1. Dr Ben McKenzie Emergency Physician

2.  13 year old girl  Drinking with friends to see who could take the most panadol and aspirin.  Took maybe 60 tablets, 12 aspirin  2 days ago  Presents with RUQ pain and vomiting

3. Yes this is a real case! Increasing pill parties in USA....

4.  90% conjugated and excreted in urine ◦ Conjugated with sulfate ◦ Conjugated with glucuronide  2% excreted unchanged in urine  Rest metabolised by cytochrome P450 mixed function oxidase system (CYP2E1, CYP1A2, CYP3A4) ◦ Forms N-acetyl-p-benzoquinoneimine (NAPQI) ◦ NAPQI is TOXIC!! But luckily is conjugated with Glutathione in the liver under in therapeutic doses of paracetamol.

5.  Once sulfation and gluronidation pathways are saturated metabolism is shunted down the CYP450 pathway of oxidation.  One glutathione is depleted then NAPQI accumulates.  NAPQI starts binding hepatic cells proteins and cell death.

7.  When there is overdose  If induction of CYT P450 enzymes ◦ Carbamazepine and phenytoin use induce CYP2E1 ◦ Malnourished – less glutathione stores. ◦ Alcoholics with repeated paracetamol insults  Induced CYP450 enzymes  Malnourished, fasting  Not increased risk with single overdose

8.  In children under 5 ◦ More conjugation and more glutathione stores

9.  <150mg/kg in adults or 7-10g toxicity unlikely  <200mg/kg in children toxicity unlikely  > 350mg/kg Most patients develop hepatoxicity

10.  Rumack-Matthew Nomogram was the original plotted graph of untreated patients paraectamol concentration against time. 60% above the line developed hepatoxicity.  This has been modified with subsequent evidence taken into account.  Lowered by 25% to allow for inaccuracies in assessment.

12.  Blood taken at 4 hours post ingestion or immediately if the patient presents after 4 hours.  Blood taken prior to 4 hours is a waste of time and money!

13.  Panadol Osteo…. Sustained release ◦ Use the same nomogram despite it not being validated for these preparations ◦ No evidence to suggest toxicity is different

14.  Some patients take supratherapeutic doses over a number of days. ◦ Dental pain ◦ Codeine abuse ◦ Illness (these patients are often dehydrated, malnourished and higher risk. Risk Assessment Guide  10grams (child 200mg/kg) in 24 hours  6 grams (child 150mg/kg) per day for 48 days

15.  You do not need to do routine paracetamol levels if a patient is cooperative and able to give a history (BestBets)  However if doubt about reliability or unconscious then it is a cheap and easy test to do.

16.  Hepatotoxicity takes 18 – 36 hours to develop.  All patients have an ALT/AST rise by 36 hours  Prior to hepatotoxity most patients develop nausea, vomiting, feel unwell. But maybe asymptomatic.  Liver toxicity – RUQ pain, nausea, unwell, jaundice.  ALT/AST peak day 3 and LFTS are repeated in a serial fashion to map the fall.  Development of liver failure depends on the amount of hepatic injury

17.  Hepatitis  Coagulopathy  Shock  Renal Failure  Lactic Acidosis  Hypoglycaemia  Cerebral oedema - hyperammonaemia  Death from multi-organ failure

18.  Charcoal if present within 1 hour  Only if they are conscious and compliant  Remember there is an antidote

19.  Thought to provide cysteine to enhance glutathione synthesis.  Not contraindicated if a patient is allergic to sulphonamides/”sulfas”  10-20% may develop flushing or anaphyactoid reaction and almost all people tolerate it when it is restarted/slowed rate.  All patients who receive NAC within 8 hours do well.

20.  ALL PATIENTS WHO RECEIVE NAC WITHIN 8 HOURS DO WELL Regime In Australia  150 mg/kg IV infusion, over 15 to 60 minutes  50 mg/kg IV infusion, over 4 hours  100 mg/kg IV infusion, over 16 hours.

21.  People over the nomogram line  People who you risk assess as potential toxicity and result will take longer than 8 hours post ingestion to obtain.  Patients with abnormal LFTs  Supratherapeutic ingestions with high risk/abnormal LFTs – base on dose ingested

22. For how long? - If the patient receives N-Acetylcysteine within 8 hours they maybe discharged after the 20 hour infusion is complete. - Continue the infusion until paracetamol levels are undetectable if hepatic damage occurs (in consultation with clinical toxicologist)

23.  Na 137 K3.5 CL98 HCO3 30 Urea 2.6 Cr 46  Alb 49 AST 7234 ALT 5896 GGT 18 ALP 224  Bili 16  Paracetamol <30  BSL 6.4  Lactate 1.6  INR 1.7 Management

24.  On presentation AST 7234 ALT 5896  18 hours later: AST 1642 ALT 3392 INR 1.4  26 hours later: AST 895 INR 1.3  34 hours later: AST 28 INR 1.1 Lucky!

25.  Refer to liver unit ICU  Liver recovery phase commences day 3  Transplant/Death

26.  Patient comes in and has taken 20 tablets of olanzepine/respiridone/quetiapine/largactil  What is your plan?

27.  Risk Assessment  Decontamination  Enhance Elimination  Antidotes  Supportive care

28.  Is the treatment you initiate to support a patients physiology.

30.  Usually GCS of 8 is indication for intubation unless short acting agent involved.  Prevent aspiration.

31.  BP low because less awake and less endogenous catecholamines  Direct pharmacological effects  Dehydration  Part of multiorgan failure

34.  Many patients can’t urinate and its an amazing ICU physiological monitor.  Will also stop patients being agitated when their bladder is full!

36.  Pressure Care  Blood sugar  Monitoring