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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

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.

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]

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

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 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.

Abstract Background Prior studies have assessed the impact of the pretransplantation recipient body mass index (BMI) on patient outcomes after lung transplantation (LT), but they have not specifically addressed early postoperative complications. Moreover, the impact of donor BMI on these complications has not been evaluated. The first aim of this study was to assess complications during hospitalization in the ICU after LT according to donor and recipient pretransplantation BMI. Methods All the recipients who underwent LT at Bichat Claude Bernard Hospital, Paris, between January 2016 and August 2022 were included in this observational retrospective monocentric study. Postoperative complications were analyzed according to recipient and donor BMIs. Univariate and multivariate analyses were also performed. The 90-day and one-year survival rates were studied. P

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. [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]

Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT. This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability. A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4–80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5–95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48–0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31–4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13–2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02–1.41) were associated with an increased risk of severe PGD. Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices. [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) remains a challenge for lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for more detailed monitoring and understanding of the pathophysiology of PGD. The measurement of particle flow rate (PFR) in exhaled breath is a novel tool to monitor and understand the disease at the proteomic level. In total, 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on postoperative day 3. Exhaled breath particles (EBPs) were evaluated by mass spectrometry and the proteome was compared to tissue biopsies and bronchoalveolar lavage fluid (BALF). Findings were confirmed in EBPs from 11 human transplant recipients. Recipients with PGD had significantly higher PFR [686.4 (449.7–8,824.0) particles per minute (ppm)] compared to recipients without PGD [116.6 (79.7–307.4) ppm, p = 0.0005]. Porcine and human EBP proteins recapitulated proteins found in the BAL, demonstrating its utility instead of more invasive techniques. Furthermore, adherens and tight junction proteins were underexpressed in PGD tissue. Histological and proteomic analysis found significant changes to the alveolar-capillary barrier explaining the high PFR in PGD. Exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD. [ABSTRACT FROM AUTHOR]

Cardiac metabolism is altered in heart failure and ischemia-reperfusion injury states. We hypothesized that metabolomic profiling during ex situ normothermic perfusion before heart transplantation (HT) would lend insight into myocardial substrate utilization and report on subclinical and clinical allograft dysfunction risk. Metabolomic profiling was performed on serial samples of ex situ normothermic perfusate assaying biomarkers of myocardial injury in lactate and cardiac troponin I (TnI) as well as metabolites (66 acylcarnitines, 15 amino acids, nonesterified fatty acids [NEFA], ketones, and 3-hydroxybutyrate). We tested for change over time in injury biomarkers and metabolites, along with differential changes by recovery strategy (donation after circulatory death [DCD] vs donation after brain death [DBD]). We examined associations between metabolites, injury biomarkers, and primary graft dysfunction (PGD). Analyses were performed using linear mixed models adjusted for recovery strategy, assay batch, donor-predicted heart mass, and time. A total of 176 samples from 92 ex situ perfusion runs were taken from donors with a mean age of 35 (standard deviation 11.3) years and a median total ex situ perfusion time of 234 (interquartile range 84) minutes. Lactate trends over time differed significantly by recovery strategy, while TnI increased during ex situ perfusion regardless of DCD vs DBD status. We found fuel substrates were rapidly depleted during ex situ perfusion, most notably the branched-chain amino acids leucine/isoleucine, as well as ketones, 3-hydroxybutyrate, and NEFA (least squares [LS] mean difference from the first to last time point −1.7 to −4.5, false discovery rate q < 0.001). Several long-chain acylcarnitines (LCAC), including C16, C18, C18:1, C18:2, C18:3, C20:3, and C20:4, increased during the perfusion run (LS mean difference 0.42-0.67, q < 0.001). Many LCACs were strongly associated with lactate and TnI. The change over time of many LCACs was significantly different for DCD vs DBD, suggesting differential trends in fuel substrate utilization by ischemic injury pattern. Changes in leucine/isoleucine, arginine, C12:1-OH/C10:1-DC, and C16-OH/C14-DC were associated with increased odds of moderate-severe PGD. Neither end-of-run nor change in lactate or TnI was associated with PGD. Metabolomic profiling of ex situ normothermic perfusion solution reveals a pattern of fuel substrate utilization that correlates with subclinical and clinical allograft dysfunction. This study highlights a potential role for interventions focused on fuel substrate modification in allograft conditioning during ex situ perfusion to improve allograft outcomes. [ABSTRACT FROM AUTHOR]

Trends in high-sensitivity cardiac troponin I (hs-cTnI) after lung transplant (LT) and its clinical value are not well stablished. This study aimed to determine kinetics of hs-cTnI after LT, factors impacting hs-cTnI and clinical outcomes. LT recipients from 2015 to 2017 at Toronto General Hospital were included. Hs-cTnI levels were collected at 0-24 h, 24-48 h and 48-72 h after LT. The primary outcome was invasive mechanical ventilation (IMV) >3 days. 206 patients received a LT (median age 58, 35.4% women; 79.6% double LT). All patients but one fulfilled the criteria for postoperative myocardial infarction (median peak hs-cTnI = 4,820 ng/mL). Peak hs-cTnI correlated with right ventricular dysfunction, >1 red blood cell transfusions, bilateral LT, use of EVLP, kidney function at admission and time on CPB or VA-ECMO. IMV>3 days occurred in 91 (44.2%) patients, and peak hs-cTnI was higher in these patients (3,823 vs. 6,429 ng/mL, p < 0.001 after adjustment). Peak hs-cTnI was higher among patients with had atrial arrhythmias or died during admission. No patients underwent revascularization. In summary, peak hs-TnI is determined by recipient comorbidities and perioperative factors, and not by coronary artery disease. Hs-cTnI captures patients at higher risk for prolonged IMV, atrial arrhythmias and in-hospital death. [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) remains a challenge for lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for more detailed monitoring and understanding of the pathophysiology of PGD. The measurement of particle flow rate (PFR) in exhaled breath is a novel tool to monitor and understand the disease at the proteomic level. In total, 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on postoperative day 3. Exhaled breath particles (EBPs) were evaluated by mass spectrometry and the proteome was compared to tissue biopsies and bronchoalveolar lavage fluid (BALF). Findings were confirmed in EBPs from 11 human transplant recipients. Recipients with PGD had significantly higher PFR [686.4 (449.7-8,824.0) particles per minute (ppm)] compared to recipients without PGD [116.6 (79.7-307.4) ppm, p = 0.0005]. Porcine and human EBP proteins recapitulated proteins found in the BAL, demonstrating its utility instead of more invasive techniques. Furthermore, adherens and tight junction proteins were underexpressed in PGD tissue. Histological and proteomic analysis found significant changes to the alveolar-capillary barrier explaining the high PFR in PGD. Exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) secondary to lung disease (Group-3 PH) is the second leading cause of PH. The role of PH as a risk factor for primary graft dysfunction (PGD) following lung transplant (LT) is controversial. To assess the impact that the new definition of PH had on the prevalence of PH in patients with advanced lung disease—candidate for LT, and its association with the occurrence of PGD. A retrospective study was performed in all patients undergoing cardiac catheterisation referred for consideration as candidates to LT in a centre between 1 January 2017 and 31 December 2022. The baseline and haemodynamic characteristics of patients were analysed, along with the occurrence of PGD and post-transplant course in those who ultimately underwent transplantation. A total of 396 patients were included. Based on the new 2022 European Society of Cardiology/European Respiratory Society definitions, as many as 70.7% of patients met PH criteria. Since the introduction of the 2022 definition, a significant reduction was observed in the frequency of severe Group-3 PH (41.1% vs 10.3%; p<0.001), with respect to the 2015 definition. As many as 236 patients underwent transplantation. None of the variables associated with PH was identified as a risk factor for PGD. The new classification did not have any impact on the prevalence of PGD after transplantation. These results exclude that any significant differences exist in the baseline characteristics or post-transplant course of patients with Group-3 PH vs unclassified PH. [ABSTRACT FROM AUTHOR]

The prevalence of end-stage heart failure and patients who could benefit from heart transplantation requires an expansion of the donor pool, relying on the transplant community to continually re-evaluate and expand the use of extended criteria donor organs. Introduction of new technologies such as the Paragonix SherpaPak Cardiac Transport System aids in this shift. We seek to analyze the impact of the SherpaPak system on recipient outcomes who receive extended criteria organs in the GUARDIAN-Heart Registry. Between October 2015 and December 2022, 1,113 adults from 15 US centers receiving donor hearts utilizing either SherpaPak (n = 560) or conventional ice storage (ice, n = 453) were analyzed from the GUARDIAN-Heart Registry using summary statistics. A previously published set of criteria was used to identify extended criteria donors, which included 193 SherpaPak and 137 ice. There were a few baseline differences among recipients in the 2 cohorts; most notably, IMPACT scores, distance traveled, and total ischemic time were significantly greater in SherpaPak, and significantly more donor hearts in the SherpaPak cohort had >4 hours total ischemia time. Posttransplant mechanical circulatory support utilization (SherpaPak 22.3% vs ice 35.0%, p = 0.012) and new extracorporeal membrane oxygenation/ventricular assist device (SherpaPak 7.8% vs ice 15.3%, p = 0.033) was significantly reduced, and the rate of severe primary graft dysfunction (SherpaPak 6.2% vs ice 13.9%, p = 0.022) was significantly reduced by over 50% in hearts preserved using SherpaPak. One-year survival between cohorts was similar (SherpaPak 92.9% vs ice 89.6%, p = 0.27). This subgroup analysis demonstrates that SherpaPak can be safely used to utilize extended criteria donors with low severe PGD rates. [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials. [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) is a known risk factor for early mortality following lung transplant (LT). However, the outcomes of patients who achieve long-term survival following index hospitalization are unknown. We aimed to determine the long-term association of PGD grade 3 (PGD3) in patients without in-hospital mortality. LT recipients were identified from the United Network for Organ Sharing Database. Patients were stratified based on the grade of PGD at 72 h (No PGD, Grade 1/2 or Grade 3). Groups were assessed with comparative statistics. Long-term survival was evaluated using Kaplan–Meier methods and a multivariable shared frailty model including recipient, donor, and transplant characteristics. The PGD3 group had significantly increased length of stay, dialysis, and treated rejection post-transplant (P < 0.001). Unadjusted survival analysis revealed a significant difference in long-term survival (P < 0.001) between groups; however, following adjustment, PGD3 was not independently associated with long-term survival (hazard ratio: 0.972; 95% confidence interval: 0.862-1.096). Increased mortality was significantly associated with increased recipient age and treated rejection. Decreased mortality was significantly associated with no donor diabetes, bilateral LT as compared to single LT, transplant in 2015-2016 and 2017-2018, and no post-transplant dialysis. While PGD3 remains a challenge post LT, PGD3 at 72 h is not independently associated with decreased long-term survival, while complications such as dialysis and rejection are, in patients who survive index hospitalization. Transplant providers should be aggressive in preventing further complications in recipients with severe PGD to minimize the negative association on long-term survival. [ABSTRACT FROM AUTHOR]

Background: Prior studies have assessed the impact of the pretransplantation recipient body mass index (BMI) on patient outcomes after lung transplantation (LT), but they have not specifically addressed early postoperative complications. Moreover, the impact of donor BMI on these complications has not been evaluated. The first aim of this study was to assess complications during hospitalization in the ICU after LT according to donor and recipient pretransplantation BMI. Methods: All the recipients who underwent LT at Bichat Claude Bernard Hospital, Paris, between January 2016 and August 2022 were included in this observational retrospective monocentric study. Postoperative complications were analyzed according to recipient and donor BMIs. Univariate and multivariate analyses were also performed. The 90-day and one-year survival rates were studied. P < 0.05 was considered to indicate statistical significance. The Paris-North Hospitals Institutional Review Board approved the study. Results: A total of 304 recipients were analyzed. Being underweight was observed in 41 (13%) recipients, a normal weight in 130 (43%) recipients, and being overweight/obese in 133 (44%) recipients. ECMO support during surgery was significantly more common in the overweight/obese group (p = 0.021), as were respiratory complications (primary graft dysfunction (PGD) (p = 0.006), grade 3 PDG (p = 0.018), neuroblocking agent administration (p = 0.008), prone positioning (p = 0.007)), and KDIGO 3 acute kidney injury (p = 0.036). However, pretransplantation overweight/obese status was not an independent risk factor for 90-day mortality. An overweight or obese donor was associated with a decreased PaO2/FiO2 ratio before organ donation (p < 0.001), without affecting morbidity or mortality after LT. Conclusion: Pretransplantation overweight/obesity in recipients is strongly associated with respiratory and renal complications during hospitalization in the ICU after LT. [ABSTRACT FROM AUTHOR]

Higher body mass index (BMI) increases the risk of developing primary graft dysfunction (PGD) after lung transplantation; whether BMI is associated with decreased survival after PGD is unknown. We utilized the Lung Transplant Outcomes Group cohort of 1,538 subjects from 2011-2018. We evaluated the association between preoperative BMI and graft survival among subjects with severe PGD using Cox proportional hazards models with linear splines. Models were stratified by center and adjusted for sex, age, Lung Allocation Score, and diagnosis. PGD developed in 383 subjects. Among subjects with PGD, low BMI was associated with increased mortality while high BMI was not associated with differential mortality, compared to normal BMI. Results were similar for 90-day and 1-year survival. While high BMI increases the risk of developing PGD, it does not appear to be associated with survival after PGD. Future work should focus on PGD prevention rather than PGD management in patients with obesity.

Patients with severe pulmonary arterial hypertension undergoing lung transplant are at risk of developing left ventricular dysfunction (LVD). We present a case of severe LVD following transplant to highlight the challenges in diagnosis and suggest measures to reduce the risk of cardiogenic shock and end-organ injury.

Jiameng Gao,1,2,&ast; Zhiyuan Zhang,1,2,&ast; Jing Yu,1,2,&ast; Nan Zhang,1,2 Yu Fu,1,2 Xuemei Jiang,1,2 Zheyu Xia,3 Qingqing Zhang,1,2 Zongmei Wen1,2 1Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Lung Transplantation, Shanghai, People’s Republic of China; 3School of Medicine, Tongji University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zongmei Wen; Qingqing Zhang, Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 507 Zhengmin Road, Shanghai, 200433, People’s Republic of China, Tel +86 13761635280 ; +86 13764542055, Email wzm1103@126.com; elfe666@163.comPurpose: Ischemia reperfusion injury (IRI) unavoidably occurs during lung transplantation, further contributing to primary graft dysfunction (PGD). Neutrophils are the end effectors of IRI and activated neutrophils release neutrophil extracellular traps (NETs) to further amplify damage. Nevertheless, potential contributions of NETs in IRI remain incompletely understood. This study aimed to explore NET-related gene biomarkers in IRI during lung transplantation.Methods: Differential expression analysis was applied to identify differentially expressed genes (DEGs) for IRI during lung transplantation based on matrix data (GSE145989, 127003) downloaded from GEO database. The CIBERSORT and weighted gene co-expression network analysis (WGCNA) algorithms were utilized to identify key modules associated with neutrophil infiltration. Moreover, the least absolute shrinkage and selection operator regression and random forest were applied to identify potential NET-associated hub genes. Subsequently, the screened hub genes underwent further validation of an external dataset (GSE18995) and nomogram model. Based on clinical peripheral blood samples, immunofluorescence staining and dsDNA quantification were used to assess NET formation, and ELISA was applied to validate the expression of hub genes.Results: Thirty-eight genes resulted from the intersection between 586 DEGs and 75 brown module genes, primarily enriched in leukocyte migration and NETs formation. Subsequently, four candidate hub genes (FCAR, MMP9, PADI4, and S100A12) were screened out via machine learning algorithms. Validation using an external dataset and nomogram model achieved better predictive value. Substantial NETs formation was demonstrated in IRI, with more pronounced NETs observed in patients with PGD ≥ 2. PADI4, S100A12, and MMP9 were all confirmed to be up-regulated after reperfusion through ELISA, with higher levels of S100A12 in PGD ≥ 2 patients compared with non-PGD patients.Conclusion: We identified three potential NET-related biomarkers for IRI that provide new insights into early detection and potential therapeutic targets of IRI and PGD after lung transplantation.Keywords: ischemia reperfusion injury, neutrophil extracellular traps, lung transplantation, primary graft dysfunction, WGCNA, machine learning

Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.

BackgroundWe sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation.MethodsPatients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders.ResultsA total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p = .0002), median LAS (38.0-47.7 p = .009) and the use of ECMO salvage for PGD (5.7%-20.9%, p = .007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p = .0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p = .66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p = .0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]).ConclusionsPGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.

Rationale: Plasma cell-free DNA levels correlate with disease severity in many conditions. Pretransplant cell-free DNA may risk stratify lung transplant candidates for post-transplant complications. Objectives: To evaluate if pretransplant cell-free DNA levels and tissue sources identify patients at high risk of primary graft dysfunction and other pre- and post-transplant outcomes. Methods: This multicenter, prospective cohort study recruited 186 lung transplant candidates. Pretransplant plasma samples were collected to measure cell-free DNA. Bisulfite sequencing was performed to identify the tissue sources of cell-free DNA. Multivariable regression models determined the association between cell-free DNA levels and the primary outcome of primary graft dysfunction and other transplant outcomes, including Lung Allocation Score, chronic lung allograft dysfunction, and death. Measurements and Main Results: Transplant candidates had twofold greater cell-free DNA levels than healthy control patients (median [interquartile range], 23.7 ng/ml [15.1–35.6] vs. 12.9 ng/ml [9.9–18.4]; P < 0.0001), primarily originating from inflammatory innate immune cells. Cell-free DNA levels and tissue sources differed by native lung disease category and correlated with the Lung Allocation Score (P < 0.001). High pretransplant cell-free DNA increased the risk of primary graft dysfunction (odds ratio, 1.60; 95% confidence interval [CI], 1.09–2.46; P = 0.0220), and death (hazard ratio, 1.43; 95% CI, 1.07–1.92; P = 0.0171) but not chronic lung allograft dysfunction (hazard ratio, 1.37; 95% CI, 0.97–1.94; P = 0.0767). Conclusions: Lung transplant candidates demonstrate a heightened degree of tissue injury with elevated cell-free DNA, primarily originating from innate immune cells. Pretransplant plasma cell-free DNA levels predict post-transplant complications. [ABSTRACT FROM AUTHOR]

Cold static storage preservation of donor hearts for periods longer than 4 hours increases the risk of primary graft dysfunction (PGD). The aim of the study was to determine if hypothermic oxygenated perfusion (HOPE) could safely prolong the preservation time of donor hearts. We conducted a nonrandomized, single arm, multicenter investigation of the effect of HOPE using the XVIVO Heart Preservation System on donor hearts with a projected preservation time of 6 to 8 hours on 30-day recipient survival and allograft function post-transplant. Each center completed 1 or 2 short preservation time followed by long preservation time cases. PGD was classified as occurring in the first 24 hours after transplantation or secondary graft dysfunction (SGD) occurring at any time with a clearly defined cause. Trial survival was compared with a comparator group based on data from the International Society of Heart and Lung Transplantation (ISHLT) Registry. We performed heart transplants using 7 short and 29 long preservation time donor hearts placed on the HOPE system. The mean preservation time for the long preservation time cases was 414 minutes, the longest being 8 hours and 47 minutes. There was 100% survival at 30 days. One long preservation time recipient developed PGD, and 1 developed SGD. One short preservation time patient developed SGD. Thirty day survival was superior to the ISHLT comparator group despite substantially longer preservation times in the trial patients. HOPE provides effective preservation out to preservation times of nearly 9 hours allowing retrieval from remote geographic locations. [ABSTRACT FROM AUTHOR]

Assessment and selection of donor lungs remain largely subjective and experience based. Criteria to accept or decline lungs are poorly standardized and are not compliant with the current donor pool. Using ex vivo computed tomography (CT) images, we investigated the use of a CT-based machine learning algorithm for screening donor lungs before transplantation. Clinical measures and ex situ CT scans were collected from 100 cases as part of a prospective clinical trial. Following procurement, donor lungs were inflated, placed on ice according to routine clinical practice, and imaged using a clinical CT scanner before transplantation while stored in the icebox. We trained and tested a supervised machine learning method called dictionary learning , which uses CT scans and learns specific image patterns and features pertaining to each class for a classification task. The results were evaluated with donor and recipient clinical measures. Of the 100 lung pairs donated, 70 were considered acceptable for transplantation (based on standard clinical assessment) before CT screening and were consequently implanted. The remaining 30 pairs were screened but not transplanted. Our machine learning algorithm was able to detect pulmonary abnormalities on the CT scans. Among the patients who received donor lungs, our algorithm identified recipients who had extended stays in the intensive care unit and were at 19 times higher risk of developing chronic lung allograft dysfunction within 2 years posttransplant. We have created a strategy to ex vivo screen donor lungs using a CT-based machine learning algorithm. As the use of suboptimal donor lungs rises, it is important to have in place objective techniques that will assist physicians in accurately screening donor lungs to identify recipients most at risk of posttransplant complications. [ABSTRACT FROM AUTHOR]

Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). We sought to determine the association between pretransplant human leukocyte antigen (HLA) sensitization, as measured using the calculated panel reactive antibody (cPRA) value, and the risk of PGD. Consecutive adult HT recipients (n = 596) from 1/2015 to 12/2019 at 2 US centers were included. Severity of PGD was based on the 2014 International Society for Heart and Lung Transplantation consensus statement. For each recipient, unacceptable HLA antigens were obtained and locus-specific cPRA (cPRA-LS) and pre-HT donor-specific antibodies (DSA) were assessed. Univariable logistic modeling showed that peak cPRA-LS for all loci and HLA-A was associated with increased severity of PGD as an ordinal variable (all loci: OR 1.78, 95% CI: 1.01-1.14, p = 0.025, HLA-A: OR 1.14, 95% CI: 1.03-1.26, p = 0.011). Multivariable analysis showed peak cPRA-LS for HLA-A, recipient beta-blocker use, total ischemic time, donor age, prior cardiac surgery, and United Network for Organ Sharing status 1 or 2 were associated with increased severity of PGD. The presence of DSA to HLA-B was associated with trend toward increased risk of mild-to-moderate PGD (OR 2.56, 95% CI: 0.99-6.63, p = 0.053), but DSA to other HLA loci was not associated with PGD. Sensitization for all HLA loci, and specifically HLA-A, is associated with an increased severity of PGD. These factors should be included in pre-HT risk stratification to minimize the risk of PGD. [ABSTRACT FROM AUTHOR]

Objective To analyze the correlation between the lung allocation score (LAS) and the risk of early death and complications in patients with idiopathic pulmonary fibrosis (IPF) after lung transplantation. Methods Clinical data of 275 patients with IPF were retrospectively analyzed. The correlation between LAS and the risk of early death in IPF patients after lung transplantation and the correlation between LAS and complications at postoperative 1 year was assessed by univariate and multivariate Cox regression analyses. Results Among 275 recipients, 62, 83, 95 and 108 cases died within postoperative 30, 90, 180 and 365 d, respectively. LAS was correlated with 30-, 90-, 180- and 365-d fatality of IPF patients (all P<0.05), whereas it was not correlated with the incidence of primary graft dysfunction (PGD) and acute kidney injury (AKI) at 365 d after lung transplantation (both P>0.05). Conclusions LAS is correlated with the risk of early death of IPF patients after lung transplantation. While, it is not correlated the incidence of PGD and AKI early after lung transplantation. Special attention should be paid to the effect of comprehensive factors upon PGD and AKI. [ABSTRACT FROM AUTHOR]

Primary Graft Dysfunction (PGD) is a major cause of both short-term and longterm morbidity and mortality following lung transplantation. Various donor, recipient, and technical risk factors have been previously identified as being associated with the development of PGD. Here, we present a comprehensive review of the current literature as it pertains to PGD following lung transplantation, as well as discussing current strategies to mitigate PGD and future directions. We will pay special attention to recent advances in lung transplantation such as ex-vivo lung perfusion, thoracoabdominal normothermic regional perfusion, and up-to-date literature published in the interim since the 2016 ISHLT consensus statement on PGD and the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

No proven treatment after the development of primary graft dysfunction (PGD) is currently available. Here, we established a novel strategy of in vivo lung perfusion (IVLP) for the treatment of PGD. IVLP involves the application of an in vivo isolated perfusion circuit to an implanted lung. This study aimed to explore the effectiveness of IVLP vs conventional post-lung transplant (LTx) extracorporeal membrane oxygenation (ECMO) treatment using an experimental swine LTx PGD model. After 1.5-hour warm ischemia of the donor lungs, a left LTx was performed. Following the confirmation of PGD development, pigs were divided into 3 groups (n = 5 each): control (no intervention), ECMO, and IVLP. After 2 hours of treatment, a 4-hour functional assessment was conducted, and samples were obtained. Significantly better oxygenation was achieved in the IVLP group (p ≤ 0.001). Recovery was confirmed immediately and maintained during the following 4-hour observation. The IVLP group also demonstrated better lung compliance than the control group (p = 0.045). A histologic evaluation showed that the lung injury score and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed significantly fewer injuries and a better result in the wet-to-dry weight ratio in the IVLP group. A 2-hour IVLP is technically feasible and allows for prompt recovery from PGD after LTx. The posttransplant short-duration IVLP strategy can complement or overcome the limitations of the current practice for donor assessment and PGD management. [ABSTRACT FROM AUTHOR]

Background: End-stage heart failure (ESHF) leads to hypoperfusion and edema formation throughout the body and is accompanied by neurohormonal and immunological alterations. Orthotopic heart transplantation (HTX) has been used as a beneficial option for ESHF. Due to the shortage of donor hearts, the ideal matching and timing of donors and recipients has become more important. Purpose: In this study, our aim was to explore the relationship between the clinical outcomes of HTX and the cytokine and apolipoprotein profiles of the recipient pericardial fluid obtained at heart transplantation after opening the pericardial sac. Materials and methods: The clinical data and the interleukin, adipokine, and lipoprotein levels in the pericardial fluid of twenty HTX recipients were investigated. Outcome variables included primer graft dysfunction (PGD), the need for post-transplantation mechanical cardiac support (MCS), International Society for Heart and Lung Transplantation grade ≥2R rejection, and mortality. Recipient risk scores were also investigated. Results: Leptin levels were significantly lower in patients with PGD than in those without PGD (median: 6.36 (IQR: 5.55–6.62) versus 7.54 (IQR = 6.71–10.44); p = 0.029). Higher ApoCII levels (median: 14.91 (IQR: 11.55–21.30) versus 10.31 (IQR = 10.02–13.07); p = 0.042) and ApoCIII levels (median: 60.32 (IQR: 43.00–81.66) versus 22.84 (IQR = 15.84–33.39); p = 0.005) were found in patients (n = 5) who died in the first 5 years after HTX. In patients who exhibited rejection (n = 4) in the first month after transplantation, the levels of adiponectin (median: 74.48 (IQR: 35.51–131.70) versus 29.96 (IQR: 19.86–42.28); p = 0.039), ApoCII (median: 20.11 (IQR: 13.06–23.54) versus 10.32 (IQR: 10.02–12.84); p = 0.007), and ApoCIII (median: 70.97 (IQR: 34.72–82.22) versus 26.33 (IQR: 17.18–40.17); p = 0.029) were higher than in the nonrejection group. Moreover, the pericardial thyroxine (T4) levels (median: 3.96 (IQR: 3.49–4.46) versus 4.69 (IQR: 4.23–5.77); p = 0.022) were lower in patients with rejection than in patients who did not develop rejection. Conclusion: Our results indicate that apolipoproteins can facilitate the monitoring of rejection and could be a useful tool in the forecasting of early and late complications. [ABSTRACT FROM AUTHOR]

IntroductionCompared with traditional static ice storage, controlled hypothermic storage (CHS) at 4–10°C may attenuate cold-induced lung injury between procurement and implantation. In this study, we describe the first European lung transplant (LTx) experience with a portable CHS device.MethodsA prospective observational study was conducted of all consecutively performed LTx following CHS (11 November 2022 and 31 January 2024) at two European high-volume centers. The LUNGguard device was used for CHS. The preservation details, total ischemic time, and early postoperative outcomes are described. The data are presented as median (range: minimum–maximum) values.ResultsA total of 36 patients underwent LTx (i.e., 33 bilateral, 2 single LTx, and 1 lobar). The median age was 61 (15–68) years; 58% of the patients were male; 28% of the transplantations had high-urgency status; and 22% were indicated as donation after circulatory death. In 47% of the patients, extracorporeal membrane oxygenation (ECMO) was used for perioperative support. The indications for using the CHS device were overnight bridging (n = 26), remote procurement (n = 4), rescue allocation (n = 2), logistics (n = 2), feasibility (n = 1), and extended-criteria donor (n = 1). The CHS temperature was 6.5°C (3.7°C–9.3°C). The preservation times were 11 h 18 (2 h 42–17 h 9) and 13 h 40 (4 h 5–19 h 36) for the first and second implanted lungs, respectively, whereas the total ischemic times were 13 h 38 (4 h 51–19 h 44) and 15 h 41 (5 h 54–22 h 48), respectively. The primary graft dysfunction grade 3 (PGD3) incidence rates were 33.3% within 72 h and 2.8% at 72 h. Intensive care unit stay was 8 (4–62) days, and the hospital stay was 28 (13–87) days. At the last follow-up [139 (7–446) days], three patients were still hospitalized. One patient died on postoperative day 7 due to ECMO failure. In-hospital Clavien–Dindo complications of 3b were observed in six (17%) patients, and 4a in seven (19%).ConclusionCHS seems safe and feasible despite the high-risk recipient and donor profiles, as well as extended preservation times. PGD3 at 72 h was observed in 2.8% of the patients. This technology could postpone LTx to daytime working hours. Larger cohorts and longer-term outcomes are required to confirm these observations.

Background: Donation after circulatory death with thoracoabdominal normothermic regional perfusion (DCD-NRP) for cardiac transplant has promising results, though data for lung transplant is lacking. This study evaluates lung transplant outcomes using DCD-NRP allografts. Methods: All patients who underwent lung transplantation (LT) from June 1, 2020, to July 5, 2023, at a single institution were evaluated. Recipients received organs from DCD-NRP or brain dead (control) donors (donation after brain death (DBD)). All DCD-NRP were adult, primary bilateral LT (BLT) without preoperative extracorporeal membrane oxygenation (ECMO). Inclusion criteria for controls were age >18 years, BLT, no preoperative ECMO, and primary transplantation. Comparison was separated by LT or heart-lung transplant (HLT). The primary outcome was primary graft dysfunction (PGD) grade 3 at 72 hours. Results: There were 8 LT and 3 HLT in the DCD-NRP cohort, and 138 BLT and 7 HL DBD controls. PGD grade 3 at 72 hours was 0% in the entire DCD-NRP cohort (vs control: 9.4% LT and 0% HLT). There were no statistically significant differences in donor and recipient characteristics, though DCD-NRP HLT had significantly shorter ischemic time (85 vs 200 minutes, p

Background: Extracorporeal membrane oxygenation (ECMO) has been frequently used instead of cardiopulmonary bypass (CPB) as extracorporeal circulatory support during cadaveric lung transplantation. This study compared the outcomes of intraoperative CPB or ECMO in living-donor lobar lung transplantation (LDLLT). Methods: CPB and ECMO were performed in 23 and 53 patients, respectively, who underwent initial bilateral LDLLT in our institution from 2008 to 2019. We retrospectively compared the short- and long-term outcomes between the 2 groups. Results: Patient background, graft size-matching data, operation time, extracorporeal circulation time, and bleeding amount were not significantly different in the 2 groups. However, the CPB group required more transfusion than the ECMO group (6,860 vs 3,840 ml, respectively; p = 0.002). The rate of increase in body weight through LDLLT was 7.4% and 4.9% in CPB and ECMO groups, respectively (p = 0.040), and primary graft dysfunction scores were significantly worse in the CPB group. Postoperative ECMO support was required in 4 cases, and hospital death occurred in 1 patient exclusively in the CPB group. Chronic lung allograft dysfunction (CLAD) was diagnosed in 43.5% and 17.0% of patients in the CPB and ECMO groups, respectively (p = 0.021), and the 5-year CLAD-free survival was 55.8% and 72.7% of patients, respectively (p = 0.013). Conclusions: Intraoperative ECMO reduced primary graft dysfunction, possibly due to the lower requirement for intraoperative transfusion and less intraoperative weight gain causing systemic edema. The beneficial effect of ECMO in the early phase may result in less CLAD development in the long-term follow-up after LDLLT.

Background: There remains significant variability in the use of intraoperative mechanical circulatory support in lung transplantation. This report details our outcomes using elective cardiopulmonary bypass (CPB) in lung transplantation. Methods: We performed a single institution analysis of consecutively enrolled patients who underwent isolated lung transplantation between August 2020 and April 2023. Primary outcomes included rates of grade 3 primary graft dysfunction (PGD) and 1-year survival. Results: Forty consecutive lung transplants were performed on CBP over the study period. The average PaO2/FiO2 at 72 hours was 369.7 ± 121.4, with grade 3 PGD occurring in 2 patients (5%). The median intraoperative packed red blood cell transfusion requirement was 300 (93.75-727.5) ml. Freedom from nonelective reoperation was 82.5% (n = 33). Mortality was 0% at 90 days, and 1-year survival was 90.5%. Conclusions: Lung transplantation can be safely performed with elective CPB support.

Trends in high-sensitivity cardiac troponin I (hs-cTnI) after lung transplant (LT) and its clinical value are not well stablished. This study aimed to determine kinetics of hs-cTnI after LT, factors impacting hs-cTnI and clinical outcomes. LT recipients from 2015 to 2017 at Toronto General Hospital were included. Hs-cTnI levels were collected at 0–24 h, 24–48 h and 48–72 h after LT. The primary outcome was invasive mechanical ventilation (IMV) >3 days. 206 patients received a LT (median age 58, 35.4% women; 79.6% double LT). All patients but one fulfilled the criteria for postoperative myocardial infarction (median peak hs-cTnI = 4,820 ng/mL). Peak hs-cTnI correlated with right ventricular dysfunction, >1 red blood cell transfusions, bilateral LT, use of EVLP, kidney function at admission and time on CPB or VA-ECMO. IMV>3 days occurred in 91 (44.2%) patients, and peak hs-cTnI was higher in these patients (3,823 vs. 6,429 ng/mL, p < 0.001 after adjustment). Peak hs-cTnI was higher among patients with had atrial arrhythmias or died during admission. No patients underwent revascularization. In summary, peak hs-TnI is determined by recipient comorbidities and perioperative factors, and not by coronary artery disease. Hs-cTnI captures patients at higher risk for prolonged IMV, atrial arrhythmias and in-hospital death.

Primary graft dysfunction (PGD) remains a challenge for lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for more detailed monitoring and understanding of the pathophysiology of PGD. The measurement of particle flow rate (PFR) in exhaled breath is a novel tool to monitor and understand the disease at the proteomic level. In total, 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on postoperative day 3. Exhaled breath particles (EBPs) were evaluated by mass spectrometry and the proteome was compared to tissue biopsies and bronchoalveolar lavage fluid (BALF). Findings were confirmed in EBPs from 11 human transplant recipients. Recipients with PGD had significantly higher PFR [686.4 (449.7–8,824.0) particles per minute (ppm)] compared to recipients without PGD [116.6 (79.7–307.4) ppm, p = 0.0005]. Porcine and human EBP proteins recapitulated proteins found in the BAL, demonstrating its utility instead of more invasive techniques. Furthermore, adherens and tight junction proteins were underexpressed in PGD tissue. Histological and proteomic analysis found significant changes to the alveolar-capillary barrier explaining the high PFR in PGD. Exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD.