PEDIATRICS Vol. 107 No. 2 February 2001, pp. 351-356

Continuous Subcutaneous Insulin Infusion Therapy for Children and Adolescents: An Option for Routine Diabetes Care

Aristides K. Maniatis, MD, Georgeanna J. Klingensmith, MD, Robert H. Slover, MD, Cathy J. Mowry, RN, CPNP, and H. Peter Chase, MD

From the Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado.

	ABSTRACT

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Objective.  The purpose of this study was to determine the feasibility of continuous subcutaneous insulin infusion (CSII) (insulin pump) therapy in routine pediatric diabetes care by comparing the HbA_1c, body mass index (BMI), and hypoglycemic episodes before and after initiation of CSII therapy.

Research Design and Methods.  Data from 56 patients (7-23 years old) were collected during regularly scheduled visits at a frequency similar to non-CSII patients.

Results.  The data were analyzed for the entire cohort and 3 subgroups (decreased, stable, or increased HbA_1c) stratified according to a 0.5% change in HbA_1c. The total cohort demonstrated a decrease in HbA_1c from 8.5% to 8.3%. The decreased cohort (39.4% of the total cohort) demonstrated a significant decrease in HbA_1c from 8.6% to 7.6%. The mean HbA_1c of the stable cohort (41.0%) was 8.7%. The increased cohort (19.6%) had an increase in HbA_1c from 7.8% to 8.8%. Thirty-six patients (64.3%) maintained or achieved a HbA_1c <8.0% or achieved a HbA_1c at least 1% lower than their pre-CSII level. Of concern, 6 patients (10.7%) demonstrated a clinically significant increase in HbA_1c from 8.3% to 9.6%. For the entire cohort, the rate of severe hypoglycemia before and on CSII therapy was 12.3 and 9.5 events per 100 patient-years, respectively. A statistically significant proportion of patients reported a decrease in seizure frequency versus an increase (17.9% vs 1.8%) as well as a decrease in overall hypoglycemic frequency versus an increase (41.1% vs 17.9%). There was not a clinically significant increase in BMI, even in the decreased HbA_1c cohort.

Conclusions.  CSII therapy is an appropriate option for some children in routine pediatric diabetes care. It can effectively decrease the HbA_1c and reduce hypoglycemic episodes, without producing an abnormal increase in BMI.  Key words:  type 1 diabetes, insulin pump (CSII), HbA_1c, hypoglycemia, pediatrics.

The concept of continuous subcutaneous insulin infusion (CSII) is not novel. It dates back to a London Hospital medical student thesis in 1934, which reported a blood glucose decrease when a few diabetic patients were given subcutaneous insulin over a few hours.¹ The therapeutic implications did not come to fruition until 1978, when a preliminary 4-day trial of an insulin pump was reported.² By 1984, a few studies had reported decreases in HbA_1c with CSII,^3,4 and 1 study revealed improvement in microvascular complications.⁵ The research on CSII, however, focused primarily on adults, and the pediatric experience remained scant, with <500 patients worldwide by 1988.⁶

With the publication of the Diabetes Control and Complications Trial (DCCT) results, there has been a renewed interest in intensive management of diabetes with CSII for both adult and pediatric patients. The DCCT reported that intensive therapy with either multiple daily injections (MDI) or CSII resulted in dramatic risk reductions compared with conventional treatment for the development and progression of retinopathy, nephropathy, and neuropathy (76%, 34%, and 69% risk reduction, respectively). However, it also revealed a threefold increase in hypoglycemia and a 33% increased risk of becoming overweight among the intensively treated cohort.⁷ On completing the DCCT study, the patients in the conventional treatment group were offered intensive therapy. All patients were treated by their own physicians, and the majority were followed in an observational study. The risk reductions for progressive retinopathy and nephropathy attributable to intensive therapy persisted for at least 4 years.⁸ The DCCT also analyzed their adolescents (13-17 years old) and reported equally striking risk reductions in retinopathy and nephropathy, also with a threefold increased risk of severe hypoglycemia and a twofold increased risk of becoming overweight among the intensively treated cohort.⁹ The mean HbA_1c for the intensive versus conventional therapy adolescent cohorts was 8.1% and 9.8%, respectively. The total number of pediatric patients in these studies, however, was small. Of the 92 adolescents on intensive therapy in the DCCT study, only 37 were on CSII, many with a mixed therapy of both CSII and MDI.¹⁰

The studies to date represent the experience of CSII in patients treated in the context of research studies with intensive contact between the patient and the health care team. In the DCCT, CSII patients were seen monthly and often had weekly contact with a diabetes educator. The Adolescents Benefit from Control of Diabetes (ABC's) study with 25 patients also included frequent contact and visits every 4 to 6 weeks.¹¹ The intensity of medical contact contributes significantly to the increased cost of CSII therapy.¹²

The current study included 56 patients (ages 7 to 23 years, mean: 17 years). The purpose of this study was to determine the feasibility of CSII therapy in routine diabetes care and to evaluate its medical efficacy by comparing the HbA_1c, body mass index (BMI), and hypoglycemic episodes of these patients before and after initiation of CSII therapy.

	RESEARCH DESIGN AND METHODS

Patient Selection

All patients were cared for in the Pediatric Clinic of the Barbara Davis Center for Childhood Diabetes, which is affiliated with the University of Colorado Health Sciences Center and the Children's Hospital of Denver. Inclusion criteria for this report were as follows: 1) HbA_1c levels available for at least 6 months before and after CSII initiation, and 2) duration of CSII therapy 6 months. All patients began CSII as outpatients as part of their diabetes management plan. The reasons for selecting CSII included inability to achieve glucose or HbA_1c targets, desire for a more flexible lifestyle, and a desire to avoid frequent insulin injections. Before initiation of CSII, patients were evaluated by the diabetes team for ability to manage intensive therapy, and they were taught dietary strategies to calculate insulin bolus dosing based on insulin to carbohydrate ratio or general meal size. After a period of stabilization on CSII therapy, visits were scheduled every 2 to 4 months. Most patients contacted the team at least monthly to review blood glucose records.

Fifty-six children and adolescents were included in the study. The mean age was 17.0 years (range: 7.1-22.9 years), with 3 children <12 years. The mean duration of CSII therapy was 12.2 months (range: 6-35 months), with 10 patients on CSII for 1 year. The following data were collected during the office visits: HbA_1c, BMI, number of severe hypoglycemic episodes (requiring assistance), seizure frequency, and hypoglycemic frequency (not requiring assistance). Frequency calculations included data from 6 months before CSII initiation and data from a given individual's duration of CSII therapy. Hypoglycemia data were collected at each visit for the preceding 3 months.

According to the National Center for Health Statistics, females and males older than 18 years are considered overweight at a BMI 27.3 kg/m² and 27.8 kg/m², respectively.¹³ These criteria were used in establishing the following 3 BMI levels: level I) <25.0 kg/m², level II) 25.0 to 27.3 kg/m² for females or 25.0 to 27.8 kg/m² for males, and level III) 27.3 kg/m² for females or 27.8 kg/m² for males.

Insulin, Infusion Systems, and HbA_1c Determination

All patients received Humalog (lis pro) insulin (Lilly, Indianapolis, IN). Both Disetronic and MiniMed infusion systems were used. The HbA_1c was determined using the Bayer DCA (Bayer Diagnostics Inc, Tarrytown, NY) 2000 instrument, with a nondiabetic range of 4.3% to 6.3%.

Statistical Analysis

The data were analyzed using the SAS statistical program. The HbA_1c data were analyzed using the nonparametric Wilcoxon signed rank test for paired data analysis. HbA_1c subgroup characteristics were analyzed using the nonparametric Kruskal-Wallis test and the ² test. The rate of severe hypoglycemia was analyzed using a generalized estimating equation approach with a Poisson regression. Data for seizure and hypoglycemia frequency changes were analyzed using the sign test. All results reported are 2-tailed and have a significance level  of 0.05. Statistical analyses were not performed on data obtained during the second year on CSII treatment because of the small sample size of that subpopulation.

	RESULTS

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HbA_1c

Analyses were performed on the entire cohort as well as on 3 subgroups (decreased, stable, or increased HbA_1c) that were defined according to a 0.5% change in HbA_1c. These subgroups were analyzed in an attempt to determine whether there were distinguishing features which would predict HbA_1c outcome with CSII therapy. The subgroups showed no difference in age, diabetes duration, or gender (Table 1). The decreased HbA_1c cohort included 22 patients (39.4% of the total cohort) with a mean decrease in HbA_1c from 8.6% to 7.6%, P < .001 (range: 7.4%-9.6% and 6.4%-8.6%, pre-CSII and on CSII, respectively). The stable HbA_1c cohort included 23 patients (41.0% of the total cohort) with a mean change in HbA_1c from 8.8% to 8.7% (range: 6.8%-11.5% and 6.5%-11.8%, pre-CSII and on CSII, respectively). As expected, the P values for this cohort represented a nonsignificant change in HbA_1c, thus defining a stable pre- and post-CSII HbA_1c. The increased HbA_1c cohort included 11 patients (19.6% of the total cohort) with a mean increase in HbA_1c from 7.8% to 8.8%, P < .001 (range: 6.0%-8.6% and 7.2%-10.1%, pre-CSII and on CSII, respectively).

The baseline HbA_1c values were different between the groups (P = .048), owing to the lower HbA_1c of the increased cohort. As expected from the study design, the change in HbA_1c was statistically significant within the increased and decreased subgroups. The cohort as a whole demonstrated a decrease in HbA_1c on CSII therapy (mean change: 8.5%-8.3%, P = .045). Overall, 25 patients (44.6% of the total cohort) either maintained or achieved a HbA_1c 8.1% on CSII treatment, the mean achieved in the DCCT adolescent cohort. This compares with 18 patients (32.1%) who had a HbA_1c 8.1% before initiation of CSII.

Two additional subpopulations (those with a HbA_1c 9.0% before initiation of CSII, and those with a HbA_1c 9.0% after 6 months on CSII) were analyzed to determine if they benefited from CSII therapy, as described below.

Pre-CSII HbA_1c 9.0% The HbA_1c levels for the entire cohort before and during CSII therapy are shown in Fig 1. Seventeen patients (30.4% of the total cohort) had an initial HbA_1c 9.0%. Six of the 17 (35.3%) improved their HbA_1c to <8.5% (mean decrease: 9.4%-8.2%, P = .03), with 2 of the 6 achieving a level <8.0%. An additional 4 patients decreased their level by at least 1 percentage point (mean decrease: 10.2%-9.0%). One patient had recurrent episodes of diabetic ketoacidosis (DKA) as the indication for CSII therapy. In the year before CSII, she had 11 DKA episodes. While on CSII for 6 months, however, she had no episodes of DKA. Six of the 17 patients did not achieve any identifiable medical benefit from CSII therapy, but they may have achieved an improved quality of life^14-16 because many of them were reluctant to discontinue CSII therapy.

View larger version (27K): [in this window] [in a new window]   Fig. 1.   HbA1c levels for the entire cohort before and during CSII therapy.

Post-CSII HbA_1c 9.0% Sixteen patients (28.6% of the total cohort) had a HbA_1c 9.0% on CSII therapy (Fig 1). Ten of the 16 (including the patient with recurrent DKA episodes) had an initial HbA_1c 9.0% and are described above. Six additional patients had their HbA_1c deteriorate to 9.0%. Five of the 6 had deterioration in the first year of CSII therapy, and 1 had deterioration during the second year. Overall, 13 of the 16 patients were male. Compared with the entire cohort, this group was slightly older (18.4 vs 17.0 years) with no difference in diabetes duration (7.9 vs 7.6 years). The differences in sex and age were not statistically significant.

BMI

The BMI levels of the total cohort as well as the stratified HbA_1c subgroups are shown in Table 1. Overall, there was a statistically significant increase in BMI for the total cohort (22.6-23.2 kg/m², P < .001), the decreased HbA_1c group (22.6-23.3 kg/m², P = .004), and the stable HbA_1c group (22.8-23.4 kg/m², P = .003). The increased HbA_1c group did not show a statistically significant difference in BMI (22.5-22.6 kg/m², P = .37).

The BMI data were also stratified according to the following 3 levels: level I) <25.0 kg/m², level II) 25.0 to 27.3 kg/m² for females or 25.0 to 27.8 kg/m² for males, and level III) 27.3 kg/m² for females or 27.8 kg/m² for males. Before CSII therapy, 42 participants (75.0% of the total cohort), 5 participants (8.9%), and 9 participants (16.1%) were in levels I, II, and III, respectively. On CSII therapy there was not a significant shift between BMI levels, with 40 participants (71.4% of the total cohort), 6 participants (10.7%), and 10 participants (17.9%) in levels I, II, and III, respectively.

Severe Hypoglycemia

Severe hypoglycemia was defined as a hypoglycemic episode requiring assistance. It was calculated as a rate expressing the number of events per 100 patient-years. The rate of severe hypoglycemia for the total cohort decreased from 12.3 to 9.5 events per 100 patient-years (Table 1). This was not statistically significant, however, likely attributable to the small number of observed events.

Seizure Frequency

Because seizures may be more accurately reported by families than other episodes of severe hypoglycemia, seizure frequency was analyzed separately. It was defined as the average number of seizures per year. Patients were categorized as having decreased, increased, or no seizures on CSII compared with baseline before CSII. The results were reported as the percentage of patients in these categories. Table 2 summarizes the frequency of seizures for both the total cohort as well as the decreased HbA_1c group. The vast majority in both the total cohort and the decreased HbA_1c group had no seizure history (80.3% and 77.3%, respectively). On CSII therapy, seizure frequency decreased among 17.9% of patients in the total cohort and 18.2% of patients in the decreased HbA_1c group. Only 1 patient (1.8% of the total cohort) reported an increased frequency. These differences in frequency categories were statistically significant for the total cohort (P = .01), but not for the decreased HbA_1c group (P = .38).

Hypoglycemic Frequency

Hypoglycemic frequency was defined as the average number of hypoglycemic episodes (not requiring assistance) per week. Patients were categorized as either experiencing decreased, increased, or no change in hypoglycemic frequency on CSII compared with baseline before CSII. As with seizure frequency, the results were reported as the percentage of patients in these categories. Data were not available for 10.6% of the patients. Table 2 summarizes the frequency of hypoglycemia for both the total cohort as well as the decreased HbA_1c group. On CSII therapy, hypoglycemic frequency decreased among 41.1% of patients in the total cohort and 36.4% of patients in the decreased HbA_1c group. In the total cohort and the decreased HbA_1c group, an increase in hypoglycemic frequency was reported by 17.9% and 9.1% of patients, whereas no change was reported by 30.4% and 40.9% of patients, respectively. Comparable to the seizure frequency results, the differences in frequency categories were statistically significant for the total cohort (P = .035), but not for the decreased HbA_1c group (P = .11).

Additional Complications With CSII Therapy

One patient reported an infection at the catheter insertion site, resulting in hyperglycemia and ketosis. The condition was easily managed over the phone with increased insulin bolus doses, change of insertion site, and topical antibiotics. A second patient also reported hyperglycemia and ketosis. The patient inadvertently denatured the insulin in the CSII device after entering a hot tub. Replacement with new insulin resolved the situation. Finally, 1 patient had 2 admissions for DKA episodes, both precipitated by inadvertent discontinuance of insulin infusion therapy.

	DISCUSSION

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The benefits of CSII intensive therapy are numerous. Recently, the ABC's study reported a decrease in HbA_1c from a baseline of 8.4% to 7.7% (at 6 months) and 7.5% (at 1 year) on CSII therapy.¹¹ In addition to improving HbA_1c levels, CSII therapy has been reported to decrease diabetic complications, improve lipoprotein profiles, improve linear growth, and prolong islet cell function.^7,8,17-19

The current study of 56 patients demonstrated a significant improvement in diabetes control with CSII therapy. The entire cohort had a statistically significant mean change in HbA_1c from 8.5% to 8.3% (P = .045). Thirty-nine percent of the total cohort (the decreased HbA_1c subgroup with 22 patients) demonstrated both a statistically and very clinically significant decrease in HbA_1c from 8.6% to 7.6% (P < .001). Additionally, 25 patients overall (44.6%) either maintained or achieved a HbA_1c <8.1% on CSII treatment. Thirty-six patients (64.3%) maintained or achieved a HbA_1c <8.1% or achieved a HbA_1c at least 1% less than baseline before CSII treatment. This was clinically significant because the DCCT reported a 21% to 49% decreased risk of microvascular complications with a 1% decrease in HbA_1c.²⁰ An additional patient significantly reduced the number of DKA episodes from 11 in the year before to 0 in the first 6 months on CSII.

Nevertheless, a few patients did poorly on CSII treatment. Ten of 17 patients with an initial HbA_1c 9.0% remained 9.0% on CSII. A common underlying factor was the failure to administer insulin bolus doses for meals and snacks. Although 3 of the 10 did decrease their HbA_1c by >1%, their control remained tenuous. More concerning were the 6 patients (10.7%) who demonstrated a clinically significant increase in HbA_1c from a pre-CSII level of 8.3% to 9.6% on CSII treatment. As a group, they were more likely to be male, although this observation was not statistically significant. Furthermore, they frequently omitted insulin bolus doses. Because many patients with poor initial metabolic control improved with CSII therapy, it seems that a highly elevated initial HbA_1c by itself should not be an exclusion factor for initiation of CSII. In fact, analysis of the HbA_1c subgroups could not identify any distinguishing features that were predictive of outcome on CSII therapy. An additional study is underway to determine prospective identifiers for those at risk for metabolic deterioration on CSII therapy, as well as reasons why some adolescents consistently neglect to administer insulin bolus doses.

A commonly reported adverse effect of CSII therapy in other studies was significant weight gain.^7,9,11,13,21 The current study, however, does not support these previous findings. Overall, 9 patients (16.1%) were overweight before CSII treatment, and 10 patients (17.8%) were overweight on CSII treatment. The BMI for the entire cohort increased by 0.6 kg/m² (P < .001) to a final BMI of 23.2 kg/m². Although this change was statistically significant, a certain increase was expected among growing children and adolescents, and the BMI of the entire cohort was consistent with the BMI seen in the general population at this age (mean BMI for 17-year-olds: 23.4 and 23.3 kg/m² for males and females, respectively).²² Prospective and ongoing counseling was given to avoid excessive weight gain as control improved, which may explain the lack of excessive weight gain in this study.

Yet another issue with CSII therapy is the effect on hypoglycemia. The DCCT reported a threefold increase in severe hypoglycemia requiring assistance among the intensively treated adolescent cohort.⁹ Other trials have shown a reduction in severe hypoglycemia on CSII compared with MDI.^11,23,24 The current study examined severe hypoglycemia (requiring assistance), seizure frequency, and frequency of hypoglycemia not requiring assistance. Overall, severe hypoglycemia decreased from 12.3 to 9.5 events per 100 patient-years. This rate was markedly lower than the previously reported rates of 62 and 76 events per 100 patient-years in the DCCT and the ABC's study, respectively.^7,11 In addition, for the total cohort, the proportion of patients reporting a decrease versus an increase in frequency of seizures (17.9% vs 1.8%, respectively, P = .01) or hypoglycemia (41.1% vs 17.9%, respectively, P = .035) was statistically significant. Furthermore, 36.4% of patients whose HbA_1c decreased reported a decreased frequency of hypoglycemia. Only 9.1% of patients in this group reported an increased frequency. Many of the hypoglycemic episodes on CSII therapy occurred during or after exercise, and the recommendations to adjust insulin dosing with exercise were reinforced.

	CONCLUSIONS

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In general, the current study revealed that CSII therapy is feasible in routine diabetes care for children and adolescents. The cohort achieved a mean HbA_1c of 8.3%, which is not dissimilar from the mean reported for the DCCT adolescents of 8.1%. In contrast to the DCCT, however, a greater proportion of patients in the current study reported a decrease in seizure and hypoglycemic frequency as well as in severe hypoglycemic episodes. CSII therapy provided this level of good metabolic control without an abnormal increase in BMI. Even patients with poor initial control may achieve success with CSII therapy. A few patients, however, did not improve with CSII. Although they tended to be male, they cannot currently be identified demographically before initiation of CSII therapy.

One final question remains. For this cohort, did quality of life improve on CSII therapy? Early studies have previously reported improvements in quality of life with CSII therapy.^14-16 To further examine that question for the current cohort, an ancillary study has been initiated, using a quality of life instrument for youths.²⁵ Preliminary results suggest that even patients with deterioration in HbA_1c are reluctant, even refuse, to discontinue CSII therapy. If the burden of diabetes is made easier with CSII therapy, should diabetologists encourage initiation of CSII regardless of patient motivation for improving their metabolic control? These are the questions that must be addressed in the future as we strive to optimize diabetes care for children and adolescents.

	ACKNOWLEDGMENTS

This research was funded in part by the National Institutes of Health Research Training Grant in Pediatric Immunology (T32AI07365).

We would like to thank the health care team at the Barbara Davis Center for their ongoing commitment to quality care for our patients.

	FOOTNOTES

Received for publication Feb 25, 2000; accepted Jun 1, 2000.

Reprint requests to (G.J.K.) The Barbara Davis Center for Childhood Diabetes, 4200 E 9th Ave B-140, Denver, CO 80262. E-mail: georgeanna.klingensmith{at}uchsc.edu

	ABBREVIATIONS

CSII, continuous subcutaneous insulin infusion; DCCT, Diabetes Control and Complications Trial; MDI, multiple daily injections; ABC, Adolescents Benefit from Control of Diabetes; BMI, body mass index; DKA, diabetic ketoacidosis.

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