Triage of V-V ECMO referrals for COVID-19 respiratory failure.

BACKGROUND: As the pandemic progressed, the use of extracorporeal membrane oxygenation (ECMO) for COVID-19-related acute respiratory distress syndrome increased, and patient triage and transfer to ECMO centers became important to optimize patient outcomes. Our objectives are to identify predictors of patient transfer for veno-venous extracorporeal membrane oxygenation (V-V ECMO) evaluation as well as to describe the outcomes of accepted patients. METHODS: This is a single-center, retrospective analysis of V-V ECMO transfer requests for adult patients with known or suspected COVID-19 and respiratory failure from March 2020 until March 2021. Data were collected prospectively during the triage process for transfer requests as part of clinical patient care at our institution. RESULTS: Of 341 referred patients, 112 (33%) were accepted for transfer to our facility, whereas 229 (67%) patients were declined for transfer. The Classification and Regression Tree analysis showed that patients' high pressure during airway pressure release ventilation (APRV) and age were the variables most significantly associated with the decision to accept or decline patients for transfer. CONCLUSIONS: Our triage process enabled one-third of referred patients to be transferred for evaluation, with nearly 70% of those patients ultimately receiving ECMO support. High ventilator settings on APRV and young age were associated with acceptance for transfer. Accepted patients also had a higher incidence of adjunctive therapies (proning and paralysis) prior to transfer request, less cardiac or renal dysfunction, and a shorter duration of mechanical ventilation. Further research is warranted to investigate the outcomes of nontransferred patients.

Functional recovery in a cohort of ECMO and non-ECMO acute respiratory distress syndrome survivors.

BACKGROUND: The mortality benefit of VV-ECMO in ARDS has been extensively studied, but the impact on long-term functional outcomes of survivors is poorly defined. We aimed to assess the association between ECMO and functional outcomes in a contemporaneous cohort of survivors of ARDS. METHODS: Multicenter retrospective cohort study of ARDS survivors who presented to follow-up clinic. The primary outcome was FVC% predicted. Univariate and multivariate regression models were used to evaluate the impact of ECMO on the primary outcome. RESULTS: This study enrolled 110 survivors of ARDS, 34 of whom were managed using ECMO. The ECMO cohort was younger (35 [28, 50] vs. 51 [44, 61] years old, p < 0.01), less likely to have COVID-19 (58% vs. 96%, p < 0.01), more severely ill based on the Sequential Organ Failure Assessment (SOFA) score (7 [5, 9] vs. 4 [3, 6], p < 0.01), dynamic lung compliance (15 mL/cmH20 [11, 20] vs. 27 mL/cmH20 [23, 35], p < 0.01), oxygenation index (26 [22, 33] vs. 9 [6, 11], p < 0.01), and their need for rescue modes of ventilation. ECMO patients had significantly longer lengths of hospitalization (46 [27, 62] vs. 16 [12, 31] days, p < 0.01) ICU stay (29 [19, 43] vs. 10 [5, 17] days, p < 0.01), and duration of mechanical ventilation (24 [14, 42] vs. 10 [7, 17] days, p < 0.01). Functional outcomes were similar in ECMO and non-ECMO patients. ECMO did not predict changes in lung function when adjusting for age, SOFA, COVID-19 status, or length of hospitalization. CONCLUSIONS: There were no significant differences in the FVC% predicted, or other markers of pulmonary, neurocognitive, or psychiatric functional recovery outcomes, when comparing a contemporaneous clinic-based cohort of survivors of ARDS managed with ECMO to those without ECMO.

Expression of human thrombomodulin by GalTKO.hCD46 pigs modulates coagulation cascade activation by endothelial cells and during ex vivo lung perfusion with human blood.

Thrombomodulin is important for the production of activated protein C (APC), a molecule with significant regulatory roles in coagulation and inflammation. To address known molecular incompatibilities between pig thrombomodulin and human thrombin that affect the conversion of protein C into APC, GalTKO.hCD46 pigs have been genetically modified to express human thrombomodulin (hTBM). The aim of this study was to evaluate the impact of transgenic hTBM expression on the coagulation dysregulation that is observed in association with lung xenograft injury in an established lung perfusion model, with and without additional blockade of nonphysiologic interactions between pig vWF and human GPIb axis. Expression of hTBM was variable between pigs at the transcriptional and protein level. hTBM increased the activation of human protein C and inhibited thrombosis in an in vitro flow perfusion assay, confirming that the expressed protein was functional. Decreased platelet activation was observed during ex vivo perfusion of GalTKO.hCD46 lungs expressing hTBM and, in conjunction with transgenic hTBM, blockade of the platelet GPIb receptor further inhibited platelets and increased survival time. Altogether, our data indicate that expression of transgenic hTBM partially addresses coagulation pathway dysregulation associated with pig lung xenograft injury and, in combination with vWF-GP1b-directed strategies, is a promising approach to improve the outcomes of lung xenotransplantation.

Increased human complement pathway regulatory protein gene dose is associated with increased endothelial expression and prolonged survival during ex-vivo perfusion of GTKO pig lungs with human blood.

INTRODUCTION: Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival of pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased human CD46 gene dose, through homozygosity or additional expression of a second hCPRP, is associated with increased protein expression and with improved protection from injury when GTKO lung xenografts are perfused with human blood. METHODS: Twenty three GTKO lungs heterozygous for human CD46 (GTKO.heteroCD46), 10 lungs homozygous for hCD46 (GTKO.homoCD46), and six GTKO.homoCD46 lungs also heterozygous for hCD55 (GTKO.homoCD46.hCD55) were perfused with human blood for up to 4 h in an ex vivo circuit. RESULTS: Relative to GTKO.heteroCD46 (152 min, range 5-240; 6/23 surviving at 4 h), survival was significantly improved for GTKO.homoCD46 (>240 min, range 45-240, p = .034; 7/10 surviving at 4 h) or GTKO.homoCD46.hCD55 lungs (>240 min, p = .001; 6/6 surviving at 4 h). Homozygosity was associated with increased capillary expression of hCD46 (p < .0001). Increased hCD46 expression was associated with significantly prolonged lung survival (p = .048),) but surprisingly not with reduction in measured complement factor C3a. Hematocrit, monocyte count, and pulmonary vascular resistance were not significantly altered in association with increased hCD46 gene dose or protein expression. CONCLUSION: Genetic engineering approaches designed to augment hCPRP activity - increasing the expression of hCD46 through homozygosity or co-expressing hCD55 with hCD46 - were associated with prolonged GTKO lung xenograft survival. Increased expression of hCD46 was associated with reduced coagulation cascade activation, but did not further reduce complement activation relative to lungs with relatively low CD46 expression. We conclude that coagulation pathway dysregulation contributes to injury in GTKO pig lung xenografts perfused with human blood, and that the survival advantage for lungs with increased hCPRP expression is likely attributable to improved endothelial thromboregulation.

Venoarterial Extracorporeal Membrane Oxygenation With or Without Advanced Intervention for Massive Pulmonary Embolism.

INTRODUCTION: Massive pulmonary embolism (MPE) is a rare but highly fatal condition. Our study's objective was to evaluate the association between advanced interventions and survival among patients with MPE treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: This is a retrospective review of the Extracorporeal Life Support Organization (ELSO) registry data. We included adult patients with MPE who were treated with VA-ECMO during 2010-2020. Our Primary outcome was survival to hospital discharge; secondary outcomes were ECMO duration among survivors and rates of ECMO-related complications. Clinical variables were compared using the Pearson chi-square and Kruskal-Wallis H tests. RESULTS: We included 802 patients; 80 (10%) received SPE and 18 (2%) received CDT. Overall, 426 (53%) survived to discharge; survival was not significantly different among those treated with SPE or CDT on VA-ECMO (70%) versus VA-ECMO alone (52%) or SPE or CDT before VA-ECMO (52%). Multivariable regression found a trend towards increased survival among those treated with SPE or CDT while on ECMO (AOR 1.8, 95% CI 0.9-3.6), but no significant correlation. There was no association between advanced interventions and ECMO duration among survivors, or rates of ECMO-related complications. CONCLUSION: Our study found no difference in survival in patients with MPE who received advanced interventions prior to ECMO, and a slight non-significant benefit in those who received advanced interventions while on ECMO.

Cardiac surgery in acute heparin-induced thrombocytopenia managed with therapeutic plasma exchange and intravenous immunoglobulin.

Background: Urgent surgery requiring heparin exposure during cardiopulmonary bypass can be challenging in patients with acute heparin-induced thrombocytopenia (HIT). The use of treatments such as therapeutic plasma exchange (TPE) to remove HIT antibodies and intravenous immunoglobulin (IVIg) to antagonize HIT antibody-mediated platelet activation are increasingly reported in patients who undergo cardiac surgery. The optimal treatment approach to mitigate the risks of heparin administration in this situation is not known. Key Clinical Question: Can TPE coupled to IVIg allow for safe heparin exposure in patients with HIT? Clinical Approach: TPE and IVIg were used to enable heparin exposure for surgical placement of a left ventricular assist device in a patient with HIT. Serial patient samples were tested in antigen-based and functional HIT assays. Conclusion: Dissociation between antigen-based (enzyme-linked immunosorbent assay) and functional (serotonin release assay) testing was noted, and TPE coupled to IVIg was associated with an excellent clinical response.

Left ventricular systolic dysfunction during acute pulmonary embolism.

BACKGROUND: Heart failure increases the risk of death in acute pulmonary embolism (PE). The role of the left ventricle (LV) in acute PE is not well defined. OBJECTIVE: To identify the prevalence of LV systolic dysfunction, morphology, and prognosis of the LV during an acute PE. METHODS: Retrospective study (26-months) of patients diagnosed with an acute PE presenting with LV systolic dysfunction at the University of Maryland. RESULTS: Among 769 acute PE patients, 78 (10.5 %) had LV systolic dysfunction and 42 (53.8 %) had history of cardiac disease. Patients without history of cardiac disease were younger (mean age [SD] 54.9 [16.8] vs. 62.6 [16.6]; p = 0.04), had a higher BMI (31.2 [12.2] vs. 29.2 [7.7]; p = 0.005), and less hypertension (20 [34.5 %] vs. 38 [65.5 %]; p = 0.0005). A massive PE was most common in patients without history of cardiac disease (8[22.2 %] vs. 2[4.7 %], p = 0.02). There was no difference in clot burden, but right ventricular strain was more frequently seen in patients without history cardiac disease in the initial CT (p = 0.001). The median troponin and lactate were similar in both groups. In 41 patients with follow-up echocardiograms, improvement in LVEF% was observed in patients without cardiac history (median Δ LVEF% [IQR]; 20 [6.2-25.0]). While patients with cardiac disease did not demonstrate similar changes (median Δ LVEF% [IQR]; 0 [-5-17.5]; p = 0.01). In hospital mortality was 12.8 % with no difference between both groups (p = 0.17). CONCLUSION: Pulmonary embolism can be associated with LV systolic dysfunction, even in patients without history of cardiac disease.

Veno-arterial extracorporeal membrane oxygenation without allogeneic blood transfusion: An observational cohort study.

INTRODUCTION: It remains unclear whether patients who will not accept allogeneic blood transfusion can be managed successfully with veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO). The objective of our study was to determine what percentage of V-A ECMO patients were managed without allogeneic blood transfusion. METHODS: This was a retrospective, observational cohort study of patients with cardiogenic shock requiring V-A ECMO between January 2016 and January 2019. The primary outcome was avoidance of any allogeneic blood transfusion. RESULTS: Of the 206 patients included, 23 (11.2%) were managed without any allogeneic blood transfusion. Fourteen (60.9%) avoided allogeneic blood transfusion during their entire hospitalization. "No-transfusion" patients were younger, more commonly men, were less likely to have a prior diagnosis of hypertension or coronary artery disease, had higher baseline hemoglobin, had higher SAVE scores, and were less likely to have received aspirin before ECMO. No patients in the "no-transfusion" group had major bleeding compared to 35% of patients in the blood transfusion group (p < 0.001). In-hospital mortality was 17.4% for those who avoided blood transfusion and 41.5% for those who received blood transfusion (p = 0.04). ECMO duration was significantly shorter in patients who avoided blood transfusion compared to those who received blood transfusion (median 3.5 vs 7 days, p < 0.001). CONCLUSIONS: Select patients can be successfully managed on V-A ECMO without allogeneic blood transfusion. Jehovah's Witnesses and other patients with objections to allogeneic transfusion might be offered V-A ECMO if its anticipated duration is short (e.g. <7 days) and baseline hemoglobin concentration is high (e.g. ≥10 mg/dL).

Decreased PRESET-Score corresponds with improved survival in COVID-19 veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: The PREdiction of Survival on ECMO Therapy Score (PRESET-Score) predicts mortality while on veno-venous extracorporeal membrane oxygenation (VV ECMO) for acute respiratory distress syndrome. The aim of our study was to assess the association between PRESET-Score and survival in a large COVID-19 VV ECMO cohort. METHODS: This was a single-center retrospective study of COVID-19 VV ECMO patients from 15 March 2020, to 30 November 2021. Univariable and Multivariable analyses were performed to assess patient survival and score differences. RESULTS: A total of 105 patients were included in our analysis with a mean PRESET-Score of 6.74. Overall survival was 65.71%. The mean PRESET-Score was significantly lower in the survivor group (6.03 vs 8.11, p < 0.001). Patients with a PRESET-Score less than or equal to six had improved survival compared to those with a PRESET-Score greater than or equal to 8 (97.7% vs. 32.5%, p < 0.001). In a multivariable logistic regression, a lower PRESET-Score was also predictive of survival (OR 2.84, 95% CI 1.75, 4.63, p < 0.001). CONCLUSION: We demonstrate that lower PRESET scores are associated with improved survival. The utilization of this validated, quantifiable, and objective scoring system to help identify COVID-19 patients with the greatest potential to benefit from VV-ECMO appears feasible. The incorporation of the PRESET-Score into institutional ECMO candidacy guidelines can help insure and improve access of this limited healthcare resource to all critically ill patients.

Body mass index does not impact survival in COVID-19 patients requiring veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: With the increased demand for veno-venous extracorporeal membrane oxygenation (VV ECMO) during the COVID-19 pandemic, guidelines for patient candidacy have often limited this modality for patients with a body mass index (BMI) less than 40 kg/m2. We hypothesize that COVID-19 VV ECMO patients with at least class III obesity (BMI ≥ 40) have decreased in-hospital mortality when compared to non-COVID-19 and non-class III obese COVID-19 VV ECMO populations. METHODS: This is a single-center retrospective study of COVID-19 VV ECMO patients from January 1, 2014, to November 30, 2021. Our institution used BMI ≥ 40 as part of a multi-disciplinary VV ECMO candidate screening process in COVID-19 patients. BMI criteria were not considered for exclusion criteria in non-COVID-19 patients. Univariate and multivariable analyses were performed to assess in-hospital mortality differences. RESULTS: A total of 380 patients were included in our analysis: The COVID-19 group had a lower survival rate that was not statistically significant (65.7% vs.74.9%, p = .07). The median BMI between BMI ≥ 40 COVID-19 and non-COVID-19 patients was not different (44.5 vs 45.5, p = .2). There was no difference in survival between the groups (73.3% vs. 78.5%, p = .58), nor was there a difference in survival between the COVID-19 BMI ≥ 40 and BMI < 40 patients (73.3, 62.7, p= .29). Multivariable logistic regression with the outcome of in-hospital mortality was performed and BMI was not found to be significant (OR 0.99, 95% CI 0.89, 1.01; p = .92). CONCLUSION: BMI ≥ 40 was not an independent risk factor for decreased in-hospital survival in this cohort of VV ECMO patients at a high-volume center. BMI should not be the sole factor when deciding VV ECMO candidacy in patients with COVID-19.

New-Onset Atrial Arrhythmias Are Independently Associated With In-Hospital Mortality in Veno-Venous Extracorporeal Membrane Oxygenation.

OBJECTIVE: To explore if atrial arrhythmias are associated with in-hospital mortality in veno-venous extracorporeal membrane oxygenation (VV-ECMO) patients. DESIGN: Retrospective observational cohort study. SETTING: Quaternary care academic medical center. PARTICIPANTS: Patients with respiratory failure requiring VV-ECMO for >24 hours between January 1, 2016, and January 1, 2019. INTERVENTIONS: None, observational study. MEASUREMENTS AND MAIN RESULTS: Two hundred nineteen VV-ECMO patients were included. Patients were stratified by absence or presence of clinically significant atrial arrhythmias during the VV-ECMO run. Atrial arrhythmias were defined as either atrial fibrillation or atrial flutter that occurred during VV-ECMO and required pharmacologic or electrical intervention. The primary outcome was in-hospital mortality. Secondary outcomes included a composite of thrombotic events, which included ischemic stroke and on-pump arterial thrombosis. Other objectives of this analysis included characterization of atrial arrhythmia incidence, risk factors, and management. A total of 67 patients (30.5%) experienced new-onset atrial arrhythmias post-ECMO cannulation. Age, male sex, and norepinephrine use were independently associated with atrial arrhythmia development. In-hospital mortality was significantly higher in the atrial arrhythmia group (38.8% v 19.1%; p = 0.003). In the multivariate logistic regression analysis, atrial arrhythmias during VV-ECMO were independently associated with increased odds of in-hospital mortality (odds ratio, 2.21; 95% confidence interval, 1.08-4.55; p = 0.03), after controlling for Respiratory Extracorporeal Membrane Oxygenation Survival Prediction score, acute renal failure, total norepinephrine dose, and total cannulation time. CONCLUSIONS: New-onset atrial arrhythmias are a frequent complication during VV-ECMO and are independently associated with excessive in-hospital mortality. Thus, their presence may serve as an important prognostic tool in this patient population.

A Dedicated Veno-Venous Extracorporeal Membrane Oxygenation Unit during a Respiratory Pandemic: Lessons Learned from COVID-19 Part I: System Planning and Care Teams.

BACKGROUND: The most critically ill patients with coronavirus disease 2019 (COVID-19) may require advanced support modalities, such as veno-venous extracorporeal membrane oxygenation (VV-ECMO). A systematic, methodical approach to a respiratory pandemic on a state and institutional level is critical. METHODS: We conducted retrospective review of our institutional response to the COVID-19 pandemic, focusing on the creation of a dedicated airlock biocontainment unit (BCU) to treat patients with refractory COVID-19 acute respiratory distress syndrome (CARDS). Data were collected through conversations with staff on varying levels in the BCU, those leading the effort to make the BCU and hospital incident command system, email communications regarding logistic changes being implemented, and a review of COVID-19 patient census at our institution from March through June 2020. RESULTS: Over 2100 patients were successfully admitted to system hospitals; 29% of these patients required critical care. The response to this respiratory pandemic augmented intensive care physician staffing, created a 70-member nursing team, and increased the extracorporeal membrane oxygenation (ECMO) capability by nearly 200%. During this time period, 40 COVID-19 patients on VV-ECMO were managed in the BCU. Challenges in an airlock unit included communication, scarcity of resources, double-bunking, and maintaining routine care. CONCLUSIONS: Preparing for a surge of critically ill patients during a pandemic can be a daunting task. The implementation of a coordinated, system-level approach can help with the allocation of resources as needed. Focusing on established strengths of hospitals within the system can guide triage based on individual patient needs. The management of ECMO patients is still a specialty care, and a systematic and hospital based approach requiring an ECMO team composed of multiple experienced individuals is paramount during a respiratory viral pandemic.

A Dedicated Veno-Venous Extracorporeal Membrane Oxygenation Unit during a Respiratory Pandemic: Lessons Learned from COVID-19 Part II: Clinical Management.

(1) Background: COVID-19 acute respiratory distress syndrome (CARDS) has several distinctions from traditional acute respiratory distress syndrome (ARDS); however, patients with refractory respiratory failure may still benefit from veno-venous extracorporeal membrane oxygenation (VV-ECMO) support. We report our challenges caring for CARDS patients on VV-ECMO and alterations to traditional management strategies. (2) Methods: We conducted a retrospective review of our institutional strategies for managing patients with COVID-19 who required VV-ECMO in a dedicated airlock biocontainment unit (BCU), from March to June 2020. The data collected included the time course of admission, VV-ECMO run, ventilator length, hospital length of stay, and major events related to bleeding, such as pneumothorax and tracheostomy. The dispensation of sedation agents and trial therapies were obtained from institutional pharmacy tracking. A descriptive statistical analysis was performed. (3) Results: Forty COVID-19 patients on VV-ECMO were managed in the BCU during this period, from which 21 survived to discharge and 19 died. The criteria for ECMO initiation was altered for age, body mass index, and neurologic status/cardiac arrest. All cannulations were performed with a bedside ultrasound-guided percutaneous technique. Ventilator and ECMO management were routed in an ultra-lung protective approach, though varied based on clinical setting and provider experience. There was a high incidence of pneumothorax (n = 19). Thirty patients had bedside percutaneous tracheostomy, with more procedural-related bleeding complications than expected. A higher use of sedation was noted. The timing of decannulation was also altered, given the system constraints. A variety of trial therapies were utilized, and their effectiveness is yet to be determined. (4) Conclusions: Even in a high-volume ECMO center, there are challenges in caring for an expanded capacity of patients during a viral respiratory pandemic. Though institutional resources and expertise may vary, it is paramount to proceed with insightful planning, the recognition of challenges, and the dynamic application of lessons learned when facing a surge of critically ill patients.

Type B Aortic Dissection Complicated by Intimo-Intimal Intussusception and Extensive Intimal Denuding: Case Report with Long-term Follow-up.

BACKGROUND: Acute aortic dissection rarely results in circumferential dissections of the aortic intima that may lead to intimo-intimal intussusception (IIS) with complete separation from the aortic wall. Circumferential dissection may then result in distal embolization of the involved intima and media, adding considerable complexity to the management of such cases. Despite the severity of this complication, the natural history of aortic disease following extensive intimal denuding and IIS is not well documented in the literature. Here we present a case with long-term follow-up of type B aortic dissection (TBAD) complicated by IIS and embolization of the intima into the distal aorta following thoracic endovascular aortic repair. METHODS: Medical records and imaging studies were retrospectively reviewed with the approval of the Institutional Review Board. A single patient underwent repair of a TBAD that was complicated by IIS, with follow-up for 6 years. Aortic recovery was monitored with serial computerized tomography scans. RESULTS: During endovascular stent deployment, the patient's dissection progressed circumferentially, leading to distal embolization of the intima and aortic occlusion. An open transabdominal aortic exploration was performed to extract the embolized intima. Despite this severe aortic structural disruption, the patient recovered well postoperatively and exhibited favorable aortic remodeling over long-term follow-up. The denuded aorta did not rupture or develop progressive worsening aneurysmal dilation and the diameter of the involved aortic segment remained stable during follow-up. CONCLUSIONS: Acute TBADs can progress to circumferential intimal separation and IIS when managed with endovascular stenting and balloon dilation. Continued endovascular management once IIS has occurred may lead to further intimal damage, resulting in distal embolization of the intima and aortic occlusion. Thus, IIS may require conversion to open repair. However, in the event that loss of the aortic intima does occur following IIS, it is possible for the denuded aorta to recover well and remain stable with favorable remodeling over long-term follow-up.

Thromboxane and histamine mediate PVR elevation during xenogeneic pig lung perfusion with human blood.

BACKGROUND: Elevated pulmonary vascular resistance (PVR), platelet adhesion, coagulation activation, and inflammation are prominent features of xenolung rejection. Here, we evaluate the role of thromboxane and histamine on PVR, and their contribution to other lung xenograft injury mechanisms. METHODS: GalTKO.hCD46 single pig lungs were perfused ex vivo with fresh heparinized human blood: lungs were either treated with 1-Benzylimidazole (1-BIA) combined with histamine receptor blocker famotidine (n = 4) or diphenhydramine (n = 6), 1-BIA alone (n = 6) or were left untreated (n = 9). RESULTS: Six of the nine control experiments (GalTKO.hCD46 untreated), "survived" until elective termination at 4 hours. Without treatment, initial PVR elevation within the first 30 minutes resolved partially over the following hour, and increased progressively during the final 2 hours of perfusion. In contrast, 1-BIA, alone or in addition to either antihistamine treatment, was associated with low stable PVR. Combined treatments significantly lowered the airway pressure when compared to untreated reference. Although platelet and neutrophil sequestration and coagulation cascade activation were not consistently altered by any intervention, increased terminal wet/dry weight ratio in untreated lungs was significantly blunted by combined treatments. CONCLUSION: Combined thromboxane and histamine pathway blockade prevents PVR elevation and significantly inhibits loss of vascular barrier function when GalTKO.hCD46 lungs are perfused with human blood. Platelet activation and platelet and neutrophil sequestration persist in all groups despite efficient complement regulation, and appear to occur independent of thromboxane and histamine antagonism. Our work identifies thromboxane and histamine as key mediators of xenolung injury and defines those pathways as therapeutic targets to achieve successful xenolung transplantation.

Selective CD28 Inhibition Modulates Alloimmunity and Cardiac Allograft Vasculopathy in Anti-CD154-Treated Monkeys.

BACKGROUND: Selective CD28 inhibition is actively pursued as an alternative to B7 blockade using cytotoxic T lymphocyte antigen 4 Ig based on the hypothesis that the checkpoint immune regulators cytotoxic T lymphocyte antigen 4 and programmed death ligand 1 will induce tolerogenic immune signals. We previously showed that blocking CD28 using a monovalent nonactivating reagent (single-chain anti-CD28 Fv fragment linked to alpha-1 antitrypsin [sc28AT]) synergizes with calcineurin inhibitors in nonhuman primate (NHP) kidney and heart transplantation. Here, we explored the efficacy of combining a 3-week "induction" sc28AT treatment with prolonged CD154 blockade. METHODS: Cynomolgus monkey heterotopic cardiac allograft recipients received sc28AT (10 mg/kg, d0-20, n = 3), hu5C8 (10-30 mg/kg, d0-84, n = 4), or combination (n = 6). Graft survival was monitored by telemetry. Protocol biopsies and graft explants were analyzed for International Society of Heart and Lung Transplantation acute rejection grade and cardiac allograft vasculopathy score. Alloantibody, T-cell phenotype and regulatory T cells were analyzed by flow cytometry. Immunochemistry and gene expression (NanoString) characterized intra-graft cellular infiltration. RESULTS: Relative to modest prolongation of median graft survival time with sc28AT alone (34 days), hu5C8 (133 days), and sc28AT + hu5C8 (141 days) prolonged survival to a similar extent. CD28 blockade at induction, added to hu5C8, significantly attenuated the severity of acute rejection and cardiac allograft vasculopathy during the first 3 months after transplantation relative to hu5C8 alone. These findings were associated with decreased proportions of circulating CD8 and CD3CD28 T cells, and modulation of inflammatory gene expression within allografts. CONCLUSIONS: Induction with sc28AT promotes early cardiac allograft protection in hu5C8-treated NHPs. These results support further investigation of prolonged selective CD28 inhibition with CD40/CD154 blockade in NHP transplants.

Comparative Evaluation of αCD40 (2C10R4) and αCD154 (5C8H1 and IDEC-131) in a Nonhuman Primate Cardiac Allotransplant Model.

BACKGROUND: Specific blockade of T cell costimulation pathway is a promising immunomodulatory approach being developed to replace our current clinical immunosuppression therapies. The goal of this study is to compare results associated with 3 monoclonal antibodies directed against the CD40/CD154 T cell costimulation pathway. METHODS: Cynomolgus monkey heterotopic cardiac allograft recipients were treated with either IDEC-131 (humanized αCD154, n = 9), 5C8H1 (mouse-human chimeric αCD154, n = 5), or 2C10R4 (mouse-rhesus chimeric αCD40, n = 6) monotherapy using a consistent, comparable dosing regimen for 3 months after transplant. RESULTS: Relative to the previously reported IDEC-131-treated allografts, median survival time (35 ± 31 days) was significantly prolonged in both 5C8H1-treated (142 ± 26, P < 0.002) and 2C10R4-treated (124 ± 37, P < 0.020) allografts. IDEC-131-treated grafts had higher cardiac allograft vasculopathy severity scores during treatment relative to either 5C8H1 (P = 0.008) or 2C10R4 (P = 0.0002). Both 5C8H1 (5 of 5 animals, P = 0.02) and 2C10R4 (6/6, P = 0.007), but not IDEC-131 (2/9), completely attenuated IgM antidonor alloantibody (alloAb) production during treatment; 5C8H1 (5/5) more consistently attenuated IgG alloAb production compared to 2C10R4 (4/6) and IDEC-131 (0/9). All evaluable explanted grafts experienced antibody-mediated rejection. Only 2C10R4-treated animals exhibited a modest, transient drop in CD20 lymphocytes from baseline at day 14 after transplant (-457 ± 152 cells/µL) compared with 5C8H1-treated animals (16 ± 25, P = 0.037), and the resurgent B cells were primarily of a naive phenotype. CONCLUSIONS: In this model, CD154/CD40 axis blockade using IDEC-131 is an inferior immunomodulatory treatment than 5C8H1 or 2C10R4, which have similar efficacy to prolong graft survival and to delay cardiac allograft vasculopathy development and antidonor alloAb production during treatment.

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.

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.