Early Impact of Cytosorb® Adsorber on Proinflammatory Cytokine Plasmatic Levels in a Porcine Model of Refractory Cardiogenic Shock Supported with VA-ECMO

Early Impact of Cytosorb® Adsorber on Proinflammatory Cytokine Plasmatic Levels in a Porcine Model of Refractory Cardiogenic Shock Supported with VA-ECMO | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Early Impact of Cytosorb® Adsorber on Proinflammatory Cytokine Plasmatic Levels in a Porcine Model of Refractory Cardiogenic Shock Supported with VA-ECMO Juliette Piccoli, Tristan Ehrlich, Francesco Ferraro, Aude Falanga, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7526597/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Dec, 2025 Read the published version in BMC Cardiovascular Disorders → Version 1 posted 14 You are reading this latest preprint version Abstract Background. Cardiogenic shock (CS) is a pejorative situation which often requires a circulatory support with VA-ECMO. However, VA-ECMO is known to trigger an inflammatory cascade with expression of proinflammatory cytokines Interleukin-6 (IL-6) and Interleukin-10 (IL-10) causing organ damages and hemodynamic deterioration. Cytokine adsorption using the Cytosorb® adsorber was recently proposed to mitigate the inflammatory response. As relevance of implementing Cytosorb® adsorber with VA-ECMO is not validated, we sought to assess whether it might early influence levels of IL-6 and IL-10 in a porcine model of ischemic refractory CS. Materials and Methods. CS was induced in 12 male pigs following acute proximal occlusion of the left anterior descending artery (LAD). After a low-flow period of 60 minutes, circulatory support with VA-ECMO was initiated and pigs were randomly assigned in two groups, Cytosorb® (−) (VA-ECMO without Cytosorb®adsorber: n = 6) and Cytosorb® (+) (VA-ECMO with Cytosorb®adsorber: n = 6). In each group, modulation of IL-6 and IL-10 was assessed during a four-hour procedure, as well as impact on arterial blood pressure, biological and biochemical, parameters. Results. After 240 minutes, the Group Cytosorb® (+) demonstrated a significant propensity to reduce levels of IL-10, (p = 0.0421*). Regarding hemodynamics, biological and biochemical parameters, Cytosorb® adsorber showed no difference with the group Cytosorb® (−). Conclusions. Despite encouraging early benefits, further studies are still necessary to validate interests of a routine use of Cytosorb®adsorber with VA-ECMO. Cardiogenic shock Porcine model VA-ECMO Cytosorb® adsorber Cytokines IL-6 - IL- 10 Inflammatory response Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 INTRODUCTION Cardiogenic shock (CS) is a life-threatening situation, resulting from an inadequate cardiac contractility and cardiac output which leads to a systemic hypoperfusion and multiorgan failure with a dismal spontaneous prognosis. Survival rate obviously depends on both a rapid access to Intensive Care Unit (ICU) and a prompt diagnosis as well as an adequate therapeutic management [1]. If CS may arise from a wide array of underlying causes, nevertheless, acute myocardial infarction remains the most frequent cause. Delmas et al [2], in a review of literature, reported an incidence of CS in Europe ranging from 60 000 to 70 000 per year with a mortality rate of 40% at 30 days. Despite significant improvements in hospital management, prognosis remains poor among patients with severe and profound CS with a low probability of recovery. Independently of initial triggering factors, CS rapidly leads to multi organ failure resulting from severe hypotension refractory to fluid loading, vasopressors agents and inotropic drugs [3,4]. Detrimental consequences of CS simultaneously result from both a severely impaired myocardial contractility with a low cardiac output syndrome and an altered peripheral microcirculatory blood flow with tissular hypoxia. Additionally, in 25% of the cases [5], CS involves complex inflammatory mechanisms similar to those identified in the Systemic Inflammatory Response Syndrome (SIRS) with activation of the inflammatory response characterized by an increased production of interleukins (IL-6 and IL-10) and Tumor Necrosis Factor (TNF-𝛼) which promote and exacerbate the production of nitric oxyde and peroxynitrite [6,7]. Furthermore, these latter inflammatory mediators and their respective metabolites produce negative inotropic and vasoplegic effects, are associated with cardiotoxicity, and therefore contribute to jeopardize hemodynamics. CS is classically managed by medical support with introtropes and vasopressors. Nevertheless, when hemodynamics deteriorate despite optimal efforts, mechanical circulatory support is increasingly considered to improve immediate outcome and survival. Among all available devices, venoarterial extracorporeal membrane oxygenation (VA-ECMO) has emerged as a salvage option in patients with CS refractory to standard therapies. However, this device is known to heighten the systemic inflammatory response syndrome and consequently worsen the CS. Recently, in order to reduce the excessive inflammatory response resulting from the «cytokine storm» observed in refractory CS, cytokine adsorption using the Cytosorb® adsorber (CytoSorbents Europe GmbH, Berlin, Germany) has been proposed. Interest of this approach is to attenuate circulating cytokine concentrations without affecting the physiological immune function. Cytosorb® contains an adsorber membrane which can reduce the level of hydrophobic molecules with a molecular mass up to 55 kDA [8]. Cytokine adsorption has been evaluated in various clinical settings including sepsis, hyper inflammatory syndromes, cardiac surgery with cardiopulmonary bypass (CPB) and occasionally with ECMO as recovery support after cardiac arrest and confirmed the safety of the adsorber membrane with no significant evidence of clinical efficacy [9–11]. Supady A et al, in a recent study [12] suggested that CS supported with VA-ECMO in combination with the Cytosorb® adsorber neither disproved nor confirmed a clinically relevant treatment effect of cytokine adsorption despite hemodynamic stabilization and reduction of catecholamine plasmatic levels within 48 hours and then required larger randomized trials to better investigate clinical benefits of cytokine adsorption after VA-ECMO. Herein, we sought to investigate whether Cytosorb®adsorber may early impact pro inflammatory cytokine response, hemodynamics and organ function, in a swine model of ischemic CS supported with VA-ECMO with Cytosorb®adsorber compared to a control group of CS supported with VA-ECMO without Cytosorb®. MATERIALS AND METHODS. All experiments were reviewed and approved by the Nancy University Ethics Committee for Animal Experimentation (APAFIS n°45230). The procedure for care and sacrifice of study animals was in accordance with the European Community Standards on the Care and Use of Laboratory Animals. 1.1. Animal model. The origin of swines is supported by an official collaboration between the School of Surgery (University of Lorraine) and an approved specific farmer specialized in breeding specific races of pigs dedicated to animal experimentation. Male pigs ( Landrace breed ) weighing approximately 50 kg were used in the study. Since female hormones may influence vasoreactivity, only males were selected. Pigs were randomly assigned in two groups: Ischemic CS supported with VA-ECMO without Cytosorb® (n = 6): Group Cytosorb® (−) Ischemic CS supported with VA-ECMo in combination with Cytosorb® (n = 6): Cytosorb® (+) 1.2. Exclusion criteria. Cardiac arrest before baseline measurements, major hemorrhagic event before randomization, failure to achieve CS and ECMO device failure to provide the theoretical pump flow were considered as exclusion criteria. 1.3. Animal preparation and surgical procedure. Following a one-day fast, animals were placed under general anesthesia and ventilation. Anesthesia was induced via the lateral auricular vein with an intravenous bolus of propofol (1 mg·kg − 1 , Propofol-lipuro 1%, B. Braun, Melsungen AG, Germany). Animals were intubated (TeleflexIsis 7.5 I.D. mm, Teleflex Medical, Athlone, Ireland) and mechanically ventilated (Evita 1 Dura, Dräger, Lübeck, Germany) in assisted-controlled mode (inspiratory fraction of oxygen (FiO2), tidal volume 10 mg·kg − 1 and respiratory rate 12 per minute). Anesthesia was maintained throughout the entire experiment with a continuous infusion of sufentanil (0.2 µg·kg − 1 ·min − 1 , sufentanil, Mylan, Canonsburg, PA, USA), propofol (7 mg·kg − 1 ·h − 1 , propofol-lipuro 2%, B. Braun Melsungen AG, Germany) and cisatracurium (0.9 mg·kg − 1 ·h − 1 , Nimbex, GlaxoSmithKline, Middlesex, Brentford, UK). The animals were monitored by continuous electrocardiogram (ECG) recording and equipped percutaneously, under ultrasound guidance, with a triple lumen catheter (8 Fr, Arrow®, Reading, PA, USA) inserted into the right external jugular vein and an arterial catheter into the carotid artery. This latter arterial catheter was used to insert a conductance catheter (Millar pressure conductance Unit Model 200. Millar Instruments Inc., Houston, Tx, USA) for a continuous measurement of arterial blood pressure (ABP). Given documented risk of both ventricular arrhythmia and atrial fibrillation in swine models [13,14], 6 mg/Kg of Amiodarone and 60 mg/Kg of magnesium sulfate were administered intravenously prior to sternotomy. After a low median laparotomy, a catheter was placed and secured into the bladder to estimate hourly urine. Core body temperature was measured via a rectal probe and maintained at 38.5 ◦C. A 50 IU·kg − 1 bolus dose of Heparin (Heparin Sodique Choay, Sanofi-Aventis, Paris, France) was administered after sternotomy, followed by a continuous intravenous infusion to maintain an activated clotting time (ACT) of 180–250 s. Values were monitored every hour using the Hemochron Jr Signature Microcoagulation System (ITC, Hudsonville, MI, USA). Immediately prior to the sternotomy, 5 or 6 Fr desilets were inserted into the femoral artery and vein under ultrasonographic guidance and cannulation of arterial and venous femoral vessels was achieved via the Seldinger technique. Femoral cannulas were then connected to the fully assembled ECMO circuit which was primed with saline solution (NaCl 0.9%, B. Braun Medical, Saint-Cloud, France). The oxygen/air flow was adjusted to maintain PaCO2 and PaO2 in the ranges of 4.0–6.5 kPa and 10–15 kPa, respectively, in blood exiting the oxygenator after initiation of VA-ECMO. After median sternotomy, and heart exposure, the left anterior descending artery (LAD) was easily located (Fig. 1 A). A 4 − 0 polypropylène suture passed through a tourniquet was placed around the proximal portion of the LAD. Then, the tourniquet was slipped and tied around the LAD to stop the coronary flow and induce a massive myocardial ischemia of the anterior wall of the left ventricle, leading within few minutes to a refractory ventricular fibrillation with CS. Patterns of myocardial ischemia were confirmed by modifications of the ST-segment displayed on the ECG monitor (Fig. 1 B), as well as a rapid modification of the color of the left ventricular myocardium (Fig. 1 C) and a severe hypokinesia of all anterior segments of the left ventricle. If ventricular fibrillation occured before initiation of VA-ECMO, internal defibrillation with internal paddles (Fig. 1 D) and cardiac massage were performed. Following a 30-minute ischemia with characterization of a CS, VA-ECMo was initiated at a nominal standard blood flow 65–70 mL·kg − 1 ·min − 1 based on a theoretical cardiac output and ELSO recommendations [ 15 ] while the LAD was unclamped. The Fig. 1 E shows femoral arterial and venous cannulations. Criteria of CS: Decrease of cardiac index > 30% of the baseline values. Decrease of mean arterial pressure (MAP) > 30% of the baseline values. Increase of plasmatic lactate levels > 2.5 mmol.L -1 . The Cytosorb®membrane was bypassed to the ECMO flow (Fig. 1 F). The overall duration of VA-ECMO circulatory support was 240 minutes. 1.4. Timing of measurements. All parameters of the study were measured at different steps: Baseline measurement: Prior to the sternotomy. H0: After 60 minutes myocardial ischemia and CS immediately prior to initiation of VA-ECMO. H1 : After 60 minutes VA-ECMO. H2 : After 120 minutes VA-ECMO H3 : After 180 minutes VA-ECMO. H4 : after 240 minutes VA-ECMO (end of the procedure). 1.5. End-point and measured parameters. End-point: Hemodynamic stabilization validated by: Heart rate (HR), arterial blood pressure (ABP), and mean arterial pressure (MAP) were continuously recorded. Doses of noradrenaline collected every hour. Plasmatic lactate levels collected at baseline, after 60 minutes of CS, and after 240 minutes of VA-ECMO initiation. Plasmatic cytokines concentrations (Il-6 and IL-10) using an ELISA test with rat interleukins (ELISA Quantikine, R&D Systems) collected at baseline, after 60 minutes of CS, and after 240 minutes of VA-ECMO initiation. Indicators of liver function evaluated via levels of plasmatic transaminases (ALAT / ASAT) collected at baseline, after 60 minutes of CS (H0), and after 240 minutes (H4) of VA-ECMO initiation. Markers of kidney function evaluated via diuresis and levels of both plasmatic creatinine and urea collected at baseline, after 60 minutes of CS (H0), and after 240 minutes (H4) of assistance with VA-ECMO initiation. In order to assess impact of Cytosorb® on vasoreactivity, a vasoreactivity test was done at the end of the procedure using increasing doses of noradrenaline given as boluses. 1.6. Protocol of euthanasia. At the end of each procedure (H4), animals were euthanized with an injection of 10 ml of pentobarbital (Exagon® 400 mg/mL Richter Pharma AG). 1. 7. Data Analysis and Statistics. In order to gain an expected effect size, an alpha risk of 0.05 as well a power of 0.9, a sample of at least 12 pigs was required using the BiostaTGV software. Statistical analyses included Student’s t-test and Mann-Whitney U test for continuous variables and unequal variances respectively. A P-value of < 0.05 was considered statistically significant. All data were analyzed using the statistical software SPSS version 28 (SPSS Inc., Chicago, IL, USA) and R version 4.2.2 (R Foundation, Vienna, Austria). RESULTS 12 pigs were successfully enrolled in the study and assigned in two respective groups: Cytosorb® (−): VA-ECMO with no Cytosorb® (n = 6). Cytosorb® (+): VA-ECMO with Cytosorb® (n = 6). There was no significant difference in age and weight of pigs (6 months / mean weight 54.71 Kg ± 3.15 as well as baseline measures of ABP (82 ± 14 mmHg) for the group Cytosorb® (−) versus (82 ± 8 mmHg) for the group Cytosorb® (+) between the two groups (P = 0.490). As illustrated in Fig. 2 , despite a similar hemodynamic management, at H0 (initiation of VA-ECMO) no significant statistical difference in values of ABP was observed in both groups (P = 0.196). ABP at H0 was 59 ± 34 mmHg in the group Cytosorb® (-) compared to 43 ± 25 mmHg in the group with Cytosorb® (+) (P = 0.196). From H1 to H4, ABP stabilized between 66 and 79 mmHg in both groups with no significant difference (P = 0.236) (Fig. 2 ). Vasopressor support with noradrenaline from H0 to H4 was not significantly different in both groups as illustrated in Fig. 3 A, 3 B. 60 minutes after initiation of VA-ECMO (H1), hemoglobin decreased to 8.3 ± 0.9 and 8.0 ± 1.1 (g/dL) in group Cytosorb® (−) and Cytosorb® (+), respectively (P = 0.316). At H4, hemoglobinemia was similar in both groups (6.7 ± 1.4 vs 6.5 ± 0.8 g/dL) as presented in Table 1. Baseline values of plasmatic lactate levels were comparable between the two groups and throughout the circulatory support with VA-ECMO (Table 1). Both kidney and liver functions were impaired during the procedure. Nevertheless, implementation of Cytosorb® adsorber membrane in VA-ECMO for the group Cytosorb® (+) could not demonstrate any benefit compared with group Cytosorb® (−) (Table 1). It is interesting to note a dramatic increase in levels of ASAT in both groups at H4, compared with moderately increased levels of ALAT (Table 1). Additionally, in both groups, no statistical difference was observed in diuresis (Fig. 4 A) although volumes of infused fluids were significantly more important in the group Cytosorb® (+) at H3 and H4, respectively (Fig. 4 B). However, no significant difference was noted regarding overall infused volumes between both groups (Fig. 4 C). Despite a tendency for higher baseline values of IL-6 in the group Cytosorb® (+), nevertheless comparison of plasmatic levels of cytokines IL-6 and IL-10 were not statistically different in both groups (Fig. 5 A). Following initiation of VA-ECMO, in both groups, plasmatic levels of cytokines IL-6 dramatically increased throughout the procedure compared with IL-10 (p = 0.0001), while IL-10 did not significantly change in group Cytosorb® (−) (P = 0.328). On the other hand, in group Cytosorb® (+), decrease of IL-10 reached a statistical significance (P = 0.0421*) as illustrated in Fig. 5 B. Biochemical data are summarized in Table 1. At the end of the procedures, all animals received four consecutive increasing doses of noradrenaline, 20𝜇g/kg, 40𝜇g/kg, 80𝜇g/kg, 160𝜇g/kg, respectively. Results are expressed through dose-response curves. Patterns of vasoreactivity did not significantly differ between group Cytosorb® (−) and group Cytosorb® (+) as illustrated in Fig. 6 . DISCUSSION The present experimental study contributed to show interesting results which may be more considered as trends rather than definitive evidence. Based on literature data, implementation of Cytosorb® in situations of CS supported by VA-ECMO might provide substantial benefits considering organ protection as well as organ recovery resulting from a delayed modulation of inflammatory response (48–72 hours) [10,11] through a reduction of the levels of pro-inflammatory cytokines (IL-6 and IL-10). It is widely admitted that multiple-depedent pejorative situations like infections, CS, use of ECMO [15], lead to an inflammatory cascade resulting in a cytokine storm which causes organ tissue damages and contribute to jeopardize the hemodynamics. In our study, several criteria were assessed regarding potential influence of Cytosorb®. Influence on pro-inflammatory cytokines IL-6 and IL-10. Regarding kinetics of plasmatic cytokines IL-6 and IL-10, our study suggests that, Cytosorb® might have a capacity to early reduce plasmatic levels of IL-10 (p = 0.0421*), while it does not apparently influence levels of IL-6. However, these findings need to be cautiously analyzed and confirmed by other studies in order to prevent a bias related to the small number of animals as well as to a time-limited procedure. Actually, because of a moderate statistical significance, our results might likely be considered much more as a trend rather than a certainty, as previously reported by Scharf [16] and Graf [17] who found neither evidence of potential clinical benefit nor harm while using Cytosorb® as modulator of the inflammatory response. Additionally, data collected tend to show a difference in the release kinetics triggered by CS, between Il-6 and IL-10 respectively (Fig. 5 B). Influence on hemodynamic parameters. While several reports [9,16] did not clearly demonstrate benefits of Cytosorb® on hemodynamics in patients on VA-ECMO, Soltesz et al [11], in a retrospective study including 58 patients showed that VA − ECMO integrated hemoadsorption treatment using Cytosorb® was associated with accelerated recovery of multiorgan and microcirculatory dysfunction, mitigated inflammatory response, less bleeding complications, and lower risk for early mortality in comparison with controls. Additionally, Akil et al [10] in a prospective study including 13 patients with pneumonic sepsis and acute respiratory distress syndrome concluded that CytoSorb®, in combination with venovenous ECMO, is an effective therapy to prevent escalation of sepsis with rapid weaning off high-dose catecholamine infusions and quick reduction in PCT and CRP levels. However, optimal timing of immunomodulatory therapy and impact on ECMO-related inflammation still need to be furtherly investigated. In our study, ABP pressure following CS induction, was lower in the group Cytosorb® (+) compared with the Group Cytosorb® (−), nevertheless without any statistical significance (43 ± 25 mmHg vs. 59 ± 34 mmHg, P = 0.196). This finding may likely result from specific differences in coronary distribution in swine as previously reported [18] independently of a similar location of LAD occlusion. It may also result from random differences in hemodynamic instability subsequently exacerbated by initiation of CS. Thereafter, at H1, ABP similarly stabilized in both groups (P = 0.479). This hemodynamic stability lasted throughout the procedure. However, the stability observed in our study is time-limited regarding longer durations − 48 or 72 hours - necessary to identify any significant differences as reported by Akil [10] and Soltesz [11], respectively. Therefore, our inability to find any differences is likely due to a potential time-dependent effect. Influence on biochemical and blood parameters. pO2, pCO2, pH, lactate levels, HCO3 - , hemoglobin, urea and creatininemia did not significantly differ between group Cytosorb® (−) and group Cytosorb® (+). At H4, levels of ASAT were markedly higher than levels of ALAT suggesting a severe multi organ dysfunction not only limited to liver. Study limitations. The first limitation is the small sample size in each group despite a statistical analysis aimed to calculate the minimal statistical power sample size of the cohort. Like many previously published experimental studies using swine models involving a small number of animals, our limitation was supported by ethical concerns to maintain a number of animals to the minimum required to achieve the goals of the research. The second obvious limitation is the limited duration of the experimental procedures (240 minutes) which probably did not enable to definitely identify any statistically significant differences between both groups. Despite the initial goal intended to assess benefits of Cytosorb®adsorber in the early phase of a CS under VA-ECMO, it is likely that a four-hour protocol is too short to draw definitive conclusions for a routine clinical practice. CONCLUSION Our study showed that implementation of Cytosorb® adsorber with VA-ECMO in a porcine model of ischemic refractory cardiogenic shock enabled to early mitigate the expression of pro inflammatory cytokine IL-10 while it did not influence levels of IL-6 in such a time-limited experimental procedure (240 minutes). This is the first reported evidence of a significant early modulation of IL-10 with Cytosorb® in such a critical hemodynamic situation. However, no clinical benefits were demonstrated in this four-hour experimental procedure. Despite a promising impact of Cytosorb® adsorber on IL-10 plasmatic levels, further studies are still necessary to pave the way for a routine and suitable therapeutic application of Cytosorb® in CS supported with VA-ECMO. Abbreviations VA-ECMO: Veno-Arterial Extracorporeal Membrane Oxygenation - CS: Cardiogenic Shock - ABP: Arterial Blood Pressure - LAD: Left Anterior Descending artery - ICU: Intensive Care Unit - TNF-𝛼: Tumor Necrosis Factor-𝛼 - CPB: Cardio-Pulmonary Bypass - IL-6: Interleukin 6 - IL-10: Interleukin 10. Declarations Author’s contributions: Juliette Piccoli achieved experimental procedures and was responsible for writing the original draft and revision; Tristan Ehrlich contributed to statistical analysis; Francesco Ferraro contributed to revise the manuscript; Aude Falanga was in charge of the technical experimental assistance and animal cares; Frédérique Groubatch-Joineau contributed to write the experimental protocol, discuss and submit the experimental protocol to the Nancy University Ethics Committee for Animal Experimentation (APAFIS n°45230) and was in charge of the technical experimental assistance; Vanessa Marie was in charge of the technical experimental assistance and animal cares; Nguyen Tran was responsible of the experimental supply assistance and revision of the original draft; Daniel Grandmougin achieved experimental procedures and was responsible for supervising the study and corrections of the original draft; Fabrice Vanhuyse was responsible of the revision of the original draft; Juan-Pablo Maureira was responsible for designing the experimental protocol and revision of the original draft. Funding: This study was supported by the University of Lorraine and the School of Surgery. Data availability: All data generated or analyzed in this study are included in this study are available from the corresponding author upon request. Ethics approval: This study was approved by the Nancy Ethics Committee for Animal Experimentation (APAFIS n°45230). Consent for publication: All authors consent for publication. Competing interests: The authors declare that they have no conflict of interest. Author’s information: ORCID numbers : Juliette Piccoli (0009-0000-8676-173X); Tristan Ehrlich (0000-0001-6217-5963); Aude Falanga (0009-0006-9605-5445); Frédérique Groubatch-Joineau (0009-0001-6830-1462); Daniel Grandmougin (0000-0003-3193-3711); Nguyen Tran (0000-0002-7037-8936); Juan-Pablo Maureira (0000-0002-3844-5692) . References Kolte D, Khera S, Aronow WS, Mujib M, Palaniswamy C, Sule S, Jain D, Gotsis W, Ahmed A, Frishman WH, Fonarow GC. Trends in incidence, management, and outcomes of cardiogenic shock complicating ST-elevation myocardial infarction in the United States. J Am Heart Assoc. 2014 Jan 13;3(1):e000590. DOI: 10.1161/JAHA.113.000590. PMID: 24419737; PMCID: PMC3959706. Delmas C, Elbaz M, Bonello L, Biendel C, Bouisset F, Lairez O, Silva S, Marcheix B, M Galinier. Place de l’assistance circulatoire dans le choc cardiogénique en France en 2018 : revue de la littérature et perspectives. Médecine Intensive Réanimation. 2018;27:97–113. https://DOI.org/10.3166/rea-2018-0023. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999 Aug 26;341(9):625-34. DOI: 10.1056/NEJM199908263410901. PMID: 10460813. Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J, Böhm M, Ebelt H, Schneider S, Schuler G, Werdan K; IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1287-96. DOI: 10.1056/NEJMoa1208410. Epub 2012 Aug 26. PMID: 22920912. Kohsaka S, Menon V, Lowe AM, Lange M, Dzavik V, Sleeper LA, Hochman JS; SHOCK Investigators. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005 Jul 25;165(14):1643-50. DOI: 10.1001/archinte.165.14.1643. PMID: 16043684. Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation 2003. Jun24;107(24):2998-3002. DOI:10.1161/01.CIR.0000075927. 67673.F2. PMID:1282185. Prondzinsky R, Unverzagt S, Lemm H, Wegener NA, Schlitt A, Heinroth KM, Dietz S, Buerke U, Kellner P, Loppnow H, Fiedler MG, Thiery J, Werdan K, Buerke M. Interleukin-6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock. Clin Res Cardiol. 2012 May;101(5):375-84. DOI: 10.1007/s00392-011-0403-3. Epub 2012 Jan 3. PMID: 22212516. Scharf C, Liebchen U, Paal M, Irlbeck M, Zoller M, Schroeder I. Blood purification with a cytokine adsorber for the elimination of myoglobin in critically ill patients with severe rhabdomyolysis. Crit Care. 2021 Jan 28;25(1):41. DOI: 10.1186/s13054-021-03468-x. PMID: 33509234; PMCID: PMC7844984. Becker S, Lang H, Vollmer Barbosa C, Tian Z, Melk A, Schmidt BMW. Efficacy of CytoSorb®: asystematic review and meta-analysis. Crit Care. 2023 May 31;27(1):215. DOI: 10.1186/s13054-023-04492-9. PMID: 37259160; PMCID: PMC10230475. Akil A, Ziegeler S, Reichelt J, Rehers S, Abdalla O, Semik M, Fischer S. Combined Use of CytoSorb and ECMO in Patients with Severe Pneumogenic Sepsis. Thorac Cardiovasc Surg. 2021 Apr;69(3):246-251. DOI: 10.1055/s-0040-1708479. Epub 2020 Apr 6. PMID: 32252114. Soltesz A, Molnar ZA, Szakal-Toth Z, Tamaska E, Katona H, Fabry S, Csikos G, Berzsenyi V, Tamas C, Edes IF, Gal J, Merkely B, Nemeth E. Influence of Venoarterial Extracorporeal Membrane Oxygenation Integrated Hemoadsorption on the Early Reversal of Multiorgan and Microcirculatory Dysfunction and Outcome of Refractory Cardiogenic Shock. J Clin Med. 2022 Nov 2;11(21):6517. DOI: 10.3390/jcm11216517. PMID: 36362744; PMCID: PMC9657372. Supady A, Zahn T, Rieder M, Benk C, Lother A, Bode C, Wengenmayer T, Staudacher D, Kellum JA, Duerschmied D. Effect of Cytokine Adsorption on Survival and Circulatory Stabilization in Patients Receiving Extracorporeal Cardiopulmonary Resuscitation. ASAIO J. 2022 Jan 1;68(1):64-72. DOI: 10.1097/MAT.0000000000001441. PMID: 33883508. Caluori G, Wojtaszczyk A, Yasin O, Pesl M, Wolf J, Belaskova S, Crha M, Sugrue A, Vaidya VR, Naksuk N, DeSimone CV, Killu AM, Padmanabhan D, Asirvatham SJ, Stárek Z. Comparing the incidence of ventricular arrhythmias during epicardial ablation in swine versus canine models. Pacing Clin Electrophysiol. 2019 Jul;42(7):862-867. DOI: 10.1111/pace.13698. Epub 2019 Apr 29. PMID: 30989679. Manninger M, Alogna A, Zweiker D, Zirngast B, Reiter S, Herbst V, Maechler H, Pieske BM, Heinzel FR, Brussee H, Post H, Scherr D. Mild hypothermia (33°C) increases the inducibility of atrial fibrillation: An in vivo large animal model study. Pacing Clin Electrophysiol. 2018 Jul;41(7):720-726. DOI: 10.1111/pace.13351. Epub 2018 May 15. PMID: 29663449. Lorusso R, Shekar K, MacLaren G, Schmidt M, Pellegrino V, Meyns B, Haft J, Vercaemst L, Pappalardo F, Bermudez C, Belohlavek J, Hou X, Boeken U, Castillo R, Donker DW, Abrams D, Ranucci M, Hryniewicz K, Chavez I, Chen YS, Salazar L, Whitman G. ELSO Interim Guidelines for Venoarterial Extracorporeal Membrane Oxygenation in Adult Cardiac Patients. ASAIO J. 2021 Aug 1;67(8):827-844. DOI: 10.1097/MAT.0000000000001510. Erratum in: ASAIO J. 2022 Jul 1;68(7):e133. DOI: 10.1097/MAT.0000000000001725. PMID: 34339398. Scharf C, Schroeder I, Paal M, Winkels M, Irlbeck M, Zoller M, Liebchen U. Can the cytokine adsorber CytoSorb® help to mitigate cytokine storm and reduce mortality in critically ill patients? A propensity score matching analysis. Ann Intensive Care. 2021 Jul 22;11(1):115. DOI: 10.1186/s13613-021-00905-6. PMID: 34292421; PMCID: PMC8295971. Graf H, Gräfe C, Bruegel M, Happich FL, Wustrow V, Wegener A, Wilfert W, Zoller M, Liebchen U, Paal M, Scharf C. Extracorporeal Elimination of Pro- and Anti-inflammatory Modulators by the Cytokine Adsorber CytoSorb® in Patients with Hyperinflammation: A Prospective Study. Infect Dis Ther. 2024 Sep;13(9):2089-2101. DOI: 10.1007/s40121-024-01028-8. Epub 2024 Aug 18. PMID: 39154299; PMCID: PMC11343926. Grandmougin D, Casse JM, Chalon A, Mourer B, Danli M, Groubatch-Joineau F, et al. Anatomie du cœur porcin. Similitudes et différences principales avec le cœur humain et conséquences potentielles en chirurgie cardiaque expérimentale porcine. Journal de Chirurgie Thoracique et Cardio-Vasculaire, Vol. 20 ; sept.2016. DOI.org/10.24399/JCTCV20–3-GRA. Tables Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Cite Share Download PDF Status: Published Journal Publication published 13 Dec, 2025 Read the published version in BMC Cardiovascular Disorders → Version 1 posted Editorial decision: Revision requested 27 Oct, 2025 Reviews received at journal 24 Oct, 2025 Reviews received at journal 08 Oct, 2025 Reviewers agreed at journal 08 Oct, 2025 Reviewers agreed at journal 07 Oct, 2025 Reviews received at journal 25 Sep, 2025 Reviewers agreed at journal 18 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers invited by journal 14 Sep, 2025 Editor assigned by journal 14 Sep, 2025 Editor invited by journal 12 Sep, 2025 Submission checks completed at journal 11 Sep, 2025 First submitted to journal 11 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7526597","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":518036205,"identity":"2d87052c-9677-4f21-b476-7eeccc0904ad","order_by":0,"name":"Juliette Piccoli","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Juliette","middleName":"","lastName":"Piccoli","suffix":""},{"id":518036208,"identity":"e09b8b06-89fc-4800-b17d-c3f248f261fd","order_by":1,"name":"Tristan Ehrlich","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Tristan","middleName":"","lastName":"Ehrlich","suffix":""},{"id":518036209,"identity":"a2148aa0-cfe7-4b13-88a8-4c2a015026b5","order_by":2,"name":"Francesco Ferraro","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Ferraro","suffix":""},{"id":518036210,"identity":"a0755185-d45b-4b70-a1d1-d136b4e951c0","order_by":3,"name":"Aude Falanga","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Aude","middleName":"","lastName":"Falanga","suffix":""},{"id":518036211,"identity":"79a2561f-d76b-48e6-b862-9f6102f33707","order_by":4,"name":"Frédérique Groubatch-Joineau","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Frédérique","middleName":"","lastName":"Groubatch-Joineau","suffix":""},{"id":518036212,"identity":"25c170d4-7f5c-4c2c-934a-153b5626a9d0","order_by":5,"name":"Vanessa Marie","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Vanessa","middleName":"","lastName":"Marie","suffix":""},{"id":518036213,"identity":"76dd3578-ab07-4125-b680-c2a59643d0e6","order_by":6,"name":"Fabrice Vanhuyse","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Fabrice","middleName":"","lastName":"Vanhuyse","suffix":""},{"id":518036214,"identity":"6ba10514-36d7-4c46-a1c3-8e8b7a2f2f62","order_by":7,"name":"Nguyen Tran","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Nguyen","middleName":"","lastName":"Tran","suffix":""},{"id":518036215,"identity":"5845b0e4-f4dd-4d05-8af4-ccbc1dc695b4","order_by":8,"name":"Daniel Grandmougin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDCCA2CSGcquIF3LGVK1MDC2EaGD7wD7tQ8/d1hH80ukXzxcOG+bHAP74aMb8GmRPMBTPLP3THruzBk5BYdnbrttzMCTlnYDnxaDAzzJDLxth3M33MhJOMy77XZigwSPGUEtjH/hWubcridCC/thZogt6QcO8zbcTmAgpEXyMA8zs2wb0C89bxgO8xy7bdhGyC98x9sfM75ts87tZ09//Jmn5rY8P/vhY3i1MDDzGEBZUAYbXuVgwP4AnTEKRsEoGAWjABUAAIVVUS5oQb6iAAAAAElFTkSuQmCC","orcid":"","institution":"University of Lorraine","correspondingAuthor":true,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Grandmougin","suffix":""},{"id":518036216,"identity":"dc059b14-c023-4ec4-9922-21d7772a6c73","order_by":9,"name":"Juan-Pablo. Maureira","email":"","orcid":"","institution":"University of Lorraine","correspondingAuthor":false,"prefix":"","firstName":"Juan-Pablo.","middleName":"","lastName":"Maureira","suffix":""}],"badges":[],"createdAt":"2025-09-03 11:38:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7526597/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7526597/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12872-025-05438-5","type":"published","date":"2025-12-13T15:59:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91847652,"identity":"38923088-e01d-4045-89ce-bdab000c06cb","added_by":"auto","created_at":"2025-09-22 10:25:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":45208,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscriptword.docx","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/4ab6787096b0086154d88ecd.docx"},{"id":91846200,"identity":"9db3d181-8f10-4048-bf64-00c6b5362938","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"json","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11213,"visible":true,"origin":"","legend":"","description":"","filename":"6657b89031fe470f8dc3392cb3a653ec.json","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/04551b6b7dd1bb4998ea64cc.json"},{"id":91846208,"identity":"c5e7d591-0348-4e3e-81c2-b36d0a61a9e0","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90165,"visible":true,"origin":"","legend":"","description":"","filename":"6657b89031fe470f8dc3392cb3a653ec1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/a8278c8c34d696e5f34d8a66.xml"},{"id":91846212,"identity":"b1bebb31-7625-4740-bee6-195a8d883210","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"pdf","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3063099,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/94988e5dfbadf1eb4f629707.pdf"},{"id":91846206,"identity":"e8aa7f98-5163-44cd-b5db-e332d9dd33d1","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"pdf","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":122195,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/8c89d648f83767da7dfe66c4.pdf"},{"id":91846209,"identity":"349d9f64-80f1-48f1-adcb-f27f014a92b1","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"pdf","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":130926,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/e97bfb0aa84c673ecfa1fad1.pdf"},{"id":91846204,"identity":"2f1a5ba2-9565-47f3-a310-dc2523287c36","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"pdf","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":176385,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/33fb76dac43c182e94c76b70.pdf"},{"id":91847656,"identity":"72aaf35c-8a80-4c50-9ef4-ac3ee69326fa","added_by":"auto","created_at":"2025-09-22 10:25:07","extension":"pdf","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":244790,"visible":true,"origin":"","legend":"","description":"","filename":"Figure5pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/2957356282f0aab2a1c5f1b1.pdf"},{"id":91847654,"identity":"b0d6b970-19ff-425f-a0af-6ce5befe1e61","added_by":"auto","created_at":"2025-09-22 10:25:07","extension":"pdf","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":115503,"visible":true,"origin":"","legend":"","description":"","filename":"Figure6pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/0afe65c2486bb3423e476564.pdf"},{"id":91848011,"identity":"365337d0-f3ba-4fa0-a434-cf7f5e9c31ca","added_by":"auto","created_at":"2025-09-22 10:33:07","extension":"xml","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":86612,"visible":true,"origin":"","legend":"","description":"","filename":"6657b89031fe470f8dc3392cb3a653ec1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/00137d4694807c95292da863.xml"},{"id":91848012,"identity":"36a398c0-35f2-4345-99e6-1de3f7252931","added_by":"auto","created_at":"2025-09-22 10:33:07","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99395,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/92a4454e41d25fdea95a7d91.html"},{"id":91848010,"identity":"7221f7dd-796a-408d-ae75-04748209ab98","added_by":"auto","created_at":"2025-09-22 10:33:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5490532,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e1A\u003c/strong\u003e. Exposure of the heart after median sternotomy showing the right atrium (RA), the right ventricle (RV), the left atrium (LA) and the left ventricle (LV). Black arrows indicate the position of the LAD (Left Anterior Descending artery).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1B\u003c/strong\u003e. Modifications of the ST-segment displayed on the ECG monitorafter LAD occlusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1C\u003c/strong\u003e. LAD occasion with a tourniquet slipped around the coronary vessel. Myocardial ischemia is identified by an obvious difference in the color of the myocardium below and above the tourniquet.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1D\u003c/strong\u003e. Internal defibrillator paddles positioned prior to defibrillation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1E\u003c/strong\u003e. Percutaneous positioning of femoral arterial (A) and venous (V) cannulas.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1F\u003c/strong\u003e. The Cytosorb® membrane bypassed to the ECMO flow.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/ebf18c49a2ba7547b3a685a9.png"},{"id":91846194,"identity":"4bea4432-0e9d-4343-a81c-451bbf2836e6","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":206039,"visible":true,"origin":"","legend":"\u003cp\u003eComparative variations of arterial blood pressure under VA-ECMO.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/91ecbc6604499e055e82dc77.png"},{"id":91846198,"identity":"a9ac6cdf-3586-4eff-9889-7cfafa55951c","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":203417,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e3A\u003c/strong\u003e. Comparative overall posologies of noradrenaline under VA-ECMO (H0 → H4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3B\u003c/strong\u003e. Time-dependent comparative posologies of noradrenaline under VA-ECMO.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/ca031371cb20407484c66fc7.png"},{"id":91848009,"identity":"66104804-ca8c-4fee-a93b-9fb6e1d2c63c","added_by":"auto","created_at":"2025-09-22 10:33:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":302953,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e4A\u003c/strong\u003e. Diuresis variations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4B\u003c/strong\u003e. Comparison of fluid administration.\u003c/p\u003e\n\u003cp\u003e4\u003cstrong\u003eC\u003c/strong\u003e. Overall infused fluid /group.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/c9697d9b9512f2fe2e7c49a9.png"},{"id":91847650,"identity":"84d4cc9e-aac9-4d1c-89a2-7235fd29199b","added_by":"auto","created_at":"2025-09-22 10:25:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":281352,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e5A\u003c/strong\u003e. Comparative baseline values of IL-6 and IL-10.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5B\u003c/strong\u003e. Comparative kinetics of plasmatic cytokines (IL-6 - IL-10).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/f1898e05d688b9bd8240bcd4.png"},{"id":91846203,"identity":"5dbec888-ab19-42fd-a4a5-2e90b2141712","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":276302,"visible":true,"origin":"","legend":"\u003cp\u003eDose-response curves to noradrenaline.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/e93ff8aa1695ec0f68fa9e60.png"},{"id":98244807,"identity":"1ce2ee34-f35d-496f-8dac-ab741ffdd547","added_by":"auto","created_at":"2025-12-15 16:15:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7564950,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/ec50883c-4701-4bcf-ae70-6a2332be6756.pdf"},{"id":91846196,"identity":"fece1d14-70ee-4ec2-bd7b-f0cf55140d0e","added_by":"auto","created_at":"2025-09-22 10:17:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17184,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7526597/v1/a14a375226d6da7dcb917297.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early Impact of Cytosorb® Adsorber on Proinflammatory Cytokine Plasmatic Levels in a Porcine Model of Refractory Cardiogenic Shock Supported with VA-ECMO","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCardiogenic shock (CS) is a life-threatening situation, resulting from an inadequate cardiac contractility and cardiac output which leads to a systemic hypoperfusion and multiorgan failure with a dismal spontaneous prognosis. Survival rate obviously depends on both a rapid access to Intensive Care Unit (ICU) and a prompt diagnosis as well as an adequate therapeutic management [1]. If CS may arise from a wide array of underlying causes, nevertheless, acute myocardial infarction remains the most frequent cause. Delmas et al [2], in a review of literature, reported an incidence of CS in Europe ranging from 60 000 to 70 000 per year with a mortality rate of 40% at 30 days. Despite significant improvements in hospital management, prognosis remains poor among patients with severe and profound CS with a low probability of recovery.\u003c/p\u003e\u003cp\u003eIndependently of initial triggering factors, CS rapidly leads to multi organ failure resulting from severe hypotension refractory to fluid loading, vasopressors agents and inotropic drugs [3,4].\u003c/p\u003e\u003cp\u003eDetrimental consequences of CS simultaneously result from both a severely impaired myocardial contractility with a low cardiac output syndrome and an altered peripheral microcirculatory blood flow with tissular hypoxia.\u003c/p\u003e\u003cp\u003eAdditionally, in 25% of the cases [5], CS involves complex inflammatory mechanisms similar to those identified in the Systemic Inflammatory Response Syndrome (SIRS) with activation of the inflammatory response characterized by an increased production of interleukins (IL-6 and IL-10) and Tumor Necrosis Factor (TNF-\u0026#120572;) which promote and exacerbate the production of nitric oxyde and peroxynitrite [6,7]. Furthermore, these latter inflammatory mediators and their respective metabolites produce negative inotropic and vasoplegic effects, are associated with cardiotoxicity, and therefore contribute to jeopardize hemodynamics.\u003c/p\u003e\u003cp\u003eCS is classically managed by medical support with introtropes and vasopressors. Nevertheless, when hemodynamics deteriorate despite optimal efforts, mechanical circulatory support is increasingly considered to improve immediate outcome and survival. Among all available devices, venoarterial extracorporeal membrane oxygenation (VA-ECMO) has emerged as a salvage option in patients with CS refractory to standard therapies. However, this device is known to heighten the systemic inflammatory response syndrome and consequently worsen the CS.\u003c/p\u003e\u003cp\u003eRecently, in order to reduce the excessive inflammatory response resulting from the \u0026laquo;cytokine storm\u0026raquo; observed in refractory CS, cytokine adsorption using the Cytosorb\u0026reg; adsorber (CytoSorbents Europe GmbH, Berlin, Germany) has been proposed. Interest of this approach is to attenuate circulating cytokine concentrations without affecting the physiological immune function.\u003c/p\u003e\u003cp\u003eCytosorb\u0026reg; contains an adsorber membrane which can reduce the level of hydrophobic molecules with a molecular mass up to 55 kDA [8]. Cytokine adsorption has been evaluated in various clinical settings including sepsis, hyper inflammatory syndromes, cardiac surgery with cardiopulmonary bypass (CPB) and occasionally with ECMO as recovery support after cardiac arrest and confirmed the safety of the adsorber membrane with no significant evidence of clinical efficacy [9\u0026ndash;11].\u003c/p\u003e\u003cp\u003eSupady A et al, in a recent study [12] suggested that CS supported with VA-ECMO in combination with the Cytosorb\u0026reg; adsorber neither disproved nor confirmed a clinically relevant treatment effect of cytokine adsorption despite hemodynamic stabilization and reduction of catecholamine plasmatic levels within 48 hours and then required larger randomized trials to better investigate clinical benefits of cytokine adsorption after VA-ECMO. Herein, we sought to investigate whether Cytosorb\u0026reg;adsorber may early impact pro inflammatory cytokine response, hemodynamics and organ function, in a swine model of ischemic CS supported with VA-ECMO with Cytosorb\u0026reg;adsorber compared to a control group of CS supported with VA-ECMO without Cytosorb\u0026reg;.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS.","content":"\u003cp\u003e All experiments were reviewed and approved by the Nancy University Ethics Committee for Animal Experimentation (APAFIS n\u0026deg;45230). The procedure for care and sacrifice of study animals was in accordance with the European Community Standards on the Care and Use of Laboratory Animals.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e1.1. Animal model.\u003c/h2\u003e\u003cp\u003eThe origin of swines is supported by an official collaboration between the School of Surgery (University of Lorraine) and an approved specific farmer specialized in breeding specific races of pigs dedicated to animal experimentation.\u003c/p\u003e\u003cp\u003eMale pigs (\u003cem\u003eLandrace breed\u003c/em\u003e) weighing approximately 50 kg were used in the study. Since female hormones may influence vasoreactivity, only males were selected. Pigs were randomly assigned in two groups:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eIschemic CS supported with VA-ECMO without Cytosorb\u0026reg; (n\u0026thinsp;=\u0026thinsp;6): Group Cytosorb\u0026reg; (\u0026minus;)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIschemic CS supported with VA-ECMo in combination with Cytosorb\u0026reg; (n\u0026thinsp;=\u0026thinsp;6): Cytosorb\u0026reg; (+)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e1.2. Exclusion criteria.\u003c/h2\u003e\u003cp\u003eCardiac arrest before baseline measurements, major hemorrhagic event before randomization, failure to achieve CS and ECMO device failure to provide the theoretical pump flow were considered as exclusion criteria.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e1.3. Animal preparation and surgical procedure.\u003c/h2\u003e\u003cp\u003eFollowing a one-day fast, animals were placed under general anesthesia and ventilation. Anesthesia was induced via the lateral auricular vein with an intravenous bolus of propofol (1 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Propofol-lipuro 1%, B. Braun, Melsungen AG, Germany). Animals were intubated (TeleflexIsis 7.5 I.D. mm, Teleflex Medical, Athlone, Ireland) and mechanically ventilated (Evita 1 Dura, Dr\u0026auml;ger, L\u0026uuml;beck, Germany) in assisted-controlled mode (inspiratory fraction of oxygen (FiO2), tidal volume 10 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and respiratory rate 12 per minute). Anesthesia was maintained throughout the entire experiment with a continuous infusion of sufentanil (0.2 \u0026micro;g\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e \u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, sufentanil, Mylan, Canonsburg, PA, USA), propofol (7 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e \u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, propofol-lipuro 2%, B. Braun Melsungen AG, Germany) and cisatracurium (0.9 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e \u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Nimbex, GlaxoSmithKline, Middlesex, Brentford, UK). The animals were monitored by continuous electrocardiogram (ECG) recording and equipped percutaneously, under ultrasound guidance, with a triple lumen catheter (8 Fr, Arrow\u0026reg;, Reading, PA, USA) inserted into the right external jugular vein and an arterial catheter into the carotid artery. This latter arterial catheter was used to insert a conductance catheter (Millar pressure conductance Unit Model 200. Millar Instruments Inc., Houston, Tx, USA) for a continuous measurement of arterial blood pressure (ABP).\u003c/p\u003e\u003cp\u003eGiven documented risk of both ventricular arrhythmia and atrial fibrillation in swine models [13,14], 6 mg/Kg of Amiodarone and 60 mg/Kg of magnesium sulfate were administered intravenously prior to sternotomy.\u003c/p\u003e\u003cp\u003eAfter a low median laparotomy, a catheter was placed and secured into the bladder to estimate hourly urine. Core body temperature was measured via a rectal probe and maintained at 38.5 ◦C.\u003c/p\u003e\u003cp\u003eA 50 IU\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e bolus dose of Heparin (Heparin Sodique Choay, Sanofi-Aventis, Paris, France) was administered after sternotomy, followed by a continuous intravenous infusion to maintain an activated clotting time (ACT) of 180\u0026ndash;250 s. Values were monitored every hour using the Hemochron Jr Signature Microcoagulation System (ITC, Hudsonville, MI, USA).\u003c/p\u003e\u003cp\u003eImmediately prior to the sternotomy, 5 or 6 Fr desilets were inserted into the femoral artery and vein under ultrasonographic guidance and cannulation of arterial and venous femoral vessels was achieved via the Seldinger technique. Femoral cannulas were then connected to the fully assembled ECMO circuit which was primed with saline solution (NaCl 0.9%, B. Braun Medical, Saint-Cloud, France). The oxygen/air flow was adjusted to maintain PaCO2 and PaO2 in the ranges of 4.0\u0026ndash;6.5 kPa and 10\u0026ndash;15 kPa, respectively, in blood exiting the oxygenator after initiation of VA-ECMO.\u003c/p\u003e\u003cp\u003eAfter median sternotomy, and heart exposure, the left anterior descending artery (LAD) was easily located (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). A 4\u0026thinsp;\u0026minus;\u0026thinsp;0 polypropyl\u0026egrave;ne suture passed through a tourniquet was placed around the proximal portion of the LAD. Then, the tourniquet was slipped and tied around the LAD to stop the coronary flow and induce a massive myocardial ischemia of the anterior wall of the left ventricle, leading within few minutes to a refractory ventricular fibrillation with CS. Patterns of myocardial ischemia were confirmed by modifications of the ST-segment displayed on the ECG monitor (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB), as well as a rapid modification of the color of the left ventricular myocardium (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC) and a severe hypokinesia of all anterior segments of the left ventricle. If ventricular fibrillation occured before initiation of VA-ECMO, internal defibrillation with internal paddles (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD) and cardiac massage were performed. Following a 30-minute ischemia with characterization of a CS, VA-ECMo was initiated at a nominal standard blood flow 65\u0026ndash;70 mL\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e based on a theoretical cardiac output and ELSO recommendations [\u003cb\u003e15\u003c/b\u003e] while the LAD was unclamped. The Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE shows femoral arterial and venous cannulations.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCriteria of CS:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eDecrease of cardiac index\u0026thinsp;\u0026gt;\u0026thinsp;30% of the baseline values.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDecrease of mean arterial pressure (MAP)\u0026thinsp;\u0026gt;\u0026thinsp;30% of the baseline values.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIncrease of plasmatic lactate levels\u0026thinsp;\u0026gt;\u0026thinsp;2.5 mmol.L\u003csup\u003e-1\u003c/sup\u003e.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThe Cytosorb\u0026reg;membrane was bypassed to the ECMO flow (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF).\u003c/p\u003e\u003cp\u003eThe overall duration of VA-ECMO circulatory support was 240 minutes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e1.4. Timing of measurements.\u003c/h2\u003e\u003cp\u003eAll parameters of the study were measured at different steps:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eBaseline measurement: Prior to the sternotomy.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eH0: After 60 minutes myocardial ischemia and CS immediately prior to initiation of VA-ECMO.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eH1 : After 60 minutes VA-ECMO.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eH2 : After 120 minutes VA-ECMO\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eH3 : After 180 minutes VA-ECMO.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eH4 : after 240 minutes VA-ECMO (end of the procedure).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e1.5. End-point and measured parameters.\u003c/h2\u003e\u003cp\u003eEnd-point: Hemodynamic stabilization validated by:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eHeart rate (HR), arterial blood pressure (ABP), and mean arterial pressure (MAP) were continuously recorded.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDoses of noradrenaline collected every hour.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePlasmatic lactate levels collected at baseline, after 60 minutes of CS, and after 240 minutes of VA-ECMO initiation.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePlasmatic cytokines concentrations (Il-6 and IL-10) using an ELISA test with rat interleukins (ELISA Quantikine, R\u0026amp;D Systems) collected at baseline, after 60 minutes of CS, and after 240 minutes of VA-ECMO initiation.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIndicators of liver function evaluated via levels of plasmatic transaminases (ALAT / ASAT) collected at baseline, after 60 minutes of CS (H0), and after 240 minutes (H4) of VA-ECMO initiation.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMarkers of kidney function evaluated via diuresis and levels of both plasmatic creatinine and urea collected at baseline, after 60 minutes of CS (H0), and after 240 minutes (H4) of assistance with VA-ECMO initiation.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eIn order to assess impact of Cytosorb\u0026reg; on vasoreactivity, a vasoreactivity test was done at the end of the procedure using increasing doses of noradrenaline given as boluses.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e1.6. Protocol of euthanasia.\u003c/h2\u003e\u003cp\u003eAt the end of each procedure (H4), animals were euthanized with an injection of 10 ml of pentobarbital (Exagon\u0026reg; 400 mg/mL Richter Pharma AG).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e1.\u003cem\u003e7. Data Analysis and Statistics.\u003c/em\u003e\u003c/h2\u003e\u003cp\u003eIn order to gain an expected effect size, an alpha risk of 0.05 as well a power of 0.9, a sample of at least 12 pigs was required using the BiostaTGV software.\u003c/p\u003e\u003cp\u003eStatistical analyses included Student\u0026rsquo;s t-test and Mann-Whitney U test for continuous variables and unequal variances respectively.\u003c/p\u003e\u003cp\u003eA P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. All data were analyzed using the statistical software SPSS version 28 (SPSS Inc., Chicago, IL, USA) and R version 4.2.2 (R Foundation, Vienna, Austria).\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\n\u003ch3\u003e12 pigs were successfully enrolled in the study and assigned in two respective groups:\u003c/h3\u003e\n\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eCytosorb\u0026reg; (\u0026minus;): VA-ECMO with no Cytosorb\u0026reg; (n\u0026thinsp;=\u0026thinsp;6).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eCytosorb\u0026reg; (+): VA-ECMO with Cytosorb\u0026reg; (n\u0026thinsp;=\u0026thinsp;6).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThere was no significant difference in age and weight of pigs (6 months / mean weight 54.71 Kg\u0026thinsp;\u0026plusmn;\u0026thinsp;3.15 as well as baseline measures of ABP (82\u0026thinsp;\u0026plusmn;\u0026thinsp;14 mmHg) for the group Cytosorb\u0026reg; (\u0026minus;) versus (82\u0026thinsp;\u0026plusmn;\u0026thinsp;8 mmHg) for the group Cytosorb\u0026reg; (+) between the two groups (P\u0026thinsp;=\u0026thinsp;0.490).\u003c/p\u003e\u003cp\u003eAs illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, despite a similar hemodynamic management, at H0 (initiation of VA-ECMO) no significant statistical difference in values of ABP was observed in both groups (P\u0026thinsp;=\u0026thinsp;0.196). ABP at H0 was 59\u0026thinsp;\u0026plusmn;\u0026thinsp;34 mmHg in the group Cytosorb\u0026reg; (-) compared to 43\u0026thinsp;\u0026plusmn;\u0026thinsp;25 mmHg in the group with Cytosorb\u0026reg; (+) (P\u0026thinsp;=\u0026thinsp;0.196).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFrom H1 to H4, ABP stabilized between 66 and 79 mmHg in both groups with no significant difference (P\u0026thinsp;=\u0026thinsp;0.236) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eVasopressor support with noradrenaline from H0 to H4 was not significantly different in both groups as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA,\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e60 minutes after initiation of VA-ECMO (H1), hemoglobin decreased to 8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 and 8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 (g/dL) in group Cytosorb\u0026reg; (\u0026minus;) and Cytosorb\u0026reg; (+), respectively (P\u0026thinsp;=\u0026thinsp;0.316). At H4, hemoglobinemia\u003c/p\u003e\u003cp\u003ewas similar in both groups (6.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 vs 6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 g/dL) as presented in Table\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eBaseline values of plasmatic lactate levels were comparable between the two groups and throughout the circulatory support with VA-ECMO (Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eBoth kidney and liver functions were impaired during the procedure. Nevertheless, implementation of Cytosorb\u0026reg; adsorber membrane in VA-ECMO for the group Cytosorb\u0026reg; (+) could not demonstrate any benefit compared with group Cytosorb\u0026reg; (\u0026minus;) (Table\u0026nbsp;1). It is interesting to note a dramatic increase in levels of ASAT in both groups at H4, compared with moderately increased levels of ALAT (Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eAdditionally, in both groups, no statistical difference was observed in diuresis (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA) although volumes of infused fluids were significantly more important in the group Cytosorb\u0026reg; (+) at H3 and H4, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). However, no significant difference was noted regarding overall infused volumes between both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eDespite a tendency for higher baseline values of IL-6 in the group Cytosorb\u0026reg; (+), nevertheless comparison of plasmatic levels of cytokines IL-6 and IL-10 were not statistically different in both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFollowing initiation of VA-ECMO, in both groups, plasmatic levels of cytokines IL-6 dramatically increased throughout the procedure compared with IL-10 (p\u0026thinsp;=\u0026thinsp;0.0001), while IL-10 did not significantly change in group Cytosorb\u0026reg; (\u0026minus;) (P\u0026thinsp;=\u0026thinsp;0.328). On the other hand, in group Cytosorb\u0026reg; (+), decrease of IL-10 reached a statistical significance (P\u0026thinsp;=\u0026thinsp;0.0421*) as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB.\u003c/p\u003e\u003cp\u003eBiochemical data are summarized in Table\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eAt the end of the procedures, all animals received four consecutive increasing doses of noradrenaline, 20\u0026#120583;g/kg, 40\u0026#120583;g/kg, 80\u0026#120583;g/kg, 160\u0026#120583;g/kg, respectively. Results are expressed through dose-response curves. Patterns of vasoreactivity did not significantly differ between group Cytosorb\u0026reg; (\u0026minus;) and group Cytosorb\u0026reg; (+) as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe present experimental study contributed to show interesting results which may be more considered as trends rather than definitive evidence.\u003c/p\u003e\u003cp\u003eBased on literature data, implementation of Cytosorb\u0026reg; in situations of CS supported by VA-ECMO might provide substantial benefits considering organ protection as well as organ recovery resulting from a delayed modulation of inflammatory response (48\u0026ndash;72 hours) [10,11] through a reduction of the levels of pro-inflammatory cytokines (IL-6 and IL-10). It is widely admitted that multiple-depedent pejorative situations like infections, CS, use of ECMO [15], lead to an inflammatory cascade resulting in a cytokine storm which causes organ tissue damages and contribute to jeopardize the hemodynamics.\u003c/p\u003e\u003cp\u003eIn our study, several criteria were assessed regarding potential influence of Cytosorb\u0026reg;.\u003c/p\u003e\u003cp\u003e\u003cem\u003eInfluence on pro-inflammatory cytokines IL-6 and IL-10.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eRegarding kinetics of plasmatic cytokines IL-6 and IL-10, our study suggests that, Cytosorb\u0026reg; might have a capacity to early reduce plasmatic levels of IL-10 (p\u0026thinsp;=\u0026thinsp;0.0421*), while it does not apparently influence levels of IL-6. However, these findings need to be cautiously analyzed and confirmed by other studies in order to prevent a bias related to the small number of animals as well as to a time-limited procedure. Actually, because of a moderate statistical significance, our results might likely be considered much more as a trend rather than a certainty, as previously reported by Scharf [16] and Graf [17] who found neither evidence of potential clinical benefit nor harm while using Cytosorb\u0026reg; as modulator of the inflammatory response. Additionally, data collected tend to show a difference in the release kinetics triggered by CS, between Il-6 and IL-10 respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003e\u003cem\u003eInfluence on hemodynamic parameters.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eWhile several reports [9,16] did not clearly demonstrate benefits of Cytosorb\u0026reg; on hemodynamics in patients on VA-ECMO, Soltesz et al [11], in a retrospective study including 58 patients showed that VA\u0026thinsp;\u0026minus;\u0026thinsp;ECMO integrated hemoadsorption treatment using Cytosorb\u0026reg; was associated with accelerated recovery of multiorgan and microcirculatory dysfunction, mitigated inflammatory response, less bleeding complications, and lower risk for early mortality in comparison with controls.\u003c/p\u003e\u003cp\u003eAdditionally, Akil et al [10] in a prospective study including 13 patients with pneumonic sepsis and acute respiratory distress syndrome concluded that CytoSorb\u0026reg;, in combination with venovenous ECMO, is an effective therapy to prevent escalation of sepsis with rapid weaning off high-dose catecholamine infusions and quick reduction in PCT and CRP levels. However, optimal timing of immunomodulatory therapy and impact on ECMO-related inflammation still need to be furtherly investigated.\u003c/p\u003e\u003cp\u003eIn our study, ABP pressure following CS induction, was lower in the group Cytosorb\u0026reg; (+) compared with the Group Cytosorb\u0026reg; (\u0026minus;), nevertheless without any statistical significance (43\u0026thinsp;\u0026plusmn;\u0026thinsp;25 mmHg vs. 59\u0026thinsp;\u0026plusmn;\u0026thinsp;34 mmHg, P\u0026thinsp;=\u0026thinsp;0.196). This finding may likely result from specific differences in coronary distribution in swine as previously reported [18] independently of a similar location of LAD occlusion.\u003c/p\u003e\u003cp\u003eIt may also result from random differences in hemodynamic instability subsequently exacerbated by initiation of CS. Thereafter, at H1, ABP similarly stabilized in both groups (P\u0026thinsp;=\u0026thinsp;0.479). This hemodynamic stability lasted throughout the procedure. However, the stability observed in our study is time-limited regarding longer durations \u0026minus;\u0026thinsp;48 or 72 hours - necessary to identify any significant differences as reported by Akil [10] and Soltesz [11], respectively. Therefore, our inability to find any differences is likely due to a potential time-dependent effect.\u003c/p\u003e\u003cp\u003e\u003cem\u003eInfluence on biochemical and blood parameters.\u003c/em\u003e\u003c/p\u003e\u003cp\u003epO2, pCO2, pH, lactate levels, HCO3\u003csup\u003e-\u003c/sup\u003e, hemoglobin, urea and creatininemia did not significantly differ between group Cytosorb\u0026reg; (\u0026minus;) and group Cytosorb\u0026reg; (+). At H4, levels of ASAT were markedly higher than levels of ALAT suggesting a severe multi organ dysfunction not only limited to liver.\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy limitations.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe first limitation is the small sample size in each group despite a statistical analysis aimed to calculate the minimal statistical power sample size of the cohort. Like many previously published experimental studies using swine models involving a small number of animals, our limitation was supported by ethical concerns to maintain a number of animals to the minimum required to achieve the goals of the research.\u003c/p\u003e\u003cp\u003eThe second obvious limitation is the limited duration of the experimental procedures (240 minutes) which probably did not enable to definitely identify any statistically significant differences between both groups. Despite the initial goal intended to assess benefits of Cytosorb\u0026reg;adsorber in the early phase of a CS under VA-ECMO, it is likely that a four-hour protocol is too short to draw definitive conclusions for a routine clinical practice.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur study showed that implementation of Cytosorb\u0026reg; adsorber with VA-ECMO in a porcine model of ischemic refractory cardiogenic shock enabled to early mitigate the expression of pro inflammatory cytokine IL-10 while it did not influence levels of IL-6 in such a time-limited experimental procedure (240 minutes). This is the first reported evidence of a significant early modulation of IL-10 with Cytosorb\u0026reg; in such a critical hemodynamic situation. However, no clinical benefits were demonstrated in this four-hour experimental procedure. Despite a promising impact of Cytosorb\u0026reg; adsorber on IL-10 plasmatic levels, further studies are still necessary to pave the way for a routine and suitable therapeutic application of Cytosorb\u0026reg; in CS supported with VA-ECMO.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eVA-ECMO: Veno-Arterial Extracorporeal Membrane Oxygenation - CS: Cardiogenic Shock - ABP: Arterial Blood Pressure - LAD: Left Anterior Descending artery - ICU: Intensive Care Unit - TNF-𝛼: Tumor Necrosis Factor-𝛼 - CPB: Cardio-Pulmonary Bypass - IL-6: Interleukin 6 - IL-10: Interleukin 10.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions:\u0026nbsp;\u003c/strong\u003eJuliette Piccoli achieved experimental procedures and was responsible for writing the original draft and revision; Tristan Ehrlich contributed to statistical analysis; Francesco Ferraro contributed to revise the manuscript; Aude Falanga was in charge of the technical experimental assistance and animal cares; Fr\u0026eacute;d\u0026eacute;rique Groubatch-Joineau contributed to write the experimental protocol, discuss and submit the experimental protocol to the Nancy University Ethics Committee for Animal Experimentation (APAFIS n\u0026deg;45230) and was in charge of the technical experimental assistance; Vanessa Marie was in charge of the technical experimental assistance and animal cares; Nguyen Tran was responsible of the experimental supply assistance and revision of the original draft; Daniel Grandmougin achieved experimental procedures and was responsible for supervising the study and corrections of the original draft; Fabrice Vanhuyse was responsible of the revision of the original draft; Juan-Pablo Maureira was responsible for designing the experimental protocol and revision of the original draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was supported by the University of Lorraine and the School of Surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed in this study are included in this study are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThis study was approved by the Nancy Ethics Committee for Animal Experimentation (APAFIS n\u0026deg;45230).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eAll authors consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s information:\u0026nbsp;\u003c/strong\u003e\u003cu\u003eORCID numbers\u003c/u\u003e: Juliette Piccoli (0009-0000-8676-173X); Tristan Ehrlich (0000-0001-6217-5963); Aude Falanga (0009-0006-9605-5445); Fr\u0026eacute;d\u0026eacute;rique Groubatch-Joineau (0009-0001-6830-1462); Daniel Grandmougin (0000-0003-3193-3711); Nguyen Tran (0000-0002-7037-8936); Juan-Pablo Maureira (0000-0002-3844-5692)\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKolte D, Khera S, Aronow WS, Mujib M, Palaniswamy C, Sule S, Jain D, Gotsis W, Ahmed A, Frishman WH, Fonarow GC. Trends in incidence, management, and outcomes of cardiogenic shock complicating ST-elevation myocardial infarction in the United States. J Am Heart Assoc. 2014 Jan 13;3(1):e000590. DOI: 10.1161/JAHA.113.000590. PMID: 24419737; PMCID: PMC3959706.\u0026nbsp;\u003c/li\u003e \u003cli\u003eDelmas C, Elbaz M, Bonello L, Biendel C, Bouisset F, Lairez O, Silva S, Marcheix B, M Galinier. Place de l\u0026rsquo;assistance circulatoire dans le choc cardiog\u0026eacute;nique en France en 2018 : revue de la litt\u0026eacute;rature et perspectives. M\u0026eacute;decine Intensive R\u0026eacute;animation. 2018;27:97\u0026ndash;113. https://DOI.org/10.3166/rea-2018-0023.\u003c/li\u003e \u003cli\u003eHochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999 Aug 26;341(9):625-34. DOI: 10.1056/NEJM199908263410901. PMID: 10460813.\u003c/li\u003e \u003cli\u003eThiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J, B\u0026ouml;hm M, Ebelt H, Schneider S, Schuler G, Werdan K; IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1287-96. DOI: 10.1056/NEJMoa1208410. Epub 2012 Aug 26. PMID: 22920912.\u003c/li\u003e\n \u003cli\u003eKohsaka S, Menon V, Lowe AM, Lange M, Dzavik V, Sleeper LA, Hochman JS; SHOCK Investigators. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005 Jul 25;165(14):1643-50. DOI: 10.1001/archinte.165.14.1643. PMID: 16043684.\u003c/li\u003e \u003cli\u003eHochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the \u0026nbsp;paradigm. Circulation 2003. Jun24;107(24):2998-3002. DOI:10.1161/01.CIR.0000075927. 67673.F2. PMID:1282185.\u003c/li\u003e \u003cli\u003eProndzinsky R, Unverzagt S, Lemm H, Wegener NA, Schlitt A, Heinroth KM, Dietz S, Buerke U, Kellner P, Loppnow H, Fiedler MG, Thiery J, Werdan K, Buerke M. Interleukin-6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock. Clin Res Cardiol. 2012 May;101(5):375-84. DOI: 10.1007/s00392-011-0403-3. Epub 2012 Jan 3. PMID: 22212516.\u003c/li\u003e \u003cli\u003eScharf C, Liebchen U, Paal M, Irlbeck M, Zoller M, Schroeder I. Blood purification with a cytokine adsorber for the elimination of myoglobin in critically ill patients with severe rhabdomyolysis. Crit Care. 2021 Jan 28;25(1):41. DOI: 10.1186/s13054-021-03468-x. PMID: 33509234; PMCID: PMC7844984.\u0026nbsp;\u003c/li\u003e \u003cli\u003eBecker S, Lang H, Vollmer Barbosa C, Tian Z, Melk A, Schmidt BMW. Efficacy of CytoSorb\u0026reg;: asystematic review and meta-analysis. Crit Care. 2023 May 31;27(1):215. DOI: 10.1186/s13054-023-04492-9. PMID: 37259160; PMCID: PMC10230475.\u003c/li\u003e \u003cli\u003e\u0026nbsp;Akil A, Ziegeler S, Reichelt J, Rehers S, Abdalla O, Semik M, Fischer S. Combined Use of CytoSorb and ECMO in Patients with Severe Pneumogenic Sepsis. Thorac Cardiovasc Surg. 2021 Apr;69(3):246-251. DOI: 10.1055/s-0040-1708479. Epub 2020 Apr 6. PMID: 32252114.\u003c/li\u003e \u003cli\u003e\u0026nbsp;Soltesz A, Molnar ZA, Szakal-Toth Z, Tamaska E, Katona H, Fabry S, Csikos G, \u0026nbsp; Berzsenyi V, Tamas C, Edes IF, Gal J, Merkely B, Nemeth E. Influence of Venoarterial Extracorporeal Membrane Oxygenation Integrated Hemoadsorption on the Early Reversal of Multiorgan and Microcirculatory Dysfunction and Outcome of Refractory Cardiogenic Shock. J Clin Med. 2022 Nov 2;11(21):6517. DOI: 10.3390/jcm11216517. PMID: 36362744; PMCID: PMC9657372.\u003c/li\u003e \u003cli\u003e\u0026nbsp;Supady A, Zahn T, Rieder M, Benk C, Lother A, Bode C, Wengenmayer T, Staudacher D, Kellum JA, Duerschmied D. Effect of Cytokine Adsorption on Survival and Circulatory Stabilization in Patients Receiving Extracorporeal Cardiopulmonary Resuscitation. ASAIO J. 2022 Jan 1;68(1):64-72. DOI: 10.1097/MAT.0000000000001441. PMID: 33883508.\u003c/li\u003e \u003cli\u003e\u0026nbsp;Caluori G, Wojtaszczyk A, Yasin O, Pesl M, Wolf J, Belaskova S, Crha M, Sugrue A, Vaidya VR, Naksuk N, DeSimone CV, Killu AM, Padmanabhan D, Asirvatham SJ, St\u0026aacute;rek Z. Comparing the incidence of ventricular arrhythmias during epicardial ablation in swine versus canine models. Pacing Clin Electrophysiol. 2019 Jul;42(7):862-867. DOI: 10.1111/pace.13698. Epub 2019 Apr 29. PMID: 30989679.\u0026nbsp;\u003c/li\u003e \u003cli\u003e\u0026nbsp;Manninger M, Alogna A, Zweiker D, Zirngast B, Reiter S, Herbst V, Maechler H, Pieske BM, Heinzel FR, Brussee H, Post H, Scherr D. Mild hypothermia (33\u0026deg;C) increases the inducibility of atrial fibrillation: An in vivo large animal model study. Pacing Clin Electrophysiol. 2018 Jul;41(7):720-726. DOI: 10.1111/pace.13351. Epub 2018 May 15. PMID: 29663449.\u003c/li\u003e \u003cli\u003e\u0026nbsp;Lorusso R, Shekar K, MacLaren G, Schmidt M, Pellegrino V, Meyns B, Haft J, Vercaemst L, Pappalardo F, Bermudez C, Belohlavek J, Hou X, Boeken U, Castillo R, Donker DW, Abrams D, Ranucci M, Hryniewicz K, Chavez I, Chen YS, Salazar L, Whitman G. ELSO Interim Guidelines for Venoarterial Extracorporeal Membrane Oxygenation in Adult Cardiac Patients. ASAIO J. 2021 Aug 1;67(8):827-844. DOI: 10.1097/MAT.0000000000001510. Erratum in: ASAIO J. 2022 Jul 1;68(7):e133. DOI: 10.1097/MAT.0000000000001725. PMID: 34339398.\u003c/li\u003e \u003cli\u003e\u0026nbsp;Scharf C, Schroeder I, Paal M, Winkels M, Irlbeck M, Zoller M, Liebchen U. Can the cytokine adsorber CytoSorb\u0026reg; help to mitigate cytokine storm and reduce mortality in critically ill patients? A propensity score matching analysis. Ann Intensive Care. 2021 Jul 22;11(1):115. DOI: 10.1186/s13613-021-00905-6. PMID: 34292421; PMCID: PMC8295971.\u003c/li\u003e \u003cli\u003e\u0026nbsp;Graf H, Gr\u0026auml;fe C, Bruegel M, Happich FL, Wustrow V, Wegener A, Wilfert W, Zoller M, Liebchen U, Paal M, Scharf C. Extracorporeal Elimination of Pro- and Anti-inflammatory Modulators by the Cytokine Adsorber CytoSorb\u0026reg; in Patients with Hyperinflammation: A Prospective Study. Infect Dis Ther. 2024 Sep;13(9):2089-2101. DOI: 10.1007/s40121-024-01028-8. Epub 2024 Aug 18. PMID: 39154299; PMCID: PMC11343926.\u003c/li\u003e\n \u003cli\u003eGrandmougin D, Casse JM, Chalon A, Mourer B, Danli M, Groubatch-Joineau F, et al. Anatomie du c\u0026oelig;ur porcin. Similitudes et diff\u0026eacute;rences principales avec le c\u0026oelig;ur humain et cons\u0026eacute;quences potentielles en chirurgie cardiaque exp\u0026eacute;rimentale porcine. Journal de Chirurgie Thoracique et Cardio-Vasculaire, Vol. 20 ; sept.2016. DOI.org/10.24399/JCTCV20\u0026ndash;3-GRA.\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cardiogenic shock, Porcine model, VA-ECMO, Cytosorb® adsorber, Cytokines IL-6 - IL- 10, Inflammatory response","lastPublishedDoi":"10.21203/rs.3.rs-7526597/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7526597/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCardiogenic shock (CS) is a pejorative situation which often requires a circulatory support with VA-ECMO. However, VA-ECMO is known to trigger an inflammatory cascade with expression of proinflammatory cytokines Interleukin-6 (IL-6) and Interleukin-10 (IL-10) causing organ damages and hemodynamic deterioration. Cytokine adsorption using the Cytosorb® adsorber was recently proposed to mitigate the inflammatory response. As relevance of implementing Cytosorb® adsorber with VA-ECMO is not validated, we sought to assess whether it might early influence levels of IL-6 and IL-10 in a porcine model of ischemic refractory CS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods.\u003c/strong\u003e CS was induced in 12 male pigs following acute proximal occlusion of the left anterior descending artery (LAD). After a low-flow period of 60 minutes, circulatory support with VA-ECMO was initiated and pigs were randomly assigned in two groups, Cytosorb® (−) (VA-ECMO without Cytosorb®adsorber: n = 6) and Cytosorb® (+) (VA-ECMO with Cytosorb®adsorber: n = 6). In each group, modulation of IL-6 and IL-10 was assessed during a four-hour procedure, as well as impact on arterial blood pressure, biological and biochemical, parameters.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults.\u003c/strong\u003e After 240 minutes, the Group Cytosorb® (+) demonstrated a significant propensity to reduce levels of IL-10, (p = 0.0421*). Regarding hemodynamics, biological and biochemical parameters, Cytosorb® adsorber showed no difference with the group Cytosorb® (−).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions.\u003c/strong\u003e Despite encouraging early benefits, further studies are still necessary to validate interests of a routine use of Cytosorb®adsorber with VA-ECMO.\u003c/p\u003e","manuscriptTitle":"Early Impact of Cytosorb® Adsorber on Proinflammatory Cytokine Plasmatic Levels in a Porcine Model of Refractory Cardiogenic Shock Supported with VA-ECMO","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 10:17:02","doi":"10.21203/rs.3.rs-7526597/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-27T09:22:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-24T19:11:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-08T09:55:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"181463434581209334548605464609556788875","date":"2025-10-08T09:12:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"338490134942506278027491270462334811222","date":"2025-10-07T16:10:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-25T07:33:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102262307485905756415780696802757527985","date":"2025-09-18T15:50:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-16T06:00:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"88228725580539227659555440320035481878","date":"2025-09-15T04:36:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-14T17:45:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-14T17:11:38+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-12T15:38:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-11T08:06:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-09-11T08:02:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"18af7832-8ca5-407a-a2d1-c9f67856472a","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-15T16:09:41+00:00","versionOfRecord":{"articleIdentity":"rs-7526597","link":"https://doi.org/10.1186/s12872-025-05438-5","journal":{"identity":"bmc-cardiovascular-disorders","isVorOnly":false,"title":"BMC Cardiovascular Disorders"},"publishedOn":"2025-12-13 15:59:31","publishedOnDateReadable":"December 13th, 2025"},"versionCreatedAt":"2025-09-22 10:17:02","video":"","vorDoi":"10.1186/s12872-025-05438-5","vorDoiUrl":"https://doi.org/10.1186/s12872-025-05438-5","workflowStages":[]},"version":"v1","identity":"rs-7526597","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7526597","identity":"rs-7526597","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}