Patients
From June 2016 to May 2018, patients with CRF (aged 40-90 years) undergoing LTOT for ≥3 months and attending an in-patient rehabilitation program were eligible to participate in the study. Based on the Japanese health insurance for LTOT, CRF was defined as follows: an arterial oxygen partial pressure (PaO2) of ≤55 Torr and a PaO2 ≤60 Torr developing marked hypoxemia during sleep or exercise. Patients with COPD, interstitial pulmonary fibrosis (IPF), or bronchiectasis and a stable clinical condition (i.e., no exacerbation reported for 3 months prior to the study) and absence of the following exclusion criteria: history of cardiovascular disease (e.g., myocardial infarction or ischemic heart disease), diabetes mellitus under treatment with hypoglycemic agents or insulin, neurological disorders, renal dysfunction (serum creatinine ≥1.2 mg/dL), and unable to undergo exercise training due to severe dyspnea or leg pain were enrolled.
In this prospective study, we assessed 42 consecutive patients with CRF receiving LTOT. Prior to enrollment, all patients underwent a 2-week screening period. Of those, seven patients were excluded (two with acute exacerbation, three with history of cardiovascular disease, and two who were unable to undergo rehabilitation), and three patients declined to participate. Thus, the remaining 32 clinically stable CRF patients receiving LTOT were enrolled (Clinical Trial Registration―URL: http://www.clinicaltrials.gov. Unique identifier: NCT02804243). This study was approved by the Ethics Committee of the National Hospital Organization Minami-Kyoto Hospital. All patients provided written informed consent prior to their participation.
Study design
On day 1, arterial blood gases (ABGs) were obtained in the supine position under a prescribed flow of oxygen via a nasal cannula and patients underwent a 6-min walking test (6MWT). On day 2, venous blood samples were obtained in the fasting state in the morning and examined for C-reactive protein (CRP), and plasma catecholamine levels. Pulmonary function tests were performed using the CHESTAC system (Chest M.I. Inc., Tokyo, Japan). In addition, patients underwent an incremental-load exercise test under prescribed oxygen on a cycle ergometer (Aerobike75XL, COMBI, Tokyo, Japan) to assess their maximal exercise capacity. In the following 3 days, the patients underwent (in random order) three constant-load exercise tests with a prescribed flow of oxygen via a nasal cannula, a flow of 6 L/min of oxygen via a nasal cannula, or an HFNC at a flow of 50 L/min with FIO2 of 1.0. The HFNC delivered a heated and humidified gas through an Optiflow system (Fisher and Paykel Healthcare, Auckland, New Zealand) using large-bore bi-nasal prongs.
After the constant-load exercise tests, patients completed a 4-week period of exercise training (five sessions per week) using the same workload achieved during the constant-load exercise tests. Prior to initiating the present study, we performed the preliminary exercise training under HFNC with 60 L/min. However, some patients who did not participate in the present study complained discomfort and nasal pain due to the high flow rate. To avoid these symptoms caused by the high flow rate, the HFNC was set to 50 L/min in this study. In the HFNC group, the HFNC was set at maximum FIO2 (FIO2 of 1.0) and near-maximum inspiratory flow rate (50 L/min) to assess its maximum effects (Figure 1). In the oxygen group, the flow rate of oxygen via a nasal cannula was set at the maximal flow rate (6 L/min).
Venous blood sampling, ABGs, pulmonary function tests and 6MWT on prescribed oxygen were conducted after 4 weeks of exercise training. In the following 3 days, subjects also underwent (in random order) three constant-load exercise tests using the same workload with that of the baseline assessment with prescribed oxygen in daily LTOT, a 6 L/min nasal cannula, or an HFNC at FIO2 of 1.0 and 50 L/min.
6MWT
The 6MWT was performed under prescribed oxygen in daily LTOT. According to the guidelines of the American Thoracic Society [22], patients were encouraged using standard methodology every minute of the 6MWT. A pulse oximeter (Anypal Walk, Fukuda Denshi, Tokyo, Japan) with a finger probe was used to measure oxygen saturation by pulse oximetry (SpO2) and the pulse rate during the 6MWT. In addition, a modified Borg scale [23] was used to quantify the levels of dyspnea perceived by patients at each minute during the 6MWT.
Exercise testing
Both incremental- and constant-load exercise tests were performed with continuous monitoring of SpO2 and the pulse rate on a cycle ergometer. In addition, continuous transcutaneous carbon dioxide partial pressure (PtcCO2) monitoring was performed using a TOSCA measurement system and TOSCA 500 monitor (Radiometer, Copenhagen, Denmark) [24, 25]. After automated calibration, the TOSCA monitor was attached to the right or left ear lobe. PtcCO2 monitoring was initiated after at least 10 min of equilibration. The incremental-load exercise test was performed according to the appropriate Japanese guidelines [26]. The incremental-load exercise test under prescribed oxygen in daily LTOT was initiated at 5 watts and increased by 5 watts every 2 min until the patient’s SpO2 was ≤85%, the pulse rate was ≥135 beats/min, or the modified Borg scale for dyspnea was ≥5. Prior to and following 4 weeks of exercise training, the patients performed three constant-load exercise tests at 80% of the maximum workload achieved with the incremental-load exercise test, with prescribed oxygen in daily LTOT, 6 L/min via a nasal cannula, or an HFNC at FIO2 of 1.0 and 50 L/min. The criteria for the termination of the constant-load exercise test were the same as those for the incremental-load exercise test. The SpO2, pulse rate, and PtcCO2 were measured at 6 min of the constant-load exercise test. All exercise testing was performed in the afternoon.
Exercise training
The patients performed supervised pulse oximeter-monitored continuous exercise training (5 sessions per week) receiving 6 L/min using a nasal cannula or an HFNC at FIO2 of 1.0 and 50 L/min. All training sessions were conducted on the same cycle ergometer and supervised by medical staff. Initially, the workload of the exercise training was the same as that of the constant-load exercise test. The criteria for the termination of exercise training sessions were SpO2 ≤85%, pulse rate ≥135 beats/min, or modified Borg scale for dyspnea ≥5. Whenever the duration of an exercise training session was ≥30 min, the workload of the subsequent session was increased by 5 watts.
Randomization
This study was randomized via blinded envelope prior to the initiation of the study.
Power analysis
Based on a previous study [27], differences of 30 meters of change in the 6MWD prior to and following 4 weeks of exercise training between the HFNC group and the oxygen group were decided to be clinically significant, and a standard deviation of 30 meters was expected. The sample size was set to achieve 80% power at a 5% significance level. The calculated sample size in each group was 16 subjects.
Statistical analysis
Data were analyzed using the JMP 9.0 software (SAS Institute, Inc. Cary, NC, USA), and values are expressed as mean ± standard deviation or absolute numbers and percentages. We compared subject characteristics, the results of the 6MWT and constant-load exercise test, and other parameters between the HFNC and oxygen groups. Continuous variables were tested using the unpaired t test or Mann–Whitney U test. Categorical variables were compared using the χ2 test or Fisher’s exact test. To investigate changes in the 6MWD, constant load exercise test, and other parameters prior to and after 4 weeks of exercise training in each group, comparisons of data between those two time points were tested using a paired t test. Moreover, each analysis of patients with COPD or IPF for investigating the change in the 6MWD prior to and after 4 weeks of exercise training in each group was performed using a paired t test. A p<0.05 denoted statistical significance.