Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

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

An Update of Armamentarium for Non Invasive Cardiac Haemodynamics and Congestion Evaluation for Acute Heart Failure Patients

In the management of Acute Heart Failure(AHF) patients ,current guidelines  suggest  to make a prompt  clinical assessments that include  patient’s congestion and perfusion status evaluation, in order to  start appropriate treatments. Unfortunately ,so far, an accurate evaluation of haemodynamic and fluid status of AHF patients is only possible using invasive methods ;conseguently there is an unmeet need for noninvasive technologies to easly detect  different phenotypes of AHF subjects based on different cardiac haemodynamic profiles . Technological advances such as: Biva,Nexfin or NICas   could  allow for routine noninvasive continuous monitoring of Cardiac Hemodymanics and Fluid content in Acute Heart Failure patients. These  non invasive measurements may provide important information  for improving diagnosis, developing individualized therapeutic management plans/disposition decisions and predicting short term mortalit

Cognitive Health of Nonagenarians in Southern Italy: A Descriptive Analysis from a Cross-Sectional, Home-Based Pilot Study of Exceptional Longevity (Cilento Initiative on Aging Outcomes Or CIAO).

Background: Nonagenarians and centenarians (NCs) are an extremely fragile population, particularly in regard to their physical and cognitive function. The aim of this study was to define the neurocognitive profiles among 29 NCs and their 49 younger cohabitants aged 50-75 years from The Cilento Initiative on Aging Outcomes (CIAO) Pilot study in the South of Italy that had provided initial hypotheses regarding positive psychological traits related to exceptional longevity. Methods: During the home visits, lifestyle information with specific questionnaires, functional autonomy and the neuropsychological Mini Mental Scale Examination (MMSE), and the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) scale were obtained by qualified study personnel. The total blood oxidative capacity was also determined by testing the reactive derivative of oxygen metabolites (d-ROM) and by the Biological Antioxidant Potential (BAP). In all individuals, the APOE genotype determination was also performed. Results: All the subjects in both groups showed high adherence to the Mediterranean Diet. None of the NCs had severe cognitive impairment, and a very low incidence of dementia was found. The data obtained on the Activities ed Instrumental Activities of Daily Living (ADL-IADL) scale showed that the majority of NCs (16/29) were autonomous in daily life activities. The comparative assessment of NCs and cohabitants showed no significant differences in the laboratory assessment of oxidative stress and APOE genotype. Conclusion: In the Cilento Region of Southern Italy, NCs seemed to have good cognitive status when compared to younger cohabitants aging 50-65 years without significant differences in oxidative stress markers or APOE genotype. These results might be related to optimal adherence to the Mediterranean diet, although other lifestyle factors and positive personality traits may also contribute to their healthy aging. Further studies on a larger population should be performed to confirm the results of this pilot study

The Added Value of Bioimpedance Analysis to NT-proBNP in Predicting Short-term outcome in Acute Heart Failure Patients

Background: Acute heart failure (AHF) is a significant clinical problem, which has a high prevalence, mortality, and rehospitalization. Congestion is critical in AHF's pathogenesis, which is also a predictor of mortality and rehospitalization in patients with AHF. Aim: Knowing the effect of adding a %Total body water (TBW) test detected by Bioimpedance Analysis to NT-proBNP as a short-term clinical outside predictor of patients with acute heart failure Method: This research is an analytical observational study using prospective cohort methods. The research was conducted at Dr. Saiful Anwar Malang Hospital in January 2018-July 2019, with research subjects taken consecutively against all AHF patients hospitalized at UD dr.UD dr. Saiful Anwar Malang. The data taken in the form of NT-proBNP value during mission and %TBW before the patient leaves the hospital detected with NICaS examination, then the outside seen is mortality rate and rehospitalization due to AHF within 90 days after exiting the hospital. Results:  This study involved 65 subjects who were 61 years old and the majority male. Non-survivor patients had a higher NYHA class, NT-proBNP, and %TBW predischarge than the survivor group. Based on statistical analysis, we found that NT-proBNP is a good predictor of mortality (HI: AUC 0.74; 95%CI 0.59-0.90) and rehospitalization (HI: AUC 0.88; 95%CI 0.78-0.97). Similarly , %TBW pre-discharge shows good predictors of mortality (HI: AUC 0.72, 95%CI 0.56-0.87) and rehospitalization (HI: AUC 0.83, 95%CI 0.73-0.94). The addition of the %TBW predischarge parameter to NT-proBNP results in the best predictor numbers among the three for both mortality (HI: AUC 0.84; 95%CI 0.72-0.96) and rehospitalization (HI: AUC 0.92; 95%CI 0.85-1.00). Conclusion: The addition of predischarge %TBW examination detected by bioimpedance analysis tool against NT-proBNP increases the predicted value of short-term clinical outpatient in the form of mortality and rehospitalization of acute heart failure patients.Keywords: acute heart failure, NT-proBNP, bioimpedance analysis, total body wate

Safety analysis of sacubitril/valsartan in patients with heart failure in Vitória, Espírito Santo

Background: Sacubitril/valsartan has proven its efficacy to reduce cardiovascular mortality, all-cause mortality and sudden death in heart failure with reduced ejection fraction (HFrEF). Thus, it becomes important to evaluate the safety profile of the medication in clinical practice. Objectives: This study aimed to assess safety outcomes on the use of sacubitril/valsartan in patients with HFrEF attended in a Brazilian specialized service. Methods: Prospective observational study that included patients with HFrEF from a specialized ambulatory service, in functional class II-IV, initiated on sacubitril/valsartan as per clinical indication, with a four-month follow-up. Primary outcomes were the occurrence of symptomatic arterial hypotension, hyperkalemia and reduction of renal function. Serum potassium values, blood pressure and creatinine clearance were analyzed at inclusion and at the end of follow-up. A 5% significance level was considered for comparisons. Results: Twenty-six patients were analyzed, 57.7% male, mean age 57.8 ± 10 years, average left ventricle ejection fraction 29.9 ± 7.7%. Symptomatic hypotension occurred in 53.8%, hyperkalemia in 19.2% and reduction of renal function in 6.7%. There was significant difference from initial to final systolic (122 ± 24mmHg versus 109 ± 15mmHg; p=0.024) and diastolic (76 ± 18mmHg versus 66 ± 12mmHg; p=0.022) blood pressure, but no difference in serum potassium (4.8 ± 0.4mEq/L versus 5.0 ± 0.3mEq/L; p=0.07) and creatinine clearance (65 ± 23mL/min/1.73m² versus 66 ± 29mL/min/1.73m²; p=0.89). Conclusions: Symptomatic hypotension was the most frequent side-effect of sacubitril/valsartan. Reduction of blood pressure was observed at the end of follow-up, but no reduction of renal function or significant increase of serum potassium

Proenkephalin and the risk of new-onset heart failure:data from prevention of renal and vascular end-stage disease

BACKGROUND: Enkephalins of the opioid system exert several cardiorenal effects. Proenkephalin (PENK), a stable surrogate, is associated with heart failure (HF) development after myocardial infarction and worse cardiorenal function and prognosis in patients with HF. The association between plasma PENK concentrations and new‐onset HF in the general population remains to be established. HYPOTHESIS: We hypothesized that plasma PENK concentrations are associated with new‐onset HF in the general population. METHODS: We included 6677 participants from the prevention of renal and vascular end‐stage disease study and investigated determinants of PENK concentrations and their association with new‐onset HF (both reduced [HFrEF] and preserved ejection fraction [HFpEF]). RESULTS: Median PENK concentrations were 52.7 (45.1–61.9) pmol/L. Higher PENK concentrations were associated with poorer renal function and higher NT‐proBNP concentrations. The main determinants of higher PENK concentrations were lower estimated glomerular filtration rate (eGFR), lower urinary creatinine excretion, and lower body mass index (all p < .001). After a median 8.3 (7.8–8.8) years follow‐up, 221 participants developed HF; 127 HFrEF and 94 HFpEF. PENK concentrations were higher in subjects who developed HF compared with those who did not, 56.2 (45.2–67.6) versus 52.7 (45.1–61.6) pmol/L, respectively (p = .003). In competing‐risk analyses, higher PENK concentrations were associated with higher risk of new‐onset HF (hazard ratio [HR] = 2.09[1.47–2.97], p < .001), including both HFrEF (HR = 2.31[1.48–3.61], p < .001) and HFpEF (HR = 1.74[1.02–2.96], p = .042). These associations were, however, lost after adjustment for eGFR. CONCLUSIONS: In the general population, higher PENK concentrations were associated with lower eGFR and higher NT‐proBNP concentrations. Higher PENK concentrations were not independently associated with new‐onset HFrEF and HFpEF and mainly confounded by eGFR

Clinical value of pre‐discharge bio‐adrenomedullin as a marker of residual congestion and high risk of heart failure hospital readmission

Aims: Recently, bio‐adrenomedullin (bio‐ADM) was proposed as a congestion marker in heart failure (HF). In the present study, we aimed to study whether bio‐ADM levels at discharge from a hospital admission for worsening HF could provide additional information on (residual) congestion status, diuretic dose titration and clinical outcomes. Methods and results: Plasma bio‐ADM was measured in 1236 acute HF patients in the PROTECT trial at day 7 or discharge. Median discharge bio‐ADM was 33.7 [21.5–61.5] pg/mL. Patients with higher discharge bio‐ADM levels were hospitalised longer, had higher brain natriuretic peptide levels, and poorer diuretic response (all P &lt; 0.001). Bio‐ADM was the strongest predictor of discharge residual congestion (clinical congestion score &gt; 3) (odds ratio 4.35, 95% confidence interval 3.37–5.62; P &lt; 0.001). Oedema at discharge was one of the strongest predictors of discharge bio‐ADM (β = 0.218; P &lt; 0.001). Higher discharge loop diuretic doses were associated with a poorer diuretic response during hospitalisation (β = 0.187; P &lt; 0.001) and higher bio‐ADM levels (β = 0.084; P = 0.020). High discharge bio‐ADM levels combined with higher use of loop diuretics were independently associated with a greater risk of 60‐day HF rehospitalisation (hazard ratio 4.02, 95% confidence interval 2.23–7.26; P &lt; 0.001). Conclusion: In hospitalised HF patients, elevated pre‐discharge bio‐ADM levels were associated with higher discharge loop diuretic doses and reflected residual congestion. Patients with combined higher bio‐ADM levels and higher loop diuretic use at discharge had an increased risk of rehospitalisation. Assessment of discharge bio‐ADM levels may be a readily applicable marker to identify patients with residual congestion at higher risk of early hospital readmission

What’s Next for Acute Heart Failure Research?

Each year over one million patients with acute heart failure (AHF) present to a United States emergency department (ED). The vast majority are hospitalized for further management. The length of stay and high postdischarge event rate in this cohort have changed little over the past decade. Therapeutic trials have failed to yield substantive improvement in postdischarge outcomes; subsequently, AHF care has changed little in the past 40 years. Prior research studies have been fragmented as either “inpatient” or “ED-based.” Recognizing the challenges in identification and enrollment of ED patients with AHF, and the lack of robust evidence to guide management, an AHF clinical trials network was developed. This network has demonstrated, through organized collaboration between cardiology and emergency medicine, that many of the hurdles in AHF research can be overcome. The development of a network that supports the collaboration of acute care and HF researchers, combined with the availability of federally funded infrastructure, will facilitate more efficient conduct of both explanatory and pragmatic trials in AHF. Yet many important questions remain, and in this document our group of emergency medicine and cardiology investigators have identified four high-priority research areas

How to estimate glomerular filtration rate in sub-Saharan Africa: design and methods of the African Research into Kidney Diseases (ARK) study.

BACKGROUND: Chronic kidney disease (CKD) is a substantial cause of morbidity and mortality worldwide with disproportionate effects in sub-Saharan Africa (SSA). The optimal methods to estimate glomerular filtration rate (GFR) and therefore to determine the presence of CKD in SSA are uncertain. We plan to measure iohexol excretion to accurately determine GFR in Malawi, South Africa and Uganda. We will then assess the performance of existing equations to estimate GFR and determine whether a modified equation can better improve estimation of GFR in sub-Saharan Africa. METHODS: The African Research on Kidney Disease (ARK) study is a three-country study embedded within existing cohorts. We seek to enrol 3000 adults > 18 years based on baseline serum creatinine. Study procedures include questionnaires on socio-demographics and established risk factors for kidney disease along with anthropometry, body composition, blood pressure, blood chemistry and urine microscopy and albuminuria. We will measure GFR (mGFR) by plasma clearance of iohexol at 120, 180 and 240 min. We will compare eGFR determined by established equations with mGFR using Bland-Altman plots. We will use regression methods to estimate GFR and compare the newly derived model with existing equations. DISCUSSION: Through the ARK study, we aim to establish the optimal approach to estimate GFR in SSA. The study has the advantage of drawing participants from three countries, which will increase the applicability of the findings across the region. It is also embedded within established cohorts that have longitudinal information and serial measures that can be used to characterize kidney disease over a period of time. This will help to overcome the limitations of previous research, including small numbers, selected population sub-groups, and lack of data on proteinuria. The ARK collaboration provides an opportunity for close working partnerships across different centres, using standardized protocols and measurements, and shared bio-repositories. We plan to build on the collaboration for this study for future work on kidney disease in sub-Saharan Africa, and welcome additional partners from across the continent