A Biomimetic Membrane Device That Modulates the Excessive Inflammatory Response to Sepsis

Abstract

ObjectiveSeptic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis.DesignLaboratory investigation.SettingUniversity of Michigan Medical School.SubjectsPigs weighing 30-35 kg.InterventionsTo assess the effect of the SCD in septic shock, pigs were administered 30×1010 bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD.Measurements and Main ResultsIn this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation.ConclusionsThese preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway.

Extracorporeal Blood Purification Therapies for Sepsis

“…After flowing through the CRRT hemofilter, the blood is diverted through to the extracapillary space of the SCD where activated leukocytes (mainly neutrophils) are adsorbed [77]. In a preclinical study on septic pigs, the SCD with citrate significantly improved the cardiovascular parameters and decreased the sequestration of activated leukocytes in the lungs as compared to control groups (SCD with heparin or no SCD); it also improved renal function and survival time [78]. A prospective, single-center study was conducted to evaluate the safety and efficacy of SCD on patients with AKI requiring RRT.…”

A selective cytopheretic inhibitory device for use during cardiopulmonary bypass surgery

“…Of interest, the finding that the number of leukocytes eluted from the SCD during citrate infusion was 10fold less than in the heparin condition while maintaining lower leukocyte concentration in blood suggests that the lowiCa envi ronment may promote adhesion of activated leukocytes, followed by release, after a time period of sequestration and deactivation. This working principle is also sup ported with published and ongoing studies utilizing in vitro shear chambers 21,24 . These in vitro and ex vivo stud ies suggest that this novel device and approach may ame liorate the natural progression of SIRS by blunting the systemic leukocyte response, leading to improved cardi ovascular stability, respiratory performance and renal function.…”

Review of Extracorporeal Membrane Oxygenation and Dialysis-Based Liver Support Devices for the Use of Nephrologists

“…The selective cytopheretic device (SCD) is a cartridge resembling a polysulfone hemofilter that is thought to preferentially bind then deactivate neutrophils and monocytes in the presence of a low calcium milieu [75,76]. The SCD is mounted on a CRRT machine circuit in series with the conventional hemodialyzer.…”