Preoperative White Blood Cell Count and Mortality and Morbidity After Coronary Artery Bypass Grafting

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1 Preoperative White Blood Cell Count and Mortality and Morbidity After Coronary Artery Bypass Grafting Lawrence J. Dacey, MD, Joseph DeSimone, MD, John H. Braxton, MD, Bruce J. Leavitt, MD, Stephen J. Lahey, MD, John D. Klemperer, MD, Benjamin M. Westbrook, MD, Elaine M. Olmstead, and Gerald T. O Connor, PhD, DSc, for the Northern New England Cardiovascular Disease Study Group Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Department of Surgery, Maine Medical Center, Portland, Maine; Department of Surgery, Fletcher-Allen Health Care, Burlington, Vermont; Department of Surgery, Beth Israel-Deaconess Medical Center, Boston, Massachusetts; Department of Surgery, Eastern Maine Medical Center, Bangor, Maine; Department of Surgery, Catholic Medical Center, Manchester, New Hampshire; and Departments of Medicine and Community & Family Medicine and the Center for the Evaluative Clinical Sciences, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Background. Arteriosclerosis is increasingly viewed as an inflammatory disease. The purpose of these analyses was to examine the preoperative white blood cell (WBC) count, a generalized marker of inflammation, and to assess its association with in-hospital mortality and other adverse outcomes after coronary artery bypass grafting. Methods. Information was collected prospectively on 11,270 consecutive patients who had isolated coronary artery bypass grafting in northern New England from 1996 through Patients were divided into five categories based on their preoperative WBC count. Crude and adjusted in-hospital mortality rates and adverse event rates were calculated using logistic regression. Results. Increasing WBC count across its entire range was associated with a linear increase in the mortality rate. This finding was highly significant (p [trend] < 0.001) and persisted after adjustment for patient and disease characteristics. Patients with preoperative WBC of at least /L had an adjusted mortality rate 2.8 times higher than those with a WBC less than /L (4.8% versus 1.7%). An increasing preoperative WBC count was also significantly associated with increasing rates of perioperative strokes and the need for an intraaortic balloon pump but was not associated with mediastinitis. Conclusions. The preoperative WBC count across its entire observed range is a statistically significant independent predictor of in-hospital death and other adverse outcomes after coronary artery bypass grafting. Although the cause of the association between increased WBC count and increased morbidity and mortality is unknown, the preoperative WBC count, which is objectively measured, inexpensive, and always available, can serve as a useful marker to help predict risk before coronary artery bypass grafting. (Ann Thorac Surg 2003;76:760 4) 2003 by The Society of Thoracic Surgeons Arteriosclerosis is increasingly viewed as an inflammatory disease [1]. Markers of inflammation, both generalized and specific, can be used to predict the risk of cardiovascular events [2 4]. The baseline white blood cell (WBC) count, a generalized marker of inflammation, has been correlated positively with the development of coronary artery disease and the risk of future acute myocardial infarction. Studies have shown that the risk of acute myocardial infarction is two to four times as great in patients with WBC counts in the high normal range (9.0 to /L) compared with patients with WBC counts in the low normal range (4.0 to /L). Accepted for publication April 3, Address reprint requests to Dr Dacey, Cardiothoracic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH ; lawrence.j.dacey@dartmouth.edu. After acute myocardial infarction, an increased WBC count on admission has been shown to be predictive of the development of congestive heart failure and death [5]. However, to date the association between the WBC count and adverse outcomes after coronary artery bypass has not been examined closely. The purpose of this study was to examine the preoperative WBC count and to assess its association with in-hospital death and other adverse outcomes after coronary artery bypass. Material and Methods Patients and Setting The Northern New England Cardiovascular Disease Study Group is a voluntary research consortium representing all medical centers in Maine, New Hampshire, and Vermont where coronary artery bypass grafting (CABG) is performed, along with the Beth Israel Deacon by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Inc PII S (03)

2 Ann Thorac Surg DACEY ET AL 2003;76:760 4 PREOPERATIVE WBC AND CABG ess Medical Center (Boston, MA). Since 1987, the Northern New England Cardiovascular Disease Study Group has maintained a prospective registry of all patients who have cardiac operations in the region. This is a multicenter study of 11,270 consecutive patients who had isolated CABG between 1996 and 2000 in northern New England. The internal review boards of the participating institutions approved this study. Risk Factors All patients had been prospectively entered into a data registry, which records patient characteristics, processes of care, and outcomes. From the registry the following data were available: patient age, gender, height, and weight; baseline laboratory studies, including blood chemistries and hematology; comorbid conditions; degree of left main coronary artery stenosis; total number of significantly diseased vessels; ejection fraction; recent myocardial infarction; prior CABG or percutaneous transluminal coronary angioplasty; and operative priority (elective or urgent/emergent). Complete definitions of these variables have been published previously [6]. The WBC count used in these analyses was the last one recorded preoperatively and was performed at various times preoperatively. Mortality and Adverse Outcomes The registry also contained information on the intraoperative or postoperative uses of intraaortic balloon pump, the development of stroke or mediastinitis, and mortality status at discharge from the hospital. Stroke was defined as a new fixed neurologic deficit lasting more than 24 hours. Mediastinitis was defined as the presence of two or more of the following findings in the absence of another recognized cause during the initial hospitalization: 1) organisms and WBCs seen on Gram stain in aspirated fluid, 2) positive results of deep wound culture, 3) radiographic evidence of infection, or 4) sternal dehiscence requiring reoperation. Analysis Patients were divided into five categories based on their preoperative WBC count ( 10 9 /L) as follows: less than 6.0, 6.0 to 7.9, 8.0 to 9.9, 10.0 to 11.9, and 12.0 or more. Mortality rates and rates of other adverse outcomes were determined for each of the five WBC count categories. Baseline patient and disease characteristics were summarized by means for the continuous variables and by percentages for the discrete variables. Nonparametric tests for trend were performed across the WBC count groups, which were treated as ordinal variables. To adjust for confounding variables, we used multivariate logistic regression and direct standardization techniques. Variables that differed significantly among groups, as well as common known risk factors for morbidity and mortality after CABG, were selected for multivariate analysis. All statistical analyses were conducted using the STATA 6.0 statistical program (Stata Corp, College Station, TX) [7]. 761 Results Patient Characteristics The preoperative WBC count ranged from 0.7 to /L, with a mean value of /L. Eighty-three percent of patients had white cell counts of less than /L (18% had /L, 38% had 6.0 to /L, and 27% had 8.0 to /L). Eleven percent of patients had values in the 10 to /L range, and 6% had values of /L or above. Patient and disease characteristics stratified by preoperative WBC counts are shown in Table 1. Patients with increasing WBC counts were slightly younger, more likely to be women, more obese, and had more comorbid conditions, including peripheral vascular disease, diabetes, chronic obstructive pulmonary disease, congestive heart failure, and renal failure. Patients with higher WBC counts also had poorer ventricular function, higher left ventricular end-diastolic pressure, more extensive coronary disease, were more likely to have had a recent myocardial infarction, and were more often in the urgent or emergent operative categories (p [trend] for all variables). There was not a significant association seen with increasing WBC count and the presence of unstable angina (p [trend] 0.058). Mortality There were 294 deaths in this group of 11,270 patients for an overall mortality rate of 2.61%. Crude mortality rates ranged from 1.40% among those with WBC count less than /L, to 7.12% among those in the highest WBC category (Fig 1). After adjusting for age, sex, body mass index, peripheral vascular disease, diabetes, chronic obstructive pulmonary disease, renal failure, congestive heart failure, ejection fraction, left ventricular enddiastolic pressure, left main disease, prior CABG or percutaneous transluminal coronary angioplasty, recent myocardial infarction, number of diseased vessels, and priority, the preoperative WBC count remained a highly significant and strong predictor of in-hospital death after CABG (Table 2). The adjusted mortality rate was 1.7% for those in the lowest WBC group and increased steadily and nearly linearly across categories to 4.8%, or 2.8 times higher, for those in the highest WBC group (p [trend] 0.001). This association of increasing WBC count and mortality rate was evident even within the normal range of the WBC count. Patients in the high normal range of WBC count (8 to /L) had a mortality rate 61% higher (2.8% versus 1.7%) than those in the low normal range ( /L). When analyzed as a continuous variable, WBC count was associated with a statistically significant (p 0.001) 13% relative increase in death per /L increase. Other Adverse Outcomes Higher WBC count was significantly associated with increased rates of perioperative stroke and the need for a postoperative intraaortic balloon pump. There was approximately a 75% higher adjusted rate of stroke from the CARDIOVASCULAR

3 762 DACEY ET AL Ann Thorac Surg PREOPERATIVE WBC AND CABG 2003;76:760 4 Table 1. Patient and Disease Characteristics by Preoperative White Blood Cell Count Variable WBC Category p Trend Number of procedures Age, (years) mean Sex, % female Mean body surface area (m 2 ) Body mass index (%) (%) Comorbid disease PVD, % yes DM, % yes COPD, % yes CHF, % yes RF, % yes Ejection fraction, mean Ejection fraction 40, % yes Mean LVEDP Coronary artery disease Left main 50, % yes Unstable angina, % yes No. of diseased vessels, mean Prior PTCA, % yes Prior CABG, % yes Recent MI ( 7 days), % yes Urgent/emergent operative status, % yes CABG coronary artery bypass grafting; CHF congestive heart failure; COPD chronic obstructive pulmonary disease; DM diabetes; LM left main disease; LVEDP left ventricular end diastolic pressure; MI myocardial infarction; PTCA percutaneous transluminal coronary angioplasty; PVD peripheral vascular disease; RF renal failure; UA unstable angina; WBC white blood cell. lowest to the highest WBC category (1.2% versus 2.1%, p [trend] 0.003). Likewise, the adjusted rate of insertion of a postoperative intraaortic balloon pump was more than twice as high among patients in the high WBC category compared with patients in the lowest WBC category (4.6% versus 2.2%, p [trend] 0.001). There was no statistically significant association between increasing Fig 1. Crude (diamonds) and adjusted (circles) in-hospital mortality rates by preoperative white blood cell (WBC) category. WBC count and adjusted rates of mediastinitis (range 0.9% to 1.5%, p[trend] 0.25). Comment In this study, the preoperative WBC count was a statistically significant and strong predictor of in-hospital death and other adverse events after CABG. There was a nearly linear monotonic increase in the adjusted mortality rates seen with increasing baseline WBC count. Patients with a WBC count of at least /L had an adjusted mortality rate 2.8 times as high as those with a WBC count less than /L. This is an increased risk similar to dialysis-dependent renal failure or a prior CABG. Patients with a WBC count in the high normal range had an adjusted mortality rate 61% higher than those with a WBC count in the low normal range. This risk is roughly equivalent to the risk associated with peripheral vascular disease or congestive heart failure. Similarly, the adjusted rate of a perioperative stroke or requirement for an intraoperative or postoperative intraaortic balloon pump increased significantly as the preoperative WBC count increased, doubling from the lowest to highest categories. Arteriosclerosis is increasingly viewed as a chronic inflammatory disease. An association between a baseline

4 Ann Thorac Surg DACEY ET AL 2003;76:760 4 PREOPERATIVE WBC AND CABG Table 2. Adjusted a Rates of Adverse Outcomes by Preoperative White Blood Cell Count Adverse Outcome WBC Category p Trend CARDIOVASCULAR In-hospital mortality (%) Perioperative stroke (%) Intra- or postoperative IABP (%) Mediastinitis (%) a Rates adjusted for age, sex, body mass index, peripheral vascular disease, diabetes, chronic obstructive pulmonary disease, preoperative renal failure, preoperative congestive heart failure, preoperative ejection fraction, preoperative left ventricular end-diastolic pressure, left main coronary artery stenosis 50%, prior coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, recent myocardial infarction, number of diseased vessels and operative priority. IABP intraaortic balloon pump. WBC count and risk of coronary heart disease has been demonstrated consistently in epidemiologic studies and includes both fatal and nonfatal events [8 13]. In general, the risk of developing coronary heart disease is two times higher in patients with WBC counts of 8 to /L compared with patients with counts of 4 to /L. This twofold difference is similar to the relative risk of standard risk factors, such as serum cholesterol, hypertension, and cigarette smoking. The relationship appears to be a dose-response effect, with higher WBC counts associated with graded increases in risk of coronary heart disease. Additionally, one study showed that a decrease in the WBC count was associated with a decrease in risk of coronary heart disease [14]. Increasing WBC count on admission to the hospital for acute myocardial infarction has been shown to be strongly predictive of later congestive heart failure and death [15 17]. The cause of the association between a higher WBC count and a higher risk of adverse outcomes is not known. It is not known whether increasing numbers of WBCs are directly responsible for increasing injury or whether the increasing WBC count may serve only as a marker of an underlying inflammatory state. White blood cells, particularly neutrophils and macrophages, have been studied extensively in myocardial reperfusion injury and are known to have deleterious effects on myocardial cells [18]. Neutrophils accumulate in ischemic and reperfused myocardium and may participate directly in myocardial injury by the forming aggregates that alter the rheologic properties of blood in the microvasculature and by the release of activated substances, including oxygen free radicals, proteases, and proinflammatory cytokines [19]. There is an ever-increasing number of inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-alpha whose levels are predictive of risk of cardiovascular events [20 27]. The preoperative WBC count may merely serve as one of these markers of risk, with higher numbers reflective of an underlying increasingly inflammatory state. Knowledge of patients at increased risk due to an underlying heightened inflammatory state could lead to targeted therapies to help ameliorate the inflammatory response. Study Limitations There are several limitations of this study. First, we have only the total WBC count, and not the cell differential, for these patients. Neutrophils and monocytes are the WBCs most commonly implicated with inflammation. The absolute number of these cells may have contributed important information. The WBC count was collected at varying times preoperatively, depending on the patient s clinical status. We do not have information on how far in advance of operation the WBC count was measured; we know only that it was the last measurement of the WBC count preoperatively. Elective patients often had their WBC count measured weeks before their operation, whereas the WBC count from urgent and emergent patients may have been performed within hours of the operation. However, the associations between the WBC count and adverse outcomes remained strong after adjusting for surgical priority. There is also a small diurnal variation in neutrophil count in most individuals, with the highest levels in the afternoon and lowest levels in the morning at rest. Thus, a patient s WBC count could have varied depending on the time of day it was drawn. However, this variation would tend to bias the results towards the null hypothesis and underestimate the association of the WBC count and outcomes. Finally, we did not collect more specific markers of inflammation, such as C-reactive protein, interleukin-6, and TNF-alpha, which may have strengthened the association of increased risk of adverse outcomes with an increased inflammatory baseline state. The preoperative WBC count is inexpensive, objectively measured, and always available before CABG. We found the preoperative WBC count across the entire observed range to be a highly significant and strong independent predictor of in-hospital death and other adverse outcomes after CABG. Supported in part by a grant from the American Heart Association ( N). References 1. Ross R. Atherosclerosis an inflammatory disease. N Engl J Med 1999;340: Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98: Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens

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