According to the results of a retrospective cohort study published in the British Journal of Clinical Pharmacology, individuals who have had a staggered overdose of paracetamol are at an increased risk of developing multi-organ failure and should be considered for early transfer to a specialist liver centre.  This research has been reported widely in the press. 

The authors note that paracetamol hepatotoxicity is the leading cause of acute liver failure in the UK.  The management of early, non-staggered overdose involves use of N-acetylcysteine (NAC) according to the Prescott nomogram; this however cannot be used on those patients who have taken repeated, sub-therapeutic doses of paracetamol (staggered overdoses).  It is thought that these overdoses, and those where patients present late (>15 hours post-overdose) are at a higher risk of developing hepatotoxicity.

Little is known about the relationship between staggered paracetamol overdoses and the development of severe complications (including need for liver transplantation) and most prognostic models do not consider the mechanism of overdose.  The current single-centre study was conducted to analyse the incidence, clinical course and outcome of staggered paracetamol overdoses and delayed presentation following overdose.

The cohort consisted of 663 patients admitted between 1992 and 2008 to the Scottish Liver Transplantation Unit with a paracetamol-induced severe, acute liver injury.  Information on the time course of the overdose was available in the majority (92.2%) of cases – 450 (73.6%) had a single time point overdose (>4g taken at a single defined time point) and 161 (26.4%) had a staggered overdose (ingestion of two or more supratherapeutic paracetamol doses over a time interval of greater than eight hours, resulting in a cumulative dose of >4 grams per day).

The main findings reported are as follows:

• Patients presenting after a staggered overdose were older (median 39 [29-46] years versus 32 [24-43] years, p<0.001) and more likely to have a history of alcohol abuse (48.9% vs. 29.2%, p<0.001) than those who had a single time point overdose.

• Relief of pain (58.2%) was the most common reason for repeated supratherapeutic ingestion in the staggered group; another 34.3% were taken deliberately as a suicide attempt.  Other causes included accidental overdose during intoxication, non-specific systemic illness, iatrogenic overdose and one overdose taken unintentionally by a patient with cognitive impairment.

• Staggered overdose patients had lower total ingested paracetamol doses and lower admission serum alanine aminotransferase levels.  Despite this, they were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation, and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, p=0.025).  Staggered overdose was not however an independent predictor of death.

• A total of 48 patients presenting with staggered overdose had consumed an overdose of compound analgesics; the majority (43.8%) had used codeine phosphate/paracetamol compounds (co-codamol)

• The King's College poor prognostic criteria (used to determine who will most likely die without transplantation) had reduced sensitivity (77.6 (95% CI 70.8-81.5) for the staggered pattern of overdose.

• Delayed presentation (>24 hours following single point overdose) was independently associated with death/liver transplantation (OR 2.25 (95% CI 1.23-4.12), p= 0.009).

The authors conclude that both staggered overdoses and delayed presentation following overdose are strongly associated with multi-organ injury and the need for liver transplantation.  Such patients should therefore be treated as high risk for progression to acute liver failure, and should receive NAC in their presenting hospitals, whilst laboratory values are awaited.  They should also be considered for early transfer to specialist liver centres.