NEW YORK (Reuters Health) – In a controlled study, clinicians didn’t see any benefit to treating patent ductus arteriosus (PDA) early (as soon as mild PDA symptoms appear) compared with delaying treatment until the onset of clear hemodynamic signs.

Based on their findings, coupled with the fact that a high number of PDAs will close spontaneously, they say “delaying therapy until a hemodynamically significant PDA is present could prevent unnecessary and potentially toxic intervention for PDA in critically ill premature infants.”

Dr. Ilene R. Sosenko and colleagues from the University of Miami Miller School of Medicine in Florida reported their study online January 30 in The Journal of Pediatrics.

In an email to Reuters Health, Dr. Sosenko said: “This is a single center study with relatively small numbers. Nonetheless, it suggests that an infant with a PDA without hemodynamically significant symptoms might not need immediate treatment and could be observed for spontaneous PDA closure or for deterioration which might then require therapy.”

“It seems to matter when a PDA is closed only if it is producing significant hemodynamic symptoms that are compromising the infant, even to the extent of threatening his/her life,” she said.

“If an infant has a PDA that is producing minimal symptoms (in situations such as in an infant on low ventilator settings or not on the ventilator, able to maintain blood pressure and urine output and feed successfully), there seems to be no rush to close that PDA and that it can be closely observed,” Dr. Sosenko added.

In their article, the study team notes that the current clinical approach to a PDA in the preterm infant is “varied and controversial,” due to a lack of definitive evidence-based data. It remains unclear as to what represents the optimal time to treat a PDA in relation to immediate clinical consequences and long-term outcomes, particularly bronchopulmonary dysplasia (BPD).

To investigate, Dr. Sosenko and colleagues studied 105 babies with gestational ages 23 to 32 weeks and birth weights 500 to 1250 grams who had echocardiography for subtle PDA symptoms, such as metabolic acidosis, systolic murmur, bounding pulses/hyperactive precordium.

The infants were randomly assigned in a double-blind fashion to early treatment (blinded ibuprofen;n=54) or to expectant management (blinded placebo;n=51). If the PDA became hemodynamically significant as evidenced by either pulmonary hemorrhage, hypotension, or respiratory decline, infants received open label ibuprofen. None of the infants had a hemodynamically significant PDA at baseline.

Infants in the early treatment group received ibuprofen at a median age of 3 days and those in the expectant management group in whom hemodynamically significant symptoms developed (n=10, 20%) received ibuprofen at a median of 11 days.

Contrary to their hypothesis, there was no benefit to early treatment over delayed treatment in terms of respiratory outcomes or other complications of prematurity.

Specifically, they failed to detect any significant between-group differences in the primary outcome (i.e., days on oxygen during the first 28 days), death, oxygen at 36 weeks, death or oxygen at 36 weeks, intestinal perforation, surgical necrotizing enterocolitis, grades III and IV intracranial hemorrhage, periventricular leukomalacia, sepsis or retinopathy of prematurity.

These findings, they conclude, suggest that infants with mild signs of PDA “do not benefit from early treatment compared with delayed treatment.”

The brand of ibuprofen used in the study, NeoProfen from Ovation (now Lundbeck) Pharmaceuticals, was recalled by the manufacturer and no longer available after two-thirds planned enrollment. This led the researchers to terminate the study early.

Despite early termination, the study had a high number of enrolled infants, relative to prior studies, which is a strength, the investigators say. The study design also allowed the team to assess the rate of spontaneous PDA closure, which was high (49%) in this very low birth weight population of infants.

Early termination was a major weakness; the choice of ibuprofen over indomethacin might also be considered a weakness, the authors say. “Despite data indicating similar rates of PDA closure with either drug, a recent meta-analysis demonstrated an increased risk of BPD with ibuprofen compared with indomethacin treatment, the authors note.

The study was supported by Lundbeck Pharmaceuticals and the University of Miami (Project: New Born). The authors declare no conflicts of interest.

SOURCE:

Timing of Patent Ductus Arteriosus Treatment and Respiratory Outcome in Premature Infants: A Double-Blind Randomized Controlled Trial

J Pediatr 2012. Published online January 30, 2012.