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BACKGROUND: Acute lung allograft dysfunction (ALAD) is an imprecise syndrome denoting concern for the onset of chronic lung allograft dysfunction (CLAD). Mechanistic biomarkers are needed that stratify risk of ALAD progression to CLAD. We hypothesized that single cell investigation of bronchoalveolar lavage (BAL) cells at the time of ALAD would identify immune cells linked to progressive graft dysfunction. METHODS: We prospectively collected BAL from consenting lung transplant recipients for single cell RNA sequencing. ALAD was defined by a ≥10% decrease in FEV1 not caused by infection or acute rejection and samples were matched to BAL from recipients with stable lung function. We examined cell compositional and transcriptional differences across control, ALAD with decline, and ALAD with recovery groups. We also assessed cell-cell communication. RESULTS: BAL was assessed for 17 ALAD cases with subsequent decline (ALAD declined), 13 ALAD cases that resolved (ALAD recovered), and 15 cases with stable lung function. We observed broad differences in frequencies of the 26 unique cell populations across groups (p = 0.02). A CD8 T cell (p = 0.04) and a macrophage cluster (p = 0.01) best identified ALAD declined from the ALAD recovered and stable groups. This macrophage cluster was distinguished by an anti-inflammatory signature and the CD8 T cell cluster resembled a Tissue Resident Memory subset. Anti-inflammatory macrophages signaled to activated CD8 T cells via class I HLA, fibronectin, and galectin pathways (p

PGD3 is the manifestation of ischemia-reperfusion injury which results from inflammation and cell death and is associated with poor outcome. This systematic-review and meta-analysis of non-randomized controlled trials on patients undergoing Ltx with reconditioned lungs via EVLP, aims to assess the association between the levels of proinflammatory biomarkers during EVLP and PGD3 development within the firsts 72 h post-Ltx. Biomarkers were categorized by timing (1-hour, T0 and 4-hours, Tend from EVLPstart) and by their biological function (adhesion molecules, chemokines, cytokines, damage-associated-molecular-patterns, growth-factors, metabolites). We employed a four-level mixed-effects model with categorical predictors for biomarker groups to identify differences between patients with PGD3 and others. The single study and individual measurements were considered random intercepts. We included 8 studies (610 measurements at T0 and 884 at Tend). The pooled effect was 0.74 (p = 0.021) at T0, and 0.90 (p = 0.0015) at Tend. The four-level model indicated a large pooled correlation between developing PGD3 at 72 h post-Ltx and inflammatory biomarkers values, r = 0.62 (p = 0.009). Chemokine group showed the strongest association with the outcome (z-value = 1.26, p = 0.042). Pooled panels of inflammation markers, particularly chemokines, measured at T0 or at Tend, are associated with the development of PGD3 within the first 72 h after Ltx. Systematic Review Registration: https://osf.io/gkxzh/. [ABSTRACT FROM AUTHOR]

Allograft dysfunction is the major cause of early morbidity and mortality following cardiac transplantation. Poor graft function can be secondary to transplant complications or, when no identifiable cause is present, primary graft dysfunction (PGD). To standardize the definition of PGD, a consensus conference was convened which produced a document that defines severity categories and criteria for assessing left and right ventricular dysfunction. A critical sub-criterion in the consensus definition of PGD is a score intended to reflect the need for inotropic support after transplant. However, during the Australian and New Zealand trial of Hypothermic Oxygenated Perfusion preservation of donor hearts, we realized that the consensus inotrope score was inflated by the disproportionate impact of norepinephrine (NE), upcoding PGD grades from mild to moderate. A review of 50 heart transplant patients at The Alfred Hospital showed that in 38% of the instances when the inotropic score exceeded the consensus cutoff value due to NE, there was no identifiable PGD or vasoplegia and in 16% of instances, the cutoff was exceeded due to vasoplegia without PGD. Given the importance of accurate PGD classification in an era when static cold storage preservation is being replaced by machine perfusion and temperature controlled static storage, we contend that NE should be removed from the inotrope score equation to prevent up coding of mild to moderate PGD. Furthermore, we think that PGD classification should incorporate sensitive load- independent cardiac performance measures in the context of given levels of pharmacological and mechanical cardiac support. [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) contributes substantially to both short- and long-term mortality after lung transplantation, but the mechanisms that lead to PGD are not well understood. Exposure to ambient air pollutants is associated with adverse events during waitlisting for lung transplantation and chronic lung allograft dysfunction, but its association with PGD has not been studied. We hypothesized that long-term exposure of the lung donor and recipient to high levels of ambient air pollutants would increase the risk of PGD in lung transplant recipients. Using data from 1428 lung transplant recipients and their donors enrolled in the Lung Transplant Outcomes Group observational cohort study, we evaluated the association between the development of PGD and zip-code-based estimates of long-term exposure to 6 major air pollutants (ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, particulate matter 2.5, and particulate matter 10) in both the lung donor and the lung recipient. Exposure estimates used daily EPA air pollutant monitoring data and were based on the geographic centroid of each subject's residential zip code. Associations were tested in both univariable and multivariable models controlling for known PGD risk factors. We did not find strong associations between air pollutant exposures in either the donor or the recipient and PGD. Exposure to ambient air pollutants, at the levels observed in this study, may not be sufficiently harmful to prime the donor lung or the recipient to develop PGD, particularly when considering the robust associations with other established PGD risk factors. [ABSTRACT FROM AUTHOR]

Objective To explore the therapeutic effect and mechanism of umbilical cord mesenchymal stem cells (UC-MSC) in rats with primary graft dysfunction after lung transplantation. Methods Twenty-four male Lewis rats were randomly divided into donor and recipient groups, with 12 rats in each group. The recipients were further divided into 3 groups: blank control group, negative control group, and treatment group, with 4 rats in each group. The color, size and texture of the transplanted lungs were observed 72 h after lung transplantation. The ventilation status and progression of consolidation in the transplant lungs of rats in each group were evaluated by micro-CT. Plasma, transplant lung tissue and alveolar lavage fluid samples of recipient rats were collected. The wet/dry ratio of lung tissue was measured to evaluate the degree of pulmonary edema. Hematoxylin-eosin (HE) staining was used to evaluate the degree of lung tissue damage. Terminal deoxyribonucleic acid transferase mediated dUTP nick end labeling (TUNEL) staining was used to evaluate cell apoptosis. Myeloperoxidase (MPO) activity in lung tissue was detected, and enzyme-linked immunosorbent assay (ELISA) was used to detect interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α levels in plasma and alveolar lavage fluid. Results The appearance of the transplant lungs in the negative control group was significantly different from that of the autologous lungs, while the transplant lungs in the treatment group were almost identical in color to the autologous lungs compared to the blank control group. Compared with the negative control group, the treatment group showed reduced alveolar exudate and more intact airway epithelial cell structure. No alveolar exudate was observed in the blank control group, and the structure of the airways and alveoli remained normal. The treatment group had lower apoptosis rate of airway epithelial cells, lung tissue wet/dry ratio, and MPO activity compared to the negative control group (all P < 0.05). The levels of IL-6 and TNF-α in the bronchoalveolar lavage fluid of the treatment group were lower than those in the negative control group, while the level of IL-10 was higher than that in the negative control group and the blank control group (all P < 0.05). There were no statistically significant differences in the levels of cytokines in plasma among each group (all P > 0.05). Conclusions UC-MSC may effectively alleviate the severity of primary graft dysfunction in rats by reducing the apoptosis rate of cells in lung tissue and inhibiting inflammatory responses. [ABSTRACT FROM AUTHOR]

Background: Currently, there are no standardized guidelines for graft allocation in heart transplants (HTxs), particularly when considering organs from marginal donors and donors after cardiocirculatory arrest. This complexity highlights the need for an effective risk analysis tool for primary graft dysfunction (PGD), a severe complication in HTx. Existing score systems for predicting PGD lack superior predictive capability and are often too complex for routine clinical use. This study sought to develop a user-friendly score integrating variables from these systems to enhance the efficacy of the organ allocation process. Methods: Severe PGD was defined as the need for mechanical circulatory support and/or death from an unknown etiology within the first 24 hours following HTx. We used a meta-analytical approach to create a derivation cohort to identify risk factors. We then applied a logistic regression analysis to generate an equation predicting severe PGD risk. We used our previous experience in HTx to create a validation cohort. Subsequently, we implemented the formula in a smartphone application. Results: The meta-analysis comprising six studies revealed a 10.5% (95% confidence interval (CI): 5.3-12.4) incidence rate of severe PGD and related 30-day mortality of 38.6%. Eleven risk factors were identified: female donors, female donor to male recipient, undersized donor, donor age, recipient on ventricular assist device support, recipient on amiodarone treatment, recipient with diabetes and renal dysfunction, re-sternotomy, graft ischemic time, and bypass time. An equation to predict the risk, including the 11 parameters (GREF-11), was created using logistic regression models and validated based on our experience involving 116 patients. In our series, 29 recipients (25%) required extracorporeal membrane oxygenation support within 24 hours post-HTx. The overall 30-day mortality was 4.3%, 3.4%, and 6.8% in the non-PGD and severe PGD groups, respectively. The area under the receiver operating characteristic (AU-ROC) curve of the model in the validation cohort was 0.804. Conclusions: The GREF-11 application should offer HTx teams several benefits, including standardized risk assessment and bedside clinical decision support, thereby helping minimize the risk of severe PGD post-HTx. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review summarizes the current literature on primary graft dysfunction highlighting the current definition, reviewing epidemiology, and describing donor, recipient, and perioperative risk factors in the contemporary era. Recent Findings: PGD, in its most severe form, complicates 8% of heart transplants and portends a 1-year mortality of close to 40%. PGD is multifactorial and heterogeneous with contributions from donor and recipient risk as well as organ recovery and preservation modalities. Biomarkers may enhance risk stratification and lend insight into the underlying mechanism of PGD. Temperature-controlled storage and hypothermic oxygenation perfusion systems, in particular, may have significant potential to mitigate PGD risk. Summary: PGD is a devastating early complication of heart transplantation that is both complex and multifactorial. Despite its incidence and impact the underlying biology of PGD remains poorly understood. Future studies mechanistic studies are needed to address the underlying pathophysiology of PGD to develop targeted prophylactic and/or therapeutic interventions. [ABSTRACT FROM AUTHOR]

Heart failure is a serious and challenging medical condition characterized by the inability of the heart to pump blood effectively, leading to reduced blood flow to organs and tissues. Several underlying causes may be linked to this, including coronary artery disease, hypertension, or previous heart attacks. Therefore, it is a chronic condition that requires ongoing management and medical attention. HF affects >64 million individuals worldwide. Heart transplantation remains the gold standard of treatment for patients with end-stage cardiomyopathy. The recruitment of marginal donors may be considered an asset at the age of cardiac donor organ shortage. Primary graft dysfunction (PGD) is becoming increasingly common in the new era of heart transplantations. PGD is the most common cause of death within 30 days of cardiac transplantation. Mechanical Circulatory Support (MCS), particularly venoarterial extracorporeal membrane oxygenation (V-A ECMO), is the only effective treatment for severe PGD. VA-ECMO support ensures organ perfusion and provides the transplanted heart with adequate rest and recovery. In the new era of heart transplantation, early use allows for increased patient survival and careful management reduces complications. [ABSTRACT FROM AUTHOR]

Lung ischemia-reperfusion injury (IRI), a common complication after lung transplantation (LTx), plays a crucial role in both primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) thereby adversely impacting the clinical outcomes in these patient cohorts. Lung IRI is characterized by several molecular events including immune cell infiltration, reactive oxygen species (ROS) generation, calcium overload, inflammation and various forms of cell death pathways. Currently, no therapeutic agents are available to clinically prevent lung IRI. While animal and cell culture models are highly valuable in understanding the pathophysiology of lung IRI, they may not completely recapitulate the complexity of human lung tissue pathology. This limitation necessitates the requirement for developing innovative preclinical human research tools that can supplement available scientific modalities. Emerging evidence suggests that precision-cut lung slices (PCLS) have become an indispensable tool in scientific research to study lung biology in an ex vivo tissue system. Recent studies using PCLS have investigated lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Although PCLS can be successfully employed to determine the deleterious events in the pathogenesis of lung IRI, including cell-cell interactions as well as hallmarks of inflammation and oxidative stress-dependent pathways, detailed studies employing PCLS to decipher these molecular events in post-LTx injury are currently limited. This review focuses on the applicability and unexplored potential of PCLS as a powerful tool in lung IRI research for understanding the pathophysiology and consequent development of new therapeutic modalities. [ABSTRACT FROM AUTHOR]

Lung transplantation is hindered by low donor lung utilization rates. Infectious complications are reasons to decline donor grafts due to fear of post-transplant primary graft dysfunction. Mesenchymal stem cells are a promising therapy currently investigated in treating lung injury. Full-term amniotic fluid-derived lung-specific mesenchymal stem cell treatment may regenerate damaged lungs. These cells have previously demonstrated inflammatory mediation in other respiratory diseases, and we hypothesized that treatment would improve donor lung quality and postoperative outcomes. In a transplantation model, donor pigs were stratified to either the treated or the nontreated group. Acute respiratory distress syndrome was induced in donor pigs and harvested lungs were placed on ex vivo lung perfusion (EVLP) before transplantation. Treatment consisted of 3 doses of 2 × 106 cells/kg: one during EVLP and 2 after transplantation. Donors and recipients were assessed on clinically relevant parameters and recipients were followed for 3 days before evaluation for primary graft dysfunction (PGD). Repeated injection of the cell treatment showed reductions in inflammation seen through lowered immune cell counts, reduced histology signs of inflammation, and decreased cytokines in the plasma and bronchoalveolar lavage fluid. Treated recipients showed improved pulmonary function, including increased PaO 2 /FiO 2 ratios and reduced incidence of PGD. Repeated injection of lung-specific cell treatment during EVLP and post transplant was associated with improved function of previously damaged lungs. Cell treatment may be considered as a potential therapy to increase the number of lungs available for transplantation and the improvement of postoperative outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVES The effect of allograft ischaemic time (AIT) on postoperative events after lung transplantation remains unclear. This study aims to assess the feasibility of extending the duration of AIT. METHODS The United Network for Organ Sharing database was queried for adult lung transplantation from 4 May 2005 to 30 June 2020. Patients were divided as per AIT into standard ischaemic time (<6 h) and prolonged ischaemic time (≥6 h) groups using propensity score matching and evaluated on a continuous scale using restricted cubic splines. The primary outcome was overall 1-year and 5-year survival. RESULTS Among 11 438 propensity-matched recipients, standard ischaemic time and prolonged ischaemic time showed no differences in overall 1-year (P  = 0.29) or 5-year (P  = 0.29) survival. Prolonged ischaemic time independently predicted early postoperative ventilator support for >48 h (OR = 1.33, 95% CI 1.22–1.44), dialysis (OR = 1.55, 95% CI 1.30–1.84), primary graft dysfunction (PGD; OR = 1.28, 95% CI 1.09–1.50), acute rejection (OR = 1.42, 95% CI 1.24–1.62), and interestingly, decreased 5-year bronchiolitis obliterans syndrome (HR = 0.91, 95% CI 0.85–0.97). In relative risk curves, 1-year mortality, prolonged ventilation, dialysis and PGD steadily increased per hour as AIT extended. The risk of acute rejection and 5-year bronchiolitis obliterans syndrome also showed significant changes between 5 and 8 h of AIT. In contrast, 5-year mortality remained constant despite rising AIT. CONCLUSIONS Prolonged AIT worsened early outcomes such as PGD, but improved bronchiolitis obliterans syndrome freedom at later time points. Despite this, both short- and long-term survival were similar between prolonged ischaemic time and standard ischaemic time patients. Dynamic risk changes in post-transplant events should be noted for prolonged ischaemia lung use. [ABSTRACT FROM AUTHOR]

OBJECTIVES This study was designed to examine the outcomes of adult living-donor lobar lung transplants (LDLLTs) using small-for-size grafts. METHODS A calculated graft forced vital capacity of <50% of the predicted forced vital capacity of the recipient was considered to indicate a small-for-size graft. Adult recipients (≥18 years) who underwent LDLLTs between 2008 and 2022 were included in this study. RESULTS We performed 80 adult LDLLTs, using small-for-size grafts in 15 patients and non-small grafts in 65 patients. Grade 3 primary graft dysfunction developed within 72 h after the transplant in 3 patients (20%) in the small group and in 3 patients (4.6%) in the non-small group (P  = 0.0763). The 1- and 5-year survival rates were 86.7% and 69.3% in the small group and 93.8% and 77.1% in the non-small group (P  = 0.742). In the small group, the native lungs were spared in 8 patients, whereas 2 lobar grafts were implanted with non-spared native lungs in the other 7 patients. The 1- and 5-year survival rates were significantly better in the spared group (both 100%) than in the non-spared group (71.4% and 23.8%; P  = 0.0375). The spared group showed a significantly higher median percent forced vital capacity after the transplant than the non-spared group (68.5% vs 44.9%; P  = 0.0027). CONCLUSIONS Although the use of small-for-size grafts was associated with a higher rate of severe primary graft dysfunction, no differences were found in survival rates. When the graft is small, the native lung should be partially spared if possible. [ABSTRACT FROM AUTHOR]

Rationale: Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. Objectives: To investigate the association of a common missense variant, MICBG406A, with ALI. Methods: We assessed MICBG406A genotypes within two multicenter observational study cohorts at risk for ALI: primary graft dysfunction (N = 619) and acute respiratory distress syndrome (N = 1,376). Variant protein functional effects were determined in cultured and ex vivo human samples. Measurements and Main Results: Recipients of MICBG406A-homozygous allografts had an 11.1% absolute risk reduction (95% confidence interval [CI], 3.2-19.4%) for severe primary graft dysfunction after lung transplantation and reduced risk for allograft failure (hazard ratio, 0.36; 95% CI, 0.13-0.98). In participants with sepsis, we observed 39% reduced odds of moderately or severely impaired oxygenation among MICBG406A-homozygous individuals (95% CI, 0.43-0.86). BAL NK cells were less frequent and less mature in participants with MICBG406A. Expression of missense variant protein MICBD136N in cultured cells resulted in reduced surface MICB and reduced NKG2D ligation relative to wild-type MICB. Coculture of variant MICBD136N cells with NK cells resulted in less NKG2D activation and less susceptibility to NK cell killing relative to the wild-type cells. Conclusions: These data support a role for MICB signaling through the NKG2D receptor in mediating ALI, suggesting a novel therapeutic approach.

Objective: Static cold storage with ice has been the mainstay of cardiac donor preservation. Early preclinical data suggest that allograft preservation at 10 °C may be beneficial. We tested this hypothesis by using a static 10 °C storage device to preserve and transport cardiac allografts. Methods: In total, 52 allografts were recovered between July 2023 and March 2024 and transported using a 10 °C storage cooler. Results were compared to a 3:1 propensity match of allografts transported on ice. Patients were excluded for the following reasons: dual viscera transplant, previous heart transplant, complex congenital heart disease, or allograft injury during procurement. Results: Among the 10 °C cooler cohort, median total ischemic time was 222 minutes at 10 °C versus 193 minutes on ice (P .99). 10 °C hearts demonstrated less change in lactate but no difference in vasoactive inotrope scores or cardiac index. In hearts with extended ischemic time, delta lactate was lower in 10 °C cooler hearts. There was no statistical difference in outcomes for donor hearts >40 years old. Conclusions: This is an early experience of static preservation in a 10 °C cooler. Postoperative allograft function was excellent, and lactate profiles lower in those allografts with extended ischemic times. Static cold storage targeting 10 °C may offer an inexpensive method for extended heart preservation. Further investigation is needed to assess long-term outcomes of 10 °C storage.

Lung transplantation (LT) is the only treatment for many end-stage lung diseases. Despite significant progress in transplantology and surgery, LT remains a high-tech surgical procedure performed at select research centers. Primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction are serious problems that can worsen lung transplant outcomes significantly. Using animal models in experimental studies to investigate these pathologic conditions is one of the more rational approaches. A literature review was conducted in order to select a suitable model that reproduces pathologic processes developing after LT. The literature was searched and ana- lyzed in MEDLINE and Elibrary databases, and the US National Institute of Health guidelines for the period up to December 2023 were reviewed. It was found that the most frequently used models are small laboratory animal models (without LT) and large animal models (with LT).

The pulmonary microbiome has emerged as a significant factor in respiratory health and diseases. Despite the sterile conditions maintained during ex vivo lung perfusion (EVLP), the use of antibiotics in the perfuse liquid can lead to dynamic changes in the lung microbiome. Here, we present the design of a study that aims to investigate the hypothesis that EVLP alters the lung microbiome and induces tissue inflammation. This pilot, prospective, controlled study will be conducted in two Spanish donor centers and will include seven organ donors after brain death or after controlled cardiac death. After standardized retrieval, the left lung will be preserved in cold storage and the right lung will be perfused with EVLP. Samples from bronchoalveolar lavage, perfusion and preservation solutions, and lung biopsies will be collected from both lungs and changes in lung microbiome and inflammatory response will be compared. [ABSTRACT FROM AUTHOR]

Background: Right heart remodeling is noted in patients with severe COVID‐19‐associated acute respiratory distress syndrome (ARDS). There is limited information regarding right heart recovery following lung transplantation in this cohort. Methods: Retrospective review of institutional transplant database from June 2020 to June 2022 was performed at Northwestern University in Chicago, Illinois. Demographic, laboratory, histopathologic, lung transplant outcomes, and pre‐ and postoperative echocardiographic data were recorded and analyzed. Results: Of the 42 patients who underwent lung transplantation for COVID‐19‐related ARDS, 6 patients were excluded due to having either a single‐lung transplant (n = 2), lobar transplant (n = 1), or dual‐organ transplant (n = 1) or for missing postoperative TTE data (n = 2) and 36 were included in the study; there were no 90‐day deaths, and the 1‐year survival rate was 88.8%. Intraoperative hemodynamics data showed a mean pulmonary artery pressure of 49 ± 23 mm Hg. Preoperative echocardiography was evaluated at a median of 15.5 (10–34.3) (IQR) days preoperatively and 140 (108–201) days (IQR) postoperatively. RV size grade improved from an average of 1.7 ± 0.85 to 1.3 ± 0.6 (p < 0.05), while RV function improved from an average of 2.2 ± 1.2 to 1 ± 1 (p < 0.05). There was a reduction in RVSP from 46.5 ± 18 mmHg to 30.1 ± 7.8 mmHg (p < 0.05) and RV free wall strain showed improvement from −13.9 ± 6.1% to −18.5 ± 5.4% (p < 0.05). Conclusions: The results showed that the RV size and systolic function demonstrate improvement with normalization in a relatively short period following lung transplantation for patients with COVID‐19‐associated ARDS. [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) is a complication of lung transplantation that continues to cause significant morbidity. The Th2 immune response has been shown to counteract tissue-damaging inflammation. We hypothesized that Th2 cytokines/chemokines in blood would be associated with protection from PGD. Utilizing pretransplant sera from the multicenter clinical trials in organ transplantation study, we evaluated Th2 cytokines/chemokines in 211 patients. Increased concentrations of Th2 cytokines were associated with freedom from PGD, namely IL-4 (odds ratio [OR] 0.66 [95% confidence interval {CI} 0.45-0.99], p = 0.043), IL-9 (OR 0.68 [95% CI 0.49-0.94], p = 0.019), IL-13 (OR 0.73 [95% CI 0.55-0.96], p = 0.023), and IL-6 (OR 0.74 [95% CI 0.56-0.98], p = 0.036). Multivariable regression performed for each cytokine, including clinically relevant covariables, confirmed these associations and additionally demonstrated association with IL-5 (OR 0.57 [95% CI 0.36-0.89], p = 0.014) and IL-10 (OR 0.55 [95% CI 0.32-0.96], p = 0.035). Higher levels of Th2 immune response before lung transplant appear to have a protective effect against PGD, which parallels the Th2 role in resolving inflammation and tissue injury. Pretransplant cytokine assessments could be utilized for recipient risk stratification. [ABSTRACT FROM AUTHOR]

Background: Early utilization of extracorporeal membrane oxygenation (ECMO) improves the clinical outcomes of patients with severe primary graft dysfunction (PGD3) after lung transplantation. Although there is a survival benefit, the impact of ECMO on airway complications has not been investigated. This study aims to describe the clinical association between posttransplant methods of support and the severity of acute airway anastomosis complications in patients with PGD3 following bilateral lung transplantation. Methods: Data from adult bilateral lung transplant patients diagnosed with PGD3 at our institution were retrospectively reviewed. Bronchial anastomosis necrosis (ischemia reperfusion injury [IRI]) that developed within a month after transplantation was graded. The data were compared among the groups of veno‐venous ECMO (VV‐ECMO) (n = 77), veno‐arterial ECMO (VA‐ECMO) (n = 14), and mechanical ventilation (MV, n = 33). Results: Higher levels of support (VV/VA‐ECMO) were associated with a lower incidence of PGD3, which was highest in recipients on MV only (M2 = 19.54, r = −0.41, p < 0.001). In a multivariable competing risk analysis, VV‐ECMO was protective against chronic allograft dysfunction (CLAD) relative to the MV group (HR: 0.36 [0.13–0.96], p = 0.042). There was no relationship between posttransplant support and survival. Conclusion: This study suggests posttransplant VV‐ECMO support in patients who develop PGD3 may confer a protective advantage over MV alone in the prevention of ischemic reperfusion injury. VV‐ECMO was associated with lower IRI grades and lower rates of BOS after transplantation. Future studies investigating the causal mechanisms are warranted. [ABSTRACT FROM AUTHOR]

• Declare the detail relationship between perioperative fluid management and early AKI incidence after lung transplantation; • Confirm the protective effect of restrict fluid strategy on the short-term renal outcomes of lung transplant recipients; • Reveal the predictive value of positive fluid balance in short-term outcomes after lung transplantation. Postoperative acute kidney injury (AKI) after lung transplantation (LTx) is an important factor affecting the short-term outcomes. The focus item of transplantation centers is how to improve the incidence of AKI through optimal management during the perioperative period. The purpose of the study is to investigate the influence of perioperative volume in the development of early AKI following LTx. The study involved patients who had undergone LTx between October 2018 to December 2021 at China-Japan Friendship Hospital in Beijing. The patients were monitored for AKI occurring within 72 hours after LTx, as well as the renal outcomes within 30 days. The perioperative volumes were compared and analyzed to determine the impact on various clinical outcomes. 248 patients were enrolled in the study ultimately, with almost half of them (49.6 %) experiencing AKI. 48.8 % of AKI patients received continuous renal replacement therapy (CRRT), with 57.7 % recovered by the end of the 30-day follow-up period. A J-shaped relationship was demonstrated between perioperative volume and AKI incidence. Moreover, maintaining a positive fluid balance would increase the 30-day mortality and lead to poor renal outcomes. Perioperative volume is an independent risk factor of early AKI after LTx. Positive fluid balance increases the risk of AKI, 30-day mortality, and adverse renal prognosis. The LTx recipients may benefit from a relatively restrict fluid strategy during and after the lung transplantation. [ABSTRACT FROM AUTHOR]

Background: Preoperative amiodarone effects on postorthotopic heart transplant (OHT) outcomes remain controversial. Objective: The purpose of this study was to determine the effect of cumulative pre-OHT amiodarone exposure on severe primary graft dysfunction (PGD). Methods: We retrospectively reviewed adult OHT recipients between August 2012 and June 2018. Primary outcome was severe PGD in patients receiving amiodarone at 3, 6, and 12 months prior to OHT compared with those not receiving amiodarone. Secondary outcomes included intensive care unit (ICU) and hospital length of stay, duration of mechanical ventilation, early graft failure (EGF), mortality at 3, 6, and 12 months post-OHT, and 30-day incidence of postoperative tachyarrhythmias, bradycardia, permanent pacemaker implantation, and rejection. Results: Incidence of severe PGD was 12.5% in those who received amiodarone compared to 6.8% in those who did not (14 vs 6, P = 0.18). Cumulative preoperative amiodarone significantly increased the odds of severe PGD at 3 months (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.001-1.06; P = 0.044) and 6 months (OR: 1.02, 95% CI: 1.003-1.044; P = 0.024) in a multivariate logistic regression. Patients on amiodarone had significantly higher rates of postoperative bradycardia (13.4% vs 4.5%, P = 0.03). Conclusion and Relevance: A trend toward increased PGD was present in patients receiving preoperative amiodarone. This finding combined with the regression showing significantly increased odds of PGD with increasing 3 and 6 month cumulative amiodarone dose is clinically concerning. Escalation of care with pacemaker implantation was required more frequently in patients on pre-OHT amiodarone. [ABSTRACT FROM AUTHOR]

OBJECTIVES Historically, the perfusion-guided sequence suggests to first transplant the side with lowest lung perfusion. This sequence is thought to limit right ventricular afterload and prevent acute heart failure after first pneumonectomy. As a paradigm shift, we adopted the right-first implantation sequence, irrespective of lung perfusion. The right donor lung generally accommodates a larger proportion of the cardiac output. We hypothesized that the right-first sequence reduces the likelihood of oedema formation in the firstly transplanted graft during second-lung implantation. Our objective was to compare the perfusion-guided and right-first sequence for intraoperative extracorporeal membrane oxygenation (ECMO) need and primary graft dysfunction (PGD). METHODS A retrospective single-centre cohort study (2008–2021) including double-lung transplant cases (N  = 696) started without ECMO was performed. Primary end-points were intraoperative ECMO cannulation and PGD grade 3 (PGD3) at 72 h. Secondary end-points were patient and chronic lung allograft dysfunction-free survival. In cases with native left lung perfusion ≤50% propensity score adjusted comparison of the perfusion-guided and right-first sequence was performed. RESULTS When left lung perfusion was ≤50%, right-first implantation was done in 219 and left-first in 189 cases. Intraoperative escalation to ECMO support was observed in 10.96% of right-first versus 19.05% of left-first cases (odds ratio 0.448; 95% confidence interval 0.229–0.0.878; P  = 0.0193). PGD3 at 72 h was observed in 8.02% of right-first versus 15.64% of left-first cases (0.566; 0.263–1.217; P  = 0.1452). Right-first implantation did not affect patient or chronic lung allograft dysfunction-free survival. CONCLUSIONS The right-first implantation sequence in off-pump double-lung transplantation reduces need for intraoperative ECMO cannulation with a trend towards less PGD grade 3. [ABSTRACT FROM AUTHOR]

In lung transplantation, postoperative outcomes favor intraoperative use of extracorporeal membrane oxygenation (ECMO) over cardiopulmonary bypass (CBP). We investigated the effect of intraoperative support strategies on endothelial injury biomarkers and short-term posttransplant outcomes. Adults undergoing bilateral lung transplantation with No-Support, venoarterial (V-A) ECMO, or CPB were included. Plasma samples pre- and post-transplant were collected for Luminex assay to measure endothelial injury biomarkers including syndecan-1 (SYN-1), intercellular adhesion molecule-1 (ICAM-1), and matrix metalloprotease-9. Fifty five patients were included for analysis. The plasma level of SYN-1 at arrival in the intensive care unit was significantly higher with CPB compared to V-A ECMO and No-Support (P < 0.01). The rate of primary graft dysfunction grade 3 (PGD3) at 72 hours was 60.0% in CPB, 40.1% in V-A ECMO, and 15% in No-Support (P = 0.01). Postoperative plasma levels of SYN-1 and ICAM-1 were significantly higher in recipients who developed PGD3 at 72 hours. SYN-1 levels were also significantly higher in patients who developed acute kidney injury and hepatic dysfunction after transplant. Postoperative, SYN-1 upon intensive care arrival was found to be a significant predictive biomarker of PGD3, acute kidney injury, and hepatic dysfunction following lung transplantation. CPB is associated with higher plasma concentrations of SYN-1, a marker of endothelial glycocalyx degradation, upon arrival to the intensive care unit. Higher levels of SYN-1 are predictive of end-organ dysfunction following lung transplantation. Our data suggests that intraoperative strategies aimed at modulating endothelial injury will help improve lung transplantation outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) is a major risk factor for chronic lung allograft dysfunction (CLAD) following lung transplantation, but the mechanisms linking these pathologies are poorly understood. We hypothesized that the replicative stress induced by PGD would lead to erosion of telomeres, and that this telomere dysfunction could potentiate CLAD. In a longitudinal cohort of 72 lung transplant recipients with >6 years median follow-up time, we assessed tissue telomere length, PGD grade, and freedom from CLAD. Epithelial telomere length and fibrosis-associated gene expression were assessed on endobronchial biopsies taken at 2 - 4 weeks post-transplant by TeloFISH assay and nanoString digital RNA counting. Negative-binomial mixed-effects and Cox-proportional hazards models accounted for TeloFISH staining batch effects and subject characteristics including donor age. Increasing grade of PGD severity was associated with shorter airway epithelial telomere lengths (P = 0.01). Transcriptomic analysis of fibrosis-associated genes showed alteration in fibrotic pathways in airway tissue recovering from PGD, while telomere dysfunction was associated with inflammation and impaired remodeling. Shorter tissue telomere length was in turn associated with increased CLAD risk, with a hazard ratio of 1.89 (95% CI 1.16 - 3.06) per standard deviation decrease in airway telomere length, after adjusting for subject characteristics. PGD may accelerate telomere dysfunction, potentiating immune responses and dysregulated repair. Epithelial cell telomere dysfunction may represent one of several mechanisms linking PGD to CLAD.

Abstract Background Lung transplantation (LT) represents a high-risk procedure for end-stage lung diseases. This study describes the outcomes of patients undergoing LT that require massive transfusions as defined by the universal definition of perioperative bleeding (UDPB). Methods Adult patients who underwent bilateral LT at a single academic center were surveyed retrospectively. Patients were grouped by insignificant, mild, or moderate perioperative bleeding (insignificant-to-moderate bleeders) and severe or massive perioperative bleeding (severe-to-massive bleeders) based on the UDPB classification. Outcomes included 1-year survival and primary graft dysfunction (PGD) of grade 3 at 72 h postoperatively. Multivariable models were adjusted for recipient age, sex, body mass index (BMI), Lung allocation score (LAS), preoperative hemoglobin (Hb), preoperative extracorporeal membrane oxygenation (ECMO) status, transplant number, and donor status. An additional multivariable model was created to find preoperative and intraoperative predictors of severe-to-massive bleeding. A p-value less than 0.05 was selected for significance. Results A total of 528 patients were included, with 357 insignificant-to-moderate bleeders and 171 severe-to-massive bleeders. Postoperatively, severe-to-massive bleeders had higher rates of PGD grade 3 at 72 h, longer hospital stays, higher mortality rates at 30 days and one year, and were less likely to achieve textbook outcomes for LT. They also required postoperative ECMO, reintubation for over 48 h, tracheostomy, reintervention, and dialysis at higher rates. In the multivariate analysis, severe-to-massive bleeding was significantly associated with adverse outcomes after adjusting for recipient and donor factors, with an odds ratio of 7.73 (95% CI: 4.27–14.4, p

Abstract Primary graft dysfunction (PGD) is a life-threatening clinical condition with a high mortality rate, presenting as left, right, or biventricular dysfunction within the initial 24 h following heart transplantation, in the absence of a discernible secondary cause. Given its intricate nature, definitive definition and diagnosis of PGD continues to pose a challenge. The pathophysiology of PGD encompasses numerous underlying mechanisms, some of which remain to be elucidated, including factors like myocardial damage, the release of proinflammatory mediators, and the occurrence of ischemia-reperfusion injury. The dynamic characteristics of both donors and recipients, coupled with the inclination towards marginal lists containing more risk factors, together contribute to the increased incidence of PGD. The augmentation of therapeutic strategies involving mechanical circulatory support accelerates myocardial recovery, thereby significantly contributing to survival. Nonetheless, a universally accepted treatment algorithm for the swift management of this clinical condition, which necessitates immediate intervention upon diagnosis, remains absent. This paper aims to review the existing literature and shed light on how diagnosis, pathophysiology, risk factors, treatment, and perioperative management affect the outcome of PGD.

Background: Primary graft dysfunction (PGD) has detrimental effects on recipients following lung transplantation. Here, we determined the contemporary trends of PGD in a national database, factors associated with the development of PGD grade 3 (PGD3) and ex vivo lung perfusion's (EVLP) effect on this harmful postoperative complication. Methods: The United Network for Organ Sharing database was queried from 2015 to 2023, and recipients were stratified into No-PGD, PGD1/2, or PGD3. The groups were analyzed with comparative statistics, and survival was determined with Kaplan–Meier methods. Multivariable Cox regression was used to determine factors associated with increased mortality. PGD3 recipients were then stratified based on EVLP use prior to transplantation, and a 3:1 propensity match was performed to determine outcomes following transplantation. Finally, logistic regression models based on select criteria were used to determine risk factors associated with the development of PGD3 and mortality within 1 year. Results: A total of 21.4% of patients were identified as having PGD3 following lung transplant. Those with PGD3 suffered significantly worse perioperative morbidity, mortality, and had worse long-term survival. PGD3 was also independently associated with increased mortality. Matched EVLP PGD3 recipients had significantly higher use of ECMO postoperatively; however, they did not suffer other significant morbidity or mortality as compared to PGD3 recipients without EVLP use. Importantly, EVLP use prior to transplantation was significantly associated with decreased likelihood of PGD3 development, while having no significant association with early mortality. Conclusions: EVLP is associated with decreased PGD3 development, and further optimization of this technology is necessary to expand the donor pool. [ABSTRACT FROM AUTHOR]

Background: Lung transplantation (LT) represents a high-risk procedure for end-stage lung diseases. This study describes the outcomes of patients undergoing LT that require massive transfusions as defined by the universal definition of perioperative bleeding (UDPB). Methods: Adult patients who underwent bilateral LT at a single academic center were surveyed retrospectively. Patients were grouped by insignificant, mild, or moderate perioperative bleeding (insignificant-to-moderate bleeders) and severe or massive perioperative bleeding (severe-to-massive bleeders) based on the UDPB classification. Outcomes included 1-year survival and primary graft dysfunction (PGD) of grade 3 at 72 h postoperatively. Multivariable models were adjusted for recipient age, sex, body mass index (BMI), Lung allocation score (LAS), preoperative hemoglobin (Hb), preoperative extracorporeal membrane oxygenation (ECMO) status, transplant number, and donor status. An additional multivariable model was created to find preoperative and intraoperative predictors of severe-to-massive bleeding. A p-value less than 0.05 was selected for significance. Results: A total of 528 patients were included, with 357 insignificant-to-moderate bleeders and 171 severe-to-massive bleeders. Postoperatively, severe-to-massive bleeders had higher rates of PGD grade 3 at 72 h, longer hospital stays, higher mortality rates at 30 days and one year, and were less likely to achieve textbook outcomes for LT. They also required postoperative ECMO, reintubation for over 48 h, tracheostomy, reintervention, and dialysis at higher rates. In the multivariate analysis, severe-to-massive bleeding was significantly associated with adverse outcomes after adjusting for recipient and donor factors, with an odds ratio of 7.73 (95% CI: 4.27–14.4, p < 0.001) for PGD3 at 72 h, 4.30 (95% CI: 2.30–8.12, p < 0.001) for 1-year mortality, and 1.75 (95% CI: 1.52–2.01, p < 0.001) for longer hospital stays. Additionally, severe-to-massive bleeders were less likely to achieve textbook outcomes, with an odds ratio of 0.07 (95% CI: 0.02–0.16, p < 0.001). Preoperative and intraoperative predictors of severe/massive bleeding were identified, with White patients having lower odds compared to Black patients (OR: 041, 95% CI: 0.22–0.80, p = 0.008). Each 1-unit increase in BMI decreased the odds of bleeding (OR: 0.89, 95% CI: 0.83–0.95, p < 0.001), while each 1-unit increase in MPAP increased the odds of bleeding (OR: 1.04, 95% CI: 1.02–1.06, p < 0.001). First-time transplant recipients had lower risk (OR: 0.16, 95% CI: 0.06–0.36, p < 0.001), whereas those with DCD donors had a higher risk of severe-to-massive bleeding (OR: 3.09, 95% CI: 1.63–5.87, p = 0.001). Conclusion: These results suggest that patients at high risk of massive bleeding require higher utilization of hospital resources. Understanding their outcomes is important, as it may inform future decisions to transplant comparable patients. [ABSTRACT FROM AUTHOR]

Severe primary graft dysfunction (PGD) is a major cause of early mortality after heart transplant, but the impact of donor organ preservation conditions on severity of PGD and survival has not been well characterized. Data from US adult heart-transplant recipients in the Global Utilization and Registry Database for Improved Heart Preservation-Heart Registry (NCT04141605) were analyzed to quantify PGD severity, mortality, and associated risk factors. The independent contributions of organ preservation method (traditional ice storage vs controlled hypothermic preservation) and ischemic time were analyzed using propensity matching and logistic regression. Among 1,061 US adult heart transplants performed between October 2015 and December 2022, controlled hypothermic preservation was associated with a significant reduction in the incidence of severe PGD compared to ice (6.6% [37/559] vs 10.4% [47/452], p = 0.039). Following propensity matching, severe PGD was reduced by 50% (6.0% [17/281] vs 12.1% [34/281], respectively; p = 0.018). The Kaplan-Meier terminal probability of 1-year mortality was 4.2% for recipients without PGD, 7.2% for mild or moderate PGD, and 32.1%, for severe PGD (p < 0.001). The probability of severe PGD increased for both cohorts with longer ischemic time, but donor hearts stored on ice were more likely to develop severe PGD at all ischemic times compared to controlled hypothermic preservation. Severe PGD is the deadliest complication of heart transplantation and is associated with a 7.8-fold increase in probability of 1-year mortality. Controlled hypothermic preservation significantly attenuates the risk of severe PGD and is a simple yet highly effective tool for mitigating post-transplant morbidity. [ABSTRACT FROM AUTHOR]

Objective To explore the establishment of a prognostic model based on machine learning algorithm to predict primary graft dysfunction (PGD) in patients with idiopathic pulmonary fibrosis (IPF) after lung transplantation. Methods Clinical data of 226 IPF patients who underwent lung transplantation were retrospectively analyzed. All patients were randomly divided into the training and test sets at a ratio of 7:3. Using regularized logistic regression, random forest, support vector machine and artificial neural network, the prognostic model was established through variable screening, model establishment and model optimization. The performance of this prognostic model was assessed by the area under the receiver operating characteristic curve (AUC), positive predictive value, negative predictive value and accuracy. Results Sixteen key features were selected for model establishment. The AUC of the four prognostic models all exceeded 0.7. DeLong and McNemar tests found no significant difference in the performance among different models (both P>0.05) Conclusions Based on four machine learning algorithms, the prognostic model for grade 3 PGD after lung transplantation is preliminarily established. The overall prediction performance of each model is similar, which may predict the risk of grade 3 PGD in IPF patients after lung transplantation. [ABSTRACT FROM AUTHOR]

Lung transplantation (LT) constitutes the last therapeutic option for selected patients with end-stage respiratory disease. Primary graft dysfunction (PGD) is a form of severe lung injury, occurring in the first 72 h following LT and constitutes the most common cause of early death after LT. The presence of pulmonary hypertension (PH) has been reported to favor PGD development, with a negative impact on patients' outcomes while complicating medical management. Although several studies have suggested a potential association between pre-LT left ventricular diastolic dysfunction (LVDD) and PGD occurrence, the underlying mechanisms of such an association remain elusive. Importantly, the heterogeneity of the study protocols and the various inclusion criteria used to define the diastolic dysfunction in those patients prevents solid conclusions from being drawn. In this review, we aim at summarizing PGD mechanisms, risk factors, and diagnostic criteria, with a further focus on the interplay between LVDD and PGD development. Finally, we explore the predictive value of several diastolic dysfunction diagnostic parameters to predict PGD occurrence and severity. [ABSTRACT FROM AUTHOR]

Static ice storage has long been the standard-of-care for lung preservation, although freezing injury limits ischemic time (IT). Controlled hypothermic storage (CHS) at elevated temperature could safely extend IT. This retrospective analysis assesses feasibility and safety of CHS with IT > 15 hours. Three lung transplant (LuTx) centers (April-October 2023) included demographics, storage details, IT, and short-term outcome from 13 LuTx recipients (8 male, 59 years old). Donor lungs were preserved in a portable CHS device at 7 (5-9.3)°C. Indication was overnight bridging and/or long-distance transport. IT of second-implanted lung was 17.3 (15.1-22) hours. LuTx were successful, 4/13 exhibited primary graft dysfunction grade 3 within 72 hours and 0/13 at 72 hours. Post-LuTx mechanical ventilation was 29 (7-442) hours. Intensive care unit stay was 9 (5-28) and hospital stay 30 (16-90) days. Four patients needed postoperative extracorporeal membrane oxygenation (ECMO). One patient died (day 7) following malpositioning of an ECMO cannula. This multicenter experience demonstrates the possibility of safely extending IT > 15 hours by CHS. [ABSTRACT FROM AUTHOR]