1 Department of Anaesthesiology and Intensive Care Unit, 2 Biology Laboratory and 3 Department of Surgery, Institut Paoli-Calmettes, 232 Boulevard Sainte Marguerite, 13273 Marseille Cedex 9, France
* Corresponding author. E-mail: mokartd{at}marseille.fnclcc.fr
Accepted for publication March 15, 2005.
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Abstract |
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Methods. Serial blood samples were collected from 50 consecutive patients for determination of IL-6, PCT and CRP serum levels. Blood samples were obtained on the morning of surgery and on the morning of the first postoperative day.
Results. Sixteen patients developed septic complications during the first five postoperative days (group 1), and 34 patients developed no septic complications (group 2). On day 1, PCT and IL-6 levels were significantly higher in group 1 (P-values of 0.003 and 0.006, respectively) but CRP levels were similar. An IL-6 cut-off point set at 310 pg ml1 yielded a sensitivity of 90% and a specificity of 58% to differentiate group 1 patients from group 2 patients. When associated with the occurrence of SIRS on day 1 these values reached 100% and 79%, respectively. A PCT cut-off point set at 1.1 ng ml1 yielded a sensitivity of 81% and a specificity of 72%. When associated with the occurrence of SIRS on day 1, these values reached 100% and 86%, respectively.
Conclusions. PCT and IL-6 appear to be early markers of subsequent postoperative sepsis in patients undergoing major surgery for cancer. These findings could allow identification of postoperative septic complications.
Keywords: complications, sepsis ; complications, SIRS ; polypeptides, cytokines, interleukin 6 ; protein, procalcitonin ; surgery
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Introduction |
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Patients and methods |
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Blood sampling
Blood samples were collected in glass tubes before surgery (day 0) and then postoperatively on the morning of day 1. Blood was processed within 2 h. It was centrifuged at 400 g for 15 min and then at 10 000 g for 15 min. Sera were stored at 80°C. Cytokines and PCT levels were measured after the clinical data were recorded. CRP was determined on the day of sampling. A group of 14 healthy adults were used as controls for the preoperative values.
PCT determination
PCT concentrations were measured in duplicate using 20 µl of serum in an immunoassay with a sandwich technique and a chemiluminescent detection system (LumiTest, Brahms Diagnostica, Berlin, Germany). The intra- and inter-assay coefficients of variation at high and low concentrations were <8% and 7%, respectively. The upper limit of normal was 0.5 ng ml1.
CRP determination
CRP was determined in 20-µl serum samples immediately after specimen collection and was measured by an immunonephelometric method (Array360-CRP, Beckmann Instruments Inc., Galway, Ireland). The minimum concentration detected was 0.04 mg litre1. The intra- and inter-assay coefficients of variation at high and low concentrations were <8% and 5%, respectively.
IL-6 determination
Circulating IL-6 was measured by enzyme immunoassay (EIA). The assays were performed in duplicate using kits provided by Immunotech (Marseille, France). The minimum concentration detected was 3 pg ml1. The intra- and inter-assay coefficients of variation of EIA kits ranged from 5% to 10%.
Statistical analysis
Statistical analysis was performed using SPSS software (version 12.0, SPSS Inc., Chicago, IL). Data for the clinical characteristics of patients are expressed as median (25th75th percentile). The clinical characteristics of the patients were compared using the 2-test or the MannWhitney U-test according to the variable type and the data distribution. The MannWhitney U-test was performed for two independent groups. The Wilcoxon signed-rank test was performed for intragroup changes. P<0.05 was considered to be significant.
The accuracy of PCT, IL-6 and CRP in the diagnosis of postoperative septic complications was assessed by comparing the area under the receiver operating characteristics curve (AUC-ROC) of each test using the methodology described by Hanley and McNeil.12
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Results |
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A similar pattern was seen with IL-6. On day 0 levels were similar in the two groups (5.8 [3.035.9] pg ml1 in septic patients vs 5.8 [3.016.9] pg ml1 in non-septic patients), and on day 1 levels were significantly higher in septic patients (741.4 [355.51300.3] pg ml1 vs 275.5 [136.2495.5] pg ml1, P=0.006) (Fig. 2).
CRP levels were similar in the two groups on day 0 (5.0 [5.033.0] mg ml1 in septic patients vs 5.0 [5.036.7] mg ml1 in non-septic patients) and day 1 (82.0 [66.2106.5] mg ml1 in non-septic patients vs 103.0 [69.0162.7] mg ml1 in septic patients) (Fig. 3).
Sensitivity, specificity, positive and negative predictive values, and ROC curves
The accuracy of the inflammatory markers in distinguishing septic from non-septic patients is shown in Table 2 and Figure 4. At a cut-off point set at 310 pg ml1, IL-6 yielded a sensitivity of 90% and a specificity of 58%. On day 1, with higher values of IL-6 (>310 pg ml1) and signs of SIRS, these values reached 100% and 79%, respectively (Table 3).
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IL-6 yielded the highest discriminative value with an AUC of 0.82 (95% confidence interval [CI] 0.660.98) followed by PCT (AUC=0.75, CI 0.60.90) and CRP (AUC=0.67, CI 0.50.83) (Table 2).
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Discussion |
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Concentrations of CRP have been used to follow septic patients, but were unable to predict the outcome of disease or severity. CRP has also failed to allow immediate diagnosis and prognosis because of the time taken to produce a reaction and the duration of increased serum concentration.1618 These facts may explain its lower sensitivity in the early postoperative period.
Major surgical trauma may induce a non-septic SIRS which can be difficult to distinguish from early postoperative septic complications.2 PCT could be helpful in the early diagnosis of postoperative infection after major surgery.19 PCT is known to be an early marker of severe sepsis,20 but it is correlated with the severity of SIRS after severe trauma21 22 and so may be distorted by major surgery.14 PCT was identified as a better discriminator than CRP in characterizing the degree of inflammation related to infection. PCT was more specific for sepsis-induced inflammation than CRP,23 but no better than CRP at identifying infection uncomplicated by sepsis or organ failure.24 Our results suggest that PCT measurements may be useful for early diagnosis of septic postoperative complications. A PCT level >1.1 ng ml1 associated with SIRS on day 1 could allow diagnosis of postoperative septic complications with a high probability (positive predictive value of 81%). This is in agreement with Reith and colleagues19 who studied the prognostic capacity of elevated PCT levels in 70 patients undergoing elective colorectal surgery and aortic surgery. An increase of PCT levels >1.0 ng ml1 the day after surgery was closely related to postoperative complications such as pneumonia or anastomotic leak. These results are also similar to those of Harbarth and colleagues20 who differentiated non-septic SIRS from a sepsis, with the same PCT cut-off value, in newly admitted ICU patients.
Our data are of importance because the epidemiology of SIRS, sepsis, severe sepsis and septic shock shows that 35% of patients who were clinically septic were prescribed antibiotics empirically without a site with positive culture.3 Early identification of patients with insidious septic illness allows early therapeutic intervention which may favourably influence outcome.4 Future studies in larger groups of patients should specifically address this issue.
In conclusion, patients who undergo major cancer surgery are at high risk of postoperative sepsis. During the early postoperative period, PCT and IL-6 are early markers of postoperative sepsis when associated with SIRS on day 1. These findings may aid early therapeutic intervention in high-risk surgical patients.
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Appendix |
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References |
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