Our ability to breathe regularly is something most of us take for granted. We owe this function to a tiny area in the brain located in the medulla oblongata.
This area of the brain sends signals via nerves to the lung telling it to breathe in and out on a regular basis. For a preterm infant or even term baby this means there should be about 40-60 breaths per minute. Preterm infants are at risk for these events due to being neurologically premature but also due to a difference in the responsiveness of such infants to carbon dioxide levels in the bloodstream. In term infants and throughout life we are very responsive to higher levels of carbon dioxide. We like to keep it pretty tightly controlled which is why if you hold your breath and your carbon dioxide levels rise you feel like you need to take a breath. In preterm infants this response is blunted.
Pauses in breathing are called apnea and when they occur in a preterm infant they are known as apnea of prematurity. These are usually defined as stoppage of breathing for 20 seconds or longer or if shorter there is bradycardia (<100 heart beats per minute), cyanosis (bluish color to the skin), or pallor. They are so common under 37 weeks that I consider them a normal part of the preterm journey. You can see how common it is in the figure below. We also know that they are far more common as gestational age decreases so that a 24 week gestation preterm infant will be far more prone to apnea than the 35 week counterpart.
often wonder if these drops in oxygen or heart rate are harmful. If the
events are called spontaneous it means that your infant recovers quickly from
these events without anyone stimulating your baby and so they are brief.
We tend not to worry about these types of events as they brain is not
likely to be affected. When events are happening more than a few times a
day and require your nurse to either stimulate your infant or require support
with a bag and mask to help your baby breathe this is where we become more concerned.
Even then the presence of bradycardia during these events is more
concerning than the oxygen levels as the poor heart rate means less blood is
going to the brain. It is hard though to determine exactly how many
events a day are actually harmful but intuitively if they are happening more
than a few times a day and needing support to recover this is where we usually
think about treatment.
The treatment of choice is caffeine. The same drug that is present in your soft drinks or coffee. It works by stimulating that centre in the brain that I talked about above. There are different dosing levels but you will see doses anywhere form 2.5 mg/g/d to sometimes 8 mg/kg/d for those babies with very resistant apnea. Some of those kids may need CPAP (mask on the nose) or intubation and a ventilator if they just won’t breathe. The good news is that they will grow out of it as shown in the next figure.
Most of our babies have their caffeine stopped sometime after they have reached the equivalent of 33 weeks (eg. born at 26 weeks this would be 7 weeks later). On rare occasion babies right up to term will have apnea as shown in the graph and for those kids if they are feeding well and otherwise ready for discharge we may choose to send you home on caffeine. Those kids though will need a follow-up study called a sleep study that will typically be done about 4 weeks later and require your child to come back for the appointment.
Inhaled nitric oxide has been around for some time now. I recall it being called at one point in medical school “endothelial relaxation factor” and then later on identified as nitric oxide. Many years later it finds itself in common usage in NICUs all over the world. Our experience though has been for treatment of pulmonary hypertension and for that it is pretty clear that for those afflicted by that condition it can be lifesaving. Over the years other uses have been looked at including prevention of BPD (turned out not to be the case). Rescue approaches therefore have found to be useful but on the prophylactic side of things not so much.
Maybe starting earlier is the key?
A group based out of Oklahoma has published a pilot study that raised an eyebrow for me at least. Krishnamurthy et al released Inhaled Nitric Oxide as an Adjunct to Neonatal Resuscitation in Premature Infants: A pilot, double blind, randomized controlled trial . The study set out to recruit 40 infants who between 30-90 seconds of life if requiring PPV would either get iNO 20 ppm with 30% oxygen or 30% oxygen and placebo for ten minutes. At ten minutes weaning of iNO by 1 ppm per minute for a total of 17 minutes was done. The primary outcome of interest was FiO2 required to achieve target oxygen saturations. As with many studies that seek enrollment prior to delivery this study was a challenge as well with early termination of the study after 28 babies (14 in each group) were recruited.
Did they find anything interesting?
In spite of the low numbers in the study, the authors did find a divergence in the FiO2 needed to achieve the target oxygen saturations.
The authors conclusions were that the cumulative exposure to FiO2 was lower in the iNO group as well as the maximum exposed FiO2 of 39% vs 48% (although this almost but not quite met statistical significance. Even then this is a pilot study so inferring too much could be a dangerous thing.
The study though does get one thinking but we need to be wary of letting our brains do some mental trickery. Lower FiO2 seems like a good thing given what we know about oxygen free radicals. What about rapid lowering of pulmonary vascular resistance with exogenous iNO? Is this a good thing or could other things be lurking around the corner? Could a larger study for example find a higher rate of pulmonary hemorrhage with rapid reductions in PVR? The authors did not find harm in the study but again with small numbers it is hard to conclude too much.
What this small study does though is raise many questions that I think could be interesting to answer. If a patient needs less FiO2 at 17 minutes after study entry might there be less perceived need for higher PEEP if ventilated or CPAP levels if on non-invasive support? Less pressure could lead to less risk of pneumothorax (or more perhaps if under treated but with respiratory distress. Less pressure might also influence longer term risks of BPD from barotrauma or volutrauma for that matter.
Regardless this is only the beginning. I have no doubt there will be further trials on the way. The trick will be as in this study to obtain consent unless a deferred consent could be obtained but I have my doubts about getting that. Nonetheless, wait for more to come!
Breast milk is certainly a hot topic these days. Allergies in childhood are almost equally hot in the media as food allergies seem to be on the rise (not my specialty by a long shot) as well as rates of other atopic illness. Given what is known about the modifiable risks in terms of a number of conditions such as NEC and late onset sepsis in preterm infants it wouldn’t be a stretch to wonder what impact avoidance of cow’s milk exposure could have in the term newborn.
A Landmark Japanese Study
Urashima et al just published in JAMA Pediatrics the following paper Primary Prevention of Cow’s Milk Sensitization and Food Allergy by Avoiding Supplementation With Cow’s Milk Formula at Birth: A Randomized Clinical Trial . This paper looked at 312 infants (≥ 36 weeks at birth) who were randomized to either receive breastfeeding plus an elemental formula if needed vs breastfeeding plus intact protein cow’s milk formula with a volume of at least 5 mL/kg per day. In order to have a group of infants truly at risk of atopic disease, all infants had to have at least one immediate relative with atopic disease. In each arm of the study, infants were followed with blood IgE levels at 5 and 24 months of age to detect a level of CM-IgE ≥ allergen units/mL. This was the primary outcome on which the power calculation was based for the study. Using an estimated incidence of 10% in the breastmilk group vs 25% in the exposed group the authors needed 300 patients to detect a difference. Secondary outcomes included detection of other allergens aside from allergy to cow’s milk.
Given that I called this a landmark study it might not be surprising to know that they found a difference favoring protection with human milk.
Also curious is the relationship to vitamin D levels. Previous research has documented an inverse relationship between vitamin D levels in children and risk of atopy. Why only the middle tertile in this study but not the higher tertile had less IgE response is unknown.
Perhaps even more surprising (at least to me) was that the risk of allergy at age 2 for other allergens was also lower.
Included in this lower risk was food allergy in general, risk of anaphylaxis and cow’s milk allergy that I presume manifested as rectal bleeding.
What Impact Could This Have
It is important to point out here that all these infants were ≥ 36 weeks so although I would love to infer that this strategy would have a huge impact on our preterm population I can’t say that yet (until a study is done). We certainly do see a fair bit of cow’s milk protein intolerance though that often leads to infants being placed NPO and on occasion worked up for NEC with a week or so of antibiotics. If this study is to be trusted, the rate of cow’s milk allergy was reduced from 6.6% to 0.7% in at risk infants (based on an immediate relative with atopy) and I would expect the risk in those without relatives to be less.
What might the impact be if we were to supplement with donor breast milk all term newborns who didn’t have enough maternal milk and take the elemental formula out of the equation entirely? If a 4 kg infant exclusively breastfed on day 1 and was give a couple ounces of supplement followed by full supplementation to 80 mL/kg/d on day 2 and then 100 mL/kg/d on day 3 that would total 26 ounces of donor milk in a worst case scenario assuming no maternal milk production during that time. At $4 per ounce we are looking at a cost to the system of about $100 a baby. Multiple that by the number of term infants in your centre to get an overall cost. In my own centre with about 12000 term deliveries a year that would come to 1.2 million dollars a year (again assuming no maternal milk at all). Is it worth the expense? I am not a health economist but I suspect if you were to add up the costs of workups/office visits etc for rectal bleeding, ED visits for asthma and anaphylaxis and the cost to families for food alleriges (let alone all the epi pens that need to be bought) it is worth it.
At the very least it does raise the question on post partum wards everywhere as to whether provision of cow’s milk formula should be one that someone has to consent to. With the publication of this study it certainly seems that it should be!
I presented this topic as a fellow many years ago after a paper came on the scene suggesting better outcomes with a faster approach. The paper Randomized trial of “slow” versus “fast” feed advancements on the incidence of necrotizing enterocolitis in very low birth weight infants. was plagued by the same issue as others created around those years which was a small number of patients at the lowest gestational ages. Any differences in sub analyses were difficult to really believe as the outcomes could have easily been explained by chance. Having said that, many centres began advancing feeds a little faster than the typical 20 ml/kg/d in favour of 30 ml/kg/d. It would take some time to coordinate a trial large enough to really answer questions about relevant issues such as time to developmental outcomes, time to full feedings and rates of NEC and the time appears to be now.
The SIFT trial
This trial was the result of a great deal of coordination between 55 different centres. For inclusion, infants had to be <1500g and <32 weeks gestational age at birth. Once the decision was made to advance feeds, babies were randomized to receive increases of 18 mL/kg/d vs 30 ml/kg/d. The primary outcome was survival without mod-erate or severe neurodevelopmental disability at 24 months CGA. What is striking about the study is its size. The number of babies in the fast arm was 1394 while 1399 in the slower group. In terms of having sufficient numbers of infants who were at the earliest gestational ages they were able to accomplish this as shown in this table.
Importantly when looking at the primary outcome 87.4% of infants in the faster group vs 88.7% in the slower group were followed up for assessment. It is also worth mentioning that this is even more impressive in terms of retention when one considers that about 6% in both arms died before assessment.
What were the findings then?
There was no difference in the primary outcome or for that matter each of its’ competing parts.
The authors in a secondary analysis did show a very marginal significant finding favouring slow feeds with respect to motor outcome. I concur with the authors though that given the small effect size and the “fishing” for results this likely is simply a chance finding. I can’t think of any reason why that would be the case either from a biological standpoint.
Not surprisingly another significant finding was shorter durations to reach full feeds (10 vs 7 days) and days on TPN at 11 vs 9 in the slow vs fast groups. In spite of having less need for central venous access, the authors were unable to show a reductoin in late onset sepsis or NEC.
Does it change your management?
I suppose that depends on what your management currently is. If you are like our centre and already advancing feedings by 30 ml/kg/d then I suspect not much. If you are in a slow centre one can take away from this study that at the very least you can lessen your patient’s need for central venous access and TPN. Based on this study and my suspicion that there will be no bigger trial forthcoming, whatever you decide to do this is about the best data that you will be getting.
My co-author Dr. Seth Marks from Pediatric Endocrinology spent countless hours reviewing the evidence and fielding seemingly endless questions from reviewers and myself. The support from the CPS was also much appreciated as the back and forth from so many who expressed opinions would have been difficult to manage without their support. What I hope you will find as you read this is the best appraisal of the evidence and directions for care that we could come to in 2019. Where things will stand by the time we make it to the next revision will be interesting to see.
For those who have used the Acute Care of At Risk Newborns (ACORN) program you will be pleased to know that the upcoming new version of this program is completely alligned with the approach outlined in the CPS statement. Given that the first version of ACORN and the CPS were not aligned and caused great discussion and distress at times, we feel this is a big accomplishment.
The algorithm for managing hypoglycemia is clean and easy to follow (I think) and we hope such clarity will greatly help with managing those infants at risk.
Main Questions for the Future
We remain a country divided (much like the recent election) with respect to dextrose gels usage. There are centres which are leary of using adult formulations of dextrose gel in newborns whereas others have adopted such treatments with success. The algorithm and statement address the approach to using dextrose gels or what to do if one wishes to avoid such use. With time, local products or a national brand designed specifically for newborn use may come to be and this will need to be addressed at some point.
Changing the threshold at 72 hours and beyond to require glucose levels of greater than or equal to 3.3 mmol/L may lead some to be worried about a ramp up in admissions but at least locally we have not seen this. In the end those with persistent causes of hypoglycemia will manifest one way or the other and whether it is before or after discharge from the hospital may be a reflection of what threshold you feel comfortable using.
Will local guidelines be affected by adopting the changes outlined in this statement? I suspect so and would welcome feedback before the next version of this document is worked on to determine what if any ramifications (positve or negative) such approaches have had.
No doubt with many changes compared to the previous version of the statement there may be some surprises. Keep an open mind and look at the evidence presented. In other cases the lack of evidence has motivated a change in position. Either way we believe this is the best approach to care for at risk newborns given what we know today.