This past week I was very appreciative of efforts by readers on my Facebook page and Twitter accounts who were able to secure a copy of an article that really grabbed my attention. I could only go by the abstract at the time but the post suggesting that the use of azithromycin could reduce BPD garnered a lot of attention. Now that I have had a chance to read the paper I believe there are some very big caveats to that claim. What was done in this study I find very interesting and the results yield even more questions and make for what I think will be a great discussion.
In the most recent paper by Nunes CR et al Use of Azithromycin for the Prevention of Lung Injury in Mechanically Ventilated Preterm Neonates: A Randomized Controlled Trial, the authors set out again to test the effect of azithromycin on modulating risk for BPD. They used the results of the Ballard trial to determine a number needed in their power calculation and came up with 38 per group and achieved 40 so they were powered to find a difference. They incuded all neonates who met inclusion criteria (invasive MV within 72 h of birth and, necessarily, invasive ventilatory support for, at least, 12 h until randomization) who were born under 1500g and randomized them to five days of azithromycin vs placebo. The strength of the study was that they also measured cytokine levels before starting azithromycin and then at 5 days after treatment. It is the outcome of interest that really puzzles me. They chose oxygen dependency at 28 days as their outcome of interest rather than 36 weeks PMA which is the more modern choice of end point for BPD. They also chose a much shorter course of 5 days compared to the study by Ballard which had previously shown no difference in outcome which I find odd as well. The baseline characteristics given that this was a small study also revealed an important difference between the two groups.
The babies in the treatment arm were on average 1.5 weeks more mature at birth which matters a great deal when you are alking about BPD. Additionally they were about 200g larger in size which was close to reaching statistical significance. Otherwise the infants were the same and the authors eventually control for these differences in the final analysis but to me at least this seems like a stark difference between groups favouring a higher expected risk of BPD from the outset regardless of treatment arm.
The main outcomes are where the authors lay claim to finding support for the intervention. At 28 days there was a statistically significant reduction in both oxygen dependency and oxygen dependency/death. As shown below though those differences did not extend to 36 weeks for either outcome.
Not surprisingly there were other differences in the groups reflective of the younger patients in the placebo arm such as higher rates of postnatal steroid use and days of TPN. One strength I suppose here is that since both groups were exposed to mechanical ventilation durations that were not different when their cytokine profiles were checked the effect of invasive positive pressure might be similar between groups. What is not known however is the mean airway pressures between groups or for that matter if any were put on high frequency ventilation so we have quantity but not quality. One could postulate that while durations were similar over 5 days, the smaller and younger patients may have been exposed to much higher pressures and/or volumes which could of course influence degree of inflammation. Looking at the cytokine profiles is interesting nonetheless.
The cytokines IL-2 and 8 were found to be significantly lower in the treatment arm and in general all others at least trended in the same direction after completing treatment with azithromycin. With less inflammation it seems probable then that the reduction in need for O2 at 28 weeks might be real and after the autors controlled for such things as gestational age and weight the finding bore out but at 36 weeks (the more meaningful outcome) the difference was gone.
What can we take from the study
Am I ready to start azithromycin in all my infants under 1500g? Not yet. This study raises too many questions for this to become standard of care. It really troubles me that the authors here used a shorter duration of azithromycin than the Ballard study and then used a less meaningful outcome of 28 days to demonstrate their difference. While they did find a difference I am concerned that there is a bit of “smoke and mirrors” here in that there is a difference in an outcome that in todays world isn’t that meaningful. I cringe at saying this but what is really needed is a larger multicentre study in which hopefully the gestational ages and weights at the outset are balanced. Even if we didn’t see a big difference in outcome at 36 weeks for BPD I would wonder if the cytokine profiles showed similar trends whether other conditions such as ROP and PDAs which can also be influenced by inflammation would demonstrate a difference between groups. We need a larger sample size and balancing of factors such as tidal volumes and ventilator pressures though to answer this in a more conclusive manner.
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.
As a Neonatologist I doubt there are many topics discussed over coffee more than BPD. It is our metric by which we tend to judge our performance as a team and centre possibly more than any other. This shouldn’t be that surprising. The dawn of Neonatology was exemplified by the development of ventilators capable of allowing those with RDS to have a chance at survival. As John F Kennedy discovered when his son Patrick was born at 34 weeks, without such technology available there just wasn’t much that one could do. As premature survival became more and more common and the gestational age at which this was possible younger and younger survivors began to emerge. These survivors had a condition with Northway described in 1967 as classical BPD. This fibrocystic disease which would cripple infants gave way with modern ventilation to the “new bpd”.
The disease has changed to one where many factors such as oxygen and chorioamnionitis combine to cause arrest of alveolar development along with abnormal branching and thickening of the pulmonary vasculature to create insufficient air/blood interfaces +/- pulmonary hypertension. This new form is prevalent in units across the world and generally appears as hazy lungs minus the cystic change for the most part seen previously. Defining when to diagnose BPD has been a challenge. Is it oxygen at 28 days, 36 weeks PMA, x-ray compatible change or something else? The 2000 NIH workshop on this topic created a new approach to defining BPD which underwent validation towards predicting downstream pulmonary morbidity in follow-up in 2005. That was over a decade ago and the question is whether this remains relevant today.
I don’t wish to make light of the need to track our rates of BPD but at times I have found myself asking “is this really important?” There are a number of reasons for saying this. A baby who comes off oxygen at 36 weeks and 1 day is classified as having BPD while the baby who comes off at 35 6/7 does not. Are they really that different? Is it BPD that is keeping our smallest babies in hospital these days? For the most part no. Even after they come off oxygen and other supports it is often the need to establish feeding or adequate weight prior to discharge that delays things these days. Given that many of our smallest infants also have apnea long past 36 weeks PMA we have all seen babies who are free of oxygen at 38 weeks who continue to have events that keep them in hospital. In short while we need to be careful to minimize lung injury and the consequences that may follow the same, does it matter if a baby comes off O2 at 36, 37 or 38 weeks if they aren’t being discharged due to apnea or feeding issues? It does matter for benchmarking purposes as one unit will use this marker to compare themselves against another in terms of performance. Is there something more though that we can hope to obtain?
When does BPD matter?
The real goal in preventing BPD or at least minimizing respiratory morbidity of any kind is to ensure that after discharge from the NICU we are sending out the healthiest babies we can into the community. Does a baby at 36 weeks and one day free of O2 and other support have a high risk of coming back to the hospital after discharge or might it be that those that are even older when they free of such treatments may be worse off after discharge. The longer it takes to come off support one would think, the more fragile you might be. This was the goal of an important study just published entitled Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. This work is yet another contribution to the pool of knowledge from the Canadian Neonatal Network. In short this was a retrospective cohort study of 1503 babies born at <29 weeks GA who were assessed at 18-21 months of age. The outcomes were serious respiratory morbidity defined as one of:
(1) 3 or more rehospitalizations after NICU discharge owing to respiratory problems (infectious or noninfectious);
(2) having a tracheostomy
(3) using respiratory monitoring or support devices at home such as an apnea monitor
or pulse oximeter
(4) being on home oxygen or continuous positive airway pressure at the time of assessment
While neurosensory impairment being one of:
(1) moderate to severe cerebral palsy (Gross Motor Function Classification System ≥3)
(2) severe developmental delay (Bayley Scales of Infant and Toddler
Development Third Edition [Bayley III] composite score <70 in either cognitive, language, or motor domains)
3) hearing aid or cochlear implant use
(4) bilateral severe visual impairment
What did they find?
The authors looked at 6 definitions of BPD and applied examined how predictive they were of these two outcomes. The combination of oxygen and/or respiratory support at 36 weeks PMA had the greatest capacity to predict this composite outcome. It was the secondary analysis though that peaked my interest. Once the authors identified the best predictor of adverse outcome they sought to examine the same combination of respiratory support and/oxygen at gestational ages from 34 -44 weeks PMA. The question here was whether the use of an arbitrary time point of 36 weeks is actually the best number to use when looking at these longer term outcomes. Great for benchmarking but is it great for predicting outcome?
It turns out the point in time with the greatest likelihood of predicting occurrence of serious respiratory morbidity is 40 weeks and not 36 weeks. Curiously, beyond 40 weeks it becomes less predictive. With respect to neurosensory impairment there is no real difference at any gestational age from 34-44 weeks PMA.
From the perspective of what we tell parents these results have some significance. If they are to be believed (and this is a very large sample) then the infant who remains on O2 at 37 weeks but is off by 38 or 39 weeks will likely fair better than the baby who remains on O2 or support at 40 weeks. It also means that the risk of neurosensory impairment is largely set in place if the infant born at < 29 weeks remains on O2 or support beyond 33 weeks. Should this surprise us? Maybe not. A baby who is on such support for over 5 weeks is sick and as a result the damage to the developing brain from O2 free radical damage and/or exposure to chorioamnionitis or sepsis is done.
It will be interesting to see how this study shapes the way we think about BPD. From a neurosensory standpoint striving to remove the need for support by 34 weeks may be a goal worth striving for. Failure to do so though may mean that we at least have some time to reduce the risk of serious respiratory morbidity after discharge.
Thank you to the CNN for putting out what I am sure will be a much discussed paper in the months to come.
Producing milk for your newborn and perhaps even more so when you have had a very preterm infant with all the added stress is not easy. The benefits of human milk have been documented many times over for preterm infants. In a cochrane review from 2014 use of donor human milk instead of formula was associated with a reduction in necrotizing enterocolitis. More recently similar reductions have been seen in retinopathy of prematurity. Interestingly with respect to the latter it would appear that any amount of breast milk leads to a reduction in ROP. Knowing this finding we should celebrate every millilitre of milk that a mother brings to the bedside and support them when it does not flow as easily as they wish. While it would be wonderful for all mothers to supply enough for their infant and even more so that excess could be donated for those who can’t themselves we know this not to be the case. What we can do is minimize stress around the issue by informing parents that every drop counts and to celebrate it as such!
Why Is Breast Milk So Protective
Whether the outcome is necrotizing enterocolitis or ROP the common pathway is one of inflammation. Mother’s own milk contains many anti-inflammatory properties and has been demonstrated to be superior to formula in that regard by Friel and no difference exists between preterm and term versions. Aside from the anti-inflammatory protection there may be other factors at work such as constituents of milk like lactoferrin that may have a protective effect as well although a recent trial would not be supportive of this claim.
Could Mother’s Own Milk Have a Dose Response Effect in Reducing The Risk of BPD?
This is what is being proposed by a study published in early November entitled Influence of own mother’s milk on bronchopulmonary dysplasia and costs. What is special about this study and is the reason I chose to write this post is that the study is unusual in that it didn’t look at the effect of an exclusive human milk diet but rather attempted to isolate the role of mother’s own milk as it pertains to BPD. Patients in this trial were enrolled prospectively in a non randomized fashion with the key difference being the quantity of mothers own milk consumed in terms of a percentage of oral intake. Although donor breast milk existed in this unit, the patients included in this particular cohort only received mother’s own milk versus formula. All told, 254 infants were enrolled in the study. As with many studies looking at risks for BPD the usual culprits were found with male sex being a risk along with smaller and less mature babies and receipt of more fluid in the first 7 days of age. What also came up and turned out after adjusting for other risk factors to be significant as well in terms of contribution was the percentage of mother’s own milk received in the diet.
Every ↑ of 10% = reduction in risk of BPD at 36 weeks PMA by 9.5%
That is a really big effect! Now what about a reduction in costs due to milk? That was difficult to show an independent difference but consider this. Each case of BPD had an additional cost in the US health care system of $41929!
What Lesson Can be Learned Here?
Donor breast milk programs are a very important addition to the toolkit in the NICU. Minimizing the reliance on formula for our infants particularly those below 1500g has reaped many benefits as mentioned above. The availability of such sources though should not deter us from supporting the mothers of these infants in the NICU from striving to produce as much as they can for their infants. Every drop counts! A mother for example who produces only 20% of the needed volume of milk from birth to 36 weeks corrected age may reduce the risk of her baby developing BPD by almost 20%. That number is astounding in terms of effect size. What it also means is that every drop should be celebrated and every mother congratulated for producing what they can. We should encourage more production but rejoice in every 10% milestone.
What it also means in terms of cost is that the provision of lactation consultants in the NICU may be worth their weight in gold. I don’t know what someone performing such services earns in different institutions but if you could avoid two cases of BPD a year in the US I would suspect that nearly $84000 in cost savings would go a long way towards paying for such extra support.
Lastly, it is worth noting that with the NICU environment being as busy as it is sometimes the question “are you planning on breastfeeding?” may be missed. As teams we should not assume that the question was discussed on admission. We need to ask with intention whether a mother is planning on breastfeeding and take the time if the answer is “no” to discuss why it may be worth reconsidering. Results like these are worth the extra effort!