Rossella Marino

In-hospital percentage BNP reduction is highly predictive for adverse events in patients admitted for acute heart failure: the Italian RED Study

IntroductionOur aim was to evaluate the role of B-type natriuretic peptide (BNP) percentage variations at 24 hours and at discharge compared to its value at admission in order to demonstrate its predictive value for outcomes in patients with acute decompensated heart failure (ADHF).MethodsThis was a multicenter Italian (8 centers) observational study (Italian Research Emergency Department: RED). 287 patients with ADHF were studied through physical exams, lab tests, chest X Ray, electrocardiograms (ECGs) and BNP measurements, performed at admission, at 24 hours, and at discharge. Follow up was performed 180 days after hospital discharge. Logistic regression analysis was used to estimate odds ratios (OR) for the various subgroups created. For all comparisons, a P value < 0.05 was considered statistically significant.ResultsBNP median (interquartile range (IQR)) value at admission was 822 (412 - 1390) pg\mL; at 24 hours was 593 (270 - 1953) and at discharge was 325 (160 - 725). A BNP reduction of >46% at discharge had an area under curve (AUC) of 0.70 (P < 0.001) for predicting future adverse events. There were 78 events through follow up and in 58 of these patients the BNP level at discharge was >300 pg/mL. A BNP reduction of 25.9% after 24 hours had an AUC at ROC curve of 0.64 for predicting adverse events (P < 0.001). The odds ratio of the patients whose BNP level at discharge was <300 pg/mL and whose percentage decrease at discharge was <46% compared to the group whose BNP level at discharge was <300 pg/mL and whose percentage decrease at discharge was >46% was 4.775 (95% confidence interval (CI) 1.76 - 12.83, P < 0.002). The odds ratio of the patients whose BNP level at discharge was >300 pg/mL and whose percentage decrease at discharge was <46% compared to the group whose BNP level at discharge was <300 pg/mL and whose percentage decrease at discharge was >46% was 9.614 (CI 4.51 - 20.47, P < 0.001).ConclusionsA reduction of BNP >46% at hospital discharge compared to the admission levels coupled with a BNP absolute value < 300 pg/mL seems to be a very powerful negative prognostic value for future cardiovascular outcomes in patients hospitalized with ADHF.

Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis

IntroductionThe incidence of death among patients admitted for severe sepsis or septic shock is high. Adrenomedullin (ADM) plays a central role in initiating the hyperdynamic response during the early stages of sepsis. Pilot studies indicate an association of plasma ADM with the severity of the disease. In the present study we utilized a novel sandwich immunoassay of bioactive plasma ADM in patients hospitalized with sepsis in order to assess the clinical utility.MethodsWe enrolled 101 consecutive patients admitted to the emergency department with suspected sepsis in this study. Sepsis was defined by fulfillment of at least two systemic inflammatory response syndrome (SIRS) criteria plus clinical suspicion of infection. Plasma samples for ADM measurement were obtained on admission and for the next four days. The 28-day mortality rate was recorded.ResultsADM at admission was associated with severity of disease (correlation with Acute Physiology and Chronic Health Evaluation II (APACHE II) score: r = 0.46; P <0.0001). ADM was also associated with 28-day mortality (ADM median (IQR): survivors: 50 (31 to 77) pg/mL; non-survivors: 84 (48 to 232) pg/mL; P <0.001) and was independent from and additive to APACHE II (P = 0.02). Cox regression analysis revealed an additive value of serial measurement of ADM over baseline assessment for prediction of 28-day mortality (P < 0.01). ADM was negatively correlated with mean arterial pressure (r = -0.39; P <0.0001), and it strongly discriminated those patients requiring vasopressor therapy from the others (ADM median (IQR): no vasopressors 48 (32 to 75) pg/mL; with vasopressors 129 (83 to 264) pg/mL, P <0.0001).ConclusionsIn patients admitted with sepsis, severe sepsis or septic shock plasma ADM is strongly associated with severity of disease, vasopressor requirement and 28-day mortality.

Comparison between white blood cell count, procalcitonin and C reactive protein as diagnostic and prognostic biomarkers of infection or sepsis in patients presenting to emergency department

Abstract Background: Procalcitonin (PCT) is currently the most studied infection biomarker and its blood levels seem to mirror the severity of illness and outcome. PCT is widely used together with other biomarkers, such as white blood cells (WBC) count and C reactive protein (CRP), in order to guide antibiotic therapy. This study aimed to verify the diagnostic and prognostic power of WBC, CRP and PCT in patients with suspected infection in emergency department (ED). Methods: A total of 513 patients presenting to the ED with signs/symptoms of local infections or sepsis were enrolled. APACHEII score and in-hospital death were recorded. Patients were subdivided into quartiles by age, and the biomarkers were measured at baseline. Receiver operating characteristics (ROC) curves for evaluating diagnostic and prognostic role of PCT, CRP and WBC were calculated for each variable alone and combined. Results: When compared each other for PCT, CRP, and WBC there was no significant difference between the four subgroups. A direct correlation between PCT and WBC was found in the II, III, and IV quartiles (the highest correlation, r=0.34, p<0.0003). PCT alone or when combined with WBC showed the best diagnostic and prognostic power at ROC analysis. Conclusions: Our data demonstrate that WBC, but more CRP and PCT are reliable diagnostic and prognostic biomarkers, when considered in combination and with severity clinical score. PCT confirms its stronger usefulness as a diagnostic marker of sepsis. A multi-diagnostic tools approach is fundamental to perform a correct and rapid diagnosis of infection and sepsis in ED.

Brain Natriuretic Peptide and N-Terminal Pro-B-Type Natriuretic Peptide Show a Different Profile in Response to Acute Decompensated Heart Failure Treatment

Brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are currently used for the diagnosis, prognosis, and therapeutic decision making in heart failure patients. The aim of the study was to compare BNP and NT-proBNP plasma concentration profiles in 42 patients with decompensated heart failure who underwent treatment in the emergency department. A significant decrease in both peptide concentrations fell beyond 24 hours of therapy. BNP concentration underwent a more responsive change from admission (-54.1%+/-8.6% at 72 hours and -57.4%+/-7.6% at discharge) than NT-proBNP concentration (-17.6%+/-5.4% at 72 hours and -18.6%+/-5.6% at discharge). Although BNP and NT-proBNP concentrations were highly correlated, no correlation in their variations was found, a finding that suggests a different kinetic behavior in response to treatment. Sequential measurements of BNP and NT-proBNP provide a reliable marker to confirm clinical improvement after 24 hours of treatment. BNP may show some advantages over NT-proBNP as a more sensitive marker of early stabilization in response to therapy.

Soluble ST2 Has a Prognostic Role in Patients With Suspected Sepsis

Background Soluble suppression of tumorigenicity 2 (sST2) has emerged as a novel biomarker for heart failure, and serum sST2 concentrations could be increased in inflammatory diseases. We explored whether sST2 is related to cardiac dysfunction/failure and has a prognostic role in patients with suspected sepsis. Methods In a total of 397 patients with suspected sepsis, sST2 concentrations were measured by using the Presage ST2 Assay (Critical Diagnostics, USA). sST2 concentrations were analyzed according to procalcitonin (PCT) concentrations, cardiovascular subscores of the sepsis-related organ failure assessment (SOFA) score, and clinical outcomes. Results sST2 concentrations were increased significantly according to the five groups of PCT concentrations and cardiovascular subscores of the SOFA score (P<0.000001 and P=0.036, respectively). In-hospital mortality was significantly higher among patients with sST2 concentrations above 35 ng/mL (P=0.0213) and among patients with increased concentrations of both sST2 and PCT (P=0.0028). Conclusions sST2 seems to be related to both cardiac dysfunction/failure and severity in sepsis. Measurement of sST2 and PCT in combination would be useful for risk stratification and prognosis prediction in patients with suspected sepsis.

IL-18 stimulates B-type natriuretic peptide synthesis by cardiomyocytes in vitro and its plasma levels correlate with B-type natriuretic peptide in non-overloaded acute heart failure patients:

Background: An altered IL-18 pathway in heart failure (HF) has recently been described and this cytokine was shown to be of clinical and prognostic utility. Cardiomyocytes are a target of this cytokine which exerts inflammatory, hypertrophic, and profibrotic activities. B-type natriuretic peptide is a cardiac hormone produced in response to cardiac filling to regulate cardiovascular homeostasis. The aim of the study was to verify the ability of IL-18 to induce B-type natriuretic peptide synthesis in vitro and to analyse the relationship between these two molecules in plasma in vivo from acute HF patients. Methods and Results: We demonstrated the ability of IL-18 to directly stimulate a murine cardiomyocyte cell line to express the B-type natriuretic peptide gene, synthesize the relative protein through a PI3K-AKT-dependent transduction, and induce a cell secretory phenotype with B-type natriuretic peptide release. A correlation between IL-18 and B-type natriuretic peptide plasma levels was found in non-overloaded acute HF patients, and in subgroups of acute HF patients with diabetes and coronary artery disease. Acute HF patients with renal failure had significantly higher IL-18 plasma levels than patients without. IL-18 plasma levels were correlated with C-reactive protein plasma levels. Conclusions: This study provides the first evidence of the ability of IL-18 to induce B-type natriuretic peptide synthesis in vitro and outlines the relationship between the two molecules in acute HF patients with an ongoing inflammatory status.

Proenkephalin, Neutrophil Gelatinase-Associated Lipocalin, and Estimated Glomerular Filtration Rates in Patients With Sepsis.

Background Proenkephalin (PENK) has been suggested as a novel biomarker for kidney function. We investigated the diagnostic and prognostic utility of plasma PENK in comparison with neutrophil gelatinase-associated lipocalin (NGAL) and estimated glomerular filtration rates (eGFR) in septic patients. Methods A total of 167 septic patients were enrolled: 99 with sepsis, 37 with septic shock, and 31 with suspected sepsis. PENK and NGAL concentrations were measured and GFR was estimated by using the isotope dilution mass spectrometry traceable-Modification of Diet in Renal Disease (MDRD) Study and three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations: CKD-EPICr, CDK-EPICysC, and CKD-EPICr-CysC. The PENK, NGAL, and eGFR results were compared according to sepsis severity, presence or absence of acute kidney injury (AKI), and clinical outcomes. Results The PENK, NGAL, and eGFR results were significantly associated with sepsis severity and differed significantly between patients with and without AKI only in the sepsis group (all P<0.05). PENK was superior to NGAL in predicting AKI (P=0.022) and renal replacement therapy (RRT) (P=0.0085). Regardless of the variable GFR category by the different eGFR equations, PENK showed constant and significant associations with all eGFR equations. Unlike NGAL, PENK was not influenced by inflammation and predicted the 30-day mortality. Conclusions PENK is a highly sensitive and objective biomarker of AKI and RRT and is useful for prognosis prediction in septic patients. With its diagnostic robustness and predictive power for survival, PENK constitutes a promising biomarker in critical care settings including sepsis.

The association of admission blood glucose level with the clinical picture and prognosis in cardiogenic shock – Results from the CardShock Study

BACKGROUND Critically ill patients often present with hyperglycemia, regardless of previous history of diabetes mellitus (DM). Hyperglycemia has been associated with adverse outcome in acute myocardial infarction and acute heart failure. We investigated the association of admission blood glucose level with the clinical picture and short-term mortality in cardiogenic shock (CS). METHODS Consecutively enrolled CS patients were divided into five categories according to plasma glucose level at the time of enrolment: hypoglycemia (glucose <4.0mmol/L), normoglycemia (4.0-7.9mmol/L), mild (8.0-11.9mmol/L), moderate (12.0-15.9mmol/L), and severe (≥16.0mmol/L) hyperglycemia. Clinical presentation, biochemistry, and short-term mortality were compared between the groups. RESULTS Plasma glucose level of 211 CS patients was recorded. Glucose levels were distributed equally between normoglycemia (26% of patients), mild (27%), moderate (19%) and severe (25%) hyperglycemia, while hypoglycemia (2%) was rare. Severe hyperglycemia was associated with higher blood leukocyte count (17.3 (5.8) E9/L), higher lactate level (4.4 (3.3-8.4) mmol/L) and lower arterial pH (7.23 (0.14)) compared with normoglycemia or mild to moderate hyperglycemia (p<0.001 for all). In-hospital mortality was highest among hypoglycemic (60%) and severely hyperglycemic (56%) patients, compared with 22% in normoglycemic group (p<0.01). Severe hyperglycemia was an independent predictor of in-hospital mortality (OR 3.7, 95% CI 1.19-11.7, p=0.02), when adjusted for age, gender, LVEF, lactate, and DM. CONCLUSIONS Admission blood glucose level has prognostic significance in CS. Mortality is highest among patients with severe hyperglycemia or hypoglycemia. Severe hyperglycemia is independently associated with high in-hospital mortality in CS. It is also associated with biomarkers of systemic hypoperfusion and stress response.

Predictive value for death and rehospitalization of 30-day postdischarge B-type natriuretic peptide (BNP) in elderly patients with heart failure. Sub-analysis of Italian RED Study.

Abstract Background: Our aim was to determine if, in elderly heart failure (eHF) patients, serial B-type natriuretic peptide (BNP) assessments obtained during follow-up after hospital discharge could have prognostic utility for death and rehospitalizations. In eHF patients, BNP assessment at hospital discharge has been demonstrated to have a high prognostic value; however, its predictive role for future cardiovascular events in eHF patients, when assessed in the period after discharge, both for the correct timing and cut-off levels, has not been completely elucidated. Methods: This study is a monocentric subanalysis of the Italian RED (Rapid Emergency Department) study. We studied 180 consecutive patients admitted for acute HF through serial BNP assessments: at hospital arrival; at discharge; and at 30, 90, and 180 days follow-up outpatient visit. Results: Both a BNP >400 pg/mL at 30 days after discharge and the percentage variation of BNP from discharge to 30 days (Δ%BNP), compared with a BNP at discharge >400 pg/mL, showed a higher area under the curve (AUC) and odds ratio (OR) in predicting events [AUC=0.842, p<0.0001; OR 7.9 (3.3–19.0), p<0.001 for 30 days BNP and AUC=0.851, p<0.0001; OR 9.5 (4.065–22.572), p<0.0001 for Δ%BNP compared with AUC=0.638, p<0.002; OR 2.4 (1.1–5.3), p=0.032 for BNP at discharge]. Conclusions: In patients at a high risk for future events, BNP levels assessed 30 days after hospital discharge in the absence of signs and symptoms could be predictive of subsequent hospitalization and death. These patients should be considered for closer monitoring and treatment adjustment.

B-Type Natriuretic Peptide and Non-Invasive Haemodynamics and Hydration Status Assessments in the Management of Patients with Acute Heart Failure in the Emergency Department

AbstractIntroduction: An impairment of cardiac haemodynamics and fluid retention may occur in patients with acute heart failure (AHF) because of left ventricular (LV) dysfunction due to volume and/or pressure overload. The measurement of B-type natriuretic peptide (BNP) represents the ‘gold standard’ of biomarker assessment for evaluating LV adaptations to AHF. More recently, Nexfin and bioelectric impedance vector analysis (BIVA) techniques have been proposed for non-invasively assessing haemodynamic and hydration status, respectively. These techniques are rapidly and easily executable and, most importantly, may be repeated over time. Aim: To validate the applicability of Nexfin and BIVA techniques, in association with BNP dosage, and changes of these parameters after treatment during hospitalization in patients with AHF referring to the emergency department (ED). Methods: We enrolled 44 patients (20 female, mean age 77 ± 7.7 years), referring to ED for AHF. During hospitalization (mean ± SD: 4.12 ± 1.45 days), all patients underwent BNP measurements at admission, 24 hours, 72 hours and at discharge. At the same time intervals, Nexfin and BIVA were also performed. According to international guidelines, all patients were treated with optimal pharmacological therapy, independently of other parameters examined during hospitalization. Results: Compared with baseline (747.61 ± 658.54 pg/mL), we observed a statistically significant reduction of BNP levels at 72 hours (357.64 ± 193.81 pg/mL; p < 0.05) and at discharge times (248.57 ± 194.46 pg/mL; p < 0.05). In addition, a significant reduction of hydration status, evaluated through BIVA, was observed at discharge compared with hospital admission (from 79.44 ± 6.47% to 76.35 ± 5.5%; p< 0.05). This was paralleled at Nexfin evaluation by a significant increase of cardiac index (from 2.32 ± 0.95 to 3.9 ± 1.18 L/min/m2) and clinical improvement of New York Heart Association class at discharge compared with hospital admission. Finally, we observed a statistically significant correlation between percentage variation of cardiac index and hydration status from admission to discharge (p < 0.05). Conclusions: In patients with AHF, admitted to ED, simultaneous monitoring of cardiac index and of hydration status by non-invasive methods may be useful for confirming clinical diagnosis, beyond dosages of BNP. These techniques could also be useful for intra-hospital management of AHF patients. In fact, their variations, coupled with the BNP ones, during hospitalization, may be of value in order to easily and rapidly identify clinical and haemodynamic improvements of AHF, which may be of key relevance for appropriate discharges from EDs.