What can I say? I have had a love affair with research on hypoglycemia. I suppose ever since my colleague and I began the quest of rewriting the Canadian Pediatric Society statement The screening and management of newborns at risk for low blood glucose it has become an interest. Embedded in the statement is commentary on the use of glucose gels for management of neonatal hypoglycemia and based on the sugar babies trial that found treatment of hypoglycemia with dextrose gel reduced admission for hypoglycemia and improved rates of breastfeeding after discharge I have been a proponent. A new approach has arisen in a large study in neonates that warrants some discussion. It tackles hypoglycemia from a preventative approach rather than as a treatment per se and is presented below.
The hPOD Study
The same group from Auckland led by Jane Harding published a preventative trial in January entitled Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): Amulticenter, double-blind randomized controlled trial. The study approached the problem of hypoglycemia by looking at whether provision of dextrose gel at 1 hour of age along with a breastfeed could reduce admission to NICU. The targeted population were babies with risk factors for hypoglcyemia such as maternal diabetes, late preterms and SGA or LGA infants. Remarkably this multicentre study managed to randomize 2149 infants into dextrose (1078) and placebo 1071) arms which for a neonatal study is pretty big! Blood glucose levels were analyzed on all at risk infants at 2 hours of age and were then followed up every 2-4 hours for the first 12 hours of age and until there were 3 consecutive measurements greater than or equal to 2.6 mmol/L. Given the size of the study it should come as no surprise that the two groups were similar in terms of baseline characteristics. The most common risk factor for hypoglycemia in each group was maternal diabetes at 81% in each group.
In the end the only thing that was different between the two groups was a diagnosis of hypoglycemia with about a 5% reduction in the outcome. Admission to NICU was no different whether it was for any reason or hypoglycemia alone. Treatment with IV therapy was also no different between groups and in addition breastfeeding rates were exceptionally high at discharge at about 96% for both groups. So the conclusion here is that prophylactic glucose gel doesn’t matter much but I have a few thoughts despite this being a VERY large trial and the authors really doing a good job of answering an important question.
My Thoughts on the Outcomes
The study demonstrates that one dose of glucose gel does not affect admission for any reason or for hypoglycemia. I can’t help but wonder if allowing the dextrose gel group to receive one or two more doses could have changed that outcome.
No difference in admission is not surprising since there are many reasons that a baby could be admitted with those underlying risk factors. Low birth weight, TTN, RDS etc would be some reasons and I wouldn’t think would be any different. It might have been better to power the study for admission for hypoglycemia as that to me is the only reason for admission that could be impacted by such prophylaxis.
When your breastfeeding rate in the placebo arm is at 95.9% there really isn’t much room for improvement so not sure a lack of improvement with dextrose gels can really be called here. There really wasn’t anywhere to go but down and previous work suggested that rates can go up. As the saying goes, can you apply the results of the study to my population. I can only wonder what would have happened if the authors were to replicate this study in a population with breastfeeding rates of 80%.
Is the outcome of reduced hypoglycemia a good enough outcome alone to adopt prophylactic dextrose gel? I don’t think so as there was no difference in groups between recurrent or severe hypoglycemia which is what likely matters most to neurodevelopmental outcome. Curiously the mean initial blood glucose was 2.97 and 3.16 in the placebo and glucose gel arms respectively so I am not sure how hypoglycemic this population really was. Yes there were about 40% in each arm that were hypoglycemic but only 10% were severe and almost 90% never had another episode. It’s possible that just by chance these children were on a very mild spectrum and therefore prophylaxis had little effect since they really were only going to have transient hypoglycemia.
In spite of my comments above I believe the authors did a fine job trying to answer an important question which to be honest others have wondered about before. For now I won’t be recommending this in my own institution but I do wonder what project will come next from this group that keeps on producing great work in the area of neonatal hypoglycemia.
For some time a recommendation has existed to keep blood sugars at or above 2.6 mmol/L at least for the first 48-72 hours. Afterwards the threshold as per our recommedation is to increase the target to 3.3 mmol/L or above. As the authors of the paper above pointed out, the evidence for these thresholds impacting long term neurodevelopmental outcome in a positive way is shaky and therefore they set out to examine two different thresholds of less than 2.0 mmol/L vs the traditional less than 2.6 mmol/L in a non-inferiority trial. They used a fairly standard Bayley test at 18 months to determine if there were any difference in outcomes between groups. I gather this had been presented in abstract form earlier and many were eagerly awaiting the publication as the scuttlebut was that there was no difference seen which would favour a change in practice to accept the lower threshold. As with many studies though the devil is in the details and did this study actually address this question properly?
To be fair, I think the authors here had a great goal in mind. What if we have been targeting the wrong threshold? How many babies would be needlessly tested and retested for glucose levels that really don’t make much of a difference to outcome? Before delving into the results though it is important to really look at what population here was studied. In order to qualify for this prospective study you had to be at risk of hypoglycemia defined by these four subgroups; Late-preterm infants (gestational age from 35 to 37 weeks), newborns who were small (below the 10th percentile) or large (above the 90th percentile) for gestational age, and infants of mothers with diabetes. Not included here are mothers who were on medications such as labetolol and those whose mothers had hypertensive disorders and were small but not small enough as examples. Importantly, none of the infants in the study could have an initial blood glucose < 1.9 mmol/L as they would be classified as severe. So we are looking at patients at risk who have moderate hypoglycemia. Already the field has been narrowed a fair bit. The next thing you had to have to get in the study if you were at risk was a blood glucose from 3-24 hours of age <2.6 mmol/L. Those kids were then randomized to either use the lower or higher thresholds for determining intervention. The authors determined to show non-inferiority they would need 200 babies in each group of at risk newborns to prove no-difference.
What Did They Find?
The authors managed to recruit 689 infants out of 5958 potential infants that were considered. The limits they put above to create moderate risk excluded many so we are talking about 10% of those at risk with hypoglcyemia who entered the trial. The findings were as follows; “Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed.”
So they didn’t find a difference. When you look into why though it becomes clear this was a tough study to really help answer the question. Here are the problems.
They didn’t enroll the 800 babies they needed for their power calculation. Failing to find a difference may not mean as much if they didn’t get enough infants. Out of the 689 they also didn’t follow up everyone so in the end they only had 582 infants.
The second issue has to do with the setting of the two thresholds. If you look at glucose at randomization they were almost equal at 41.4 mg/dL vs 41.2 mg/dL. In table three the big issue with the study becomes evident.
These kids were so low risk for recurrent hypoglycemia by excluding the more severe patients at entry that very few regardless of threshold actually became hypoglcyemic again. Roughly half of both groups never had another low. Of those that had another low blood glucose, 70% in the low group and 82% in the high group had either no or only one other episode after entry in the study. Looking at the previous work of Allan Lucas who demonstrated five or more low readings could impact long term outcomes, only 9% in the low and 2% of the high group had another low blood sugar,
3. Also from table 3 one can see that the number of patients with true severe hypoglcyemia which might be expected to impact long term outcome was also low at only 10% and 5% of the study population.
4. The authors did note in the secondary outcomes that there was a much higher need for IV therapy 21% in the high vs 6% in the low group. Moreover, bolus glucose was 12% vs 6%. This study though recruited patients before the adoption of glucose gel so we have to take the benefit here with a grain of salt since use of glucose gel would in the modern era lessen the effect.
Finally would you put your money where your mouth is?
Looking at this from a practical standpoint, in this at risk population, the vast majority would have at most one more episode of hypoglcyemia after randomization. You can’t avoid the needle poke to recheck a low glucose and with glucose gel the need for IV therapy is less. The question I guess is whether you would be confident enough in these results to be find for the first 48 hours with your own child having blood sugars of 2.1. 2.0, 2.2 etc. I suspect if many people were forced to answer that question with their own child they might based on this study alone feel more comfortable with a supplemental feed +/- glucose gel.
I suspect there is more to be told regarding this topic but for the time being I don’t think this one study is enough to move the needle and change our approach to hypoglcyemia thresholds.
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.
Glucose metabolism in the newborn can be a tricky thing to manage. Neonates can have significant fluctuation in their serum glucose in the first few days of life which can lead heels to look like pin cushions. How many times have you been asked as a physician if there is anything we can do to reduce the number of pokes? That something may have arrived at least in a feasibility study that could pave the way for this becoming the standard approach to hypo/hyperglycemia in the newborn. This is an important area to improve tightness of control as hyperglycemia has been associated in VLBW infants with such adverse outcomes as IVH, ROP and NEC.
Continuous glucose monitoring (CGM) with closed loop insulin delivery
The study was a pilot of 20 patients randomized to have an automated system to regulate glucose based on CGM data from 48-72 hours of age vs a paper based algorithm to manage dextrose or insulin infusion rates during the same period. The sample size was one of convenience to test the concept and the period was chosen to allow for time to recruit patients. The sensor used was an Enlite attached to a laptop with software capable of delivering infusion rates to two alaris pumps (one with 20% dextrose and the other with insulin). Target serum glucose levels were set to be between 4-8 mmol/L. The babies included were all under 1200g and had mean weights of 962g in the closed loop and 823g in the control arm.
The Results were fairly dramatic in my mind at least. A remarkable 91% of the infants in the closed loop system had glucose levels in the target range vs 26% in the control arm. Nutritional intakes and mean insulin dosing were not any different between groups. No harm in addition was noted from use of the CGMs. You don’t escape pokes all together though as the device does require q6h checks to calibrate and ensure it is reading properly. Every 6 hours is better though than every three for those with brittle control!
Tightly regulating blood glucose and avoiding both lows and highs has benefits on the low end to neurological preservation. On the high end some complications such as IVH, NEC and ROP may be avoided by better control. The challenge with the system as is at the moment is that it is not widely available. I am eager for a company out there to create software for mass distribution that would enable us to try this out. While the calibration is still required I can’t help but think this is an improvement over what we have at the moment. Stay tuned as I think this one is for real and will appear in NICUs sooner than you think!
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.
In 2015 the Pediatric Endocrine Society (PES) published new recommendations for defining and managing hypoglycaemia in the newborn. A colleague of mine and I discussed the changes and came to the conclusion that the changes suggested were reasonable with some “tweaks”. The PES suggested a change from 2.6 mmol/L (47 mg/dL) at 48 hours of age as a minimum goal glucose to 3.3 mmol/L (60 mg/dL) as the big change in approach. The arguments for this change was largely based on data from normal preterm and term infants achieving the higher levels by 48-72 hours and some neuroendocrine data suggesting physiologically, the body would respond with counter regulatory hormones below 3.3 mmol/L.
As it turned out, we were “early adopters” as we learned in the coming year that no other centre in Canada had paid much attention to the recommendations. The inertia to change was likely centred around a few main arguments.
1. How compelling was the data really that a target of 2.6 and above was a bad idea?
2. Fear! Would using a higher threshold result in many “well newborns” being admitted to NICU for treatment when they were really just experiencing a prolonged period of transitional hypoglycaemia.
3. If its not broken don’t fix it. In other word, people were resistant to change itself after everyone was finally accustomed to algorithms for treatment of hypoglcyemia in their own centres.
What effect did it actually have?
My colleagues along with one of our residents decided to do a before and after retrospective comparison to answer a few questions since we embraced this change. Their answers to what effect the change brought about are interesting and therefore at least a in my opinion worth sharing. If any of you are wondering what effect such change might have in your centre then read on!
Once the protocol was in place we went from arbitrary consults to mandatory so these results are not surprising. What is surprising though is that the median critical plasma glucose was 2.2 mmol/L, with no significant difference pre or post (2.0 mmol/L pre versus 2.6 mmol/L post, P=0.4) Ninety percent of the infants who were hypoglycemic beyond 72 hours of age were so in the first 72 hours. Of these infants, 90% were diagnosed with hyperinsulinemia. What this tells us is that those who are going to go on to have persistent hypoglycemia will demonstrate similar blood sugars whether you use the cutoff of 2.6 or 3.3 mmol/L. You will just catch more that present a little later using the higher thresholds. How would these kids do at home if discharged with true hyperinsulinemia that wasn’t treated? I can only speculate but that can’t be good for the brain…
Now comes the really interesting part!
Of the total infants in the study, thirteen infants or 40% had plasma glucose values of 2.6 to 3.2 mmol/L at the time of consultation after November 2015. Think about that for a moment. None of these infants would have been identified using the old protocol. Nine of these infants went on to require treatment with diazoxide for persistent hyperinsulinemia. All of these infants would have been missed using the old protocol. You might ask at this point “what about the admission rate?”. Curiously an internal audit of our admission rates for hypoglycemia during this period identified a decline in our admission rates. Concurrent with this change we also rolled out the use of dextrose gels so the reduction may have been due to that as one would have expected admission rates to rise otherwise. The other thing you might ask is whether in the end we did the right thing as who says that a plasma blood glucose threshold of 3.3 mmol/L is better than using the tried and true 2.6 mmol/L cutoff?
While I don’t have a definitive answer to give you to that last question, I can leave you with something provocative to chew on. In the sugar babies study the goal glucose threshold for the first 7 days of life was 2.6 mmol/L. This cohort has been followed up and I have written about these studies before in Dextrose gel for hypoglycemia. Safe in the long run? One of the curious findings in this study was in the following table.
Although the majority of the babies in the study had only mild neurosensory impairment detectable using sophisticated testing the question is why should so many have had anything at all? I have often wondered whether the goal of keeping the blood sugar above 2.6 mmol/L as opposed to a higher level of say 3.3 mmol/L may be at play. Time will tell if we begin to see centres adopt the higher thresholds and then follow these children up. I don’t know about you but a child with a blood sugar of 2.7 mmol/L at 5 or 6 days of age would raise my eyebrow. These levels that we have used for some time seem to make sense in the first few days but for discharge something higher seems sensible.