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Ann Thorac Surg 2003;75:1550-1557
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

Preoperative high leukocyte count: a novel risk factor for stroke after cardiac surgery

Alexander A. Albert, MDa*, Carsten J. Beller, MDa, Jörg A. Walter, PhDb, Bert Arnrich, MSb, Ulrich P. Rosendahl, MDa, Horst Priss, MDc, Jürgen Ennker, MDa

a Clinic for Cardiothoracic Surgery, Heart Institute Lahr/Baden, Lahr, Germany, Germany
b Institute of Neuroinformatics, University of Bielefeld, Bielefeld, Germany
c Department of Neurology, Regional Hospital Lahr, Lahr, Germany, Germany

Accepted for publication August 29, 2002.

* Address reprint requests to Dr Albert, Hohbergweg 2, 77933 Lahr, Germany
e-mail: alexander.albert{at}heart-lahr.com


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Stroke after cardiac surgery is a devastating complication. The relationship between white blood cell count (WBC) and perioperative cerebrovascular accident (CVA) has not been investigated. An effort was made to identify how preoperative WBC may relate to CVA development during or after cardiac surgery.

METHODS: Prospective data were collected from 7,483 patients who underwent coronary artery bypass grafting or valvular surgery or both. WBC was determined preoperatively and postoperatively. Differentiation of WBC was examined only preoperatively.

RESULTS: There were a total of 125 CVAs (10 transient ischemic attacks [TIAs], 115 strokes). WBC was significantly higher preoperatively and directly postoperatively in patients with stroke. Qualitative changes in preoperative WBC were also found in these patients ({chi}2; p < 0.001). The predictive power of the stepwise logistic regression model for CVA was greater when preoperative WBC was included. The risk for perioperative CVA increased starting at preoperative WBC of 9 x 109/L (p = 0.044) and progressed in higher WBC ranges. WBC had a significant impact on CVA outcome (analysis of variance, p = 0.001).

CONCLUSIONS: Our studies have established the correlation between high preoperative WBC and stroke during or after cardiac surgery. Furthermore, elevated preoperative WBC was related to the clinical outcome of CVA. Preoperative measures aimed at preventing or treating conditions such as infections that may cause elevated WBC may be beneficial in the prevention of stroke during or after cardiac surgery.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Despite different strategies aimed at reducing neurologic injury the incidence of neurologic disorders after cardiac surgery remains high [1]. Several risk factors have been identified [2, 3, 4]. Cerebral hypoperfusion—either global or regional—seems to play a major role in the pathogenesis of perioperative stroke and may be linked to embolism [5]. Hemorheologic and inflammatory changes associated with cardiopulmonary bypass (CPB) may also contribute to the development of stroke after cardiac surgery [5]. There are however no data about the correlation of preoperative quantitative and qualitative changes in the white blood cell count (WBC) with development of stroke during or after cardiac surgery.

Experimental data suggest that leukocytes are involved in the pathogenesis of ischemic brain damage [6, 7]. Numerous studies also demonstrate that recent infection and chronic inflammation are indeed risk factors for cerebrovascular ischemia [8–10]. These studies are based mostly on data obtained from the patient history, antibody titers, and long-term immunologic markers. An epidemiologic study identified a high WBC determined several months to a few years before the onset of stroke as an independent risk factor [11]. No laboratory data are available for the majority of stroke patients before the onset of stroke. Our study examines the possible significance of WBC on the development of stroke during or after cardiac surgery. Also using cardiac surgery as a model, we wanted to contribute to the understanding of stroke in general.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
From March 1997 to December 2000, 8,008 adult patients underwent cardiac surgical procedures at the Heart Institute Lahr/Baden, Germany. Patients who had had thoracic aortic surgery, off-pump coronary artery bypass grafting, and simultaneous carotid endarterectomy were excluded from the study. That left us with 7,483 patients, of whom 5,596 underwent isolated coronary artery bypass grafting (CABG), 567 had CABG with simultaneous valvular procedures, 634 had isolated aortic valve replacements, 190 had isolated mitral valve surgery, 55 had double valve replacements, 75 had redo valve replacements, 252 had redo CABG, and 114 had other major cardiac surgical procedures. Data for quality assessment were collected prospectively on all patients as part of a national quality assessment trial of cardiothoracic surgery ([Quadra] Quality Assurance Data Review Analysis) and cardioanesthesia using standardized protocols of the German Society of Thoracic and Cardiovascular Surgery and Intensive Care Medicine [12, 13]. A technical assistant for data collection and medical documentation controlled the data collection and tested the interrater reliability.

Variables such as preoperative medications (class of substances, eg, ß-blocker, diuretics), data concerning the operating team (eg, individual surgeon), the degree of carotid stenosis if present (all degrees were recorded but only stenoses with 50% or more were included for the analysis), the degree of aortic arteriosclerosis (graded: none, mild, moderate, severe), and history of neurologic disease (eg, history of CVA or other neurologic diseases) were recorded. WBC was measured preoperatively and directly postoperatively but differential WBC was measured only preoperatively (Automatic Analyzer Sysmex K4500; Sysmex, Hamburg, Germany). Leukocytes were classified as granulocytes, lymphocytes, or as a "mixed group" that included monocytes, basophiles, and eosinophiles. Lower and upper limits of "normal" WBC were 4.3 to 10.8 x 109/L [14]. Yearly controls of blood cell measurements were performed by the Institute for Standardization and Documentation in Medical Laboratories, according to instructions of the German Medical Association. Comprehensive results were obtained the entire time from 1997 to 2001. The data were stored perioperatively in three commercially available electronic databases (Medwork, Datapec, Clinicom, Düsseldorf, Germany), consolidated, and transmitted to a "datamart" system. The laboratory data were implemented automatically in our datamart system. Several plausibility checks during data collection and data consolidation in our datamart system were performed.

For the present study, we analyzed 37 variables from the more than 160 attributes collected for each patient.

Clinical preoperative studies included routine Doppler ultrasonography of the carotid and the vertebral arteries and spirometry. A neurologist examined patients with high-grade carotid stenosis or history of neurologic disorders to assess existing preoperative neurologic deficits and to facilitate a distinction from possible perioperative neurologic events. Assessment of aortic calcification was obtained through intraoperative palpation or direct inspection through the aortotomy or the punch-holes for the proximal anastomoses since 1998. Postoperatively all patients were evaluated for possible neurologic deficits by nurses and doctors. If focal neurologic defects or prolonged decreases of consciousness were detected a neurologic consultation was obtained. Depending on the severity of symptoms, a computed tomography (CT) scan of the brain was performed and interpreted independently by a radiologist and a neurologist. Patients in whom brain damage developed after resuscitation or cardiac arrest were excluded from the study.

Classification of cerebrovascular accidents
The clinical characteristics and temporal course of postoperative CVAs were described according to a classification of the National Institute of Neurologic Disorders and Stroke [15]: as transient ischemic attack (TIA) if symptoms lasted less than 24 hours, as reversible ischemic neurologic deficit (RIND) if symptoms lasted longer than 24 hours up to 3 weeks, or as completed stroke if neurologic symptoms persisted beyond 3 weeks. The latter was further classified as minor or major completed stroke to assess the clinical outcome. Major completed strokes were defined as those with subsequent death from stroke or severely affecting ambulation or day-to-day functioning still persisting 4 to 6 weeks after discharge. Minor completed strokes were defined as those with mild residual deficits. RINDs and minor or major completed strokes were summarized in terms of "stroke" in contrast to TIAs in this article. For patients with preexisting neurologic deficits a new CVA was diagnosed if new neurologic symptoms developed or there was obvious prolonged worsening of already existing symptoms. In the course of clinical data analysis, systematic chart review was done for the 125 patients who suffered a CVA.

Perioperative management
The patients were operated on by 12 different surgeons. The patients received heparin (375 KIE/kg) at the completion of median sternotomy to obtain an activated clotting time in excess of 400 seconds. Cardiopulmonary bypass was established with an ascending aortic cannulation in an area free of atherosclerotic plaque and a single two-stage right atrial cannula (except for mitral valve procedures). Jostra HL 20 heart-lung machines (Jostra, Hirrlingen, Germany) with capillary oxygenators and arterial filters (pore size 40 µm) were used. Roller pumps generated nonpulsatile flow. Target CPB flow was between 90% and 120% of the calculated value (body surface area multiplied by 2.5), the target pressure was 60 mm Hg and higher for patients with known carotid stenoses (60 to 80 mm Hg), maintained with noradrenalin if necessary. Moderate hemodilution (hematocrit 24% to 30%, age dependent) and moderate hypothermia (32°C to 35°C) was used. From 1998 on, patients were kept normothermic (>35°C) during most CABG. Heparin was neutralized by protamine. Aprotinin (2.5 to 5 million KIE) was used in nearly all patients. Patients with low cardiac output or who needed adrenalin more than 0,2 µg · kg-1 · min-1 were placed on intraaortic balloon pump. All patients were treated with a third-generation cephalosporin (cefazolin) before, during, and after surgery.

Statistical analysis
Univariate comparisons between subjects with and without CVA were performed with {chi}2 tests and Fisher’s exact test for categorical data and with Spearman’s rank order and Kendall’s {tau} test for ordinal data. Continuous variables were evaluated by unpaired Student’s t test or analysis of variance (ANOVA). Stepwise forward logistic and linear regression methods were used to determine predictors of CVA. We employed the SPSS v10.0 package (Chicago, IL) for the statistical tests. Model discrimination was evaluated by the area under the receiver operating characteristic (ROC) curve.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Characteristics of patients with CVA
The prevalence of CVA was 1.7% (n = 125); 65% of these were diagnosed within 72 hours postoperatively. The in-hospital mortality rate was 9% (n = 11) of patients with CVAs versus 2.5% (n = 187) of patients without CVA (n = 7,358). In 50% (n = 62) of the CVA victims a marked alteration of vigilance developed: 41 of those were somnolent, 12 were soporous, and 9 were comatose. Nine patients were reintubated owing to CVA and 35 patients (28%) were maintained on prolonged mechanical ventilation. In 120 patients the CVA was classified as right (40%), left anterior (29.2%), posterior (13.3%), or bilateral (17.5%). In 5 cases localization was not possible. CT scans of the brain were performed in 98 patients (78%). Brain infarction was classified as "borderline" in 6.1% of cases and as lacunar in 9.2%. Twenty percent showed combined territorial and lacunar infarction and 64.7% showed isolated territorial infarction. After 4 to 6 weeks (mean: 35 days) 7.2% of patients with completed strokes had severe residual deficits.

Predictors of CVA
All univariate risk factors (Table 1) were included as dichotomous or ordinal variables in a stepwise logistic regression analysis. There was no association between the individual surgeon and CVA ({chi}2, p = 0.224).


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  		Table 1. Preoperative, Intraoperative, and Postoperative Univariate Predictors of Cerebrovascular Accident (CVA) Ordered by CVA Rate

 
Preoperative WBC was analyzed in three categories according to the "normal" WBC range: WBC less than 4.3 x 109/L, WBC 4.4 x 109/L to 10.8 x 109/L, and WBC more than 10.8 x 109/L. For the first time a high preoperative WBC was identified as one of seven independent predictors of perioperative CVA: use of intraaortic balloon pump, carotid stenosis, history of stroke, preoperative atrial fibrillation, preoperative WBC, postoperative atrial fibrillation, and age (Table 2). The area under the ROC curve was calculated as 0.741 (95% confidence interval [CI]: 0.696 to 0.786). Excluding the preoperative WBC reduced the area under the ROC curve to 0.737 (95% CI: 0.691 to 0.783). To validate the clinical importance of the WBC effect an additional stepwise logistic regression analysis was carried out only for patients with isolated CABG (n = 5,498; 84 CVAs; CVA rate, 1.5%) in our study population (Table 3). This CVA score identified except for postoperative atrial fibrillation the same independent risk factors: the influence of preoperative WBC on the discriminative ability of the model was even higher in this subgroup (area under the ROC curve: 0.771 [95% CI: 0.716 to 0.826] with preoperative WBC versus 0.761 [95% CI: 0.706 to 0.815] without preoperative WBC). Additionally a stepwise logistic regression analysis was carried out only for patients with stroke (TIA excluded, see Appendix Table 1). This CVA score identified eight independent risk factors including again preoperative WBC: the discriminative ability of this model was good (area under the ROC curve 0.748; 95% CI 0.69 to 0.79).


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  		Table 2. Multivariate Logistic Regression Analysis for Cerebrovascular Accidenta

 

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  		Table 3. Multivariate Logistic Regression for Cerebrovascular Accidenta

 

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  		Table 1. Multivariate Regression Analysis, All Cases (n = 7,483, intercept {alpha} = -7.67), Only for Strokes Excluding Transient Ischemic Attacks

 
Relative risk for CVA depending on different preoperative WBC ranges
Figure 1 shows the WBC histograms for the two groups with and without CVA. For the WBC groups up to 6 x 109/L there was a lower frequency for CVA; for WBC more than 9 x 109/L the CVA frequency was progressively growing. The relative CVA risk for several top percentile ranges of WBC were computed (Table 4). We found a significantly lower relative CVA risk for low preoperative WBC levels (WBC < 6.2 x 109/L), Patients with a preoperative WBC more than 9 x 109/L had a significantly elevated relative risk for perioperative CVA. To capture the clinical relevance we conducted the following "gedankenexperiment." We assumed the underlying causes for elevated preoperative WBC could be treated and WBC could be reduced to an average level (the average level to be reached is the mean of the group without CVA approximately 7 x 109/L (6.7 x 109/L to 7.7 x 109/L)): the number of potentially preventable CVA would be as high as 10%.



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  		Fig 1. White blood cell count (WBC) histograms with and without cerebrovascular accident (CVA), scaled to equal size. The WBC values were truncated (eg, "5" bin indicates the interval [5, 6]) and some bins were aggregated to remain visible. The CVA columns are magnified relative to patients without CVA by the factor 58.86 (equals ratio no-CVA/CVA cases) such that the area sums were equal (the null hypothesis of equal stroke risk would approximately yield columns of pair-wise same size). Gray bars = no CVA; hatched bars = CVA. (Preop. = preoperative.)

 

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  		Table 4. Relative Risk for Cerebrovascular Accident (CVA) Depending on Different Preoperative White Blood Cell Count (WBC) Ranges

 
Analysis of WBC differentiation count
Preoperative differentiation of WBC of patients with CVAs showed significantly higher preoperative granulocyte and "mixed" cell counts. There was a nonsignificant drop in the lymphocyte count. Results are displayed in Table 5.


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  		Table 5. Preoperative Granulocyte, Lymphocyte, and Mixed Cell Count in Patients With and Without Cerebrovascular Accident (CVA) (x 109/L)

 
Clinical manifestation of CVA
CVA was classified as TIA in 10 patients, as RIND in 16 patients, as minor completed stroke in 78 patients, and as major completed stroke in 21 patients. Clinical manifestation of CVA varied significantly with preoperative WBC (p < 0.001 ANOVA; Fig 2). The severity of CVA outcome correlated the level of preoperative WBC. Compared with patients suffering RIND (mean WBC 8.5 ± 2.2 x 109/L SD) or completed strokes (mean WBC for minor completed strokes: 8.7 ± 3.7 x 109/L SD; mean WBC for major completed strokes: 9.3 ± 4.5 x 109/L SD) lower values were measured for patients suffering a TIA (mean WBC: 6.9 ± 0.8 x 109/L SD; p < 0.001; t test). Patients with RIND or TIA had lower values than patients with minor or major strokes (p = 0.012; t test). In patients with TIA, WBC was even lower than in patients without CVA (mean WBC: 7.8 ± 2.7 x 109/L SD; p = 0.005, t test). Mean WBC differences between major versus minor completed strokes were of marginal significance (p = 0.078; t test).



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  		Fig 2. Accumulated frequency diagram for different severity stages of cerebrovascular accident (CVA) (patients without CVA as reference) in relation to preoperative white blood cell count (WBC) 109/L. Solid line = no stroke; fuzzy line = completed stroke; X line = RIND; diamond line = TIA. (Preop. = preoperative; RIND = reversible ischemic neurologic deficit; TIA = transient ischemic attack.)

 
Characteristics of patients according to WBC
A stepwise forward linear regression model showed a very poor impact of evaluated preoperative variables on preoperative WBC (R = 0.176, see Appendix Table 2). There was a low inverse correlation for age, mitral stenosis, and aortic insufficiency. There was a low direct correlation between higher WBC and diabetes, peripheral artery disease, the emergent nature of the operation, postinfarction ventricular septal defect, pulmonary hypertension, and chronic obstructive pulmonary disease (COPD).


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  		Table 2. Factors Correlating Preoperative White Blood Cell Count, Stepwise Linear Regression Analysis (R = 0.176)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Our study confirmed the well-known risk factors for perioperative CVA such as age, history of stroke, preoperative and postoperative atrial fibrillation, carotid stenosis, diabetes, and intraaortic balloon pump [2–4]. In this context, embolism and hypoperfusion as interrelating factors seemed to play a major role [5]. Although hemorheologic factors have also been suspected to play a role in the development of stroke after cardiac surgery the main focus remained the well-known inflammatory response after CPB and its impact on endothelial function [5].

We now have identified a new predictor of stroke occurring during or after cardiac surgery: preoperative WBC. Preoperative WBC remained an independent risk factor also in cases with isolated CABG. The risk for perioperative CVA increased starting at preoperative WBC of 9 x 109/L and progressed in higher WBC ranges. In addition we demonstrated that the level of preoperative WBC strongly correlated with the severity of the stroke outcome.

So far studies of patients with stroke unrelated to cardiac surgery could only demonstrate a correlation between leukocyte count after stroke onset and infarct size or initial stroke severity [16, 17]. Patients with completed stroke showed a significantly higher aggregation of leukocytes than patients with TIA, suggesting that changes in aggregability of leukocytes may play a role in the evolution of the disease [18]. Our finding that the preoperative leukocyte level had an impact on CVA outcome is concordant with animal experiments in rats in which decreased WBC (induced by the antineoplastic agent vinblastine before cerebral ischemia) reduced infarct size and enhanced evoked potentials [6]. Interestingly patients with a TIA had lower preoperative WBC than patients without completed strokes.

In an attempt to establish the possible causes of elevated preoperative WBC we performed a stepwise forward linear regression analysis. The correlation found was too low to exclusively explain the reason for the elevation of WBC. In other studies some of these factors were associated with leukocytosis. Higher WBC in patients with peripheral artery disease possibly reflects the immunoinflammatory nature of arteriosclerosis [19]. A low-grade inflammation with relatively elevated leukocytes, C-reactive protein, and fibrinogen levels was also shown to be associated with both peripheral artery disease and ischemic vascular events [8]. Elevated WBC in diabetic patients is well described and postulated to be caused by microvascular inflammation [20]. In our study, age was inversely correlated with WBC. That is probably an indication of declining immune response with age [21]. Preoperative high WBC may also be caused by myocardial infarction (acute ventricular septal defects) or by emergent operations leading to a stress response [22].

The differentiation of WBC in our patients with stroke showed a significant elevation of neutrophils and probably monocytes. That could be a marker for severe arteriosclerosis [19]. Infections may also cause this elevation of neutrophils and monocytes, an event that could predispose these patients to CVA. Severe preceding infection, either pneumonia or endocarditis, could only be found in 43 patients (0.5%), two of whom suffered a stroke postoperatively. Mild or subclinical infections were not assessed in this study. That may explain why patients with stroke showed an elevated WBC. Both viral and bacterial infections of the respiratory and urinary tract especially have been identified as predisposing risk factors for brain infarction [8–11]. The average time interval between infection and stroke onset was 1 week [10]. Even low-grade inflammation was associated with vascular risk factors and may contribute to the risk of end-organ ischemia [8].

The link between infection and stroke is still not fully understood. The underlying mechanism may be an altered leukocyte rheology causing aggregation that leads to obstruction of small vessels [18]. The release of vasoreactive or cytotoxic mediators could cause injury to endothelial cells further potentiating the ischemic damage [7]. Infections also seem to affect the protein-C pathway and endogenous fibrinolysis leading to a procoagulant state [9]. Elevated systemic C-reactive protein levels associated with chronic periodontal infections could also contribute to the higher risk for stroke in these patients [23]. Furthermore a persistent inflammatory response was found with higher leukocyte and neutrophil levels in stroke survivors. In these cases fibrinogen also remained significantly elevated and was associated with increased risk for recurrent vascular events [24]. That may explain why a previous stroke is one of the major risk factors for stroke after cardiac surgery [2–4].

In several studies COPD, a univariate predictor in our study, was found to be an independent risk factor for stroke after cardiac surgery [2–4]. It was postulated that retained carbon dioxide alters the cerebral vasoregulation and compromises the ability to compensate for embolic events [2, 3]. Prolonged mechanical ventilation in these patients was suspected to cause a decreased cerebral perfusion and hypoxia [3]. Elevated hemoglobin could not be proved to be a possible risk factor for stroke in these patients [4]. In the context of our findings it is also possible that acute exacerbation of chronic obstructive pulmonary disease with elevated WBC may contribute to the development of stroke. In this process elevation of plasma fibrinogen and increased serum interleukin-6 levels have been suspected to be responsible for the increased cardiovascular morbidity and mortality [25].

Additional studies assessing the role of mild or subclinical infections (eg, periodontal, urinary tract, and pulmonary infections) may help to determine whether elevated WBC per se is a risk factor or is but a marker for an underlying condition that causes both elevated WBC and stroke during or after cardiac surgery.

In conclusion we found that a high preoperative WBC was an independent risk factor for CVA during or after cardiac surgery. Additionally, the preoperative WBC was related to CVA outcome. This phenomenon should be further investigated. Patients with a high leukocyte count before cardiac surgery may benefit from treating the underlying cause of the leukocytosis.

Limitations of the study
The actual frequency of CVA may have been underestimated in patients with subtle neurologic deficits. Although we did not assess severity of stroke by using a standardized published stroke scale, our classification was simple and clinically oriented. The role of postoperative leukocytosis was not investigated further because it would have been difficult to interpret. We did not study other variables of infection such as C-reactive protein or fibrinogen levels. Aortic calcification was not assessed by ultrasonography and received proper attention only after 1997. While our study established a correlation between WBC and stroke occurring during or after cardiac surgery, it did not define WBC as being a risk factor per se or as a marker for underlying causes.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We would like to acknowledge the expert assistance of the Department of Perfusion in this study. We thank Mrs Drescher-Rentner and the team of the laboratory for their support.


   Appendix
 


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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  11. Noto D., Barbagallo C.M., Cavera G., et al. Leukocyte count, diabetes mellitus and age are strong predictors of stroke in a rural population in southern Italy: an 8-year follow-up. Atherosclerosis 2001;157:225-231.[Medline]
  12. Struck E., De Vivie E.R., Hehrlein F., et al. Multicentric quality assurance in cardiac surgery. Quadra study of the German Society and Cardiovascular Surgery (QUADRA: quality retrospective analysis). Thorac Cardiovasc Surg 1990;38:123-134.[Medline]
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Preoperative White Blood Cell Count is Independently Associated With Higher Perioperative Cardiac Enzyme Release and Increased 1-Year Mortality After Coronary Artery Bypass Grafting
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