Introducing the concept of semielective lung transplantation through the use of ex vivo lung perfusion
2018; Elsevier BV; Volume: 156; Issue: 6 Linguagem: Inglês
10.1016/j.jtcvs.2018.05.056
ISSN1097-685X
AutoresMarcelo Cypel, Jonathan Yeung, Shaf Keshavjee,
Tópico(s)Renal Transplantation Outcomes and Treatments
ResumoCentral MessageWith the advent of normothermic ex vivo lung perfusion, donor lungs are routinely preserved for more than 12 hours. Preservation times of 12 to 24 hours were recently shown to be clinically safe.See Editorial Commentary page 2353. With the advent of normothermic ex vivo lung perfusion, donor lungs are routinely preserved for more than 12 hours. Preservation times of 12 to 24 hours were recently shown to be clinically safe. See Editorial Commentary page 2353. Lung transplantation (LTx) has enjoyed remarkable successes during the past decade, and this is reflected in the significant increase in the number of procedures year to year.1Valapour M. Lehr C.J. Skeans M.A. Smith J.M. Carrico R. Uccellini K. et al.OPTN/SRTR 2016 annual data report: lung.Am J Transplant. 2018; 18: 363-433Crossref PubMed Scopus (107) Google Scholar Since the inception of successful clinical LTx by Cooper and colleagues in Toronto in 1983, however, donor lung preservation techniques have not significantly changed, and the practical intention continues to be to minimize preservation time. Although experimental work has shown that donor lungs can be reliably preserved for at least 12 hours of cold static preservation,2Cypel M. Yeung J.C. Hirayama S. Rubacha M. Fischer S. Anraku M. et al.Technique for prolonged normothermic ex vivo lung perfusion.J Heart Lung Transplant. 2008; 27: 1319-1325Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar the usual acceptable time frame in the clinical setting has largely been limited to less than 8 hours of cold preservation. This is well documented by a recent United Network for Organ Sharing database analysis, which showed a mean cold preservation time of 5 hours in the United States.3Hayes Jr., D. Hartwig M.G. Tobias J.D. Tumin D. Lung transplant center volume ameliorates adverse influence of prolonged ischemic time on mortality.Am J Transplant. 2017; 17: 218-226Crossref PubMed Scopus (24) Google Scholar Clinically, the impact of cold preservation time remains unclear. Some studies have reported a deleterious effect of cold static preservation, whereas others have shown no significant impact, especially in high-volume specialized centers.3Hayes Jr., D. Hartwig M.G. Tobias J.D. Tumin D. Lung transplant center volume ameliorates adverse influence of prolonged ischemic time on mortality.Am J Transplant. 2017; 17: 218-226Crossref PubMed Scopus (24) Google Scholar, 4Kuntz C.L. Hadjiliadis D. Ahya V.N. Kotloff R.M. Pochettino A. Lewis J. et al.Risk factors for early primary graft dysfunction after lung transplantation: a registry study.Clin Transplant. 2009; 23: 819-830Crossref PubMed Scopus (100) Google Scholar, 5Lee J.C. Christie J.D. Keshavjee S. Primary graft dysfunction: definition, risk factors, short- and long-term outcomes.Semin Respir Crit Care Med. 2010; 31: 161-171Crossref PubMed Scopus (115) Google Scholar A recent study, however, has actually shown worse outcomes for pediatric LTx when donor organs were preserved for less than 4 hours.6Hayes Jr., D. Joy B.F. Reynolds S.D. Tobias J.D. Tumin D. Influence of graft ischemic time and geographic distance between donor and recipient on survival in children after lung transplantation.J Heart Lung Transplant. 2016; 35: 1220-1226Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar This variability in results can be explained in part by the lack of standardization of organ procurement and preservation. Donor lung preservation is not a trivial process and includes donor management in the intensive care unit, proper organ handling after the chest is opened, proper lung ventilation and recruitment, quality of the cold flush, selection of the preservation solution and additives, degree of lung inflation for storage after explantation, and proper organ storage for transportation.7Munshi L. Keshavjee S. Cypel M. Donor management and lung preservation for lung transplantation.Lancet Respir Med. 2013; 1: 318-328Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar All these steps can make a significant difference in the maintenance of organ quality during the preservation period. Although cold preservation has several advantages in protecting the organ during preservation by slowing down cellular metabolism, this method of preservation is limited in its ability to assess organ function or to deliver treatment to the injured donor organ. Normothermic (EVLP) in the contemporary experience was reintroduced by Steen and colleagues8Steen S. Sjöberg T. Pierre L. Liao Q. Eriksson L. Algotsson L. Transplantation of lungs from a non-heart-beating donor.Lancet. 2001; 357: 825-829Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar for short-term donor lung assessment. In Toronto, we extended the concept of normothermic EVLP not only for organ assessment but also for maintenance, extended preservation, and treatment. We subsequently translated this to routine clinical practice.2Cypel M. Yeung J.C. Hirayama S. Rubacha M. Fischer S. Anraku M. et al.Technique for prolonged normothermic ex vivo lung perfusion.J Heart Lung Transplant. 2008; 27: 1319-1325Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 8Steen S. Sjöberg T. Pierre L. Liao Q. Eriksson L. Algotsson L. Transplantation of lungs from a non-heart-beating donor.Lancet. 2001; 357: 825-829Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 9Cypel M. Yeung J.C. Liu M. Anraku M. Chen F. Karolak W. et al.Normothermic ex vivo lung perfusion in clinical lung transplantation.N Engl J Med. 2011; 364: 1431-1440Crossref PubMed Scopus (760) Google Scholar This practice has been increasingly applied worldwide, including in the United States, Austria, France, and various European countries.10Aigner C. Slama A. Hötzenecker K. Scheed A. Urbanek B. Schmid W. et al.Clinical ex vivo lung perfusion–pushing the limits.Am J Transplant. 2012; 12: 1839-1847Crossref PubMed Scopus (139) Google Scholar, 11Slama A. Schillab L. Barta M. Benedek A. Mitterbauer A. Hoetzenecker K. et al.Standard donor lung procurement with normothermic ex vivo lung perfusion: a prospective randomized clinical trial.J Heart Lung Transplant. 2017; 36: 744-753Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 12Sage E. Mussot S. Trebbia G. Puyo P. Stern M. Dartevelle P. et al.Lung transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience.Eur J Cardiothorac Surg. 2014; 46: 794-799Crossref PubMed Scopus (84) Google Scholar, 13Valenza F. Citerio G. Palleschi A. Vargiolu A. Fakhr B.S. Confalonieri A. et al.Successful transplantation of lungs from an uncontrolled donor after circulatory death preserved in situ by alveolar recruitment maneuvers and assessed by ex vivo lung perfusion.Am J Transplant. 2016; 16: 1312-1318Crossref PubMed Scopus (50) Google Scholar, 14Wallinder A. Riise G.C. Ricksten S.E. Silverborn M. Dellgren G. Transplantation after ex vivo lung perfusion: a midterm follow-up.J Heart Lung Transplant. 2016; 35: 1303-1310Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 15Warnecke G. Moradiellos J. Tudorache I. Kuhn C. Avsar M. Wiegmann B. et al.Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients.Lancet. 2012; 380: 1851-1858Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar In a recent study, we reported on our experience with the routine use of donor lungs with greater than 12 hours of preservation when normothermic EVLP was added to the lung preservation phase, leading to excellent recipient outcomes.16Yeung J.C. Krueger T. Yasufuku K. de Perrot M. Pierre A.F. Waddell T.K. et al.Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study.Lancet Respir Med. 2017; 5: 119-124Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The clinical application of EVLP continues to grow. Its principal use to date has been to test "questionable" donor organs before LTx. With EVLP, although significantly longer preservation times were observed, rates of primary graft dysfunction remained low.16Yeung J.C. Krueger T. Yasufuku K. de Perrot M. Pierre A.F. Waddell T.K. et al.Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study.Lancet Respir Med. 2017; 5: 119-124Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 17Cypel M. Yeung J.C. Machuca T. Chen M. Singer L.G. Yasufuku K. et al.Experience with the first 50 ex vivo lung perfusions in clinical transplantation.J Thorac Cardiovasc Surg. 2012; 144: 1200-1206Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar It is important to recognize that when using EVLP, total lung preservation time is now the sum of 4 intervals (Figure 1 and Table 1): (1) cold ischemic time 1 (CIT1, the period of cold static preservation from crossclamp and cold flush in the donor to the start of normothermic EVLP); (2) normothermic EVLP time; (3) cold ischemic time 2 (CIT2), the period of cold static preservation after EVLP and before placement in the recipient's chest; and (4) implantation time, the time from placement in the chest to reperfusion, also known as warm ischemic time.Table 1Definition of preservation timesPreservation timesDefinitionCold ischemic time 1From cold flush in donor to initiation of EVLP perfusionEVLP timeFrom normothermic EVLP initiation until EVLP termination at 10°CCold ischemic time 2From EVLP termination at 10°C to insertion of graft in the chest cavityWarm ischemic timeFrom graft insertion in chest cavity to opening of pulmonary artery clampEVLP, Ex vivo lung perfusion. Open table in a new tab EVLP, Ex vivo lung perfusion. In our study, we demonstrated that patients receiving lungs exposed to 12 to 24 hours of total lung preservation time had early and late outcomes similar to those of patients receiving lungs with the standard 6 to 8 hours of lung preservation time. Of note, clinical EVLP time was fixed at 4 to 6 hours, and thus the bulk of the preservation time was due to prolonged CIT1 and CIT2. This period of normothermic preservation with increased metabolic function may serve to interrupt cold preservation injury and clear away accumulated metabolic debts. We therefore posed the question as to whether EVLP might interrupt inflammatory and ischemic injury and "restart the clock" after CIT1. A large animal model was used to study this, confirming that after a long CIT1 (10 hours) and 6 hours of EVLP, lungs could tolerate a CIT2 as long as 10 hours, for a total preservation time of 26 hours, without any measurable deleterious effect to the graft after LTx.18Hsin M.K. Iskender I. Nakajima D. Chen M. Kim H. dos Santos P.R. et al.Extension of donor lung preservation with hypothermic storage after normothermic ex vivo lung perfusion.J Heart Lung Transplant. 2016; 35: 130-136Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Another study has demonstrated that a period of 4 hours of CIT1 was actually beneficial to lungs from donors after cardiac death relative to direct normothermic perfusion after organ retrieval.19Mulloy D.P. Stone M.L. Crosby I.K. Lapar D.J. Sharma A.K. Webb D.V. et al.Ex vivo rehabilitation of non–heart-beating donor lungs in preclinical porcine model: delayed perfusion results in superior lung function.J Thorac Cardiovasc Surg. 2012; 144: 1208-1215Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Clearly, more data are required for transplant centers at large to generalize these findings and safely adopt this concept. As we continue to confirm these results in subsequent clinical trials, however, LTx could conceivably be transformed into a more elective procedure. This will have a major impact on the current practice of LTx. For example, LTx could be delayed until the daytime hours with obvious advantages for surgical, anesthesia and operating room staff performing under optimal conditions. In addition, an elective delay of LTx could be used to address donor- or recipient-related logistic challenges. Indeed, although exact data are not available, logistics often plays a major role in declining organs for transplantation. Additional advantages of safe prolongation of donor lung preservation could include opportunities for expanding the geographic reach for donors, improving donor-recipient immunologic matching,20De Wolf J. Puyo P. Bonnette P. Roux A. Le Guen M. Parquin F. et al.Logistic ex vivo lung perfusion for hyperimmunized patients.Ann Thorac Surg. 2016; 102: e205-e206Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar avoiding the need to rush during difficult lung explantation procedures, and allowing patients to live several hours away from the transplant center as to avoid the adverse financial and social consequences of relocation. In addition, because 30% to 50% of donors after cardiac death do not have arrest after withdrawal of life support therapy in a suitable time for organ donation,21Machuca T.N. Mercier O. Collaud S. Tikkanen J. Krueger T. Yeung J.C. et al.Lung transplantation with donation after circulatory determination of death donors and the impact of ex vivo lung perfusion.Am J Transplant. 2015; 15: 993-1002Crossref PubMed Scopus (103) Google Scholar it has been our practice not to admit a potential recipient to the hospital until full assessment of the retrieved lungs from a donor after cardiac death has been performed, and we then use the EVLP period to call in and prepare the recipient. It is also evident as we enter the exciting era of biologic engineering that this added preservation time will provide the opportunity to repair donor lungs and create immunologically preprepared lungs that will be tolerated better by the recipient for superior long-term survival in times to come. This truly heralds the era of opportunity to create "super organs" provided in a fashion in which health care systems will be equipped to be able to deliver transplantation in far more effective and efficient manner. In summary, combining properly performed cold static preservation and normothermic EVLP can substantially prolong donor lung preservation times without adverse effects to recipients. We are entering an era in which semielective LTx is a reality, with several important potential advantages to LTx recipients. M.C. and S.K. are cofounders of Perfusix Canada and XOR Labs Toronto, are consultants for Lung Bioengineering, and receive research support from Xvivo Perfusion. J.C.Y. has nothing to disclose with regard to commercial support. A first start for lung transplantation?The Journal of Thoracic and Cardiovascular SurgeryVol. 156Issue 6PreviewThey told me there was not enough blood available. "YOU CANNOT BE SERIOUS," I said in a not-so-satisfied tone. A donor was available for a 20-year-old inpatient with pulmonary fibrosis and short telomere syndrome who had associated dyskeratosis congenita and myelodysplastic syndrome. This would be reoperative chest surgery because of a previous right middle lobectomy. The patient was listed for lung and bone marrow transplants through a clinical protocol in which we do the lung transplant first and 3 months later the bone marrow transplant occurs. Full-Text PDF Open Archive
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