Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function.

Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer's disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.

Ketamine infusions as an adjunct for sedation in critically ill children.

OBJECTIVE: Limited reports have described ketamine's role as an adjunct sedative. The purpose was to describe ketamine's role as an adjunct to achieve goal sedation in mechanically ventilated children. DESIGN: Retrospective, descriptive study. SETTING: Thirteen-bed pediatric intensive care unit (ICU) and 12-bed pediatric cardiovascular ICU. PARTICIPANTS: Seventy-three ketamine courses were included, representing 62 mechanically ventilated children <18 years receiving ketamine for ≥12 hours. MAIN OUTCOME MEASURE(S): The primary outcome was to determine the median dose and time to achieve goal sedation (80 percent of State Behavioral Scale scores between 0 and -1) based on ketamine's place in therapy as an adjunct in the sedation regimen. Secondary outcomes included a comparison of sedative dosing pre- and post-ketamine initiation between place in therapy groups and paralyzed/nonparalyzed patients, and identification of ketamine-attributed adverse drug event (ADEs) or iatrogenic withdrawal syndrome (IWS). RESULTS: The median age was 1.0 years (interquartile range: 0.4-4.9). Ketamine was initiated as first-line (n = 7; 9.6 percent), second-line (n = 39; 53.4 percent), third-line (n = 26; 35.6 percent), or fourth-line (n = 1; 1.4 percent) sedation. The median initial and peak doses were 0.6 mg/kg/h (0.3-0.6) and 0.9 mg/kg/h (0.9-1.2), respectively. The median dose and time to achieve goal sedation was 0.8 mg/kg/h (0.6-1.1) and 2 hours (1-7), respectively. ADEs were noted during three courses (4.1 percent) and IWS after discontinuation of one course (1.4 percent). CONCLUSIONS: The majority were initiated on ketamine as a second- or third-line adjunct sedative. The median initial dose was 0.6 and dose to achieve goal sedation was 0.8 mg/kg/h. Ketamine-attributed ADEs and IWS episodes were rare.

Comparison of Amikacin Pharmacokinetics in Neonates With and Without Congenital Heart Disease.

OBJECTIVES: The primary objective was to compare the volume of distribution (Vd), clearance (CL), elimination rate (Ke), and half-life (t½) of amikacin in neonates with cyanotic defects, acyanotic defects, and controls, adjusted for gestational and postnatal age. Secondary objectives were to compare the incidence of acute kidney injury (AKI) between controls and the congenital heart disease (CHD) group and to identify potential risk factors. METHODS: This retrospective cohort study included neonates receiving amikacin from January 1, 2013 to August 31, 2016. Patients were excluded if concentrations were not appropriately obtained or if AKI or renal anomalies were identified prior to amikacin initiation. Congenital heart disease was classified as acyanotic or cyanotic. Patients with CHD were matched 1:1 with non-CHD controls according to postmenstrual age. Bivariate analyses were performed using Wilcoxon-Mann-Whitney test, Pearson χ2 tests, or Fisher exact as appropriate with a p value <0.05. Regression analyses included logistic and analysis of covariance. RESULTS: Fifty-four patients with CHD were matched with 54 controls. Median (IQR) postnatal age (days) at amikacin initiation significantly differed between CHD and controls, 3.0 (1.0-16.0) versus 1.0 (1.0-3.0), p = 0.016. After adjusting for gestational and postnatal age, there was no difference in the mean (95% CI) Vd (L/kg) and CL (L/kg/hr) between CHD and controls, 0.47 (0.44-0.50) versus 0.46 (0.43-0.49), p = 0.548 and 0.05 (0.05-0.05) versus 0.05 (0.05-0.05), p = 0.481, respectively. There was no difference in Ke or t½ between groups. There was no difference in AKI between the CHD and controls, 18.5% versus 9.3%, p = 0.16. CONCLUSIONS: Clinicians should consider using standard amikacin dosing for neonates with CHD and monitor renal function, since they may have greater AKI risk factors.

Pediatric Pharmacists' Participation in Cardiopulmonary Resuscitation Events.

The Pediatric Pharmacy Advocacy Group (PPAG) understands the dilemma and varying factors that many institutions face concerning the routine participation of pharmacists in emergency resuscitation events. Acknowledging these obstacles, the PPAG encourages all institutions to strongly consider creating, adopting, and upholding policies to address pharmacists' participation in cardiopulmonary resuscitation (CPR) as evidenced by the impact pharmacist participation has shown on the reduction of hospital medication error and mortality rates in children. The PPAG advocates that pharmacists be actively involved in the institution's CPR, medical emergency team committees, and preparation of emergency drug kits and resuscitation trays. The PPAG advocates that all institutions requiring a pharmacist's participation in CPR events consider adoption of preparatory training programs. Although the PPAG does not advocate any one specific program, consideration should be taken to ensure that pharmacists are educated on the pharmacotherapy of drugs used in the CPR process, including but not limited to basic life support, Advanced Cardiac Life Support, and Pediatric Advanced Life Support algorithms; medication preparation and administration guidelines; medication compatibility; recommended dosing for emergency medications; and familiarity with the institutional emergency cart.