5.4 Paracetamol & Salicylate Poisoning
Key Takeaways
- Acetylcysteine is given when the 4-hour or later paracetamol level is on or above the single 100 mg/L nomogram treatment line, and immediately in staggered or unknown-time overdose.
- King's College criteria for paracetamol-induced acute liver failure are arterial pH below 7.30, or the triad of INR above 6.5, creatinine above 300 micromol/L and grade III-IV encephalopathy.
- Salicylate poisoning causes early respiratory alkalosis then high anion gap metabolic acidosis; haemodialysis is indicated above about 700 mg/L or for acidosis, renal failure or altered consciousness.
[!NOTE] Curriculum Focus: The MRCP(UK) Part 1 examination rigorously tests acute poisoning emergencies. Candidates must master paracetamol metabolism, UK TOXBASE management nomograms, King's College liver transplantation criteria, mixed acid-base disorders in salicylate poisoning, rapid toxidrome recognition, carbon monoxide and cyanide rescue protocols, and toxic alcohol diagnostics.
Acute poisoning constitutes approximately 1% of all UK emergency department attendances. Systematic management rests upon rapid physiological stabilisation (Airway, Breathing, Circulation), toxidrome recognition, diagnostic acid-base and osmolar analysis, and prompt administration of targeted antidotes.
Paracetamol Hepatotoxicity & Acute Liver Failure
Paracetamol (acetaminophen) is the most common pharmaceutical agent involved in intentional self-poisoning in the United Kingdom.
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| Paracetamol Hepatic Metabolism Pathways |
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| [ PARACETAMOL ] |
| | | | |
| Glucuronidation (~55%) Sulfation (~30%) CYP2E1 Oxidation (~5-10%) |
| | | | |
| v v v |
| [ Non-Toxic Metabolites ] [ NAPQI ] (Highly Reactive) |
| | |
| +--------------+--------------+ |
| | (Normal Stores) | (Depletion) |
| v v |
| [ Glutathione ] Centrilobular Necrosis |
| | (Zone 3) Hepatotoxicity|
| v |
| [ Mercapturic Acid ] |
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Pathophysiology
- At therapeutic doses, over 85% of paracetamol is safely conjugated via glucuronidation and sulfation into non-toxic metabolites excreted in urine. A small fraction (5–10%) is oxidised by CYP2E1 into the highly electrophilic, toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI).
- Under normal conditions, NAPQI is instantaneously detoxified by conjugation with hepatic glutathione to form non-toxic cysteine and mercapturic acid conjugates.
- In acute overdose, the primary sulfation and glucuronidation pathways saturate. CYP2E1 oxidation shunts an enormous burden of paracetamol into NAPQI formation. Once hepatic glutathione stores are depleted by > 70%, free unconjugated NAPQI binds covalently to cysteinyl sulfhydryl groups on hepatocellular proteins and mitochondrial membranes. This initiates oxidative stress, mitochondrial permeability transition pore opening, ATP depletion, and fulminant centrilobular (Zone 3) hepatic necrosis.
UK TOXBASE Management Guidelines
- Nomogram Utility: Plasma paracetamol concentration must be timed against the single treatment line on the UK TOXBASE nomogram, which starts at 100 mg/L at 4 hours post-ingestion (extrapolating to 15 mg/L at 16 hours). Samples drawn prior to 4 hours post-ingestion cannot be interpreted due to ongoing gastrointestinal absorption.
- Treatment Timeline:
- Presentation < 8 hours: Draw bloods at exactly 4 hours post-ingestion. If concentration is on or above the treatment line, initiate N-acetylcysteine (NAC). Ingestion presenting < 8 hours carries virtually zero risk of hepatic necrosis if NAC is started within 8 hours.
- Presentation 8–24 hours: Start intravenous NAC immediately without waiting for laboratory results. If subsequent paracetamol level is below the line, ALT is normal, and patient is asymptomatic, NAC can be stopped.
- Presentation > 24 hours or Staggered Overdose: In a staggered overdose (tablets taken over an interval > 1 hour), the nomogram cannot be used. Commence IV NAC immediately regardless of the paracetamol level.
Intravenous N-Acetylcysteine (NAC) Protocols
NAC acts as a synthetic glutathione precursor by supplying cysteine, replenishing intracellular glutathione reserves, and directly binding free NAPQI. In late-presenting acute liver failure, NAC additionally improves microcirculatory perfusion, oxygen delivery, and cerebral oedema via free radical scavenging.
- Traditional 21-Hour Regimen: 3-bag infusion (150 mg/kg over 1h, 50 mg/kg over 4h, 100 mg/kg over 16h; total 300 mg/kg).
- Simplified 12-Hour Regimen (SNAP Regimen): Increasingly standard in UK emergency departments: 100 mg/kg over 2 hours, followed by 200 mg/kg over 10 hours. Halves the infusion time and drastically reduces adverse events.
- Anaphylactoid Reactions to NAC: Up to 15% of patients experience a non-IgE-mediated anaphylactoid reaction (histamine release causing erythema, flushing, pruritus, urticaria, or mild wheezing), predominantly during the initial rapid loading infusion. Management: Do NOT permanently discontinue NAC. Temporarily halt the infusion, administer IV chlorphenamine, give nebulised salbutamol if bronchospastic, and restart the NAC infusion at a reduced rate once symptoms resolve.
King's College Hospital Criteria for Liver Transplantation
These criteria identify patients with acute liver failure who have a > 85% predicted mortality without emergency orthotopic liver transplantation:
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| King's College Criteria for Liver Transplantation |
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| PARACETAMOL-INDUCED ACUTE LIVER FAILURE: |
| |
| Arterial Blood pH < 7.30 (sampled >= 24h post-ingestion, following fluid resuscitation) |
| -- OR -- |
| ALL THREE of the following clinical parameters occurring within a 24-hour window: |
| 1. International Normalised Ratio (INR) > 6.5 (Prothrombin Time > 100 seconds) |
| 2. Serum Creatinine > 300 umol/L (3.4 mg/dL) |
| 3. Hepatic Encephalopathy Grade III (somnolent, confused) or Grade IV (coma) |
| |
| *Note: Arterial lactate > 3.0 mmol/L at 12h or > 3.5 mmol/L at 4h after resuscitation |
| is also a strong independent indicator for urgent transplant listing. |
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Salicylate (Aspirin) Poisoning
Salicylates exhibit complex toxicity characterised by a signature mixed acid-base disturbance:
Pathophysiology
- Direct Medullary Stimulation (Early): Salicylates directly stimulate the respiratory centre in the brainstem medulla oblongata, driving hyperventilation and causing a primary respiratory alkalosis (pCO2 decreased, pH elevated).
- Uncoupling of Mitochondrial Oxidative Phosphorylation (Late): Salicylates disrupt the mitochondrial proton gradient, halting ATP synthesis while oxygen consumption and heat generation escalate. Cells shift to anaerobic glycolysis, generating massive amounts of lactic acid and pyruvic acid. Additionally, enhanced lipolysis produces ketoacids, while salicylate molecules contribute exogenous unmeasured anions, establishing a high anion gap metabolic acidosis (HAGMA).
- Classic Acid-Base Blood Gas Profile: In adults, arterial blood gas typically demonstrates a combined primary respiratory alkalosis with a primary high anion gap metabolic acidosis (e.g., normal or near-normal pH, low pCO2, markedly low HCO3-, high anion gap).
Clinical Presentation & Management
- Symptoms: Tinnitus (classic early sign, due to altered cochlear microvascular blood flow), sensorineural deafness, hyperpnoea (Kussmaul-like breathing), pyrexia, profuse sweating, nausea, vomiting, confusion, seizures, non-cardiogenic pulmonary oedema, and cardiovascular collapse.
- Urinary Alkalinisation: Salicylic acid has a pKa of 3.0. In an acidic environment, it remains non-ionised, diffusing freely across renal tubular membranes back into the bloodstream. Administering intravenous 1.26% or 8.4% sodium bicarbonate alkalinises the renal tubular fluid (target urine pH = 7.5 - 8.5). Under alkaline conditions, salicylic acid dissociates into its ionised, charged salicylate form, which cannot cross lipophilic tubular membranes and is trapped in urine (ion trapping), increasing renal excretion up to 20-fold.
- Prerequisite: Must aggressively correct hypokalaemia before alkalinisation will succeed. If hypokalaemia is present, renal intercalated cells will excrete hydrogen ions into the tubular lumen via the H+/K+ ATPase to conserve potassium, rendering urine stubbornly acidic despite systemic alkalaemia.
- Indications for Emergency Haemodialysis:
- Plasma salicylate level > 700 mg/L (5.1 mmol/L) in acute overdose.
- Refractory severe metabolic acidosis (pH < 7.20).
- Severe neurological manifestations (seizures, coma, altered mental state).
- Acute kidney injury or acute pulmonary oedema (preventing fluid/bicarbonate administration).
A 23-year-old woman is brought to the emergency department by emergency medical services after being found unresponsive in her bedroom. Beside her are two empty packets of co-codamol and a suicide note. Her friends state she was last seen intact approximately 36 hours ago. On arrival, she is deeply jaundiced, somnolent, and responds only to painful stimuli with incomprehensible sounds (Grade III hepatic encephalopathy). Vital signs show BP 95/55 mmHg, pulse 115 bpm, respiratory rate 24/min. Arterial blood gas on room air reveals: pH 7.24, PaO2 12.1 kPa, PaCO2 3.8 kPa, HCO3- 12 mmol/L, Base Excess -14 mmol/L, Lactate 5.2 mmol/L. Laboratory investigations confirm: Paracetamol level 18 mg/L, ALT 6,450 U/L, Bilirubin 185 umol/L, INR 7.8 (PT 118 seconds), Serum Creatinine 345 umol/L. Following initial intravenous fluid resuscitation, repeat arterial pH remains 7.26. What is the most definitive and appropriate management priority?
A 31-year-old man presents to the emergency department five hours after intentionally ingesting 50 tablets of dispersible aspirin 300 mg (15 g total). He complains of loud bilateral tinnitus, deafness, and upper abdominal pain. On physical examination, he is flushed, sweating profusely, and breathing rapidly with deep, unlaboured respirations. Vital signs show: Pulse 110 bpm, BP 130/80 mmHg, Respiratory rate 32/min, Temperature 38.2 C. Arterial blood gas reveals: pH 7.46, PaO2 14.2 kPa, PaCO2 2.6 kPa, HCO3- 14 mmol/L, Base Excess -9 mmol/L, Anion Gap 24 mmol/L (normal < 12). Serum potassium is 3.1 mmol/L. His 5-hour serum salicylate concentration is 580 mg/L (therapeutic reference < 200 mg/L). What is the mandatory immediate pharmacotherapeutic intervention?