sign in sign up
<<
Home , Hypercapnia, Hypocapnia, PCO2, Respiratory system

28 1991;46:28-32 Effects of and on respiratory resistance in normal and asthmatic subjects Thorax: first published as 10.1136/thx.46.1.28 on 1 January 1991. Downloaded from

F J J van den Elshout, C L A van Herwaarden, H Th M Folgering

Abstract tigate the effect of change in end tidal Pco2 on The effects of hypercapnia and hypocap- airway calibre without the confounding effects nia on respiratory resistance were of heat and water loss from the airway studied in 15 healthy subjects and 30 mucosa. The forced oscillation technique was asthmatic subjects. Respiratory resis- used because the measurements obtained with tance (impedance) was measured with this method are collected during spontaneous the pseudo-random noise forced oscilla- . Forced expiratory manoeuvres, tion technique while the subjects which may influence bronchial tone," were rebreathed from a wet spirometer in a thus avoided. closed respiratory circuit in which end tidal tension (Pco2) could be controlled. Hypercapnia was induced Methods by partially short circuiting the carbon EQUIPMENT dioxide absorber, and hypocapnia by Oscillatory respiratory resistance (impedance) voluntary . The cir- was measured with the pseudo-random noise culating air was saturated with water forced oscillation technique using the vapour and kept at body apparatus developed by Landser et al and ambient . A rise of end tidal (Oscillaire, Jones, Chicago).'2 '3 A loudspeaker Pco2 of 1 kPa caused a significant fall in generates pressure changes at the in the respiratory resistance in both normal form of a pseudo-random noise signal contain- and asthmatic subjects (15% and 9% res- ing all harmonics of 4-52 Hz superimposed on pectively). A fall of Pco2 of 1 kPa did not spontaneous breathing. Mouth pressure and cause any significant change in flow signals are recorded by two identical impedance in the control group. In the differential transducers (Validyne MP 445). asthmatic patients resistance increased Fourier analysis allows the calculation of http://thorax.bmj.com/ by 13%, reactance fell by 45%, and the impedance at 4-52 Hz from the data, which frequency dependence of resistance rose were collected over eight seconds. The validity 240%. These findings confirm that of the measurements was evaluated by a hypocapnia may contribute to airway coherence function that assessed the amount of obstruction in asthmatic patients, even noise and alinearity in the signals'2 14; only data when water and heat loss are prevented. with a coherence function of 095 or more were retained. The impedance data were subdivided

into resistance and reactance and were com- on October 1, 2021 by guest. Protected copyright. Many specific and non-specific broncho- puted over the range 4-52 Hz in steps of 4 Hz. constrictor challenges are used to measure Resistance (Rrs), computed as the ratio of the bronchial reactivity, including allergens, in phase components of pressure and flow, is irritants, cholinergic drugs, mediators, exer- determined by the resistive properties of the cise, and hyperventilation. For and (airways, , and hyperventilation challenge respiratory heat chest wall). Reactance (Xrs) was computed as loss and increased osmolarity of the airway the ratio of the components of pressure and mucosa are probably the most important fac- flow, which are 90° out of phase. This part of tors contributing to ,1-3 impedance is determined by the elasticity and though hypocapnia may also contribute.' mass inertia of the airways, lung tissue, and Ventilation is increased in both hypocapnia, thorax and the inertia of the air within the when this is induced experimentally by volun- bronchi."1-'5 The variables measured in this tary hyperventilation, and hypercapnia, which study were (1) total respiratory resistance (Rrs) stimulates ventilation. The increase in ventila- at each frequency tested (4-8-12 .. . 52 Hz) Department of tion may obscure the effects of Pco2 on airway and the average value for all frequencies; (2) Pulmonary Diseases, University of resistance, by increasing respiratory heat loss total respiratory reactance (Xrs) at each Nijmegen, Medical or osmolarity changes. frequency tested and the average value for all Centre Dekkerswald, Acute and chronic airways obstruction in frequencies; (3) resonant frequency-that is, PO Box 9001, 6560 GB Groesbeek, The patients with or chronic obstructive the frequency at which the reactance is zero; (4) Netherlands lung diseases is often accompanied by frequency dependence of the resistance, F JJ van den Elshout hyperventilation."'0 It is still uncertain defined in this study as the ratio (Rrs 12 Hz- C L A van Herwaarden H Th M Folgering whether patients with bronchial hyperrespon- Rrs 52 Hz)/Rrs 52 Hz. siveness to histamine are also hyperresponsive The Oscillaire apparatus was connected to a Reprint requests to: Dr van den Elshout to hypocapnia and hypercapnia. wet spirometer (Pulmotest, Godart, De Bitt, Accepted 11 October 1990 The aim of the present study was to inves- Utrecht, Holland) to form a closed respiratory Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects 29

histamine causing a decrease in the forced expiratory volume in one second (FEVI) of 20% or more was less than 8 mg/ml'6). The characteristics of the subjects are shown in

table 1. Thorax: first published as 10.1136/thx.46.1.28 on 1 January 1991. Downloaded from The patients used inhaled medication only (beta agonist or corticosteroids or both) and this was discontinued at least eight hours before testing. Patients who had had a res- piratory in the past six weeks were excluded. The study was approved by the local ethical committee and informed consent was obtained from all subjects.

PROCEDURE To establish whether connecting the side tube for C02 sampling spirometer to the Oscillaire changed the capnograph measurements, impedance was measured with Figure 1 Oscillatory resistance apparatus connected to a wet spirometer toform a the Oscillaire alone in 15 subjects (seven heal- closed respiratory circuit to which was supplied and in which carbon dioxide could be absorbed. thy subjects and eight patients) and, a few minutes later, with the Oscillaire connected to the wet spirometer circuit. In a further 10 circuit to which oxygen was added. Carbon subjects (five healthy subjects and five dioxide could be absorbed as desired by par- patients) the humidity of the air in the tially or totally short circuiting the carbon spirometer circuit was measured continuously dioxide absorber. End tidal Pco2 was measured during the whole procedure. continuously with a rapid infrared analyser All subjects and patients were studied in (Jaeger,Wurzburg, Germany), the sampled air three different conditions: (1) normocapnic (all being returned to the closed spirometer circuit. carbon dioxide was absorbed in the closed End tidal Pco2 was controlled by changing the circuit); (2) hypercapnic (with the carbon di- fraction ofinspiratory air, bypassing the carbon oxide absorber partially shortcircuited); (3) dioxide absorber (fig 1). The air in the res- hypocapnic (the subjects breathing quietly piratory circuit was kept in the BTPS condi- immediately after one minute of voluntary tion. The temperature was maintained at 37°C hyperventilation). by a heating element and water saturation ofair

at 90% or more. DATA ANALYSIS http://thorax.bmj.com/ The subjects had their cheeks and submental The data from three adequate measurements muscles supported and they wore a clip were averaged for each of the three conditions during the impedance measurements. (hypocapnia, normocapnia, and hypercapnia). The average values ofRrs and Xrs calculated at SUBJECTS intervals of 4 Hz in the range 4-52 Hz were Forty five subjects were studied: 15 healthy plotted against the frequency at which they subjects and 30 patients with a history of were measured.'2 '3 The changes in impedance data from normocapnic (A) to hypercapnic and asthma and bronchial hyperresponsiveness to on October 1, 2021 by guest. Protected copyright. histamine (the provocative of hypocapnic conditions (B) were calculated for each individual as [(A-B)/(A)] x 100%. For statistical analysis Wilcoxon's test for paired Table 1 Characteristics of the subjects (mean (SEM) values unless otherwise observations was used. The differences be- specified) tween the two groups were tested with the Mann-Whitney U test. Normal Asthmatic

Age (y) 28-0 (0 98) 31-7 (1-6) Sex (F:M) 5:10 12:18 Results FEV, (% pred") 107-2 (3-4) 85-5 (3-1) PRELIMINARY STUDIES MEF,0 (% pred34) 95-6 (4 5) 52-4 (3 7) Rrs (cm H2O/l/s) There were no significant differences between At 8 Hz 2-44 (0-14) 4-55 (0-33) the results obtained with the Oscillaire alone (I) At 52 Hz 2 94 (0-19) 4-09 (0-17) and those obtained with the Oscillaire connec- of Average frequencies tested 265 (015) 4-01 (0-19) ted with the wet spirometer circuit (II). The Xrs, average (cm H2O/l/s) 0-89 (0-07) 087 (0-17) Resonant frequency (Hz) 7-46 (0 39) 16-4 (1-65) data measured with I and II were compared by Frequency dependence of the resistance* +0 19 (0-02) -0-01 (0-04) means of a two way linear regression analysis ( test with 18 allergens: No of subjects) and analysis of variance. The coefficient of Any positive result 0 27 Negative results 15 3 correlation ranged from 0-94 to 0-98, with a Medication (No of subjects) slope of 0 95 to 1 03, an intercept of -0-03 to Inhaled beta agonist 0 26 +0 05 (p < 0-0001). The SE to the regression Inhaled 0 15 PC20 (mg histamine/ml, geometric mean value) >8 0-44 line varied from 0-02 to 0-06 (2-7%). The relative humidity of the circulating air *A negative slope means a decrease in Rrs with increasing oscillatory frequency. was above 90% within two minutes in the five FEV,-forced expiratory volume in one second; MEF,6-maximal expiratory flow at 50% of forced ; PC,0-concentration of histamine causing a 20% fall in FEV16; RrEs- healthy subjects and five patients when they oscillatory resistance; Xrs-reactance. Conversion to SI units: 1 cm H,O/l/s; 0-1 kPa. were breathing in the closed respiratory circuit. 30 van den Elshout, van Herwaarden, Folgering

Table 2 Mean (SEM) values and changes in end tidal carbon dioxide tension (Pco2, hyperventilation, at a time when end tidal Pco2 kPa) in normocapnic, hypocapnic, and hypercapnic conditions in the two groups of was still low. No significant change in FRC was subjects observed during hypercapnia in either group. Normal Asthmatic The normal subjects had a higher resting end

tidal Pco2 (5 3 kPa) than the asthmatic subjects Thorax: first published as 10.1136/thx.46.1.28 on 1 January 1991. Downloaded from Pco2 APco2 Pco2 APcq2 (5-3 v 4-8 kPa, p < 0 05: table 2). Mean end tidal Pco2 fell by about 1 kPa during hyperven- Normocapnia 5-3 (0-18) 4-8 (0-11)* Hypercapnia 6-4 (0-23) + 11 (0-08) 5 9 (0-13) + 10 (0-07) tilation and rose by about 1 kPa during Hypocapnia 4-2 (0-19) -1-1 (0-14) 3-8 (0-11) -1-0 (0 08) rebreathing (table 2). Neither the changes nor the final end tidal Pco2 values differed sig- *Significant difference between normal and asthmatic subjects: p < 005 (Mann-Whitney U test). nificantly between the two groups. In the control group all the resistance values fell during hypercapnia (fig 2a, table 3). The All further measurements were therefore other impedance results did not change sig- taken after at least two minutes' closed circuit nificantly during hypercapnia or hypocapnia breathing. (figs 2a and 2b, table 3). In the patients hypercapnia also caused a HYPERCAPNIC AND HYPOCAPNIC STUDIES significant decrease in resistance measured at During voluntary hyperventilation there was a 4-20 Hz (fig 2c). The increase in reactance mean (SEM) increase in functional residual (table 3) and the changes in the other capacity (FRC) of 0-5 (0 03) 1 in the healthy impedance data (resonant frequency and subjects and patients, and this disappeared frequency dependence of resistance) were not within two to three breaths of stopping significant. Hypocapnia induced an increase in

Rrs (cm H2O/l/s) Rrs 4 1 (cm H2O/l/s)

6

3- *

5. http://thorax.bmj.com/

2 Z I I I I 4 12 20 28 36 44 52 (a) Oscillatory frequency (Hz)

Xrs on October 1, 2021 by guest. Protected copyright. (cm H20/l/s) 3 3

4 12 20 28 36 44 52 2 (c) Oscillatory frequency (Hz) Xrs 1 - (cm H20/l/s)

0 -

2 - 1 -

1 - 2 -

...... 4 12 20 28 36 44 52 0 (b) Oscillatory frequency (Hz) -1 Figure 2 Mean (SEM) valuesfor respiratory resistance (Rrs) and reactance (Xrs) plotted against oscillatory frequencyfor the controlgroup (a and b) and -2 for patients with asthma (c and d) in normocapnic (*), hypercapnic ( A ), and hypocapnic conditions ( ). **p < 001, *p < 005 in the comparison with 4 12 20 28 36 44 52 normocapnic condition (Wilcoxon's rank sum test). Conversion to SI units: 1 cm H20 = - 0-1 kPa. (d) Oscillatory frequency (Hz) Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects 31

Table 3 Mean (SEM) changes in resistance measured at 8 Hz (Rrs 8) and mean reactance values at all frequencies and the reactance for allfrequencies (Xrs(av) ) in asthmatic patients and normal subjects during average value confirmed the presence of hypercapnia and hypocapnia increased airway obstruction.'4 The frequency Hypercapnia Hypocapnia dependence of resistance (a decrease in resis-

tance with increasing frequency) is thought Thorax: first published as 10.1136/thx.46.1.28 on 1 January 1991. Downloaded from Normal Asthmatic Normal Asthmatic to indicate peripheral airway obstruction.29 Frequency dependence was enhanced in our Rrs8 - 14-6% (4-8)*** -9 3% (2.8)*** -1-7% (6 7) + 13-2% (4-2)*** -13-3% +0-3% -45-5% patients, which suggests that hypocapnia Xrs (av) (7O0) +21-3% (8-6) (15-8) (22-1)** causes peripheral airway narrowing in patients Significance according to Wilcoxon's test: ***p < 0-01; **p < 0-02, in the comparison with the with asthma. normocapnic condition. Hypocapnia, achieved by hyperventilation or by occlusion of the pulmonary , may resistance at 4-12 Hz (fig 2c), a decrease in cause bronchoconstriction by vagal reflex path- reactance values at all frequencies and in the ways or by a direct effect on bronchial smooth average value for all frequencies (fig 2d, table muscle. Hypocapnia caused increased activity 3), and an increase in the frequency depen- of both the slowly adapting stretch receptors dence of resistance (mean (SEM) 240-3% and the irritant receptors in anaesthetised dogs, (59-9%); Wilcoxon's p < 0-01). The mean and airway calibre consequently decreased. increase in the resonant frequency (28-9% These effects were reversed by the administra- (16-8%)) was not significant. The increase in tion of carbon dioxide, which resulted in reflex resistance at 4-12 Hz and the decrease in all bronchodilation.0 3' Several investigators have reactance values during hypocapnia differed shown that carbon dioxide tension in the air- significantly between normal and asthmatic way rather than in tissue or was the subjects (p < 0-02, Mann-Whitney U test). stimulus.3' 32 In dogs a decrease in end tidal Pco2 of nearly 2 kPa after pulmonary arterial occlusion caused Discussion an increase in resistance of about 20% and fall By using this circuit respiratory impedance can in compliance of 18%. Vagotomy diminished be measured while the subject breathes from a the increase in resistance but did not affect the spirometer, as we observed previously.'7 fall in compliance, which suggests a direct Change in functional residual capacity and effect.3' These results are in can be observed directly. keeping with our finding of an increase in Functional residual capacity is often increased resistance of 13% due to a fall in Pco2 of 1 kPa. in an attack of asthma.'8 In this study all We conclude that hypercapnia decreases impedance data were obtained at the same measured by the forced FRC, so no correction was made for lung oscillation technique in both healthy and asth- volume. matic individuals. Hypocapnia appeared to The air in the circuit was kept in the BTPS increase both central and peripheral airway http://thorax.bmj.com/ condition to exclude possible effects due to resistance in the asthmatic patients but not in water or heat loss from the airway mucosa. This the healthy subjects. These results suggest that probably explains why the changes during our an enhanced response to hypocapnia (and hyperventilation studies were smaller than hypercapnia) is a component of bronchial those in previous studies, in which the subjects hyperresponsiveness in asthmatic patients. breathed room air or cold air.920 Hypocapnia, which occurs in an early stage of Hypercapnia caused a decrease in airway an asthmatic attack as a result of hyperven- resistance in both groups, the changes at 4- tilation,'°33 is an additional stimulus for on October 1, 2021 by guest. Protected copyright. 20 Hz being statistically significant in the bronchoconstriction, independent of drying patients. This is in accordance with the results and cooling of the airways. of previous studies, where measurements of resistance of 6 or 8 Hz have been the most The authors gratefully acknowledge the financial support of Glaxo BV, The Netherlands, and the valuable advice of Dr F sensitive and reproducible indices of change in Landser, Leuven, Belgium, and Dr J W Lammers, Nijmegen, airway diameter in bronchial challenge tests or The Netherlands. in chronic airways obstruction.'421 22 The cen- tral of the medulla are thought to play a part in the reflex constriction and 1 Hahn A, Anderson SD, Morton AR, Black JL, Fitch KD. A reinterpretation of the effect of temperature and water relaxation of the airways.23 Reported direct content ofthe inspired air in exercise-induced asthma. Am effects of hypercapnia on airway calibre have Rev Respir Dis 1984;130:575-9. been contradictory, increased 25 2 Kilham J, Tooley M, Silverman M. Runnning, walking and resistance,24 hyperventilation causing asthma in children. Thorax decreased resistance,26 and no effecte7 all hav- 1979;34:582-6. ing been described. Hypercapnia possibly 3 Deal CE Jr, McFadden ER Jr, Ingram RH Jr, Jaegher JJ. and heat flux: initial reaction sequence in decreases bronchial muscle contractility exercise induced asthma. J Appl Physiol: Respirat Environ directly. Hypercapnic has been found Physiol 1979;46:476-83. to cause a reduction in bronchial (but not 4 Newhouse MT, Becklake MR, Macklem PT, McGregor M. Effect of alterations in end tidal CO, tension on flow tracheal) muscle contractility in the isolated resistance. J Appl Physiol 1964;19:745-9. of the dog."8 5 Sterling GM. The mechanism ofbronchoconstriction due to hypocapnia in man. Clin Sci 1968;34:277-85. A reduction in end tidal Pco2 of 1 kPa by 6 Cutillo A, Omboni E, Perondi R, Tana F. Effect of voluntary hyperventilation caused no sig- hypocapnia on pulmonary mechanics in normal subjects nificant changes in impedance in the control and in patients with chronic . Am Rev Respir Dis 1974;110:25-33. group. In the asthmatic subjects resistance at 7 Oliven A, Chemiack NS, Deal CE, Kelsen SB. The effects 4-12 Hz rose. The concomitant decrease in the of acute bronchoconstriction on respiratory activity in 32 van den Elshout, van Herwaarden, Folgering

patients with chronic obstructive pulmonary disease. Am J Respir Dis 1987;70:102-9. Rev Respir Dis 1985;131:236-41. 21 Duiverman EJ, Neijens HJ, Van der Snee-Van Smaelen M, 8 Loveridge B, West P, Anthonissen NR, Krijger MH. Kerrebijn KF. Comparison of forced oscillometric and Breathing patterns in patients with chronic obstructive forced expirations for measuring dose-related responses to pulmonary disease. Am Rev Respir Dis 1984;130:730-3. inhaled methacholine in asthmatic children. Bull Eur 9 Lavietes MH. Ventilatory control in asthma. Clin Chest Med Physiopathol Respir 1986;22:433-6. 1984;4:607-17. 22 Van Noord JA, Clement J, Van de Woestijne KP, Demedts Thorax: first published as 10.1136/thx.46.1.28 on 1 January 1991. Downloaded from 10 Kesten S, Reza Malecki-Yazdi M, Sanders BR, et al. M. Total respiratory resistance and reactance as a during acute asthma. Chest 1990;97: measurement of response to bronchial challenge with 58-62. histamine. Am Rev Respir Dis 1989;139:921-6. 11 Orchek J, Nicoli MM, Delpierre S, Beaupre A. Influence of 23 Deal CE Jr, Haxihiu MA, Norcia MP, Mitra J, Cherniack the previous deep inspiration on the sphirometric NS. Influence of the ventral surface of the medulla on measurement of proyoked bronchoconstriction in asthma. trachael responses to CO,. J Appl Physiol 1986;61:1091-7. Am Rev Respir Dis 1981;123:269-72. 24 Sly PD, Bates JHT, Kochi T, Okubo S, Milic-Emili J. 12 Landser FJ, Nagels J, Demedts M, Billiet L, Van de Frequency-dependent effects of hypercapnia on res- Woestijne KP. A new method to determine frequency piratory mechanics of cats. J Appl Physiol 1987;62: characteristics of the respiratory system. J Appl Physiol 444-50. 1976;41: 101-6. 25 Green M, Widdicombe JG. The effects ofventilation ofdogs 13 Landser FJ, Polko AH, Visser BF. Oscillatory measurement with different mixtures on airway calibre and lung of total repiratory impedance with extended spectrum up mechanics. J Physiol Lond 1966;186:363-8 1. to 52 Hz. Arch Internat Physiol Biochem 1983;91:12. 26 Delpierre S, Jammes Y, Mei N, Mathiot MJ, Grimaud C. 14 Clement J, Landser FJ, Van de Woestijne KP. Total Mise en evidence de l'origine vagale reflexe des effets resistance and reactance in patients with respiratory bronchoconstricteurs du CO2 chez le chat. J Physiol Paris complaints with and without airways obstruction. Chest 1980;76:889-9 1. 1 983;83:2 15-20. 27 Butler J, Caro CG, Alcala R, Dubois AB. Physiological 15 Solymar L, Landser FJ, Duiverman E. Measurement of factors affecting airway resistance in normal subjects and resistance with the forced oscillation technique. Eur Respir in patients with obstructive . J Clin J 1989;2(suppl 4):150-3S. Invest 1960;39:584-91. 16 Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE. 28 Stephens NL, Meyers JL, Cherniack RM. Oxygen, carbon Bronchial reactivity to inhaled histamine: a method and dioxide, H+ ion, and bronchial length-tension relation- clinical survey. Clin Allergy 1977;7:235-43. . J Appl Physiol 1968;25:376-83. 17 Van den Elshout FJJ, Van de Woestijne KP, Folgering 29 Kjeldgaard JM, Hyde RW, Speers DM, Reichert WW. HThM. Variations of respiratory impedance with lung Frequency dependence of total respiratory resistance in volume in bronchial hyperreactivity. Chest 1990;98: early airway disease. Am Rev Respir Dis 1976;114:501-8. 358-64. 30 Coleridge HM, Coleridge JCG, Banzett RB. Effect of CO2 18 Flenley DC. Physiological and pharmacological control of on afferent vagal endings in the canine lung. Respir Physiol the respiratory drive in asthma. In: Kay AB, Austen KF, 1978;34: 135-5 1. Lichtenstein LM, eds Asthma. London: Academic Press, 31 Ingram RH Jr. Effects of airway versus arterial CO2 changes 1984:375-90. on lung mechanics in dogs. J Appl Physiol 1975;38:603-7. 19 Decramer M, Demedts M, Van de Woestijne KP. Isocapnic 32 Luijendijk SCM. Within-breath PCO2 levels in the airways hyperventilation with cold air in healthy non-smokers, and at the pulmonary stretch receptor sites. J Appl Physiol smokers and asthmatic subjects. Bull Eur Physiopathol 1983;55:1333-40. Respir 1984;20:237-43. 33 McFadden ER Jr, Lyons HA. gas tension in 20 Dejaegher Ph, Rochette F, Clarysse I, Demedts M. asthma. N Engl J Med 1968;278:1027-32. Hypocapnic hyperventilation versus isocapnic hyperven- 34 Quanjer Ph H. Standardized lung function testing. Bull Eur tilation with ambient air or with dry air in asthmatics. Eur Physiopathol Respir 1983;19(suppl 5):1-92. http://thorax.bmj.com/ on October 1, 2021 by guest. Protected copyright.