Evaluation of a shorter 12h acetylcysteine regimen & development of a simpler acetylcysteine (SNAP) protocol for the treatment of paracetamol poisoning

Abstract

Paracetamol is the commonest drug involved in hospital admissions with poisoning in the UK. Acetylcysteine (NAC) is the antidote of choice for treatment of paracetamol overdose, but the original 3-bag NAC regimen, designed in Edinburgh, is associated with infusion-related adverse reactions related to high peak plasma acetylcysteine concentrations from the high loading infusion of 600mg/kg/h. The Scottish and Newcastle Antiemetic Pre-treatment (SNAP) study has shown that a simpler 12 h regimen (SNAP) consisting of a reduced loading infusion rate of 50mg/kg/h, causes significantly fewer adverse reactions (1). The SNAP regimen was implemented in 3 UK hospitals with the approval of their local medicines management committees with prospective audit of clinical outcomes. In this thesis, I have compared the efficacy in preventing hepatotoxicity of a 12h (‘SNAP’) regimen with the conventional 21 h NAC regimen used to treat paracetamol poisoning, including in patients at high risk of developing hepatotoxicity. Secondly, I have developed and validated a simple clinical decision rule for safe discharge of patients at the end of the 12h NAC treatment. Thirdly, I have developed a simpler 12 h NAC (‘SNAP’) protocol and care pathway to facilitate implementation in clinical practice. The major findings and conclusions of the thesis are: i) development of hepatotoxicity (peak ALT >1000) and hepatic synthetic dysfunction (INR greater than 2) in patients treated with the SNAP regimen were not significantly different compared to the conventional regimen both in high-risk and low-risk patients (14.6% SNAP vs 15.2% standard, 95% CI, - 8.2 to 9.8), and (3.2% SNAP vs 2.6% standard, 95% CI, - 0.7 to 1.8), respectively; ii) paracetamol-aminotransferase multiplication product (APAP×AT) >1500 mg L-1× IU L-1 h is a predictor of hepatotoxicity in patients treated with NAC and an important confounding variable, particularly in patients presenting late (P=0.001); iii) The SNAP regimen can interfere with coagulation activity with a median INR increase of 0.3 from baseline, even in the absence of liver injury, indicating that re-measurement of the INR at least 24 h post exposure if there is no other evidence of hepatic injury can avoid unnecessary additional treatment with NAC; iv) a simple clinical decision rule (paracetamol <10 and ALT≤ ULN, and ALT not doubled or more than doubled from admission value) accurately predicted patients who were eligible to discharge safely after a shorter 12 h SNAP regimen with 100% positively predictive value, which can be used to facilitate earlier discharge of low-risk patients.