肺移植手术中供肺保存液的研究现状

肺移植手术是治疗终末期肺部疾病的惟一有效方法，但仍然有许多相关问题须待解决。除了供肺严重缺乏外，因缺血-再灌注损伤导致的移植肺功能异常是肺移植手术患者最常见的早期死亡原因之一。保存移植肺的最佳状态对减轻肺移植术后缺血器官功能障碍至关重要。因此，寻找一种高度可靠的肺保存液，对减轻移植肺的缺血-再灌注损伤、提高肺移植术后肺功能有着十分重要的意义。现就供肺保存液的种类、灌注方式、灌注条件及其改良措施的研究现状进行综述。     

Lung preservation.

Pulmonary transplantation is now a clinical reality that offers hope to large numbers of patients with end-stage lung disease. Current methods of preserving pulmonary function allow for transplantation, but operation must be expeditious, and transportation time and operating time become critical factors in determining outcome. The ability to preserve lungs for longer time intervals could potentially allow for more widespread distribution of donor organs of unusual size or blood type, and could set the stage for more appropriate HLA matching between donor and recipient. Furthermore, a more thorough understanding of the pathophysiology of preservation injury will likely lead to a better understanding of the pathophysiology of other types of lung injury. In turn, this could increase the size of the pulmonary donor pool by allowing transplantation of lungs with suboptimal gas exchange function at the time of donor brain death. Finally, a more thorough understanding of lung metabolism and determinants of cellular viability in the lung would be useful for the potential application of the use of lungs from circulation-arrested cadavers for transplantation.     

Lung transplantation

The supply of donor organs remains extremely limited, and improved methods of maintaining the lungs of potential donors to allow for transplantation must be developed. Currently the upper limit of donor lung ischemic even with our "best" preservation techniques is approximately 4 to 6 hours. Improved methods for preservation will increase the supply of suitable lungs and will considerably simplify the logistics of transplantation just as has occurred with liver transplantation. Efficient use of donor organs remains of paramount importance. We recently performed two single-lung transplants utilizing lungs from one donor. Likewise, there is no reason why a lung could not be sent to another center for transplantation if the harvesting group uses only one lung. Sufficient progress has been achieved to date to warrant continued application of lung transplantation for end-stage pulmonary disease. With increasing experience, one can anticipate refinement of techniques and broader application of these procedures. Single lung transplantation, initially restricted to patients with end-stage pulmonary fibrosis, has now been successfully applied to patients with emphysema, pulmonary hypertension, and other conditions. Although transplantation currently can offer real benefit only to a limited number of persons, it serves to create hope for many others. An additional benefit may prove to be the interest and attention that transplantation focuses on patients with end-stage lung disease and on the pathophysiology of chronic respiratory failure. Knowledge gained may ultimately result in the prevention of many of the disorders for which lung transplantation currently offers the only hope.     

Lung preservation

Better understanding of the mechanisms of ischemia-reperfusion injury, improvement in the technique of lung preservation, and the recent introduction of a new preservation solution specifically developed for the lungs have helped to reduce the incidence of primary graft dysfunction after lung transplantation. Currently, the limitation in extending the ischemic time is more often related to the increasing use of non-ideal lung donors rather than to poor lung preservation. In this review, we have focused our attention on the experimental and clinical work performed to optimize the methods of lung preservation from the time of retrieval to the period of reperfusion after graft implantation.     

Pulmonary transplantation: the role of brain death in donor lung injury

The paucity of suitable lung donors and the high early mortality as the result of primary graft failure remain major challenges in pulmonary transplantation. There is evidence that the lung is injured in the donor by the process of brain death and often is made unusable or fails posttransplantation after amplification of the injury by the process of ischemia-reperfusion. An understanding of the mechanism of donor lung injury could lead to the development of new treatment strategies for the donor to reduce lung injury, increase the number of donors with acceptable lungs, and improve the results of transplantation. The pathophysiology of brain death is complex and involves sympathetic, hemodynamic, and inflammatory mechanisms that can injure the lung. The literature is reviewed, and these mechanisms are discussed together with their possible interrelations.     

Pulmonary Recruitment Protocol For Organ Donors: A New Strategy to Improve the Rate of Lung Utilization

Because lung transplantation is the only effective therapy for terminal respiratory failure, the demand for donor lungs has increased steadily. However, the number of donors has remained fairly constant over the years, which results in an increasing duration of waiting for lung transplantation. To overcome the lack of organs, various strategies have been developed by transplant centers including use of marginal donors. To increase the lung utilization rate in multiorgan donors, we implemented a simple lung recruitment protocol involving a brief period of controlled sustained inflation. In 2005, the lung utilization rate in the transplant program at our institution was only 20% in multiorgan donors. With the lung recruitment protocol, the rate of lung utilization for transplantation increased to 33%, in 2006, 24% in 2007, and 24% in 2008. Following the lung recruitment protocol, the arterial oxygen tension/fraction of inspired oxygen ratio increased to greater than 15% in more than 40% of donors. We were able to improve gas exchange sufficiently that as many as two-thirds of the lungs were suitable for transplantation. During the protocol, no complications were reported, and no patient became hemodynamically unstable, precluding organ procurement. We believe that optimization of multiorgan donor management with simple interventions may improve oxygenation, reducing the number of inadequate donor lungs and increasing the overall donor pool and organ availability.     

Normothermic Ex Vivo Perfusion Prevents Lung Injury Compared to Extended Cold Preservation for Transplantation

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°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 (PaO₂ 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.     

Lung transplantation

Over the past 20 years, many advances in surgical methods, transplantation immunology, donor organ procurement and preservation techniques, and postsurgical care regimens have influenced greatly the field of lung transplantation. The single remaining obstacle to widespread clinical success is donor lung availability. Improved methods of ex vivo lung preservation, organ donor maintenance, and donor lung retrieval after the completion of cardiac donation should help to ameliorate this problem.     

Lung transplantation from donation after cardiac death (non-heart-beating) donors

Although lung transplantation is a well-accepted treatment for advanced lung diseases, donor shortage remains a significant limiting factor resulting in an increasing number of deaths of people on waiting lists. Recently, some transplant centers have begun to use lungs retrieved from donors after circulatory arrest. This review outlines the relevant published experimental data and clinical experiences with lung transplantation from donation after cardiac-death donors (DCDs) or non-heart-beating donors (NHBDs). Techniques for lung preservation and ex vivo lung assessment of DCD (NHBD) lungs are reviewed, and aspects of primary graft dysfunction after DCD (NHBD) lung transplantation are discussed. This review was submitted at the invitation of the editorial committee.     

Lung transplantation: present international status and basic approach

Lung transplantation has been established as an optional treatment for irreversible diffuse lung disease. To date, more than 8,000 patients have undergone lung transplantation, while heart-lung transplantation is confined to a very limited number of cases due to the severe shortage of donors. There are various problems in clinical lung transplantation, including limited preservation time, post-transplantation edema, acute and chronic rejection, and a shortage of donor organs. Several solutions to these problems have been found in recent experimental studies. For example, potential therapies for posttransplantation edema have been proposed, and the possibility of long-term preservation has been suggested. Research on xenotransplantation and cadaveric lung transplantation is ongoing, and this may result in options to solve the problem of the shortage of donor organs. In particular, we believe that cadaveric lung transplantation has the potential to become a clinically useful therapy in the near future.     

Lung transplantation. Donor selection

The demand for donor lungs currently exceeds the supply of suitable grafts by a significant margin. Legal backgrounds and organizational and logistic issues are of major impact on the available donor pool. Re-evaluation of the donor criteria currently in use and new, innovative approaches such as living donor lung transplantation and non-heart-beating donation will hopefully contribute to improve this situation and reduce waiting time and waiting list mortality.     

Lung transplantation from out-of-hospital non-heart-beating lung donors. one-year experience and results.

There is currently no method for preservation and functional evaluation of clinical out-of-hospital non-heart-beating lung donors (NHBLD) that can be applied practically and systematically in clinical lung transplantation programs. A new method of preservation and functional evaluation of the lung has been developed in NHBLD that is based on the knowledge of various experimental studies. Initially, the viability of lungs harvested this way was proved from preliminary functional and histologic tests. In November 2002, we started using lung allografts from non-heart-beating donors. Five lung transplantations (4 bipulmonary and 1 unipulmonary) were performed successfully. The short and mid-term results have been excellent and all recipients are alive. We report our initial experience, which we hope will be of help to those involved in clinical lung transplantation programs worldwide.     

Current Trends in Lung Transplantation

Lung transplantation provides very good short- and acceptable long-term survival for patients with advanced lung disease. More widespread use of marginal and distant donors can be employed in selected recipients without compromising early or late results. Lack of suitable donor lungs and the development of BOS represent the biggest obstacles to more widespread application and long-term success of lung transplantation. The high rate of acute rejection and subsequent BOS clearly indicates that current immunosuppression strategies are inadequate. Further clinical and laboratory research into the pathogenesis of BOS will perhaps reveal new treatment options.     

Lung transplantation: state of the art and current practice

Lung transplantation remains the standard of care for selected patients with progressive respiratory failure with advanced chronic lung disease. In the late 1980s, early surgical pioneers of lung transplantation developed programmes which included the surgical techniques and patient management principles that remain in use today. Since then, development of technology and advancements in clinical care to support patients on the lung transplant waiting list, along with advances in immunosuppression, have led to increased numbers of lung transplants and improved recipient outcomes. There are currently 339 patients on the UK lung transplant waiting list, with 270 new registrations in 2018/19. A total of 166 lung and heart–lung transplants were performed in the UK in 2018/19. In the modern era, research has focused on bridging this gap between the number of patients listed for lung transplantation and the number of available organs. Here, the focus is not only increasing the number of potential organ donors, but improving our ability to select, evaluate and improve the utilization of donor lungs.     

Clinical Ex Vivo Lung Perfusion—Pushing the Limits

Ex vivo lung perfusion (EVLP) provides the ability to evaluate donor lungs before transplantation. Yet, limited prospective clinical data exist with regard to its potential to recondition unacceptable donor lungs. This paper summarizes the results of a prospective study of lung transplantation using only initially unacceptable donor lungs, which were improved by EVLP for 2–4 h. From March 2010–June 2011, 13 lungs were evaluated ex vivo. Median donor PaO₂ at FiO₂1.0/PEEP5 was 216 mmHg (range 133–271). Four lungs, all with trauma history, showed no improvement and were discarded. Nine lungs improved to a ΔPO₂ higher than 350 mmHg. Median PvO₂ at final assessment in these lungs was 466 mmHg (range 434–525). These lungs were transplanted with a median total ischemic time of 577 min (range 486–678). None of the patients developed primary graft dysfunction grades 2 or 3 within 72 h after transplantation. One patient with secondary pulmonary hypertension was left on a planned prolonged extracorporeal membrane oxygenation postoperatively. Median intubation time was 2 days. Thirty‐day mortality was 0%. During the observation period, 119 patients received standard lung transplantation with comparable perioperative outcome. EVLP has a significant potential to improve the quality of otherwise unacceptable donor lungs.     

外源性一氧化碳改善供体肺功能的实验研究

目的观察一氧化碳(CO)对长时间低温保存的供体肺的保护作用。方法建立大鼠肺移植离体肺灌注实验模型:SD大鼠24只随机分为空白对照组、实验组(CO组),每组6对作为肺移植的供体鼠和受体鼠。对照组大鼠供肺移植全程吸入100%氧气直至再灌注后1h;CO组移植全程吸入500×10-6CO和O2的混合气,并且供体肺在冷保存的12h内肺内仍充盈着CO和O2的混合气,余同对照组。于供体肺循环灌注l,20,40,60min测定供肺氧合后动脉血氧分压(PaO2)、平均肺动脉压、气道峰压;灌注结束后测定肺组织湿干比、丙二醛(MDA)含量、髓过氧化物酶(MPO)活性、白细胞介素8(IL-8)的含量。结果作为受体的12只(每组6只)进入结果分析:①CO组供体肺的PaO2在再灌注20、40、60min明显高于对照组,平均动脉压、气道峰压分别在再灌注20、40、60min和40、60min明显低于对照组(P<0.05);②与空白对照组比较,CO组供体肺再灌注后湿干比、MDA、MPO、IL-8含量均明显降低(P<0.05)。结论在肺移植的全程吸入低剂量CO可以减轻供肺的缺血再灌注损伤,改善供肺功能。     

Ex Vivo Lung Perfusion Increases the Pool of Lung Grafts: Analysis of Its Potential and Real Impact on a Lung Transplant Program

Background

Among the strategies to increase the number of lung transplants, ex vivo lung perfusion (EVLP) represents a novel technique to expand the donor pool.

Methods

Data from donors referred to our center were retrospectively analyzed to identify grafts that could potentially be potentially reconditioned by EVLP and for comparison with those obtained by clinical application of EVLP program in our center.

Results

Among 75 rejected lungs, 23 organs have been identified as potentially treatable with EVLP with a hypothetic increase of lung transplant activity of 53%. After the introduction of the EVLP program in our center, lung transplantation with reconditioned grafts was performed in 7 (23%) patients with a 30% increase in transplant procedures.

Conclusion

Although less than expected, EVLP increased the number of lungs suitable for transplantation.     

Successful transplantation of marginally acceptable thoracic organs.

OBJECTIVE: This study evaluates the efficacy of personally inspecting marginal thoracic organ donors to expand the donor pool. SUMMARY BACKGROUND DATA: The present donor criteria for heart and lung transplantation are very strict and result in exclusion of many potential thoracic organ donors. Due to a limited donor pool, 20-30% of patients die waiting for transplantation. METHODS: The authors have performed a prospective study of personally inspecting marginal donor organs that previously would have been rejected by standard donor criteria. RESULTS: Fourteen marginal hearts and eleven marginal lungs were inspected. All 14 marginal hearts and 10 of the marginal lungs were transplanted. All cardiac transplant patients did well. The mean ejection fraction of the donor hearts preoperatively was 39 +/- 11% (range 15-50%). Postoperatively, the ejection fraction of the donor hearts improved significantly to 55 +/- 3% (p < 0.002). Nine of the ten lung transplant patients did well and were operative survivors. Our donor pool expanded by 36% over the study period. CONCLUSIONS: The present donor criteria for heart and lung transplantation are too strict. Personal inspection of marginal thoracic donor organs will help to maximize donor utilization.     

Towards donor lung recovery—gene expression changes during ex vivo lung perfusion of human lungs

We and others have demonstrated that acellular normothermic ex vivo lung perfusion of high‐risk donor lungs can result in posttransplant outcomes equivalent to that of contemporaneous lung transplantation using standard donor lungs. However, the mechanism of this effect remains unclear. Given the restoration of cellular metabolic activity during normothermic perfusion, one possibility is that of lung healing via natural innate recovery mechanisms. We explored this by examining the gene expression changes occurring in human lungs during ex vivo lung perfusion. Human lungs clinically rejected for transplantation were perfused for 12 hours of EVLP with biopsies taken at the start, at 1 hour, at 3 hours, and then every 3 hours thereafter to 12 hours. Temporal changes were identified in 2585 genes using the Short Time‐series Expression Miner and used for pathway analysis. Despite increases in endothelial markers of inflammation, circulating leukocyte cell‐specific gene expression fell over 12 hours of ex vivo lung perfusion (EVLP), suggesting an interrupted inflammation response secondary to washout of circulating leukocytes. Analysis of these gene changes suggests lung recovery follows specific stages: cellular death, cellular preservation, cellular reorganization, and cellular invasion. EVLP may improve posttransplant lung function by washout of leukocytes and facilitating innate mechanisms of repair.     

Strategies for Maximizing Heart and Lung Transplantation Opportunities in Japan

Introduction

Because the donor shortage is extremely severe in Japan because of a strict organ transplantation law, special strategies must be established to maximize heart transplantation (HTx) and lung transplantation (LTx) opportunities. The purpose of this study was to review our strategies to identify and manage heart and lung donors.

Method

Transplantation doctors themselves assessed their own donor heart and lung function before starting the procurement operation; skillful staff surgeons harvested the organs. Since November 2002, a special transplantation consultant doctor assessed donor organ function to identify useful organs and intensively cared for the donor to improve cardiac and lung function.

Results

Only 63 brain-dead donors have been available in Japan. However, 49 HTx (77.7%) and 39 LTx (19 bilateral and 20 single) were performed from 36 donors (57.1%). Thirty-six HTx donors were marginal, requring sustained high doses of inotropes (n = 26), low left ventricular ejection fraction (n = 5), cardiopulmonary resuscitation (n = 15), and age older than 55 years (n = 6). Twenty LTx donors had infected sputa or showed pneumonia using chest X-ray. None of 49 HTx recipients died of primary graft failure (PGF). Patient survival at 3 years after HTx was 98.0%. Although 5/39 LTx died early, including 2 of PGF, patient survival rate at 3 years was 66.9%.

Conclusion

Although the number of cases was still small, the availability of hearts and lungs has been high and the transplantation outcomes were acceptable. These strategies may be useful to maximize HTx/LTx opportunities.