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.
In the first part of this series of posts called Can prophylactic dextrose gel prevent babies from becoming hypoglycemic? the results appeared to be a little lackluster. The study that this blog post was based on was not perfect and the lack of a randomized design left the study open to criticism and an unbalancing of risks for hypoglycemia. Given these faults it is no doubt that you likely didn’t run anywhere to suggest we should start using this right away as a protocol in your unit.
Dosing was given either once at 1 h of age (0.5 ml/kg or 1 ml/kg) or three more times (0.5 ml/kg) before feeds in the first 12 h, but not more frequently than every 3 h. Each dose of gel was followed by a breastfeed. The groups given prophylaxis fell into the following risk categories;
IDM (any type of diabetes), late preterm (35 or 36 wk gestation), SGA (BW < 10th centile or < 2.5 kg), LBW (birthweight > 90th centile or > 4.5 kg), maternal use of β-blockers.
Blood glucose was measured at 2 h of age and then AC feeds every 2 to 4 h for at least the first 12 h. This was continued until an infant had 3 consecutive blood glucose concentrations of 2.6 mmmol/L. With a primary outcome of hypoglycemia in the first 48 hours their power calculation dictated that a total sample size of 415 babies (66 in each treatment arm, 33 in each placebo arm) was needed which thankfully they achieved which means we can believe the results if they found no difference!
What did they find?
One might think that multiple doses and/or higher doses of glucose gel would be better than one dose but curiously they found that the tried and true single dose of 0.5 mL/kg X 1 offered the best result. “Babies randomised to any dose of dextrose gel were less likely to develop hypoglycaemia than those randomised to placebo (RR 0.79, 95% CI 0.64–0.98, p = 0.03; number needed to 10.”
Looking at the different cumulative doses, the only dosing with a 95% confidence interval that does not cross 1 was the single dosing. Higher and longer dosing showed no statistical difference in the likelihood of becoming hypoglycemic in the first 48 hours. As was found in the sugar babies study, admission to NICU was no different between groups and in this study as with the sugar baby study if one looked at hypoglycemia as a cause for admission there was a slight benefit. Curiously, while the previous study suggested a benefit to the rate of breastfeeding after discharge this was not noted here.
How might we interpret these results?
The randomized nature of this study compared to the one reviewed in part I leads me to trust these findings a little more than the previous paper. What this confirms in my mind is that giving glucose gel prophylaxis to at risk infants likely prevents hypoglycemia in some at risk infants and given that there were no significant adverse events (other than messiness of administration), this may be a strategy that some units wish to try out. When a low blood glucose did occur it was later in the group randomized to glucose gel at a little over 3 hours instead of 2 hours. The fact that higher or multiple dosing of glucose gel given prophylactically didn’t work leads me to speculate this may be due to a surge of insulin. Giving multiple doses or higher doses may trigger a normal response of insulin in a baby not at risk of hypoglycemia but in others who might already have a high baseline production of insulin such as in IDMs this surge might lead to hypoglycemia. This also reinforces the thought that multiple doses of glucose gel in babies with hypoglycemia should be avoided as one may just drive insulin production and the treatment may become counterproductive.
In the end, I think these two papers provide some food for thought. Does it make sense to provide glucose gel before a problem occurs? We already try and feed at risk babies before 2 hours so would the glucose gel provide an added kick or just delay the finding of hypoglycemia to a later point. One dose may do the trick though.
A reader of my Facebook page sent me a picture of the hPOD trial which is underway which I hope will definitively put this question to rest. For more on the trial you can watch Dr. Harding speak about the trial here.
I have written a number of times already on the topic of dextrose gels. Previous posts have largely focused on the positive impacts of reduction in NICU admissions, better breastfeeding rates and comparable outcomes for development into childhood when these gels are used. The papers thus far have looked at the effectiveness of gel in patients who have become hypoglycemic and are in need of treatment. The question then remains as to whether it would be possible to provide dextrose gel to infants who are deemed to be at risk of hypoglycemia to see if we could reduce the number of patients who ultimately do become so and require admission.
Answering that question
Recently, Coors et al published Prophylactic Dextrose Gel Does Not Prevent Neonatal Hypoglycemia: A Quasi-Experimental Pilot Study. What they mean by Quasi-Experimental is that due to availability of researchers at off hours to obtain consent they were unable to produce a randomized controlled trial. What they were able to do was compare a group that had the following risk factors (late preterm, birth weight <2500 or >4000 g, and infants of mothers with diabetes) that they obtained consent for giving dextrose gel following a feed to a control group that had the same risk factors but no consent for participation. The protocol was that each infant would be offered a breastfeed or formula feed after birth followed by 40% dextrose gel (instaglucose) and then get a POC glucose measurement 30 minutes later. A protocol was then used based on different glucose results to determine whether the next step would be a repeat attempt with feeding and gel or if an IV was needed to resolve the issue.
To be sure, there was big hope in this study as imagine if you could prevent a patient from becoming hypoglycemic and requiring IV dextrose followed by admission to a unit. Sadly though what they found was absolutely no impact of such a strategy. Compared with the control group there was no difference in capillary glucose after provision of dextrose gel (52.1 ± 17.1 vs 50.5 ± 15.3 mg/dL, P = .69). One might speculate that this is because there are differing driving forces for hypoglycemia and indeed that was the case here where there were more IDMs and earlier GA in the prophylactic group. On the other hand there were more LGA infants in the control group which might put them at higher risk. When these factors were analyzed though to determine whether they played a role in the lack of results they were found not to. Moreover, looking at rates of admission to the NICU for hypoglycemia there were also no benefits shown. Some benefits were seen in breastfeeding duration and a reduction in formula volumes consistent with previous studies examining the effect of glucose gel on both which is a win I suppose.
It may also be that when you take a large group of babies with risks for hypoglycemia but many were never going to become hypoglycemic, those who would have had a normal sugar anyway dilute out any effect. These infants have a retained ability to produce insulin in response to a rising blood glucose and to limit the upward movement of their glucose levels. As such what if the following example is at work? Let’s say there are 200 babies who have risk factors for hypoglycemia and half get glucose gel. Of the 100 about 20% will actually go on to have a low blood sugar after birth. What if there is a 50% reduction in this group of low blood sugars so that only 10 develop low blood glucose instead of 20. When you look at the results you would find in the prophylaxis group 10/100 babies have a low blood sugar vs 20/100. This might not be enough of a sample size to demonstrate a difference as the babies who were destined not to have hypoglycemia dilute out the effect. A crude example for sure but when the incidence of the problem is low, such effects may be lost.
A Tale of Two Papers
This post is actually part of a series with this being part 1. Part 2 will look at a study that came up with a different conclusion. How can two papers asking the same question come up with different answers? That is the story of medicine but in the next part we will look at a paper that suggests this strategy does work and look at possible reasons why.