UNUSUAL ACETAMINOPHEN TOXICITY SCENARIOS. Gosselin

Transcription

1 UNUSUAL ACETAMINOPHEN TOXICITY SCENARIOS

2 Objec-ves Management of acetaminophen inges-ons when the Rumack- Ma<hew doesn t apply Staggered inges-ons Repeated supratherapeu-c inges-ons Mitochondrial acetaminophen toxicity

3 Acetaminophen Easy access, perceived as benign Combina-on products with other medica-ons Most common cause of drug induced FHF. (Larson et al Hepatology 2005;42: ) Well- known an-dote: N- acetylcysteine

4 What is the toxic dose of acetaminophen? A. Adults 150 mg/kg B. Adults 200 mg/kg C. Adults 100 mg/kg D. It depends E. I don t remember

5 Acetaminophen Toxicity Single inges-on -me Toxic dose mg/kg (country specific) Rumack BH Acetaminophen misconcep-ons. Hepatology 40: Phase 1 asymptoma-c or mild GI (< 12h) Phase 2 Hepatotoxicity AST/ALT >1000 IU/L (12h- 24h) Phase 3 FHF, encephalopathy (24-72h) Phase 4 Resolu-on, death or transplant

6 Acetaminophen Toxicity Single inges-on -me > 4h; < 16h Rumack- Ma<hews nomogram

7 Acetaminophen Toxicity

8 Risk Assessment 28 year old male, intractable migraines Took 4 tablets of acetaminophen 500 mg every 2 hours from 8 AM un-l 6 PM Presents 2 hours afer the last dose (because no pain relief)

9 Risk Assessment 8 AM 2 g 10 AM 2 g Noon 2 g 2 PM 2 g 4 PM 2 g 6 PM triage Weight 80 kg Total 10 grams = 125 mg/kg

10 Is this toxic? A. Yes B. No C. Not sure

11 Management Staggered Inges-ons Poorly studied, risk of HT uncertain (higher?) Op-ons 1. transform them mathema-cally in single inges-on with the earliest -me of inges-on as T0 [APAP] now; if above threshold à treat [APAP] 4h afer last dose; if above threshold à treat 2. Treat all Same NAC protocol as single acute inges-on Craig et al. Staggered overdose pa<ern and delay to hospital presenta-on are associated with adverse outcomes following paracetamol- induced hepatotoxicity.bjcp :3;

12 A pa-ent took APAP with diphenhydramine (cold remedy) in unknown quan-ty. 4h APAP is 840 umol/l below the nomogram. A. You send him to psychiatry B. You start treatment with NAC C. You call your Poison Control D. You wait and you repeat the level

13 Extended release APAP inges-on Prolonged absorp-on Diphenhydramine, Opiates Peak delayed Might be afer 4 hours If 4h concentra-on non- toxic, repeat 2 hours later Peak should occur by 8h unless significant ileus, bezoar or other situa-on decreasing absorp-on

14 Supratherapeu-c / Chronic Defini-ons change according to authors. Staggered 8h ( 24h) vs. RSTI/ Chronic 24h Mul-ple inges-on -mes Over more than 24 hours Cannot use the Rumack- Ma<hews nomogram Treat all With any detectable [APAP] Abnormal aminotransferases 50 IU/L Time of sampling to inges-on not specified... Daly et al. Prospec-ve Evalua-on of Repeated Supratherapeu-c Acetaminophen Inges-on. Ann Emerg Med :4

15 Risk Assessment 18 years old female Brought to ER 90 minutes post inges-on 200 tablets of 500 mg acetaminophen Weight 80 kg Toxic load = 1250 mg/kg

16 1250 mg/kg inges-on 90 minutes ago A. I start NAC right away B. I give ac-vated charcoal C. I call my poison centre D. Follow procedure as usual

17 Acetaminophen? 90 minutes PI = [APAP] 6499 umol/l Becoming lethargic and tachypneic Lactate 8 Bicarbonate 16 ph 7.20 Normal INR and LFT s No other medica-on ingested How would you manage this result?

18 Will NAC be enough for this pa-ent? Rumack- Ma<hews Nomogram

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20 APAP Mitochondrial Toxicity Rarer presenta-on Massive inges-on > mg/kg Efficacy of NAC imprecise ([APAP] 3300umol/k at 4h) Amount of NAC to give? Coma, metabolic acidosis < 12h post- inges-on Before evidence of hepatotoxicity Toxicity from APAP, NAPQI, both? Gene-c suscep-bility? Bruno et al. Toxicology and Applied Pharmacology 1998 Shah et al. Understanding lac-c acidosis in paracetamol poisoning. BJCP :1 Jaeschke & Bajt. Mechanisms of Acetaminophen Hepatotoxicity in Comprenhensive Toxicoogy Ed McQueen CA. Elsevier Science;2010

21 Jaeschke & Bajt. Mechanisms of Acetaminophen Hepatotoxicity in Comprenhensive Toxicoogy Ed McQueen CA. Elsevier Science;2010

22 Acetaminophen Animal studies NAPQI is detoxified by GSH No glutathione Binding to hepatocellular AND mitochondrial protein Inhibi-on of mitochondrial respira-on (cytochrome B) Doses > mg/kg Peroxynitrite forma-on DNA damage Oxida-ve stress, Opening of transi-on pore with membrane poten-al collapse Cohen 1997, Tirmenstein 1989, Qiu 2011, Jaeschke 2003, Jaeschke 2006, Saito 2010, Hinson 1998, Cover 2005.

23 Animal study With N- AC 500 mg/kg Important % death APAP > 500 mg/kg

24 Treatment Op-ons NAC same dose protocol 150 mg/kg bolus 50 mg/kg over 4h (12.5 mg/kg) 100 mg/kg over 16h (6.25 mg/kg) NAC double dose 3rd infusion (200 mg/kg in 16h) Empirical- always get advice from PCC. Based on molar NAPQI to molar NAC es-ma-on Hemodialysis 4- MP (fomepizole)

25 Fomepizole? Inhibi-on of alcohol dehydrogenase Also inhibi-on of cytochrome P MP prevented hepatotoxicity in rats afer 2000 mg/kg APAP 4- MP vs NAC both prevented hepatotoxicity Theore-cal and rat studies no human report Brennan Ann. Emerg Med 1994 Küçükardali et al. Cur Med Res Op 2002

26 Evidence for Hemodialysis Acetaminophen Molecular weight D Volume of distribu-on L/kg Protein binding 25% Half life 1-2 hours Toxicokine-c No major change in volume of distribu-on Half life increases > 4hours NAC also hemodialysed 50% of dose with IHD

27 Conclusions Different acetaminophen scenarios Rumack- Ma<hew not always applicable Delayed presenta-ons carry worse prognosis Supratherapeu-c (staggered and chronic) Early acidosis with mental status changes Will NAC be enough?? Risk assessment with toxic load in mg/kg Call your Poison Control for help

28 Ques-ons?