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)
•
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
9.
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?
12.
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
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
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.
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
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