Is Procalcitonin Useful in Pediatric Critical Care Patients?

Abstract

This review examines the use of procalcitonin in different clinical situations in the pediatric patient, with special emphasis on those requiring intensive care. We review the latest articles on its potency as a biomarker in both infectious processes at diagnosis and on the response to treatment.

Keywords

PCT infections PICU stewarship biomarker

Introduction

Infections are one of the most prevalent pathologies in pediatric intensive care units (PICU). In fact, invasive bacterial infection (IBI) is a major cause of morbidity and mortality in adult and pediatric populations, affecting up to 20% to 70% of hospitalized cases.^1,2 Patients with severe infection may develop an systemic inflammatory response syndrome (SIRS)³ which, in fact, has been part of the diagnosis criteria of septic patients.⁴ The differential diagnosis between IBI and viral infection is not always easy, especially in younger patients. What’s more, SIRS may occur in other pathologies besides IBI,⁵ as happens post-surgery^6,7 and in polytrauma patients.⁸

Another important issue related to IBI is that the correct control of the infection requires an early specific diagnosis,^9–11 both in adults and in pediatric patients. Some analytical data such as leukocyte count, immature white cell count,¹² and C-reactive protein value (CRP)^13,14 have been classically used to distinguish between bacterial and viral infection, but they are unspecific.¹⁵ A correct approach to IBI management focuses on individualized and appropriate duration of the antibiotic treatment, to prevent antibiotic resistance and improve the prognosis. During the past 15 years, different publications have reported the use of procalcitonin (PCT) to help at different points in the approach to IBI—in diagnosis, monitoring, and prognosis—and as a guide to the duration of antibiotic treatment.^16,17

The aim of this review was to determine whether PCT might be a useful marker in critically ill pediatric patients with IBI. For the present review, articles published up to January 2018 were reviewed. The search was performed in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. In this review, studies of the adult population have been included due to the lack of data in pediatric patients in some situations.

What Is Procalcitonin?

Procalcitonin is a 116 peptide of 13-kDa amino acid, without any hormonal activity, and a precursor of calcitonin hormone. Routinely produced in the C cells of thyroid gland, PCT reaches the bloodstream where levels below ng/mL may be detected.¹⁸ However, in 1993, the behavior of PCT in the context of sepsis was described¹⁹ and its use as a biomarker became widespread in the last 10 years.^20–22 Procalcitonin increases after exposure to endotoxins,²³ which makes it more or less specific for bacterial infections, depending on the invasiveness of the pathogen. In addition, the cytokines released in viral infections appear to attenuate PCT levels.^24,25

A biomarker is an indicator of a normal or pathological biological process. It can be analyzed in different biological liquids. A good biomarker allows for the diagnosis of the disease, determination of its severity, follow-up on its evolution, and evaluation of a response to treatment.²⁶ Procalcitonin is a biomarker that meets many of these requirements, especially in infectious processes, both for early diagnosis and to monitor antimicrobial treatment. Bacterial infection induces the expression of the PCT gene (calcitonin gene-related peptide 1 [CALC-1]) in different organs, raising PCT levels.^18,27 In healthy volunteers, it is detected at 4 hours after an Escherichia coli endotoxin infusion, with a plateau at between 8 and 24 hours, and a mean life of 24 to 36 hours.²³ It is minimally dependent on renal function. The utility of PCT has been documented in different clinical situations that will be discussed in separate points.

Procalcitonin and Bacterial Infection Diagnosis

Procalcitonin and infection

Procalcitonin seems to have better Sensitivity (Sn) and Specificity (Sp) than CRP for IBI diagnosis. The multicenter study by Lopez et al²⁸ showed that in an emergency department, PCT allowed an early IBI diagnosis in febrile infants (under 36 months), with better cutoffs than CRP: PCT 0.69 ng/mL (Sn 85.7%; Sp 98.5%) and for CRP, 19 mg/L (Sn, 61.3%; Sp, 80%). The authors considered IBI in the following infectious diseases confirmed by specific cultures: meningitis infections, sepsis, bone or joint infections (local isolation or in blood culture of the microorganism), acute pyelonephritis infections, lobar pneumonia, bacterial enteritis in infants under 3 months, and occult bacteremia.

In sepsis cases, Rey et al²⁹ demonstrated similar results, with a better diagnosis area under the curve (AUC) for PCT (0.91; 95% confidence interval [CI], 0.882-0.943) than for CRP (0.75; 95% CI, 0.699-0.802) in sepsis. Another important factor suggested by Rey was the possibility of classifying patients according to severity using PCT: the higher the value of PCT, the greater the severity of sepsis. Procalcitonin values more than 24.5 ng/mL were present in septic shock, values between 1.16 and 9.33 ng/mL corresponded to both sepsis and SIRS, and values below 0.89 ng/mL were rarely present in septic patients. Another important factor suggested by Rey was the possibility of classifying patients according to severity using PCT.

Fever without source (FWS) is a major problem in young infants in an emergency department. Luaces-Cubells et al³⁰ reported that PCT was the most useful biomarker to predict IBI in infants with FWS, even in rapidly evolving cases with fever duration of less than 8 hours, establishing the optimum cutoff for PCT: 0.9 ng/mL (Sn 86.7%, Sp 90.5%) and the optimum cutoff for CRP 91 mg/L (Sn 33.3%, Sp 95.6%). There are other publications with similar results.^31–33 Moreover, whereas PCT increases in severe bacterial infections, the levels remain low (<1 ng/mL) in common viral infections.³⁴ Interestingly, PCT can be introduced in models to explain the differing evolution of sepsis such as the PIRO concept: predisposing, infection, response, and organism.³⁵ It would appear as a patient response part. In the same way, it is included in the sepsis guidelines, as a criterion of the SIRS definition, with abnormal results up to 2 standard deviations from normal values.^36,37 To decide on patient transfer from the ICU to the general ward, PCT seems to be useful too.¹⁶ All data from the pediatric studies regarding the usefulness of PCT in fever with unknown focus or invasive infections are summarized in Table 1.

Table 1.

PCT to discriminate invasive infections, fever of unknown origin.

Study	Type	Population	n	Age	Aim	Gold standard	AUC	Cutoff^a	Sn (%)	Sp (%)	PPV (%)	NPV (%)	Conclusions
Mahajan (2014)³²	P, M	ED, febrile fever of unknown origin	226 SBI 30	<36 mo	PCT compared with traditional screening tests for detecting SBI	CRX, cultures	0.80	0.6	51	93	13	86	SBI = bacteremia, urinary tract infections, bacterial meningitis, lobar pneumonia, or bacterial enteritis. PCT is accurate for identifying young febrile infants and children with serious SBIs.
Luaces-Cubells (2012)³⁰	P, M	ED, febrile and non-toxic appearance	868 IBI 15	1-36 mo	PCT for IBI	CRX, cultures	0.87	0.9	86.7	90.5	—	—	IBI = meningitis, bacteriemia oculta or sepsis. PCT as a useful biomarker to predict IBI in non-toxic-appearing children less than 3 years of age with fever without apparent focus and absence of leukocytes in urine.
Rey (2007)²⁹	P	PICU, all patients admitted	94	0-14 y	PCT for detecting sepsis and to stratify according to severity	CRX, cultures	0.91	1.16	92	76	—	—	PCT is a better diagnostic marker of sepsis in critically ill children than CRP.
Lopez et al (2003)²⁸	P, M	ED, febrile children	445 IBI 150	1-36 mo	PCT for distinguishing viral and bacterial infection and for early diagnosis of IBI	CRX, cultures microbial tests, DMSA	0.95	0.59	91	94	90.8	90.1	PCT offers better E than CRP for differentiating viral and bacterial cause of the fever and offers better Sn and Sp than CRP to differentiate IBI.
Gendrel (1999)³⁴	P	ED. Hospital admission for fever	360 IBI 46	1 mo-15 y	PCT for distinguishing viral and bacterial infection	Microbial test and cultures	0.94	1	83	93	86	91	PCT was a better marker than CRP, IL-6, or IFN-alpha for distinguishing between bacterial and viral infections in children in the ED. PCT is a useful indicator of the severity of IBI
Chakravarti (2016)⁷⁹	R	CICU Infection suspected after CS	98	0-21 y	PCT to distinguish between the presence or absence of IBI	CRX, cultures	0.74	2	81.8	66.7	23.7	96.7	All included patients were suspected of infection. PCT levels were higher in the confirmed IBI
Bobillo (2016)⁸¹	P	NICU, after CS	51	<1 mo	Kinetics of PCT and its usefulness for diagnosis IBI	Clinical examination, CRX, cultures	0.87	5	87.5	72.6	29	97.8	No differences in PCT after CS with CPB and non-CPB. PCT could determine the absence of sepsis at 24 h after CS
Garcia (2012)³⁹	P	PICU, after CPB in CS	231	1 mo-16 y	PCT to distinguish between SIRS and postsurgical infection after CPB	Clinical examination, CRX, cultures	0.86 (48 h)	4	62	87.9	61.5	—	PCT after CPB is useful in the diagnosis of IBI. Values above the limit for each period should alert IBI to initiate or modify antibiotic treatment.

Abbreviations: AUC, area under the curve; CAP, community acquired pneumonia; CICU, cardiac intensive care unit; CPB, cardiopulmonary bypass; CRP, C-reactive protein; CRX, chest x-ray; CS, cardiothoracic surgery; DMSA, ^99mTc-dimercaptosuccinic acid; ED, emergency department; IBI, invasive bacterial infection; IFN, interferon; IL-6, interleukin 6; M, multicenter study; NICU, neonatal intensive care unit; NPV, negative predictive value; P, prospective study; PCT, procalcitonin; PICU, pediatric intensive care unit; PPV, positive predictive value; R, retrospective study; SBI, serious bacterial infection; SIRS, systemic inflammatory response syndrome; Sn, sensitivity; Sp, specificity.

Cutoff value for procalcitonin. Values expressed in ng/mL.

Other studies have determined that PCT levels increase in other causes of bacterial infection. Although not all of them compared PCT with other biomarkers or gold standards, results on the usefulness of PCT appear to be promising, and they are detailed below in subsections.

Urinary tract infections

Another use of PCT in febrile patients is the differential diagnosis of lower urinary tract infection and pyelonephritis, with an upper cutoff point of 0.5 to 1 ng/mL.^41–44 In a more recent meta-analysis, levels > 0.5 ng/mL predict the presence of renal parenchymal involvement. Therefore, PCT has been included in a clinical practice guideline.⁴⁵ Table 2 summarizes the main studies to analyze the use of PCT in urinary tract infections.

Table 2.

PCT in urinary tract infections.

Study	Type	Population	n	Age	Aim	Gold standard	AUC	Cutoff^a	Sn (%)	Sp (%)	PPV (%)	NPV (%)
Liao et al (2014)⁴⁵	P	First febrile UTI	278 (75 RS)	⩽2 y	PCT to detect RS and VUR	US, DMSA, VCUG	—	—	—	—	—	—
Bressan et al (2009)⁴⁴	P	First febrile UTI	72 (14 RS)	7 d-3 y	PCT to detect RS	DMSA VCUG	—	0.5	85.7	51	—	—
Prat et al (2003)⁴³	—	First febrile UTI	77 (13 RS)	1 mo-12 y	PCT to distinguish uncomplicated vs severe UTI with RS	DMSA	0.83	1	92	92	32	98
Smolkin et al (2002)⁴²	P	First febrile UTI	64 (18 RS)	15 d-3 y	PCT to distinguish uncomplicated vs severe UTI	DMSA	—	0.5	94	90	86	98
Gervaix et al (2001)⁴¹	P	Febrile UTI	54 (34 RS)	7 d-16 y	PCT to distinguish uncomplicated vs severe UTI	DMSA	—	0.5	74	85	—	—

Abbreviations: AUC, area under the curve; DMSA, ^99mTc-dimercaptosuccinic acid; NPV, negative predictive value; PCT, procalcitonin; P, prospective; PPV, positive predictive value; R, retrospective; RS, renal scars; Sn, sensitivity; Sp, specificity; US, ultrasound; UTI, urinary tract infection; VCUG, voiding cystourethrography; VUR, vesicoureteral reflux.

Cutoff value for procalcitonin. Values expressed in ng/mL.

Respiratory infections

An important indication of PCT is in suspected pneumonia, especially in pediatric patients in whom viral infections are clinically similar to bacterial infections, when radiology and other laboratory data do not increase diagnostic accuracy.⁴⁶ There are no recent studies in this area in pediatrics (Table 3). In the Toikka et al⁴⁶ study, the median PCT value in bacterial pneumonia was 2.09 ng/mL vs 0.56 ng/mL in viral pneumonia (P = .019). Therefore, PCT levels >2 ng/mL could suggest bacterial pneumonia but it has to be noted that cases with normal values of short evolution should be monitored.^49,50 Lower values of PCT do not permit one to distinguish between bacterial and viral pneumonia.^47,48 Furthermore, PCT does not allow us to distinguish between viral infection and infection with Mycoplasma pneumoniae or Chlamydia pneumonia⁵¹ nor has it been proven to reduce the duration of antibiotic treatment in adults.⁵²

Table 3.

PCT in respiratory tract infections.

Study	Type	Population	n	Age	Aim	Gold standard	AUC	Cutoff^a	Sn (%)	Sp (%)	PPV (%)	NPV (%)	Conclusions
Korppi (2003)⁵¹	P	CAP confirmed by CRX. Primary health care settings	190	0-15 y	1, 2	CRX, microbial tests	0.58	0.5	46	52	—	—	PCT has no role in diagnosis of bacterial CAP in primary health care settings
Prat (2003)⁴⁷	—	CAP. Clinical or RX diagnosis in ED	85	6 mo-10 y	1	CRX, microbial tests	0.76	2	69	80	—	—	PCT shows good S for distinguishing pneumococcal form other pneumonias. PCT can help to rationalize antibiotic therapy
Hatzistilianou (2002)⁵⁰	P	Hospital admission for clinical pneumonia	73	2-14 y	1, 3	CRX, microbial tests	—	2	100	98	93	—	PCT is a good marker of bacterial pneumonia
Korppi (2001)⁴⁸	P	Hospital admission for pneumonia	132	—	1, 2	CRX, microbial tests	—	1	32	88	—	—	PCT does not discriminate between viral and bacterial pneumonia
Moulin (2001)⁴⁹	—	ED. Hospital admission for severe CAP	72	2 mo-13 y	1	CRX, microbial tests	0.93	1	86	87.5	90.2	80	PCT differentiates between bacterial and viral pneumonia
Toikka (2000)⁴⁶	—	Hospital admission	126	1 mo-17 y	1	CRX, microbial tests	—	2	50	80	—	—	If PCT > 2 ng/mL, bacterial pneumonia is highly probable

Abbreviations: AUC, area under the curve; CAP, community acquired pneumonia; CRX, chest x-ray; ED, emergency department; NPV, negative predictive value; P, prospective study; PCT, procalcitonin; Sn, sensitivity; Sp, specificity.

PCT to distinguish between bacterial and viral pneumonia.

PCT to differentiate the specific cause of pneumonia (chlamydia, mycoplasma.).

PCT to reduce the antibiotic treatment.

Cutoff value for procalcitonin. Values expressed in ng/mL.

Neonatal infections

Neonates present a physiological induction of an acute inflammatory reaction in the peripartum.^53,54 Therefore, there is some difficulty in interpreting the PCT values in this situation to make a diagnosis of infection. In addition, some reports have detected elevated PCT levels in newborns with respiratory distress syndrome in the absence of any other signs of infection.^55,56 There are even studies in which PCT is analyzed in umbilical cord blood for the diagnosis of early onset sepsis,⁵⁷ although this use has not been extended to neonatal units. There are modified charts for this situation that help with the diagnosis and interpretation of PCT in the neonatal patient, along with clinical judgment.^58–60 In addition, a repeated measurement of PCT can be performed and if there is a progressive increase in its levels, an infectious complication should be suspected. From the third day of life in small infants, PCT values should be the same as those discussed in pediatrics and in adults and older children.⁵⁸ So PCT could lead to reduced antibiotic therapy duration.⁵⁴ A number of studies performed in newborns are summarized in Table 4. Interestingly, Hahn et al⁶⁸ reported that reference levels in low premature newborns with gestational age <32 weeks were different according to postnatal age: higher in those with lower gestational age or with fewer days. This must be considered.

Table 4.

PCT in other situations.

Study	Type	Population	n	Age	Aim	Conclusions
Stocker (2010)⁵⁴	P, I	NICU, GA > 34, suspected of early onset sepsis	121	<3 d	PCT-guided decision-making on antibiotic	Serial PCT measurements allowed shortening the duration of empiric antibiotic therapy 22.4 h. The age-adjusted PCT nomogram with a safety cutoff value of 10 ng/mL seems to be reasonable.
Kordek (2003)⁵⁷	P	NICU, all newborns (preterm and term)	187	Umbilical cord	PCT for diagnosis of intrauterine IBI	AUC, 0.75 PCT cutoff 1.2 ng/mL, Sn 69%, Sp 81%, PPV 42%, NPV 93%. PCT in preterm infants with IBI is significantly higher than in term neonates.
Chiesa (1998)⁵⁸	P	NICU, all newborns (preterm and term)	318 143 sepsis 175 controls	0-48 h 3-30 d	PCT for diagnosis early and late-onset sepsis	PCT can be a marker of early onset sepsis. PCT for early detection of late-onset infections and for monitoring the follow-up of clinical course.
Hemming (2017)⁶⁹	P	Febrile neutropenia in children with cancer	48 episodes	0-18 y	PCT for diagnosis severe IBI	PCT > 2 ng/mL is associated with increased risk of severe infection. Data suggest that the clinical decision rules are largely ineffective in risk stratification.
Fleischhack (2000)⁷⁰	R	Febrile neutropenia in children with cancer	122 episodes	0.7-31.8 y	PCT to detected IBI. PCT to monitor response to antibiotic	PCT cutoff 0.5 ng/mL, Sn 60%, Sp 85%. PCT was superior to other parameters in the early detection of gram-negative bacteraemia and fever of unknown origin.
Ozsurekci (2016)⁷⁵	P	Fever with unknown focus and a central venous catheter	62	1 mo-18 y	PCT for diagnosis of catheter-related bloodstream infections	AUC 0.68, PCT cutoff 1.18 ng/mL, Sn 71%, Sp 80%, PPV 77%, NPV 74%. PCT may be a useful rapid diagnostic biomarker for suspected catheter-related bloodstream infections.
Butbul-Aviel (2005)⁶¹	—	ED Child with fever and limp	44	15 d-19 y	PCT for diagnosis of osteomyelitis and septic arthritis	Clinical diagnosis, pus and culture. PCT cutoff 0.5 ng/mL, Sn 43.5%, Sp 100%, PPV 100%. PCT as a useful marker in the diagnosis of osteomyelitis but not in septic arthritis.
Bobillo (2018)⁷⁸	P	PICU, assisted with ECMO	40	<18 y	Kinetics of PCT and its relationship with morbidity and mortality	PCT could be useful in the same situations as in patients without ECMO.
Sariego-Jamardo (2017)³⁸	P	PICU After different types of surgery	115	—	Kinetics of PCT increase above the suggested cutoff level for PCT for the diagnosis of sepsis	PCT showed an early peak at 24 h after surgery with a rapid decrease. PCT showed no increase after clean and clean-contaminated surgery. PCT seems to be a useful tool to guide diagnosis and antibiotic approach to nosocomial sepsis in the postoperative period
Launes (2016)⁹⁵	P	PICU Bacterial nosocomial infection confirmed by cultures	96	1 mo-18 y	To analyze results after implementation of antibiotics de-escalation protocol guided by PCT	Protocol of stewardship: PCT decreasing >50% in comparison with its value at diagnosis, or <0.5 ng/mL. After the implementation of the protocol, 75% of the children were treated for 10 days, compared with 14 days of the pre-implementation period. PCT-guided protocol reduced the exposure to antibiotics in nosocomial infections without adverse outcomes.
Rungatscher (2013)⁶³	P	PICU, assisted with veno-arterial ECMO	20	<2 y	PCT for predicting infection, organ dysfunction, and clinical outcome	Higher PCT values in patients non-infected (Infected, 2.4 ng/mL and non- infected, 8.8 ng/mL). Higher PCT values in patients with multi-organ dysfunction (10.9 vs 1.85 ng/mL).
Davidson (2013)⁴⁰	P	CICU After CS	69	<3 mo	Kinetics of PCT	PCT rises after cardiothoracic surgery but decreases by 72 h. Higher PCT levels at 72 h are independently associated with increased circulatory support at 72 h and a trend toward increased length of intubation. PCT may be better than CRP as a sepsis biomarker.

Abbreviations: AUC, area under the curve; CICU, cardiac intensive care unit; CRP, C-reactive protein; CS, cardiothoracic surgery; ECMO, extracorporeal membrane oxygenation; ED, emergency department; GA, gestational age; I, interventional study; IBI, invasive bacterial infection; NICU, neonatal intensive care unit; NPV, negative predictive value; P, prospective study; PCT, procalcitonin; PICU, pediatric intensive care unit; R, retrospective study; Sn, sensitivity; Sp, specificity.

Infections in hemato-oncology

In hemato-oncology patients, PCT can be used as a marker of infection and severity,⁶⁹ although some authors emphasize that further studies are needed to define the cutoff for this protein in situations of immunologic deficit⁷⁰ (Table 4). In patients with neutropenia, PCT induction may be reduced but not inhibited, so lower limit values, probably between 0.1 and 1.5 ng/mL, would be recommendable.⁷⁰ Paraneoplastic syndromes and small cell lung cancer may induce PCT elevation.^62,71–73 Regarding localized bone infections, septic arthritis, and soft tissue infections, PCT has not been shown to be a good biomarker. It is possible that the cutoff level to differentiate this localized pathology is much lower than the one currently available.⁶¹ There is a new ultrasensitive PCT method, which quantifies PCT levels below 0.5 ng/mL. Perhaps this ultrasensitive method⁷⁴ will play a leading role in the management of localized infectious disease in the coming years.

Nosocomial infections

Procalcitonin in the critically ill patient is very important because of its contribution to warning of risk of nosocomial infection and its implications in life prognosis. High PCT should serve to warn about nosocomial infection in those patients without other causes of higher PCT such as cardiopulmonary arrest and some kinds of surgeries, especially with PCT levels up to 2 ng/mL.⁶⁶ It is also useful for diagnosis of catheter-related-infection in those patients in whom other infections are also under study⁷⁵ (Table 4).

Procalcitonin in extracorporeal membrane oxygenation support

The contact of the blood with extracorporeal circulation initiates activation of proinflammatory cytokines that leads to SIRS.⁷⁶ In spite of improvement in the materials of the extracorporeal membrane oxygenation (ECMO) circuit, the SIRS that is developed continues to be a problem in these patients, both adult and pediatric. There is a paucity of data about PCT kinetics after entering in ECMO support, as well as about its response to an ECMO infection. An article published in 2013 on pediatrics⁶³ seemed to indicate that PCT values were especially low in patients infected during ECMO. According to the authors’ results, it appeared that PCT was related to patient morbidity (secondary to organ dysfunction), but not to the presence of infection. In adults, recent data shows PCT’s ability to detect general postoperative complications after long-term ventricular assist device more than infectious complications.⁷⁷ However, an article on adults⁶⁴ concluded that PCT was not modified by entry into ECMO and that it might be a good biomarker of severe infection in these patients. In a recent article that analyzed 40 pediatric patients in ECMO,⁷⁸ PCT seemed to produce the expected kinetics for the pathology that conditioned ECMO support, but data about the relation of PCT and infection in ECMO are still weak (Table 4). Therefore, more studies are required to evaluate the usefulness of PCT as a biomarker of infection and morbidity in these patients.

Procalcitonin in surgical procedures

After surgery, there is frequently a SIRS with fever. It is extremely important to find a specific biomarker that could differentiate between bacterial infection and its absence, to avoid unnecessary antibiotics. In adults, studies on postoperative PCT suggest that it may increase depending on the severity, type, and duration of the procedure.⁶⁷ In children, the response of PCT also varies depending on the characteristics of the surgery. In major abdominal surgery, PCT levels may rise 2 ng/mL, especially in dirty surgery. This increase is short-lived, and PCT levels fall 24 to 36 hours after surgery. In this context, a daily determination of PCT could be helpful in detecting increases after this time, thereby alerting of infectious complications.³⁸ In cardiopulmonary bypass (CPB) patients, PCT may also increase in relation to CPB time, as CPB is a potent inducer of SIRS. Many factors influence this increase (anesthesia, endotoxins, trauma, and tissue ischemia).⁴⁰ In these postoperative periods, the normal cutoff values should probably start from higher normal values, around 2 ng/mL⁷⁹ and therefore it is important to monitor them daily. Values greater than 10 ng/mL should be considered as septic complications.^39,80 Although there are few studies on PCT in neonates after CPB, it appears that PCT values above 4 ng/mL at 24 hours and 5 ng/mL at 48 hours post-CBP should alert the clinician to infectious complications.⁸¹ Procalcitonin has also been proven to be a useful tool to identify patients at risk of delayed complications after CPB in adults.⁷

However, PCT has not proved useful during the first 7 days after liver transplant in pediatric patients, taking a week to fall to normal levels (0.5 ng/mL).⁸² Nevertheless, there are several studies which have proven the useful strategy of monitoring PCT values after abdominal surgery to predict infection or major complications when PCT increase is detected, especially at 48 hours after surgery.^83–85

In newborn populations, even surgical procedures without CPB may increase serum cytokines and other inflammatory markers, interfering with postoperative infection diagnosis. Pavcnik-Arnol et al⁸⁶ and Bölke et al⁸⁷ found in their studies higher PCT levels prior to and after surgery in newborns affected by gastroschisis compared with other patients (congenital diaphragmatic hernia or intestinal atresia), explaining this difference by bacterial contamination of the exterior gastrointestinal tract and decreased intestinal circulation.

Procalcitonin usefulness in polytrauma

The evolution and utility of PCT in trauma has not been assessed to date in children. The value of PCT in traumatic adults depends on the type and severity of the trauma. In isolated peripheral lesions, PCT induction (as opposed to CRP) is mild. In abdominal trauma, the levels increase to ranges similar to those for extensive abdominal surgery. A daily measurement is necessary for differential diagnosis (PCT progression). It is associated with increased overall risk of complications (prolonged ICU stay, severe sepsis, septic shock, and higher mortality rate).⁸⁸ It appears that PCT rises proportionally to the severity of tissue damage and hypovolemia.⁸⁹

Procalcitonin as Antibiotic Guideline

In recent years, numerous studies, especially in adults, have been published on the usefulness of PCT as a biomarker of response to antimicrobial treatment and stewardship guided by PCT. In adults, the first report was the PRORATA trial, by Bouadma,⁹⁰ which analyzed the use of PCT to reduce patients’ exposure to antibiotics in intensive care units. This multicenter randomized controlled trial evaluated adult patients with severe bacterial infection. Antibiotics were started and concluded depending on the PCT levels. The PCT-guided group had a significantly shorter antibiotic duration with respect to the control group, with an absolute difference of 2.7 days, and without any complications. Other studies in adults have demonstrated similar results,^65,91,92 as summarized in some meta-analyses of randomized controlled trials.^93,94 In pediatric PICU patients, there are few data. Launes et al⁹⁵ demonstrated a 2-day antibiotic reduction in nosocomial infections, without an increase in complications. Also in newborns with early onset sepsis, there was demonstrated to be a reduction of almost a day (22.4 hours) in antibiotic therapy⁵⁴ (Table 4).

Financial Assessment of Procalcitonin-Guided Protocols

The only data available at this time come from studies conducted in the adult population. We refer to them for their possible extrapolation to future studies in the pediatric population. Daren reviewed and analyzed previously published interventional studies, which reported reduction of antibiotic exposure in PCT-guided protocols, to determine the financial cost. There was assumed to be a mean of 2 days of antibiotic reduction overall.⁹⁶ In the PCT-guided group, the total antibiotic duration resulted in a mean of 6 days, and 8 in the non-PCT guided group. There was detected to be a 15% lower cost in the PCT group, when including antibiotic and PCT analysis. Wilke et al⁹⁷ conducted a similar study, which analyzed 6 relevant studies about PCT-guided treatment (in septic and mechanical ventilation-associated pneumonia patients) with very similar results.

Procalcitonin Limitations

Procalcitonin, like any other biomarker, needs to be used in line with patient clinical symptoms and signs and, more importantly, with medical judgment. Procalcitonin could yield false positive values in some cases. This can be seen in the first 48 hours of life in neonatal patients (physiological increase),^98,99 for example. In adults, there is more published evidence, with literature supporting an increase in the value of PCT during the first 24 to 48 hours following a major surgical procedure,¹⁰⁰ severe trauma,¹⁰¹ or burns,¹⁰² and in severe or prolonged cardiac shock.^24,103 The OKT3 antibody treatment and other inflammatory procytokines may raise PCT levels as well. Higher PCT baseline levels in some types of lung cancer and in thyroidal C-cell carcinoma have been reported.¹⁰⁴ In any case, the highest levels in these situations are not normally that high, so that PCT levels up to 10 ng/mL may be considered as a septic situation. In the same line, when PCT in these doubtful patients increases continuously, one should be on the alert for an infectious complication. At the beginning of bacterial infection cases (first 12 hours of evolution), in localized infections, and in subacute endocarditis, PCT levels may be inappropriately low, so caution in monitoring may be indicated in these patients. Most of these limitations may be avoided with close PCT monitoring, especially at the beginning of a clinical situation that suggests analyzing this biomarker.

Conclusions

Procalcitonin seems to be a good biomarker to diagnose and monitor critically ill pediatric patients with mild-to-moderate as well as severe bacterial infections. Procalcitonin also seems to decrease antibiotic exposure and it shortens the PICU stay. However, more studies are needed to confirm its usefulness for stewardship as has already been demonstrated in adults.

Footnotes

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

JRF, IJS and BP designed the review. RF and BP wrote the first draft of the manuscript. IJC revised all the different drafts and reviews of the manuscript. All authors reviewed and approved final version of the manuscript.

References

Maoldomhnaigh

Drew

Gavin

Cafferkey

Butler

KM.

Invasive meningococcal disease in children in Ireland, 2001–2011. Arch Dis Child. 2016;101:1125–1129. http://adc.bmj.com/lookup/doi/10.1136/archdischild-2015-310215.

Schrag

Farley

Petit

et al . Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics. 2016;138: e20162013. http://pediatrics.aappublications.org/cgi/doi/10.1542/peds.2016-2013.

Davies

Hagen

P-O.

Systemic inflammatory response syndrome. Br J Surg. 1997;84:920–935.

Goldstein

Giroir

Randolph

International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2–8.

Bell

Wattie

Byth

et al . Procalcitonin: a marker of bacteraemia in SIRS. Anaesth Intensive Care. 2003;31:629–636.

Takenaka

Ogawa

Wada

Hirata

Systemic inflammatory response syndrome and surgical stress in thoracic surgery. J Crit Care. 2006;21:48–53.

Klingele

Bomberg

Schuster

Schäfers

Groesdonk

HV.

Prognostic value of procalcitonin in patients after elective cardiac surgery: a prospective cohort study. Ann Intensive Care. 2016;6:116. http://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-016-0215-8.

Jacome

Tatum

Systemic inflammatory response syndrome (SIRS) score independently predicts poor outcome in isolated traumatic brain injury. Neurocrit Care. 2018;28:110–116. http://link.springer.com/10.1007/s12028-017-0410-y.

Kalich

Maguire

Campbell-Bright

et al . Impact of an antibiotic-specific sepsis bundle on appropriate and timely antibiotic administration for severe sepsis in the emergency department. J Emerg Med. 2016;50:79–88.e1. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.jemermed.2015.09.007.

10.

Wallgren

Antonsson

Castrén

Kurland

Longer time to antibiotics and higher mortality among septic patients with non—specific presentations—a cross sectional study of emergency department patients indicating that a screening tool may improve identification. Scand J Trauma Resusc Emerg Med. 2016;24:1. http://www.sjtrem.com/content/24/1/1.

11.

Weiss

Fitzgerald

Balamuth

et al . Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis. Crit Care Med. 2014;42:2409–2417.

12.

Das

Critical advances in septicemia and septic shock. Crit Care. 2000;4:290–296. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=137258&tool=pmcentrez&rendertype=abstract.

13.

Martínez

Ferrer

Torrents

et al . Impact of source control in patients with severe sepsis and septic shock. Crit Care Med. 2017;45:11–19. http://insights.ovid.com/crossref?an=00003246-201701000-00002.

14.

Berg

Inchley

Fjaerli

Leegaard

Lindbaek

Nakstad

Clinical features and inflammatory markers in pediatric pneumonia: a prospective study. Eur J Pediatr. 2017;176:629–638.

15.

Díaz

García

Gamero

et al . Lack of accuracy of biomarkers and physical examination to detect bacterial infection in febrile infants. Pediatr Emerg Care. 2016;32:664–668. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00006565-201610000-00003.

16.

de Jong

van Oers

Beishuizen

et al . Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16:819–827. https://dx-doi-org.web.bisu.edu.cn/10.1016/S1473-3099(16)00053-0.

17.

Esposito

Tagliabue

Picciolli

et al . Procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia. Respir Med. 2011;105:1939–1945. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.rmed.2011.09.003.

18.

Davies

Procalcitonin. J Clin Pathol. 2015;68:675–679.

19.

Assicot

Gendrel

Carsin

Raymond

Guilbaud

Bohuon

High serum procalcitonin concentrations in patients with sepsis and infection. Lancet (London, England). 1993;341:515–518. http://www.ncbi.nlm.nih.gov/pubmed/8094770.

20.

Nath

Jayapalan

Nair

et al . Comparative diagnostic test evaluation of serum procalcitonin and C-reactive protein in suspected bloodstream infections in children with cancer. J Med Microbiol. 2017;66:622–627.

21.

Pontrelli

Crescenzo

De Buzzetti

et al . Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis. BMC Infect Dis. 2017;17:302.

22.

Giacobbe

Mikulska

Tumbarello

et al . Combined use of serum (1,3)-β-D-glucan and procalcitonin for the early differential diagnosis between candidaemia and bacteraemia in intensive care units. Crit Care. 2017;21:176.

23.

Dandona

Nix

Wilson

et al . Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab. 1994;79:1605–1608.

24.

Ostermann

Ayis

Tuddenham

et al . Cardiac troponin release is associated with biomarkers of inflammation and ventricular dilatation during critical illness. Shock. 2017;47:702–708.

25.

Henriquez-Camacho

Losa

Biomarkers for sepsis. Biomed Res Int. 2014;2014:547818.

26.

Atkinson

Colburn

DeGruttola

et al . Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.

27.

Muller

White

Nylen

Snider

Becker

Habener

JF.

Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab. 2001;86:396–404.

28.

Lopez

Cubells

García

Pou

JF.

Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and utility of a rapid qualitative test for this marker. Pediatr Infect Dis J. 2003;22:895–904. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00006454-200310000-00010.

29.

Rey

Los Arcos

Concha

et al . Procalcitonin and C-reactive protein as markers of systemic inflammatory response syndrome severity in critically ill children. Intensive Care Med. 2007;33:477–484.

30.

Luaces-Cubells

Mintegi

García-García

J-J

et al . Procalcitonin to detect invasive bacterial infection in non-toxic-appearing infants with fever without apparent source in the emergency department. Pediatr Infect Dis J. 2012;31:645–647. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00006454-201206000-00027.

31.

van der Does

Rood

PPM

Haagsma

Patka

van Gorp

ECM

Limper

Procalcitonin-guided therapy for the initiation of antibiotics in the ED: a systematic review. Am J Emerg Med. 2016;34:1286–1293. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.ajem.2016.03.065.

32.

Mahajan

Grzybowski

Chen

et al . Procalcitonin as a marker of serious bacterial infections in febrile children younger than 3 years old. Acad Emerg Med. 2014;21:171–179.

33.

Prat

Domínguez

Rodrigo

et al . Use of quantitative and semiquantitative procalcitonin measurements to identify children with sepsis and meningitis. Eur J Clin Microbiol Infect Dis. 2004;23:136–138.

34.

Gendrel

Raymond

Coste

et al . Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections. Pediatr Infect Dis J. 1999;18:875–881.

35.

Opal

SM.

Concept of PIRO as a new conceptual framework to understand sepsis. Pediatr Crit Care Med. 2005;6: S55–S60. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00130478-200505001-00013.

36.

Dellinger

Levy

Rhodes

et al . Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228.

37.

Rhodes

Evans

Alhazzani

et al . Surviving sepsis campaign. Crit Care Med. 2017. https://journals.lww.com/ccmjournal/Fulltext/2017/03000/Surviving_Sepsis_Campaign___International.15.aspx.

38.

Sariego-Jamardo

Rey

Medina

et al . C-reactive protein, procalcitonin and interleukin-6 kinetics in pediatric postoperative patients. J Crit Care. 2017;41:119–123. http://linkinghub.elsevier.com/retrieve/pii/S0883944117301673.

39.

Garcia

Gargallo

Torné

et al . Procalcitonin: a useful biomarker to discriminate infection after cardiopulmonary bypass in children. Pediatr Crit Care Med. 2012;13:441–445. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00130478-201207000-00011.

40.

Davidson

Tong

Hauck

Lawson

da Cruz

Kaufman

Kinetics of procalcitonin and C-reactive protein and the relationship to postoperative infection in young infants undergoing cardiovascular surgery. Pediatr Res. 2013;74:413–419.

41.

Gervaix

Geletto-Lacour

Gueron

Vadas

Zamora

Suter

SGE

. Usefulness of procalcitonin and C-reactive protein rapid tests for the management of children with urinary tract infection. Pediatr Infect Dis J. 2001;20:507–511.

42.

Smolkin

Koren

Raz

Colodner

Sakran

Halevy

Procalcitonin as a marker of acute pyelonephritis in children. Pediatr Nephrol. 2002;17:409–412.

43.

Prat

Domínguez

Rodrigo

et al . Elevated serum procalcitonin values correlate with renal scarring in children with urinary tract infection. Pediatr Infect Dis J. 2003;22:438–442. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00006454-200305000-00010.

44.

Bressan

Andreola

Zucchetta

et al . Procalcitonin as a predictor of renal scarring in infants and young children. Pediatr Nephrol. 2009;24:1199–1204.

45.

Liao

Tsai

et al . Comparison of procalcitonin and different guidelines for first febrile urinary tract infection in children by imaging. Pediatr Nephrol. 2014;29:1567–1574.

46.

Toikka

Irjala

Juven

et al . Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis J. 2000;19:598–602. http://www.ncbi.nlm.nih.gov/pubmed/10917215.

47.

Prat

Dominguez

Rodrigo

et al . Procalcitonin, C-reactive protein and leukocyte count in children with lower respiratory tract infection. Pediatr Infect Dis J. 2003;22:963–968.

48.

Korppi

Remes

Serum procalcitonin in pneumococcal pneumonia in children. Eur Respir J. 2001;17:623–627. http://www.ncbi.nlm.nih.gov/pubmed/11401055.

49.

Moulin

Raymond

Lorrot

et al . Procalcitonin in children admitted to hospital with community acquired pneumonia. Arch Dis Child. 2001;84:332–336. http://www.ncbi.nlm.nih.gov/pubmed/11259234.

50.

Hatzistilianou

Hitoglou

Gougoustamou

et al . Serum procalcitonin, adenosine deaminase and its isoenzymes in the aetiological diagnosis of pneumonia in children. Int J Immunopathol Pharmacol. 2002;15:119–127.

51.

Korppi

Remes

Heiskanen-Kosma

Serum procalcitonin concentrations in bacterial pneumonia in children: a negative result in primary healthcare settings. Pediatr Pulmonol. 2003;35:56–61.

52.

Shehabi

Sterba

Garrett

et al . Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med. 2014;190:1102–1110.

53.

Marchini

Berggren

Djilali-Merzoug

Hansson

LO.

The birth process initiates an acute phase reaction in the fetus-newborn infant. Acta Paediatr Int J Paediatr. 2000;89:1082–1086.

54.

Stocker

Fontana

El Helou

Wegscheider

Berger

TM.

Use of procalcitonin-guided decision-making to shorten antibiotic therapy in suspected neonatal early-onset sepsis: prospective randomized intervention trial. Neonatology. 2010;97:165–174.

55.

Monneret

Labaune

Isaac

Bienvenu

Putet

Bienvenu

Procalcitonin and C-reactive protein levels in neonatal infections. Acta Paediatr. 1997;86:209–212.

56.

Rossum

AMC

Van Wulkan

Oudesluys-Murphy

AM.

Procalcitonin as an early marker of infection in neonates and children. Lancet Infect Dis. 2004;4:620–630.

57.

Kordek

Giedrys-Kalemba

Pawlus

Podraza

Czajka

Umbilical cord blood serum procalcitonin concentration in the diagnosis of early neonatal infection. J Perinatol. 2003;23:148–153.

58.

Chiesa

Panero

Rossi

et al . Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. Clin Infect Dis. 1998;26:664–672. http://www.ncbi.nlm.nih.gov/pubmed/9524841.

59.

Turner

Hammerman

Rudensky

Schlesinger

Goia

Schimmel

Procalcitonin in preterm infants during the first few days of life: introducing an age related nomogram. Arch Dis Child Fetal Neonatal Ed. 2006;91:283–286.

60.

Fukuzumi

Osawa

Sato

et al . Age-specific percentile-based reference curve of serum procalcitonin concentrations in Japanese preterm infants. Sci Rep. 2016;6:23871. https://dx-doi-org.web.bisu.edu.cn/10.1038/srep23871.

61.

Butbul-Aviel

Koren

Halevy

Sakran

Procalcitonin as a diagnostic aid in osteomyelitis and septic arthritis. Pediatr Emerg Care. 2005;21:828–832. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00006565-200512000-00004.

62.

Reinhart

Bauer

Riedemann

Hartog

CS.

New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev. 2012;25:609–634.

63.

Rungatscher

Merlini

De rita

et al . Diagnosis of infection in paediatric veno-arterial cardiac extracorporeal membrane oxygenation: role of procalcitonin and C-reactive protein. Eur J Cardiothorac Surg. 2013;43:1043–1049.

64.

Pieri

Greco

De Bonis

et al . Diagnosis of infection in patients undergoing extracorporeal membrane oxygenation: a case-control study. J Thorac Cardiovasc Surg. 2012;143:1411–1416.e1. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.jtcvs.2012.01.005.

65.

Nobre

Harbarth

Graf

Rohner

Pugin

Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med. 2008;177:498–505.

66.

Charles

Kus

Aho

et al . Serum procalcitonin for the early recognition of nosocomial infection in the critically ill patients: a preliminary report. BMC Infect Dis. 2009;9:1–9. http://www.biomedcentral.com/1471-2334/9/49.

67.

Carr

JA.

Procalcitonin-guided antibiotic therapy for septic patients in the surgical intensive care unit. J Intensive Care. 2015;3:36. https://dx-doi-org.web.bisu.edu.cn/10.1186/s40560-015-0100-9.

68.

Hahn

Song

Park

Kim

Park

MH.

Reference intervals of serum procalcitonin are affected by postnatal age in very low birth weight infants during the first 60 days after birth. Neonatology. 2015;108:60–64.

69.

Hemming

Jakes

Shenton

Phillips

Prospective cohort study of procalcitonin levels in children with cancer presenting with febrile neutropenia. BMC Pediatr. 2017;17:2. http://www.ncbi.nlm.nih.gov/pubmed/28056911; http://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-016-0766-8.

70.

Fleischhack

Kambeck

Cipic

Hasan

Bode

Procalcitonin in paediatric cancer patients: its diagnostic relevance is superior to that of C-reactive protein, interleukin 6, interleukin 8, soluble interleukin 2 receptor and soluble tumour necrosis factor receptor II. Br J Haematol. 2000;111:1093–1102.

71.

Karagiannis

AKA

Girio-Fragkoulakis

Nakouti

. Procalcitonin: a new biomarker for medullary thyroid cancer? A systematic review. Anticancer Res. 2016;36:3803–3810. http://www.ncbi.nlm.nih.gov/pubmed/27466480.

72.

Limper

de Kruif

Duits

Brandjes

DPM

van Gorp

ECM

. The diagnostic role of Procalcitonin and other biomarkers in discriminating infectious from non-infectious fever. J Infect. 2010;60:409–416. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.jinf.2010.03.016.

73.

Becker

Snider

Nylen

ES.

Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med. 2008;36:941–952.

74.

Shao

Wang

Xie

Wang

Liang

WW.

Rapid and sensitive lateral flow immunoassay method for procalcitonin (PCT) based on time-resolved immunochromatography. Sensors (Switzerland). 2017;17: E480.

75.

Ozsurekci

Oktay Arıkan

Bayhan

et al . Can procalcitonin be a diagnostic marker for catheter-related blood stream infection in children? J Pediatr (Rio J). 2016;92:414–420. http://linkinghub.elsevier.com/retrieve/pii/S0021755716300249.

76.

Millar

Fanning

McDonald

McAuley

Fraser

JF.

The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Crit Care. 2016;20:387. http://ccforum.biomedcentral.com/articles/10.1186/s13054-016-1570-4.

77.

Kettner

Holek

Franekova

et al . Procalcitonin dynamics after long-term ventricular assist device implantation. Hear Lung Circ. 2017;26:599–603. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.hlc.2016.09.014.

78.

Bobillo

Rodríguez-Fanjul

Solé

et al . Kinetics of procalcitonin in pediatric patients on extracorporeal membrane oxygenation. Biomark Insights. 2018;13. http://journals.sagepub.com/doi/10.1177/1177271917751900.

79.

Chakravarti

Reformina

Lee

Malhotra

Mosca

Bhatla

Procalcitonin as a biomarker of bacterial infection in pediatric patients after congenital heart surgery. Ann Pediatr Cardiol. 2016;9:115–119. http://www.annalspc.com/text.asp?2016/9/2/115/180665.

80.

Sponholz

Sakr

Reinhart

Brunkhorst

Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature. Crit Care. 2006;10: R145. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1751067&tool=pmcentrez&rendertype=abstract.

81.

Bobillo Pérez

Rodríguez-Fanjul

García

Hernando

Sanz

MI.

Procalcitonin is a better biomarker than C-reactive protein in newborns undergoing cardiac surgery: the PROKINECA study. Biomark Insights. 2016;11:123–129.

82.

Cousin

Lambert

Trabelsi

et al . Procalcitonin for infections in the first week after pediatric liver transplantation. BMC Infect Dis. 2017;17:149.

83.

Slieker

Aellen

Eggimann

Guarnero

Schäfer

Demartines

Procalcitonin-guided antibiotics after surgery for peritonitis: a randomized controlled study. Gastroenterol Res Pract. 2017;2017:3457614. https://www.hindawi.com/journals/grp/2017/3457614/.

84.

Ren

et al . Prediction of procalcitonin for postoperative intraabdominal infections after definitive operation of intestinal fistulae. J Surg Res. 2016;206:280–285. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.jss.2016.08.055.

85.

Giaccaglia

Salvi

Antonelli

et al . Procalcitonin reveals early dehiscence in colorectal surgery. Ann Surg. 2015;263:967–972. https://insights.ovid.com/pubmed?pmid=26528879.

86.

Pavcnik-Arnol

Bonac

Groselj-Grenc

Derganc

Changes in serum procalcitonin, interleukin 6, interleukin 8 and C-reactive protein in neonates after surgery. Eur J Pediatr Surg. 2010;20:262–266.

87.

Bölke

Jehle

Trautmann

et al . Different acute-phase response in newborns and infants undergoing surgery. Pediatr Res. 2002;51:333–338.

88.

Meisner

Adina

Schmidt

Correlation of procalcitonin and C-reactive protein to inflammation, complications, and outcome during the intensive care unit course of multiple-trauma patients. Crit Care. 2006;10: R1.

89.

Mimoz

Benoist

Edouard

Assicot

Bohuon

Samii

Procalcitonin and C-reactive protein during the early posttraumatic systemic inflammatory response syndrome. Intensive Care Med. 1998;24:185–188.

90.

Bouadma

Luyt

Tubach

et al . Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010;375:463–474. https://dx-doi-org.web.bisu.edu.cn/10.1016/S0140-6736(09)61879-1.

91.

Hochreiter

Köhler

Schweiger

et al . Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care. 2009;13: R83. http://ccforum.biomedcentral.com/articles/10.1186/cc7903.

92.

Stolz

Smyrnios

Eggimann

et al . Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J. 2009;34:1364–1375.

93.

Kopterides

Siempos

Tsangaris

Tsantes

Armaganidis

Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med. 2010;38:2229–2241.

94.

Huang

H-B

Peng

J-M

Weng

Wang

C-Y

Jiang

Procalcitonin-guided antibiotic therapy in intensive care unit patients: a systematic review and meta-analysis. Ann Intensive Care. 2017;7:114. https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-017-0338-6.

95.

Launes

Esteban

Balaguer

Alsina

Cambra

Jordan

Procalcitonin-guidance reduces antibiotic exposure in children with nosocomial infection (PRORANI). J Infect. 2016;72:250–253.

96.

Heyland

Johnson

Reynolds

Muscedere

Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation. Crit Care Med. 2011;39:1792–1799. http://www.ncbi.nlm.nih.gov/pubmed/21358400.

97.

Wilke

Grube

Bodmann

KF.

The use of a standardized PCT-algorithm reduces costs in intensive care in septic patients—a DRG-based simulation model. Eur J Med Res. 2011;16:543-548. http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L51043106%5Cnhttp.

98.

Mithal

Palac

Yogev

Ernst

Mestan

KK.

Cord blood acute phase reactants predict early onset neonatal sepsis in preterm infants. PLoS ONE. 2017;12: e0168677.

99.

Lee

Bang

Lee

Choi

Hong

YS.

The influencing factors on procalcitonin values in newborns with noninfectious conditions during the first week of life. Korean J Pediatr. 2017;60:10–16.

100.

Giardino

Spolverato

Regi

et al . C-reactive protein and procalcitonin as predictors of postoperative inflammatory complications after pancreatic surgery. J Gastrointest Surg. 2016;20:1482–1492. https://dx-doi-org.web.bisu.edu.cn/10.1007/s11605-016-3171-6.

101.

Ahmed

Soliman

Samir

Cell free DNA and procalcitonin as early markers of complications in ICU patients with multiple trauma and major surgery. Clin Lab. 2016;62:2395–2404.

102.

Cabral

Afreixo

Almeida

Paiva

JA.

The use of procalcitonin (PCT) for diagnosis of sepsis in burn patients: a meta-analysis. PLoS ONE. 2016;11: e0168475.

103.

Bro-Jeppesen

Kjaergaard

Wanscher

et al . The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33°C or 36°C. Resuscitation. 2014;85:1480–1487. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.resuscitation.2014.08.007.

104.

Nozieres

Chardon

Goichot

et al . Neuroendocrine tumors producing calcitonin: characteristics, prognosis and potential interest of calcitonin monitoring during follow-up. Eur J Endocrinol. 2016;174:335–341.