METHODS

Subjects and physiological testing

The analysis was performed on 21 subjects who underwent bilateral LVRS using either video assisted thorascopy (n=17) or median sternotomy (n=4) between June 1994 and June 1997. Patients were selected if they could complete radiological, physiological, and cardiopulmonary exercise tests at baseline and at 3 months after LVRS using previously described techniques.^12,17 The institutional review board of the University of Pittsburgh Medical Center approved the study design and all patients provided informed consent.

Physiological testing was performed using previously described techniques.¹⁷ Spirometry and tests of lung volume and carbon monoxide transfer factor were measured using standard techniques with the subjects seated in a pressure body plethysmograph. Incremental symptom limited maximal exercise testing was performed on an electronically braked cycle ergometer (Model KEM III, Mijnhart, Holland).

Computed tomographic morphometry (CTM)

All subjects received a conventional transverse CT scan (10 mm thick contiguous slices) on a GE Highlight Advantage CT scanner (General Electric Medical Systems, Milwaukee, WI, USA) with the subject supine while breath holding at full inspiration. No intravenous contrast medium was used.

Analysis of the CT scans has been described in detail elsewhere.^18,19 Briefly, the lung parenchyma was segmented from the chest wall and large central blood vessels using a contour-following algorithm. Lung volume was calculated by summing the number of voxels in all slices and multiplying by the voxel volume. The CT density of the lung (g/ml) was estimated from radiographic attenuation of each of the CT voxels.^18,20 Inflation of the lung (ml gas/g tissue) was calculated by subtracting the inverse of tissue density from the inverse of the measured density.^18,19,21,22

Emphysematous lesions were defined as clusters of connected pixels beyond a threshold value using a “density mask” method (>10.2 ml/g, <−910 HU).^12,23 The size of these lesions (A) was calculated by simply summing the number of connected pixels below the density mask. For example, an emphysematous lesion in a particular CT image could be very small (consisting of a single pixel) or very large (consisting of a cluster of many connected pixels). Figure 1 shows two representative CT scans which illustrate that there may be many small lesions (figs 1A and B) or fewer larger lesions (figs 1C and D). The number of lesions of all sizes (measured in numbers of pixels) was counted and the cumulative number (Y) of these lesions larger than a given size was plotted against that lesion size (A) on a log-log plot (fig 2).^16,24 Least squares regression on logY versus logA found the best fit linear equation logY=logK − D logA corresponding to a power law equation Y=KA^−D. The parameter logK is the intercept or number of lesions larger than area A=1 pixel (1 pixel=0.004 cm²). The slope D is the power law exponent. According to this calculation, lungs with predominantly small lesions have a steep slope and a large D while lungs with larger lesions have a slope that is less steep resulting in a smaller D.

To determine regional differences in the extent of emphysema and lesion size, the lungs were divided at the carina into an apical and basal region.

Analysis of data

Differences in pulmonary function, exercise, lung volume, percentage emphysema, and D following LVRS were tested using a paired two tailed t test. Correlation coefficients were calculated to test the goodness of fit of the power equations. The change in exercise data was correlated with D and with the percentage emphysema using simple regression analysis. A p value of less than 0.05 was considered significant.

RESULTS

Subject demographic data (table 1) show that, following surgery, there was an improvement in both the static (TLC, FRC, RV) and dynamic lung volumes (FEV₁, FVC) (p<0.0001) with no change in the carbon monoxide transfer factor (p=0.81). There was also an improvement in the cardiopulmonary exercise ability as measured by cycle ergometry (p<0.001).

There was a negative correlation between the log cumulative number of lesions greater than a given area versus the log of that area (preoperative: r=0.96 (SD 0.04), postoperative: r=0.94 (SD 0.06)). Figure 2 shows the power law analysis of the preoperative and postoperative data from one subject in whom the exercise performance increased by 40 Watts. The data in fig 2 show an increase in the power law relationship (D) (steeper slope) and the Y intercept (K), indicating that there is a shift in the size distribution towards smaller lesions following LVRS. When expressed as a percentage of total lung volume, there was also a decrease in the percentage of the lung occupied by emphysematous lesions (preoperative 49%, postoperative 27%).

Table 2 shows the total lung volume, percentage emphysema, and the power law exponent (D) for the whole lung and for the apical and basal regions. These data show that there is more emphysema and larger lesions (smaller D) in the region of the lung above the carina than below it. The postoperative decrease in percentage emphysema is significant for the whole lung and each of the two regions, while only the whole lung D was significantly different.

The change in cardiopulmonary exercise (Watts) measured before and after surgery correlated with the change in percentage emphysema (r=0.62, p=0.003; fig 3A) and less strongly with the change in whole lung D following LVRS (r=0.47, p=0.03; fig 3B). The change in exercise correlated with the preoperative percentage emphysema (r=0.51, p=0.02; fig 4A) but not with the preoperative D (r=−0.13, p=0.5; fig 4B).

The regional heterogeneity of the emphysema distribution in the lung was examined by dividing the lung into regions above and below the carina. These data show that there was a correlation between the change in exercise and the preoperative percentage emphysema which was strongest in the apical region (r=0.63, p=0.002) and not significant in the basal region (r=0.16, p<0.5; table 3). The preoperative apical D was also correlated with the change in exercise following surgery (r=−0.60, p=0.004; table 3). The preoperative D for the apical region was very strongly correlated with the percentage emphysema in the apical region (r=−0.94, p<0.001) and both predicted the change in exercise.

DISCUSSION

The data reported here show that, despite a wide range of responses, there is a mean improvement in functional outcome parameters following LVRS (table 1) which is consistent with other investigators.^1–5 The results also confirm previous reports of a decrease in overall lung volume, measured both by body plethysmography (table 1) and CT (table 2), and a decrease in the volume of the lung occupied by emphysematous lesions larger than 5 mm in diameter. The power law analysis extends these observations by providing a quantitative method for reliably detecting the location and size of the emphysematous lesions. This observation confirms previous results using qualitative^8,10 and quantitative assessments^15,25 of disease distribution and provides an objective tool for making this prediction.

Several studies have shown that subjects with a heterogeneous pattern of emphysema on CT scanning respond better to LVRS than those with a homogeneous distribution.^{6,8,10,15,25–28} Furthermore, the recent report by the NETT study that patients with homogeneous disease and very low carbon monoxide transfer factor do not benefit from LVRS⁷ stresses the importance of defining criteria whereby patients can be selected who will have the best response to surgery. However, the definition of “heterogeneous/homogeneous pattern” is ambiguous and difficult to apply in clinical settings. Qualitative scoring systems developed for CT scans show variability between observers and institutions.^10,11,29 Quantitative CT scanning allows the separation of mild from severe disease^16,19,24 and the quantification of structural changes following surgery.^12–14 Although CT scanning provides a method of quantifying the size and extent of emphysema within the lungs of living subjects, no single method of CT assessment is universally accepted by all investigators. Emphysema has been quantified using the lowest fifth percentile of the radiographic attenuation distribution,³⁰ a “density mask” cut off of attenuation values,²³ and by expansion of the lung volume beyond normal,¹⁹ but none of these techniques quantifies the size of the lesions. Recent attempts to quantify the distribution of emphysema have focused on the relative proportion of upper versus lower²⁵ and/or central versus peripheral¹⁵ emphysema. Both of these techniques show some promise in predicting outcome, but neither quantifies the size of the emphysematous lesion.

This study was performed using conventional CT images. The standard clinical practice is to assess emphysema on thin slice CT images reconstructed using an edge enhancing algorithm. However, it has been shown that the decreased signal to noise ratio in these high resolution CT images diminishes the ability to discriminate different densities within the lung.³¹ While slice thickness and reconstruction algorithm will have an effect on the apparent size of the lesion (partial volume effect), we have used the CT images of the same thickness both before and after surgery and a density mask cut off appropriate for these images.^19,23

The results presented here confirm the reports of Sakai et al²⁴ and Mishima et al¹⁶ who showed that the number and size of emphysematous lesions is described by a power law relationship. Mishima et al further illustrated this effect using an elastic spring network model of the lung that showed a large decrease in the exponent (D) of the power law relationship (less steep slope) with a minimal change in the percentage of the model occupied by “lesions”. They concluded that a decrease in the power law relationship (D) (less steep slope) reflects coalescence into larger lesions and not just more low attenuation voxels on the CT scan.¹⁶ Our data also show that the slope is steeper (larger D) when small lesions predominate and becomes less steep (smaller D) as more large lesions appear (fig 2).

Cardiopulmonary exercise is a valuable quantitative outcome measurement for LVRS,³² and our data show improvement in exercise, measured in Watts, in relation to both a decrease in percentage emphysema and an increase in D following surgery. The present analysis confirms previous results showing that the percentage emphysema in the surgically accessible upper lung regions is more strongly correlated with exercise improvement than the percentage emphysema in the lower lung.¹⁵ More importantly, it extends this analysis by showing that the size and number of lesions (D) in the upper lung predicts exercise improvement following LVRS. When large emphysematous lesions were removed (increasing D), there was a significant increase in the exercise capacity of the subject (fig 3). Interestingly, some patients had a lower D (change in D <0) following surgery (fig 3), which suggests that removing lung tissue allowed an expansion of the remaining lung and created larger emphysematous lesions. The fact that some of these subjects did show a modest increase in exercise following surgery shows that removal of emphysema may be important. The spatial distribution of the lesions can be determined by dividing the lung into upper and lower regions at the carina. This analysis shows (table 2) that before surgery there was more emphysema and that the lesions were larger in the upper regions than in the lower. Furthermore, the patients with the largest lesions in the upper lung had the greatest improvement in exercise following surgery (table 3).

The analysis presented here is somewhat limited by its retrospective nature and small number of subjects. While the results have a degree of scatter, the overall trend is sufficient to generate the hypothesis that a power law analysis of the CT scan can determine the extent and severity of emphysema and predict the outcome of LVRS. This analysis adds information to the currently used algorithms that use CT measurements to determine lung structure, density, volume, surface area, and airway dimensions by providing an estimate of both the size and location of the emphysematous lesions. We suggest that the analytical method reported here could provide a powerful tool for preoperative selection of patients most likely to benefit from LVRS, that deserves to be tested in a larger clinical trial.