Budesonide (800 mg bid, for 2 months) was administered to 12 asthmatic children (mean age, 11.293.3 years) with lung
hyperinflation (TGV]130% predicted and:or RV]140% predicted) in a randomised, placebo controlled, double blind, crossover
study. Body plethysmography (panting frequency controlled at 1·s 1) was performed at the beginning, 2 months afterwards
(before crossover) and at the end of the study. Budesonide significantly reduced TGV (2.3590.90 l BTPS or 126924% predicted)
compared with placebo (2.5491.08 l BTPS, P 0.014 or 140921% predicted, PB0.05). In addition, budesonide significantly
increased mean specific conductance (0.0690.02 cm H2O 1 l s 1 to 0.0790.01 cm H2O 1 l s 1, PB0.05). It was concluded
that budesonide reduced lung hyperinflation most likely by decreasing airway inflammation

Gamboa, T

Neuparth, N

Pereira, C

Rendas, A

Rosado-Pinto, J

Repositório do Centro Hospitalar de Lisboa Central, EPE

Pathophysiology 6 (1999) 199–204Budesonide reverses lung hyperinflation in childhood asthma: acontrolled studyN. Neuparth a,b,*, T. Gamboa a, C. Pereira c, J. Rusado Pinto b, A. Rendas aa Departamento Uni6ersita´rio de Fisiopatologia, Faculdade de Cieˆncias Me´dicas, Uni6ersidade No6a de Lisboa, Campo de Santana, 130,1198 Lisboa CODEX, Portugalb Ser6ic¸o de Imunoalergologia, Hospital de Dona Estefaˆnia, Lisboa, Portugalc Ser6ic¸o Uni6ersita´rio de Fisiologia, Faculdade de Cieˆncias Me´dicas, Uni6ersidade No6a de Lisboa, Campo de Santana, 130,1198 Lisboa CODEX, PortugalReceived 26 February 1999; accepted 9 August 1999AbstractIt was investigated whether inhaled budesonide reduces lung volumes in a group of asthmatic children with lung hyperinflation.Budesonide (800 mg bid, for 2 months) was administered to 12 asthmatic children (mean age, 11.293.3 years) with lunghyperinflation (TGV]130% predicted and:or RV]140% predicted) in a randomised, placebo controlled, double blind, crossoverstudy. Body plethysmography (panting frequency controlled at 1·s1) was performed at the beginning, 2 months afterwards(before crossover) and at the end of the study. Budesonide significantly reduced TGV (2.3590.90 l BTPS or 126924% predicted)compared with placebo (2.5491.08 l BTPS, P0.014 or 140921% predicted, PB0.05). In addition, budesonide significantlyincreased mean specific conductance (0.0690.02 cm H2O1 l s1 to 0.0790.01 cm H2O1 l s1, PB0.05). It was concludedthat budesonide reduced lung hyperinflation most likely by decreasing airway inflammation. © 1999 Elsevier Science Ireland Ltd.All rights reserved.Keywords: Asthma; Lung hyperinflation; Bronchial inflammation; Budesonidewww.elsevier.com:locate:pathophys1. IntroductionIn a clinical context, hyperinflation implies an abnor-mal increase in the volume of gas in the lungs at theend of tidal expiration [1]. However, when it was at-tempted to relate hyperinflation with the airway nar-rowing occurring in asthma, the picture is much lessdefined as suggested in a recent review [2] which statesthat, in this context, there is no clear definition ofhyperinflation and of its underlying mechanisms. Theauthors suggest that both altered properties of airwaysand lung parenchyma are involved in the developmentof hyperinflation and point to the importance of mea-suring residual volume (RV), thoracic gas volume(TVG) and total lung capacity (TLC) to understand theunderlying pathophysiological mechanisms.During an acute attack of asthma [3] there is anincrease in all lung volumes which is due not only tothe expiratory flow limitation but also to the persistentinspiratory muscle contraction throughout expiration,caused by a reflex mechanism from the constrictedairways, which increases end-expiratory volume andproduces hyperinflation [4–7]. On the other hand,chronic increases of functional residual capacity (FRC),RV and occasionally of TLC can be observed in someasthmatic patients away from the exacerbations ofasthma [2,8] but the mechanisms responsible for thesechanges, such as loss of bronchial-to-parenchyma inter-dependence, are still under discussion. A prior studyperformed in seven asthmatic patients, found a decreasein FRC after a week of systemic steroids that wasattributed to an improvement of lung elastic recoil [9]as was later demonstrated [10].* Corresponding author. Tel.: 351-1-885-3000; fax: 351-1-885-1920.E-mail address: nneuparth.fpat@fcm.unl.pt (N. Neuparth)0928-4680:99:$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.PII: S09 2 8 -4680 (99 )00017 -6N. Neuparth et al. : Pathophysiology 6 (1999) 199–204200Although it is accepted that the treatment withsteroids reduces inflammation both in the airways andin the parenchyma [11,12], the authors were not awareof any study relating such treatment with measurementsof lung volumes that are dependent, amongst otherfactors, upon lung elastic recoil. In order to do that, aninhaled steroid was given to a group of hyperinflatedasthmatic children and lung volumes were monitored ina controlled study.2. Material and methods2.1. Study subjectsPatients were selected from all asthmatics that haveperformed lung function tests in an Allergy Clinicduring 1 year. From these, 13 children with asthma andlung hyperinflation, aged 6–18 years old were included.The diagnosis of asthma was made according to ac-cepted criteria [13]. All patients were free from inhaledand systemic steroids and from an exacerbation ofasthma for at least 6 weeks before the beginning of thestudy. During the study period all patients were onlytaking inhaled budesonide regularly and a short-actingb2 agonist in a prn basis.According to their clinical symptoms and:or to dailymedication required, 11 patients were classified as hav-ing moderate persistent asthma, whereas two were la-belled as mild persistent [14]. Symptoms of asthma weredetected for the first time, in average, since 8.594.2years ago, with a range between 3.1 and 17.3 years.Chronic lung hyperinflation was considered wheneverTGV was repeatedly (in three different occasions dur-ing the previous year) equal or higher than 130%predicted [15] and:or RV was equal or higher than140% predicted [16]. The predicted values were calcu-lated from Zapletal equations [17].2.2. Study designThe study was performed in two phases (Phase 1 andPhase 2), with a duration of 4 months. It was acontrolled study, double blind, against placebo accord-ing to randomisation in two groups (G1 and G2) of sixpatients each. A crossover was done at the end of Phase1. Budesonide (400 mg dose1) or placebo was adminis-tered to each patient through a Turbohaler® devicetwice a day. The content of the inhaler was blindedboth to patients and investigators. Lung volumes weremeasured three times during the study — before start-ing budesonide (day 0), at crossover (day 57) and at theend of the study (day 113). Patients were instructed toavoid taking b2 agonists during the 12-h period preced-ing the lung function measurements. An informed con-sent was obtained from the tutors in every case and thestudy was approved by the Hospital Ethics Committee.2.3. MethodsA body plethysmograph MasterLab Jaeger(Wu¨rzburg, Germany) was used to measure lung vol-umes (TGV, RV and TLC) and specific conductance(sGaw) according to the method described by Ref. [18].The procedure followed during measurements was thatrecommended by the European Respiratory Society[19]. Nevertheless, panting frequency was settled at 1Hz, using a tachometer as a biofeedback signal to thepatient, because lung volumes measured by bodyplethysmography with high panting frequencies areoverestimated in asthma [20,21].2.4. AnalysisThe key questions addressed in this study were: didbudesonide modify lung volumes (TGV, RV and TLC)and sGaw, compared with placebo? Did lung volumescorrelate with airway calibre before and after treatmentwith budesonide?Analysis of variance was used to evaluate the effectsof budesonide and placebo according to the methodsdescribed in Ref. [22]. Each analysis was tested forperiod effect and for the presence of carry-over. Deltalung volumes (lung volumes after budesonide — lungvolumes after placebo) were correlated with delta con-ductance (Gaw).3. Results3.1. Patient characteristicsDistribution by age and sex of the children includedin this study is shown on Table 1. One of the patientswas excluded because he had an asthma attack treatedwith oral steroids during placebo phase. For thisreason only 12 patients concluded the study. This grouphad the following mean baseline volumes (Table 2):TGV, 2.791.10 l (141921% pred.); RV, 1.5990.80 l(170953% pred.); and TLC, 4.5291.62 l (118913%pred.).3.2. Effect of budesonide on lung 6olumesWhen compared with placebo, only TGV was signifi-cantly reduced (PB0.05) after 2 months of inhaledbudesonide, from 2.5491.08 to 2.3591.08 l. Therewere no differences between basal volumes and volumesafter placebo (Fig. 1).N. Neuparth et al. : Pathophysiology 6 (1999) 199–204 2013.3. Effect of budesonide on airway calibreAs patients were evaluated through body plethysmog-raphy, only resistance (or its reciprocal-conductance)was measured. Specific conductance (sGaw) after 2months of budesonide increased significantly (PB0.05)when compared with sGaw after placebo (from 0.0690.02 to 0.0790.01 cm H2O1·1·s1, Fig. 1). Thisincrease corresponds to a 17% variation.3.4. Relation between lung 6olumes and airway calibreDelta TGV (as defined in Section 2) was significantlycorrelated with delta Gaw (r 0.78, PB0.005, Fig. 2).4. DiscussionWith this study it has been shown, in a group of 12young asthmatics with lung hyperinflation, that TGVbut not RV or TLC decreased significantly after treat-ment with an inhaled steroid. This was shown througha double blind, placebo controlled, crossover design.The reduction of TGV after treatment with budes-onide implies that the anti-inflammatory medicationreduced end-expiratory volume. Based on the inflamma-tory theory of asthma, it was hypothesised that this wasdue, not only to an increase in airway calibre [23–25],but also to a reduction in peribronchial and alveolarinflammation [26] which, when present, causesTable 1Characteristics of the asthmatic children with lung hyperinflation studiedaAge SexNo. TGV RV TLC% Pred l % Predl % Pred l1.36 144 3.93 105F 2.221 120111246.742442.841632 4.40M151.03 142 3.42 118M 1.873 133813 F 3.64 1814 2.47 243 5.31 1301164.691681.561275 2.51M1010 M 2.68 1466 0.97 110 1023.831.26 161 3.64 1207 8 F 1.92 1290.96 146 3.01 1198 7 M 1.60 1303.171774.78 272 147M 7.999 181170.88122 2.651471.35F9100.991322.17M 1221111 3.36 995.7014 114M 3.22 131 1.58 1461212 170 4.52 1189M:4F 2.70 141Mean 1.59533 1.62 13– 1.10 21 0.80S.D.a M, male; F, female; % Pred, % predicted values; S.D., standard deviation.Table 2sGaw evolution of asthmatic children with lung hyperinflation during the studyaBasal After budesonideNo. After placebo% Predcm H2O1 l s1 % Pred cm H2O1 l s1 % Pred cm H2O1 l s190 900.0821 740.082 0.0672 1230.0761080.067480.030.081630.076 68500.0630.047 564 0.0620.028 74330.079 925 0.0660.041 7748890.082970.0896 990.0917 44 0.049 43 0.065 570.058 580.08430.059520.0720.056630.039 90850.053910 41 0.028 18 0.06 390.0630.066 64 0.0511 49 0.059 57940.0651280.08812 1320.09179*0.072*670.06065Mean 0.0600.021 29 0.018S.D. 27 270.012a % Pred, % predicted values; S.D., standard deviation.* PB0.05 when compared with post placebo.N. Neuparth et al. : Pathophysiology 6 (1999) 199–204202Fig. 1. Comparison of lung volumes (residual volume (RV), upper left panel; thoracic gas volume (TGV), upper right panel; total lung capacity(TLC), lower left panel) and of specific conductance (sGaw) before budesonide or placebo (basal), after placebo (placebo) and after budesonide(Bud) treatment of asthmatic children with lung hyperinflation. On the left hand side of each graphic is represented the individual variation. Onthe right hand side is represented the mean variation (9standard variation); * PB0.05.a temporary loss of the relationship between smallbronchi and parenchyma, thus reducing elastic recoil[27,28]. This is suggested in this study by the fact that asmall improvement in airway calibre after budesonide,demonstrated by the increase in sGaw, was not accom-panied by a change in RV, which remained higher andnot different from placebo. This probably means that ahigher RV depends not only on airway calibre but alsoon persistent parenchymal changes such as a reductionin lung elastic recoil that also contributes to the expira-tory flow limitation. Similar observations were made byS¸ekerel et al. [8] who found a reduction of TLC after 8weeks of treatment with budesonide, 400 mg day1.A recent study [29] has shown that, in chronic stableasthma, lung volumes assessed by measurements ofTLC, can be larger than predicted at the start ofadolescence and suggested that this change was due tothe mitogenic effect of inflammatory mediators whichstimulated alveolar multiplication during childhood.This hypothesis is different from a previous one [30]which explained the hyperinflation in chronic asthmat-ics by a process of alveolar destruction because of thestretching caused by the trapped gas. In this regard it isinteresting to note that the younger cases, also at thebeginning of adolescence, had higher baseline values ofTLC than the older patients, a finding which agreeswith the above mentioned hypothesis. The authors areaware that the measurement of TLC by plethysmogra-phy can produce methodological errors, however, theywere minimised by a panting frequency B1 Hz. So itwas confirmed, as others, that TLC is increased in someof these patients with asthma, whether this is caused byN. Neuparth et al. : Pathophysiology 6 (1999) 199–204 203Fig. 2. Graphic representation of the statistically significant correla-tion between delta thoracic gas volume (TGV) and delta Gaw (beforeand after budesonide) of asthmatic children with lung hyperinflation.References[1] G.J. Gibson, Pulmonary hyperinflation: a clinical overview, Eur.Respir. J. 9 (1996) 2640–2649.[2] R. Pellegrino, V. Brusasco, On the causes of lung hyperinflationduring bronchoconstriction, Eur. Respir. J. 10 (1997) 468–475.[3] A.J. Woolcock, J. Read, Lung volumes in exacerbations ofasthma, Am. J. Med. 41 (1966) 259–273.[4] J. Martin, E. Powell, S. Shore, J. Emrich, L.A. Engel, The roleof respiratory muscles in the hyperinflation of bronchial asthma,Am. Rev. Respir. Dis. 121 (1980) 441–447.[5] N. Mu¨ller, A.C. Bryan, N. Zamel, Tonic inspiratory muscleactivity as a cause of hyperinflation in histamine-inducedasthma, J. Appl. Physiol. 49 (1980) 869–874.[6] R. Pellegrino, B. Violante, S. Nava, C. Rampulla, V. Brusasco,J.R. Rodarte, Relationship between expiratory airflow limitationand hyperinflation during methacholine-induced bronchocon-striction, J. Appl. Physiol. 75 (1993a) 1720–1727.[7] P.W. Collet, T. Brancatisano, L.A. Engel, Changes in the glotticaperture during bronchial asthma, Am. Rev. Respir. Dis. 128(1983) 719–723.[8] B.E. S¸ekerel, A. Tuncer, Y. Sarac¸lar, G. Adaliulu, Inhaledbudesonide reduces lung hyperinflation in children with asthma,Acta Paediatr. 86 (1997) 932–936.[9] W.M. Gold, H.S. Kaufman, J.A. Nadel, Elastic recoil of thelungs in chronic asthmatic patients before and after therapy, J.Appl. Physiol. 23 (1967) 433–438.[10] A.J. Woolkock, J. Read, The static elastic properties of the lungsin asthma, Am. Rev. Respir. Dis. 98 (1968) 788–794.[11] S. Pedersen, Can steroids cause asthma to remit? Am. J. Crit.Care Med. 153 (1996) S31[12] V. Keatings, A. Jatakanon, Y. Worsdell, P. Barnes, Effects ofinhaled and oral glucocorticoids on inflammatory indices inasthma and COPD, Am. J. Crit. Care Med. 155 (1997) 542–548.[13] International Consensus Report on Diagnosis and Treatment ofAsthma, Eur. Respir. J. 5 (1992) 601–641.[14] National Institutes of Health (NHLBI), Global strategy forasthma management and prevention. Publication no 95–3659(1995).[15] S.P. Blackie, S. Al-Majed, C.A. Staples, C. Hilliam, P.D. Pare´,Changes in total lung capacity during acute spontaneous asthma,Am. Rev. Respir. Dis. 142 (1990) 79–83.[16] B.E. Pennock, J.J. Cottrell, R.M. Rogers, Pulmonary functiontesting. What is normal?, Arch. Intern. Med. 143 (1983) 2123–2127.[17] Working Group Paediatrics, Standardisation of Lung Functionin Paediatrics. Compilation of reference values for lung functionmeasurements in children, Eur. Respir. J. 2 (Suppl. 4) (1989)184–264.[18] A.B. DuBois, S.Y. Botelho, G.N. Bedell, J.H.J.r. Comroe, Anew method for measuring airway resistance in man using abody plethysmograph: values in normal subjects and in patientswith respiratory disease, J. Clin. Invest. 35 (1956) 322–326.[19] Official Statement of the European Respiratory Society, Stan-dardised Lung Function Testing. Lung volumes and forcedventilatory flows, Eur. Respir. J. 6 (Suppl. 16) (1993) 5–40.[20] D.O. Rodenstein, D.C. Stanescu, Frequency dependence ofplethysmograph volume in heathy and asthmatic subjects, J.Appl. Physiol. 52 (1982) 159–165.[21] S.A. Shore, O. Huk, S. Mannix, J.G. Martin, Effect of pantingfrequency on the pletysmographic determination of thoracic gasvolume in chronic obstructive pulmonary disease, Am. Rev.Respir. Dis. 128 (1983) 54–59.[22] D.A. Ratkowsky, M.A. Evans, J.R. Alldredge, Crossover exper-iments. Design: analysis and application, in: D.A. Ratkoswsky,M.A. Evans, J.R. Alldredge (Eds.), Statistics: Textbooks andMonographs, Dekker, New York, 1993, pp. 77–120.a higher rate of alveolar multiplication or by remod-elling of lung tissues or both it is not yet clear.Another explanation for the increase in TLC couldbe related to an increase in respiratory muscle strengthin chronic asthmatics due to the persistent tonic activityof the inspiratory muscle during expiration. Since res-piratory pressures have not been measured, the involve-ment of the respiratory muscles on the genesis ofhyperinflation cannot be excluded, although thesechanges are considered less likely than those of lungparenchyma. However, the authors’ research findings[31], have shown that, at least maximal mouth pressuresare similar in children and adolescents with asthma anda group of age matched controls.The results show that an inhaled steroid, budesonide,can decrease lung volumes in a group of young asth-matics with lung hyperinflation. This reduction in lungvolumes was closely related with the increase of airwaycalibre thus suggesting a major role of airway inflam-mation in the genesis of chronic lung hyperinflation inasthma.AcknowledgementsThe authors would like to acknowledge Astra Por-tuguesa for the logistic support given to this study. Wewould also like to acknowledge Mrs Carole Caswellfrom Astra Charnwood (GB) for all the help withstatistical analysis. This work was supported by a grantfrom PRAXIS XXI, PSAU:P:SAU:92:96. Drugs sup-plied by Astra Portuguesa.N. Neuparth et al. : Pathophysiology 6 (1999) 199–204204[23] A. Mansell, C. Dubrawsky, H. Levison, A.C. Bryan, H. Langer, C.Collins-Williams, R.P. Orange, Lung mechanics in antigen-in-duced asthma, J. Appl. Physiol. 37 (1974) 297–301.[24] S.A. Freedman, A.E. Tattersfield, N.B. Pride, Changes in lung me-chanics during asthma induced by exercise, J. Appl. Physiol. 38(1975) 974–982.[25] R. Pellegrino, B. Violante, E. Crimi, V. Brusasco, Effects of aero-sol methacholine and histamine on airways and lung parenchymain healthy humans, J. Appl. Physiol. 74 (1993b) 2681–2686.[26] M. Kraft, R. Djukanovic, S. Wilso, S.T. Holgate, R. Martin, Alve-olar tissue inflammation in asthma, Am. J. Crit. Care Med. 154(1996) 1505–1510.[27] R. Marshall, J.G. Widdicombe, Stress relaxation of the humanlung, Clin. Sci. 20 (1961) 19–31.[28] K.E. Finnucane, H.J.H. Colebatch, Elastic behaviour of the lungin patients with airway obstruction, J. Appl. Physiol. 26 (1969)330–338.[29] P.J. Merkus, E.M. van Essen-Zandvliet, J.M. Kouwenberg, E.J.Duiverman, H.C. Van Houwelingen, K.F. Kerrebijn, P.H. Quan-jer, Large lungs after childhood asthma: a case-control study, Am.Rev. Respir. Dis. 148 (1993) 1484–1489.[30] I.A. Greaves, H.J.H. Colebatch, Large lungs after childhoodasthma: a consequence of enlarged aispaces, Aust. N. Z. J. Med. 15(1985) 427–434.[31] N. Neuparth, Hiperinsuflac¸a˜o pulmonar cro´nica: um estudo nacrianc¸a asma´tica. PhD Thesis, Faculdade de Cieˆncias Me´dicas,Universidade Nova de Lisboa, 1995..

Budesonide Reverses Lung Hyperinflation in Childhood Asthma: a Controlled Study

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Budesonide Reverses Lung Hyperinflation in Childhood Asthma: a Controlled Study

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