Pharmacokinetics of Commonly Used Antimicrobials in Critically Ill Pediatric Patients During Extracorporeal Membrane Oxygenation: A Systematic Review.

PURPOSE: Adequate dosing of antimicrobials is critical to properly treat infections and limit development of resistance and adverse effects. Limited guidance exist for antimicrobial dosing adjustments in patients requiring extracorporeal membrane oxygenation (ECMO) therapy, particularly in the pediatric population. A systematic review was conducted to delineate the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in critically ill neonates and children requiring ECMO therapy. METHODS: Medline, EMBASE, Global Health and All EBM Reviews databases were queried. Grey literature was examined. All clinical studies reporting PK/PD parameters of antimicrobials in critically ill pediatric patients treated with ECMO were included, except for case reports and congress abstracts. Two independent reviewers applied the inclusion and exclusion criteria. Reviewers were then paired to independently extract data and evaluate the methodological quality of studies using the ROBINS-I tool and the compliance with ClinPK reporting guidelines. Patient and study characteristics, key PK/PD findings, details of ECMO circuits and co-treatments were summarized qualitatively. Broad dosing recommendations were formulated based on the available data for specific antimicrobials. RESULTS: Twenty-nine clinical studies were included; most were observational and uncontrolled. Patient characteristics and co-treatments were often missing. The effect of ECMO on PK/PD parameters of antimicrobials varied depending on the drugs and population studied. It was only possible to formulate dosing recommendations for a few antimicrobials given the paucity of data, its overall low quality and heterogeneity in reporting. CONCLUSION: Limited data exists on the PK/PD of antimicrobials during ECMO therapy in the pediatric population. Rigorously designed population PK studies are required to establish empiric dosing guidelines for antimicrobials in patients requiring this therapeutic modality. The use of therapeutic drug monitoring for antimicrobials in pediatric patients on ECMO should be encouraged to optimize dosing. TRIAL REGISTRY: PROSPERO registration number: CRD42018099992 (Registered: July 24th 2018).

Left ventricular ejection fraction using a simplified wall motion score based on mid-parasternal short axis and apical four-chamber views for non-cardiologists.

BACKGROUND: There is a need for a convenient, yet reliable method to assess left ventricular ejection fraction (LVEF) with point-of-care ultrasound study (POCUS). We aim to validate a novel and simplified wall motion score LVEF based on the analysis of a simplified combination of echocardiographic views. METHODS: In this retrospective study, transthoracic echocardiograms of randomly selected patients were analysed by the standard 16-segments wall motion score index (WMSI) to derive the reference semi-quantitative LVEF. To develop our semi-quantitative simplified-views method, a limited combination of imaging views and only 4 segments per view were tested: (1) A combination of the three parasternal short-axis views (PSAX BASE, MID-, APEX); (2) A combination of the three apical views (apical 2-chamber, 3-chamber and 4-chamber) and (3) A more limited combination of PSAX-MID and apical 4-chamber is called the MID-4CH. Global LVEF is obtained by averaging segmental EF based on contractility (normal = 60%, hypokinesia = 40%, and akinesia = 10%). Accuracy of the novel semi-quantitative simplified-views WMS method compared to the reference WMSI was evaluated using Bland-Altman analysis and correlation was assessed in both emergency physicians and cardiologists. RESULTS: In the 46 patients using the 16 segments WMSI method, the mean LVEF was 34 ± 10%. Among the three combinations of the two or three imaging views analysed, the MID-4CH had the best correlation with the reference method (r2 = 0.90) with very good agreement (mean LVEF bias = - 0.2%) and precision (± 3.3%). CONCLUSIONS: Cardiac POCUS by emergency physicians and other non-cardiologists is a decisive therapeutic and prognostic tool. A simplified semi-quantitative WMS method to assess LVEF using the easiest technically achievable combination of mid-parasternal and apical four-chamber views provides a good approximative estimate for both non-cardiologist emergency physicians and cardiologists.

Transcatheter occlusion of a left ventricular outflow tract pseudoaneurysm using a "plug and coil" strategy.

Left ventricular outflow tract pseudoaneurysm is a rare and potentially fatal complication of aortic valve replacement. Surgical repair is the most common treatment and is particularly suitable for large pseudoaneurysms. Recently, there has been significant breakthroughs in the management of postoperative pseudoaneurysms via endovascular techniques. We report a case of a large postoperative pseudoaneurysm of the left ventricular outflow tract that occurred 1 year following a redo mechanical aortic valve replacement in a patient with previous valve sparing procedure performed 5 years earlier. The pseudoaneurysm was anatomically located antero-laterally between the right atrium and the ascending aorta. Successful occlusion was achieved with an Amplatzer Vascular Plug 2 (Abbott) and several coils (Terumo) via a transapical approach.

The Evolution of Antiplatelet Therapy After Percutaneous Coronary Interventions: A 40-Year Journey.

Antiplatelet therapy has a critical role to play in the successful management of patients undergoing percutaneous coronary intervention (PCI). Over the past 40 years, a multitude of participants worldwide have been enrolled in trials evaluating the impact of antiplatelet agents on clinical outcomes. The use of aspirin in unstable angina in the Canadian Aspirin trial was key to establishing the benefit of aspirin in acute coronary syndrome. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial demonstrated that the P2Y12 inhibitor clopidogrel, when added to aspirin, reduced major cardiovascular events. While the use of antiplatelet agents in coronary artery disease antedates the introduction of PCI and remains the cornerstone of secondary prevention of atherosclerotic cardiovascular disease, strategies aiming to optimise their best use are still constantly evolving. In this review, the major randomised trials shaping current clinical practice for the use of aspirin and P2Y12 inhibitors in patients undergoing PCI are summarised, with a focus on aspirin-free strategies and on the role of P2Y12 inhibitor treatment before PCI, two major topics of ongoing investigation that are critical to patient care but that are not addressed in current practice guidelines. Multiple questions remain regarding the use of antiplatelet agents after PCI, including the personalisation of dosing, intensity, pharmacologic formulation, and duration of antiplatelet therapy based on individual patient characteristics and the optimal treatment of patients at high bleeding risk.

Aspirin for Primary Cardiovascular Prevention in Patients with Diabetes: Uncertainties and Opportunities.

The use of the antiplatelet agent aspirin (acetylsalicylic acid) was previously routinely recommended for the primary prevention of cardiovascular (CV) events in patients with diabetes, but recent large-scale randomized trials have failed to demonstrate a sizeable net clinical benefit with a once-daily, low-dose (81-100 mg) regimen in this population. Previous pharmacokinetic and pharmacodynamic studies have suggested that the aspirin formulation (enteric-coated) and dosing schedule (once daily) studied in randomized trials for primary prevention of CV events defining contemporary clinical practice may not leverage the full potential of the drug, particularly in patients with diabetes. Indeed, the diabetic platelets bear characteristics that increase their thrombotic potential and alter their pharmacologic response to the drug. Consequently, the appropriateness of studying a uniform aspirin regimen in landmark primary prevention trials needs to be revisited. In this review, we present the evidence showing that diabetes not only increases baseline platelet reactivity, but also alters platelet response to aspirin through different mechanisms including a faster platelet turnover rate. Obesity, which is frequently associated with diabetes, also impacts its pharmacokinetics via an increase in distribution volume. Small-scale pharmacokinetic and pharmacodynamic studies have suggested that the relative aspirin resistance phenotype observed in patients with diabetes may be reversed with a twice-daily dosing schedule, and with nonenteric-coated aspirin formulations. Properly powered randomized controlled trials investigating the efficacy and safety of aspirin dosing schedules and formulations tailored to the population of patients with diabetes are urgently required to optimize patient care.

Pharmacokinetics of Commonly Used Antimicrobials in Critically Ill Adults During Extracorporeal Membrane Oxygenation: A Systematic Review.

PURPOSE: Adequate dosing of antimicrobials is critical to properly treat infections and limit development of resistance and adverse effects. Limited guidance exists for antimicrobial dosing adjustments in patients requiring extracorporporeal membrane oxygenation (ECMO) therapy. A systematic review was conducted to delineate the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in critically ill adult patients requiring ECMO. METHODS: Medline, EMBASE, Global Health, and All EBM Reviews databases were searched. Grey literature was examined. All studies reporting PK/PD parameters of antimicrobials in critically ill adults treated with ECMO were included, except for case reports and congress abstracts. Ex vivo studies were included. Two independent reviewers applied the inclusion and exclusion criteria. Reviewers were then paired to independently abstract data and evaluate methodological quality of studies using the ROBINS-I tool and the compliance with ClinPK guidelines. Patients' and studies' characteristics, key PK/PD findings, details of ECMO circuits and co-treatments were summarized qualitatively. Dosing recommendations were formulated based on data from controlled studies. RESULTS: Thirty-two clinical studies were included; most were observational and uncontrolled. Fourteen ex vivo studies were analysed. Information on patient characteristics and co-treatments was often missing. The effect of ECMO on PK/PD parameters of antimicrobials varied depending on the studied drugs. Few dosing recommendations could be formulated given the lack of good quality data. CONCLUSION: Limited data exist on the PK/PD of antimicrobials during ECMO therapy. Rigorously designed and well powered populational PK studies are required to establish empiric dosing guidelines for antimicrobials in patients requiring ECMO support. PROSPERO REGISTRATION NUMBER: CRD42018099992 (Registered: July 24th 2018).