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Posted on May 7, 2017 by winnineo In our journey as Neonatologists and interdisciplinary teams we are forever seeking to rid or at least reduce the plague of BPD in the patients we care for. The PREMILOC trial was a double-blind, multicenter, randomized, placebo-controlled trial designed to test just that concept by introducing a low dose of hydrocortisone within 24 hours of birth. They enrolled infants born between 24 – 26+6 weeks of gestation and assigned them to receive either placebo or low-dose hydrocortisone 0.5mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days. The trial has been the subject of a previous post A Shocking Change in Position. Postnatal steroids for ALL microprems? Although the trial was stopped early due to financial concerns the authors demonstrated a 9% reduction in BPD using this strategy. The theory here in part is that the presence of hydrocortisone reduces inflammation and that this in turn may allow for better growth of lungs with time. Why Not Adopt The Results Based on These Fantastic Results? Steroids in preterm infants have a bad name. As discussed in previous posts on the topic the concern in all trials has been the potential impact of such medications on the developing brain. A nice summary of these concerns can be found in a paper in the CMAJ by the other “Canadian Neonatal Blogger” from 2001 in which he quoted the risk of cerebral palsy increasing from about 1 in 6 babies to 1 in 3 if babies born at < 28 weeks were exposed to postnatal steroids. Neurodevelopmental impairment overall would change from 1 in 4 to 1 in 3 if such exposure occurred. This paper and others expressing concerns over the effect of postnatal steroids led to a change in practice from more ubiquitous use to one restrained to only in those cases where the patient was nearing the end of all other options. This meant holding out for such therapy until such patients were at 90% or more O2 and on high mean airway pressures. Although not formally studied I was very concerned at the time with using this approach as I felt it was a “fait de complet” that they would either die or have significant developmental impairment should they survive due to the complications of having such severe BPD. It is critical to note though that the outcomes from these long term studies were in infants exposed to much longer courses of dexamethasone and at high doses that are used today. Over the years with the development of the DART protocol and other more gentle approaches to steroids we as a group relaxed and certainly rescue courses of lower dose steroids have crept into practice when patients seem to be “stuck” on the ventilator. Drumroll Please… The results of the PREMILOC follow-up study are now here and in short they look good. Patients were followed up at an average age of 22 months and included a medical history, anthropometric measures, respiratory status, standardized neurological examination based on specific definitions of disabilities, and quantitative neurodevelopmental assessment using the revised Brunet-L.zine (RBL) scale. Follow-up was 93% in the hydrocortisone and 90% in the placebo arm which is important as we need not worry about the missed patients influencing the results to a significant degree if they had been included. Although some post-hoc analyses were done what I am most interested in is the primary outcome which is shown below. There was no difference in either neurodevelopment overall or any of the subcategories. This provides a great deal of reassurance to those who provide steroids this way. There will be those however that argue the study is too small. While a larger study might be better able to address whether there is a small difference in outcome I don’t think we will see one anytime soon. It is one of the challenges we face in Neonatology. Unlike the adult world with studies of thousands of patients, due to the small number of patients born at <28 weeks it is always a challenge to recruit into such large volume trials. We can compare trials by doing meta analyses or systematic reviews and perhaps that is where we will head with this study although given that different steroids will have been used (thinking dexamethasone as in the DART study) this will always be left open to question. Is it worth it? I suppose the real question here is the following for a parent to consider. “Would you like your baby to receive hydrocortisone shortly after birth with a 7% reduction in the risk of BPD at 36 weeks bearing in mind that although we don’t think there is an impact on long term development we aren’t certain yet”. I guess to answer this question you need to think about the first part of the question. Is BPD at 36 weeks a good outcome to look at for benefit? The Canadian Neonatal Network has recently called for a rethink on this The New BPD That Matters. It turns out that it is 40 weeks and not 36 weeks that has the greatest prediction for respiratory morbidity after discharge. If you were to move the goal post to 40 weeks from 36 I strongly suspect one would see the 9% reduction in BPD as shown in the PREMILOC trial vanish. If that is the case, would a slightly earlier extubation time be enough to motivate families to take the plunge? Although I often cringe at the expression “more trials are needed”, I think at least a combination of studies to achieve greater confidence in outcome may be needed. Barring that, we might just have to sit tight and accept that while there may be a little bit to be gained with the use of the PREMILOC protocol it may just not be enough to be clinically warranted at this time. May want to wait for the next big thing to tackle BPD…
The rise of donor milk banks and depots in recent years has been a welcome addition to the care of preterm infants. We have known for many years that “breast is best” and advocate for mother’s own milk whenever possible. When this is not possible we previously turned to formula but with the availability of pooled pasteurized donor milk many hospitals have focused on expanding the indications for use. Through personal communications in Canada we are a bit all over the map in terms of indications with some centres restricting use based on birth weight while others taking into account, gestational age as the main criteria. With respect to duration some centres use 2 weeks, others 4 and then others until a gestational age is reached which may mean up to 10 weeks of use for a baby born in that centre at 24 weeks. While variation exists it is hard to find anyone who would suggest this is a bad thing to provide. The main reason for pushing expansion of programs is the strong evidence that avoidance of bovine milk is associated with a reduction in the risk of NEC. Many studies have been done in this regard and the Cochrane systematic review concluded that formula increased the risk of necrotising enterocolitis: typical risk ratio 2.77 (95% CI 1.40 to 5.46); risk difference 0.04 (95% CI 0.02 to 0.07). While donor milk is a wonderful nutritional product for sure it does have one issue which is a lower protein content than mother’s own milk and as such dieticians will commonly increase the protein content from 0.9 g/dL to 1.2 g/dL by adding powder or more recently liquid protein supplements. One might expect then that doing so would provide a reduction is NEC, and an optimal source of nutrition for the growing preterm brain. Avoidance of NEC should reduce the risk of adverse neurodevelopmental outcome as the two have been linked before. Enter the DOMINO Study This Ontario, Canada based study utilized four NICUs to provide in a randomized fashion either donor human milk or formula with matching protein and caloric densities to 363 infants (181 donor milk, 182 formula). All infants were preferentially fed mother’s own milk but supplemented with donor or formula if unavailable and planned to use one or the other for up to 90 days or discharge whichever came first. The exposure to donor milk was quite long in comparison to our own units practice (1 month duration if born at < 1500g) . The median number of days for donor milk was 65 (IQR, 41-90). A significant risk to the results would be if there was a difference in amounts of mother’s own milk provided between the two groups but there was none. Exclusive feeding of mother’s own milk occurred in the Donor milk group (28.2%) and formula group (26.9%) respectively. Among infants requiring a supplement, there was no statistically significant difference between the donor milk and formula groups in the proportion of total enteral feeds for each infant consumed as mother’s milk (58.4% [IQR, 13.6%-96.0%] vs 63.3% [IQR, 9.6%-97.2%], respectively, P = .96). Short term but not long term gains Curiously (at least to me) I would have expected differences in some of the morbidities other than NEC but such was not the case. The strength of using human milk though can not be understated as any reduction in NEC is an extremely important outcome regardless of whether long term neurodevelopment is affected positively or not. in terms of the latter outcome no difference was observed between the two groups. The Bayley III findings were quite similar at 18 months which on the surface may cause everyone’s shoulders to sag as the benefit everyone hoped for did not transpire. Additionally, linear growth, head circumference and weight gain were not different between groups. This may simply reflect that protein and caloric intakes were indeed matched between groups whereas in the past, the lack of protein fortification led to delays in growth in the donor milk groups. At the risk of sounding like the end of a Cochrane review I am not sure this is the final word on donor milk and outcome. Larger studies may be needed to get at the real truth. This was not a pure sample of donor milk vs formula as a significant percentage (over 20% in both groups) received purely mother’s own milk. Furthermore, in those that received supplements there was still a significant percentage that received some of mother’s own milk. The authors suggest that a larger sample size would unlikely have detected a difference and that may be the case but is it so due to where the study was done. What if the study were done in a centre with a very low rate of breastfeeding? I am concerned that the lack of response in outcome may reflect a dilution of the impact of the strategy by having such a successful rate of providing mother’s own milk. All Is Not Lost Using a glass is half full view, I think it is worth pointing out that this study should also provide some comfort for those centres that use formula as a supplement. Clearly the higher rate of NEC is not comforting to anyone but for those who survive to discharge the neurodevelopmental outcome is promising. Formula in some circles has taken on a view as almost a toxic substance but I often remind residents and fellows that while we prefer breast milk, formula has been used in NICUs for decades and not every patient who receives it will develop NEC. Yes it is a risk factor for NEC and when you don’t have an alternative it is an acceptable form of nutrition to use. What I think may be lost in the DOMINO study is that if you are a centre that uses formula as there is no access to DBM this should help provide reassurance to the families you care for. All is not lost after the DOMINO study. Every cloud has a silver lining and fear not this will not be the last study to test this hypothesis. At the moment it is just the best we have and this is not the last we will hear on this topic.
Guest posted a topic in Congresses and coursesFew places left for this unique symposium. It is a collaboration between UCL, KCL and Imperial College London and brings together 3 active research centres in the field of Neonatal Neuroprotection. The course will cover current and future treatments, Insight in imaging modalities and discuss outcomes Will also offer the opportunity for practical small group workshops on imaging, EEG, aEEG, legal aspects To register please go to http://www.guysandstthomasevents.co.uk/paediatrics-training/london-neonatal-neuroprotection-symposium/ A4 flyer - Neuroprotection 2014 low res.pdf