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Extending Preservation and Assessment Time of Donor Lungs Using the Toronto EVLP System™ at a Dedicated EVLP Facility

Overview

Información sobre este estudio

This is a safety study to compare the safety of receiving a lung treated with the Toronto EVLP System™ by SPONSOR in SPONSOR's dedicated facility against standard lung transplantation.

Elegibilidad para la participación

Los requisitos de elegibilidad de los participantes incluyen la edad, el sexo, el tipo y el estadio de la enfermedad, y los problemas de salud o tratamientos previos. Las pautas difieren de un estudio a otro e identifican quiénes pueden o no pueden participar. No hay garantía de que cada persona elegible que desee participar en un ensayo se inscribirá. Comunícate con el equipo del estudio para analizar la elegibilidad del estudio y la posible participación.

Subject Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

  • Male or female patients
  • All patients, 18 years of age or older
  • Patient already on or added to the active waiting list for a single or bilateral lung transplant
  • Patient or patient's representative provides informed consent for participation in the study at the time of study commencement or time of listing for transplant
  • Patient or patient's representative reconfirms informed consent for the study on the day of lung transplant

Subject Exclusion Criteria:

A subject who meets any of the following criteria will be excluded from participation:

  • Patients listed for same-side lung re-transplantation
  • Patients listed for multiple organ transplantation including lung and any other organ
  • Patients listed for live donor lobar transplant
  • Patients with HIV, active Hepatitis B/C, or Burkholderia Cepacia
  • Patients not initially consented into the study prior to the time of lung transplant
  • Patients in the ICU at the time of initial lung offer requiring mechanical ventilation, ECMO or other Extracorporeal life support (ECLS).

Donor Lung Inclusion Criteria for EVLP Assessment:

The donor lung must meet at least one of the following criteria to proceed with EVLP:

  • At the time of the clinical evaluation, the donor PaO2/FiO2 < 300 mmHg
  • Donor received ≥ 10 units of blood transfusions
  • Donation after Cardiac Death (DCD) donor
  • Expected cold ischemic time > 6 hours
  • Donor age ≥ 55 years old
  • Study Center Investigator requires additional assessment ex vivo and/or extended preservation time

Donor Lung Exclusion Criteria for EVLP Assessment:

The donor lung is excluded from EVLP if at least one of the following criteria have been met:

  • The donor lung has confirmed pneumonia and/or persistent purulent secretions identified via bronchoscopy
  • Non-persistent purulent secretions that do not clear by hour 3 on EVLP
  • The donor lung has confirmed evidence of aspiration
  • The donor lung has significant mechanical lung injury or trauma
  • The cold ischemic time, starting at donor aortic cross clamp/ initial flush (CIT-1), required to transport the lung from the donor site to start of the EVLP procedure at SPONSOR's facility > 10 hours

EVLP Lung Inclusion Criteria for Transplantation:

The donor lung must meet each of the following conditions post-EVLP for transplant suitability consideration by the Study Center Investigator:

  • PvO2/FiO2 ≥ 350 mmHg at final EVLP evaluation time period
  • and < 15% increase from baseline value (defined as the first hour collection point) to final value of pulmonary vascular resistance (PVR)
  • and < 15% increase from baseline value to final value of peak airway pressure (PawP)
  • and < 15% decrease from baseline value to final value of static lung compliance (Cstat)
  • and the total preservation time (TPT) does not exceed the following:
    • the initial CIT-1 time from donor to EVLP > 1 hour and ≤ 10 hours
    • the EVLP time > 3 hours and ≤ 6 hours
    • the second CIT-2 from EVLP cool down to beginning of recipient implantation must be > 1 hour and ≤ 6 hours for the first lung
    • the second CIT-2 from EVLP cool down to beginning of recipient implantation must be > 1 hour and ≤ 10 hours for the second lung
  • and Study Center Investigator deems lung function suitable for intended subject

EVLP Lung Exclusion Criteria for Transplantation:

The donor lung is excluded from transplant inclusion if at least one of the following criteria have been met:

  • PvO2/FiO2 < 350 mmHg at final EVLP evaluation time period
  • or ≥ 15% increase from baseline value to final value of pulmonary vascular resistance (PVR)
  • or ≥ 15% increase from baseline value to final value of peak airway pressure (PawP)
  • or ≥ 15% decrease from baseline value to final value of static lung compliance (Cstat)
  • or TPT exceeds any of the following conditions:
    • CIT-1 < 1 hour or > 10 hours
    • EVLP < 3 hours or > 6 hours
    • CIT-2 < 1 hour or > 6 hours for first lung or > 10 hours for second lung
  • or Study Center investigator deems lung function unsuitable for intended subject

More information

Publicaciones

  • Primary graft dysfunction (PGD) is a syndrome encompassing a spectrum of mild to severe lung injury that occurs within the first 72 hours after lung transplantation. PGD is characterized by pulmonary edema with diffuse alveolar damage that manifests clinically as progressive hypoxemia with radiographic pulmonary infiltrates. In recent years, new knowledge has been generated on risks and mechanisms of PGD. Following ischemia and reperfusion, inflammatory and immunological injury-repair responses appear to be key controlling mechanisms. In addition, PGD has a significant impact on short- and long-term outcomes; therefore, the choice of donor organ is impacted by this potential adverse consequence. Improved methods of reducing PGD risk and efforts to safely expand the pool are being developed. Ex vivo lung perfusion is a strategy that may improve risk assessment and become a promising platform to implement treatment interventions to prevent PGD. This review details recent updates in the epidemiology, pathophysiology, molecular and genetic biomarkers, and state-of-the-art technical developments affecting PGD. Read More on PubMed
  • Although lung transplantation has become a life-saving option for patients with end-stage lung disease, this intervention is hampered by a shortage of lungs in view of the growing number of people on the waiting list. Lungs are retrieved from only a small percentage of multiorgan donors, and the transplantation and intensive-care communities have recognised the need to develop innovative methods to expand the donor pool. Advancements in lung-preservation techniques in the preretrieval and postretrieval periods have increased the pool of available donors, and novel research and discoveries in this area have steadily improved post-transplantation adverse events. This Review summarises current best practice and the latest research on intensive-care management of a potential lung donor. We also discuss lung-preservation techniques, including advancements in normothermic ex-vivo lung perfusion, and the potential for a personalised medicine approach to the organ. Read More on PubMed
  • Normothermic ex vivo lung perfusion is a novel method to evaluate and improve the function of injured donor lungs. We reviewed our experience with 50 consecutive transplants after ex vivo lung perfusion. Read More on PubMed
  • The evaluation of donor lungs by normothermic ex vivo acellular perfusion has improved the safety of organ utilization. However, this strategy requires a critical re-evaluation of the parameters used to assess lungs during ex vivo perfusion compared with those traditionally used to evaluate the donor lung in vivo. Using a porcine model, we studied the physiology of acellular lung perfusion with the aim of improving the accuracy of clinical ex vivo evaluation. Read More on PubMed
  • A recent clinical trial provided evidence that ex vivo lung perfusion (EVLP) results in optimized human donor lungs for transplantation. Excellent recipient outcomes were documented after 4 h of normothermic perfusion. We report a clinical case utilizing remote EVLP to assess and improve function of initially otherwise unacceptable injured donor lungs followed by transportation and subsequent bilateral lung transplantation in a patient with virally induced refractory respiratory failure supported with extracorporeal membrane oxygenation. This is the first lung transplantation with the application of remote EVLP, wherein the donor lungs were transported from the donor hospital to a center for EVLP and then transported to another hospital for transplantation. It is also the first case of lung transplantation in the United States utilizing EVLP for functional optimization leading to successful transplantation. Organ procurement data, EVLP assessment, and the pre- and postoperative course of the recipient are presented. The available evidence supporting EVLP, the humanitarian and cooperative utilization of lungs otherwise discarded, are discussed. Read More on PubMed
  • The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of both a shortage of organ donors and a low utilization rate of donor lungs. Normothermic ex vivo lung perfusion (EVLP) is a method that maintains the organ in physiologically protective conditions outside the body during preservation, and shows great promise to increase utilization of donor lungs by allowing more accurate evaluation, as well as treatment and repair, of damaged donor lungs prior to transplantation. This article will cover the rationale, technical details and results of experimental and clinical studies with EVLP. The significant potential applications of EVLP in lung transplantation, lung regeneration and oncology are discussed. Read More on PubMed
  • Plasma lactate has been used as a marker of poor prognosis in clinical conditions. However, the relationship between lactate production and lung function during acellular normothermic ex vivo lung perfusion (EVLP) is unclear. We investigated the kinetics of lactate metabolism during EVLP and the correlation of this marker with outcomes after transplant. Read More on PubMed
  • Two novel approaches have been developed to potentially increase the availability of donor lungs for lung transplantation. In the first approach, lungs from donation after cardiac death (DCD) donors are used to increase the quantity of organ donors. In the second approach, a newly developed normothermic ex vivo lung perfusion (EVLP) technique is used as a means of reassessing the adequacy of lung function from DCD and from high-risk brain death donors prior to transplantation. This EVLP technique can also act as a platform for the delivery of novel therapies to repair injured organs ex vivo. Read More on PubMed
  • More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP. Read More on PubMed
  • Treatment of injured donor lungs ex vivo to accelerate organ recovery and ameliorate reperfusion injury could have a major impact in lung transplantation. We have recently demonstrated a feasible technique for prolonged (12 h) normothermic ex vivo lung perfusion (EVLP). This study was performed to examine the impact of prolonged EVLP on ischemic injury. Pig donor lungs were cold preserved in Perfadex for 12 h and subsequently divided into two groups: cold static preservation (CSP) or EVLP at 37 degrees C with Steen solution for a further 12 h (total 24 h preservation). Lungs were then transplanted and reperfused for 4 h. EVLP preservation resulted in significantly better lung oxygenation (PaO(2) 531 +/- 43 vs. 244 +/- 49 mmHg, p < 0.01) and lower edema formation rates after transplantation. Alveolar epithelial cell tight junction integrity, evaluated by zona occludens-1 protein staining, was disrupted in the cell membranes after prolonged CSP but not after EVLP. The maintenance of integrity of barrier function during EVLP translates into significant attenuation of reperfusion injury and improved graft performance after transplantation. Integrity of functional metabolic pathways during normothermic perfusion was confirmed by effective gene transfer and GFP protein synthesis by lung alveolar cells. In conclusion, EVLP prevents ongoing injury associated with prolonged ischemia and accelerates lung recovery. Read More on PubMed
  • More than 80% of potential donor lungs are injured during brain death of the donor and from complications experienced in the intensive care unit, and therefore cannot be used for transplantation. These lungs show inflammation and disruption of the alveolar-capillary barrier, leading to poor gas exchange. Although the number of patients in need of lung transplantation is increasing, the number of donors is static. We investigated the potential to use gene therapy with an adenoviral vector encoding human interleukin-10 (AdhIL-10) to repair injured donor lungs ex vivo before transplantation. IL-10 is an anti-inflammatory cytokine that mainly exerts its suppressive functions by the inactivation of antigen-presenting cells with consequent inhibition of proinflammatory cytokine secretion. In pigs, AdhIL-10-treated lungs exhibited attenuated inflammation and improved function after transplantation. Lungs from 10 human multiorgan donors that had suffered brain death were determined to be clinically unsuitable for transplantation. They were then maintained for 12 hours at body temperature in an ex vivo lung perfusion system with or without intra-airway delivery of AdhIL-10 gene therapy. AdhIL-10-treated lungs showed significant improvement in function (arterial oxygen pressure and pulmonary vascular resistance) when compared to controls, a favorable shift from proinflammatory to anti-inflammatory cytokine expression, and recovery of alveolar-blood barrier integrity. Thus, treatment of injured human donor lungs with the cytokine IL-10 can improve lung function, potentially rendering injured lungs suitable for transplantation into patients. Read More on PubMed
  • Organ donation after cardiac death (DCD) has the potential to alleviate some of the shortage of suitable lungs for transplantation. Only limited data describe outcomes after DCD lung transplantation. This study describes the early and intermediate outcomes after DCD lung transplantation in Canada. Read More on PubMed
  • The shortage of adequate organ donors remains a great challenge in clinical lung transplantation. With increasing experience in the medical management and surgical technique of lung transplantation, gradual expansion of the criteria for lung donor selection has occurred with beneficial effects on the donor pool. Interest in donation after cardiac death also is increasing as the gap increases between donors and the needs of listed patients. Successful use of these new sources of lungs depends on the accurate assessment and prediction of transplanted lung function. Promising techniques for lung assessment and diagnostics include investigating key genes associated with graft failure or good graft performance using molecular approaches, and ex vivo evaluation. Further studies are needed to answer remaining questions about the best technique and solution to reperfuse human lungs for several hours without edema formation. As the predictive ability to discern good from injured donor lungs improves, strategies to repair donor lungs become increasingly important. Prolonged normothermic EVLP seems to be a platform on which many reparative strategies can be realized. With these new methods for assessing and resuscitating lungs accurately, it is hoped that inroads will be made toward providing every listed patient a chance for successful lung transplantation. Read More on PubMed
  • As short- and long-term survival rates for lung transplantation continue to improve, and as more lung transplantations are occurring with each year, a multitude of medical complications are encountered by the clinician. This article reviews the long-term non-pulmonary noninfectious medical complications that arise beyond the postoperative period in patients who have undergone lung transplantation. This article reviews the development of renal failure, diabetes, cardiovascular complications of hypertension and atherosclerosis, osteoporosis and avascular necrosis, hematologic complications, thromboembolic disease, gastrointestinial complications, neurologic complications, and malignancy, including post-transplant lymphoproliferative disorder. Read More on PubMed
  • The inhibition of cellular metabolism induced by hypothermia obviates the possibility of substantial reparative processes occurring during organ preservation. The aim of this study was to develop a technique of extended (12-hour) ex vivo lung perfusion (EVLP) at normothermia for assessment and protective maintenance of the donor lung. Read More on PubMed
  • In this study, mechanical trauma to red blood cells was evaluated by conventional hemolysis test and a newly developed cyclically reversing shear flow generator. The fresh porcine blood obtained from a local slaughterhouse was subjected to the conventional hemolysis test using a commercial centrifugal blood pump for the duration of 8 h. The measurements consisted of (i) plasma-free hemoglobin based on the standard optical measurement and (ii) the deformability of red blood cells (RBCs) using a cyclically reversing shear flow generator and microscope image acquisition system. The deformability of RBCs was expressed by the L/W value where L and W were the longer and shorter axes of the elongated RBCs' images. Although the plasma-free hemoglobin level increased with the pumping duration, the L/W remained unchanged for the duration of 8 h of pumping to indicate no alteration in the deformability. It was speculated that (i) although RBCs might have been circulated for so many times through the test pump, after each exposure to mechanical stress, RBCs might have recovered, and net effect due to shear stress-exposure time might have been small; and (ii) RBCs' deformability might be maintained near normal until sudden burst or membrane rupture, or the hemoglobin might have continuously leaked through the pores of the thinned membrane created by the mechanical stress. The deformability testing under a fluctuating shear flow could be a new method to quantify subhemolytic mechanical damage that has been accumulated in the RBCs' membrane and that may not be assessed by the conventional hemolysis test. Read More on PubMed
  • Sympathetic discharge and hypertensive crisis often accompany brain death, causing neurogenic pulmonary edema. Progressive systemic inflammatory response develops, which can injure the lung further. We investigated whether (a) early hemodynamic injury during donor brain death increases reperfusion injury after lung transplantation and (b) delaying lung recovery would augment reperfusion injury further, because of the progressive systemic inflammatory response in the donor. Brain death was induced by intracranial balloon inflation in rats, with or without alpha-adrenergic blockade pretreatment to prevent the hypertensive crisis. Another group of rats had a sham procedure. Lungs were retrieved 15 min after brain death or sham procedure and reperfused using recipient rats. In a fourth group, brain death was induced and the lungs were retrieved 5 h after brain death and reperfused. Postreperfusion, lungs retrieved early from untreated brain-dead donors developed more severe reperfusion injury, as assessed by functional parameters and inflammatory markers, than those from sham or alpha-blockade-treated donors. Lungs retrieved late from brain-dead donors had similar inflammatory markers after reperfusion to those retrieved early, but significantly lower pulmonary vascular resistance. Early hemodynamic damage during donor brain death increases reperfusion injury after lung transplantation. Delaying retrieval may allow the lung to recover from the hemodynamic injury. Read More on PubMed
  • Some reports have documented a higher early mortality with the use of extended criteria donors in lung transplantation. None have evaluated how outcomes compare with the use of these organs for single and bilateral transplantation or whether this practice results in a higher incidence of early bronchiolitis obliterans syndrome. Read More on PubMed
  • Lung transplantation is currently limited by the number of suitable donor organs. Many lung-transplant programs use lungs that do not meet the formal criteria for acceptability; however, the immediate and long-term consequences of this approach remain unclear. Read More on PubMed
  • Centrifugal pumps are superior to roller pumps for extended support durations in terms of pump-induced haemolysis. In this study, we evaluated the commonly used Biomedicus BP 50 and compared it with the Jostra Rotaflow and a standard roller pump in an in vitro test circuit. Each circuit was run for a six-day period and repeated five times. Plasma haemoglobin values showed the roller pump to become more haemolytic than the Biomedicus (p = 0.022) and the Rotaflow. A statistically significant difference between the Biomedicus and the Rotaflow was observed on day six of the trial (p = 0.016), with the Rotaflow showing lower levels of haemolysis than the Biomedicus. These results support the use of the new generation centrifugal pump, the Rotaflow, as a suitable device for short-term ventricular assist. Read More on PubMed
  • Present criteria for donor-lung selection exclude more than 85% of lungs. We aimed to establish if potentially suitable lungs are rejected for transplantation. We obtained 29 pairs of rejected lungs and assessed them by physiological, microbiological, and histological methods. Most donor lungs had no or mild pulmonary oedema (24/29 [83%]), intact alveolar fluid clearance (17/23 [74%]), and normal or mildly abnormal histological findings (18/29 [62%]). When all factors were considered, including microbiological and non-lung donor factors, 12 (41%) of 29 pairs of rejected lungs would have been potentially suitable for transplantation. Our findings emphasise the urgent need for prospective scientific assessment of selection of donors for lung transplantation. Read More on PubMed
  • Lung transplantation is limited by the shortage of suitable donors. To overcome this problem, many programs have begun to use marginal or extended donors after reports suggesting equivalent outcomes with no additional risk. As our use of extended donor lungs increased and our recipient selection criteria expanded, we believed it was appropriate to reevaluate outcomes with extended donor lungs compared with outcomes with standard donor lungs and recipients outside of the currently accepted guidelines. Read More on PubMed

Otros temas en investigación

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CLS-20144043

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