Risk Factors For Primary Graft Dysfunction Research Articles

Impact of the New Definition of Pulmonary Hypertension on the Prevalence of Primary Graft Dysfunction in Lung Transplant Recipients

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

The International Consortium on Primary Graft Dysfunction: Redefining Clinical Risk Factors in the Contemporary Era of Heart Transplantation

Background: Primary Graft Dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplant (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were to 1) assess the incidence of severe PGD in an international cohort, 2) evaluate the performance of the most validated PGD risk tool, the RADIAL score, in a contemporary cohort, and 3) redefine clinical risk factors for severe PGD in the current era of HT. Methods: This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada, and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis and its calibration was assessed by plotting the percentage of PGD predicted versus observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability. Results: A total of 2,746 patients have been enrolled in the registry to date, including 2,015 (73.4%) from North America, and 731 (26.6%) from Europe. 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (p-value for trend by difference sign test = 0.004). The Kaplan Meier estimate for 1-year survival was 75.7% [95%CI 69.4-80.9%] in patients with severe PGD as compared to 94.4% [95% CI 93.5-95.2%] in those without severe PGD (log-rank p-value <0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD with an AUC of 0.53 (95%CI 0.48-0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31 – 4.43), durable LVAD support (OR 1.77, 95% CI 1.13 – 2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02 – 1.41) were associated with an increased risk of severe PGD. Conclusions: Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices.

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

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. 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. 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. 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.

Chicken or Egg: Tricuspid Regurgitation-The Cause or the Consequence of Post-Heart Transplant Allograft Dysfunction.

Tricuspid regurgitation (TR) is the most common valvular abnormality in cardiac transplant recipients.1 The causes of posttransplant TR are often obscure and can be multifactorial.2,3 The prognostic significance of posttransplant TR and the clinical implications of the severity of TR remain unclear and undefined.4-6 To clarify these questions, Bart et al7 conducted a retrospective study of their heart transplant patients over a 6-y period, examining transthoracic echocardiograms in 163 patients. Of these patients, 142 had a transthoracic echocardiograms before their first posttransplant endomyocardial biopsy (EMB). At month 0 posttransplant, 127 patients (78%) had no or mild TR before their first EMB, whereas 36 patients (22%) had moderate–severe TR.7 In patients with no or mild TR, 9 (7%) progressed to moderate–severe TR by 6 mo and 1 underwent tricuspid valve (TV) surgery.7 Of the patients with moderate–severe TR before the first biopsy, by 2 y, 3 had undergone TV surgery. Furthermore, in the moderate–severe TR before first biopsy group, postoperative extracorporeal membrane oxygenation (ECMO) use was significantly more common (78%; P < 0.05), as was rejection frequency (P = 0.02).7 Patients with late progressive moderate–severe TR had a significantly higher 2-y mortality than those who had moderate–severe TR immediately.7 Severe TR post–heart transplant is associated with a worse outcome8 although the clinical outcomes are otherwise variable.4 The consequences of severe TR can result in right ventricular dilatation with hepatic and renal congestion and subsequent dysfunction. Major causes of posttransplant TR include damage to the TV from the EMB and perioperative complications such as primary graft dysfunction (PGD), which often requires ECMO. This would explain the association of ECMO with moderate–severe TR. Additionally, rejection frequency was associated with greater severity of TR. This may be because of injury to the allograft from rejection as well as performing more EMB to make the diagnosis of rejection with concomitant damage to the TV. There has been some evidence that bicaval heart transplants are less likely to develop severe TR as opposed to the older biatrial transplant technique.9,10 However, the current study did not observe a difference. This retrospective study has significant limitations, which are clearly delineated by the authors. A retrospective, single-center study is likely not able to determine if there are specific factors that have causality in the development of TR, its severity, and its progression. The predominant use of the biatrial approach among this study’s patients would limit the ability to distinguish one surgical approach from another in terms of causality of TR. The increasing use of the bicaval approach may reduce the likelihood of developing TR or severe TR. The correlation of ECMO with the development of moderate–severe TR and worse prognoses would suggest that the presence of moderate–severe TR would be a consequence of severe allograft dysfunction posttransplant, necessitating resorting to ECMO for postoperative support. These patients would have worse prognoses on the basis of having PGD, and the severity of TR would, in essence, be an epiphenomenon and a surrogate marker of severe allograft dysfunction posttransplant, given the increased likelihood of developing hepatic and renal congestion and subsequent end-organ dysfunction with severe TR. We can conclude from the results of the current study that TR severity and progression are unsurprisingly associated with severe posttransplant allograft dysfunction with damage to the valve and allograft function. This and the concomitant TV valve damage would adversely affect posttransplant outcomes. The association of rejection frequency with TV severity could be associated with EMB-induced TR, which is also not surprising. What is missing from this study is a more prospective assessment of the relationship of pretransplant and posttransplant pulmonary hemodynamics and volume status to the development of and the severity of TR as well as the relationship with risk factors of PGD. This article serves as a starting point for future investigations. Ultimately, to resolve the questions raised by this article and to better understand the causes and risk factors of TR and prognostic factors of TR development and severity, a larger, prospective, multicenter study collecting echocardiographic information of TR severity, relationship of TR with type of transplant surgery performed, correlation of pulmonary hemodynamics with severity of TR, and prognosis and correlation of number of biopsies and rejection episodes with severity of TR should be performed. The care of transplant patients has changed with greater reliance on noninvasive biomarkers to assess the need for performing EMB, thus reducing the numbers of EMB. This may reduce the incidence and severity of TR. Given the large number of heart transplant programs in the United States that have switched to a biomarker-guided posttransplant strategy (donor-derived cell-free DNA, gene expression profiling) with biopsy minimization, it may be difficult to compare this approach with the more traditional biopsy-guided approach in terms of the impact on TR.

Impact of anastomosis time during lung transplantation on primary graft dysfunction

Primary graft dysfunction (PGD) is a major obstacle after lung transplantation (LTx), associated with increased early morbidity and mortality. Studies in liver and kidney transplantation revealed prolonged anastomosis time (AT) as an independent risk factor for impaired short- and long-term outcomes. We investigated if AT during LTx is a risk factor for PGD. In this retrospective single-center cohort study, we included all first double lung transplantations between 2008 and 2016. The association of AT with any PGD grade 3 (PGD3) within the first 72h post-transplant was analyzed by univariable and multivariable logistic regression analysis. Data on AT and PGD was available for 427 patients of which 130 (30.2%) developed PGD3. AT was independently associated with the development of any PGD3 ≤72h in uni- (odds ratio [OR] per 10min 1.293, 95% confidence interval [CI 1.136-1.471], p<.0001) and multivariable (OR 1.205, 95% CI [1.022-1.421], p=.03) logistic regression analysis. There was no evidence that the relation between AT and PGD3 differed between lung recipients from donation after brain death versus donation after circulatory death donors. This study identified AT as an independent risk factor for the development of PGD3 post-LTx. We suggest that the implantation time should be kept short and the lung cooled to decrease PGD-related morbidity and mortality post-LTx.

The Heart Awakens

<h3>Introduction</h3> Primary graft dysfunction (PGD) after orthotopic heart transplant (OHT) can be a challenging complication to manage. We present a 70 year-old male with severe PGD immediately after OHT that required mechanical circulatory support. <h3>Case Report</h3> The patient developed myocarditis at age 63 leading to dilated cardiomyopathy. By age 69, despite guideline-directed medical therapy, he required a HeartMate 3 ventricular assist device (VAD) as a bridge to transplant for progressive heart failure. He was discharged and listed for OHT. Five months later, he was admitted for ventricular tachycardia storm and his listing status was upgraded. After 3 days, a donor organ with mild left ventricular (LV) systolic dysfunction was accepted for OHT. Intra-operatively, the transplanted heart showed limited contractility, despite epicardial pacing (cross clamp time 237 minutes, warm ischemic time 60 minutes). Therefore, biventricular CentriMag VADs were implanted. Post-operative ECG showed a slow ventricular escape rhythm (Figure 1A). On post-operative day (POD) 5, due to left hemothorax, he returned to the operating room, where improved cardiac contractions were noted. Serial cardiac biopsies showed normal myocardium and no rejection (Figure 1B, 1D). Over the next 2 days, the heart regained contractility. ECG showed a junctional escape rhythm (Figure 1C). On POD 7, the transplanted heart showed recovery and the Centrimag VADs were explanted. By POD 12, he was weaned off vasoactive medications and transferred to the ward. Eventually, on POD 23, he was discharged home with a permanent pacemaker. <h3>Summary</h3> This case demonstrates severe PGD in the context of pre-existing mild donor LV dysfunction that was successfully managed by mechanical circulatory support as a bridge to recovery. A potential contributor to graft dysfunction may be myocyte stunning by antiarrhythmic medications infused pre-operatively for ventricular tachycardia storm. This case shows the utility of donor hearts with LV systolic dysfunction even in the presence of other risk factors for PGD.

Donor Alkalemia is Associated with Severe Primary Graft Dysfunction

<h3>Purpose</h3> Primary graft dysfunction (PGD) following heart transplant (HT) is a significant cause of early mortality. Donor management goals (DMG) are 9 predefined endpoints used to optimize donors before procurement. We evaluated the relationship between meeting DMGs and the development of severe PGD after HT. <h3>Methods</h3> We identified 648 HT recipients at our center between 1/1/2012 and 12/31/2019 with donor data and complete covariates in the UNOS DMG Registry. DMGs were collected at consent, 12-18 hours into management, and at procurement. PGD was defined according to modified ISHLT criteria. The ABCE (ACE inhibitor/Beta-blocker/Cardiac surgery/ischemic timE) prediction score for severe PGD was also used. DMG registry variables were subject to single variable and multivariable multinomial modeling with development of severe PGD as the response variable. The DMG goal range for pH is 7.3-7.5. <h3>Results</h3> 110 (17%) of the cohort had mild/moderate PGD and 43 (6%) had severe PGD. In single variable modeling, the only DMG associated with severe PGD was donor pH within goal range at procurement. There were 576 donors (89%) at goal pH, 66 (10%) alkalotic, and 6 (1%) acidotic/missing. Donor alkalemia at procurement was associated with an increased risk for severe PGD (OR 2.45, 95% CI 1.02-5.91, p=0.046). When added to the ABCE prediction score for severe PGD, donor alkalemia at procurement was not independently associated with severe PGD (Table 1). <h3>Conclusion</h3> In this cohort, donor alkalemia at procurement was associated with an increased risk of severe PGD, but not beyond recipient factors associated with severe PGD (ABCE score). Donor alkalemia is a novel risk factor for PGD that may be related to donor ventilation. Given the need for novel markers that predict PGD, additional studies in larger, multi-institutional cohorts are warranted.

Ratio of Pulmonary Artery to Ascending Aortic Diameter Predicts Primary Graft Dysfunction After Cardiac Transplantation

<h3>Purpose</h3> Primary graft dysfunction (PGD) is associated with high mortality rates after heart transplantation. Described risk factors for PGD include pulmonary hypertension. This study aimed to evaluate a noninvasive parameter of pulmonary hemodynamics based on the ratio of pulmonary and aortic diameters (PA/Ao ratio) as a predictive tool for severe PGD <h3>Methods</h3> All adult patients who underwent heart transplantation in our center from January 2011 to December 2020 were included. Measurement of main pulmonary artery and aortic diameters were performed. Primary outcome was the occurence of severe PGD <h3>Endpoints</h3> 46 over 176 included patients had severe PGD (26.1%) with a 30-day mortality of 34.8% compared to 5.4% for patients without severe PGD (p<0.0001). Variables associated with severe PGD in multivariate analysis were redo surgery (OR 2.546 [1.226; 5.289], p=0.012), time between heart failure diagnosis and transplantation (OR 1.046 [1.003; 1.091], p=0.037) and PA/Ao ratio (OR 1.509 [1.062; 2.145], p=0.022). PA/Ao ratio was positively correlated with systolic and mean pulmonary artery pressure (r=0.311, p<0.0001 and r=0.326), pulmonary wedge pressure (r=0.306 <0.0001) and pulmonary vascular resistance (r=0.217, p=0.007). A PA/Ao diameter ratio > 1.06 was associated with severe PGD (OR 2,766 [1,167; 6,558], p=0,021) and achieved a specificity 80 % and sensitivity of 39 %. High PA/Ao diameter ratio is associated with elevated pulmonary pressures and outmatches pulmonary hemodynamic parameters for predicting severe PGD in this cohort. PA/Ao ratio may be a valuable tool to be integrated in predictive scores for PGD.

Sensitization is Independently Associated with Increased Risk of Primary Graft Dysfunction After Heart Transplantation

<h3>Purpose</h3> Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). We sought to determine the association between pre-transplant calculated panel reactive antibody (cPRA) value and the incidence of PGD while controlling for other known risk factors. <h3>Methods</h3> Consecutive adult HT recipients (n=672) from 1/2015 to 12/2019 at two high-volume centers were included. Definition and severity PGD were based on the 2014 ISHLT consensus statement. Peak cPRA values were collected for each patient prior to HT and high cPRA was defined as >50%. The primary outcome was the incidence of all PGD. Multi-variable logistic regression model was used to identify risk factors for PGD. <h3>Results</h3> The cohort was predominantly male (72.3%), with a mean age of 54.3±12.1 years and 23.1% had a durable left ventricular assist device as a bridge to HT. There were 150 (22.3%) cases of all PGD. Severe PGD occurred in 44 (6.6%) and mild-moderate PGD occurred in 106 (15.8%) patients. A total of 105 (15.6%) patients had high cPRA prior to HT. Univariable model identified PGD risk factors including ischemic time greater than 4 hours, pre-HT angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with and without neprilysin inhibitor use, donor and recipient age, and predicted heart mass ratio <0.86. Multivariable modeling showed that high cPRA was associated with increased incidence of all PGD (OR 1.72, 95% CI 1.07-2.76, p=0.025) when adjusted for co-variates (Table 1). Patients with no cPRA (0%) had significantly lower incidence of severe PGD compared to those with any detectable cPRA (>0%) (4.78 vs. 10.2%, p=0.018). <h3>Conclusion</h3> Patients with high pre-HT cPRA is associated with increased incidence of PGD, after adjustment for donor and recipient characteristics.

Primary graft dysfunction: what we know.

Many advances in lung transplant have occurred over the last few decades in the understanding of primary graft dysfunction (PGD) though effective prevention and treatment remain elusive. This review will cover prior understanding of PGD, recent findings, and directions for future research. A consensus statement updating the definition of PGD in 2016 highlights the growing complexity of lung transplant perioperative care taking into account the increasing use of high flow oxygen delivery and pulmonary vasodilators in the current era. PGD, particularly more severe grades, is associated with worse short- and long-term outcomes after transplant such as chronic lung allograft dysfunction. Growing experience have helped identify recipient, donor, and intraoperative risk factors for PGD. Understanding the pathophysiology of PGD has advanced with increasing knowledge of the role of innate immune response, humoral cell immunity, and epithelial cell injury. Supportive care post-transplant with technological advances in extracorporeal membranous oxygenation (ECMO) remain the mainstay of treatment for severe PGD. Future directions include the evolving utility of ex vivo lung perfusion (EVLP) both in PGD research and potential pre-transplant treatment applications. PGD remains an important outcome in lung transplant and the future holds a lot of potential for improvement in understanding its pathophysiology as well as development of preventative therapies and treatment.

Lung Allograft Epithelium DNA Methylation Age Is Associated With Graft Chronologic Age and Primary Graft Dysfunction.

Advanced donor age is a risk factor for poor survival following lung transplantation. However, recent work identifying epigenetic determinants of aging has shown that biologic age may not always reflect chronologic age and that stressors can accelerate biologic aging. We hypothesized that lung allografts that experienced primary graft dysfunction (PGD), characterized by poor oxygenation in the first three post-transplant days, would have increased biologic age. We cultured airway epithelial cells isolated by transbronchial brush at 1-year bronchoscopies from 13 subjects with severe PGD and 15 controls matched on age and transplant indication. We measured epigenetic age using the Horvath epigenetic clock. Linear models were used to determine the association of airway epigenetic age with chronologic ages and PGD status, adjusted for recipient PGD risk factors. Survival models assessed the association with chronic lung allograft dysfunction (CLAD) or death. Distributions of promoter methylation within pathways were compared between groups. DNA methyltransferase (DNMT) activity was quantified in airway epithelial cells under hypoxic or normoxic conditions. Airway epigenetic age appeared younger but was strongly associated with the age of the allograft (slope 0.38 per year, 95% CI 0.27–0.48). There was no correlation between epigenetic age and recipient age (P = 0.96). Epigenetic age was 6.5 years greater (95% CI 1.7–11.2) in subjects who had experienced PGD, and this effect remained significant after adjusting for donor and recipient characteristics (P = 0.03). Epigenetic age was not associated with CLAD-free survival risk (P = 0.11). Analysis of differential methylation of promoters of key biologic pathways revealed hypomethylation in regions related to hypoxia, inflammation, and metabolism-associated pathways. Accordingly, airway epithelial cells cultured in hypoxic conditions showed suppressed DNMT activity. While airway methylation age was primarily determined by donor chronologic age, early injury in the form of PGD was associated with increased allograft epigenetic age. These data show how PGD might suppress key promoter methylation resulting in long-term impacts on the allograft.

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant

Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. PGD occurred in 24% of the cohort (n=178) of whom 6% (n=44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Primary Graft Dysfunction.

Primary graft dysfunction (PGD) is a form of acute lung injury after transplantation characterized by hypoxemia and the development of alveolar infiltrates on chest radiograph that occurs within 72 hours of reperfusion. PGD is among the most common early complications following lung transplantation and significantly contributes to increased short-term morbidity and mortality. In addition, severe PGD has been associated with higher 90-day and 1-year mortality rates compared with absent or less severe PGD and is a significant risk factor for the subsequent development of chronic lung allograft dysfunction. The International Society for Heart and Lung Transplantation released updated consensus guidelines in 2017, defining grade 3 PGD, the most severe form, by the presence of alveolar infiltrates and a ratio of PaO2:FiO2 less than 200. Multiple donor-related, recipient-related, and perioperative risk factors for PGD have been identified, many of which are potentially modifiable. Consistently identified risk factors include donor tobacco and alcohol use; increased recipient body mass index; recipient history of pulmonary hypertension, sarcoidosis, or pulmonary fibrosis; single lung transplantation; and use of cardiopulmonary bypass, among others. Several cellular pathways have been implicated in the pathogenesis of PGD, thus presenting several possible therapeutic targets for preventing and treating PGD. Notably, use of ex vivo lung perfusion (EVLP) has become more widespread and offers a potential platform to safely investigate novel PGD treatments while expanding the lung donor pool. Even in the presence of significantly prolonged ischemic times, EVLP has not been associated with an increased risk for PGD.

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.

Incidence and impact of primary graft dysfunction in adult heart transplant recipients: A systematic review and meta-analysis

Primary graft dysfunction (PGD) is a leading cause of early mortality after heart transplant (HTx). To identify PGD incidence and impact on mortality, and to elucidate risk factors for PGD, we systematically reviewed studies using the ISHLT 2014 Consensus Report definition and reporting the incidence of PGD in adult HTx recipients.We conducted a systematic search in January 2020 including studies reporting the incidence of PGD in adult HTx recipients. We used a random effects model to pool the incidence of PGD among HTx recipients and, for each PGD severity, the mortality rate among those who developed PGD. For prognostic factors evaluated in ≥2 studies, we used random effects meta-analyses to pool the adjusted odds ratios for development of PGD. The GRADE framework informed our certainty in the evidence.Of 148 publications identified, 36 observational studies proved eligible. With moderate certainty, we observed pooled incidences of 3.5%, 6.6%, 7.7%, and 1.6% and 1-year mortality rates of 15%, 21%, 41%, and 35% for mild, moderate, severe and isolated right ventricular-PGD, respectively. Donor factors (female sex, and undersized), recipient factors (creatinine, and pre-HTx use of amiodarone, and temporary or durable mechanical support), and prolonged ischemic time proved associated with PGD post-HTx.Our review suggests that the incidence of PGD may be low but its risk of mortality high, increasing with PGD severity. Prognostic factors, including undersized donor, recipient use of amiodarone pre-HTx and recipient creatinine may guide future studies in exploring donor and/or recipient selection and risk mitigation strategies.

Predictors of Primary Graft Dysfunction Following Bilateral Lung Transplantation

<h3>Purpose</h3> 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 smoking^2,3 or heavy donor alcohol use⁴, longer graft ischemic times², volume of intraoperative fluid administered⁵, and higher recipient BMI^2,3,6. Our aim was to identify additional intraoperative risk factors for PGD after lung transplantation. <h3>Methods</h3> 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. <h3>Results</h3> 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. <h3>Conclusion</h3> 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.

Quick Action is the Ticket to a New Life: Appropriate Recognition and Response with VA ECMO Use for Primary Graft Dysfunction

Introduction Primary graft dysfunction (PGD) is a dreaded complication in heart transplant patients. Several risk factors have been associated with PGD with recent recognition of amiodarone use contributing significantly to severe PGD. While overall incidence can be relatively low, the mortality for PGD approaches up to 40%. Case Report A 67 yo male with NICM (EF 10-15%), CRT-D implant in 2015, and HVAD as BTT in 5/2019 due to VT and cardiogenic shock presented with sudden nausea, diaphoresis, and subsequently received several consecutive shocks from his CRT-D. He was found to be in VT/VF storm despite multiple device shocks and dofetilide and mexilitine therapy. Device interrogation later revealed that the defibrillation threshold was higher than before and that he had received 2 rounds of ATP degenerating VT into VF and then received 8 41J shocks, all unsuccessful in converting his rhythm. He was trialed on lidocaine infusion without effect and then received external cardioversion with initiation of amiodarone infusion. Patient was progressing well but had recurrent slow VT while hospitalized. This episode required 3 rounds of ATP and required re-initiation of amiodarone infusion despite dual oral anti-arrhythmic therapy. He was upgraded to UNOS status 2 and underwent orthotopic heart transplant during the hospitalization. While in the OR, patient was quickly recognized to have mild-moderate PGD thought to be secondary to the necessary amiodarone. From prior experience, it was decided to place patient on VA ECMO circuit while in the OR rather than maintain inotropic therapy despite limited use of MCS outside of severe PGD. He remained on minimal VA ECMO support for a few days and was transitioned onto inotropic therapy. The patient did well through the remainder of the hospitalization and was discharged several weeks later with fully recovered cardiac function. Summary This case displays that prompt recognition of PGD and early initiation of MCS therapies like VA ECMO might be prudent for patient survival. With cardiac transplants increasing nationally, it is important to be cognizant of risk factors for PGD including recent amiodarone use as a risk factor. The decision to use VA ECMO early allowed us to be prepared for worsening graft function and provide optimal support early if needed rather than await an emergent situation which has known poor patient 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

Right Heart Failure While on Left Ventricular Assist Device Support Is Associated with Primary Graft Dysfunction.

Primary graft dysfunction (PGD) is a potentially devastating complication of heart transplantation. Understanding the risk factors for PGD in the modern era of heart transplantation is of vital importance. This study investigated the relationship between post-left ventricular assist device (LVAD) right heart failure (RHF) and transplant outcomes. Patients with durable, continuous-flow LVADs who were transplanted between 2010 and 2016 at Barnes-Jewish Hospital were included in the study. Data collection was performed through retrospective chart review. The primary outcome was the incidence of PGD stratified by pretransplant incidence of RHF while on LVAD support. Among the 141 patients included in the study, 41 developed RHF. In the RHF cohort, 18 patients developed PGD as compared to 14 patients in the group without RHF (44% vs. 14%; p < 0.001). Mortality was significantly higher in the RHF group at 30 days (20% vs. 1%; p < 0.001) and 1 year (22% vs. 6%; p = 0.013). In a multivariable logistic regression model adjusted for confounding variables, RHF was associated with a nearly fourfold increased risk of PGD (odds ratio, 3.91; p = 0.003). The results of this study show that patients supported with LVADs who develop early severe RHF or late RHF are at increased risk of PGD and death following cardiac transplantation.

Mitigating Risks of Primary Graft Dysfunction with Antegrade Myocardial Perfusion

Primary Graft Dysfunction (PGD) is the leading cause of early mortality after heart transplantation. Several risk factors of PGD have been identified, including; prolonged warm ischaemic time, advanced donor age, gender mismatch and recipient diabetes mellitus. We adopted a novel method of implantation using "antegrade myocardial perfusion (AMP)" during implantation and compared this to the conventional approach. We obtained the retrospective data retrospectively from the Golden Jubilee National Hospital heart transplant database, ClinicalPortal and CIS databases from January/2012-May/2018. Missing data were obtained from the hard copy case notes. We performed AMP utilising continuous cold blood (4-6°C) antegrade cardioplegia to achieve aortic root pressures of 60-70 mmHg. Leucocyte filer was utilised. The infusion would continue with an LV vent insitu until the left atrial and aortic anastomoses were complete. "Hotshot" warm blood was then infused prior to removal of the cross clamp. Multivariable logistic regression with moderate/severe PGD as the outcome measure. Confounders were adjusted for recipient age, total ischaemic time, bypass time, predicted left ventricular (LV) mass mismatch, recipient diabetes mellitus and donor age. A total of 75 patients were included in this study. 44% (n=33) underwent AMP and 56 % (n=42) had orthotopic heart transplantation with the conventional approach. There was no statistically significant difference in age, gender, incidence of diabetes mellitus, preoperative utilisation of mechanical circulatory support between the AMP and the control group. We found that total ischaemia time was significantly shorter in the AMP cohort (154+/-50.2 vs. 181+/-47.1 min, p=0.018). The rate of postoperative VA ECMO support was significantly lower in the AMP cohort (15% vs. 54%, p<0.001). The rate of moderate-severe PGD was significantly lower in the AMP cohort (21% vs. 69%, p<0.001). The odds ratio of PGD in patients in the historical cohort vs AMP was 4.15 (1.21-14.24). Our implantation technique utilising AMP significantly lowers the rate of moderate and severe PGD when compared to the standard implantation technique employed by the historical cohort.