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.