Pre-transplant Anemia as a Marker of Short-term Outcomes in Lung Transplant Recipients.

BACKGROUND: Anemia is a risk factor for increased morbidity and mortality in multiple medical conditions, yet the impact of pretransplant anemia in patients with advanced lung disease on post-transplant outcomes remains under-explored. We sought to determine whether pretransplant anemia serves as a marker of altered inflammation in the host and associates with short-term outcomes following lung transplantation. STUDY DESIGN AND METHODS: We performed a single-center, retrospective analysis of 238 lung transplant recipients. We assessed for risk factors of pretransplant anemia and identified associations with short-term post-transplant outcomes. RESULTS: Pretransplant anemia was associated with increased intraoperative transfusion of packed red blood cells and a trend towards increased index hospital length of stay and 1-year mortality. Conversely, pretransplant anemia was associated with a decreased incidence of acute cellular rejection. CONCLUSION: These preliminary data suggest that anemia may be a biomarker of altered inflammation in the host recipient and influences post-transplant outcomes.

Three-year outcomes after bridge to transplantation ECMO-pre- and post-2018 UNOS revised heart allocation system.

BACKGROUND: Utilization of temporary mechanical circulatory support, including veno-arterial extra-corporeal membrane oxygenation as a bridge to heart transplantation (HT) has increased significantly under the revised United Network for Organ Sharing (UNOS) donor heart allocation system. The revised heart allocation system aimed to lower waitlist times and mortality for the most critically ill patients requiring biventricular, nondischargeable, mechanical circulatory support. While previous reports have shown improved 1-year post-HT survival in the current era, 3-year survival and factors associated with mortality among bridge-to-transplant (BTT) extra-corporeal membrane oxygenation (ECMO) patients are not well described. METHODS: We queried the UNOS database for all adult (age ≥ 18 years) heart-only transplants performed between 2010 and 2019. Patients were stratified as either pre- (January 2010-September 2018; era 1) or post-allocation change (November 2018-December 2019; era 2) cohort based on their HT date. Baseline recipient characteristics and post-transplant outcomes were compared. A Cox regression analysis was performed to explore risk factors for 3-year mortality among BTT-ECMO patients in era 2. For each era, 3-year mortality was also compared between BTT ECMO patients and those transplanted without ECMO support. RESULTS: During the study period, 116 patients were BTT ECMO during era 1 and 154 patients during era 2. Baseline recipient characteristics were similar in both groups. Median age was 48 (36-58 interquartile range (IQR)) years in era 2, while it was 51 (27-58 IQR) years in era 1. The majority of BTT-ECMO patients were males in both era 2 and era 1 (77.7% vs 71.5%, p = 0.28). Median ECMO run times while listed for HT were significantly shorter (4 days vs 7 days, p < 0.001) in era 2. Waitlist mortality among BTT ECMO patients was also significantly lower in era 2 (6.3% vs 19.3%, p < 0.001). Post-HT survival at 6 months (94.2% vs 75.9%, p < 0.001), 1 year (90.3% vs 74.2%, p < 0.001), and 3 years (87% vs 66.4%, p < 0.001) was significantly improved in era 2 as compared to era 1. Graft failure at 1 year (10.3% vs 25.8%, p = 0.0006) and 3 years (13.6% vs 33.6%, p = 0.0001) was also significantly lower in era 2 compared to era 1. Three-year survival among BTT ECMO patients in era 2 was similar to that of patients transplanted in era 2 without ECMO support (87% vs 85.7%, p = 0.75). In multivariable analysis of BTT-ECMO patients in era 2, every 1 kg/m2 increase in body mass index was associated with higher mortality at 3 years (hazard ratio (HR) 1.09, 95% CI 1.02-1.15, p = 0.006). Similarly, both post-HT stroke (HR 5.58, 95% CI 2.57-12.14, p < 0.001) and post-HT renal failure requiring hemodialysis (HR 4.36, 95% CI 2.43-7.82, p < 0.001) were also associated with 3-year mortality. CONCLUSIONS: Three years post-HT survival in patients bridged with ECMO has significantly improved under the revised donor heart allocation system compared to prior system. BTT ECMO recipients under the revised system have significantly shorter ECMO waitlist run times, lower waitlist mortality and 3-year survival similar to those not bridged with ECMO. Overall, the revised allocation system has allowed more rapid transplantation of the sickest patients without a higher post-HT mortality.

Five-day Wearable Respiratory Support With a Novel Ambulatory Pulmonary Assist System in an Awake Ovine Model.

BACKGROUND: The pulmonary assist system (PAS) is a wearable respiratory support system that is currently under development for patients with chronic lung disease as a bridge to lung transplantation or as destination therapy. This study evaluates the long-term performance and biocompatibility of the PAS in a 5-d awake, ovine model. METHODS: The PAS was attached to normal sheep in venovenous configuration. Components of the PAS included a 0.9 m2 surface area oxygenator and a lightweight, battery-powered axial flow pump. The system was also tested using the Abbott PediMag as the control pump. Each sheep was supported on the PAS for 5 d with 2 L/min blood flow and 4 L/min sweep gas. Activated clotting times of 200-240 s were maintained using intravenous heparin. Pump performance, oxygen transfer, oxygenator resistance, and hematologic parameters were measured throughout the support. RESULTS: The PAS, either using the axial flow pump or PediMag (n = 4 each), was well tolerated by the sheep without signs of device-related organ damage or hemolysis. All the studies achieved the full, 5-d study duration. The oxygenator resistance remained consistent without significant clot formation in all experiments with an average resistance of 2.55 ±â€…0.10 mm Hg/(L/min). The system achieved an average oxygen transfer rate of 116.4 ±â€…5.5 mL/min, with an average Hb concentration of 9.2 ±â€…0.6 g/dL. White blood cell, platelet, and hematocrit levels also remained stable and within normal limits throughout the study period. CONCLUSIONS: The PAS provided 5 d of uncomplicated ambulatory respiratory support with minimal clot formation, stable gas exchange, blood flow resistance, and hematologic parameters.

Enhancing Cytoplasmic Expression of Exogenous mRNA through Dynamic Mechanical Stimulation.

Ionizable lipid nanoparticles (LNPs) have been pivotal in combating COVID-19, and numerous preclinical and clinical studies have highlighted their potential in nucleic acid-based therapies and vaccines. However, the effectiveness of endosomal escape for the nucleic acid cargos encapsulated in LNPs is still low, leading to suboptimal treatment outcomes and side effects. Hence, improving endosomal escape is crucial for enhancing the efficacy of nucleic acid delivery using LNPs. Here, a mechanical oscillation (frequency: 65 Hz) is utilized to prompt the LNP-mediated endosomal escape. The results reveal this mechanical oscillation can induce the combination and fusion between LNPs with opposite surface charges, enhance endosomal escape of mRNA by 14%, and increase the transfection efficiency of mRNA up to 1.67 times in the current study. Additionally, cell viability remains high at 99.3% after treatment with oscillation, which is comparable to that of untreated cells. Furthermore, there is no obvious damage to other membranous organelles. Thus, this work presents a user-friendly and safe approach to enhancing endosomal escape of mRNA and boosting gene expression. As a result, our work can be potentially utilized in both research and clinical fields to facilitate LNP-based delivery by enabling more effective release of LNP-encapsulated cargos from endosomes.

Hemocompatibility Evaluation of a Novel Ambulatory Pulmonary Assist System Using a Lightweight Axial-Flow Pump.

The Pulmonary Assist System (PAS) is currently under development as a wearable respiratory assist system. In this study, the hemocompatibility of the PAS's axial-flow mechanical pump (AFP) was compared to other contemporary mechanical pumps in an acute ovine model. The PAS was attached to a normal sheep in a venovenous configuration using one of three pumps: 1) AFP, 2) ReliantHeart HeartAssist 5 (control), or 3) Abbott Pedimag (control) (n = 5 each). Each sheep was supported on the PAS for 12 hours with two L/minute of blood flow and four L/minute of sweep gas. Hemolysis, coagulation, inflammation, and platelet activation and loss were compared among the groups. In this study, the plasma-free hemoglobin (pfHb) was less than 10 mg/dl in all groups. The pfHb was significantly lower in the AFP group compared to other groups. There was no significant clot formation in the pumps and oxygenators in all groups. Furthermore, no significant differences in coagulation (oxygenator resistance, fibrinopeptide A), inflammation (white blood cell counts, IL-8), and platelet activation and loss (p-selectin, platelet counts) were observed among the groups (all, p > 0.05). This study demonstrates equivalent hemocompatibility of the PAS's AFP to other contemporary mechanical pumps with a reduced level of hemolysis on startup.

A Dynamic Sheep Model to Induce Pulmonary Hypertension and Right Ventricular Failure.

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing novel therapeutics for PH requires a clinically relevant large animal model of increased pulmonary vascular resistance and RVF. This manuscript describes the method to induce an ovine PH-RVF model that utilizes left pulmonary artery (LPA) ligation, progressive main pulmonary artery (MPA) banding, and insertion of an RV pressure line for monitoring. The PA cuff and RV pressure tubing are connected to subcutaneous access ports. This model of PH-RVF is a versatile platform to control not only the disease severity, but also the RV's phenotypic response. Subjects undergo progressive PA band adjustments twice per week for approximately 9 weeks with sequential measures of RV pressure, PA cuff pressures, and mixed venous blood gas (SvO2). Subjects can further be exercised on a livestock treadmill while hemodynamic parameters are captured. At the initiation and endpoint of this model, ventricular function and dimensions are assessed using echocardiography. In this model, RV mean and systolic pressure increased to 28 ± 5 and 57 ± 7 mmHg at week 1, and further to 44 ± 7 and 93 ± 18 mmHg by week 9, respectively. Echocardiography demonstrates characteristic findings of PH-RVF, notably RV dilation, increased wall thickness, and septal bowing. The rate of PA banding has a significant impact on SvO2 and thus the model can be titrated to elicit varying RV phenotypes. When the PA cuff is tightened rapidly, it can lead to a precipitous decline in SvO2, leading to RV decompensation, whereas a slower, more paced strategy leads to an adaptive RV stress-load response that maintains physiologic SvO2. A faster rate of PA banding will also lead to more severe liver fibrosis. The addition of controlled exercise provides a useful platform for assessing the effects of physical exertion in a PH-RVF model. This chronic PH-RVF model provides a valuable tool for studying molecular mechanisms, developing diagnostic biomarkers, and evaluating mechanical circulatory support systems.

Cell-type-specific and disease-associated expression quantitative trait loci in the human lung.

Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis. Defining the genetic control of gene expression in a cell-type-specific and context-dependent manner is critical for understanding the mechanisms through which genetic variation influences complex traits and disease pathobiology. To this end, we performed single-cell RNA sequencing of lung tissue from 66 individuals with pulmonary fibrosis and 48 unaffected donors. Using a pseudobulk approach, we mapped expression quantitative trait loci (eQTLs) across 38 cell types, observing both shared and cell-type-specific regulatory effects. Furthermore, we identified disease interaction eQTLs and demonstrated that this class of associations is more likely to be cell-type-specific and linked to cellular dysregulation in pulmonary fibrosis. Finally, we connected lung disease risk variants to their regulatory targets in disease-relevant cell types. These results indicate that cellular context determines the impact of genetic variation on gene expression and implicates context-specific eQTLs as key regulators of lung homeostasis and disease.

Impact of anticoagulation intensity on blood transfusion for venoarterial extracorporeal membrane oxygenation during lung transplantation.

Venoarterial extracorporeal membrane oxygenation is increasingly used for mechanical circulatory support during lung transplant. Optimal intensity of intraoperative anticoagulation would be expected to mitigate thromboembolism without increasing bleeding and blood product transfusions. Yet, the optimal intensity of intraoperative anticoagulation is unknown. We performed a retrospective cohort study of 163 patients who received a bilateral lung transplant at a single center. We categorized the intensity of anticoagulation into 4 groups (very low to high) based on the bolus dose of unfractionated heparin given during lung transplant and compared the rates of intraoperative blood transfusions and the occurrence of thromboembolism between groups. When compared to the very low-intensity group, each higher intensity group was associated with higher red blood cell, fresh frozen plasma, and platelet transfusions. The occurrence of thromboembolism was similar across groups. These preliminary data suggest that lower intensity anticoagulation may reduce the rate of intraoperative blood transfusions, although further study is needed.

Lung-Mimetic Hydrofoam Sealant to Treat Pulmonary Air Leak.

Pulmonary air leak is the most common complication of lung surgery, contributing to post-operative morbidity in up to 60% of patients; yet, there is no reliable treatment. Available surgical sealants do not match the demanding deformation mechanics of lung tissue; and therefore, fail to seal air leak. To address this therapeutic gap, a sealant with structural and mechanical similarity to subpleural lung is designed, developed, and systematically evaluated. This "lung-mimetic" sealant is a hydrofoam material that has alveolar-like porous ultrastructure, lung-like viscoelastic properties (adhesive, compressive, tensile), and lung extracellular matrix-derived signals (matrikines) to support tissue repair. In biocompatibility testing, the lung-mimetic sealant shows minimal cytotoxicity and immunogenicity in vitro. Human primary monocytes exposed to sealant matrikines in vitro upregulate key genes (MARCO, PDGFB, VEGF) known to correlate with pleural wound healing and tissue repair in vivo. In rat and swine models of pulmonary air leak, this lung-mimetic sealant rapidly seals air leak and restores baseline lung mechanics. Altogether, these data indicate that the lung-mimetic sealant can effectively seal pulmonary air leak and promote a favorable cellular response in vitro.

Perioperative Characteristics and Outcomes of Fontan Versus Non-Fontan Patients Undergoing Combined Heart-Liver Transplantation: A Retrospective Cohort Study.

OBJECTIVES: Combined heart-liver transplantation (CHLT) is becoming increasingly frequent as a maturing population of patients with Fontan-palliated congenital heart disease develop advanced liver fibrosis or cirrhosis. The authors present their experience with CHLT for congenital and noncongenital indications, and identify characteristics associated with poor outcomes that may guide intervention in high-risk patients. DESIGN: This was a single-center retrospective cohort study. SETTING: This study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee. PARTICIPANTS: The study included 16 consecutive adult recipients of CHLT at the authors' institution between April 2017 and February 2022. INTERVENTIONS: Eleven patients underwent transplantation for Fontan indications, and 5 were transplanted for non-Fontan indications. MEASUREMENTS AND MAIN RESULTS: Compared with non-Fontan patients, Fontan recipients had longer cardiopulmonary bypass duration (199 v 119 minutes, p =m0.002), operative times (786 v 599 minutes, p = 0.01), and larger blood product transfusions (15.4 v 6.3 L, p = 0.18). Six of 16 patients required extracorporeal membrane oxygenation (ECMO), of whom 4 were Fontan patients who subsequently died. Patients who required ECMO had lower 5-hour lactate clearance (0.0 v 3.5 mmol/L, p = 0.001), higher number of vasoactive infusions, lower pulmonary artery pulsatility indices (0.58 v 1.77, p = 0.03), and higher peak inspiratory pressures (28.0 v 18.5 mmHg, p = 0.01) after liver reperfusion. CONCLUSIONS: Combined heart-liver transplantation in patients with Fontan-associated end-organ disease is particularly challenging and associated with higher recipient morbidity compared with non-Fontan-related CHLT. Early hemodynamic intervention for signs of ventricular dysfunction may improve outcomes in this growing high-risk population.

Ambulatory 7-day mechanical circulatory support in sheep model of pulmonary hypertension and right heart failure.

BACKGROUND: Right heart failure is the major cause of death in pulmonary hypertension. Lung transplantation is the only long-term treatment option for patients who fail medical therapy. Due to the scarcity of donor lungs, there is a critical need to develop durable mechanical support for the failing right heart. A major design goal for durable support is to reduce the size and complexity of devices to facilitate ambulation. Toward this end, we sought to deploy wearable mechanical support technology in a sheep disease model of chronic right heart failure. METHODS: In 6 sheep with chronic right heart failure, a mechanical support system consisting of an extracorporeal blood pump coupled with a gas exchange unit was attached in a right atrium-to-left atrium configuration for up to 7 days. Circuit performance, hematologic parameters, and animal hemodynamics were analyzed. RESULTS: Six subjects underwent the chronic disease model for 56 to 71 days. Three of the subjects survived to the 7-day end-point for circulatory support. The circuit provided 2.8 (0.5) liter/min of flow compared to the native pulmonary blood flow of 3.5 (1.1) liter/min. The animals maintained physiologically balanced blood gas profile with a sweep flow of 1.2 (1.0) liter/min. Two animals freely ambulated while wearing the circuit. CONCLUSIONS: Our novel mechanical support system provided physiologic support for a large animal model of pulmonary hypertension with right heart failure. The small footprint of the circuit and the low sweep requirement demonstrate the feasibility of this technology to enable mobile ambulatory applications.

Recovery of extracorporeal lungs using cross-circulation with injured recipient swine.

OBJECTIVE: Lung transplantation remains limited by the shortage of healthy organs. Cross-circulation with a healthy swine recipient provides a durable physiologic environment to recover injured donor lungs. In a clinical application, a recipient awaiting lung transplantation could be placed on cross-circulation to recover damaged donor lungs, enabling eventual transplantation. Our objective was to assess the ability of recipient swine with respiratory compromise to tolerate cross-circulation and support recovery of donor lungs subjected to extended cold ischemia. METHODS: Swine donor lungs (n = 6) were stored at 4 °C for 24 hours while recipient swine (n = 6) underwent gastric aspiration injury before cross-circulation. Longitudinal multiscale analyses (blood gas, bronchoscopy, radiography, histopathology, cytokine quantification) were performed to evaluate recipient swine and extracorporeal lungs on cross-circulation. RESULTS: Recipient swine lung injury resulted in sustained, impaired oxygenation (arterial oxygen tension/inspired oxygen fraction ratio 205 ± 39 mm Hg vs 454 ± 111 mm Hg at baseline). Radiographic, bronchoscopic, and histologic assessments demonstrated bilateral infiltrates, airway cytokine elevation, and significantly worsened lung injury scores. Recipient swine provided sufficient metabolic support for extracorporeal lungs to demonstrate robust functional improvement (0 hours, arterial oxygen tension/inspired oxygen fraction ratio 138 ± 28.2 mm Hg; 24 hours, 539 ± 156 mm Hg). Multiscale analyses demonstrated improved gross appearance, aeration, and cellular regeneration in extracorporeal lungs by 24 hours. CONCLUSIONS: We demonstrate that acutely injured recipient swine tolerate cross-circulation and enable recovery of donor lungs subjected to extended cold storage. This proof-of-concept study supports feasibility of cross-circulation for recipients with isolated lung disease who are candidates for this clinical application.

Pilot Testing of a Lightweight, Pulmonary Assist System in an Ambulatory Sheep Model of Destination Therapy Respiratory Support.

A new, lightweight (2.3 kg), ambulatory pulmonary assist system (PAS) underwent preliminary evaluation in ambulatory sheep. The PAS was purposefully designed for long-term extracorporeal respiratory support for chronic lung disease and utilizes a novel, small (0.9 m 2 surface area) gas exchanger, the pulmonary assist device, with a modified Heart Assist 5 pump fitting in a small wearable pack. Prototype PAS were attached to two sheep in venovenous configuration for 7 and 14 days, evaluating ability to remain thrombus free; maintain gas exchange and blood flow resistance; avoid biocompatibility-related complications while allowing safe ambulation. The PAS achieved 1.56 L/min of flow at 10.8 kRPM with a 24 Fr cannula in sheep one and 2.0 L/min at 10.5 kRPM with a 28 Fr cannula in sheep 2 without significant change. Both sheep walked freely, demonstrating the first application of truly ambulatory ECMO in sheep. While in vitro testing evaluated PAS oxygen transfer rates of 104.6 ml/min at 2 L/min blood flow, oxygen transfer rates averaged 60.6 ml/min and 70.6 ml/min in studies 1 and 2, due to average hemoglobin concentrations lower than humans (8.9 and 10.5 g/dl, respectively). The presented cases support uncomplicated ambulation using the PAS.

Extracorporeal Life Support for Cardiogenic Shock in Adult Congenital Heart Disease-An ELSO Registry Analysis.

There are minimal data on the use of venoarterial extracorporeal membrane life support (VA-ECLS) in adult congenital heart disease (ACHD) patients presenting with cardiogenic shock (CS). This study sought to describe the population of ACHD patients with CS who received VA-ECLS in the Extracorporeal Life Support Organization (ELSO) Registry. This was a retrospective analysis of adult patients with diagnoses of ACHD and CS in ELSO from 2009-2021. Anatomic complexity was categorized using the American College of Cardiology/American Heart Association 2018 guidelines. We described patient characteristics, complications, and outcomes, as well as trends in mortality and VA-ECLS utilization. Of 528 patients who met inclusion criteria, there were 32 patients with high-complexity anatomy, 196 with moderate-complexity anatomy, and 300 with low-complexity anatomy. The median age was 59.6 years (interquartile range, 45.8-68.2). The number of VA-ECLS implants increased from five implants in 2010 to 81 implants in 2021. Overall mortality was 58.3% and decreased year-by-year (ß= -2.03 [95% confidence interval, -3.36 to -0.70], p = 0.007). Six patients (1.1%) were bridged to heart transplantation and 21 (4.0%) to durable ventricular assist device. Complications included cardiac arrhythmia/tamponade (21.6%), surgical site bleeding (17.6%), cannula site bleeding (11.4%), limb ischemia (7.4%), and stroke (8.7%). Utilization of VA-ECLS for CS in ACHD patients has increased over time with a trend toward improvement in survival to discharge.

Mortality in Patients with Obesity and Acute Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation: The Multicenter ECMObesity Study.

Rationale: Patients with obesity are at increased risk for developing acute respiratory distress syndrome (ARDS). Some centers consider obesity a relative contraindication to receiving extracorporeal membrane oxygenation (ECMO) support, despite growing implementation of ECMO for ARDS in the general population. Objectives: To investigate the association between obesity and mortality in patients with ARDS receiving ECMO. Methods: In this large, international, multicenter, retrospective cohort study, we evaluated the association of obesity, defined as body mass index ⩾ 30 kg/m2, with ICU mortality in patients receiving ECMO for ARDS by performing adjusted multivariable logistic regression and propensity score matching. Measurements and Main Results: Of 790 patients with ARDS receiving ECMO in our study, 320 had obesity. Of those, 24.1% died in the ICU, compared with 35.3% of patients without obesity (P < 0.001). In adjusted models, obesity was associated with lower ICU mortality (odds ratio, 0.63 [95% confidence interval, 0.43-0.93]; P = 0.018). Examined as a continuous variable, higher body mass index was associated with decreased ICU mortality in multivariable regression (odds ratio, 0.97 [95% confidence interval, 0.95-1.00]; P = 0.023). In propensity score matching of 199 patients with obesity to 199 patients without, patients with obesity had a lower probability of ICU death than those without (22.6% vs. 35.2%; P = 0.007). Conclusions: Among patients receiving ECMO for ARDS, those with obesity had lower ICU mortality than patients without obesity in multivariable and propensity score matching analyses. Our findings support the notion that obesity should not be considered a general contraindication to ECMO.

Safety and utility of indwelling pleural catheters in lung transplant recipients.

INTRODUCTION: The safety and efficacy of indwelling pleural catheters (IPCs) in lung allograft recipients is under-reported. METHODS: We performed a multicenter, retrospective analysis between 1/1/2010 and 6/1/2022 of consecutive IPCs placed in lung transplant recipients. Outcomes included incidence of infectious and non-infectious complications and rate of auto-pleurodesis. RESULTS: Seventy-one IPCs placed in 61 lung transplant patients at eight centers were included. The most common indication for IPC placement was recurrent post-operative effusion. IPCs were placed at a median of 59 days (IQR 40-203) post-transplant and remained for 43 days (IQR 25-88). There was a total of eight (11%) complications. Infection occurred in five patients (7%); four had empyema and one had a catheter tract infection. IPCs did not cause death or critical illness in our cohort. Auto-pleurodesis leading to the removal of the IPC occurred in 63 (89%) instances. None of the patients in this cohort required subsequent surgical decortication. CONCLUSIONS: The use of IPCs in lung transplant patients was associated with an infectious complication rate comparable to other populations previously studied. A high rate of auto-pleurodesis was observed. This work suggests that IPCs may be considered for the management of recurrent pleural effusions in lung allograft recipients.