Blood Purification for Critical Illness: Cytokines Adsorption Therapy

Abstract

Blood purification therapies have been clinically applied to treat cytokine-induced pathological effects. The effects of broad-spectrum adsorption using Lixelle (beta2-microglobulin adsorption column; Kaneka Corporation, Osaka, Japan) for the condition of hypercytokinemia in vitro, in an animal model and in humans with sepsis were investigated. We found that Lixelle could selectively adsorb not only beta2-microglobulin but also cytokines composed of glycoproteins in vitro. In addition, Lixelle beads could adsorb not only endotoxin (ET) but also microbial fragments such as peptidoglycan (PG) which is a component of Gram-positive bacteria. Hypercytokinemic rats were connected to a direct hemoperfusion (DHP) system using a mini Lixelle column and time-course changes in plasma levels of inflammatory cytokines were examined. In addition, a Lixelle column was used in direct hemoperfusion in patients with systemic inflammatory response syndrome (SIRS), and the relationship between a decrease in cytokines and clinical course was examined. The increases in plasma levels of IL-6 and tumor necrosis factor-alpha (TNF-alpha) were significantly inhibited in the group treated with the Lixelle column in an animal model. In humans with sepsis, for IL-1beta, IL-1Ra, IL-6, IL-8, and TNF-alpha, the adsorbing rates in vivo before and after the use of the Lixelle column tended to decrease with time. However, the reduction rates at 5 min after the start were 31.4, 39.3, 36.4, 76.2 and 71.6%, respectively, and at 3 h after the start, the rates were 18.0, 17.7, 12.9, 31.8, and 32.9%, respectively. Clinically, their blood pressure increased and they recovered from shock status. These results suggest that SIRS and sepsis with hypercytokinemia can be treated with the DHP using the Lixelle column.

Direct Hemoperfusion With a β2‐Microglobulin‐selective Adsorbent Column Eliminates Inflammatory Cytokines and Improves Pulmonary Oxygenation

“…Furthermore, TNFα is related to ARDS/ALI and plays a role same as IL‐1β. However, we did not measure TNFα because it was previously reported that TNFα was not adsorbed in the column (22). We were not able to measure IL‐1α, a member of the IL‐1 family, because we did not have a measurement method.…”

Newly Designed CRRT Membranes for Sepsis and SIRS—A Pragmatic Approach for Bedside Intensivists Summarizing the More Recent Advances

“…Recently, new forms of AN69 (AN69 ST and AN69 Oxiris) do not anymore induce a bradykinin syndrome when in the presence of angiotensinconverting enzyme inhibitors. 55 They can still run with an hemoperfusion device. 18,47 Conclusions So far, after the failure of the major randomized studies on dose, attention is now drawn to new membranes that could better in wide spectrum and also could eliminate massive amounts of unbound mediators in great magnitude.…”

Characterizing accelerated capture of deoligomerized TNF within hemoadsorption beads used to treat sepsis

“…TNF, a 51 kD pro‐inflammatory cytokine, is removed at a slow rate within the device compared with smaller cytokines, putatively due to hindered diffusion of the large trimeric TNF molecule within the sorbent pores. Similar deficiencies in TNF capture have been reported using other cytokine‐targeted sorbent materials 26–29. Small sorbent pores are necessary to prevent essential large plasma proteins such as albumin from being removed by the device; hence, our goal was to develop strategies to accelerate TNF removal while maintaining an optimal pore size for whole blood filtration.…”

“…Similar deficiencies in TNF capture have been reported using other cytokine-targeted sorbent materials. [26][27][28][29] Small sorbent pores are necessary to prevent essential large plasma proteins such as albumin from being removed by the device; hence, our goal was to develop strategies to accelerate TNF removal while maintaining an optimal pore size for whole blood filtration. This work investigated the structural behavior of oligomeric TNF in vitro, and sought to quantify how specific perturbations of TNF quaternary structure would affect TNF capture within the hemoadsorption device.…”