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 thriving. The 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.
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.
If you work in Neonatology then chances are you have ordered or assisted with obtaining many chest x-rays in your time. If you look at home many chest x-rays some of our patients get, especially the ones who are with us the longest it can be in the hundreds. I am happy to say the tide though is changing as we move more and more to using other imaging modalities such as ultrasound to replace some instances in which we would have ordered a chest x-ray. This has been covered before on this site a few times; see Point of Care Ultrasound in the NICU, Reducing Radiation Exposure in Neonates: Replacing Radiographs With Bedside Ultrasound. and Point of Care Ultrasound: Changing Practice For The Better in NICU.This post though is about something altogether different.
If you do a test then know what you will do with the result before you order it.
If there is one thing I tend to harp on with students it is to think about every test you do before you order it. If the result is positive how will this help you and if negative what does it tell you as well. In essence the question is how will this change your current management. If you really can’t think of a good answer to that question then perhaps you should spare the infant the poke or radiation exposure depending on what is being investigated. When it comes to the baby born before 30 weeks these infants are the ones with the highest risk of developing chronic lung disease. So many x-rays are done through their course in hospital but usually in response to an event such as an increase in oxygen requirements or a new tube with a position that needs to be identified. This is all reactionary but what if you could do one x-ray and take action based on the result in a prospective fashion?
In this study they looked retrospectively at 336 preterm infants weighing less than 1500g and less than 32 weeks at birth. Armed with the knowledge that many infants who have an early abnormal x-ray early in life who go on to develop BPD, this group decided to test the hypothesis that an x-ray demonstrating a pneumonia like pattern at day 7 of life predicts development of BPD. The patterns they were looking at are demonstrated in this figure from the paper. Essentially what the authors noted was that having the worst pattern of the lot predicted the development of later BPD. The odds ratio was 4.0 with a confidence interval of 1.1 – 14.4 for this marker of BPD. Moreover, birthweight below 1000g, gestational age < 28 weeks and need for invasive ventilation at 7 days were also linked to the development of the interstitial pneumonia pattern.
What do we do with such information?
I suppose the paper tells us something that we have really already known for awhile. Bad lungs early on predict bad lungs at a later date and in particular at 36 weeks giving a diagnosis of BPD. What this study adds if anything is that one can tell quite early whether they are destined to develop this condition or not. The issue then is what to do with such information. The authors suggest that by knowing the x-ray findings this early we can do something about it to perhaps modify the course. What exactly is that though? I guess it is possible that we can use steroids postnatally in this cohort and target such infants as this. I am not sure how far ahead this would get us though as if I had to guess I would say that these are the same infants that more often than not are current recipients of dexamethasone.
Would another dose of surfactant help? The evidence for late surfactant isn’t so hot itself so that isn’t likely to offer much in the way of benefit either.
In the end the truth is I am not sure if knowing concretely that a patient will develop BPD really offers much in the way of options to modify the outcome at this point. Having said that the future may well bring the use of stem cells for the treatment of BPD and that is where I think such information might truly be helpful. Perhaps a screening x-ray at 7 days might help us choose in the future which babies should receive stem cell therapy (should it be proven to work) and which should not. I am proud to say I had a chance to work with a pioneer in this field of research who may one day cure BPD. Dr. Thebaud has written many papers of the subject and if you are looking for recent review here is one Stem cell biology and regenerative medicine for neonatal lung diseases.Do I think that this one paper is going to help us eradicate BPD? I do not but one day this strategy in combination with work such as Dr. Thebaud is doing may lead us to talk about BPD at some point using phrases like “remember when we used to see bad BPD”. One can only hope.
It has been over two years since I have written on this subject and it continues to be something that I get excited about whenever a publication comes my way on the topic. The last time I looked at this topic it was after the publication of a randomized trial comparing in which one arm was provided automated FiO2 adjustments while on ventilatory support and the other by manual change. Automated adjustments of FiO2. Ready for prime time? In this post I concluded that the technology was promising but like many new strategies needed to be proven in the real world. The study that the post was based on examined a 24 hour period and while the results were indeed impressive it left one wondering whether longer periods of use would demonstrate the same results. Moreover, one also has to be wary of the Hawthorne Effect whereby the results during a study may be improved simply by being part of a study.
The Real World Demonstration
So the same group decided to look at this again but in this case did a before and after comparison. The study looked at a group of preterm infants under 30 weeks gestational age born from May – August 2015 and compared them to August to January 2016. The change in practice with the implementation of the CLiO2 system with the Avea ventilator occurred in August which allowed two groups to be looked at over a relatively short period of time with staff that would have seen little change before and after. The study in question is by Van Zanten HA The effect of implementing an automated oxygen control on oxygen saturation in preterm infants. For the study the target range of FiO2 for both time periods was 90 – 95% and the primary outcome was the percentage of time spent in this range. Secondary outcomes included time with FiO2 at > 95% (Hyperoxemia) and < 90, <85 and < 80% (hypoxemia). Data were collected when infants received respiratory support by the AVEA and onlyincluded for analysis when supplemental oxygen was given, until the infants reached a GA of 32 weeks
As you might expect since a computer was controlling the FiO2 using a feedback loop from the saturation monitor it would be a little more accurate and immediate in manipulating FiO2 than a bedside nurse who has many other tasks to manage during the care of an infant. As such the median saturation was right in the middle of the range at 93% when automated and 94% when manual control was used. Not much difference there but as was seen in the shorter 24 hour study, the distribution around the median was tighter with automation. Specifically with respect to ranges, hyperoxemia and hypoxemia the following was noted (first number is manual and second comparison automated in each case).
Time spent in target range: 48.4 (41.5–56.4)% vs 61.9 (48.5–72.3)%; p<0.01
Hyperoxemia >95%: 41.9 (30.6–49.4)% vs 19.3 (11.5–24.5)%; p<0.001
< 90%: 8.6 (7.2–11.7)% vs 15.1 (14.0–21.1)%;p<0.0001
< 85%: 2.7 (1.4–4.0)% vs 3.2 (1.8–5.1)%; ns
Hypoxemia < 80%: 1.1 (0.4–1.7)% vs 0.9 (0.5–2.1)%; ns
What does it all mean?
I find it quite interesting that while hyperoxemia is reduced, the incidence of saturations under 90% is increased with automation. I suspect the answer to this lies in the algorithmic control of the FiO2. With manual control the person at the bedside may turn up a patient (and leave them there a little while) who in particular has quite labile saturations which might explain the tendency towards higher oxygen saturations. This would have the effect of shifting the curve upwards and likely explains in part why the oxygen saturation median is slightly higher with manual control. With the algorithm in the CLiO2 there is likely a tendency to respond more gradually to changes in oxygen saturation so as not to overshoot and hyperoxygenate the patient. For a patient with labile oxygen saturations this would have a similar effect on the bottom end of the range such that patients might be expected to drift a little lower then the target of 90% as the automation corrects for the downward trend. This is supported by the fact that when you look at what is causing the increase in percentage of time below 90% it really is the category of 85-89%.
Is this safe? There will no doubt be people reading this that see the last line and immediately have flashbacks to the SUPPORT trial which created a great deal of stress in the scientific community when the patients in the 85-89% arm of the trial experienced higher than expected mortality. It remains unclear what the cause of this increased mortality was and in truth in our own unit we accept 88 – 92% as an acceptable range. I have no doubt there are units that in an attempt to lessen the rate of ROP may allow saturations to drop as low as 85% so I continue to think this strategy of using automation is a viable one.
For now the issue is one of a ventilator that is capable of doing this. If not for the ventilated patient at least for patients on CPAP. In our centre we don’t use the Avea model so that system is out. With the system we use for ventilation there is also no option. We are anxiously awaiting the availability of an automated system for our CPAP device. I hope to be able to share our own experience positively when that comes to the market. From my standpoint there is enough to do at the bedside. Having a reliable system to control the FiO2 and minimize oxidative stress is something that may make a real difference for the babies we care for and is something I am eager to see.
As someone with an interest in neonatal abstinence (NAS) I am surprised that I missed this study back in May. Anyone who says they aren’t interested in NAS research must be turning a blind eye to the North American epidemic of patients filling neonatal units or postpartum wards in need of treatment for the same. News feeds such as CNN have covered this story many times with concerning articles such as this published “Opioid Crisis Fast Facts” even the Trump White House has officially declared it as an emergency at this point. With NICU resources stretched and care providers fatigue levels wearing thin (these patients are typically very challenging to take care of due to the crying and agitation with neurological excitability that is at the core of the symptoms, something needs to be done. The vast majority of neonatal care providers treat such patients with an approach that promotes first non pharmacologic strategies such as keeping mom and baby together when possible, breast feeding and disturbing these infants as little as possible to name a few points. For those patients though who require pharmacologic support though, the mainstay has been oral morphine. At least in our units though once a patient is admitted and undergoes treatment we are still looking at anywhere from 3-4 weeks on average that they will occupy a hospital bed. If only there was a better way.
Could Buprenorphine do the trick?
While morphine is widely used to treat NAS symptoms unresponsive to other non pharmacologic methods of control, buprenorphine has a similar profile as an opioid but has less risk of respiratory depression as a partial agonist. A small but important trial has been published directly comparing the use of morphine to buprenorphine for treatment of NAS symptoms with the primary outcome being days of treatment and the second important point being length of stay. The trial, Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome.by Kraft WK et al was entitled the BBORN trial for short. This was a single centre trial in which a double blind/double dummy approach was used. By double dummy this meant that after randomization those babies randomized to morphine received morphine plus a buprenorphine placebo and the other arm received a buprenorphine dose and a morphine placebo. In total 33 infants were randomized to buprenorphine and 30 to morphine (hence my comment about this being a small study). Their power calculation had called for 40 infants per arm to detect a 28% difference in the primary end point of duration of treatment but in the end that didn’t matter so much as they found a significant difference exceeding their estimate anyway. A lack of power would have become important mind you had they not found a difference as they wouldn’t have actually had the numbers to do so.
A strength of the study up front was that all care providers scored NAS symptoms the same way (need to take into account there is some subjectivity in scoring altogether though) and escalations and decreases of medication were done following a strict protocol both ways. In both arms, once a maximal dose of 60 mcg/kg of body weight for buprenorphine and 1.2 mg/kg for morphine was reached phenobarbital was added. When comparing the two groups at the outset there were no significant differences in characteristics so two generally similar populations of infants were being treated.
The Results Were Indeed Impressive
Before launching into the table, there were 21 babies in both groups that were bottle fed and 12 in the burprenorphine group and 9 in the morphine group that breastfed.
Median days of treatment
Hospital stay in days
No difference was seen in those who needed phenobarbital. Looking at the table, a couple things really stand out to me. They were looking for a 28% reduction in days of treatment. The results came in far excess of that at a 46% reduction. Curiously, breastfeeding which has classically been associated with a reduction in scores and therefore faster weaning due to less symptoms seemed to have the opposite effect here. Does this imply that breastfeeding slows down both duration of treatment and length of stay as a result? With a study this small it is difficult to say with so few breastfed babies but if I had to guess I would suggest those mothers that worked at breastfeeding may have had longer stays.
Should we all jump on the buprenorphine train?
For now I would give this a big maybe. One of the concerns about burprenorphine is that it comes as a solution of 30% alcohol. Giving multiple doses (3 per day in this study) of such a solution could in part contribute to these results of lower NAS symptoms. Is giving alcohol to reduce symptoms a good idea here? Not sure if there are any long term effects and moreover if the cumulative dose of this medication would be of a concern. Definitely something to check with your local pharmacist before rolling this out. On the other hand if the dose of alcohol provided was truly significant I might have expected the burprenorphine group to be poorer feeders due to intoxication which we certainly did not see.
With increasing volumes of newborns afflicted with symptoms of NAS we do need to find a way to stem the tide. Ideally, primary preventative strategies would be best but until that solution is found could burprenorphine be the next step in tackling this epidemic?
We can always learn and we can always do better. At least that is something that I believe in. In our approach to resuscitating newborns one simple rule is clear. Fluid must be replaced by air after birth and the way to oxygenate and remove CO2 is to establish a functional residual capacity. The functional residual capacity is the volume of air left in the lung after a tidal volume of air is expelled in a spontaneously breathing infant and is shown in the figure. Traditionally, to establish this volume in a newborn who is apneic, you begin PPV or in the spontaneously breathing baby with respiratory distress provide CPAP to help inflate the lungs and establish FRC.
Is there another way?
Something that has been discussed now for some time and was commented on in the most recent version of NRP was the concept of using sustained inflation (SI) to achieve FRC. I have written about this topic previously and came to a conclusion that it wasn’t quite ready for prime time yet in the piece Is It Time To Use Sustained Lung Inflation In NRP?
The conclusion as well in the NRP textbook was the following:
“There are insufficient data regarding short and long-term safety and the most appropriate duration and pressure of inflation to support routine application of sustained inflation of greater than 5 seconds’ duration to the transitioning newborn (Class IIb, LOE B-R). Further studies using carefully designed protocols are needed”
So what now could be causing me to revisit this concept? I will be frank and admit that whenever I see research out of my old unit in Edmonton I feel compelled to read it and this time was no different. The Edmonton group continues to do wonderful work in the area of resuscitation and expand the body of literature in such areas as sustained inflation.
Can you predict how much of a sustained inflation is needed?
This is the crux of a recent study using end tidal CO2 measurement to determine whether the lung has indeed established an FRC or not. Dr. Schmolzer’s group in their paper (Using exhaled CO2 to guide initial respiratory support at birth: a randomised controlled trial) used end tidal CO2 levels above 20 mmHg to indicate that FRC had been established. If you have less CO2 being released the concept would be that the lung is actually not open. There are some important numbers in this study that need to be acknowledged. The first is the population that they looked at which were infants under 32 6/7 weeks and the second is the incidence of BPD (need for O2 or respiratory support at 36 weeks) which in their unit was 49%. This is a BIG number as in comparison for infants under 1500g our own local incidence is about 11%. If you were to add larger infants closer to 33 weeks our number would be lower due to dilution. With such a large number though in Edmonton it allowed them to shoot for a 40% reduction in BPD (50% down to 30%). To accomplish this they needed 93 infants in each group to show a difference this big.
So what did they do?
For this study they divided the groups in two when the infant wouldn’t breathe in the delivery room. The SI group received a PIP of 24 using a T-piece resuscitator for an initial 20 seconds. If the pCO2 as measured by the ETCO2 remained less than 20 they received an additional 10 seconds of SI. In the PPV group after 30 seconds of PPV the infants received an increase of PIP if pCO2 remained below 20 or a decrease in PIP if above 20. In both arms after this phase of the study NRP was then followed as per usual guidelines.
The results though just didn’t come through for the primary outcome although ventilation did show a difference.
Duration of mechanical ventilation (hrs)
The reduction in hours of ventilation was impressive although no difference in BPD was seen. The problem though with all of this is what happened after recruitment into the study. Although they started with many more patients than they needed, by the end they had only 76 in the SI group and 86 in the PPV group. Why is this a problem? If you have less patients than you needed based on the power calculation then you actually didn’t have enough patients enrolled to show a difference. The additional compounding fact here is that of the Hawthorne Effect. Simply put, patients who are in a study tend to do better by being in a study. The observed rate of BPD was 33% during the study. If the observed rate is lower than expected when the power calculation was done it means that the number needed to show a difference was even larger than the amount they originally thought was needed. In the end they just didn’t have the numbers to show a difference so there isn’t much to conclude.
What I do like though
I have a feeling or a hunch that with a larger sample size there could be something here. Using end tidal pCO2 to determine if the lung is open is in and of itself I believe a strategy to consider whether giving PPV or one day SI. We already use colorimetric devices to determine ETT placement but using a quantitative measure to ascertain the extent of open lung seems promising to me. I for one look forward to the continued work of the Neonatal Resuscitation–Stabilization–Triage team (RST team) and congratulate them on the great work that they continue doing.