clinicaltrials.gov Identifier: NCT00921960.

This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

No abstract

AimsPrevious large-scale, retrospective studies have shown increased mortality in heart failure (HF) patients using b2-agonists (B2As). We further examined the relationship between B2A use and mortality in a well-characterized population by adjusting for natriuretic peptide levels as a measure of HF severity. Methods and resultsThis was a retrospective cohort study of patients attending an HF Disease Management Programme with mean follow-up of 2.9 + 2.4 years. Chart review confirmed B2A use, dose and duration of use, and documented pulmonary function evaluation. The primary endpoint was the effect of B2A use compared with no B2A use on mortality using unadjusted and adjusted Kaplan2Meier survival curves. Data were available for 1294 patients (age 70.6 + 11.5 years) of whom 64% were male and 22.2% were taking B2As. b2-Agonist users were older, more likely to be male, to have smoked, to have chronic obstructive pulmonary disease (COPD) and asthma, and less likely to take beta-blockers. Multivariable associates of mortality included: B-type natriuretic peptide (BNP), coronary artery disease, age, and beta-blocker use. Unadjusted mortality rates for B2A users were found to be significantly higher than non-B2A users [hazard ratio (HR) 1.304, 95% confidence interval (CI) 1.030-1.652, P ¼ 0.028]. However, when adjusted for age, sex, medication, co-morbidity, smoking, COPD, and BNP differences, overall mortality rates were similar [HR 1.043, 95% CI (0.771 -1.412), P ¼ 0.783]. ConclusionUnlike previous reports, this retrospective evaluation of B2A therapy in HF patients shows no relationship with longterm mortality when adjusted for population differences including BNP. Large, prospective studies are required to define the risk/benefit ratio of B2As in patients with heart failure.--

AimsWe evaluated the extent to which left ventricular diastolic dysfunction (LVDD) contributes to the high false-positive rates observed when natriuretic peptides (NPs) are used to screen for left ventricular systolic dysfunction (LVSD), and the use of NPs in combination with electrocardiogram (ECG) to screen for pre-clinical ventricular dysfunction (PCVD). Methods and resultsEight hundred and fourteen patients over 40 years of age and with at least one cardiovascular risk factor were recruited. Screening strategies for LVSD included brain natriuretic peptide (BNP) alone at cut-offs of 20, 50, and 100 pg/mL, and BNP and abnormal ECG combined. Systolic and diastolic function was assessed by Doppler echocardiography. A left ventricular ejection fraction (LVEF) of ,50% was present in 33 (4.1%) of subjects, while 11 (1.4%) had LVEF ,40%. At a cut-off of 20, 50, and 100 pg/mL, sensitivity for BNP alone when screening for LVSD was 88, 70, and 45%, and specificity 46, 77, and 90%, respectively. Of those labelled 'false positive' in the 20, 50, and 100 pg/mL cut-off groups, 26, 46, and 65%, respectively, were found to have significant LVDD (left atrial volume index .34 mL/m 2 ). Optimal sensitivity (80%) and specificity (72%) for PCVD was obtained when BNP at a cut-off of 50 pg/mL or an abnormal ECG were defined as a positive screen so that only this group would be sent for Doppler echocardiography. ConclusionsA significant number of patients at risk for LVSD and labelled false positive with screening were found to have LVDD. Identifying this at-risk cohort may improve outcomes, but the clinical and economic benefit of this screening strategy requires formal assessment.--

Summary Introduction The safety of cuffed endotracheal tubes in the neonatal and critically ill pediatric population continues to be questioned due to the theoretical risk of acquired subglottic stenosis. The incidence of acquired subglottic stenosis in the high‐risk mixed surgical and medical critically ill pediatric cohort using high‐volume, low‐pressure cuffed endotracheal tube policy has not yet been described. The aim of our study was to describe and evaluate the use and complication rate of cuffed ETT's in our unit over a 5‐year period. Methods We defined clinically significant subglottic stenosis as a positive stenotic finding of endotracheal tube‐related pathology on a microlaryngoscopy within 6 months of invasive ventilation. All patients admitted through our pediatric critical care unit from January 10, 2012 to January 25, 2017 were matched against our theater management system database for the same period. We reviewed all matching patients’ baseline demographics, comorbidities, intubation/endotracheal tube history, and subsequent surgical management. Results Of 5309 pediatric critical care unit admissions (61% ventilated) and 1251 microlaryngoscopies, 23 children had endoscopic findings of clinically significant endotracheal tube‐related pathology, reflecting 0.68% of all intubated patients. Eight patients developed acquired subglottic stenosis. All those requiring major surgical correction were ex‐premature neonates initially intubated with uncuffed tubes in an external neonatal intensive care. No patient initially intubated with a cuffed endotracheal tube developed subglottic stenosis requiring surgical correction. Conclusion We report no single case of acquired subglottic stenosis in our cohort that required major surgical correction from a cuffed endotracheal tube during a 5‐year period. The introduction of a policy of appropriate placement and maintenance of low‐pressure, high‐volume cuffed endotracheal tubes in the pediatric critical care unit was not associated with an increased rate of endotracheal tube‐related subglottic trauma.

Background Clonidine is in widespread off‐label use as a sedative in mechanically ventilated children, despite limited evidence of efficacy. A variety of dosage regimens have been utilized in clinical practice and in research studies. Within these studies, clonidine has inconsistently shown useful sedation properties. One of the reasons attributed to the inconsistent signs of efficacy is suboptimal clonidine dosing. Aims This study aims to propose a target plasma concentration and simulate clonidine pharmacokinetics (PK) in a cohort of mechanically ventilated children to evaluate the adequacy of clonidine dosage regimens used in clinical practice and research studies. Methods A literature search was undertaken to identify a clonidine pharmaockinetic‐pharmacodynamics (PKPD) model, from which a target concentration for sedation was defined. Using a previously published PK model, the projected plasma concentrations of 692 mechanically ventilated children (demographics taken from a recent study) were generated. Doses from recently published clinical studies were investigated. Adequacy of each regimen to attain therapeutic clonidine plasma concentrations was assessed. Results A target plasma concentration of above 2 µg/L was proposed. Nine dosage regimens (four intravenous boluses, four intravenous infusions, and one nasogastric route boluses) were evaluated ranging from 1 µg/kg eight hourly intravenous boluses to a regimen up to 3 µg/kg/hr continuous intravenous infusion. Regimens with a loading dose of 2 µg/kg followed by variable continuous infusion of up to 2 µg/kg/hr titrated according to sedation score appear most suitable. Doses should be halved in neonates. Conclusion The variety of dosage regimens in the previous studies of clonidine along with difficulties in the conduct of interventional studies may have contributed to the lack of efficacy data to support its use. Simulations of clonidine plasma concentrations based on known population pharmacokinetic parameters suggest a loading dose followed by higher than current practice maintenance dose infusion is required to achieve adequate steady‐state concentrations early in treatment. Further PKPD studies will aid in the determination of the optimal clonidine dosage regimen.

Aims Limited data are available concerning the evolution of the left atrial volume index (LAVI) in pre‐heart failure (HF) patients. The aim of this study was to investigate clinical characteristics and serological biomarkers in a cohort with risk factors for HF and evidence of serial atrial dilatation. Methods and results This was a prospective substudy within the framework of the STOP‐HF cohort (NCT00921960) involving 518 patients with risk factors for HF electively undergoing serial clinical, echocardiographic, and natriuretic peptide assessment. Mean follow‐up time between assessments was 15 ± 6 months. ‘Progressors’ (n = 39) were defined as those with serial LAVI change ≥3.5 mL/m2 (and baseline LAVI between 20 and 34 mL/m2). This cut‐off was derived from a calculated reference change value above the biological, analytical, and observer variability of serial LAVI measurement. Multivariate analysis identified significant baseline clinical associates of LAVI progression as increased age, beta‐blocker usage, and left ventricular mass index (all P < 0.05). Serological biomarkers were measured in a randomly selected subcohort of 30 ‘Progressors’ matched to 30 ‘Non‐progressors’. For ‘Progressors’, relative changes in matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1 (TIMP1), and the TIMP1/MMP9 ratio, markers of interstitial remodelling, tracked with changes in LAVI over time (all P < 0.05). Conclusion Accelerated LAVI increase was found to occur in up to 14% of all pre‐HF patients undergoing serial echocardiograms over a relatively short follow‐up period. In a randomly selected subcohort of ‘Progressors’, changes in LAVI were closely linked with alterations in MMP9, TIMP1, and the ratio of these enzymes, a potential aid in highlighting this at‐risk group.