Intravenous linezolid was efficient and well tolerated in critically ill premature infants. PNA was the main determinant of clearance.

Objective: To compare the safety and efficacy of phenobarbital and levetiracetam in a cohort of neonates with seizures following cardiac surgery. Methods: We performed a retrospective single-center study of consecutive neonates with electrographically confirmed seizures managed with antiseizure medication after cardiac surgery from June 15, 2012 to December 31, 2018. We compared the safety and efficacy of phenobarbital and levetiracetam as first-line therapy. Results: First-line therapy was phenobarbital in 31 neonates and levetiracetam in 22 neonates. Phenobarbital was associated with more adverse events (P = .006).Eight neonates (14%) experienced an adverse event related to phenobarbital use, including seven with hypotension and one with respiratory depression. No adverse events were reported with levetiracetam use. The cessation of electrographic seizures was similar in both groups, including 18 neonates (58%) with seizure cessation after phenobarbital and 12 neonates (55%) with seizure cessation after levetiracetam (P = 1.0). The combined cessation rates of phenobarbital and levetiracetam when used as first-or second-line therapy were 58% and 47%, respectively (P = .47). Significance: Phenobarbital was associated with more adverse events than levetiracetam, and the two drugs were equally but incompletely effective in treating electrographically confirmed seizures in neonates following cardiac surgery.Given its more acceptable safety profile and potential noninferiority, levetiracetam may be a reasonable option for first-line therapy for treatment of seizures in this population. Further prospective studies are needed to confirm these results. K E Y W O R D Scardiology, congenital, critical care, heart diseases, infant 628 | THIBAULT eT AL.

Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

Objectives: To develop a population pharmacokinetic model for IV phenobarbital in neonates following cardiac surgery and perform simulations to identify optimal dosing regimens. Design: Retrospective single-center pharmacokinetic study. Setting: Cardiac ICU at Children’s Hospital of Philadelphia. Patients: Consecutive neonates who received greater than or equal to one dose of IV phenobarbital and had greater than or equal to one phenobarbital concentration drawn per standard of care from June 15, 2012, to October 15, 2018. Interventions: None. Measurements and Main Results: A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model variables. Optimal phenobarbital loading doses were determined based on attainment of peak and maintenance concentrations between 20 and 40 mg/L. A total of 37 neonates contributed 159 pharmacokinetic samples. The median (range) weight, postmenstrual age, and postnatal age were 3.2 kg (1.3–3.8), 39 2/7 weeks (28 2/7 to 42 6/7), and 5 days (0–26 d), respectively. Twelve patients (32%) were on extracorporeal membrane oxygenation. An one-compartment model best described the data. The final population pharmacokinetic model included (1) weight and postnatal age for clearance and (2) weight, extracorporeal membrane oxygenation, and albumin for volume of distribution. In neonates not on extracorporeal membrane oxygenation, loading doses of 30 and 20 mg/kg reached goal concentration with albumin values less than or equal to 3 and 3.5 mg/dL, respectively. Loading doses of 30 mg/kg reached goal concentration on extracorporeal membrane oxygenation regardless of albumin values. Maintenance doses of 4–5 mg/kg/d reached goal concentration in all neonates. Conclusions: In neonates following cardiac surgery, phenobarbital clearance increased with postnatal age. Volume of distribution increased with extracorporeal membrane oxygenation and lower albumin values. Loading doses of 30 mg/kg on extracorporeal membrane oxygenation and 20–30 mg/kg without extracorporeal membrane oxygenation were needed to reach goal concentration based on simulations.

BACKGROUND: Atomized intranasal dexmedetomidine is an attractive option when sedation is required for pediatric patients as either premedication or the sole agent for noninvasive, nonpainful procedures. While intranasal dexmedetomidine is used frequently in this population, it is still unclear what dose and time of administration relative to the procedure will result in the optimal effect. Knowledge regarding the maximum concentration (C max ) and time to reach maximum concentration (T max ) of intranasally administered dexmedetomidine is the first step toward this. The risk of hemodynamic instability caused by increasing doses of dexmedetomidine necessitates a greater understanding of the pharmacokinetics in children. METHODS: Sixteen pediatric patients 2 to 6 years of age undergoing elective cardiac catheterization received 2 or 4 μg/kg dexmedetomidine intranasally. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry with a validated assay. Descriptive noncompartmental analysis provided estimates of peak concentrations and time to reach peak concentrations. A population pharmacokinetic model was developed using nonlinear mixedeffects modeling. Simulations were performed using the final model to assess dose concentrations with an alternative dosing regimen of 3 µg/kg. RESULTS: A median peak plasma concentration of 413 pg/mL was achieved 91 minutes after 2 μg/kg dosing, and a median peak plasma concentration of 1000 pg/mL was achieved 54 minutes after 4 μg/kg dosing. A 1-compartment pharmacokinetic model adequately described the data. Three subjects in the 4 μg/kg dosing cohort achieved a dose-limiting toxicity (DLT), defined as a plasma dexmedetomidine concentration >1000 pg/mL. None of these subjects had any significant hemodynamic consequences. Simulations showed that no subjects would experience a level >1000 pg/mL when using a dose of 3 µg/kg. CONCLUSIONS: Concentrations associated with adequate sedation can be achieved with intranasal dexmedetomidine doses of 2 to 4 µg/kg in children 2 to 6 years of age. However, 50% of our evaluable subjects in this cohort reached a plasma concentration >1000 pg/mL. Doses of 3 µg/kg may be optimal in this population, with simulated concentrations remaining below this previously established toxicity threshold. Further studies correlating concentrations with efficacy and adverse effects are needed.

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