Intensive Care Med (2007) 33:477–484 DOI 10.1007/s00134-006-0509-7
Corsino Rey Marta Los Arcos Andrés Concha Alberto Medina Soledad Prieto Pablo Martinez Belen Prieto
Received: 4 April 2006 Accepted: 13 December 2006 Published online: 27 January 2007 © Springer-Verlag 2007
C. Rey (u) · A. Concha · A. Medina · S. Prieto University of Oviedo, Department of Paediatrics, Paediatric Intensive Care Unit, Hospital Universitario Central de Asturias, Celestino Villamil s/n., 33006 Oviedo, Spain e-mail:
[email protected] M. Los Arcos Hospital Alvarez-Buylla, Belonga s/n., 33600 Mieres, Spain P. Martinez University of Tamaulipas, Academic Multidisciplinary Unit of Agronomy and Science, Adolfo López Mateos, 87149 CD, Victoria, Tamaulipas, Mexico B. Prieto University of Oviedo, Biochemical Laboratory, Hospital Universitario Central de Asturias, Celestino Villamil s/n., 33006 Oviedo, Spain
PE D I A T R I C O R I G I N A L
Procalcitonin and C-reactive protein as markers of systemic inflammatory response syndrome severity in critically ill children
Abstract Objectives: To analyse the clinical value of procalcitonin (PCT), C-reactive protein (CRP) and leucocyte count in the diagnosis of paediatric sepsis and in the stratification of patients according to severity. Design: Prospective, observational study. Setting: Paediatric intensive care unit (PICU). Patients: Ninetyfour children. Measurement and results: Leucocyte count, PCT and CRP were measured when considered necessary during the PICU stay. Patients were classified, when PCT and CRP were measured, into one of six categories (negative, SIRS, localized infection, sepsis, severe sepsis, and septic shock) according to the definitions of the American College of Chest Physicians /Society of Critical Care Medicine. A total of 359 patient day episodes were obtained. Leucocyte count did not differ across the six diagnostic classes considered. Median plasma PCT concentrations were 0.17, 0.43, 0.79, 1.80, 15.40 and 19.13 ng/ml in negative, systemic inflammatory
Introduction Sepsis is a common cause of morbidity and mortality in paediatric intensive care unit (PICU). Diagnosis of sepsis can be difficult because clinical and laboratory signs are similar to those presented in different severities of systemic inflammatory response syndrome (SIRS) caused by infectious or non-infectious disease [1, 2]. Moreover, signs of sepsis, such as tachycardia, tachypnoea and
response syndrome (SIRS), localized infection, sepsis, severe sepsis, and septic shock groups, respectively, whereas median plasma CRP concentrations were 1.35, 3.80, 6.45, 5.70, 7.60 and 16.2 mg/dl, respectively. The area under the ROC curve for the diagnosis of septic patients was 0.532 for leucocyte count (95% CI, 0.462–0.602), 0.750 for CRP (95% CI, 0.699–0.802) and 0.912 for PCT (95% CI, 0.882–0.943). We obtained four groups using CRP values and five groups using PCT values that classified a significant percentage of patients according to the severity of the different SIRS groups. Conclusions: PCT is a better diagnostic marker of sepsis in critically ill children than CRP. The CRP, and especially PCT, may become a helpful clinical tool to stratify patients with SIRS according to disease severity. Keywords Systemic inflammatory response syndrome · Sepsis · Shock · Procalcitonin · C-reactive protein
fever, need a special interpretation in children due to the variable-range normality depending on the patient age [3]; therefore, an early diagnosis is even more difficult in children than in adults. It is very important that clinicians have the tools to recognize and diagnose sepsis promptly, so that effective therapies for infection which are widely and readily available can be used [4]. Early diagnosis and treatment may lead to improved both, mortality and morbidity, in these
478
critically ill children. A marker that is able to distinguish sepsis from localized infection and non-infectious causes of SIRS would be of great clinical use. Traditional markers, such as body temperature, heart rate, respiratory rate or white blood cell (WBC) count, may be unspecific [5]. The 2001 International Sepsis Definitions Conference [4] tried to identify methodologies for increasing the accuracy, reliability and/or clinical utility of the diagnosis of sepsis. During the deliberations on the signs and symptoms that characterize sepsis, the Conference turned toward the day-to-day “reality” for bedside clinicians. They introduced plasma C-reactive protein (CRP) and procalcitonin (PCT) as inflammatory markers in the diagnostic criteria for sepsis. The cut-off value was established in > 2 SD above the normal value for both parameters. The CRP and procalcitonin were also proposed as non-specific markers of activated inflammation to develop a clinically useful staging system that stratifies patients with SIRS according to disease severity. It would be of great clinical value to establish cut-off values for PCT and CRP in the different steps of SIRS. In the present study, we measured leucocyte count, CRP and PCT plasma concentrations in children admitted to our PICU when we considered it was clinically necessary; therefore, we were able to analyse their real clinical value in the diagnosis of sepsis and in the stratification of patients in correlation with its severity.
Materials and Methods We designed a prospective observational study set in the eight-bed PICU of a university hospital. The study protocol was approved by the hospital ethics committee. During a period of 2 years (from August 2002 to August 2004) 94 children younger than 14 years who were admitted to the medico-surgical PICU of the “Hospital Universitario Central de Asturias” were prospectively included in the study. Each enrolled patient was examined, as usual in our PICU, for signs and symptoms of infection at admission and when suspicion of SIRS was present. Heart rate, respiratory rate, blood pressure, urine rate and administration of vasopressor agents were recorded hourly. Radiographic and microbiological diagnostics were performed when indicated. Blood cultures were performed if a patient’s temperature was > 38 °C. Cultures of urine, tracheal aspirate, surgical wounds and removed catheters were systematically performed. Because the clinical spectrum from SIRS to septic shock is a continuum that can progress rapidly, patients were classified when they had a blood analysis that included CRP and PCT, in one of the following six categories (negative, SIRS, localized infection, sepsis, severe sepsis and septic shock) according to the definitions of the American College of Chest Physicians /Society of Critical Care Medicine [6] modified for use in paediatrics [3, 7]; therefore, the same patient could be classified as be-
ing in septic shock during several days and, after adequate treatment, as having sepsis, and at the end of the process, as negative. Classification was made double blinded to the results of plasma PCT and CRP level by two physicians that were not taking care of the patients (M. Arcos and S. Prieto). Infection was considered when a clear source of infection, microbiologically confirmed, or positive blood cultures, were present. Leucocyte count, PCT and CRP plasma concentrations were measured within the first 24 h of admission and when considered necessary by the physician responsible for the patient clinical care. Blood samples were drawn into green-top vacutainer tubes, containing lithium-heparin as anticoagulant, for the determination of CRP and PCT. Plasma CRP was measured on a Vitros 250 Dry Chemistry System (Ortho Clinical Diagnostics, Buckinghamshire, UK). For the determination of PCT, time-resolved amplified cryptate emission (TRACE) technology was used on a Kryptor analyzer (Brahms, Hennigsdorf, Germany). This test is based on a non-radioactive transfer of energy that takes place between two fluorescent tracers in an immunometric automated assay which provides results in less than 1 h. Limits of detection were 0.7 mg/dl and 0.02 ng/ml for CRP and PCT methods, respectively. We assessed leucocyte count, PCT and CRP as markers of sepsis by comparing their plasma levels during inpatient days with sepsis (sepsis, severe sepsis or septic shock) and inpatient days without sepsis (negative, SIRS, localized infection). Statistical analysis was performed using SPSS statistical software (version 11.0; SPSS, Chicago, Ill.). Taking into account that data were non-normally distributed, a Mann-Whitney U-test was used to compare two independent samples. Receiver operating characteristics curves (ROC) and the respective areas under the curve were calculated [8]. A p-value < 0.05 was considered significant. We used the chi-square test to find PCT and CRP cut-off values for the different SIRS groups.
Results Ninety-four children having a mean age of 62 months (range 1–203 months) were enrolled. Admission diagnosis included respiratory (21.3%), cardiac (2.1%),
Table 1 Episodes distribution according to SIRS severity SIRS group
No. of cases
Percentage
Negative SIRS Localized infection Sepsis Severe sepsis Septic shock Total
85 92 57 43 39 43 359
23.7 25.6 15.9 12 10.9 12 100
479
neurological (13.8%), infectious (19.1%), renal (4.3%), traumatic (13.8%), postoperatory (23.4%) and other (2.1%) problems. A total of 359 samples were obtained during the period children were in the PICU; therefore,
359 patient-day episodes could be analysed. Classification of the episodes according to SIRS criteria [6] modified for use in paediatrics [3, 7] are presented in Table 1.
Fig. 1 Box plot of leucocyte count, C-reactive protein (CRP) and procalcitonin (PCT) plasma concentrations in the different diagnostic groups. Central line: median; boxes: 25th to 75th percentiles; whiskers: 95% confidence intervals. p < 0.05 between CRP groups,
except between localized infection vs sepsis, localized infection vs severe sepsis, and severe sepsis vs septic shock. p < 0.05 between PCT groups, except between localized infection vs systemic inflammatory response syndrome (SIRS) and severe sepsis vs septic shock
480
Leucocyte count, CRP and PCT concentrations in the SIRS groups Leucocyte count did not differ across the six diagnostic classes considered, whereas PCT increased according to disease severity from negative group to septic shock (median values of 0.17, 0.43, 0.79, 1.80, 15.40 and 19.13 ng/ml; Fig. 1). The CRP also increased according to disease severity (median values of 1.35, 3.80, 6.45, 5.70, 7.60 and 16.2 mg/dl), except in the group of sepsis which had lower values than the group of localized infection. Diagnosis of sepsis Figure 2 shows ROC curves that illustrate sensitivity and specificity of leucocyte count, CRP and PCT for the diagnosis of septic patients (sepsis, severe sepsis and septic shock). The area under the ROC curve was 0.532 for leucocyte count (95% CI, 0.462–0.602), 0.750 for CRP (95% CI, 0.699–0.802), and 0.912 for PCT (95% CI, 0.882–0.943). The difference was statistically significant (p < 0.0001) when comparing CRP and leucocytes, PCT and leucocytes, or PCT and CRP. A CRP concentration higher than 5.65 mg/dl had 72% sensitivity and 66% specificity, whereas a CRP concentration higher than 6.55 mg/dl had 64% sensitivity and 73% specificity for sepsis diagnosis. A PCT concentration higher than 1.16 ng/ml had 92% sensitivity and 76% specificity, whereas a PCT concentration higher than
1.63 ng/ml had 85% sensitivity and 83% specificity for sepsis diagnosis. Diagnosis of the different SIRS groups Leucocyte count was not used in this estimation because there were no differences between the SIRS groups. We obtained four groups using CRP values and five groups using PCT values because the correlation between SIRS groups and PCT was better than the correlation with CRP. Figure 3 shows the cut-off values of the four CRP groups and the percentage of SIRS groups classified in each CRP group. CRP values < 2 mg/dl (group 1) were seen in children without a septic process except in 10% of cases. The CRP values > 27.9 mg/dl (group 4) were only present in sepsis, severe sepsis and septic shock, except in six cases (17.1%) of localized infection and two cases (5.7%) of SIRS. The CRP values between 2 and 6.5 mg/dl (group 2) were more common in non-septic patients, but 35% of patients were septic. The CRP values between 6.5 and 27.9 (group 3) were seen in all groups of patients, but were uncommon (5.6%) in the negative group. Figure 4 shows the cut-off values of the five PCT groups and the percentage of SIRS groups classified in each group. The PCT values < 0.89 ng/ml (group 1) were not present in severe sepsis and septic shock and were very uncommon (4.5%) in sepsis. The PCT values > 24.5 ng/ml (group 5) were only present in severe sepsis and septic shock, except in two cases (5.7%) of hypovolaemic shock. The PCT values between 9.33 and 24.5 ng/ml (group 4) were very common in septic patients. The PCT values between 1.16 and 9.33 ng/ml (group 3) were frequent in septic problems, but a significant percentage of SIRS (22.2%) and localized infection (18.1%) were included in this range. The PCT values between 0.89 and 1.16 ng/ml (group 2) were not usually present in septic patients.
Discussion The aim of our study was to determine, in critically ill children, the value of PCT, CRP and leucocyte count in diagnosing septic patients and in classifying patients in correlation with its severity in the different SIRS groups. We tried to characterize sepsis, as 2001 International Sepsis Definitions Conference suggested [4], following the dayto-day “reality” for bedside clinicians. We measured PCT, CRP and leucocyte count every time we considered it was clinically necessary, and we had the results in less than 1 h; therefore, our results were directly related to common clinical practice reporting the use of an automated analyzer. Early diagnosis of sepsis in paediatric intensive care, allowing early therapeutic intervention, would be of great Fig. 2 Receiver operating characteristics (ROC) curves compares leucocyte count, procalcitonin and C-reactive protein for prediction value in improving the outcome of these patients. The presof sepsis ence of sepsis, severe sepsis and septic shock was associ-
481
Fig. 3 Cut-off values of the four C-reactive-protein groups and percentage of SIRS groups, according to the definitions of the American College of Chest Physicians/Society of Critical Care Medicine [6], modified for use in paediatrics [3, 7], correctly classified in each group
ated with an increasing severity of illness, increased number of organ dysfunctions and a distinct risk of mortality among critically ill children [9]. We found that CRP and PCT, but not leucocyte count, were useful in diagnosing bacterial sepsis in children admitted to our PICU. These results agree with those reported by Hatherill et al. [5] in children and Castelli et al. [10] in adults. Published CRP cut-off values range from 5 to 10 mg/dl [5, 11, 12, 13, 14, 15, 16]. Our cut-off value of 5.65 mg/dl was in the lower part of this range, and the sensitivity and specificity we found were similar to those found in the majority of studies [5, 11, 12, 13, 14, 15, 16]. Contrary to the data of Suprin et al. [15] and Ugarte et al. [16], we found that PCT proved to be more sensitive and specific than CRP. This finding is similar to that reported by Luzzani et al. [17] in critically ill adults, Geppert et al. [18] in patients with cardiogenic shock and Arkader et al. [19] in critically ill children. A meta-analysis of 49 published studies comparing PCT and CRP as diagnostic test
for sepsis in critically ill adults [20] found PCT superior to CRP. We consider a PCT concentration of 1.1 ng/ml as the best cut-off value for sepsis diagnosis because it is better to have more sensitivity and less specificity when managing children with risk of sepsis. Different PCT cut-off values were published for the diagnosis of sepsis [11, 12, 13, 15, 18, 20] with a range from 0.6 ng/ml in 190 adults [16] to 20.0 ng/ml in 120 neonates and children [5]. The heterogeneity in the study design, including the diverse age range, the definition of sepsis and the different nature of the control groups, might explain the differences. Our study included a typical, heterogeneous critically ill paediatric population similar to that of the majority of European multidisciplinary PICUs. We have previously reported a PCT cut-off value of 8.05 ng/ml to differentiate bacterial sepsis for a control group [12]. To explain this difference in the cut-off value we have to take into account the different kind of septic patients we have in both studies. In the first study the majority of bacterial sepsis were meningococcal.
482
Fig. 4 Cut-off values of the five procalcitonin groups and percentage of SIRS groups, according to the definitions of the American College of Chest Physicians/Society of Critical Care Medicine [6], modified for use in paediatrics [3, 7], correctly classified in each group
Although Hatherill et al. [21] reported similar PCT levels in children with meningococcal or non-meningococcal sepsis, in our experience, meningococcal sepsis produces a severe SIRS, increasing PCT levels to high values very quickly; therefore, meningococcal septic patients had high PCT level raising the cut-off level. In the present study, our sepsis group included all kind of sepsis, but only a few were meningococcal, and some did not increase PCT levels more than 1 ng/ml. Our PCT cut-off value of 1.1 ng/ml was similar to the value of 1.2 ng/ml obtained by Castelli et al. [22] for the prediction of sepsis vs SIRS in adult
patients and the value of 1.0 ng/ml obtained by Clec’h et al. [23] in adult medical patients. The sensitivity was 92% in our study, 63% in the study by Castelli et al. [22] and 80% in the study by Clec’h et al. [23], and the specificity was 73, 94 and 87%, respectively. Arkader et al. [19] obtained a PCT cut-off concentration of 2 ng/ml to differentiate SIRS from sepsis in critically ill children with 88% sensitivity and 100% specificity. Recently, Celebi et al. [24] found that daily PCT measurements in paediatric patients with SIRS and organ failure after open heart surgery may help identify the postoperative infection.
483
Following the recommendations of 2001 International Sepsis Definitions Conference [4] we have tried to develop a useful staging system using CRP and PCT values that stratifies patients with SIRS according to disease severity. As shown in Fig. 1, PCT increased in direct relation to disease severity, whereas CRP had problems in classifying sepsis as a more severe disease than localized infection. These findings are similar to those reported by Castelli et al. [22], Luzzani et al. [17], Meisner et al. [25] and Harbarth et al. [26] in adult patients, and to Hatherill et al. [21] and Casado-Flores et al. [27] in paediatric patients, demonstrating that admission PCT was related to the severity of organ failure. Consequently, in our patients the capacity of stratification was higher for PCT with five groups than for CRP with only four groups. Moreover, the percentage of agreement between CRP or PCT groups, and the standard classification of SIRS [6], was better for PCT than for CRP (Figs. 3, 4). The CRP levels between 2.00 and 27.89 mg/dl (groups 2 and 3) had a lower capacity to differentiate SIRS groups. The PCT had problems to differentiate SIRS groups between 1.16 and 9.33 ng/ml (group 3). Levels of CRP and PCT out of these ranges were useful in the stratification of patients; therefore, they can be used as another tool to be considered in the staging of sepsis. Hatherill et al. [5] reported a PCT cut-off level of 20 ng/ml for optimum prediction of septic shock in paediatric patients. In our experience, PCT levels higher than 24 ng/ml were only present in severe sepsis and septic shock, although they could be present in severe hypovolaemic shock as previously described by Mimoz et al. [28]. We diagnosed SIRS groups based on well-defined and widely accepted consensus guidelines [29]; however, because “gold standards” for the diagnosis of infection do not exist, ambiguity in clinical classification of critically ill patients remains, both in trials and in routine bedside practice. The use of biomarkers of sepsis activity may be the most ideal definition criterion. Because rapid assays for meaningful biomarkers of sepsis activity have been unavailable, clinical criteria have been used for SIRS classification [4, 30]. In our experience, PCT is sensitive enough to be included in a staging system for SIRS in paediatric patients. The assay to determine PCT, currently available with an automated analyser allows the result to be ready in less than an hour; therefore, we agree with Uzzan et al.
meta-analysis [20] results which suggest that PCT should be included in diagnostic guidelines for sepsis, but not only in intensive care units for adults, also for children. In the classification of SIRS, evolution from negative patients to septic shock is a continuum that can progress rapidly. At the same time, when the response to treatment is adequate, progression from septic shock group to negative can occur during several days. In this sense, as seen in Fig. 1, our methodology was useful to validate the capacity of CRP and PCT to increase at the same time that SIRS progresses and to descend at the same time that SIRS decreases. We found that the CRP median level was lower during days with sepsis than during days with localized infection (Fig. 1). These data agree with those reported by Luzzani [17] who found lower CRP levels during severe sepsis days than during SIRS days. By contrast, PCT levels were higher during sepsis days than localized infection days (Fig. 1); therefore, PCT was a better marker of SIRS progression and recovery than CRP. Our study has limitations. The main problem is the lack of a gold standard against which the diagnostic criteria can be calibrated. We used SIRS/sepsis definitions [6] modified for use in paediatrics [3, 7], because despite the controversy, they were used as inclusion criteria for a large number of observational studies and therapeutic trials [29]. Moreover, the generalization of our findings is limited by the fact that cut-off values are dependent on the characteristics of our patients: pretest probability could change in specific groups of patients and there are some conditions where PCT can be induced by non-bacterial causes of inflammation, e.g. severe hypovolaemic shock. This should be regarded when PCT results are interpreted in the individual patient.
Conclusion In conclusion, PCT is a better diagnostic marker of sepsis in critically ill children than CRP. The CRP, and especially PCT, may become a helpful clinical tool in stratifying paediatric patients with SIRS according to disease severity, and should be included in clinical practice in PICU. Acknowledgements. The authors gratefully acknowledge the assistance of the medical and nursing staff of the PICU of Hospital Universitario Central de Asturias.
484
References 1. Brun-Buisson C (2000) The epidemiology of the systemic inflammatory response. Intensive Care Med 26: (Suppl. 1) S64–S74 2. Parrillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477 3. Hayden WR (1994) Sepsis terminology in pediatrics. J Pediatr 124:657–658 4. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 29:530–538 5. Hatherill M, Tibby SM, Sykes K, Turner C, Murdoch IA (1999) Diagnostic markers of infection: comparison of procalcitonin with C reactive protein and leucocyte count. Arch Dis Child 81:417–421 6. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874 7. Carcillo JA (2003) Pediatric septic shock and multiple organ failure. Crit Care Clin 19:413–440 8. Hanley JA, McNeil BA (1982) The meaning and use of the area under a receiver operating (ROC) curve. Radiology 143:29–36 9. Goh A, Lum L (1999) Sepsis, severe sepsis and septic shock in paediatric multiple organ dysfunction syndrome. J Paediatr Child Health 35:488–492 10. Castelli GP, Pognani C, Cita M, Stuani A, Sgarbi L, Paladini R (2006) Procalcitonin, C-reactive protein, white blood cells and SOFA score in ICU: diagnosis and monitoring of sepsis. Minerva Anestesiol 72:69–80 11. Carrol ED, Newland P, Riordan FA, Thomson AP, Curtis N, Hart CA (2002) Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash. Arch Dis Child 86:282–285 12. Enguix A, Rey C, Concha A, Medina A, Coto D, Dieguez MA (2001) Comparison of procalcitonin with C-reactive protein and serum amyloid for the early diagnosis of bacterial sepsis in critically ill neonates and children. Intensive Care Med 27:211–215
13. Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR, Zimmerli W, Ritz R (2000) Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 28:977–983 14. Povoa P, Almeida E, Moreira P, Fernandes A, Mealha R, Aragao A, Sabino H (1998) C-reactive protein as an indicator of sepsis. Intensive Care Med 24:1052–1056 15. Suprin E, Camus C, Gacouin A, Le Tulzo Y, Lavoue S, Feuillu A, Thomas R (2000) Procalcitonin: A valuable indicator of infection in a medical ICU? Intensive Care Med 26:1232–1238 16. Ugarte H, Silva E, Mercan D, Mendonca A de, Vincent JL (1999) Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med 27:498–504 17. Luzzani A, Polati E, Dorizzi R, Rungatscher A, Pavan R, Merlini A (2003) Comparison of procalcitonin and Creactive protein as markers of sepsis. Crit Care Med 31:1737–1741 18. Geppert A, Steiner A, Delle-Karth G, Heinz G, Huber K (2003) Usefulness of procalcitonin for diagnosing complicating sepsis in patients with cardiogenic shock. Intensive Care Med 29:1384–1389 19. Arkader R, Troster EJ, Lopes MR, Junior RR, Carcillo JA, Leone C, Okay TS (2006) Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome. Arch Dis Child 91:117–120 20. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY (2006) Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 34:1996–2003 21. Hatherill M, Tibby SM, Turner C, Ratnavel N, Murdoch IA (2000) Procalcitonin and cytokine levels: relationship to organ failure and mortality in pediatric septic shock. Crit Care Med 28:2591–2594 22. Castelli GP, Pognani C, Meisner M, Stuani A, Bellomi D, Sgarbi L (2004) Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care 8:R234-R242
23. Clec’h C, Fosse JP, Karoubi P, Vincent F, Chouahi I, Hamza L, Cupa M, Cohen Y (2006) Differential diagnostic value of procalcitonin in surgical and medical patients with septic shock. Crit Care Med 34:102–107 24. Celebi S, Koner O, Menda F, Balci H, Hatemi A, Korkut K, Esen F (2006) Procalcitonin kinetics in pediatric patients with systemic inflammatory response after open heart surgery. Intensive Care Med 32:881–887 25. Meisner M, Tschaikowsky K, Palmaers T, Schmidt J (1999) Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS. Crit Care (Lond) 3:45–50 26. Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, Vadas L, Pugin J (2001) Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 164:396–402 27. Casado-Flores J, Blanco-Quiros A, Asensio J, Arranz E, Garrote JA, Nieto M (2003) Serum procalcitonin in children with suspected sepsis: a comparison with C-reactive protein and neutrophil count. Pediatr Crit Care Med 4:190–195 28. Mimoz O, Benoist JF, Edouard AR, Assicot M, Bohuon C, Samii K (1998) Procalcitonin and C-reactive protein during the early posttraumatic systemic inflammatory response syndrome. Intensive Care Med 24:185–188 29. Carcillo JA (2004) Mannose-binding lectin deficiency provides a genetic basis for the use of SIRS/sepsis definitions in critically ill patients. Intensive Care Med 30:1263–1265 30. Trzeciak S, Zanotti-Cavazzoni S, Parrillo JE, Dellinger RP (2005) Inclusion criteria for clinical trials in sepsis: Did the American College of Chest Physicians/Society of Critical Care Medicine consensus conference definitions of sepsis have an impact? Chest 127:242–245
