What is the most appropriate dose of N-acetylcysteine after massive acetaminophen overdose?

While the traditional intravenous N-acetylcysteine (NAC) dosing regimen works well for the vast majority of acetaminophen overdoses, there may be cases of massive overdose where additional NAC may be necessary. Recent evidence suggests that patients with acetaminophen concentrations above the “300-line” develop hepatotoxicity at a higher rate than those below the 300-line, suggesting that an increase of dose may be beneficial at this cut-off. Additional clinical data suggest a further increase in doses at the 450-line and 600-lines. I propose a strategy for step-wise increases in NAC dosing in response to high acetaminophen concentrations at the 300-, 450-, and 600-lines after acute massive acetaminophen overdoses.