Methods: Between September 2003 and April 2004, 121 consecutive patients (99 males, 22 females; mean age 61.2±7.5 years; range 39 to 78 years) undergoing elective CABG surgery were included to the study. The patients were divided into two groups according to the absence [group-SR (sinus ryhtym), n=92] or presence [group-AF, n=29] of post- CABG AF. Variables were compared by Fischer’s exact test, chi-square and independent samples t-test. Multivariate logistic regression analysis was used for independent predictors of post-CABG AF.
Results: Post-CABG AF was detected in 23.9%. Mean age (66.6±7.2 vs 59.4±7.9, p=0.0001) and the incidence of chronic obstructive pulmonary disease (13.8 vs 2.2%, p=0.012) were higher in group-AF. The patient is older than 63 years of age (41.3 vs 13.3%, p=0.0001, area under the ROC curve of 0.748) have an increased prevalance of post-CABG AF. Much more frequent occurrence of post-CABG AF was in the patients without using β-blocker drug (40% vs 19.8%, p=0.035). Post-CABG AF was lower in the patients receiving statin than the patients not receiving statin (15.9% vs 34.6%, p=0.017). Post-CABG AF was lower in the patients receiving β-blocker plus statin therapy (13.3 vs 43.8%, p=0.015) than the patients not receiving these drugs. White blood cell (WBC) count of the patients receiving statin were lower than the patients not receiving statin (10618±3540 vs 13038±5661, p=0.005) in postoperative day 2 (POD 2). Chest tube drainage (1048.6±776.2 vs 641.5±514.6, p=0.001), and WBC count (13210±5550 vs 11160±4320, p=0.041), serum BUN (33.8±32.5 vs 21.6±13, p=0.004) in POD 2 were higher in group-AF. Intensive care unit stay (69.8±47.1 vs 53.6±19.2, p=0.008) and lenght of stay (LOS>7 days, 58.6 vs 37%, p=0.039) were higher in group-AF. Advanced age (OR=1.099, p=0.018) and increased postoperative drainage (OR=1.001, p=0.045) were independent predictors of post-CABG AF.
Conclusions: Age and postoperative blood loss are independent predictors of post-CABG AF. β-blocker plus statin therapy seems to be the best medication of choice on reducing the incidence of post-CABG AF. However, new prospective studies about the efficacy of this combination therapy are required.
Atrial fibrillation is the most frequently encountered arrhythmic complication following coronary artery bypass grafting (CABG) surgery which incurs significant cost to the health care system because of the increased length of intensive care unit and hospital stay.[2] The incidence of post-CABG AF has been reported to be substantial, ranging from 10 to 40% in various studies. Post-CABG AF most often develops between second and fifth day, with a peak incidence in the first 2 to 3 days after the operation.[2,3] Although anesthetic regimes, surgical techniques, myocardial protection, cardiopulmonary bypass and care of the patients in intensive care unit improve in CABG surgery, the incidence of post-CABG AF has not changed and it may even increase with the aging patient population. Off-pump surgery reduces the incidence of post-CABG AF but not eliminates.[4]
Despite post-CABG AF is often regarded as transient, benign and well-tolerated condition, it may lead to severe life-threatening complications such as significant hemodynamic instability and thromboembolic events with mortal sequela.[4,5] A pathophysiological mechanism responsible for post-CABG AF is still unknown, and is most likely multifactorial. An advanced age, male sex, preoperative β-blockers withdrawal, chronic obstructive pulmonary disease, longer aortic cross-clamp time, increased postoperative sympathetic activation, prolonged P-wave duration, increased preoperative atrial effective refractory period (AERP) dispersion, inflammation and atrial structural changes, left atrial enlargement, atrial ischemia, severe coronary artery disease, an obstructive disease of the sino-atrial and atrioventricular nodal arteries play a role in occurrence of post-CABG AF.[2,6-11]
Prophylactic β-blocker therapy is clearly effective in reducing the incidence and the number of episodes of post CABG AF.[1] Statins (hydroxymethylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are known as lipid-lowering agents; also have antioxidative, antiinflammatory and CRP-lowering effects.[9] A recent study has demonstrated that statin therapy reduces the incidence of atrial fibrillation in patients with coronary heart disease independent of its lipid-lowering effects.[12] The aim of this study was to define the incidence and determinants of post-CABG AF and the effect of β-blocker plus statin use on preventing and reducing of post-CABG AF.
Patient characteristics and variables. Demographic data collected for each patient included age, sex, hypertension, diabetes mellitus, chronic obstructive pulmonary disease (COPD), smoking, preoperative cardiac status and medications, left ventricle (LV) ejection fraction, left main coronary artery (LMCA) disease, associated valvular heart disease, peripheric arterial occlusive disease (PAOD), previous cerebrovascular accident (CVA). Also operative and postoperative data recorded for each patients included number of distal anastomosis, X-clamp time, cardiopulmonary bypass (CPB) time, extubation time, mean blood pressure during ICU, total drainage amount, CBC and serum BUN value in postoperative day 2 (POD 2), stay in ICU (including ICU readmission), lenght of stay (>7 days) [LOS].
Cardiac rhythm evaluation and diagnosis of post- CABG AF. Heart rate and ECG lead II were continuously monitored in intensive care unit. Post-CABG AF was defined by the documentation of AF any duration at any time in the postoperative period on a physician assessment, on the basis of a rhythm strip or 12-lead electrocardiogram (ECG) recording. The diagnosis of AF was established by an irregular random ventricular rate without vissible P waves on 12-lead ECG.
Anesthesia. In all groups, anesthesia was induced with a continuous infusion of remifentanil (Ultiva® GlaxoSmithKline) at 0.2 µg.kg-1.min-1 and propofol (Diprivan® AstraZeneca) at 150-200 mg. Anesthesia was maintained with 0.2–0.4 µg.kg-1.min-1 remifentanil and desflurane (Suprane® Baxter) (3%-4% endexpiratory concentration). Controlled mechanical ventilation with 50% oxygen in air was provided to achieve normocapnia as indicated by continuous end-tidal CO2 monitoring and intermittent arterial blood gas studies. Muscle relaxation was obtained with 0.1 mg/kg vecuronium (Norcuron® Organon).
Surgical techniques and anticoagulation protocol. For all of the patients, median sternotomy incision was performed first and then IMA was harvested according to the pedunculated technique. When the IMA harvesting was completed, pericardium was opened and heparin (300 U/kg) was administered. Heparin dosage was adjusted according to an activated coagulation time (ACT) level. Supplemental doses of heparin were administered to maintain ACT of greater than 480 seconds. All the CABG operation was performed on cardiopulmonary bypass. The distal anastomoses were done during a single period of total aortic occlusion, whereas the proximal ones were performed after removal of the total occluding clamp.
Cardiopulmonary bypass and myocardial protection. CPB was established in standard manner. Aortic cannulation (24F) and two-stage venous cannulation was performed for CPB. A roller pump, membrane oxygenator and pulsatile flow were used, flow rate was 2.4 l/m2/min. Moderate hypothermia (28 º C) was employed. Intermittent antegrade cold (4 º C) blood cardioplegia (4/1 ratio) was used in every 20 minutes. Topical cooling was also used for myocardial protection. Terminal warm blood cardioplegia was used routinely for all the patients. Arterial blood pressure was kept in range of 60- 80 mmHg during CPB. After the termination of CPB and administration of protamin, ACT was maintained between 100 and 120 seconds.
Postoperative protocols. Postoperative ventilation protocol were as following; SIMV (12-14/min.), tidal volume of 8 ml/kg, PEEP 5-10 cm H2O, I/E ratio of 1/2. Arterial blood sample were taken for blood gases analysis in every one hour in entubated patients to adjust ventilation rate and keep the arterial pH between 7.35 and 7.45. Extubation was accomplished when the patient was haemodynamically stable and alert and able to maintain adequate blood gases during a short trial on pressure support ventilation of 5 cmH2O. Invasive/noninvasive blood pressure, central venous pressure, heart rate, ECG, oxygen saturation, temperature, chest tube drainage and urine output were continuously monitored in intensive care unit. Potassium, calcium, sodium and magnesium suplements were provided as necessary to maintain electrolytic balance within the normal range. An inotropic support and intra aortic balloon pump, if indicated, were provided in order to achieve stable haemodynamic condition. Preoperative β-blockers were continued postoperatively to avoid withdrawal.
Statistical analysis. SPSS (SPSS for windows, version 10.0, SPSS Inc, Chicago) was used for statistical analysis. Data are reported as a mean±SD or as a percent. Variables regarding preoperative, intraoperative and postoperative parameters between groups were compared by using Fischer’s exact test, chi-square and independent samples t test. A P-value of less than 0.05 was considered statistically significant. Univariate factors exhibiting a P-value of less than 0.035 were entered into multivariate logistic regression analysis in order to assess the independent correlates for post- CABG AF. Again, statistical significance was obtained only for P-value of less than 0.05. Recevier-operator characteristic (ROC) curve analysis was used for determining cut off value of age as a predictor of post- CABG AF.
Table 1: Preoperative patient’s characteristics and operative parameters
Table 4: Postoperative parameters
The COPD patients with post CABG AF had lower FEV1 value (1.68±0.3) than the other COPD patients without post CABG AF. Prolonged ventilation was needed in one of them and re-intubation in postoperative day 2 was done in the other.
Multivariate logistic regression analysis identified an advanced age and increased postoperative drainage to be independent predictors of post-CABG AF. The OR and the P-value for each multivariate predictor are shown in table 5.
A pathophysiological mechanism of post-CABG AF is still unknown. Many factors related to the occurrence of post-CABG AF have been documented. The most reliable predictors were patient’s age and preoperative β-blockers withdrawal.[2,13,14] However, some authors underlined the importance of other variables, such as the left atrial enlargement and severe coronary artery disease, atrial structural changes, atrial ischemia, an obstructive disease of the sino-atrial and atrioventricular nodal arteries, right coronary artery stenosis, an increased P-wave duration, increased preoperative AERP dispersion, longer aortic cross-clamp time, postoperative fluid and electrolytes shifts, sympathetic hyperactivation, an increased postoperative drainage and inflammation.[2,7,9-11,15-17] Age-related structural changes, such as increased atrial fibrosis and atrial dilation, might explain the increased incidence of post- CABG AF in old patients.[18] It is well known that aging causes degenerative changes in the atrial myocardium that lead to alterations in electrical properties of the SA and AV nodes and atria, which contribute to fragmentation of the propagating impulse.[19] In our study, an advanced age (p=0.018) and increased postoperative drainage (p=0.045) were independent predictors of post-CABG AF, and an age greater than 63 years was the strongest predictor of post-CABG AF (41.3% in age<63 vs 13.3% in age≥, p=0.0001, area under the ROC curve of 0.748). Age is not a changeable factor, but the strategies reducing postoperative drainage such as minimal dissection, a meticulous haemostatic control, the use of heparin-bounded circuits, and the use of antifibrinolytic drugs reduce the incidence of post- CABG AF and as a consequence, improve postoperative course of the patients.
The association of COPD and an increased incidence of post-CABG AF is well established.[20,21] We found that the incidence of COPD were higher in group-AF than group-SR (13.8% vs 2.2%, p=0.012). The occurrence of post-CABG AF is attributable to several factors such as hypoxemia, hypercapnia and medications for COPD (methylxantine and β2 mimetics therapy).[20] There is strong relation between FEV1 and post-CABG AF. Preoperative FEV1 value is known as major predetermining factors of mortality, morbidity and supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, multifocal atrial tachycardia) after CABG in patients with COPD. Hypoxemia is a predominant mechanism in occurrence of post CABG AF.[20] In our study, the COPD patients with post-CABG AF had lower FEV1 value (1.68±0.3) than the other COPD patients without post-CABG AF. Prolonged ventilation was needed in one of them and re-intubation in postoperative day 2 was done in the other.
The hyperadrenergic state of the heart in early postoperative period is one of the factors related to the occurrence of post-CABG AF. CABG surgery has been known to significantly increase epinephrine and norepinephrine levels, and these abnormal levels may persist for up to 3 postoperative days. The presence of a hyperadrenergic state may explain why β-blocker drugs are effective in preventing and controlling of post-CABG AF in some individuals. Prevention of post-CABG AF is the most desirable course for management. Prophylactic β-blocker therapy, starting preoperatively and continuing postoperatively, is clearly helpful in reducing the incidence and the number of episodes of post-CABG AF. It is clear from the research on prevention of post-CABG AF that β-blocker agents are the most effective means of prevention. β-blocking agents reduce catecholamine secretion, depress AV node conduction, and reduce myocardial ischemia.[1] In our study, post-CABG AF was significantly lower in the patients receiving β-blockers than the patients not receiving these drugs (19.8% vs 40%, p=0.035).
Cardiac surgery triggers an inflammatory response that includes the activation of the complement system and the release of inflammatory mediators.[22,23] White blood cell count, an inexpensive and readily available marker of systemic inflammation, usually peaks after 36 to 60 hours in patients who undergo on-pump surgery, which coincides with the time course for the occurrence of post-CABG AF.[23,24] Our study showed that postoperative WBC counts in POD 2 (13210±5550 vs 11160±4320, p=0.041) were significantly greater in patients with post-CABG AF. The complement system is activated and proinflammatory cytokines is released during and after cardiac surgery. Bruins et al.[22] reported a biphasic activation of the complement system after cardiac surgery, with the second phase involving CRP. Acutely, complement activation during CPB occurs from the contact of blood with the extracorporeal circuits, as well as by the formation of heparin-protamine complexes. A second phase then occurs, with an increase in CRP, peaking on the second postoperative day, and increases complement-CRP complexes, peaking on the second on third postoperative day.[22] The incidence of post-CABG AF similary peaks at these times. The present study, showing a strong association between WBC count elevation and the occurence of post-CABG AF supports a role for inflammation in the pathogenesis of post-CABG AF. Aside from lipids-lowering effect, statins have been shown to have other effects such as improvement of endothelial function, reduced oxidative stress, antiinflammatory and antithrombotic properties, CRP-lowering effect, and anti-arrhythmogenic effect.[9] A recent study has demostrated that statin therapy reduces the incidence of atrial fibrillation in patients with coronary heart disease independent of its lipid-lowering effects.[12] In our study we found that post-CABG AF was lower in the patients receiving statin than the patients not receiving statin (15.9% vs 34.6%, p=0.017) and also, statin was significantly reduced postoperative WBC count (10618±3540 vs 13038±5661, p=0.005), and reduced postoperative inflammation.
Although numerous potential postoperative factors have been identified, one potential factor is atrial mechanical remodeling. In the postoperative period it is quite possible that mechanical stretch injury of atrial tissue results in post-CABG AF. Although cardiac dysrhythmias have been traditionally viewed as electrical disorders of the heart, recent evidence has supported the possibility of mechanical or stretch-mediated dysrhythmias.[25] The term for this mechanically induced change in electrophysilogy is mechanoelectrical feedback. This injury can be induced by acute stretch or chronic stretch of atria or ventricules.[25] Through a similar mechanism, an abrupt increase in afterload can have a similar effect.[1] Preoperative left atrial enlargement and elevated atrial pressures have been associated with an increased risk of post-CABG AF.[26-29] In early postoperative period, the clinical conditions increasing postoperative BUN level such as renal and/or cardiac dysfunction result in volume overload. These may cause acute stretch injury in the susceptible atrial myocardium, resulting in electrophysiologic changes that trigger post-CABG AF. In our study, higher BUN values were associated with increased risk of post-CABG AF (33.8±32.5 vs 21.67±13, p=0.004).
We suggested that atrial fibrosis, inflammation, ischemia, and acute or chronic atrial stretching frequently contribute to the development of post-CABG AF.
Study limitations
1. WBC was used only as a marker of postoperative inflammation in our study. If hsCRP, IL-6, IL-1β, TNFα, complement (C3,C4,C9) could be used as an inflammatory marker, results would be concluded better.
2. New prospective studies are required in order to define;
- The relation between inflammation and the occurrence
of atrial fibrillation after on-pump CABG surgery.
- An efficient cause of statin on reducing of post-
CABG inflammation.
- The type, dosage and duration of preoperative usage of statin on prevention of post-CABG atrial fibrillation.
3. Atrial stretching may trigger the occurrence of post-CABG AF. But, further studies are required for refining this issue.
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