Determinants of inspiratory muscle function in healthy children

Theodore Dassios *,Gariel Dimitriou

a Department of Child Health, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK

b Department of Paediatrics, University of Patras Medical School, Patras, Rio 26504, Greece

Abstract Background: Children are affected by disorders that have an impact on the respiratory muscles.Inspiratory muscle function can be assessed by means of the noninvasive tension-time index of the inspiratory muscles (TTImus). Our objectives were to identify the determinants of TTImus in healthy children and to report normal values of TTImus in this population.Methods: We measured weight,height,upper arm muscle area(UAMA),and TTImus in 96 children aged 6-18 years.The level and frequency of aerobic activity was assessed by questionnaire.Results: TTImus was significant y lower in male subjects(0.095±0.038,mean±SD)compared with female subjects(0.126±0.056)(p=0.002).TTImus was significant y lower in regularly exercising (0.093±0.040) compared with nonexercising subjects (0.130±0.053) (p ＜0.001).TTImus was significant y negatively related to age (r=-0.239, p=0.019), weight (r=-0.214, p=0.037), height (r=-0.355, p ＜0.001), and UAMA(r=-0.222, p=0.030). Multivariate logistic regression analysis revealed that height and aerobic exercise were significant y related to TTImus independently of age, weight, and UAMA.The predictive regression equation for TTImus in male subjects was TTImus=0.228-0.001×height(cm),and in female subjects it was TTImus=0.320-0.001×height(cm).Conclusion: Gender,age,anthropometry,skeletal muscularity,and aerobic exercise are significant y associated with indices of inspiratory muscle function in children.Normal values of TTImus in healthy children are reported.2095-2546/©2019 Production and hosting by Elsevier B.V.on behalf of Shanghai University of Sport.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Aerobic exercise;Children;Inspiratory muscle function; Maximal inspiratory pressure;Skeletal muscle function;Tension-time index of the inspiratory muscles

1. Introduction

Respiratory muscle impairment has been increasingly recognized as an independent pathophysiological contributor to disorders that affect the pediatric population. Children with cystic fibrosi (CF)1-3and neuromuscular diseases4are at increased risk of respiratory muscle fatigue. Obese individuals have impaired respiratory muscle function compared with controls owing to increased mechanical loading of the respiratory muscles.5Impaired respiratory muscle function has been identifie as an independent predictor of extubation outcome in children.6Furthermore,anthropometry,7genetic polymorphisms,8and aerobic exercise9,10also contribute to respiratory muscle function in children.

Respiratory muscle strength can be noninvasively determined by the measurement of the maximal inspiratory pressure(PImax)and the maximal expiratory pressure(PEmax).11Although PImaxand PEmaxdescribe a snapshot of respiratory muscle performance at a specifi time point,respiratory muscle function and the risk for muscle fatigue can be better assessed by indices that additionally describe the respiratory load,which consists of the chest wall and lung elastic loads plus the resistive loads. Such an index is the noninvasive tension-time index of the inspiratory muscles(TTImus).12TTImusis a composite dimensionless index that incorporates measurements of pressure and time and describes the efficien y of the total work undertaken by the respiratory muscles.13Higher values of TTImusare indicative of inefficien inspiratory muscle function and increased risk of inspiratory muscle fatigue and respiratory failure.12,13

Clinical assessment of the relative risk of inspiratory muscle fatigue and respiratory failure in children may facilitate decisions aimed at either instituting treatment modalities such as noninvasive ventilation and inspiratory muscle training or implementing strategies for weaning from mechanical ventilation.

To our knowledge, studies reporting values of TTImusin healthy children are scarce,7and patient-derived data and data from ventilated subjects would be affected by distorted lung mechanics. In this study we describe patterns of change of TTImusin healthy children and report the demographic and anthropometric parameters that contribute to alterations of inspiratory muscle function in this population.

2. Methods

2.1. Subjects

Ninety-six healthy children without respiratory problems who were able to perform reproducible maximal respiratory maneuvers were prospectively recruited.They were studied in the outpatient department of the University Hospital of Patras,Greece.Their age ranged from 6 to18 years.The subjects were healthy children recruited from the community and siblings of children attending the outpatient department. Children with pre-existing respiratory conditions such as asthma or CF, children with genetic disorders such as thalassemia, and children who were unwell were excluded from the study.Children younger than 6 years of age were excluded because they could not reliably execute reproducible maneuvers requiring a maximal effort. Suitability of inclusion was assessed by questionnaire.

All respiratory and nutrition measurements were performed by the same examiner (TD).The study protocol was approved by the Research Ethics Committee of the University Hospital of Patras. Parents or legal guardians provided informed written consent prior to the study, and children provided informed assent.

2.2. Measurements

2.2.1. Equipment

A pneumotachograph (Mercury F100L; GM Instruments,Kilwinning, UK) was used to record airway fl w. This was connected to a differential pressure transducer (DP45,range±3.5 cmH2O; Validyne Engineering, Northridge, CA,USA). A side port on the pneumotachograph connected to a differential pressure transducer(DP45,range±225 cmH2O)was used to measure airway pressure.The signals from the differential pressure transducers were amplifie by a portable amplifie(Validyne CD280;Validyne Engineering).The fl w and pressure signals were recorded and displayed in real time on a portable computer (Dell GX620; Dell Inc., Round Rock, TX, USA)running a LabVIEW application (National Instruments,Austin,TX,USA).Analog to digital sampling was at 100 Hz(16-bit NI PCI-6036E;National Instruments).

2.2.2. Measurement of the respiratory pressures

Respiration rate, tidal volume, airway pressure generated 0.1 s after an occlusion(P0.1),PImax,PEmax,inspiratory time(Ti),and total time of respiration (Ttot) were measured for each participating subject. Minute ventilation was calculated as the product of tidal volume times respiratory rate. P0.1was calculated as the airway pressure generated 100 ms after an occlusion while the subject was breathing quietly.A minimum of 4 airway occlusions were undertaken, and the average P0.1value was estimated.11A rubber mouthpiece (dead space 3.5 mL) was pressed tightly against the lips, and the respiratory circuit was occluded at the end of expiration. Any leak around the mouthpiece was minimized. The occlusions were performed with a unidirectional valve(dead space 8 mL)connected to the mouthpiece.PImaxwas measured on a maximal inspiratory effort from residual volume against an occluded airway,and PEmaxwas measured on a maximal expiratory effort from total lung capacity against an occluded airway.14Five maximal reproducible respiratory efforts were undertaken, and the maximum achieved values for PImaxand PEmaxwere recorded.14A 1-2 mm leak in the respiratory line was allowed to avoid closure of the glottis.11Only PImaxand PEmaxwaveforms with minimum plateau pressure of 1 s were accepted for subsequent analysis.11

2.2.3. Calculation of the TTImus

The TTImuswas calculated as

where Tiis the inspiration time and Ttotis the total time for each breath,calculated from the airway fl w signal;PImeanis the mean airway pressure during inspiration(calculated from the formula PImean=5×P0.1×Ti); and PImaxis the maximum inspiratory pressure.3,12

2.3. Nutritional parameters

Body weight and height were measured,and the body mass index (BMI) Z-score was calculated.15Because respiratory muscle function is strongly associated with indices of somatic muscularity,1,3the upper arm muscle area (UAMA) was measured; midarm muscle circumference was measured midway between the olecranon process and the tip of the acromion with the right hand hanging relaxed.16Triceps skinfold thickness was measured by a Harpenden Skinfold Caliper(Baty International,West Sussex,UK)halfway over the triceps muscle and with the skinfold parallel to the longitudinal axis of the humerus.16UAMA was subsequently calculated from midarm muscle circumference and triceps skinfold thickness.17

2.4. Exercise

The level of physical activity (PA) was evaluated with a questionnaire.The exercise group was formed by subjects who engaged in moderate-to-vigorous aerobic activity a minimum of 3 times per week, 45 min each time, over the past 3 months.10,18,19Running, cycling, football, swimming, athletics,basketball,volleyball,martial arts,tennis,and gymnastics were accepted as moderate-to-vigorous PA.19The control group consisted of subjects who did not take part in structured PA.

2.5. Statistics

Normality of distribution was assessed using the Shapiro-Wilk and Kolmogorov-Smirnoff tests. Differences between 2 groups were assessed for significanc using the student’s t test.Pearson correlation analysis was used to examine the univariate relation of P0.1, PImax, and TTImusto age, weight, height, BMI Z-score, and UAMA. Multivariate logistic regression was performed to determine which variables contribute to alterations of TTImus.Regression equations for predictive values of TTImusin males and females were calculated with the corresponding coefficien of determination(R2)and standard error of the estimate.A p value of ＜0.05 was accepted as significant Multicollinearity among the independent variables in the regression analysis was assessed by calculation of the tolerance for the independent variables.A retrospective sample size justificatio was conducted to confi m that the number of participating subjects in the exercising and nonexercising groups were sufficien to detect differences in TTImusat a level of significanc of 0.01 with power of 95%.Statistical analysis was performed using SPSS software (Version 17.0; SPSS Inc., Chicago, IL,USA).

3. Results

All recruited subjects were able to complete the respiratory measurements and the nutrition assessment. Power analysis was conducted to assess the sample size required to identify TTImusdifferences between the groups of exercising and nonexercising subjects. TTImusstandard deviation was set at 0.014.3The power analysis indicated that to detect an increase in TTImusof 0.0161at a power of 95%and a level of statistical significanc of 0.01, a sample size of at least 32 subjects was required for each group.Anthropometric, nutrition, and respiratory function data in male and female subjects are presented in Table 1.PImax(p=0.043)and PEmax(p=0.001)were signifi cantly higher in male subjects compared with female subjects.PImean/PImaxand TTImuswere significant y lower in male subjects compared with female subjects (p=0.001 and p=0.002,respectively).Values of PImaxand TTImusin different age groups in males and females are presented in Table 2. Respiratory function data in exercising and nonexercising participants are presented in Table 3. PImaxand PEmaxwere significant y higher in exercising compared with nonexercising subjects(p=0.002 and p=0.015,respectively).TTImuswas significant y lower in exercising compared with nonexercising subjects(p ＜0.001).

P0.1was significant y negatively related to age (r=-0.415,p ＜0.001), weight (r=-0.245, p=0.016), height (r=-0.386,p ＜0.001;Fig.1A),and UAMA(r=-0.222,p=0.029)but not significant y related to BMI Z-score. PImaxwas significant y related to weight (r=0.221, p=0.031), height (r=0.320,p=0.001; Fig. 1B), and UAMA (r=0.201, p=0.049) but not significant y related to age and BMI Z-score. TTImuswas significant y negatively related to age (r=-0.239, p=0.019),weight (r=-0.214, p=0.037), height (r=-0.355, p ＜0.001;Fig. 1C), and UAMA (r=-0.222, p=0.030) but not signifi cantly related to BMI Z-score. Multivariate logistic regression analysis revealed that height (p=0.004) and aerobic exercise(p=0.002)were significant y related to TTImusindependently of age, weight, and UAMA(Table 4).

Table 1 Anthropometric, nutrition, and respiratory muscle function data in male and female participants (mean±SD).

Table 2 Mean values of PImax and TTImus according to age in males and females(mean±SD).

Table 3 Respiratory function data in exercising and nonexercising participants(mean±SD).

Fig.1. P0.1(A),PImax(B),TTImus(C),and height linear regression analysis.Data for individual subjects, line of regression, and 95% confidenc intervals are presented.P0.1=inspiratory pressure 100 ms after onset of inspiration;PImax=maximal inspiratory pressure; TTImus = tension-time index of the respiratory muscles.

Table 4Multivariate regression analysis with TTImus as the outcome variable.

Predictive regression equations for TTImuswere as follows:

Coefficien of determination:R2=0.401,standard error of estimation: 0.037.

Coefficien of determination:R2=0.315,standard error of estimation: 0.053.

4. Discussion

Our study demonstrated that inspiratory muscle function is enhanced in regularly exercising children compared with nonexercising ones.We reported that TTImusvalues are normal in healthy children and are negatively related to height,weight,age,and muscular state.Furthermore,we calculated predictive regression equations for TTImusin male and female children.

TTImusin our study attained comparable values to previously published data for nonventilated children.1-4,7Assessment of respiratory muscle function by means of TTImushas demonstrated that measurement of TTImuscan accurately predict extubation outcome in ventilated children.6Children with CF exhibit increased TTImusvalues, signaling compromised respiratory muscle function,which is determined by a combination of increased load and decreased strength owing to airway obstruction and malnutrition, respectively.1-3,20Children with neuromuscular disorders also attain higher TTImusvalues,mainly secondary to decreased respiratory muscle strength as a direct consequence of the disease.4Obese individuals exhibit increased TTImusvalues as a result of the excessive mechanical load imposed on the respiratory muscles.5Our study reconfi med the range of values of TTImusreported in previous studies and complemented the literature with novel, previously unreported parameters that determine TTImus, such as the state of skeletal muscularity and the effect of aerobic exercise on the respiratory muscles in healthy children. Given the reported impact of genetic polymorphisms on respiratory muscle function,8another strength of our study is that it is the firs to report normal values of TTImusin healthy southern European,predominantly Greek, children.

Male children exhibited lower values of TTImusin our study compared with age-matched females.Male muscles are known to generate a higher maximum power output than female muscles.The mechanisms behind gender-related differences in skeletal muscle function are not known, but they are likely a consequence of different sex hormonal status.21

Respiratory muscle function in children can be affected by increased respiratory load, decreased muscle strength, or a combination of both.Hence,TTImusis an index ideally equipped to describe and assess this compromise.Furthermore,TTImusis a global inspiratory muscle index that does not preferentially assess diaphragm function,and it is also noninvasive and simple to perform. Other methods have been utilized to assess respiratory muscle function,such as diaphragmatic electromyography22or sniff nasal inspiratory pressure (SNIP).23However, surface diaphragmatic electromyography in children would be considerably affected by electrical noise from neighboring muscle groups, whereas nostril occlusion for measurement of SNIP might be poorly tolerated in young children, and SNIP values might vary substantively for anatomic reasons in children of different ethnic backgrounds.24

Our study reported values of P0.1that decrease with age.P0.1is a reproducible index25that was introduced to assess respiratory drive in children with chronic intrinsic loaded breathing.11,26Although it is perceived that the timing of the P0.1is such that it is independent of lung compliance and airway resistance, the age-related decrease in P0.1in our study might reflec developmental changes, which is consistent with the tendency of lung compliance to increase through childhood into early adult life.27

In our study PImaxincreased with age;this probably reflect a maturation process related to increasing muscle mass and body growth.28Values of PImaxhave been previously reported in children.23Our study reports values for maximal respiratory pressures similar to previously published data from healthy children.7,29-32Both PImaxand PEmaxpositively correlated with increasing age and anthropometric indices that describe muscular state;given that respiratory muscles are skeletal muscles,this is a logical finding

In terms of clinical significance our data demonstrate that TTImusin children is influence by gender, anthropometry,indices of muscularity,and aerobic exercise.Incorporating this information into clinical practice could enhance the use of TTImusas an objective monitoring parameter of inspiratory muscle function in children and could assist in predicting respiratory muscle fatigue in conjunction with clinical and pulmonary function data.Early recognition of impending respiratory failure would allow for timely application of treatment modalities such as noninvasive ventilation, inspiratory muscle training,and mechanical ventilation.The protective role of aerobic exercise in maintaining inspiratory muscle strength is reinforced by our results.

Assessment of inspiratory muscle function by the TTImusmight be restricted by some potential limitations.In calculating the TTImus,PImeanis extrapolated from P0.1over the entire Tiby a single power function of time,assuming that pressure increases linearly over Ti. In reality, this might overestimate the actual value of PImean. Furthermore, the critical fatigue isopleth for TTImushas been established by Ramonatxo et al.12to correspond to a specifi fatigue threshold of the transdiaphragmatic pressure-time index,but the TTImusthreshold itself has not been electromyographically determined in children.13Finally, in clinical practice,measurement of P0.1might be affected by the elevated time constant and the subsequent relatively delayed transmission of the pressure changes from the alveoli to the mouth in diseases characterized by airway obstruction,such as CF.33

We also acknowledge that although self-report data might be widely accepted, the validity of the study would have been enhanced if exercise journals approved by coaches or trainers had been used. Furthermore, our population—however suffi cient to describe physiological associations—was relatively modest in size to generate predictive equations and did not undergo lung function testing to confi m that no individuals with impaired pulmonary function were included. Further research in this area might clarify whether certain forms of aerobic exercise in children might be more beneficia for respiratory muscle function than others.

5. Conclusion

This study demonstrated that inspiratory muscle function in healthy children is determined by height and that aerobic exercise might enhance respiratory muscle strength. This knowledge is essential to assess the respiratory muscles and to monitor respiratory muscle dysfunction and disease progression in children.

Acknowledgment

The statistical guidance of Dr.Richard Parker of the Center for Applied Medical Statistics,University of Cambridge,UK,is gratefully acknowledged.

Authors’ contributions

TD contributed to study design,acquired and interpreted the data,and wrote the firs draft of the manuscript;GD conceived of the study,contributed to study design and data interpretation,and critically appraised the manuscript.Both authors have read and approved the fina manuscript,and agree with the order of presentation of the authors.

Competing interests

Both authors declare that they have no competing interests.