The ESTS-AIR database-initial results of a multi-institutional database on airway surgery.

OBJECTIVES: Compared to lung resections, airway procedures are relatively rare in thoracic surgery. Despite this, a growing number of dedicated airway centres have formed throughout Europe. These centres are characterized by a close interdisciplinary collaboration and they often act as supra-regional referring centres. To date, most evidence of airway surgery comes from retrospective, single-centre analysis as there is a lack of large-scale, multi-institutional databases. METHODS: In 2018, an initiative was formed, which aimed to create an airway database within the framework of the ESTS database (ESTS-AIR). Five dedicated airway centres were asked to test the database in a pilot phase. A 1st descriptive analysis of ESTS-AIR was performed. RESULTS: A total of 415 cases were included in the analysis. For adults, the most common indication for airway surgery was post-tracheostomy stenosis and idiopathic subglottic stenosis; in children, most resections/reconstructions had to be performed for post-intubation stenosis. Malignant indications required significantly longer resections [36.0 (21.4-50.6) mm] when compared to benign indications [26.6 (9.4-43.8) mm]. Length of hospital stay was 11.0 (4.1-17.3) days (adults) and 13.4 (7.6-19.6) days (children). Overall, the rates of complications were low with wound infections being reported as the most common morbidity. CONCLUSIONS: This evaluation of the 1st cases in the ESTS-AIR database allowed a large-scale analysis of the practice of airway surgery in dedicated European airway centres. It provides proof for the functionality of ESTS-AIR and sets the basis for rolling out the AIR subsection to all centres participating in the ESTS database.

Current use of extracorporeal life support in airway surgery: a narrative review.

Background and Objective: Extracorporeal life support (ECLS) is widely used in patients with severe respiratory or cardiocirculatory failure. The most commonly used extracorporeal membrane oxygenation (ECMO) modes are veno-venous (V-V) and veno-arterial (V-A) ECMO, which can both be achieved by various types of vascular cannulation. Within the scope of tracheobronchial surgery, intraoperative ECLS may occasionally be necessary to provide sufficient oxygenation to a patient throughout a procedure, especially when conventional ventilation strategies are limited. Additionally, V-A ECMO can provide cardiopulmonary support in emergencies and in cases where hemodynamic instability can occur. Methods: This narrative literature review was carried out to identify the use and the specifics of ECLS in airway surgery over the last years. Data from 168 cases were summarized according to the indication for surgery and the mode of ECLS (V-V, V-A). Key Content and Findings: The most common tracheobronchial pathologies in which support was needed were: primary malignant disease of the airways, malignant infiltration, tracheal stenosis, injury of the airway, and congenital airway disease. With increasing experience in ECLS, the number of reported cases performed with intraoperative ECLS increased steadily over the last decade. Conclusions: A trend favoring the use of V-V ECMO over V-A ECMO was identified. These approaches should now be considered indispensable tools for managing challenging surgical cases.

The nodule in the emphysematous lung: an appeal for surgery in a lung volume reduction concept.

Background: Emphysema patients, who are candidates for lung volume reduction surgery (LVRS) usually present with an extensive smoking history and thus have an increased risk for lung. The incidence of pulmonary nodules in emphysematous lungs is high. We therefore aimed to analyse the incidence and histological findings of pulmonary nodules in our LVRS program. Methods: We conducted a retrospective review of all patients who underwent LVRS between 2016 and 2018. Data concerning preoperative workup, 30 days mortality and histopathological findings analysed. Results: Between 2016 and 2018, LVRS was performed in 66 patients. In 18 (27%) a nodule was found in the preoperative computed tomography (CT) scan. Histological findings revealed in two cases squamous cell lung cancer. In two other cases, histopathological findings revealed an anthracotic intrapulmonary lymph node. In eight cases, a tuberculoma was found with a positive culture in one case. The other six histopathological findings were hamartoma, granuloma or sequelae of pneumonia. Conclusions: Malignancy was found in 11.1% of patients presenting with a nodule in preoperative LVRS workup. The relative risk of lung cancer in emphysema patients is increased and if LVRS criteria are fulfilled surgical resection of a pulmonary nodule is a meaningful way to verify the histology.

DOTATOC PET/CT imaging of a typical carcinoid tumor in a human ex-vivo perfused lung lobe.

The use of Isolated lung perfusion (ILP), combined with medical imaging modalities such as positron emission tomography-computed tomography (PET/CT), provides real-time visualization of tumors in ventilated and perfused vital lung tissue. This experiment intends to show the feasibility and benefits of using ILP combined with PET/CT imaging. Following lung surgery on a 49-year-old male, his left lower lobectomy specimen, which held a typical carcinoid tumor, was preserved on normothermic ILP. Gallium-68-Edotreotide ([68Ga]-DOTATOC) was administered into the ILP circuit, and dynamic emission data from PET/CT was acquired. ILP was carried out for 120 minutes. Near physiologic gas exchange and glucose metabolism were preserved throughout the experiment. The time activity curves (TAC) of 5 different volumes of interest (VOI) showed notable differences in tracer uptake over time. The peripheral area of the carcinoid exhibited delayed but high somatostatin receptor agonist uptake compared to the surrounding parenchyma and the intrapulmonary artery. However, the central area of the carcinoid showed very low [68Ga]-DOTATOC uptake. This experiment demonstrates the potential of ILP combined with PET/CT for kinetic modeling in experimental nuclear medicine imaging. By providing visualization of tracer uptake in perfused lung tissue, this model could potentially improve our understanding of tumor physiology and molecular imaging.

Histological Validation of FDG and PSMA-Targeted PET/CT Imaging in a Rare Tracheal Adenoid Cystic Carcinoma.

ABSTRACT: Adenoid cystic carcinomas are the second most common entity of tracheal malignancies, which have an overall incidence as low as only 0.2 in 100,000 persons per year. We present the case of a 64-year-old man with a histologically confirmed adenoid cystic carcinoma who sequentially underwent 18F-FDG PET/CT and 68Ga-PSMA-11 PET/CT within 1 day for staging 3 days before surgical resection of the tumor. Immunohistochemistry revealed PSMA expression of the tumor corroborating the PSMA PET findings.

Lung Volume Reduction Followed by Lung Transplantation in Emphysema-A Multicenter Matched Analysis.

Objective: The impact of previous lung volume reduction surgery (LVRS) or endoscopic lung volume reduction (ELVR) on lung transplantation (LuTX) remains unclear. This study assesses the risk of previous lung volume reduction on the outcome of a later LuTX. Methods: Patients suffering from emphysema who underwent bilateral LuTX were included in this multicenter analysis. Study groups were defined as: previous LVRS, previous ELVR, controls. Imbalances were corrected by coarsened exact matching for center, gender, age, diagnosis, and BMI. A comparative analysis of intraoperative characteristics, perioperative outcome and long-term survival was performed. Results: 615 patients were included (LVRS = 26; ELVR = 60). Compared to controls, LVRS patients had a higher rate of postoperative ECMO (15.4 vs. 3.9%; p = 0.006), whereas ELVR patients suffered more often from wound infections (8.9% vs. 2.5%; p = 0.018). Perioperative outcome, duration of ventilation, ICU stay, and hospital stay were comparable between groups. Bacterial colonization of the airway differed significantly between both LVR groups and controls in pre- and post-LuTX cultures. Survival was not impacted (1-/3-/5-year survival for LVRS: 92.3%/85.7%/77.1%; controls: 91.3%/82.4%/76.3%; p = 0.58 | ELVR: 93.1%/91%/91%; controls 91.2%/81.7%/75.3%; p = 0.17). Conclusion: Lung volume reduction does not impact short and long-time survival after bilateral LuTX. Due to differences in airway colonization after LVR, caution to prevent infectious complications is warranted.

Reversible occlusion of the pulmonary vasculature by transarterial embolisation with degradable starch microspheres: preclinical assessment in a human isolated lung perfusion model.

BACKGROUND: Transpulmonary embolisation (TPE) using degradable starch microspheres (DSM) is a potential approach to treat pulmonary metastases. However, there is a paucity of detailed information on perfusion dynamics. The aim of this study was to establish a human ex vivo isolated lung perfusion (ILP) model to observe and evaluate the effects of DSM-TPE in a near-physiologic setting. METHODS: ILP was carried out on six surgically resected lung lobes. At baseline, computed tomography (CT), including CT perfusion imaging (CTPI), and histopathological sampling were performed (t30). DSM-TPE was initiated and increased stepwise (t45, t60, t75, and t90) to be followed by CT imaging, histopathological sampling, and pulmonary arterial pressure (PAP). After the last assessment (t90), alpha-amylase was injected into the pulmonary artery to allow for DSM hydrolysation and two additional assessments (t105; t120). Histopathological specimens were evaluated using a semiquantitative ordinal score. CTPI was used for time to peak (TTP) analysis. RESULTS: After DSM administration, PAP and TTP increased significantly: PAP slope 95% confidence interval (CI) 0.104-0.483, p = 0.004; TTP t30 versus t45, p = 0.046. After the addition of alpha-amylase, functional parameters reverted to values comparable to baseline. In histopathological samples, embolisation grades increased significantly until t90 (slope 95% CI 0.027-0.066, p < 0.001) and decreased after addition of alpha-amylase (slope 95% CI -0.060-0.012, p = 0.165), CONCLUSIONS: The ILP model demonstrated successfully both the physiologic effect of DSM-TPE on human lungs and its reversibility with alpha-amylase. Thus, it can be used as a near-physiologic preclinical tool to simulate and assess later clinical approaches.

Tracheal Resection after Previous Treatment Provides Comparable Outcome to Primary Surgery.

BACKGROUND: Tracheal and laryngotracheal surgery provides both excellent functional results and long-term outcomes in the treatment of tracheal stenosis. Consequently, challenging re-resections are rarely necessary. The purpose of this study was to compare the outcome of (laryngo-)tracheal re-resection and surgery after bronchoscopic interventions with that of primary surgery. METHODS: Patients undergoing resection for benign tracheal stenosis at our center between 1/2016 and 4/2020 were included. Perioperative characteristics and functional outcomes of patients were used for statistical analysis. RESULTS: Sixty-six patients who underwent (laryngo-)tracheal resection were included (previous resection [A = 6], previous stent [B = 6], previous bronchoscopic intervention w/o stenting [C = 19], untreated [D = 35]). Baseline parameters were largely comparable between groups with exception from group B that had significantly worse lung function. Group A necessitated more complex reconstructions (end-to-end: n = 1: 17%| cricotracheal n = 2: 33%| cricotracheal with mucosectomy n = 2: 33%| laryngoplasty: n = 1: 17%) than patients in group D (end-to-end n = 21: 60%| cricotracheal n = 14: 40%). Postoperative outcomes were comparable throughout groups (intensive care unit: 1[1-18] days; hospital stay: 8[5-71] days). Anastomotic complications were higher after previous stenting (A: 0%; B: 33.3%; C: 10.5%; D: 2.9%; B/D p = 0.008| surgical revisions: A: 16.7%; B: 33.3%; C: 0%; D: 5.7%; B/D, p = 0.035). Overall, postoperative lung function was significantly better (forced expiratory volume in 1 second: 63% ± 24 vs. 75% ± 20; p = 0.001 | PeakEF 3.3 ± 1.9 vs. 5.0 ± 2.2L; p = 0.001). No 90-day mortality was observed in any group. Median follow-up was 12(1-47) months. CONCLUSION: In carefully selected patients treated in a specialized center, tracheal or laryngotracheal resection after previous tracheal interventions provides comparable outcome to primary surgery.

Extracorporeal life support as a bridge to pulmonary retransplantation: prognostic factors for survival in a multicentre cohort analysis.

OBJECTIVES: Pulmonary retransplant (ReTx) is considered a controversial procedure. Despite literature reporting outcomes following ReTx, limited data exist in recipients bridged to their ReTx on extracorporeal life support (ECLS). The goal of this study was to investigate the outcomes of recipients bridged to a first-time ReTx by ECLS. METHODS: We performed a retrospective multicentre cohort analysis from 10 centres in Europe, Asia and North America. The primary outcome was overall survival. Risk factors were analysed using Cox regression models. RESULTS: ECLS as a bridge to a first-time ReTx was performed in 50 recipients (ECLS-ReTx). During the study period, 210 recipients underwent a first-time ReTx without bridging on ECLS (regular-ReTx) and 4959 recipients had a primary pulmonary transplant (index-Tx). The overall 1-year (55%) and 5-year (29%) survival was significantly worse for the ECLS-ReTx group.Compared to the index-Tx group, the mortality risk was significantly higher after ECLS-ReTx [hazard ratio 2.76 (95% confidence interval 1.94-3.91); P < 0.001] and regular-ReTx [hazard ratio 1.65 (95% confidence interval 1.36-2); P < 0.001].In multivariable analysis, recipient age ≥35 years, time interval <1 year from index-Tx, primary graft dysfunction as transplant indication, venoarterial-extracorporeal membrane oxygenation and Zurich donor score ≥4 points were significant risk factors for mortality in ECLS-ReTx recipients. CONCLUSIONS: Recipients for ECLS-ReTx should be carefully selected. Risk factors, such as recipient age, intertransplant interval, primary graft dysfunction as transplant indication and type of ECLS should be kept in mind before bridging these patients on ECLS to ReTx.

Cardiopulmonary response to high-altitude mountaineering in lung transplant recipients-The Jebel Toubkal experience.

OBJECTIVES: Only a small proportion of lung transplant recipients achieve a physical status comparable to healthy individuals in the long term. It is reasonable to hypothesize that the necessary cardiopulmonary adaptation required for strenuous physical exercise may be impaired. Exposure to high altitude provides an optimal platform to study the physiological cardiopulmonary adaptation in lung transplant recipients under aerobic conditions. To gain a deeper understanding, 14 healthy lung transplant recipients and healthcare professionals climbed the highest peak in North Africa (Mount Jebel Toubkal; 4167 m) in September 2019. METHODS: Monitoring included daily assessment of vital signs, repeated transthoracic echocardiography, pulmonary function tests, and capillary blood sampling throughout the expedition. RESULTS: Eleven out of fourteen lung transplant recipients reached the summit. All recipients showed a stable lung function and vital parameters and physiological adaptation of blood gases. Similar results were found in healthy controls. Lung transplant recipients showed worse results in the 6-minute walk test at low and high altitude compared to controls (day 1: 662 m vs. 725 m, p < 0.001, day 5: 656 m vs. 700 m, p = 0.033) and a lack of contractile adaptation of right ventricular function with increasing altitude as measured by tricuspid plane systolic excursion on echocardiography (day 2: 22 mm vs. 24 mm, p = 0.202, day 5: 23 mm vs. 26 mm, p = 0.035). CONCLUSIONS: Strenuous exercise in healthy lung transplant recipients is safe. However, the poorer cardiopulmonary performance in the 6-minute walk test and the lack of right ventricular cardiac adaptation may indicate underlying autonomic dysregulation.

The vascular nature of lung-resident mesenchymal stem cells.

Human lungs bear their own reservoir of endogenous mesenchymal stem cells (MSCs). Although described as located perivascular, the cellular identity of primary lung MSCs remains elusive. Here we investigated the vascular nature of lung-resident MSCs (LR-MSCs) using healthy human lung tissue. LR-MSCs predominately reside within the vascular stem cell niche, the so-called vasculogenic zone of adult lung arteries. Primary LR-MSCs isolated from normal human lung tissue showed typical MSC characteristics in vitro and were phenotypically and functionally indistinguishable from MSCs derived from the vascular wall of adult human blood vessels (VW-MSCs). Moreover, LR-MSCs expressed the VW-MSC-specific HOX code a characteristic to discriminate VW-MSCs from phenotypical similar cells. Thus, LR-MSC should be considered as VW-MSCs. Immunofluorescent analyses of non-small lung cancer (NSCLC) specimen further confirmed the vascular adventitia as stem cell niche for LR-MSCs, and revealed their mobilization and activation in NSCLC progression. These findings have implications for understanding the role of MSC in normal lung physiology and pulmonary diseases, as well as for the rational design of additional therapeutic approaches.

Dataset of a study investigating autologous blood patch pleurodesis in postoperative prolonged air leaks after lung resection.

Prolonged air leak (PAL) after pulmonary resection is one if the most common complications in thoracic surgery. The dataset was obtained from a prospective randomized study investigating autologous blood patch pleurodesis in PAL. Patients were randomized to either receiving 100 ml autologous blood injected at postoperative days five and six (group A) or to watchful waiting (group B). The primary and secondary endpoints focused on differences in the duration of PAL in each group and possible complications. The results were reported in The Journal of Surgical Research. In this Data in Brief article, we provide additional data concerning pain medication and pain score during the first ten postoperative days. This should provide additional insights into the trial.

A Prospective Study Investigating Blood Patch Pleurodesis for Postoperative Air Leaks After Pulmonary Resection.

BACKGROUND: Prolonged air leaks (PALs) after lung resection are one of the most common complications in thoracic surgery. Several options are available to treat PALs. The autologous blood patch pleurodesis is commonly used but has not been thoroughly investigated. MATERIALS AND METHODS: We conducted a prospective randomized study including all consecutive patients with PALs after pulmonary resections. Patients were randomized to either having received pleurodesis by injecting 100 mL autologous blood at d 5 and 6 (Group A) or being placed under observation (Group B). Patients from either group undergoing revisions were further investigated by a post hoc analysis and formed Group C. RESULTS: A total of 24 patients were included: 10 patients were randomized to group A and 14 to group B. Six patients (3 from each group) underwent surgical revision and were included in Group C. Groups A and B did not differ in baseline characteristics. The median time to drainage removal was 9 d (range: 5-23 d) in Group A; 9 d (range: 2-20 d) in Group B; and 6 d in Group C (range: 3-10 d), (A/B versus C, P < 0.04; A versus B was not significant). CONCLUSIONS: There is no evidence indicating a benefit for blood patch pleurodeses in patients undergoing lung resections and presenting with postoperative PALs for more than 5 d. An early operative closure of postoperative air leakage seems to be more effective.

Impact of normothermic ex vivo lung perfusion on early post-transplantation cytomegalovirus infection.

BACKGROUND: The low acceptance rates in lung transplantation underline the importance to use every potential transplantable organ. With the use of normothermic ex vivo lung perfusion (EVLP) there is a potential to use more donor lungs for transplantation. Aim of this study was to evaluate if EVLP has an effect on cytomegalovirus (CMV) infection after lung transplantation. METHODS: Between May 2016 and October 2018, 57 lung transplants were performed. Out of these 21 extended criteria lungs were evaluated by EVLP and 16 transplanted. In a retrospective study, results of EVLP treated lungs were compared with lungs after cold storage preservation (CSP). Donor/recipient CMV IgG status and seroconversion rate was examined. RESULTS: Donors were CMV IgG+ in EVLP 69% and CSP 61% (n.s.). Best pO2 on procurement at FiO2 1.0 was in EVLP 278±76 versus CSP 413±96 mmHg (P≤0.05). Recipients were CMV IgG+ in EVLP 38% and CSP 63% (P<0.07). CMV seroconversion: EVLP 12%, CSP 20% (P<0.05), in the CSP group in 5% recipients with more than 1,000 copies/mL were diagnosed by PCR and treated for CMV infection. Procalcitonin (PCT) levels from day 1 to day 5 were significantly lower for CSP group (P<0.05). 30-day mortality was 12% for EVLP recipients. CONCLUSIONS: Normothermic EVLP did not influence CMV infection rate, however early PCT levels were higher in EVLP group. Short-term results were comparable to standard lung transplantation.

Implementation of an experimental isolated lung perfusion model on surgically resected human lobes.

Isolated lung perfusion (ILP) is an ideal model to study treatment effects on a variety of pathologies. As published research mostly relies on rejected donor lungs or animal organs, this study investigates the use of surgically resected human lobes as an alternative and novel model for personalized experimental research. Ten surgically resected lobes were perfused in acellular and normothermic condition. The indication for surgery was lung cancer. Perfusion and ventilation were adapted to the size of the lobes and both functional and metabolic parameters were assessed during ILP. Patients (age 67.5 y (59-81)|♀n = 3|♂n = 7) underwent anatomic pulmonary lobectomy. Ischemic time between arterial ligation and ILP was 226 minutes (161-525). Median duration of ILP was 135 (87-366) minutes. Gas exchange and mechanical respiratory parameters remained steady during ILP (pulmonary venous pO2 196(151-219) mmHg | peak AWP: 14.5(11-22) cmH2O). Metabolism stayed constant during ILP (Glucose consumption: 1.86 mg/min/LTLC (95%CI: -2.09 to -1.63) | lactate production: 0.005 mmol/min/ LTLC (95%CI: 0.004 to 0.007)). ILP of surgically resected human lobes is a feasible and promising method. By maintaining a near physiological setting, this model may pave the way for future experimental lung research including cancer research, transplantation, physiology, pharmacology and mechanical ventilation.

Inhibition of Radiation-Induced Ccl2 Signaling Protects Lungs from Vascular Dysfunction and Endothelial Cell Loss.

Aims: Radiation-induced normal tissue toxicity often precludes the application of curative radiation doses. Here we investigated the therapeutic potential of chemokine C-C motif ligand 2 (Ccl2) signaling inhibition to protect normal lung tissue from radiotherapy (RT)-induced injury. Results: RT-induced vascular dysfunction and associated adverse effects can be efficiently antagonized by inhibition of Ccl2 signaling using either the selective Ccl2 inhibitor bindarit (BIN) or mice deficient for the main Ccl2 receptor CCR2 (KO). BIN-treatment efficiently counteracted the RT-induced expression of Ccl2, normalized endothelial cell (EC) morphology and vascular function, and limited lung inflammation and metastasis early after irradiation (acute effects). A similar protection of the vascular compartment was detected by loss of Ccl2 signaling in lungs of CCR2-KO mice. Long-term Ccl2 signaling inhibition also significantly limited EC loss and accompanied fibrosis progression as adverse late effect. With respect to the human situation, we further confirmed that Ccl2 secreted by RT-induced senescent epithelial cells resulted in the activation of normally quiescent but DNA-damaged EC finally leading to EC loss in ex vivo cultured human normal lung tissue. Innovation: Abrogation of certain aspects of the secretome of irradiated resident lung cells, in particular signaling inhibition of the senescence-associated secretory phenotype-factor Ccl2 secreted predominantly by RT-induced senescent epithelial cells, resulted in protection of the endothelial compartment. Conclusions: Radioprotection of the normal tissue via Ccl2 signaling inhibition without simultaneous protection or preferable radiosensitization of tumor tissue might improve local tumor control and survival, because higher doses of radiation could be used.

[Extracorporeal membrane oxygenation in Thoracic Surgery - Lung Transplantation]. / Extrakorporale Membranoxygenierung in der Thoraxchirurgie ­ Lungentransplantation.

Extracorporeal membrane oxygenation (ECMO) has become a routine method in thoracic surgery. Recent developments in lung transplantation have led to its widespread acceptance. Firstly, ECMO is increasingly being used to bridge patients to transplantation. The best results in this setting have been described with "awake ECMO". Secondly, ECMO has replaced cardio-pulmonary bypass as the intraoperative standard device in most centres and is used for treatment and prevention of primary graft dysfunction. Refinements of the devices in use and the cannula design allow an individualised approach tailored to the respiratory and haemodynamic situation of the patients and the anticipated duration of ECMO support.

Lung volume reduction followed by lung transplantation-considerations on selection criteria and outcome.

Lung transplantation (LuTX) and lung volume reduction (LVR), either surgical (LVRS: lung volume reduction surgery) or endoscopic (ELVR: endoscopic lung volume reduction), are established therapies in the treatment of end-stage chronic obstructive pulmonary disease (COPD) patients. Careful patient selection is crucial for each intervention. If these techniques are sequentially applied there is a paucity of available data and individual center experiences vary depending on details in selection criteria and operative technique. This review aims to summarize the published data with a focus on LuTX after LVRS. This review covers patient selection for LuTX and LVR, technical considerations, limitations and outcomes. Published literature was identified by systematic search on Medline and appropriate papers were reviewed. Seven case reports/series, 7 comparative observational studies and one multicenter database analysis incorporating a total of 284 patients with LuTX and LVR were evaluated. Prior LVR can significantly affect intraoperative and postoperative risks after subsequent LuTX. Careful patient selection and timing and the choice of appropriate techniques such as minimal invasive LVRS and using ECMO as extracorporeal support during LuTX if required can minimize those risks, ultimately leading to very good postoperative outcomes in terms of lung function and survival. LVRS has the potential to delay listing and to bridge patients to LuTX by improving their physical condition while on the waiting list. After single lung transplantation (SLuTX) contralateral LVRS can counteract the deleterious effects of native lung hyperinflation (NLH). LVR and LuTX are adjunct therapies in the treatment of end-stage COPD. The combination of both can safely be considered in selected patients.

One-year experience with ex vivo lung perfusion: Preliminary results from a single center.

OBJECTIVE: To enlarge the donor pool for lung transplantation, an increasing number of extended criteria donor lungs are used. However, in more than 50% of multi-organ donors the lungs are not used. Ex vivo lung perfusion offers a unique possibility to evaluate and eventually recondition the injured donor lungs. The aim of our study was to assess the enlargement of the donor pool and the outcome with extended criteria donor lungs after ex vivo lung perfusion. PATIENTS AND METHODS: Data were prospectively collected in our lung transplant database. We compared the results of lung transplants after ex vivo lung perfusion with those after conventional cold static preservation. In total, 11 extended criteria donor lungs processed with ex vivo lung perfusion and 41 cold static preservation lungs transplanted consecutively between May 2016 and May 2017 were evaluated. Normothermic ex vivo lung perfusion was performed according to the Toronto protocol for 4 h. Cold static preservation lungs were stored in low-potassium dextran solution. RESULTS: Ex vivo lung perfusion lungs before procurement had significantly lower PaO2/FiO2 (P/F) ratios and more X-ray abnormalities. There were no statistically significant differences for pre-donation ventilation time, smoking history, or sex. After reconditioning with ex vivo lung perfusion, 9 out of 11 processed lungs were considered suitable and successfully transplanted. The mean postoperative ventilation time and in-hospital stay were not significantly different in ex vivo lung perfusion and cold static preservation recipients. CONCLUSION: Ex vivo lung perfusion can safely be used in the evaluation of lungs initially considered not suitable for transplantation. The primary outcome was not negatively affected and normothermic ex vivo lung perfusion is a useful tool to increase the usage of potentially transplantable lungs.

Treatment of primary graft dysfunction after lung transplantation with orally inhaled AP301: A prospective, randomized pilot study.

BACKGROUND: Primary graft dysfunction (PGD) after lung transplantation (LTx) carries significant morbidity and mortality in the early post-operative period and is associated with the development of chronic lung allograft dysfunction. AP301, an activator of epithelial sodium channel-mediated Na+ uptake represents a new concept for prevention and treatment of pulmonary edema and has shown promising results in the pre-clinical setting. This pilot study investigated the clinical effect of inhaled AP301 on patients with development of PGD > 1 according to International Society of Heart and Lung Transplantation criteria after primary LTx in a high-volume center and was conducted as a randomized, placebo-controlled, single-center pilot-study including 20 patients. All consecutive patients fulfilling inclusion criteria were screened for PGD at arrival on the intensive care unit (ICU) after LTx. After randomization, inhaled AP301 or placebo was administered by nebulizer twice daily for 7 days or until extubation. Otherwise, patients were treated according to routine clinical protocol. Partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2) values were obtained until extubation and assessed as a primary outcome parameter. Patients were monitored for 30 days within the study protocol. RESULTS: From July 2013 to August 2014, 20 patients were randomized 1:1 to AP301 (Group 1) or placebo (Group 2). Both groups were comparable with regard to sex (40% women/60% men vs 50% women/50% men), mean age (55 ± 13 vs 54 ± 6 years), comorbidities, and diagnosis leading to LTx. The Pao2/Fio2 ratio at the time of inclusion was comparable in both groups, with a mean 235.65 ± 90.78 vs 214.2 ± 95.84 (p = 0.405), and there was no significant difference in the extravascular lung water index (13.88 ± 5.28 vs 16 ± 6.29 ml/kg, p = 0.476). The primary end point was mean Pao2/Fio2 ratio values between baseline and Day 3. In the AP301 group, only 1 patient was ventilated at Day 4 and no patients were ventilated after Day 4. In the placebo group, 5 patients were ventilated on Day 4 and 2 patients on Days 5, 6, and 7. The mean increase in the Pao2/Fio2 ratio was significantly higher in Group 1 patients, and the mean between baseline and at 72 hours was 365.6 ± 90.4 in Group 1 vs 335.2 ± 42.3 in Group 2 (p = 0.049). The duration of intubation was shorter in Group 1 than in Group 2 patients (2 ± 0.82 vs 3.7 ± 1.95 days; p = 0.02). ICU stay was 7.5 ± 3.13 days in Group 1 vs 10.8 ± 8.65 days in group 2 (p = 0.57). Survival at 30 days was 100%. No severe adverse events were recorded. CONCLUSIONS: This study was designed as a proof-of-concept pilot study. Although it was not powered to achieve statistical significances, the study demonstrated relevant clinical effects of inhaled AP301 on patients with PGD after primary LTx. The improved gas exchange led to a significantly shorter duration of mechanical ventilation and a trend towards a shorter ICU stay. Further investigation of AP301 for treatment of PGD in larger studies is warranted. TRIAL REGISTRATION: The trial is registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000716-21/AT.