High-Dose Ibuprofen for Patent Ductus Arteriosus in Extremely Preterm Infants: A Randomized Controlled Study

Abstract

Our aim was to assess the hypothesis that a high-dose regimen of ibuprofen is more effective than the standard-dose regimen in closing patent ductus arteriosus (PDA) without increasing adverse effects. Infants of gestational age <29 weeks, with respiratory distress syndrome (RDS) and echocardiographic evidence of significant PDA at 12-24 h of life, were randomized to receive a standard (10-5-5 mg/kg/day) or high-dose (20-10-10 mg/kg/day) course of ibuprofen. We studied 70 infants, 35 of whom received the standard dose of ibuprofen and the other 35 the high dose. Of the infants treated with the standard-dose regimen, 37% had persistent PDA as compared with 14% of those treated with the high-dose regimen (P = 0.03). No differences in the occurrence of adverse effects were observed between the two groups. The high-dose ibuprofen regimen is more effective than the standard-dose regimen in closing PDA in preterm infants <29 weeks of gestation without increasing the adverse effect rate.

Continuous Infusion of Ibuprofen for Treatment of Patent Ductus Arteriosus in Very Low Birth Weight Infants

“…We found a significantly better PDA responsiveness to continuous infusion after a second course (efficacy of boluses vs. continuous infusion: 64.3 vs. 83.6%; p = 0.020), possibly thanks to a more constant dose being maintained, instead of the peaks and troughs obtained using boluses. This could be demonstrated by pharmacokinetic and plasma level studies, though interindividual variability is known to be high and there is no clear link between plasma levels and PDA responsiveness to pharmacological treatment [5,10,11]. As a matter of fact, the effective plasma IBU concentrations needed to close the ductus are not known.…”

“…Double doses can be used in the first 12-24 h (20/10/10 mg/kg), or the interval between administrations can be reduced (12-18 h), in order to improve PDA closure rates, but this may affect toxicity (especially renal side effects). Dani et al [11] recently demonstrated that early administration (within the first 12-24 h of life) of double doses of IBU was more effective than the standard regimen in closing HsPDA (86 vs. 63% of PDA closures), but marked interindividual variations in the drug's pharmacokinetics and pharmacodynamics [9,21] make these higher doses potentially harmful in more immature infants. The trial was underpowered for detecting differences in toxicity between standard and high doses, so further evidence is needed before it can become standard practice.…”

“…Efforts to optimize IBU regimens have recently focused on anticipating PDA treatment (in the first 24 h of life) and/or increasing the dosage to reduce the cases of refractory PDA and the need for surgical ligation [9,10,11]. …”

“…The reported closure rate using IBU is between 57 and 89% and is inversely related to gestational age [8]. Increased and earlier doses of IBU have recently been recommended in an effort to improve its efficacy [9,10,11], but the tolerability and safety of these regimens need to be assessed in larger populations. Also, the oral route has been tested, but the results need to be confirmed in larger trials, especially in extremely low birth weight infants [12].…”

Persistent ductus arteriosus and in-hospital morbidities in newborns of very low birth weight

“…La indometacina y el ibuprofeno reducen la vasodilatación por inhibición de la ciclooxigena y la peroxidasa; la eficacia disminuye postnatalmente por un cambio en el sistema de regulación de los vasodilatadores. Aunque la indometacina y el ibuprofeno han demostrado ser eficaces en el cierre del conducto, los efectos a largo plazo del DAP sobre la enfermedad pulmonar crónica, enterocolitis necrotizante o la supervivencia siguen (9)(10)(11) siendo temas de estudio . Más recientemente se han estudiado los efectos del paracetamol (acetaminofeno) (12,13) y el ibuprofeno oral como opciones de tratamiento .…”