Blood pressure response to exposure to moderate altitude in patients with COPD.

Purpose: Patients with COPD might be particularly susceptible to hypoxia-induced autonomic dysregulation. Decreased baroreflex sensitivity (BRS) and increased blood pressure (BP) variability (BPV) are markers of impaired cardiovascular autonomic regulation and there is evidence for an association between decreased BRS/increased BPV and high cardiovascular risk. The aim of this study was to evaluate the effect of short-term exposure to moderate altitude on BP and measures of cardiovascular autonomic regulation in COPD patients. Materials and methods: Continuous morning beat-to-beat BP was noninvasively measured with a Finometer® device for 10 minutes at low altitude (490 m, Zurich, Switzerland) and for 2 days at moderate altitude (2,590 m, Davos Jakobshorn, Switzerland) - the order of altitude exposure was randomized. Outcomes of interest were mean SBP and DBP, BPV expressed as the coefficient of variation (CV), and spontaneous BRS. Changes between low altitude and day 1 and day 2 at moderate altitude were assessed by ANOVA for repeated measurements with Fisher's exact test analysis. Results: Thirty-seven patients with moderate to severe COPD (mean±SD age 64±6 years, FEV1 60%±17%) were included. Morning SBP increased by +10.8 mmHg (95% CI: 4.7-17.0, P=0.001) and morning DBP by +5.0 mmHg (95% CI: 0.8-9.3, P=0.02) in response to altitude exposure. BRS significantly decreased (P=0.03), whereas BPV significantly and progressively increased (P<0.001) upon exposure to altitude. Conclusion: Exposure of COPD patients to moderate altitude is associated with a clinically relevant increase in BP, which seems to be related to autonomic dysregulation. Clinical trial registration: ClinicalTrials.gov (NCT01875133).

Right and Left Heart Function in Lowlanders with COPD at Altitude: Data from a Randomized Study.

BACKGROUND: Changes in pulmonary hemodynamics and cardiac function in patients with chronic obstructive pulmonary disease (COPD) traveling to altitude have not been assessed despite an increasing prevalence of the disease. OBJECTIVES: We hypothesized that pulmonary artery pressure (PAP) significantly increases and cardiac function deteriorates during exposure to hypobaric hypoxia as encountered by traveling to moderate altitude or air flight. METHODS: A total of 37 patients (17 female; median age [quartiles] 66 years [60; 69] with COPD GOLD grade 2-3 [FEV1 57% predicted (49; 71)]) living < 800 m underwent echocardiography in Zurich (490 m) and after 1 night at Davos Jakobshorn (2,590 m) in a randomized order of allocation. RESULTS: The transtricuspid pressure gradient increased from 23 mm Hg (18; 29) to 32 mm Hg (25; 41) (p < 0.0001; Δmedian [95% CI] 7.5 [2.0; 13.0]), the right ventricular fractional area change decreased from 45% (39; 49) to 38% (33; 43) (p = 0.002), while the heart rate and systolic blood pressure increased from 70 bpm (64; 78) to 82 bpm (70; 86) (p < 0.0001) and from 133 mm Hg (123; 141) to 136 mm Hg (126; 148) (p = 0.002), respectively, and left ventricular diastolic dysfunction was more prevalent (24-54%, p = 0.02). CONCLUSIONS: This is a first study assessing changes in pulmonary hemodynamics and cardiac function in patients with COPD during a short altitude sojourn. Despite the increase in PAP and indications of change in cardiac function, the exposure was well tolerated. None of the patients had to descend to lower altitude for symptomatic altitude-related disease.

Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial.

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.

Mechanisms of Improved Exercise Performance under Hyperoxia.

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).

Pain in IBD Patients: Very Frequent and Frequently Insufficiently Taken into Account.

BACKGROUND: Pain is a common symptom related to inflammatory bowel disease (IBD). In addition to abdominal pain, pain can also be an extraintestinal manifestation of IBD. Pain treatment is challenging and a substantial part of IBD patients are treated with opioids. Therefore, a better knowledge on pain symptoms is crucial for a better therapeutic approach to this clinical problem. METHODS: Patients of the Swiss IBD Cohort Study (SIBDCS) (n = 2152) received a questionnaire regarding pain intensity, pain localization and impact of pain on daily life and social activities. Furthermore, the questionnaire investigated the use of pain-specific medication. RESULTS: A vast majority of patients (71%) experienced pain during the disease course. For a substantial part of patients (49% in UC and 55% in CD) pain is a longstanding problem (>5 years). Pain in UC was of shorter duration compared to CD (p < 0.01). Abdominal pain (59.5%) and back pain (38.3%) were the main pain localizations. 67% of patients took pain medication; 24% received no pain treatment. The general quality of life was significantly lower in patients suffering of pain compared to those without pain (38 vs. 77; (-100 very bad; 100 very good) p<0.0001). CONCLUSIONS: Prevalence of pain is high in patients of the SIBDCS. It is a longstanding problem for the majority of the patients affected. Pain was found to be undertreated in the SIBDCS and was significantly associated with health-related quality of life. Thus, an increased awareness is mandatory to address this frequent complication in the course of IBD.

Pressure-Flow During Exercise Catheterization Predicts Survival in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension manifests with impaired exercise capacity. Our aim was to investigate whether the mean pulmonary arterial pressure to cardiac output relationship (mPAP/CO) predicts transplant-free survival in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Hemodynamic data according to right heart catheterization in patients with PAH and CTEPH at rest and during supine incremental cycle exercise were analyzed. Transplant-free survival and predictive value of hemodynamics were assessed by using Kaplan-Meier and Cox regression analyses. RESULTS: Seventy patients (43 female; 54 with PAH, 16 with CTEPH; median (quartiles) age, 65 [50; 73] years; mPAP, 34 [29; 44] mm Hg; cardiac index, 2.8 [2.3; 3.5] [L/min]/m(2)) were followed up for 610 (251; 1256) days. Survival at 1, 3, 5, and 7 years was 89%, 81%, 71%, and 59%. Age, World Health Organization-functional class, 6-min walk test, and mixed-venous oxygen saturation (but not resting hemodynamics) predicted transplant-free survival. Maximal workload (hazard ratio [HR], 0.94 [95% CI, 0.89-0.99]; P = .027), peak cardiac index (HR, 0.51 [95% CI, 0.27-0.95]; P = .034), change in cardiac index, 0.25 [95% CI, 0.06-0.94]; P = .040), and mPAP/CO (HR, 1.02 [95% CI, 1.01-1.03]; P = .003) during exercise predicted survival. Values for mPAP/CO predicted 3-year transplant-free survival with an area under the curve of 0.802 (95% CI, 0.66-0.95; P = .004). CONCLUSIONS: In this collective of patients with PAH or CTEPH, the pressure-flow relationship during exercise predicted transplant-free survival and correlated with established markers of disease severity and outcome. Right heart catheterization during exercise may provide important complementary prognostic information in the management of pulmonary hypertension.

Disease-Targeted Treatment Improves Cognitive Function in Patients with Precapillary Pulmonary Hypertension.

BACKGROUND: Patients with pulmonary hypertension (PH) may suffer from cognitive deficits that potentially relate to reduced oxygen delivery and cerebral tissue oxygenation (CTO). OBJECTIVE: To evaluate the hypothesis that cognitive function improves with therapy, along with improved CTO. METHODS: Twenty incident patients with arterial or chronic thromboembolic PH had CTO monitoring by near-infrared spectroscopy during diagnostic right heart catheterization. Cognitive tests [Trail Making Tests (TMTs), Victoria Stroop tests and the Five-Point Test (5PT)], the 6-min walk distance (6MWD) test, New York Heart Association (NYHA) class and health-related quality of life (HRQoL) were assessed and repeated after 3 months of disease-targeted medication. RESULTS: At baseline, 45% of PH patients had cognitive deficits. At 3 months, the patients had improved on the TMT A and the Stroop 2 test [37 s (27; 55) versus 30 s (24; 42), p < 0.05, and 18 s (16; 22) versus 16 s (15; 20), p < 0.01], whereas CTO remained unchanged. Arterial oxygen saturation, NYHA class, 6MWD and HRQoL had also improved. Baseline CTO was the strongest predictor of cognitive function, even in multivariate analysis including age, 6MWD and HRQoL. Improvements in cognitive function were not associated with changes in CTO. CONCLUSIONS: In patients with PH, 3 months of disease-targeted medication resulted in better cognitive function. Although CTO was the strongest predictor of cognitive function at baseline, it did not change during target therapy. The results of this pilot study should be confirmed in an adequately powered controlled trial.

Effects of exercise and vasodilators on cerebral tissue oxygenation in pulmonary hypertension.

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 ≥25 mmHg, 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 6 min 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.

Experience with exercise right heart catheterization in the diagnosis of pulmonary hypertension: a retrospective study.

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.

Long-term effect of vasodilator therapy in pulmonary hypertension due to COPD: a retrospective analysis.

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, 6 min walk distance (6MWD) and oxygen saturation (SpO(2)) at baseline, 3, 6, 12 and 24 months 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 3 months and 3 (2; 3.5) after 6 months (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 12 months (p = .005, .006 and .011) with unchanged resting-SpO(2) but decreased peak-exercise SpO(2). 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 1,2,3 years was 92,69,54 % and was similar for GOLD stages 1-4, but worse for patients with mPAP ≥40 mmHg (p = .026), 6MWD <370 m (p = 0.008), resting SpO(2) <92 % (p = 0.02) and peak-walk SpO(2) <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 SpO(2) and high mean pulmonary artery pressure at baseline but not airflow obstruction were associated with unfavourable outcome.

Effect of oxygen and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in precapillary pulmonary hypertension and sleep-disturbed breathing.

BACKGROUND: Sleep-disturbed breathing (SDB) is common in patients with precapillary pulmonary hypertension (PH). Nocturnal oxygen therapy (NOT) and acetazolamide improve SDB in patients with PH, and NOT improves exercise capacity. We investigated the effect of NOT and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in patients with PH and SDB. METHODS: In a randomized, placebo-controlled, double-blind, crossover trial, 23 patients with arterial (n = 16) or chronic thromboembolic PH (n = 7) and SDB defined as a mean nocturnal oxygen saturation < 90% or dips (> 3%) > 10/h with daytime Pao2 ≥ 7.3 kPa were studied. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo each during 1 week separated by a 1-week washout period. Three-lead ECG was recorded during overnight polysomnography at the end of each treatment period. Repolarization indices were averaged over three cardiac cycles at late evening and at early morning, and nocturnal arrhythmias were counted. RESULTS: NOT was associated with a lower overnight (68 ± 10 beats/min vs 72 ± 9 beats/min, P = .010) and early morning heart rate compared with placebo. At late evening, the heart rate-adjusted PQ time was increased under acetazolamide compared with placebo (mean difference, 10 milliseconds; 95% CI, 0-20 milliseconds; P = .042). In the morning under NOT, the heart rate-adjusted QT (QTc) interval was decreased compared with placebo (mean difference, -25 milliseconds; 95% CI, -45 to -6 milliseconds; P = .007), and the interval between the peak and the end of the T wave on the ECG was shorter compared with acetazolamide (mean difference, -11 milliseconds; 95% CI, -21 to -1 milliseconds; P = .028). Arrhythmias were rare and similar with all treatments. CONCLUSIONS: In patients with PH with SDB, NOT reduces nocturnal heart rate and QTc in the morning, thus, favorably modifying prognostic markers. TRIAL REGISTRY: ClinicalTrials.gov; No.: NTC-01427192; URL: www.clinicaltrials.gov.