Joseph Costa

Decellularization of Human and Porcine Lung Tissues for Pulmonary Tissue Engineering

BACKGROUNDnThe only definitive treatment for end-stage organ failure is orthotopic transplantation. Lung extracellular matrix (LECM) holds great potential as a scaffold for lung tissue engineering because it retains the complex architecture, biomechanics, and topologic specificity of the lung. Decellularization of human lungs rejected from transplantation could provide ideal biologic scaffolds for lung tissue engineering, but the availability of such lungs remains limited. The present study was designed to determine whether porcine lung could serve as a suitable substitute for human lung to study tissue engineering therapies.nnnMETHODSnHuman and porcine lungs were procured, sliced into sheets, and decellularized by three different methods. Compositional, ultrastructural, and biomechanical changes to the LECM were characterized. The suitability of LECM for cellular repopulation was evaluated by assessing the viability, growth, and metabolic activity of human lung fibroblasts, human small airway epithelial cells, and human adipose-derived mesenchymal stem cells over a period of 7 days.nnnRESULTSnDecellularization with 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) showed the best maintenance of both human and porcine LECM, with similar retention of LECM proteins except for elastin. Human and porcine LECM supported the cultivation of pulmonary cells in a similar way, except that the human LECM was stiffer and resulted in higher metabolic activity of the cells than porcine LECM.nnnCONCLUSIONSnPorcine lungs can be decellularized with CHAPS to produce LECM scaffolds with properties resembling those of human lungs, for pulmonary tissue engineering. We propose that porcine LECM can be an excellent screening platform for the envisioned human tissue engineering applications of decellularized lungs.

Insertion of bicaval dual lumen extracorporeal membrane oxygenation catheter with image guidance.

Correct placement of the Avalon Elite Bicaval Dual Lumen catheter (Avalon Laboratories, LLC, CA) for single-site venovenous extracorporeal membrane oxygenation (VV ECMO) is safe using image guidance. Using this technique, 26 of 27 patients (96%) had uneventful placement of the cannula in the right internal jugular vein. One patient had a superior vena cava injury during serial dilation, and another patient required cannula repositioning for improved flows. We recommend using both fluoroscopy and transesophageal echocardiogram (TEE) for training purposes or during initial use of the Avalon Elite. As proficiency improves, TEE at the bedside provides an excellent standard of care. Double-lumen ECMO catheters can be effectively placed under image guidance with minimal need for repositioning.

Subclavian artery cannulation for venoarterial extracorporeal membrane oxygenation.

Femoral artery cannulation for venoarterial extracorporeal membrane oxygenation (ECMO) can be associated with ischemic and neurologic complications. The subclavian artery offers an alternative cannulation site, which is helpful in patients with peripheral vascular disease, in those who have sustained pelvic trauma, or when ambulation is anticipated. This is a single-institution review of 20 adults who were placed on venoarterial ECMO using subclavian arterial cannulation over a 2 year period. Technical success with subclavian venoarterial ECMO was 100%. Median ECMO time was 168 hours (2.4–720 hours). Sufficient flows (median 4.24 L/min), oxygenation (median postcannulation PaO2 315 mm Hg), and ventricular unloading confirmed with intraoperative transesophageal echocardiogram were achieved in all patients. Seventy-five percent of patients were decannulated, 50% were extubated, and 45% were discharged. Seven patients (35%) had an entirely upper body ECMO configuration with the internal jugular vein serving as the venous drainage site. Complications included arterial cannula site hematoma and infection, as well as ipsilateral arm swelling. Each required conversion to femoral artery cannulation. There were no ischemic or neurologic complications. Patients with acute cardiopulmonary failure can safely be placed on subclavian venoarterial ECMO for prolonged periods with full flows, adequate oxygenation, and sufficient ventricular unloading.

Donor Age and Early Graft Failure After Lung Transplantation: A Cohort Study

Lungs from older adult organ donors are often unused because of concerns for increased mortality. We examined associations between donor age and transplant outcomes among 8860 adult lung transplant recipients using Organ Procurement and Transplantation Network and Lung Transplant Outcomes Group data. We used stratified Cox proportional hazard models and generalized linear mixed models to examine associations between donor age and both 1‐year graft failure and primary graft dysfunction (PGD). The rate of 1‐year graft failure was similar among recipients of lungs from donors age 18–64 years, but severely ill recipients (Lung Allocation Score [LAS] >47.7 or use of mechanical ventilation) of lungs from donors age 56–64 years had increased rates of 1‐year graft failure (p‐values for interactionu2009=u20090.04 and 0.02, respectively). Recipients of lungs from donors <18 and ≥65 years had increased rates of 1‐year graft failure (adjusted hazard ratio [HR] 1.23, 95% CI 1.01–1.50 and adjusted HR 2.15, 95% CI 1.47–3.15, respectively). Donor age was not associated with the risk of PGD. In summary, the use of lungs from donors age 56 to 64 years may be safe for adult candidates without a high LAS and the use of lungs from pediatric donors is associated with a small increase in early graft failure.

Peripheral Blood Gene Expression Changes Associated with Primary Graft Dysfunction after Lung Transplantation.

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation‐03 study using a panel of 100 hypothesis‐driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome‐related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long‐term implications of these gene expression differences on the outcome of the allograft.

Minimally invasive Ivor Lewis oesophagogastrectomy in a patient with situs inversus totalis

Situs inversus totalis (SIT) is a rare congenital condition in which the internal organs of the thoracic and abdominal cavities experience a right-to-left reflection across the sagittal plane. We describe a case of locally advanced adenocarcinoma of the oesophagus treated with minimally invasive oesophagectomy using a laparoscopic and left video-assisted thoracoscopic surgery approach in a patient with situs inversus totalis.

Chapter 12: Long Term Outcomes and Management of the Lung Transplant Recipient

Lung transplantation is an established treatment for patients with end-stage lung disease. Improvements in immunosuppression and therapeutic management of infections have resulted in improved long-term survival and a decline in allograft rejection. Allograft rejection continues to be a serious complication following lung transplantation, thereby leading to acute graft failure and, subsequently, chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS), the most common phenotype of CLAD, is the leading cause of late mortality and morbidity in lung recipients, with 50% having developed BOS within 5 years of lung transplantation. Infections in lung transplant recipients are also a significant complication and represent the most common cause of death within the first year. The success of lung transplantation depends on careful management of immunosuppressive regimens to reduce the rate of rejection, while monitoring recipients for infections and complications to help identify problems early. The long-term outcomes and management of lung transplant recipients are critically based on modulating natural immune response of the recipient to prevent acute and chronic rejection. Understanding the immune mechanisms and temporal correlation of acute and chronic rejection is thus critical in the long-term management of lung recipients.

Use of Lung Allografts From Donation After Cardiac Death Donors: A Single-Center Experience

BACKGROUNDnLung transplantation remains the only treatment for end-stage lung disease. Availability of suitable lungs does not parallel this growing trend. Centers using donation after cardiac death (DCD) donor lungs report comparable outcomes with those from brain-dead donors. Donor assessment protocols and consistent surgical teams have been advocated when considering using the use of DCD donors. We present our experience using lungs from Maastricht category III DCD donors.nnnMETHODSnStarting 2007 to July 2016, 73 DCD donors were assessed, 44 provided suitable lungs that resulted in 46 transplants. A 2012 to October 2016 comparative cohort of 379 brain-dead donors were assessed. Recipient and donor characteristics and primary graft dysfunction (PGD) and survival were monitored.nnnRESULTSnSeventy-three DCD (40% dry run rate) donors assessed yielded 46 transplants (23 double, 6 right, and 17 left). Comparative cohort of 379 brain-dead donors yielded 237 transplants (112 double, 43 right, and 82 left). One- and 3-year recipient survival was 91% and 78% for recipients of DCD lungs and 91% and 75% for recipients of lungs from brain-dead donors, respectively. PGD 2 and 3 in DCD recipients at 72 hours was 4 of 46 (9%) and 6 of 46 (13%), respectively. Comparatively, brain-dead donor recipient cohort at 72 hours with PGD 2 and 3 was 23 of 237 (10%) and 41 of 237 (17%), respectively.nnnCONCLUSIONSnOur experience reaffirms the use of lungs from DCD donors as a viable source with favorable outcomes. Recipients from DCD donors showed equivalent PGD rate at 72 hours and survival compared with recipients from brain-dead donors.

Modified Transverse Thoracosternotomy and Cost-Effective Reinforced Sternal Closure

The bilateral transverse thoracosternotomy clamshell incision provides excellent exposure to the mediastinal structures in double lung transplantation. The use of a modified transverse sternotomy and a figure of 8 configuration with one monofilament metal wire, along with two longitudinal wires across the sternal division, results in greater stability and equally distributed oblique tension. Our described technique was more cost effective and resulted in no incidence of dehiscence. We present our experience using a modified transverse sternotomy and reinforced sternal closure method.

Physician assistant model for lung procurements: a paradigm worth considering.

BACKGROUNDnThoracic procurements have traditionally been performed by surgical fellows or attending cardiothoracic surgeons. Donor lung procurement protocols are well established and fairly standardized; however, specific procurement training and judgment are essential to optimizing donor utilization. Although the predicted future deficits of cardiothoracic surgeons are based on a variety of analytic models and scenarios, it appears evident that there will not be a sufficient number of trained cardiothoracic surgeons over the next 2 decades. Over the past 5 years in our institution, lung procurements have been performed by a specifically trained physician assistant; as the lead donor surgeon. This model may serve as a cost effective, reproducible, and safe alternative to using surgical fellows and attending surgeons, assuring continuity, ongoing technical expertise, and teaching while addressing future workforce issues as related to transplant.nnnMETHODSnThis is a single institution review of 287 consecutive lung procurements performed by either a physician assistant or fellow over 5 years. This study was approved by the Institutional Review Board of Columbia University, which waived the need for informed consent (IRB#AAAL7107).nnnRESULTSnFrom 2008 to 2012, fellows served as senior surgeon in 90 cases (31.4%) versus 197 cases (68.6%) by the physician assistant, including 12 Donations after Cardiac Death and 6 reoperative donors. Injury rate was significantly lower for the physician assistant compared with the resident cohort (1 of 197 [0.5%] vs 22 of 90 [24%], respectively). Rates for pulmonary graft dysfunction grade 2 and 3 were found to be significantly lower in cases where the physician assistant served as senior surgeon (combined rates of 32.2% [29 of 90] vs 9.6% [19 of 197] in the physician assistant group) (p < 0.01).nnnCONCLUSIONSnUse of experienced physician assistants in donor lung procurements is a safe and viable alternative offering continuity of technical expertise and evaluation of lung allografts.