Population Pharmacokinetics of Phenobarbital in Neonates and Infants on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy

Thibault, Céline; Massey, Shavonne L.; Abend, Nicholas S.; Naim, Maryam Y.; Zoraian, Alexandra; Zuppa, Athena F.

doi:10.1002/jcph.1743

Cited by 10 publications

(5 citation statements)

References 45 publications

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“…Conversely, Thibault et al reported the increasing effect of ECMO therapy on phenobarbital Vd, but no effect on CL [36]. In another larger group of patients, the same research group found no effect of ECMO on Vd, but reported a 6-fold increase of phenobarbital CL in patients undergoing CVVHDF compared to the patients without CVVHDF [50]. Given the small number of patients included in these analyses, larger studies are needed to elucidate the pharmacokinetic changes induced by ECMO to recommend phenobarbital dosing in this specific clinical setting.…”

Section: Discussionmentioning

confidence: 95%

“…Urea level was not found to be a significant covariate for the phenobarbital CL. Additionally, creatinine was also not found to be a significant descriptor of the phenobarbital CL variability [33,45,50], while Moffett et al described a relationship between serum creatinine and phenobarbital CL [39]. As inflammation can influence CYP450 enzyme activity, the C-reactive protein (CRP) level was also tested as a predictor of phenobarbital CL in the critically-ill neonates undergoing ECMO (47), but no relation was found.…”

Section: Laboratory Parametersmentioning

confidence: 99%

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What Is the Best Predictor of Phenobarbital Pharmacokinetics to Use for Initial Dosing in Neonates?

2021

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Phenobarbital is a first-line treatment of various seizure types in newborns. Dosage individualization maximizing the proportion of patients with drug levels in therapeutic range or sufficient treatment response is still challenging. The aim of this review was to summarize the available evidence on phenobarbital pharmacokinetics in neonates and to identify its possible covariates suitable for individualization of initial drug dosing. Several covariates have been considered: body weight and height, body surface area, gestational and postnatal age, laboratory parameters of renal and hepatic functions, asphyxia, therapeutic hypothermia, extracorporeal membrane oxygenation (ECMO), drug interactions, and genetic polymorphisms. The most frequently studied and well-founded covariate for the estimation of phenobarbital dosing is actual body weight. Loading dose of 15–20 mg/kg followed by a maintenance dose of 3–5 mg/kg/day seems to be accurate. However, the evidence for the other covariates with respect to dosing individualization is not sufficient. Doses at the lower limit of suggested range should be preferred in patients with severe asphyxia, while the upper limit of the range should be targeted in neonates receiving ECMO support.

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Section: Discussionmentioning

confidence: 95%

Section: Laboratory Parametersmentioning

confidence: 99%

What Is the Best Predictor of Phenobarbital Pharmacokinetics to Use for Initial Dosing in Neonates?

2021

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“…Previous clinical trials comparing newborns and infants following PB administration have revealed differences in the characteristics between the two development stages [ 3 , 4 ]. For pediatric patients, specifically for newborns, infants, toddlers, and preschoolers, organ and body development can make a big difference in one year.…”

Section: Discussionmentioning

confidence: 99%

“…Phenobarbital (PB) was approved as a treatment for epileptic seizures in 1912; it remains a first-line drug for treating neonatal seizures even more than 100 years after its approval [ 1 , 2 ]. Therefore, multiple studies have investigated PB administration in pediatric patients [ 3 , 4 ]. PB exerts its effect through the enhancement of GABA-ergic inhibition and reduction of glutamatergic excitation via inhibition of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Adverse Events Following Phenobarbital Administration for Pediatric Patients Categorized by One-Year Age Increments Using the U.S. Food and Drug Administration Adverse Event Reporting System

Ogura,

Shiraishi

2024

Cureus

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Background Organ and body development greatly varies in pediatric patients from year to year. Therefore, the incidence of each adverse event following phenobarbital (PB) administration would vary with age. However, in clinical trials, increasing the sample size of pediatric patients in each age group has been challenging. Therefore, previous studies were conducted by dividing pediatric patients into three or four age groups based on the development stage. Although these results were useful in clinical settings, information on adverse events that occurred at one-year age increments in pediatric patients could further enhance treatment and care. Objectives This study investigated in one-year age increments the occurrence tendency of each adverse event following PB administration in pediatric patients. Methods This study used data obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Two inclusion criteria were set: (1) treatment with PB between January 2004 and June 2023 and (2) age 0-15 years. Using the cutoff value obtained using the Wilcoxon-Mann-Whitney test by the minimum p-value approach, this study explored changes in the occurrence tendency of each adverse event in one-year age increments. At the minimum p-value of <0.05, the age corresponding to this p-value was determined as the cutoff value. Conversely, at the minimum p-value of ≥0.05, the cutoff value was considered nonexistent. Results This study investigated all types of adverse events and explored the cutoff value for each adverse event. We identified 34, 16, 15, nine, five, five, eight, three, and eight types of adverse events for the cutoff values of ≤3/>3, ≤4/>4, ≤5/>5, ≤6/>6, ≤7/>7, ≤8/>8, ≤9/>9, ≤10/>10, and ≤11/>11 years, respectively. Conclusions This study demonstrated that adverse events requiring attention in pediatric patients varied with age. The findings help in the improvement of treatment and care in the pediatric clinical settings.

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“…This failure in response may be partially explained by the effects of ECMO on medication pharmacokinetics (31). The ECMO-related larger volume of distribution (i.e., from blood/fluid boluses circuit volume) may contribute to hemodilution and in turn to subtherapeutic antiseizure medication concentration may contribute to these issues (32, 33). Additionally, hemodynamic instability during ECMO may affect liver perfusion, thereby limiting drug metabolism (33).…”

Section: Discussionmentioning

confidence: 99%

Extracorporeal Membrane Oxygenation for Neonates With Congenital Diaphragmatic Hernia: Prevalence of Seizures and Outcomes

Danzer

Massey

Flohr

et al. 2023

Pediatric Critical Care Medicine

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OBJECTIVES:We aimed to determine the prevalence of electrographic seizures and associated odds of adverse outcomes of electrographic seizures in neonates with congenital diaphragmatic hernia (CDH) receiving extracorporeal membrane oxygenation (ECMO). DESIGN:Retrospective, descriptive case series. SETTING:Neonatal ICU (NICU) in a quaternary care institution. PATIENTS:All neonates with CDH receiving ECMO undergoing continuous electroencephalographic monitoring (CEEG) and follow-up between January 2012 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:All eligible neonates with CDH receiving ECMO underwent CEEG (n = 75). Electrographic seizures occurred in 14 of 75 (19%): they were exclusively electrographic-only in nine of 14, both electrographic-only and electroclinical in three of 14, and electroclinical only in two of 14. Two neonates developed status epilepticus. We identified an association between presence of seizures, rather than not, and longer duration of initial session of CEEG monitoring (55.7 hr [48.2-87.3 hr] vs 48.0 hr [43.0-48.3 hr]; p = 0.001). We also found an association between presence of seizures, rather than not, and greater odds of use of a second CEEG monitoring (12/14 vs 21/61; odds ratio [OR], 11.43 [95% CI,; p = 0.0026). Most neonates with seizures (10/14), experienced their onset of seizures more than 96 hours after the start of ECMO. Overall, the presence of electrographic seizures, compared with not, was associated with lower odds of survival to NICU discharge (4/14 vs 49/61; OR 0.10 [95% CI 0.03 to 0.37], p = 0.0006). Also, the presence of seizures-rather than not-was associated with greater odds of a composite of death and all abnormal outcomes on follow-up (13/14 vs 26/61; OR, 17.5; 95% CI, 2.15-142.39; p = 0.0074). CONCLUSIONS:Nearly one in five neonates with CDH receiving ECMO developed seizures during the ECMO course. Seizures were predominantly electrographic-only and when present were associated with great odds of adverse outcomes. The current study provides evidence to support standardized CEEG in this population.

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Population Pharmacokinetics of Phenobarbital in Neonates and Infants on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy

Cited by 10 publications

References 45 publications

What Is the Best Predictor of Phenobarbital Pharmacokinetics to Use for Initial Dosing in Neonates?

What Is the Best Predictor of Phenobarbital Pharmacokinetics to Use for Initial Dosing in Neonates?

Analysis of Adverse Events Following Phenobarbital Administration for Pediatric Patients Categorized by One-Year Age Increments Using the U.S. Food and Drug Administration Adverse Event Reporting System

Extracorporeal Membrane Oxygenation for Neonates With Congenital Diaphragmatic Hernia: Prevalence of Seizures and Outcomes

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