Blood Purification and Mortality in Sepsis and Septic Shock

A Systematic Review and Meta-analysis of Randomized Trials

Alessandro Putzu, M.D.; Raoul Schorer, M.D.; Juan Carlos Lopez-Delgado, M.D., Ph.D.; Tiziano Cassina, M.D.; Giovanni Landoni, M.D.

Disclosures

Anesthesiology. 2019;131(3):580-593. 

In This Article

Discussion

We performed a comprehensive systematic review and meta-analysis on the mortality effects of blood purification with extracorporeal techniques in sepsis. The certainty of evidence underlying the use of blood purification therapies in sepsis is very low, and does not support their systematic use in patients with sepsis with or without septic shock.

Hemoperfusion

A variety of hemoperfusion techniques exists. Only a few randomized clinical trials were published on hemoperfusion techniques other than polymyxin B–immobilized filter column (e.g., CytoSorb, Alteco endotoxin hemoadsorber), suggesting the need for further clinical trials. However, polymyxin B immobilized fiber column hemoperfusion emerged as a promising therapy in septic shock with elevated endotoxin levels, and several studies were published on the topic in the past 20 yr. This technique consists of using a sorbent cartridge containing fibers coated with polymyxin B, an antibiotic with high affinity for lipopolysaccharide.[9] Lipopolysaccharide is a cell wall component in Gram-negative bacteria that acts as an endotoxin by stimulating the production of inflammatory mediators by macrophages in a dose-dependent way and enhancing the inflammatory response.[9,64] Endotoxemia seems to be more pronounced when tissue hypoperfusion is present and lipopolysaccharide blood levels seem to correlate with sepsis severity.[9,65] Promising results in pilot studies showed improvement in inflammatory mediators,[10] cardiac and renal dysfunction,[56] hemodynamics, organ dysfunction, and 28-day mortality[30] in patients with abdominal septic shock. All these promising findings, together with the significant increase in arterial pressure after therapy initiation,[15,17,30] made polymyxin B immobilized fiber column hemoperfusion an attractive therapy for clinicians. Conversely, recent large high-quality trials such as the EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled trial of Adults Treated for Endotoxemia and Septic Shock)[17] and the ABDO-MIX (Effects of Hemoperfusion With a Polymyxin B Membrane in Peritonitis With Septic Shock) group[46] trials yielded inconclusive results and reported a nonsignificant increase in mortality with polymyxin B immobilized fiber column hemoperfusion at the longest follow-up assessed.

The EUPHRATES trial, which is the largest and highest-quality randomized clinical trial performed so far, randomized 450 patients with septic shock and a high endotoxin activity assay level to two sessions of polymyxin B immobilized fiber column hemoperfusion of 90 to 120 min at a 24 h distance or to a sham treatment aiming at reducing 28-day mortality. The trial found no significant difference in the primary endpoint in the overall population or in the higher disease severity subgroup.[17]

Our meta-analysis including 13 trials on polymyxin B immobilized fiber column hemoperfusion is the largest and most comprehensive to date. Recently, some meta-analyses[14,15,66] on polymyxin B immobilized fiber column hemoperfusion have appeared but failed to include some old and new randomized clinical trials. A meta-analysis concluded that this therapy may reduce mortality in patients with severe sepsis and septic shock in high disease severity subgroups based upon the aggregate analysis of 12 nonrandomized trials and 5 small randomized clinical trials representing a very low-quality evidence.[14] Two other meta-analyses respectively including only six and seven randomized clinical trials concluded that only low-quality evidence supported polymyxin B immobilized fiber column hemoperfusion for mortality reduction in sepsis.[15,66] Since the release of EUPHRATES and other trials, a more comprehensive analysis was made possible. The positive results previously reported regarding polymyxin B immobilized fiber column hemoperfusion were driven by small randomized clinical trials conducted in Asia of low methodologic quality. Interestingly, when limiting the analysis to trials published after 2010 and including the two largest randomized clinical trials performed on the topic,[17,46] polymyxin B immobilized fiber column hemoperfusion is associated with a higher mortality rate at the longest follow-up available. This together with inconclusive results on trial sequential analysis suggests that the current aggregate randomized evidence cannot consistently refute potential positive or detrimental effects on mortality. These findings do not support the use of polymyxin B immobilized fiber column hemoperfusion in sepsis and septic shock.

Hemofiltration

The use of hemofiltration techniques as a blood purification treatment in patients without renal failure has also been suggested, with controversial results and insufficient evidence to recommend its use outside of experimental clinical settings.[16,67] High-volume hemofiltration, further increasing plasma exchanges, was also investigated with limited results in patients with or without renal failure.[29,68] We found a positive survival trend associated to hemofiltration, although those results are driven by small, low-quality randomized trials, and further investigation is therefore warranted.

Plasmapheresis

The first randomized clinical trial to ever address plasmapheresis as a blood purification technique reported a decrease in the intensity of acute-phase response.[50] A second randomized clinical trial with a larger sample population found an absolute mortality risk reduction of 20.5%.[28] Despite those promising results, the evidence is still too weak to recommend the use of plasmapheresis for blood purification in sepsis.[69]

Disease Severity

Previous meta-analyses found that hemoperfusion was associated with a large positive effect in trials with a control group mortality rate greater than 60%, suggesting that hemoperfusion could be useful in the setting of higher disease severity.[14,66] Our study yielded similar findings and also found a trend toward increased mortality in the lower disease severity subgroup (mortality less than 30%). Meta-regressions on APACHE II and sepsis-related organ failure assessment scores, both predictors of sepsis mortality, did not find any significant trend supporting those findings. Furthermore, most trials with a greater than 60% control group mortality are at unclear/high risk of bias, are small in size, and were conducted in Asia. In the EUPHRATES trial, the per-protocol subgroup analysis with high disease severity, including patients with a Multiple Organ Dysfunction Score greater than 9 at randomization and a control group 1-year mortality rate of 50%, was inconclusive and did not suggest any trend favoring polymyxin B immobilized fiber column hemoperfusion.[17]

Those inconsistencies make a beneficial effect of hemoperfusion or polymyxin B immobilized fiber column hemoperfusion in high-disease-severity patients unlikely. This specific question merits further investigation.

Future Directions

Current randomized evidence cannot support the use of extracorporeal blood purification techniques; further trials are warranted before systemic implementation of these techniques. Furthermore, an increase in mortality related to extracorporeal therapies should not be excluded. Some randomized clinical trials describe a trend toward higher mortality with polymyxin B immobilized fiber column hemoperfusion[46] or CytoSorb-HP,[54] for example. Numerically higher adverse events with polymyxin B immobilized fiber column hemoperfusion[17,46] and greater disease severity with hemofiltration[45] were also reported. Our meta-analysis found an increased mortality at the longest follow-up available with polymyxin B immobilized fiber column hemoperfusion in a post hocsubgroup analysis including only the trials published after 2010. The unspecific removal of cytokines may remove mediators necessary to the function of the immune system, eventually provoking a deleterious outcome. Furthermore, the complex interaction between extracorporeal devices and inflammatory systems, micronutrients,[70] trace elements, electrolytes, and antibiotics levels and activity remain uninvestigated. Only few studies assessed the impact of those therapies on antibiotics, the only proven therapy in sepsis. A recent study on in vitroremoval of antiinfective agents by CytoSorb-HP showed that all tested antibiotics were adsorbed by the cartridge in substantial amounts.[71] The authors speculated that an additional dose within the first hours of treatment and therapeutic drug monitoring should be considered in this population.[71] Similarly, an in vitro study assessing the effects of polymyxin B immobilized fiber column hemoperfusion on nine antibiotics reported adsorption of linezolid, suggesting a necessity for the monitoring of blood antimicrobial concentrations during polymyxin B immobilized fiber column hemoperfusion.[72,73] A larger literature is present on hemofiltration, suggesting an increased antibiotic clearance with these devices.[74–76]

Strengths and Limitations

We performed a comprehensive meta-analysis on blood purification techniques in sepsis and septic shock, which represents an important update to the literature in comparison to previous meta-analyses.[13–16] Limitations of this study may appear similar to those of previous meta-analyses. Most included studies are small in size and at unclear or high risk of bias. Some studies assessed technical feasibility, but side effects were rarely reported, and a systematic assessment of adverse events is warranted in future trials. Heterogeneity in sepsis management, blood purification regimens (e.g., modality, hemofiltration volume, duration of the session, filter and cartridge change, and so forth), and populations across different centers is evident, but we made an attempt at an exploration through several subanalyses in order to further assess the clinical potential of blood purification modalities in sepsis. The positive treatment effect found in trials conducted in Asia was also reported elsewhere[13] and could be explained by publication bias, small studies effect, low methodologic quality, or a higher burden of disease as suggested by the high control group mortality. Furthermore, seven polymyxin B immobilized fiber column hemoperfusion trials from Japan were performed before 2005, and the progress in conventional therapy management and outcome in the past years could have diluted or cancelled the beneficial effects of this treatment.

Conclusions

Very low-quality randomized evidence demonstrates that the use of hemoperfusion, hemofiltration, or plasmapheresis may reduce mortality in sepsis or septic shock. Moderate-certainty evidence supports that polymyxin B immobilized fiber column hemoperfusion is not associated with any significant difference in mortality in comparison to conventional treatment regimen. Detrimental effects on survival could not be excluded by aggregate randomized evidence. Further high-quality randomized controlled trials adequately powered for mortality are needed to assess the real impact of blood purification techniques before such therapies can be systematically implemented in clinical practice.

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