SN5 SHORT NOTE 5M ★ High-yield

Describe paracetamol poisoning with its stages and management.

Forensic Medicine · 2nd Professional — Para-Clinical

Mechanism and the Course

Paracetamol (acetaminophen) is among the commonest agents in self-poisoning worldwide, precisely because it is regarded as harmless and is available without prescription everywhere
Mechanism — at therapeutic doses about 90% is conjugated with glucuronide and sulphate and excreted, and a small fraction is oxidised by cytochrome P450 (CYP2E1) to the highly reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine), which is immediately detoxified by conjugation with glutathione
In overdose the conjugation pathways are saturated, more paracetamol is diverted to the P450 route, and glutathione is depleted. Free NAPQI then binds covalently to hepatocyte proteins, causing centrilobular (zone 3) hepatic necrosis
Toxic dose — generally above 150 mg/kg, or about 10 to 15 g in an adult; and lower in those at higher risk — chronic alcoholics and those on enzyme-inducing drugs (rifampicin, phenytoin, carbamazepine), in whom P450 is induced and glutathione already depleted; and the malnourished, in whom glutathione stores are low — a consideration of real importance in India

Stage	Time	Features
I	0 to 24 hours	Nausea, vomiting, malaise, pallor — or, very often, nothing AT all. The patient feels and looks well
II — the latent phase	24 to 72 hours	Symptoms settle; right upper quadrant pain and tenderness appear; and the transaminases begin to rise steeply while the patient still feels well
III — hepatic failure	72 to 96 hours	Jaundice, coagulopathy, hypoglycaemia, encephalopathy, lactic acidosis and acute kidney injury. Transaminases in the thousands. This is when death occurs
IV	4 days to 2 weeks	Either progressive liver failure and death, or complete recovery with no residual damage — there is no chronic sequel in survivors

CLINICAL PEARL

The paracetamol patient looks completely well for the first day, and the antidote works best in exactly that window. N-acetylcysteine is almost fully protective within 8 hours and progressively less effective thereafter — so the decision to treat has to be made on the dose and the level, never on how the patient appears. By the time they look ill, the liver is already necrotic.

Assessment and Treatment

The paracetamol level at 4 hours or later after a single acute ingestion, plotted on the RUMACK-matthew nomogram, determines treatment. A level before 4 hours cannot be interpreted, since absorption is incomplete
Treat without waiting for the level where the time is unknown, the ingestion was staggered over hours, the presentation is late, or the history suggests a large dose — the nomogram applies only to a single acute overdose at a known time
N-acetylcysteine (NAC) is the antidote. It replenishes glutathione, acts as a glutathione substitute, and enhances the sulphate pathway. Given intravenously in three sequential infusions over 21 hours, or orally
Timing — NAC is essentially completely protective if started within 8 hours, and its efficacy declines progressively thereafter; but it is still beneficial even in established hepatic failure and should be given however late the presentation
Adverse reactions — an anaphylactoid reaction with flushing, urticaria and bronchospasm is common with the intravenous form; it is rate-related and not a true allergy, and is managed by slowing or pausing the infusion and giving an antihistamine, not by abandoning the antidote
Other measures — activated charcoal within an hour; glucose for hypoglycaemia; vitamin K and fresh frozen plasma; and referral for liver transplantation where the king’S college criteria are met — an arterial pH below 7.3 after resuscitation, or the combination of a prothrombin time above 100 seconds, creatinine above 300 micromol/L and grade III or IV encephalopathy

Applied Aspects

Never be reassured by a well-looking patient; the first 24 hours are characteristically asymptomatic, and the decision to treat rests on the dose and the level
Take the level at 4 hours, not before; an earlier sample is uninterpretable and may falsely reassure
Start NAC empirically where the timing is unknown or staggered; the nomogram does not apply, and the cost of unnecessary treatment is trivial beside the cost of missing it
Do not stop NAC for an anaphylactoid reaction; slow the infusion, give an antihistamine and continue — abandoning the antidote for a rate-related reaction has caused deaths
Lower your threshold in alcoholics, the malnourished and those on enzyme-inducers; they are damaged by doses that would be safe in others, which is directly relevant in Indian practice
Give NAC however late they present; it remains beneficial in established hepatic failure, and lateness is not a reason to withhold it
Check the glucose repeatedly in established hepatic failure; hypoglycaemia is profound, recurrent and easily missed in an encephalopathic patient

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