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Found 15 results

  1. This must be one of my favourite topics as I have been following the story of early hydrocortisone to reduce BPD for quite some time. It becomes even more enticing when I have met the authors of the studies previously and can see how passionate they are about the possibilities. The PREMILOC study was covered on my site twice now, with the first post being A Shocking Change in Position. Postnatal steroids for ALL microprems? and the second reviewing the 22 month outcome afterwards /2017/05/07/early-hydrocortisone-short-term-gain-without-long-term-pain/. The intervention here was that within 24 hours of birth babies born between 24-27 weeks gestational age were randomized to receive placebo or hydrocortisone 1 mg/kg/d divided q12h for one week followed by 0.5 mg/kg/d for three days. The primary outcome was rate of survival without BPD at 36 weeks PMA. The finding was a positive one with a 9% reduction in this outcome with the use of this strategy. Following these results were the two year follow-up which reported no evidence of harm but the planned analysis by gestational age groupings of 24-25 and 26-27 weeks was not reported at that time but it has just been released this month. Is there a benefit? Of the original cohort the authors are to be commended here as they were able to follow-up 93% of all infants studied at a mean age of 22 months. The methods of assessing their neurological status have been discussed previously but essentially comprised standardized questionnaires for parents, assessment tools and physical examinations. Let’s start off with what they didn’t find. There was no difference between those who received placebo vs hydrocortisone in the 26-27 week group but where it perhaps matters most there was. The infants born at 24-25 weeks are certainly some of our highest risk infants in the NICU. It is in this group that the use of hydrocortisone translated into a statistically significant reduction in the rate of neurodevelopmental impairment. The Global Neurological Assessement scores demonstrated a significant improvement in the hydrocortisone group with a p value of 0.02. Specifically moderate to severe disability was noted in 18% compared to 2% in the group receiving hydrocortisone.They did not find a difference in the neurological exam but that may reflect the lack of physical abnormalities with cognitive deficit remaining. It could also be explained perhaps by the physical examination not being sensitive enough to capture subtle differences. Why might this be? Adding an anti-inflammatory agent into the early phase of a preemies life might spare the brain from white matter damage. Inflammation is well known to inflict injury upon the developing brain and other organs (think BPD, ROP) so dampening these factors in the first ten days of life could bring about such results via a mechanism such as that. When you look at the original findings of the study though, a couple other factors also pop up that likely contribute to these findings as well. Infants in the hydrocortisone group had a statistical reduction in the rate of BPD and PDA ligations. Both of these outcomes have been independently linked to adverse neurodevelopmental outcome so it stands to reason that reducing each of these outcomes in the most vulnerable infants could have a benefit. In fact when you add everything up, is there much reason not to try this approach? Ten days of hydrocortisone has now been shown to reduce BPD, decrease PDA ligations and importantly in the most vulnerable of our infants improve their developmental outcome. I think with this information at our fingertips it becomes increasingly difficult to ignore this approach. Do I think this will become adopted widely? I suspect there will be those who take the Cochrane approach to this and will ask for more well designed RCTs to be done in order to replicate these results or at least confirm a direction of effect which can then be studied as part of a systematic review. There will be those early adopters though who may well take this on. It will be interesting to see as these centres in turn report their before and after comparisons in the literature what the real world impact of this approach might be. Stay tuned as I am sure this is not the last we will hear on this topic!
  2. What is old is new again as the saying goes. I continue to hope that at some point in my lifetime a “cure” will be found for BPD and is likely to centre around preventing the disease from occurring. Will it be the artificial placenta that will allow this feat to be accomplished or something else? Until that day we unfortunately are stuck with having to treat the condition once it is developing and hope that we can minimize the damage. When one thinks of treating BPD we typically think of postnatal steroids. Although the risk of adverse neurodevelopmental outcome is reduced with more modern approaches to use, such as with the DART protocol,most practitioners would prefer to avoid using them at all if possible. We know from previous research that a significant contributor to the development of BPD is inflammation. As science advanced, the specific culprits for this inflammatory cascade were identified and leukotrienes in particular were identified in tracheal lavage fluid from infants with severe lung disease. The question then arises as to whether or not one could ameliorate the risk of severe lung disease by halting at least a component of the inflammatory cascade leading to lung damage. Leukotriene Antagonists In our unit, we have tried using the drug monteleukast, an inhibitor of leukotrienes in several patients. With a small sample it is difficult to determine exactly whether this has had the desired effect but in general has been utilized when “all hope is lost”. The patient has severe disease already and is stuck on high frequency ventilation and may have already had a trial of postnatal steroids. It really is surprising that with the identification of leukotriene involvement over twenty years ago it took a team in 2014 to publish the only clinical paper on this topic. A German team published Leukotriene receptor blockade as a life-saving treatment in severe bronchopulmonary dysplasia.in 2014 and to date as far as I can see remains the only paper using this strategy. Given that we are all looking for ways to reduce BPD and this is the only such paper out there I thought you might want to see what they found. Would this be worth trying in your own unit? Well, read on and see what you think! Who was included? This study had an unusual design that will no doubt make statistical purists cringe but here is what they did. The target population for the intervention were patients with “life threatening BPD”. That is, in the opinion of the attending Neonatologist the patient had a greater than 50% likelihood of dying and also had to meet the following criteria; born at < 32 weeks GA, <1500g and had to be ventilated at 28 days. The authors sought a blinded RCT design but the Research Ethics Board refused due to the risk of the drug being low and the patients having such a high likelihood of death. The argument in essence was if the patients were likely to die and this drug might benefit them it was unethical to deny them the drug. The authors attempted to enroll all eligible patients but wound up with 11 treated and 11 controls. The controls were patients either with a contraindication to the drug or were parents who consented to be included in the study as controls but didn’t want the drug. Therapy was started for all between 28 – 45 days of age and continued for a wide range of durations (111+/-53 days in the study group). Lastly, the authors derived a score of illness severity that was used empirically: PSC = FiO2 X support + medications – support was equal to 2.5 for a ventilator. 1.5 for CPAP and 1 for nasal cannulae or an oxygen hood – medications were equal to 0.2 for steroids, 0.1 for diruetics or inhaled steroids, 0.05 for methylxanthines or intermittent diruetics. Did it make a difference? The study was very small and each patient who received the medication was matched with one that did not receive treatment. Matching was based on GA, BW and the PSC with matching done less than 48 hours after enrollment in an attempt to match the severity of illness most importantly. First off survival in the groups were notably different. A marked improvement in outcome was noted in the two groups. Of the deaths in the control group, the causes were all pulmonary and cardiac failure, although three patients died with a diagnosis of systemic inflammatory response syndrome. That is quite interesting given that monteleukast is an anti-inflammatory medication and none of the patients in the treatment arm experienced this diagnosis. The second point of interest is the trend in the illness severity score over time. The time points in the figure are time 1 (start of study), time 2 (4 weeks of treatment), time 3 (end of treatment). These patients improved much more over time than the ones who did not receive treatment. The Grain of Salt As exciting as the results are, we need to acknowledge a couple things. The study is small and with that the risk of the results appearing to be real but in actual fact there being no effect is not minimal. As the authors knew who was receiving monteleukast it is possible that they treated the kids differently in the unit. If you believed that the medication would work or moreover wanted it to work, did you pay more attention on rounds and during a 24 hour period to those infants? Did the babies get more blood gases and tighter control of ventilation with less damage to the lungs over time? There are many reasons why these patients could have been different including earlier attempts to extubate. The fact is though the PSC scores do show that the babies indeed improved more over time so I wouldn’t write it off entirely that they did in fact benefit. The diagnosis of SIRS is a tough one to make in a newborn and I worry a little that knowing the babies didn’t receive an anti-inflammatory drug they were “given” that diagnosis. Would I use it in spite of these faults? Yes. We have used it in such cases but I can’t say for sure that it has worked. If it does, the effect is not immediate and we are left once we start it not knowing how long to treat. As the authors here say though, the therapeutic risk is low with a possibly large benefit. I doubt it is harmful so the question we are left asking is whether it is right for you to try in your unit? As always perhaps a larger study will be done to look at this again with a blinded RCT structure as the believers won’t show up I suspect without one!
  3. Zsofia Dombi

    CLD, volumen gurarantee

    Dear All, I would like to ask about your experience with volumen guaranteed mechanical ventillation in case of early onset CLD. We have 24 weeker, who is now 2 weeks old, and having bronchospasms, typical XR signs of CLD, and spontaneous hypoxemic episodes. We try to wean her from MV, but her weight and irregular respiratory activity makes the thing trickier. I was thinking about lowering the PIP, and TV to prevent the further damage, she recieves supportive care for the CLD. I would like to read your experience. Thank you for your answers.
  4. AllThingsNeonatal

    Can a chest x-ray predict the future?

    If you work in Neonatology then chances are you have ordered or assisted with obtaining many chest x-rays in your time. If you look at home many chest x-rays some of our patients get, especially the ones who are with us the longest it can be in the hundreds. I am happy to say the tide though is changing as we move more and more to using other imaging modalities such as ultrasound to replace some instances in which we would have ordered a chest x-ray. This has been covered before on this site a few times; see Point of Care Ultrasound in the NICU, Reducing Radiation Exposure in Neonates: Replacing Radiographs With Bedside Ultrasound. and Point of Care Ultrasound: Changing Practice For The Better in NICU.This post though is about something altogether different. If you do a test then know what you will do with the result before you order it. If there is one thing I tend to harp on with students it is to think about every test you do before you order it. If the result is positive how will this help you and if negative what does it tell you as well. In essence the question is how will this change your current management. If you really can’t think of a good answer to that question then perhaps you should spare the infant the poke or radiation exposure depending on what is being investigated. When it comes to the baby born before 30 weeks these infants are the ones with the highest risk of developing chronic lung disease. So many x-rays are done through their course in hospital but usually in response to an event such as an increase in oxygen requirements or a new tube with a position that needs to be identified. This is all reactionary but what if you could do one x-ray and take action based on the result in a prospective fashion? What an x-ray at 7 days may tell you How many times have you caught yourself looking at an x-ray and saying out loud “looks like evolving chronic lung disease”. It turns out that Kim et al in their publication Interstitial pneumonia pattern on day 7 chest radiograph predicts bronchopulmonary dysplasia in preterm infants.believe that we can maybe do something proactively with such information. In this study they looked retrospectively at 336 preterm infants weighing less than 1500g and less than 32 weeks at birth. Armed with the knowledge that many infants who have an early abnormal x-ray early in life who go on to develop BPD, this group decided to test the hypothesis that an x-ray demonstrating a pneumonia like pattern at day 7 of life predicts development of BPD. The patterns they were looking at are demonstrated in this figure from the paper. Essentially what the authors noted was that having the worst pattern of the lot predicted the development of later BPD. The odds ratio was 4.0 with a confidence interval of 1.1 – 14.4 for this marker of BPD. Moreover, birthweight below 1000g, gestational age < 28 weeks and need for invasive ventilation at 7 days were also linked to the development of the interstitial pneumonia pattern. What do we do with such information? I suppose the paper tells us something that we have really already known for awhile. Bad lungs early on predict bad lungs at a later date and in particular at 36 weeks giving a diagnosis of BPD. What this study adds if anything is that one can tell quite early whether they are destined to develop this condition or not. The issue then is what to do with such information. The authors suggest that by knowing the x-ray findings this early we can do something about it to perhaps modify the course. What exactly is that though? I guess it is possible that we can use steroids postnatally in this cohort and target such infants as this. I am not sure how far ahead this would get us though as if I had to guess I would say that these are the same infants that more often than not are current recipients of dexamethasone. Would another dose of surfactant help? The evidence for late surfactant isn’t so hot itself so that isn’t likely to offer much in the way of benefit either. In the end the truth is I am not sure if knowing concretely that a patient will develop BPD really offers much in the way of options to modify the outcome at this point. Having said that the future may well bring the use of stem cells for the treatment of BPD and that is where I think such information might truly be helpful. Perhaps a screening x-ray at 7 days might help us choose in the future which babies should receive stem cell therapy (should it be proven to work) and which should not. I am proud to say I had a chance to work with a pioneer in this field of research who may one day cure BPD. Dr. Thebaud has written many papers of the subject and if you are looking for recent review here is one Stem cell biology and regenerative medicine for neonatal lung diseases.Do I think that this one paper is going to help us eradicate BPD? I do not but one day this strategy in combination with work such as Dr. Thebaud is doing may lead us to talk about BPD at some point using phrases like “remember when we used to see bad BPD”. One can only hope.
  5. AllThingsNeonatal

    The New BPD That Matters

    As a Neonatologist I doubt there are many topics discussed over coffee more than BPD. It is our metric by which we tend to judge our performance as a team and centre possibly more than any other. This shouldn't be that surprising. The dawn of Neonatology was exemplified by the development of ventilators capable of allowing those with RDS to have a chance at survival. As John F Kennedy discovered when his son Patrick was born at 34 weeks, without such technology available there just wasn't much that one could do. As premature survival became more and more common and the gestational age at which this was possible younger and younger survivors began to emerge. These survivors had a condition with Northway described in 1967 as classical BPD. This fibrocystic disease which would cripple infants gave way with modern ventilation to the "new bpd". The New BPD The disease has changed to one where many factors such as oxygen and chorioamnionitis combine to cause arrest of alveolar development along with abnormal branching and thickening of the pulmonary vasculature to create insufficient air/blood interfaces +/- pulmonary hypertension. This new form is prevalent in units across the world and generally appears as hazy lungs minus the cystic change for the most part seen previously. Defining when to diagnose BPD has been a challenge. Is it oxygen at 28 days, 36 weeks PMA, x-ray compatible change or something else? The 2000 NIH workshop on this topic created a new approach to defining BPD which underwent validation towards predicting downstream pulmonary morbidity in follow-up in 2005. That was over a decade ago and the question is whether this remains relevant today. Benchmarking I don't wish to make light of the need to track our rates of BPD but at times I have found myself asking "is this really important?" There are a number of reasons for saying this. A baby who comes off oxygen at 36 weeks and 1 day is classified as having BPD while the baby who comes off at 35 6/7 does not. Are they really that different? Is it BPD that is keeping our smallest babies in hospital these days? For the most part no. Even after they come off oxygen and other supports it is often the need to establish feeding or adequate weight prior to discharge that delays things these days. Given that many of our smallest infants also have apnea long past 36 weeks PMA we have all seen babies who are free of oxygen at 38 weeks who continue to have events that keep them in hospital. In short while we need to be careful to minimize lung injury and the consequences that may follow the same, does it matter if a baby comes off O2 at 36, 37 or 38 weeks if they aren't being discharged due to apnea or feeding issues? It does matter for benchmarking purposes as one unit will use this marker to compare themselves against another in terms of performance. Is there something more though that we can hope to obtain? When does BPD matter? The real goal in preventing BPD or at least minimizing respiratory morbidity of any kind is to ensure that after discharge from the NICU we are sending out the healthiest babies we can into the community. Does a baby at 36 weeks and one day free of O2 and other support have a high risk of coming back to the hospital after discharge or might it be that those that are even older when they free of such treatments may be worse off after discharge. The longer it takes to come off support one would think, the more fragile you might be. This was the goal of an important study just published entitled Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. This work is yet another contribution to the pool of knowledge from the Canadian Neonatal Network. In short this was a retrospective cohort study of 1503 babies born at <29 weeks GA who were assessed at 18-21 months of age. The outcomes were serious respiratory morbidity defined as one of: (1) 3 or more rehospitalizations after NICU discharge owing to respiratory problems (infectious or noninfectious); (2) having a tracheostomy (3) using respiratory monitoring or support devices at home such as an apnea monitor or pulse oximeter (4) being on home oxygen or continuous positive airway pressure at the time of assessment While neurosensory impairment being one of: (1) moderate to severe cerebral palsy (Gross Motor Function Classification System ≥3) (2) severe developmental delay (Bayley Scales of Infant and Toddler Development Third Edition [Bayley III] composite score <70 in either cognitive, language, or motor domains) 3) hearing aid or cochlear implant use (4) bilateral severe visual impairment What did they find? The authors looked at 6 definitions of BPD and applied examined how predictive they were of these two outcomes. The combination of oxygen and/or respiratory support at 36 weeks PMA had the greatest capacity to predict this composite outcome. It was the secondary analysis though that peaked my interest. Once the authors identified the best predictor of adverse outcome they sought to examine the same combination of respiratory support and/oxygen at gestational ages from 34 -44 weeks PMA. The question here was whether the use of an arbitrary time point of 36 weeks is actually the best number to use when looking at these longer term outcomes. Great for benchmarking but is it great for predicting outcome? It turns out the point in time with the greatest likelihood of predicting occurrence of serious respiratory morbidity is 40 weeks and not 36 weeks. Curiously, beyond 40 weeks it becomes less predictive. With respect to neurosensory impairment there is no real difference at any gestational age from 34-44 weeks PMA. From the perspective of what we tell parents these results have some significance. If they are to be believed (and this is a very large sample) then the infant who remains on O2 at 37 weeks but is off by 38 or 39 weeks will likely fair better than the baby who remains on O2 or support at 40 weeks. It also means that the risk of neurosensory impairment is largely set in place if the infant born at < 29 weeks remains on O2 or support beyond 33 weeks. Should this surprise us? Maybe not. A baby who is on such support for over 5 weeks is sick and as a result the damage to the developing brain from O2 free radical damage and/or exposure to chorioamnionitis or sepsis is done. It will be interesting to see how this study shapes the way we think about BPD. From a neurosensory standpoint striving to remove the need for support by 34 weeks may be a goal worth striving for. Failure to do so though may mean that we at least have some time to reduce the risk of serious respiratory morbidity after discharge. Thank you to the CNN for putting out what I am sure will be a much discussed paper in the months to come.
  6. AllThingsNeonatal

    Mother’s milk and BPD; Every Drop Counts

    Producing milk for your newborn and perhaps even more so when you have had a very preterm infant with all the added stress is not easy. The benefits of human milk have been documented many times over for preterm infants. In a cochrane review from 2014 use of donor human milk instead of formula was associated with a reduction in necrotizing enterocolitis. More recently similar reductions have been seen in retinopathy of prematurity. Interestingly with respect to the latter it would appear that any amount of breast milk leads to a reduction in ROP. Knowing this finding we should celebrate every millilitre of milk that a mother brings to the bedside and support them when it does not flow as easily as they wish. While it would be wonderful for all mothers to supply enough for their infant and even more so that excess could be donated for those who can’t themselves we know this not to be the case. What we can do is minimize stress around the issue by informing parents that every drop counts and to celebrate it as such! Why Is Breast Milk So Protective Whether the outcome is necrotizing enterocolitis or ROP the common pathway is one of inflammation. Mother’s own milk contains many anti-inflammatory properties and has been demonstrated to be superior to formula in that regard by Friel and no difference exists between preterm and term versions. Aside from the anti-inflammatory protection there may be other factors at work such as constituents of milk like lactoferrin that may have a protective effect as well although a recent trial would not be supportive of this claim. Could Mother’s Own Milk Have a Dose Response Effect in Reducing The Risk of BPD? This is what is being proposed by a study published in early November entitled Influence of own mother’s milk on bronchopulmonary dysplasia and costs. What is special about this study and is the reason I chose to write this post is that the study is unusual in that it didn’t look at the effect of an exclusive human milk diet but rather attempted to isolate the role of mother’s own milk as it pertains to BPD. Patients in this trial were enrolled prospectively in a non randomized fashion with the key difference being the quantity of mothers own milk consumed in terms of a percentage of oral intake. Although donor breast milk existed in this unit, the patients included in this particular cohort only received mother’s own milk versus formula. All told, 254 infants were enrolled in the study. As with many studies looking at risks for BPD the usual culprits were found with male sex being a risk along with smaller and less mature babies and receipt of more fluid in the first 7 days of age. What also came up and turned out after adjusting for other risk factors to be significant as well in terms of contribution was the percentage of mother’s own milk received in the diet. Every ↑ of 10% = reduction in risk of BPD at 36 weeks PMA by 9.5% That is a really big effect! Now what about a reduction in costs due to milk? That was difficult to show an independent difference but consider this. Each case of BPD had an additional cost in the US health care system of $41929! What Lesson Can be Learned Here? Donor breast milk programs are a very important addition to the toolkit in the NICU. Minimizing the reliance on formula for our infants particularly those below 1500g has reaped many benefits as mentioned above. The availability of such sources though should not deter us from supporting the mothers of these infants in the NICU from striving to produce as much as they can for their infants. Every drop counts! A mother for example who produces only 20% of the needed volume of milk from birth to 36 weeks corrected age may reduce the risk of her baby developing BPD by almost 20%. That number is astounding in terms of effect size. What it also means is that every drop should be celebrated and every mother congratulated for producing what they can. We should encourage more production but rejoice in every 10% milestone. What it also means in terms of cost is that the provision of lactation consultants in the NICU may be worth their weight in gold. I don’t know what someone performing such services earns in different institutions but if you could avoid two cases of BPD a year in the US I would suspect that nearly $84000 in cost savings would go a long way towards paying for such extra support. Lastly, it is worth noting that with the NICU environment being as busy as it is sometimes the question “are you planning on breastfeeding?” may be missed. As teams we should not assume that the question was discussed on admission. We need to ask with intention whether a mother is planning on breastfeeding and take the time if the answer is “no” to discuss why it may be worth reconsidering. Results like these are worth the extra effort!
  7. AllThingsNeonatal

    The Art of Doing Nothing

    There may be nothing that is harder in medicine. We are trained to respond to changes in patients condition with a response that more often than not suggests a new treatment or change in management. Sometimes the best thing for the patient is in fact to do nothing or at least resist a dramatic response to the issue in front of you. This may be the most common issue facing the new trainee who is undoubtedly biased towards doing something. Take for instance the situation in which the trainee who is new to the service finding out that their 26 week infant has a PDA. Their mind races as they digest this information from morning signover. There is less than 2 hours until they come face to face with their attending who no doubt will ask them the dreaded question. “What are you going to do about it?”. When having to choose a path, if they state “I want to sit tight and watch” they fear the thought of the attending thinking they don’t know what to do. Conversely they could stick their neck out and choose to treat with a variety of approaches but then might they be seen as too aggressive?! The likely path is suggesting treatment but in fact the more I think about it the option of benign neglect may be the best approach or at least one in which if you treat and it doesn’t work the first time you just shrug your shoulders and say “I’ll deal with it till it closes on it’s own”. This post really is a follow-up to a previous one entitled The Pesky PDA. A Puzzle After All These Years. What triggered this writing was another before and after comparison of two periods in which the management of PDAs for a unit took a 180 degree turn. Know When to Hold Em And No When to Fold Em This is the essence of the issue for one unit. Sung SI et al published a paper this month entitled Mandatory Closure Versus Nonintervention for Patent Ductus Arteriosus in Very Preterm Infants. They describe a before and after comparison of 81 infants from 2009-11 and 97 infants from 2012-14. All babies were born between 23-26 weeks gestational age. In the first time period their unit had a mandatory PDA closure policy. That is they gave one course of indomethacin and if possible a second course followed by surgical ligation. A significant PDA was defined as one that had a left to right shunt and was at least 2 mm in diameter and the patient had to be ventilated. Any patient who had been extubated regardless of need for CPAP did not have to have their PDA closed. In the second time period the group attempted to avoid indomethacin and ligation at all costs and in fact in this cohort none received either. So What Happened? In the first time period 52 (64%) received indomethacin but only 29% responded and a full 37/52 (71%) went on to receive surgical ligation. Of the 29 that did not receive indomethacin due to contraindications they underwent primary ligation for a total of 82% receiving surgical ligation. The average day of closure for period 1 was 12.9 days. In period 2 a number of interesting findings occurred. The average day of closure was at 44.2 days. Five infants were discharged with a PDA with 3 experiencing spontaneous closure after discharge and the remaining infants undergoing transcatheter occlusion. In period 2 there were more diuretics and fluid restriction employed. Comparing the two periods for a number of other outcomes reveals some other intriguing findings. Even with such differing approaches there is no difference in mortality, severe IVH, ROP, PVL, NEC or sepsis. What is different though is the diagnosis of BPD yet there is no difference in total ventilation. In period 2 there is a shift towards more of this ventilation being HFOV less CPAP use at the same time. What Might It All Mean? It is retrospective and therefore we cannot be certain that there are not other variables that are not affecting the results that would have had a better chance of being evened out in an RCT. Having said that it is intriguing that having a PDA has been associated with BPD in the past but in this study having a PDA for a longer time is associated with a reduction in BPD. We know that longer periods of invasive mechanical ventilation increase the risk of developing BPD so it is intriguing that that there is no difference in mechanical ventilation yet there is more BPD when you are aggressive with the PDA. You might postulate that the need for surgery leads to greater need for ventilatory support and therefore damages the lungs but the needs for HFOV was higher in the second phase which at least hints that in terms of aggressiveness, Period 2 infants had a tougher go. The culprit may be the heart. In period 1 there was a significantly increased rate of myocardial dysfunction and need for inotropes following ligation. It could well be that left ventricular dysfunction led to pulmonary edema such that in the 24-28 hours after the surgery ventilator requirements were increased and damaged the lung. The lack of a difference in overall ventilation days supports this possibility. Looking at the other common risk factors for BPD such as chorioamnionitis and lack of antenatal steroids these are no different between groups. Although not statistically significant there are more male infants in period 2 which would usually tip the scales towards worse outcome as well. It does need to be stressed as well that the rate of surgical ligation is higher than any study I have come across so the contribution of the surgery itself to the disparate outcome needs to be seriously considered. What would I do? Despite this study and some others that have preceded it I am not at the point of saying we shouldn’t treat at all. Our own approach is to give prophylactic indomethacin to such babies and then for the most part if a PDA remains treat one more time but at all costs try and avoid ligation. An RCT sounds like it is in the works though comparing the two approaches so that will certainly be interesting to see. It is tough to say what the future holds but to any young trainees who are reading this, the next time you are asked what to do about a PDA you are well within your rights to suggest “Maybe we should do nothing”!
  8. Breast milk has many benefits and seems to be in the health care news feeds almost daily. As the evidence mounts for long term effects of the infant microbiome, more and more centres are insisting on providing human milk to their smallest infants. Such provision significantly reduces the incidence of NEC, mortality and length of stay. There is a trade-off though in that donor milk after processing loses some of it’s benefits in terms of nutritional density. One such study demonstrated nutritional insufficiencies with 79% having a fat content < 4 g/dL, 56% having protein content< 1.5 g/dL, and 67% having an energy density < 67 kcal/dL (< 20 Kcal/oz). It is for this reason that at least in our unit many infants on donor milk ultimately receive a combination of high fluid volumes, added beneprotein or cow’s milk powders to achieve adequate caloric intake. Without such additions, growth failure ensues. Such growth failure is not without consequence and will be the topic of a future post. One significant concern however is that failure of our VLBW infants to grow will no doubt impact the timing of discharge as at least in our unit, babies less than 1700g are unlikely to be discharged. With the seemingly endless stream of babies banging on the doors of the NICU to occupy a bed, any practice that leads to increasing lengths of stay will no doubt slow discharge and cause a swelling daily patient census. What if increasing volume was not an option? Such might be the case with a baby diagnosed with BPD. Medical teams are often reluctant to increase volumes in these patients due to concerns of water retention increasing respiratory support and severity of the condition. While diuretics have not been shown to be of long term benefit to BPD they continue to be used at times perhaps due to old habits or anecdotal experiences by team members of a baby who seemed to benefit. Such use though is not without it’s complications as the need to monitor electrolytes means more needle sticks for these infants subjecting them to painful procedures that they truly don’t need. Alternatively, another approach is to restrict fluids but this may lead to hunger or create little room to add enough nutrition again potentially compromising the long term health of such infants. Amy Hair and colleagues recently published the following study which takes a different approach to the problem Premature Infants 750–1,250 g Birth Weight Supplemented with a Novel Human Milk-Derived Cream Are Discharged Sooner This paper is essentially a study within a study. Infants taking part in an RCT of Prolacta cream (Prolacta being the subject of a previous post) were randomized as well to a cream supplement vs no cream. The cream had a caloric density of 2.5 Kcal/mL and was added to donor milk or mother’s own milk when the measured caloric density was less than 19 Kcal/oz. The study was small (75 patients; control 37, cream 38) which should be stated upfront and as it was a secondary analysis of the parent study was not powered to detect a difference in length of stay but that was what was reported here. The results for the groups overall were demonstrated an impact in length of stay and discharge with the results shown below. Control (N=37) Cream (N=38) p PDA ligation % 8.1 2.6 0.36 PDA treated medically % 27 29 0.85 Sepsis % 5.4 7.9 1 NEC% 0 0 – BPD% 32.4 23.7 0.4 Death % 0 0 – Length of stay, days 86+/-39 74+/-22 0.05 PMA at discharge, weeks 39.9+/-4.8 38.2+/-2.7 0.03 What about those with sensitivity to fluid? Before we go into that let me state clearly that this group comparison is REALLY SMALL (control with BPD=12 vs cream with BPD=9). The results though are interesting. BPD control (N=12) BPD cream N=9 p Length of stay, days 121 +/-49 104+/-23 0.08 PMA at discharge, weeks 44.2+/-6.1 41.3+/-2.7 0.08 So they did not reach statistical significance yet one can’t help but wonder what would have happened if the study had been larger or better yet the study was a prospective RCT examining the use of cream as a main outcome. That of course is what no doubt will come with time. I can’t help but think though that the results have biologic plausibility. Providing better nutrition should lead to better growth, enhanced tissue repair and with it earlier readiness for discharge. One interesting point here is that the method that was used to calculate the caloric density of milk was found to overestimate the density by an average of 1.2 Kcal/oz when the method was compared to a gold standard. Given that fortification with cream was only to be used if the caloric density of the milk fell below 19 Kcal/oz where average milk caloric density is 20 Kcal/oz there is the distinct possibility that the eligible infants for cream were underestimated. Could some of the BPD be attributable to infants being significantly undernourished in the control group as they actually were receiving <19 Kcal/oz but not fortified? Could the added fortification have led to faster recovery from BPD? Interesting question’s in need of answers. I look forward to seeing where this goes. I suspect that donor milk is not enough, adding a little cream may be needed for some infants especially those who have trouble tolerating cow’s milk fortification.
  9. Daniele Mezzetti

    morning fever in chronic bpd

    I am following an infant at home with chronic severe bpd; he's 11 months old, 7.5 months corrected age, on oxygen 23-27% plus inhaled steroids. He has morning fever from about 7:30 AM to 10:00. Remission is spontaneous, peak ranges from 37.5 °C to 38.5 °C. There is no evidence whatsoever of infection (CRP is null, the infant is well, urinalysis etc etc). This has happened from about three months now, with small fluctuations: some days there is no fever, but mostly there is, We thought that in some way the fever could be linked to some dehydration, but it has persisted after stopping diuretics and increasing hydration. I've seen a similar picture in a few other bpd babies, but never so lasting. Anyone?
  10. 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.
  11. Stefan Johansson

    Survey on vitamin A and BPD prevention

    We would like to invite all our members to join a short survey on parenteral vitamin A, as a preventive therapy against BPD in preterm infants. We are distributing the survey on behalf of Orphanix, an Austrian start-up company that is developing innovative medicines with a strong focus on neonatology. In return Orphanix will support 99nicu with an educational grant for 2016, a mostly welcome contribution! Please use this URL to complete the survey: https://www.surveymonkey.com/r/W8JG8BR
  12. I wonder about hands-on experience with sildenafil for ex-preterm infants with severe bronchopulmonary dysplasia. The literature is not very convincing, seems that right ventricular strain improves (echo) but that clinical benefits (the babies!) is less clear. http://www.ncbi.nlm.nih.gov/pubmed/25824807 http://www.ncbi.nlm.nih.gov/pubmed/25796626 http://www.ncbi.nlm.nih.gov/pubmed/21941230 Please share your comments and experience!
  13. I would like to hear about your choices when it comes to diuretics as BPD treatment. Which drugs and doses do you use?
  14. A one day study day covering hot topics in Neonatal ventilation Organised by the Evelina London Children's Hospital and King's College London Details: http://www.guysandstthomasevents.co.uk/paediatrics-training/neonatal-ventilation-updates-hot-topics-and-workshops/ A4 flyer - Neonatal Ventilation 2014 - low res.pdf
  15. monica

    Terminology of BPD

    Now we are writting the guide for the bronhopulmonary displasia and there are discussion about the terminology: BPD or pulmonary chronic lung diseases. Which term is correct?
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