An Old Drug Finds A New  Home In The Treatment of BPD.

An Old Drug Finds A New Home In The Treatment of BPD.

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 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!

Can a chest x-ray predict the future?

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.