A real change is coming and with this post you will get a glimpse into where the next big thing in Neonatology is likely to be. A catchy title for sure and also an exaggeration as I don’t see us abandoning the endotracheal tube just yet. There has been a lot of talk about less invasive means of giving surfactant and the last few years have seen several papers relating to giving surfactant via a catheter placed in the trachea (MIST or LISA techniques as examples). There may be a new kid on the block so to speak and that is aerosolized surfactant. This has been talked about for some time as well but the challenge had been figuring out how to aerosolize the fluid in such a way that a significant amount of the surfactant would actually enter the trachea. This was really a dream of many Neonatologists and based on a recently published paper the time may be now for this technique to take off.
A Randomized Trial of Aerosolized Surfacant
Minocchieri et al as part of the CureNeb study team published Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. This trial set out to obtain a sample size of 70 patients between 29 0/7 to 33 6/7 weeks to demonstrate a difference in need for intubation from 30% down to 5% in patients treated with CPAP (30% was based on the historical average). The authors recognizing that the babies in this GA bracket might behave differently, further stratified the randomization into two groups being 29 0/7 – 31 6/7 weeks and 32 0/7 to 33 6/7 weeks. Those babies who were on CPAP and met the following criteria for intubation were either intubated in the control group and given surfactant (curosurf) using the same protocol as those nebulized or had surfactant delivered via nebulisation (200 mg/kg: poractant alfa) using a customised vibrating membrane nebuliser (eFlow neonatal). Surfactant nebulisation(100 mg/kg) was repeated after 12 hours if oxygen was still required. The primary dichotomous outcome was the need for intubation within 72 hours of life, and the primary continuous outcome was the mean duration of mechanical ventilation at 72 hours of age.
Criteria for intubation
1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at
2. More than four apnea/hour OR two apnea requiring BVM
3. Two cap gases with pH <7.2 and PaCO2 >65 mm Hg (or) >60 mm Hg if arterial blood gas sample).
4. Intubation deemed necessary by the attending physician.
Did It Work?
Eureka! It seemed to work as 11 of 32 infants were intubated in the surfactant nebulisation group within 72 hours of birth vs.22 out of 32 infants receiving CPAP alone (RR (95% CI)=0.526 (0.292 to 0.950)). The reduction though was accounted for by the bigger babies in the 32 0/7 to 33 6/7 weeks group as only 1 of 11 was intubated when given nebulized surfactant compared to 10 of 13 managed with CPAP. The duration of ventilation in the first 72 hours was not different between the groups: the median (range) 0 (0–62) hour for the nebulization group and 9 (0–64) hours for the control group (p=0.220). It is important in seeing these results that the clinicians deciding whether infants should be intubated for surfactant administration were blind to the arm the infants were in. All administration of curosurf via nebulization or sham procedures were done behind a screen.
The total number of infants randomized were 66 so they did fall shy of the necessary recruitment but since they did find a difference the results seem valid. Importantly, there were no differences in complications although I can’t be totally confident there really is no risk as this study was grossly underpowered to look at rarer outcomes.
Breaking down the results
This study has me excited as what it shows is that “it kind of works“. Why would larger babies be the ones to benefit the most? My guess is that some but not a lot of surfactant administered via nebulization reaches the alveoli. Infants with lesser degrees of surfactant deficiency (32 0/7 to 33 6/7) weeks might get just enough to manage without an endotracheal tube. Those infants (in particular less than 32 0/7 weeks) who have more significant surfactant deficiency don’t get enough and therefore are intubated. Supporting this notion is the overall delay in time to intubation in those who were intubated despite nebulization (11.6 hours in the nebulization group vs 4.9 hours in the control arm). They likely received some deposition in the distal alveoli but not enough to completely stave off an endotracheal tube.
One concerning point from the study though had to do with the group of infants who were intubated despite nebulization of surfactant. When you look at total duration of ventilation (hours) it was 14.6 (9.0–24.8) in the control arm vs 25.4 (14.6–42.2) p= 0.029*. In other words infants who were intubated in the end spent about twice as long intubated as those who were intubated straight away. Not a huge concern if you are born at 32 weeks or more but those additional thousands of positive pressure breaths are more worrisome as a risk for CLD down the road.
As it stands, if you had an infant who was 33 weeks and grunting with an FiO2 of 35% might you try this if you could get your hands on the nebulizer? It appears to work so the only question is whether you are confident enough that the risk of such things as pneumothorax or IVH isn’t higher if intubation is delayed. It will be interesting to see if this gets adopted at this point.
The future no doubt will see a refinement of the nebulizer and an attempt to see how well this technique works in infants below 29 weeks. It is in this group though that prolonging time intubated would be more worrisome. I don’t want to dismiss this outright as I see this as a pilot study that will lead the way for future work that will refine this technique. If we get this right this would be really transformative to Neonatology and just might be the next big leap.
Much has been written about methylxanthines over the years with the main questions initially being, “should we use them?”, “how big a dose should we use” and of course “theophylline vs caffeine”. At least in our units and in most others I know of caffeine seems to reign supreme and while there remains some discussion about whether dosing for maintenance of 2.5 -5 mg/kg/d of caffeine base or 5 – 10 mg/kg/d is the right way to go I think most favour the lower dose. We also know from the CAP study that not only does caffeine work to treat apnea of prematurity but it also appears to reduce the risk of BPD, PDA and duration of oxygen therapy to name a few benefits. Although initially promising as providing a benefit by improving neurodevelopmental outcomes in those who received it, by 5 and 11 years these benefits seem to disappear with only mild motor differences being seen.
Turning to a new question
The new query though is how long to treat? Many units will typically stop caffeine somewhere between 33-35 weeks PMA on the grounds that most babies by then should have outgrown their irregular respiration patterns and have enough pulmonary reserve to withstand a little periodic breathing. Certainly there are those who prove that they truly still need their caffeine and on occasion I have sent some babies home with caffeine when they are fully fed and otherwise able to go home but just can’t seem to stabilize their breathing enough to be off a monitor without caffeine. Then there is also more recent data suggesting that due to intermittent hypoxic episodes in the smallest of infants at term equivalent age, a longer duration of therapy might be advisable for these ELBWs. What really hasn’t been looked at well though is what duration of caffeine might be associated with the best neurodevelopmental outcomes. While I would love to see a prospective study to tackle this question for now we will have to do with one that while retrospective does an admirable job of searching for an answer.
The Calgary Neonatal Group May Have The Answer
Lodha A et al recently published the paper Does duration of caffeine therapy in preterm infants born ≤1250 g at birth influence neurodevelopmental (ND) outcomes at 3 years of
age? This retrospective study looked at infants under 1250g at birth who were treated within one week of age with caffeine and divided them into three categories based on duration of caffeine therapy. The groups were as follows, early cessation of caffeine ≤ 14 days (ECC), intermediate cessation of caffeine 15–30 days (ICC), and late cessation of
caffeine >30 days (LCC). In total there were 508 eligible infants with 448 (88%) seen at 3 years CA at follow-up. ECC (n = 139), ICC (n = 122) and LCC (n = 187). The primary outcome here was ND at 3 years of age while a host of secondary outcomes were also examined such as RDS, PDA, BPD, ROP as typical morbidities. It made sense to look at these since provision of caffeine had previously been shown to modify such outcomes.
Did they find a benefit?
Sadly there did not appear to be any benefit regardless of which group infants fell in with respect to duration of caffeine when it came to ND. When looking at secondary outcomes there were a few key differences found which favoured the ICC group. These infants had the lowest days of supplemental oxygen, hospital stay ROP and total days of ventilation. This middle group also had a median GA 1 week older at 27 weeks than the other two groups. The authors however did a logistic regression and ruled out the improvement based on the advanced GA. The group with the lowest use of caffeine had higher number of days on supplemental oxygen and higher days of ventilation on average than the middle but not the high caffeine group. It is tempting to blame the result for the longer caffeine group on these being babies that were just sicker and therefore needed caffeine longer. On the other hand the babies that were treated with caffeine for less than two weeks appear to have likely needed it longer as they needed longer durations of oxygen and were ventilated longer so perhaps were under treated. What is fair to say though is that the short and long groups having longer median days of ventilation were more likey to have morbidities associated with that being worse ROP and need for O2. In short they likely had more lung damage. What is really puzzling to me is that with a median GA of 27-28 weeks some of these kids were off caffeine before 30 weeks PMA and in the middle group for the most part before 32 weeks! If they were in need of O2 and ventilation for at least two weeks maybe they needed more caffeine or perhaps the babies in these groups were just less sick?
What is missing?
There is another potential answer to why the middle group did the best. In the methods section the authors acknowledge that for each infant caffeine was loaded at 10 mg/kg/d. What we don’t know though is what the cumulative dose was for the different groups. The range of dosing was from 2.5-5 mg/kg/d for maintenance. Lets say there was an over representation of babies on 2.5 mg/kg/d in the short and long duration groups compared to the middle group. Could this actually be the reason behind the difference in outcomes? If for example the dosing on average was lower in these two groups might it be that with less respiratory drive the babies in those groups needed faster ventilator rates with longer durations of support leading to more lung damage and with it the rest of the morbidities that followed?
It would be interesting to see such data to determine if the two groups were indeed dosed on average lower by looking at median doses and total cumulative doses including miniloads along the way. We know that duration may need to be prolonged in some patients but we also know that dose matters and without knowing this piece of information it is tough to come to a conclusion about how long exactly to treat.
What this study does though is beg for a prospective study to determine when one should stop caffeine as that answer eludes us!
For almost a decade now confirmation of intubation is to be done using detection of exhaled CO2. The 7th Edition of NRP has the following to say about confirmation of ETT placement “The primary methods of confirming endotracheal tube placement within the trachea are detecting exhaled CO2 and a rapidly rising heart rate.” They further acknowledge that there are two options for determining the presence of CO2 “There are 2 types of CO2 detectors available. Colorimetric devices change color in the presence of CO2. These are the most commonly used devices in the delivery room. Capnographs are electronic monitors that display the CO2 concentration with each breath.” The NRP program stops short of recommending one versus the other. I don’t have access to the costs of the colorimetric detectors but I would imagine they are MUCH cheaper than the equipment and sensors required to perform capnography using the NM3 monitor as an example. The real question though is if capnography is truly better and might change practice and create a safer resuscitation, is it the way to go?
Fast but not fast enough?
So we have a direct comparison to look at. Hunt KA st al published Detection of exhaled carbon dioxide following intubation during resuscitation at delivery this month. They started from the standpoint of knowing from the manufacturer of the Pedicap that it takes a partial pressure of CO2 of 4 mm Hg to begin seeing a colour change from purple to yellow but only when the CO2 reaches 15 mm Hg do you see a consistent colour change with that device. The capnograph from the NM3 monitor on the other hand is quantitative so is able to accurately display when those two thresholds are reached. This allowed the group to compare how long it took to see the first colour change compared to any detection of CO2 and then at the 4 and 15 mm Hg levels to see which is the quicker method of detection. It is an interesting question as what would happen if you were in a resuscitation and the person intubates and swears that they are in but there is no colour change for 5, 10 or 15 seconds or longer? At what point do you pull the ETT? Compare that with a quantitative method in which there is CO2 present but it is lower than 4. Would you leave the tube in and use more pressure (either PIP/PEEP or both?)? Before looking at the results, it will not shock you that ANY CO2 should be detected faster than two thresholds but does it make a difference to your resuscitation?
The Head to Head Comparison
The study was done retrospectively for 64 infants with a confirmed intubation using the NM3 monitor and capnography. Notably the centre did not use a colorimetric detector as a comparison group but rather relied on the manufacturers data indicating the 4 and 15 mm Hg thresholds for colour changes. The mean age of patients intubated was 27 weeks with a range of 23 – 34 weeks. The results I believe show something quite interesting and informative.
Median time secs (range)
Earliest CO2 detection
3.7 (0 – 44s)
4 mm Hg
5.3 (0 – 727)
15 mm Hg
8.1 (0 – 727)
I wouldn’t worry too much about a difference of 1.6 seconds to start getting a colour change but it is the range that has me a little worried. The vast majority of the patients demonstrated a level of 4 or 15 mm Hg within 50 seconds although many were found to take 25-50 seconds. When compared to a highest level of 44 seconds in the first detection of CO2 group it leads one to scratch their head. How many times have you been in a resuscitation and with no CO2 change you keep the ETT in past 25 seconds? Looking closer at the patients, there were 12 patients that took more than 30 seconds to reach a threshold of 4 mm Hg. All but one of the patients had a heart rate in between 60-85. Additionally there was an inverse relationship found between gestational age and time to detection. In other words, the smallest of the babies in the study took the longest to establish the threshold of 4 and 15 mm Hg.
Putting it into context?
What this study tells me is that the most fragile of infants may take the longest time to register a colour change using the colorimetric devices. It may well be that these infants take longer to open up their pulmonary vasculature and deliver CO2 to the alveoli. As well these same infants may take longer to open the lung and exhale the CO2. I suppose I worry that when a resuscitation is not going well and an infant at 25 weeks is bradycardic and being given PPV through an ETT without colour change, are they really not intubated? In our own centre we use capnometry in these infants (looks for a wave form of CO2) which may be the best option if you are looking to avoid purchasing equipment for quantitative CO2 measurements. I do worry though that in places where the colorimetric devices are used for all there will be patients who are extubated due to the thought that they in fact have an esophageal intubation when the truth is they just need time to get the CO2 high enough to register a change in colour.
Anyways, this is food for thought and a chance to look at your own practice and see if it is in need of a tweak…
Intubation is not an easy skill to maintain with the declining opportunities that exist as we move more and more to supporting neonates with CPAP. In the tertiary centres this is true and even more so in rural centres or non academic sites where the number of deliveries are lower and the number of infants born before 37 weeks gestational age even smaller. If you are a practitioner working in such a centre you may relate to the following scenario. A woman comes in unexpectedly at 33 weeks gestational age and is in active labour. She is assessed and found to be 8 cm and is too far along to transport. The provider calls for support but there will be an estimated two hours for a team to arrive to retrieve the infant who is about to be born. The baby is born 30 minutes later and develops significant respiratory distress. There is a t-piece resuscitator available but despite application the baby needs 40% oxygen and continues to work hard to breathe. A call is made to the transport team who asks if you can intubate and give surfactant. Your reply is that you haven’t intubated in quite some time and aren’t sure if you can do it. It is in this scenario that the following strategy might be helpful.
Surfactant Administration Through and Laryngeal Mask Airway (LMA)
Use of an LMA has been taught for years in NRP now as a good choice to support ventilation when one can’t intubate. The device is easy enough to insert and given that it has a central lumen through which gases are exchanged it provides a means by which surfactant could be instilled through a catheter placed down the lumen of the device. Roberts KD et al published an interesting unmasked but randomized study on this topic Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial. Due to size limitations (ELBWs are too small to use this in using LMA devices) the eligible infants included those from 28 0/7 to 35 6/7 weeks and ≥1250 g. The infants needed to all be on CPAP +6 first and then fell into one of two treatment groups based on the following inclusion criteria: age ≤36 hours,
(FiO2) 0.30-0.40 for ≥30 minutes (target SpO2 88% and 92%), and chest radiograph and clinical presentation consistent with RDS. Exclusion criteria included prior mechanical ventilation or surfactant administration, major congenital anomalies, abnormality of the airway, respiratory distress because of an etiology other than RDS, or an Apgar score <5 at 5 minutes of age.
Procedure & Primary Outcome
After the LMA was placed a y-connector was attached to the proximal end. On one side a CO2 detector was placed and then a bag valve mask in order to provide manual breaths and confirm placement over the airway. The other port was used to advance a catheter and administer curosurf in 2 mL aliquots. Prior to and then at the conclusion of the procedure the stomach contents were aspirated and the amount of surfactant determined to provide an estimate of how much surfactant was delivered to the lungs. The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life. Treatment failure was defined upfront and required 2 of the following: (1) FiO2 >0.40 for >30
minutes (to maintain SpO2 between 88% and 92%), (2) PCO2 >65 mmHg on arterial or capillary blood gas or >70 on venous blood gas, or (3) pH <7.22 or 1 of the following: (1) recurrent or severe apnea, (2) hemodynamic instability requiring pressors, (3) repeat surfactant dose, or (4) deemed necessary by medical provider.
Did it work?
It actually did. Of the 103 patients enrolled (50 LMA and 53 control) 38% required intubation in the LMA group vs 64% in the control arm. The authors did not reach their desired enrollment based on their power calculation but that is ok given that they found a difference. What is really interesting is that they found a difference in the clinical end point despite many infants clearly not receiving a full dose of surfactant as measured by gastric aspirate. Roughly 25% of the infants were found to have not received any surfactant, 20% had >50% of the dose in the stomach and the other 50+% had < 10% of the dose in the stomach meaning that the majority was in fact deposited in the lungs. I suppose it shouldn’t come as a surprise that among the secondary outcomes the duration length of mechanical ventilation did not differ between two groups which I presume occurred due to the babies needing intubation being similar. If you needed it you needed it so to speak. Further evidence though of the effectiveness of the therapy was that the average FiO2 30 minutes after being treated was significantly lower in the group with the LMA treatment 27 vs 35%. What would have been interesting to see is if you excluded the patients who received little or no surfactant, how did the ones treated with intratracheal deposition of the dose fare? One nice thing to see though was the lack of harm as evidenced by no increased rate of pneumothorax, prolonged ventilation or higher oxygen.
Should we do this routinely?
There was a 26% reduction in intubations in te LMA group which if we take this as the absolute risk reduction means that for every 4 patients treated with an LMA surfactant approach, one patient will avoid intubation. That is pretty darn good! If we also take into account that in the real world, if we thought that little of the surfactant entered the lung we would reapply the mask and try the treatment again. Even if we didn’t do it right away we might do it hours later.
In a tertiary care centre, this approach may not be needed as a primary method. If you fail to intubate though for surfactant this might well be a safe approach to try while waiting for a more definitive airway. Importantly this won’t help you below 28 weeks or 1250g as the LMA is too small but with smaller LMAs might this be possible. Stay tuned as I suspect this is not the last we will hear of this strategy!
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.