Eur Respir J 1988, 1, 139-144

Influence of exercise and C02 on breathing pattern in patients with chronic obstructive lung disease (COLD)

G. Scano*, F. Gigliotti*, A. van Meerhaeghe**, A. De Coster**, R. Sergysels**

Influence of exercise and C02 on breathing pattern in patients with chronic • Clinica Medica III, Universita di Firenze, obstructive lung disease (COLD). G. Scano, F. Gigliotti, A. van Meerhaeghe. Italy. A. De Coster, R. Sergyse/s. •• Pulmonary Division, Hopital Universitaire ABSTRACT: In ten eucapnic patients with chronic obstructive lung disease St. Pierre (ULB), Brussels, Belgium. (COLD) we evaluated the breathing pattern during induced progressive Keywords: Breathing pattern; exercise; COPD; hypercapnia (C0 rebreathing) and progressive exercise on an ergometric 1 col rebreathing. bicycle (30 W /3 min). The time and volume components of the respiratory cycle were measured breath by breath. When compared to hypercapnia, the increase Received: January 30, 1987; accepted after in ventilation (VE) during exercise was associated with a smaDer increase in revision: September 17, 1987. tidal volume (VT) and a greater increase in respiratory frequency (fl). Plots of tidal volume (VT) against both inspiratory time (Tt) and expiratory time (TE) showed a greater decrease in both TI and TE during exercise than with hypercapnia. Analysis of YE in terms of flow (VT/TI) and timing (Tt/'I'r) showed VE to increase by a similar increase to that in VT/TI during both exerci.se and hypercapnia, while Tt/TT did not change significantly. When the patients were matched for a given VE (28 I· min -J ), exercise induced a smaller increase in VT (p < 0.05), a greater increase in fl (p < 0.025); Tl (p < 0.025) and TE (p < 0.01) were found to be smaller during exercise than hypercapnia. The change in the off-switch mechanism during exercise and hypercapnia could account for our results. Eur Respir J. 1988, I, 139-144.

Many recent studies have been devoted to the between ventilation and tidal volume (Hey's plot) [18] analysis of breathing patterns and ventilatory control during C02 inhalation and exercise. at rest in patients with chronic obstructive lung In patients with COLD, however, comparative data disease (COLD) [27, 30-33). Rapid and shallow have been reported only in terms of ventilatory breathing characterizes the breathing pattern in response to carbon dioxide and exercise without patients with chronic hypercapnia when compared analysing the breathing pattern (19). with normocapnic ones (27, 33]. The increased To control the different behaviour during induced neuromuscular drive noted in patients with COLD hyperventilation in COLD patients who underwent during induced hyperventilation (30- 32] seems to C02 rebreathing and progressive exercise, we ana­ depend not only on mechanical input to the respira­ lysed the breathing pattern by measuring the time and tory centre [5] but also on mechanical afferences from volume components of the respiratory cycle. the thoraco-pulmonary system (5, 7, 30, 32]. Alterna­ tively, the rapid shallow breathing could depend on Materials and methods the mechanical limitation for ventilation (4, 15]. In both normal subjects and patients with COLD, We studied ten normoxic and eucapnic male hyperventilation may be achieved in different ways, patients with chronic obstructive lung disease such as C02 inhalation and metabolic load during (COLD), according to the American Thoracic Society exercise. In the former, chemical input to the criteria [I]. Spirometric pulmonary functional data respiratory centre is mainly related to the stimulation (Pulmonet Godart) included vital capacity (VC), of central chemoreceptors [25]. In the latter, several forced expiratory volume in one second (FEV 1), and factors such as C02 production (25, 28, 36], changes functional residual capacity (FRC) by the helium in arterial oxygen tension (Pao2 ) [17, 23, 25], dilution technique, which allowed us to calculate mechanical afferences from the lung [26], and pro­ residual volume (RV) and total lung capacity (TLC); prioceptive muscular afferent information [7, 10] thoracic gas volume (TGV) and the resistance of the could play a role. airway (Raw) were measured by a pressure-variable Comparisons between stimulation with exogenous body plethysmograph, which allowed the calculation C02 and metabolic load have been made in normal of specific airway resistance (sRaw = Raw x TGV). subjects [2, 18, 21] and show a variable relationship Diffusing lung properties and the permeability coeffi- 140 G. SCANO ET AL .

cient for carbon monoxide (Kco) were determined by for 3- 4 min from a 6 to 8 litre bag. The inspiratory the single-breath technique. The normal values for line was separated from the expiratory one by a one­ lung volumes and Kco are those proposed by GRIMBY way valve (Hans-Rudolph), connected to a Lilly type and SODERHOLM (16) and ENGLERT (12], respectively. pneumotachograph. The flow signal was integrated The patients were selected on the basis of both clinical into ventilation. The mouth occlusion pressure history and functional evidence of airway obstruction against an occluded airway at end-expiratory level 0.1 (FEV 1/VC::; 60%) when they were clinically stable; s after the onset of inspiration (P0 . 1) [37) was any therapy which was being taken was withheld for measured as previously described [30- 32, 35]. A at least 12 h before the study. Functional data are pressure transducer (Statham SC 1001) was used to summarized in table I. measure the mouth pressure developed at 0.1 s. On After the evaluation of the baseline respiratory the expiratory side of the valve, gas was continuously pattern, each patient, from a seated position, sampled with an infrared C02 meter (Godart) to underwent a C02 rebreathing test. The apparatus has measure the C02 level; the sampled gas was returned been previously described (31] and the procedure was to the rebreathing bag. The dead space and the that recommended by READ [29). A gas mixture resistance of the system were evaluated as 178 ml and 1 containing 7%C02 + 50%02 + 43 %N2 was inhaled 0.09 kPa. r •s, respectively.

Table I.- Pulmonary function data at rest in 10 patients with COLD breathing room-air n Age vc RV FRC sRaw TLC FEV1NC Kco y kPa·s-1 % min-1

1 61 2.04 4.2 4.9 6.25 L47 1.0 49 2.05 (43) (158) (119) (85) (57)

2 38 3.2 2.0 3.4 5.2 1.08 1.9 60 4.16 (70) (125) (104) (84) (97)

3 49 4.15 2.6 3.9 6.8 0.49 2.5 59 1.76 (91) (120) (107) (102) (44)

4 55 3.0 3.8 5.1 6.9 1.76 LO 35 2.12 (69) (165) (141) (104) (57)

5 63 3_5 3.7 4.6 7.2 1.57 1.6 42 2.24 (67) (161) (116) (96) (58)

6 74 2.16 5.5 6.0 7.7 2.65 0.6 28 3.0 (44) (186) (134) (98) (79)

7 38 2.7 3.5 4.9 6.3 1.27 L4 51 5.5 (61) (140) (132) (90) (128)

8 51 2.4 3.9 4.5 6.3 2.29 0.82 35 3.1 (52) (165) (132) (96) (80)

9 56 3.5 4.3 5.4 7.6 1.27 1.3 40 1.65 (74) (173) (135) (107) (45)

10 40 4.0 2.4 4.4 6.5 0.95 2.3 57 3.5 (80) (114) (116) (91) (84) - X 52.5 3.1 3.58 4.7 6.67 1.48 1.44 45.6 2.9

SD 11.8 0.73 1.03 0.73 0.74 0.63 0.63 11.2 1.21

Values between parenthesis are in% of the predicted value. VC: vital capacity; RV: residual volume; FRC: functional residual capacity; sRaw: specific resistance of the airways; FEY : forced expiratory volume in 1 sec; Kco: Krogh's factor for lung transfer 1 for CO. EXERCISE AND C0 2 ON BREATHING PATTERN 141

From the flow signal we derived time and volume Table II.- Respiratory pattern in 10 COLD patients (mean components of the respiratory cycle: tidal volume values ±1so) (VT), mean inspiratory flow (VT/TI), 'duty cycle' (TI/TT), respiratory frequency (fR) and ventilation Before rebreathing Before exercise (VE). VT(fl was related to mouth occlusion pressure 1 (P0 .1) measured during the following breath. Since VE /·min- 13.9 ± 1.69 13.95 ± 3.2 P 0 . 1 represents an index of inspiratory drive [37], the VT/ 0.61 ±0.11 0.72±0.3 relationship between P0 . 1 and VT/TI represents the TI sec 1.13 ± 0.24 1.3 ±0.25 effectiveness of the thoraco-pulmonary system to TEsec 1.5 ±0.3 1.76 ± 0.46 convert this signal into mean inspiratory flow and 1'r sec 2.66±0.56 3.0 ±0.68 ventilation. Therefore, the relationship between P 0 .1 VT/TI 1·s·1 0.55 ± 0.09 0.56±0.15 and VT/TI is considered as the 'effective' inspiratory TI/I'r 0.43 ± 0.03 0.42±0.04 impedance (8]. fR cycles·1 23.5 ± 5.8 20.0±5.2 The resistance of the circuit used on rebreathing was such that the mouth pressure during unoccluded breathing was always between +0.2 kPa (expiration) There was no significant difference between the two experimen­ and - 0.2 kPa (inspiration) with respect to the tal conditions. VE: minute ventilation; VT: tidal volume; TI: atmospheric pressure. inspiratory time; TE: expiratory time; Tr: total time of the respi­ The output of the C02 meter and the integrated ratory cycle; VT{fi: mean inspiratory flow; TI/I'r: ratio between flow signal, as well as the mouth pressure, were inspiratory time and total breath duration (duty cycle); continuously recorded on a multi-channel linear fR:respiratory frequency, P . : mouth occlusion pressure. recorder. The patients, who wore a noseclip, were 0 1 comfortably seated and were not able to predict Results which breath would be occluded. The following day the study was repeated under The respiratory pattern of the patients under control conditions and during progressive exercise control conditions is shown in table II. There was no with the subject seated on an ergometric bicycle with significant difference between the values obtained on a progressive increase in load (30 W/3 min) until the the two different days, before ventilatory stimulation. patient felt dyspnoea or pain in the legs. Pedalling A ventilatory level of 28 /·min - 1 was chosen to was held at 50 rpm; the breathing circuit was the compare exercise and C02 rebreathing, because this same as that used during the rebreathing test in level was achieved by all patients and located below terms of both resistance and dead space. The same the maximum symptom-limited Vo2 achieved and probably below the anaerobic ventilatory threshold. parameters, as well as C02 output (Vco2), obtai11ed 1 by analysing mixed fractional expiratory carbon At that level of ventilation (28/· min - ) VT (p <0.05), dioxide (FEco2) in a 'mixing box', were measured at Tr (p<0.025), TT (p

Ve II m•n-1 l Ve (l .min-1) Vdl min-1) Ve ( l·min-1)· 60 '- 60 l 60 l l 30 / 30 }t 30 0. ~ "19- ~ Vt ITt tt sec-1) T,/I T Vr tR(r les-1) I ' ' ' ' 5 I 2 3 4 10 20 30 40 0 2 3 0 3 4 6

Fig. 2. Analysis of pulmonary ventilation (VB) in terms of tidal Fig. 4. Minute ventilation (VE) is analyzed in terms of mean volume (VT) (left panel) and respiratory frequency (fR) (right inspiratory flow (VT/TI) and 'timing' (Tl/TT). (e) exercise; (0) rcbreathing. panel). Mean values ± I S£ for all subjects are shown at rest and at each level of exercise (30 to 120W) or minute of rebrcathing (I" to 4'b). c•>exercise; (0) rebreathing. Table Ill.- Arteria( blood gases at rest, during exercise and 1 ). C02 rebreathing for a given ventilation (28 fmin· Mean increase in VT during exercise (from rest to 90 W) is values ±1 so and statistical comparison evident when compared to C02 rebreathing (from 1 control to the 4 b minute). Furthermore, an increase Pao2 Paco2 pH in VE was also related to a significant increase in fR kPa kPa (p

(Hey's plot) [18] during C02 rebreathing and progres­ 6 sive exercise. The main difference we noted was a limitation of VT during exercise compared to hyper­ capnic stimulation and, consequently, an increase in 2 the respiratory frequency necessary to achieve a T• (sec) Tdsecl similar level of ventilation . 16 14 .6 I 0 I 6 12 1.6 2 The increase in respiratory frequency was achieved Fig. 3. Tidal volume (VT) is plotted against inspiratory time (T1) by a proportional decrease in T1 (p (p

In normal subjects, ventilatory responses during ship, an index of the effective inspiratory impedance acute hypercapnia and exercise have been compared of the thoraco-puJmonary system [8]- previously [2, 18, 21]. According to AsKANAZI et a!. ii) a decrease in T1 has been observed in response to a (2], an increase in ventilation d uring hypercapnic progressive hypoxia (8 to 4 kPa) [23]. However, our stimulation depends mostly on an increase in tidal data did not show a significant decrease in arterial volume, whereas during exercise, an increase in Po 2 for a given VE, during either exercise or ventilation depends on an increase in both tidal hypercapnia, as compared to control conditions. volume and respiratory frequency with a significant These data arc consistent with our previous ones (30, decrease in inspiratory time. The authors supposed 35] in patients with COLD during moderate ergome­ that a change in the 'inspiratory off-switch' mechan­ tric exercise.

ism [14] during exercise could account for the different iii) C02 stimulation is known to increase central responses in terms of tidal volume and respiratory inspiratory activity (13, 23] and to raise the volume frequency [2]. In contrast, H EY et al. [18] showed that (VT) threshold for the reflex inspir atory off-switch the relationship between ventilation and tidal volume [13]. Furthermore, elevated Pco 2 in the bronchial is similar during hypercapnia and exercise. airways is sufficient to lower stretch receptor activity To our knowledge, there are no comparative data [3], necessary for reaching the threshold for the in the breathing pattern during C02 stimulation and Hering-Breuer inhibitory reflex; this causes VT to exercise in patients with chronic obstructive lung increase. In terms of changes in breathing pattern, on disease. GARRARD and LANE [15] showed a progres­ the one hand, larger inflation causes greater expira­ sive decrease in inspiratory and expiratory time tory prolongation [34], i.e. greater VT increases are during rebreathing with a progressive but small accompanied by greater TE and viceversa (see also fig. increase in tidal volume, related to volume restriction I); on the other hand, a small fall in Paco2 with d ue to a progressive increase in lung volume at end­ exercise measurably influences ventilatory pattern expiratory level. while the addition of C02, which prevents hypocap­ During exercise in patients with COLD, the slope nia, enhances the VT plateau by increasing TJ [24]. of the relationship between tidal volume and inspira­ These data could, at least in part, account for our tory time tends to be shifted to the left, when results showing a greater VT increase and lower TE compared to normal subjects [4, 32]. This results in a decrease with hypercapnia compared with exercise. shorter inspiratory time and a smaller VT with a rapid iv) part of these data [24) are consistent with the and shallow breathing [4, 32, 35]. Synchronization of hypothesis of metabolic drive to breathing with respiratory rate during exercise with pedalling speed exercise [28, 36]. This hypothesis maintains that the or stepping frequency has been noted in normal man hyperpnoea of exercise is completely attributable to [18]. However, this observation has not been the increased delivery of C02 to the lungs [28, 36]. confirmed in more recent papers [20- 22] where Contrary to the metabolic hypothesis, the neuro­ respiratory frequency and both VT/Tl and VT/TE humoral hypothesis holds that during exercise, venti­ relationships were found to be similar at two different lation is augmented by neural stimuli, in addition to pedalling speeds [20, 21]. Our data in patients are metabolic stimuli [6, 7]. In this context it should be consistent with these [20, 21] and seem to indicate no mentioned that in normal man and patients with link between movement frequency and respiratory COLD, pulmonary congestion during muscular exer­ frequency of bicycle exercise. cise represents a natural stimulus for J receptors [17, The differences we noted in the respiratory pattern 26], with an increase in the inhibitory vagal activity during C02 rebreathing and exercise in patients with limiting inspiratory volume. On the contrary, the COLD are consistent with the data of ASKANAZJ eta/. effects of acute hypercapnia on pulmonary circulation who studied normal man in the supine position [2]. are unimportant in normal man [25]. In terms of These differences could be explained as follows: respiratory timing, ELDRIDGE and GILL-KUMAR (10) i) mechanical differences observed in COLD patients have recently shown that stimulation of afferents during induced hypercapnia [15] and exercise [9] from limb muscles in cats causes different changes in could be due to different changes in lung volume at timing variables, i.e. greater frequency and shorter end-expiratory level. These volume changes restrict expiratory time than those associated with chemore­ any substantial increase in tidal volume [9, 15]. We ceptor afferent stimulation. These findings could were unable to control the possible changes in lung provide a further explanation for the increased volume at end-expiratory level during rebreathing respiratory frequency and shorter TE we noted with and exercise. However, for the chosen level of bicycle exercise. 1 ventilation (28/·min- ), P0 .1 was found to be similar That mechanical afferences are also involved in in the two experimental conditions. As an increase in sustaining ventilation in patients with COLD during lung volume put the inspiratory muscles in a less progressive exercise is indicated by the fact that their favourable condition to generate inspiratory pressure P0 .JVco2 ratio, an index of the respiratory drive per [I I] we argue that end-expiratory volume was not unit of met3bolic load (Vco2), is higher than that of dissimilar with exercise and C02 rebreathing for the normal subjects [30, 32]. chosen VE. This could also be indicated by the In summary, we found that in eucapnic and similarity of the slopes of the P0 • 1/(VT/TI) relation- normoxic patients with COLD, exercise and C02 144 G. SCANO ET AL.

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