for example in palliative or postoperative patients), titrate smaller increments such as 100–200 micrograms.
• Pharmacokinetics: Naloxone has a short half-life (30–90 minutes). Long-acting opioids (e.g., methadone, sustained-release oxycodone) will outlast naloxone; observe closely for rebound resedation and initiate an IV naloxone infusion if recurrent hypoventilation occurs.

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Salicylate (Aspirin) Poisoning

• Pathophysiology: Salicylates directly stimulate the medullary respiratory center, causing hyperventilation and a primary respiratory alkalosis. Simultaneously, salicylates uncouple mitochondrial oxidative phosphorylation, leading to anaerobic glycolysis, accumulation of lactic acid and ketoacids, and a primary high anion gap metabolic acidosis.
• Classic Acid-Base Finding: Mixed respiratory alkalosis and metabolic acidosis.
• Clinical Presentation: Tinnitus, vertigo, nausea, vomiting, diaphoresis, hyperpyrexia, tachypnoea, confusion, seizures, pulmonary oedema.
• Management:
  1. Activated Charcoal (50 g): If presenting within 1–2 hours of ingestion (repeat doses considered for large ingestions with bezoar formation).
  2. Urinary Alkalinisation: Administer intravenous Sodium Bicarbonate (1.26% or 8.4%) with potassium chloride to maintain urine pH between 7.5 and 8.5. Alkalinising the urine ionizes salicylic acid to salicylate, 'ion-trapping' it within the renal tubules and accelerating urinary excretion.
  3. Haemodialysis Indications: Salicylate level >700 mg/L (5.1 mmol/L), severe refractory metabolic acidosis (pH <7.20), renal failure, pulmonary oedema, or progressive neurological deterioration (coma, seizures).

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Carbon Monoxide (CO) Poisoning

• Mechanism: CO binds haemoglobin with an affinity >200 times higher than oxygen, forming carboxyhaemoglobin (COHb). This severely impairs oxygen-carrying capacity and shifts the oxyhaemoglobin dissociation curve to the left (inhibiting tissue oxygen release), while inhibiting cytochrome c oxidase.
• Clinical Features: Headache, nausea, dizziness, lethargy, cognitive impairment, myocardial ischaemia, arrhythmias. Cherry-red skin is a rare post-mortem sign.
• Diagnostic Trap: Standard pulse oximetry (SpO2) cannot distinguish carboxyhaemoglobin from oxyhaemoglobin and reads falsely normal. Diagnosis requires venous or arterial blood gas co-oximetry measuring COHb percentage (>10% in smokers, >3% in non-smokers).
• Treatment: Immediate 100% high-flow normobaric oxygen via non-rebreathe mask (reduces COHb half-life from 320 to 80 minutes). Hyperbaric oxygen (HBO) is discussed with TOXBASE or a hyperbaric unit for severe cases (for example loss of consciousness, neurological signs, myocardial ischaemia, pregnancy or very high COHb); evidence of benefit is mixed, so 100% normobaric oxygen remains the universal first step.

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Core UK Clinical Antidotes Summary