Patent Ductus Arteriosus: Is There Evidence for Treatment? William E. Benitz, M.D. Division of Neonatal and Developmental Medicine Stanford University School of Medicine Lucile Packard Children’s Hospital

Patent Ductus Arteriosus: Is There Evidence for Treatment? William E. Benitz, M.D. Disclosures: I have no financial or other conflicts of interest to disclose. There will be no discussion of off-label uses of pharmaceutical products in this presentation. I have been a long-time practitioner of an aggressive approach to management of persistent ductal patency in preterm infants.

PDA Treatment: Cochrane Reviews 2002 2003 2006 2008 2008

PDA Treatment: Cochrane Reviews Indomethacin Treatment Strategies

PDA Treatment: Cochrane Reviews Prophylaxis Strategies

Patent Ductus Arteriosus: A Look at the Evidence Pubmed searches for “patent ductus”, “persistent ductus”, or “delayed ductus closure” and “infant-newborn” produced nearly 4000 citations. Almost 1500 citations were relevant to management of PDA in preterm human infants, beginning with Burnard in 1959. 75 randomized clinical trials were found. 19 comparisons of indomethacin and ibuprofen, 5 comparing long and short courses of indomethacin, and 2 using very early crossover to treatment were excluded, as PDA closure rates did not differ between groups. Meta-analyses were performed using the remaining 49 trials (4728 subjects) to ascertain the impact of earlier PDA closure. Inclusion criteria were permissive rather than rigorous. Trials were grouped by treatment, route, indications, and timing.

Patent Ductus Arteriosus: Effects of Treatment Benitz: J Perinatol 2010; 30:241

Patent Ductus Arteriosus: Effects of Treatment Benitz: J Perinatol 2010; 30:241

Patent Ductus Arteriosus: Effects of Prophylaxis Benitz: J Perinatol 2010; 30:241

Patent Ductus Arteriosus: Effects of Prophylaxis Benitz: J Perinatol 2010; 30:241

Patent Ductus Arteriosus: Effects of Treatment or Prophylaxis Benitz: J Perinatol 2010; 30:241

Patent Ductus Arteriosus: Effects of Timing of Treatments Benitz: J Perinatol 2010; 30:241 Studies categorized as suggested by Clyman: J Pediatr 1996; 128: 601

Patent Ductus Arteriosus: Effects of Timing of Treatments Benitz: J Perinatol 2010; 30:241 Studies in panel A selected as suggested by Clyman: J Pediatr 2007; 150:216. Studies in panels B & C selected as described in Benitz: J Perinatol 2010; 30:241.

Does Closing the PDA Reduce Pulmonary Morbidity? 27 randomized trials reported effects of treatment on duration of oxygen administration or mechanical ventilation. Neither the Cochrane reviews nor my analyses revealed any beneficial effect on duration of oxygen use, assisted ventilation, or hospitalization. Early indomethacin has been associated with prolongation of need for ventilator support (Vincer, 1987), increased oxygen and surfactant use (Yaseen, 1997), higher mean airway pressures (Van Overmire, 2001), and increased oxygen requirements (Van Overmire, 2001; Schmidt, 2006).

Conclusions of Meta-Analyses The data do not permit rejection of the null hypothesis: Early treatment of PDA does not improve outcomes in preterm infants

Summary – Conclusions Ligation, indomethacin, and ibuprofen are effective for achieving ductal closure (reducing symptomatic PDA and ligation rates). Prophylactic indomethacin reduces the incidence of severe IVH, but does not improve neurodevelopmental outcomes. Interventions to close the ductus – prophylactically or as treatment of asymptomatic or symptomatic PDA – do not reduce the incidence of death, BPD, NEC, or other morbidity. Short-term benefits may be illusory or overestimated, as randomized trials of early indomethacin demonstrate use of more oxygen and distending pressure for longer periods of time in treated infants.

Summary – Recommendations There is no evidence to support use of early treatments to close a patent ductus arteriosus in the preterm infant. It is time for a moratorium on routine use of COX inhibitors or surgery to achieve early ductal closure in preterm infants. Given the evidence that medical induction of ductal closure is of no benefit, it may no longer be ethical to enroll infants in randomized trials of therapies now known to be ineffective. A new hypothesis to explain the relationship between PDA and long-term morbidities in preterm infants is required. If there is a causal linkage of PDA to adverse outcomes, new methods are required for identification of infants at risk.