Skip to main content

Eliminating endotoxin by polymyxin B hemoperfusion and/or continuous renal replacement therapy: should the focus be on timing, dosing, and type of renal epuration?

In a recent issue of Annals of Intensive Care, Navas et al. reported their experience with adjuvant polymyxin B hemoperfusion (PMX-HP) therapy in suspected Gram-negative septic shock [1]. PMX-HP is an extracorporeal technique that selectively adsorbs and eliminates endotoxin from the circulation [2]. Although theoretically only beneficial in endotoxin-driven Gram-negative sepsis, effective PMX-HP treatment does not depend upon type of microorganism or infection site. PMX-HP may offer a particular survival benefit in patients with plasma endotoxin activity (EA) levels between 0.6 and 0.9 EU/mL [3].

The study of Navas et al. is original because it compared for the first time the use of continuous renal replacement therapy (CRRT) plus PMX-HP with CRRT alone in patients who potentially would benefit most from such treatment (i.e., carefully selected type of infection, presence of multi-organ failure, and an EA cutoff level > 0.6 EU/mL as predetermined “biomarker”). All CRRT/PMX-HP patients underwent hemofiltration through an acrylonitrile (AN) 69 membrane. The main study conclusion was that adding PMX-HP to CRRT resulted in faster decrease of EA without improving respiratory, hemodynamic, biological, and outcome parameters [1].

The authors deserve all respect for their tenacity in conducting the study (it took nearly 3.5 years to recruit 18 patients!) but also for mustering an impressive amount of clinical and laboratory data. Obvious study weaknesses are the paucity of patients, an excess mortality at day 2 in the CRRT-only group, the failure to recruit pure Gram-negative infection in half of the population, and the lack of information regarding individual fluid balances. Also, differences in antibiotic-induced endotoxin-liberating potential might have caused less endotoxin load in the almost exclusively meropenem-treated CRRT-only patients [4].

Binding of circulating endotoxin by the PMX-HP column may decrease endotoxin levels by up to 90% after two treatments [2]. Therefore, it is remarkable that the EA level after completion of PMX-HP therapy was still high and not different from that obtained with CRRT treatment alone (0.59 vs. 0.57 EU/mL). Fast removal of endotoxin as the prime culprit associated with severity and mortality of sepsis is a reasonable therapeutic approach [5], but it remains to be proven whether it will interrupt or modulate an already ongoing inflammatory cascade. Despite comparable disease severity, degree of organ failure, and baseline EA levels in both treatment arms of the Navas study, the cytokine profile suggested that inflammation was more pronounced in patients only undergoing CRRT. Moreover, pretreatment levels of interleukin-6, a “distal” cytokine that intensifies and perpetuates the inflammatory response, were significantly lower in CRRT/PMX-HP patients as compared with CRRT-treated subjects. This implies that CRRT/PMX-HP was probably started at an earlier stage of septic shock rendering the hemoperfusion component more effective. Differences in inflammatory state and time of introducing hemoperfusion may have accounted for the observed high mortality within the first days of treatment in the CRRT group.

The standard use of PMX-HP applied as a 2-h session on 2 consecutive days may be challenged. Endotoxin release indeed is a dynamic process characterized by a continuous production at the site of infection but also by leakage from the gut reservoir. Mitaka et al. showed that a 24-h PMX-HP treatment removed endotoxin at a rate of 74.4% in septic shock patients [6] suggesting a role for “prolonged” PMX-HP approach. Navas et al. applied hemofiltration with an AN69 membrane which has no endotoxin-adsorptive capacity. The modified oXiris AN69 membrane has a surface polarity that facilitates adsorption of endotoxin. This membrane exhibits in vitro removal capacities for endotoxin that match those of PMX-HP [7]. In addition, oXiris AN69 effectively adsorbs a wide range of inflammatory cytokines and mediators [8]. The theoretical usefulness of applying CRRT using the oXiris AN69 membrane has not yet been assessed clinically except for a small study in Gram-negative sepsis-induced acute kidney injury, reporting reduced organ failure in patients undergoing continuous veno-venous hemofiltration with this particular hemofilter [9].

The data reported by Navas et al. contribute to creating a backbone for further investigation of PMX-HP/CRRT treatment in appropriately selected patients. However, future studies need to carefully consider aspects of timing and duration of therapy. Blood purification techniques that combine endotoxin removal with elimination of relevant inflammatory mediators may be a promising option.



polymyxin B hemoperfusion


endotoxin activity


continuous renal replacement therapy




  1. Navas A, Ferrer R, Martínez ML, Gomà G, Gili G, Masip J, et al. Impact of hemoperfusion with polymyxin B added to hemofiltration in patients with endotoxic shock: a case–control study. Ann Intensive Care. 2018;8(1):121.

    Article  Google Scholar 

  2. Ronco C, Klein DJ. Polymyxin B hemoperfusion: a mechanistic perspective. Crit Care. 2014;18(3):309.

    Article  Google Scholar 

  3. Dellinger RP, Bagshaw SM, Antonelli M, Foster DM, Klein DJ, Marshall JC, et al. Effect of targeted polymyxin B hemoperfusion on 28-day mortality in patients with septic shock and elevated endotoxin level. The EUPHRATES randomized clinical trial. JAMA. 2018;320(14):1455–63.

    Article  CAS  Google Scholar 

  4. Lepper PM, Held TK, Schneider EM, Bölke E, Gerlach H, Trautmann M. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Med. 2002;28(7):824–33.

    Article  CAS  Google Scholar 

  5. Marshall JC, Foster D, Vincent JL, Cook DJ, Cohen J, Dellinger RP, et al. Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis. 2004;190:527–34.

    Article  CAS  Google Scholar 

  6. Mitaka C, Fujiwara N, Yamamoto M, Toyofuku T, Haraguchi G, Tomita M. Polymyxin B-immobilized fiber column hemoperfusion removes endotoxin throughout a 24-hour treatment period. J Crit Care. 2014;29(5):728–32.

    Article  CAS  Google Scholar 

  7. Honoré PM, De Bels D, Spapen HD. An update on membranes and cartridges for extracorporeal blood purification in sepsis and septic shock. Curr Opin Crit Care. 2018;24(6):463–8.

    Article  Google Scholar 

  8. Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp. 2018;6(1):12.

    Article  Google Scholar 

  9. Shum HP, Chan KC, Kwan MC, Yan WW. Application of endotoxin and cytokine adsorption haemofilter in septic acute kidney injury due to Gram-negative bacterial infection. Hong Kong Med J. 2013;19(6):491–7.

    CAS  PubMed  Google Scholar 

Download references

Authors’ contributions

PMH and HDS designed the paper. All authors participated in drafting and reviewing. All authors read and approved the final manuscript.



Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.



Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Patrick M. Honore.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Honore, P.M., De Bels, D., Redant, S. et al. Eliminating endotoxin by polymyxin B hemoperfusion and/or continuous renal replacement therapy: should the focus be on timing, dosing, and type of renal epuration?. Ann. Intensive Care 9, 35 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: