Determinants of inspiratory muscle function in healthy children.

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 significantly lower in male subjects (0.095 ± 0.038, mean ± SD) compared with female subjects (0.126 ± 0.056) (p = 0.002). TTImus was significantly lower in regularly exercising (0.093 ± 0.040) compared with nonexercising subjects (0.130 ± 0.053) (p < 0.001). TTImus was significantly 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 significantly 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 significantly associated with indices of inspiratory muscle function in children. Normal values of TTImus in healthy children are reported.

Introduction

Respiratory muscle impairment has been increasingly recognized as an independent pathophysiological contributor to disorders that affect the pediatric population. Children with cystic fibrosis (CF)1, 2, 3 and neuromuscular diseases are 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. Impaired respiratory muscle function has been identified as an independent predictor of extubation outcome in children. Furthermore, anthropometry, genetic polymorphisms, and aerobic exercise9, 10 also 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). Although PImax and PEmax describe a snapshot of respiratory muscle performance at a specific 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). TTImus is a composite dimensionless index that incorporates measurements of pressure and time and describes the efficiency of the total work undertaken by the respiratory muscles. Higher values of TTImus are indicative of inefficient 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 TTImus in healthy children are scarce, and patient-derived data and data from ventilated subjects would be affected by distorted lung mechanics. In this study we describe patterns of change of TTImus in healthy children and report the demographic and anthropometric parameters that contribute to alterations of inspiratory muscle function in this population.

Methods

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.

Measurements

Equipment

A pneumotachograph (Mercury F100L; GM Instruments, Kilwinning, UK) was used to record airway flow. 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 amplified by a portable amplifier (Validyne CD280; Validyne Engineering). The flow 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).

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. P0.1 was 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 P0.1 value was estimated. A 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. PImax was measured on a maximal inspiratory effort from residual volume against an occluded airway, and PEmax was measured on a maximal expiratory effort from total lung capacity against an occluded airway. Five maximal reproducible respiratory efforts were undertaken, and the maximum achieved values for PImax and PEmax were recorded. A 1–2 mm leak in the respiratory line was allowed to avoid closure of the glottis. Only PImax and PEmax waveforms with minimum plateau pressure of 1 s were accepted for subsequent analysis.

Calculation of the TTImus

The TTImus was calculated aswhere Ti is the inspiration time and Ttot is the total time for each breath, calculated from the airway flow signal; PImean is the mean airway pressure during inspiration (calculated from the formula PImean = 5 × P0.1 × Ti); and PImax is the maximum inspiratory pressure.3, 12

Nutritional parameters

Body weight and height were measured, and the body mass index (BMI) Z-score was calculated. Because respiratory muscle function is strongly associated with indices of somatic muscularity,1, 3 the 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. Triceps 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. UAMA was subsequently calculated from midarm muscle circumference and triceps skinfold thickness.

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, 19 Running, cycling, football, swimming, athletics, basketball, volleyball, martial arts, tennis, and gymnastics were accepted as moderate-to-vigorous PA. The control group consisted of subjects who did not take part in structured PA.

Statistics

Normality of distribution was assessed using the Shapiro-Wilk and Kolmogorov-Smirnoff tests. Differences between 2 groups were assessed for significance using the student's t test. Pearson correlation analysis was used to examine the univariate relation of P0.1, PImax, and TTImus to 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 TTImus in males and females were calculated with the corresponding coefficient 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 justification was conducted to confirm that the number of participating subjects in the exercising and nonexercising groups were sufficient to detect differences in TTImus at a level of significance of 0.01 with power of 95%. Statistical analysis was performed using SPSS software (Version 17.0; SPSS Inc., Chicago, IL, USA).

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 TTImus differences between the groups of exercising and nonexercising subjects. TTImus standard deviation was set at 0.014. The power analysis indicated that to detect an increase in TTImus of 0.016 at a power of 95% and a level of statistical significance 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 significantly higher in male subjects compared with female subjects. PImean/PImax and TTImus were significantly lower in male subjects compared with female subjects (p = 0.001 and p = 0.002, respectively). Values of PImax and TTImus in 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. PImax and PEmax were significantly higher in exercising compared with nonexercising subjects (p = 0.002 and p = 0.015, respectively). TTImus was significantly lower in exercising compared with nonexercising subjects (p < 0.001).

Table 1

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

	Male (n = 48)	Female (n = 48)	p
Age (year)	12 ± 3	12 ± 3	0.800
Age 6–12 years (n (%))	26 (54)	26 (54)	1.000a
Height (cm)	158 ± 16	153 ± 14	0.105
Weight (kg)	53 ± 19	49 ± 13	0.149
BMI Z-score	0.66 ± 0.87	0.49 ± 0.88	0.347
TST (mm)	14 ± 5	16 ± 5	0.026
MAMC (cm)	24.9 ± 4.2	24.1 ± 2.9	0.276
UAMA	3455 ± 1097	2918 ± 609	0.004
RR	21 ± 5	20 ± 5	0.514
TV (L)	0.56 ± 0.23	0.61 ± 0.23	0.026
TV/kg (mL/kg)	10.9 ± 4.3	13.2 ± 5.8	0.268
MV (L/min)	11.2 ± 3.9	12.0 ± 4.5	0.026
P0.1 (cmH2O)	2.75 ± 1.11	3.15 ± 1.42	0.134
PImean (cmH2O)	17.3 ± 6.0	20.9 ± 9.1	0.028
PImax (cmH2O)	87 ± 27	76 ± 23	0.043
PImean/PImax	0.22 ± 0.09	0.29 ± 0.12	0.001
Ti/Ttot	0.44 ± 0.02	0.44 ± 0.03	0.203
TTImus	0.095 ± 0.038	0.126 ± 0.056	0.002
PEmax (cmH2O)	90 ± 27	75 ± 19	0.001
Sport (n (%))	27 (56)	21 (44)	0.683a

Abbreviations: BMI Z-score = body mass index Z-score; MAMC = midarm muscle circumference; MV = minute ventilation; P0.1 = inspiratory pressure 100 ms after onset of inspiration; PEmax = maximal expiratory pressure; PImax = maximal inspiratory pressure; PImean = mean airway pressure during inspiration; RR = respiratory rate; Ti = inspiratory time; TST = triceps skinfold thickness; TTImus = tension–time index of the respiratory muscles; Ttot = total time of respiration; TV = tidal volume; TV/kg = tidal volume per kilogram of body weight; UAMA = upper arm muscle area.

χ2.

Table 2

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

Age (year)	Male			Female
	n	PImax (cmH2O)	TTImus	n	PImax (cmH2O)	TTImus
6–8	7	79 ± 20	0.118 ± 0.042	7	75 ± 27	0.167 ± 0.049
9–11	13	79 ± 28	0.112 ± 0.040	11	77 ± 27	0.135 ± 0.060
12–14	17	94 ± 25	0.089 ± 0.031	19	78 ± 22	0.127 ± 0.040
15–18	11	95 ± 31	0.076 ± 0.040	11	75 ± 21	0.106 ± 0.057

Abbreviations: PImax = maximal inspiratory pressure; TTImus = tension–time index of the respiratory muscles.

Table 3

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

	Exercise (n = 50)	Nonexercise (n = 46)	p
Age (year)	13 ± 3	12 ± 3	0.061
TV/kg (mL/kg)	11.7 ± 4.1	12.5 ± 6.2	0.469
MV (L/min)	12.0 ± 4.2	11.1 ± 4.1	0.275
P0.1 (cmH2O)	2.69 ± 1.13	3.23 ± 1.40	0.041
PImax (cmH2O)	89 ± 26	74 ± 23	0.002
Ti/Ttot	0.44 ± 0.03	0.44 ± 0.03	0.395
TTImus	0.093 ± 0.040	0.130 ± 0.053	<0.001
PEmax (cmH2O)	89 ± 24	76 ± 24	0.015
Male n (%)	27 (54)	21 (46)	0.688a

Abbreviations: MV = minute ventilation; P0.1 = inspiratory pressure 100 ms after onset of inspiration; PEmax = maximal expiratory pressure; PImax = maximal inspiratory pressure; Ti = inspiratory time; Ttot = total time of respiration; TTImus = tension–time index of the respiratory muscles; TV/kg = tidal volume per kilogram of body weight.

χ2.

P0.1 was significantly 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 significantly related to BMI Z-score. PImax was significantly 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 significantly related to age and BMI Z-score. TTImus was significantly 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 significantly related to BMI Z-score. Multivariate logistic regression analysis revealed that height (p = 0.004) and aerobic exercise (p = 0.002) were significantly related to TTImus independently of age, weight, and UAMA (Table 4).

Fig. 1

P0.1 (A), PImax (B), TTImus (C), and height linear regression analysis. Data for individual subjects, line of regression, and 95% confidence 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 4

Multivariate regression analysis with TTImus as the outcome variable.

	Standardized coefficient (95%CI)	p
Age	0.124 (−0.003 to 0.007)	0.410
Weight	0.413 (0.000 to 0.003)	0.056
UAMA	−0.175 (0.000 to 0.000)	0.275
Aerobic exercise	−0.295 (−0.048 to −0.011)	0.002
Height	−0.606 (−0.003 to −0.001)	0.004

Abbreviations: CI = confidential confidence; TTImus = tension–time index of the respiratory muscles; UAMA = upper arm muscle area.

Predictive regression equations for TTImus were as follows:

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

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

Discussion

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

TTImus in our study attained comparable values to previously published data for nonventilated children.1, 2, 3, 4, 7 Assessment of respiratory muscle function by means of TTImus has demonstrated that measurement of TTImus can accurately predict extubation outcome in ventilated children. Children with CF exhibit increased TTImus values, 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, 2, 3, 20 Children with neuromuscular disorders also attain higher TTImus values, mainly secondary to decreased respiratory muscle strength as a direct consequence of the disease. Obese individuals exhibit increased TTImus values as a result of the excessive mechanical load imposed on the respiratory muscles. Our study reconfirmed the range of values of TTImus reported 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, another strength of our study is that it is the first to report normal values of TTImus in healthy southern European, predominantly Greek, children.

Male children exhibited lower values of TTImus in 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.

Respiratory muscle function in children can be affected by increased respiratory load, decreased muscle strength, or a combination of both. Hence, TTImus is an index ideally equipped to describe and assess this compromise. Furthermore, TTImus is 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 electromyography or sniff nasal inspiratory pressure (SNIP). However, 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.

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

In our study PImax increased with age; this probably reflects a maturation process related to increasing muscle mass and body growth. Values of PImax have been previously reported in children. Our study reports values for maximal respiratory pressures similar to previously published data from healthy children.7, 29, 30, 31, 32 Both PImax and PEmax positively 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 TTImus in children is influenced by gender, anthropometry, indices of muscularity, and aerobic exercise. Incorporating this information into clinical practice could enhance the use of TTImus as 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 TTImus might be restricted by some potential limitations. In calculating the TTImus, PImean is extrapolated from P0.1 over the entire Ti by 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 TTImus has been established by Ramonatxo et al. to correspond to a specific fatigue threshold of the transdiaphragmatic pressure–time index, but the TTImus threshold itself has not been electromyographically determined in children. Finally, in clinical practice, measurement of P0.1 might 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.

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 sufficient to describe physiological associations—was relatively modest in size to generate predictive equations and did not undergo lung function testing to confirm 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 beneficial for respiratory muscle function than others.

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.

Authors' contributions

TD contributed to study design, acquired and interpreted the data, and wrote the first 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 final manuscript, and agree with the order of presentation of the authors.

Competing interests

Both authors declare that they have no competing interests.