I feel like this has been a story in the making for some time. Next to caffeine, the story of prophylactic hydrocortisone must be one of my more popular topics and has been covered more than once before as in A Shocking Change in Position. Postnatal steroids for ALL microprems or Early Hydrocortisone: Short term gain without long term pain. and the last post Hydrocortisone after birth may benefit the smallest preemies the most! After reporting on this topic about once a year, a recent paper may wrap it all up in a bow for the holidays and present to us the conclusion after all this work on the topic. I was extremely interested in this topic not just because I believe this therapy may have a future in the standard approach to neonatal care for VLBWs but because I have served on the CPS Fetus and Newborn committee with two of the authors of the paper. Dr. Lacaze and Dr. Watterberg have an exceptional understanding of this topic and so when they band together with other experts in the field I take notice.
An Individual Patient Data Meta-Analysis
If you have read my previous posts then you know the story of why hydrocortisone given over the first 10-12 days of life might help those born before 30 weeks or < 1250g. In essence the concept is that it has been shown previously that many infants with relative adrenal insufficiency may go on to develop BPD. If you treat all such infants at risk you could theoretically reduce BPD. Typically after a few studies examining a similar topic come out, one can combine them in a meta-analysis using aggregate data (averages of effect sizes for the individual studies) and see what the larger sample shows. Another way to do it though is to go back to the original data and examine the infants at a more granular level allowing a greater identification and control of variables that might influence outcomes. This is what the authors led my Michele Shaffer did here in the paper Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. There were a total of 5 studies on this topic but one study of 40 patients no longer had individual data so was excluded from analysis leaving 4 to look at. The details of the four studies are shown below. You can see that the inclusion criteria differed slightly but in general these were all infants up to 27 – 29 completed weeks and 500 – 1250g maximum who were treated with regimens as shown in the table.
What were the results?
Treatment with early low-dose hydrocortisone was associated with greater odds of survival without BPD at 36 weeks PMA after adjustment for sex, gestational age, and antenatal steroid use (aOR, 1.45; 95% CI, 1.11-1.90; I 2 = 0%). Also found were lower individual odds of BPD (aOR, 0.73; 95% CI, 0.54-0.98; I 2 = 0%), but not with a significant decrease in death before 36 weeks PMA (aOR, 0.76; 95% CI, 0.54-1.07; I 2 = 0%). Importantly although death by 36 weeks was not different, a decrease in death before discharge (aOR, 0.70; 95% CI, 0.51-0.97; I 2 = 0%) was found. Also noted and important was a reduction in medical treatment for PDA OR 0.72 (0.56-0.93)
All of these outcomes sound important but in a subgroup analysis other interesting findings emerged.
When dividing the patients into those less then 26 weeks and those at or greater than that gestational age, the benefits appear to be limited to those in the latter group. Levels of significance are high once you reach that GA suggesting that issues affecting those at younger gestational ages are less amenable to treatment. On the other hand one could say that the benefits seen at 26 – 29 weeks GA are relatively strong using a glass is half full approach. An important outcome worth noting is that while spontaneous intestinal perforation is noted to be a risk with prophylactic hydrocortisone, when you remove indomethacin from the equation the risk disappears. For those units using prophylactic hydrocortisone one would likely need to choose between the two but if you are like our unit where we don’t have that option this may be one strategy to consider.
In terms of risk to giving such therapy the big one noted in the paper was an increase in risk for late onset sepsis. Interestingly, this was limited though to the group under 26 weeks GA. In essence then the messaging would appear to be that under 26 weeks there may be less benefit to such treatment and therefore the increased risk of late onset sepsis without such benefits on BPD would suggest not using it in this GA group.
Where do we land then?
It would be easy to cast this aside I suppose as the group you are most worried about (22-25 weeks) doesn’t seem to really benefit but has a risk of late onset sepsis. That leaves us though with the group from 26-29 weeks. They do seem to benefit and may do so to a significant degree. They do develop BPD and to be honest we don’t have much outside of trying our best to use gentle ventilation to ameliorate their course in hospital. It is worth noting that the one group that does seem to show the greatest benefit are those exposed to chorioamnionitis. It is this group in particular that may be the best target for this intervention and I gather this has been discussed at a recent EPIQ meeting.
If one says no to trying this approach then the question that needs to be asked is whether doing nothing for this group is better than supporting them with hydrocortisone? If your centre’s rates of BPD are top notch then maybe you don’t want to add something in. If not though maybe it is time to rock the boat and try something different.
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!
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!
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?
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.
We can always learn and we can always do better. At least that is something that I believe in. In our approach to resuscitating newborns one simple rule is clear. Fluid must be replaced by air after birth and the way to oxygenate and remove CO2 is to establish a functional residual capacity. The functional residual capacity is the volume of air left in the lung after a tidal volume of air is expelled in a spontaneously breathing infant and is shown in the figure. Traditionally, to establish this volume in a newborn who is apneic, you begin PPV or in the spontaneously breathing baby with respiratory distress provide CPAP to help inflate the lungs and establish FRC.
Is there another way?
Something that has been discussed now for some time and was commented on in the most recent version of NRP was the concept of using sustained inflation (SI) to achieve FRC. I have written about this topic previously and came to a conclusion that it wasn’t quite ready for prime time yet in the piece Is It Time To Use Sustained Lung Inflation In NRP?
The conclusion as well in the NRP textbook was the following:
“There are insufficient data regarding short and long-term safety and the most appropriate duration and pressure of inflation to support routine application of sustained inflation of greater than 5 seconds’ duration to the transitioning newborn (Class IIb, LOE B-R). Further studies using carefully designed protocols are needed”
So what now could be causing me to revisit this concept? I will be frank and admit that whenever I see research out of my old unit in Edmonton I feel compelled to read it and this time was no different. The Edmonton group continues to do wonderful work in the area of resuscitation and expand the body of literature in such areas as sustained inflation.
Can you predict how much of a sustained inflation is needed?
This is the crux of a recent study using end tidal CO2 measurement to determine whether the lung has indeed established an FRC or not. Dr. Schmolzer’s group in their paper (Using exhaled CO2 to guide initial respiratory support at birth: a randomised controlled trial) used end tidal CO2 levels above 20 mmHg to indicate that FRC had been established. If you have less CO2 being released the concept would be that the lung is actually not open. There are some important numbers in this study that need to be acknowledged. The first is the population that they looked at which were infants under 32 6/7 weeks and the second is the incidence of BPD (need for O2 or respiratory support at 36 weeks) which in their unit was 49%. This is a BIG number as in comparison for infants under 1500g our own local incidence is about 11%. If you were to add larger infants closer to 33 weeks our number would be lower due to dilution. With such a large number though in Edmonton it allowed them to shoot for a 40% reduction in BPD (50% down to 30%). To accomplish this they needed 93 infants in each group to show a difference this big.
So what did they do?
For this study they divided the groups in two when the infant wouldn’t breathe in the delivery room. The SI group received a PIP of 24 using a T-piece resuscitator for an initial 20 seconds. If the pCO2 as measured by the ETCO2 remained less than 20 they received an additional 10 seconds of SI. In the PPV group after 30 seconds of PPV the infants received an increase of PIP if pCO2 remained below 20 or a decrease in PIP if above 20. In both arms after this phase of the study NRP was then followed as per usual guidelines.
The results though just didn’t come through for the primary outcome although ventilation did show a difference.
Duration of mechanical ventilation (hrs)
The reduction in hours of ventilation was impressive although no difference in BPD was seen. The problem though with all of this is what happened after recruitment into the study. Although they started with many more patients than they needed, by the end they had only 76 in the SI group and 86 in the PPV group. Why is this a problem? If you have less patients than you needed based on the power calculation then you actually didn’t have enough patients enrolled to show a difference. The additional compounding fact here is that of the Hawthorne Effect. Simply put, patients who are in a study tend to do better by being in a study. The observed rate of BPD was 33% during the study. If the observed rate is lower than expected when the power calculation was done it means that the number needed to show a difference was even larger than the amount they originally thought was needed. In the end they just didn’t have the numbers to show a difference so there isn’t much to conclude.
What I do like though
I have a feeling or a hunch that with a larger sample size there could be something here. Using end tidal pCO2 to determine if the lung is open is in and of itself I believe a strategy to consider whether giving PPV or one day SI. We already use colorimetric devices to determine ETT placement but using a quantitative measure to ascertain the extent of open lung seems promising to me. I for one look forward to the continued work of the Neonatal Resuscitation–Stabilization–Triage team (RST team) and congratulate them on the great work that they continue doing.