Evidence-based Practice for Improving Quality or EPIQ is a collaborative group here in Canada that is producing incredible work to examine the evidence to come up with the best approaches for treating conditions. One such target has been bronchpulmonary dysplasia or BPD. I was sent a document recently summarizing this work and thought it was definitely worth sharing with the masses.
Especially as we are all locked in somewhat with the expansion of COVID-19, a post on a lung disease seemed apropos. Our babies keep being born and with some preterm and at risk of developing BPD, what can you do to try and prevent this condition and moreover if an infant has developed it, what can we do to limit its severity and begin the healing phase?
Choosing to provide postnatal systemic steroids to preterm infants for treatment of evolving BPD has given many to pause before choosing to administer them. Ever since K Barrington published his systematic review The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. and found a 186% increase in risk of CP among those who received these treatments, efforts have been made to minimize risk when these are given. Such efforts have included shortening the exposure from the length 42 day courses and also decreasing the cumulative dose of dexamethasone. Fortunately these efforts have led to findings that these two approaches have not been associated with adverse neurodevelopmental outcomes. Having said that, I doubt there is a Neonatologist that still doesn’t at least think about long term outcome when deciding to give dexamethasone. The systemic application certainly will have effects on the lung but the circulating steroid in the brain is what occupies our thoughts.
All of the included studies used a prophylactic approach of giving between the first 4 hours and the 14th day of postnatal age doses of pulmonary steroids with the goal of preventing death or BPD. The GA of enrolled infants ranged from 26 to 34 weeks, and the birth weight ranged from 801 to 1591 g. Out of 870 possible articles only 12 made the cut and compromised the data for the analysis.
Routes of steroid were by inhalation, liquid instillation though the endotracheal tube or by mixing in surfactant and administering through the ETT.
What Did They Find?
Using 36 weeks corrected age as a time point for BPD or death, the forrest plot demonstrated the following. A reduction in risk of BPD or death of 15% with a range of 24% to only a 4% reduction.
Looking at the method of administration though is where I find things get particularly interesting.
What this demonstrates is that how you give the steroids matters. If you use the inhalational or intratracheal instillation (without a vehicle to distribute the steroids) there is no benefit in reduction of BPD or death. If however you use a vehicle (in both Yeh studies it was surfactant) you find a significant reduction in this outcome. In fact if you just look at the studies by Yeh the reduction is 36% (CI 34 – 47%). In terms of reduction of risk these are big numbers. So big one needs to question if the numbers are real in the long run.
Why might this work though?
In the larger study by Yeh, budesonide was mixed with surfactant and delivered to intubated infants every 8 hours until FiO2 was less than 30%, they were extubated or a maximum of 6 doses were reached. We know that surfactant spreads throughout the lung very nicely so it stands to reason that the budesonide could have been delivered evenly throughout the lung. Compare this with inhalational steroid that most likely winds up on the plastic tubing or proximal airway. The anti-inflammatory nature of steroids should decrease damage in the distal airways offsetting the effects of positive pressure ventilation.
I am excited by these findings (if you couldn’t tell). What we don’t know though is whether the belief that the steroid stays in the lung is true. Are we just making ourselves feel better by believing that the steroid won’t be absorbed and move systemically. This needs to be tested and I believe results of such testing will be along in the near future.
Secondly, we need a bigger study or at least another to add to the body of research being done. Such a study will also need long term follow-up to determine if this strategy does at least have equal neurodevelopmental outcomes to the children who don’t receive steroid. The meta-analysis above does show in a handful of studies that long term outcome was no different but given the history of steroids here I suspect we will need exceptionally strong evidence to see this practice go mainstream.
What I do believe is whether you choose to use steroids prophylactically using hydrocortisone or using intratracheal surfactant delivered budesonide, we will see one or both of these strategies eventually utilized in NICUs before long.
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!