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\begin{document}

\title{Large paracetamol overdose -- higher dose NAC is required}



\author[1]{D Bateman}%
\affil[1]{University of Edinburgh Division of Clinical and Surgical Sciences}%


\vspace{-1em}



  
  \date{June 10, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Paracetamol poisoning continues to be a worldwide problem and despite
the availability of an affective antidote, N-acetylcysteine (NAC), the
optimal way to use this antidote, particularly following very large
doses of paracetamol, has not been established. Recent case series have
shown an increased toxicity from paracetamol, even in those receiving
prompt NAC therapy, at high doses of paracetamol, particularly in
patients above the 300 mg/L nomogram treatment line. Clinical trial
evidence supporting shorter NAC dosing now allows the possibility for
intensifying treatment without the risk of very high rates of ADRs. New
biomarkers also show the possibility of early identification of patients
at risk of liver injury who might also benefit from increased intensity
treatment. This article discusses these data and proposes a logical
therapy for increasing NAC dosing which now requires clinical trial
testing.%
\end{abstract}%



\sloppy


\textbf{Large paracetamol overdose -- higher dose NAC is required}



\textbf{What is already known}

\textbf{Paracetamol poisoning is the commonest acute poisoning
presentation in the UK and frequent worldwide. It causes a
well-recognised clinical syndrome, resulting in death from liver failure
in the most severe cases. Risk of death is greater in larger overdoses
and later hospital presentation.}

\textbf{In the 1970's a treatment for paracetamol poisoning was
developed, intravenous N-acetylcysteine (NAC). This was enormously
effective, but the first dose used in published studies, 300mg/kg body
weight is still used for every case of paracetamol poisoning, whatever
the dose.}

\textbf{Some authors have recently advocated more intense use of NAC in
larger paracetamol overdoses.}

\textbf{Novel methods of delivering IV NAC that reduce ADR rates
facilitate this approach.}

\textbf{What this article adds}

An argument for a focussed use of more intensive NAC in large
paracetamol overdose is presented.

A method for giving such higher doses is discussed.

Formal studies of this approach are proposed, and their challenges
discussed.



\textbf{Abstract}

\textbf{Paracetamol poisoning continues to be a worldwide problem and
despite the availability of an affective antidote, N-acetylcysteine
(NAC), the optimal way to use this antidote, particularly following very
large doses of paracetamol, has not been established. Recent case series
have shown an increased toxicity from paracetamol, even in those
receiving prompt NAC therapy, at high doses of paracetamol, particularly
in patients above the 300 mg/L nomogram treatment line.}

\textbf{Clinical trial evidence supporting shorter NAC dosing now allows
the possibility for intensifying treatment without the risk of very high
rates of ADRs. New biomarkers also show the possibility of early
identification of patients at risk of liver injury who might also
benefit from increased intensity treatment. This article discusses these
data and proposes a logical therapy for increasing NAC dosing which now
requires clinical trial testing.}

\textbf{Introduction}

It is hard to imagine a clinical pharmacologist today approaching the
dose an antidote based on a strategy of the same dose for every case.
Nevertheless, for paracetamol (acetaminophen) this approach has been
successful has been used for almost 50 years, and there is little doubt
has saved many lives. Is it now time to reassess this `one dose for all'
policy?

\emph{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.\textsuperscript{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.\textsuperscript{1,2} Prescott first showed
the efficacy of NAC in a series of cases of paracetamol overdose in
Edinburgh.\textsuperscript{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.\textsuperscript{2,4} An alternative 3
day, 4 hourly dose, oral regimen was developed in the United States
following discussions between Rumack and the FDA.\textsuperscript{5,6}In
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.\textsuperscript{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.
\textsuperscript{7}Toxicity 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. \textsuperscript{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.\textsuperscript{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.

\textbf{Methods}

In approaching this topic, a search of PubMed was done using index
terms: paracetamol; acetylcysteine; dose; toxicity; massive paracetamol
overdose.

Of the many thousand references identified the author has manually
chosen those that specifically deal with the areas to be covered in this
discussion and identified references also using a large personal
collection that are relevant.

A focus on the 3 areas most apposite to the issue of increasing doses of
NAC in large paracetamol overdose has been adopted, these being evidence
that:-

\begin{enumerate}
\tightlist
\item
  \emph{larger doses of paracetamol cause increased toxicity even with
  NAC therapy}
\item
  \emph{increasing NAC dose may have efficacy in large paracetamol
  overdoses}
\item
  \emph{the various modes of action suggested for NAC that may be
  relevant to any increased efficacy from a larger NAC dose.}
\end{enumerate}

\textbf{Results}

\emph{Larger doses of paracetamol}

Rumack and Bateman reviewed the then chosen doses of NAC in
2012\textsuperscript{6}. 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.\textsuperscript{11}Rumack 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.\textsuperscript{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.\textsuperscript{12}A 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 (\textsuperscript{13,14}) and one from
Australia. (\textsuperscript{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.

\emph{Increasing NAC dose efficacy in large paracetamol overdoses}

The term `massive overdose' has been used by some as a term to cover
this kind of patient, but we currently lack hard clinical trial evidence
on this approach. While there are case reports using increased NAC doses
to date there has been a lack of a clear research strategy. These cases
are rare and will therefore require multicentre studies, making expense
a significant barrier to clinical trials under current UK regulations.
There is nevertheless clear theoretical base for such an approach as
discussed above.

The if the patient presents with a large overdose, and presentation is
delayed beyond 8-12 h, making the need to treat more urgent a dose
corrected for body weight of

500mg/kg body weight seems an alternative simple cut-off for considering
a higher, doubled intensity treatment.\textsuperscript{16} This has the
advantage of simplicity as opposed to more complex algorithms with
varying NAC doses across a range of higher

paracetamol doses.\textsuperscript{6,17}

\emph{Modes of action of NAC}

The mechanisms of paracetamol-induced hepatic damage are now understood
to be more complex than just cysteine depletion, and a series of other
targets in the process of liver injury have been suggested for therapy,
particularly for mitochondrial injury, the response and process of
necrotic hepatocyte death including cell signalling processes, tumour
suppressor proteins that modify the cell cycle (p53) and nuclear factor
erythroid 2-related factor 2 (Nrf2) and as a hydrogen sulfide
precursor.\textsuperscript{18--21} Furthermore NAC might exert
therapeutic effects in other organs rather than just as a sulfhydryl
donor\textsuperscript{22,23}. If relevant to the liver in human acute
paracetamol induced liver failure these mechanisms would help to explain
benefit of NAC in later stages of paracetamol-induced hepatic
failure.\textsuperscript{24,25}

\textbf{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.\textsuperscript{26,27} Similarly metabolic antidotes,
including fomepizole and \selectlanguage{english}calmangafodipir, which are both in clinical
trial and have been studied on a case basis.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.

\textbf{Conclusion}

The time has come to use a higher dose of NAC in patients presenting
with high-dose overdose, over 500mg/kg body weight, or with evidence of
developing hepatic damage while a standard 12 h does of NAC is being
used. The animal and human data show that the earlier NAC is used the
better the outcome, and it would be illogical not to assume the same in
larger paracetamol overdose, further justifying an earlier
intensification of NAC and supporting early assessment of response that
is facilitated by the shorter SNAP NAC regimen.\textsuperscript{8}

\textbf{Data sharing statement.}

No research data are shared in this article

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