Techniques of extracorporeal cytokine removal: a systematic review of human studies

Figures & data

Figure 1. Flow diagram summarizing the manuscript identification and selection process.

Table 1. Number of papers and total number of patients studied for each technique.

Technique	No of papers studying technique	Total no of patients exposed to technique
Standard continuous hemofiltration (Std/HF)	1313,17,18,20,22,23,35,39^–41,43,49,51	201
Standard continuous hemodialysis (Std/HD)	318,27,45	28
Standard continuous hemodiafiltration (Std/HDF)	521,24^–26,36	72
Standard high volume hemofiltration (Std/HVHF)	219,49	26
High cut-off continuous hemofiltration (HCO/HF)	313,15,16	48
High cut-off continuous (HCO/HD)	115	12
Plasmafiltration	242,47	22
Combined plasma filtration adsorption (CPFA)	132	10
Ultrafiltration during cardiopulmonary bypass (UF in CPB)	328,37,44	41
Extracorporeal liver support (MARS and Prometheus)	112	8
Adsorption techniques using direct hemoperfusion (Adsorption/DHP)	246,52	14
Conventional ultrafiltration (CUF)	329^--31	54
Modified ultrafiltration (MUF)	430,33,34,38	80
Zero-balance ultrafiltration (ZBUF)	148	15
Combined standard hemodiafiltration and adsorption (Std HDF + Adsorption)	114	5
Adsorption via sustained high efficiency daily diafiltration using a mediator adsorbing membrane
(Adsorption/SHEDD-fA)	150	25
Combined standard hemodiafilration and plasmafiltration (Std HDF + PF)	147	5

Table 2. Clearance (CL) data according to techniques, devices and treatment characteristics.

Technique	Device code	n	Qb (mL/min)	Qf (mL/hr)	Qd (mL/hr)	RF	IL1-b	IL2	IL2R	IL6	IL6R	IL8	IL9	IL10	IL1RA	TNFa	sTNFaRI	sTNFaRII	Albumin
Std/HF13	4	10		2500		post				0.2					4.43
Std/HF17	7	13	100–150	2000			2.17			1.8						1.47
Std/HF18	8	11	150–200	2000		post				3.3				0		0
Std/HF20	8	13	150	1000						4.92						0
Std/HF22	10	33	150–200	1000		post	7.03	0	0.43	0.56	0	2.19		0	6.62	3.57		0
Std/HF39	12	16		2000						0						0
Std/HF51	41	38	180	2000–2400		pre				1.97		3.33
Std/HD18	8	12	150–200		2000					1.9				0		0
Std/HD27	35	1			2000											0
Std/HDF21	9	9	∼100		1000	pre									4	0.15	0.77	0.12
Std/HDF24	12	10	150		1000					1.38		2.74
Std/HDF25	9	20	92	525	1000	pre				2.71						0.069
Std/HDF26	12	18	150		1000		25.1									21.3
Std/HVHF19	34	15		7800						2.01						3.88
HCO/HF13	3	20		2500		post				38.3					39
HCO/HF15	2	6		1000		post				8.43					16.23	0			0.13
HCO/HF15	2	6		2500		post				24.6					41.43	0			0.87
HCO/HF16	6	16	150	1000		post				14.67						0
HCO/HD15	2	6			1000	post				9					15.43	0			0.16
HCO/HD15	2	6			2500	post				21.8					28.33	0			0.35
Adsorption/DHP52^d	42	9	80–100				24.3			22.4		0.26	14.6	14	6.93
UF in bypass28^a	14	20		1000			0			0		0
MARS12^b	1	8	200		18000^c					3		17		16		29	2
Prometheus12^b	2	8	200		18000^c					4		3		46		25	12

All clearance values are in mL/min.

n = number of patients studied for each technique and treatment characteristics.

^aUltrafiltration conducted throughout the whole duration of cardiopulmonary bypass.

^bCell-free extracorporeal liver support systems.

^c300 mL/min.

^dOther clearances (mL/min) obtained from paper: IL-12 47.3, IL-17A 25.1, FGF basic 31.4, G-CSF 16.1, IFN-γ 15.1, PDGF-bb 26.3, VEGF 50.1, TGF-β 5.32.

Refer Table 4 for device code.

RF, replacement fluid either pre or postdilution; Qb, blood flow; Qf, ultrafiltration rate; Qd, dialysate flow; HCO, high cut-off; HF, hemofiltration; HD, hemodialysis; HDF, hemodiafiltration; Std, standard; HVHF, high volume hemofiltration; DHP, direct hemoperfusion; UF, ultrafiltration; MARS, molecular adsorbents recirculation system.

Table 2.1. Summary of CL values for Std/CVVH and HCO/CVVH.

Technique	Device code	n	Qb (mL/min)	Qf (mL/hr)	Qd (ml/hr)	RF	IL1-b	IL2	IL2R	IL6	IL6R	IL8	IL10	IL1ra	TNFa	sTNFaRI	sTNFaRII	Albumin
HCO/HF13	3	20		2500		post				38.3				39
HCO/HF15	2	6		1000		post				8.43				16.23	0			0.13
HCO/HF15	2	6		2500		post				24.6				41.43	0			0.87
HCO/HF16	6	16	150	1000		post				14.67					0
Median	26.49										40.22
IQR	(13.1–28.0)										(27.6–40.2)
Std/HF13	4	10		2500		post				0.2				4.43
Std/HF17	7	13	100–150	2000			2.17			1.8					1.47
Std/HF18	8	11	150–200	2000		post				3.3			0		0
Std/HF20	8	13	150	1000						4.92					0
Std/HF22	10	33	150–200	1000		post	7.03	0	0.43	0.56	0	2.19	0	6.62	3.57		0
Std/HF39	12	16		2000						0					0
Std/HF51	41	38	180	2000–2400		pre				1.97		3.33
Median	1.09										0.735
IQR	(0.38–2.64)										(0–1.47)

Table 3. Sieving coefficient (SC) data for different techniques and devices with specific treatment characteristics.

Technique	Device code	n	Qb (mL/min)	Qf (mL/h)	Qd (mL/h)	RF	IL1-b	IL2	IL2R	IL6	IL6R	IL8	IL10	IL1ra	TNFa	sTNFa R1	sTNFa RII	Alb	GCSF	LIF
Std/HF13	4	10		2500		post				0.007				0.1
Std/HF17	7	13	100–150	2000			0.073			0.067					0.053
Std/HF22	10	33	150–200	1000		post	0.42	0	0.05	0.04	0	0.12	0	0.41	0.22		0
Std/HF23	11	16	150	2000		post	0.02			0	0.62				0
Std/HF40	25	13	250–300	2000–4000		pre	0.33								0.16
Std/HF41	26	7	200	2500		post						0.62
Std/HF43	28	15	100–200	25.4–44.3 mL/min		post	0.22			0.18			0	0.28	0.16	0.006	0.003
Std/HF35	20	5		2000			0.18			0		0.25			0
Std/HF39	12	16		2000						0					0
Std/HF51	41	38	180	2000–2400		pre				0.05		0.09
Std/HD45	20	16		2000		post	0.09			0		0.68			0
Std/HDF36	21	15	100–150	10.4–4.3 mL/min	10–30 mL/min	post						0.19			0.18
Std/HDF21	9	9	∼100		1000	pre								0.45	0.02	0.09	0.01
Std/HDF25	9	20	92	525	1000	pre				0.27					0.017
HCO/HF13	3	20		2500		post				0.9				0.92
HCO/HF15	2	6		1000		post				0.92				1	0
HCO/HF15	2	6		2500		post				>0.92				1	0
HCO/HF16	6	16	150	1000		post				0.82					0			0.026
HCO/HD15	2	6			1000	post				0.92				1	0
HCO/HD15	2	6			2500	post				>0.92				1	0
PF42	27	14		a						0.93								0.99	1.29	0.66
UF in bypass28^b	14	20		1000			0			0		0			2.3
UF in bypass37^c	22	11								<0.001		0.004
UF in bypass44^d	39	16								1.246
CUF30	16	11		62 mL/min						0.035			poor		1.01
CUF30	17	10		42 mL/min						0.037			poor		2.72
CUF29	15	10	100–120				0.67			0.04		0.22			0.9				0.04
MUF30	16	11		82 mL/min						0.005			0.1		2.22
MUF30	17	9		93 mL/min						0.003			poor		2.01
MUF34	12	20								0.03		0.12
MUF38	23	20	10–15 ml/kg/min												0.23
MUF33	38	20	300–400(during MUF)	*						0.25		0.06	0
ZBUF48	32	15		#			0.39			0.019					194
Std/HDF +  adsorption14	5	10	90–130	2000	NA	pre	0.05			0.03		0.07			0

n = number of patients studied for each technique and treatment characteristics.

a = 100 mL/kg for first 4–6 h and then 150 mL/kg over 28–30 h.

b, ultrafiltration conducted throughout the whole duration of cardiopulmonary bypass.

c, from aortic cross clamp until end of CPB.

d, from aortic cross clamp until within 5 minutes of clamp removal.

*1200 to 1800 mL total during MUF.

#Fluid removal of 1 L every 10 min until 3 L/m2 BSA removed.

Refer Table 4 for device code

RF, replacement fluid either pre or postdilution; Qb, blood flow; Qf, ultrafiltration rate; Qd, dialysate flow; HCO, high cut-off; HF, hemofiltration; HD, hemodialysis; HDF, hemodiafiltration; Std, standard; PF, plasmafiltration; UF, ultrafiltration; CUF, conventional ultrafiltration; MUF, modified ultrafiltration; ZBUF, zero balance ultrafiltration.

Table 4. Percentage removal data for different cytokines.

Technique	Device code	n	Qb (mL/min)	Qf (ml/H)	Qd (mL/min)	RF	IL1-b	IL2	IL6	IL8	IL10	IL1ra	IL18	TNFa
CUF31	18	23	100	100–300 ml/kg					28	59
Std/HF49	25	11	200	1000		pre		0		0	3.15			0
Std/HVHF49	33	11	300	6000		1/3pre 2/3post		0		0	3.45			0
Adsorption/DHP46	29	5	100				24.7		24.65	54		28.5		52.25
PF47	31	8	80	b					0				42.9
CPFA32	19 + 36 + 37	10	155	a							99.8			99.6
Std HDF + PF47	30( + 31)	5	100 (CHDF) +  80 (PE)	b					0				38.8
Adsorption/ SHEDD-fA50	40	25	150	1500		post			21

n = number of patients studied for each technique and treatment characteristics.

a = 30–40 mL/min (Qp); (32–38 mL/min UF + dialysate outflow).

b = 3.6–4.0 L plasma exchanged per session.

Refer Table 4 for device code.

RF, replacement fluid either pre or postdilution; Qb, blood flow; Qf, ultrafiltration rate; Qd, dialysate flow cut-off; HF, hemofiltration; HD, hemodialysis; HDF, hemodiafiltration; HVHF, high volume hemofiltration; Std, standard; PF, plasmafiltration; CUF, conventional ultrafiltration; CPFA, combined plasmafiltration adsorption; DHP, direct hemoperfusion; PD, peritoneal dialysis; MUF, modified ultrafiltration; ZBUF, zero balance ultrafiltration; SHEDD-fA, sustained high efficiency daily diafiltration using a mediator adsorbing membrane.

Table 5. Device codes.

Reference	Device name	Device code	Filter type	Filter size (m^2)	Molecular cut-off point	Features
12	MARS	1	albumin impermeable membrane + charcoal + anion exchange resin + dialyzer		60 kDa	*
12	Prometheus	2	albumin filter (polysulfone) + neutral resin adsorber + anion exchange adsorber + dialyzer (polysulfone)		250 kDa	#
13,15	P2SH	3	polyamide	1.1	60 kDa in vivo
13,16	Polyflux 11 s	4	polyamide	1.1	30 kDa
14	Multiflow 60 +  polymyxin B	5	AN69 (polyacrylonitrile) with Polymyxin B immobilized fibre	0.6
16	PSH1	6	Polyamide	0.6	60 kDa
17	Prisma	7	AN69	0.9	35–40 kDa
18,20	Multiflow 60	8	AN69	0.6	40 kDa
21,25	AN69HF	9	AN69
22	AV600	10	polysulfone	1.35	30 kDa
23	FH66	11	polyamide
24,26,34	AN69S	12	polyacrylonitrile
28	650 SF 1.3	14	polyacrylonitrile		30 kDa
29	Diafilter 20	15	polysulfone
30	Jostra BC20	16	polyamide	0.2
30	Jostra BC60	17	polysulfone	0.65
31	DHF02	18	polyethersulfane	0.25
32	MPS 07	19	polyethersulfone	0.7
35	FH66D	20	polyamide
36	AN69	21	polyacrylonitrile	1.6
37	PF40	22	polysulfone		40 kDa
38	Bently Hemoconcentrator	23	polysulfone	0.3
40	AN69	25	AN69	1.2
41	BL627	26	polysulfone
42	PF1000	27	polypropylene	0.14
43	Multiflow 100	28	AN69	0.9	35–40 kDa
46	Lixelle	29	β2-microglobulin adsorption column (cellulose beads + hexadecyl groups)		30 kDa
47	Panflow APF06S	30	polyacrylonitrile
47	Plasmaflow OP08W	31	plasma filter
48	HPH1400	32	polysulfone	1.3	65 kDa
49	Filtral 16	33	AN69	1.6
19	Flat plate filter (15 parallel membranes)	34	polyacrylonitrile	0.43	30–40 kDa
27	Hemoflow F60	35	polysulfone
32	BLS 627	36	polysulfone	1.2
32	Amberchrom	37	reverse phase styrenic polymer resin	surface 600 to 800 m^2/g
33	Diafilter D30-NR	38	polysulfone
44	Hemocor HPH1000	39	polysulfone
50	Filtrizer BG-PO	40	polymethylmethacrylate
51	NI-PRO UF-205	41	cellulose triacetate	1.9
52	Toraymyxin 20R	42	polymyxin B

Note: *20% human serum albumin as dialysate which then passes thru columns of charcoal and anion exchange resins. Water soluble substances cleared by low flux dialyzer in a secondary circuit.

#Following separation plasma passes through two columns containing different adsorbents. Water soluble substances cleared by high-flux dialyzer directly inserted into the blood circuit.

Morgera S, Haase M, Kuss T, et al. Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure. Crit Care Med. 2006;34:2099–2104

 PubMed Web of Science ®Google Scholar

Dahaba AA, Elawady GA, Rehak PH, List WF. Procalcitonin and proinflammatory cytokine clearance during continuous venovenous hemofiltration in septic patients. Anaesth Intensive Care. 2002;30:269–274

 PubMed Web of Science ®Google Scholar

Kellum JA, Johnson JP, Kramer D, Palevsky P, Brady JJ, Pinsky MR. Diffusive vs. convective therapy: effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome. Crit Care Med. 1998;26:1995–2000

 PubMed Web of Science ®Google Scholar

Sander A, Armbruster W, Sander B, Daul AE, Lange R, Peters J. Hemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNF alpha plasma concentrations. Intensive Care Med. 1997;23:878–884

 PubMed Web of Science ®Google Scholar

Heering P, Morgera S, Schmitz FJ, et al. Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration. Intensive Care Med. 1997;23:288–296

 PubMed Web of Science ®Google Scholar

Hoffmann JN, Hartl WH, Deppisch R, Faist E, Jochum M, Inthorn D. Effect of hemofiltration on hemodynamics and systemic concentrations of anaphylatoxins and cytokines in human sepsis. Intensive Care Med. 1996;22:1360–1367

 PubMedGoogle Scholar

Hoffmann JN, Werdan K, Hartl WH, Jochum M, Faist E, Inthorn D. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock. 1999;12:174–180

 Google Scholar

Hoffmann JN, Faist E, Deppisch R, Hartl WH, Inthorn D. Hemofiltration in human sepsis: evidence for elimination of immunomodulatory substances. Contrib Nephrol. 1995;116:76–79

 Google Scholar

Mariano F, Tetta C, Guida G, Triolo G, Camussi G. Hemofiltration reduces the serum priming activity on neutrophil chemiluminescence in septic patients. Kidney Int. 2001;60:1598–1605

 PubMed Web of Science ®Google Scholar

De Vriese AS, Colardyn FA, Philippé JJ, Vanholder RC, De Sutter JH, Lameire NH. Cytokine removal during continuous hemofiltration in septic patients. J Am Soc Nephrol. 1999;10:846–853

 PubMed Web of Science ®Google Scholar

Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P. High-volume hemofiltration in human septic shock. Intensive Care Med. 2001;27:978–986

 PubMed Web of Science ®Google Scholar

Schilder L, Nurmohamed SA, ter Wee PM, et al. Effect of anticoagulation regimens on handling of interleukin-6 and -8 during continuous venovenous hemofiltration in critically ill patients with acute kidney injury. Cytokine. 2012;60:601–607

 Google Scholar

Byrick RJ, Goldstein MB, Wong PY. Increased plasma tumor necrosis factor concentration in severe rhabdomyolysis is not reduced by continuous arteriovenous hemodialysis. Crit Care Med. 1992;20:1483–1486

 Google Scholar

Hoffmann JN, Hartl WH, Deppisch R, Faist E, Jochum M, Inthorn D. Hemofiltration in human sepsis: evidence for elimination of immunomodulatory substances. Kidney Int. 1995;48:1563–1570

 PubMed Web of Science ®Google Scholar

van Bommel EF, Hesse CJ, Jutte NH, Zietse R, Bruining HA, Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome. Ren Fail. 1997;19:443–454

 Web of Science ®Google Scholar

Bellomo R, Tipping P, Boyce N. Interleukin-6 and interleukin-8 extraction during continuous venovenous hemodiafiltration in septic acute renal failure. Ren Fail. 1995;17:457–466

 PubMed Web of Science ®Google Scholar

Bellomo R, Tipping P, Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med. 1993;21:522–526

 PubMed Web of Science ®Google Scholar

Toft P, Kehler D, Brandslund I I, Tønnsen E. The immunological effects of continuous veno-venous hemodiafiltration in critically ill patients. Crit Care. 1999;3:159–165

 PubMedGoogle Scholar

Sanchez-Izquierdo JA, Perez Vela JL, Lozano Quintana MJ, Alted Lopez E, Ortuño de Solo B, Ambros Checa A. Cytokines clearance during venovenous hemofiltration in the trauma patient. Am J Kidney Dis. 1997;30:483–488

 Google Scholar

Morgera S, Slowinski T, Melzer C, et al. Renal replacement therapy with high-cutoff hemofilters: impact of convection and diffusion on cytokine clearances and protein status. Am J Kidney Dis. 2004;43:444–453

 PubMed Web of Science ®Google Scholar

Morgera S, Rocktäschel J, Haase M, et al. Intermittent high permeability hemofiltration in septic patients with acute renal failure. Intensive Care Med. 2003;29:1989–1995

 PubMed Web of Science ®Google Scholar

Reeves JH, Butt WW, Shann F, et al. Continuous plasma filtration in sepsis syndrome. Plasma filtration in Sepsis Study Group. Crit Care Med. 1999;27:2096–2104

 PubMed Web of Science ®Google Scholar

Yonekawa C, Nakae H, Tajimi K, Asanuma Y. Effectiveness of combining plasma exchange and continuous hemodiafiltration in patients with postoperative liver failure. Artif Organs. 2005;29:324–328

 Google Scholar

Ronco C, Brendolan A, Lonnemann G, et al. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med. 2002;30:1250–1255

 PubMed Web of Science ®Google Scholar

Antunes N, Dragosavc D, Petrucci Junior O, et al. The use of ultrafiltration for inflammatory mediators removal during cardiopulmonary bypass in coronary artery bypass graf surgery. Rev Bras Cir Cardiovasc. 2008;23:175–182

 Google Scholar

Watanabe T, Sakai Y, Mayumi T, et al. Effect of ultrafiltration during cardiopulmonary bypass for pediatric cardiac surgery. Artif Organs. 1998;22:1052–1055

 Google Scholar

Clar A, Bowers MC, Larson DF. Derivation of sieving coefficients to determine the efficacy of the hemoconcentrator in removal of four inflammatory mediators produced during cardiopulmonary bypass. ASAIO J. 1997;43:163–170

 Google Scholar

Stadlbauer V, Krisper P, Aigner R, et al. Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure. Crit Care. 2006;10:R169--R175

 PubMed Web of Science ®Google Scholar

Tsuchida K, Takemoto Y, Sugimura K, Yoshimura R, Nakatani T. Direct hemoperfusion by using Lixelle column for the treatment of systemic inflammatory response syndrome. Int J Mol Med. 2002;10:485–488

 Google Scholar

Oishi K, Mimura-Kimura Y, Miyasho T, et al. Association between cytokine removal by polymyxin B hemoperfusion and improved pulmonary oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis. Cytokine. 2013;61:84–89

 PubMed Web of Science ®Google Scholar

Brancaccio G, Villa E, Girolami E, et al. Inflammatory cytokines in pediatric cardiac surgery and variable effect of the hemofiltration process. Perfusion. 2005;20:263–268

 Google Scholar

Dittrich S, Aktuerk D, Seitz S, et al. Effects of ultrafiltration and peritoneal dialysis on proinflammatory cytokines during cardiopulmonary bypass surgery in newborns and infants. Eur J Cardiothorac Surg. 2004;25:935–940

 PubMed Web of Science ®Google Scholar

Berdat PA, Eichenberger E, Ebell J, et al. Elimination of proinflammatory cytokines in pediatric cardiac surgery: analysis of ultrafiltration method and filter type. J Thorac Cardiovasc Surg. 2004;127:1688–1696

 Google Scholar

Kiziltepe U, Uysalel A, Corapcioglu T, Dalva K, Akan H, Akalin H. Effects of combined conventional and modified ultrafiltration in adult patients. Ann Thorac Surg. 2001;71:684–693

 Google Scholar

Bogă M, Islamoğlu F, Badak I, et al. The effects of modified hemofiltration on inflammatory mediators and cardiac performance in coronary artery bypass grafting. Perfusion. 2000;15:143–150

 Google Scholar

Wang W, Huang HM, Zhu DM, Chen H, Su ZK, Ding WX. Modified ultrafiltration in paediatric cardiopulmonary bypass. Perfusion. 1998;13:304–310

 Google Scholar

Tallman RD, Dumond M, Brown D. Inflammatory mediator removal by zero-balance ultrafiltration during cardiopulmonary bypass. Perfusion. 2002;17:111–115

 Google Scholar

Peng Y, Yuan Z, Li H. Removal of inflammatory cytokines and endotoxin by veno-venous continuous renal replacement therapy for burned patients with sepsis. Burns. 2005;31:623–628

 PubMed Web of Science ®Google Scholar

Nishida O, Nakamura T, Kuriyama N, et al. Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA) in the treatment of patients with severe sepsis. Contrib Nephrol. 2011;173:172–181

 Google Scholar

van Bommel EF, Hesse CJ, Jutte NH, Zietse R, Bruining HA, Weimar W. Cytokine kinetics (TNF-alpha, IL-1 beta, IL-6) during continuous hemofiltration: a laboratory and clinical study. Contrib Nephrol. 1995;116:62–75

 PubMedGoogle Scholar

Xie H, Ji D, Gong D, et al. Continuous veno venous hemofiltration in treatment of acute necrotizing pancreatitis. Chin Med J (Engl). 2003;116:549–553

 PubMed Web of Science ®Google Scholar