Abstract:
Paracetamol overdose is common in developed countries but less than 10%
involve large ingestions exceeding 30g or 500mg/kg. High dose
acetylcysteine (NAC) has been proposed in patients taking large
paracetamol overdoses based on reports of hepatotoxicity despite early
initiation of NAC treatment with the commonly used 300 mg/kg intravenous
acetylcysteine regimen. The evidence from cohorts of patients treated
with the standard NAC regimen after large paracetamol overdoses shows
that it is effective in most patients. Small studies in patients whose
paracetamol concentration are above the 300mg/L nomogram line show that
modification of the standard NAC regimen to provide a total of 400-500
mg/kg NAC over 21-22h may reduce the risk of hepatotoxicity (peak
ALT>1000 IU/L) but the impact on development of hepatic
failure, liver transplantation and mortality with this approach is
presently unknown. Better risk stratification of patients taking
paracetamol overdose may allow higher dose NAC and adjunctive treatments
such as CYP2E1 inhibition and extracorporeal removal of paracetamol to
be targeted to those patients at the highest risk of hepatotoxicity
after a large paracetamol overdose.
Paracetamol is one of the commonest drugs taken in overdose and a
significant cause of acute liver injury in developed countries. The
hepatic toxicity of paracetamol results from its metabolic oxidation to
a reactive metabolite, N-acetyl-para-benzoquinoneimine metabolite
(NAPQI) by cytochrome P450 enzymes when the normal sulphation and
glucuronidation detoxification pathways become saturated in overdose. In
human liver microsomes, CYP2E1, CYP1A2 and CYP2A6 isoforms have been
shown to convert paracetamol to NAPQI, with a reported Km for the CYP2E1
isoform of 100-200 mg/L. Studies with healthy human volunteers
pre-treated with the CYP2E1 inhibitor, disulfiram, confirmed the role of
CYP2E1 in paracetamol oxidation. It is unclear whether the generation of
NAPQI by CYP2E1 follows linear kinetics or is saturable at high
paracetamol concentrations.
NAPQI is detoxified by conjugation with glutathione but when endogenous
glutathione stores are depleted, NAPQI binds to cysteine groups on
cellular proteins to form protein adducts. Intravenous
acetylcysteine(NAC) was developed as an antidote to restore glutathione
stores. The original total dose (300 mg/kg bodyweight) of intravenous
NAC, given as three separate infusions (150 mg/kg over 15 minutes, 50
mg/kg over 4 hours and 100 mg/kg over 16 hours) was empirical and
designed to deliver a high proportion of antidote
rapidly.1 This fixed weight-based regimen regardless
of the paracetamol dose ingested has given rise to much debate about
whether it can adequately replenish glutathione following massive
paracetamol ingestions.
Rumack & Bateman reported that a suggested toxic human paracetamol dose
of 15.9g in an average 70kg patient with a 1.5 kg liver and a
paracetamol half-life of 4h can be adequately detoxified using the
300mg/kg intravenous NAC regimen with a 6.25mg/kg/h infusion in the
third infusion. They proposed using these assumptions that a patient
ingesting 35g (500mg/kg) of paracetamol warranted an increase in
infusion rate in the third bag to 13.75 mg/kg/h.1 The
median reported dose of paracetamol ingested in large cohort studies of
patients treated with NAC in the UK and Australia is around 16g
(210-250mg/kg) but the rates of hepatotoxicity (defined as peak
ALT>1000 IU/L) is only around 4-8%, depending on the
nomogram used to determine treatment2,3, suggesting
that the vast majority of patients ingesting >16g
paracetamol fare well with the current 300 mg/kg NAC dose. Hendrickson
used similar stoichiometric calculations to propose infusion rates of
12.5, 18.75 and 25 mg/kg/h for patients above the 300 mg/L, 450 mg/L and
600 mg/L nomogram lines respectively.4 These
theoretical calculations for the “average” patient assuming linear
paracetamol pharmacokinetics most likely overestimate the infusion rate
required in most patients as they do not account for the large
inter-individual variability in metabolic clearance of paracetamol in
overdose resulting from differences in glucuronidation, sulphation and
CYP2E1 capacity which influence the paracetamol half-life.
Several studies have consistently reported a concentration-dependent
increase in risk of hepatotoxicity (peak ALT >1000 IU/L) in
patients despite early treatment with acetylcysteine. Overall 3.6-4.3%
of patients in large cohort studies in the UK3,5,6 and
8% in Australia2 develop hepatotoxicity but a graded
increase at higher nomogram-related concentrations is observed, with
reported rates of hepatotoxicity of 10.2-15% and 13.6-30.8% in those
patients with a 4h extrapolated paracetamol concentration greater than
300 mg/L and 500 mg/L respectively.5,6 A recent
retrospective review of 104 massive paracetamol overdoses treated with
the standard 21h NAC regimen from a US poison centre reported
hepatotoxicity in 25 cases (24%), of which 9 cases (14%) were in the
300-449 mg/L nomogram group, 1 case (7%) in the 450-599 mg/L nomogram
group, and 15 cases (56%) in the >600 mg/L nomogram group.
Only 4/44 (9%) who were treated within 8h developed
hepatotoxicity.7 These findings have fuelled the
debate over whether higher doses of NAC are required for these perceived
“NAC failures” even though all of these patients recovered and no
deaths and liver transplants were reported in these large cohorts of
patients.
Smilkstein reported in their landmark study using the oral NAC protocol
consisting of a 140 mg/kg loading dose followed by 70 mg/kg every 4h for
17 doses that hepatotoxicity occurred in 2-5% of all cases that receive
NAC within 8h of ingestion even with increasing paracetamol
concentrations. The total oral dose administered in the first 21h is 490
mg/kg and is delivered directly to the liver versus the 300 mg/kg
intravenous dose which is dependent on hepatic extraction of NAC from
the systemic circulation for efficacy.8
The ATOM-2 study, an observational study of massive paracetamol overdose
(defined as 40g or more ingested over 8h or less) in several Australian
hospitals, reported that 28/200 (14%) developed hepatotoxicity (peak
ALT>1000), including 6/200 (3%) of those treated within
8h. 79/200 patients were above the 300mg/L nomogram line and were
treated within 16h of ingestion with either a standard 300 mg/kg NAC
regimen or an increased NAC dose consisting of doubling the dose in the
16-hourly infusion to 200mg/kg (infusion rate 12.5mg/kg/h), giving a
total dose of 400 mg/kg. There was a significant reduction in the rates
of hepatotoxicity from 10/36 (27.7%) in the standard regimen group to
4/43 (9.3%) in the increased NAC regimen (OR 0.27; 95% CI:
0.08–0.94), with most of the beneficial effect observed in those
patients above the triple nomogram line (4h extrapolated concentration
of 450 mg/L).9 It is noteworthy that even in this very
small high-risk subgroup of patients ingesting 40g paracetamol or more
and above the 300 mg/L nomogram line, almost 75% of patients did not
develop hepatotoxicity with the standard 300 mg/kg regimen. It is
uncertain whether this modified regimen would actually alter clinically
important outcomes such as the development of fulminant hepatic failure,
liver transplant and deaths. The modified increased dose regimen used in
the ATOM-2 study is a pragmatic alteration of the existing 21h regimen
and it is unclear whether the benefit seen results from an increased
total dose of NAC or the increased infusion rate and whether a similar
benefit would not have been achieved by a regimen delivering the same
total dose with a higher infusion rate.
Such an approach underpins the SNAP regimen which was based on the
premise that an optimal NAC regimen should provide an initial loading
dose to restore hepatic glutathione stores and an infusion high enough
for glutathione synthesis to exceed NAPQI generation for the vast
majority of patients. We calculated using probabilistic modelling that a
regimen delivering a total dose of 300mg/kg with an initial loading dose
of 100mg/kg over 2h followed by 200 mg/kg over 10h (infusion rate
20mg/kg/h) would be sufficient in most patients.10,11In the small minority of patients with liver injury or persistently
elevated paracetamol concentrations, an extension of the 10h infusion
would provide a 500 mg/kg total dose over 22h. 16/105 (15.2%) patients
with paracetamol overdose above the 300mg/L nomogram line treated within
24h of ingestion with the SNAP regimen developed hepatotoxicity, of
which 3/40 (7.5%) and 9/82 (11%) were treated within 8h and 16h
respectively. All 16 patients who developed hepatotoxicity had evidence
of acute liver injury (ALT>150) at the end of the 12h
infusion (unpublished data).
There is no agreed definition of a massive overdose, with Marks et
al5 and Chiew et al.9 using
arbitrary cut-offs of 30 and 40g or an extrapolated 4h paracetamol
concentration above 250mg/L and 300mg/L respectively and Hendrickson et
al4 suggesting a dose of 32g or a paracetamol
concentration above the 300 mg/L nomogram line. It is also difficult to
define precisely which group of patients might benefit from an increased
dose of NAC and the optimal way of delivering this higher dose. Bateman
and Dear suggested that those who may require a high dose NAC regimen
include doses above 500 mg/kg bodyweight paracetamol, a nomogram
concentration above the 500mg/L line for those with ingestions over a
shorter time (e.g less than 2 h), or a dose likely to result in
mitochondrial paralysis (~1 g/kg).12However, in the presence of mitochondrial dysfunction associated with
paracetamol concentrations greater than 900mg/L, extracorporeal
treatment to enhance clearance of paracetamol is recommended by the
EXTRIP international panel.13 The anecdotal use of
fomepizole as a CYP2E1 inhibitor in conjunction with haemodialysis and
NAC has also been reported following massive paracetamol overdose.
Although the evidence for benefit of higher NAC dose is scanty, pending
newer evidence which is difficult to generate for this small subset of
patients, the most recent guidelines in Australia and New Zealand
pragmatically recommend doubling the concentration of the 16-hour
infusion of NAC from 100 mg/kg to 200 mg/kg (giving a total of 400 mg/kg
over 21h) in patients who ingest more than 30g or 500mg/kg and in those
with a paracetamol concentration more than the 300mg/L nomogram
line.14 Clinicians treating these patients need to
balance the potential benefit in up to 15% of these high-risk patients
against the risk of administration errors with a change of regimen in
some patients. An alternative approach which appears similarly effective
is an extension of the 10h infusion in those patients with abnormal ALT
or persistently elevated paracetamol concentrations at the end of the
12h SNAP regimen.
It is evident from several large patient cohorts that most patients with
large paracetamol overdoses do well with the 300 mg/kg intravenous NAC
regimen (whether given over 12h or 21h) and do not require high dose
NAC. There will undoubtedly be a small proportion of patients with
either abnormally low glucuronidation and sulphation capacity, high
CYP2E1 activity or low gluthathione stores who may benefit from higher
NAC dose or adjunctive treatments. Further research is required to
assess the effectiveness of modified NAC regimens, CYP2E1 inhibition,
extracorporeal elimination either alone or in combination in at-risk
patients. Better risk stratification of patients with paracetamol
overdose at presentation to identify those at high risk of developing
hepatotoxicity would facilitate multi-centre prospective studies to
evaluate the optimal strategy for managing this small subset of
high-risk patients with a view to improving clinically important
outcomes other than a historically determined clinical endpoint of peak
ALT>1000. Novel biomarkers including mir-122 and
paracetamol adduct concentration at presentation have been shown to
predict subsequent development of hepatotoxicity.15,16The development of point-of-care tests that can quantify paracetamol
concentration, ALT and novel biomarkers would be a major advance in
facilitating such stratified trials in future.