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Background: Arterial and thromboembolic pulmonary hypertension (PH) lead to arterial hypoxaemia. Objective: To investigate whether cerebral tissue oxygenation (CTO) in patients with PH is reduced and whether this is associated with reduced exercise tolerance. Methods: 16 patients with PH (mean pulmonary arterial pressure ≥25mmHg, 14 arterial, 2 chronic thromboembolic) and 15 controls underwent right heart catheterisation with monitoring of CTO at rest, during maximal bicycle exercise and during inhalation of oxygen and NO. The 6min walk distance (6MWD) was measured. Results: Median CTO in PH-patients at rest was 62% (quartiles 53; 71), during exercise 60% (53; 65); corresponding values in controls were 65% (73; 73) (P=NS) and 68% (66; 70) (p=.013 vs. PH). Inhalation of NO and oxygen improved CTO in PH. In multivariate regression analysis CTO at maximal exercise predicted the work load achieved when controlled for age, pulmonary vascular resistance and mixed venous oxygen saturation (R 2=.419, p<.000); in addition, the 6MWD was predicted by CTO (adjusted R 2=.511, p<.000). Conclusion: In PH-patients but not in controls CTO decreased during exercise. Since CTO was an independent predictor of the work load achieved and the 6MWD cerebral hypoxia may contribute to exercise limitation in PH. Clinicaltrials.gov: NCT01463514.

Purpose: Pulmonary hypertension (PH) due to COPD has dismal prognosis. We reviewed the long-term effect of PH-target therapy in severe PH-COPD. Method: Patients attending our PH-clinic were reviewed for PH-COPD receiving PH-target therapy. Baseline characteristics, death/transplantation until 2014, therapy, NYHA functional class, 6min walk distance (6MWD) and oxygen saturation (SpO2) at baseline, 3, 6, 12 and 24months were analysed. Results: Of 48 PH-COPD identified 21 were excluded (insufficient data, comorbidity). 27 patients (7 females, 21 smokers, 23 emphysema) with median (quartiles) baseline age 70 (60; 76)years, FEV1 60 (46; 78)%, FEV1/FVC 57 (51; 64)%, DLCO 42 (36; 59)%, mean pulmonary artery pressure 39 (32;44) mmHg under inhaled iloprost (10), subcutaneous prostanoids (2), intravenous prostanoids (3), endothelin receptor antagonists (15) and phosphodiesterase-5-inhibitors (25) were included. Under therapy, NYHA functional class improved from 3.5 (3; 4) to 3 (2; 4) after 3months and 3 (2; 3.5) after 6months (p=.02 and .008). The 6MWD improved from 373 (236; 452) to 395 (339; 472), 414 (285; 492) and 396 (308; 497)m at 3, 6 and 12months (p=.005, .006 and .011) with unchanged resting-SpO2 but decreased peak-exercise SpO2. During median follow-up of 5.9 (2.3; 8.4) years, 10 died, 2 were transplanted and 2 were lost to follow-up. Transplant-free survival at 1,2,3years was 92,69,54% and was similar for GOLD stages 1-4, but worse for patients with mPAP ≥40mmHg (p=.026), 6MWD <370m (p=0.008), resting SpO2 <92% (p=0.02) and peak-walk SpO2 <87% (p=0.012). Conclusion: PH-target vasodilator therapy improved NYHA functional class and 6MWD up to one year in highly selected patients with severe PH-COPD. Poor exercise capacity, low SpO2 and high mean pulmonary artery pressure at baseline but not airflow obstruction were associated with unfavourable outcome.

Aims The purpose of the current trial was to test the hypothesis that breathing oxygen-enriched air increases exercise performance of patients with pulmonary arterial or chronic thrombo-embolic pulmonary hypertension (PAH/CTEPH) and to investigate involved mechanisms. Methods and results Twenty-two patients with PAH/CTEPH, eight women, means ± SD 61 ± 14 years, resting mPAP 35 ± 9mmHg, PaO2 ambient air >7.3 kPa, underwent four bicycle ergospirometries to exhaustion on different days, while breathing oxygen-enriched (FiO2 0.50, hyperoxia) or ambient air (FiO2 0.21, normoxia) using progressively increased or constant load protocols (with 75% maximal work rate under FiO2 0.21), according to a randomized, sham-controlled, single-blind, cross-over design. ECG, pulmonary gas-exchange, arterial blood gases, cerebral and quadriceps muscle tissue oxygenation (CTO and QMTO) by near-infrared spectroscopy were measured. In ramp exercise, maximal work rate increased from 113 ± 38 W with normoxia to 132 ± 48 W with hyperoxia, mean difference 19.7 (95% CI 10.5-28.9) W, P < 0.001. Constant load exercise endurance increased from 571 ± 443 to 1242 ± 514 s, mean difference 671 (95% CI 392-951) s, P < 0.001. At end-exercise with hyperoxia PaO2, CTO, QMTO, and PaCO2 were increased, and ventilatory equivalents for CO2 were reduced while the physiological dead space/tidal volume ratio remained unchanged. Conclusion In patients with PAH/CTEPH, breathing oxygen-enriched air provides major increases in exercise performance. This is related to an improved arterial oxygenation that promotes oxygen availability in muscles and brain and to a reduction of the excessive ventilatory response to exercise thereby enhancing ventilatory efficiency. Patients with PAH/CTEPH may therefore benefit from oxygen therapy during daily physical activities and training. Trial registration clinicaltrials.gov Identifier: NCT01748474.

BACKGROUND The impact of hyperoxia on exercise limitation is still incompletely understood. OBJECTIVES We investigated to which extent breathing hyperoxia enhances the exercise performance of healthy subjects and which physiologic mechanisms are involved. METHODS A total of 32 healthy volunteers (43 ± 15 years, 12 women) performed 4 bicycle exercise tests to exhaustion with ramp and constant-load protocols (at 75% of the maximal workload [Wmax] on FiO2 0.21) on separate occasions while breathing ambient (FiO2 0.21) or oxygen-enriched air (FiO2 0.50) in a random, blinded order. Workload, endurance, gas exchange, pulse oximetry (SpO2), and cerebral (CTO) and quadriceps muscle tissue oxygenation (QMTO) were measured. RESULTS During the final 15 s of ramp exercising with FiO2 0.50, Wmax (mean ± SD 270 ± 80 W), SpO2 (99 ± 1%), and CTO (67 ± 9%) were higher and the Borg CR10 Scale dyspnea score was lower (4.8 ± 2.2) than the corresponding values with FiO2 0.21 (Wmax 257 ± 76 W, SpO2 96 ± 3%, CTO 61 ± 9%, and Borg CR10 Scale dyspnea score 5.7 ± 2.6, p < 0.05, all comparisons). In constant-load exercising with FiO2 0.50, endurance was longer than with FiO2 0.21 (16 min 22 s ± 7 min 39 s vs. 10 min 47 s ± 5 min 58 s). With FiO2 0.50, SpO2 (99 ± 0%) and QMTO (69 ± 8%) were higher than the corresponding isotime values to end-exercise with FiO2 0.21 (SpO2 96 ± 4%, QMTO 66 ± 9%), while minute ventilation was lower in hyperoxia (82 ± 18 vs. 93 ± 23 L/min, p < 0.05, all comparisons). CONCLUSION In healthy subjects, hyperoxia increased maximal power output and endurance. It improved arterial, cerebral, and muscle tissue oxygenation, while minute ventilation and dyspnea perception were reduced. The findings suggest that hyperoxia enhanced cycling performance through a more efficient pulmonary gas exchange and a greater availability of oxygen to muscles and the brain (cerebral motor and sensory neurons).

BACKGROUND: Data on exercise pulmonary hemodynamics in healthy people and patients with pulmonary hypertension (PH) are rare. We analyzed exercise right heart catheterization (RHC) data in a symptomatic collective referred with suspected PH to characterize the differential response by diagnostic groups, to correlate resting with exercise hemodynamics, and to evaluate safety. METHODS: This is a retrospective single-center study reviewing data from patients in whom an exercise RHC was performed between January 2006 and January 2013. Patients with follow-up RHC under PH -therapy were excluded. RESULTS: Data from 101 patients were analyzed, none of them had an adverse event. In 35% we detected a resting PH (27.8% precapillary, 6.9% postcapillary). Exercise PH (mean pulmonary arterial pressure (mPAP) >30 mmHg at exercise) was found in 38.6%, whereas in 25.7% PH was excluded. We found a remarkable number of exercise PH in scleroderma patients, the majority being postcapillary. 83% of patients with mPAP-values between 20 and 24.9 mmHg at rest had exercise PH. Patients with resting PH had worse hemodynamics and were older compared with exercise PH ones. CONCLUSION: In this real-life experience in symptomatic patients undergoing exercise RHC for suspected PH, we found that exercise RHC is safe. The facts that the vast majority of patients with mPAP-values between 20 and 24.9 mmHg at rest had exercise PH and the older age of patients with resting PH may indicate that exercise PH is a precursor of resting PH. Whether earlier treatment start in patients with exercise PH would stabilize the disease should be addressed in future studies.

Background: Arterial and thromboembolic pulmonary hypertension (PH) lead to arterial hypoxaemia. Objective: To investigate whether cerebral tissue oxygenation (CTO) in patients with PH is reduced and whether this is associated with reduced exercise tolerance. Methods: 16 patients with PH (mean pulmonary arterial pressure ≥25mmHg, 14 arterial, 2 chronic thromboembolic) and 15 controls underwent right heart catheterisation with monitoring of CTO at rest, during maximal bicycle exercise and during inhalation of oxygen and NO. The 6min walk distance (6MWD) was measured. Results: Median CTO in PH-patients at rest was 62% (quartiles 53; 71), during exercise 60% (53; 65); corresponding values in controls were 65% (73; 73) (P=NS) and 68% (66; 70) (p=.013 vs. PH). Inhalation of NO and oxygen improved CTO in PH. In multivariate regression analysis CTO at maximal exercise predicted the work load achieved when controlled for age, pulmonary vascular resistance and mixed venous oxygen saturation (R 2=.419, p<.000); in addition, the 6MWD was predicted by CTO (adjusted R 2=.511, p<.000). Conclusion: In PH-patients but not in controls CTO decreased during exercise. Since CTO was an independent predictor of the work load achieved and the 6MWD cerebral hypoxia may contribute to exercise limitation in PH. Clinicaltrials.gov: NCT01463514.

Purpose: Pulmonary hypertension (PH) due to COPD has dismal prognosis. We reviewed the long-term effect of PH-target therapy in severe PH-COPD. Method: Patients attending our PH-clinic were reviewed for PH-COPD receiving PH-target therapy. Baseline characteristics, death/transplantation until 2014, therapy, NYHA functional class, 6min walk distance (6MWD) and oxygen saturation (SpO2) at baseline, 3, 6, 12 and 24months were analysed. Results: Of 48 PH-COPD identified 21 were excluded (insufficient data, comorbidity). 27 patients (7 females, 21 smokers, 23 emphysema) with median (quartiles) baseline age 70 (60; 76)years, FEV1 60 (46; 78)%, FEV1/FVC 57 (51; 64)%, DLCO 42 (36; 59)%, mean pulmonary artery pressure 39 (32;44) mmHg under inhaled iloprost (10), subcutaneous prostanoids (2), intravenous prostanoids (3), endothelin receptor antagonists (15) and phosphodiesterase-5-inhibitors (25) were included. Under therapy, NYHA functional class improved from 3.5 (3; 4) to 3 (2; 4) after 3months and 3 (2; 3.5) after 6months (p=.02 and .008). The 6MWD improved from 373 (236; 452) to 395 (339; 472), 414 (285; 492) and 396 (308; 497)m at 3, 6 and 12months (p=.005, .006 and .011) with unchanged resting-SpO2 but decreased peak-exercise SpO2. During median follow-up of 5.9 (2.3; 8.4) years, 10 died, 2 were transplanted and 2 were lost to follow-up. Transplant-free survival at 1,2,3years was 92,69,54% and was similar for GOLD stages 1-4, but worse for patients with mPAP ≥40mmHg (p=.026), 6MWD <370m (p=0.008), resting SpO2 <92% (p=0.02) and peak-walk SpO2 <87% (p=0.012). Conclusion: PH-target vasodilator therapy improved NYHA functional class and 6MWD up to one year in highly selected patients with severe PH-COPD. Poor exercise capacity, low SpO2 and high mean pulmonary artery pressure at baseline but not airflow obstruction were associated with unfavourable outcome.