Hydrocortisone after birth may benefit the smallest preemies the most!
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By AllThingsNeonatal in All Things NeonatalThis 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!
By AllThingsNeonatal in All Things NeonatalIntubation is not an easy skill to maintain with the declining opportunities that exist as we move more and more to supporting neonates with CPAP. In the tertiary centres this is true and even more so in rural centres or non academic sites where the number of deliveries are lower and the number of infants born before 37 weeks gestational age even smaller. If you are a practitioner working in such a centre you may relate to the following scenario. A woman comes in unexpectedly at 33 weeks gestational age and is in active labour. She is assessed and found to be 8 cm and is too far along to transport. The provider calls for support but there will be an estimated two hours for a team to arrive to retrieve the infant who is about to be born. The baby is born 30 minutes later and develops significant respiratory distress. There is a t-piece resuscitator available but despite application the baby needs 40% oxygen and continues to work hard to breathe. A call is made to the transport team who asks if you can intubate and give surfactant. Your reply is that you haven’t intubated in quite some time and aren’t sure if you can do it. It is in this scenario that the following strategy might be helpful.
Surfactant Administration Through and Laryngeal Mask Airway (LMA)
Use of an LMA has been taught for years in NRP now as a good choice to support ventilation when one can’t intubate. The device is easy enough to insert and given that it has a central lumen through which gases are exchanged it provides a means by which surfactant could be instilled through a catheter placed down the lumen of the device. Roberts KD et al published an interesting unmasked but randomized study on this topic Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial. Due to size limitations (ELBWs are too small to use this in using LMA devices) the eligible infants included those from 28 0/7 to 35 6/7 weeks and ≥1250 g. The infants needed to all be on CPAP +6 first and then fell into one of two treatment groups based on the following inclusion criteria: age ≤36 hours,
(FiO2) 0.30-0.40 for ≥30 minutes (target SpO2 88% and 92%), and chest radiograph and clinical presentation consistent with RDS.
Exclusion criteria included prior mechanical ventilation or surfactant administration, major congenital anomalies, abnormality of the airway, respiratory distress because of an etiology other than RDS, or an Apgar score <5 at 5 minutes of age.
Procedure & Primary Outcome
After the LMA was placed a y-connector was attached to the proximal end. On one side a CO2 detector was placed and then a bag valve mask in order to provide manual breaths and confirm placement over the airway. The other port was used to advance a catheter and administer curosurf in 2 mL aliquots. Prior to and then at the conclusion of the procedure the stomach contents were aspirated and the amount of surfactant determined to provide an estimate of how much surfactant was delivered to the lungs. The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life. Treatment failure was defined upfront and required 2 of the following: (1) FiO2 >0.40 for >30
minutes (to maintain SpO2 between 88% and 92%), (2) PCO2 >65 mmHg on arterial or capillary blood gas or >70 on venous blood gas, or (3) pH <7.22 or 1 of the following: (1) recurrent or severe apnea, (2) hemodynamic instability requiring pressors, (3) repeat surfactant dose, or (4) deemed necessary by medical provider.
Did it work?
It actually did. Of the 103 patients enrolled (50 LMA and 53 control) 38% required intubation in the LMA group vs 64% in the control arm. The authors did not reach their desired enrollment based on their power calculation but that is ok given that they found a difference. What is really interesting is that they found a difference in the clinical end point despite many infants clearly not receiving a full dose of surfactant as measured by gastric aspirate. Roughly 25% of the infants were found to have not received any surfactant, 20% had >50% of the dose in the stomach and the other 50+% had < 10% of the dose in the stomach meaning that the majority was in fact deposited in the lungs. I suppose it shouldn’t come as a surprise that among the secondary outcomes the duration length of mechanical ventilation did not differ between two groups which I presume occurred due to the babies needing intubation being similar. If you needed it you needed it so to speak. Further evidence though of the effectiveness of the therapy was that the average FiO2 30 minutes after being treated was significantly lower in the group with the LMA treatment 27 vs 35%. What would have been interesting to see is if you excluded the patients who received little or no surfactant, how did the ones treated with intratracheal deposition of the dose fare? One nice thing to see though was the lack of harm as evidenced by no increased rate of pneumothorax, prolonged ventilation or higher oxygen.
Should we do this routinely?
There was a 26% reduction in intubations in te LMA group which if we take this as the absolute risk reduction means that for every 4 patients treated with an LMA surfactant approach, one patient will avoid intubation. That is pretty darn good! If we also take into account that in the real world, if we thought that little of the surfactant entered the lung we would reapply the mask and try the treatment again. Even if we didn’t do it right away we might do it hours later.
In a tertiary care centre, this approach may not be needed as a primary method. If you fail to intubate though for surfactant this might well be a safe approach to try while waiting for a more definitive airway. Importantly this won’t help you below 28 weeks or 1250g as the LMA is too small but with smaller LMAs might this be possible. Stay tuned as I suspect this is not the last we will hear of this strategy!
By Stefan Johansson in Reflections incubated in the 99nicu HQI would like to open a secret box of mine
Like many others, I have been trying to get hold on a probiotics product for the preterm infants I care for. For years.
I discussed the lack of a suitable probiotics product with Philipp Novak, founder of the orphan drug start-up company Orphanix, and together we set out on a mission - to provide a probiotics product specifically designed for preterm infants. In a non-profit business model, "from the community - to the community"
Since early 2016, we have been working with this project, framed within Neobiomics AB, our non-profit company registered in Sweden.
Thanks to our supportive CSR partners, we have reached the final stages of the project. The product will go into production according to GMP and in an FDA-approved facility during Q4-2017.
By Stefan Johansson in Reflections incubated in the 99nicu HQAs 2017 comes to an end, I'd like to post an update on the probiotics project.
You may have read previous blog posts about Neobiomics (here and here), a not-for-profit project that will provide probiotics specifically manufactured for preterm infants, “from the community, to the community”. Launch is planned for Q1 2019.
The probiotics will fulfill specific needs:
three bacterial strains documented in a large clinical trial (i.e. the ProPrems trial) manufactured according to GMP, fulfilling the highest possible quality grade (21 CFR Part 106, “Infant Formula grade”) freeze-dried bacterias with superior stability and long shelf-life single dose units (aluminium foil stickpack) to virtually eradicate the risk of contamination If you would be interested to use this probiotics product in your NICU, visit this page and submit the form to ensure yourself to learn when this product will become available.
That's all for now about this exciting project
By AllThingsNeonatal in All Things Neonatal
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.
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!
09 March 2018 Until 10 March 2018
Oxygen And Ventilation
22 March 2018
0The 2018 Stockholm Conference on Ultra-Early Intervention
Pleasurable feeding for premature infants:
- Food for thought!
Thursday 22 March in Nanna Svartz Aula, ”Old” Karolinska University Hospital in Solna
The 9th Stockholm Conference on Ultra-Early Intervention will 2018 continue the theme on how to achieve the optimal long-term outcomes by an active involvement of families in the care of the newborn infant. . There will be a section for short presentations.
The conference with handouts will be available free on the Internet two weeks after the meeting as in previous years. We usually have 2-3,000 visitors from all over the world. Please view 2017 Ultra-Early: http://ultra-early-intervention.creo.tv/2017/ultra-early-convention
Registration and submission of abstracts by mail to firstname.lastname@example.org
Deadline is 28 February 2018
Conference fee is 3000 SEK, including coffee, lunch and conference dinner [corresponding fee for accepted speakers for the short presentations is SEK 1100]. Conference language is English.
Stina Klemming, Björn Westrup, Ann-Sofi Ingman, Veronica Berggren and Lena Westas
09 April 2018 Until 12 April 2018
2Welcome to the “Future of Neonatal Care – advancing the management of newborns”,
in Vienna, 9-12 April 2018!
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23 April 2018 Until 26 April 2018
0Barnveckan 2018 i Västerås
Neonatologiprogram med bl.a. inledningstalare samt föreläsare Professor Lex Doyle, Australien samt Edward Shepherd, MD, USA om Ohio-modellen/BPD
se det preliminära programmet på www.barnveckan.se
och följ på instagram: barnveckan2018
17 May 2018 Until 18 May 2018
02ND NEONATAL NEUROLOGY CONFERENCE
Neonatal neurology is ever evolving and new knowledge is always emerging. Assessment techniques have become more advanced. Newer imaging modalities are increasingly used to help map the extent of brain injury and its implications for neurodevelopment. This meeting lines up exciting talks from experts in the field.
More info on: https://www.lutonneocon.co.uk/fom-neurology