Long-Term Oxygen Therapy in COPD Patients Who Do Not Meet the Actual Recommendations

Figures & data

Table 1. Definitions.

Resting hypoxemia	Resting PaO2 ≤55 mmHg or SaO2 ≤88%
	OR
	Resting PaO2 between 56-59 mmHg (or SaO2 ≤88%) with evidence of either pulmonary hypertension, cor pulmonale or polycythemia (hematocrit >55%)
Moderate hypoxemia	Resting PaO2 ranging between 56 and 69 mmHg
Nocturnal desaturation	Spending ≥30% sleep time with SaO2 < 90% without evidence of associated sleep apnea
	OR
	A fall in SaO2 below 90% for 5 minutes or more with a nadir SaO2 below 85% during sleep
Exercise-induced desaturation	SaO2 ≤ 88% during exercise
	OR
	A fall in SaO2 ≥ 4% during exercise

Abbreviations:

PaO₂: partial pressure of oxygen in arterial blood, SaO₂: oxygen saturation

Figure 1. Flow chart for articles included in the review (RCT, Randomized controlled trial).

Table 2. Randomized Controlled Trials For Long-Term Oxygen Therapy In COPD Patients wit Moderate Hypoxemia.

				Resting
	Study population	Comparison (n)	FEV1 (L and/or % predicted)	PaO2 (mmHg)	SaO2	Mean O2 use (hours/day)	Study duration	Impact on outcomes
Gorecka^35 1997	Patients with PaO2 between 56-65 mmHg	LTOT (68): Oxygen was prescribed with a flow rate adjusted to maintain a PaO2 >65 mmHg and >17 hours/day	0.85 L (29.7%)	60	NA	13.5	3 years	Primary outcome: LTOT did not prolong survival
		Control (67)	0.81 L (29.8%)	61	NA	-		Secondary outcome: There was no correlation between the duration of oxygen use and survival in LTOT group
Haidl^37 2004	COPD patients with reversible hypercapnia (PaCO2 > 45 mmHg at rest on 2 different days or increase in PaCO2 after cycle testing > 45 mmHg) with PaO2 at rest > 55 mmHg and a mean nocturnal oxygen saturation > 90%, and before discharge, PaCO2 at rest should have returned to ≤45 mm Hg)	LTOT (14): Oxygen was prescribed at 2 L/min for ≥15 hours/day	38.8%	67	NA	10.4	1 year (the planned study duration was 3 years, but due to the high drop-out rate, assessment after one year was chosen by the authors)	Primary outcome: LTOT did not decrease mortality in COPD patients with reversible hypercapnia
		Control (14)	42.7%	66	NA	-		Secondary outcomes: LTOT stopped the decline in endurance time and reduced the exertional dyspnea score significantly after 1 year compared to controls
The Long Term Oxygen Treatment Trial Group^38 2016	Patients with moderate resting hypoxemia (SpO2 89-93%) or resting SpO2 >93% and exercise-induced moderate desaturation (SpO2 ≥ 80% for ≥ 5 min and <90% for ≥10 seconds during 6 MWT)	LTOT (386): Oxygen (2 L/min) was prescribed 24 hours in patients with moderate hypoxemia (220) and during exercise and sleep in patients with exercise-induced desaturation (148)	47%	NA	93%	15.1 hours in the 24-hour group and 11.3 hours in the sleep–exercise group	1-6 years (median follow-up: 18.4 months)	Primary outcome: LTOT for patients with resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization for any cause.
		Control (370)	46%	NA	94%	1.8 hours (median 0 hours)*		Secondary outcomes: There was no difference between groups for the rates of all hospitalizations and COPD exacerbations. There was no difference between the groups in the change from baseline in measures of quality of life (assessed with quality of well being scale, SF 36, SGRQ, Pittsburgh sleep quality index), depression and anxiety (assessed with HAD scale), lung function, distance for 6MWT and other measures of functional status

 

 

Abbreviations:

6MWT: 6-minute walk test, COPD: chronic obstructive pulmonary disease, FEV₁: forced expiratory volume in one second (% predicted), L/min: liters per minute, LTOT: long-term oxygen therapy, NA: data not available, O₂: oxygen, PaCO₂: partial pressure of carbon dioxide in arterial blood, PaO₂: partial pressure of oxygen in arterial blood, SaO₂: oxygen saturation, SpO₂: oxygen saturation with pulse oximetry

* Use of supplemental oxygen limited to periods of severe resting desaturation (SpO₂ ≤88%) or severe exercise-induced desaturation (SpO₂ <80% for ≥1 minute); the oxygen requirement was reassessed after 30 days

Table 3. Randomized Controlled Trials For Nocturnal Oxygen Therapy In COPD Patients With Nocturnal Desaturation.

	Study population	Definition for nocturnal desaturation	PSG	Comparison (n: recruited/completed the study)	FEV1 (L and/or % predicted)	Resting PaO2 (mmHg)	Nocturnal SaO2	T Sa <90%	Mean O2 use (hours)	Study duration	Impact on outcomes
Fletcher^49 1992	Patients with resting daytime PaO2 ≥60 mm and nocturnal desaturation	i. Baseline awake and non-rapid eye movement (NREM) ear oximeter saturation ≥ 90%,	Yes	Nocturnal oxygen therapy 3 L/min (19/7)	1.42L	74	91%	29%	7.6	3 years	Primary outcome: Nocturnal desaturating patients who received oxygen during sleep for 3 years showed a significant downward trend in pulmonary artery pressure compared to desaturators treated with compressed air
		ii. A fall below this value for 5 min or more, usually coinciding with but not limited to REM sleep, iii. A nadir SaO2 value reaching 85% or lower		Compressed air (19/9)	1.42L	77	91%	24%	9.4		Secondary outcomes: There was no statistically significant difference between groups for mortality. and nonvascular parameters (hemoglobin, red blood cell mass).
Chaouat^50 1999	Patients with daytime PaO2 between 56-69 mmHg and nocturnal desaturation	Spending ≥30% of the recording time with transcutaneous arterial O2 sat <90%	Yes	Nocturnal oxygen therapy 2 L/min (41/24)	1.1L (41%)	63	88%	63%	8.9	2 years	Primary outcome: Nocturnal oxygen therapy did not alter the evalution of pulmonary hemodynamics
				Control (35/22)	0.98L (35%)	63	89%	65%	-		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, FEV₁: forced expiratory volume in one second (% predicted), L/min: liters per minute, LTOT: long-term oxygen therapy, O₂: oxygen, PaO2: partial pressure of oxygen in arterial blood, PSG: polysomnography, SaO₂: oxygen saturation, SpO₂: oxygen saturation with pulse oximetry, T Sa <90%: recording time spent with an oxygen saturation <90%

Table 4. Randomized Controlled Trials For Long-Term Oxygen Therapy For Pulmonary Rehabilitation And Exercise Training In COPD Patients.

	Study population	Comparison (n recruited/ Completed the study)	FEV1 (L and/or % predicted)	Resting		Training type	Training duration	Impact on outcomes
				PaO2 (mmHg)	SaO2
Rooyackers^66 1997	Patients with SaO2 <90% at the peak incremental cycle exercise	Oxygen 4 L/min (12/12)	0.9 L (29%)	77	NA	In-patient pulmonary rehabilitation program (general exercise training included dynamic and isometric strength training and specific training of daily life activities like breathing retraining, physical therapy)	80 minutes5x/week10 weeks	Primary outcome: Although supplemental oxygen had acute beneficial effects on exercise performance, oxygen-supplemented exercise training did not add to the effects of training while breathing room air.
		Room air (12/12)	1.2 L (38%)	79	NA			Secondary outcomes: Pulmonary rehabilitation improved exercise performance and quality of life (assessed with CRQ) in both groups.
Fichter ^67 1999	Patients with stable disease	Oxygen 35% (5/5)	43.2%	74	NA	Cycle ergometer training at a constant workload of 80% of their highest achieved work-rate	45 minutes5x/week4 weeks	Primary outcome: Change in maximally achieved power in the incremental exercise test after training was 15.9% in the supplemental oxygen group and 36.3% in room air group
		Room air (5/5)
Garrod^68 2000	Patients with limited exercise tolerance due to dyspnea and having a fall in arterial saturation of at least 4% from baseline to 90% or below upon exercise testing	Oxygen 4 L/min (13/11)	0.77 L (28.5%)	64	92%	Upper and lower limb training	60 minutes3x/week6 weeks	Primary outcome: There was no l benefit of oxygen on exercise tolerance or health status (no change in SWT, CRQ, HAD or London Chest Activity of Daily Living scales)
		Compressed air (12/11)	0.84 L (35.0%)	64	93%			Secondary outcome: The supplemental oxygen group had a greater reduction in dyspnea upon exertion, as measured with the Borg scale compared with the air group
Wadell^69 2001	Patients with PaO2 >60 mmHg at rest and hypoxemia during exercise (SaO2 ≤92% in the 6MWD)	Oxygen 5 L/min (11/10)	39.3%	71	95%	Interval walking on a treadmill (intensity set according to Borg ratings)	30 minutes3x/week8 weeks	Primary outcome: Supplemental oxygen did not improve the training effect compared with training with air
		Compressed air (11/10)	51.6%	70	95%			Secondary outcomes: Training significantly improved distance in 6MWT 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 SaO2<90% during the test
Emtner^70 2003	Patients who do not experience appreciable desaturation during exercise (SpO2 ≥88% during a constant work rate test)	Oxygen 3 L/min (15/14)	1.0 L (35%)	72	94%	High-intensity endurance training with a cycle ergometer	45 minutes3x/week7 weeks	Primary outcome: Supplemental oxygen group achieved higher training intensity and endurance capacity and the breathing pattern improved significantly
		Compressed air (15/15)	1.0 L (38%)	74	93%			Secondary outcome: Quality of life (assessed with CRQ) increased significantly in both groups
Scorsone^71 2010	Patients with FEV₁ <60% predicted	Oxygen 40% (10/10)	47%	74	NA	Leg-cycle training at 80% of the initial peak work rate for at least 20 minutes	40 minutes3x/week8 weeks	Primary outcome: Supplemental oxygen and heliox did not provide an advantage for improving exercise tolerance and symptoms over air
		Humidified air (10/10)	50%	76	NA			Secondary outcomes: Physical training resulted in a significant improvement in peak oxygen consumption, power output and exercise endurance time in all groups
		Heliox 60-40 (10/10)	49%	77	NA
Dyer^72 2012	Patients desaturated by >4% and to <90% upon exertion, and walked 10% or more further with ambulatory oxygen on ESWT	Oxygen 2-6 L/min to keep SpO2 >90% (28/24)	0.96 L (39%)	NA	94%	Strengthening and endurance exercise tailored to suit individual needs with aerobic exercise (walking) set at 85% the estimated peak oxygen uptake together with an education program	2x/week6-7 weeks	Primary outcome: Supplemental oxygen significantly improved the endurance walking distance during pulmonary rehabilitation program
		Room air (27/23)	1.12 L (44%)	NA	94%	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		Secondary outcome: There was no statistically significant change in quality of life (assessed with CRQ, HAD scale, SIFT questionnaire)
Ringbaek^73 2013	Patients desaturated by >4% and <90% during ESWT	Oxygen 2 L/min (22/12)	32.8 %	NA	94%	Supervised walking and cycling and unsupervised home training (patients were instructed to continue the unsupervised training at home at least 30 min every day during the whole study period)	1st phase: 30 minutes 2x/week for 7 weeks;2nd phase: 30 minutes 1x/week for 12 weeks;3rd phase: Only unsupervised home training at least 30 minutes for 12 weeks	Primary outcome: Supplemental oxygen improved oxygen saturation during ESWT but there was no difference between the groups at 33-weeks of evaluation with regard to the change in ESWT
		Control (23/17)	10.9%	NA	94%	Participants randomized to the oxygen group were asked to use oxygen during supervised and unsupervised training		Secondary outcomes: Oxygen therapy did not provide an additional benefit in terms of quality of life (assessed with SGRQ), risk of acute exacerbations and hospitalizations
Spielmanns^74 2014	Patients who were normoxemic (SaO2 >90%) at rest and during exercise without an oxygen supply	Oxygen 4 L/min (42/19)	1.2 L (44%)	NA	> 90%	Endurance training program with progressively increasing loads involving large muscle groups	30 min3x/week24 weeks	Primary outcome: Supplemental oxygen during the training program did not result additional change in 6MWT distance
		Compressed air (43/17)	1.5 L (43%)					Secondary outcomes: Endurance training resulted in significant improvements in quality of life (assessed with SF-36) and exercise capacity in subjects with moderate-to-severe COPD

 

Abbreviations:

6MWT: 6-minute walk test, COPD: chronic obstructive pulmonary disease, CRQ: chronic respiratory disease questionnaire, CRQ: chronic respiratory questionnaire, ESWT: endurance shuttle walk test, FEV₁: 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, O₂: oxygen, PaO₂: partial pressure of oxygen in arterial blood, SaO₂: oxygen saturation, SF 36: short form 36, SGRQ: St George's respiratory questionnaire, SIFT: surrey information on fuctional tool, SpO₂: oxygen saturation with pulse oximeter

Table 5. Randomized Controlled Trials For Long-Term Oxygen Therapy For Exertional Dyspnea in COPD Patients.

	Study population	Comparison	FEV1 (L and/or % predicted)	Resting		Study Duration	Impact on Outcomes
				PaO2 (mmHg)	SaO2
McDonald^77 1995	Patients describing exertional dyspnea sufficient to interfere with daily activities	Oxygen (4 L/min)	0.9 L	69	94%	6 weeks of oxygen and 6 weeks of air	Primary outcome: Suplemental oxygen increased 6MWT distance and steps achieved by small, statistically significant increments acutely at baseline and after 6 and 12 weeks without corresponding falls in Borg dyspnea scores in the acute studies however there was no difference in 6MWT distance, the number of steps achieved and Borg dyspnea scores between oxygen and air group in domiciliary studies
	Study with crossover design: 33 participants-26 completed	Compressed air					Secondary outcomes: Quality of life indices improved by statistically significant amounts after home oxygen therapy. Quality of life (assessed with CRQ) did not change after 6 weeks use of domiciliary oxygen supplementation during exertion compared to domiciliary supplemental air
Eaton^78 2002	Patients who experience exertional dyspnea impacting daily activities and having exertional desaturation ≤88% on air	Oxygen 4 L/min	25.9%	69	94%	6 weeks of oxygen and 6 weeks of air	Primary outcome: Improvements were seen in all domains of the disease-specific CRQ, both domains of the HAD and several domains of the SF-36 for oxygen compared with cylinder air
	Study with crossover design: 50 participants-41 completed	Compressed air					Secondary outcome: Baseline characteristics and acute response to oxygen therapy did not predict short-term (12 weeks) response
Nonoyama^79 2007	Patients who experience dyspnea limiting daily activities, and with desaturation ≤88% for 2 continuous minutes during room-air 6MWT	Oxygen 2 L/min (Range 1-3 L/min)	NA	NA	NA	Three pairs of 2-week home treatment periods, with oxygen provided during one period of each pair and a placebo mixture for the other period	Primary outcome: No apparent effect of ambulatory oxygen was observed on any of the four domains of the CRQ or the SGRQ
	N-of-1 RCT design: 38 participants-27 completed	Placebo mixture*					Secondary outcome: Ambulatory oxygen improved constant power exercise saturation and increased endurance, 5-min home walking test and dyspnea when compared to placebo in acute studies
Moore^62 2011	Patients with moderate to severe exertional dyspnea (Medical Research Council Dyspnea Scale grade >3)	Oxygen 6 L/min	1.15 L (47%)	70	NA	12 weeks	Primary outcome: Domiciliary ambulatory oxygen did not cause any improvement in dyspnea assessed with dyspnea domain of the CRQ
	Study with parallel groups: 143 participants-139 completed	Compressed air	1.17 L (47%)	73	NA		Secondary outcomes: There was no difference between groups for baseline/transition dyspnea index, quality of life (CRQ, HAD and assessment of quality of life utility index) or function (6MWT)

Abbreviations:

6MWT: 6-minute walk test, COPD: chronic obstructive pulmonary disease, CRQ: chronic respiratory disease questionnaire, HAD: hospital anxiety and depression scale, NA: data not available FEV₁: forced expiratory volume in one second (% predicted), L/min: liters per minute, LTOT: long-term oxygen therapy, O₂: oxygen, PaO2: partial pressure of oxygen in arterial blood, SaO₂: oxygen saturation, SF 36: short form 36, SGRQ: St George's respiratory questionnaire

*24% oxygen diluted with ambient air provided an FiO₂ of approximately 21.2% inhaled at 2 L/min.

Table 6. 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 training	There is insufficient evidence to confirm the benefits of supplemental oxygen during exercise training but oxygen 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.