This was another large multicenter trial, designed to determine if routine attempts to close a moderate to large PDA at the end of the first postnatal week decreases the duration of patency, and the incidence of the combined outcome “need for ligation or need for post-discharge PDA follow-up”. The comparison group, the “conservative approach” required pre-specified respiratory and hemodynamic criteria before rescue treatment.
The trial was registered as NCT01958320 but I can’t see a publication of the protocol.
At 1 to 2 weeks of age there were 855 infants of those who were screened (about half of the screened babies were eligible for the trial) who had a moderate/large PDA shunt and required at least 0.25 FiO2 and either ventilation non-invasive ventilation CPAP more than 2 L/min high-flow.
Echo criteria were internal ductus diameter ≥1.5 mm/kg (or PDA:LPA ratio ≥0.5), ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus <8 mm, LA/Ao ratio ≥1.5, left pulmonary artery diastolic (or mean) flow velocity >0.2 (or >0.42) m/sec, respectively, and/or reversed diastolic flow in the descending aorta. Those are the criteria copied from the registration, I don’t know how many were needed to be eligible.
202 babies between 23 and 28 weeks gestation were randomized between 6 and 14 days of age half of whom were intubated. Half of them got immediate treatment, and the other half were in the conservative arm.
As fas as I can tell the pharmacologic treatment of the PDA could be either indomethacin or ibuprofen. The criteria for later treatment in the conservative arm are not in the registration document, nor in the abstract. Apparently nearly 2/3 of the conservative arm met treatment criteria (62%), but only half of the group (48%) actually received it.
The primary outcome was needing ligation (criteria not given) or being discharged with an open PDA (confirmed by a pre-discharge echo). That outcome was less common with early treatment (Relative Risk 0.72, no confidence intervals in the abstract). PDA ligation was the same in both groups at 12%, as there is no overlap between, ligation and PDA patency at discharge that means the difference is there, being in the later treatment group means your duct is more likely to stay open at discharge. I would guess that this is both among those who actually were treated (as treatment is known to be less effective later) and among those who didn’t actually receive the later treatment even though they met criteria.
In other outcomes, more of the conservative group received dopamine for 3 days or more. In our unit receiving dopamine (or another catecholamine) after 5 days of age, which was the entry limit for the study is very unusual, even among the subgroup who showed the greatest effect for this secondary outcome, those under 26 weeks. It would be interesting to know if there were standardized criteria for this, or if babies were getting dopamine because their diastolic pressures were a bit low…
Also of interest in the secondary outcomes, mortality and late onset sepsis were more frequent among the early treatment group, with relative risks of 1.79 and 1.52 respectively. These effects were more evident in infants of 26 weeks or more. Feeding progression was slower with early treatment, but again that might be because of unit specific guidelines for holding or slowing feeds during PDA treatment, rather than a problem with feed tolerance.
An important study, but the limitations of the abstract format, and the lack of a published protocol preclude much more in the way of definitive interpretation. Also there are several other trials which are in progress, examining similar questions. If earlier treatment (by these criteria) really does lead to increased mortality then the rest of the results are really irrelevant; being alive with an open PDA, I think anybody would agree, is better than being dead with a PDA firmly closed!
Should we tolerate the PDA? Probably; but how tolerant, and when to become intolerant, are still unclear.