The Effect of Cytokine Adsorption on Leukocyte and Platelet Activation after Extracorporeal Cardiopulmonary Resuscitation.

BACKGROUND: Post-cardiac arrest syndrome (PCAS) is a frequent complication following successful cardiopulmonary resuscitation and correlates with poor outcome. PCAS is characterized by an excessive inflammatory response to whole-body ischemia and reperfusion. Cytokine adsorption was suggested as an adjunctive treatment option for the removal of cytokines from the patients' blood to restore the physiological equilibrium of pro- and anti-inflammatory activity and thus mitigate hemodynamic instability and end-organ complications. MATERIAL AND METHODS: To better understand the cellular effects of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after in- and out-of-hospital cardiac arrest, we compared the activation status of neutrophils, monocytes, and platelets as well as the formation of platelet-leukocyte complexes in intravenous whole blood samples from an exploratory subgroup (n = 24) from the randomized CYTER study. RESULT: At 48 hours after initiation of ECPR, flow cytometry analyses did neither reveal significant differences in neutrophil (CD11b, CD66b, L-selectin, and PSGL-1) and monocyte (CD11b, L-selectin, and PSGL-1) surface molecule expression nor in circulating platelet-monocyte complexes between patients receiving cytokine adsorption and those without. CONCLUSION: Data did not show a relevant effect of cytokine adsorption on neutrophil and monocyte activation during the first 48 hours after initiation of ECPR.

Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding.

Introduction: Serotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and mice. A possible link and interaction between the inflammatory effects of serotonin and metabolic derangements in SERT-deficient mice has not been investigated so far. Methods: SERT-deficient (Sert -/-) and wild type (WT) mice were fed a high-fat diet, starting at 8 weeks of age. Metabolic phenotyping (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, qPCR, histology) and assessment of adipose tissue inflammation (flow cytometry, histology, qPCR) were carried out at the end of the 19-week high-fat diet feeding period. In parallel, Sert -/- and WT mice received a control diet and were analyzed either at the time point equivalent to high-fat diet feeding or as early as 8-11 weeks of age for baseline characterization. Results: After 19 weeks of high-fat diet, Sert -/- and WT mice displayed similar whole-body and fat pad weights despite increased relative weight gain due to lower starting body weight in Sert -/-. In obese Sert -/- animals insulin resistance and liver steatosis were enhanced as compared to WT animals. Leukocyte accumulation and mRNA expression of cytokine signaling mediators were increased in epididymal adipose tissue of obese Sert -/- mice. These effects were associated with higher adipose tissue mRNA expression of the chemokine monocyte chemoattractant protein 1 and presence of monocytosis in blood with an increased proportion of pro-inflammatory Ly6C+ monocytes. By contrast, Sert -/- mice fed a control diet did not display adipose tissue inflammation. Discussion: Our observations suggest that SERT deficiency in mice is associated with inflammatory processes that manifest as increased adipose tissue inflammation upon chronic high-fat diet feeding due to enhanced leukocyte recruitment.

Cytokine adsorption in patients with post-cardiac arrest syndrome after extracorporeal cardiopulmonary resuscitation (CYTER) - A single-centre, open-label, randomised, controlled trial.

AIM: To investigate the effect of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after cardiac arrest. METHODS: CYTER was a single-centre, open-label, randomised, controlled trial. Patients selected for ECPR at the University Medical Center Freiburg (Freiburg, Germany) were assigned to extracorporeal membrane oxygenation (ECMO) support with or without cytokine adsorption (1:1) using the CytoSorb adsorber, incorporated into the ECMO, replaced every 24 hours, and removed after 72 hours. The primary endpoint was serum interleukin (IL)-6 concentration at 72 hours (intention-to-treat analysis). Secondary endpoints included 30-day survival, vasopressor support and biomarkers of end-organ injury. RESULTS: Of 50 patients enrolled in the trial, 26 (52%) were treated with cytokine adsorption and 24 (48%) without. Nine patients were excluded (informed consent could not be obtained); 41 patients were therefore included in the primary analysis. Median IL-6 levels (IQR) decreased from 408.0(93.4-906.5) to 324.0 (134.3-4617.3) pg/mL and increased from 133.0 (56.2-528.5) to 241.0 (132.8-718.0) pg/mL in the cytokine adsorption and control group, respectively (linear regression for treatment [cytokine adsorption vs control]: p = 0.48). Three (14%) of 22 patients treated with cytokine adsorption and 8 (42%) of 19 patients treated without cytokine adsorption survived to day 30 (HR = 1.85, 95% CI 0.86-4.01; p = 0.10). Vasopressor support and NSE, S100b, troponin T, CRP and PCT levels were similar between groups. CONCLUSION: Cytokine adsorption in patients receiving ECPR did not reduce serum IL-6 and had no significant effect on survival, vasopressor support, or biomarkers of injury. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03685383.

Effect of Cytokine Adsorption on Survival and Circulatory Stabilization in Patients Receiving Extracorporeal Cardiopulmonary Resuscitation.

Even after the introduction of extracorporeal cardiopulmonary resuscitation (ECPR), survival after cardiac arrest remains poor. Excess release of vasoactive cytokines may be a reason for cardiovascular instability and death after ECPR. Recently, an extracorporeal cytokine adsorption device (CytoSorb) to reduce elevated levels of circulating cytokines has been introduced. So far, it remains unclear if this device may improve survival and cardiovascular stabilization after ECPR. We report data from our investigator-initiated, single-center ECPR registry. We compared 23 ECPR patients treated with cytokine adsorption with a propensity-matched cohort of ECPR patients without cytokine adsorption. We analyzed survival, lactate clearance, vasopressor need, and fluid demand in both groups and performed between-group comparisons. Survival to discharge from intensive care unit (ICU) was 17.4% (4/23) in the cytokine adsorption group and 21.7% in the control group (5/23, P > 0.99). In both groups, we observed a decrease of serum-lactate, need for vasopressors, and fluid demand during the first 72 hours after ECPR. However, in direct comparison, we did not find significant between-group differences. In this retrospective registry study employing propensity score matching, cytokine adsorption in severely ill patients after ECPR was not associated with improved ICU survival nor a decrease of lactate, fluid, or vasopressor levels. Due to small case numbers and the retrospective design of the study, our results neither disprove nor confirm a clinically relevant treatment effect of cytokine adsorption. Results from larger trials, preferably randomized-controlled trials are required to better understand the clinical benefit of cytokine adsorption after ECPR.

Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial.

BACKGROUND: We sought to clarify the benefit of cytokine adsorption in patients with COVID-19 supported with venovenous extracorporeal membrane oxygenation (ECMO). METHODS: We did a single-centre, open-label, randomised, controlled trial to investigate cytokine adsorption in adult patients with severe COVID-19 pneumonia requiring ECMO. Patients with COVID-19 selected for ECMO at the Freiburg University Medical Center (Freiburg, Germany) were randomly assigned (1:1) to receive cytokine adsorption using the CytoSorb device or not. Randomisation was computer-generated, allocation was concealed by opaque, sequentially numbered sealed envelopes. The CytoSorb device was incorporated into the ECMO circuit before connection to the patient circuit, replaced every 24 h, and removed after 72 h. The primary endpoint was serum interleukin-6 (IL-6) concentration 72 h after initiation of ECMO analysed by intention to treat. Secondary endpoints included 30-day survival. The trial is registered with ClinicalTrials.gov (NCT04324528) and the German Clinical Trials Register (DRKS00021300) and is closed. FINDINGS: From March 29, 2020, to Dec 29, 2020, of 34 patients assessed for eligibility, 17 (50%) were treated with cytokine adsorption and 17 (50%) without. Median IL-6 decreased from 357·0 pg/mL to 98·6 pg/mL in patients randomly assigned to cytokine adsorption and from 289·0 pg/mL to 112·0 pg/mL in the control group after 72 h. One patient in each group died before 72 h. Adjusted mean log IL-6 concentrations after 72 h were 0·30 higher in the cytokine adsorption group (95% CI -0·70 to 1·30, p=0·54). Survival after 30 days was three (18%) of 17 with cytokine adsorption and 13 (76%) of 17 without cytokine adsorption (p=0·0016). INTERPRETATION: Early initiation of cytokine adsorption in patients with severe COVID-19 and venovenous ECMO did not reduce serum IL-6 and had a negative effect on survival. Cytokine adsorption should not be used during the first days of ECMO support in COVID-19. FUNDING: None.

Cytokine Adsorption in Severe Acute Respiratory Failure Requiring Veno-Venous Extracorporeal Membrane Oxygenation.

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is a last resort treatment option for patients with acute respiratory failure (acute respiratory distress syndrome [ARDS]). Cytokine adsorption has been incorporated in the management of some of these patients on an individual basis to control the imbalance of danger-associated molecular patterns and proinflammatory cytokines. However, little is known about the combination of V-V ECMO and cytokine adsorption as earlier reports contained mixed patient cohorts in terms of disease and mode of ECMO, veno-venous and veno-arterial. We here report single-center registry data of nine all-comers with severe ARDS treated with V-V ECMO and cytokine adsorption using the CytoSorb adsorber compared with a control group of nine propensity score matched patients undergoing V-V ECMO support without cytokine adsorption. Even though Respiratory ECMO Survival Prediction and PRedicting dEath for SEvere ARDS on V-V ECMO scores predicted a higher mortality in the cytokine adsorption group, mortality was numerically reduced in the patients undergoing V-V ECMO and cytokine removal compared with V-V ECMO alone. The need for fluid resuscitation and vasopressor support as well as lactate levels dropped significantly in the cytokine adsorption group within 72 hours, whereas vasopressor need and lactate levels did not decrease significantly in the control group. Therefore, our data suggest that cytokine adsorption might be beneficial in patients with severe ARDS requiring V-V ECMO support.