- Research article
- Open access
- Published:
Diaphragmatic ultrasound findings correlate with dyspnea, exercise tolerance, health-related quality of life and lung function in patients with fibrotic interstitial lung disease
BMC Pulmonary Medicine volume 19, Article number: 183 (2019)
Abstract
Background
Fibrotic interstitial lung disease (FILD) patients are typically dyspneic and exercise-intolerant with consequent impairment of health-related quality of life (HRQoL). Respiratory muscle dysfunction is among the underlying mechanisms of dyspnea and exercise intolerance in FILD but may be difficult to diagnose. Using ultrasound, we compared diaphragmatic mobility and thickening in FILD cases and healthy controls and correlated these findings with dyspnea, exercise tolerance, HRQoL and lung function.
Methods
We measured diaphragmatic mobility and thickness during quiet (QB) and deep breathing (DB) and calculated thickening fraction (TF) in 30 FILD cases and 30 healthy controls. We correlated FILD cases’ diaphragmatic findings with dyspnea, exercise tolerance (six-minute walk test), lung function and HRQoL (St. George’s Respiratory Questionnaire).
Results
Diaphragmatic mobility was similar between groups during QB but was lower in FILD cases during DB when compared to healthy controls (3.99 cm vs 7.02 cm; p < 0.01). FILD cases showed higher diaphragm thickness during QB but TF was lower in FILD when compared to healthy controls (70% vs 188%, p < 0.01). During DB, diaphragmatic mobility and thickness correlated with lung function, exercise tolerance and HRQoL, but inversely correlated with dyspnea. Most FILD cases (70%) presented reduced TF, and these patients had higher dyspnea and exercise desaturation, lower HRQoL and lung function.
Conclusion
Compared to healthy controls, FILD cases present with lower diaphragmatic mobility and thickening during DB that correlate to increased dyspnea, decreased exercise tolerance, worse HRQoL and worse lung function. FILD cases with reduced diaphragmatic thickening are more dyspneic and exercise-intolerant, have lower HRQoL and lung function.
Background
Dyspnea and exercise intolerance characterize fibrotic interstitial lung diseases (FILD) [1, 2]. Both are determinants of impaired health-related quality of life (HRQoL) observed in FILD patients [1, 3, 4]. Dyspnea and exercise intolerance in FILD have several underlying mechanisms [5]. Among them is respiratory muscle dysfunction [6, 7], which is usually difficult to diagnose [6].
In ILD, increased lung elastic recoil overloads the respiratory muscles [5, 8]. In addition, many other factors present in ILD, such as chronic hypoxemia, corticosteroids, systemic inflammation, physical inactivity and malnutrition may promote muscle dysfunction [6]. However, the few studies that have evaluated diaphragmatic function in ILD report conflicting results. While some authors have found preserved inspiratory muscle strength in ILD [5, 8,9,10], Walterspachen et al. [7] found reduced diaphragmatic strength, assessed with non-volitional measures, in a subset of ILD subjects with severe disease.
The diaphragm is the main inspiratory muscle being responsible for 60 to 70% of the tidal volume during quiet breathing [11, 12]. Due to its location and size, its function can be assessed by ultrasound (US). Initially, standardized techniques for mobility and diaphragmatic thickening measurements were reported in healthy volunteers [13,14,15,16,17]. Later, thoracic ultrasound (TUS) focusing on the diaphragm was employed in patients with respiratory disorders such as asthma [18], chronic obstructive pulmonary disease (COPD) [19], cystic fibrosis [20] and respiratory failure [21,22,23]. Recently, TUS was applied in FILD patients [24] and results have shown decreased diaphragmatic mobility during deep breathing that is associated with reduced lung volumes [24].
Improvement of HRQoL, including relief of dyspnea and exercise intolerance, is the cornerstone of the care of FILD patients, most of whom have irreversible lung diseases [25, 26]. In cases where TUS findings were correlated with dyspnea, exercise tolerance, HRQoL and lung function, US could be used to propose and monitor interventions such as rehabilitation and to assess disease progression [27].
Firstly, we hypothesized that diaphragmatic mobility and thickness, assessed by TUS, would be associated with dyspnea, exercise tolerance, HRQoL and lung function in FILD cases. Secondly, we hypothesized that a proportion of FILD cases would present with reduced diaphragmatic thickening and they would have different clinical and functional characteristics from FILD cases without reduced thickening.
Methods
Study design and subjects
We performed a prospective, observational study, involving 30 FILD cases and 30 healthy controls consecutively recruited from February 2014 to February 2016. Our local research ethics committee (Comissão de Ética para Análise de Projetos de Pesquisa do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo - CAPPesq 0835/11) approved the study and all subjects signed an informed consent.
FILD cases were recruited from an outpatient interstitial lung disease (ILD) clinic at a tertiary care teaching hospital. Diagnosis of ILD was based on established criteria which involved clinical features, lung function, chest computed tomography, bronchoalveolar lavage and, eventually, lung biopsy. Fibrotic interstitial lung disease was defined as ILD patients with radiological evidence of fibrosis and physiologic impairment (restrictive pattern in pulmonary function tests – FVC < 80% of predicted). FILD cases had to be clinically stable and without change of therapeutic regimen during the last 3 months. Exclusion criteria were a concurrent disorder, such as COPD, active infection or neuromuscular disease. In addition, we excluded subjects with ILD associated with connective tissue disease that had any sign, symptom (muscle pain or fatigue) or laboratorial suggestion of muscle involvement like myositis or myopathy (indicated by abnormal muscle enzymes or the presence of antisynthetase antibody). None of the patients suffered from dermato-polymyositis. Healthy controls were at least 18 years old and without any cardiopulmonary or neuromuscular disease.
For all subjects, we recorded demographic data including smoking habits. From FILD cases, we recorded comorbidities, medications in use (eg. corticosteroids and immunosuppressants) and resting dyspnea, quantified by the Medical Research Council (MRC) scale [28]. Dyspnea was classified as mild (MRC = 1), moderate (MRC = 2 or 3) and severe (MRC = 4 or 5). All subjects underwent pulmonary function test (PFT) and TUS. Only FILD cases answered a HRQoL questionnaire and performed a six-minute walk test (6MWT).
PFT (Elite Dx, Medical Graphics Corporation, St. Paul, MN, USA) measured the forced vital capacity (FVC), forced expiratory volume during the first second (FEV1) and inspiratory capacity (IC). FILD cases also underwent functional residual capacity (FRC) and total lung capacity (TLC) measurements. Tests were performed according to ERS/ATS Statement [29] and predicted values were derived from a sample of the Brazilian population [30].
An Additional file 1: Methods and Results describes further details about the measurement of respiratory muscle strength, quality of life assessment (HRQoL) and exercise capacity evaluation (6MWT).
Maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP) and sniff nasal inspiratory pressure (SNIP) were measured (Respiratory Pressure Meter, CareFusion, CA-USA) in all subjects according to standardized criteria [31]. For MIP and MEP, the highest value of three maneuvers was recorded for analysis. For SNIP, the highest value of ten efforts was used for analysis [31]. Predicted values were derived from a sample of the Brazilian population [32, 33].
The HRQoL was quantified using the St. George’s Respiratory Questionnaire (SGRQ), a respiratory-specific HRQoL questionnaire with three different domains: respiratory symptoms, activity and psychosocial impact of the disease. Higher scores (range from 0 to 100) correspond to worse HRQoL. Although developed for COPD, validity and reliability of the SGRQ in ILD patients has been determined [1, 34, 35].
The 6MWT was performed according to standardized criteria [36]. Before and after the test, heart rate, peripheral oxygen saturation and modified Borg scale [37] were measured. Predicted values were derived from a sample of the Brazilian population [38].
Thoracic ultrasound focused on diaphragm (TUS)
TUS was performed using a portable system (Nanomaxx, Sonosite, Bothell, WA, USA) or another machine (M-Turbo, Sonosite) with subjects in a semi-recumbent position. For diaphragmatic mobility evaluation, a convex transducer (2–5 MHz) was placed over the right anterior subcostal region between the midclavicular and anterior axillary lines. The transducer was directed medially, cephalad and dorsally, so that the US beam reached perpendicularly the posterior third of the right diaphragm. After obtaining the best view on two-dimensional mode, the mobility was measured through the M-mode, from the amplitude of cranio-caudal diaphragmatic excursion during quiet breathing (QB) and deep breathing (DB). To record the TUS at DB, all subjects were asked to perform a maximum inspiratory effort (maximum inspiratory capacity maneuver) for at least 2 s, to attain a maximal lung volume close to the total lung capacity (TLC) [14, 15, 17]. For diaphragmatic thickness evaluation, a linear transducer (6–13 MHz) was placed over the zone of apposition of the diaphragm to the rib cage, between the right anterior and medial axillary lines. Using the two-dimensional mode, the diaphragm was observed as a structure composed of a non-echogenic central bordered by two hyperechogenic (peritoneal and pleural) layers [13, 15, 16]. Diaphragmatic thickness was measured from the deepest pleural line to the deepest peritoneal line. First, we measured the thickness during QB at FRC (Tmin) and then, after a maximal DB, at TLC (Tmax). The diaphragm’s thickening fraction (TF) was calculated as TF = [(Tmax − Tmin)/Tmin] × 100.
One physician (PVS) with experience in TUS performed all measurements. At least three measurements of the diaphragm excursion and thickness were taken for all subjects and the average of the individual values was reported.
Statistical analysis
Statistical analyses were performed with SPSS software version 20.0 (IBM Corporation, Armonk, NY-USA). Data are presented as mean ± standard deviation or median and 25–75% interquartile range, as appropriate. Categorical data are presented as absolute and relative frequency. Student’s T-test was used to compare the normally distributed data (means) and Mann–Whitney test was used to compare data that were not normally distributed (medians). Categorical variables were compared using the chi-squared test or Fisher’s exact test. Correlations were analyzed using Spearman’s coefficient. Reduced diaphragmatic thickening was defined by diaphragmatic thickening fraction values below the 95% confidence interval of values obtained from the healthy controls. P values < 0.05 were considered statistically significant. We calculated the sample size based on data from a previous study by our group that examined diaphragmatic mobility and thickness in FILD patients. Considering a two-sided type I error of 0.05, a type II error of 0.20 and an expected difference of thickness at total lung capacity of 0.8 cm, at least 25 subjects per group were estimated to compare TUS findings between FILD cases and healthy controls.
Results
Demographic and clinical data of FILD cases and healthy controls are depicted in Table 1. The diaphragmatic mobility and thickness were measured for all subjects. The classification of FILD patients and the current use of steroids are presented in Table 1. Two patients were on long-term oxygen therapy. Respiratory muscle strength was similar between FILD cases and healthy controls (Table 1). The prevalence of comorbidities was similar between FILD cases and healthy controls (Additional file 1: Methods and Results). The scores of SGRQ revealed a reduction in HRQoL in all domains (Additional file 1: Table SA1, Results) in FILD cases when compared to reference values [39].
FILD cases walked less than predicted and presented peripheral oxygen desaturation, increased heart rate, dyspnea and leg fatigue at the end of the 6MWT (Additional file 1: Table SA2).
Diaphragmatic mobility during QB was similar between FILD and control groups (p = 0.95). However, during DB, diaphragmatic mobility was lower in the FILD cases when compared to healthy controls (p < 0.01). During QB, at FRC, the diaphragm of FILD cases was significantly thicker than the healthy controls (p = 0.01). But, after a maximal DB, at TLC, the diaphragm of FILD cases was significantly thinner than the healthy controls (p < 0.01), resulting in a lower TF in the FILD cases (p < 0.01). (Table 2 and Additional file 2: Figure S1).
During DB, diaphragmatic mobility and thickness correlated with lung function (FVC, FEV1, TLC and DLCO), exercise tolerance and HRQoL but negatively correlated with resting dyspnea. During DB, lesser diaphragmatic mobility and thickness correlated with more resting dyspnea, more desaturation and dyspnea at the end of the 6MWT; quality of life is worse (mainly respiratory symptoms and activity domain of SGRQ). (Table 3 and Additional file 3: Figure S2 and Additional file 4: Figure S3). However, nor corticosteroid use, nor a specific group of FILD diagnoses were associated with diaphragmatic mobility and thickness in FILD cases.
For the healthy controls, the 95% confidence interval for TF during DB was 101 to 354%. To define the FILD cases with reduced diaphragmatic thickening, the choice of TF < 101% represents the values below which only 5% of the healthy controls’ values fall (5th percentile). Seventy percent of FILD cases presented reduced diaphragmatic thickening (Table 4). FILD cases with reduced diaphragmatic thickening had lower lung volumes (FVC and FEV1), higher resting dyspnea, worse HRQoL (activity and total domains of SGRQ), higher desaturation and dyspnea after the 6MWT (Table 4). Age, sex, BMI and corticosteroid were similar among FILD cases with and without reduced diaphragmatic thickening.
Discussion
The novel findings of this study are that in FILD cases compared to healthy adults, lower deep breathing diaphragmatic mobility and thickening correlated with increased dyspnea, decreased exercise tolerance, worse HRQoL and worse lung function. Most FILD cases (75%) presented reduced diaphragmatic thickening and these patients had higher dyspnea, higher desaturation, worse HRQoL and lung function than FILD cases without reduced diaphragmatic thickening. In addition, FILD cases presented a thicker diaphragm at rest compared to healthy controls. Using US, we assessed the diaphragm function of a heterogeneous sample of FILD patients. Findings of higher dyspnea, exercise intolerance, worse HRQoL and lung function in FILD cases with reduced diaphragmatic mobility and thickening are novel and provide further evidence that diaphragm function affects FILD patients clinically.
Few studies explored the relationship between diaphragmatic function, dyspnea, HRQoL and exercise tolerance in FILD. In our study, FILD cases with lower DB diaphragmatic mobility and TF had more resting and exertional dyspnea and worse HRQoL. Further, the lower the DB diaphragmatic mobility and the TF, the greater the desaturation at the end of the 6MWT. The reduced diaphragmatic mobility and thickening in FILD cases may compromise the overloaded inspiratory muscles [40, 41] eliciting early onset breathlessness [5, 41] resulting in poor HRQoL [1, 3]. In addition, impairment in diaphragm function may hinder ventilation throughout exercise causing additional mismatch on the ventilation to perfusion ratio, leading to desaturation similar to that shown in diaphragm paralysis [42].
The relationship between muscle function, dyspnea and HRQoL has been explored in sarcoidosis [43, 44] lung cancer patients [45] and in COPD [46]. Interestingly, in COPD, Paulin et al. [46] used TUS to assess diaphragm function and showed that COPD patients with lower diaphragmatic mobility also had lower 6MWT performance and higher exertional dyspnea [46]. Furthermore, air trapping influenced the diaphragmatic mobility in COPD. The authors hypothesize that COPD patients with air trapping imposed a mechanical disadvantage of the inspiratory muscles due to their shortened lengths, which was accentuated during exertion and elicited breathlessness [46].
In our study, diaphragmatic mobility and TF was associated with dyspnea and desaturation, but did not influence the 6MWT distance covered by FILD cases.
To the best of our knowledge, only two studies used the TUS to investigate the diaphragmatic function in ILD. He et al. [47] showed that diaphragmatic mobility, but not thickness, was similar between a small sample of idiopathic pulmonary fibrosis patients and healthy controls. In contrast, we previously recorded that FILD patients presented reduced diaphragmatic mobility and TF during DB when compared to healthy controls [24]. Diaphragmatic mobility during DB was associated with FVC, FEV1 and TLC in FILD [24].
The present study reinforced those findings. We found a strong correlation between diaphragmatic mobility and TF with lung function. Although expected and intuitive, these correlations are not consistent findings even in healthy adults. While some studies found a linear relationship between diaphragmatic mobility and lung volumes in healthy volunteers [48, 49], another study showed that diaphragmatic mobility measured during QB and DB or inspiratory capacity maneuvers poorly correlated with lung volumes [50]. Recently, in 210 healthy volunteers, Boussuges et al. [14] found only a weak correlation between diaphragmatic mobility and lung volumes. This controversy may be explained by the fact that inspiratory lung volumes are determined by diaphragmatic mobility, and also by recruitment of extra diaphragmatic muscles [51] and thoracoabdominal compliance [14]. These factors also influence the thickening of diaphragm. In healthy subjects, thickening of diaphragm is greatest in the zone of apposition, during a primarily abdominal breath [52] and is affected by the diaphragm curvature [53].
In previous studies in COPD, both diaphragmatic mobility [54] and thickening [55] have been correlated with air trapping and airway obstruction. In our study, decreased diaphragmatic mobility seen in FILD patients during DB may reflect the reduced lung volume. The reduced diaphragmatic thickening may be due to an intrinsic muscle dysfunction associated with several causal factors (inflammatory and oxidative stress, corticosteroid use, physical inactivity and malnutrition) usually present in ILDs [6, 7]. We cannot rule out that the curvature of the diaphragm may have affected diaphragmatic thickening. The lower lung volumes in ILDs decrease the radius of the diaphragmatic curvature, which may explain our finding of increased diaphragmatic thickness in patients with FILD. Increased diaphragmatic thickness could also represent muscle hypertrophy consistent with a training effect, and has been showed in other respiratory diseases such as chronic asthma [18] and cystic fibrosis [20].
Respiratory muscle strength was similar between the two FILD subgroups (with and without reduced diaphragmatic thickening). Respiratory muscle function is often neglected in ILD and the few studies that have addressed it report conflicting results. Preserved inspiratory strength in ILD has been described [8,9,10], but recently reduced diaphragmatic strength in a sample of patients with more severe ILD was shown [7]. These conflicting results may reflect a “set of opposing forces” in ILD. ILD subjects have a mechanical advantage of inspiratory force generation at lower operating lung volumes and a “training effect” on the diaphragm because of the lung stiffness and increased elastic recoil [6]. However, several factors (hypoxemia, inflammatory status, corticosteroids, physical inactivity and malnutrition) may be harmful for the respiratory muscles in ILD [6]. Overall, the impaired diaphragmatic function (reduction of mobility and thickening) may represent the harmful effects on respiratory muscles, while “training effect” maintains preserved inspiratory strength in these ILD patients. Further, the heterogeneity and severity of the underlying ILD may be a confounding factor in the interpretation of respiratory muscle assessment.
In our study, corticosteroid was not associated with impaired diaphragmatic function in FILD cases possibly because only 5 patients (16,6%) were actually using a dosage of prednisone higher than 20 mg/day which is recognized as myotoxic. Corticosteroid use has been associated with mitochondrial dysfunction and oxidative stress leading to corticosteroid-induced myopathy [56]. However, the occurrence of corticosteroid-induced myopathy may be influenced by the dosage. Unfortunately, we did not investigate prospectively before and under steroid treatment for FILD. Our findings suggest that TUS may be used to monitor variables that are clinically relevant and prognostic determinants in FILD. In addition, identifying impairment of diaphragm function may alert physicians to avoid or minimize the use of myotoxic drugs, such as corticosteroids. Characterization of diaphragm function with TUS could further suggest targeted actions to improve function, such as rehabilitation, a recognized intervention to improve exercise tolerance and HRQoL and to decrease dyspnea.
Our study has some limitations. First, we studied a heterogeneous sample of FILD patients, which could be a confounding factor. However, heterogeneity is usual among FILD and gives a pragmatic character to the present study. Secondly, lung volumes were not measured concurrently with diaphragm thickness and mobility. Normalizing the mobility and thickness for lung volumes measured during the protocol could add to our understanding about the relationship between diaphragm function and lung volume restriction. Thirdly, TUS was assessed only on the right side. Fourthly, only one observer performed the TUS. However, we used M-mode to measure diaphragm mobility and standardized technique to evaluate diaphragm thickness, and both have shown to have a high reproducibility. A fifty consideration was that respiratory muscle strength was similar, which might be a reflection of a volitional measurement of overall respiratory muscle strength. Perhaps TUS discloses diaphragm function impairment before strength reduction, or the activity of global inspiratory muscle may compensate for diaphragmatic weakness. A sixth consideration was the performance of multiple comparisons in our study, which present the risk of erroneously finding a significant difference by chance. However, our study aimed to understand whether diaphragmatic ultrasound findings would correlate with clinically relevant parameters for ILD subjects, such as dyspnea and exercise intolerance that are determinants of their impaired quality of life (HRQoL). Lastly, our healthy controls did not have TLC measurements, but we have no reasons to believe that they could have any restriction or hyperinflation.
Conclusions
Compared with healthy controls, FILD cases had higher diaphragmatic thickness at rest, but lower diaphragmatic mobility and thickening fraction during deep breathings that correlate to dyspnea, exercise tolerance, HRQoL and lung function. FILD cases with diaphragmatic reduced thickening have higher dyspnea, less exercise tolerance, lower HRQoL and lung function than FILD cases without reduced thickening.
Diaphragmatic US in FILD cases may be a useful tool to investigate and monitor diaphragm function, to propose and monitor interventions such as rehabilitation and use of pharmacological treatments such as corticosteroids.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- 6MWT:
-
Six-minute walk test
- ATS:
-
American thoracic society
- COPD:
-
Chronic obstructive pulmonary disease
- DB:
-
Deep breathing
- DLCO :
-
Diffusing capacity of the lung for carbon monoxide
- FEV1:
-
Forced expiratory volume during the first second
- FHP:
-
Fibrotic hypersensitivity pneumonitis
- FILD:
-
Fibrotic interstitial lung diseases
- FRC:
-
Functional residual capacity
- FVC:
-
Forced vital capacity
- HRQoL:
-
Health-related quality of life
- IC:
-
Inspiratory capacity
- ILD associated with CTD:
-
Interstitial lung disease associated with connective tissue disease
- MEP:
-
Maximal expiratory pressure
- MIP:
-
Maximal inspiratory pressure
- MRC:
-
Medical Research Council
- Non-classified IIP:
-
Non-classified idiopathic interstitial pneumonia
- NSIP with fibrosing pattern:
-
Non-specific interstitial pneumonia with fibrosing pattern
- QB:
-
Quiet breathing
- SGRQ:
-
Saint George’s respiratory questionnaire
- SNIP:
-
Sniff nasal inspiratory pressure
- SpO2:
-
Peripheral oxygen saturation
- TF:
-
Thickening fraction
- TLC:
-
Total lung capacity
- TUS:
-
Thoracic ultrasound (TUS) focused on diaphragm
- UIP:
-
Usual interstitial pneumonia
- US:
-
Ultrasound
References
Chang JA, Curtis JR, Patrick DL, Raghu G. Assessment of health-related quality of life in patients with interstitial lung disease. Chest. 1999;116(5):1175–82.
Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M, Wells AU. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733–48.
Nishiyama O, Taniguchi H, Kondoh Y, Kimura T, Ogawa T, Watanabe F, Nishimura K. Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor? Respir Med. 2005;99(4):408–14.
O’Donnell DE, Elbehairy AF, Berton DC, Domnik NJ, Neder JA. Advances in the evaluation of respiratory pathophysiology during exercise in chronic lung diseases. Front Physiol. 2017;8:82.
O’Donnell DE, Chau LK, Webb KA. Qualitative aspects of exertional dyspnea in patients with interstitial lung disease. J Appl Physiol. 1998;84(6):2000–9.
Panagiotou M, Polychronopoulos V, Strange C. Respiratory and lower limb muscle function in interstitial lung disease. Chron Respir Dis. 2016;13(2):162–72.
Walterspacher S, Schlager D, Walker DJ, Müller-Quernheim J, Windisch W, Kabitz H-J. Respiratory muscle function in interstitial lung disease. Eur Respir J. 2013;42(1):211–9.
De Troyer A, Yernault J-C. Inspiratory muscle force in normal subjects and patients with interstitial lung disease. Thorax. 1980;35(2):92–100.
García-Río F, Pino JM, Ruiz A, Díaz S, Prados C, Villamor J. Accuracy of noninvasive estimates of respiratory muscle effort during spontaneous breathing in restrictive diseases. J Appl Physiol. 2003;95(4):1542–9.
Mendoza L, Gogali A, Shrikrishna D, Cavada G, Kemp SV, Natanek SA, Jackson AS, Polkey MI, Wells AU, Hopkinson NS. Quadriceps strength and endurance in fibrotic idiopathic interstitial pneumonia. Respirology. 2014;19(1):138–43.
Faithfull D, Jones J, Jordan C. Measurement of the relative contributions of rib cage and abdomen/diaphragm to tidal breathing in man. Br J Anaesth. 1979;51(5):391–8.
Gibson G. Diaphragmatic paresis: pathophysiology, clinical features, and investigation. Thorax. 1989;44(11):960.
Boon AJ, Harper CJ, Ghahfarokhi LS, Strommen JA, Watson JC, Sorenson EJ. Two-dimensional ultrasound imaging of the diaphragm: quantitative values in normal subjects. Muscle Nerve. 2013;47(6):884–9.
Boussuges A, Gole Y, Blanc P. Diaphragmatic motion studied by m-mode ultrasonography: methods, reproducibility, and normal values. Chest. 2009;135(2):391–400.
Cardenas LZ, Santana PV, Caruso P, de Carvalho CRR, de Albuquerque ALP. Diaphragmatic ultrasound correlates with inspiratory muscle strength and pulmonary function in healthy subjects. Ultrasound Med Biol. 2018;44(4):786–93.
Carrillo-Esper R, Pérez-Calatayud ÁA, Arch-Tirado E, Díaz-Carrillo MA, Garrido-Aguirre E, Tapia-Velazco R, Peña-Pérez CA, Espinoza-de los Monteros I, Meza-Márquez JM, Flores-Rivera OI. Standardization of sonographic diaphragm thickness evaluations in healthy volunteers. Respir Care. 2016;61(7):920–4.
Testa A, Soldati G, Giannuzzi R, Berardi S, Portale G, Silveri NG. Ultrasound M-mode assessment of diaphragmatic kinetics by anterior transverse scanning in healthy subjects. Ultrasound Med Biol. 2011;37(1):44–52.
De Bruin P, Ueki J, Watson A, Pride N. Size and strength of the respiratory and quadriceps muscles in patients with chronic asthma. Eur Respir J. 1997;10(1):59–64.
Baria MR, Shahgholi L, Sorenson EJ, Harper CJ, Lim KG, Strommen JA, Mottram CD, Boon AJ. B-mode ultrasound assessment of diaphragm structure and function in patients with COPD. Chest. 2014;146(3):680–5.
Dufresne V, Knoop C, Van Muylem A, Malfroot A, Lamotte M, Opdekamp C, Deboeck G, Cassart M, Stallenberg B, Casimir G. Effect of systemic inflammation on inspiratory and limb muscle strength and bulk in cystic fibrosis. Am J Respir Crit Care Med. 2009;180(2):153–8.
DiNino E, Gartman EJ, Sethi JM, McCool FD. Diaphragm ultrasound as a predictor of successful extubation from mechanical ventilation. Thorax. 2014;69(5):431–5.
Goligher EC, Fan E, Herridge MS, Murray A, Vorona S, Brace D, Rittayamai N, Lanys A, Tomlinson G, Singh JM. Evolution of diaphragm thickness during mechanical ventilation. Impact of inspiratory effort. Am J Respir Crit Care Med. 2015;192(9):1080–8.
Kim WY, Suh HJ, Hong S-B, Koh Y, Lim C-M. Diaphragm dysfunction assessed by ultrasonography: influence on weaning from mechanical ventilation. Crit Care Med. 2011;39(12):2627–30.
Santana PV, Prina E, Albuquerque ALP, Carvalho CRR, Caruso P. Identifying decreased diaphragmatic mobility and diaphragm thickening in interstitial lung disease: the utility of ultrasound imaging. J Bras Pneumol. 2016;42(2):88–94.
Bajwah S, Ross JR, Peacock JL, Higginson IJ, Wells AU, Patel AS, Koffman J, Riley J. Interventions to improve symptoms and quality of life of patients with fibrotic interstitial lung disease: a systematic review of the literature. Thorax. 2013;68(9):867–79.
Raghu G, Richeldi L. Current approaches to the management of idiopathic pulmonary fibrosis. Respir Med. 2017;129:24–30.
Crimi C, Heffler E, Augelletti T, Campisi R, Noto A, Vancheri C, Crimi N. Utility of ultrasound assessment of diaphragmatic function before and after pulmonary rehabilitation in COPD patients. Int J Chron Obstruct Pulmon Dis. 2018;13:3131.
Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest. 1984;85(6):751–8.
Brusasco V, Crapo R, Viegi G, American Thoracic Society; European Respiratory Society. Coming together: the ATS/ERS consensus on clinical pulmonary function testing. Eur Respir J. 2005;26(1):1–2.
Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in white adults in Brazil. J Bras Pneumol. 2007;33(4):397–406.
Caruso P, Albuquerque ALP, Santana PV, Cardenas LZ, Ferreira JG, Prina E, Trevizan PF, Pereira MC, Iamonti V, Pletsch R. Diagnostic methods to assess inspiratory and expiratory muscle strength. J Bras Pneumol. 2015;41(2):110–23.
Araújo PR, Resqueti VR, Nascimento Junior J, Carvalho Lde A, Cavalcanti AG, Silva VC, Silva E, Moreno MA, Andrade Ade F, Fregonezi GA. Reference values for sniff nasal inspiratory pressure in healthy subjects in Brazil: a multicenter study. J Bras Pneumol. 2012;38(6):700–7.
Neder JA, Andreoni S, Lerario MC, Nery LE. Reference values for lung function tests: II. Maximal respiratory pressures and voluntary ventilation. Braz J Med Biol Res. 1999;32(6):719–27.
Sousa T, Jardim JR, Jones P. Validação do Questionário do Hospital Saint George na Doença Respiratória (SGRQ) em pacientes portadores de doença pulmonar obstrutiva crônica no Brasil. J Bras Pneumol. 2000;26(3):119–28.
Zimmermann C, Carvalho C, Silveira K, Yamaguti W, Moderno E, Salge J, Kairalla R, Carvalho C. Comparison of two questionnaires which measure the health-related quality of life of idiopathic pulmonary fibrosis patients. Braz J Med Biol Res. 2007;40(2):179–87.
Laboratories ACoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–7.
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377–81.
Iwama AM, Andrade GND, Shima P, Tanni SE, Godoy ID, Dourado VZ. The six-minute walk test and body weight-walk distance product in healthy Brazilian subjects. Braz J Med Biol Res. 2009;42(11):1080–5.
Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, Masa J, Viejo J, Jimenez-Ruiz C, Miravitlles M. Interpretation of quality of life scores from the St George's Respiratory Questionnaire. Eur Respir J. 2002;19(3):405–13.
O’Donnell DE, Hong HH, Webb KA. Respiratory sensation during chest wall restriction and dead space loading in exercising men. J Appl Physiol. 2000;88(5):1859–69.
Scano G, Innocenti-Bruni G, Stendardi L. Do obstructive and restrictive lung diseases share common underlying mechanisms of breathlessness? Respir Med. 2010;104(7):925–33.
Loh L, Hughes JM, Newsom-Davis J. The regional distribution of ventilation and perfusion in paralysis of the diaphragm [proceedings]. Am Rev Respir Dis. 1979;119(2 P2):121.
Baydur A, Alsalek M, Louie SG, Sharma OP. Respiratory muscle strength, lung function, and dyspnea in patients with sarcoidosis. Chest. 2001;120(1):102–8.
Wirnsberger R, Drent M, Hekelaar N, Breteler M, Drent S, Wouters E, Dekhuijzen P. Relationship between respiratory muscle function and quality of life in sarcoidosis. Eur Respir J. 1997;10(7):1450–5.
Bye A, Sjøblom B, Wentzel-Larsen T, Grønberg BH, Baracos VE, Hjermstad MJ, Aass N, Bremnes RM, Fløtten Ø, Jordhøy M. Muscle mass and association to quality of life in non-small cell lung cancer patients. J Cachexia Sarcopenia Muscle. 2017;8(5):759–67.
Paulin E, Yamaguti W, Chammas M, Shibao S, Stelmach R, Cukier A, Carvalho C. Influence of diaphragmatic mobility on exercise tolerance and dyspnea in patients with COPD. Respir Med. 2007;101(10):2113–8.
He L, Zhang W, Zhang J, Cao L, Gong L, Ma J, Huang H, Zeng J, Zhu C, Gong J. Diaphragmatic motion studied by M-mode ultrasonography in combined pulmonary fibrosis and emphysema. Lung. 2014;192(4):553–61.
Cohen E, Mier A, Heywood P, Murphy K, Boultbee J, Guz A. Excursion-volume relation of the right hemidiaphragm measured by ultrasonography and respiratory airflow measurements. Thorax. 1994;49(9):885–9.
Houston J, Angus R, Cowan M, McMillan N, Thomson N. Ultrasound assessment of normal hemidiaphragmatic movement: relation to inspiratory volume. Thorax. 1994;49(5):500–3.
Scott S, Fuld JP, Carter R, McEntegart M, MacFarlane NG. Diaphragm ultrasonography as an alternative to whole-body plethysmography in pulmonary function testing. J Ultrasound Med. 2006;25(2):225–32.
Soilemezi E, Tsagourias M, Talias MA, Soteriades ES, Makrakis V, Zakynthinos E, Matamis D. Sonographic assessment of changes in diaphragmatic kinetics induced by inspiratory resistive loading. Respirology. 2013;18(3):468–73.
Wait J, Johnson R. Patterns of shortening and thickening of the human diaphragm. J Appl Physiol. 1997;83(4):1123–32.
Greybeck BJ, Wettergreen M, Hubmayr RD, Boriek AM. Diaphragm curvature modulates the relationship between muscle shortening and volume displacement. Am J Phys Regul Integr Comp Phys. 2011;301(1):R76–82.
Dos Santos Yamaguti WP, Paulin E, Shibao S, Chammas MC, Salge JM, Ribeiro M, Cukier A, Carvalho CRF. Air trapping: the major factor limiting diaphragm mobility in chronic obstructive pulmonary disease patients. Respirology. 2008;13(1):138–44.
Smargiassi A, Inchingolo R, Tagliaboschi L, Berardino ADM, Valente S, Corbo GM. Ultrasonographic assessment of the diaphragm in chronic obstructive pulmonary disease patients: relationships with pulmonary function and the influence of body composition-a pilot study. Respiration. 2014;87(5):364–71.
Mitsui T, Azuma H, Nagasawa M, Iuchi T, Akaike M, Odomi M, Matsumoto T. Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle. J Neurol. 2002;249(8):1004–9.
Acknowledgements
The authors thank for the participation of all the patients and volunteers and also for the participating investigators of the Respiratory Muscles Group (Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo) for their contribution during data collection, and São Paulo Research Foundation (Fapesp) for supporting this research.
Funding
This study was supported by São Paulo Research Foundation (Fapesp). Protocol number: 2012/18404–8, a governmental nonprofit agency. No restrictions were placed on authors regarding the statements made in the manuscript.
Author information
Authors and Affiliations
Contributions
PVS, LZC, ALPA, CRRC and PC contributed to the study conception and design. PVS, LZC and ALPA contributed to data acquisition. PVS, LZC, ALPA, and PC contributed to data analysis. PVS and PC contributed to manuscript drafting. All authors contributed to the final manuscript approval.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Our local research ethics committee (Comissão de Etica para Análise de Projetos de Pesquisa do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo - CAPPesq 0835/11) approved the study and all subjects signed an informed consent.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Additional file 1:
Additional file methods and results. This file contains information regarding to methodology and results. The subsection Additional file results present two tables. Table SA1. Health related quality of life according to St. George’s Respiratory Questionnaire in fibrotic interstitial lung disease (FILD) cases. Table SA2. Results of six-minute walk test in the fibrotic interstitial lung disease (FILD) cases.
Additional file 2:
Line graph depicting diaphragmatic mobility at quiet (QB) and deep breathing (DB) and diaphragmatic thickness at functional (FRC) and total lung capacity (TLC) of all subjects (healthy controls and FILD cases). Figure S1. Comparison of diaphragmatic mobility between healthy controls and FILD cases. Diaphragmatic mobility during QB was similar between groups (p = 0.95), but during DB, diaphragmatic mobility was lower in the FILD cases when compared to healthy controls (p < 0.01). At FRC, the diaphragm of FILD cases was significantly thicker (p 0.01) than the healthy controls. But, at TLC, the diaphragm of FILD cases was significantly thinner than the healthy controls (p < 0.01).
Additional file 3: Figure S2.
Correlation of diaphragmatic mobility during deep breathing and healthy-related quality of life (SGRQ), basal dyspnea (MRC), lung function (FVC) and exercise tolerance during the six-minute walk test among the fibrotic interstitial lung disease (FILD) patients.
Additional file 4: Figure S3.
Correlation of diaphragmatic thickening fraction with quality of life (SGRQ), basal dyspnea (MRC), lung function (FVC) and exercise tolerance (desaturation and dyspnea at the end of the six-minute walk test) in patients with fibrotic interstitial lung disease (FILD) patients.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Santana, P.V., Cardenas, L.Z., de Albuquerque, A.L.P. et al. Diaphragmatic ultrasound findings correlate with dyspnea, exercise tolerance, health-related quality of life and lung function in patients with fibrotic interstitial lung disease. BMC Pulm Med 19, 183 (2019). https://doi.org/10.1186/s12890-019-0936-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12890-019-0936-1