CytoSorb Therapy - Extracorporeal Blood Purification
he CytoSorb therapy* is based on an extracorporeal blood purification procedure that was shown to effectively reduce excessive levels of inflammatory mediators (see “The Adsorber”). This is intended to alleviate the excess systemic inflammatory response (“cytokine storm”) associated with systemic hyperinflammation or septic shock. Thus, the life-threatening complications of a cytokine storm can potentially be avoided and, above all, the stabilization of hemodynamics promoted.
Clinical Aspects
The clinical effects of using CytoSorb therapy are highly dependent on the indication, the clinical situation and the treatment regimen. The therapy is not to be used as a last resort treatment treatment, but rather for its positive clinical effects, especially with careful patient selection, timely use and appropriate use. Existing therapeutic principles, such as focal source removal and early anti-infective therapy in sepsis remain of utmost importance. Goals for the use of CytoSorb therapy are the aimed at the following clinical effects:
Support of hemodynamic stabilization
A frequently described an reproducible effects observed from the removal of cytokines with significant decreases in vasopressor needs as observed in clinical investigations. (Ref: 1-11)
Influence on capillary leak
The reduction in systemic peak cytokine levels might also reduce their impact on the vascular integrity. In preclinical studies, the group led by Dr John Kellum of Pittsburgh (USA) clearly demonstrated this effect, and in vitro measurements on human endothelial cell layers with untreated and treated plasma have tentatively confirmed this. Even previous clinical observations appear to confirm these results. By removing excess cytokines, CytoSorb can help the body potentially stops the passage of fluid, proteins, and immune cells into various tissues and prevents the progression of organ damage. At the same time, the improvement of organ function has been observed may also be promoted by these effects. (Ref: 12-18)
Prevention or mitigation of excess systemic inflammation under extracorporeal circulation
Study results in cardiac surgery patients show that the use of CytoSorb therapy might prevent or significantly reduce systemic inflammation due to the use of the heart-lung machine (HLM). This has previously been seen in pre-clinical projects. The lack of, or greatly reduced, systemic inflammation might then induce less complications, such as hemodynamic instability or secondary organ dysfunction. The precise setting in which this approach is best used is still under investigation. (Ref 21-22)
Product Details
The CytoSorb therapy is an adjunctive therapy. The principles of causal and supportive therapy, such as dealing with the focal source and early anti-infective therapy, of course, retain their outstanding importance even under CytoSorb therapy. While these are primarily intended to treat the infection, CytoSorb was developed to modulate the excess immune response and thereby contribute to circulatory stabilization and increase the chance of recovery.
Safety: CytoSorb therapy has been used more than 152,000 times worldwide in more than 800 clinical departments, and its application has been proven to be well-tolerated and safe. The CytoSorb adsorber can be used for up to 24 hours after which a change is necessary if the treatment indication persists. Patients have been treated for up to seven consecutive days, for 24 hour periods.
Easy to use: The adsorber is a standard whole blood cartridge and can be used with conventional dialysis and hemofiltration equipment, as well as heart-lung machines, extracorporeal life support machines, or as a stand-alone therapy with blood pumps in hemoperfusion mode. The treatment can be prepared after a short training and can be easily integrated into routine procedures.
- Improvement of hemodynamics with significant reduction in catecholamine requirements
- Reduce the excess plasma levels of a variety of inflammatory mediators (including pathogen associated molecular patterns PAMPS and damage associated molecular patterns DAMPs)
- Mitigation of secondary organ failure
Clinical conditions that commonly are associated w...
Clinical conditions that commonly are associated with systemic hyperinflammation include:
Intensive Care:
- Septic and vasoplegic shock
- Toxic shock syndrome, necrotizing fasciitis
- Hemophagocytic Lymphohistiocytosis (HLH)
- Acute Respiratory Distress Syndrome (ARDS)
- Systemic hyperinflammation after cardiac surgery with cardiopulmonary bypass (CPB)
- Cardiogenic shock
- Resuscitation or ECPR
- Polytrauma with high myoglobinemia
- Severe pancreatitis
- Liver failure of various origins (e.g., alcoholic hepatitis, acute liver failure, secondary liver failure)
- Severe burns
- Severe influenza and flu, particular requiring ECMO
- Others
Intraoperative applications in cardiac and thoracic surgery:
- Patients with long, complex procedures aortic dissections, heart transplant, complex combination interventions, re-operations
- Patients with pre-existing activation of the immune system, i.e. endocarditis, shock
- Patients with increased comorbidity including chronic impaired liver and / or kidney function
Therapeutic Aspects
Removal of cytokines
The main focus of CytoSorb therapy* is the removal of cytokines, so inflammatory mediators, from the patient’s blood. With CytoSorb not a single defined cytokine (like e.g. IL-6) is removed, but a broad spectrum of pro- and anti-inflammatory cytokines. This is of particular importance since different messenger substances cause in part redundant effects and previous attempts to reduce individual substances have not proved to be successful.
CytoSorb provides a concentration-dependent removal based on physicochemical mechanisms. At high concentrations of a substances (e.g. cytokines) a high removal efficiency is given and large quantities can be removed very quickly. with decreasing concentrations, the removal efficiency decreases, too. This autoregulation supports to prevent complete removal of physiologic mediators like cytokines, which helps to prevent restoration of a physiologic immune response. Furthermore, while used as intended it was observed a significant removal of C3a and C5a as well as procalcitonin (Ref: 1-10).
Removal of other endogenous molecules
(e.g. myoglobin and bilirubin))
In addition to the removal of cytokines, the removal of substances that play an important role outside the systemic inflammation in the pathophysiology of certain critical diseases has also been identified in several clinical trials. These include:
Myoglobin: Acute renal failure secondary to rhabdomyolysis is the main reason for the desire to rapidly reduce high levels of myoglobin in the patient’s blood. Rhabdomyolysis, a disintegration of muscle fibers with subsequent flooding of muscle proteins and cell components, can occur in trauma, burns, infections or muscle overuse. The 17 kD molecule myoglobin can be effectively removed from the blood using CytoSorb. (Ref: 11-13)
Free hemoglobin: Free hemoglobin, like free iron, is toxic. Hemoglobin released by hemolysis is normally bound to haptoglobin and then degraded. With increasing hemolysis, the binding capacity of haptoglobin is exhausted. Freeing hemoglobin can then no longer be bound and occurs freely in the plasma. Hemolyses can be triggered by mechanical influences (ECMO, HLM), infections / toxins (malaria, streptococci, EHEC), immune reactions (rhesus incompatibility) or other causes. REFRESH I clinical study observed a substantial removal of the substance from the patient’s blood can be achieved with CytoSorb. (Ref: 9)
Bilirubin: Bilirubin and biliverdin are breakdown products of hemoglobin and are massively increased in the blood, if a disproportionate amount of hemoglobin is broken down by haemolysis or if accumulation occurs in the blood due to a liver function or dissolution disorder (cholestasis). Various publications have shown excellent removability of bilirubin (0.6 kDa) by CytoSorb. (Ref: 17-18)
Bile Acids: Bile acids, or their accumulation in plasma, play a significant, previously often underestimated role in critical diseases, e.g. Sepsis, systemic inflammation and liver failure. During use of CytoSorb decrease of bile acids was observed which could have the effect of prevention of toxic effects (Ref: 19).
Removal of exogenous molecules
Various preclinical and clinical investigations have observed substantial removal of the following exogenous molecules. Use of CytoSorb in an attempt to adsorb substances other than cytokines, bilirubin, myoglobin, ticagrelor, or rivaroxaban is considered off-label use and is the sole liability of the treating physician after individual risk benefit assessment. The list below, however, is also providing safety information on potential side effects and interactions by unwanted drug/substance removal.
Enterotoxins: Enterotoxins can also be used as biological weapons. It has been observed that CytoSorb quickly and safely removes a number of these toxins from the blood. (Ref: 20)
Medicines: Substances which are either intended to replace naturally occurring substances in the human body because of a deficiency, or which are to induce certain effects on account of their chemical properties, are subject to the same physical laws of transport, metabolization and excretion as endogenous substances. Like other extracorporeal blood purification methods, e.g. Dialysis or hemofiltration, CytoSorb was also observed to interact with both endogenous and exogenous molecules in the blood. The influence of CytoSorb on certain drugs should be considered when dosing and ensuring drug therapies. This can also be used to advantage in certain drugs for the removal of undesirably high plasma levels due to overdose or intoxication.
In this context, successful therapeutic trials for venlaflaxin overdoses are published. In addition, in patients who need to undergo emergency intervention while receiving treatment with P2Y12-Inhibitor Ticagrelor or Factor Xa-Inhibitor Rivaroxaban, the intraoperative removal of the substance during cardio-pulmonary bypass by CytoSorb was shown to reduce bleeding complications. (Ref: 21-26)
Metabolic Aspects
Attenuation of the excessive acute phase reaction
The acute phase reaction is a nonspecific immune response of the body and part of the inflammatory response. An excessive acute phase response is associated with a number of potential complications.
These relate in particular to coagulation and microcirculation disorders with consequent deterioration of tissue oxygenation and secondary organ dysfunction due to impaired homeostasis. The attenuation of an excessive acute phase reaction by removal of elevated levels of cytokines is the primary approach with CytoSorb therapy. (Ref: 1-5)
Fields of Application
CytoSorb Therapy can potentially help in the following clinical settings:
CytoSorb therapy* is designed to help manage the serious complications caused by excessively high levels of cytokines that can lead to a hyperinflammatory condition. This constellation of life-threatening complications is found in a variety of clinical situations, as systemic inflammation is a common feature in many critical acute conditions. An excessive systemic immune response can lead to shock, multiple organ failure, and death in many of these syndromes.
Apart from the use in patients with septic shock and vasoplegic shock in the context of non-infectious triggers (e.g. cardiac surgery patients) there are published data on the use of CytoSorb in:
CytoSorbents focuses on two major areas of application:
- Septic shock
- Vasoplegic shock in the context of non-infectious triggers (e.g., cardiac surgery patients)
Other areas of application where systemic hyperinflammation exists are:
- Polytrauma and severe burns
- Severe acute pancreatitis
- Different types of liver failure
- Severe cardiogenic shock
Antithrombotic removal
Ticagrelor/rivaroxaban removal during cardiopulmonary bypass to reduce the bleeding risk
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