Q&A

The CytoSorb Therapy

CytoSorb is, in contrast to other blood purification technologies, the only whole blood adsorber which is explicitly CE approved for the removal of specific substance groups. For this purpose, the CytoSorb adsorber is quickly and easily integrated into an extracorporeal circuit.

  • Along with cytokines, other inflammatory mediators such as chemokines are also removed.
  • Substances such as free hemoglobin, myoglobin, bilirubin and bile acids, bioactive lipids, antibody light chains, toxins, bacterial exotoxins (toxins such as shiga, alpha-hemolysin, gas gangrene, diphtheria) and other toxic metabolites can be removed by the CytoSorb adsorber.

CytoSorb is indicated intraoperatively during surgical procedures involving cardiopulmonary bypass for the removal of the P2Y12 inhibitor ticagrelor and/or the Factor Xa inhibitor rivaroxaban.

Yes. CytoSorb can generally remove hydrophobic substances with a molecular weight of up to approx. 60 kDa. Due to the concentration-dependent removal, substances at high concentrations are removed more effectively than those at low concentrations. This autoregulation protects against the uncontrolled removal of endogenous substances and helps maintain the physiological immune response.

  • The spectrum of removable substances includes both pro- and anti-inflammatory mediators with elevated plasma levels. Physiologically important plasma components such as albumin are removed – as shown in studies – but only in non-clinically relevant quantities.
  • The CytoSorb therapy is intended to reduce the excessive immune response. Inflammatory mediators are reduced and thereby modulation of the immune system is effected.
  • As described in the literature, high concentrations of both pro- and anti-inflammatory cytokines are associated with high mortality.

The key to preventing and treating secondary organ failure is to prevent or minimize the impact of the cytokine storm on primary non-diseased tissues (remote organs).

Based on current knowledge, it can be assumed that:

  • A reduction in cytokines and mediators in the plasma by removal and also by reduced new production takes place.
  • Improved hemodynamics (macro- and microcirculation), thereby reducing catecholamine requirements.
  • A positive effect on capillary leak syndrome can be achieved by reducing cytokine levels (integrity of the glycocalyx).
  • By lowering levels of cytokines and inflammatory mediators, the cause of any inflammation-related tissue damage and resulting (multiple) organ dysfunction is favorably influenced. This should favorably influence the otherwise very high morbidity and mortality.
  • The immune response is remodulated and immune cells are redirected to the inflammatory focus: CytoSorb restores the chemokine gradient responsible for leukocyte migration to the focus (infection or tissue damage). This allows the inflammatory focus to be unmasked and the previously systemic immune response to be refocused more strongly on the local focus.

No. CytoSorb does not remove endotoxin, which is primarily involved in gram-negative sepsis.

  • In contrary to endotoxin adsorbers, CytoSorb can also be used for gram-positive bacterial sepsis, and other systemic infections (viruses, fungi, parasites).
  • In addition to cytokines, exotoxins such as the diphtheria toxin, alpha-hemolysin, Clostridium perfringens toxin or Shiga toxin can also be effectively removed from the circulation using CytoSorb.
  • In addition, CytoSorb can be used for all non-infectious causes of systemic hyperinflammation syndrome (e.g.: polytrauma, burn injuries, inhalation trauma, pancreatitis)

No. CytoSorb is an adsorber technology in which substances selectively bind physicochemically to the adsorbent material (hydrophobic molecules with a molecular weight of up to approximately 60 kDa).

Adsorber:

  • CytoSorb is a “blood in – blood out” product (whole blood adsorber). There is no secondary circulation with albumin, no dialysate, no ultrafiltrate.
  • Hydrophobic substances with a molecular weight of up to approx. 60 kDa are adsorbed on the surface within the porous structure of the polymer beads.

Hemofilter/Dialyzer:

  • Water-soluble substances are filtered out of the blood.
  • Dialyzers are based on the principles of diffusion and convection.
  • Blood components interact with a dialyzing solution through a semipermeable membrane.
  • High cut-off membranes have higher thresholds for the elimination of substances. In addition to the desired substances, however, useful molecules such as albumin can also be removed in the process.

CytoSorb is CE certified and can be used in all countries where this is the basis for use or for local registration.

Please check availability and our representative in your country https://cytosorb-therapy.com/en/about-us/cytosorbents-worldwide/

The adsorbers should be stored in its outer packaging, at an ambient temperature between 1- 40° C. If possible, the adsorber should be stored upright so that gas bubbles, which can arise e.g. due to temperature fluctuations, migrate upwards to the outlet.

CytoSorb can be disposed of together with potentially infectious waste, as with dialysis filters and infusion systems.

  • Local hygiene guidelines apply.
  • Bacterial colonization of the cartridge’s contents are not a concern, even when used in septic patients.
  • CytoSorb does not contain any toxic ingredients that would prevent disposal with other standard infectious waste.
  • From a hygienic point of view, the adsorber should be used as soon as possible after priming. Basically, the adsorber should be handled according to hygienic guidelines, similar to prepared infusion solutions or extracorporeal circulation systems ready for use.
  • When handled hygienically, CytoSorb with the adapters is similar to the extracorporeal system itself. Identical materials are used from the material side.
  • Data on hygiene beyond the maximum 24 h specified in the IFU are not available.
  • The adsorber should be changed after a maximum of 24 hours to ensure sufficient capacity for adsorption. It may make sense to change the adsorber earlier if the adsorber becomes saturated during therapy in severe cases (e.g.: an increasing need for vasopressors again, …).
  • In the current version of the CytoSorb therapy booklet “Indications & Practical Aspects” it is recommended: “Treatment duration and indication for adsorber exchange depend on the clinical course. The maximum treatment time per adsorber is 24h.”
  • The instructions for use (IFU) of a medical device, identical to those of a drug, are part of the approval documents which are reviewed by the notified body during CE approval and which contain the intended purpose, indication, type of use and safety instructions. Accordingly, these specifications are binding for “on-label use”, i.e. use in accordance with the approval.
  • In the case of so-called “off-label use”, physicians can also use a medical device for other indications within its specifications as defined in the IFU and individual risk-benefit considerations. The treating physician assumes liability for the indication.
  • Use of a medical device outside its specification is not permitted.
  • e.g. blood flow rate < 100 ml/min or > 700 ml/min during CytoSorb therapy.
  • Introductions and other sources of information such as: Quick Setup Guides map the specifications of the IFU.

Fields of Application

  • The use of CytoSorb is indicated in the presence of excessive cytokine and/or bilirubin and/or myoglobin levels in the blood. CytoSorb is also indicated for intraoperative removal of the P2Y12 inhibitor ticagrelor and the factor Xa inhibitor rivaroxaban during cardiopulmonary bypass.

CytoSorb is currently used regularly primarily in two main indications:

  • Therapy-refractory septic and vasoplegic shock.
  • Cardiac surgery intra- and postoperatively

CytoSorb has also been used successfully in hyperinflammatory conditions of a non-infectious origin. A number of case series and case reports on the initial clinical use in some of the areas listed below have been presented or published:

  • Polytrauma and rhabdomyolysis.
  • Severe burns
  • Severe acute pancreatitis
  • Various types of liver failure
  • Severe cardiogenic shock
  • Complications of cardiac surgery
  • Necrotizing fasciitis

Systemic hyperinflammation associated with ECMO therapy.

Clinical experience and data to date indicate that:

  • Treatment should begin in the early phase of septic shock or systemic hyperinflammation (early SIRS), when organ dysfunction is still inflammatory and thus reversible.
  • CytoSorb use is less effective in cases of pre-existing irreversible organ failure.

CytoSorbents offers a “best practice” guide (not evidence-based) for patient selection. Basically, “It is better to prevent organ failure than to treat it.”

General indicators for CytoSorb therapy may include:

  • Disease pattern of systemic hyperinflammation.
  • Patient is a non-responder with respect to standard medical treatment.
    Possible clinical criteria:
  • Norepinephrine > 0.3 μg/kg/min or rapidly increasing requirements within the last 24 hours.
  • Signs of a pronounced capillary leak – e.g.: marked positive fluid balance.
  • A high Interleukin-6 level (e.g., > 500 pg / ml) may support the treatment decision, but also low levels do not preclude the usefulness of treatment.


In case of doubt, the clinical picture of the patient should always be decisive when determining the indication and assessing the effectiveness of CytoSorb therapy.

The evaluation of therapy success is primarily based on the clinical course.

Signs of therapy success can be,
for example:
• Stabilization in hemodynamics
– Decrease in vasopressor requirements (or no further dose increases necessary).
– Decrease in fluid requirements.
– No further increase in lactate levels.

• Decrease in Interleukin-6 (if measured) and other inflammation/infection parameters (leukocytes, Procalcitonin (PCT), C-Reactive Protein):
– When assessing PCT progression, note that PCT is partially removed directly by CytoSorb.
Accordingly, an increase in PCT during ongoing CytoSorb therapy should be critically evaluated.

• Stabilization in other organ functions:
– No further deterioration in liver function (synthesis and detoxification).
– No increase in respiratory support necessary.
– Improvement of the coagulation situation.

The duration of CytoSorb treatment depends on the patient’s clinical improvement:

  • CytoSorb treatment should be continued until stabilization:
    – No need or sharply decreasing catecholamine doses.
    – Reversal of fluid balance.
    – Normalization of lactate levels.
  • – Improvement in impaired organ function:
    – Significant reduction in ventilatory support.
    – Improvement in liver function.
  • Worsening of condition after cessation of CytoSorb treatment may indicate the need to resume CytoSorb therapy (inadequate focal control or “second hit”).
  • A patient-specific decision must be made as to how long to treat with CytoSorb.
  • CytoSorb has a particularly positive effect in most cases if therapy can be started as early as possible.
  • Please reconsider the use in patients who are already in therapy-refractory shock for several days.

Indication

CytoSorb can be combined with standard hemoperfusion devices, CRRT devices, ECMO/ECLS systems or heart-lung machines commonly already available in hospitals.

  • Preparation and set-up require only a few minutes.
  • For this purpose, the CytoSorb adsorber cartridge is safely and easily integrated into an existing extracorporeal circulation (ECC) system.
  • CytoSorb can be used in alone hemoperfusion mode or in combination with dialysis filters.
  • Standardized adapter kits for preparation and integration into different ECC systems are available.

All staff involved in CytoSorb therapy must be trained by the manufacturer or qualified distributors in accordance with legal requirements regarding set-up, operation and safety.

The same access is needed to basically operate an extracorporeal circuit. Accordingly, the access chosen must be suitable for this. CytoSorb is always integrated into an extracorporeal circuit. It is up to the physician to decide where suitable access is to be established for this purpose.

  • The safety and effectiveness of CytoSorb therapy is not dependent on the puncture site.
  • The requirements of the extracorporeal circulation are
    dependent on the type of
    catheterization.
  • Ideally, vascular access should allow the extracorporeal circulation to maximize blood flow.

The recommended blood flow rate is between 150 to 700 ml/min. The minimum blood flow rate is 100 ml/min. Please refer to the primary circuit manufacturer’s instructions for use.

Yes, it is possible with a CRRT system.

  • CytoSorb is a single use product.
  • Interruption of therapy e.g.: in CRRT systems is possible as long as the adsorber remains part of the extracorporeal circuit. Return the blood from the extracorporeal circuit to the patient as prescribed by the CRRT circuit manufacturer. Allow the CRRT device to circulate even whilst no patient is connected. Local hygiene guidelines and specifications of the machine manufacturer apply.
  • Removal of the CytoSorb cartridge (e.g. from the Heart Lung Machine) and reinstallation into another system is not permitted for hygienic reasons.

Therapy control

Treatment is possible with both heparin and citrate. If CytoSorb is used as a stand-alone therapy, only heparin may be used for anticoagulation. Citrate is contraindicated in this setup.

In general, no special protocol adjustments are required for CytoSorb. The device manufacturer’s instructions must be followed.

In case of systemic anticoagulation with heparin the following applies:

In principle, anticoagulation must be effective before starting treatment. This means: Firstly, raising the aPTT to the target value and secondly starting the extracorporeal procedure.

Recommended target values when using heparin:

  • aPTT: 60-80 sec (activated partial thromboplastin time. This value corresponds to 2-3 times the baseline value).
  • ACT: 160-210 sec (activated clotting time standard value 100-130 sec)
  • AT III: 75-120% (antithrombin III)
  • Caution: HIT (heparin-induced thrombocytopenia).

These target values are controlled according to the respective standards of the critical care unit. The decision regarding dosage and target values is always the responsibility of the attending physician.

For regional anticoagulation with citrate, the following applies:

  • Initial dose, blood flow rate, control and adjustment of calcium and citrate is according to protocol.
  • Citrate and calcium are added at the usual points of the extracorporeal circulation.
  • Control of ionized calcium (CRRT circuit and patient) a few minutes after the start of treatment and at regular intervals of between 8 – 12 hours is recommended.

The decision regarding dosage and target levels is always the responsibility of the treating physician.

The use of IL-6 as a surrogate marker for clinical assessment is possible. However, the absolute level of the baseline value does not necessarily reflect the severity of the disease.
The course of the IL-6 value should always be considered in the context of the patient’s clinical picture.

  • In case of doubt, the patient’s clinical picture should always be decisive in determining the indication and assessing the effectiveness of CytoSorb therapy.
  • Cytokine levels can only be meaningfully assessed during the course of the therapy, but not on the basis of a single measurement.
  • After the IL-6 blood sample has been taken, the sample must be:immediately cooled and transported to the laboratory for immediate measurement or frozen for delayed measurement.
  • IL-6 has a very short half-life (in the range of minutes).

The duration of CytoSorb therapy should be based on the clinical evolution of the patient, not just on individual parameters. Significantly decreasing infection markers and decreasing catecholamine requirements, possibility of a negative fluid balance, decreasing ventilatory invasiveness and other factors characterize an improvement in the clinical picture

Yes, this can occur under certain circumstances and may indicate,

  • That the cause of cytokine release persists (e.g., insufficient focal control), or
  • A new trigger for systemic hyperinflammation has occurred.

CytoSorb therapy itself does not trigger a specific rebound effect.

Reimbursement

Information on reimbursement in Germany can be found here, for all other countries please contact us.

Studies

A number of studies on various CytoSorb indications (e.g. cardiac surgery, sepsis, pancreatitis) are currently being conducted in collaboration with well-known scientific partners. For an overview of already published literature on Cytosorb-Therapy, please visit our literature database:

https://literature.cytosorb-therapy.com

Further information also available at:
www.clinicaltrials.gov Search term: CytoSorb
https://cytosorb-therapy.com/en/the-studies/monocenter-studies/

Further clinical studies are in preparation.

A collection of publications with different levels of evidence, abstracts and links to articles can be found in our CytoSorb Literature Database. 

literature.cytosorb-therapy.com

  • To date, all clinical publications have reported on the safety of the procedure.
  • As of Januar 2022, there are more than 750 papers on CytoSorb therapy recorded. Of these, 276 papers have peer reviewed status.
  • With over 162,000 individual applications in various patient populations as of January 2022, CytoSorb has a very favorable safety profile.  There are no “confirmed unexpected device related Severe Adverse Events.”

It can be assumed that CytoSorb therapy is a safe and well-tolerated treatment.

 

 
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