We report a case of massive acetaminophen overdose successfully treated with early administration of intravenous NAC, fomepizole, and prolonged intermittent hemodialysis. There are theoretical benefits in rapid acetaminophen elimination and early correction of metabolic acidosis however, this remains an area of ongoing research. Massive overdose may require treatment with IV NAC beyond 21 hours and may expose the patient to prolonged intubation and ICU admission with potential complications of hospital-acquired infections and neuromuscular weakness. Currently, there is no consensus on when to initiate these therapies. Novel adjuvant therapies include the addition of fomepizole via inhibition of CYP2E1 and extracorporeal removal. There is less evidence surrounding the management of massive overdoses however, the literature is supportive of the use of additional therapies. In such cases, protective effects of NAC may be overwhelmed by the ingested dose. In massive overdoses (above 500 mg/kg), clinical deterioration may occur rapidly (within 12 hours) with decreased level of consciousness and mitochondrial injury characterized by a high anion gap metabolic acidosis preceding severe liver injury. Patients who survive stage 3 progress to stage 4 with a slow recovery and normalization of liver chemistry (4 days to two weeks). Development of multiorgan failure and death commonly occur in this phase. Depending on the degree of poisoning, hepatic failure with jaundice, hepatic encephalopathy, and bleeding diathesis occur. In stage 3 (72-96 hours), liver function abnormalities peak. Stage 2 (24 to 27 hours) involves improvement in nausea and vomiting, with development of right upper quadrant pain, and worsening hepatic and renal toxicity. Stage 1 occurs within 24 hours and is characterized by nausea, vomiting, lethargy, and malaise. Clinical manifestations of APAP poisoning are typically nonspecific however can be divided into four stages.
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NAC has multiple therapeutic actions including acting as both a glutathione precursor and substitute, enhancing the nontoxic sulfation metabolic pathway (thereby reducing production of NAPQI, improving of hepatic blood flow, and scavenging of free radicals). Management consists of gastric decontamination and early administration of N-acetylcysteine (NAC) if the is potentially toxic when plotted on the Rumack-Matthew acetaminophen treatment nomogram. With supratherapeutic ingestions, up to 50% of absorbed APAP is metabolized by CYP2E1, leading to production of N-acetyl-p-benzoquinone imine (NAPQI), the hepatotoxic metabolite. With therapeutic dosing, APAP is metabolized primarily via glucuronidation and sulfation to nontoxic metabolites. Poisoning can occur through single or repeated ingestions. IntroductionĪcetaminophen (APAP) toxicity is among the most common medication-related overdoses and accounts for nearly half of all liver transplantations in the United States. 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. 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. She was treated with gastric decontamination with activated charcoal, IV NAC, fomepizole, and hemodialysis. 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.
In such ingestions, the role of adjuvant treatments such as fomepizole and extracorporeal removal is unclear. However, there is less clarity in the management of massive overdoses (acute, single mg/kg with 4-hour equivalent concentrations ~6000 μmol/L) which are often associated with metabolic acidosis and multiorgan dysfunction. There is strong evidence for N-acetylcysteine (NAC) as a safe and effective antidote for acetaminophen toxicity. Acetaminophen overdose is one of the most common causes of acute hepatic failure in the developed world.
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