To the best of our knowledge, we report the first case of in-vivo CPH clearance by means of HCO-based CVVHD treatment. HCO filters have been designed to improve clearance of middle-sized molecules that were not previously cleared by normal filters, such as pro- and anti-inflammatory cytokines [
7‐
10]. The possibility to clear CPH has been recently examined in an in-vitro model, in which the authors demonstrated the efficacy of the same HCO filter that we used, with a SC for CPH of 0.35 and a clearance of approximately 22 ml/min [
5]. However, in our case the initial SC was of only 0.08, decreasing to 0.02 in the following 24 h, presumably due to the phenomenon of protein-coating. CPH clearance was reduced as well, with values below 3 ml/min initially: albeit not negative, this clearance is far from being clinically relevant. In order to explain the striking difference with the results obtained in the in-vitro model, we should consider the dissociation characteristics of the hemoglobin tetramers (62.6 kDa) into dimers (31.3 kDa). Indeed, the hemoglobin dimer is the part of the molecule that is cleared by the HCO filter under study, whose cut-off is 60 kDa. As the dissociation of tetramers into dimers is maximum at low concentrations of CPH, the best results are obtained with CPH concentrations lower than 1 g/L. In the above-cited in-vitro study, indeed, the CPH concentration was within this range and the approximate dissociation degree at this concentration was around 40%. On the other side, our patient had much higher CPH concentration (4.24 g/L). At this level, the expected dissociation degree is lower than 10% [
5]. Therefore, the lower SC for CPH observed in our case is probably due to the lesser degree of dissociation of the molecule. This point provides an important indication, since it demonstrates that those patients that would benefit the most from this treatment are those presenting CPH levels lower than 1 g/L. Presumably, patients with massive hemolysis and already established kidney injury are less likely to benefit from HCO-based CPH clearance. On the other side, critically ill patients with smoldering hemolysis and lower concentrations of CPH should theoretically take more advantage from it. For example, pediatric patients submitted to two different types of ECMO treatment had mean CPH values between 0.36 and 0.58 g/l [
11], while CPH values in septic patients ranged from 0.034 to 0.185 g/L [
4]. It is worthy to underline that even these low levels of CPH are not harmless. In a rat model, purified hemoglobin enhanced TNF-α synthesis in LPS-stimulated macrophages by a factor of 1.000 [
2]. In another model, the administration of hemoglobin in LPS-treated mice resulted in an increase in TNF-α levels and mortality [
3]. In humans, CPH was strongly associated with decreased survival in severe septic patients, even after substantial correction with already known risk factors including age, inflammatory biomarkers, Simplified Acute Physiology (SAPS-II) and Sequential Organ Failure Assessment (SOFA) scores [
4].