COPD: Journal of Chronic Obstructive Pulmonary Disease

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Long-Term Oxygen Therapy in COPD Patients Who

Do Not Meet the Actual Recommendations

Begum Ergan & Stefano Nava

To cite this article: Begum Ergan & Stefano Nava (2017) Long-Term Oxygen Therapy in COPD
Patients Who Do Not Meet the Actual Recommendations, COPD: Journal of Chronic Obstructive
Pulmonary Disease, 14:3, 351-366, DOI: 10.1080/15412555.2017.1319918

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Published online: 16 May 2017.

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COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
, VOL. , NO. , –
https://doi.org/./..

INVITED REVIEW

Long-Term Oxygen Therapy in COPD Patients Who Do Not Meet the Actual
Recommendations
Begum Ergana and Stefano Navab
a
Department of Pulmonary and Critical Care, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey; b Department of Clinical, Integrated and
Experimental Medicine (DIMES), Respiratory and Critical Care Unit, S. Orsola-Malpighi Hospital, Alma Mater University, Bologna, Italy

ABSTRACT ARTICLE HISTORY

Chronic respiratory failure due to chronic obstructive pulmonary disease (COPD) is an increasing problem Received  March 
worldwide. Many patients with severe COPD develop hypoxemic respiratory failure during the natural pro- Accepted  April 
gression of disease. Long-term oxygen therapy (LTOT) is a well-established supportive treatment for COPD KEYWORDS
and has been shown to improve survival in patients who develop chronic hypoxemic respiratory failure. The Chronic obstructive
degree of hypoxemia is severe when partial pressure of oxygen in arterial blood (PaO2 ) is ࣘ55 mmHg and pulmonary disease;
moderate if PaO2 is between 56 and 69 mmHg. Although current guidelines consider LTOT only in patients long-term oxygen; moderate
with severe resting hypoxemia, many COPD patients with moderate to severe disease experience moderate hypoxemia; exercise;
hypoxemia at rest or during special circumstances, such as while sleeping or exercising. The efficacy of LTOT nocturnal; desaturation
in these patients who do not meet the actual recommendations is still a matter of debate, and extensive
research is still ongoing to understand the possible benefits of LTOT for survival and/or functional outcomes
such as the sensation of dyspnea, exacerbation frequency, hospitalizations, exercise capacity, and quality
of life. Despite its frequent use, the administration of “palliative” oxygen does not seem to improve dyspnea
except for delivery with high-flow humidified oxygen. This narrative review will focus on current evidence
for the effects of LTOT in the presence of moderate hypoxemia at rest, during sleep, or during exercise in
COPD.

Introduction
by the observation that lung function does not predict sur-
With recent advances both in the treatment and management vival in established hypoxemic patients (8). Emphysematous
of chronic obstructive pulmonary disease (COPD), mortality COPD has been reported as a risk factor for exercise-induced
in patients with chronic respiratory failure has decreased over hypoxemia but not for resting hypoxemia (9,10). In addition,
time, and end-stage disease with chronic respiratory failure has recent studies suggest that race and some genetic variations
become a more evident problem (1,2). End-stage COPD patients (polymorphisms in chromosomes 14 and 15) may be predictive
can present with gas exchange abnormalities either with hypox- of resting hypoxemia (11).
emia only or with hypoxemia accompanied by hypercapnia. The degree of hypoxemia is directly related to mortality in
Long-term oxygen therapy (LTOT) has long been the standard COPD, and correcting hypoxemia with LTOT increases survival
of care for hypoxemic COPD patients. However, domiciliary (12). Most national and international guidelines recommend the
non-invasive ventilation support added to LTOT may be ben- use LTOT in the presence of resting hypoxemia, which is defined
eficial in hypercapnic respiratory failure when daytime arterial as a resting partial pressure of oxygen in arterial blood (PaO2 )
carbon dioxide level is ࣙ 45–50 mmHg in the stable period. ࣘ55 mmHg (or oxygen saturation [SaO2 ] ࣘ 88%) or resting
Approximately 7% of patients with moderate to severe COPD PaO2 between 56 and 59 mmHg (or SaO2 ࣘ 88%) with evidence
develop resting hypoxemia within 5 years (3,4). The main risk of pulmonary hypertension, cor pulmonale, or polycythemia
factors for the development of hypoxemia in COPD are still with a hematocrit value greater than 55% (Table 1) (13–18). The
not clear; however, male sex, living at a high altitude, increased current recommendation is based on the results of two histor-
body mass index, lower forced expiratory volume in one second ical studies published in the early 1980s: the Nocturnal Oxy-
(FEV1 ), increased functional residual capacity (%), presence of gen Therapy Trial (NOTT) in 1980 and the Medical Research
heart failure, pulmonary artery enlargement on computerized Council (MRC) study in 1981 (19,20). Although both studies
tomography, previous history of severe COPD exacerbation, had relatively few patients when compared to current random-
low baseline resting oxygen saturation, and increased resting ized controlled trials (RCTs; MRC study included 87 patients,
heart rate have been reported as possible risk factors (3–6). NOTT study included 203 patients) and did not represent the
Although FEV1 is an important parameter for the assessment ideal group for LTOT (e.g., 25–52% of patients were still smok-
of disease severity, there is a weak correlation between FEV1 ers and all patients are aged < 70 years in the MRC study, smok-
and the degree of hypoxemia. (7). This finding is also supported ing status was not declared in NOTT), the results showed that

CONTACT Begum Ergan [email protected] Department of Pulmonary and Critical Care, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/icop.
©  Taylor & Francis Group, LLC
352 B. ERGAN AND S. NAVA

Table . Definitions.

Resting hypoxemia Resting PaO ࣘ mmHg or SaO ࣘ%

OR
Resting PaO between - mmHg (or SaO ࣘ%) with evidence of either pulmonary hypertension,
cor pulmonale or polycythemia (hematocrit >%)
Moderate hypoxemia Resting PaO ranging between  and  mmHg
Nocturnal desaturation Spending ࣙ% sleep time with SaO < % without evidence of associated sleep apnea
OR
A fall in SaO below % for  minutes or more with a nadir SaO below % during sleep
Exercise-induced desaturation SaO ࣘ % during exercise
OR
A fall in SaO ࣙ % during exercise

Abbreviations:
PaO : partial pressure of oxygen in arterial blood, SaO : oxygen saturation

LTOT increased survival in hypoxemic patients, and this effect these patients. In this review, we touch upon the answers of some
on mortality was directly correlated with the duration of LTOT clinical questions of utmost importance regarding the effects of
use. LTOT in moderate hypoxemia at rest and during sleep or exer-
However, approximately 20% of COPD patients were pre- cise in COPD.
scribed LTOT outside published guidelines, and there is still We searched Medline, EmBase, and the Cochrane database,
debate whether the use of oxygen therapy is beneficial dur- using the keywords “COPD and oxygen therapy,” “COPD
ing the earlier phase of the disease before the development of and moderate hypoxemia,” “COPD and nocturnal desatu-
resting hypoxemia, especially for symptom relief (21). Patients ration,” “COPD and exercise induced desaturation” for all
with moderate to severe COPD often have moderate hypox- reports of adults published up to January 2017 (Figure 1).
emia (PaO2 : 56–69 mmHg) at rest, and patients who do not Our search was not limited to publications in English. We
have hypoxemia at rest become hypoxemic during exercise or selected relevant reports and comprehensive reviews. We also
sleep (22). Although these patients are not qualified for oxy- searched the reference lists of the identified publications, select-
gen therapy with current indications, research is still ongoing ing relevant articles with an emphasis on oxygen therapy
whether oxygen therapy may have potential positive effects in research.

Figure . Flow chart for articles included in the review (RCT, Randomized controlled trial).
 COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 353

The rationale of LTOT use in COPD therapy. Comparing the two periods, there were no differences
in admission rates or the number of patients with at least one
Consequences of chronic hypoxemia hospitalization (36). They concluded that home oxygen therapy
does not reduce hospitalization in patients with COPD without
The main mechanisms of hypoxemia in COPD are ventila-
severe hypoxemia. In a trial performed in hypercapnic COPD
tion perfusion mismatch and emphysematous destruction of the
patients with a mean PaO2 of 67 mmHg at rest, LTOT did
alveolocapillary membrane. Pulmonary vasoconstriction occurs
not provide a survival benefit. However, it halted the decline
in response to alveolar hypoxia in an effort to match ventilation
in endurance time and reduced the exertional dyspnea score
and perfusion (12). However, ongoing pulmonary vasoconstric-
significantly after 1 year compared to the controls (37).
tion causes pulmonary remodeling and pulmonary hyperten-
A recent multicenter study provided important insight
sion, resulting in right heart failure. The degree of pulmonary
concerning this issue (38). This is the largest study to date
hypertension is inversely correlated with the severity of resting
examining the efficacy of LTOT in resting or exercise-induced
hypoxemia. Pulmonary hypertension in COPD is also related
moderate hypoxemic patients (n = 738). In the LTOT Trial
to an increased hospitalization frequency and decreased sur-
Research Group study, patients were randomized to either sup-
vival (23–25). From a cardiac perspective, hypoxemia causes
plemental oxygen or no supplementation. In the supplemental
peripheral vasodilation, which induces compensatory tachycar-
oxygen group, patients with moderate resting desaturation
dia with a subsequent increase in cardiac output to improve oxy-
(Oxygen saturation with pulse oxymeter [SpO2 ] 89–93%) were
gen delivery (24). Persistent hypoxemia may induce secondary
prescribed 24-hour oxygen, and those with desaturation only
erythrocytosis, causing polycythemia and increasing the serum
during exercise (during the 6-minute walk test [6MWT], SpO2
viscosity. Muscle dysfunction, neurocognitive impairment, and
ࣙ 80% for more than 5 minutes and < 90% equal to or more
impaired quality of life (QoL) (13,25,26). All these consequences
than 10 seconds) were prescribed oxygen during exercise and
contribute to increased mortality in COPD.
sleep. The median follow-up time was 18 months. LTOT had
no effect on time to death or time to first hospitalization. In
Physiological and clinical effects of oxygen therapy addition, the exacerbation rate, QoL, and functional mea-
sures (depression, anxiety, and functional status) were similar
If hypoxemia persists, tissue hypoxia and organ dysfunction between the study groups. The study also had some limitations.
will be inevitable. Thus, the correction of hypoxemia is impor- There is the possibility of the exclusion of patients with a greater
tant for survival. Oxygen therapy may reverse pulmonary vaso- number of symptoms because they might have declined to
constriction and stabilize or reduce pulmonary artery pres- participate. Second, neither nocturnal desaturation nor effects
sure (24,27,28). Improvement of pulmonary hemodynamics is of oxygen on exercise performance were assessed in the study.
enhanced if oxygen is used continuously, and this effect seems Finally, the estimated use was 13 hours/day in the supplemental
to be sustainable over the years (19,29). Oxygen administration oxygen group, and it is uncertain whether oxygen use for longer
improves breathlessness, especially during exercise in hypox- periods of time in these patients might have provided different
emic subjects. Moreover, exercise tolerance in the acute setting results. This is especially important because we know that based
is improved with oxygen, including in patients with mild to on NOTT results, the duration of oxygen use is predictive of
moderate hypoxemia (30). Selinger et al. showed that positive survival in hypoxemic COPD patients
changes induced by oxygen are reversible by the interruption of Although theoretically initiating LTOT in the early phase
therapy (31). LTOT may improve the sleep profile and quality by of COPD, before the onset of irreversible changes, seems to be
preventing nocturnal hypoxemia (24). In addition, LTOT may reasonable, the data reported to date have shown no benefit.
be helpful for improving respiratory and general health-related Regarding current evidence, oxygen therapy is not indicated in
QoL (32). COPD patients with moderate hypoxemia.

Oxygen therapy in COPD patients with moderate Oxygen therapy in COPD patients with nocturnal
hypoxemia desaturation
PaO2 has been shown to exhibit a decreasing trend that is Chronic obstructive pulmonary disease patients experience
directly related to mortality in COPD (33,34). Therefore, theo- oxygen desaturation of clinical importance during sleep due
retically, oxygen supplementation to achieve higher PaO2 levels to worsening of ventilation/perfusion mismatch and nocturnal
in the presence of moderate hypoxemia may have a positive alveolar hypoventilation (39–41). Most of these patients have
impact on disease outcomes. There are a limited number of near normal oxygen saturation during wakefulness, and day-
studies assessing the effect of LTOT in moderately hypoxemic time PaO2 values may not be helpful for the discrimination of
COPD patients (Table 2). Gorecka et al. randomized COPD nocturnal desaturators (41–43). The prevalence of nocturnal
patients with moderate hypoxemia into control (n = 67) and desaturation varies widely according to the definitions used for
LTOT (n = 68) groups and followed them for at least three years nocturnal desaturation and the selected patient populations in
or until death (35). There were no significant differences in the studies. Fletcher et al. defined nocturnal desaturation as a
survival rates between patients treated with LTOT and controls. fall in SaO2 below 90% for 5 minutes or more, reaching a nadir
Longer oxygen use (>15 hours per day) did not improve sur- saturation of at least 85%, and reported that approximately
vival. Ringbaek et al. studied 170 moderately hypoxemic COPD one-third of patients with a PaO2 greater than 60 mmHg, have
patients before and after 10 months of initiation of home oxygen nocturnal desaturation (44). Other studies used the definition
 354
B. ERGAN AND S. NAVA

Table . Randomized Controlled Trials For Long-Term Oxygen Therapy In COPD Patients wit Moderate Hypoxemia.

Resting
FEV (L and/or % PaO Mean O use
Study population Comparison (n) predicted) (mmHg) SaO (hours/day) Study duration Impact on outcomes

Gorecka  Patients with PaO LTOT (): Oxygen was . L (.%)  NA .  years Primary outcome: LTOT did not prolong
between - mmHg prescribed with a survival
flow rate adjusted to Secondary outcome: There was no
maintain a PaO correlation between the duration of
> mmHg and > oxygen use and survival in LTOT
hours/day group
Control () . L (.%)  NA -

Haidl  COPD patients with LTOT (): Oxygen was .%  NA .  year (the planned Primary outcome: LTOT did not
reversible hypercapnia prescribed at  L/min study duration decrease mortality in COPD patients
(PaCO >  mmHg at for ࣙ hours/day was  years, but with reversible hypercapnia
rest on  different days due to the high Secondary outcomes: LTOT stopped
or increase in PaCO drop-out rate, the decline in endurance time and
after cycle testing >  assessment after reduced the exertional dyspnea
mmHg) with PaO at one year was score significantly after  year
rest >  mmHg and a chosen by the compared to controls
mean nocturnal authors)
oxygen saturation >
%, and before
discharge, PaCO at
rest should have
returned to ࣘ mm
Hg)
Control () .%  NA -
 The Long Term Patients with moderate LTOT (): Oxygen ( % NA % . hours in the - years (median Primary outcome: LTOT for patients
Oxygen resting hypoxemia L/min) was -hour group follow-up: . with resting or exercise-induced
Treatment (SpO -%) or prescribed  hours and . hours in months) moderate desaturation did not affect
Trial Group resting SpO >% in patients with the the time to death or first
 and exercise-induced moderate sleep–exercise hospitalization for any cause.
moderate desaturation hypoxemia () and group Secondary outcomes: There was no
(SpO ࣙ % for ࣙ during exercise and difference between groups for the
 min and <% for sleep in patients with rates of all hospitalizations and COPD
ࣙ seconds during  exercise-induced exacerbations. There was no difference
MWT) desaturation () between the groups in the change
Control () % NA % . hours (median  from baseline in measures of quality of
hours)∗ life (assessed with quality of well being
scale, SF , SGRQ, Pittsburgh sleep
quality index), depression and anxiety
(assessed with HAD scale), lung
function, distance for MWT and other
measures of functional status

Abbreviations:
MWT: -minute walk test, COPD: chronic obstructive pulmonary disease, FEV : forced expiratory volume in one second (% predicted), L/min: liters per minute, LTOT: long-term oxygen therapy, NA: data not available, O : oxygen,
PaCO : partial pressure of carbon dioxide in arterial blood, PaO : partial pressure of oxygen in arterial blood, SaO : oxygen saturation, SpO : oxygen saturation with pulse oximetry
∗ Use of supplemental oxygen limited to periods of severe resting desaturation (SpO ࣘ%) or severe exercise-induced desaturation (SpO <% for ࣙ minute); the oxygen requirement was reassessed after  days
COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
355
356 B. ERGAN AND S. NAVA

of spending more than 30% of at least one of two nights with Due to the paucity of data and the relatively small sample size
an oxygen saturation of less than 90% and showed that 50–70% of the studies mentioned above, the role of oxygen therapy in
of patients with mild to moderate hypoxemia have nocturnal clinically relevant outcomes remains unclear. An ongoing study,
desaturation (41,45). Although nocturnal oximetry is the sim- the International Nocturnal Oxygen Trial (INOX), will address
plest way to show nocturnal desaturations, polysomnography is this question and facilitate our understanding of whether
the best tool for the evaluation of sleep disorder breathing prob- supplemental oxygen during sleep is effective (53). This study
lems in COPD patients, especially for the differential diagnosis is a three-year, multicenter, placebo-controlled, randomized
of obstructive sleep apnea (46). trial of nocturnal oxygen therapy added to usual care, and the
The impact of nocturnal desaturation on pulmonary hemo- primary outcome is a composite of all-cause mortality or the
dynamics is still not well understood. Levi-Valensi et al. requirement for LTOT.
reported that COPD patients who desaturated at night have
a higher mean pulmonary artery pressure when compared to
patients who did not desaturate (19 vs 17 mmHg; p < 0.05).
Oxygen therapy in COPD patients with exercise-induced
In addition patients who developed pulmonary hypertension
desaturation
had higher number of desaturation dips, longer dip durations,
and lower mean nocturnal arterial oxygen saturation compared Approximately 20% of COPD patients without resting hypox-
with patients who desaturated but did not develop pulmonary emia develop desaturation during exercise (10,54,55). Exercise-
hypertension and patients who did not desaturate (42). In induced desaturation (EID) is defined as a fall in oxygen
contrast to this finding, Chaouat and colleagues showed that saturation to 88% or lower during exercise (Table 1). EID is
the mean pulmonary artery pressure was not correlated with considered an important risk factor for pulmonary hyperten-
the degree and duration of nocturnal desaturation in COPD sion, rapid decline in lung function, and recurrent exacerbations
patients with mild daytime hypoxemia (45). (54–57). It has been reported that patients with low oxygen sat-
The prognostic significance of nocturnal desaturation uration at rest, emphysematous phenotype, and low diffusion
for mortality in COPD is not clear. Fletcher et al. studied capacity are more likely to desaturate during exercise (10,58).
non-hypoxemic COPD patients (daytime PaO2 greater than EID diagnosis is usually confirmed by the 6MWT, and it has
60 mmHg) with and without nocturnal desaturation and been shown that desaturation during the 6MWT can predict a
reported that survival was significantly improved in patients future need for LTOT (59). In addition, patients who desaturate
without nocturnal desaturation (48). They defined noctur- during the 6MWT have been reported to have an approximately
nal desaturation based on two different definitions: episodic twofold increased risk of death compared with those who did
desaturation associated mainly with REM sleep (definition not desaturate (55,60).
1) and desaturation > 30% of the time spent in bed below Oxygen supplementation during exercise results in signifi-
an oxygen saturation of 90% (definition 2). When stratified cant improvements in exercise tolerance both in healthy people
for supplemental oxygen use, survival was only improved in and in COPD patients. Oxygen administration causes less
subjects referencing definition 1. A double-blind, randomized breathlessness and improves exercise capacity by decreasing
trial evaluated the long-term effect of oxygen supplementation minute ventilation and dynamic hyperinflation, improving
in COPD subjects with nocturnal desaturation (Table 3) (49). pulmonary hemodynamics by alleviating hypoxic vasoconstric-
Patients treated with supplemental oxygen during sleep for 36 tion and increasing cardiac output and oxygen delivery in the
months showed a significant downward trend in pulmonary acute setting (24). It has been shown that supplemental oxygen
artery pressure (−3.7 mmHg) compared to patients treated with protects against desaturation during exercise in COPD patients
room air (+3.9 mmHg). In another RCT, nocturnal oxygen without severe resting hypoxemia (61). Moreover, oxygen sup-
supplementation did not affect the evolution of pulmonary plementation improves exercise duration, exercise endurance,
hypertension and mortality in COPD patients with nocturnal and symptom perception in non-hypoxemic patients (30). The
desaturation (50). Nocturnal oxygen supplementation did not likely underlying mechanism is a reduction of the hypoxemia-
prevent initiation of conventional LTOT as well. related increase in ventilatory demand, dynamic hyperinflation,
Nocturnal desaturation is a known factor in sleep fragmenta- and increased exertional breathlessness (25,30).
tion and the decrease in QoL in patients with COPD. However, However, evidence for the long-term use of oxygen to pre-
Lewis et al. reported that patients with nocturnal desaturation vent EID during exercise in non-hypoxemic COPD patients
did not have worsened sleep quality, QoL, and daytime som- outside the laboratory setting is limited. Moore et al. showed
nolence when compared to patients without desaturation (41). that ambulatory oxygen had no benefit in terms of exercise
Studies assessing the effects of the correction of desaturation capacity (62). Similar to this finding, the LTOT trial subgroup
with nocturnal oxygen therapy on sleep and QoL also had analysis showed that patients with an exercise desaturation pro-
heterogeneous results. Nocturnal oxygen supplementation in file (43% of patients) experienced no benefit from ambulatory
COPD patients with isolated nocturnal hypoxemia did not oxygen supplementation with respect not only to mortality
improve QoL within 6 weeks (51). A recent study showed that and hospitalizations but also to nadir oxygen saturation during
nocturnal oxygen therapy may be beneficial for improving exercise, distance walked in the 6MWT, functional status, and
QoL only in emphysematous but not in chronic bronchitis other measures of QoL (38). In a meta-analysis, it was shown
type COPD (52). The authors explained this finding as a con- that the clinical utility and effectiveness of ambulatory oxygen
sequence of various responses to the hypoxemic ventilation in improving mortality and exercise capacity were not evident
stimulus in these two phenotypes. in patients who were not hypoxemic at rest (63).
Table . Randomized Controlled Trials For Nocturnal Oxygen Therapy In COPD Patients With Nocturnal Desaturation.

Comparison
(n: recruited/ FEV (L
Definition for nocturnal completed and/or % Resting PaO Mean O use
Study population desaturation PSG the study) predicted) (mmHg) Nocturnal SaO T Sa <% (hours) Study duration Impact on outcomes

Fletcher Patients with resting i. Baseline awake and Yes Nocturnal .L  % % .  years Primary outcome:
 daytime PaO non-rapid eye movement oxygen Nocturnal desaturating
ࣙ mm and (NREM) ear oximeter therapy  patients who received
nocturnal saturation ࣙ %, L/min oxygen during sleep
desaturation (/) for  years showed a
significant downward
trend in pulmonary
artery pressure
compared to
desaturators treated
with compressed air
ii. A fall below this value for Compressed .L  % % . Secondary outcomes:
 min or more, usually air (/) There was no
coinciding with but not statistically significant
limited to REM sleep, iii. A difference between
nadir SaO value reaching groups for mortality.
% or lower and nonvascular
parameters
(hemoglobin, red
blood cell mass).

Chaouat Patients with daytime Spending ࣙ% of the Yes Nocturnal .L (%)  % % .  years Primary outcome:
 PaO between recording time with oxygen Nocturnal oxygen
- mmHg and transcutaneous arterial O therapy  therapy did not alter
nocturnal sat <% L/min the evalution of
desaturation (/) pulmonary
hemodynamics
Control .L (%)  % % - Secondary outcomes:
(/) Nocturnal oxygen
therapy did not
prevent initiation of
conventional LTOT
(number of patients
who required LTOT
during follow-up).
Nocturnal oxygen
therapy did not
improve survival

Abbreviations:
COPD: chronic obstructive pulmonary disease, FEV : forced expiratory volume in one second (% predicted), L/min: liters per minute, LTOT: long-term oxygen therapy, O : oxygen, PaO: partial pressure of oxygen in arterial blood, PSG:
polysomnography, SaO : oxygen saturation, SpO : oxygen saturation with pulse oximetry, T Sa <%: recording time spent with an oxygen saturation <%
COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
357
358 B. ERGAN AND S. NAVA

We can conclude that oxygen supplementation during exer- available data remain inconsistent due to small sample sizes and
cise may prevent desaturation and improve exercise capacity methodological variations among the studies (75).
and symptoms in the acute setting in patients who are not There is insufficient evidence for the beneficial effects of
eligible for LTOT; however, long-term domiciliary oxygen use oxygen supplementation during PR and exercise training. A
for EID has no effect on important outcomes such as mortality, recent trial protocol was published to understand the role
functional capacity, and QoL. of oxygen in PR (SuppORT trial). This randomized con-
trolled study will recruit COPD patients who demonstrate
oxygen desaturation lower than 90% during the 6MWT and
Oxygen therapy during pulmonary rehabilitation and
address whether supplemental oxygen during exercise train-
exercise training in COPD patients
ing is more effective than medical air in improving exercise
It is well established that pulmonary rehabilitation (PR) and capacity and QoL (76). The results will help us to further
physical training enhance functionality and QoL in patients understand the role of oxygen supplementation during exercise
with COPD. It also has positive impacts such as improvements training.
in exercise capacity and breathlessness. However, as most of
these patients have limited exercise capacity because of desat-
uration episodes during training, supplemental oxygen during
Oxygen therapy for the relief of dyspnea in COPD
training would be beneficial. Voduc et al. evaluated the effect of
supplemental oxygen during PR and showed that exercise dura-
Relief of dyspnea during exercise
tion increased with oxygen (64). Neunhauserer et al. showed
that supplemental oxygen in non-hypoxemic COPD doubled Many COPD patients experience breathlessness during small
the effect of endurance training but had no effect on strength tasks even if they are not hypoxemic. Oxygen relieves dyspnea
gain (65). Several RCTs assessed the effects of oxygen on long- and improves recovery from breathlessness (25). Oxygen sup-
term PR and training (66–74; Table 4). Emtner et al. studied plementation may be helpful for patients to carry on their daily
non-hypoxemic COPD patients undergoing high-intensity routine activities and therefore may improve QoL. However, the
endurance training with a cycle ergometer for 7 weeks while results of RCTs (Table 5) have shown that the use of ambulatory
breathing either supplemental oxygen or room air and showed oxygen therapy for daily activities have limited effects for the
that the oxygen training group had an improved maximal work relief of dyspnea, exercise performance, and QoL (62,77–79).
rate, increased endurance, and reduced exercise breathing fre- Eaton et al. conducted a 12-week double-blind randomized
quency than the air group (70). Dyer et al. analyzed the effects cross-over trial in severe COPD patients with exertional desat-
of supplemental oxygen during the PR program (72). They uration (78). Approximately 70% of the patients had a reduced
compared the results of PR undertaken either with or without Borg dyspnea score and improved health-related QoL with
ambulatory oxygen in patients with a demonstrable benefit from supplemental oxygen. In contrast, McDonald et al. reported
oxygen at baseline (patients who walked an additional 10% or that supplemental oxygen increased the walking distance in the
more with ambulatory oxygen in an endurance shuttle walk acute setting but did not provide any long-term benefit in terms
test). Participants who were randomized to the oxygen group of dyspnea and QoL (77). Similar results were also reported
were asked to use oxygen at their prescribed flow rate at home by Nonoyama et al., who showed that only a small proportion
during all activities that induced dyspnea. It was shown that sup- of patients with mild hypoxemia experienced a benefit from
plemental oxygen significantly improved the endurance walking home oxygen after long-term use (79). Moore et al. evaluated a
distance. 12-week, parallel, double-blinded, randomized trial of cylinder
In contrast to these findings, some studies have reported air versus cylinder oxygen, provided at 6 liters/minute for use
negative results. Exercise training has been shown to result during any activity provoking breathlessness, and no benefits
in significant improvements in exercise capacity and QoL in were observed in terms of dyspnea or QoL (62).
subjects with moderate-to-severe COPD; however, oxygen In a recent Cochrane review, the efficacy of oxygen therapy
supplementation did not accentuate the benefits of training for breathlessness and health-related QoL was assessed in
(66,68,69). Spielmanns et al. used oxygen during a 24-week COPD patients who do not meet the criteria for LTOT (80).
training program with progressively increasing loads involving They included 44 studies encompassing 1195 participants in
the large muscle groups in a randomized controlled study, and the review, among which 33 studies (901 participants) were
showed that training caused statistically significant improve- included. The results showed that breathlessness during exer-
ments in QoL, the maximal tolerated load during cycling, cise or daily activities was reduced by oxygen compared with
peak oxygen uptake, and the 6MWT. However this benefit air (low-quality evidence) and that short-burst oxygen given
was independent of oxygen supplementation (74). Ringbaek before exercise was ineffective (low-quality evidence). Oxygen
et al. randomized normoxemic COPD patients to control or reduced breathlessness during exercise tests (moderate-quality
ambulatory oxygen of 2 liters/minute during exercise and evidence), but the effect on breathlessness in daily life was
reported that there was no difference between the groups in limited (low-quality evidence). There was no effect on health-
the endurance shuttle walk test, change in St George’s Respi- related QoL (low-quality evidence). The authors concluded that
ratory Questionnaire scores, or number of patients with acute oxygen can relieve breathlessness when given during exercise to
exacerbation, hospital admission or dropout (73). In a meta- mildly hypoxemic and non-hypoxemic people with COPD who
analysis, it was reported that oxygen supplementation during would not otherwise qualify for home oxygen therapy. Most
training may augment the benefits of exercise; however, the evidence is attributable to acute effects during exercise tests,
Table . Randomized Controlled Trials For Long-Term Oxygen Therapy For Pulmonary Rehabilitation And Exercise Training In COPD Patients.

Comparison (n recruited/
Completed the study) Resting
Training
Study population FEV (L and/or % predicted) PaO (mmHg) SaO Training type duration Impact on outcomes

Rooyackers Patients with SaO <% at the Oxygen  L/min (/) . L (%)  NA In-patient pulmonary  minutes Primary outcome: Although
 peak incremental cycle rehabilitation program x/week supplemental oxygen had acute
exercise (general exercise  weeks beneficial effects on exercise
training included performance, oxygen-supplemented
dynamic and isometric exercise training did not add to the
strength training and effects of training while breathing
specific training of room air.
daily life activities like Secondary outcomes: Pulmonary
breathing retraining, rehabilitation improved exercise
physical therapy) performance and quality of life
Room air (/) . L (%)  NA (assessed with CRQ) in both groups.

Fichter   Patients with stable disease Oxygen % (/) .%  NA Cycle ergometer training  minutes Primary outcome: Change in maximally
at a constant workload x/week achieved power in the incremental
of % of their highest  weeks exercise test after training was .%
achieved work-rate in the supplemental oxygen group
and .% in room air group
Room air (/)

Garrod  Patients with limited exercise Oxygen  L/min (/) . L (.%)  % Upper and lower limb  minutes Primary outcome: There was no l
tolerance due to dyspnea and training x/week benefit of oxygen on exercise
having a fall in arterial  weeks tolerance or health status (no
saturation of at least % from change in SWT, CRQ, HAD or London
baseline to % or below Chest Activity of Daily Living scales)
upon exercise testing Secondary outcome: The supplemental
oxygen group had a greater
reduction in dyspnea upon exertion,
as measured with the Borg scale
Compressed air (/) . L (.%)  % compared with the air group

Wadell  Patients with PaO > mmHg Oxygen  L/min (/) .%  % Interval walking on a  minutes Primary outcome: Supplemental
at rest and hypoxemia during treadmill (intensity set x/week oxygen did not improve the training
exercise (SaO ࣘ% in the according to Borg  weeks effect compared with training with
MWD) ratings) air
Compressed air (/) .%  % Secondary outcomes: Training
significantly improved distance in
MWT in both groups. Oxygen
group showed no decrease in Borg
ratings for dyspnea, higher increase
in lactate during exercise after
training and increase in time for
SaO<% during the test
COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

(Continued on next page)

359
 360

Table . Continued
Comparison (n recruited/ Resting
Completed the study)
Study population FEV (L and/or % predicted) PaO (mmHg) SaO Training type Training Impact on outcomes
duration
B. ERGAN AND S. NAVA

Emtner  Patients who do not experience Oxygen  L/min (/) . L (%)  % High-intensity  minutes Primary outcome: Supplemental
appreciable desaturation endurance training x/week oxygen group achieved higher
during exercise (SpO ࣙ% with a cycle ergometer  weeks training intensity and endurance
during a constant work rate capacity and the breathing pattern
test) improved significantly
Compressed air (/) . L (%)  % Secondary outcome: Quality of life
(assessed with CRQ) increased
significantly in both groups

Scorsone Patients with FEV1 <% Oxygen % (/) %  NA Leg-cycle training at %  minutes Primary outcome: Supplemental
 predicted of the initial peak work x/week oxygen and heliox did not provide
rate for at least   weeks an advantage for improving exercise
minutes tolerance and symptoms over air
Humidified air (/) %  NA Secondary outcomes: Physical training
resulted in a significant
improvement in peak oxygen
consumption, power output and
exercise endurance time in all
groups
Heliox - (/) %  NA

Dyer  Patients desaturated by >% Oxygen - L/min to keep SpO . L (%) NA % Strengthening and x/week Primary outcome: Supplemental oxygen
and to <% upon exertion, >% (/) endurance exercise - weeks significantly improved the endurance
and walked % or more tailored to suit walking distance during pulmonary
further with ambulatory individual needs with rehabilitation program
oxygen on ESWT aerobic exercise Secondary outcome: There was no
(walking) set at % statistically significant change in
the estimated peak quality of life (assessed with CRQ, HAD
oxygen uptake scale, SIFT questionnaire)
together with an
education program
Room air (/) . L (%) NA % Home exercise program:
Participants
randomized to the
oxygen group were
asked to use oxygen at
their prescribed flow
rate at home during all
activities that induced
dyspnea
Table . Continued
Comparison (n recruited/ Resting
Completed the study)
Study population FEV (L and/or % predicted) PaO (mmHg) SaO Training type Training Impact on outcomes
duration

Ringbaek Patients desaturated by >% Oxygen  L/min (/) . % NA % Supervised walking and st phase:  Primary outcome: Supplemental oxygen
 and <% during ESWT cycling and minutes improved oxygen saturation during
unsupervised home x/week for  ESWT but there was no difference
training (patients were weeks; between the groups at -weeks of
instructed to continue nd phase:  evaluation with regard to the change
the unsupervised minutes in ESWT
training at home at x/week for  Secondary outcomes: Oxygen therapy did
least  min every day weeks; not provide an additional benefit in
during the whole rd phase: Only terms of quality of life (assessed with
study period) unsupervised SGRQ), risk of acute exacerbations and
Control (/) .% NA % Participants randomized home training hospitalizations
to the oxygen group at least 
were asked to use minutes for 
oxygen during weeks
supervised and
unsupervised training

Spielmanns Patients who were normoxemic Oxygen  L/min (/) . L (%) NA > % Endurance training  min Primary outcome: Supplemental
 (SaO >%) at rest and program with x/week oxygen during the training program
during exercise without an progressively increasing  weeks did not result additional change in
oxygen supply loads involving large MWT distance
Compressed air (/) . L (%) muscle groups Secondary outcomes: Endurance
training resulted in significant
improvements in quality of life
(assessed with SF-) and exercise
capacity in subjects with
moderate-to-severe COPD

Abbreviations:
MWT: -minute walk test, COPD: chronic obstructive pulmonary disease, CRQ: chronic respiratory disease questionnaire, CRQ: chronic respiratory questionnaire, ESWT: endurance shuttle walk test, FEV : forced expiratory volume in
one second (% predicted), HAD: hospital anxiety and depression scale, L/min: liters per minute, LTOT: long-term oxygen therapy, NA: data not available, O : oxygen, PaO : partial pressure of oxygen in arterial blood, SaO : oxygen
saturation, SF : short form , SGRQ: St George’s respiratory questionnaire, SIFT: surrey information on fuctional tool, SpO : oxygen saturation with pulse oximeter
COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
361
Table . Randomized Controlled Trials For Long-Term Oxygen Therapy For Exertional Dyspnea in COPD Patients.
362

Resting

FEV (L and/or PaO

Study population Comparison % predicted) (mmHg) SaO Study Duration Impact on Outcomes

McDonald Patients describing exertional dyspnea Oxygen ( L/min) . L  %  weeks of oxygen and  Primary outcome: Suplemental oxygen
 sufficient to interfere with daily weeks of air increased MWT distance and steps
activities achieved by small, statistically significant
increments acutely at baseline and after 
and  weeks without corresponding falls
B. ERGAN AND S. NAVA

in Borg dyspnea scores in the acute studies

however there was no difference in MWT
distance, the number of steps achieved
and Borg dyspnea scores between oxygen
and air group in domiciliary studies
Study with crossover design:  Compressed air Secondary outcomes: Quality of life indices
participants- completed improved by statistically significant
amounts after home oxygen therapy.
Quality of life (assessed with CRQ) did not
change after  weeks use of domiciliary
oxygen supplementation during exertion
compared to domiciliary supplemental air

Eaton  Patients who experience exertional Oxygen  L/min .%  %  weeks of oxygen and  Primary outcome: Improvements were seen
dyspnea impacting daily activities weeks of air in all domains of the disease-specific CRQ,
and having exertional desaturation both domains of the HAD and several
ࣘ% on air domains of the SF- for oxygen compared
with cylinder air
Study with crossover design:  Compressed air Secondary outcome: Baseline characteristics
participants- completed and acute response to oxygen therapy did
not predict short-term ( weeks) response

Nonoyama Patients who experience dyspnea Oxygen  L/min NA NA NA Three pairs of -week home Primary outcome: No apparent effect of
 limiting daily activities, and with (Range - treatment periods, with ambulatory oxygen was observed on any of
desaturation ࣘ% for  continuous L/min) oxygen provided during the four domains of the CRQ or the SGRQ
minutes during room-air MWT one period of each pair Secondary outcome: Ambulatory oxygen
and a placebo mixture for improved constant power exercise saturation
the other period and increased endurance, -min home
N-of- RCT design:  participants- Placebo mixture∗ walking test and dyspnea when compared to
completed placebo in acute studies

Moore  Patients with moderate to severe Oxygen  L/min . L (%)  NA  weeks Primary outcome: Domiciliary ambulatory
exertional dyspnea (Medical oxygen did not cause any improvement in
Research Council Dyspnea Scale dyspnea assessed with dyspnea domain of
grade >) the CRQ
Study with parallel groups:  Compressed air . L (%)  NA Secondary outcomes: There was no difference
participants- completed between groups for baseline/transition
dyspnea index, quality of life (CRQ, HAD
and assessment of quality of life utility
index) or function (MWT)

Abbreviations:
MWT: -minute walk test, COPD: chronic obstructive pulmonary disease, CRQ: chronic respiratory disease questionnaire, HAD: hospital anxiety and depression scale, NA: data not available FEV : forced expiratory volume in one second
(% predicted), L/min: liters per minute, LTOT: long-term oxygen therapy, O : oxygen, PaO: partial pressure of oxygen in arterial blood, SaO : oxygen saturation, SF : short form , SGRQ: St George’s respiratory questionnaire
∗% oxygen diluted with ambient air provided an FiO of approximately .% inhaled at  L/min.
 COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 363

Table . Summary of evidence for long-term oxygen use in in specific circumstances in COPD.

Moderate hypoxemia Current evidence does not support the use of LTOT in COPD patients with moderate desaturation
Nocturnal desaturation The benefit of LTOT for clinically relevant outcomes remains unclear due to the paucity of data
Exercise-induced desaturation Oxygen administration causes less breathlessness and improves exercise capacity during exercise however the
effectiveness of long term use of ambulatory oxygen on exercise capacity and mortality is not evident
Pulmonary rehabilitation and exercise There is insufficient evidence to confirm the benefits of supplemental oxygen during exercise training but oxygen
training administration may reduce breathlessness and improve exercise tolerance
Relief of dyspnea for palliation Current evidence does not support the use of LTOT for the relief of dyspnea in non-hypoxemic COPD patients

Abbreviations:
COPD: chronic obstructive pulmonary disease, LTOT: long-term oxygen therapy.

and no evidence indicates that oxygen is beneficial for reducing the desired FiO2 when the patient have high peak inspiratory
breathlessness in daily life and improving QoL. flow rates due to respiratory distress (91,92). Compared to
standard oxygen delivery systems, HFNO improves ventilatory
efficiency by washing out carbon dioxide from the anatomic
Relief of dyspnea for palliative purposes dead space and causes a positive end expiratory pressure, when
End-stage COPD patients suffer from a high burden of the mouth is closed (93). It has recently been shown that HFNO
symptoms. Dyspnea is the most debilitating symptom in reduces the work of breathing in patients with both hypoxemic
advanced COPD and profoundly affects QoL. Patients who and hypercapnic COPD. (94,95). HFNO may reduce dyspnea
have intractable dyspnea usually have a fear of death by suffo- successfully with greater comfort and tolerance when compared
cation (81), and it was shown that COPD patients usually suffer with standard conventional oxygen masks (96,97). The effect
from poor symptom control including dyspnea in the last week of HFNO for palliative oxygen therapy is promising and merits
of their life (82). Supplemental oxygen is commonly used as further research.
palliative treatment in end-stage COPD patients for the relief of
distress experienced by patients and their families (83). Palliative
oxygen therapy is defined as the use of oxygen to relieve the sen- Conclusion
sation of refractory persistent breathlessness in advanced dis-
The evolution of oxygen therapy in the medical field has been
ease or life-limiting illness irrespective of the underlying pathol-
a long journey (98). Despite relatively good evidence for the
ogy, in which all reversible causes have been or are being treated
benefits of LTOT in hypoxemic COPD patients in improving
optimally (14). Despite the widespread use, data supporting
survival, similar benefits have not been demonstrated in the
this approach are contradictory, and there is limited evidence
majority of COPD patients with moderate or intermittent
to support the routine use of supplemental oxygen to reduce
hypoxemia, either nocturnal or exercise-induced (Table 6). The
dyspnea in non-hypoxemic patients with advanced COPD (84–
role of oxygen in symptom relief, such as dyspnea, has also been
87). In a RCT conducted in patients with life-limiting illnesses
controversial both during exercise and as a palliative tool. New
who were ineligible for LTOT, supplemental oxygen provided
studies are currently in the pipeline (the INOX and SuppORT
no additional symptomatic benefit compared to room air (86).
trials), and thus, it is likely that in the next few years, the “oxygen
There were no statistically significant differences between
journey” will continue.
the two groups in terms of breathlessness, frequency of side
effects, or change in QoL. Campbell et al. showed that when
compared to air, oxygen therapy did not decrease respiratory
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