Extracorporeal Removal of Endotoxin: The Polymyxin B-Immobilized Fiber Cartridge

Abstract

Endotoxin, which consists of lipopolysaccharide (LPS), is an outer membrane component of the Gram-negative bacterial cell wall. Endotoxin in the blood stream from an infectious focus or through translocation from the gut plays an important role in the pathogenesis of severe sepsis and septic shock. It binds to monocytes and macrophages, activating them to trigger the production of a variety of mediators. These mediators injure endothelial cells and induce microcirculatory dysfunction. This leads to subsequent organ dysfunction and multiorgan failure. The neutralization or elimination of endotoxin in the blood is an enticing approach for treating severe sepsis and septic shock. Selective adsorbent therapy targeting blood endotoxin has been clinically applied for more than 15 years, mainly in Japan and more recently in Italy and other countries. Toraymyxin(TM) (PMX;Toray, Tokyo, Japan) is a selective blood endotoxin removal cartridge. PMX is composed of polymyxin B (PL-B) covalently bonded to polystyrene-derivative fibers. It is well known that PL-B binds endotoxin and has bactericidal activity. PL-B has a strong affinity to endotoxin and is able to bind the lipid A portion of endotoxin through ionic and hydrophobic interactions. Intravenous injection of PL-B has significant nephrotoxic and neurotoxic effects. However, covalently immobilized PL-B on the adsorbents of PMX do not leak out into the blood stream, thus allowing the clinical application without the known toxic effects of PL-B. Within each cartridge, an adsorbent structure made of PL-B-fixed fabrics is included. Blood flow direction is well controlled by adopting a radial flow system. PMX treatment occurs by hemoperfusion at a blood flow rate of about 80-120 ml/min. Heparinis preferably used as an anticoagulant. In Japan, PMX has been clinically used since 1994under the national health insurance system. It is estimated that over 80,000 patients have received PMX treatment in Japan. Not only has PMX been clinically used safely in Japan, but also in other countries.

In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine

“…However, intravenous infusion of PMXB in humans leads to neurotoxicity and nephrotoxicity, thereby limiting its use. To circumvent this problem, a novel approach was developed whereby PMXB was adsorbed to polystyrene fibers to create an extracorporeal direct hemoperfusion device - toraymyxin [68]. Toraymyxin is currently available for the treatment of sepsis in Japan and Europe, and results have been encouraging.…”

Low-basic anion exchangers based on glycidyl methacrylate for selective sorption of endotoxin

“…At present, Toraymyxin sorbents (Toray, Japan) are widely used in clinical practice to cure sepsis [3].…”

“…It has high affi nity for lipid A, the "active" center of an endotoxin. However, Polymyxin B has side effects, such as neuro-and nephrotoxicity [3,4]. Also, the hemosorption system MATISSE® is being actively tested in clinics.…”

Adsorption Techniques: Dialysis Sorbents and Membranes

“…The mechanism of action of adsorption is based on the attraction between the sorbent and the solute through hydrophobic interactions, ionic or electrostatic forces, hydrogen bonding or van der Waals forces, which are weak intermolecular attractions caused by molecular dipoles that result in electrostatic interactions of neutral molecules due to fluctuations in their charge distribution [1]. Current technologies allow for the manipulation of the sorbents' structure in order to increase their ability to selectively isolate molecules based on specific molecular weights.…”