“Massive Acetaminophen Ingestion with Early Metabolic Acidosis and Coma: Treatment with IV NAC and Continuous Venovenous Hemodiafiltration” by Wiegand et al., Clin Toxicol (Phila) 48:156–159

To the Editor:

We read the article by Wiegand et al.¹ describing a case of massive acetaminophen ingestion treated with intravenous N-acetylcystein and continuous venovenous hemodialfiltration (CVVHDF) with much interest. We believe that CVVHDF holds promise for extracorporal drug elimination after massive overdose, especially in hypotensive patients not eligible for hemodialysis.

However, we would like to address several points in the reported pharmacokinetic analysis. First, the authors did not provide the reader with CVVHDF adjustments, most importantly blood flow and dialysate flow and dilution measures. This makes it impossible to assess how the authors calculated the reported dialysis clearance. How many dialysate acetaminophen concentrations were measured? Second, we believe that total body clearance (CL_Total) cannot be calculated from the data presented since terminal half-life of elimination (t_1/2,el), both during and after CVVHDF, is unknown. What the authors report as “half-life” was not the t_1/2,el but an apparent half-life, likely estimated using linear pharmacokinetics during CVVHDF (although not stated by the authors). Consequently, the use of Equation 1 was not appropriate since it is derived and used for description of elimination using first-order pharmacokinetics after complete absorption and distribution has occurred.

Back-calculation of the apparent half-life likely used by the authors to determine CL_Total applying Equation (1) and using the reported CL_Total of 3.82 L/h yields an apparent half-life of 7.3 h.

This long apparent half-life despite ongoing CVVHDF, absence of liver dysfunction and taking into consideration the delayed peak concentration estimated from Figure 1, is most likely explained by the on-going absorption during the reported time span. Prolonged absorption has been reported several times^2–4 for extended release acetaminophen. Applying Equation 1 using the apparent half-life of elimination instead of t_1/2,el, is inadequate and results in a substantial underestimation of CL_Total.

In addition, assuming a normal volume of distribution of 40 L (0.9 L/kg) in this massive overdose may be an oversimplification in massive overdose, as has been demonstrated for midazolam,⁵ and would likely lead to further underestimation of CL_Total.

The authors state correctly that CVVHDF was mainly helpful for the correction of acid base and fluid abnormalities. However, since the optimal dose and duration of treatment with NAC in such massive overdose is largely unknown, such overdoses themselves are associated with renal failure, and acetaminophen is readily dialysable, use of hemodialysis or CVVHDF, in hemodynamically unstable patients, may be reasonable. We believe toxicokinetic data are needed and can only be derived from cases such as the one presented. We encourage authors to provide the necessary clinical data to accurately calculate toxicokinetic variables as they may differ significantly from normal pharmacokinetics.