The aim of this multicenter crossover trial is to describe the effect of adding a therapeutic dose of exertional oxygen therapy, in terms of exercise performance, gas exchange, heart rate, symptoms perception and subjective easiness of performance, in a cohort of subjects hospitalized in specialized pulmonary rehabilitation centers with a diagnosis of chronic respiratory failure and/or exertional hypoxemia due to chronic obstructive pulmonary disease or interstitial lung disease.

Researchers will compare the walking performance during 6-minute walk test performed with the liters of oxygen administered as prescribed at rest (for patients with chronic respiratory failure) or in room air (for patients with exertional hypoxemia only), to the performance during a 6-minute walk test performed with the double the flow rate prescribed at rest, or with 2 L/min for patients with exertional hypoxemia only. The two tests will be performed in random order, at least 3 hours apart and no later than 24 hours apart from each other.

The main outcome will be the difference between the distance walked in the two 6-minute walk test in the two conditions. Furthermore, will be also collected and compared: the oxygen saturation and heart rate every minute, the initial and final dyspnea and fatigue, as assessed by Borg scale, and the easiness of performance through a dedicated questionnaire. The estimated sample size will be 114 patients.

This study will provide some basis for a more accurate prescription of exercise-related oxygen therapy, offering insights into the phenotype of patients who may derive the greatest benefit from this intervention. It will also stimulate discussion regarding the optimal timing and dosing of oxygen administration during exertion in patients with respiratory failure.

Although supplemental oxygen enhances acute exercise performance in COPD, its long-term impact on quality of life and mortality remains unproven. Current guidelines suggest treating exertional desaturation (SpO2<90%), but the lack of standardized titration protocols, particularly using the 6MWT, limits clinical consistency. While many patients with chronic respiratory failure (CRF) receive dual-level oxygen prescriptions (rest vs. exercise), it is unclear if this approach yields significant functional gains. Therefore, In light of these considerations, the present multicenter crossover study aims to describe the effect of adding a therapeutic dose of exertional oxygen therapy in terms of:

1. exercise performance
2. gas exchange
3. heart rate
4. symptom perception
5. subjective easiness of performance in a cohort of patients hospitalized in specialized pulmonary rehabilitation centers with a diagnosis of chronic respiratory failure and/or exertional hypoxia due to a chronic respiratory disease at the time of discharge from an inpatient rehabilitation attempt.

As secondary aim, the study will also evaluate any difference in the response among different diseases.

This study will be conducted on subjects with chronic respiratory diseases admitted to the Pulmonary Units of the ICS Maugeri , for rehabilitation will be evaluated for inclusion in the protocol. After approval of the project by the Ethical Committee, those who meet the following criteria at the time of discharge will be enrolled in the study.

We will enroll 3 different groups of patients:

A) Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) with EH, with an exertional oxygen prescription and a PaO2 > 60mmHg breathing room air at rest; B) Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) with Chronic Respiratory Failure, with a daytime long-term oxygen therapy (LTOT) prescription and a PaO2 < 60mmHg breathing room air at rest; C) Diagnosis of Interstitial Lung Disease (ILD) with Chronic Respiratory Failure with a daytime long-term oxygen therapy (LTOT) and a PaO2 < 60mmHg breathing room air at rest.

All patients have to be in a clinically stable condition for at least one month with optimized therapy during hospitalization.

Exclusion criteria will include: presence of lung diseases other than COPD or ILD; patients requiring a resting oxygen flow rate greater than 6 L/min; patients with orthopedic, cognitive, or neurological conditions that may affect test outcomes; patients with recent cardiovascular or cerebrovascular events within the previous three months; and cognitive impairment evaluated by Mini-Mental State Examination (MMSE) score as < 25.

With a cross-over multicenter randomized design, at the time of discharge, all patients will perform two 6-Minute Walking Tests in a random order under the following conditions:

1. O2REST: Liters of oxygen will be administered as prescribed at rest (for patients with CRF), or in room air (for patients with EH only);
2. O2PLUS: Liters of oxygen therapy will be set at double the flow rate compared to the resting prescription, or at 2 L/min for patients with EH.

The 6MWT will be performed, according to the ATS/ERS guidelines, along a flat corridor of at least 20 meters. Each patient will receive standardized pre-test instructions and verbal encouragement at every minute during the test. The two tests will be performed at least 3 hours apart and no later than 24 hours apart from each other. All patients will perform the tests using nasal prongs and a stroller (liquid oxygen). The stroller will be either held by the patients or transported via a backpack or rollator. When patients perform the test in room air, they will carry the stroller with no oxygen supply.

The following anthropometric and clinical measures will be collected at admission: age, BMI, diagnosis, blood gas analysis (PaO2, PaCO2, pH) at rest breathing room air, time from diagnosis, time from first oxygen prescription, spirometry (FEV1, FVC, IT, RV).

The following data will be recorded during the two 6MWT tests:

• every minute: distance walked; oxygen saturation, heart rate;
• initial and final: blood Pressure, Borg Dyspnea Scale (BORGD), Borg Fatigue Scale (BORGF);
• after three minutes (recovery phase): oxygen saturation, heart rate, Borg Dyspnea Scale (BORGD), Borg Fatigue Scale (BORG).

To evaluate the patient-reported easiness of performance at the end of the second test, a dedicated questionnaire will be administered.

The "oxygen response" will be the primary outcome, defined as the 6-min walk distance using supplemental oxygen (O2PLUS) minus the 6-min walk distance using O2 quantity prescribed at rest (O2REST).

The sample size calculation was done about previous literature study data on 6-minute walk distance, assuming a two-sided α level of 0.01 and a power of 90% and including a 15% dropout rate, according to the diseases: in GROUP A, a sample size of at least 41 patients will be necessary to detect a clinically relevant difference of 28 meters in 6MWD (SD 44); in GROUP B, a sample size of at least 22 patients will be necessary to detect a clinically relevant difference of 37 meters in 6MWD (SD 40); in GROUP C, a sample size of at least 50 patients will be necessary to detect a clinically relevant difference in 6MWD of 13 meters (SD 30) between the two conditions.

The data will be analyzed using STATA 12 (StataCorp, LLC) and GraphPad Prism 8 (GraphPad Software, Boston, MA, US). Baseline characteristics and outcomes will be summarized with descriptive statistics. Continuous variables will be expressed as mean ± standard deviation (SD) or median (interquartile range, IQR) if not normally distributed. Categorical variables will be presented as percentages.

Patients who increased their 6MWD by at least 30 meters due to O2_suppl. were defined as "oxygen responders". A statistical comparison between tests for paired data will be performed using paired t-tests if the variables are normally distributed, or the Wilcoxon signed-rank test if the variables are not normally distributed. The analysis will be conducted within groups, and an additional analysis will be performed by pooling the data into a single group. Furthermore, a linear regression analysis will be carried out to assess whether the changes induced by oxygen administration are associated with baseline clinical or anthropometric factors. Differences in all recorded parameters between the two conditions, both in terms of delta (change) and kinetics, will be also calculated. Statistical significance will be set at p < 0.05.

We expect to observe an improvement gap in terms of performance or symptoms in a high proportion of patients when tested under hyperoxia. However, the proportion of patients who respond to the hyperoxic stimulus, as well as the characteristics of this phenotype, remain unclear to date.

This study will provide some basis for a more accurate prescription of exercise-related oxygen therapy, offering insights into the phenotype of patients who may derive the greatest benefit from this intervention. It will also stimulate discussion regarding the optimal timing and dosing of oxygen administration during exertion in patients with respiratory failure. In practice, it will help to characterize the acute effects of oxygen administration during exertion, considering the benefits in terms of physical performance and symptom relief. Furthermore, it will support reflections on the economic and social impact of oxygen prescription, initiating a discussion on the appropriate dosing strategy for exertional oxygen therapy.

Condition or disease:

• Chronic Respiratory Failure
• Exertional Hypoxemia
• Chronic Obstructive Pulmonary Disease (COPD)
• Interstitial Lung Disease

Intervention/treatment

• Usual Oxygen During 6-Minute Walk Test
• Supplemental Oxygen During 6-Minute Walk Test

Inclusion Criteria:

• Adults aged 18 years or older
• Diagnosis of chronic respiratory disease admitted for pulmonary rehabilitation
• One of the following conditions at discharge:
• Chronic obstructive pulmonary disease with exertional hypoxemia
• Chronic obstructive pulmonary disease with chronic respiratory failure requiring long-term oxygen therapy
• Interstitial lung disease with chronic respiratory failure requiring long-term oxygen therapy
• Clinically stable condition for at least one month
• Optimized medical therapy during hospitalization
• Ability to perform the 6-minute walk test
• Signed informed consent

Exclusion Criteria:

• Lung diseases other than chronic obstructive pulmonary disease or interstitial lung disease
• Resting oxygen flow requirement greater than 4 liters per minute
• Orthopedic, neurological, or cognitive conditions that may limit walking performance
• Recent cardiovascular or cerebrovascular events within the previous 3 months