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(Chest. 2000;118:721-727.)
© 2000 American College of Chest Physicians

Quantitation of Regional Ventilation During the Washout Phase of Lung Scintigraphy*

Measurement in Patients With Severe COPD Before and After Bilateral Lung Volume Reduction Surgery

John M. Travaline, MD, FCCP; Alan H. Maurer, MD; N. David Charkes, MD; Jean Luc Urbain, MD; Satoshi Furukawa, MD and Gerard J. Criner, MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Drs. Travaline and Criner), Department of Diagnostic Imaging (Drs. Maurer, Charkes, and Urbain), and Cardiothoracic Surgery (Dr. Furukawa), Temple University School of Medicine, Philadelphia, PA.

Correspondence to: John M. Travaline, MD, FCCP, Pulmonary and Critical Care, Temple University School of Medicine, 3401 North Broad St, Philadelphia, PA 19140; e-mail: trav{at}astro.ocis.temple.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: We sought to investigate the effect of lung volume reduction surgery (LVRS) on regional lung ventilation.

Design: Retrospective analysis of routinely acquired data before and after LVRS.

Setting: Large, urban, university medical center.

Patients: Twenty-nine patients with severe emphysema.

Intervention: Bilateral LVRS.

Measurements and results: 133Xe washout curves during lung scintigraphy exhibit a biphasic pattern (the first component of the washout curve [mr] corresponds to an initial rapid phase in washout that reflects larger airways emptying, and the second component [ms] reflects a slower phase of washout that is attributed to gas elimination via smaller airways). We analyzed six standardized regions of the lung (upper, mid, and lower zones of the right and left lung), and calculated mr and ms for each lung region. The mean (± SE) baseline FEV1 was 0.69 ± 0.04 L, total lung capacity (TLC) was 139 ± 4% predicted, and the residual volume (RV)/TLC ratio was 65 ± 2%. The mean improvement in FEV1 3 months post-LVRS was 38%. Post-LVRS, mr and ms increased in 79 and 74 lung regions, respectively, and there was no relationship with respect to lung regions that had or had not been operated on. The increase in ms, however, significantly correlated with the increase in FEV1 (r = 0.66; p < 0.0001) and the decrease in RV/TLC (r = -0.67; p < 0.0001). An increase in ms also correlated with a decrease in PaCO2 (r = -0.39; p = 0.03), but mr showed no relationship with any parameter.

Conclusions: Small airways ventilation in lung regions that had and had not been operated on is associated with a greater improvement in lung mechanics following LVRS.

Key Words: emphysema • lung scintigraphy • lung volume reduction surgery • ventilation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Lung volume reduction surgery (LVRS) is thought to enhance airway conductance by increasing lung elastic recoil. This improvement is thought to occur at the level of the small airways; however, little information exists to support this contention. Moreover, the current methods of assessing regional lung function and small airways function are limited. Spirometry provides information about global lung airflow. Emphysema, however, rarely affects the entire lung homogenously. An evaluation that characterizes regional lung function may be more valuable than spirometry in assessing the effects of LVRS on regional lung function.

Lung scintigraphy has evolved as a useful clinicaltool to assess lung ventilation and is particularly sensitive in the detection of obstructive lung disease.1 2 Ventilation during the washout phase of lung scintigraphy exhibits a biexponential pattern. The first component of the washout phase (mr) corresponds to the slope of the initial rapid washout phase, which reflects large airways emptying. The second component of the washout phase (ms) reflects the slope of a slower washout phase that is attributed to gas elimination via smaller airways. We analyzed a biexponential model based on the ability of lung quantitative scintigraphy to examine regional ventilation to investigate two effects of LVRS on lung function. First, we wanted to study the effect of LVRS on small airways ventilation as determined by the slow component of washout during ventilation scintigraphy. Second, we wanted to assess the relationship of LVRS to regional lung ventilation (ie, to determine how regional and global ventilation were affected with respect to the location of lung resection).


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection
Patients who underwent LVRS at Temple University Hospital between February 1995 and April 1997 are included in this analysis. Patients were enrolled into the LVRS program after meeting the specified enrollment criteria (Table 1 ). After informed written consent, all patients underwent 6 to 8 weeks of pulmonary rehabilitation just prior to LVRS. This study was approved by our institutional review board.


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  		Table 1. LVRS Enrollment Criteria*

 
Lung Imaging
High-resolution CT (HRCT) scanning (PQ 5000 scanner; Picker Corp; Cleveland, OH, and GE Highlight Advantage; General Electric; Milwaukee, WI) was performed preoperatively using 1.5-mm collimation at 10-mm intervals from the lung apices to the lung bases.

Pulmonary scintigraphy was performed using a large-field-of-view gamma camera (GE 535; General Electric) interfaced to a computer acquisition work station (Nuc Lear Mac; Scientific Imaging; Denver, CO). Ventilation lung images were acquired in the posterior projection during inhalation, equilibration, and washout of 133Xe gas. For the inhalation phase, 10 mCi of 133Xe gas was introduced into a closed rebreathing system (Ventil-Con II; Radx; Houston, TX), and the patient breathed at the usual rate as computer images were acquired at 4-s intervals for 16 s (wash-in phase). With the patient still breathing at the usual rate, a 3-min equilibration phase was recorded with the patient rebreathing a mixture of room air and Xe gas. This was followed by a washout phase during which the patient inspired room air, and the expired 133Xe and room air mixture was vented to a charcoal trap ventilation system. Washout images were recorded every 30 s for a total of 4 min. All images were acquired in a 128 x 128-byte mode matrix. Following the ventilation study, perfusion images were acquired after the IV administration of 4 mCi 99mTc-macroaggregated albumin. All images were in a 128 x 128-word matrix for 500,000 counts.

Lung-imaging studies were performed approximately 4 to 6 weeks prior to LVRS and then 3 months following LVRS. Preoperative and postoperative ventilation-perfusion (/) scans in a representative patient are shown in Figure 1 . The lung-imaging studies all were performed while the patients remained in stable condition and were performed within 2 weeks of the pulmonary function studies



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  		Figure 1. Top left, A: a representative preoperative posterior view ventilation scan showing equilibrium images (frames 1 to 6) and washout images (frames 7 to 12). Note the decreased ventilation to both apices during the washout portion of the study. Top right, B: in the postoperative study, there is reduction in gas trapping. Bottom, C: the preoperative and postoperative perfusion studies demonstrate apical region perfusion abnormalities that match the ventilatory abnormalities (top left, A, and top right, B). Note the improvement in perfusion to the apices in the postoperative study (arrows).

 
Operative Procedure
The operative methods for LVRS included the following: (1) biapical resection, the removal of emphysematous lung tissue using a linear stapling device via a standard median sternotomy or sequential video-assisted thoracostomy; and (2) nonapical resection, the removal of the worst emphysematous portions of each lung, regardless of location. Regardless of which of the two operative methods was used, 30 to 50% of the volume of each lung was surgically resected. The areas targeted for resection were based on a preoperative determination of the worst areas of emphysema, determined by experienced thoracic radiologists and nuclear medicine physicians, using visual inspection and quantitation of lung perfusion scans and HRCT scanning. The same cardiothoracic surgeon (S.F.) performed LVRS in all patients.

Analysis of Ventilation Scans
The 133Xe lung images were divided into six equally sized regions using computer manual regions of interest that were superimposed on both the pre-LVRS and post-LVRS scans. For each of the six regions, the computer generated time/activity curves (Fig 2 ) with the activity in each region expressed as counts per second. Accordingly, a biexponential curve was fit to the washout data:

where At is activity in the lung region at any time t, Ar is the coefficient of the rapid component, and As is the coefficient of the slow component, using a data analysis and graphing software tool (KaleidaGraph; Synergy Software; Reading, PA). To confirm the validity of the biexponential model, washout data were analyzed by a software program (DIMSUM [J DiStefano III]; Biocybernetics Laboratory, University of California; Los Angeles, CA) for optimal fit to a multiexponential function using statistical and goodness-of-fit criteria. The best fit was to a sum of two exponentials.



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  		Figure 2. Ventilation curves for each region in a representative patient. Note that the initial wash-in phase is followed by an equilibrium period and then by a two-component washout portion. The bottom two curves are regions where this patient’s emphysema was worse.

 
Lung Function Measurements, 6-Min Walk Test, and Arterial Blood Gas Analysis
Spirometry and lung volume determination were performed using both the gas dilution method and body plethysmography (System 6200 Autobox DL plethysmograph; SensorMedics; Yorba Linda, CA) under standard American Thoracic Society guidelines.3 Postbronchodilator values are reported. The usual parameters of airflow obstruction (ie, FEV1, forced expiratory flow between 25% and 75% of maximal expiratory flow [FEF25–75%], and forced expiratory flow at 50% of the maximal expiratory flow curve [FEF50%]) and of gas trapping (residual volume [RV]/total lung capacity [TLC] ratio) were examined.

On a separate day, the total distance that the patient was able to ambulate in a corridor for 6 min was recorded4 as the 6-min walk distance (6MWD).

Arterial blood gas was sampled from the radial artery with the patients seated 20 min after receiving a bronchodilator and breathing room air.

Follow-up
Lung scintigraphy and pulmonary function studies were repeated at 3 months post-LVRS in the same manner as pre-LVRS (ie, within 2 weeks of one another) and while the patients were in stable condition.

Determination of Regions of Resection and Correlation With Physiologic Parameters and Washout Components
Operative reports were reviewed to determine the actual areas of the lung resected. In each operative report, the surgeon indicated the location and extent of resection. The terms used were either "wedge resection" or some numeric estimate (eg, "40% of the right upper lobe"). Regions were considered operated on when so indicated in the operative report. The six regions used in the analysis of the ventilation scans corresponded to the upper and lower lobes, as indicated in the operative report. The middle regions on both the left and right were considered operated on if either the operative report indicated right middle lobe resection (one patient) or if the report stated that >= 50% of an upper lobe was resected. Changes (ie, > 10% of the pre-LVRS value) in mr and ms then were correlated with physiologic parameters and the regions of resection.

Statistical Analysis
Data are expressed as mean ± SD except where otherwise noted. All statistical analyses were performed using a commercially available software program (SigmaStat, version 2.0; SPSS; Chicago, IL). Student’s paired t test was used to compare physiologic parameters before and after surgery. Relationships between parameters were determined using Pearson’s correlation.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Eighty-seven patients underwent LVRS. Fifty-eight patients were not included in this study for the following reasons: 30 patients did not have post-LVRS follow-up ventilation scans; 12 patients died prior to obtaining a follow-up ventilation scan; 9 patients did not have ventilation scans digitized for analysis; 5 patients did not have pre-LVRS ventilation scans because they were receiving mechanical ventilation just prior to LVRS; and 2 patients had LVRS following lung transplantation. Twenty-nine patients (mean age, 56 ± 9 years; 16 women) who underwent LVRS had pre-LVRS and post-LVRS lung ventilation scans available for analysis and, therefore, are included in this study.

Effect of LVRS on Ventilation Washout Parameters
The overall (all regions in all patients) mean values for rapid component of washout (mr) and the slow component (ms) pre-LVRS are 1.4% and 0.8% of maximum activity per second, respectively. Following LVRS, mr decreased to 1.2% of maximum activity per second (p = 0.03), while ms remained unchanged (0.8% maximum activity per second; p = 0.9).

The values for mr increased in 79 regions (45%), and those for ms increased in 74 regions (43%). The combined values for mr and ms increased in 34 regions (19%). The mean numbers of regions with an increase in mr and ms per patient were 2.7 and 2.6, respectively. For the regions that showed an increase in mr, the mean pre-LVRS value was 0.8% maximum activity per second, and the mean post-LVRS value was 1.6% maximum activity per second (p < 0.001). For the regions that showed an increase in ms, the mean pre-LVRS value was 0.4% maximum activity per second, and the mean post-LVRS value was 1.3% maximum activity per second (p < 0.001). This represented a greater than twofold increase in the magnitude of ms following LVRS.

Relationship Between Ventilation Washout Parameters and Physiologic Outcome
The number of regions in which ms increased correlated with various measures of airflow (FEV1, FEF25–75%, and FEF50%), RV/TLC ratio, PaCO2, and 6 MWD (Table 2 ). Figure 3 shows the relationship between the number of regions in which ms increased per patient and FEV1 (Fig 3 , left, A) and RV/TLC ratio (Fig 3 , right, B) post-LVRS. mr showed no relationship with any physiologic parameters (Table 2) .


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  		Table 2. Relationship Between Ventilation Washout and Physiologic Parameters Post-LVRS

 


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  		Figure 3. Plots showing the relationship between the number of regions in which ms increased and FEV1 (left, A) and RV/TLC ratio (right, B) following LVRS.

 
Relationship Between mr, ms, and Physiologic Parameters and the Region of Resection
Of 174 total lung regions analyzed (6 regions in each of 29 patients), 82 regions (47%) were operated on. All patients had at least two regions operated on, and one patient had five regions operated on. The mean number of regions operated on was 2.8 ± 0.9.

In the 74 regions where ms increased, the increases occurred regardless of whether or not the region was operated on, and the magnitude of the increase was no different between the regions that had been operated on and those that had not (p = 0.7). Similarly, in the 79 regions where there was an increase in mr, the increase was irrespective of whether the region was operated on (Fig 4 ).



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  		Figure 4. Plot showing the relationship between the number of regions in which washout parameters increased and resection.

 
There was no relationship between the number of regions operated on and any physiologic parameter.

Effect of LVRS on Physiologic Parameters
Baseline and post-LVRS physiologic data are shown in Table 3 . There were significant differences between the pre-LVRS and post LVRS values for forced vital capacity, FEV1, RV/TLC ratio, FEF25–75%, FEF50%, PaCO2, and 6MWD. There was no significant change in the ratio of PaO2/fraction of inspired oxygen (FIO2) ratio following LVRS.


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  		Table 3. Changes in Physiologic Parameters Following LVRS (n = 29)

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These data suggest that LVRS (1) produces an increase in ms, reflecting improved small airways ventilation, which significantly correlates with physiologic parameters of airflow (FEV1, FEF25–75%, and FEF50%), gas trapping (RV/TLC ratio), reduction in PaCO2, and exercise (6 MWD), and (2) affects regional ventilation, independent of the area or extent of resection.

Airflow obstruction in emphysema is principally related to a loss in lung elastic recoil.5 6 The loss of elastic recoil is associated with decreased airflow. LVRS, by increasing elastic recoil,5 7 facilitates greater airway traction and support, thereby increasing airway caliber, thus improving airflow, all factors that presumably contribute to improved lung function and a reduction in dyspnea in patients undergoing this procedure.5

Airflow through the lung is principally characterized by two different properties. In the large conducting airways (trachea down to the terminal bronchiole), gas flow is convective. The flow is relatively rapid. At the level of the terminal bronchiole, as airways become smaller and give rise to alveoli, the flow pattern is markedly reduced, and gas transport occurs predominantly by molecular diffusion.8 This change in flow pattern at the level of the terminal bronchiole is related to the abrupt increase in cross-sectional area of the airways.

When we examined the washout phase of 133Xe during lung ventilation scanning, we found a biphasic pattern of gas washout. We hypothesized that this biphasic pattern initially reflects the gas emptying of the large airways (bulk flow or convective gas transport), followed by gas emptying from the smaller, more distal airways. When we apply this observation to examine specific regions of the lung, we can appreciate the relative differences in the degree of gas emptying, but, more precisely, we can distinguish the relative contribution of each type of gas flow in each particular region.

The retention of xenon in the lung is indicative of obstructive airways disease, and inhomogenous clearance of xenon from the lung is an indication of regional airways disease.2 Early washout images are related to the clearance of xenon from healthy airways, while later washout images show evidence of regions with prolonged time constants.2 Since small airways (ie, those < 2 mm in diameter) are the major site of obstruction in emphysema,9 and since the time constant is therefore prolonged, the later portion of washout reflects these abnormal airways with prolonged time constants. Washout curves, particularly in patients with obstructive lung disease, are not monoexponential.2 Rather, the pattern of xenon clearance can best be described as a biexponential equation reflecting early, rapid washout from more normal (ie, larger) airways, and in the subsequent portion, delayed clearance from the small abnormal airways.

In emphysema, because of alveolar destruction, we expect the slow component of washout to be less. There is delayed lung emptying in emphysema in part due to a loss of elastic lung recoil. This delay in lung emptying is evident in the washout phase of the ventilation scan. When this washout component is examined quantitatively, the delay in emptying is particularly slow during the second exponential phase. This observation is consistent with the concept of small airways being affected in emphysema.

The reduction in PaCO2 and the nonsignificant change in the PaO2/FIO2 ratio that we observed following LVRS are consistent with the notion that there is a variable effect of LVRS on gas exchange based on the / ratio of both the lung units resected and the units remaining.10 In our patients, a reduction in PaCO2 suggests that proportionately fewer high / units remained following LVRS.

We conclude the following about LVRS: (1) that it globally enhances lung function, which is suggested by improved spirometry, lower PaCO2, and increased 6MWD; (2) that it improves ventilation through small airways; (3) that it is associated with an improvement in physiologic parameters that correlate with the enhancement in small airways function; and (4) that it improves regional ventilation in the lung independent of the area resected.


   Footnotes
 
Abbreviations: FEF25–75% = forced expiratory flow between 25% and 75% of maximal expiratory flow; FEF50% = forced expiratory flow at 50% of maximal expiratory flow; FIO2 = fraction of inspired oxygen; HRCT = high-resolution CT; LVRS = lung volume reduction surgery; mr = first component of the washout phase; ms = second component of the washout phase; 6MWD = 6-min walk distance; RV = residual volume; TLC = total lung capacity; / = ventilation/perfusion

Received for publication December 9, 1999. Accepted for publication April 6, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Alderson, PO, Lee, H, Summer, WR, et al (1979) Comparison of Xe-133 washout and single-breath imaging for the detection of ventilation abnormalities. J Nucl Med 20,917-922[Abstract/Free Full Text]
  2. Alderson, PO, Line, BR (1980) Scintigraphic evaluation of regional pulmonary ventilation. Semin Nucl Med 10,218-241[CrossRef][ISI][Medline]
  3. . American Thoracic Society. (1991) Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 144,1202-1218[ISI][Medline]
  4. Guyatt, GH, Pugsley, SO, Sullivan, MJ, et al (1984) Effect of encouragement on walking test performance. Thorax 39,818-822[Abstract]
  5. Gelb, AF, Zamel, N, McKenna, RJ, et al (1996) Mechanism of short-term improvement in lung function after emphysema resection. Am Rev Respir Dis 154,945-951
  6. Zamel, N, Hogg, J, Gelb, A (1976) Mechanisms of maximal expiratory flow limitation in clinically unsuspected emphysema and obstruction of the peripheral airways. Am Rev Respir Dis 113,337-345[ISI][Medline]
  7. Sciurba, FC, Rogers, RM, Keenan, RJ, et al (1996) Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N Engl J Med 334,1095-1099[Abstract/Free Full Text]
  8. West, JB (1994) Ventilation, blood flow, and gas exchange. Murray, JF Nadel, JA eds. Textbook of respiratory medicine (vol 1) 2nd ed. ,51-89 WB Saunders Philadelphia, PA.
  9. Hogg, JC, Macklem, PT, Thurlbeck, WM (1968) Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 278,1355-1360
  10. Albert, RK, Benditt, JO, Hildebrandt, J, et al (1998) Lung volume reduction surgery has variable effects on blood gases in patients with emphysema. Am J Respir Crit Care Med 158,71-76[Abstract/Free Full Text]



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