The Predictive Value of Graft Viability and Bioenergetics Testing Towards the Outcome in Liver Transplantation.

Donor organ biomarkers with sufficient predictive value in liver transplantation (LT) are lacking. We herein evaluate liver viability and mitochondrial bioenergetics for their predictive capacity towards the outcome in LT. We enrolled 43 consecutive patients undergoing LT. Liver biopsy samples taken upon arrival after static cold storage were assessed by histology, real-time confocal imaging analysis (RTCA), and high-resolution respirometry (HRR) for mitochondrial respiration of tissue homogenates. Early allograft dysfunction (EAD) served as primary endpoint. HRR data were analysed with a focus on the efficacy of ATP production or P-L control efficiency, calculated as 1-L/P from the capacity of oxidative phosphorylation P and non-phosphorylating respiration L. Twenty-two recipients experienced EAD. Pre-transplant histology was not predictive of EAD. The mean RTCA score was significantly lower in the EAD cohort (-0.75 ± 2.27) compared to the IF cohort (0.70 ± 2.08; p = 0.01), indicating decreased cell viability. P-L control efficiency was predictive of EAD (0.76 ± 0.06 in IF vs. 0.70 ± 0.08 in EAD-livers; p = 0.02) and correlated with the RTCA score. Both RTCA and P-L control efficiency in biopsy samples taken during cold storage have predictive capacity towards the outcome in LT. Therefore, RTCA and HRR should be considered for risk stratification, viability assessment, and bioenergetic testing in liver transplantation.

Computed Tomography Volumetrics for Size Matching in Lung Transplantation for Restrictive Disease.

BACKGROUND: There is no consensus on the optimal allograft sizing strategy for lung transplantation in restrictive lung disease. Current methods that are based on predicted total lung capacity (pTLC) ratios do not account for the diminutive recipient chest size. The study investigators hypothesized that a new sizing ratio incorporating preoperative recipient computed tomographic lung volumes (CTVol) would be associated with postoperative outcomes. METHODS: A retrospective single-institution study was conducted of adults undergoing primary bilateral lung transplantation between January 2016 and July 2020 for restrictive lung disease. CTVol was computed for recipients by using advanced segmentation software. Two sizing ratios were calculated: pTLC ratio (pTLCdonor/pTLCrecipient) and a new volumetric ratio (pTLCdonor/CTVolrecipient). Patients were divided into reference, oversized, and undersized groups on the basis of ratio quintiles, and multivariable models were used to assess the effect of the ratios on primary graft dysfunction and survival. RESULTS: CTVol was successfully acquired in 218 of 220 (99.1%) patients. In adjusted analysis, undersizing on the basis of the volumetric ratio was independently associated with decreased primary graft dysfunction grade 2 or 3 within 72 hours (odds ratio, 0.42; 95% CI, 0.20-0.87; P =.02). The pTLC ratio was not significantly associated with primary graft dysfunction. Oversizing on the basis of the volumetric ratio was independently associated with an increased risk of death (hazard ratio, 2.27; 95% CI, 1.04-4.99; P =.04], whereas the pTLC ratio did not have a significant survival association. CONCLUSIONS: Using computed tomography-acquired lung volumes for donor-recipient size matching in lung transplantation is feasible with advanced segmentation software. This method may be more predictive of outcome compared with current sizing methods, which use gender and height only.

Temporal correlation between postreperfusion complement deposition and severe primary graft dysfunction in lung allografts.

Growing evidence implicates complement in the pathogenesis of primary graft dysfunction (PGD). We hypothesized that early complement activation postreperfusion could predispose to severe PGD grade 3 (PGD-3) at 72 hours, which is associated with worst posttransplant outcomes. Consecutive lung transplant patients (n = 253) from January 2018 through June 2023 underwent timed open allograft biopsies at the end of cold ischemia (internal control) and 30 minutes postreperfusion. PGD-3 at 72 hours occurred in 14% (35/253) of patients; 17% (44/253) revealed positive C4d staining on postreperfusion allograft biopsy, and no biopsy-related complications were encountered. Significantly more patients with PGD-3 at 72 hours had positive C4d staining at 30 minutes postreperfusion compared with those without (51% vs 12%, P < .001). Conversely, patients with positive C4d staining were significantly more likely to develop PGD-3 at 72 hours (41% vs 8%, P < .001) and experienced worse long-term outcomes. In multivariate logistic regression, positive C4d staining remained highly predictive of PGD-3 (odds ratio 7.92, 95% confidence interval 2.97-21.1, P < .001). Hence, early complement deposition in allografts is highly predictive of PGD-3 at 72 hours. Our data support future studies to evaluate the role of complement inhibition in patients with early postreperfusion complement activation to mitigate PGD and improve transplant outcomes.

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Restrictive allograft dysfunction rather than bronchiolitis obliterans syndrome had a major impact on the overall survival after living-donor lobar lung transplantation.

PURPOSE: Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). METHODS: We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. RESULTS: Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). CONCLUSIONS: CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restriction on PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT.

Effect of antifibrotic agents on postoperative complications after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Antifibrotic agents (AFAs) are now standard-of-care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx). METHODS: We performed a multi-centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri-operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post-operative complications and the survival of patients according to AFA exposure. RESULTS: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6-24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90-day mortality was lower (7% vs. 18%, p = 0.046). CONCLUSIONS: AFA therapy did not increase airway, bleeding or wound post-operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90-day mortality.

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

In vivo lung perfusion for prompt recovery from primary graft dysfunction after lung transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

HLA sensitization is associated with an increased risk of primary graft dysfunction after heart transplantation.

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Transcriptomic Landscape of Circulating Extracellular Vesicles in Heart Transplant Ischemia-Reperfusion.

Ischemia-reperfusion injury (IRI) is an inevitable event during heart transplantation, which is known to exacerbate damage to the allograft. However, the precise mechanisms underlying IRI remain incompletely understood. Here, we profiled the whole transcriptome of plasma extracellular vesicles (EVs) by RNA sequencing from 41 heart transplant recipients immediately before and at 12 h after transplant reperfusion. We found that the expression of 1317 protein-coding genes in plasma EVs was changed at 12 h after reperfusion. Upregulated genes of plasma EVs were related to metabolism and immune activation, while downregulated genes were related to cell survival and extracellular matrix organization. In addition, we performed correlation analyses between EV transcriptome and intensity of graft IRI (i.e., cardiomyocyte injury), as well as EV transcriptome and primary graft dysfunction, as well as any biopsy-proven acute rejection after heart transplantation. We ultimately revealed that at 12 h after reperfusion, 4 plasma EV genes (ITPKA, DDIT4L, CD19, and CYP4A11) correlated with both cardiomyocyte injury and primary graft dysfunction, suggesting that EVs are sensitive indicators of reperfusion injury reflecting lipid metabolism-induced stress and imbalance in calcium homeostasis. In conclusion, we show that profiling plasma EV gene expression may enlighten the mechanisms of heart transplant IRI.

Outcomes of lung transplantation for chronic obstructive pulmonary disease.

Introduction: Chronic obstructive pulmonary disease is a progressive airway disease that can progress to the terminal stage requiring oxygen supply. In this period, lung volume reduction therapies and/or lung transplantation may be considered. Morbidity and mortality risks due to transplant surgery and posttransplant immunosuppressive therapy show the importance of selecting the best candidates who will benefit from transplantation. In this context, BODE index criteria serve as important markers. This study aimed to analyze the outcomes of lung transplantation in patients with chronic obstructive pulmonary disease and to identify variables that may affect post-transplant clinical outcomes. Materials and Methods: Lung transplants diagnosed with chronic obstructive pulmonary disease performed in our center between March 2013 and January 2023 were included in the study. Demographic information and both pre-op and post-op clinical data of the transplant patients were collected. The effect of BODE index criteria and other pre-transplant clinical data on short- and long-term outcomes after transplantation were investigated. Results: During the study period, 34 lung transplants were performed for chronic obstructive pulmonary disease. One patient died during the operation, three patients received single transplants, and 30 received double transplants. Post-operative primary graft dysfunction was more common in single transplant recipients. The results were comparable between single and double transplants in terms of post-transplant pulmonary function and the development of chronic lung allograft dysfunction. BODE index criteria had no effect on early and late post-operative clinical data, however intra-operative use of extracorporeal membrane oxygenation, primary graft dysfunction, and prolonged extubation were significantly higher in recipients younger than 60 years. Conclusion: Our study suggests that prelisting demographic and clinical data of chronic obstructive pulmonary disease patients had no significant effect on post-operative outcomes, however, intra-operative ECMO use, prolonged extubation, primary graft dysfunction (p< 0.05 for each) and chronic rejection (p> 0.05) were more common in patients who are <60 years of age. These data need to be confirmed by larger studies.

Hemodynamic failure and graft dysfunction after lung transplant: A possible clinical continuum with immediate and long-term consequences.

INTRODUCTION: The postoperative hemodynamic management after lung transplant (LUTX) is guided by limited evidence. We aimed to describe and evaluate risk factors and outcomes of postoperative vasoactive support of LUTX recipients. METHODS: In a single-center retrospective analysis of consecutive adult LUTX, two cohorts were identified: (1) patients needing prolonged vasoactive support (>12 h from ICU admission) (VASO+); (2) or not (VASO-). Postoperative hemodynamic characteristics were thoroughly analyzed. Risk factors and outcomes of VASO+ versus VASO- cohorts were assessed by multivariate logistic regression and propensity score matching. RESULTS: One hundred and thirty-eight patients were included (86 (62%) VASO+ versus 52 (38%) VASO-). Vasopressors (epinephrine, norepinephrine, dopamine) were used in the first postoperative days (vasoactive inotropic score at 12 h: 6 [4-12]), while inodilators (dobutamine, levosimendan) later. Length of vasoactive support was 3 [2-4] days. Independent predictors of vasoactive use were: LUTX indication different from cystic fibrosis (p = .003), higher Oto score (p = .020), longer cold ischemia time (p = .031), but not preoperative cardiac catheterization. VASO+ patients showed concomitant hemodynamic and graft impairment, with longer mechanical ventilation (p = .010), higher primary graft dysfunction (PGD) grade at 72 h (PGD grade > 0 65% vs. 31%, p = .004, OR 4.2 [1.54-11.2]), longer ICU (p < .001) and hospital stay (p = .013). Levosimendan as a second-line inodilator appeared safe. CONCLUSIONS: Vasoactive support is frequently necessary after LUTX, especially in recipients of grafts of lesser quality. Postoperative hemodynamic dysfunction requiring vasopressor support and graft dysfunction may represent a clinical continuum with immediate and long-term consequences. Further studies may elucidate if this represents a possible treatable condition.

Cardiac Transplantation: Physiology and Natural History of the Transplanted Heart.

Heart transplantation (HT) is one of the prodigious achievements in modern medicine and remains the cornerstone in the treatment of patients with advanced heart failure. Advances in surgical techniques, immunosuppression, organ preservation, infection control, and allograft surveillance have improved short- and long-term outcomes thereby contributing to greater clinical success of HT. However, prolonged allograft and patient survival following HT are still largely restricted by the development of late complications, including allograft rejection, infection, cardiac allograft vasculopathy (CAV), and malignancy. The introduction of mTOR inhibitors early after HT has demonstrated multiple protective effects against CAV progression, renal dysfunction, and tumorigenesis. Therefore, several HT programs increasingly use mTOR inhibitors with partial or complete withdrawal of calcineurin inhibitor (CNI) in stable HT patients to reduce complications risk and improve long-term outcomes. Furthermore, despite a substantial improvement in exercise capacity and health-related quality of life after HT as compared to advanced heart failure patients, most HT recipients remain with a 30% to 50% lower peak oxygen consumption (Vo 2 ) than that of age-matched healthy subjects. Several factors, including alterations in central hemodynamics, HT-related complications and alterations in the musculoskeletal system, and peripheral physiological abnormalities, presumably contribute to the reduced exercise capacity following HT. Cardiac denervation and subsequent loss of sympathetic and parasympathetic regulation are responsible for various physiological alterations in the cardiovascular system, which contributes to restricted exercise tolerance. Restoration of cardiac innervation may improve exercise capacity and quality of life, but the reinnervation process is only partial even several years after HT. Multiple studies have shown that aerobic and strengthening exercise interventions improve exercise capacity by increasing maximal heart rate, chronotropic response, and peak Vo 2 after HT. Novel exercise modalities, such as high-intensity interval training (HIT), have been proven as safe and effective for further improvement in exercise capacity, including among de novo HT recipients. Further developments have recently emerged, including donor heart preservation techniques, noninvasive CAV and rejection surveillance methods, and improvements in immunosuppressive therapies, all aiming at increasing donor availability and improving late survival after HT. © 2023 American Physiological Society. Compr Physiol 13:4719-4765, 2023.

Impact of total ischaemic time and disease severity class on graft function after bilateral lung transplantation.

OBJECTIVES: Total ischaemic time (IT) is considered a limiting factor in lung transplantation. In this retrospective study, we investigate effects of IT and disease burden on outcomes after bilateral lung transplantation. METHODS: A total of 1298 patients undergoing bilateral lung transplantation between January 2010 and May 2022 (follow-up 100%, median 54 months) were included. Pre-transplant diseases' severity (recipient body mass index, recipient age, previous lung transplantation, Tacrolimus immunosuppression, preoperative recipient extracorporeal membrane oxygenation support, lung volume reduction) for graft failure was individually calculated and-as IT-categorized. Vice versa adjusted Cox models were calculated. Considering competing risks, we assessed cumulative incidences of airway obstructive complications and chronic lung allograft dysfunction with death as competing risk factors for primary graft dysfunction were assessed by binary logistic regression. RESULTS: Higher disease burden significantly accelerated chronic lung allograft dysfunction and death occurrence (P < 0.001); IT did not. IT-adjusted disease burden strata showed 50% graft survival differences at 11 years after transplantation (range 24-74%), disease burden-adjusted IT strata 18% for all and 6% (54-60%) among those above 7 h. All significant primary graft dysfunction risk factors were diagnoses related, IT was not significantly important and odds ratios did not increase with IT. CONCLUSIONS: The eventual graft survival disadvantage that results from an IT between 7 and at least 11 h is negligible in contrast to frequent recipients' disease-based risk levels.

Development and validation of a nomogram model to predict primary graft dysfunction in patients after lung transplantation based on the clinical factors.

BACKGROUND: Primary graft dysfunction (PGD), a significant complication that can affect patients' prognosis and quality of life, develops within 72 h post lung transplantation (LTx). Early detection and prevention of PGD should be given special consideration. The purpose of this study was to create a clinical prediction model to forecast the occurrence of PGD. METHODS: We collected information on 622 LTx patients from Wuxi People's Hospital from 2016 to 2020 and used the data to construct the prediction model. Information on 224 patients from 2021 to June 2022 was used for external validation. We used LASSO regression for variable screening. A nomogram was developed for model presentation. Distinctness, fit, and calibration were used to evaluate the performance of the model. RESULTS: Subjects with respiratory failure, who received fresh frozen plasma, donor age, donor gender, donor mechanism of death, donor smoking, donor ventilator use time, and donor PaO 2/FiO 2 ratio were independent predictor variables for the occurrence of PGD. The area under the curve of the nomogram was .779. The Hosmer-Lemeshow test showed a good model fit (P = .158). The calibration curve of the nomogram is fairly close to the ideal diagonal. Moreover, the decision curve analysis revealed a positive net benefit of the model. External validation also confirmed the reliability of the model. CONCLUSIONS: The nomogram of PGD based on clinical risk factors in postoperative LTx patients was established with high reliability. It provides clinicians and nurses with a new and effective tool for early prediction of PGD and early intervention.

Effect of targeted coagulopathy management and 5% albumin as volume replacement therapy during lung transplantation on allograft function: a secondary analysis of a randomized clinical trial.

BACKGROUND: Primary graft dysfunction (PGD) after lung transplantation (LuTx) contributes substantially to early postoperative morbidity. Both intraoperative transfusion of a large amount of blood products during the surgery and ischemia-reperfusion injury after allograft implantation play an important role in subsequent PGD development. METHODS: We have previously reported a randomized clinical trial of 67 patients where point of care (POC) targeted coagulopathy management and intraoperative administration of 5% albumin led to significant reduction of blood loss and blood product consumption during the lung transplantation surgery. A secondary analysis of the randomized clinical trial evaluating the effect of targeted coagulopathy management and intraoperative administration of 5% albumin on early lung allograft function after LuTx and 1-year survival was performed. RESULTS: Compared to the patients in the control (non-POC) group, those in study (POC) group showed significantly superior graft function, represented by the Horowitz index (at 72 h after transplantation 402.87 vs 308.03 with p < 0.001, difference between means: 94.84, 95% CI: 60.18-129.51). Furthermore, the maximum doses of norepinephrine administered during first 24 h were significantly lower in the POC group (0.193 vs 0.379 with p < 0.001, difference between the means: 0.186, 95% CI: 0.105-0.267). After dichotomization of PGD (0-1 vs 2-3), significant difference between the non-POC and POC group occurred only at time point 72, when PGD grade 2-3 developed in 25% (n = 9) and 3.2% (n = 1), respectively (p = 0.003). The difference in 1-year survival was not statistically significant (10 patients died in non-POC group vs. 4 patients died in POC group; p = 0.17). CONCLUSIONS: Utilization of a POC targeted coagulopathy management combined with Albumin 5% as primary resuscitative fluid may improve early lung allograft function, provide better circulatory stability during the early post-operative period, and have potential to decrease the incidence of PGD without negative effect on 1-year survival. TRIAL REGISTRATION: This clinical trial was registered at ClinicalTrials.gov (NCT03598907).

Effect of donor smoking and substance use on post-lung transplant outcomes.

OBJECTIVE: The study objective was to determine effects of donor smoking and substance use on primary graft dysfunction, allograft function, and survival after lung transplant. METHODS: From January 2007 to February 2020, 1366 lung transplants from 1291 donors were performed in 1352 recipients at Cleveland Clinic. Donor smoking and substance use history were extracted from the Uniform Donor Risk Assessment Interview and medical records. End points were post-transplant primary graft dysfunction, longitudinal forced expiratory volume in 1 second (% of predicted), and survival. RESULTS: Among lung transplant recipients, 670 (49%) received an organ from a donor smoker, 163 (25%) received an organ from a donor with a 20 pack-year or more history (median pack-years 8), and 702 received an organ from a donor with substance use (51%). There was no association of donor smoking, pack-years, or substance use with primary graft dysfunction (P > .2). Post-transplant forced expiratory volume in 1 second was 74% at 1 year in donor nonsmoker recipients and 70% in donor smoker recipients (P = .0002), confined to double-lung transplant, where forced expiratory volume in 1 second was 77% in donor nonsmoker recipients and 73% in donor smoker recipients. Donor substance use was not associated with allograft function. Donor smoking was associated with 54% non-risk-adjusted 5-year survival versus 59% (P = .09) and greater pack-years with slightly worse risk-adjusted long-term survival (P = .01). Donor substance use was not associated with any outcome (P ≥ 8). CONCLUSIONS: Among well-selected organs, lungs from smokers were associated with non-clinically important worse allograft outcomes without an inflection point for donor smoking pack-years. Substance use was not associated with worse allograft function. Given the paucity of organs, donor smoking or substance use alone should not preclude assessment for lung donation or transplant.

Intraoperative Red Blood Cell Transfusion and Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: In this international, multicenter study of patients undergoing lung transplantation (LT), we explored the association between the amount of intraoperative packed red blood cell (PRBC) transfusion and occurrence of primary graft dysfunction (PGD) and associated outcomes. METHODS: The Extracorporeal Life Support in LT Registry includes data on LT recipients from 9 high-volume (>40 transplants/y) transplant centers (2 from Europe, 7 from the United States). Adult patients who underwent bilateral orthotopic lung transplant from January 2016 to January 2020 were included. The primary outcome of interest was the occurrence of grade 3 PGD in the first 72 h after LT. RESULTS: We included 729 patients who underwent bilateral orthotopic lung transplant between January 2016 and November 2020. LT recipient population tertiles based on the amount of intraoperative PRBC transfusion (0, 1-4, and >4 units) were significantly different in terms of diagnosis, age, gender, body mass index, mean pulmonary artery pressure, lung allocation score, hemoglobin, prior chest surgery, preoperative hospitalization, and extracorporeal membrane oxygenation requirement. Inverse probability treatment weighting logistic regression showed that intraoperative PRBC transfusion of >4 units was significantly ( P < 0.001) associated with grade 3 PGD within 72 h (odds ratio [95% confidence interval], 2.2 [1.6-3.1]). Inverse probability treatment weighting analysis excluding patients with extracorporeal membrane oxygenation support produced similar findings (odds ratio [95% confidence interval], 2.4 [1.7-3.4], P < 0.001). CONCLUSIONS: In this multicenter, international registry study of LT patients, intraoperative transfusion of >4 units of PRBCs was associated with an increased risk of grade 3 PGD within 72 h. Efforts to improve post-LT outcomes should include perioperative blood conservation measures.