Risk Of Primary Graft Dysfunction Research Articles

High Pre-Donation Vasoactive Inotropic Score (VIS) May Be Associated with Increased Risk of Primary Graft Dysfunction in Cardiac Transplantation

Purpose Primary Graft Dysfunction (PGD) is one of the primary causes of 30 day mortality after heart transplantation. Optimal donor management is crucial to ensure effective organ procurement and favourable transplant outcomes. The prognostic impact of pre-donation inotropes use on PGD remains controversial, and its implication on organ preservation strategy and acceptance decision remains unclear. The purpose of this study is to investigate the relationship between donor heart inotrope dose and the incidence of PGD defined using the standard definition of PGD from the ISHLT consensus statement, and 30 day mortality post heart transplant. Methods Retrospective study of all patients who underwent isolated cardiac transplantation in a single centre between January 2017 and December 2019. Donor data was obtained de-identified from the Australian and New Zealand Cardiothoracic Organ transplant registry and electronic donor records (EDR). Inotropes were pooled into a vasoactive inotropic score (VIS). The primary outcome was a composite of PGD and 30 day mortality. Results There were 43 heart transplants and 40 were included for analysis. One patient was excluded as they underwent combined cardiac and kidney transplant, and there was incomplete donor data for 2 patients. 7 out of 40 patients (17.5%) developed primary graft dysfunction, and 4 patients (10%) died within 30 days of transplant. The primary composite endpoint occurred in 10 (25%) patients. Of the 7 patients that developed PGD, 1 died within 30 days. Patients were stratified into two groups according to their VIS (High versus Low). Multivariate logistic regression demonstrated that patients in the High VIS group (VIS> 26) had a higher incidence of the primary composite outcome occurring in 40% of patients when compared to the Low VIS group (VIS Conclusion Our single centre retrospective study demonstrated an increase risk of PGD and 30 day mortality associated with pre-donation high dose inotropes use. This preliminary finding suggests the potential utility of VIS to quantify pre-donation inotropes use and may inform donor organ management and acceptance decisions.

Inhaled Selective Pulmonary Vasodilators for Adult Lung Transplantation

<h3>Purpose</h3> Inhaled pulmonary vasodilators (iPVD) are commonly used in lung transplant recipients to mitigate the risk of primary graft dysfunction (PGD). While inhaled nitric oxide (iNO) is the gold standard for iPVD therapy, inhaled epoprostenol (Veletri®) has been introduced as a cost-conscious iNO-alternative without high-grade evidence. Thus, we conducted a clinical trial to primarily determine if inhaled epoprostenol is equivalent to iNO in the ability to modify grade 3 PGD after orthotopic lung transplantation. <h3>Methods</h3> Our group has enrolled 200 lung transplant recipients in a triple-blinded (clinician, patient, statistician) randomized controlled trial conducted between June 2017-October 2020 (NCT03081052). Participants were first grouped into strata according to key clinical, prognostic features (Fig.1). Within each stratum, patients were assigned to receive either iNO or inhaled epoprostenol via 1:1 randomization. For our primary outcome analysis, to assess equivalency between the two treatment groups, we will calculate absolute and relative risk estimates and corresponding confidence intervals (CI). If the CI do not contain the margin of difference (15%), then we will conclude there is sufficient evidence that the risk of the primary outcome in each treatment group is similar. For each secondary outcome, we will construct univariable effect estimates and corresponding CI, which will allow for assessment of difference between treatment groups. In the case that patients have switched to the other treatment arm, we will perform the intent-to-treat (ITT) analysis without reclassifying treatment assignment. To verify ITT results, we will perform a per-protocol analysis. <h3>Endpoints</h3> Primary. PGD-3 as defined by ISHLT 2016 criteria and an adjudicated PGD score at 72-hours after surgery. Secondary. Duration of postoperative mechanical ventilation, iPVD duration and cost, ICU and hospital lengths-of-stay, postoperative acute kidney Injury, and early postoperative mortality (in-hospital, 30-days, 90-days).

High Donor Inotrope Requirements are Associated with Significantly Diminished Post-Transplant Outcomes

<h3>Purpose</h3> Primary graft dysfunction (PGD) is a potentially fatal complication following heart transplantation and careful donor selection is key to reducing its incidence. This study investigated whether high-dose inotropic requirements in donors predicts short-term post-transplant survival and allograft function. <h3>Methods</h3> A retrospective review of the United Network for Organ Sharing database assessed the impact of donor inotropy on post-transplant outcomes. Univariate and adjusted multivariable regression first evaluated the impact of inotropy at a global scale on a combined primary outcome of primary graft dysfunction (PGD), mortality or re-transplant at 90 days. Inotropy was then further stratified by high- and low-dose support. Definition of high-dose was >10 mcg/kg/min for dopamine, >0.5 mcg/kg/min for epinephrine and >19 mcg/kg/min for dobutamine. Regression analyses were again performed to assess the impact of inotropic dose on post-transplant outcomes. <h3>Results</h3> 6230 donors required inotropic support (890 high-dose and 5,340 low-dose). Inotropy at a global scale was not predictive of poor outcomes. After stratifying by degree of support, high-dose inotropic support conferred worse outcomes relative to low-dose support (HR 1.34, p=0.03). Adjusted multivariable regression again demonstrated high-dose inotropy as independently predictive of worse outcomes (HR 1.43, p=0.02). <h3>Conclusion</h3> High-dose inotropic donor support is predictive of poor graft function and mortality following heart transplantation. Caution should be taken when considering these organs, particularly in patients already at risk for PGD.

High Immunologic Risk Lung Transplantation Using Risk Stratified Induction

<h3>Purpose</h3> Donor specific antibodies (DSA) are associated with antibody-mediated rejection, chronic lung allograft dysfunction (CLAD) and increased mortality, making lung transplant in the presence of DSA high risk. Our center transplants these patients using risk-stratified induction. We sought was to assess survival and time to CLAD onset in these patients compared to low risk recipients. <h3>Methods</h3> We reviewed lung transplant recipients transplanted from January 2010 to December 2017. Recipients were assigned to three risk categories: low [no DSA, negative crossmatch (XM)], moderate [positive DSA, negative XM] and high [positive DSA, positive XM]. Patients with DSA were treated with anti-thymocyte globulin and intravenous immune globulin, with five cycles of pheresis for positive XM. Low risk patients received basiliximab. We used Cox regression to test the association between risk category and time to death or retransplant as well as time to CLAD onset, and logistic regression to test the relationship between risk category and severe primary graft dysfunction (PGD). <h3>Results</h3> 313 patients met inclusion criteria and 76 died during follow up. 256 (81%) were low risk, 27 (9%) moderate and 30 (10%) high. Patients with pre-transplant DSA were younger and more likely to be bridged to transplant. There was no effect of risk status on survival either unadjusted (Figure 1, p=0.83) or adjusted for age, diagnosis, bridging status and transplant type (p=0.65). There was no relationship to time to CLAD onset (p=0.61). Patients with DSA were at increased risk of severe PGD, both unadjusted (p=0.002) and adjusted for age, diagnosis and bridging status (p=0.01), mainly high vs. low risk (adjusted odds ratio 0.29, [95% CI 0.12-0.70]). <h3>Conclusion</h3> Using a risk stratified induction strategy, DSA at time of transplant was not associated with increased risk of death or CLAD onset in lung transplant recipients, suggesting this is a safe way to improve access for sensitized recipients. The novel PGD association warrants further investigation.

Donor Substance Abuse is Not Associated with Late High-Grade Primary Graft Dysfunction (PGD) in Lung Transplant

<h3>Purpose</h3> The donor pool for lung transplantation (LT) may be expanded by procuring from donors with substance abuse (SA) history. Scant data exists on the early course of recipients of these lungs. We assessed the association between donor SA and perioperative outcomes. <h3>Methods</h3> We reviewed LTs at our center from Jan. 2014-Jan. 2019 and donor data from the United Network for Organ Sharing. SA was defined as reported use of illicit substances (cannabis, cocaine, amphetamines, opioids)/tobacco 1+ times/month or positive post-mortem screen, or consumption of 2+ alcoholic drinks/day. The primary outcome was late high-grade PGD due to its risk for chronic lung allograft dysfunction (CLAD). Late high-grade PGD was defined as PGD 2-3 at 48-72 hours. Secondary outcomes were ventilator hours (VH), initial intensive care unit (ICU) hours, initial hospital length of stay (LOS), 30-day mortality, and first year FEV1% predicted trends. <h3>Results</h3> 350 LT patients were included in this study. 198/350 (57%) patients received SA donor lungs, while 152/350 (43%) patients received non-SA donor lungs. 82/198 (42%) in the SA donor group developed late high-grade PGD vs. 61/152 (42%) in the non-SA donor group. On multivariable logistic regression (Figure 1), late high-grade PGD was not associated with donor SA (OR 1.11, 95% CI 0.67-1.85, p=0.687). Bivariate comparison found no association between donor SA and VH, ICU hours, and LOS. 30-day survival was 98.99% (n=196) in the SA donor group vs. 98.68% (n=150) in the non-SA donor group. The log rank test detected no difference in 30-day survival between the groups (p=0.789). An estimating equation model and analysis found no evidence that donor SA had an effect on FEV1% predicted over time (p=0.907). <h3>Conclusion</h3> Donor SA does not impact risk for late high-grade PGD, perioperative outcomes, 30-day survival, or first-year FEV1% predicted. Lungs from donors with history of SA may be considered for use in transplant to help reduce waitlist mortality.

Predicting PGD after Lung Transplantation

<h3>Purpose</h3> Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies highlight the role of donor smoking in poor post-transplant outcomes. We therefore aimed to identify clinical risk factors for PGD after lung transplantation, more accurately assess the impact of donor smoking, and develop an accurate, generalizable PGD prediction model. <h3>Methods</h3> We performed a 10-center prospective cohort study of patients in the Lung Transplant Outcomes Group from 2012-2018. PGD was defined as grade 3 PGD at 48 or 72 hours after lung reperfusion. We defined donor smoking history by clinical documentation, UNOS-reported donor smoking, or donor cotinine >9 mg/ml from urine collected at organ procurement. Building on our prior PGD prediction models, multivariable logistic regression was used to identify PGD risk factors and develop regularized predictive models with a simple user interface (R shiny). <h3>Results</h3> Of 1180 patients, 26% developed PGD and 633 (53%) received an organ from a previously smoking donor. The PGD predictive model included novel predictors of center and donor distance plus recipient age, lung allocation score (LAS), body mass index, pulmonary artery pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor distance; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The predictive model offers decision making benefit in the PGD risk range of 0.15-0.5. Donor smoking was associated with increased risk of PGD but not patient mortality (Figure 1). <h3>Conclusion</h3> We developed a clinically applicable PGD predictive algorithm based on modern lung transplant practices to aid in transplant decision making, post-transplant care, and to facilitate development of enriched PGD treatment trials. Donor smoking is a risk factor for PGD development but is not associated with increased mortality, potentially because of a lower risk phenotype of PGD occurring in smoking donor recipients.

Donor Neutrophils and B Cells in EVLP Perfusate are Associated with Severe Primary Graft Dysfunction

<h3>Purpose</h3> Primary graft dysfunction (PGD) remains a major obstacle to lung transplantation (LT) success and is classified as severe (PGD3) in 10-15% of all LT recipients. Ex vivo lung perfusion (EVLP) allows for evaluation of donor lungs prior to LT and measurement of circulating cells and soluble factors in the perfusate. The contributions of donor cells to PGD are unknown, and whether specific cells might confer a risk of PGD is unclear. We hypothesized that larger quantities of donor myeloid cells in EVLP perfusate might predict PGD3. <h3>Methods</h3> In this retrospective study, we selected consecutive clinical EVLP cases and grouped them based on Pa_O2/F_IO2 (P/F) ratio at 72h post-LT, resulting in two groups: PGD3 (n = 33, P/F = 183 ± 48mmHg) and PGD0/1 (n = 25, P/F = 395 ± 71mmHg). Cryopreserved perfusate cells from the first and last hour of EVLP were subjected to multiparameter flow cytometry to identify major leukocyte populations. Time and PGD-dependent differences were assessed by two-way ANOVA with post-hoc testing adjusted for multiple comparisons. <h3>Results</h3> In the first hour of EVLP, the total cells/mL was higher in the PGD3 group compared to PGD0/1 (12.1 × 10⁵ versus 8.4 × 10⁵ cells/ml, p = 0.0573) - the cell/ml decreased in both groups to similar densities by the end of EVLP (Fig A). In the PGD3 group, neutrophils (Fig B) and B cells (Fig C) were significantly higher than in the PGD0/1 group in the first hour and significantly decreased over time. Macrophages (Fig D) and classical monocytes (Fig E) were also elevated in PGD3 group in the first hour, although this observation did not reach statistical significance. <h3>Conclusion</h3> Neutrophils and B cells in the 1-hour perfusate are associated with PGD3 development at 72h post-LT. While these findings suggest that higher numbers of these donor cells may play a role in PGD pathogenesis, PGD3 developed even though these populations were reduced by the end of EVLP. Studies of cellular activation states will be conducted to validate these findings and explore donor cellular contributions to PGD.

Utility of Total Cardiac and Right Ventricular Mass Ratios in Recipients with Pulmonary Hypertension: A UNOS Database Analysis

<h3>Purpose</h3> Cardiac mass ratio (CMR) is validated for donor-recipient sizing, and as a predictor of transplant outcomes. However, there is a lack of data reviewing the role CMR plays in transplant recipients with pulmonary hypertension (pHTN). In particular, the right ventricular (RV) mass ratio (RVMR) is a component of CMR not yet studied separately for this purpose. We aimed to review the relationship of CMR and RVMR with pHTN in terms of development of primary graft dysfunction (PGD) and overall survival. <h3>Methods</h3> The United Network for Organ Sharing (UNOS) database was queried for primary heart transplant patients from 1987 to 2020. Missing data was imputed using a Bayesian network. Left ventricular (LV), RV, total cardiac mass (CM), and their ratios were calculated for donors and recipients. Relevant hemodynamic variables were included in logistic regression and cox proportional-hazards models to evaluate a relationship to PGD and overall survival. A stepwise regression created parsimonious models. Covariates with statistically significant relationships to the outcomes were included in tensor product spline models. <h3>Results</h3> 62,169 patients were identified. A parsimonious logistic model for odds of PGD included RVMR (OR 0.99, p<0.001) and mean PAP (mPAP) (OR 1.00, p<0.001). A parsimonious cox model for survival included diastolic PAP (HR 1.01, p<0.001), systolic PAP (HR 1.01, p<0.001), mPAP (HR 0.98, p<0.001), transpulmonary gradient (TPG) (HR 1.01, p<0.001), and CMR (HR 0.76, p<0.001). A tensor product spline model evaluating PGD demonstrated increasing odds of PGD in patients with elevated mPAP and smaller RVMR (Figure, p<0.001). Comparable models evaluating overall survival demonstrated smaller CMR was associated with reduced survival at elevated mPAP (p<0.001) and TPG (p<0.001). <h3>Conclusion</h3> In patients with pHTN, RVMR is significantly associated with odds of developing PGD, and CMR is with overall survival. Some RV oversizing may be beneficial to mitigate the risk of PGD.

Primary heart dysfunction is greater with combined heart and lung compared with isolated heart procurement

ObjectiveCombined heart and lungs (CHL) procurement differs from isolated heart (IH) procurement in several aspects, including lung recruitment, cannulation, and preservation requirements. We aimed to investigate whether CHL versus IH procurement contributes to the development of primary graft dysfunction (PGD) after heart transplantation (HT). MethodsBetween 1999 and 2019, we assessed 175 patients undergoing HT at a single center. Patients were divided into IH (n = 61) or CHL (n = 114) procurement groups. End points included PGD (defined according to the International Society for Heart and Lung Transplantation consensus statement) and long-term survival. ResultsThe incidence of PGD was significantly greater in CHL recipients compared with IH recipients (53.5% vs 16.4%, P < .001). Multivariable analysis showed that CHL procurement was independently associated with a significant 4.6-fold increased risk for PGD (95% confidence interval, 2.1-11, P < .001). Univariable and multivariable analyses showed that the overall survival was not significantly affected by the procurement group (log-rank P = .150, hazard ratio, 1.13; 95% confidence interval, 0.68-1.88, P = .646). The simultaneous procurement of abdominal organs was not associated with an increased risk of PGD in HT recipients. These results remained consistent in a propensity-matched analysis. ConclusionsCombined procurement of heart and lungs is independently associated with an increased risk of PGD. Further prospective studies are needed to validate this hypothesis-generating study.

Risk of primary graft dysfunction following lung transplantation in selected adults with connective tissue disease-associated interstitial lung disease

Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients. We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF. A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008). Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.

Effects of Donor Age and Ischemia Time on Outcome After Heart Transplant: A 10-Year Single-Center Experience.

In heart failure patients, heart transplant still remains the gold standard of care. Controversy prevails whether organs from older donors or with expected prolonged ischemia times may be accepted for transplant. Between 2010 and 2020, a total of 149 patients underwent heart transplant at our department. In a retrospective analysis, 4 different groups were defined according to donor age and total ischemia time. The younger group with short ischemia time consisted of 62 donors age < 50 years and total ischemia time < 240 minutes; the younger group with long ischemia time consisted of 32 donors age < 50 years and total ischemia time ≥ 240 minutes; the older group with short ischemia time consisted of 43 donors age ≥ 50 years and total ischemia time < 240 minutes; and the older group with long ischemia time consisted of 12 donors age ≥ 50 years and total ischemia time ≥ 240 minutes. Prolonged total ischemia time increased the risk of primary graft dysfunction (P = .02) and perioperative neurological events (P = .04). In contrast, there were no differences regarding durations of intensive care unit stay and hospital stay, perioperative bleeding, and renal failure. Although the younger donor age group showed excellent short-term survival (30-day survival rates of 97% for the younger group with short ischemia time and 91% for the younger group with long ischemia time), short-term and mid-term survival rates were impaired in patients with prolonged total ischemia time and older donor age (P = .02). Our results indicate that, in younger donors, prolonged ischemia times may be acceptable. However, in donors older than 50 years, the decision for acceptance as a donor should be made with great caution if the presumed ischemia time exceeds 4 hours.

Abstract 14296: Differential Left and Right Ventricle Response to Cold Storage Followed by Reperfusion in Heart Transplantation

Introduction: In heart transplantation, the supply of donor hearts is contributed by the short tolerable preservation period with risk for primary graft dysfunction. Understanding the differential biological responses to preservation between the left ventricle (LV) and right ventricle (RV) may provide critical insights. Methods: Murine donor hearts were infused with cold HTK solution and stored on ice for 0h, 4h and 8h followed by 90minutes perfusion with Krebs Buffer. The LV and RV were collected at the end of reperfusion for gene expression and protein analysis by RNA-sequencing and western blot. Results: Differential gene expression analysis showed that RV has 1092 upregulated genes and 291 downregulated genes compared to LV after cold storage followed by perfusion. GO analysis show that gene sets related to immune response (padj=7e-27), cell responses to interferon-beta (padj=8.90e-19) were enriched in RV upregulated genes (figure). We also confirmed the upregulation of immune response genes such IL1-β, Myd88 by qPCR and western blot. Moreover, we found that active β-catenin, a potential upstream regulator of IL1- β, also upregulated in RV. Wnt/β-catenin downstream target genes were also enriched in human donor RVs during prolonged preservation. Importantly, donor hearts from murine Myd88-/- showed reduced differences in the transcriptome of the LV vs RV (figure) and demonstrated improved heart function after prolonged cold storage with reperfusion. Conclusions: The RV demonstrates more extensive inflammatory response to storage compared to the LV. Selective upregulation of Wnt/β-catenin signaling in the RV may be important for enhancing this inflammatory response to preservation. Deficiency of MyD88 mediated innate immune signaling improved cardiac contractility after prolonged preservation and likely have important clinical implications for transplantation.

Clinical outcomes associated with computed tomography-based body composition measures in lung transplantation: a systematic review.

Computed tomography (CT) is gaining increased recognition in the assessment of body composition in lung transplant (LTx) candidates as a prognostic marker of post-transplant outcomes. This systematic review was conducted to describe the methodology of CT measures of body composition used in LTx patients and its association with post-transplant outcomes. Six databases were searched (inception-April 2020) for studies of adult LTx patients with thoracic or abdominal CT measures [muscle cross-sectional area (CSA) and/or adiposity]. Thirteen articles were included with 1911 LTx candidates, 58% males, mean age range (48-61years) and body mass index of 21.0-26.1kg/m2 . Several methods were utilized using thoracic or abdominal CT scans to assess skeletal muscle (n=11) and adiposity (n=4) at various anatomic locations (carina, thoracic, and lumbar vertebrae), differing muscle groups, and adipose tissue compartments. Low muscle mass was associated with adverse outcomes in 6/11 studies, including longer mechanical ventilation days (n=2), intensive care (n=2) and hospital stay (n=2), and mortality (n=4). Greater subcutaneous and mediastinal fat were associated with increased risk of primary graft dysfunction (n=2), but implications of adiposity on survival were variable across four studies. Further standardization of CT body composition assessments is needed to assess the prognostic utility of these measures on LTx outcomes.

HIGHER DONOR PAO2/FIO2 RATIO APPEARS TO BE ASSOCIATED WITH INCREASED INCIDENCE OF PRIMARY GRAFT DYSFUNCTION IN LUNG TRANSPLANT RECIPIENTS

SESSION TITLE: Transplantation Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Severe primary graft dysfunction (PGD) is the most common cause of early mortality in lung transplantation and is a significant risk factor for the development of chronic lung allograft dysfunction. Although numerous risk factors for PGD have been identified, little data exists on the impact of donor mechanical ventilation parameters on the incidence of PGD. Given the detrimental effects of hyperoxia on the pulmonary alveolar epithelium and capillary endothelium, we hypothesized that donor hyperoxia may increase the risk of PGD. METHODS: We reviewed 175 lung transplants performed at our institution from 2012 to 2019. The last reported arterial blood gas and ventilator parameters in the UNOS database were collected. Recipient PGD grade was calculated at 48-72 hours post-transplant. Other transplant variables were collected: intraoperative cardiopulmonary bypass use, donor smoking history, as well as recipient diagnosis and BMI. RESULTS: Mean donor P/F ratio was lower for recipients with PGD grades 0-2 (438±69) vs. PGD grade 3 (469±64.8);p=0.006. There was a significant difference in the mean donor P/F ratio between the extremes, PGD grade 0 (430±65.5) and the PGD grade 3 (469±64.8);p=0.005. Notably, the incidence of PGD grade 3 increased with an increase in the donor P/F ratio, with the highest incidence of PGD grade 3 observed when the P/F ratio was >500 (Fig. 1). Mean donor tidal volume (ml/kg of ideal body weight) was similar among all groups: 8.7, 8.8, 8.9, and 8.4 for PGD 0, 1, 2, or 3, respectively. CONCLUSIONS: Recipients with PGD grade 3 had significantly higher donor P/F ratios than those with PGD grade 0-2. Donor P/F ratio >500 was associated with an increased incidence of PGD grade 3. CLINICAL IMPLICATIONS: This preliminary data suggests that donor hyperoxia may lead to an increased risk for severe PGD. More research is needed to further delineate the effects of donor mechanical ventilation strategies and transplant recipient outcomes. DISCLOSURES: No relevant relationships by Kareem Ahmad, source=Web Response No relevant relationships by Shambhu Aryal, source=Web Response Speaker/Speaker's Bureau relationship with Genentech Please note: $5001 - $20000 Added 06/12/2020 by Anne Brown, source=Web Response, value=Honoraria Advisory Committee Member relationship with Vertex Please note: $1001 - $5000 Added 06/12/2020 by Anne Brown, source=Web Response, value=Honoraria Advisory Committee Member relationship with Promedior Please note: $5001 - $20000 Added 06/12/2020 by Anne Brown, source=Web Response, value=Consulting fee No relevant relationships by Vikramjit Khangoora, source=Web Response Advisory Committee Member relationship with Boehringer Ingelheim Please note: $5001 - $20000 Added 04/16/2020 by Christopher King, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Actelion Please note: $5001 - $20000 Added 04/16/2020 by Christopher King, source=Web Response, value=Honoraria Advisory Committee Member relationship with Actelion Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Boehringer Ingelheim pharmaceuticals Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Actelion Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Genentech Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Honoraria Advisory Committee Member relationship with United therapeutics Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Consulting fee Consultant relationship with Veracyte Please note: $1001 - $5000 Added 04/03/2020 by Steven Nathan, source=Web Response, value=Honoraria Consultant relationship with United Therapeutics Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Consultant relationship with Bellerophon Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Roche-Genentech Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boerhinger-Ingelheim Please note: $20001 - $100000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with Johnson & Johnson Please note: $1001 - $5000 Added 04/22/2020 by Oksana Shlobin, source=Web Response, value=Consulting fee Scientific Medical Advisor relationship with Bayer Please note: $1001 - $5000 Added 04/22/2020 by Oksana Shlobin, source=Web Response, value=Grant/Research Support Scientific Medical Advisor relationship with United Therapeutics Please note: $1001 - $5000 Added 04/22/2020 by Oksana Shlobin, source=Web Response, value=Consulting fee

ASSOCIATION OF DONOR ALLOCATION SEQUENCE WITH OUTCOMES AFTER LUNG TRANSPLANTATION

SESSION TITLE: Transplantation Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: There is limited data regarding the association of donor allocation sequence number with early complications such as primary graft dysfunction (PGD) and survival after lung transplantation (LT). METHODS: We included 152 consecutive patients who underwent LT over a two-year period (11/2014-12/2016; mean age 56.8±13.2 years; M:F 93:59). The data regarding the allocation characteristics as well as graft survival were obtained directly from the United Network for Organ Sharing (UNOS) database. This data was merged with the institutional recipient database. Recipient data included baseline characteristics, peri-operative and post-operative course, complications and hospital outcomes. Primary graft dysfunction was analyzed as the primary outcome variable whereas the hospital length of stay and survival at one, and three-year post transplant were secondary outcome variables. RESULTS: The most common diagnostic group was restrictive lung diseases (n=81, 52.2%) with a mean lung allocation score (LAS) of 44.8±15 and majority underwent bilateral LT (n=98). The median allocation sequence was 4.5 for the study group (IQR 2-13). The study group was divided into patients who were transplanted at sequence #1 (n=29) vs those transplanted with organs accepted at lower allocation sequence. Patients with higher mean LAS (56.4±19.5 vs 42.1±12.4, p<0.001), restrictive disorders as the transplant indication (72% vs 48.7%, p=0.03), hospitalized at the time of LT (28% vs 9%, p=0.06) and bridged to LT using ECMO (21% vs 3%, p=0.001) were significantly more likely to be transplanted at sequence #1. Despite being sicker, recipients of allocation sequence #1 had significantly lower incidence of PGD 2 or 3 at 0 hours (24%, vs 61%, p<0.001; mean PF ratio: 357±81 vs 273±107, p<0.001) and 72 hours (14% vs 28%, p=0.15 mean PF ratio: 303±147 vs 198±167, p=0.002). Although, the recipients of allocation at sequence #1 experienced equivalent hospital survival, their survival trended lower at one-year and three-year follow up (p=NS). CONCLUSIONS: While patients transplanted at allocation sequence #1 tend to be sicker, they have better oxygenation during the first 72 hours after LT and lower risk of PGD. Nonetheless, a higher donor allocation sequence is not associated with superior one-year or three-year survival. CLINICAL IMPLICATIONS: By virtue of being prioritized for LT, sicker recipients may be transplanted with better quality donor lungs. While this allocation strategy may be successful in reducing early complications, it fails to improve post-LT survival. DISCLOSURES: My spouse/partner as a Employee relationship with Abbott Labs Please note: $20001 - $100000 Added 06/05/2020 by Amit Banga, source=Web Response, value=Salary No relevant relationships by SRINIVAS Bollineni, source=Web Response No relevant relationships by John Joerns, source=Web Response No relevant relationships by Vaidehi Kaza, source=Web Response No relevant relationships by Adrian Lawrence, source=Admin input No relevant relationships by Manish Mohanka, source=Web Response No relevant relationships by John Murala, source=Web Response No relevant relationships by Matthias Peltz, source=Web Response No relevant relationships by Lauren Shaffer, source=Web Response No relevant relationships by Fernando Torres, source=Web Response No relevant relationships by Michael Wait, source=Web Response

Ex vivo lung perfusion for donor lung assessment and repair: a review of translational interspecies models.

For patients with end-stage lung disease, lung transplantation is a lifesaving therapy. Currently however, the number of patients who require a transplant exceeds the number of donor lungs available. One of the contributing factors to this is the conservative mindset of physicians who are concerned about transplanting marginal lungs due to the potential risk of primary graft dysfunction. Ex vivo lung perfusion (EVLP) technology has allowed for the expansion of donor pool of organs by enabling assessment and reconditioning of these marginal grafts before transplant. Ongoing efforts to optimize the therapeutic potential of EVLP are underway. Researchers have adopted the use of different large and small animal models to generate translational preclinical data. This includes the use of rejected human lungs, pig lungs, and rat lungs. In this review, we summarize some of the key current literature studies relevant to each of the major EVLP model platforms and identify the advantages and disadvantages of each platform. The review aims to guide investigators in choosing an appropriate species model to suit their specific goals of study, and ultimately aid in translation of therapy to meet the growing needs of the patient population.

A Novel Risk Scoring System for Predicting Primary Graft Dysfunction after Orthotopic Heart Transplantation

Introduction Despite advances in graft survival following orthotopic heart transplantation (OHT), primary graft dysfunction (PGD) remains a major problem. PGD - defined as ventricular dysfunction occurring within 24 hours after OHT not associated with a discernible cause - is the leading cause of death in the first 30 days post OHT. The etiology of PGD is multifactorial including donor age, recipient inotropic support and amiodarone use. Hypothesis We would be able to identify novel donor and recipient factors associated with increased incidence of PGD. Methods We analyzed patients undergoing OHT from January 2014 to December 2019. Patients without 1-year follow up data were excluded. PGD was diagnosed based on the 2013 ISHLT consensus definition. Donor and recipient characteristics were analyzed using chi-square or Fisher exact test as appropriate, 2-tailed, with p Results 122/143 OHT recipients had 1 year followup. PGD occurred in 36 (29.5%) patients. Patient proportions with donor-recipient height mismatch>20% (0 vs 0), weight mismatch>20% (34% vs 42%, p=0.32), and sex mismatch (13.8% vs 10.5%, p=0.76) were similar for PGD and non-PGD groups. Independent predictors of PGD were donor pH 50% (OR 13.85, 95%CI 3.3-58, p=0.01). Based on beta coefficients in the regression model, we allotted 1 point to milrinone use, 2 to amiodarone use, and 3 points each to donor pH 50%. The derived risk score demonstrated a powerful association with PGD occurrence (per point increase OR 2.0; p Conclusion We identified novel factors associated with the development of PGD, including recipient milrinone use and elevated class 2 PRA, while confirming prior well-validated risk factors such as amiodarone use and donor acidemia. A PGD risk score incorporating these factors powerfully predicts PGD occurrence, and may assist in future donor utilization and identification of recipients at risk for PGD.

Cell-free DNA in human ex vivo lung perfusate as a potential biomarker to predict the risk of primary graft dysfunction in lung transplantation

BackgroundCell-free DNA (cfDNA), such as mitochondrial DNA (mtDNA) and nuclear DNA (nuDNA), are known to be released from injured cells and as such have been explored as biomarkers for tissue injury in different clinical settings. Ex vivo lung perfusion (EVLP) has been developed as an effective technique for marginal donor lung functional assessment. We hypothesized that the level of cfDNA in EVLP perfusate may reflect tissue injury and thus can be developed as a biomarker to quantify the degree of donor lung injury or predict the development of primary graft dysfunction (PGD) after lung transplantation (LTx). MethodsThe perfusate from 62 donor lungs transplanted at our institution between May 2010 and December 2015 was sampled for cfDNA at 1 and 4 hours of perfusion. Sequences of genes encoding nicotinamide adenine dinucleotide dehydrogenase 1 (NADH-1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were used to represent mtDNA and nuDNA, respectively. Levels were quantified by real-time polymerase chain reaction and correlated with clinical outcome after LTx. ResultsIn our entire cohort, 14 patients developed PGD grade 3 (PGD3) within 72 hours after LTx. The non-PGD group included 48 patients (PGD0-1). Concentrations of mtDNA in the perfusate of the PGD3 group were significantly higher than those in non-PGD group at 1 hour of EVLP (1874 ± 844 vs 1259 ± 885 copies/μL; P = .011). The perfusate of the PGD3 group had significantly higher levels of nuDNA compared with the non-PGD group at both 1 hour (1498 ± 1895 vs 675 ± 391 copies/μL; P = .008) and 4 hours (4521 ± 5810 vs 1764 ± 1494 copies/μL; P = .001). In donation after cardiac death (DCD) cases, mtDNA levels were significantly higher in the PGD3 group compared with the non-PGD group at 1 hour of EVLP (2060 ± 997 vs 1184 ± 782 copies/μL; P = .040), and the levels of nuDNA were significantly higher in the PGD3 group compared with the non-PGD group at both 1 hour (1021 ± 495 vs 606 ± 305 copies/μL; P = .041) and 4 hours (2358 ± 1028 vs 1185 ± 967 copies/μL; P = .006). In donation after brain death (DBD) cases, cfDNA scores did not show a significant difference. ConclusionsWe found that the amount of cfDNA, especially nuDNA, in EVLP perfusate was higher in the severe PGD group (PGD3) compared with the non-PGD group. This proof-of-concept study supports the concept that the analysis of cfDNA levels in EVLP perfusate can help estimate the damage to donor lungs before implantation. Larger studies are needed to validate this concept.

The Association of Increased FFP:RBC Transfusion Ratio to Primary Graft Dysfunction in Bleeding Lung Transplantation Patients

Lung transplantation is associated with a significant risk of needed transfusion. Although algorithm-based transfusion strategies that promote a high fresh frozen plasma:red blood cells (FFP:RBC) ratio have reduced overall blood product requirements in other populations, large-volume transfusions have been linked to primary graft dysfunction (PGD) in lung transplantation, particularly use of platelets and plasma. The authors hypothesized that in lung transplant recipients requiring large-volume transfusions, a higher FFP:RBC ratio would be associated with increased PGD severity at 72 hours. Observational retrospective review. Single tertiary academic center. Adult patients undergoing bilateral or single orthotopic lung transplantation and receiving >4 U PRBC in the first 72 hours from February 2014 to March 2019. None. Patient demographics, operative characteristics, blood transfusions, and outcomes including PGD scores and length of stay were collected. Eighty-nine patients received >4U PRBC, had available 72-hour PGD data, and were included in the study. These patients were grouped into a high-ratio (>1:2 units of FFP:RBC, N = 38) or low-ratio group (<1:2 units of FFP:RBC, N = 51). Patients in the high-ratio group received more transfusions and factor concentrates and had significantly longer case length. The high-ratio group had a higher rate of severe PGD at 72 hours (60.5% v 23.5%, p = 0.0013) and longer hospital length of stay (40 v 32 days, p = 0.0273). In bleeding lung transplantation patients at high risk for PGD, a high FFP:RBC transfusion ratio was associated with worsened 72-hour PGD scores when compared with the low-ratio cohort.

Donor thyroid hormone therapy is associated with an increased risk of graft dysfunction after heart transplantation

Heart transplantation (HT) is uniquely associated with the potential impact of thyroid hormone therapy at three intersecting levels-donor, operation, and recipient. We aimed to study the effect of thyroid hormone therapy of the donor on primary graft dysfunction (PGD). A retrospective cohort study was conducted on 209 HT recipients assessed from 1997 to 2018; for 33 of the recipients, the donors had received T4 (DT4 group), and for 176, the donors had not (NoDT4 group). The primary endpoint was PGD defined according to the International Society for Heart and Lung consensus statement. Both the incidence (58% vs 35%, P=.022) and the severity of PGD (42% vs 25% moderate/severe, P=.007) were significantly higher in the DT4 recipients. Multivariable analysis showed donor T4 therapy to be independently associated with a ~3.5-fold increased risk for PGD (OR=3.44, 95% CI 1.26-9.86). These results remained consistent after propensity score analysis. Donor thyroid hormone therapy is independently associated with an increased risk of PGD. Hypothesizing a "withdrawal effect" as the cause, we suggest that administration of thyroid hormone to the recipient at time of reperfusion could counter this negative effect. Prospective studies are needed to validate this hypothesis-generating study.