Your SlideShare is downloading. ×
Sean Kelly on Paracetamol Toxicity
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Sean Kelly on Paracetamol Toxicity

1,486
views

Published on

Sean Kelly is an Emergency Physician and Intensivist who's the director at Gosford ICU in New South Wales. He's also the medical director at ICCMU. He gave this great talk at Bedside Critical Care …

Sean Kelly is an Emergency Physician and Intensivist who's the director at Gosford ICU in New South Wales. He's also the medical director at ICCMU. He gave this great talk at Bedside Critical Care 2012 on Daydream Island. He'll be at SMACC. Check out the ICCMU website.


0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,486
On Slideshare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
44
Comments
0
Likes
1
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • Single most common tablet taken in overdose.Single most important cause of acute fulminant hepatic failure in Western Countries.Complexity around different approaches egsupratherapeutic, paediatric,sustained release, different nomograms etc.
  • The patient who presents more than 24 hrs after overdose with no detectable paracetamol and normal transaminases has little risk of developing clinically significant hepatoxicity.
  • Peak serum concentration after therapeutic doses do no usually exceed 130mmol/LNAPQI N-acetyl-p-benzoquinone imine
  • Elevated production of NAPQI leads to depletion of glutathione. At a threshold of 30% of normal NAPQI binds to other proteins causing hepatocyte injury..
  • NAC reduces mortality if commenced late in patients with established paracetamol induced fulminant hepatic failure. ? Mechanism of action. Decreases cerebral oedema and increases the rate of survival by about 30%.Three stage infusion.10ml ampoules containing 2000mg. (20%)Recommend that dosing tables providing the volume required be used.Lean body weight to nearest 10 kg.
  • Decrease LOC and lactic acidosis only in exceptional cases.
  • If NAC started within 8 hours of acute ingestion only a paracetamol level is required.Level at 4 and 8 hours maybe useful if slow release tablets taken.Magnitude of ALT or AST not linked to outcome.All about risk assessment: Dose and concentration (early)Clinical and laboratory features suggesting liver damage (late)Any history suggesting increased susceptibility.
  • Prescottnomogram: 200mg/L at 4 hours to 30mg/l at 15 hours.R M based on same data but extrapolated to 24 hours. Uses treatment line that is 25% lower at 4 hours (US FDA requirement). No deaths in patients who were treated within 15 hours (1500 patients)Both use log scale making plotting difficult.Aim of the new treatment nomogram.Lowers the old Australian nomogram line by 25%. Ie starts at 150mg/L at 4hours.Provides margin of safety for patients with risk factors and a small margin of error for estimation of time of ingestion and avoids the need for potentially confusing additional lines. “It is also the treatment threshold with the most clinical data to support its efficacy and safety.” Daly 2008.
  • Best case scenario is the cooperative patient who presents within the first hour after OD. May decrease 4 hour paracetamol level such that NAC not required. Never justified with small children.Benefit irrespective of time NAC started within first 8 hours therefore can wait until 4 hours for level.Presentation after eight hours start NAC if reported dose is greater than 150 mg / kg or RUQ tenderness etcUnknown start NAC. At end of infusion stop NAC if ALT is normal or decreasing.
  • Staggered Od if less than eight hours then treat as per 1-8 hrs.If more than eight hours since first dose treat as per > 8 hours. Ie Start NAC. Measure paracetamol level (assume earliest possible ingestion) and ALT.If level over TX line start NAC unless ALT elevated.
  • Risk factors for paracetamolindiced liver injury include states that induce P450 system eg chronic alcoholism, isoniazid, rifampicin and carbamazepine. However lowering of nomogram thresholds is not supported.Time anchoring using nomogram: ie plot the measured paracetamol level on the nomogram line and determine the time before which the ingestion must have taken place to be of concern. It should then be determined whether it is possible for the overdose to have occurred before that time.
  • Although there are no reports of death following single acute non intentional exposure in children under 8 years of age.Ingestion of <200 mg/kg as a single dose or over a period of <8 hours does not warrant decontamination, referral to hospital, serum paraectamol level, liver function tests, antidote treatment or follow-up.>200mg/kg/24 hours ( or 10 grams)>150mg/kg/24 hours in 48 hour period. (or 6 grams)>4grams per day in patient with predisposing factors for liver toxicity.O GradyParacetamol overdose accounts for about 40% ofcases of ALF in the UK but is falling sincelegislation limited the amounts that can bepurchased over the counter.2 It is usually takenwith suicidal or parasuicidal intent, but up to8%–30% cases are consequent upon therapeuticuse. Factors increasing susceptibility to paracetamoltoxicity include regular alcohol consumption,antiepileptic therapy (via enzymeinduction), and malnutrition. ALF develops inonly 2%–5% of those taking overdoses,. There issome dose dependent relation with mortality,which is highest at doses over 48 grams.
  • NAC reduces mortality if commenced late in patients with established paracetamol induced fulminant hepatic failure. Decreases cerebral oedema and increases rate of survival by about 30%.
  • Any group of chemicals derived form salicylic acid.Aspirin is acetyl salicylic acid metabolised to salicylic acid after ingestion.Originally derived from willow bark.Epidemiology: incidence of chronic aspirin poisoning is not known.Number of presentations decreased in countries where limited package formulations.
  • The presence of salicylate molecules probably contributes little to the acidotic state.
  • In acidaemia, more salicylate is unionisedfavouring movement into extravascular fluid compartments including the CNS.pKa 3. 50% ionised and 50% unionised in acid environment of stomach.
  • Classic triad of salicylate OD is hyperventilation, tinnitus and GI upset.Patients who present in the late stages of salicylate toxicity often are misdiagnosed as sepsis, myocardial infarction.
  • Symptoms are dose related and progress over hours.Chronic poisoning has an increased risk of adverse outcome.
  • Gastric irritation and pyloric spasm mean aspiration risk is high with gastric decontamination.MAC shown to reduce absorption of aspirin and results in decreased serum levels but this does not translate into decreased mortality or morbidity.
  • Exchange transfusion has been reported as a viable alternative in children.
  • Transcript

    • 1. Paracetamol Toxicity. Sean Kelly CCLHD
    • 2. Be not tooproud……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 2008Consult Poisons Information and /or your local Toxicologist.htpp://www.toxinz.com
    • 3. Buy the book.
    • 4. 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.
    • 5. 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.
    • 6. Toxic Mechanism.Depletes hepaticglutathione.Elevated NAPQI (N-acetylbenzoquinoneimine)Centrilobular necrosis.
    • 7. N-acetylcysteineNAC is a cure for paracetamol OD if given within 8 hoursof ingestion.No contraindiactionsMechanism of action: Increased glutathione availability.Direct binding to NAPQI. Sulphate donor. Antioxidant.Complex pharmacokinetics. 30% eliminated in the urine.Mild anaphylactoid reaction. 10-50%
    • 8. Clinical Phases.<24 hours Asymptomatic to N&V1-3 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.
    • 9. Which investigations when?Time of ingestion known? Paracetamol level at 4hours or more. ? risk ?need for treatmentIf NAC started > 8 hours. AST/ALT to monitor hepaticinjury.Paracetamol levels at 4 and 8 hours after ingestionmaybe useful following ingestion of extendedrelease paracetamol preparations
    • 10. 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.
    • 11. Acute Paracetamol Overdose.If time of ingestion known: decision to treat is guided byserum paracetamol level plotted on a nomogram. OtherwiseThe decision to treat is based on the serum paracetamoland hepatic transaminase levels.
    • 12. Management.Resuscitation.Oral decontamination not helpful. Perhaps a role withinone 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.
    • 13. Extended Release.Start NAC immediately if > 200mg/kg or 10 gramingested.Check serum paracetamol levels at 4 and 8 hours.Discontinue NAC if levels fall beneath the treatmentline.
    • 14. Criteria for transfer to Liver Unit.INR>3.0 at 48hrs or >4.5 at any time.ARF.Acidosis.Hypotension.Hyopoglycaemia.Thrombocytopenia.Encephalopathy.
    • 15. 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 hepaticencephalopathy in paracetamol overdose: a prospective and validated study.Scand J Gastroenterol. 1999 Jul;34(7):723-8
    • 16. Tips and cautions.Time anchoring using nomogram.With multiple ingestions. Construct worse casescenario.Start NAC immediately if presentation> 8 hours.Wary of NAC dosing errors.Care with units micromol/L v mol/L v mg/L
    • 17. Toxicity withTherapeutic intention.Responsible for all deaths related to paracetamol inchildren less than 6years of age and up to 15% ofthose deaths in adults.Nomograms not useful.Risk assessment is based on dose history andbiochemical testing.
    • 18. Management Flow chart for repeated supratherapeutic paracetamol ingestion.
    • 19. 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.
    • 20. Salicylates
    • 21. Toxic MechanismIrreversible inhibition of cyclooxygenase enzymesresulting in decreased PG synthesis.Stimulation (direct)of respiratory system.Lactic acidosis (uncoupling of mitochondrial oxidativephosphorylation).Promotion of FFA metabolism -> Ketosis.Hypoglycaemia. (glycogen depletion)Target of lethal effects is the CNS
    • 22. Toxicokinetics.Rapid oral absorption.VD 0.1 -0.3L/kg.Saturatable Kinetics in OD ie First Order to ZeroOrder. Elimination half life increasing from 2 to 24hours.Alkaline urine: increases ionised form whichdecreases renal tubular reabsorption.*
    • 23. 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
    • 24. SalicylateDose Related Risk Assessment:Acute Aspirin Dose.Dose. Effect<150 mg/kg Minimal Symptoms150-300mh/kg Hyperpnoea, tinnitus, vomiting>300mg/kg Metabolic Acidosis, altered mental status.>500mg/kg Potentially lethal
    • 25. Chronic Salicylate Intoxication.Often missed!Non specific symptoms eg. Delerium,Cerebral and Pulmonary oedema.
    • 26. Salicylate Levels.Therapeutic is 1.1-2.2 mmol/L (15-30mg/dL)Poor correlation particularly in chronic overdosebetween levels and severity of toxicity.Slow release: serial levels.
    • 27. Decontamination Oral 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.From: Murray et al Toxicology Handbookwith permission.
    • 28. Enhanced Elimination.Urinary Alkalinisation.Hemodialysis. Effective but rarely needed.
    • 29. Indications for Dialysis in Salicylate Toxicity.Urinary alkalinisation not feasible.Very high salicylate levels ie >4.4 mmol/L with acutepoisoning or greater than 7.2 mmol/L in Chronicpoisoning.Urgent haemodialysis is indicated in any patient whorequires intubation for salicylate poisoning ( Not ifsecondary to coingested drugs)
    • 30. Methyl Salicylate….a sip isdangerous a mouthful can kill.Non aspirin salicylate (oil of wintergreen is 98%methyl salicylate). Also found in Tiger Balm Liniment28% etc. Asian Herbal oils.Absorbed rapidly and metabolised to salicylic acid.5-15 mls oil of wintergreen may cause serious toxicityor death.
    • 31. Tips and Traps Intubation 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 NthAmerica 2007** Done. Pediatrics 1978 62 (Suppl):88-7