Can prophylactic dextrose gel prevent babies from becoming hypoglycemic?

Can prophylactic dextrose gel prevent babies from becoming hypoglycemic?

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.

A Cure For Neonatal Hypoglycemia

A Cure For Neonatal Hypoglycemia

I have probably received more requests for our glucose gel protocol than any other question since I started writing on this blog.  Dextrose gel has been used more and more often for treatment of hypoglycemia such that it is now a key strategy in the management of low blood sugar in ours and many other institutions.  If you are interested in the past analyses of the supporting trials they can be found in these posts; Glucose gel For Managing Hypoglycemia. Can We Afford Not To Use It? and Dextrose gel for hypoglycemia: Safe in the long run?  As you can tell from these posts I am a fan of dextrose gel and eagerly await our own analysis of the impact of using gel on NICU admission rates for one!

But What If You Could Prevent Hypoglycemia Rather Than Treating It?

This is the question that the same group who has conducted the other trials sought to answer in their dose finding study entitled Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study).  I suppose it was only a matter of time that someone asked the question; “What if we prophylactically gave at risk babies dextrose gel?  Could we prevent them from becoming hypoglycemic and reduce admissions and improve breastfeeding rates as has been seen with treatment of established hypoglycemia?”  That is what they went out and did.  The group selected at risk patients such as those born to mothers with any type of diabetes, late preterm infants, SGA and others typically classified as being at risk but who did not require NICU admission at 1 hour of age when treatment was provided.  The primary outcome was hypoglcyemia (<2.6 mmol/L) in the first 48 hours.  Secondary outcomes included NICU admissions, breastfeeding rates in hospital and after discharge as well as formula intake at various time points.

The study sought really to serve as a pilot whose goal was to determine when compared to placebo whether several different regimens could prevent development of hypoglycemia.  The groups were (with the first dose in each case given at 1 hour of age):

  1. Single dose of 40% dextrose gel – 0.5 mL/kg
  2. Single dose of 40% dextrose gel – 1 ml/kg
  3. Four doses of 0.5 mL/kg given every three hours with breastfeeding
  4. A single dose of 1 mL/kg then 3 X 0.5 mL/kg given q3h before each breastfeed.

In total 412 patients were randomized into 8 different groups (4 treatment and 4 placebo).

As The Saying Goes, Less Is More

odds-of-hypoglycemia

The only dose of dextrose that reduced the risk of hypoglycemia in the first 48 hours was 0.5 mL/kg which provides 200 mg/kg of dextrose which is the same as a bolus of IV dextrose when giving 2 mL/kg of D10W.  Curiously using a higher dose or using multiple doses had no effect on reducing the risk.  Based on a difference of 14% between placebo and this group you would need to treat roughly 7 patients with dextrose gel once to prevent one episode of hypoglycemia.  Also worth noting is that admission to NICU was no different but if one restricted the reason for admission to hypoglycemia the difference was significant (13% vs 2% risk; p = 0.04).  What was not seen here was a difference in rates of breastfeeding and much effect on use of formula.

Why Might These Results Have Occurred?

Insulin levels were not measured in this study but I truly wonder if the reason for hypoglycemia in the other groups may have been transient hyperinsulinemia from essentially receiving either a very large load of glucose (1 mL/kg groups) or effectively 4 boluses of glucose in the first 12 hours of feeding.  Rebound hypoglycemia from IV boluses is a known phenomenon as insulin levels surge to deal with the large dextrose load and I can’t help but wonder if that is the reason that all but the single dose regimen had an effect.  It is also worth commenting that with so many secondary outcomes in this study the p values needed to reach significance are likely much smaller than 0.05 so I would take the reduction in NICU admissions for hypoglycemia with a grain of salt although at least the trend is encouraging.

I wouldn’t change my practice yet and the authors do acknowledge in the article that a much larger study is now being done using the single dose of 0.5 mL/kg to look at outcomes and until that is published I don’t think a practice change is in order.  What this study does reinforce though is that providing multiple doses of dextrose gel may yield diminishing returns.  While the goal here was prophylaxis, I can’t help but think about the patients who are symptomatic and receive two or three gels and still wind up with an IV.  Could it be the same rebound hypoglycemia at play?

We also have to acknowledge that even if this is an effective preventative strategy, is it in the best interests of the babies to all receive such treatment when at least in 6 babies they wouldn’t have needed any?  Could such treatment simply be reserved as has been done for those who develop hypoglycemia?  Those who question the safety of the ingredients such as dyes that are found in the product may want some long term safety data before this becomes routine in at risk babies but it won’t surprise me if such strategies become commonplace pending the results of the larger trial on the way.