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* From the Department of Internal Medicine (Drs. Flaherty and Martinez), Division of Pulmonary and Critical Care Medicine, the Department of Radiology (Dr. Kazerooni), Chest Division, and the Department of Surgery (Dr. Iannettoni), Division of Cardiothoracic Surgery, University of Michigan Health System; the Department of Biostatistics (Drs. Lange and Schork), University of Michigan School of Public Health; and the Medical Service (Dr. Curtis), Pulmonary and Critical Care Medicine Section, Department of Veterans Affairs Medical Center, Ann Arbor, MI.
Correspondence to: Fernando J. Martinez, MD, Division of Pulmonary and Critical Care Medicine, 3916 Taubman Center, Box 0360, 1500 E Medical Center Dr, University of Michigan Medical Center, Ann Arbor, MI 48109-0360; e-mail: fmartine{at}umich.edu
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Abstract |
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Methods: Eighty-nine consecutive patients with severe emphysema who underwent bilateral LVRS were prospectively followed up for up to 3 years. Patients underwent preoperative pulmonary function testing, 6-min walk, chest CT, and answered a baseline dyspnea questionnaire. CT scans in 65 patients were analyzed for emphysema extent and distribution using the percentage of emphysema in the lung, percentage of normal lower lung, and the CT emphysema ratio (CTR, an index of the craniocaudal distribution of emphysema). All patients underwent at least 6 weeks of pulmonary rehabilitation prior to surgery. Outcome measures were FEV1, 6-min walk distance, and transitional dyspnea index (TDI).
Results: Compared to baseline, FEV1
was significantly increased at 3, 6, 12, 18, 24, and 36 months after
surgery (p 
0.008). The 6-min walk distance increased from 871 feet
(baseline) to 1,110 feet (3 months), 1,214 feet (6 months), 1,326 feet
(12 months), 1,342 feet (18 months), 1,371 feet (24 months), and 1,390
feet (36 months) after surgery. Despite a decline in FEV1
over time, 6-min walk distance was preserved. Dyspnea as measured by
TDI improved at 3, 6, 12, 18, 24, and 36 months after surgery. A high
CTR was the best predictor of a 12% increase over baseline and an
absolute increase of 200 mL in FEV1, although with a low
area under the receiver operating characteristic curve. In addition,
the sensitivity and negative predictive value of the CTR were limited.
No radiographic or physiologic predictor was able to consistently
predict a successful increase in walk distance or TDI.
Conclusion: LVRS improves pulmonary function, decreases dyspnea, and enhances exercise capacity in many patients with severe emphysema, although improvement wanes 36 months after surgery.
Key Words: CT • emphysema • exercise capacity • lung volume reduction
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been shown that surgically reducing lung volume can result in decreased dynamic hyperinflation, a finding that correlated with decreased exertional dyspnea.4 If improvement following LVRS is simply related to preoperative hyperinflation, then the majority of patients with emphysema may benefit from this surgery. However, patients with diffuse emphysema have been reported to have lesser postoperative improvement compared to patients with focal upper-lobe-predominant emphysema.5 6 7 8 9
We prospectively assessed the long-term clinical outcome after bilateral LVRS in a cohort of 89 patients followed up for up to 36 months. We additionally examined the ability of measures of emphysema distribution from CT and baseline pulmonary function parameters to predict successful clinical outcomes.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To be considered for LVRS, patients needed clinical and CT scan
evidence of emphysema, physiologic evidence of severe airflow
obstruction, and hyperinflation (residual volume [RV] > 180%
predicted or total lung capacity [TLC] > 105% predicted). In an
effort to exclude patients with chronic bronchitis, patients with more
than three teaspoons of sputum production per day were excluded. All
patients were required to have stopped smoking for at least 6 months.
Patients were tested and excluded from this analysis if positive for
1-antiprotease deficiency to maximize the
homogenous nature of the study group. The decision to advance to
further testing was based on these data and consensus decision by our
LVRS study group (pulmonologists, thoracic surgeons, thoracic
radiologist, and clinical coordinator).
Patients eligible for surgery underwent dobutamine echocardiography to exclude inducible coronary ischemia and screen for pulmonary hypertension.11 Patients with evidence of pulmonary hypertension underwent right-heart catheterization. Patients not excluded were enrolled in or asked to continue with pulmonary rehabilitation. If patients had previously completed a course of pulmonary rehabilitation, they were asked to reenroll prior to undergoing LVRS. The preoperative target for successful rehabilitation was to exercise for 30 min (continuous) on a level treadmill at 1 to 1.5 miles per hour. The protocol was approved by the University of Michigan Health System Institutional Review Board. Eighty-nine of the 476 screened patients were eligible and elected to undergo LVRS.
Pulmonary Function Tests and 6-min Hall Walk
Pulmonary function tests were performed on a single day after
administration of 2.5 mg of albuterol via nebulizer. All baseline
measures were obtained during a period of clinical stability and within
3 months of surgery. Spirometric studies were performed on a calibrated
pneumotachograph (Medical Graphics; St. Paul, MN); best overall effort
was chosen and values expressed relative to standards of Morris et
al.12
Lung volumes were measured by whole-body
plethysmography and expressed as a percentage of normal values of
Miller et al.13
DLCO was measured by
single-breath technique using normal values of Miller et
al.13
Exercise testing was measured by a standard 6-min
walk performed in an air-conditioned hall after standard
instructions,4
with distance measured in feet. As the
6-min walk is dependent on effort, technique, and
coaching,14
we used a constant measuring technique and two
tests were performed at each visit to minimize variability.
Supplemental oxygen was titrated to maintain oxygen saturation
> 88%.
Chest CT
High-resolution CT was performed in all cases at 1.0-mm to
1.5-mm collimation at 1-cm intervals throughout the lungs using a
General Electric HiSpeed or CT/i scanner operating in nonhelical mode
(GE Medical Systems; Milwaukee, WI) for visual confirmation of
emphysema. In the last 65 consecutive patients undergoing surgery,
helical CT was also performed during a single inspiratory breath-hold
lasting 15 to 20 s at 10-mm collimation and pitch 2 (table speed
of 2 cm/s). Scanning was from the caudal to cranial direction. Patients
took several hyperventilatory breaths prior to scanning. If patients
were not able to breath-hold for the entire acquisition, they were
instructed to slowly exhale during the final seconds of data
acquisition through the lung apices; no significant motion artifact was
detected. Given the severe emphysema with trapping of air at the
apices, little change in lung volume and attenuation was noted.
From the helical CT data, total lung volume and emphysema volume were
quantified and displayed using attenuation thresholds by density mask
analysis15
16
17
rendered on a GE Windows Workstation (GE
Medical Systems). Shaded surface displays, demonstrating emphysema as
evident at the edge of the lung, were used to visually demonstrate the
results of the three-dimensional density mask, but were not used for
analysis. For the 65 patients undergoing helical CT, the following
analysis was performed. Total lung volume was defined as all pixels
< - 700 Hounsfield units and emphysema as all pixels < - 900
Hounsfield units, acknowledging that mild emphysema may be
missed.16
17
18
19
The percentage of emphysema was calculated
for the upper and lower halves of the lung, divided midpoint between
lung apices and the diaphragm.20
The CT emphysema ratio
(CTR) was calculated using the following equation:
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Follow-up Data
Patients were seen by their LVRS pulmonologist at 3, 6, 12, 18,
24, and 36 months postoperatively, at which time spirometry, static
lung volumes, DLCO, arterial blood gas, 6-min walk
distance, and transition dyspnea index (TDI) measures were collected.
Patients not returning for physiologic testing were contacted by phone
to ascertain why they had missed their follow-up appointment. Patients
undergoing lung transplantation (n = 3) were censored from further
analysis at the time of transplant.
Definitions of Response
Three separate outcomes were evaluated, including spirometry,
6-min walk distance, and TDI. Each outcome was assessed at 3, 6, 12,
18, 24, and 36 months.
Spirometry:
For FEV1, a responder was defined as
both an absolute increase of 200 mL and a 12% increase compared to
baseline adopting the American Thoracic Society recommendations for
spirometric response to a bronchodilator.21
6-min Walk Distance:
This was defined as an increase of
200 feet. This threshold was chosen from the minimum improvement in
walk distance reported by investigators studying pulmonary
rehabilitation alone22
and LVRS in emphysema
patients.23
24
TDI:
A change of 3 was considered significant. A TDI of
3 was chosen as a significant response to reflect an improvement in
dyspnea in excess of that generally reported in the literature
resulting from pulmonary rehabilitation alone in patients with very
severe airflow obstruction.25
Statistical Analysis
Baseline and post-LVRS FEV1, 6-min walk
distance, and TDI were compared using a mixed-model analysis of
variance with time as the repeated measure. Data are expressed as the
mean ± SE. In order to determine the optimal preoperative predictors
of a response (defined above), the following predictor variables were
used for individual logistic regression analysis:
FEV1, FEV1 (% predicted),
RV (% predicted); TLC (% predicted), RV/TLC, DLCO (%
predicted), CTR, percentage of normal lower lung, total percentage of
emphysema, and age. Data analyses were adjusted for pulmonary
rehabilitation status before initial 6-min walk testing. Receiver
operating characteristic (ROC) curves were generated for each of the
individual predictors at each follow-up time for each outcome
(FEV1, 6-min walk distance, and TDI) and the area
under the ROC curve (AZ) was calculated. Following this
initial analysis, individual predictor variables associated with a p
value of < 0.1 from simple linear regression analysis, at any of the
six follow-up time periods, for any outcome, were used in combination
as the input variables for multiple logistic regression. ROC curves
were then generated for each combination. ROC analysis was performed
using SAS software (SAS Institute; Cary, NC). ROC curves were compared
as described by Metz et al.26
Positive predictive value
(PPV), reflecting the likelihood of having a positive outcome given a
positive test result, and negative predictive value (NPV), reflecting
the likelihood of having a negative outcome given a negative test
result, were calculated using the prevalence of response calculated
from the data at each follow-up time point. The influence of age on
survival was analyzed using Cox regression analysis.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Postoperative Outcomes
There was improvement in FEV1 from baseline
in the majority of patients at all time points of follow-up, although
FEV1 declined over time (Fig 2
). The FEV1 at each follow-up time was
significantly (p < 0.008) higher than baseline. The degree of
improvement in FEV1 was varied by patient as
demonstrated in Table 2
.
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0.1 at any time during follow-up. Using this approach, a model
incorporating CTR and RV/TLC was able to improve the predictive ability
of CTR alone. However, comparison of the ROC curves was not
statistically different (p > 0.25 for all time points). The
AZ at each time point for CTR, RV/TLC, and combination of
CTR and RV/TLC is shown in Table 3
. The sensitivity, specificity, PPV, and NPV of predicting a successful
FEV1 outcome for various CTR values are shown in Table 4
. Importantly, the highest CTR scores (> 2.5) were associated with a
> 90% specificity at each time point up to 36 months, although the
sensitivity was low. The PPV of this threshold was at least 75% up to
36 months after surgery. The NPV remained moderate at all thresholds
throughout 36 months of follow-up.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LVRS transiently improved FEV1 in the majority of patients. The magnitude of improvement noted in our patients is similar to that reported by other groups performing bilateral LVRS via median sternotomy23 27 28 or thoracoscopy.7 23 Also documented was a steady deterioration in FEV1 over time extending the findings of previous studies29 30 and confirming the recent findings of another group.31 Although the FEV1 declined over time after surgery, it is important to note the natural history of emphysema is one of progressive deterioration. It is likely that the FEV1 at the end of the study would be significantly lower if those patients had never undergone LVRS, as has been suggested by other investigators.32 Future prospective studies are needed to definitively address this issue.
An important finding in this study, however, was the poor correlation between improvement in FEV1 and 6-min walk distance. Twenty-two patients failed to show a significant increase in FEV1 at any time during follow-up; 11 of these patients were able to demonstrate a significant improvement in 6-min walk distance. Additionally, the improvement in 6-min walk distance persisted over time despite a decrease in FEV1. This phenomenon may be secondary to rehabilitation as opposed to a benefit of the surgery. However, as all patients completed a course of pulmonary rehabilitation prior to surgery and were encouraged to continue rehabilitation after surgery, it is unlikely that this explains all of the increased walk distance. This interpretation is supported by the short-term improvement noted after LVRS in a randomized trial of pulmonary rehabilitation with or without bilateral, surgical volume reduction.28 In a minority of patients, we measured baseline 6-min walk distance before completion of pulmonary rehabilitation. Although the initial 6-min walk distance in this group was lower than in those patients in whom the data were collected after an initial course of rehabilitation, the subsequent responses after surgery were remarkably similar. This finding suggests a beneficial effect of the surgical procedure, confirms that FEV1 is a poor predictor of functional capacity in this group of patients, and indicates that additional outcomes such as RV or dynamic lung volumes during exercise should be investigated in future studies.
It is also notable that all patients experienced at least a transient relief of dyspnea following LVRS, even though a significant number of patients failed to meet response criteria for an improvement in FEV1. Given our previous findings that LVRS can result in decreased dynamic hyperinflation, improved diaphragmatic strength, and decreased dyspnea,4 we hypothesize that at least some of the improvement in dyspnea is related to improved dynamic hyperinflation that is not reflected through measurement of the FEV1. An additional possibility is that the improvement in dyspnea reflects the scoring system we utilized that strongly weighs functional improvement. It is notable that the improvement in dyspnea waned over time and tended to be most improved in those patients experiencing the greatest improvement in FEV1.
As it was evident that not all patients responded equally to LVRS, we sought to determine the relative contribution of different preoperative parameters in predicting successful LVRS outcomes. Theoretical reports33 and results of short-term follow-up7 have suggested that preoperative hyperinflation is important in determining spirometric improvement after LVRS. Of the parameters we evaluated, only the CTR was consistently able to predict a successful FEV1 outcome, albeit with a low AZ. The combination of the CTR with a physiologic measure of hyperinflation (RV/TLC) failed to significantly improve the AZ. Emphysema distribution has been suggested to be important in determining physiologic outcome after LVRS.6 7 34 Previous studies have shown moderate correlation between radiographic measures of emphysema heterogeneity and outcome during short-term (3 months and 6 months)7 8 24 35 36 and longer-term (24 months) follow-up.9 Although some studies have demonstrated improvement in patients with more diffuse emphysema, the magnitude of improvement appears to be less than that noted in patients with heterogeneous emphysema.8 9 These studies are limited by short-term follow-up5 6 7 24 and, potentially, by qualitative estimates of emphysema heterogeneity.6 7 8 9
A quantitative analysis of emphysema, long-term follow-up, and the use of ROC analysis that defined the sensitivity and specificity of different CTR thresholds strengthens our approach. Potential advantages of this technique include the avoidance of slice misregistration due to inconsistent breath-holds,37 38 39 the inclusion of the entire lung,15 and an improved interobserver estimation of emphysema.40 We demonstrate the high specificity but low sensitivity of having strongly upper-lobe-predominant disease as measured by a CTR of > 2.5. In this way, we suggest the good PPV (reflecting the likelihood of having a positive outcome given a positive test result) for a CTR of > 2.5, although the predictive value was lower at lower CTR thresholds. Additionally, we confirm that the NPV was much lower at all CTR thresholds. These predictive values are calculated with the assumption that our prevalence of response is generalizable to other patients with emphysema undergoing bilateral LVRS. This seems reasonable as our data are similar to the limited, published long-term results of other groups.9 31 As such, our data suggest those patients with strongly upper-lobe-predominant emphysema as measured by a CTR > 2.5 are more likely to experience a significant improvement in FEV1. However, due to the low NPV of this test, excluding patients without a CTR > 2.5 will likely exclude some patients who would also experience an improvement in FEV1. Other investigators have shown a greater short-term improvement in walk distance6 7 8 9 24 and dyspnea8 9 in patients with greater emphysema heterogeneity, suggesting that baseline radiographic parameters may be useful in predicting these outcomes. Importantly, we were unable to consistently predict a positive outcome in 6-min walk distance or TDI using quantitative CT and/or physiologic indexes.
An important finding of this study is the increased risk of surgical mortality in older patients. This supports the findings of other investigators who have demonstrated an increased perioperative mortality in older individuals,41 42 particularly in those > 70 years old.42 Similarly, others have noted an increased long-term mortality in older patients after bilateral LVRS.43 These findings highlight the importance of assessing the risks and long-term benefits of LVRS in an older, higher-risk population.
Our study population consisted of patients selected with a prejudice
for individuals with focal areas of particularly severe disease
amenable for resection. Diffuse emphysema was not an initial exclusion
criterion; however, as the study progressed, data presented at
scientific meetings and later published5
6
7
8
9
suggested that
patients with diffuse emphysema had less improvement after surgery than
patients with focal upper-lobe-predominant disease, introducing
potential bias. Since statistical significance was achieved with a
relatively small number of patients with diffuse disease (37% had a
CTR 1.5),24
this should reinforce and not detract from
the results.
A potential limitation of this and most published data are incomplete follow-up, which could bias long-term results. In our series, at each time point, a minority of patients failed to return for follow-up physiologic testing. When contacted by phone, the patients fell into four groups. One group included patients who had experienced marked functional improvements that allowed them to return to work, thereby precluding return for follow-up testing (eg, four of nine patients who could be contacted 36 months after surgery). A second group experienced significant functional deterioration that impeded their ability to return for physiologic testing (eg, two of nine patients at 36 months after surgery). Two patients considered themselves in stable condition but were not willing to travel to the medical center for follow-up testing. One additional patient underwent lung transplantation. As such, we believe that a consistent bias was not likely in our patients. Nevertheless, future controlled trials must ensure complete long-term follow-up to minimize potential bias in the interpretation of long-term physiologic and clinical outcomes.
In summary, our prospective assessment of LVRS confirms improvement in physiologic function, exercise capacity, and breathlessness in many patients. Although pulmonary function deteriorates after the initial 12 months, exercise capacity and dyspnea improvement are partly preserved up to 36 months after bilateral LVRS. Importantly, we document that emphysema distribution, as measured by quantitative helical CT, is the best predictor of a successful FEV1 outcome, albeit with a low AZ. In addition, it less consistently predicted successful 6-min walk or TDI outcomes. Unfortunately, the lack of correlation between spirometric improvement and improved walk distance and the inability of the CT scan to accurately predict functional improvement in these same parameters suggest a limited value to radiographic screening.
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Footnotes |
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Preliminary data on a subset of patients were presented at the Annual Scientific Session of the Radiologic Society of North America, Chicago, IL, December 1996 and December 1998, and also at the Annual Scientific Session of the American Thoracic Society, San Francisco, CA, May 1997.
This research was supported by National Institutes of Health NHLBI grant P50HL46487, NIH/NCRR 3 MO1 RR00042–33S3, NIH/NIA P60 AG08808–06, RO1 HL56309, a General Electric Radiology Research Academic Fellowship, a grant from General Electric Medical Systems, CT Division, and by Research Funds from the Department of Veterans Affairs. Dr. Kazerooni is a General Electric – Association of University Radiologists Fellow. Dr. Curtis is a Career Investigator of the American Lung Association of Michigan.
Received for publication April 7, 2000. Accepted for publication December 5, 2000.
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