Alexis Slama

Clinical ex vivo lung perfusion--pushing the limits.

Ex vivo lung perfusion (EVLP) provides the ability to evaluate donor lungs before transplantation. Yet, limited prospective clinical data exist with regard to its potential to recondition unacceptable donor lungs. This paper summarizes the results of a prospective study of lung transplantation using only initially unacceptable donor lungs, which were improved by EVLP for 2–4 h. From March 2010–June 2011, 13 lungs were evaluated ex vivo. Median donor PaO2 at FiO21.0/PEEP5 was 216 mmHg (range 133–271). Four lungs, all with trauma history, showed no improvement and were discarded. Nine lungs improved to a ΔPO2 higher than 350 mmHg. Median PvO2 at final assessment in these lungs was 466 mmHg (range 434–525). These lungs were transplanted with a median total ischemic time of 577 min (range 486–678). None of the patients developed primary graft dysfunction grades 2 or 3 within 72 h after transplantation. One patient with secondary pulmonary hypertension was left on a planned prolonged extracorporeal membrane oxygenation postoperatively. Median intubation time was 2 days. Thirty‐day mortality was 0%. During the observation period, 119 patients received standard lung transplantation with comparable perioperative outcome. EVLP has a significant potential to improve the quality of otherwise unacceptable donor lungs.

Standard donor lung procurement with normothermic ex vivo lung perfusion: A prospective randomized clinical trial

BACKGROUND Ex vivo lung perfusion (EVLP) was primarily developed for evaluation of impaired donor lungs. The good clinical results raise the question for its possible impact on lungs meeting standard criteria. Before application of EVLP on such lungs enters routine clinical practice, it must be demonstrated whether EVLP would affect or improve outcome when used in standard donor lungs. We performed a prospective randomized trial to investigate the role of EVLP in standard lung transplantation (Tx). METHODS This prospective randomized clinical trial compared patients who underwent Tx with ex vivo evaluated donor lungs with an equivalent patient population without previous EVLP. RESULTS From October 2013 to May 2015, 193 lung Tx were performed at the Medical University of Vienna. During this period, 80 recipient/donor pairs that met the inclusion criteria were included in this trial, 41 pairs in the control group, and 39 in the EVLP group. In the EVLP group, 4 lungs (10.2%) ultimately did not qualify for Tx and were rejected for lung Tx owing to technical reasons (n = 2) and quality criteria (n = 2). Donor and recipient characteristics were comparable in both groups. Total cold ischemic time in the EVLP group was significantly longer for both implanted lungs (first side, 372 minutes vs 291 minutes, p < 0.001; second side, 437 minutes vs 370 minutes, p = 0.001); median duration of surgery showed no differences (277 minutes vs 275 minutes). Median oxygen partial pressure/fraction of inspired oxygen ratio at 24 hours after Tx was 516 (range, 280-557) in the EVLP group and 491 (range, 352-575) in the control group (p = 0.63). Incidence of primary graft dysfunction >1 was lower in the EVLP group at all time points compared with the control group (24 hours, 5.7% vs 19.5%, p = 0.10), and need for post-operative prolonged extracorporeal membrane oxygenation was lower in the EVLP group (5.7% vs 12.2%, p = 0.44). Short-term clinical outcomes did not differ between recipients in the 2 groups. Patients remained intubated (1.6 days vs 1.6 days, p = 0.67), in the intensive care unit (6 days vs 6 days, p = 0.76), and in the hospital (23 days vs 19 days, p = 0.42) for a comparable period of time. The 30-day survival was 97.1% vs 100% (p = 0.46). CONCLUSIONS This study provides evidence that EVLP can safely be used in standard donor lungs. Functional results and perioperative outcome are comparable to those achieved with standard donor lung preservation techniques. As an evaluation tool, EVLP allows clinicians to identify and to possibly exclude lungs with functional impairment. Finally, EVLP can safely extend total preservation time.

Lobar lung transplantation--is it comparable with standard lung transplantation?

Lobar lung transplantation is used mainly for urgent small recipients who are less likely to obtain size matched lungs in due time. Only limited numbers have been published, and we herewith report the largest series of lobar‐LuTX. We analyzed our LuTX database from 1/2001 to 12/2012 and compared the outcome of lobar‐LuTX recipients with those receiving standard LuTX. Seven hundred and seventy‐eighty LuTX (group 1) were performed either in standard technique by implanting the whole lungs (n = 539) or with downsizing by wedge resection of the right middle lobe and/or the left lingula (n = 239). One hundred and thirty‐eight LuTX were performed in lobar technique (group 2) to overcome more pronounced size discrepancies. Patients in group 1 had a different spectrum of diagnoses and were less frequently bridged to LuTX (P < 0.001). Intubation time, ICU stay, and hospital stay were shorter in group 1 (P < 0.001). One‐year survival was 84.8% vs. 65.1%, and 5‐years survival 69.9% vs. 54.9% (P < 0.001). In multivariate analyzes, procedure, diagnosis, and pre‐operative bridging were shown to be significant prognostic factors in survival. Early postoperative outcome in Lobar LuTX was significantly inferior to standard LuTX recipients. However, survival rates of successfully dismissed patients were comparable with standard LuTX (P = 0.168); thereby, Lobar‐LuTX remains an important option in the management of urgent small recipients.

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.

A rare indication for lung transplantation – pulmonary alveolar microlithiasis: institutional experience of five consecutive cases

Pulmonary alveolar microlithiasis (PAM) is a rare lung disease caused by calcifications within the alveolar space. The only known effective treatment for an end‐stage PAM is lung transplantation (LuTX).

Towards a better understanding of ex vivo lung perfusion

Ex vivo lung perfusion (EVLP) is probably the most promising technique currently available to substantially increase the number of acceptable donor lungs and to improve the outcome after lung transplantation. Several ongoing prospective single and multicentre trials are currently investigating the potential and the individual advantages of different platforms available for EVLP. So far, a number of centres have published their individual experiences with EVLP for reassessment and reconditioning of initially unacceptable donor organs. These reports uniformly confirm that shortand mid-term outcome of recipients receiving lungs after EVLP are comparable with those receiving standard donor lungs during the same observation period. This issue of the EJCTS adds two papers on institutional experiences with EVLP to the existing literature. These papers originate from departments with substantially different backgrounds and nicely illustrate some important issues in the development of EVLP programmes. Both centres are using the Toronto technique with acellular Steen Solution [1]. The Foch group reports their results from April 2011 to May 2013. During this time frame, 81 standard double-lung transplants were compared with 31 transplants after EVLP, while 19 high-urgency procedures were excluded [2]. The study was conducted on a national basis in France and 32 of 53 grafts rejected by all other French transplant centres were accepted for EVLP. The outcomes of EVLP and standard donor lung recipients were comparable in all aspects. Furthermore, the introduction of EVLP led to an impressive decrease in waiting time by 60%. A striking feature in this study is that, once accepting the lung into the study, no further efforts to improve or reassess gas exchange within the donor or during the procurement procedure were made. This most likely had an influence on the high conversion rate (96%) after EVLP. An additional evaluation during the procurement procedure should be performed on a routine basis and might avoid the necessity for assessment by EVLP. In contrast to other centres, the Foch group already takes the final decision on acceptance after 2 h of EVLP. In our experience, truly borderline lungs can be more accurately judged by the development of functional values over time rather than by a single measurement reaching a predefined threshold value. The second paper comes from the smaller centre in Turin and reports on the results of 28 standard lung transplants compared with 8 lungs transplanted after EVLP during a similar observation period from July 2011 to February 2013 [3]. In their experience, the conversion rate after EVLP was 72.7% (8/11). Again no significant differences between the groups were observed in terms of clinical outcome parameters, even though the reported primary graft dysfunction (PGD) 3 rates differ substantially from the Foch group. This paper nicely illustrates that, even in departments with a relatively low number of lung transplant procedures, the logistical barriers of implementing an EVLP programme can be overcome. In Turin, the number of transplantations was raised by 29% due to the implementation of EVLP. In smaller centres, the relative increase of transplantable donor lungs might even be higher than in larger centres. Beyond reassessment and reconditioning of initially unacceptable donor organs, the role of EVLP in the preservation of standard donor lungs is currently intensively investigated. A prospective randomized clinical trial assessing a potential benefit of EVLP according to the Toronto protocol in standard donor lungs has been suggested in the discussion of the Turin paper. Such a trial is ongoing in Vienna since October 2013. Additionally, all multicentre trials investigating the different EVLP platforms are listed in the review article from the Newcastle group [4]. This comprehensive overview outlines in detail the development, current knowledge, unsolved questions and potential future directions of EVLP. It might be critically seen that some current trials and some of the recent publications are to a certain extent driven by the competition of different commercially available EVLP platforms. Until now, a thorough scientific evaluation of some differences in the available systems and perfusion strategies is still missing. Furthermore, the best parameters to assess outcome after EVLP are yet to be defined. The frequently used PGD score seems to be a weak measurement in non-blinded trials as the classification of PDG 0 or 3 might depend on the subjective interpretation of a chest X-ray, e.g. in a patient with a P/F ratio of 199. Even though many questions remain to be solved, EVLP is an exciting tool to increase the number of available donor lungs. The role in the procurement of standard donor lungs will become clearer within the next months when the results of multiple ongoing prospective randomized trials are available. Given the intensity of current research, a range of therapeutic interventions might become realistic once longer perfusion periods can be achieved.

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.

Comparison of two strategies for ex vivo lung perfusion

BACKGROUND Two clinically used strategies for ex vivo lung perfusion (EVLP) were compared in a porcine model with respect to lung function, metabolism, inflammatory response, oxidative stress, and cell viability. METHODS Porcine lungs (n = 20) were preserved, harvested, and kept cooled for 2 hours. After randomization, EVLP was performed using a cellular perfusate and open left atrium (COA group) or an acellular perfusate and a closed left atrium (ACA group). Oxygenation (partial pressure of arterial oxygen/fraction of inspired oxygen), compliance, dead space, weight, and perfusate oncotic pressure were registered before and after a 4-hour period of reconditioning. Lung tissue samples were collected before and after EVLP for quantitative polymerase chain reaction analysis of gene expression for inflammatory markers, measurement of tissue hypoxia (hypoxia inducible factor-1α) and oxidative stress (ascorbyl radical), and viability (trypan blue staining) and lung histopathology. RESULTS In 3 of 10 lungs undergoing EVLP in the ACA group, EVLP was terminated prematurely because of severe lung edema and inability to perfuse the lungs. There were no significant differences in changes of lung oxygenation or pulmonary vascular resistance between groups. Compliance decreased and lung weights increased in both groups, but more in the ACA group (p = 0.083 and p = 0.065, respectively). There was no obvious difference in gene expression for hypoxia inducible factor-1α, inflammatory markers, free radicals, or lung injury between groups. CONCLUSIONS Lung edema formation and decreased lung compliance occurs with both EVLP techniques but were more pronounced in the ACA group. Otherwise, there were no differences in lung function, inflammatory response, ischemia/reperfusion injury, or histopathologic changes between the EVLP techniques.

Response to: Sizing considerations in lobar lung transplantation

In Response: We thank Robert Reed and Michael Eberlein for their insightful comments and take the opportunity to clarify the mentioned aspects[6]. Given our possibility of ‘centre allocation’ of donor lungs, our choice of recipient and potential downsizing is dependent on the recipients urgency, real TLC, predicted TLC and chest configuration. Even though the anticipated size mismatch prior to retrieval allows to plan an operative strategy, the definite choice of downsizing procedure is made intraoperatively by size comparison of the open chest cavity and the inflated donor lung. In reduced-size lung transplantation, the estimation of the actually implanted lung volume is difficult and to our knowledge there is yet no generally accepted computational approach [1]. The mentioned value of 20% TLCp difference as an indicator for the need of lobar transplantation is derived from the retrospective review of our data and can be used as an additional parameter in the planning of the transplant procedure; however, it is certainly not to be seen as a definite stand-alone cut-off value. Although we agree that the TLCp-ratio is a valid parameter in decision making, we think that other relevant factors such as TLCr and chest configuration must always be taken into consideration. Our current approach is to aim for an optimal size matching. Even though undersizing was shown to have a worse short-term survival [2] and a higher rate of BOS [3], broad scientific evidence is still missing and another study claims that a wide range of size discrepancies can be accepted without affecting outcome [4]. Oversizing of lungs can be problematic as well with a higher likelihood of oedema, atelectasis, retained secretion and impaired breathing mechanics [5]. The crucial question whether or not to perform lobarLuTX or to wait for a perfectly matched organ cannot be answered definitely by our paper and also strongly depends on local circumstances like donor organ availability and possibilities for patients with bridging acute deteriorating. Finally, we commend Reed and Eberlein on their efforts to further elucidate the importance of optimal size matching and size-reducing measures.