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Paracetamol poisoning
Nick BuckleyProfessorial Medicine Unit UNSWNSW Poisons Information Centre
South Asian Clinical Toxicology Research Collaboration (www.sactrc.org)
March 2013
Paracetamol poisoning for the distracted
90% Conjugation
NAPQI
P450
Glutathione
Free Radical
Paracetamol Toxicity
Paracetamol overdose – Would you like social media with that?
(or acetylcysteine)• A 24 yo woman takes 15 grams of
paracetamol• Paracetamol level at 12 hours
= 300 nmol/mL (45 mg/L)
The State of the art Hypertox
APAP-APP
Questions
M According to guidelines, should she be treated with acetylcysteine?MWhere is she? MWhat year is it?
M What is the risk of hepatotoxicity and death if she is treated with acetylcysteine?
M What is the risk of hepatotoxicity & death if she if not?
What threshold for treatment?
& ? “The high risk line” UK circa 1995
& Schmidt LE, Dalhoff K. Br J Clin Pharmacol 2001 Jan;51:87-91
& Rumack BH, Mathew H. Paediatrics 1975; 55:871-876
& Prescott LF et al Lancet 1971; 519-522
Treatment Nomograms
0 5 10 15 20
10
25
50
100
150200
300
Time
mg
/L
What threshold for treatment?
& Rumack BH, Mathew H. Paediatrics 1975; 55:871-876
& Prescott LF et al Lancet 1971; 519-522
Treatment Nomograms
0 5 10 15 20
10
25
50
100
150200
300
Time
mg
/L
MHRA (UK) – August 2012
& MHRA UK (estimated to prevent one death in UK every 37.5 years vs using 150 line)
& Rumack BH, Mathew H. Paediatrics 1975; 55:871-876
Treatment Nomograms
0 5 10 15 20
10
25
50
100
150200
300
Time
mg
/L
Questions
M According to guidelines, should she be treated with acetylcysteine?MWhere is she? MWhat year is it?
M What is the risk of hepatotoxicity & death if she if not?
M What is the risk of hepatotoxicity and death if she is treated with acetylcysteine?
Time to acetylcysteine (hours) and hepatotoxicity (%)
» Smilkstein MJ et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319:1557-1562.
0
5
10
15
20
25
30
0 to 4, 4 to 8, 8 to 12, 12 to 16, 16 to 20, 20 - 24
CAOS theory – Individualised risk estimates are
as easy as Psi.
Sivilotti et al 2005
APAP-APP
Remaining ‘controversies’ in antidotes for paracetamol
poisoning?• What is the role of liver transplant???
King’s College criteria for transplant in
paracetamol induced liver disease
Arterial pH < 7·3 after adequate fluid
resuscitation.OR (all of)
Grade or IV encephalopathy and
Prothrombin time > 100 seconds and
Serum creatinine > 300 � mol/L
In a 24 hour period.
Q J Med 2008; 101:723–729
Survival curves depending ondecision to transplant with
"Kings criteria"
0 10 20 30 40 50 600
50
100
Transplanted
Not transplantedextrapolationsQALYs
Years
Su
rviv
al %
Other ‘first world problems’
• Slow release paracetamol preparations• Diagnosis of occult overdose
presentations with acute liver failure • Very Early vs 4-8 hour NAC treatment
Extended release OD
» MJA 2008; 188: 310-311
» James LP, Letzig L, Simpson PM etal. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metabolism and Disposition. 2009: 37(8); 1779-1784.
» James LP, Capparelli EV, Simpson PM etal. Acetaminophen-Associated Hepatic Injury: Evaluation of Acetaminophen Protein Adducts in Children and Adolescents With Acetaminophen Overdose. Nature. 2008: 84(6); 684-690.
Dose-related, long-half-life
Given acetylcysteine is about as proven an antidote as we
have – how does it work?• Antioxidant
– Direct– Conversion to cysteine –
• rate limiting step in glutathione synthesis
• “Free radical” scavenger
How quickly should you
scavenge free radicals?
Five decades of paracetamol poisoning - but still more than meets the eye or iphone
• New evidence still needed• No RCTs comparing different NAC regimens• Early risk prediction with adducts?• Duration of NAC in established
hepatotoxicity?• Better & earlier prediction of likely fatal
outcome• Decision support tools
• Risk prediction
Questions?