Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers.

BACKGROUND AND AIMS: The scarcity of suitable donor livers highlights a continuing need for innovation to recover organs with reversible injuries in liver transplantation. APPROACH AND RESULTS: Explanted human donor livers (n = 5) declined for transplantation were supported using xenogeneic cross-circulation of whole blood between livers and xeno-support swine. Livers and swine were assessed over 24 hours of xeno-support. Livers maintained normal global appearance, uniform perfusion, and preservation of histologic and subcellular architecture. Oxygen consumption increased by 75% ( p = 0.16). Lactate clearance increased from -0.4 ± 15.5% to 31.4 ± 19.0% ( p = 0.02). Blinded histopathologic assessment demonstrated improved injury scores at 24 hours compared with 12 hours. Vascular integrity and vasoconstrictive function were preserved. Bile volume and cholangiocellular viability markers improved for all livers. Biliary structural integrity was maintained. CONCLUSIONS: Xenogeneic cross-circulation provided multisystem physiological regulation of ex vivo human livers that enabled functional rehabilitation, histopathologic recovery, and improvement of viability markers. We envision xenogeneic cross-circulation as a complementary technique to other organ-preservation technologies in the recovery of marginal donor livers or as a research tool in the development of advanced bioengineering and pharmacologic strategies for organ recovery and rehabilitation.

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.

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.

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.

Multiplatform Single-Cell Analysis Identifies Immune Cell Types Enhanced in Pulmonary Fibrosis.

Immune cells have been implicated in idiopathic pulmonary fibrosis (IPF), but the phenotypes and effector mechanisms of these cells remain incompletely characterized. We performed mass cytometry to quantify immune cell subsets in lungs of 12 patients with IPF and 15 organ donors without chronic lung disease and used existing single-cell RNA-sequencing data to investigate transcriptional profiles of immune cells overrepresented in IPF. Among myeloid cells, we found increased numbers of alveolar macrophages (AMØs) and dendritic cells (DCs) in IPF, as well as a subset of monocyte-derived DCs. In contrast, monocyte-like cells and interstitial macrophages were reduced in IPF. Transcriptomic profiling identified an enrichment for IFN-γ response pathways in AMØs and DCs from IPF, as well as antigen processing in DCs and phagocytosis in AMØs. Among T cells, we identified three subsets of memory T cells that were increased in IPF, including CD4+ and CD8+ resident memory T cells (TRM) and CD8+ effector memory cells. The response to the IFN-γ pathway was enriched in CD4 TRM and CD8 TRM cells in IPF, together with T cell activation and immune response-regulating signaling pathways. Increased AMØs, DCs, and memory T cells were present in IPF lungs compared with control subjects. In IPF, these cells possess an activation profile indicating increased IFN-γ signaling and upregulation of adaptive immunity in the lungs. Together, these studies highlight critical features of the immunopathogenesis of IPF.

Simulation Versus Interactive Mobile Learning for Teaching Extracorporeal Membrane Oxygenation to Clinicians: A Randomized Trial.

OBJECTIVES: Extracorporeal membrane oxygenation has become integral to critical care. Data informing optimal extracorporeal membrane oxygenation education modalities are lacking. We aimed to compare the effect of high-fidelity simulation versus interactive mobile learning on extracorporeal membrane oxygenation knowledge acquisition and retention among clinicians. DESIGN: Observer-blinded, randomized controlled trial. SETTING: A single academic medical center. SUBJECTS: Forty-four critical care clinicians with limited extracorporeal membrane oxygenation experience. INTERVENTIONS: Participants were randomized to receive: 1) simulation: three high-fidelity training scenarios, 2) QuizTime: 15 total multiple-choice questions delivered over 3 weeks via mobile device, or 3) experiential: no formal training. Participants completed a survey, written knowledge examination, and simulation assessment prior to randomization, immediately following the intervention, and 4 month postintervention. MEASUREMENTS AND MAIN RESULTS: The primary outcome was knowledge about extracorporeal membrane oxygenation assessed by score on the immediate postintervention written examination. Secondary outcomes included performance in extracorporeal membrane oxygenation simulation postintervention and 4 months later assessed by a rater blinded to group assignment. Clinicians randomized to simulation (n = 15), QuizTime (n = 14), and experiential (n = 15) had similar baseline characteristics. Adjusting for baseline knowledge, postintervention examination scores were higher in the simulation group (90.0%; interquartile range, 85.0-90.0%) than the QuizTime group (70.0%; interquartile range, 65.0-80.0%; p = 0.0003) and the experiential group (75.0%; interquartile range, 65.0-80.0%; p = 0.001). Scores did not differ between the groups at 4 months (p > 0.05 in all analyses). In postintervention extracorporeal membrane oxygenation simulations, the simulation group demonstrated shorter time to critical action compared with QuizTime (80.0 s [interquartile range, 54.0-111.0 s] vs 300.0 s [interquartile range 85.0-300.0 s]; p = 0.02) and compared with both QuizTime (45.0 s [interquartile range, 34.0-92.5 s] vs 255.5 s [interquartile range, 102.0-300.0 s]; p = 0.008) and experiential (300.0 s [interquartile range, 58.0-300.0 s]; p = 0.009) at 4 months. CONCLUSIONS: Simulation was superior to QuizTime and experiential learning with regard to extracorporeal membrane oxygenation knowledge acquisition. Further studies are needed to ascertain the effect of these interventions on knowledge retention, clinical performance, and patient outcomes.

Left Ventricular Unloading During Extracorporeal Life Support: Current Practice.

Venoarterial extracorporeal life support (VA-ECLS) is a powerful tool that can provide complete cardiopulmonary support for patients with refractory cardiogenic shock. However, VA-ECLS increases left ventricular (LV) afterload, resulting in greater myocardial oxygen demand, which can impair myocardial recovery and worsen pulmonary edema. These complications can be ameliorated by various LV venting strategies to unload the LV. Evidence suggests that LV venting improves outcomes in VA-ECLS, but there is a paucity of randomized trials to help guide optimal strategy and the timing of venting. In this review, we discuss the available evidence regarding LV venting in VA-ECLS, explain important hemodynamic principles involved, and propose a practical approach to LV venting in VA-ECLS.

Clinical course of SARS-CoV-2 infection and recovery in lung transplant recipients.

BACKGROUND: Reports on outcomes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in lung transplant recipients remain limited. METHODS: We performed a single-center, observational study of outcomes in lung transplant recipients diagnosed with SARS-CoV-2 between 5/1/2020 and 3/15/2022 that were followed for a median of 123 days. We analyzed changes in spirometry, acute lung allograft dysfunction (ALAD) incidence, hospitalization, mechanical ventilation needs, secondary infection, and survival. RESULTS: In our cohort of 336 patients, 103 developed coronavirus disease (COVID) (27 pre-Delta, 20 Delta, and 56 Omicron-era). Twenty-five patients (24%) required hospitalization and 10 patients ultimately died (10%). Among 85 survivors who completed ambulatory spirometry, COVID-19 did not alter change in forced expiratory volume in 1 s (FEV1 ) or forced vital capacity (FVC) over time compared to the preceding 6 months. The pre-COVID FEV1 change was -0.05 ml/day (IQR -0.50 to 0.60) compared to -0.20 ml/day (IQR -1.40 to 0.70) post-COVID (p = .16). The pre-COVID change in FVC was 0.20 ml/day (IQR -0.60 to 0.70) compared to 0.05 ml/day (IQR -1.00 to 1.10) post-COVID (p = .76). Although the cohort overall had stable lung function, 33 patients (39%) developed ALAD or accelerated chronic lung allograft dysfunction (FEV1 decline >10% from pre-COVID baseline). Nine patients (35%) with ALAD recovered lung function. Within 3 months of acute COVID infection, 18 patients (17%) developed secondary infections, the majority being bacterial pneumonia. Finally, vaccination with at least two doses of mRNA vaccine was not associated with improved outcomes. CONCLUSIONS: This study describes the natural history of SARS-CoV-2 infection in a large cohort of lung transplant recipients. Although one third of patients develop ALAD requiring augmented immunosuppression, infection with SARS-CoV-2 is not associated with worsening lung function.

Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplant.

Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary technology capable of supporting cardiac and respiratory function in the presence of end-stage lung disease. Initial experiences using ECMO as a bridge to lung transplant (ECMO-BTLT) were characterized by high rates of ECMO-associated complications and poor posttransplant outcomes. More recently, ECMO-BTLT has garnered success in preserving patients' physiologic condition and candidacy prior to lung transplant due to technological advances and improved management. Despite recent growth, clinical practice surrounding use of ECMO-BTLT remains variable, with little data to inform optimal patient selection and management. Although many questions remain, the use of ECMO-BTLT has shown promising outcomes suggesting that ECMO-BTLT can be an effective strategy to ensure that complex and rapidly decompensating patients with end-stage lung disease can be safely transplanted with good outcomes. Further studies are needed to refine and inform practice patterns, management, and lung allocation in this high-risk and fragile patient population.

Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection. METHODS: This open-label, multicentre, single-arm, phase 2 trial was done at three hospitals in the USA. Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1, and a history of smoking exposure. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1, of each 21-day cycle. Patients without disease progression after two cycles proceeded to receive two further cycles, which were then followed by surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting participants. FINDINGS: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12·9 months (IQR 6·2-22·9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response. The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths. INTERPRETATION: Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection. FUNDING: Genentech and Celgene.

Extracorporeal Carbon Dioxide Removal in the Treatment of Status Asthmaticus.

OBJECTIVES: Venovenous extracorporeal carbon dioxide removal may be lifesaving in the setting of status asthmaticus. DESIGN: Retrospective review. SETTING: Medical ICU. PATIENTS: Twenty-six adult patients with status asthmaticus treated with venovenous extracorporeal carbon dioxide removal. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic data and characteristics of current and prior asthma treatments were obtained from the electronic medical record. Mechanical ventilator settings, arterial blood gases, vital signs, and use of vasopressors were collected from the closest time prior to cannulation and 24 hours after initiation of extracorporeal carbon dioxide removal. Extracorporeal carbon dioxide removal settings, including blood flow and sweep gas flow, were collected at 24 hours after initiation of extracorporeal carbon dioxide removal. Outcome measures included rates of survival to hospital discharge, ICU and hospital lengths of stay, duration of invasive mechanical ventilation and extracorporeal carbon dioxide removal support, and complications during extracorporeal carbon dioxide removal. Following the initiation of extracorporeal carbon dioxide removal, blood gas values were significantly improved at 24 hours, as were peak airway pressures, intrinsic positive end-expiratory pressure, and use of vasopressors. Survival to hospital discharge was 100%. Twenty patients (76.9%) were successfully extubated while receiving extracorporeal carbon dioxide removal support; none required reintubation. The most common complication was cannula-associated deep venous thrombosis (six patients, 23.1%). Four patients (15.4%) experienced bleeding that required a transfusion of packed RBCs. CONCLUSIONS: In the largest series to date, use of venovenous extracorporeal carbon dioxide removal in patients with status asthmaticus can provide a lifesaving means of support until the resolution of the exacerbation, with an acceptably low rate of complications. Early extubation in select patients receiving extracorporeal carbon dioxide removal is safe and feasible and avoids the deleterious effects of positive-pressure mechanical ventilation in this patient population.

Opioid and Benzodiazepine Requirements in Obese Adult Patients Receiving Extracorporeal Membrane Oxygenation.

Background: The use of extracorporeal membrane oxygenation (ECMO) sometimes requires deep levels of sedation (Richmond Agitation Sedation Scale [RASS] -5) in patients with acute respiratory distress syndrome (ARDS). The role of obesity in opioid and sedative requirements remains unclear in patients receiving ECMO. Objective: This study sought to determine whether obesity increases midazolam and opioid requirements in patients receiving venovenous (vv)-ECMO up to the first 7 days after initiation. Methods: This was a retrospective cohort study of adult patients with ARDS managed with vv-ECMO. Results: The obese (n = 38) and nonobese (n = 43) groups had similar baseline characteristics. Fentanyl equivalents were significantly higher on day 3 in the obese group (P = 0.02) despite similar RASS scores with no differences in midazolam requirements. There were no differences in duration of ECMO, length of stay, or mortality. Conclusion and Relevance: Daily midazolam requirements were not significantly different, and opioid requirements were only significantly higher in the obese group on day 3 despite similar levels of sedation. The impact of obesity with the addition of ECMO and how to adapt doses of medications remains elusive.

Geographic disparities in donor lung supply and lung transplant waitlist outcomes: A cohort study.

Despite the Final Rule mandate for equitable organ allocation in the United States, geographic disparities exist in donor lung allocation, with the majority of donor lungs being allocated locally to lower-priority candidates. We conducted a retrospective cohort study of 19 622 lung transplant candidates waitlisted between 2006 and 2015. We used multivariable adjusted competing risk survival models to examine the relationship between local lung availability and waitlist outcomes. The primary outcome was a composite of death and removal from the waitlist for clinical deterioration. Waitlist candidates in the lowest quartile of local lung availability had an 84% increased risk of death or removal compared with candidates in the highest (subdistribution hazard ratio [SHR]: 1.84, 95% confidence interval [CI]: 1.51-2.24, P < .001). The transplantation rate was 57% lower in the lowest quartile compared with the highest (SHR: 0.43, 95% CI: 0.39-0.47). The adjusted death or removal rate decreased by 11% with a 50% increase in local lung availability (SHR: 0.89, 95% CI: 0.85-0.93, P < .001) and the adjusted transplantation rate increased by 19% (SHR: 1.19, 95% CI: 1.17-1.22, P < .001). There are geographically disparate waitlist outcomes in the current lung allocation system. Candidates listed in areas of low local lung availability have worse waitlist outcomes.

Frailty phenotypes and mortality after lung transplantation: A prospective cohort study.

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score-adjusted Cox models. We calculated postestimation marginalized standardized risks for 1-year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1- and 4-year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6-36.0 and aHR 3.8; 95%CI: 1.8-8.0, respectively). Each 1-point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08-1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%-21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1-13.2) but not over longer follow-up. Preoperative frailty is associated with an increased risk of death after lung transplantation.

When the momentum has gone: what will be the role of extracorporeal lung support in the future?

PURPOSE OF REVIEW: There has been expanding interest in and use of extracorporeal support in respiratory failure concurrent with technological advances and predominantly observational data demonstrating improved outcomes. However, until there is more available data from rigorous, high-quality randomized studies, the future of extracorporeal support remains uncertain. RECENT FINDINGS: Outcomes for patients supported with extracorporeal devices continue to show favorable trends. There are several large randomized controlled trials that are in various stages of planning or completion for extracorporeal membrane oxygenation (ECMO) and extracorporeal carbon dioxide removal (ECCO2R) in the acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), which may help clarify the role of this technology for these disease processes, and which stand to have a significant impact on a large proportion of patients with acute respiratory failure. Novel applications of extracorporeal lung support include optimization of donor organ quality through ex-vivo perfusion and extracorporeal cross-circulation, allowing for multimodal therapeutic interventions. SUMMARY: Despite the ongoing rise in ECMO use for acute respiratory failure, its true value will not be known until more information is gleaned from prospective randomized controlled trials. Additionally, there are modalities beyond the current considerations for extracorporeal support that have the potential to revolutionize respiratory failure, particularly in the realm of chronic lung disease and lung transplantation.