American Journal of Respiratory and Critical Care Medicine

As forced expiratory volume in 1 second (FEV1) is a major predictor of outcome in patients with cystic fibrosis (CF), we investigated the effect of FEV1 on pulmonary mechanics in children and young adults with CF. We measured respiratory rate; tidal volume; minute ventilation; arterial blood gases; sniff esophageal pressure; dynamic lung compliance; total pulmonary resistance; intrinsic positive end expiratory pressure; and total, elastic, and resistive work of breathing in 32 patients (FEV1 range: 12–49% predicted). We observed correlations between FEV1 and PaO2 (r = 0.76, p < 0.0001) and PaCO2 (r = −0.70, p < 0.0001), FEV1 and respiratory rate/tidal volume (r = −0.41, p = 0.02), FEV1 and dynamic lung compliance (r = 0.64, p < 0.0001), and FEV1 and total work of breathing (r = −0.52, p = 0.002) and elastic work of breathing (r = −0.60. p = 0.0003). No correlations were observed between FEV1 and sniff esophageal pressure (p = 0.5), minute ventilation (p = 0.9), total pulmonary resistance (p = 0.3), intrinsic positive end expiratory pressure (p = 0.3), or resistive work of breathing (p = 0.1). As FEV1 declines in children and young adults with CF, there is an increase in the elastic load and work of breathing, resulting in a rapid shallow breathing pattern, that is associated with further impairment of gas exchange.

The majority of patients with cystic fibrosis (CF) die from respiratory failure (1, 2). Forced expiratory volume in 1 second (FEV1) and rate of decline in FEV1 have been shown to be the best independent predictors of survival (35) and the major indicators for lung transplantation (4). Although pulmonary mechanics have been investigated in adults at rest and during exercise (610) and in children with moderate impairment of lung function (1113), there are no studies that have investigated the relationship between FEV1 and pulmonary mechanics in children and young adults with more advanced pulmonary disease. Although the study of Gaultier and colleagues (14) demonstrated changes in pulmonary mechanics and increased risk of respiratory muscle fatigue in children with severe chronic obstructive pulmonary disease, these data cannot be uncritically applied to children with CF who have a different pulmonary disease from chronic obstructive pulmonary disease that is characterized not only by progressive airflow obstruction, caused by mucus plugging and inflammation within the bronchial walls, but also by the destruction of the lung parenchyma secondary to bronchiectasis (15, 16). Therefore, the aim of this study was to investigate the pathophysiologic changes in breathing pattern, gas exchange, and pulmonary mechanics that occur as FEV1 falls with increasing severity of pulmonary disease in children and young adults with CF.

Inclusion Criteria

The study was approved by the local hospital ethics committee. Patients were recruited from our CF center, and both patients and parents gave their informed consent. Patients were included if they were 20 years of age or younger, had an FEV1 of less than 50% predicted, and had been clinically stable for at least 1 month before the study.

Pulmonary Function Tests

Arterialized earlobe capillary blood gases (17) and spirometry were measured within 24 hours of the study according to standard guidelines (18). FEV1 and vital capacity were expressed as a percentage of published values (18). Carbon dioxide was corrected (cPaCO2) for a pH of 7.4 (19), and alveolar–arterial oxygen gradient was calculated according to the ideal alveolar–arterial oxygen equation (20).


Flow was measured with a pneumotachograph head (Fleisch #1, Lausanne, Switzerland) inserted into the distal end of a mouthpiece and connected to a pressure transducer (MP 45 model, Validyne ± 2 cm H2O; Validyne Corp., Northridge, CA). Airway pressure was measured with a differential pressure transducer (MP 45 model, Validyne ± 100 cm H2O; Validyne Corp.) connected via plastic tubing to the mouthpiece. Esophageal pressure (Pes) was measured following insertion of a catheter-mounted pressure transducer system (Gaeltec, Dunvegan, UK). Appropriate placement of the esophageal pressure transducer was assessed with the method described by Baydur and colleagues (2123). All signals were sampled at 128 Hz and were passed to a computer (Elonex, Gennevilliers, France). Data were acquired and analyzed using the Biopac system (MP 100; Biopac Systems, Goletta, CA) and Acknowledge software. All values were recorded as pressure changes.

Study Protocol

All studies were performed in the afternoon 1 hour following chest physiotherapy. Patients performed 10–15 sniff maneuvers from functional residual capacity determined by the end-expiratory Pes level (24, 25); maximum sniff Pes was recorded (24). Following a 15-minute period of stabilization, measurements were taken during 5 minutes of spontaneous breathing.

Data Analysis

Minute ventilation, tidal volume (VT), respiratory rate (RR), inspiratory time/total time for the breath cycle, and mean inspiratory flow rate were calculated from the flow trace (see online data supplement). Total inspiratory work of breathing (WOBtot) was calculated as described by Fauroux and colleagues (26) and was expressed per minute (J · minute−1) and per liter of ventilation (J · L−1). WOBtot was partitioned into the elastic (WOBel) and resistive work of breathing components by a line drawn between Pes values at points of zero flow. The slope of this line indicated dynamic lung compliance (CL dyn). Total pulmonary resistance (RL) was calculated by dividing mean resistive pressure by mean inspiratory flow. Intrinsic positive end-expiratory pressure (PEEPi) was taken as the difference in Pes between the starting Pes value and the value at the point of zero flow (27, 28). We calculated Pes pressure time product/minute (PTPes) as an indicator of load (29) and PTPes · cPaCO2 product and PTPes · cPaCO2 · RR/VT product as indices of the efficiency of the respiratory muscle pump to clear carbon dioxide (30). Ten to 30 successive breaths were used to for analysis.

Statistical Analysis

Data are expressed as mean ± SD. Correlations between FEV1 and breathing pattern, gas exchange, respiratory muscle function, respiratory muscle pump efficiency to clear carbon dioxide, pulmonary mechanics, and work of breathing were assessed by simple linear regression analysis using FEV1 as a continuous variable. Stepwise regression analysis was also used to demonstrate the relationship between PEEPi and RL and RR. A p value of less than 0.05 was considered statistically significant.

Thirty-two patients with CF and an FEV1 of less than 50% predicted were studied. Clinical characteristics for the individual patients are shown in Table E1 in the online data supplement. All patients tolerated the procedures well, and no problems were encountered during insertion of the pressure-monitoring catheter. Mean age and body mass index of the patients were 14.2 ± 2.9 years and 16.5 ± 2.1 kg · m−2, respectively. Table 1

TABLE 1. Mean values ± sd and range for all the measured variables during resting breathing in 32 children and young adults with cystic fibrosis

 (% Pred)

 (% Pred)




Mean ± SD28.7 ± 10.242.1 ± 13.4 8.4 ± 1.4 6.0 ± 0.822.6 ± 7.8409 ± 120

 (cm H2O)
Mean Pes
 (cm H2O)
 (cm H2O · s · min−1)
PTPes · cPaCO2(cm H2O · s · min1 · kPa · 10−2)
PTPes · cPaCO2 · RR/VT
 (cm H2O · s · min1 · kPa · bpm · L1 · 10−5)
Mean ± SD84.3 ± 23.414.7 ± 5.140.2 ± 4.6345 ± 11221.4 ± 8.814.5 ± 11.2

Cl dyn
 (ml · cm H2O−1)
 (cm H2O)
 (cm H2O · s−1 · L−1)
 (J · min−1)
 (J · min−1)
 (J · min−1)
Mean ± SD42.1 ± 33.0 1.1 ± 1.617.1 ± 9.7 12.6 ± 5.0 7.6 ± 3.05.1 ± 2.5

Definition of abbreviations: Cl dyn = dynamic lung compliance; cPaCO2 = corrected partial pressure of arterial carbon dioxide; FEV1 = forced expiratory volume in 1 second; Mean Pes = mean decline in esophageal pressure per breath cycle; PEEPi = intrinsic positive end expiratory pressure; Pesmax = maximum negative esophageal pressure during a sniff maneuver; % Pred = percent predicted; PTPes = esophageal pressure time product per minute; PTPes · cPaCO2 and PTPes · cPaCO2 · RR/VT = indices of efficiency of respiratory muscle pump to clear carbon dioxide (30); Rl = total pulmonary resistance; RR = respiratory rate; Ti/Ttot = inspiratory time as a fraction of the time for the total breath cycle; VC = vital capacity; VT = tidal volume; WOBel = elastic work of breathing; WOBres = resistive work of breathing; WOBtot = total work of breathing.

shows the mean ± SD and range of the data for all of the variables measured.

Respiratory Pattern and Gas Exchange

In addition to the direct correlation between FEV1 and PaO2 (r = 0.76, p < 0.0001), we observed a negative correlation between FEV1 and cPaCO2 (r = −0.70, p < 0.0001) (Figure 1)

. There was no correlation between body mass index and FEV1 (p = 0.1). As expected, there was a fall in the percentage of predicted vital capacity as FEV1 decreased (r = 0.77, p < 0.0001), but no correlation was observed between FEV1 and minute ventilation (p = 0.9). Nevertheless, we observed that the reduction in FEV1 as disease progressed was accompanied by a rise in RR (r = −0.38, p = 0.03), a decrease in VT (r = 0.37, p = 0.04), and a subsequent rise in the RR/VT ratio (r = −0.41, p = 0.02) (Figure 2) . There was no correlation between FEV1 and Ti/Ttot (p = 0.4) or mean inspiratory flow rate (p = 0.6). We observed, however, that FEV1 correlated with the alveolar–arterial oxygen gradient, and as FEV1 fell, the alveolar–arterial oxygen gradient widened (r = −0.54, p = 0.001).

Inspiratory Muscle Strength, Respiratory Muscle Load, and Carbon Dioxide

Although there was no correlation between sniff Pes and FEV1 (p = 0.5), mean Pes decline and mean PTPes increased as FEV1 declined (r = −0.57, p = 0.001 and r = −0.55, p = 0.001, respectively) (Figure 3B)

. Furthermore, both PTPes · cPaCO2 product (Figure 4) and PTPes · cPaCO2 · RR/VT product increased as FEV1 decreased (r = −0.64, p < 0.0001 and r = −0.60, p = 0.0003, respectively).

Pulmonary Mechanics and Work of Breathing

Although there was a direct correlation between CL dyn and FEV1 (r = 0.64, p < 0.0001) (Figure 3A), we observed no such correlations between FEV1 and PEEPi (p = 0.3) or RL (p = 0.3). This difference between CL dyn, PEEPi and RL, and FEV1 was further highlighted as WOBtot (J · minute−1) and WOBel (J · minute−1) both correlated indirectly with FEV1 (r = −0.52, p = 0.002 and r = −0.60, p = 0.0003, respectively) (Figures 3C and 3D), but there was no correlation observed between FEV1 and resistive work of breathing (J · minute−1) (p = 0.1). Similar results were obtained if WOBtot, WOBel, and resistive work of breathing were expressed in J · L−1. However, we performed stepwise linear regression analysis to assess correlations with PEEPi and observed that PEEPi correlated with RL (r = 0.67, p < 0.0001) and RR (r = 0.72, p < 0.0001); VT and CL dyn conferred no further benefit to the correlation.

The main findings of this study are that in children and young adults with advanced CF, as judged by FEV1, there is a change in breathing pattern as the pulmonary disease progresses. Specifically, patients adopt a more rapid shallow breathing pattern that is associated with further impairment of gas exchange. Although global inspiratory muscle strength does not fall with progression of the pulmonary disease, the load on the respiratory muscles is increased. There is a decrease in the CL dyn during resting breathing but little change in RL or PEEPi. These changes in pulmonary mechanics are reflected as an increase in the WOBtot and WOBel with minimal change in the resistive work of breathing.

Critique of Method

For a discussion of the limitations of this study, see the online data supplement.

Significance of Findings

Pulmonary mechanics. The adaptations in breathing strategy observed in our patients with increasing disease severity are presumed to be a consequence of the increased respiratory load. The predominant increase in load observed as FEV1 fell was due to a reduction in CL dyn. Although there was no correlation observed between RL or PEEPi and FEV1, it is important to point out that PEEPi was present in 29 of the patients and that RL was noticeably elevated compared with the published data for normal young adults (31). This disparity between FEV1 and RL as FEV1 declined is a consequence of the different factors that determine FEV1 and RL. RL is measured during the inspiratory phase of resting breathing, when intrathoracic airways collapse would be minimal and is calculated as the sum of both lung tissue and airway resistance. In contrast, FEV1 is a maximal expiratory forced maneuver that is dependent on a combination of the static elastic recoil forces and the resistance upstream from the point of dynamic compression within the airways (32, 33). Although elastic recoil is relevant to the development of maximum expiratory flow in patients with CF, airways obstruction is a much greater determinant factor of FEV1 in these patients (34). Thus, we must presume that mucus plugging, bronchomalacia, and destruction of the lung parenchyma by bronchiectasis as well as the ongoing inflammation within the bronchial walls are important factors causing the reduction in FEV1. However, RL is directly related to the difference in total pleural pressure and lung elastic pressure and is inversely related to flow (35). Therefore, the uniform RL as FEV1 decreases can be explained by the fact that the difference between elastic pressure and pleural pressure as FEV1 declines is constant with no difference observed in airflow. This is supported by the correlation between CL dyn, as a reciprocal indicator of elastic pressure, and the mean decline in Pes as FEV1 falls (r = 0.66, p < 0.0001). Furthermore, we observed that mean inspiratory flow rate remains unchanged as FEV1 decreases.

As stated previously here, the predominant factor responsible for the increase in load as FEV1 decreased was the reduction in CL dyn. In fact, there was a positive correlation between FEV1 and CL dyn that was reflected, as expected, as an increase in the WOBel and the WOBtot. We presume that the declining FEV1 is associated with greater inflammatory changes in and destruction of the lung parenchyma, which would result in a reduction of lung elasticity and CL dyn. An additional cause for the observed reduction in CL dyn is a consequence of the frequency-dependent nature of dynamic lung compliance (36). Thus, the patients with very severe pulmonary disease could be expected to have a lower CL dyn as a result of the increase in RR.

The majority of the patients we studied had PEEPi, and thus, by definition were hyperinflated. Furthermore, alveolar expiratory pressure at the end of expiration, which can be described as a single exponential function of time, is equivalent to PEEPi and can be expressed as

where Te is expiratory time, R is resistance, C is compliance, and RC is the time constant of the respiratory system. In this study, we observed that the decrease in FEV1 was paralleled by a reduction in CL dyn. Therefore, as CL dyn is directly related to C and was associated with a reduction in VT and Te as FEV1 decreased, when VT is normalized for C, and Te for RC, the overall result is that there is little change in PEEPi during resting breathing. Furthermore, similar to the studies in adult CF patients (8), PEEPi correlated with RL (r = 0.65, p = 0.001). In addition, we observed that PEEPi correlated, using stepwise regression analysis, with RL and RR (r = 0.72, p < 0.0001). Therefore, although the PEEPi is relatively low during stable state resting breathing, during an exacerbation, one would expect an increase in PEEPi to accompany the expected increases in RL and RR.

Change in breathing strategy breathing, work of breathing, and respiratory muscle load. As the pulmonary disease progresses, there is a change to a rapid shallow pattern of breathing (Figure 2) but little change in minute ventilation. According to the Campbell diagram, WOBel increases exponentially with increases in VT. Thus, as RL was not correlated with FEV1, but CL dyn decreased directly as FEV1 decreased, we presume that with a reduction in FEV1, the patients adopted a breathing strategy to reduce the WOBel and partitioned minute ventilation into a greater number of respiratory cycles to reduce the VT but maintain ventilation. In effect, the patients increased the RR/VT ratio to reduce the increase in WOBel while preserving the same mean inspiratory flow rate.

This hypothesis is also supported by the PTPes data, which also take into account the duration of the respiratory effort. The change in breathing pattern caused by the high respiratory load imposed on the inspiratory muscles results in an adaptation to minimize this increase in load. This is achieved by decreasing VT and thus reducing the pressure required for breathing relative to the inspiratory muscle strength (37, 38). In effect, this is an adaptive breathing strategy to reduce the increase in the load/capacity ratio (29) while still trying to maintain ventilation. Although we observed no difference in inspiratory muscle capacity, as assessed by sniff Pes, as FEV1 decreased, there was a significantly higher load imposed on the inspiratory muscles, as shown by the PTPes. Despite patients with a low FEV1 decreasing VT in an attempt to reduce the increase in pressure load, the overall effect is an increase in PTPes. However, there was decrease in inspiratory time (r = 0.44, p = 0.002) accompanied by an increase in RR as FEV1 decreased, and therefore, the Ti/Ttot did not change as FEV1 fell (p = 0.4). Consequently, the rise in PTPes was mainly dependent on an increase in the mean Pes decline during inspiration (correlation with FEV1: r = −0.57, p = 0.001). Therefore, as pulmonary disease progresses in children and young adults with CF, a rapid shallow breathing strategy is adopted to minimize the mean decrease in Pes while attempting to maintain ventilation.

Gas exchange. We observed a positive correlation between FEV1 and PaO2 (r = 0.76, p < 0.0001) and a negative correlation between FEV1 and cPaCO2 (r = −0.70, p < 0.0001); that is, increasing airways obstruction resulted in a fall in PaO2 and a rise in cPaCO2. A mechanism to explain this alteration in gas exchange with increasing disease severity could be dependent on the respiratory muscle load. Jubran and Tobin have previously reported in adults with chronic obstructive pulmonary disease that PaCO2 increases as the inspiratory effort of the patient increases (30). Furthermore, these investigators suggested that PaCO2 is inversely related to PTPes such that the product of PaCO2 · PTPes reflects the efficiency of the respiratory pump to clear carbon dioxide. In this study, we observed that a decrease in FEV1 was associated with an increase in cPaCO2 · PTPes. Thus, the inefficient clearing of CO2 appears to be the consequence of the increased respiratory muscle load. Furthermore, Jubran and Tobin suggested that a rapid shallow breathing pattern combined with the respiratory load also contributes to the inefficient clearing of carbon dioxide (PTPes · cPaCO2 · RR/VT), as a decrease in VT inevitably causes an increase in dead space ventilation that results in alveolar hypoventilation and hypercapnia (30). Accordingly, we observed that PTPes · cPaCO2 · RR/VT was indirectly correlated with FEV1. Furthermore, previous studies have demonstrated that dead space increases in patients with CF and that this increase is related to the severity of the disease (39, 40). Thus, the indirect correlations between cPaCO2 and efficient clearing of carbon dioxide and FEV1 and the inverse relationship of cPaCO2 with VD/VT, where VD equals dead space, can explain the rise in PaCO2 as the pulmonary function declines in children and young adults with CF.

In conclusion, we have observed in children and young adults with advanced stable pulmonary CF disease that as FEV1 falls there is an increase in the respiratory muscle load, WOBel, and WOBtot; the increase in load is predominated by a decrease in CL dyn rather than an increase in RL or PEEPi. As a result, these patients develop a compensatory mechanism of a rapid shallow breathing pattern in an attempt to reduce the increase in load. Although this breathing strategy maintains the level of ventilation, the cPaCO2 rises, and thus, the efficiency of the respiratory muscle pump to clear carbon dioxide decreases. These clinical data, combined with the previous short-term physiologic studies that have demonstrated an increase in VT with a reduction in RR, a reduction in respiratory muscle load and WOB, and an improvement in alveolar ventilation using noninvasive ventilation in patients with CF (26, 41), provide further evidence for long-term trials to be undertaken to investigate the effects of noninvasive ventilation in children and young adults with CF.

Supported by a European Respiratory Society Long Term Fellowship, the Scadding-Morriston Davies Joint Respiratory Medicine Fellowship, and a grant from the Association Française Contre Les Myopathies (N. H.); Vaincre La Mucoviscidose and the Societé de Pneumologie de Langue Francaise (B. F.); the Cystic Fibrosis Trust (UK) and the Peel Medical Research Trust (M. P.).

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Correspondence and requests for reprints should be addressed to Dr. Brigitte Fauroux, Pediatric Pulmonary Department, Armand Trousseau Hospital, 28 Avenue du Docteur Arnold Netter, 75012 Paris, France. E-mail:


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