Blood purification: can we purify our patients from sepsis?

September 2013 • Volume 41 • Number 9 Severe sepsis remains one of the most vexing conditions with inadmissibly high mortality, which we face in our daily clinical practice. Despite the acute need for an effective treatment, currently there is no Food and Drug Administration specific treatment to prevent the initiation or interrupt the harmful effects from the sepsis cascade. Sepsis pathogenesis, not yet fully understood, involves a complex interaction among leukocytes, platelets, endothelial cells, innate and adaptive immunity, the complement system, and an array of proinflammatory and anti-inflammatory mediators (1). Based on the putative role of these inflammatory/anti-inflammatory mediators in the pathogenesis of sepsis, attempts have been made to remove them from the bloodstream with the goal to better modulate the response to sepsis. Several blood purification techniques have been used to remove the poorly understood “bad humors” purportedly responsible for the patients’ condition; for example, hemodialysis has been used for the treatment of schizophrenia (2) and plasmapheresis for the treatment of multiple sclerosis (3). Several extracorporeal blood purification techniques have been tried in sepsis. In this setting, it is important to understand the characteristics of the techniques being used. Hemofiltration and its variants such as hemodialysis, continuous venovenous hemofiltration, sustained low-efficiency dialysis, to mention just a few, use a semipermeable membrane to nonselectively remove low–molecular weight plasma components. The amount of plasma components removed is a function of many factors: molecular weight and degree of binding to large nonfilterable plasma molecules, dialysis filter surface and pores size, blood flow used for the treatment, and the length of the hemofiltration procedure. Plasma exchange (i.e., plasmapheresis) nonselectively removes large plasma molecules. Hemoperfusion uses a sorbent placed in direct contact with the blood in an extracorporeal circuit to selectively remove plasma components. At this time, we still don’t know all the mediators involved in the pathogenesis of sepsis, which mediators are beneficial and should be preserved and which are harmful and should be removed; in addition, we do not have the technology to selectively remove the “bad” mediators and to keep the “good” ones, let alone the optimal timing to start such therapy in the sepsis continuum. As described above, different blood purification techniques can target different molecular weight plasma components. Let us take the example of hemofiltration. In a patient with severe sepsis, this technique will remove an unknown amount of the largely unknown proinflammatory and anti-inflammatory mediators with a low enough molecular weight to fit through the filters, in the hope that this intervention will establish a better mediators’ balance to ameliorate the response to sepsis. The same would be true for plasma exchange techniques with the difference that large molecular mediators would be removed instead. This seems like shooting in the dark hoping to get only the “bad guys” but not harming the “good guys. ” A more recently developed purification technique called polymyxin B hemoperfusion tried to address this “shooting in the dark” problem by targeting the specific removal of endotoxin. An old antibiotic called polymyxin B has the capability to bind endotoxin with high affinity. When polymyxin B is added to the hemoperfusion technique, circulating endotoxin gets bound and retained by the filter. All these purification techniques described above were evaluated in patients with sepsis in a new study by Zhou et al (4) in this issue of Critical Care Medicine. Zhou et al (4) performed a systematic review and meta-analysis on the effect of blood purification techniques (hemoperfusion, hemofiltration, and plasma exchange) on survival outcomes in patients with sepsis and severe sepsis. They found a significant 31% (16–44%) reduction in the relative risk of death with this technique compared with the standard of care. This mortality reduction remained significant with both 28-day and hospital mortality outcomes. In addition, the beneficial effects were predominantly observed in patients treated with hemoperfusion. Does that mean that we should start “purifying” our patients with sepsis and severe sepsis right now? In order to respond this question, we need to further dissect the strengths and limitations of this new study. The term blood purification is quite broad and includes several different techniques, which may or may not be comparable from the statistical or clinical perspectives. Hence, the use of randomeffects model for all analyses was a wise approach. That being said, this approach brings a more conservative take on the data, but it does not eliminate heterogeneity. Thus, stratification was performed to see the mortality effects from each specific technique, which showed that hemoperfusion alone was associated with the largest benefit, that is, 47% (20–50%) relative risk reduction, whereas hemofiltration alone or with plasma exchange did not reduce mortality. Plasma exchange alone reduced mortality, but the very large 95% CI brought too much uncertainty. Lack of power can always be an issue with any stratification analysis 0090-3493