Diaphragm Length and Neural Drive after Lung Volume Reduction Surgery
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《美国呼吸和危急护理医学》
Prince of Wales Medical Research Institute and University of New South Wales, Sydney, Australia
ABSTRACT
Rationale: Patients with chronic obstructive pulmonary disease have shorter inspiratory muscles and higher motor unit firing rates during quiet breathing than do age-matched healthy subjects. Lung volume reduction surgery (LVRS) in patients with chronic obstructive pulmonary disease improves lung function, exercise capacity, and quality of life.
Objectives: We studied the effect of LVRS on length and motor unit firing rates of diaphragm and scalene muscles.
Methods: Diaphragm length was estimated by ultrasound and magnetometers, and firing rates were recorded with needle electrodes in patients (five females and seven males) with severe chronic obstructive pulmonary disease, before and after surgery.
Measurements and Main Results: Pre-LVRS total lung capacity was 135 ± 10% predicted (mean ± SD), and FEV1 was 30 ± 12% predicted. After surgery, median firing frequency of diaphragmatic motor units fell from 17.3 ± 4.2 to 14.5 ± 3.4 Hz (p < 0.001), and scalene motor unit firing rates were reduced from 15.3 ± 6.9 to 13.4 ± 3.8 Hz (p < 0.001). Tidal volume and diaphragm length change during quiet breathing did not change, but at end expiration, the zone of apposition length of diaphragm against the rib cage (LZapp) increased (30 ± 28%, p = 0.004). Improvements in quality-of-life measures and exercise performance after surgery were related to increased forced vital capacity and LZapp.
Conclusions: Increased diaphragm length resulted in lower motor unit firing rates and reduced breathing effort, and this is likely to contribute to improved quality of life and exercise performance after LVRS.
Key Words: chronic obstructive pulmonary disease electromyography emphysema pneumonectomy ultrasound
Inspiratory muscles of patients with chronic obstructive pulmonary disease (COPD) operate under an increased load and at shorter length than in healthy subjects (1–3), and neural drive to the inspiratory muscles is also increased (4–6). This increased neural drive allows the diaphragm in COPD to shorten and descend normally during quiet breathing (7, 8), although there is a greatly reduced reserve capacity to increase tidal volume (VT).
Lung volume reduction surgery (LVRS) is used to treat patients with severe emphysema to reduce hyperinflation by removing up to 30% of the worst affected pulmonary areas (9, 10). After LVRS, lung function, exercise performance, and measures of quality of life improve (11–13). These improvements have been attributed to increased vital capacity (VC) (14, 15) and increased lung elastic recoil (16).
Improvements in diaphragm function may also contribute to the functional improvement after LVRS (17). Diaphragm length is increased after LVRS (18–20), resulting in increased maximal transdiaphragmatic pressures (20, 21). The transdiaphragmatic pressure required to generate a given VT is decreased after LVRS (21). During inspiratory threshold loading to task failure, the relative increase in neural drive to the diaphragm, assessed by esophageal EMG, is decreased after LVRS (22).
To assess the mechanisms by which LVRS improves exercise performance and quality of life in patients with COPD, we measured changes in diaphragm length and inspiratory neural drive in patients before and after LVRS. Diaphragm length was estimated by ultrasound at fixed lung volumes and during breathing (8). Neural drive was determined from single motor unit firing rates during quiet breathing (4, 5, 23). Some data from this study have been previously presented as abstracts (24, 25).
METHODS
Patients and Protocol
Twelve patients (five females and seven males) with severe COPD were studied before and after LVRS. Patient anthropometric and lung function data are listed in Table 1. Most patients (10 of 12) had completed preoperative pulmonary rehabilitation. All patients received bilateral video-assisted thoracoscopic LVRS. Patients provided written, informed consent to the procedures, which were approved by the institutional ethics committee.
Ultrasound and EMG studies were performed on the same day except for one subject with 4 wk between studies. Subjects were seated and given no instructions on breathing strategies or feedback on performance. In separate sessions the patients received standard lung function tests, a cardiopulmonary exercise test, and a 6-min walk test, including 10-point Borg scales for dyspnea and exertion, and they completed a quality-of-life (QOL) questionnaire focused on chronic respiratory diseases (26). The QOL scores quantified feelings of dyspnea, fatigue, emotional function, and mastery. We report the dyspnea score and the average, with a maximum score of 35 for best function. After LVRS (14 ± 6 mo), the ultrasound and EMG studies were repeated. The lung function tests, exercise test, 6-min walk test, and QOL questionnaire were repeated after 10 ± 4 mo.
Measurement of Neural Drive
Single motor unit activity in the diaphragm and scalenes was recorded with monopolar electrodes, using methods reported previously (4, 5, 23). The diaphragm electrode was inserted at the ventral end of the seventh or eighth intercostal space. The scalene electrode was inserted 1–2 cm above the clavicle in the posterior triangle of the neck. At each of 10 sites in each muscle, about five quiet breaths were recorded and motor units were subsequently sorted on the basis of spike shape (Figure 1). The instantaneous firing frequency of each unit was smoothed with a 200-ms moving average and the peak was measured for each breath. Rib cage and abdominal movement were measured with inductance bands, and VT was measured with a pneumotachograph.
Measurement of Zone of Apposition and Chest Diameters
We measured the length of the zone of apposition of the diaphragm against the chest wall (LZapp), using our previously described method (8). In brief, diaphragm movement was visualized by ultrasound (120-mm linear probe) just anterior to the right midaxillary line. The costal origin of the diaphragm was identified when the patient breathed to total lung capacity (TLC), where LZapp approaches zero with active inspiration (8). The distance between the costal origin of the diaphragm and the point where the diaphragm peeled away from the chest wall (costal recess) was measured to give LZapp at any lung volume or time point (± 1 mm). The change in LZapp with quiet breathing was measured over 5–10 breaths, LZapp was measured at FRC and residual volume (RV), and measurements were repeated several times. The thickness of the diaphragm and its depth under the skin at FRC were measured midway between the origin and costal recess (± 0.5 mm; 50-mm linear probe).
The anteroposterior diameter (sagittal plane, DAp) and lateral diameter (coronal plane, DLat) of the chest wall were measured with magnetometers taped to the skin at approximately the level of the diaphragm at FRC (8), and the signals were adjusted for diaphragm depth. Length of the diaphragm (LDi) in the midaxillary coronal plane was estimated from measurements of LZapp and DLat, using an equation validated for patients with COPD (8, 27, 28).
Statistics
Firing rate of all motor units was compared before and after LVRS by analysis of variance with "subject," "muscle," and "surgery" (pre- or post-LVRS) as main effects. All other measurements were compared before and after LVRS with paired t tests. Linear mixed model analysis (SPSS version 11; SPSS Inc., Chicago, IL) with "surgery" as a repeated effect within subjects was used to investigate linear relationships between measurements and changes after surgery. Pearson correlation coefficients and linear regression analyses were used to investigate relationships between changes in measurements after LVRS. Not all patients had a complete dataset, so most comparisons contained data from 10 or 11 patients. Data are presented as means ± SD and significance was set at p < 0.05.
RESULTS
Lung Function
After LVRS, there were significant changes in lung function among patients with COPD (Table 2). TLC, RV, and RV/TLC were reduced in 11 of 11 patients to 88 ± 4% of TLC presurgery and to 75 ± 9% of RV presurgery, and were reduced by 10 ± 6% from RV/TLC presurgery. FVC increased in 8 of 12 patients and the average increase for all patients was 12 ± 16% of FVC presurgery. In 8 of 12 patients FEV1 increased, but the average increase for all patients was not significant (21 ± 29% of FEV1 presurgery). There was a significant negative relationship between RV/TLC and FEV1 (percentage of predicted value) before and after surgery (Figure 2A). A mixed model analysis (see METHODS) showed no significant effect of surgery on the slope of this relationship, but showed a significant effect on the intercept (p = 0.004). The relationship was shifted to the left after surgery, so that the increase in FEV1 was not as great as expected given the reduction in RV/TLC.
Diaphragm and Rib Cage Dimensions
At FRC, the LZapp increased by 30 ± 28% after LVRS (p = 0.004; Table 2), and total LDi increased slightly (5 ± 6%; p = 0.023). At RV, there were nonsignificant increases in LZapp (20 ± 27%; p = 0.059) and LDi (4 ± 7%; p = 0.091). LDi at TLC did not change significantly. The small increase in LDi at FRC reflected the substantial increase in LZapp (11 mm), countered by a slight reduction in the lateral diameter of the rib cage (DLat) at FRC (5 ± 13 mm, p = 0.238). At TLC, FRC, and RV both the anteroposterior diameter of the rib cage (DAp) and DLat decreased slightly after LVRS, but these changes were not significant. The calculated cross-sectional area of the rib cage (8) was slightly decreased (96, 94, and 94% of presurgery values for TLC, FRC, and RV, respectively; p = 0.19, 0.08, and 0.08). There was a significant relationship between LZapp at FRC and RV/TLC (Figure 2B), but no difference in the relationship before and after LVRS. The negative relationship between LDi and lung volume relative to predicted TLC (Figure 3) did not change slope, but was shifted to the left after LVRS (p < 0.001), so that for a given lung volume LDi was reduced (8).
VT during quiet breathing did not change significantly after LVRS. Similarly, there was no significant change in LZapp during quiet breathing. However, during quiet breathing there was increased inspiratory reserve for diaphragm shortening because LZapp at end inspiration increased by 12 ± 9 mm (p = 0.001) and LDi increased by 6 ± 6% (p = 0.006; Table 2). Before LVRS, seven patients showed paradoxical inward motion of the lateral rib cage during quiet breathing (DLat < 0; Hoover's sign) (29), but after LVRS, only four patients exhibited Hoover's sign. After LVRS, expansion of the lateral rib cage during quiet breathing was significantly increased (DLat increased by 1.2 ± 1.6 mm; p = 0.038). The small decrease in DAp during tidal breathing after LVRS (1.6 ± 3.5 mm; p = 0.164) was not significant.
Motor Unit Firing Rates
Measurements were made from 110 motor units in the diaphragm before LVRS and from 227 after LVRS (Figure 4). The firing frequency of diaphragmatic motor units (FDi) during quiet breathing was reduced after LVRS in 9 of 11 patients with COPD, with an average for all patients of 87 ± 23% of FDi before surgery (p < 0.001; Table 2 and Figure 4). In the scalenes 203 motor units were measured before surgery and 223 were measured after surgery (Figure 4). The firing frequency of scalene motor units (FScal) was slightly decreased after LVRS (98 ± 35% of pre-LVRS, p < 0.001; Table 2), but only 6 of 11 patients had a decrease in firing rate. FDi was significantly greater than FScal both before and after surgery (p < 0.001). The analysis of variance revealed significant effects due to "subject," "muscle," and "surgery," as well as significant interactions between these effects. The effect of LVRS on motor unit firing rate depended on the muscle and the subject. Figure 5 shows that for both muscles the change in motor unit firing rate after LVRS was linearly related to firing rate before surgery, so that the change was greater for those subjects with high firing rates pre-LVRS (diaphragm: R2 = 0.44, p = 0.025; scalenes: R2 = 0.71, p = 0.001). The proportion of volume change measured at the rib cage increased from 56 ± 9% of tidal volume before surgery to 69 ± 9% afterward (p = 0.006).
Blood Gases, Exercise, and Quality of Life
There were no significant changes in blood gas concentrations after LVRS (Table 2). The 6-min walk distance was greater in 10 of 12 patients, but this change was not significant (114 ± 22% of presurgery values; p = 0.058). However, the Borg scores for exertion and dyspnea during the 6-minute walk test declined after LVRS (by 1.3 ± 1.1, p = 0.002 and 1.2 ± 1.6, p = 0.032, respectively). There was an increase in distance walked during the cardiopulmonary exercise test in 8 of 12 patients (mean increase for all patients, 220 ± 226%; p = 0.012). After LVRS, there was also a significant increase of 10 ± 7 (p < 0.001) in QOL scores related to dyspnea and of 8 ± 6 (p = 0.002) for the average QOL scores (Table 2).
Correlations
There was a significant negative relationship between FDi and LZapp at end inspiration before and after LVRS (Figure 6). After surgery, the increase in LZapp was associated with a decrease in FDi, such that the relationship did not change. The 6-min walk distance was positively correlated with DLat during quiet breathing (p < 0.001; Figure 7), with Hoover's sign (negative DLat) more prominent in patients with a shorter 6-min walk distance. After surgery, the relationship did not change and the increase in DLat was associated with increased 6-min walk distance.
The variable outcomes of the surgery are illustrated in Figure 8. Although the increase in 6-min walk distance after LVRS was not significant (p = 0.058), it was positively corre- lated with the increase in QOL score for dyspnea (p = 0.012; Figure 8A). Increased 6-min walk distance after surgery also correlated with increased FVC (p = 0.005; Figure 8B). In addition, the increase in LZapp at FRC was linearly related to increased FVC after LVRS (p = 0.023; Figure 8C). In summary, the increase in FVC after surgery was the best predictor for the increase in LZapp at FRC and the 6-min walk distance. In turn, patients with greater increases in 6-min walk distance reported greater increases in their QOL score for dyspnea.
The patients with the greatest hyperinflation had the largest decrease in TLC after surgery (p = 0.015; Figure 9A). Similarly, those patients with lowest QOL scores for dyspnea had the greatest increase in QOL score after surgery (p = 0.014; Figure 9B).
DISCUSSION
In the present study, diaphragm dimensions and neural drive were examined in 12 patients with severe emphysema and COPD before and after LVRS, which reduced TLC by an average of 12%. After LVRS, there was a significant increase in the LDi and the LZapp at FRC and RV. Tidal changes in LDi and LZapp during quiet breathing were not different after LVRS, so that LZapp at end inspiration was increased, providing a greater reserve capacity for diaphragm shortening (8).
After LVRS, the firing rate of motor units in the costal diaphragm (FDi) during quiet breathing decreased, despite no change in VT or tidal movement of the diaphragm, consistent with a net reduction in neural drive. FScal during quiet breathing was also decreased after LVRS. However, in both the diaphragm and scalenes, the reduction in firing rate was most apparent in patients with high firing rates before surgery. The firing rate of motor units in the diaphragm was greater than that in the scalenes, which is consistent with our previous findings in healthy subjects when inspiratory drive is increased (23) and in patients with COPD compared with control subjects (4, 5).
The firing rates for diaphragm motor units in the present study before LVRS are similar to those reported in patients with COPD in previous studies using the same methods (17 vs. 18 Hz, respectively) (4), but the scalene firing rates were greater in the present study (15 vs. 11 Hz, respectively) (5). By comparison, in healthy subjects in whom inspiratory drive is increased threefold, the motor unit firing rates averaged 18 Hz in the diaphragm and 10 Hz in scalenes (23). After LVRS, the firing rates of motor units in the patients with COPD fell to 15 Hz for the diaphragm and 13 Hz for the scalenes, still greater than those of age-matched control subjects in the previous studies (11 and 9 Hz, respectively) (4, 5). Motor unit firing rate is unaffected by changes in recording conditions (30) and is therefore a more reliable measure of neural drive than surface EMG. However, the present results are still consistent with previous findings that during inspiratory threshold loading, diaphragm EMG from esophageal electrodes was reduced after LVRS (22).
Previous studies have measured LDi and LZapp in patients with COPD (2, 3, 27, 31, 32). The values measured in the present study largely agree with the previous studies, given methodologic differences related to identification of the diaphragm origin, posture, and muscle contraction (see also Reference 8). For comparison, LDi and LZapp at FRC were 456 and 71 mm, respectively, in matched healthy subjects, compared with 381 and 35 mm in patients with COPD (8), and 379 and 40 mm in the present study before surgery. In other studies of diaphragm dimensions after LVRS, similar results were found by Bellemare and colleagues (20), but Lando and colleagues (19) reported a small increase in LDi at TLC, unlike the present study in which LDi increased only at FRC and RV after LVRS. The tidal change in LZapp during quiet breathing (LZapp) was similar to that in our previous study (8), with average values unchanged after LVRS (only one patient participated in both studies). After LVRS, LZapp and LDi at FRC and end inspiration approached, but did not reach, values for control subjects (8).
Some tests were conducted on different days, so there is a potential source of variability in the relationships between measurements. Diaphragm mechanics and neural drive were measured about 4 mo after the other post-LVRS measurements and this may have reduced the ability to find statistically significant correlations between the variables measured. We attempted to reduce measurement errors with multiple motor units measured for each person, and with ultrasound and chest diameter measurements averaged over a number of breaths or maneuvers.
The improvement in lung volume, exercise performance, and QOL found in these patients with COPD was related to their presurgical status. In general, patients with more severe disease before surgery improved the most after LVRS. This was consistent with the findings of Fessler and coworkers (33) that the more severely affected patients with the largest RV/TLC ratio exhibited the biggest changes in FVC after surgery. The change in VC has been considered the main determinant of improvement in FEV1 (15, 34). It is likely that the patients with the greatest hyperinflation had more diseased lung removed and this would also help account for the relationships between pre- and postsurgical measurements (35).
This study was conducted on the earliest patients in the LVRS program in one hospital, so with changes in criteria for LVRS, the outcomes of surgery for these patients may not reflect current outcomes. The improvement in FEV1 and other measures of lung function and in exercise capacity were less than often reported (40–80% increase in FEV1) (10, 36), but in agreement with a large randomized trial ( 21% in FEV1 at 12 mo postsurgery) (37). The long period between pre- and postsurgical observations (up to 30 mo) also contributed to the lack of significant improvement in FEV1, which after the initial increase post-LVRS declines at a relatively fast rate in the first 1–2 yr and then declines at a rate similar to presurgical values (35, 38, 39). The lack of significant change in FEV1 and its variability may have mitigated against finding significant changes in other measures of lung and respiratory function and exercise performance. However, with this sample we have a large range in the changes resulting from LVRS, which may have increased the likelihood of finding relationships between measures of lung function, diaphragm function, exercise capacity, and quality of life.
A further limitation of this study was that we did not study the effect of preoperative pulmonary rehabilitation on inspiratory muscle firing rates and diaphragm mechanics. Nevertheless, pulmonary rehabilitation may improve exercise capacity and quality of life measures, but it has no effect on pulmonary function (34).
At a given LDi, absolute lung volume was decreased after surgery (Figure 3) suggesting that rib cage volume had also decreased (8), although the cross-sectional area of the lower rib cage was not significantly decreased. The firing rate of diaphragmatic motor units during quiet breathing decreased after LVRS, probably because the diaphragm was operating at a longer length. The length–tension relationship of the diaphragm is shifted in patients with COPD compared with normal subjects and there is evidence that after LVRS, the relationship returns toward that for healthy subjects (20, 21, 40). Patients with COPD have chronic adaptations of the diaphragm, with reduced length and/or number of sarcomeres in series (41), and changes in fiber type composition (42, 43). After LVRS, the rat diaphragm undergoes remodeling, increasing the number of sarcomeres in series (44). Other changes post-LVRS may also contribute to a reduced load on the diaphragm, such as decreased intrinsic positive end-expiratory pressure (45), resulting in reduced neural drive.
The patients with COPD significantly improved in QOL and distance walked in the exercise test after LVRS. The improvement in QOL scores for dyspnea correlated best with increases in 6-min walk distance, which in turn was best predicted by the increase in FVC after surgery. The patients in whom FVC increased the most after surgery also had the greatest increase in LZapp at FRC. In addition, the decrease in firing rate of diaphragm motor units was related to the increase in LZapp at end inspiration after surgery. The data suggest that after LVRS, improvements in quality of life and exercise performance are associated with improvements in diaphragm function, with reduced neural drive, and increased reserve capacity for shortening. Improvements in diaphragm function are a result of improved lung volumes. Other studies have shown that increased end-expiratory volume or reduced inspiratory capacity are the best predictors for increased breathing discomfort in patients with COPD (46, 47). In the present patients, the reduction in QOL scores for dyspnea after LVRS may, therefore, be a result of improved diaphragm function with reduced lung volume.
This study has confirmed previous reports that patients with COPD have shortened diaphragms and reduced zones of apposition against their rib cages, requiring high firing rates in diaphragm and scalene motor units. We report for the first time that patients with COPD have reduced firing rates of motor units in the diaphragm and scalenes after LVRS. This reduction in neural drive was accompanied by an increase in LDi and LZapp. This improved diaphragm function is likely to contribute to improved quality of life after surgery, especially in dyspnea and exercise capacity.
FOOTNOTES
Supported by funds from the Asthma Foundation of NSW and the National Health and Medical Research Council of Australia. J. F. T. was a Boehringer Ingelheim Research Fellow of the Australian Lung Foundation.
Originally Published in Press as DOI: 10.1164/rccm.200412-1695OC on August 18, 2005
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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ABSTRACT
Rationale: Patients with chronic obstructive pulmonary disease have shorter inspiratory muscles and higher motor unit firing rates during quiet breathing than do age-matched healthy subjects. Lung volume reduction surgery (LVRS) in patients with chronic obstructive pulmonary disease improves lung function, exercise capacity, and quality of life.
Objectives: We studied the effect of LVRS on length and motor unit firing rates of diaphragm and scalene muscles.
Methods: Diaphragm length was estimated by ultrasound and magnetometers, and firing rates were recorded with needle electrodes in patients (five females and seven males) with severe chronic obstructive pulmonary disease, before and after surgery.
Measurements and Main Results: Pre-LVRS total lung capacity was 135 ± 10% predicted (mean ± SD), and FEV1 was 30 ± 12% predicted. After surgery, median firing frequency of diaphragmatic motor units fell from 17.3 ± 4.2 to 14.5 ± 3.4 Hz (p < 0.001), and scalene motor unit firing rates were reduced from 15.3 ± 6.9 to 13.4 ± 3.8 Hz (p < 0.001). Tidal volume and diaphragm length change during quiet breathing did not change, but at end expiration, the zone of apposition length of diaphragm against the rib cage (LZapp) increased (30 ± 28%, p = 0.004). Improvements in quality-of-life measures and exercise performance after surgery were related to increased forced vital capacity and LZapp.
Conclusions: Increased diaphragm length resulted in lower motor unit firing rates and reduced breathing effort, and this is likely to contribute to improved quality of life and exercise performance after LVRS.
Key Words: chronic obstructive pulmonary disease electromyography emphysema pneumonectomy ultrasound
Inspiratory muscles of patients with chronic obstructive pulmonary disease (COPD) operate under an increased load and at shorter length than in healthy subjects (1–3), and neural drive to the inspiratory muscles is also increased (4–6). This increased neural drive allows the diaphragm in COPD to shorten and descend normally during quiet breathing (7, 8), although there is a greatly reduced reserve capacity to increase tidal volume (VT).
Lung volume reduction surgery (LVRS) is used to treat patients with severe emphysema to reduce hyperinflation by removing up to 30% of the worst affected pulmonary areas (9, 10). After LVRS, lung function, exercise performance, and measures of quality of life improve (11–13). These improvements have been attributed to increased vital capacity (VC) (14, 15) and increased lung elastic recoil (16).
Improvements in diaphragm function may also contribute to the functional improvement after LVRS (17). Diaphragm length is increased after LVRS (18–20), resulting in increased maximal transdiaphragmatic pressures (20, 21). The transdiaphragmatic pressure required to generate a given VT is decreased after LVRS (21). During inspiratory threshold loading to task failure, the relative increase in neural drive to the diaphragm, assessed by esophageal EMG, is decreased after LVRS (22).
To assess the mechanisms by which LVRS improves exercise performance and quality of life in patients with COPD, we measured changes in diaphragm length and inspiratory neural drive in patients before and after LVRS. Diaphragm length was estimated by ultrasound at fixed lung volumes and during breathing (8). Neural drive was determined from single motor unit firing rates during quiet breathing (4, 5, 23). Some data from this study have been previously presented as abstracts (24, 25).
METHODS
Patients and Protocol
Twelve patients (five females and seven males) with severe COPD were studied before and after LVRS. Patient anthropometric and lung function data are listed in Table 1. Most patients (10 of 12) had completed preoperative pulmonary rehabilitation. All patients received bilateral video-assisted thoracoscopic LVRS. Patients provided written, informed consent to the procedures, which were approved by the institutional ethics committee.
Ultrasound and EMG studies were performed on the same day except for one subject with 4 wk between studies. Subjects were seated and given no instructions on breathing strategies or feedback on performance. In separate sessions the patients received standard lung function tests, a cardiopulmonary exercise test, and a 6-min walk test, including 10-point Borg scales for dyspnea and exertion, and they completed a quality-of-life (QOL) questionnaire focused on chronic respiratory diseases (26). The QOL scores quantified feelings of dyspnea, fatigue, emotional function, and mastery. We report the dyspnea score and the average, with a maximum score of 35 for best function. After LVRS (14 ± 6 mo), the ultrasound and EMG studies were repeated. The lung function tests, exercise test, 6-min walk test, and QOL questionnaire were repeated after 10 ± 4 mo.
Measurement of Neural Drive
Single motor unit activity in the diaphragm and scalenes was recorded with monopolar electrodes, using methods reported previously (4, 5, 23). The diaphragm electrode was inserted at the ventral end of the seventh or eighth intercostal space. The scalene electrode was inserted 1–2 cm above the clavicle in the posterior triangle of the neck. At each of 10 sites in each muscle, about five quiet breaths were recorded and motor units were subsequently sorted on the basis of spike shape (Figure 1). The instantaneous firing frequency of each unit was smoothed with a 200-ms moving average and the peak was measured for each breath. Rib cage and abdominal movement were measured with inductance bands, and VT was measured with a pneumotachograph.
Measurement of Zone of Apposition and Chest Diameters
We measured the length of the zone of apposition of the diaphragm against the chest wall (LZapp), using our previously described method (8). In brief, diaphragm movement was visualized by ultrasound (120-mm linear probe) just anterior to the right midaxillary line. The costal origin of the diaphragm was identified when the patient breathed to total lung capacity (TLC), where LZapp approaches zero with active inspiration (8). The distance between the costal origin of the diaphragm and the point where the diaphragm peeled away from the chest wall (costal recess) was measured to give LZapp at any lung volume or time point (± 1 mm). The change in LZapp with quiet breathing was measured over 5–10 breaths, LZapp was measured at FRC and residual volume (RV), and measurements were repeated several times. The thickness of the diaphragm and its depth under the skin at FRC were measured midway between the origin and costal recess (± 0.5 mm; 50-mm linear probe).
The anteroposterior diameter (sagittal plane, DAp) and lateral diameter (coronal plane, DLat) of the chest wall were measured with magnetometers taped to the skin at approximately the level of the diaphragm at FRC (8), and the signals were adjusted for diaphragm depth. Length of the diaphragm (LDi) in the midaxillary coronal plane was estimated from measurements of LZapp and DLat, using an equation validated for patients with COPD (8, 27, 28).
Statistics
Firing rate of all motor units was compared before and after LVRS by analysis of variance with "subject," "muscle," and "surgery" (pre- or post-LVRS) as main effects. All other measurements were compared before and after LVRS with paired t tests. Linear mixed model analysis (SPSS version 11; SPSS Inc., Chicago, IL) with "surgery" as a repeated effect within subjects was used to investigate linear relationships between measurements and changes after surgery. Pearson correlation coefficients and linear regression analyses were used to investigate relationships between changes in measurements after LVRS. Not all patients had a complete dataset, so most comparisons contained data from 10 or 11 patients. Data are presented as means ± SD and significance was set at p < 0.05.
RESULTS
Lung Function
After LVRS, there were significant changes in lung function among patients with COPD (Table 2). TLC, RV, and RV/TLC were reduced in 11 of 11 patients to 88 ± 4% of TLC presurgery and to 75 ± 9% of RV presurgery, and were reduced by 10 ± 6% from RV/TLC presurgery. FVC increased in 8 of 12 patients and the average increase for all patients was 12 ± 16% of FVC presurgery. In 8 of 12 patients FEV1 increased, but the average increase for all patients was not significant (21 ± 29% of FEV1 presurgery). There was a significant negative relationship between RV/TLC and FEV1 (percentage of predicted value) before and after surgery (Figure 2A). A mixed model analysis (see METHODS) showed no significant effect of surgery on the slope of this relationship, but showed a significant effect on the intercept (p = 0.004). The relationship was shifted to the left after surgery, so that the increase in FEV1 was not as great as expected given the reduction in RV/TLC.
Diaphragm and Rib Cage Dimensions
At FRC, the LZapp increased by 30 ± 28% after LVRS (p = 0.004; Table 2), and total LDi increased slightly (5 ± 6%; p = 0.023). At RV, there were nonsignificant increases in LZapp (20 ± 27%; p = 0.059) and LDi (4 ± 7%; p = 0.091). LDi at TLC did not change significantly. The small increase in LDi at FRC reflected the substantial increase in LZapp (11 mm), countered by a slight reduction in the lateral diameter of the rib cage (DLat) at FRC (5 ± 13 mm, p = 0.238). At TLC, FRC, and RV both the anteroposterior diameter of the rib cage (DAp) and DLat decreased slightly after LVRS, but these changes were not significant. The calculated cross-sectional area of the rib cage (8) was slightly decreased (96, 94, and 94% of presurgery values for TLC, FRC, and RV, respectively; p = 0.19, 0.08, and 0.08). There was a significant relationship between LZapp at FRC and RV/TLC (Figure 2B), but no difference in the relationship before and after LVRS. The negative relationship between LDi and lung volume relative to predicted TLC (Figure 3) did not change slope, but was shifted to the left after LVRS (p < 0.001), so that for a given lung volume LDi was reduced (8).
VT during quiet breathing did not change significantly after LVRS. Similarly, there was no significant change in LZapp during quiet breathing. However, during quiet breathing there was increased inspiratory reserve for diaphragm shortening because LZapp at end inspiration increased by 12 ± 9 mm (p = 0.001) and LDi increased by 6 ± 6% (p = 0.006; Table 2). Before LVRS, seven patients showed paradoxical inward motion of the lateral rib cage during quiet breathing (DLat < 0; Hoover's sign) (29), but after LVRS, only four patients exhibited Hoover's sign. After LVRS, expansion of the lateral rib cage during quiet breathing was significantly increased (DLat increased by 1.2 ± 1.6 mm; p = 0.038). The small decrease in DAp during tidal breathing after LVRS (1.6 ± 3.5 mm; p = 0.164) was not significant.
Motor Unit Firing Rates
Measurements were made from 110 motor units in the diaphragm before LVRS and from 227 after LVRS (Figure 4). The firing frequency of diaphragmatic motor units (FDi) during quiet breathing was reduced after LVRS in 9 of 11 patients with COPD, with an average for all patients of 87 ± 23% of FDi before surgery (p < 0.001; Table 2 and Figure 4). In the scalenes 203 motor units were measured before surgery and 223 were measured after surgery (Figure 4). The firing frequency of scalene motor units (FScal) was slightly decreased after LVRS (98 ± 35% of pre-LVRS, p < 0.001; Table 2), but only 6 of 11 patients had a decrease in firing rate. FDi was significantly greater than FScal both before and after surgery (p < 0.001). The analysis of variance revealed significant effects due to "subject," "muscle," and "surgery," as well as significant interactions between these effects. The effect of LVRS on motor unit firing rate depended on the muscle and the subject. Figure 5 shows that for both muscles the change in motor unit firing rate after LVRS was linearly related to firing rate before surgery, so that the change was greater for those subjects with high firing rates pre-LVRS (diaphragm: R2 = 0.44, p = 0.025; scalenes: R2 = 0.71, p = 0.001). The proportion of volume change measured at the rib cage increased from 56 ± 9% of tidal volume before surgery to 69 ± 9% afterward (p = 0.006).
Blood Gases, Exercise, and Quality of Life
There were no significant changes in blood gas concentrations after LVRS (Table 2). The 6-min walk distance was greater in 10 of 12 patients, but this change was not significant (114 ± 22% of presurgery values; p = 0.058). However, the Borg scores for exertion and dyspnea during the 6-minute walk test declined after LVRS (by 1.3 ± 1.1, p = 0.002 and 1.2 ± 1.6, p = 0.032, respectively). There was an increase in distance walked during the cardiopulmonary exercise test in 8 of 12 patients (mean increase for all patients, 220 ± 226%; p = 0.012). After LVRS, there was also a significant increase of 10 ± 7 (p < 0.001) in QOL scores related to dyspnea and of 8 ± 6 (p = 0.002) for the average QOL scores (Table 2).
Correlations
There was a significant negative relationship between FDi and LZapp at end inspiration before and after LVRS (Figure 6). After surgery, the increase in LZapp was associated with a decrease in FDi, such that the relationship did not change. The 6-min walk distance was positively correlated with DLat during quiet breathing (p < 0.001; Figure 7), with Hoover's sign (negative DLat) more prominent in patients with a shorter 6-min walk distance. After surgery, the relationship did not change and the increase in DLat was associated with increased 6-min walk distance.
The variable outcomes of the surgery are illustrated in Figure 8. Although the increase in 6-min walk distance after LVRS was not significant (p = 0.058), it was positively corre- lated with the increase in QOL score for dyspnea (p = 0.012; Figure 8A). Increased 6-min walk distance after surgery also correlated with increased FVC (p = 0.005; Figure 8B). In addition, the increase in LZapp at FRC was linearly related to increased FVC after LVRS (p = 0.023; Figure 8C). In summary, the increase in FVC after surgery was the best predictor for the increase in LZapp at FRC and the 6-min walk distance. In turn, patients with greater increases in 6-min walk distance reported greater increases in their QOL score for dyspnea.
The patients with the greatest hyperinflation had the largest decrease in TLC after surgery (p = 0.015; Figure 9A). Similarly, those patients with lowest QOL scores for dyspnea had the greatest increase in QOL score after surgery (p = 0.014; Figure 9B).
DISCUSSION
In the present study, diaphragm dimensions and neural drive were examined in 12 patients with severe emphysema and COPD before and after LVRS, which reduced TLC by an average of 12%. After LVRS, there was a significant increase in the LDi and the LZapp at FRC and RV. Tidal changes in LDi and LZapp during quiet breathing were not different after LVRS, so that LZapp at end inspiration was increased, providing a greater reserve capacity for diaphragm shortening (8).
After LVRS, the firing rate of motor units in the costal diaphragm (FDi) during quiet breathing decreased, despite no change in VT or tidal movement of the diaphragm, consistent with a net reduction in neural drive. FScal during quiet breathing was also decreased after LVRS. However, in both the diaphragm and scalenes, the reduction in firing rate was most apparent in patients with high firing rates before surgery. The firing rate of motor units in the diaphragm was greater than that in the scalenes, which is consistent with our previous findings in healthy subjects when inspiratory drive is increased (23) and in patients with COPD compared with control subjects (4, 5).
The firing rates for diaphragm motor units in the present study before LVRS are similar to those reported in patients with COPD in previous studies using the same methods (17 vs. 18 Hz, respectively) (4), but the scalene firing rates were greater in the present study (15 vs. 11 Hz, respectively) (5). By comparison, in healthy subjects in whom inspiratory drive is increased threefold, the motor unit firing rates averaged 18 Hz in the diaphragm and 10 Hz in scalenes (23). After LVRS, the firing rates of motor units in the patients with COPD fell to 15 Hz for the diaphragm and 13 Hz for the scalenes, still greater than those of age-matched control subjects in the previous studies (11 and 9 Hz, respectively) (4, 5). Motor unit firing rate is unaffected by changes in recording conditions (30) and is therefore a more reliable measure of neural drive than surface EMG. However, the present results are still consistent with previous findings that during inspiratory threshold loading, diaphragm EMG from esophageal electrodes was reduced after LVRS (22).
Previous studies have measured LDi and LZapp in patients with COPD (2, 3, 27, 31, 32). The values measured in the present study largely agree with the previous studies, given methodologic differences related to identification of the diaphragm origin, posture, and muscle contraction (see also Reference 8). For comparison, LDi and LZapp at FRC were 456 and 71 mm, respectively, in matched healthy subjects, compared with 381 and 35 mm in patients with COPD (8), and 379 and 40 mm in the present study before surgery. In other studies of diaphragm dimensions after LVRS, similar results were found by Bellemare and colleagues (20), but Lando and colleagues (19) reported a small increase in LDi at TLC, unlike the present study in which LDi increased only at FRC and RV after LVRS. The tidal change in LZapp during quiet breathing (LZapp) was similar to that in our previous study (8), with average values unchanged after LVRS (only one patient participated in both studies). After LVRS, LZapp and LDi at FRC and end inspiration approached, but did not reach, values for control subjects (8).
Some tests were conducted on different days, so there is a potential source of variability in the relationships between measurements. Diaphragm mechanics and neural drive were measured about 4 mo after the other post-LVRS measurements and this may have reduced the ability to find statistically significant correlations between the variables measured. We attempted to reduce measurement errors with multiple motor units measured for each person, and with ultrasound and chest diameter measurements averaged over a number of breaths or maneuvers.
The improvement in lung volume, exercise performance, and QOL found in these patients with COPD was related to their presurgical status. In general, patients with more severe disease before surgery improved the most after LVRS. This was consistent with the findings of Fessler and coworkers (33) that the more severely affected patients with the largest RV/TLC ratio exhibited the biggest changes in FVC after surgery. The change in VC has been considered the main determinant of improvement in FEV1 (15, 34). It is likely that the patients with the greatest hyperinflation had more diseased lung removed and this would also help account for the relationships between pre- and postsurgical measurements (35).
This study was conducted on the earliest patients in the LVRS program in one hospital, so with changes in criteria for LVRS, the outcomes of surgery for these patients may not reflect current outcomes. The improvement in FEV1 and other measures of lung function and in exercise capacity were less than often reported (40–80% increase in FEV1) (10, 36), but in agreement with a large randomized trial ( 21% in FEV1 at 12 mo postsurgery) (37). The long period between pre- and postsurgical observations (up to 30 mo) also contributed to the lack of significant improvement in FEV1, which after the initial increase post-LVRS declines at a relatively fast rate in the first 1–2 yr and then declines at a rate similar to presurgical values (35, 38, 39). The lack of significant change in FEV1 and its variability may have mitigated against finding significant changes in other measures of lung and respiratory function and exercise performance. However, with this sample we have a large range in the changes resulting from LVRS, which may have increased the likelihood of finding relationships between measures of lung function, diaphragm function, exercise capacity, and quality of life.
A further limitation of this study was that we did not study the effect of preoperative pulmonary rehabilitation on inspiratory muscle firing rates and diaphragm mechanics. Nevertheless, pulmonary rehabilitation may improve exercise capacity and quality of life measures, but it has no effect on pulmonary function (34).
At a given LDi, absolute lung volume was decreased after surgery (Figure 3) suggesting that rib cage volume had also decreased (8), although the cross-sectional area of the lower rib cage was not significantly decreased. The firing rate of diaphragmatic motor units during quiet breathing decreased after LVRS, probably because the diaphragm was operating at a longer length. The length–tension relationship of the diaphragm is shifted in patients with COPD compared with normal subjects and there is evidence that after LVRS, the relationship returns toward that for healthy subjects (20, 21, 40). Patients with COPD have chronic adaptations of the diaphragm, with reduced length and/or number of sarcomeres in series (41), and changes in fiber type composition (42, 43). After LVRS, the rat diaphragm undergoes remodeling, increasing the number of sarcomeres in series (44). Other changes post-LVRS may also contribute to a reduced load on the diaphragm, such as decreased intrinsic positive end-expiratory pressure (45), resulting in reduced neural drive.
The patients with COPD significantly improved in QOL and distance walked in the exercise test after LVRS. The improvement in QOL scores for dyspnea correlated best with increases in 6-min walk distance, which in turn was best predicted by the increase in FVC after surgery. The patients in whom FVC increased the most after surgery also had the greatest increase in LZapp at FRC. In addition, the decrease in firing rate of diaphragm motor units was related to the increase in LZapp at end inspiration after surgery. The data suggest that after LVRS, improvements in quality of life and exercise performance are associated with improvements in diaphragm function, with reduced neural drive, and increased reserve capacity for shortening. Improvements in diaphragm function are a result of improved lung volumes. Other studies have shown that increased end-expiratory volume or reduced inspiratory capacity are the best predictors for increased breathing discomfort in patients with COPD (46, 47). In the present patients, the reduction in QOL scores for dyspnea after LVRS may, therefore, be a result of improved diaphragm function with reduced lung volume.
This study has confirmed previous reports that patients with COPD have shortened diaphragms and reduced zones of apposition against their rib cages, requiring high firing rates in diaphragm and scalene motor units. We report for the first time that patients with COPD have reduced firing rates of motor units in the diaphragm and scalenes after LVRS. This reduction in neural drive was accompanied by an increase in LDi and LZapp. This improved diaphragm function is likely to contribute to improved quality of life after surgery, especially in dyspnea and exercise capacity.
FOOTNOTES
Supported by funds from the Asthma Foundation of NSW and the National Health and Medical Research Council of Australia. J. F. T. was a Boehringer Ingelheim Research Fellow of the Australian Lung Foundation.
Originally Published in Press as DOI: 10.1164/rccm.200412-1695OC on August 18, 2005
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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