We searched PubMed and Medline (from 1949, to August, 2010), Trip and Embase (from 1974, to August, 2010) with combinations of the following keywords: “polymyxin”, “hemoperfusion”, “endotoxin”, “endotoxin removal”, “endotoxin apheresis”, “shock”, and “sepsis”. Only articles available in English or in English translation were included. Other searches included ClinicalTrials.gov for terms related to sepsis, and EU and US patents for endotoxin removal. The initial literature search was done
ReviewEndotoxin removal devices for the treatment of sepsis and septic shock
Introduction
The burden of sepsis in terms of morbidity, mortality, and financial costs remains high.1, 2, 3, 4 Despite the introduction of new agents such as drotrecogin alfa, and efforts to encourage the use of standardised care (“bundles”) by the Surviving Sepsis Campaign, improvements in outcome have been mainly incremental and there is still room for new approaches.5, 6, 7 Substantial evidence suggests that removal of endotoxin from the circulation would be of benefit. In this Review we explore the pathogenic role of endotoxin in sepsis, the unusual ability of polymyxin antibiotics to bind and neutralise endotoxin, and how this knowledge can be used in clinical practice.
Section snippets
Role of endotoxin in sepsis
Lipopolysaccharide, a bacterial endotoxin, is a component of the outer membrane of Gram-negative bacteria and consists of three sections: an outer variable polysacc-haride O side chain, a relatively conserved core region, and a highly conserved lipid A component. Lipid A is a unique phospholipid normally embedded in the cell membrane, and is released when bacteria are either multiplying or being destroyed. Activation of the host innate immune system has been shown to be dependent on the
Polymyxin B
Polymyxins are a group of cyclic cationic polypeptide antibiotics derived from Bacillus polymyxa. Only polymyxin B and colistin (polymyxin E) have been used in clinical practice. Polymyxin B differs from colistin by only one aminoacid. Although they both have useful antimicrobial activity against Gram-negative bacteria, their clinical use has been limited due to nephrotoxicity and neurotoxicity.18 However, in addition to their antimicrobial property, polymyxins have the unusual ability to bind
Removal of endotoxin
The removal of endotoxin from solution is well established within the biotechnology industry by the use of Gram-negative bacteria for the production of recombinant DNA products such as peptides and proteins. Solutions for intravenous use must be cleared of endotoxin before use to prevent potent pyrogenic reactions. Endotoxins are heat and pH stable and thus can be difficult to separate from proteins. The removal from protein-free solutions is relatively straightforward by taking advantage of
Polymyxin columns
As long as polymyxin is tightly bound to the column and the endotoxin is tightly bound to the polymyxin, polymyxin columns might offer a way of taking advantage of the “anti-endotoxin” properties of polymyxin without incurring the disadvantages of its systemic toxicity. Initial studies found that the polymyxin remained tightly bound to the column and no polymyxin activity was detected within the elute.32 The practical use of this approach was then assessed in experiments in rats that were
Mechanism of action
Several studies have investigated the exact mechanism by which haemoperfusion with polymyxin filtration works. Kojika and colleagues51 confirmed, by high-sensitivity assay, that endotoxin had been removed from the blood of patients with sepsis. Tani and collegaues52 reported reduction in various cytokines (ie, interleukin 6 and interleukin 10) after polymyxin filtration. Cytokines themselves are not removed and the hypothesis is that removal of lipopolysaccharide inhibits activation of cells,
Alternative methods
Other adsorption columns apply the same basic principle of a ligand with high affinity for endotoxin attached to a solid phase that allows the passage of blood with sufficient contact for endotoxin removal. Ligands and solid phases other than polymyxin have been tried, but only a few have been assessed in human trials.
The MATISSE–Fresenius system (Fresenius SE, Bad Homburg, Germany) is based on the endotoxin-binding abilities of human albumin. The extracorporeal circuits are maintained by the
Conclusions
Despite a strong scientific rationale, endotoxin-removal devices have been seen as inconvenient, time consuming to set up, non-specific in their action, and potentially too expensive. But with the failure of other new drugs (which are potentially just as expensive), and the ease and frequency with which haemofiltration and haemodialysis are now carried out in ICUs, there is renewed interest in this approach. The main limiting factor is good evidence of efficacy, and it is an interesting
Search strategy and selection criteria
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2021, Acta Pharmaceutica Sinica BCitation Excerpt :PMB has a unique advantage in Gram-negative sepsis therapy, due to its bacterial endotoxin LPS-binding ability233. Since 1994, PMB has been well applied for immobilization in columns to remove endotoxins from the bloodstream, for the treatment of severe sepsis and septic shock234–238. Recently, the development of nano-drug delivery systems has led to significant improvements in the bioavailability and safety of AMPs in vivo.
Anticoagulant chitosan-kappa-carrageenan composite hydrogel sorbent for simultaneous endotoxin and bacteria cleansing in septic blood
2020, Carbohydrate PolymersCitation Excerpt :Abundant endotoxin sorbents have been developed to cleanse endotoxin in human plasma (Cao, Zhu, Zhang, & Dong, 2016; Huang, Yuan et al., 2019; Vorobii et al., 2019), whole blood (Didar et al., 2015; Herrmann et al., 2013; Kang et al., 2014) and protein solution (Guo, Meng, Jing, & Huang, 2013; Konwar, Chowdhury, & Dan, 2019; Vagenende, Ching, Chua, Thirumoorthi, & Gagnon, 2013) so far. Usually, cationic ligands such as polymyxin B (Cao et al., 2016; Davies & Cohen, 2011; Herrmann et al., 2013; Huang, Yuan et al., 2019; Vorobii et al., 2019), lysine (Fang, Wei, & Yu, 2004; Zhang et al., 2012), serine (Huang et al., 2013), polyethyleneimine (Hanora, Plieva, Hedstrom, Galaev, & Mattiasson, 2005; Morimoto, Sakata, Iwata, Esaki, & Hirayama, 1995) and chitosan (Konwar et al., 2019; Li et al., 2003; Machado, de Arruda, Santana, & Bueno, 2006) are utilized to achieve electrostatic adsorption of endotoxin because endotoxin is negatively charged due to the presence of bisphosphorylated groups in its backbone (Huang et al., 2013). However, the biocompatibilities of these sorbents were not evaluated systemically.
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