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Load dependence of secondary diaphragm inflammation and injury after acute inspiratory loading.

Chronic or prolonged low-intensity loading of the inspiratory muscles has recently been shown to produce diaphragm injury. The present study was designed to examine whether an acute episode of inspiratory resistive loading (IRL) could produce secondary diaphragm inflammation and injury. On Day 1, three groups of anesthetized and intubated New Zealand White rabbits were subjected to moderate IRL (Pao of approximately 30 cm H2O), high IRL (Pao of approximately 45 cm H2O), or no load for 1.5 h. On Day 3, costal and crural diaphragms, parasternals, and gastrocnemius muscles were taken to assess injury by point counting. Normal muscle, abnormal and inflamed muscle, and connective tissue on hematoxylin and eosin-stained cross-sections were expressed as percentage of the total points for that cross-section. For the costal diaphragm, both the abnormal muscle (7.3 +/- 0.6% versus 1.1 +/- 0.2%; p < 0.001) and connective tissue (8.0 +/- 0.6% versus 5.7 +/- 0.2%; p < 0.01) in the high IRL group were higher than control, whereas in the moderate IRL group they were not significantly different from control. Total calpain-like activity was increased in the moderate IRL group but not in the high IRL group. Injury was observed in the parasternal muscles but to a lesser extent. No injury was observed in the gastrocnemius muscle. We conclude that secondary diaphragm injury occurs after acute IRL but only when the IRL exceeds the fatigue threshold.

Acute Disease↗

Assessment of inspiratory flow limitation invasively and noninvasively during sleep.

To define the standard of airway flow limitation, pharyngeal pressure and flow rate were measured during wakefulness and sleep in seven habitual snorers with widely varying degrees of sleep-induced increases in upper airway resistance. Inspiratory pressure:flow relationships were used to group breaths into four categories of flow limitation, including linear (Level 1), mildly alinear (Level 2), constant flow rate with no pressure dependence (Level 3), and decreasing flow rate throughout significant portions of inspiration, i.e., negative pressure dependence (Level 4). These pressure:flow rate gold standards of flow limitation were used to evaluate a flow limitation index derived from the time profile (or "shape") of three noninvasive estimates of flow rate: (1) pneumotach flow rate, (2) differentiated sum respiratory inductance plethysmography (RIP), and (3) nasal pressure. A nonflow limited template for each of these noninvasive measurements was taken from awake breaths and the difference in area determined between the template breath and each of the noninvasive signals measured during nonrapid eye movement (NREM) sleep. The noninvasive flow limitation indices were found to be effective in differentiating severe types of inspiratory flow limitation, i.e., Level 1 versus Level 3 or Level 4 (sensitivity/specificity > 80%). On the other hand, these indirect indices were not able to consistently detect mild levels of flow limitation (Level 1 versus Level 2; sensitivity/specificity = 62 to 72%); nor were these noninvasive estimates of flow rate "shape" sensitive to breaths with a high but fixed resistance throughout inspiration. The area index derived from measurements of pressure at the nares (Pn) was the most sensitive, nonperturbing, noninvasive measure of flow rate and flow limitation, and we recommend its use for recognizing most of the common types of moderate to severe levels of airway flow limitation in sleeping subjects.

Adult↗

Inspiratory muscle function and body composition in cystic fibrosis.

Loss of body mass, which occurs in the later stages of cystic fibrosis (CF), probably affects all body compartments. We hypothesized that loss of skeletal muscle mass would include inspiratory muscles and impair their function. To test this, we determined the effect of body mass index (BMI) and lean body mass (LBM) depletion on handgrip (HG) force and inspiratory muscle function (IMF). The maximum inspiratory pressure (MIP) and the sustained maximum inspiratory pressure (SMIP) were measured with a computerized system. The relationship of IMF and reduced BMI to survival was studied in 49 patients, and a further 25 patients were studied to define the link between IMF and LBM. LBM was assessed by anthropometry. In the survival study a BMI < 20 kg/m2 was associated with a low SMIP (p < 0.001) and reduced survival, whereas MIP was relatively preserved. In the cross-sectional study SMIP (p < 0.001), MIP (p < 0.01), and HG (p < 0.01) were all reduced in the low LBM group, but not when related to total LBM. C-reactive protein and LBM were inversely related (r = -0.71, p < 0.01). Impaired IMF was chiefly a loss of sustained muscle contraction secondary to a reduced skeletal muscle mass, which may be related to pulmonary inflammation.

Adult↗

Effect of different pressure levels on the dynamics of lung collapse and recruitment in oleic-acid-induced lung injury.

The effects of different inspiratory and expiratory airway pressures (Paw) on the dynamics of lung collapse and recruitment were studied in 14 anesthetized, mechanically ventilated, pigs with oleic-acid-induced lung injury. Repetitive CT scans of the same slice were obtained every 0.8 s during different inspiration and expiration hold procedures. The mean lung density and amount of atelectasis were measured in each scan. Inspiration to a Paw of 15 cm H2O above PEEP resulted in recruitment of collapsed lung tissue, mainly within 1.4 s. During expiration lung density increased rapidly and at an almost even rate within the first 1.4 s, whereas a rapid increase of atelectasis occurred after an initial delay period of 0.6 s with PEEP = 10 or 15 cm H2O. PEEP of 20 or 25 cm H2O almost prevented lung collapse during expiration. Thus, in order to avoid cyclic alveolar collapse during mechanical ventilation in oleic-acid-induced lung injury, a PEEP level >= 20 cm H2O or an expiration time <= 0.6 s is required. Long inspiratory time intervals, as used in inverse ratio ventilation, seem to be of minor importance for the recruitment of collapsed lung tissue in this experimental model.

Analysis of Variance↗

Respiratory resistive impedance as an index of airway obstruction during nasal continuous positive airway pressure titration.

Esophageal pressure amplitude (DeltaPes), inspiratory pulmonary resistance (RLI) and inspiratory flow limitation score (FS) are used as indices of upper airway obstruction for the titration of nasal continuous positive airway pressure (nCPAP) in patients with obstructive sleep apnea syndrome (OSAS). This study was designed to determine whether oscillatory respiratory resistive impedance at 16 Hz (RFO) might be proposed as an alternative index. Eleven OSAS patients were studied during a night of polysomnography-controlled nCPAP titration. Nasal flow (V) and airway opening and esophageal pressures (Pao and Pes, respectively) were continuously measured during nasal breathing, and forced-flow oscillations (FO) were applied for 5 min at each nCPAP level. RLI was calculated by linear regression analysis of resistive pressure versus V over inspiration. R FO was obtained by linear regression analysis of respiratory resistive impedance versus frequency. Application of FO affected neither sleep nor pulmonary mechanics. RFO correlated with RLI in all patients. RFO did not correlate with DeltaPes in two patients, and was not significantly related to FS in five patients. This study demonstrates the applicability of the FO technique in sleeping patients receiving nCPAP, and the reliability of RFO for assessing pulmonary resistance. RFO might therefore be proposed as a quantitative index of airway obstruction for nCPAP titration.

Aged↗

Determinants of maximal inspiratory pressure. The Baltimore Longitudinal Study of Aging.

A variety of methods for subject selection and test procedures have been used for the determination of normal values and reference equations for maximal inspiratory pressure (MIP). In the cross-sectional study described here, we made MIP measurements on 668 men and women in the Baltimore Longitudinal Study of Aging (BLSA), using a standardized electronic procedure. Results were combined with spirometric and anthropometric measurements. After subjecting them to rigorous health screening, we analyzed a well-defined, healthy subgroup of 139 men and 128 women with a wide age range (20 to 90 yr), using multiple linear regression, for the purpose of determining the effect of age, other correlates, normal values, and gender-specific reference equations for MIP. The gender effect was strong, with the average MIP values of the men being about 30% higher than those of the women (101 cm H2O and 72 cm H2O, respectively). The reference equation for men is: MIP +/- standard error of the estimate (SEE) = 126 - 1.028 x age + 0.343 x weight (kg) +/- (22.4); and for women: MIP +/- SEE = 171 - 0.694 x age + 0. 861 x weight (kg) - 0.743 x height (cm) +/- (18.5). These equations may be used for the assessment of inspiratory muscle strength.

Adult↗

Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS.

Because animal studies have demonstrated that mechanical ventilation at high volume and pressure can be deleterious to the lungs, limitation of airway pressure, allowing hypercapnia if necessary, is already used for ventilation of acute respiratory distress syndrome (ARDS). Whether a systematic and more drastic reduction is necessary is debatable. A multicenter randomized study was undertaken to compare a strategy aimed at limiting the end-inspiratory plateau pressure to 25 cm H2O, using tidal volume (VT) below 10 ml/kg of body weight, versus a more conventional ventilatory approach (with regard to current practice) using VT at 10 ml/kg or above and close to normal PaCO2. Both arms used a similar level of positive end-expiratory pressure. A total of 116 patients with ARDS and no organ failure other than the lung were enrolled over 32 mo in 25 centers. The two groups were similar at inclusion. Patients in the two arms were ventilated with different VT (7.1 +/- 1.3 versus 10.3 +/- 1.7 ml/kg at Day 1, p < 0.001) and plateau pressures (25.7 +/- 5. 0 versus 31.7 +/- 6.6 cm H2O at Day 1, p < 0.001), resulting in different PaCO2 (59.5 +/- 15.0 versus 41.3 +/- 7.6 mm Hg, p < 0.001) and pH (7.28 +/- 0.09 versus 7.4 +/- 0.09, p < 0.001), but a similar level of oxygenation. The new approach did not reduce mortality at Day 60 (46.6% versus 37.9% in control subjects, p = 0.38), the duration of mechanical ventilation (23.1 +/- 20.2 versus 21.4 +/- 16. 3 d, p = 0.85), the incidence of pneumothorax (14% versus 12%, p = 0. 78), or the secondary occurrence of multiple organ failure (41% versus 41%, p = 1). We conclude that no benefit could be observed with reduced VT titrated to reach plateau pressures around 25 cm H2O compared with a more conventional approach in which normocapnia was achieved with plateau pressures already below 35 cm H2O.

Adolescent↗

Demographic and anthropometric correlates of maximum inspiratory pressure: The Atherosclerosis Risk in Communities Study.

Maximum inspiratory pressure (MIP), an indicator of inspiratory muscle strength, is reported on 13,005 African-American and white participants from the Atherosclerosis Risk in Communities Study. Sex-specific associations between MIP and age, anthropometric measures, physical activity, health status, smoking status, and education level are presented. In this cohort of subjects 47 to 68 yr of age, MIP decreased 0.93 cm H2O (p </= 0.0001) in women and 1.2 cm H2O (p </= 0.0001) in men for each 1-yr increase in age. In both sexes, after adjusting for age, the associations between MIP and current body weight, weight at 25 yr of age, waist girth, body mass index, and calf girth were statistically significant and nonlinear (convex quadratic). MIP was positively associated with standing height in both sexes after controlling for age (p </= 0.03). The age-adjusted association between MIP and sitting height was nonlinear in men and linear in women. MIP was also associated (positively) with education level, health status, physical activity, and (negatively) cigarette smoking. The study was not designed to evaluate associations with race, but data patterns suggest the absence of a race effect on MIP.

Aged↗

Perceived inspiratory difficulty during inspiratory threshold and hyperinflationary loadings.

Dynamic hyperinflation loads the inspiratory muscles by increasing end-expiratory lung volume (EELV) and imposing intrinsic positive end-expiratory pressure (PEEPi), the latter behaving as an inspiratory threshold load (ITL). The major purpose of this study was to describe the independent effects of the imposed ITL and changes in operating lung volume on the perception of inspiratory difficulty. In eight healthy subjects, independent increases in EELV and ITL were induced by continuous positive airway pressure (CPAP) and external ITL applications, respectively; increase in both EELV and PEEPi (thus the imposed ITL) was induced by application of positive end-expiratory pressure (PEEP). The perceived inspiratory difficulty increased significantly when either EELV or ITL was increased, and was always greater during combined increase in EELV and the imposed ITL (during PEEP) than when either factor was increased independently, suggesting that the imposed ITL and EELV each contribute independently to inspiratory difficulty. Inspiratory difficulty of each subject under all conditions was then fitted into a step-forward multiple regression model. The imposed ITL was a significant contributor to inspiratory difficulty in all subjects and was the first parameter to be selected in six of the eight subjects. When the results of all the subjects were pooled, the imposed ITL alone explained 40% of variations in inspiratory difficulty. Adding the change in end-inspiratory lung volume (DeltaEILV) to the model explained an additional 24% of variations in inspiratory difficulty. The coefficients (slopes) of the imposed ITL and DeltaEILV were 0.21 +/- 0.02 cm H2O-1 and 0.051 +/- 0.006 %IC-1, respectively. It is concluded that under our experimental conditions, the imposed ITL is a better predictor for explaining the variability of the perceived inspiratory difficulty than the operating lung volume.

Adult↗

The relationship of skin test positivity, high serum total IgE levels, and peripheral blood eosinophilia to symptomatic and asymptomatic airway hyperresponsiveness.

The relationships of skin test positivity, high serum total IgE levels (> 100 kU/L), and peripheral blood eosinophilia (>/= 275 cells/microliter) to symptomatic (either chronic cough, chronic phlegm, bronchitis episodes, dyspnea, wheeze, or asthma) and asymptomatic bronchial hyperresponsiveness (BHR) were studied cross-sectionally in 620 adult subjects who participated in the Vlagtwedde-Vlaardingen Study of 1989 and 1990. Eosinophilia (OR = 2.06, 95% CI = 1.28 to 3.31) and skin test positivity (OR = 1.66, 95% CI = 1.02 to 2.71) were both significantly associated with BHR independent of age, sex, smoking, and urban area of residence. High serum total IgE levels were not associated with BHR (OR = 1.29, 95% CI = 0.81 to 2.03). Separate analyses for symptomatic and asymptomatic subjects showed that the higher risk of BHR with skin test positivity applied only to symptomatic subjects (OR = 5.78, 95% CI = 1.63 to 20.51), independent of eosinophilia and high serum total IgE levels. The higher risk of BHR with eosinophilia was not different between symptomatic and asymptomatic subjects, and independent of skin test positivity and high serum total IgE levels. The results of this study show that, in the general adult population, eosinophilia is associated with BHR both in symptomatic and asymptomatic persons, whereas skin test positivity is associated with BHR only in symptomatic subjects.

Adult↗

Time course of increased airway narrowing caused by inhibition of deep inspiration during methacholine challenge.

Inhibition of deep inspiration (DI) enhances methacholine-induced airway narrowing in normal subjects. However, the time course over which excessive airway narrowing develops during inhibition of DI is not known. We hypothesized that the development of enhanced airway narrowing when DI is inhibited is time dependent. Ten normal volunteers (five males and five females) inhaled five doses of methacholine (16 mg/ml for 2 min) at 5-min intervals during an initial methacholine challenge. FEV(1) was measured at baseline and after each dose. On four subsequent days, the subjects again inhaled two, three, four, or five doses, in random order, without DIs during the challenge. FEV(1) was measured only at baseline and after the last dose. Baseline FEV(1) was normal in all subjects. The maximal mean percent decrease in FEV(1) after the initial challenge was 10 +/- 1.5%, but was 28 +/- 6.0% when DIs were inhibited throughout the five inhalations (p < 0.01). The difference in decrease in FEV(1) between days with and without DI became significant after 10 min (three doses), and remained stable thereafter when the response plateaued. The reversal of airway narrowing after three DIs was incomplete after 15 min (four doses). In conclusion, the increased airway narrowing associated with inhibition of DI during airway smooth-muscle contraction occurs after 10 min in normal subjects, at which time the response plateaus. However, the ability of DI to reverse airway narrowing appears to diminish progressively.

Adult↗

Cycle ergometer and inspiratory muscle training in chronic obstructive pulmonary disease.

In patients with chronic obstructive pulmonary disease (COPD) the intensity of aerobic training is limited by dyspnea. Improving strength of the inspiratory muscles could enhance aerobic exercise training by reducing exercise-related dyspnea. We examined effects of home-based inspiratory muscle training (IMT) and cycle ergometry training (CET) in 53 patients with moderate to severe COPD (FEV(1)% pred, 50 +/- 17 [mean +/- SD]). Patients were randomly assigned to 4 mo of training in one of four groups: IMT, CET, CET + IMT, or health education (ED). Patients were encouraged to train to the limits of their dyspnea. Inspiratory muscle strength and endurance increased in IMT and CET + IMT groups compared with CET and ED groups (p < 0. 01). Peak oxygen uptake increased and heart rate, minute ventilation, dyspnea, and leg fatigue decreased at submaximal work rates in the CET and CET + IMT groups compared with the IMT and ED groups (p < 0. 01). There were no differences between the CET and CET + IMT groups. Home-based CET produced a physiological training effect and reduced exercise-related symptoms while IMT increased respiratory muscle strength and endurance. The combination of CET and IMT did not produce additional benefits in exercise performance and exercise-related symptoms. This is the first study to demonstrate a physiological training effect with home-based exercise training.

Aged↗

Diaphragm strength in chronic heart failure.

Reduced respiratory muscle strength has been reported in chronic heart failure (CHF) in several studies. The data supporting this conclusion come almost exclusively from static inspiratory and expiratory mouth pressure maneuvers (MIP, MEP), which many subjects find difficult to perform. We therefore performed a study using measurements that are less dependent on patient aptitude and also provide specific data on diaphragm strength. In 20 male patients and 15 control subjects we measured MIP and MEP as well as esophageal and transdiaphragmatic pressure during maximal sniffs (Sn Pes, Sn Pdi) and cervical magnetic phrenic nerve stimulation (Tw Pdi). In a subgroup the response to paired phrenic nerve stimulation (pTw Pdi) at interpulse intervals from 10 to 200 ms (5 to 100 Hz) was also determined. As expected, MIP was significantly reduced in the CHF group (CHF, 69.5 cm H(2)O; control, 96.7 cm H(2)O; p = 0.01), but differences were much less marked for Sn Pes (CHF, 95.2 cm H(2)O; control, 104.8 cm H(2)O; p = 0.20) and MEP (CHF, 109.1 cm H(2)O; control, 135.7 cm H(2)O; p = 0.09). Diaphragm strength was significantly reduced (Sn Pdi: CHF, 123.8 cm H(2)O; control 143.5 cm H(2)O; p = 0.04. Tw Pdi: CHF, 21.4 cm H(2)O; control, 28.5 cm H(2)O; p = 0.0005). Paired phrenic nerve stimulation suggested a trend to increased twitch summation at 5 to 20 Hz in CHF, although this did not reach significance. We conclude that mild reduction in diaphragm strength occurs in CHF, possibly because of an increased proportion of slow fibers, but overall strength of the respiratory muscles remains well preserved.

Adult↗

Inspiratory flow dynamics during phrenic nerve stimulation in awake normals during nasal breathing.

The loss of upper airway (UA) dilators preactivation before inspiratory muscle contraction is an important determinant of the pathophysiology of obstructive sleep apnea. We hypothetized that phrenic nerve stimulation could provide a practical way to explore the effects of the dissociation between UA dilators and inspiratory muscles, and possibly to determine UA critical closing pressure during wakefulness. The pattern of inspiratory airflow was therefore studied in normal awake subjects during diaphragm twitches induced by either electrical phrenic stimulation (ES) or cervical magnetic stimulation (CMS) (n = 9) and with and without a nasal stent during ES (n = 7). End-expiratory stimulations applied during exclusive nasal breathing induced 200 to 300 ms twitch inspiratory flow. The average maximal twitch flow of flow-limited twitches was higher during CMS than ES (1.18 +/- 0.29 L.

Adult↗

Model of functional restriction in chronic obstructive pulmonary disease, transplantation, and lung reduction surgery.

Mechanical interactions between lung and chest wall are important determinants of respiratory function. When chest wall expansion during maximal inhalation generates insufficiently negative pleural pressures, the lungs remain functionally underinflated; this may be termed functional restriction. To explore mechanisms and effects of functional restriction in patients with emphysema, and to predict effects of single lung transplantation and lung volume reduction surgery (LVRS), we used a computational model based on standard physiology and measurements from individual patients. The model's lungs, separated by a compliant mediastinum, exhibit flow limitation according to the equal pressure point approach of Mead and coworkers. Pulmonary elastic recoil pressure is characterized by an exponential equation modified to reflect airway closure. Simulated respiratory maneuvers can be specified by variations in flow or pressure at the airway opening or in respiratory muscle activation. Model simulations successfully mimic recordings from individual patients. Input parameter values may then be altered to predict effects of surgical interventions in these same patients. The model simulations show the following. Single lung transplantation in emphysema can cause functional restriction of the normal transplanted lungs, and larger transplanted lungs may perform less well than smaller ones. LVRS improves lung and chest wall function in emphysema, but not in normal states. Surgical reduction of the native emphysematous lung after single lung transplantation can reduce functional restriction of the transplant and thereby improve its function.

Humans↗

Respiratory control and respiratory sensation in a patient with a ganglioglioma within the dorsocaudal brain stem.

We encountered a young woman with severe central sleep apnea caused by a medullary glioma located slightly dorsal to and to the right of the midline, a region not generally associated with CO(2) chemosensitivity. The patient had normal spirometric readings, lung volumes, diffusing capacity, maximal inspiratory pressure, and alveolar-arterial oxygen difference. While awake, she displayed marked irregularity in her breathing pattern; her end-tidal CO(2) (FET(CO(2))) ranged from 5.3 to 10.9%. During voluntary hyperpnea, she could quickly reduce her FET(CO(2)) to 4.2%, but her PCO(2) did not change after administration of acetazolamide or progesterone. Like patients with congenital central hypoventilation syndrome (CCHS), our patient had a relatively intact ventilatory response to exercise; her PCO(2) was high at the start of exercise and increased slightly thereafter. In contrast to CCHS patients, however, our patient had an intact hypoxic ventilatory response (DeltaVE/ DeltaSa(O(2)) = -0.37 L/min/Sa(O(2))). In further contrast to CCHS patients, our patient had a very short breathholding time and described a sensation of air hunger as the factor limiting her breathholding ability. Her heart rate and blood pressure responses to the Valsalva maneuver were normal.

Adolescent↗

Breathing He-O2 increases ventilation but does not decrease the work of breathing during exercise.

We previously observed an increase in minute ventilation (V E) with resistive unloading (He-O2 breathing) in healthy elderly subjects with normal pulmonary function. To investigate the effects of resistive unloading in elderly subjects with mild chronic airflow limitation (FEV(1)/FVC: 61 +/- 4%), we studied 10 elderly men and women 70 +/- 3 yr of age. These subjects performed graded cycle ergometry to exhaustion, once breathing room air and once breathing a He-O2 gas mixture (79% He, 21% O2). V E, pulmonary mechanics, and PET(CO2) were measured during each 1-min increment in work rate. Data were analyzed by paired t test at rest, at ventilatory threshold (VTh), and during maximal exercise. V E was significantly (p < 0.05) increased at VTh (3.4 +/- 4.0 L/min or 12 +/- 15% increase) and maximal exercise (15.2 +/- 9.7 L/min or 22 +/- 13% increase) while breathing He-O2. Concomitant to the increase in V E, PET(CO2) was decreased at all levels (p < 0.01), whereas total work of breathing against the lung was not different. We concluded that V E is increased during He-O2 breathing because of resistive unloading of the airways and the maintenance of the relationship between the work of breathing and exercise work rate.

Age Factors↗

Inspiratory muscle relaxation rate slows during exhaustive treadmill walking in patients with chronic heart failure.

Exercise intolerance is a feature of chronic heart failure (CHF). We hypothesized that excessive loading of the respiratory muscle pump might contribute to exertional breathlessness. One marker of excessive muscle-loading is slowing of maximum relaxation rate (MRR) and, therefore, to test our hypothesis, we investigated the effect of exhaustive treadmill walking on inspiratory muscle MRR in patients with CHF. We studied eight stable patients with mild-moderate CHF walking on a treadmill until termination because of severe dyspnea. Inspiratory muscle MRR was determined from esophageal pressure (Pes) change during submaximal sniffs (Sn) before and immediately after exercise to a mean (SD) minute ventilation of 77 () L/min. For comparison, nine healthy subjects performed a similar protocol; exercise was terminated either by severe dyspnea or when minute ventilation reached 100 L/min. There were no significant differences in terms of heart rate, respiratory rate, tidal volume, or inspiratory duty cycle at cessation of exercise. The mean slowing of Sn Pes MRR in the first minute after termination of exercise in the CHF group was 22.4% and in the normal control group it was 2.8% (p < 0.01). Our data show that slowing of inspiratory muscle relaxation rate occurs in patients with CHF walking to severe breathlessness. We conclude that severe loading of the inspiratory muscles is a feature of exertional dyspnea in CHF.

Adult↗