Evaluation of Respiratory Dynamics by Volumetric

Jornal de Pediatria ISSN: 0021-7557 ISSN: 1678-4782 Sociedade Brasileira de Pediatria

Parazzi, Paloma L.F.; Marson, Fernando A.L.; Ribeiro, Maria A.G.O.; Schivinski, Camila I.S.; Ribeiro, José D. Evaluation of respiratory dynamics by volumetric capnography during submaximal exercise protocol of six minutes on treadmill in cystic fibrosis patients☆ Jornal de Pediatria, vol. 95, no. 1, 2019, January-February, pp. 76-86 Sociedade Brasileira de Pediatria

DOI: https://doi.org/10.1016/j.jped.2017.10.007

Available in: https://www.redalyc.org/articulo.oa?id=399759173012

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J Pediatr (Rio J). 2019;95(1):76---86

www.jped.com.br

ORIGINAL ARTICLE

Evaluation of respiratory dynamics by volumetric

capnography during submaximal exercise protocol of

ଝ

six minutes on treadmill in cystic ﬁbrosis patients

a,∗ a,b,∗ a

Paloma L.F. Parazzi , Fernando A.L. Marson , Maria A.G.O. Ribeiro ,

c a

Camila I.S. Schivinski , José D. Ribeiro

a Universidade

Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brazil

Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas, Departamento de Genética Médica, Campinas,

SP, Brazil

Universidade do Estado de Santa Catarina (UDESC), Centro de Educac¸ão Física e Esporte, Florianópolis, SC, Brazil

Received 17 July 2017; accepted 20 October 2017

Available online 29 November 2017

KEYWORDS Abstract

Objectives:

Breath; Volumetric capnography provides the standard CO2 elimination by the volume

CFTR; expired per respiratory cycle and is a measure to assess pulmonary involvement. Thus, the

Exercise; objective of this study was to evaluate the respiratory dynamics of healthy control subjects

and those with cystic ﬁbrosis in a submaximal exercise protocol for six minutes on the tread-

Pulmonary function;

mill, using volumetric capnography parameters (slope 3 [Slp3], Slp3/tidal volume [Slp3/TV],

Slope 2;

and slope 2 [Slp2]). Slope 3

Methods:

This was a cross-sectional study with 128 subjects (cystic ﬁbrosis, 64 subjects; con-

trols, 64 subjects]. Participants underwent volumetric capnography before, during, and after six

minutes on the treadmill. Statistical analysis was performed using the Friedman, Mann---Whitney,

and Kruskal---Wallis tests, considering age and sex. An alpha = 0.05 was considered.

Results:

Six minutes on the treadmill evaluation: in cystic ﬁbrosis, volumetric capnography

parameters were different before, during, and after six minutes on the treadmill; the same

was observed for the controls, except for Slp2. Regarding age, an Slp3 difference was observed

in cystic ﬁbrosis patients regardless of age, at all moments, and in controls for age ≥ 12 years;

a difference in Slp3/TV was observed in cystic ﬁbrosis and controls, regardless of age; and an

Slp2 difference in the cystic ﬁbrosis, regardless of age. Regarding sex, Slp3 and Slp3/TV differ-

ences were observed in cystic ﬁbrosis regardless of sex, and in controls in male participants;

an Slp2 difference was observed in the cystic ﬁbrosis and female participants. The analysis

between groups (cystic ﬁbrosis and controls) indicated that Slp3 and Slp3/TV has identiﬁed the

CF, regardless of age and sex, while the Slp2 showed the CF considering age.

ଝ

Please cite this article as: Parazzi PL, Marson FA, Ribeiro MA, Schivinski CI, Ribeiro JD. Evaluation of respiratory dynamics by volumetric

capnography during submaximal exercise protocol of six minutes on treadmill in cystic ﬁbrosis patients. J Pediatr (Rio J). 2019;95:76---86. ∗

Corresponding authors.

E-mails: [email protected] (P.L. Parazzi), [email protected] (F.A. Marson).

https://doi.org/10.1016/j.jped.2017.10.007

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Slope 3 and slope 2 in cystic ﬁbrosis 77

Conclusions: Cystic ﬁbrosis showed greater values of the parameters before, during, and after

exercise, even when stratiﬁed by age and sex, which may indicate ventilation inhomogeneity

in the peripheral pathways in the cystic ﬁbrosis.

access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/

4.0/).

PALAVRAS-CHAVE Avaliac¸ão da dinâmica respiratória por capnograﬁa volumétrica durante o protocolo

Respirac¸ão; de exercício submáximo por seis minutos em esteira em pacientes com ﬁbrose cística CFTR; Exercício; Resumo

Objetivos:

A capnograﬁa volumétrica fornece o padrão de eliminac¸ão do CO2, pelo volume

Func¸ão pulmonar;

expirado por ciclo respiratório, e avalia o comprometimento pulmonar. O objetivo do estudo

Slope 2;

foi avaliar a dinâmica respiratória de indivíduos controles saudáveis e em indivíduos com ﬁbrose

Slope 3

cística, em um protocolo de exercício submáximo por seis minutos em esteira, por parâmetros

da capnograﬁa volumétrica [slope 3(Slp3), Slp3/volume corrente (Slp3/TV) e slope 2(Slp2)].

Métodos:

Estudo de corte transversal com 128 indivíduos [(ﬁbrose cística) 64 indivíduos; (con-

troles) 64 indivíduos]. Os participantes realizaram capnograﬁa volumétrica antes, durante e

após seis minutos em esteira. Análise estatística realizada pelos testes de Friedman, Mann-

Whitney e Kruskal-Wallis, considerado a idade e o sexo. Alpha = 0,05.

Resultados:

Avaliac¸ão de seis minutos em esteira: na ﬁbrose cística, os parâmetros da capno-

graﬁa volumétrica foram diferentes antes, durante e após seis minutos em esteira, o mesmo

ocorreu nos controles, exceto para o Slp2. Considerando a idade: (Slp3) diferenc¸a na FC, inde-

pendentemente da idade, em todos os momentos e nos controles apenas para ≥12 anos;

(Slp3/TV) diferenc¸a para ﬁbrose cística e controles independentemente da idade; (Slp2)

diferenc¸a apenas para o grupo ﬁbrose cística, independentemente da idade. Considerando

o sexo: (Slp3 e Slp3/TV) diferenc¸a para ﬁbrose cística, independentemente do sexo, e con-

troles apenas no sexo masculino; (Slp2) diferenc¸a para ﬁbrose cística e sexo feminino. Análise

entre grupos (fibrose cística versus controles): Slp3 e Slp3/TV identificou a fibrose cística, inde-

pendentemente da idade e sexo, enquanto o Slp2 evidenciou a ﬁbrose cística considerando a idade.

Conclusão:

A ﬁbrose cística apresentou maiores valores dos parâmetros antes, durante e após

exercício, inclusive quando se considerou idade e sexo, podendo indicar não homogeneidade

da distribuic¸ão da ventilac¸ão nas vias periféricas.

Open Access sob uma licenc¸a CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.

0/).

Introduction to administer, that is well tolerated and does not require a

maneuver that is forced or hard to understand. In addition,

5,6

it can detect early pulmonary alterations.

In cystic ﬁbrosis (CF; OMIM: #219700) there is a progressive

Therefore, the objective of this study was to evaluate the

decline of lung function that is determinant of patients’

respiratory dynamics of healthy control children and adoles-

mortality. However, recently, favorable CF prognosis have

cents and those with CF in a submaximal exercise protocol on

been demonstrated in subjects with better aerobic condi-

1,2 treadmill for six minutes (SMWT) considering VCap param-

tioning and nutritional status. For this reason, markers

eters (slope 3, slope 3/exhaled tidal volume [slope 3/TV],

that show limitations to exercise and that evaluate progres-

2,3 and slope 2).

sive pulmonary deterioration have been studied.

CF shows progressive involvement of peripheral airways

(pulmonary silent zone), considering that conventional pul- Methods

monary function tests are ineffective to correctly assess the

4,5

region. Thus, volumetric capnography (VCap) arises as an

This was a cross-sectional study with 128 subjects, 64 with

alternative to assess the partial pressure of carbon dioxide

CF and 64 healthy control volunteers. The study included

(VCO2) in the gas that comes in and out of the lungs over

subjects with CF who agreed to participate in the study and

time and to detect homogenization of the pulmonary periph-

who met the inclusion criteria. A signed informed consent

ery at the beginning of the gas washout. VCap provides gas

was obtained from all participants included in the study. The

transport indexes in the alveolar airways of the lung periph-

study followed the ethical criteria of the Helsinki Convention

ery, slope 3. In summary, VCap is a low cost procedure, easy

78 Parazzi PL et al.

and was approved by the Ethics Committee of the institution CL 5004, SP, Brazil) for six minutes to analyze the behav-

(No. 1182/2009). ior of the VCap variables. SMWT started with the treadmill

paused. The speed was progressively increased every minute

according to the individual’s tolerance to walking, with-

CF group

out running, and respecting the submaximal effort of each

individual.3,10

Inclusion criteria were: age between 6 and 25 years; CF

Immediately before the SMWT, the participant remained

diagnosis by two sweat tests with chloride values above

at rest for four minutes to assess the VCap. Then, the SMWT

60 mEq/L and/or presence of two mutations in the (cys-

3,7,8 was started, and the VCap data were measured during the

tic ﬁbrosis transmembrane regulator (CFTR) gene ; and

SMWT.

clinical stability determined by two clinical scores: Cystic

The exercise was accompanied by verbal stimuli, which

Fibrosis Foundation Clinical Score and Cystic Fibrosis Clini-

9,10 was provided on the ﬁrst minute and at the end of each

cal Score. Disease severity was classiﬁed in accordance

11 minute.

with the Shwachman-Kulczycki score.

The exercise protocol was based on the SMWT and on

3,10---15

protocols developed on treadmill.

Control group

Healthy subjects aged between 6 and 25 years were ran-

domly selected among students of public and private schools

Statistical analysis

located in the same neighborhood as this university. Partici-

pants answered a questionnaire about health conditions and

For each moment of evaluation during the exercise, the

did not present acute respiratory disease or modiﬁcation in

VCap data are presented by the mean, standard deviation,

the spirometry variables.

median, minimum, maximum, and the conﬁdence interval

for the mean. The moments evaluated were: (1) baseline;

Volumetric capnography (2) 1st and 2nd minutes of SMWT; (3) 3rd and 4th minutes of

SMWT; (4) 5th and 6th minutes of SMWT; and (5) after SMWT.

The subjects underwent the VCap on a treadmill. In VCap, Statistical analysis was performed in the software SPSS, ver-

the Co2smo Plus Dx-8100 monitor (Novametrix, Medical Sys- sion 24 (IBM Corp. Released 2016. IBM SPSS Statistics for

tems, USA) was used to evaluate the participants four Windows, Version 24.0 --- Armonk, NY: IBM Corp.) using Fried-

minutes before SMWT, six minutes during it, and four min- man, Mann---Whitney, and Kruskal---Wallis tests. The analyses

utes after the test. The system is not invasive and is considered the age and sex of subjects. An alpha = 0.05 was

composed of a monitor containing a capnograph, pulse considered.

oximetry, and pneumotachograph. VCap and pneumotacho-

graph measurements were obtained in real time by the

expired gas analysis. The Co2smo Plus Dx-8100 monitor was

linked to a computer equipped with the software to record Results

ﬂow, volume, pressure, pressure-volume, volume ﬂow, and

VCap and curves measurements.

In the CF and control groups, slope 3, slope 3/TV, and

The sensor of the monitor was connected to a nozzle,

slope 2 presented differences among the moments analyzed

and a nasal clip was used to avoid air escape through the p

( < 0.05). Slope 3 showed higher values in the CF and con-

nose. At the end of collection, an ofﬂine sequence of respi-

trol groups at moments 1, 3, 4, and 5 (p < 0.05), while slope

ratory cycles was selected to admit a coefﬁcient of variation

3/TV showed higher values in the CF and control groups for

for the TV lower than 25% of the mean TV, and a coefﬁ-

all the moments (p < 0.05; Table 1 and Fig. 1).

cient of variation lower than 10% in millimeters of mercury

Considering the subjects by age group, the slope 3

(mmHg) was admitted for EtCO2. Respiratory cycles with

showed difference in CF between the analyzed moments

zero value for the slope 3 were eliminated. The result was

regardless of age, whereas the controls only showed dif-

obtained from the mean of variables during the minutes of

ference in subjects aged ≥ 12 years (p < 0.05; Table 2 and

monitorization.3,5,9

Fig. 1). The slope 3/TV showed difference in the CF and

In this study, the following measures were assessed:

control groups regardless of age, in all the moments ana-

(i) TV: volume of air exhaled in one breath, measured in

lyzed (Table 2 and Fig. 1). When stratiﬁed by age group,

milliliters (mL); (ii) Slope of phase II of the VCap curve (slope

slope 3, slope 3/TV, and slope 2 were able to differentiate

2), measured in mmHg/L; (iii) Slope of phase III of VCap

the groups (CF and controls), at all moments and in all the

curve (slope 3): measured in mmHg/L.

analyses (Table 2).

Regarding sex, no differences were observed between the

Submaximal exercise of six minutes on the moments in the parameters slope 3 and slope 3/TV for the

treadmill (SMWT) controls of the female sex ( > 0.05) (Table 3; Fig. 1). In turn,

slope 2 only showed differences between the moments for

the females from the CF group (p < 0.05; Table 3). The slope

Before starting the SMWT on the treadmill, the anthropo-

3 and slope 3/TV were able to differentiate the groups (CF

metric assessment was conducted, which included weight

and controls), at all moment and in all the analyses, when

(kg), height (cm), and calculation of body mass index (BMI).

sex was considered (Table 3).

Participants walked on a treadmill (Caloi Electronics Pro

Slope 3 and slope 2 in cystic ﬁbrosis 79 3 4

the 4 4; 4;

and 4) 3, 2,

3, 1 / / 5; 4) 5; 4) = =

and and after /

/ = and

3 3

volumetric (1 (1

5, 3

and and and and (1

2, 2, / = 1 3 1 3 4; 5) 5)

the

/ / = =

5 / / / / = = = =

-Value SMWT; of

and and 5 5 and 4 4 5; <0.001 (1 <0.001 p <0.001 (1 0.101 <0.001 0.019 the

moments

24.91 19.65

3.75 2.77

± ± 0.03 0.02

minutes ± ±

± ±

6th

different 5 <0.001 <0.001 0.052 33.77 6.85 170.58 30.55---45.55 12.57 1 163.67 12.71---23.78 0.1 0.01 2.05 0.1---0.25 0.02 0 1.41 0.02---0.11 462.7 139 1366.24 433.84---533.42 400.36 240.28 1184.37 389.72---468.26

and in

5th 64)

= 4,

n ( 24.02 483.63

2.8 38.05 2.01 18.24 16.18 428.99

± 0.01 0.07

± ± ± 0.01 0.17

± SMWT;

the controls

4 <0.001 <0.001 0.86 23.74 6.51 99.34 25.36---36.59 12.31 3.5 78.08 13.52---21.58 0.05 0 0.52 0.07---0.13 0.02 0 0.85 0.02---0.08 385.18 161.66 1173.23 395.28---491.3 388.58 207.76 779.63 376.75---441.44

healthy

minutes 16.88 409.1

2.6 17.55 21.44 443.29

± and 2.75 30.98 0.01 0.05

4th ± ± 0.01 0.1

Moment

± ±

64)

and =

3 <0.001 <0.001 0.216 26.41 6.24 99.47 25.71---36.7 13.4 4.58 97.61 13.28---23.7 0.06 0 0.54 0.07---0.14 0.02 0 0.76 0.02---0.09 402.71 167.4 1070.96 407.95---493.65 380.12 207.82 816.03 374.53---442.02 n (

3rd

bold.

ﬁbrosis in

20.28 450.8 15.35 408.27

SMWT; 2.65 18.49

± ± 4.52 31.2 0.04 0.1 0.02 0.05

± ± ± the

cystic

2 0.052 0.003 0.596 27.29 6.05 246.48 26.76---44.84 12.75 4.63 147.71 15.13---25.76 0.06 0.01 3.04 0.05---0.25 0.02 0 1.74 0.01---0.12 439.04 147.49 1003.17 409.39---490.48 401.39 228.65 791.22 385.04---446.41 presented

with

are

minutes

21.57 449.93 21.17 415.73 2nd subjects

-values 3.01 35.8 2.25 20.44

p ± ± 0.02 0.15 0.01 0.07

± ±

and ± ±

1st among

1 34.5 5 140.1 31.58---43.64 16.15 1.5 91 16.45---25.45 0.13 0.01 1.4 0.11---0.21 0.04 0 0.67 0.04---0.09 480.63 140 940.17 444.43---530.68 440.06 225.88 1215.58 413.64---498.25 <0.001 <0.001 2 positive 2,

0.05.

with

slope

Alpha

baseline; Data

and SD 37.61 SD 20.95 SD 0.16 SD 0.07 SD 487.55 SD 455.95

± ± ± ± ± ±

CI CI CI CI CI CI

used.

3/TV, -Value -Value -Value 0.596

treadmill.

Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Mean Mean Mean p p p Mean Mean Mean interval; were

the

slope

3, tests

test

fibrosis fibrosis fibrosis confidence slope

walk

CI, of Friedman

Group Cystic Controls Controls Controls and

six-minute deviation;

Association

SMWT, 1 3 Cystic 3/tidal 2 Cystic

Kruskal---Wallis standard

capnography. Slope Slope SMWT; volume The Table Markers Slope SD,

80 Parazzi PL et al. of

5; 5) 2, 4, 3, 4;

5; 1,

1, 1, 3, 2, 3,

5; 5) 3, / / / / =

/ / = = = = =

1, 2, 5) 3 2, 5 5

moments

(3 (4 (1

/ = 1, 1, 4; 1,

5) and 2 and / / / / = = = =

-Value 4 3, 5) 4 4; 2 p 3 0.034 0.445 0.006 0.028 <0.001 (1 0.005 (1 different

C) D; D; age

B, B, 5.1 4.56 5.24 1.38 C,

the B, ± ± ± ±

0.03 0.04

A, A, A,

/ ± ± =

/ / / = = =

C B D 5 44.38 22.85 33.43 11.93 0.2 0.1 <0.001 (A 36.84 11.71 135.6 33.9---54.87 14.84 1 163.67 13.6---32.1 27.52 6.85 170.58 22.80---44.07 10.21 1.21 32.95 9.08---14.77 0.18 0.02 0.98 0.12---0.27 0.03 0 1.41 0.02---0.18 A,

considering C) /

64)

C, =

A, D; 4.47 3.16 3.41 1.48

0.02 0.02

( B, ± ± ± ± /

= A,

± ±

/ = D / =

D; C 4 37.76 21.63 26.03 11.96 0.14 0.07 <0.001 (A 28.51 12.15 99.34 28.55---46.96 13.54 6.7 78.08 15.2---28.06 20.06 6.51 85.1 19.09---32.96 9.37 3.5 36.25 8.92---15 0.08 0.02 0.52 0.09---0.2 0.02 0.01 0.85 0.02---0.12 controls

C) /

healthy

A, D; 4.54 4.3 3.33 1

0.02 0.02

B, ± ± ± ± /

Moment = A,

and ± ±

/ = D / =

64)

D; C 3 36.29 23.35 27.49 11.89 0.15 0.09 <0.001 (A 27.09 13.25 99.47 26.95---45.64 13.5 7.52 97.61 14.62---32.07 24.56 6.24 84.87 20.73---34.25 11.9 4.58 23.6 9.77---13.9 0.07 0.02 0.54 0.09---0.2 0.02 0.01 0.76 0.03---0.14 =

n (

C) / =

ﬁbrosis C,

A, D; 8.84 4.3 4.15 1.55

0.11

B, ± ± ± ± / 0.04

/ ± =

D / cystic =

D; C 0.004 (A 2 45.79 25.32 28.51 13.77 0.25 0.1 32.01 15.4 246.48 27.6---63.98 19.04 7.17 147.71 16.58---34.05 18.13 6.05 123.5 20.10---36.93 10.84 4.63 36.72 10.57---16.96 0.09 0.02 3.04 0.02---0.48 0.03 0.01 1.74 0.01---0.2 with

/ =

D; D

C, subjects

B, 4.91 3.51 3.61 1.98 C;

0.04 0.02

B, ± ± ± ±

A, A,

± ±

/ = / / = =

among

C) B C 1 44.69 24.57 32.44 15.99 <0.001 (A 0.21 0.09 38.04 16.38 140.1 34.59---54.8 17.63 1.5 91 17.43---31.71 31.6 5 102.12 25.11---39.78 13.05 4.79 39.04 11.91---20.07 0.14 0.04 1.4 0.11---0.32 0.05 0 0.67 0.05---0.13 2

slope

and

SD SD SD SD SD SD

± ± ± ± ± ±

CI CI CI CI CI CI

3/TV,

-Value Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% p Mean Mean Mean Mean Mean Mean slope

12 <12 ≥ <12

years years years

slope 12

<12 ≥ <12 of

fibrosis fibrosis fibrosis

old old old

Controls Cystic Controls Controls old (B) old (B) (A) (C) (A) Group years years years old (D) Cystic capnography.

Association

2 3 Cystic 3/tidal

volumetric Slope volume Table Markers Slope

Slope 3 and slope 2 in cystic ﬁbrosis 81 2 4,

5) the 2,

3, 4)

5; 1,

2, 4; 3, /

4, 5) =

2, / after

/ /

= = 1,

3 3, 3,

5, 4 1, 5 5

/ =

2, 1,

/ = 1; and 5

/ / = = and 4 and 2 / =

-Value SMWT;

3 5) and 4; 5; 0.017 (1 0.497 0.003 (4 0.244 p <0.001 (1 0.001 (1 the A,

bold. A,

of / in =

C) D; /

D; C B,

B C) C,

28.59 28.59 35.87 13.67

C, D; /

A, = B, D;

± ± ± ± 0.05 0

minutes C, B, B

/ = A, A,

± ±

presented / /

= = D D; / / 6th = =

are D C <0.001 (A 5 0.16 490.97 434.15 344.05 B, D; <0.001 (A 0.07 0.01 2.05 0.04---0.27 0.01 0 0.09 0.01---0.03 553.21 304.51 871.09 492.66---610.2 462.52 277.14 1184.37 432.98---548.96 430.06 139 1366.24 361.39---506.92 341.68 240.28 501.23 315.94---372.17

and

A, C,

5th

C) / / =

= -values

4, p D;

B, B)

B B

33.79 551.43 22.44 29.75 13.72 D;

A, A, D; B;

± ± ± ± 0.01 0 0.02

C, B, / / = = SMWT; A, A,

± ±

positive / / = =

D D / / = =

the

C D; <0.001 (A 4 0.07 462.76 380.49 335.55 C D; <0.001 (A 0.03 0 0.49 0.03---0.1 0.01 0 0.08 0.01---0.02 566.16 277.46 919.83 459.87---598.8 427 293.25 779.63 417.23---508.29 366.42 161.66 1173.23 320.14---440.84 340.32 207.76 519.02 307.34---363.76 of with

A, C,

C) Data / /

B, B)

B B minutes

24.62 24.47 12.33 D;

A, A, used. D; B;

± ± ± 4th 0.01 0 0.01

32.3 529.34 B, C, / /

Moment = = A, A, ± ±

± / /

= = D D and were / / = =

D; C 3 0.07 460.03 390.08 337.35 C <0.001 (A D; <0.001 (A 0.03 0 0.51 0.04---0.11 0.01 0 0.04 0.01---0.02 549.36 279.94 1070.96 467.59---600.41 421.89 287.67 816.03 410.09---509.97 347.12 167.4 924 340.45---439.72 338.1 207.82 471.01 311.99---362.71 3rd

tests

3, A, C,

C) / / =

B, B)

B B

SMWT; 29.71 534 20.77 22.62 12.55

A, A, D; B; Friedman

± ± ± ± 0.02 0 0.01

B, C, the / / = = A, A,

± ±

and / /

= = of D D / /

= =

D; C <0.001 (A 2 0.08 470.71 386.08 C D; <0.001 (A 0.03 0.01 0.57 0.04---0.12 0.01 0 0.07 0.01---0.03 554.58 340.24 1003.17 476.35---598.52 450.06 272.59 791.22 428.58---512.84 381.25 147.49 708.09 340.18---431.97 334.85 228.65 464.55 314.56---366.18 A, C,

minutes

C) / / =

B, B)

B B 2nd

Kruskal---Wallis 28.52 537.44 30.66 28.01

A, A, D; B; 17.82 340.37

± ± ± 0.02 0 0.02

and

B, C,

± / /

The = = A, A,

± ±

/ / = = 1st D D / /

= =

2, <0.001 (A <0.001 (A D; C 1 0.12 517.42 432.98 C D; 0.07 0.01 0.64 0.07---0.16 0.02 0.01 0.15 0.02---0.05 548.63 332.84 940.17 503.7---620.97 476.5 273 1215.58 455.22---579.62 400.21 140 833.67 376.17---489.79 351 225.88 602.15 335.07---408.33 0.05.

Alpha

baseline;

SD SD 0.04 SD 562.34 SD SD SD 371.7

± ± ± ± ± ±

CI CI CI CI CI CI

treadmill.

-Value -Value Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% p p Mean Mean Mean Mean Mean Mean interval;

the

12 12 test ≥ <12 ≥

years years years

conﬁdence

12 12 walk

≥ <12 ≥ CI,

)

fibrosis fibrosis fibrosis

old old old

Controls Controls Cystic Controls old (B) (C) (A) (C) Group Cystic years years years old (D) old (D) six-minute deviation;

Continued

(

SMWT, 2 2 Cystic

standard

Slope SMWT; Table Markers SD,

82 Parazzi PL et al. of

1, 4) 3, 3,

5; / =

/ = 3, 2,

4 4, 5

/ / = =

2) 4)

1, 5; 5 5

moments

1, 2, and / = 1,

2 / / = =

and and 2 5) / =

-Value 2, 4; 4) p <0.001 (1 0.001 (1, 3 0.008 (1 0.04 (3 0.029 (1 0.230 different

C) in

B, A,

sex /

= / =

3.58 2.74 6.63 4.64

D the ± ± ± ±

0.03 0.04

± ±

and

B <0.001 (A 5 35.45 19.89 40.65 16.79 0.2 0.1 37.12 6.85 84.58 28.14---42.75 14.87 4.17 59.21 14.27---25.51 32.31 8.14 170.58 27.13---54.18 11.37 1 163.67 7.34---26.24 0.18 0.02 0.98 0.12---0.27 0.03 0 1.41 0.02---0.18 D;

C) considering

/ 64) =

/ =

3.63 3.94 4.3 1.25

C n 0.02 0.02

( ± ± ± ±

± ±

and

B 4 28.81 21.93 33.14 13.68 0.14 0.07 <0.001 (A 24.02 6.57 85.66 21.4---36.23 13.72 3.5 78.08 13.87---30 23.74 6.51 99.34 24.36---41.92 11.76 4.89 36.25 11.13---16.23 0.08 0.02 0.52 0.09---0.2 0.02 0.01 0.85 0.02---0.12 controls

/ = / =

healthy

3.46 5.36 4.25 0.91

C 0.02 0.02

± ± ± ±

Moment ± ± and

and

B 3 27.97 23.51 34.44 14.06 0.15 0.09 <0.001 (A 19.95 6.65 81.12 20.91---35.02 12.96 4.58 97.61 12.54---34.48 27.32 6.24 99.47 25.76---43.12 13.84 4.75 28.5 12.2---15.92 0.07 0.02 0.54 0.09---0.2 0.02 0.01 0.76 0.03---0.14 64),

n (

/ = 7.98 5.29 4.37 1.25

ﬁbrosis

0.11 B

± ± ± ± 0.04

C, ±

cystic

0.038 (A, 2 38.16 26.88 33.44 14.77 0.25 0.1 24.96 9.15 246.48 21.88---54.44 19.67 4.82 147.71 16.05---37.7 27.29 6.05 105.14 24.51---42.37 12.32 4.63 35.56 12.20---17.33 0.09 0.02 3.04 0.02---0.48 0.03 0.01 1.74 0.01---0.2 with D;

/ = / =

4.62 3.69 3.94 2.7

C 0.04 0.02

subjects D

± ± ± ±

± ±

and

B 1 37.67 23.36 37.55 18.83 <0.001 (A 0.21 0.09 34.5 6.95 140.1 28.23---47.11 17.25 1.5 91 15.81---30.91 34.1 5 104.26 29.5---45.6 15.29 4.78 90.04 13.32---24.34 0.14 0.04 1.4 0.11---0.32 0.05 0 0.67 0.05---0.13 among

slope

SD SD SD SD SD SD

and

± ± ± ± ± ±

CI CI CI CI CI CI

-Value 3/TV, Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Median Minimum Maximum 95% Mean Mean Mean Mean Mean Mean p

slope

3, and and and

and and and slope

fibrosis fibrosis fibrosis

Group masculine (A) feminine (C) masculine (A) masculine (B) feminine (D) masculine (B) Cystic Controls Cystic Controls Controls capnography.

Association

3 3 Cystic 3/tidal

volumetric Slope volume Table Markers Slope

Slope 3 and slope 2 in cystic ﬁbrosis 83 the 3 4, 4)

2, 1, 3, 5; 5) after

/ / /

= = = ,

5, 2 1, 5 2 5

/ = 1, 4;

and 3 and / =

-Value SMWT;

and 5; 4 <0.001 (1 0.23 p 0.068 0.238 0.001 (1 0.189 the

bold.

C) of

B, A, / = / 28.59 28.59 35.87 13.67 =

C ± ± ± ± 0.05 0

minutes

± ±

presented

and 6th

and

<0.001 (A B 5 0.16 551.43 490.97 434.15 344.05 0.129 0.07 0.01 2.05 0.04---0.27 0.01 0 0.09 0.01---0.03 553.21 304.51 871.09 492.66---610.2 462.52 277.14 1184.37 432.98---548.96 430.06 139 1366.24 361.39---506.92 341.99 240.28 501.23 315.94---372.17 are

and

C) 5th

B, -values A, 4,

/ = / 33.79 22.44 29.75 13.72 =

C ± ± ± ± 0.01 0 0.02

± ± SMWT;

positive and

and

the

<0.001 (A B 4 0.07 529.34 462.76 380.49 335.55 0.801 0.03 0 0.49 0.03---0.1 0.01 0 0.08 0.01---0.02 566.16 277.46 919.83 459.87---598.8 427 293.25 779.63 417.23---508.29 366.42 161.66 1173.23 320.14---440.84 340.32 207.76 519.02 307.34---363.76 of with

Data B,

/ = minutes / 24.62 24.47 12.33

C used. ± ± ± 0.01 0 0.01

32.3 4th

Moment

± ±

and

and and were

<0.001 (A B 3 0.07 534 460.03 390.45 0.463 0.03 0 0.51 0.04---0.11 0.01 0 0.04 0.01---0.02 549.36 279.94 1070.96 467.59---600.41 421.89 287.67 816.03 410.09---509.97 347.12 167.4 924 340.45---439.72 338.1 207.82 471.01 311.99---362.71 3rd

tests

29.71 20.77 22.62 12.55 337.35 C)

SMWT;

± ± ± ± 0.02 0 0.01

Friedman

± ± the

/ = and

0.01 (D 2 0.08 470.71 386.08 0.808 0.03 0.01 0.57 0.04---0.12 0.01 0 0.07 0.01---0.03 554.58 340.24 1003.17 476.35---598.52 450.06 272.59 791.22 428.58---512.84 381.25 147.49 708.09 340.18---431.97 334.85 228.65 464.55 314.56---366.18 D;

minutes

B, A,

/ = / 28.52 537.44 30.66 28.01 2nd =

17.82 340.37

Kruskal---Wallis

± ± ± 0.02 0 0.02

and ± ±

The

and

and 1st

B 1 0.12 517.42 0.07 0.01 0.64 0.07---0.16 0.02 0.01 0.15 0.02---0.05 548.63 332.84 940.17 503.7---620.97 476.5 273 1215.58 455.22---579.62 400.21 140 833.67 376.17---489.79 351 225.88 602.15 335.07---408.33 <0.001 (A 2, 0.05.

Alpha

baseline;

SD SD 0.04 SD 562.34 SD SD 432.98 SD 371.7

± ± ± ± ± ±

CI CI CI CI CI CI

-Value -Value 0.222 treadmill.

the

and and and

test

conﬁdence

and and and

walk

fibrosis fibrosis fibrosis CI,

)

Group Cystic feminine (D) masculine feminine feminine (C) masculine feminine Controls Controls Cystic Controls six-minute deviation;

Continued

(

SMWT, 3 2 Cystic

standard

Slope SMWT; Table Markers SD,

84 Parazzi PL et al.

A. Slope 3 B. Slope 3/ TV

Group 45 Group 0.2 1 1 40 2 2 35 30 0.1 25 Slope 3 20 Slope 3/TV 15 10 0.0 1 2 3 4 5 1 2 3 4 5 11Moment Moment

Age 50 Age 0.3 11 45 11 12 40 12 21 21 22 35 22 0.2 30 25

Slope 3 20 0.1 15 Slope 3/TV 10 5 0.0

2 1 2 3 4 5 2 1 2 3 4 5 Moment Moment

Genre 50 Genre 0.2 11 11 45 12 12 40 21 21 22 35 22 30 0.1 25

Slope 3 20 15 Slope 3/TV 10 5 0.0 1 2 3 4 5 1 2 3 4 5

3 Moment Moment

Figure 1 Volumetric capnography association among subjects with cystic ﬁbrosis. A. Slope 3 association among subjects with

cystic ﬁbrosis (CF, 1) (n = 64) and healthy controls (2) (n = 64) considering age and sex in different moments of volumetric capnog-

raphy. 1. Association of slope 3 with CF and controls. (moment 1) 1 = 34.5, 2 = 16.15, (moment 2) 1 = 27.29, 2 = 12.75. (moment

3) 1 = 26.41, 2 = 13.4. (moment 4) 1 = 23.74, 2 = 12.31. (moment 5) 1 = 33.77, 2 = 12.57. 2. Association of slope 3 with CF and

controls considering age. (moment 1) 11 (CF + <12 years) = 38.04, 12 (CF + ≥12 years) = 31.6, 21 (controls + <12 years) = 17.63, 22

(controls + ≥12 years) = 13.05. (moment 2) 11 = 32.01, 12 = 18.13, 21 = 19.04, 22 = 10.84. (moment 3) 11 = 27.09, 12 = 24.56, 21 = 13.5,

22 = 11.9. (moment 4) 11 = 28.51, 12 = 20.06, 21 = 13.54, 22 = 9.37. (moment 5) 11 = 36.84, 12 = 27.52, 21 = 14.84, 22 = 10.21. 3.

Association of slope 3 with CF and controls considering sex. (moment 1) 11 (CF + masculine) = 34.5, 12 (CF + feminine) = 34.1, 21

(controls + masculine) = 17.25, 22 (controls + feminine) = 15.29. (moment 2) 11 = 24.96, 12 = 27.29, 21 = 19.67, 22 = 12.32. (moment

3) 11 = 27.97, 12 = 27.32, 21 = 12.96, 22 = 13.84. (moment 4) 11 = 24.02, 12 = 23.74, 21 = 13.72, 22 = 11.76. (moment 5) 11 = 37.12,

12 = 32.31, 21 = 14.87, 22 = 11.37. B. Slope 3/tidal volume association among subjects with CF (1) (n = 64) and healthy controls (con-

trols, 2) (n = 64) considering the age and sex in different moments of volumetric capnography. 1. Association of slope 3 with CF and

controls. (moment 1) 1 = 0.13, 2 = 0.04, (moment 2) 1 = 0.06, 2 = 0.02. (moment 3) 1 = 0.06, 2 = 0.02. (moment 4) 1 = 0.05, 2 = 0.02.

(moment 5) 1 = 0.1, 2 = 0.02. 2. Association of slope 3 with CF and controls considering age. (moment 1) 11 (CF + <12 years) = 0.14, 12

(CF + ≥12 years) = 0.07, 21 (controls + <12 years) = 0.05, 22 (controls + ≥12 years) = 0.02. (moment 2) 11 = 0.09, 12 = 0.03, 21 = 0.03,

22 = 0.01. (moment 3) 11 = 0.07, 12 = 0.03, 21 = 0.02, 22 = 0.01. (moment 4) 11 = 0.08, 12 = 0.03, 21 = 0.02, 22 = 0.01. (moment 5)

11 = 0.18, 12 = 0.07, 21 = 0.03, 22 = 0.01. 3. Association of slope 3/tidal volume with CF and controls considering sex. (moment

1) 11 (CF + masculine) = 0.14, 12 (CF + feminine) = 0.07, 21 (controls + masculine) = 0.05, 22 (controls + feminine) = 0.02. (moment

2) 11 = 0.09, 12 = 0.03, 21 = 0.03, 22 = 0.01. (moment 3) 11 = 0.07, 12 = 0.03, 21 = 0.02, 22 = 0.01. (moment 4) 11 = 0.08, 12 = 0.03,

21 = 0.02, 22 = 0.01. (moment 5) 11 = 0.18, 12 = 0.07, 21 = 0.02, 22 = 0.01. (moments) 1, baseline time in the SMWT; 2, 1st and 2nd

minutes of the SMWT; 3, 3rd and 4th minutes of the SMWT; 4, 5th and 6th minutes of the SMWT; 5, after the SMWT; SMWT, six-minute

walk test on the treadmill. TV, tidal volume. We used the Mann---Whitney, Kruskal---Wallis and Friedman tests. Alpha = 0.05. The

medians and the 95% conﬁdence interval are represented in the graphs.

Discussion Speciﬁcally, VCap presented numerous indexes, such as

the slope 3, which provides data about the dynamics of gas

transport in the alveolar airways of the lung periphery. The

The authors believe that this is the ﬁrst time the VCap

inclination of slope 3 is determined by the emptying nature

parameters during exercise are compared in healthy sub-

16,17

of the alveolar units: synchronous or asynchronous.

jects and CF subjects. The study demonstrated the possibil-

Emptying is synchronous when the gas simultaneously

ity of obtaining markers in a non-invasive way and through a

expires from the alveoli, resulting in phase III horizontal or

submaximal effort protocol that is tolerable by participants.

Slope 3 and slope 2 in cystic ﬁbrosis 85

with minimal tilt. In turn, sequential/late emptying occurs does not differ between sexes in prepubescent individu-

when the alveolar units are emptied in an asynchronous als, but it increase proportionally in males from puberty

manner, i.e., with longer time constants, making the PCO2 onwards. All of that is due to the development of muscle

higher, resulting in a growing inclination of slope 3. Slope 3 mass and effect of hormonal maturation on the functional

27---30

depends on the numerous alveoli emptying patterns with dif- musculoskeletal characteristics.

ferent ventilation/perfusion ratios (V/Q), as the continuous Although the CF group presented reduction of the alveo-

elimination of CO2 in the alveoli, making the VCap a use- lar ventilation and change in the V/Q ratio, as evidenced

ful tool to detect anomalies in the maladjustment between by the curve of slope 3, the patients in this group were

9,18,19

V/Q. able to perform the physical exercise protocol without

Slope 3 presented higher values in the CF, indicating a complications.

ventilation inhomogeneity in the distal airspaces in com- VCap is not widely used in clinical practice mainly due

5,17

parison with controls. Veronez et al. described that the to little understanding of the data obtained, as well as

increase in slope 3 in subjects with bronchiectasis, related the scarcity of published studies. This study described the

or not to the CF, indicated diffuse disease of small airways. behavior of slope 2 and slope 3 during submaximal physi-

The behavior of slope 3 during physical exercise observed cal exercise in CF patients; it was observed that patients

in this research was similar in the CF and control groups. A show functional alterations from the baseline period, which

decrease in the values of the index was noted during the are accentuated during exercise. In addition, although no

physical exercise, followed by a quick recovery. However, ventilation homogeneity was observed in the pulmonary

higher values of slope 3 inclination probably occurred in periphery in the CF group, patients were able to perform

the CF due to greater retention of exhaled carbon dioxide submaximal exercises for short periods of time. Data from

(VCO2), but it is necessary to consider other hypothesis, such slope 2 and slope 3 showed that even asymptomatic patients

as earlier emptying of alveolar dead space regions (V/Q rela- presented changes in lung function, which indicates the

tionships) and variations in cardiac output. Therefore, the need for earlier intervention to minimize chronic lung degra-

CF group presented increased values of slope 3 during the dation.

evaluation, indicating initial ventilation inhomogeneity dur- In conclusion, the VCap parameters analysis demon-

ing the rest. This fact is justiﬁed in the CF by the largest strated that CF subjects present alterations in respiratory

CO2 production and retention, increase in airway resistance, dynamics during physical exercise and that these alterations

decreased functional residual capacity, and changes in car- are related to the distal airspaces with heterogeneity of

diac debit during physical activity --- these factors can affect emptying gases.

20---23

the V/Q ratio and inﬂuence the height/slope 3.

Still considering the slope 3, some authors suggest that

5,6,9

it should be standardized by TV. Almeida et al. noted Funding

increased slope3/TV in subjects with asthma, in compari-

son with controls, suggesting ventilation inhomogeneity in Fundac¸ão de Amparo à Pesquisa do Estado de São

the distal airspaces and indicating chronic airway struc- Paulo (FAPESP) for research support and scholarships

tural disorders and acute reversible changes observed in the (#2011/12939-4, #2011/18845-1, #2015/12183-8 and

bronchial challenge test. Moreover, Ribeiro et al., when #2015/12858-5 to FALM and JDR); Fundo de Apoio à

using spirometry and the VCap to assess lung function in Pesquisa, ao Ensino e à Extensão da Universidade Estad-

CF, identiﬁed an increase in slope 3/TV, even in subjects ual de Campinas for research support (#0648/2015 to

with normal spirometry. The present study corroborates FALM). Conselho Nacional de Desenvolvimento Cientíﬁco e

those ﬁndings and identiﬁed an increased slope 3/TV during Tecnológico for scholarship to PLFP.

physical exercise in the CF when compared with controls.

The slope 3 and/or slope 3/TV show association even in

the CF with age younger than 12 years. Thus, since a young Conﬂicts of interest

age, the CF group present alterations in the respiratory

dynamics, but does not compromise the physical activity The authors declare no conﬂicts of interest.

performance.

Numerous features on the physiology of physical effort

considering the age group and sex are observed. In this Acknowledgments

line, the higher values of slope 3 were observed in male

participants from the CF group. However, when normaliz- The authors would like to thank Adyléia Aparecida Contr-

ing by TV (slope 3/TV), the higher values were observed era Dalbo Toro, Arthur Kmit, Roberto José Negrão Nogueira,

in female participants from the CF group. This observa- Kátia Cristina Alberto Aguiar, Aléthea Guimarães Farias,

tion is due to the increase of maximal oxygen consumption Taís Daiene Russo Hortêncio, Aline Gonc¸alves, Gabriel Hes-

(VO2max) in absolute terms throughout the age groups, with sel, Renan Marrichi Mauch, Andressa de Oliveira Peixoto,

greater acceleration in boys than in girls. This event is Luciana Cardoso Bonadia, Carmen Sílvia Bertuzzo, Stéphanie

closely related to the increase in muscle mass, in a way that Villa-Nova Pereira, Antônio Fernando Ribeiro, Carla Cristina

when considering the VO2max ﬁxed by indicators of mus- de Souza Gomez, and Silvana Dalge Severino, who con-

cle mass, there is no increase with age in male children tributed to the studies on cystic ﬁbrosis in this reference

and adolescents (VO2max/kg --- body weight remains cons- center. They would also like to thank the Espac¸o da Escrita

tant), while there is a progressive decline in girls (decrease project/General Coordination of Unicamp for the English

24---26

in VO2max/kg-body weight). Thus, the anaerobic power translation of this article.

86 Parazzi PL et al.

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