Premature birth has always been a challenge, but the past few decades have seen revolutionary advances in neonatal care. On this World Prematurity Day – November 17th, I wanted to reflect on how far we have come in the last few decades. If you are a parent on your journey through the NICU and struggling with the day to day ups and downs you may find this journey enlightening. Let’s take a look at both a personal journey, the broader neonatal landscape and how things changed Nationally and even locally over time. Stay with me and I think you will be amazed at just how far we’ve come.
Much like Dr. Suess’s book I wonder if the people that came before me ever envisioned the places we would go!
1974: My personal preterm story
In the 1970s, neonatal care faced significant limitations. For preterm babies, respiratory distress syndrome (RDS) was a leading cause of death. Without adequate treatment for underdeveloped lungs, survival was uncertain, especially for extremely premature infants. We had ventilators of course but with lungs that were immature the risk of air leaks called pneumothoraces was high. Being premature was a very risk proposition.My own family was affected by this as my siblings were born at 34 weeks gestation and my brother had respiratory distress syndrome. In 2024 a baby at 34 weeks with RDS would not cause anyone to worry as we are well equipped with fancy ventilators and most of all surfactant which quickly helps to open up lungs that are “stuck” together. This wasn’t available in those days and it’s hard to believe that just 50 years ago my parents were faced with the knowledge that their son had a 50% chance of survival. He did make it through but survival in the interim has crept up to well over 99%. On this front we have done “real good”.
1980: Preemie treated with surfactant!
We knew sine the 1960s that surfactant deficiency was the cause of hyaline membrane disease or RDS as it is also known. If you weren’t aware of it, let me tell you , that we in medicine are a cautious bunch. It took almost two decades for the first produced surfactant to be given to a preterm baby. This monumental event which really changed Neonatology occurred in 1980. Fujiwara and colleagues reported a landmark paper Artificial surfactant therapy in hyaline-membrane disease which demonstrated that in ten infants given exogenous surfactant their oxygen needs declined quickly along with support needed on the ventilator. It would take another ten years before the FDA in the United States would approved exogenous surfactant use broadly for preterm infants. What can I say? I told you we are a cautious bunch!. This widespread adoption of surfactant was a landmark change in practice that singlehandedly marked a dramatic shift in the chances of survival for preterm infants.
1998: My Journey Begins – 28 Weeks is Thrilling!
By 1998I entered the field of neonatal care as a Pediatric resident. I witnessed firsthand the thrill of saving lives once considered impossible to rescue. While many centres are now offering resuscitation at 22 or 23 weeks gestation it is hard to believe that babies born at 27 – 28 weeks were considered high risk at this point. In 2024 a baby born at such an age is considered a bigger preemie compared to those at 27 and 28 weeks which I suppose has a lot to do with perspective! Nonetheless, the past 26 years have seen our expectations for survival and importantly survival without morbidities increase dramatically for those born at 26 – 28 weeks for sure.
2015: Challenging the Threshold of Prematurity to 23 Weeks
Fast forward to 2015, and the threshold of viability was pushed even further. Babies born at 23 weeks gestation in our centre had traditionally been considered too small to survive. Prior to 2015 we would seldom see a baby born at this gestational age resuscitated. It was apparent though when taking the temperature of the room so to speak in North America that the tide was turning and resuscitation was being offered. An important paper in this regard that gave everyone in neonatal care some pause to reflect was the paper Between-hospital variation in treatment and outcomes in extremely preterm infants by M Rysavy et al. The paper demonstrated variability in outcomes at the edge of viability around 22 to 23 weeks but really enlightened many by showing that not only were some hospitals resuscitating infants at these ages but they could actually do reasonably well enough.
The scatterplots are taken from the same paper and demonstrated a lot of variation in outcomes between 24 hospitals. Some did not have great outcomes while others did. The data begged for Neonatologists to ask a critical question. What are some centres doing to achieve such incredible results and secondly if results can be so good, should we continue our patriarchal ways and decide for families what we are and are not prepared to do or should families be central to the decision?
2017: A Shift Toward Shared Decision-Making
The Canadian Pediatric Society was under pressure between 20015 – 2017 to change the recommendations for periviable births. The statement from the CPS was quite prescriptive in its approach to offering resuscitation with fairly rigid goal posts at 23 weeks for consideration of resuscitation and language which insisted resuscitation should or should not be offered at a given gestational age.
In 2017, neonatal care saw a significant shift in approach, emphasizing shared decision-making between medical teams and families. The CPS statement was revised to reflect carefor extremely preterm infants that became more personalized, with parents playing an active role in decisions about their baby’s care. This collaborative approach fostered trust, empowered families, and ensured that care aligned with their values and goals. The current statement Counselling and management for anticipated extremely preterm birth included the following recommendation:
“When both early intensive care and palliative care are considered to be equal care options, the management plan should be decided upon after engaging in a SDM process with parents. The SDM process should be ongoing as the pregnancy continues”
Shared decision making or SDM became front and centre in this statement and continues to be the standard for discussions with families today. In the event of equipoise and uncertainty it should be the family that ultimately decides based on their beliefs and values whether one tries to resuscitate or not. After birth the extent to which we continue care needs to centre around the family as well.
2023: Redefining Viability at 22 Weeks
In 2023, the line between impossible and possible was redrawn yet again. Advances in neonatal technology and medical expertise made it feasible to care for babies born at just 22 weeks gestation in our centre and elsewhere. We were a little later to the game so to speak as other centres had already been doing so but we arrived. Publications from Sweden and Japan were growing and demonstrating that not only was survival possible at this gestational age but that survival without significant disability was a real possibility. In Japan for example a publication last year Management and outcomes of periviable neonates born at 22 weeks of gestation: a single-center experience in Japan found a survival rate of 83% at 22 weeks gestation. There remain questions about whether populations in Sweden and Japan are perhaps different from other areas of the world but at the end of the day both countries forced all of us Neonatologists to question what was impossible and possible. No doubt the next decade will see refinements that don’t just focus on survival but optimizing outcomes as well!
2024: Breastfeeding and Kangaroo Care Take Center Stage
Looking to 2024, we have seen a focus on the benefits of breastfeeding and skin to skin or kangaroo care.
Breastfeeding and kangaroo care (skin-to-skin contact) have emerged as vital components of neonatal care, offering powerful benefits for both babies and their families. These practices not only promote bonding but also improve immune function, growth, and neurological outcomes for preemies. Looking at the sections that preceded this one you no doubt can see the importance of research and technological development in the care of these babies. We certainly could not have achieved levels of survival without disability without advances in our understanding of ventilators, ultrasound to assess organs and the hemodynamics system and more.
What is astounding to me though is that the focus has shifted back to the basics. Breast milk, love and caring. Increasing rates of breast milk consumption by preterm infants have been linked to reductions in sepsis and chronic lung disease to name just a couple of benefits. Skin to skin care has led to reduction in oxygen need, apneas and bradycardia and more. Technology is amazing but more and more we are getting back to the basics which once again centres around the family unit.
The Future: Hope and Innovation
The story of neonatal care is one of hope, perseverance, and constant innovation. From the early days of battling RDS to redefining viability and promoting family-centered care, every milestone represents a step closer to ensuring that every baby, no matter how small, gets the best possible start in life.
As we honor World Prematurity Day, let us celebrate the progress we’ve made and continue working toward a future where preterm birth no longer carries the same risks. Together, we can ensure that every baby—no matter how tiny—is given the chance to thrive.
Here’s to the tiny warriors and the big-hearted teams who fight for them every day.
When it comes to non-invasive ventilation the field has become a little more crowded in recent years at least in our institution. In the recent past if one decided to extubate an ELGAN the biggest decision was what CPAP pressure to use. These days we have the option of high frequency nasal ventilation (nHFOV) or non-invasive positive pressure ventilation (NIPPV) to choose from as additional options. Both of these modalities have their uses and I have written about nHFOV before as in Nasal High Frequency Oscillatory Ventilation For Preventing Intubation. On this post though I want to look at NIPPV which has actually been around longer as a modality. The gist of this mode is that one chooses a delta P, peep, Ti and rate much like you would on a conventional ventilator. When ventilating through a nasal interface the device provides ventilation although it is questionable I suppose how much of that is alveolar ventilation. The study we are going to talk about here caught my eye as the information gleaned from it gives me at least an idea of how this mode may work to help prevent reintubations.
In this study each patient served as their own control and alternated between either a start of a rate of 10 BPM or a rate of 30 BPM as shown in the following diagram. The infants were all between 24 +0 and 32 +6 weeks gestation to be included in the study. Delivery of NIPPV was through the Leoni Ventilator using RAM cannulae and importantly the mode was non-synchronized. Each infant needed to be stable on their settings for at least 6 hours before being included. The authors hypothesis was that rate matters to clear carbon dioxide. To monitor CO2 levels they used transcutaneous CO2 measurements to allow for continuous measurement over each hour of the study. Given this belief, there was safety built into the protocol such that patients were excluded if on the set rate of 10 bpm the tcCO2-related pCO2 was <40 mmHg, or on NIPPV if the set rate of 30 bpm had a tcCO2-related-pCO2 is 60 mmHg, In other words, if rate matters and your tcCO2 was already less than 40 on a low rate then it would not be safe to blow off more CO2 and vice versa with high CO2 and low rates. To ensure that only rate affected the results “during the 3 h of the study no changes in PIP, PEEP or FiO2 were allowed with the following exceptions: if spO2 was <90% or >95% for more than 20 s, an increase or decrease in FiO2 were allowed to keep spO2 90–94%, and were documented”.
So does rate matter?
It turns out the authors found no difference in CO2 levels based on rate changes alone.
This of course is contrary to what the authors expected to find. The question is why this might be. What follows now is just speculation on my part but given the finding of no difference I can offer a few thoughts. The first is that NIPPV does not involve a distal delivery of gas like the situation of an endotracheal tube near the carina. With an endotracheal tube in place the delta P or pressure above the set peep is delivered to the gas exchanging areas of the lung. With NIPPV you are delivering the pressure at the nose and therefore there is a fair amount of dead space in between the exit of the gas into the baby and the lung. Might you just be really ventilating dead space for the most part?
Secondly, depending on the fit of the mask or the degree that the mouth was open how do we know how much of the non-invasive ventilation reached the infant? Lastly, in our own centre we have not been impressed with the RAM cannulae as we have found that whether the prongs are in or out of the nose the pressure being detected as being delivered seems to stay the same at least as the ventilator sees it. If the prongs were not in the nose properly and the atmosphere was being ventilated would one really know that the pressures weren’t really getting into the nose?
Lastly, the Leoni ventilator is not capable of delivering synchronized NIPPV. Now that there is the availability of synchronization on ventilators such as on the Puritan Bennett 980 ventilator it would be interesting to see the same study done again. If you are delivering non-synchronized breaths which are not in sync with the patient should we expect a change in CO2? What if half the breaths for example by chance are delivered on exhalation? Not much effect on CO2 I would think.
I am not saying that rate doesn’t matter at all but I suppose I am saying within the context of this study it doesn’t matter to CO2. My best guess as to how NIPPV works to prevent reintubation may be secondary to two things. The first would be by irritating the baby with the puffs of delta P. Think of it like intermittent stimulation. The second possibility is that the same puffs of air help keep the pharynx open and minimizes the obstructive portion of apnea of prematurity. Whatever the reason NIPPV appears to work to prevent reintubation in some infants!
I have no doubt the group here will look at the effect of delta P on CO2 soon enough and I wonder if we will see much difference there either. It also will be important to look at the effect of rate in a synchronized fashion! Time will tell.
Over the last number of years clinicians have sought more and more to limit the experience of babies to painful stimuli. In the area of surfactant administration this has focused on “less invasive” strategies such as use of small catheters while on CPAP (LISA or MIST) and surfactant via LMA or Surfactant Administration Through Laryngeal or Supraglottic Airways (SALSA) as it is sometimes known. Intubation Surfactant Extubation (INSURE) while not generally included in the less invasive approach is to a degree fitting since it involves at least intubating for a very brief period after surfactant is administered. SALSA has been growing in popularity due to its “extreme” non-invasiveness since babies are receiving surfactant without instrumentation of the airway at all. It should come as no surprise then that head to head comparisons will be done to determine which should be reigned king!
The Contenders
A group out of Albany, NY has looked at SALSA vs INSURE before in which they used morphine for premedication prior to the procedure. You might ask why any premedication is needed at all but I would suggest that covering one’s airway and dripping liquid into it might cause some irritation so why not keep them calm. The authors in their paper Randomized trial of laryngeal mask airway versus endotracheal intubation for surfactant delivery found a high rate of failure in the intubation arm which more than likely was attributable to the respiratory depressive effect of the same.
This time around in the current paper Randomized Trial of Surfactant Therapy via Laryngeal Mask Airway Versus Brief Tracheal Intubation in Neonates Born Preterm they switched to remifentanil for its brief duration of action. Babies in the SALSA arm received that drug while those in the ETT group received atropine as well. The authors included infants born from 27 weeks to 36 weeks gestation who were larger than 800g at birth. This was a non-inferiority trial with the primary outcome being Our primary outcome was failure of surfactant therapy to prevent the need for invasive mechanical ventilation or its surrogate indicators, namely, more than 2 doses of surfactant therapy, sustained need for FiO2 >0.60 to maintain target O2 saturations, or a second dose of surfactant within 8 hours of the first dose.
Surfactant redosing criteria were the same for both groups: FiO2 >0.60 or FiO2 >0.30 with clinical signs of worsening RDS. If surfactant needed to be given a second time it was via intubation. The decision to ultimately intubate though was in the hands of the practitioners.
Unfortunately, the trial was stopped after only 51 patients were enrolled into the LMA and 42 into the INSURE groups respectively. Randomization was by block design and the authors were looking for 130 patients per group so they fell far short of that. The reasons for falling short were interesting as they demonstrate one of the challenges of research and changing beliefs. At the start of the trial there was equipoise among practitioners with respect to the two modes of surfactant delivery but part way through people preferred SALSA. The authors changed the randomization to try and deal with that to a 2:1 favoring SALSA but with the combination of that and COVID they had to stop. They did manage to get enough though to determine the primary outcome in spite of this.
What did they find in the end?
Well first of all it is worth noting that there were no differences in baseline characteristics between the two groups. As it turns out, while the numbers were small it didn’t seem to lead to an unbalancing of groups.
With respect to inferiority the finding was that it was in fact not inferior as per the figure below.
In table 2 some interesting findings emerge
Early failure of surfactant which was defined as within 1 hour of surfactant administration was found to be significantly increased in the intubation group. Late failure through at 5 days of age was not any different. An early failure is suggestive of the procedure not working to deliver the surfactant. When you look at the bottom half of table 2 the answer may be there. As part of the planned procedure the authors aspirated a gastric tube after surfactant administration to ensure that it went to the right place. There was no difference in surfactant volume aspirated via this route. There was however 9.7% of infants in the ETT group that experienced reflux in the ETT vs zero with observed reflux in the SALSA group (in the mouth perhaps?). Is surfactant without PPV better tolerated maybe?
There was a trend overall to more failures in the ETT arm although this was not found to be significant either in the intention to treat or per protocol analysis.
Where do we go from here?
First off it is important to look at who was chosen for this strategy. You may have noticed that there were no micropreemies in this trial. The reason for this is likely two-fold. The first is that prior trials on SALSA have found it doesn’t work as well to prevent intubations in babies below 27 weeks. This is very similar to the findings of studies using aerosolized surfactant. It may well be that there just isn’t enough of the total dose getting to the alveoli. If you can get some of the dose in deep into the lung for those with less severe RDS it may work ok for those babies. The second reason likely has to do with using LMAs in those in that weight range as they generally are designed for larger preemies although I understand smaller ones are becoming more readily available.
The second point is that this was not a blinded study. This could have become an issue as the authors acknowledge that there was a growing institutional preference for SALSA as the study went on. If the Neonatologist subconsciously believes it is better, might that have influenced some of the decisions to intubate again since one of the criteria was “clinical signs of worsening RDS”. It is quite possible this could have led to a few more intubations in the INSURE group for repeat doses. We can’t prove that but it is a weakness of the study.
At the very least it can be argued that the use of SALSA works as a small percentage overall failed the procedure. The largest groups of infants though were above 29 weeks so we also might not expect a high rate of failure after one dose though. It works but how well is tough to say.
Where I think this study is really important though is what it tells us for centers in particular who don’t intubate as often. Intubation is a skill that is declining in opportunity, both because of a turn to more use of non-invasive support as a primary mode of treatment. It also has become scarcer at an individual level due to there being more practitioners who can perform the skill. Having an option to use SALSA for those who aren’t as comfortable with intubation will no doubt be of much interest to many in this situation.
What is no doubt going to come next is the LISA/MIST vs SALSA trials. I hope that in the future pain scores are included in these sorts of analyses to really determine if in being less invasive we are also ensuring that we are also not undertreating discomfort. I suppose the lesson being learned from all of this is that less very well may be more.
I couldn’t think of a better topic for World Prematurity Day 2021 than what constitutes the edge of viability. Thinking back over my career, when I was a resident and fellow infants born at 25 and 26 weeks were deemed about as low as “we should” go but we certainly resuscitated infants at 24 weeks but this was considered heroic. Jump ahead to the last decade and we began caring for infants at birth at 23 weeks so commonly that the thought of offering comfort care only to infants at 24 weeks became almost unthinkable for many health care providers. Before I get jumped on, let me say that I am not saying I agree or disagree with that sentiment but it is something that is felt by many.
The Shared Decision Model
In the last few years a rethink again has occurred whereby the concept of the treating team knowing best has been replaced by the “shared decision model”. In this line of thinking, it is not up to us as health care providers to “tell the parents” what to do but rather come to a shared decision based on an assessment of the wishes and values of the parents in conjunction with hearing about both short and long term problems their infants may face if resuscitated. This concept was central to the statement by the Canadian Pediatric Society that I am proud to have been part of with respect to its development. The statement for those that are interested is Counselling and management for anticipated extremely preterm birth
What’s next? Going below 22 weeks?
The challenge of the shared decision model is that there comes a point where the answer is simply “no”. If for example a family at 19 weeks gestation demanded an attempt at resuscitation I would have to inform them that survival is not possible (assuming ultrasound confirmed anthropometric measurements consistent with that age). The question though becomes a little more difficult to answer at 21 weeks and was the subject of a recent article in the New York Times about a survivor at 21 weeks gestation.
Even with the best gestational age dating the estimate can be off by up to 5 days so it’s possible that the infant in this story was closer to 22 weeks or even midpoint between 22 and 23 weeks in reality. Regardless it does raise the question about what to do at 21 weeks and I suspect we will begin to see more stories about this now that the glass ceiling of 22 weeks has been breached. What about below 21 weeks? Sounds impossible I know but with research that remains at the stage of animal studies this may become possible. Maybe not in the next 5-10 years but it could happen in my lifetime in this chosen field.
The Artificial Placenta
This made headlines a few years ago with the news that the Children’s Hospital of Philadelphia had successfully kept a lamb alive for a period of 4 weeks using an artificial placenta and amniotic fluid.
You might think that this was a one-off experiment that will never see the light of day but similar work is being done in Toronto, Canada where they have been able to do similar work with preterm piglets in their paper Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus. Incidentally as my colleague Dr. Ayman Sheta worked on this project while in Toronto I am particularly pleased to share this research. Similar to the experience in CHOP the team in Toronto has been able to keep piglets alive for progressively longer durations. My understanding is that despite the best efforts infectious complications over arise limiting how long one can sustain such animals.
This leads me to my final thoughts on where we might be able to go. I see a future where we apply such technology to humans but not in the way that people might have thought. Keeping a fetus after delivery at 21 or 20 weeks on an artificial placenta for many weeks is not likely a realistic goal. What if we could get 1 or 2 weeks though and allow the fetus to be oxygenated without using positive pressure on their developing lungs and transition them at 23 or 24 weeks gestation? We may in this way be able to allow for postnatal maturation in a artificial uterine environment and give babies a chance who would otherwise never had the opportunity for a shared decision with medical staff.
Sound like science fiction? Well the beauty of the internet as my friend told me today is that once it’s out there it out there for good. Let’s see how this post stands the test of time and to all the babies out there in NICUs and to their families I wish you all a good and uneventful World Prematurity Day wherever you may be!
Extubation is a regular occurrence in the NICU. We do our best to predict who will succeed and who will fail but it isn’t always easy to figure out who they are in advance. We use techniques such as looking at oxygenation histograms and using thresholds for PIP, PEEP or MAP but in the end sometimes it works and other times it doesn’t. In an effort to improve on intubation success, some creative researchers in Switzerland employed a technique called end-expiratory lung impedance or EELI to measure lung volume before, during and after the extubation process. The use of EELI is based on the impendance of the lung changing with the distribution of tissue and air and by placing electrodes one can generate a cross sectional volume that has been shown in neonates to be representative of total lung volume. The EELI technique creates an image like this which is use to generate the estimate of lung volume.
The researchers in this study were seeking to do a quality improvement project and use EELI to estimate lung volume at different time points in an extubation. The time points were all 30 seconds including, immediately before first handling of the infant (baseline), tracheal suctioning (suction), start and end of adhesive tape removal (adhesive tape begin and adhesive tape end), pulling the endotracheal tube (extubation), initiation of non-invasive ventilation (NIV), immediately before and after turning the infant to prone position (supine and prone, respectively), and 10 min after turning to prone position (prone10). As per unit policy all babies were ventilated with Draeger VN500 ventilators and if <28 weeks went on to NIPPV when extubated or if 28 weeks or more straight CPAP. The purpose of this quality initiative was to determine using EELI at what point in the extubation process infants might be losing lung volume and then based on the information see if they could ultimately use this to improve the chances of successful extubation in the future.
What makes this study interesting is that the infants were found to lose volume but at a time when I would not have expected it.
The Reveal
Below is a graphical depiction of EELI and estimates of FRC during the different time points. The changes in electrical impedance by EELI were converted on the right Y axis to an FRC in mL/kg.
What is surprising at least to me here is the loss of volume occurs not with extubation but rather when the tape removal process happens. With the placement of the prongs on the infant at extubation the FRC gradually rises and recovery occurs. Moreover as shown in the 12 patients included in this study, the recovery once non-invasive ventilation is provided is quite rapid and evident within 1-2 breaths.
A couple other things to note. The loss of FRC during tape removal was about 10 mL/kg and if typical FRC in a preterm infant is 20-25 mL/kg you can see the impact this would have on lung volume and reserve. As this was a small study it could not detect a threshold at which extubation would fail but one infant who developed a pneumothorax and required reintubation did not get back to their baseline FRC.
What is this signaling?
Yes this is a small study but it did look at about 3000 breaths so there is a fair amount of data to look at. What the paper demonstrates I think is that there is a vulnerable time during tape removal where likely due to the fact that we use uncuffed ETTs in neonatology it is possible for these infants to lose lung volume. It may be that as they strain and bear down the ventilator may not be as effective at delivering volume to them. Measures that might help during this time could be skin to skin care, breastmilk drops or scent, sucrose or a variety of other non-pharmacologic measures to keep them calm. This might help to minimize such volume loss. Secondly, knowing the significant risk of volume loss it underlines the importance of placing nasal prongs on as quickly as possible during the transition from invasive to non-invasive ventilation as recovery of lung volume is possible. It think it also suggests that if we are “peepaphobic” and use an insufficient amount of support at extubation these infants may be vulnerable to experience significant volume loss as well.
While EELI may not be perfect, this study is the first of its kind and may shed some light into why some infants fail after extubation. While usually I say less is more, I do wonder if in the case of extubation, this study gives some evidence to support starting with a higher PEEP than you think you need non-invasively and then backing off after one has successfully extubated. This may be the first study I have seen on this but I am certain it won’t be the last.
