PEDIATRICS Vol. 107 No. 2 February 2001, pp. 222-226

Continuous Subcutaneous Glucose Monitoring in Children With Type 1 Diabetes

H. Peter Chase, MD^*, Laura M. Kim, BS^*, Susie L. Owen, RN^*, Todd A. MacKenzie, PhD, Georgeanna J. Klingensmith, MD^*, Robert Murtfeldt^§, and Satish K. Garg, MD^*

From the ^* Department of Pediatrics, Barbara Davis Center for Childhood Diabetes, Denver, Colorado;  Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado; and ^§ MiniMed, Sylmar, California.

	ABSTRACT

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Purpose.  To determine whether the use of continuous subcutaneous glucose monitoring will help in detecting unrecognized nocturnal hypoglycemia and in lowering hemoglobin A1c (HbA1c) levels (without increasing the risk for severe hypoglycemia) in children with type 1 diabetes.

Methods.  Eleven children with type 1 diabetes and HbA1c values consistently >8.0% were randomized either to the Continuous Glucose Monitoring System (CGMS) group or to the control group. The CGMS group used 6 3-day sensors within a 30-day period. Both groups self-monitored their blood glucose levels a minimum of 4 times daily. HbA1c levels were measured at the start, at 1-month, and after 3 months of study.

Results.  The 5 children using the CGMS had 17 asymptomatic episodes (85%) of glucose levels below 60 mg/dL (3.25 mmol/L) and 3 symptomatic episodes (15%) during the night in the study month. The 6 control children had 4 symptomatic nocturnal low episodes during the month. After the 30-day period of wearing the CGMS, the 5 children had a significantly lower mean HbA1c value compared with their initial value (mean ± standard error of the mean [SEM] decrease = .36% ± .07%). The mean decrease for the controls was .2% ± .2%. After 3 months, 4 of the 5 children who used the CGMS continued to have lower HbA1c values in comparison to their initial values (mean ± SEM decrease = 1.04% ± .43%). Three of the 6 control participants also had lower HbA1c values at 3 months (mean ± SEM decrease for the group = .62% ± .44%). No severe hypoglycemic events occurred in either the CGMS or the control groups.

Conclusion.  In this pilot trial, continuous subcutaneous glucose monitoring was helpful in detecting asymptomatic nocturnal hypoglycemia as well as in lowering HbA1c values without increasing the risk for severe hypoglycemia in children with type 1 diabetes.  Key words:  continuous glucose monitoring.

The Diabetes Control and Complications Trial (DCCT) showed the importance of improving glucose control to reduce the risk for the microvascular complications of type 1 diabetes.^1-3 Frequent glucose monitoring was considered an important factor in attaining better glucose control for the intensively treated participants in the DCCT. Most of these participants self-monitored their blood glucose levels a minimum of 4 times daily. Unfortunately, the intensively treated group in the DCCT had a threefold increase in severe hypoglycemia.

Because of many factors, including pain and inconvenience, many children with diabetes do not accept frequent fingersticks for self blood glucose monitoring (SBGM) levels. The SBGM result gives the data for only a few seconds, without any information on glucose trends before or after the glucose value. One parent of a child with diabetes compared his daughter's daily 4 SBGM values to hearing 4 notes of a symphony. In addition, families frequently do not measure blood glucose levels during the night, although 55% of severe hypoglycemic events in the DCCT occurred during sleep.⁴ Similarly a 1-year prospective study of 350 children with diabetes found 56% of severe hypoglycemic episodes to occur during the night.⁵ It is likely that the management of type 1 diabetes in the future will involve regular or intermittent periods of continuous glucose monitoring. The purpose of this pilot trial was to determine whether continuous subcutaneous glucose monitoring might be helpful in detecting unrecognized nocturnal hypoglycemia and in lowering hemoglobin A1c (HbA1c) values in children with type 1 diabetes and poor glucose control.

	METHODS

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Participants

Eleven children 10 to 17 years of age with type 1 diabetes (duration: 2.1-11.6 years) participated in this study. A 12th participant who had signed the consent form to participate did not successfully complete any of the Continuous Glucose Monitoring System (CGMS) attempts and was thus eliminated. All participants (including parents) signed a consent form approved by the Colorado Multiple Institutions Review Board. Each child had a mean HbA1c level >8.0% (range: 8.3%-10.3%) for the 6 months before participating in the study (Table 1). All participants were on intensive insulin treatment with 6 receiving continuous subcutaneous insulin infusion (or insulin pump therapy) and 5 receiving multiple daily injections (MDIs). There were 5 females and 6 males.

Glucose Sensor

The MiniMed (Sylmar, CA) CGMS was used for subcutaneous glucose monitoring. The system consists of a subcutaneous sensor connected by a cable to a pager-sized glucose monitor. Glucose readings are acquired by the monitor every 10 seconds and an average glucose value is stored in the monitor memory once every 5 minutes (up to 288 measurements per day). Each glucose sensor provides glucose information for up to 72 hours. The stored values in the monitor are downloaded by the MiniMed Com-Station and presented in graphical and statistical form via a computer program.

Procedure

The 11 children were randomized to either receive the CGMS or to serve as controls. The children receiving the CGMS were each asked to wear 6 sensors (18 total sensor days) within a 30-day period. The CGMS and the glucose meters were brought to the Barbara Davis Center for downloading after each sensor use. The control children were asked to fax their SBGM values 6 times (every 5 days) in the same 1-month period. Families were asked to not change their dietary practices during the study.

While using the CGMS, the test participants had to perform at least 4 SBGM tests per day and enter these values into the CGMS monitor to obtain correlation coefficients between the SBGM and the CGMS values. Control children were also asked to perform a minimum of 4 daily SBGM tests. All insulin dose adjustments were made by telephone by one person (H.P.C.) using both the SBGM values and, for test children, the CGMS and SBGM values.

Each participant completed the Fear of Hypoglycemia⁶ and the DCCT Quality of Life⁷ questionnaires at the start, after 1 month, and after 3 months of the study. Both questionnaires are based on a 5-point Likert scale (1 = disease has no impact; 5 = highly impacted by disease). Each participant's questionnaire was assigned a total value based on the sum of the individual question responses. The range for the Fear of Hypoglycemia and the Quality of Life questionnaires were 27 to 135 and 44 to 220, respectively, with lower totals meaning less fear or more satisfied, respectively.

The HbA1c values of each child were determined at the start, after the first month, and at the 3-month point of the study. HbA1c values were determined using the Bayer (Tarrytown, NY) DCA 2000 instrument, with a nondiabetic range of 4.3% to 6.3%. The laboratory in which the determinations were performed is Clinical Laboratory Improvements Amendments-approved, and the College of American Pathology standards, which are run 3 times annually, have never been outside of the accepted values.

All SBGM tests were performed using the Accu-Chek Complete meter and Comfort Curve glucose strips (Roche Diagnostics, Inc., Indianapolis, IN).

Statistics

Mean levels of HbA1c and changes from baseline in HbA1c were compared between the 2 study arms using the Student's t test. In both groups, HbA1c levels were tested for significant reductions from baseline using a paired t test. Changes from baseline in HbA1c at 1 month were compared in favor of comparing actual HbA1c at 1 month because of the high ratio of between participant variation to within participant variation, and because it reduces the possibility of confounding. The number of hypoglycemic events and insulin changes were compared between the 2 study arms using a Poisson model likelihood ratio test. S-Plus, 4.5 Statistical Software was used.⁸

	RESULTS

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There was a significant difference (P = .001) in the number of hypoglycemic events (SBGM or CGMS values <60 mg/dL [3.25 mmol/L]) detected between the CGMS and the control children during the study month. The CGMS group had a mean (± standard error of the mean [SEM]) of 12.8 (± 1.6) hypoglycemic episodes detected per participant during the first month. Collectively, 17 of their episodes were during the night and were detected only by the CGMS (no symptoms). Three other episodes occurring during sleep caused symptoms and the person to awaken. The control participants had 6.7 (± 1.1) hypoglycemic events detected per participant during the 1-month period. Of the 40 episodes, 4 (10%) were symptomatic during the night. No participant in either group had a seizure, an episode requiring the help of another, or an unconscious episode at any time during the study.

There was a significant difference in the mean (± SEM) number of insulin dosage changes made per participant during this 1-month period: 11.5 (± 1.5) insulin changes were made per participant in the CGMS group versus 5.2 (± .9) changes per participant for the controls (P = .001).

Although the mean (± 1 standard deviation [SD]) HbA1c values for the 6 months before beginning the study were higher for the CGMS group (9.3 ± .7) than for the control group (8.9 ± .7), these differences were not statistically significant (P > .05). Similarly, the mean (± 1 SD) HbA1c values at baseline in the CGMS and control groups, 10.0 ± .7 and 9.0 ± 1.2, respectively, were not significantly different. All 5 of the CGMS participants decreased their HbA1c levels by at least .2% (Table 1) after using the CGMS for 1 month (mean ± SEM decrease = .36% ± .07%; P < .01 in comparison to their initial value). Three of the 6 control participants also lowered their HbA1c values by at least .2% after the 1 month of increased attention (mean ± SEM decrease = .2% ± .2%; P = .37 in comparison to their initial value). After 3 months, 4 of the 5 children who used the CGMS continued to have lower HbA1c values (Fig 1) than their initial levels (mean ± SEM decrease = 1.04% ± .43%). Although the mean reduction was greater at 3 months than at 1 month, because of the wide variance the reduction was not statistically significant (P = .07). Three of the 6 control participants also maintained a lower HbA1c at 3 months (mean ± SEM decrease = .62% ± .44%; P > .05).

View larger version (18K): [in this window] [in a new window]   Fig. 1.   Changes in HbA1c levels for the CGMS participants (solid lines) and the control participants (broken lines). At 1-month, all 5 of the CGMS participants had lower HbA1c values (P < .01), while 3 of the 6 control participants had lower levels (P = .39).

There were no significant differences in results for the Fear of Hypoglycemia or the Quality of Life surveys between the test and control participants at any time. There were also no significant differences in comparing the survey results before versus after 1 or 3 months of study for either group. The mean group total for the Fear of Hypoglycemia questionnaire decreased slightly (meaning less fear) from 61.8 at the beginning of the study to 56.6 at 3 months for the CGMS group (P > .05).

The mean number of glucose readings and the mean number of hours per sensor of usable data (correlation coefficient between SBGM and CGMS values .78) are shown in Table 2. The participants attained an average of 421 (of 864 possible) usable readings per sensor. The main reason for the lower numbers of usable CGMS data were patient noncompliance, with failure to enter the minimum four SBGM levels each day and waiting too long to enter the SBGM values in the monitor.

	DISCUSSION

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This pilot trial is the first report of continuous subcutaneous glucose monitoring in children. Bode et al^9,10 previously studied 9 adults (mean age: 42.7 years) in a pilot trial, 5 of whom were on insulin pumps and 4 on MDI. The 9 adults decreased their HbA1c from an initial value of 9.9% to 8.8% (1.1%; P < .0006) over a 5-week period.⁹ They maintained the decrease at 10 weeks, when the mean HbA1c was 8.6% (P < .019), confirming that the effect "was not merely a study effect, but due to the therapy adjustments made based on CGMS results."¹⁰ In the present study, all 5 of the children who used the CGMS showed some decline in HbA1c after 1 month. In contrast, only 3 of the 6 control children (who had equal attention and SBGM testing, but not the CGMS) showed a reduction in HbA1c. After 3 months, the decrease in mean HbA1c levels for the CGMS group was from 10.0% to 8.8%, almost identical to the decline showed by Bode et al. However, the controls also showed a decrease from 9.0% to 8.4% at 3 months, confirming the well-recognized effect of increased attention. All reductions were impressive, as the participants had been very resistant to improvement despite insulin pump or MDI therapy.

The CGMS involves the insertion of a subcutaneous sensor, which is easier for some patients compared with others. Three of the 12 adults chosen by Bode et al⁹ did not participate, and 1 of the 12 children who initially volunteered to participate in this trial did not complete any sensors. In retrospect, the use of 6 sensors (18 days) in a 30-day period was probably excessive. A better plan would have been to spread the 6 sensors over the 90-day period.

There was initial concern as to whether subcutaneous glucose values would accurately reflect blood glucose levels. This has since been shown to not be a problem.^11-14 In the most recent study (using the CGMS), it was noted that interstitial glucose levels always fell 13 minutes behind the blood glucose values.¹⁴ This did not differ when the blood glucose was increasing, decreasing or remaining the same. As noted in Table 2, the CGMS did not consistently give complete 3-day data, mainly because of patient compliance. Several youth admitted that they delayed entering SBGM values into the CGMS monitor, thus the 2 numbers did not correlate well with each other because of delayed human entry of data. Some also failed to enter the minimum 4 SBGM values during the day so that usable data were not obtained. Despite the various problems, the children still averaged 140 five-minute glucose readings per day from the sensor, which was considerably better than the usual 2 to 4 values per day using SBGM.

The children using the CGMS in addition to SBGM testing had a mean of 12.8 glucose values below 60 mg/dL (3.25 mmol/L) detected, compared with 6.7 episodes for the controls in the study month. This resulted in significantly more insulin dose changes for the CGMS group (11.5 per participant) in comparison to the controls (5.2 per participant). The close communication during the study month (6 contacts per family) and the increased glucose monitoring (SBGM and CGMS) allowed the changes in insulin dosage to be made without increasing the incidence of severe hypoglycemia as found in the DCCT. In our study, one 15-year-old male (participant 2) decreased his HbA1c from 10.9% to 7.5% after 6 months (data not shown). This participant's initial CGMS graph is shown in Fig 2A. The low values during the night were no longer detected by his final use of the CGMS (Fig 2B). In a recent study of nocturnal hypoglycemia in 50 children with diabetes who were hospitalized overnight, it was found that 47% had a blood glucose level below 60 mg/dL (<3.3 mmol/L) during the night (using hourly blood glucose determinations).¹⁵ They found that 49% of cases were asymptomatic. The data from our study, measuring glucose levels with the CGMS every 5 minutes during the night, with normal evening home activity, suggest that the incidence of asymptomatic episodes is closer to 85% (17 of 20). Fortunately, all episodes were self-correcting without seizures or other severe sequellae.

View larger version (32K): [in this window] [in a new window]   Fig. 2.   A, The first glucose sensor profile from a 15-year-old male (participant 2 in Table 1) who had undetected low glucose levels during the night followed by a high glucose level at 6:00 AM. He did not take noon insulin injections and was then very high in the afternoon. B, The same participant's final glucose sensor profile. He no longer had low glucose values during the night. He continued to refuse a noon insulin injection and had high glucose levels after lunch.

	CONCLUSION

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Continuous subcutaneous glucose monitoring was very helpful in detecting low blood sugars, particularly during the night. Glucose control, as monitored by HbA1c levels, also showed improvement. In the future, the ability for patients to read their glucose values, as well as to have alarms for high and low glucose levels, will likely result in the routine use of continuous glucose monitoring.

	ACKNOWLEDGMENTS

This research was funded by the Children's Diabetes Foundation at Denver. MiniMed Inc provided the equipment for continuous glucose monitoring.

	FOOTNOTES

Received for publication Sep 26, 2000; accepted Nov 13, 2000.

Reprint requests to (H.P.C.) Barbara Davis Center, 4200 E 9th Ave, B140, Denver, CO 80262. E-mail: peter.chase{at}uchsc.edu

	ABBREVIATIONS

DCCT, Diabetes Control and Complications Trial; SBGM, self blood glucose monitoring; HbA1c, hemoglobin A1c; MDI, multiple daily injection; CGMS, Continuous Glucose Monitoring System; SEM, standard error of the mean; SD, standard deviation.

	REFERENCES

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1. The Diabetes Control and Complications Trial Research Group (DCCT) The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986 [Abstract/Free Full Text]
2. The DCCT Research Group Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr 1994; 125:177-188 [CrossRef][Medline]
3. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 342:381-38
4. The DCCT Research Group. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med. 1991;90:450-459
5. Bergada I, Suissa S, Dufresne J, Schiffrin A Severe hypoglycemia in IDDM children. Diabetes Care 1989; 12:239-244 [Abstract]
6. Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J Fear of hypoglycemia: quantification, validation and utilization. Diabetes Care 1987; 10:617-621 [Abstract]
7. Diabetes Control and Complications Trial Research Group Reliability and validity of a diabetes quality-of-life measure for the Diabetes Control and Complications Trial (DCCT). Diabetes Care 1988; 11:725-732 [Abstract]
8. Mathsoft. S-PLUS 4.5 Guide to Statistics. Seattle, WA: Mathsoft, Data Analysis Products Division; 1999
9. Bode BW, Gross TM, Thornton KR, Mastrototaro JJ Continuous glucose monitoring used to adjust diabetes therapy improved glycosylated hemoglobin: a pilot study. Diabetes Res Clin Pract 1999; 46:183-190 [CrossRef][Medline]
10. Bode BW, Gross TM, Thornton KR, Mastrototaro JJ Continuous glucose monitoring facilitates sustainable improvements in glycemic control. Diabetes 2000; 49:393
11. Rebrin K, Steil GM, Van Antwerp WP, Mastrototaro JJ Subcutaneous glucose predicts plasma glucose independent of insulin: implications for continuous monitoring. Am J Physiol 1999; 40:E561-E571
12. Garg SK, Potts RO, Ackerman NR, Fermi SI, Tamada JA, Chase HP Correlation of finger stick blood glucose measurements with glucowatch biographer glucose results in young subjects with type 1 diabetes. Diabetes Care 1999; 22:1708-1714 [Abstract/Free Full Text]
13. Tamada JA, Garg SK, Jovanovic L, Noninvasive glucose monitoring comprehensive clinical results. JAMA 1999; 282:1839-1844 [Abstract/Free Full Text]
14. Boyne MS, Silver DM, Kaplan J, Saudek CD Timing of changes in interstitial and blood glucose measured with a continuous subcutaneous glucose sensor. Diabetes 2000; 49:398
15. Beregszaszi M, Tubiana-Rufi N, Benali K, Noel M, Bloch J, Czernichow P Nocturnal hypoglycemia in children and adolescents with insulin-dependent diabetes mellitus: prevalence and risk factors. J Pediatr 1997; 131:27-33 [CrossRef][Medline]