It seems like a sensational title I know but it may not be as far fetched as you may think. The pendulum certainly has swung from the days of liberal post natal dexamethasone use in the 1990s to the near banishment of them from the clinical armamentarium after Keith Barrington published an article entitled The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs in BMC Pediatrics in 2011. This article heralded in the steroid free epoch of the first decade of the new millennium, as anyone caring for preterm infants became fearful of causing lifelong harm from steroid exposure. Like any scare though, with time fear subsides and people begin asking questions such as; was it the type of steroid, the dose, the duration or the type of patient that put the child at risk of adverse development? Moreover, when death from respiratory failure is the competing outcome it became difficult to look a parent in the eye when their child was dying and say “no there is nothing more we can do” when steroids were still out there.
Over the last decade or so, these questions in part have been studied in at least two important ways. The first was to ask whether we use a lower dose of dexamethasone for a shorter period to improve pulmonary outcomes without adverse neurodevelopment? The target population here were babies on their way to developing chronic lung disease as they were ventilated at a week of age. The main study to answer this question was the DART study. This study used a very low total dose of 8.9 mg/kg of dexamethasone given over ten days. While the study was stopped due to poor recruitment (it was surely difficult to recruit after the 2001 moratorium on steroids) they did show a benefit towards early extubation. This was followed up at 2 years with no difference in neurodevelopmental outcomes. Having said that the study was underpowered to detect any difference so while reassuring it did not prove lack of harm. Given the lack of evidence showing absolute safety practitioners have continued to use post natal steroids judiciously.
The second strategy was to determine whether one could take a prophylactic approach by providing hydrocortisone to preterm infants starting within the first 24 hours to prevent the development of CLD. The best study to examine this was by Kristi Watterberg in 2004 Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Strangely enough the same issue of early stoppage affected this study as an increased rate of spontaneous gastrointestinal perforation was noted leading to early closure. The most likely explanation is thought to be the combination of hydrocortisone and indomethacin prophylaxis which some centres were using at the same time. An interesting finding though was that in a subgroup analysis, infants with chorioamnionitis who received hydrocortisone had less incidence of chronic lung disease. (more on this later) Although this of course is subject to the possible bias of digging too deep with secondary analyses there is biologic plausibility here as hydrocortisone could indeed reduce the inflammatory cascade that would no doubt be present with such infants exposed to chorioamnionitis in utero.
Has the answer finally come?
The DART study at 360 patients was the largest study to date to look at prophylaxis as a strategy. That is until this past week. The results of the PREMILOC study have been published which is the long awaited trial examining a total dose of 8.5 mg/kg of hydrocortisone over 10 days. We can finally see the results of a trial without the complicating prophylactic indomethacin trials interfering with results. Surprisingly this study was also stopped early (a curse of such trials?!) due to financial reasons this time. Prior to stoppage though they managed to recruit 255 to hydrocortisone and 266 to control groups. All infants in this study were started on hydrocortisone within 24 hours of age and the primary outcome in this case was survival without BPD at 36 weeks of age.
All infants were less than 28 weeks at birth and therefore had a high risk of the combined outcome and despite the study being stopped early there was indeed a better outcome rate in the hydrocortisone group (60% vs 51%). Another way of looking at this is that to gain one more patient who survived without BPD you needed to treat 12 which is not bad at all. What is additionally interesting are some of the findings in the secondary analyses.
The lack of a difference in males may well reflect the biologic disadvantage that us males face overcoming any benefit from the hydrocortisone. In fact for the females studied the number needed to treat improves to 6 patients only! Short term outcomes of less ventilation are sure to please everyone especially parents. Lastly, a reduction in PDA ligation is most probably related to an antiprostaglandin effect of steroids and should be cause for joy all around. Lastly, a tip of the hat to Dr. Watterberg is in order as those infants who were exposed to chorioamnionitis once again show that this is where the real benefit may be.
But what about side effects?
The rate of NEC is quite high but is so for both groups but otherwise there is nothing much here to worry the reader. Once and for all we also see that by excluding concurrent treatment with indomethacin or ibuprofen the rate of GI perforation is no different this time around. Reassuring results indeed, but alas the big side effect, the one that would tip the scale towards us using or abandoning treatment has yet to be presented. Steroids no doubt can do great things but given the scare from 2001 we will need to see how this cohort of babies fares in the long run.
The follow-up is planned for these infants and the authors have done an incredible job of recruiting enough patients to make the results likely believable. I for one can’t wait to see what the future holds. If I was a betting man though I would say this ultra low dose of hydrocortisone may be just the thing to bring this therapy finally into the toolbox of neonatal units worldwide. We have been looking for the next big thing to help improve outcomes and good old hydrocortisone may be just what the doctor ordered.
What a hard topic to resist commenting on. This was all over twitter and the general media this week after the New England Journal published the following paper; Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. The fact that it is the NEJM publishing such a paper in and of itself suggests this is a top notch study…or does it?
Is there a benefit to giving antenatal steroids from 34 0/7 – 36 5/7 weeks?
That is the central question the authors here sought to answer. Would women who had a high risk of delivering during this time period have less risk of a composite primary outcome of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery.
On the surface this seems like a very worthwhile set of outcomes to look at and the authors found in the end some pretty remarkable findings in a total of 2827 women randomized to placebo or betamethasone.
Looking at the results one sees that the primary outcome showed a significant difference with 2.8% less infants experiencing these conditions. However, when one looks at the details the only contributor to this difference was the need for CPAP or HFNC for >= 2 hours. A need for over 30% FiO2 for > 4 hours was also not different. No differences were noted in mechanical ventilation, ECMO, deaths whether stillbirths or neonatal deaths. Curiously, significant differences for secondary outcomes were seen with incidence of severe respiratory distress, and need for CPAP for over 12 hours.
These results are not truly that surprising at least for the primary outcome as if you asked most people working in the field of Neonatology how likely death, need for ECMO or even mechanical ventilation are from 34 – 36 weeks they would tell you not very likely. The other thing to consider is that the only real significant difference was noted for infants needing CPAP or HFNC for at least 2 hours. While this would interrupt maternal infant bonding, it wouldn’t necessarily mean an admission but rather in some cases observation and then transfer to the mother’s room.
Is it worth it?
To answer this question you need to know the best and worst case scenarios I suppose. Based on the reduction of 2.8%, you would need to treat 35 women with betamethasone to avoid the primary outcome but of course there is a range based on the confidence intervals around this estimate. The true estimate lies somewhere between 18 – 259 to avoid the outcome. Having said that, the estimate to avoid severe distress is 25 patients with a range of 16 – 56 which is pretty good value. In a perfect world I would probably suggest to women that there seems to be a benefit especially if one notes that in this study only 60% of the women received 2 dose of betamethasone so if rates of administration were higher one might expect and even better outcome. Ah but the world is not perfect….
There is only so much betamethasone to go around.
I find it ironic but the same day that this article came across my newsfeed so did a warning that we were about to run out of betamethasone vials in a certain concentration and would need to resort to another manufacturer but that supply may also run out soon as well. The instructions were to conserve this supply in the hospital for pregnant women.
In Canada as reported by the Canadian Neonatal Network in 2010, 38.1% of babies admitted to NICUs were below 34 weeks. Given that all babies would be admitted to NICUs at this gestational age and below that likely represents the percentage of births in those ages. An additional 31.8% or almost an equal number of babies will be born between 34 0/7 to 37 0/7 weeks meaning that if we were to start treating women who were deemed to be at risk of preterm delivery in that age range we would have a lot of potential women to choose from as these are the exact women in this strata who actually delivered early in Canada.
If I am forced to choose whether to give betamethasone to the mothers under 34 weeks or above when the resource we need is in scarce supply I don’t think there is much choice at all. Yes, this article comes from a reputable journal and yes there are some differences some of which are highly significant to consider but at least at this time my suggestion is to save the supply we have the babies who will benefit the most.
In the spirit of full disclosure I have to admit I have never placed a laryngeal mask airway (LMA) in a newborn of any gestational age. I have played with them in simulated environments and on many occasion mentioned that they are a great alternative to an ETT especially in those situations where intubation may not be possible due to the skill of the provider or the difficulty of the airway in the setting of micrognathia for example.
In recent years though we have heard of examples of surfactant delivery via these same devices although typically these were only case reports. More recently a small randomized study of 26 infants by Attridge et al demonstrated in the group randomized to surfactant administration through an LMA that oxygen requirements were reduced after dosing. This small pilot provides sufficient evidence to show that it is possible to provide surfactant and that at least some gets into the airway of the newborn. This proof of concept though while interesting, did not answer the question of whether such delivery of surfactant would be the same or better than through an ETT. As readers of my blog posts know, my usual stance on things is that the less invasive the better and as I look through the literature, I am drawn to concepts such as this to see if they can be added to our toolbox of non or less invasive strategies in the newborn.
A Minimally Invasive Technique For The Masses?
This past month, a small study by Pinheiro et al sought to answer this question by using 61 newborns between 29 0/7 – 36 6/7 weeks and greater than 1000g and randomizing them to either surfactant via the INSURE technique or LMA. I cannot stress enough so will get it out of the way at the start that this strategy is not for those <1000g as the LMA is not designed to fit them properly and the results (to be shown) should not be generalized to this population. Furthermore then study included only those infants who needed surfactant between 4 – 48 hours of age, were on CPAP of at least 5 cm H2O and were receiving FiO2 between 30 – 60%. All infants given surfactant via the insure technique were premedicated with atropine and morphine while those having an LMA received atropine only. The primary outcome of the study was need for subsequent intubation or naloxone within 1 hour of surfactant administration. The study was stopped early after an interim analysis (done as the fellow involved was finishing their fellowship – on a side note I find this an odd reason to stop) demonstrated better outcomes in the group randomized to the LMA.
Before we get into the results let’s address the possible shortcomings of the study as they might already be bouncing around your heads. This study could not be blinded and therefore there could be a significant bias to the results. The authors did have predetermined criteria for reintubation and although not presented, indicate that those participating stuck to these criteria so we may have to acknowledge they did the best they could here. Secondly the study did not reach their numbers for enrolment based on their power calculation. This may be ok though as they found a difference which is significant. If they had found no difference I don’t think I would be even writing this entry! Lastly this study used a dose of surfactant at 3 mL/kg. How well would this work with the formulation that we use BLES that requires 5 mL/kg?
What were the results?
What do these results tell us? The majority of failures occurred within an hour of delivery of surfactant in the ETT group? How does this make any sense? Gastric aspirates for those in the LMA group but not the INSURE group suggest some surfactant missed the lung in the former so one would think the intubation group should have received more surfactant overall however it would appear to be the premedication. The rate of needing surfactant afterwards is no different and in fact there is a trend to needing reintubation more often in the LMA group but the study was likely underpowered to detect this difference. Only two patients were given naloxone to reverse the respiratory depressive effects of morphine in those given the INSURE technique so I can’t help but speculate that if this practice was more frequent many of the reintubations might have been avoided. This group was quite aggressive in sticking to the concept of INSURE as they aimed to extubate following surfactant after 5 – 15 minutes. I am a strong advocate of providing RSI to those being electively intubated but if the goal is to extubate quickly then I believe one must be ready to administer naloxone soon after extubation if signs of respiratory depression are present and this did not happen effectively in this study. Some may argue those getting the INSURE technique should not be given any premedication at all but that is a debate that will go on for years I am sure but they may have a valid point given this data.
Importantly complications following either procedure were minimal and no different in either group.
Where do we go from here?
Despite some of the points above I think this study could prove to be important for several reasons. I think it demonstrates that in larger preterm infants it is possible to avoid any mechanical ventilation and still administer surfactant. Many studies using the minimally invasive surfactant treatment (MIST) approach have been done but these still require the skill of laryngoscopy which takes a fair bit of skill to master. The LMA on the other hand is quite easy to place and is a skill that can be taught widely. Secondly, we know that even a brief period of over distension from PPV can be harmful to the lung therefore a strategy which avoids intubation and direct pressure to the lung may offer some longer term benefit although again this was not the study to demonstrate that.
Lastly, I see this as a strategy to look at in more rural locations where access to highly skilled level III care may not be readily available. We routinely field calls from rural sites with preterm infants born with RDS and the health care provider either is unable to intubate or is reluctant to try in favour of using high flow oxygen via mask. Many do not have CPAP either to support such infants so by the time our Neonatal Transport team arrives the RDS is quite significant. Why not try surfactant through the LMA? If it is poorly seated over the airway and the dose goes into the stomach I don’t see them being in any worse shape than if they waited for the team to arrive. If some or all of the dose gets in though there could be real benefit.
Might this be right for your centre? As we think about outreach education and NRP I think this may well become a strong reason to spend a little more time on LMA training. We may be on to something!
I will admit it. I resist change at times just like many others. This may come as a surprise to some of you who have worked with me and accused me of bringing too much change at times to the units. The truth though is that when one understands something and is enthusiastic about implementation the change does not seem so difficult. When it isn’t your idea though we may find ourselves a little uneasy about adopting this unfamiliar practice.
Such has been my experience with nasal HFOV. It is a strategy that has been around for over five years but has seen slow adoption among centres in Canada and has trickled into practice in Winnipeg on a few occasions. In each occasion when I have been asked about either continuing or perhaps starting this therapy I have shrugged my shoulders and confessed my inexperience with the modality. Sure I have used HFOV through an ETT but through prongs or a mask?! How would it work? Could it cause harm? What would the actual indications be? How would our in house physicians and NNPs respond to abnormal gases overnight even if I felt comfortable with using it? These sorts of questions have led to virtual inertia in my acceptance of the strategy.
Before I go on it would be good to see an example of how it is set up. The MedinCNO device is capable of delivering such non-invasive HFOV and can be seen in this short video.
One could use the strategy either prophylactically to extubate an infant or as rescue to prevent reintubation if trials of either CPAP or NIPPV were unsuccessful. HFOV is known to be very effective at clearing CO2 when used through an ETT so perhaps nasal application could also lower pCO2 and achieve a similar effect. This was tested using a neonatal lung simulator by Mukeji A et al Nasal high-frequency oscillation for lung carbon dioxide clearance in the newborn. In this study CO2 was introduced into the manequin and the amount of exhaled CO2 determined while on CPAP, NIPPV and nasal HFOV. Interestingly during CPAP no exhaled CO2 could be detected while CO2 clearance occurred during NIPPV and nasal HFOV although it was three-fold greater with HFOV. In theory then CO2 clearance would appear to be better so in the case of ventilatory failure as evidenced by CO2 retention this modality would seem to win out.
Clinical Evidence for Use
There is one RCT in term infants with TTN to support the practice while the rest are unblinded case series with no controls. Four Canadian NICUs recently described their experience however using a retrospective analysis. Included were 79 instances of HFOV distributed as follows; 73% utilized as rescue from another mode and in 27% used as the primary mode for extubation. The outcomes are shown in the table:
In 45% of cases the patients needed intubation after first trialing CPAP or NIPPV while in 33% of cases following extubation the infants needed replacement of the endotracheal tube. The numbers here are small so it is difficult to truly compare them to other studies with confidence but reintubation rates of 40-44% have been noted recently when using NIPPV or CPAP so the numbers are at least consistent.
One aspect though that caught my eye was the duration of use for HFOV across these 79 patients. The median use was 57 hours with the longest duration being just over 400 hours. It would seem that the use of this modality for the most part is as a bridge to something else. The median duration of 2.5 days is much shorter than the weeks that some of our smallest infants remain on CPAP/NIPPV for. Whether for rescue or prophylaxis this is not a long term option.
Another point worth noting though is the question of whether it is the pressure or oscillatory wave that is leading to success. As the authors note, there were a wide range in applications of MAP, delta P and frequency.
MAP ranges from 8 – 24 cm H2O while frequency from 6 – 14 hz and amplitude varied widely depending on the device used but was as high as 100%. While high MAP has been used invasively though an ETT I can’t help but wonder if in some cases the real benefit was the high MAP. What would happen for example if the centres had simply raised the CPAP to 10, 12 or even higher?
In the end it would seem that in principal it is an effective therapy that may be able to remove CO2 more efficiently than the other modes. What we don’t have are RCTs in the smallest babies comparing HFOV to NIPPV or CPAP with adequate power to detect differences. I suspect these will come soon enough but what do we do in the meantime? The main reservation I have has to do with safety. We truly have little if any data on this without proper trials to ease such worry. When a patient is in front of us though and is failing CPAP or NIPPV what are we to do? Should we intubate or trial this modality based on the evidence thus far?
I might be tempted to trial HFOV in this circumstance but as with any new therapy we need education for all staff. Everyone caring for our infants need to understand what they are using and how to respond based on clinical findings. This is the real issue with safety that I see and until such time that we have widespread education across RRT, nursing and medicine I would suggest we use this with trepidation. This is not a rejection of the modality in the least but rather a call to come together as a team and see how implement this in such a way that will provide direction to caregivers, provide a consistent approach with respect to length of use, indications and when to change direction entirely. Time to call a meeting of the minds I think.
Another year has passed and another World Prematurity Day is upon us. I thought about what to write for this day that draws attention to premature infants worldwide and was hit with many ideas which no doubt will form the basis for many posts to come. There was one thought that struck me though as being so important to think about as we push forward, striving to improve survival across the globe for our smallest patients. There is no doubt that you will have heard the expression “just because we can do something, should we?” In 2015 I don’t think this applies more than at this very moment.
At a Tipping Point
You see we are at a tipping point as Malcolm Gladwell explained so brilliantly in his book by the same name. In April of 2015 Rysavy et al published the results of survival and morbidity data for infants born in 24 US hospitals between the ages of 22 – 26 weeks. The nearly 5000 infants included demonstrated two very important things. Firstly, survival is possible at 22 and 23 weeks and there is a chance, albeit less than 50% that these infants will survive without moderate or severe disability. Secondly, at these gestational ages 75% of hospitals included provided active resuscitation to these infants. Given that this is the largest study out there and shows that survival is possible and we can expect to see some good outcomes it would seem logical to move forward with universal resuscitation of these infants would it not?
You Are Going To Practice on What?!
As the saying goes though, “Perfect Practice Makes Perfect”. Not all hospitals have equal performance at these gestational ages which is demonstrated in the ranges of outcomes across hospitals as shown in the Rysavy paper. To even suggest that we need to practice on premature babies will no doubt leave many of you feeling queasy but in essence that is what is truly needed to improve our outcomes further. An infant born at 22 – 24 weeks is vastly different than one born at a later gestational age. Their skin is extremely fragile and prone to breakage with resultant risk of infection. Their lungs are in a stage of development that has yet to produce any real abundance of gas exchanging alveoli and their brains lacking the sulci and gyri that are to come many weeks later. They are in need of meticulous “best practice” care and without that their outcomes are certainly to be influenced. Depending on the centre though, you may see 5, 10, 15, 20 patients a year at these ages. How can a team possibly gain enough experience in treating these children appropriately if they see 1 or 2 every two months? Add to this that you may have 10 different Neonatologists so on average each of you may take care of one patient a year at birth. This is a recipe prone to poor outcomes if you ask me.
The Evolution of the Small Baby Unit
The answer no doubt will lie in creating smaller teams; so called “Small Baby Units”. Such units have small groups of health care providers dedicated to treating such infants thereby increasing the frequency of individuals exposure to these babies. There is some recent evidence published in Pediatrics that supports this notion. Small Baby Unit Improves Quality and Outcomes in Extremely Low Birth Weight Infants. In this study a period of two years before and four years after opening such a unit were compared across a number of measures. The findings were as follows “There was a reduction in chronic lung disease from 47.5% to 35.4% (P = .097). The rate of hospital-acquired infection decreased from 39.3% to 19.4% (P < .001). Infants being discharged with growth restriction (combined weight and head circumference <10th percentile) decreased from 62.3% to 37.3% (P = .001). Reduced resource utilization was demonstrated as the mean number per patient of laboratory tests decreased from 224 to 82 (P < .001) and radiographs decreased from 45 to 22 (P < .001).” I hope you would agree that achievements such as these are worth the effort to create such an environment. Future studies I believe will confirm these findings although having the gold standard RCT may be difficult to achieve as I suspect we will have lost equipoise.
This brings me to the final point though and that is whether we are ready as a health care system for the increase patient load that this change will bring about. Based on an expected stay of 4 months for a baby born at this age and knowing the average number of such babies delivered per year, we would be looking at about 600 patient days per year added to each hospital’s occupancy in our two centres. This represents about a 5% increase in patient bed days per year. Five percent may not seem like a large increase at first blush but when we like many hospitals have been trying to deal with staffing issues and many days in which we are at or near capacity, this is not an insignificant challenge. It is a challenge though that we must face head on. Resources must be found, and space provided to accommodate for these children. We live in a world now where it is not solely up to us but to the family as well who must be integral to any such decision to either pursue or withdraw care. News of such infants surviving has spread to the public and I have no doubt that many families will have heard stories of such survivors. The next phase of care for these infants must address the shortcomings in care at the moment.
How do we educate families about what to expect in the long run?
How do we support these families when they make such difficult decisions either way?
How do we support our front line staff who may hold quite discrepant viewpoints about what is “right” yet expect them to function as one team moving clearly in a direction that supports the family?
How do we ensure that our focus on our smallest infants does not distract us from the attention needed by those born at later gestational ages?
I could go on but these are just some of the questions that I hope the next year begins to tackle. We are in the midst of an evolutionary point in Neonatology and we owe it to ourselves and the families we care for to navigate this change as best we can.
Something kind of big happened today. I received a notice on my Facebook Page that there were now 3000 “likes” for this little community that I started back in February of this year. I was asked early on what the purpose of this blog and Facebook page were and in response I wrote the piece Inside the mind of a Neonatal Blogger. Why am I doing this?. If you are curious, this gives you a good glimpse into my motivations.
Truth be told though I wasn’t really sure what this would become and early on my goal was to have 300 likes and then when that was passed 1000. What has happened since has been quite the surprise. I could not have imagined the growth in the page and the blog since that time.
The map above actually represents all the countries that have read posts from this blog. The red colour aside from being Canada indicates the top country in terms of views, the USA is second in orange and then yellow being the rest of the countries on the map. The white areas are as of yet countries that have not read a piece but who knows what will happen given a little more time!
An interesting shift though has occurred on the Facebook page and that is over the last month a real community has evolved. Up until recently a given post might generate one or two comments but I have noticed something quite special evolving on this site. That is that not only have the comments increased with each post but you the readers are beginning to use this site as I had envisioned. Comments are being made and you are responding rather than leaving it all up to me. Don’t take this the wrong way though, I am more than happy to respond but I am enjoying reading your own thoughts as well. We come from such a wide variety of backgrounds and experiences and these differences are beginning to express themselves in your written words.
As much as I enjoy finding interesting Neonatal content to share with you, I equally enjoy seeing how you respond. An additional complement is that the interactions are almost always respectful, productive and generating of even more dialogue. I learn from you just as you learn from me so let me say thank you for that!
Lastly, I have come to understand that “All Things Neonatal” really does have to be just that. Try as I might I have not been able to unlock the secret of what truly interests the reader. Topics that I would have predicted would “go viral” have been put out into the internet only to produce a sound “thud” as they fall flat which others that I might have thought would generate mild interest have exploded. It is this unpredictability that keeps me excited about putting out each post as I continue to be fascinated by my inability to predict what leads to a boom or a bust.
In case you are wondering though the top three posts have been:
If you haven’t read these then you may be missing out as your fellow readers seemed to think these were a big hit.
Thanks to each of you for following and keep the comments coming. Also if you try something out that you see on this site and adopt it in your hospital please let me know how it has gone. We can all learn plenty from each other. As our base grows so does our collective knowledge and in my opinion that is a good thing.