Rik C. Schoemaker, I. Ruys-Dudok van Heel, M.M.J. van der Vorst, J.E. Kist-van Holthe tot Echten, J. Burggraaf & A.F. Cohen.
Pediatric Pharmacology Network, Zernikedreef 10, 2333 CL Leiden, The Netherlands.
Background Furosemide is frequently used in children to increase urinary output after cardiopulmonary bypass, but the optimal dosing strategy is unknown. In order to provide a rational choice for such a regime, data were collected on 19 pediatric patients after cardiac surgery during routine clinical care. The current strategy starts with bolus dosages of 1 or 2 mg/kg followed by a continuous infusion of 0.1 mg/kg.hr if needed. If response is insufficient, the infusion rate is increased in steps of 0.1 mg/kg.hr. Furosemide administration was recorded along with urine production and urinary excretion of creatinine and furosemide over 6 hour periods. Plasma furosemide and creatinine samples were taken every 6 hours.
Methods Furosemide clearance was assumed to be directly proportional to creatinine clearance which was described by a linear change over time. Urine production was assumed to be directly proportional to the product of predicted plasma furosemide and creatinine clearance. This time-dependent furosemide clearance was modelled using a one-compartment differential equation where plasma furosemide, creatinine clearance and urine production were estimated simultaneously, meaning one can influence the other. Parameters were estimated using NONMEM V (NONMEM Project Group, UCSF, CA, USA) with first order conditional estimation. Alternative infusion regimes were investigated that adapt according to dynamic response (simulated urine production) aiming to keep urinary output around 4 ml/kg.hr and above 2 ml/kg.hr.
Results Furosemide pharmacology dictates high furosemide plasma levels when renal function is low which may be lowered when renal function improves. The proposed regime starts with a bolus dose of 1 mg/kg and continuous infusion with a rate of 0.2 mg/kg.hr. This rate may be increased or lowered in steps of 0.1 mg/kg.hr every 12 hours if urine production is insufficient or excessive. Simulations of this regime suggest that furosemide plasma levels are below ototoxic concentrations and adequate urine production is reached faster than using the current regime.
Reference: PAGE 9 (2000) Abstr 87 [www.page-meeting.org/?abstract=87]
Poster: oral presentation