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!

Stubborn PDAs despite prophylactic indomethacin!

Stubborn PDAs despite prophylactic indomethacin!

As time goes by, I find myself gravitating to reviews of Canadian research more and more.  We have a lot of great research happening in this country of ours and especially when I see an author or two I know personally I find it compelling to review such papers.  Today is one of those days as the lead author for a paper is my colleague Dr. Louis here in Winnipeg.  Let me put his mind at ease in case he reads this by saying that what follows is not a skewering of the paper he just published using Canadian Neonatal Network data (CNN).  Over the last twenty years that I have had the privilege of working in the field of Neonatology we continue to discuss the same things when it comes to the PDA.  Does it really cause problems or is it an association for many outcomes? Does treatment make a difference?  If you treat then what should you use (ibuprofen, indomethacin, paracetamol)? When should you treat and if you treat early should it be in the first few days or right after birth using a prophylactic approach (provided within 12 hours of delivery)?  It is the prophylactic approach which is the subject of this post!

Why treat prophylactically?

The TIPP trial reported the results in 2001 of the study whose goal was to determine if prophylactic indomethacin use could improve neurosensory impairment at 18 months by reducing rates of severe IVH.  The results of the study are well known and showed that while the rates of severe IVH and PDA ligations were reduced through this approach, there was no actual effect on long term outcome.  The use of this approach fell off after that for many years but recently resurfaced as some units in Canada opted to start the practice again as the two benefits seen above appeared to be worth using the approach.  The thought from a family centred approach, was that eliminating the stress for families of informing them their tiny preterm infant had a serious intracranial bleed and potentially avoiding a surgical ligation with probably vocal cord impairment afterwards were good enough outcomes to warrant this practice.  Having used this approach myself I have to admit one consequence is that indomethacin was so effective at closing the PDA most of the time that over time one begins to assume the PDA is in fact closed and is less likely to go hunting for one when the baby is misbehaving later on in their course.  What if it didn’t close though?  Are there any predictors that can increase our index of suspicion?

Answering the question

The CNN provides a large database to look retrospectively to answer such a question.  In this article, the authors looked at a period from 2010 to 2015 including all infants < 28 weeks gestational age at birth yielding a very large sample of 7397 infants.  Of these 843 or 12% received prophylactic indomethacin and from there a little over half (465) still had a PDA.  From there, 367 received treatment with eventually 283 needing only medical, 11 having a PDA ligation and 73 having both medical and surgical closure.  From this analysis so far I can tell you that providing prophylactic indomethacin certainly does not guarantee closure!

When a myriad of risk factors were put into logistic regression a number of interesting risk factors arose accounting for more of less risk of a PDA that needed surgical ligation despite prophylactic treatment.  Much like all infants in the NICU, the risk for a persistent PDA was highest with declining GA.  The combination of outborn status and short interval of ruptured membranes predicted higher risk.  No doubt this is reflective of less frequent antenatal steroid use and even if provided time for it to work.  Looking at medical or surgical treatment, surfactant therapy increased risk which may be explained by an improvement in oxygenation contributing to increased left to right shunting as PVR drops.  Maternal hypertension and longer duration of rupture of membranes again play a role in reducing risk likely through the mechanism of the former increasing endogenous steroid production and the latter again allowing for steroids to be provided.

What can we learn from this paper?

I suppose the biggest benefit here is the realization that even with prophylactic indomethacin we are not assured of closure.  In particular if there is a lack of antenatal steroid use or a stressed fetus one should be vigilant for the PDA.  Interestingly, all of the risks seem to point towards antenatal steroid use.  The bottom line then is that this reinforces what is already known and should be the focus of improvement strategies for centres.  Increase the rate of antenatal steroid use and you will reduce the risk of a PDA even in the baby receives prophylactic indomethacin.  I am happy to report that our centre has taken one step towards this goal by reinforcing to our Obstetrical colleagues that when they receive a call from a referring centre and have a woman who might be in labour it is better to err on the side of caution and just give the steroid course.  If they are wrong on arrival then one can always repeat a course later on as we do although repeated courses of steroids are in and of themselves a contentious issue.  What can your centre do to improve your results when it comes to antenatal steroid coverage?

Continuous glucose monitoring in NICU may be around the corner

Continuous glucose monitoring in NICU may be around the corner

We sure do poke a lot of babies to test their blood glucose levels.  Some of these babies don’t have so much blood to spare either so checking sugars multiple times a day can drain the body of that precious blood they so need for other functions.  Taking too much can always be addressed with a blood transfusion but that as I see it may be avoidable so shouldn’t we do what we can to cut down on blood work? Those with diabetes will be familiar with a continuous glucose monitor (CGM) which is implanted in the skin and can stay in place up to 7 days.  The device does require calibration twice a day with a capillary sample to verify it is reading well but this saves a couple pokes a day for those who check four times a day.  Such a device could be useful in the NICU where those with hypoglycemia may be checked 6 or more times per day if they are either hypo or hyperglycemic.  Cutting this down to two a day would certainly we something worth striving for and if not for the reduction in blood loss then for the minimization of painful procedures.

Does it work in small babies?

A natural question for sure.Uettweller et al published Real-time continuous glucose monitoring reduces the duration of hypoglycemia episodes: a randomized trial in very low birth weight neonates. In babies with a BW < 1500g they were able to demonstrate in 43 babies (21 with traditional intermittent glucose checks vs 22 with CGM)  a  reduction in duration of hypoglycemia episodes per patient (CGM 44[10-140] min versus IGM 95[15-520] min, p<0.05). Moreover in this brief study of the first three days of life they also found a reduction in the total number of pokes per patient of 5 pokes (22 vs 16).  The numbers however are small and the duration short in only being three days so it did not provide a perfect answer as to whether this technology would work in babies from 500-750g reliably but certainly for older babies, continuous knowledge of the blood glucose in theory would allow for faster response to low sugars and as a result as evidenced by the results led to a decrease in time with a low blood glucose.

Improving on these results

Galderisi et al just published Continuous Glucose Monitoring in Very Preterm Infants: A Randomized Controlled Trial.  The study remains small at 50 and the target group ranging from 28-31 weeks (all < 1500g) but the study followed babies for a longer time frame of 7 days. This study employed an algorithm for adjustments in glucose infusion that required staff to first put data into an excel spreadsheet and then the predictive algorithm dictated whether to increase or decrease the rate of dextrose infusion.  In one arm, CGM results were unblinded and the practitioners relied on the rate of change to determine the predicted glucose 15 minutes into the future while in the blinded group the CGM was used but results were not available (retrospectively yes) so changes were made based on the usual practice of obtaining point of care results and modifying glucose infusion rates based on that result.  The primary outcome of interest here was percentage of time in the euglycemic range of 72 – 144 mg/dL (4-8 mmol/L).   Secondary outcomes were time spent hypo or hyperglycemic (mild hypoglycemia (M-HYPO) (47–71 mg/dL); severe hypoglycemia (S-HYPO) (<47 mg/dL); mild hyperglycemia (M-HYPER) (145–180 mg/dL); and severe hyperglycemia (S-HYPER) (>180 mg/dL)).  The study lasted a total of seven days allowing the use of one subcutaneous probe per patient as they can last one week after insertion.

How did the approaches compare?

As you might have expected, having a predictive model proved superior.  Overall after adjusting for sex, gestational age and weight mean time in target using the unblinded CGM was 83% [95% CI, 79%–87%] and of 71% [95% CI, 67%–76%] in B-CGM [P < .001]).

As for secondary outcomes one can see that the time spent in the hypo/hyper areas was much less as a percentage of time than using traditional methods of intermittent sampling.  One interesting outcome was that the total number of samples used over the study was an average of 2.4 tests per day in the unblinded group vs 2.59 per day in the intermittent sampling group which although statistically different does not seem to have much clinical impact.

A few questions remain

The idea of using an implanted CGM for infants in the NICU is one that excites me.  The lack of a reduction in pokes in a meaningful way is disappointing but I can’t help but wonder if the effect was different whether you were in the first or second half of the week.  What if glycemic control in these 29-31 week infants had stabilized by 2-3 days such that you only needed one or two glucose checks in the last half of the week per day?  The CGM requires calibration twice daily with POC samples so the lack of a difference my be due to those issues.  Future, calibration is rumoured to be possible with one sample so that may change.

There is no disputing though that the use of the predictive algorithm made a difference in terms of avoidance of hypo/hyperglycemic episodes.  A larger study would be needed to look at whether this impacts harm that may be associated with such variability such as IVH or ROP but it certainly is promising.  The biggest issue here is that I cannot see people manually inputting glucose readings on the CGM into an excel sheet in everyday practice.  For this to become widely adopted, a simplified approach to prediction would be required or even better a feedback loop whereby data from the CGM would relay to the infusion pump and rates adjusted automatically (with manual override available).

The use of CGM is coming though and I can’t help but think in the larger babies born to mothers with diabetes there would be a real heal sparing effect with these.  Might this be the next study?



Resuscitating before 22 weeks. It’s happening.

Resuscitating before 22 weeks. It’s happening.

Given that today is world prematurity day  it seems fitting to talk about prematurity at the absolute extreme of it.

It has been some time since as a regional program we came to accept that we would offer resuscitation to preterm infants born as early as 23 weeks gestational age.  This is perhaps a little later in the game that other centers but it took time to digest the idea that the rate of intact survival was high enough to warrant a trial of resuscitation.  This of course is not a unilateral decision but rather a decision arrived at after consultation with the family and interprofessional team.  To be sure it is not an easy one.  Other centers have argued that resuscitation should be offered to those infants as young as 22 weeks gestational age and data now exists due to enough centres doing so to provide families with some guidance as to expected survival rates and importantly the likelihood of disability. This topic has been covered previously in /2015/09/25/winnipeg-hospital-about-to-start-resuscitating-infants-at-23-weeks/. Why cover this topic again?  Well an article on CNN might have something to do with it.

Resuscitating Below 22 weeks

This week as I was perusing the news I came across a rather shocking article on CNN. Born before 22 weeks, ‘most premature’ baby is now thrivingThe article tells the tale of a baby delivered at 21 weeks and 4 days that now as a three year old is reaching appropriate milestones without any significant impairments.  It is a story that is filled with inspiration and so I am not mistaken I am delighted for this child and their family that this outcome has occurred.  When the lay press latches onto stories like this there is no doubt a great deal of sensationalism to them and in turn that gathers a lot of attention.  This in turn is a great thing for media.

A Few Caveats Though

With the exception of pregnancies conceived through IVF the best dating we have is only good to about +/- 5 days when an early first trimester ultrasound is performed or the date of the last menstrual period is fairly certain.  A baby though who is born at 21 weeks + 4 days may in fact be 22 +3 days or even more depending on when the dating was done (second trimester worse).  Let’s not take away though from the outcome being this good even at 22 weeks.  That is a pretty perfect outcome for this family but the point is that this baby may in fact be older than 21 weeks.

Secondly, there are millions of babies born each year in North America.  Some of these infants are born at 22 weeks.  How do they fare overall?  From the paper by Rysavy et al from 2015 the results are as follows.

If you look at the overall rate of survival it is on an average of 5.1%.  If you take a look though at those infants in whom resuscitation is provided that number increases to a mean of 23%.  Intact survival is 9% overall.  The odds aren’t great but they are there and I suspect the infant in the article is one of those babies.  Flipping the argument though to the glass is half empty, 91% of infants born at 22 weeks by best estimate who are offered resuscitation will have a moderate or severe disability or die. I am not saying what one should do in this situation but depending on how a family processes the data they will either see the 110 chance of intact survival as a good thing or a 9/10 chance of death or disability as a very bad thing.  What a family chooses though is anyone’s best guess.

Should we resuscitate below 22 weeks if the family wishes?

I guess in the end this really depends on a couple things.  First off, how certain are the dates?  If there is any degree of uncertainty then perhaps the answer is yes.  If the dates are firm then I at least believe there is a barrier at which futility is reached.  Perhaps this isn’t at 21 weeks as some patients may indeed be older but think about what you would offer if a family presented at 20 weeks and wanted everything done.  What if it were 19 weeks?  I suspect the point of futility for all lies somewhere between 19-21 weeks.

As I prepare to attend the annual meeting in Ottawa tomorrow for the Fetus and Newborn Committee I think it is prudent to point out just how difficult all of this is.  The current statement on Counselling and management for anticipated extremely preterm birth I think hits on many of these issues.  The statement is the product on not only the think tank that exists on this committee but was the product of a national consultation.  I know I may be biased since I sit on the committee but I do believe it really hits the mark.

Should we be thinking about resuscitating at 21 weeks?  For me the answer is one clouded by a whole host of variables and not one that can be easily answered here.  What I do think though is that the answer in the future may be a yes provided such infants can be put onto an artificial placenta.  Even getting a few more weeks of growth before aerating those lungs is necessary may make all the difference.  The NICUs of tomorrow certainly may look quite different than they do now.

In the Opioid Crisis is Burprenorphine The Answer?

In the Opioid Crisis is Burprenorphine The Answer?

It would seem that the Opioid crisis is continuing to be front and centre in the news.  Just today the President of the United States declared an Opioid Epidemic Emergency. Of course he was speaking primarily about the damage these drugs do on the family unit and those around them, the impact on the unborn child is significant as well.  If this sounds familiar it is because I have written about this topic recently and in the past in the posts A Magic Bullet to Reduce Duration of Treatment and Hospital Stays for Newborns With NAS and Mandatory Drug-Testing ni PRegnancy: Lesson learned.  I suppose I write about this topic often as at least where I work this is a problem which just won’t go away and takes up a tremendous amount of resources.

What Can a Large Data Set Tell us?

Pediatrix medical group that you may well be familiar with has a lot of data that can be mined from the hospitals in their network.  When it comes to buprenorphine there is a lot of data to look at.  In this case the question posed by VN Tolia et al in thier paper Antenatal methadone vs buprenorphine exposure and length of hospital stay in infants admitted to the intensive care unit with neonatal abstinence syndrome was whether there is a difference in infants born to mothers who have been exposed to methadone vs burprenorphine.  Specifically they chose to use length of stay as the primary outcome in a retrospective review of 3364 infants admitted for management of NAS.  Of these infants, 2202 (65%) were exposed to methadone and 1162 (34%) to buprenorphine.  Before we get into what the results actually were it is important to highlight what this study will not tell us.  By looking only at admissions for NAS we do not know whether the use of buprenorphine in mothers actually reduced admission for NAS so we are only speaking of the babies who were afflicted with NAS.

When looking at the two groups, the median length of stay was 24 days for the methadone group and 21 for the buprenorphine which was found to be significantly different.  In the secondary analysis another interesting finding (at least to me) was noted.  When looking at the percentage of babies with a length of stay > 30 days the difference was significant at 34% vs 22% for buprenorphine.  The authors here did a good job of doing their best to control for factors which could have influenced the results as they did a regression analysis to determine whether other factors such as gestational age, sex, type of treatment provided etc would explain the shortened length of stay and they found that it remained significant controlling for a wide variety of factors.

Is three days worth it?

It would be tempting to look at the 3 day median difference and shrug it off as no big deal.  Remember though that we are in an epidemic are we not?  What the study does not account for as well are the number of babies who could have been managed in a postpartum ward and also had a shortened length of stay.  Let’s look at a city though where about 100 babies are admitted a year with NAS.  A three day reduction in length of stay would translate into 300 patient days per year.  By simply changing the medication a woman is being treated with in pregnancy from methadone to buprenorphine we could save almost one NICU bed for the whole year.  That is nothing to sneeze at!  Moreover if the reduction in admission rates are also true another one, two or more beds per year could be spared depending on the effectiveness of the drug.

In the last post that spoke of using buprenorphine to treat NAS in babies I was concerned about the alcohol content of the syrup for administration in babies.  Here we are talking about treating women rather than babies so this is not a concern (plus they would not be taking the pediatric suspension).  I see little downside to using buprenorphine over methadone so the real question is how do we get the care providers for the mothers to make the switch?  I have a feeling that is coming sooner rather than later.