Larger doses of paracetamol
Rumack and Bateman reviewed the then chosen doses of NAC in 20126. They discuss in detail how in the 1970’s work in animals and man was used to calculate the amount of the mercapturate conjugate of paracetamol, the end point of NAPQI metabolism before cysteine depletion and hence determine an estimated effective dose of NAC for human poisoning based on Mitchell et al who had suggested that a dose of 15 g of paracetamol was the toxic threshold.11Rumack and Bateman used these data to establish likely NAC requirements (dose/kg/h) in a 70kg patient ingesting from 15.9 to 47.7g paracetamol, these doses being chosen to simplify the calculations. At the highest dose they estimated the NAC requirement to be a 17.75mg/kg/h. Their calculations are untested in patients, and subject to potential error.6 Thus at this concentration a 70 kg patient with a VD of approximately 0.9 L/kg would have 18.9g of paracetamol in their body 4h after their initial dose. As the bioavailability of paracetamol at therapeutic dose is about 75% and half-life in untreated patients of the order of 2 h it is clear that a dose well above 20g would be necessary to achieve these concentrations.12A problem with such calculations is that clearance of paracetamol is impaired in overdose, but as the half-life in non-toxic patients is of the order of 2 h, it can be seen that suggestions of 50g as a cut off for “massive overdose” may have some basis in theory.
Supportive evidence for inadequacy of current NAC doses in large overdose that this has
been found in 2 UK case series (13,14) and one from Australia. (15) All three showed a dose dependant increase in toxicity with a clear upturn in risk with a nomogram concentration above the 300 mg/L nomogram line (300mg/L at 4 h post OD; line half-life 4 h) in those treated within 8 h in the 2 UK studies.