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* From the Division of Thoracic Surgery, "Umberto I" Regional Hospital, Ancona, Italy.
Correspondence to: Alessandro Brunelli, MD, Via S. Margherita 23, Ancona 60129, Italy; email: alexit_2000{at}yahoo.com
Abstract
Background: Lung resections determine a variable functional reduction depending on the extent of the resection and the time elapsed from the operation. The objectives of this study were to prospectively investigate the postoperative changes in FEV1, carbon monoxide lung diffusion capacity (DLCO), and exercise tolerance after major lung resection at repeated evaluation times.
Methods: FEV1, DLCO, and peak oxygen consumption (
O2peak) calculated using the stair climbing test were measured in 200 patients preoperatively, at discharge, and 1 month and 3 months after lobectomy or pneumonectomy. Preoperative and repeated postoperative measures were compared, and a time-series, cross-sectional regression analysis was performed to identify factors associated with postoperative O2peak.
Results: One month after lobectomy, FEV1, DLCO, and O2peak values were 79.5%, 81.5%, and 96% of preoperative values and recovered up to 84%, 88.5%, and 97% after 3 months, respectively. One month after pneumonectomy, FEV1 percentage of predicted, DLCO percentage of predicted, and O2peak values were 65%, 75%, and 87% of preoperative values, and were 66%, 80%, and 89% after 3 months, respectively. Three months after lobectomy, 27% of patients with COPD had improved FEV1, 34% had improved DLCO, and 43% had improved O2peak compared to preoperative values. The time-series, cross-sectional regression analysis showed that postoperative O2peak values were directly associated with preoperative values of O2peak, and postoperative values of FEV1 and DLCO, and were inversely associated with age and body mass index.
Conclusions: Our findings may be used during preoperative counseling and for deciding eligibility for operation along with other more traditional measures of outcome.
Key Words: carbon monoxide lung diffusion capacity • exercise test • follow up • lung cancer • oxygen consumption • pulmonary function tests • pulmonary resection
Many articles123456789101112131415 have shown that lung resection may reduce pulmonary function and exercise capacity by 10 to 40% depending on the extent of the resection and the time elapsed from the operation. Most of the series, however, included < 100 patients, who were operated on, in most cases, more than a decade ago through a posterolateral thoracotomy, and with variable repeat evaluation times, making it difficult to draw definitive conclusions on long-term functional effects of lung resection. The objectives of this study were to evaluate the changes of pulmonary function (FEV1 and carbon monoxide lung diffusion capacity [DLCO]) and exercise tolerance (peak oxygen consumption [O2peak] calculated using stair climbing test) in a prospective series of > 200 patients submitted to major lung resections for lung cancer at a single center in a 30-month period, and to assess the factors associated with these changes.
Materials and Methods
Two hundred fifty-three patients were submitted to major lung resection for non-small cell lung cancer at our unit from June 2003 through December 2005 and were prospectively enrolled in this study. The study was approved by the local Institutional Review Board of the hospital, and all patients gave informed consent to participate in the study. Postoperative 30-day or in-hospital mortality was 4% (10 patients). Patients were evaluated using pulmonary function testing (PFT) and symptom-limited stair climbing tests before the operation (usually 2 to 3 days before surgery), at discharge (median, 8 days; range, 4 to 14 days), and 1 month and 3 months postoperatively. Patients submitted to chest wall or diaphragm resection were not included. Five patients were not able to perform the preoperative stair climbing test for severe limiting musculoskeletal or neurologic disorders. Twenty patients did not perform the repeat examination at discharge for the occurrence of complications that contraindicated PFT or exercise testing (prolonged air leak with chest tube in place, atrial fibrillation, myocardial ischemia) but were reexamined at 1 month. This left a total of 218 patients with complete cardiopulmonary assessment at discharge (193 lobectomies, 25 pneumonectomies) and 238 patients at 1 month (212 lobectomies, 26 pneumonectomies). At 3 months, 38 patients dropped out for several reasons (lung cancer recurrence, current chemotherapy, refusal), leaving 200 patients (180 lobectomies, 20 pneumonectomies) with complete cardiopulmonary assessment (FEV1, DLCO, and stair climbing test).
Patients were operated on by qualified thoracic surgeons and were managed in a dedicated thoracic surgery unit. Patients were considered inoperable in case of predicted postoperative FEV1 (ppoFEV1) and predicted postoperative DLCO (ppoDLCO) values < 30%, in association with an insufficient exercise tolerance (height at preoperative stair climbing test < 12 m or O2peak measured at cycle ergometry < 10 mL/kg/min). As a rule, lung resections were performed through a muscle-sparing lateral thoracotomy. No patients underwent video-assisted thoracic surgical lobectomy. Postoperative management included chest physiotherapy, mobilization as early as possible, antibiotic and antithrombotic prophylaxis, and thoracotomy chest pain control by continuous IV infusion of ketorolac and tramadol to keep the visual analog score < 3 to 4 in the first 72 h (on a scale from 0 to 10, assessed twice daily). No formal preadmission or postdischarge physiotherapy programs were administered.
PFT was performed according to American Thoracic Society criteria. DLCO was measured by the single-breath method. Results of spirometry were collected after bronchodilator administration and were expressed as percentage of predicted for age, sex, and height according to the European Community for Steel and Coal prediction equations.16 Thoracotomy chest pain at the time of repeat PFT was assessed and, if any, controlled by administration of oral analgesics. In all cases, the visual analog scores before PFT and repeat exercise testing were kept < 2 (on a scale from 0 to 10).
Exercise Test Methods
The stair climbing test was performed as symptom-limited exercise. Our hospital has 16 flights of stairs, each flight having 11 steps. Each step is 0.155 m in height. The patients were asked to climb, at a pace of their own choice, the maximum number of steps and to stop only for exhaustion, limiting dyspnea, leg fatigue, or chest pain. During the exercise, pulse rate and capillary oxygen saturation were monitored using a portable pulse oximeter. For each patient, the number of steps climbed and the time taken to complete the test was recorded in order to deduce the following ergometric variables: work (height of the step in meters x steps per minute x body weight in kilograms x 0.1635)1718 and O2peak in milliliters per minute (5.8 x body weight in kilograms + 151 + 10.1 x work).1718 The same equations were used to calculate work and O2peak in the preoperative and postoperative tests.
Statistical Analysis
Preoperative and repeat postoperative (discharge, 1 month, 3 months) values of FEV1, DLCO, and O2peak were compared by means of the repeated-measures analysis of variance with adjusted (Games-Howell post hoc test) pairwise comparisons.19 A correlation analysis between O2peak and PFT results at different evaluation times was performed by using the Spearman rank correlation test.
A random-effects, time-series, cross-sectional regression analysis was performed to identify factors associated with postoperative O2peak. For this analysis, the dependent variable (postoperative O2peak) and the repeat postoperative FEV1 and DLCO values were analyzed as panel longitudinal data. The other variables were used in the regression analysis: age, body mass index, type of operation (lobectomy vs pneumonectomy); neoadjuvant chemotherapy; smoking history (pack-years); preoperative values of FEV1, DLCO, and O2peak; COPD status; cardiac comorbidity; and percentage of functioning parenchyma removed during operation (details are given in the Appendix).
There are two kinds of information in panel data: the cross-sectional information reflected in the differences between subjects, and the time-series information reflected in the changes within subjects over time. Panel data regression techniques allow one to take advantage of both types of information. The analysis was performed under the XTreg command on Stata 8.2 software (StataCorp; College Station, TX).
The regression analysis was subsequently validated by bootstrap analysis.202122 All the statistical tests were two tailed with a significance level of p = 0.05, and were performed using statistical software (Stata 8.2).
Results
Table 1
shows the characteristics of the patients analyzed in this study. Table 2
shows the preoperative and postoperative values of percentage of predicted FEV1 (FEV1%), percentage of predicted DLCO (DLCO%), and O2peak in patients submitted to lobectomy or pneumonectomy. The analysis of variance showed a significant impact of time on the dependent variables. Table 3
shows the reductions of postoperative FEV1 and DLCO after different surgical procedures. Figure 1
shows the values of the residual FEV1%, DLCO%, and O2peak with respect to preoperative values at different postoperative evaluation times.
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O2peak values were 79.5%, 81.5%, and 96% of preoperative values, respectively, and recovered up to 84%, 88.5%, and 97% after 3 months, respectively. One month after pneumonectomy, FEV1%, DLCO%, and O2peak values were 65%, 75%, and 87% of preoperative values, respectively, and were 66%, 80% and 89% after 3 months, respectively.
The correlation coefficients between O2peak and PFT results at different evaluation times were all < 0.2, indicating poor correlation. Conversely, the correlation coefficients between predicted postoperative measures (ppoFEV1, ppoDLCO, and predicted postoperative O2peak) and the corresponding observed measures (FEV1, DLCO, and O2peak) at 3 months were 0.75 (p < 0.0001), 0.71 (p < 0.0001), and 0.41 (p < 0.0001), respectively. Table 4
shows the percentage losses of FEV1, DLCO, and O2peak at different postoperative times and with respect to preoperative values in patients with and without COPD submitted to lobectomy.
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O2peak after operation in both groups at 3 months (43% vs 40%, respectively).
Table 5
shows the results of the time-series, cross-sectional regression analysis. The residual postoperative O2peak was directly associated with preoperative value of O2peak, postoperative values of FEV1 and DLCO, and inversely associated with age and body mass index.
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The objectives of the present study were to evaluate the changes of pulmonary function and exercise tolerance after major lung resection in patients with lung cancer, and to assess the factors associated with postoperative exercise capacity at repeated postoperative evaluation times. This prospective series differs from previous works on similar subjects insofar as it is a large, homogeneous group of patients treated over a relatively short period of time (30 months) at a single center, including an early evaluation time at discharge in addition to repeated evaluations at 1 month and 3 months, which allowed us to better analyze the trend of postoperative recovery of pulmonary or exercise capacity. Furthermore, the large sample size (200 patients at 3 months) made it possible to stratify the analysis by different procedures or by COPD status.
As all our patients were operated on for lung cancer, we chose the 3-month period as the latest evaluation time with the main intent to limit the dropout rate. Indeed, at 3 months, 16% of patients evaluated at 1 month dropped out for several reasons (recurrence, adjuvant chemotherapy, refusal to show at follow-up). Concerns of dropout rates have been reported in other studies,810 and they may certainly affect the results. In fact, patients who did not present at follow-up should presumably be considered the patients with worse conditions, and prolonging the last evaluation time (ie, 6 months or 12 months) could falsely improve the results for a selection bias ("cream-skimming" effect).
We used the stair climbing test as a form of exercise testing. Some authors2324 have shown a good correlation between stair climbing and cycle ergometry with, however, higher values of O2peak measured during stair climbing.
Although the accuracy of the calculation of O2peak during the stair climbing test is not universally accepted,2526 and a comparison between the calculated O2peak at stair climbing test and the O2peak measured at cycle ergometry was never reported, we used the same method of calculation in the preoperative and in the repeated postoperative exercise tests. Therefore, we considered the differences of this parameter between preoperative and postoperative evaluations reliable.27
Being simple, economical, and brief, the stair climbing test appears suitable for multiple evaluations on a large number of patients. Moreover, it more closely resembles a normal daily activity than cycle ergometry, and it has been shown to be more stressful than any other form of exercise testing,232425 making it particularly useful for uncovering deficits in the oxygen transport system.
We found that after lobectomy FEV1 and DLCO increased by 15 to 18% from discharge to 3 months, and reached 84 to 89% of the preoperative values. O2peak showed a lower loss at discharge (88% of preoperative values) and reached 97% of the preoperative value at 3 months. The percentage of reduction of FEV1 and DLCO at 3 months291011121314 and the minimal loss in O2peak1014 were in line with those reported by other authors,813 who found a greater loss in O2peak after lobectomy. Differences in the type of exercise test and sample size may contribute to explain the discrepancy. Nevertheless, it appears that after lobectomy, patients had a more complete recovery of exercise tolerance compared to their airflow and gas exchange capacities, presumably due to other compensatory mechanisms related to the cardiovascular system and the peripheral oxygen extraction capacity. Consistent with previous findings, postoperative O2peak showed a poor correlation with postoperative PFT results.
After pneumonectomy, we found that although FEV1 remained substantially stable from discharge to 3 months, DLCO recovered up to 80% of preoperative values (+ 30% compared to value at discharge). This finding may be explained by pulmonary vascular and hemodynamic compensatory mechanisms. Although the loss of O2peak after pneumonectomy was considerably lower than the loss of O2peak reported by most of the studies,89101314 its residual value did not improve much from discharge to 3 months (from 82 to 89%, respectively).
In line with previous reports,11 we found that the exercise capacity after major lung resection was poorly correlated with FEV1 or DLCO values, indicating its multifactorial nature and the limited role of PFT alone in predicting the residual postoperative physical activity. Similarly to other studies,28293031323334 we found that patients with COPD had a significantly lower reduction of FEV1 compared to non-COPD patients after lobectomy. Improvement in elastic recoil and relief of airways obstruction may contribute to explain this finding. In contrast to a previous study,35 mean O2peak values neared 100% of preoperative values in both groups, 3 months after lobectomy. This finding may have important clinical implications in the selection of patients with COPD, who will have an almost complete recovery of their exercise tolerance after lobectomy.
Time-series, cross-sectional regression analysis showed that younger patients with higher preoperative O2peak, higher postoperative FEV1 and DLCO, and lower body mass index will be the patients to have higher values of postoperative O2peak. However, the model explained only 30% of the between-subject and within-subject variability of the postoperative exercise capacity. Further analyses factoring additional variables (ie, cardiovascular and peripheral oxygen extraction parameters) are needed.
Limitations of the Study
A possible limitation of this study is one common to most of the follow-up analyses and concerns the patients who dropped out. As these patients could have been patients with the worst functional status, their inclusion in the analysis could have perhaps changed the results, and this should be taken into account when interpreting the results.
A certain proportion of our patients received adjuvant chemotherapy. As chemotherapy has been proven to impair gas exchange,36 the inclusion of these patients could have influenced the results. As most of our patients started chemotherapy 4 to 6 weeks after operation, the problem refers mainly to the last evaluation time (3 months). However, only 20 of the 200 patients studied at 3 months were submitted to adjuvant chemotherapy. Twenty-one patients who performed the 1-month evaluation test dropped out for concomitant chemotherapy at 3 months. We selected to include the 20 patients receiving chemotherapy after a preliminary analysis that did not show differences in PFT results and O2peak at 3 months compared to the other patients. Finally, it must be noted that the results obtained in this study refer to calculated values of O2peak after a constant work rate exercise test, and they may differ from those obtained after incremental work rate tests (such as cycling or treadmill).
Conclusions and Clinical Implications
We think our findings may be used during preoperative counseling and for deciding eligibility for operation along with other more traditional measures of outcome, such as morbidity and mortality. In fact, what the patients fear most of their operation is their inability to resume a normal daily life,37 and the knowledge of their estimated residual function at different postoperative times may influence their decision to be operated on. We also showed that PFT has a limited role in predicting the residual postoperative physical activity. In this regard, the systematic use of exercise testing should be recommended. Nevertheless, further investigations are needed to identify other factors associated with the recovery of postoperative exercise tolerance, and for developing predictive models of the residual function, which may be used both for patients selection and as an additional measure of outcome in quality-of-care analyses.
Appendix
For the purpose of this study, a concomitant cardiac disease (cardiac comorbidity) was defined as follows: previous cardiac surgery, previous myocardial infarction, history of coronary artery disease, current treatment for hypertension, arrhythmia, or cardiac failure. All the patients with a concomitant cardiac disease underwent a specialized cardiac evaluation before performing the stair climbing test, and they were allowed to perform the test only when deemed in a hemodynamically stable state. No patients with a concomitant cardiac disease were excluded from this study after cardiac evaluation.
We computed the number of pack-years of smoking as the total number of years smoked multiplied by the average number of cigarettes smoked per day, divided by 20. Predicted postoperative pulmonary functions (ppoFEV1 and ppoDLCO) were estimated based on the number of functioning segments removed during operation.
The percentage of functional parenchyma removed during operation was estimated by means of CT scan, bronchoscopy and, when performed, quantitative perfusion lung scan (in all pneumonectomy candidates and in patients with preoperative FEV1 < 70% of predicted). COPD was defined according to Global Initiative for Chronic Obstructive Lung Disease criteria (FEV1 < 80% and FEV1/FVC < 0.7).
Footnotes
Abbreviations: DLCO = carbon monoxide lung diffusion capacity; DLCO% = percentage of predicted carbon monoxide lung diffusion capacity; FEV1% = percentage of predicted FEV1; PFT = pulmonary function testing; ppoDLCO = predicted postoperative DLCO; ppoFEV1 = predicted postoperative FEV1; O2peak = peak oxygen consumption
None of the authors have any conflicts of interest to disclose.
Received for publication May 27, 2006. Accepted for publication July 26, 2006.
References
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