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Dr Paul I DarganDr Paul I Dargan
Clinical ToxicologyClinical Toxicology
GuyGuy’’s and St Thomass and St Thomas’’ NHS Foundation TrustNHS Foundation Trust
London, UKLondon, UK
IV NACIV NAC
Is the 21 hour regime Is the 21 hour regime
appropriate for all patients? appropriate for all patients?
DisclaimerDisclaimer
� I have been an adviser to the FDA and McNeil
pharmaceuticals on paracetamol availability and
its impact on paracetamol poisoning
� I have received research grant funding from
McNeil pharmaceuticals for research investigating
paracetamol availability
This session will consider IV NAC onlyThis session will consider IV NAC only
The focus will be on early presenting patientsThe focus will be on early presenting patients
Breakdown of this sessionBreakdown of this session
Interactive session!
� Three cases to focus the discussion on
– Criteria for cessation of IV NAC
–Whether the 21 hour regime is appropriate for
all paracetamol poisoned patients
I won’t discuss recent UK changes in paracetamol poisoning
management, but would be happy to over a beer …
IV NAC IV NAC –– 21 Hour Regime21 Hour Regime
1st bag 2nd bag 3rd bag
Duration 1 hour 4 hours 16 hours
NAC dose 150mg/kg 50mg/kg 100mg/kg
NAC dose/hr 150mg/kg/hr 12.5mg/kg/hr 6.25mg/kg/hr
Case 1
� A 26 year old man presents 6 hours after ingestion
of 24x 500mg paracetamol tablets
� Presentation blood tests
– Paracetamol concentration 152mg/L
– INR 1.05, ALT 24IU/L, normal creatinine
� He receives the standard 21 hour IV NAC regime
� Post NAC blood tests
– INR 1.29, ALT 26IU/L, normal creatinine
� Does he need more NAC?
� What are the three potential influences on INR in
patients with paracetamol poisoning
1.
2.
3.
How can we differentiate between these three causes?
INR in paracetamol poisoningINR in paracetamol poisoning
1. Coagulopathy in patients with hepatotoxicity
� Occurs later and in context of abnormal LFT
� Prognostically important,
– key component of liver transplantation criteria
INR in paracetamol poisoningINR in paracetamol poisoning
2. Direct paracetamol effect
� Occurs early and in context of normal liver function
INR in paracetamol poisoningINR in paracetamol poisoning
3. Direct NAC effect
� Intermediate timing in context of normal liver function
INR in paracetamol poisoningINR in paracetamol poisoning
� A 26 year old man presents 6 hours after ingestion
of 24x 500mg paracetamol tablets
� Presentation blood tests
– Paracetamol concentration 152mg/L
– INR 1.05, ALT 24IU/L, normal creatinine
� He receives the standard 21 hour IV NAC regime
� Post NAC blood tests
– INR 1.29, ALT 26IU/L, normal creatinine
� Does he need more NAC?
Case 1
Case 2� A 24 year old man presents 4 hours after ingestion
of 64x 500mg paracetamol tablets
� Presentation blood tests
– Paracetamol concentration 548mg/L
– INR 1.05, ALT 24IU/L, normal creatinine/lactate
� He receives the standard 21 hour IV NAC regime
� Post NAC blood tests
– INR 1.09, ALT 28 IU/L, normal creatinine
� Is this all of the information we need to determine
whether more NAC is required?
Paracetamol concentration at end of NAC
� Which patients may need a post-NAC
paracetamol concentration?
� Why?
Paracetamol T½ - On NAC
Half-life (hours)
Range
No hepatotoxicity(n=48)
3 0.8 – 10
ALT > 1000 IU/L
(n=43)6.4 1.3 – 19
Encephalopathy
(n=21)18.4 4.6 – 120
Schiodt Clin Pharm Ther 2002
Paracetamol poisoning cases with altered Paracetamol poisoning cases with altered
paracetamol pharmacokinetics & paracetamol pharmacokinetics &
hepatotoxicityhepatotoxicity despite IV NACdespite IV NAC
� 77 patients treated with IV NAC within 8 hours
of ingestion
– 7 patients received NAC > than 21 hrs
Case 3
� A 32 year old woman presents 9 hours after ingestion
of 36x 500mg paracetamol tablets
� Presentation blood tests
– Paracetamol concentration 88mg/L
– INR 1.05, ALT 24IU/L, normal creat
� She receives the standard 21 hour IV NAC regime
� Post NAC blood tests
– INR 1.7, ALT 680IU/L, normal creat, [pmol]
<10mg/L
� Does this patient require more NAC
� Continue “16 hour” bag
– 100mg/kg over 16 hours
� How long should the NAC be continued?
� What should the end points of NAC therapy be?
� Some data to show effectiveness of NAC in
patients with established ALF
� Limited data to guide therapy in patients with
moderate hepatoxicity
Case 3
Current UK Practice Current UK Practice
� At or just before end of 21 hour infusion
– INR, LFT, bicarbonate, creatinine
Continue NAC at 100mg/kg over 16 hours if
� ALT more than doubles OR
� INR > 1.3 with abnormal ALT
In patients receiving extended course NAC
� Repeat bloods every 6-12 hours
� Continue NAC until
– INR < 1.3 or
– INR decreased on two consecutive tests and < 3.0
What about shorter course IV NAC?What about shorter course IV NAC?
� 12 hour NAC regime
– 2hrs 100mg/kg, 10hrs 200mg/kg, glucose 5% 8hrs