Dear Editor,

We have carefully reviewed the recent study by Gräfe et al. [1], titled “Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb® and Mortality in Critically Ill Patients with Hyperbilirubinemia,” published in Blood Purification on October 11, 2023. We would like to express some concerns and seek clarification on certain aspects of the study.

First, the authors investigated whether extracorporeal elimination of bilirubin with the cytokine adsorber CytoSorb® (CS) reduces mortality in patients with hyperbilirubinemia and they suggested that randomized and controlled studies with mortality as the primary outcome measure are needed in the future to justify their use. We would like to raise some doubts regarding this position because mortality as the primary endpoint in critically ill patients is challenging, due to the variability in sepsis phenotypes [2]. Acute liver failure (ALF), acute-on-chronic liver failure, and cirrhosis exhibit significant similarities with septic shock, involving the interaction of systemic inflammation, immune dysfunction, and organ failure. By targeting pro-inflammatory molecules, hemadsorption holds good promise as a potential treatment strategy in the management of acute liver failure and acute-on-chronic liver failure [3‒5]. Therefore, bilirubin represents not only a toxic molecule but also a marker of the degree of systemic intoxication and of the effectiveness of a purification therapy. Finally, while the real objectives of a hemadsorption therapy like CytoSorb is to act as a bridge to recovery or transplantation, only transplantation can make a true difference in the mortality of these patients.

The authors did not find any significant differences in bilirubin concentration between groups. This finding contradicts previous studies, which [6] reported significant bilirubin, AST and vasopressor reduction by hemadsorption. As Gräfe et al. [1] did not quantify bilirubin removal by hemadsorption, it becomes challenging to assess the effectiveness of this particular blood purification technique in the described scenario. Moreover, the quantitative impact of all the extracorporeal therapies, including CytoSorb, on bilirubin levels may not be assessed by means of systemic measurements alone. In this regard, mass balance (MB) can be calculated easily using known formulas as follows:
MBmg=C0t0Cft0+C0txCftx/2×Qplasma×tx
with C0 and Cf being the concentration pre- and post-removal system at every tx interval, respectively.

We would then like to address one of the claims in this study, where the authors state that the removal of bilirubin and biliary acids is practically irrelevant after 6 h. In contrast, a previous study by Gemelli et al. [7] demonstrated the in vitro capability of CytoSorb to efficiently remove bilirubin over 24 h, with minimal albumin loss and no detectable bilirubin release from the charged resin. Furthermore, they showed how the adsorption percentage obtained from the 8th hour to the 24th h is lower but provide a MB virtually equivalent to the first 8 h.

These data are confirmed by an in vivo study, recently published by Riva et al. [8]. The study showed higher total bilirubin, direct bilirubin, and biliary acids adsorption with CytoSorb, with average 5-fold higher MB for CytoSorb than for the other methods (shown in Fig. 1). CytoSorb presented a significantly higher bilirubin adsorption capability for compared to other extracorporeal systems (shown in Fig. 2). In fact, the data indicate that toxin concentrations in the CytoSorb group decreased significantly over time until end of the treatment period (t = 25 h), while in the other treatment groups, the reduction was present only up to 9 h, after which there was an observed increase in serum levels. The above data also refute Greimel’s et al. study [9] about a saturation of the CytoSorb adsorber after 6 h. In our opinion, the reason for such a contradiction lies in the observed parameter (removal ratio) that is unable to distinguish the effect of purification from generation (as MB does).

Fig. 1.

TB, DB, and BA total MB regarding all the techniques comparison for the overall treatments (Kruskal-Wallis). *Total MB – TB, DB, BA: p < 0.05 CytoSorb versus CPFA, MARS, and PROM. +Limited number of samples PAP (n = 2), MARS (n = 3), and PROM (n = 5). TB, total bilirubin; DB, direct bilirubin.

Fig. 1.

TB, DB, and BA total MB regarding all the techniques comparison for the overall treatments (Kruskal-Wallis). *Total MB – TB, DB, BA: p < 0.05 CytoSorb versus CPFA, MARS, and PROM. +Limited number of samples PAP (n = 2), MARS (n = 3), and PROM (n = 5). TB, total bilirubin; DB, direct bilirubin.

Close modal
Fig. 2.

TB and BA MB and reduction/h comparison regarding CytoSorb versus CPFA during the course of the time (repeated-measures ANOVA). *p < 0.05 CytoSorb versus CPFA. **p < 0.01 CytoSorb versus CPFA. ***p < 0.001 CytoSorb versus CPFA. TB, total bilirubin.

Fig. 2.

TB and BA MB and reduction/h comparison regarding CytoSorb versus CPFA during the course of the time (repeated-measures ANOVA). *p < 0.05 CytoSorb versus CPFA. **p < 0.01 CytoSorb versus CPFA. ***p < 0.001 CytoSorb versus CPFA. TB, total bilirubin.

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The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Ivano Riva and Stefano Faenza conceived the study, drafted the paper, and jointly approved the current version.

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