Blood and plasma treatments: the rationale of high-volume hemofiltration.

Since the early 1990s, experts in the field have thought that a reduction in cytokines in the blood compartment could, in theory, reduce mortality, but this is perhaps too naive as the pharmacodynamics and pharmacokinetics of cytokines throughout the body are not well known and are probably much more complicated than previously thought. This ha now led to three leading theories and concepts. Ronco and Bellomo conceived the peak concentration hypothesis in which clinicians concentrate their efforts to remove mediators and cytokines from the blood compartment at the proinflammatory phase of sepsis. By reducing the amount of free cytokines, it is hoped that the level of remote organ (associated) damages can be dramatically decreased and, as a consequence, the overall death rate. In this regard, it is still not known what will happen at the interstitial and tissue level with regard to mediators and cytokines which are obviously the most important part in terms of consequences at the tissue level. In this setting, techniques that can more rapidly and substantially remove great amounts of cytokines or mediators are privileged. Among these, there is high-volume and very high-volume hemofiltration and a number of hybrid therapies encompassing high-permeability hemofiltration, super high-flux hemofiltration, hemo-adsorption or coupled filtration and adsorption and other types of adsorption using physical or chemical forces rather than driving forces as used normally in hemofiltration-derived techniques. The second concept is called the threshold immunomodulation hypothesis, also called the Honoré concept. In this concept the view of the system is much more dynamic. In experiments when removal is occurring on the blood compartment side, the level on the interstitial side and the tissue side is also changing and, because not only mediators but also pro-mediators are being removed, some pathways have really stopped when enough pro-mediators have been removed by this technique. At this point, the cascade is blocked and this point is called the threshold point. At this level, the cascade is lost and no further harm can be done to the tissue of the organism. Obviously, it is difficult to know when this point has been reached once high-volume hemofiltration is applied. But what is known, is that hemodynamics and survival can be improved in some patients as shown by various studies using high-volume hemofiltration without any significant drop in mediators inside the blood compartment itself. This effect is obtained without a dramatic fall Honoré/Joannes-Boyau/Gressens 388 in the plasma cytokine level because the cytokine or mediator levels should fall at the tissue level and not specifically at the blood compartment level. Nevertheless, the exact mechanism by which high-volume hemofiltration increases the flow of mediators and cytokines between the interstitial compartment and the blood compartment (and back to the blood side) is not known. Before the end of 2005, it was found that this missing step is perhaps well explained by the last theory and/or concept. The third theory and concept is called the mediator delivery hypothesis and has also been called the Alexander concept. In this theory, the use of high-volume hemofiltration and especially high intakes of incoming fluids (3-5 l/h) is able to increase the lymphatic flow 20- to 40-fold, even more so for mediators and cytokine lymphatic flow (drag). This has been demonstrated by several reports and is obviously extremely important. Perhaps this can explain why some very recent studies using high-permeability hemofiltration in sepsis have not been effective in improving hemodynamics and survival in septic acute animal models. In summary various brand new theories will be reviewed here in depth.