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Leukocyte count: a risk factor for coronary artery bypass graft mortality
BRIEF OBSERVATION
Leukocyte Count: A Risk Factor for Coronary Artery Bypass Graft Mortality Jens Peder Bagger, MD, Dlear Zindrou, MD, Ken M. Taylor, MD
C
hronic low-grade inflammation has been associated with the development of atherosclerosis (1). Accordingly, increased levels of various plasma markers of inflammation, including leukocyte count, have been shown to predict coronary and cerebrovascular events (2,3). However, markers of inflammation are also elevated in the presence of infections, unspecific inflammation, as well as a variety of diseases and conditions (4), and they have been associated with risk factors such as smoking and obesity that may influence outcome in cardiovascular disease (2). The importance of increased levels of inflammatory markers for outcome in relation to a major cardiac intervention is not known. We therefore evaluated the association between a single, preoperative, baseline leukocyte count before coronary artery bypass grafting and operative mortality.
METHODS All patients undergoing isolated coronary artery bypass graft surgery at the Hammersmith Hospital between Jan-
uary 1, 1993, and December 31, 1997, were eligible for the study. Preoperative data included the following: age ⱖ70 years, sex, obesity (body mass index ⬎30 kg/m2), emergent operative priority (cardiovascular instability, including cardiogenic shock), prior coronary artery bypass surgery, prior coronary angioplasty, left ventricular ejection fraction ⬍35%, left main coronary artery disease (ⱖ50% stenosis), disease of three or more major coronary arteries, history of heart failure, recent myocardial infarction (⬍4 weeks), chronic lung disease, and current smoking. We also recorded the presence or absence of unstable angina pectoris, diabetes mellitus, peripheral vascular disease, impaired renal function (serum creatinine level ⱖ1.7 mg/dL, and body surface area. We also noted the use of glucocorticoids because of the reported relation between corticosteroids and leukocyte count (5). Preoperative leukocyte count was stratified into quartiles. A range of 3.2 to 11.0 ⫻ 103/L is reported as normal by our laboratory. Outcome was 30-day mortality. We have previously reported on the operative procedure (6).
Statistical Analysis Differences between groups were evaluated using the t test, Mann-Whitney U test, chi-squared test, or Fisher exact test, as appropriate. Univariate logistic regression tests were used for analysis of predictors of mortality, and variables with a P value ⬍0.2 were included in a forward stepwise multiple logistic regression analysis. Insignificant variables were adjusted for in the final analysis. Odds ratios (OR) are given with 95% confidence intervals (CI).
Table 1. Baseline Characteristics of Patients by Preoperative White Blood Cell Count Quartiles 1 to 3 (ⱕ8.5 ⫻ 103/L) (n ⫽ 1544)
Quartile 4 (ⱖ8.6 ⫻ 103/L) (n ⫽ 514)
P Value
Number (%) or Mean ⫾ SD Age (years) Women Serum creatinine ⱖ1.7 mg/dL Body mass index ⬎30 kg/m2 Body surface area (m2) Current smoking Corticosteroid use Heart failure Unstable angina Respiratory disease Myocardial infarction ⬍4 weeks Peripheral vascular disease Diabetes mellitus Reoperation Prior percutaneous transluminal coronary angioplasty Emergent operative priority Left ventricular ejection fraction ⬍35% Number of diseased coronary arteries Main stem stenosis ⱖ50% 660
© 2003 by Excerpta Medica Inc. All rights reserved.
61.4 ⫾ 9 243 (16) 73 (5) 231 (15) 1.9 ⫾ 0.2 933 (60) 37 (2) 189 (12) 114 (7) 134 (9) 92 (6) 157 (10) 333 (22) 92 (6) 130 (8) 45 (3) 177 (12) 2.8 ⫾ 0.5 16 (1)
59.8 ⫾ 10 92 (18) 44 (9) 96 (19) 1.9 ⫾ 0.2 305 (59) 11 (2) 81 (16) 66 (13) 67 (13) 50 (10) 78 (15) 139 (27) 32 (6) 52 (10) 36 (7) 77 (15) 2.8 ⫾ 0.5 3 (1)
0.01 0.2 0.001 0.05 0.6 0.6 0.7 0.04 ⬍0.001 0.004 0.01 0.002 0.01 0.8 0.2 ⬍0.001 0.04 0.4 0.5
0002-9343/03/$–see front matter doi:10.1016/S0002-9343(03)00438-8
Leukocytes and Coronary Bypass Graft Mortality/Bagger et al
Figure. Mortality by preoperative leukocyte count. P ⬍0.0001 for trend. Numbers in the bars represent median values for white blood cell count; numbers at the top of the bars represent the number of deaths/number of patients. Q ⫽ quartile.
P values ⬍0.05 (two-sided) were regarded as statistically significant. Analyses were performed using the STATA statistics software package (Timberlake Consultants, Kent, United Kingdom).
RESULTS A total of 2058 consecutive patients had isolated coronary artery bypass surgery, of whom 335 were women (Table 1). One patient with chronic lymphatic leukemia was excluded. Mortality increased with leukocyte count (P ⬍0.0001 for trend; Figure). Patients in the highest leukocyte quartile (range, 8.6 to 19.1 ⫻ 103/L) had significantly higher mortality (7.6% [39/514]; 95% CI: 5.5% to 10.2%) than patients in any of the lower quartiles (P ⱕ0.002 for all) and patients in quartiles 1 to 3 combined (2.6% [40/1544]; 95% CI: 1.9% to 3.5%; P ⬍0.0001). After adjustment for body surface area, smoking, and a history of heart failure, respiratory disease, recent myocardial infarction, diabetes mellitus, or peripheral vascular disease, several variables were independently associated with mortality (Table 2), including the number of diseased vessels, emergency operation, serum creatinine level ⱖ1.7 mg/dL, repeat operation, and left ventricular ejection fraction ⬍35%. There was no interaction be-
tween a high leukocyte count and any of the other variables (P ⬎0.05). We then excluded patients with ongoing or recent worsening of heart disease (recent myocardial infarction, unstable angina pectoris, and emergency operation). Among the remaining 1734 patients (including 265 women), mortality increased with leukocyte count (P ⫽ 0.005 for trend). Mortality was higher among patients in the upper quartile (4.4% [19/433]; 95% CI: 2.7% to 6.8%) than among those in the lower three quartiles (2.1% [27/1301]; 95% CI: 1.4% to 3.0%; P ⫽ 0.009), and the upper quartile white blood cell count (range, 8.5 to 18.9 ⫻ 103/L) was independently associated with mortality (OR ⫽ 2.2; 95% CI: 1.2 to 4.2; P ⫽ 0.01). We further excluded patients with a history of heart failure, noncardiac diseases known to be associated with elevated leukocyte count (diabetes mellitus, respiratory disease, obesity, impaired kidney function), and corticosteroid use. Among the remaining 924 patients (including 109 women), mortality increased with leukocyte count (P ⫽ 0.04 for trend), with the highest mortality observed among patients in the upper leukocyte quartile (4.3% [10/231]; 95% CI: 2.1% to 7.8%) as compared with those in quartiles 1 to 3 (1.6% [11/693]; 95% CI: 0.8% to 2.8%; P ⫽ 0.02). A high white blood cell count (range, 8.4 to 18.9 ⫻ 103/L) remained independently
December 1, 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 115 661
Leukocytes and Coronary Bypass Graft Mortality/Bagger et al
Table 2. Variables Associated with 30-Day Mortality* (n ⫽ 2058) Variable Age (years) ⬍70 ⱖ70 White blood cell count Quartile 1 to 3 Quartile 4 Sex Male Female Left ventricular ejection fraction ⱖ35% ⬍35% Reoperation No Yes Serum creatinine ⬍1.7 mg/dL ⱖ1.7 mg/dL Emergent operative priority No Yes Number of diseased vessels ⬍3 ⱖ3
No. of Deaths/ No. of Patients (%)
Odds Ratio (95% Confidence Interval)
48/1671 (2.9) 31/387 (8.0)
1 2.2 (1.3–3.7)
40/1544 (2.6) 39/514 (7.6)
1 2.2 (1.3–3.6)
52/1723 (3.0) 27/335 (8.1)
1 2.8 (1.5–5.3)
49/1804 (2.7) 30/254 (12)
1 3.1 (1.8–5.3)
67/1934 (3.5) 12/124 (9.7)
1 3.8 (1.9–7.8)
60/1941 (3.1) 19/117 (16)
1 4.4 (2.4–8.2)
62/1977 (3.1) 17/81 (21)
1 4.7 (2.2–9.8)
3/395 (0.8) 76/1663 (4.6)
1 5.1 (1.5–16.9)
P Value 0.003
0.002
0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
0.008
* Adjusted for body surface area, history of heart failure, respiratory disease, smoking, recent myocardial infarction, diabetes mellitus, and peripheral vascular disease.
associated with mortality (OR ⫽ 3.1; 95% CI: 1.2 to 7.8; P ⫽ 0.02).
DISCUSSION Our study showed that mortality increased with leukocyte count in both the entire study sample and in subgroups of patients after the exclusion of acute coronary syndromes and noncardiac diseases known to be associated with an elevated white blood cell count. Mortality was much higher among patients in the upper leukocyte quartile as compared with all of the lower leukocyte quartiles. Moreover, a leukocyte count in the upper quartile was independently associated with mortality in all patients. Thus, a cutoff level of 8.4 ⫻ 103/L identified patients from all groups who had increased mortality after coronary artery bypass surgery. This value is well within the normal leukocyte range in our laboratory. The other variables that were independently associated with mortality after bypass surgery are well-established risk factors (7,8). We found, as expected, a significantly higher prevalence of acute coronary syndromes (recent myocardial infarction, unstable angina, and emergency operation) among patients in the upper leukocyte quartile. Similarly, 662
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THE AMERICAN JOURNAL OF MEDICINE威
impaired kidney function, diabetes mellitus, heart failure, and respiratory disease were more common among patients with leukocyte counts in the upper quartile. These cardiac and noncardiac diseases may explain the elevated leukocyte count and the markedly high mortality among these patients. There is no obvious explanation for the relation between mortality and an elevated leukocyte count in the remaining patients in whom the most likely confounders were adjusted. An increased leukocyte count is a nonspecific response to a variety of injuries (4). Thus, an increased number of circulating leukocytes could be the result of hematological diseases, persistent infections, malignant disease, lowgrade systemic inflammation, silent myocardial ischemia, and steroid treatment (4,5). We excluded 1 patient with known leukemia and we were not aware of ongoing infections or malignant disease at the time of the operation. The use of corticosteroids was similar among patients with normal and above normal leukocyte levels, and preoperative monitoring of patients to evaluate the presence of silent myocardial ischemia is nowhere a routine precaution. We do not know whether pain and emotional stress among patients awaiting surgery resulted in an increased catecholamine surge and increased leuko-
Volume 115
Leukocytes and Coronary Bypass Graft Mortality/Bagger et al
cyte levels (4,9), which would have likely influenced outcomes. It has been suggested that a high leukocyte count itself may lead to myocardial injury by plugging of microvascular vessels and by activation of and contribution to thrombus formation (10 –12). Furthermore, leukocytes may release cytotoxic substances and participate in reperfusion injury (13,14). Previous studies have shown that a high leukocyte count is an independent predictor of outcome in cohort studies and in patients with stable angina or acute coronary syndromes (15–17). Moreover, it has been hypothesized that patients with high levels of inflammatory markers and increased thrombotic activity may particularly benefit from an invasive strategy (anti-inflammatory effect of revascularization) (18). We used only one preoperative measurement of leukocyte count, which may have been a major limitation to this study. Serial measurements would be needed to adjust for acute fluctuations of individual leukocyte levels. This might have played a role in acutely ill patients but probably not in those with stable disease and a low prevalence of comorbid conditions. In conclusion, a leukocyte count in the upper quartile was independently associated with 30-day mortality after coronary artery bypass grafting in this consecutive series of patients. We observed that an increased leukocyte level was associated with mortality even among patients with stable disease and minimal comorbidity, which suggests that an elevated preoperative leukocyte count may be regarded as a general marker of operative risk in relation to coronary artery bypass grafting in both patients with established risk factors as well as those without known risk factors who are at a higher risk after the procedure.
REFERENCES 1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–126. 2. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998; 279:1477–1482. 3. Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001;104:1336 –1342.
4. Dale DC. Neutropenia and neutrophilia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams Hematology. 6th ed. New York, New York: McGraw-Hill; 2001:823–834. 5. Crockard AD, Boylan MT, Droogan AG, et al. Methylprednisolone-induced neutrophil leukocytosis— down-modulation of neutrophil L-selectin and Mac-1 expression and induction of granulocyte colony-stimulating factor. Int J Clin Lab Res. 1998;28:110 –115. 6. Zindrou D, Taylor KM, Bagger JP. Comparison of operative mortality after coronary artery bypass grafting in Indian Subcontinent Asians versus Caucasians. Am J Cardiol. 2001;88:313–316. 7. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA guidelines for coronary artery bypass graft surgery: executive summary and recommendations. Circulation. 1999;100:1464 –1480. 8. O’Connor GT, Plume SK, Olmstead EM, et al. A regional intervention to improve the hospital mortality associated with coronary artery bypass graft surgery. The Northern England Cardiovascular Disease Study Group. JAMA. 1996;275:841–846. 9. Benschop RJ, Rodriguez-Feuerhahn M, Schedlowski M. Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain Behav Immun. 1996;10:77–91. 10. Engler RL, Schmid-Schonbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol. 1983;111:98 –111. 11. Barron HV, Cannon CP, Murphy A, Braunwald E, Gibson CM. Association between white blood cell count, epicardial blood flow, myocardial perfusion, and clinical outcomes in the setting of acute myocardial infarction. Circulation. 2000;102:2329 –2334. 12. Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation. 2001;103:1718 –1720. 13. Ernst E, Hammersmidt DE, Bagge U, et al. Leukocytes and the risk of ischemic diseases. JAMA. 1987;257:2318 –2324. 14. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985;76:1713–1719. 15. Brown DW, Giles WH, Croft JB. White blood cell count: an independent predictor of coronary heart disease mortality among a national cohort. J Clin Epidemiol. 2001;54:316 –322. 16. Held C, Hjemdahl P, Wallen NH, et al. Inflammatory and hemostatic markers in relation to cardiovascular prognosis in patients with stable angina pectoris. Results from the APSIS study. Atherosclerosis. 2000;148:179 –188. 17. Sabatine MS, Morrow DA, Cannon CP, et al. Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes. J Am Coll Cardiol. 2002;40:1761–1768. 18. Diegeler A, Doll N, Rauch T, et al. Humoral immune response during coronary artery bypass grafting. A comparison of limited approach, “off-pump” technique, and conventional cardiopulmonary bypass. Circulation. 2000;102(suppl III):95–100. From Imperial College, and Cardiothoracic Directorate, Hammersmith Hospital, London, United Kingdom. Requests for reprints should be addressed to Jens Peder Bagger, MD, Cardiothoracic Directorate, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom, or [email protected] Manuscript submitted January 10, 2003, and accepted in revised form June 23, 2003.
December 1, 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 115 663
Leukocyte Count: A Risk Factor for Coronary Artery Bypass Graft Mortality Jens Peder Bagger, MD, Dlear Zindrou, MD, Ken M. Taylor, MD
C
hronic low-grade inflammation has been associated with the development of atherosclerosis (1). Accordingly, increased levels of various plasma markers of inflammation, including leukocyte count, have been shown to predict coronary and cerebrovascular events (2,3). However, markers of inflammation are also elevated in the presence of infections, unspecific inflammation, as well as a variety of diseases and conditions (4), and they have been associated with risk factors such as smoking and obesity that may influence outcome in cardiovascular disease (2). The importance of increased levels of inflammatory markers for outcome in relation to a major cardiac intervention is not known. We therefore evaluated the association between a single, preoperative, baseline leukocyte count before coronary artery bypass grafting and operative mortality.
METHODS All patients undergoing isolated coronary artery bypass graft surgery at the Hammersmith Hospital between Jan-
uary 1, 1993, and December 31, 1997, were eligible for the study. Preoperative data included the following: age ⱖ70 years, sex, obesity (body mass index ⬎30 kg/m2), emergent operative priority (cardiovascular instability, including cardiogenic shock), prior coronary artery bypass surgery, prior coronary angioplasty, left ventricular ejection fraction ⬍35%, left main coronary artery disease (ⱖ50% stenosis), disease of three or more major coronary arteries, history of heart failure, recent myocardial infarction (⬍4 weeks), chronic lung disease, and current smoking. We also recorded the presence or absence of unstable angina pectoris, diabetes mellitus, peripheral vascular disease, impaired renal function (serum creatinine level ⱖ1.7 mg/dL, and body surface area. We also noted the use of glucocorticoids because of the reported relation between corticosteroids and leukocyte count (5). Preoperative leukocyte count was stratified into quartiles. A range of 3.2 to 11.0 ⫻ 103/L is reported as normal by our laboratory. Outcome was 30-day mortality. We have previously reported on the operative procedure (6).
Statistical Analysis Differences between groups were evaluated using the t test, Mann-Whitney U test, chi-squared test, or Fisher exact test, as appropriate. Univariate logistic regression tests were used for analysis of predictors of mortality, and variables with a P value ⬍0.2 were included in a forward stepwise multiple logistic regression analysis. Insignificant variables were adjusted for in the final analysis. Odds ratios (OR) are given with 95% confidence intervals (CI).
Table 1. Baseline Characteristics of Patients by Preoperative White Blood Cell Count Quartiles 1 to 3 (ⱕ8.5 ⫻ 103/L) (n ⫽ 1544)
Quartile 4 (ⱖ8.6 ⫻ 103/L) (n ⫽ 514)
P Value
Number (%) or Mean ⫾ SD Age (years) Women Serum creatinine ⱖ1.7 mg/dL Body mass index ⬎30 kg/m2 Body surface area (m2) Current smoking Corticosteroid use Heart failure Unstable angina Respiratory disease Myocardial infarction ⬍4 weeks Peripheral vascular disease Diabetes mellitus Reoperation Prior percutaneous transluminal coronary angioplasty Emergent operative priority Left ventricular ejection fraction ⬍35% Number of diseased coronary arteries Main stem stenosis ⱖ50% 660
© 2003 by Excerpta Medica Inc. All rights reserved.
61.4 ⫾ 9 243 (16) 73 (5) 231 (15) 1.9 ⫾ 0.2 933 (60) 37 (2) 189 (12) 114 (7) 134 (9) 92 (6) 157 (10) 333 (22) 92 (6) 130 (8) 45 (3) 177 (12) 2.8 ⫾ 0.5 16 (1)
59.8 ⫾ 10 92 (18) 44 (9) 96 (19) 1.9 ⫾ 0.2 305 (59) 11 (2) 81 (16) 66 (13) 67 (13) 50 (10) 78 (15) 139 (27) 32 (6) 52 (10) 36 (7) 77 (15) 2.8 ⫾ 0.5 3 (1)
0.01 0.2 0.001 0.05 0.6 0.6 0.7 0.04 ⬍0.001 0.004 0.01 0.002 0.01 0.8 0.2 ⬍0.001 0.04 0.4 0.5
0002-9343/03/$–see front matter doi:10.1016/S0002-9343(03)00438-8
Leukocytes and Coronary Bypass Graft Mortality/Bagger et al
Figure. Mortality by preoperative leukocyte count. P ⬍0.0001 for trend. Numbers in the bars represent median values for white blood cell count; numbers at the top of the bars represent the number of deaths/number of patients. Q ⫽ quartile.
P values ⬍0.05 (two-sided) were regarded as statistically significant. Analyses were performed using the STATA statistics software package (Timberlake Consultants, Kent, United Kingdom).
RESULTS A total of 2058 consecutive patients had isolated coronary artery bypass surgery, of whom 335 were women (Table 1). One patient with chronic lymphatic leukemia was excluded. Mortality increased with leukocyte count (P ⬍0.0001 for trend; Figure). Patients in the highest leukocyte quartile (range, 8.6 to 19.1 ⫻ 103/L) had significantly higher mortality (7.6% [39/514]; 95% CI: 5.5% to 10.2%) than patients in any of the lower quartiles (P ⱕ0.002 for all) and patients in quartiles 1 to 3 combined (2.6% [40/1544]; 95% CI: 1.9% to 3.5%; P ⬍0.0001). After adjustment for body surface area, smoking, and a history of heart failure, respiratory disease, recent myocardial infarction, diabetes mellitus, or peripheral vascular disease, several variables were independently associated with mortality (Table 2), including the number of diseased vessels, emergency operation, serum creatinine level ⱖ1.7 mg/dL, repeat operation, and left ventricular ejection fraction ⬍35%. There was no interaction be-
tween a high leukocyte count and any of the other variables (P ⬎0.05). We then excluded patients with ongoing or recent worsening of heart disease (recent myocardial infarction, unstable angina pectoris, and emergency operation). Among the remaining 1734 patients (including 265 women), mortality increased with leukocyte count (P ⫽ 0.005 for trend). Mortality was higher among patients in the upper quartile (4.4% [19/433]; 95% CI: 2.7% to 6.8%) than among those in the lower three quartiles (2.1% [27/1301]; 95% CI: 1.4% to 3.0%; P ⫽ 0.009), and the upper quartile white blood cell count (range, 8.5 to 18.9 ⫻ 103/L) was independently associated with mortality (OR ⫽ 2.2; 95% CI: 1.2 to 4.2; P ⫽ 0.01). We further excluded patients with a history of heart failure, noncardiac diseases known to be associated with elevated leukocyte count (diabetes mellitus, respiratory disease, obesity, impaired kidney function), and corticosteroid use. Among the remaining 924 patients (including 109 women), mortality increased with leukocyte count (P ⫽ 0.04 for trend), with the highest mortality observed among patients in the upper leukocyte quartile (4.3% [10/231]; 95% CI: 2.1% to 7.8%) as compared with those in quartiles 1 to 3 (1.6% [11/693]; 95% CI: 0.8% to 2.8%; P ⫽ 0.02). A high white blood cell count (range, 8.4 to 18.9 ⫻ 103/L) remained independently
December 1, 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 115 661
Leukocytes and Coronary Bypass Graft Mortality/Bagger et al
Table 2. Variables Associated with 30-Day Mortality* (n ⫽ 2058) Variable Age (years) ⬍70 ⱖ70 White blood cell count Quartile 1 to 3 Quartile 4 Sex Male Female Left ventricular ejection fraction ⱖ35% ⬍35% Reoperation No Yes Serum creatinine ⬍1.7 mg/dL ⱖ1.7 mg/dL Emergent operative priority No Yes Number of diseased vessels ⬍3 ⱖ3
No. of Deaths/ No. of Patients (%)
Odds Ratio (95% Confidence Interval)
48/1671 (2.9) 31/387 (8.0)
1 2.2 (1.3–3.7)
40/1544 (2.6) 39/514 (7.6)
1 2.2 (1.3–3.6)
52/1723 (3.0) 27/335 (8.1)
1 2.8 (1.5–5.3)
49/1804 (2.7) 30/254 (12)
1 3.1 (1.8–5.3)
67/1934 (3.5) 12/124 (9.7)
1 3.8 (1.9–7.8)
60/1941 (3.1) 19/117 (16)
1 4.4 (2.4–8.2)
62/1977 (3.1) 17/81 (21)
1 4.7 (2.2–9.8)
3/395 (0.8) 76/1663 (4.6)
1 5.1 (1.5–16.9)
P Value 0.003
0.002
0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
0.008
* Adjusted for body surface area, history of heart failure, respiratory disease, smoking, recent myocardial infarction, diabetes mellitus, and peripheral vascular disease.
associated with mortality (OR ⫽ 3.1; 95% CI: 1.2 to 7.8; P ⫽ 0.02).
DISCUSSION Our study showed that mortality increased with leukocyte count in both the entire study sample and in subgroups of patients after the exclusion of acute coronary syndromes and noncardiac diseases known to be associated with an elevated white blood cell count. Mortality was much higher among patients in the upper leukocyte quartile as compared with all of the lower leukocyte quartiles. Moreover, a leukocyte count in the upper quartile was independently associated with mortality in all patients. Thus, a cutoff level of 8.4 ⫻ 103/L identified patients from all groups who had increased mortality after coronary artery bypass surgery. This value is well within the normal leukocyte range in our laboratory. The other variables that were independently associated with mortality after bypass surgery are well-established risk factors (7,8). We found, as expected, a significantly higher prevalence of acute coronary syndromes (recent myocardial infarction, unstable angina, and emergency operation) among patients in the upper leukocyte quartile. Similarly, 662
December 1, 2003
THE AMERICAN JOURNAL OF MEDICINE威
impaired kidney function, diabetes mellitus, heart failure, and respiratory disease were more common among patients with leukocyte counts in the upper quartile. These cardiac and noncardiac diseases may explain the elevated leukocyte count and the markedly high mortality among these patients. There is no obvious explanation for the relation between mortality and an elevated leukocyte count in the remaining patients in whom the most likely confounders were adjusted. An increased leukocyte count is a nonspecific response to a variety of injuries (4). Thus, an increased number of circulating leukocytes could be the result of hematological diseases, persistent infections, malignant disease, lowgrade systemic inflammation, silent myocardial ischemia, and steroid treatment (4,5). We excluded 1 patient with known leukemia and we were not aware of ongoing infections or malignant disease at the time of the operation. The use of corticosteroids was similar among patients with normal and above normal leukocyte levels, and preoperative monitoring of patients to evaluate the presence of silent myocardial ischemia is nowhere a routine precaution. We do not know whether pain and emotional stress among patients awaiting surgery resulted in an increased catecholamine surge and increased leuko-
Volume 115
Leukocytes and Coronary Bypass Graft Mortality/Bagger et al
cyte levels (4,9), which would have likely influenced outcomes. It has been suggested that a high leukocyte count itself may lead to myocardial injury by plugging of microvascular vessels and by activation of and contribution to thrombus formation (10 –12). Furthermore, leukocytes may release cytotoxic substances and participate in reperfusion injury (13,14). Previous studies have shown that a high leukocyte count is an independent predictor of outcome in cohort studies and in patients with stable angina or acute coronary syndromes (15–17). Moreover, it has been hypothesized that patients with high levels of inflammatory markers and increased thrombotic activity may particularly benefit from an invasive strategy (anti-inflammatory effect of revascularization) (18). We used only one preoperative measurement of leukocyte count, which may have been a major limitation to this study. Serial measurements would be needed to adjust for acute fluctuations of individual leukocyte levels. This might have played a role in acutely ill patients but probably not in those with stable disease and a low prevalence of comorbid conditions. In conclusion, a leukocyte count in the upper quartile was independently associated with 30-day mortality after coronary artery bypass grafting in this consecutive series of patients. We observed that an increased leukocyte level was associated with mortality even among patients with stable disease and minimal comorbidity, which suggests that an elevated preoperative leukocyte count may be regarded as a general marker of operative risk in relation to coronary artery bypass grafting in both patients with established risk factors as well as those without known risk factors who are at a higher risk after the procedure.
REFERENCES 1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–126. 2. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998; 279:1477–1482. 3. Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001;104:1336 –1342.
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December 1, 2003
THE AMERICAN JOURNAL OF MEDICINE威
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