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The purpose of this study was to examine the influence of extracorporeal membrane oxygenation (ECMO) as a bridge to reoperative lung transplantation (LT) on outcomes and survival. A total of 1960 LT recipients transplanted a second time between 2005 and 2017 were analyzed using the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN). Of these recipients, 99 needed ECMO as a bridge to reoperative LT. Mean age was 50 ± 14 years, 47% were females, and the group with ECMO was younger [42 (30–59) vs. 55 (40–62) years]. In both univariate and multivariable analyses (adjusting for age and gender), the ECMO group had greater incidence of prolonged ventilation >48 h (83% vs. 40%, P < 0.001) and in-hospital dialysis (27% vs. 7%, P < 0.001). There were no differences in incidence of acute rejection (15% vs. 11%, P = 0.205), airway dehiscence (4% vs. 2%, P = 0.083), stroke (3% vs. 2%, P = 0.731), or reintubation (20% vs. 20%, P = 0.998). Kaplan–Meier survival analysis showed the ECMO group had reduced 1-year survival (66.6% vs. 83.0%, P < 0.001). After covariate adjustment, the ECMO group only had increased risk for 1-year mortality in the 2005–2011 era (HR = 2.57, 95% CI = 1.45–4.57, P = 0.001). For patients who require reoperative LT, bridging with ECMO was historically a significant predictor of poor outcome, but may be improving in recent years.

Lung transplantation (LT) is definitive therapy for end-stage lung disease. Donor allocation based on medical urgency has led to an increased trend in the transplantation of sicker and older patients. Mechanical ventilation (MV) formerly was the only method of bridging high-acuity patients to LT. When the physiological demands of ventilatory support exceeds the capability of MV, extracorporeal membrane oxygenation (ECMO) may become necessary. Recent improvements in ECMO technology and component design have led to a resurgence of interest in its use before, during, and after LT. Survival with ECMO as a bridge to LT has improved over time, now with many centers reporting little or no difference in outcomes, and some even reporting better outcomes, as compared with MV. Extracorporeal life support may also be used intraoperatively. In many studies to date, ECMO or cardiopulmonary bypass (CPB) has been reserved for patients who became hemodynamically unstable during the procedure or patients who could not tolerate single-lung ventilation. Both methods of support are fraught with potential complications. However, multiple studies comparing ECMO with CPB have shown that intraoperative use of ECMO resulted in improved outcomes and overall survival as well as lower rates of bleeding complications. In order to further reduce complications associated with ECMO, planned intraoperative ECMO use is occasionally reserved for high-risk patients who might otherwise require CPB. Future studies will need to improve patient selection to fully take advantage of the use of ECMO in LT while minimizing its costs.

The purpose of this study was to examine outcomes and survival with mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (LT) using a national registry.The United Network for Organ Sharing database was analyzed for recipients in the period 2005 to 2017. Recipients were categorized into 3 groups based on pre-transplant bridging. Multivariable regression analyses examined the effect of bridging on post-LT outcomes adjusting for clinical characteristics, including era (early = 2005-2011, late = 2012-2017) and center volume.There were 21,576 LT recipients: no bridge (n = 19,783), MV (n = 1,129), and ECMO (n = 664). Mean age was 54 ± 15 years (41% female). Use of ECMO increased significantly in the late era (1% vs 5%, p0.001). Compared with no bridge, patients with MV and ECMO had greater odds for peri-operative outcomes including ventilator support48 hours, acute rejection, and dialysis. Patients with MV had reduced odds for ventilator support48 hours (p = 0.003), dialysis (p = 0.003), post-operative ECMO (p = 0.006), and greater odds for reintubation (p = 0.005) compared with ECMO. Patients in both MV (hazard raio [HR] 1.45, p0.001) and ECMO (HR 1.48, p0.001) groups had greater risk for 5-year mortality, but MV and ECMO groups did not differ (HR 0.98, p = 0.817). Risk for mortality in the ECMO group decreased in the later era (HR 0.54, p = 0.006).ECMO as a bridge to LT has increased 271%, while MV has decreased 38% over the past decade. Survival with ECMO has significantly improved and is now equivalent to survival in recipients bridged on MV. These results suggest gains in use, outcomes, and safety of ECMO in this patient cohort.

Although lung transplantation is an effective treatment for end-stage lung failure, its limitations have led to renewed interest in artificial lung support for patients with lung failure. The use of ventricular assist devices has significantly improved the quality of life and survival of patients with end-stage heart failure. In contrast, there are no devices that can be used long term as destination therapy for end-stage lung failure, and there is a strong need for them. Extracorporeal membrane oxygenation is widely used as a temporary treatment for acute lung failure and as a bridge to lung transplant. Many patients with advanced lung failure cannot return home with good quality of life once they are hospitalized. In this review, the authors discuss the history, status, and future of artificial lungs, focusing on long-term artificial respiratory support as a destination therapy. Respiratory assist devices, such as artificial lungs, could eventually become analogous to ventricular assist devices.

Lung transplantation may be a final destination therapy in lung failure, but limited donor organ availability creates a need for alternative management, including artificial lung technology. This invited review discusses ongoing developments and future research pathways for respiratory assist devices and tissue engineering to treat advanced and refractory lung disease. An overview is also given on the aftermath of the coronavirus disease 2019 pandemic and lessons learned as the world comes out of this situation. The first order of business in the future of lung support is solving the problems with existing mechanical devices. Interestingly, challenges identified during the early days of development persist today. These challenges include device-related infection, bleeding, thrombosis, cost, and patient quality of life. The main approaches of the future directions are to repair, restore, replace, or regenerate the lungs. Engineering improvements to hollow fiber membrane gas exchangers are enabling longer term wearable systems and can be used to bridge lung failure patients to transplantation. Progress in the development of microchannel-based devices has provided the concept of biomimetic devices that may even enable intracorporeal implantation. Tissue engineering and cell-based technologies have provided the concept of bioartificial lungs with properties similar to the native organ. Recent progress in artificial lung technologies includes continued advances in both engineering and biology. The final goal is to achieve a truly implantable and durable artificial lung that is applicable to destination therapy.

Background Despite the benefits of ex vivo lung perfusion (EVLP) such as lung reconditioning, preservation and evaluation prior to transplantation, deleterious effects including activation of proinflammatory cascades and alteration of metabolic profiles have been reported. Although patient outcomes have been favorable, further studies addressing optimal conditions are warranted. In this study, we investigated the role of the immunosuppressant drug Cyclosporine A (CyA), in preserving mitochondrial function and subsequently preventing proinflammatory changes in lung grafts during EVLP. Methods Using rat heart-lung blocks after 1 hour cold preservation, an acellular normothermic EVLP system was established for 4 hours. CyA was added into perfusate at a final concentration of 1 µM. The evaluation included lung graft function, lung compliance and pulmonary vascular resistance as well as biochemical marker measurement in the perfusate at multiple time points. After EVLP, single orthotopic lung transplantation was performed and the grafts were assessed 2 hours after reperfusion. Results Lung grafts on EVLP with CyA exhibited significantly better functional and physiological parameters as compared to those without CyA treatment. CyA administration attenuated proinflammatory changes and prohibited glucose consumption during EVLP through mitigating mitochondrial dysfunction in lung grafts. CyA-preconditioned lungs showed better posttransplant lung early graft function and less inflammatory events compared to control. Conclusions During EVLP, CyA administration can have a preconditioning effect through both its anti-inflammatory and mitochondrial protective properties leading to improved lung graft preservation which may result in enhanced graft quality after transplantation.

Background Compromised microvasculature resulting from disrupted bronchial arterial circulation appears to trigger chronic lung allograft dysfunction. Maintaining the microvasculature throughout the transplant process could improve the long-term health of transplanted lungs. We recently developed a bronchial-arterial-circulation-sparing (BACS) lung preservation approach and tested whether this approach would decrease microvascular damage and improve allograft function. Methods The lungs of Lewis rats were procured using either the BACS approach, where the bronchial and pulmonary arteries were synchronously perfused; a conventional approach, where only the pulmonary artery was perfused; or a conventional approach with a prostaglandin flush. After 4 hours of cold ischemia, physiologic function and vascular tone of the grafts were evaluated during ex vivo lung perfusion (EVLP), and microvasculature damage was assessed using 2-photon microscopy analysis. Lung function was compared after transplant among the groups. Results After 4 hours of cold ischemia, the BACS group exhibited significantly higher adenosine triphosphate levels and lower expression of phosphorylated myosin light chain, which is essential for vascular smooth muscle contraction. On EVLP, the BACS and prostaglandin groups showed lower pulmonary vascular resistance and less arterial stiffness. BACS attenuated microvasculature damage in the lung grafts when compared with conventional preservation. After transplantation, the lungs preserved with the BACS approach exhibited significantly better graft function and lower expression of phosphorylated myosin light chain. Conclusions Our data suggest that BACS lung preservation protects the dual circulation inherent to the lungs, facilitating robust microvasculature in lung grafts after transplantation, leading to better posttransplant outcomes.

In aging populations, many patients have multiple diseases characterized by acceleration of the aging process including cardiovascular diseases, metabolic diseases, and chronic kidney disease. Remarkable progress in minimally invasive, interventional therapies, such as percutaneous coronary intervention and transcatheter aortic valve replacement has enabled patients who were previously not transplant candidates because of co-existing problems to become potentially viable candidates for lung transplantation. Recently, we have observed an outstanding and steady increase in patients older 70 years of age with multiple comorbidities who are referred to our high-volume center as potential candidates for lung transplantation. However, the impact of diseases characterized by an accelerated aging process and their treatments on transplant outcomes remains unclear. This review aims to highlight these challenges in the current era of lung transplantation, review the prior literature, and discuss future directions with a multidisciplinary view including translational research, transplant medicine, and surgery, as well as from a programmatic and administrative standpoint.

Over the past 30 years, lung transplantation has emerged as the definitive treatment for end-stage lung disease. In 2005, the lung allocation score (LAS) was introduced to allocate organs according to disease severity. The number of transplants performed annually in the United States continues to increase as centers have become more comfortable expanding donor and recipient criteria and have become more facile with the perioperative and long-term management of these patients. We report a single-center experience with lung transplants, looking at patients before and after the introduction of LAS.We retrospectively reviewed 1500 adult lung transplants at a single center performed between 1988 and 2016. Patients were separated into 2 groups, before and after the introduction of LAS: group 1 (April 1988 to April 2005; 792 patients) and group 2 (May 2005 to September 2016; 708 patients).Differences in demographic data were noted over these periods, reflecting changes in allocation of organs. Group 1 patient average age was 48 ± 13 years, and 404 subjects (51%) were male. Disease processes included emphysema (52%; 412), cystic fibrosis (18.2%; 144), pulmonary fibrosis (16.1%; 128) and pulmonary vascular disease (7.2%; 57). Double lung transplant (77.7%; 615) was performed more frequently than single lung transplant (22.3%; 177). Group 2 average age was 50 ± 14 years, and 430 subjects (59%) were male. Disease processes included pulmonary fibrosis (46%; 335), emphysema (25.8%; 188), cystic fibrosis (17.7%; 127) and pulmonary vascular disease (1.6%; 11). Double lung transplant (96.2%; 681) was performed more frequently than single lung transplant (3.8%; 27). Overall incidence of grade 3 primary graft dysfunction (PGD) in group 1 was significantly lower at 22.1% (175) than in group 2 at 31.6% (230) (P .001). Nonetheless, overall hospital mortality was not statistically different between the 2 groups (4.4% vs 3.5%; P .4). Most notably, survival at 1 year was statistically different at 646 (81.6%) for group 1 and 665 (91.4%) for group 2 (P .02).Patient demographics over the study period have changed with an increased number of fibrotic patients transplanted. In addition, more aggressive strategies with donor/recipient selection appear to have resulted in a higher incidence of primary graft dysfunction. This does not, however, appear to affect patient survival on index hospitalization or at 1 year. In fact, we have observed a significant improvement in survival at 1 year in the more recent era. This observation suggests that continued expansion of possible donors and recipients, coupled with a more sophisticated understanding of primary graft dysfunction and long-term chronic rejection, can lead to increased transplant volume and prolonged survival.

Purpose Practice standardization may decrease donor lung shortages, however, the cause of organ acceptance pattern variation is not known. Our objective was to compare donor call practices in diverse settings. Methods This was a prospective, multi-center study of 10 centers from 6 distinct regions. Characteristics of consecutive, first-recipient eligible, donor offers (aged ≥13) received by participating centers with definitive decisions from May 1, 2016 to October 31, 2016 were abstracted along with reasons for organ offer turn downs (as applicable) and final organ disposition. A discrepant decision was defined as a donor lung offer declined by one center that was then accepted for transplant by an alternate center. Results We evaluated 2,000 consecutive offers; the majority (89.9%) were brain dead donors (BDD). Mean transplant volume was 33 transplants/year (range 11-98). Most centers had ex vivo lung perfusion and all had extra-corporeal membrane oxygenation bridging programs. Surgeons made final acceptance determinations at all centers. Declined organs had a mean donor age of 39 years, with a mean PaO2 to FiO2 (P/f) ratio of 352. The most common primary reason for offer decline was abnormal imaging followed by a low or decreasing P/f ratio. There were 412 (20.7%) discrepant offer decisions (8.1 to 41.2% of offers depending on center). Discrepant decisions significantly differed from non-discrepant decisions by transplant center mean annual volume, donor age, absolute and decreasing P/f ratio, and donor type (BDD versus circulatory death) (p Conclusion One in five donor offers that were initially declined by one transplant center were accepted for transplantation by another, highlighting significant variability in donor practices. Key donor and center factors were associated with discrepant decisions.

Purpose The previously described University of MN Donor Lung Quality Index (UMN-DLQI) score is a consensus-based decision tool that includes 16 risk-related components receiving 0-5 points, with higher scores signifying lower risk. A score >39 is considered favorable for transplant. We evaluated the UMN-DLQI score's performance across a diversity of US lung transplant centers. Methods We modified the UMN-DLQI to include standardized response choices for all parameters to enhance inter rater consistency. A co investigator at each site was trained in UMN-DLQI scoring, including hypothetical donor test cases to ensure proficiency. We included consecutive primary donor offers (age> 11) to participating sites between May 1 and October 31, 2016 that were either accepted for transplant or turned down for quality by the participating center. UMN-DLQI scores were calculated after donor acceptance decisions. We excluded donations after circulatory death and turn downs exclusively for size, HLA, known malignancy, unmet multi-organ or laterality needs, other recipient or donor issues, or excess travel time. We explored associations between the UMN-DLQI score with discrepant donor decisions (organs turned down that were subsequently transplanted elsewhere) and recipient outcomes. Results Eleven centers participated. 183 donor organs were accepted and transplanted. Accepted donors averaged 35 years old and 16% met increased risk criteria. The median UMN-DLQI score was 43 (range 32 - 50). One in five transplanted organs scored 6 hours, donor size mismatch, or pneumonia risk (57, 53, and 61%, respectively). The mean LAS was 45.5. Conclusion Multi center use of a standardized scoring instrument offers insight into donor acceptance practices and may be useful in understanding discrepant organ decisions in lung transplantation.

Chronic allograft dysfunction (CLAD) remains a major complication, causing the poor survival after lung transplantation (Tx). Although strenuous efforts have been made at preventing CLAD, surgical approaches for lung Tx have not been updated over the last 2 decades. The bronchial artery (BA), which supplies oxygenated blood to the airways and constitutes a functional microvasculature, has occasionally been revascularized during transplants, but this technique did not gain popularity and is not standard in current lung Tx protocols, despite the fact that a small number of studies have shown beneficial effects of BA revascularization on limiting CLAD. Also, recent basic and clinical evidence has demonstrated the relationship between microvasculature damage and CLAD. Thus, the protection of the bronchial circulation and microvasculature in lung grafts may be a key factor to overcome CLAD. This review revisits the history of BA revascularization, discusses the role of the bronchial circulation in lung Tx, and advocates for novel bronchial-arterial-circulation sparing approaches as a future direction for overcoming CLAD. Although there are some already published review articles summarizing the surgical techniques and their possible contribution to outcomes in lung Tx, to the best of our knowledge, this review is the first to elaborate on bronchial circulation that will contribute to prevent CLAD from both scientific and clinical perspectives: from bedside to bench to bedside, and beyond.

For the patients with progressively decompensating acute or acute-on-chronic respiratory failure, the first-choice treatment remains as mechanical ventilation. Despite the consistent value of mechanical ventilation, the majority of lung specialists are aware of its limitations, in particular for the patients with advanced lung failure, and inherent drawbacks that augment disease progression. More recently, the concept of allowing the lungs to 'rest and recover' has been supported by quite a few clinical studies. The pressure and volume of gas delivered to the lungs are reduced compared with mechanical ventilation. Based on recent remarkable evidence and experiences using extracorporeal lung support (ECLS) before, during and after lung transplant, there is growing interest in and expectations for the use of ECLS beyond lung transplant to encompass the entire field of pulmonary medicine. The purpose of this review article is to provide an update on evolving ECLS technologies and their effectiveness and discuss the future of ECLS for advanced lung failure as a new subspecialty in cardiothoracic surgery.

Purpose Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridging strategy to lung transplantation (LT). This trend has been largely influenced by increasing acuity among recipients. The purpose of this study was to examine factors related to death prior to LT for patients on ECMO at the time of registration. Methods Patients included those who were on ECMO when registered in the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network Database between 2005-2017. At registration for LT, 402 adult patients were on ECMO as a bridge, 324 of whom were transplanted or died prior to LT. Multivariable logistic regression was used to examine factors associated with mortality prior to LT. Results Mean age was 44.7±15.4 years and 38% were female. In this sample, 21% died before LT (n =68) with 44% for pulmonary reasons, 15% for graft failure , 9% for cardiac arrest, 7% for infection, and 24% for other reasons. Most common indication for LT was interstitial-restrictive disease (49%) whereas pulmonary hypertension patients had highest mortality (39%) although not significant. In multivariable analysis, female gender was associated with more than double risk for mortality prior to LT (OR=2.40, P=0.005; TABLE). However, female patients were younger (39 vs 48 years, P creatinine (0.6 vs 0.8, P Conclusion Female gender and elevated serum creatinine were independently associated with higher risk for mortality in patients with ECMO as a bridge to LT.

Current allocation of lungs is based on prioritizing candidates based on a risk benefit ratio. Since the current algorithm does not account for recipient size, waitlist candidates with short stature may wait longer for optimal organs resulting in waitlist mortality. Understanding the pitfalls of lung volume measurements, complications of size mismatch and alternate options for optimizing size may help us better utilize the donor pool. With the advent of ex vivo lung perfusion systems the donor supply is expected to slowly increase. Despite this, concerns with size matching will remain. Finding alternate options such as lobar lung transplant may be a reasonable option for these patients. While lobar lung transplant may not be equivalent to size matched grafts it will continue to be a viable option for those waiting with continued functional decline.

A sleeve lobectomy is an established general thoracic surgical procedure. To improve clinical outcomes following the procedure, we reviewed the records of 60 patients who underwent a bronchoplasty procedure in our department from 1992 to 2007. Induction chemotherapy was performed for 20, of whom 10 underwent radiotherapy as well. For all subjects, the postoperative mortality and morbidity rates were 1.7% and 33.3%, respectively. Induction therapy did not significantly affect those rates, though complications related to bronchial anastomoses occurred exclusively in subjects who received that therapy. The overall 5-year survival rate was 51.0%, while subjects with pN0 (67.9%) and pN1 (60.0%) disease, and those in stage I (79.1%) and stage II (59.9%) had better survival as compared with patients with pN2 (16.9%) disease, and those in stage III (21.8%) and stage IV (0%). Furthermore, the survival rate of yp-stage I and II patients was significantly greater than that of those in yp-stage III and IV (59.9% vs. 14.3%, p = 0.0158). We concluded that patients in stages I, II or with pN0-1 disease are good candidates for a bronchoplasty procedure, though induction therapy should be considered thereafter. In addition, due diligence for postoperative complications is necessary.

Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca2+-activated K(+) (BK(Ca)) channels.Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BK(Ca) channel gatings of porcine coronary artery smooth muscle cells were evaluated.Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 microM) (hydrophobic), but not simvastatin Na+ (hydrophilic), inhibited the BK(Ca) channels with a minimal recovery upon washout. Isopimaric acid (10 microM)-mediated enhancement of the BK(Ca) amplitude was reversed by external simvastatin. Simvastatin Na+ (10 microM, applied internally), markedly attenuated isopimaric acid (10 microM)-induced enhancement of the BK(Ca) amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin -elicited inhibition. Mevalonolactone (500 microM) and geranylgeranyl pyrophosphate (20 microM) only prevented simvastatin (1 and 3 microM)-induced responses. simvastatin (10 microM ) caused a rottlerin (1 microM)-sensitive (cycloheximide (10 microM)-insensitive) increase of PKC-delta protein expression.Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BK(Ca) channels of the arterial smooth muscle cells through multiple intracellular pathways.

This study examined the immunohistochemical detection of activated caspase-3, and its association with apoptosis, during tooth morphogenesis of the mouse lower first molar. The distribution of cells positive for caspase-3 closely corresponded with the localization of the terminal deoxynucleotidyl transferase-mediated deoxyuridine-5'-triphosphate-biotin nick end labelling (TUNEL)-positive apoptotic cells through the developmental course of tooth germs from embryo day 12 (E12) to E19, thus showing that the apoptosis occurring in the developing odontogenic tissue was induced by the activation of the caspase family. The specific distribution pattern of apoptotic cells in the developing odontogenic epithelial tissue from the initiation (E12) of tooth germ to the completion of tooth crown morphology (E19) also suggests that apoptotic events are related not only to a deletion of functionally suspended cells, but also participate in initiation and the completion of tooth morphogenesis. Electron microscopic examination revealed that apoptotic cells were present in the primary enamel knot, and these apoptotic cells were phagocytized by neighbouring odontogenic epithelial cells, thus indicating the prompt disposal of any dead cells by epithelial cells.