determinar os pontos de corte de resposta ao broncodilatador do vef1 , vef0,75 , vef0,5 e fef25 - 75% em crianas pr - escolares saudveis e gerar valores de referncia para o vef0,75 .
foi realizado um estudo transversal de base comunitria em crianas de 3 - 5 anos de idade .
foram definidos os pontos de corte dessa resposta como o percentil 95 de variao em cada parmetro .
foram recrutadas 266 crianas , e 160 ( 60,0% ) foram capazes de gerar manobras expiratrias aceitveis e reprodutveis antes e depois do uso de broncodilatador . as mdias de idade e estatura
dos participantes foram 57,78  7,86 meses e 106,56  6,43 cm , respectivamente . a taxa de sucesso para o vef0,5 foi de 35% , 68% e 70% , respectivamente , nos participantes com 3 , 4 e 5 anos de idade .
o percentil 95 de variao percentual do valor previsto na resposta ao broncodilatador foram , respectivamente , de 11,6% , 16,0% , 8,5% e 35,5% , para vef1 , vef0,75 , vef0,5 e fef25 - 75% .
nossos resultados definiram pontos de corte de resposta ao broncodilatador para o vef1 , vef0,75 , vef0,5 e fef25 - 75 em crianas pr - escolares saudveis .
os achados deste estudo podem melhorar a avaliao fisiolgica da funo respiratria em pr - escolares .
although spirometry with bronchodilator testing is routinely used in order to investigate respiratory diseases in children and adults , it is rarely used in preschool children . in children ,
only a few studies have defined bronchodilator response cut - off points ( for fev1 ) , the established change in baseline fev1 and in percent predicted fev1 in response to bronchodilator use having varied across studies , from 9% to 14% and from 9% to 10% , respectively . 


  the american thoracic society ( ats ) and the european respiratory society ( ers ) have yet to determine the best cut - off points for children .
in addition , given the lack of studies , the ats and the ers have not been able to determine cut - off points for preschool children . 



 
one obstacle is that only a low proportion ( 34 - 90% ) of preschoolers are able to exhale for 1 s or more . 


 
therefore , measurements of fev during the first 0.5 s of fvc ( fev0.5 ) or during the first 0.75 s of fvc ( fev0.75 ) can be used as surrogates for fev1 . according to the ats and the ers , fev0.5 and fev0.75
several reference equations for fev0.5 and fev0.75 have been established in various populations . 



  in a case - control study , 
  bronchodilator response cut - off points of 14% , 14% , and
33% were found for baseline fev1 , fev0.75 , and fef25 - 75% , respectively . in another study , 
  cut - off points of 10% , 11% , and 25% were found for baseline fev1 , fev0.5 , and fef25 - 75% , respectively ; however , their sensitivity for the diagnosis of asthma was found to be low ( 12% , 30% , and 41% , respectively ) , their specificity being 84% , 90% , and 80% , respectively . 

 
given that spirometry is a low - cost and noninvasive test , and given that several studies 








  have demonstrated that preschool children can perform acceptable and reproducible fev0.5 and fev0.75 measurements , there is a need to determine bronchodilator response cut - off points for children in this age group so that spirometry can be used in daily clinical practice .
only two studies 


  have assessed bronchodilator response using spirometry exclusively in preschool children .   in the present study we sought to determine bronchodilator response cut - off points for fev1 , fev0.75 , fev0.5 , and fef25 - 75% using the 95th percentile of the change in each parameter and
establish reference values for fev0.75 in healthy preschool children ( i.e. , preschoolers without respiratory symptoms ) .
this was a community - based study of preschool children 3 - 5 years of age selected from among those attending any one of 18 public day care centers and schools in the city of recife , brazil .
we selected a convenience sample , giving priority to the schools and day care centers attended by the highest number of children and located in central , northern , and western recife .
we calculated the sample size required to achieve a mean increase in fev0.75 , after bronchodilator use , of 4.5% and a standard deviation of 5.1% , a value found in a study by borrego et al . , 
  with 95% confidence , assuming an estimation error of 1% , in accordance with the sample size calculation of pardos et al . 
 
the minimum sample size was calculated to be 100 .   in order to characterize the study sample
, we used the ats and division of lung diseases questionnaire for the diagnosis of asthma - designated ats - dld-78-c - previously adapted and validated for use in brazil in children 4 months to 13 years of age . 
 
the inclusion criteria were as follows : being 3 - 5 years of age ; having been a full - term infant ; having had a birth weight  2,500 g ; and having no respiratory symptoms , i.e. , having no symptoms of asthma ( dyspnea , wheezing , recurrent cough , or exertional dyspnea ) or other respiratory diseases .
the exclusion criteria were as follows : respiratory disease at birth requiring the use of oxygen for more than 24 h ; chronic respiratory disease ( including bronchopulmonary dysplasia , cystic fibrosis , and bronchiolitis obliterans ) ; thoracic and pulmonary malformations ; acute viral bronchiolitis in the last 6 months ; acute nasopharyngitis ; heart disease ; and other severe diseases ( including immunodeficiencies , neurological diseases , and genetic syndromes ) . a questionnaire administered up to one week before testing was used in order to determine whether prospective participants met any of the aforementioned criteria .
testing was not performed if there were signs of acute nasopharyngitis at the time of testing .  
all tests were performed by the principal investigator , having been performed in the morning in all participating schools and day care centers
. a back - extrapolated volume of < 80 ml or 12.5% of fvc was accepted , as recommended for preschool children . 
 
the objective was to obtain two acceptable maximal expiratory curves , the variation between the two highest values of fvc , fev1 , and fev0.75 being equal to or less than 10% and the variation between the two highest values of fev0.5 being equal to or less than 5% .
curves with a forced expiratory time ( fet ) of at least 0.5 s were accepted regardless of whether or not they ended abruptly .
encouragement screens were used , and each session of testing was preceded by a brief ( 5-min ) session of training .
spirometry was repeated 15 min after administration of 400 g of albuterol delivered by a metered dose inhaler , as recommended by the ats / ers . 
 
an aluminum spacer with a face mask was used ( inal - air ; rsmed , belo horizonte , brazil ) .
no nose clips were used in the present study , because the use of nose clips in children undergoing spirometry has been shown to have no clear advantage . 
 
testing was performed with a portable spirometer validated by the ats ( koko ; ferraris respiratory , louisville , co , usa ) .
calibration was performed at the testing site , before each session of testing , with the use of a 3-l syringe , within the acceptable range of volume and flow . 
 
room temperature and humidity were measured , and the data collected were entered into the software . in order to obtain acceptable maneuvers , testing sessions were suspended after an average of eight attempts or , before that , if the child showed fatigue or disinterest in continuing .  
the following spirometric parameters were assessed : fvc ; fev1 ; fev0.75 ; fev0.5 ; and fef25 - 75% .
the values of the aforementioned parameters were obtained from the two best flow - volume curves , both of which were acceptable and reproducible . 
 
the criteria for determining the values of fef25 - 75% were as follows : for curves with a maximum fet of < 0.75 s , fef25 - 75% was obtained from the curve with the highest fev0.5 value and the highest fev0.5 + fvc value ; for curves with a maximum fet of < 1 s , fef25 - 75% was obtained from the curve with the highest fev0.75 value and the highest fev0.75 + fvc value ; for curves with a maximum fet  1 s , fef25 - 75% was obtained from the curve with the highest fev1 value and the highest fev1 + fvc value .
the variables used in order to determine bronchodilator response cut - off points for fev1 , fev0.75 , fev0.5 , and fef25 - 75% were the percent change regarding the predicted values , the percent change regarding the baseline values , and the change in absolute values .
statistical analysis was performed with the ibm spss statistics software package , version 21 ( ibm corporation , armonk , ny , usa ) .
the reproducibility of the spirometric measurements was tested by the intraclass correlation coefficient ( icc ) .
the student 's t - test for paired samples was used in order to compare mean baseline and post - bronchodilator values of all spirometric parameters .  
the changes in response to bronchodilator use were calculated by the following formulas :   ( post - bronchodilator value  baseline value )  100/baseline value ( post - bronchodilator value  baseline value )  100/predicted value the predicted values were derived from a reference equation for preschool children developed by our research group in a previous study . 
 
because the aforementioned equation 
  does not include reference values for fev0.75 , they were calculated in the present study by linear regression .   in order to determine bronchodilator response cut - off points for fev1 , fev0.75 , fev0.5 , and fef25 - 75% , the 95th percentile of the change in each parameter was calculated for baseline , predicted , and absolute values .  
spearman 's correlation coefficient was calculated in order to evaluate the correlation of the bronchodilator response indices tested with age , height , and baseline fevt ( fev1 , fev0.75 , and fev0.5 ) .  
the study project was approved by the research ethics committee of the professor fernando figueira institute of integrative medicine ( protocol no .
the parents or legal guardians of all participating preschoolers gave written informed consent , and the researchers signed a statement of responsibility .
of those 447 children , 41 ( 9% ) met the exclusion criteria and 34 ( 8% ) constituted losses : 26 for missing school on the day of testing and 8 for declining to undergo testing . of the remaining 372 preschoolers , 266 ( 71% )
those 266 children , 56 ( 21.0% ) failed to perform spirometry correctly and 50 ( 19.0% ) failed to perform bronchodilator testing correctly . the final sample consisted of 160 asymptomatic preschool children ( 60% of the initial sample of 266 asymptomatic children ) .
the demographic characteristics of the sample are presented in table 1 . of the children who performed acceptable measurements , 19 ( 12% )
were 3 years old , 74 ( 46% ) were 4 , and 67 ( 42% ) were 5 .
curves with a back - extrapolated volume  5% were obtained in 99% of the tests , and , in 95% of those , the difference between the two highest fvc , fev1 , fev0.75 , and fev0.5 values was < 5% , demonstrating a high reproducibility .  

table 1sociodemographic characteristics of the study population , recife , brazil , february - december of 2014 . 

variableresultmale gender84 ( 52.5)age , months57.8  7.8race 
 white33 ( 20.6)black11 ( 6.9)mulatto116 ( 72.5)weight - for - age ( z score ) 
 0.20  1.18height - for - age ( z score ) 
 0.38  1.03bmi ( z score ) 
 0.65  1.20avalues expressed as n ( % ) or mean  sd .
we calculated the iccs for the two highest values of each of the spirometric variables tested .
mean iccs ( and their respective 95% cis ) for fvc and fev1 were 0.994 ( 0.990 - 0.996 ) and 0.993 ( 0.989 - 0.996 ) , respectively .
mean iccs ( and their respective 95% cis ) for fev0.75 , fev0.5 , and fef25 - 75% were 0.993 ( 0.990 - 0.995 ) , 0.992 ( 0.990 - 0.994 ) , and 0.935 ( 0.913 - 0.951 ) , respectively
.   among the 3-year - olds in the initial sample of 266 children , fvc , fev1 , fev0.75 , and fev0.5 measurements were considered acceptable and reproducible in 5% , 7% , 9% , and 37% , respectively ; among the 4-year - olds , they were considered acceptable and reproducible in 23% , 29% , 39% , and 68% , respectively ; and among the 5-year - olds , they were considered acceptable and reproducible in 23% , 26% , 44% , and 70% , respectively .  
spirometry was considered unacceptable in 63% of the 3-year - olds , in 32% of the 4-year - olds , and in 30% of the 5-year - olds .
bronchodilator response testing was considered inadequate in 19% of the 3-year - olds , in 20% of the 4-year - olds , and in 20% of the 5-year - olds , proportions that were very similar .  
mean baseline and post - bronchodilator fvc , fev1 , fev0.75 , fev0.5 , and fef25 - 75% values are shown in table 2 .
there were significant differences between mean pre- and post - bronchodilator values of the aforementioned parameters ( p < 0.005 ) .
proportionally , mean and median pre- and post - bronchodilator changes in fvc , fev1 , fev0.75 , fev0.5 , and fef25 - 75% with non - normal distribution can be seen in table 2 .  

table 2means and dispersion of baseline and post - bronchodilator spirometric parameters in the preschoolers studied .
variablebaseline post - bd change ( pre- and post - bd ) , % p * 
 nmean  sdnmean  sdmean  sd ( median ) 

 fvc , l941.06
 0.21521.09  0.182.3  4.3 ( 0.71 ) < 0.001fev1 , l931.00  0.18611.06  0.174.5  4.7 ( 2.67 ) < 0.001fev0.75 , l940.94  0.17921.00  0.175.6  5.6 ( 4.32 ) < 0.001fev0.5 , l1600.80  0.161600.86  0.166.8  6.4 ( 5.47 ) < 0.001fef25 - 75% , l / s941.52  0.40921.79  0.4220.0  20.2 ( 15.48 ) < 0.001bd : bronchodilator ; fev0.5 : fev during the first 0.5 s of fvc ; and fev0.75 : fev during the first 0.75 s of fvc .
amean and median of the changes observed after bronchodilator use ( variables with non - normal distribution ) .
the greatest differences between mean and median values are due to a lower n of fvc and fev1 measurements after bronchodilator use . *
bd : bronchodilator ; fev0.5 : fev during the first 0.5 s of fvc ; and fev0.75 : fev during the first 0.75 s of fvc .   mean and median of the changes observed after bronchodilator use ( variables with non - normal distribution ) .
the greatest differences between mean and median values are due to a lower n of fvc and fev1 measurements after bronchodilator use . * student 's t - test for paired samples . in order to calculate reference values for fev0.75 ,
the equation and the lower limit ( ll ) are as follows :   fev0.75 = height  0.013 + weight  0.010 ll = predicted value  0.21(5th percentile of the residual ) for females , the equation and the ll are as follows :   fev0.75 = height  0.008 + age  0.008 + weight  0.013 ll = predicted value  0.19 the dispersion of fev0.75 values is shown in figure 2 .  

figure 2scatter plots of fev during the first 0.75 s of fvc ( fev0.75 ) in relation to height and weight in male preschoolers ( a and b ) and in female preschoolers ( c and d ) . 
 

table 3 shows all cut - off points established by the 95th percentile of the change in fev1 , fev0.75 , fev0.5 , and fef25 - 75% in response to bronchodilator use .  

table 3percentiles of the changes in fev1 , fev0.5 , fev0.75 , and fef25 - 75% in response to bronchodilator use , the parameters being expressed as percentages of the predicted values , percent changes from baseline , and absolute changes in the preschoolers studied .
fev0.5 : fev during the first 0.5 s of fvc ; and fev0.75 : fev during the first 0.75 s of fvc .
fev0.5 : fev during the first 0.5 s of fvc ; and fev0.75 : fev during the first 0.75 s of fvc .
table 4 shows the spearman 's correlations of the bronchodilator response cut - off points for baseline , percent predicted , and absolute values of fev0.5 and fev0.75 with age , height , and baseline fevt ( fev0.5 and fev0.75 ) .  

table 4spearman 's coefficients correlating the bronchodilator response indices with age , height , fev during the first 0.5 s of fvc ( fev0.5 ) , and fev during the first 0.75 s of fvc ( fev0.75 ) in the study sample .
variableabsolute change from baseline fev0.5 after bronchodilator use , lpercent change from baseline fev0.5 after bronchodilator usechange in percent predicted fev0.5 after bronchodilator use 
 scc ( p)scc ( p)scc ( p)age , months0.04 ( 0.60)0.1 ( 0.28)0.05 ( 0.50)height , cm0.11 ( 0.17)0.05 ( 0.50)0.03 ( 0.70)baseline fev0.5 , l0.16 ( 0.47)3.27 ( 0.00)0.25 ( 0.02 ) 
 absolute change from baseline fev0.75 after bronchodilator use , lpercent change from baseline fev0.75 after bronchodilator usechange in percent predicted fev0.5 after bronchodilator use 
 scc ( p)scc ( p)scc ( p)age , months0.17 ( 0.11)0.24 ( 0.02)0.23 ( 0.03)height , cm0.53 ( 0.62)0.05 ( 0.66)0.01 ( 0.89)baseline fev0.75 , l / s0.06 ( 0.60)0.18 ( 0.10)0.17 ( 0.11)scc : spearman 's correlation coefficient . 
 
this is the first study to establish , by means of spirometry , bronchodilator response cut - off points in preschoolers , the cut - off points being expressed as the change in percent predicted fev1 , fev0.75 , fev0.5 , and fef25 - 75% .
of the 4-year - olds in the study sample , 67% were able to perform fev0.5 measurements and 39% were able to perform fev0.75 measurements .
of the 5-year - olds in the study sample , 70% were able to perform fev0.5 measurements and 44% were able to perform fev0.75 measurements .
therefore , in preschoolers , fev0.5 measurements are more useful than fev0.75 measurements because the proportion of children who can perform the former is higher . in community - based samples , spirometry is not useful in 3-year - olds due to the high rate of unacceptable tests .  
the low proportion of children who were able to perform acceptable and reproducible pre- and post - bronchodilator measurements of fvc , fev1 , fev0.75 , and fef25 - 75% can be explained by the fact that ours was a community - based sample , the children therefore being more inexperienced in performing such measurements ; in general , children selected from among those treated at respiratory outpatient clinics have previously been evaluated by their physicians regarding their motor coordination to perform such tests .
given that it is difficult for children to perform pre- and post - bronchodilator spirometry , the proportion of preschoolers who can perform it is lower .
the high iccs for the spirometric parameters tested in the present study constitute evidence of the low variability and high reproducibility of the measurements performed , as well as of the technical skills of the professional who performed the tests .  
the mean changes in the percentage of the predicted values of fvc , fev1 , and fev0.75 in response to bronchodilator use in the present study were 2.3% , 4.5% , and 5.6% , respectively , being similar to those found in another study ( 2.5% , 4.7% , and 4.5% , respectively ) . 
  for fef25 - 75% , borrego et al
. 
  found a change of 11.7% , compared with 20.0% in the present study .
this difference can be explained by the difference in study sample between the two studies : ours was a community - based sample , whereas that in the study by borrego et al . 
 
in addition , the high reproducibility and , consequently , low variability of fef25 - 75% measurements in the present study increase the power to detect differences between pre- and post - bronchodilator values . in the present study , the mean post - bronchodilator percentage changes of fev1 , fev0.5 , and fef25 - 75% were 4.5% , 6.8% , and 20.0% , respectively , whereas , in another study , 
  they were 8.9% , 2.9% , and 8.1% , respectively . the type of sample used in ours and in that study 
  ( community - based and case - control samples , respectively ) , as well as the fact that dose of albuterol was lower in that study ( 200 g ) , 
  might have contributed to those differences . for fev1 ,
the cut - off point found in the present study ( a change of 13% from baseline in response to bronchodilator use ) was similar to that found in another study ( 14% ) 
  but different from that found by linares et al .
( 10% , with a sensitivity of 12% and a specificity of 84% ) . 
 
this low sensitivity suggests that there were no significant differences between the groups regarding bronchodilator response or that the administered dose of albuterol ( 200 g ) was insufficient to produce a bronchodilator effect . because the aforementioned study was a case - control study involving patients with moderate to severe persistent asthma
, it is more likely that the administered dose of albuterol was insufficient to provide effective bronchodilation . with regard to the change in the percentage of the predicted fev1 in response to bronchodilator use in the present study ( i.e. , 11.6% )
, we found no other studies evaluating this parameter in samples composed exclusively of preschool children .   for fev0.5 ,
the cut - off point found in the present study ( a change of 20% from baseline in response to bronchodilator use ) differs from that found by other authors ( 11% , with a sensitivity of 30% and a specificity of 90% ) . 
 
the high iccs for the measurements performed in the present study increase its power regarding the reliability of those measurements .
it should also be taken into account that the cut - off points for a community - based study should be higher than those for studies comparing patients and healthy controls , as was the case of the two aforementioned studies . 


  with regard to the change in the percentage of the predicted fev0.5 in response to bronchodilator use in the present study ( 16% )
, the fact that there have been no studies evaluating this parameter makes it impossible to make comparisons .   for baseline fev0.75 ,
the bronchodilator response cut - off point found in the present study ( 18% ) was higher than that found in another study ( 14% ) . 
 
this difference might be due to the type of study ( a case - control study ) 
  and how the cut - off point was calculated ( mean + 2 standard deviations after bronchodilator use in healthy participants ) . 
  with regard to the change in the percentage of the predicted fev0.75 in response to bronchodilator use in the present study ( 8.5% )
, the lack of evidence in the literature makes it impossible to make comparisons .  
although some studies have included fef25 - 75% in the analysis of bronchodilator response , 




  fef25 - 75% is not given weight in studies evaluating bronchodilator response , because it varies widely . 


 
for fef25 - 75% , the cut - off point found in the present study ( a change of 61% from baseline in response to bronchodilator use ) is different from those found by borrego et al .
( 33% ) 
  and other authors ( 25% , with a sensitivity of 41% and a specificity of 80% ) . 
 
unlike the present study , the aforementioned studies were both case - control studies , and this might explain these discrepancies .
the high icc for fef25 - 75% in the present study indicates good reproducibility . with regard to the change in the percentage of the predicted fef25 - 75% in response to bronchodilator use in the present study ( 35.5% )
the use of this parameter in the evaluation of bronchodilator response in preschool children will require further studies .  
some studies have shown that , in children , it is best to express bronchodilator response as a percentage of the predicted values , because percent predicted values do not depend on age , height , or baseline fev1 . 


 
however , for preschool children , the present study showed correlations of baseline fev0.5 with the percent change from baseline after bronchodilator use and the percent change in the predicted value after bronchodilator use . with regard to fev0.75 , regarding this age group , age correlates with the percent change from baseline after bronchodilator use and the percent change in the predicted value after bronchodilator use .
therefore , in preschool children , there is no difference between the percent change from baseline after bronchodilator use and the percent change in the predicted value after bronchodilator use for the two parameters .  
one of the strengths of the present study is that it was a community - based study , the results of which are more generalizable than are those of studies conducted in secondary or tertiary care settings .
another strength of the present study is that we used predicted values that had been derived from preschoolers in the same region as those in the present study , thus increasing the reliability of the results obtained .
the high reproducibility of the spirometric measurements in the present study shows that they are reliable .   to our knowledge
, this is the first study to determine , in preschool children , bronchodilator response cut - off points for fev1 , fev0.75 , fev0.5 , and fef25 - 75% , expressed as percentages of the predicted values .
that fev0.5 is reproducible and that fev0.5 measurements can be performed by a higher proportion of preschoolers , it is the most useful of all of the parameters studied here .
in community - based samples , spirometry is not useful in 3-year - olds due to the high rate of unacceptable tests . for clinical practice ,
the recommended bronchodilator response cut - off points for percent predicted fev1 , fev0.75 , and fev0.5 are  12% ,  8% , and  16% , respectively ; for baseline fev1 , fev0.75 , and fev0.5 , the recommended cut - off points are  13% ,  18% , and  20% , respectively . for percent predicted and baseline fef25 - 75% , the recommended cut - off points are  35% and  61% , respectively . given that fef25 - 75% showed good reproducibility , it might be useful in the evaluation of bronchodilator response .
further studies are needed in order to test the utility of these cut - off points in samples of patients with respiratory symptoms treated at respiratory outpatient clinics .
 abstractobjective : to determine the cut - off points for fev1 , fev0.75 , fev0.5 , and fef25 - 75% bronchodilator responses in healthy preschool children and to generate reference values for fev0.75 . 
 methods : this was a cross - sectional community - based study involving children 3 - 5 years of age . 
 healthy preschool children were selected by a standardized questionnaire . 
 spirometry was performed before and after bronchodilator use . 
 the cut - off point of the response was defined as the 95th percentile of the change in each parameter . 
 results : we recruited 266 children , 160 ( 60% ) of whom were able to perform acceptable , reproducible expiratory maneuvers before and after bronchodilator use . 
 the mean age and height were 57.78  7.86 months and 106.56  6.43 cm , respectively . 
 the success rate for fev0.5 was 35% , 68% , and 70% in the 3- , 4- , and 5-year - olds , respectively . 
 the 95th percentile of the change in the percentage of the predicted value in response to bronchodilator use was 11.6% , 16.0% , 8.5% , and 35.5% for fev1 , fev0.75 , fev0.5 , and fef25 - 75% , respectively . 
 conclusions : our results provide cut - off points for bronchodilator responsiveness for fev1 , fev0.75 , fev0.5 , and fef25 - 75% in healthy preschool children . 
 in addition , we proposed gender - specific reference equations for fev0.75 . our findings could improve the physiological assessment of respiratory function in preschool children . 