CLINICAL SCIENCE WITHIN-BREATH ANALYSIS OF RESPIRATORY MECHANICS IN ASTHMATIC PATIENTS BY FORCED OSCILLATION

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1 CLINICS 2009;64(7): CLINICAL SCIENCE WITHIN-BREATH ANALYSIS OF RESPIRATORY MECHANICS IN ASTHMATIC PATIENTS BY FORCED OSCILLATION Juliana Veiga, I Agnaldo José Loes, II José Manoel Jansen, II Pedo Loes de Melo I doi: /S Veiga J, Loes AJ, Jansen JM, de Melo PL. Within-Beath analysis of esiatoy mechanics in asthmatic atients by foced oscillation. Clinics. 2009;64(7): INTRODUCTION: The within-beath analysis of esiatoy mechanics by the monofequency Foced Oscillation Technique (mfot) is of geat inteest in both hysioathology studies and the diagnosis of esiatoy diseases. Howeve, thee ae limited data on the use of this technique in the analysis of asthma. This study evaluates within-beath mechanics of asthmatic individuals and the contibution of the mfot in the asthma diagnosis. METHODS: Twenty-two healthy and twenty-two asthmatic subjects, including atients with mild (n=8), modeate (n=8), and sevee (n=6) obstuction, wee studied. Foced Oscillation Technique data wee inteeted using the mean esiatoy imedance (Zt), the imedance duing insiation (Zi), exiation (Ze), at the beginning of insiation (Zii), and at exiation (Zie). The eakto-eak imedance (Z) was also calculated by the subtaction of Zii fom Zie. Receive oeating chaacteistic cuves wee used to detemine the sensitivity (Se) and secificity (S) of m Foced Oscillation Technique aametes in identifying asthma. RESULTS: Resiatoy imedance values wee significantly highe in asthmatics: Zt (<0.001), Zi (<0.001), Ze (<0.001), Zii (<0.001), Zie (<0.001), and Z (<0.003). The best aametes fo detecting asthma wee Zi, Zii, and Zie (Se=90.9%, S=90.9%), followed by Zt and Ze. These esults ae in close ageement with ecently ublished theoies and athohysiological fundamentals. CONCLUSIONS: mfot emits a non-invasive and detailed analysis in diffeent hases of the esiatoy cycle, oviding aametes that ae adequate fo the diagnosis of asthma with high accuacy. These esults confim the high clinical and scientific otential of this methodology in the evaluation of asthmatic atients. KEYWORDS: Beathing cycle; Asthma; Foced oscillations; Resiatoy imedance; Diagnostic. INTRODUCTION The eal-time identification of alteations in esiatoy mechanics is of geat inteest in both hysioathology studies and in the diagnosis of beathing diseases. 1,2 This analysis allows a detailed evaluation of the diffeent hases of the beathing cycle, and it can be made using the inteution technique. Howeve, this method still has technical difficulties, such as undeestimation of the I Biomedical Instumentation Laboatoy and BioVasc Clinical and Exeimental Reseach Laboatoy, Institute of Biology, State Univesity of Rio de Janeio - Rio de Janeio/RJ, Bazil. II Pulmonay Function Laboatoy, Faculty of Medical Sciences, State Univesity of Rio de Janeio - Rio de Janeio/RJ, Bazil. loes@uej.b Tel: Received fo ublication on Febuay 18, 2009 Acceted fo ublication on Ail 15, 2009 measued esistance due to the slow balance between the alveola essue and the essue esent in the mouth. 3 Anothe altenative efes to the measuement of ulmonay esistance. The clinical alication of this methodology, howeve, is limited due to the use of an esohageal cathete. 3 The method of the least squaes, on the othe hand, may oveestimate the insiatoy esistance and undeestimate the exiatoy esistance. 4 In actice, we still do not have a simle, low-cost technique that monitos mechanical alteations duing the esiatoy cycle. Studies using the Foced Oscillations Technique (FOT) often use seveal excitation fequencies (multifequency) to obtain an aveage esult fom seveal beathing cycles. 5 Recently, a vesion of the FOT that uses a single excitation fequency (monofequency) was develoed and allows eal-time analysis of the esiatoy mechanics. 6 Fo this uose, the system evaluates, in eal time, the module of the 649

2 Within-beath esiatoy mechanics in asthmatics CLINICS 2009;64(7): esiatoy imedance (Zs), a vaiable that eesents the total mechanical load offeed by the esiatoy system. This instument was successfully used to study the fast events associated with slee anea 6,7 and swallowing. 8 Recently, othe eseach gous have obtained omising esults using this methodology fo the detection of exiatoy flow limitations in COPD atients, 1,9 investigating hysiological ecovey fom an exacebation of COPD, 10 and analyzing the esonse to dee inhalation in asthmatic childen 11 and adults. 12 A detailed evaluation of the shot-tem vaiability of aiway calibe in asthma was also ecently obtained using this technique. 13,14 Howeve, thee ae limited data on the use of monofequency FOT in the analysis of diffeent hases of the beathing cycle and in the diagnosis of asthma in adult subjects. In this context, the objectives of the esent study wee: (1) to comae the esiatoy mechanics of nomal and asthmatic individuals, with an emhasis on the diffeences between the hases of the esiatoy cycle, and (2) to evaluate the contibution of the monofequency FOT in the diagnosis of asthma. METHODS The esent wok is a tansvese study develoed at the Biomedical Instumentation Laboatoy and Pulmonay Function Laboatoy at the State Univesity of Rio de Janeio. The Reseach Ethics Committee of this institution aoved this study. The objectives of the study wee exlained to all individuals, and thei witten consent was obtained befoe inclusion in the study. The system used fo the analysis of esiatoy mechanics eesents the evolution of equiment descibed eviously that was dedicated to the study of esiatoy diseases duing slee. 6,7 The instument alies a single fequency (5Hz), low essue (2.0 cmh 2 O), sinusoidal signal to the individual s esiatoy system, which emains unde sontaneous ventilation. Pessue (P) and flow (Q) tansduces ae used to measue these vaiables, and the esulting signals ae used to calculate the Zs (Zs=P/Q). The develoed ogam emits contol of the beginning and end of the exam, as well as visualization of esiatoy imedance alteations along seveal hases of the beathing cycle. Resiatoy imedance was measued in fou exams of 20 s each. These exams wee accomlished with the individual seated, beathing sontaneously, using a nasal cli, and holding thei cheeks and mouth floo with thei hands to avoid the shunt effect of the ue aiways. In ode to chaacteize the mechanical alteations along the beathing cycle, the following seconday aametes to the Zs wee calculated: The mean esiatoy imedance (Zt) was calculated fo the whole exam; The mean of the imedance duing the insiation cycles (Zi); The mean of the imedance duing the exiation cycles (Ze); The mean imedance obseved at the beginning of insiation (Zii); The mean of the imedance at the beginning of exiation (Zie); The eak-to-eak imedance (Z), subtaction of Zii fom Zie. The esults ae esented as the means±sd. The chaacteistics of the distibutions wee initially veified by the Shaio-Wilk test. An indeendent t-test was used when the data esented a statistically nomal distibution. In all othe cases, a non-aametic test (Mann-Whitney) was alied. The associations between FOT and siometic aametes wee analyzed using Peason s coelation coefficient fo the entie gou of studied voluntees. These tests wee assumed to be statistically significant at a level of <0.05 and wee conducted using a commecial softwae ackage (Oigin fo Windows, vesion 8.0). The clinical otential of the cited indices in detection of the esiatoy alteations in asthmatic atients was also evaluated. Fo this uose, the sensitivity and secificity of the mentioned aametes wee obtained though Receive Oeating Chaacteistic (ROC) analyses. These gahs descibe the obability of a tue ositive occuence (sensitivity) as a function of the obability of a false ositive occuence (1-secificity) fo seveal cut-off oints. Thus, a lage aea unde the cuve (AUC) eesents geate validity of the test. Tests with AUCs above 0.8 ae consideed aoiate fo clinical use, 15 and those with values above 0.9 eflect high diagnostic accuacy. 16 This analysis was efomed using MedCalc 7.3 softwae. The cut-off oint was selected in ode to balance the values of sensitivity and secificity. The estimate of the samle s size was based on the citeion of identifying an aoiate AUC fo clinical actice (0.80) 15 and not meely one that simly emits a andom evaluation (0.50). 15,16 This estimate was made by consideing eos of tye I and tye II of 10% and 20%, esectively, and using MedCalc 7.3 softwae. This estimate esulted in a minimum numbe of 22 individuals in each gou. A total of 44 individuals (22 with a clinical diagnosis of asthma 17 and 22 nomal subjects) wee studied. Using a flow siomete (Mico Loo; Mico Medical, Rocheste, England), measuements fo the Foced Vital Caacity (FVC), Foced Exiatoy Volume fo the fist second (FEV 1 ), FEV 1 /FVC, and atio of Foced Exiatoy 650

3 CLINICS 2009;64(7): Within-beath esiatoy mechanics in asthmatics Flow (FEF) between 25% and 75% of the FVC to FVC (FEF/FVC) wee obtained fo atients in a seated osition. These aametes wee esented as aw data and ecentiles of the edicted values (% ed). Pedicted values fo siomety wee obtained fom Knudson et al. 18 and Peeia et al. 19 Foced exiatoy maneuves wee eeated until thee sequential measuements wee obtained. The indices studied wee those obtained fom the best cuve, which was selected as the cuve with the highest value of FEV 1 lus FVC. FOT exams wee caied out fist, and the delay between FOT and siometic exams was less than thity minutes. The aiway obstuction classification used in the esent wok was based on the FEF /FVC and FEV 1 /FVC elationshis. These aametes ae consideed a ecocious indicato of aiway obstuction, 24 and they ae associated with diffuse aiway obstuction, esectively. 25,26 Thus, FEF /FVC was used to classify obstuction in the initial hases, and FEV 1 /FVC in the classification in most advanced hases 21,22. Patients wee ambulatoy subjects efeed by hysicians to the laboatoy fo outine ulmonay function testing. The studied gou was comosed of atients esenting mild (n=8), modeate (n=8), and sevee (n=6) aiway obstuction. The diagnosis of asthma was based on the esence of dysnea, chonic cough, chest tightness, o thoacic discomfot. Sontaneous imovement of these symtoms afte bonchodilato use was also indicative of asthma (>12% imovement of the FEV 1 -edicted baseline afte b 2 -agonist inhalation). Exclusion citeia fo this study wee the inability to efom technically adequate siomety o FOT measuements, smoking histoy, evidence of cuent aiway infection, acute exacebation, o any cadioesiatoy disease othe than asthma. All atients wee in stable clinical condition. The contol gou was comised of 22 healthy subjects with nomal siomety and without any histoy of ulmonay o cadiac disease o tobacco use. Baseline data, including age, sex, and height, wee obtained fo each atient at the time of the ocedues. RESULTS The anthoometic and siometic chaacteistics of the studied gous ae descibed in Table 1. All siometic aametes showed significant eductions in the asthmatic gou. A eesentative examle of the tyical mohology of the aiflow and imedance signals obtained in a contol (A) and asthmatic (B) individual is esented in Figue 1. Notice the diffeence in the imedance scales. The deived esults of the eal-time analysis ae esented in Figue 2. These seconday vaiables wee significantly highe in asthmatics: Zt (<0.001), Zi (<0.001), Ze (<0.001), Zii (<0.001), Zie (<0.001), and Z (<0.003). Coelations between FOT and siometic aametes ae esented in Table 2. All FOT aametes esented statistically significant invese coelations with all siometic aametes, excluding Z and FVC. The values obtained fo the AUC, sensitivity, and secificity descibing the clinical otential of the studied indices ae descibed in Table 3. Table 1 - Anthoometic and siometic chaacteistics of the study gou Zt Zi Ze Zii Zie Z FEV 1 (L) <0.01 FVC (L) ns FEV 1 /FVC (%) <0.003 FEF/FVC (%) <

4 Within-beath esiatoy mechanics in asthmatics CLINICS 2009;64(7): Figue 1 - Tyical aiflow and esiatoy imedance analyzed in the contol gou (A) and asthmatic (B) individuals. Notice the diffeence in the imedance scales. Figue 2 - Comaison among the total imedance (Zt, figue A), mean imedance duing the insiatoy (Zi, B) and exiatoy (Ze, C) hases, imedance at the beginning of insiation (Zii, D) and of exiation (Zie, E), and eak-to-eak vaiation of the imedance (Z, F) in the studied gous. The to and bottom of the box lot eesent the 25 th - to 75 th -ecentile values, while the cicle eesents the mean value and the ba acoss the box the median. The whiskes outside the box eesent the 5 th - to 95 th -ecentile values. Data esented a statistically nomal distibution. 652

5 CLINICS 2009;64(7): Within-beath esiatoy mechanics in asthmatics Table 2 - Peason coelation coefficient (), coefficient of detemination ( 2 ), and -value () between FOT and siomety. DISCUSSION Contol (n=22) Asthma (n=22) Age (yeas) 56.5± ±15.2 ns Weight (kg) 70.1± ±15.2 ns Height (cm) 159.9± ±5.3 ns IMC 27.4± ±5.7 ns Gende (M/F) 5/17 4/18 -- FEV 1 (L) 2.3± ±0.8 <0.001 FVC (L) 2.9± ±0.9 <0.05 FEV 1 /FVC (%) 80.6± ±15.2 <0.001 FEF/FVC (%) 79.2± ±16.6 <0.001 Table 3 - Values of the aea unde the ROC cuve (AUC), sensitivity (Se), secificity (S), and esective cut-off oints fo the FOT aametes. AUC Se (%) S (%) The anthoometic chaacteistics of the two studied gous wee well matched, and thee wee no significant diffeences between the gous (Table 1). The eductions in volumes and flows obseved in asthmatic individuals wee coheent with the hysioathology involved. 17,27 The imedance module eesents the total mechanical load of the esiatoy system, descibing the wok necessay to omote the movement of ai into the esiatoy system. At the fequency used (5Hz), this aamete mainly descibes the esulting effect of the total esistance and esiatoy system comliance. 6 Figue 1A demonstates the flow and imedance behavio with time in a healthy individual. A eduction in the imedance values duing insiation can be obseved. On the othe hand, a gadual incease of the imedance values is aaent duing exiation. This behavio is in ageement with Poiseuille s law; thee is an incease in the intenal diamete of the aiways duing insiation, wheeas exiation esults in Cut-off oint Zt Z Zi Ze Zii Zie a eduction in aiway diamete. In asthma (Figue 1B), we can obseve a simila behavio with highe imedance values. These values can be exlained by the obstuctive natue of this disease. Additionally, thee is a delay between the imedance and flow cuves. The imedance begins its deceasing hase some time afte initiation of the incease in flow; in othe wods, this occus some time afte the initiation of insiation. In the exiatoy hase, thee is a delay in the imedance incease elative to the beginning of the flow decease. In asthma, the delay in the imedance signal elative to the flow signal may be associated with eductions in esiatoy system comliance. This can be exlained, at least in at, by modifications in the aiways, including bonchoconstiction as well as thickening and emodeling of the aiway wall. The combination of these factos can esult in bonchial igidity, leading to difficulty of the bonchial stuctue to esond quickly to vaiations in aiflow. The asthmatic gou esented significantly highe imedances in all of the analyzed aametes (Figue 2). The hysioathological ocesses elated to asthma include inflammation of the aiways and bonchial hye-eactivity, esulting in the obstuction of aiflow with consequent alteations of the esistive and elastic oeties of the esiatoy system. 21 These alteations ae consistent with the obseved incease in the Zt of asthmatic subjects (Figue 2A), and with the significant invese coelations between Zt and siometic aametes (Table 2). The esiatoy imedance module is associated with esistive and eactive oeties of the esiatoy system. 5 Dellacà et al. 1 ointed out that indices elated to the esiatoy system eactance ae able to detect flow limitations, which ae deendent on the mechanical oeties of the aiway walls and the choke oint location. The concet of a choke oint was intoduced by these authos and descibes the difficulty that the oscillatoy signals emitted by the FOT esent when cossing segments of the bonchial tee; this difficulty is esonsible fo the flow limitation. This event oduces a fall in the dynamic comliance, and consequently an incease in the imedance module. In ageement with this theoy, all of the analyzed aametes esented a significant incease in asthmatic subjects (Figue 2), and wee significantly associated with aiway obstuction (Table 2). It is also inteesting to note that the highest coefficients of detemination wee obseved between FEV 1 /FVC and FOT aametes, which link the studied FOT aametes to diffuse aiway obstuction. LaPad and Lutchen 28 ointed out that asthmatics esent a deceased ability to distend thei aiways in comaison with healthy individuals due to the igidification and thickening of the aiway walls. This facto, associated with othe tyical hysioathological events in 653

6 Within-beath esiatoy mechanics in asthmatics CLINICS 2009;64(7): asthma (e.g. bonchial hye-eactivity and hyeinflation), causes dislacement of ventilation fo highe volumes and inceases the wok associated with beathing. 27 It can thus exlain the incease obseved in the Zi value of asthmatics (Figue 2B). In these atients, thee is a tendency towad lage Zi in comaison to Ze values (Figue 2B and C; t-test = ns). This tendency indicates that the incease in esiatoy imedance in asthmatics does not necessaily descibe limitations in exiatoy flow. 21 The small elevation in the Zi value can be elated to the incease in the esistive and elastic wok of beathing, and may also eflect a combination of diffeences in aiway calibe, glottic calibe, and effects of muscula activation in the thoacic wall. A ecent study 29 demonstated that asthmatic individuals esent an initial limitation of dilation duing a maneuve of dee insiation; this is followed in the exiatoy hase by a faste etun of the aiways to thei initial diamete. This fact could be exlained at least in at by emodeling and the esence of hyetohied musculatue, which could detemine the fast eduction obseved in the aiway calibe afte the end of the insiatoy hase. Consequently, at the end of exiation, this henomenon would esult in a highe value of imedance (Zii) in that gou elative to the contol gou. The esults esented in Figue 2D ae in ageement with these inciles. In asthmatics, Zii showed a tendency to incease in comaison to Zie (Figue 2D and E, t-test = ns). These esults ae consistent with those esented by Caubeghs and Van de Woestijne 30 fo atients with chonic obstuctive ulmonay disease. This tendency can be exlained at least in at by Poiseuille s law. At the beginning of insiation (i.e., when the ulmonay volume and aiway diamete ae educed), the imedance is lage. On the othe hand, at the beginning of exiation (i.e., when the ulmonay volume and aiway diamete ae highe), the imedance is educed. Consideing the contibution of the esiatoy muscles to the esults esented in Figue 2, we initially obseve that the esiatoy system of asthmatic atients is geneally subjected to a high mechanical load (Figue 2A). This usually esults in the maintenance of ost-insiatoy activity of the diahagm and thoacic wall insiatoy muscles. These muscles act as a estaining facto in exiatoy flow, and thei activity esults in hyeinflation. In this condition, the time constant of the esiatoy system exceeds the time necessay fo nomal basal exiation. Consequently, a loss of elastic ecoil occus, esulting in an incease in the elastic wok of beathing in addition to the incement of the esistive wok descibed eviously. 31 These changes esult in the inceased exiatoy load shown in Figue 2C. Additionally, hyeinflation equies muscles to incease thei wok duing insiation, and this contibutes to the esults descibed in Figue 2B. We obseved highe Z values in asthmatics (Figue 2F). Hyeinflation is associated with a deficit in insiatoy muscle foce in asthma; this deficit is usually the edominant facto that detemines dysnea in those atients. 32 Theefoe, although the total mechanical load of the beathing system is inceased duing the whole cycle (Figue 2A), it is likely that such a henomenon is moe evident duing the insiatoy hase. This finding, associated with that descibed by McConnell and Alison 33 that the sensation most clealy elated to execise intoleance in asthmatics is esiatoy effot, emhasizes the elevance of muscula theaeutic inteventions in these atients. Table 3 descibes the analysis of the contibution of the monofequency FOT to the diagnosis of asthma. The aametes Zt, Zi, Ze, Zii, and Zee esented AUCs above 0.9, indicating high diagnostic accuacy. 16 Guo and collaboatos 34 investigated the identification of DPOC in eldely subjects though multifequency FOT and obtained maximum AUC values of Pevious studies fom ou gou using the multifequency FOT in asthmatic atients evealed maximum AUCs of Simila analyses in atients with sacoidosis showed maximum AUCs of The values found in the esent wok ae sueio to those obtained in evious wok, indicating that monofequency FOT can esent highe diagnostic accuacy than its coesonding multifequency vesion. Based on these omising esults, futhe lage-scale studies to confim these findings in well-defined gous of asthmatic atients with mild, modeate, and sevee aiflow obstuction ae being undetaken. Studies including bonchodilato tests ae also in ogess. In conclusion, the cuent study shows that monofequency FOT emits a non-invasive and detailed analysis of the changes in esiatoy mechanics in asthmatic atients. This analysis ovides new aametes associated with diffeent hases of the esiatoy cycle. Seveal of these aametes ae adequate fo the diagnosis of asthma with high accuacy. These esults confim the high clinical and scientific otential of this methodology in the evaluation of asthmatic atients. ACKNOWLEDGEMENTS The authos wish to thank Mesquita J. J.A., Santos, J.G., Faia A.C., Costa G.M., and Mianda I.A. fo thei technical assistance. This study was suoted by the Bazilian Council fo Scientific and Technological Develoment (CNPq) and Rio de Janeio State Reseach Suoting Foundation (FAPERJ). 654

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