� What protocol should we be following for IV N-acetylcysteine in acute acetaminophen toxicity?
Acetaminophen toxicity remains at the forefront of liver-related transplantation in the United States of America. As a result, multiple regimens for treatment with N-acetylcysteine (NAC) have been proposed in countries around the world. So which protocol is best?
For our Emerging Insights review on Acetaminophen toxicity and Fomepizole administration please click here.
� How does N-acetylcysteine work?
Restoring Glutathione Levels:
Normally, acetaminophen is metabolized safely in the liver.
Overdose: liver loses ability to metabolize acetaminophen, leading to oxidation and depletion of glutathione. This shunts the pathway, leading to increased NAPQI (N-acetyl-p-benzoquinone imine) formation, a hepatotoxic metabolite.
Binding NAPQI: By restoring glutathione, NAC allows the liver to enhance sulfate conjugation, bind, neutralize, and reduce NAPQI formation. NAPQI binds to liver cells, causing oxidative damage, mitochondrial stress, and cellular death, leading to liver injury or failure.
Direct Antioxidant Effects: NAC has antioxidant properties, which helps reduce the oxidative stress on liver cells, protecting the liver from the impact of NAPQI.
Timing: NAC works best when started early, to reduce NAPQI formation and hepatocellular death.
� What IV N-acetylcysteine protocols are currently available?
Three-bag Regimen:
Loading dose: 150 mg/kg over 1 hour
2nd-bag: 12.5 mg/kg/hr over 4 hours (total: 50 mg/kg)
3rd-bag: 6.25 mg/kg/hr over 16 hours (total: 100 mg/kg)
Total dose: 300 mg/kg
Total time: 21 hours
Two-Bag Regimen:
1st-bag: 50 mg/kg/hr over 4 hours (total: 200 mg/kg)
2nd-bag: 6.25 mg/kg/hr over 16 hours (total: 100 mg/kg)
Total dose: 300 mg/kg
Total time: 20 hours
One-Bag Regimen:
Loading dose: 150 mg/kg over 1 hour
Same-bag: 12.5 mg/kg/hr over 20 hours (total: 250 mg/kg)
Total dose: 400 mg/kg
Total time: 21 hours
➊ Let's break it down!:
What is the issue with the traditional three-bag system?
At the fundamental basis of the protocol, you have 3 separate preparations at varying doses hung at separate rates. This increases the opportunity for adverse outcomes due to dosing and medication errors. As pointed out in this study, Ferner et al. (United Kingdom) measured concentrations with only 37% of NAC being the correct dose, with deviation of over 50%. This is a huge potential for adverse outcomes and delay in transitioning from each bag. It is a large burden on pharmacy, the ordering physician, and the nursing staff to change both bags and pumps. A total of 12 steps are noted to have the potential for error!
What is the advantage of a two-bag system?
As outlined in this report, there is a personalized concentration, 1 preparation of the bags by the pharmacist, and a reduction from 12 to 8 steps. Error rates noted to fall to 34%.
What is the advantage of a one-bag system?
Simply, a singular preparation of 30 grams in 1 Liter of D5W set as a bolus and followed by an infusion rate calculated by a pump protocol. This has become increasingly accepted in North America. This is also shown by multiple other studies to decrease adverse reactions.
➋ What does this study suggest?
A standard concentration of 30 mg/mL of IV NAC over 20-24 hours adopted universally in North America.
➌ Tox Talk Thoughts:
Whether a two or one-bag regimen, a standard concentration of NAC with reduction in steps will reduce adverse outcomes by directly reducing opportunity for error. A one-bag regimen appears to be favorable for both reduction of error, cost, labor, and adverse events.
� Conclusions:
N-acetylcysteine remains the forefront standard of therapy for acute acetaminophen toxicity. It is currently an opportunity for improvement in error reduction, simplification, and standardized dosing. Three regimens are currently being practiced with a suggestion for universal dosing of 30 mg/mL over 20-24 hours. Studies appear to be promising and further studies should be performed to analyze 30 mg/mL IV NAC protocol to evaluate patient outcomes (liver enzymes, adverse effects, LOS, etc) when compared to traditional three-bag, two-bag, and single-bag NAC protocols.
Read the full article here.
Resources:
Nguyen, KL.R., Mullins, M.E. Intravenous Acetylcysteine: What Should Replace the Prescott “Three-Bag” Protocol?. J. Med. Toxicol. 20, 348–349 (2024). https://doi.org/10.1007/s13181-024-01017-w