Original Article
Contractile Properties of the Human Diaphragm during Chronic Hyperinflation
N Engl J Med 1991; 325:917-923September 26, 1991
- Abstract
- Abstract
Background.
In patients with chronic obstructive pulmonary disease (COPD) and hyperinflation of the lungs, dysfunction of the diaphragm may contribute to respiratory decompensation. We evaluated the contractile function of the diaphragm in well-nourished patients with stable COPD, using supramaximal, bilateral phrenic-nerve stimulation, which provides information about the strength and inspiratory action of the diaphragm.
Methods.
In eight patients with COPD and five control subjects of similar age, the transdiaphragmatic pressure generated by the twitch response to phrenic-nerve stimulation was recorded at various base-line lung volumes, from functional residual capacity to total lung capacity, and during relaxation and graded voluntary efforts at functional residual capacity (twitch occlusion).
Results.
At functional residual capacity, the twitch transdiaphragmatic pressure ranged from 10.9 to 26.6 cm of water (1.07 to 2.60 kPa) in the patients and from 19.8 to 37.1 cm of water (1.94 to 3.64 kPa) in the controls, indicating considerable overlap between the two groups. The ratio of esophageal pressure to twitch transdiaphragmatic pressure, an index of the inspiratory action of the diaphragm, was -0.50±0.05 in the patients, as compared with -0.43±0.02 in the controls (indicating more efficient inspiratory action in the patients than in the controls). At comparable volumes, the twitch transdiaphragmatic pressure and esophageal-to-transdiaphragmatic pressure ratio were higher in the patients than in normal subjects, indicating that the strength and inspiratory action of the diaphragm in the patients were actually better than in the controls. Twitch occlusion (a measure of the maximal activation of the diaphragm) indicated near-maximal activation in the patients with COPD, and the maximal transdiaphragmatic pressure was 106.9±13.8 cm of water (10.48±1.35 kPa).
Conclusions.
The functioning of the diaphragms of the patients with stable COPD is as good as in normal subjects at the same lung volume. Compensatory phenomena appear to counterbalance the deleterious effects of hyperinflation on the contractility and inspiratory action of the diaphragm in patients with COPD. Our findings cast doubt on the existence of chronic fatigue of the diaphragm in such patients and therefore on the need for therapeutic interventions aimed at improving diaphragm function. (N Engl J Med 1991; 325:917–23.)
Article Activity
- Article
HYPERINFLATION of the lungs impairs the function of the diaphragm by placing it at mechanical disadvantage, shortening its operating length, and changing the mechanical linkage between its various parts. These factors decrease the tension that can be developed and the amount of transdiaphragmatic pressure produced in response to a given tension.1 2 3 4 5 Furthermore, as lung volume increases, the fraction of transdiaphragmatic pressure that can be applied to the lungs with a resultant fall in transpulmonary pressure decreases.5 The action of the diaphragm may thus be altered in patients with chronic obstructive pulmonary disease (COPD) and may contribute to their disability and respiratory failure. Surprisingly little is known about the contractile properties and function of the diaphragm in such patients. Some studies have used voluntary contractions to measure the strength of static diaphragmatic contractions.6 7 8 The reported values for transdiaphragmatic pressure ranged from -80 to -170 cm of water (-8 to -17 kPa). More detailed information on diaphragm functioning can now be obtained with supramaximal bilateral phrenic-nerve stimulation,9 , 10 which produces uniform contractions of the entire diaphragm (twitches) independently of any spontaneous or voluntary effort. Used in isolation, it provides information about the contractile properties of the diaphragm and its mechanical interactions with the chest wall.5 , 11 Used in combination with naturally occurring or voluntary contractions, it helps distinguish the intrinsic function of the diaphragm from the level of diaphragm activation by the central nervous system.10 , 12 , 13 As will be seen, our results indicate that patients with COPD are capable of almost maximal voluntary activation of the diaphragm.
The aim of this study was to describe in detail the contractile properties and inspiratory action of the diaphragm in patients with stable COPD and hyperinflation of the lungs. In such patients, chronic diaphragm fatigue has often been postulated as a mechanism of respiratory dysfunction.
Methods
Patients
Eight men with COPD, 50 to 72 years of age, were studied (Table 1Table 1
Characteristics and Pulmonary Function of the Patients and the Control Subjects.*). All the patients were smokers or former smokers, with a cumulative cigarette consumption ranging from 25 to 120 pack-years. None of them had a history of asthma, and their airflow obstruction was largely irreversible. None were known to have alpha1-antitrypsin deficiency; Patient 1 had a history of pulmonary tuberculosis.The criteria for admission to the study were (1) severe airflow obstruction, defined as a forced expiratory volume in one second (FEV1) less than 50 percent of the predicted value, together with a ratio of FEV1 to vital capacity less than 55 percent of the predicted value; (2) hyperinflation, defined as a functional residual capacity greater than 130 percent of the predicted value; (3) a stable clinical state, defined as the absence of any episode of acute respiratory decompensation in the two months before the study; and (4) good nutritional status (a ratio of real to ideal weight above 0.9), because the importance of this factor for diaphragmatic performance has been emphasized.14 The protocol was approved by the ethics committee of our institution, and all the subjects gave written informed consent.
Control Subjects
Five men with normal lung function, 51 to 73 years of age, served as controls (Table 1). They did not differ significantly from the patients with respect to age, height, or weight (Mann—Whitney U test).
Measurements
Esophageal and gastric pressures were measured by means of two identical balloon catheters1 , 15 connected to two linear-pressure transducers (0 to 150 cm of water; Microswitch 160 PC, Honey-well, Scarborough, Ont.). Values for transdiaphragmatic pressure were obtained on-line by subtracting the esophageal from the gastric pressure electronically; transdiaphragmatic pressure was monitored on an oscilloscope placed in front of the subject. For six patients, dimensions and displacements of the rib cage were assessed with magnetometers. One pair of magnetometers measured the anteroposterior dimension of the upper rib cage at the level of the second rib. This part of the rib cage is exposed to pleural pressure over the lung surface and has been referred to as the pulmonary rib cage.16 The other pair of magnetometers measured the lateral dimension of the lower rib cage at the 10th rib, which is exposed to pleural pressure in the area of apposition and has been termed the abdominal rib cage.16
The phrenic nerves were simultaneously stimulated transcutaneously at their motor points in the neck17 with 0.1-msec square-wave pulses delivered from two stimulators (Teca NS6, Teca, Pleasantville, N.Y.) whose output of current could be adjusted independently, from 0 to 50 mA. The details of the procedure have been described elsewhere.10 , 13 , 17 18 19 The diaphragmatic electromyogram was recorded with two pairs of 5-mm surface-cup electrodes taped over the sixth and seventh right and left intercostal spaces near the costal margin. The signal was amplified by alternating current and band-pass filtered (16 to 16,000 Hz). The compound action potentials (M waves) evoked from each hemidiaphragm by the stimulation were monitored on a storage oscilloscope. At the beginning of each test, the current required for maximal stimulation was established for each phrenic nerve as described elsewhere.10 , 13 Currents 20 percent stronger than the minimum required to achieve maximal stimulation were used throughout the experiments.
Procedures
All the tests were done while the subjects were sitting. The subjects breathed into the mouthpiece through a two-way Hans—Rudolph valve equipped at each side with a shutter and connected in closed circuit to a bag-in-box spirometer for measurement of changes in lung volume. For all the patients, the twitch responses to bilateral phrenic-nerve stimulation were recorded at functional residual capacity, with the diaphragm relaxed. The patients were instructed to breathe out and to relax at end-expiration. Then the inspiratory and expiratory lines of the circuit were closed, and one to five stimuli were delivered. The resulting twitches were considered valid only if they met the following criteria: (1) maximal M-wave amplitude (with the data rejected in the event of contamination by a QRS complex of the electrocardiogram); (2) actual functional residual capacity, as determined on the basis of the end-expiratory esophageal pressure and the volume tracing from the spirometer; (3) relaxation of the diaphragm, as determined by the absence of transdiaphragmatic pressure as compared with base line and of spontaneous electrical activity; and (4) relaxation of the abdominal muscles, as determined on the basis of the base-line gastric pressure. Data from at least 10 valid twitches were collected for each subject.
In six of the patients, the following two additional tests were carried out.
Effects of Acute Change in Lung Volume
The patients inspired to total lung capacity and then relaxed against an expiratory resistance, which allowed stimulations to be administered at various lung volumes. The criteria for relaxation were the same as before.
Twitch Occlusion
To measure twitch occlusion, stimulations were superimposed on voluntary contractions of the diaphragm during inspiratory efforts.10 , 13 Several levels of transdiaphragmatic pressure were marked on the oscilloscope screen, and the patients were asked to target them by pulling on the inspiratory valve that had been closed at functional residual capacity. No instructions were given about the type of effort to be made. Each effort was sustained for about five seconds, during which two to four stimulations were administered. Finally, the patients were asked to produce what they considered a maximal effort, during which stimulations were again administered.
Signal Processing and Data Analysis
All the signals were recorded on FM tape and replayed through an analogue-to-digital converter to an IBM-compatible personal computer for analysis with custom-designed software and subsequent storage. All the twitches that fulfilled the criteria for acceptance were analyzed. For each twitch we measured the peak amplitude of the left and right M waves relative to the isoelectric line. The amplitude of transdiaphragmatic, esophageal, and gastric pressure was measured as the difference between the peak value reached by each pressure signal during the twitch and the preceding base-line value, which was also recorded. In the case of transdiaphragmatic pressure, we also measured several indexes of the velocity of the twitch. The contraction time was measured from the onset of the rise in pressure to the peak value. The half-relaxation time was measured as the time from the peak pressure to a pressure half as great. The maximal contraction rate and maximal relaxation rate were defined as the maximal values reached by the first derivative of the transdiaphragmatic pressure during the contraction and the relaxation of the twitch, respectively. For comparison purposes, these indexes were normalized in relation to the peak twitch pressure.
Standard linear-regression techniques using the least-squares method were employed for all relations with changes in lung volume or voluntary effort. Comparisons within a group and between groups were done with paired and unpaired t-tests, respectively. A two-tailed P value less than 0.05 was considered to indicate statistical significance. Values are expressed as means ±SE.
Results
Characteristics of the Twitches at Functional Residual Capacity
The amplitude of the twitch transdiaphragmatic pressure in the patients ranged from 10.92 to 26.55 cm of water (1.07 and 2.60 kPa), as compared with 19.80 and 37.10 cm of water (1.94 and 3.64 kPa) in the control group (P = 0.03) (Table 2Table 2
Velocity of the Contraction and Relaxation of Twitch Transdiaphragmatic Pressure (Pdi,t) in the Eight Patients, with Reference to the Control Group.*). These measurements were satisfactorily reproducible, with a mean coefficient of variation for values within the same subject of less than 19 percent. In our subjects, there was no correlation between twitch amplitude and age, degree of hyperinflation, or airway obstruction.The ratio of the esophageal to the twitch transdiaphragmatic pressure reflects the ability of the diaphragm to generate a useful fall in intrathoracic pressure — in other words, to exert an inspiratory action on the lungs. The mean values for this ratio were -0.50 in the patients, as compared with -0.43 in the control group, the lowest values being observed in the patients with hyperinflated lungs. The mean time to peak pressure was longer in the patients than in the controls (84.6 vs. 65.6 msec, P<0.02), and the velocity of contraction slower, whereas the characteristics of relaxation were similar.
In the six patients in whom rib-cage displacements were measured during phrenic-nerve stimulation, the pulmonary rib cage moved inward by 0.211±0.073 cm, or 0.89±0.33 percent of the end-expiratory ribcage dimension. The abdominal rib cage moved outward in four patients and inward in the other two (Patients 1 and 5), with an average displacement of 0.57±0.17 percent of the end-expiratory dimension.
Effects of Acute Change in Lung Volume
Figure 1Figure 1
Effect of Lung Volume on the Amplitude of the Twitch Transdiaphragmatic Pressure (Pdi,t; Upper Panels) and on the Inspiratory Nature of the Diaphragm Contraction (Pes,t:Pdi,t Ratio; Lower Panels). shows the effect of lung volume on the twitch transdiaphragmatic pressure and on the inspiratory action of the diaphragm. The decrease in the twitch transdiaphragmatic pressure was always linear (Table 3Table 3
Effects of Lung Volume on the Twitch Transdiaphragmatic Pressure and Its Pleural Component.*). The same was true for the increase in the twitch esophageal pressure and in the esophageal-to-transdiaphragmatic pressure ratio. Except in the case of one control subject (Control 4), at comparable lung volume the diaphragms of the patients performed as well as or better than those of the controls. This was true in terms of the pressure generated and even more so in terms of the fraction of this pressure that could be used to drive inspiration. By extrapolation, at 125 percent of total lung capacity the diaphragm would have only a negligible inspiratory action for all the controls, whereas this was the case for only one of the patients. Similarly, at 125 percent of predicted total lung capacity, the transdiaphragmatic pressure generated would be about 0 for four of the five controls, whereas it remained at about 10 cm of water in the patients. It is noteworthy that no positive swings in esophageal pressure were observed in thepatients (i.e., the diaphragm never had an expiratory effect on the lungs), whereas this was observed in one of the controls.
Figure 1 also shows the mean values for the two groups at functional residual capacity and total lung capacity. The twitch transdiaphragmatic pressure at functional residual capacity was significantly lower in the patients (P<0.05), but this difference disappeared at total lung capacity despite a significant difference in lung volume.
Increasing lung volume did not markedly affect either the amplitude of the gastric twitch pressure or the direction and importance of the displacements of both components of the rib cage. A shorter-lasting twitch was found in only one patient (Patient 2). On the other hand, a significant direct correlation was found between lung volume and the maximal relaxation rate of the twitch transdiaphragmatic pressure in the six patients.
Twitch Occlusion
The twitch transdiaphragmatic pressure decreased linearly with the intensity of the voluntary contraction on which stimulation was superimposed (Fig. 2Figure 2
Results of the Twitch-Occlusion Technique.). By definition,10 , 13 , 20 the maximal voluntary contraction possible corresponded to the abolition of the twitch response. This can be estimated as the ratio of the intercept to the slope of the relation between the amplitude of the twitch and the intensity of the underlying contraction (extrapolation to the x-axis). In our patients, this potential maximal level of contraction ranged from 64.76 to 150.61 cm of water (6.35 to 14.77 kPa), with a mean of 106.86±13.81 cm of water (10.48±1.35 kPa). During their best effort, our patients generated 95±2 percent of that maximum (range, 88 to 100 percent), indicating that they were capable of close-to-maximal or maximal activation of their diaphragms.The inspiratory efforts performed at functional residual capacity reduced the duration of the twitch: significant decreases were found in contraction time and half-relaxation time, and significant increases in maximal contraction and relaxation rates.
Discussion
In this study, the strength and inspiratory action of the diaphragm in a group of well-nourished patients with stable COPD and hyperinflated lungs were generally better than would be expected on the basis of similar measurements in normal subjects with comparable lung volumes. We are aware that the small size of the group does not allow us to draw general conclusions. However, our patients constitute a rather homogeneous group of subjects with moderate-to-severe COPD and hyperinflation of the lungs, and our results were consistent. Before these results are interpreted, several methodologic issues need to be considered. First, because lung volume was of obvious importance in our experiments, it was carefully controlled throughout. Second, we paid particular attention to keeping other respiratory muscles as relaxed as possible, in order not to interfere with the action of the diaphragm. Although concern has been occasionally expressed about the specificity with which the diaphragm is activated by phrenic-nerve stimulation,21 in our eight patients it was not only possible to avoid brachial-plexus stimulation, but stimulation of neck muscles without costimulation of the phrenic nerves (during the search for the best location for the stimulus) was also not associated with negative deflections in esophageal pressure. Thus, without actual phrenic-nerve stimulation, no inspiratory action occurred. Finally, supramaximality of the stimulus, which is crucial if one wishes the twitch response to reflect intrinsic muscle properties, proved easy to obtain and maintain in all our subjects throughout the experiments.
The usual assumption that increased functional residual capacity is associated with a shorter diaphragm leads to the prediction of reduced generation of transdiaphragmatic pressure in patients with COPD.6 7 8 , 22 In line with this prediction, the twitch pressure at functional residual capacity was significantly lower in the patients than in the control subjects. Nevertheless, a wide overlap in pressures was found between the patients and the controls at their respective functional residual capacities, and no difference between the two groups was found at total lung capacity. When they were compared at similar lung volumes (Fig. 1), the transdiaphragmatic pressures were often higher in the patients than in the control subjects. This may be the result of the chronic overload imposed on the diaphragms of the patients, leading to a "training hypertrophy." However, histologic studies show that atrophy, rather than hypertrophy, of the fibers of the diaphragm is present in COPD and that it correlates with the severity of airflow obstruction.23 From another point of view, preservation of the strength of a muscle placed at a shorter-than-optimal length can be explained by structural muscle changes consisting of loss of sarcomeres24 25 26 27 28 and referred to as a length adaptation. As a result, the diaphragm would produce maximal active tension at shorter lengths, as has been demonstrated in the hamster model of emphysema.25 26 27 28 We were unable to find data on the number of sarcomeres in the diaphragms of patients with COPD.14 , 29 30 31 Nevertheless, the data in our study are compatible with length adaptation. Although they preserve tension, these compensatory adjustments (training hypertrophy and length adaptation) may not restore the overall ability of the diaphragm to generate pressure in vivo, because of persistent changes in the diaphragmatic geometry and coupling with the chest wall and in the mechanical linkage between the costal and crural parts.32 , 33
The ability of the diaphragm to transform transdiaphragmatic pressure into an inspiratory fall in intrathoracic pressure decreased similarly with increasing lung volume in the control subjects and the patients with COPD (Fig. 1). This effect of changes in lung volume in both groups is consistent with previous measurements in normal subjects5 and with theoretical predictions based on associated changes in the extent of the zone of apposition of the diaphragm with the abdominal rib cage, as well as in the orientation of diaphragmatic fibers at their insertions with the costal margin.32 , 33 These factors should not account, however, for the marked difference in the inspiratory action of the diaphragm between the control subjects and the patients with COPD at the same lung volume, since the extent of the zone of apposition and the orientation of diaphragmatic fibers should also be the same. To account for the better inspiratory action of the diaphragm in our patients with COPD, therefore, other factors should be considered. Whatever the mechanism or mechanisms involved, this well-preserved inspiratory function of the diaphragm in COPD should compensate at least in part for any fall in transdiaphragmatic pressure caused by chronic hyperinflation.
The values for maximal transdiaphragmatic pressure estimated on the basis of the twitch-occlusion procedure in our study are virtually identical to the average static values reported in patients with COPD.6 7 8 , 22 They indicate that both the twitch and the static maximal transdiaphragmatic pressure are similarly reduced in such patients, as compared with normal subjects.
Our twitch-occlusion data demonstrate that after only a few attempts, patients with hyperinflated lungs were able to activate their diaphragms maximally or near-maximally with voluntary contractions. This should rule out central diaphragmatic inhibition as a limiting factor during maximal inspiratory efforts in these patients. We wish to emphasize, however, that this conclusion may not be extended to other patients with COPD who are unstable or in acute respiratory failure. Indeed, recent studies have shown that normal subjects who were capable of activating their diaphragms maximally in the fresh, nonfatigued state could no longer do so after a short period of severely fatiguing resistive loading.12
This study suggests that in well-nourished patients with stable COPD the strength of the diaphragm and to a greater extent its inspiratory action are restored by compensatory mechanisms, among which may be training hypertrophy and length adaptation. Morphologic studies are needed to demonstrate this, however. This study also shows, unexpectedly, that the transformation of tension into inspiratory driving pressure is better in patients with COPD than in normal subjects, for reasons that remain unclear.
From a clinical point of view, the preserved diaphragm function, the absence of central inhibition, and the absence of evidence of chronic fatigue in this group of well-nourished patients with stable COPD cast doubt on the need to treat such patients with interventions intended to improve diaphragmatic strength or activation, including the administration of theophylline,34 or to improve the contractility of the diaphragm by resting.
Supported by the J.T. Costello Memorial Research Fund and the Medical Research Council of Canada. Dr. Similowski is the recipient of a Bourse Lavoisier from the Ministère des Affaires Etrangères, Paris.
Source Information
From the Meakins–Christie Laboratories, Royal Victoria Hospital, and the Centre Hospitalier Thoracique de Montréal, McGill University, both in Montreal. Address reprint requests to Dr. Bellemare at the Meakins–Christie Laboratories, McGill University, 3626 St. Urbain St., Montreal, PQ H2X 2P2, Canada.
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