Paracetamol Overdose

Introduction

Paracetamol overdose is the commonest single-agent poisoning presenting to UK emergency departments, and one of the most heavily examined, because its danger is almost entirely hidden: a patient can feel completely well for 24 hours or more while a toxic metabolite is already destroying their liver. Missing the diagnosis, or delaying treatment while waiting for symptoms that will not appear until it is too late, is the central risk this article is built around avoiding.¹ Its wide availability without prescription, combined with this delayed and initially silent toxicity, is exactly why it remains a common means of both deliberate and accidental serious poisoning.

Paracetamol is normally metabolised safely, with only a small fraction converted by the cytochrome P450 system to a reactive, hepatotoxic metabolite, NAPQI, which is immediately conjugated by glutathione and rendered harmless. In overdose, the normal conjugation pathways are saturated, more paracetamol is shunted through the P450 route, and glutathione stores become depleted - once glutathione runs out, NAPQI accumulates and binds hepatocyte proteins directly, causing centrilobular (zone 3) hepatic necrosis.

Pattern of clinical features over time

The clinical course unfolds in a recognisable sequence that is worth knowing explicitly, since the patient's apparent wellbeing on day one is exactly what makes this overdose dangerous.

Assessment and the treatment nomogram

Establish, as precisely as possible: what was taken, the estimated total dose, the time of ingestion (or the time of the first and last doses if staggered), any co-ingestants (including alcohol and other analgesics), and whether the ingestion is a single acute event or has occurred over a longer period.

• Single, acute ingestion with a known time: take a paracetamol level at or after 4 hours post-ingestion and plot it on the treatment nomogram - a level taken before 4 hours may still be rising and cannot be interpreted
• Presentation within 1 hour of a large ingestion: consider activated charcoal (50 g) in addition to awaiting the level
• Staggered overdose (taken over more than 1 hour) or uncertain timing: the nomogram cannot be used - start N-acetylcysteine immediately without waiting for a level, and send baseline bloods
• Presentation after 8 hours with a significant reported ingestion: start N-acetylcysteine immediately while awaiting the level, since delaying treatment for the level to return risks missing the window of maximum efficacy

The treatment nomogram

UK guidance was simplified in 2012: the previous two-line nomogram (a standard and a lower 'high-risk' treatment line for patients with risk factors for enhanced toxicity) was replaced with a single treatment line, running from 100 mg/L at 4 hours to 15 mg/L at 15 hours. Any level on or above this line indicates treatment with N-acetylcysteine; risk factors for enhanced toxicity are no longer used to lower the treatment threshold, but are still relevant to overall clinical risk and monitoring.²

N-acetylcysteine

N-acetylcysteine (NAC) works by replenishing glutathione stores, allowing NAPQI to be safely conjugated again, and by providing substrate for the sulfation pathway. It is highly effective when started within 8 hours of ingestion, with efficacy falling progressively the longer treatment is delayed - but it is still given, and still reduces the risk of severe hepatotoxicity, even when started later, so a late presentation is never a reason to withhold it.

• Indications: a level on or above the treatment line, any staggered or uncertain-timing overdose, or any significant ingestion presenting after 8 hours pending the level
• Regimen: given as a weight-based IV infusion; many UK centres now use a modified two-bag ('SNAP') regimen given over 12-21 hours rather than the traditional three-bag regimen over 21 hours, since the modified regimen has been shown to reduce the frequency and severity of anaphylactoid reactions while maintaining effectiveness - follow local protocol for the specific regimen in use
• Monitoring during treatment: repeat LFTs, INR, U&Es and venous bicarbonate/lactate at completion of the infusion (or per local protocol), to assess whether hepatotoxicity has developed and whether treatment needs to continue

Repeated supratherapeutic ingestion

A distinct and easily missed scenario is repeated ingestion of doses above the recommended maximum over a period of days - for example someone taking paracetamol for pain relief who unintentionally exceeds 4 g a day for several days, rather than taking one large single overdose. This pattern cannot be assessed with a single level and nomogram, since there is no single ingestion time to plot against.

• Take a paracetamol level, LFTs, INR and U&Es regardless of the level, since a 'normal' level does not exclude significant cumulative toxicity in this pattern
• Treat with N-acetylcysteine if there is any suggestion of hepatotoxicity (deranged LFTs or INR), a detectable paracetamol level, or a history suggesting a total ingestion that could plausibly cause toxicity
• Have a low threshold to start NAC in this group while results are pending, since the risk of under-treating a genuine chronic excess outweighs the relatively low risk of NAC itself

Investigations

• Paracetamol level - timed as above
• LFTs - baseline ALT is a key marker; a normal ALT at presentation with a low-risk level and asymptomatic patient supports discharge, while a rising ALT signals hepatotoxicity
• INR/clotting - prothrombin time (or INR) is one of the most sensitive markers of hepatic synthetic dysfunction and rises before other signs of liver failure
• U&Es and creatinine - paracetamol can cause acute kidney injury independent of liver failure in severe overdose
• Venous or arterial blood gas - metabolic acidosis is a marker of severity and features in the King's College Criteria
• Salicylate level and a pregnancy test where relevant, and screening for co-ingestants

Severe hepatotoxicity and King's College Criteria

Patients who develop or are at risk of fulminant hepatic failure need early discussion with a liver unit, ideally before they meet formal transplant listing criteria, since deterioration can be rapid. The King's College Criteria for paracetamol-induced liver failure are used to identify patients who should be discussed for transplantation:

• Arterial pH below 7.3 (after adequate fluid resuscitation), 24 hours or more after ingestion, or all three of the following together:
• INR greater than 6.5 (prothrombin time over 100 seconds)
• Creatinine above 300 micromol/L
• Grade III or IV hepatic encephalopathy

Discharge and follow-up

Patients with a level below the treatment line, a normal ALT, and who are asymptomatic at the appropriate time point (generally once at least 8-24 hours have passed since ingestion, per local protocol) can usually be discharged once medically clear. Every deliberate overdose needs a structured psychiatric risk assessment before discharge, addressing ongoing suicidal ideation, protective factors, and a safety plan - this should run in parallel with medical treatment, not be deferred until the medical episode is fully resolved.

Red flags

Prognosis

Most patients treated appropriately, particularly those started on N-acetylcysteine within 8 hours of ingestion, make a full recovery with no lasting liver injury. Outcome worsens with delayed presentation, delayed treatment, and larger ingestions, and a small proportion of patients with severe hepatotoxicity progress to fulminant liver failure requiring transplantation, which is why early recognition and prompt treatment - not waiting for symptoms that may never appear before it is too late - defines good management of this overdose.