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Title: Evaluation of a shorter 12h acetylcysteine regimen & development of a simpler acetylcysteine (SNAP) protocol for the treatment of paracetamol poisoning
Authors: Alrossies, Amani Saleh
Issue Date: 2022
Publisher: Newcastle University
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.
Description: PhD Thesis
Appears in Collections:Translational and Clinical Research Institute

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