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Despite limited pharmacokinetic (PK) data, dexmedetomidine is increasingly being used off-label for sedation in infants. We aimed to characterize the developmental PK changes of dexmedetomidine during infancy. In this open-label, single-center PK study of dexmedetomidine in infants receiving dexmedetomidine per clinical care, ≤10 blood samples per infant were collected. A set of structural PK models and residual error models were explored using nonlinear mixed effects modeling in NONMEM. Covariates including postmenstrual age (PMA), serum creatinine, and recent history of cardiac surgery requiring cardiopulmonary bypass were investigated for their influence on PK parameters. Univariable generalized estimating equation models were used to evaluate the association of hypotension with dexmedetomidine concentrations. 89 PK samples were collected from 20 infants with a median PMA of 44 weeks (range, 33–61). The median maximum dexmedetomidine infusion dose during the study period was 1.8 μg/kg/hr (0.5–2.5), and 16/20 infants had a maximum dose >1 μg/kg/hr. A one-compartment model best described the data. Younger PMA was a significant predictor of lower clearance. Infants with a history of cardiac surgery had ~40% lower clearance compared to those without a history of cardiac surgery. For infants with PMA of 33–61 weeks and body weight of 2–6 kg, the estimated clearance and volume of distribution were 0.87–2.65 L/kg/h and 1.5 L/kg, respectively. No significant associations were found between dexmedetomidine concentrations and hypotension. Infants with younger PMA and recent cardiac surgery may require relatively lower doses of dexmedetomidine to achieve exposure similar to older patients and those without cardiac surgery.
; for the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee IMPORTANCE Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required. OBJECTIVE To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. DESIGN, SETTING, AND PARTICIPANTS Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population. INTERVENTIONS Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies. MAIN OUTCOMES AND MEASURES The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration. RESULTS For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL). CONCLUSIONS AND RELEVANCE This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.
Objectives This study aimed to determine whether personal protective equipment (PPE) results in deterioration in chest compression (CC) quality and greater fatigue for administering health care providers (HCPs). Methods In this multicenter study, HCPs completed 2 sessions. In session 1 (baseline), HCPs wore normal attire; in session 2, HCPs donned full PPE. During each session, they performed 5 minutes of uninterrupted CCs on a child manikin. Chest compression rate, depth, and release velocity were reported in ten 30-second epochs. Change in CC parameters and self-reported fatigue were measured between the start and 2- and 5-minute epochs. Results We enrolled 108 HCPs (prehospital and in-hospital providers). The median CC rate did not change significantly between epochs 1 and 10 during baseline sessions. Median CC depth and release velocity decreased for 5 minutes with PPE. There were no significant differences in CC parameters between baseline and PPE sessions in any provider group. Median fatigue scores during baseline sessions were 2 (at start), 4 (at 2 minutes), and 6 (at 5 minutes). There was a significantly higher median fatigue score between 0 and 5 minutes in both study sessions and in all groups. Fatigue scores were significantly higher for providers wearing PPE compared with baseline specifically among prehospital providers. Conclusions During a clinically appropriate 2-minute period, neither CC quality nor self-reported fatigue worsened to a significant degree in providers wearing PPE. Our data suggest that Pediatric Basic Life Support recommendations for CC providers to switch every 2 minutes need not be altered with PPE use.
Objective To characterize administration of sedatives, analgesics, and paralytics in a large cohort of mechanically ventilated, premature infants. Study design Retrospective cohort study including all infants <1500 g birth weight and <32 weeks gestational age mechanically ventilated at 348 Pediatrix Medical Group neonatal intensive care units (NICU) from 1997–2012. The primary outcome is the proportion of mechanically ventilated days in which infants were administered drugs of interest. Multivariable logistic regression was used to evaluate the predictors of administration of drugs of interest. Results We identified 85,911 mechanically ventilated infants. Infants received a drug of interest (opioids, benzodiazepines, other sedatives, and paralytics) on 433,587/1,305,413 (33%) of mechanically ventilated infant-days. The administration of opioids increased during the study period from 5% of infant-days in 1997 to 32% in 2012. The administration of benzodiazepines increased during the study period from 5% of infant-days in 1997 to 24% in 2012. Use of paralytics and other drugs remained ≤1% throughout the study period. Predictors of drug administration included younger gestational age, small for gestational age status, male sex, major congenital anomaly, older postnatal age at intubation, exposure to high frequency ventilation, exposure to inotropes, more recent year of discharge, and NICU site. Conclusion Administration of opioids and benzodiazepines in mechanically ventilated premature infants increased over time. Because infant characteristics were unchanged, site-specific differences in practice likely explain our observations. Increased administration over time is concerning given limited evidence of benefit and potential for harm.
Background The combination of major congenital heart disease (CHD) and prematurity is associated with poor prognosis, but previous studies have not fully characterized morbidity and mortality in this population. We conducted a retrospective cohort study of very low birth weight (VLBW) infants with major CHD to describe outcomes, including mortality, over time. Methods We included all infants <1500 g birth weight with major CHD discharged from Pediatrix Medical Group neonatal intensive care units from 1997–2012. We report incidences of major CHD in VLBW infants and compare mortality and morbidity by infant birth weight, type of major CHD, and time period. Results Of 105,539 VLBW infants, 299 (0.3%) were diagnosed with 15 different major CHDs. Coarctation of the aorta (n=67, 22%), atrioventricular septal defect (n=58, 19%), and tetralogy of Fallot (n=53, 18%) were the most common major CHDs identified. Overall mortality was 163/299 (55%). Mortality was ≥70% for 10 lesions and <30% for isolated aortic valve stenosis (6/30, 20%). Mortality in infants with major CHD did not significantly change over time: 76/133 (57%) in 1997–2005, 49/95 (52%) in 2006–2009, and 38/71 (54%) in 2010–2012 (p=0.70). The majority of infants suffered ≥1 comorbidity or died (218/299, 73%). Conclusion Major CHD is associated with high morbidity and mortality. While mortality varies by lesion, overall survival and incidence of major morbidity have not improved over time.
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