Intraoperative Use of Extracorporeal Cytokine Adsorption During Orthotopic Heart Transplantation

The Impact of Pre-emptive Intraoperative Use of Extracorporeal Cytokine Adsorption During Orthotopic Heart Transplantation

There are several factors initiating cytokine storm and dysregulated systemic inflammatory response during cardiac transplantation. This may lead to serious perioperative complications: circulatory collapse, respiratory insufficiency, acute renal and liver failure, multi-organ dysfunction etc.

On the other hand the high level of cytokines may play an important role in the development of graft rejection which is still a relevant problem in this patient group.

There are some new data showing that the use of extracorporeal cytokine adsorber during long cardiopulmonary bypass time (>120min) may be beneficial to prevent SIRS (Systemic Inflammatory Response Syndrome) with decreasing the level of cytokines in patients undergoing elective cardiac surgery. However there is lack of data and studies regarding the effect of extracorporeal cytokine adsorption during cardiac transplantation.

The aim of the study is to investigate the effect of extracorporeal cytokine adsorber built in the cardiopulmonary bypass circle during heart transplantation. The hypothesis is that removal of cytokines during heart transplantation prevents the development of extreme systemic inflammatory response, hemodynamic collapse dominated by vasoplegia, and contribute to reduce the incidence of severe perioperative complications and early graft rejection.

Study Overview

• Status: Completed
• Conditions: Cardiopulmonary Bypass; Cardiac Transplantation
• Intervention / Treatment: Device: CytoSorb®

Detailed Description

Patients undergoing cardiac transplantation will be enrolled in the study after giving a written, signed informed consent.

The participants will be randomized into two groups:

• intervention group (30 patients): a cytokine adsorber (CytoSorb®) will be installed into the cardiopulmonary bypass circle during the operation
• control group (30 patients): no cytokine adsorber will be used during cardiopulmonary bypass

The investigators will collect demographic, clinical and laboratory data about patients before, during and after the operation.

The the use of vasopressors and inotropes in the perioperative period, length of mechanical ventilation, ICU and hospital stay, and incidence of perioperative complications, early cellular or humoral graft rejection, and survival will be documented.

The level of cytokines (IL-1, IL-6, IL-10, IL-17, tumor necrosis factor-alfa) and complements before, during and after the use of cardiopulmonary bypass will be determined if the investigators find relevant difference between the two groups in clinical variables.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary
    • Semmelweis University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patients undergoing heart transplantation
• no medical or mechanical circulatory support straight before transplantation
• age > 18 years

Exclusion Criteria:

• age < 18 years
• septic condition (controlled infection) before transplantation
• prolonged hospital stay straight before transplantation
• use of positive inotropes or vasopressors straight before transplantation
• use of mechanical circulatory support straight before transplantation
• acute liver or kidney failure straight before transplantation
• high urgency transplantation
• retransplantation
• the patient declines participating in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CytoSorb®; The CytoSorb® filter will be installed into the cardiopulmonary bypass circle during cardiac transplantation in this study group (30 patients)	Device: CytoSorb®; CytoSorb® is a biocompatible, high adsorptive polymer indicated in conditions where cytokine levels are extremely elevated.
No Intervention: Control; No filter will be installed into the cardiopulmonary bypass circle in this group (30 patients).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early postoperative hemodynamic instability	Hemodynamic instability described by Vasoactive Inotropic Score and calculated for the first two postoperative days. Vasoactive Inotropic Score is considered as 'high' if values ≥ 30 points, representing higher risk for worse outcomes.	24-48 hours
Postoperative vasoplegia syndrome	Severity of postoperative vasoplegia based on criteria of vasoplegia syndrome: Norepinephrine reqirements ≥ 0.3 μg/kg/min AND arginine vasopressin requirements at any dose	24-48 hours
Cytokine and complement levels	Level of pro- and anti-inflammatory cytokines (IL-1, IL-6, IL-10, IL-17, tumor necrosis factor-alfa) and complements immediately after induction of anesthesia, before initiation of cardiopulmonary bypass (CPB), 2 hours after initiation of CPB, at termination of CPB, 6-12-24 hours after initiation of CPB	24-48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory reaction	Level of C reactive protein (CRP), white blood cells and procalcitonin immediately after induction of anesthesia, before initiation of cardiopulmonary bypass (CPB), 2 hours after initiation of CPB, at termination of CPB, 6-12-24 hours after initiation of CPB	24-48 hours
Mechanical ventilation	Length of mechanical ventilation	up to 6 months
Hospital stay	Length of ICU and hospital stay	up to 6 months
Length of survival	Length of survival after heart transplantation	1 year
Medical circulatory support	Use and dosage of vasopressors and inotropes immediately after induction of anesthesia, before initiation of cardiopulmonary bypass (CPB), 2 hours after initiation of CPB, at termination of CPB, 6-12-24 hours after initiation of CPB, on 2nd and 3rd postoperative day	72 hours
Perioperative complications	Incidence of perioperative complications after heart transplantation during ICU stay (sepsis, SIRS, respiratory failure, acute renal failure, acute liver failure, postoperative cognitive dysfunction, graft failure)	up to 1 month
The incidence of early rejection	The incidence of early (< 1 month) cellular or humoral rejection after heart transplantation	1 month

Collaborators and Investigators

• Sponsor: Semmelweis University

Publications and helpful links

General Publications

• Bernardi MH, Rinoesl H, Dragosits K, Ristl R, Hoffelner F, Opfermann P, Lamm C, Preissing F, Wiedemann D, Hiesmayr MJ, Spittler A. Effect of hemoadsorption during cardiopulmonary bypass surgery - a blinded, randomized, controlled pilot study using a novel adsorbent. Crit Care. 2016 Apr 9;20:96. doi: 10.1186/s13054-016-1270-0.
• Kellum JA, Venkataraman R, Powner D, Elder M, Hergenroeder G, Carter M. Feasibility study of cytokine removal by hemoadsorption in brain-dead humans. Crit Care Med. 2008 Jan;36(1):268-72. doi: 10.1097/01.CCM.0000291646.34815.BB.
• Liang TB, Yu ZY, Zheng SS. [Expression of non-T cell derived cytokines in acute rejection after heart transplantation: experiment with mouse model]. Zhonghua Yi Xue Za Zhi. 2006 Jan 3;86(1):26-30. Chinese.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2018
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: May 4, 2017
• First Posted (Actual): May 9, 2017

Study Record Updates

• Last Update Posted (Actual): September 27, 2022
• Last Update Submitted That Met QC Criteria: September 22, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: SU-AITK/VM-2017/1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes