iv nac is the 21 hour regime appropriate for all patients?

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 …

Patient tailored IV NAC

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


� 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


2. Direct paracetamol effect

� Occurs early and in context of normal liver function


Factor IX also lower VIIIc not affected

3. Direct NAC effect

� Intermediate timing in context of normal liver function


� A 26 year old man presents 6 hours after ingestion








� Does he need more NAC?

Case 1

Case 2� A 24 year old man presents 4 hours after ingestion




– INR 1.05, ALT 24IU/L, normal creatinine/lactate



– 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 - No NAC

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




– INR 1.05, ALT 24IU/L, normal creat

� She receives the standard 21 hour IV NAC regime


– 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

The Future?

Alternative IV NAC Regimes?

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

What about shorter course IV NAC?What about shorter course IV NAC?

4 arms

� 12 hour NAC / ondansetron

� 12 hour NAC / placebo

� Standard NAC / ondansetron

� Standard NAC / placebo

� Reporting 2013/14

iv nac is the 21 hour regime appropriate for all patients?

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