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IV NAC

Is the 21 hour regime

appropriate for all patients

Dr Paul I Dargan

Clinical Toxicology

Guy’s s and St Thomas’ NHS Foundation Trust

London, UK


Disclaimer

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 only

The focus will be on early presenting patients


Breakdown 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 – 21 Hour Regime

1 st bag 2 nd bag 3 rd 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.

INR in paracetamol poisoning

How can we differentiate between these three causes


INR 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 poisoning

2. Direct paracetamol effect

Occurs early and in context of normal liver function


Factor IX also lower

VIIIc not affected


INR in paracetamol poisoning

3. Direct NAC effect

Intermediate timing in context of normal liver function


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

Case 1

– INR 1.29, ALT 26IU/L, normal creatinine

Does he need more NAC


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 - No NAC


Paracetamol T½ - On NAC

No hepatotoxicity

(n=48)

ALT > 1000 IU/L

(n=43)

Encephalopathy

(n=21)

Half-life

(hours)

Range

3 0.8 – 10

6.4 1.3 – 19

18.4 4.6 – 120

Schiodt Clin Pharm Ther 2002


Paracetamol poisoning cases with altered

paracetamol pharmacokinetics &

hepatotoxicity despite 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]


Continue “16 hour” bag

Case 3

– 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


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

12 hour NAC regime

– 2hrs 100mg/kg, 10hrs 200mg/kg, glucose 5% 8hrs


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

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