Journal of Applied Physiology
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J Appl Physiol 85: 1103-1112, 1998;
8750-7587/98 $5.00
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Vol. 85, Issue 3, 1103-1112, September 1998

Does resistive loading decrease diaphragmatic contractility before task failure?

Franco Laghi, Arzu Topeli, and Martin J. Tobin

Division of Pulmonary and Critical Care Medicine, Edward Hines, Jr., Veterans Administration Hospital, and Loyola University of Chicago Stritch School of Medicine, Hines, Illinois 60141

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

While sustaining a load that leads to task failure, it is unclear whether diaphragmatic fatigue develops progressively or occurs only at task failure. We hypothesized that incremental loading produces a progressive decrease in diaphragmatic contractility ever before task failure. Ten subjects generated 60% of maximal transdiaphragmatic pressure (Pdimax) for 2 min, 4 min, and until task failure. Before loading, 20 min after each period of loading, and ~20 h after the last period of loading, Pdimax, nonpotentiated and potentiated Pdi twitch pressure (Pditw), and the pattern of respiratory muscle recruitment during a CO2 challenge were recorded. Sensation of inspiratory effort at the 4th min of the task-failure protocol was greater than at the same time in the preceding 4-min protocol. Surprisingly, potentiated Pditw and Pdimax were reduced after 2 min of loading and decreased further after 4 min of loading and after task failure; nonpotentiated Pditw was reduced after 4 min of loading and after task failure. The gastric pressure contribution to tidal breathing during a CO2 challenge decreased progressively in relation to duration of the preceding loading period, whereas expiratory muscle recruitment progressively increased. A rest period of ~20 h after task failure was not sufficient to normalize these alterations in respiratory muscle recruitment or fatigue-induced changes in diaphragmatic contractility. In conclusion, while sustaining a mechanical load, the diaphragm progressively fatigued, ever before task failure, and when challenged the rib cage-to-diaphragmatic contribution to tidal breathing and recruitment of the expiratory muscles increased pari passu with duration of the preceding loading.

transdiaphragmatic twitch pressure; twitch potentiation; carbon dioxide rebreathing

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

WHEN THE INSPIRATORY muscles contract against a high load, they are able to maintain the target level of contraction for a limited period of time, i.e., until "task failure," after which the load cannot be sustained any longer. Task failure is believed to be due to various degrees of central inhibition (termed central fatigue) (1), contractile fatigue (1), and occasionally lack of motivation. The contractile fatigue that occurs with a high load is believed to be due to mechanical damage to the muscle (26, 36). The threshold of loading necessary to produce such damage has not been defined precisely. It seems reasonable to expect that the length of time that a load is sustained, i.e., endurance time, may also be an important factor in the development of muscle injury and the functional consequences.

The precise contribution of progressively developing contractile fatigue to task failure is unclear. In seven subjects performing isocapnic hyperpnea, Babcock et al. (3) reported significant diaphragmatic fatigue [~26% decrease in transdiaphragmatic twitch pressure (Pditw)] without evidence of task failure. Their study does not elucidate completely the relationship between the progressive development of contractile fatigue and the occurrence of task failure, however, because inspiratory loading was not maintained to the point of task failure and the study was not designed to investigate the progression of diaphragmatic fatigue during loading.

Bellemare and Bigland-Ritchie (5) reported that inspiratory resistive loading produced a decrease in Pditw during the first 40% of endurance time, but thereafter Pditw showed no further decrease. This result is surprising and raises the possibility that contractile fatigue is not a progressive process, despite continued diaphragmatic loading. This interpretation is not tenable because of two limitations in the study design. 1) Forceful diaphragmatic contractions during inspiratory resistive loading induce fatigue and twitch potentiation (14). Because of these opposing effects, it is difficult to know whether the failure of Pditw to decrease progressively during loading indicated that contractile fatigue is truly a nonprogressive process or is due to the offsetting effect of twitch potentiation (8). 2) Inspiratory loading results in a decrease in lung volume (9), and the associated increase in diaphragmatic length will cause Pditw to increase (15), further confounding data interpretation. Recently, Eastwood et al. (9) evaluated the influence of progressive threshold loading on diaphragmatic contractility, assessed by Pditw corrected for load-induced changes in end-expiratory lung volume (EELV). Unlike Bellemare and Bigland-Ritchie (5), they noted that Pditw increased progressively until just before task failure, at which point Pditw decreased. That is, impaired contractility and task failure appeared to occur almost simultaneously (9). However, as in the case of the investigation of Bellemare and Bigland-Ritchie (5), the influence of twitch potentiation on Pditw was not assessed.

Another unanswered question is whether the pattern of respiratory muscle recruitment in the presence of increased ventilatory demands is affected by the progression (or lack of progression) of contractile fatigue to task failure. After the induction of diaphragmatic fatigue, Yan et al. (35) noted that the respiratory system responded to increased ventilatory demands (CO2 rebreathing) by recruiting rib cage muscles. This interpretation is confounded by the fact that the response to CO2 was tested shortly after the completion of the inspiratory resistive loading run (i.e., <= 5 min); at this time, high-frequency fatigue, which could modulate the recruitment of respiratory muscles during increased ventilatory demands, is expected to be present (2). In other words, by performing CO2 rebreathing shortly after task failure, it is not possible to discriminate between the effects of high- and low-frequency fatigue or their combination on the diaphragm. As the same investigators pointed out (34), high-frequency fatigue may have more limited physiological and clinical relevance than low-frequency fatigue. Second, their study was not designed to elucidate the adaptive response of the respiratory muscles to increased ventilatory demands during progressive inspiratory resistive loading.

The purpose of our study was threefold: 1) to determine whether inspiratory resistive loading sustained for periods of increasing duration produces a parallel decrease in diaphragmatic contractility, ever before task failure, 2) to determine whether the pattern of respiratory muscle recruitment during CO2 rebreathing is altered as the period of inspiratory resistive loading is progressively increased, and 3) to determine whether a 20-h period of recovery after task failure could normalize fatigue-induced changes in the pattern of respiratory muscle recruitment during increased ventilatory demands.

    METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Subjects. Ten nonsmoking healthy men (26-36 yr of age, mean 30 yr) volunteered for the study, which was approved by the Human Studies Subcommittee of Edwards Hines, Jr., Veterans Administration Hospital. Informed consent was obtained from all subjects.

Flow, volume, and pressure measurements. Inspiratory flow (V) was measured with a heated Fleisch pneumotachograph (Hans Rudolph, Kansas City, MO) connected to a differential pressure transducer (model MP-45, Validyne, Northridge, CA). Volumes were obtained by electronic integration of the V signal. Inspiratory and expiratory timing were based on the V signal. Esophageal (Pes) and gastric (Pga) pressures were separately measured with two thin-walled, latex balloon-tipped catheters (Erich Jaeger, Wurzberg, Germany) coupled to pressure transducers (model MP-45, Validyne). An esophageal balloon containing 1 ml of air was positioned in the midesophagus using the occlusion technique (4); a gastric balloon containing 2 ml of air was advanced 70 cm from the nares. Transdiaphragmatic pressure (Pdi) was obtained by electronic subtraction of Pes from Pga. Airway pressure was measured at the mouthpiece using a tap connected to a third transducer (model MP-45, Validyne). Maximal Pdi (Pdimax) was recorded while the subjects performed a maximal Müller expulsive effort of >= 1-s duration against an occluded airway at EELV (16). Oscilloscope recordings of Pdi provided visual feedback.

Electromyography. Compound diaphragmatic motor action potentials (CDAPs) were recorded bilaterally with surface electromyogram (EMG) electrodes placed at the seventh and eighth intercostal spaces in the anterior axillary line. The subject's skin was marked with indelible ink to ensure that the electrodes were placed at the same location during the ~20-h follow-up study performed in 6 of the 10 subjects. All EMG signals were amplified, band-pass filtered (bandwidth 10 Hz-1 kHz; Gould, Valley View, OH), and displayed on a storage oscilloscope (Gould, Ilford, UK).

CO2 rebreathing. To determine whether the pattern of respiratory muscle recruitment was altered when ventilatory demands were increased, the subjects rebreathed CO2 according to the method of Read (25). Subjects breathed through a mouthpiece connected to a 7-liter bag filled with a balance of 7% CO2 and O2. The rebreathing bag remained flaccid so that the pressure within it was atmospheric. End-tidal PCO2 (PETCO2) was measured at the mouthpiece (CO2SMO, Novametrix, Wallingford, CT). The procedure was terminated when PETCO2 reached ~70 Torr, which generally took 3-4 min. During the whole protocol, O2 saturation was measured with a pulse oximeter (CO2SMO, Novametrix). During CO2 rebreathing, as during the rest of the experiment, all subjects sat upright in an armchair with a high back. An investigator always remained in front of the subject to ensure that the subject sat straight, with his back against the back of the chair, while resting the arms on his lap.

Phrenic nerve stimulation. Magnetic stimulation of both phrenic nerves was performed using a magnetic stimulator (model 200, Magstim) with a 90-mm coil (P/N 9784-00). This device stimulates neuromuscular structures by inducing electrical currents in the tissue secondary to a time-varying magnetic field of brief duration (<1-ms total pulse duration) (29). At maximal output of the stimulator, the magnetic field is 2.0 T. To achieve stimulation of the phrenic nerves, the subject's neck was flexed and the coil was placed over the cervical spine. While the subject relaxed at EELV, the site of optimal stimulation was determined by moving the coil between C5 and C7 (29). Stimulus maximality was then assessed by progressively increasing the intensity of the stimulus until Pditw and CDAPs displayed no further increases (29). This position was marked with indelible ink, and all subsequent stimulations were performed at this point. Subjects were studied without abdominal binding (14), waist belts were removed, trousers were unbuttoned, and alterations in abdominal compliance during stimulations were minimized by instructing the subjects to relax their diaphragm and abdominal wall muscles during each stimulation. Relaxation was confirmed by the absence of diaphragmatic EMG activity. Respiratory inductive plethysmography (Non-Invasive Monitoring Systems, Miami Beach, FL) was used to identify EELV.

Air hunger and effort scores. The intensity of dyspnea, defined as "the unpleasant sensation of labored or difficult breathing" (24), was evaluated using a modified Borg scale every minute during inspiratory resistive loading until task failure. Subjects were asked to score their sensation of air hunger and effort, respectively, by answering the following questions (30): 1) How much air hunger do you feel? 2) How much effort does your breathing require?

Inspiratory resistive load. Subjects were instructed to sustain an inspiratory resistive load that consisted of breathing through a mouthpiece attached to a one-way valve (Hans Rudolf), the inspiratory side of which was connected to a variable alinear resistor. The subject was instructed to breathe through the load while maintaining a Pdi of 60% of Pdimax. Resistance was achieved by a screw clamp on a compressible tube, adjusted to help the subject reach the predetermined fraction of Pdimax; the expiratory side, where PETCO2 was monitored, was not loaded. The subject was instructed to maintain a constant Pdi throughout inspiration, as reflected by a square-wave pattern on the oscilloscope. The duty cycle was 0.50, and the frequency (f) was 15 breaths/min. Each subject was allowed to choose his own tidal volume (VT), and the relative contributions of Pga and Pes to Pdi were not controlled (14, 35). Subjects were encouraged to maintain the target Pdi in the desired fashion and to continue with the protocol.

Experimental protocol. After placement of all transducers, Pdimax (best of >= 5 efforts) was determined. The phrenic nerves were stimulated twice at relaxed EELV immediately after each Pdimax maneuver, and thus the recorded twitches represent potentiated Pditw (14, 19, 33) (Fig. 1). To obtain nonpotentiated values of Pditw, the subjects breathed quietly for 20 min, and then 10 twitches were recorded at EELV (14, 19, 33). At 3-5 min after the last nonpotentiated Pditw, the ventilatory demands were increased by CO2 rebreathing.


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  		Fig. 1.   Schematic representation of experimental protocol. Respiratory muscle testing before loading (extreme left) and ~20 h after last period of loading (extreme right) consisted of maximal transdiaphragmatic pressure (Pdimax) followed by potentiated transdiaphragmatic twitch pressure (Pditw) and, after a 20-min rest, by nonpotentiated Pditw and CO2 rebreathing. Respiratory (Resp) muscle testing performed 20 min after each period of loading also included recordings of Pdimax and potentiated Pditw.

At 10 min after the conclusion of the CO2 challenge, subjects were instructed to sustain an inspiratory resistive load (see above) for 2 min. The sensations of air hunger and inspiratory effort were quantified immediately before the load, at 1 min of loading, and just before the conclusion of loading (30) (Fig. 1). Within 1 min after discontinuation of the load, subjects performed three Pdimax maneuvers, each followed by a recording of two potentiated Pditw values. These data sought to determine whether this period of loading was sufficient to alter diaphragmatic contractility. To avoid the confounding influence of twitch potentiation (14, 33), subjects breathed at rest for 20 min after removal of the load, and then 10 nonpotentiated Pditw values were recorded. The rest period of 20 min was also used to allow resolution of high-frequency fatigue (2) and thus permit the effect (if any) of low-frequency fatigue on Pdimax and potentiated Pditw to be determined. After the 10 nonpotentiated Pditw values had been recorded, three Pdimax maneuvers were performed, each followed by two potentiated Pditw maneuvers (Fig. 1). At 3-5 min after the last potentiated Pditw was recorded, the pattern of respiratory muscle recruitment during the increased ventilatory demands of CO2 rebreathing was determined.

To determine the effect of loading for a longer period of time, the subjects sustained for 4 min the same inspiratory resistive load they had sustained for 2 min. Air hunger score, effort score, Pdimax, potentiated and nonpotentiated Pditw, and CO2 rebreathing were recorded again at the time intervals described for the first period of loading (Fig. 1).

At 8-10 min after the third episode of CO2 rebreathing, the subjects again breathed through the inspiratory resistive load. On this occasion, loading was continued to the point of task failure, defined as the inability to achieve the target pressure for three consecutive breaths despite exhortation. Pdimax, potentiated and nonpotentiated Pditw, and CO2 rebreathing were again recorded at the time intervals described for the first two periods of loading (Fig. 1).

About 20 h after the task-failure protocol, 6 of the 10 subjects returned to the laboratory. After placement of all transducers (same as the previous day), five Pdimax maneuvers were recorded. Each Pdimax maneuver was followed by two measurements of potentiated Pditw. After 20 min of resting breathing, 10 nonpotentiated Pditw values were recorded. At 3-5 min after the last nonpotentiated Pditw was recorded, CO2 rebreathing was performed (Fig. 1).

Data analysis. All signals were recorded and digitized at 2,000 Hz using a 12-bit analog-to-digital converter (CODAS, DATAQ Instruments, Akron, OH) connected to a computer (EMPAC, Fremont, CA). Individual twitch responses were rejected from analysis according to previously described criteria (14).

During CO2 rebreathing, Pes, Pga, and Pdi were measured as a pressure difference between the end of expiration and the end of inspiration (Delta Pes, Delta Pga, and Delta Pdi, respectively) and as the absolute value at the end of expiration and at the end of inspiration (18). The contribution of the inspiratory rib cage muscles was inferred from tidal Delta Pes relative to Delta Pga as a function of PETCO2. Expiratory muscle recruitment was assessed by measuring the decrease in transpulmonary pressure (PL) and the increase in Pga at end expiration (18).

Changes in Pdimax, potentiated Pditw, and nonpotentiated Pditw over time were compared using ANOVA with repeated measures. If ANOVA was significant, a Newman-Keuls multiple range test was employed to determine differences between variables at specific times or after specific challenges.

The effect of inspiratory resistive loading for different durations on respiratory muscle recruitment during CO2 rebreathing was assessed by multivariate ANOVA with repeated measures (SAS System, version 6, SAS Institute, Cary, NC). The design was that of double repeated measures, with CO2 rebreathing session as one repeated measure and PETCO2 as the other repeated measure (28). If multivariate ANOVA revealed that a factor was significant by Wilk's lambda F statistics, post hoc comparison using a single degree of freedom contrast test was employed to determine differences between respiratory muscle recruitment during CO2 rebreathing performed at the various time intervals described in the protocol. Values are means ± SE, and P < 0.05 was considered significant.

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Air hunger and effort scores. Air hunger increased after the onset of each inspiratory resistive loading protocol (Fig. 2). During the first 2 min of loading, the increase in air hunger was the same for the three protocols; during the 2nd-4th min of loading the rise in air hunger was the same during the 4-min protocol and task-failure protocol. At task failure, the air hunger score was 7 ± 1 arbitrary units. The sense of effort also increased after the onset of each protocol. During the task-failure protocol, the sense of effort was greater at the 4th min than at the 4th min of the 4-min protocol (P < 0.05; Fig. 2). In all instances, the sense of effort was maximal at task failure.


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  		Fig. 2.   Scores for air hunger and effort recorded every minute during periods of inspiratory resistive loading (IRL) lasting 2 min, 4 min, and until task failure. A: sense of air hunger increased after onset of each loading protocol; rate of rise did not change as period of loading was progressively increased. B: sense of effort increased after onset of each loading protocol; effort was greater at 4th min of task-failure protocol than at 4th min of 4-min protocol. Values are means ± SE; AU, arbitrary units. * Significantly different from baseline, P < 0.05.

Pdimax. Baseline Pdimax was 194 ± 7 (SE) cmH2O (range 165-230 cmH2O). After 2 min of inspiratory resistive loading, Pdimax decreased to 161 ± 5 cmH2O (P < 0.01; Fig. 3). After 20 min of resting breathing, Pdimax increased to 176 ± 7 cmH2O (P < 0.05), which was still less than baseline (P < 0.01). After the 4-min period of loading, Pdimax decreased to 158 ± 6 cmH2O, which was less than that recorded at baseline (P < 0.01) and just before this second period of loading (P < 0.01). After 20 min of resting breathing, Pdimax increased to 177 ± 6 cmH2O (P < 0.01), which was less than baseline but not different from that recorded just before this second period of loading. At the conclusion of the task-failure protocol, Pdimax decreased to 153 ± 8 cmH2O, which was less than that recorded at baseline (P < 0.01) or just before the task-failure protocol (P < 0.01). After 20 min of resting breathing, Pdimax increased to 171 ± 6 cmH2O (P < 0.01), which was less than baseline but not different from that recorded just before the task-failure protocol. After ~20 h, Pdimax was 172 ± 16 cmH2O (n = 6), which was less than the value at baseline (P < 0.05; Fig. 3).


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  		Fig. 3.   Pdimax recorded before and after inspiratory resistive loading (hatched bars) sustained for 2 min, 4 min, and until task failure. After each period of loading, Pdimax was recorded immediately and after 20 min (n = 10) and at ~20 h after conclusion of task-failure protocol (n = 6). After only 2 min of loading, Pdimax was reduced from baseline. Nadir of Pdimax was reached just after conclusion of loading to task failure. Pdimax values at ~20 h remained lower than baseline. Values are means ± SE. Significantly different from baseline: * P < 0.05; ** P < 0.01.

Nonpotentiated Pditw. Nonpotentiated Pditw at baseline was 35.4 ± 2.4 cmH2O (range 22.1-44.4 cmH2O). Inspiratory resistive loading for 2 min did not produce any significant change in nonpotentiated Pditw (Fig. 4). After the 4-min period of loading, the nonpotentiated Pditw was 32.0 ± 2.2 cmH2O, which was less than that at baseline (P < 0.01). Loading to task failure decreased nonpotentiated Pditw to 30.0 ± 1.7 cmH2O at 20 min, which was less than the values at baseline (P < 0.01) and 20 min after the conclusion of 2 min of loading (P < 0.01; Fig. 4). After ~20 h, nonpotentiated Pditw was 30.1 ± 1.8 cmH2O (n = 6), which was less than the value at baseline (P < 0.01) and unchanged from the Pditw value recorded ~20 h earlier (Fig. 4). The amplitude of the right and left CDAPs was the same throughout this ~20-h period (Fig. 5), indicating a constant level of diaphragmatic recruitment.


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  		Fig. 4.   Pattern of decrease and recovery of potentiated and nonpotentiated Pditw after inspiratory resistive loading (hatched bars) sustained for 2 min, 4 min, and until task failure. After each period of loading, potentiated Pditw was recorded immediately and after 20 min (n = 10) and at ~20 h after conclusion of task-failure protocol (n = 6). Potentiated Pditw was reduced from baseline values after first 2 min of loading, and nadir was reached 20 min after conclusion of inspiratory resistive loading to task failure. Potentiated Pditw at ~20 h from task failure remained lower than baseline. Nonpotentiated Pditw was reduced after 4-min period of loading, and at ~20 h from task failure it remained lower than baseline. Values are means ± SE. ** Significantly different from baseline, P < 0.01.


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  		Fig. 5.   Changes in potentiated (A) and nonpotentiated (B) Pditw and associated right and left compound diaphragmatic action potentials (CDAPs) after inspiratory resistive loading (hatched bars) to task failure (n = 6). Twitches were recorded before loading (baseline) and at 20 min and ~20 h after task failure. Potentiated and nonpotentiated Pditw were reduced from baseline after inspiratory resistive loading, and at ~20 h from task failure they remained lower than baseline. Degree of diaphragmatic recruitment elicited during potentiated and nonpotentiated Pditw recordings remained constant over time, as demonstrated by constancy in CDAP amplitudes. Values are means ± SE. ** Significantly different from baseline, P < 0.01.

Potentiated Pditw. Potentiated Pditw at baseline was 54.1 ± 2.7 cmH2O (range 34.4-64.3 cmH2O). Inspiratory resistive loading for 2 min decreased potentiated Pditw to 48.2 ± 2.8 cmH2O (P < 0.01; Fig. 4). After 20 min of resting breathing, potentiated Pditw was 44.7 ± 2.7 cmH2O, which was less than the values at baseline (P < 0.01) and immediately after conclusion of 2 min of loading (P < 0.01; Fig. 4). After the 4-min period of loading, potentiated Pditw was 43.4 ± 2.3 cmH2O, which was less than that at baseline (P < 0.01). After 20 min of resting breathing, potentiated Pditw decreased further to 41.3 ± 2.4 cmH2O, which was less than the Pditw values recorded at baseline (P < 0.01) and just before 4 min of loading (P < 0.05). At the conclusion of the task-failure protocol, potentiated Pditw was 40.0 ± 2.2 cmH2O, which was less than that recorded at baseline (P < 0.01). After 20 min of resting breathing, potentiated Pditw decreased to 38.0 ± 2.1 cmH2O, which was less than baseline (P < 0.01). Interestingly, the percent fall in the potentiated Pditw was greater than that recorded for the nonpotentiated Pditw (P < 0.001). After ~20 h, potentiated Pditw increased to 48.2 ± 2.6 cmH2O (n = 6), which was greater than the value recorded ~20 h earlier but was still less than baseline (P < 0.01; Fig. 4). As was the case for nonpotentiated Pditw, the amplitudes of the right and left CDAPs of potentiated Pditw were the same throughout this ~20-h period (Fig. 5), indicating a constant level of diaphragmatic recruitment.

CO2 rebreathing. PETCO2 values immediately before each CO2 rebreathing challenge did not differ among the five experimental conditions (Table 1). The total time of rebreathing and the rate of PETCO2 increase were similar at baseline, after the three periods of inspiratory resistive loading, and ~20 h later (Table 1).

                              
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  		Table 1.   PETCO2 measurements during CO2 rebreathing maneuvers

In Fig. 6, f, VT, and minute ventilation (VE) are plotted against PETCO2. Resistive loading did not cause a significant change in the response of f and VT to increased CO2 compared with the responses before loading. After 2 min of loading, the response of VE to CO2 at 50-70 Torr PETCO2 was not different from that before loading. After loading for 4 min and to task failure, the VE response to CO2 at 50-70 Torr PETCO2 was greater than that before loading (P < 0.01), and ~20 h later the VE response to CO2 at 50-70 Torr PETCO2 was still greater than that recorded before loading (P < 0.025).


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  		Fig. 6.   Tidal volume (VT), breathing frequency (f), and minute ventilation (VE) during CO2 rebreathing plotted against end-tidal PCO2 (PETCO2). Neither VT nor f was affected by preceding loading period sustained for 2 min, 4 min, and until task failure (n = 10). At 20 h after task-failure protocol, VT and f response to CO2 was the same as before loading (n = 6). VE response to CO2 increased after 4th min of loading, and after ~20 h it was still greater than that recorded before loading. Values are means ± SE.

In Fig. 7 the mean values of Delta Pes, Delta Pga, and Delta Pdi during CO2 rebreathing are plotted against PETCO2. During CO2 rebreathing performed before resistive loading, Delta Pga increased initially with increasing CO2, reaching a peak at ~63 Torr PETCO2 and decreased thereafter. After 2 min of loading, Delta Pga displayed a similar pattern of rise and fall as PETCO2 increased, but for any given PETCO2 a lower Delta Pga was noted than before loading (P < 0.025). After loading for 4 min and to the point of task failure, Delta Pga did not increase with increasing PETCO2; this pattern was different from the pattern recorded before loading (P < 0.01). After 20 h, Delta Pga did not increase with increasing PETCO2; this pattern again was different (P < 0.05) from that recorded before loading. Before loading, Delta Pes increased progressively with increasing PETCO2 (Fig. 7); this response pattern was also observed after the three periods of loading. The CO2-induced rate of rise in Delta Pes was not affected by the preceding duration of resistive loading (Fig. 7). At baseline and after three periods of loading, Delta Pdi increased progressively with increasing PETCO2. The CO2-induced rate of rise in Delta Pdi was not affected by the preceding duration of resistive loading (Fig. 7). The uniformity in the Delta Pdi response to increasing levels of CO2 was due to a relative increase in Delta Pes (Fig. 7).


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  		Fig. 7.   Inspiratory pressure changes for esophageal pressure (Delta Pes), gastric pressure (Delta Pga), and transdiaphragmatic pressure (Delta Pdi) plotted as a function of PETCO2. Recordings were obtained at baseline, after inspiratory resistive loading for 2 min, 4 min, and until task failure (n = 10), and ~20 h later (n = 6). Pga contribution to tidal breathing was progressively decreased in relation to duration of preceding loading (P < 0.025), whereas Pes contribution to tidal breathing was not affected by preceding duration of resistive loading. Delta Pdi tended to progressively decrease in proportion to duration of preceding loading, but this pattern did not reach statistical significance. These patterns were still present ~20 h after conclusion of loading to task failure. Values are group means ± SE.

The relationship between the end-expiratory and end-inspiratory PL and end-expiratory and end-inspiratory Pga is shown in Fig. 8. Before resistive loading the slope of the PL-Pga relationship became steeper as PETCO2 increased, indicating greater rib cage muscle recruitment during tidal breathing; this was accompanied by a simultaneous increase in end-expiratory Pga and decrease in end-expiratory PL, indicating expiratory muscle recruitment. These changes in rib cage muscle contribution to tidal breathing became even more pronounced after the three periods of resistive loading, and they were still evident ~20 h after loading to task failure. The decreases in end-expiratory PL after loading for 4 min and loading to task failure were greater than the corresponding values before loading (P < 0.05). After 20 h the decrease in end-expiratory PL tended to be greater than the corresponding values before loading (P = 0.08).


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  		Fig. 8.   Relationship between transpulmonary pressure (PL) and Pga before and after inspiratory resistive loading sustained for 2 min, 4 min, and until task failure at different levels of PETCO2. PL and Pga values (which represent start and end of inspiratory PL and Pga values, respectively) were obtained during CO2 rebreathing performed 20 min after each period of loading (n = 10) and at ~20 h after conclusion of loading to task failure (n = 6). Before fatigue there was a consistent increase in slope of PL-Pga relationship with increase in PETCO2, indicative of an increase in rib cage muscle contribution to tidal breathing. This pattern was more pronounced after 3 periods of loading starting at 51-55 Torr PETCO2. Before fatigue, at beginning of inspiration there was a progressive decrease in PL and increase in Pga with increase in PETCO2, which is consistent with expiratory muscle recruitment. This pattern was present and more pronounced after loading. A rest period of ~20 h after task failure was not sufficient to normalize these alterations in respiratory muscle recruitment. Values are means ± SE.

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

Inspiratory resistive loading sustained for periods of increasing duration decreased diaphragmatic contractility in proportion to the duration of loading, ever before task failure (Figs. 3 and 4). In addition, the pattern of respiratory muscle recruitment during an increase in ventilatory demand (CO2 rebreathing) was altered as the duration of loading was increased (Figs. 7 and 8), and a rest period of ~20 h after task failure was not sufficient to normalize this alteration in respiratory muscle recruitment or the fatigue-induced changes in diaphragmatic contractility.

Sensations of air hunger and inspiratory effort. The sensation of inspiratory effort at the 4th min of the task-failure protocol was greater than at the same time in the preceding 4-min protocol (Fig. 2). Sense of effort during forceful muscle contractions is thought to be due to the magnitude of the central motor command to contracting muscles: the greater the command signal, the greater the neuronal corollary discharge being transmitted from the motor regions to sensory areas (i.e., subcortical postcentral areas and dorsal prefrontal cortex) (10). These corollary discharges are thought to be experienced as an increase in the sense of effort for a given load (13). We speculate that the loads sustained for 2 and 4 min had already initiated a contractile fatigue process in the diaphragm. Progressive diaphragmatic fatigue, in turn, required increased diaphragmatic recruitment (i.e., an increase in the magnitude of the central motor command signal) to maintain the target pressure during loading to task failure, i.e., sense of effort was greater at 4th min of the taskfailure protocol than at 4th min of 4-min protocol. Moreover, Ward et al. (32) reported that when the diaphragm becomes fatigued during resistive loaded breathing, the sensation of inspiratory effort increases in association with the increases in activity of the rib cage and sternomastoid muscles. Therefore, inspiratory muscles other than the diaphragm may have gradually increased their participation over the time of loaded breathing, accounting for the increasing inspiratory effort sensation in the present study.

Contrary to the sensation of inspiratory effort, the sensation of air hunger was not affected by the duration of the preceding period of loading, and it was not maximal at the conclusion of the task-failure protocol. The mechanism likely to be responsible for this finding may depend on the fact that task failure was not accompanied by hypercapnia, i.e., PETCO2 of 41 ± 2 Torr at task failure and 41 ± 1 Torr at baseline; in other words, the inspiratory resistive loading was not sufficient to decrease VE (20).

Inspiratory resistive loading and Pdimax. Pdimax decreased after loading sustained for only 2 min and continued to decrease further after loading for 4 min and after loading to task failure (Fig. 3). At ~20 h of rest after the task-failure protocol, Pdimax had not returned to the preloading value. The decrease in Pdimax immediately after each of the three periods of loading could have resulted from central fatigue and/or contractile fatigue. Because the extent of voluntary activation of the diaphragm was not measured, we can only speculate on the likelihood of central fatigue. McKenzie et al. (21) measured the degree of voluntary diaphragmatic activation in healthy subjects during Pdimax maneuvers recorded 10 s after each of three sets of 10 maximal expulsive efforts. Pdimax decreased progressively, a maximal decrement of ~22% of the initial value, but the degree of diaphragmatic voluntary activation did not change over time. This suggests that contractile fatigue, rather than central fatigue, was probably responsible for the decrease in Pdimax in our subjects.

It has been suggested that Pdimax is achieved by high-frequency (50- to 100-Hz) motoneuron discharge (27). If this is true, a fatigue-induced decrease in Pdimax should exhibit a rapid recovery pattern (<10 min), as expected for high-frequency fatigue (2). Interestingly, when our subjects rested for 20 min after each episode of loading, recovery of Pdimax was still incomplete. These data are inconsistent with the notion that high-frequency motoneuron discharge is necessary for the development of Pdimax. This issue is not fully resolved, however, since human phrenic motoneuron discharge has not been directly measured during a Pdimax maneuver.

The discharge frequency of phrenic motoneurons during the generation of Pdimax in humans can be extrapolated from studies in limb muscles (6, 7, 17). During maximal voluntary contraction of the biceps brachii, Bellemare et al. (6) recorded a motor unit firing frequency of 31.1 ± 10.1 (SD) Hz, with 50 Hz being the highest value. They concluded that a motoneuron firing frequency of 30 Hz results in 85-90% of maximal voluntary force generation, with the remaining 10-15% resulting from activity in motor units that require discharge rates >30 Hz. Likewise, Bigland-Ritchie et al. (7) recorded a motor unit firing frequency of 28.2 ± 0.6 (SE) Hz during maximal voluntary contractions of the tibialis, with a maximum motor unit firing frequency of 61.9 Hz (7, 17). Recordings during phrenic pacing in patients with spinal cord injury (23) suggest that the phrenic motoneurons have discharge frequencies similar to the skeletal muscles described above. Thus, using Pdimax to detect the presence or absence of high-frequency fatigue is an oversimplification. For the portion of maximal force (10-15%) resulting from high-frequency discharge, high-frequency fatigue may indeed decrease Pdimax. This could explain the rapid but incomplete recovery of Pdimax during each of the 20-min recovery periods: after inspiratory resistive loading was sustained for 2 min, 4 min, and to task failure, Pdimax increased by 10 ± 4, 12 ± 3, and 13 ± 3%, respectively, from the respective nadir value (Fig. 3). For the 85-90% of force that appears to be produced by motoneurons discharging at a lower frequency, low-frequency fatigue will modulate the force output. This could explain the incomplete recovery of Pdimax over the ~20-h follow-up period (Fig. 3).

Inspiratory resistive loading and Pditw. A decrease in nonpotentiated Pditw was observed after inspiratory resistive loading for 4 min and to task failure (Fig. 4). These results suggest that contractile fatigue is not an all-or-none phenomenon that occurs only when the respiratory muscles are loaded to task failure, as reported by Eastwood et al. (9). Our hypothesis is further supported by the decrease in potentiated Pditw and Pdimax after as little as 2 min of loading (Figs. 3 and 4). Also, the diaphragmatic contribution to tidal breathing in the presence of increased ventilatory demands (CO2 rebreathing) tended to decrease after 2 min of loading (see below; Fig. 7). The early onset of contractile fatigue is further supported by the additional decreases in Pdimax, potentiated Pditw, and diaphragmatic contribution to tidal breathing during CO2 rebreathing (see below) after 4 min of resistive loading.

The load-induced fall in potentiated Pditw was greater than that of the nonpotentiated Pditw (P < 0.01). These differences between patterns of load-induced decreases in potentiated and nonpotentiated Pditw can be explained by three possible mechanisms. 1) A rest period of 20 min might have been insufficient to allow resolution of twitch potentiation. If this is true, the nonpotentiated Pditw values would have been systematically overestimated. This possibility seems unlikely, in that other investigators observed complete resolution of twitch potentiation within 20 min of Pdimax maneuvers (33), and 20 min is double the time needed for resolution of twitch potentiation after sniff maneuvers (14). 2) The load-induced decrease in Pdimax was sufficient to hinder the induction of complete twitch potentiation. This possibility is unlikely, since Mador et al. (19) demonstrated that the magnitude of twitch potentiation was equivalent for contractions of 66 and 100% of Pdimax. In our investigation, the nadir of Pdimax was 79 ± 3% just after task failure, which is above the value reported to induce complete twitch potentiation (19). 3) The mechanism(s) that determines the magnitude of potentiation of Pditw [i.e., phosphorylation of the P light chain myosin subunits (31) and/or contraction-induced efflux of potassium from the contracting muscle (11)] might be more sensitive to the process of low-frequency fatigue than are the mechanisms that determine the nonpotentiated values of Pditw. In other words, recordings of potentiated Pditw may be more sensitive in detecting changes in diaphragmatic contractility that precede task failure than are recordings of nonpotentiated Pditw.

Inspiratory resistive loading and respiratory muscle recruitment. To study the recruitment patterns of respiratory muscles in response to increased ventilatory demands, the subjects rebreathed CO2. Juan et al. (12) showed that CO2 per se depresses diaphragmatic contractility, but the exposure in their study was longer (10-15 min) than in the present study (3-4 min). Yan et al. (35) did not observe a decrease in the amplitude of Pditw during CO2 rebreathing, indicating that a brief period of hypercapnia does not impair diaphragmatic contractility. Therefore, the changes we observed in muscle recruitment are unlikely to be due to a direct depressant effect of CO2 on the diaphragm per se but rather a consequence of the preceding periods of resistive loading. Despite what we interpret as progressively greater degrees of diaphragmatic fatigue (Figs. 3 and 4), our subjects showed no decrease in the ventilatory response to CO2 (Fig. 6); this was achieved by even greater recruitment of rib cage and expiratory muscles. The alterations in the pattern of respiratory muscle recruitment had not reverted to normal after ~20 h of rest after task failure.

When the ventilatory demands were increased before inspiratory resistive loading, the slope of the PL-Pga relationship and end-expiratory Pga increased, whereas end-expiratory PL decreased (Fig. 8). These findings are consistent with the viewpoint that the respiratory muscles exhibit two different response patterns when exposed to an inspiratory challenge: augmented activity of the rib cage muscles out of proportion to the diaphragm (22) and increased activation of the expiratory muscles (22).

After resistive loading was sustained for periods of increasing duration, the ventilatory response to CO2 was achieved by even greater recruitment of the rib cage and expiratory muscles than before resistive loading (Fig. 8). For <= 55 Torr PCO2, the ventilatory response was achieved mainly by greater recruitment of rib cage muscles, as reported by Yan et al. (35) after diaphragmatic resistive loading sustained to task failure; for >55 Torr PCO2, greater activity of the expiratory muscles was also recorded. This modulation of respiratory muscle recruitment is advantageous, in that the other respiratory muscle groups assist the action of the diaphragm (Figs. 7 and 8). Viewed in and of itself, the decrease in diaphragmatic contribution to tidal breathing during CO2 rebreathing after inspiratory resistive breathing could represent the adoption of a strategy by the respiratory centers to delay muscle fatigue. Although we cannot prove or disprove this possibility (see above), the fact that potentiated and nonpotentiated Pditw and Pdimax were significantly decreased, ever before task failure (Figs. 3 and 4), indicates that diaphragmatic contractile fatigue was taking place before the conclusion of the task-failure protocol.

In summary, inspiratory resistive loading sustained for periods of increasing duration produced a proportional decrease in diaphragmatic contractility, ever before task failure. This progressive diaphragmatic fatigue may account for the increased sense of effort during loading to task failure compared with the preceding 4-min load. Moreover, the progressive decrease in diaphragmatic contractility was accompanied by progressive recruitment of the rib cage and expiratory muscles during CO2 rebreathing. A ~20-h period of recovery after task failure did not normalize these fatigue-induced alterations in respiratory muscle recruitment. Incidentally, potentiated Pditw may be more sensitive than nonpotentiated Pditw in detecting early diaphragmatic fatigue. In conclusion, inspiratory resistive loading rapidly initiated a fatiguing process in the diaphragm, and as a result the rib cage and expiratory muscles were recruited progressively to handle increased ventilatory demands.

    ACKNOWLEDGEMENTS

The authors thank Saurabh Khandelwal for technical support and J. Corliss, A. Long, and Y. Liao for statistical assistance.

    FOOTNOTES

This study was supported by grants from the Veterans Administration Research Service, the American Lung Association of Metropolitan Chicago, and the Gaylord and Dorothy Donnelley Foundation.

Address for reprint requests: F. Laghi, Div. of Pulmonary and Critical Care Medicine, Edward Hines, Jr., VA Hospital, Hines, IL 60141.

Received 23 June 1997; accepted in final form 7 May 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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