Critical Care Medicine 2009;37:1845-1849

The primary aim of this study was to investigate the diagnostic value of procalcitonin (PCT) and C-reactive protein (CRP) in septic complications after major trauma. A secondary aim was to determine whether there was a prognostic value of PCT for severity of injury, organ dysfunction, and sepsis.

Design
Prospective study.

Setting
Medical/surgical intensive care unit (ICU).

Patients
Ninety-four patients with consecutive trauma >=16 years who were admitted to the ICU for an expected stay of >24 hours.

Interventions
None.

Measurements
PCT and CRP were collected at admission and every day thereafter. The American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definition was used to identify sepsis criteria. The Sequential Organ Failure Assessment score was used to describe the severity of organ dysfunction. We retrospectively analyzed the occurrence of systemic inflammatory response syndrome and sepsis using the collected variables (criteria fulfilled at least during three continuous days).

Main results
Patients with trauma presented an early and significant increase in PCT at the moment of septic complications compared with concentrations measured 1 day before the diagnosis of sepsis: 0.85 vs. 3.32 ng/mL for PCT (p < 0.001) and 135 vs. 175 mg/L for CRP (p = not significant). The areas under the respective curve at admission in the diagnosis of sepsis were 0.787 (p < 0.001) and 0.489 for PCT and CRP, respectively.

Conclusion
PCT plasma reinduction marks possible septic complication during systemic inflammatory response syndrome after major trauma. In addition, high PCT concentration at admission after trauma in ICU patients indicates an increased risk of septic complications.

Critical Care 2009, 13:R83

The development of resistance by bacterial species is a compelling issue to reconsider indications and administration of antibiotic treatment. Adequate indications and duration of therapy are particularly important for the use of highly potent substances in the intensive care setting. Until recently, no laboratory marker has been available to differentiate bacterial infection from viral or non-infectious inflammatory reaction; however, over the past years, procalcitonin (PCT) is the first among a large array of inflammatory variables that offers this possibility. The present study aimed to investigate the clinical usefulness of PCT for guiding antibiotic therapy in surgical intensive care patients.

Methods
All patients requiring antibiotic therapy based on confirmed or highly suspected bacterial infections and at least two concomitant systemic inflammatory response syndrome criteria were eligible. Patients were randomly assigned to either a PCT-guided (study group) or a standard (control group) antibiotic regimen. Antibiotic therapy in the PCT-guided group was discontinued, if clinical signs and symptoms of infection improved and PCT decreased to <1 ng/ml or the PCT value was >1 ng/ml, but had dropped to 25 to 35% of the initial value over three days. In the control group antibiotic treatment was applied as standard regimen over eight days.

Results
A total of 110 surgical intensive care patients receiving antibiotic therapy after confirmed or high-grade suspected infections were enrolled in this study. In 57 patients antibiotic therapy was guided by daily PCT and clinical assessment and adjusted accordingly. The control group comprised 53 patients with a standardized duration of antibiotic therapy over eight days. Demographic and clinical data were comparable in both groups. However, in the PCT group the duration of antibiotic therapy was significantly shorter than compared to controls (5.9 +/- 1.7 versus 7.9 +/- 0.5 days, P < 0.001) without negative effects on clinical outcome.

Conclusions
Monitoring of PCT is a helpful tool for guiding antibiotic treatment in surgical intensive care patients. This may contribute to an optimized antibiotic regimen with beneficial effects on microbial resistance and costs in intensive care medicine.

Critical Care 2007,11

The aim of this study was to compare the early postoperative kinetics of procalcitonin (PCT) and C-reactive protein (CRP) serum levels in patients undergoing orthotopic liver transplantation (OLTx) with different immunosuppressive regimens.

Methods
PCT and CRP serum concentrations were measured in a group of 28 OLTx recipients before induction of anesthesia, at 4 and 8 hours following graft reperfusion, and daily until postoperative day 4. The same parameters were determined in 12 patients undergoing liver resection without conjunctive immunosuppressive therapy. Summary data are expressed as medians and ranges. Two-tailed nonparametric tests were performed and considered significant at p values of less than 0.05.

Results
The highest serum levels of PCT (median 3.0 ng/mL, minimum 1.4 ng/mL, maximum 13.9 ng/mL) were found in patients after OLTx without ATG therapy, on postoperative day 1. In patients with ATG administration, PCT levels were highly increased on postoperative day 1 (median 53.0 ng/mL, minimum 7.9 ng/mL, maximum 249.1 ng/mL). Thereafter, PCT values continuously decreased independently of further ATG administration in both groups of patients. No evidence of infection was present in either group. In 12 patients undergoing liver resection, peak serum PCT levels did not exceed 3.6 ng/mL. CRP serum levels in a group of patients with and without ATG therapy increased significantly on postoperative day 1, followed by a decrease. The highest levels of CRP were found in patients after liver resection on postoperative day 2 and decreased thereafter.

Conclusion
ATG administration to patients with OLTx is associated with an increase in serum PCT levels, with peak values on postoperative day 1, and this was in the absence of any evidence of infection. The results of this study indicate that ATG immunosuppressive therapy is a stimulus for the synthesis of PCT.

Neth J Crit Care 2007;11:81-86

Can plasma procalcitonin differentiate sepsis from systemic inflammatory response? Is plasma procalcitonin level a measure of severity of illness and can it be a prognostic factor in sepsis patients in an intensive care unit (ICU)?

Search strategy
Review of medical literature. Prospective studies published in the MEDLINE database that evaluated plasma procalcitonin as marker of sepsis in the intensive care unit were included. Positive and negative likelihood ratios were constructed for each study if possible.

Summary of findings
From the search of the MEDLINE database 11 prospective studies that evaluated plasma procalcitonin as a diagnostic marker in sepsis and systemic inflammatory response patients in the ICU were included. A further four articles were found by searching the bibliographies. Sepsis and systemic inflammatory response populations differed between studies. The total number sepsis patients was 688 and total number of systemic inflammatory response patients 507. PCT values were reported as mean +/- sd in sepsis and systemic inflammatory response patients in five studies, and as median with interquartile range in sepsis and SIRS in 10 studies. Cut-off points were established by using area under the curve in receiver operating characteristics curves. Median cut-off point 1.1 ng/ml; interquartile range 1.0-2.42. area under the curve in the receiver operating characteristics was between 0.66 and 0.97. Sensitivity was between 63% and 100% and for specificity 54% to 94%. Positive likelihood ratios (LR+) and negative likelihood ratios (LR-) could be calculated in 11 studies. The median LR+ was 3.31, interquartile range 2.17-6 and the median LR- was 0.11, interquartile range 0.06-0.16. Pre-test probability ranged from 32% to 83% and was modified by positive negative likelihood ratios to a range of 55%-96% and by negative likelihood ratios – to a range of 0-68%. Severity indexes (SOFA score, SAPS II score and APACHE II score) were used in 11 of the 14 studies. Correlation between plasma procalcitoninlevel and severity index was sporadically reported. In four studies plasma procalcitonin levels in survivors and non-survivors of the sepsis group were measured. Only in the surgical patients of one study there was no significant difference.

Conclusion
Although area under the curve , sensitivity and specificity are fairly good for a diagnostic test to differentiate sepsis from systemic inflammatory response , there is serious doubt whether this influences the decision to treat. The pre-test probability is too high to withhold antibiotics and perform diagnostics procedures. Positive test results will not lead to more prescription and negative test results will not lead to stopping of antibiotics. There are not enough data to draw conclusions about the power of plasma procalcitonin as a measure of severity or prognostic factor.

To investigate day-by-day changes in procalcitonin and maximum obtained levels as predictors of mortality in critically ill patients.

Design
Prospective observational cohort study.

Setting
Multidisciplinary intensive care unit at Rigshospitalet, Copenhagen University Hospital, a tertiary reference hospital in Denmark.

Patients
Four hundred seventy-two patients with diverse comorbidity and age admitted to this intensive care unit.

Interventions
Equal in all patient groups: antimicrobial treatment adjusted according to the procalcitonin level.

Measurements and Main Results
Daily procalcitonin measurements were carried out during the study period as well as measurements of white blood cell count and C-reactive protein and registration of comorbidity. The primary end point was all-cause mortality in a 90-day follow-up period. Secondary end points were mortality during the stay in the intensive care unit and in a 30-day follow-up period. A total of 3,642 procalcitonin measurements were evaluated in 472 critically ill patients. We found that a high maximum procalcitonin level and a procalcitonin increase for 1 day were independent predictors of 90-day all-cause mortality in the multivariate Cox regression analysis model. C-reactive protein and leukocyte increases did not show these qualities. The adjusted hazard ratio for procalcitonin increase for 1 day was 1.8 (95% confidence interval 1.3-2.7). The relative risk for mortality in the intensive care unit for patients with an increasing procalcitonin was as follows: after 1 day increase, 1.8 (95% confidence interval 1.4-2.4); after 2 days increase, 2.2 (95% confidence interval 1.6-3.0); and after 3 days increase: 2.8 (95% confidence interval 2.0-3.8).

Conclusions
A high maximum procalcitonin level and a procalcitonin increase for 1 day are early independent predictors of all-cause mortality in a 90-day follow-up period after intensive care unit admission. Mortality risk increases for every day that procalcitonin increases. Levels or increases of C-reactive protein and white blood cell count do not seem to predict mortality.

Critical Care Medicine 2006;34:1996-2003

To quantify the accuracy of serum procalcitonin as a diagnostic test for sepsis, severe sepsis, or septic shock in adults in intensive care units or after surgery or trauma, alone and compared with C-reactive protein. To draw and compare the summary receiver operating characteristics curves for procalcitonin and C-reactive protein from the literature.

Data source
MEDLINE (keywords: procalcitonin, intensive care, sepsis, postoperative sepsis, trauma); screening of the literature.

Study selection
Meta-analysis of all 49 published studies in medical, surgical, or polyvalent intensive care units or postoperative wards. Children, medical patients, and immunocompromised patients were excluded.

Data extraction
Thirty-three studies fulfilled inclusion criteria (3,943 patients, 1,828 males, 922 females; mean age: 56.1 yrs; 1,825 patients with sepsis, severe sepsis, or septic shock; 1,545 with only systemic inflammatory response syndrome); eight studies could not be analyzed statistically. Global mortality rate was 29.3%.

Data synthesis
Global odds ratios for diagnosis of infection complicated by systemic inflammation were 15.7 for the 25 studies (2,966 patients) using procalcitonin (95% confidence interval, 9.1-27.1) and 5.4 for the 15 studies (1,322 patients) using C-reactive protein (95% confidence interval, 3.2-9.2). The summary receiver operating characteristics curve for procalcitonin was better than for C-reactive protein. In the 15 studies using both markers, the Q* value (intersection of summary receiver operating characteristics curve with the diagonal line where sensitivity equals specificity) was significantly higher for procalcitonin than for C-reactive protein (0.78 vs. 0.71, p = .02), the former test showing better accuracy.

Conclusions
Procalcitonin represents a good biological diagnostic marker for sepsis, severe sepsis, or septic shock, difficult diagnoses in critically ill patients. Procalcitonin is superior to C-reactive protein. Procalcitonin should be included in diagnostic guidelines for sepsis and in clinical practice in intensive care units.

Critical Care 2005, 9:R344-350 http://ccforum.com/content/9/4/R344

The aim of this study was to describe the change in serum procalcitonin levels during treatment for community acquired acute bacterial meningitis.

Methods
Out of 50 consecutive patients presenting with bacterial meningitis and infection at no other site, and who had received no prior antibiotic treatment, 48 had a serum procalcitonin level above 0.5 ng/ml on admission and were enrolled in the study.
Results
The mean age of the patients was 55 years, and mean Glasgow Coma Scale score on admission was 13. The time from symptom onset to admission was less than 24 hours in 40% of the patients, 24–48 hours in 20%, and more than 48 hours in 40%. The median (interquartile) interval between admission and initial antibiotic treatment was 160 min (60–280 min). Bacterial infection was documented in 45 patients. Causative agents included Streptococcus pneumoniae (n = 21), Neisseria meningitidis (n = 9), Listeria monocytogenes (n = 6), other streptococci (n = 5), Haemophilus influenzae (n = 2) and other bacteria (n = 2). The initial antibiotic treatment was effective in all patients. A lumbar puncture performed 48–72 hours after admission in 34 patients showed sterilization of cerebrospinal fluid. Median (interquartile) serum procalcitonin levels on admission and at day 2 were 4.5 (2.8–10.8) mg/ml and 2 (0.9–5.0) mg/ml, respectively ( P < 0.0001). The corresponding values for C-reactive protein were 120 (21–241) mg/ml and 156 (121–240) mg/ml, respectively. Five patients (10%) died from noninfectious causes during their hospitalization.

Conclusions
Serum procalcitonin levels decrease rapidly with appropriate antibiotic treatment, diminishing the value of lumbar puncture performed 48–72 hours after admission to assess treatment efficacy.

Critical Care 2006, 10:R53 http://ccforum.com/content/10/2/R53

Introduction
Clinicians are in need of better diagnostic markers in diagnosing infections and sepsis. We studied the ability of procalcitonin, lipopolysaccharide-binding protein, IL-6 and C-reactive protein to identify patients with infection and sepsis.

Methods
Plasma and serum samples were obtained on admission from patients with suspected community-acquired infections and sepsis. Procalcitonin was measured with a time-resolved amplified cryptate emission technology assay. Lipopolysaccharide-binding protein and IL-6 were measured with a chemiluminescent immunometric assay.

Results
Of 194 included patients, 106 had either infection without systemic inflammatory response syndrome or sepsis. Infected patients had significantly elevated levels of procalcitonin, lipopolysaccharide-binding protein, C-reactive protein and IL-6 compared with noninfected patients (P < 0.001). In a receiver-operating characteristic curve analysis, C-reactive protein and IL-6 performed best in distinguishing between noninfected and infected patients, with an area under the curve larger than 0.82 (P < 0.05). IL-6, lipopolysaccharide-binding protein and C-reactive protein performed best in distinguishing between systemic inflammatory response syndrome and sepsis, with an area under the curve larger than 0.84 (P < 0.01). Procalcitonin performed best in distinguishing between sepsis and severe sepsis, with an area under the curve of 0.74 (P < 0.01).

Conclusion
C-reactive protein, IL-6 and lipopolysaccharide-binding protein appear to be superior to procalcitonin as diagnostic markers for infection and sepsis in patients admitted to a Department of Internal Medicine. Procalcitonin appears to be superior as a severity marker.

Critical Care 2005, 9:E5
Citation
Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, Muller B. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomized, single-blinded intervention trial. Lancet 2004, 363:600–607.

Background
Lower respiratory tract infections are often treated with antibiotics without evidence of clinically relevant bacterial disease. Serum calcitonin precursor concentrations, including procalcitonin, are raised in bacterial infections, but not in viral infections.

Hypothesis
Procalcitonin (PCT)-guided treatment of suspected lower respiratory tract infection substantially reduces antibiotic use without compromising clinical or laboratory outcomes.

Design
Prospective, cluster-randomized, controlled, single-blinded intervention trial.

Setting
Medical emergency department of a 784-bed academic tertiary care hospital in Basel, Switzerland.

Subjects
243 patients presenting to the emergency department who were admitted with suspected lower respiratory tract infection as the main diagnosis.

Intervention
Patients were randomly assigned to either standard care (n = 199) or PCT-guided treatment (n = 124). In the latter group, serum PCT concentrations were used to advise clinicians. Use of antibiotics was: strongly discouraged (PCT <0.1 µg/L), discouraged (= 0.1 and <0.25 µg/L), advised (= 0.25 and <0.5 µg/L), or strongly advised (= 0.5 µg/L). Re-evaluation was possible after 6–24 hours in both groups.

Outcomes
The primary endpoint was antibiotic use with analysis by intent to treat. Secondary endpoints included clinical and laboratory outcomes.

Results
Final diagnoses were pneumonia (36%), acute exacerbation of chronic obstructive pulmonary disease (25%), acute bronchitis (24%), asthma (5%), and other respiratory affections (10%). Serological evidence of viral infection was recorded in 141 of 175 tested patients (81%). Bacterial cultures were positive from sputum in 51 (21%) and from blood in 16 (7%). In the procalcitonin group, the adjusted relative risk of antibiotic exposure was 0.49 (95% CI 0.44–0.55; p < 0.0001) compared with the standard group. Antibiotic use was significantly reduced in all diagnostic subgroups. Clinical and laboratory outcomes were similar in both groups.

Conclusion
PCT-guided therapy of suspected lower respiratory tract infection substantially reduced antibiotic use without compromising clinical or laboratory outcomes.

Critical Care Medicine: Volume 34(1) January 2006 pp 102-107

Design
Prospective observational study.

Setting
Intensive care unit of the Avicenne teaching hospital, France.

Patients
All patients with septic shock or noninfectious systemic inflammatory response syndrome within 48 hrs after admission.

Interventions
None.

Measurements and Main Results
Patients were allocated to one of the following groups: group 1 (surgical patients with septic shock), group 2 (surgical patients with noninfectious systemic inflammatory response syndrome), group 3 (medical patients with septic shock), and group 4 (medical patients with noninfectious systemic inflammatory response syndrome). Procalcitonin at study entry was compared between group 1 and group 2 and between group 3 and group 4 to determine the diagnostic cutoff value in surgical and in medical patients, respectively. Procalcitonin was compared between survivors and nonsurvivors from group 1 and group 3 to determine its prognostic cutoff value. One hundred forty-three patients were included: 31 in group 1, 36 in group 2, 36 in group 3, and 40 in group 4. Median procalcitonin levels (ng/mL [interquartile range]) were higher in group 1 than in group 3 (34.00 [7.10-76.00] vs. 8.40 [3.63-24.70], p = .01). In surgical patients, the best diagnostic cutoff value was 9.70 ng/mL, with 91.7% sensitivity and 74.2% specificity. In medical patients, the best diagnostic cutoff value was 1.00 ng/mL, with 80% sensitivity and 94% specificity. Procalcitonin was a reliable early prognostic marker in medical but not in surgical patients with septic shock. A cutoff value of 6.00 ng/mL had 76% sensitivity and 72.7% specificity for separating survivors from nonsurvivors.

Conclusions
The diagnostic cutoff value of procalcitonin was higher in surgical than in medical patients. Early procalcitonin was of prognostic interest in medical patients.