Atrial fibrillation after pulmonary lobectomy for lung cancer affects long-term survival in a prospective single-center study

Between January 1996 and June 2009, 473 consecutive patients undergoing lobectomy for primary lung cancer at Varese University Hospital were considered for this study; none of the operations was an emergency. Of these patients 19 were excluded from analysis because they had chronic AF (n = 8), pace-maker devices (n = 4), or incomplete data (n = 7). Patients with a history of paroxysmal AF, but in sinus rhythm at operation, were included [3]. The final study cohort comprised 454 patients (81.3% male), with mean age of 65.4 ± 8.8 years (range 28 to 84). Patient characteristics are listed in Table 1.

Throughout the study period the patients' data were prospectively recorded in a computerized database. The latter included information about demographics, comorbidities, medical and surgical history, preoperative respiratory and cardiac testing, operative details and postoperative events during the hospital stay (Table 1 and 2). After discharge, follow-up was conducted according to the American College of Chest Physicians (ACCP) guidelines [8], with physical examination and imaging study (chest x-rays (CXR) or computed tomography (CT)) every 6 months for 2 years and then annually. For patients who died during follow-up, the date of death was recorded. For patients lost to follow-up, the vital status were ascertained at the end of study, by linkage with the Lombardy Region Health System Registry. The vital status of residents outside this region were ascertained by contacting family members or the respective general practitioner. Survival follow-up was closed on October 30, 2010.

With the aim to analyze mortality profile of all discharged patients, we recorded the cause of death by linkage with the Varese Province Mortality Registry. The cause of death was classified by disease groups, according to the International Classification of Diseases, Edition IX (ICD-IX) as follows: cardiovascular diseases (ICD-IX: 390-459); lung cancer (ICD-IX: 162.2-162.9); all cancers other than lung cancer (ICD-IX:140-162.0, 163-239); all other causes of deaths.

The protocol of this study was in compliance with the local Institutional Review Board and received full approval. Written informed consent was obtained from the participants of this study.

All patients underwent preoperative clinical cardiologic and anesthesiologic evaluation, CXR and CT, and pulmonary function tests. Preoperative medications, including β-blockers, diuretics, antihypertensives, statins, and calcium-channel blockers were routinely omitted on the day of the operation and were restarted on postoperative day one, unless clinically contraindicated. Operability was determined according to established guidelines for lobectomy [9, 10]. All pulmonary resections were performed by open thoracotomy, by the same thoracic surgical team throughout the study period. Standardized surgical approach and anesthesiologic management were used and remained constant during the study. Briefly, short-term antibiotic prophylaxis was routinely administered intravenously (ampicillin/sulbactam 3 gr) before anaesthesia. An epidural catheter for postoperative pain relief was offered to all patients and premedication with midazolam was done before induction of general anaesthesia. After administration of rocuronium bromide (0.15 mg/kg) and orotracheal intubation with double-lumen tube, anaesthesia was maintained by 50% O₂ and 2% sevoflurane. Mediastinal sampling lymphadenectomy was routinely performed. Pathological lung cancer staging was assessed according to the 1997 TNM classification [11]. Two chest tubes were placed on water seal at the end of the operation and removed when no air leaks were present and pleural drainage output was < 150 mL/24 h. Postoperative pain control was achieved mainly by epidural analgesia and/or by systemic opioids combined with non-steroidal anti-inflammatory drugs. Low molecular weight heparin was administered for 2-4 weeks postoperatively.

After surgery patients were transferred to a general intensive care unit (ICU) for the first 12/24 hours. Heart rate, electrocardiography (ECG), central venous and arterial pressures, and acid-base blood gases were continuously monitored during the ICU stay. Inotropic support was provided if the ventricular contractility was markedly impaired. Perioperative need of blood products was determined on an individual, patient-by-patient basis; in general, blood transfusions were administered when haemoglobin was < 8 g/dL. Postoperative fibrobronchoscopy (FBS) was performed in case of lung atelectasis, and in order to obtain bronchial secretion samples for microbiological examinations. All patients had an active program of postoperative physiotherapy including deep-breathing exercises.

Cardiac rhythm assessment followed the daily practice of an integrated clinic encompassing ICU and ward level, sharing the same routines and data collection system. Patients were monitored by continuous ECG during a minimum of 48 hours postoperatively. Subsequent monitoring was by repeated daily observations by nurses and physicians, at least every 2 hours. In case of rhythm disturbance reported by nurse or patient, a 12-lead ECG recording was obtained, and continuous ECG monitoring was restarted if necessary. Additional recordings were collected at clinical suspicion of AF. The arrhythmia was defined by physician assessment, on the basis of a telemetry strip or a 12-lead ECG recording. Amiodarone, either orally or intravenously administered, constituted the standard pharmacological treatment of AF. Digoxin was administered if necessary to reduce high ventricular rate. In case of AF recurrence, the same protocol was applied. In this study the definition of postoperative AF includes the successfully treated AF as well as AF persistent at discharge.

Extracted database variables were tabulated using Microsoft Excel^® (Microsoft Corp, Redmond, WA) and statistical analysis was computed using SPSS, release 16.0 for Windows^® (SPSS Inc., Chicago, IL). Continuous variables were tested for normal distribution by the Kolmogorov-Smirnov test and compared between groups with unpaired Student's t test for normally distributed values; otherwise, the Mann-Whitney U test was employed. In case of dichotomous variables, group differences were examined by chi-square or Fisher exact tests as appropriate.

Kaplan-Meier estimates and log-rank test were performed for the postoperative mortality rate comparison of patients with or without postoperative AF. Mortality hazard ratios (HRs) were generated by a multivariable Cox regression analysis, using univariable Cox predictors with p < 0.15 (Table 3). Patients who died within 30 days of operation were excluded from the final analysis of survival.

Hospital mortality accounted for 7 (1.5%) subjects, while AF occurred in 9.9% of patients (45 of 454) and its frequency peaked on the second postoperative day (69% of cases). Mean AF duration was 9.2 ± 7.1 hours (range: 1-24). Of the 45 patients with postoperative AF, 29 (64%) had a single arrhythmia episode, while 16 (35%) experienced multiple episodes. Among the 45 patients with postoperative AF, 27 (60%) were treated by amiodarone, 7 (16%) by digoxin, 4 (9%) by calcium-channel blocker, and 2 (4%) by beta-blocker. The remained 5 patients were treated with a simple correction of the electrolyte imbalance (potassium). In all cases the choice of medication was based on Cardiologist prescription. At discharge, persistent AF was present in 2 of 45 (4.4%) patients.

Patients with AF compared to patients without it were older and more frequently had a history of paroxysmal AF or coronary artery disease (p = 0.008, p < 0.001 and p = 0.009, respectively) (Table 1). Other comorbidities, pulmonary function tests and preoperative medications, with the exception of β-blocker agents, did not reveal significant differences between patients with AF and without it. No correlation was observed between postoperative AF and neo-adjuvant chemotherapy, lung cancer stage and histological type of cancer (p = 0.756, p = 0.568, p = 0.281 respectively). Subjects with cancer location in the left lung were more frequently affected by AF (p = 0.011). Postoperatively, patients with AF had a higher prevalence of respiratory failure (p < 0.001), of postoperative FBS (p < 0.001) and required more frequently blood transfusions (p < 0.001). Moreover, patients with AF had longer hospital stay (p = 0.001), higher ICU admission rate (p = 0.015), and higher hospital mortality (p = 0.024) (Table 2).

At multivariate analysis, independent predictors of postoperative AF were preoperative paroxysmal AF (OR 5.91, 95%CI 2.07 to 16.88), need of peri-operative blood transfusion (OR 3.61, 95%CI 1.67 to 7.82), and postoperative FBS (OR 3.39; 95%CI 1.48 to 7.79). The Hosmer-Lemeshow goodness-of-fit test (χ² [1 d.f.] = 0.61, p = 0.433) and ROC analysis (AUC of 0.70) revealed good calibration and discrimination for the multivariate analysis.

Follow-up was completed for 445/447 (99.6%) patients discharged after resection, with median follow-up of 36 months (maximum: 179 months). Kaplan-Meier analysis of subjects without AF revealed 1-, 5- and 10-year overall survival of 99%, 49% and 34%, respectively, similar to 98%, 42%, and 31% survival of patients with AF (p = 0.085) (Figure 1).

At multivariable Cox regression analysis of 445 discharged patients with complete follow-up, postoperative AF was not an independent predictor of late mortality (HR 1.17; 95%CI 0.76 to 1.79), while independent predictors were: lung cancer UICC stage (HR 2.09; 95%CI 1.60 to 2.74), diabetes (HR 1.64; 95%CI 1.17 to 2.29), male gender (HR 1.51; 95%CI 1.07 to 2.13), and age (HR 1.02; 95%CI 1.00 to 1.04) (Table 4). Among the 151 patients alive at 5 years from cancer resection, the multivariable Cox regression analysis revealed that postoperative AF was the strongest independent predictor (HR 3.75; 95%CI 1.44 to 9.81) along with forced expiratory volume in 1 second (FEV₁) < 80% of predicted (HR 2.07; 95%CI 1.09 to 3.93) (Table 4).

Among the 445 discharged subjects with complete follow-up, death from cardiovascular diseases occurred more frequently in patients affected by postoperative AF than in those without it (21% vs.10%, p = 0.073). Among 151 5-year survivors, a similar difference of cardiovascular disease mortality was also observed (40% vs. 21%, p = 0.336).