INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Dynamic hyperinflation is a frequently encountered respiratory mechanical abnormality in patients with chronic obstructive pulmonary disease (COPD) (1). Two pathophysiologic consequences arise from this abnormality: dynamic increase in end-expiratory lung volume (EELV), which puts inspiratory muscles at mechanical disadvantage, and a resultant intrinsic positive end-expiratory pressure (PEEPi), which behaves as an inspiratory threshold load (ITL) (4). Both presumably contribute to breathlessness (7).

Although dynamic hyperinflation has been thought to be an important contributor to resting (7) and exertional dyspnea (8, 9), partitioning of the effects of increasing operating lung volume and PEEPi on breathing sensation is difficult in patients. Recently, we loaded healthy subjects by external ITL, positive end-expiratory pressure (PEEP), and continuous positive airway pressure (CPAP) in order to simulate the effects of a dynamic increase in operating lung volume and PEEPi-imposed ITL on breathing (10). We demonstrated that the imposed ITL is a stronger predictor of the perceived inspiratory difficulty than acute increase in operating lung volume (10).

In addition to dynamic hyperinflation, patients with COPD usually have a reduced capacity to generate maximal inspiratory pressure, known as inspiratory muscle weakness caused by chronic hyperinflation (11, 12). Acute reduction in inspiratory muscle strength known as fatigue may also be present in these patients, especially when critically ill (13). In the present study, we partitioned, in healthy humans, the effects of increasing the imposed ITL and operating lung volume on perception of inspiratory difficulty as we performed recently (10). The aim of the present study was to evaluate how the change in inspiratory muscle strength affects the partitioning of the perceived inspiratory difficulty in response to increased ITL and lung volume.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Subjects

Seven healthy male subjects, having given their informed consent, volunteered for the experiment. None of the subjects knew the scientific purpose of the study. The protocol was approved by the Ethics Committee of the Montreal Chest Institute.

Study Design

The study design has been described in detail in our previous report (10). In Figure 1 the Campbell diagram is shown (solid line), which is composed of the static pressure-volume curve of the chest wall (PVst(w)) and the mirror image of the pressure-volume curve of the lung (-PVst(l)) (14). The two relationships intersect at point D, which represents volume-pleural pressure (Ppl) relationship at relaxation volume. If an appropriate level of positive end-expiratory pressure (PEEP) is applied to the airway opening of normal subjects, EELV will increase to the level of AB, and a PEEPi given by the pressure difference between points A and B, which represents the elastic recoil pressure of the respiratory system at that volume, will be established. This PEEPi has to be overcome before inspiratory flow can be started. The pathophysiologic consequence of such a change is as if the subjects had dynamic hyperinflation. Application of an appropriate level of continuous positive airway pressure (CPAP) also elevates EELV to the level of AB. However, no PEEPi is produced because CPAP moves the relationship between lung volume and Ppl during inspiration to the right along the pressure axis. Application of an external ITL as given by CD (CD = AB) requires the inspiratory pressure equal to CD (therefore equal to AB) to be generated before inspiratory flow gets started, as external ITL moves the lung volume-Ppl relationship during inspiration to the left along the pressure axis. The external ITL thus mimics the effect of PEEPi except that EELV does not increase. In this way, the isolated effect of increasing EELV alone (during CPAP) and ITL alone (external ITL) on inspiration can be assessed independently, and compared with the effect of PEEP with which both increasing EELV and PEEPi are present as during dynamic hyperinflation.

View larger version (18K): [in this window] [in a new window]   Figure 1.   Schematic presentation of the Campbell diagram and the changes in position of the inspiratory lung volume-pleural pressure relationship (lung curve) during application of external inspiratory threshold load (ITL), continuous positive airway pressure (CPAP), and positive end-expiratory pressure (PEEP) in healthy subjects. See text for detailed explanation.

Experiments

Measurements. Respiratory flow was measured by a Fleisch No. 2 pneumotachograph (Fleisch, Lausanne, Switzerland) and a differential pressure transducer (Validyne Corp., Northridge, CA). Esophageal pressure (Pes) was measured by a conventional balloon-catheter placed in the lower esophagus. The balloon-catheter was connected to a differential pressure transducer (Validyne). Mouth pressure (Pmo) was measured by an additional differential pressure transducer (Validyne), which was connected through a tube to the mouthpiece.

The perceived sensation of inspiratory difficulty (9) during the loading experiments was quantified by the modified Borg scale (15), which was shown to the subjects. The subjects were required to choose a number between 0 and 10 that represented the level of the perceived inspiratory difficulty, with 0 indicating no difficulty and 10 the maximal difficulty. Two reasons prompted us to choose "inspiratory difficulty" as the descriptor for breathing sensation in the present study. First, inspiratory difficulty has been chosen by patients with COPD as the unique descriptor for exertional breathlessness, reflecting its close relationship with dynamic hyperinflation (9). Second, an inspiratory sensation index was selected in order to minimize the possible contribution from expiratory muscle recruitment to the overall breathing sensation (16). All subjects said that they were able to distinguish between inspiratory and expiratory sensations, and the inspiratory difficulty was an appropriate descriptor of breathing sensation during loading in the current study.

Application of external ITL, CPAP, and PEEP. External ITL was applied by a custom-built constant negative pressure system that was connected to the inspiratory port of a two-way Hans-Rudolph nonrebreathing valve (type 2700; Hans-Rudolph Inc., St. Louis, MO). The adjustable negative pressure from the system was directly applied to the inspiratory port and served to close the inspiratory valve. An equal inspiratory pressure in the mouth side of the valve must be developed by the inspiratory muscles to open the valve before inspiratory flow can be initiated. The system provides a pure threshold load without inducing additional flow resistance, and it has been described in detail elsewhere (17). PEEP and CPAP were provided by a BiPAP Ventilatory Support System (BiPAP S; Respironics Inc., Murrysville, PA) attached to the breathing circuit.

Induction of inspiratory muscle fatigue. To induce fatigue, the subjects underwent an inspiratory resistive loaded breathing protocol (18, 19). They inspired from a resistor while developing, with each inspiratory effort, a target Pmo that was 75 to 80% of the predetermined maximal inspiratory pressure (PImax). The subjects had to maintain the target Pmo as a square wave, as illustrated by a storage oscilloscope, and to keep the inspiratory time as 50% of the total respiratory cycle time. Expiration was not loaded. This procedure continued until the subjects could not meet the required target by any means for five consecutive breathing efforts. The endurance time of our subjects was between 11 and 19 min.

Protocol. Each subject, with his back and head firmly supported while seated, breathed through a mouthpiece and wore a noseclip. The experiments were composed of applications of external ITL at approximately 2.5, 5, and 10 cm H₂O, and PEEP and CPAP at 2.5, 7.5, and 12.5 cm H₂O. Thus, the experiment before fatigue consisted of nine loading runs. The sequence of these nine loading runs was completely randomized for each subject, and the subjects did not know the type and the level of the run when they were loaded. There was a short period of unloaded breathing before each run, and each loading run lasted for 2 min. Between each run, the subjects were allowed to leave the mouthpiece and have 1 min of rest. Before and at the end of each loading run, inspiratory capacity (IC) maneuver was performed to measure changes in EELV. Immediately after each loading run, the subjects chose a number on the modified Borg scale to represent the magnitude of the perceived inspiratory difficulty. This experimental procedure was repeated after induction of inspiratory muscle fatigue. However, the sequence of the runs was again randomized in each subject, so that for each subject, the sequence of the loading runs after fatigue was different from that before fatigue. PImax was measured before, immediately after the fatigue run, and after all the loading experiments.

Data Analysis

Respiratory flow and pressure signals were preamplified, passed through a 12 bit analog-to-digital converter, and recorded on a desktop computer at 200 Hz. Lung volume change was calculated by integration of flow. Changes in EELV were calculated as the mirror image of changes in IC. Changes in end-inspiratory lung volume (EILV) were calculated as tidal volume plus EELV.

The imposed ITL caused by PEEPi during PEEP was not often equal to the level of PEEP applied. This was due to the unavoidable expiratory muscle recruitment during PEEP application. Therefore, the imposed ITL during PEEP was measured as the Pes value at the beginning of inspiratory flow relative to that on the predicted PVst(w) for a given EELV (10, 20). The slope of the predicted PVst(w) was obtained from the literature (21).

As shown in Figure 1, external ITL imposes the subjects to an ITL without changing EELV, CPAP increases EELV without imposing an ITL, and PEEP both increases EELV and imposes an ITL. Taken together, the design provided a balanced model by which partitioning of the effects of increasing operating lung volume and the imposed ITL on inspiratory difficulty can be performed (10). The results were further compared before and after the inspiratory muscle fatigue protocol.

The individual results or group mean ± 1 SD were presented. The difference of the PImax among before, after fatigue, and after whole experiments were tested by repeated ANOVA analysis. The difference of the perceived inspiratory difficulty between before and after the fatigue run was examined by general linear model analysis of variance. Simple linear regression and multiple linear step forward regression were employed to analyze the contribution of the three independent variables, the imposed ITL, EELV, and EILV, to the perceived inspiratory difficulty. A t test was used to examine the difference of the slopes and intercepts for each relationship before and after the fatigue run. A p value less than 0.05 was taken as statistical significance. All statistical analysis was performed using SYSTAT 7.0.1 software (SPSS Inc., Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

As shown in Table 1, PImax decreased from 120 ± 8 to 93 ± 9 cm H₂O immediately after fatigue. At the end of the whole experiments, PImax was 106 ± 11 cm H₂O. This remained significantly lower than before fatigue but already significantly higher than immediately after fatigue, suggesting the continuing presence of fatigue despite considerable recovery. EELV did not change significantly during external ITL. With the external ITL at 10 cm H₂O, EELV was 0.01 ± 0.03 and 0.03 ± 0.03 L for before and after the fatigue protocol, respectively.

As shown in Figure 2, there was no significant change in the Pes value at the peak lung volume (zero flow) during IC maneuvers either at different loads or after decrease in inspiratory muscle strength. Taking the Pes values from all IC efforts into account, the within-subject coefficient variation was between 4.2 to 10.7% (mean, 8.3%).

View larger version (12K): [in this window] [in a new window]   Figure 2.   The values of esophageal pressure (Pes) at the peak volume (zero flow) during the inspiratory capacity maneuvers. ITL = inspiratory threshold load; PEEP = positive end-expiratory pressure; CPAP = continuous positive airway pressure; UB = unloaded breathing; open circles = before the fatigue run; closed circles = after the fatigue run.

The mean perceived inspiratory difficulty during loading is shown in Figure 3. Inspiratory difficulty scores were compared between external ITL and PEEP for a given imposed ITL, and between CPAP and PEEP for a given increase in EELV. The results show that fatigue significantly increased inspiratory difficulty during PEEP (p < 0.001) and CPAP (p < 0.001) as EELV increased. In contrast, fatigue did not significantly increase inspiratory difficulty when loaded by the external ITL without changing EELV.

View larger version (14K): [in this window] [in a new window]   Figure 3.   The perceived inspiratory difficulty plotted as a function of the imposed inspiratory threshold load (ITL) (left panel ) during external ITL (circles) and PEEP (triangles) applications, and as a function of the increase in end-expiratory lung volume (EELV) (right panel ) during continuous positive airway pressure (CPAP) (circles) and PEEP (triangles) applications. Closed and open symbols show the results of before and after the fatigue protocol, respectively.

In Figure 4, inspiratory difficulty scores from all subjects under all loading runs were plotted against the normalized ITL, EELV, and EILV. The r², intercept, and slope of the simple regressions through each set of data are shown in Table 2. All relationships were significant (p < 0.05). The intercept of the relationship between inspiratory difficulty and the imposed ITL was slightly but significantly greater after than before fatigue. After fatigue, the slope of inspiratory difficulty to EELV and EILV became greater, whereas that to the imposed ITL did not. The data were further analyzed by performing the step forward regression of the perceived inspiratory difficulty using the imposed ITL, EELV, and EILV as independent variables. The results are summarized in Table 3. Before the fatigue run, the first entered variable was the imposed ITL, which explained 38% of the variability of inspiratory difficulty. Adding EILV into the model explained 67% of the variability of inspiratory difficulty. After the fatigue run, the first entered variable became EILV (r², 0.50) and the second variable was the imposed ITL, which increased r² to 0.66. EELV was insignificant under both conditions. The coefficient of EILV increased significantly after fatigue (p < 0.001), whereas the coefficient of the imposed ITL did not change.

View larger version (13K): [in this window] [in a new window]   Figure 4.   The perceived inspiratory difficulty plotted against the imposed inspiratory threshold load (ITL), the change in end-expiratory lung volume (EELV), and end-inspiratory lung volume (EILV). The imposed ITL is expressed as a percentage of the maximal inspiratory pressure (% PImax). EELV and EILV are expressed as a percentage of inspiratory capacity (% IC). Results from each subject under all loading conditions are shown. Each point represents the result from one subject at a given level for a particular type of load. Closed and open symbols show the results of before and after the fatigue protocol, respectively. Simple linear regression is performed through each set of data.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

We have recently partitioned, in healthy subjects, the effects of dynamically increasing operating lung volume and the imposed ITL on perception of inspiratory difficulty (10), and demonstrated that the imposed ITL was a better predictor than lung volume for the variability of inspiratory difficulty. The present results provide further support to this finding. However, the current study also suggests that the relative importance of lung volume in determining the variability of inspiratory difficulty increased after inspiratory muscle fatigue. Indeed, as shown in Table 3, after the fatigue protocol, EILV became the first entered independent variable in the multiple step forward regression analysis, whereas under fresh conditions, the imposed ITL was always the first entered independent variable, as shown by our previous (10) and present results. Furthermore, the sensitivity of inspiratory difficulty in response to changes in operating lung volume, as reflected by the slopes in Table 2 and the coefficients in Table 3, increased significantly after fatigue. In contrast, the responses of inspiratory difficulty to the imposed ITL were similar before and after the induction of fatigue.

Although results from previous studies (22) imply that the PEEPi-imposed ITL and increasing operating lung volume itself may contribute to breathing effort sensation independently, partitioning of the effects of these two factors on breathing sensation is difficult in patients because these two factors always occur simultaneously with one being dependent on the other. The experimental design employed by our recent (10) and current studies provides a well-balanced model, by which step regression can be performed to quantitatively partition the effect of the imposed ITL and volume on inspiratory difficulty. Despite the similarity of the current protocol to the one we performed previously (10), a few technical points of the present study need to be addressed.

The PEEPi-imposed ITL was measured as the Pes value at the beginning of inspiratory flow relative to PVst(w) (20), which was obtained from the literature (21). The possible random errors originated from the variations in the true slope of the individual PVst(w) were presumably canceled by comparison of the results before and after fatigue, provided that the current fatigue protocol did not alter the elastic properties of the respiratory system. This assumption is probably true as previous studies (25, 26) have demonstrated that PVst(w) remained unchanged after a fatigue protocol similar to what was performed in the current study.

The changes in EELV during PEEP and CPAP were measured by the mirror image of changes in IC. This measurement has proved reliable in both healthy subjects (27) and patients with COPD (8, 28, 29). In the present study, however, fatigue would have reduced the ability of the subjects to reach the true TLC, leading to overestimation of EELV during CPAP and PEEP. The results of our previous and current studies do not support this possibility. Firstly, earlier studies have demonstrated that TLC did not change after fatigue (25, 26). Secondly, if our subjects had failed to reach their true TLC after fatigue, EELV during PEEP and CPAP would have been overestimated, leading to even greater underestimation of the volume effect on inspiratory difficulty after fatigue. In fact, EELV of our subjects for a given PEEP and CPAP was smaller instead of being greater after than before the fatigue protocol (Figure 3). This presumably reflects greater recruitment of expiratory muscles after fatigue (16, 17). Thirdly, the Pes values at peak volume (zero flow) during IC efforts were not significantly different before and after fatigue (Figure 2). We are therefore confident that the measurement of the change in EELV in the present study is reliable.

Generally speaking, sense of breathing effort increases with respiratory muscle fatigue (30, 31). This has been attributed to the necessity to increase central motor output to the fatigued inspiratory muscles in order to maintain a given mechanical output from these muscles. Accordingly, after inspiratory muscle fatigue, a greater reduction in contractile property that demands greater increase in central motor output will translate into greater increase in breathing effort sensation. For inspiratory muscles, loss of the ability to generate force after fatigue actually depends on the lung volume at which the contraction is made. Previous studies have demonstrated that at least for the diaphragm, the decrease in force in response to a constant activation is proportionately greater at higher lung volumes (25, 26, 32) or at shorter length after fatigue (33). Under such a condition, if ventilation is to be maintained after fatigue, the fractional increase in central activation to the inspiratory muscles would have to be greater when the inspiration is taken at a higher than at a lower lung volume. This would inevitably result in a tightened relationship and increased sensitivity between inspiratory difficulty and lung volume after fatigue.

What makes inspiratory threshold load different from other types of breathing loads is that during the initial part of inspiratory effort, inspiratory muscle contraction does not produce any flow and volume change. The mechanism for the imposed ITL to produce sensation of inspiratory difficulty may be largely explained by "afferent mismatch" (34, 35). In this theory, the brain "expects" a certain level of feedback from the periphery for a given effort, and unpleasant sensation of breathing occurs if the feedback signal does not match the expected. The afferent signal may be an appropriate change in volume, flow, or simply muscle length as a result of the inspiratory effort. Inspiratory threshold load is an extreme example of afferent mismatch because initial inspiratory muscle contraction produces no flow and no change in volume and muscle length, and the impedance of the system can be considered as infinite. O'Donnell and coworkers (22, 36) used the term "neuromechanical uncoupling" of the ventilatory pump to describe the afferent mismatch caused by inspiratory threshold load (PEEPi) during dynamic hyperinflation in patients with COPD. These investigators (9, 22, 36) further proposed that, presumably, sensory feedback from a variety of peripheral mechanoreceptors that provide precise instantaneous proprioceptive information about muscle displacement, tension development, and change in inspired volume and flow plays an important role for afferent mismatch or neuromechanical uncoupling of the ventilatory pump during inspiratory threshold loading. For a given imposed ITL, the afferent signal from the periphery, at least for the initial part of inspiratory effort, is "fixed" (no change in flow and volume) no matter whether the inspiratory muscles are fresh or fatigued. Therefore, decreased capacity for the inspiratory muscles to generate pressure by fatigue can reset the relationship between inspiratory difficulty and the imposed ITL, as reflected by an increase in intercept (Table 2), but the slope of the relationship (sensitivity) is unlikely affected by fatigue.

In summary, decrease in inspiratory muscle strength increased the importance of operating lung volume in determining the perceived inspiratory sensation. This is evidenced by the tightening of the relationship between inspiratory difficulty and EILV (Table 3), as well as the increased response of inspiratory difficulty to EILV and EELV (Tables 2 and 3) after fatigue.