We studied 20 clinically stable patients with advanced COPD (FEV₁ < 60% predicted) and varying degrees of hypoxemia. All patients were ventilatory limited during exercise and experienced severe activity-related breathlessness with a modified Baseline Dyspnea Index focal score (10) of six or less. Exclusions included clinical evidence of significant cardiovascular disease, other pulmonary disease, including cor pulmonale, and other disorders that could contribute to dyspnea or exercise limitation.

The study was a randomized, blinded, placebo-controlled, crossover trial with local university/hospital research ethics approval. After giving written informed consent, patients were familiarized with testing procedures and completed a symptom-limited incremental exercise test. In a subsequent visit, subjects performed two constant-load cycle exercise tests. The order of tests was randomized so that subjects breathed either 60% O₂ or room air (21% O₂) for at least 10 minutes at rest before exercising at approximately 50% of their previously determined maximal work rate while breathing the same oxygen mixture. There was a 60- to 90-minute washout period after testing on one oxygen mixture and then a crossover to the alternate mixture for identical testing. Subjects were blinded to the oxygen concentration being breathed.

In this article, we only consider the resting data during room air and O₂ and the exercise tests on room air. Changes in exercise responses with hyperoxia will be discussed in a subsequent article.

Subjects performed pulmonary function tests as previously described (2). Measurements during rest and symptom-limited cycle exercise tests were performed as previously described (2), with patients breathing either room air or 60% O₂ on demand from a 200-L Douglas bag reservoir. In addition to the usual measurements collected during cardiopulmonary exercise testing, subjects rated their intensity of dyspnea (defined as breathing discomfort) and perceived leg discomfort using the modified Borg Scale (11); operating lung volumes were derived from dynamic inspiratory capacity (IC) measurements (12), and arterial blood gas samples were obtained from the radial artery (2).

Results are reported as means ± SEM. A statistical significance of 0.05 was used for all analyses. Subgroup comparisons were made using unpaired t tests. Comparisons between measurements on room air and 60% O₂ were made using paired t tests. For subgroup comparisons and regression analyses, pulmonary function measurements were standardized as a percentage of predicted normal values (13–17). Pearson correlations were used to establish associations between the change (Δ) in Pa_CO2 from rest to peak exercise and concurrent changes in relevant independent variables, which included _V^·e, _V^·e/_V^·co₂, _V^·a, _V^·co₂, breathing frequency, inspiratory time, expiratory time, tidal volume (Vt), IC, inspiratory reserve volume, EELV, end-inspiratory lung volume (EILV), oxygen saturation, Pa_O2, and Vd/Vt. Forward stepwise multiple regression analysis was performed with these variables and relevant covariates (baseline lung function, gas exchange measurements, and the ΔPa_CO2 response to the hyperoxic test at rest) to establish the best predictive equation for ΔPa_CO2 from rest to peak exercise. Similar analyses were performed to examine inter-relationships between (1) hyperoxia-induced ΔPa_CO2 at rest and concurrent changes in a similar pool of candidate variables and (2) resting Pa_CO2, baseline lung function, and gas exchange measurements.

Finally, to determine factors associated with progressive hypercapnia during exercise, we used a multivariable linear model with the change (Δ) in Pa_CO2 from rest as the dependent variable and concurrent changes in relevant independent variables (similar to those described previously here). Because of dependency between serial measurements within subjects, “subjects” (categorical variable) were treated as random effects in the regression model.

Subjects with COPD included 10 males and 10 females with severe expiratory airflow obstruction, lung hyperinflation, functional inspiratory muscle weakness (decreased inspiratory muscle strength) and reduction of diffusing capacity of the lung for carbon monoxide (Dl_CO) (Table 1)

The magnitude of change (Δ) in Pa_CO2 from rest to the end of symptom-limited exercise while breathing room air was variable (range, −6 to 25 mm Hg). One subject showed a fall in Pa_CO2 (−6 mm Hg). One subject had no change in Pa_CO2 (1 mm Hg). Nine subjects experienced small increases in Pa_CO2 of between 3 and 5 mm Hg, and the remaining nine subjects increased Pa_CO2 by greater than 5 mm Hg (i.e., by a mean of 11.6 ± 2.2 mm Hg). The change in Pa_CO2 from rest to peak exercise did not correlate with the resting Pa_CO2 (r = −0.03, p = 0.91). Likewise, the magnitude of change in Pa_CO2 from rest to peak exercise was similar in a subgroup of patients with resting hypercapnia (Pa_CO2 ⩾ 45 mm Hg, n = 7) as in the patients with resting eucapnia (Pa_CO2 < 45 mm Hg, n = 13). Pa_CO2 increased by 7 ± 3 and 6 ± 2 mm Hg, respectively (p = 0.77). However, compared with patients with resting eucapnia, the subgroup of individuals with resting hypercapnia had greater resting hyperinflation (FRC was 206 ± 15% versus 165 ± 7% predicted, p = 0.01), a limited ability to increase ventilation during exercise (peak _V^·e was 19 ± 2 versus 29 ± 5 L/minute), greater Vd/Vt at rest and throughout exercise (peak Vd/Vt was 47 ± 2 versus 40 ± 2%, p < 0.05), and greater Pa_CO2 values throughout exercise (peak Pa_CO2 was 58 versus 44 mm Hg, p = 0.001). Likewise, resting Pa_CO2 correlated best with the baseline residual volume (RV) percentage predicted (r = 0.725, p = 0.001) and FRC expressed as either percent predicted (r = 0.666, p = 0.001) or as percentage TLC (r = 0.659, p = 0.001), but did not correlate with baseline Vd/Vt, _V^·e, _V^·e/_V^·co₂, or functional inspiratory muscle strength.

The best correlate of the magnitude of change (Δ) in Pa_CO2 from rest to peak exercise was the hyperoxia-induced change in resting Pa_CO2 (r = 0.79, p < 0.0005). Those with the greatest hyperoxia-induced hypercapnia had the greatest exercise-induced hypercapnia. The ΔPa_CO2 from rest to peak exercise did not correlate with any resting measurements of pulmonary function or gas exchange other than FEF_25–75% (expressed percentage predicted; r = −0.58, p = 0.007) and oxygen saturation on room air (r = −0.55, p = 0.011). These relationships were maintained even after removing the one outlier from the analysis; this patient had developed significantly greater hypercapnia during both exercise (25 mm Hg) and hyperoxic breathing (27 mm Hg) than the rest of the sample.

After accounting for serial measurements within each subject, the strongest correlates of serial ΔPa_CO2 measurements during exercise included concurrent measurements of change in oxygen saturation (partial correlation coefficient [R] = 0.816, p < 0.0005) and ΔEELV expressed as a percentage of TLC (partial r = 0.562, p < 0.0005) or as a percentage of predicted TLC (partial r = 0.562, p < 0.0005) (Figure 1)

Figure 1. During exercise, serial changes in Pa_CO2 from rest correlated significantly (p < 0.0005) with concurrently measured increases in the EELV/TLC ratio (after treating for the random effects of subjects in the regression model, partial r = 0.562). Arterial blood gas and lung volume measurements were collected during steady state breathing at rest, every 2–3 minutes during exercise, and at the peak of exercise.

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After breathing the 60% oxygen mixture for 10 minutes at rest, there were two distinct Pa_CO2 response patterns (Figure 2)

Figure 2. Two COPD subgroups were identified after breathing 60% O₂ for 10 minutes or more at rest: (1) “CO₂ retainers” increased Pa_CO2 ⩾ 3.6 mm Hg, that is, outside of the 95% confidence interval (CI) measured on room air, and (2) “nonretainers” changed Pa_CO2 ⩽ 3 mm Hg. The distribution of these changes within each subgroup are shown.

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Mean resting changes in gas exchange, breathing pattern, and various other cardioventilatory parameters in response to hyperoxia are reported in Table 3

The hyperoxia-induced change in resting Pa_CO2 correlated significantly with resting Pa_O2 on room air (r = −0.50, p = 0.04), baseline FEF_75% (r = −0.48, p= 0.33), and the concurrent changes in _V^·a (r = −0.45, p = 0.05) and Vd/Vt (r = 0.44, p = 0.05). After accounting for the baseline Pa_O2, the combination of FEF_75% and the change in Vd/Vt best predicted the oxygen-induced change in Pa_CO2 (r² = 0.64, p = 0.001).

To illustrate differences in exercise response patterns between CO₂ retainers and nonretainers, subgroups were divided on the basis of the Pa_CO2 response to hyperoxia (discussed previously here) (18). Aside from gas exchange parameters, variables measured at rest and at peak exercise were similar for both subgroups while breathing room air (Table 2). Gas exchange and ventilatory responses are shown relative to the metabolic load (_V^·co₂) in Figure 3

Figure 3. Ventilation, Pa_CO2, Pa_O2, and Vd/Vt are shown for CO₂ retainers (R) and nonretainers (NR) relative to the _V^·co₂ during exercise. Although, R and NR subgroups were divided on the basis of the Pa_CO2 response to hyperoxia at rest, there was also a clear distinction between Pa_CO2 responses in these subgroups during exercise. Values shown are means ± SEM.

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Figure 4. Exertional dyspnea intensity (Borg Scale ratings) is shown expressed against _V^·co₂ during exercise in carbon dioxide retainers (R) and nonretainers (NR). Values shown are means ± SEM. Slopes are not significantly different between subgroups.

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In both subgroups, exercise was ventilatory limited due to mechanical constraints on tidal volume expansion, that is, Vt approached the dynamic IC as EILV encroached on the TLC envelope. Peak Vt correlated very strongly with the concurrent IC (r = 0.97, p < 0.0005). However, CO₂ retainers reached this mechanical limitation earlier and tended to have a lower peak _V^·e and _V^·co₂ than CO₂ nonretainers (Figure 5)

Figure 5. Operating lung volumes are shown relative to ventilation during exercise in CO₂ retainers (R) and nonretainers (NR). For comparison, data from an age-matched normal healthy group are also shown (10). Ventilation during exercise was limited by mechanical constraints on Vt expansion in both R and NR, that is, by dynamic hyperinflation from below and by the TLC envelope mentioned earlier here. As the EILV approaches TLC, we refer to the upper volume boundary as the “minimal inspiratory reserve volume” that can be achieved at the peak of symptom-limited exercise.

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This is the first study to show a strong correlation between the hypercapnic response to hyperoxia and the change in Pa_CO2 from rest to peak exercise. In chronically hypoxemic patients with COPD, resting eucapnia can be maintained by the development of adaptive mechanisms, which include (1) regional intrapulmonary vasoregulatory adjustments to minimize ·_V/Q· inequalities (i.e., hypoxic vasoconstriction) and (2) increased respiratory drive as the result of increased peripheral chemosensitivity (i.e., hypoxic drive). That these adaptations were present in many of our patients is evidenced by their response to hyperoxic breathing. In agreement with the study of Sassoon and colleagues (9), which was conducted in a similar group of clinically stable patients, hyperoxia caused release of hypoxic vasoconstriction with worsening of ·_V/Q· mismatching, expansion of dead space ventilation, and reduction of CO₂ elimination. Our study similarly showed that the change in Pa_CO2 while breathing 60% oxygen was mainly explained by the induced increase in Vd/Vt, as _V^·e and _V^·co₂ (other determinants of Pa_CO2) fell in proportion and by a small amount. Both studies suggest that CO₂ retention during hyperoxia primarily reflects worsening ·_V/Q· relationships rather than suppression of hypoxic drive per se. The hyperoxic test is, therefore, an indirect measure of the extent of prevailing ·_V/Q· inequalities at rest. Previously, studies using multiple inert gas elimination techniques have demonstrated that when hyperoxia caused release of vasoconstriction in previously underperfused and poorly ventilated alveolar units, blood was diverted from alveolar units with relatively well preserved ·_V/Q· ratios (18). These latter units became converted into units with high ·_V/Q· ratios, which contributed to increased Vd/Vt. In addition, it has been proposed that increased oxygenation of low ·_V/Q· units will increase Pa_CO2 via the Haldane effect (19). This effect was not measured in this study but is likely to be small (19, 20).

In hypoxic healthy individuals living at high altitude, acute hyperoxia may result in a small decrease in _V^·e (21). During hyperoxia in our group of COPD patients, ventilation fell by a mean of 3% (and by 8% in the subgroup retaining CO₂), likely reflecting suppression of hypoxic drive. The inability to augment further ventilation could not be explained by mechanical constraints, as our CO₂ retainers were capable of increasing ventilation, at least to an average peak of 22 L/minute during exercise. It is possible that reduced sensitivity of the central respiratory controller may partly explain CO₂ retention during both hyperoxia and exercise.

Seven of the nine patients in the CO₂ subgroup were receiving long-term continuous home oxygen. Fleetham and colleagues clearly demonstrated a measurable decline in the ventilatory response to added CO₂ in such individuals after 12 months of receiving home oxygen therapy (22). However, no definitive conclusions could be made about ventilatory control status in our patients as we do not know to what extent suppression of hyperoxic drive during hyperoxia counterbalanced the stimulatory effects of the increased CO₂. Any assessment of ventilatory control during exercise is extremely difficult in the setting of coexistent severe mechanical constraints in COPD patients. Therefore, the relative contribution of reduced central respiratory drive to exercise CO₂ retention could not be ascertained in this study.

Clearly, intrapulmonary vasoregulation was an important mechanism responsible for preventing resting hypercapnia on room air in these hypoxic COPD patients. We postulate that this compensatory mechanism was quickly overwhelmed during exercise in the setting of increased _V^·co₂, worsening ·_V/Q· relations (i.e., lack of the usual improvement in ·_V/Q· relations), and critical dynamic mechanical constraints on ventilation.

All of our patients had advanced COPD with clinical and physiological features of emphysema. They had severe resting hyperinflation with further dynamic hyperinflation during exercise. At a peak symptom-limited _V^·o₂ of only 24% predicted, IC decreased by 17% of its already reduced resting value. As in a previous study (12), symptom-limited peak _V^·co₂ correlated well with peak Vt, which in turn correlated strongly with both the resting and peak exercise IC (expressed as the percentage predicted). This indicates that in the group as a whole, mechanical factors formed the predominant limitation to exercise.

There was a good correlation between resting Pa_CO2 and measures of resting hyperinflation, suggesting that mechanical factors play a role in CO₂ retention in patients with the worst ·_V/Q· inequalities. In addition, this is the first study to show a strong statistical correlation between exercise-induced increases in Pa_CO2 and simultaneous increases in dynamic EELV/TLC in patients with advanced COPD (Figure 1). In fact, as much as 56% of the variance in exercise ΔPa_CO2 was explained by this mechanical factor alone. The strong association between exercise arterial oxygen desaturation and exercise-induced changes in Pa_CO2 was not surprising, as the progressive arterial oxygen desaturation primarily reflects the effects of worsening alveolar hypoventilation as a result of dynamic mechanical restriction. It is noteworthy that other important exercise variables such as Vd/Vt, breathing pattern, and _V^·co₂ did not additionally contribute to the variance in exercise-induced hypercapnia in the group as a whole.

In accordance with a previous study by Robinson and colleagues (18), subgroups were arbitrarily divided on the basis of their Pa_CO2 response to hyperoxic breathing at rest. This approach permitted a clear demarcation of the subgroups (Figures 2 and 3). Hyperoxic CO₂ retainers had greater mechanical constraints on ventilation than nonretainers and reached their maximal EILV of 95% of the TLC at a peak _V^·e of only 22 L/minute. This peak _V^·e was substantially less (by an average of 7 L/minute) than that of nonretainers at a similar peak EILV. The lower resting Pa_O2, greater hyperoxic hypercapnia, and more pronounced arterial oxygen desaturation with a widened arterial-end tidal difference in Pco₂ difference during exercise also indicates greater ·_V/Q· inequalities in those who developed exercise hypercapnia. In keeping with previous studies (1), breathing pattern responses to exercise were almost identical in these subgroups. There appeared to be a greater disparity between ventilatory capacity and ventilatory demand in the CO₂ retainer subgroup at any given _V^·co₂. Clearly, this subgroup of patients was incapable of increasing ventilation further despite marked ventilatory stimulation as a result of the combination of profound hypercapnia, hypoxia, and acute metabolic acidosis, as well as stimulatory inputs from peripheral ergoreceptors and the cortical “locomotor” center.

In COPD patients with chronic hypoxia, a near-normal resting Pa_CO2 on room air does not preclude the existence of extensive ·_V/Q· abnormalities. Such abnormalities can be uncovered by a hyperoxic breathing test, which acutely reverses the adaptive vasoregulatory adjustments that normally help to maintain resting eucapnia. These patients who have more compromised gas exchange capabilities are more likely to develop hypercapnia when challenged with increasing _V^·co₂ and progressive mechanical restriction during exercise. In advanced COPD, the propensity to develop CO₂ retention during exercise in patients with marked ·_V/Q· inequalities primarily reflects the severe mechanical constraints on ventilation as a consequence of lung hyperinflation.