A Clinical Prediction Rule for Pulmonary Complications After Thoracic Surgery for Primary Lung Cancer

David Amar, MD,* Daisy Munoz, MD,* Weiji Shi, MS,† Hao Zhang, MD,* and Howard T. Thaler, PhD†

BACKGROUND: There is controversy surrounding the value of the predicted postoperative diffusing capacity of lung for carbon monoxide (DLCOppo) in comparison to the forced expired volume in 1 s for prediction of pulmonary complications (PCs) after thoracic surgery. METHODS: Using a prospective database, we performed an analysis of 956 patients who had resection for lung cancer at a single institution. PC was defined as the occurrence of any of the following: atelectasis, pneumonia, pulmonary embolism, respiratory failure, and need for supplemental oxygen at hospital discharge. RESULTS: PCs occurred in 121 of 956 patients (12.7%). Preoperative chemotherapy (odds ratio 1.64, 95% confidence interval 1.06–2.55, P ϭ 0.02, point score 2) and a lower DLCOppo (odds ratio per each 5% decrement 1.13, 95% confidence interval 1.06–1.19, P Ͻ 0.0001, point score 1 per each 5% decrement of DLCOppo less than 100%) were independent risk factors for PCs. We defined 3 overall risk categories for PCs: low Յ10 points, 39 of 448 patients (9%); intermediate 11–13 points, 37 of 256 patients (14%); and high Ն14 points, 42 of 159 patients (26%). The median (range) length of hospital stay was significantly greater for patients who developed PCs than for those who did not: 12 (3–113) days vs 6 (2–39) days, P Ͻ 0.0001, respectively. Similarly, 30-day mortality was significantly more frequent for patients who developed PCs than for those who did not: 16 of 121 (13.2%) vs 6 of 835 (0.7%), P Ͻ 0.0001. CONCLUSIONS: These data show that PCs after thoracic surgery for lung cancer can be predicted with moderate accuracy based on DLCOppo and whether patients had chemotherapy. Forced expired volume in 1 s was not a predictor of PCs. (Anesth Analg 2010;110:1343–8)

espite improvements in patient selection, anesthesia testing of cardiopulmonary interaction was not considered and surgical techniques, and intensive care man- here. The rationale for undertaking this study was to Dagement, clinically important pulmonary compli- examine known clinical and frequently used spirometric cations (PCs) occur in 10%–20% of patients after thoracic characteristics reported to be associated with clinically surgery.1 PCs are more prevalent in this population than important PCs in a large cohort of patients undergoing severe cardiovascular complications such as heart failure surgical resection for lung cancer, with a goal of developing (3%–4%) or acute coronary syndromes (2%–3%) and have a prediction rule so that future therapeutic strategies can be been identified as a leading cause of mortality after lung targeted to decrease hospital length of stay and health care resections.1,2 The spectrum of PCs may range from atelec- costs. tasis and pneumonia to acute lung injury (ALI), with the most severe form being acute respiratory distress syn- METHODS drome (ARDS).3 Previous reports examining risk factors for With IRB approval, the records of 956 patients who had PCs after pulmonary resection have reported conflicting undergone resection of primary lung cancer at our institu- results regarding which preoperative clinical, spirometric, tion between 1992 and 2003 were retrospectively reviewed. or laboratory data to include for risk estimation. The These records were part of a continuing prospective greater controversy is whether the frequently used forced database that included 1191 patients who participated in consecutive studies focused on cardiovascular complica- expired volume in 1 s (FEV1) is better able to predict PCs than the diffusing capacity of lung for carbon monoxide tions and PCs after thoracic surgery. Patients who under- (DLCO).4–13 There is a growing body of evidence suggest- went surgery for tumors other than primary lung cancer ϭ ing that the predicted postoperative DLCO (DLCOppo) is were excluded (n 235). Neoadjuvant chemotherapy regi- the stronger independent predictor of PCs.10–13 The evalu- mens used at our institution before surgery consisted of ation of maximal oxygen consumption or 6-min walk cisplatin and etoposide before 1995 and then mitomycin, vinblastine, and cisplatin until 2004. Carboplatin and pac- ϭ ϭ From the Departments of *Anesthesiology and Critical Care Medicine, and litaxel (n 10) and other regimens (n 7) were used in †Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, patients treated at other institutions. Similarly, with the New York, New York. exception of 2 patients, radiotherapy before surgery was Accepted for publication August 27, 2009. not used. Pulmonary function studies were performed after Supported by departmental funding. chemotherapy but before surgery. DLCO measurements Address correspondence and reprint requests to David Amar, MD, Memo- were adjusted for hemoglobin. Postoperative PCs consid- rial Sloan-Kettering Cancer Center, 1275 York Ave., Room M-304, New York, NY 10021. Address e-mail to [email protected]. ered as study end points and recorded throughout the Copyright © 2010 International Anesthesia Research Society hospital stay were: respiratory failure requiring intensive DOI: 10.1213/ANE.0b013e3181bf5c99 care unit admission and/or intubation, pneumonia (new

May 2010 • Volume 110 • Number 5 www.anesthesia-analgesia.org 1343 Pulmonary Complications and Thoracic Surgery pulmonary infiltrate with fever treated with IV antibiotics), predictive model was performed using jackknifing. We atelectasis requiring bronchoscopy (need determined by defined an integer-valued point scoring system as a pro- the surgical team), pulmonary embolism (diagnosed by portional simplification of the logistic regression prediction computed tomographic scan and treated), and need for function. We further classified patients as at low, interme- supplemental oxygen at hospital discharge. Pulmonary diate, or high risk of PCs by partitioning into 3 groups, each embolism was considered as an end point of pulmonary with at least 3 contiguous point values. We evaluated the morbidity that may lead to oxygen requirement at hospital statistical significance of the grouped data for predicting discharge.7,11 No patient had required use of oxygen before risk of PCs using the Armitage test for trend in proportions surgery. Transient hypoxemia and bronchospasm were not and selected the most significant partition. We then re- study end points. In contrast, patients who had cardiogenic evaluated the P value using the Bonferroni correction for causes of pulmonary edema, such as congestive heart multiple testing (78 possible partitions). failure, were excluded. Once discharged, patients were Statistical significance of the grouping was confirmed monitored by an investigator or research nurse for 30 days using the Bonferroni procedure. SAS release 9.1.3 (SAS from the time of surgery for complications, intercurrent Institute, Cary, NC) was used for all analyses. Data are hospitalizations, or emergency department visits. presented as mean value Ϯ sd or n (%). All statistical tests Standard anesthesia induction regimens, vecuronium were 2-tailed, and P Ͻ 0.05 was regarded as significant. for muscle relaxation, and maintenance of anesthesia using fentanyl and isoflurane in oxygen were used for all pa- RESULTS tients. Our standard of care is to use fluid restriction in the Patient and operative characteristics are shown in Table 1. perioperative period. During 1-lung ventilation, a fraction Preoperative chemotherapy was given to 193 of 956 pa- of inspired oxygen of 1.0 and volume-controlled ventilation tients (20.2%) and consisted of mitomycin, vinblastine, and were used with a tidal volume of 6–8 mL/kg, keeping peak cisplatin in 155 patients and other regimens in 38 patients. Ͻ inspiratory pressure 35 cm H2O. The respiratory rate was One or more PCs occurred in 121 of 956 patients (12.7%) Ͻ adjusted to maintain an end-tidal CO2 45 mm Hg. and consisted of respiratory failure in 23 (2.1%), pneumonia Postoperative analgesia was surgeon specific and con- in 71 (7.4%), atelectasis in 15 (1.6%), pulmonary embolism ϭ sisted of IV morphine patient-controlled analgesia (n in 12 (1.3%), and oxygen need on discharge in 24 (2.5%). 133) or epidural fentanyl with bupivacaine 0.05% patient- Significant univariate associations with PCs were preopera- ϭ controlled analgesia (n 823). In all patients, pulmonary tive serum albumin level (P ϭ 0.03), preoperative chemo- resection was performed via standard posterolateral thora- therapy, DLCO, and DLCOppo (Table 1). Stepwise logistic cotomy using single-lung ventilation. It is our standard regression analysis showed that preoperative chemotherapy practice in patients who have anatomic lung resection to (odds ratio 1.64, 95% confidence interval 1.06–2.55, P ϭ 0.02, perform systemic mediastinal lymph node dissection. estimated coefficient 0.250) and a lower DLCOppo (odds Corticosteroids are not given routinely during surgery. ratio per each 5% decrement in DLCOppo 1.13, 95% confi- Specific risk factors to be examined were defined a priori dence interval 1.06–1.19, P Ͻ 0.0001, estimated coefficient by searching the literature. Studies of PCs after anatomic 0.118) were independent risk factors for PCs. As a simple Ͼ pulmonary resection that included 200 patients were function of the model, we assigned point score 2 for history 4–13 considered. Based on this review, the examined factors of preoperative chemotherapy and point score 1 per each included volume of intraoperative fluid administered, ex- 5% decrement of DLCOppo less than 100%. The predictive tent of surgical resection, use of induction chemotherapy, model based on these 2 variables had a concordance index laterality, and postoperative predicted lung function. Postop- of 0.63 and an area under the ROC curve of 0.63; the erative predicted lung function was calculated as follows: Hosmer-Lemeshow goodness-of-fit statistic suggested ϫ Ϫ preoperative measured lung function (1 number of good calibration (P ϭ 0.43). Internal validation of the segments resected/total number of segments). Wedge re- predictive model showed that the model is mildly overfit- section was defined as 1 segment. Data on patient charac- ted (area under the jackknife-adjusted ROC curve ϭ 0.59). teristics, operative details, and postoperative recovery were Figure 1 plots were observed and predicted probabilities of collected in a prospective database approved by the IRB. postoperative PCs were based on the computed point score from the final model. The partition of point scores into Statistical Analysis low-, intermediate-, and high-risk groups that was most Univariate characteristics between patients with and strongly related to occurrence of PCs, as described in without PCs were compared using Student’s t or ␹2 tests. Methods, was 0–10, 11–13, and 14–19 points, respectively A model was built using stepwise logistic regression to (Table 2). The high-risk category included 159 patients with identify the subset of variables that jointly predicted a 26% risk of PCs. This grouping was statistically signifi- postthoracic surgery PC risk. All variables whose univar- cant at P Ͻ 0.0001 even after applying the Bonferroni iate tests resulted in a P value Յ0.05 were considered in correction for multiple testing. the model. There were 93 patients for whom DLCO We also created a stepwise logistic regression model measurements were not available. Concordance index (per- including all variables whose univariate tests resulted in cent concordance) and area under the receiver operating a P value Ͻ0.2 (Table 1). Only body mass index Ն30 characteristic (ROC) curve were computed as descriptive (P ϭ 0.03) and history of hypertension (P ϭ 0.05) were tools for measuring the discrimination of the model. The statistically significant after adjusting for preoperative che- Hosmer-Lemeshow goodness-of-fit statistic was computed motherapy and DLCOppo. However, neither of the 2 for examining the fit of the model. Internal validation of the factors added enough predictive power (concordance index

1344 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Table 1. Patient Characteristics No Complications Complications Variable n ϭ 835 n ϭ 121 P* Age (yr) 65.4 Ϯ 10.3 66.1 Ϯ 10.2 0.49 Male sex 434 (52.0) 72 (59.5) 0.12 Former/current smoker 711 (85.2) 111 (91.7) 0.05 Hypertension 260 (31.1) 46 (38.0) 0.13 Diabetes mellitus 55 (6.6) 11 (9.1) 0.31 Preoperative chemotherapy 157 (18.8) 36 (29.8) 0.005 a Ϯ Ϯ FEV1 , % of predicted 82.0 20.7 78.4 22.7 0.08 a Ϯ Ϯ FEV1ppo 59.5 20.4 55.9 19.9 0.07 DLCOa, % of predicted 77.8 Ϯ 21.8 67.6 Ϯ 20.2 Ͻ0.0001 DLCOppoa 56.2 Ϯ 19.7 48 .0 Ϯ 17.2 Ͻ0.0001 Albuminb, mg/dL 4.2 Ϯ 0.4 4.1 Ϯ 0.5 0.03 Cancer stage I 439 (55.9) 55 (47.8) 0.26 II 129 (16.4) 19 (16.5) III 193 (24.6) 35 (30.4) IV 24 (3.1) 6 (5.2) BMI Ն30a, kg/m2 146 (18.3) 30 (25.0) 0.08 Surgical procedurea Wedge resection 62 (7.4) 11 (9.1) 0.76 Lobectomy 560 (67.2) 78 (64.5) Pneumonectomy 212 (25.4) 32 (26.5) Right-sided cases 497 (59.5) 82 (67.8) 0.08 Intraoperative fluids, La 1.5 Ϯ 1.0 1.6 Ϯ 1.3 0.50b

Data are mean Ϯ SD or n (%). ϭ ϭ ϭ ϭ PPO predicted postoperative values; FEV1 forced expired volume in one second; DLCO diffusion capacity of lung for carbon monoxide; BMI body mass index. a Number of patients did not add up to 956 due to nonavailable data. b Based on Box-Cox transformation. * By Student’s t-or␹2 tests.

Figure 1. Predicted probability of devel- oping pulmonary complications (PCs) by the point score. Circles indicate observed probability of postoperative PCs. Areas of the circles are proportional to the number of patients with each score value in the study population. Curve indicates pre- dicted probability of postoperative PCs generated from a spline smooth of the logistic regression model based on point score. Vertical dashed lines represent cutoffs of point scores of the 3 risk categories for PCs.

of 0.64, and an area under the ROC curve of 0.65 and 0.64, those who did not: 12 (3–113) days vs 6 (2–39) days, P Ͻ respectively) to be included in our final model. 0.0001, t-test based on logarithm transformed data. Simi- The median (range) length of hospital stay was signifi- larly, 30-day mortality was significantly more frequent cantly longer for patients who developed PCs than for for patients who developed PCs than for those who did

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the 6 studies with Ն200 patients examining predictors of Table 2. Prediction Rule and Risk Stratification PCs where the FEV1 but not DLCO was recorded, 3 showed Risk factors Point score ϭ (combined n 1219) that FEV1 was an independent Preoperative 2 points predictor4–6 and 3 (combined n ϭ 1506) did not.7–9 In chemotherapy contrast, in studies that included both variables, DLCO was DLCOppo 1 point for each 5% decrement ϭ of DLCOppo below 100% an independent predictor of PCs in all 4 (combined n 10–13 10 Risk categories by Cases/n (%) of patients 2471). Yano et al. found that DLCO Ͻ70% of point score predicted was an independent predictor of non–life- Low (Յ10 points) 39/448 (9%) threatening as well as life-threatening complications in 291 Intermediate 37/256 (14%) patients after pulmonary resection. Using a continuous (11–13 points) Ͼ High (Ն14 points) 42/159 (26%) database over a span of 2 decades, Ferguson and Vigneswaran13 retrospectively studied 1008 patients under- DLCO ϭ diffusion capacity of lung for carbon monoxide; PPO ϭ predicted postoperative values. going major anatomic pulmonary resection and reported that DLCOppo was the single strongest predictor of PCs and operative mortality in patients with or without chronic obstructive pulmonary disease. Brunelli et al.12 not: 16 of 121 (13.2%) vs 6 of 835 (0.7%), P Ͻ 0.0001. The retrospectively reviewed the records of 872 patients causes of mortality were respiratory failure/ARDS (n ϭ undergoing lung resection in 2 surgical units and found 11), multisystem organ failure (n ϭ 2), myocardial infarc- that DLCOppo Ͻ40% and age were independently asso- tion (n ϭ 2), pulmonary embolism (n ϭ 2), and unknown ciated with postoperative cardiopulmonary morbidity. (n ϭ 5). In a study similar to ours, Licker et al.15 concluded that Ͻ FEV1 60% was the main predictor of PCs after resection DISCUSSION for lung cancer, but DLCO was not available in the The main findings of this study are that preoperative majority of patients. chemotherapy and a low DLCO independently contribute The impact of neoadjuvant chemotherapy on morbidity to the risk for clinically important postoperative PCs. A low and mortality after lung cancer surgery is controver- 16–20 DLCO was the strongest predictor, whereas FEV1 was not sial. In a retrospective study of 470 patients from our an independent predictor at all. Using 2 easily available institution, Martin et al.16 reported that right pneumonec- risk factors, we were able to develop a simple prediction tomy, blood loss, and FEV1 were independent predictors of rule and scoring system to estimate the likelihood of combined cardiac, pulmonary, and other postoperative postoperative PC occurrence. Although DLCO in itself was complications. Finally, in another large retrospective study highly associated with PCs, we used DLCOppo because it of 758 patients, Matsubara et al.18 showed that patients who incorporates the extent of pulmonary resection with preop- received induction chemotherapy had a lower DLCO com- erative function.10–13 These risk factors are easily available pared with those who did not. However, when examining before surgery, with DLCOppo contributing 1 point per risk factors for combined cardiopulmonary and other com- each 5% decrement in DLCOppo from 100%, and preop- plications, the authors did not consider DLCO in their erative chemotherapy 2 points in the point scoring system. model.18 For example, a patient with a history of preoperative ALI and ARDS are the most severe forms of lung injury chemotherapy exposure (2 points) and a DLCOppo of 50% and have been shown to occur in 2%–8% of patients after ([100% Ϫ 50%]/5 ϭ 10 points) had a total of 12 points and lung resection.1,3 In a recent study of 1428 patients under- a probability of 14% for developing postoperative PCs, going lung cancer resection, we observed a 5.3% overall compared with a similar patient without exposure to rate of lung injury and a 3.1% rate of severe injury in the chemotherapy (10 points total) who had a 9% chance for form of ALI or ARDS.3 The overall in-hospital mortality PCs. We have previously reported that DLCOppo but not rate was 25% in the lung injury patients, compared with the FEV1 was a predictor of PCs in a study of 300 patients only 2.6% in the control group. Although larger intraopera- designed to determine the effects of timing of smoking tive fluid administration was an independent predictor of cessation on PCs.11 Our results are likely explained by the ALI, DLCOppo was the strongest risk factor. Licker et al.21 fact that smokers are likely to have a greater incidence of reviewed 879 patients who underwent pulmonary resec- primary lung cancer, require preoperative chemotherapy, tion and showed in multivariate analysis that “excessive” and have significant reductions in preoperative diffusing fluid administration, high intraoperative ventilatory pres- capacity as a result of neoadjuvant chemotherapy and/or sures, pneumonectomy, and preoperative alcohol abuse smoking.14 Of the patients who received neoadjuvant che- were independent risk factors for ALI.21 Protective lung motherapy, 80% were treated with mitomycin, a drug ventilation strategies have been shown to reduce inflam- known to induce pulmonary toxicity.14 Patients who devel- matory markers of barotrauma during thoracic surgery.22 oped PCs had twice the length of hospital stay and a Although it is still controversial whether to use protective Ͼ10-fold increase in 30-day mortality, with respiratory lung ventilation in all patients undergoing thoracic surgery failure as the predominant cause. regardless of risk for postoperative ALI, many would agree DLCO estimates alveolar oxygen exchange, is generally that patients with impaired lung function or those who not dependent on patient effort, and may be influenced by have received chemotherapeutic drugs with potential pul- the patient’s age, sex, height, and hemoglobin level. The monary toxicity before surgery are a subset of patients at measurement of DLCO before surgery is not universal. Of greater risk.23

1346 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Our study has several limitations. Epidural analgesia REFERENCES was used by most surgeons, in 833 of 956 cases (86%), and 1. Allen MS, Darling GE, Pechet TT, Mitchell JD, Herndon JE II, this may have affected the incidence of PCs. However, our Landreneau RJ, Inculet RI, Jones DR, Meyers BF, Harpole DH, Putnam JB Jr, Rusch VW. Morbidity and mortality of observed incidence of PCs is consistent with nationally re- major pulmonary resections in patients with early-stage 1 ported prospective data. Because our study examined pa- lung cancer: initial results of the randomized, prospective tients undergoing thoracotomy only, our conclusions may not ACOSOG Z0030 trial. Ann Thorac Surg 2006;81:1013–9; apply to those undergoing thoracic surgery using minimally discussion 1019–20 invasive techniques. The most significant single predictor of 2. Jaroszewski DE, Huh J, Chu D, Malaisrie SC, Riffel AD, Gordon HS, Wang XL, Bakaeen F. Utility of detailed preop- complications was DLCO, but there were 93 patients for erative cardiac testing and incidence of post-thoracotomy whom DLCO measurements were not available. Although myocardial infarction. J Thorac Cardiovasc Surg they comprise approximately 10% of the study population, 2008;135:648–55 this subgroup did not differ significantly from the remainder 3. Alam N, Park BJ, Wilton A, Seshan VE, Bains MS, Downey RJ, of the patients in terms of other covariates or incidence of Flores RM, Rizk N, Rusch VW, Amar D. Incidence and risk factors for lung injury after lung cancer resection. Ann Thorac complications. Furthermore, there was no combination of Surg 2007;84:1085–91; discussion 1091 covariates that predicted DLCO accurately enough to impute 4. Kearney DJ, Lee TH, Reilly JJ, DeCamp MM, Sugarbaker DJ. missing DLCO values in order to include the additional cases Assessment of operative risk in patients undergoing lung in the model. 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