Hemoadsorption Device Research Articles

CytoSorb hemoadsorption of apixaban during cardio-pulmonary bypass for heart transplantation

IntroductionHeart transplantation is an emergency surgery requiring cardio-pulmonary bypass (CPB) and its timing is unpredictable. Patients on the transplant waiting list often have multiple reasons for being anticoagulated. Direct oral anticoagulants (DOACs) such as apixaban are very popular due to their well-known advantages. Intraoperative removal of apixaban using CytoSorb® (CytoSorbents Inc., Princeton, NJ, USA), seems to be an interesting solution for patients on DOACs requiring an emergency CPB intervention. The aim of this short communication is to describe the perioperative effects of the use of the CytoSorb® hemoadsorption device during emergency CPB for a heart transplant patient Case presentationA 61-year-old male patient (75kg/173cm) wait-listed for heart transplantation was admitted to our hospital (Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France) to benefit from a heart transplantation. This patient, with many comorbidities, has an end-stage heart failure with multiple episodes of decompensation over the previous year. He was anticoagulated with a Vitamin K antagonist (VKA) due to atrial fibrillation and was switched to apixaban (5mg twice daily) 9 days before surgery based on poor clotting control. A NaCl 0.9% primed CytoSorb cartridge was inserted into the CPB circuit. Hemoadsorption was performed during the entire CPB duration. Anti-Factor Xa Activity (AFXaA) levels were taken at multiple time points before, during and after surgery in order to monitor anticoagulation. Results. Preoperatively, activated Clotting Time (ACT) was 146 seconds. The ACT reached 545 seconds after administration of 25,000IU of unfractionated heparin (UFH). Surgery consisted of an orthotopic heart transplantation with bi-caval anastomoses.CPB duration was 133 minutes with 83 minutes of aortic cross clamping. Total graft ischemic time was 249 minutes. At the time of anesthesia induction and after UFH administration, AFXaA levels were 330ng/mL and 317ng/mL, respectively. Thereafter, AFXaA decreased to 137ng/mL during CPB and to 57ng/mL after the end of CPB and 250mg (=25,000IU) of protamine administration.After surgery, AFXaA levels stabilized over 50ng/mL over the next 14 hours. Postoperative anticoagulation was performed with the use of UFH starting 6 hours after surgery.No primary graft dysfunction (PGD) was observed, and during the post-operative period of 72 hours, the patient did not have any bleeding events requiring reintervention or transfusion. ConclusionIn conclusion, we observed that CytoSorb® could be a potential solution to remove apixaban intraoperatively. If this efficacy is confirmed in larger trials, it would allow transplant candidates to be treated with DOACs without requiring a switch to VKAs.

#1398 Linezolid adsorption during in vitro model of hemoadsorption with mini-module of HA380 cartridge

Abstract Background and Aims Septic shock is one of the most frequent causes in Intensive Care Unit (ICU) admission and is related to a very high risk of mortality. About one third of patients with sepsis develops acute kidney injury (AKI) which contributes to a worsening prognosis. AKI due to sepsis is the result of a dysregulated host immune response to infection, with the production of inflammatory mediators and cytokines that cause hemodynamic alterations, endothelial damage, apoptosis and, finally, immunoparalysis. The Jafron HA380 cartridge has been specifically designed for use in clinical conditions characterized by cytokine storm such as sepsis. Given the growing application of these hemoadsorption device in cases of septic AKI in ICU, an unsolved problem is whether these polymers adsorb drugs, including antibiotics. In vitro experiments were conducted to determine its adsorption capacity towards Linezolid (LZD) antibiotic. Method In vitro circulation was performed using a dedicated testing platform Galileo. A customized cartridge was built assembling mini-module components scaled in dimension towards HA380 and filled with 75 g of HA380 beads (25% of the regular size cartridge). Peristaltic pump was set at 250 mL/min. Four circulations were performed varying the initial mass of Linezolid in the tested solution (200, 400, 600, 1200 mg). Samples were collected after the first passage (FP) through the cartridge and every 5 or 10 minutes and Linezolid concentrations were measured. Adsorption was assessed considering the Removal Ratio (RR) and its kinetics. Results In vitro circulation confirms the affinity of beads material in binding Linezolid molecules. The kinetics shows an instantaneous and rapid adsorption in the very first part of the experiments. After that the adsorption rate decreases due to the decrease of antibiotic available in the solution. Among all the experiments, after the first passage of the solution through the cartridge, a RR higher than 70% has been achieved. After 100 passages of the solution into the cartridge, the adsorption reached about the 100% of RR. None of the amounts of Linezolid tested led to the cartridge saturation. A linear behavior between the mass injected in the solution and the mass adsorbed can be ascribable to the linear phase of Langmuir isotherm (see Fig.). Conclusion HA380 adsorbs significant amounts of Linezolid. The linear trend of the isotherm reveals a direct proportionality between binding sites of the sorbent material and the Linezolid tested. Further investigation using a higher quantity of Linezolid is necessary to reach the saturation of the cartridge and to understand the sorbent material capacity. These preliminary results highlight that there is an interaction that could affect the clinical outcome.

Adjunctive Hemoadsorption Therapy with CytoSorb in Patients with Septic/Vasoplegic Shock: A Best Practice Consensus Statement

A dysregulated host response is a common feature in critically ill patients due to both infectious and non-infectious origins that can lead to life-threatening organ dysfunction, which is still the primary cause of death in intensive care units worldwide. In its course, pathologic, unregulated levels of inflammatory mediators are often released into the circulation, a phenomenon also referred to as a “cytokine storm”. To date, there are no approved therapies to modulate the excessive immune response and limit hyperinflammation with the goal of preventing related organ failure and death. In this context, extracorporeal blood purification therapies aiming at the alteration of the host inflammatory response through broad-spectrum, non-selective removal of inflammatory mediators have come into focus. A novel hemoadsorption device (CytoSorb®, CytoSorbents Inc., Princeton, NJ, USA) has shown promising results in patients with hyperinflammation from various origins. Although a significant body of literature exists, there is ongoing research to address many important remaining questions, including the optimal selection of patient groups who might benefit the most, optimal timing for therapy initiation, optimal schedule for adsorber exchanges and therapy duration, as well as an investigation into the potential removal of concomitant antibiotics and other medications. In this review, we discuss the existing evidence and provide a consensus-based best practice guidance for CytoSorb® hemoadsorption therapy in patients with vasoplegic shock.

Cost-Effectiveness and Budget Impact of a Novel Antithrombotic Drug Removal System to Reduce Bleeding Risk in Patients on Preoperative Ticagrelor Undergoing Cardiac Surgery.

Antithrombotic drugs, including the P2Y12 inhibitor ticagrelor, increase the risk of perioperative bleeding in patients requiring urgent cardiac surgery. Perioperative bleeding can lead to increased mortality and prolong intensive care unit and hospital stays. A novel sorbent-filled hemoperfusion cartridge that intraoperatively removes ticagrelor via hemoadsorption can reduce the risk of perioperative bleeding. We estimated the cost-effectiveness and budget impact of using this device versus standard practices to reduce the risk of perioperative bleeding during and after coronary artery bypass grafting from the US healthcare sector perspective. We used a Markov model to analyze the cost-effectiveness and budget impact of the hemoadsorption device in three cohorts: (1) surgery within 1 day from last ticagrelor dose; (2) surgery between 1 and 2 days from last ticagrelor dose; and (3) a combined cohort. The model analyzed costs and quality-adjusted life years (QALYs). Results were interpreted as both incremental cost-effectiveness ratios and net monetary benefits (NMBs) at a cost-effectiveness threshold of $100,000/QALY. We analyzed parameter uncertainty using deterministic and probabilistic sensitivity analyses. The hemoadsorption device was dominant for each cohort. Patients with less than 1 day of washout in the device arm gained 0.017 QALYs at a savings of $1748(USD), for an NMB of $3434. In patients with 1-2 days of washout, the device arm yielded 0.014 QALYs and a cost savings of $151, for an NMB of $1575. In the combined cohort, device gained 0.016 QALYs and a savings of $950 for an NMB of $2505. Per-member-per-month cost savings associated with device was estimated to be $0.02 for a one-million-member health plan. This model found the hemoadsorption device to provide better clinical and economic outcomes compared with the standard of care in patients who required surgery within 2 days of ticagrelor discontinuation. Given the increasing use of ticagrelor in patients with acute coronary syndrome, incorporating this novel device may represent an important part of any bundle to save costs and reduce harm.

Intraoperative ticagrelor removal via hemoadsorption during on-pump coronary artery bypass grafting

ObjectivesPatients on ticagrelor undergoing urgent cardiac surgery are at high risk for perioperative bleeding complications. We sought to determine whether intraoperative hemoadsorption could remove ticagrelor and lower circulating drug concentrations. MethodsThe hemoadsorption device was incorporated in the cardiopulmonary bypass (CPB) circuit and remained active for the duration of the pump run. Blood samples were collected before and after CPB. The main objective of the current analysis was to compare mean total plasma ticagrelor levels (ng/mL) at baseline with ticagrelor levels obtained at the end of CPB. Plasma ticagrelor levels were measured at a certified outside laboratory (LabConnect). Data are presented as mean ± standard deviation. ResultsA total of 11 patients undergoing urgent coronary artery bypass grafting at 3 institutions were included (mean age, 67.9 ± 9.9 years; 91% male; mean European System for Cardiac Operative Risk Evaluation II of 3.0 ± 3.3%; range, 0.7%-12.4%). Mean intraoperative hemoadsorption duration was 97.1 ± 43.4 minutes with a mean flow rate through the device of 422.9 ± 40.3 mL/min. Mean ticagrelor levels pre-CPB were 103.5 ± 63.8 ng/mL compared with mean post-CPB levels of 34.0 ± 17.5 ng/mL, representing a significant 67.1% reduction (P < .001). Intraoperative integration of the device was simple and safe without any device-related adverse events reported. ConclusionsThis is the first in vivo report demonstrating that intraoperative hemoadsorption can efficiently remove ticagrelor and significantly reduce circulating drug levels. Whether active ticagrelor removal can reduce serious perioperative bleeding in patients undergoing urgent cardiac surgery is currently being evaluated in the double-blinded, randomized Safe and Timely Antithrombotic Removal–Ticagrelor (STAR-T) trial.

CytoSorb hemoperfusion markedly attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo

BackgroundThe CytoSorb hemoadsorption device has been demonstrated to be capable of clearing inflammatory cytokines, but has not yet been shown to attenuate plasma cytokine concentrations. We investigated the effects of CytoSorb hemoperfusion on plasma levels of various cytokines using the repeated human experimental endotoxemia model, a highly standardized and reproducible human in vivo model of systemic inflammation and immunological tolerance induced by administration of bacterial lipopolysaccharide (LPS).MethodsTwenty-four healthy male volunteers (age 18–35) were intravenously challenged with LPS (a bolus of 1 ng/kg followed by continuous infusion of 0.5 ng/kg/hr for three hours) twice: on day 0 to quantify the initial cytokine response and on day 7 to quantify the degree of endotoxin tolerance. Subjects either received CytoSorb hemoperfusion during the first LPS challenge (CytoSorb group), or no intervention (control group). Plasma cytokine concentrations and clearance rates were determined serially. This study was registered at ClinicalTrials.gov (NCT04643639, date of registration November 24th 2020).ResultsLPS administration led to a profound increase in plasma cytokine concentrations during both LPS challenge days. Compared to the control group, significantly lower plasma levels of tumor necrosis factor (TNF, − 58%, p < 0.0001), interleukin (IL)-6 ( − 71%, p = 0.003), IL-8 ( − 48%, p = 0.02) and IL-10 ( − 26%, p = 0.03) were observed in the CytoSorb group during the first LPS challenge. No differences in cytokine responses were observed during the second LPS challenge.ConclusionsCytoSorb hemoperfusion effectively attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo, whereas it does not affect long-term immune function. Therefore, CytoSorb therapy may be of benefit in conditions characterized by excessive cytokine release.

Effect of Continuous Renal Replacement Therapy with the oXiris Hemofilter on Critically Ill Patients: A Narrative Review.

Critically ill patients with sepsis and severe COVID-19 are commonly characterized by a dysregulated immune response and an acute kidney injury. Continuous renal replacement therapy (CRRT) is now proposed as a promising adjuvant therapy to treat these critically ill patients by removing cytokines, pathogen-associated molecular patterns, and damage-associated molecular patterns from the blood. Although multiple hemofilters, including high-cutoff membranes, the oXiris hemofilter, the CytoSorb hemoadsorption device, and the Toraymyxin hemoperfusion cartridge, have been used in current clinical practice, the use of the oXiris hemofilter in critically ill patients is of particular interest because it is the only kind of hemofilter that can provide renal replacement therapy, remove endotoxins, and adsorb cytokines simultaneously. During the past five years, a growing body of literature has shown that CRRT with the oXiris hemofilter can improve hemodynamics and organ function and can decrease cytokines and endotoxins in both septic and COVID-19 patients. Here, we performed a narrative review to describe the development history of the oXiris hemofilter and to discuss the therapeutic effect of oXiris-CRRT on critically ill patients by searching the PubMed, Web of Science, and clinicaltrials.gov databases for articles published from inception to 8 September 2022 (updated on 1 November) with an English language restriction. We also summarized the current knowledge on anticoagulation techniques and safety concerns when delivering oXiris-CRRT sessions.

Blood purification therapy in patients with severe COVID-19 requiring veno-venous ECMO therapy: A retrospective study.

Patients with severe manifestations of COVID-19 might exhibit characteristics of a sepsis-like syndrome that can progress to multiple organ failure and ultimately death. Underlying mechanism have been explored and suggest a profound dysregulation of the immune system associated with hyperinflammation, hemodynamic instability and respiratory failure. Besides standard intensive care treatment, approaches modulating the dysregulated immune response, such as CytoSorb hemoadsorption, have been used. However, data of ECMO-dependent patients in comparison to a control cohort remain scarce. Included were 26 critically ill COVID-19 patients requiring high-flow veno-venous extracorporeal membrane oxygenation (high-flow VV ECMO) therapy due to severe acute respiratory distress syndrome (ARDS), of whom 16 were additionally treated with an extracorporeal hemoadsorption device, and compared to a control group of 10 patients. Assessed were levels of inflammatory markers, vasopressor requirements, oxygenation parameters, as well as clinically relevant outcome variables. Data were prospectively recorded and retrospectively analyzed. Treatment with the applied multimodal therapy approach resulted in a stabilization in hemodynamics, a control of the hyperinflammatory response as evidenced by a significant reduction in inflammatory mediators, as well as a marked improvement in lung function. No device related adverse events were observed while treatment appeared safe and feasible. Treatment of a critically ill COVID-19 ARDS patients with combined VV ECMO support and hemoadsorption therapy led to a rapid and sustained hemodynamic stabilization, a control of the uncontrolled inflammatory response and an improvement in oxygenation. Given these signals pointing toward a patient-oriented benefit of extracorporeal hemoadsorption therapy in those patients, future controlled, randomized studies should focus on the investigation of the appropriate timing and dosing of this promising treatment modality.

Mechanistic Considerations and Pharmacokinetic Implications on Concomitant Drug Administration During CytoSorb Therapy.

OBJECTIVE:The CytoSorb hemoadsorption device (CytoSorbents Inc, Monmouth Junction, NJ) is increasingly used in many critical disease states. The potential impact on the pharmacokinetic (PK) of concomitantly administered drugs must be considered in clinical practice. The current review summarizes relevant mechanistic principles, available preclinical and clinical data, and provides general guidance for the management of concomitant drug administration during CytoSorb therapy.DATA SOURCES:Detailed search strategy using the PubMed and OVID MEDLINE databases, as well as presented congress abstracts for studies on drug removal by the CytoSorb device.STUDY SELECTION:Human, animal, and bench-top studies with PK or drug-removal data during CytoSorb therapy were selected for inclusion. Publications reporting on CytoSorb treatments for drug overdose were not considered.DATA EXTRACTION:Relevant PK data were examined and synthesized for narrative review.DATA SYNTHESIS:To date, PK data during CytoSorb hemoadsorption are available for more than 50 drugs, including analgesics, antiarrhythmics, anticonvulsants, antidepressants, antihypertensives, antiinfectives, antithrombotics, anxiolytics, and immunosuppressants. Based on available PK data, drugs were categorized into low (<30%), moderate (30–60%), or high rates of removal (>60%), or, alternatively, according to clearance increase relative to endogenous clearance: negligible (<25%), low (25–100%), moderate (100–400%), or high (>400%). In most reports, additional impact of the extracorporeal platform where CytoSorb was integrated was not available. Based on available data and considering drug, patient, and setup-specific aspects, general dosing guidance for clinical practice was developed.CONCLUSIONS:CytoSorb therapy may increase drug elimination through active removal. However, the extent of removal is heterogeneous, and its clinical significance, if any, depends on the broader clinical context, including a patient’s specific endogenous drug clearance and the underlying extracorporeal platform used. The available data, although not definitive, allow for general guidance on dosing adjustments during CytoSorb therapy; however, any treatment decisions should always be complemented by clinical judgment and therapeutic drug monitoring, when available.

Rationale and design of the safe and timely antithrombotic removal - ticagrelor (STAR-T) trial: A prospective, multi-center, double-blind, randomized controlled trial evaluating reductions in postoperative bleeding with intraoperative removal of ticagrelor by the drugsorb™-ATR device in patients undergoing cardiothoracic surgery within 48 hours from last ticagrelor dose

Ticagrelor is often administered to patients with acute coronary syndromes. However, when these patients require urgent or emergent cardiothoracic (CT) surgery the presence of ticagrelor significantly increases surgical bleeding. The goal of the current trial is to evaluate the effectiveness and safety of the DrugSorb-ATR hemoadsorption device for the intraoperative removal of ticagrelor to reduce postoperative bleeding in the above patient population. The Safe and Timely Antithrombotic Removal - Ticagrelor (STAR-T) Trial is a multi-center, double-blind, randomized, controlled trial enrolling patients who require cardiothoracic surgery on cardiopulmonary bypass (CPB) within 48 hours of last ticagrelor dose. Subjects will be randomized 1:1 to receive either the DrugSorb-ATR device or an identical sham device during CPB. The study will enroll up to 120 subjects at 20 U.S centers, and the primary outcome is the composite of fatal perioperative bleeding, moderate/severe/massive bleeding according to the Universal Definition of Perioperative Bleeding in Cardiac Surgery (UDPB), and 24 hours chest tube drainage. The components of the composite are hierarchically ranked according to clinical significance and the primary analysis will utilize the Win Ratio method. Percent change in ticagrelor levels before and after CPB (drug removal) will be the key secondary endpoint. An independent Clinical Events Committee will adjudicate all clinical endpoints including safety endpoints relating to postoperative thrombotic events. Subjects will be followed through 30 days after the index operation. The results from STAR-T, if positive, will potentially support FDA market approval for DrugSorb-ATR, and provide a solution to an important unmet clinical need.

Efficient removal of apixaban with extracorporeal hemoadsorption

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): CytoSorbents Medical Incorporation Background A hemadsorption device containing biocompatible porous polymer beads is easily incorporated into extracorporeal circuits including cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT), and hemoperfusion. This device has been shown to safely and effectively remove the P2Y12 receptor antagonist ticagrelor and the direct oral anticoagulant (DOAC) rivaroxaban during CPB in patients undergoing emergent cardiac surgery. Importantly, drug removal was associated with significant reductions in surgical bleeding and improved clinical outcomes resulting in CE Mark approval. Apixaban, another DOAC, has gained increasing popularity given its proven efficacy and lower risk of bleeding in clinical use. However, a pressing unmet medical need exists for the mitigation of the bleeding risk encountered in patients on apixaban who require urgent or emergent surgery. Currently approved reversal agents are only indicated in the case of uncontrolled or life-threatening bleeding, but not as preventive measures to mitigate surgical bleeding. Purpose To demonstrate the ability of the extracorporeal hemoadsorption device to remove apixaban from whole blood. Methods The hemoadsorption device was evaluated for removal of apixaban in an in vitro benchtop model using bovine whole blood. The 4L of blood were continuously circulated through a 300 mL porous polymer device over 6 hours at a flow rate of 300 mL/min to evaluate the drug removal kinetics of apixaban. Starting apixaban concentration of 300ng/mL was utilized in the model to reflect standard therapeutic levels. Plasma levels of apixaban over time were measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS). A control setup utilized an identical flow circuit, minus the hemoadsorption device. Results Mean plasma concentration of apixaban was reduced to ∼9.1 ng/mL (equivalent to ∼96.3% removal) over the first 60 min of hemoperfusion with the device. Specifically, mean percent remaining plasma concentration of apixaban following device treatment was 42.2%, 18.6%, 8% and 3.7% after 15, 30, 45 and 60 min of therapy, respectively. Overall, ∼99.7% blood concentration of apixaban was removed over the total 6 h. Drug concentrations remained unchanged in the control circuit, with a statistically significant difference between the control and treatment groups at all time points except 0 h (p &amp;lt; 0.01). Conclusion Apixaban is efficiently removed with hemoadsorption using porous polymer device technology. Drug concentrations were reduced &amp;gt;96% after 60 min. Similarly, efficient benchtop removal utilizing the same technology was observed for ticagrelor and rivaroxaban, and subsequently translated into significant clinical benefit in patients requiring emergent cardiac surgery. The results of the current study hold significant promise for the future clinical applicability of apixaban removal. Abstract Figure. Percent of remaining apixaban over time

Use of Hemoadsorption in Patients With Severe Intoxication Requiring Extracorporeal Cardiopulmonary Support-A Case Series.

Drugs intoxications often lead to severe vasoplegia and cardiogenic shock, and VA-ECMO represents a viable therapy option. However, as cardiopulmonary support is not contributing to the removal of the causal agent from the blood, detoxification by a new hemoadsorption device (CytoSorb) could represent a potential therapeutic tool due to its highly efficient elimination capacity of endogenous but also exogenous hydrophobic substances for which otherwise no effective antidote exist. In this case series, four anecdotal cases of acute intoxications requiring VA-ECMO support used as extracorporeal cardiopulmonary resuscitation after intoxication-induced out-of-hospital cardiac arrest (OHCA) are presented, who were additionally treated with CytoSorb hemoadsorption in combination with renal replacement therapy. Combined treatment was associated with a considerable decrease in plasma levels of the overdosed drugs. Additionally, the combination of applied techniques was safe, practical, and technically feasible with no adverse or any device-related side effects documented during or after the treatment sessions. Based on the reported dramatic decline in drug levels during treatment, that fits in the device's characteristics, we strongly suggest to further investigate the potentially lifesaving role of CytoSorb therapy in patients with acute intoxications requiring multiple organ support techniques.

Hemoadsorption by extracorporeal cytokine adsorption therapy (CytoSorb®) in the management of septic shock: A retrospective observational study.

Sepsis results in immunologic disturbances with the release of various inflammatory mediators such as cytokines. Cytokines can damage the cells, and the continuous release of inflammatory mediators leads to severely impaired immunity. Therefore, the reduction in cytokine levels by hemoadsorption represents a new concept for blood purification. CytoSorb® as a hemoadsorption device is a detoxification system, which aims to decrease the cytokines levels. This study was conducted to understand any beneficial effects of CytoSorb® therapy in septic patients. This was a retrospective and observational study, approved by the scientific and ethics committee of Max Super Specialty Hospital, Patparganj, Delhi, India and conducted in compliance with current International Council for Harmonization, Good Clinical Practice, Schedule Y, and Indian Council of Medical Research guidelines. Subjects of either gender (age > 18 year) were included in the study. The data were presented as mean ± standard deviation and categorical as frequency and percentage (%). A p value less than 0.05 (p < 0.05) was considered to be statistically significant. A total number of 36 patients were included in the study. Majority of the patients were male with mean age (56.36 ± 14.83). After therapy, procalcitonin and total leucocyte count levels decreased within 24 h. Post therapy, sepsis-related organ failure assessment (SOFA) score of Day (D)1, D2, and D3 reduced to 10.4 ± 3.63, 8.7 ± 4.02, and 7.8 ± 3.67, respectively. The Acute Physiology and Chronic Health Evaluation (APACHE) II score and predicted mortality were lower in the survivor group as compared to the non-survivor group. Hemoadsorption using the extracorporeal adsorption device (CytoSorb®) might be an effective rescue therapy in stabilizing septic shock patients.

A RETROSPECTIVE ANALYSIS OF EFFICACY OF HEMOADSORPTION (CYTOSORB®) IN REFRACTORY SEPTIC SHOCK PATIENTS AS AN ADJUVANT.

Dysregulated response of cytokines can result in hyper-inflammatory conditions called cytokine storm,commonly seen in sepsis and septic shock..The current study assessed hemoadsorption device - CytoSorb® for its efficiency as an adjuvant in treating patients suffering from septic shock. Total 8 patients enrolled were subjected to hemoadsorption therapy along with the standard treatment.The results of the study revealed significant improvement in clinical and haemodynamic parameters before and after initiation of CytoSorb® therapy. Out of 8 patients, 6 showed a positive outcome while 2 did not survive.The results of this study show that the use of hemoadsorption therapy can be considered in critically ill ICU patients as a safe and effective adjuvant therapy along with the standard treatment for a better outcome in patients.

A RETROSPECTIVE ANALYSIS OF EFFICACY OF HEMOADSORPTION (CYTOSORB®) IN REFRACTORY SEPTIC SHOCK PATIENTS AS AN ADJUVANT

Dysregulated response of cytokines can result in hyper-inflammatory conditions called cytokine storm,commonly seen in sepsis and septic shock..The current study assessed hemoadsorption device - CytoSorb® for its efficiency as an adjuvant in treating patients suffering from septic shock. Total 8 patients enrolled were subjected to hemoadsorption therapy along with the standard treatment.The results of the study revealed significant improvement in clinical and haemodynamic parameters before and after initiation of CytoSorb® therapy. Out of 8 patients, 6 showed a positive outcome while 2 did not survive.The results of this study show that the use of hemoadsorption therapy can be considered in critically ill ICU patients as a safe and effective adjuvant therapy along with the standard treatment for a better outcome in patients.

Hemoadsorption does not Have Influence on Hemolysis During Cardiopulmonary Bypass.

Cardiopulmonary bypass (CPB) induces hemolysis, which manifests as plasma free hemoglobin. We investigated in a post hoc analysis of a single-center, blinded, controlled study whether the use of a novel hemoadsorption device (CytoSorb, CytoSorbents Europe GmbH, Berlin, Germany) affects hemolysis during CPB. A total of 35 patients undergoing elective CPB surgery with an expected CPB duration of more than 120 min were included in the analysis. The hemoadsorption device was used in 17 patients (intervention group) and not used in 18 patients (control group). The primary outcome was differences of postoperative free hemoglobin and haptoglobin levels. As secondary outcomes, we investigated differences in postoperative lactate dehydrogenase and bilirubin levels. Postoperative free hemoglobin levels were not significantly different between the groups. However, there were statistically significant differences between the treatment and control groups in the median levels of haptoglobin (58.4 vs. 17.9 mg/dL, respectively; P < 0.01) and lactate dehydrogenase (353.0 vs. 432.0 U/L, respectively; P < 0.05) on postoperative day 1. Thus, in this study, we did not find an effect on hemolysis in patients treated with hemoadsorption, though lower haptoglobin level and higher secondary hemolysis markers on postoperative day 1 in patients not treated with the hemoadsorber may be an indication of some moderate effect of the device. Studies with larger samples are needed to clarify the significance of the small differences detected in this study.

Surface-Engineered Blood Adsorption Device for Hyperphosphatemia Treatment.

Correspondence: Melanie S. Joy, PharmD, PhD, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Mail Stop C238, Room V20-4108, 12850 East Montview Blvd, Aurora, CO 80045. Email: Melanie.Joy@ucdenver.edu The research employed surface engineering methods to develop, optimize, and characterize a novel textile-based hemoadsorption device for hyperphosphatemia in hemodialysis-dependent end-stage kidney disease. Phosphate adsorbent fabrics (PAFs) were prepared by thermopressing alumina powders to polyester filtration fabrics and treatment with trimesic acid (TMA). For static experiments, phosphate adsorption capacity in buffer solution, plasma, and blood were evaluated by submersing the PAFs in 100 ml. For dynamic experiments, PAFs were equipped in a device prototype and incorporated in a pump-driven circuit. Phosphates were determined by a colorimetric assay and an Ortho Clinical Diagnostics Vitros 5600 Integrated analyzer. The maximum loading amount of TMA-alumina on PAFs was approximately 35 g/m under 260°C processing temperature. Phosphate adsorption capacity increased with initial concentration. Adsorption isotherms from buffer demonstrated a maximum phosphate adsorption capacity of approximately 893 mg/m at 37.5°C, pH 7.4, with similar results from plasma and whole blood. Measured phosphate concentrations during simulations demonstrated a 42% reduction, confirming the high capacity of the PAFs for removing phosphate from whole blood. Results from the current study indicated that an alumina-TMA treated PAF can dramatically reduce phosphate concentrations from biological samples. The technology could potentially be used as a tunable adsorbent for managing hyperphosphatemia in kidney disease.

Hemoadsorption by CytoSorb in septic patients: a case series

BackgroundSeptic shock, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a highly lethal condition that causes substantial morbidity and mortality among critically ill patients. One of the hallmarks of sepsis is the excessive release of cytokines and other inflammatory mediators causing refractory hypotension, tissue damage, metabolic acidosis and ultimately multiple organ failure. In this context, cytokine reduction by hemoadsorption represents a new concept for blood purification, developed to attenuate the overwhelming systemic levels of pro-inflammatory and anti-inflammatory mediators released in the early phase of sepsis.MethodsIn the present case series, we evaluated the impact of a new hemoadsorption device (CytoSorb) used as adjunctive therapy, on hemodynamics and clinically relevant outcome parameters in 26 critically ill patients with septic shock and in need of renal replacement therapy.ResultsWe found that treatment of these patients with septic shock was associated with hemodynamic stabilization and a reduction in blood lactate levels. Actual mortality in the overall patient population was lower than mortality predicted by acute physiology and chronic health evaluation II (APACHE II). These effects seem to be more pronounced in patients in whom therapy started within 24 h of sepsis diagnosis, whereas a delay in the start of therapy was associated with a poor response to therapy in terms of reduction of catecholamine demand and survival. Moreover, from our patient population, medical patients seemed to benefit more than post-surgical patients in terms of survival. Treatment using the CytoSorb device was safe and well-tolerated with no device-related adverse events during or after the treatment sessions.ConclusionHemoadsorption using CytoSorb resulted in rapid hemodynamic stabilization and increased survival, particularly in patients in whom therapy was started early. Given the positive clinical experience of this case series, randomized controlled trials are urgently needed to define the potential benefits of this new treatment option.

Modeling and Hemofiltration Treatment of Acute Inflammation.

The body responds to endotoxins by triggering the acute inflammatory response system to eliminate the threat posed by gram-negative bacteria (endotoxin) and restore health. However, an uncontrolled inflammatory response can lead to tissue damage, organ failure, and ultimately death; this is clinically known as sepsis. Mathematical models of acute inflammatory disease have the potential to guide treatment decisions in critically ill patients. In this work, an 8-state (8-D) differential equation model of the acute inflammatory response system to endotoxin challenge was developed. Endotoxin challenges at 3 and 12 mg/kg were administered to rats, and dynamic cytokine data for interleukin (IL)-6, tumor necrosis factor (TNF), and IL-10 were obtained and used to calibrate the model. Evaluation of competing model structures was performed by analyzing model predictions at 3, 6, and 12 mg/kg endotoxin challenges with respect to experimental data from rats. Subsequently, a model predictive control (MPC) algorithm was synthesized to control a hemoadsorption (HA) device, a blood purification treatment for acute inflammation. A particle filter (PF) algorithm was implemented to estimate the full state vector of the endotoxemic rat based on time series cytokine measurements. Treatment simulations show that: (i) the apparent primary mechanism of HA efficacy is white blood cell (WBC) capture, with cytokine capture a secondary benefit; and (ii) differential filtering of cytokines and WBC does not provide substantial improvement in treatment outcomes vs. existing HA devices.

Improved treatment of systemic blood infections using antibiotics with extracorporeal opsonin hemoadsorption

Here we describe development of an extracorporeal hemoadsorption device for sepsis therapy that employs commercially available polysulfone or polyethersulfone hollow fiber filters similar to those used clinically for hemodialysis, covalently coated with a genetically engineered form of the human opsonin Mannose Binding Lectin linked to an Fc domain (FcMBL) that can cleanse a broad range of pathogens and endotoxin from flowing blood without having to first determine their identity. When tested with human whole blood in vitro, the FcMBL hemoadsorption filter (FcMBL-HF) produced efficient (90–99%) removal of Gram negative (Escherichia coli) and positive (Staphylococcus aureus) bacteria, fungi (Candida albicans) and lipopolysaccharide (LPS)-endotoxin. When tested in rats, extracorporeal therapy with the FcMBL-HF device reduced circulating pathogen and endotoxin levels by more than 99%, and prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver and kidney when compared to controls. Studies in rats revealed that treatment with bacteriocidal antibiotics resulted in a major increase in the release of microbial fragments or ‘pathogen-associated molecular patterns’ (PAMPs) in vivo, and that these PAMPs were efficiently removed from blood within 2 h using the FcMBL-HF; in contrast, they remained at high levels in animals treated with antibiotics alone. Importantly, cleansing of PAMPs from the blood of antibiotic-treated animals with the FcMBL-hemoadsorbent device resulted in reduced organ pathogen and endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs compared to treatment with antibiotics alone. As PAMPs trigger the cytokine cascades that lead to development of systemic inflammatory response syndrome and contribute to septic shock and death, co-administration of FcMBL-hemoadsorption with antibiotics could offer a more effective approach to sepsis therapy.