Acetaminophen and acetylcysteine dose and duration: Past, present and future

Abstract

Acetylcysteine has been utilized successfully in the treatment of acetaminophen overdose since the 1970s. Although prospective trials as to efficacy and safety of acetylcysteine were conducted, there were no randomized controlled trials. This commentary addresses the reasons for this, and the background to choice of dose of acetylcysteine utilized in the oral and IV dosing regimens. Nomograms to predict possible hepatotoxicity based upon time of ingestion of acetaminophen were developed from a relatively arbitrary definition of toxicity as an aspartate aminotransferase/alanine aminotransferase (ALT/AST) greater than 1000 IU/L. While these have proved generally useful, patients still continue to develop hepatic damage after acetaminophen overdose, particularly if they present late after ingestion. The optimum management of these patients remains unclear, and one area of uncertainty is the dose and duration of acetylcysteine in various circumstances. This article discusses the issues that need to be elucidated to better target changes in acetylcysteine dose. The potential for measurements of other markers to improve treatment selection is the subject of further research.

The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond

“…N-acetylcysteine (NAC) has been available for decades and is extremely effective at managing and preventing acute injury to acetaminophen overdose (243,245). Oral and IV formulations appear equally effective (246) The use of liver assist devices such as molecular adsorbent recirculating systems ( MARS) or plasma exchange have proven effective as a bridge to transplant, but remain largely investigational (68,69,(251)(252)(253).…”

Changing the Management of Paracetamol Poisoning

“…The rationale was that 150 mg was half the concentration of 300 mg/L, which at that time was believed to cause death. 12 Subsequent reports have found that deaths can occur in untreated patients at concentrations below the 200 mg/L line and, in very rare patients who are fasting, even below 100 mg/L. 5,13,14 In the 1990s, the United Kingdom changed its policy to include a risk assessment in those patients with paracetamol concentrations between the 100 and 200 mg/L nomograms.…”

“…The dose of acetylcysteine is likely to be excessive as a glutathione replacement for all but the largest of paracetamol overdoses, that is, with concentrations 4500 or 600 mg/L. 12 Some have suggested it might be possible to model acetylcysteine requirements based on estimated paracetamol dose, but this has yet to be tested in practice. 33 …”

ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose

“…The administration of an additional NAC bolus or extending the duration of the 6.25 mg/kg/h infusion may be appropriate in certain clinical scenarios [13][14][15][16]. Treatment beyond 21 h is indicated when patients have evidence of hepatotoxicity evidenced by elevations in aminotransferases, abnormalities in predictors of poor prognosis, or persistent APAP detected by laboratory testing.…”