Review
Endotoxin removal devices for the treatment of sepsis and septic shock

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Summary

A substantial body of experimental and clinical evidence suggests that neutralising or removing lipopolysaccharide endotoxin would be an effective adjunctive approach to the management of Gram-negative sepsis. Polymyxins are a group of cyclic cationic polypeptide antibiotics. Although they have useful antimicrobial activity against Gram-negative bacteria, their clinical use has been limited because of toxicity. However, in addition to their antimicrobial property, polymyxins can bind to and neutralise endotoxin. Thus, investigators have explored the possibility of using polymyxin bound to a solid-phase carrier for specific haem-adsorption in patients with sepsis, thereby retaining the lipopolysaccharide-binding properties but minimising systemic toxic effects. This system has been widely used in Japan for many years, but convincing clinical evidence of efficacy is lacking. A recent Italian study has some promising data. Although polymyxin has been the principal agent used to explore this approach, other molecules have the ability to bind endotoxin, and some of these have very recently been proposed as the basis for other endotoxin-removal devices. The available evidence is reviewed to assess the potential use of such devices in clinical practice.

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

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

References (71)

  • DA Harrison et al.

    The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database

    Crit Care

    (2006)
  • JL Vincent et al.

    Sepsis in European intensive care units: results of the SOAP study

    Crit Care Med

    (2006)
  • JL Vincent et al.

    International study of the prevalence and outcomes of infection in intensive care units

    JAMA

    (2009)
  • GR Bernard et al.

    Efficacy and safety of recombinant human activated protein C for severe sepsis

    N Engl J Med

    (2001)
  • E Abraham et al.

    Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death

    N Engl J Med

    (2005)
  • RP Dellinger et al.

    Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock [published erratum in Crit Care Med 2008; 36: 1394–96]

    Crit Care Med

    (2008)
  • R Shimazu et al.

    MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4

    J Exp Med

    (1999)
  • A Aderem et al.

    Toll-like receptors in the induction of the innate immune response

    Nature

    (2000)
  • A Poltorak et al.

    Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in TLR4 gene

    Science

    (1998)
  • DL Dunn et al.

    Protective capacity of polyclonal and monoclonal antibodies directed against endotoxin during experimental sepsis

    Arch Surg

    (1988)
  • BJ Appelmelk et al.

    The protective role of antibodies to the lipopolysaccharide core region

  • AM Taveira da Silva et al.

    Shock and multiple organ dysfunction after self-administration of Salmonella endotoxin

    N Engl J Med

    (1993)
  • JC Marshall et al.

    Diagnostic and prognostic implications of endotoxaemia in critical illness. Results of the MEDIC trial

    J Infect Dis

    (2004)
  • P Brandtzaeg et al.

    Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease

    Lancet

    (1989)
  • SM Opal et al.

    Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock

    J Infect Dis

    (1999)
  • M Vaara et al.

    Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents

    Antimicrob Agents Chemother

    (2008)
  • VM Bhor et al.

    Polymyxin B: an ode to an old antidote for endotoxic shock

    Mol Biosyst

    (2005)
  • CJ Thomas et al.

    Kinetics and mechanism of the recognition of endotoxin by Polymyxin B

    J Am Chem Soc

    (1998)
  • S Srimal et al.

    Titration calorimetric studies to elucidate the specificity of the interactions of polymyxin B with lipopolysaccharides and lipid A

    Biochem J

    (1996)
  • D Rifkind et al.

    Neutralization of endotoxin toxicity in chick embryos by antibiotics

    J Bacteriol

    (1966)
  • D Rifkind

    Prevention by polymyxin B of endotoxin lethality in mice

    J Bacteriol

    (1967)
  • AH From et al.

    Polymyxin B sulfate modification of bacterial endotoxin: effects on the development of endotoxin shock in dogs

    Infect Immun

    (1979)
  • B Hughes et al.

    Polymyxin B sulphate protects cats against the haemodynamic and metabolic effects of E coli endotoxin

    Br J Pharmacol

    (1981)
  • K Hanasawa et al.

    A new treatment for endotoxemia with direct hemoperfusion by polymyxin immobilized fiber

    Ther Apher

    (2000)
  • RM Bannatyne et al.

    Protective effect of polymyxin B sulfate in experimental enterobacterial infection in mice

    Can J Microbiol

    (1979)

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