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!
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 continuousglucosemonitoring 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?
