Historical background
The management of paracetamol poisoning was changed fundamentally in the 1970s by the discovery of the mechanism of toxicity of paracetamol, metabolic transfer to a reactive metabolite N-acetyl benzoquinoneimine (NABQI), and depletion of hepatic cysteine as the cause of toxicity.1 Studies in animals and man clearly showed a dose response relationship between paracetamol dose, hepatotoxicity, risk of liver failure and death. Treatment with sulfhydryl donors was shown to be very effective in preventing this process in animal models, with good evidence for the time criticality of treatment but weaker evidence of a dose response relationship to the effects of sulfhydryl donors such as cysteamine.1,2 Prescott first showed the efficacy of NAC in a series of cases of paracetamol overdose in Edinburgh.3
At that time the science of clinical trials was it in its infancy and dose ranging studies in man of NAC were not done. The first dose used in the UK IV acetylcysteine (NAC) proved highly effective and soon became the antidote of choice. The dose used (300mg NAC/kg) was intravenous given over 20.5 hours in three aliquots, 150mg/kg over 15 min, 50mg/kg over 4 h and 100 mg/g over 20 h.2,4 An alternative 3 day, 4 hourly dose, oral regimen was developed in the United States following discussions between Rumack and the FDA.5,6In both cases the total dose of antidote was based empirically on calculations using estimates of the rates of production of the toxic metabolite of paracetamol, NABQI.6 Once an effective dose was decided in the 1970’s it was deemed unethical to conduct further clinical trials on IV NAC dose in the UK.
Since the original case series of untreated cases in the early 1970’s the use of NAC has been determined by paracetamol dose, optimally assessed by plasma concentration, ideally 4-12 hours after ingestion, although intervention doses and concentrations vary worldwide with implications for numbers of patients treated. 7Toxicity prediction is more difficult following multiple ingestions or in delayed presentation.
IV NAC causes adverse reactions in a significant proportion of patients, their frequency over 60% for vomiting and 30% for anaphylactoid reactions in clinical trial conditions, are related to the initial dosing rate. We showed they can be significantly reduced by a modified NAC regimen as shown in the SNAP trial that used 100mg IV over 2h and 200mg/kg over 10 h. 8,9 Additionally such reactions are more common in patients with lower concentrations of paracetamol, and although very rarely fatal, they are nevertheless problematic in clinical practice as they require interruption to NAC treatment. Despite these advances the standard intravenous dose of NAC has remained based on the patient’s weight, rather than the dose of paracetamol.
Since NAC was introduced there has been discussion on which groups of patients should receive it. Policies across the world still vary from the extreme ‘treat everybody’ in Denmark to a more structured framework operated everywhere else based on a combination of plasma concentration of paracetamol, stated ingested dose and timeframe, time from ingestion to presentation and blood tests taken to assess liver function and clotting factors both to determine need for initial therapy in late presentations and to decide whether to continue treatment in patients developing liver injury.10 This article will therefore focus on exploring what evidence there is to change this approach in the face of high paracetamol overdoses, and at what points in therapy intensification of NAC therapy might be considered and put into practice.