Intensive Care Med (2006) 32:881–887DOI 10.1007/s00134-006-0180-z PEDIATRIC ORIGINAL

Serdar CelebiOzge KonerFerdi MendaHuriye BalciAlican HatemiKubilay KorkutFigen Esen

Procalcitonin kinetics in pediatric patientswith systemic inflammatory response afteropen heart surgery

Received: 5 August 2005Accepted: 31 March 2006Published online: 28 April 2006© Springer-Verlag 2006

S. Celebi (�) · O. Koner · F. MendaIstanbul University, Cardiology Institute,Anesthesiology and Intensive CareDepartment,Istanbul, Turkeye-mail: sdrcelebi@yahoo.com

H. BalciIstanbul University, Cerrahpasa MedicalFaculty, Central Research Laboratory,Istanbul, Turkey

A. Hatemi · K. KorkutIstanbul University, Cardiology Institute,Cardiovascular Surgery Department,Istanbul, Turkey

F. EsenIstanbul University Istanbul MedicalFaculty, Anesthesiology and Intensive CareDepartment,Istanbul, Turkey

Abstract Objective: To evaluateprocalcitonin and C-reactive proteinas markers of inflammation sever-ity and their value in predictingdevelopment of organ failure afterpediatric open heart surgery. Design:Prospective, observational, clinicalstudy. Setting: Single university hos-pital. Patients: Thirty-three pediatricpatients with systemic inflammatoryresponse syndrome (SIRS; n = 19)and SIRS+organ failure (SIRS+OF;n = 14) following open heart surgerywere included. Measurements andresults: Plasma procalcitonin andC-reactive protein levels were mea-sured before and after the operation,and 1, 2, 3, and 4 days after surgery.Patients were evaluated daily to assessorgan failure. Postoperative procal-citonin levels in the SIRS+OF groupwere significantly higher than in theSIRS group. C-reactive protein levelswere similar between the groupsthroughout the study period. Peakprocalcitonin levels were found tobe positively correlated with aortic

cross-clamp and cardiopulmonarybypass times, duration of mechanicalventilation, intensive care unit andhospital stay, mortality and organ fail-ure development. Peak procalcitoninwas found to be a good predictorof postoperative organ failure devel-opment and mortality. However, thepredictive value of peak C-reactiveprotein for organ failure and mortalitywas found to be weak. Double-peakprocalcitonin curves were observedin SIRS+OF patients with infec-tion during the intensive care unitstay. Conclusion: In the SIRS+OFgroup peak procalcitonin levels werefound to be highly predictive formortality and organ failure devel-opment, whereas C-reactive proteinlevels were not. Daily procalcitoninmeasurements in SIRS+OF patientsmay help identify the postoperativeinfection during the follow-up period.

Keywords Inflammation · Organfailure · Pediatric heart surgery ·Procalcitonin · C-reactive protein

Introduction

Extracorporeal circulation used during cardiac surgery isassociated with systemic inflammatory response syndrome(SIRS) [1]. This inflammatory response may result fromendotoxin translocation, ischemia–reperfusion, surgicaltrauma, and contact of the blood with non-endothelialsurfaces during cardiac surgery, and once exacerbatedmay lead to severe organ dysfunction, increased mortality,and morbidity [2, 3, 4]. Multiple organ failure in pediatric

patients is frequently associated with death soon after thediagnosis [5, 6]. Multiple organ dysfunction syndromeaccompanying SIRS has a mortality rate of 40%, whichis close to the rate found among pediatric patients withseptic shock-related organ failure [7].

Procalcitonin (PCT) is an acute-phase protein and it hasbeen described as an infection marker in critically ill pa-tients [8]. It has also been introduced into clinical practiceas a marker of noninfectious inflammatory response [9,10]. PCT is used as a parameter to estimate the severity

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of sepsis and SIRS [11]. Recently, it has been shown toidentify development of organ failure in the presence ofSIRS after adult open heart surgery [12]. Scores assessingseverity of organ failure have been found to be correlatedwith plasma PCT levels in the postoperative period [13].Another acute-phase protein, C-reactive protein (CRP), isincreased in both infectious and noninfectious inflamma-tory states.

Despite being a reliable marker of bacterial and fungalinfections in both adults and young children [8, 14, 15],PCT is not reliable in differentiating SIRS from sepsis inthe early days following cardiac surgery, and it has beensuggested that the only way to make a decision is to ob-serve “double-peak” curves or consistently high PCT lev-els in infectious states [16]. The value of CRP as a markerin differentiating SIRS from sepsis is also debatable.

It is not clear how SIRS and accompanying organ fail-ure affect the PCT and CRP kinetics in pediatric patientsafter open heart surgery. We conducted this study to eval-uate the PCT and CRP kinetics of pediatric patients withSIRS in the presence or absence of accompanying organfailure after open heart surgery. In addition, we evaluatedthe predictive value of these markers for organ failure de-velopment and mortality.

Materials and methodsFollowing ethics committee approval and written informedconsent, 33 children were enrolled into the study. Nineteenof the children met the SIRS criteria, while the remaining14 met both SIRS and organ failure criteria within theirfirst week in the ICU. Patients with proven preoperative in-fection, hepatic and/or renal disturbances and patients whoneeded catecholamine preoperatively were excluded fromthe study.

Total intravenous anesthesia technique was used in allthe patients. Following anesthesia induction, percutaneousradial arterial and jugular venous catheterization wasperformed. All the patients received 40 mg/kg intravenouscefazolin 1 h before the surgical incision. Following300 IU/kg heparin and activated clotting time > 480 s, car-diopulmonary bypass (CPB) was instituted. A membraneoxygenator [Dideco 902 Liliput (BSA < 1 m2), Dideco705 Midiflo (BSA = 1–1.5 m2); Dideco, Mirandola, Italy]and a nonpulsatile roller pump (Jostra, HL-20, Lund,Sweden) were used. Prime solution constituted of Ringer’slactate solution, heparin, cefazolin, methyl prednisolone30 mg/kg, mannitol 0.5 mg/kg and red blood cells toachieve a hematocrit level of about 25%. Moderate hy-pothermia (28°C) was used during CPB. Pump flow rateswere 1.8–2 l/min/m2 and 2.4 l/min/m2 during hypothermicand normothermic periods, respectively. Ultrafiltration(AN-69, Hospal Ind, Meyzieu, France) was performed,if necessary, during the rewarming period. At the endof the CPB, heparin was antagonized with protamine

chloride. A hematocrit value of 30–35% was the aim atthe end of the CPB, and catecholamine was infused whennecessary. All the patients were transferred into the ICUunder mechanical ventilation. Patients were divided intotwo groups in the ICU according to their postoperativecourse: SIRS and SIRS+organ failure (SIRS+OF).

Biochemistry and chest X-ray were evaluated preop-eratively in all the patients. Blood samples were taken tomeasure arterial blood gases, CRP, PCT, leukocyte andplatelet count, bilirubin, creatinine, blood urea nitrogen,aspartate aminotransferase, alanine aminotransferase,albumin, international normalized ratio, D-dimer and ac-tivated partial prothrombin time preoperatively and dailyduring the study period. Neurologic examinations wereperformed daily. All the patients were given 40 mg/kgIV cefazolin every 12 h for 72 h including the operationday. Cultures of blood, bronchial secretions, urine andcentral venous catheter tip were performed as clinicallyindicated. The postoperative culture indications were:child fulfilling SIRS criteria beyond 24 h postoperatively,pulmonary infiltrates on the chest X-ray, change in thecharacteristic of sputum, prolonged intubation (> 48 h),and inflammation around the catheter insertion sites.SIRS was defined according to the criteria suggestedby the ACCP/SCCM Consensus Conference [17] withadjustments for age [18], if ≥ 2 of the following signswere met: body temperature > 38°C or < 36°C, whiteblood cell count < 4,000/mm3 or > 12,000/mm3 or> 10% immature neutrophils, hyperventilation indicatedby PaCO2 < 32 mmHg or tachypnea with a respiratoryrate > 90th percentile for age in the absence of metabolicacidosis, heart rate > 90th percentile for age. Patientswho needed pacemaker support due to the atrioventricularblock following the surgery were excluded from thestudy. Multiple organ failure was defined as simultaneousfailure of ≥ 2 organs and diagnosed according to modifiedWilkinson’s [5, 7] criteria by daily evaluation.

Two milliliters of arterial blood collected into theEDTA tube was centrifuged for 10 min at 4°C. Plasmasamples were stored at –80°C. PCT was measured by im-munofluorescent assay (KRYPTOR® PCT B.R.A.H.M.SDiagnostica, Henningsdorf, Germany). CRP was meas-ured in whole blood by turbidimetric assay (Spinreact SA,Girona, Spain; reference value < 0.5 mg/dl). Blood sam-ples for hemogram, total bilirubin, platelet and leukocytecount, CRP, PCT, and serum creatinine were drawn beforethe operation, at the end of the surgery, and 1, 2, 3, and 4days after the surgery. Plasma samples from six patientswith pneumonia in the SIRS+OF group were collecteddaily and stored for measurement of PCT and CRP levels.

The PCT and CRP levels are reported as medians. Theother results are expressed as mean ± SD. The ANOVAtest was used for repeated measurements, and the non-parametric Mann–Whitney U test was used to comparethe groups. Comparisons between the variables were donewith Spearman’s rho correlation test. To evaluate the in-

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dependent role of each variable, multivariate analysis wasperformed, including all significant data of the univariateanalysis. A receiver operating curve (ROC) was drawn tofind the best cut-off value of PCT and CRP for the corre-lated variables. A p value of < 0.05 was considered sta-tistically significant. Unistat version 5.0 (Unistat Ltd. UK)for Windows was used for the statistical analysis.

Results

The perioperative data and diagnoses of the patients areshown in Table 1 and 2. Five patients in the SIRS+OFgroup died postoperatively: one died of septic shock onpostoperative day 14, three died due to low cardiac outputon postoperative days 75, 16, and 16, and one died of pul-monary hypertensive crisis on postoperative day 5. Noneof the patients required a second surgical intervention. Pe-

Table 1 The sociodemographic and clinical characteristics of pa-tients in the SIRS+OF and SIRS groups

SIRS+OF SIRS pa

(n = 14) (n = 19)

Gender (M/F) 6/8 9/10 nsAge (months) 24 ± 29 40 ± 35 <0.01Weight (kg) 8 ± 6 11 ± 5,8 <0.01ACC time (min) 93 ± 35 59 ± 21 <0.01CPB time (min) 158 ± 57 102 ± 40 <0.01Mechanical ventilation (h) 152 ± 280 17 ± 23 <0.01ICU stay (h) 233 ± 301 60 ± 31 =0.01Hospitalization (days) 22 ± 24 12 ± 19 <0.01No. of infected patients 6 –Mortality 5 –

a p < 0.05 compared to SIRS group

Table 2 Diagnoses

Diagnosis SIRS+OF SIRS(n = 14) (n = 19)

TOF 2 8VSD 3 6CAVCD 4 –VSD+tricuspid hypoplasia 1 –VSD+AoCoA+LV hypoplasia 1 –Truncus arteriosus type I 1 –Simple TGA – 2DORV+VSD+ASD 1 –TAPVR+ASD 1 1ASD – 1Tricuspid atresia+RV – 1hypoplasia+VSD+ASD

Abbreviations: AoCoA aortic coarctation; ASD, atrial septal defect;CAVCD, complete atrioventricular channel defect; DORV, double-outlet right ventricle; LV, left ventricle; RV, right ventricle; TAPVR,total abnormal venous return; TOF, tetralogy of Fallot; TGA, trans-position of the great arteries; VSD, ventricular septal defect

rioperative ultrafiltration was applied to 18 patients: 12 ofthem were in the SIRS+OF group, 6 in the SIRS group.Six patients with organ failure required peritoneal dialysisin the postoperative period. Six patients in the SIRS+OFgroup were infected postoperatively, and daily PCT andCRP measurements were performed (Figs. 1 and 2).

In the SIRS group, 12 patients received 5.6 ±1.4 µg/kg/min dopamine and 9 received additional 0.015 ±0.02 µg/kg/min epinephrine infusion (lower than theSIRS+OF group; p = 0.004 and p = 0.04, respectively).In the SIRS+OF group, all the patients received 8.0 ±2.6 µg/kg/min dopamine, while additional infusions ofepinephrine and dobutamine, respectively, were admin-istered at 0.05 ± 0.02 µg/kg/min to 13 patients and at11.5 ± 4.0 µg/kg/min to 7 patients. Two patients inthe SIRS+OF group received additional 0.04 µg/kg/minnorepinephrine infusion. Blood and urine and bronchialsecretion cultures were taken from nine SIRS patientsand found to be negative. However, endotracheal aspiratecultures of six patients and blood culture of one patient inthe SIRS+OF group were found to be positive (Table 3).

Fig. 1 PCT kinetics in six infected patients in the SIRS+OF group.POD Postoperative day

Fig. 2 CRP kinetics in six infected patients in the SIRS+OF group.The straight line represents the reference value of the CRP forhealthy subjects

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Table 3 Infections in the SIRS+OF group

Patient Postoperative Pathogen No. ofno. day of infection organism failed

diagnosis organs

1 10 Klebsiella pneumonia 42 13 Acinetobacter spp. 53 11 Pseudomonas aeruginosa 34 6 Pseudomonas aeruginosa 45 6 Pseudomonas aeruginosa 36 6 (blood) MRSA 2

10 (lung) Klebsiella pneumonia7 – 38 – 39 – 210 – 211 – 212 – 213 – 214 – 3

MRSA, methicillin-resistant Staphylococcus aureus

Except for the baseline values, PCT levels of patientswith SIRS+OF were significantly higher than those ofSIRS patients after the surgery. In both groups PCTlevels increased significantly from baseline, peaked atpostoperative day 1, and then decreased until postopera-tive day 4, although PCT levels were significantly highcompared with the baseline at the end of the study (Fig. 3).CRP values were similar among the groups throughoutthe study with a peak on postoperative day 2 (Fig. 4).White blood cell counts were the same in both groupsuntil postoperative day 3, then increased significantlyin the SIRS+OF group compared with the SIRS groupon postoperative days 3 and 4 (15.0 ± 5.6 × 103 µl vs.11.0 ± 3.0 × 103µl, p = 0.03, and 14.3 ± 5.2 × 103 µl vs.10.0 ± 3.0 × 103µl, p = 0.02, respectively).

Peak PCT levels were found to be correlated withACC (r = 0.4, p = 0.02) and CPB times (r = 0.4, p = 0.02),mechanical ventilation (r = 0.4, p = 0.01), ICU period(r = 0.5, p = 0.002), mortality (r = 0.5, p = 0.001), hospital-

Fig. 3 Median PCT values (ng/ml) of the groups. *Significantly highvalues compared with SIRS group (p>0.05)

Fig. 4 Median CRP values (mg/dl) of the groups

ization (r = 0.46, p = 0.007) and organ failure development(r = 0.85, p < 0.001), whereas peak CRP values correlatedonly with mechanical ventilation (r = -0.44, p = 0.01)and ICU periods (r = -0.41, p = 0.01). Postsurgery PCTvalues were found to be correlated only with organfailure development (r = 0.5, p = 0.002), while CRPvalues showed a correlation neither with organ failurenor mortality. Postoperative organ failure was found tobe correlated with ACC (r = 0.5, p = 0.001) and CPB(r = 0.5, p = 0.001) times, whereas no correlation wasfound between mortality and those variables.

Postsurgery (p = 0.005) and peak PCT values(p = 0.001), ACC (p < 0.001), CPB times (p < 0.001),ICU stay (p = 0.007), and mechanical ventilation peri-ods (p = 0.02) were found to be significantly correlatedwith postoperative organ failure by univariate analysis.Mortality was found to be correlated with peak PCTvalues (p = 0.002) ICU stay (p = 0.008), and mechanicalventilation periods (p < 0.001) by univariate analysis.Multivariate tests revealed that CPB (p < 0.001) and ACC(p < 0.001) times, peak PCT (p = 0.001) values, mechan-ical ventilation time (p = 0.02), and ICU stay (p = 0.07)were independently correlated with postoperative or-gan failure. Peak PCT (p = 0.002) values, mechanicalventilation time (p < 0.001), and ICU stay (p = 0.008)were found to be independently correlated with mortalityby multivariate tests, whereas CPB and ACC times,hospitalization period, and peak CRP values were not.

The organ failure predictive value of postsurgical PCTlevels had a sensitivity of 85% and specificity of 58%for a cut-off value of 0.7 ng/ml (PPV 63%, NPV 80%),while peak PCT values revealed very high sensitivity andspecificity (100% and 100%, respectively) for cut-offvalues of 7.7 ng/ml (PPV 100%, NPV 100%), 5 ng/ml(sensitivity100%, specificity 95%) and 4 ng/ml (sensitivity100%, specificity 85%). Area under the curve (AUC)for peak PCT levels to predict organ failure was 100%(95% CI 1.0–1.0). Peak PCT levels (39.2 ng/ml) predictedmortality with high sensitivity and specificity (100% and90%, respectively; PPV 63%, NPV 100%), whereas peakPCT levels of 5ng/ml (sensitivity 100%, specificity 65%)

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and 10 ng/ml (sensitivity 100%, specificity 72%) werealso useful. The AUC value for peak PCT levels to predictmortality was 94% (95% CI 0.86–1.02). CRP valuespredicted neither mortality nor organ failure (Figs. 5and 6).

The AUC for CPB and ACC times to predict organfailure was 83% (95% CI 0.7–0.97) and 82% (95% CI0.65–0.98), respectively. The sensitivity of CPB and ACCcut-off values of 106 and 72 min for organ failure wasfound to be 85% and 78%, respectively. The specificity ofthese cut-off values for organ failure was 69% in each case.

The SIRS group received 20 ± 12 ml/kg RBC, whilethe SIRS+OF group received 19.5 ± 9.2 ml/kg RBC dur-ing the operation. Throughout the PCT follow-up period,the SIRS group received 11 ± 4.3 ml/kg RBC, whereas the

Fig. 5 Specificity and sensitivity of the CRP and PCT values forpredicting mortality

Fig. 6 Specificity and sensitivity of the CRP and PCT values forpredicting organ failure

SIRS+OF group received 15 ± 3.4 ml/kg RBC. The trans-fusion requirements did not differ significantly between thegroups.

Discussion

In this study we found that the postoperative PCT lev-els in the SIRS+OF group were significantly higher thanin the SIRS group without signs of infection. Secondly,we showed that the peak PCT levels in the group withSIRS+OF correlated with CPB, ACC, mechanical venti-lation, ICU stay, and hospitalization period, whereas peakCRP values did not. Thirdly, we demonstrated that peakPCT levels predicted mortality and development of organfailure with high sensitivity and specificity, whereas CRPvalues did not. Finally, we observed “double-peak” or con-sistently high PCT curves in the six infected patients of theSIRS+OF group.

We found that PCT levels increased after cardiacsurgery in both groups, with a peak on postoperativeday 1. Peak median PCT levels in the SIRS group were3 ng/ml. In a study consisting of 14 pediatric SIRSpatients undergoing open heart surgery, it was shownthat the peak median PCT levels remained under 2ng/ml postoperatively [19]. Despite being slightly higherthan in that study, the PCT values in our investigationare correlated with the findings of previous studies inadult and pediatric cardiac surgery with CPB [20–24].In our study, high median PCT levels (53 ng/ml) wereobserved in the SIRS+OF group without the signs ofan infection on postoperative day 1 (highest value 430ng/ml). A previous study claimed that PCT had bettersensitivity and specificity than other routine laboratoryparameters in predicting postoperative complications(single organ failure) related to CPB in adults [12]. PCTlevels were reported to be high following a complicatedpostoperative course after pediatric cardiac surgery; thecomplications were defined as death, reoperation within5 days of surgery, more than 3 days’ ventilatory support,and an ICU stay exceeding 5 days [21]. In the same study,peak PCT levels were shown to be positively correlatedwith prolonged CPB and ACC times and values as highas 73.2 µg/l were reported on the first postoperative day,which is consistent with our findings. However, the au-thors did not specify the underlying cause of the so-calledcomplications.

Despite the high median PCT levels compared withbaseline on the 4th postoperative day in the SIRS+OFgroup, the declining trend makes this marker a reliableinfection marker in the early postoperative period in SIRSpatients with accompanying organ failure. Furthermore,some patients in the SIRS group had peak PCT levels ashigh as 2.3 ng/ml on postoperative day 4. Considering thePCT kinetics in both groups, the best way to diagnosethe infection postoperatively is daily blood sampling and

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showing the consistently high or double-peak PCT curves,as in our study.

CRP is another marker of systemic inflammation whichhas been shown to increase after cardiac surgery withoutan infection [20, 25]. In our study postsurgery CRP lev-els did not differ between the groups. Furthermore, CRPis of no value in predicting mortality or organ failure, incontrast with PCT. In both groups CRP values were signi-ficantly higher than baseline on postoperative day 4, de-spite the decreasing trend. Consistently high CRP levelsduring the first 8 days following CPB without an infectionhave been reported [26]. As a result PCT should be pre-ferred to CRP to diagnose infection postoperatively, as itskinetics is faster than that of CRP.

In a medical ICU it was shown that SIRS patients withaccompanying severe heart failure and liver dysfunctionhad marked PCT elevations (range 6.9–148.7 ng/ml) [27].Elsewhere, acute lung injury, circulatory failure, andtransient bacteremia were shown to be responsible forthe increased postoperative PCT levels independent ofinfection [23, 28]. The mechanism of increased PCTand CRP release in CPB-induced SIRS has not yetbeen clarified. Proinflammatory cytokines such as tumornecrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6trigger CRP release from the liver cells [29, 30]. Therelationship between the cytokines, endotoxin, and PCThas been shown experimentally [31]. An increase inserum TNF-alpha, IL-6, and IL-8 has been previouslydocumented in circulatory failure [32]. These findingsmay support the idea that the increased cytokine levels,caused by endotoxin release from the underperfusedsplanchnic region, may lead to increased PCT levelsduring circulatory failure. Another study evaluating serumlevels of bacterial endotoxins showed that 40% of the chil-dren undergoing open heart surgery were toxemic beforesurgery, whereas 96% of them were toxemic followingCPB [33]. In our opinion neither acute lung injury norcirculatory failure alone seems to be the reason for theexcessively high PCT levels in our study. Consideringthe extremely high PCT levels, it is more likely that thepeak PCT levels are correlated with the severity of theinflammatory response.

Prolonged CPB and ACC times have been shown tobe positively correlated with PCT as well as postoperativeorgan failure, prolonged mechanical ventilation, and mor-tality [34, 35, 36]. In a study involving pediatric patientsundergoing open heart surgery, ACC time over 80 min hasalso been shown to lead to higher PCT levels on postoper-ative day 1 [37]. However, in our study organ failure wasfound to be correlated with ACC and CPB times, whereasmortality was not.

Consecutive PCT sampling in patients with organ fail-ure may help identify the course of the disease and allowus to devise therapeutic interventions on time. However,since we stopped PCT sampling on postoperative day 4,except for the infected patients, it is not possible to drawa conclusion regarding the PCT trend beyond that periodduring organ failure development.

There are some limitations to our study. The mostimportant one is the antibiotic (cefazolin) prophylaxisfor 72 h, which may affect our PCT results or maskan underlying infection. However, none of the patientssuffered an infection after the cessation of the antibiotictherapy during the follow-up period except for the sixpatients in the SIRS+OF group. Besides, PCT levelsdecreased rapidly following its peak on postoperativeday 1 which would not be the case in the presence of aninfection. Another limitation is the small number of thepatients enrolled. A study involving more patients mighthave given more reliable results.

In conclusion, PCT levels increased excessively inSIRS with accompanying organ failure after CPB, and thepeak PCT levels measured on postoperative day 1 werefound to be positively correlated with prolonged ACC,CPB times, prolonged mechanical ventilation, ICU stayand hospitalization. Peak PCT levels have been shownto be valuable in predicting organ failure and mortality.Daily PCT measurements in patients with SIRS andorgan failure may help identify the postoperative infectionduring the follow-up period, whereas CRP may not beuseful.

Acknowledgements. This study was supported by the Fund of Is-tanbul University.

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