Update on procalcitonin measurements.

Procalcitonin (PCT) is used as a biomarker for the diagnosis of sepsis, severe sepsis and septic shock. At the same time, PCT has also been used to guide antibiotic therapy. This review outlines the main indications for PCT measurement and points out possible pitfalls. The classic indications for PCT measurement are: (i) confirmation or exclusion of diagnosis of sepsis, severe sepsis, or septic shock, (ii) severity assessment and follow up of systemic inflammation mainly induced by microbial infection, and (iii) individual, patient adapted guide of antibiotic therapy and focus treatment. Using serially monitored PCT levels, the duration and need of antibiotic therapy can be better adapted to the individual requirements of the patient. This individualized approach has been evaluated in various studies, and it is recommended to be a part of an antibiotic stewardship program.

Evaluation of mid-regional pro-atrial natriuretic peptide, procalcitonin, and mid-regional pro-adrenomedullin for the diagnosis and risk stratification of dyspneic ED patients.

OBJECTIVE: The aim of this study was to evaluate the diagnostic and the prognostic value of a laboratory panel consisting of mid-regional pro-atrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and mid-regional pro-adrenomedullin (MR-proADM) for patients presenting to the emergency department (ED) with acute dyspnea. METHODS: We prospectively enrolled ED patients who presented with a chief complaint of dyspnea and who had an uncertain diagnosis after physician evaluation. Final primary diagnosis of the cause of shortness of breath was confirmed through additional testing per physician discretion. We recorded inpatient admission and 30-day mortality rates. RESULTS: One hundred fifty-four patients were enrolled in the study. Congestive heart failure exacerbation was the final primary diagnosis in 42.2% of patients, while infectious etiology was diagnosed in 33.1% of patients. For the diagnosis of congestive heart failure exacerbation, MR-proANP had a sensitivity of 92.7% and specificity of 36.8%, with a negative likelihood ratio (LR-) of 0.16 and a positive likelihood ratio (LR+) of 1.44 (cut-off value: 120 pmol/L). For the diagnosis of an infectious etiology, PCT had a 96.5% specificity and 48.8% sensitivity (LR-: 0.58, LR+: 13.8, cutoff value: 0.25 ng/mL). As a prognostic indicator, MR-proADM demonstrated similar values: odds ratio for 30-day mortality was 8.5 (95% CI, 2.5-28.5, cutoff value: 1.5 nmol/L) and the area under the receiver operating characteristic curve in predicting mortality was 0.81 (95% CI, 0.71-0.91). CONCLUSION: The good negative LR- of MR-proANP and the good positive LR+ of PCT may suggest a role for these markers in the early diagnosis of ED patients with dyspnea. Furthermore, MR-proADM may assist in risk stratification and prognosis in these patients..

Biomarkers in the critically ill patient: procalcitonin.

Infection and/or sepsis biomarkers should help to make the diagnosis and thus initiate therapy earlier, help to differentiate between infectious and sterile inflammation, allow the use of more-specific antimicrobials, shorten the time of antimicrobial use, and ideally identify distinct phenotypes that may benefit from specific adjunctive sepsis therapies. Procalcitonin (PCT) was proposed as a sepsis and infection marker more than 15 years ago. Meanwhile, PCT has been evaluated in various clinical settings. In this review the present use of PCT on the ICU and in critically ill patients is summarized, included it's role for diagnosis of severe sepsis and septic shock and antibiotic stewardship with PCT.

Early changes of procalcitonin may advise about prognosis and appropriateness of antimicrobial therapy in sepsis.

PURPOSE: The objective of this study is to define if early changes of procalcitonin (PCT) may inform about prognosis and appropriateness of administered therapy in sepsis. METHODS: A prospective multicenter observational study was conducted in 289 patients. Blood samples were drawn on day 1, that is, within less than 24 hours from advent of signs of sepsis, and on days 3, 7, and 10. Procalcitonin was estimated in serum by the ultrasensitive Kryptor assay (BRAHMS GmbH, Hennigsdorf, Germany). Patients were divided into the following 2 groups according to the type of change of PCT: group 1, where PCT on day 3 was decreased by more than 30% or was below 0.25 ng/mL, and group 2, where PCT on day 3 was either increased above 0.25 ng/mL or decreased less than 30%. RESULTS: Death occurred in 12.3% of patients of group 1 and in 29.9% of those of group 2 (P < .0001). Odds ratio for death of patients of group 1 was 0.328. Odds ratio for the administration of inappropriate antimicrobials of patients of group 2 was 2.519 (P = .003). CONCLUSIONS: Changes of serum PCT within the first 48 hours reflect the benefit or not of the administered antimicrobial therapy. Serial PCT measurements should be used in clinical practice to guide administration of appropriate antimicrobials.

Prognostic value of midregional pro-atrial natriuretic peptide in ventilator-associated pneumonia.

OBJECTIVE: This study aimed to investigate the correlation of midregional pro-atrial natriuretic peptide (MR-proANP) with severity of septic status in patients with ventilator-associated pneumonia (VAP) and the usefulness of MR-proANP for mortality prediction in VAP. DESIGN: Prospective observational cohort study. SETTING: University Hospital. PATIENTS: Seventy-one patients consecutively admitted to ICU who developed VAP. Patients were followed for 28 days after diagnosis, when they were considered survivors. There were no interventions. RESULTS: MR-proANP levels increased from sepsis to severe sepsis and septic shock on D0 and D4 of VAP (0.002 and 0.02 respectively). Median MR-proANP levels on day 0 and day 4 (pmol/L [interquartile range]) were 149.0 (79.8-480.0) and 249.0 (93.6-571.0) in septic patients, 438.5 (229.3-762.0) and 407.5 (197.8-738.0) in severe sepsis, 519.5 (369.5-1282.3) and 632.0 (476.0-1047.5) in septic shock. On day 0 and day 4, MR-proANP levels were significantly higher in non-survivors (525.0 [324.0-957.8] and 679.5 [435.0-879.5], respectively) than in survivors (235.0 [102.0-535.0] and 254.0 [110.0-571.0], respectively; P = 0.004). Univariate logistic regression model for mortality included age, gender, APACHE II score, creatinine, logarithmic transformed MR-proANP (LnMR-proANP). Mortality was directly related to LnMR-proANP on D0 and D4, with odds ratios (OR) of 2.06 (95% CI 1.21-3.51) and 2.63 (1.33-5.23), respectively. In multivariate logistic regression, only LnMR-proANP D0 with OR = 2.35 (1.05-5.26) and LnMR-proANP D4 with OR = 3.76 (1.39-10.18) remained significant. CONCLUSIONS: Our data demonstrated that MR-proANP levels increase progressively with the severity of sepsis and are independent predictors of mortality in VAP.

Copeptin, a novel prognostic biomarker in ventilator-associated pneumonia.

BACKGROUND: The present study sought to investigate the correlation of copeptin with the severity of septic status in patients with ventilator-associated pneumonia (VAP), and to analyze the usefulness of copeptin as a predictor of mortality in VAP. METHODS: The prospective observational cohort study was conducted in a teaching hospital. The subjects were 71 patients consecutively admitted to the intensive care unit from October 2003 to August 2005 who developed VAP. Copeptin levels were determined on day 0 and day 4 of VAP. Patients were followed for 28 days after the diagnosis, when they were considered survivors. Patients who died before day 28 were classified as nonsurvivors. There were no interventions. RESULTS: Copeptin levels increased from sepsis to severe sepsis and septic shock both on day 0 and day 4 (P = 0.001 and P = 0.009, respectively). Variables included in the univariable logistic regression analysis for mortality were age, gender, Acute Physiology and Chronic Health Evaluation II score and ln copeptin on day 0 and day 4. Mortality was directly related to ln copeptin levels on day 0 and day 4, with odds ratios of 2.32 (95% confidence interval, 1.25 to 4.29) and 2.31 (95% confidence interval, 1.25 to 4.25), respectively. In a multivariable logistic regression model for mortality, only ln copeptin on day 0 with odds ratio 1.97 (95% confidence interval, 1.06 to 3.69) and ln copeptin on day 4 with odds ratio 2.39 (95% confidence interval, 1.24 to 4.62) remained significant. CONCLUSION: Our data demonstrate that copeptin levels increase progressively with the severity of sepsis and are independent predictors of mortality in VAP.

Decreases in procalcitonin and C-reactive protein are strong predictors of survival in ventilator-associated pneumonia.

INTRODUCTION: This study sought to assess the prognostic value of the kinetics of procalcitonin (PCT), C-reactive protein (CRP) and clinical scores (clinical pulmonary infection score (CPIS), Sequential Organ Failure Assessment (SOFA)) in the outcome of ventilator-associated pneumonia (VAP) at an early time point, when adequacy of antimicrobial treatment is evaluated. METHODS: This prospective observational cohort study was conducted in a teaching hospital. The subjects were 75 patients consecutively admitted to the intensive care unit from October 2003 to August 2005 who developed VAP. Patients were followed for 28 days after the diagnosis, when they were considered survivors. Patients who died before the 28th day were non-survivors. There were no interventions. RESULTS: PCT, CRP and SOFA score were determined on day 0 and day 4. Variables included in the univariable logistic regression model for survival were age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, decreasing DeltaSOFA, decreasing DeltaPCT and decreasing DeltaCRP. Survival was directly related to decreasing DeltaPCT with odds ratio (OR) = 5.67 (95% confidence interval 1.78 to 18.03), decreasing DeltaCRP with OR = 3.78 (1.24 to 11.50), decreasing DeltaSOFA with OR = 3.08 (1.02 to 9.26) and APACHE II score with OR = 0.92 (0.86 to 0.99). In a multivariable logistic regression model for survival, only decreasing DeltaPCT with OR = 4.43 (1.08 to 18.18) and decreasing DeltaCRP with OR = 7.40 (1.58 to 34.73) remained significant. Decreasing DeltaCPIS was not related to survival (p = 0.59). There was a trend to correlate adequacy to survival. Fifty percent of the 20 patients treated with inadequate antibiotics and 65.5% of the 55 patients on adequate antibiotics survived (p = 0.29). CONCLUSION: Measurement of PCT and CRP at onset and on the fourth day of treatment can predict survival of VAP patients. A decrease in either one of these marker values predicts survival.

Markers for sepsis diagnosis: what is useful?

Timely diagnosis of the different severities of septic inflammation is potentially lifesaving because therapies that have been shown to lower mortality should be initiated early. Sepsis and severe sepsis are accompanied by clinical and laboratory signs of systemic inflammation but patients with inflammation caused by noninfectious causes may present with similar signs and symptoms. It is important to identify markers for an early diagnosis of sepsis and organ dysfunction. This article presents currently interesting sepsis biomarkers. Other novel markers and their potential role are discussed.

Correlation of procalcitonin and C-reactive protein to inflammation, complications, and outcome during the intensive care unit course of multiple-trauma patients.

BACKGROUND: A comparison of the amount of and the kinetics of induction of procalcitonin (PCT) with that of C-reactive protein (CRP) during various types of and severities of multiple trauma, and their relation to trauma-related complications, was performed. METHODS: Ninety adult trauma patients admitted to the intensive care unit of our tertiary care hospital were evaluated in a prospective case study. During the initial 24 hours after trauma the Injury Severity Score, the Sepsis-related Organ Failure Assessment score, and the Acute Physiology and Chronic Health Evaluation II score were evaluated. PCT, CRP, the sepsis criteria (American College of Chest Physicians/Society of Critical Care Medicine definitions), and the Sepsis-related Organ Failure Assessment score were measured at days 1-7, as well as at days 14 and 21, concluding the observation period with the 28-day survival. RESULTS: The induction of PCT and CRP varied in patients suffering from trauma. PCT increased only moderately in most patients and peaked at day 1-2 after trauma, the concentrations rapidly declining thereafter. CRP ubiquitously increased and its kinetics were much slower. Complications such as sepsis, infection, blood transfusion, prolonged intensive care unit treatment, and poor outcome were more frequent in patients with initially high PCT (>1 ng/ml), whereas increases of CRP showed no positive correlation. CONCLUSION: In patients with multiple trauma due to an accident, the PCT level provides more information than the CRP level since only moderate amounts of PCT are induced, and higher concentrations correlate with more severe trauma and a higher frequency of various complications, including sepsis and infection. Most importantly, the moderate trauma-related increase of PCT and the rapidly declining concentrations provide a baseline value near to the normal range at an earlier time frame than for CRP, thus allowing a faster and more valid prediction of sepsis during the early period after trauma.

Mannan-binding lectin and procalcitonin measurement for prediction of postoperative infection.

INTRODUCTION: Postoperative infection is a major cause of morbidity and mortality. We investigated two serum markers for their ability to identify patients at risk for postoperative infection. Mannan-binding lectin (MBL) is a central molecule of the innate immune system and MBL deficiency is known to predispose to infection. Procalcitonin (PCT) is a sensitive marker for bacterial infection. METHODS: We investigated 162 patients undergoing elective surgery for cancer of the gastrointestinal tract. Patients were classified as having no complications (group A), having infection for unknown reason (group B) or having sepsis after events like aspiration or anastomotic leakage (group C). Analysis was done pre- and postoperatively for serum levels of MBL, PCT and C-reactive-protein. DNA was preoperatively sampled and stored and later analysed for genetic polymorphisms of MBL. RESULTS: The preoperative serum levels of MBL were significantly lower in group B patients than in group A patients (1332 +/- 466 ng/ml versus 2523 +/- 181 ng/ml). PCT measured on day one post-surgery was significantly higher in group B patients than in group A (3.33 +/- 1.08 ng/ml versus 1.38 +/- 0.17 ng/ml). Patients with an aberrant MBL genotype had a significantly higher risk of postoperative infections than wild-type carriers (p < 0.05). CONCLUSION: Preoperative MBL and early postoperative PCT measurement may help identify patients at risk for postoperative infection.

Biomarkers of sepsis: clinically useful?

PURPOSE OF REVIEW: The purpose of this review is to indicate recent developments in biomarkers of sepsis and to evaluate their impact on clinical use. According to the 'surviving sepsis campaign,' diagnosis of sepsis and infection is urgent; early and specific treatment is most effective to reduce complications and to decrease mortality. RECENT FINDINGS: A variety of biomarkers of sepsis is presently available. The diagnostic spectrum of the various markers, however, is different. Some primarily indicate severity of inflammation (e.g. interleukin-6), others respond to infection, but do not indicate the host response well (endotoxin, lipoprotein binding protein, triggering receptor on myeloid cells). There are new markers with limited clinical experience, for example triggering receptor on myeloid cells or mid-pro atrial natriuretic peptide (Seristra, Brahms AG, Hennigsdorf, Germany). Procalcitonin is a well-established biomarker of sepsis that fulfills several criteria of clinical needs: it responds both to infection and severity of inflammation and thus has an impact on therapy. Recent studies indicate that antibiotic treatment can also be guided by procalcitonin. Further indications, including diagnosis of invasive bacterial infections and diagnosis of sepsis in neonates and children have been reported recently. SUMMARY: Recent data and cumulative analyses indicate that biomarkers of sepsis improve diagnosis of sepsis. However, only a few markers have impact on therapy and fulfill the clinical requirements. Procalcitonin is a well-established marker, indicating infection, sepsis, and progression to the more severe stages of the disease. Today, this biomarker should be in the diagnostic portfolio of an intensive care unit or emergency ward.

Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction.

INTRODUCTION: Both C-reactive protein (CRP) and procalcitonin (PCT) are accepted sepsis markers. However, there is still some debate concerning the correlation between their serum concentrations and sepsis severity. We hypothesised that PCT and CRP concentrations are different in patients with infection or with no infection at a similar severity of organ dysfunction or of systemic inflammatory response. PATIENTS AND METHODS: One hundred and fifty adult intensive care unit patients were observed consecutively over a period of 10 days. PCT, CRP and infection parameters were compared among the following groups: no systemic inflammatory response syndrome (SIRS) (n = 15), SIRS (n = 15), sepsis/SS (n = 71) (including sepsis, severe sepsis and septic shock [n = 34, n = 22 and n = 15]), and trauma patients (n = 49, no infection). RESULTS: PCT and CRP concentrations were higher in patients in whom infection was diagnosed at comparable levels of organ dysfunction (infected patients, regression of median [ng/ml] PCT = -0.848 + 1.526 sequential organ failure assessment [SOFA] score, median [mg/l] CRP = 105.58 + 0.72 SOFA score; non-infected patients, PCT = 0.27 + 0.02 SOFA score, P < 0.0001; CRP = 84.53 - 0.19 SOFA score, P < 0.005), although correlation with the SOFA score was weak (R = 0.254, P < 0.001 for PCT, and R = 0.292, P < 0.001 for CRP). CRP levels were near their maximum already during lower SOFA scores, whereas maximum PCT concentrations were found at higher score levels (SOFA score > 12).PCT and CRP concentrations were 1.58 ng/ml and 150 mg/l in patients with sepsis, 0.38 ng/ml and 51 mg/l in the SIRS patients (P < 0.05, Mann-Whitney U-test), and 0.14 ng/ml and 72 mg/l in the patients with no SIRS (P < 0.05). The kinetics of both parameters were also different, and PCT concentrations reacted more quickly than CRP. CONCLUSIONS: PCT and CRP levels are related to the severity of organ dysfunction, but concentrations are still higher during infection. Different sensitivities and kinetics indicate a different clinical use for both parameters.

Induction of procalcitonin and proinflammatory cytokines in an anhepatic baboon endotoxin shock model.

Our objective was to evaluate the role of the liver for procalcitonin (PCT) and cytokine induction in a baboon endotoxin shock model. Complete liver resection with portocaval anastomosis was established in a baboon prior to the induction of endotoxin shock by intravenous administration of endotoxin (100 microg/kg LPS Escherichia coli). Two baboons without surgical intervention were used as controls. Plasma concentrations of PCT, tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, IL-8, endotoxin, and hemodynamic and metabolic parameters were measured pre- and postoperatively and until 6 h after endotoxin administration. PCT concentrations increased to 1.2 and 4.6 ng/mL in control animals at 6 h, but remained below 0.3 ng/mL in the anhepatic baboon. IL-6 and IL-8 increased only for few hours in controls, but remained elevated in the hepatectomized animal near their maximum (IL-6, 2-6 ng/mL) or several-fold higher (IL-8, 30-35 ng/mL), whereas TNF-alpha response was only a small fraction (0.3 ng/mL) of the controls. Endotoxin was much higher and longer persisting in the hepatectomized animal compared with controls. The near absence of PCT production in the anhepatic baboon suggests a primary role for the liver as a source of PCT production during endotoxin shock. Furthermore, the liver also seems to be an important source of TNF-alpha, but not IL-6 or IL-8.

Pathobiochemistry and clinical use of procalcitonin.

Induction of the protein procalcitonin during infection and inflammation was first described approximately 10 years ago. A large number of publications, primarily clinical studies, demonstrate the increasing use of procalcitonin in modern clinical practice. However, data on the biological function and origin of procalcitonin is scarce. Findings regarding the possible role and source of procalcitonin in sepsis and infection were recently published, and the pathophysiology of the protein has meanwhile been investigated in various experimental models. Procalcitonin obviously has certain biological functions, and it is also known to be specifically induced. Given the hormonal origin of the mature protein and the inflammation-related functions of its propeptides, some investigators suggest that procalcitonin should be referred to as a "hormokine," although its biological functions should be studied in more detail. This review will survey the data now available in recent publications on the induction, production sources, possible biological functions and clinical uses of procalcitonin.

Markers of endothelial damage in organ dysfunction and sepsis.

OBJECTIVES: To review the literature on direct and indirect markers of endothelial activation and damage in patients with sepsis and systemic inflammation and to assess their clinical usefulness for diagnosis and outcome. Various markers derived from or activated by endothelial cells are described, such as adhesion molecules, thrombomodulin, von Willebrand factor, parameters of the coagulation system, and interleukin-6. Furthermore, the association of these markers with the severity of sepsis, systemic inflammation, and outcome is evaluated. DATA EXTRACTION AND SYNTHESIS: Published research and review articles related to these parameters, with special emphasis on clinical studies. CONCLUSIONS: Endothelial activation and damage occur early during sepsis and play a major role in the pathophysiology of systemic inflammation. Various markers of endothelial activation are increased during sepsis and systemic inflammation, and in most studies, the level of markers such as soluble intercellular adhesion molecule, vascular cell adhesion molecule, and E selectin correlate well with the severity of inflammation and the course of the disease. However, to date, it remains unclear whether adhesion molecules and coagulation parameters are superior in this respect to interleukin-6 and procalcitonin, as direct comparisons are lacking. In addition, it is evident that markers of endothelial activation and coagulation parameters lack specificity for infection-induced endothelial damage and organ dysfunction.