Increased indomethacin dosing for persistent patent ductus arteriosus in preterm infants: a multicenter, randomized, controlled trial.
OBJECTIVE
We conducted a multicenter, randomized, controlled trial to determine whether higher doses of indomethacin would improve the rate of patent ductus arteriosus (PDA) closure.


METHODS
Infants (<28 weeks gestation) who received a conventional, prophylactic 3-dose course of indomethacin were eligible if they had continued evidence of persistent ductus patency on an echocardiogram obtained before the third prophylactic indomethacin dose. Infants (n = 105) were randomized to receive an extended 3-day course of either low-dose (0.1 mg/kg/d) or higher-dose (0.2 or 0.5 mg/kg/d) indomethacin. An echocardiogram was obtained 24 hours after the last dose of study drug.


RESULTS
Despite increasing serum indomethacin concentrations by 2.9-fold in the higher-dose group, we failed to detect a significant decrease in the rate of persistent PDA (low = 52%; higher = 45%, P = .50). The higher-dose group had a significantly higher occurrence of serum creatinine >2 mg/100 mL (low = 6%, higher = 19%, P < .05) and moderate/severe retinopathy of prematurity (ROP) (low = 15%, higher = 36%, P < .025). The incidence of moderate/severe ROP was directly related to the poststudy indomethacin concentrations (odds ratio = 1.75, confidence interval: 1.15-2.68, P < .01).


CONCLUSIONS
Increasing indomethacin concentrations above the levels achieved with a conventional dosing regimen had little effect on the rate of PDA closure but was associated with higher rates of moderate/severe ROP and renal compromise.
Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California 94143-0544, USA.
Priya
P
Jegatheesan
Vlad
V
Ianus
Basharat
B
Buchh
Grace
G
Yoon
Nancy
N
Chorne
Audrey
A
Ewig
Emil
E
Lin
Scott
S
Fields
Anita
A
Moon-Grady
Terri
T
Tacy
Jay
J
Milstein
Michael
M
Schreiber
James
J
Padbury
Ronald
R
Clyman
D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004374:Ductus Arteriosus, Patent / Q000175:diagnosis / Q000188:drug therapy*; D004452:Echocardiography; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage* / Q000009:adverse effects; D007231:Infant, Newborn; D007234:Infant, Premature; D019102:Infant, Very Low Birth Weight; D008297:Male; D051437:Renal Insufficiency / Q000209:etiology; D012178:Retinopathy of Prematurity / Q000209:etiology; D016896:Treatment Outcome
D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin