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Extracorporeal Cytokine Adsorption in Cardiac Surgery (IMEECCACS)

This study is currently recruiting participants.
See Contacts and Locations
Verified November 2016 by Gordana Taleska, University Medical Centre Ljubljana
Sponsor:
Collaborator:
Slovenian Research Agency
Information provided by (Responsible Party):
Gordana Taleska, University Medical Centre Ljubljana
ClinicalTrials.gov Identifier:
NCT02666703
First received: January 17, 2016
Last updated: November 2, 2016
Last verified: November 2016
  Purpose

The modern era of cardiac surgery began in early 1950s with the introduction of cardiopulmonary bypass (CPB). Although it has been clearly shown that CPB is almost unavoidable for most open heart operations, an undesirable systemic inflammatory response syndrome (SIRS) is associated with its use. This complex chain of events has strong similarities with sepsis and may contribute to the development of postoperative complications and multiple organ failure (MOF). It has been shown that an excessive compensatory anti-inflammatory response (CARS) after SIRS can lead to immune paralysis and increased rate of hospital acquired infection. The balance of pro-inflammatory and anti-inflammatory mediators determines the inflammatory response and the clinical outcome. Accordingly, great efforts have been focused on therapeutic interventions aimed at reducing the inflammatory reactions during CPB, including pharmacologic strategies and modification of surgical techniques or mechanical devices. Such therapies may provide improvements in patient outcome after open heart operations. Among pharmacologic strategies is the prophylaxis with corticosteroids, which have been used during open heart surgery for more than 30 years. Many studies, both experimental and clinical, failed to produce evidence in favor of steroid treatment. As far as medical devices are concerned, the use of extracorporeal cytokine filter CytoSorb looks promising in cardiac surgery. It was recently approved by European Medicines Agency as an active treatment to fight cytokine storm.

Serum paraoxonase 1 (PON1) is a lipo-lactonase, being associated with HDL that has an anti-inflammatory role and protects against atherosclerosis. Low levels of PON1 are associated with venous graft occlusion in patients with coronary artery bypass grafting. PON1 reduces monocyte chemotaxis and adhesion to endothelial cells, leading to inhibition of the differentiation of monocytes into macrophages. The effects of cytokine adsorption therapy on PON1 are unknown.

The aim of the study is to explore the effects of extracorporeal immunoadsorption during CPB on pro-inflammatory and anti-inflammatory protective mediators and cellular immune status in cardiac surgery.


Condition Intervention Phase
Cardiopulmonary Bypass Device: CytoSorb Drug: Methylprednisolone Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single Blind (Participant)
Primary Purpose: Treatment
Official Title: Immunomodulatory Effect of Extracorporeal Cytokine Adsorption in Cardiac Surgery

Resource links provided by NLM:


Further study details as provided by Gordana Taleska, University Medical Centre Ljubljana:

Primary Outcome Measures:
  • Evolution of pro-inflammatory and anti-inflammatory cytokines [TNF-alfa, IL-1, IL-6, IL-8 and IL-10 [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]
  • Evolution of complement C5a [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]
  • Evolution of CD 64 and CD 163 markers [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]
  • Evolution of miRNA [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]
  • Evolution of PON1, HDL and LDL [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]

Secondary Outcome Measures:
  • Changes in serum hs-CRP [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]
  • Changes in serum PCT [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]
  • Changes in white blood count [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]
  • Changes in serum albumin and fibrinogen [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day); only for Study group-1 h after start of CPB: 7)from blood entering CytoSorb and 8)from blood leaving CytoSorb ]

Other Outcome Measures:
  • Duration of postoperative mechanical ventilation [ Time Frame: duration of ICU stay, an expected average of 2 days ]
  • Length of ICU stay [ Time Frame: duration of ICU stay, an expected average of 2 days ]
  • Use of inotropic/vasoactive drugs and insulin [ Time Frame: 1) before induction of anesthesia; 2)at the end of CPB; 3) at the end of surgical procedure; 4) 24 h; 5) 48 h; 6) 5th postoperative day ]
    assessed by the dose - mcg/kg/min for inotropic/vasoactive drugs and IU/h for insulin

  • Length of hospital stay [ Time Frame: through study completion, an average of 1 year ]
  • 30 days mortality [ Time Frame: at day 30 ]

Estimated Enrollment: 60
Study Start Date: January 2016
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Study (CytoSorb)
In the study group (20 patients) the CytoSorb filter will be installed in the CPB in a parallel circuit. An additional roller pump will drive the blood through the filter with a constant flow of 400 ml/min (max flow).
Device: CytoSorb
CytoSorb is a first-in-class extracorporeal cytokine adsorber, now approved in the European Union, and broadly indicated for use in any clinical situation where cytokines are elevated.
No Intervention: Control
In the control group (20 patients) no filter will be installed on the CPB.
Active Comparator: Corticosteroid
In the corticosteroid group (20 patients), 1 gram of methylprednisolone will be added in the priming solution of CPB machine. No filter will be installed on the CPB.
Drug: Methylprednisolone

Detailed Description:
Patients undergoing complex cardiac surgery with CPB (eg: combined valve and coronary bypass grafting surgery, concomitant valve surgery, surgery of the ascending aorta and aortic arch, as well as re-operations of the same type) will be enrolled in the study after giving the signed informed consent. They will be randomized into 3 groups: 1. study (CytoSorb) group, 2. control group, and 3. corticosteroid group. Immune response [TNF-alfa (tumor necrosis factor-alpha), IL(interleukin)-1, IL-6, IL-8, IL-10, complement C5a, lymphocyte cellular markers (CD64, CD163), miRNA (micro RNA), PON1 activity, as well as lipid status, hs-CRP (high sensitivity C-reactive protein), PCT (procalcitonin) and acute phase proteins, will be determined before CPB, during CPB, immediately after, 24h, 48h and 5 days after CPB. We will document demographic characteristics of patients, their preoperative medical status, as well as intraoperative data (type and duration of surgery, duration of CPB, period of ischemia, hemodynamic parameters, usage of inotropic/vasoactive therapy, insulin, fluids, blood and blood components); duration of mechanical ventilation in intensive care unit (ICU), duration of ICU stay, 30-day mortality and morbidity, as well as postoperative complications (bleeding, hemodynamic instability, impaired respiratory function, infection, worsening of renal, liver and cognitive function).
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Elective complex cardiac surgery (combined valve and coronary bypass grafting surgery, concomitant valve surgery, surgery of the ascending aorta and aortic arch, as well as re-operations of the same type)
  • Age > 18 years

Exclusion Criteria:

  • Disagreement to participate in the study
  • Age < 18 years
  • Pregnancy
  • Emergency procedure
  • Heart transplantation
  • Implantation of LVAD (left ventricular assist device), RVAD (right ventricular assist device) or TAH (total artificial heart)
  • Treatment with chemotherapy, immunosuppressive therapy
  • Treatment with anti-leukocyte drugs or TNF-alfa blockers
  • Immunocompromised patients (AIDS), leucopenia (< 4,0x109 / L)
  • Clinical and/or laboratory signs of infection (CRP >2 mg/dl)
  • Serum creatinine >2 mg/dl
  • Bilirubin >2 mg/dl
  • History of stroke
  • Malnourished patients, BMI < 18
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02666703

Contacts
Contact: Gordana Taleska, MD, MSc 040745091 ext +386 taleskagordana@gmail.com
Contact: Matej Podbregar, MD, PhD 040215960 ext +386 podbregar.matej@gmail.com

Locations
Slovenia
University Medical Center Recruiting
Ljubljana, Slovenia, 1000
Contact: Gordana Taleska, MD, MSc    040745091 ext +386    taleskagordana@gmail.com   
Contact: Matej Podbregar, MD, PhD    040215960 ext +386    podbregar.matej@gmail.com   
Principal Investigator: Gordana Taleska, MD, MSc         
Sponsors and Collaborators
University Medical Centre Ljubljana
Slovenian Research Agency
Investigators
Study Director: Maja Sostaric, MD, PhD University Medical Centre Ljubljana
Study Director: Matej Podbregar, MD, PhD University Medical Centre Ljubljana
Principal Investigator: Gordana Taleska, MD, MSc University Medical Centre Ljubljana
Study Director: Tomislav Klokocovnik, MD, PhD University Medical Centre Ljubljana
  More Information

Responsible Party: Gordana Taleska, MD, MSc, Spec., University Medical Centre Ljubljana
ClinicalTrials.gov Identifier: NCT02666703     History of Changes
Other Study ID Numbers: ARRS-RPROJ-2014-191
Study First Received: January 17, 2016
Last Updated: November 2, 2016

Keywords provided by Gordana Taleska, University Medical Centre Ljubljana:
cardiac surgery
systemic inflammatory response
immunoadsorption

Additional relevant MeSH terms:
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 21, 2017