Paracetamol Overdose — SAQ

Stem

A 19-year-old female university student is brought to the emergency department by her flatmate, who found her drowsy in her room alongside an empty blister pack of paracetamol and an empty bottle of wine. The flatmate states the patient had been arguing with her boyfriend earlier that day. The patient reports ingesting 24 tablets of 500 mg paracetamol (12 g total) "in one go" approximately 5 hours ago, with a glass of wine. She weighs 60 kg. She takes the combined oral contraceptive pill, has no significant past medical history, drinks alcohol most weekends, and is not on any regular medications.^[1]

On examination she is drowsy but rousable (GCS 14), pale and diaphoretic, with mild nausea. Pulse 96/min, BP 110/70 mmHg, RR 18/min, SpO2 98 percent on room air, temperature 36.8 degrees C, capillary glucose 5.2 mmol/L. Abdomen is soft with no organomegaly. No stigmata of chronic liver disease. The 5-hour serum paracetamol level is 140 mg/L. ALT 32 U/L, AST 28 U/L, bilirubin 12 micromol/L, INR 1.0, creatinine 70 micromol/L, venous pH 7.38, lactate 1.1 mmol/L, salicylate undetectable.^[2]

Questions

a) What is your diagnosis, what is the underlying toxic mechanism, and is N-acetylcysteine indicated? Give the rationale. (3 marks)^[1]

The diagnosis is single acute paracetamol (acetaminophen) overdose^[1] (12 g = 200 mg/kg, well above the 150 mg/kg toxic threshold) at 5 hours post-ingestion. N-acetylcysteine (NAC) IS indicated. The mechanism: at therapeutic doses paracetamol is safely metabolised by glucuronidation (40 to 67 percent) and sulfation (20 to 46 percent); only 5 to 10 percent goes through CYP2E1 producing the toxic intermediate NAPQI (N-acetyl-p-benzoquinone imine), which is immediately detoxified by glutathione (GSH). In overdose the safe pathways saturate, CYP2E1 metabolism surges, GSH is depleted (toxicity when GSH under 30 percent of normal), and free NAPQI binds covalently to hepatocyte proteins producing centrilobular (zone 3) necrosis. The 5-hour level of 140 mg/L is above the UK/ANZ 100 mg/L treatment line and close to the US Rumack-Matthew 150 mg/L line - either way, NAC is indicated. NAC works by replenishing glutathione (it is a cysteine donor, the rate-limiting GSH substrate), and is nearly 100 percent protective if given within 8 hours.

b) Outline the complete IV NAC protocol with the three-bag regimen, the total dose, and the duration. (2 marks)^[1]

The standard IV 21-hour three-bag regimen:^[1]

• Bag 1 (loading): 150 mg/kg in 200 mL 5 percent dextrose over 1 hour = 9000 mg (9 g) for a 60 kg patient.^[1]
• Bag 2: 50 mg/kg in 500 mL 5 percent dextrose over 4 hours = 3000 mg (3 g).^[1]
• Bag 3: 100 mg/kg in 1000 mL 5 percent dextrose over 16 hours = 6000 mg (6 g).^[1]
• Total: 300 mg/kg over 21 hours = 18 g for this patient.

In children the diluent volumes are reduced to avoid fluid overload and hyponatraemia, especially under 20 kg or under 5 years.^[2]

c) During the first hour of NAC she develops flushing and urticaria over her chest with normal blood pressure and oxygen saturation. What is this reaction, and how will you manage it? (2 marks)^[1]

This is an anaphylactoid (non-IgE) reaction to intravenous NAC^[2] — documented in 8.2 percent of 6455 courses in the Canadian national cohort, 75.4 percent cutaneous, 95.4 percent within the first 5 hours (around the loading infusion). It is more common with LOW paracetamol levels (high paracetamol inhibits the reaction) and in atopic patients. It is NOT true IgE anaphylaxis (no hypotension, no bronchospasm, no hypoxia).

Management: (1) pause the infusion; (2) give an antihistamine - chlorphenamine 10 mg IV (or diphenhydramine 25 to 50 mg IV); (3) once symptoms settle, resume the infusion at a slower rate (e.g. over 2 hours instead of 1 hour); (4) do NOT abandon NAC - its life-saving benefit outweighs the reaction. Adrenaline is reserved for true anaphylaxis with hypotension, bronchospasm, or hypoxia. Hydrocortisone has no role in pure non-IgE reactions.^[1]

d) What are the King's College Criteria for paracetamol-induced acute liver failure, and at what stage of management would they be applied? (2 marks)^[1]

King's College Criteria (O'Grady 1989) trigger urgent liver transplant referral^[3] at over 80 percent predicted mortality. Either arm met = refer:

• Arterial pH under 7.3 AFTER adequate fluid resuscitation (irrespective of grade of encephalopathy), OR
• ALL THREE of: INR over 6.5 (PT over 100 s) AND serum creatinine over 300 micromol/L AND grade III or IV encephalopathy (West Haven).

An admission arterial lactate is one of the key prognostic variables in validated dynamic outcome models alongside age, conscious level, pH, creatinine, INR and cardiovascular failure.^[3]

These criteria are applied at any point during the admission when hepatotoxicity has developed - typically at 24 to 96 hours post-ingestion (Phase 2 to 3). Critically, do NOT correct the INR with FFP or vitamin K before transplant assessment, as this confounds the prognostic INR (the key KCC variable). NAC should be continued (Keays 1991 showed improved survival in established ALF).^[3]

e) Name two further mandatory steps before this patient is discharged. (1 mark)

1. Mandatory psychiatric assessment^[1] before discharge in all deliberate self-harm overdoses (a medico-legal requirement in many jurisdictions, including India under the Mental Healthcare Act 2017) - assess suicide risk, underlying mental health, and arrange follow-up. She must not be left unattended in the interim.
2. Counsel the patient that complete hepatic recovery is expected (no cirrhosis) and advise on the dangers of further paracetamol use, with a documented safety plan and crisis contact numbers.

References3ShowHide

1. [1]Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med, 1988.PMID 3059186
2. [2]Yarema M, Chopra P, Sivilotti MLA, et al. Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning. J Med Toxicol, 2018.PMID 29423816
3. [3]O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology, 1989.PMID 2490426