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Use of real-time continuous glucose monitoring (rtCGM) systems has been shown to be a low-pain, safe, and effective method of preventing hypoglycemia and hyperglycemia in people with diabetes of various age groups. Evidence on rtCGM use in infants and in patients with conditions other than diabetes remains limited.
This case study describes the off-label use of rtCGM and the use of an open-source app for glucose monitoring in a newborn with prolonged hypoglycemia secondary to transient congenital hyperinsulinism during the perinatal period.
The Dexcom G6 rtCGM system (Dexcom, Inc) was introduced at 39 hours of age. Capillary blood glucose checks were performed regularly. In order to benefit from customizable alert settings and detect hypoglycemic episodes, the open-source rtCGM app xDrip+ was introduced at 9 days of age.
Time in range (45-180 mg/dL) for interstitial glucose remained consistently above 90%, whereas time in hypoglycemia (<45 mg/dL) decreased. Mean glucose was maintained above 70 mg/dL at 72 hours of life and thereafter. Daily sensor glucose profiles showed cyclic fluctuations that were less pronounced over time.
While off-label use of medication is both common practice and a necessity in newborn infants, there are few examples of off-label uses of medical devices, rtCGM being a notable exception. Real-time information allowed us to better understand glycemic patterns and to improve the quality of glycemic control accordingly. Severe hypoglycemia was prevented, and measurement of serum levels of insulin and further lab diagnostics were performed much faster, while the patient’s individual burden caused by invasive procedures was reduced. Greater customizability of threshold and alert settings would be beneficial for user groups with glycemic instability other than people with diabetes, and for hospitalized newborn infants in particular. Further research in the field of personal and off-label rtCGM use, efficacy studies evaluating the accuracy of low glucose readings, and studies on the differences between algorithms in translating raw sensor data, as well as customization of commercially available rtCGM systems, is needed.
Transient and persistent congenital hyperinsulinism (CHI) are rare diseases affecting 1 to 2 in 50,000 newborns. At least 12 genetic defects have been identified that result in dysregulated and increased insulin secretion and subsequently severe hypoglycemia, which may be transient or persistent [
Real-time continuous glucose monitoring (rtCGM) and intermittently scanned continuous glucose monitoring (isCGM), as designed for and commonly used by people with diabetes, provide information on current interstitial glucose levels and trends, and alert the user of current or predicted hypoglycemia and hyperglycemia as well as rapid changes in glucose levels. With regular measurements up to every 5 minutes, they also provide statistics on time spent in hypoglycemia, in hyperglycemia, and within range.
Evidence on rtCGM use for glycemic management in neonates is limited, and there is no evidence of calibration-free rtCGM systems in infants so far. Benefits with respect to glycemic control [
The off-label use of rtCGM in children with CHI was first described in 2004 [
To our knowledge, this case study describes the first use of the rtCGM app xDrip+ in a hospital and intensive care unit (ICU) setting and the first off-label use of rtCGM in a newborn with severe hypoglycemia secondary to transient CHI soon after birth.
A male infant was delivered full term with a birth weight of 3575 g. An emergency cesarean delivery was performed in response to fetal heart rate monitoring indicating fetal distress. The infant presented with bradypnea, floppiness, and sporadic myoclonic jerks and was transiently treated with noninvasive positive pressure resuscitation. A CBG level of 12 mg/dL was detected at 60 minutes of life. Despite feeding attempts and buccal administration of 40% dextrose gel, the blood glucose level decreased further to 1 mg/dL at 120 minutes of life. The patient was started on continuous intravenous glucose and admitted to the neonatal intensive care unit (NICU) for further diagnostics and treatment. The continuous intravenous glucose administration required to maintain blood glucose levels above 50 mg/dL was incrementally increased from 8 mg/kg/min to over 18 mg/kg/min. This required placement of a central venous line at 37 hours of age to allow for administration of hypertonic glucose solutions. In addition, the infant received copious enteral feedings.
The child’s father and the paternal uncle were both reported to have experienced transient postnatal hypoglycemia, requiring hospitalization for 3 weeks after birth. The child’s father reported having often experienced mild hypoglycemia symptoms such as hunger and craving for sweets when fasting. However, blood glucose levels were reported to be within normal range during routine checkups as an adult. There was no history of diabetes in either of the parents, and screening for gestational diabetes during pregnancy was reported to be negative. However, the paternal grandmother was reported to have been diagnosed with type 1 diabetes at 7 years of age.
Next-generation sequencing (quality level type A; SureSelect XT, Custom Constitutional Panel 17 Mb; Agilent Technologies, Inc) of a CHI panel, including
To reduce the frequency of capillary blood samples and estimate the right moment for further lab diagnostics, the Dexcom G6 rtCGM system (Dexcom, Inc) was introduced for off-label use at 39 hours of age. In addition, CBG checks were performed regularly, at least 3 times per day (
During the first week, the sensor was paired with a Dexcom G6 handheld device with customizable alert settings; however, the urgent low glucose alarm threshold at a glucose level of 55 mg/dL, which was frequently passed in this neonate but does not meet the requirements in neonates within the first week of life, could not be further reduced. Furthermore, glucose levels below 40 mg/dL could not be further differentiated. In order to benefit from customizable alert settings and include potential hypoglycemic levels below 40 mg/dL, the informed decision was made to pair the sensors with the caregivers’ personal Android phone using the app xDrip+.
Upper thigh as a suitable rtCGM application site in neonates.
Upper arm as a suitable rtCGM application site in neonates.
xDrip+ [
For the first 7 days of sensor data, rtCGM readings were exported from the Dexcom handheld device using the Dexcom Clarity software. For the following days when xDrip+ was used, sensor data was exported through the built-in data export function in the xDrip+ app. For the analysis of sensor data, we computed statistical properties (arithmetic mean and standard deviation) in the programming language Python 3.7. Furthermore, time in hypoglycemia and time in range were calculated as follows:
As there is currently no standardized definition for treatment consequences in response to low and high glucose levels in neonates, but their physiological range tends to be lower than in older individuals [
The infant responded well to a single subcutaneous injection of 30 µg/kg of glucagon (GlucaGen Hypokit; Novo Nordisk A/S). Therefore, a glycogen storage disease was unlikely to be the underlying condition and congenital hyperinsulinism was suspected. According to CHI treatment guidelines [
Initial hypoglycemia screening revealed hyperinsulinemia with no ketonemia present (blood glucose 29 mg/dL, insulin 9.03 mU/L, C-peptide 2.34 µg/L). After terminating the intravenous glucose and the subcutaneous glucagon infusion and with increasing improvement of oral feeding and hence regular and reliable enteral glucose uptake, no new hypoglycemic episodes occurred between days 17 and 20. Consequently, we suspected normalization of insulin secretion, which was substantiated by an analysis after a strict fasting period of 6.5 hours (blood glucose 86 mg/dL, insulin 1.5 mU/L, C peptide 0.54 µg/L, ketone bodies 0.4 mmol/L) on day 20. With these results, we were able to terminate rtCGM use and discharge the infant on the same day in good health.
Genetic testing did not reveal any disease-relevant pathologic variation in genes that are most frequently associated with CHI:
Time in range (sensor glucose readings between 45 and 180 mg/dL or 2.5 and 10 mmol/L) remained consistent above 90%, whereas time in hypoglycemia (<45 mg/dL or <2.5 mmol/L) decreased, and mean glucose was maintained above 70 mg/dL or 3.8 mmol/L at 72 hours of life and after (
rtCGM readings were found to be mostly accurate compared to CBG (
Analysis of rtCGM readings within the first 16 days of life in a neonate with transient CHI, including mean sensor glucose (SD), time in hypoglycemia (defined as the percentage of sensor readings below 45 mg/dL), and time in range (defined as the percentage of sensor readings between 45 mg/dL and 180 mg/dL).
Patient age, d (h) | Sensor readings, n | Glucose, mg/dL, mean (SD) | Readings in range, n | TIRa, % | Readings in hypoglycemia, n | TIHb, % |
2 (39-48) | 74 | 68 (16) | 71 | 95.9 | 3 | 4.1 |
3 (49-72) | 291 | 69 (29) | 240 | 82.5 | 51 | 17.5 |
4 (73-96) | 288 | 98 (34) | 288 | 100.0 | 0 | 0.0 |
5 (97-120) | 290 | 79 (16) | 286 | 98.6 | 4 | 1.4 |
6 (121-144) | 291 | 82 (17) | 280 | 96.2 | 11 | 3.8 |
7 (145-168) | 282 | 94 (36) | 274 | 97.2 | 8 | 2.8 |
8 (169-192) | 287 | 77 (21) | 270 | 94.1 | 17 | 5.9 |
9 (193-216) | 203 | 85 (29) | 190 | 93.6 | 13 | 6.4 |
10 (217-240) | 213 | 81 (22) | 197 | 92.5 | 16 | 7.5 |
11 (241-264) | 284 | 81 (25) | 261 | 91.9 | 23 | 8.1 |
12 (265-288) | 281 | 86 (24) | 274 | 97.5 | 7 | 2.5 |
13 (289-312) | 296 | 81 (19) | 284 | 95.9 | 12 | 4.1 |
14 (313-336) | 288 | 73 (20) | 265 | 92.0 | 23 | 8.0 |
15 (337-360) | 248 | 72 (18) | 235 | 94.8 | 13 | 5.2 |
16 (361-372) | 138 | 83 (17) | 138 | 100.0 | 0 | 0.0 |
aTIR: time in range.
bTIH: time in hypoglycemia.
This case study describes the use of a Dexcom G6 rtCGM system in a neonate with transient CHI during the perinatal period, using two different algorithms. The real-time information provided by the rtCGM system allowed us to better understand glycemic patterns of the underlying condition and to improve the quality of glycemic control of our patient accordingly. Severe hypoglycemia was successfully prevented and measurement of serum levels of insulin and further lab diagnostics were performed much faster, while the patient’s individual burden caused by invasive procedures could be reduced.
To our knowledge, this is the first report on the use of open-source apps for glucose monitoring such as xDrip+ in a hospital and ICU setting, as well as the first study reporting an off-label use of a precalibrated rtCGM system in a neonate. Furthermore, we described the first use of rtCGM in an infant with transient CHI in the most critical phase during the first days of life.
While off-label use of medication is both common practice and a necessity in newborn infants, there are few examples of off-label uses of medical devices, rtCGM being a notable exception [
It is important to note that although rtCGM provides information about glucose dynamics and variability, these systems might be less accurate when it comes to direct comparison with point-of-care testing of blood glucose levels. In order to keep invasive diagnostics for the patient reduced to a minimum, there were not enough CBG data points available to allow for a robust calculation of the mean absolute relative difference. This limits our ability to evaluate the accuracy of rtCGM readings, particularly of glucose levels <40 mg/dL. As rtCGM systems correlate the electric signal of the sensor with interstitial glucose concentrations in a linear fashion, they are not designed to detect the low glucose levels that occur in newborn infants after birth. Moreover, alert settings are not fully customizable to threshold values that seem reasonable to use in infants, who have a much lower physiological glucose range compared to older children and adults [
The app xDrip+, which was used in this case study, originates from an online community of people living with type 1 diabetes. The Android application package needed for setup, the app’s source code, and instructions on how to install and use the app are openly available on the internet. Recently, open-source rtCGM apps such as xDrip+ for Android phones [
The use of rtCGM can be considered in neonatal patients at risk of hypoglycemia, such as infants with transient or permanent CHI, to reduce the frequency of blood glucose measurements and focus them on potential decision-making points. However, these devices have been designed to be used by people with diabetes and are currently not approved for use in children younger than 2 years of age. Other use cases, such as infants with glycemic instability and other patients with rare conditions that might benefit from continuous glucose monitoring, are currently not being addressed sufficiently by the medical device market. Further investigation on the use and accuracy of rtCGM in wider patient groups, as well as further customization of rtCGM systems, is needed to address unmet needs of wider population groups.
Daily profiles of sensor glucose and therapeutic management of a newborn with transient CHI. Sensor glucose readings [mg/dL] are shown in blue, i.v. glucose distribution in green [mg/kg/min) and s.c. glucagon infusion in orange [µg/kg/h]. Low sensor glucose threshold (45 mg/dL) is shown in red. Capillary blood glucose (CBG) measurements are marked in magenta.
capillary blood glucose
congenital hyperinsulinism
intensive care unit
intermittently scanned continuous glucose monitoring
neonatal intensive care unit
real-time continuous glucose monitoring
We would like to thank the developers of xDrip+ of the diabetes online community for their cooperation, helpful comments, and thorough review of the paper.
The caregivers gave their consent for the off-label use of xDrip+ and for the publication of this case study.
The authors received no financial funding for the research conducted. We acknowledge support from the German Research Foundation and the Open Access Publication Funds of Charité – Universitätsmedizin Berlin for the publication of this paper.
KB, MW, and SH performed the literature search. KB, OB, and CB designed the study design and methods. KB, ML, DH, NJR, and SH collected the data. KB and MW performed the data analysis. KB wrote the initial draft for the paper. All authors have reviewed and revised the manuscript and have read and approved the final version of the paper.
All authors have completed the Unified Competing Interest form and declare the following: KB received research grants from the Berlin Institute of Health Junior Clinician Scientist and Digital Clinician Scientist program, the European Commission’s Horizon 2020 Research and Innovation program, the Wellcome Trust, Stiftung Charité, and the German Diabetes Association. She has served as a speaker and advisory board member for Medtronic Diabetes and Hi.Health and received fees for medical consulting and public speaking from Roche Diabetes Care, Dexcom, Medtronic Diabetes, Diabeloop, BCG Digital Ventures, and Bertelsmann Stiftung; all outside the submitted work. MW reports research grants from the European Commission’s Horizon 2020 Research and Innovation program outside the submitted work and was employed by Medtronic Diabetes Germany until 2018. TU reports research grants from the European Commission’s Horizon 2020 Research and Innovation program outside the submitted work. ML received research grants from the Berlin Institute of Health and the Berlin Cancer Society outside the submitted work. CB is supported by the German Federal Department of Research and Education and has received lecture fees from Chiesi paid to his employer, both outside the submitted work. All other coauthors have no conflict of interest to declare.