I had the opportunity recently to give a talk on strategies to reduce BPD in our preemie population. For the talk, I used as a springboard the recommendations for reducing BPD as laid out by the Evidence Based Practice for Improving Quality (EPIQ) group. There are far too many recommendations for optimal care to go through but the point of this post is to highlight one strategy that I think is deserving of discussion.
That volume targeted ventilation is recommended is no surprise. Setting a desired volume and allowing pressures to fluctuate rather than fixing a pressure and allowing volumes to fluctuate reduces the risk of both atelectotrauma and volutrauma. A recent paper Early volume targeted ventilation in preterm infants born at 22-25 weeks of gestational age has added further arguments in those at the smallest gestational ages by reducing episodes of hypocapnia and increasing likelihood of extubation by 24 hours compared to those on pressure limited ventilation.
Are Bigger Volumes Better With Time?
It is the second highlighted piece above that has left me scratching my head. Going way back to my residency I was taught that the ideal tidal volume is somewhere between 3.5 – 4.5 mL/kg and we should try and keep PIPs less than 35 cm H2O as an absolute maximum. In reality we typically would switch to the high frequency jet ventilator if pressures were increasing above 25 cm H2O in an effort to avoid volutrauma by increasing volumes further or barotrauma from excessive pressure. The main thrust of the argument was that big volumes hurt the lung so one is better off being gentle and inflating the lung with PEEP and then using the more gentle pulse of the HFJV after that. To be sure in the early stages of the neonatal course excessive volumes and pressure can commit the patient to a significant risk of BPD and meticulous attention to respiratory care is needed. The question for today is whether after 2 or 3 weeks of age, babies with developing lung injury need more volume on conventional ventilation or whether continuing on the HFJV is the way to go. I will let you in on a secret right away though. There is a systematic review on the subject.
The problem is it only includes one study from 1991 which is before antenatal steroids and surfactant as standards of care so not much to take from this paper.
As shown in the table above the needed tidal volumes rise over time. The PIPs remain acceptable (below the set limits) but the volumes rise to close to 6 mL/kg by three weeks of age. If these results are generalizable to our own population this would mean that using our units current levels of 3.5 – 4.5 mL/kg would leave these older infants short. If so is it any wonder we see high pCO2 triggering a need for HFJV. The authors conclude here that the progressive dilation of the trachea and proximal bronchi over time from ventilation increase dead space and are responsible for the rise in needed Vt.
One did not see a significant improvement in work of breathing until 7 mL/kg was reached and you can see a progressive rise in minute ventilation needed to maintain normocapnia over time. This study supports the previous one in suggesting that over time there is an increase in dead space and if we want to reduce air hunger which could be represented by work of breathing we need to consider higher volumes.
The Damage is Done
Its an imperfect science that we are looking at and there is no doubt there will be readers of this post that will cringe at the volumes being discussed. I think what this really comes down to is whether you think the damage is done by 2-3 weeks. We of course don’t officially classify babies as having BPD until 36 weeks but if we are being honest we often know or can predict which ones are destined to get it. Is it better for the babies to be put on high frequency ventilation for weeks or to be given some larger volumes on conventional ventilation? Hard to say based on the evidence as there really isn’t much to go by. One thing that does need to be considered is long term high frequency ventilation and the need for sedation. Many of our kids on weeks of such therapy need progressively more sedation and what effect does that have on the developing brain. On the other hand if excessive volumes even at 2-3 weeks lead to increased damage to the lungs are you risking a prolongation on the ventilator or increasing the need at some point for a tracheostomy?
In the end I don’t think at the moment anyone knows. If you move from one center to another though and see completely different approaches I hope that by reading this post you will at least understand where the differences in practice come from.
In the end we are all just trying to do what we believe is best for the baby.
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.
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.