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Table of Contents
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 15  |  Issue : 3  |  Page : 199-205
N-terminal pro-brain natriuretic peptide identifies patients at risk for occurence of postoperative atrial fibrillation in cardiac surgery with cardiopulmonary bypass


1 Department of Anesthesia and Intensive Care, Habib Bourguiba Hospital, Sfax, Tunisia
2 Department of Biology, Habib Bourguiba Hospital, Sfax, Tunisia
3 Department of Thoracic and Cardiac Surgery, Habib Bourguiba Hospital, Sfax, Tunisia

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Date of Submission03-Dec-2011
Date of Acceptance17-Apr-2012
Date of Web Publication4-Jul-2012
 

   Abstract 

Atrial fibrillation (AF) is the most common arrhythmia after cardiac surgery with cardiopulmonary bypass (CPB).The value of N-terminal (Nt)-pro brain natriuretic peptide (BNP) in predicting AF complicating cardiac surgery is not well studied. Our objective is to determine its predictive value in the occurrence of AF after cardiac surgery with CPB. In a prospective observational study, including patients scheduled for cardiac surgery with CPB, we collected blood samples for each patient: the first one immediately after the induction of anesthesia and before CPB. The subsequent samples were taken at the end of the CBP (H0), 4 hours later (H4), and every day during the first four days (H24, H48, H72 and H96). Nt-proBNP and cardiac troponin (cTnI) were measured in each sample. The levels of Nt-proBNP were significantly increased in patients who developed AF. The receiver operating characteristic curve (ROC) analysis of Nt-proBNP studied at different times showed that assays at the end of the CPB and at H4 had the maximum area under the curve (AUC). A threshold value of 353.5 pg/mL of Nt-proBNP at the end of the CPB showed a sensitivity of 71% and a specificity of 84% for the prediction of AF and an AUC of 0.711. The threshold value (307.5 pg/mL) of Nt- proBNP measured at H4 had the same sensitivity but a lower specificity (74%) and AUC = 0.709. We conclude that Nt-proBNP values of 353 and 307 pg/mL at 0 and 4 hour after CPB could predict occurrence of AF.

Keywords: Atrial fibrillation, Cardiac surgery, Pro-brain natriuretic peptide

How to cite this article:
Samy K, Anouar J, Mnif E, Imed F, Fatma A, Abdelhamid K. N-terminal pro-brain natriuretic peptide identifies patients at risk for occurence of postoperative atrial fibrillation in cardiac surgery with cardiopulmonary bypass. Ann Card Anaesth 2012;15:199-205

How to cite this URL:
Samy K, Anouar J, Mnif E, Imed F, Fatma A, Abdelhamid K. N-terminal pro-brain natriuretic peptide identifies patients at risk for occurence of postoperative atrial fibrillation in cardiac surgery with cardiopulmonary bypass. Ann Card Anaesth [serial online] 2012 [cited 2019 Nov 18];15:199-205. Available from: http://www.annals.in/text.asp?2012/15/3/199/97976



   Introduction Top


Postoperative rhythm disorders are a serious complication of cardiac surgery. Its occurrence in the postoperative period is associated with an increased risk of systemic embolism and hemodynamic complications which can results in longer stay in intensive care units (ICU) and higher mortality rates.

The incidence of postoperative supraventricular arrhythmias has been reported to be from 11% to 54%, and the incidence of ventricular arrhythmia from 1.8% to 13%. [1] Arrhythmias are frequently seen during the first 48 hours following open-heart surgery, necessitating effective postoperative monitoring. The incidence of AF after surgery seems to be increasing despite advances in techniques of anesthesia, myocardial protection and cardiac surgical techniques.­ [2] Several studies [3] recommend prophylactic use of magnesium sulphate and amiodarone. Both the drugs were effective at preventing arrhythmia that may occur after coronary artery bypass grafting. Brain natriuretic peptide (BNP) and its precursor N-terminal pro-BNP (Nt -ProBNP) are secreted by the ventricles and considered markers of severity and prognosis of acute coronary syndromes [4],[5] and heart failure. [6],[7] Recent studies have found that postoperative BNP concentrations have also interesting prognostic value. [8],[9] The value of Nt- proBNP in predicting AF after cardiac surgery is not well studied. Our objective is to determine its role in predicting the postoperative AF after cardiac surgery with cardiopulmonary bypass (CPB).


   Materials and Methods Top


Patient selection

After approval from the university ethics committee and written informed consent, 42 consecutive eligible patients undergoing cardiac surgery with CPB were enrolled prospectively in this study. All patients were free from active preoperative infection or inflammatory disease. Inclusion criteria were age > 18 years, programmed or semi-urgent heart surgery under CPB and postoperative care in the ICU of the cardiovascular surgery ward of Habib Bourguiba University Hospital of Sfax. Patients with history of recent myocardial infarction (MI) (less than 7days), preoperative renal or hepatic failure, infective endocarditis or documented infection within the last 7 days before surgery were excluded. Two patients were withdrawn from the study because of death in the first 24 h.

Anesthesia and surgery

Patients were premedicated with oral hydroxyzin (Atarax® ) 1 mg/kg, the night before surgery and 2 hours before surgery. After preoxygenation, intravenous anesthesia was induced with midazolam (Hypnovel® ) 0.1 mg/kg and remifentanil 1 μg/kg administered over 1 min. Tracheal intubation was performed after adequate neuromuscular blockade with cisatracurium, 0.2 mg/kg. Anesthesia was maintained with remifentanil 0.2-0.4 μg/kg/min, cisatracurium 0.1 mg/kg/h, and midazolam 0.05 mg/kg/h. Sevoflurane was used for myocardial preconditioning in case of CABG.

The patient's lungs were mechanically ventilated with the ventilator set to deliver an inspired fraction of oxygen of 0.5, tidal volume around 7 to 10 mL/kg, and respiratory rate adjusted to maintain PaCO2 between 35 and 40 mmHg. All patients were monitored by a 5 lead electrocardiogram, pulse oximetry, end-tidal carbon dioxide (capnography) and arterial catheter; right heart catheterization (pulmonary artery catheter) was used only when preoperative left ventricular ejection fraction was <0.4. All patients received antibiotic prophylaxis with intravenous cefazol 2 g before induction and 1 g every 4 hours during surgery then every 8 hours for 24 hours in case of CABG and 48 hours in case of valve replacement (VR). Vancomycin 1 g at induction and 1 g every 12 hours was used in patients allergic to cefazolin or high-risk patients.

During surgery, temperature was maintained with a warming blanket. After intravenous administration of heparin (300 IU / kg) and attaining an activating clotting time (ACT) greater than 400 seconds, CPB was initiated using an occlusive roller pump (Stockert S3) and a membrane oxygenator with integrated arterial filter (Synthesis). The priming solution contained 1500 mL Ringer's lactate, 100 mL 20% mannitol and 50 mL 8.4% sodium bicarbonate. If the hematocrit was below 30%, saline was replaced by two units of blood. During CPB pump flow was maintained at about 2.4 l/min/m 2 and mean arterial pressure was maintained between 60 and 80 mmHg. Myocardial protection was provided by anterograde cold crystalloid cardioplegia (St Thomas II). At the end of surgery, i.v. protamine sulphate was administered to reverse anticoagulation and obtain ACT<160s.

Tracheal extubation was performed when patients met the following criteria: hemodynamic stability, adequate muscle strength, full consciousness, stable body temperature (37°C to 38.5°C), and adequate ventilation (breathing rate: 10 to 30 breaths/min, PaO2/IFO2 > 80/0.4, PaCO2, 30 to 50 mmHg).

Blood samples

We performed seven blood samples for each patient: the first one immediately after the induction of anesthesia and before CPB (described as baseline level). The subsequent samples were taken - at the end of the CBP (H0), 4 hours later (H4) and every day during the first four days (H24, H48, H72 and H96). Nt-proBNP was measured in each sample. Blood samples were collected from the radial artery and immediately centrifuged for 10 min. Plasma samples frozen at < 20°C were stable for assays for >20 days after sampling, and all samples were analysed within 2 weeks.

Nt-proBNP determinations

Nt-proBNP concentrations were measured with a sandwich immunoassay using polyclonal antibodies that recognize epitopes located in the N-terminal part (1-76) of pro- BNP (1-108). An electrochemiluminescence immunoassay was performed using an Elecsys analyser (Roche Diagnostics, Mannheim, Germany). The intra-assay coefficients of variation were 2.7% (at 175 pg ml _1 ) and 1.9% (at 1068 pg ml _1 ), respectively, and the interassay coefficients of variation were 3.2% (at 175 pg ml _1 ) and 2.6% (at 1068 pg ml _1 ).

Definitions

The postoperative AF was defined as any documented episode of AF lasting at least 15 min and recorded within the first 3 post operative days. Post operative acute renal failure was defined by increased levels of plasma creatinine of more than 20% in the first three post operative days compared to the baseline levels.

Statistical analysis

Statistical analysis was performed with the software Statistical Package for Social Sciences (SPSS) for Windows (version11.0). Quantitative variables were expressed as mean ± SD or median [minimum-maximum] depending on the nature of the distribution. Categorical variables were expressed as frequencies. For the comparison of means, we used the Student's t test or Mann-Whitney U test whenever the normality of the distributions was not observed (non Gaussian distribution) or the size of one of the groups was small (<10). Categorical variables were analyzed by Chi square test or the Fisher exact test whenever a workforce was <5. Differences between results were considered significant at a value of P <0.05. For multiple comparisons we used the Bonferroni correction. The connection between two continuous variables was tested by the Pearson correlation in the case of Gaussian distribution and by Spearman correlation whenever the normality of the distributions was not respected. To determine the different threshold values, we used the ROC (receiver operating characteristic) curve. The best threshold value is the value having the best sensitivity and specificity.


   Results Top


A total of 42 patients were selected. Two patients were excluded due to their death at first post operative day. Patients were divided in 23 CABG and 17 VR. The mean age of patients was 56.1 ± 14.9 years and the sex ratio was 1.3. No difference in preoperative morbidity was observed except for the higher incidence of diabetes in the coronary population [Table 1]. The most common post operative cardiovascular complication was the AF (17.5%). [Table 2] shows the post operative cardiovascular complications in different surgeries.
Table 1: Demographic characteristics and comorbidities

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Table 2: Postoperative cardiovascular complications

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The Nt-proBNP levels increased significantly compared to baseline level from the first postoperative day [Figure 1]. The differences between the levels of Nt- proBNP during the 4 postoperative days were not significant. The levels of Nt-proBNP at H0, H4, H24 and H96 were positively correlated with baseline levels (P<0.05). The levels of Nt-proBNP were higher at H48 in VR patients as compared to CABG patients; however, the difference was not significant [Figure 2]. The Euroscore correlated with baseline levels of Nt- proBNP (r=0.343, P=0.03) and at H24 (r=0.353, P=0.03) [Figure 3]. The Parsonnet score was correlated to the levels of Nt-proBNP at H24 (r=0.331, P=0.04) [Figure 4]. The levels of Nt-proBNP correlated to the duration of CPB, the aortic clamping and surgery [Table 3]. Postoperatively, the duration of dobutamine use was positively correlated with levels of Nt-proBNP at H24 (r=0.600, P<0.0001) and H48 (r=0.346, P=0.03). The duration of noradrenalin use was not correlated with the levels of Nt-proBNP.
Figure 1: The kinetics of Nt-proBNP

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Figure 2: Kinetics of Nt-proBNP in the 2 groups (CABG and VR)

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Figure 3: Correlation between the Euroscore and Nt-proBNP levels at H24

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Figure 4: Correlation between Parsonnet score and Nt-proBNP levels at H24

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Table 3: Correlation between Nt-proBNP and peroperative data

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The levels of Nt-proBNP were significantly increased in patients with severe SIRS from the first post operative day. The levels of Nt-proBNP showed no significant difference among patients without SIRS and those with SIRS without organ dysfunction [Table 4]. After binary logistic regression, using severe SIRS as the dependent variable and the duration of CPB, duration of surgery, extubation time, length of catecholamines administration and the levels of Nt-proBNP on the first post operative day as covariates, only the Nt-proBNP on H24 was independently associated with the occurrence of severe SIRS. (P = 0.02, OR = 1.008,95% CI = 1.001 to 1.015).
Table 4: Nt-proBNP levels according to the existence and severity of SIRS

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Levels of Nt-proBNP were significantly increased in patients who developed postoperative AF. The ROC analysis of Nt-proBNP at different times studied for the prediction of AF showed that assays at the end of the CPB and at the 4 th postoperative hour (H4) had the best area under the curve (AUC) [Figure 5]. A threshold value of 353.5 pg / ml of Nt-proBNP at the end of CPB (H0) showed a sensitivity of 71% and a specificity of 84% for the prediction of the AF and an AUC of 0.711. The threshold value 307.5 pg/ml of Nt-proBNP measured at H4 had the same sensitivity but a lower specificity (74%) and AUC = 0.709.
Figure 5: Receiver operating characteristic curves of Nt-proBNP at different time study for the prediction of AF

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The levels of Nt-proBNP were significantly increased in cases of cardiovascular dysfunction (pulmonary edema) in first, second and third postoperative days (P = 0.007, P = 0.007, P = 0.02 respectively) compared with patients who did not develop cardiovascular dysfunction. According to the ROC curve [Figure 6], a threshold value of Nt-proBNP of 1728 pg / mL measured at day 1 after surgery predicted cardiovascular dysfunction with a sensitivity of 87%, a specificity of 72% and AUC = 0.805 (95%:0,66-0, 94).
Figure 6: Receiver operating characteristic curve of Nt-proBNP at H0 for the prediction of cardiovascular dysfunction

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The levels of Nt-proBNP were also significantly increased at H24 (P = 0.04) in patients who developed postoperative acute renal failure as compared to those who did not. According to the ROC curve [Figure 7], a threshold value of Nt-proBNP of 1595 pg / ml measured in the first postopérative day predicted postoperative acute renal failure with a sensitivity of 75% and a specificity of 71% and AUC = 0.729 (95%:0,57-0, 88).
Figure 7: Receiver operating characteristic curve of Nt-proBNP at H4 for predicting acute postoperative renal dysfunction

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   Discussion Top


In our study, we found a large variability in the levels of Nt-proBNP after cardiac surgery. The levels of Nt- proBNP increased significantly compared to baseline levels from the first to the 4 th postoperative day with a peak at 2 nd day. Our results are consistent with those of Reyes et al. [10] In this study, preoperative levels of Nt-proBNP (1371 ± 759.9 pg / ml with a median of 366 pg/ml) increased significantly after CPB surgery from postoperative day 1 to the 4 th postoperative day. In their study including 83 patients, no difference in the type of surgery was reported. [10] The study of Berendes et al[11] also showed a significant increase in BNP levels after cardiac surgery. However, in their study, including 60 CABG and 43 VR patients, BNP levels were significantly increased in VR patients as compared to CABG ones. [11]

In our study, the levels of Nt-proBNP on the first day correlated with the Euroscore and Parsonnet score. This is in line with the literature data. [12],[13] Earlier, Padrazzini et al.[13] has shown that preoperative Nt- proBNP predicted mortality better than the Euroscore after aortic valve replacement.

In our study, the level of postoperative Nt-proBNP was associated with the occurrence of postoperative complications. This result is in accordance with that of Provenchère et al[14] they found that only the BNP postoperatively is associated with the occurrence of postoperative cardiac dysfunction in a prospective study of 92 patients. In our study, the levels of Nt- proBNP were significantly increased in patients with organ dysfunction from the first postoperative day. To our knowledge, this is the first study that showed that the level of Nt-proBNP on H24 were independently associated with the occurrence of severe SIRS after cardiac surgery with CPB. For patients without SIRS and those with SIRS without organ dysfunction, levels of Nt-proBNP showed no significant difference. Our results are in line with the study of Kerbaul et al[15] which showed that the severe SIRS with cardiovascular dysfunction has been associated with high levels of Nt-proBNP after off-pump coronary artery surgery. In our study and that of Kerbaul et al, [15] the levels of Nt-proBNP were correlated with greater use of positive inotropic drugs (dobutamine). This may reflect the myocardial failure in these patients. Shor et al[16] have shown that increased levels of BNP in septic shock and severe sepsis (pathophysiology similar to severe SIRS) is due to the intense inflammatory state that characterizes these conditions. Indeed, intense inflammation results in the release of proinflammatory cytokines in the blood such as IL6, IL1β and TNF. These cytokines cause myocardial failure as they are cardiodepressant. [17] In addition, these substances directly stimulate the secretion of BNP by cardiomyocytes. [18],[19] The influence of cytokines on the release of BNP might explain the correlation we found between the postoperative levels of these markers. The occurrence of severe SIRS after cardiac surgery with CPB worsens the prognosis. Nt-proBNP appears to be a predictor of this syndrome. A level> 1662 pg / ml on day 1 postoperatively should alarm the clinician.

In cardiac surgery, the incidence of AF is 60%. [20] In our study, the incidence of AF was much lower (17.5%), this could be secondary to the use of corticosteroids. Our study showed a Nt-proBNP level of 353 and 307 pg/ ml, could predict the occurrence of AF. In this case, primary prevention may be considered. Wazni et al[21] studied the BNP which is secreted in equimolar amount with Nt-proBNP in myocardial cells, and showed that the level of preoperative BNP is an independent predictor of AF. In our study, the predictive value of baseline levels has not been demonstrated. This can be explained by the small size of our sample. The predictive value of BNP for predicting postoperative AF has been demonstrated also in case of non-cardiac surgery such as pulmonary resection. [22] Sarzi et al[23] used Nt-proBNP to predict "late AF" definied as AF occurring during the rehabilitation period (20+/-5 days) in contrast to 'early' AF defined as AF documented in the surgical department soon after surgery. Late AF was observed in 17% of patients. AF patients had higher BNP levels than event-free patients (459+/-209 vs. 401+/-449 pg/ml, P=0.01). At multivariate analysis, BNP levels more than 322 pg/ml (P=0.02) and early AF (P=0.003) showed an independent association with late AF occurrence. In a recent study, Litton and Ho assessed predictive ability of pre-operative BNP or Nt-proBNP for post-operative AF. [24] The summary areas under the ROC curve for post-operative AF were 0.61 (95% CI 0.58-0.64).

In our study, levels of Nt-proBNP were significantly increased in patients who developed post operative renal dysfunction (PORD) at H24. A threshold value of Nt-proBNP of 1595 pg / mL measured at H24 allow prediction of postoperative acute renal failure with a sensitivity of 75% and a specificity of 71%. Although, the increase of Nt-proBNP in this case may be due to the SIRS complicated by a renal dysfunction, [15] Eliasdottir et al[12] showed in a recent study, including 135 patients undergoing cardiac surgery that the preoperative levels of Nt-proBNP were greater in patients who developed PORD. But these authors did not study the predictive levels of postoperative Nt-proBNP. The association between preoperative Nt-proBNP and PORD has not been demonstrated in our study. This may be due to the difference in adapted definitions: these authors defined PORD by plasma creatinin> 200 mmol/L. While in our study, PORD was defined by an increase of over 20% of baseline levels of creatinine.


   Conclusion Top


In our study we have shown that Nt-proBNP at H0 or H4, of 353 and 307 pg / mL could predict the occurrence of the AF. In this case, a primary prevention could be planned. Early assay for Nt-proBNP (first postoperative day) may provide better care for patients. Our results need to be confirmed by larger studies.

 
   References Top

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2.Halpin LS, Barnett SD, Burton NA. National databases and clinical practice specialist: decreasing postoperative atrial fibrillation following cardiac surgery. Outcomes Manag 2004;8:33-8.  Back to cited text no. 2
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3.Tiryakioglu O, Demirtas S, Ari H, Tiryakioglu SK, Huysal K, Selimoglu O, et al. Magnesium sulphate and amiodarone prophylaxis for prevention of postoperative arrhythmia in coronary by-pass operations. J Cardiothorac Surg 2009;4:8.  Back to cited text no. 3
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4.de Lemos JA, Morrow DA. Brain natriuretic peptide in acute coronary syndromes: ready for clinical application? Circulation 2002;106:2868-70.  Back to cited text no. 4
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6.Selvais PL, Donckier JE, Robert A, Laloux O, van Linden F, Ahn S, et al. Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary artery diseases on cardiac hormonal activation. Eur J Clin Invest 1998;28:636-42.  Back to cited text no. 6
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9.Provenchère S, Berroeta C, Reynaud C, Baron G, Poirier I, Desmonts JM, et al. Plasma brain natriuretic peptide and cardiac troponin I concentrations after adult cardiac surgery: Association with postoperative cardiac dysfunction and 1-year mortality. Crit Care Med 2006;34:995-1000.  Back to cited text no. 9
    
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12.Eliasdottir SB, Klemenzson G, Torfason B, Valsson F. Brain natriuretic peptide is a good predictor for outcome in cardiac surgery. Acta Anesthesiol Scand 2008;52:182-7.  Back to cited text no. 12
    
13.Pedrazzini GB, Masson S, Latini R, Klersy C, Rossi MG, Pasotti E, et al. Comparison of brain natriuretic peptide plasma levels versus logistic euroscore in predicting in-hospital and late postoperative mortality in patients undergoing aortic valve replacement for symptomatic aortic stenosis. Am J Cardiol 2008;102:749-54.  Back to cited text no. 13
    
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15.Kerbaul F, Giorgi R, Oddoze C, Collart F, Guidon C, Lejeune PJ, et al. High concentrations of N-BNP are related to non-infectious severe SIRS associated with cardiovascular dysfunction occuring after off-pump coronary artery surgery. Br J Anesth 2004;93:639-44.  Back to cited text no. 15
    
16.Shor R, Rozenman Y, Bolshinsky A, Harpaz D, Tilis Y, Matas Z, et al. BNP in septic patients without systolic myocardial dysfunction. Eur J Intern Med 2006;17:536-40.  Back to cited text no. 16
    
17.Torre-Amoine G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular dysfunction. J Am Coll Cardiol 1996;27:1201-6.  Back to cited text no. 17
    
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19.Ma KK, Ogawa T, de Bold AJ. Selective upregulation cardiac brain natriuretic peptide at transcriptional and translocational levels by pro-inflammatory cytokines and by conditioned medium derived from mixed lymphocyte reactions via p 38 MAP kinase. J Mol Cell Cardiol 2004;36:505-13.  Back to cited text no. 19
    
20.Aranki S, Shaw D, Adams DH, Rizzo RJ, Couper GS, VanderVliet M, et al. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation 1996;94:390-7.  Back to cited text no. 20
    
21.Wazni OM, Martin DO, Marrouche NF, Latif AA, Ziada K, Shaaraoui M, et al. Plasma B-type natriuretic peptide levels predict postoperative atrial fibrillation in patients undergoing cardiac surgery. Circulation 2004;110:124-7.  Back to cited text no. 21
    
22.Nojiri T, Maedaa H, Takeuchi Y, Funakoshi Y, Kimura T, Maekura R, et al. Predictive value of B-type natriuretic peptide for postoperative atrial fibrillation following pulmonary resection for lung cancer. Eur J Cardiothorac Surg 2010;37:787-91.  Back to cited text no. 22
    
23.Sarzi Braga S, Vaninetti R, Pedretti RF. Plasma B-type natriuretic peptide predicts atrial fibrillation during rehabilitation after cardiac surgery. Eur J Cardiovasc Prev Rehabil 2008;15:460-6.  Back to cited text no. 23
    
24.Litton E, Ho KM. The use of pre-operative brain natriuretic peptides as a predictor of adverse outcomes after cardiac surgery: a systematic review and meta-analysis. Eur J Cardiothorac Surg 2012;41:525-34.  Back to cited text no. 24
    

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Correspondence Address:
Kallel Samy
Habib Bourguiba University Hospital, Anesthesiology, Sfax 3000
Tunisia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.97976

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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