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Ann Thorac Surg 1999;67:134-138
© 1999 The Society of Thoracic Surgeons

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Original Articles

Increased preoperative C-reactive protein plasma levels as a risk factor for postoperative infections

^a Department of Cardiopulmonary Surgery, University Hospital Maastricht, Maastricht, The Netherlands
^b Department of Clinical Chemistry, University Hospital Maastricht, Maastricht, the Netherlands

Accepted for publication June 25, 1998.

Address reprint requests to Dr Maessen, Department of Cardiopulmonary Surgery, University Hospital Maastricht, P. Debyelaan 25, 6202 AZ Maastricht, the Netherlands
e-mail: jma{at}scpc.azm.nl

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. We examined the possible predictive role of preoperative C-reactive protein (CRP) levels for postoperative infections in patients who have cardiac operations.

Methods. CRP levels were determined on the day before the operation and on postoperative days 1 to 4 and 6 in 593 consecutive patients. Furthermore, we documented infectious disease-related data.

Results. Patients in whom an infection developed during the postoperative course (n = 87) had significantly higher CRP levels on the day before operation (17.8 ± 3.9 mg/L compared with 7.7 ± 0.7 mg/L; p < 0.001) and on postoperative days 4 and 6. The incidence of postoperative infections was significantly higher in patients with increased preoperative CRP levels than in those with normal preoperative CRP levels (25.3% versus 11.2%, respectively; p < 0.001). Furthermore, patients with higher preoperative CRP levels had a significantly longer postoperative hospital stay than those with normal preoperative CRP levels (10.8 ± 1.2 days versus 7.8 ± 0.3 days; p < 0.001). Multivariate analysis, including classic risk factors and increased preoperative CRP levels, demonstrated that higher preoperative CRP was the most important variable predicting postoperative infection (odds ratio = 2.7; 95% confidence interval = 1.7 to 4.3; p < 0.001).

Conclusions. Patients with higher preoperative CRP levels are at increased risk for postoperative infections. Therefore, preoperative measurement of CRP might be a useful, predictive marker in risk stratification for postoperative infections in patients scheduled for cardiac operations.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
C-reactive protein (CRP), the prototypical acute-phase reactant in humans, is a sensitive, although nonspecific, marker of inflammation. Circulating plasma levels of CRP were shown to be increased in a variety of clinical and pathologic situations [1, 2]. In some patients with angina pectoris, increased CRP levels were demonstrated recently [3]. Because these patients are potential candidates for cardiac operation, some patients will be operated on with preoperatively increased CRP levels. Postoperatively increased CRP levels in cardiac surgical patients have been shown to correlate with the incidence of infections [4–6]. However, whether there is a relationship between preoperatively increased CRP levels and postoperative infection has yet to be established.

Although CRP measurements have been used for early detection of postoperative complications, preoperative CRP levels have not been used as a risk factor for postoperative complications. The impact of higher preoperative CRP levels on the incidence of postoperative infections in patients who have cardiac operations is therefore unknown. Because infections are important determinants of morbidity and mortality in these patients [7], markers identifying patients at risk for postoperative infections are valuable for risk stratification. We hypothesized that patients with higher preoperative CRP levels are at increased risk for the development of postoperative infections.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Study population
We studied 593 consecutive patients who had cardiac operations. None of the patients had clinical signs of infection preoperatively. All operations were performed by members of the attending staff of the Department of Cardiopulmonary Surgery. The study was approved by the local ethical and research council and performed according to their rules.

Intraoperative procedures
Standard anesthetic (lorazepam, fentanyl citrate, sufentanil citrate, alfentanil hydrochloride, midazolam hydrochloride, pancuronium bromide) and monitoring techniques (electrocardiogram, central venous or pulmonary and arterial pressure monitoring, urinary output, rectal and skin temperature monitoring) were used. Before connection of the extracorporeal circuit for cardiopulmonary bypass (CPB), heparin was administered (300 IU/kg, Heparin Leo; Leo Pharmaceutical Products BV, Weesp, The Netherlands) to achieve an activated coagulation time greater than 480 seconds (Hemochron 400; International Technidyne Corp, Edison, NJ). Specifications on the extracorporeal circulation circuit, CPB procedures, and surgical procedures have been described previously [8]. Postoperative patient treatment in the coronary care unit was standardized and similar for all patients.

Clinical data
The following variables were recorded: age, sex, angina pectoris type (stable versus unstable), diabetes mellitus, preoperative use of intraaortic balloon pump, type of procedure, CPB time, aortic cross-clamp time, incidence of postoperative infection, length of postoperative hospitalization, and death.

Definitions for infections were derived from Garner and associates [9]. Infectious disease-related data, including reports of microbiologic studies, were recorded in the central automation program of our department.

Measurements
Blood samples were taken on the day before operation and daily on postoperative days 1 to 4 and 6. All samples were collected in Corvac integrated serum separator tubes (10 mL; Corvac, Sherwood Medical, St. Louis, MO). The CRP concentrations were measured using a turbidimetric method. A CRP reagent (Beckman test kit number 445855), in conjunction with the Synchron CX Systems CX CRP Calibrator Set (Beckman, number 445915; Beckman Instruments, Inc, Brea, CA) was used for the quantitative determination of CRP in serum. The normal reference value from 50 healthy volunteers in our hospital was 4.8 ± 0.4 mg/L.

Data analysis
All data are presented as mean ± standard error of the mean. Student’s t test for independent samples was used for comparisons between two variables at the same time point. A Wilcoxon matched-pairs signed-ranks test was used for comparisons of values from one variable between two time points. A ² test was used to test nonnumeric variables. Independent predictive value of each variable was assessed by multiple regression analysis. The level of significance was set at p less than 0.05.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Patients
A total of 593 consecutive patients who had cardiac operations were evaluated. The mean age of the patients was 63 ± 0.4 years (range, 28 to 84 years); 409 (69%) patients were men and 184 (31%) patients were women. The surgical procedures included 443 (74.7%) coronary artery bypass grafting operations, 86 (14.5%) valve operations, 48 (8.1%) combined coronary artery bypass grafting and valve operations, and 16 (2.7%) miscellaneous cardiac operations. Mean duration of cardiopulmonary bypass was 95 ± 2 minutes, and mean duration of aortic cross-clamp time was 61 ± 1 minutes. Only 7 patients had a preoperatively introduced intraaortic balloon pump; therefore, this variable was not used in statistical analyses.

C-reactive protein levels
On the day before operation, the mean CRP level was 9.4 ± 0.8 mg/L (median value, 3 mg/L). Cardiac operations induced a sharp increase in CRP levels to 80.9 ± 1.4 mg/L on the first postoperative day. CRP levels peaked on the third postoperative day (203.4 ± 8.7 mg/L) and declined thereafter toward postoperative day 6 (77.9 ± 2.8 mg/L).

Postoperative infections
According to our definitions, 87 (14.7%) patients developed at least one postoperative infection. Infections included pulmonary infections, urinary tract infections, sternal wound infections, surgical wound infections, sepsis, or a combination of these. Patients with an infection during the postoperative course had significantly higher preoperative CRP levels, 17.8 ± 3.9 mg/L compared with 7.7 ± 0.7 mg/L in patients who did not have a postoperative infection (p < 0.001) (Fig 1). Furthermore, CRP levels in patients who had an infection were significantly higher on day 4 (173.4 ± 8 versus 137.3 ± 2.8 mg/L, p < 0.001) and on day 6 (116.5 ± 7.8 versus 67.7 ± 2.4 mg/L, p < 0.001) (Fig 1). Patients who had an infection had a significantly longer postoperative hospital stay than patients without an infection (19.4 ± 2.2 versus 6.9 ± 0.2 days) (p < 0.001). In the total patient group, 10 (1.7%) patients died during hospitalization, all of whom had at least one infection.

View larger version (15K): [in this window] [in a new window]   Fig 1. Mean plasma levels of C-reactive protein (CRP) in cardiac surgical patients with an infection during the postoperative course (filled bars) and patients who did not develop an infection during the postoperative course (open bars). Data are presented as mean ± standard error. *p < 0.05, between groups. (PRE = the day before the operation.)

View larger version (15K): [in this window] [in a new window]   Fig 2. Mean plasma levels of C-reactive protein in cardiac surgical patients with enhanced preoperative C-reactive protein (CRP) levels (>8 mg/L, filled bars) and patients with normal preoperative CRP levels (8 mg/L, open bars). Data are presented as mean ± standard error. *p < 0.05, between groups. (PRE = the day before the operation.)

The odds ratios for possible risk factors of postoperative infections are shown in Table 2. Multivariate analysis including the variables preoperative CRP ( or >8 mg/L), CPB duration ( or >112 minutes, third quartile), advanced age ( or >72 years, third quartile), sex, diabetes mellitus, and unstable angina demonstrated that a preoperatively increased CRP concentration was the most important independent variable predicting postoperative infection (odds ratio = 2.7; 95% confidence interval = 1.7 to 4.3) (p = 0.001) (Table 2).

The mortality rate in patients with increased preoperative CRP levels (2.7%) was not significantly different from that in patients with normal preoperative CRP levels (1.3%) (Table 1).

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
In the present study we demonstrated that patients with increased CRP levels on the day before operation are at increased risk for postoperative infections. Our data indicate that preoperative CRP levels might be useful as a predictive marker in risk stratification for postoperative infections in patients scheduled for cardiac operations.

Potential mechanisms of increased preoperative C-reactive protein plasma levels
C-reactive protein has many biologic activities related to nonspecific host defense. It acts as an opsonin for bacteria, parasites, and immune complexes and can activate the classic pathway of complement [10]. Increased CRP levels reflect cytokine-mediated hepatic response triggered by an inflammatory stimulus. The underlying stimulus for the preoperatively increased CRP levels in patients in the present study is not known. As mentioned before, patients did not show clinical signs of inflammation, yet CRP levels were increased in many of them. Recently it was shown that increased levels of CRP in adults with neutropenia preceded the clinical diagnosis of a subsequently demonstrable infection [11]. Therefore, some of our patients with increased CRP levels on the day before operation might have had unsuspected infection. It has also been shown that in patients with acute myocardial infarction, mediators of the acute phase response (eg, interleukin-6) are increased for 4 weeks or more [12]. Therefore, it cannot be ruled out that in some patients CRP levels were increased as a result of a myocardial infarction in the month preceding the operation. More recently it was shown that in patients with unstable angina, CRP levels are increased as a result of active atherosclerotic lesions [13]. Other studies showed that increased circulating CRP concentrations are predictive of coronary events in patients with stable as well as unstable angina [3, 14]. Therefore, in patients with coronary heart disease, increased CRP levels might reflect inflammation of the arteries that is associated with changes in plaque morphology, rupture, and thrombosis. Furthermore, long-term activation of immune cells has been linked to atherogenesis and progression of atherosclerosis [15]. Recently, we showed that inflammatory processes are activated in patients with heart failure and are related directly to the severity of heart failure [16]. The severity of heart failure and the stage of decompensation have also been related to CRP [17], which might explain some of the variance in our preoperative CRP data.

The inflammatory response to cardiac operations
The inflammatory response to surgical procedures has been described in numerous studies. Remarkably, this response has been shown to be identical for all kinds of surgical interventions, including cardiac operations, joint replacement, gastric restrictive operations, various types of abdominal operations, and abdominal aortic aneurysm repair [1, 2, 18]. In patients with serious trauma it was shown that the acute inflammatory response to trauma and not the severity of injury is the important determinant of outcome [19]. Until now, CRP analyses were used in the diagnosis of an infective complication only after the operation [1]. One study of a small number of patients found that preoperative plasma CRP levels are increased in patients who develop an infection during the postoperative course [5]. Other studies also showed that postoperative CRP levels are increased in patients who develop an infection but were unable to demonstrate a predictive value of preoperative CRP levels [6], possibly because of the small sample size. In the present study, however, we showed not only that preoperative CRP levels in patients who have cardiac operations are increased in patients who develop an infection during the postoperative course, but also that this higher preoperative CRP level is the most important predictor of postoperative infective complications among classic risk factors of infection, including advanced age, female sex, diabetes mellitus, and duration of cardiopulmonary bypass [20–22].

We suggest that the preoperative balance between proinflammatory reactions and antiinflammatory reactions is important in determining the extent of the inflammatory response and the clinical outcome after cardiac operations. In low-risk patients who have coronary artery bypass grafting, markers of immune cell activation (eg, interleukin-2) were shown to be decreased perioperatively probably as a result of reduced production [23]. In addition, both proinflammatory and antiinflammatory cytokines are increased in response to surgical procedures [24]. The extent of the inflammatory response is not only determined by the surgical procedure, but also by intrinsic patient factors, such as genetic susceptibility and premorbid health. Our data show that patients with preoperatively increased CRP levels had significantly higher CRP levels on postoperative days 1 to 4, and 6 (p < 0.001 at all timepoints). This finding indicates that preoperative CRP levels determined the increase in postoperative CRP levels. Furthermore, it is known that the ability of a cell to synthesize proinflammatory and antiinflammatory mediators is influenced by its previous state [25]. Therefore, we suggest that in patients with preoperatively increased CRP levels who have cardiac operations, preexisting chronically activated immune cells or chronically activated inflammation might result in an inadequate response to the short-term release of proinflammatory mediators induced by the operation. Consequently, in the perioperative period the immune system is deregulated and these patients are at increased risk for developing infections.

In the present study we showed that preoperatively increased CRP levels are associated with an increased risk of postoperative infections. We retrospectively created two groups of patients based on preoperative CRP plasma levels according to the method of Tracey and colleagues [3]. Consequently, neither patient group was matched for other variables, such as age and unstable angina. However, when these variables were included in a multiple regression analysis together with normal or increased preoperative CRP levels, preoperatively increased CRP plasma concentration was found to be the most important independent variable predicting postoperative infection.

Future studies should focus on identifying the underlying stimulus for the preoperatively increased CRP levels in patients who have cardiac operations. These higher preoperative CRP levels might reflect subclinical disease and an enhanced proinflammatory state. We conclude that preoperative measurement of CRP is a valuable predictive marker in risk stratification for postoperative infections in patients scheduled for cardiac operations.

	References

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