Table 4.

Extracorporeal techniques for blood purification in sepsis

Type of techniques	Mechanism	Published year	Study type	Population	Study subjects	Clinical outcomes		Comments	Source
						Primary	Secondary
Short term high-volume hemofiltration (HVHF)	Capable of maintaining azotaemic, acid–base, and fluid homeostasis and removal of toxins and inflammatory mediators, experimental studies showed that HVHF can improve myocardial performance and systemic hemodynamics while also removal of cytokines. Clinical studies conducted in refractory septic shock also observed similar results	2006	Prospective nonrandomized study	20	Severe septic shock patients unresponsive to multi-intervention approach in surgical unit	NE requirements and perfusion parameters	Feasibility, tolerance, and adverse events	As a salvage therapy, HVHF might be beneficial in septic shock patients	451
		2008	ACT, Phase III RCT	1124	Critically ill AKI patients with failure of at least one nonrenal organ failure or sepsis patients in need of renal replacement therapy	60-day mortality rate	In-hospital death and recovery of kidney function	No significant improvements	452
		2013	IVOIRE, Phase III RCT	137	Critically ill patients with septic shock and AKI at early phase	28-day mortality rate	SOFA, hemodynamic profile, mechanical ventilation, prognostic outcome	No significant improvements	453
		2014	Meta-analysis	241	Sepsis or septic shock patients	28-day mortality rate	Recovery of kidney function, lengths of stay, vasopressor dose reduction. and adverse events	Insufficient evidences support therapeutic benefits for routine use of HVHF for septic AKI	454
		2017	Meta-analysis	200	Severe sepsis and septic shock patients	Mortality rate	Length of stay, severity of organ dysfunction, adverse events	Studies on the use of HVHF in critically ill patients with sepsis or septic shock remains scarce	455
Continuous venovenous hemofiltration (CVHF)	With benefits from early application of short-term HVHF observed in septic shock patients, the classic CVVH technique was also suggested to limit inflammation in septic shock	2009	Phase III RCT	80	Severe sepsis patients with organ failure at early phase	Number, severity, and duration of organ failures	14-day mortality rate and time to death	Early application of CVVH is deleterious in severe sepsis patients	456
Hemodialysis with high cut-off membrane (HCO)	Designed with larger pore size, HCO membrane application with standard RRT modality showed greater cytokine removal capacity but with albumin loss	2006	Pilot study	30	Sepsis-induced acute renal failure	N/A	N/A	HCO hemofiltration exert beneficial effects in terms of reduction in vasopressors dose and clearance for IL-6 and IL-1ra	457
		2007	Phase I RCT	10	Septic patients with acute renal failure	Relative change in plasma IL-6 concentrations	Relative change in other plasma cytokines and albumin	High cut-off intermittent hemodialysis achieved both uremic control and diffusive cytokine clearances and a greater relative decrease in plasma cytokine concentrations	458
		2016	Retrospective study	16	Sepsis patients with AKI	N/A	N/A	Significant improvements on ICU mortality, days of vasopressors, and mechanical ventilation	459
Polymyxin B hemoperfusion (PMX-HP/Toraymycin)	As a cyclic cationic polypeptide antibiotic, polymyxin B (PMX) showed high affinity for endotoxin. When immobilized into polystyrene fibers in a hemoperfusion device, PMX function to remove circulating endotoxin by adsorption and modulate dysregulated host responses without nephron toxicity	2009	EUPHAS, Phase III RCT	64	Severe sepsis or septic shock from intra-abdominal Gram-negative infections	Change in MAP and vasopressor requirement	28-day mortality rate, SOFA score, PaO2/FIO2	Significant improvement in hemodynamics, organ dysfunction, and reduced 28-day mortality	460
		2015	Abdomi, Phase III RCT	243	Postoperative intra-abdominal septic shock patients	28-day mortality rate	SOFA score, time to withdraw catecholamine, adverse events	No significant improvements	461
		2018	EUPHRATE, Phase III RCT	450	Septic shock patients with high endotoxin activity (EAA ≥ 0.60)	28-day mortality rate	N/A	No significant improvements	462
		2017	Propensity-matched cohort study	522	Septic shock patients	All-cause hospital mortality	ICU mortality and number of ICU-free days (ICUFDs) in the first 28 days	PMX-HP reduce all-cause hospital mortality and length of ICU stay	389
		2018	Post hoc analysis of EUPHRATES	450	Septic shock patients with high endotoxin activity (EAA ≥ 0.60)	28-day mortality rate	Changes in MAP, cumulative vasopressor index, EAA reduction, and other prognostic outcomes	Patients with septic shock and high EAA experience reduced 28-day mortality rate and improvements in other prognostic outcomes	463
		2018	Meta-analysis	857	Critically ill adult patients with sepsis or septic shock	N/A	N/A	No significant benefit for 28-day mortality and organ dysfunction scores	464
Polymyxin B hemoperfusion (PMX-HP) with recombinant thrombomodulin (rTM)	PMX-HP directly adsorb endotoxin and activated mononuclear cells (cytokines) so as to improve hemodynamics. rTM exerts not only anticoagulation but also anti-inflammatory properties via anti-HMGB1 activity. Combination of PMX-HP and rTM is expected to block the vicious cycle of a cytokine storm	2013	Historical controlled trial	22	Septic shock associated with DIC	60-day survival rate	SOFA score	60-day survival rate is significantly higher in the treatment group	465
		2020	Post hoc analysis from the dataset of Japan septic DIC registry	2350	Sepsis patients who were given combination therapy of PMX-HP with ART123	Hospital mortality	N/A	Significant beneficial effect modification on survival outcome was observed from patients coadministrated with ART-123 and PMX-HP	466
Continuous hemodiafiltration using a PMMA membrane (PMMA-CHDF)	PMMA-CHDF remove cytokines from blood continuously and efficiently by adsorption to membrane matrix of a hemofilter	2008	Observational cohort study	43	Septic shock patients	N/A	N/A	Significant improvements in hemodynamics, urine output, hypercytokinemia, and dysoxia	467
		2011	Comparative study	30	Septic shock patients with acute renal failure	28-day survival	Hemodynamic profile	Compared with polyacrylonitrile membrane CHDF, PMMA-CHDF-treated patients have improved hemodynamics and 28-day survival	468
AN69ST	AN69ST membrane has excellent cytokines adsorption capacity. Surface treatment (ST) with polyethyleneimine and heparin allow greater bulk adsorption (HMGB1)	2014	Randomized, prospective, single-center trial	34	Septic shock patients	28-day mortality rate	Sequential changes in lactate, cytokine blood levels, and hemodynamics	Significant reduction in IL-6 and lactate levels were observed, though APACHE II score and 28-day mortality were high	469
		2017	Retrospective observational study	156	Critically ill patients receiving CRRT with AN69ST membrane	In-hospital mortality	ICU length of stay	CRRT with AN69ST membrane is associated with better in-hospital mortality	470
Modified AN69ST membranes (Oxiris)	Compared with AN69ST, modified coated layer allowed additional adsorption of endotoxin and cytokines with better anticoagulation properties	2019	Randomized trial	16	Septic shock-associated acute renal failure requiring CRRT	Change in plasma endotoxin	Change in cytokine levels	Effective removal of endotoxin and TNF-α, IL-6, IL-8, and IFN-γ in patients with septic shock-associated acute renal failure	471
		2019	Observational study	31	Septic shock patients requiring CRRT	Hospital mortality	SOFA score, norepinephrine reduction, hemodynamic, respiratory, and biological parameters	Higher survival was observed than predicted. Hemodynamic status and lactatemia were improved in intra-abdominal sepsis and Gram-negative infections	472
Coupled plasma filtration adsorption (CPFA)	CPFA is a complex circuit that includes a hemofilter, a plasma filter, and an adsorbing cartridge, which requires an adequate balance of flows, dilutions, and anticoagulation. It is an extracorporeal technique intended to non-selectively remove the majority of soluble inflammatory mediators from systemic circulation	2014	COMPACT-1, phase III RCT	192	Septic shock patients	Mortality at discharge from hospital	90-day mortality, new organ failures and ICU-free days within 30 days	No significant improvements in mortality or other prognostic outcomes. Subgroup suggested survival benefits when high volume plasma is treated. CPFA is not encouraged in everyday clinical practice	388
		2015	Meta-analysis	242	Severe sepsis patients	28-day mortality	Mediator adsorption, mean arterial BP and oxygenation ratio	Evidence for CPFA in severe sepsis is sparse and of poor quality. However, improvements in survival rate is noted in this meta-analysis	473
		2020	Retrospective study	39	Severe burn septic shock in need of renal replacement therapy	N/A	N/A	CPFA treatment for burn patients with AKI-RRT and septic shock was associated with lower mortality rate compared to CRRT alone	474
Cytosorb	Containing hemocompatible porous polymeric beads, Cytosorb is capable for removal of cytokines (IL-1 β, IL-6, IL-8, IL-10, and TNF-α) and mild molecular weight toxins (myoglobin, hemoglobin, bilirubin, bile acid, toxin etc.)	2017	Prospective single-center study	20	Refractory septic shock	Noradrenaline requirements	SOFA scores, resolution of shock and lactate clearance	Significant improvements in noradrenaline reduction, lactate clearance, SOFA scores, shock reversal achievement, and 28-day survival	475
		2017	Phase II RCT	97	Sepsis or septic shock with ARDS	Normalized IL-6 serum concentration before and after treatment	Ventilation time, normalized levels of other cytokines, vascular endothelial growth factor (VEGF), CD4+ T cell activation, 28-day mortality, P/F ratio, and multiple organ dysfunction score	Hemoadsorption removed IL-6 but did not lead to lower plasma IL-6 levels. No significant improvement for organ dysfunction score, ventilation time, and time course of oxygenation	476
		2019	Pilot trial	20	Early-onset sepsis or septic shock with ARDS	N/A	N/A	Safe with significant improvements on norepinephrine requirements, PCT, and Big-endothelin-1 concentrations	391
		2021	Prospective observational multi-center study	45	Sepsis and septic shock	Change in MAP, vasopressor reduction	SOFA and APACHE scores, vital parameters	CytoSorb might be an effective adjunctive therapy in sepsis and is advised to start at an early stage	477