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Found 17 results

  1. 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 principle here is that a meter is inserted subcutaneously that detects blood glucose fluctuations and responds by either increasing infusion of dextrose for low glucose or delivery of insulin. The technology has been around for some time and used in the adult population but is relatively new in this population. I have written about it before in Continuous glucose monitoring in NICU may be around the corner. What follows is the latest pilot study to test this out coupled with glucose or insulin delivery in a closed loop system. The study in this case is out of Cambridge in the UK and entitled Feasibility of automated insulin delivery guided by continuous glucose monitoring in preterm infants . What did they do? 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! The Benefit 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!
  2. How to calculate insulin glucose ratio?. Insulin reported as microIU/L and glucose as mg/dl.do u need to convert insulin to picomll/l or glucose to mol/Lt, before putting the ratio? The reference value said as<.2 normal and >.4 abnormal is without unit conversion or what? Do u take insulin levels only during hypoglycemia or induced hypoglycemia to detect hyper insulin em is.
  3. I have seen 2 newborns recently with hyperinsulinemic hypoglycemia. Both of them settled down with diazoxide.How common is the transient form?
  4. 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.
  5. 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! Skovrlj R, Marks S and C. Rodd published Frequency and etiology of persistent neonatal hypoglycemia using the more stringent 2015 Pediatric Endocrine Society hypoglycemia guidelines. They had a total of 58 infants in the study with a primary outcome being the number of endocrine consults before and after the change in practice. Not surprisingly as the graph demonstrates the number went up. 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.
  6. 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. Another Study Though May Raise Some Eyebrows New Zealand researchers who have been at the forefront of publications on the use of dextrose gel recently published another article on the topic Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study). As the short study name suggests “Pre-hPOD” this was a preliminary study to determine which dosing of dextrose gel would provide the greatest benefit to prevent neonatal hypoglycemia. The study is a little complex in design in that there were eight groups (4 dextrose gel vs 4 placebo) with the following breakdown. 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.
  7. 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.
  8. Hypoglycemia has to be one of the most common conditions that we screen for or treat in the NICU and moreover in newborn care in general. The Canadian Pediatric Society identifies small for gestational age infants (weight <10th percentile), large for gestational age (LGA; weight > 90th percentile) infants, infants of diabetic mothers (IDMs) and preterm infants as being high risk for hypoglycemia. It is advised then to screen such babies in the absence of symptoms for hypoglycemia 2 hours after birth after a feed has been provided (whether by breast or bottle). I am sure though if you ask just about any practitioner out there, they will tell you a story about a baby with “no risk factors” who had hypoglycemia. These one-off cases have the effect though of making us want to test everyone for fear that we will miss one. If that is the case though should we be recommending that all babies get at least one check? The Canadian Pediatric Surveillance Program (CPSP) The CPSP is a branch of the Canadian Pediatric Society that “provides an innovative means to undertake active paediatric surveillance and increase awareness of childhood disorders that are high in disability, morbidity, mortality and economic cost to society, despite their low frequency. I submit my surveys each month as i hope other Canadian Pediatricians do and help to determine the impact of these rare conditions in our Canadian population. Like with any survey we rely on people taking the time to submit but there is always the risk that what is being sent in under represents the true burden of illness as some cases may not be identified. Having said that, it is the best we have! Turning our attention to hypoglycemia in low risk newborns From April 2014 to March 2016 the CPSP searched for these types of patients and just published the results of their findings in Hypoglycemia in unmonitored full-term newborns—a surveillance study by Flavin MP et al. What I like about the study is that they have been able to look at a group of babies that fall outside those identified as being at risk in the CPS statement Screening guidelines for newborns at risk for low blood glucose. They were looking for severe hypoglycemia by using a threshold of < 2.0 mmol/L (36 mg/dl) and all infants must have received IV dextrose. In the end after excluding ineligible cases they had 93 babies who met criteria. Based on the Canadian birth rate this translates to an incidence of 1 in every 8378 births. These babies were all supposed to be low risk but there were in fact clues that while not strictly identified as risks in the CPS statement could have increased the likelihood of a low blood glucose. Twenty three percent of mothers had maternal hypertension and another 23% were obese while 47% had excessive weight gain during pregnancy. Furthermore, 8% of mothers were treated with a beta blocker (most likely labetalol I would think) during pregnancy which is a risk factor for hypoglycemia although not specifically cited in the current CPS statement. A concerning finding as well was the likelihood of severe symptoms in this group on presentation. Twenty percent presented with major clinical signs (seizure, apnea or cyanosis). Median glucose levels at presentation were much lower than those without major signs (median = 0.8 mmol/L, interquartile range [IQR] = 0.5 versus 1.6 mmol/L, IQR = 0.7; P < 0.001). Lastly, providers were asked about neurodevelopmental concerns at discharge approximately 20% were thought to have issues. Are these patients really low risk though? Twenty five percent of the patients submitted had a birth weight less than the 10%ile for GA. These patients as per the CPS guideline recommendations are actually considered at risk and should have been screened. The second issue to address has to do with the way we diagnose diabetes in pregnancy. All women are provided with the oral glucose tolerance test around 28 weeks of pregnancy. No test is perfect but it is the best we have. Women who have excessive weight gain in pregnancy (almost 50% of the cohort) are at higher risk of developing diabetes or some degree of insulin resistance as are those who are classified as obese. I have long suspected and think it may be the case here that some babies who do not meet the criteria for screening as their mothers do not have a diagnosis of GDM actually are at risk due to some degree of insulin resistance or perhaps their mothers develop GDM later. The evidence for this are the occasional LGA babies who are born to mothers without a GDM diagnosis but who clearly have been exposed to high insulin levels as they behave like such affected infants with poor feeding and low sugars in the newborn period. The authors here comment on those that were SGA but how many in this cohort were LGA? The effect of hypertension can also not be minimized which was present in about a quarter of patients. These babies while not being officially SGA may have experienced a deceleration in weight gain in the last few weeks but remained above the 10%ile. These infants would not have the glycogen stores to transition successfully but would not be targeted as being at risk by the current definitions. Should we be screening everyone then? If we acknowledge that about 25% were IUGR in this study (<10%ile) and should have been screened, the expected rate would be 1:1170 births alone. In Manitoba with our 17000 births a year we would capture about two extra babies a year which translates into a low of pokes for a lot of healthy babies. Given the further information that 1:5 babies who are identified may have neurodevelopmental concerns it would take about 2-3 years of testing to prevent one concern. That pick up rate for me is far too low to subject so many babies to testing. What this study though does highlight is the need to view risk factors a little less strictly. Babies who are almost meeting the criteria for being LGA or those whose mother’s have taken lebetalol should have a low threshold for screening. Should hypertension on medications, excessive maternal weight gain or obesity in the mother be considered a risk? What I didn’t see in the end of this study were patients who truly were AGA, being born to healthy non overweight mothers presenting as high risk. Maybe what is really needed based on this study is to re-evaluate what we consider at risk. In the meantime, maybe we should be testing a few extra babies who fall into these “lesser” risk categories. Better yet a study isolating such patients and looking at the frequency of hypoglycemia in these patients is warranted to get a better idea of whether they are indeed risks.
  9. Hypoglycemia has to be one of the most common conditions that we treat in the newborn admitted to NICU. For many infants the transitional phase of hypoglycemia can be longer than a couple low blood sugars and as nurses commonly express, it doesn’t take long before the heels of these infants begin to resemble hamburger. For those of you who have used diazoxide in the treatment of hypoglycemia you know that it works and it works quickly to raise the blood sugar. It works by blocking the production of insulin from the pancreas, so particularly in the setting of an infant with detectable insulin levels while hypoglycemic (should be undetectable with a low blood sugar) it can be quite effective. In my own practice I have found that often within one or two doses of the medication with treatment being 5-15 mg/kg/d it can seem to work miracles. Years ago I heard rumours of a trial from birth of this medication in infants of diabetic mothers but saw nothing come to fruition. As someone though who really strives to critically look at every needle poke and strongly consider the need I have always leaned towards the use of this medication if only to reduce what I suspected would be a large number of heel lances. A Study Comes Forward Balachandran B et al published a paper on this topic this week in Acta Paediatrica entitled Randomised controlled trial of diazoxide for small for gestational age neonates with hyperinsulinaemic hypoglycaemia provided early hypoglycaemic control without adverse effects. To be clear this is a very small study with only 30 patients in total (15 in the diazoxide and 15 in the placebo arms) and as they had nothing to go on for determining a sample size needed there was no power calculation. The authors chose to look at a very specific group of neonates that were SGA and had hypoinsulinemic hypoglycemia so we need to resist extrapolating to other patient groups such as IDMs in case there is a positive effect here. With those warnings though, what they did was devise a stepwise approach to initiating diazoxide at 8 mg/kg/d and escalating the dose to as much as 12 mg/kg/d followed by a standardized wean following blood glucose stability. The primary outcome in this case was the number of hours required to achieve a stable glucose with a glucose infusion rate of =< 4mg/kg/min. They examined a number of secondary outcomes as well including duration of IV fluids, episodes of sepsis and time to achieve full feeds as well as mortality. Given the small sample size though I would resist drawing too many conclusions about these secondary outcomes but they are reported nonetheless. From the paper the Kaplan Meier curve indicates a faster time to stability of blood sugars for 6 hours favouring the diazoxide group. Importantly there were no differences in baseline insulin or cortisol levels between the groups which might explain differing times to glycemic control. Intravenous reductions with feeding increments were also standardized for the study to ensure comparable treatment strategies aside from the provided diazoxide or placebo. Claim of Safety The authors note there were no differences in mortality or number of sepsis episodes between the groups. They did find a statistically significant reduction in duration of IV fluid requirements which is likely believable despite my earlier warning as the length of time to achieve control was significantly reduced. The fact remains though with such few patients I would take claims of safety with a grain of salt. You might think at this point though that I would be a champion for the therapy but despite my earlier enthusiasm I do have some reservations. The median time to achieve glycemic control was 40 vs 72.5 hours with a p value of 0.015 which is certainly significant but really we are talking about nearly 2 vs 3 days of management. Is diazoxide truly safe enough to warrant the 30 hour reduction in time to glycemic control? Assuming q3h point of care glucose checks this would be about 8-10 less pokes as a best case scenario but more likely 4-6 less as near the end of checking glucoses as the patient becomes more stable the number of pokes usually decreases. Is diazoxide worth it though? Back in 2015 the FDA issued a warning that diazoxide can lead to pulmonary hypertension. In truth we have seen it in babies where I practice and as such now routinely have an ECHO done before starting the drug to determine if there is any pulmonary hypertension prior to starting the drug and if there is even a hint it is contraindicated. It isn’t too common a complication as in the FDA bulletin (read here) there have been only 11 cases reported since 1973 but it is a risk nonetheless. Thirty patients sadly isn’t enough to rule out this complication and it is worth nothing that the authors did not look for this outcome so we don’t know if any patients suffered this. Am I saying that one should never use diazoxide? Absolutely not but I am suggesting that if you use it then use it with great caution. Although I am delighted the authors chose to perform this study taking all risks into account and looking at the benefit in terms of time on IV and that needed to gain control of blood sugars I can’t say this should be standard of care.
  10. We sure do poke a lot of babies to test their blood glucose levels. Some of these babies don’t have so much blood to spare either so checking sugars multiple times a day can drain the body of that precious blood they so need for other functions. Taking too much can always be addressed with a blood transfusion but that as I see it may be avoidable so shouldn’t we do what we can to cut down on blood work? Those with diabetes will be familiar with a continuous glucose monitor (CGM) which is implanted in the skin and can stay in place up to 7 days. The device does require calibration twice a day with a capillary sample to verify it is reading well but this saves a couple pokes a day for those who check four times a day. Such a device could be useful in the NICU where those with hypoglycemia may be checked 6 or more times per day if they are either hypo or hyperglycemic. Cutting this down to two a day would certainly we something worth striving for and if not for the reduction in blood loss then for the minimization of painful procedures. Does it work in small babies? A natural question for sure.Uettweller et al published Real-time continuous glucose monitoring reduces the duration of hypoglycemia episodes: a randomized trial in very low birth weight neonates. In babies with a BW < 1500g they were able to demonstrate in 43 babies (21 with traditional intermittent glucose checks vs 22 with CGM) a reduction in duration of hypoglycemia episodes per patient (CGM 44[10-140] min versus IGM 95[15-520] min, p<0.05). Moreover in this brief study of the first three days of life they also found a reduction in the total number of pokes per patient of 5 pokes (22 vs 16). The numbers however are small and the duration short in only being three days so it did not provide a perfect answer as to whether this technology would work in babies from 500-750g reliably but certainly for older babies, continuous knowledge of the blood glucose in theory would allow for faster response to low sugars and as a result as evidenced by the results led to a decrease in time with a low blood glucose. Improving on these results Galderisi et al just published Continuous Glucose Monitoring in Very Preterm Infants: A Randomized Controlled Trial. The study remains small at 50 and the target group ranging from 28-31 weeks (all < 1500g) but the study followed babies for a longer time frame of 7 days. This study employed an algorithm for adjustments in glucose infusion that required staff to first put data into an excel spreadsheet and then the predictive algorithm dictated whether to increase or decrease the rate of dextrose infusion. In one arm, CGM results were unblinded and the practitioners relied on the rate of change to determine the predicted glucose 15 minutes into the future while in the blinded group the CGM was used but results were not available (retrospectively yes) so changes were made based on the usual practice of obtaining point of care results and modifying glucose infusion rates based on that result. The primary outcome of interest here was percentage of time in the euglycemic range of 72 – 144 mg/dL (4-8 mmol/L). Secondary outcomes were time spent hypo or hyperglycemic (mild hypoglycemia (M-HYPO) (47–71 mg/dL); severe hypoglycemia (S-HYPO) (<47 mg/dL); mild hyperglycemia (M-HYPER) (145–180 mg/dL); and severe hyperglycemia (S-HYPER) (>180 mg/dL)). The study lasted a total of seven days allowing the use of one subcutaneous probe per patient as they can last one week after insertion. How did the approaches compare? As you might have expected, having a predictive model proved superior. Overall after adjusting for sex, gestational age and weight mean time in target using the unblinded CGM was 83% [95% CI, 79%–87%] and of 71% [95% CI, 67%–76%] in B-CGM [P < .001]). As for secondary outcomes one can see that the time spent in the hypo/hyper areas was much less as a percentage of time than using traditional methods of intermittent sampling. One interesting outcome was that the total number of samples used over the study was an average of 2.4 tests per day in the unblinded group vs 2.59 per day in the intermittent sampling group which although statistically different does not seem to have much clinical impact. A few questions remain The idea of using an implanted CGM for infants in the NICU is one that excites me. The lack of a reduction in pokes in a meaningful way is disappointing but I can’t help but wonder if the effect was different whether you were in the first or second half of the week. What if glycemic control in these 29-31 week infants had stabilized by 2-3 days such that you only needed one or two glucose checks in the last half of the week per day? The CGM requires calibration twice daily with POC samples so the lack of a difference my be due to those issues. Future, calibration is rumoured to be possible with one sample so that may change. There is no disputing though that the use of the predictive algorithm made a difference in terms of avoidance of hypo/hyperglycemic episodes. A larger study would be needed to look at whether this impacts harm that may be associated with such variability such as IVH or ROP but it certainly is promising. The biggest issue here is that I cannot see people manually inputting glucose readings on the CGM into an excel sheet in everyday practice. For this to become widely adopted, a simplified approach to prediction would be required or even better a feedback loop whereby data from the CGM would relay to the infusion pump and rates adjusted automatically (with manual override available). The use of CGM is coming though and I can’t help but think in the larger babies born to mothers with diabetes there would be a real heal sparing effect with these. Might this be the next study?
  11. I guess many of you read about the Sugar Babies Study, about giving dextrose gel to (well) infants at risk of developing hypoglycemia. Link to the paper in Lancet: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961645-1/abstract I would be glad to hear more from people with experience from this treatment, involved in the trial or having experience outside the trial. - is the gel produced by pharmacies "in-house" or bought from a manufacturer? - who is administrating the gel (midwife, nurse, doctor?) - dose weight-dependent (SGA vs LGA babies)? - experience regarding b-glucose and admissions to the NICU? etc...
  12. 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): Single dose of 40% dextrose gel – 0.5 mL/kg Single dose of 40% dextrose gel – 1 ml/kg Four doses of 0.5 mL/kg given every three hours with breastfeeding 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 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.
  13. The Sugar Babies trial was the subject of a post earlier this year as the largest trial to date examining the effects of using dextrose gel to treat hypoglycemia. For an analysis of the use of gel in this situation please see the original post Glucose Gel For Neonatal Hypoglycemia: Can We Afford Not To Use It? In summary though, the trial involved 118 infants who received 40% dextrose gel vs 119 who received a placebo gel. All of the infants in this study were selected based on risk factors for hypoglycemia (IDM, IUGR, LBW, LGA, near term) and were all 35 weeks or greater. Each infant had to be less than 48 hours of age when enrolled. Infants received 0.5 mL/kg 40% dextrose gel (200 mg/kg). This was designed to deliver the same amount of sugar as would be given with a D10W bolus of 2 mL/kg. In order to receive the treatment the blood glucose had to be < 2.6 mmol/L so equivalent to our own standards in Canada and the US. Treatment failure, which was the primary outcome was defined as a blood glucose < 2.6 mmol/L despite two treatments with gel. The studies most important findings were a reduction in NICU admission and greater breastfeeding rates at 2 weeks of age (due to avoidance of formula feeding to keep the glucose stable). But Is It Safe? With any new strategy though, questions arise regarding safety of the product in the long term. As one reader commented after the original post, could the red dye be harmful in some way or perhaps some other constituent of the gel? The authors of the original study have now published the follow-up paper entitled Outcome at 2 Years after Dextrose Gel Treatment for Neonatal Hypoglycemia: Follow-Up of a Randomized Trial. The findings were a little concerning to me in that there was a high rate of neurosensory impairment in both arms (sham and glucose gel) with the following findings. None of the differences were significant however. Looking at these results you could be dismayed that the glucose gel did not show any benefit compared to standard therapies for hypoglycemia but if you look at the original study one could equally ask why would we have expected it to? Should The Results Surprise Us? All of the newborns in either arm had an episode of hypoglycemia recorded in order to qualify for entry into the study. The glucose gel was effective compared to placebo in reducing admissions and increasing breastfeeding rates (which one might think would improve outcomes) but we don't know what the drop off rate in breastfeeding was after 2 weeks. What I can say though is that if there were significant adverse side effects with the glucose gel I would have expected to see some differences in outcome favouring the placebo group which did not occur. An additional issue is we know that the placebo group had more treatment failures meaning they would have had more newborns in the original study with a second low glucose. Would this favour a worse outcome in the placebo group? If so does the equivalence in groups suggest that the dextrose gel might worsen outcomes? Unfortunately, what this study is really missing is some indication of how low and how long the blood sugars remained under 2.6 mmol/L in both arms of the study. We know the mean low glucoses were similar but what about duration and range? While the rates of mild, moderate and severe impairment are the same we don't know how severe the hypoglycemia was which if unbalanced between the groups could actually lead to very different conclusions here. For example, let's say the glucose gel group had an over representation of infants with 3 or more episodes of hypoglycemia compared to the placebo arm. The fact that the outcomes are equivalent would suggest that the glucose gel is in fact protective. What Can We Say? I suspect that while glucose gel is effective, to truly assess harm across many different aspects of development we will need larger sample sizes. We also have to take the results of this study with a grain of salt as so many that have come before it have seen outcomes at school age reveal different findings than when assessed at 2 years of age as in this study. From my standpoint though I will continue to advocate for the use of glucose gel as the reduction in NICU admissions and enhancement of breastfeeding rates especially if sustained are well worth the efforts to implement this strategy if you aren't using it already.
  14. We are quite dis-satisfied with our current equipment (Freestyle light, Abbott) https://www.abbottdiabetescare.com/products/patient/fs-lite-overview.html as we often feel that the instrument gives false low values. So... what equipment do you use for routine blood sugar measurements in the NICU and maternity ward? What method do you use for blood sampling?
  15. I am interested to learn more about microdialysis in newborns, for monitoring of subcutaneous glucose monitoring. We have an idea for a research project and would need a good way to monitor glucose homeostasis contineously. Microdialysis would be an option(?). This article here catches well what we want to learn more about: http://www.ncbi.nlm.nih.gov/pubmed/11694701 If you have experience from technologies (commercially available or DIY) and the use if such technologies, please share!
  16. We currently use the Freestyle glucose monitoring device (a variant of this one http://www.abbottdiabetescare.com/freestyle-lite-blood-glucose-monitoring-system.html) but feel frustrated about it. This monitoring system was evaluated at Karolinska about ten years ago (http://www.ncbi.nlm.nih.gov/pubmed/16299875) and the correlation with our previous "gold standard" - venous blood sugars measured with the Hemocue machine - was found to be good. Now, we often see that low values obtained with the Freestyle are commonly normal when venous samples are measured by the regular lab or with Hemocue. What equipment do you use for blood glucose monitoring in your unit? Does anyone have experience from micro-dialysis of newborns/preterms?
  17. 5 wk old infant came to ER with scalp discoloration (grayish) for 2 days. Baby was treated soon after birth for persistent hypoglycemia (in another hospital) and diagnosed as hyperinsulinism. Infant was sent home on po hydrochlorthiazide and diazoxide. Exam showed active, alert baby. Grayish area of discoloration covering most of scalp. No edema. BMP showed Na 133 K 7.8 (heelstick). Rest normal. CBC normal. What is the cause of this discoloration? Can this be acanthosis nigricans though i have never seen it this early in life? What other things should one look for?
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