Ventilatory and cerebrovascular responses in normocapnic and hypercapnic COPD patients

Subjects

The study was performed on 33 patients with COPD as defined by the American Thoracic Society. Ten males and six females, aged (mean±sd) 60±11 yrs, were normocapnic (P_a,CO2 ⪕6.0 kPa) and 15 males and two females, aged 63±8 yrs were hypercapnic (P_a,CO2 >6.0 kPa). Patients were excluded if they: 1) had evidence of obstructive sleep disorders or restrictive pulmonary function; 2) had an exacerbation in the 6 weeks before enrollment; 3) had a history of cardiopulmonary, cerebrovascular or other chronic diseases; and 4) took medications other than pulmonary bronchodilating agents, theophyllines and (systemic) corticosteriods. Three normocapnic and two hypercapnic patients were current smokers, all other patients stopped smoking for >6 months. An age-matched healthy control group (56±10 yrs, six males, 10 females) was also studied. None of them were on medication. A description of the patients is presented in table 1⇓.

At least 2 h prior to the experiments, all participants were asked to abstain from caffeinated drinks and cigarettes, but were allowed to continue their pulmonary medication. All volunteers gave informed consent. The study was approved by the ethical committee of the Department of Pulmonology Dekkerswald, University of Nijmegen.

Measurements

Ventilation measurements

The subjects were in a comfortable, reclining position. They were breathing through a face mask with low-resistance valves for inspiratory and expiratory gas mixture. First, dead space ventilation (V_D/V_T) was measured using the Bohr equation. Expiratory air was collected in a Douglas bag for 10 min for measurements of expiratory P_CO2 (capnograph N1000, Nellcor Puritan Bennet, MO, USA). Next, the inspiratory port of the mask was connected via a Fleisch pneumotachograph (Phipps & Bird, Richmond, VA, USA) to an inspiratory reservoir (fig. 1⇓). The flow signal was integrated into V′_I. Air was sampled from the expiratory port of the mask to a capnograph to monitor end-tidal CO₂ (P_ET,CO2, kPa) and respiratory rate (RR, min⁻¹). Changes in inspiratory gas mixture of oxygen (O₂), nitrogen (N₂) and CO₂ were induced by means of a computer-controlled mass flow system (Bronckhorst, Hitec, Veenendaal, the Netherlands). The fraction of inspired O₂ (F_I,O2) was monitored continuously using an oxygen analyser (OM-11, Beckman Inc., CA, USA). Fast changes in the inspiratory gas mixture could be induced; the aimed changes were reached within one breath. Hypercapnia (ΔP_ET,CO2 >1 kPa) was induced by giving adequate amounts of CO₂ (F_I,CO2 3–5%) in the inspired air.

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Fig. 1.—

Experimental set-up. Flow of oxygen (O₂), nitrogen (N₂), and carbon dioxide (CO₂) are regulated with a mass-flow controller. Arterial oxygen saturation (S_a,O2) and heart rate (HR) are measured with pulse-oximetry. NIRS: near-infrared spectroscopy; V′_I: inspired minute ventilation, measured by pneumotachography; P_0.1: mouth occlusion pressure; MABP: mean arterial blood pressure; P_ET,CO2 and RR: end-tidal CO₂ and respiratory rate measured by capnograph. For safety reasons, a back-up volume of 10 L was created. Arterial blood was sampled from the left brachial artery.

Protocol

All patients underwent routine spirometry and blood analysis of haemoglobin, haematocrit and resting arterial blood gases to assign the individual patients into the normocapnic and chronic hypercapnic COPD group. A canula was introduced in the left brachial artery to collect arterial blood samples. Arterial oxygen saturation (S_a,O2) and heart rate (HR) were monitored with a pulse-oximeter (N200; Nellcor Puritan Bennet, MO, USA), with the sensor attached to the right-frontal forehead (fig. 1⇑).

Hypercapnia was induced by giving adequate amounts of CO₂ in the inspired air. Duplicate measurements of CBV and P_0.1 during normo- and hypercapnia were performed after a period of 10-min equilibration. Arterial pressure was measured manually during each CO₂ condition. Mean arterial blood pressure (MABP) was calculated as: diastolic pressure+1/3×(systolic-diastolic) pressure. All data (except MABP) were linked directly to the NIRS computer for real time display and simultaneous storage with the NIRS data.

Statistics

During the whole experiment, time-averaged values of V′_I, P_ET,CO2, S_a,O2, HR and RR were recorded, expressed as mean±sd during each CO₂ challenge. Anthropometric characteristics, pulmonary function, MABP and arterial blood gas values were compared between the three groups by the Mann-Whitney U-test for two independent samples. Within the groups, values during normocapnia were compared to values during hypercapnia using a paired t-test. Between the groups, unpaired t-tests were used to compare outcome variables. For each individual, CBV, V′_I and P_0.1 was plotted against corresponding P_a,CO2 values and subjected to linear regression analysis. The individual slopes of CBV, V′_I and P_0.1 responses to acute CO₂ changes were calculated using linear regression analysis. Mean slopes of the three groups were compared with an unpaired test. The level of statistical significance was set at p<0.05. All tests should be regarded as explorative due to the multiplicity of tests.

Ventilation and ventilatory responses

Both COPD groups had significantly higher resting values of V′_I compared to healthy subjects (table 2⇑). The ventilatory response to CO₂ (ΔV′_I/ΔP_a,CO2) was lower in both COPD groups when compared to the controls, but was only significantly different (p<0.01) in the hypercapnic group compared to controls (table 3⇓). When both COPD groups were compared and the median rather than the average value of ΔV′_I/ΔP_a,CO2 was taken, a significant, different slope of ΔV′_I/ΔP_a,CO2 between the two COPD groups was found (p<0.05). Average responses (V′_I: L·min⁻¹; P_a,CO2: kPa) are displayed in figure 2b⇓.

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Fig. 2.—

Ventilatory and cerebrovascular responses to carbon dioxide. Regression equations were obtained for data from each individual subject and averaged for the group. All values of a) cerebral blood volume (CBV) and b) inspired minute ventilation (V′_I) were indexed to similar carbon dioxide tension in arterial blood (P_a,CO2) values to show average group results. –––: controls; ——: normocapnic chronic obstructive pulmonary disease; - - - -: hypercapnic chronic obstructive pulmonary disease.

In contrast to COPD patients, V′_I is a good parameter for neuromuscular output of ventilatory drive in healthy subjects. Both absolute values of P_0.1 (table 2⇑) and its reactivity (ΔP_0.1/ΔP_a,CO2, table 3⇑) were not significantly different between the COPD groups, even after correction for MIP.

Cerebral blood volume and cerebrovascular responses

Twelve out of 192 measurements were rejected and excluded from the CBV calculations because of inadequate measurements. Values of CBV were lower in the normocapnic patients as compared to the hypercapnic patients (p<0.01) (table 2⇑). Both COPD groups showed a significant, lower value of CBV compared to the healthy subjects. The cerebrovascular response to CO₂, ΔCBV/ΔP_a,CO2, was lower in both COPD groups compared to controls, however, this was only significantly lower (p<0.05) in the hypercapnic group (table 3⇑). Average equations of CBV as a function of P_a,CO2 are displayed in figure 2⇑.

Correlation between the different outcome parameters

A poor correlation was seen in the control group between the individual CBV and V′_I responses to acute hypercapnia (ΔCBV/ΔP_a,CO2 and ΔV′_I/ΔP_a,CO2). A low, but significant correlation was found for all COPD patients (fig. 3⇓). When the COPD group was subdivided, the normocapnic patients tended to show a steeper slope (ΔV′_I/ΔP_a,CO2/ΔCBV/ΔP_a,CO2) as compared to the hypercapnic patients (fig. 4⇓). However, the latter correlations were poor and not significant. In addition, when V′_I was related to MVV% and V′_I (MVV%)/ΔP_a,CO2 was correlated to ΔCBV/ΔP_a,CO2 (not displayed), correlations remained poor. Nevertheless, the slope of these correlations was positive, showing that high cerebrovascular responses were accompanied by high ventilatory responses to CO₂.

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Fig. 3.—

Correlation between ventilatory and cerebrovascular carbon dioxide (CO₂)-responsiveness in healthy subjects (control) and chronic obstructive pulmonary disease (COPD) patients. The relationship between a) the individual ventilatory/CO₂ tension in arterial blood (ΔV′_I/ΔP_a,CO2) and cerebrovascular (ΔCBV/ΔP_a,CO2) CO₂-responsiveness in healthy subjects and b) in normo- and hypercapnic COPD patients. The regression equation, describing the inter-individual relationship between a) V′_I/ΔP_a,CO2 and ΔCBV/ΔP_a,CO2 is ΔV′_I/ΔP_a,CO2=0.99×ΔCBV/ΔP_a,CO2+11.80 (r=0.2; p=0.5) and b) ΔV′_I/ΔP_a,CO2=2.36×ΔCBV/ΔP_a,CO2+3.99 (r=0.38; p<0.05). V′_I: inspired minute ventilation (L·min⁻¹); CBV: cerebral blood volume (mL·100 g⁻¹).

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Fig. 4.—

Correlation between ventilatory and cerebrovascular carbon dioxide (CO₂)-responsiveness in normocapnic and chronic hypercapnic chronic obstructive pulmonary disease (COPD) patients. The relationship between a) the individual ventilatory/CO₂ tension in arterial blood (ΔV′_I/ΔP_a,CO2) and cerebrovascular (ΔCBV/ΔP_a,CO2) CO₂-responsiveness in normocapnic and b) chronic hypercapnic patients. The regression equation, describing the inter-individual relationship between a) ΔV′_I/ΔP_a,CO2 and ΔCBV/ΔP_a,CO2 is ΔV′_I/ΔP_a,CO2=2.66×ΔCBV/ΔP_a,CO2+5.22 (r=0.20; p=0.47) and b) ΔV′_I/ΔP_a,CO2=1.43×ΔCBV/ΔP_a,CO2+3.79 (r=0.21; p=0.41). V′_I: inspired ventilation (L·min⁻¹); CBV: cerebral blood volume (mL·100 g⁻¹).

Correlations between the individual CBV and P_0.1 slopes (ΔCBV/ΔP_a,CO2 and ΔP_0.1/ΔP_a,CO2) were poor and not significant in both COPD groups (r=0.28 and 0.04 in the normocapnic and hypercapnic COPD group, respectively). In order to evaluate CBV with respect to parasympathetic tone, CBV and HR were correlated. There was no correlation between absolute values of CBV and HR in normocapnic (r=0.1) and hypercapnic COPD patients (r=0.2) and controls (r<0.1).

Ventilation and ventilatory responses

Ventilatory responsiveness to CO₂ were highest in healthy subjects and lowest in hypercapnic COPD patients. The results are in line with those of others 1, 8, 16, although the present study measured higher absolute values of responsiveness. The latter can be explained by various causes. Firstly, the present study used P_a,CO2 instead of P_ET,CO2 as an independent variable. Secondly, the (significantly) increased value of P_a,O2 during hypercapnic challenge may have resulted in an overestimated value of ventilatory CO₂ responses, as previous reports found a reduced CO₂ sensitivity during hyperoxia in healthy subjects 17. Thirdly, chronic hypercapnic patients were exposed to chronic hypoxaemia (mean P_a,O2 value 8.31 kPa). Superimposed desaturation changes to obtain absolute CBV values may have led to greater values of ventilation under both baseline conditions and during hypercapnic challenge, possibly leading to higher values of ventilatory slopes. Finally, all COPD patients have inhaled β₂-adrenergic agonists, resulting in additional increases in ventilatory responses to hypercapnia, presumably by central chemoreceptor stimulation 18.

The sex ratio in healthy controls' and patients' groups is different. As all the subjects investigated were postmenopausal, this study is not predominantly biased by sex.

To ascertain whether and to what extent the reduced ventilatory response to a hypercapnic stimulus in COPD patients depends on a blunted chemoresponsiveness of central origin or to mechanical impairment, Scano et al. 8 measured rebreathing CO₂ responses in normocapnic and hypercapnic COPD patients with similar degrees of airway obstruction and hyperinflation. Their study population was comparable to the present investigated group on pulmonary mechanics and arterial blood gas parameters. In contrast to Gelb et al. 16 and the present study, they found a lower P_0.1 responsiveness (cmH₂O·kPa⁻¹) in hypercapnics (1.08±0.43) relative to normocapnics (2.72±2.08) and healthy controls (2.57±0.49). Conversely, when the normalization of P_0.1 for individual differences in muscle strength was performed by expressing P_0.1 as a percentage of MIP 15, a significant difference between the two groups did not occur, which is in line with the present results.

Cerebral blood volume and cerebrovascular responses

Cerebrovascular responsiveness was expressed as a change of CBV over a change in P_a,CO2. It is important to consider the advantages of measurements of CBV over CBF measurements. Firstly, there is a close relationship (r=0.9) between CBV and CBF that has been extensively investigated 19. Secondly, the use of CBV instead of CBF eliminates the problems related to the mean cerebral transit time 20. Finally, near-infrared absorption changes reflect changes in the oxygenation of blood in the microvasculature, and thus the CBV of the brain tissue 21. Changes of CBV also reflects capillary recruitment, which are considered a better reflection of cerebrovascular responses than CBF responses to acid-base stimuli 20.

CBV was measured in the frontal cortex, which may not react in the same way as the brain-stem region, where the central chemoreceptors are located 22. However, Hida et al. 23 used transcranial Doppler to determine changes in blood flow velocity and could not find any differences in CO₂ responses between the brain-stem artery and the middle-cerebral artery using transcranial Doppler. The latter paper would support the present measurements of frontal-lobe vasoresponsiveness to be representative of overall CBV changes. However, since there is no general agreement on cerebrovascular CO₂-responsiveness, one has to be cautious to draw this conclusion.

Prior to this study, the reproducibility of CBV measurements during resting conditions using NIRS was evaluated; an intra-individual coefficient of variation of ±10% was found 24. These results are in agreement with others 25. CBV values of the present study during normocapnia (range 1.60–4.30 mL·100 g⁻¹) are consistent with other studies using NIRS: 2.85±0.97 mL·100 g⁻¹ 25.

Absolute values of CBV were lower in both COPD groups, relative to healthy subjects. Increased age 26, haematocrit 27 and HR may lower CBF and, therefore, CBV. HR was significantly increased in both COPD groups. HR responses primarily test the parasympathetic system. Stewart et al. 28 showed a parasympathetic autonomic dysfunction in 93% (28 out of 30) of severe hypoxaemic, hypercapnic COPD patients and in 65% (39 out of 60) of moderately to severely hypoxic, normocapnic COPD patients. Only 18% (four out of 22) of the control group had evidence of an age-related autonomic dysfunction. However, a correlation between absolute values of CBV and HR was not found in the present study. Additionally, no correlation was found between absolute values of CBV and age.

Medication, like theophyllines and systemic corticosteroids, may reduce CBV 29, 30. Theophylline was chronically used by nine of 16 (56%) normocapnic and 11 of 17 (64%) hypercapnic patients, which may have contributed to the low CBV in both COPD groups. Systemic corticosteroids were used in four out of 16 normocapnic and four out of 17 hypercapnic patients. To assess the effect of medical intervention, average CBV was recalculated after subdividing both COPD groups in users and nonusers of theophyllines and/or oral corticosteroids. In contrast to others 29, 30, CBV was slightly, but not significantly higher in the group of theophylline users, relative to the nonusers in both COPD groups. In addition, CBV values measured in corticosteroid-users and nonusers were not different. Both the small size of the subgroups and the high variation of CBV values among the subjects may mask the well-documented effects of theophyllines. Intravenous salbutamol (1 µg·kg⁻¹) leads to an increased CBV in rats 31. Since the present study showed a low CBV in all COPD patients, it is unlikely that the inhaled salbutamol (⪕400 µg) of the patients affected the CBV values substantially.

MABP was relatively higher in all COPD patients and remained unchanged during hypercapnia. Although their MABP values fell well within the range of autoregulation, pressure-dependent sensors may dominate flow-dependent sensors in the cerebral circulation during chronic elevated blood pressure, leading to a lowering of CBF and CBV. This might partly explain a blunted cerebrovascular responsiveness in both COPD groups, compared to healthy subjects.

There are only a few studies describing CBV reactivity in adults using NIRS. Gupta et al. 32 used the same method as the present study to calculate CBV and found a higher mean CBV of 5.38 mL·100 g⁻¹ and a lower CBV reactivity of 1.25 mL·100 g⁻¹·kPa⁻¹, in young adults. However, they induced deeper desaturations (Δ10–15%, instead of ∼5%), assumed equal Hb values for each individual and used the fractional concentration of CO₂ in expired gas to correlate with CBV. As they suggested, a deeper desaturation possibly gives rise to concomittant hypoxic vasodilation and thereby, a higher CBV and different CBV reactivity. Other studies applied the same “O₂-desaturation-method” in neonates 33, or used O₂Hb derived reactivity values, and are therefore not comparable with this study 34.

Conclusions

Normocapnic and chronic hypercapnic COPD patients had lower absolute values of CBV relative to healthy subjects; autonomic dysfunction was suggested as a possible reason for this difference. There was a poor, but positive correlation between ventilatory and cerebrovascular CO₂ responsiveness (ΔCBV/ΔP_a,CO2 and ΔV′_I/ΔP_a,CO2) in COPD patients and healthy subjects, thus refuting the hypothesis concerning an inverse relationship between cerebrovascular and ventilatory responses to P_a,CO2.

As compared to healthy subjects, both chronic obstructive pulmonary disease groups showed lower ventilatory as well as cerebrovascular carbon dioxide-responses, with significantly lower responses in the chronic hypercapnic group. Since similar mouth occlusion pressure reactivity was measured in both chronic obstructive pulmonary disease groups and cerebral blood volume- and inspired minute ventilation-reactivity were not significantly different, the present study was not able to elucidate why some patients with chronic obstructive pulmonary disease become hypercapnic, whereas others with the same degree of airway obstruction remain normocapnic.