Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review

Mullins, Michael E.; Yeager, Lauren H.; Freeman, William E.

doi:10.1080/15563650.2020.1798979

Cited by 21 publications

(12 citation statements)

References 86 publications

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“…4-Methylpyrazole, also known as fomepizole, is an alcohol dehydrogenase competitive antagonist [14] and a potent inhibitor of CYP2E1, the major isozyme in acetaminophen metabolism to NAPQI [15]. In addition to the inhibition of CYP2E1, fomepizole inhibits the c-jun N-terminal kinase (JNK) pathway responsible for mitochondrial dysfunction [16,17]. In vitro studies with human hepatocytes and in vivo murine models have shown that cotreatment with fomepizole and acetaminophen has hepatoprotective effects with reduced plasma alanine aminotransferase concentrations and decreased hepatocyte necrosis [15].…”

Section: Discussionmentioning

confidence: 99%

Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis

Chiu

Jaworska

et al. 2021

Case Reports in Critical Care

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Acetaminophen overdose is one of the most common causes of acute hepatic failure in the developed world. There is strong evidence for N-acetylcysteine (NAC) as a safe and effective antidote for acetaminophen toxicity. However, there is less clarity in the management of massive overdoses (acute, single ingestions > 500 mg/kg with 4-hour equivalent concentrations ~6000 μmol/L) which are often associated with metabolic acidosis and multiorgan dysfunction. In such ingestions, the role of adjuvant treatments such as fomepizole and extracorporeal removal is unclear. We present a case of a 20-year-old female presenting with an acute ingestion of over 120 grams (1764.7 mg/kg) and an acetaminophen concentration of 5880 μmol/L who developed refractory shock, decreased level of consciousness, and metabolic acidosis requiring mechanical ventilation and vasopressor support. She was treated with gastric decontamination with activated charcoal, IV NAC, fomepizole, and hemodialysis. The patient had complete clearance of acetaminophen by 32 hours after presentation and normalization of her acid base and hemodynamic status without any organ failure. This case highlights the potential benefit of a triple strategy of NAC, fomepizole, and early hemodialysis in massive acetaminophen overdose, potentially sparing complications of prolonged intubation and ICU hospitalization.

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Section: Discussionmentioning

confidence: 99%

Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis

Chiu

Jaworska

et al. 2021

Case Reports in Critical Care

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“…Similarly metabolic antidotes, including fomepizole and calmangafodipir ([Ca0.8, Mn0.2]Na3DPDP) have been studied on a case basis 18,29–31 …”

Section: Discussionmentioning

confidence: 99%

Large paracetamol overdose—Higher dose acetylcysteine is required

Bateman

2022

Brit J Clinical Pharma

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Paracetamol poisoning continues to be a worldwide problem and, despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from high doses of paracetamol, even in those receiving prompt NAC therapy, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.

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“…26,27 Similarly metabolic antidotes, including fomepizole and calmangafodipir, which are both in clinical trial and have been studied on a case basis. 17,[28][29][30] Identifying patients at increased risk may be difficult as there is a variability in the susceptibility to paracetamol which is still not fully understood. 31 Obviously very high doses present a risk, but newer molecular techniques now allow identification of patients at risk of liver injury at hospital presentation.…”

Section: Discussionmentioning

confidence: 99%

Large paracetamol overdose -- higher dose NAC is required

Bateman

2021

Preprint

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Paracetamol poisoning continues to be a worldwide problem and despite the availability of an affective antidote, N-acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from paracetamol, even in those receiving prompt NAC therapy, at high doses of paracetamol, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.

show abstract

Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review

Cited by 21 publications

References 86 publications

Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis

Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis

Large paracetamol overdose—Higher dose acetylcysteine is required

Large paracetamol overdose -- higher dose NAC is required

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