Lung cancer is generally a disease of older adults, and

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1 B-Type Natriuretic Peptide as a Predictor of Postoperative Cardiopulmonary in Elderly Patients Undergoing Pulmonary Resection for Lung Cancer Takashi Nojiri, MD, Masayoshi Inoue, MD, PhD, Kazuhiro Yamamoto, MD, PhD, Hajime Maeda, MD, PhD, Yukiyasu Takeuchi, MD, PhD, Yasunobu Funakoshi, MD, PhD, and Meinoshin Okumura, MD, PhD Departments of General Thoracic Surgery and Cardiology, Osaka University Graduate School of Medicine, Suita City; and Department of General Thoracic Surgery, Toneyama National Hospital, Toyonaka City, Osaka, Japan Background. The objective of the present study was to evaluate the utility of B-type natriuretic peptide for prediction of postoperative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. Methods. A prospective observational study was performed involving 80 consecutive patients aged 75 years or older who underwent a scheduled pulmonary resection for lung cancer in two specialized thoracic centers between January 2008 and June Baseline clinical details were obtained, and spirometry and examination of serum B-type natriuretic peptide levels were performed before surgery. The primary endpoint was the incidence of postoperative cardiopulmonary complications. Results. Postoperative cardiopulmonary complications were identified in 34 (43%) patients; these patients had significantly higher preoperative B-type natriuretic peptide levels than those without cardiopulmonary complications ( pg/ml vs pg/ml; p < ). The area under the receiver operating characteristic curve for B-type natriuretic peptide to predict postoperative cardiopulmonary complications after pulmonary resection for lung cancer was 0.85 (95% confidence interval 0.76 to 0.94; p < ). A B-type natriuretic peptide value of 30 pg/ml had a sensitivity of 79% and a specificity of 83% for predicting postoperative cardiopulmonary complications after pulmonary resection for lung cancer. The incidences of both cardiovascular and respiratory complications were significantly higher in patients with preoperative B-type natriuretic peptide levels of 30 pg/ml or more. Conclusions. Preoperative B-type natriuretic peptide level could be a useful predictor of postoperative cardiopulmonary complications in elderly patients after pulmonary resection for lung cancer. (Ann Thorac Surg 2011;92:1051 5) 2011 by The Society of Thoracic Surgeons Lung cancer is generally a disease of older adults, and age has been shown to be an important risk factor for morbidity and mortality after pulmonary resection [1, 2]. Because of these increased risks, elderly patients are offered curative surgery for lung cancer less often than younger patients [3, 4]. However, it is not appropriate that elderly patients be considered as unable to undergo curative surgery solely because of their advanced age. Because conventional methods of assessing operative risk provide only a limited ability to predict postoperative complications in elderly patients, it is important to identify more specific and more sensitive markers. B-type natriuretic peptide (BNP) is a useful prognostic predictor in patients with left ventricular (LV) dysfunction independent of hemodynamic parameters, such as LV ejection fraction [5]. Excluding cardiac diseases, an Accepted for publication March 21, Address correspondence to Dr Nojiri, Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2 (L5), Suita City, Osaka , Japan; nojirit@thoracic.med. osaka-u.ac.jp. increased BNP level was associated with some pulmonary diseases [6 9]. Therefore, it is plausible to expect that preoperative BNP levels could be useful for predicting postoperative cardiopulmonary complications. We previously reported that patients in all age groups with mildly elevated preoperative BNP levels have an increased risk of developing postoperative atrial fibrillation after pulmonary resection for lung cancer [10]. In this study, elderly patients ( 75 years) were enrolled, and they are known to have an increased risk for postoperative complications after pulmonary resection [11]. The purpose of the present study was to evaluate the utility of serum BNP levels for predicting postoperative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. Patients and Methods Study Design and Population Of 470 patients who underwent an elective pulmonary resection procedure for lung cancer at our institute from January 2008 to June 2010, this prospective observational 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 1052 NOJIRI ET AL Ann Thorac Surg COMPLICATIONS PREDICTED BY BNP 2011;92: study included 96 consecutive elderly patients aged 75 years or older. Complete preoperative and follow-up data were obtained for all of these patients. This study was performed at Osaka University Graduate School of Medicine and National Toneyama Hospital. The study protocol was approved by the Institutional Review Boards of both institutions, and all patients provided their written informed consent before participation. Exclusion criteria for the present analysis were cardiac rhythm other than sinus, previous atrial fibrillation, antiarrhythmic drug use, thyroid dysfunction, renal failure requiring hemodialysis, repeated pulmonary resection, and recent ( 1 month) angina pectoris, myocardial infarction, or pneumonia. As a result, 16 patients were excluded. Thus, 80 patients were finally chosen. Surgical Procedure All patients underwent anterolateral thoracotomy or videoassisted thoracic surgery (VATS). In VATS, 3 access ports were inserted through 1 to 2 cm skin incisions in the side of the chest. One of these skin incisions was extended by 4 to 5 cm, and the resected lung lobe was removed in a plastic bag without using a rib retractor. Patients in whom VATS was replaced intraoperatively with open thoracotomy were classified as open thoracotomy patients. All patients received preoperative epidural anesthesia for pain management, which usually remained in place for 2 to 4 days or until the chest drainage tubes were removed, after which they were switched to oral analgesia. Other postoperative management methods included early ambulation and low-flow nasal oxygen supplementation, as necessary. Preoperative Examinations Preoperative evaluations included a detailed history and physical examination, blood gas analysis, 12-lead electrocardiogram, spirometry, and determination of serum BNP levels. None of the patients had symptomatic coronary artery disease or congestive heart failure. Physical examinations and electrocardiographic findings at rest were unremarkable in the study population. The serum BNP concentrations were determined using a chemiluminescence enzyme immunoassay (MI02 Shionogi BNP; Shionogi Pharmaceutical, Osaka, Japan). The minimum concentration of BNP detectable with this system is 4 pg/ml. Postoperative All patients were followed up prospectively after surgery, and complications occurring during the same hospitalization as the index procedure were recorded. Cardiopulmonary complications were defined to include respiratory complications, such as pneumonia (fever 38 C, purulent sputum, abnormal findings on chest X-ray), acute respiratory distress syndrome (partial pressure of oxygen in arterial blood-fraction of inspired oxygen less than 200 mm Hg), respiratory insufficiency requiring tracheostomy, respiratory failure requiring mechanical ventilation, atelectasis with bronchoscopic therapy, home oxygen treatment, and cardiovascular complications, including arrhythmias (atrial fibrillation, paroxysmal supraventricular tachycardia, ventricular tachycardia), angina pectoris, myocardial infarction, congestive heart failure, and thromboembolic events. As prolonged air leak and bronchopleural fistulas are considered surgical factors, they were excluded. Finally, operative mortality was defined as death within 30 days after surgery. Statistical Analysis Data are expressed as means SD or as proportions. All data were analyzed using SPSS version 11.0 (SPSS Inc, Chicago, IL). Comparisons among all parameters were analyzed by one-way analysis of variance. Comparisons between the 2 groups were made using the Mann- Whitney test, with the 2 test for categoric variables. Logistic regression analyses were used to explore the risk factors for complications. Receiver operating characteristic curves were constructed to determine optimal sensitivity and specificity. Probability values of less than 0.05 were considered significant. Results The patients mean age was 78.4 years. Postoperative cardiopulmonary complications were identified in 34 (43%) of the 80 cases and are listed in Table 1. Overall, the most common complications were arrhythmias, especially atrial fibrillation, while pneumonia was the most common respiratory complications. The clinical and surgical characteristics of patients with and without postoperative cardiopulmonary complications are summarized in Table 2. Operative mortality was 1.3% (n 1). Postoperative cardiopulmonary complications were associated with male sex, smoking, and hypertension. There were no significant differences between patients with and without cardiopulmonary complications with respect to type of procedure, VATS procedure, combined resection, operating time, intraoperative blood loss, mediastinal lymph node dissection, or pathologic stage. In a comparison of the results of pulmonary function parameters between the 2 groups, patients with cardiopulmo- Table 1. Postoperative Cardiopulmonary Number (%) All complications 34 (43) Cardiovascular complications 28 (35) Atrial fibrillation 18 (23) Paroxysmal supraventricular tachycardia 6 (8) Ventricular tachycardia 1 (1) Acute myocardial infarction 2 (3) Acute arterial occlusion of the lower 1 (1) extremity Respiratory complications 12 (15) Pneumonia 6 (8) Home oxygen therapy 4 (5) Acute respiratory distress syndrome 2 (3) Acute exacerbation of interstitial pneumonia 1 (1)

3 Ann Thorac Surg NOJIRI ET AL 2011;92: COMPLICATIONS PREDICTED BY BNP 1053 Table 2. Patient Characteristics Without Cardiopulmonary With Cardiopulmonary (n 46) (n 34) p Value Age (years) Male 24 (52) 27 (79) a Smoking history 21 (46) 26 (76) a Hypertension 21 (46) 27 (79) a Hypercholesterolemia 10 (22) 10 (29) 0.44 Diabetes mellitus 4 (9) 3 (9) 0.64 Ischemic heart disease 3 (7) 7 (21) 0.06 Type of procedure: Segmentectomy or wedge resection 8 (17) 7 (21) 0.54 Lobectomy or bilobectomy 38 (83) 27 (79) 0.54 VATS procedure 32 (70) 15 (44) 0.12 Combined resection 1 (2) 2 (6) 0.39 Operating time (minutes) Blood loss (ml) Mediastinal lymph node dissection 26 (57) 14 (41) 0.12 Lung cancer staging IA, IB 38 (83) 25 (74) 0.33 IIA, IIB 4 (9) 3 (9) 0.98 IIIA, IIIB, IV 4 (9) 6 (18) 0.24 Values are shown as numbers (%) or means SD, unless otherwise indicated. VATS video-assisted thoracoscopic surgery. nary complications had significantly impaired percentpredicted forced expiratory volume in 1 second (FEV 1,% predicted) (p 0.02) and forced expiratory volume in 1 second/forced vital capacity (FEV 1 /FVC) (p 0.03) compared with those without cardiopulmonary complications (Table 3). Figure 1 shows the preoperative BNP levels in patients with and without postoperative cardiopulmonary complications. Patients with cardiopulmonary complications had significantly higher BNP levels than those without cardiopulmonary complications ( pg/ml vs pg/ml; p ). The preoperative serum Table 3. Preoperative Pulmonary Function Without Cardiopulmonary With Cardiopulmonary (n 46) (n 34) p Value VC, % predicted FEV 1,% a predicted FEV 1 /FVC, % a Dlco, % predicted RV/TLC ph Pao 2, Torr Paco 2, Torr Values are the means SD, unless otherwise indicated. Dlco carbon monoxide diffusing capacity; FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; Paco 2 carbon dioxide blood partial pressure; Pao 2 arterial oxygen blood partial pressure; RV/TLC ratio of residual volume to total lung capacity; Torr non-si unit of pressure; VC vital capacity. Fig 1. Preoperative B-type natriuretic peptide (BNP) levels in patients with and without postoperative cardiopulmonary complications. Patients with cardiopulmonary complications have significantly higher preoperative BNP levels than those without complications (p ).

4 1054 NOJIRI ET AL Ann Thorac Surg COMPLICATIONS PREDICTED BY BNP 2011;92: Table 4. Univariate and Multivariate Analyses of Factors for Predicting Postoperative Cardiopulmonary Univariate Analysis Multivariate Analysis Relative Risk (95% CI) p Value Relative Risk (95% CI) p Value Male ( ) ( ) 0.82 Smoking ( ) a ( ) 0.21 Hypertension ( ) a ( ) 0.11 FEV 1, % predicted ( ) a ( ) 0.10 BNP ( ) a ( ) a a Significant (p 0.05). BNP B-type natriuretic peptide; CI confidence interval; FEV 1 forced expiratory volume in 1 second. BNP level of the patient who died postoperatively of acute myocardial infarction was 143 pg/ml. On univariate and multivariate analyses (Table 4), an elevated BNP level was the most significant predictor of postoperative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. The area under the receiver operating characteristic curve for preoperative BNP levels to predict postoperative cardiopulmonary complications after pulmonary resection for lung cancer was 0.85 (95% confidence interval 0.76 to 0.94; p ), and the BNP level of 30 pg/ml had a sensitivity of 79%, specificity of 83%, positive predictive value of 82%, and negative predictive value of 85% for predicting postoperative cardiopulmonary complications. Finally, the patients were classified into 2 groups based on the preoperative BNP level; less than 30 pg/ml and 30 pg/ml or greater. As shown in Table 5, the incidences of both cardiovascular and respiratory complications were significantly higher in patients with preoperative BNP levels of 30 pg/ml or more. Comment The present results indicate that elderly patients with elevated preoperative BNP levels are at increased risk for postoperative cardiopulmonary complications after pulmonary resection for lung cancer. The preoperative BNP level was also found to be an independent predictor of postoperative cardiopulmonary complications. The risk of surgery is usually higher in elderly patients with concomitant, age-related respiratory or cardiac disease. However, surgery still represents the main curative treatment modality for non-small cell lung cancer, and the performance of curative surgery in the elderly still represents a clinical challenge frequently faced by thoracic surgeons. Therefore, more appropriate preoperative evaluations are necessary for elderly patients undergoing pulmonary resection for lung cancer. The BNP level has been shown to be accurate enough for diagnosing, monitoring, and predicting prognosis in patients with congestive heart failure [12], while more recently it was reported that an increased BNP level may predict postoperative cardiovascular events in patients undergoing emergency noncardiac surgery [13]. We also previously reported that lung cancer patients with mildly elevated preoperative BNP levels had an increased risk of developing postoperative atrial fibrillation [10]. Relatively younger patients were enrolled in our previous study (mean age 66.1 years). However, in this analysis of elderly patients, the incidences of not only cardiovascular Table 5. Postoperative Cardiopulmonary by Preoperative Serum BNP Level BNP 30 pg/ml BNP 30 pg/ml (n 48) (n 32) p Value All complications 7 (15) 27 (84) a Cardiovascular complications 7 (15) 21 (66) a Atrial fibrillation 5 13 Paroxysmal supraventricular tachycardia 1 5 Ventricular tachycardia 1 0 Acute myocardial infarction 0 2 Acute arterial occlusion of the lower extremity 0 1 Respiratory complications 1 (2) 11 (34) a Pneumonia 0 6 Home oxygen therapy 1 3 Acute respiratory distress syndrome 0 2 Acute exacerbation of interstitial pneumonia 0 1 BNP B-type natriuretic peptide.

5 Ann Thorac Surg NOJIRI ET AL 2011;92: COMPLICATIONS PREDICTED BY BNP 1055 but also respiratory complications were significantly higher in patients with elevated preoperative BNP levels. Recently it was reported that an increased BNP level was associated with primary pulmonary hypertension [6, 7], chronic thromboembolic pulmonary hypertension [8], and chronic pulmonary disease, especially when associated with cor pulmonale [9]. The common pathway to BNP elevation in these pulmonary diseases seems to be right ventricular (RV) overload. In addition, some recent studies found that patients with RV pressure or volume overload had a leftward shift of the ventricular septum toward the center of the LV cavity [14], resulting in geometric distortion of the left ventricle. Leftward ventricular septal shift in patients with RV overload leads to an LV filling abnormality; that is, LV diastolic dysfunction. Left ventricular diastolic dysfunction has been reported to be a risk factor for arrhythmias [15], pulmonary edema [16], and mild elevation of BNP levels [17, 18]. Thus, it appears that pulmonary disease and cardiac dysfunction are closely related. Moreover, it has been reported that patients with postoperative arrhythmias frequently developed respiratory complications at the same time [19]. In this study, 6 patients developed both cardiovascular and respiratory complications. To the best of our knowledge, this is the first study to evaluate BNP levels as a possible predictor for postoperative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. Serum BNP levels should be measured in elderly patients before surgery and effective prophylactic strategies should be considered for elderly patients with elevated preoperative BNP levels. This study was a two-institution clinical study, which restricted our ability to generalize the results. In addition, the number of patients in the study cohort was relatively small; thus, additional investigations are necessary to define the ability of BNP to predict postoperative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. Finally, since echocardiographic examinations were not performed, there are no data regarding the presence of RV overload or LV diastolic dysfunction. The results of the present study demonstrate that the preoperative serum BNP level could be a useful predictor of postoperative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. This finding allows stratification of patients at high risk for postoperative cardiopulmonary complications for planning an effective prophylactic strategy. We acknowledge statistical advice from Yuko Ohno, PhD and Akiko Kada, PhD. References 1. Birim O, Kappetein AP, Waleboer M, et al. 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