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Ann Thorac Surg 2006;82:1057-1061
© 2006 The Society of Thoracic Surgeons

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Original article: General thoracic

Leukocytosis and Increased Risk of Atrial Fibrillation After General Thoracic Surgery

^a Department of Anesthesiology and Critical Care Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
^b Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
^c Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York

Accepted for publication March 29, 2006.

^_* Address correspondence to Dr Amar, Director of Thoracic Anesthesia, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, M-304, New York, NY 10021 (Email: amard{at}mskcc.org).

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
BACKGROUND: In older patients who are known to be at greater risk for atrial fibrillation, we aimed to determine whether patients who develop atrial fibrillation-flutter (AF) after major thoracic surgery have an exaggerated white blood cell (WBC) count in response to surgical stress compared with those who do not develop AF.

METHODS: Using a prospective database, 272 patients 60 years or older who were in sinus rhythm before surgery and had elective lobectomy, pneumonectomy, or esophagectomy were studied. Patients did not receive perioperative medications to prevent AF. Clinical characteristics and preoperative 12-lead electrocardiogram were examined and WBC counts were recorded for patients prior to and for up to five days after surgery.

RESULTS: Atrial fibrillation-flutter was observed in 74 of 272 (27%) patients a median of 3 days after surgery. The increase in WBC count from preoperative to postoperative day 1 and age were jointly significant predictors of AF by multiple logistic regression (area under the receiver operating characteristic curve = 0.69). Using this model, a twofold increase in WBC from presurgery to postoperative day 1 corresponded to a 3.3-fold increase in the odds of developing AF (95% confidence interval [CI] 2.0 to 8.3) and for each 10 year increase in age, a 1.8-fold increase in risk of AF (95% CI 1.1 to 2.8) was seen.

CONCLUSIONS: Increments in WBC were greater in patients with AF and coincided with the peak onset of AF. These prospective data support an important role for stress-mediated autonomic mechanisms in the pathogenesis of AF after major thoracic surgery. We aim to examine further whether WBC elevations on postoperative day one can help further risk stratify patients younger than 60 years or those with the highest risk who could benefit from one or more AF prevention strategies.

	Introduction

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Postoperative atrial arrhythmias, and atrial fibrillation/flutter (AF) specifically, are seen in more than 20% of elderly patients undergoing noncardiac thoracic surgery [1]. Patients with postoperative AF have an extended hospital stay with accompanying increased costs as well as greater risk of stroke [1, 2]. As in AF unrelated to surgery, age 60 years or greater is consistently the only independent preoperative risk factor most strongly associated with postoperative AF [1–3]. It is well known that aging causes degenerative changes in atrial anatomy that are accompanied by related changes in atrial physiology, atrial stiffening, and splitting of the atrial excitation waveform [4, 5]. Beyond older age, however, our ability to further identify those patients at greatest risk for postoperative AF is limited. A better understanding of the mechanisms responsible for postoperative AF could help design more targeted prophylactic or therapeutic measures.

Evidence for an inflammatory contribution to AF was initially suggested by the high incidence of AF seen two or three days after cardiac surgery and corresponding to a similar elevation in C-reactive protein (CRP) in one [6], but not other [7–9], studies. More recently, elevated postoperative white blood cell (WBC) count has been associated with the development of AF after cardiac surgery [10]. Whether increments in WBC in the early postoperative period reflect a systemic inflammatory response is controversial. Furthermore, data on the relationship of perioperative changes in WBC and AF occurrence after noncardiac thoracic surgery are unavailable. Therefore, we examined a prospective database of patients who had major thoracic surgery to test the hypothesis that an exaggerated WBC response to surgery is associated with risk for postoperative AF and to assess the potential use of WBC count as a perioperative predictor of AF.

	Material and Methods

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With Institutional Review Board approval and waiver of informed consent, we used a prospective database of 856 patients who had thoracic surgery between the years 1991 and 2003 and studied 272 patients aged 60 years or older who had pulmonary lobectomy (n = 231), pneumonectomy (n = 32), or esophagectomy (n = 9). Excluded were patients who were not in sinus rhythm prior to surgery, those taking antiarrhythmic drugs, or systemic corticosteroids. Also excluded from this study were patients who had been consented prior to surgery but had an exploratory thoracotomy only, or patients who had a limited resection (wedge or segment) and therefore were at very low risk for AF. No prophylactic diltiazem or other drugs to prevent postoperative AF were given. However, preoperative beta-blockers were continued postoperatively to avoid withdrawal, and patients who were taking calcium channel blockers for hypertension or coronary artery disease resumed taking these medications on the first postoperative day. History of smoking, hypertension, coronary artery disease, diabetes mellitus, and preoperative chemotherapy exposure was recorded. Routine care for all patients included prophylactic antibiotic therapy administered before skin incision and maintained for 24 hours after surgery.

The operations were performed using standard thoracotomy approaches designed to remove completely all neoplastic disease along with an ipsilateral mediastinal lymph node dissection. Based on surgeon's preference, postoperative pain relief was provided to all patients by continuous administration of either epidural opioid (usually fentanyl and bupivacaine 0.05%) administration or intravenous opioid (usually morphine) patient-controlled analgesia. After an overnight stay in the postanesthesia care unit patients were transferred to the thoracic surgical floor on the first postoperative day. Major postoperative cardiac or pulmonary complications were recorded throughout the hospital stay. An endpoint of the study was the new onset of AF greater than 5 minutes detected by continuous telemetry (72 to 96 hours), or AF episodes requiring intervention because of symptoms or hemodynamic compromise. Atrial fibrillation-flutter was defined by an irregularly irregular cardiac rhythm without clear P waves that was confirmed by 12-lead electrocardiogram. Routine WBC counts done for patients for up to 5 days after surgery were recorded.

To determine the difference of patient and operative characteristics between patients with and without AF, all variables were examined by the univariate analysis Student t test and Fisher exact test. Due to non-normal distribution, WBC data were log-transformed prior to analysis. A change in log-counts between two time points corresponds to the log of the ratio of counts, and the mean of log-values corresponds to the geometric mean of the original values. Univariate variables with p less than 0.2 were entered into a stepwise multiple logistic regression to assess statistical significance of combinations of covariates. Data are presented as mean value ± standard deviation unless otherwise indicated and p less than 0.05 was considered significant. Statistical analysis was performed with the software SPSS version 10.0 (SPSS, Chicago, IL) and SAS version 9.1 (SAS Institute, Cary, NC).

	Results

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Atrial fibrillation-flutter was observed in 74 of 272 (27%) patients a median of 3 days (range, 1 to 7 days) after surgery, as shown in Figure 1. The mean age of patients who developed AF was greater than patients that did not; 74 ± 8 years vs 70 ± 6 years, p = 0.027, respectively. With the exception of a clinically small but statistically significant difference in preoperative PR interval in patients who later developed AF, there was no other significant difference between the two groups at baseline (Table 1). Patients who developed AF had higher WBC values on postoperative days 1 to 3 than those who did not (*p < 0.01; Fig 2). Relative to baseline values, AF patients had a greater elevation in WBC percent change on postoperative days 1 to 3 than those without AF (Table 2).

View larger version (10K): [in this window] [in a new window]   Fig 1. Atrial fibrillation (AF) onset beginning from the time of surgery.

View larger version (15K): [in this window] [in a new window]   Fig 2. White blood cell count presented as mean ± standard deviation. (*p < 0.01, AF vs no-AF patients; solid lines = AF patients; dashed lines = no-AF patients; AF = atrial fibrillation; PACU = postanesthesia care unit; POD = postoperative day; preop = preoperative.)

The incidence of postoperative respiratory complications, such as pneumonia and acute respiratory failure, did not differ between patients who developed postoperative AF when compared with those without AF (Table 1). However, the rate of intensive care unit (ICU) admission was greater for AF patients (14% vs 3%, p < 0.001; Table 1). Comorbidities in patients with AF requiring ICU admission were pneumonia (n = 5), acute respiratory failure (n = 3), and acute coronary syndrome (n = 2); pneumonia (n = 4) and acute respiratory failure (n = 2) for patients without AF. Length of hospital stay was significantly greater for patients with AF compared with those without AF (9 ± 4 days vs 7 ± 4 days), p = 0.01, respectively.

	Comment

Top Abstract Introduction Material and Methods Results Comment References

 
The main findings of this study are that, in addition to older age, there is a significant association between an increase in postoperative WBC count and patients who develop AF after thoracic surgery. In comparison with baseline values, AF patients had greater increases in WBC count on postoperative days 1to 3 than those that did not develop AF. These increments in WBC occurred during a time period that corresponds to the median peak of AF onset. Practically, each patient can serve as their own control. Using a ratio of postoperative day 1 to preoperative WBC of 1.5, predicted AF with a sensitivity of 0.76 and specificity of 0.51 and odds ratio of 3.4. Patients with AF had a statistically greater PR interval than those without AF. We were able to show a similar difference in PR interval in one [11] but not other [3, 12, 13] studies of patients who were likely to develop postoperative AF. While a greater PR interval may reflect prolonged interatrial conduction as well as intraatrial activity, the clinical usefulness of the PR interval in predicting risk of postoperative AF needs to be elucidated. Consistent with prior studies, patients who developed postoperative AF had significant comorbidity, required more ICU admissions, and had a greater length of hospitalization [1–3].

The phenomenon of catecholamine-induced lymphocytosis and leukocytosis has been characterized by two phases: a quick (< 30 minutes) mobilization of lymphocytes, followed by an increase in granulocytes with decreasing lymphocyte numbers [14]. The changes in lymphocytes seem to be mediated by beta-2 adrenoceptors of the spleen and venular system, whereas granulocytes increase by an alpha-adrenoceptor stimulation of the lung and peripheral veins [14]. In a study of autonomic changes in response to major thoracic or abdominal surgery, we demonstrated significant and persistent decrements in lymphocyte beta-adrenoceptor system function during the first postoperative week without change in total lymphocyte or lymphocyte subpopulation counts [15]. We interpreted these findings to represent the continued presence of adaptive regulatory mechanisms after surgical stress. Because we measured lymphocytes starting on the first postoperative morning it is likely that we did not detect the acute phase (< 30 minutes) rise in lymphocytes in response to surgery and their subsequent decrease [15]. Using analyses of heart rate variability two hours prior to the onset of AF in this patient population, we demonstrated significant increases in time and frequency domain parameters during a time when heart rate also increased, implying that vagal resurgence competing in the setting of sympathetic predominance serves as the trigger for postoperative AF [16]. We recently reported a rise in sensitive markers of inflammation interleukin-6 [IL-6] and CRP in response to surgical stress, but without finding a difference in these markers whether or not patients developed AF after major thoracic surgery [11]. Taken together, these studies all support our contention that the increase in WBC count seen in the AF group is due to an adrenergic phenomenon and likely not to an early systemic inflammatory response [11, 15, 16].

The role of an inflammatory response in the pathogenesis of postoperative AF is unclear. Unrelated to surgery, elevated CRP levels were reported in patients with existing paroxysmal or persistent AF and in patients who were more likely to develop AF in the future if their baseline CRP was elevated [17, 18]. These investigators speculated that the known pathologic changes associated with AF, such as normal atrial myocyte loss and eventual fibrosis seen with aging, may be contributing to this low-level inflammatory response. However, a more recent study of patients with chronic AF suggested that increased CRP and IL-6 are related to indices of a prothrombotic state and may be related to the clinical variables of the patient's comorbidities rather than to AF itself [19]. Early after cardiac or thoracic surgery the presence of an intense inflammatory process has been suggested by activation of the complement system and release of proinflammatory cytokines [6–9, 11, 20, 21]. Although increases in CRP and complement-CRP complexes were observed in 7 of 19 patients with atrial arrhythmias after cardiac surgery [6], no other study has confirmed these findings in patients with postoperative AF [7–9, 21]. Abdelhadi and colleagues [10] were the first to report an association between leukocytosis and AF after heart surgery. Fontes and colleagues [9] also showed that patients developing AF after cardiac surgery had a significant postoperative increase in WBC without differences in CRP or neutrophil myeloperoxidase activity, another measure of inflammation. It appears from the above studies that it is unlikely that inflammation is the cause of the increased WBC count in patients who develop AF within several days of surgery.

Limitations of the Study
Although this study examined laboratory data retrospectively, all clinical and laboratory data were recorded prospectively in an ongoing database. The area under the receiver operating characteristic curve of 0.69 for our multivariate model suggests moderate ability for WBC to predict AF. Considering the multifactorial etiology of postoperative AF, the strength of our model is consistent with recently published models examining other risk factors for AF [13, 22]. We did not measure plasma catecholamine levels but it is well known these merely reflect a "spillover" from that present at the neurosynaptic level. In fact, we have previously shown no significant postoperative changes in plasma catecholamines in patients having major thoracic or abdominal surgery in conjunction with significant down-regulation of the lymphocyte beta-adrenergic receptor function and corresponding changes in heart rate variability analysis [11]. We acknowledge that while we have made comparisons in our discussion between patients undergoing cardiac surgery and those having noncardiac thoracic surgery due to the similarly high incidence of postoperative AF common to both populations, the two differ in many aspects including severity of preoperative coronary or valvular disease, exposure to cardiopulmonary bypass, and need for postoperative vasoactive agents.

Conclusions and Clinical Implications
Postoperative AF was a frequent complication in patients greater than 60 years of age undergoing major thoracic surgery and was a comorbid event in patients with increased resource utilization of ICU and hospital stay. In addition to increasing age, a twofold increase in WBC count on the first postoperative day in comparison with baseline was associated with a threefold increase risk for postoperative AF. The results of this study support an important role for stress-mediated autonomic mechanisms as responsible for the early leukocytosis seen after surgery. WBC count is routine, adds no further costs, and easy to use in addition to other published prediction rules for AF risk [13]. Intuitively, prophylactic beta-blockers should be employed as first line measures to counteract adrenergic stress mechanisms responsible for postoperative AF [23–25]. Practically, however, beta-blockers are often limited by the high incidence of hypotension, bradycardia, and reduced cardiac index associated with their use in postthoracotomy patients who are often kept intentionally fluid restricted [23–25]. This is likely due to the fact that beta-blockers are rate dependent for their efficacy and in order to prevent arrhythmia or myocardial ischemia large doses are often needed. In contrast, use of the L-type calcium channel blocker diltiazem is not rate dependent for its efficacy and has been found to be safe and effective in the largest randomized, placebo-controlled blinded study to reduce significantly postthoracotomy AF [23, 26]. Our current standard of care is to use diltiazem prophylaxis in patients 60 years and older undergoing major pulmonary or esophageal resection who are not requiring beta-blockers for hypertension or coronary artery disease. We aim to examine further whether WBC elevations on postoperative day 1 can help further risk stratify patients younger than 60 years old or those with the highest risk who could benefit from one or more AF prevention strategies.

	References

Top Abstract Introduction Material and Methods Results Comment References

 

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