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The Association Among Blood Transfusions, White Blood Cell Count, and the Frequency of Post–Cardiothoracic Surgery Atrial Fibrillation: A Nested Cohort Study From the Atrial Fibrillation Suppression Trials I, II, and III
The Association Among Blood Transfusions, White Blood Cell Count, and the Frequency of Post–Cardiothoracic Surgery Atrial Fibrillation: A Nested Cohort Study From the Atrial Fibrillation Suppression Trials I, II, and III Nitesh Sood, MD,* Craig I. Coleman, PharmD,†‡ Jeffrey Kluger, MD, FACC,*§ C. Michael White, PharmD, FCP, FCCP,†‡ Arun Padala, MD,* and William L. Baker, PharmD, BCPS† Objective: To evaluate the impact of postoperative red blood cell transfusions and white blood cell (WBC) counts on post– cardiothoracic surgery atrial fibrillation. Design: A nested cohort study of 550 patients from the Atrial Fibrillation Suppression Trials I, II, and III. Setting: A large urban teaching hospital. Participants: Patients undergoing cardiothoracic surgery. Measurements and Results: Endpoints included postoperative atrial fibrillation occurrence and maximum white blood cell counts during the first 5 days postoperatively. Multivariate logistic regression was used to control for potential confounders and calculate adjusted odds ratios (AOR) with 95% confidence intervals (95% CIs). Of the 173 patients (31.5%) who developed postoperative atrial fibrillation, 110 patients (63.5%) received postoperative transfusions and 63 patients (36.5%) did not (crude odds ratio ⴝ 1.89; 95% CI, 1.31-2.74; p ⴝ 0.001). Postoperative white blood cell counts were significantly greater in patients who developed atrial
fibrillation on postoperative days 3 to 5. There were no differences in WBC between patients who did and did not receive transfusions. Upon multivariate logistic regression, the use of postoperative red blood cell transfusions was found to be associated with a 2-fold increase in postoperative atrial fibrillation (AOR 1.95; 95% CI, 1.24-3.06; p ⴝ 0.004). Similarly, the maximum white blood cell count also was associated with increased atrial fibrillation odds (AOR 1.09 K/L; 95% CI, 1.04-1.13; p < 0.001). Conclusions: Postoperative red blood cell transfusion use was found to be a strong independent predictor for the development of postoperative atrial fibrillation, although no direct link between red blood cell transfusion and an increased white blood cell count was seen. © 2009 Elsevier Inc. All rights reserved.
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RBC transfusions and increased serum levels of the lipopolysaccharide-binding protein and interleukin-6, both acutephase inflammatory proteins. However, the relationship between RBC transfusions and WBC count as a marker of inflammation has not been shown, including how it relates to post-CTS atrial fibrillation. The authors have conducted 3 randomized, controlled clinical trials evaluating the impact of therapeutic strategies on the incidence of post-CTS atrial fibrillation (Atrial Fibrillation Suppression Trials [AFIST] I, II, and III).13-15 In this nested cohort study of 550 CTS patients, the authors tested the hypothesis that post-CTS RBC transfusions increased patients’ risk for developing atrial fibrillation and that higher WBC levels may be a marker of inflammation, which is responsible for this outcome.
TRIAL FIBRILLATION IS one of the most common post– cardiothoracic surgery (CTS) complications and has been shown to occur in about 30% of 50% of the patients undergoing cardiac surgery.1 Despite improvements in surgical and anesthesia techniques, the incidence of post-CTS atrial fibrillation remains high and may result in hemodynamic instability, cerebrovascular events, and an increase in the length of hospital stay as well as overall health care costs.1-4 Inflammation has been proposed as a physiologic etiology for the development of post-CTS atrial fibrillation.5,6 This inflammatory response is evidenced by the increased serum levels of acute phase proteins including C-reactive protein, interleukin 6, and white blood cell (WBC) count.1,5-8 A higher peak WBC count recently has been shown to be an independent predictor of post-CTS atrial fibrillation.7,8 These peaks have most commonly been seen on postoperative day 2, which is the most common day post-CTS atrial fibrillation occurs.7,8 Transfusion of allogeneic red blood cells (RBCs) recently has been shown to be an independent risk factor for adverse post-CTS outcomes.9-11 This includes an association with an increased risk of post-CTS atrial fibrillation.9 Tissue hypoxia and systemic inflammation have been postulated to be 2 common mechanisms causing such adverse outcomes.12 Fransen et al12 showed a relationship between the use of perioperative
From the Divisions of *Cardiology and †Drug Information, Hartford Hospital, Hartford, CT; ‡University of Connecticut School of Pharmacy, Storrs, CT; and §University of Connecticut School of Medicine, Farmington, CT. Address reprint requests to William L. Baker, PharmD, BCPS, Evidence-Based Practice Center, Hartford Hospital, 80 Seymour Street, CB309, Hartford, CT 06102. E-mail: [email protected] © 2009 Elsevier Inc. All rights reserved. 1053-0770/09/2301-0004$36.00/0 doi:10.1053/j.jvca.2008.06.009 22
KEY WORDS: atrial fibrillation, red blood cell transfusion, white blood cell count, cardiac surgery
METHODS This was a prospective cohort evaluation of 550 patients undergoing coronary artery bypass graft (CABG) surgery and/or valvular surgery from the AFIST I, AFIST II, and AFIST III studies conducted at an urban teaching hospital.13-15 Patients over 50 years (AFIST II and III)14,15 or over 60 years (AFIST I)13 of age scheduled to undergo CABG surgery or heart valve surgery were screened. Patients were excluded for the following reasons: chronic atrial fibrillation or flutter; known amiodarone hypersensitivity; current use of class I or class III antiarrhythmics; current use of implantable cardioverter-defibrillators or pacemakers; cardiogenic shock or advanced congestive heart failure (New York Heart Association class IV); marked sinus bradycardia (heart rate ⬍50 beats/min) or secondor third-degree atrioventricular block; moderate-to-severe liver disease; or current use of cyclosporine, cimetidine, phenytoin, or cholestyramine. AFIST was a randomized, double-blind placebo-controlled trial that assessed the effect of oral amiodarone or placebo on the incidence of post-CTS atrial fibrillation.13 Patients enrolled less than 5 days before surgery received 6 g of amiodarone or placebo over 6 days beginning on preoperative day 1. Patients enrolled at least 5 days before surgery received 7 g over 10 days beginning on preop-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 23, No 1 (February), 2009: pp 22-27
POST–CARDIOTHORACIC SURGERY ATRIAL FIBRILLATION
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erative day 5. AFIST II was a 2 ⫻ 2 factorial study that assessed the effect of 2 active treatments (amiodarone and atrial septal pacing) on the incidence of post-CTS atrial fibrillation.14 Patients were initially randomized to either amiodarone (the oral equivalent of 6.9 g) or placebo and then randomized further to either atrial septal pacing or no pacing. AFIST III was a randomized controlled trial that looked at the impact of anterior fat pad maintenance on the incidence of post-CTS atrial fibrillation in patients undergoing CABG surgery for the first time.15 In AFIST I, II, and III, post-CTS atrial fibrillation was defined as any documented atrial fibrillation event of more than 5 minutes’ duration, which is a standard definition used in post-CTS intervention clinical trials. In each trial, the primary endpoint was the development of post-CTS atrial fibrillation within 30 days of cardiac
surgery. For the purposes of the current evaluation, postoperative RBC transfusion was defined as any RBC blood product received from the day of surgery until either the development of atrial fibrillation or hospital discharge, whichever came first. Data with respect to patient demographics, surgical characteristics, medication utilization, and post-CTS atrial fibrillation were uniformly collected as part of the AFIST I, II, and III trials.13-15 The Institutional Review Board at Hartford Hospital, Hartford, CT, approved the study with a waiver of consent. Assuming an ␣ level of 0.05, the present study would have 80% power to detect a 12% absolute increase in the risk of developing atrial fibrillation in patients receiving RBC transfusions if 460 patients were included. Thus, the authors decided a priori to include all of the patients enrolled in the AFIST I-III studies (n ⫽ 550).
Table 1. Patient Demographics, Surgical Characteristics, and Medication Utilization by Postoperative Cardiothoracic Surgery Atrial Fibrillation Status Variable
Preoperative characteristics Age, years (mean ⫾ SD) Sex (male) Participant in AFIST I Participant in AFIST II Participant in AFIST III History of hypertension History of smoking History of myocardial infarction Family history of CAD History of angina History of heart failure EF, % (mean ⫾ SD) Prior atrial fibrillation History of cerebrovascular disease History of COPD History of mitral regurgitation Vessels ⬎50% occluded Preoperative medical therapy -Blocker CCB Digoxin Statin ACE inhibitor/ARB Surgical characteristics Valve surgery On-pump surgery Duration of surgery, min (mean ⫾ SD) Number of grafts, n (mean ⫾ SD) Number of arterial grafts, n (mean ⫾ SD) Number of venous grafts, n (mean ⫾ SD) Postoperative medication use Amiodarone -Blocker CCB Digoxin Corticosteroids NSAIDs Statin Postoperative RBC transfusions -Blocker intolerance
No Post-CTS AF (n ⫽ 377), n (%)
Post-CTS AF (n ⫽ 173), n (%)
p Value
66.8 ⫾ 8.5 297 (68.5) 152 (40.3) 110 (29.2) 115 (30.5) 277 (73.5) 226 (59.9) 137 (36.3) 147 (39.0) 286 (75.9) 37 (9.8) 50.2 ⫾ 12.6 15 (4.0) 17 (4.5) 45 (11.9) 64 (17.0) 2.8 ⫾ 0.9
70.3 ⫾ 8.3 126 (72.8) 64 (37.0) 49 (28.3) 60 (34.7) 128 (74.0) 97 (56.1) 65 (37.6) 67 (38.7) 120 (69.4) 33 (19.1) 49.2 ⫾ 12.3 19 (11.0) 10 (5.8) 31 (17.9) 48 (27.7) 2.6 ⫾ 1.1
⬍0.001 0.12 0.46 0.84 0.33 0.90 0.39 0.78 0.95 0.11 0.002 0.35 0.002 0.52 0.06 0.004 0.07
287 (76.1) 63 (16.7) 16 (4.2) 235 (62.3) 180 (47.7)
117 (67.6) 34 (19.7) 12 (6.9) 92 (53.2) 82 (47.4)
0.04 0.40 0.18 0.04 0.94
42 (11.1) 256 (67.9) 282.2 ⫾ 78.4 3.8 ⫾ 7.5 1.6 ⫾ 1.2 2.2 ⫾ 1.4
39 (22.5) 114 (65.9) 303.0 ⫾ 124.4 3.7 ⫾ 1.7 1.6 ⫾ 1.2 2.1 ⫾ 1.5
⬍0.001 0.64 0.02 0.49 0.73 0.28
189 (50.1) 325 (86.2) 31 (8.2) 70 (18.6) 100 (26.5) 100 (26.5) 210 (55.7) 181 (48.0) 26 (6.9)
54 (31.2) 139 (80.3) 23 (13.3) 77 (44.5) 47 (27.2) 26 (15.0) 89 (51.4) 110 (63.6) 21 (12.1)
⬍0.001 0.08 0.06 ⬍0.001 0.87 0.003 0.35 0.001 0.04
Abbreviations: ARB, angiotensin receptor blocker; SD, standard deviation; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CCB, calcium channel blocker; CTS, cardiothoracic surgery; EF, ejection fraction; NSAIDs, nonsteroidal anti-inflammatory drugs.
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SOOD ET AL
Continuous variables are presented as means with standard deviations and were compared among groups by using a Student t test or Mann-Whitney U test when appropriate (nonparametric data). Dichotomous variables are presented as percentages and were compared among groups by using a chi-square or Fisher exact test when appropriate. Because this was a retrospective analysis of clinical trial data, the investigators had no control over which patients received a blood product and which did not. As a result, significant differences in important observed demographic, surgical, and medication utilization characteristics were likely to occur, which could lead to a biased estimate of treatment effect. Therefore, the authors conducted multivariate logistic regression. Univariate analysis was first performed to examine the relationship between different variables (as listed on the admission sheet, demographic, surgical, and medical utilization characteristics) and the development of post-CTS
atrial fibrillation (dependent variable). All variables showing a univariate association (p ⱕ 0.20) with atrial fibrillation occurrence (Table 1) were then entered into a backwards, stepwise multivariate logistic regression model. The following variables were included in the multivariate model: preventative amiodarone use, use of HMGCoA reductase inhibitors before surgery, age ⬎70, male sex, history of atrial fibrillation, history of congestive heart failure, history of diabetes mellitus, history of smoking, history of chronic obstructive pulmonary disease, valve replacement surgery, a history of angina, -blocker use before surgery, calcium channel blocker use before surgery, duration of surgery, number of grafts performed, number of vessels ⬎50% occluded, post-CTS -blocker use, post-CTS corticosteroid use, post-CTS NSAID use, -blocker intolerance, the use of postoperative RBC transfusions, and maximum postoperative WBC count. A p value ⬍0.05 was considered significant in the multivariate logistic regression model. Adjusted odds ratios
Table 2. Patient Demographics, Surgical Characteristics, and Medication Utilization by RBC Transfusion Use Variable
Preoperative characteristics Age, years (mean ⫾ SD) Sex (male) Participant in AFIST I Participant in AFIST II Participant in AFIST III History of hypertension History of smoking History of myocardial infarction Family history of CAD History of angina History of heart failure EF, % (mean ⫾ SD) Prior atrial fibrillation History of cerebrovascular disease History of COPD History of Mitral Regurgitation Vessels ⬎50% occluded Preoperative medical therapy -Blocker CCB Digoxin Statin ACE inhibitor/ARB Surgical characteristics Valve surgery On-pump surgery Duration of surgery, min (mean ⫾ SD) Number of grafts, n (mean ⫾ SD) Number of arterial grafts, n (mean ⫾ SD) Number of venous grafts, n (mean ⫾ SD) Postoperative medication use Amiodarone -Blocker CCB Digoxin Corticosteroids NSAIDs Statin -Blocker Intolerance
No RBC Transfusion (n ⫽ 259), n (%)
RBC Transfusion (n ⫽ 291), n (%)
p Value
65.6 ⫾ 8.6 215 (83.0) 70 (27.0) 68 (26.3) 121 (46.7) 195 (75.3) 158 (61.0) 98 (37.8) 107 (41.3) 195 (75.3) 26 (10.0) 49.8 ⫾ 12.3 11 (4.2) 10 (3.9) 31 (12.0) 35 (13.5) 2.8 ⫾ 0.8
69.9 ⫾ 8.1 208 (71.5) 146 (50.2) 91 (31.3) 54 (18.6) 210 (72.3) 165 (56.7) 104 (35.7) 107 (36.8) 211 (72.5) 44 (15.1) 50.0 ⫾ 12.7 23 (7.9) 17 (5.8) 45 (15.5) 77 (26.5) 2.7 ⫾ 1.1
⬍0.001 0.001 ⬍0.001 0.20 ⬍0.001 0.41 0.31 0.61 0.28 0.46 0.07 0.87 0.08 0.28 0.24 ⬍0.001 0.56
202 (78.0) 37 (14.3) 8 (3.1) 170 (65.6) 117 (45.2)
202 (69.4) 60 (20.6) 20 (6.9) 157 (54.0) 145 (50.0)
19 (7.3) 142 (54.8) 276.3 ⫾ 65.5 3.9 ⫾ 1.4 1.8 ⫾ 1.2 2.1 ⫾ 1.3
62 (21.6) 228 (78.4) 299.8 ⫾ 115.1 3.6 ⫾ 1.7 1.5 ⫾ 1.1 2.2 ⫾ 1.5
⬍0.001 ⬍0.001 0.004 0.04 0.003 0.88
109 (42.1) 219 (84.6) 29 (11.2) 44 (17.0) 72 (27.8) 73 (28.2) 163 (62.9) 24 (9.3)
134 (46.0) 245 (84.2) 25 (8.6) 103 (35.4) 75 (26.8) 53 (18.2) 136 (46.7) 23 (7.9)
0.35 0.91 0.31 ⬍0.001 0.59 0.005 ⬍0.001 0.57
0.02 0.05 0.04 0.005 0.28
Abbreviations: ARB, angiotensin receptor blocker; SD, standard deviation; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CCB, calcium channel blocker; EF, ejection fraction; NSAIDs, nonsteroidal anti-inflammatory drugs.
POST–CARDIOTHORACIC SURGERY ATRIAL FIBRILLATION
(AORs), 95% confidence intervals (CIs), and 2-tailed p values were calculated for all variables retained in the multivariate logistic regression model. Statistical analysis was performed with SPSS version 15.0 (SPSS Inc, Chicago, IL). RESULTS
Overall, the population averaged 67.8 ⫾ 8.6 years of age, 77.1% were male, 14.6% underwent valve surgery, 6.1% had a history of prior atrial fibrillation, 12.6% had heart failure, and 84.0% and 44.1% received postoperative -blockade and prophylactic amiodarone, respectively. Comparisons of demographic, surgical approach, and medication utilization were made between those receiving and not receiving transfusions and those developing and not developing atrial fibrillation as delineated in Tables 1 and 2. In this population of 550 patients undergoing CABG ⫾ valve surgery, a total of 291 patients (52.9%) received postoperative RBC transfusions and 259 (47.1%) did not. The total number of RBC transfusions received by each patient was not collected in the database. Of the 173 patients (31.5%) who developed post-CTS atrial fibrillation, 110 patients (63.5%) received transfusions and 63 patients (36.5%) did not (crude odds ratio, 1.89; 95% CI, 1.31-2.74; p ⫽ 0.001). In the 377 (68.5%) patients who did not develop post-CTS atrial fibrillation, 181 (48.0%) patients received transfusions and 196 (52.0%) did not (p ⫽ not significant). Post-CTS WBC counts were significantly greater in patients who developed atrial fibrillation on postoperative day 3 (12.25 K/L ⫾ 4.70 v 10.91 K/L ⫾ 3.55, p ⫽ 0.002), day 4 (12.47 K/L ⫾ 5.43 v 10.61 K/⫾L ⫾ 3.31, p ⫽ 0.013), and day 5 (12.20 K/L ⫾ 4.24 v 9.99 ⫾ 3.72, p ⫽ 0.008), with a trend toward a difference on day 2 (13.31
Fig 1. (A) WBC count (mean and standard error of the mean) at baseline and on postoperative days 1 through 5 in patients who both experienced and did not experience AF. (B) WBC count (mean and standard error of the mean) at baseline and on postoperative days 1 through 5 in patients who both received and did not receive RBC transfusions.
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Table 3. Results of Multivariate Logistic Regression Variable*
AOR (95% CI)
p Value
Prophylactic amiodarone use Age ⬎70 years History of atrial fibrillation History of heart failure History of diabetes mellitus Preoperative -blocker use RBC transfusion use Max WBC (per K/L)
0.37 (0.20-0.50) 1.91 (1.24-2.96) 5.18 (2.11-12.74) 1.88 (1.05-3.38) 1.64 (1.05-2.56) 0.60 (0.37-0.96) 1.95 (1.24-3.06) 1.09 (1.04-1.13)
⬍0.001 0.004 ⬍0.001 0.03 0.03 0.03 0.004 ⬍0.001
*The Hosmer-Lemeshow goodness-of-fit test (chi-square test statistic ⫽ 2.95, degrees of freedom ⫽ 8, p ⫽ 0.94).
K/L ⫾ 4.72 v 12.08 ⫾ 4.28, p ⫽ 0.07) (Fig 1). There was no significant difference in WBC counts between patients who received and did not receive RBC transfusions (Fig 1). Upon multivariate logistic regression, the use of postoperative RBC transfusions was found to be associated with a significant increase in post-CTS atrial fibrillation (AOR, 1.95; 95% CI, 1.24-3.06; p ⫽ 0.004). Similarly, maximum WBC was also found to be associated with a significant increase in postCTS atrial fibrillation (AOR, 1.09 per K/L; 95% CI, 1.041.13; p ⬍ 0.001). Prophylactic amiodarone and preoperative -blocker use were found to be negative independent predictors of post-CTS atrial fibrillation (Table 3). Prior atrial fibrillation, age ⬎70 years, a history of heart failure, and a history of diabetes were each found to be positive independent predictors (p ⱕ 0.05 for all). DISCUSSION
The study has a few important findings. First, RBC transfusion was strongly associated with the development of post-CTS atrial fibrillation. Patients who received transfusions had 2-fold greater odds of developing post-CTS atrial fibrillation versus those who did not. Next, patients who developed post-CTS atrial fibrillation, regardless of whether they received RBC transfusion or not, had higher WBC counts starting on postoperative day 3 and continuing through day 5. Patients had a 9% increase in their relative odds of developing post-CTS atrial fibrillation for every K/L increase in their WBC count. As seen in previous studies,7,8 this may suggest that these patients are experiencing an inflammatory response that could be contributing to the development of post-CTS atrial fibrillation. Finally, RBC transfusion was not found to be associated with a significant increase in WBC count. It is possible that although transfusions are known to elicit an inflammatory response in patients, this may not be reflected by increases in WBC counts in CTS patients. It has been estimated that patients undergoing CTS account for 10% of the blood transfusions given annually in the United States.16 Surveys have estimated that 25% to 95% of CTS patients receive blood products, with most patients receiving treatment in response to a low hematocrit with no commonly acceptable threshold available.17-19 Common risk factors for the need for RBC transfusions include advancing age, female sex, preoperative renal insufficiency, preoperative aspirin therapy, duration of cardiopulmonary bypass,
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recent fibrinolytic therapy, and reoperative CABG surgery.10,20,21 Some of the well-documented complications of RBC transfusions include infectious transmission, postoperative infections, renal insufficiency, multiple-organ failure, increased hospital length of stay, and long-term mortality.10,22-25 Murphy et al11 recently confirmed these findings by showing an increased risk of adverse ischemic outcomes as well as mortality in patients who received RBC transfusions. Post-CTS atrial fibrillation also has been independently linked with RBC transfusion administration in a previous analysis.9 Koch et al9 showed that the use of RBC transfusions in the intensive care unit after CTS resulted in an 18% increase in the odds for developing atrial fibrillation per unit of RBC transfused. The present study showed that patients who received transfusions at any time during the postoperative period had a 2-fold increase in their odds of developing post-CTS atrial fibrillation. The mechanism underlying this phenomenon may be related to an exaggerated inflammatory response in these patients. Numerous studies have suggested that increased inflammatory biomarkers have been associated with the development of atrial fibrillation in patients undergoing CTS.5-8,26 This exaggerated response may be the result of blood coming in contact with the extracorporeal cardiopulmonary bypass circuit and the formation of heparin-protamine complexes within patients undergoing CTS. Some of these acute-phase biomarkers include interleukin-6, C-reactive protein, and WBC. Indeed, prior studies have linked an elevated WBC count to an increased risk of atrial fibrillation.7,8 The authors also showed that a higher WBC count was associated with increased odds of developing atrial fibrillation, with a 10% increase in atrial fibrillation odds per K/L increase in the WBC count. This relationship was significant on postoperative days 3 to 5 with a trend (p ⫽ 0.07) on day 2. Another possible mechanism explaining the present results could be related to fluid volume. A substudy of the AFIST II trial showed that patients who developed post-CTS atrial fibrillation received 1.3 L more fluid than those who did not develop atrial fibrillation.27 Excess fluid volume, as can be provided by the use of RBC transfusions, could elevate intra-atrial pressures, resulting in atrial dilation, which, in animal studies, increases atrial fibrillation vulnerability.28,29 However, given that the total volume of RBC transfusion patients received was not available, this hypothesis could not be investigated in the current study. It should, however, be the focus of future investigations. RBC transfusion use has been shown to elicit an inflammatory response by direct infusion of inflammatory mediators, as evidenced by increased serum levels of interleukin-6 after intraoperative administration.12 Thus, the authors also tested the theory that patients receiving transfusions would have elevated WBC counts. However, no significant difference in WBC count was seen on any of the evaluated postoperative days when examined by the use of blood transfusions. This most likely can be explained by the fact that all RBC transfusions during the AFIST study period underwent leukoreduction and, therefore, contained comparably lower levels of inflammatory mediators. However, given that the authors were testing the impact of transfusion
SOOD ET AL
on WBC and not on other inflammatory mediators such as C-reactive protein or interleukin-6, the impact of leukoreduction should be minimal. It is possible that the increased WBC counts seen in these patients are related to the presence of infection. Tang et al30 hypothesized that postoperative infections, such as those caused by Chlamydia pneumonia, have been linked not only to increased inflammatory biomarkers but to the development of atrial fibrillation as well. Data on the link between infection and WBC as well as atrial fibrillation could not be made as that information is unavailable in the database. It is important to consider the results of the present study in the context of its potential limitations. Although the AFIST trials were prospective, controlled trials, patients were not randomized to receive RBC transfusions or not. As a result, some baseline characteristics of the included patients may have differed. To minimize these differences, the authors conducted multivariate logistic regression to control for most known predictors of post-CTS atrial fibrillation. In addition, data concerning the use of intraoperative transfusions, total number of RBC transfusions received, timing of administration related to surgery, and total volume received were not available. As such, the authors were not able to determine the effect these factors may have had on the desired outcomes. Similarly, the time correlation between patients receiving transfusions and obtaining WBC samples was not controlled for. As such, it is possible that patients had peak WBC levels, before receiving RBC transfusions. The present results suggest that a relationship exists between patients receiving RBC transfusions and the development of post-CTS atrial fibrillation. It is possible that patients receiving RBC transfusions are higher risk patients and thus also more likely to develop atrial fibrillation. This relationship requires validation in a prospective study. An additional issue is the potentially differential impact that perioperative and postoperative RBC transfusions may have on post-CTS outcomes. Because the authors only had data on WBC count, assessments of other inflammatory biomarkers could not be made and must be evaluated in future studies. The fact that patients receiving RBC transfusions were more likely to develop atrial fibrillation and that patients with higher WBC counts were also at higher risk supports the contribution of transfusions to the postoperative inflammatory response; however, this theory needs to be investigated further in a prospective, randomized trial. CONCLUSION
RBC transfusion use was found to be a strong independent predictor for the development of post-CTS atrial fibrillation. The present study also supports the role of inflammation in the etiology of atrial fibrillation as shown by increases in WBC count starting on postoperative days 2 and 3, the most common days of atrial fibrillation development. Although no direct link between RBC transfusion and an increased WBC count was made, the present study supports the overall hypothesis that RBC transfusions may be associated with adverse outcomes after CTS. Subsequent prospective, randomized trials are required to better investigate the associations seen in the present study.
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REFERENCES 1. Baker WL, White CM: Postcardiothoracic surgery atrial fibrillation: a review of preventive strategies. Ann Pharmacother 41:587-598, 2007 2. Mathew JP, Fontes ML, Tudor IC, et al: A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 291:1720-1729, 2004 3. Gillespie EL, White CM, Kluger J, et al: A hospital perspective on the cost-effectiveness of beta-blockade for prophylaxis of atrial fibrillation after cardiothoracic surgery. Clin Ther 27:1963-1969, 2005 4. Kim MH, Deeb GM, Morady F, et al: Effect of postoperative atrial fibrillation on length of stay after cardiac surgery (The Postoperative Atrial Fibrillation in Cardiac Surgery Study [PACS2]). Am J Cardiol 87:881-885, 2001 5. Bruins P, te Velthuis H, Yazdanbakhsh AP, et al: Activation of the complement system during and after cardiopulmonary bypass surgery. Postsurgery activation involves c-reactive protein and is associated with postoperative arrhythmia. Circulation 96:35423548, 1997 6. Gaudino M, Andreotti F, Zamparelli R, et al: The ⫺174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation 108:II-195-II-199, 2003 (suppl II) 7. Abdelhadi RH, Gurm HS, Van Wagoner DR, et al: Relation of an exaggerated risk in white blood cells after coronary bypass or cardiac valve surgery to development of atrial fibrillation postoperatively. Am J Cardiol 93:1176-1178, 2004 8. Lamm G, Auer J, Weber T, et al: Postoperative white blood cell count predicts atrial fibrillation after cardiac surgery. J Cardiothorac Vasc Anesth 20:51-56, 2006 9. Koch CG, Li L, Van Wagoner DR, et al: Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 82:1747-1757, 2006 10. Koch CG, Li L, Duncan AI, et al: Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 34:1608-1616, 2006 11. Murphy GJ, Reeves BC, Rogers CA, et al: Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 116:2544-2552, 2007 12. Fransen E, Maessen J, Dentener M, et al: Impact of blood transfusions on inflammatory mediator release in patients undergoing cardiac surgery. Chest 116:1233-1239, 1999 13. Giri S, White CM, Dunn AB, et al: Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): A randomized placebo-controlled trial. Lancet 357:830-836, 2001 14. White CM, Caron MF, Kalus JS, et al: Intravenous plus oral amiodarone, atrial septal pacing, or both strategies to prevent postcardiothoracic surgery atrial fibrillation: The Atrial Fibrillation Suppression Trial II (AFIST II). Circulation 108:II-200-II-206, 2003 (suppl II) 15. White CM, Sander S, Coleman CI, et al: Impact of epicardial anterior fat pad retention on postcardiothoracic surgery atrial fibrilla-
tion incidence: The Atrial Fibrillation Suppression Trial III (AFIST III). J Am Coll Cardiol 49:298-303, 2007 16. Graves EJ: National hospital discharge survey: Annual summary, 1991. Vital Health Stat 13:1-62, 1993 17. Stover EP, Siegel LC, Parks R, et al: Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: A 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology 88:327-333, 1998 18. Moise SF, Higgins MJ, Colquhoun AD: A survey of blood transfusion practice in UK cardiac surgery units. Crit Care 5:4, 2005 (suppl a, abstr) 19. Bracey AW, Radovancevic R, Riggs SA, et al: Lowering the hemoglobin threshold for transfusion in coronary artery bypass procedures: Effect on patient outcome. Transfusion 39:1070-1077, 1999 20. Ferraris VA, Gildengorin V: Predictors of excessive blood use after coronary artery bypass grafting: A multivariate analysis. J Thorac Cardiovasc Surg 98:492-497, 1989 21. Cosgrove DM, Loop FD, Lytle BW, et al: Determinants of blood utilization during myocardial revascularization. Ann Thorac Surg 40: 380-384, 1985 22. Schreiber GB, Busch MP, Kleinman SH, et al: The risk of transfusion-transmitted viral infections: The Rotovirus Epidemiology Donor Study. N Engl J Med 334:1685-1690, 1996 23. Leal-Noval SR, Rincon-Ferrari MD, Garcia-Curiel A, et al: Transfusion of blood components and postoperative infection in patients undergoing cardiac surgery. Chest 119:1461-1468, 2001 24. Chelemer SB, Prato BS, Cox PM Jr, et al: Association of bacterial infection and red blood cell transfusion after coronary artery bypass surgery. Ann Thorac Surg 73:138-142, 2002 25. Engoren MC, Habib RH, Zacharias A, et al: Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 74:1180-1186, 2002 26. Ishii Y, Schuessler RB, Gaynor SL, et al: Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation 111:2881-2888, 2005 27. Kalus JS, Caron MF, White CM, et al: Impact of fluid balance on incidence of atrial fibrillation after cardiothoracic surgery. Am J Cardiol 94:1423-1425, 2004 28. Ravelli F, Allessie M: Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation 96:1686-1695, 1997 29. Deroubaix E, Folliguet T, Rucker-Martin C, et al: Moderate and chronic hemodynamic overload of sheep atria induces reversible cellular electrophysiologic abnormalitites and atrial vulnerability. J Am Coll Cardiol 44:1918-1926, 2004 30. Tang RB, Dong JZ, Liu XP, et al: Inflammation and atrial fibrillation: is Chlamydia pneumonia a candidate pathogen of atrial fibrillation? Med Hypotheses 67:462-466, 2006
fibrillation on postoperative days 3 to 5. There were no differences in WBC between patients who did and did not receive transfusions. Upon multivariate logistic regression, the use of postoperative red blood cell transfusions was found to be associated with a 2-fold increase in postoperative atrial fibrillation (AOR 1.95; 95% CI, 1.24-3.06; p ⴝ 0.004). Similarly, the maximum white blood cell count also was associated with increased atrial fibrillation odds (AOR 1.09 K/L; 95% CI, 1.04-1.13; p < 0.001). Conclusions: Postoperative red blood cell transfusion use was found to be a strong independent predictor for the development of postoperative atrial fibrillation, although no direct link between red blood cell transfusion and an increased white blood cell count was seen. © 2009 Elsevier Inc. All rights reserved.
A
RBC transfusions and increased serum levels of the lipopolysaccharide-binding protein and interleukin-6, both acutephase inflammatory proteins. However, the relationship between RBC transfusions and WBC count as a marker of inflammation has not been shown, including how it relates to post-CTS atrial fibrillation. The authors have conducted 3 randomized, controlled clinical trials evaluating the impact of therapeutic strategies on the incidence of post-CTS atrial fibrillation (Atrial Fibrillation Suppression Trials [AFIST] I, II, and III).13-15 In this nested cohort study of 550 CTS patients, the authors tested the hypothesis that post-CTS RBC transfusions increased patients’ risk for developing atrial fibrillation and that higher WBC levels may be a marker of inflammation, which is responsible for this outcome.
TRIAL FIBRILLATION IS one of the most common post– cardiothoracic surgery (CTS) complications and has been shown to occur in about 30% of 50% of the patients undergoing cardiac surgery.1 Despite improvements in surgical and anesthesia techniques, the incidence of post-CTS atrial fibrillation remains high and may result in hemodynamic instability, cerebrovascular events, and an increase in the length of hospital stay as well as overall health care costs.1-4 Inflammation has been proposed as a physiologic etiology for the development of post-CTS atrial fibrillation.5,6 This inflammatory response is evidenced by the increased serum levels of acute phase proteins including C-reactive protein, interleukin 6, and white blood cell (WBC) count.1,5-8 A higher peak WBC count recently has been shown to be an independent predictor of post-CTS atrial fibrillation.7,8 These peaks have most commonly been seen on postoperative day 2, which is the most common day post-CTS atrial fibrillation occurs.7,8 Transfusion of allogeneic red blood cells (RBCs) recently has been shown to be an independent risk factor for adverse post-CTS outcomes.9-11 This includes an association with an increased risk of post-CTS atrial fibrillation.9 Tissue hypoxia and systemic inflammation have been postulated to be 2 common mechanisms causing such adverse outcomes.12 Fransen et al12 showed a relationship between the use of perioperative
From the Divisions of *Cardiology and †Drug Information, Hartford Hospital, Hartford, CT; ‡University of Connecticut School of Pharmacy, Storrs, CT; and §University of Connecticut School of Medicine, Farmington, CT. Address reprint requests to William L. Baker, PharmD, BCPS, Evidence-Based Practice Center, Hartford Hospital, 80 Seymour Street, CB309, Hartford, CT 06102. E-mail: [email protected] © 2009 Elsevier Inc. All rights reserved. 1053-0770/09/2301-0004$36.00/0 doi:10.1053/j.jvca.2008.06.009 22
KEY WORDS: atrial fibrillation, red blood cell transfusion, white blood cell count, cardiac surgery
METHODS This was a prospective cohort evaluation of 550 patients undergoing coronary artery bypass graft (CABG) surgery and/or valvular surgery from the AFIST I, AFIST II, and AFIST III studies conducted at an urban teaching hospital.13-15 Patients over 50 years (AFIST II and III)14,15 or over 60 years (AFIST I)13 of age scheduled to undergo CABG surgery or heart valve surgery were screened. Patients were excluded for the following reasons: chronic atrial fibrillation or flutter; known amiodarone hypersensitivity; current use of class I or class III antiarrhythmics; current use of implantable cardioverter-defibrillators or pacemakers; cardiogenic shock or advanced congestive heart failure (New York Heart Association class IV); marked sinus bradycardia (heart rate ⬍50 beats/min) or secondor third-degree atrioventricular block; moderate-to-severe liver disease; or current use of cyclosporine, cimetidine, phenytoin, or cholestyramine. AFIST was a randomized, double-blind placebo-controlled trial that assessed the effect of oral amiodarone or placebo on the incidence of post-CTS atrial fibrillation.13 Patients enrolled less than 5 days before surgery received 6 g of amiodarone or placebo over 6 days beginning on preoperative day 1. Patients enrolled at least 5 days before surgery received 7 g over 10 days beginning on preop-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 23, No 1 (February), 2009: pp 22-27
POST–CARDIOTHORACIC SURGERY ATRIAL FIBRILLATION
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erative day 5. AFIST II was a 2 ⫻ 2 factorial study that assessed the effect of 2 active treatments (amiodarone and atrial septal pacing) on the incidence of post-CTS atrial fibrillation.14 Patients were initially randomized to either amiodarone (the oral equivalent of 6.9 g) or placebo and then randomized further to either atrial septal pacing or no pacing. AFIST III was a randomized controlled trial that looked at the impact of anterior fat pad maintenance on the incidence of post-CTS atrial fibrillation in patients undergoing CABG surgery for the first time.15 In AFIST I, II, and III, post-CTS atrial fibrillation was defined as any documented atrial fibrillation event of more than 5 minutes’ duration, which is a standard definition used in post-CTS intervention clinical trials. In each trial, the primary endpoint was the development of post-CTS atrial fibrillation within 30 days of cardiac
surgery. For the purposes of the current evaluation, postoperative RBC transfusion was defined as any RBC blood product received from the day of surgery until either the development of atrial fibrillation or hospital discharge, whichever came first. Data with respect to patient demographics, surgical characteristics, medication utilization, and post-CTS atrial fibrillation were uniformly collected as part of the AFIST I, II, and III trials.13-15 The Institutional Review Board at Hartford Hospital, Hartford, CT, approved the study with a waiver of consent. Assuming an ␣ level of 0.05, the present study would have 80% power to detect a 12% absolute increase in the risk of developing atrial fibrillation in patients receiving RBC transfusions if 460 patients were included. Thus, the authors decided a priori to include all of the patients enrolled in the AFIST I-III studies (n ⫽ 550).
Table 1. Patient Demographics, Surgical Characteristics, and Medication Utilization by Postoperative Cardiothoracic Surgery Atrial Fibrillation Status Variable
Preoperative characteristics Age, years (mean ⫾ SD) Sex (male) Participant in AFIST I Participant in AFIST II Participant in AFIST III History of hypertension History of smoking History of myocardial infarction Family history of CAD History of angina History of heart failure EF, % (mean ⫾ SD) Prior atrial fibrillation History of cerebrovascular disease History of COPD History of mitral regurgitation Vessels ⬎50% occluded Preoperative medical therapy -Blocker CCB Digoxin Statin ACE inhibitor/ARB Surgical characteristics Valve surgery On-pump surgery Duration of surgery, min (mean ⫾ SD) Number of grafts, n (mean ⫾ SD) Number of arterial grafts, n (mean ⫾ SD) Number of venous grafts, n (mean ⫾ SD) Postoperative medication use Amiodarone -Blocker CCB Digoxin Corticosteroids NSAIDs Statin Postoperative RBC transfusions -Blocker intolerance
No Post-CTS AF (n ⫽ 377), n (%)
Post-CTS AF (n ⫽ 173), n (%)
p Value
66.8 ⫾ 8.5 297 (68.5) 152 (40.3) 110 (29.2) 115 (30.5) 277 (73.5) 226 (59.9) 137 (36.3) 147 (39.0) 286 (75.9) 37 (9.8) 50.2 ⫾ 12.6 15 (4.0) 17 (4.5) 45 (11.9) 64 (17.0) 2.8 ⫾ 0.9
70.3 ⫾ 8.3 126 (72.8) 64 (37.0) 49 (28.3) 60 (34.7) 128 (74.0) 97 (56.1) 65 (37.6) 67 (38.7) 120 (69.4) 33 (19.1) 49.2 ⫾ 12.3 19 (11.0) 10 (5.8) 31 (17.9) 48 (27.7) 2.6 ⫾ 1.1
⬍0.001 0.12 0.46 0.84 0.33 0.90 0.39 0.78 0.95 0.11 0.002 0.35 0.002 0.52 0.06 0.004 0.07
287 (76.1) 63 (16.7) 16 (4.2) 235 (62.3) 180 (47.7)
117 (67.6) 34 (19.7) 12 (6.9) 92 (53.2) 82 (47.4)
0.04 0.40 0.18 0.04 0.94
42 (11.1) 256 (67.9) 282.2 ⫾ 78.4 3.8 ⫾ 7.5 1.6 ⫾ 1.2 2.2 ⫾ 1.4
39 (22.5) 114 (65.9) 303.0 ⫾ 124.4 3.7 ⫾ 1.7 1.6 ⫾ 1.2 2.1 ⫾ 1.5
⬍0.001 0.64 0.02 0.49 0.73 0.28
189 (50.1) 325 (86.2) 31 (8.2) 70 (18.6) 100 (26.5) 100 (26.5) 210 (55.7) 181 (48.0) 26 (6.9)
54 (31.2) 139 (80.3) 23 (13.3) 77 (44.5) 47 (27.2) 26 (15.0) 89 (51.4) 110 (63.6) 21 (12.1)
⬍0.001 0.08 0.06 ⬍0.001 0.87 0.003 0.35 0.001 0.04
Abbreviations: ARB, angiotensin receptor blocker; SD, standard deviation; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CCB, calcium channel blocker; CTS, cardiothoracic surgery; EF, ejection fraction; NSAIDs, nonsteroidal anti-inflammatory drugs.
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SOOD ET AL
Continuous variables are presented as means with standard deviations and were compared among groups by using a Student t test or Mann-Whitney U test when appropriate (nonparametric data). Dichotomous variables are presented as percentages and were compared among groups by using a chi-square or Fisher exact test when appropriate. Because this was a retrospective analysis of clinical trial data, the investigators had no control over which patients received a blood product and which did not. As a result, significant differences in important observed demographic, surgical, and medication utilization characteristics were likely to occur, which could lead to a biased estimate of treatment effect. Therefore, the authors conducted multivariate logistic regression. Univariate analysis was first performed to examine the relationship between different variables (as listed on the admission sheet, demographic, surgical, and medical utilization characteristics) and the development of post-CTS
atrial fibrillation (dependent variable). All variables showing a univariate association (p ⱕ 0.20) with atrial fibrillation occurrence (Table 1) were then entered into a backwards, stepwise multivariate logistic regression model. The following variables were included in the multivariate model: preventative amiodarone use, use of HMGCoA reductase inhibitors before surgery, age ⬎70, male sex, history of atrial fibrillation, history of congestive heart failure, history of diabetes mellitus, history of smoking, history of chronic obstructive pulmonary disease, valve replacement surgery, a history of angina, -blocker use before surgery, calcium channel blocker use before surgery, duration of surgery, number of grafts performed, number of vessels ⬎50% occluded, post-CTS -blocker use, post-CTS corticosteroid use, post-CTS NSAID use, -blocker intolerance, the use of postoperative RBC transfusions, and maximum postoperative WBC count. A p value ⬍0.05 was considered significant in the multivariate logistic regression model. Adjusted odds ratios
Table 2. Patient Demographics, Surgical Characteristics, and Medication Utilization by RBC Transfusion Use Variable
Preoperative characteristics Age, years (mean ⫾ SD) Sex (male) Participant in AFIST I Participant in AFIST II Participant in AFIST III History of hypertension History of smoking History of myocardial infarction Family history of CAD History of angina History of heart failure EF, % (mean ⫾ SD) Prior atrial fibrillation History of cerebrovascular disease History of COPD History of Mitral Regurgitation Vessels ⬎50% occluded Preoperative medical therapy -Blocker CCB Digoxin Statin ACE inhibitor/ARB Surgical characteristics Valve surgery On-pump surgery Duration of surgery, min (mean ⫾ SD) Number of grafts, n (mean ⫾ SD) Number of arterial grafts, n (mean ⫾ SD) Number of venous grafts, n (mean ⫾ SD) Postoperative medication use Amiodarone -Blocker CCB Digoxin Corticosteroids NSAIDs Statin -Blocker Intolerance
No RBC Transfusion (n ⫽ 259), n (%)
RBC Transfusion (n ⫽ 291), n (%)
p Value
65.6 ⫾ 8.6 215 (83.0) 70 (27.0) 68 (26.3) 121 (46.7) 195 (75.3) 158 (61.0) 98 (37.8) 107 (41.3) 195 (75.3) 26 (10.0) 49.8 ⫾ 12.3 11 (4.2) 10 (3.9) 31 (12.0) 35 (13.5) 2.8 ⫾ 0.8
69.9 ⫾ 8.1 208 (71.5) 146 (50.2) 91 (31.3) 54 (18.6) 210 (72.3) 165 (56.7) 104 (35.7) 107 (36.8) 211 (72.5) 44 (15.1) 50.0 ⫾ 12.7 23 (7.9) 17 (5.8) 45 (15.5) 77 (26.5) 2.7 ⫾ 1.1
⬍0.001 0.001 ⬍0.001 0.20 ⬍0.001 0.41 0.31 0.61 0.28 0.46 0.07 0.87 0.08 0.28 0.24 ⬍0.001 0.56
202 (78.0) 37 (14.3) 8 (3.1) 170 (65.6) 117 (45.2)
202 (69.4) 60 (20.6) 20 (6.9) 157 (54.0) 145 (50.0)
19 (7.3) 142 (54.8) 276.3 ⫾ 65.5 3.9 ⫾ 1.4 1.8 ⫾ 1.2 2.1 ⫾ 1.3
62 (21.6) 228 (78.4) 299.8 ⫾ 115.1 3.6 ⫾ 1.7 1.5 ⫾ 1.1 2.2 ⫾ 1.5
⬍0.001 ⬍0.001 0.004 0.04 0.003 0.88
109 (42.1) 219 (84.6) 29 (11.2) 44 (17.0) 72 (27.8) 73 (28.2) 163 (62.9) 24 (9.3)
134 (46.0) 245 (84.2) 25 (8.6) 103 (35.4) 75 (26.8) 53 (18.2) 136 (46.7) 23 (7.9)
0.35 0.91 0.31 ⬍0.001 0.59 0.005 ⬍0.001 0.57
0.02 0.05 0.04 0.005 0.28
Abbreviations: ARB, angiotensin receptor blocker; SD, standard deviation; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CCB, calcium channel blocker; EF, ejection fraction; NSAIDs, nonsteroidal anti-inflammatory drugs.
POST–CARDIOTHORACIC SURGERY ATRIAL FIBRILLATION
(AORs), 95% confidence intervals (CIs), and 2-tailed p values were calculated for all variables retained in the multivariate logistic regression model. Statistical analysis was performed with SPSS version 15.0 (SPSS Inc, Chicago, IL). RESULTS
Overall, the population averaged 67.8 ⫾ 8.6 years of age, 77.1% were male, 14.6% underwent valve surgery, 6.1% had a history of prior atrial fibrillation, 12.6% had heart failure, and 84.0% and 44.1% received postoperative -blockade and prophylactic amiodarone, respectively. Comparisons of demographic, surgical approach, and medication utilization were made between those receiving and not receiving transfusions and those developing and not developing atrial fibrillation as delineated in Tables 1 and 2. In this population of 550 patients undergoing CABG ⫾ valve surgery, a total of 291 patients (52.9%) received postoperative RBC transfusions and 259 (47.1%) did not. The total number of RBC transfusions received by each patient was not collected in the database. Of the 173 patients (31.5%) who developed post-CTS atrial fibrillation, 110 patients (63.5%) received transfusions and 63 patients (36.5%) did not (crude odds ratio, 1.89; 95% CI, 1.31-2.74; p ⫽ 0.001). In the 377 (68.5%) patients who did not develop post-CTS atrial fibrillation, 181 (48.0%) patients received transfusions and 196 (52.0%) did not (p ⫽ not significant). Post-CTS WBC counts were significantly greater in patients who developed atrial fibrillation on postoperative day 3 (12.25 K/L ⫾ 4.70 v 10.91 K/L ⫾ 3.55, p ⫽ 0.002), day 4 (12.47 K/L ⫾ 5.43 v 10.61 K/⫾L ⫾ 3.31, p ⫽ 0.013), and day 5 (12.20 K/L ⫾ 4.24 v 9.99 ⫾ 3.72, p ⫽ 0.008), with a trend toward a difference on day 2 (13.31
Fig 1. (A) WBC count (mean and standard error of the mean) at baseline and on postoperative days 1 through 5 in patients who both experienced and did not experience AF. (B) WBC count (mean and standard error of the mean) at baseline and on postoperative days 1 through 5 in patients who both received and did not receive RBC transfusions.
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Table 3. Results of Multivariate Logistic Regression Variable*
AOR (95% CI)
p Value
Prophylactic amiodarone use Age ⬎70 years History of atrial fibrillation History of heart failure History of diabetes mellitus Preoperative -blocker use RBC transfusion use Max WBC (per K/L)
0.37 (0.20-0.50) 1.91 (1.24-2.96) 5.18 (2.11-12.74) 1.88 (1.05-3.38) 1.64 (1.05-2.56) 0.60 (0.37-0.96) 1.95 (1.24-3.06) 1.09 (1.04-1.13)
⬍0.001 0.004 ⬍0.001 0.03 0.03 0.03 0.004 ⬍0.001
*The Hosmer-Lemeshow goodness-of-fit test (chi-square test statistic ⫽ 2.95, degrees of freedom ⫽ 8, p ⫽ 0.94).
K/L ⫾ 4.72 v 12.08 ⫾ 4.28, p ⫽ 0.07) (Fig 1). There was no significant difference in WBC counts between patients who received and did not receive RBC transfusions (Fig 1). Upon multivariate logistic regression, the use of postoperative RBC transfusions was found to be associated with a significant increase in post-CTS atrial fibrillation (AOR, 1.95; 95% CI, 1.24-3.06; p ⫽ 0.004). Similarly, maximum WBC was also found to be associated with a significant increase in postCTS atrial fibrillation (AOR, 1.09 per K/L; 95% CI, 1.041.13; p ⬍ 0.001). Prophylactic amiodarone and preoperative -blocker use were found to be negative independent predictors of post-CTS atrial fibrillation (Table 3). Prior atrial fibrillation, age ⬎70 years, a history of heart failure, and a history of diabetes were each found to be positive independent predictors (p ⱕ 0.05 for all). DISCUSSION
The study has a few important findings. First, RBC transfusion was strongly associated with the development of post-CTS atrial fibrillation. Patients who received transfusions had 2-fold greater odds of developing post-CTS atrial fibrillation versus those who did not. Next, patients who developed post-CTS atrial fibrillation, regardless of whether they received RBC transfusion or not, had higher WBC counts starting on postoperative day 3 and continuing through day 5. Patients had a 9% increase in their relative odds of developing post-CTS atrial fibrillation for every K/L increase in their WBC count. As seen in previous studies,7,8 this may suggest that these patients are experiencing an inflammatory response that could be contributing to the development of post-CTS atrial fibrillation. Finally, RBC transfusion was not found to be associated with a significant increase in WBC count. It is possible that although transfusions are known to elicit an inflammatory response in patients, this may not be reflected by increases in WBC counts in CTS patients. It has been estimated that patients undergoing CTS account for 10% of the blood transfusions given annually in the United States.16 Surveys have estimated that 25% to 95% of CTS patients receive blood products, with most patients receiving treatment in response to a low hematocrit with no commonly acceptable threshold available.17-19 Common risk factors for the need for RBC transfusions include advancing age, female sex, preoperative renal insufficiency, preoperative aspirin therapy, duration of cardiopulmonary bypass,
26
recent fibrinolytic therapy, and reoperative CABG surgery.10,20,21 Some of the well-documented complications of RBC transfusions include infectious transmission, postoperative infections, renal insufficiency, multiple-organ failure, increased hospital length of stay, and long-term mortality.10,22-25 Murphy et al11 recently confirmed these findings by showing an increased risk of adverse ischemic outcomes as well as mortality in patients who received RBC transfusions. Post-CTS atrial fibrillation also has been independently linked with RBC transfusion administration in a previous analysis.9 Koch et al9 showed that the use of RBC transfusions in the intensive care unit after CTS resulted in an 18% increase in the odds for developing atrial fibrillation per unit of RBC transfused. The present study showed that patients who received transfusions at any time during the postoperative period had a 2-fold increase in their odds of developing post-CTS atrial fibrillation. The mechanism underlying this phenomenon may be related to an exaggerated inflammatory response in these patients. Numerous studies have suggested that increased inflammatory biomarkers have been associated with the development of atrial fibrillation in patients undergoing CTS.5-8,26 This exaggerated response may be the result of blood coming in contact with the extracorporeal cardiopulmonary bypass circuit and the formation of heparin-protamine complexes within patients undergoing CTS. Some of these acute-phase biomarkers include interleukin-6, C-reactive protein, and WBC. Indeed, prior studies have linked an elevated WBC count to an increased risk of atrial fibrillation.7,8 The authors also showed that a higher WBC count was associated with increased odds of developing atrial fibrillation, with a 10% increase in atrial fibrillation odds per K/L increase in the WBC count. This relationship was significant on postoperative days 3 to 5 with a trend (p ⫽ 0.07) on day 2. Another possible mechanism explaining the present results could be related to fluid volume. A substudy of the AFIST II trial showed that patients who developed post-CTS atrial fibrillation received 1.3 L more fluid than those who did not develop atrial fibrillation.27 Excess fluid volume, as can be provided by the use of RBC transfusions, could elevate intra-atrial pressures, resulting in atrial dilation, which, in animal studies, increases atrial fibrillation vulnerability.28,29 However, given that the total volume of RBC transfusion patients received was not available, this hypothesis could not be investigated in the current study. It should, however, be the focus of future investigations. RBC transfusion use has been shown to elicit an inflammatory response by direct infusion of inflammatory mediators, as evidenced by increased serum levels of interleukin-6 after intraoperative administration.12 Thus, the authors also tested the theory that patients receiving transfusions would have elevated WBC counts. However, no significant difference in WBC count was seen on any of the evaluated postoperative days when examined by the use of blood transfusions. This most likely can be explained by the fact that all RBC transfusions during the AFIST study period underwent leukoreduction and, therefore, contained comparably lower levels of inflammatory mediators. However, given that the authors were testing the impact of transfusion
SOOD ET AL
on WBC and not on other inflammatory mediators such as C-reactive protein or interleukin-6, the impact of leukoreduction should be minimal. It is possible that the increased WBC counts seen in these patients are related to the presence of infection. Tang et al30 hypothesized that postoperative infections, such as those caused by Chlamydia pneumonia, have been linked not only to increased inflammatory biomarkers but to the development of atrial fibrillation as well. Data on the link between infection and WBC as well as atrial fibrillation could not be made as that information is unavailable in the database. It is important to consider the results of the present study in the context of its potential limitations. Although the AFIST trials were prospective, controlled trials, patients were not randomized to receive RBC transfusions or not. As a result, some baseline characteristics of the included patients may have differed. To minimize these differences, the authors conducted multivariate logistic regression to control for most known predictors of post-CTS atrial fibrillation. In addition, data concerning the use of intraoperative transfusions, total number of RBC transfusions received, timing of administration related to surgery, and total volume received were not available. As such, the authors were not able to determine the effect these factors may have had on the desired outcomes. Similarly, the time correlation between patients receiving transfusions and obtaining WBC samples was not controlled for. As such, it is possible that patients had peak WBC levels, before receiving RBC transfusions. The present results suggest that a relationship exists between patients receiving RBC transfusions and the development of post-CTS atrial fibrillation. It is possible that patients receiving RBC transfusions are higher risk patients and thus also more likely to develop atrial fibrillation. This relationship requires validation in a prospective study. An additional issue is the potentially differential impact that perioperative and postoperative RBC transfusions may have on post-CTS outcomes. Because the authors only had data on WBC count, assessments of other inflammatory biomarkers could not be made and must be evaluated in future studies. The fact that patients receiving RBC transfusions were more likely to develop atrial fibrillation and that patients with higher WBC counts were also at higher risk supports the contribution of transfusions to the postoperative inflammatory response; however, this theory needs to be investigated further in a prospective, randomized trial. CONCLUSION
RBC transfusion use was found to be a strong independent predictor for the development of post-CTS atrial fibrillation. The present study also supports the role of inflammation in the etiology of atrial fibrillation as shown by increases in WBC count starting on postoperative days 2 and 3, the most common days of atrial fibrillation development. Although no direct link between RBC transfusion and an increased WBC count was made, the present study supports the overall hypothesis that RBC transfusions may be associated with adverse outcomes after CTS. Subsequent prospective, randomized trials are required to better investigate the associations seen in the present study.
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REFERENCES 1. Baker WL, White CM: Postcardiothoracic surgery atrial fibrillation: a review of preventive strategies. Ann Pharmacother 41:587-598, 2007 2. Mathew JP, Fontes ML, Tudor IC, et al: A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 291:1720-1729, 2004 3. Gillespie EL, White CM, Kluger J, et al: A hospital perspective on the cost-effectiveness of beta-blockade for prophylaxis of atrial fibrillation after cardiothoracic surgery. Clin Ther 27:1963-1969, 2005 4. Kim MH, Deeb GM, Morady F, et al: Effect of postoperative atrial fibrillation on length of stay after cardiac surgery (The Postoperative Atrial Fibrillation in Cardiac Surgery Study [PACS2]). Am J Cardiol 87:881-885, 2001 5. Bruins P, te Velthuis H, Yazdanbakhsh AP, et al: Activation of the complement system during and after cardiopulmonary bypass surgery. Postsurgery activation involves c-reactive protein and is associated with postoperative arrhythmia. Circulation 96:35423548, 1997 6. Gaudino M, Andreotti F, Zamparelli R, et al: The ⫺174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation 108:II-195-II-199, 2003 (suppl II) 7. Abdelhadi RH, Gurm HS, Van Wagoner DR, et al: Relation of an exaggerated risk in white blood cells after coronary bypass or cardiac valve surgery to development of atrial fibrillation postoperatively. Am J Cardiol 93:1176-1178, 2004 8. Lamm G, Auer J, Weber T, et al: Postoperative white blood cell count predicts atrial fibrillation after cardiac surgery. J Cardiothorac Vasc Anesth 20:51-56, 2006 9. Koch CG, Li L, Van Wagoner DR, et al: Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 82:1747-1757, 2006 10. Koch CG, Li L, Duncan AI, et al: Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 34:1608-1616, 2006 11. Murphy GJ, Reeves BC, Rogers CA, et al: Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 116:2544-2552, 2007 12. Fransen E, Maessen J, Dentener M, et al: Impact of blood transfusions on inflammatory mediator release in patients undergoing cardiac surgery. Chest 116:1233-1239, 1999 13. Giri S, White CM, Dunn AB, et al: Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): A randomized placebo-controlled trial. Lancet 357:830-836, 2001 14. White CM, Caron MF, Kalus JS, et al: Intravenous plus oral amiodarone, atrial septal pacing, or both strategies to prevent postcardiothoracic surgery atrial fibrillation: The Atrial Fibrillation Suppression Trial II (AFIST II). Circulation 108:II-200-II-206, 2003 (suppl II) 15. White CM, Sander S, Coleman CI, et al: Impact of epicardial anterior fat pad retention on postcardiothoracic surgery atrial fibrilla-
tion incidence: The Atrial Fibrillation Suppression Trial III (AFIST III). J Am Coll Cardiol 49:298-303, 2007 16. Graves EJ: National hospital discharge survey: Annual summary, 1991. Vital Health Stat 13:1-62, 1993 17. Stover EP, Siegel LC, Parks R, et al: Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: A 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology 88:327-333, 1998 18. Moise SF, Higgins MJ, Colquhoun AD: A survey of blood transfusion practice in UK cardiac surgery units. Crit Care 5:4, 2005 (suppl a, abstr) 19. Bracey AW, Radovancevic R, Riggs SA, et al: Lowering the hemoglobin threshold for transfusion in coronary artery bypass procedures: Effect on patient outcome. Transfusion 39:1070-1077, 1999 20. Ferraris VA, Gildengorin V: Predictors of excessive blood use after coronary artery bypass grafting: A multivariate analysis. J Thorac Cardiovasc Surg 98:492-497, 1989 21. Cosgrove DM, Loop FD, Lytle BW, et al: Determinants of blood utilization during myocardial revascularization. Ann Thorac Surg 40: 380-384, 1985 22. Schreiber GB, Busch MP, Kleinman SH, et al: The risk of transfusion-transmitted viral infections: The Rotovirus Epidemiology Donor Study. N Engl J Med 334:1685-1690, 1996 23. Leal-Noval SR, Rincon-Ferrari MD, Garcia-Curiel A, et al: Transfusion of blood components and postoperative infection in patients undergoing cardiac surgery. Chest 119:1461-1468, 2001 24. Chelemer SB, Prato BS, Cox PM Jr, et al: Association of bacterial infection and red blood cell transfusion after coronary artery bypass surgery. Ann Thorac Surg 73:138-142, 2002 25. Engoren MC, Habib RH, Zacharias A, et al: Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 74:1180-1186, 2002 26. Ishii Y, Schuessler RB, Gaynor SL, et al: Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation 111:2881-2888, 2005 27. Kalus JS, Caron MF, White CM, et al: Impact of fluid balance on incidence of atrial fibrillation after cardiothoracic surgery. Am J Cardiol 94:1423-1425, 2004 28. Ravelli F, Allessie M: Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation 96:1686-1695, 1997 29. Deroubaix E, Folliguet T, Rucker-Martin C, et al: Moderate and chronic hemodynamic overload of sheep atria induces reversible cellular electrophysiologic abnormalitites and atrial vulnerability. J Am Coll Cardiol 44:1918-1926, 2004 30. Tang RB, Dong JZ, Liu XP, et al: Inflammation and atrial fibrillation: is Chlamydia pneumonia a candidate pathogen of atrial fibrillation? Med Hypotheses 67:462-466, 2006