Hemofiltration in the early phase of sepsis: Friend or foe?*

Severe sepsis has long been attributed to an overwhelming, predominantly cytokine-mediated, inflammatory response of the host to a microbial toxin. Large efforts have been made to either neutralize the causative toxin or mitigate the cytokine response to it. In this respect, hemofiltration has remained a promising technique, because it is both able to eliminate the bacterial toxin and the cytokines produced in its response. Nevertheless, the small randomized controlled trials performed until now were unable to demonstrate an impact of hemofiltration on mortality or the resolution of organ failure. In this issue of Critical Care Medicine, Payen et al (1) report the results of the largest randomized controlled trial on hemofiltration in sepsis performed so far, comparing 96 hours of isovolemic continuous venovenous hemofiltration in standard dose (2 L/hr) early in the course of severe sepsis to standard sepsis management. The study, performed in the period 1997–2000 and originally intending to include 400 patients, was ended preliminarily for safety reasons. Seventysix patients were analyzed: 37 in the hemofiltration group and 39 in the control group. In the hemofiltration group, organ dysfunction as quantified by the Sequential Organ Failure Assessment score progressed more rapidly than in the control group, and the Sequential Organ Failure Assessment score in the hemofiltration group remained higher during the entire observation period. Importantly, more patients in the hemofiltration group developed oliguric renal failure over time. In addition, weaning from mechanical ventilation and catecholamines took longer in the hemofiltration group. Cytokine levels and mortality rates after 14 days were similar in both groups. This important study not only confirms the finding by Cole et al (2) that standard hemofiltration is unable to reduce cytokine levels and organ dysfunction occurring during sepsis, but also suggests that the use of standard hemofiltration in the early phase of sepsis is detrimental to organ function, in general, and to renal function, in particular. However, the influence of a difference in support intensity cannot be excluded, because patients in the hemofiltration group were more often treated with norepinephrine (54% vs. 39%, not significant). The fact that this difference did not reach statistical significance may be due to the relatively small number of patients. Indeed, in a retrospective cohort study among 185 septic surgical intensive care unit patients, Hoste et al (3) found a similar but significant difference in vasoactive support between patients who did and did not develop acute renal failure (56.7% vs. 36.1%, p 0.035). Similarly, Soubrier et al (4) identified septic shock requiring vasoactive support as the most important prognostic factor for mortality among 197 critically ill patients requiring renal replacement therapy (odds ratio 16.15, 95% confidence interval 2.15– 121.33, p 0.01). An important limitation of the current study is the use of a polysulfone membrane. Because baseline cytokine levels are related to the outcome in severe sepsis (5), it was hypothesized that extracorporeal elimination of cytokines might have a beneficial effect on sepsis outcome. However, among different types of membranes, polysulfone has been demonstrated to be least suitable for the removal of cytokines (6). Furthermore, in the modern concept of the pathogenesis of sepsis, mortality is related to an unbalanced host response, involving hyperinflammation on one hand and immunosuppression on the other. In both pathways, cytokines are involved: hyperinflammation is likely mediated by the activation of caspase-1, responsible for the secretion of three interleukin (IL)-1 family members, whereas immunosuppression is thought to be mediated by IL-10 and transforming growth factor , inhibiting the capacity of circulating leukocytes to release proinflammatory cytokines (7). At the time the study by Payen et al was performed (1997–2000), techniques for the removal of anti-inflammatory cytokines were limited. By means of a technique similar to the one used in the current study (hemofiltration with an 0.6-m AN69 hemofilter and an ultrafiltration [UF] flow of 2 L/hr), Kellum et al (8) were unable to clear IL-10 from the blood of 13 critically ill patients. However, by means of modern hemofilters, removal of both proand anti-inflammatory cytokines is feasible. Morgera et al (9) demonstrated that a high-flux hemofilter with a larger hollow fiber diameter and an increased pore size can achieve a higher clearance rate for IL-6 and IL-1-ra than a conventional hemofilter, resulting in a significant decline of the corresponding plasma levels. Furthermore, in patients hemofiltrated with a high-flux hemofilter, vasopressor use decreased over time and both polymorphonuclear phagocytosis and mononuclear cell proliferation were normalized, supporting the hypothesis that removal of antiinflammatory cytokines by means of hemofiltration is indeed able to restore the normal leukocyte inflammatory response (10, 11). A second limitation of the current study is the use of a low UF rate (2 L/hr), for which the inability to reduce cytokine levels and organ dysfunction had already been proven (2). Because IL-6 can be detected in the ultrafiltrate during hemofiltration, it is conceivable that an UF rate of 2 L/hr is simply too low to influence serum IL-6 levels. Indeed, Ghani et al (12) demonstrated that high-volume hemofiltration (UF rate 6 L/hr) significantly reduced IL-6 levels, whereas conventional hemofiltration (UF rate 2 L/hr) did not. Furthermore, a significant decrease in vasopressor need during high-volume hemofiltration was demonstrated by several authors (12–14). The improvement of blood purification techniques and membranes has *See also p. 803.