Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study)

Wong, Andy; McNulty, Richard; Isoardi, Katherine Z; Harris, Keith; Chiew, Angela L.; Greene, Shaun L; Gunja, Naren; Buckley, Nicholas A; Page, Colin B.; Graudins, Andis

doi:10.1016/j.eclinm.2020.100288

Cited by 31 publications

(31 citation statements)

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“…N-acetylcysteine is reported to facilitate scavenging of APAP derived reactive metabolites and is the only treatment for APAP overdose. (Wong et al, 2020). The mechanism of APAP metabolism associated with changes in liver is presented in Figure 1.…”

Section: Metabolism Of Acetaminophenmentioning

confidence: 99%

Acetaminophen Induced Liver Injury: Metabolism and Inflammation Perspectives

2021

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Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the US, and decades of intense study of its pathogenesis resulted in the development of the antidote N-acetylcysteine, which facilitates scavenging of the reactive metabolite and is the only treatment in clinical use. However, the narrow therapeutic window of this intervention necessitates a better understanding of the intricacies of APAP-induced liver injury for the development of additional therapeutic approaches that can benefit late-presenting patients. More recent investigations into APAP hepatotoxicity have established the critical role of mitochondrial dysfunction in mediating liver injury as well as clarified mechanisms of APAPinduced hepatocyte cell death facilitates scavenging of the reactive metabolite and is the only treatment in clinical use. Mitochondrial oxidative and nitrosative stress is a key mechanistic feature involved in downstream signaling after APAP overdose. The identification of specific mediators of necrotic cell death further establishes the regulated nature of APAP-induced hepatocyte cell death. In addition, the discovery of the role of mitochondrial dynamics and autophagy in APAP-induced liver injury provides additional insight into the elaborate cell signaling mechanisms involved in the pathogenesis of this important clinical problem. In spite of these new insights into the mechanisms of liver injury, significant controversy still exists on the role of innate immunity in APAP-induced hepatotoxicity.

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Section: Metabolism Of Acetaminophenmentioning

confidence: 99%

Acetaminophen Induced Liver Injury: Metabolism and Inflammation Perspectives

2021

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“…They proposed using these assumptions that a patient ingesting 35g (500mg/kg) of paracetamol warranted an increase in infusion rate in the third bag to 13.75 mg/kg/h. 1 The median reported dose of paracetamol ingested in large cohort studies of patients treated with NAC in the UK and Australia is around 16g (210-250mg/kg) but the rates of hepatotoxicity (defined as peak ALT>1000 IU/L) is only around 4-8%, depending on the nomogram used to determine treatment 2,3 , suggesting that the vast majority of patients ingesting >16g paracetamol fare well with the current 300 mg/kg NAC dose. Hendrickson used similar stoichiometric calculations to propose infusion rates of 12.5, 18.75 and 25 mg/kg/h for patients above the 300 mg/L, 450 mg/L and 600 mg/L nomogram lines respectively.…”

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confidence: 99%

Large paracetamol overdose -- higher dose NAC is required - CON

Thanacoody

2021

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Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30g or 500mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. Small studies in patients whose paracetamol concentration are above the 300mg/L nomogram line show that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22h may reduce the risk of hepatotoxicity (peak ALT>1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.

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“…1 Both are associated with less adverse reactions, and in large observational studies have been shown to have similar efficacy to the traditional regimen. 8,9 Unfortunately, paracetamol overdoses have become more problematic with increased availability of larger pack sizes (massive overdoses) and the introduction of modified release preparations in some parts of the world. It is now recognised that the dose of acetylcysteine used for decades may not be effective for these cases, so clinicians now challenge the illogical 'one size fits all' to antidote dosing for paracetamol.…”

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confidence: 99%

“…In the United Kingdom, the Scottish and Newcastle Anti‐emetic Pre‐treatment for Paracetamol Poisoning (SNAP) 12‐h regimen (100 mg/kg over 2 h followed by 200 mg/g over 10 h) is being adopted, 7 while in Australia, a two‐bag simplification (200 mg/kg over 4 h followed by 100 mg/kg over 16 h) of the three‐bag regimen is now recommended 1 . Both are associated with less adverse reactions, and in large observational studies have been shown to have similar efficacy to the traditional regimen 8,9 …”

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confidence: 99%