A pilot study assessing the effect of bronchodilator on dynamic hyperinflation in LAM

Positive responses to bronchodilators (BDs) on spirometry can be found in up to 30% of patients with lymphangioleiomyomatosis (LAM). However, no previous studies have investigated the impact of BDs on exercise outcomes, including dynamic
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  This article appeared in a journal published by Elsevier. The attachedcopy is furnished to the author for internal non-commercial researchand education use, including for instruction at the authors institutionand sharing with colleagues.Other uses, including reproduction and distribution, or selling orlicensing copies, or posting to personal, institutional or third partywebsites are prohibited.In most cases authors are permitted to post their version of thearticle (e.g. in Word or Tex form) to their personal website orinstitutional repository. Authors requiring further informationregarding Elsevier’s archiving and manuscript policies areencouraged to visit:http://www.elsevier.com/authorsrights  Author's personal copy A pilot study assessing the effect of bronchodilator on dynamic hyperinflationin LAM * Bruno Guedes Baldi*, Andre´ Luis Pereira de Albuquerque,Suzana Pinheiro Pimenta, Joa˜o Marcos Salge,Ronaldo Adib Kairalla, Carlos Roberto Ribeiro Carvalho Pulmonary Division, Heart Institute (InCor), University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil Received 15 February 2013; accepted 30 August 2013Available online 8 September 2013 KEYWORDS Adrenergic beta-2receptor agonists;Exercise test;Lymphangioleiomyo-matosis;Pulmonary functiontests Summary Introduction:  Positive responses to bronchodilators (BDs) on spirometry can be found in up to30% of patients with lymphangioleiomyomatosis (LAM). However, no previous studies haveinvestigated the impact of BDs on exercise outcomes, including dynamic hyperinflation (DH). Methods:  A randomised, double-blind, placebo-controlled, crossover trial was conducted on 38patients with LAM, comparing inhaled placebo  versus  salbutamol. Pulmonary function testsand a cycle endurance test at 75% of the maximal work capacity, with evaluation of DH by se-rial measurement of inspiratory capacity (IC), which was the primary endpoint, were per-formed after each intervention. Results:  Although salbutamol produced a slight improvement in airway obstruction, comparedwith placebo, there was no significant variation in resting IC or air trapping. A total of 18% ofthe patients met the criteria for a positive response to BD. During submaximal exercise, BD didnot reduce DH or dyspnoea nor did it improve exercise tolerance in the entire population. Inaddition, BD produced only slight improvement in FEV 1  and air trapping in patients who hadDH during incremental cardiopulmonary exercise testing, without the beneficial effects onexercise outcomes. Conclusions:  Although salbutamol produced a slight improvement in airway obstruction, it didnot lead to a reduction in DH or increase in exercise tolerance in patients with LAM. Clinical trial registration:  Brazilian Registry of Clinical Trials (ReBEC); www.ensaiosclinicos.gov.br ; registration number: RBR-49sk2j. ª  2013 Elsevier Ltd. All rights reserved. * This article has not been published previously nor has been submitted or accepted for publication elsewhere.* Corresponding author. Dr. Ene´as de Carvalho Aguiar Avenue, 44, Fifth Floor, 05403-900 Sa˜o Paulo, Brazil. Tel./fax:  þ 55 112661 5695. E-mail address:  bruno.guedes2@terra.com.br  (B.G. Baldi).0954-6111/$ - see front matter   ª  2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.rmed.2013.08.045  Available online at www.sciencedirect.com ScienceDirect  journal homepage: www.elsevier.com/locate/rmed Respiratory Medicine (2013)  107 , 1773 e 1780  Author's personal copy Introduction Lymphangioleiomyomatosis (LAM) is a rare disease thatmainly affects women of childbearing age and is charac-terised by peribronchial, perivascular and lymphatic pro-liferation of abnormal muscle cells (LAM cells), which canlead to vascular and airway obstruction and cyst formation[1]. The pulmonary function tests (PFTs) in LAM are char-acterised by an obstructive pattern, air trapping andreduced diffusion capacity of the lung for carbon monoxide(DL CO ) [2 e 5]. The prevalence of positive response tobronchodilators (BDs), which is characterised by changes inforced expiratory volume in the first second (FEV 1 ) and/or forced vital capacity (FVC) of   12% and 200 mL over baseline, according to American Thoracic Society/EuropeanRespiratory Society (ATS/ERS) criteria, ranges from 6 to 30%in LAM [3 e 8]. The pathophysiology of airflow limitationinvolves increased resistance due to LAM cell proliferationaround the airways rather than changes in elastic recoil dueto connective tissue matrix destruction caused by theimbalance between the activity of matrix metal-loproteinases (MMPs) and their inhibitors in LAM lesions[5,9,10].Previous studies showed that reduced maximal workload and oxygen consumption (VO 2 ) are frequent in LAM;although multiple mechanisms are responsible for exerciselimitation, it is mainly caused by ventilatory and gas ex-change abnormalities [2,11 e 13]. Recently, we have shownthat the development of dynamic hyperinflation (DH) dur-ing incremental cardiopulmonary exercise testing (CPET) iscommon in patients with LAM, and is associated with theseverity of disease and augmented dyspnoea [2].Despite the positive effects of BDs on spirometry in LAM,none of these studies have investigated the effects of BDson air trapping, as measured by residual volume (RV) andRV/TLC ratio (TLC, total lung capacity), or on exerciseoutcomes, such as dyspnoea and exercise tolerance[3 e 5,7,8]. Studies in COPD showed a poor correlation be-tween increases in FEV 1  and improvements in dyspnoea andexercise performance after the administration of BDs,which is also plausible for patients with LAM [14,15].Therefore, the primary endpoint of this study was toinvestigate the impact of the short-acting BD salbutamol onreducing DH during a cycle endurance test exercise in pa-tients with LAM, and to determine secondarily the impacton PFTs, including reduction of air trapping, and if thistreatment would improve dyspnoea and exerciseperformance. Methods Subjects The study population comprised all patients diagnosed withLAM based on the guidelines of the ERS and were enrolled inthe outpatient clinic of the Pulmonary Division of the Hos-pital das Clinicas of the University of Sao Paulo [1]. Thestudy population comprised the same group evaluated in astudy recently published that showed a high prevalence ofDH and its repercussions in LAM [2]. The protocol wasapproved by the local research ethics committee and theinformed consent form was obtained from all patients. Theresearch protocol has been listed in the Brazilian Registryof Clinical Trials, available at ensaiosclinicos.gov.br , under the identification number RBR-49sk2j and follows datasetrequirements set forth by the International Committee ofMedical Journal Editors.Patients were excluded if they used supplemental oxy-gen, underwent lung transplantation, or had musculoskel-etal disorders, heart disease or any other disablingcondition that could interfere with testing. Patients wereclinically stable for at least 6 weeks prior to the study. Study protocol This was a single-centre, randomised, double-blind, pla-cebo-controlled, crossover trial. Patients were instructedto discontinue all  b 2 agonists for 48 h before the submaxi-mal exercises. The protocol was performed on 3 consecu-tive days (1 visit every day).At visit 1, patients underwent a clinical evaluation,including a questionnaire of dyspnoea (Baseline DyspnoeaIndex, BDI), and data obtained in a recent incrementalCPET performed was reviewed [2]. In this incrementalCPET, patients performed a symptom-limited incrementalCPET on a cycle ergometer, from which the maximumwork rate was obtained. Before visit 2, patients wererandomised to 400 mcg salbutamol via a metered-doseinhaler (Aerolin  Spray, GlaxoSmithKline) or an identicalplacebo [16]. The random allocation was balanced (1:1)and performed by using 38 sealed envelopes containingthe first intervention (19 salbutamol and 19 placebo),which was administrated by a blinded technician who didnot take part of the measurements. At visit 3, patientscrossed over to receive the alternative intervention. Atvisits 2 and 3, 30 min after inhaling salbutamol or placebo,patients performed PFTs and a cycle endurance test at75% of the maximal work reached on the incrementalCPET (Fig. 1). Measurements Pulmonary function tests: Spirometry was performed usinga calibrated pneumotachograph (Medical Graphics Corpo-ration, St. Paul, MN) and lung volumes and DL CO  were ob-tained with a body plethysmograph (Elite Dx, Elite Series;Medical Graphics Corporation). The following variableswere obtained at visits 2 and 3 after each intervention:FVC, FEV 1 , inspiratory capacity (IC), TLC, RV, and maximalvoluntary ventilation (MVV). DL CO  was measured during visit2. All measurements were made according to the ATS/ERSrecommendations, and predicted values were derived fromthe Brazilian population [17 e 22].Cardiopulmonary exercise test: CPETs were performedusing a cycle ergometer (Corival, Lode B.V.; MedicalTechnology, The Netherlands). Oxygen saturation (SpO 2 ), asmeasured by pulse oximetry (Onyx, model 9500; Nonin,Plymouth, MN), and electrocardiography (Welch Allyn Car-dioPerfect, Inc., NY) were monitored continuously duringthe tests. The following variables were recorded (CardioO 2 System; Medical Graphics Corporation) breath-by-breathand expressed as the average of the last 15 s of rest, of1774 B.G. Baldi et al.  Author's personal copy each second minute during exercises and at the end of thetests: work rate (WR), VO 2 , minute ventilation (V E ), carbondioxide production (VCO 2 ), tidal volume (V T ), respiratoryrate (f), respiratory exchange rate (RER) and heart rate(HR). Blood pressure, modified Borg scales for leg discom-fort and dyspnoea, and IC manoeuvers were obtained atrest, every 2 min during testing, and at the end of testing[23]. In the incremental CPET whose data was reviewed atvisit 1, patients performed a ramp symptom-limited CPETthat consisted of 2 min of rest, a 2-min warm-up (unloadedpedalling) and an incremental work-rate period (increasefrom 10 to 20 W/min). DH was established during incre-mental CPET based on an IC reduction of at least 10% frombaseline, assuming that TLC remained constant during ex-ercise [2,24]. At visits 2 and 3, after inhalation of salbuta-mol or placebo, the patients performed endurance exercisetests. The protocol consisted of 2 min of rest, a 2-minwarm-up (unloaded pedalling) and a constant work-rateperiod at 75% of the maximal WR reached on the incre-mental CPET. Exercise (endurance) time was defined as theduration of constant-loaded pedalling. To compare the re-sponses between the endurance CPETs, a standardised ex-ercise time (isotime) was established for each patient andconsisted of the point where the exercise with shorter duration ended. The isotime in the test with the longer duration was defined by rounding down to the nearestminute of the isotime of the test with the shortest durationwhere there were available data. All variables werecompared between endurance CPETs at isotime. Predictedvalues for CPET were obtained from the Brazilian popula-tion [25]. Statistical analysis The sample size of 28 patients provides the power (80%) todetect a treatment difference in IC variation (isotime  e baseline) of 10%,  a  Z  0.05. Data are reported as themean    SD for variables with normal distribution or as themedian (25th e 75th percentiles) for variables with non-normal distribution. Unpaired  t -tests or the Man-n e Whitney  U   test were used to compare continuous vari-ables between different groups. Paired  t -tests or Wilcoxontests were used to compare within-subject results. A two-way repeated measures ANOVA was performed to examinethe effect of interaction between treatment period andintervention. Differences were considered significant if  p was less than 0.05. The data were analysed with SigmaStatversion 3.5 (Systat Software, Inc., San Jose, CA). Results Population characteristics and incrementalcardiopulmonary exercise testing Seven patients refused to participate in the study, and 10out of 55 patients were excluded (6 because of their useof supplemental oxygen, 2 due to their history ofarrhythmia with the use of BD, 1 because of joint diseaseand 1 due to severe obesity). Then, 38 patients with LAMwere enrolled in the study: 6 patients (16%) were ex-smokers, 23 (60%) had a history of pneumothorax, 6 (16%)had a history of chylothorax, 5 (13%) had tuberous scle-rosis, and 17 (45%) had a history of pleurodesis. The meanage of the patients enrolled in the study was 41    10years, and the median time from diagnosis was 27 months.Only 1 patient was continuously using a long-acting  b 2agonist. No patient was using inhaled corticosteroid or rapamycin, whereas 12 patients were using doxycyclineand 13 were receiving hormonal therapy (gonadotropin-releasing hormone agonist).The general characteristics and data at peak of incre-mental CPET are shown in Table 1. The patients experi-enced mild dyspnoea for daily activities (BDI) anddiminished exercise performance (WR). DH occurred in 19patients (50%) during incremental CPET. Pulmonary function tests after placebo  versus salbutamol After inhalation of salbutamol, there was a slight increasein FEV 1 , with improvement in the degree of airflowobstruction. However, there was no significant change inresting IC or air trapping (RV and RV/TLC ratio) (Table 2).Seven patients (18%) met the criteria for positive responseto BDs (changes in FEV 1  and/or FVC of   12% and 200 mLover baseline) [6]. No significant interaction effect be-tween treatment period and intervention was demon-strated for FEV 1  ( F  Z 1.52;  p Z 0.22). Submaximal endurance exercise responses afterplacebo  versus  salbutamol Table 3 shows data from submaximal endurance exercisetests after interventions. The endurance time in CPETs wassimilar after inhalation of placebo and salbutamol. Therewas also no difference in IC variation from baseline, thus Figure 1  Study design. Definition of abbreviations: PFTs: pulmonary function tests; CPET: cardiopulmonary exercise test. Bronchodilator in lymphangioleiomyomatosis 1775  Author's personal copy salbutamol (400 mcg) did not reduce DH during submaximalCPET on a cycle ergometer, and also did not increasebreathing reserve. In addition, salbutamol did not producesignificant variation in other ventilatory variables (f andV T ); there was also no significant effect on dyspnoea in-tensity upon exercise cessation. Salbutamol treatment wasassociated with a slight increase in SpO 2 . No significantinteraction effect between treatment period and inter-vention was demonstrated for IC variation ( F   Z  0.48;  p  Z  0.49), exercise time ( F   Z  1.1;  p  Z  0.3) and Borgdyspnoea score ( F  Z 0.38;  p Z 0.54). Comparison between the DH and non-DH subgroups As shown in Tables 4 and 5, we compared the PFTs and endurance CPET data after each intervention between pa-tients with LAM who had DH during incremental CPET(subgroup DH) and those who did not develop DH (subgroupnon-DH).In the PFTs (Table 4), the patients with DH were char-acterised by airflow obstruction, air trapping and dimin-ished DL CO , and had a slightly greater variation in FEV 1 , RVand RV/TLC ratio after salbutamol in comparison with thesubgroup non-DH. However, there was no difference be-tween the subgroups in resting IC after BD. Six patients(32%) in the subgroup DH showed a positive response to BDbased on ATS/ERS criteria, compared with 1 patient (5%) inthe subgroup non-DH (  p Z 0.09) [6].In the evaluation of endurance CPETs after each inter-vention, exercise time after administration of placebo wassimilar, and there was no significant improvement in exer-cise time after BD, comparing the subgroups (Table 5).Salbutamol did not produce significant increases in isotimeIC (DH reduction) and did not lead to beneficial effects onother ventilatory variables (isotime f, V T  and breathingreserve), even in the subgroup DH. However, there was agreater decrease in dyspnoea intensity at exercise cessa-tion and a slightly greater increase in SpO 2  after salbutamolin the subgroup DH.We analysed the endpoints taking into account thetreatment with doxycycline and with hormonal blockage,and also the prior history of pleurodesis, and there was nodifference in the results obtained (data not shown). Responders  versus  non-responders tobronchodilators We also compared the patients with positive responses tosalbutamol, based on spirometry (responders to BD), withpatients without positive responses (non-responders to BD).Although salbutamol produced significant increases in FEV 1 and FEV 1 /FVC ratio, and a reduction in air trapping in theresponders to BD, there was no difference in exercisetolerance, reduction of DH or dyspnoea intensity, or  Table 2  Comparison of pulmonary function tests of pa-tients with lymphangioleiomyomatosis after administrationof placebo or salbutamol.Placebo( n Z 38)Salbutamol( n Z 38) P  FEV 1 , L 2.27    0.7 2.4    0.67  < 0.001*% predicted 79    23 84    22  < 0.001*FVC, L 3.27    0.58 3.32    0.59 0.08% predicted 94    15 96    15 0.08FEV 1 /FVC 0.73 (0.61 e 0.8) 0.78 (0.66 e 0.83)  < 0.001*IC, L 2.29 (2.07 e 2.54) 2.3 (1.99 e 2.65) 0.52% predicted 98    18 95    20 0.37TLC, L 5.03 (4.54 e 5.54) 4.95 (4.68 e 5.44) 0.32% predicted 104    15 104    14 0.47RV, L 1.86 (1.27 e 2.11) 1.74 (1.43 e 2.12) 0.19% predicted 127 (103 e 151) 127 (103 e 146) 0.19RV/TLC 0.34 (0.29 e 0.43) 0.34 (0.29 e 0.42) 0.28DL CO , mL/min/mmHg17.8    6.5% predicted 68    24 Values are the mean    SD or median (25th e 75th percentiles).Paired  t -test or Wilcoxon test was used to compare data.Definition of abbreviations: DL CO : diffusion capacity of the lungsfor carbon monoxide; FEV 1 : forced expiratory volume in the firstsecond; FVC: forced vital capacity; IC: inspiratory capacity; RV:residual volume; TLC: total lung capacity.*  p  <  0.05 Z statistical significance. Table 1  Population characteristics and peak data of theincremental cardiopulmonary exercise testing of the pa-tients with lymphangioleiomyomatosis. a Patients with LAM( n Z 38)Age, years 41    10BMI, kg/m 2 24.4    3.9Baseline dyspnoea index 11 (9 e 12)Exercise time, min 7.3 (5.4 e 8.2)Work rate, W 100    26% predicted 75    18VO 2 , mL/kg/min 19.6    5.9RER 1.23    0.14VE/VCO 2  slope 32.1 (29.7 e 38.4)VE, L/min 54    16Breathing reserve, %MVV 36    18VT, L 1.49    0.31f, breaths/min 37    8HR, beats/min 151    17% predicted 86    9SpO 2 , % 96 (90 e 97)Borg dyspnoea score 5 (3 e 8)Borg leg discomfort score 7 (5 e 9) D IC from rest, L   0.21    0.31%   9    13 Values are the mean    SD or median (25th e 75th percentiles).Definition of abbreviations:  D IC: inspiratory capacity variation;BMI: body mass index; f: respiratory rate; HR: heart rate; LAM:lymphangioleiomyomatosis; MVV: maximal voluntary ventila-tion; RER: respiratory exchange rate; SpO 2 : oxyhaemoglobinsaturation by pulse oximetry; VCO 2 : carbon dioxide production;VE: minute ventilation; VO 2 : oxygen consumption; VT: tidalvolume. a Data of a recent incremental cardiopulmonary exercisetesting was reviewed from a study that had already been pub-lished [2]. 1776 B.G. Baldi et al.
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