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Background: Frailty is prevalent in patients awaiting lung transplant (LTx) and is associated with delisting, death while on the waiting list and death after LTx. Decreasing frailty of LTx-candidates could therefore be important to improve pre- and post-LTx-status. Objective: Primary aim was to investigate the effects of a comprehensive PR-program on physical frailty in LTx-candidates. Methods: 32 participants from an inpatient PR-program with a confirmed diagnosis of COPD or interstitial lung disease who were listed or were in the process to be listed for a LTx were consecutively included in this trial. Primary outcome was the change in physical frailty measured by short physical performance battery test (SPPB; score 0-12) performed at PR-admission and discharge. SPPB results can be categorized into frail (SPPB≤7), pre-frail (SPPB=8-9) and not-frail (SPPB≥10). Participants with an SPPB score≤11 were considered for final analyses. Results: 28 participants (60±5years; FEV1 49±26%pred., SPPB-baseline: frail: n=5 [17.9%], pre-frail: n=10 [35.7%]; not-frail: n=13 [46.4%]) were analysed. Baseline SPPB-score (8.8±2.2) significantly (p Conclusion: Our findings show that a comprehensive PR-program can significantly and to a clinically meaningful extent, reduce frailty in LTx-candidates.

Background: International guidelines recommend the use of supplemental oxygen (O2) in IPF patients who suffer from exercise-induced hypoxemia (EIH). As short-term effects of O2 during exercise are not known in IPF patients yet, the aim of our study was to investigate the effects of O2 on the endurance walking capacity in hypoxemic IPF patients. Methods: 53 IPF patients with EIH were investigated in a prospective double-blinded randomized-controlled cross-over trial. Following an initial incremental shuttle walk test (ISWT) which assess the individual maximum gait speed, each patient performed 3 endurance shuttle walk tests (ESWT) at 85%max under following conditions: (A) with medical air (compressed room air)(ESWTMA), (B) with 2 liters/min O2 (ESWT2L) and (C) with 4 liters/min O2 (ESWT4L). Walking endurance time during ESWT was the primary outcome. Data of secondary outcomes (oxygen saturation [SpO2], heart rate [HR], breathing frequency [BF]) were compared at the end of the shortest ESWT ("isotime"). Results: 50 patients (69 y, FVC 72%pred., DLCO 33%pred., ISWT: 389m) completed the study. Endurance walking time was longer during ESWT4L> ESWT2L >ESWTMA (585 sec vs. 462 sec vs. 404 sec, F=3.483, p=0.03). SpO2ISO was higher by breathing O2 and by using a higher flow rate (ESWT4L 88% vs. ESWT2L 85% vs. ESWTMA 80%, F=123.204, p Discussion: O2 showed significant and clinically relevant benefits on walking capacity and oxygen saturation compared to compressed room air in IPF patients with EIH. A dose-dependent effect has been found showing higher vs. lower oxygen flow rates to be more beneficial.

Background: In patients with IPF exercise intolerance is often associated with hypoxemia. Therefore, SOT may be offered. The Oxymizer® is a nasal cannula incorporating an internal reservoir with the potential to deliver higher oxygen (O2) doses to the patient on the same O2-flow compared to a conventional nasal cannula (CNC). Objectives: Primary aim was to investigate the effects of SOT delivered via Oxymizer compared to a CNC in hypoxemic IPF-patients on walking capacity. Secondary aim was to evaluate the effects on O2-saturation (SpO2), heart- and breathing rate at isotime (end of shortest endurance shuttle walk test; ESWT). Methods: 26 patients with a confirmed diagnosis of IPF and SOT-indication during exercise were consecutively included in this trial. After an initial incremental shuttle walk test, patients performed, in randomized order and with a 24h-resting period between tests, two ESWTs - one with Oxymizer and one with CNC. Results: 22 patients (70±7years; VC:54±15%/pred) completed all tests. Walking capacity was significantly greater while using the Oxymizer compared to CNC (523±369vs.419±332sec, p=0.027). 15 patients (68%) walked longer with the Oxymizer. At isotime, SpO2 (81.6±8.8 vs.78.5±8.1%, p=0.001) was significantly higher while heart- (112±16vs.118±13bpm) and breathing rate (38±8vs.41±8bpm) were significantly (p Conclusion: SOT when provided by the Oxymizer showed significant and clinically relevant benefits on walking capacity in IPF-patients by improving physiological parameters. However, only 8 (36%) patients would prefer the Oxymizer for their daily use.

Background: Pulmonary rehabilitation (PR) has been shown to improve cognitive performance in COPD patients even after adjusting for sociodemographic factors. This favourable effect of PR, however, has not been evaluated in COPD lung-transplant (LTx) recipients where immunosuppressant toxicity and/or central nervous system events may be associated with cognitive decline. We investigated the effects of PR on cognitive function in LTx-recipients for COPD. Methods: Twenty-four COPD LTx-recipients (FEV1: 75±22%pred.) were assigned to a 3-week inpatient PR program. A comprehensive neuropsychological battery was used to assess memory, learning skills, attention/ flexibility, visuospatial abilities, psychomotor speed and behavioural activation before and after PR. The magnitude of changes was interpreted by d-Effect Size (ES). Results: In response to PR, LTx-recipients presented small to large improvements (ES range: 0.23 to 1.00, all p ≤0.34) in 50% of the administered cognitive tests. Learning skills and memory ability presented the greatest benefits (Composite scores ES: 0.31 and 0.62; Figure1) that remained similar after stratification by single or bilateral LTx, and sex. Conclusions: PR has a beneficial effect on cognitive function improving memory, learning skills and psychomotor speed in post-transplant phase. Improvements in cognitive function may facilitate recovery in COPD LTx-recipients.

Background The benefits of pulmonary rehabilitation (PR) on fatigue-resistant skeletal muscle fibre type I have been found to be smaller in COPD patients with alpha-1 antitrypsin deficiency (AATD) than in those without AATD. Alpha-1 antitrypsin (AAT) augmentation therapy was suggested as a potential factor of influence. Whether this finding mirrors different improvements in 6-min walk distance (6MWD) between both groups remains unknown. Methods 140 patients with AATD-related COPD (phenotype PiZZ, FEV 1 : 31 ± 8%pred.) and 280 COPD patients without AATD (FEV 1 : 31 ± 8%pred.) were matched for baseline 6MWD and included in a retrospective analysis. AATD patients were divided into those “on” (AATD AUG+ ) or “off” (AATD AUG- ) augmentation therapy. 6MWD was assessed pre and post an inpatient 4-week PR program. Plasma level of creatinine was analysed at baseline. Results In AATD and COPD patients with comparable initial 6MWD (331 ± 106 m and 326 ± 101 m, p = n.s.), improvements in 6MWD following PR were similar (+49 ± 49 m and +53 ± 52 m, intra-group change: p AUG+ : +51 ± 55 m, AATD AUG- : +47 ± 40 m, p = n.s.). Only in AATD group, higher baseline creatinine levels and lower 6MWD were positive predictors for the PR-related increase in 6MWD. Conclusions Independently of the genetic variant of AAT, COPD patients achieved the same training-related benefit in 6MWD. Augmentation therapy showed no effect on 6MWD adaptation during PR.

Aim: To compare the effect of Pulmonary Rehabilitation (PR) on cognitive function, health status, and exercise outcomes in cognitive normal (CN) and cognitive impaired (CI) patients with COPD. Methods: 60 COPD patients (FEV1: 47±15%; 42%women) referred to 3-week in-patient PR and classified as “CN” or “CI” according to the Montreal Cognitive Assessment (MoCA) cutoff-score (≤25points). Domain-specific cognitive function (MoCA, SMMSE, ACER, TICS), health status (CAT), health-related quality of life (SF-36), the 6MWT and cerebral oxygen availability during cycle endurance test (CET) at 75%WR, were assessed on admission and discharge. Results: 25 patients (42%) presented evidences of CI and low performance in cognitive tests. Compared to CN, CI patients improved visuospatial skills and fluency (effect size; ES: 0.44; 0.48), whilst similar improvements in memory (ES: 0.75), physical and social function (ES: 0.45; 0.47), vitality (ES: 0.56), general and mental health (ES: 0.47; 0.67) were observed, respectively. CI patients did not improve body pain and limitations from emotional problems as assessed by SF-36 but increased 6MWD (from 378 to 403m, p=0.052), CET (from 10.0 to 12.3min, p Conclusion: CI patients gain significant benefits in cognitive function from PR but are not responsive to improvements in body pain and emotional limitations compared to CN. Persistent body pain may have limited the effectiveness of PR and improvements in the 6MWT in CI patients with COPD.

Background: Whole-body vibration training (WBVT) has been shown to be a feasible and effective exercise modality in patients directly following lung transplantation (LTx). Aim of this study was to investigate WBVT effects in long-term LTx patients (LTx>1year). Methods: 70 long-term LTx patients (mean duration since LTx: 5.7±4.5 years) participated in this randomized controlled trial. All patients performed a comprehensive pulmonary rehabilitation program of 3-weeks duration including a standardized endurance and strength training program on 5 days per week. On top, patients were randomized into squat training groups 3x/wk performing dynamic squat exercises for 4x2 min either on a side-alternating WBVT platform at high frequencies of 24-26 Hz (WBVT group) or for the same amount on the floor (control group, CON). Results: Patients in both groups reached a significant increase in 6-minute walk distance (WBVT: 44±44m versus CON: 22±34m) which was significantly superior in favor of the WBVT-group (delta: 22m, p=0.027). Also peak cycling work rate increased significantly more in the WBVT group (15±9W versus 10±9W, between-group difference: 5W, p=0.044). Furthermore, LTx patients who performed WBVT showed a significant increase in insulin-like growth factor (+18±49ng/ml) compared to control (-14±51ng/ml, between-group difference: 32ng/ml, p=0.035). Conclusion: Squat training on a vibration platform induced significantly higher improvements in exercise capacity compared to squat training on the floor. Therefore, WBVT seems to be an effective add-on exercise modality also in long-term LTx patients.

Background: There is only little evidence on the acute effects of non-invasive ventilation (NIV) during exercise in hypercapnic COPD patients. Methods: Fifteen hypercapnic COPD patients (age: 62±7 yrs, FEV1: 18±4 %pred., pCO2: 51±5mmHg) were recruited. Patients underwent a two-day assessment. On the first day an incremental cycling test was performed to determine peak work rate. On the second day patients performed two constant work rate cycling tests (CWRT) at 60% of peak work rate until exhaustion. CWRTs were randomly assigned to 2 conditions; a) with oxygen supplementation (4±2lpm) only, and b) with the same oxygen supplementation plus effective NIV (inspiratory pressure: 25±2 cmH20, expiratory pressure: 6±1 cmH20) including one hour of rest in between. Results: There was a clinically relevant change concerning a longer cycle endurance time with the use of NIV (627±384 sec versus 506±291 sec, p=0.34). Furthermore, NIV limited CO2 retention. At isotime (the shortest test between the two experimental conditions in a given subject) CO2 increased from 50.7±6.8mmHg up to 55.7±6.9mmHg without NIV and from 45.1±5.8mmHg to 49.9±5.8mmHg with NIV (p=0.019). Furthermore, oxygen saturation at isotime tended to be higher with NIV (96.0±4.5% versus 92.5±5.9%, p=0.081). Dyspnea rated on the Borg scale was significantly lower at the end of the CWRT with NIV (3.2±1.9 pts versus 5.3±1.5 pts, p=0.006). Conclusion: NIV during exercise in hypercapnic COPD patients prevented CO2 retention and reduced dyspnea. This might provide the basis for a feasible and safe endurance training program in this specific cohort of patients with very advanced COPD.

Background: Cognitive impairment (CI) is a prevalent extrapulmonary manifestation in COPD. Potential disturbances in cerebral circulation and oxygen delivery due to reduced ventilatory efficiency and ventilatory drive may be associated with higher rates of CI. We assessed cerebral tissue oxygen index (TOI) and cerebral hemodynamics at exertion in COPD patient with and without CI. Method: 52 COPD patients (aged: 68±8yrs; FEV1: 45±14%; 40%women) underwent a comprehensive cognitive assessment. Patients were assigned to “CI” and “non-CI” groups according to Montreal Cognitive Assessment (MoCA) cutoff score ≤25points. Patients performed cycle endurance test (CET) at 75% of peak work rate while transcutaneous carbon-dioxide partial-pressure (TCPCO2), cerebral tissue oxygen index (TOI) and hemoglobin responses were recorded by SenTec and Portalite systems, respectively. Results: 23 patients (44%) presented evidences of CI (MoCA≤25) with also lower scores in other cognitive tests (all p Conclusion: COPD patients have the capacity to autoregulate cerebral cortex blood flow in response to hypercapnia and hypoxemia, at least during exercise, and thus to normalize cerebral tissue oxygenation. These findings suggest that exercise is safe and can be beneficial regarding to cognitive function in COPD.

Background: Chronic respiratory failure can be associated with CO2 retention and hypercapnia during exercise in COPD patients. A continuously monitoring of transcutaneous CO2 levels (TcPCO2) may be useful to screen CO2 trends and to identify patients with exercise-induced hypercapnia (EIH). Objective: The aim of this study was to investigate the accuracy of the SenTec Digital Monitoring System (SDMS, SenTec AG, Therwil, Switzerland) during the 6-minute walk test (6MWT) in COPD patients. Methods: 10 COPD patients were enrolled in this prospective, pilot study. Capillary blood gases (CBG) from the earlobe were taken by the same investigator pre-6MWT and directly following 6MWT withTcPCO2 levels recorded simultaneously. To ensure a valid comparison between CBG and TcPCO2, values were taken at the same time point. An independent person set digital markers in the SenTec device concurrently with the taking of the CBG. Results: The agreement of PCO2 recording between CBG and SenTec device showed a very strong intra-class correlation coefficient for pre-walk (ICC=0.98, 95%CI: 0.93-0.99) and post-walk (ICC=0.98, 95CI: 0.73-0.99) values of the 6MWT (see Figure). Conclusion: Transcutaneously measured PCO2 values by the SDMS during 6MWT were highly accurate. The strong correlation with CBG and the continuous, non-invasive method could be advantageous to detect patients with EIH during the 6MWT.

Background: Cognitive impairment (CI) is a prevalent extrapulmonary manifestation in COPD. We assessed the prevalence and the determinants of CI in COPD. Method: 52 COPD patients (aged: 68±8yrs; FEV 1 : 45±14%; 40%women) underwent a comprehensive cognitive assessment. Patients were assigned to “CI” and “non-CI” groups according to Montreal Cognitive Assessment (MoCA) cutoff score ≤25points. Clinical data including medical history, respiratory function, health/ mood status evaluation by Saint-George respiratory questionnaire (SGRQ) and hospital anxiety-depression scale (HADS) were collected. Patients performed six-minute walk test (6MWT) and cycle endurance test (CET) at 75% of peak work rate. Results: 23 patients (44%) presented evidences of CI (MoCA≤25) with also lower scores in the other cognitive tests (all p 1 %, health and mood status (SGRQ, HADS), and exercise capacity (6MWD: 359 ±85m vs 380 ±116m, p=0.48; CET: 616 ±329sec vs 551 ±370sec, p=0.51) but greater oxygen desaturation during the CET (SpO 2 nadir: 92.3 ±2.9% vs 89.9 ±3.9%, p=0.014). Certain threshold of SpO 2 nadir (≤90%) increased the risk for CI after adjustment for oxygen-use (p=0.026). Conclusion: CI is highly prevalent in patients with COPD and affects several cognitive domains. It is associated with the years of education and the oxygen desaturation during the CET, however, it seems that is not associated with exercise capacity in COPD patients.