Buckley analyses the details and prescribes a more logical remedy for a toxic overdose.

1. Paracetamol poisoning
Nick Buckley
Professorial Medicine Unit UNSW
NSW Poisons Information Centre
South Asian Clinical Toxicology Research
Collaboration (www.sactrc.org)
March 2013

2. Paracetamol poisoning
for the distracted

3. Paracetamol Toxicity
90% Conjugation
P4
50
Glutathione
NAPQI
Free
Radical

4. 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)
•

5. The State of the art
Hypertox
APAP-APP

6. Questions
M
According to guidelines, should she be
treated with acetylcysteine?
MWhere
is she?
MWhat year is it?
M
M
What is the risk of hepatotoxicity and
death if she is treated with
acetylcysteine?
What is the risk of hepatotoxicity &
death if she if not?

7. What threshold for treatment?
Treatment Nomograms
300
&
200
150
Prescott LF et al Lancet
1971; 519-522
m g /L
100
&
50
25
&
&
10
0
5
10
Time
15
20
Rumack BH, Mathew H.
Paediatrics 1975; 55:871-876
? “The high risk line”
UK circa 1995
Schmidt LE, Dalhoff K. Br J Clin
Pharmacol 2001 Jan;51:87-91

8. What threshold for treatment?
Treatment Nomograms
300
&
200
150
Prescott LF et al Lancet
1971; 519-522
m g /L
100
&
50
25
10
0
5
10
Time
15
20
Rumack BH, Mathew H.
Paediatrics 1975; 55:871-876

10. MHRA (UK) – August 2012
Treatment Nomograms
300
200
150
mg/L
100
&
50
25
&
10
0
5
10
Time
15
20
Rumack BH, Mathew H.
Paediatrics 1975; 55:871-876
MHRA UK
(estimated to
prevent one death in UK every 37.5
years vs using 150 line)

11. Questions
M
According to guidelines, should she be
treated with acetylcysteine?
MWhere
is she?
MWhat year is it?
M
M
What is the risk of hepatotoxicity &
death if she if not?
What is the risk of hepatotoxicity and
death if she is treated with
acetylcysteine?

13. Time to acetylcysteine (hours)
and hepatotoxicity (%)
30
25
20
15
10
5
0
0 to 4,
4 to 8,
8 to 12, 12 to 16, 16 to 20, 20 - 24

14. CAOS theory –
Individualised risk estimates are
as easy as Psi.

15. Sivilotti et al 2005

16. APAP-APP

22. 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
In a 24 hour period.
mol/L

23. Survival curves depending on
decision to transplant with
"Kings criteria"
100
Survival %
Transplanted
QALYs
extrapolations
Not transplanted
50
0
0
10
20
30
40
50
60
Years
Q J Med 2008; 101:723–729

24. 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

25. Extended release OD
»
MJA 2008; 188: 310-311

26. »
»
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.

27. Dose-related, long-half-life

28. 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

30. How quickly
should you
scavenge free
radicals?

32. 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

33. Questions?