Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients

Abstract

OBJECTIVESPatients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations.METHODS A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. CONCLUSION Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation

“…According to our knowledge, phenobarbital drug loss due to ECMO circuit absorption in a centrifugal pump circuit was less than predicted as only 12.5% phenobarbital serum concentrations were lower than the target range, as Vd was lower and CL was found almost similar to the reported data. 11,24 In routine clinical practice, phenobarbital dosing is commonly based on body weight. In accordance, we observed strong relationships between Vd (L) and body weight and between CL (mL/h) and body weight ( Figure 1).…”

Pharmacokinetics Alterations in Critically Ill Pediatric Patients on Extracorporeal Membrane Oxygenation: A Systematic Review

“…In addition, 17 studies (41%) did not report the type of ECMO used. 8,9,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Of those that reported the type of ECMO used, 10 studies (24%) employed both veno-venous (VV) and venousarterial (VA) ECMO, [26][27][28][29][30][31][32]32,33 10 studies (24%) used VA ECMO only, 10,[34][35][36][37][38][39][40][41][42] and the remaining 4 studies (10%) used VV ECMO only. [43][44][45][46] Only 7 studies (17%) were conducted with intra-study comparisons to non-ECMO controls.…”

“…[43][44][45][46] Only 7 studies (17%) were conducted with intra-study comparisons to non-ECMO controls. 12,18,25,28,31,39,46…”

“…Of the 23 drugs studied, V d values were reported for 16 drugs (70%), 8,11,12,17,18,20,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][38][39][40]42,43,[45][46][47][48] with the remaining 7 other drugs having only clearance values reported without V d values. 9,10,13,14,19,21,37,41,44 Relative to non-ECMO controls, significant alterations in V d were observed in pediatric patients supported on ECMO for 11 of 16 studied drugs ( increase relative to non-ECMO controls), suggesting the need for higher initial dosing.…”

“…9,10,13,14,19,21,37,41,44 Relative to non-ECMO controls, significant alterations in V d were observed in pediatric patients supported on ECMO for 11 of 16 studied drugs ( increase relative to non-ECMO controls), suggesting the need for higher initial dosing. 19,23,24,[31][32][33][34][35][36] Decreased V d was reported for 2 drugs: acyclovir and ribavirin (50 and 69%, respectively). 8,34 V d of the following drugs were not substantially altered in patients supported on ECMO relative to non-ECMO controls: vancomycin, voriconazole, fos-phentyoin, phenobarbital and bumetanide.…”