Michael Meisner

Markers of endothelial damage in organ dysfunction and sepsis.

ObjectivesTo 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 SynthesisPublished research and review articles related to these parameters, with special emphasis on clinical studies. ConclusionsEndothelial 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.

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

BackgroundA 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.MethodsNinety 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.ResultsThe 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.ConclusionIn 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.

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

IntroductionThis 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.MethodsThis 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.ResultsPCT, 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 ΔSOFA, decreasing ΔPCT and decreasing ΔCRP. Survival was directly related to decreasing ΔPCT with odds ratio (OR) = 5.67 (95% confidence interval 1.78 to 18.03), decreasing ΔCRP with OR = 3.78 (1.24 to 11.50), decreasing ΔSOFA 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 ΔPCT with OR = 4.43 (1.08 to 18.18) and decreasing ΔCRP with OR = 7.40 (1.58 to 34.73) remained significant. Decreasing ΔCPIS 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).ConclusionMeasurement 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.

Copeptin, a novel prognostic biomarker in ventilator-associated pneumonia

BackgroundThe 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.MethodsThe 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.ResultsCopeptin 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.ConclusionOur data demonstrate that copeptin levels increase progressively with the severity of sepsis and are independent predictors of mortality in VAP.

Clinical experiences with a new semi-quantitative solid phase immunoassay for rapid measurement of procalcitonin.

Abstract A self-developing solid-phase immunoassay (B.R.A.H.M.S. PCT-Q, B.R.A.H.M.S.-Diagnostica GmbH, Hennigsdorf, Germany) has recently become available for the semi-quantitative and rapid measurement of procalcitonin (PCT). In this study we examined the validity of this assay at daily clinical routine conditions at five different hospitals in a prospective study. After development of the assay (200 μl plasma, 30 minutes incubation), PCT levels were categorized into four groups (< 0.5 μg/l; ≥ 0.5−< 2 μg/l; ≥ 2−< 10 μg/l; ≥ 10 μg/l) according to the provided reference scale. Samples from patients with suspected elevation of PCT of different etiology (n=237) were read by various analyzers and compared with the results of the Lumitest® PCT (B.R.A.H.M.S.-Diagnostica GmbH, Hennigsdorf, Germany). A total of 74.7% of measurements were categorized according to the results of the Lumitest®PCT, 24.5% were read within the next lower or higher category. Using a ± 10% range at the reference concentrations (20% at 0.5 μg/l), 82.7% of samples were correctly categorized and 16.4% within the next categories. Using a cut-off value of 2.0 μg/l, 92.0% (94.1% for ± 10%) of the results were correctly categorized. The semi-quantitative solid phase immunoassay allows a rapid, simple and semi-quantitative measurement of plasma PCT. The validity of the test results and its ease of use are sufficient to support acute diagnostic decisions. However, for the follow-up of PCT concentrations and routine daily measurements, the quantitative luminometric assay should be preferred, when available.

Procalcitonin - Influence of temperature, storage, anticoagulation and arterial or venous asservation of blood samples on procalcitonin concentrations

In this study we have analysed the influence of temperature and time of storage and of repeated freezing on procalcitonin plasma concentrations ex vivo. We have also analysed the difference of procalcitonin concentrations in arterial or venous blood samples and the influence of different anticoagulation techniques on procalcitonin concentrations (serum, EDTA-, lithium-heparin- or citrate plasma). At room temperature (25 degrees C) a loss of procalcitonin plasma concentrations of 6.4% +/- 2.6% (mean, 2 standard error of the mean) after 3 hours (4.6% +/- 5.2% at 4 degrees C) and 12.3% +/- 3.1% after 24 hours occurred (6.3% +/- 5.0% at 4 degrees C, n = 17 each). Comparing the procalcitonin concentrations of blood samples with different anticoagulants (n = 24 each), there was only a significant difference between procalcitonin concentrations in heparinized plasma and serum (+ 7.6%, difference of the mean). There was no significant influence of the blood sampling technique (arterial or venous line) and of repeated freezing/thawing cycles (up to 3 times) on the procalcitonin concentrations measured. Although the difference of sampling and storage of the blood on procalcitonin concentrations is not significant, multiple factors may act synergistically on the result of procalcitonin measurement. To keep variations of ex vivo conditions as minimal as possible, a standardized technique of anticoagulation, time and temperature of storage is recommended, e.g. the use of EDTA-plasma and storage at room temperature, when samples are measured within 4 hours after blood drawing.

Blood volume determination using hydroxyethyl starch: a rapid and simple intravenous injection method.

OBJECTIVE To develop and evaluate a new method for blood volume measurements using hydroxyethyl starch as a dilution marker. DESIGN Laboratory and clinical investigation. SETTING Neurosurgical operating rooms and anesthesiological laboratories of a university hospital. PATIENTS Twelve patients who underwent a neurosurgical operation. INTERVENTIONS Anesthesia and operations were carried out by physicians who were not involved in the study. In addition, blood samples were drawn from 50 volunteers. MEASUREMENTS AND MAIN RESULTS Blood volume measurements by the hydroxyethyl starch method were validated in vivo by comparison with a conventional carbon monoxide technique. Patients were intravenously injected with hydroxyethyl starch (100 mL) and received simultaneously an injection of carbon monoxide (50 mL) into a closed-circuit ventilation system. Blood samples obtained before and 5 mins after injection were analyzed for carboxyhemoglobin and glucose plasma concentrations after acidic hydrolysis of hydroxyethyl starch. Blood volume was calculated from the difference between glucose concentrations measured after hydrolysis in the plasma, before and after the addition of hydroxyethyl starch. In vitro, the hydroxyethyl starch method had an error and a precision of approximately 2%. In vivo, simultaneous measurements of blood volume using hydroxyethyl starch and carbon monoxide demonstrated a high correlation (r2 = .96, p < .001) between these methods. The mean difference between the two methods relative to their average value was 1.0 +/- 3.5%; the bias was 52.3 mL, and the 95% confidence interval was -64.0 to +168.7 mL. CONCLUSIONS Blood volume determination by the hydroxyethyl starch method is accurate and rapid and may enhance perioperative monitoring of fluid and blood therapy.

Plasma concentrations and clearance of procalcitonin during continuous veno-venous hemofiltration in septic patients.

We determined the elimination characteristics of procalcitonin (PCT) during continuous veno-venous hemofiltration (CVVHF) and the resulting effect on PCT plasma levels. A prospective study was conducted in patients with sepsis and acute oliguric renal failure, treated with CVVHF using a polysulfone membrane (Baxter Renaflo II PSHF 1200). Patients had sepsis and PCT plasma levels > 4 ng ml(-1) (n = 26). PCT was measured in the pre- and post-filter plasma and the ultrafiltrate at 0, 5, 10, and 15 min and 1, 2, 4, 6, 12, and 24 h after setup of CVVHF. PCT sieving coefficient was 0.24. Elimination of PCT, however, depended on the duration of filtration, because filter adsorption was the main mechanism of PCT clearance during the first hour of hemofiltration, finally increasing to a clearance of PCT into the ultrafiltrate of 2.8-5.5 mL/min after 2 h. PCT plasma levels were not significantly altered during CVVHF (96% of the initial concentration after 24 h, P = 0.72). Similar to what has been observed with cytokines and other proteins of a comparable molecular weight, PCT is removed from the plasma during CVVHF, but plasma PCT levels are unchanged. Thus, PCT can be used as a diagnostic parameter even in patients with acute renal failure undergoing CVVHF.

Induction of nitric oxide synthase activity in phagocytic cells inhibited by tricyclodecan-9-yl-xanthogenate (D609)

1 The synthesis of nitric oxide (NO) by immune‐stimulated murine phagocytic cells (J774) and the modulation of this synthesis by tricyclodecan‐9‐yl‐xanthogenate (D609), a specific inhibitor of phosphatidylcholine‐specific phospholipase C (PC‐PLC), was investigated. D609 dose‐dependently suppressed production of NO, as measured by the release of nitrite and nitrate, in response to lipopolysac‐charide (LPS) and interferon‐γ (IFN‐γ) in intact cultured cells with an IC50 of approximately 20 μg ml−1. D609 at 40 μg ml−1 completely abrogated immune‐stimulated nitrite production. 2 The inhibitory effects of D609 on nitrite production were time‐dependent and restricted to the first 18 h post‐stimulation. D609 did not inhibit nitrite production in the cytosol of immune‐stimulated phagocytes. 3 These findings indicate that the xanthogenate, D609, is a potent inhibitor of the induction of NO‐synthase activity in immune‐stimulated phagocytes. Furthermore, since D609 has been demonstrated to inhibit PC‐PLC specifically, our findings suggest that the activation of this enzyme by LPS and IFN‐γ is a proximal step in the signal transduction of inducible NO‐synthase in phagocytic cells.