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.
Recent statements by the American Academy of Pediatric’s, NICHD, the American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), and recommend selective approaches to mothers presenting between 22 0/7 to 22 6/7 weeks. The decision to provide antenatal steroids is only recommended if delivery is expected after 23 weeks. Furthermore the decision to resuscitate is based on an examination of a number of factors including a shared decision with the family. In practice this leads to those centres believing this is mostly futile generally not resuscitating or offering steroids while other more optimistic hospitals having higher rates of proactive (steroids and resuscitation) rates. Then there are other centres where the standard approach is proactive such as one in Uppsala, Sweden where this approach is used almost exclusively.
What would happen then if one compared the outcome for infants born at 22 weeks between this hospital and another where a selective approach is generally offered. In this case you would have a lot of experience with resuscitating infants at 22 weeks and the other a fraction of all presenting as a few to many would receive compassionate care. This is exactly what has now happened.
The authors examined a period from 2006-2015, dividing this time into two epochs with the first being 2006-2010 to account for differing practices and resources over time. Given that Uppsala took a proactive approach to all of their 40 live born infants during this time, it provided an opportunity to look at the 72 infants who were live born in the Ohio and examine their differences. In Ohio the approach was as follows; 16 (22%) received proactive care, 18 (25%) received inconsistent care (steroids but no resuscitation), and 38 (53%) received comfort care. In other words, although the total number of infants live born in Ohio was almost double that of Uppsala, only 16 were proactively treated in Ohio compared to all 40 in Uppsala.
The differences in outcome are striking
Survival in delivery room: (38/40, 95% vs 12/16, 75%; P = 0.049)
Provision of delivery room surfactant: (40/40, 100% vs 9/16, 56%; P<0.01)
Survival at 24 h (37/40, 93% vs. 9/16, 56%; P < 0.01).
Survival to 1 year (21/40, 53% vs. 3/16, 19%; P < 0.05).
Among the infants treated proactively, median age of death (17 postnatal days at range 0 h–226 days vs. 3 postnatal hours at NCH, range 0 h–10 days; P < 0.01).
All surviving infants had BPD All infants surviving to initial hospital discharge were alive at 18 months’ postnatal age.
With respect to long term outcome the authors note:
“Outpatient follow-up (qualitative or non-qualitative neurodevelopmental testing) was available in 26 out of 27 infants (96%) Eleven of the 26 (42%) were unimpaired, and all unimpaired infants were in the UUCH cohort. Among the 15 infants with impairment at UUCH, 3 had mild impairment and 12 had moderate or severe impairment. All surviving infants at NCH had moderate or severe impairment.”
A word about antenatal steroids as well. In Uppsala 85% of mothers received 2 doses of antenatal steroids vs 25% in Ohio. People sometimes question whether ANS at this age are effective. It is interesting to note that 44% of babies in the Ohio group vs 3% p<0.01 received chest compressions +/- epinephrine in the delivery room. Might this explain the better state of some of these infants at birth?
The Power of Belief
When I do rounds I often remark that try as we might we can’t will babies to do better. I also commonly say however that we need to be optimistic and although I am accused of seeing the world through rose coloured glasses I think there is an important lesson to be learned from this study. This comparison is really a contrast between a system that believes they can do a good thing for these families by actively promoting a proactive approach vs a system in which I imagine a reluctant approach exists even for those infants where a proactive plan is enacted. One sign of this might be that in Sweden 100% of these deliveries had a Neonatologist present vs 75% in the US. It could be due to other factors such as ability of the Neo to get in within time of the delivery however rather than a sign they didn’t feel they were needed due to futility.
There is evidence as well that the aggressiveness of the proactive approach also differs between the two sites based on a couple observations. The first is the rate of surfactant provision in the delivery room which was 100% in Sweden but only 56% in the US. The other thing of note is the time of death for those who did not survive. The median time of death in the US was 3 hours vs 17 days in Uppsala. What does this tell us about the approaches? I would imagine (although the numbers are small) that the teams in the US were much more likely to lose hope (or faith) and withdraw early while the other centre possibility motivated by their past successes pushed forward.
Remarkably, although one might think that the teams in Uppsala were simply creating significantly impaired survivors, 42% of the survivors were unimpaired from a developmental standpoint in follow-up. All surviving infants though from Ohio had moderate to severe impairment.
What this story may also really be about is practice. The reality is that the team in Sweden had over twice the exposure to such infants over time. Although the number presenting at this GA was higher, the ones that actually were resuscitated and given steroids was less than half. One cannot take away though that Uppsala in the end demonstrated that a proactive approach is definitely not futile. Not only can these children survive but almost half will be developmentally intact.
We must acknowledge as well though that since this is a retrospective study there may be factors that may have affected the results. As the saying goes “Individual results may vary”. Are the teams the same in both centres in terms of number of Neonatologists? Are there more residents caring for these infants vs fellows? Are the resources the same? What about proximity of the Neonatologist to the hospital? There are other factors such as cohesiveness of the team and communication between team members that may be influencing the results.
In the end though, this is a story of a team that believed it could and did. Perhaps seeing the world through rose coloured glasses is not such a bad thing in the end.
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.