Effects of High-Flow Nasal Cannula on Exercise Outcomes in Lung Transplant Candidates: A Pilot Study
Phase: NA
Conditions: Pulmonary Diseases, Oxygen Therapy, High-flow Nasal Cannula, Exercise Tolerance
Sponsor: Hospital Israelita Albert Einstein

 
Version 1 - June 19, 2024 
 
Effects of High-Flow Nasal Cannula on Exercise Outcomes in Lung 
Transplant Candidates: A Pilot Study 
 
Isabela Belarmino Oliveiraa, Elaine Cristina Pereiraa, José Eduardo Afonso 
Júniorb, Melline Della Torre de Almeidaa, Priscila Borelli Pereira Leitec, Thaise de 
Lucca Cappelinea, Thais Melatto Loschia, Vanuza Ferreira dos Santosc, Luciana 
Diniz Nagem Janot de Matosd 
 
aPhysical Therapist, Albert Einstein Israelite Hospital, São Paulo, Brazil 
bMedical Coordinator of Transplants, Albert Einstein Israelite Hospital, São Paulo, Brazil 
cNurse, Albert Einstein Israelite Hospital, São Paulo, Brazil 
dMedical Reference for Rehabilitation, Albert Einstein Israelite Hospital, São Paulo, Brazil 
 
 
Corresponding author: Isabela Belarmino Oliveira, Albert Einstein Israelite 
Hospital, Av. Albert Einstein 627/701 - Morumbi, São Paulo - SP, CEP 05652- 
900, email: isabela.belarmino@einstein.br 
 
Keywords: pulmonary diseases, oxygen therapy, high-flow nasal cannula, 
exercise tolerance, cardiopulmonary rehabilitation. 
 
Sources of Support: No author received support from funding sources. 
 
Conflicts of Interest: All authors declare no conflicts of interest that could have 
influenced the study. 
 
Project number SGPP: 3856 
CAAE number: 26495219.1.0000.0071 

 
Version 1 - June 19, 2024 
 
ABSTRACT 
 
 
Introduction: Pulmonary diseases have a significant global prevalence, and lung 
transplantation is indicated for advanced cases. Rehabilitation is essential for 
patients on the waiting list and requires ventilatory devices for symptom control 
during exertion. The high-flow nasal cannula (HFNC) is a promising alternative, 
but its effects on exercise outcomes are uncertain. Objectives: To assess the 
effects of HFNC on the outcomes of the six-minute walk test (6MWT). Method: 
A randomized crossover clinical trial evaluated ten volunteers listed on the 
national lung transplant waiting list. Three functional tests were performed: 
6MWT, incremental lower limb test with arterial blood gas analysis, and lower 
limb endurance test with inspiratory capacity measurement. Each test was 
conducted on different days with different devices: HFNC and conventional 
oxygen therapy, totaling six test days. The inspired oxygen fraction (FiO2) was 
titrated to maintain normoxia between 90% to 96% and was kept constant for 
both interfaces. Results: The 6MWT distance was significantly greater in the 
HFNC group (mean difference 437.6m ± 40.24m, p=0.001). PaCO2 kinetics were 
lower in exhaustive exercise with HFNC (mean difference: -3.29mmHg; 95% CI: 
-4.20 to -2.38mmHg; p<0.001) with less dynamic hyperinflation (mean difference: 
0.26L; 95% CI: 0.07 to 0.44L; p=0.007). Conclusion: Acute use of HFNC 
increased the distance covered in the 6MWT with lower physiological stress on 
blood gas variables and inspiratory capacity, suggesting less dynamic 
hyperinflation with fewer subjective symptoms. 

 
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METHOD 
 
 
Subjects 
 
 
Ten volunteers of both sexes, aged 30 to 69 years, listed on 
the national lung transplant waiting list who presented clinical stability in the last 
thirty days with diagnoses of COPD, idiopathic or familial pulmonary fibrosis, 
bronchiectasis, and sarcoidosis under follow-up at the cardiopulmonary 
rehabilitation outpatient clinic of the Vila Mariana unit of Albert Einstein Israelite 
Hospital, São Paulo, Brazil, were selected. Exclusion criteria were patients with 
osteoarticular limitation, neuromuscular disease, anemia (Hb < 11g/dL), 
hyperglycemia (glucose > 250mg/dL), or other uncontrolled endocrine disease, 
uncontrolled arrhythmia, left heart failure, and patients diagnosed with pulmonary 
hypertension. 
The study was conducted at a single rehabilitation center 
following the physiotherapeutic evaluation routine used in the unit. All 
assessments were performed by the same physiotherapist. At the time of 
assessments, all patients were undergoing rehabilitation and were at different 
training times. 
The specific material for high-flow therapy used was the 
MyAirvo™ 2 device. The initial interface was randomly assigned (draw) through 
conventional oxygen therapy (Venturi mask or adult high concentration non- 
rebreathing oxygen mask) or through HFNC (Figure 1). The sequence was 
obtained through the site http://randomization.com which organized the block 
randomization. Each patient's assessment forms were stored in brown envelopes 
identified as the initial HFNC group or the initial conventional oxygen therapy 
group. 
The established physical performance tests were conducted 
on a treadmill, tending to maximum or submaximal efforts. Subjects were 
evaluated over six days, with each functional test applied on different days to 
avoid potential fatigue bias. 
On the first evaluation day, the 6MWT was conducted to 
determine walking speed and distance covered in six minutes. During the test, 
FiO2 was titrated depending on the patient's need, sufficient to maintain 

 
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peripheral oxyhemoglobin saturation (SpO2) between 90% to 96%. For the initial 
HFNC group, the highest inspiratory flow according to ventilatory demand, 
tolerance, and patient comfort was applied. These parameters were used on all 
other test days. On the second evaluation day, a new 6MWT was conducted, but 
the oxygen therapy instrument used was the opposite of the previous evaluation. 
On the third and fourth days, the incremental lower limb test 
was applied with the same previously titrated FiO2 and flow. Arterial blood gas 
samples were collected before and up to two minutes after the tests. 
On the fifth and sixth days, the lower limb endurance test was 
conducted. Inspiratory capacity (IC) measurements before and after the tests 
were evaluated. 
 
Statistical Analysis 
 
 
For the pilot study, international recommendations for small- 
scale study protocols were considered escala21, 22. We estimated the difference 
between the two modalities regarding the distance covered in the 6MWT. To 
evaluate differences between interfaces, generalized estimating equations 
models23 with Gamma distribution and logarithmic link function were adjusted, 
considering therapeutic modality and the sequence in which they were used as 
explanatory variables. Mean differences between the measurements estimated 
by the models were accompanied by 95% confidence intervals. For the modified 
Borg scale scores, Gamma and Poisson mixture distributions (Tweedie 
Distribution) with a logarithmic link function were used. Analyses were performed 
using the SPSS statistical package with a significance level of 5%. 

 
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RESULTS 
 
 
Participant Characterization Data 
 
 
The study flowchart is detailed in Figure 2. Ten patients on the 
national lung transplant list were included. No patients were excluded from the 
sample. Evaluations were conducted between June 2021 and March 2023. The 
mean age was 58.7 ± 9 years. 40% were former smokers. 80% of pulmonary 
diseases were of a restrictive nature. Pulmonary function impairment was 
classified as moderate to severe (forced vital capacity 47.7% ± 15.1 of predicted, 
carbon monoxide diffusion 28.9% ± 11.5 of predicted). Patients experienced 
dyspnea during activities of daily living (ADLs), with a mean score of 5 on the 
modified Borg scale (Table 1). 

 
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Analyzed (n = 10) 
Excluded from analysis (n = 0) 
Statistical Analysis 
Final HFNC group (n = 06) 
1 Six-minute walk test 
1 Incremental lower limb test 
Pre and post-exercise blood gas analysis 
1 Lower limb endurance test 
Pre and post-exercise inspiratory capacity 
Final conventional oxygen therapy group (n = 04) 
1 Six-minute walk test 
1 Incremental lower limb test 
Pre and post-exercise blood gas analysis 
1 Lower limb endurance test 
Pre and post-exercise inspiratory capacity 
Conventional oxygen therapy initial group (n = 06) 
1 Six-minute walk test 
1 Incremental lower limb test 
Pre and post-exercise blood gas analysis 
1 Lower limb endurance test 
Pre and post-exercise inspiratory capacity 
Randomized 1:1 (n = 10) 
Excluídos (n = 0) 
Evaluated for eligibility (n = 10) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol (n = 10)  
Initial HFNC group (n = 04) 
 1 Six-minute walk test 
 1 Incremental lower limb test 
 Pre and post-exercise blood gas analysis 
 1 Lower limb endurance test 
 Pre and post-exercise inspiratory capacity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Flowchart of data collection and processes 

 
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Table 1. Demographic, clinical, and functional characteristics of patients with pulmonary 
diseases in cardiopulmonary rehabilitation protocol (n=10) 
Age (years) 
Mean (SD) 
58,7 (9,0) 
Diagnosis 
COPD Gold D 
2 (20,0%) 
Pulmonary fibrosis 
1 (10,0%) 
Familial pulmonary fibrosis 
1 (10,0%) 
Idiopathic pulmonary fibrosis 
2 (20,0%) 
Progressive pulmonary fibrosis 
1 (10,0%) 
Progressive fibrosing interstitial lung disease 
1 (10,0%) 
Stage 4 sarcoidosis 
2 (20,0%) 
Disease Type 
Obstructive 
2 (20,0%) 
Restrictive 
8 (80,0%) 
Comorbidities 
COVID-19 
4 (40,0%) 
Diabetes mellitus 
3 (30,0%) 
Dyslipidemia 
3 (30,0%) 
Obesity 
3 (30,0%) 
Systemic arterial hypertension 
6 (60,0%) 
Gastroesophageal reflux disease 
4 (40,0%) 
Depression 
3 (30,0%) 
Polycythemia 
1 (10,0%) 
Asthma 
1 (10,0%) 
Former smoker 
4 (40,0%) 
Stroke 
1 (10,0%) 
Spirometry 
Forced expiratory volume in 1 second (FEV1) (% predicted) 
Mean (SD) 
43,4 (11,4) 
Forced vital capacity (FVC) (% predicted) 
Mean (SD) 
47,7 (15,1) 
Diffusion capacity for carbon monoxide (DLCO) (% predicted) 
Mean (SD) 
28,9 (11,5) 
Modified Borg Scale of Perceived Exertion 
Limitation of activities of daily living – Mobility 
Median (Q1; Q3) 
5,0 (5,0; 7,0) 
Limitation of activities of daily living – Personal hygiene 
Median (Q1; Q3) 
5,0 (4,0; 5,0) 
Limitation of activities of daily living – Bathing 
Median (Q1; Q3) 
5,0 (4,0; 5,0) 
SD: standard deviation; Q1: first quartile; Q3: third quartile; n: number of patients 

 
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Effects of HFNC on 6MWT 
 
 
The estimated mean FiO2 for the tests was 0.58. During the 
6MWT, the achieved velocity was significantly higher during exercise with HFNC 
(mean difference: 0.28 km/h; 95% CI: 0.02 to 0.54 km/h; p=0.037), resulting in an 
increased distance covered (mean distance: 35.25 m; 95% CI: 14.24 to 56.26 m; 
p=0.001), as demonstrated in Table 2. 
 
 
Table 2. Estimated Means and Confidence Intervals (95% CI) for the 6MWT Outcomes of Patients with 
Pulmonary Diseases Undergoing Cardiopulmonary Rehabilitation Protocol (n=10) 
Measurements 
Therapeutic Modality 
HFNC – Mask 
HFNC 
Mask 
Difference 
p-value 
Achieved Speed (km/h) 
4,7 (4,3; 5,3) 
4,5 (4,0; 4,9) 
0,28 (0,02; 0,54) 
0,037 
O2 Flow Rate (L/min) 
36,7 (31,4; 42,9) 
14,7 (13,6; 15,8) 
22,05 (16,29; 27,81) 
<0,001 
Distance Covered (m) 
437,6 (396,3; 483,2) 402,4 (366,4; 441,8) 35,25 (14,24; 56,26) 
0,001 
Values expressed as estimated means and 95% confidence intervals (95% CI) 
 
Effects of HFNC on Blood Gases 
 
 
Arterial blood gas analyses provide evidence of differences 
between therapeutic modalities (Table 3) in the mean pH levels before (mean 
difference: 0.03; 95% CI: 0.02 to 0.04; p<0.001) and after the test (mean 
difference: 0.03; 95% CI: 0.02 to 0.04; p<0.001), as well as in PaCO2 levels 
before (mean difference: -3.32 mmHg; 95% CI: -4.26 to -2.37 mmHg; p<0.001) 
and after the test (mean difference: -3.29 mmHg; 95% CI: -4.20 to -2.38 mmHg; 
p<0.001). There is no evidence of differences between therapeutic modalities for 
other measures obtained from arterial blood gas analyses (p>0.05). 

 
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Table 3. Estimated Means and 95% Confidence Intervals (95% CI) for Measurements Obtained from Arterial 
Blood Gas Analyses Conducted Before and After the Incremental Lower Limb Exercise Test in Patients with 
Pulmonary Diseases Undergoing Cardiopulmonary Rehabilitation Protocol (n=10) 
Measurements 
Therapeutic Modality 
HFNC – Mask 
HFNC 
Mask 
Difference 
p-value 
Arterial pH 
Pre-Test 
7,4 (7,4; 7,5) 
7,4 (7,4; 7,4) 
0,03 (0,02; 0,04) 
<0,001 
Post-Test 
7,4 (7,4; 7,4) 
7,4 (7,4; 7,4) 
0,03 (0,02; 0,04) 
<0,001 
Arterial Partial Pressure of Carbon 
Dioxide (mmHg) 
Pre-Test 
37,5 (35,0; 40,2) 
40,8 (38,2; 43,6) 
-3,32 (-4,26; -2,37) 
<0,001 
Post-Test 
37,2 (34,2; 40,4) 
40,5 (37,4; 43,7) 
-3,29 (-4,20; -2,38) 
<0,001 
Arterial Partial Pressure of Oxygen 
(mmHg) 
Pre-Test 
184,3 (138,4; 245,5) 
179,2 (147,2; 218,2) 
5,11 (-30,20; 40,42) 
0,777 
Post-Test 
176,9 (138,2; 226,5) 
172,0 (153,5; 192,7) 
4,90 (-29,03; 38,84) 
0,777 
Arterial Base Excess (mEq/L) 
Pre-Test 
2,4 (1,1; 3,6) 
2,1 (1,0; 3,2) 
0,24 (-0,09; 0,57) 
0,154 
Post-Test 
-0,3 (-1,9; 1,3) 
-0,5 (-2,2; 1,2) 
0,24 (-0,09; 0,57) 
0,154 
Arterial Bicarbonate (mEq/L) 
Pre-Test 
26,3 (24,7; 28,1) 
26,8 (25,3; 28,3) 
-0,48 (-1,08; 0,12) 
0,118 
Post-Test 
24,0 (22,4; 25,8) 
24,5 (22,8; 26,3) 
-0,44 (-1,00; 0,12) 
0,126 
Arterial Oxygen Saturation (%) 
Pre-Test 
98,5 (97,7; 99,2) 
98,8 (98,4; 99,2) 
-0,36 (-1,11; 0,38) 
0,343 
Post-Test 
98,4 (97,8; 99,1) 
98,8 (98,6; 99,0) 
-0,36 (-1,10; 0,38) 
0,343 
Arterial Lactate (mmol/L) 
Pre-Test 
11,6 (9,6; 14,0) 
11,4 (8,7; 15,0) 
0,15 (-1,95; 2,26) 
0,886 
Post-Test 
28,6 (19,5; 42,0) 
28,3 (19,6; 40,7) 
0,38 (-4,90; 5,66) 
0,887 
Values expressed as estimated means and 95% confidence intervals (95% CI); p-values corrected using the sequential Bonferroni method 
 
 
 
Effects of HFNC on Dynamic Hyperinflation and Exercise-Induced Dyspnea 
 
 
There is evidence of differences between therapeutic 
modalities (Table 4) in the mean IC at baseline (mean difference: 0.32 L; 95% CI: 
0.07 to 0.57 L; p=0.013) and at the end of the endurance test (mean difference: 
0.26 L; 95% CI: 0.07 to 0.44 L; p=0.007), as well as in the scores of the modified 
Borg Scale of Perceived Exertion at rest (mean difference: -0.23; 95% CI: -0.43 
to -0.03; p=0.025), after maximal exercise with HFNC (mean difference: -1.55; 
95% CI: -2.87 to -0.23; p=0.021), and during recovery (mean difference: -0.46; 
95% CI: -0.81 to -0.10; p=0.011). 

 
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Table 4. Estimated Means and 95% Confidence Intervals (95% CI) for Inspiratory Capacity Measures and Scores on 
the Modified Borg Scale of Perceived Exertion During the Lower Limb Endurance Test in Patients with Pulmonary 
Diseases Undergoing Cardiopulmonary Rehabilitation Protocol (n=10) 
Measurements 
Therapeutic Modality 
HFNC – Mask 
HFNC 
Mask 
Diferença 
HFNC 
Inspiratory Capacity (L) 
Initial 
2,0 (1,6; 2,6) 
1,7 (1,3; 2,2) 
0,32 (0,07; 0,57) 
0,013 
Final 
1,6 (1,3; 2,0) 
1,4 (1,1; 1,8) 
0,26 (0,07; 0,44) 
0,007 
Modified Borg Scale of Perceived Exertion 
Rest 
0 (0,6; 1,5) 
1 (0,7; 1,8) 
-0,23 (-0,43; -0,03) 
0,025 
Maximum 
6 (5,0; 7,7) 
8 (6,3; 9,6) 
-1,55 (-2,87; -0,23) 
0,021 
Recovery 
1 (1,3; 2,6) 
2 (1,7; 3,1) 
-0,46 (-0,81; -0,10) 
0,011 
Values expressed as estimated means and 95% confidence intervals (95% CI); p-values corrected using the sequential Bonferroni method