A Case Report of Massive Acetaminophen Poisoning Treated with a Novel “Triple Therapy”: N-Acetylcysteine, 4-Methylpyrazole, and Hemodialysis

Abstract

Massive acetaminophen (N-acetyl-p-aminophenol; APAP) ingestion is characterized by a rapid onset of mitochondrial dysfunction, including metabolic acidosis, lactemia, and altered mental status without hepatotoxicity which may not respond to the standard doses of N-acetylcysteine (NAC). A 64-year-old woman without medical history presented comatose after an ingestion of 208 tablets of Tylenol PM™ (APAP 500 mg and diphenhydramine 25 mg). The initial APAP concentration measured 1,017 µg/mL (therapeutic range 10-30 µg/mL), and elevated anion gap metabolic acidosis, lactemia, and 5-oxoprolinemia were detected. High-dose intravenous (IV) NAC, 4-methylpyrazole (4-MP), and hemodialysis (HD) were initiated. She was transferred to a liver transplant center and continued both NAC and HD therapies until complete resolution of metabolic acidosis and coma without developing hepatitis. She was discharged without sequelae. This is the fourth highest APAP concentration recorded in a surviving patient. Moreover, this is the first report of a novel “triple therapy” using NAC, 4-MP, and HD in the setting of massive APAP ingestion that presents with coma, elevated anion gap metabolic acidosis, and lactemia. Emergency physicians should recognize these critically ill patients and consider high-dose NAC, 4-MP, and HD to be initiated in the emergency department (ED).

Massive acetaminophen overdose with metabolic acidosis refractory to N-acetylcysteine, fomepizole, and renal replacement therapy

“…In most cases of early lactic acidosis in APAP overdose, the lactatemia persists for less than 48 h, even when renal replacement therapy is not used to mitigate the patient’s acidosis [ 9 ]. When renal replacement therapy is employed, however, APAP clearance is more efficient with a rapid improvement of the associated acidosis, typically within hours of first IHD treatment in most reports [ 3 , 4 , 7 , 10 , 11 ]. In these cases, additional runs of IHD are not necessary in order to improve the patient’s lactate, and IHD use coincides with clinical improvement as well.…”

Continuous Venovenous Hemofiltration as a Rescue Therapy for Severe Acetaminophen Toxicity in a Toddler

“…The suggested strategies in such scenarios are to increase the dose and duration of NAC, removal of acetaminophen from blood by an extracorporeal therapy (SLED, CVVH, PLEX, or MARS), and in dire circumstances, liver transplantation. [3][4][5][6][7][8][9][10][11]13 The Extracorporeal Treatments in Poisoning workgroup recommends extracorporeal therapies such as intermittent HD, CVVH, or PLEX in acetaminophen poisoning, where there is evidence of mitochondrial dysfunction and exceedingly high drug levels. 7 The Pediatric Continuous Renal Replacement Therapy workgroup recommended to startrenal replacement therapy (RRT) with HD for severe acetaminophen toxicity.…”

“…There are only few case reports among adults with massive acetaminophen toxicity where HD or CRRT was used as a rescue measure with a favorable outcome. [4][5][6][7] In patients with fulminant liver failure with suspected or proven cerebral edema, CRRT is more beneficial than intermittent HD due to increased risk of worsening cerebral edema with later. 5 Also, with HD, there is concern of removal of NAC along with acetaminophen which may require increase in dose of NAC.…”

“…2 If there is no improvement, extracorporeal therapies such as hemodialysis (HD), sustained low efficiency dialysis (SLED), continuous venovenous hemofiltration (CVVH), high-volume plasma exchange (PLEX), and molecular adsorbent recirculating system (MARS) can be used as rescue measures. [3][4][5][6][7][8][9][10][11][12] Here, we present an 18-month-old male infant who had presented with fulminant liver failure following accidental ingestion of acetaminophen. CVVH was used as a rescue therapy, which led to complete recovery.…”

Use of fomepizole as an adjunct in the treatment of acetaminophen overdose: a case series

“…In one case, hemodialysis was used in part due to coingestion of salicylate, and the beneficial effect of our use of fomepizole may have been partly overshadowed. Other case reports describe hemodialysis in conjunction with IV NAC and fomepizole [13], although extracorporeal removal of acetaminophen is necessary only in rare cases [14].…”