Extracorporeal blood purification strategies in sepsis and septic shock: An insight into recent advancements

Table 1 Studies showing efficacy of different devices for cytokine and endotoxin removal

Ref.	Study type	Population	Modality	Intervention	Outcomes
Tapia et al[28], 2012	Prospective cohort study	31 severe septic shock patients	HVHF, Cytokine removal	HVHF – single short term – 6 h at 40 mL/kg/h	25/31 responded to HVHF. Decrease in NE dose and improvement in hemodynamic, metabolic and respiratory parameters were significantly improved by 4 h
Joannes-Boyau et al[29], 2013	Prospective, randomized, open multicentre trial	137 septic shock patients (AKI < 24 h)	HVHF, Cytokine removal	HVHF – 70 mL/kg/h vs standard volume hemofiltration at 35 mL/kg/h	No difference in hemodynamic stability, severity scores, 28-d mortality, length of stay and vasopressor free days
Livigni et al[30], 2014	Prospective, randomized, multicentre parallel group trial	192 septic shock patients	CPFA, Cytokine & endotoxin removal	Conventional therapy (n = 93) vs CPFA (n = 91)	Decreased mortality in patients receiving high dose of CPFA. No difference in length of ICU stay and new organ failures in 30 d
Atan et al[31], 2018	Randomized controlled trial	76 critically ill patients with AKI	CVVH -HCOCytokine removal	CVVH-HCO (n = 38) – cut off point 100 kDa vs CVVH -Std (n = 38) – cut off point 30 kDa	No difference was observed in mortality, duration of hemofiltration, norepinephrine dose, serum albumin levels and filter life
Dellinger et al[32], 2018	Randomized, multicentre trial	449 septic shock patients	Polymyxin B hemoperfusion; Endotoxin removal	Polymyxin B hemoperfusion + Standard therapy vs Sham hemoperfusion + Standard therapy	No significant difference in 28 d mortality in overall population or in patients with MODS score of > 9
Kaçar et al[33], 2020	Prospective observational study	23 septic shock patients with AKI	HA 330 Cytokine removal	HA 330 hemoperfusion + CVVH for 2 h once daily for 3 d	Increase in pH was observed after 1st application HA330 hemoperfusion; CRP and PCT levels decreased significantly after 2nd application

HVHF: High volume hemoperfusion; CPFA: Coupled plasma filtration adsorption; CVVH: Continuous veno-venous hemoperfusion; HCO: High cut off membrane; ICU: Intensive care unit; NE: Norepinephrine; AKI: Acute kidney injury; CRP: C-reactive protein; PCT: Procalcitonin.

Table 2 Multiple logistic regression analysis to predict 30 d mortality

Ref.	Study design	Population	Intervention	Outcomes
Friesecke et al[62], 2017	Prospective, single center study	20 septic shock patients	CytoSorb hemoperfusion	Norepinephrinedose reduced after 6 and 12 h; Improved lactate clearance; SOFA scores unchanged; Shock reversal achieved in 65% of patients; 28-d survival – 45%
Kogelmann et al[63], 2017	Case series	26 septic shock patients	CytoSorb+CVVHD	Rapid hemodynamic stabilization; Reduction in Vasopressor dose by 67%; Decrease in blood lactate by 26.4%; Shock reversal in 38.5% patients; Decreased mortality than predicted by APACHE II; No adverse events reported
Friesecke et al[52], 2017	International registry	135 septic shock patients	CytoSorb hemoperfusion	Reduced observed mortality of 65% than predicted by APACHE II of 78%; Marked reduction in IL6 levels; No significant reduction in SOFA scores; Safe and well tolerated without any adverse events
Brouwer et al[59], 2019	Retrospective, investigator-initiated study	116 septic shock patients	CytoSorb +CRRT	In CytoSorb group, the mean predicted mortality rate was 74.5%, while 28 d mortality rate was 47.8%; In CRRT group, the mean predicted mortality rate was 67.9%, while 28-d mortality was 51.0%; CytoSorb group was associated with a reduced 28-d mortality in comparison to CRRT (53% vs 72.3%)
			CRRT alone
Brouwer et al[60], 2021	Long term follows up	116 septic shock patients	CytoSorb +CRRT	CytoSorb was significantly associated with long term outcome compared to CRRT
	Retrospective cohort study		CRRT alone
Mehta et al[53], 2020	Retrospective, observational study	40 septic shock patients	CytoSorb hemoperfusion (Survivor group vs non survivor group)	Improvement in MAP (62.82 ± 9.73mmHg); Reduction in vasopressor dose; Reduction IL-6 levels (87%) and TNF levels (24%); Decrease in SOFA scores by 16.2%
Paul et al[68], 2021	Prospective, real time, observational multicentre study	45 septic shock patients	CytoSorb+ Standard therapy	26 patients survived post therapy; Reduction in vasopressor dose (NE- 51.4%, Epinephrine – 69.4% and Vasopressin -13.9%); 52.3% reduction in IL-6 levels; Reduction in APACHE II and SOFA scores, 20.1 ± 2.47 and 9.04 ± 3.00 respectively
			(Survivor vs non survivor group)
Akil et al[69], 2020		20 patients with pneumogenic sepsis and ARDS	CytoSorb + Combined high flow veno-venous ECMO (CytoSorb group); ECMO therapy alone (Control group)	The 30-d mortality rate was 0% in CytoSorb group, whereas 57% was observed in control group; Significant reduction in procalcitonin and C-reactive levels were observed in CytoSorb group in comparison to control group
Rugg et al[61], 2020	Retrospective single center study	42 septic shock patients compared to 42 matched controls	Cytosorb +RRT	Catecholamines requirements decreased to 0.26 µg/kg/min within 24 h of therapy with CytoSorb; In hospital mortality was significantly lower in CytoSorb group as compared to controls (35.7% vs 61.9%); Risk factors in CytoSorb group were high lactate levels and low thrombocyte counts proior to therapy. Lactate value of 7.5 mmol/L, predicted mortality with high specificicty (88.9%)

CVVHD: Continuous veno-venous hemodilation; NE: Norepinephrine; MAP: Mean arterial pressure; SOFA: Sequential organ failure assessment; APACHE: Acute physiology and chronic health evaluation; IL: Interleukin; TNF: Tumor necrosis factor; ARDS: Acute respiratory distress syndrome; CRRT: Continuous renal replacement therapy; RRT: Renal replacement therapy.

Table 3 Studies determining efficacy of CytoSorb in coronavirus disease 2019 infection

Ref.	Study type	Population	Intervention	Outcomes
Alharthy et al[70], 2020	Retrospective case series	50 COVID-19 patients with AKI, ARDS, Sepsis and hyperinflammation	CytoSorb + CRRT [Survivors (n = 35) vs non survivors (n = 15)]	Decreased SOFA score, lactate levels, ferritin, D-dimers, CRP and IL-6 levels in th survivor group after 2 ± 1 sessions of CRRT + CytoSorb
Mehta et al[64], 2021	Case series	3 critically ill COVID-19 patients	CytoSorb hemoperfusion other prescribed medications (tocilizumab, antivirals, hydroxychloroquine, azithromycin)	Significant improvement in biochemical parameters and clinical outcomes post CytoSorb therapy; Reduction in CRP levels by 91.5%, 97.4% and 55.75%, respectively; Improvement in MAP by 18%, 23% and 17% by 7th day post therapy
Nassiri et al[71], 2021	Retrospective case series	26 COVID-19 patients with ARDS	CytoSorb hemadsorption therapy	21 patients survived; Significant decrease in NE requirement; PCT, CRP and ferritin reduced post therapy; Significant improvement in SOFA scores; Therapy was well tolerated
Paisey et al[72], 2021	Retrospective case series	15 severely ill COVID-19 patients	CytoSorb hemadsorption therapy	Adjunctive treatment with CytoSorb lead to reduction in ferritin, CRP, PCT and lactate levels
Song et al[73], 2021	Multicenter observational study	52 ICU COVID -19 patients on ECMO	ECMO + CytoSorb hemadsorption therapy	ICU mortality was 17.3% on day 30, 26.9% on day 90, and 30.8% at final follow up of 143 d; Lower baseline D-Dimer levels were observed among survivors (2.3 ± 2.5 vs 19.8 ± 32.2 µg/mL) compared to non survivors; Borderline association observed between baseline D-Dimer levels and mortality with a 32% increase in risk of death per 1 µg/mL increase

COVID-19: Coronavirus disease 2019; CRRT: Continuous renal replacement therapy; SOFA: Sequential organ failure assessment; CRP: C-reactive protein; IL: Interleukin; AKI: Acute kidney injury; ARDS: Acute respiratory distress syndrome; MAP: Mean arterial pressure; NE: Norepinephrine; ECMO: Extracorporeal membrane oxygenation.

Table 4 Multiple logistic regression analysis to predict 30 d mortality

Feature	CytoSorb 300[84,85,86]	Jafron HA-series (80, 130, 180, 230, 280, 330, 380)[87]	Biosky MG-Series[88]
Manufacturer	CytoSorbents™ Inc, United States	Jafron Biomedical Co., Ltd. No. 98, Technology Sixth Road, High-tech Zone, Zhuhai City, 519085, Guangdong, China	Biosun Medical Technology Co. Ltd, China
IFU version	October 1, 2021[87]	11-Sep-19	1-Aug-18
Adsorbent	Crosslinked Divinylbenzene	Neutral Macroporous Resin	Medical Neutral Macroporous Synthetic Resin
Coating	Polyvinylpyrollidone	Collodion	No data
Adsorbent Surface	> 45000 m2	100000m2	No data
Storage fluid	Isotonic saline	Water for injection	Sterile water
Use time/cartridge	24 h, Can be administered up to 7 consecutive days	Depending on mode of operation: Hemoperfusion 100-250 mL/ min; Dialysis < 320 ml/ min with use upto 4 h; CRRT 150-250 mL/min with use upto 12 h; CPB up to 700 mL/ min with use upto 2.5 h	120-180 min, Not suggested to use more than 3 times within 24 h
Blood flow	100-700 mL/min, Recommended > 150 mL/min	100-700 mL/min	100-400 mL/min; Highest rate is 250 mL/min
Pmax	760 mmHg	750 mmHg	750 mmHg
Mode of operation covered	Hemoperfusion, Intermittent hemodialysis, CRRT, Cardiopulmonary bypass (CPB) ECMO	Hemoperfusion; Hemodialysis; CRRT; CPB	Hemoperfusion; Hemodialysis; CRRT; CPB only as comment in anticoagulation, not in setup
Shelf life	3 yr	2 yr	2 yr
Safety report status	As of 2021: > 162000 treatments distributed without confirmed serious device related events	No data	No data

IFU: Instructions for use; CRRT: Continuous renal replacement therapy; CPB: Cardiopulmonary bypass; ECMO: Extracorporeal membrane oxygenation.

Table 5 Studies determing oxiris efficacy for removal of endotoxins and cytokines

Ref.	Study type	Population	Intervention	Outcomes
Shum et al[98], 2013	Prospective case series with historical controls	6 patients with septic AKI	oXiris + CVVH	Significant reduction in SOFA scores by 37% after 48 h of therapy
Ugurov et al[96], 2020	Single centre case series	15 COVID -19 patients	oXiris hemofilter	Early initiation of oXiris was associated with stable or reducing levels of IL-6,8,10 and TNFα
Zhang et al[49], 2021	Case series	5 COVID-19 patients	CRRT followed by oXiris hemofilter therapy	Reduced levels of cytokines, haemodynamic stabilization and improvement of organ function was observed with oXiris.
Rosalia et al[100], 2020	Prospective cohort study	44 COVID 19 cases	CVVH + oXiris	Reduction in CRP, ferritin, fibrinogen and other inflammatory mediators were observed

COVID-19: Coronavirus disease 2019; CRRT: Continuous renal replacement therapy; SOFA: Sequential organ failure assessment; CRP: C-reactive protein; IL: Interleukin; CVVH: Continuous veno venous hemofiltration; TNFα: Tumornectrosis factor alpha.