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.

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.

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Table 1. Trials Characteristics
Trial	Country	Sample Size	Major Inclusion Criteria	Blood Purification Technique	Treatment Duration	Control Group Mortality	Risk of Bias
Hemoperfusion
Polymyxin B–immobilized filter column hemoperfusion
Cantaluppi 2008	Italy	16	Sepsis with positive culture for Gram-negative bacteria	PMX-HP	2 sessions of 2 h at 24-h interval	38%	Unclear
Cruz 2009	Italy	64	Severe sepsis or septic shock from an abdominal source	PMX-HP	2 sessions of 2 h at 24-h interval	67%	Low
Dellinger 2018	USA and Canada	449	Septic shock and an high endotoxin activity assay level	PMX-HP	2 sessions of 2 h at 24-h interval	42%	Low
Nakamura 1999	Japan	50	Septic shock	PMX-HP	2 sessions of 2 h at 24-h distance	70%	Unclear
Nakamura 2002(a)	Japan	18	Sepsis and trauma	PMX-HP	2 sessions of 2 h at 24-h interval	78%	Unclear
Nakamura 2002(b)	Japan	14	Sepsis	PMX-HP	2 sessions of 2 h at 24-h interval	86%	Unclear
Nakamura 2003(a)	Japan	20	Sepsis and MRSA-associated glomerulonephritis	PMX-HP	2 sessions of 2 h at 24-h interval	80%	Unclear
Nakamura 2003(b)	Japan	60	MRSA sepsis	PMX-HP	2 sessions of 2 h at 24-h interval	64%	Unclear
Nemoto 2001	Japan	98	Sepsis, severe sepsis, or septic shock	PMX-HP	1 or 2 sessions of 4 h	89%	Unclear
Payen 2015	France	232	Septic shock from and abdominal source	PMX-HP	2 sessions of 1.5 h at 22–24-h interval	24%	Low
Srisawat 2018	Thailand	59	Severe sepsis or septic shock, high endotoxin activity assay level, mostly under renal replacement therapy	PMX-HP	2 sessions of 2 h at 24-h interval	50%	High
Suzuki 2002	Japan	48	Septic shock	PMX-HP	1 HP session of 4 h, then 1 CVVHDF session until 24 h	75%	Unclear
Vincent 2005	Europe	35	Severe sepsis or septic shock from an intraabdominal source	PMX-HP	1 session of 2 h	28%	Unclear
Other hemoperfusion devices
Hawchar 2019	Hungary	20	Septic shock of medical origin	HP with CytoSorb	1 session of 24 h	20%	High
Huang 2010	China	44	Severe sepsis or septic shock	HP with HA330 resin cartridge (Lizhu Industries, China)	3 sessions of 2 h at 24-h interval	55%	Unclear
Huang 2013	China	46	Severe sepsis or septic shock with acute lung injury from extrapulmonary source	HP with HA330 resin cartridge	3 sessions of 2 h at 24-h interval	67%	High
Reinhart 2004	Europe	143	Severe sepsis or septic shock	HP with Matisse EN500 endotoxin adsorber (Fresenius HemoCare Adsorber Technology GmbH, Germany).	A daily session for the first 4 d	25%	High
Schädler 2017	Germany	97	Severe sepsis or septic shock and ALI/ARDS	HP with CytoSorb	1 daily session of 6 h up to 7 d	26%	High
Shum 2014	China	15	Septic shock from an intra-abdominal source	HP with Alteco endotoxin hemoadsorber (Alteco Medical AB, Sweden)	2 sessions of 2 h at 24-h interval	25%	High
Zheng 2017	China	20	Sepsis, severe sepsis, or septic shock	HP with Adsorba 300 filter (manufacturer not reported)	1 HP session of 2.5 h	80%	Unclear
Hemofiltration
Chung 2017	USA	37	Septic shock and burn	CVVH	nr	57%	Unclear
Cole 2002	nr	24	Severe sepsis with end-organ dysfunction or septic shock	CVVH with AN69 Filtral 12 filter (Hospal, France)	1 session of 2 d	33%	Unclear
Guo 2017	China	22	Severe sepsis or septic shock	CVVH with AN69 filter	1 session of 2 d	45%	Unclear
Han 2011	China	45	Severe sepsis	CVVH with AN69 filter	1 session of 3 d	41%	Unclear
Jing 2015	China	97	Severe sepsis or septic shock	CVVH	1 session of at least 3 d	37%	High
Meng 2016	China	56	Septic shock and ARDS	CVVH with AN69 filter (Gambro Industries, France)	1 session of 3 d	32%	High
Payen 2009	France	76	Severe sepsis or septic shock	CVVH with Duraflo II filter (Edwards Lifesciences, USA)	1 session of at least 4 d	44%	Unclear
Peng 2010	China	22	Severe sepsis	CVVH with AN69 filter	1 session of 3 d	18%	Unclear
Quenot 2015	France	60	Septic shock	CVVH	1 session of 2 d	48%	High
Sander 1997	Germany	26	Severe sepsis or septic shock	CVVH with AN69 Multiflow 60 filter (Hospal, France)	1 session of at least 2 d	92%	High
Wang 2009	China	89	Septic shock	CVVH	1 session of 7 d	17	Unclear
Xu 2014	China	22	Sepsis and burn	CVVHDF	1 session of 12 h	18%	Unclear
Zheng 2017	China	20	Sepsis, severe sepsis, or septic shock	CVVH with M100 set (manufacturer not reported)	1 session of 24 h	80%	Unclear
Combined hemofiltration and hemoperfusion
Hassan 2013	Malaysia	23	Severe sepsis or septic shock	CPFA with DF-140 (Infomed, Switzerland)	1 session of 24 h or until clinical improvement	83%	High
Livigni 2014	Italy	184	Septic shock	CPFA with Lynda (Bellco, Italy)	5 session of at least 10 h, in 5 consecutive days	49%	Unclear
Peng 2005	China	20	Sepsis and burn	CVVH with AN69 Multiflow-60 filter (manufacturer not reported) + PMX-HP	nr	20%	Unclear
Zheng 2017	China	20	Sepsis, severe sepsis, or septic shock	CVVH with M100 filter + HP with Adsorba-300 (manufacturers not reported)	1 CVVH-session of 24 h and 1 HP session of 2.5 h	80%	Unclear
Plasmapheresis
Busund 2002	Russia	106	Severe sepsis or septic shock	na	2 sessions of about 2 h in 24 h	54%	High
Reeves 1999	Australia	22	Severe sepsis	na	1 session of 36 h	46%	Unclear

ALI, acute lung injury; ARDS, acute respiratory distress syndrome; CVVH, continuous veno-venous hemofiltration; CVVHDF, continuous veno-venous hemodiafiltration; CPFA, coupled plasma filtration adsorption; HP, hemoperfusion; MRSA, methicillin-resistant Staphylococcus aureus; PMX, polymyxin B–immobilized fiber column; na, not applicable; nr, not reported.