Site of Airway Obstruction in Asthma As Determined by Measuring Maximal Expiratory Flow Breathing Air and a Helium- Oxygen Mixture

Home , Airway obstruction, Elastic recoil

Site of Airway Obstruction in Asthma as Determined by Measuring Maximal Expiratory Flow Breathing Air and a Helium- Oxygen Mixture

P. J. Despas, … , M. Leroux, P. T. Macklem

J Clin Invest. 1972;51(12):3235-3243. https://doi.org/10.1172/JCI107150.

Research Article

Because maximum expiratory flow-volume rates in normal subjects are dependent on gas density, the resistance between alveoli and the point at which dynamic compression begins (Rus) is mostly due to convective acceleration and turbulence. We measured maximum expiratory flow-volume (MEFV) curves in asthmatics and chronic bronchitics breathing air and He-O2. In the latter and in some asthmatics, MEFV curves did not change, indicating that Rus is mostly due to laminar flow. Therefore, the point at which dynamic compression begins must be further upstream than in normal subjects and the site of obstruction must be in small airways. In other asthmatics, flow increased normally indicating obstruction in larger airways. The response to He-O2 did not correlate with initial values of pulmonary resistance, the initial MEFV curves or the response to bronchodilators. We conclude that the site of airway obstruction varies among asthmatics and that the site of obstruction is not detectable by measurement of the usual parameters of lung mechanics.

Find the latest version: https://jci.me/107150/pdf Site of Airway Obstruction in Asthma as Determined by Measuring Maximal Expiratory Flow Breathing Air and a Helium-Oxygen Mixture

P. J. DESPAS, M. LERoux, and P. T. MACKILEM From the Respiratory Division, Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Canada

A B S T R A C T Because maximum expiratory flow-vol- may be a simple way of defining the site of airway ob- ume rates in normal subjects are dependent on gas den- struction in asthmatics. According to Mead maximum sity. the resistance between alveoli and the point at which expiratory flow rate at a particular lung volume is deter- dynamic compression begins (R..) is mostly due to con- mined by the elastic recoil pressure of the lung at that vective acceleration and turbulence. We measured maxi- volume and the resistance of the airways between the mum expiratory flow-volume (MEFV) curves in asth- alveoli and the points where the lateral intraluminal matics and chronic bronchitics breathing air and He-02. pressure equals pleural pressure (equal pressure points, In the latter and in some asthmatics, MEFV curves did EPP). This resistance is defined as the upstream re- not change, indicating that Ru. is mostly due to laminar sistance (Ru.) (8). If EPP are in large airways most flow. Therefore, the point at which dvnamic compression of Ru. will be due to convective acceleration and turbu- begins must be further upstream than in normal subjects lence. Because pressure losses due to both of these are and the site of obstruction must be in small airways. In dependent on gas density, changes in gas density will other asthmatics, flow increased normally indicating ob- alter Ru. and thus maximum expiratory flow. This is struction in larger airways. The response to He-02 did the case in normal subjects: EPP are in large airways not correlate with initial values of pulmonary resistance, at lung volumes above 40% vital capacity (VC) (9) the initial MEFV curves or the response to bronchodi- and maximum expiratory flow rates over these lung vol- lators. We conclude that the site of airway obstruction umes are density dependent (10-12). In the presence of varies among asthmatics and that the site of obstruction airway obstruction in small airways, EPP will be fur- is not detectable by measurement of the usual parameters ther upstream (toward the alveoli) than in normal sub- of lung mechanics. jects and maximum expiratory flow will be less density dependent than normal to the extent that the resistance to laminar flow (which is independent of gas density) INTRODUCTION makes up a greater portion of the total resistance up- The site of airway obstruction in most patients with stream from EPP. Obstruction in larger airways might chronic obstructive lung disease is in airways less than have a lesser influence on the normal response to a 2-3 mm in diameter (1). Less is known about the site change in gas density. of airway obstruction in asthmatics. Bronchography in- Previous studies in patients with airway obstruction dicates that central airways may be constricted (2-4) reveal a marked variation in the changes in dynamic during an acute attack, while in remission there is evi- lung function that occur when gas density is altered dence that considerable obstruction may affect peripheral (13-16). The variation is not obviously related to the airways ( a5-7). residual capacity; MEFV, maximum expiratory flow-volume; Examination of the effects of altered gas density on Pca, pressure drop due to convective acceleration; P.t (1), the maximum expiratory flow-volume (MEFV)' curve elastic recoil pressure of the lung; Rca, resistance due to convective acceleration; Rfr, frictional resistance to airflow; Received for puiblicationt 2 March 1972 autd int revised RL, pulmonary resistance; Ru., upstream resistance; RV, form 8 August 1972. residual volume; TLC, total lung capacity; VC, vital ca- 1 Abbreviatiouis used int this paper: Aeppy cross-sectional pacity; Vmax5o, maximum expiratory flow at 50% vital ca- area at EPP; EPP, equal pressure points; FRC, functional pacity. The Journal of Clinical Investigation Volume 51 December 1972 3235 TABLE I Physical Characteristics and Lung Function of Patients Studied

RL cm H20/liters per sec Before After broncho- broncho- Subject Age Sex Height VC FRC RV TLC dilator dilator yr cm % predicted$ Asthma responders Bou 38 M 154 85 148 193 117 7.5 4.0 101 126 150 117 6.5 5.0 Mar 35 M 172 83 156 219 119 10.0 4.8 Hec 43 F 167 100 110 139 111 8.0 5.0 Kru 29 M 175 84 108 132 95 12.0 3.0 100 3.8 Pre 54 F 163 91 100 113 100 5.5 3.8 92 120 153 112 2.3 Lew 23 F 161 100 122 128 112 1.9 1.5 Sis 32 .i 170 75 126 170 100 5.5 2.0 77 137 189 108 3.8 1.7 77 163 252 120 9.8 3.8 Ste 28 .4 168 87 90 59 99 3.0 1.5 McC 50 F 165 63 186 260 128 15.0 7.5 103 - - 6.3 3.7 Hen 15 .4 160 91 109 101 99 2.8 2.7 Des 54 M 170 100 114 131 111 6.0 4.0 Sal 25 M 165 86 90 123 103 5.0 1.8 Asthma Nonrresponders Jac 45 .I 170 88 166 220 131 4.1 2.5 Bro 24 M 170 69 163 252 117 12.0 4.5 Ioi 35 M 170 100 86 102 97 2.3 2.0 His 67 M 170 86 105 122 106 4.8 2.8 Has 28 M 162 95 93 101 100 5.0 107 110 107 107 2.0 Dum 50 F 163 65 211 330 160 9.5 4.0 Hol 59 F 165 78 169 213 129 5.5 4.0 Cup 30 lvI 177 99 136 180 121 6.0 4.0 110 118 120 124 4.7 3.0 Dal 46 MI 173 86 117 143 106 5.0 3.0 Alt 45 'vI 178 91 111 128 103 6.0 4.0 Eva 44 F 158 75 178 242 250 7.0 3.8 Bar 35 M 162 100 125 242 139 4.3 2.0 O'K 60 Xi 167 100 185 224 149 12.0 5.5 137 170 177 150 3.5 2.6 Irreversible airway obstruction * 63.4 166 67 136 180 110 5.80 Normal * 29.7 175 102 101 92 104 1.9 VC, vital capacity; FRC, functional residual capacity; TLC, total lung capacity; RV, residual volume; RL, pulmonary resistance. * Mean values. I Predicted values from Bates, 'Macklem, and Christie (25). severity of the airway obstruction or to the type of ob- minant of the effects of gas density on dynamic lung structive lung disease. Barnett (17) suggested that the function. The laws of aerodynamics as they apply to the site of airway obstruction may be an important deter- airways support this suggestion and he showed that with 3236 P. J. Despas, M. Leroux, and P. T. Mackilem tracheal obstruction, pulmonary resistance was density measured again. Breathing helium oxygen does not influence dependent but when obstruction was in peripheral air- the static pressure volume curves of the lung (13), so that the vital capacity was unchanged in any subject. Further- ways the resistance was not density dependent (17). more no changes in FRC were detected. The curves were Stimulated by Barnett's observations, we have stud- stored and traced with an oscillotracer (R. A. Waters Co., ied the effects of 20% oxygen in helium on the MEFV Waltham, Mass.). Pressure, flow, and volume were also curves and pulmonary resistance (RL) in asthmatics. recorded on a four-channel direct writing Sanborn recorder. were those obtained The body plethysmograph was pressure compensated and These effects compared with in nor- had a frequency response adequate to 8 counts/sec. It was mal subjects and in patients with irreversible airways calibrated with a calibrating syringe of 500 ml capacity for obstruction. The mixture's density is only 36% that of large volume recordings and with a 50 ml syringe for air but it is 12% more viscous. small volume recordings. The pressure transducers were calibrated with water manometers. The pneumotachograph was calibrated for air and for the He-02 by passing the METHODS gases through the pneumotachograph which was coupled by 2 inch diameter smooth bore tubing to a 120 liter Tissot We studied 25 asthmatics with significant reversible air- spirometer. The pneumotachograph resistance was linear way obstruction who had been repeatedly studied in the for both gases up to flow rates of 6 liters/sec. routine laboratory. Most were symptomatic when we studied them and had a significant reduction in pulmonary resistance immediately following a bronchodilator aerosol RESULTS (Table I). We also studied seven patients with irreversible airway obstruction. They had chronic bronchitis and dyspnea Results obtained in the lung function tests for the three and showed little change in the degree of airway obstruc- groups of subjects are given in Table I. The asthmatics tion over several years. The control group were normal, were further subdivided into responders and nonre- nonsmoking subj ects and included medical and laboratory staff. sponders according to their change in maximum expira- While the subjects were breathing air we measured the tory flow when they breathed He-02 (see below). Mean subdivisions of lung volume, the static deflation pressure values only are reported for the normal subjects and volume curve of the lung, pulmonary resistance at functional those with irreversible airway obstruction. Among asth- residual capacity (FRC), and the maximal expiratory flow- matics RL was increased in all but one subject (Lew) volume curves. Change in lung volume was measured by a Krogh spirometer attached to the body plethysmograph. either at the initial study or at a subsequent study. RL Absolute lung volume was obtained by the gas compression was markedly increased in several subjects. technique based on Boyle's law (18). The static deflation MEFV curves. There was a substantial increase in pressure volume curve of the lung was obtained by plotting maximum expiratory flow rates in all normal subjects transpulmonary pressure (as assessed by the difference between mouth and esophageal pressure) during 1-2-sec peri- breathing He-G2 compared with the curves obtained when ods of zero-airflow, against lung volume on deflation to they were breathing air. The increase was in good agree- residual volume (RV) after a full inspiration to total lung ment with the data of Wood and Bryan (10). Only one capacity (TLC). Esophageal pressure was measured by an patient with irreversible airway obstruction increased his esophageal balloon catheter (balloon length 10 cm, circum- maximum expiratory flow rates. The others demonstrated ference 3.5 cm, volume 0.5 ml of air, catheter PE 200 tubing 60 cm long) coupled to a Sanborn 267B differential no change. The asthmatic subjects fell into two groups. pressure transducer (Sanborn Div., Hewlett-Packard Co., In twelve there was an increase in maximum expiratory Waltham, Mass.), the other side of which was connected flow rates comparable to the increase observed in normal via a catheter to the mouthpiece. Pulmonary resistance dur- subjects. In 13 there was little or no increase in mnaxi- ing inspiration (RL) was taken as the ratio of the component of transpulmonary pressure in phase with inspiratory mum expiratory flow, the response to He-O2 being simi- flow to flow during tidal breathing. Flow was measured by lar to that observed in irreversible airway obstruction. a Fleisch pneumotachograph coupled to a Sanborn 270 dif- Representative MEFV curves from each group are ferential pressure transducer. The component of transpul- shown in Fig. 1. Those asthmatics in whom maximum monary pressure in phase with flow was measured by sub- expiratory flow at 50% vital capacity tracting from transpulmonary pressure a signal proportional (Vmax5o) increased to lung volume, so that the pressure flow loop, as displayed less than 20% in He-Oa were classified as nonresponders on the x-y coordinates of a long persistence display oscillo- and those in whom \mao increased by more than 20% scope, became a line (19). The slope of this line as it passed were classified as responders. In normal subjects Vrnaxno through zero flow was read directly by a rotatable overlying increased by a mean value of 48%+11.7 in pa- grid and gave us inspiratory pulmonary resistance. The (SEM); MEFV curves were obtained by displaying flow against tients with irreversible airway obstruction 'i7maxwo increased volume on the x-y coordinates of a Tektronix 564 storage by a mean value of 13.0%+32.6 (sEM).The large stan- oscilloscope (Tektronix, Inc., Beaverton, Ore.) during dard error in this group is due to one subject who in- forced expiration from TLC to RV. Each MEFV curve creased Vrno by 85%. The others ranged between + 12 was repeated several times and curves that were not highly reproducible were rejected. After completing these mea- and - 13%. In responders Vraxno increased by 53.5%+ surements the subject breathed a 20%o oxygen in helium 19.7 (SEM), and in nonresponders Vmxso increased by mixture for 10 min, when RL and MEFV curves were 1.5%±+5.25 (SEM). Among asthmatics there was no cor- Site of Airway Obstruction in Asthma 3237 73%+25.5 (sEM) of the air value; in nonresponders it was 90%±+22 (SEM). Although the change in pulmonary resistance with gas density was similar to the change in Vmrno when the groups were compared, there were several striking indi- 6- vidual exceptions to this within each group accounting 4- for the larger standard errors. There were three normal subjects in whom the RL when breathing He-O2 was Stw Irreversible Has Asthma greater than 90% of RL when breathing air but in whom E AiwA obstn ction Nonresponder lVmax5o increased by 35-61%. By contrast, among > 12 RL 5-1-5-5 RL 20-2-2 the 10 patients with irreversible airway obstruction there was one in whom RL when breathing He-O2 was only 68% 8 - of the RL when breathing air, 6- whereas Vmaxsm increased only 7% in 4- response to He-O2. These two patterns were reflected among the responders and nonresponders. 2 In the former group, there were three subjects in whom 0 20 40 60 80 0 20 40 60 80 100 there was either no change or a slight increase in RL PER CENT VC when breathing He-O but in whom Vmax,o increased FIGURE 1 Representative maximum expiratory flow-volume 34-80%. In the latter group, there were three subjects curves for the four groups of subjects. - - -- MEFV curves in whom RL on He-02 was 42, 67, and 73% of the value on air; MEFV curves on He-02; .. predicted MEFV curves on He-02 from the data of Wood and Bryan assuming that Vma. a (density) -0.5 (10). Values for pul- .--I monary resistance (RL) in cm H20/liters per sec breathing o 100 F air and breathing He-02 are given for each case. 0 x > 80 . relation between the change in Vmaxsm and the severity of the a 60 0 obstruction as assessed either by the initial values E F * 0 for Vmraxzo or for pulmonary resistance, RL (Figs. 2 and 0 3). '-40 I- a 0 Pulmonary resistance. In normal subjects breathing E He-O2, pulxnonary resistance fell to 77%±+ 17.9 (SEM) of 20 0 the value breathing air; in patients with irreversible air- E 0 o way obstruction these measurements were made in only 5 10 15 five of the seven subjects. In these subjects when breath- RL AIR (cmKH2/Jiters./sc) ing He-O2, the resistance was 100% of the value breathing air; in responders, pulmonary resistance fell to FIGURE 3 Per cent increase in Vmax5o induced by breathing He-02 (ordinate) plotted against the initial pulmonary resistance (R,.) breathing air (abscissa) in asthmatics.

0 V1001- 0 on breathing air but in whom there was no change in Vmaxso. Among asthmatics there was no correlation be- 801 0 tween the severity of the obstruction as assessed either 601 0 by the initial values of Vrnax.o or RL and the change in RL between air and He-02 4 and * 0 (Figs. 5). 0 S . Upstream resistance. By plotting maximum expiratory E<0 40! 0 flow against the static deflation elastic recoil pressure at 0 equal lung volumes, the pressure-flow curve for the air- 20F 0 ways upstream from EPP is obtained (8). From these EX curves the between volume and goess 0 a ., relationship lung Ru. may 1 2 3 4 5 be obtained. This is plotted in Fig. 6 for the responders VmaX AIR (liters/sec ) and the nonresponders. It appears that the shape of the Ru. vs. VC curve is different between responders and FIGURE 2 Per cent increase in maximum flow at 50% VC (Vmax5o) induced by breathing He-02 (ordinate) plotted nonresponders. In nine of the 12 responders, R.. de- against the initial Vmaxso breathing air (abscissa) in asth- creased as lung volume decreased over at least part of the matics. vital capacity range. The mean value for Ru. was essen-

3238 P. J. Despas, M. Leroux, and P. T. Macklem tially unchanged between 50% VC and the highest lung 1301 volune at which Ru. was recorded in each subject, as it * a Responders . 0 O changed only by + 0.008 cm H}O/liters per sec/per cent a Nonresponderso

VC. In only four of 11 nonresponders, Ru. decreased as x 0 oC 0 0 volume decreased over a part of the vital capacity. In all CK others R.. increased as volume decreased. In contrast to 0 0 the the mean R.. increased 5.5 cm 0 responders, by H20/ N\ 70 a liters per sec/per cent VC between the highest lung E S recorded and VC in each volume at which Ru. was 50% -i 0 subject. I 5 Three nonresponders and five responders were studied 5 10 15 on more than one occasion. Although the severity of their RL AIR (cmnH80/ liters /sec) asthma was substantially different during the different FIGURE 5 Pulmonary resistance breathing He-02 as a per- studies, the pattern of response was always the same in centage of that breathing air (ordinate) plotted against the that the responders remained responders and nonre- initial value of RL breathing air (abscissa) in asthmatics. sponders remained nonresponders (Fig. 7). As the asthmatics as a group were selected on the basis of demon- The nonresponders behaved similarly to patients with strable improvement in their obstruction resulting from irreversible airway obstruction when gas density was bronchodilator therapy, the responders and nonresponders altered. Neither maximum expiratory flow nor RL was much changed. In both nonresponders and patients with Responders - irreversible obstruction paradoxical responses occurred 130 Nonresponders o in which there was no increase in maximum expiratory 0 o S 0 0 flow, but there was a substantial reduction in RL. R.. x 110 0 0 tended to decrease at lung volumes above 50% VC in the * 0 0 00 nonresponders. 4 90 . The similarity between responders and normal sub- 0 jects on one hand and between nonresponders and pa- S0 o0 0 tients with airway E 0 irreversible obstruction on the other 70- 0 0 ._ 0 0 is circumstantial evidence that the mechanisms limiting 0 maximum expiratory flow were also similar between nor- 0 cr 50. mal subjects and responders and between patients with I 0 irreversible airways obstruction and nonresponders. 1 4 5 2 3 Maximum expiratory flow at any lung volume is equal VmaxSOVmx50 AIR Uliters/sec ) to the ratio of lung elastic recoil at that volume, to the FIGURE 4 Pulmonary resistance breathing He-Q2 as a per- resistance of airways upstream from equal pressure centage of that breathing air (ordinate) plotted against the points (8). This is expressed in the following relationship: initial value for Vma.. breathing air (abscissa) in asthmatics. Pst (1) Im = p axc RU6 could not be distinguished on this basis. Similarly, there did not appear to be any difference in the degree of wheezing between the two groups although this was RESPONDERS NONRESPONDERS specifically looked for.

DISCUSSION s 0 It is apparent that the responders behaved in a qualita- z tively similar way to normal subjects when gas density 0. was altered. Maximum expiratory flow rates increased and pulmonary resistance decreased. Furthermore, in both _. normals and responders there were the same paradoxical -o 40 W D00 40 60 80 100 responses in which increased maximal expiratory flow PER CENT VC rates were observed with little or no change in RL. Fi- FIGURE 6 Relationship between resistance upstream from nally, in both groups Ru. tends to increase at lung vol- equal pressure points (R..) and lung volume expressed as umes above 50% VC (8). per cent VC in responders and nonresponders.

Site of Airway Obstruction in Asthma 3239 creased VVmaxso by 53.5%, indicating that the laminar conm- ponent of R.8 was relatively small and that most of the resistance upstream from EPP was either due to convective acceleration or turbulence or both. 6 RL"5~ 12-0-*458 5-5-28 2-3-1-5 The lack of response to He-02 among the nonre- 4) sponders indicates that R.8 is not density dependent in 2 7- this group. Thus, neither turbulence nor convective Sis Sis Has Has acceleration, nor even the density-dependent formation 6 RL3-82 26 98-a48 50-o54 20--22 of parabolic velocity profile (20) contributes substan- 542 E tially to Ru.. Flow upstream from EPP must have been .>2 ~ - almost entirely fully developed laminar flow, in which Cidp O'K O'K for a given pressure drop, flow is inversely proportional 6 Ru. 6--4 4-7-.3*5 3*5--o3*5 12-0 -m"1 1-5 to viscosity and independent of density. If the total R.8 4- was composed of fully developed laminar flow we would 2 -- have expected to see a 12% fall in maximum expiratory C25 5075 25 50 75 25 50 75 25 5075 flow rates because of the higher viscosity of the He-O2 PER CENT VC mixture. This was not observed. Schilder, Roberts, and FIGURE 7 MEFV curves on separate occasions in eight Fry (11) observed a decrease in flow at very low lung asthmatics. ---- Breathing air; breathing He-02. volumes in normal subjects breathing He-02 as compared Values for RL breathing air and breathing He-02 are given in each case. with air. This may have been present in our normal subjects as well, but because we were particularly interested in the effects at higher lung volumnes we did not look for where Pat (1) is the elastic recoil pressure of the lung at it and thus lacked sensitivity to detect small changes at the particular lung volume. Because change in gas density low flow rates. On the other hand reference to 4 does not influence the static pressure-volume Figs. relationships and 5 reveals that four nonresponders and one responder of the lung, any change in VVmax must be due to a change increased RL by 10-20% breathing He-02, which is con- in R.8. When not Vmax. did change with gas density, Ru. sistent with pulmonary resistance must have been independent of being directly propor- density. tional to viscosity in these R.- is the sum of two subjects. components, the frictional re- The essential difference between the responders and sistance to airflow (Rfr) and the resistance due to con- the nonresponders then is a difference in the vective acceleration (Rca) between alveoli and components EPP. Rca of Rus. Rus in responders is similar to that in normal sub- is given by the following relationship: jects and at high lung volumes is principally made up of Pca _K-pVmax convective and turbulent components. In nonresponders Rca = - 2' Ru. is similar to that in subjects with irreversible airway Vmax 2g.Aepp2(1 obstruction and is principally due to fully developed where Pca is the pressure drop due to convective accelera. laminar flow. tion, K is a constant relating to the velocity profile, p is Do known differences in airway dynamics between gas density, g is the acceleration due to gravity, and Aepp normal subjects and patients with irreversible airway is the cross-sectional area at EPP. obstruction shed light on the cause of the differences be- Rearranging, tween responders and nonresponders? Because EPP are at the level of segrmental or lobar bronchi, in normal lungs where the cross-sectional area at equal pressure Vmaxvmx (2g- PcaV5 (2)2 KKp) 'Aepp points approximates to the trachea, Rca is the major component of Rus at high lung volumes (9, 21). The density- Thus if all other variables remain constant and Rea > > Rfr, dependent component of Rfr is presumably larger than it Vmax is proportional to p'-6. Rvr is the sum of a laminar would be if EPP were further upstream, because Ru. and turbulent component. If the turbulent component contains airways with higher Reynold's numbers in were much greater than the laminar component and which fully developed laminar flow would be the excep- Rfr > > Rca, then VVmna would be proportional to p'.4 (8). tion rather than the rule. This accounts for the density If both the turbulent component of Rfr and Rca con- dependence of maximum expiratory flow in normal sub- tributed substantially to R.8, V..a would be proportional jects (10, 12). to gas density to a power ranging between - 0.5 and In patients with chronic bronchitis and emphysema, - 0.43. This would result in an increase of 56-70% in there is obstruction in peripheral airways smaller than Vm.a on switching from air to He-02. The responders in- 2 mm diameter (1). This results in an upstream move- 3240 P. J. Despas, M. Leroux, and P. T. Macklem ment of EPP into airways where the total cross-sectional expiratory flow. During the measurements of RL the area at equal pressure points is presumably substantially subjects were breathing quietly. Resistance due to con- increased. Because Rca is inversely proportional to the vective acceleration is not a component of RL. Thus any square of this cross-sectional area and because V\ma is response to He-02 must have been due to density de- greatly reduced, one would predict that Rca would be- pendence of the frictional resistance of the airways. If come small (see equation 1). In order for the density- the frictional resistance was principally due to laminar dependent component of Rfr to become small as well it flow, very little density dependence would be apparent. would seem likely that the upstream motion of EPP During forced expirations, however, Rca does contribute would have to be quite considerable indeed, but one can- to Rus and is directly proportional to density (equation not state exactly how far. Thus, in order to account for 1). The paradoxical finding that Vra30o increased while density independence of maximum flow it is necessary to RL remained unchanged may be explained if Rea was a postulate peripheral airway obstruction with EPP situ- major component of Rus but in the absence of dynamic ated where the total cross-sectional area at EPP is large compression during the measurement of RL (to which Rez and the flow upstream is laminar and fully developed. does not contribute) flow was essentially laminar through The upstream displacement of EPP is consistent with those airways with the highest resistance. If this were the what is known about airway dynamics in irreversible case it seems likely that the cross-sectional area at the airway obstruction (22). site of EPP, where the transmural pressure across these We suggest that the nonresponders were similar to airways is presumably close to zero, would have to be the patients with irreversible airway obstruction and that substantially less than it is during quiet breathing when EPP were in airways where the total cross-sectional these airways are distended. This might well be con- area was large and the flow upstream laminar. We sug- sistent with an increase in bronchomotor tone at this site. gest that this was due to obstruction in small airways. The other paradoxical response (a decrease in RL with- The responders had a similar degree of airway ob- out substantial change in Vma3cso) also requires explana- struction as assessed by RL and Vrnas5o. In spite of this, tion. An increase in the tone of large airways makes we suggest that the site of obstruction was different and them less compressible but increases their resistance to was located in larger airways so that EPP did not move airflow (23). During quiet breathing at a given flow so far upstream, with the result that the cross-section at rate, this would increase the Reynold's numbers, and the EPP was sufficiently small so that Rca was a large com- degree of turbulence within them, which would render ponent of R.8 or the flow upstream was turbulent or both. the frictional resistance more density dependent. Be- Our data do not permit us to determine the exact location cause they are less compressible, however, EPP would of EPP, but if Rca were substantial there may well have move further upstream so that Ru. would not contain the been bronchoconstriction at the site of EPP. We return frictional resistance of these airways. Thus, the para- to this point later. doxical change in RL without much change in Vmax,a If these considerations are correct, the site of ob- would be explained if EPP were located upstream from struction in asthma is different in different individuals, narrowed airways whose frictional resistance was den- being located in small airways in some and in larger air- sity dependent and contributed substantially to RL but not ways in others. Because responders do not appear to be- at all to RU.. come nonresponders and vice versa, it appears likely that A curious finding among most responders, similar to the site remains fixed in any given asthmatic although a that in normal subjects was, that Rus increased as lung more prolonged longitudinal study would be necessary volume increased above 50% VC (Fig. 6). In normal to make this statement unequivocally. subjects this has been attributed to changes in Rca with Our conclusions are consistent with the experimental lung volume. As volume decreases, EPP move upstream evidence published by Barnett (17). He found that the so that the cross-sectional area at EPP increases. Fur- resistance produced by obstruction in a large airway thermore, as volume decreases V..a. decreases. Both of (the trachea) was decreased when He-02 was breathed these will result in a decrease in Rca as volume decreases compared with air, whereas when the obstruction was (equation 1). If a similar mechanism were operating in more peripheral, induced by histamine, the resistance was the responders to account for the change in Ru. with vol- essentially independent of gas density. Vagal stimulation ume, the contribution of Rca to Ru. would have to be produced an intermediate response. large. Because Vmax was markedly reduced, the cross- How can our conclusions and Barnett's observations section at EPP would also have to be reduced in order be reconciled with the paradoxical responses that we ob- for Rca to be large. Mead, Turner, Macklem, and Little served? Among the responders and the normal subjects plotted Vmar against Pat(l) at the same lung volumes to there were individuals in whom RL did not change, but obtain pressure-flow curve of the airways upstream from in whom there were substantial increases in maximal EPP. They also plotted isopleths of Rca using different Site of Airway Obstruction in Asthma 3241 reason we favor the explanation that the cross-sectional area at EPP in asthmatics who respond to He-O0, is substantially smaller than the trachea, that this reduction is due to bronchospasm and that it results in a resistance to convective acceleration that is a major component of the upstream resistance even though flow rates are mark- edlv reduced.

ACKNOWLEDGMENTS This work was supported by a grant from the Medical Re- IV5~~~~~~~~ search Council of Canada. REFERENCES TRANSPULMONARY PRESSURE (cm H20) 1. Hogg, J. C., P. T. Macklem, and W. M. Thurlbeck. FIGURE 8 Relationship between V1ax and static elastic recoil 1968. Site and nature of airway obstruction in chronic pressure breathing air in responders. Dashed lines are the obstructive lung disease. N. Engl. J. Med. 278: 1355. graphical solution of the equation 2. Dulfano, M. J., and J. Hewetson. 1966. Radiologic con- ji tributions to the nosology of obstructive lung disease 2g.Pca \0° entities. Dis. Chest. 50: 270. 3. Epstein, B. S., J. Sherman, and E. E. Walzer. 1948. for different values of .Aepp (given at the enld of each isopleth) Bronchography in asthmatic patients, with the aid of constructed Gas exchange in mild bronchitis and asympto- came asymptotic to the one or other of the Rca isopleths. matic asthma. N. Engl. J. Med. 282: 1277. They suggested that if Rca > > f the isopleth to which 6. McFadden, E. R., Jr., and H. A. Lyons. 1969. Serial the curve became asymptotic would give the cross-sec- studies of factors influencing airway dynamics during tional area at EPP in each subject. Cross-sectional areas recovery from acute asthma attacks. J. Appl. Physiol. 27: 452. so determined correlated well with the cross-sectional 7. Woolcock, A. J., N. J. Vincent, and P. T. Mackleni. area of the trachea in their subjects (8). 1969. Frequency dependence of compliance as a test for Similar curves in the responders are shown in Fig. 8. obstruction in the small airways. J. Cliii. Intvest. 48: 1097. If the decrease in Ru8 with an increase in volumle iS due 8. Mead, J., J. M. Turner, P. T. Macklem, and J. B. Little. to the same mechanisan as in normals, the cross-sectional 1967. Significance of the relationship between lung recoil area at EPP would in most cases fall between 1.0 and and maximum expiratory flow. J. Appl. Physiol. 22: 95. 0.25 cm2. In normal subjects the cross-section at EPP 9. Macklem, P. T., and N. J. Wilson. 1965. Measurement of intrabronchial pressure in man. J. 4pp!. Physiol. 20: ranged between 1.1 and 2.7 cm2 (8). Thus in responders 653. the cross-section at EPP would have to be substantially 10. Wood, L. D. H., and A. C. Bryan. 1969. Effect of in- smaller than the diameter of the trachea, but this is creased ambient pressure on flow-volume curve of the lungs. J. Appl. Physiol. 27: 4. feasible given an increase in bronchomotor tone. 11. Schilder, D. P., A. Roberts, and D. L. Fry. 1963. The alternative explanation for the change in Ru wvith Effect of gas density and viscosity on the maximal ex- volume is a fall in Rfr as volume decreases. This could piratory flow-volume relationship. J. Clin. Invest. 42: 1705. in part be due to the decrease in flow if Rfr was turbulent 12. Anthonisen, N. R., M. E. Bradley, J. Vorosmarti, and but it does not seem likely that this could account for all P. G. Linaweaver. 1971. Mechanics of breathing with of the change. It has recently been shown that airway helium-oxygen and neon-oxygen mixtures in deep satu- ration diving. In Underwater Physiology. C. J. Lambert- resistance increases in humans and dogs at high lung vol- son, editor. Academic Press, Inc., New York. 339. umes, although the mechanisml for this is obscure (24). 13. Grape, B., E. Channin, and J. M. Tyler. 1960. The effect If this were present in asthma to a greater degree than of helium and oxygen mixtures on pulmonary re- normal then this could account for the change in Ru5. If sistances in emphysema. Am. Rev. Respir. Dis. 81: 823. 14. Wood, W. B., and T. B. Barnett. 1965. Effects of helium so one might expect to see sianiilar curves in nonre- mixtures on ventilatory response to C02 in subj ects sponders. but this wsas not the case (Fig. 6). For this with airway obstruction. Clin. Res. 13: 77. (Abstr.) .3242 P. J. Despas, M. Leroux, and P. T. Macklem 15. Gold, M., A. Marks, and J. S. Bocles. 1964. Effects of drop, fluid flow regime and velocity profile of air in- reduction in air density on dynamic function in ob- spired into the human lung. Fed. Proc. 27: 228 (Abstr. structive airway disease. Am. Rev. Respir. Dis. 90: 62) 316. (Abstr.) 21. Macklem, P. T., and J. Mead. 1968. Factors determining 16. Schiller, I. W., F. C. Lowell, M. T. Lynch. and W. maximum expiratory flow in dogs. J. Appl. Physiol. Franklin. 1955. The effect of helium oxygen mixtures 25: 159. on pulmonary function in asthmatic patients. J. Allergy. 22. Macklem, P. T., R. G. Fraser, and W. G. Brown. 1965. 26: 11. Bronchial pressure measurements in emphysema and 17. Barnett, T. B. 1967. Effects of helium and oxygen mix- bronchitis. J. Clin. Invest. 44: 897. tures on pulmonary mechanics during airway constric- 23. Olsen, C. R., A. E. Stevens, and M. B. McIlroy. 1967. tion. J. Appl. Physiol. 22: 707. Rigidity of tracheae and bronchi during muscular con- 18. Mead, J. 1960. Volume displacement body plethysmo- striction. J. Appl. Physiol. 23: 27. graph for respiratory measurements in human subjects. 24 Vincent, M. J., R. Knudson, D. E. Leith, P. T. Mack- J. Appl. Physiol. 15: 736. lem, and J. Mead. 1970. Factors influencing pulmonary 19. Mead, J., and J. L. Whittenberger. 1953. Physical prop- resistance. J. Appl. Physiol. 29: 236. erties of human lungs measured during spontaneous 25. Bates, D. V., P. T. Macklem, and R. V. Christie. respiration. J. Appl. Physiol. 5: 779. 1971. Respiratory Function in Disease. W. B. Saunders 20. Olson, D. E., and J. W. Gersten. 1968. The pressure & Co., Philadelphia. 2nd edition.

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