Discussion
Cases of very large paracetamol overdoses are unusual, but these patients present specific
problems for management. There is clearly a sound theoretical basis for using an
increased dose of NAC as soon as practicable in the management of such patients.(Rumack
and Bateman 2012) Other treatments have been suggested, including haemodialysis, for
which there is reasonable evidence of efficacy in removal of paracetamol, but much less of
hepato-protection.26,27 Similarly metabolic antidotes, including fomepizole and calmangafodipir, which are both in clinical trial and have been studied on a case basis.17,28–30
Identifying patients at increased risk may be difficult as there is a variability in the
susceptibility to paracetamol which is still not fully understood.31 Obviously very high doses present a risk, but newer molecular techniques now allow identification of patients at risk of liver injury at hospital presentation.32–34 As these are introduced into therapy routinely the management of this common poisoning should change again. One significant advance has happened the use of a modified NAC dosing regimen (SNAP) first described in 2014 which now has both clinical trial evidence and reasonable outcome data.8,35 This regimen uses a 12-hour tailored infusion of 300 mg per kilogram NAC. It therefore delivers the current international standard dose but over a shorter period. It effectively intensifies early overdose management but with far fewer adverse effects. This offers opportunities to further intensify NAC therapy.
The first opportunity is at presentation, if there is a clear history of large overdose, when doubling of the infusion should provide reasonable protection for the vast majority of high quantity overdoses, if administered within the first 12 hours. A second opportunity for continuing this higher dose, or increasing a standard dose occurs at the end of this 12 hour period. At present in this regimen bloods are taken 10 hours into the infusion in order that clear therapeutic decisions can be made prior to the end of the infusion. Thus, even if a standard dose of 300 mg per kilogram is used initially this can be repeated, or even doubled, if blood test suggest liver damage is occurring, or paracetamol clearance is significantly delayed. This is in contrast to standard regimens which, allow intensification at presentation or at 21 h and with dose doubling of this will therefore deliver a smaller dose in this first 21 hours than intensifying the SNAP regimen.
This intensified regimen has not been subject to clinical trial, and it seems unlikely that it would be possible to do this within the present environment of the UK and the numbers of very high ingestions seen. Most likely an international collaborative study with you would be required. The present evidence base is however far stronger for this approach than for any other currently being proposed.