Oxygen Therapy in COPD: The Unknowns

Oxygen therapy is widely used to treat a variety of patients with chronic obstructive pulmonary disease. The evidence supporting this practice is best established for those patients with severe resting hypoxemia. Yet the role of oxygen in the broader population of COPD patients without severe resting hypoxemia requires additional data collection and understanding to define risk and benefit.

Given the existing gaps in evidence, the National Heart, Lung and Blood Institute and the Centers for Medicare and Medicaid Services are conducting a multicenter study in the U.S. – the Long-term Oxygen Treatment Trial (LOTT).

Long-term oxygen therapy (LTOT) is commonly used in treatment plans for patients with COPD. LTOT can be considered in patients with severe resting hypoxemia, moderate resting hypoxemia, exertional hypoxemia, or nocturnal hypoxemia, while short bursts of oxygen may be considered for specific clinical situations.

A recent analysis of Medicare patients in the U.S. documented that 33.7 percent of patients hospitalized for a COPD exacerbation were subsequently treated with supplemental oxygen.1 Importantly, there were significant geographical differences in oxygen prescriptions, with regions at high elevation exhibiting greater utilization. Patients who were younger, male, white, suffering from more co-morbidities, or experiencing more hospitalizations were also more likely to be prescribed oxygen.

Use in severe resting hypoxemia

The benefits of oxygen therapy are best established for patients with severe disease associated with resting hypoxemia.2 Two sentinel studies provide key data. The Medical Research Council examined the impact of at least 15 hours per day of oxygen in 87 COPD subjects with a resting PaO2 between 40 to 60 mmHg in the stable state.4 Survival was better with oxygen utilization compared to no oxygen.

At approximately the same time, the National Institutes of Health’s Nocturnal Oxygen Therapy Trial (NOTT) compared continuous LTOT (17.7 hours per day) with nocturnal (12 hours per day) oxygen in 203 COPD patients with a resting PaO2 less than 55 mm Hg or PaO2 less than 59 mm HG with either edema, polycythemia, or P pulmonale on EKG.5 During a mean follow-up of 19.3 months, survival was better in those using continuous vs. nocturnal oxygen.

The mechanisms for this improved survival remain elusive. Limited data suggest that LTOT may ameliorate pulmonary vasculopathy, at least during intermediate follow-up.6,7 A non-randomized Danish study suggested that oxygen therapy in hypoxemic COPD patients reduces hospitalizations.8 The totality of these data provide the firmest indications for LTOT.

Use in other types of hypoxemia

The role of supplemental oxygen in COPD patients with moderate hypoxemia at rest has been less certain.2,3 A meta-analysis of two small randomized trials in such patients did not support a mortality benefit in this population (summary odds ratio 1.39, 95 percent CI 0.74-2.59).9 The data regarding whether oxygen therapy improves survival in COPD patients with normoxemia at rest and desaturation during exercise are inconclusive.2,3 The studies are limited by small size and inconsistent definitions of exertional desaturation. Similarly, inconclusive data have been reported regarding the effect of oxygen supplementation on exercise capacity, symptoms, and health status in these desaturating patients.

The role of oxygen therapy in COPD patients experiencing nocturnal desaturation also remains controversial.2 A meta-analysis of small, randomized controlled trials did not support a mortality benefit (OR 0.97, 95 percent CI 0.41, 2.31).9 Data on sleep quality, pulmonary hemodynamics, and cardiac arrhythmias also have been inconclusive for nocturnal oxygen supplementation.2 It is evident that the database for LTOT in subjects with other types of hypoxemia is much more limited than for subjects with severe resting hypoxemia. Nevertheless, LTOT is frequently prescribed in these patients.

An analysis of severe emphysema subjects participating in the National Emphysema Treatment Trial provides important insight.10 At enrollment, 33.8 percent of subjects who were nonhypoxemic at rest were using LTOT. When compared to similar participants in the NETT who were not using LTOT, the participants who were prescribed oxygen were more likely to have worse dyspnea and quality of life, more frequent oxygen desaturation during exercise, and a higher mortality rate. After adjusting for age, body mass index, and FEV1 percent predicted, the presence of exercise desaturation accounted for the higher mortality within the nonhypoxemic patients using continuous oxygen.

These data suggested that the presence of oxygen desaturation may increase patient mortality, but the beneficial or potential detrimental effects of oxygen could not be assessed.

Exercise tolerance, symptoms

The evidence regarding the ability of oxygen therapy to improve exercise tolerance is not consistent.2,3,11 As-needed or short-term burst therapy has been suggested to improve symptoms or the outcome of pulmonary rehabilitation.2

One investigative group examined 22 COPD patients who felt that short-burst oxygen therapy provided symptomatic relief.12 For the group as a whole, recovery time improved modestly when using oxygen compared with air in a blinded fashion; however, only five of 22 patients correctly identified oxygen vs. inhaled air after activities.

A randomized controlled trial examined the role of at least 15 hours oxygen or medical air per day for seven days in patients with refractory dyspnea (59 percent to 68 percent with COPD).13 The primary endpoint of breathlessness, recorded in the morning or evening, was not different between the intervention groups. Morning dyspnea seemed to improve to a greater extent in the oxygen group, while evening breathlessness improved in the air group. Change in quality of life did not vary.

A meta-analysis of short burst oxygen therapy concluded that breathlessness did not improve with oxygen therapy.14 The totality of these data raises questions regarding the role of oxygen therapy to reduce symptoms and increase exercise capacity in COPD patients without severe hypoxemia at rest.

Negative effects of oxygen therapy

Despite potential benefits of LTOT in COPD patients, adverse effects can be seen, and it must be used carefully. A randomized, controlled trial in patients with acute respiratory symptoms (approximately half with confirmed COPD) compared treatment with inspired oxygen titrated to a saturation of 88 percent to 92 percent vs. high flow oxygen (8 to 10 L/min via non-rebreather mask) during initial paramedic evaluation and management of acute respiratory distress. Patients treated with high flow oxygen were more likely to die during hospitalization and to experience acute respiratory acidosis.15

Oxygen therapy may induce oxidative stress and associated inflammation in patients with COPD. Short-term oxidative stress has been reported in stable patients who inhaled 2 L/min supplemental oxygen for 18 hours.16 A separate group confirmed that inhalation of 28 percent oxygen increased exhaled levels of isoprostane and interleukin-6.17

Future studies of oxygen therapy

Given the existing gaps in evidence supporting oxygen therapy in COPD, a NHLBI workshop suggested that additional studies were required, paving the way for LOTT.18 LOTT investigators will randomize 1,134 COPD patients who meet the inclusion and exclusion criteria to continuous oxygen therapy for those subjects with resting O2 saturations between 89 percent to 93 percent or oxygen therapy during exercise, and sleep for subjects with resting saturation greater than 93 percent but exertional desaturation to less than 90 percent.

The goal of this study is to examine if oxygen therapy prolongs the time from randomization to the first occurrence of either hospitalization from any cause or death from any cause. Subjects are actively being recruited at 33 centers strategically located throughout the U.S. The LOTT trial will make these data available within the next several years.

View a reference list.

Fernando J. Martinez, MD, MS, principal investigator of the University of Michigan LOTT regional clinical center, is professor of internal medicine and director of pulmonary diagnostic services at the University of Michigan Health System, Ann Arbor, Mich. Gerard J. Criner, MD, principal investigator of Temple University LOTT regional clinical center, is professor of medicine and chief of the pulmonary and critical care section at Temple University School of Medicine, Philadelphia. Alice L. Sternberg, ScM, an associate scientist at the Johns Hopkins Bloomberg School of Public Health, is a biostatistician and project manager for the LOTT data coordinating center. James Tonascia, PhD, is a professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health and is the director of the LOTT data coordinating center. William C. Bailey, MD, chairman of the LOTT steering committee, is professor of medicine and Eminent Scholar chair in pulmonary diseases at the University of Alabama at Birmingham.

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