Since the dawn of my time in Neonatology there has been cibophobia! What is this you ask? It is the fear of food and with some flexibility in the definition I would apply this to large volumes of milk rather than the fear of food itself. Most units in the world seem to use a volume range of about 135 – 165 mL/kg/d as a range considered to mean “at full feeds”. As I was discussing this on rounds today I was quick to point out though that babies with neonatal opioid withdrawal syndrome (NOWS) frequently take in excess of 200 mL/kg/d and we don’t worry about it. The counter argument though is that these infants are “bigger” and should be able to tolerate a larger volume. As readers of this blog know I truly enjoy coming across papers that suggest a change to something considered dogma. Today is one of those days as I am choosing to explore in more depth an abstract that I posted to Twitter and Facebook last month.
On the day of this blog release I also took a poll on Twitter and found some interesting results that make this post all the more important to share. Take a look!
Are Bigger Volumes Better?
Travers CP et al chose to challenge this long held practice in their recent paper Higher or Usual Volume Feedings in Very Preterm Infants: A Randomized Clinical Trial. It was a simple yet wonderful trial that asked the question of whether for infants < 32 weeks GA at birth with BW from 1000-2500g would higher volume feedings of 180-200 vs 140-160 ml/kg/d help increase growth velocity. Randomization occurred after infants had reached 120 mL/kg/d of oral feedings. In both arms advancements from this point were the same and fortification occurrred as per usual practrice but in each arm strategies targeted individual fortification to weight gain.
The authors were seeking a 3 g/kg/d difference in growth and needed 224 infants to demonstrate this difference. They enrolled the same at a mean GA of 30.5 weeks and a BW of 1445 grams. Birth characteristics including gestational age, weight, sex, race/ethnicity, Apgar scores, head circumference, length, and proportion of infants with a weight <10th percentile at birth did not differ between groups.
The outcomes showed differences as shown below.
Looking at the results
All in all I would say the results are a smashing success. Growth velocity was improved and not just in weight but in head circumference and length. What I find interesting is that if fortification of milk was targeted regardless of the volume used I am a bit baffled as to why the growth rate would still be better but it was. The difference in caloric intake received between groups was approximately 9 kcal/kg/day at day 7 after study entry (126 kcal/kg/day versus 117 kcal/kg/day) and 16 kcal/kg/day from day 14 after study entry onwards (139 kcal/kg/day versus 123 kcal/kg/day).
Blinding here would have been a challenge as nurses and other health care providers would have been able to calculate the expected volumes at different fluid administration levels. Nonetheless there was a difference.
The question though that many would ask is whether this better growth came at the expense of greater morbidity. Let’s be clear here that the study was not powered to look at adverse outcomes and the numbers in the above table are small but no difference was seen nonetheless. To appease the most cautious of Neonatologists I suspect a larger study powered to look at adverse outcomes will be needed. What this study does though is raise the question of whether we can and should try larger volumes. As the title suggests I wonder about getting bigger faster so one can go home. With this more rapid rate of growth can we expect a faster maturation as well? I doubt it but it is something to certainly question in a larger study!
After developing a community of over 23000 people unfortunately I had to close my Facebook site due to concerns over a hack. Not to worry as I have created a new independent site to share information daily in Neonatology. I look forward to building an audience at this site and working to continue the dialogue I have come to enjoy with all the followers.
Once upon a time we would use our gut instinct to inform our decisions as to whether it was reasonable to try and extubate (take out a breathing tube) or to lower or stop CPAP (continuous positive airway pressure). We used to look at home much oxygen a baby needed and what the pressures were on the machine offering them support and combined with what we saw on the patient monitor for oxygen saturation make a decision as to what to do next.
In the last decade or so people realized (as did one of our own respiratory therapists) that buried within all of this data on the patient monitor one could get a report on what percentage of time each infant has spent at different levels of systemic oxygen saturation. A sample report might look like this.
>95% – 10%
90 – 94% – 55%
85-89% – 20%
80 – 84% – 10%
<80% – 5%
Seeing this report though is only half the story. Without knowing how much oxygen on average an infant has received in the last twenty four hours to achieve this range it is somewhat meaningless. The amount of oxygen given may show that we the baby is doing better or worse. For example, if the above histogram was achieved using a range of 25-35% oxygen and was no different than the day before but the infant had been on 30-40% oxygen and pressure the day earlier then we have gotten somewhere! This infant has actually improved. The histogram is unchanged but we have given less oxygen on the same amount of pressure. If the histogram was unchanged but the amount of oxygen was 21-25% the day before, the lungs have gotten worse assuming the same pressure.
It is also worth noting that higher numbers are not alway indicative of a good thing. Take for example this histogram:
>95% – 50%
90-94% – 35%
85-89% – 8%
80-84% – 7%
<80% – 0%
If this infant was on room air and having these numbers I would be overjoyed. What if this was a baby though who was on 30-40% oxygen? These numbers are too good! We know that too much oxygen can be bad for the lungs and eyes. For babies on oxygen we typically target 88-92 % oxygen saturation (others use 90-94%). If we have 50% of the time above 95% oxygen we clearly are using too much and have to cut it back.
As parents you will hear us talk about histograms on rounds and use the information to make decisions about oxygen and the amount of breathing support your baby needs. If you have wondered how we use this information and what this seemingly random assortment of numbers really means, this is how we interpret it. The next time someone says that your infant needs more or less support ask for the histogram information if your unit uses it and you will see whether the data support the change.
Delayed cord clamping has been written about before on this blog. In fact between the blog and facebook posts I think it has been discussed many times. What hasn’t really been touched upon whether one type of cord management is superior to another. Is delayed cord clamping equivalent to cord milking or is one better than the other? The answer is a complicated one as you first need to define what both are. For delayed cord clamping it could be as short as 3 minutes and as long as 5 minutes or so as was seen in the post on physiological based cord clamping. For cord milking I suppose the definition is a little less broad but typically involves stripping of the cord after allowing the cord to fill with placental blood to enhance flow over a shorter time than DCC from the placenta to the newborn.
A Head to Head Comparison
Katheria A et al published Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants this past month in JAMA. The authors compared two well defined approaches to care after delivery. Delayed cord clamping was defined as being at least 60 seconds (mean time was about that) while cord milking was done by using 20 cm of the umbilical cord and milking for 2 seconds allowing refill, and then repeating 3 more times. The primary outcome under study was the incidence of death or severe IVH at 6 month’s corrected gestational age. The goal was to enroll 502 per group based on their power calculation. Furthermore the study design included randomization into two strata of 23 weeks 0 days to 27 weeks and 6 days and 28 weeks o days to 31 weeks 6 days. They managed to enroll 474 infants and in each arm there was good compliance with the allocated intervention (98% for cord milking and 93% for delayed cord clamping. What makes the study interesting though is that it was stopped by the data safety monitoring board after 236 were enrolled in the cord milking group and 238 in the delayed arm.
There were no significant differences between the maternal and neonatal demographics between groups. The mean time to clamping in the delayed group was 57.5 seconds compared to 22.8 seconds in the cord milking arm. The primary outcome at this point showed no difference between groups. What was concerning though was the pre-planned secondary outcome of severe intraventricular bleeding alone and is shown below.
The incidence of death from the above table was no different but in the group of infants between 23+0 and 27 +6 weeks there was a finding of 22% with severe IVH compared to only 6% in the delayed cord clamping group. This finding was understandably enough to shut down the study from enrolling further patients.
Why could this have happened?
I suppose we don’t know for sure but one of the benefits of writing a blog is that I get to speculate! The cerebral vasculature of small infants is quite fragile and furthermore is very poor at autoregulating its circulation. With cord milking I imagine it is similar to small boluses of blood. In a small preterm infant it may be that the baby is unable to limit the flow of blood adequately into the cerebral circulation leading to acute bleeding. Contrast this with the slow trickle of blood that one gets over a minute while the cord is not clamped.
This study is going to be a tough one to get past I suspect for those centres grappling with whether cord milking or delayed cord clamping in the best strategy. The question I think really these days should not be between these two but rather as I have written about before, how long should a delay in clamping really be? One minute is likely far too short while 5 minutes probably too long for most to be comfortable. I suspect the 2-3 minute range is where things will settle out. Additionally, strategies to allow resuscitation with an intact cord can and should be explored as those who are most sick at birth are likely the ones who could most benefit from a delay in clamping. More research is needed and I suspect you will hear about some before long on this site!
Hypoglycemia has been a frequent topic of posts over the last few years. Specifically, the use of dextrose gels to avoid admission for hypoglycemia and evidence that such a strategy in not associated with adverse outcomes in childhood. What we know is that dextrose gels work and for those centres that have embraced this strategy a reduction in IV treatment with dextrose has been noted as well.
Dextrose gels however in the trials were designed to test the hypothesis that use of 0.5 mL/kg of 40% dextrose gel would be an effective strategy for managing hypoglycemia. In the Sugar Babies trial the dextrose gel was custom made and in so doing an element of quality control was made possible.
In Canada we have had access to a couple products for use in the newborn; instaglucose and dex4. Both products are listed as being a 40% dextrose gel but since they are not made in house so to speak it leaves open the question of how consistent the product is. Researchers in British Columbia sought to examine how consistent the gels were in overall content and throughout the gel in the tube. The paper by A. Solimano et al is entitled Dextrose gels for neonatal transitional hypoglycemia: What are we giving our babies? As an aside, the lead author Alfonso was just announced as the 2019 recipient of the Canadian Pediatric Society Distinguished Neonatologist award so I couldn’t see a better time to provide some thoughts on this paper!
What did they find?
The study examined three tubes each of instaglucose and dex4. For each tube the researchers sampled dextrose gel from the top, middle and bottom and then the dextrose content per gram of gel determined as well as gel density. Glucose concentrations were analyzed high-pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and gas chromatography mass spectrometry (GCMS) were used to determine glucose concentrations and identify other carbohydrates, respectively. In terms of consistency the gels were found to be quite variable with dextrose content that for instaglucose could be as much as 81% and 43% different for dex4. Differences also existed between the different sections of the tubes so depending on the whether it was a fresh tube you were using or not the amount of dextrose could vary.
The authors also discovered that while dex4 contained almost exclusively dextrose, instaglucose contained other carbohydrates not listed on the manufacturer’s ingredient list.
What does it all mean?
The differences are interesting for sure. If the glucose gels are not consistent though should we stop using them? I think the answer to that at least for me is no. Although the data is unpublished, our own centres experience has been that admissions for hypoglycemia have indeed fallen since the introduction of dextrose gel usage (we use instaglucose). What I can only surmise is that in some cases patients may be getting 40% but perhaps in others they are getting as little as 20% or as much as 60% (I don’t know exactly what the range would be but just using this as an example). In some cases of “gel failure” perhaps it is for some babies, receipt of low dextrose containing gel that is at fault or it may be they just have high glucose requirements that gel is not enough to overcome. Other infants who respond quickly to glucose gel may be getting a large dose of dextrose in comparison. Overall though, it still seems to be effective.
What I take from this study is certainly that there is variation in the commercially prepared product. Producing the gel in the hospital pharmacy might allow for better quality control and would seem to be something worth pursuing.
Look around an NICU and you will see many infants living in incubators. All will eventually graduate to a bassinet or crib but the question always is when should that happen? The decision is usually left to nursing but I find myself often asking if a baby can be taken out. My motivation is fairly simple. Parents can more easily see and interact with their baby when they are out of the incubator. Removing the sense of “don’t touch” that exists for babies in the incubators might have the psychological benefit of encouraging more breastfeeding and kangaroo care. Both good things.
Making the leap
For ELBW and VLBW infants humidity is required then of course they need this climate controlled environment. Typically once this is no longer needed units will generally try infants out of the incubator when the temperature in the “house” is reduced to 28 degrees. Still though, it is not uncommon to hear that an infant is “too small”. Where is the threshold though that defines being too small? Past research studies have looked at two points of 1600 vs 1800g for the smallest of infants. One of these studies was a Cochrane review by New K, Flenady V, Davies MW. Transfer of preterm infants for incubator to open cot at lower versus higher body weight. Cochrane Database Syst Rev 2011;(9). This concluded that early transition was safe for former ELBWs at the 1600g weight cut off.
Infants in this gestational age range with a birth weight <1600g were randomly assigned to a weaning weight of 1600 or 1800 g. Within 60 to 100 g of weaning weight, the incubator temperature was decreased by 1.0°C to 1.5°C every 24 hours until 28.0°C. Weaning to the crib occurred when axillary temperatures were maintained 36.5°C to 37.4°C for 8 to 12 hours. Clothing and bedcoverings were standardized. The primary outcome was LOS from birth to discharge.
What did they find?
A total of 366 babies were enrolled (187 at 1600g and 179 at 1800g. Baseline characteristics of the two groups revealed no statistical differences. Mean LOPS was a median of 43 days in the lower and 41 days in the higher weight group (P = .12). After transition to a crib weight gain was better in the lower weight group, 13.7 g/kg/day vs 12.8 g/kg/ day (P = .005). Tracking of adverse events such as the incidence of severe hypothermia did not differ between groups. The only real significant difference was a better likelihood of weaning from the incubator in the higher group at 98% success vs 92% on the first attempt. Putting. That in perspective though, a 92% success rate by my standards is high enough to make an attempt worthwhile!
The authors have essentially shown that whether you wean at the higher or lower weight threshold your chances of success are pretty much the same. Curiously, weight gain after weaning was improved which seems counter intuitive. I would have thought that these infants would have to work extra hard metabolically to maintain their temperature and have a lower weight gain but that was not the case. Interestingly, this finding has been shown in another study as well; New K, Flint A, Bogossian F, East C, Davies MW. Transferring preterm infants from incubators to open cots at 1600 g: a multicentre randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2012;97:F88-92. Metabolic rate has been shown to increase in these infants but skin fold thickness has been shown to increase as well in infants moved to a crib. How these two things go together is a little beyond me as I would have thought that as metabolic rate increases storage of tissue would slow. Not apparently the case but perhaps just another example of the bodies ability to overcome challenges when put in difficult situations. A case maybe of “what doesn’t kill you makes you stronger?”
The authors do point out that the intervention was unmasked but the standardization of weaning procedure and garments used in the cribs should have overcome that. There were 36% of parents who did not consent to the study so their inclusion could have swayed the results perhaps but the sample size here was large despite that. That the final results agree with findings in ELBW infants suggests that the results are plausible.
What I think this study does though is tell us overall that weaning at a smaller weight is at least alright to try once one is at minimal settings in an incubator. Will this change your units practice? It is something that at least merits discussion.