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* From the Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine (Drs. Sciurba and Rogers), and the Division of Thoracic Surgery, Department of Surgery (Dr. Keenan) at the University of Pittsburgh Medical Center and School of Medicine, Pittsburgh, PA; and the University of British Columbia Pulmonary Research Laboratory (Drs. Coxson, Whittall, and Hogg), St. Paul’s Hospital, Vancouver, Canada.
Correspondence to: Robert M. Rogers, MD, FCCP, Division of Pulmonary, Allergy and Critical Care Medicine, 440 Scaife Hall, 3550 Terrace St, Pittsburgh, PA; e-mail: rogersrm{at}msx.upmc.edu
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Abstract |
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Design: A histologically validated CT algorithm was used to quantify the volume and severity of emphysema in 35 patients before and after LVRS: total lung volume (TLV), normal lung volume (< 6.0 mL gas per gram of tissue), volume of mild/moderate emphysema (ME; 6.0 to 10.2 mL gas per gram of tissue), volume of severe emphysema (> 10.2 mL gas per gram of tissue), surface area/volume (SA/V; meters squared per milliliter), and surface area (SA; meters squared). Outcome parameters included maximal cardiopulmonary exercise (CPX) performance in 21 patients and routine pulmonary function in all patients. We hypothesized that baseline CTM parameters predict response to LVRS and that the change in these parameters may offer insight into mechanisms of improvement.
Patients and intervention: Thirty-five patients with severe emphysema who had successful LVRS.
Results: The significant decrease in TLV following LVRS was entirely accounted for by a decrease in severe emphysema. The SA/V and the SA both increased significantly following LVRS. The change in maximal CPX in watts following surgery correlated significantly with baseline values of severe emphysema (r = 0.60), which was collinear with TLV, and SA/V. The change in diffusing capacity of the lung for carbon monoxide revealed a significant positive linear relationship with preoperative severe emphysema (r = 0.37) and a negative relationship with ME (r = -0.37). Change in watts revealed a strong relationship with changes in severe emphysema (r = -0.75) and weaker but significant relationships with change in TLV, ME, SA/V, and SA. Other measures of pulmonary function revealed significant albeit less dominant relationships with baseline CTM and change in these indexes.
Conclusion: Using CTM, we have identified a close relationship between baseline severe emphysema, or change in severe emphysema, and the improvement in CPX after LVRS. These observations support a potential role of CTM in future clinical trials for predicting responders to LVRS and identifying mechanisms of improvement.
Key Words: CT • emphysema • exercise • lung volume reduction surgery
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the more important tools in assessing the extent of emphysema in LVRS candidates is CT. The CT images are conventionally interpreted using a subjective visual analysis of the image. This visual approach results in inconsistent interpretation, with interobserver agreement of < 0.6 and a tendency to overestimate the amount of emphysema when compared to pathologic measurements.5 Others have shown that by using lung attenuation values as a quantitative evaluation, they had moderately strong correlation with preoperative physiology and outcome.6 The purpose of this study is to extend these observations by utilizing a recently described quantitative method of analysis that we will refer to as CT morphometry (CTM).7 CTM is a quantitative analytic technique that measures lung volume, volume of emphysema, surface area (SA; meters squared), and SA per total lung volume (TLV) (SA/V; meters squared per milliliter) from CT density values. This technique was validated in resected lungs of patients with varying degrees of emphysema using standard histologic analyses. In this study, we used CTM to analyze the CT scans from 35 consecutive patients who underwent LVRS. Physiologic measures before and 3 months after LVRS were correlated with the volume and severity of preoperative LVRS emphysema, as identified by CTM, to predict the physiologic and clinical response of this group of patients after LVRS. Our results strongly suggest that CTM analysis yields valuable information about lung structure in terms of lung volume, volume of emphysema, and SA, and these values may be useful in preoperative evaluation and postoperative follow-up of patients undergoing LVRS.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pulmonary Function Studies
Spirometry and lung volumes were measured preoperatively and
postoperatively using previously described standard techniques and
normal reference values.3
CPX Testing
Group E patients performed incremental, symptom-limited CPX
testing on an electronically braked cycle ergometer (model KEM III;
Mijnhardt BV; Bunnik, Holland). This ergometer produces a
resistance equivalent to 14 W during "unloaded" pedaling. The
protocol utilized a ramp increment of 4 W or 8 W following 3 min of
unloaded pedaling. Maximal watts were recorded when pedaling frequency
fell and remained < 40 revolutions/min.
Quantitative CT Analysis "CTM"
The subjects in the study received a conventional,
noncontrast CT scan (10-mm thick axial slices) on a GE 9800 Highlight
Advantage CT scanner (General Electric Medical Systems; Milwaukee, WI)
approximately 1 week prior to surgery. All scans were performed with
the subject supine during end-inspiratory breath holding. The image
data were transferred to a Silicon Graphics Indy Workstation (Silicon
Graphics; Mountainview, CA). CTM was performed using a recently
described technique,7
whereby the TLV was calculated by
summing the lung voxels on the CT scan, and multiplying by the voxel
dimension. A voxel (volume element) is defined as the individual
picture element (pixel) of a CT image, which has dimensions in the x
and y plane, and includes the CT slice thickness as the third dimension
(z axis). The lung volume was also partitioned into three compartments
occupied by severe and mild/moderate emphysematous lesions, as well as
normal lung (NL). Briefly, this was performed by converting the
radiograph attenuation values, measured in Hounsfield units (HU), into
a measurement of the volume of gas per gram of tissue (milliliters per
gram) and applying two cutoff values.7
The first cutoff is
at 10.2 mL/g, which corresponds to - 910 HU.11
It has
been shown that lung inflated > 10.2 mL/g (< - 910 HU) represents
emphysematous lesions > 5 mm in diameter7
12
and is
referred to as severe emphysema. The second cutoff is 6.0 mL/g, which
corresponds to - 856 HU. Lung inflated between this cutoff and the
severe emphysema cutoff (ie, 6.0 to 10.2 mL/g) has been
shown to represent emphysematous lesions < 5 mm in diameter, referred
to as mild/moderate emphysema (ME). The remainder of the lung volume
inflated <6.0 mL/g was considered to be representative of NL
parenchyma.7
The volume of these three categories (severe
emphysema, ME, and NL) was calculated by summing the number of CT
voxels identified by each cutoff and multiplying by the voxel
dimension. It should be noted that, while CT images obtained using
narrow beam collimation (1 mm) and high-resolution reconstruction
algorithms produce images that allow the visualization of emphysema,
thicker sections and lower-resolution algorithms allow a more reliable
discrimination of different densities within the lung.13
Secondly, the SA of the lung parenchyma and SA/V were estimated using a prediction equation derived by correlating measurements of radiograph attenuation values with quantitative histology.7
Statistical Analysis
Descriptive data were analyzed using a paired two-tailed
t test. The relationship between the changes in
physiologic and functional indexes as a function of preoperative CTM
variables following LVRS was analyzed first using descriptive simple
regression analysis, followed by a stepwise forward multiple regression
analysis. The primary dependent variable chosen was the change in
maximal watts (group E) because it is an objective functional parameter
that integrates the myriad of potential physiologic changes following
LVRS.14
Secondary dependent variables used in the analysis
were change in FEV1, FVC, residual volume (RV), total lung
capacity (TLC), and diffusing capacity of the lung for carbon monoxide
(DLCO); these were analyzed in group T. Independent CTM
parameters were preoperative TLV, volume of severe emphysema, volume of
ME, volume of NL, lung SA, and SA/V.
A similar approach was used to compare the relationship between the changes in physiologic and functional indexes as a function of changes in CT variables following LVRS. Because we considered that the change in DLCO, in particular, might be related more to the preoperative proportion of the TLV occupied by our morphologic categories (ie, severe emphysema/TLV, ME/TLV, NL/TLV) rather than the absolute volume, we performed linear regression analysis to compare these volume-adjusted CT parameters to the change in DLCO. A p value of < 0.05 was considered significant.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Changes in CTM Indexes Following LVRS
TLV, measured by CTM, decreased significantly following LVRS (Fig 1
and Table 2
) and was similar to the decrease in TLC determined using
plethysmography (888 mL vs 1,004 mL, respectively). The change in TLV
was entirely due to a decrease in the size of the compartment
representing severe emphysema; the changes in NL and ME were not
statistically significant, although the mean ME value tended to
decrease and the NL tended to increase (Fig 1)
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A major problem in assessing candidates for LVRS is the characterization of their emphysema, which is a pathologic diagnosis that can only be suspected clinically by using physiologic surrogates such as the DLCO27 and pulmonary mechanical indicators of hyperinflation. The chest roentgenogram and CT of the chest, however, give us visual evidence of the pathologic findings of emphysema. All these studies can assess the presence or absence of emphysema, but are inadequate to precisely localize or quantify the emphysematous lesions in the lung. Early studies on LVRS combined the chest roentgenogram and 131I macroaggregated lung scan to locate the very poorly perfused areas of the lung16 28 ; however, this failed to give a three-dimensional estimate of the lung. A major advance in emphysema research was the advent of quantitative CT scans using either a density mask11 or a density histogram analysis.29 30 These techniques, combined with the spatial resolution of the CT, have provided the investigator with truly quantitative three-dimensional data on the lung structure. Further, CTM allows the quantification of lung parenchymal features, such as SA, which were previously only available after removal of the organ from the body. Furthermore, our CTM analysis extends previous quantitative CT work, by translating the more obscure density measurements (in our experience, a term not easily understood by nonradiologists) into clinical and pathophysiologically meaningful indexes.
The purpose of this investigation is to utilize a newly described CTM technique7 to retrospectively analyze the volume and severity of emphysematous lesions in the preoperative CT and the subsequent changes following a clinically successful LVRS. We compared these CTM measurements to the changes in pulmonary function in 35 patients, and formal CPX testing in 21 patients. Because of the complexity of the pulmonary physiologic response, we chose to use CPX as an objective measure of improvement because it is an integration of the entire cardiopulmonary system.14 These patients were not selected on the basis of clinical improvement, but merely on the basis of having completed the above studies. Our patients’ responses to LVRS are similar to those of other published reports with statistically significant improvement of FVC, FEV1, RV, FRC, TLC, and variable response of the DLCO.9 10 18 20
We confirm the results of others31 32 who have shown that there is a reduction of the TLV after LVRS, both by CT and plethysmography measurements.32 We have further shown that this decrease is predominantly due to reduction in the lung volume that is considered to have the worst emphysematous lesions, ie, inflated > 10.2 mL/g,7 which we have called severe emphysema. Because the surgical technique removes not only severely diseased lung, but also mild/moderate disease and normal lung, the fact that there is no change in the latter two categories suggests that there is some reexpansion of the remaining lung. This is also demonstrated by the increase in both SA and SA/V of the lung parenchyma. We speculate that, following LVRS, the remaining lung expands and may change categories from either the mild/moderate to the severe range, or from the normal to the mild/moderate range. The increase in SA and SA/V is probably due to this reexpansion of underinflated alveoli, particularly in the NL compartment, thereby increasing the SA of the lung.
The clinical importance of the CTM technique is reflected in the close relationship between baseline emphysema volume, or change in emphysema volume, and the improvement in functional performance demonstrated with change in CPX performance. These observations support a potential role of CTM in predicting responders to surgery and in identifying mechanisms of improvement. When one examines the subgroup of patients on whom we had formal CPX testing (Table 3) , it is clear that the baseline values for TLV, SA/V, and severe emphysema in the preoperative CT scan predict improvement in CPX response, although the former two parameters are codependent on the severe emphysema value. This suggests that the preoperative volume of severe emphysema has predictive value with respect to improvement in CPX response following LVRS.
A low DLCO has been used as the standard physiologic marker for emphysema when associated with reduced expiratory flow and an increase in RV.27 This relationship has been viewed as a reflection of capillary destruction by the emphysematous process. However, a low DLCO could also be a result of compression of pulmonary vessels or cardiopulmonary interaction. When we examined change in DLCO, it improved in 15 patients, decreased in 9 patients, and did not change in 11 patients (Fig 4) , although the preoperative LVRS and postoperative LVRS mean values were not significantly different. The magnitude of change of DLCO showed a strong positive relationship with the preoperative volume of severe emphysema (Fig 3) and a strong, independent, negative relationship with the preoperative volume of ME (Fig 5) . We propose that these findings may reflect a greater removal of functional capillaries in the latter group and the removal of fewer capillaries in regions of poorly perfused severe emphysema. Pulmonary capillary volume can theoretically increase or decrease following LVRS. What determines an increase or decrease in capillary volume is the balance between the changes in regional lung mechanics and physical removal of capillaries. Our data support the concept that capillary volume can be increased in patients who have greater proportions of severe emphysema lung surgically removed. These data are consistent with recent report of weight gain after LVRS that was statistically significantly related to improvement in DLCO and not measurement of mechanics at 12 months.33
The physiologic data on patients undergoing LVRS presented in this article are very similar to those reported by many other large centers, ie, statistically significant improvement in the mean values for standard clinical physiologic parameters except for DLCO. Hence, while these improved mean values are statistically significant, it should be noted that there is significant variation from individual to individual in the magnitude of the change in each of these parameters. Thus far, no physiologic parameter has been found that predicts successful clinical outcome of LVRS, suggesting to us that the variability in response may rest in the amount and distribution of severe emphysema. A recent study20 of patients who had LVRS who were followed up to 4 years confirmed the early reports16 17 that the clinical and physiologic improvement is not sustained in the majority of patients (less then one third of their patients). These authors showed that the patients who had a sustained improvement had a statistically higher FVC and vital capacity at baseline. We would offer as an additional hypothesis that it may be related to the volume and distribution of severe emphysema.
In summary, CTM allows an objective assessment of lung structure and shows that the preoperative volume of emphysema predicts which patients will have the greatest improvement in cardiopulmonary function following LVRS. Further, it has the added advantage that well-trained technicians can perform this analysis across multiple centers, thereby increasing the sample size and minimizing any institutional bias. It is the authors’ hypothesis that CTM will give us better insight into the preoperative and postoperative abnormalities of the lungs of patients who have LVRS, and will allow us to predict, with quantitative methods, which patients will benefit from LVRS. Because the number of patients in this study is small and we do not have a control group, we view this study as hypothesis generating, and suggest that this analysis could be applied to a larger group of subjects, including patients who were rejected for surgery and those who do not survive the procedure. In addition, the appeal of CTM includes the following: (1) that it can be utilized on a standard personal computer, (2) that it can be analyzed across centers without the need for subjective visual analysis, (3) that it easily lends itself to "blinding" the person conducting the analysis, and (4) that future development could potentially develop a pathologic map to guide the surgery.
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Acknowledgements |
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Footnotes |
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Supported by a grant from the George H. Love research fund.
Received for publication October 25, 1999. Accepted for publication May 5, 2000.
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