Is the Preoperative Level of Procalcitonin a Valid Indicator for Predicting Postoperative Fever After Percutaneous Nephrolithotomy?

Abstract

Objective:

To evaluate the risk factors for postoperative fever and to identify the value of preoperative procalcitonin (PCT) in predicting postoperative fever after percutaneous nephrolithotomy (PNL).

Patients and Methods:

Patients who underwent PNL between January 2014 and March 2017 were studied. In total, 363 medical records with complete data were determined to be eligible for analysis. Patients were classified into a control or febrile group according to the presence of a body temperature over 38°C. Demographic and perioperative data were compared between the groups. Variables found to be statistically significant were included in a binary logistic regression analysis.

Results:

Ninety-one (25.1%) patients experienced postoperative fever. Univariate analysis revealed a statistically significant difference between postoperative fever and factors, such as sex (p = 0.009), preoperative fever (p < 0.001), stone burden (p < 0.001), pyuria (p = 0.013), urine culture (p < 0.001), and serum levels of C-reactive protein (CRP) (p = 0.003), PCT (p < 0.001), and interleukin-6 (IL-6) (p = 0.003). Binary logistic regression analysis indicated the presence of preoperative fever (p = 0.037), stone burden >353 mm² (p = 0.002), PCT >0.05 ng/mL (p < 0.001), or positive urine culture (p = 0.004) as independent risk factors for postoperative fever following PNL.

Conclusions:

We concluded that patients with preoperative fever, stone burden >353 mm², PCT >0.05 ng/mL, or positive urine culture were more likely to develop postoperative fever and that routinely detecting PCT levels before PNL would be helpful in predicting postoperative fever.

Introduction

Urolithiasis is one of the most common urological diseases, and its incidence increases yearly.¹ In a recent study, it was reported that kidney stones affected ∼1 in 17 adults in China, with an adjusted prevalence rate of 5.8%.² Manipulations for urolithiasis include extracorporeal shock wave lithotripsy, ureteroscopic lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy (PNL). With advancements in endourological instrumentation, PNL is now regarded as the first-line approach for large, multiple, or inferior calyx renal stones, with a high stone-free rate of over 90%.³ However, complications due to PNL may occur, with an overall complication rate of 83%, including urinary extravasation (7.2%), bleeding necessitating transfusion (11.2%–17.5%), and postoperative fever (21%–32.1%).⁴ Infectious complications are still the most common complications following PNL, which can progress to potentially life-threatening sepsis, with incidence rates between 0.3% and 4.7%.⁴ Once urosepsis forms, catastrophic progression is difficult to reverse. Kumar and colleagues reported a survival rate of 79.9% in patients with septic shock who were administered sensitive antibiotics for pathogens within the first hour of documented hypotension. Over the following 6 hours, every additional hour delay of effective antimicrobial treatment was associated with a significant decrease in the survival rate of 7.6%.⁵ Consequently, predicting postoperative sepsis is an exceedingly difficult clinical challenge that must be overcome. The goal of this study was to analyze demographic and perioperative data to evaluate the risk factors for postoperative fever and to identify the value of procalcitonin (PCT) in predicting postoperative fever after PNL to direct therapeutic strategies.

Patients and Methods

We retrospectively reviewed all consecutive cases of PNL between January 2014 and March 2017 in Shanghai General Hospital. Of the 391 cases, 5 involved the presence of uncontrolled infectious diseases (n = 1) or patients who were taking immunosuppressants (n = 4) and were excluded, which may have interfered with the outcomes. The operation on eleven patients were stopped after placing a nephrostomy tube because of intraoperative complications, including pyonephrosis (n = 6), bleeding (n = 4), and ventricular premature beat (n = 1) and were excluded. Twelve patients who experienced embolization were also excluded from the current research due to its tendency to be associated with the development of postoperative fever and elevated inflammatory markers. In total, 363 eligible cases were ultimately included for further analysis.

Patients' medical histories were documented. The results of blood and urine tests, including urine cultures, were obtained before antibiotic treatment, usually 3–5 days before PNL, according to the duration of antibiotic treatment. Hydronephrosis and kidney stones were demonstrated by noncontrast CT (NCCT) before PNL. Total stone burden was calculated by length × width × 3.14 × 0.25.⁶ Patients were assigned to groups with low (up to and including the median stone burden of 353 mm²) or high (above 353 mm²) stone burden according to stone load.⁷

PNL was not performed in patients with positive bacterial cultures for the sake of safety until their urine culture results were negative (patients were usually rechecked 3 days after culture-specific antibiotics treatment), and antibiotic treatment continued until PNL. For patients with negative urine cultures, a 3-day dose of intravenous antibiotic treatment was administered.⁸ As indicated by Gravas and colleagues antibiotic prophylaxis significantly reduces the rate of fever after PNL, even in patients with a negative baseline urine culture.⁹ All of the surgeries were performed by the same surgeon (Dr. Jun Lu) and adhered to the standard technique.^10,11 Percutaneous tracts were located at the 11th intercostal space or the 12th subcostal site under ultrasonic guidance with an 18-gauge needle. Serial dilation of the tracts was performed with a fascial dilator up to 16F. Stones were fragmented with a Holmium laser lithotripter. Large fragments were extracted by a grasper, and fragments smaller than 3 mm were primarily pushed out. The surgeries were considered complete when residual fragments were not detected under an endoscope. A 6F Double-J ureteral stent and a 14F nephrostomy tube were placed in an antegrade fashion. Operation time was measured from insertion of the ureteral catheter until the placement of the nephrostomy tube after completion of the procedure. After PNL, patients received a 3-day dose of intravenous antibiotic treatment. Vital signs were closely monitored, and abdominal plain film examinations (KUB) were rechecked the next morning. Postoperative complications were stratified according to the modified Clavien classification system.¹² A stone-free status was regarded as no detectable stones on KUB films 1 month after PNL. Additionally, NCCT would likely be required if KUB showed any signs of high density. Fragments less than 4 mm were also considered nonmeaningful stones when determining stone clearance.^13,14

Patients were classified into two groups, a febrile group and a control group, according to the presence of a body temperature over 38°C. Demographic and perioperative data considered for the univariate analysis were age (years), sex, history of diabetes mellitus, hypertension, preoperative fever (defined as the presence of body temperature over 38°C before PNL with no evidence of other sources of infections except urinary tract infection), duration of operation (minutes), hydronephrosis, stone burden (mm²), white blood cell counts (WBCs), neutrophilic granulocytes (NEUT), serum levels of CRP (mg/L), PCT (ng/mL) and IL-6 (pg/mL), pyuria (defined as >5 WBCs per high-power field), and urine culture (>10,000 cfu/mL was considered positive). PCT (≤0.05 or >0.05 ng/mL), CRP (≤10 or >10 mg/L), and IL-6 (≤7 or >7 pg/mL) were classified according to the expert consensus on clinical application of PCT in emergency in China or the reference ranges in our hospital.¹⁵ Variables were described as the mean ± standard deviations (SD) or medians (interquartile ranges, IQR). Continuous variables were compared by the independent samples t-test, and categorical variables were compared by Pearson's χ ² test or Fisher's exact test. Variables found to be statistically significant were enrolled for binary logistic regression analysis. Statistical analysis was performed using SPSS 23.0 (IBM). Two-tailed p-values of <0.05 were considered statistically significant.

This study was accepted by the Ethics Review Board of Shanghai General Hospital. All participated patients were required to write informed consent for their data to be used for research purposes.

Results

From January 2014 to March 2017, 363 patients who underwent PNL with complete medical records were enrolled in this research study. Patient characteristics and operative parameters are listed in Table 1. PNL was performed in our institution with a stone-free rate of 85.1%. Complications included systemic inflammatory response syndrome (SIRS) (n = 50, 13.8%, Clavien grade II), transfusion (n = 17, 4.7%, Clavien grade II), transaminase elevation (n = 3, 0.8%, Clavien grade II), and urosepsis (n = 2, 0.6%, Clavien grade IIIIb). These patients recovered without any sequelae, and no patients died of postoperative complications in our research.

Table 1.

Patient Characteristics And Operative Parameters

Index	Value
Age, years, mean ± SD	49.9 ± 11.4
Gender, male:female	244:119
Diabetes mellitus, yes:no	40:323
Hypertension, yes:no	103:260
Preoperative fever, yes:no	21:342
Hydronephrosis, yes:no	220:143
Stone burden, mm², median (IQR)	251.2 (124.0–486.7)
Urine culture, yes:no	47:316
Pyuria, yes:no	215:148
White blood cell, × 10⁹/L, mean ± SD	6.42 ± 1.71
Percentage of neutrophils, %, mean ± SD	57.11 ± 8.82
Creatinine, μmol/L, mean ± SD	82.61 ± 24.95
C-reactive protein, mg/L, median (IQR)	1.0 (0.50–3.0)
Procalcitonin, ng/mL, median (IQR)	0.028 (0.021–0.043)
Interleukin-6, pg/mL, median (IQR)	2.57 (1.62–4.54)
Residual calculi, yes:no	54:272
Operation time, minutes, mean ± SD	48.1 ± 20.8
Complications, n (%)
SIRS (Clavien grade II)	50 (13.8)
Transfusion (Clavien grade II)	17 (4.7)
Transaminase elevation (Clavien grade II)	3 (0.8)
Urosepsis (Clavien grade IIIIb)	2 (0.6)

IQR = interquartile range; SD = standard deviations; SIRS = systemic inflammatory response syndrome.

Ninety-one (25.1%) patients experienced postoperative fever, including 50 (13.8%) cases of SIRS and 2 (0.6%) cases of urosepsis. Evidence of bacterial colonization was found in 25 (27.5%) urine samples from the febrile group and 22 (8.1%) urine samples from the control group. Escherichia coli (12 in the febrile group and 6 in the control group) was the most common organism found in urine samples in both groups followed by Enterococcus faecalis (3 in the febrile group and 4 in the control group). The urine culture results are listed in Table 2.

Table 2.

Results Of Preoperative Urine Culture

Results of urine culture	Control group, n = 272 (74.9%)	Febrile group, n = 91 (25.1%)	Total (n = 363)
Negative urine culture	250	66	316
Escherichia coli (G)	6	12	18
Enterococcus faecalis (G+)	4	3	7
Streptococcus agalactiae (G+)	2	1	3
Citrobacter freundii (G−)	2	1	3
Staphylococcus haemolyticus (G+)	0	1	1
Klebsiella pneumoniae (G−)	3	1	4
Acinetobacter baumannii (G−)	0	1	1
Serratia fonticola (G−)	0	1	1
Proteus mirabilis (G−)	1	1	2
Staphylococcus lugdunensis (G+)	0	1	1
Streptococcus mitis (G+)	0	1	1
Enterococcus gallinarum (G+)	0	1	1
Staphylococcus epidermidis (G+)	1	0	1
Serratia liquefaciens (G−)	1	0	1
Streptococcus gallolyticus (G+)	1	0	1
Enterococcus faecium (G+)	1	0	1
Total	272	91	363

The abovementioned parameters were compared between the groups. Univariate analysis revealed statistical significance between postoperative fever and factors, such as sex (p = 0.009), preoperative fever (p < 0.001), stone burden (p < 0.001), pyuria (p = 0.013), urine culture (p < 0.001), and serum levels of CRP (p = 0.003), PCT (p < 0.001), and IL-6 (p = 0.003). Binary logistic regression analysis indicated the presence of preoperative fever (p = 0.037), stone burden >353 mm² (p = 0.002), PCT >0.05 ng/mL (p < 0.001), and positive urine culture (p = 0.004) as independent risk factors for postoperative fever following PNL. The results are presented in Tables 3 and 4.

Table 3.

Univariate Analysis of Patient Demographic And Perioperative Data

Variable	Control group, n = 272 (74.9%)	Febrile group, n = 91 (25.1%)	p
Age, years, mean ± SD^a	49.7 ± 11.2	50.4 ± 12.0	0.609
Gender, male:female^b	193:79	51:40	0.009
Diabetes mellitus, yes:no^b	30:242	10:81	0.991
Hypertension, yes:no^b	78:194	25:66	0.825
Preoperative fever, yes:no^c	6:266	15:76	<0.001
Hydronephrosis, yes:no^b	163:109	57:34	0.647
Stone burden >353 mm², yes:no^b	80:192	47:44	<0.001
Urine culture, yes:no^b	22:250	25:66	<0.001
Pyuria, yes:no^b	151:121	64:27	0.013
White blood cell, × 10⁹/L, mean ± SD^a	6.4 ± 1.7	6.4 ± 1.6	0.948
Percentage of neutrophils, %, mean ± SD^a	57.1 ± 8.7	57.1 ± 9.2	0.973
Creatinine, μmol/L, mean ± SD^a	82.7 ± 23.1	82.3 ± 30.0	0.893
C-reactive protein >10 mg/L, yes:no^b	17:255	15:76	0.003
Procalcitonin >0.05 ng/mL, yes:no^b	17:255	42:49	<0.001
Interleukin-6 > 7 pg/mL, yes:no^b	22:250	18:73	0.003

Independent samples t-test.

Pearson χ ² test.

Fisher^'s exact test.

Bold values indicate significant p value (p < 0.05).

Table 4.

Binary Logistic Regression Analysis of Risk Factors in Univariate Analysis

			OR Exp (B)
Variables	B	Exp(B)	Lower	Upper	p
Gender, female	0.425	1.530	0.826	2.832	0.176
Preoperative fever, yes	1.243	3.566	1.080	11.124	0.037
Stone burden, >353 mm²	0.938	2.556	1.419	4.605	0.002
Positive urine culture, yes	1.144	3.140	1.451	6.795	0.004
Pyuria, yes	0.425	1.530	0.824	2.842	0.178
C-reactive protein >10 mg/L	0.333	1.395	0.463	4.208	0.554
Procalcitonin >0.05 ng/mL	2.380	10.808	5.326	21.934	<0.001
Interleukin-6 > 7 pg/mL	0.489	1.631	0.660	4.029	0.289

CI = confidence interval.

Bold values indicate significant p value (p < 0.05).

Discussion

The risk factors following PNL have been widely studied, although the conclusiveness of the results has been difficult to determine. The Clinical Research Office of the Endourological Society (CROES), the largest clinical research group evaluating PNL, reported that ∼10% of PNL-treated patients develop fever despite antibiotic prophylaxis.¹⁶ The postoperative fever rate was 25.1% in this study, which was slightly higher due to the definition of postoperative fever as a body temperature over 38°C. Previous studies have demonstrated that female sex, positive urine culture, preoperative nephrostomy, stone size, hydronephrosis, paraplegia, serum creatinine, operative time, diabetes, and even age are risk factors for postoperative fever.¹⁷ Univariate analysis in our research demonstrated statistically significant correlations between postoperative fever and sex, preoperative fever, stone burden, pyuria, urine culture, CRP, PCT, and IL-6, whereas binary logistic regression analysis indicated preoperative fever, stone burden >353 mm², PCT >0.05 ng/L, and positive urine culture as independent risk factors for postoperative fever following PNL. The relatively small sample size may partially contribute to the differences in the results.

Urine culture has long been used for predicting the chances of postoperative fever after PNL.¹⁸ Gutierrez and colleagues found that in PNL-treated patients, 8.8% with negative preoperative urine cultures and 18.2% with positive urine cultures developed postoperative fever.¹⁶ Urinary calculus may develop from urinary tract infections. For example, infection-related stones are formed as a result of persistent infection caused by urease-producing bacteria.¹⁹ In turn, the development of renal calculus impairs the drainage of the urinary system, creating an abscess-like niche for bacterial growth.¹⁷ Mariappan and colleagues indicated that positive stone culture and pelvic urine are better predictors of potential urosepsis than bladder urine,¹⁸ with the barriers of calculus and bacterial heterogeneity between the upper urinary tract and bladder urine contributing to the results. Our finding that patients with total stone burden >353 mm² were more likely to develop postoperative fever partially supported this hypothesis. It seems logical to harbor the idea that large stones are more likely to carry pathogens; furthermore, fragments of stones may release bacteria or products of metabolism, such as endotoxins, and cause subsequent infectious complications.²⁰ In addition, a heavy stone burden is also correlated with more complicated conditions, indicating increased surgical difficulty and prolonged duration. Therefore, how stone size impacts the development of infectious complications requires further investigation.

PCT is a 116-amino acid polypeptide produced by C cells, with serum levels of less than 0.1 ng/mL in healthy individuals. In a state of infection, PCT is constitutively released from neutrophils and parenchymal cells in the lungs, liver, intestine, and brain, resulting in serum concentrations that often exceed 100 ng/mL.²¹ In fact, when bacterial infection starts, PCT is upregulated in response to microbial toxins or proinflammatory mediators, such as endotoxin, IL-1, IL-6, and tumor necrosis factor-alpha (TNF-α), and it is downregulated as the concentrations of these substances decrease in the circulation during recovery.²² Zheng and colleagues found that PCT concentrations were higher in patients with uroseptic shock vs severe urosepsis vs urosepsis vs the control group following PNL.²³ Furthermore, in patients with successfully treated urosepsis, PCT concentrations declined significantly, whereas WBC scores failed to manifest such dynamic changes.²³

Another topic of debate is whether PCT could guide antibiotic therapies. de Jong et al. indicated that if PCT concentrations had decreased by 80% or more of their peak values or to concentrations of 0.5 ng/mL or lower, it would be safe to downregulate the antibiotic strategy with low mortality, resulting in reduced antibiotic consumption.²⁴ Lavrentieva et al. reported that daily monitoring of PCT could be useful for assessing the appropriateness of empirical antibiotic therapy at an earlier stage.²⁵ Bouadma et al. reported that PCT-guided strategies to treat suspected bacterial infections in nonsurgical patients in intensive care units could reduce antibiotic exposure, with a slightly higher mortality.²⁶ Jensen et al. indicated that PCT-guided antimicrobial escalation in the intensive care unit did not improve survival, but did lead to organ-related harm and prolonged admission to the intensive care unit.²⁷ It appears that PCT alone as a suitable director for antimicrobial escalation treatment is ill founded, but studies have confirmed that serum PCT could function as a rule-out indicator. If the serum PCT level is less than 0.5 ng/mL, the presence of severe sepsis or septic shock could be eliminated; if the level is below 0.1 ng/mL, infection would be unlikely.^28,29 In our current research, PCT was classified according to the cutoff point of 0.05 ng/mL in light of expert consensus on the clinical application of PCT in emergencies, which is applied widely in China.¹⁵ We also demonstrated its role in predicting postoperative fever after PNL. Binary logistic regression analysis indicated that PCT >0.05 ng/L was an independent risk factor for postoperative fever. To the best of our knowledge, this study is the first to evaluate preoperative serum PCT levels for predicting postoperative fever following PNL. PCT appears to be a superior inflammatory marker for predicting postoperative fever when compared with other biomarkers, such as CRP, IL-6, and WBC.

The correlation between preoperative and postoperative fever is another finding in our research. Few studies have indicated preoperative fever as an independent risk factor for postoperative fever following PNL. The relatively small sample size (15 in the febrile group and 6 in the control group) may partially contribute to this difference. However, it is well known that patients with fever before surgery are more likely to have fever after surgery; after eliminating the possibility of infection in other locations, such as the respiratory or digestive system, preoperative fever seems to be associated with the presence of calculus. In general, calculus-associated fever usually implies obstruction of parts or all of the urinary system or the presence of infectious stones requiring antibiotic treatment or urgent drainage. To identify the role of preoperative fever in predicting postoperative fever, further investigations with larger sample sizes are needed.

One of the characteristics in this research that may contribute to differences from previous investigations is that the parameters we collected and analyzed for postoperative fever were all preoperative. The major limitations of this study should also be addressed; for example, for financial reasons, we did not collect PCT levels after antibiotic treatment or after PNL, which would make more sense for evaluating PCT in predicting postoperative fever or antibiotic treatment. Additionally, we did not conduct intraoperative stone cultures or renal pelvis urine cultures, which have been demonstrated to be of paramount importance in guiding antibiotic therapies and predicting postoperative fever or septicemia. This research was retrospectively conducted in a single center with a limited sample size. To better understand our current findings and to identify new risk factors, further prospective studies based on larger samples in multiple centers are needed.

Conclusions

In the current study, the occurrence of postoperative fever following PNL was 25.1%. Preoperative fever, stone burden >353 mm², PCT >0.05 ng/mL, and positive urine culture were determined to be independent risk factors for postoperative fever. Patients with these risk factors should be monitored carefully for postoperative fever and potentially life-threatening sepsis. Routinely detecting PCT levels before PNL would be helpful in predicting postoperative fever.

Footnotes

Acknowledgment

This study was funded by the National Natural Science Foundation of China (Grant No. 81200504).

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

Scales

Jr , Smith

, Hanley

, et al. Prevalence of kidney stones in the United States. Eur Urol, 2012; 62:160–165.

Zeng

, Mai

, Xia

, et al. Prevalence of kidney stones in China: An ultrasonography based cross-sectional study. BJU Int, 2017; 120:109–116.

, Autorino

, Kim

, et al. Percutaneous nephrolithotomy versus retrograde intrarenal surgery: A systematic review and meta-analysis. Eur Urol, 2015; 67:125–137.

Michel

, Trojan

, Rassweiler

. Complications in percutaneous nephrolithotomy. Eur Urol, 2007; 51:899–906.

Kumar

, Roberts

, Wood

, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med, 2006; 34:1589–1596.

Tiselius

, Andersson

. Stone burden in an average Swedish population of stone formers requiring active stone removal: How can the stone size be estimated in the clinical routine?. Eur Urol, 2003; 43:275–281.

Labate

, Modi

, Timoney

, et al. The percutaneous nephrolithotomy global study: Classification of complications. J Endourol, 2011; 25:1275–1280.

Olvera-Posada

, Tailly

, Alenezi

, et al. Risk factors for postoperative complications of percutaneous nephrolithotomy at a tertiary referral center. J Urol, 2015; 194:1646–1651.

Gravas

, Montanari

, Geavlete

, et al. Postoperative infection rates in low risk patients undergoing percutaneous nephrolithotomy with and without antibiotic prophylaxis: A matched case control study. J Urol, 2012; 188:843–847.

10.

Druskin

, Ziemba

. Minimally invasive (“Mini”) percutaneous nephrolithotomy: Classification, indications, and outcomes. Curr Urol Rep, 2016; 17:30.

11.

Shao

, Li

, Hasimu

, et al. Urgent percutaneous nephrolithotomy for acute kidney injury secondary to bilateral stones: Is it safe and effective in infants?. World J Urol, 2015; 33:1345–1349.

12.

Dindo

, Demartines

, Clavien

. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg, 2004; 240:205–213.

13.

Ghani

, Wolf

Jr . What is the stone-free rate following flexible ureteroscopy for kidney stones?. Nat Rev Urol, 2015; 12:281–288.

14.

Deters

, Jumper

, Steinberg

, et al. Evaluating the definition of “stone free status” in contemporary urologic literature. Clin Nephrol, 2011; 76:354–357.

15.

Procalcitonin emergency clinical application of Expert consensus group. [Expert consensus on clinical application of procalcitonin (PCT) in emergency]. Chin J Emerg Med, 2012; 9:944–951.

16.

Gutierrez

, Smith

, Geavlete

, et al. Urinary tract infections and post-operative fever in percutaneous nephrolithotomy. World J Urol, 2013; 31:1135–1140.

17.

Kreydin

, Eisner

. Risk factors for sepsis after percutaneous renal stone surgery. Nat Rev Urol, 2013; 10:598–605.

18.

Mariappan

, Smith

, Bariol

, et al. Stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: A prospective clinical study. J Urol, 2005; 173:1610–1614.

19.

Griffith

. Urease stones. Urol Res, 1979; 7:215–221.

20.

McAleer

, Kaplan

, Bradley

, et al. Endotoxin content in renal calculi. J Urol, 2003; 169:1813–1814.

21.

Bozza

, Bozza

, Castro Faria Neto

. Beyond sepsis pathophysiology with cytokines: What is their value as biomarkers for disease severity?. Mem Inst Oswaldo Cruz, 2005; 100:217–221.

22.

Bréchot

, Hékimian

, Chastre

, et al. Procalcitonin to guide antibiotic therapy in the ICU. Int J Antimicrob Agents, 2015; 46:S19–S24.

23.

Zheng

, Li

, Fu

, et al. Procalcitonin as an early diagnostic and monitoring tool in urosepsis following percutaneous nephrolithotomy. Urolithiasis, 2015; 43:41–47.

24.

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.

25.

Lavrentieva

, Papadopoulou

, Kioumis

, et al. PCT as a diagnostic and prognostic tool in burn patients. Whether time course has a role in monitoring sepsis treatment. Burns, 2012; 38:356–363.

26.

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.

27.

Jensen

, Hein

, Lundgren

, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial. Crit Care Med, 2011; 39:2048–2058.

28.

Pantelidou

, Giamarellos-Bourboulis

. Can procalcitonin monitoring reduce the length of antibiotic treatment in bloodstream infections?. Int J Antimicrob Agents, 2015; 46:S10–S12.

29.

Dreger

, Degener

, Ahmad-Nejad

, et al. Urosepsis—Etiology, Diagnosis, and Treatment. Dtsch Arztebl Int, 2015; 112:837–847, quiz 848.