Extracorporeal Cytokine Adsorption in Cardiac Surgery

NCT02666703 | Completed Phase 3 DMC

• 1 other identifier: ARRS-RPROJ-2014-191
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cardiopulmonary Bypass

Keywords

cardiac surgery; systemic inflammatory response; immunoadsorption

Outcome Measures

Primary Outcomes (5)

• Evolution of pro-inflammatory and anti-inflammatory cytokines [TNF-alfa, IL-1, IL-6, IL-8 and IL-10

  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

  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

  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

  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

  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 Outcomes (4)

• Changes in serum hs-CRP

  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

  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

  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

  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 Outcomes (5)

• Duration of postoperative mechanical ventilation

  duration of ICU stay, an expected average of 2 days

• Length of ICU stay

  duration of ICU stay, an expected average of 2 days

• Use of inotropic/vasoactive drugs and insulin

  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

Study Arms (3)

Study (CytoSorb)

EXPERIMENTAL

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

Control

NO INTERVENTION

In the control group (20 patients) no filter will be installed on the CPB.

Corticosteroid

ACTIVE COMPARATOR

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

Interventions

CytoSorb DEVICE

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.

Study (CytoSorb)

Methylprednisolone DRUG

Corticosteroid

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead
• Slovenian Research Agency: collaborator

Study Sites (1)

University Medical Center

Ljubljana, 1000, Slovenia

Location

Related Publications (1)

• Taleska Stupica G, Sostaric M, Bozhinovska M, Rupert L, Bosnic Z, Jerin A, Ihan A, Klokocovnik T, Podbregar M. Extracorporeal Hemadsorption versus Glucocorticoids during Cardiopulmonary Bypass: A Prospective, Randomized, Controlled Trial. Cardiovasc Ther. 2020 Mar 27;2020:7834173. doi: 10.1155/2020/7834173. eCollection 2020.

  PMID: 32292492 DERIVED

MeSH Terms

Interventions

Methylprednisolone

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Maja Sostaric, MD, PhD

  University Medical Centre Ljubljana

  STUDY DIRECTOR

• Matej Podbregar, MD, PhD

  University Medical Centre Ljubljana

  STUDY DIRECTOR

• Gordana Taleska, MD, MSc

  University Medical Centre Ljubljana

  PRINCIPAL INVESTIGATOR

• Tomislav Klokocovnik, MD, PhD

  University Medical Centre Ljubljana

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, MSc, Spec.

Study Record Dates

• First Submitted: January 17, 2016
• First Posted: January 28, 2016
• Study Start: February 1, 2016
• Primary Completion: December 1, 2017
• Study Completion: June 1, 2018
• Last Updated: March 25, 2020

Record last verified: 2020-03

Locations

SL (1)