ARTICLE IN PRESS doi:10.1510/icvts.2008.181099
Interactive CardioVascular and Thoracic Surgery 7 (2008) 1039–1043 www.icvts.org
Institutional report - Thoracic general
Incidence of atrial fibrillation after extrapleural pneumonectomy vs. pleurectomy in patients with malignant pleural mesothelioma Siyamek Neragi-Miandoaba, *, Shoshana Weinerb, David J. Sugarbakerc Department of Surgery, St Vincent Medical Center, New York Medical College, School of Medicine, 170 West 12th Street, New York, NY 10011, USA b Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA c Division of Thoracic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, 15 Francis Street, Boston, MA 02115, USA a
Received 2 April 2008; received in revised form 28 May 2008; accepted 29 May 2008
Abstract Extrapleural pneumonectomy (EPP) and pleurectomy are the surgical procedures for the treatment of pleural mesothelioma. However, EPP increases the risk for postoperative atrial fibrillation (AF). We conducted a retrospective chart review of 130 patients who underwent EPP or pleurectomy. Seventy patients (excluding three patients with a prior history of AF) underwent EPP and 57 patients underwent pleurectomy. The mean ages were 60"11 and 63"13 years, and the male to female ratios were 50y20 and 44y13, respectively. Postoperative AF was observed in 45 patients with 36 (51%) of these cases occurring after EPP and 9 (17%) after pleurectomy (P-0.0001). There were no significant differences between the two treatment groups for gender, age, side of affected lung, preoperative heart rate, history of beta-blocker use, coronary heart disease, and chronic obstructive pulmonary disease. Through logistic regression, EPP (ORs7.1, 95% CI: 2.9, 17.8) and age over 65 years (ORs2.9, 95% CI: 1.2, 6.8) were found to be risk factors for AF. We conclude that EPP vs. pleurectomy and age over 65 years are risk factors for postoperative AF. The increased odds of having AF after EPP could be due to right heart stress caused by pneumonectomy. 䊚 2008 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Right heart stress; Extrapleural pneumonectomy; Pleurectomy; Atrial fibrillation
Inclusion criteria:
1. Introduction Thoracic surgery remains a high-risk procedure for many patients, and atrial fibrillation (AF) is the most frequent complication with the highest morbidity rates in this patient population w1, 2x. The etiology and risk factors for AF following thoracotomy have not been completely identified. It has a multifactorial etiology including change in hemodynamics of the right heart, violation of chest cavity, operative stress, pain leading to increased sympathetic activity, and irritation of the epicardium following violation of the pericardium and patch repair after extrapleural pneumonectomy. Other risk factors include myocardial infarction, presence of coronary artery disease, and postoperative lung embolism w1x. 2. Methods Out of the 130 patients identified, three were excluded due to a prior history of AF. Patients were considered eligible for the study if they experienced AF within the first three days following surgery, and the remaining patients served as controls. *Corresponding author: Tel.: q212-604-7000. E-mail address:
[email protected] (S. Neragi-Miandoab). 䊚 2008 Published by European Association for Cardio-Thoracic Surgery
–
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All patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy or pleurectomy in a time frame between November 2001 and October 2003 Age 18 years or older Exclusion criteria:
– – – –
Pediatric population Intraoperative intracavitary heated chemotherapy Previous atrial fibrillation Neoadjuvant therapy
All patients following extrapleural pneumonectomy and pleurectomy are monitored on surgical intensive care unit (SICU) and step down units with cardiac telemetry at Brigham and Women’s Hospital on the Thoracic Floors. Once the arrhythmias were noticed on the monitor, they were documented with a 12 lead ECG. Atrial fibrillation was defined as irregularly irregular heart rate. With 55% of our population sample having received EPP, we could detect an odds ratio of 5.5 with a power of 81% at a significance level of 0.05 (NCSSyPASS). An additional post hoc model with fewer patients was created in order to evaluate the role of structural and functional abnormalities of the heart in AF. Collinearity was assessed by
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tolerance and variance inflation factors, and the fit of the models was evaluated using Hosmer and Lemeshow goodness-of-fit tests. Calculations were preformed using SAS version 9.1. 3. Results Seventy-three patients underwent EPP, and 57 patients had pleurectomy and decortication. Three patients from the EPP group were excluded due to a prior history of AF. A total of 45 patients experienced AF within the first three days of surgery. Thirty-six of these cases occurred in the EPP group, and nine occurred in the pleurectomy group (Table 1). Univariate analyses were conducted in order to compare differences between the two treatment groups for postoperative AF and previously identified risk factors including: age, gender, affected lung, preoperative heart rate, history of coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), and previous betablocker therapy (Table 1). Different histological types are associated with better or worse prognosis. Only postoperative AF (P-0.0001) and cell type (Ps0.03) were significantly different between the two groups. The EPP group had a significantly larger proportion of patients with postoperative AF and epithelial-type cancer compared to the pleurectomy group. The majority of patients with epithelial histology received EPP, which potentially has significantly prolonged survival compared to pleurectomy w3, 4x. Pleurectomy is considered a purely palliative approach. An additional univariate analysis was conducted in order to evaluate correlations between individual risk factors and AF within three days of surgery (Table 2). COPD was not included in further analyses due to the small sample size, and cell-type was also withheld since the histology of mesothelioma is not a direct risk factor for AF. Preoperative Table 1 Patient characteristics Patient characteristics Post-op AF Age Mean ("S.D.) F 65 )65 Gender Male Female Affected lung Right Left Cell type** Epithelial Non-epithelial Pre-op heart rate* Mean ("S.D.) F72 )72 Medical Hx CAD COPD噛 b-Blocker
Pleurectomy ns57 (45%) n (%)
EPP ns70 (55%) n (%)
P-value
9 (17%)
36 (51%)
-0.0001
63 ("13) 25 (44%) 32 (56%)
60 ("11) 22 (31%) 48 (69%)
0.3 0.2
44 (79%) 12 (21%)
50 (71%) 20 (29%)
0.3
32 (56%) 25 (44%)
37 (53%) 33 (47%)
0.7
37 (67%) 18 (33%)
58 (84%) 11 (16%)
0.03
79 ("15) 22 (41%) 32 (59%)
80 ("16) 21 (32%) 44 (68%)
0.7 0.3
10 (18%) 3 (6%) 8 (14%)
19 (27%) 8 (12%) 10 (14%)
0.2 0.5 0.97
;
噛
*Eight patients missing data, **3 patients missing data, t-tests, Fisher exact test (1 patient missing data).
Table 2 Univariate analysis of risk factor variables Variable
OR (95% CI)
P-value
EPP Above 65-year-old Male gender Left lung affected HR )72 bpm Hx of CAD b-blocker
5.8 1.6 0.5 1.0 0.8 1.5 2.2
-0.0001 0.2 0.1 0.99 0.7 0.4 0.2
(2.5, (0.7, (0.2, (0.5, (0.4, (0.6, (0.8,
13.9) 3.4) 1.2) 2.1) 1.9) 3.6) 6.1)
heart rate and age were dichotomized since the small sample size of our study would not permit an accurate analysis of these risk factors as continuous variables. Only EPP was found to be significantly correlated with AF in this analysis (5.8, 95% CI: 2.5, 13.9). In order to further evaluate the presence of confounders, a full logistic model was created with all the risk factor variables (Table 3). In this model, the odds ratio (OR) for EPP increases to 7.2 (2.8, 18.5) and the OR for age 2.8 (1.1, 7.2) becomes significant (Ps0.03). The reduced model (Table 4) demonstrates that the change in the OR for EPP can be explained by placing only age in the model. None of the other risk factors were shown to improve the model based on the use of maximum likelihood ratios (data not shown), and the fit model was determined to be satisfactory based on the non-significant Homser–Lemeshow goodness-of-fit test. Therefore, age is an additional risk factor for AF in our analysis, and patients who are older than 65 years have 2.9 (1.2, 6.8) times the odds of experiencing AF as compared to patients who are 65-yearold and younger. A subgroup of 56 patients, who received postoperative echocardiogram, 16 of 38 EPP and 3 of 18 pleurectomy patients had at least one structural or functional abnormality (diagnosed in echocardiogram) that predisposed the patient to AF (Table 5). Twenty-one of the 38 EPP patients and six of the 18 pleurectomy patients experienced AF. In a univariate analysis the presence of an abnormality was significantly correlated with the occurrence of AF (OR: 2.9, CI 95%: 0.9, 9.6). In addition, we adjusted the correlation Table 3 Full model (ns119) Variable
OR (95% CI)
P-value
EPP Above 65-year-old HR )72 bpm Left lung affected Male gender Hx of CAD
7.2 2.8 0.8 0.9 1.3 0.4
-0.0001 0.03 0.6 0.7 0.6 0.07 HL GOF test Ps0.9
(2.8, (1.1, (0.3, (0.4, (0.5, (0.1,
18.5) 7.2) 1.9) 2.0) 3.4) 1.1)
Table 4 Parsimonious model (ns127) Variable
OR (95% CI)
P-value
EPP Above 65-year-old
7.1 (2.9, 17.8) 2.9 (1.2, 6.8)
-0.0001 0.02 HL GOF test Ps0.99
ARTICLE IN PRESS S. Neragi-Miandoab et al. / Interactive CardioVascular and Thoracic Surgery 7 (2008) 1039–1043 Table 5 Functional and structural abnormalities by treatment group
Totals
Table 6 Model controlling for structural and functional abnormalities (ns54)
Pleurectomy (ns7)
Variable
OR (95% CI)
P-value
3 1
0 0
EPP Above 65-year-old Abnormality on echo
6.4 (1.2, 35.3) 13.9 (2.6, 72.9) 2.31 (0.6, 9.0)
0.03 0.002 0.2 HL GOF test Ps0.31
0 1 2 5 2 12 1 1 0 0 0 4 0
1 0 0 1 1 0 0 0 2 1 1 0 1
32
8
EPP (ns16) Functional Decreased LVF* Decreased RVF* Structural R. atrium enlarged* L. atrium enlarged* Aortic insufficiency* Mitral regurg* Tricuspid regurg* R. ventricle enlarged* RV hypertrophy* Atrial septal defect* Aortic stenosis Aortic root dilation Mital valve calcification LV hypertrophy Wall akinesis
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sample size. However, our results shed light into new aspects in the etiology of postoperative AF. In addition to preexisting cardiac conditions, another significant factor that may contribute to postoperative AF is pneumonectomy. In our series, EPP significantly correlated with AF (5.8, 95% CI: 2.5, 13.9). The increased pulmonary pressure and right atrial stress after complete removal of one lung causes right heart distention in the early postoperative phase, which could increase the risk of arrhythmias. The atrial stretch and dilatation favors the development of atrial ectopy and AF. The role of the left atrial dilation and myocardial stretch has been well studied; however, there is limited literature about the role of the right heart stress in the development of AF. Xiao et al. w5x evaluated the dilation of the right and left atria in 56 consecutive patients with AF. Right atrial dilatation was found in 34, left atrial dilatation in 36, and bi-atrial dilatation in 31 patients. Other authors reported the role of right heart stress in postoperative atrial fibrillation w6, 7x. Some studies have identified right-sided EPP as a risk factor for AF, in addition to other complications w8, 9x. A patch reconstruction of pericardium after pericardial resection with right-sided EPP to prevent herniation of the heart might cause irritation of the epicardium, contributing to arrhythmias. Pericardial patch reconstruction is necessary after right-sided EPP procedures only w8–10x. We were not able to compare right- and left-sided EPP directly in our model since we are primarily comparing pleurectomy to EPP. However, we conducted a univariate analysis of our data to evaluate the relationship between AF and the affected side in EPP patients alone, and we did not observe a significant correlation (Table 2, OR 0.9, Ps0.7).
*Patients considered at risk for AF.
between EPP and AF for the presenceyabsence of a structural abnormality in a logistic model with 56 patients, who had echocardiogram. When only EPP and age were added to the model, the OR for EPP was 7.982 (1.546, 41.217). The OR decreased to 6.4 (1.2, 35.3) when the presencey absence of an abnormality was added to the model (Table 6) implying that these abnormalities may prove to be significant confounders in a better powered model. Therefore, EPP is most likely an independent risk factor for postoperative AF. Although the charts under review did not extensively comment on pulmonary pressures, seven patients in our dataset had a record of increased pulmonary arterial pressures (Table 7). Five of these patients experienced postoperative AF. It is likely that increased rightheart stress contributes to, but is not sufficient to cause postoperative AF. 4. Discussion The major limitations in our study were the retrospective nature of the study, lack of randomization, and small Table 7 Patients with RV enlargment andyor increased pulmonary arterial pressure (ns14)
1 4 6 2 3 5 7 8 9 10 11 12 13 14
Treatment group
Age
Gender
Increased PAP
RV enlarged
AF
Other cardiac structural abnormalities
Cell-type
Side affected
Post-op echo
Pleurectomy EPP EPP EPP EPP EPP EPP EPP EPP EPP EPP EPP EPP EPP
61 60 69 71 58 76 64 77 37 62 52 57 55 48
F M M M M M M M M M F F M M
Yes Yes Yes Yes Yes Yes Yes No No No No No No No
No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes No Yes Yes No Yes Yes No No Yes Yes No Yes No
Aortic stenosis
E E E E E M M E E S E E E E
R L R L R L R R L L L R L R
Yes No Yes Yes Yes Yes No No Yes Yes Yes No No Yes
Tricuspid regurgitation*
Mitral regurgitation*
Decreased LV function* RV hypertrophy* Decreased RV function* Atrial septal defect*
*Considered increased risk for AF, 8y14 with at least one had AF, 3y4 with both RV enlargement and increase PAP had AF.
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Structural heart disease including CAD and valve dysfunction increases the risk of postoperative dysrhythmias w1x. In patients with postoperative AF following EPP (ns16), the echocardiogram demonstrated right ventricular dilation in 12 of 16 patients (75%) and one additional patient had AF and right ventricular hypertrophy after EPP; considering the hypertrophy of right ventricle in this patient, we assume that the patient had longstanding pulmonary hypertension. Structural abnormality of the heart significantly correlated with the occurrence of AF (OR: 2.9, CI 95%; 0.9, 9.6). In addition, we adjusted the correlation between EPP and AF for the presenceyabsence of a structural abnormality in a logistic model with 56 patients. Using EPP and age in the model showed an OR of 7.982 (1.546, 41.217), which decreased to 6.4 (1.2, 35.3) when the structural abnormalities were added to the model. When the presencey absence of an abnormality alone was used in the model, the OR was 2.3 (Ps0.2, Table 6) implying that these abnormalities may be significant confounders. However, in this current model, the addition of this variable did not improve the model according to maximum likelihood ratios. EPP remains most likely an independent risk factor for postoperative AF (Table 6, OR 6.4, Ps0.03) in our series. Age has been reported to be a significant risk factor for postoperative AF w11x. Our data demonstrate that patients receiving EPP and who are older than 65 years have greater odds of experiencing postoperative AF as compared to patients receiving EPP and younger than 65 years. The univariate analysis in our series showed that age is not a risk factor (Table 2, OR 1.6, Ps0.2); however, a multivariate analysis in a full model (Table 3) demonstrated the age to be a risk factor for postoperative AF (OR 2.8, Ps0.03). A multivariate analysis in a Parsimonious model confirmed the role of age as a significant risk factor for AF (Table 4, OR 2.9, Ps0.02). From a multivariate analysis in a model that controlled for structural and functional abnormalities and the role of age )65 years, age was found to have a significant impact on postoperative AF (Table 6, OR 13.9, Ps0.002). The univariate (Table 2) and multivariate analysis (Table 3) demonstrated that gender, the affected side, preoperative heart rate, presence of coronary artery disease, and preoperative use of beta-blockers were not significant risk factors for postoperative AF in this cohort. In a series of 856 patients, Passman et al. w11x reported that 17.2% of patients had AF following major, non-cardiac thoracic surgery. The authors reported that male gender, advanced age, and preoperative heart rate G72 beats per minute were independent predictors of postoperative AF. A risk score was assigned with male gender and heart rate G72 beats per minute each receiving 1 point, and age 55– 74 and G75 years receiving 3 and 4 points, respectively. The authors suggested that their scoring system might be able to predict the risk of postoperative AF w11x. Based on our observation, we suggest that the extension of the incision and the size of the dissected lung might be included in Passman’s scoring system. In contrast to Passman’s data, our analysis did not demonstrate any correlation between preoperative HR and AF (Table 2, univariate analysis, OR 0.8, Ps0.7, Table 3 Full model, OR 0.8, Ps0.6). The
postoperative heart rate was considerably higher in patients with AF, which explains the natural course of AF; therefore, we did not include the postoperative HR in our analysis, which could have caused bias in our series. 5. Limitations of the study Our study is limited by the smaller sample size and by additional biases that are associated with retrospective studies. We were limited to the information provided in the charts. The EPP group had a significantly larger proportion of epithelial-type cancer as compared to the pleurectomy group. 6. Conclusion This cohort highlights the impact of pneumonectomy on hemodynamics change leading to postoperative arrythmias, most likely secondary to right heart stress. Our data demonstrated a significant increase of arrhythmias after extrapleural pneumonectomy compared to pleurectomy. We recommend that any prophylactic measure should address the right heart stress as a significant risk factor for postoperative atrial fibrillation. References w1x Vaporciyan AA, Correa AM, Rice DC, Roth JA, Smythe WR, Swisher SG, Walsh GL, Putnam JB Jr. Risk factors associated with atrial fibrillation after noncardiac thoracic surgery: analysis of 2588 patients. J Thorac Cardiovasc Surg 2004;127:779–786. w2x Bobbio A, Caporale D, Internullo E, Ampollini L, Bettati S, Rossini E, Carbognani P, Rusca M. Postoperative outcome of patients undergoing lung resection presenting with new-onset atrial fibrillation managed by amiodarone or diltiazem. Eur J Cardiothorac Surg 2007;31:70–74. w3x Paul S, Neragi-Miandoab S, Jaklitsch MT. Preoperative assessment and therapeutic options for patients with malignant pleural mesothelioma. Thorac Surg Clin 2004;14:505–516,ix. w4x Neragi-Miandoab S, Richards WG, Sugarbaker DJ. Morbidity, mortality, mean survival, and the impact of histology on survival after pleurectomy in 64 patients with malignant pleural mesothelioma. Int J Surg 2008 Aug;6:293–297. w5x Xiao HB, Rizvi SA, McCrea D, Kaufman B. The association of chronic atrial fibrillation with right atrial dilatation and left ventricular dysfunction in the elderly. Med Sci Monit 2004;10:CR516–520. w6x Zeltser I, Gaynor JW, Petko M, Myung RJ, Birbach M, Waibel R, Ittenbach RF, Tanel RE, Vetter VL, Rhodes LA. The roles of chronic pressure and volume overload states in induction of arrhythmias: an animal model of physiologic sequelae after repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 2005;130:1542–1548. w7x Hirose M, Takeishi Y, Miyamoto T, Kubota I, Laurita KR, Chiba S. Mechanism for atrial tachyarrhythmia in chronic volume overloadinduced dilated atria. J Cardiovasc Electrophysiol 2005;16:760–769. w8x Harpole DH, Liptay MJ, DeCamp MM Jr, Mentzer SJ, Swanson SJ, Sugarbaker DJ. Prospective analysis of pneumonectomy: risk factors for major morbidity and cardiac dysrhythmias. Ann Thorac Surg 1996;61: 977–982. w9x Sugarbaker DJ, Jaklitsch MT, Bueno R, Richards W, Lukanich J, Mentzer SJ, Colson Y, Linden P, Chang M, Capalbo L, Oldread E, Neragi-Miandoab S, Swanson SJ, Zellos LS. Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 2004;128:138–146. w10x Neragi-Miandoab S. Multimodality approach in management of malignant pleural mesothelioma. Eur J Cardiothorac Surg 2006;29:14–19. w11x Passman RS, Gingold DS, Amar D, Lloyd-Jones D, Bennett CL, Zhang H, Rusch VW. Prediction rule for atrial fibrillation after major noncardiac thoracic surgery. Ann Thorac Surg 2005;79:1698–1703.
ARTICLE IN PRESS S. Neragi-Miandoab et al. / Interactive CardioVascular and Thoracic Surgery 7 (2008) 1039–1043 eComment: Postoperative atrial fibrillation following extrapleural pneumonectomy – which atrium is the driving force?
Author: Karsten Knobloch, Plastic, Hand and Reconstructive Surgery, Hannover Medical School, 30625 Hannover, Germany doi:10.1510/icvts.2008.181099A I appreciate the retrospective analysis of Dr. Neragi-Miandoab and coworkers w1x assessing the risk for atrial fibrillation (AF) following extrapleural pneumonectomy in contrast to pleurectomy. An odds ratio of 7.1 (95% CI 2.9–17.8) was reported for AF following extrapleural pneumonectomy followed by age (ORs2.9, 95% CI 1.2–6.8). The authors suggested that right atrial stress is to be attributed for this arrhythmia. Short atrial effective refractory periods (ERP) and increased dispersion of refractoriness are known predisposing factors for atrial fibrillation or atrial flutter (AFL) in experimental models as well as in patients w2x. The baseline differences in ERP between left and right atrium may result from quantitative or qualitative differences in the expression of different ion channels. Often, the left atrium is driving atrial fibrillation, while the right atrium typically is involved in atrial flutter. It is well known that atrial flutter is a macro re-entry phenomenon almost always located in the right atrium in humans and animals w3x. It would be of great interest to know whether atrial flutter was encountered among the patients undergoing extrapleural pneumonectomy? Interestingly, given the differential distribution of ion channels such as Ikr, Iks, Ikur, IkAch between both atria, antiarrhythmic drugs exert differential effects on the atrium, too w4x. ACE inhibitors, by exerting antifibrotic
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activity by TGF-beta-inhibition, might reduce the incidence of atrial fibrillation too, which should be considered in this regard as well w5x. References w1x Neragi-Miandoab S, Weiner S, Sugarbaker DJ. Incidence of atrial fibrillation after extrapleural pneumonectomy versus pleurectomy in patients with malignant pleural mesothelioma. Interact CardioVasc Thorac Surg 2008;7:1039–1043. w2x Boutjdir M, Le Heuzey JY, Lavergne T, Chauvaud S, Guize L, Carpentier A, Peronneau P. Inhomogeneity of cellular refractoriness in human atrium: factor or arrhythmia? Pacing Clin Electrophysiol 1986;9:1095– 1100. w3x Olshansky B, Okumura K, Hess PG, Waldo AL. Demonstration of an area of slow conduction in human atrial flutter. J Am Coll Cardiol 1990; 16:1639–1648. w4x Knobloch K, Brendel J, Peukert S, Rosenstein B, Busch AE, Wirth KJ. Electrophysiological and antiarrhythmic effects of the novel I(Kur) channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide, azimilide, d,l-sotalol and ibutilide. Naunyn Schmiedebergs Arch Pharmacol 2002;366:482– 487. w5x Knobloch K, Gohritz A, Spies M, Vogt PM. ACE inhibitors as antifibrotic agents in atrial fibrillation: potential relevance in cardiac surgery. Interact CardioVasc Thorac Surg 2008;7:475–476.
