Effect of hypoxia and hyperoxia on exercise performance in healthy individuals and in patients with pulmonary hypertension: A systematic review

Exercise performance is determined by oxygen supply to working muscles and vital organs. In healthy individuals, exercise performance is limited in the hypoxic environment at altitude, when oxygen delivery is diminished due to the reduced alveolar and arterial oxygen partial pressures. In patients with pulmonary hypertension, exercise performance is already reduced near sea level due to impairments of the pulmonary circulation and gas exchange and, presumably, these limitations are more pronounced at altitude. In studies performed near sea level in healthy subjects as well as in patients with pulmonary hypertension (PH) maximal performance during progressive ramp exercise and endurance of submaximal constant load exercise were substantially enhanced by breathing oxygen-enriched air. Both in healthy individuals and in PH-patients these improvements were mediated by a better arterial, muscular and cerebral oxygenation along with a reduced sympathetic excitation, as suggested by the reduced heart rate and alveolar ventilation at submaximal isoloads, and an improved pulmonary gas exchange efficiency, especially in patients with PH. In summary, in healthy individuals and in patients with pulmonary hypertension, alterations in the inspiratory PO2 by exposure to hypobaric hypoxia or normobaric hyperoxia reduce or enhance exercise performance, respectively, by modifying oxygen delivery to the muscles and the brain, by effects on cardiovascular and respiratory control and by alterations in pulmonary gas exchange. The understanding of these physiologic mechanisms helps counselling individuals planning altitude or air travel and prescribing oxygen therapy to patients with pulmonary hypertension

Automatic Processing of Nasal Pressure Recordings to Derive Continuous Side-Selective Nasal Airflow and Conductance

Monitoring of nasal airflow and conductance provides crucial insights into the variable nature of the nasal resistance, nasal cycle, and ventilation. We have previously shown that tracking of pressure swings at the entrance of each nasal passage by a dedicated catheter system allows bilateral monitoring of nasal airflow over several hours but requires complex linearization and calibration procedures. Side-selective nasal conductance is derived from linearized and calibrated bilateral nasal pressure swings and corresponding driving pressure, i.e., the transnasal pressure difference derived from an epipharyngeal catheter. Manual analysis of such recordings and computation of instantaneous conductance as the ratio of flow to driving pressure over several hours is extremely tedious, time consuming, and therefore not suitable for routine practice. To address this point, we developed and validated a software for automatic processing of nasal and epipharyngeal pressure recordings as a convenient tool for studying the nasal ventilation. The software applies an eight-parameter logistic model to transform nasal pressure swings into side-selective estimates of airflow that are calibrated and further processed along with epipharyngeal pressure to compute bilateral nasal conductance over consecutive, user-selectable time-segments. Essential processing steps include (1) offset correction, (2) low-pass filtering, (3) cross-correlation, (4) cutting of signals into individual breaths, (5) normalization, (6) ensemble averaging to obtain a mean pressure signal for each nasal side, (7) derivation of airflow, conductance, and further variables. Among four evaluated algorithms for calculation of nasal conductance, the derivative of the airflow-pressure curve according to the mean value theorem agreed closest with the gold standard, i.e., the conductance derived from airflow measured by a pneumotachograph attached to an oral-nasal mask and transnasal pressure. In combination with the nasal catheter system, our novel software represents a valuable tool for use in clinical practice and research to conveniently investigate nasal ventilation and its changes occurring spontaneously or in response to various exposures and therapeutic interventions

Daytime measurements underestimate nocturnal oxygen desaturations in pulmonary arterial and chronic thromboembolic pulmonary hypertension

Background: Nocturnal hypoxemia is important in precapillary pulmonary hypertension (pPH) as it worsens pulmonary hemodynamics. Whether daytime oxygen saturation (SpO(2)) predicts nocturnal hypoxemia in pPH patients has not been conclusively studied. Objectives: To investigate the prevalence of nocturnal hypoxemia in comparison to daytime SpO(2) and disease severity in ambulatory patients with pulmonary hypertension. Methods: Consecutive patients diagnosed with pPH classified as either pulmonary arterial (PAH) or chronic thromboembolic pPH (CTEPH) had daytime resting and exercise SpO(2) (at the end of a 6-min walk test); thereafter, they underwent overnight pulse oximetry at home. Functional class, pro-brain natriuretic peptide (pro-BNP) and the tricuspid pressure gradient were assessed. Results: Sixty-three patients [median (quartiles) age 62 (53; 71), 43 females] with PAH (n = 44) and CTEPH (n = 19) were included. The resting SpO(2), exercise SpO(2), and mean nocturnal SpO(2) were 95% (92; 96), 88% (81; 95), and 89% (85; 92), respectively. Forty-nine patients (77%) spent >10% of the night with SpO(2) 50% of the night with SpO(2) 90% for being a nocturnal nondesaturator or sustained nondesaturator were 25 and 53%, respectively. Nocturnal SpO(2) was negatively correlated with the tricuspid pressure gradient, but not with functional class, 6-min walk test, or pro-BNP. Conclusions: Nocturnal hypoxemia is very common in PAH and CTEPH despite often normal daytime SpO(2) and reflects disease severity. Nocturnal pulse oximetry should be considered in the routine evaluation of pPH patients and research should be directed toward the treatment of nocturnal desaturation in pPH

The effects of continuous positive airway pressure therapy withdrawal on cardiac repolarization: data from a randomized controlled trial†

Aims The preliminary evidence supports an association between obstructive sleep apnoea (OSA), disturbed cardiac repolarization, and consequent cardiac dysrhythmias. The aim of the current trial was to assess the effects of continuous positive airway pressure (CPAP) therapy withdrawal on the measures of cardiac repolarization in patients with OSA. Methods and results Forty-one OSA patients established on CPAP treatment were randomized to either CPAP withdrawal (subtherapeutic CPAP) or continue therapeutic CPAP for 2 weeks. Polysomnography was performed, and indices of cardiac repolarization (QTc, TpTec intervals) and dispersion of repolarization (TpTe/QT ratio) were derived from 12-lead electrocardiography (ECG) at baseline and 2 weeks. Continuous positive airway pressure withdrawal led to a recurrence of OSA. Compared with therapeutic CPAP, subtherapeutic CPAP for 2 weeks was associated with a significant increase in the length of the QTc and TpTec intervals (mean difference between groups 21.4 ms, 95% CI 11.3-1.6 ms, P < 0.001 and 14.4 ms, 95% CI 7.2-21.5 ms, P < 0.001, respectively) and in the TpTe/QT ratio (mean difference between groups 0.02, 95% CI 0.00-0.03, P = 0.020). There was a statistically significant correlation between the change in apnoea/hypopnoea index (AHI) from baseline, and both the change in the QTc interval and the TpTec interval (r = 0.60, 95% CI 0.36-0.77, P < 0.001 and r = 0.45, 95% CI 0.17-0.67, P = 0.003, n = 41, respectively). Conclusion Continuous positive airway pressure withdrawal is associated with the prolongation of the QTc and TpTec intervals and TpTe/QT ratio, which may provide a possible mechanistic link between OSA, cardiac dysrhythmias, and thus sudden cardiac deat

Partial Pressure of Arterial Oxygen in Healthy Adults at High Altitudes: A Systematic Review and Meta-Analysis

Importance: With increasing altitude, the partial pressure of inspired oxygen decreases and, consequently, the Pao$_{2}$ decreases. Even though this phenomenon is well known, the extent of the reduction as a function of altitude remains unknown. Objective: To calculate an effect size estimate for the decrease in Pao$_{2}$ with each kilometer of vertical gain among healthy unacclimatized adults and to identify factors associated with Pao$_{2}$ at high altitude (HA). Data Sources: A systematic search of PubMed and Embase was performed from database inception to April 11, 2023. Search terms included arterial blood gases and altitude. Study Selection: A total of 53 peer-reviewed prospective studies in healthy adults providing results of arterial blood gas analysis at low altitude (&amp;lt;1500 m) and within the first 3 days at the target altitude (≥1500 m) were analyzed. Data Extraction and Synthesis: Primary and secondary outcomes as well as study characteristics were extracted from the included studies, and individual participant data (IPD) were requested. Estimates were pooled using a random-effects DerSimonian-Laird model for the meta-analysis. Main Outcomes and Measures: Mean effect size estimates and 95% CIs for reduction in Pao$_{2}$ at HA and factors associated with Pao$_{2}$ at HA in healthy adults. Results: All of the 53 studies involving 777 adults (mean [SD] age, 36.2 [10.5] years; 510 men [65.6%]) reporting 115 group ascents to altitudes between 1524 m and 8730 m were included in the aggregated data analysis; 13 of those studies involving 305 individuals (mean [SD] age, 39.8 [13.6] years; 185 men [60.7%]) reporting 29 ascents were included in the IPD analysis. The estimated effect size of Pao$_{2}$ was −1.60 kPa (95% CI, −1.73 to −1.47 kPa) for each 1000 m of altitude gain (τ$^{2}$ = 0.14; I$^{2}$ = 86%). The Pao$_{2}$ estimation model based on IPD data revealed that target altitude (−1.53 kPa per 1000 m; 95% CI, −1.63 to −1.42 kPa per 1000 m), age (−0.01 kPa per year; 95% CI, −0.02 to −0.003 kPa per year), and time spent at an altitude of 1500 m or higher (0.16 kPa per day; 95% CI, 0.11-0.21 kPa per day) were significantly associated with Pao$_{2}$. Conclusions and Relevance: In this systematic review and meta-analysis, the mean decrease in Pao$_{2}$ was 1.60 kPa per 1000 m of vertical ascent. This effect size estimate may improve the understanding of physiological mechanisms, assist in the clinical interpretation of acute altitude illness in healthy individuals, and serve as a reference for physicians counseling patients with cardiorespiratory disease who are traveling to HA regions

The Characteristics of Sleep Apnea in Tibetans and Han Long-Term High Altitude Residents

Purpose: Obstructive sleep apnea (OSA) is common both at low and high altitude. Since adaptations to high altitude and respiratory control may differ among Tibetans and Hans, we compared characteristics of sleep-disordered breathing in the two ethnic groups at high altitude. Materials and methods: This was a prospective observational study including 86 Tibetan and Han long-term (>5 years) high altitude residents with chief complaints of snoring and/or witnessed apnea underwent clinical evaluation and polysomnography at 3200 meters in Shangri-La, China. Results: In 42 Tibetans, 38 men, median (quartiles) age was 50.0 (41.0; 56.0)y, total apnea/hypopnea index (AHI) 53.9 (32.0; 77.5)/h, obstructive AHI 51.0 (28.0; 72.2)/h and central AHI 1.5 (0.2; 3.1)/h. In 44 Hans, 32 men, median (quartiles) age was 47.0 (43.5; 51.0)y, total AHI 22.2 (12.8; 39.2)/h, obstructive AHI 17.7 (12.0; 33.0)/h and central AHI 2.4 (0.5; 3.4)/h (p < 0.001 total and obstructive AHI vs Tibetans). In Tibetans, mean nocturnal oxygen saturation was lower [median 85.0 (83.0; 88.0)% vs 88.5 (87.0; 90.0)%] and obstructive apnea and hypopnea duration was longer [22.0 (19.6; 24.8) sec vs 18.3 (16.7; 20.6) sec] than in Hans (all p < 0.001). In regression analysis, Tibetan ethnicity, neck circumference and high-altitude living duration were the predictors of total AHI. We also found that with every 10/h increase in total AHI, there were an approximately 0.9 beat/min and 0.8 beat/min increase in mean heart rate during rapid eye movement (REM) and non-REM sleep and 1.9 mmHg and 2.0 mmHg increase in evening and morning systolic blood pressure. Conclusion: Our data suggest that Tibetans presented more severe obstructive sleep apnea, hypoxemia and longer apnea duration compared to Hans at 3200 meters, which was correlated with higher heart rate and blood pressure suggesting a greater cardiovascular risk. Keywords: Tibetan; high altitude; long-term Han resident; obstructive sleep apnea

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)

Effect of nocturnal oxygen and acetazolamide on exercise performance in patients with pre-capillary pulmonary hypertension and sleep-disturbed breathing: randomized, double-blind, cross-over trial

Aim Sleep-disturbed breathing (SDB) is common in pre-capillary pulmonary hypertension (PH) and impairs daytime performance. In lack of proven effective treatments, we tested whether nocturnal oxygen therapy (NOT) or acetazolamide improve exercise performance and quality of life in patients with pre-capillary PH and SDB. Methods This was a randomized, placebo-controlled, double-blind, three period cross-over trial. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo tablets each during 1 week with 1-week washout between treatment periods. Twenty-three patients, 16 with pulmonary arterial PH, 7 with chronic thromboembolic PH, and with SDB defined as mean nocturnal oxygen saturation 10 h−1 with daytime PaO2 ≥7.3 kPa participated. Assessments at the end of the treatment periods included a 6 min walk distance (MWD), SF-36 quality of life, polysomnography, and echocardiography. Results Medians (quartiles) of the 6 MWD after NOT, acetazolamide, and placebo were 480 m (390;528), 440 m (368;468), and 454 m (367;510), respectively, mean differences: NOT vs. placebo +25 m (95% CI 3-46, P= 0.027), acetazolamide vs. placebo −9 m (−34-17, P = 0.223), and NOT vs. acetazolamide +33 (12-45, P < 0.001). SF-36 quality of life was similar with all treatments. Nocturnal oxygen saturation significantly improved with both NOT and acetazolamide. Right ventricular fractional area change was greater on NOT compared with placebo (P = 0.042) and acetazolamide (P = 0.027). Conclusions In patients with pre-capillary PH and SDB on optimized pharmacological therapy, NOT improved the 6 MWD compared with placebo already after 1 week along with improvements in SDB and haemodynamics. ClinicalTrials.gov NTC0142719

The Impact of Breathing Hypoxic Gas and Oxygen on Pulmonary Hemodynamics in Patients With Pulmonary Hypertension

BackgroundPure oxygen breathing (hyperoxia) may improve hemodynamics in patients with pulmonary hypertension (PH) and allows to calculate right-to-left shunt fraction (Qs/Qt), whereas breathing normobaric hypoxia may accelerate hypoxic pulmonary vasoconstriction (HPV). This study investigates how hyperoxia and hypoxia affect mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PH and whether Qs/Qt influences the changes of mPAP and PVR.Study Design and MethodsAdults with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) underwent repetitive hemodynamic and blood gas measurements during right heart catheterization (RHC) under normoxia [fractions of inspiratory oxygen (FiO$_{2}$) 0.21], hypoxia (FiO$_{2}$ 0.15), and hyperoxia (FiO$_{2}$ 1.0) for at least 10 min.ResultsWe included 149 patients (79/70 PAH/CTEPH, 59% women, mean ± SD 60 ± 17 years). Multivariable regressions (mean change, CI) showed that hypoxia did not affect mPAP and cardiac index, but increased PVR [0.4 (0.1–0.7) WU, p = 0.021] due to decreased pulmonary artery wedge pressure [−0.54 (−0.92 to −0.162), p = 0.005]. Hyperoxia significantly decreased mPAP [−4.4 (−5.5 to −3.3) mmHg, p &lt; 0.001] and PVR [−0.4 (−0.7 to −0.1) WU, p = 0.006] compared with normoxia. The Qs/Qt (14 ± 6%) was &gt;10 in 75% of subjects but changes of mPAP and PVR under hyperoxia and hypoxia were independent of Qs/Qt.ConclusionAcute exposure to hypoxia did not relevantly alter pulmonary hemodynamics indicating a blunted HPV-response in PH. In contrast, hyperoxia remarkably reduced mPAP and PVR, indicating a preserved vasodilator response to oxygen and possibly supporting the oxygen therapy in patients with PH. A high proportion of patients with PH showed increased Qs/Qt, which, however, was not associated with changes in pulmonary hemodynamics in response to changes in FiO$_{2}$