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?
One of the most common conditions afflicting ex-preterm infants is chronic lung disease. Through advances in antenatal steroids, surfactant and modern ventilation we have done what we can to try and prevent this condition from occurring yet despite our best efforts CLD remains a common problem among those born at less than 1500g as is shown in the 2018 Canadian Neonatal Network data.
Primary prevention is of course the ideal strategy to reduce disease but when you try and your best and an infant still has chronic lung disease what is one to do? For now we bide our time focusing on nutrition and minimizing harm from ventilation. Something new is coming and I hope it comes soon.
Stem Cells to Heal BPD
My former colleague Bernard Thebaud has done much work already in this field. A recent review he was part of is a good starting point to bring you up to speed; Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges. As the field advances though and we continue to see additional animal trials such as the one I will discuss here, the interest in this field continues to grow. I was drawn to a recent paper on this topic as it is not dissimilar to another trial I wrote about in which stem cells were given via breastmilk intranasally to improve outcome after IVH; Can intranasal application of breastmilk cure severe IVH? In this new trial though instead of delivering stem cells in a cephalad direction they place the rat vertically to deliver the stem cells from wharton’s jelly to the trachea and damaged lung.
The results are quite impressive. Looking at the histology of the four different groups reveals the curative property of these types of cells.
In essence the lung tissue architecture at the alveolar level looks almost identical to normal rat lung on the far left if the stem cells are provided through the intranasal route.
Moreover, when one looks at the impact on the blood vessels in the lung using Von Willebrand Factor staining similar healing is observed.
Lastly, not only were the numbers of blood vessels recovered but the thickness of the smooth muscle was reduced to that of normal rats without BPD after such treatment.
Why is this so important?
Past research has delivered stem cell treatment to the alveoli through an endotracheal tube. What this demonstrates is that rats held in a vertical position can have stem cells delivered into the lung where they are sorely needed. Could one take an infant on CPAP who is developing signs of CLD and do the same? The day may be coming when we prevent such infants from being reintubated just for CLD in the future.
The road is long though and the use of stem cells in humans has not begun yet. The effects seen in this rat model are dramatic but will they translate into the same thing in the human? I believe so and am waiting ever so patiently for such trials to start in humans. If you are looking for the next big leap in Neonatology I suspect this is what we are looking at. The question now is when.
First off I should let you know that we do not do transpyloric feeding for our infants with BPD. Having said that I am aware of some units that do. I suspect the approach is a bit polarizing. A recent survey I posted to twitter revealed the following findings:
I think the data from this small poll reveal that while there is a bias towards NG feeds, there is no universal approach (as with many things in NICU).
Conceptually, units that are using transpyloric feeds would do so based on a belief that bypassing the stomach would lead to less reflux and risk of aspiration. The question though is whether this really works or not.
New N of 1 Trial
I don’t think I have talked about N of 1 trials before on this site. The trials in essence allow one patient to serve as a study unto themselves by randomizing treatments over time for the single patient. By exposing the patient to alternating treatments such as nasogastric or nasoduodenal feedings one can look at an outcome and get a sense of causality if a negative or positive outcome occurs during one of the periods consistently. That is what was done in the study Individualising care in severe bronchopulmonary dysplasia: a series of N-of-1 trials comparing transpyloric and gastric feeding by Jensen E et al from the Children’s Hospital of Philadelphia. The authors in this study determined that using a primary outcome of frequency of daily intermittent hypoxaemic events (SpO2 ≤80% lasting 10–180 s) they would need 15 patients undergoing N of 1 trials between nasogastric and nasoduodenal feeding. Included infants were born at <32 weeks and were getting positive airway pressure and full enteral nutrition at 36 0/7 to 55 6/7 weeks PMA. Infants who were felt to be demonstrating signs of reflux or frank regurgitation were enrolled.
Thirteen of 15 enrolled patients completed the study. The two who did not complete did so as their oxygen requirements increased shortly after starting the trial and the clinical team removed them and chose their preferred route of feeding. Randomization looked like this:
Of the 13 though that completed and using an intention to treat analysis of the other two the findings were somewhat surprising. Contrary to what one might have thought that transpyloric would be a lung protective strategy, the findings were opposite.
Overall the combined results from these 15 patients demonstrated that nasogastric feedings were protective from having intermittent hypoxic events.
How can this be explained?
To be honest I don’t really know but it is always fun to speculate. I can’t help but wonder if the lack of milk in the stomach led to an inability to neutralize the stomach pH. Perhaps distension has nothing to do with reflux and those with BPD who have respiratory distress with some degree of hyperinflation simply are prone to refluxing acid contents due to a change in the relationship of the diaphragmatic cura? It could simply be that while the volume in the stomach is less, what is being refluxed is of a higher acidity and leads to more bronchospasm and hypoxemic events.
What seems to be clear even with this small study is that there really is no evidence from this prospective trial that transpyloric feeding is better than nasogastric. Given the size of the study it is always worth having some degree of caution before embracing wholeheartedly these findings. No doubt someone will argue that a larger study is needed to confirm these findings. In the meantime for those who are routinely using the transpyloric route I believe what this study does at the very least is give reason to pause and consider what evidence you have to really support the practice of using that route.
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.
Much has been written about methylxanthines over the years with the main questions initially being, “should we use them?”, “how big a dose should we use” and of course “theophylline vs caffeine”. At least in our units and in most others I know of caffeine seems to reign supreme and while there remains some discussion about whether dosing for maintenance of 2.5 -5 mg/kg/d of caffeine base or 5 – 10 mg/kg/d is the right way to go I think most favour the lower dose. We also know from the CAP study that not only does caffeine work to treat apnea of prematurity but it also appears to reduce the risk of BPD, PDA and duration of oxygen therapy to name a few benefits. Although initially promising as providing a benefit by improving neurodevelopmental outcomes in those who received it, by 5 and 11 years these benefits seem to disappear with only mild motor differences being seen.
Turning to a new question
The new query though is how long to treat? Many units will typically stop caffeine somewhere between 33-35 weeks PMA on the grounds that most babies by then should have outgrown their irregular respiration patterns and have enough pulmonary reserve to withstand a little periodic breathing. Certainly there are those who prove that they truly still need their caffeine and on occasion I have sent some babies home with caffeine when they are fully fed and otherwise able to go home but just can’t seem to stabilize their breathing enough to be off a monitor without caffeine. Then there is also more recent data suggesting that due to intermittent hypoxic episodes in the smallest of infants at term equivalent age, a longer duration of therapy might be advisable for these ELBWs. What really hasn’t been looked at well though is what duration of caffeine might be associated with the best neurodevelopmental outcomes. While I would love to see a prospective study to tackle this question for now we will have to do with one that while retrospective does an admirable job of searching for an answer.
The Calgary Neonatal Group May Have The Answer
Lodha A et al recently published the paper Does duration of caffeine therapy in preterm infants born ≤1250 g at birth influence neurodevelopmental (ND) outcomes at 3 years of
age? This retrospective study looked at infants under 1250g at birth who were treated within one week of age with caffeine and divided them into three categories based on duration of caffeine therapy. The groups were as follows, early cessation of caffeine ≤ 14 days (ECC), intermediate cessation of caffeine 15–30 days (ICC), and late cessation of
caffeine >30 days (LCC). In total there were 508 eligible infants with 448 (88%) seen at 3 years CA at follow-up. ECC (n = 139), ICC (n = 122) and LCC (n = 187). The primary outcome here was ND at 3 years of age while a host of secondary outcomes were also examined such as RDS, PDA, BPD, ROP as typical morbidities. It made sense to look at these since provision of caffeine had previously been shown to modify such outcomes.
Did they find a benefit?
Sadly there did not appear to be any benefit regardless of which group infants fell in with respect to duration of caffeine when it came to ND. When looking at secondary outcomes there were a few key differences found which favoured the ICC group. These infants had the lowest days of supplemental oxygen, hospital stay ROP and total days of ventilation. This middle group also had a median GA 1 week older at 27 weeks than the other two groups. The authors however did a logistic regression and ruled out the improvement based on the advanced GA. The group with the lowest use of caffeine had higher number of days on supplemental oxygen and higher days of ventilation on average than the middle but not the high caffeine group. It is tempting to blame the result for the longer caffeine group on these being babies that were just sicker and therefore needed caffeine longer. On the other hand the babies that were treated with caffeine for less than two weeks appear to have likely needed it longer as they needed longer durations of oxygen and were ventilated longer so perhaps were under treated. What is fair to say though is that the short and long groups having longer median days of ventilation were more likey to have morbidities associated with that being worse ROP and need for O2. In short they likely had more lung damage. What is really puzzling to me is that with a median GA of 27-28 weeks some of these kids were off caffeine before 30 weeks PMA and in the middle group for the most part before 32 weeks! If they were in need of O2 and ventilation for at least two weeks maybe they needed more caffeine or perhaps the babies in these groups were just less sick?
What is missing?
There is another potential answer to why the middle group did the best. In the methods section the authors acknowledge that for each infant caffeine was loaded at 10 mg/kg/d. What we don’t know though is what the cumulative dose was for the different groups. The range of dosing was from 2.5-5 mg/kg/d for maintenance. Lets say there was an over representation of babies on 2.5 mg/kg/d in the short and long duration groups compared to the middle group. Could this actually be the reason behind the difference in outcomes? If for example the dosing on average was lower in these two groups might it be that with less respiratory drive the babies in those groups needed faster ventilator rates with longer durations of support leading to more lung damage and with it the rest of the morbidities that followed?
It would be interesting to see such data to determine if the two groups were indeed dosed on average lower by looking at median doses and total cumulative doses including miniloads along the way. We know that duration may need to be prolonged in some patients but we also know that dose matters and without knowing this piece of information it is tough to come to a conclusion about how long exactly to treat.
What this study does though is beg for a prospective study to determine when one should stop caffeine as that answer eludes us!
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!