[Polymyxin-B direct hemoperfusion (PMX-DHP) in gram negative sepsis]

Severe sepsis and septic shock have a mortality rate that may range between 28 and 50%. It is estimated that approximately 200,000 patients die per annum in the USA as a consequence of sepsis. The reduction of plasma endotoxin levels to achieve a favourable outcome for septic patients has been previously demonstrated but the effectiveness of treatments targeting single inflammatory mediators during established sepsis has been disappointing. Furthermore,some clinical study clinically showed valuable reduction in cytokine levels by hemofiltration alone. The prompt removal of endotoxins could be an effective way to reduce the immunological activation and the amount of NO produced by endotoxin-activated inducible NO-synthase in many tissues and cells. The polymyxin B cartridge is an extracorporeal hemoperfusion device (PMX-DHP) known to remove circulating endotoxins. Open-label clinical trials testing PMX-DHP have demonstrated its safety in the septic shock treatment while the overall survival rate significantly improved in comparison with the control groups. The purpose of this study was to investigate the effects of PMX-DHP on redox status, inflammatory cytokine profile, monocytes and PMN leukocyte activation in Gram-negative sepsis. Prospective study: six patients, 2 males and 4 females 60.5+/-24.5 years old, in ICU for severe Gram-negative sepsis (emergency surgery for intra abdominal infection). Two PMX-DHP runs, at T0 and T1; 2 hours each; the first within 24 hours from sepsis diagnosis or 12 hours after emergency surgery, the first PMX-DHP at T0, the second after 24 hours.; APACHE II score at T0: 20.1+/-3.7; SOFA score 14.2+/-2.5; organ failure: 3+/-1.5; norepinephrine(Ne) in 1 patient; Ne + dopamine (DA) in 4 patients; DA in 1 patient only. Mean dosage: Ne 0.24 mcg/kg/min; DA 8.9 mcg/kg/min. Four patients in CRRT (continuous veno-venous hemofiltration, AN69 hemofilter) for the entire length of the study. QB 100+/-10 ml/min. Pre and post PMX-DHP, plasma endotoxins as well as anti-IL 1-beta, IL2, IL4, IL5, IL6, IL8, IL10, TNF-alpha, GM-CSF, IFN-gamma levels were measured. Expression of CD64 on monocytes and PMN leukocytes and I -2r CD25 on CD4+ T cells by flow cytometry. Total and reduced plasma cysteine, homocysteine, glutathione (GSH); plasma glutathione peroxidase (GSH-Px) and reductase (GSH-Rx); erythrocyte GSH (eGSH), eGSH-Px and eGSH-Rx; NADP and NADPH and their ratio assessed pre and post PMX-DHP, all compared with 15 age and gender-matched healthy subjects for complete REDOX characterization.

We observed a significant reduction of endotoxin levels post PMX-DHP; CD64 monocytes and PMN leukocytes overexpression returned to normal; pro-inflammatory cytokines Il6, Il 10 and TNF-alpha were significantly reduced. We detected no differences in plasma levels of anti-IL 1-beta, IL2, IL4, IL5, IL8, GM-CSF, IFN-gamma pre versus post PMX-DHP. SOFA score from 14.2+/-2.5 to 8.9+/-2.1 post PMX-DHP runs. Four out of six patients survived and were discharged; mortality was 33% versus the anticipated 51%.

PMX-DHP reduces circulating endotoxins, down-activates monocytes and PMN leukocytes, reduces pro-Inflammatory cytokines and corrects the redox environment imbalance preventing oxidative damage to endothelial cells and the metabolic and functional microvascular derangements that usually lead to multi-organ failure and septic shock.