Elon Musk, a name synonymous with technology in our time (as the brains behind the all-electric Tesla automobile), had this to say about the “Good Old Days”
“If anyone thinks they’d rather be in a different part of history, they’re probably not a very good student of history. Life sucked in the old days. People knew very little, and you were likely to die at a young age of some horrible disease…”
I wonder what he would say though about Sister J Ward who worked in the premature unit at Rochford General Hospital, Essex in the 1950s. It was during this time that she took a baby outside with her to enjoy a warm afternoon. Upon returning to the unit and taking off the sheet that accompanied the child she noticed a discrepancy between the yellow colour which remained under the covered skin and that which had been exposed to sunlight. Her observation led her to conclude that the sunlight had in fact been responsible for the change (and she was right!) but her conclusion was largely ignored.
Soon thereafter a tube of blood provided the convincing evidence that the sun was in fact directly responsible for such a change. This tube which had been left on the windowsill in the sun was tested for a bilirubin level and found to be low. As the care providers felt the test was inaccurate a repeat sample was drawn and the fresh tube contained a much higher level. A repeat sample of the blood that was again left in the sun showed an even lower level than previously seen inspiring researchers to seek out the effect of light on bilirubin. This ushered in the age of phototherapy lamps that are used around the world today. The design of such lamps has undergone many changes with the current models mostly focusing on the generation of light in the blue spectrum. Mostly gone in the developed world are the long phototherapy bright light tubes that were ubiquitous when I was in residency. It didn’t start off that way though. All you needed was a little golden sun!
A Randomized Trial of Sunlight to….
This month in the New England Journal of Medicine a non-inferiority study has been published comparing conventional phototherapy with BiliBlankets to you guessed it…sunlight. The study took place in Nigeria where such a study is both practical and possible. Conducting the study in Winnipeg for example would yield a treatment that could be used for 3-4 months a year at best but in a more temperate part of the world it indeed is a reasonable question to ask. The infants randomized to sunlight were placed under filtered light using either a canopy made of an Air Blue 80 film on overcast days or when sunny, in a Gila Titanium film. These films have been shown to essentially block all UV light while allowing light in the blue spectrum through. Aside from Sister Ward demonstrating that sunlight was an effective treatment for jaundice over 60 years ago, a significant motivation for determining if sunlight could be employed is the cost difference of the two strategies. A BiliBlanket will cost between 2-3000 dollars each while these canopies can be made for $0.55 and $1.50 per square foot of film type respectively and $44 and $120 for a canopy for six to eight mother–infant pairs with Titanium and Air Blue 80 films. In countries where resources are scarce one can see the compelling reason to try such a strategy.
The criteria for efficacy were twofold. The first outcome was achieving a rate of increase in total serum bilirubin of less than 0.2 mg per deciliter per hour for infants up to 72 hours of age or secondly a decrease in total serum bilirubin for infants older than 72 hours of age who were receiving at least 5 hours of phototherapy. After comparing 250 courses using sunlight to 311, five hour exposures to BiliBlankets, sunlight was found to be equally effective. Interestingly, the spectral irradiance (measure of the intensity of the light source) however was significantly higher in the group receiving sunlight 40 vs. 17 μW per square centimeter per nanometer, P<0.001. Additionally, the total area covered was greater under the canopy which may help to explain why in a secondary analysis the rate of decline in bilirubin was found to be faster with sunlight.
But is it safe?
Putting babies under the sun for 5 hours would seem to go against everything we have been taught but remember this was filtered light so sunburn was not a concern. Temperatures were monitored for all children and if necessary they were moved into the shade to cool off or in other cases on quite hot days prophylactic cool towels were applied intermittently. In the end though only one baby recorded a short-lived temperature over 39 degrees, no babies became dehydrated and in only one case was a doctor called to see a child.
We are blessed to live in a country where we have ready access to phototherapy blankets, overhead lights that are either independent free units or integrated into expensive neonatal beds. This is not always the case in the developing world. I find it simply amazing that a discovery over 50 years ago that led to the development of an entire industry would one day be simplified back to where it all began. We must not forget that while bilirubin encephalopathy leading to kernicterus is rare in the developed world, in places without access to phototherapy it is a real and present danger. We now know that the most naturopathic treatment of all; the sun which is free and readily available is just as effective and possibly more than our high-tech devices.
Elon Musk may be one of the most brilliant inventors of the modern era but with respect to caring for babies with yellowing of the skin, Sister Ward had a leg up on him.
On occasion two articles will be published in short succession and have discrepant findings. This appears to be one of those times. Hishikawa K in Japan published a paper in September entitled Pulmonary air leak associated with CPAP at term birth resuscitation while Calebi MY from Turkey published Impact of Prophylactic Continuous Positive Airway Pressure on Transient Tachypnea of the Newborn and Neonatal Intensive Care Admission in Newborns Delivered by Elective Cesarean Section in August of this year.
The findings as we will discuss were quite discrepant which on the surface leaves the practitioner in a quandry. How do I best treat my patients? The key difference between the two studies was the finding of an increased rate of pneumothorax in the study by Hishikawa when CPAP was used in term infants with respiratory distress after delivery. Curiously prophylactic CPAP of +5 was used in both studies but the populations under study were quite different. The study by Calebi targeted infants between 34 0/7 weeks and 38/6/7 weeks vs term infants in the study from the Japanese group.
Another important difference is the utilization of CPAP which in the study by Calebi involved prophylactic administration within twenty minutes of birth and in the Japanese cohort the indication was the development of symptoms. Thinking about this for a moment, these two groups are actually quite different. A newborn with TTN has an increased amount of interstitial fluid that has not made it’s way to the hilum for reabsorption in the lymphatic system. The lungs of these infants are heavier with fluid than comparable infants without such pathology and therefore are also less compliant. Non compliant lungs are prone to microatelectasis as the infants progressively experience alveolar collapse. The longer the clinician waits to start supportive CPAP the more the lungs collapse and greater negative pressure is required to open these closing alveoli. Furthermore if there is fluid in the airway itself there is the potential for a ball valve mechanism to come into effect whereby air is able to pass through the dilated airways during inspiration but on expiration the collapse leads to air trapping. Such trapping places the infant at risk for air leak. CPAP is used to establish an adequate functional residual capacity (FRC) as indicated in this picture. Failure to do so results in atelectasis.
The Japanese study examines the impact of CPAP after a change in guidelines in 2010 suggesting that CPAP should be utilized in the delivery suite for those infants with ongoing respiratory distress. The study by Calebi really examines a different patient group being those who are near term patients with TTN who have early CPAP implemented. The early administration of CPAP may be the technique that prevents alveolar collapse as mentioned above and avoids the requirement by the infant to generate such high negative pressure with its inherent risk of air leak.
Is All CPAP The Same?
Another important distinction between the two papers is the way in which CPAP was administered. The Japanese utilized a flow inflating bag with a pressure valve and manometer while the study by Calebi employed a T-piece resuscitator. When it comes to maintaining CPAP there is no question having used both devices that I find the T-piece resuscitator much easier to use and over longer periods the reliability of the pressure delivered by the T-piece would be superior to that with the flow inflating bag. The Neopuff T-Piece Resuscitator possesses a pressure relief valve which could help during an instance when the patient is crying or breath holding. The constant flow without a relief valve could lead to airleak which is precisely the situation that may occur during the use of a flow inflating bag.
Yes there was over a three fold increase in airleak at near term gestational age in the Japanese cohort but this was not seen at all in the Turkish study in which CPAP was implemented early. So the message here is that if you start CPAP early enough you can prevent airleaks from occurring. This in and of itself is worth implementing.
Can CPAP Reduce Hospital Admission to NICU?
There is more to the story however. The Turkish group demonstrated a significant difference in admission rates to the NICU as shown in the following figure. The results here although just achieving significance should not be minimized. Avoiding progressive atelectasis decreases admission rates. The conclusion here is that there is little benefit in adopting a wait and see approach to those kids born by elective c-section. While it is true that you may be treating a significant number of healthy patients between 34 0/7 – 38 6/7 weeks with CPAP it is for a brief period and makes a significant difference in frequency of admission.
We live in an era of bed shortages and I would argue that anything we can do to reduce admissions and moreover keep babies with their parents is worth exploring. From my perspective treating these kids with the appropriate CPAP device for twenty minutes after birth is well worth it. Perhaps your unit should consider the same.
I often catch myself saying that Neonatology being a relatively young speciality has so much more to discover. Any Pediatric resident can attest to this when they scan their journals and see so many articles exploring uncharted territory. As we continue to march forward it gave me pause to realize that we had lost someone in August who quite literally put the intensive in Neonatal Intensive Care.
Dr. Forrest Bird was an inventor and a pilot who was inspired to create a device to deliver oxygen to pilots flying at high altitude. This was needed due to the inability of the allied airforce to fly as high as the German planes. He was able to reverse engineer of sorts a solution to the lack of oxygen the airforce experienced and thereby level the playing field. This technology became the backbone behind the Bird Respirator first produced in 1950. This device is considered to be the dawn of the ventilator and was soon to put the iron lung out of business.
In 1963, following the death of John F. Kennedy’s son Patrick at 34 weeks from RDS research in the field of Neonatology blossomed bringing something positive out of tragedy. Funding for research in the area uncovered the cause of RDS as surfactant deficiency by Dr. Avery and a great number of papers followed exploring the concepts of surface tension, atelectasis and the effects of pressure on expansion of the newborn lung. While I clearly was not working in the field back then I have no doubt the clear need for a device to help these newborns with collapsable lungs inspired Dr. Bird to search for a solution. In 1970 he produced the Baby Bird Ventilator which was essentially a smaller version of the original. Up until this point, there was little that could be done for such preemies and other children in respiratory failure. By some accounts the ability to ventilate a newborn with positive pressure led to a reduction in mortality from 70% to 10% due to respiratory distress.
How Big An Impact Did It Have?
According to the World Health Organization approximately 15 Million babies are born before 37 weeks each year in the world. In the US alone about 1 in 9 babies are born at these gestational ages which translates to about 450000 babies per year. If we take a conservative estimate that 50% will have some degree of respiratory distress and need ventilation or CPAP that translates into 7.5 million babies every year helped by technology that Dr. Bird brought into this world. While true that the Baby Bird would be replaced by more advanced technology as years passed and ventilators of today bear little resemblance to the original design, every device owes a nod to the its ancestor the Baby Bird.
It has been 45 years since the Baby Bird came to market and there are few people working in the field today who would remember using this particular ventilator. Its inventor both directly and indirectly is responsible for saving the lives of millions of babies over a 45 year span. How many of us working in the field today can say that we know someone who has made such an impact in recent memory. Dr. Bird was a hero in Medicine and in particular Neonatology and for that reason in received the National Medal of Technology and Innovation from President Obama in 2009.
I hope that this piece helps to educate even a few people about this modern day hero. It also serves to remind me as we begin to lose the pioneers in our field that perhaps we aren’t such an young specialty anymore after all.
* I would like to thank Jennifer Degl for providing permission to use her photo for this post. She is the author of From Hope to Joy and does great work which can be found at: www.micropreemie.net
A publication this past week has been featured in multiple news stories across North America due to it’s impact on mortality and morbidity in the NICU. Shielding Parenteral Nutrition From Light Improves Survival Rate in Premature Infants: A Meta Analysis made the splash that it did because it’s premise is so simple yet has such an impact. In essence, protect TPN from light (including phototherapy) and you can cut mortality in the NICU in half!
A Canadian Research Story
The CBC has covered this as well with the following piece that also indicates that a survey of NICUs from 4 years ago indicated about half of hospitals did not employ such shielding. In fairness the meta-analysis has just been published which combined 4 studies and about 800 patients to yield these findings but the understanding that such practice could benefit newborns in NICU has been known for many years. What makes this story even more interesting to me is it’s Canadian origin in that Dr. Chessex performed much of the work in this field and his dedication to the area of oxidative stress in large part led to this finding.
In fact in 1999 he published the following paper Protecting solutions of parenteral nutrition from peroxidation which demonstrated that simply covering the bag of TPN was not enough to prevent oxidation from occurring. The whole set up including the bag, lines and during the preparation of TPN needed to be shielded or peroxide concentrations increased by 1.5 -2 times compared to when a clear set up was used. Furthermore phototherapy led to a further rise in the concentration of these oxidative harmful molecules. Ironically it is the necessary components of TPN including riboflavin and lipid that create the environment for light to create these oxidative products that can damage tissue.
You may ask yourself at this point why something that was known nearly 17 years ago did not lead to widespread adoption by NICUs across Canada and perhaps North America. For one, medicine is notoriously slow to change practice especially when there is an effort and cost that will need to be considered. Sourcing such materials is actually more difficult than it may seem as we learned locally two years ago when one of our hospitals began this change. Secondly, Neonatology is littered with bench research that while striking in its findings simply did not translate into a clinically relevant outcome. For example we know that phenobarbital increases the conjugation of bilirubin in the liver and therefore in theory should be a great adjunctive treatment to phototherapy for the usual newborn jaundice but that didn’t pan out in human trials. What is the story here though?
The Landmark Study Results That Made Headlines
The meta-analysis mentioned in the start of this piece and causing all this attention included four studies that examined possible reductions in mortality. In 2007 Chessex studied the effect of light protection (LP) on the incidence of BPD finding a 30% reduction in those infants in a randomized study of LP vs none. This finding alone should be enough to raise some eyebrows and it did as many centres were adopting LP around this time. The second study done in Egypt in 2009 demonstrated a similar finding in reduced BPD rates. The third study was by Chessex again in 2009 and once more demonstrated reductions in oxidant stress and BPD. Curiously the largest of the studies based out of France with 587 patients in 2014 randomized to LP or none found no difference in BPD or death but the latter was very close to meeting statistical significance. In all of these studies no difference in mortality was noted however when they were combined and examined as a group the following was identified. Herein lies the power so to speak of the meta-analysis. Small studies may not demonstrate a difference that reaches significance in the desired outcome of interest but if several studies that have very similar measurements are pooled together the power to find a difference may emerge. That would seem to be the case here in that not only is there a halving of mortality that reaches statistical significance but a specific disadvantage for males was uncovered in that they had a two fold risk compared to females of dying if their TPN was uncovered.
Are These Results Relevant to Modern Practice
The results of this study are profound in terms of the impact that they could have on both BPD and mortality in our NICUs. One caveat needs to be mentioned however and that is the utlilization of oxygen in the NICU now and during the time of these studies. Since the time periods that these studies were undertaken, the use of oxygen for many units including our own has become more tightly regulated. As per NRP guidelines we resuscitate our newborns with room air and use every effort at the bedside to avoid wide swings of FiO2 when addressing an episode of desaturation. Furthermore, antenatal steroids, surfactant, liberal use of CPAP have all led to marked reductions in need for FiO2 such that the days of infants being on 30% FiO2 by nasal prongs have been replaced by room air on CPAP for the most part (at least in our units). What would these results be now if these studies were repeated? My suspicion is not as dramatic but there is no question that for at least 17 years we have known about the risk of such oxidative stress.
Is there any logic behind waiting for more evidence in a modern cohort before implementing a strategy of protecting these solutions from light? I don’t think so and hope that the rest of our community agrees and does not wait many more years to implement such precautions. How many other conditions such as ROP could be affected by simply protecting these solutions from light? Quite frankly I don’t need to know. The time has come for change.
Thank you Dr. Chessex for your dedication in bringing this translational research from the bench to the bedside.
This piece is a short follow-up to the blog post originally posted on June 20th of this year entitled:
Since that post, an incredible shift has occurred in the way that we as a team view attempts at resuscitation at 23 weeks. It took a great deal of dialogue among all health care providers and a deeper understanding of concerns of both Obstetrical and Neonatal colleagues to come to a mutual understanding that could yield a path to move forward. Through dialogue, the damage that had been done by the development of a “broken telephone” was repaired and trust emerged across disciplines which was the only way forward from the beginning.
Why not 22 weeks?
Yes, gestational age is so much more than just a number and must include estimates of fetal size, certainty of dates, parental wishes and several other factors to arrive at a decision that incorporates the wishes of the family. There are certainly significant challenges to informing families during a time of incredible stress as to the options that lay before them but we have to do our best in the time that we have.
When you are crossing that barrier of 24 weeks gestation, despite the caution above about the uncertainty surrounding gestational age dating there is a significant mental leap to move to 23 weeks. The leap to consider 22 weeks is even larger and I would suggest several fold. Is it possible that we would resuscitate such an infant? Absolutely if the dating was uncertain, the family had strong wishes and the team was on board with such a decision but for now this will not be advocated for at all in our city. I suspect similar discussions are happening all over North America and it will be fascinating to see where we land in 5, 10 and more years into the future.
What was the most important change to practice to enable progress?
Prior to 2015 we had one survivor at 23 weeks in a five year period. This year out of five actively resuscitated 3 have survived and at early assessments seem to be doing well. The overwhelming consensus was that skin care needed to be of paramount importance in this process. To that end we began a new process for cleaning the umbilical cord for line insertion with the goal to minimize skin burns on the abdomen. I am proud to report that since we change our technique there have been no skin burns found where once this was commonplace.
The process can be found in this short video here.
For now though, we are about to embark on a new journey in our city and I look forward to the continued collaboration with Obstetricians, Ethicists and all members of the Neonatal team as we explore this new frontier together.
I thought you may find it useful to see how this journey began and where we think it may go by watching this video of myself, Dr. Craig Burym (Obstetrics) and Dr. Aviva Goldberg (Ethics) presenting the approach to resuscitation at 23 weeks from the Neonatal, Obstetrical and Ethical standpoints. The video is about 50 minutes in length but truly addresses issues from multiple vantage points so if you missed it or are interested in how these issues were dealt with please have a look.
(If you are watching this on an Apple computer please use Safari to view)
My friend Nick Hall asked a very important question on Linkedin today in the following post
Nick is a tremendous advocate for premature infants and their families everywhere and as President and Co-Founder of Graham’s Foundation certainly puts himself front and centre. For more information on the incredible work he and his team are doing please see their website at and if you are in the New York area please consider attending their charity benefit to help raise some funds to continue the work that they do.
As it pertains to his question though it did get me thinking. How does a National body like the AAP determine best practice suggestions for a country with 50 states in which roughly 320 million people reside? Using 2013 USA census data ,showing 23.1% of it’s citizens are under 18 this equates to nearly 74 million children. This is a daunting task no doubt and due to regional variation in terms of expertise and available resources not all policies or guidelines are possible to implement equally or at all.
The article that is being addressed in his question of the day is from Med City News which addresses the latest statement from the AAP on managing an anticipated birth before 25 weeks. For the actual statement that the article refers to please see this link which will direct you to the actual paper.
When the Canadian Pediatric Society (CPS) reaffirmed their statement in January 2015 it drew a fair bit of criticism from Canadian Neonatologists and others from abroad due to it’s draconian approach to infants at 22 and 23 weeks gestation. In the CPS statement the following was written in the recommendations section with respect to these two gestational ages which also encompassed 24 weeks as well.
“At 22 weeks’ GA since survival is uncommon, a non-interventional approach is recommended with focus on comfort care”
“At 23 and 24 weeks’ GA active treatment is appropriate for some infants”
What drew the ire of these health care providers was the apparent limitation of resuscitation based on gestational age. It did not seem that consideration was being given to potential inaccuracies with gestational age dating which at best in the first trimester are +/- a few days and in the second trimester may be off up to 1-2 weeks. Furthermore no mention was made of accounting for other factors such as the findings on an ultrasound which if very discrepant might suggest an older fetus or perhaps equally important the wishes of the parents. What were their past experiences, religious beliefs or lengths to which they had tried for this pregnancy. The 16 year old single mother who conceived via rape might be expected to have a vastly different perspective than the mother at 43 who has tried 5 rounds of IVF and has finally conceived her first baby. Many of these points were highlighted in a response by a large group of care providers in a paper entitled “CPS position statement for prenatal counselling before a premature birth: Simple rules for complicated decisions.”
Now we have a new statement from the American Academy of Pediatrics which I have to complement as it addresses a number of concerns that the above group had with the Canadian version.
1. Fetal gestational age, as currently estimated, is an imprecise predictor of neonatal survival, but 22 weeks of gestation is generally accepted as the lower threshold of viability.
2. Although most infants delivered between 22 and 24 weeks’ gestation will die in the neonatal period or have significant long-term neurodevelopmental morbidity, outcomes in individual cases are difficult to predict.
3. Outcomes of infants delivered at 22 to 24 weeks of gestation vary significantly from center to center.
4. Because of the uncertain outcomes for infants born at 22 to 24 weeks’ gestation, it is reasonable that decision-making regarding the delivery room management be individualized and family centered, taking into account known fetal and maternal conditions and risk factors as well as parental beliefs regarding the best interest of the child.
The first four points address the issues of uncertainty in dates, variable outcomes and the importance of taking a family centred approach. On the surface this seems like the perfect statement but I have highlighted the third point as it really gets to what Nick Hall is referring to (or at least my interpretation). We know that there is a great variability in outcomes from 22-26 weeks across the US based on the recent study by Rysavy et al. In this study which involved 24 hospitals with tertiary care centres, the median survival across all hospitals at 22 weeks (who actively resuscitated infants) ranged from 0 – 14.6% and at 23 weeks 23.8 – 37.1%. Imagine you are a parent at a centre that has a zero percent survival rate at 22 weeks. Should the hospital inform you of that and if after hearing that you still want “everything done” should the Neonatal team resuscitate your infant? There is no doubt that the parental wishes as outlined in point 4 are important but I would counter that there is also little point in putting a family through a futile exercise.
Vince Lombardi the former head coach of the Green Bay Packers produced the following quote that has been used many times since his heyday in the 1960s. “Practice does not make perfect. Only perfect practice makes perfect”
This could not be more applicable to the situation in many centres thoughout the US. Resuscitating 22 and 23 week infants can be done and in a manner of speaking is a form of practice. Should centres though who have not “perfected” their approach by having rigorous audits of their practice, a “golden hour” approach and lastly the best equipment for resuscitation continue to offer families who wish to “do everything” just that? I would say no. While the AAP certainly endorses this type of approach centres need to be honest and disclose their success with such resuscitations. If you have zero survivors and know that there is a non standard approach at delivery of such patients and substandard equipment such as the absence of blenders to allow less than 100% O2 resuscitation do you not have a moral and ethical obligation to draw the line and say no?
The AAP offers the best approach to resuscitation from 22-25 weeks that I have seen but I don’t believe it is for every centre at the moment. Only those centres who believe that they have all the infrastructure and processes in place to achieve “perfect practice” should be routinely resuscitating infants at 22 and 23 weeks. To continue to offer these families everything and perform less than perfect practice will not lead to any improvements in their rate of success and do the families that come to their hospitals a disservice.
The first step in medicine is to pledge to do no harm. I would hope that hospitals would be honest with themselves and if they don’t have everything in place to achieve great results will spare families the experience of false hope when the only outcome will be the inevitable loss of a child.