Clinical pharmacology of the loop diuretics furosemide and bumetanide in neonates and infants.

The loop diuretics furosemide and bumetanide are used widely for the management of fluid overload in both acute and chronic disease states. To date, most pharmacokinetic studies in neonates have been conducted with furosemide and little is known about bumetanide. The aim of this article was to review the published data on the pharmacology of furosemide and bumetanide in neonates and infants in order to provide a critical analysis of the literature, and a useful tool for physicians. The bibliographic search was performed electronically using PubMed and EMBASE databases as search engines and March 2011 was the cutoff point. The half-life (t(½)) of both furosemide and bumetanide is considerably longer in neonates than in adults and consequently the clearance (CL) of these drugs is reduced at birth. In healthy volunteers, plasma t(½) of furosemide ranges from 33 to 100 minutes, whereas in neonates it ranges from 8 to 27 hours. The volume of distribution (V(d)) of furosemide undergoes little variation during neonate maturation. The dose of furosemide, administered by intermittent intravenous infusion, is 1 mg/kg and may increase to a maximum of 2 mg/kg every 24 hours in premature infants and every 12 hours in full-term infants. Comparison of continuous infusion versus intermittent infusion of furosemide showed that the diuresis is more controlled with fewer hemodynamic and electrolytic variations during continuous infusion. The appropriate infusion rate of furosemide ranges from 0.1 to 0.2 mg/kg/h and when the diuresis is <1 mL/kg/h the infusion rate may be increased to 0.4 mg/kg/h. Treatment with theophylline before administration of furosemide results in a significant increase of urine flow rate. Bumetanide is more potent than furosemide and its dose after intermittent intravenous infusion ranges from 0.005 to 0.1 mg/kg every 24 hours. The t(½) of bumetanide in neonates ranges from 1.74 to 7.0 hours. Up to now, no data are available on the continuous infusion of bumetanide. Extracorporeal membrane oxygenation (ECMO) is used for a variety of indications including sepsis, persistent pulmonary hypertension, meconium aspiration syndrome, cardiac defects and congenital diaphragmatic hernia. There are two studies of furosemide in neonates undergoing ECMO and only one on the pharmacokinetics of bumetanide under ECMO. When ECMO was conducted for 72 hours, the total amount of furosemide administered was 7.0 mg/kg, and the urine production in the 3 days of treatment was about 6 mL/kg/h, which is the target value. The t(½) of bumetanide in neonates during ECMO was extremely variable. CL, t(½), and V(d) were 0.63 mL/min/kg, 13.2 hours, and 0.45 L/kg, respectively. Furosemide may be administered by inhalation and inhibits the bronco-constrictive effect of exercise, cold air ventilation and antigen challenge. However, inhaled furosemide is not active in infants with viral bronchiolitis and its effect on broncho-pulmonary dysplasia is still uncertain. Furosemide does not significantly increase the risk of failure of patent ductus arteriosus closure when indomethacin or ibuprofen have been co-administered. Infants with low birth weight treated long-term with furosemide are at risk for the development of intra-renal calcification. Furosemide therapy above 10 mg/kg bodyweight cumulative dose had a 48-fold increased risk of nephrocalcinosis. The use of furosemide in combination with indomethacin increased the incidence of acute renal failure. The maturation of the kidney governs the pharmacokinetics of furosemide and bumetanide in the infant. CL and t(½) are influenced by development, and this must be taken into consideration when planning a dosage regimen with these drugs.