Study participants
Patients with IPF diagnosis, according to the 2018 international consensus guidelines [1], were consecutively recruited from specialized Interstitial Lung Disease (ILD) clinics in two tertiary teaching hospitals. Eligible patients were those reaching a mean pulse oximeter oxygen saturation (SpO2) ≤ 85% (WirstOx2 TM Model 3150 Oximeter. Nonin Medical, INC. Plymouth, MN, USA) during the 6-min walking test (6MWT) performed at room air [17]. Exclusion criteria were fibrotic ILD other than IPF, coexistence of COPD, asthma or moderate-to-severe pulmonary hypertension [18], and inability to perform a cardiopulmonary exercise test (CPET) due to osteo-articular or cognitive limitations.
Study design
This was a randomized crossover clinical trial conducted in three visits (Fig. 1). Patients were included from March 2019 to February 2020 and were subsequently randomized. The study was approved by the local ethics committee, carried out according to the principles of the Declaration of Helsinki for human investigations and registered as a clinical trial (NCT04564664). All participants signed the appropriate informed consent prior to their inclusion.
An initial screening visit was performed according to the study protocol. Sociodemographic and clinical variables were also collected including GAP (Gender-Age-Physiology) and body mass (BMI) indices, individual comorbidities, Charlson comorbidity index and treatments received. Conventional pulmonary function tests and the 6MWT were performed according to international guidelines [17, 19, 20]. In addition, quadriceps and hand-grip strength were also measured following the previously described methodology [21], and the highest value of at least three correct maneuvers was chosen for both measurements.
First exercise evaluation
To assess maximum exercise capacity (WRmax) and to determine the FIO2 (Venturi mask) necessary to always maintain a SpO2 > 85%, a symptom-limited incremental CPET was performed by all patients. Subjects were randomized consecutively with a 1:1 allocation sequence to perform the first CPET with either HFNC or SOT.
Second and third evaluation
Following randomization all individuals performed two consecutive, submaximal CPET (75% of their WRmax) with at least 24 h apart. Half of them started with the HFNC O2 supplementation and the remaining with SOT.
Definitions and variables
The above mentioned three CPET were performed using a cycloergometer (Ergoline Medical Graphics Corporation, St. Paul, MN, USA) and a gas analyzer (Cardiorespiratory Diagnostic System, Ultimaseries TM, MediGraphics, Orlando, FL, USA). The tests were interrupted if adverse effects such as chest pain, changes in the electrocardiographic record or desaturation reaching SpO2 < 80% appeared despite oxygen supplementation.
Symptom-limited incremental CPET
This was performed to evaluate the patient’s WRmax according to the ATS/ACCP standardization statement [22]. In this regard, a conventional increasing protocol (10 Watts/min) was used and subjects had to maintain a 50–60 rpm constant speed at all time. As previously mentioned, the appropriate FIO2 needed to maintain a SpO2 > 85% was obtained.
Submaximal CPET with SOT
This was performed using a conventional Venturi system at the FIO2 chosen in the incremental CPET.
Submaximal CPET with HFNC
This exercise test was also carried out at the FIO2 obtained in the incremental CPET using an AIRVO2 device in this case (Optiflow TM, Fisher and Paykel, New Zealand), with flows ranging between 40 and 60 l/min, heat and humidification. The endurance time (Tlim) for the latter two tests was defined as the point at which the patient was unable to maintain 60 rpm speed despite very active encouragement and was measured in seconds.
Vital and ventilation variables during all CPETs
SpO2 and heart rate (HR) were monitored with a pulse oximeter (Biox, OHMEDA, Madison, WI, USA) and blood pressure was assessed every 2 min. In addition, respiratory rate (RR) and tidal volume (VT) were recorded from the above mentioned exercise system. Inspiratory capacity (IC) maneuvers were carried out at the beginning and immediately following the end of the tests. The same was done for dyspnea and leg fatigue assessment through Borg scales.
Leg muscle saturation (StO2)
Leg muscle saturation (StO2) was also monitored using NIRS, (NIRO-200NX, Hamamatsu, Japan) during all CPET procedures in 7 patients, and specific data obtained at rest, during free-pedaling, submaximal exercise and recovery were further analyzed. The system was calibrated before each study following manufacturer’s recommendations and the output frequency was 1 Hz in all cases, with the sensor being placed on the left quadriceps (vastus medialis) [16]. Two specific values were considered for the analysis of StO2 behavior. On the one hand, its mean value during submaximal exercise (75% WRmax) and on the other, the isotime value at task failure. Moreover, two derived variables were also evaluated: exercise induced StO2 fall (i.e. Mean StO2 at submaximal exercise − StO2 at rest) and exercise unloading-induced rebound (i.e. StO2 in the recovery phase − mean value at submaximal exercise).
Sample size estimation and statistical analysis
Based on previous studies, a sample size of at least 8 subjects was required to detect a mean difference in Tlim equal or higher than 33% between HFNC and SOT [23], considering a 20% dropout rate [15, 23, 24]. Categorical variables were expressed as frequencies and continuous variables as mean and standard deviation (SD) or median and 25, 75 percentiles (p25–p75). Paired t-test was used for comparisons between the two O2 supplementation methods in normally distributed variables, and Wilcoxon test for those with non-normal distribution. Correlation analysis was performed using Spearman correlation coefficient. A p value < 0.05 was always considered as statistically significant. The analysis was performed using the IBM SPSS statistics pack for Windows (Version 23.0, IBM Corp., Armonk, NY, USA).