Bronchopulmonary Dysplasia in preterm infants - do you use the new definitions proposed in 2019 by Jensen? What do you think about it?
Join our Webinar Journal Club on neonatal airway management, 9 June at 1630-1715 CET, with the great panelists Joyce O’Shea, Charles Christoph Roehr, Gemma Edwards and Alexandra Scrivens!
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Latest Blog Entries
By Jelli KA in Bubbly Girl in NICUFantastic put together webinar by neonatal transport Seneo work neonatal transport group. Here are some favorite suggestions.
🔷Blanky with mum swell
🔷Thank the Drivers : Be aware of G force driver have take with sudden break.
🔹Consider 🚑 design allow all to have a better transport experience.
From my perspective it was Interesting the neonatal transport Landscape is diverse from the pioneering region Catalonia that NICU/PICU in 1995(🟢) to other regions that don’t. For example, Galicia have a private providers. Madrid & Valencia have dedicated Neonatal teams ( light 🔵). Some team's like the Balear region team have available helicopters/planes. Below is map showing the situation.Regions in
🛑 done by regional Emergency Teams.
Benchmarking there work in a effort to improve the quality, provide constructive feedback and find ways to better ways to collaborate. Benchmarking and humanize care are interlinked with each other.
They also underlined that need to keep in constant communication between the transport teams and the coordination hub.
By AllThingsNeonatal in All Things NeonatalGiving bronchodilators to preemies on a ventilator has certainly been tried before. The major issue to contend with is getting the drug to where it is supposed to be. Anyone reading who has a child with asthma knows that you should use an aerochamber when taking a puff to help with better distribution to the lung. Giving a puff or two without it largely ends up on the back of the throat. Similarly, giving puffs through an endotracheal tuberaises questions about how much of the medication winds up on the plastic tube rather than the smooth muscle of the airways where the medication is intended to be. This has been looked at in a cochrane review as well entitled Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants
Can Albuterol Save The Day?
Albuterol is a beta agonist much like ventolin that can act on the smooth muscle of airways to achieve bronchodilation. Considering that preemies with immature lungs may have issues with both resistance and compliance, Raffay TM et al in their paper Response to first dose of inhaled albuterol in mechanically ventilated preterm infants chose to examine responsiveness in a group of 33 infants (all < 30 weeks at birth) to albuterol. Ideally, responsiveness would be done by pulmonary function testing but given that this was not possible in these infants they chose to examine other indicators of impact. After giving two puffs of 90 mcg of albeterol via a metered dose inhaler without an aerochamber the authors looked at changes in FiO2 as well as compliance and resistance measurements on the ventilator as a means of determining responsiveness. Ultimately, could they get drug into the distal airway in patients who were ventilated at about a month of age as shown in table 1 along with other baseline characteristics?
What makes this different than other studies I suppose is the use of the ventilator measurements and their use of histogram data on oxygen saturation to ascertain responsiveness to treatment. This was an observational study based on a secondary analysis of a previous study so we don’t have sham controls to compare to. Having said that by administering the medication and seeing what happens immediately afterwards it is possibile to get a sense of whether the drug had an effect.
So What if Any Effect Did It Have?
From the figure in the paper the answer is some effect. Overall, post albuterol resistance for the 33 patients overall was found to decrease. Compliance and FiO2 (not shown in the graphs below) did not change though. What did change however was the percentage of time spent below 80 and 85% respectively comparing a 4 hour window pre and a 4 hour window post with respect to histograms from the patient monitor.
Putting it together
Ok so this isn’t a gold standard RCT looking at placebo treatments vs albuterol. It is hypothesis generating though as if resistance was decreased by albuterol one could expect improved delivery of O2 to the distal alveoli and therefore better oxygenation which is what is seen here. Should we be surprised that no difference in compliance is seen with albuterol therapy? I don’t think so as the effect of the drug is not on the distal alveoli and parenchyma but rather the more proximal branching airways. SInce airway resistance is governed by Poiseuille’s Law (you thought physics was over in high school?!) you can see that resistance (R) is directly proportional to the viscosity (n) and length (l) of the airway but inversely affected by the radius (r) to the 4th power. In other words if the radius of the airway after albuterol increases by 25% that effect is amplified to the 4th power in terms of reducing resistance.
I suppose I am buying what they are selling here but again the key is finding a method of getting the drug to deposit not in the trachea or proximal bronchi but to the lower airways. I can’t help but wonder if use of high frequency jet ventilation which carries flow down the centre of the airway might be a very effective way of getting such puffs further into the lung. Speculation of course but perhaps someone a little more creative than I can figure out how to do that and test deposition.
Should we use this routinely? Probably not as an everyday approach but it does make me wonder about those babies who are having a bad day so to speak. If one can glean from the ventilator that resistance has increased from one day to another might this be something worth trying? The authors found that the first treatment was effective but second and third not so much so to me this may just be a “hail mary” that is worth trying when nothing else seems to be working to reduce FiO2 in the presence of increased resistance.
If anyone is doing this routinely I would be curious in hearing your own experiences.
By AllThingsNeonatal in All Things NeonatalA couple years back at the Canadian Pediatric Society annual meeting a discussion broke out about extubating infants to higher levels of CPAP. Conventional thinking had been to use levels between 5 – 8 cm H2O typically. I shared with the group the experience we had in Winnipeg (unpublished) of using higher levels from 9 -12 cm H2O with some degree of success in allowing earlier extubation. The group thought it was interesting but pointed out the lack of robust research in the area so were not so keen to “try it out”. Non-invasive positive pressure ventilation (NIPPV) has been used for some time in the neonatal world and has been compared to CPAP for extubation success and found to be superior as in this review Comparison of Complications and Efficacy of NIPPV and Nasal CPAP in Preterm Infants With RDS. In this review though as in others more typical CPAP levels are used so the question is whether the same efficacy would be seen with high level CPAP vs NIPPV.
Canadian Study to the Rescue
The study here is by Ahmad HA et al Comparison of High CPAP versus NIPPV in Preterm
Neonates: A Retrospective Cohort Study and seeks to answer this question albeit in a retrospective fashion. The study is not well controlled since it is retrospective but it may be the best we have for now. Over a 3 year period the authors examined the outcomes for babies trialed on high CPAP (hCPAP of at least 9 cm H20) vs NIPPV. In each case they looked at the first episode of use. The modalities could have been used for extubation or as a primary means of support. The primary outcome was failure of the modality as defined by either intubation or change to the other strategy within 7 days. A total of 53 infants received hCPAP vs 119 NIPPV. Why the big difference? Since this was retrospective and not randomized it was up to the individual practioner which modality they wanted to try. If the majority of the unit favoured NIPPV this is why there would be such a difference. Herein lies the benefit of the primary outcome as if “conventional wisdom” was wrong and the other modality would be better then we should see a greater movement to the other strategy or more intubations in one group suggesting superiority of one vs the other.
The groups however aren’t entirely equivalent at baseline. The babies in the hCPAP group are quite a bit smaller on the one hand which would favour the NIPPV group. On the other hand there is almost a significant difference in surfactant provision for the hCPAP arm which might favour the hCPAP group. The other thing also nearing statistical significance is when the intervention was trialed. The median time is 2 days for teh NIPPV group and 7 for hCPAP suggesting one may have been used more prophylactically and the other post extubation. Different strategies might make a difference to outcome? Also no infants received MIST or INSURE and all were started on traditional lower levels of CPAP prior to surfactant.
The results tell an interesting story (I think) with the primary outcome being no different 62% in the hCPAP vs 55% with NIPPV. Looking at the patient outcomes in the figure from the paper one gets a little more detail and can surmise how people viewed the two modalities as a strategy and can see they were a bit different.
There seems to have more confidence in the unit with NIPPV as a way to prevent intubation. For those that failed hCPAP 12/33 were intubated as the next step (about a third) while the other 2/3 were trialed on NIPPV. Looking at those started out on NIPPV, 38/66 were intubated directly 58% or almost 2/3 while 28/66 were trialed on hCPAP. Of the ones trialed on hCPAP 20/28 or 71% were still intubated. Comparatively of those who were changed from nCPAP to NIPPV 11/21 were intubated or about 50%.
The authors find no difference in the primary outcome which is true. The problem of course with this analysis though is that there was no standardization with determining when one would choose to intubate. This issue can really play with the results. Let’s say for example that one Neonatologist really believes for the most part that NIPPV is the mode that can really prevent intubation more than hCPAP. It is conceivable that the reason in crossover intubations are less with NIPPV is that people were willing to tolerate a slightly higher pCO2 or a couple more apneas since they believe the modality is best and the infant will “get better soon”. On the other hand, infants already on NIPPV who are deteriorating might be intubated more readily as the attending might think “this hCPAP is a bunch of malarky”
It is worth mentioning that the incidence of air leak was no different between the two, nor was NEC or feeding intolerance from exposing the babies to such high pressures.
The study doesn’t “prove” anything. I don’t see it as a complete waste though as it does a number of things. It does show that small infants can be managed with hCPAP in NICU without any significant increase in complications. It also sets the stage for a couple future prospective trials I can see. Firstly, a trial of traditional CPAP vs hCPAP is needed as some units don’t have access to NIPPV or simply don’t use. The second is a prospective trial with clear parameters for failure between hCPAP and NIPPV.
Lastly, the authors ran the NIPPV and CPAP off ventilators in the units. The work of breathing would be potentially different with the use of devices solely designed for CPAP with fluidic flips. It would be important to use optimal devices for both modalities in such a trial and I for one can’t wait to see them.
By AllThingsNeonatal in All Things NeonatalPrecision medicine is a growing field in which genetic factors, environment, metabolism and even lifestyle are taken into account when deciding who should receive a treatment or not. When it comes to bronchopulmonary dysplasia I believe anyone who works in Neonatal care can attest it is a mystery why some infants go on to develop BPD while others don’t. We do know that certain treatment strategies may increase risk such as using excessive volumes or pressure to ventilate and in the last 25 years the notion that your level of cortisol in the blood may make a difference as well. I have written about prophylactic hydrocortisone use before in Hydrocortisone after birth may benefit the smallest preemies the most! When looking at the literature thus far and taking into account the results of the individual patient meta-analysis the following table can be generated highlighting a summary of benefits.
The question thus becomes if there is benefit for some infants under 26 weeks and then for some that are 26 and 27 weeks but there is also risk of harm, is there a way to select out those who are most likely to benefit with the least risk of harm.
A baby’s initial cortisol level may be the answer
The PREMILOC study was a double-blond multicentred trial of 523 infants randomly assigned to either prophylactic hydrocortisone in the first 24 hours of life or placebo. All infants were under 28 weeks at birth and received 1 mg/kg/d of hydrocortisone 1 mg/kg/d for 7 days followed by 3 days of 0.5 mg/kg/d for three days. In a pre-planned study coming out of the PREMILOC study, researchers looked at the role of baseline cortisol in predicting response to treatment or risk of adverse outcomes.
What they found in examining baseline levels for both treatment and placebo groups was that a relationship exists between the baseline level and such outcomes.
From Table 4 they found a relationship between survival without BPD and a higher initial level of cortisol but found no such relationship in the treatment arm. The threshold of what was considered high was 880 nmol/L although the mean cortisol was in the 400-500 nmol/L range. in other words, if having adequate physiologic levels of cortisol is the goal and a baby already has that, giving more non-antiinflammatory dosing of hydrocortisone doesn’t yield benefit.
Similarly, when looking at side effects a positive correlation was found between higher baseline levels of cortisol and risk of grade III/IV IVH and spontaneous intestinal perforation. It would seem therefore that if a baby has the level of cortisol that they would normally have from a physiologic perspective they are no different than a placebo arm patient when given hydrocortisone as you bring them to where they need to be. When you double the dose however that they should have, side effects begin to rear their ugly head.
How can you use this information?
From personal conversations I know that many centres are struggling with what to do about giving hydrocortisone. On the one hand there isn’t much benefit (if at all) for BPD in the 24 and 25 week infants but they do better from a neurodevelopmental standpoint. On the other hand there is a benefit in the 26 and 27 week infants but you may predispose them to side effects as well.
This is where precision medicine comes in. One option for centers unsure of who to provide this to (if at all) could be to use a threshold of 880 nmol/L and if the initial level is above this you would not treat but if below offer treatment. This level while found in the study to be predictive of side effects in particular if high does seem very high to me. I would think most babies would qualify which is not necessarily a bad thing but in our center we have typically used levels above 400 or 500 as an adequate stress response. Regardless of the level picked one would be using physiologic data to determine who to give hydrocortisone to as a way to try and maximize benefit and minimize harm for the individual patient.
Make no mistake. Regardless of whether you decide to try this for your patients I don’t believe this is a magic bullet. The best chances for our patients come from having bundles of evidence based based practices and applying them to the patient population if we hope to reduce BPD and minimize risk from any side effects of our treatments. The question is whether prophylactic hydrocortisone should be part of this bundle.
What do you think?
11 September 2021 12:00 PM
0Perinatal Care of the Preterm Baby-Epidemiology and Ethics
This is an online module being organised by the MPROvE Academy starting from the 12th of February till the end of April 2021. The content covered includes limits of viability, prenatal counselling, communication, prognostication, decision making, and a lot more as outlined below. The course has been broken up into content that can be imbibed weekly with a webinar covering that topic. The course has online content, and videos for review by the participants. Participants can access this from anywhere in the world. For more details a video of the course is attached.
For registration please contact Dr Alok Sharma Consultant Neonatologist on firstname.lastname@example.org
01 October 2021 Until 03 October 2021
2First announcement of
Recent advances in neonatal medicine
IXth International symposium honoring prof. Richard B. Johnston, MD, Denver, US
1-3 Octobe 2021, in Würzburg, Germany
Find more information in the attached folder.
17 November 2021
1The 17th of November each year is the World Prematurity Day. Originally started by parent organisations in Europe in 2008, the World Prematurity Day is an international event aiming at high-lighting the ~15 million infants born preterm each year.
Read more about this day on the March of Dimes web site, and on Facebook.