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COPD May Increase the Incidence of Refractory Supraventricular Arrhythmias Following Pulmonary Resection for Non-small Cell Lung Cancer^*

^* From the Department of Surgery (Drs. Y. Sekine, Kesler, and Brown, and Mr. E. Sekine), Division of Cardiothoracic Surgery, and the Department of Medicine (Drs. Behnia and Brooks-Brunn), Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indiana University Medical Center, Indianapolis, IN.

Correspondence to: Kenneth A. Kesler, MD, FCCP, Division of Cardiothoracic Surgery, Indiana University Medical Center, 545 Barnhill Dr, EH No. 215, Indianapolis, IN 46202; e-mail: kkesler{at}iupui.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Purpose: This study investigated the association of COPD and postoperative cardiac arrhythmias, specifically supraventricular tachycardia (SVT), as well as mortality in patients undergoing pulmonary resection for non-small cell lung cancer (NSCLC).

Methods: A retrospective chart review of 244 patients who had undergone lung resection for NSCLC at Indiana University Hospital between 1992 and 1997 was undertaken. COPD, which was defined as an FEV₁ of 70% predicted and an FEV₁/FVC ratio of 70% based on the results of a preoperative pulmonary function test (PFT), was diagnosed in 78 of the 244 patients (COPD group). In the remaining 166 patients, the results of preoperative PFTs did not meet these criteria (non-COPD group). Both groups were otherwise well-matched with respect to multiple variables, including age, comorbid conditions, extent of pulmonary resection, and final pathologic stage. The incidence of cardiac arrhythmias and operative mortality were compared between the two groups using univariate and multivariate analysis.

Results: Seventy-six patients (31.9%) experienced new onsets of postoperative SVT, with 58 of these patients (76.3%) demonstrating atrial fibrillation. The COPD group had a 58.7% incidence of SVT (n = 44) compared to a 27.0% incidence (n = 44) in the non-COPD group (p < 0.0 0 1). Moreover, following initial digoxin therapy, the COPD group required more second-line antiarrhythmic therapy than did the non-COPD group (66.7% vs 37.8%, respectively; p = 0.0 03). Overall, there were 16 operative deaths (6.6%), and the mortality rate was significantly higher in the COPD group (14.1%) than in the non-COPD group (3.0%; p = 0.0 04). Patients who developed SVT had a significantly longer hospital course than did patients who did not (p < 0.0001). Thirteen of the 16 patients who died experienced SVT; however, SVT was not an independent risk factor for death. Finally, of the 19 variables evaluated, major resection (ie, pneumonectomy and bilobectomy) and COPD were identified as independent risk factors for the development of cardiac arrhythmias (p = 0.0 033 and p = 0.0 009, respectively).

Conclusion: Patients with COPD, as defined by the results of preoperative PFTs, are at significantly higher risk for SVT, and in particular SVT refractory to digoxin, following pulmonary resection for NSCLC. Although SVT was not an independent risk factor for death, a significantly longer hospitalization was observed.

Key Words: cardiac arrhythmia • COPD • multivariate analysis • non-small cell lung cancer • postoperative cardiac complications • pulmonary resection

	Introduction

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Mortality due to lung cancer currently far surpasses death rates from all other solid-organ malignancies in the United States. Smoking is the preeminent risk factor not only for non-small cell lung cancer (NSCLC), but also for COPD. It has been well-established that due to diminished cardiopulmonary reserve, patients with COPD are more prone to perioperative complications following pulmonary resection for NSCLC.¹ Despite the fact that numerous sophisticated tests now can be utilized to assess cardiopulmonary reserve preoperatively, including several types of cardiac stress evaluation, split perfusion-ventilation lung scans, maximum oxygen uptake, and multifactorial cardiopulmonary risk indexes, routine pulmonary function tests (PFTs) and arterial blood gas analyses remain the standard screening tests utilized for virtually all patients for risk assessment prior to pulmonary resection.^{1 2 3 4 5 6 7} Although respiratory complications represent a significant source of morbidity for COPD patients undergoing pulmonary resection, the relationship between COPD, as quantitated by formal PFT and postoperative cardiac complications (in particular, atrial arrhythmias), has not been well-established. We undertook a study to identify the incidence of postoperative complications and risk factors associated with postoperative cardiac arrhythmias in the presence of COPD.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Three hundred fifteen patients with NSCLC who underwent thoracotomy and pulmonary resection between January 1992 and August 1997 at Indiana University Hospital were retrospectively reviewed. Of those 315 patients, 244 underwent formal preoperative PFTs and blood gas analyses. For the remaining 71 patients, a comprehensive panel of the above tests was not available, and these patients were therefore excluded from analysis. Preoperative evaluation for all patients otherwise included a detailed history and physical examination, CBC count, serum electrolytes and renal profile, spirometry, and a 12-lead ECG. The predicted postoperative FEV₁ was estimated by the following equation: postoperative FEV₁ = preoperative FEV₁ x [1 - (S x 5.26)/100] (where S signifies the number of resected bronchopulmonary segments).⁸ Airway obstruction was defined as an FEV₁ 70% of predicted and an FEV₁/FVC ratio of 70%.⁹ Seventy-eight patients fulfilled these criteria (COPD group), and the other 166 patients were categorized as being in the non-COPD group. All resections were undertaken through a standard posterior-lateral thoracotomy approach, usually dividing the latissimus dorsi muscle while mobilizing the serratus anterior muscle without division. At the time of surgery, a complete perihilar and mediastinal lymph node dissection was performed in all patients for accurate pathologic staging.

Sixteen preoperative and 3 intraoperative variables that may affect postoperative morbidity and mortality were recorded for all patients (see "Appendix"). More specific criteria of risk factors were defined as follows: coronary artery disease included a history of myocardial infarction or angina pectoris, and diabetes mellitus requiring either oral or insulin therapy for control of hyperglycemia. Charts were subsequently reviewed for eight pulmonary complications, including prolonged air leak for 10 days, segmental or lobar atelectasis, prolonged oxygen supplementation for 14 days, requirement for prolonged mechanical ventilation for 7 days, bacterial pneumonia, bronchial stump dehiscence, empyema, and ARDS. GI complications including significant ileus, gastric ulcer, bleeding, and perforation were recorded. Postoperative rhythm strips were reviewed for the following dysrhythmias: atrial fibrillation, paroxysmal atrial tachycardia, atrial flutter, frequent premature ventricular contractions (PVCs) > 5 min, ventricular tachycardia (VT), and all degrees of atrioventricular (AV) block. Finally, operative mortality was defined as death within 30 days following surgery or death prior to hospital discharge.

Due to the retrospective nature of this study, there was no standard supraventricular tachycardia (SVT) treatment algorithm; however, digitalis loading was the first-line therapy for all patients. If the rapid ventricular response was not controlled with an initial digoxin loading dose, then an IV ß-blocker or calcium channel blocker was added to the regimen. In general, if cardioversion had not occurred within 48 h of complete digoxin loading, then either a class IA (procainamide) or class III (amiodarone) antiarrhythmic agent was added to the therapeutic regimen. Electrical cardioversion was reserved for cases of severe hypotension or was performed electively prior to hospital discharge if cardioversion had not occurred despite therapeutic levels of all antiarrhythmic agents. All patients received subcutaneous heparin postoperatively for lower-extremity thromboembolism prophylaxis during the study period. Patients who remained in SVT at the time of hospital discharge received anticoagulation therapy with warfarin (Coumadin).

Data were analyzed using a software package (SAS, version 6.10; SAS Institute; Cary, NC). To compare the differences between the COPD and non-COPD groups, a Student’s t test was utilized to analyze continuous variables, and a Wilcoxon rank sum test and the ² test (ie, Fisher’s Exact Test) were utilized for categoric variables to determine the predictors of postoperative cardiac arrhythmias and mortality. All variables with a p value of < 0.15 by univariate analysis were entered into a stepwise method of logistic regression to identify variables that were independently predictive of postoperative morbidity, including arrhythmia and mortality.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Preoperative Patient Characteristics
Patient characteristics are summarized in Table 1 . Men were more predominant in the COPD group (74.4%) compared to the non-COPD group (57.2%; p = 0.01). The distributions of age, body mass index (BMI), and hematocrit were otherwise similar between the two groups. There were no statistical differences between the groups with respect to preoperative hypertension, ECG abnormalities, cardiac disease, or neoadjuvant therapy. Smoking was significantly more prevalent in the COPD group (p = 0.0 1). Although the distribution of pathologic NSCLC stage, the extent of resection, and the degree of intraoperative blood loss were similar between the two groups, operating time was prolonged in the COPD group, but did not reach statistical significance (p = 0.0 58). Comparing the results of PFTs between the two groups, COPD patients had a significantly diminished FEV₁ and FVC (p < 0.001), PaO₂ (p < 0.001), predicted postoperative FEV₁ (p < 0.001), and a significantly higher PaCO₂ (p = 0.031) than the non-COPD group (Table 2 ).

Postoperative Cardiac Arrhythmia
Eighty-eight patients (37.0%) experienced new-onset postoperative cardiac arrhythmias, and of those patients, 76 (86.4%) experienced SVTs. Atrial fibrillation was most frequent, occurring in 58 patients (24.4%). Other arrhythmias, including multifocal PVCs (two patients), VT (three patients), and transient third-degree AV block (two patients), occurred much less frequently (Table 3 ). Forty-four of 163 patients (27.0%) in the non-COPD group and 44 of 75 patients (58.7%) in the COPD group experienced postoperative cardiac arrhythmias. Although there was no statistical difference with respect to ventricular tachyarrhythmias or AV block, patients in the COPD group were statistically more prone to all forms of SVT collectively (p < 0.001) as well as to each specific category of SVT (Table 3) . Logistic regression analysis identified major resection (ie, pneumonectomy or bilobectomy) (p = 0.00 33) and COPD (p = 0.0009) as independent risk factors for arrhythmia (Table 5) .

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Onset of SVT after surgery. Time of onset of SVT was similar between the non-COPD and COPD groups.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Comparison of the postoperative pharmacologic management of atrial arrhythmias between COPD and non-COPD patients. Second-line antiarrhythmic agents were used more frequently after either initial digoxin dosage or formal digoxin loading in the COPD group compared to the non-COPD group (p = 0.003).

	Discussion

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The risk of supraventricular arrhythmias following pulmonary resection has been documented in several reported series^{12 13 14 15} with an incidence ranging between 10% and 28%. Von Knorring et al¹⁵ reported on 598 patients undergoing pulmonary resection for NSCLC and found ischemic changes on ECG, cardiac enlargement, and pneumonectomy to be risk factors for postoperative arrhythmias. In this study, a predicted postoperative FEV₁ of < 1 L was not found to be a risk factor for arrhythmia; however, specific PFT criteria to establish a diagnosis of COPD were not utilized. Similarly, our data did not demonstrate that postoperative predicted FEV₁ was a risk factor for arrhythmia; however, COPD, as defined by standard criteria, was clearly a significant and independent risk factor. Our data appear to be consistent with a report by Polanczyk and coworkers¹⁶ who reviewed > 4,000 patients undergoing pulmonary resections and found that a history of chronic lung disease was independently predictive of SVT; however, formal PFT data again were lacking. Other studies by Harpole et al¹³ and Krowka et al,¹⁷ examining risk factors for the development of arrhythmias following pneumonectomy, failed to demonstrate a relationship to poor preoperative PFT results. In both of these series, a standard, but somewhat arbitrary, FEV₁ value of 2 L was utilized to distinguish "good-risk" from "bad-risk" patients as opposed to criteria based on the predicted percentages of measured FEV₁ and FVC. In our study, 37% of patients experienced postoperative arrhythmia, a value that appears to be higher than other reports. A significant number of our patients who underwent resection met the PFT criteria for COPD; however, they had a 58.7% incidence of atrial arrhythmias, which may have biased our results. In addition, all patients in our series underwent complete peribronchial and mediastinal lymph node dissection, which may also predispose a patient to postoperative arrhythmia.¹⁸

In contrast to patients with COPD, the finding that major pulmonary resections were also an independent risk factor for the development of postoperative atrial arrhythmias is not surprising. It has been well-established that atrial tachycardias represents one of the most frequent complications following pneumonectomy.^{13 14 15 17} Although the exact cause or causes of SVT following pulmonary resection has not been completely elucidated, these reports and our data would support that a short-term change in the atrial pressure-volume relationship plays a not insignificant role. Amar et al¹⁹ demonstrated that increased tricuspid regurgitation on echocardiography following noncardiac thoracic surgery is a risk factor. Similarly, Lindgren et al²⁰ reported that an increase in right ventricular diastolic pressures was predictive of atrial tachyarrhythmias. Following major pulmonary resection, a short-term increase in pulmonary artery afterload, in addition to intravascular fluid shifts, would likely change the atrial pressure-volume relationships to a more significant degree compared to lesser resections.

In the hemodynamically stable patient, the initial goal of therapy is to reduce the rapid ventricular rate. Although ß-blockers and calcium channel blockers are occasionally utilized for this purpose, the possibility of potentiating or worsening hypotension with these agents exists. Moreover, in patients with COPD, nonselective ß-blockade could have deleterious effects on preexisting compromised respiratory function. Digoxin, therefore, has traditionally been the first-line drug of choice for increasing AV block through vagal pathways, and secondarily, for reducing the ventricular rate. Occasionally, digoxin loading will result in a conversion to sinus rhythm or, more frequently, will diminish ventricular response to acceptable rates until spontaneous conversion occurs. Unfortunately, although typically used as a first-line therapy, digoxin has not been shown to be of benefit for SVT prophylaxis.²¹ Similarly, ß-blockers and calcium channel blockers do not appear to be efficacious when used for SVT prophylaxis; however, diltiazem, in particular, is frequently utilized as a second-line treatment of unacceptably rapid ventricular rates after an initial digoxin dose or complete digoxin loading.^{22 23} A typical treatment algorithm, which was used at our institution during this study period, employs either a class IA (ie, procainamide) or a class III antiarrhythmic agent (ie, amiodarone) following rate stabilization and if conversion to sinus rhythm has not occurred within 48 h. A concern over the development of pulmonary complications has previously limited the use of amiodarone. Procainamide has most frequently been used for pharmacologic cardioversion in this regard. Ciriaco et al,²⁴ however, recently reported a 90% rate of conversion to sinus rhythm using amiodarone without pulmonary toxicity in 22 patients who had undergone lung resection. Six patients in that report, and the majority of patients experiencing digoxin-refractory SVT at our institution subsequent to this series, have been treated in the short term with amiodarone following pulmonary resection without apparent toxicity. Based on these preliminary data, the administration of amiodarone, at least in the short-term setting, appears to be safe in many patients with underlying pulmonary disease. However, the use of amiodarone, which is arguably more efficacious than other antiarrhythmic agents such as procainamide, clearly warrants further investigation in this patient population prior to widespread usage. In summary, speculation to explain the propensity of COPD patients for developing more frequent digoxin-refractory SVT would include preexisting abnormal atrial pressure-volume relationships that further deteriorate following pulmonary resection by increases in both right heart afterload and intravascular fluid volume.

Although 13 of 16 patients who suffered operative deaths experienced SVT following resection, none of these deaths were directly attributed to SVT nor was SVT independently predictive of death. Brathwaite and Weissman²⁵ reviewed 462 patients undergoing noncardiac thoracic surgery and found that 47 patients experienced new-onset atrial tachyarrhythmias with a 23% mortality rate. Although a multivariate analysis model was not utilized in that series, SVT was only directly attributable to two deaths. The most significant identifiable morbidity attributable to postoperative SVT in our series was a prolonged hospital stay compared to patients who did not develop SVT. Polanczyk et al,¹⁶ reporting on the largest series of patients undergoing noncardiac thoracic surgery to date, also found postoperative SVT to be predictive of a prolongation in hospital stay. While seemingly not independently associated with postoperative mortality, many patients who develop SVTs appear to experience other significant complications including death. At the very least, the development of a successful prophylactic strategy for postresection SVT would represent substantial cost savings by reductions in hospital stays.

Our findings that both COPD and major resections were independently predictive of operative mortality would be anticipated by and are supportive of data in previous reports in the literature. These data additionally suggest, however, that not only major resections but also COPD, with diagnoses based on standard PFT criteria, are independently significant risk factors for the development of SVT following pulmonary resection for NSCLC. Moreover, the majority of COPD patients who developed postoperative SVT required second-line antiarrhythmic therapy following either an initial digoxin dose or complete digoxin loading, which is suggestive of more refractory SVT. Future prospective trials investigating preoperative variables that are predictors of SVT following pulmonary resections should include quantitative PFTs. Moreover, future atrial arrhythmia prophylaxis trials should consider stratifying for COPD based on standard PFT criteria, and strategies developed for SVT prophylaxis in COPD patients, as well as patients undergoing major resections, should be aggressive.

	Appendix 1

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Risk Factor Variables Analyzed for Postoperative Morbidity and Mortality
Preoperative Variables 1. Age 70 years

2. Male gender

3. BMI > 25 kg/m²

4. Hematocrit < 30%

5. Abnormal preoperative ECG

6. Smoking history of > 40 pack-years

7. Hypertension (systolic BP > 140 beats/min and/or diastolic BP > 90 beats/min)

8. Coronary artery disease

9. Diabetes mellitus

10. Neoadjuvant chemotherapy and/or radiation therapy

11. Arterial blood gas values

A. pH < 7.3 or > 7.5

B. PaO₂ 60 mm Hg

C. PaCO₂ 45 mm Hg

12. Pulmonary function testing

A. FEV₁< 1.2 L

B. Criteria of COPD (FEV₁ 70% predicted and FEV₁/FVC ratio 70%)

C. Postoperative predicted FEV₁ of < 1.0 L

Intraoperative Variables 1. Major resection (ie, pneumonectomy or bilobectomy)

2. Length of operation of > 200 min

3. Intraoperative blood loss of > 300 mL

	Footnotes

 
Abbreviations: AV = atrioventricular; BMI = body mass index; NSCLC = non-small cell lung cancer; PFT = pulmonary function test; PVC = premature ventricular contraction; SVT = supraventricular tachycardia; VT = ventricular tachycardia

Received for publication November 14, 2000. Accepted for publication May 22, 2001.

	References

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 

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