Cytokine Adsorption in Lung Transplantation

Study Overview
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Brief Summary
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Lung transplantation (LTx) remains the gold standard for treating patients with irreversible end-stage pulmonary disease. Of the major organs transplanted, survival in LTx recipients remains the lowest (mean 5 years). Despite improvements, primary graft dysfunction (PGD), as defined by respiratory insufficiency and edema up to 72 hours post LTx, remains the leading cause of early mortality and contributes to the development of chronic lung allograft dysfunction (CLAD) which is the leading cause of late mortality (2). PGD develops within the first 72 hours after LTx. The development of CLAD increases quickly with cumulative incidence of 40-80 % within the first 3-5 years. There is a general lack of efficient treatments for PGD and CLAD. Prevention of PGD is therefore of crucial importance and has a direct impact on survival. The present study is a randomized controlled pilot study which aims to compare patients undergoing LTx with and without the utilization of cytokine adsorption.

Detailed Description
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Early intolerance to the newly transplanted lung starts at the time of transplantation and results in PGD driven by an intense inflammatory response. Cytokines play a critical role as signaling molecules that initiate, amplify, and maintain inflammatory responses both locally and systemically. The use of cytokine filtration devices to target middle- and low-molecular weight molecules has been shown to reduce levels of a diverse number of cytokines. These results have been demonstrated in the in vitro reduction of pathogen-associated molecular pattern molecules (PAMPS) and damage associated molecular patterns (DAMPS) as well as in in vivo studies involving orthotopic heart transplantation and kidney transplantation. Cytokine adsorption has been used successfully in clinical applications to both heart and kidney transplantation. The present study is a randomized controlled pilot study which aims to collect preliminary data on the efficacy of a medical device through the comparison of patients undergoing LTx with and without cytokine adsorption.

Official Title
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Cytokine Adsorption in Lung Transplantation: a Randomized Controlled Pilot Study

Conditions
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Lung Transplant Failure, Lung Transplant; Complications

Intervention / Treatment
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* Device: CytoSorb


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Double lung transplantation Single organ failure Exclusion Criteria: Re-transplantation Drug abuse Kidney failure Liver failure Diabetes mellitus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The model consists of a randomized controlled pilot in human patients using a cytokine adsorption device. Lung transplant recipients are randomized to either the treatment group which undergoes cytokine adsorption using the medical device compared to the control group which has not received the cytokine adsorber.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treated<br>Treatment using the medical cytokine adsorption device in conjunction with lung transplantation | Device: CytoSorb<br>* Medical device used hemoperfusion and cytokine adsorption in conjunction with lung transplantation.<br>|
| No Intervention: Non-treated<br>No additional treatment in conjunction with lung transplantation | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation at 24 hours | Oxygenation expressed as the PaO2/FiO2 ratio at 24 hours | 24 hours after lung transplantation | 
| Oxygenation at 48 hours | Oxygenation expressed as the PaO2/FiO2 ratio at 48 hours | 48 hours after lung transplantation | 
| Oxygenation at 72 hours | Oxygenation expressed as the PaO2/FiO2 ratio at 72 hours | 72 hours after lung transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diffusion capacity of the lungs (DLCO) | The primary function of the lungs is oxygenation of the blood and exhalation of carbon dioxide (CO2) from the blood. The ability of the lungs to perform this depends on a good alveolar ventilation, an even relationship between perfusion and ventilation, and good diffusion potential for oxygen (O2) and CO2 between alveolar, capillary and hemoglobin. This outcome will be measured through the diffusing capacity for carbon monoxide (DLCO) | 3 months after transplantation | 
| Primary Graft dysfunction after 24 hours | Primary graft dysfunction (PGD) remains the leading cause of early mortality and contributes to the development of chronic lung allograft dysfunction (CLAD) which is the leading cause of late mortality. PGD develops over the first 72 hours after transplantation and is defined by evaluation of both the PaO2/FiO2 ratio and presence of lung edema on chest x-ray. | 24 hours after lung transplantation | 
| Primary Graft dysfunction after 48 hours | PGD must also be assessed throughout the 72 hour period following completion of the transplantation and as such, this outcome will consist of the evaluation for PGD in the recipient 48 hours post-transplantation. | 48 hours after lungtransplantation | 
| Primary Graft dysfunction after 72 hours | PGD must also be assessed throughout the 72 hour period following completion of the transplantation and as such, this outcome will consist of the evaluation for PGD in the recipient 72 hours post-transplantation. | 72 hours after lungtransplantation | 
| Urinary output as a measure of kidney function | Kidney function is often impaired in transplant subjects due to the surgery itself but also secondary to drugs. The degree of acute kidney injury (AKI) can be assessed in part through measure of the urinary output. | First 3 months | 
| Creatinine levels and clearance as a measure of kidney function | To further assess the incidence of AKI, creatinine levels and its clearance will be measured. | First 3 months | 
| Urea levels as a measure of kidney function | Urea levels will also be measured to assess kidney function. | First 3 months | 
| Rates of dialysis as a measure of kidney function | The incidence of patients requiring dialysis will be also used to assess the frequency of AKI in the study population. | First 3 months | 
| Volume blood loss | Given the nature of the transplantation itself as a major surgery, blood loss is expected after surgery and the volume of blood loss (mL) after surgery will be measured as a surgical outcome. | First 24 hours |