In a comment on a recent post, Martin Kluckow pointed out that they have just had published a moderately sized RCT. It was supposed to be larger, but intravenous indomethacin became unavailable, so they had to stop the trial. (Kluckow M, Jeffery M, Gill A, Evans N: A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus. Archives of Disease in Childhood – Fetal and Neonatal Edition 2013).
The trial design was to perform a cardiac ultrasound prior to 12 hours of age, and then to randomize the babes to be treated or not with indomethacin if they found a large PDA, which was defined by the size of the PDA on colour Doppler (>1.8 mm in the first 5 hours of life, then progressively smaller threshold until 12h). The primary outcome was survival without serious brain injury on head ultrasound, and the plan had been to randomize 170 babies < 29 weeks to each group. When indomethacin became unavailable they terminated the trial with 44 indo and 48 placebo babies.
The trial is a fascinating example of the questions we need to be addressing to figure out what to do about the PDA. Infants who were screened and did not have a large PDA were followed and treated according to clinical criteria. One thing I would really have liked in this article is a description of the outcomes of the screened babies who did not have a large PDA, there is a statement in the discussion that the babies with a small PDA had an 80% chance of spontaneous closure, but I see no other data from those babies, which I think would be super interesting.
Placebo group babies could be treated with open label indomethacin within the 1st 72 hours if they had a pulmonary hemorrhage, or severe hypotension thought to be PDA related, and a large PDA on echo. They could also get treated after 72 hours if they had a clinical diagnosis of PDA confirmed to be large on echo.
As for the results, there were fewer intraventricular hemorrhages in the indomethacin group (2/44 vs 6/48), but this may just be due to chance (p=0.21) the primary outcome was very similar between the 2 groups, 8 vs 9. Early pulmonary hemorrhages were much less frequent in the indomethacin group, 1/44 vs 10/48, pulmonary hemorrhage in total was less common with indomethacin, a difference which was probably not due to chance, but did not reach conventional significance (p=0.07).
The reduction in significant pulmonary hemorrhage (to be included there had to be a significant clinical deterioration with the bleeding), is consistent with the secondary analysis of the TIPP trial, and with what we know about the likely pathogenesis of this complication.
Infants were not included in this study if they already had a significant bleed on the ultrasound done at the same time as the echocardiogram. In this way it resembles the multicenter IVH prevention trial by Laura Ment and colleagues, who screened with head ultrasound before 12 hours, and randomized babies to indomethacin or placebo if the head ultrasound was normal, so they could be treated by 12 hours. In the TIPP trial in contrast, there was no ultrasound before indomethacin, and the infants were all treated by 6 hours of age. The relative reduction in IVH was similar in those 2 trials. The reason for bringing up these details is that the babies in this new trial were treated at a mean age of 9 hours, I think it is likely that to have the greatest effect on IVH treatment needs to be started within 6 hours, but clearly from Ment’s trial, even at 12 hours there is a major reduction in serious IVH if you haven,t already had a bleed.
I think this trial really shows us one way forward. If we can confirm in a larger trial that these results are generalizable, and that long term outcomes are at least as good or better with very early targeted treatment, then it should become standard of care, and will force us all to find a way of having echocardiogram capabilities available 24 hours a day at short notice for all of the small preterm infants that we admit.
One more comment, the authors of the trial note that TIPP showed a reduction in severe IVH, but no improvement in long term neurological or developmental outcomes. They, and others, suggest that this may be due to balancing cerebral vasoconstriction, which impairs cerebral perfusion in infants who don’t have IVH. I would suggest another explanation, that, if the only cerebral effect of indomethacin is prevention of IVH (which TIPP confirmed; a reduction from 13% to 9%) then the study was very underpowered. In other words if 4% of the indomethacin babies had a benefit, and there was no adverse effect of indomethacin then a study of several thousand babies would be required to demonstrate improved outcomes. (This is not meant as a criticism of TIPP which was an important trial, it just point out the limitation of most of our evidence in neonatology). Alternatively, secondary analysis of higher risk subgroups might show a benefit, which is exactly what the results of TIPP do show, in boys, who have more IVH, there actually were better long term outcomes with indomethacin compared to placebo. What this suggests to me is that targeting the babies at highest risk for severe IVH may well be a reasonable approach.
It is also possible to reduce the impacts on the cerebral circulation by simply giving the indomethacin slowly. One study using Doppler ultrasound found a major reduction in the adverse changes with indomethacin simply by giving it over 30 minutes.
Finally this trial also confirms my other impression: that PH is getting more common. In the TIPP trial, with an average GA of about 26 weeks, similar to this trial, the incidence was about 12% in the controls and about 8% with indomethacin. In this new study the control group incidence was over 20%. Perhaps this is related to improving survival in the first few days, overall mortality in TIPP was 20% (to 18 months) in this study it was 10% (to discharge). There were also probably fewer 23 week gestation babies in TIPP despite the similar mean gestation. Perhaps that is why there are more PH today, but what is clear is that this is a serious complication, with a high rate of developing severe IVH simultaneously with the pulmonary hemorrhage, and a high rate of bronchopulmonary dysplasia.
Keith – thanks for your thoughts on the trial – perceptive as always! The data on small PDA babies was edited out in the review process but briefly when we compared the 48 large PDA who received placebo to the 70 with small PDA we found IVH Grd 2-4 was 6 vs 7, PH was 11 vs 4 (p=0.006) as well as closure rate of 80% in small PDA group. Other outcomes not different. One other thought re the apparent increasing pulmonary haemorrhage rate. Ironically as we get better at respiratory management and have very immature infants in air/ready for CPAP within hours of birth, the rate of PDA constriction postnatally has not kept up with these advances. Consequently we often end up with a rapid decrease in pulmonary pressure relative to systemic pressure in an infant with a relatively large PDA, which potentially results in a larger left to right shunt early on. We have previously shown that PH is more likely in this setting. Agree with your thoughts re the way forward is subgroup selection and targeting – as it is with many of our modern neonatal CVS dilemmas including treatment of hypotension and use of iNO in preterm infants.In these areas meta-analysis of large numbers of physiologically heterogenous infants is unlikely to give us the answer….