Paracetamol overdose

Risk assessment

• Life-threatening hepatotoxicity is uncommon and death is rare
• Risk of hepatic injury following a single acute ingestion without NAC is predicted by nomogram
  • Probability of hepatotoxicity (AST or ALT >1000) is
    • 1-2% if 4 hour level <200mg/L
    • 30% if 4 hour level 200-300mg/L
    • 90% if 4 hour level is >300mg/L
• Risk of hepatic injury with NAC is determined by time of ingestion to commencement of NAC
  • Survival 100% if NAC started within 8 hours
  • Benefit reduced if NAC started 8-24 hours after ingestion
  • Benefit not established if >24 hours after ingestion unless fulminant hepatic failure in which case NAC decreases cerebral oedema, inotrope requirements and mortality

Risk assessment

• Dosing with hepatotoxicity risk
  • Acute single ingestion >200mg/kg or >10g (whichever is lower) over a period <8 hours
  • Repeated supratherapeutic ingestion
    • >200mg/kg or 10g (whichever is lower) over a single 24 hour period
    • >300mg/kg or >12g (whichever is less) over a single 48 hour period
    • >60mg/kg or 4g/day (whichever is lower) per 24 hour period, for more than 48 hours in those with symptoms indicating possible liver injury

Risk factors

• Glutathione depletion
• Malnutrition
• Alcoholism
• Pregnancy
• Prolonged fasting
• Febrile illness
• Chronic use of CYTP450 inducers e.g. carbamazepine

Risk assessment

• If presents >8 hours after ingestion and elevated LFT’s are assumed to have paracetamol-induced hepatotoxicity
• If presents >24 hours after ingestion with normal LFT’s and no detectable paracetamol level – little risk of developing clinically significant hepatotoxicity
• Massive ingestions >30g/>500mg/kg may be insufficiently managed with standard NAC protocols
• Children
  • No reports of death in single acute non-intentional paracetamol exposure under 8yo
  • <200mg/kg as a single dose or a period <8 hours does NOT warrant hospital treatment

Toxic mechanism

• Elevated N-acetylparabenzoquinone imine (NAPQI) leads to depletion of hepatic glutathione stores
• Free NAPQI, a strong electrophile and oxidant, in the absence of glutathione, reacts readily with cysteine residues on cellular proteins
• Once glutathione <30% of normal, NAPQI starts binding other proteins leading to hepatocyte injury and centrilobular necrosis (lower O2 content and higher CYP2E1 concentrations)
• Massive ingestions (>500mg/kg)
  • ALOC, metabolic acidosis and raised lactate from mitochondrial dysfunction
  • Usually within 12 hours and prior to hepatotoxicity
  • Para levels >750mg/L in most cases
  • Overwhelming reactive O2 species and glutathione depletion
  • It appears paracetamol itself can induce mitochondrial toxicity in high enough concentrations
  • AKI secondary to NAPQI production by kidney

toxicokinetics

• Absorption – Well absorbed, peak levels at 1-2 hours for standard preparations and within 30 minutes for liquid preparations. May be delayed to 12 hours for slow-release
• Distribution – Vd 0.9L/kg
• Metabolism
  • 90% undergoes hepatic glucuronidation or sulfation with excretion of conjugates in urine
  • Other 10% undergoes oxidation by CytP450 to form NAPQI (toxic intermediate)
  • Normally NAPQI is immediately bound by glutathione and eliminated in urine as mercapturic adducts
• Excretion
  • Conjugates ad mercapturic adducts in urine

Clinical features

• Phase 1 (<24 hours) – Asymptomatic or nausea/vomiting
• Phase 2 (1-3 days) – RUQ tenderness, ALT/AST rise to peak at 48-72 hours. PT peaks around same time. May have hyperbilirubinaemia/renal impairment
• Phase 3 (3-4 days) – Fulminant hepatic failure in severe cases. Non-survivors demonstrate lactic acidosis, renal failure
• Phase 4 (4 days to 2 weeks) – Recovery phase during which hepatic function and structure return to normal in survivors
• Transient coma and early metabolic acidosis can be seen with massive overdose

investigations

management

• Resus only required for coma in massive OD or delayed hepatotoxicity
• Decontamination
  • Offer AC to cooperative adult who presents within 2 hours after immediate release or 4 hours following sustained release (if taken possibly toxic dose) as may reduce 4 hour level to a degree that NAC is no longer necessary
  • If taken massive overdose (>30g or 500mg/kg) offer to those who present within 4 hours of ingestion of immediate release and all patients following sustained release ingestion
  • Never justified in small children
  • Not lifesaving but may reduce NAC requirements
• Enhanced elimination N/A
  Antidotes
  • NAC

Management

• Disposition and follow-up
  • If rising INR and rising ALT indicating fulminant hepatic failure – liver transplant service referral
    • High-risk criteria include (also see Kings College criteria):
      • INR >3 at 48 hours or >4.5 at any time
      • Oliguria or creatinine >200
      • Acidosis with pH <7.3 despite resuscitation
      • SBP <80mmHg
      • Hypoglycaemia
      • Severe thrombocytopaenia
      • Encephalopathy of any degree
  • Kings College Criteria indications for liver transplant
    • pH <7.3, or INR >6
    • Creatinine >300
    • Grade III/IV Hepatic Encephalopathy

Handy tips

• Time-anchoring
  • If unknown time of ingestion, plot measured paracetamol level on nomogram and then work-out the time before which the ingestion must have occurred to be of concern, then determine if overdose could have occurred before that time
  • If multiple ingestions over hours, can assume entire dose was taken at earliest time point (unlike other drugs)
• Always consider in differential of metabolic acidosis and AST/ALT >1000
• Pitfalls
  • Failure to commence NAC if presents >8 hours after overdose
  • NAC dosing errors
  • Failure to check paracetamol units

controversies

• Which nomogram matters a lot less than accurate use
• Extrapolation of treatment line from 15 to 24 hours has not been formally validated
• Chronic alcoholism (>5 standard drinks per day), prolonged fasting and inducers of CytP450 2E1 and 3A4 (isoniazid, rifampicin, carbamazepine) may increase risk of hepatotoxicity
• Massive OD (>30g or >500mg/kg) may require higher rates of NAC therapy or at least continuing 16 hour bag until paracetamol no longer detectable

NAC

• Sulfhydryl donor to replete glutathione stores
• Toxicological indications
  • Acute paracetamol overdose
  • Repeated supratherapeutic paracetamol ingestion
  • Paracetamol-induced fulminant hepatic failure
  • All above based on risk assessment of hepatotoxicity
• No contraindications
• Mechanism of action
  • Increased glutathione availability
  • Direct binding to NAPQI
  • Provision of inorganic sulfate
  • Reduction of NAPQI back to paracetamol
  • Antioxidant properties may be of benefit in any oxidative stress situation and liver failure of any cause

NAC

• Pharmacokinetics
  • Producing a variety of sulfur containing compounds
  • Plasma half-life 6 hours and 30% eliminated unchanged in urine
• Administration
  • Monitor for anaphylactoid reactions and monitored for initial dose only
  • 1^st bag 200mg/kg of NAC in 500mL 5% dextrose over 4 hours
  • 2^nd bag 100mg/kg of NAC in 1000mL 5% dextrose over 16 hours
• Changes
  • In massive ingestion, 2^nd bag has 200mg/kg in same volume over 16 hours
  • 2 bag regime has similar efficacy but significantly reduced adverse reactions compared to traditional 3-bag regime
• Who gets >20 hours of NAC?
  • Evidence of ALT/AST rise >50 and failure to fall at end of infusion

NAC

• Angioedema
  • 10-15% of cases
  • Hypotension, flushing, rash and angio-edema
  • Usually during or shortly after first dose
  • Loratadine 10mg PO or promethazine 12.5mg IV
  • Can only cease infusion if severe, in which case it should be re-started as soon as reaction is settling
• Use in pregnancy is unchanged as crosses placenta and is beneficial for baby
• Children
  • 150/50/50/50 mg/kg dosing in smaller diluents of 5% dextrose over 15min/4hrs/8hrs/8hrs

Other cares

• Supportive measures
  • SSW
  • Full diet as tolerated + PRN antiemetics
  • MH review 
• Disposition
  • For slow release preparations you need both levels under the treatment line and falling
  • Liver transplant service if established toxicity as above
• Handy tips
  • Massive OD >1g/kg is associated with early ALOC and lactic acidosis with significant morbidity and mortality – d/w Tox team early
  • Bronchodilators may be helpful for anaphylactoid reactions
  • Severe anaphylactoid reactions should be treated as for anaphylaxis
  • Nephrotoxicity has a good prognosis and manifests as reversible ATN

Acute immediate release ingestion

• <2 hours
  • Activated charcoal 50g (1g/kg)
  • Measure level and ALT at 4-8 hours
  • If level under nomogram medical treatment is not required
  • If on or over nomogram start NAC
  • If double nomogram give double dose second bag (200mg/kg over 16 hours)
  • 2 hours before completion of NAC check ALT and paracetamol level if original level was > double nomogram
  • Continue NAC if ALT >50 and increasing (if baseline ALT >50) or para level >10 mg/L

Acute immediate release ingestion

• 2-8 hours
  • Measure level and ALT within 4-8 hours
  • Same as above

Acute immediate release ingestion

• 8-24 hours
  • Commence NAC
  • Measure para and ALT
  • If para < nomogram and ALT <50  Cease NAC
  • If Para > nomogram or ALT >50  Continue NAC
  • Double dose NAC if para level > double nomogram
  • 2 hours before end of NAC measure ALT and para
  • Continue NAC if para >10 or ALT >50 or rising

Acute immediate release

• >24 hours
  • Commence NAC
  • Measure para and ALT
  • If para >10 or ALT >50 complete standard NAC protocol
  • 2 hours prior to end of NAC measure para and ALT
  • Continue NAC if para >10 or ALT >50 or rising

Acute immediate release ingestion

• When to involve toxicologist
  • >50g or >1g/kg
    • AC +- repeat dose AC proven to reduce risk of hepatotoxicity (Chiew et al.)
  • Paracetamol level > triple nomogram
    • Unclear how much to increase NAC infusion concentrations

Multiple or staggered overdose

• Over >2 hours
• Distinct from supratherapeutic as this is with self-harm intent
• Staggered should be treated as acute immediate release ingestions using the earliest time of ingestion for the nomogram
• If first level taken within 2 hours of last ingestion, should repeat 2 hours later to insure level not rising
  • If either of these levels is above the nomogram, commence NAC

Modified release ingestions

• >10g or >200mg/kg (whichever is less)
  • Offer AC if within 4 hours
  • Commence NAC
  • Measure 2 para levels at least 4 hours after ingestion and 4 hours apart
  • If either level is above nomogram continue NAC
  • If either level is > double nomogram  Doube dose NAC
  • Continue NAC until para <10 and ALT <50 and falling
• >30g or >500mg/kg (whichever is less)
  • AC if within 24 hours
  • Commence double-dose NAC
  • Measure 2 para levels at least 4 hours after ingestion and 4 hours apart
  • Continue NAC until para <10 and ALT <50 and falling

Modified-release preparations

• Handy tips
  • Consider SR preparations if multiple of 18 or large packets containing 96 or 192 tablets
• Pitfalls
  • Failure to realise SR preparation taken
  • Failure to commence NAC awaiting second level and missing 8 hour window
  • Failure to check paracetamol units
• Chiew et al. showed early NAC and AC are not enough to prevent hepatotoxicity in all of these patients

Repeated supratherapeutic ingestion

• Responsible for all deaths in children under 6 and 15% of adult deaths
• Nomogram does NOT apply
• Decision to treat based on estimation of dose with biochemical testing
• Risk assessment
  • >200mg/kg or 10g (whichever is lower) in a single 24 hour period
  • >300mg/kg or >12g (whichever is lower) in a single 48 hour period
  • >60mg/kg or 4g (whichever is lower) in each 24 hour period for more than 48 hours with clinical signs of toxicity or are at risk (alcoholism, isoniazid, prolonged fasting)
  • Biochemical testing then performed
    • ALT <50 and paracetamol <20mg/L – Good prognosis. No further Ix or Rx regardless of reported dose
    • ALT >50 or paracetamol >20mg/L – Higher risk group. Commence NAC

Repeated supratherapeutic dosing

• GI decontamination not indicated
• NAC
  • NAC then continued for 8 hours and repeat para level and ALT performed
    • ALT <50 or static + Para <10  Cease NAC
    • If ALT >50 or rising or para >10  Continue NAC with q12h ALT checks
• Handy tips
  • Enquire about analgesic use in all patients with severe dental, back or pelvic pain with low threshold for Ix
• Pitfalls
  • Failure to recognise!

Paediatric liquid preparations

• If under 6yo and >200mg/kg is suspected, a level should be taken at 2 hours
• If 2-4 hour level is <150mg/L NAC is not required
• If 2-4 hour level is >150, should be repeated at 4 hours to ensure remains below this
• If present >4 hours after or >6yo, use adult guideline

Cessation of NAC

• Any patient requiring NAC >20 hours must meet all criteria for cessation:
  • ALT or AST decreasing
  • INR <2.0
  • Patient clinically well
  • For MR or initial level > double nomogram need para level <10

Extrip Intermittent HD

• Paracetamol is dialyzable
• Recommended IHD for severe paracetamol poisoning
• Consider if NAC contraindicated (i.e. anaphylaxis)
• Promptly corrects metabolic acidosis seen with massive OD and may remove NAPQI
• Indications
  • If NAC is not given and paracetamol level >1000mg/L
  • If NAC is not given and patients presents with ALOC, metabolic acidosis, raised lactate and paracetamol > 700mg/L
  • If NAC is given and patient presents with ALOC, metabolic acidosis, raised lactate and para > 900mg/L

Last Updated on October 14, 2020 by Andrew Crofton