Paracetamol Toxicity.Sean Kelly CCLHD

Be not too proud……some

tips.Refer to Guidelines.

Guidelines for the management of paracetamol poisoning in Australia and New Zealand –explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australian poisons information centres.

Daly et al MJA V 188 5 2008

Consult Poisons Information and /or your local Toxicologist.

htpp://www.toxinz.com

Buy the book.

Risks.

Fatalities are rare.

Hepatotoxicty threshold >150mg/kg (>10 gram)

Hepatoxicity is determined primarily by the time from overdose to commencement of NAC with survival of 100% when NAC started within 8 hours of ingestion. (appears to be no benefit beyond 24 hrs)

Children < 8 hrs there has been no reported fatalities in unintentional overdose.

95kg*150/mg=14250 mg=28.5 500mg tablets.

Toxicokenetics…..just think glutathione

depletion.Absorbed from small intestine.

Peak level in 1-2 hours (30 min in liquid preparations)

Glucoronidation or Sulphation with excretion of conjugates in the urine. Small amount oxidised by P450 to form NAPQI (toxic). NAPQI is bound by intracellular glutathione and excreted in the urine

Absorption kinetics for for sustained release paracetamol preparations is poorly described.

Toxic Mechanism.

Depletes hepatic glutathione.

Elevated NAPQI (N-acetylbenzoquinoneimine)

Centrilobular necrosis.

N-acetylcysteineNAC is a cure for paracetamol OD if given within 8 hours of ingestion.

No contraindiactions

Mechanism of action: Increased glutathione availability. Direct binding to NAPQI. Sulphate donor. Antioxidant.

Complex pharmacokinetics. 30% eliminated in the urine.

Mild anaphylactoid reaction. 10-50%

Clinical Phases.

<24 hours Asymptomatic to N&V

1-3 days ALT/AST peak at 55 hours. PT/INR peaks similar time.

3-4 days Fulminant hepatic failure. Lactic acidosis. Renal Failure.

4 days to 2 weeks.

Recovery phase.

Which investigations

when?Time of ingestion known? Paracetamol level at 4 hours or more. ? risk ?need for treatment

If NAC started > 8 hours. AST/ALT to monitor hepatic injury.

Paracetamol levels at 4 and 8 hours after ingestion maybe useful following ingestion of extended release paracetamol preparations

Prescott v Rumack Mathew

v the OZ version.Does not much matter what you use as long as you get the time of ingestion, units and NAC dose right.

Reproduced from Daly et al 2008 with permission.

Acute Paracetamol Overdose.If time of ingestion known: decision to

treat is guided by serum paracetamol level plotted on a nomogram.

OtherwiseThe decision to treat is based on the serum paracetamol and hepatic transaminase levels.

Management.Resuscitation.

Oral decontamination not helpful. Perhaps a role within one hour of ingestion.

Intravenous NAC. Presentation;less than 8 hours defer NAC until result of 4 hour level.

8-24 hours: start NAC immediately until paracetamol level plotted on nomogram.

Unknown. Paracetamol detected: Start NAC immediately and review with Hx and AST/ALT

>24hrs. Paracetamol detected and transaminitis. Continue NAC until until transaminases are falling and patient improving.

Extended Release.

Start NAC immediately if > 200mg/kg or 10 gram ingested.

Check serum paracetamol levels at 4 and 8 hours.

Discontinue NAC if levels fall beneath the treatment line.

Criteria for transfer to Liver

Unit.INR>3.0 at 48hrs or >4.5 at any time.

ARF.

Acidosis.

Hypotension.

Hyopoglycaemia.

Thrombocytopenia.

Encephalopathy.

Predicting Encephalopthy

The risk of hepatic encephalopathy can be predicted by calculating the Schiodt score.

Factors to predict the risk of hepatic encephalopathy:

1.Time interval between paracetamol ingestion and commencement of NAC

2.INR

3.Platelet countSchiødt FV, Bondesen S, Tygstrup N, Christensen E. Prediction of hepatic encephalopathy in paracetamol overdose: a prospective and validated study. Scand J Gastroenterol. 1999 Jul;34(7):723-8

Tips and cautions.Time anchoring using nomogram.

With multiple ingestions. Construct worse case scenario.

Start NAC immediately if presentation> 8 hours.

Wary of NAC dosing errors.

Care with units micromol/L v mol/L v mg/L

Toxicity with Therapeutic intention.Responsible for all deaths related to

paracetamol in children less than 6years of age and up to 15% of those deaths in adults.

Nomograms not useful.

Risk assessment is based on dose history and biochemical testing.

Management Flow chart for repeated supratherapeutic paracetamol ingestion.

Tips Pitfalls and Controversies.

Tip: Use NAC package insert (volume rather than mls decreases errors)

Pitfall: failure to start NAC in patents presenting >8 hours with ingestion > 200mg/kg.

Tip: Initial dose of NAC over 60 rather than 10 minutes does not seem to decrease risk of anaphylactoid reactions

Controversy. What is the value of NAC >in patients who present > 24hrs with a transaminitis?*

Keays BMJ 1991.

Salicylates

Toxic MechanismIrreversible inhibition of cyclooxygenase enzymes resulting in decreased PG synthesis.

Stimulation (direct)of respiratory system.

Lactic acidosis (uncoupling of mitochondrial oxidative phosphorylation).

Promotion of FFA metabolism -> Ketosis.

Hypoglycaemia. (glycogen depletion)

Target of lethal effects is the CNS

Toxicokinetics.Rapid oral absorption.

VD 0.1 -0.3L/kg.

Saturatable Kinetics in OD ie First Order to Zero Order. Elimination half life increasing from 2 to 24 hours.

Alkaline urine: increases ionised form which decreases renal tubular reabsorption.*

Acute: OverdoseN&V*

Tinnutus*, agitation, seizures, cerebral oedema.

Respiratory alkalosis.*

Increased Anion Gap Metabolic Acidosis (late)

Hyperthermia, hyper/hypoglycaemia, hypokalaemia.

Severe toxicity may not be evident until 6-12 hours.

Bezoars

SalicylateDose Related Risk Assessment: Acute Aspirin Dose.

Dose. Effect

<150 mg/kg Minimal Symptoms

150-300mh/kg>300mg/kg

Hyperpnoea, tinnitus, vomitingMetabolic Acidosis, altered mental status.

>500mg/kg Potentially lethal

Chronic Salicylate Intoxication.

Often missed!

Non specific symptoms eg. Delerium,

Cerebral and Pulmonary oedema.

Salicylate Levels.Therapeutic is 1.1-2.2 mmol/L (15-30mg/dL)

Poor correlation particularly in chronic overdose between levels and severity of toxicity.

Slow release: serial levels.

From: Murray et al Toxicology Handbook with permission.

DecontaminationOral AC 50 g up to 8 hours following acute OD of >150 mg/kg.

NG AC (via NG) 50 g up to 8 hours following acute OD of >300mg/kg.

Repeat at 4 hours if level continues to increase.

Enhanced Elimination.

Urinary Alkalinisation.

Hemodialysis. Effective but rarely needed.

Indications for Dialysis in Salicylate Toxicity.Urinary alkalinisation not feasible.

Very high salicylate levels ie >4.4 mmol/L with acute poisoning or greater than 7.2 mmol/L in Chronic poisoning.

Urgent haemodialysis is indicated in any patient who requires intubation for salicylate poisoning ( Not if secondary to coingested drugs)

Methyl Salicylate….a sip is dangerous a mouthful

can kill.Non aspirin salicylate (oil of wintergreen is 98% methyl salicylate). Also found in Tiger Balm Liniment 28% etc. Asian Herbal oils.

Absorbed rapidly and metabolised to salicylic acid.

5-15 mls oil of wintergreen may cause serious toxicity or death.

Tips and TrapsIntubation equals haemodialysis except if intubated because of co ingestant. ( beware ventilation without hyperventilation)

DDX of delerium in elderly.

Misinterpretation of low salicylate levels as non toxic.

Not treating hypokalaemia.

Watch for delayed absorption.

Ensure alkalaemia after intubation ventilation.

Care with standard v SI units.

The Done is done!**

* Modified from O Malley Emerg Med Clin Nth America 2007** Done. Pediatrics 1978 62 (Suppl):88-7