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Scaling Issues in the Article Entitled “Cytokines in Blood From Septic Patients Interact With Surface-Immobilized Heparin”

DiLeo, Morgan V.; Federspiel, William J.

doi: 10.1097/MAT.0b013e3181e4bfc3
Letters to the Editor

McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania (DiLeo)

McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, Departments of Bioengineering, Chemical Engineering, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Federspiel)

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To the Editor:

The main conclusion of the article entitled “Cytokines in blood from septic patients interact with surface-immobilized heparin” by Axelsson et al. published in the ASAIO Journal is that “passing blood from septic patients through a column packed with surface-heparinized beads significantly reduce (d) concentrations of the proinflammatory cytokine tumor necrosis factor (TNF)-α from initially very high levels.”1 Indeed, Heparin has been shown to have some affinity for several cytokines, including TNF, which may hold the potential for selective reduction of cytokine concentration as a therapy for septic patients.2–4 However, the scaling of the parameters used in their experiments provides a misleading representation of the efficacy of these beads for such a treatment.

The authors report the initial concentration of TNF to be 50.3 pg/ml as measured using the Quantikine enzyme-linked immunosorbent assay (ELISA) (R&D Systems; Cat HSTA00D, Minneapolis, MN). A single pass of 1 ml of blood through a column containing 1 and 10 g of the heparin-coated beads reduced the concentration to 21.1 pg/ml (−58%) and 20.6 pg/ml (−59%), respectively. To maintain this level of removal in a full-scale device, the device would have to contain a minimum of 5 kg of material. For a void fraction of 30%, this would result in a priming volume of at least 1.5 L.

A more realistic device would be sized at approximately 300–500 g of material per patient, similar to the CytoSorb device5 (CytoSorbents Inc., Princeton, NJ). Thus, for their experiments, Axelsson et al. should have either used 0.1 g of material and 1 ml of blood or 1 g of material and 10 ml of blood. The authors showed that 1 g of the heparin-coated beads removed a total of 29.2 pg of TNF. In an appropriately scaled experimental setup containing 10 ml of blood instead of 1 ml, the actual amount of removal would have only been 29.2/503 pg TNF or 5.8%. We have been working with a similar device containing the porous CytoSorb beads that remove cytokines via nonspecific adsorption.6 Our analyses have shown that our device containing unmodified CytoSorb removes 20% of TNF in a single-pass setup mimicking that of Axelsson et al. and that this amount is not significantly increased when we incorporate the same amount of heparin on the adsorbent material.

Although we do not argue the potential benefits of a device that can effectively remove cytokines from septic patients, we do feel that the conclusions from the article in question were exaggerated because of improper scaling of device parameters. A quick assessment of capacity of the device shows that a full-scale device at a reasonable size may not remove sufficient amounts of TNF to be beneficial to patients.

Morgan V. DiLeo

McGowan Institute for Regenerative Medicine

Pittsburgh, Pennsylvania

Department of Bioengineering

University of Pittsburgh

Pittsburgh, Pennsylvania

William J. Federspiel

McGowan Institute for Regenerative Medicine

Pittsburgh, Pennsylvania

Departments of Bioengineering, Chemical Engineering, and Critical Care Medicine

University of Pittsburgh

Pittsburgh, Pennsylvania

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References

1. Axelsson J, Ferreira M, Adolfsson L, et al: Cytokines in blood from septic patients interact with surface-immobilized heparin. ASAIO J 56: 48–51, 2010.
2. Kenig M, Gaberc-Porekar V, Fonda I, Menart V: Identification of the heparin-binding domain of TNF-alpha and its use for efficient TNF-alpha purification by heparin-Sepharose affinity chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 867: 119–125, 2008.
3. Mummery RS, Rider CC: Characterization of the heparin-binding properties of IL-6. J Immunol 165: 5671–5679, 2000.
4. Salek-Ardakani S, Arrand JR, Shaw D, Mackett M: Heparin and heparan sulfate bind interleukin-10 and modulate its activity. Blood 96: 1879–1888, 2000.
5. Kellum JA, Venkataraman R, Powner D, et al: Feasibility study of cytokine removal by hemoadsorption in brain-dead humans. Crit Care Med 36: 268–272, 2008.
6. DiLeo MV, Kellum J, Federspiel WJ: A simple mathematical model of cytokine capture using a hemoadsorption device. Ann Biomed Eng 37: 222–229, 2008.
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