1. NAC Study Reaction Rates to NAC with Different Infusion Rates

2. Background Paracetamol – n.o. 1 drug taken in overdose 12% of our tox presentations in 2011 year 25% approx get NAC (antidote)

3. Background Reactions to NAC – 6-23% + (how you study it) – “Allergic reaction” – Rash, n&v, itchiness, tachycardia/hypotension & SOB – Non IgE mediated (anaphylactoid) & do not need prior exposure – Coincides with peak concentration of NAC – Histamine related – Tryptase levels unchanged

4. Background Risk factors – Female – FHx of allergy – Paracetamol concentration (inverse relationship)

5. Background NAC infusion guidelines (old) – 150mg/kg over 15 mins, 50mg/kg over 4 hours & 100mg/kg over 16 hours (300mg/kg) – Dosing Large initial dose 150mg/kg based on glutathione depletion at presentation Not so in vast majority of cases – Duration of infusion Based on paracetamol half life

6. RCT of 15mins vs. 60mins for 150mg/kg dose of NAC 180 patients 45% (15min) vs. 38% (60min) – p 0.36 & 95% CI -8 to22% ?Concentration of NAC still to high

7. Simulation study using known NAC pharmacokinetics Compares current regimen vs. starting NAC early Assumptions o 4h level & NAC started 6 hours (current regimen) o Most patients present by & NAC commenced at 2 hours (proposed regimen)

9. Simulated current regimen (bold) 150mg/kg over 1 hour followed by 50mg/kg over 4 hours commencing at 6 hours (completed by 11 hours post overdose) Simulated proposed regimen (dash) 200mg/kg over 9 hours commencing on arrival (2 hours post overdose) & completed by 11 hours post overdose. Same or higher AUC (area under curve) for proposed regimen c.f. current regimen (figure D)

10. Proposal Combined first 2 doses/infusions into 1 – 150mg/kg & 50mg/kg = 200mg/kg Start on presentation – Infusion to be completed by 11 hours post ingestion – Variable infusion 200mg/kg (min of 4 hours) – 16 hour infusion of 100mg/kg is unchanged Outcome measures – Adverse effects using same recording as TACTIC study as comparison – Effectiveness on NAC with 24/24 LFT’s & INR