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Found 2 results

  1. 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…
  2. It seems like a sensational title I know but it may not be as far fetched as you may think. The pendulum certainly has swung from the days of liberal post natal dexamethasone use in the 1990s to the near banishment of them from the clinical armamentarium after Keith Barrington published an article entitled The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs in BMC Pediatrics in 2011. This article heralded in the steroid free epoch of the first decade of the new millennium, as anyone caring for preterm infants became fearful of causing lifelong harm from steroid exposure. Like any scare though, with time fear subsides and people begin asking questions such as; was it the type of steroid, the dose, the duration or the type of patient that put the child at risk of adverse development? Moreover, when death from respiratory failure is the competing outcome it became difficult to look a parent in the eye when their child was dying and say "no there is nothing more we can do" when steroids were still out there. Over the last decade or so, these questions in part have been studied in at least two important ways. The first was to ask whether we use a lower dose of dexamethasone for a shorter period to improve pulmonary outcomes without adverse neurodevelopment? The target population here were babies on their way to developing chronic lung disease as they were ventilated at a week of age. The main study to answer this question was the DART study. This study used a very low total dose of 8.9 mg/kg of dexamethasone given over ten days. While the study was stopped due to poor recruitment (it was surely difficult to recruit after the 2001 moratorium on steroids) they did show a benefit towards early extubation. This was followed up at 2 years with no difference in neurodevelopmental outcomes. Having said that the study was underpowered to detect any difference so while reassuring it did not prove lack of harm. Given the lack of evidence showing absolute safety practitioners have continued to use post natal steroids judiciously. The second strategy was to determine whether one could take a prophylactic approach by providing hydrocortisone to preterm infants starting within the first 24 hours to prevent the development of CLD. The best study to examine this was by Kristi Watterberg in 2004 Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Strangely enough the same issue of early stoppage affected this study as an increased rate of spontaneous gastrointestinal perforation was noted leading to early closure. The most likely explanation is thought to be the combination of hydrocortisone and indomethacin prophylaxis which some centres were using at the same time. An interesting finding though was that in a subgroup analysis, infants with chorioamnionitis who received hydrocortisone had less incidence of chronic lung disease. (more on this later) Although this of course is subject to the possible bias of digging too deep with secondary analyses there is biologic plausibility here as hydrocortisone could indeed reduce the inflammatory cascade that would no doubt be present with such infants exposed to chorioamnionitis in utero. Has the answer finally come? The DART study at 360 patients was the largest study to date to look at prophylaxis as a strategy. That is until this past week. The results of the PREMILOC study have been published which is the long awaited trial examining a total dose of 8.5 mg/kg of hydrocortisone over 10 days. We can finally see the results of a trial without the complicating prophylactic indomethacin trials interfering with results. Surprisingly this study was also stopped early (a curse of such trials?!) due to financial reasons this time. Prior to stoppage though they managed to recruit 255 to hydrocortisone and 266 to control groups. All infants in this study were started on hydrocortisone within 24 hours of age and the primary outcome in this case was survival without BPD at 36 weeks of age. All infants were less than 28 weeks at birth and therefore had a high risk of the combined outcome and despite the study being stopped early there was indeed a better outcome rate in the hydrocortisone group (60% vs 51%). Another way of looking at this is that to gain one more patient who survived without BPD you needed to treat 12 which is not bad at all. What is additionally interesting are some of the findings in the secondary analyses. The lack of a difference in males may well reflect the biologic disadvantage that us males face overcoming any benefit from the hydrocortisone. In fact for the females studied the number needed to treat improves to 6 patients only! Short term outcomes of less ventilation are sure to please everyone especially parents. Lastly, a reduction in PDA ligation is most probably related to an antiprostaglandin effect of steroids and should be cause for joy all around. Lastly, a tip of the hat to Dr. Watterberg is in order as those infants who were exposed to chorioamnionitis once again show that this is where the real benefit may be. But what about side effects? The rate of NEC is quite high but is so for both groups but otherwise there is nothing much here to worry the reader. Once and for all we also see that by excluding concurrent treatment with indomethacin or ibuprofen the rate of GI perforation is no different this time around. Reassuring results indeed, but alas the big side effect, the one that would tip the scale towards us using or abandoning treatment has yet to be presented. Steroids no doubt can do great things but given the scare from 2001 we will need to see how this cohort of babies fares in the long run. The follow-up is planned for these infants and the authors have done an incredible job of recruiting enough patients to make the results likely believable. I for one can't wait to see what the future holds. If I was a betting man though I would say this ultra low dose of hydrocortisone may be just the thing to bring this therapy finally into the toolbox of neonatal units worldwide. We have been looking for the next big thing to help improve outcomes and good old hydrocortisone may be just what the doctor ordered.