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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.

Background: With an increasing number of potential recipients and a comparatively static number of donors, lung transplantation (LT) in the elderly has come under significant scrutiny. Previous studies have been limited by single-center experiences with small population sizes and often mixed results. Using a national registry, we sought to evaluate the following: (1) differences in survival outcomes in septuagenarians compared with sexagenarians; and (2) the effect of temporal trends on the development of other comorbidities in this population., Methods: We analyzed the Scientific Registry of Transplant Recipients (SRTR) data files from the United Network for Organ Sharing (UNOS) database to identify recipients who underwent LT between the years 2000 and 2013. The study period was divided into two equal eras. Using Kaplan-Meier analysis, we compared the 30-day, 3-month, 1-year, 3-year and 5-year patient survival between septuagenarians and sexagenarians in both eras. Separate multivariate analyses were performed to estimate the risk of renal failure, risk of rejection and length of hospital stay (LOS) post-LT in each of these time periods., Results: A total of 6,596 patients were identified comprising 1,726 (26.2%) during 2000 to 2005 and 4,870 (73.8%) during 2006 to 2012. In the "early era," 32 (1.9%) septuagenarians and 1,694 (98.1%) sexagenarians underwent LT, whereas 543 (11.1%) septuagenarians and 4,327 (88.9%) sexagenarians underwent transplantation in the "latter era." A comparison of patient survival between the two groups in the early era revealed no difference at 30 days (95.7% vs 93.8%, p = 0.65). However, 3-month (91.2% vs 75%, p = 0.04) and 1-year patient survival (79.5% vs 62.5%, p = 0.048) were both lower in the septuagenarian group. In the later era, however, there were no differences in 30-day (96.2% vs 96.8, p = 0.5), 3-month (92.7% vs 91.9%, p = 0.56) or 1-year (81.7% vs 78.6%, p = 0.12) patient survival between the two age groups. Survival rates at 3 years (63.7% vs 49.3%, p < 0.001) and 5 years (47.5% vs 28.2%, p < 0.001) were each significantly lower in the septuagenarian group., Conclusion: Overall, LT outcomes for the elderly have improved significantly over time and early outcomes in the modern era rival those found in younger recipients., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Improvements in technology have led to a resurgence in the use of extracorporeal membrane oxygenation as a bridge to lung transplantation. By using a national registry, we sought to evaluate how short-term survival has evolved using this strategy., Methods: With the use of the United Network for Organ Sharing database, we analyzed data from 12,458 adults who underwent lung transplantation between 2000 and 2011. Patients were categorized into 2 cohorts: 119 patients who were bridged to transplantation using extracorporeal membrane oxygenation and 12,339 patients who were not. The study period was divided into four 3-year intervals: 2000 to 2002, 2003 to 2005, 2006 to 2008, and 2009 to 2011. With Kaplan-Meier analysis, 1-year survival was compared for the 2 cohorts of patients in each of the time periods. A propensity score-adjusted Cox regression model was used to estimate the risk of 1-year mortality., Results: Of the total number of recipients, 4 (3.4%) were bridged between 2000 and 2002, 17 (14.3%) were bridged between 2003 and 2005, 31 (26.1%) were bridged between 2006 and 2008, and 67 were bridged (56.3%) between 2009 and 2011. Recipients bridged using extracorporeal membrane oxygenation were more likely to be younger and diabetic and to have higher serum creatinine and bilirubin levels. The 1-year survival for those bridged with extracorporeal membrane oxygenation was significantly lower in subsequent periods: 25.0% versus 81.0% (2000-2002), 47.1% versus 84.2% (2006-2008), and 74.4% versus 85.7% (2009-2011). However, this survival progressively increased with each period, as did the number of patients bridged using extracorporeal membrane oxygenation., Conclusions: Short-term survival with the use of extracorporeal membrane oxygenation as a bridge to lung transplantation has significantly improved over the past few years., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The intraoperative use of cardiopulmonary bypass (CPB) in lung transplantation has been associated with increased rates of pulmonary dysfunction and bleeding complications. More recently, extracorporeal membrane oxygenation (ECMO) has emerged as a valid alternative method of support and has been our preferred method of support since March 2012. We compared early and midterm outcomes of these 2 support methods., Methods: Between July 2007 and April 2013, 271 consecutive patients underwent lung transplant using CPB (n = 222) or ECMO (n = 49). We retrospectively reviewed the outcomes of these patients requiring CPB or ECMO during lung transplant., Results: The CPB and ECMO groups had comparable demographic and operative characteristics; however, the ECMO group had higher mean lung allocation scores (73 vs 52, p < 0.001). In the CPB group, more patients required reintubation (35.6% vs 20.4%, p = 0.04) or temporary tracheostomy (44.6% vs 28.6%, p = 0.05). Patients in the CPB group had a higher rate of renal failure requiring dialysis than the ECMO group (22.1% vs 8.2 %, p = 0.028). There were no differences in severe PGD requiring postoperative circulatory support (p = 0.83) or the need for perioperative red blood cell transfusions (p = 0.64) between the groups. No differences in 30-day (5% CPB vs 4.1% ECMO) or 6-month mortality (14.4% CPB vs 14.3% ECMO) were noted., Conclusions: The use of ECMO in lung transplant is safe and in our experience was associated with decreased rates of pulmonary and renal complications, as compared with CPB. Extracorporeal membrane oxygenation has become our preferred method of intraoperative support during lung transplantation., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial., Methods: We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA)., Results: We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001)., Conclusions: Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The relative paucity of donors heightens the debate and scrutiny surrounding retransplantation. To date, risk factors associated with retransplantation are poorly characterized in the literature. We sought to identify those risk factors that may independently serve to predict lung retransplantation., Methods: We performed a retrospective evaluation of the United Network for Organ Sharing data over 25 years from 1987 to 2012. Competing risk analysis was used to evaluate the cohort for cumulative incidence of retransplantation. Recipient-related, donor-related, and transplant-related characteristics were assessed using Cox regression to identify risk factors associated with lung retransplantation., Results: We identified 23,180 adult lung transplant recipients, of which 791 (3.4%) had also undergone retransplantation. Factors associated with lung retransplantation at 1 year included recipient age (hazard ratio [HR], 0.97; p=0.005), admission to the intensive care unit (HR, 2.89; p=0.002), donor age (HR, 1.02; p=0.004), and bilateral lung transplantation (HR, 0.41; p<0.001). Moreover, predictors of 5-year risk of retransplantation included recipient age (HR, 0.95; p<0.001), intensive care unit hospitalization (HR, 1.87; p=0.005), and bilateral lung transplant (HR, 0.46; p<0.001), as well as recipient body mass index of 25 to 29 kg/m2 (HR, 1.29; p=0.04) and a diagnosis of chronic obstructive pulmonary disease (HR, 0.68; p=0.008)., Conclusions: We identified factors associated with retransplantation that may afford a better prediction of graft failure and need for retransplantation. These may further serve to better guide donor selection and assist in the development and validation of a risk-scoring model to further guide preoperative counseling., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: A shortage of donors has compelled the use of extended-criteria donor organs in lung transplantation. The purpose of this study was to evaluate the impact of using older donors on outcomes after lung transplantation using current protocols., Methods: From January 2003 to August 2009, 593 lung transplants were performed at our institution. We compared 87 patients (14.7%) who received lungs from donors aged 55 years or older with 506 patients who received lungs from donors less than 55 years old. We also examined risk factors for mortality in recipients of lungs from older donors., Results: The incidence of major complications including severe primary graft dysfunction and early mortality rates were similar between the groups. However, posttransplant peak FEV1 was lower in the patients who received lungs from older donors (71.7% vs. 80.7%, P<0.05). In multivariate analysis, recipient pulmonary hypertension (transpulmonary pressure gradient >20 mm Hg) and prolonged intraoperative cardiopulmonary bypass were significant risk factors for mortality in the recipients of lungs from older donors., Conclusions: This large, single-center experience demonstrated that transplanting lungs from donors older than 55 years did not yield worse short- or long-term outcomes as compared with transplanting lungs from younger donors. However, transplanting lungs from older donors into recipients with pulmonary hypertension or recipients who required prolonged cardiopulmonary bypass increased the risk for mortality. Although lungs from older donors should not be excluded because of donor age alone, surgeons should carefully consider their patient selection criteria and surgical plans when transplanting lungs from older donors.

Background: Although the benefits of ex vivo lung perfusion (EVLP) have been globally advocated, the potentially deleterious effects of applying EVLP, in particular activation of proinflammatory cascades and alteration of metabolic profiles, are rarely discussed. This study examined proinflammatory events and metabolic profiles in lung grafts on EVLP and tested whether preconditioning lung grafts with inhaled hydrogen, a potent, cytoprotective gaseous signaling molecule, would alter the lungs' response to EVLP., Methods: Rat heart-lung blocks were mounted on an acellular normothermic EVLP system for 4 hr and ventilated with air or air supplemented with 2% hydrogen. Arterial and airway pressures were monitored continuously; perfusate was sampled hourly to examine oxygenation. After EVLP, the lung grafts were transplanted orthotopically into syngeneic rats, and lung function was examined., Results: Placing lung grafts on EVLP resulted in significant upregulation of the messenger RNAs for several proinflammatory cytokines, higher glucose consumption, and increased lactate production. Hydrogen administration attenuated proinflammatory changes during EVLP through upregulation of the heme oxygenase-1. Hydrogen administration also promoted mitochondrial biogenesis and significantly decreased lactate production. Additionally, in the hydrogen-treated lungs, the expression of hypoxia-inducible factor-1 was significantly attenuated during EVLP. These effects were maintained throughout EVLP and led to better posttransplant lung graft function in the recipients of hydrogen-treated lungs., Conclusions: Lung grafts on EVLP exhibited prominent proinflammatory changes and compromised metabolic profiles. Preconditioning lung grafts using inhaled hydrogen attenuated these proinflammatory changes, promoted mitochondrial biogenesis in the lungs throughout the procedure, and resulted in better posttransplant graft function.

Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca(2+)]i responses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

The transcription factor Nrf2 (Nfe2l2 nuclear factor, erythroid 2-like 2) regulates gene expression directly, controlling pharmacological and toxicological responses. These processes may also be influenced by the structure of the hepatic vasculature, which distributes blood flow through compartmentalized microenvironments to maintain organismal stability. Castings of the hepatic portal vasculature of albino C57BL/6J but not ICR Nrf2(-/-) mice revealed a congenital intrahepatic shunt that was present in two thirds of Nrf2-disrupted mice. This shunt directly connected the portal vein to the inferior vena cava and displayed characteristics of a patent ductus venosus. Immunohistochemistry revealed that Nrf2(-/-) mice with an intrahepatic shunt manifest changes to hepatic oxygen and protein expression gradients when compared with wild-type (WT) and non-shunted Nrf2(-/-) mice. Centrilobular hypoxia found in WT and Nrf2(-/-) mice without shunts was reduced in Nrf2(-/-) livers with a shunt. Hepatic protein expression of phosphoenolpyruvate carboxykinase (Pepck), normally confined to the periportal zone, exhibited both periportal and centrilobular zonal expression in livers from Nrf2(-/-) mice with an intrahepatic shunt. Centrilobular expression of Cytochrome P450 2E1 (Cyp2e1) was diminished in shunted Nrf2(-/-) livers compared with WT and Nrf2(-/-) livers without shunts. The intrahepatic shunt in Nrf2(-/-) mice was further found to diminish acetaminophen hepatoxicity compared with WT and Nrf2(-/-) non-shunted mice following a 6 h challenge with 250 mg/kg acetaminophen. The presence of an intrahepatic shunt influences several physiological and pathophysiological properties of Nrf2(-/-) mice through changes in blood flow, hepatic oxygenation, and protein expression that extent beyond loss of canonical transactivation of Nrf2 target genes., (© The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Most of the experimental work assessing optimal lung inflation during lung graft preservation was performed in the late 1990s. Since that time, lung preservation before transplantation has been more standardized, and the optimal lung inflation techniques used during lung preservation in the current clinical setting remain undefined. Nonetheless, lung inflation during storage may play a pivotal role in optimal lung preservation., Materials and Methods: Lewis rat lungs were perfused with and stored in cold, low-potassium dextran solution (Perfadex, Vitrolife, Göteborg, Sweden) for 6 hours at different levels of lung inflation (25, 50, 75, or 100% of vital capacity [VC]). Orthotopic left lung transplantation using cuff techniques was performed in syngeneic Lewis rats. Posttransplant allograft function, expression of proinflammatory mediators, and expression of lung surfactants were evaluated., Results: Lungs inflated to 75 or 100% VC showed a significantly better oxygenation in blood gas analysis than lungs inflated to 25 or 50% VC. The levels of mRNAs for tumor necrosis factor-α, pro-interleukin-1β, intracellular adhesion molecule 1 were attenuated in lungs inflated to 75 or 100% VC as compared with deflated lungs, suggesting reduced ischemia/reperfusion injury. In addition, transmission electron microscopy demonstrated better preserved lung surfactants in the alveolar space in the lungs inflated to 75 or 100% VC., Conclusions: Inflating lungs to 75 or 100% VC during preservation may be beneficial and result in better posttransplant allograft function through attenuated reperfusion injury and better preserved lung surfactants., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Delayed chest closure (DCC) after lung transplantation is a viable option to be taken in the cases of prolonged cardiopulmonary bypass time, prolonged ischemic time, coagulopathic problems or oversized donor lung grafts. Decision-making for DCC in the operating room remains challenging to surgeons, because the impact of DCC on outcomes after lung transplantation has not yet been fully elucidated., Methods: We performed a retrospective review of 90 lung transplantations with DCC and 783 cases with primary chest closure to clarify the reasons for DCC, complications of DCC, and the risk factors for adverse outcomes., Results: The 30- and 90-day mortality in the DCC group was 7.8% and 9.9%, respectively. Early post-operative bleeding and severe primary graft dysfunction (PGD) were higher in the DCC group (p<0.05). In multivariate analysis, prolonged cardiopulmonary bypass use (>4 hours), post-operative extracorporeal oxygen requirement and use of a DCC technique with open skin and retracted ribs were significantly associated with mortality (p<0.05), whereas prolonged duration of DCC was not. In a matched cohort study to compare the results of a DCC technique with skin closure to similarly matched controls with primary closure, DCC contributed to significantly decreased incidence of severe PGD (9.6% vs. 26%, p<0.05), leading to an improved post-transplant survival and functional status as compared with primary closure., Conclusions: Our technical approaches to prevent possible problems in DCC cases are described. DCC can be safely performed with acceptable procedure-related risks. DCC should not be considered a sub-optimal option after lung transplantation., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

A simple technique for reconstructing a short recipient left atrial cuff during lung transplantation is described. After opening the confluence of the pulmonary veins, the cut ends of the pulmonary veins are sutured together, posteriorly and anteriorly. This effectively lengthens the cuff allowing safe left atrial anastomosis. This technique has been applied in 3 patients with no technique-related complications., (© The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Ex vivo lung perfusion (EVLP) strategies represent a new frontier in lung transplantation technology, and there have been many clinical studies of EVLP in lung transplantation. The establishment of a reliable EVLP model in small animals is crucial to facilitating translational research using an EVLP strategy. The main objective of this study was to develop a reproducible rat EVLP (R-EVLP) model that enables prolonged evaluation of the explanted lung during EVLP and successful transplantation after EVLP., Methods: The donor heart-lung blocks were procured with cold low-potassium dextran solution and immersed in the solution for 1 h at 4 °C. And then, the heart-lung blocks were flushed retrogradely and warmed up to 37 °C in a circuit perfused antegradely with acellular perfusate. The perfusate was deoxygenated with a gas mixture (6% O2, 8% CO2, 86% N2). The perfusion flow was maintained at 20% of the entire cardiac output. At 37 °C, the lungs were mechanically ventilated and perfusion continued for 4 h. Every hour, the perfused lung was evaluated for gas exchange, dynamic lung compliance (Cdyn) and pulmonary vascular resistance (PVR)., Results: R-EVLP was performed for 4 h. Pulmonary oxygenation ability (pO2/pCO2) was stable for 4 h during EVLP. It was noted that Cdyn and PVR were also stable. After 4 h of EVLP, pO2 was 303 ± 19 mmHg, pCO2 was 39.6 ± 1.2 mmHg, PVR was 1.75 ± 0.10 mmHg/ml/min and Cdyn was 0.37 ± 0.03 ml/cmH2O. Lungs that were transplanted after 2 h of R-EVLP resulted in significantly better post-transplant oxygenation and compliance when compared with those after standard cold static preservation., Conclusions: Our R-EVLP model maintained stable lung oxygenation, compliance and vascular resistance for up to 4 h of perfusion duration. This reliable model should facilitate further advancement of experimental work using EVLP.

The Notch signaling pathway enables regulation and control of development, differentiation, and homeostasis through cell-cell communication. Our investigation shows that Notch signaling directly activates the Nrf2 stress adaptive response pathway through recruitment of the Notch intracellular domain (NICD) transcriptosome to a conserved Rbpjκ site in the promoter of Nrf2. Stimulation of Notch signaling through Notch ligand expression in cells and by overexpression of the NICD in Rosa(NICD/-)::AlbCre mice in vivo induces expression of Nrf2 and its target genes. Continuous and transient NICD expression in the liver produces a Notch-dependent cytoprotective response through direct transcriptional activation of Nrf2 signaling to rescue mice from acute acetaminophen toxicity. This response can be reversed upon genetic disruption of Nrf2. Morphological studies showed that the characteristic phenotype of high-density intrahepatic bile ducts and enlarged liver in Rosa(NICD/-)::AlbCre mice could be at least partially reversed after Nrf2 disruption. Furthermore, the liver and bile duct phenotypes could be recapitulated with constitutive activation of Nrf2 signaling in Keap1(F/F)::AlbCre mice. It appears that Notch-to-Nrf2 signaling is another important determinant in liver development and function and promotes cell-cell cytoprotective signaling responses.

Detection of tastes is critical for animals. Sweet, umami and bitter taste are mediated by G-protein-coupled receptors that are expressed in the taste receptor cells. TAS1Rs which belong to class C G-protein-coupled receptors form heterodimeric complexes to function as sweet (TAS1R2 + TAS1R3) or umami (TAS1R1 + TAS1R3) taste receptors. Umami taste is also considered to be mediated by mGluRs. TAS2Rs belong to class A G-protein-coupled receptors and are responsible for bitter taste. After activation of these receptors, their second messenger pathways lead to depolarization and intracellular calcium increase in taste receptor cells. Then, transmitter is released from taste receptor cells leading to activation of taste nerve fibers and taste information is sent to the central nervous system. Recent studies on heterologous expression system and molecular modeling lead to better understanding of binding site of TAS1Rs and TAS2Rs and molecular mechanisms for interaction between taste substances and these receptors. TAS1Rs and TAS2Rs have multiple and single binding sites for structurally diverse ligands, respectively. Sensitivities of these receptors are known to differ among individuals, strains, and species. In addition, some species abolish these receptors and signaling molecules. Here we focus on structure, function, signaling, polymorphism, and molecular evolution of the taste G-protein-coupled receptors.

Objectives: A sternal-sparing approach for bilateral lung transplantation was recently applied to reoperative lung transplant cases and is compared with the traditional clamshell approach., Methods: A retrospective analysis of 15 consecutive reoperative bilateral lung transplants performed from January 2008 to April 2011 was conducted. Outcomes were compared between the first 11 patients who underwent the traditional clamshell and the most recent 4 patients who underwent the sternal-sparing approach., Results: The indication for retransplantation was obliterative bronchiolitis in all patients. Both groups were similar with regard to age, allograft ischaemic time and operative time. Cardiopulmonary bypass was more frequent in the sternal-sparing group although required for a shorter period of time. The need for postoperative extracorporeal membrane oxygenation for primary graft dysfunction was similar in both groups. The length of ICU care and total hospitalization length of stay were similar for the sternal-sparing group compared with the traditional clamshell approach. Operative mortality and overall survival also did not differ., Conclusions: Reoperative bilateral lung transplantation with a sternal-sparing approach is feasible and may yield outcomes similar to those in the traditional clamshell approach. Further analysis with larger numbers of patients is warranted to delineate the benefits of this approach for patients requiring reoperative lung transplantation.

Background: Lung volume reduction surgery (LVRS) as a bridge to lung transplantation was first advocated in 1995 and published studies have supported the concept but with limited data. The risk-benefit tradeoffs of the combined procedure have not been thoroughly examined, although substantial information regarding LVRS has emerged., Methods: Of 177 patients who underwent lung transplantation for end-stage emphysema between 2002 and 2009 at our center, 25 had prior LVRS (22 bilateral and 3 unilateral). Lung transplantation was performed 22.9±15.9 months after LVRS. We compared in-hospital morbidity, functional capacity, and long-term outcomes of patients who underwent LVRS before lung transplantation with a matched cohort of patients without prior LVRS to assess the influence of LVRS on posttransplantation morbidity and mortality., Results: The incidence of postoperative bleeding requiring reexploration and the incidence of renal dysfunction requiring dialysis were higher in patients with LVRS before lung transplantation. Posttransplantation peak forced expiratory volume in 1 s was worse in patients with LVRS before lung transplantation (56.7% vs. 78.8%; P<0.05). Five-year survival was not significantly different (59.7% in patients with LVRS before lung transplantation vs. 66.2% in patients with lung transplantation alone). In multivariate analysis, age more than 65 years, prolonged cardiopulmonary bypass time, and severe pulmonary hypertension were significant predictors for mortality (P<0.05)., Conclusions: Although LVRS remains a viable option as a bridge to lung transplantation in appropriately selected patients, LVRS before lung transplantation can impart substantial morbidity and compromised functional capacity after lung transplantation. LVRS should not be easily considered as a bridge to transplantation for all lung transplant candidates.

We conducted a retrospective study of deep surgical site infections (SSIs) among consecutive patients who underwent lung transplantation (LTx) at a single center from 2006 through 2010. Thirty-one patients (5%) developed SSIs at median 25 days after LTx. Empyema was most common (42%), followed by surgical wound infections (29%), mediastinitis (16%), sternal osteomyelitis (6%), and pericarditis (6%). Pathogens included Gram-positive bacteria (41%), Gram-negative bacteria (41%), fungi (10%) and Mycobacterium abscessus, Mycoplasma hominis and Lactobacillus sp. (one each). Twenty-three percent of SSIs were due to pathogens colonizing recipients' native lungs at time of LTx, suggesting surgical seeding as a source. Patient-related independent risk factors for SSIs were diabetes and prior cardiothoracic surgery; procedure-related independent risk factors were LTx from a female donor, prolonged ischemic time and number of perioperative red blood cell transfusions. Mediastinitis and sternal infections were not observed among patients undergoing minimally invasive LTx. SSIs were associated with 35% mortality at 1 year post-LTx. Lengths of stay and mortality in-hospital and at 6 months and 1 year were significantly greater for patients with SSIs other than empyema. In conclusion, deep SSIs were uncommon, but important complications in LTx recipients because of their diverse microbiology and association with increased mortality., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: With the implementation of the lung allocation score (LAS) system, an increased number of critically ill patients are considered for transplantation. However, LAS does not take size matching between donor and recipient lungs into consideration. Mortality on the waiting list is high (as high as 25%) for short-stature patients and for patients with restrictive lung disease. Here, we review our experience using cadaveric lobar lung transplantation as a surgical option in an attempt to decrease mortality while waiting., Methods: We retrospectively reviewed patients with end-stage lung diseases and an LAS greater than 70 who underwent cadaveric lobar lung transplantation between 2010 and 2012 (n = 25) at our institution, a high-volume lung transplant center. Anatomic lobectomy was performed on all donor lungs before double lung transplantation., Results: Median LAS was 85.6 (range, 72 to 94). Average waiting time after the patients' LAS was updated to greater than 70 was 10 days (range, 1 to 41). There were 2 in-hospital deaths. The 90-day and 1-year survivals were 88% and 76%, respectively. Patient major comorbidities included severe primary graft dysfunction requiring postoperative extracorporeal membrane oxygenation (7 patients), acute renal insufficiency (4 patients), and bleeding requiring reoperation (4 patients). No technical problems were identified, and repeated bronchoscopy demonstrated satisfactory healing of the bronchial stump after lobectomy. The average posttransplant peak for forced expiratory volume in 1 second was 85%., Conclusions: Our initial experience supports the option of lobar lung transplantation for critically ill patients whose opportunities for transplant are limited by their stature. Long-term functional studies are warranted., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Advanced donor age is one of the risk factors for graft failure and is the leading cause of early death after heart transplantation. Better myocardial preservation methods should reduce graft failure. The purpose of this study was to determine if adenosine, which is known to enhance cardioplegic protection, enhances myocardial preservation during heart transplantation using older donors., Methods: We used a rat heterotopic heart transplantation model with Lewis rats that were at least 60 weeks old as donors. We injected saline (control) or adenosine (0.1 or 0.2 mg/kg) before cardioplegia, perfused with cold Celsior and stored the hearts in Celsior for 6 h at 4°C. The grafts were transplanted into syngenic, 12-16-week old recipients, and blood and tissue were collected 3 h after reperfusion., Results: Bolus injection of adenosine led to faster mechanical arrest after perfusion with Celsior and faster reanimation after reperfusion compared with controls. Adenosine treatment significantly reduced myocardial injury, as indicated by serum troponin I and creatine phosphokinase levels. The mRNAs for inflammatory cytokines were markedly increased in the control grafts, but were less upregulated in the grafts treated with adenosine. The grafts treated with adenosine also exhibited less mitochondrial damage, fewer infiltrating cells and a higher adenosine triphosphate content., Conclusions: Adenosine injection prior to perfusion of cardioplegia significantly reduced cold ischaemia/reperfusion injury in cardiac grafts from older donors and improved the stores of cellular energy after reperfusion. This procurement protocol may be clinically feasible and should be considered in the clinical setting, particularly for older donors.

The field of lung transplantation has seen an exciting evolution recently, with novel approaches to increasing the number of organs available for patients with end-stage lung disease. We review 2 recent reports describing the approach of lobar lung transplant as a successful and viable option for those recipients who are challenged by size mismatch and clinical course decline while on the transplant waiting list., (© 2013 Elsevier Inc. All rights reserved.)

Hyperoxic lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen.

Understanding the mechanisms underlying gustatory detection of dietary sodium is important for the prevention and treatment of hypertension. Here, we show that Angiotensin II (AngII), a major mediator of body fluid and sodium homeostasis, modulates salty and sweet taste sensitivities, and that this modulation critically influences ingestive behaviors in mice. Gustatory nerve recording demonstrated that AngII suppressed amiloride-sensitive taste responses to NaCl. Surprisingly, AngII also enhanced nerve responses to sweeteners, but had no effect on responses to KCl, sour, bitter, or umami tastants. These effects of AngII on nerve responses were blocked by the angiotensin II type 1 receptor (AT1) antagonist CV11974. In behavioral tests, CV11974 treatment reduced the stimulated high licking rate to NaCl and sweeteners in water-restricted mice with elevated plasma AngII levels. In taste cells AT1 proteins were coexpressed with αENaC (epithelial sodium channel α-subunit, an amiloride-sensitive salt taste receptor) or T1r3 (a sweet taste receptor component). These results suggest that the taste organ is a peripheral target of AngII. The specific reduction of amiloride-sensitive salt taste sensitivity by AngII may contribute to increased sodium intake. Furthermore, AngII may contribute to increased energy intake by enhancing sweet responses. The linkage between salty and sweet preferences via AngII signaling may optimize sodium and calorie intakes.

Background: Preoperative extracorporeal membrane oxygenation (ECMO) is a risk factor for poor outcome and currently considered a contraindication to lung transplantation. The lung allocation score system was introduced in May 2005 and prioritizes lung allocation to those with the greatest respiratory impairment. The purpose of this study is to determine whether ECMO as a bridge to lung transplantation is an acceptable option to support those in respiratory failure until donor lungs become available in the lung allocation score era., Method: A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011 was conducted using a prospectively collected institutional registry database. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pretransplant ECMO; 7 patients who received ECMO patients did not survive or were deemed unfit for transplantation. These patients were compared with a control group of 691 patients who did not receive pretransplant ECMO., Results: The duration of pretransplant ECMO was 171 ± 242 hours (median, 91 hours). Venovenous ECMO was used for respiratory failure in 15 patients, whereas venoarterial ECMO was used for circulatory collapse due to pulmonary hypertension in 9 patients. Patients in the retransplant ECMO group were younger (46 ± 15 years vs 57 ± 14 years, P < .01) compared with the control group, with no difference in recipient gender (male/female: 10/14 vs 380/311), donor age (33 ± 14 years vs 36 ± 15 years), or donor gender (male/female: 10/14 vs 352/339). Emphysema was less common (1, 4% vs 260, 38%, P < .01), and cystic fibrosis (5, 21% vs 72, 10%, P = .09), redo lung transplant (3, 13% vs 28, 4%, P = .08), and bronchiectasis (2, 8% vs 6, 1%, P = .03) were more common in the pretransplant ECMO group. Patients in the pretransplant ECMO group had a significantly higher lung allocation score (87 ± 9 vs 44 ± 15, P < .01). All patients in the pretransplant ECMO group underwent double lung transplants on pump (cardiopulmonary bypass/ECMO), and single lung transplants were performed in 171 patients (25%) and pump was used in 243 patients (35%) in the control group. The cardiopulmonary bypass time was longer in the pretransplant ECMO group (277 ± 69 minutes vs 225 ± 89 minutes, P = .02), with no difference in ischemic time (343 ± 93 minutes vs 330 ± 98 minutes, P = .54). Cadaveric lobar lung transplants were performed because of the urgency to overcome size mismatch with an oversized donor more frequently in 25% (n = 6, no mortality with the longest follow-up at 6 years) of patients in the pretransplant ECMO group versus 0.3% (n = 2) of patients in the control group (P < .01). Post-transplant ECMO was used for primary graft dysfunction in 13 patients (54%) in the pretransplant ECMO group and 41 patients (6%) in the control group (P < .01). The median hospital stay was 46 days in the pretransplant ECMO group versus 27 days in the control group (P = .16). The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pretransplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group (P = .787)., Conclusions: Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pretransplant ECMO, the graft survival is good (2-year survival, 74%). ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Early major neurologic complications after lung transplantation represent a major source of morbidity for patients and compromise their quality of life; however, the mechanisms underlying neurologic complications and their impact on outcomes in lung transplantation remain largely unknown., Methods: Patients who received lung transplants at our institution between January 2004 and December 2010 were identified (n=759). Data on complications including occurrence, timing, management, and outcome were extracted from our transplant database and medical record review. Major neurologic complications were defined as those that were potentially life threatening, required urgent treatment/intubation, or required admission to the intensive care unit., Results: Seventy (9.2%) patients experienced major neurologic complications within 2 weeks after lung transplantation. Most common complications were stroke (41%) and severe toxic/metabolic encephalopathy (37%). Multivariate analysis demonstrated that advanced age, history of coronary artery disease, prolonged use of cardiopulmonary bypass, and severe primary graft dysfunction increased the risk for death in patients with early major neurologic complications (P<0.05). There was a significant difference in survival between patients with neurologic complications and without (90-day mortality: 15% of patients who developed neurologic complications versus 4% of patients who did not; P=0.03; 5-year survival: 51.1% in patients who developed neurologic complication versus 62.1% in patients who did not; P<0.05)., Conclusions: Early major neurologic complications after lung transplantation are common and carry substantial morbidity and mortality. Given the risk factors identified in this study, additional pretransplantation workup and intraoperative and postoperative monitoring for high-risk patients may help reduce the incidence of neurologic complications.

Taste receptor cells play a major role in detection of chemical compounds in the oral cavity. Information derived from taste receptor cells, such as sweet, bitter, salty, sour and umami is important for evaluating the quality of food components. Among five basic taste qualities, sweet taste is very attractive for animals and influences food intake. Recent studies have demonstrated that sweet taste sensitivity in taste receptor cells would be affected by leptin and endocannabinoids. Leptin is an anorexigenic mediator that reduces food intake by acting on leptin receptor Ob-Rb in the hypothalamus. Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known as orexigenic mediators that act via cannabinoid receptor 1 (CB1) in the hypothalamus and limbic forebrain to induce appetite and stimulate food intake. At the peripheral gustatory organs, leptin selectively suppresses and endocannabinoids selectively enhance sweet taste sensitivity via Ob-Rb and CB1 expressed in sweet sensitive taste cells. Thus leptin and endocannabinoids not only regulate food intake via central nervous systems but also modulate palatability of foods by altering peripheral sweet taste responses. Such reciprocal modulation of leptin and endocannabinoids on peripheral sweet sensitivity may play an important role in regulating energy homeostasis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: When selecting a donor for lung transplantation, it is generally believed that the best outcomes occur when the donor has no smoking history. Because we experienced unexpected adverse outcomes after transplant of lungs from teenaged donors with no smoking history, this study revisited the effects of donor smoking history in relation to age on transplant outcomes., Methods: We conducted a retrospective review of 532 consecutive lung transplants performed at our institution. Most donors (293, 55%) had a history of smoking; 239 donors were nonsmokers. The smoking donors were further subgrouped based on consumption (<20, 20-40, or >40 pack-years). The nonsmoking donors were subgrouped by age (<20 years or ≥20 years). Recipients' characteristics and outcomes were compared., Results: The recipients of lungs from donors with a smoking history showed better 5-year survival than recipients of lungs from nonsmokers (65.8% vs. 48.3%, P<0.05), but recipients of lungs from heavy smokers (>40 pack-years smoking history) exhibited a significantly higher incidence of severe primary graft dysfunction and higher short- and long-term mortality than the recipients of lungs from donors who smoked less. Surprisingly, recipients of lungs from teenaged donors with no smoking history exhibited a higher morbidity and mortality than recipients of lungs from adult nonsmoking donors but did not exhibit decreased posttransplant forced expiratory volume in 1 sec., Conclusions: In this large, single-center experience, the absence of smoking history in the donor did not result in better long-term outcomes after lung transplantation. Potential problems with lungs from teenaged donors with no smoking history were suggested.

Background: Exogenously administered hydrogen exerts cytoprotective effects through anti-oxidant, anti-inflammatory, and anti-apoptotic mechanisms in various disease settings, including organ transplantation. Our objective in this study was to evaluate the efficacy of a novel cold storage device equipped with a hydrogen-rich water bath., Methods: The study used an established rat heterotopic transplantation model. Syngeneic heart grafts from elderly donors (60- to 70-week-old Lewis rats) or allografts from adult donors (12-week-old Brown Norway rats) were exposed to prolonged cold preservation. The cardiac grafts were stored in plastic bags containing Celsior, which were immersed in the cold water bath equipped with an electrolyzer to saturate the water with hydrogen. The cardiac grafts then were heterotopically engrafted into Lewis rat recipients., Results: In both experimental settings, serum troponin I and creatine phosphokinase were markedly elevated 3 hours after reperfusion in the control grafts without hydrogen treatment. The grafts exhibited prominent inflammatory responses, including neutrophil infiltration and the upregulation of messenger RNAs for pro-inflammatory cytokines and chemokines. Myocardial injury and inflammatory events were significantly attenuated by organ storage in the hydrogen-rich water bath. The grafts stored using the hydrogen-rich water bath also exhibited less mitochondrial damage and a higher adenosine triphosphate content., Conclusions: Hydrogen delivery to cardiac grafts during cold preservation using a novel hydrogen-supplemented water bath efficiently ameliorated myocardial injury due to cold ischemia and reperfusion. This new device to saturate organs with hydrogen during cold storage merits further investigation for possible therapeutic and preventative use during transplantation., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Recent evidence suggests that molecular hydrogen has therapeutic value for disease states that involve inflammation. We hypothesized that drinking hydrogen-rich water (HW) daily would protect cardiac and aortic allograft recipients from inflammation-associated deterioration. Heterotopic heart transplantation with short-course tacrolimus immunosuppression and orthotopic aortic transplantation were performed in allogeneic rat strains. HW was generated either by bubbling hydrogen gas through tap water (Bu-HW) or via chemical reaction using a magnesium stick [Mg + 2H(2) O → Mg (OH)(2)  + H(2) ] immersed in tap water (Mg-HW). Recipients were given either regular water (RW), Mg-HW, Bu-HW, or Mg-HW that had been subsequently degassed (DW). Graft survival was assessed by daily palpation for a heartbeat. Drinking Mg-HW or Bu-HW was remarkably effective in prolonging heart graft survival and reducing intimal hyperplasia in transplanted aortas as compared with grafts treated with RW or DW. Furthermore, T cell proliferation was significantly inhibited in the presence of hydrogen in vitro, accompanied by less production of interleukin-2 and interferon-γ. Hydrogen treatment was also associated with increased graft ATP levels and increased activity of the enzymes in mitochondrial respiratory chain. Drinking HW prolongs survival of cardiac allografts and reduces intimal hyperplasia of aortic allografts., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

Video-assisted thoracic surgery is useful during a typical lobectomy procedure, though challenging in complicated cases. We report successful video-assisted thoracic surgery lobectomy procedures performed after coronary artery bypass grafting in two lung cancer patients, with severe adhesion of lung parenchyma to grafts of the internal thoracic artery. We avoided dissection of the lung from the grafts and divided the lung parenchyma. No intrathoracic infection or local recurrence was found 5 years after surgery in either patient. The present 'non-dissection technique' is a feasible and safe optional procedure during a lobectomy after coronary artery bypass grafting using internal thoracic artery grafts.

Background: Staphylococcus aureus infections among lung transplant recipients are poorly studied., Methods: We conducted a 5-year retrospective study of the epidemiology, clinical manifestations, risk factors, and outcomes of patients infected with S aureus within the first 90 days after lung transplantation., Results: An S aureus infection developed in 109 of 596 lung transplant (18%) recipients. Methicillin-susceptible S aureus (MSSA; 62%) was more common than methicillin-resistant S aureus (MRSA; 38%); however, the proportion of infections caused by MRSA increased over time. Pneumonia (48%) was the most common infection, followed by tracheobronchitis (26%), bacteremia (12%), intrathoracic infections (7%), and skin/soft tissue infections (7%). Risk factors included mechanical ventilation for > 5 days and isolation of S aureus from recipients' sterility cultures. Patients with MRSA cultured from the nares or respiratory tract at the time of transplant were at an increased risk for MRSA infection (p < 0.0001 and p = 0.02, respectively). Infected patients required longer hospital and intensive care unit stays (p < 0.0001 for both), but the 30- and 90-day mortality rates from the onset of infection were only 7% and 12%, respectively. However, infected patients had higher rates of acute and chronic rejection at 1 (p = 0.048) and 3 years (p = 0.002), and higher rates of mortality at 1 (p = 0.058) and 3 years (p = 0.009)., Conclusions: S aureus infections within the first 90 days of lung transplant were associated with low short-term mortality but increased long-term rates of mortality and acute and chronic rejection. Future studies are needed to explore the utility of S aureus eradication strategies in reducing disease burden and improving outcomes., (Published by Elsevier Inc.)

Background: We previously demonstrated that donor treatment with inhaled hydrogen protects lung grafts from cold ischemia/reperfusion (I/R) injury during lung transplantation. To elucidate the mechanisms underlying hydrogen's protective effects, we conducted a gene array analysis to identify changes in gene expression associated with hydrogen treatment., Methods: Donor rats were exposed to mechanical ventilation with 98% oxygen and 2% nitrogen or 2% hydrogen for 3 h before harvest; lung grafts were stored for 4h in cold Perfadex. Affymetrix gene array analysis of mRNA transcripts was performed on the lung tissue prior to implantation., Results: Pretreatment of donor lungs with hydrogen altered the expression of 229 genes represented on the array (182 upregulated; 47 downregulated). Hydrogen treatment induced several lung surfactant-related genes, ATP synthase genes and stress-response genes. The intracellular surfactant pool, tissue adenosine triphosphate (ATP) levels and heat shock protein 70 (HSP70) expression increased in the hydrogen-treated grafts. Hydrogen treatment also induced the transcription factors C/EBPα and C/EBPβ, which are known regulators of surfactant-related genes., Conclusion: Donor ventilation with hydrogen significantly increases expression of surfactant-related molecules, ATP synthases and stress-response molecules in lung grafts. The induction of these molecules may underlie hydrogen's protective effects against I/R injury during transplantation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We investigated endothelial function of both pulmonary arteries and veins in patients with chronic obstructive pulmonary disease (COPD) of varying severity in regard to the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Lung tissues were obtained from patients undergoing lobectomy or pneumonectomy. Patients were grouped to control, moderate COPD, and severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Pulmonary arteries and veins were studied for endothelium-dependent relaxations. NO concentration was measured by electrochemical method. Protein expressions of eNOS and phosphorylated eNOS were determined by Western-blot. Endothelium-dependent relaxation was more significant in pulmonary arteries than in veins. The vasorelaxation was decreased in patients of moderate COPD and further decreased in severe COPD. The severity of endothelial dysfunction in both pulmonary arteries and veins correlated with the degree of airflow obstruction. COPD patients exhibited reduced endothelial NO production, decreased eNOS protein expression and decreased eNOS phosphorylation. The EDHF component was abolished in the pulmonary vasculature of patients with severe COPD. NO and EDHF pathways are both involved in the regulation of vascular tone in human pulmonary arteries and veins. Both pathways are impaired in COPD patients and the severity of the impairment increases with the progress of the disease. Downregulation of eNOS expression and inhibition of eNOS activation underlie the reduction of NO in COPD patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The full spectrum of prior cardiothoracic procedures in lung transplant candidates and the impact of prior procedures on outcomes after lung transplantation (LTx) remain unknown, though the impact is considered to be large. Patients transplanted at our institution from 2004 to 2009 were identified (n = 554) and divided into two groups: patients who had undergone cardiothoracic surgical (CTS) procedures prior to LTx (n = 238) and patients who had not (non-CTS: n = 316). Our primary endpoint was survival. Secondary endpoints included allograft function and the incidence of major complications including reexploration due to bleeding, prolonged ventilation, renal insufficiency and primary graft dysfunction. Long-term survival was not significantly different between the groups whereas postoperative bleeding, nerve injury, respiratory and renal complications were higher in the CTS group. Posttransplant peak FEV1 was lower in the CTS group (73.4% vs. 86.9%, p < 0.05). In multivariate analysis, performance of a chemical pleurodesis procedure and prolonged cardiopulmonary bypass were significantly associated with mortality (OR, 1.7; CI, 1.5-2.0; p < 0.005). Our results suggest that patients with LTx and prior CTS remain technically challenging and experience worse outcomes than patients without prior CTS. A surgical strategy to minimize cardiopulmonary bypass time is critical for these challenging LTx patients., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The lung allocation score (LAS) assigns organ allocation priority based on medical urgency and the likelihood of posttransplant survival. This study is a review of a single institutional experience for lung transplantation in the era of LAS., Methods: We performed a retrospective review of 527 consecutive patients, from May 2005 to February 2010, who underwent lung transplant at our institution, comprising a high LAS group (LAS≥50, n=108) and a low LAS group (LAS<50, n=419). Kaplan-Meier and univariate analyses were performed to assess postoperative mortality as a primary outcome, and length of ventilator support and intensive care unit stay as secondary outcomes. Risk factors, including demographics, pulmonary status, and surgical and donor variables, were compared. Predictors of mortality were determined using a Cox proportional hazard model., Results: Survivals after 30 days, 90 days, 1 year, and 3 years were 92.6%, 87.8%, 71.5%, and 52.0%, respectively, in the high LAS group, and 96.9%, 93.5%, 83.2%, and 73.9% in the low LAS group (p<0.001). The incidence of prolonged ventilator support and the need for tracheostomy were higher, and intensive care unit stay was longer in the high LAS group. In the high LAS group, ischemic time greater than 8 hours was an independent predictor for mortality (hazard ratio: 3.080; 95% confidence interval 1.101 to 8.161, p=0.032)., Conclusions: Lung transplant in patients with high a LAS is associated with significantly decreased survival and increased complications compared with patients with a low LAS. Ischemic time greater than 8 hours is a significant predictor of death in patients with a high LAS., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Up to 66% of giant pulmonary artery aneurysms are associated with severe pulmonary hypertension. For these patients, lung or heart-lung en bloc transplantation is the only definitive therapy available. To date, there have been only two reports of concomitant double lung transplant and resection of a giant pulmonary artery aneurysm. We report a case of combined mitral and pulmonary valve repair, resection of a giant pulmonary artery aneurysm, and double lung transplant in a patient with primary pulmonary hypertension., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Extracorporeal membrane oxygenation (ECMO) is used occasionally as a bridge to lung transplantation. The impact on mid-term survival is unknown. We analyzed outcomes after lung transplant over a 19-year period in patients who received ECMO support., Methods: From March 1991 to October 2010, 1,305 lung transplants were performed at our institution. Seventeen patients (1.3%) were supported with ECMO before lung transplant. Diagnoses included retransplantation (n = 6), pulmonary fibrosis (n = 6), cystic fibrosis (n = 4), and chronic obstructive pulmonary disease (n = 1). Fifteen patients underwent double lung transplant, one patient had single left lung transplant and one patient had a heart-lung transplant. Venovenous and venoarterial ECMO were implanted in eight and nine cases, respectively. Median duration of support was 3.2 days (range, 1 to 49 days). Mean patient follow-up was 2.3 years., Results: Thirty-day, 1-year, and 3-year survivals were 81%, 74%, and 65%, respectively, for the supported patients and 93%, 78%, and 62% in the control group (p = 0.56). Two-year survival was not affected by ECMO type, with survival of five out of nine patients supported by venoarterial ECMO vs seven out of eight patients supported by venovenous ECMO (p = 0.17). At 1- year follow-up, allograft function for the ECMO-supported patients did not differ from the control group (forced expiratory volume in one second, 2.35 L vs 2.09 L, p = 0.39) (forced vital capacity, 3.06 L vs 2.71 L, p = 0.34)., Conclusions: Extracorporeal membrane oxygenation as a bridge to lung transplantation is associated with higher perioperative mortality but acceptable mid-term survival in carefully selected patients. Late allograft function did not differ in patients who received ECMO support before lung transplant from those who did not receive ECMO., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Concomitant tricuspid valve repair (TVR) and double lung transplantation (DLTx) has been a surgical option at our institution since 2004 in an attempt to improve the outcome of DLTx for end-stage pulmonary hypertension, severe tricuspid regurgitation, and right ventricle (RV) dysfunction. This study is a review of that single institutional experience., Methods: Consecutive cases of concomitant TVR and DLTx performed between 2004 and 2009 (TVR group, n = 20) were retrospectively compared with cases of DLTx alone for severe pulmonary hypertension without TVR (non-TVR group, n = 58)., Results: There was one in-hospital death in the TVR group. The 90-day and 1- and 3-year survival rates for the TVR group were 90%, 75%, and 65%, respectively, which were not significantly different from those for the non-TVR group. The TVR group required less inotropic support and less prolonged mechanical ventilation in the ICU. Follow-up echocardiography demonstrated immediate elimination of both volume and pressure overload in the RV and tricuspid regurgitation in the TVR group. Notably, there was a significantly lower incidence of primary graft dysfunction following transplantation in the TVR group (P < .05). Pulmonary functional improvement shown by an FEV(1) increase after 6 months was also significantly better in the TVR group (40% vs 20%, P < .05)., Conclusions: Combined TVR and DLTx procedures were successfully performed without an increase in morbidity or mortality and contributed to decreased primary graft dysfunction. In our experience, this combined operative approach achieves clinical outcomes equal or superior to the outcomes seen in DLTx patients without RV dysfunction and severe tricuspid regurgitation.

Background: Gastroesophageal reflux disease (GERD) is common in patients with end-stage lung disease (ESLD). GERD may cause obliterative bronchiolitis after lung transplantation (LTx), represented by a decline in forced expiratory volume in 1 second (FEV(1))., Objectives: To identify the patterns of reflux in patients with ESLD and to determine whether antireflux surgery (ARS) positively impacts lung function., Design: Retrospective review of prospectively collected data., Setting: Tertiary care university hospital., Patients: Forty-three patients with ESLD and documented GERD (pre-LTx, 19; post-LTx, 24)., Interventions: Antireflux surgery., Main Outcome Measures: Reflux patterns including laryngopharyngeal reflux as measured by esophageal impedance, and FEV(1), and episodes of pneumonia and acute rejection before and after ARS., Results: Before ARS, 19 of 43 patients (44%) were minimally symptomatic or asymptomatic. Laryngopharyngeal reflux events, which occurred primarily in the upright position, were common in post-LTx (56%) and pre-LTx (31%) patients. At 1 year after ARS, FEV(1) significantly improved in 91% of the post-LTx patients (P < .01) and 85% of the pre-LTx patients (P = .02). Of patients with pre-ARS declining FEV(1), 92% of post-LTx and 88% of pre-LTx patients had a reversal of this trend. Episodes of pneumonia and acute rejection were significantly reduced in post-LTx patients (P = .03) or stablilized in pre-LTx patients (P = .09)., Conclusions: There should be a low threshold for performing objective esophageal testing including esophageal impedance because GERD may be occult and ARS may improve or prolong allograft and native lung function.

Background: Because inhaled hydrogen provides potent anti-inflammatory and antiapoptotic effects against acute lung injury, we hypothesized that treatment of organ donors with inhaled hydrogen during mechanical ventilation would decrease graft injury after lung transplantation., Methods: Orthotopic left lung transplants were performed using a fully allogeneic Lewis to Brown Norway rat model. The donors were exposed to mechanical ventilation with 98% oxygen plus 2% nitrogen or 2% hydrogen for 3 h prior to harvest, and the lung grafts underwent 4 h of cold storage in Perfadex (Vitrolife, Göteborg, Sweden). The graft function, histomorphologic changes, and inflammatory reactions were assessed., Results: The combination of mechanical ventilation and prolonged cold ischemia resulted in marked deterioration of gas exchange when the donors were ventilated with 2% nitrogen/98% oxygen, which was accompanied by upregulation of proinflammatory cytokines and proapoptotic molecules. These lung injuries were attenuated significantly by ventilation with 2% hydrogen. Inhaled hydrogen induced heme oxygenase-1, an antioxidant enzyme, in the lung grafts prior to implantation, which might contribute to protective effects afforded by hydrogen., Conclusion: Preloaded hydrogen gas during ventilation prior to organ procurement protected lung grafts effectively from ischemia/reperfusion-induced injury in a rat lung transplantation model., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Redo lung transplantation remains a major clinical challenge and its indication for patients with early allograft dysfunction is difficult to determine. We report a case of potentially fatal early allograft dysfunction owing to possible acute cellular rejection after single lung transplantation in a patient who underwent redo double lung transplantation after successful use of extracorporeal membrane oxygenation as a bridge, which resulted in a successful outcome., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We recently demonstrated the inhalation of hydrogen gas, a novel medical therapeutic gas, ameliorates ventilator-induced lung injury (VILI); however, the molecular mechanisms by which hydrogen ameliorates VILI remain unclear. Therefore, we investigated whether inhaled hydrogen gas modulates the nuclear factor-kappa B (NFκB) signaling pathway. VILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg or 10 ml/kg without positive end-expiratory pressure). The ventilator delivered either 2% nitrogen or 2% hydrogen in balanced air. NFκB activation, as indicated by NFκB DNA binding, was detected by electrophoretic mobility shift assays and enzyme-linked immunosorbent assay. Hydrogen gas inhalation increased NFκB DNA binding after 1h of ventilation and decreased NFκB DNA binding after 2h of ventilation, as compared with controls. The early activation of NFκB during hydrogen treatment was correlated with elevated levels of the antiapoptotic protein Bcl-2 and decreased levels of Bax. Hydrogen inhalation increased oxygen tension, decreased lung edema, and decreased the expression of proinflammatory mediators. Chemical inhibition of early NFκB activation using SN50 reversed these protective effects. NFκB activation and an associated increase in the expression of Bcl-2 may contribute, in part, to the cytoprotective effects of hydrogen against apoptotic and inflammatory signaling pathway activation during VILI., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The growing number of patients awaiting heart transplantation, coupled with the worldwide donor shortage, has led to increased use of marginal organs, specifically hearts from older donors. This study compared the protective effects of two widely used preservation solutions, histidine-tryptophan-ketoglutarate (HTK) and Celsior (CEL; Sangstat Medical, Menlo Park, CA), for ischemia-reperfusion injury using a rat heterotopic heart transplantation model with older donors., Methods: The hearts were excised from 16- and 80-week-old Lewis donor rats, stored in HTK, CEL, or saline for 6 hours and heterotopically transplanted into syngenic young Lewis recipients. Serum troponin I and creatine phosphokinase, graft infiltrating cells, graft apoptosis, graft proinflammatory messenger ribonucleic acid levels, and adenosine monophosphate-activated protein kinase phosphorylation were analyzed 3, 6, and 12 hours after reperfusion as markers of graft injury. Tissue adenosine triphosphate levels were measured after cold storage for 0, 6, 12, and 18 hours., Results: The HTK and CEL reduced injury comparably in grafts from young donors. The recipients of grafts from older donors and stored in HTK for 6 hours had lower levels of serum troponin I and creatine phosphokinase, less upregulation of the messenger ribonucleic acid for interleukin-6, intercellular adhesion molecule-1, and tumor necrosis factor-α, fewer infiltrating cells, less apoptosis, and less phosphorylated adenosine monophosphate-activated protein kinase than recipients of grafts stored in CEL. Adenosine triphosphate levels in the hearts stored in HTK were significantly higher than those stored in CEL or saline., Conclusions: Cold storage in HTK exhibited superior protective effects against ischemia-reperfusion injury of hearts from older donors in this rat transplantation model., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Successful abrogation of ischemia/reperfusion (I/R) injury of lung grafts could significantly improve short- and long-term outcomes for lung transplant (LTx) recipients. Hydrogen gas has potent antioxidant and antiapoptotic properties and has been recently used in number of experimental and clinical studies. The purpose of this research was to investigate whether inhaled hydrogen gas could reduce graft I/R injury during lung transplantation., Methods: Orthotopic left LTxs were performed in syngenic Lewis rats. Grafts were perfused with and stored in low potassium dextran solution at 4°C for 6 hr. The recipients received 100% O2 or 98% O2 with 2% N2, 2% He, or 2% H2 during surgery and 1 hr after reperfusion. The effects of hydrogen were assessed by functional, pathologic, and molecular analysis., Results: Gas exchange was markedly impaired in animals exposed to 100% O2, 2% N2, or 2% He. Hydrogen inhalation attenuated graft injury as indicated by significantly improved gas exchange 2 hr after reperfusion. Graft lipid peroxidation was significantly reduced in the presence of hydrogen, demonstrating antioxidant effects of hydrogen in the transplanted lungs. Lung cold I/R injury causes the rapid production and release of several proinflammatory mediators and epithelial apoptosis. Exposure to 2% H2 significantly blocked the production of several proinflammatory mediators and reduced apoptosis with induction of the antiapoptotic molecules B-cell lymphoma-2 and B-cell lymphoma-extra large., Conclusion: Treatment of LTx recipients with inhaled hydrogen can prevent lung I/R injury and significantly improve the function of lung grafts after extended cold preservation, transplant, and reperfusion.

Background: Increasing allograft ischemic time is a significant risk factor for mortality following heart transplantation (HTx). The purpose of this study was to evaluate the protective effects of histidine-tryptophan-ketoglutarate (HTK) and Celsior (CEL) using a rat HTx model with prolonged cold storage., Methods: The hearts were excised from donor rats, stored in cold preservation solution for either 6 or 18 hours, and heterotopically transplanted into syngeneic recipients. Serum creatine phosphokinase (CPK), serum troponin I, graft-infiltrating cells, graft mRNA levels for inflammatory mediators, and tissue adenosine triphosphate (ATP) levels were analyzed, as markers of graft injury., Results: The recipients of grafts stored in HTK for 18 hours of prolonged cold ischemia had lower levels of serum CPK and tissue malondialdehyde, less upregulation of the mRNAs for IL-6 and inducible nitric oxide synthase, less apoptosis, and higher ATP levels than those receiving grafts stored in CEL and Saline. Cardiac contraction 3 hours after reperfusion was observed in 43% of the cardiac grafts stored in HTK for 18 hours, while no cardiac wall movement was seen in grafts stored in either saline or CEL., Conclusion: Cold storage in HTK exhibited superior protective effects against prolonged cold ischemia in a syngeneic rat transplantation model., (Copyright 2010 Mosby, Inc. All rights reserved.)