Therapeutic effects

  • Direct Physiochemical effects
  • Metabolic effects
  • Clinical effects

Removal of inflammatory mediators (cytokines, chemokines, anaphylatoxins etc.)

The main focus of CytoSorb therapy is the removal of inflammatory mediators, particularly cytokines and chemokines, from the patient´s blood.  The CytoSorb adsorber removes a wide range of pro- and anti-inflammatory mediators between a 5-60 kDa molecular weight range, where most cytokines can be found. Standard high-flux dialysis or CRRT is only capable of removing substances generally below 15 kDa in size. CytoSorb’s broad spectrum removal is important because of the overlapping redundancy in function amongst different cytokines, PAMPs, and DAMPs.  For example, therapies focused on reducing single cytokines or inflammatory mediators have not historically been effective in improving outcomes in critically-ill patients, presumably because they are only one of many. CytoSorb can also remove many other potent mediators of inflammation such as anaphylatoxin C3a (~9 kDa) and procalcitonin (13 kDa).  (Ref: 1 – 8)

il8 il_6

 

 

 

 

 

One unique aspect of CytoSorb is that it is concentration dependent.  At high concentrations of a particular substance, CytoSorb can remove large amounts very quickly.  Conversely, at low concentrations, the clearance becomes negligible.  This self auto-regulation makes it difficult to over-treat, improving the safety of the therapy.

Removal of other endogenous molecules (myoglobin, free hemoglobin, bilirubin, bile acids)

Because CytoSorb targets the reduction of substances in a molecular weight range between 5 and 60 kDa, it can reduce other substances that play an important role outside the SIRS response.  For example, in rhabdomyolysis due to severe trauma, burn injury, muscle overuse, or statin usage, myoglobin (17 kDa) can be released in massive quantities, leading to fouling and damage of the renal tubules and acute kidney injury. Myoglobin can be efficiently removed from the blood using CytoSorb. (Ref: 9-10)

hemo_ENFree hemoglobin: Hemolysis of red blood cells results in the release of free plasma hemoglobin. Hemolysis can be caused by high flow extracorporeal circulation (e.g. cardiopulmonary bypass, ECMO or extracorporeal membrane oxygenation), infections (e.g. malaria, streptococcus, EHEC), genetic disorders (e.g. Sickle cell anemia) and other causes. When levels of free hemoglobin exceed the body’s natural haptoglobin scavenging system, it can accumulate and become toxic through free oxygen radical generation and endothelial injury, as well as potent nitric oxide scavenging. CytoSorb is capable of removing plasma free hemoglobin efficiently.

bil1Bilirubin: Bilirubin and biliverdin are by-products of hemoglobin metabolism following breakdown of heme in the spleen and liver. They can be found in abnormally high levels in blood in hemolytic disorders, impaired liver function, and intra-hepatic and extra-hepatic cholestasis (e.g. bile duct obstruction). Several publications have shown excellent removal of unconjugated bilirubin (0.6 kDa) and conjugated bilirubin (0.8 kDa) by CytoSorb, with binding confirmed by the beads turning yellow.

 

bileacidsBile acids: Bile acids, and their accumulation in the plasma, play an important, yet often underestimated role during critical illnesses such as sepsis, systemic inflammation, and liver failure. Because they are surfactants/detergents, they can cause injury to cellular membranes.  CytoSorb use has been associated with rapid reduction in plasma bile acids, potentially reducing their toxic effects.

 

 

 

Removal of exogenous molecules (Toxins, metals, drugs and substances with high protein binding)

Toxins: A wide variety of pathogens synthesize and manufacture deadly toxins that enhance virulence. Many of these are in the size range that CytoSorb can remove, permitting a novel strategy to treat severe sepsis or septic shock mediated by toxins. For example, CytoSorb has demonstrated the in vitro ability to reduce Staph aureus and MRSA alpha hemolysin exotoxin (33 kDa monomers), and Shiga-like enterotoxins (STX-1 and STX-2: both ~70 kDa) that are absorbed from the intestines during E. coli O157:H7 and enterohaemorrhagic E. coli (EHEC) mediated gastroenteritis. CytoSorb has been used successfully in human cases of Staphylococcus aureus infection, toxic shock syndrome (TSST-1 toxin: 22kDa), Streptococcal pneumonia (Pneumolysin: 53 kDa), Streptococcal necrotizing fasciitis, endocarditis, fungal infections (Aflatoxin B1: 0.3 kDa), EHEC (when used with plasmapheresis), and others. The ability of CytoSorb to remove endotoxin is unknown.

Metals: The ability to effectively remove metals from the blood, such as iron, copper or mercury is suspected, but has yet to be systematically investigated.

Drugs: Like other extracorporeal blood purification procedures (e.g. dialysis or hemofiltration), CytoSorb can also reduce certain drugs and endogenous molecules in blood. Currently a number of antibiotics have been tested with CytoSorb. Meropenem is reduced less than 20% (vs natural clearance) and is considered compatible. Vancomycin is reduced, however dosing based on drug levels is being used successfully in clinical practice.  Removal of anti-influenza medication such as oseltamivir, zanamivir, or peramivir is not expected with CytoSorb.  As with dialysis, giving antibiotics after CytoSorb therapy eliminates the risk of removal. CytoSorb has been also used to help treat drug overdose, including the removal of the calcium channel blocker, amlodipine, and the anti-depressant, venlafaxine.  CytoSorb has been used to successfully help treat acute liver failure following the overdose of acetaminophen, but is not believed to remove the drug directly.


References 

Removal of inflammatory mediators

(1) Treatment of post-cardiopulmonary bypass SIRS by hemoadsorption: a case series
Trager K, Fritzler D, Fischer G, Schroder J, Skrabal C, Liebold A, Reinelt H
Int J Artif Organs 2016; 39(3): 141-146
(2) Systemic Inflammatory Response Syndrome in der Herzchirurgie: Neue Therapiemöglichkeiten durch den Einsatz eines Cytokin-Adsorbers während EKZ?
Born F, Pichlmaier M, Peterß S, Khaladj N, Hagl C
Kardiotechnik 2/2014
(3) Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model.
Peng ZY, Bishop JV, Wen XY, Elder MM, Zhou F, Chuasuwan A, Carter MJ, Devlin JE, Kaynar AM, Singbartl K, Pike F, Parker RS, Clermont G, Federspiel WJ, Kellum JA.
Crit Care. 2014 Jul 3;18(4):R141
(4) A multicenter randomized controlled study of an extracorporeal cytokine hemoadsorption device in septic patients
Schädler D, Porzelius C, Jörres A, Marx G, Meier-Hellmann A, Putensen C, Quintel M, Spies C, Engel C, Weiler N, Kuhlmann M
Critical Care 2013, 17(Suppl 2):P62
(5) Hemoadsorption Reprograms Inflammation in Experimental Gram-Negative Septic Peritonitis: Insights from In Vivo and In Silico Studies.
Namas RA, Namas R, Lagoa C, Barclay D, Mi Q, Zamora R, Peng Z, Wen X, Fedorchak MV, Valenti IE, Federspiel WJ, Kellum JA, Vodovotz Y
Mol Med. 2012 Dec 20;18:1366-74
(6) Effects of hemoadsorption on cytokine removal and short-term survival in septic rats
Peng X, Carter M, Kellum J.A.
Crit Care Med. 2008 May;36(5):1573-7
(7) Feasibility study of cytokine removal by hemoadsorption in brain-dead humans
Kellum JA, Venkataraman R, Powner D, Elder M, Hergenroeder G, Carter M
Crit Care Med. 2008 Jan;36(1):268-72
(8) Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-кB DNA binding, and improves short-term survival in lethal endotoxemia
Kellum JA, Song M, Venkataraman R
Crit Care Med. 2004 Mar;32(3):801-5

Removal of other endogenous molecules – Myoglobin

(9) Cytosorb™ in a patient with legionella-pneumonia associated rhabdomyolysis
Wiegele M, Krenn CG.
ASAIO J. 2015; 61 (3): e14-6
(10) In-Vitro Myoglobin Clearance by a Novel Sorbent System
Viktoriya I. Kuntsevich, Donald A. Feinfeld, Pat F. Audia, Wendell Young, Vincent Capponi, Marianna Markella and James F. Winchester
Artificial Cells, Blood Substitutes, and Biotechnology. 2009;37:45-47

Removing the “Fuel to the Fire” of Inflammation in SIRS and Sepsis
As previously mentioned, SIRS is a normally adaptive response to injury and infection.  It is characterized by a hyper-metabolic state that can rapidly deplete the body’s energy stores, not just at a systemic level, but at a cellular level as well.  The SIRS response can become maladaptive when high levels of immune stimulation persist and SIRS continues over a prolonged time.  This can lead to excessive inflammation that can cause cellular and organ injury, while inhibiting proper healing.  This can be seen in the development of organ failure in sepsis, the hypercatabolic state in burn injury, cancer cachexia in end-stage cancers, and the post-operative SIRS response following cardiac surgery.

Born-1024x619_ENThe ongoing triggers of the immune response in life-threatening illnesses include cytokines, anaphylatoxins, PAMPs, DAMPs, acute phase reactants such as C-reactive protein and procalcitonin, platelet activating factor, oxygen radicals, prostaglandins and leukotrienes, and general conditions such as ischemia.  Cytokines are particularly potent, because they trigger the synthesis and release of more cytokines, creating a vicious  upward spiral in the inflammatory cascade.  By removing the “fuel to the fire“ of ongoing inflammation, CytoSorb is designed to modulate the immune response, allowing it to function while removing the dangerous excesses. This can be seen by the reduction in the production of IL-6 post-operatively (1: immediately post-op, 2: Day 1 post-op, 3: Day 2 post-op, 4:  Day 3 post-op) when CytoSorb was used only intra-operatively during complex cardiac surgery. (Ref: 1-4)

Reduction of cytokine storm may have many positive effects
The clinical effects of CytoSorb therapy are only partly based on the direct removal of cytokines and chemokines. CytoSorb can also indirectly reduce the production of cytokines by removing the paracrine stimulus for ongoing cytokine transcription and synthesis. Also, by reducing high levels of circulating cytokines, CytoSorb can also reduce “immune confusion“ and help redirect activated leukocytes away from otherwise healthy tissues and towards the true area of infection, thereby improving source control, while preventing latent organ injury of uninfected organs. (Ref: 5-8)


References 

Damping of excessive acute-phase response

(1) Treatment of post-cardiopulmonary bypass SIRS by hemoadsorption: a case series
Trager K, Fritzler D, Fischer G, Schroder J, Skrabal C, Liebold A, Reinelt H
Int J Artif Organs 2016; 39(3): 141-146
(2) Systemic Inflammatory Response Syndrome in der Herzchirurgie: Neue Therapiemöglichkeiten durch den Einsatz eines Cytokin-Adsorbers während EKZ?
Born F, Pichlmaier M, Peterß S, Khaladj N, Hagl C
Kardiotechnik 2/2014
(3) Feasibility study of cytokine removal by hemoadsorption in brain-dead humans
Kellum JA, Venkataraman R, Powner D, Elder M, Hergenroeder G, Carter M
Crit Care Med. 2008 Jan;36(1):268-7
(4) Effects of hemoadsorption on cytokine removal and short-term survival in septic rats
Peng X, Carter M, Kellum J.A.
Crit Care Med. 2008 May;36(5):1573-7

Reduction of cytokine production
(5) Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-кB DNA binding, and improves short-term survival in lethal endotoxemia
Kellum JA, Song M, Venkataraman R
Crit Care Med. 2004 Mar;32(3):801-5

Redirection of activated leukocytes
(6) Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model
Peng ZY, Bishop JV, Wen XY, Elder MM, Zhou F, Chuasuwan A, Carter MJ, Devlin JE, Kaynar AM, Singbartl K, Pike F, Parker RS, Clermont G, Federspiel WJ, Kellum JA
Crit Care 2014, 18(4):R141
(7) Hemoadsorption reprograms inflammation in experimental gram-negative septic peritonitis: insights from in vivo and in silico studies.
Namas RA, Namas R, Lagoa C, Barclay D, Mi Q, Zamora R, Peng Z, Wen X, Fedorchak MV, Valenti IE, Federspiel WJ, Kellum JA, Vodovotz, Y.
Mol Med 2012; 18:1366-74.
(8) Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis
Peng ZY, Wang HZ, Carter MJ, Dileo MV, Bishop JV, Zhou FH, Wen XY, Rimmelé T, Singbartl K, Federspiel WJ, Clermont G, Kellum JA
Kidney Int. 2012 Feb;81(4):363-9

The clinical impact of CytoSorb therapy is dependent upon the application, the initial clinical situation, and the treatment parameters. CytoSorb is NOT intended to be used as a last resort therapy for end-of-life patients. Rather, it has been used best with rational patient selection, timely usage, and adequate dosing. It is also important that it be used with standard of care medicine, such as source control and early antibiotic use in sepsis, for example. Objectives of CytoSorb therapy are:

Hemodynamic Stabilization (micro- and macro circulation)
A frequently reported effect of CytoSorb therapy has been the stabilization of hemodynamics and mean arterial blood pressure. This is often associated with a marked reduction in vasopressor requirements. The magnitude of cytokine levels appears to play a role in the severity of the hemodynamic disorder and similarly, the extent of reduction appears to correlate with the therapeutic effect. These early observations are currently being evaluated systematically in clinical trials. It is important to note that the effects on hemodynamics may be quite different depending on the clinical picture. (Ref 1 – 10)

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Influence on capillary leak syndrome
High levels of cytokines such as IL-2, TNF-α, and IL-1β, and circulating enzymes, have been implicated in tight junction and glycocalyx disruption and subsequent loss of endothelial integrity. This leads to a common phenomenon seen in critically-ill patients called capillary leak syndrome, that can lead to tissue edema, pulmonary edema and respiratory failure, and an infiltration of inflammatory fluid and cells into the interstitium. Use of CytoSorb hemoperfusion in rat models of sepsis has led to decreased infiltration of leukocytes into the lung compared to untreated controls. In addition, usage of CytoSorb in preliminary in vitro experiments with cultured human endothelial cells suggest a similar protective effect. Clinical observations from a number of published case studies reporting improved hemodynamic stability and reduced oxygen requirements, also support the potential benefit of CytoSorb in helping to prevent, reduce, or even repair capillary leak syndrome. (Ref: 11-16)

Re-direction of cellular immunity
kellum_EActivated leukocytes are an essential part of the immune response to injury or infection. Activated neutrophils, for example, secrete a potent mixture of proteases, toxic oxygen radicals, cytokines, prostaglandins, and leukotrienes that can lead to effective antigen presentation and killing of pathogens. A misdirection of these cells to healthy tissues, as often occurs in sepsis, trauma, and other inflammatory conditions, can lead to rapid cell-mediated organ injury. Seminal work done at University of Pittsburgh in animal models of sepsis demonstrate that a reduction in high levels of circulating cytokines by CytoSorb can “unmask” the true area of infection, allowing improved targeting of activated neutrophils to the site of infection, resulting in reduced bacterial growth, while reducing remote organ injury. The translation of this finding in humans is being pursued. (Ref: 17-18)

Organ protection and treatment of multiple organ dysfunction syndrome (MODS)
The end result of most of the proposed mechanisms of CytoSorb activity is the prevention or treatment of multiple organ dysfunction syndrome (MODS) or multiple organ failure (MOF), the cause of nearly half of all deaths in the ICU. CytoSorb targets this in many ways. For example:

  • Removal of exotoxins and cytotoxic substances such as cytokines, anaphylatoxins, and bile acids that can cause widespread tissue injury or destruction
  • Improved flow of oxygenated blood to tissues through improved hemodynamic stabilty, reduced vasopressor use, improved NO homeostasis, and decreased tissue edema caused by capillary leak syndrome
  • Reduction of nephrotoxins such as myoglobin in rhabdomyolysis and trauma, or free plasma hemoglobin during cardiac surgery
  • Reduction in inflammation may help to spare the central nervous system by improving cerebral perfusion and restoring blood-brain barrier function
  • Reduction in cell-mediated injury to otherwise healthy tissues by reducing “immune confusion“


Control of Peri-operative Inflammation in Cardiac Surgery
CytoSorb has been used hundreds of times either intra-operatively in a bypass circuit in a heart-lung machine in complex cardiac surgeries, or post-operatively using a hemodialysis machine in patients that develop post-operative SIRS. The goal is the same – to prevent post-operative complications and adverse outcomes such as organ dysfunction or failure. In addition to the recent 20 vs 20 retrospective study using CytoSorb intra-operatively during cardiac surgery, showing a statistically significant reduction in inflammatory mediators in the 3 days following surgery, there are many investigator initiated studies enrolling to further evaluate intra-operative use as well as post-operative use of CytoSorb, including a US FDA approved 20 patient feasibility study. (Ref: 19-20)


References

Stabilization of hemodynamics (micro- and macro circulation)
(1) Treatment of post-cardiopulmonary bypass SIRS by hemoadsorption: a case series
Trager K, Fritzler D, Fischer G, Schroder J, Skrabal C, Liebold A, Reinelt H
Int J Artif Organs 2016; 39(3): 141-146
(2) Combination of ECMO and cytokine adsorption therapy for severe sepsis with cardiogenic shock and ARDS due to Panton-Valentine leukocidin-positive Staphylococcus aureus pneumonia and H1N1
Lees NJ, Rosenberg A, Hurtado-Doce AI, Jones J, Marczin N, Zeriouh M, Weymann A, Sabashnikov A, Simon AR, Popov AF
J Artif Organs 2016 epub
(3) Septic shock secondary to β-hemolytic streptococcus-induced necrotizing fasciitis treated with a novel cytokine adsorption therapy.
Hetz H, Berger R, Recknagel P, Steltzer H.
Int J Artif Organs. 2014 37(5): 422-6
(4) CytoSorb, a novel therapeutic approach for patients with septic shock: a case report
Hinz B, Jauch O, Noky T, Friesecke S, Abel P, Kaiser R
Int J Artif Organs 2014 38(8): 461-46
(5) First description of SPAD combined with cytokine adsorption in fulminant liver failure and hemophagocytic syndrome due to generalized HSV-1 infection.
Frimmel S, Schipper J, Henschel J, Yu TT, Mitzner SR, Koball S.
Liver Transpl. 2014 Dec;20(12):1523-4
(6) Use of a novel hemoadsorption device for cytokine removal as adjuvant therapy in a patient with septic shock with multi-organ dysfunction: A case study
Basu R, Pathak S, Goyal J, Chaudhry R, Goel RB, Barwal A
Indian J Crit Care Med 2014;18:822-4
(7) Effects of a novel cytokine haemoadsorbtion system on inflammatory response in septic shock after cephalic pancreatectomy – a case report
Tomescu D, Dima SO, Tănăsescu S, Tănase CP, Năstase A , Popescu M
Romanian Journal of Anaesthesia and Intensive Care 2014;21(2):134-138
(8) Improvement of hemodynamic and inflammatory parameters by combined hemoadsorption and hemodiafiltration in septic shock: a case report.
Mitzner SR, Gloger M, Henschel J, Koball S
Blood Purif. 2013;35(4):314-5.
(9) Effects of hemoadsorption on cytokine removal and short-term survival in septic rats
Peng ZY, Carter MJ, Kellum JA
Crit Care Med. 2008 May;36(5):1573-7
(10) Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-кB DNA binding, and improves short-term survival in lethal endotoxemia
Kellum JA, Song M, Venkataraman R
Crit Care Med. 2004 Mar;32(3):801-5

Influence on capillary leak
(11) Cytokine Reduction in the Setting of an ARDS-Associated Inflammatory Response with Multiple Organ Failure
Trager K, Schutz C,Fischer G, Schroder J, Skrabal C, Liebold A, Reinelt H
Case Rep Crit Care 2016: 9852073
(12) CytoSorb, a novel therapeutic approach for patients with septic shock: a case report
Hinz B, Jauch O, Noky T, Friesecke S, Abel P, Kaiser R
Int J ArtifOrgans. 2015 Sep 18;38(8):461-4
(13) Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model.
Peng ZY, Bishop JV, Wen XY, Elder MM, Zhou F, Chuasuwan A, Carter MJ, Devlin JE, Kaynar AM, Singbartl K, Pike F, Parker RS, Clermont G, Federspiel WJ, Kellum JA.
Crit Care. 2014 Jul 3;18(4):R141
(14) Effect of cytokine hemoadsorption on brain death-induced ventricular dysfunction in a porcine model.
Mikhova KM, Don CW, Laflamme M, Kellum JA, Mulligan MS, Verrier ED, Rabkin DG
J Thorac Cardiovasc Surg. 2013 Jan;145(1):215-24
(15) Hemoadsorption Reprograms Inflammation in Experimental Gram-Negative Septic Peritonitis: Insights from In Vivo and In Silico Studies.
Namas RA, Namas R, Lagoa C, Barclay D, Mi Q, Zamora R, Peng Z, Wen X, Fedorchak MV, Valenti IE, Federspiel WJ, Kellum JA, Vodovotz Y
Mol Med. 2012 Dec 20;18:1366-74
(16) Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis
Peng ZY, Wang HZ, Carter MJ, Dileo MV, Bishop JV, Zhou FH, Wen XY, Rimmelé T, Singbartl K, Federspiel WJ, Clermont G, Kellum JA
Kidney Int. 2012 Feb;81(4):363-9

Re-direction of cellular immune defense
(17) Hemoadsorption Reprograms Inflammation in Experimental Gram-Negative Septic Peritonitis: Insights from In Vivo and In Silico Studies.
Namas RA, Namas R, Lagoa C, Barclay D, Mi Q, Zamora R, Peng Z, Wen X, Fedorchak MV, Valenti IE, Federspiel WJ, Kellum JA, Vodovotz Y
Mol Med. 2012 Dec 20;18:1366-74
(18) Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model.
Peng ZY, Bishop JV, Wen XY, Elder MM, Zhou F, Chuasuwan A, Carter MJ, Devlin JE, Kaynar AM, Singbartl K, Pike F, Parker RS, Clermont G, Federspiel WJ, Kellum JA.
Crit Care. 2014 Jul 3;18(4):R141

Preventing or slowing down an excessive systemic inflammation
(19) Treatment of post-cardiopulmonary bypass SIRS by hemoadsorption: a case series
Trager K, Fritzler D, Fischer G, Schroder J, Skrabal C, Liebold A, Reinelt H
Int J Artif Organs 2016; 39(3): 141-146
(20) Systemic Inflammatory Response Syndrome in der Herzchirurgie: Neue Therapiemöglichkeiten durch den Einsatz eines Cytokin-Adsorbers während EKZ?
Born F, Pichlmaier M, Peterß S, Khaladj N, Hagl C
Kardiotechnik 2/2014