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.