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).

Effect of metal ions on Alzheimer's disease.

Alzheimer's disease (AD) is a degenerative disease of the nervous system. The typical pathological changes of AD are Aß deposition, neurofibrillary tangles, neuron loss, and chronic inflammation. The balance of metal ions is essential for numerous physiological functions, especially in the central nervous system. More studies showed that metal ions participate in the development of AD. However, the involvement of metal ions in AD is controversial. Thus, we reviewed articles about the relationship between metal ions and AD and discussed some contradictory reports in order to better understand the role of metal ions in AD.

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).

Assessment of Surgical Antibiotic Prophylaxis Compliance in Pediatrics: A Pre-post Quasi-experimental Study.

OBJECTIVE: Data from rigorous evaluations of the impact of interventions on improving surgical antibiotic prophylaxis (SAP) compliance in pediatrics are lacking. Our objective was to assess the impact of a multifaceted intervention on improving pediatric SAP compliance in a hospital without an ongoing antimicrobial stewardship program. STUDY DESIGN: A multidisciplinary team at the Montreal Children's Hospital performed a series of interventions designed to improve pediatric SAP compliance in June 2015. A retrospective, quasi-experimental study was performed to assess SAP compliance before and following the interventions. Our study included patients under 18 years old undergoing surgery between April and September in 2013 (preintervention) and in 2016 (postintervention). A 10-week washout period was included to rigorously assess the persistence of compliance without ongoing interventions. SAP, when indicated, was qualified as noncompliant, partially compliant (adequate agent and timing) or totally compliant (adequate agent, dose, timing, readministration, duration). RESULTS: A total of 982 surgical cases requiring SAP were included in our primary analysis. The composite partial and total compliance increased from 51.4% to 55.8% [adjusted odds ratio 1.3; 95% confidence interval: 1.0-1.8; P = 0.06]. Although improvements in correct dose and readministration were significant, there was no significant improvement in correct timing, agent selection or duration. CONCLUSION: Our study demonstrated that overall SAP compliance did not significantly improve following a washout period, illustrating the importance of ongoing surveillance and feedback from an antimicrobial stewardship program. Our strict approach in evaluating the timing criterion may also explain the lack of a significant impact on SAP compliance.

Enantioseparation of flurbiprofen enantiomers using chiral ionic liquids by liquid-liquid extraction.

Flurbiprofen is a kind of nonsteroidal anti-inflammatory drug, which has been widely used in clinic for treatment of rheumatoid arthritis and osteoarthritis. It has been reported that S-flurbiprofen shows good performance on clinic anti-inflammatory treatment, while R-enantiomer almost has no pharmacological activities. It has important practical values to obtain optically pure S-flurbiprofen. In this work, chiral ionic liquids, which have good structural designability and chiral recognize ability, were selected as the extraction selector by the assistance of quantum chemistry calculations. The distribution behaviors of flurbiprofen enantiomers were investigated in the extraction system, which was composed of organic solvent and aqueous phase containing chiral ionic liquid. The results show that maximum enantioselectivity up to 1.20 was attained at pH 2.0, 25°C using 1,2-dichloroethane as organic solvent, 1-butyl-3-methylimidazole L-tryptophan ([Bmim][L-trp]) as chiral selector. The racemic flurbiprofen initial concentration was 0.2 mmol L-1 , and [Bmim][L-trp] concentration was 0.02 mol L-1 . Furthermore, the recycle of chiral ionic liquids has been achieved by reverse extraction process of the aqueous phase with chiral selector, which is significant for industrial application of chiral ionic liquids and scale-up of the extraction process.

The impact of a quality improvement project to standardize pain, agitation, and withdrawal assessments on the use of morphine and midazolam in the Pediatric Intensive Care Unit.

BACKGROUND: This study aims to assess the impact of a quality improvement initiative to increase assessments of pain, agitation, and iatrogenic withdrawal syndrome, on the use of sedative and analgesic medication in a pediatric intensive care unit. METHODS: This is a retrospective pre and post, observational, quality improvement study conducted in an 18-bed medical-surgical-cardiac, tertiary intensive care unit. We included patients consecutively admitted from October 1 to March 31 (pre-period 2015-2016, post-period 2016-2017) who were mechanically ventilated beyond 48 hours. A multidisciplinary team, including a family advisor, implemented the following interventions using rapid "Plan-Do-Study-Act cycles:" (a) standardized pain and sedation assessments, (b) standardized sedation goal setting, and (c) non-pharmacological strategies to manage pain and agitation. We did not implement any specific sedation protocol. We used audit and feedback to reinforce change. RESULTS: The post-intervention phase started once sedation scores were documented q12h for >60% of patients. The groups (n = 45 per group) were similar regarding demographics, severity of illness, and mechanical ventilation duration, but different in length of intensive care stay. The cumulative dose of midazolam equivalent was significantly lower in the post-intervention period (3.71 vs 2.65 mg/kg/mechanical ventilation day, P = 0.009, 95% CI: -1.12 (-1.89, -0.31)). Morphine equivalent usage went from 3.51 to 2.57 mg/kg/mechanical ventilation day (P = 0.066, 95% CI: -0.67 [-1.44, 0.05]). There were no significant pre-post-differences in the use of other sedative agents, rates of iatrogenic withdrawal syndrome or severe pain, nor medication cost. CONCLUSION: Implementation of a multifaceted QI project was successful at increasing standardized assessments of pain and agitation, and was associated with a significant reduction in midazolam use. We also observed a decrease in morphine use without increasing rates of severe pain. Incidence of iatrogenic withdrawal syndrome and cost were unchanged.

Impact of Azithromycin on Pregnancy Prolongation in Women at Risk of Preterm Labor: A Time-to-Event Analysis.

BACKGROUND: Since 2006, the empiric use of azithromycin in women at risk of premature birth has become prevalent in our institution without any evidence of its efficacy. Although antibiotics can prolong pregnancy in preterm prolonged rupture of membranes, no published data are available for women with intact membranes. OBJECTIVES: To describe the purpose of adding azithromycin to the usual treatments (cerclage, tocolysis, rest, etc.) to prolong pregnancy in women with intact membranes who are at risk of or already in preterm labour. METHODS: A retrospective observational cohort study was done at a Mother-Child University Hospital Centre. Patients admitted to obstetric ward who received azithromycin between January 1st, 2006 and August 1st, 2010 were included. A total of 127 exposed women were matched to 127 controls through medical records and pharmacy software. A time-to-event analysis was done to compare gestational age at the time of the recorded composite event (delivery, or rupture of membranes, or second intervention to prolong pregnancy). To compare proportions of composite event at different time points, χ2 tests were used. RESULTS: Patients who received azithromycin had a more severe condition at presentation. Once adjusted for confounding factors, prolongation of pregnancy (HR =1.049; CI 95%: 0.774-1.421 [p=0.758]) and gestational age at the event (HR=1.200; CI 95%: 0.894-1.609 [p=0.225]) did not differ between the groups. The proportions of women with an event ≥7 days post-diagnosis or ≥37 gestational weeks were similar. CONCLUSIONS: Azithromycin was added to medical therapy in a more at-risk population and no clear benefit was measured.