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Background: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients.Methods: The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later.Results: Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality.Conclusions: Admission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015. [ABSTRACT FROM AUTHOR]

Background: Growth hormone (GH) has been linked to cardiovascular disease but the exact mechanism of this association is still unclear. We here test if the fasting levels of GH are cross-sectionally associated with carotid intima media thickness (IMT) and whether treatment with fluvastatin affects the fasting level of GH.Methods: We examined the association between GH and IMT in 4425 individuals (aged 46-68 years) included in the baseline examination (1991-1994) of the Malmö Diet and Cancer cardiovascular cohort (MDC-CC). From that cohort we then studied 472 individuals (aged 50-70 years) who also participated (1994-1999) in the β-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS), a randomized, double blind, placebo-controlled, single-center clinical trial. Using multivariate linear regression models we related the change in GH-levels at 12 months compared with baseline to treatment with 40 mg fluvastatin once daily.Results: In MDC-CC fasting values of GH exhibited a positive cross-sectional relation to the IMT at the carotid bulb independent of traditional cardiovascular risk factors (p = 0.002). In a gender-stratified analysis the correlation were significant for males (p = 0.005), but not for females (p = 0.09). Treatment with fluvastatin was associated with a minor reduction in the fasting levels of hs-GH in males (p = 0.05) and a minor rise in the same levels among females (p = 0.05).Conclusions: We here demonstrate that higher fasting levels of GH are associated with thicker IMT in the carotid bulb in males. Treatment with fluvastatin for 12 months only had a minor, and probably not clinically relevant, effect on the fasting levels of hs-GH. [ABSTRACT FROM AUTHOR]

Substantial attention and resources have been directed to improving outcomes of patients with critical illnesses, in particular sepsis, but all recent clinical trials testing various interventions or strategies have failed to detect a robust benefit on mortality. Acute heart failure is also a critical illness, and although the underlying etiologies differ, acute heart failure and sepsis are critical care illnesses that have a high mortality in which clinical trials have been difficult to conduct and have not yielded effective treatments. Both conditions represent a syndrome that is often difficult to define with a wide variation in patient characteristics, presentation, and standard management across institutions. Referring to past experiences and lessons learned in acute heart failure may be informative and help frame research in the area of sepsis. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on dyspnea assessments and all-cause mortality as the primary measures of efficacy, and recent trials have been designed to assess novel clinical composite endpoints assessing organ dysfunction and mortality while still assessing all-cause mortality as a separate measure of safety. Applying the lessons learned in acute heart failure trials to severe sepsis and septic shock trials might be useful to advance the field. Novel endpoints beyond all-cause mortality should be considered for future sepsis trials. [ABSTRACT FROM AUTHOR]

Background: Circulating levels of endothelin-1 are increased in sepsis and correlate with severity of disease. A rapid and easy immunoassay has been developed to measure the more stable ET-1 precursor peptides proET-1. The objective of this study was to assess the diagnostic and prognostic value of proET-1 in a prospective cohort of mainly septic patients with community-acquired pneumonia. Methods: We evaluated 281 consecutive patients with community acquired pneumonia. Serum proET-1 plasma levels were measured using a new sandwich immunoassay. Results: ProET-1 levels exhibited a gradual increase depending on the clinical severity of pneumonia as assessed by the pneumonia severity index (PSI) and the CURB65 scores (p < 0.001 and p < 0.01). The diagnostic accuracy to predict bacteraemia of procalcitonin (AUC 0.84 [95% 0.74-0.93]) was superior than C-reactive protein (AUC 0.67 [95%CI 0.56-0.78]) and leukocyte count (AUC 0.66 [95%CI 0.55-0.78]) and in the range of proET-1(AUC of 0.77 [95%CI 0.67-0.86]). ProET-1 levels on admission were increased in patients with adverse medical outcomes including death and need for ICU admission. ROC curve analysis to predict the risk for mortality showed a prognostic accuracy of proET-1 (AUC 0.64 [95%CI 0.53-0.74]), which was higher than C-reactive protein (AUC 0.51 [95%CI 0.41-0.61]) and leukocyte count (AUC 0.55 [95%CI 0.44-0.65]) and within the range of the clinical severity scores (PSI AUC 0.69 [95%CI 0.61-0.76] and CURB65 0.67 [95%CI 0.57-0.77]) and procalcitonin (AUC 0.59 [95% 0.51-0.67]). ProET-1 determination improved significantly the prognostic accuracy of the CURB65 score (AUC of the combined model 0.69 [95%CI 0.59-0.79]). In a multivariate logistic regression model, only proET1 and the clinical severity scores were independent predictors for death and for the need for ICU admission. Conclusion: In community-acquired pneumonia, ET-1 precursor peptides correlate with disease severity and are independent predictors for mortality and ICU admission. If confirmed in future studies, proET-1 levels may become another helpful tool for risk stratification and management of patients with community-acquired pneumonia. Trial registration: ISRCTN04176397 [ABSTRACT FROM AUTHOR]

Background: Sepsis is a leading cause of death worldwide and a major challenge for physicians to predict and manage. Proenkephalin A 119-159 (penKid) is a reliable surrogate marker for the more unstable endogenous opioid peptide enkephalin, which has previously been shown to predict both acute and chronic kidney disease. The aim of this prospective observational study was to assess penKid as a predictor of acute kidney injury (AKI), multi-organ failure and mortality in sepsis among unselected sepsis patients presenting to the emergency department (ED).Method: We enrolled 644 patients consecutively during office-hours (6 AM-6 PM) between December 1, 2013 and February 1, 2015. Fifty-six patients were excluded due to incomplete data. We measured penKid in 588 adult patients (patients under 18 years of age were excluded) with sepsis (≥2SIRS criteria + suspected infection) upon admission to the ED at Skåne University Hospital, Malmö, Sweden. Logistic regression analysis was used to relate levels of penKid at presentation to AKI, multi-organ failure, 28-day mortality and progression of renal SOFA subscore. Odds ratios are presented as the number of standard deviations from the mean of log-transformed penKid.Results: In age and sex adjusted models, penKid predicted AKI within 48 h and 7 days, but these associations were attenuated after additional adjustment for estimated creatinine-based glomerular filtration rate (eGFR). In models adjusted for age, sex and eGFR, penKid significantly predicted progression from rSOFA = 0 and ≤ 1 to higher rSOFA scores as well as multi-organ failure and mortality. In contrast, eGFR did not predict 28-day mortality.Conclusion: PenKid is an effective predictor of renal injury, severe multi-organ failure and mortality in unselected sepsis patients presenting to the emergency department. [ABSTRACT FROM AUTHOR]

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial.Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock.Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8).Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial.Trial Registration: ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015. [ABSTRACT FROM AUTHOR]

Introduction: Post cardiac surgery vasodilatation (PCSV) is possibly related to a vasopressin deficiency that could relate to chronic stimulation of adeno-hypophysis. To assess vasopressin system activation, a perioperative course of copeptin and vasopressin plasma concentrations were studied in consecutive patients operated on for cardiac surgery.Methods: Sixty-four consecutive patients scheduled for elective cardiac surgery with cardiopulmonary bypass were studied. Hemodynamic, laboratory and clinical data were recorded before and during cardiopulmonary bypass, and at the eighth postoperative hour (H8). At the same time, blood was withdrawn to determine plasma concentrations of arginine vasopressin (AVP, radioimmunoassay) and copeptin (immunoluminometric assay). PCSV was defined as mean arterial blood pressure < 60 mmHg with cardiac index ≥ 2.2 l/min/m², and was treated with norepinephrine to restore mean blood pressure > 60 mmHg. Patients with PCSV were compared with the other patients (controls). Student's t test, Fisher's exact test, or nonparametric tests (Mann-Whitney, Wilcoxon) were used when appropriate. Correlation between AVP and copeptin was evaluated and receiver-operator characteristic analysis assessed the utility of preoperative copeptin to distinguish between controls and PCSV patients.Results: Patients who experienced PCSV had significantly higher copeptin plasma concentration before cardiopulmonary bypass (P < 0.001) but lower AVP concentrations at H8 (P < 0.01) than controls. PCSV patients had preoperative hyponatremia and decreased left ventricle ejection fraction, and experienced more complex surgery (redo). The area under the receiver-operator characteristic curve of preoperative copeptin concentration was 0.86 ± 0.04 (95% confidence interval = 0.78 to 0.94; P < 0.001). The best predictive value for preoperative copeptin plasma concentration was 9.43 pmol/l with a sensitivity of 90% and a specificity of 77%.Conclusions: High preoperative copeptin plasma concentration is predictive of PSCV and suggests an activation of the AVP system before surgery that may facilitate depletion of endogenous AVP stores and a relative AVP deficit after surgery. [ABSTRACT FROM AUTHOR]