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University of Zurich and University Hospital of Zurich, Clinic of Pulmonology, University Hospital Zurich, Raemistrasse 100, Zurich 8091, SwitzerlandDepartment Health, Eastern Switzerland University of Applied Sciences, St. Gallen, Bogenstrasse 7, St. Gallen 9000, Switzerland
There is convincing evidence that short-term supplemental oxygen therapy (SOT) improves pulmonary hemodynamics and prolongs exercise capacity.
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Long-term beneficial effects of SOT on exercise capacity and quality of life were demonstrated in patients with pulmonary vascular diseases (PVD) who have sleep- or exercise-induced hypoxemia.
•
The exact dose, the duration of application, and the situations of application of SOT have not yet been precisely defined in PVD.
Introduction
Pulmonary hypertension (PH) is diagnosed by right heart catheterization (RHC) when mean pulmonary artery pressure (mPAP) is greater than 20 mm Hg and classified as precapillary PH when pulmonary capillary wedge pressure is less than 15 mm Hg and pulmonary vascular resistance (PVR) greater than 2 Wood units (WU).
In the absence of severe lung disease, the main pulmonary vascular diseases (PVD) characterized by precapillary PH are pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) and chronic thromboembolic PH (CTEPH, WHO Group 4). The cardinal symptoms of PVD are dyspnea on exertion with impaired exercise performance, daily activity, and quality of life.
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.
The pharmaceutical treatment of PVD according to guidelines is mainly based on medication targeting 3 biochemical pathways, which counteract pulmonary vasoconstriction and/or promote pulmonary vasodilatation.
Interventional therapies such as pulmonary endarterectomy or balloon angioplasty are highly effective options for patients with CTEPH. In severe cases, lung transplantation as ultimate treatment option should be offered.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
Supportive measures such as diuretics, iron supplementation, anticoagulation, and treatment of arrhythmias are important players in the management of patients with PVD and should be optimally adjusted at each patient visit.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
Another major supportive treatment measure is the use of supplemental oxygen therapy (SOT); however, circumstances in which to apply SOT are still debated.
However, the scientific basis of this recommendation derives from the prescription of SOT in hypoxemic patients with chronic obstructive pulmonary disease (COPD) with a threshold to install long-term SOT for more than 16 hours/day for patients with PH with a partial pressure of oxygen at rest lesss than 8 kPa, as trials performed in the early 1980s showed a survival benefit in those patients.
Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party.
a vasomotor response of the pulmonary arterial circulation to hypoxia, an essential mechanism of matching perfusion to ventilation and thus optimizing oxygen uptake and delivery. HPV might be global, for example, as response to altitude exposure, or local in pathological lung areas. To a certain degree, HPV may also be promoted by a low mixed-venous oxygen tension, which is also supported by studies in patients with PVD who acutely received SOT during RHC.
Consequently, the idea of using SOT in PVD is to increase alveolar oxygen tension and ventilatory efficacy, decrease ventilation-perfusion mismatch and thus induce pulmonary vasodilation, improve blood and tissue oxygenation, and consequently reduce pulmonary vascular resistance and improve right ventricular function and cardiac index.
In current PH guidelines, the use of SOT is recommended for patients with PH with a partial pressure of oxygen at rest less than 8 kPa (60 mm Hg).
Until 2016, there was no randomized and especially no placebo (sham ambient air) controlled data for the use SOT in PAH apart from one small long-term randomized controlled trial (RCT), which did not show a survival benefit with SOT versus standard of care in patients with Eisenmenger syndrome.
However, as several studies on SOT in PH including placebo-controlled RCTs have been published in recent years, it is time to summarize the current knowledge on acute and longer-term effect of SOT in PVD. The aim is to identify gaps in knowledge and to provide an expert opinion on the subject based on clinical experience and several physiologic and interventional clinical studies from our PH center.
Methods
Study Design
A systematic review, and where possible a quantitative meta-analysis, on the effects of SOT on pulmonary hemodynamics, exercise performance, and quality of life in patients with PVD was performed.
Search Strategy
A systematic literature search was conducted in PubMed, EMBASE, Google Scholar, and Cochrane register of clinical trial databases to identify studies published up to September 25th 2022. The MeSH terms “pulmonary hypertension,” “pulmonary arterial hypertension,” “chronic thromboembolic pulmonary hypertension,” “pulmonary vascular disease,” “oxygen therapy,” “oxygen supplementation,” “hyperoxia,” and “oxygen” occurring in Title and/Abstract were used and combined with “AND” or “OR.”
In addition, a search for other potentially eligible studies was performed by searching the reference lists of included studies, systematic reviews, and meta-analyses.
Study Inclusion
Studies were included if they were RCTs, in English language, full text available, and comparing oxygen therapy versus placebo and/or versus baseline in pulmonary vascular disease. Identified records were afterward screened for studies on patients with PVD (mostly PAH or CTEPH) (Fig. 1). Case reports were excluded. Studies were separated by short-term effects of SOT on pulmonary hemodynamics and cycling exercise performance and longer-term effects on walk distance as well as quality of life.
Fig. 1Flow diagram of the systematic literature search.
Two reviewers performed the literature search and extracted data independently. The following information was recorded: author, year, number of participants, diagnosis and WHO functional class, oxygen delivery, baseline hemodynamics and oxygenation, change in hemodynamics, and other outcomes.
Statistical Analysis
A random and fixed effects model depending on heterogeneity with the I2 statistic was used to conduct a meta-analysis and assess the effect of short-term SOT on mPAP and PVR. All statistical analyses were performed with the R software, version 4.3.1.
Results
Effects of Short-Term Supplemental Oxygen Therapy (Minutes to Hours) on Pulmonary Hemodynamics
Ten eligible publications (Table 1) that focused on acute effects of SOT in patients with PVD were identified, of which 8 reported on its effects on invasive hemodynamic measurements, whereas the rest used echocardiography.
Table 1Summary of publications assessing short-term oxygen therapy
A randomized placebo-control trial of the acute effects of oxygen supplementation on exercise hemodynamics, autonomic modulation, and brain oxygenation in patients with pulmonary hypertension.
N = 23 13 PAH 4 PortoPul 2 COPD 2 CHD (1ASD & 1VSD) 1 syst.skler 1 HIV
FiO21.0 via facemask for 5 min
mPAP 56 ± 3 mm Hg RAP 8 ± 1 mm Hg PAWP 8 ± 1 mm Hg PVR 14.6 ± 1.4WU CI 2.1 ± 0.1 L/min/m2
SaO2 91 ± 1% PaO2 8.53 ± 0.4 kPa
mPAP −3 ± 2 mm Hg (−5%) RAP no change PAWP no change PVR -4 ± 1.0WU (−27%) CI + 0.4 ± 0.2 L/min/m2 (+19%)
SaO2 99 ± 1% PaO2 41 ± 3.7 kPa PVR/systemic vascular resistance, 0.53 ± 0.04 to 0.48 ± 0.03 The beneficial effect on PVR was independent of the etiology of pulmonary hypertension
Carta and colleagues assessed the effect of SOT on pulmonary hemodynamics by RHC in a very large cohort of patients with PVD (149 patients, 79 PAH, 70 CTEPH) compared with normoxia (FiO2 0.21 vs 1.0, for 10 min each). SOT significantly reduced mPAP by −4.4 mm Hg (−5.5 to −3.3 mm Hg, p < 0.001) corresponding to −12% and PVR by −0.4 WU (−0.7 to −0.1WU, p = 0.006) corresponding to −8%.
Another small study demonstrated a significant reduction in PVR with SOT (FiO2 0.6 for 30 min) in hypoxemic patients with PAH associated with Scleroderma but not in idiopathic PAH.
investigated the effect of FiO2 0.5 to 0.7 for 20 to 30 minutes on pulmonary hemodynamics in 14 patients with PVD. They reported significant reductions in mPAP of −8% and in RAP of −16%. Roberts and colleagues
included 23 patients with PH of whom 19 had PVD. In their study, they used FiO2 1.0 for 5 minutes and found significant reductions in mPAP of −5%, in PVR of −27%, as well as an increase in cardiac index by +19%.
observed hemodynamic changes in 13 patients with mild CTEPH and 18 patients with severe CTEPH before and after 20 minutes of 10 L/min of SOT. They reported significant reductions in mPAP of −11% in patients with mild and of −5% in patients with severe PH in response to SOT. Shigetoshi and colleagues
showed similar results. They reported significantly reduced mPAP by −9% and PVR by −8% in 52 patients with CTEPH after inhaling 5 L/min of SOT for 10 minutes.
Interestingly, the group of Leuchte found that a reduction of heart rate less than 72 bpm in response to SOT in patients with PVD was even of prognostic significance during a median follow-up of 25 months.
In a meta-analysis on the acute effect of SOT on mPAP and PVR, the homogeneity assumptions led to a fixed effect model for mPAP (Fig. 2) and a random effect model for PVR (Fig. 3). Pooled data from 7 studies including 378 patients that reported mean differences in mPAP showed that SOT significantly reduced mPAP by −4.1 mm Hg (95% confidence interval [CI], −4.4 to −3.7). Pooled data from 4 studies including 356 patients that reported mean differences in PVR showed that PVR was nonsignificantly reduced by −1.3 WU (95% CI, −2.7 to 0.2) by SOT.
Fig. 2Forest plot of the effect of short-term supplemental oxygen therapy on mean pulmonary artery pressure (mm Hg) in patients with pulmonary vascular disease.
Fig. 3Forest plot of the effect of short-term supplemental oxygen therapy on pulmonary vascular resistance (WU) in patients with pulmonary vascular disease.
Effects of Short-Term Supplemental Oxygen Therapy (Minutes to Hours) on Exercise Performance
We identified 2 randomized, placebo-controlled trials that examined the effects of short-term SOT (FiO2 0.5) on cycling exercise tolerance in patients with PVD.
A randomized placebo-control trial of the acute effects of oxygen supplementation on exercise hemodynamics, autonomic modulation, and brain oxygenation in patients with pulmonary hypertension.
Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial.
It was shown that short-term SOT significantly increases maximal exercise capacity during incremental ramp protocols versus placebo (room air)—on average by +17%—and constant load (75%Wmax) endurance time—on average by +117%—in 22 patients with PVD with exercise-induced hypoxemia. Those marked improvements were in relation to the increase in arterial oxygen content and consecutive reduction of the excessive ventilatory response to exercise and thereby enhancement of the ventilatory efficiency in this patient collective.
Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial.
The second study showed an improvement of submaximal load constant work-rate cycling from 10.3 to 14.9 minutes in 9 patients with PAH/CTEPH and demonstrated an improved baroreceptor sensitivity, amelioration of cerebral deoxygenation, and higher cardiac output (measured by photoplethysmography).
A randomized placebo-control trial of the acute effects of oxygen supplementation on exercise hemodynamics, autonomic modulation, and brain oxygenation in patients with pulmonary hypertension.
Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial.
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.
Effect of oxygen and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in precapillary pulmonary hypertension and sleep-disturbed breathing.
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.
Two randomized, placebo-controlled, crossover trials assessed the effect of nocturnal or domiciliary SOT on exercise capacity: the first study assessed nocturnal SOT versus placebo for 1 week in 23 patients with sleep-induced hypoxemia.
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.
Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial.
In both studies, SOT significantly improved daytime exercise capacity on ambient air measured by 6-minute walking test and also quality of life assessed by the SF 36 physical functioning scale. Echocardiographic measurements of systolic pulmonary arterial pressure were unchanged. The investigators concluded that functional improvement in response to SOT might mainly be based on enhanced ventilatory efficiency
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.
Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial.
The aforementioned 1-week study by Ulrich and colleagues also assessed the effect of nocturnal SOT on sleep-disordered breathing and found an improvement not only in mean nocturnal oxygen saturation but also in oxygen desaturation index and apnea-hypopnea index. In this study, nocturnal oxygen therapy furthermore improved right ventricular fractional area change and WHO functional class.
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.
Further analysis of those data in terms of prognostic markers revealed a reduction of nocturnal and early morning heart rate as well as morning QTc time in electrocardiogram with supplemental oxygen, which might be interpreted as a favorable modification of the patients’ cardiovascular risk profile.
Effect of oxygen and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in precapillary pulmonary hypertension and sleep-disturbed breathing.
One small, randomized crossover trial assessed the effect of nocturnal SOT versus placebo in patients with PVD during a 48-hour stay at high altitude (2048 m), but no significant changes in hemodynamic assessed by echocardiography the day after the treatment were found, although nocturnal hypoxemia and altitude-induced sleep-disordered breathing improved with SOT.
Farber and colleagues published a large observational study on the effects of SOT on survival in PAH (>3000 patients) with a follow-up over 5 years using data from the REVEAL Registry of the United States. They compared survival of patients with PAH with versus without SOT. Although oxygen users had worse prognostic factors (worse New York heart Association functional class, a higher REVEAL risk score, higher right atrial pressure, higher mPAP, lower mixed venous oxygen saturation, greater shortness of breath as indicated by the Borg dyspnea scale, and shorter 6MWD) and used more PAH-specific medication, only those with severe diffusing capacity for carbon monoxide (DLCO) reduction (<40%) had a significant risk reduction of all-cause mortality when using oxygen therapy as compared with those with no, mild, or moderate DLCO impairment.
To put it in a nutshell, there is convincing evidence that short-term SOT improves pulmonary hemodynamics and prolongs exercise capacity. Long-term beneficial effects of SOT on exercise capacity and quality of life were demonstrated in patients with PVD who have sleep- or exercise-induced hypoxemia, and a lower risk of all-cause mortality has been reported in patients with PVD with reduced DLCO less than 40% using SOT. However, the exact dose, the duration of application, and the situations of application as well as the mode of application of SOT have not yet been precisely defined in PVD so far, and many underlying mechanisms of its beneficial effect are still not completely understood.
Studies show that short-term SOT leads to a reduction in PVR
and thereby reduce the right ventricular load, but the extent to which this effect is sustained when long-term oxygen therapy is used and if it contributes to improved patient-reported outcomes, exercise tolerance, or even reduced mortality is unclear. Because the large observational study of Farber and colleagues
showed a significant risk reduction of all-cause mortality with long-term SOT only in patients with severe DLCO impairment, the question arises whether the correction of hypoxemia itself is of greater relevance for prognosis independent of the change in right heart hemodynamics as found in patients with COPD and cor pulmonale under long-term SOT.
Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party.
Two trials performed in the 1980s investigating the relevance of SOT in COPD with cor pulmonale showed that patients who used SOT greater than 15 h/d survived longer compared with those who only used nocturnal or no SOT. However, in those studies, SOT was not associated with relevant improvements in right heart hemodynamics in selected patients, and in some patients, PVR even increased during 500 days of follow-up. Long-term SOT also seemed to reduce mortality in patients with COPD with low mPAP and PVR.
Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party.
This assumption is also supported by an observational study from the French Pulmonary Hypertension Registry by Valentin and colleagues that found that a large subset of patients with PAH (exclusive pulmonary veno-occlusive disease) experience a greater than or equal to 3% decrease in SaO2 when treated with PH drugs. This drop in SaO2 was associated with worse long-term outcomes and reduced survival despite having a lower mPAP compared with those who did not experience a greater than or equal to 3% decrease in SaO2.
However, it needs to be taken into account that the underlying reasons for hypoxemia in PAH may differ from those in COPD, for example, the low cardiac output, vascular remodeling, ventilation/perfusion mismatch, and changes in respiratory drive.
Face the Truth in Supplemental Oxygen Therapy
Considering SOT in PVD, caregivers need to be aware of the indications, practicability, acceptability by patients, the necessary infrastructure, and financing. Adherence to SOT can be difficult for patients, as the therapy may need to be used for several hours a day/night or during exercise and may be associated with side effects such as dry-nose potentially leading to epistaxis but also to possible ignition and burning.
Moreover, due to high costs of purchasing and maintaining the devices as well as the necessary equipment, coverage by health insurers has decreased in recent years, making the therapy unaffordable for some patients or at least reducing acceptance due to financial concerns.
Beyond these hurdles, there are technical limitations in relation to the maximum of flow (provided by the device as well as tolerated by the patient), weight, and thereby portability, which limits the amount of the oxygen reservoir or independent power supply. As depicted in Fig. 4, these limitations and advantages of each supply solution should be kept in mind and aligned with the patient’s needs
; this is especially important in patients with PVD, as regular exercise and respiratory training improves exercise capacity and quality of life, and a stationary or too heavy oxygen device might reduce mobility and possibly even outweigh potential benefits of oxygen therapy.
The 2022 European Society of Cardiology/European Respiratory Society guidelines recommend the use of SOT in selected patients with PH based on data from studies in patients with COPD performed over more than 3 decades ago.
Taking into account the differences in the pathophysiology of COPD and PAH/CTEPH, the need for robust evidence further evaluating the role of SOT in PVD is obvious. However, since the publication of the 2015 guidelines, several RCTs have provided sound evidence that SOT is beneficial for selected patients with PVD, which may be included in future recommendations.
The evidence presented in this review shows that SOT improves right-heart hemodynamics according to a large collective of patients with PVD and also improves exercise capacity, quality of life, and can act as an effective therapeutic agent in certain patients with PVD and by that favorably modify clinical course and maybe even survival.
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.
A randomized placebo-control trial of the acute effects of oxygen supplementation on exercise hemodynamics, autonomic modulation, and brain oxygenation in patients with pulmonary hypertension.
Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial.
Effect of oxygen and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in precapillary pulmonary hypertension and sleep-disturbed breathing.
Larger, RCTs evaluating long-term SOT in patients with PVD are necessary to further evaluate how it affects clinical outcome and possibly even mortality. Doing this, the relevance of hypoxemia itself apart from hemodynamic alterations for prognosis in patients with PVD should be further investigated as already discussed earlier.
Moreover, correlation between acute response to SOT and long-term effect is unknown. Taking into account the effects of SOT on exercise tolerance in PVD, the meaning of SOT in rehabilitation and training in general in patients with PVD should also be assessed.
Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial.
Given the burden associated with long-term SOT, dosing studies should also be conducted to optimize the duration of oxygen supply and thus quality of life in terms of mobility.
Clinics care points
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SOT should be offered to hypoxemic patients with PH to use during exercise but also at rest and during the night.
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When subscribing supplemental oxygen therapy, be aware of the limitations and practicability of the different devices.
Disclosure and funding
None of the authors have any conflicts of interest or financial interests to report regarding the material presented in this manuscript. There was no funding from outside sources or foundations for this work.
References
Humbert M.
Kovacs G.
Hoeper M.M.
et al.
2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.
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.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party.
A randomized placebo-control trial of the acute effects of oxygen supplementation on exercise hemodynamics, autonomic modulation, and brain oxygenation in patients with pulmonary hypertension.
Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial.
Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial.
Effect of oxygen and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in precapillary pulmonary hypertension and sleep-disturbed breathing.
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