Positive pressure ventilation puts infants at risk of developing chronic lung disease (CLD). Chronic lung disease in turn has been linked many times over, as a risk for long term impacts on development. So if one could reduce the amount of positive pressure breaths administered to a neonate over the course of their hospital stay, that should reduce the risk of CLD and by extension developmental impairment. At least that is the theory. Around the start of my career in Neonatology one publication that carried a lot of weight in academic circles was the Randomized Trial of Permissive Hypercapnia in Preterm Infants which randomized 49 surfactant treated infants to either a low (35-45) or high (45-55) PCO2 target with the thought being that allowing for a higher pCO2 should mean that lower settings can be used. Lower settings on a ventilator would lead to less lung damage and therefore less CLD and in turn better outcomes. The study in question did show that the primary outcome was indeed different with almost a 75% reduction in days of ventilation and with that the era of permissive hypercapnia was born.
The Cochrane Weigh in
In 2001 a systematic review including this and another study concluded that there was insufficient evidence to support the strategy in terms of a benefit to death or chronic lung disease. Despite this lack of evidence and a recommendation from the Cochrane group that permissive hypercapnia be used only in the context of well designed trials the practice persisted and does so to this day in many places. A little lost in this discussion is that while the end point above was not different there may still be a benefit of shorter term ventilation.
A modern cohort
It would be unwise to ignore at this point that the babies of the late 90s are different that the ones in the current era. Surfactant and antenatal steroid use are much more prevalent now. Ventilation strategies have shifted to volume as opposed to pressure modes in many centres with a shift to early use of modalities such as high frequency ventilation to spare infants the potential harm of either baro or volutrauma. Back in 2015 the results of the PHELBI trial were reported Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. This large trial of 359 patients randomized to a high or low target pCO2 again failed to show any difference in outcomes in terms of the big ones “death or BPD, mortality alone, ROP, or severe IVH”. What was interesting about this study was that they did not pick one unified target for pCO2 but rather set different targets as time went on reflecting that with time HCO3 rises so what matters more is maintaining a minimum pH rather than targeting a pCO2 alone which als0 reflects at least our own centre’s practice. There is a fly in the ointment here though and that is that the control group has a fault (at least in my eyes)
Day of life
In the original studies of permissive hypercapnia the comparison was of a persistent attempt to keep normal pCO2 vs allowing the pCO2 to drift higher. Although I may get some argument on this point, what was done in this study was to compare two permissive hypercapnia ranges to each other. If it is generally accepted that a normal pCO2 is 35-45 mmHg then none of these ranges in the low target were that at all.
How did these babies do in the long run?
The two year follow-up for this study was published in the last month; Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. At the risk of sounding repetitive the results of Bayley III developmental testing found no benefit to developmental outcome. So what can we say? There is no difference between two strategies of permissive hypercapnia with one using a higher and the other a lower threshold for pCO2. It doesn’t however address the issue well of whether targeting a normal pCO2 is better or worse although the authors conclude that it is the short term outcomes of shorter number of days on ventilation that may matter the most.
The Truth is Out There
I want to believe that permissive hypercapnia makes a difference. I have been using the strategy for 15 or so years already and I would like to think it wasn’t poor strategy. I continue to think it makes sense but have to admit that the impact for the average baby is likely not what it once was. Except for the smallest of infants many babies these days born at 27 or more weeks of gestation due to the benefits of antenatal steroids, surfactant and modern ventilation techniques spend few hours to days on the ventilator. Meanwhile the number of factors such chorioamniotitis, early and late onset sepsis and genetic predisposition affect the risks for CLD to a great degree in the modern era. Not that they weren’t at play before but their influence in a period of more gentle ventilation may have a greater impact now. That so many factors contribute to the development of CLD the actual effect of permissive hypercapnia may in fact not be what it once was.
What is not disputed though is that the amount of time on a ventilator when needed is less when the strategy is used. Let us not discount the impact of that benefit as ask any parent if that outcome is of importance to them and you will have your answer.
So has permissive hypercapnia failed to deliver? The answer in terms of the long term outcomes that hospitals use to benchmark against one and other may be yes. The answer from the perspective of the baby and family and at least this Neonatologist is no.
A strange title perhaps but not when you consider that both are in much need of increasing muscle mass. Muscle takes protein to build and a global market exists in the adult world to achieve this goal. For the preterm infant human milk fortifiers provide added protein and when the amounts remain suboptimal there are either powdered or liquid protein fortifiers that can be added to the strategy to achieve growth. When it comes to the preterm infant we rely on nutritional science to guide us. How much is enough? The European Society For Pediatric Gastroenterology, Hepatology and Nutrition published recommendations in 2010 based on consensus and concluded:
“We therefore recommend aiming at 4.0 to 4.5 g/kg/day protein intake for infants up to 1000 g, and 3.5 to 4.0 g/kg/day for infants from 1000 to 1800 g that will meet the needs of most preterm infants. Protein intake can be reduced towards discharge if the infant’s growth pattern allows for this. The recommended range of protein intake is therefore 3.5 to 4.5 g/kg/day.”
These recommendations are from six years ago though and are based on evidence that preceded their working group so one would hope that the evidence still supports such practice. It may not be as concrete though as one would hope.
Let’s Jump To 2012
Miller et al published an RCT on the subject entitled Effect of increasing protein content of human milk fortifier on growth in preterm infants born at <31 wk gestation: a randomized controlled trial. This trial is quite relevant in that it involved 92 infants (mean GA 27-28 weeks and about 1000g on average at the start), 43 of whom received a standard amount of protein 3.6 g/kg/day vs 4.2 g/kg/d in the high protein group. This was commenced once fortification was started and carried through till discharge with energy intakes and volume of feeds being the same in both groups. The authors used a milk analyzer to ensure consistency in the total content of nutrition given the known variability in human milk nutritional content. The results didn’t show much to write home about. There were no differences in weight gain or any measurements but the weight at discharge was a little higher in the high protein group. The length of stay trended towards a higher number of days in the high protein group so that may account for some of the difference. All in all though 3.6 or 4.2 g/kg/d of protein didn’t seem to do much to enhance growth.
Now let’s jump to 2016
This past month Maas C et al published an interesting trial on protein supplementation entitled Effect of Increased Enteral Protein Intake on Growth in Human Milk-Fed Preterm Infants: A Randomized Clinical Trial. This modern day study had an interesting question to answer. How would growth compare if infants who were fed human milk were supplemented with one of three protein contents based on current recommendations. The first group of 30 infants all < 32 weeks received standard protein intake of 3.5 g/kg/d while the second group of 30 were given an average intake of 4.1 g/kg/d. The second group of 30 were divided though into an empiric group in which the protein content of maternal or donor milk was assumed to be a standard amount while the second 15 had their protein additive customized based on an analysis of the human milk being provided. Whether the higher intake group was estimated or customized resulted in no difference in protein intake on average although variability between infants in actual intake was reduced. Importantly, energy intake was no different between the high and low groups so if any difference in growth was found it would presumably be related to the added protein.
Does it make a difference?
The results of this study failed to show any benefit to head circumference, length or weight between the two groups. The authors in their discussion postulate that there is a ceiling effect when it comes to protein and I would tend to agree. There is no question that if one removes protein from the diet an infant cannot grow as they would begin to break down muscle to survive. At some point the minimum threshold is met and as one increases protein and energy intake desired growth rates ensue. What this study suggests though is that there comes a point where more protein does not equal more growth. It is possible to increase energy intakes further as well but then we run the risk of increasing adiposity in these patients.
I suppose it would be a good time to express what I am not saying! Protein is needed for the growing preterm infant so I am not jumping on the bandwagon of suggesting that we should question the use of protein fortification. I believe though that the “ceiling” for protein use lies somewhere between 3.5 – 4 g/kg/d of protein intake. We don’t really know if it is at 3.5, 3.7, 3.8 or 3.9 but it likely is sitting somewhere in those numbers. It seems reasonable to me to aim for this range but follow urea (something outside of renal failure I have personally not paid much attention to). If the urea begins rising at a higher protein intake approaching 4 g/kg/d perhaps that is the bodies way of saying enough!
Lastly this study also raises a question in my mind about the utility of milk analyzers. At least for protein content knowing precisely how much is in breastmilk may not be that important in the end. Then again that raises the whole question of the accuracy of such devices but I imagine that could be the source of a post for another day.
It’s World Prematurity Day today and if you are a parent or are caring for a baby who has just entered this world before 37 weeks GA you are now part of a membership that counts 15 million new babies each year according to the WHO’s data. As I tell most new parents who have a baby admitted to our unit “It’s ok to take some time to adjust to this. You didn’t plan on being here”. That is true for most who go into spontaneous labour but of course those who are electively delivered due to maternal or fetal indications that have been followed closely often have time to prepare for the journey to the NICU. Many of these parents will have had the opportunity to visit the NICU or even connect with other parents before the anticipated birth of their child to at least get a glimpse into what life is like in the NICU. Much has been written about parental stress and methods to reduce it and I find that a piece that appeared in the Huffington Post offers some good pointers to helping parents manage the transition from pregnancy to NICU. The piece is entitled 5 Things Never To Say To Parents Of Preemies (And What To Say Instead).It is well worth a read but the one thing that stuck out in my mind is one very important thing to say.
Congratulations on the birth of your baby
There is no doubt that the family who gives birth to a preterm infant is experiencing stress. What may be lost in the first few days of surfactant, central lines and looking for sepsis among other things is that a new member of the 15 million strong has entered this world. They have a new child and just like anyone else should receive a congratulations. No one needs to tell them to be worried. They already are and likely view many of the possibilities more pessimistically than you do. Taking a moment to say congratulations though may go a long way to reminding them that amidst all this stress there is something to rejoice in and look to the future. If we aren’t supportive then I have no doubt the subconscious message is that they shouldn’t have hope either. I am not suggesting that we sugarcoat what is really going on but one can be honest about likely outcomes and still celebrate the arrival of a new baby. Much has also been written recently about a number of strategies to reduce stress in the NICU such as skin to skin care, integration of families more closely into the patient care team and forming parent support groups just to name a few. What else can be done to improve the quality of life for parents going through this journey?
Enrol Your Baby In A Research Study
I work in an academic centre and given the volume of research projects at any given time there is a need to approach families and sometimes quite soon after delivery. interestingly, I have heard from time to time that individuals have been hesitant to approach families due to a feeling that they are overwhelmed and won’t be receptive to being approached in this fragile state. I am guilty of the same thoughts from time to time but maybe it is time I reconsider. Nordheim T et al just published an interesting study on this topic entitled Quality of life in parents of preterm infants in a randomized nutritional intervention trial. This study was actually a study of parents within a study that called the PreNu trial that involved an intervention of a energy and protein supplemental strategy to enhance weight at discharge. The trial was an RCT and unfortunately although well intentioned was stopped when the intervention group was found to have an unexpected increase in sepsis rates. Although this study did not ultimately find a positive outcome there were additional analyses performed of quality of life and parental stress at two time points the first being during the hospital stay and the second at 3.5 years of age. The patients were all treated the same aside from the nutritional intake and in the end 30 intervention parents and 31 single parents not enrolled in a study (many in couples) participated in the study. In followup a little less than 70% completed the stress measures at 3.5 years. The results are found below.
How Do We Interpret This
The parents in this study who were part of the intervention group were about 3 years older so perhaps with more life experience may have developed some better coping strategies but during the hospital stay those who participated in research had better measures of quality of life and at three years better reports of sleep and energy levels. The study is quite small so we need to take all of this with a grain of salt with respect to the 3.5 year outcomes as there are so many variables that could happen along the way to explain this difference but I think it may be fair to acknowledge the quality of life measure during the stay. Why might parents report these findings? The finding of better quality of life is especially interesting given that more patients in this study had sepsis which one would think would make for a worse result. Here are a few thoughts.
Involvement in research may have increased their knowledge base as they learned about nutrition and expected weight gain in the NICU.
Frequent interaction with researchers may have given them more attention and with it more education.
Some parents may have simply felt better about knowing they were helping others who would come after them. I have heard this comment myself many times and suspect that it would be attributable at least to a certain extent.
A better understanding of the issues facing their infants through education may have reduced stress levels due to avoiding “fear of the unknown”.
Regardless of the exact reason behind the findings what stands out in my mind is that participation in research likely provides comfort for parents who are in the midst of tremendous stress. Is it the altruistic desire to help others or being able to find something good in the face of a guarded outlook? I don’t know but I do believe that what this study tells us is that we shouldn’t be afraid to approach families.
After first congratulating them give them a little time to absorb their new reality and then offer them the chance to improve the care for the next 15 million that will come this time next year for World Prematurity Day 2017.
I had a chance recently to drive a Tesla Model S with autopilot. Taking the car out on a fairly deserted road near my home I flicked the lever twice to activate the autopilot feature and put my hands behind my head while the vehicle took me where I wanted to go. As I cruised down the road with the wheel automatically turning with the curves in the road and the car speeding up or slowing down based on traffic and speed limit notices I couldn’t help but think of how such technology could be applied to medicine. How far away could the self driving ventilator or CPAP device be from development?
I have written about automatic saturation adjustments in a previous post but this referred to those patients on mechanical ventilation. Automatic adjustments of FiO2. Ready for prime time? Why is this goal so important to attain? The reasoning lies in the current design trends in modern NICUs. We are in the middle of a large movement towards single patient room NICUs which have many benefits such as privacy which may lead to enhanced breastfeeding rates and increased parental visitation. The downside, having spoken to people in centres where such designs are already in place is the challenge nursing faces when given multiple assignments of babies on O2. If you have to go from room to room and a baby is known to be labile in their O2 saturations it is human nature to turn the O2 up a little more than you otherwise would to give yourself a “cushion” while you are out of the room. I really don’t fault people in this circumstance but it does pose the question as to whether in a few years we will see a rise in oxygen related tissue injury such as CLD or ROP from such practice. In the previous post I wrote about babies who are ventilated but these infants will often be one to one nursed so the tendency to overshoot the O2 requirements may be less than the baby on non- invasive ventilation.
A System For Controlling O2 Automatically For Infants on Non-Invasive Ventilation
The study was really a proof of concept with 20 preterm infants (mean GA 27.5 weeks, 8 days of age on average) included who each underwent two hours of manual control by nursing to keep saturations between 90-94% and then 4 hours of automated control (sats 91 – 95%) then back to manual for two hours. The slightly shifted ranges were required due to the way in which midpoint saturations are calculated. The essential setup was a computer equipped with an algorithm to make adjustments in FiO2 using an output to a motor that would adjust the O2 blender and then feedback from an O2 saturation monitor back to the computer. The system was equipped with an override to allow nursing to adjust in the event of poor signal or lack of response to the automatic adjustment.
The results though demonstrate that the system works and moreover does a very good job! The average percentage of time that the saturations were in the target range were significantly better with automated control (81% automated, 56% manual). As well as depicted in the following figure the amount of time spent in both hypoxic and hyperoxic ranges was considerable with manual control but non-existent on either tail with automated control (defined as < 85% or > 98% where black bars are manual control and white automatic).
From the figure you can see that the amount of time the patients are in target range are much higher with automatic control but is this simply because in addition to automatic control, nurses are “grabbing the wheel” and augmenting the system here? Not at all.
“During manual control epochs, FiO2 adjustments of at least 1% were made 2.3 (1.3–3.4) times/hour by bedside staff. During automated control, the minimum alteration to FiO2 of 0.5% was being actuated by the servomotor frequently (9.9 alterations/min overall), and changes to measured FiO2 of at least 1% occurred at a frequency of 64 (49–98) /hour. When in automated control, a total of 18 manual adjustments were made in all 20 recordings (0.24 adjustments/hour), a reduction by 90% from the rate of manual adjustments observed during manual control (2.3/hour).”
From the above quote from the paper it is clear that automated control works to keep the saturation goal through roughly 7 X the number of adjustments than nursing makes per hour. It is hard to keep up with that pace when you have multiple assignments but that is what you need I suppose! The use of the auto setting here reduced the amount of nursing interventions to adjust FiO2 by 90% and yields tighter control of O2 saturations.
Dare to Dream
Self driving oxygen administration is coming and this proof of concept needs to be developed and soon into a commercial solution. The risk of O2 damage to developing tissues is too great not to bring this technology forward to the masses. As we prepare to move into a new institution I sincerely hope that this solution arrives in time but regardless I know our nurses and RRTs will do their best as they always do until such a device comes along. When it does imagine all of the time that could be devoted to other areas of care once you were able to move away from the non-invasive device!
I think it is safe to say that this topic stirs up emotions on both sides of the argument of how aggressive to be when it comes to resuscitating some of these infants, particularly those at 22 and 23 weeks. Where I work we have drawn a line at 23 weeks for active resuscitation but there are those that would point out the challenge of creating such a hard-line when the accuracy of dating a pregnancy can be off by anywhere from 5 – 14 days. Having said that, this is what we have decided after much deliberation and before entertaining anything further it is critical to determine how well these infants are doing not just in terms of survival but also in the long run. In the next 6 months our first cohort should be coming up for their 18 month follow ups so this will be an informative time for sure.
Do Days Matter?
This is the subject of a short report out of Australia by Schindler T et al. In this communication they looked at the survival alone for preterm infants in a larger study but broke them down into 3 and four-day periods from 23 to 25 weeks as shown below.
The asterisk over the two bars means that the improvement in survival was statistically significant between being born in the last half of the preceding week and the first half of the next week. In this study in other words days make a difference. A word of caution is needed here though. When you look at the variation in survival in each category one sees that while the means are statistically different the error bars show some overlap with the previous half week. At a population level we are able to say that for the average late 23 week infant survival is expected to be about 30% in this study and about 55% at 24 +0-3 days. What do you say to the individual parent though? I am not suggesting that this information is useless as it serves to provide us with an average estimate of outcome. It also is important I believe in that it suggests that dating on average is fairly accurate. Yes the dates may be off for an individual by 5 – 14 days but overall when you group everyone together when a pregnancy is dated it is reasonably accurate for the population.
Don’t become a slave to the number
The goal of this post is to remind everyone that while these numbers are important for looking at average outcomes they do not provide strict guidance for outcome at the individual level. For an individual, the prenatal history including maternal nutrition, receipt of antenatal steroids, timing of pregnancy dating and weight of the fetus are just some of the factors that may lead us to be more or less optimistic about the chances for a fetus. Any decisions to either pursue or forego treatment should be based on conversations with families taking into account all factors that are pertinent to the decision for that family. Age is just a number as people say and I worry that a graph such as the one above that is certainly interesting may be used by some to sway families one way or another based on whether the clock has turned past 12 AM. At 23 weeks 3 days and 23 hours do we really think that the patient is that much better off than at 24 weeks 4 days and 1 hour?
It is hard to believe but All Things Neonatal is a year old. When I started this little concept I had no idea what was to come but am delighted with where it has gone. While the Blog site itself has about 200 followers, the Facebook page is home to nearly 4200 followers with twitter accounting for over 500 more. What began as a forum for me to get some thoughts off my chest about neonatal topics or articles of interest has morphed into a place to create change. As I look back over the last year I thought I would update the readers of this page and other social media platforms what the outcome has been for some of the ideas that I have brought forward. We have implemented some of these suggestions into our own unit practices, so without further ado here are the updates for some (but not all!) of the changes we have introduced.
Articles pertaining to use of Telehealth in all aspects of medicine are becoming commonplace. Locally we have seen expansion of rural sites that can connect with us and a strong desire by existing sites to connect via telehealth for a variety of reasons. While the thrust of the program was to deliver advice to rural practitioners and support our level I and II units we have found such support leading to possibilities we had not dreamed of. Initial discussions via telehealth and in person have occurred examining whether such treatments as CPAP stabilization and NG feedings could be done in these sites. Being able to provide such care will no doubt lead to more stable infants being transported to our site and moreover the possibility of moving the care for infants needing only gavage feeding back to their home communities. Who knows what the future will hold for us as we also look forward to the hiring of a telehealth coordinator for NICU!
This has been one of my favourite topics to write about. The ability to sample CO2 from an area near the carina has been demonstrated to be accurate and to save pokes in the long run. Since writing this piece we have tried it on several babies by using a double lumen tube and found the results to be as accurate as described in the Israeli papers. In practice though, secretions have proved difficult to handle for longer periods of use as they can travel up the sampling lines and damage the filters in the analyzers. A costly issue to deal with that we are currently trying to solve. Being able to continuously sample CO2 and adjust ventilation without drawing frequent blood gases is somewhat of a dream for me and we will continue to see how we can go about making this an established practice but there is work to be done!
I think most people in Winnipeg would say the answer is yes. On this front two major positive changes have occurred in the last year in this regard. The first is that through a generous donation and the blessing of our health region we have been able to expand the use of donor breast milk from < 1250g for a two week period to < 1500g for a one month period. This wonderful change came about after much effort and was celebrated in December as we not only expanded the eligibility criteria but partnered with the NorthernStar Mother’s Milk Bank to provide donor milk to Manitobans (Manitobans Now Able To Support Premature Infants Through Donor Milk Program!). The other change which the above post also spoke of was the potential to eliminate bovine milk altogether with the use of Prolacta (Human based human milk fortifier). While we don’t have the approval to use the product as traditionally indicated, we have used it as a “rescue” for those patients who demonstrate a clear intolerance of bovine fortifier. Such patients would traditionally receive inadequate nutrition with no other option available but now several have received such rescue and we look forward to analyzing the results of such a strategy shortly!
Without question the most talked about change was the change in threshold for recommending resuscitation from 24 to 23 weeks. The change took almost a year to roll out and could not have been done without a massive educational rollout that so many people (a special thank you to our nurse educators!) took part in. Looking back on the year we have now seen several infants at 23 weeks who survived with a small minority dying in the newborn period. It is too early to look at long term outcomes but I think many of us have been surprised with just how well many of these children have done. Moreover I believe we may be seeing a “creep effect” at work as the outcomes of infants under 29 weeks have also improved as we developed new guidelines to provide the best care possible to these vulnerable infants. Antenatal steroid use is up, IVH down and at least from January to September of last year no infants died at HSC under 29 weeks! I look forward to seeing our results in the future and cannot tell you how impressed I am with how our entire team came together to make this all happen!
I wanted to share some of the initiatives that came forward or were chronicled on these pages over the last year to show you that this forum is not just a place for my mind to aimlessly wander. It is a place that can create change; some good, some great and no doubt some that won’t take. It has also been a place where ideas are laid out that have come from afar. From readers anywhere in the world who ask a question on one of the social media sites that get me thinking! I have enjoyed the past year and expect I will continue to enjoy what may spring forth from these pages for some time to come. Thank you for your contributions and I hope you get a little something out of this as well!