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

Abstract and Introduction

Abstract

Background: Sepsis and septic shock are severe inflammatory conditions related to high morbidity and mortality. We performed a systematic review with meta-analysis of randomized trials to assess whether extracorporeal blood purification reduces mortality in this setting.

Methods: Electronic databases were searched for pertinent studies up to January 2019. We included randomized controlled trials on the use of hemoperfusion, hemofiltration without a renal replacement purpose, and plasmapheresis as a blood purification technique in comparison to conventional therapy in adult patients with sepsis and septic shock. The primary outcome was mortality at the longest follow-up available. We calculated relative risks and 95% CIs. The grading of recommendations assessment, development and evaluation methodology for the certainty of evidence was used.

Results: Thirty-seven trials with 2,499 patients were included in the meta-analysis. Hemoperfusion was associated with lower mortality compared to conventional therapy (relative risk = 0.88 [95% CI, 0.78 to 0.98], P = 0.02, very low certainty evidence). Low risk of bias trials on polymyxin B immobilized filter hemoperfusion showed no mortality difference versus control (relative risk = 1.14 [95% CI, 0.96 to 1.36], P = 0.12, moderate certainty evidence), while recent trials found an increased mortality (relative risk = 1.22 [95% CI, 1.03 to 1.45], P = 0.02, low certainty evidence); trials performed in the United States and Europe had no significant difference in mortality (relative risk = 1.13 [95% CI, 0.96 to 1.34], P = 0.15), while trials performed in Asia had a positive treatment effect (relative risk = 0.57 [95% CI, 0.47 to 0.69], P < 0.001). Hemofiltration (relative risk = 0.79 [95% CI, 0.63 to 1.00], P = 0.05, very low certainty evidence) and plasmapheresis (relative risk = 0.63 [95% CI, 0.42 to 0.96], P = 0.03, very low certainty evidence) were associated with a lower mortality.

Conclusions: Very low-quality randomized evidence demonstrates that the use of hemoperfusion, hemofiltration, or plasmapheresis may reduce mortality in sepsis or septic shock. Existing evidence of moderate quality and certainty does not provide any support for a difference in mortality using polymyxin B hemoperfusion. Further high-quality randomized trials are needed before systematic implementation of these therapies in clinical practice.

Introduction

Today, sepsis remains one of the main causes of morbidity and mortality in the intensive care unit. Despite recent advancement in intensive care unit and sepsis management, mortality still remains high.[1–4]

The pathogenesis of sepsis involves many complex cellular and biochemical interactions between leukocytes, platelets, endothelial cells, and the complement system that trigger an inflammatory response.[5] Inflammation is caused by the production of pro- and antiinflammatory mediators, such as cytokines, in the presence of infection and/or bacterial toxins, and the imbalance between these mediators or their excessive production may lead to multiorgan failure due to a prolonged or inadequate systemic inflammatory response syndrome.[5,6]

Extracorporeal blood purification techniques have been proposed as adjunctive therapy in sepsis. These techniques are based on the principle that removal and modulation of blood pro- and antiinflammatory mediators or bacterial toxins (or both) could attenuate the sepsis-related massive systemic inflammatory response, reducing morbidity and mortality.[7,8] Several different extracorporeal techniques have been studied for this purpose.

Hemoperfusion involves the placement of a sorbent cartridge in direct contact with blood via an extracorporeal circuit. The removal characteristics of hemoperfusion are dependent on the different types of sorbent used and could also target high-molecular-weight molecules, usually not captured by conventional hemofilters. The most studied therapy is polymyxin B immobilized fiber column hemoperfusion with Toraymyxin (Toray Industries Ltd., Japan), that could capture circulating bacterial endotoxin[9] and modulate the inflammatory response.[10] Another device is the CytoSorb (CytoSorbents Corporation, USA), a novel filter potentially able to remove both pro-inflammatory and antiinflammatory cytokines.[11]

Renal replacement devices such as hemofiltration or hemodiafiltration could be used to remove part of the inflammatory mediators and toxins in septic patients without renal indication for kidney replacement therapy, by employing standard or special filters with adsorptive properties.[12] Limited data are available on plasmapheresis, a technique based on plasma replacement with fresh frozen plasma or albumin,[12] that has the potential to remove inflammatory cytokines and restore deficient plasma proteins.

Despite the large number of available techniques, actual evidence is scarce, and these therapies have not entered into daily clinical practice around the world yet. Several small trials were published on various devices, and the most comprehensive meta-analysis summarizing the evidence on blood purification is outdated.[13] Some more recent meta-analyses focusing on polymyxin B immobilized fiber column hemoperfusion[14,15] or hemofiltration[16] did not include some relevant trials nor the final results of the largest randomized study performed on the topic so far.[17] Therefore, we performed a meta-analysis of randomized control trials in order to determine whether extracorporeal blood purification decreased mortality in patients with sepsis and septic shock.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....