Rationale: Hyperoxia and normoxic helium independently reduce dynamic hyperinflation and improve the exercise tolerance of patients with chronic obstructive pulmonary disease (COPD). Combining these gases could have an additive effect on dynamic hyperinflation and a greater impact on respiratory mechanics and exercise tolerance.
Objective: To investigate whether helium-hyperoxia improves the exercise tolerance and respiratory mechanics of patients with COPD.
Methods: Ten males with COPD (FEV1 = 47 ± 17%pred [mean ± SD]) performed randomized constant-load cycling at 60% of maximal work rate breathing air, hyperoxia (40% O2, 60% N2), normoxic helium (21% O2, 79% He), or helium-hyperoxia (40% O2, 60% He).
Measurements: Exercise time, inspiratory capacity (IC), work of breathing, and exertional symptoms were measured with each gas.
Results: Compared with air (9.4 ± 5.2 min), exercise time was increased with hyperoxia (17.8 ± 5.8 min) and normoxic helium (16.7 ± 9.1 min) but the improvement with helium-hyperoxia (26.3 ± 10.6 min) was greater than both these gases (p = 0.019 and p = 0.007, respectively). At an isotime during exercise, all three gases reduced dyspnea and both helium mixtures increased IC and tidal volume. Only helium-hyperoxia significantly reduced the resistive work of breathing (15.8 ± 4.2 vs. 10.1 ± 4.1 L · cm H2O−1) and the work to overcome intrinsic positive end-expiratory pressure (7.7 ± 1.9 vs. 3.6 ± 2.1 L · cm H2O−1). At symptom limitation, tidal volume remained augmented with both helium mixtures, but IC and the work of breathing were unchanged compared with air.
Conclusion: Combining helium and hyperoxia delays dynamic hyperinflation and improves respiratory mechanics, which translates into added improvements in exercise tolerance for patients with COPD.
Patients with chronic obstructive pulmonary disease (COPD) exhibit a reduced exercise capacity (1–5) and often curtail exercise due to severe dyspnea (2, 5). In recent years, a growing body of evidence (2, 3, 6–8) has identified a strong relationship between the degree of dynamic hyperinflation and the intensity of breathlessness experienced by these patients. Due to the expiratory flow limitation that is characteristic of COPD, end-expiratory lung volume (EELV) rises during exercise and end-inspiratory lung volume (EILV) encroaches on total lung capacity (TLC) in an attempt to augment or maintain tidal volume. The resulting dynamic hyperinflation reduces lung compliance and increases the elastic work of breathing, while placing the respiratory muscles at a mechanical disadvantage to generate pressure (9, 10). In addition, any increase in EELV above relaxation volume results in an intrinsic positive end-expiratory pressure (PEEPi), which must be overcome before inspiratory flow can start (11). Unfortunately, even with an increase in inspiratory effort, ventilatory constraint often ensues and it is the resulting mismatch between respiratory effort and ventilatory output that has been implicated as the primary mechanism responsible for the dyspnea experienced during exercise in this population (3, 12).
Previous investigations have demonstrated that hyperoxia (HOX) reduces ventilatory demand, increases expiratory time (Te), and delays dynamic hyperinflation, which leads to a reduction in dyspnea and improved exercise tolerance in patients with COPD (6, 13, 14). However, at symptom limitation in both incremental exercise tests and in constant load trials where there is an upward drift in ventilation (V̇e) (13–15), lung volumes, V̇e, and dyspnea are unchanged from breathing air, indicating that the ventilatory constraints to exercise are delayed but not removed with hyperoxia (13). In contrast, a normoxic helium gas (HE-OX) decreases turbulence within medium to large airways and increases expiratory flow rate, which reduces dynamic hyperinflation and dyspnea and improves exercise tolerance (16). We hypothesized that combining helium and 40% O2 would maximize the effect of oxygen for reducing V̇e and increasing expiratory time, while still maintaining the improved laminar flow and reduced airway resistance associated with breathing helium. We further hypothesized that the resultant effect would be a greater reduction in dynamic hyperinflation, which would decrease the work of breathing and result in reduced dyspnea and improved exercise tolerance. Some of the data from this study have previously been reported in abstract form (17).
See the online supplement for a more detailed version of these methods.
Ten clinically stable males with moderate to severe COPD (FEV1/FVC = 56 ± 10%pred, PaO2 = 68 ± 6 mm Hg) volunteered to participate in the study. Individuals dependent on supplemental oxygen, with cardiovascular disease, and/or with musculoskeletal abnormalities were excluded. All patients signed an informed consent form that had received institutional ethics review board approval. The patient characteristics are presented in Table 1.
|Age, yr||65 ± 11|
|Height, cm||179 ± 5|
|Mass, kg||82 ± 15|
|Body mass index, kg/m2||26 ± 5|
|FEV1, L||1.66 ± 0.59||47 ± 17|
|FVC, L||3.81 ± 0.99||83 ± 21|
|FEV1/FVC, %||42.8 ± 8.0||56 ± 10|
|TLC, L||9.04 ± 1.44||136 ± 20|
|RV, L||4.82 ± 1.60||192 ± 63|
|FRC, L||5.87 ± 1.63||157 ± 44|
|IC, L||3.18 ± 0.97|
|DlCO, ml/min/mm Hg||19.0 ± 4.4||71 ± 16|
|sRaw, cm H2O/L/s||4.36 ± 0.22|
|PaO2, mm Hg||68.3 ± 6.4|
|PaCO2, mm Hg||36.7 ± 3.3|
|PH||7.43 ± 0.02|
|HCO3, mmol/L||23.7 ± 1.8|
|Hb, g/dl||14.7 ± 1.2|
|Hct, %||45.0 ± 3.6|
The study was a randomized crossover design, which required three separate visits to the laboratory. The first visit consisted of a pulmonary function test to confirm the severity of COPD and a symptom-limited incremental exercise test to ensure the absence of cardiovascular contraindications to exercise. During the other two visits, four constant-load symptom-limited exercise trials were performed in a random order (two per visit) to examine the effect of each gas on exercise tolerance, work of breathing, lung volumes, and exertional symptoms. The patients were asked to refrain from exercise in the 24 h before a test and to avoid smoking, alcohol, and caffeine on testing days.
The four gas mixtures studied were as follows: air (21% O2, 79% N2), HOX (40% O2, 60% N2), HE-OX (21% O2, 79% He), and helium-hyperoxia (HE-HOX; 40% O2, 60% He). A 40% O2 mixture was used to maximize the benefits of O2 while still obtaining the benefits of helium (18). Throughout exercise, humidified gases were passed into a reservoir bag and supplied through a low-resistance two-way breathing valve (2700 series; Hans Rudolph, Kansas City, MO). The patients were blinded to the gas mixture used and were asked not to talk during, or for a short period after, exercise due to the change in vocal tone with helium.
Spirometry, single-breath diffusion capacity for carbon monoxide (DlCO), and lung volumes determined by body plethysmograph (6200 Autobox; SensorMedics, Yorba Linda, CA) were measured before entry into the study. Resting arterial blood gases and pH were measured from a radial artery taken at rest while breathing room air.
Before inclusion in the study, an incremental cycle-exercise stress test to symptom limitation was performed with expired gas analysis (TrueOne 2400; Parvo Medics, Salt Lake City, UT). The results from this test are presented in Table 2.
|V̇o2, ml · kg−1 · min−1||18.5 ± 4.9|
|V̇o2, L · min−1||1.52 ± 0.4|
|V̇o2, %pred||59 ± 17|
|PO, W||118 ± 37|
|PO, %pred||61 ± 17|
|HR, beats · min−1||130 ± 17|
|HR, %pred||84 ± 13|
|SpO2, %||88 ± 4|
|ΔSpO2, %||6 ± 4|
|RER||1.04 ± 0.09|
|V̇e, L · min−1||57.6 ± 21.9|
|V̇e, %pred||98 ± 44|
|V̇t, L||1.80 ± 0.55|
|F||32 ± 9|
|Dyspnea||6.7 ± 1.8|
|Leg discomfort||5.3 ± 2.1|
|Reason for stopping|
After adequate wash-in, spirometry was performed to obtain resting pulmonary function on each gas mixture. Patients then exercised at 60% of their previously determined maximal work rate on an electronically braked cycle ergometer (Ergoline 800S; SensorMedics) until symptom limitation. After exercise, subjects rested for 60 to 90 min before the second exercise trial was performed with a different gas. Two research assistants, blinded to the gas mixture used, consistently encouraged patients to exercise for as long as possible.
Ventilatory parameters were measured every 2 min by switching the patient from the reservoir bag to a bag-in-box in series with a low-resistance spirometer (SensorMedics 1022; SensorMedics, Yorba Linda, CA). Calibration of the spirometer was confirmed with the experimental gas mixture before each pulmonary function test and exercise trial. Esophageal pressure was measured with a 10-cm latex balloon catheter (Ackrad Laboratories, Inc., Cranford, NJ) with a 1-ml inflation volume, connected to a differential pressure transducer (MP45; Validyne, Northridge, CA). Signals from the spirometer and pressure transducers were converted to a digital signal using a data acquisition system (Powerlab ML785; ADI Instruments, Colorado Springs, CO). The volume signal from the spirometer was differentiated to obtain flow. All data were sampled at 100 Hz and stored on a computer for analysis at a later date. A schematic of the experimental setup is depicted in Figure E1 of the online supplement.
Assuming that TLC does not change with exercise (19, 20), repetitive inspiratory capacity (IC) maneuvers were performed every 2 min to track changes in EELV (TLC − IC). This technique has previously been shown to be reliable during exercise in this population (20, 21).
The work of breathing was estimated using Campbell diagrams and the technique of Yan and coworkers (22), which allows the inspiratory elastic work of breathing to be separated into the work to overcome PEEPi (WIP) and the work required to overcome the elastic recoil of the lung or the non-PEEPi inspiratory elastic load (WINP) (11, 22). In brief, the chest wall compliance curve was obtained from the literature (23) and was positioned as previously described (11, 22). Esophageal pressure–volume loops during tidal breathing were then superimposed on the static chest wall pressure–volume compliance line. The points of zero flow at the start and end of inspiration were joined to identify dynamic lung compliance. Inspiratory resistive work was then calculated as the area inside the pressure–volume curve and to the left of the lung compliance line. The total elastic work performed on inspiration was calculated as the area enclosed by the lung compliance line and the chest wall compliance curve. Additional work performed by the respiratory muscles during expiration was calculated as the portion of the pressure–volume loop positioned to the right of the chest wall compliance curve. This process was performed on three esophageal pressure–volume loops at rest, symptom limitation, and the two isotimes.
A one-way repeated-measures analysis of variance (ANOVA) was performed at symptom limitation, and at two isotimes during the exercise tolerance trials using commercially available software (Statistica; Statsoft, Oklahoma City, OK). Isotimes 1 and 2 were defined as symptom limitation in the air and HOX trials, respectively. When a patient exercised longer on air than on an experimental gas (n = 1) or shorter on HE-HOX than HOX (n = 2), the end-exercise responses were carried forward. When the ANOVA detected a significant effect, a Tukey post hoc multiple comparison test was performed.
To test for associations between the change in exercise time and changes in EELV, V̇e, work of breathing, and/or dyspnea, simple regression analyses using Pearson correlations were performed. In addition, the strongest significant contributors to the improvement in exercise time were selected by multiple stepwise regression analysis. For all analyses and post hoc comparisons the α level was set a priori at 0.05.
All results are reported as mean ± SD. The effect of each gas mixture on exercise tolerance is depicted in Figure 1. An increase in exercise time was observed with all three gas mixtures compared with breathing air. Exercise time to symptom limitation was 9.4 ± 5.2 min on air, 17.8 ± 5.8 min on HOX, and 16.7 ± 9.1 min on HE-OX. The combination of helium and hyperoxia had a significantly greater effect on exercise tolerance compared with all other gases (26.3 ± 10.6 min).
During exercise, dyspnea was decreased with all three experimental gases at isotime 1 (Figure 2A, Table 3). At this time point, the reduction in dyspnea was greatest with HE-HOX as the Borg rating was reduced from 5.8 ± 2.2 in the air trial to 1.9 ± 1.4 with HE-HOX. HE-HOX also reduced dyspnea at isotime 2 compared with HOX (5.3 ± 2.0 vs. 3.7 ± 1.8, p = 0.029). Concomitant to the reductions in dyspnea, both hyperoxic gases reduced the sensation of leg discomfort at isotime 1 compared with air (Figure 2B) and HE-HOX also reduced leg discomfort compared with HE-OX (2.2 ± 1.5 vs. 3.6 ± 2.2, p = 0.049).
|V̇e, L · min−1||52.7 ± 22.4*†||43.5 ± 12.6‡§||54.0 ± 20.7*†||44.4 ± 13.7‡§|
|V̇t, L||1.69 ± 0.55†‡||1.72 ± 0.55‡||1.90 ± 0.44*§||1.85 ± 0.49§|
|f||32.3 ± 12.6*†||25.9 ± 5.3§||27.8 ± 6.9||23.9 ± 3.8§|
|V̇co2, L · min−1||1.30 ± 0.40||1.22 ± 0.33||1.32 ± 0.40||1.24 ± 0.35|
|PetCO2, mm Hg||34.9 ± 7.2*‡||38.9 ± 5.1†‡§||31.2 ± 4.3*†§||35.2 ± 3.7*‡|
|Ti||0.85 ± 0.42||0.91 ± 0.16||0.84 ± 0.20||1.02 ± 0.15|
|Te||1.27 ± 0.44†||1.51 ± 0.41||1.45 ± 0.43||1.55 ± 0.31§|
|Ti/TTOT||0.39 ± 0.04||0.38 ± 0.03||0.37 ± 0.02||0.40 ± 0.04|
|IC, L||2.24 ± 0.91†‡||2.39 ± 0.85||2.51 ± 0.85§||2.53 ± 0.90§|
|IRV, L||0.56 ± 0.39||0.67 ± 0.40||0.60 ± 0.48||0.68 ± 0.49|
|EILV/TLC, %||93.9 ± 3.8||92.7 ± 3.8||93.4 ± 4.7||92.5 ± 4.9|
|PEEPi, cm H2O||4.4 ± 1.7†‡||3.5 ± 3.0||2.4 ± 2.1§||2.0 ± 1.9§|
|Peak Pesexp, cm H2O||18.0 ± 18.6||10.7 ± 7.0||7.7 ± 5.5||8.9 ± 4.1|
|Peak Pesins, cm H2O||−19.9 ± 5.8*†‡||−16.0 ± 4.5§||−15.8 ± 4.4§||−14.7 ± 5.2§|
|PEF, L · s−1||3.00 ± 1.40*†||2.10 ± 0.63§‡||3.00 ± 1.04*†||2.28 ± 0.63‡§|
|MEF, L · s−1||1.53 ± 0.61*||1.22 ± 0.36§‡||1.62 ± 0.59*†||1.34 ± 0.41‡|
|PIF, L · s−1||−3.16 ± 0.94*†||−2.09 ± 1.10§‡||−3.17 ± 0.91*†||−2.65 ± 0.62‡§|
|MIF, L · s−1||−2.32 ± 0.79*||−1.83 ± 0.37§‡||−2.05 ± 1.45*||−2.00 ± 0.54|
|SpO2, %||89.3 ± 4.4*†||97.7 ± 1.3§‡||91.4 ± 2.2*†||98.4 ± 1.1‡§|
|Dyspnea||5.8 ± 2.2*†‡||2.7 ± 0.9§||3.1 ± 1.1§||1.9 ± 1.4§|
|Leg discomfort||5.0 ± 1.6*†||2.8 ± 1.6§||3.6 ± 2.2†||2.2 ± 1.5‡§|
At end exercise, dyspnea was significantly lower with HE-OX but unchanged with the two hyperoxic gases (Table 4). No difference in leg discomfort was observed at symptom limitation with any gas. In the air trial, dyspnea was the primary symptom limiting exercise in eight subjects, whereas two subjects stopped due to leg discomfort. In contrast, leg discomfort was reported as the principal reason for exercise termination with HOX (n = 5), HE-OX (n = 4), and HE-HOX (n = 7), with four, three and two subjects, respectively, stopping primarily due to dyspnea. Two subjects reported the combination of leg discomfort and dyspnea as the primary reason for stopping in the HE-OX trial. One subject stopped due to “other” reasons with each of the experimental gas mixtures. These reasons included mouthpiece discomfort (HOX), general fatigue (HE-OX), and discomfort from the bicycle seat (HE-HOX).
|V̇e, L · min−1||52.7 ± 22.4‡||50.5 ± 19.1‡||61.1 ± 27.4*†§||54.2 ± 22.5‡|
|V̇t, L||1.69 ± 0.55†‡||1.74 ± 0.56‡||1.90 ± 0.62*§||1.84 ± 0.64§|
|f||32.3 ± 12.6||29.8 ± 9.8||32.1 ± 10.6||29.7 ± 7.8|
|V̇co2, L · min−1||1.30 ± 040||1.34 ± 0.38||1.39 ± 0.43||1.36 ± 0.41|
|PetCO2, mm Hg||34.9 ± 7.2*‡||39.0 ± 5.9†‡§||30.2 ± 5.4*†§||34.1 ± 5.1*‡|
|Ti||0.85 ± 0.42||0.83 ± 0.25||0.68 ± 0.22||0.76 ± 0.18|
|Te||1.27 ± 0.44||1.36 ± 0.39||1.35 ± 0.41||1.40 ± 0.46|
|Ti/TTOT||0.39 ± 0.04‡||0.38 ± 0.02||0.34 ± 0.06§||0.36 ± 0.03|
|IC, L||2.24 ± 0.91||2.27 ± 0.82||2.40 ± 0.80||2.35 ± 0.85|
|IRV, L||0.56 ± 0.39||0.53 ± 0.29||0.51 ± 0.24||0.51 ± 0.26|
|EILV/TLC, %||93.9 ± 3.8||94.1 ± 2.9||94.4 ± 2.5||94.4 ± 2.7|
|PEEPi, cm H2O||4.4 ± 1.7†‡||4.6 ± 2.3||3.4 ± 2.1§||4.1 ± 3.6§|
|Peak Pesexp, cm H2O||18.0 ± 18.6||17.5 ± 14.6||10.8 ± 7.4||12.8 ± 8.1|
|Peak Pesins, cm H2O||−19.9 ± 5.8‡||−18.7 ± 4.2||−16.4 ± 3.8§||−18.1 ± 5.01|
|PEF, L · s−1||3.00 ± 1.40||2.69 ± 1.15‡||3.46 ± 1.50*†||2.61 ± 1.05‡|
|MEF, L · s−1||1.53 ± 0.61||1.41 ± 0.49‡||1.68 ± 0.75‡||1.48 ± 0.51|
|PIF, L · s−1||−3.16 ± 0.94||−2.69 ± 1.44‡||−3.83 ± 1.36*†||−2.97 ± 0.68‡|
|MIF, L · s−1||−2.32 ± 0.79||−2.22 ± 0.56‡||−2.73 ± 1.05*†||−2.28 ± 0.55‡|
|SpO2, %||89.3 ± 4.4*†||97.4 ± 1.2‡§||91.2 ± 2.8*†||97.8 ± 1.1‡§|
|Dyspnea||5.8 ± 2.2‡||5.4 ± 2.6||4.9 ± 2.7§||5.2 ± 2.1|
|Leg discomfort||5.0 ± 1.6||5.4 ± 2.1||5.6 ± 1.7||5.5 ± 2.1|
Similar resting spirometry was observed with HOX compared with air (Table 5). Both helium-based mixtures significantly increased peak expiratory flow rates, FEV1, and forced expiratory flow at 50% of FVC (FEF50) without changing FVC or FEF at 75% of FVC (FEF75). The volume of isoflow was similar between the two helium mixtures, occurring at 36 ± 13 and 37 ± 15% of FVC with HE-OX and HE-HOX, respectively.
|FEV1, L||1.54 ± 0.73||1.58 ± 0.70||1.89 ± 0.82*||1.82 ± 0.77*|
|FVC, L||3.76 ± 1.13||3.73 ± 1.15||3.86 ± 1.18||3.83 ± 1.13|
|PEF, L · s−1||4.64 ± 1.88||4.88 ± 1.89||5.98 ± 2.29*||5.72 ± 2.06*|
|FEF50, L · s−1||0.78 ± 0.45||0.78 ± 0.46||1.02 ± 0.55*||1.07 ± 0.75*|
|FEF75, L · s−1||0.32 ± 0.17||0.32 ± 0.15||0.37 ± 0.16||0.35 ± 0.14|
|VisoV, L||N/A||N/A||1.35 ± 0.56||1.37 ± 0.62|
|VisoV, %FVC||N/A||N/A||36 ± 13||37 ± 15|
At rest, ventilatory parameters were unaffected by any gas (Figure 3). At isotime 1, V̇e was unchanged with HE-OX but reduced with both HOX and HE-HOX due to a decrease in breathing frequency (Table 3, Figure 3). Even with the reduction in V̇e, tidal volume was increased with HE-HOX compared with air (p = 0.04) but not with HOX (p = 0.92). Tidal volume was also increased with HE-OX compared with both air and HOX. The reduction in breathing frequency with HE-HOX resulted in a longer Te at isotime 1 (Figure 3E) but no significant difference in Ti/TTOT (inspiratory time/total time) was observed with any gas (Figure 3F). Compared with air at isotime 1, inspiratory and expiratory flow rates were unchanged with HE-OX. In contrast, peak inspiratory and expiratory flow rates were decreased with both hyperoxic gases (Table 3), whereas only HOX significantly reduced mean inspiratory and expiratory flow rates.
At symptom limitation, there was no difference in the ventilatory responses between air and hyperoxia. In contrast, V̇e was increased with HE-OX compared with all other gas mixtures due to a larger tidal volume (Table 4). There was considerable variation in the individual ventilatory responses observed with HE-OX, as V̇e ranged from a decrease of 1.8 L · min−1 to an increase of 25.8 L · min−1. This finding was strongly correlated with resting FEV1 (r = 0.78, p = 0.008) such that those with the greatest FEV1 showed the largest increases in V̇e with HE-OX. At end exercise, V̇e was similar to air with HE-HOX (p = 0.94), whereas tidal volume remained increased by 0.15 L (p = 0.04).
Baseline IC, EILV, and inspiratory reserve volume (IRV) were unchanged with any gas (Figure 4). From quiet breathing at rest to symptom limitation, all patients dynamically hyperinflated as demonstrated by the significant reduction in IC. The rise in EELV during exercise resulted in a mean PEEPi at the end of the air trial of 4.4 ± 1.7 cm H2O (range, 2.6–7.7 cm H2O). At symptom limitation with air, the degree of dynamic hyperinflation averaged 0.43 ± 0.18 L (range, 0.17–0.69 L) and EILV reached 94% of TLC. No difference in IC, EILV, IRV, or PEEPi was observed with any gas and the increased tidal volume with both helium gas mixtures was primarily due to a trend toward a lower EELV.
At isotime 1, IC was significantly increased with both HE-OX and HE-HOX but not HOX (Figure 4, Table 3). Concomitant to the reduction in dynamic hyperinflation with the helium gases, PEEPi was also reduced from 4.4 ± 1.7 cm H2O in air to 2.4 ± 2.1 and 2.0 ± 1.9 cm H2O with HE-OX and HE-HOX, respectively. Interestingly, the decrease in dynamic hyperinflation with both helium gases was not associated with a significant reduction in EILV because tidal volume was increased at the expense of IRV. HE-HOX also had a greater effect on dynamic hyperinflation than did HOX, as IC was greater (2.45 ± 0.85 L) at isotime 2 compared with HOX (2.27 ± 0.82 L, p = 0.03).
The work of breathing was measured in eight subjects and is presented in Figure 5. At rest, both helium mixtures reduced the resistive work of breathing compared with air (Figure 5A). In addition, the total elastic work of inspiration was reduced with HE-HOX (p = 0.011) predominantly due to a reduction in WINP, as the work to overcome PEEPi was not different between conditions (Figures 5B and 5C). When the total work of breathing per minute was calculated, only HE-HOX was lower than with air (291 vs. 165 L · cm H2O−1 · min−1 in air and HE-HOX, respectively; p = 0.008).
During the first 5 min of exercise, all three experimental gas mixtures reduced the resistive work of breathing and the work to overcome PEEPi. By isotime 1, only the 33.3 ± 17.4% reduction in the resistive work of breathing and the 51.9 ± 29.8% decrease in WIP with HE-HOX remained lower than air. At isotime 1, there was no significant difference in WINP with any gas, even though tidal volume was increased with the helium mixtures. When the total resistive and elastic components of the work of breathing were averaged over 1 min, both parameters were reduced with the two hyperoxic gas mixtures, due to the significant reductions in breathing frequency. However, the total work of breathing was only reduced at isotime 1 with HE-HOX (940 ± 317 L · cm H2O−1 · min-1) compared with air (1,938 ± 1,457 L · cm H2O−1 · min−1). At isotime 2 and symptom limitation, there were no significant differences in the work of breathing with any gas.
The increase in exercise time to symptom limitation with HOX significantly correlated with the decrease in V̇e (r = −0.82) and breathing frequency (r = −0.67) at isotime 1. The increase in exercise time with HE-OX correlated best with the change in peak inspiratory flow (r = 0.93), EELV expressed as %TLC (r = −0.93), IC (r = 0.89), breathing frequency (r = −0.88), and total work of breathing per minute (r = −0.85). Stepwise multiple regression analysis demonstrated that the combination of improved peak inspiratory flow, EELV as %TLC, and the reduction in the total work of breathing explained 99% of the variance associated with increased endurance time with HE-OX (r2 = 0.99, p < 0.0001).
The improved exercise time with HE-HOX was associated with a reduction in the work of breathing and improved inspiratory flow rates. The strongest correlates of improved exercise time with HE-HOX were the change in total elastic work of breathing per minute (r = −0.87), total inspiratory resistive work of breathing per minute (r = −0.83), peak inspiratory (r = 0.82) and expiratory flow rates (r = −0.81), and mean expiratory flow rate (r = −0.79). In addition, significant correlations were also observed between the improvement in exercise time and the decrease in V̇e (r = −0.71) and breathing frequency (r = 0.68) with HE-HOX. Stepwise multiple regression analysis of these variables demonstrated that the decrease in the total elastic work of breathing with HE-HOX explained 75% of the variance in exercise time. The favorable decrease in mean expiratory flow rate then added approximately 8% to the explained variance (r2 = 0 0.83, p < 0.01).
The principal finding of this study supported our hypotheses that HE-HOX would improve exercise tolerance to a greater degree than HOX or HE-OX. As postulated, these improvements in exercise tolerance were related to the greater effect of this gas for delaying dynamic hyperinflation, alleviating dyspnea, and reducing the work of breathing.
HOX has consistently been reported to improve the exercise capacity of patients with COPD, with (13, 25) and without hypoxemia (6, 14, 24). More recently, Palange and colleagues (16) reported that HE-OX improved the exercise tolerance of patients with COPD performing high-intensity cycle exercise by 114%. The improvements in exercise time with HOX (118 ± 74%) and HE-OX (91 ± 103%) found in the present study are similar to those previously reported. However, the primary finding of this investigation was that HE-HOX improved the exercise tolerance of patients with COPD by 245 ± 208% compared with air and by 54 ± 56% and 92 ± 116% compared with HOX and HE-OX, respectively. These findings complement those of Laude and colleagues (26), who demonstrated that a 28:72 O2–He mixture improved walking distance in a shuttle walk test by 64% in patients with COPD. However, our results demonstrate how a combination of helium and hyperoxia has a greater effect on reducing dynamic hyperinflation and work of breathing than either HE-OX or HOX alone, which explains the underlying physiologic mechanisms responsible for the improved exercise tolerance.
In the present study, the majority of subjects terminated exercise because of dyspnea when breathing air. However, leg discomfort was the principal reason for stopping exercise with HE-HOX. This change in the symptom responsible for limiting exercise suggests that HE-HOX decreases the ventilatory constraints associated with COPD to an extent that skeletal muscle function becomes more of a limiting factor.
The significant reduction in V̇e observed with HOX is consistent with others (6, 13, 14, 24) and has been attributed to reduced chemoreceptor drive (6, 24). As a result, inspiratory and expiratory flow rates were decreased, EELV was maintained closer to resting lung volumes, and the progression of dynamic hyperinflation was delayed, which improved exercise tolerance, independent of the level of hypoxemia (r = 0.28, p = 0.48). At symptom limitation, the magnitude of dynamic hyperinflation, V̇e, and tidal volume were all unchanged from air, which supports the previous findings of O'Donnell and coworkers (13), and indicates that the ventilatory constraints to exercise are delayed but not removed with HOX.
A number of previous studies have reported that HE-OX increases V̇e during exercise in patients with COPD (5, 16, 27). In the present study, V̇e was increased 16 ± 21% with HE-OX, which is comparable to that reported by others (28, 29). Improvements in IC with HE-OX were primarily due to an increase in the maximal flow volume envelope, as inspiratory and expiratory flow rates were similar to that observed with air but EELV was reduced. A significant correlation was observed between the change in EELV as %TLC and the change in dyspnea with HE-OX (r = 0.71, p = 0.02), which is not surprising as EELV was one of the primary predictors of improved exercise performance with this gas. Interestingly, no relationship was observed between the increase in maximal V̇e with HE-OX and exercise time (r = 0.10, p = 0.79), which suggests that the ability of HE-OX to reduce dynamic hyperinflation is more important than its effect on V̇e for improving exercise tolerance.
The ventilatory response to exercise with HE-HOX was similar to HOX, with V̇e and breathing frequency being reduced. Lower expiratory flow rates combined with a significantly lengthened Te reduced EELV to a greater extent than HOX and increased tidal volume. At symptom limitation, IC was not significantly increased with HE-HOX but tidal volume was still augmented, due again to the slight but nonsignificant increase in Te (r = 0.65, p = 0.04). These positive effects of HE-HOX on lung volumes demonstrate the additive benefit of combining helium and 40% O2, as the increase in FiO2 reduced expiratory flow rates and increased expiratory time whereas helium increased the maximal flow–volume envelope, allowing for a greater reduction in dynamic hyperinflation.
The effect of each gas on the resistive work of breathing was evident early in the constant-load trials and was related to the physical properties of both helium and oxygen. The lower density of helium reduces the pressure needed to overcome airway resistance at higher flow rates by maintaining laminar flow, whereas oxygen reduces ventilatory drive and expiratory flow rate, which decreases airway resistance. The further reduction in resistive work only with HE-HOX at isotime 1 demonstrates that there is a synergistic effect of combining these two gases on airway resistance that is related to the reduced density of helium and the ability of oxygen to decrease V̇e.
To interpret the different elastic work of breathing responses observed in this study, it is also important to consider the effects of helium and oxygen (both separately and in combination) on lung volumes and V̇e during exercise. At isotime 1, HOX decreased the total inspiratory elastic work per minute primarily due to a reduction in ventilatory drive because EELV and tidal volume were unchanged compared with air. In contrast, EELV was decreased with HE-OX, but the total inspiratory elastic work was unaffected because tidal volume was increased at the expense of maintaining the inspiratory work needed to overcome the elastic recoil of the lung. HE-HOX combined these effects because the total elastic work of breathing was reduced even with an increase in tidal volume. This finding can be attributed to both the greater reduction in dynamic hyperinflation, which decreased the work to overcome PEEPi, and the HOX-induced reduction in V̇e.
The significant relationship observed between the reduced work of breathing and the improved exercise time with HE-HOX is likely due to alleviation of dyspnea, because a significant relationship was observed between the change in the total work of breathing and dyspnea reduction (r = 0.63, p = 0.048). However, another benefit of the reduced work of breathing may be a better distribution of cardiac output to the exercising muscles. In healthy individuals, the respiratory muscles can demand 13 to 15% of total body oxygen consumption during heavy exercise (30) and 14 to 16% of total cardiac output (31). Reducing the work of breathing decreases respiratory muscle demand and has been shown to increase leg blood flow during exercise (32). The increased work of breathing in patients with COPD is estimated to govern as much as 35 to 40% of total body oxygen consumption (33), which would demand a much greater proportion of cardiac output. Therefore, it is possible that unloading the respiratory system with HE-HOX allowed a greater portion of total cardiac output to be distributed to the working muscles. Improved leg blood flow combined with a higher oxyhemoglobin saturation would increase O2 supply and decrease metabolic acidosis (13), which would conceivably reduce leg fatigue and improve exercise tolerance.
A potential limitation of the present methodology could be an inaccurate positioning of the static chest wall compliance curve in our calculation of the elastic work of breathing. The curve is positioned assuming that EELV during quiet breathing is an accurate representation of the relaxation volume and pressure of the respiratory system. However, this may not be accurate because dynamic hyperinflation is often present in patients with COPD at rest and EELV may actually be above relaxation volume even during quiet breathing. Continued expiratory muscle recruitment at end expiration can also artificially increase PEEPi above that due to dynamic hyperinflation, which would increase end-expiratory pressure independent of the chest wall elasticity. To correct for this, previous studies have subtracted the expiratory rise in gastric pressures from the esophageal pressure at EELV (11, 22). This could not be done in this study because gastric pressures were not measured. As a result, the work needed to overcome PEEPi may be slightly overestimated. However, only four subjects demonstrated evidence of PEEPi at rest and no significant difference was observed in EELV or PEEPi with the four gas mixtures at baseline. Therefore, any error in WIP would be consistent across the four conditions, and considering the magnitude of the reduction in WIP observed with HE-HOX (52 ± 30%), we believe that a possible overestimation in WIP did not affect our conclusions.
In summary, combining 40% O2 with helium greatly increased exercise tolerance in patients with moderate to severe COPD due to the additional benefits of this gas on lung mechanics, dynamic hyperinflation, and dyspnea alleviation. The ability of HE-HOX to acutely reduce dyspnea and improve exercise tolerance is an important clinical finding and could be useful within rehabilitation practice. It is now well recognized that exercise training as a part of pulmonary rehabilitation can lead to important improvements in exercise capacity, dyspnea reduction, and health-related quality of life (34, 35). However, patients who suffer from debilitating dyspnea often cannot perform a sufficient volume of exercise to gain these benefits. Breathing HE-HOX during exercise should reduce dyspnea and increase the ability of patients with COPD to exercise, which could translate into improved outcomes from a pulmonary rehabilitation program.
The authors thank the Caritas Centre for Lung Health for its support with patient recruitment and Chris Sellar and Tim Hartley for providing assistance with data collection throughout this study.
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