Faculty Bibliography

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

OBJECTIVE/UNASSIGNED:This study aimed to evaluate the impact of cardiopulmonary bypass for thoraco-abdominal normothermic regional perfusion on the metabolic milieu of donation after cardiac death organ donors before transplantation. METHODS/UNASSIGNED:Local donation after cardiac death donor offers are assessed for suitability and willingness to participate. Withdrawal of life-sustaining therapy is performed in the operating room. After declaration of circulatory death and a 5-minute observation period, the cardiac team performs a median sternotomy, ligation of the aortic arch vessels, and initiation of thoraco-abdominal normothermic regional perfusion via central cardiopulmonary bypass at 37 °C. Three sodium chloride zero balance ultrafiltration bags containing 50 mEq sodium bicarbonate and 0.5 g calcium carbonate are infused. Arterial blood gas measurements are obtained every 15 minutes after every zero balance ultrafiltration bag is infused, and blood is transfused as needed to maintain hemoglobin greater than 8 mg/dL. Cardiopulmonary bypass is weaned with concurrent hemodynamic and transesophageal echocardiogram evaluation of the donor heart. The remainder of the procurement, including the abdominal organs, proceeds in a similar controlled fashion as is performed for a standard donation after brain death donor. RESULTS/UNASSIGNED:.001) . On average, donation after cardiac death donors received transfusions of 2.3 ± 1.5 units of packed red blood cells. Of the 18 donors who underwent normothermic regional perfusion, all hearts were deemed suitable for recovery and successfully transplanted, a yield of 100%. Other organs successfully recovered and transplanted include kidneys (80.6% yield), livers (66.7% yield), and bilateral lungs (27.8% yield). CONCLUSIONS/UNASSIGNED:The use of cardiopulmonary bypass for thoraco-abdominal normothermic regional perfusion is a burgeoning option for improving the quality of organs from donation after cardiac death donors. Meticulous intraoperative management of donation after cardiac death donors with a specific focus on improving their metabolic milieu may lead to improved graft function in transplant recipients.

OBJECTIVE:This pilot study sought to evaluate the feasibility of our donation after circulatory death (DCD) heart transplantation protocol using cardiopulmonary bypass (CPB) for normothermic regional reperfusion (NRP). METHODS:Suitable local DCD candidates were transferred to our institution. Life support was withdrawn in the operating room (OR). On declaration of circulatory death, sternotomy was performed, and the aortic arch vessels were ligated. CPB was initiated with left ventricular venting. The heart was reperfused, with correction of any metabolic abnormalities. CPB was weaned, and cardiac function was assessed at 30-minute intervals. If accepted, the heart was procured with cold preservation and transplanted into recipients in a nearby OR. RESULTS:Between January 2020 and January 2021, a total of 8 DCD heart transplants were performed: 6 isolated hearts, 1 heart-lung, and 1 combined heart and kidney. All donor hearts were successfully resuscitated and weaned from CPB without inotropic support. Average lactate and potassium levels decreased from 9.39 ± 1.47 mmol/L to 7.20 ± 0.13 mmol/L and 7.49 ± 1.32 mmol/L to 4.36 ± 0.67 mmol/L, respectively. Post-transplantation, the heart-lung transplant recipient required venoarterial extracorporeal membrane oxygenation for primary lung graft dysfunction but was decannulated on postoperative day 3 and recovered uneventfully. All other recipients required minimal inotropic support without mechanical circulatory support. Survival was 100% with a median follow-up of 304 days (interquartile range, 105-371 days). CONCLUSIONS:DCD heart transplantation outcomes have been excellent. Our DCD protocol is adoptable for more widespread use and will increase donor heart availability in the United States.

BACKGROUND:Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS:We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS:in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS:Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).

BACKGROUND:Measuring an accurate blood pressure (BP) in ambulatory patients is critical for therapeutic decisions. An accurate noninvasive device that measures BP continuously could provide a more comprehensive assessment of BP. The aim of this study was to determine whether the LiveOne device, a cuffless wristband that provides continuous BP measurements, is accurate in comparison to an invasive arterial line (A-line). METHODS:We enrolled hospitalized patients and healthy volunteers in this multicenter study. All patients had an invasive A-line. Waveforms were simultaneously downloaded from the A-line and LiveOne device. The primary outcome was the correlation between the LiveOne device and the A-line for systolic BP (SBP) and diastolic BP (DBP). RESULTS:34 patients with 233 measurement periods were included. Mean age was 60.7 ± 15.2 years, and 15 (44%) were female. The correlation for SBP was 0.91 and for DBP was 0.85. The mean band error was 0.0 ± 6.9 mmHg for SBP and 1.2 ± 5.7 mmHg for DBP. The mean absolute error was 8.2 ± 5.8 mmHg for SBP and 6.4 ± 3.9 mmHg for DBP. For SBP, 98% of LiveOne measurements were within 15 mmHg and for DBP, 92% of LiveOne measurements were within 10 mmHg. CONCLUSIONS:The LiveOne device provides continuous, noninvasive BP measurements that are accurate in comparison to A-line measurements. The portability and unobtrusive nature of this device and the ability to provide continuous BP measurements may offer advantages over currently available BP monitors. (NCT03919136).

Intra-aortic balloon pumps (IABPs) can be used to provide hemodynamic support in patients with end-stage heart failure as a bridge to transplantation (BTT). The IABP is commonly inserted via the common femoral artery, which can limit patients' mobility. The Ramsey protocol, developed by a critical care physical therapist, allows patients with femoral IABPs to ambulate with the assistance of a tilt table. The aim of this study was to determine the safety and feasibility of a modified Ramsey protocol for early mobilization of patients with femoral IABPs as BTT. This is a retrospective single-center review of patients with femoral IABPs as BTT using a tilt table protocol from May 2019 to May 2020. Primary outcomes were time to successful ambulation, number of successful ambulation events, and ambulation-associated adverse events, including IABP augmentation, waveform, positioning changes, and vascular complications at the insertion site. Twenty-four patients (mean age 55 ± 16 years) underwent femoral IABP insertion as BTT and were mobilized following our protocol. Nineteen patients (79.2%) successfully ambulated with a median of three sessions (interquartile range, 2-4) per patient. The median time from IABP insertion to ambulation was 3 days (interquartile range, 2-5). Twenty-one patients underwent heart transplantation, of which all 19 who ambulated were successfully bridged to transplantation. Early mobilization in select patients with femoral IABPs can be performed safely and successfully, avoiding the deleterious effects of bed rest that have been historically seen in this patient population.

Purpose: In the U.S., heart transplantation from donation after circulatory death (DCD) is increasing. We present our institutional experience of DCD transplantation by using a thoracoabdominal-normothermic regional perfusion (TA-NRP) protocol and compare the results to a cohort concomitantly transplanted, from standard brain death (

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) provides life-saving support in severe coronavirus disease-19 (COVID-19) infections resulting in acute hypoxemic respiratory failure refractory to conventional medication support. We examine the trend of inflammatory markers, including D-dimers, in COVID-19 patients requiring extracorporeal support.
METHOD(S): We retrospectively analyzed 29 patients with COVID-19 infection requiring veno-venous (VV) ECMO. Demographics, pre-ECMO characteristics, complications, and blood product requirements were compared between patients with D-dimer levels < 3,000 versus >3,000 ng/ mL using independent two-sample Student's t-tests for continuous variables and chi-squared test for categorical variables. Inflammatory marker levels for patients before and after circuit exchanges were compared using paired samples t-tests.
RESULT(S): COVID-19 patients with pre-cannulation D-dimer levels >3,000 ng/mL had a significantly shorter time from admission to cannulation (4.78 vs 8.44 days, p=0.049) compared to those with D-dimer < 3,000 ng/mL. Furthermore, patients with D-dimer >3,000 ng/mL had a trend of lower pH (7.24 vs 7.33), higher pCO2 (61.33 vs 50.69), and higher VIS scores (7.23 vs 3.97) at time of cannulation, however these were not statistically significant. This cohort of patients also required longer duration of ECMO support (51.44 vs 31.25 days). 13 patients required at least one ECMO-circuit exchange and 16 patients did not require any exchanges. There was a consistent drop in D-dimer values after every circuit exchange, which was not observed in any of the other examined inflammatory markers including Ferritin, LDH, or CRP.
CONCLUSION(S): Elevated D-dimer levels (>3,000 ng/mL) likely reflect increased disease severity in COVID-19, and predict a longer ECMO course. Once on ECMO, however, the D-Dimer level consistently decreased with circuit exchange and may reflect thrombus within the oxygenator rather than disease severity

INTRODUCTION: An extracorporeal membrane oxygenation (ECMO) circuit exchange is a commonly encountered procedure with potential for significant hemodynamic risks in patients with already compromised physiology. We aim to examine potential predictors and safety of circuit exchanges (CE) in COVID-19 patients receiving veno-venous (VV) ECMO support.
METHOD(S): This is a single-center, retrospective study of 29 patients with COVID-19 infection requiring VV ECMO support between March 2020 and April 2020. Pre- ECMO characteristics, complications, and blood product requirements were compared between patients with and without CE using independent two-sample Student's t-tests for continuous variables and chi-squared test for categorical variables.
RESULT(S): Overall survival to discharge was 97% (28/29). 13 patients did not require any CE and 16 patients required a total of 42 CEs. There was no difference in baseline characteristics, pre-ECMO ventilator settings, SOFA, or VIS scores between patients who required a circuit exchange versus those who did not. However, patients who required circuit exchanges had a higher lactate at time of cannulation (1.83 vs 1.32, p=0.011). The CE group had a longer duration of ECMO support (53.31 vs 13.31 days, p=0.004), higher pulmonary complications defined as hemothorax or pneumothorax (8/16 vs 0/13, p=0.003), and higher blood product transfusions including packed red blood cell (5,525 mL vs 1,261 mL, p=0.0001), cryoprecipitate (1,735 mL vs 501 mL, p=0.004), and platelet (486 mL vs 111 mL, p=0.019). In the 42 CEs, no major complications, including hemodynamic instability or cardiac arrest, occurred during the exchange.
CONCLUSION(S): Severity of underlying lung injury, ECMO duration, and pre-cannulation lactate may be markers for potential CE in COVID-19 patients requiring ECMO. They may be associated with higher blood product transfusion requirements and while CEs are procedures performed in hemodynamically tenuous patients, they are able to be performed safely