Gregory J. Bittle

State of Art: Clinical ex vivo lung perfusion: Rationale, current status, and future directions

In recent years, ex vivo lung perfusion has emerged as an effective tool for increasing the number of available lungs accepted for transplant. As ex vivo lung perfusion use becomes more widespread, questions have arisen regarding the metabolic activity of the donor lung during ex vivo lung perfusion, optimal perfusion-ventilation strategy, and which parameters best define organ improvement or deterioration. Answers to many of these questions can be found in the published experience with the isolated perfused lung in the study of lung mechanics, pulmonary metabolism, and the effects of various interventions on lung quality. The purpose of this review is to summarize past and present evidence and to provide important background for clinicians and investigators using the ex vivo lung perfusion/isolated perfused lung system.

The use of lung donors older than 55 years: a review of the United Network of Organ Sharing database.

BACKGROUND Current lung transplantation guidelines stipulate that the ideal donor is aged younger than 55 years, but several institutions have reported that outcomes using donors aged 55 years and older are comparable with those of younger donors. METHODS We retrospectively reviewed the United Network for Organ Sharing (UNOS) database to identify all adult lung transplants between 2000 and 2010 in the United States. Patients were stratified by donor age 18 to 34 (reference), 35 to 54, 55 to 64, and ≥ 65 years. Primary outcomes included survival at 30 days and at 1, 3, and 5 years and rates of bronchiolitis obliterans syndrome (BOS). Survival was assessed using the Kaplan-Meier method. Risk factors for mortality were identified by multivariable Cox and logistic regression. RESULTS We identified 10,666 recipients with median follow-up of 3 years (range, 0-10 years). Older donors were more likely to have died of cardiovascular or cerebrovascular causes, but there were no differences in recipient diagnosis, lung allocation score, or incidence of BOS as a function of donor age. The use of donors aged 55 to 64 years was not a risk factor for mortality at 1 year (odds ratio, 1.1; p = 0.304) or 3 years (odds ratio, 0.923; p = 0.571) compared with the reference group; however, use of donors aged > 65 years was associated with increased mortality at both time points (odds ratio, 2.8 and 2.4, p < 0.02). CONCLUSIONS Outcomes after lung transplantation using donors aged 55 to 64 years were similar to those observed with donors meeting conventional age criteria. Donors aged ≥ 65 years, however, were associated with decreased intermediate-term survival, although there was no increased risk of BOS for this group.

Transapical Beating-Heart Mitral Valve Repair With an Expanded Polytetrafluoroethylene Cordal Implantation Device: Initial Clinical Experience.

Background: Degenerative mitral valve (MV) disease is a common cause of severe mitral regurgitation (MR) and accounts for the majority of MV operations. Conventional MV surgery requires cardiopulmonary bypass, aortic cross-clamping, cardioplegia, and a thoracotomy or sternotomy and, therefore, is associated with significant disability, risks, and unpredictable rates of MV repair. Transesophageal echocardiography–guided beating-heart MV repair with expanded polytetrafluoroethylene cordal insertion has the potential to significantly reduce surgical morbidity. We report the first-in-human clinical experience with a novel preformed expanded polytetrafluoroethylene knot implantation device (Harpoon TSD-5) designed to treat degenerative MR. Methods: Through a small left thoracotomy, the device was inserted into the heart and guided by transesophageal echocardiography to the ventricular surface of the prolapsed leaflet. Multiple expanded polytetrafluoroethylene cords were anchored in the leaflet and then adjusted to the correct length to restore MV leaflet coaptation and secured at the epicardium. Results: Eleven patients with posterior leaflet prolapse and severe MR, with mean±SD age of 65±13 years and mean ejection fraction of 69±7%, were treated with 100% procedural success. Immediate postprocedural mean MR grade was trace. At 1 month, the mean MR grade was mild with significant decreases in end-diastolic volume (139 to 107 mL; P=0.03) and left atrial volume (118 to 85 mL; P=0.04). Conclusions: A novel device used for beating-heart image-guided MV repair demonstrates a significant reduction in MR with favorable left ventricular and left atrial reverse remodeling. This approach has the potential to decrease invasiveness and surgical morbidity. Further follow-up is necessary to assess long-term efficacy. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02432196.

Ex vivo lung evaluation of prearrest heparinization in donation after cardiac death.

Objective: To evaluate the effects of prearrest heparin administration on lung quality in a model of donation after cardiac death (DCD), and to assess the potential application of ex vivo lung perfusion (EVLP) in the identification of better grafts from the DCD donor pool. Methods: Cardiac death was induced by electric shock in 10 pigs. One group received a prearrest heparin dose of 300 units/kg (H group, n = 5) and the other did not (NH group, n = 5). Animals remained at room temperature for 1 hour without ventilation, defining the warm ischemic time. After harvest, the lungs underwent 6 hours of cold ischemia before being evaluated with EVLP for 4 hours. Results: Static compliance 28 ± 3 versus 29 ± 2 (Cstat—cm H2O), pulmonary vascular resistance (PVR) 593 ± 127 versus 495 ± 70 (PVR—dyn·s/cm5), and oxygenation 327 ± 32 versus 330 ± 28 (&Dgr;PO2—mm Hg) remained stable from the beginning until the end of EVLP in the H group. In the NH group, Cstat started to decline after the first hour (25 ± 2 vs 21 ± 2), &Dgr;PO2 after hour 2 (265 ± 44 vs 207 ± 44), and PVR started to increase after hour 3 (765 ± 132 vs 916 ± 168). Significant differences between the groups were observed at the end of EVLP (P < 0.001). Parameters of lung quality after EVLP also showed significant differences between the groups: wet weight-to-dry weight ratio (P < 0.001), protein in the bronchial lavage (P < 0.01), Na+ + K+-ATPase activity (P < 0.001), and E-selectin (P < 0.001) in the perfusate. Conclusions: Prearrest heparin administration improved organ function by preserving endothelial homeostasis. EVLP proved to be a useful platform for assessing DCD lungs, providing reliable means of discriminating injured grafts.

Class III Obesity is Not a Contraindication to Venovenous Extracorporeal Membrane Oxygenation Support

BACKGROUND The use of venovenous extracorporeal membrane oxygenation (ECMO) has increased as a bridge to recovery for acute respiratory distress syndrome (ARDS) refractory to conventional support. Morbid obesity can pose a significant challenge to obtaining indexed flows, and outcomes in this population are not well described. METHODS Patients requiring ECMO for ARDS between January 2009 and November 2012 were retrospectively reviewed. Demographics, ECMO variables, and outcomes were assessed. Morbid obesity and super obesity were defined as a body mass index (BMI) greater than 40 kg/m(2) and greater than 50 kg/m(2), respectively. RESULTS Fifty-five patients with ARDS were placed on ECMO during the study period. Twelve were morbidly obese with a BMI of 49.0 kg/m(2) (interquartile range [IQR]: 45.4-57.3 kg/m(2)). Pre-ECMO mechanical ventilatory support and indices of disease severity were similar between the 2 groups, as were cannulation strategy and duration of ECMO support. Nine (75%) morbidly obese patients and 27 (63%) non-morbidly obese patients were successfully weaned from ECMO support, and patient survival to time of discharge was 67% and 58%, respectively. In the subset of super obese patients (n = 6; BMI, 57.3 kg/m(2) [IQR: 51.3-66.5 kg/m(2)]), recovery and midterm survival was 100%. CONCLUSIONS In this review, class III obesity was not associated with poorer outcomes, and based on these data, ECMO support should not be withheld from this patient population.

Outcomes after surgical pulmonary embolectomy for acute submassive and massive pulmonary embolism: A single-center experience

Objectives: Ideal treatment strategies for submassive and massive pulmonary embolism remain unclear. Recent reports of surgical pulmonary embolectomy have demonstrated improved outcomes, but surgical technique and postoperative outcomes continue to be refined. The aim of this study is to describe in‐hospital survival and right ventricular function after surgical pulmonary embolectomy for submassive and massive pulmonary embolism with excessive predicted mortality (≥5%). Methods: All patients undergoing surgical pulmonary embolectomy (2011‐2015) were retrospectively reviewed. Patients with pulmonary embolism were stratified as submassive, massive without arrest, and massive with arrest. Submassive was defined as normotensive with right ventricular dysfunction. Massive was defined as prolonged hypotension due to the pulmonary embolism. Preoperative demographics, intraoperative variables, and postoperative outcomes were compared. Results: A total of 55 patients were identified: 28 as submassive, 18 as massive without arrest, and 9 as massive with arrest. All patients had a right ventricle/left ventricle ratio greater than 1.0. Right ventricular dysfunction decreased from moderate preoperatively to none before discharge (P < .001). In‐hospital and 1‐year survival were 93% and 91%, respectively, with 100% survival in the submassive group. No patients developed renal failure requiring hemodialysis at discharge or had a postoperative stroke. Conclusions: In this single institution experience, surgical pulmonary embolectomy is a safe and effective therapy to treat patients with a submassive or massive pulmonary embolism. Although survival in this study is higher than previously reported for patients treated with medical therapy alone, a prospective trial comparing surgical therapy with medical therapy is necessary to further elucidate the role of surgical pulmonary embolectomy in the treatment of pulmonary embolism.

Long-Term Venovenous Extracorporeal Membrane Oxygenation Support for Acute Respiratory Distress Syndrome

BACKGROUND Given substantial advances in venovenous extracorporeal membrane oxygenation (ECMO) technology, long-term support is increasingly feasible. Although the benefits of short-term ECMO as a bridge to recovery in acute respiratory distress syndrome (ARDS) are well described, the utility and outcomes of long-term support remain unclear. METHODS Patients requiring ECMO for ARDS between January 2009 and November 2012 were retrospectively reviewed and analyzed separately for those requiring ECMO support for less than 3 weeks or for 3 weeks or longer. Demographic factors, ECMO variables, and outcomes were assessed. RESULTS Fifty-five patients with ARDS received ECMO during the study period, with 11 patients requiring long-term ECMO support and a median duration of 36 (interquartile range: 24 to 68) days. Recovery was the initial goal in all patients. Pre-ECMO mechanical ventilatory support, indices of disease severity, and the ECMO cannulation strategy were similar between the two groups. Eight (73%) patients receiving long-term support were bridged to recovery, and 1 patient was bridged to transplantation after a refractory course. Eight (73%) patients receiving long-term support and 25 (57%) patients receiving short-term support survived to 30 days and hospital discharge. CONCLUSIONS Previously, long-term ECMO support was thought to be associated with unfavorable outcomes. This study, however, may provide support for the efficacy of ECMO support even for 3 weeks or more as a bridge to recovery or transplantation.

Pim-1 mediated signaling during the process of cardiac remodeling following myocardial infarction in ovine hearts.

UNLABELLED The serine/threonine kinase Pim-1 was recently identified as a cardiomyocyte survival regulator downstream of Akt. The present study aims to examine Pim-1 activity and its association with the post MI remodeling myocardium in a clinically relevant large animal model. Apical myocardial infarction of approximately 25% left ventricular mass was created in an ovine model. Regional post-infarction deformation of the left ventricle was monitored by sonomicrometry and quantified using areal remodeling strain (i.e., areal expansion). Myocardial tissues were harvested at 12weeks from the adjacent and remote regions of the infarct for analysis of Pim-1 mediated survival signaling proteins as well as apoptotic activity. The cDNA coding sequences of two ovine Pim-1 kinase isoforms, 44 and 33kDa, were identified. Both isoforms were detected in heart tissue and the overall Pim-1 expression was found to be tightly controlled at multiple molecular levels. Pim-1 as well as the Pim-1 mediated survival signaling proteins Bcl-2, Bcl-xL, and phospho-Bad (Ser112) were upregulated in the adjacent region at 12weeks post-infarction and their expression correlated positively with the degree of the remodeling, which was accompanied by significant upregulations of the PP2A/BAD mediated apoptotic signaling proteins. However these upregulations were imbalanced, such that p-BAD (Ser112)/BAD decreased in the adjacent region of the infarcted hearts. Apoptotic activity also increased with remodeling strain. Despite an observed intrinsic upregulation of survival proteins, the imbalanced activation of apoptotic pathways resulted in evident apoptosis in the adjacent region. ULTRAMINI-ABSTRACT Pim-1 mediated survival signaling in myocardial tissues from infarcted ovine hearts was studied. It was shown that the adjacent region of the infarct experienced higher remodeling strain and exhibited increased levels of Pim-1 and related anti-apoptotic proteins. Despite this elevation of survival activity, however, the imbalanced activation of PP2A/BAD mediated apoptotic pathway resulted in evident apoptosis in the adjacent region.

Triage and optimization: A new paradigm in the treatment of massive pulmonary embolism

Background Massive pulmonary embolism (PE) remains a highly fatal condition. Although venoarterial extracorporeal membrane oxygenation (VA‐ECMO) and surgical pulmonary embolectomy in the management of massive PE have been reported previously, the outcomes remain less than ideal. We hypothesized that the institution of a protocolized approach of triage and optimization using VA‐ECMO would result in improved outcomes compared with historical surgical management. Methods All patients with a massive PE referred to the cardiac surgery service between 2010 and 2017 were retrospectively reviewed. Patients were stratified by treatment strategy: historical control versus the protocolized approach. In the historical control group, the primary intervention was surgical pulmonary embolectomy. In the protocol approach group, patients were treated based on an algorithmic approach using VA‐ECMO. The primary outcome was 1‐year survival. Results A total of 56 patients (control, n = 27; protocol, n = 29) were identified. All 27 patients in the historical control group underwent surgical pulmonary embolectomy, whereas 2 of 29 patients in the protocol approach group were deemed appropriate for direct surgical pulmonary embolectomy. The remaining 27 patients were placed on VA‐ECMO. In the protocol approach group, 15 of 29 patients were treated with anticoagulation alone and 14 patients ultimately required surgical pulmonary embolectomy. One‐year survival was significantly lower in the historical control group compared with the protocol approach group (73% vs 96%; P = .02), with no deaths occurring after surgical pulmonary embolectomy in the protocol approach group. Conclusions A protocolized strategy involving the aggressive institution of VA‐ECMO appears to be an effective method to triage and optimize patients with massive PE to recovery or intervention. Implementation of this strategy rather than an aggressive surgical approach may reduce the mortality associated with massive PE.

Clinical Progress in Cell Therapy for Single Ventricle Congenital Heart Disease

One of the fundamental goals of congenital cardiac surgery is to correct the circulatory and structural physiology of congenital heart disease (CHD) by skillfully reconstructing the cardiac anatomy. In the majority of CHD patients, complete correction is achieved with low mortality and reasonable durability, a tribute to surgical strides during the last 2 decades. However, the most challenging CHD patients present with a developmentally hypoplastic heart chamber, which necessitates heroic palliative operations to establish a single ventricle that delivers oxygenated blood to the body, leaving deoxygenated blood to be delivered passively to the pulmonary circulation. Article, see p 1162 This anatomy is crafted in a staged fashion. Typically, the stage I palliative operation (Norwood operation) is performed in the first weeks of life and commits the single ventricle to pumping to both the systemic and pulmonary circulations. The stage II operation (bidirectional cavo-pulmonary anastomosis), at ≈6 months, redirects superior vena caval blood to the pulmonary circulation by transecting the proximal superior vena caval and performing a direct anastomosis to the right pulmonary artery. The stage III operation (Fontan), at ≈3 years, directs the remaining inferior vena caval blood flow to the pulmonary artery. Though outcomes have been improving over the past few decades, these procedures are not curative, and overall life expectancy with these conditions remains markedly diminished.1 Much of this mortality is because of dysfunction of the single ventricle, which is usually the morphological right ventricle (RV). The RV is not intended to pump against systemic pressures long term and in the best circumstances fails by the second or third decade of life.2 The only viable option for the failing ventricle is heart transplantation; however, survival after heart transplantation is poor after single ventricle staged palliation.3 Along with increased mortality because of inevitable failure, there is …