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

• Toxicology Conundrum 045 — Paracetamol-induced hepatotoxicity
• Flashcard – Acetaminophen overdose

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

• ALIEM — Are Acetaminophen Levels Necessary in All Overdose Patients? (2013)