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Heart, Lung and Circulation

Use of Cytokine Filters During Cardiopulmonary Bypass: Systematic Review and Meta-Analysis

Open AccessPublished:August 27, 2022DOI:https://doi.org/10.1016/j.hlc.2022.07.015

      Introduction

      Cardiac surgery involving cardiopulmonary bypass (CPB) activates an inflammatory response releasing cytokines that are associated with less favourable outcomes.
      This study aims to compare i) CPB during cardiac surgery (control) versus ii) CPB with haemoadsorption therapy; and assess the effect of adding this therapy in reducing the inflammatory cytokines burden.

      Methods

      A systematic literature review with meta-analysis was conducted regarding the main outcomes (operative mortality, ventilation duration, intensive care unit [ICU] and hospital stays) and day-1 inflammatory markers levels post-surgery. Fifteen (15) studies were included for final analysis (eight randomised controlled trials, seven observational studies) with no evidence of publication bias.

      Results

      Subgroup analysis of non-elective surgeries across observational studies (emergency and infective endocarditis) significantly favoured cytokine filters in terms of 30-day mortality (OR 0.40, 95% CI 0.20, 0.83; p=0.01) and shorter ICU stay (MD -42.36, 95% CI -68.07, -16.65; p=0.001). At day-1 post-surgery, there was a significant difference favouring the cytokine filter group in c-reactive protein (CRP) (MD -0.71, 95% CI -0.84, -0.59; p<0.001) with no differences in white blood count (WBC), procalcitonin (PCT), tumour necrosis factor-alpha (TNF-α), IL-6, IL-8 and lactate. When comparing cytokine filters and control across all studies there was no significant difference in operative mortality, ventilation duration, hospital stay and ICU length of stay. Also, there were no statistical differences in randomised controlled trials (RCTs) using haemadsorption filters.

      Conclusions

      A significant reduction in 30-day mortality and ICU stay could be obtained by using haemadsorption therapy during non-elective cardiac surgery, especially emergency surgery and in patients with higher inflammatory burden such as infective endocarditis.

      Keywords

      Introduction

      Cardiac surgery involving cardiopulmonary bypass (CPB) activates a systemic inflammatory response leading to the productions of pro- and anti-inflammatory cytokines [
      • Tomic V.
      • Russwurm S.
      • Möller E.
      • Claus R.A.
      • Blaess M.
      • Brunkhorst F.
      • et al.
      Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting.
      ,
      • Franke A.
      • Lante W.
      • Fackeldey V.
      • Becker H.P.
      • Thode C.
      • Kuhlmann W.D.
      • et al.
      Proinflammatory and antiinflammatory cytokines after cardiac operation: different cellular sources at different times.
      ]. The release of inflammatory molecules such as IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-α), interleukin- 1β (IL- 1β) during CPB leads to increased vascular permeability, thrombosis, increased lactate levels, systemic hypotension and subsequent organ failure [
      • Warren O.J.
      • Smith A.J.
      • Alexiou C.
      • Rogers P.L.B.
      • Jawad N.
      • Vincent C.
      • et al.
      The inflammatory response to cardiopulmonary bypass: part 1--mechanisms of pathogenesis.
      ,
      • Miller B.E.
      • Levy J.H.
      The inflammatory response to cardiopulmonary bypass.
      ,
      • Day J.R.S.
      • Taylor K.M.
      The systemic inflammatory response syndrome and cardiopulmonary bypass.
      ].
      Il-1β and TNF-α inflammatory cytokines increase immediately after surgery while IL-6 and IL-8 tend to peak between 3 and 24 hours postoperatively [
      • Laffey J.G.
      • Boylan J.F.
      • Cheng D.C.H.
      The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist.
      ,
      • Rothenburger M.
      • Soeparwata R.
      • Deng M.C.
      • Schmid C.
      • Berendes E.
      • Tjan T.D.
      • et al.
      Prediction of clinical outcome after cardiac surgery: the role of cytokines, endotoxin, and anti-endotoxin core antibodies.
      ]. During CPB, the resulting production of cytokine mediators is related to factors such as blood coming in contact with foreign surfaces, non-pulsatile blood flow, ischaemic-reperfusion injury and trauma of the surgery itself [
      Systemic hyperinflammation in cardiac surgery patients [Internet]. CytoSorbents Europe GmbH. [cited 2020 Sep 23].
      ].
      An increased imbalance between pro- and anti-inflammatory cytokines is associated with less favourable outcomes including correlations with acute kidney injury, decreased systemic vascular resistance, increased postoperative rate of infections and reduced lung functions, all of which prolong the discharge from intensive care units [
      • Zhang W.R.
      • Garg A.X.
      • Coca S.G.
      • Devereaux P.J.
      • Eikelboom J.
      • Kavsak P.
      • et al.
      Plasma IL-6 and IL-10 concentrations predict AKI and long-term mortality in adults after cardiac surgery.
      ,
      • Cremer J.
      • Martin M.
      • Redl H.
      • Bahrami S.
      • Abraham C.
      • Graeter T.
      • et al.
      Systemic inflammatory response syndrome after cardiac operations.
      ,
      • Sander M.
      • von Heymann C.
      • von Dossow V.
      • Spaethe C.
      • Konertz W.F.
      • Jain U.
      • et al.
      Increased interleukin-6 after cardiac surgery predicts infection.
      ,
      • Halter J.
      • Steinberg J.
      • Fink G.
      • Lutz C.
      • Picone A.
      • Maybury R.
      • et al.
      Evidence of systemic cytokine release in patients undergoing cardiopulmonary bypass.
      ]. It has thus been hypothesised that the removal of cytokines may improve postoperative outcomes.
      Haemoadsorption (HA) is the elimination of inflammatory cytokines by adsorption depending on their plasma concentration by using biocompatible highly porous polymer cartridges. One example is the Cytosorb (RenalTech International, New York, NY, USA) adsorber which demonstrated its initial efficacy of cytokines removal in, in vitro studies [
      • Kellum J.A.
      • Song M.
      • Venkataraman R.
      Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia.
      ]. Septic shock leads to an uncontrolled release of pro-inflammatory cytokines and mediators known as “cytokine storm” leading to increased mortality. Additional case reports and case series revealed beneficial outcomes with improved haemodynamics and inflammatory parameters when treating septic patients with Cytosorb adsorbers [
      • Song M.
      • Winchester J.
      • Albright R.L.
      • Capponi V.J.
      • Choquette M.D.
      • Kellum J.A.
      Cytokine removal with a novel adsorbent polymer.
      ,
      • Rimmelé T.
      • Kellum J.A.
      Clinical review: blood purification for sepsis.
      ,
      • Mitzner S.R.
      • Gloger M.
      • Henschel J.
      • Koball S.
      Improvement of hemodynamic and inflammatory parameters by combined hemoadsorption and hemodiafiltration in septic shock: a case report.
      ,

      David S, Thamm K, Schmidt BMW, Falk CS, Kielstein JT. Effect of extracorporeal cytokine removal on vascular barrier function in a septic shock patient. J Intensive Care [Internet]. 2017 [cited 2020 Jul 29];5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251288/

      ,
      • Schädler D.
      • Pausch C.
      • Heise D.
      • Meier-Hellmann A.
      • Brederlau J.
      • Weiler N.
      • et al.
      The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial.
      ,
      • Hetz H.
      • Berger R.
      • Recknagel P.
      • Steltzer H.
      Septic shock secondary to β-hemolytic streptococcus-induced necrotizing fasciitis treated with a novel cytokine adsorption therapy.
      ].
      This therapeutic removal of a wide range of inflammatory cytokines has recently been applied in treating the novel SARS-CoV-2 virus (commonly known as COVID-19). Severe vasodilation and release of high levels of IL-6 have been identified as predictors of fatal outcomes in COVID-19 disease. Randomised clinical trials are currently being conducted to investigate outcomes when using Cytosorb adsorbers in patients suffering from COVID-19 [

      Supady DA. Cytokine adsorption in severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation [Internet]. clinicaltrials.gov; 2020 Mar [cited 2020 Sep 22]. Report No.: NCT04324528. Available from: https://clinicaltrials.gov/ct2/show/NCT04324528

      ,

      Universitätsklinikum Hamburg-Eppendorf. Effect of CytoSorb adsorber on hemodynamic and immunological parameters in critical Ill patients with COVID-19 [Internet]. clinicaltrials.gov; 2020 Apr [cited 2020 Sep 22]. Report No.: NCT04344080. Available from: https://clinicaltrials.gov/ct2/show/NCT04344080

      ].
      The theoretical benefits for the application of cytokine filters during CPB in cardiac surgery include the effective reduction of cytokines produced and thus cytokine-induced organ damage, improved haemodynamics, resulting in reduced postoperative complications and therefore costs [
      Systemic hyperinflammation in cardiac surgery patients [Internet]. CytoSorbents Europe GmbH. [cited 2020 Sep 23].
      ].
      The aim of this study is to systematically review the literature for studies that compare the use of haemoadsorption during CPB against patients in whom haemoadsorption is not used. By assimilating the data and subgroup analysis we aimed to conduct a meta-analysis to accurately determine whether haemoadsorption during CPB is favourable in reducing the burden from high inflammatory cytokines.

      Materials and Methods

      Literature Search

      A systematic review was conducted following a structured protocol to determine the extent of published literature on the use of cytokine filters during cardiopulmonary bypass.
      This was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
      In October 2021 the search was performed using PubMed and Cochrane databases by using the following search terms: (hemoadsorption [all fields] OR adsorber [All fields] OR hemoperfusion [all fields] OR cytosorb [all fields]) AND (“cardiac surgery” [all fields] OR “intraoperative” [all fields]).
      Articles were first screened based on their titles and abstracts by two authors. Eligibility of studies for inclusion was cross-checked by senior authors (V.N. and M.Y.S.). The full texts of the remaining articles were then screened for study type, intervention and outcomes.

      Inclusion and Exclusion Criteria

      We included studies that compared use of a cytokine filter to the absence of it (control) during cardiopulmonary bypass in cardiac surgery. Studies that reported outcomes from only one of either group without comparison or those that compared intraoperative to the postoperative use of haemoadsorption without a control group, were excluded. Only articles in the English language were considered.
      Although most of the studies used the Cytosorb adsorber as a method of haemoadsorption, there was no restriction on other types being used such as the Alteco Lipopolysaccharide Adsorber (Alteco Medical AB, Lund, Sweden) and polymxin-B immobilised fibre column (Toray-myxin; Toray Industries, Tokyo, Japan). There was no restriction on the types of cardiac procedures, including cardiac transplantation and infective endocarditis.

      Data Extraction

      A summary of the data extraction process is provided in Supplementary File 1.

      Statistical Analyses

      A summary of the data analysis methodology is provided in Supplementary File 1.

      Results

      Summary of Included Papers

      After applying the inclusion criteria, 15 studies [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ,
      • Blomquist S.
      • Gustafsson V.
      • Manolopoulos T.
      • Pierre L.
      Clinical experience with a novel endotoxin adsorbtion device in patients undergoing cardiac surgery.
      ] in cardiac surgery (yrs 2009–2021) were included in the meta-analysis (Supplementary File 1). Full summary of included papers is provided in Supplemetary File 1.

      Preoperative and Operative Characteristics

      The majority of the studies reported preoperative characteristics: age (15/15) [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ,
      • Blomquist S.
      • Gustafsson V.
      • Manolopoulos T.
      • Pierre L.
      Clinical experience with a novel endotoxin adsorbtion device in patients undergoing cardiac surgery.
      ], gender (13/15) [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ], body mass index (BMI) (11/15) [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ] and EuroSCORE (10/15) [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ]. There was no heterogeneity in the methods of reporting of these variables.
      Cardiopulmonary bypass duration was described in all 15 studies and there was no statistically significant difference or heterogeneity between cytokine filter and control (mean difference 3.10, 95% confidence interval [CI] -7.36, 13.55; p 0.560).
      The studies in the meta-analyses included a variety of cardiac surgery operations. Eight (8) studies reported elective CPB surgery including coronary artery bypass graft surgery, valve operations and ascending aorta surgery [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Blomquist S.
      • Gustafsson V.
      • Manolopoulos T.
      • Pierre L.
      Clinical experience with a novel endotoxin adsorbtion device in patients undergoing cardiac surgery.
      ], one study only described emergency cardiac surgery [
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ], one study reported a mixture of elective and emergency aortic surgery with hypothermic circulatory arrest [
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ], four studies only described cardiac surgeries due to infective endocarditis [
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ] and one study reported cardiac transplantation patients only [
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ].

      Outcomes

      Operative mortality up to 30 days post-surgery was reported in 13 studies with 4 stating no mortality [
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ]. There was no significant difference in operative mortality when comparing cytokine filters and control (OR 0.69, 95% CI 0.31–1.52; p=0.350) (Figure 1A) with evidence of low heterogeneity.
      Figure thumbnail gr1
      Figure 1Forest plot: meta-analyses for difference in operative mortality; (A) all studies included; (B) only elective surgery included; (C) only non-elective surgery included.
      Duration of postoperative ventilation (hours) was described in eight studies [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ] and no statistical difference was noted between the two groups (mean difference -1.39, 95% CI -7.59, 4.81; p=0.660) (Figure 2A). Evidence of high heterogeneity was reported for this outcome.
      Figure thumbnail gr2
      Figure 2Forest plot: meta-analyses for differences in ventilation duration (hours). (A) all studies included; (B) only elective surgery included; (C) only non-elective surgery included.
      Intensive care unit length of stay (13/15 studies) did not demonstrate any significant difference among the cytokine filter group and the non-cytokine filter group (mean difference -9.00, 95% CI -28.70, 10.69; p=0.37) (Figure 3A). Evidence of high heterogeneity was reported for this outcome.
      Figure thumbnail gr3
      Figure 3Forest plot: meta-analyses for differences in intensive care unit (ICU) length of stay (hours); (A) all studies included; (B) only elective surgery included; (C) only non-elective surgery included.
      Overall hospital length of stay (12/15 studies) also illustrated no statistically significant difference between the two groups (mean difference 0.60, 95% CI -1.35, 2.56; p=0.540) (Figure 4A). Evidence of high heterogeneity was reported for this outcome.
      Figure thumbnail gr4
      Figure 4Forest plot: meta-analyses for differences in hospital length of stay (days); (A) all studies included; (B) only elective surgery included; (C) only non-elective surgery included.
      Findings were consistent after only including the eight elective surgeries [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Blomquist S.
      • Gustafsson V.
      • Manolopoulos T.
      • Pierre L.
      Clinical experience with a novel endotoxin adsorbtion device in patients undergoing cardiac surgery.
      ] and excluding emergency surgery, transplantation and infective endocarditis studies. This subgroup analysis showed no statistically significant difference between the two groups for operative mortality (OR 1.28, 95% CI 0.27–6.05; p=0.750) (Figure 1B), ventilation duration (mean difference 1.52, 95% CI -3.14, 6.17; p=0.52) (Figure 2B) and hospital length of stay (OR 0.61, 95% CI -0.58, 1.80; p=0.320) (Figure 4B). Nevertheless, the ICU length of stay was statistically significant favouring cytokine filter use when only including elective cardiac surgery (mean difference -11.62, 95% CI -21.91, -1.34; p=0.03) (Figure 3B).
      Further subgroup analysis was performed including only studies that compared non-elective surgeries: these included aortic surgery with hypothermic circulatory arrest [
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ], emergency surgery for patients on ticagrelor or rivaroxaban [
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ], cardiac transplantation [
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ] and infective endocarditis [
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ]. Operative mortality (OR 0.40, 95% CI 0.20–0.83; p=0.01) (Figure 1C) as well as ICU length of stay (mean difference -42.36, 95% CI -68.07, -16.65; p=0.001) (Figure 3C) demonstrated a statistically significant difference favouring cytokine filter use. Both outcomes demonstrated evidence of low heterogeneity. A trend favouring cytokine filters but no statistically significant difference was achieved between the two groups for ventilation duration (mean difference -29.84, 95% CI -63.19, 3.50; p=0.08) (Figure 2C). There was no statistically significant difference for hospital length of stay (mean difference 0.39, 95% CI –0.91, 1.68; p=0.560) (Figure 4C). Both outcomes illustrated evidence of low heterogeneity.
      Comparing the 12 studies that only used Cytosorb as a filter [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ] there was no statistical significant difference for operative mortality (OR 0.74, 95% CI 0.32–1.70; p=0.480) or ventilation duration (mean difference 1.18, 95% CI -4.29, 6.64; p=0.670) or ICU length of stay (mean difference -8.73, 95% CI -33.04, 15.58; p=0.480) or hospital length of stay (mean difference 0.31, 95% CI -1.78, 2.39; p=0.770) (Supplementary Figure 3A-C).
      An analysis of other postoperative outcomes such as acute kidney injury and atrial fibrillation was not possible due to the lack of data. Renal replacement therapy demonstrated a borderline significant difference favouring the non-cytokine filter group (OR 2.32, 95% CI 0.99, 5.44; p=0.05) (Supplementary Figure 4).
      The funnel plot analysis disclosed an asymmetry around the axis for ICU length of stay in the overall population only (Supplementary File 1). No asymmetry around the axis in any of the other outcomes was illustrated through the funnel plots, thus making publication bias related to all outcomes but ICU length of stay unlikely.

      Biochemical Markers

      There was variability in the reporting of postoperative day-one inflammatory markers across different studies.
      TNFα was reported in 3/15 studies, IL-6 in 4/15, IL-8 in 3/15, white blood count (WBC) in 5/15, c-reactive protein (CRP) in 6/15 and procalcitonin (PCT) in 4/15.
      A statistically significant difference favouring cytokine filter was found for CRP levels (Supplementary Figure 2A) at day 1 post-surgery (mean difference -0.71, 95% CI -0.84, -0.59; p<0.001). There was no statistically significant difference in the levels of the following inflammatory markers between the two groups at day 1 post-surgery: WBC (mean difference 0.51, 95% CI -0.69, 1.72; p=0.40) (Supplementary Figure 2B), PCT (mean difference -0.27, 95% CI -0.56, 0.01; p=0.06) (Supplementary Figure 2C), IL-6 (mean difference: 26.08, 95% CI-6.52, 58.69; p=0.12), TNF-α (mean difference -0.27, 95% CI -1.15, 0.60; p=0.540), IL-8 (mean difference -0.08, 95% CI -21.38, 21.24; p=0.99).
      Two (2) studies reported lactate levels and there was no statistical difference between the two groups (mean difference -0.01, 95% CI -0.45, 0.43; p=0.960). Furthermore, four studies [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ] compared the use of noradraneline (μg/kg/min) at day 1 postoperatively, showing no statistically significant difference between the cytokine filter group and the no cytokine filter group (MD 0.00, 95% CI, -0.03, 0.03; p=0.97).
      There was no variation in reporting that was attributable to heterogeneity for any of the above biochemical markers.
      After only including the eight elective surgeries [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • De Silva R.J.
      • Armstrong J.
      • Bottrill F.
      • Goldsmith K.
      • Colah S.
      • Vuylsteke A.
      A lipopolysaccharide adsorber in adult cardiopulmonary bypass: a single centre randomised controlled pilot trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Blomquist S.
      • Gustafsson V.
      • Manolopoulos T.
      • Pierre L.
      Clinical experience with a novel endotoxin adsorbtion device in patients undergoing cardiac surgery.
      ] and excluding emergency surgery, transplantation and infective endocarditis studies, this subgroup analysis showed no statistically significant difference between the two groups for day 1 postoperative levels of IL-6 (mean difference 39.73, 95% CI -4.67, 84.13; p=0.08) and WBC (mean difference 1.16, 95% CI -1.35, 3.66; p=0.36). However, consistent with previous results CRP was significantly lower in the cytokine filter group (mean difference -0.71, 95% CI –0.84, -0.59; p<0.001). Similar findings were noted for the 12 studies that used the Cytosorb filter only [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • Gleason T.G.
      • Argenziano M.
      • Bavaria J.E.
      • Kane L.C.
      • Coselli J.S.
      • Engelman R.M.
      • et al.
      Hemoadsorption to reduce plasma-free hemoglobin during cardiac surgery: results of REFRESH I pilot study.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Wagner R.
      • Soucek P.
      • Ondrasek J.
      • Fila P.
      • Sterba J.
      • Spacilova H.
      • et al.
      Plasma levels of myocardial MicroRNA-133a increase by intraoperative cytokine hemoadsorption in the complex cardiovascular operation.
      ,
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ] with no statistically significant difference for day 1 postoperative levels of IL-6 (mean difference 21.51, 95% CI -13.50, 56.52; p=0.23), WBC (OR 0.74, 95% CI -0.73, 2.21, p=0.33) and CRP (mean difference -0.55, 95% CI -1.52, 0.43; p=0.270).

      Meta-Regression

      In the presence of some heterogeneity in some of the meta-analyses, we performed meta-regression to assess the effect of relevant covariates on the main outcomes (Supplementary Table 1).
      Age, male gender, BMI, EuroSCORE and CPB duration were analysed and none had any significant influence on operative mortality rate, ventilation duration, length of ICU and hospital stay (p>0.05).

      Discussion

      Cardiac surgery is associated with an increased activation of the immune system due to blood coming into contact with artificial surfaces during cardiopulmonary bypass (CPB) which has been linked to adverse events [
      • Day J.R.S.
      • Taylor K.M.
      The systemic inflammatory response syndrome and cardiopulmonary bypass.
      ,
      • Nebelsiek T.
      • Beiras-Fernandez A.
      • Kilger E.
      • Möhnle P.
      • Weis F.
      Routine use of corticosteroids to prevent inflammation response in cardiac surgery.
      ]. Finding a method to remove the inflammatory cytokines during cardiopulmonary bypass could show improved outcomes. Haemoadsorption devices have shown benefits by removing cytokines such as TNF- α, IL-6 and IL-10 in animal studies using polymyxin B-immobilised haemoperfusion [
      • Ohki S.
      • Oshima K.
      • Takeyoshi I.
      • Matsumoto K.
      • Morishita Y.
      Endotoxin removal with a polymyxin B-immobilized hemoperfusion cartridge improves cardiopulmonary function after cardiopulmonary bypass.
      ] and in vitro by using Cytosorb adsorber [
      • Kellum J.A.
      • Song M.
      • Venkataraman R.
      Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia.
      ].
      Subsequent case reports and case series have been published demonstrating the use of the Cytosorb adsorber for treating septic shock resulting in decreased vasopressor need, effective removal of pro-inflammatory cytokines after 24 hours and improved haemodynamics [
      • Mitzner S.R.
      • Gloger M.
      • Henschel J.
      • Koball S.
      Improvement of hemodynamic and inflammatory parameters by combined hemoadsorption and hemodiafiltration in septic shock: a case report.
      ,

      David S, Thamm K, Schmidt BMW, Falk CS, Kielstein JT. Effect of extracorporeal cytokine removal on vascular barrier function in a septic shock patient. J Intensive Care [Internet]. 2017 [cited 2020 Jul 29];5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251288/

      ,
      • Schädler D.
      • Pausch C.
      • Heise D.
      • Meier-Hellmann A.
      • Brederlau J.
      • Weiler N.
      • et al.
      The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial.
      ,
      • Hetz H.
      • Berger R.
      • Recknagel P.
      • Steltzer H.
      Septic shock secondary to β-hemolytic streptococcus-induced necrotizing fasciitis treated with a novel cytokine adsorption therapy.
      ]. The Cytosorb adsorber might function at the level of the immune effector cells which leads to decreased activation of NfκB in neutrophils and Kupffer cells by a reduced cytokine load in the circulation and therefore a reduced production of cytokines [
      • Peng Z.Y.
      • Wang H.Z.
      • Carter M.J.
      • Dileo M.V.
      • Bishop J.V.
      • Zhou F.H.
      • et al.
      Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis.
      ].
      In the last decade there have been an increasing number of randomised control trials and observational studies for the use of cytokine filters in cardiac surgery to demonstrate the similar benefits seen for septic patients.
      Several studies have confirmed the safety and feasibility of using cytokine filters during CPB and did not observe any adverse device-related side effects [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ].
      To our knowledge, our present study is the first meta-analysis to date for the use of cytokine filters during cardiopulmonary bypass in cardiac surgery.

      Effect on ICU Outcome

      The shorter ICU length of stay in the cytokine filter group among elective and non-elective procedures is similar to the findings noted in some of the papers that included high-risk patients or surgery: emergency cardiac surgery in patients on ticagrelor or rivaroxaban [
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ], cardiac transplantation [
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ] and infective endocarditis patients [
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ].
      Hassan et al. described that the use of Cytosorb virtually eliminated postoperative bleeding after emergency cardiac surgery in patients on ticagrelor or rivaroxaban, which in turn resulted in reduced ICU stay [
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ].
      Nemeth et al. presented that patients receiving Cytosorb therapy during CPB group were associated with less severe post-cardiac transplantation vasoplegia, thus diminishing the vasopressor demand in the first 48 hours and reducing ICU stay [
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ]. Totsugawa et al. reported that the reduced inotropic support favoured an early extubation leading to shorter ICU stay for the cytokine filter group after being treated for emergency infective endocarditis surgery [
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ].
      Similarly to elective surgery, in non-elective surgeries only [
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ,
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ], cytokine filter favoured shorter ICU length of stay compared to control. An analysis of other postoperative outcomes such as atrial fibrillation and acute kidney injury was not possible, although a borderline difference favouring the non-cytokine filter group was found for renal replacement therapy.
      The reported effects of reduced inotropic support favouring shorter ICU stay [
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ] were not supported in our study. These results can be explained due to following reasons. First, only four studies [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ,
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ] reported numerical values of noradrenaline as μg/Kg/min unit that have been included in our analysis, too small to derive any conclusions. Second, the remaining four studies that reported inotropic results, were removed for this analysis as they described intraoperative levels only [
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ,
      • Saller T.
      • Hagl C.
      • Woitsch S.
      • Li Y.
      • Niedermayer S.
      • Born F.
      • et al.
      Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.
      ], combination of dopamine, dobutamine, noradrenaline and adrenaline [
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ] and only graphical representation without numerical value obtained [
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ].
      Although these analyses exhibited moderate heterogeneity for ventilation duration, ICU length of stay and hospital length of stay, this was reduced when only comparing elective surgery or non-elective surgery. Meta-regression analyses were also conducted to account for this heterogeneity and confirmed that relevant covariates did not influence on the main outcomes.

      Effect on Inflammatory Markers

      Similar to Bernardi et al. (moderate preoperative risk patients) and Poli et al. (high-risk for perioperative complications patients), the use of cytokine filters was not effective in reducing inflammatory cytokines like TNFα, IL-6 and IL-8 or markers such as WBC, and PCT at day 1 post-surgery [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ]. Further subgroup analysis within elective and non-elective surgeries could not be carried out due to very limited observations being recorded.
      Our analysis did find a significant difference in favour of a cytokine filter with regards to CRP values. Nevertheless, it has to be noted that inflammatory markers such as CRP have a lower predictive value for inflammatory responses after cardiac surgery [
      • Stoppelkamp S.
      • Veseli K.
      • Stang K.
      • Schlensak C.
      • Wendel H.P.
      • Walker T.
      Identification of predictive early biomarkers for sterile-SIRS after cardiovascular surgery.
      ]. In the early postoperative stage, CRP increases after cardiac surgery regardless of the severity of the inflammatory response and its usefulness for interpretation after cytokine filter is questionable [
      • Delannoy B.
      • Guye M.L.
      • Slaiman D.H.
      • Lehot J.J.
      • Cannesson M.
      Effect of cardiopulmonary bypass on activated partial thromboplastin time waveform analysis, serum procalcitonin and C-reactive protein concentrations.
      ]. Procalcitonin is used as diagnostic and follow-up marker for both infective and non-infective inflammatory responses. Our analysis demonstrated a trend towards cytokine filters favouring reduced PCT levels compared to control, but it did not reach statistical significance. Pro-inflammatory cytokines contribute to PCT induction after surgery leading to peak levels within 24 hours which correlates well with duration of CPB and can be used as a prognostic indicator for complications after cardiac surgery [
      • Sponholz C.
      • Sakr Y.
      • Reinhart K.
      • Brunkhorst F.
      Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature.
      ,
      • Meisner M.
      • Rauschmayer C.
      • Schmidt J.
      • Feyrer R.
      • Cesnjevar R.
      • Bredle D.
      • et al.
      Early increase of procalcitonin after cardiovascular surgery in patients with postoperative complications.
      ].
      In our analysis we did not include IL-10 as very few studies reported this numerically. It has been shown that higher IL-10 levels post cardiac surgery is associated with a decreased risk of mortality [
      • Zhang W.R.
      • Garg A.X.
      • Coca S.G.
      • Devereaux P.J.
      • Eikelboom J.
      • Kavsak P.
      • et al.
      Plasma IL-6 and IL-10 concentrations predict AKI and long-term mortality in adults after cardiac surgery.
      ]. Interestingly Bernardi et al. observed a slower decrease of postoperative IL-10 in the haemoadsorption groups compared to control with effects up to 48 hours after surgery [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ]. However this was not reported by the other two randomised control trials by Poli et al. and Stupica et al. [
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ,
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ].
      The surprising absence of the cytokine filter effects on other inflammatory markers levels might be related to two key factors: an insufficient duration of treatment and a lower inflammatory response compared to septic patients.

      Effect on Mortality

      Our analysis showed a significant decrease in 30-day mortality in the non-elective group which included emergency cardiac surgery [
      • Hassan K.
      • Kannmacher J.
      • Wohlmuth P.
      • Budde U.
      • Schmoeckel M.
      • Geidel S.
      Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding.
      ], cardiac transplantation [
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ], and infective endocarditis patients [
      • Asch S.
      • Kaufmann T.P.
      • Walter M.
      • Leistner M.
      • Danner B.C.
      • Perl T.
      • et al.
      The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.
      ,
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ,
      • Totsugawa T.
      • Kuinose M.
      • Yoshitaka H.
      • Tsushima Y.
      • Ishida A.
      • Chikazawa G.
      • et al.
      Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis.
      ]. In contrast, there was no statistically significant difference in the elective patients. To our knowledge, this is the first time a mortality advantage is illustrated in a comparative assessment of cytokine filters within cardiac surgery. In patients with infective endocarditis, an important cause of in-hospital mortality is postoperative multiorgan failure, which is a consequence of sepsis from a severe systemic inflammatory reaction from the cardiopulmonary bypass [
      • Haidari Z.
      • Wendt D.
      • Thielmann M.
      • Mackowiak M.
      • Neuhäuser M.
      • Jakob H.
      • et al.
      Intraoperative hemoadsorption in patients with native mitral valve infective endocarditis.
      ]. The decrease in mortality in this group of patients could in fact reflect the effects of the multiple factors involved in the inflammatory processes which cytokine filters aim to reduce. In addition, the effects of cytokine filters on mortality post-cardiac surgery have previously not reached statistical significance often due to small samples sizes [
      • Nemeth E.
      • Kovacs E.
      • Racz K.
      • Soltesz A.
      • Szigeti S.
      • Kiss N.
      • et al.
      Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.
      ]. However, the correlation between increased cytokine levels and mortality of sepsis have been demonstrated previously [
      • Kellum J.A.
      • Kong L.
      • Fink M.P.
      • Weissfeld L.A.
      • Yealy D.M.
      • Pinsky M.R.
      • et al.
      Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study.
      ].
      In the setting of acutely unwell and septic patients, previous studies in the literature have already outlined a 30-day mortality advantage associated with the use of Cytosorb. Brouwer and colleagues in an analysis of ICU patients having septic shock, reported a significant decrease in the observed 28-day mortality rates when compared to expected mortality rates [
      • Brouwer W.P.
      • Duran S.
      • Kuijper M.
      • Ince C.
      Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study.
      ]. In particular, pre-haemadsorption lactate levels have been demonstrated to be an independent predictor of mortality [
      • Brouwer W.P.
      • Duran S.
      • Kuijper M.
      • Ince C.
      Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study.
      ]. Similar results were also reported by Friesecke and colleagues in their analysis of 20 consecutive refractory septic shock patients receiving cytokine filters, who also underlined the importance of considering lactate levels [
      • Friesecke S.
      • Stecher S.S.
      • Gross S.
      • Felix S.B.
      • Nierhaus A.
      Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: a prospective single-center study.
      ]. Unfortunately, due to lack and inconsistency in the reported data of preoperative lactate levels, an analysis within our work was not possible, therefore leaving a window open for future studies. While promising for non-elective cardiac surgical patients, we believe that these results should be interpreted with caution and warrant the further need for a large scale randomised control trial assessing mortality associated factors in this cohort.

      Duration of CPB

      The average duration of CPB during which the cytokine filter is utilised was 157.9±46.4 minutes in the Cytosorb group and 152.2±53.3 minutes in the control one. This might be too short to allow a significant reduction of cytokine levels and thus difficult to show efficacy [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ]. In fact, there is a complex intracellular signalling of upregulation, expressions and secretion which might take longer in order to release cytokines [
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ]. Previous animal studies in rats and case reports showed that optimal cytokine removal occurred when treatment was at least 4 hours up to 4 days [
      • Kellum J.A.
      • Song M.
      • Venkataraman R.
      Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia.
      ,
      • Song M.
      • Winchester J.
      • Albright R.L.
      • Capponi V.J.
      • Choquette M.D.
      • Kellum J.A.
      Cytokine removal with a novel adsorbent polymer.
      ,
      • Bruenger F.
      • Kizner L.
      • Weile J.
      • Morshuis M.
      • Gummert J.F.
      First successful combination of ECMO with cytokine removal therapy in cardiogenic septic shock: a case report.
      ].
      Extending the use of cytokine filters to post-surgery could be considered with previous studies showing benefits by using modified ultrafiltration post-CPB with significant reduction in cytokines [
      • Grünenfelder J.
      • Zünd G.
      • Schoeberlein A.
      • Maly F.E.
      • Schurr U.
      • Guntli S.
      • et al.
      Modified ultrafiltration lowers adhesion molecule and cytokine levels after cardiopulmonary bypass without clinical relevance in adults.
      ]. More recently, a comparative study on intraoperative versus intraoperative plus postoperative use of CytoSorb in infective endocarditis patients showed benefits when patients developed perioperative renal failure with severe haemodynamic instability and high-grade intraoperative findings. However, both groups showed a comparable stabilisation in haemodynamics and inflammatory parameters with similar ICU and 90-day survival compared to patients treated only intraoperatively [
      • Kühne L.U.
      • Binczyk R.
      • Rieß F.C.
      Comparison of intraoperative versus intraoperative plus postoperative hemoadsorption therapy in cardiac surgery patients with endocarditis.
      ].

      Degree of Inflammatory Response

      It is possible that CPB duration is not the only factor for this reduced haemoadsorption effectiveness during cardiopulmonary bypass.
      Recent data from Garau et al. showed a significant decrease in inflammatory cytokine IL-8 and TNF-α which were short lasting despite lower CPB durations [
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ]. These differences could be explained by higher EuroSCORE and higher inflammatory responses in their study [
      • Taleska Stupica G.
      • Sostaric M.
      • Bozhinovska M.
      • Rupert L.
      • Bosnic Z.
      • Jerin A.
      • et al.
      Extracorporeal hemadsorption versus glucocorticoids during cardiopulmonary bypass: a prospective, randomized, controlled trial.
      ]. Poli et al. suggest the lack of haemoadsorption efficacy could be explained by the lower inflammatory responses in their trial and that of Bernardi et al. [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ].
      A positive correlation has been demonstrated between IL-6 concentrations after CPB and duration of it [
      • Whitten C.
      • Ge H.
      • R I.
      • Pe G.
      • Jm L.
      Does the duration of cardiopulmonary bypass or aortic cross-clamp, in the absence of blood and/or blood product administration, influence the IL-6 response to cardiac surgery?.
      ]. Cytokines would be eliminated depending on their plasma concentration during haemoadsorption. In fact, the cytokine load in septic patients is superior to the elective cardiac surgical patients and therefore Cytosorb adsorbers would be more effective in septic patients [
      • Garau I.
      • März A.
      • Sehner S.
      • Reuter D.A.
      • Reichenspurner H.
      • Zöllner C.
      • et al.
      Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor α serum levels in cardiac surgery: a randomized controlled trial.
      ].
      Träger et al. demonstrated the concentration of IL-6 cytokine release with levels of up to 5,000 pg/mL post-CPB in their infective endocarditis surgical patients and compared it to the modest levels seen in Bernardi et al. which did not exceed 254 pg/ml in elective cardiac surgery [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ]. IL-6 levels reduced significantly in Träger et al. while Bernardi et al. did not notice any difference between the Cytosorb and control groups [
      • Bernardi M.H.
      • Rinoesl H.
      • Dragosits K.
      • Ristl R.
      • Hoffelner F.
      • Opfermann P.
      • et al.
      Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent.
      ,
      • Träger K.
      • Skrabal C.
      • Fischer G.
      • Datzmann T.
      • Schroeder J.
      • Fritzler D.
      • et al.
      Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - a case series.
      ].
      This illustrates that cytokine adsorption may be preferentially more effective in patients with high inflammatory response, such as infective endocarditis. Similarly, this inflammatory response is also more pronounced in cardiac transplant patients than conventional cardiac surgeries due to already activated immune systems in advanced stages of heart failure [
      • Wan S.
      • Marchant A.
      • DeSmet J.M.
      • Antoine M.
      • Zhang H.
      • Vachiery J.L.
      • et al.
      Human cytokine responses to cardiac transplantation and coronary artery bypass grafting.
      ].
      It is becoming clearer that duration of CPB and cytokine load in the inflammatory response play roles in the effectiveness of haemoadsorption. Although, we did find a shorter ICU length of stay with Cytokine filters in elective studies, haemadsorption devices could be considered not likely to be beneficial in a majority of elective cardiac surgeries with moderate inflammatory responses [
      • Poli E.C.
      • Alberio L.
      • Bauer-Doerries A.
      • Marcucci C.
      • Roumy A.
      • Kirsch M.
      • et al.
      Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.
      ]. This benefit seems to be more pronounced in patients with a high inflammatory load such as infective endocarditis and emergency surgeries.

      Cost Consideration

      In line with all interventions offered within health care costs, considerations for cytokine filters also remain an important topic of debate. While a decrease in cost would appear logical with improved health outcomes, the economical evidence with regards to the application of cytokine filters in cardiac surgery remains limited. Interestingly, Javanbakht and colleagues analysed the cost-utility of Cytosorb for ticagrelor removal in patients undergoing emergency or urgent cardiac surgery [
      • Javanbakht M.
      • Trevor M.
      • Rezaei Hemami M.
      • Rahimi K.
      • Branagan-Harris M.
      • Degener F.
      • et al.
      Ticagrelor removal by CytoSorb® in patients requiring emergent or urgent cardiac surgery: a UK-based cost-utility analysis.
      ]. Their results demonstrate that Cytosorb was less costly than the control group without Cytosorb (GBP£12,933 vs £16,874). Nevertheless, it is to be understood that these cost savings, while promising, are a result of fewer complications, such as fewer transfusions, shorter ICU and hospital stay.

      Future Recommendations

      The need for further evidence and large scale randomised controlled trials persists with regards to cytokine filters in the setting of cardiac surgery. In line with our findings, it has become clear that patients undergoing emergency or urgent cardiac surgery might be the ones to benefit the most from haemadsorption devices. Nevertheless, owing to the difficulties in the recruitment of these patients in RCTs, the evidence remains limited to observational studies. In the daily clinical treatment of patients undergoing cardiac surgery we recommend a team based approach to select the most appropriate patients for cytokine filter. Based on the findings of this study, patients undergoing cardiac surgical operations at risk of higher inflammatory response seem to be adequate candidates for cytokine filter consideration. Interestingly, machine learning and artificial intelligence could play an important role in the identification of non-traditionally recognised risk factors and modifying factors which could identify patients better suited for cytokine therapy [

      Naruka V, Arjomandi Rad A, Subbiah Ponniah H, Francis J, Vardanyan R, Tasoudis P, et al. Machine learning and artificial intelligence in cardiac transplantation: a systematic review. Artif Organs [Internet]. [cited 2022 Jun 23];n/a(n/a). Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/aor.14334

      ].

      Limitations

      This meta-analysis has some limitations. There is a limited number of studies included, despite only a small number of studies available in the literature after applying the inclusion and exclusion criteria. Of the 15 studies included in this meta-analysis, only eight are RCTs and the remaining seven are observational, the latter include the non-elective surgeries and those with infective endocarditis. Although our funnel plot showed no significant risk for publication bias, this could be still present, and caution is required when interpreting these results.
      The level of heterogeneity present for some of the outcomes was high due to variability in operation types (emergency and elective), disease (coronary artery disease, aortic disease or infective endocarditis) and patients included with variable EuroSCOREs. This was reduced when only analysing elective or non-elective operations, but the degree of heterogeneity could not be completely eliminated.
      In addition, some variables such as TNF-α, IL-8, PCT and lactate at day 1 post-surgery were not regularly reported in the studies included and therefore only limited analyses could be performed. Lastly, some of the variables (mainly inflammatory markers and inotropes levels) that were reported in the individual studies were only described graphically with no numerical values. Although attempts were made to contact corresponding authors for numerical values, the ones that were not provided were excluded in the analysis.

      Conclusions

      After more than a decade of multiple randomised controlled trials and observational studies, it is becoming clearer that haemoadsorption devices are likely to be more beneficial in patients with higher inflammatory response such as infective endocarditis and emergency operations. At present there are only observational studies for this cohort of patients. We recommend designing well-conducted, large scale RCTs in patients with infective endocarditis will likely provide further results on the benefits of cytokine filters use.
      This meta-analysis demonstrates no benefit in using cytokine filters during cardiopulmonary bypass in hospital length of stay or for reducing the inflammatory markers levels other than CRP. In contrast, there is significant reduction in ICU stay and 30-day mortality afforded by the use of cytokine filters during non-elective cardiac surgery, especially in patients with high inflammatory burden such as infective endocarditis.

      Funding

      This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

      Conflict of Interest

      None declared.

      Appendices. Supplementary Data

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