Acute Paracetamol Toxicity

OVERVIEW

  • most common OD in the west
  • hepatic metabolism
  • following overdose glucuronidation and sulphation pathways are rapidly saturated -> increased metabolism to NAPQI (N-acetyl-P-benzoquineimine)
  • glutathione is required to inactivate NAPQI and when levels depleted -> hepatocellular death takes place

CLINICAL FEATURES

  • overdose of > 10g or > 200mg/kg
  • doses of > 250mg/kg associated with massive hepatic necrosis and liver faillure
  • be aware of the late presenters (> 8 hours since OD and start NAC empirically)

Stage 1 (0-24hrs)

  • asymptomatic or GI upset only

Stage 2 (24-48 hrs)

  • resolution or nausea and vomiting
  • RUQ pain and tenderness
  • progressive elevation of transaminases, bilirubin, PT

Stage 3 (48-96 hrs)

  • hepatic failure (jaundice, coagulopathy, encephalopathy)

Stage 4

  • death from hepatic failure
  • normalisation of LFT’s and complete resolution of hepatic architecture by 3 months

RISK FACTORS FOR TOXICITY

Underlying hepatic impairment

  • viral hepatitis
  • alcoholic liver disease

Microsomal enzyme induction

  • phenobarbitone
  • carbamazepine
  • phenytoin
  • rifampicin
  • OCP
  • chronic alcohol ingestion
  • starvation

Acute glutathione depletion states

  • acute illness with decreased nutrient intake
  • anorexia/bulimia/malnutrition
  • chronic alcoholism
  • HIV

INVESTIGATIONS

  • paracetamol (APAP) levels:
    -> compare to Australasian nomogram (modified version of Rumack-Matthews nomogram)
    -> no role in chronic toxicity
    -> treat if above threshold @ 4 hrs
    -> a level of > 153mg/L is above treatment threshold regardless of time of ingestion
    -> NAC must be given within 8 hours of OD (if level going to take longer than 8 hours start NAC empirically)
  • transaminases: peak @ 72 hrs
  • PT: if >180 seconds on day 4 will need transplantation
  • renal failure
  • metabolic acidosis = poor prognostic marker

MANAGEMENT

Resuscitation

A: may require intubation and intubation if polypharmacy overdose and unrousable
B: lung protective ventilation
C: volume resuscitation
D: dextrose for hypoglycaemia

Evaluation

History

  • timing
  • quantity
  • dose
  • other meds
  • psychiatric history

Examination

  • fuliminant hepatic failure signs
  • signs of other drug toxicity

Investigations

  • LFTs
  • paractamol level
  • urine tox
  • coag’s
  • ECG
  • lactate
  • amylase
  • blood alcohol
  • pregnancy test
  • ECG

Treatment

Specific

  • decrease absorption: activated charcoal if presented within 4 hours (controversial as if NAC given then this is a benign OD)
  • N-acetyl cystine in D5W (based on 4 hour level or empirically if > 8 hours since OD):
    -> 150mg/kg LD
    -> 50mg/kg over 4 hours
    -> 100mg/kg over 16 hours
  • can be administered at any time of presentation (up to 72 hours post ingestion with some improvement in outcome)
  • can be administered orally but efficacy reduced by 40% if given with activated charcoal
  • provides a substrate of glutathione and acts as an alternative substrate for NAPQI metabolism via the cytochrome P450 pathway
  • watch for adverse effects: rash, bronchospasm, hypotension, angioedema (antihistamines helpful and also slowing of infusion)

Liver failure management

  • don’t correct coagulopathy unless bleeding (vitamin K IV, blood products)
  • arterial ammonia (aids in prognostication: absolute level and failure to fall)
  • glucose monitoring
  • avoid hypothermia
  • reverse jugular venous saturation monitoring
  • ICP monitoring (controversial)
  • avoid hyponatraemia
  • ventilate to normocapnia
  • thiopentone and indomethacin infusions (consult with liver unit)
  • renal failure management
  • MARS therapy: some benefit shown in paracetamol OD as a bridge to transplantation

General

  • don’t give FFP until discussed with transplant unit as indicated or liver function (unless bleeding)
  • metabolic acidosis from hepatic and renal failure -> supportive care
  • withhold any renal or hepatotoxic medications
  • intubation and ventilation if indicated
  • GI prophylaxis
  • attention to pressure areas
  • feed
  • airway toilet

Disposition

  • discuss early with transplantation team (develop liver failure within 48 hours)
  • admit to medical/gastro unless requires ICU
  • will require psychiatric assessment if was an intentional overdose

Prognostication — can use the O’Grady criteria:

  • acidaemia (pH < 7.3)
  • renal impairment (creatinine > 300micromoles/L)
  • hepatic encephalopathy (grade III or IV)
  • PT > 100 seconds (INR > 6.5)
  • factor V level < 10%

References and links

LITFL

Journal articles

  • Dargan PI, Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care. 2002 Apr;6(2):108-10. Epub 2002 Mar 14. Review. PubMed PMID: 11983032; PubMed Central PMCID: PMC137288.
  • O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439-45. PubMed PMID: 2490426.
  • Shah AD, Wood DM, Dargan PI. Understanding lactic acidosis in paracetamol (acetaminophen) poisoning. Br J Clin Pharmacol. 2011 Jan;71(1):20-8. doi: 10.1111/j.1365-2125.2010.03765.x. PubMed PMID: 21143497; PubMed Central PMCID: PMC3018022.

FOAM and web resources


CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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