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J Thorac Cardiovasc Surg 2004;127:779-786
© 2004 The American Association for Thoracic Surgery
Cardiopulmonary support and physiology |
a Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Tex, USA
Received for publication May 1, 2003; revisions received June 23, 2003; revisions received July 14, 2003; accepted for publication July 31, 2003.
* Address for reprints: Ara A. Vaporciyan, MD, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 445, Houston, TX 77030, USA
avaporci{at}mdanderson.org
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Abstract |
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METHODS: A comprehensive prospective database was used to identify patients undergoing major thoracic surgery from January 1, 1998, through December 31, 2002. Data collection was performed at point of contact: at preoperative evaluation, the time of the operation, discharge, and postoperative visits. All patients undergoing resection of a lung, the esophagus, the chest wall, or a mediastinal mass were included in this study. Univariate and multivariate analyses of factors associated with the development of atrial fibrillation were analyzed.
RESULTS: There were 2588 patients who met the inclusion criteria. The overall incidence of atrial fibrillation was 12.3% (n = 319). Categories of disease were primary lung cancer, pulmonary metastasis, esophageal cancer, intrathoracic metastasis, benign lung disease, other mediastinal tumors, mesothelioma, chest wall tumors, benign esophagus, and "other." Patients with atrial fibrillation had increased mean lengths of hospital stay, mortality rates, and mean hospital charges. Univariate analysis evaluated age, sex, disease category, comorbidities, preoperative therapy, and procedure, and significant variables were entered into the multivariate analysis. Significant variables (relative risk; 95% confidence interval) in the multivariate analysis were male sex (1.72; 1.29-2.28), age 50 to 59 years (1.70; 1.01-2.88), age 60 to 69 years (4.49; 2.79-7.22), age 70 years or greater (5.30; 3.28-8.59), history of congestive heart failure (2.51; 1.06-6.24), history of arrhythmias (1.92; 1.22-3.02), history of peripheral vascular disease (1.65; 0.93-2.92), resection of mediastinal tumor or thymectomy (2.36; 0.95-5.88), lobectomy (3.89; 2.19-6.91), bilobectomy (7.16; 3.02-16.96), pneumonectomy (8.91; 4.59-17.28), esophagectomy (2.95; 1.55-5.62), and intraoperative transfusions (1.39; 0.98-1.98).
CONCLUSIONS: The significant variables identified by means of multivariate analysis were associated with the occurrence of atrial fibrillation. Preventive therapies in selected populations might reduce the incidence of atrial fibrillation.
| See related editorial on page 629.
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Since initially reported by Bailey and Betts1 in 1943, supraventricular tachyrhythmias, particularly atrial fibrillation (AF), have remained one of the most frequent complications that occur after noncardiac thoracic surgery. The occurrence of AF is associated with substantial morbidity, such as increased hospital stay, risk of stroke, postoperative mortality, and significant increases in cost.2-6 Efforts to prevent AF have included multiple pharmacologic attempts at prophylaxis, with partial success.7-10 In addition, new implantable cardioversion techniques are becoming available.11 These medications and cardioversion techniques involve some risk and increase costs. Therefore identification of all high-risk populations will allow targeted use and hence more cost-effective and successful application of these methods.
A number of attempts at identifying risk factors for postoperative AF have been made.2,4,5,12-16 These studies have identified age and extent of pulmonary resection as apparent risk factors. However, these studies have examined small numbers of patients or specific groups of patients, such as those undergoing selected surgical procedures or with a specific diagnosis. The applicability of these findings to all patients encountered in a general noncardiac thoracic surgery practice is limited. The relative contributions of chest wall resection, mediastinal tumor resection, metastasectomy, and esophagectomy to the risk of AF are less clearly understood. A more comprehensive assessment of the risk of AF in all patients undergoing noncardiac thoracic surgery could determine the roles that these events play. The purpose of this study was to identify preoperative and intraoperative factors that are associated with an increased risk of postoperative AF in patients undergoing noncardiac thoracic surgery.
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Methods |
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All patients, regardless of diagnosis, who underwent resection of the lung, the esophagus, the chest wall, or a mediastinal mass from January 1, 1998, through December 31, 2002, were included in this analysis. Information was recorded in the database about demographics, comorbidity, medical and surgical histories, preoperative functional testing, operative details, postoperative events, and long-term symptomatic and oncologic outcomes. During this 4-year period, the database was modified by the addition of further data-entry fields to collect more detailed information about each patient. Consequently, some of the patients who were enrolled early in the database had incomplete data relative to more recently entered patients. Only those data that were collected throughout the entire 4-year study period were included in the analysis.
The demographic data that we analyzed were patient age, sex, and category of disease. Preoperative and perioperative factors examined were weight loss, neoadjuvant therapy, smoking history, timing of smoking cessation relative to the operation, alcohol use (defined as 
4 oz/d or its equivalent), hypertension, congestive heart failure, angina, prior myocardial infarction, arrhythmia, diabetes, peripheral vascular disease, chronic obstructive pulmonary disease (COPD; defined as a disease requiring chronic bronchodilator use), prior cardiothoracic surgery, prior cardiac surgery, prior thoracotomy, procedure performed, mediastinal lymph node dissection, and intraoperative transfusions (defined as the use of any blood products intraoperatively).
All patients had continuous telemetric monitoring of electrocardiography and oxygen saturation for at least the first 72 hours after resection. No routine prophylaxis for AF was in place during the study period, with the exception of a small number of patients undergoing extrapleural pneumonectomy. To identify clinically relevant episodes of AF or atrial flutter, our database definition of AF is a sustained or repetitive electrocardiographically documented AF or atrial flutter that requires initiation of antiarrhythmic therapy. Data on 30-day mortality rates, length of hospital stay, and hospital charges were also collected.
Statistical analysis consisted of univariate analysis of all variables. All variables were treated as categoric. Variables with a P value of less than .25 were entered into a multivariate logistic regression model. A stepwise backward elimination using the likelihood ratio test with elimination defined by a P value of .1 or greater was performed. For variables that contained multiple categories, such as the procedure performed, a reference category was chosen to perform the multivariate analysis.
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Results |
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.01) were age, sex, preoperative diagnosis, weight loss, any smoking history, timing of smoking cessation, hypertension, congestive heart failure, angina, arrhythmias, peripheral vascular disease, COPD, prior thoracotomy, procedure performed, mediastinal node dissection, and intraoperative transfusion. The results of the univariate analysis were used to construct the multivariate model. All variables with a P value of .25 or less were included. In addition to the variables that were highly significant in the univariate analysis, neoadjuvant therapy, alcohol use, and prior cardiac surgery fulfilled these criteria for inclusion in the multivariate analysis. Two variables were excluded from entry into the multivariate model. Preoperative diagnosis correlated closely with the procedure performed, and therefore only one of these variables, the procedure performed, was included in the multivariate analysis. For similar reasons, any smoking history was included, but the timing of smoking cessation was not. An additional reason not to include the timing of smoking cessation was that these data were missing for 138 patients. The multiple-wedge variable was initially entered into the multivariate model as 2 separate variables: multiple-wedge resections of 2 to 9 nodules and multiple-wedge resections of more than 9 nodules. Neither variable was associated with an increased risk of AF, and therefore the 2 were combined into the single variable of multiple wedges in the final multivariate analysis.
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The development of AF after thoracic surgery significantly increased mortality rate (2.0% vs 7.5%, P < .001), length of hospital stay (mean ± SD, 8.2 ± 11.0 days vs 16.6 ± 18.6 days; P < .001), and hospital charges (mean ± SD, $28,325.98 ± $40,126.15 vs $56,426.57 ± $88,924.53; P < .001). When patients without any complications (n = 1422) were compared with patients with only AF (n = 104), there still was a significant increase in hospital cost (mean ± SD, $21,425.38 ± $19,427.57 vs $27,859.38 ± $12,017.99; P = .001).
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Discussion |
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Previous attempts to identify factors associated with the development of AF after noncardiac thoracic surgery have been performed. Although most have examined specific subgroups of patients undergoing pulmonary resection, primarily for lung cancer14-16,18 or esophagectomy,2 a few investigators have examined a broader population of patients similar to our patient population.5,12,13 The most frequent risk factors identified in these studies have been increasing age and extent of pulmonary resection. Other reported factors have included a history of hypertension, ischemic changes on electrocardiography, cardiac enlargement, prior myocardial infarction, congestive heart failure, mediastinal lymph node dissection, intraoperative cardiac arrest, and need for repeat thoracotomy.
The association between age and AF was closely examined by Amar and colleagues.12 In their analysis of 527 patients undergoing lobectomy, pneumonectomy, or esophagectomy over a 10-year period, they found incidences of AF to be 4%, 8%, 14%, and 25% in patients younger than 50 years, 50 to 59 years, 60 to 69 years, and 70 or more years of age, respectively. These findings are very similar to those of our univariate analysis and support the association of increasing incidence of AF with increasing age.
The association between the extent of pulmonary resection and AF has been identified by a number of investigators. Asamura and associates13 examined 267 nonesophageal operations in a 1-year period and reported increasing incidence of AF with increasing volume of lung resected. Likewise, other investigators have found the highest incidence of AF after pneumonectomy.14-16 Our analysis had similar findings; in our study, however, it appeared that the manipulation of the hilum might be as important as the total volume of lung resected. This is a likely hypothesis because it has been shown in patients with chronic AF that the pulmonary veins are an important source of ectopic beats that can initiate paroxysms of AF.19 Supporting evidence from our analysis includes the similarity between the single-wedge and multiple-wedge groups (neither was associated with an increased risk of AF despite more lung being resected in the multiple-wedge group) and the association of AF with esophagectomy but not with chest wall or sternal resections. However, patients with a large volume (>9 wedges) of lung resected during multiple-wedge resections or patients undergoing chest wall or sternal resections represented only 3% and 7%, respectively, of the total patient population. Repeat analysis with a greater number of patients should be performed.
The association between male sex and AF has not been commonly identified by other investigators, most likely because of the small numbers of patients analyzed. Polanczyk and coworkers5 examined 4181 patients undergoing major noncardiac thoracic or abdominal procedures (hospital stay 2 days). Their multivariate analysis identified male sex as a predictor of AF, with an odds ratio (odds ratio, 1.3; 95% confidence interval, 1.0 to 1.7; P = .04) similar to that seen in our relative risk data. This association might be explained by the effect of sex on immune response. One hypothesis for the cause of postoperative AF is atrial or pulmonary vein inflammation.20 After trauma, male patients have an increased proinflammatory immune response compared with that of female patients,21 and this might lead to increased AF after surgical trauma.
The association between intraoperative transfusions and AF found in our analysis has not been previously demonstrated. Although it is possible that there are immunologic effects of transfusion that lead to increased arrhythmias, it is more likely that transfusions represent a marker of more complex or difficult dissection.
The association of cardiac disease with AF has been demonstrated inconsistently by other investigators.5,13,15,16 The selection criteria imposed by thoracic surgeons might prevent patients with clinically relevant cardiac disease from undergoing surgical intervention. This is certainly demonstrated in our data because patients with congestive heart failure, angina, prior myocardial infarction, arrhythmias, or peripheral vascular disease represented only 1.0%, 1.5%, 3.9%, 4.5%, and 2.7%, respectively, of all the patients examined. The common occurrence of AF after cardiac surgery supports the association of cardiac disease with AF after thoracic surgery.22,23 Our study demonstrated associations of congestive heart failure, arrhythmias, and peripheral vascular disease with AF. Both arrhythmias and congestive heart failure have been identified by various investigators. The association of peripheral vascular disease and AF appears novel. Peripheral vascular disease is predominantly an inflammatory process, and therefore the increased risk of AF in these patients, like male sex, might be due to an intrinsic heightened inflammatory response.
The lack of association between hypertension and AF in our analysis is also noteworthy. Other investigators have shown this association, but their analyses were limited to only 598 or 233 patients with lung cancer.15,18 Hypertension occurred commonly in our population (28.4%) and was associated with a higher incidence of AF by means of univariate analysis; our multivariate model, however, failed to demonstrate any association. The larger patient population along with inclusion of many different diagnoses and procedures in our analysis might have led to this difference.
The presence of COPD, the performance of a mediastinal lymph node dissection, or the use of neoadjuvant chemotherapy, radiotherapy, or combined chemotherapy and radiotherapy was not associated with the development of AF in our study. Other investigators have found that the association between COPD and AF is inconsistent.24,25 The definition of COPD might vary between different authors and might lead to this inconsistency. Our definition was based on the presence or absence of bronchodilator treatment and not strict pulmonary function testing. Unfortunately, data on pulmonary function were inconsistently collected in our database during the 4-year period of this study. Future analysis could allow inclusion of these parameters into our multivariate model.
Mediastinal node dissection was performed in 22.8% of the patients in this study, and although it was associated with a higher incidence of AF in the univariate analysis, it was not predictive of AF in the multivariate model. Finally, the use of neoadjuvant chemotherapy, radiotherapy, or combination therapy was not associated with an increased risk of AF. Investigators have shown a decrease in cardiac perfusion and an increased frequency of cardiac symptoms, ischemia, and mortality after left-breast radiation therapy.26-30 Our database does not collect information on the dose and ports used during radiation therapy treatment. Further analysis will be performed, with more detailed attention paid to the cardiac radiation therapy dose and its effect on the development of AF.
In conclusion, our analysis of 2588 patients undergoing a variety of general thoracic procedures demonstrated an association of AF with age, male sex, a history of congestive heart failure, arrhythmia, peripheral vascular disease, the procedure performed (specifically mediastinal tumor resection or thymectomy, lobectomy, bilobectomy, pneumonectomy, and esophagectomy), and the use of intraoperative transfusions. These results in this large cohort of patients confirm the findings of a number of different investigators. The identification of patients with a high risk of AF will allow more directed application of pharmacologic and alternative methods of prophylaxis.
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Discussion |
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I have 4 questions, and in the interest of time, I will collapse the first and the third into a single question. A study like this is very much dependent on both the definitions that you use and the practices that are used at your institution. You required echocardiographic evidence for an atrial arrhythmia. That then was acted on, somebody intervened, which would seem to limit the number, lower the report, and perhaps understate the incidence. On the other hand, your practice is that patients are monitored for 72 hours after the operation, which is more than we do, and that would tend to raise the incidence. Can you comment on how your definition has affected the incidence that you report? Also, was there any prophylaxis against arrhythmias used in any of these subgroups that might have lowered the incidence?
Dr Vaporciyan. I will answer the second question first because that is easier. There is no established method of prophylaxis at our institution, except recently for the extrapleural pneumonectomies, in which the incidence has been high. Patients received diltiazem intraoperatively as a continuous infusion, which is continued postoperatively. But that group actually represented a small portion of the total number of patients, and therefore I do not think it had an effect on the incidence of AF.
As far as the definitions, we have a stepdown unit that all of our patients go to, where they are started automatically on a cardiac monitor and an oxygen monitor. Therefore it is standard practice for all our patients to be monitored. Any tachyarrhythmias identified there are followed up with a 12-lead echocardiogram. If a diagnosis of AF with tachyarrhythmia is made, at that point the patients are treated. That is our standard definition of how they become identified.
Dr Downey. The second question is about the cause of atrial arrhythmias. These have been attributed to either trauma to the pulmonary vein and hence to the atrium and also to damage to the sympathovagal fibers. It was interesting that the anatomic resections were associated with a higher incidence, which is what you would expect, but the mediastinal lymph node dissection was not. Do you have any comments on what your data show about the possible causes of patients going into AF?
Dr Vaporciyan. The thought from the data is that the manipulation of the hilum is probably the most important, specifically the pulmonary veins, and that is something we are going to look into in an animal model in the future. Mediastinal node dissection is not done on all patients undergoing lobectomy because we have a high percentage of metastasectomies at our institution, and some of those require anatomic resections without the addition of mediastinal node dissection. Therefore I was able to dissect out mediastinal node dissection separate from the actual procedure performed. The esophagectomies also have manipulation of the hilum and the posterior left atrial wall, and they also lead to that cause as well. The wedge resections and the actual amount of parenchyma removed did not seem to make a difference. We segregated our multiple-wedge resections by low numbers of wedge resections and high numbers of wedge resections, and there were at least 80 or 90 patients who had greater than 10 wedge resections, which would come close to anatomically about a lobectomy of removal of lung parenchyma. Those patients had the same incidence of AF as patients who underwent a single-wedge resection. Therefore I think it is more the manipulation of the hilum than it is the actual lung volume resected or vagal fibers from a mediastinal node dissection.
Dr Downey. My last question has to do with your multivariable analysis. If I understand your data correctly, you are at high risk for development of an atrial arrhythmia if you are male, if you are over 60 years of age, or if you have an operation other than a wedge resection or an isolated chest wall resection. Obviously I think your risk factors are going to have to be brought together. How are you planning to define the highest-risk group of patients within the overall population?
Dr Vaporciyan. We actually looked at the way the model predicts, and despite the fact that we have entered 2600 patients in 32 variables, it is still not as robust a model as it could be. It actually predicts about 25% or 30% of the cases at best and usually about 22% of the cases. Therefore there are obviously a lot of factors that are involved that we were not able to detect, even with 2600 patients enrolled in this analysis. That being said, I think you still can make the comment that patients undergoing pneumonectomy who are male with advanced age have a high risk and should be considered for some sort of prophylactic therapy.
Dr Daniel L. Miller (Atlanta, Ga). It is interesting that as we go back and look at these AF data, there is not a lot of discussion in regard to the onset of AF, which day it occurred, postoperative day number 1, number 3, or number 5. Did you look at that at all to see whether that made a difference in hospital stay, morbidity, and so forth? And the second part of that, you had a correlation with increased mortality, which a lot of studies with AF these days do not. Was it that the patients that were already going down the tubes on day 7 or 8 who had AF, that it was going on in a sequence? If you could comment on both of those, that would be great.
Dr Vaporciyan. The database does not capture such detailed hospital data. Essentially, at the time of discharge, all complications are entered in the database. We do not make a note of when it happened. Just speaking anecdotally from taking care of the patients, it is usually between 24 and 96 hours, about the second hospital day to the fourth hospital day, that they occur.
In reference to the other aspect about how AF usually accompanies other complications, in the article we examined patients with AF as their only complication, looked at the hospital charges of those patients and the hospital stays of those patients, and compared these values with those of the patients who had no other complications. We found that when you exclude all other complications and look at patients who only had AF, there still was a significant increase in cost and length of stay of about 30% to 50%. We did not look at mortality yet, and we will look at that as well.
Dr David H. Harpole, Jr (Durham, NC). Dr Putnam and his group at M. D. Anderson deserve credit for putting together this very large prospective database to answer some of these questions. This afternoon we have had a very nice presentation on probably the largest series of pneumonectomies in North America and now a nice prospective series looking at complications. The Society of Thoracic Surgeons database general thoracic module is out. If we want to learn more about these complications and ways to treat them, I encourage all of you to participate in this database, and hopefully over the next 10 years we will have a lot more articles coming out in the Association on this subject.
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