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(Chest. 2002;121:1898-1910.)
© 2002 American College of Chest Physicians

Effects of Emphysema and Lung Volume Reduction Surgery on Transdiaphragmatic Pressure and Diaphragm Length*

François Bellemare, PhD; Marie-Pierre Cordeau, MD; Jacques Couture, MD; Edwin Lafontaine, MD; Pierre Leblanc, MD and Louise Passerini, MD

* From the Research Center (Dr. Bellemare), and Departments of Anesthesiology (Dr. Couture), Radiology (Dr. Cordeau), Surgery (Dr. Lafontaine), and Pneumology (Drs. Leblanc and Passerini), University of Montreal Health Center, Hôtel-Dieu, Montréal, PQ, Canada.

Correspondence to: François Bellemare, PhD, Center de recherche, CHUM - Hôtel-Dieu, 3850, rue St-Urbain, Montréal, PQ, Canada H2W 1T8; e-mail: francois.bellemare{at}umontreal.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Summary
 References
 
Study objectives: To determine the effect of emphysema and lung volume reduction surgery (LVRS) on diaphragm length (Ldi) and its capacity to generate transdiaphragmatic pressure (Pdi).

Design: Prospective clinical trial with a parallel group design.

Setting: Laboratory investigations in normal volunteers recruited by advertisement and in emphysema outpatients being evaluated for elective LVRS.

Study population: Thirteen normal subjects and 13 emphysema patients matched for age and sex. Six emphysema patients underwent LVRS.

Measurements: Ldi and maximal Pdi during static inspiratory efforts (PdiMax) were measured at three different lung volumes (LVs). Pdi during maximal bilateral phrenic nerve twitch stimulation (PdiTw) was measured at functional residual capacity (FRC). All measurements were repeated at 3, 6, and 12 months postoperatively.

Results: Ldi, PdiMax, and PdiTw were lower in emphysema patients than in normal subjects at their respective LVs. PdiMax and PdiTw at FRC returned within the normal range after LVRS in emphysema patients. The relationships between PdiMax and LV or Ldi were shifted respectively to higher LV and shorter Ldi in emphysema patients relative to normal subjects, both before and after LVRS. LVRS effected craniad displacement of the diaphragm but no change in rib cage dimensions. Improvements in dyspnea and quality of life after LVRS correlated with changes in LV and Ldi but not with changes in airway caliber.

Conclusion: Adaptive mechanisms, consistent with sarcomere deletion, tend to restore diaphragm strength in emphysema patients at FRC, which are fully expressed after LVRS. Lung remodeling by LVRS may alter pleural surface pressure distribution, causing a sustained change in chest wall shape.

Key Words: bilateral phrenic nerve stimulation • chest radiographs • diaphragm length • diaphragm strength • emphysema • lung volume reduction surgery


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Summary
 References
 
Pulmonary hyperinflation, as occurs in emphysema patients, impairs thoracoabdominal mechanics and the function of inspiratory muscles, both factors that may contribute to dyspnea and poor exercise tolerance.1 2 Conversely, lung volume reduction surgery (LVRS), a procedure that reduces hyperinflation and air trapping, has been shown to improve dyspnea and exercise tolerance in emphysema patients.3 4 A decrease in the strength of inspiratory muscles with pulmonary hyperinflation is frequently invoked to explain the increased sense of effort and dyspnea in emphysema patients,1 2 as well as their reversal by LVRS.5 6 Shortening of the inspiratory muscles, particularly the diaphragm,7 and a change in its geometry secondary to lung hyperinflation8 are the two factors most frequently linked to the reduction of inspiratory muscle strength of emphysema patients.

So far, only a few studies have measured diaphragm length (Ldi) in emphysema patients,7 9 10 11 12 and none have determined the relationship between the strength-generating capacity of the diaphragm and Ldi or how this relationship may be modified by LVRS. In a recent investigation,12 we have shown, in accord with others,7 9 11 that Ldi is shorter in emphysema patients than in age-matched and sex-matched normal subjects at their respective lung volumes (LVs), and that Ldi increases after LVRS to values close to those found in normal subjects at functional residual capacity (FRC). In the present study, we report in the same patients the relationship between diaphragm strength and Ldi over vital capacity (VC) and how this is modified after LVRS. The effects of emphysema and LVRS on the diaphragm are contrasted with those on rib cage dimensions.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Summary
 References
 
Control and Patient Characteristics
After approval by the local ethics committee, informed consent was obtained from 13 emphysema patients and 13 age-matched and sex-matched normal control subjects. The physical and pulmonary function characteristics of the two groups in relation to predicted normal values13 14 15 are given in Table 1 . In addition to having severe signs of airway obstruction and air trapping, all emphysema patients had radiographic signs of diffuse emphysema on high-resolution CT.


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  		Table 1. Physical and Pulmonary Function Characteristics in Normal Control Subjects and Emphysema Patients*

 
LVRS
Six patients in the emphysema group underwent elective LVRS by the median sternotomy approach described by Cooper et al.3 Pulmonary function characteristics, resting room air arterial blood gas measures, 6-min walking distance (6MWD), oxygen desaturation during exercise ({Delta}SaO2), and pulse rate during 6MWD exercise and quality of life (QOL), as assessed by the chronic respiratory questionnaire (CRQ),16 are enumerated in Table 2 . Serum {alpha}1-antitrypsin level was normal in all but one patient. On high-resolution CT, all had heterogeneous emphysema distribution predominantly affecting the upper lobes in five patients and the lower lobes in one patient. Fluoroscopically determined diaphragm displacements (± SD) in the supine posture were 3.9 ± 0.7 cm on the left side and 2.4 ± 1.4 cm on the right side. Systolic pulmonary artery pressure measured by echocardiography (five patients) or by direct catheterization (one patient) averaged 30.4 ± 8.4 mm Hg. An adapted physiotherapy program was offered to all patients prior to surgery. All patients were evaluated before surgery and at 3 months postoperatively, with five patients also being assessed at 6 months and 12 months postoperatively. One patient could not come to the final two evaluations. In addition to the tests described below, the pulmonary function tests, arterial blood gases, QOL, and 6MWD were reevaluated postoperatively (Table 2) .


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  		Table 2. -Effects of LVRS on Lung Function*

 
Chest Radiographs
In all normal subjects and emphysema patients, chest radiographs served to measure thoracic dimensions and Ldi (Table 3 ).12 17 To ensure constancy of spinal attitude, normal subjects and emphysema patients stood on a specially designed platform,12 with their heel, calf, buttocks, back, and head against a vertical backboard mounted on the platform. Head position was fixed with a strap. Lateral and anteroposterior radiographs were obtained at the end of a normal expiration, ie, FRC, after a full inspiration to total lung capacity (TLC) and at the end of a full expiration to residual volume (RV). For each radiograph, the subjects were instructed to indicate with a fist when the specified LV was attained, and to hold this position for the time required to obtain the radiograph.


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  		Table 3. Effects of Emphysema on Thoracic Dimensions and Diaphragm Function*

 
Thoracic Dimensions
Anteroposterior diameters of the rib cage were measured at the level of the third, fifth, seventh, and ninth thoracic vertebral bodies, using the anterior aspect of the chest wall as the posterior limit and the posterior aspect of the sternum as the anterior limit. Average anteroposterior diameter of the rib cage from the posterior chest wall (APrc) was then calculated as the mean of the four determinations. Also measured was the APrc with the anterior aspect of the vertebrae as the posterior limit (APrc_v). Lateral rib cage diameters were measured at the level of the third, fifth, seventh, and ninth ribs, using the internal aspect of each rib as the external limit, and an average rib cage lateral diameter (LArc) was calculated as the mean of the four determinations. The height of each hemidiaphragm dome below the first thoracic vertebra was also measured on anteroposterior radiographs midway between the internal aspect of the ninth rib and the center of the spine and averaged (average height of diaphragm dome [Hdi]). The average internal rib cage cross-section area (Arc) was estimated as the product of APrc and LArc taken as the minor axis and major axis of an ellipse, respectively.

Ldi
Ldi was measured from the diaphragmatic contours.18 12 First, the intersections of the diaphragm silhouette with the chest wall were marked on anteroposterior and lateral radiographs obtained at TLC. These intersections are assumed to correspond to the insertions of the diaphragm on the chest wall. The same sites were then located on radiographs obtained at FRC and at RV, using skeletal landmarks. The lateral rib position served as a landmark for the lateral insertion on anteroposterior projections. On lateral projections, the distance below the sternomanubrial junction was employed as a landmark for the anterior insertion, and the vertebral level was used as a landmark for the posterior insertion. The contours of the diaphragm were traced with a digitizing tablet, starting from these points of insertions along the chest wall (ie, along the zone of apposition of the diaphragm with the rib cage) and along the visible silhouette of the diaphragm. Ldi contours were measured between the right lateral insertion and the center of the spine on anteroposterior projections, and between the anterior and posterior insertions on lateral projections, and divided into the length of visible contours of the diaphragm (Lvis) and Ldi in the zone of apposition with the rib cage (Lzap). An Ldi index (DLI) was calculated as the sum of the lengths (in centimeters) of the diaphragm contours on anteroposterior and lateral projections divided by height (in meters).18 For comparison with other studies using the same technique, a correction factor of 0.9 for the magnification of the thoracic structures was applied to all linear dimensions. A shape factor for the diaphragm dome (Kdome) was calculated for the anteroposterior radiographs (Kdome_AP) and lateral radiographs (Kdome_LA) as the ratio between the Lvis and the length of the chord relating the points of intersection of the visible contours with the chest wall.

Diaphragm Strength
In all normal subjects and emphysema patients, diaphragm strength was measured while seated during maximum transdiaphragmatic pressure (Pdi) during static inspiratory efforts (PdiMax) performed at RV, FRC, and TLC, and Pdi during supramaximal bilateral phrenic nerve twitch stimulation (PdiTw) performed at FRC. In all instances, Pdi was measured as the difference between esophageal pressure (Pes) and gastric pressure (Pga), each registered conventionally with balloon-tipped catheters and pressure transducers. LV changes were measured by integration of the mouth flow signal recorded with a pneumotachograph.

Static Inspiratory Efforts
PdiMax at TLC:
Subjects were instructed to increase their LV as much as possible. The highest Pdi value generated at the time the highest LV was attained, as judged from the volume tracing, was noted.

PdiMax at FRC:
Subjects were asked to make a maximum inspiratory effort against an obstructed airway at the end of a normal expiration. In 11 normal subjects and 6 emphysema patients, PdiMax during combined inspiratory-expulsive efforts (PdiMax_comb) was measured at FRC, in which the subjects were asked to make a maximum inspiratory effort while recruiting the abdominal muscles antagonistically.19 They are helped in this task by monitoring Pes and Pga on the computer screen.

PdiMax at RV:
Subjects were instructed to exhale maximally. When LV reached a stable value, as judged from the volume tracing, the airways were occluded and the subject was asked to make a maximum inspiratory effort against the obstructed airway.

For each of the above-mentioned maneuvers, a minimum of three maximum efforts, each lasting 1 to 3 s, were performed by each subject. Strong verbal encouragement was given during each effort. The highest Pdi value noted in any one maneuver was retained for analysis. Maximal Pes changes in the same maneuvers were also noted (maximal Pes during static inspiratory efforts [PesMax], and maximal Pes during combined inspiratory-expulsive efforts [PesMax_comb]). In each subject, Pes, Pga, and Pdi, measured at end-expiration, was subtracted from all pressure measurements.

Bilateral Phrenic Nerve Twitch Stimulation
For PdiTw, the phrenic nerves were stimulated bilaterally with supramaximal electric shocks delivered with handheld cathodes positioned in the neck area, and compound motor action potentials from each hemidiaphragm were recorded with two pairs of surface electrodes positioned over the left and right eighth intercostal spaces.20 After at least 10 min of quiet breathing, between 10 and 15 twitches were recorded in each normal subject or emphysema patient during relaxation at FRC. PdiTw was measured from baseline to peak, and the average of all values was noted.

Statistical Analysis
Descriptive statistics and a general linear model of analysis of variance (ANOVA) were used for between-group comparisons of thoracic dimensions, Ldi, DLI, PdiMax, PesMax, and PdiTw. A two-sample t test compared PdiMax and DLI between the two groups at comparable LVs. A paired t test compared PdiMax and PdiMax_comb at FRC in the same subjects. The effects of LVRS on all variables was evaluated by ANOVA for repeated measures. When appropriate, LV was entered as a cofactor in this analysis. In all comparisons, a p < 0.05 was considered statistically significant. All statistical computations were carried with commercially available statistical software (SPSS version 10 for Windows; SPSS; Chicago, IL). For the comparison of PdiMax vs LV and PdiMax vs DLI relationships, LV and DLI at FRC and RV were corrected for alveolar gas expansion, using Pes change as a measure of alveolar pressure change and the relationship between DLI and LV obtained in normal subjects and patients in the emphysema group combined respectively (DLI = 48.2 to 3.07 LV0.46, with DLI in centimeters per meter and LV expressed as percent predicted; r2 = 0.81).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Summary
 References
 
Findings in the Two Groups
Thoracic Dimensions:
As indicated in Table 3 , APrc was significantly greater in emphysema patients than in normal subjects, both at RV and FRC but not at TLC. APrc_v, LArc, and Arc also tended to be greater in patients in the emphysema group than in normal subjects, but not significantly so. As shown in Figure 1 , top, A, the APrc vs LArc relationship of patients in the emphysema group remained close to that seen in normal subjects, showing minimal changes in rib cage shape. By contrast, Hdi was significantly greater in emphysema patients than in normal subjects at all LVs. As seen in Figure 1 , bottom, B, the relationship between Arc and Hdi was shifted to the right of that seen in normal subjects, revealing preferential axial distribution of pulmonary hyperinflation in emphysema group patients.



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  		Figure 1. Relationships between APrc and LArc (top, A) and between Arc and Hdi (bottom, B) in normal subjects and emphysema patients. Data points represent group means with SE.

 
Diaphragm Length:
Ldi and Lzap were significantly shorter in patients in the emphysema group than in normal subjects at all LVs, whereas Lvis was not. Changes in DLI over inspiratory capacity (IC) [2.18 ± 2.4 cm/m vs 5.92 ± 2.75 cm/m] and over VC (5.4 ± 1.57 cm/m vs 10.9 ± 3.1 cm/m) were significantly smaller in patients in the emphysema group than in normal subjects. Kdome_AP and Kdome_LA were both significantly lower in patients in the emphysema group than in normal subjects at all LVs, and both decreased significantly with increasing LV in patients in the emphysema group.

Diaphragm Strength:
PdiMax, PdiMax_comb, and PdiTw were significantly smaller in patients in the emphysema group than in normal subjects at their respective LVs. However, the relationship between PdiMax and LV was shifted to a higher LV in patients in the emphysema group, showing greater PdiMax at FRC than in normal subjects at comparable LVs (Fig 2 ). In both groups, PdiMax_comb at FRC was significantly greater than PdiMax whereas PesMax_comb was significantly smaller than PesMax, revealing a similar effect of antagonistic abdominal muscle recruitment in both groups.



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  		Figure 2. Relationships between LV and changes in Pdi, Pes, and Pga during static inspiratory efforts in normal subjects (N; continuous lines) and emphysema patients (E; dotted lines). Data points represent group means with SE. %pred = percent predicted.

 
Diaphragm Strength vs Length Relationship:
The relationship between PdiMax and DLI in patients in the emphysema group appeared to be shifted to the left along the length axis, compared to normal subjects (Fig 3 ). Because of this shift, PdiMax at FRC in patients in the emphysema group was significantly greater than PdiMax at TLC in normal subjects, even though DLI was not significantly different. By contrast, PdiMax at RV in patients in the emphysema group was significantly smaller than PdiMax at FRC in normal subjects, even though DLI was not significantly different.



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  		Figure 3. Relationship between PdiMax and DLI in normal subjects and emphysema patients. Data points represent group means with SE.

 
Effects of LVRS
Clinical Findings:
Surgery was successfully completed in all six patients, and all were discharged within 17 days postoperatively. At the 3-month visit, five patients had subjective improvements of their dyspnea and QOL. This subjective improvement was maintained up to 12 months postoperatively. Surgery was considered a success in these five patients. The remaining patient felt well at the 3-month visit, but reported no subjective improvement in his dyspnea or QOL. LVRS was less effective in this patient, the reduction of RV (17%) being about half that achieved in the other patients. Spirometric findings were unchanged at 3 months in this patient. His condition deteriorated rapidly in the following months, and he could not come for the 6-month and 12-month evaluations. He became oxygen dependent, and at 12 months was confined to a wheelchair. He was referred to our lung transplantation program but died before receiving the graft. Surgery in this case was considered a failure.

Pulmonary Function:
As shown in Table 2 , RV, FRC, and TLC were all significantly reduced 3 months postoperatively, whereas VC, FVC, and FEV1 were all increased significantly. These changes tended to revert toward preoperative values after 3 months. The most sustained improvements were in RV, VC, and FVC, which remained significantly different from preoperative values up to 12 months postoperatively. Plethysmographically determined airway resistance (Raw) in the neighborhood of FRC and lung diffusing capacity for carbon monoxide (DLCO) were not modified by surgery. QOL, dyspnea, and 6MWD all increased significantly after surgery. The four dimensions of the CRQ used to compute QOL (dyspnea, fatigue, emotions, and self control) all improved in the same proportion after surgery. Improvements in QOL were maintained up to 12 months postoperatively and correlated best with RV and FVC changes. {Delta}SaO2 and maximum pulse rate during the 6MWD test did not change significantly after surgery.

Thoracic Dimensions:
For all thoracic dimensions measured, the effect of LV was highly significant but the interaction terms between LVRS and LV were not, thus showing comparable effects of LVRS at all LVs. The analysis, therefore was not extended to individual LV. As shown in Table 4 , none of the rib cage dimensions measured changed significantly after LVRS. By contrast, Hdi decreased significantly at 3 months and 6 months postoperatively. As a result, the relationship between Arc and Hdi was shifted to the left after surgery, a change that persisted up to 12 months postoperatively (Fig 4 ).


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  		Table 4. Effects of LVRS on Thoracic Dimensions and Diaphragm Function*

 


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  		Figure 4. Relationships between Arc and Hdi in emphysema patients before and 3, 6, and 12 months after LVRS. Data points represent group means. Mean values for all data obtained after surgery are also shown. Error bars represent the SEM. Post-op = postoperative; Pre-op = preoperative.

 
Ldi:
In the analysis of Ldi, DLI, PdiMax, and PesMax, LV and LVRS were significant cofactors. However, the interaction term between LVRS and LV was also significant, thus showing a different effect of LVRS on these variables at different LVs. When TLC measurements were removed from the model, the interaction term was no longer significant. Therefore a separate analysis was carried for TLC measurements. As seen in Table 4 , Ldi and DLI at RV and FRC increased after LVRS, being significant at 3 months and 12 months postoperatively. By contrast, Ldi and DLI at TLC did not change significantly. As a result, changes in DLI over IC and over VC increased markedly after LVRS (Fig 5 ). The changes in Ldi at FRC and RV were associated with corresponding alterations in Lzap, whereas Lvis did not vary significantly (Table 4) .



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  		Figure 5. Changes in DLI over IC and over VC before and after LVRS. Data points are emphysema group means with SE. The asterisks indicate a significant difference from control value with a p value less than 0.05.

 
Diaphragm Strength:
As seen in Table 4 , PdiMax and PesMax at TLC did not change significantly after LVRS. By contrast, PdiMax and PesMax at RV and FRC and PdiTw at FRC all increased significantly postoperatively. At 6 months and 12 months postoperatively, PdiTw at FRC and PdiMax at RV and FRC were not significantly different from corresponding values in normal subjects. By contrast, PdiMax at TLC remained significantly different from normal subjects throughout.

PdiMax vs LV and DLI:
The relationships between PdiMax and LV and between PdiMax and DLI were respectively shifted along the LV and DLI axes after LVRS, approaching those found in normal subjects at 3 months postoperatively (Fig 6 ). At 6 months and 12 months postoperatively, PdiMax at FRC and RV was seen to approach the values found in normal subjects but at a substantially higher LV and shorter DLI.



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  		Figure 6. Relationships between PdiMax and LV (top, A) or DLI (bottom, B) in normal subjects and in emphysema patients before and 3, 6, and 12 months after LVRS. Data points represent group means with SE. See Figure 4 legend for expansion of abbreviation.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Summary
 References
 
This study is the first to compare the relationships between PdiMax and LV or Ldi in emphysema patients and age-matched and sex-matched normal subjects. It is also the first investigation to show the effect of LVRS on these relationships. Our results reveal that the strength of the diaphragm is reduced in emphysema patients but returns to essentially normal values after LVRS in spite of persistent hyperinflation and shortening. PdiMax at FRC in patients in the emphysema group was greater than in normal subjects at comparable LV and Ldi, both before and after LVRS, suggesting the presence of an adaptive mechanism tending to restore diaphragm strength in patients with severe emphysema. LVRS also effected marked and sustained changes in lung and chest wall shape. Before discussing these findings, some comments regarding the methods employed are in order.

Assessment of Diaphragm Function
In this study, static inspiratory efforts were used to evaluate diaphragm strength at different LVs. As reported by Gibson et al21 and Laporta and Grassino,19 and as confirmed here, greater PdiMax values could be obtained with combined inspiratory-expulsive efforts at FRC. While the reason for this difference has been the object of much speculation, Gandevia et al22 have now shown, by rapid sequential radiography, that the greater PdiMax of the combined maneuver can be explained by elongation of the diaphragm that, under the action of the abdominal muscles, is displaced cranially. Because elongation of the diaphragm could distort the relationship between PdiMax and Ldi and between PdiMax and LV, we elected to use the simpler static inspiratory maneuver. As shown in Figure 2 , Pga swings were relatively small at all LVs in our subjects during inspiratory efforts, suggesting that abdominal muscle recruitment was also relatively small. Thus, comparisons at different LVs in the same and in different subjects should be valid.

In the present study, we did not assess the extent to which the diaphragm was maximally or submaximally activated during voluntary efforts. However, the ratio of PdiMax (61.3%) and PdiMax_comb (61.2%) at FRC in the two groups was comparable to the PdiTw ratio (67%). Because during PdiTw the level of diaphragm activation was maximal and the same in both groups, this comparison suggests that during PdiMax maneuvers the level of diaphragm activation was also the same in both groups. Because PdiTw was not recorded at TLC and RV, this comparison cannot be extended to other LVs. In what follows we assume diaphragm activation to be the same at all LVs in both groups, although we acknowledge that diaphragm activation could be reduced at volume extremes.

Several imaging techniques can be employed to measure Ldi and diaphragm shape, including MRI and spiral CT.23 The radiographic technique,18 however, is the only one that can be employed in upright subjects for comparison with PdiMax measurements. This technique was shown to provide reliable and reproducible measures of diaphragm insertions12 and Ldi.18 In this study, PdiMax and Ldi were not measured simultaneously. Therefore, uncertainties exist as to the exact relationship between these two variables. Gandevia et al22 used rapid sequential radiography to obtain simultaneous measurements of PdiMax and Ldi in two normal subjects at FRC. This is a very complex technique that involves considerably more radiation than ours, and that would preclude repeated measurements in the same subject at the same and at different LVs, as well as on different days. Furthermore, because of the limited number of attempts permitted by this technique, subjects must be highly trained in performing the required maneuvers. Although it is not possible to evaluate the error introduced by not making the measurements simultaneously, variability should have been greater and this could have prevented significant differences from being detected. Nevertheless, the fact that highly significant differences could be demonstrated between the two groups as well as in response to a surgical intervention in the same subjects suggests that, in spite of uncertainties as to the exact nature of this relationship, the comparisons shown here provide a reasonable estimate of diaphragm function in emphysema patients and of how this was modified by LVRS. Furthermore, the relationships between PdiMax and LV and between PdiMax and DLI lead to qualitatively similar conclusions. These two independent analyses thus reinforce each other as well as the conclusions derived from them.

Diaphragm Strength in Emphysema Patients
In line with other studies,24 25 we find pulmonary hyperinflation in our patients in the emphysema group to be preferentially distributed axially, forcing the diaphragm to assume a lower axial position than could be anticipated from changes in LV alone. As was suggested recently,17 these changes in chest wall configuration in emphysema patients could be explained by weight loss. We also observed that, in spite of this preferential axial distribution of air trapping, patients in the emphysema group can generate even higher PdiMax at FRC than normal subjects at the same LV. In line with Similowski et al,26 we interpret these findings as showing the presence of an adaptive mechanism tending to restore diaphragm strength of patients in the emphysema group at the prevailing LV, ie, FRC. Training hypertrophy caused by the increased work of breathing and Ldi adaptation caused by sarcomere deletion have both been postulated as possible underlying mechanisms. The present finding of a shift of the PdiMax vs DLI relationship along the DLI axis, as depicted in Figures 3 and 6 , supports Ldi adaptation as the underlying mechanism. Indeed, training hypertrophy would be expected to increase diaphragm strength at all LVs and DLIs and not only at the LV or DLI that prevail at FRC.

Ldi adaptation has been demonstrated to occur in an animal emphysema model in which the diaphragm was shown to lose 10 to 15% of its sarcomeres.27 28 By this mechanism, the muscle fibers, when tested in vitro, were able to generate their full tetanic tension at an overall shorter muscle length. Necropsy studies in humans29 30 31 32 are unanimous in showing a reduction in diaphragm muscle surface area in emphysema patients compared to normal subjects, supporting the suggestion of Ldi adaptation also in human emphysema patients. Although sarcomere deletion can best explain the striking similarity of PdiMax and of PdiTw at FRC in normal subjects and patients in the emphysema group after LVRS, in spite of persistent hyperinflation and shortening of the diaphragm in patients in the emphysema group, it cannot explain the lower PdiMax and PdiTw found in patients in the emphysema group before surgery and, hence, the striking changes seen after LVRS. Thus, other factors must contribute.

Several neural and systemic factors could reduce diaphragm strength independently of Ldi adaptation, including decreased voluntary drive, malnutrition, disturbances in blood gas tension, electrolytes, or minerals, and a lower mechanical advantage of the diaphragm. Neural factors can probably be discarded on the basis of our findings of proportionate reductions in PdiMax and PdiTw in patients in the emphysema group and of proportionate gains after LVRS. Body weight and arterial blood gas composition did not change in the subgroup of patients who underwent LVRS. Thus, malnutrition, hypoxemia, or hypercapnia can also probably be discarded, as these factors clearly cannot explain the improvement of PdiMax and PdiTw after surgery. Serum electrolytes and minerals were not measured and, therefore, cannot be ruled out. The mechanical advantage of the diaphragm is determined by the shape of its dome8 and possibly by the mechanical coupling between its crural and costal parts.33 In our study, the shape factors, Kdome_AP and Kdome_LA, were both significantly smaller in patients in the emphysema group than in normal subjects at their respective LVs, and decreased with increasing LV in patients in the emphysema group. A decreased Kdome implies an increase in the radius of curvature of the diaphragm and, according to Laplace’s law, predicts a smaller Pdi for any given muscular tension. While this mechanism could explain the smaller PdiMax values found in patients in the emphysema group at a given LV or Ldi, it cannot explain the marked improvement in diaphragm strength observed after LVRS, as the Kdome values did not change significantly after surgery. On theoretical grounds,33 a change from parallel to in-series mechanical coupling of the costal and crural parts of the diaphragm with increasing LV could reduce PdiMax, but direct evidence in favor of this mechanism is lacking.

Alternatively, there could be a limit to the extent to which the diaphragm can adapt its length by losing sarcomeres. In the cat, the soleus muscle can lose up to 40% of its sarcomeres when the hind limb is immobilized in full plantarflexion,34 but in emphysematous hamsters, the diaphragm was shown to lose only about 10 to 15% of its sarcomeres.27 28 The in situ shortening of the diaphragm in this animal model is unknown. However, because the changes in FRC in this animal model (180%)28 is comparable to that of our patients in the emphysema group (178%), the amount of in situ shortening should also be comparable. To estimate the fractional shortening of the diaphragm using our technique, the length of the central tendon must be subtracted from DLI measurements. From the data of Braun et al,18 25% of the total resting Ldi is occupied by the central tendon. In upright normal subjects at FRC, the diaphragm is not passively tensed, and its in situ length (27.1 cm/m)12 is almost identical to the excised resting length (26.7 cm/m).18 Thus, approximately 25% of that length (6.8 cm/m) should be tendon. Subtracting this tendon length from the measured lengths in Table 3 , diaphragm muscle length at FRC in patients in the emphysema group can be estimated to be about 26.5% shorter than in normal subjects at FRC. This is approximately twice as much as the chronic shortening produced by sarcomere deletion in the hamster emphysema model, and also twice as much as the amount of chronic shortening reported for human emphysema patients at necropsy by Arora and Rochester.32 Shortening in excess of the capacity of the diaphragm to adapt its length by deleting sarcomeres could thus explain our finding of partial PdiMax and PdiTw compensation in patients in the emphysema group. In the subset of emphysema patients who underwent LVRS, diaphragm muscle length at FRC calculated this way was on average 10.3% shorter than in normal subjects. This amount of shortening is compatible with the sarcomere deletion demonstrated in the hamster emphysema model and with the chronic shortening found in human emphysema patients at necropsy. Thus, the striking changes in PdiMax and PdiTw that we found after LVRS could be explained by diaphragm elongation to a length just compatible with full compensation by sarcomere deletion. Lahgi et al6 were also impressed by the marked improvements in PdiMax (37%) and PdiTw (51%) at FRC in relation to LV reduction (10%) 3 months after LVRS, which they attributed to diaphragm reconditioning. However, the mechanism proposed here seems more likely.

While sarcomere deletion could restore diaphragm strength at FRC, it does so by shifting PdiMax vs Ldi and PdiMax vs LV relationships along the Ldi and LV axes. As a result of this shift, changes of PdiMax at volume extremes, ie, at active TLC and active RV, are small. This has important implications, not only for respiratory muscle function testing, but also for LVRS. Fessler and Permutt35 were the first to relate the reductions in maximum expiratory flow rates in emphysema patients to a mismatch between the size of the lungs and the size of the chest wall as reflected by the elevated RV to TLC ratio. According to their model, resizing of the lungs by LVRS would reduce the mismatch and in this way increase maximum expiratory flow and FEV1. The key feature of their analysis is the expected rise in maximum inspiratory muscle pressure at TLC after LVRS. This increased expanding muscle force would augment FVC and lung recoil at TLC and FEV1 in a proportionate manner. However, contrary to these expectations, inspiratory muscle pressure, as reflected by PdiMax and PesMax at active TLC, did not increase significantly after LVRS. Therefore, changes in maximum lung recoil at TLC should have been small and should explain the relatively small changes in FEV1 that we observed. Static deflation pressure-volume curves of the lungs were not recorded in our study, but in a recent investigation by Ingenito et al,36 maximum lung recoil at TLC increased on average from 9.2 to 11.3 cm H2O. These changes in lung recoil are indeed small, and certainly much less than could have been anticipated on the basis of the change in LV alone. By interpolation of the relationship between PdiMax and LV obtained preoperatively (Fig 6 , top, A), PdiMax at active TLC should have increased from a value of approximately 14 cm H2O before LVRS to approximately 70 cm H2O at 3 months, 50 cm H2O at 6 months, and approximately 30 cm H2O at 12 months after LVRS. Instead, PdiMax remained at approximately 15 cm H2O throughout. We attribute this finding to adaptation of the inspiratory muscles to their new operating length at FRC, an adaptation that optimizes force generation at that length but not at shorter lengths. The consequence of this is that FVC and FEV1 did not increase as much as could have been anticipated on the basis of the preoperative PdiMax vs LV relationship.

Therefore, it was of interest to determine how the changes in FVC in our study compared with others. This is shown in Figure 7 , in which FVC and FEV1 from 11 previous investigations5 6 37 38 39 40 41 42 43 44 45 and from the present study are plotted against the RV/TLC ratio. As predicted by Fessler and Permutt,35 FVC was negatively correlated to the RV/TLC ratio (analysis of covariance [ANCOVA], p < 0.002). ANCOVA showed these relationships to be not significantly different before and after LVRS. Thus, in previous studies, as in the present study, changes in FVC could also have been limited by the same mechanisms. As predicted by the model, FEV1 was also significantly and negatively correlated with the RV/TLC ratio. However, contrary to model predictions, in these previous studies the relationship was shifted upward in a nearly parallel fashion after LVRS, showing an additive effect on FEV1. ANCOVA revealed this shift to be significant (p < 0.025). By contrast, in the present investigation, FEV1 appeared to follow the same relationship before and after LVRS. Thus, in our study, the decrease in the degree of mismatch and the consequent increase in FVC were solely responsible for the rise in FEV1 after LVRS, whereas in previous investigations,5 6 37 38 39 40 41 42 43 44 45 another factor contributed. In these studies, the FEV1/FVC ratio increased in the same proportion as FVC, whereas in our investigation, it did not increase or even decrease at 6 months and 12 months postoperatively. The reason for this difference is unclear. It is of interest that two studies4 36 reported no change in the FEV1/FVC ratio after LVRS. Unfortunately, RV and TLC were not reported in these two studies so that no further comparisons could be made. Nevertheless, these studies and ours suggest that the increase in FVC is a major determinant of the extent to which FEV1 can rise after LVRS. However, as our results also show, adaptive mechanisms at the muscular level (or perhaps centrally and affecting their neural control) appear to limit the extent to which FVC can increase after LVRS. It would be of interest to determine whether this limitation can be overcome by other forms of adaptation such as those that can be produced by training. Neural mechanisms could also explain the delayed increase of PdiMax in relation to PdiTw after LVRS.



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  		Figure 7. Relationships between FVC (top, A) or FEV1 (bottom, B) and the ratio between RV and TLC in emphysema patients before (closed symbols) and after (open symbols) LVRS. Circles refer to group mean values as reported.5 6 37 38 39 40 41 42 43 44 45 Linear regression lines before LVRS (continuous lines) and after LVRS (dashed line) are drawn through each of these data sets. Triangles refer to individual values in the six patients of the present investigation. See Figure 4 legend for expansion of abbreviations.

 
A striking feature of LVRS in the present study was the leftward shift of the Arc vs Hdi relationship. Theoretically, a leftward shift of this relationship could be caused by abdominal muscle recruitment. However, no evidence could be found in favor of this hypothesis. Indeed, Pga during inspirations to TLC (4.26 ± 10.01 cm H2O vs 5.46 ± 9.31 cm H2O) and during expirations to RV (51.36 ± 38.77 cm H2O vs 55.43 ± 32.25 cm H2O), a measure reflecting abdominal muscle recruitment, did not differ significantly before and after LVRS. Alternatively, remodeling of the lungs by LVRS could have altered the distribution of stresses within the lungs and, hence, the distribution of pleural surface pressure. Indeed, because LVRS principally involves resection of the apical parts of the lungs, axial stress could have increased more than radial stress, thereby causing preferential axial displacement of the diaphragm while maintaining radial dimensions relatively unchanged. Additional studies would be required to test this possibility and to evaluate the effect this change in chest wall configuration may have on pleural surface pressure and maximum expiratory flow.

Subjective benefits have been reported to occur in a majority of emphysema patients after LVRS. These include a reduction in the sensation of dyspnea during daily living, improved exercise tolerance and better QOL.3 4 5 6 Improvements in lung mechanics3 4 and in the function of the inspiratory muscles5 6 are the two mechanisms most commonly invoked to explain these findings. In our study, changes in QOL, dyspnea, and exercise tolerance were better correlated with changes in RV and FVC than with changes in lung mechanics, such as FEV1 and Raw. The improvements in RV and FVC were mostly attributable to diaphragm displacements. Therefore, improvements in diaphragm function after LVRS appear to have played a dominant role in the subjective improvements reported by these patients after surgery. It is of particular interest that all four dimensions of the CRQ improved to the same extent after LVRS, suggesting that diaphragm dysfunction in patients with severe emphysema impinges on all aspects of their living, and that improving this function should be a valuable clinical objective.


   Summary
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Summary
References
 
In summary, this study has shown that adaptive mechanisms tend to restore diaphragm strength of emphysema patients at their usual operating LV, ie, FRC, but not at TLC. These adaptive mechanisms were fully expressed after LVRS, which restored the strength-generating capacity of the diaphragm at FRC to normal. Our observations are compatible with an adaptation of Ldi by sarcomere deletion. This mechanism appears to be limited and more effective at moderate degrees of pulmonary hyperinflation, such as seen after LVRS. At the highest degree of pulmonary hyperinflation and shortening encountered in this study, adaptation was incomplete. LVRS also effected a change in axial position of the diaphragm within the thorax but no change in radial dimensions of the rib cage. These changes in chest wall configuration are possibly related to a redistribution of stresses within the lungs caused by LVRS. Ldi adaptation at FRC and, possibly, nonuniform stress distribution within the lungs could limit the extent to which FVC and FEV1 can increase after LVRS. The decrease in FVC and FEV1 in our patients in the emphysema group as well as the changes in FVC and FEV1 after LVRS are consistent with a model of functional restriction by the chest wall.


   Footnotes
 
Abbreviations: ANCOVA = analysis of covariance; ANOVA = analysis of variance; APrc = average anteroposterior diameter of the rib cage from posterior chest wall; APrc_v = average anteroposterior diameter of the rib cage with the anterior aspect of the vertebrae as the posterior limit; Arc = average internal rib cage cross-section area; CRQ = chronic respiratory questionnaire; {Delta}SaO2 = oxygen desaturation during exercise; DLCO = single-breath lung diffusing capacity for carbon monoxide; DLI = diaphragm length index; FRC = functional residual capacity; Hdi = average height of diaphragm dome; IC = inspiratory capacity; Kdome = shape factor for the diaphragm dome; Kdome_AP = shape factor for the diaphragm dome on anteroposterior radiographs; Kdome_LA = shape factor for the diaphragm dome on lateral chest roentgenograms; LArc = average rib cage lateral diameter; Ldi = diaphragm length; LV = lung volume; Lvis = length of visible contours of the diaphragm; LVRS = lung volume reduction surgery; Lzap = length of the diaphragm in the zone of apposition with the rib cage; PdiMax = maximal transdiaphragmatic pressure during static inspiratory efforts; PdiMax_comb = maximal transdiaphragmatic pressure during combined inspiratory-expulsive efforts; PdiTw = transdiaphragmatic pressure during supramaximal bilateral phrenic nerve twitch stimulation; Pes = esophageal pressure; PesMax = maximal esophageal pressure during static inspiratory efforts; PesMax_comb = maximal esophageal pressure during combined inspiratory-expulsive efforts; Pga = gastric pressure; QOL = quality of life; Raw = airway resistance; RV = residual volume; 6MWD = 6-min walking distance; TLC = total lung capacity; VC = vital capacity

This study was supported by Canadian Institutes of Health Research grants MA12275 and MT14730.

Received for publication July 12, 2001. Accepted for publication December 5, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Summary
 References
 

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