Paracetamol

Content by David Gibson.

Introduction

1. DGRI is using the Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) regime – for the treatment of paracetamol excess.
2. The SNAP consists of IV N-acetylcysteine (NAC) 100mg/kg over 2 hours then 200mg/kg over 10 hours. The IV NAC prescribing and administration charts are given here.
3. The new regimen is:
   • Shorter – potentially fewer interruptions to infusion, shorter length of stay.
   • Safer – less chance of anaphylactoid reactions (loading dose is slower).
   • As good at preventing toxicity as standard 21 hour regimen.
4. For further advice please consult the online TOXBASE resource (www.toxbase.org (password required)) and if necessary call the National Poisons Information Service (NPIS) for clinical advice in complex situations – telephone number on TOXBASE.

Overview

1. Paracetamol is the most common drug taken in intentional overdoses, accounting for 48% of UK hospital poisoning admissions.
2. Paracetamol is metabolised by the cytochrome P450 enzyme system to a toxic metabolite that is normally detoxified by glutathione – toxicity occurs when glutathione stores are depleted.
3. Risk of hepatotoxicity should no longer be stratified according to the presence of risk factors like glutathione deficiency or liver inducing enzymes.
4. 4g of paracetamol (or 75mg/kg) over 24 hours is the recommended dose for most adult patients – any ingestion over this is an overdose.
5. 3g of Parcetamol over 24 hours is the maximum adult dose for patients <50kg and for those whose body weight is unknown but look as if they might be <50kg.
6. In overdose the risk of significant liver damage is directly proportional to the amount of paracetamol ingested – very unlikely if <75mg/kg ingested, rarely if 75-150mg/kg and can be serious if >150mg/kg.

Paracetamol Overdoses Are Categorised Into Five Different Categories:

1. Ingested over a period of one hour or less and presenting 0 – 8 hours after acute ingestion.
2. Ingested over a period of one hour or less and presenting 8 – 24 hours after acute ingestion.
3. Ingested over a period of one hour or less and presenting more than 24 hours after acute ingestion.
4. Ingestion of a therapeutic excess of paracetamol.
5. Staggered paracetamol overdose (Repeated doses taken over more than 1 hour, in the context of self-harm).

The Paracetamol Nomogram

1. The Nomogram should only be used in single (rather than staggered) overdoses where the dose is known and timing fairly clear
2. Management has been simplified to a single treatment line on the new paracetamol treatment nomogram.
3. Paracetamol plasma < 4 hours after ingestion cannot be interpreted.
4. Risk of severe liver damage if plasma paracetamol falls above a single line joining 100mg/l at 4 hours with 15mg/l at 15 hours
5. If ALT above upper limit of normal consider NAC even if plasma paracetamol below treatment line

Dosing N-Acetylcystine (Parvolex)

1. Once the need to start N-acetylcysteine has been determined, please consult the paper Intravenous Acetylcysteine prescribing and administration chart for Adults and Children 6 years or more – this can be downloaded here. This chart provides all the necessary information for dosing and administration of acetylcysteine.
2. If the patient is under 13 years of age but >30kg consider discussion with Paediatrician.
3. For pregnant patients, the toxic dose is calculated using the patient’s pre-pregnancy weight.
4. For patients weighing >110 kg, the toxic dose should be calculated using a maximum of 110 kg instead of the patient’s actual weight.
5. Patients on Renal Replacement Therapy (any type) need a doubling of the dose of NAC.

End of Treatment

1. Refer to appropriate TOXBASE section (end of Infusion 2 guidance on printed chart for ease of reference but any treatment longer than this needs reference to the TOXBASE system online)

If Criteria for Discontinuation Are Not Met

1. Continue extended treatment by prescribing acetylcysteine on a new chart at the dose and infusion rate used in the 2nd treatment infusion.
2. Recheck U&Es, bicarbonate, LFTs, FBC and INR every 10 hours to assess course of liver injury. See Toxbase regarding when to discontinue extended treatment.

Adverse Reaction with N-Acetylcysteine (Parvolex)

1. Anaphylactoid reactions occur in 5-20% of patients treated with NAC. These are generally mild such as flushing, itching, rashes and more rarely bronchospasm and hypotension.
2. Previous anaphylactoid reactions to acetylcysteine are not contraindications for a further treatment course. The “SNAP” regimen does offer the benefits of lower rates of reactions than the previous regimen.
3. If mild – stop NAC, give antihistamine e.g. chlorphenamine if required, then seek senior advice.
4. If bronchospasm or hypotension – stop NAC, treat as anaphylaxis (click here for section on Anaphylaxis), then discuss with senior whether to restart NAC at slower rate.
5. If previous reaction to NAC then pre-treat with Chlorphenamine 10mg IV and Ranitidine 50mg diluted to 20ml, given IV over at least 2 min.

Incipient Liver/Renal Failure

1. These patients are best managed in CCU and the ICU team (and renal team in cases of renal failure) should be made aware early
2. Beware hypoglycaemia as cause of coma early in course of incipient liver failure.
3. Rx Lactulose to prevent encephalopathy when INR >2.
4. Edinburgh recommend that we don’t correct coagulation defects unless actively bleeding, as they use INR to assess prognosis.
5. Peak liver necrosis occurs 72 – 96 hours after OD. If INR on way down by this time, can go home when medically fit.
6. Consider referral to Liver Unit, Edinburgh Royal if:
   • INR >2.0
   • Prolonged PT >100seconds
   • H+ >50
   • Hypoglycaemia
   • Conscious level impaired
   • Creatinine >200 micromol/l
7. For more information, check Edinburgh Liver Unit website.

Incipient Renal Failure

1. Albuminuria and micro haematuria in first 24-36 hours suggest incipient renal failure.
2. Plasma creatinine better marker of renal failure than urea when liver damage present.
3. Keep careful fluid balance chart and monitor creatinine daily.
4. Peak renal necrosis will be reached at 72 to 96 hours. If no organ damage by this time the patient can be discharged.

Links

• J.M. Pettie, T.M. Caparrotta, R.W. Hunter, et al. Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose.