Purpose Primary Graft Dysfunction Research Articles

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

PurposePrimary 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 peri-operative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision making. MethodsWe derived a predictive model in a prospective cohort study of subjects from 2012-2018, 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 (DCA), we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. ResultsThe 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 10-75% in the derivation centers and 2-10% in the validation cohort, a range incorporating the incidence in that cohort. ConclusionWe developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision making, post-transplant care, and enrich samples for PGD treatment trials.

Pretransplant Medications and Primary Graft Dysfunction Risk in Lung Transplant Recipients

PurposePrimary graft dysfunction (PGD) is a serious complication of lung transplantation marked by acute lung injury and reperfusion edema in the immediate post-transplant period, but the effect of pretransplant medication use on PGD risk is not known. We hypothesized that some pretransplant medications could be associated with PGD risk, particularly those with anti-inflammatory activity (macrolide antibiotics, statins) and vasoactives (anti-hypertensives, pulmonary vasodilators).MethodsWe reviewed a previously published cohort of adult patients who underwent lung transplant in our program between 2004 and 2016. The primary outcome was the development of grade 3 PGD (PGD3) at 48- or 72-hours post-transplant. We assessed use of medication classes from listing records, with a sample of these verified against transplant admission records. We evaluated the relationship between pretransplant medication class and PGD3 using Fisher's exact testing and multivariable logistic regression, adjusting for known PGD risk factors including recipient pulmonary diagnosis, body mass index, mean pulmonary arterial pressure, donor age and donor smoking status.Results19% of 330 patients who underwent lung transplant during the study timeframe developed PGD3. Phosphodiesterase inhibitor (PDE5i), endothelin receptor antagonist, proton pump inhibitor, and beta blocker (BB) use showed unadjusted associations with PGD3 risk, and PDE5 and BB use remained associated after adjustment (table 1). BB use remained significantly associated after further correction for left ventricular end diastolic pressure.ConclusionOur exploratory analysis showed no association between pretransplant use of medications with anti-inflammatory properties - including macrolides and statins - and PGD3 risk, but PDE5i and BB use increased PGD risk despite adjustment for indication, suggestive vasoactive medications may play a role. These associations would benefit from further study. Primary graft dysfunction (PGD) is a serious complication of lung transplantation marked by acute lung injury and reperfusion edema in the immediate post-transplant period, but the effect of pretransplant medication use on PGD risk is not known. We hypothesized that some pretransplant medications could be associated with PGD risk, particularly those with anti-inflammatory activity (macrolide antibiotics, statins) and vasoactives (anti-hypertensives, pulmonary vasodilators). We reviewed a previously published cohort of adult patients who underwent lung transplant in our program between 2004 and 2016. The primary outcome was the development of grade 3 PGD (PGD3) at 48- or 72-hours post-transplant. We assessed use of medication classes from listing records, with a sample of these verified against transplant admission records. We evaluated the relationship between pretransplant medication class and PGD3 using Fisher's exact testing and multivariable logistic regression, adjusting for known PGD risk factors including recipient pulmonary diagnosis, body mass index, mean pulmonary arterial pressure, donor age and donor smoking status. 19% of 330 patients who underwent lung transplant during the study timeframe developed PGD3. Phosphodiesterase inhibitor (PDE5i), endothelin receptor antagonist, proton pump inhibitor, and beta blocker (BB) use showed unadjusted associations with PGD3 risk, and PDE5 and BB use remained associated after adjustment (table 1). BB use remained significantly associated after further correction for left ventricular end diastolic pressure. Our exploratory analysis showed no association between pretransplant use of medications with anti-inflammatory properties - including macrolides and statins - and PGD3 risk, but PDE5i and BB use increased PGD risk despite adjustment for indication, suggestive vasoactive medications may play a role. These associations would benefit from further study.

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.

Veno-Arterial-Venous ECMO in Severe Primary Lung Graft Dysfunction, a Retrospective Monocenter Study

Purpose Primary graft dysfunction (PGD) occurs in about 20-35% of lung transplantations (LT), with a mortality rate approaching 50% in grade 3 PGD. The treatment remains symptomatic with reports showing favorable survival rates when ECMO is used intra- and postoperatively. It exists two classical configurations, Veno-Venous (VV) and Veno-Arterial (VA) ECMO, with the former providing respiratory support, and the latter giving an additional hemodynamic one. The aim is to highlight the use and results of Veno-Arterial-Venous (VAV) ECMO in the management of Grade 3 PGD, as it combines the benefits of both types. Methods We performed a single-centre retrospective study based on our institutional database. In our VAV ECMO setting, the drainage cannula is placed in the femoral vein, while reinfusion cannulas are put in the femoral artery and the internal jugular vein. Flow is monitored using sensors, and regulated using a screw clamp on the reinfusion venous line. Our protocol is to wean the arterial cannula first when the patients become hemodynamically stable, then VV ECMO once respiratory support is longer required. Results Between April 2016, and April 2020, a total of 280 patients were transplanted at our center. 125 patients needed circulatory assistance intraoperatively. Of those, ECMO was maintained in 65 cases postoperatively (group 1). While 7 patients without intraoperative ECMO, required it during the postoperative 72 hours (group 2). VAV ECMO was used in a total of 8 patients, 6 belonging to group 1, and 2 to group 2. Median age was 40,8 [29,0-56,6] years All of the patients underwent bilateral LT with one patient having a combined liver transplantation as well. The indication of LT was cystic fibrosis in n=5, Idiopathic pulmonary fibrosis in n=2, and re-transplantation for chronic rejection in n=1. The arterial cannula was kept for a median of 5 [3-5] days, while total ECMO weaning was done at a median of 9 [6-17,25]. days. Median ventilation duration was 22 [8-29]. 2 patients died, while the other 6 patients are alive and well up to the date of the abstract. Conclusion VAV ECMO can safely be applied in case of severe refractory hypoxemia despite a VA ECMO in grade 3 PGD patients after LT. It provides a bridge to progressive weaning, with encouraging survival rates. However, more data is needed for further evaluation.

Donor-Derived-Cell-Free DNA to Identify Primary Graft Dysfunction Patients at Risk of Chronic Lung Allograft Dysfunction

Primary Graft Dysfunction (PGD) is a risk factor for Chronic Lung Allograft Dysfunction (CLAD). However, this association requires further examination for better risk stratification of PGD patients. Donor-derived cell-free DNA (%ddcfDNA) is a biomarker for lung allograft injury and early post-transplant %ddcfDNA levels may predict long-term outcomes. This study leverages %ddcfDNA to assess the association of PGD and allograft injury, as well as the ability of %ddcfDNA to identify PGD patients who are at greater risk of developing long-term complications. Lung Transplant recipients (n=52) enrolled in two prospective cohort studies were included. Serial post-transplant clinical data and plasma samples were obtained. An adjudication committee reviewed Day 3 chest x-rays and arterial blood gases and used standard ISHLT definitions to categorize patients as PGD or non PGD. Other endpoints, such as CLAD were also defined by ISHLT standards. Plasma %ddcfDNA on Day 1, Day 3, Day 7 were quantified by shotgun sequencing. Within subject mean values for Day 1-7 were computed. %ddcfDNA levels were compared between PGD versus non PGD patients. In the PGD subgroup, %ddcfDNA levels were also compared between PGD patients who subsequently developed CLAD vs PGD patients who did not develop CLAD. Median post-transplant follow-up was 38.3 months. %ddcfDNA levels were higher in PGD than in non PGD patients; Day 1 (27.5% vs 20.0% p=0.043), Day 3 (11.2% vs 6.6 %, p=0.003), mean Day 1-7 (17.83% vs 10.58%, p=0.008). PGD patients who developed CLAD had higher within-subject Day 1-7 mean %ddcfDNA levels than PGD patients who did not develop CLAD (22.6% vs 15.2%, p = 0.0438). PGD patients demonstrated increased early post-transplant allograft injury, as measured by %ddcfDNA, than non PGD patients. In addition, early post-transplant %ddcfDNA levels may serve as a predictor for the development of CLAD in patients who experience PGD.

Role of Glucose Regulated Protein 78 in Primary Cardiac Allograft Dysfunction

Primary graft dysfunction (PGD) refers to the loss of contractility in cardiac allograft within 24 hours after heart transplantation. The mortality among PGD population could be as high as 40% in the modern era. Biological clues for early detection of PGD may ensure prompt management and improvement in patient survival. The applicant proposes in this project that grp78 might be a promising biomarker to predict or to show the severity of PGD in heart transplantation. Clinical variables were collected from patients with and without PGD in National Cheng Kung University from Dec. 2005 to Aug. 2018. The serum levels of grp78 were tested using ELISA. Myocardial tissue expression of endoplasmic reticulum (ER) stress proteins including grp78, hsp70, eIF2α, ATF4 and ATF6 were evaluated using Western blot method. A total of 59 patients received heart transplantation in our institution from Dec. 2005 to Aug. 2018. However, not all but 21 patients who meet the inclusion criteria were included in this study. There were 6 patients were suffered from PGD among the 59 heart transplantation patients. The data from another 15 patients were analyzed as the control data. There was significant increase of serum grp78 among patients with PGD, P=0.034. Myocardial tissue expression of grp78 was on the contrary decreased, although this was not statistically significant. There were significantly reduced abundances of eIF2α and increased protein abundances of hsp70 and ATF6. This study importantly showed the potential of predicting PGD using serum grp78. Due to the limited case number, we were not able to show a cut-off value of prediction. The future study of mechanism for ER stress in PGD is also important to reveal the potential etiologies.

Predictors of Primary Graft Dysfunction Following Bilateral Lung Transplantation

Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality following lung transplantation, affecting up to 30% of recipients within 72 hours of transplantation1. Published perioperative risk factors include a history of donor smoking2,3 or heavy donor alcohol use4, longer graft ischemic times2, volume of intraoperative fluid administered5, and higher recipient BMI2,3,6. Our aim was to identify additional intraoperative risk factors for PGD after lung transplantation. In this single center, retrospective cohort study evaluating all primary, double lung transplants (DLT) performed at our institution between January 1, 2016 and December 31, 2018, data was collected from several hospital registries as well as our electronic medical record and UNOS data to evaluate donor and recipient demographics as well as intraoperative management strategies that may be associated with PGD. The primary outcome was grade 3 PGD, based on the ISHLT definition. Continuous variables are expressed as medians with range, and categorical variables as n (%). A multivariate regression model was built from our univariate analysis. 105 patients underwent primary DLT during the study period; 6 refused research participation. Data from 99 patients was collected and analyzed. Eighteen patients (18%) met criteria for the primary outcome of PGD. Recipient etiology of respiratory failure, intraoperative requirement for inhaled pulmonary vasodilator (IPV), degree of HLA mismatching, and the use of intraoperative blood products were associated with PGD (Table 1). The use of an inhaled pulmonary vasodilator, degree of HLA mismatch and increased red cell transfusion were independently associated with PGD. In this retrospective analysis, we identify additional independent perioperative risk factors associated with PGD following double lung transplant. Future efforts will focus on identifying risk factors for massive intraoperative red blood cell transfusion and the need for IPV.

Primary Graft Dysfunction Increases the Risk of Baseline Lung Allograft Dysfunction but Not Chronic Lung Allograft Dysfunction after Lung Transplantation

Primary graft dysfunction (PGD) after lung transplantation has been shown to limit survival and increase chronic lung allograft dysfunction (CLAD) risk. The relationship between PGD and baseline lung allograft dysfunction (BLAD), a physiologic state associated with poor survival where graft function fails to normalize, is not known. Our objective was to assess the association between severe PGD, BLAD and CLAD in a single cohort. We hypothesized that PGD survivors would be at increased risk of both CLAD and BLAD. We reviewed all double lung transplant recipients transplanted in our program between 2004 and 2016. We defined grade 3 PGD (PGD3) as lung edema on chest x-ray as interpreted by a radiologist and PaO2/FiO2 ratio <200 mmHg at 48 or 72 hours' after transplant. We defined CLAD status and grade according to the 2019 ISHLT consensus and BLAD according to our prior study (failure to achieve both FEV1 and FVC ≥80% predicted on 2 consecutive tests ≥3 weeks apart). We used logistic regression modelling to evaluate the association between PGD3 and BLAD, adjusting for diagnosis, recipient age and gender, donor age and donor smoking status. We used proportional hazards models to evaluate the association between PGD3 with CLAD, both unadjusted and adjusted for BLAD status. 446 patients met inclusion criteria. 76 (17%) developed PGD3 at 48- or 72-hours post-transplant. Patients with PGD3 were more likely to have had interstitial lung disease or pulmonary vascular disease and to have higher BMIs and older donors. Those patients with PGD3 more frequently developed BLAD (58% vs. 36%; p=0.0008) and more severe BLAD grades (p<0.0001). PGD3 was not associated with time to CLAD onset in an unadjusted model (HR 1.18 (95%CI 0.71-1.86), p = 0.5174) or adjusted for BLAD status (HR 1.08 (95%CI 0.65-1.73), p = 0.7483). PGD3 increased the odds of BLAD in unadjusted (OR 2.39 (95% CI 1.45-3.98), p=0.0006) and adjusted models (OR 2.09 [95% CI 1.19-3.70]; p = 0.0105). Severe PGD was associated with increased risk and severity of baseline lung allograft dysfunction (BLAD), but not CLAD. This is plausible, given the injury of PGD is confined to the perioperative period rather than a sustained injury resulting in progressive loss. The mechanisms via which PGD mediate poor baseline function require further investigation.

Outcome of Right Ventricular Primary Graft Dysfunction after Heart Transplantation

Primary graft dysfunction (PGD) is observed in approximately 7% of all heart transplant (HTx) patients (pts). According to the International Society for Heart and Lung Transplantation (ISHLT), a new PGD scale includes left ventricular (PGD-LV), or right ventricular (PGD-RV). PGD-LV when severe is noted to have increased mortality. PGD-RV has been described as hemodynamics with RAP >15 mmHg, PCWP <15 mmHg, CI < 2.0 L/min/m2, or need for RV temporary support. PGD-RV has not been well studied. Between Dec 2013 and Dec 2018, we assessed 13 HTx pts who developed PGD-RV within 24 hours after HTx and compared them to pts without PGD. Endpoints included 1-year survival, need for temporary kidney dialysis, need for RV unloading with sildenafil, first year rejection including any treated rejection (ATR), 1-year freedom from cardiac allograft vasculopathy (CAV), and 1-year freedom from non-fatal major adverse cardiac events (NF-MACE, defined as myocardial infarction, percutaneous coronary intervention/angioplasty, new congestive heart failure, pacemaker/implantable cardioverter-defibrillator placement, and stroke). Pts with PGD-RV compared to pts without PGD had similar 1-year survival, freedom from CAV, freedom from NF-MACE, and rejection. 90% of pts with PGD-RV required RV unloading therapy which may have affected outcome. There was a trend for a lower freedom from temporary kidney dialysis in the PGD-RV group. PGD-RV after HTx appears to have acceptable outcome with good recovery. RV unloading therapy may be helpful. However, there was an associated increased need for temporary kidney dialysis within the first year after HTx. Larger numbers are warranted to confirm these findings.

Incidence and Impact of Primary Graft Dysfunction in Adult Heart Transplant Recipients: A Systematic Review and Meta-Analysis

Primary graft dysfunction (PGD) is a life-threatening complication and a leading cause of early mortality post heart transplant (HTx). Recent studies evaluating the incidence and prognosis of PGD have benefited from the ISHLT 2014 Consensus Report which clearly defines this condition. Our objective was to systematically review all studies that reported the incidence of PGD in adult HTX recipients since 2014 to more accurately identify its incidence and impact on mortality. We conducted a systematic search of the literature in Medline in October 2019. We included studies that reported the incidence of PGD in adult HTx recipients, based on the 2014 ISHLT Consensus Report. Two independent reviewers screened citations and performed data abstraction. We used a random effects meta-analysis to pool the incidence among HTx recipients, as well as the rate of mortality among those who developed PGD. We applied the GRADE instrument for incidence and mortality separately to determine our certainty in the pooled estimates. Of 127 publications screened, we included 36 observational studies. HTx recipient age ranged from 24-69 years and 24% were female. Donor age ranged from 23-50 years, sex mismatch occurred in 21% and ischemic time ranged from 86-273 minutes. We observed similar incidence for each severity of PGD but increasing risk of 1-year mortality (Table 1). Estimates of 30-day mortality were only available for severe PGD: 39% (95% CI 32% - 46%, 9 studies, high certainty). Based on the 2014 ISHLT criteria, the published pooled incidence of PGD is low, and its prognosis is poor. The extensive heterogeneity in incidence and mortality suggests inconsistencies in the recognition and/or management of PGD. This represents an opportunity for improved risk stratification, prevention and management strategies.

Severe Primary Graft Dysfunction: Impact of the New UNOS Heart Allocation System

Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HTx). The purpose of this study was to determine the mortality risk and incidence of PGD pre- and post-implementation of the new UNOS heart allocation policy. A total of 426 consecutive adult patients underwent HTx from 1/2010 to 5/2019. Recipients of combined organ transplants were excluded. Definition of severe PGD was based on the 2014 ISHLT consensus statement which includes dependence on mechanical circulatory support, excluding requirement for intra-aortic balloon pump (IABP). The primary outcome was the incidence of PGD and overall 1-year survival. The cohort studied was predominantly male (70.8%), with a mean age of 53.4±12.8 years; 31.6% were supported with a left ventricular assist device as a bridge to HTx, and 38.4% were blood type O. There were 17 (4.0%) cases of severe PGD, all of which required extracorporeal membrane oxygenation support. Baseline characteristics pre-HTx were similar in those with and without PGD (Figure 1). There was no difference in the incidence of severe PGD following the introduction of the new allocation policy in October 18, 2018 (5.9 vs. 4.5%, p=0.70), but there was a significant increase in the use of post-transplant IABP (23.5 vs. 9.1%, p=0.009). There was no correlation between RADIAL score and incidence of severe PGD (p=0.41). Severe PGD was associated with reduced 30-day survival (97.6% [95% CI: 95.5-98.8] vs. 68.7% [40.5-85.6], p<0.001) and 1-year survival (92.4% [95% CI: 89.1-94.7] vs. 50.0% [95% CI: 24.5-71.1], p<0.001). (Figure 1). Patients with severe PGD had an 8.6-fold increased risk of death when adjusted for age (p<0.001). Incidence of severe PGD has not increased in the contemporary era with the new UNOS heart allocation policy. PGD is associated with poor 1-year survival and is not predicted by the RADIAL score, which underscores the need for a new risk prediction model.

Primary Graft Dysfunction is Associated with Increased Radiographic Atelectasis at Three Months Post-Lung Transplant

Primary graft dysfunction (PGD) contributes to mortality and impaired lung function after lung transplant but little is known about future radiographic manifestations. We assessed radiographic features on 3-month post-transplant chest computed tomography (CT) studies and the association with future risk of baseline lung allograft dysfunction (BLAD) and chronic lung allograft dysfunction (CLAD). We hypothesized radiographic abnormalities would be more frequent after PGD and be associated with increased risk of BLAD and CLAD. We studied double-lung transplant recipients from 2010-2016. Grade 3 PGD (PGD3) was defined as CXR edema + PaO2/FiO2<200mmHg at 48/72 hours. We reviewed 3-month chest CTs for eight abnormalities: effusion, ground glass, centrilobular nodules, interlobular septal thickening (ILS), atelectasis, consolidation (all as number of involved lobes [0-5]) and presence of fibrosis or air trapping (binary). We assessed for clinically relevant microbiology on 3-month bronchoscopy as potential radiographic confounders. We used trend tests and chi squared tests for the relationship between PGD3 and CT features. We tested relationships between associated CT features and future risk of BLAD (failure to reach both FEV1 and FVC>80%) and CLAD (ISHLT 2019 definition) using logistic and Cox models respectively. 237 patients met inclusion criteria, 50 (21%) of whom developed post-operative PGD3. PGD3 was associated with more frequent and/or widely distributed ILS (p=0.0389) and atelectasis (p<0.0001) on 3-month CT, but only atelectasis remained after multiple testing correction (threshold p = 0.05/8 = 0.00625). We found no association with lung microbiology on 3 month bronchoscopy. Atelectasis at 3 months increased the risk of BLAD both unadjusted (odds ratio 3.83 [95% CI 1.90-8.03], p=0.0002) and adjusted for PGD3 status (OR 3.44 [95% CI 1.68-7.28], p=0.0007). Neither the unadjusted nor adjusted risk of CLAD was affected. Grade 3 PGD is associated with radiographic atelectasis at 3-months post-transplant. Atelectasis increases the risk of BLAD but not CLAD. This latter finding is plausible given the injury of PGD is confined to the post-operative period rather than sustained. Post-PGD atelectasis may suggest persistent surfactant/type II pneumocyte dysfunction, but this requires further study.

Isolation and Characterization of Exosomes from Ex Vivo Perfused Human Lungs

Primary graft dysfunction (PGD) is an important cause of morbidity and mortality following lung transplantation and results in part from injuries sustained in the donor. Exosomes, a class of extracellular vesicles ranging from 30-150nm in size, are increasingly being recognized as key modulators of inflammation. Exosomes have been implicated in the anti-donor response to the lung allograft and may play a role in the pathogenesis of PGD. Perfusate from ex-vivo lung perfusion (EVLP) represents a potential platform to interrogate donor exosomes which may serve as non-invasive, predictive biomarkers for subsequent PGD. In this study, we aim to identify and characterize exosomes in EVLP perfusate. One-hour perfusate samples of 5 donor human lungs undergoing EVLP were collected, precleared at 2,000xg and 10,000xg, and then ultracentrifuged at 100,000xg for 90mins. The concentration and size distribution of particles in the resuspended pellets were obtained via nanoparticle tracking analysis (NTA). The presence of exosomes was validated by probing for exosome-enriched protein markers via Western Blotting and flow cytometry. Nanoparticle analysis of EVLP perfusates revealed an average of 1.257 × 1011 particles/mL (Fig. 1) with sizes ≤ 200nm. CD9 and CD81, canonical tetraspanin exosome surface markers were identified by Western Blotting (Fig. 2) in the EVLP perfusates but not in fresh perfusate (Steen® solution). The other canonical tetraspanin, CD63 was not seen using this technique. In contrast, flow cytometry (Fig. 3) showed the presence of all 3 tetraspanins in exosomes from EVLP perfusate samples. Clinical EVLP perfusates contain donor-derived lung exosomes as confirmed by NTA, Western Blotting, and flow cytometry. We are currently examining their protein and nucleic acid contents and their relationship to PGD and risk factors of PGD, like donor mode of death.

Clinical Outcomes and Financial Implications of Using Extra Corporeal Membrane Oxygenation (ECMO) for Primary Graft Dysfunction Following Heart Transplantation: A Single Centre Experience

Primary graft dysfunction (PGD) after heart transplant is associated with high morbidity and mortality. Extracorporeal membrane oxygenation (ECMO) can be used to wean patients from cardiopulmonary bypass and provides the opportunity to rest the transplanted heart until it regains function. This study retrospectively reviews a single centre experience of post-transplant ECMO in regard to outcomes and associated costs. Between May 2006 and May 2019, 267 adult heart transplants were performed. We compared donor and recipient variables, ECMO duration and the incidence of renal failure, bleeding and infection between ECMO and non-ECMO groups. Economic analysis was performed to determine differences in cost for equipment, blood transfusion, renal dialysis, and critical care/postoperative ward stay. ECMO support was required postoperatively to manage PGD in 72 (27%) patients. The mean duration of ECMO support was 6 ± 3.2 days. Donor and recipient demographic variables, including mean ischaemic time were similar between the groups. ECMO patients were associated with longer duration of stay in CCU (p<0.0001) and total hospital stay (p<0.0001). ECMO patients more frequently developed renal failure (p<0.0001), postoperative bleeding (p<0.0001), had a higher re-exploration rate (p<0.0001), and a higher rate of infection (p<0.0001) compared with the non-ECMO group. Greater mortality was observed in the ECMO group (p<0.0001). The mean cost of providing ECMO was £18,250±7,396 per patient with an additional £49,637.90 for CCU stay whilst on ECMO. The total mean cost per patient inclusive of hospital stay, ECMO and dialysis costs was £85,944±58,180 in the non-ECMO group compared to £178,056±137,026 per patient in the ECMO group (p<0.0001). Extracorporeal membrane oxygenation support can be utilised for management of PGD following heart transplantation. Patients with PGD following heart transplantation who require ECMO are frequently bridged to a recovery, however, the medium and longer-term survival for these patients is poorer than for patients who have no requirement for ECMO. It remains unclear whether this inferiority is related to donor/recipient related factors or ECMO-related effects are implicated.

Levosimendan Treatment in Patients with Primary Graft Dysfunction after Heart Transplantation

Primary graft dysfunction or even failure (PGD/PGF) after heart transplantation (htx) remains a main problem causing poor outcome. Besides mechanical support Ca 2+-sensitizer such as levosimendan play an important role and are known to improve cardiac function. We aimed to analyse our patients particularly with regard to timing of levosimendan application. 139 patients underwent htx between 2010 and 2019 in our department, including 28 patients (22.4%) suffering from primary graft dysfunction or failure (PGD/PGF) and treated with levosimendan (group L). Patients who received the treatment within or after 48h after ECLS implantation form group Learly or Llate. Control group C consists of patients not treated with Ca 2+-sensitizer postoperatively. The groups were comparable regarding further preoperative status, including cardiac function and allograft ischemia time. 89.3% of group L were treated with extracorporeal life support (ECLS) compared to 13.4% of controls. In group Learly 100% of patients were successfully weaned from ECLS, in group Llate 60% and in group C 46.2% (p<0.05). However, thirty-day mortality was 17.9% in group L compared to 9.3% in controls (p>0.05). 1-year-survival was also comparable between the groups with 73.7% in group L and 77.6% in group C. Besides a more frequent use of postoperative ECLS, renal failure and need for resternotomy occurred significantly more often in group L compared to controls (p<0.05). Furthermore, stay on ICU and in hospital and duration of mechanical ventilation after htx were significantly prolonged (p<0.05). Patients receiving levosimendan early within the first 48 postoperative hours displayed lower thirty-day mortality and an improved 1-year-survival with 90% compared to 55.6% in group Llate (p>0.05). With our results, we could clearly show that levosimendan application in patients with PGD or even PGF after cardiac transplant represents a valuable treatment option to realize still acceptable results in these severely affected patients. Furthermore, it is obvious that the timely decision for early treatment with Ca 2+-sensitizer is an inevitable requirement to achieve those outcomes.

Does the Pretransplant Use of Statins in Recipients Have a Role in the Incidence of Primary Graft Dysfunction after Lung Transplantation? R-ESTAcitos: Multicenter Clinical Study

Primary graft dysfunction (PGD) is the main cause of mortality during the first month and the second one within the first year after lung transplant (LT) Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have shown to have immunomodulatory and antiinflamatory effects unrelated to their cholesterol-lowering function. We hypothesized that recipient's preoperative statin therapy is associated with decreased incidence of PGD after LT. Multicenter retrospective analysis of all consecutive adult LTs performed in 5 university transplant centers between 2015 and 2017. Combined multiple organ transplantation and lung retransplant recipients were excluded from the analysis. Comparison between groups according to recipient previous use of statins(E+/E-)) was performed. Factors associated with the development of PGD and its severity were analyzed using Chisquare and U-Mann Whitney Test. Logistic regression model was built including those variables with p≤0.1 in the univariate analysis. Significance level p<0.05. A total of 474 adult LT recipients were reviewed, 110 of them (E+=23%) were on statins treatment (SG). LT recipients in the statin group were older (60±7 vs 53±12; p<0.05) and had higher Body Mass Index (BMI) (26.3±3.8 vs 24.8±4.2;p<0.05) than those in not taking statins. The rest of recipient and donor characteristics were similar between groups. A total of 161 patients developed PGD (34%), without significative differences between groups (32.2% vs 39%). However PGD in E+ group was significantly less severe as stated by the percentage of patients with grade 3 PGD at 72h (55.9% vs 37.2%,p<0.036). After propensity score adjustments, only the need for hemoderivates transfusion during the implant (OR 4.50 IC 1.51 - 13.38 p<0.007) remained significant. Recipient statin use was not identified as a protective factor (OR 0.38 CI 0.12 - 1.206, p=0.10). Statin use may contribute to lessen the severity of PGD. Prospective and multicentric studies with larger samples are needed to confirm such results.

Induction Therapy in Patients with Prolonged Ischemic Times May Be Protective for Early Graft Failure

Primary graft dysfunction (PGD) in heart transplantation (HTx) patients is the leading cause of death within the first 30 days of HTx. Ischemic time >4 hours has been associated with a significant increase in mortality at 30 days post-transplant and up to 6 years post-transplant. The optimal immunosuppression regimen including induction therapy to prevent allograft failure is unclear. Induction therapy may have a protective effect against ischemia-reperfusion injury, a main mechanism of allograft injury after HTx. We sought to evaluate the effect of induction therapy in heart transplant recipients with longer ischemic times in both early and long-term graft failure. This retrospective cohort study used the United Network for Organ Sharing (UNOS) and included adult (>21yr) heart transplant patients from Jun 30, 2004 to Mar 2015. The effect of induction therapy, either basiliximab (IL-2Rab) or ATG/ALG/thymoglobulin, on all-cause early and late graft failure was estimated by a logistic regression adjusted for the covariates ischemic time, age, African American race, serum creatinine >2.5, HLA mismatch > 4, and acute rejection episodes. The Inverse Probability Treatment Weighting (IPTW) was used to control for imbalanced propensity of receiving induction given the covariates. At 30 days, induction was shown to reduce graft failure OR 0.69 (95% CI, 0.57-0.82) in all comers with no additional benefit for patients with prolonged ischemic time OR 1.08 (95% CI 0.87-1.36). Induction had no effect on long term graft failure up to 5.6 years OR 0.96 (95% CI 0.88 -1.04), except in patients with prolonged ischemic time OR 0.88 (95%CI 0.79-0.98). Our results suggest that induction therapy may be protective against graft failure at 30 days, and late graft failure up to five years in a subset of patients with prolonged ischemic times.

Cardiac Biomarkers for Early Identification of Primary Graft Dysfunction

Purpose Primary graft dysfunction (PGD) is a leading cause of mortality and morbidity following heart transplantation . Our study aimed to determine the feasibility of measuring cardiac biomarkers in the donor heart directly after preservation and use as predictors for PGD. Methods Data were collected from 64 patients who underwent heart transplantation between 2015 and 2018. The donor hearts were flushed and stored with ice cold cardioplegic preservation solution. The concentration of creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) was measured from sinus coronarius when the first dose of blood cardioplegia was given to the donor heart at transplantation. The primary end-point was severe PGD, defined according to ISHLT definition of 2014. Results The mean age was 49 years, 28% of the patients were female. Six patients developed a moderate left ventricular PGD (10%) and eight patients a severe PGD (13%) following the transplantation. No recipient developed a ACR >1R. Recipients developing a severe PGD had an increased concentration of CK-MB (15.1 ±9.5 vs 8.9 ±11.4 ng/ mL, p=0.020) and cTnI (4.1 ±2.1 vs 2.7 ±3.3 ng/ mL, p=0.072) compared with recipients not developing severe PGD. The area under the ROC curve for CK-MB and cTnI were 0.77 (95% CI 0.63-0.92) and 0.73 (95% CI 0.59-0.87), respectively (Figure A and B). The odds ration for severe PGD due to CK-MB>10 ng/ mL was 5.3 (95% CI 1.01-28, p=0.049), and for cTnI>3 ng/ mL 4.0 (95% CI 0.66-24.4), p=0.133. Recipients with severe PGD had an increased length of stay at ICU (32 vs 6 days, p=0.006) and a higher mortality at 30 days after transplantation (43% vs 5.8%, p=0.018). There was a trend to an increased CK-MB concentration for recipients developing severe PGD, measured 12 hours’ post-transplant, 141 ±97 vs 98 ±70 ng/ mL, p=0.131. Conclusion By measuring CK-MB in the donor heart it is possibly to identified patients at increased risk for severe PGD after heart transplantation.

Incidence and Effect of VA-ECMO Use in Primary Graft Failure Patients after Heart Transplantation

Purpose Primary graft dysfunction (PGD) is a complication associated with high mortality after heart transplant, which may require veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) support. However, the outcomes of VA-ECMO use for heart transplant recipients remains unclear in limited studies. Methods Between September 2014 and August 2018, 169 patients underwent heart transplantation in our single center. 10 patients who required VA-ECMO support were analyzed retrospectively. Incidence, pre-operative recipient and donor demographics, intraoperative variables, VA-ECMO support duration, short and long-term survival were analyzed. The outcomes were stratified by PGD severity. Results Of 10 patients, the incidence of severe PGD requiring immediate VA-ECMO support from primary heart transplant was 70.0% (n = 7). The incidence of non-severe PGD requiring non-immediate VA-ECMO support was 30.0% (n = 3). Median ischemic time and interquartile range (IQR) was 189 [158-212] minutes. The survival to discharge rate was 71.4% and 100% for severe and non-severe PGD patients, respectively (Figure 1). Median survival days and IQR was 580 [80-877] for severe PGD patients and 366 [64-381] for non-severe PGD patients. 30-day survival rate was 85.7% and 100% for severe and non-severe PGD patients. 1-year survival rate was 66.7% for severe PGD and 100% for non-severe PGD patients, respectively (Table 1). Conclusion VA-ECMO support following heart transplant led to acceptable results in PGD patients. However, further stratified research with larger cohorts is needed to evaluate the effects of VA-ECMO and to improve outcomes.

The Effect of the Elective Intra-Operative Use of Mechanical Circulatory Support on the Development of Primary Graft Dysfunction Following Bilateral Lung Transplantation

Purpose Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplant. Studies have identified the intraoperative use of cardiopulmonary bypass (CPB) as a risk factor for PGD. There has been an increase in the use of extracorporeal membrane oxygenation (ECMO) for intraoperative support over the last decade. We sought to further evaluate the differential risk of PGD across various extracorporeal life support (ECLS) modalities. Methods Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplant. Studies have identified the intraoperative use of cardiopulmonary bypass (CPB) as a risk factor for PGD. There has been an increase in the use of extracorporeal membrane oxygenation (ECMO) for intraoperative support over the last decade. We sought to further evaluate the differential risk of PGD across various extracorporeal life support (ECLS) modalities. Results A model including age, race, body mass index, diagnosis and pulmonary artery pressure was developed to predict ECLS use. Our analysis included 238 patients who underwent BLT (figure 1). 49 patients who received elective intra-operative ECMO after 2015 were matched with 49 patients who received intraoperative CPB before 2015. There was no difference in the development of severe PGD (p=0.4) or any PGD (p=0.6) between the two groups. Seventy patients who underwent BLT with no ECLS after 2015 were matched with 70 patients who underwent BLT before 2015 with CPB support. There was no difference in the development of severe PGD (p=0.2) or any PGD (p=0.3) between the two groups. Exclusion of patients bridged to transplant with ECMO didn't alter the results. Conclusion In a single center study of BLT recipients, there was no difference in the development of PGD across different ECLS modes. Future analysis will compare the impact of ECMO vs. CPB on biomarkers associated with lung and endothelial injury.