The Diabetes Control and Complications Trial (DCCT) conclusively demonstrated that tight metabolic control in patients with type I diabetes mellitus could delay the onset and progression of microvascular complications.1 The study was set up as follows.
Patients in the conventional therapy cohort received insulin injections once or twice daily, including mixed intermediate and rapid-acting insulins, daily self-monitoring of urine or blood glucose, and education about diet and exercise. The goals of therapy were the absence of symptoms related to hyperglycemia or glycosuria, the absence of ketonuria, normal growth and development, maintenance of ideal body weight, and the absence of frequent or severe hypoglycemia. Patients in this group had clinic follow-up every 3 months and did not frequently adjust their insulin dose.
Patients in the intensive therapy cohort received insulin injections three or more times daily or insulin delivered by continuous subcutaneous infusion via an external insulin pump, dosages of which were frequently adjusted based on anticipated activities, dietary intake, and the results from self-monitoring of blood glucose that was performed at least four times daily. The goals of intensive therapy included glucose concentrations before meals of between 70 and 120 mg/dL, postprandial concentrations less than 180 mg/dL, an early morning glucose concentration greater than 65 mg/dL performed at least weekly at 3 am, and a monthly hemoglobin A level within the normal range (less than 6.05% in the assay used in this study). The patients in this cohort were seen monthly in clinic and had frequent telephone contact to adjust and review their regimens.
The general pediatrician will recognize several critical elements in this intensive treatment program: (1) an optimal glycémie target range was determined for each patient; (2) patients were aware of the glycémie target and whether their own blood glucose and hemoglobin Alc values were within this target range; (3) patients were empowered to adjust their insulin doses to improve day-to-day glycémie control; and (4) patients were supported in their efforts to achieve these goals through weekly telephone contact and frequent clinic visits.
The data obtained from young patients with diabetes (13 to 17 years of age) confirmed that intensive therapy had beneficial effects on the risk of microvascular complications, even in adolescents.2 There were 195 adolescent patients (14% of the total study group) enrolled in the DCCT, and, although they were unable to achieve hemoglobin AJc levels as low as those of adults (8.1% vs 7.2%), their risks of retinopathy and microalbuminuria were significantly reduced. However, the risks of severe hypoglycemia and obesity were increased threefold.
As impressive as the results of the DCCT are, they raise several unanswered questions regarding ideal management for the child with type I diabetes mellitus. Is it valid to extrapolate treatment recommendations to children younger than 13 years of age? What are the long-term effects of hypoglycemia in the very young child? What is the impact of the prepubertal diabetic years on the risk of microvascular complications? How tight is too tight for metabolic control in the young child with diabetes? What is the cost-benefit ratio of intensive management? Should a general pediatrician or a family practitioner manage the therapy of children with diabetes or should they all be seen in regional diabetes centers?
NEGOTIATING GLYCEMIC TARGETS
Negotiating the optimal glycémie target is most difficult for intensive insulin treatment. The clinician must balance the long-term benefits of improved glycémie control against the risks of hypoglycemia, which increase as the glycémie targets are lowered. The most common complication of diabetes management is hypoglycemia. Furthermore, hypoglycemia is the most limiting factor in achieving excellent glycémie control in adherent patients.
Recurrent hypoglycemia has been implicated as the possible cause of neurocognitive abnormalities in children and adolescents who have diabetes prior to 5 years of age.3,4 Other studies, however, have failed to confirm this association.1,5 It is especially worrisome that the majority of hypoglycemic episodes in children with diabetes occur overnight and are frequently asymptomatic.6,7 Younger children appear to be most susceptible. Rates are as high as 57% in children younger than 5 years of age and 36% at 5 to 9 years of age.7
Unfortunately, ingestion of a carbohydrate bedtime snack did not prevent hypoglycemia in this study. Furthermore, the blood sugar at 11 pm was a poor predictor of the severity of nocturnal hypoglycemia. In another study of children during the first 2 years after diagnosis of diabetes, severe hypoglycemia (defined as coma or seizure) occurred in 55% of children younger than 2 years of age, 45% of those 2 to 5 years of age, and 13% of those 5 to 9 years of age.8 Even more disturbing was that hypoglycemia was unpredictable in the youngest patients.
The risk of severe hypoglycemia increases as glycémie control improves. It rises threefold with a decrease in hemoglobin A by as little as 15% (from 10.2% to 8.8%).9 The risk was even higher for patients younger than 6 years of age. Some studies have identified a threshold hemoglobin A value (usually < 1.4 times the upper limit of the normal range) below which hypoglycemia is much more frequent.7,10 Other studies have failed to confirm this. Despite this controversy, the American Diabetes Association states that tight control is contraindicated in infants younger than 2 years of age and recommends that tight control be undertaken with extreme caution in children between the ages of 2 and 7 years.11
If hypoglycemia is so prevalent in young children, and the DCCT studied only intensive therapy for patients older than 13 years, what data suggest benefit from improved glycémie control in younger children? Retinopathy is the most common chronic complication of diabetes mellitus and the leading cause of blindness in most Western countries. Diabetic retinopathy, nephropathy, and neuropathy occur in the pediatric population, but with a lower incidence than in adults. Publications from the 1980s concluded that the duration of diabetes prior to puberty had little impact on future risk of complications. This fostered the belief that the prepubertal duration of diabetes contributed little to the long-term prognosis.12 More recent studies have shown that retinopathy occurs after a shorter postpuberal duration in children who had diabetes prior to puberty when compared with children with pubertal or postpuberal onset.13"15 Furthermore, improved long-term metabolic control delayed the onset of retinopathy by approximately 2 to 3 years.13 Another study assessed the effects of diabetes duration and metabolic control on the risk of microvascular complications. Retinopathy correlated only with the duration of diabetes, whereas microalbuminuria and neuropathy correlated with metabolic control and diabetes duration.16 Puberty was felt to be an important factor in the onset of microalbuminuria.
Age-Specific Glucose Levels
Based on these data, the American Diabetes Association recommends routine annual screening for retinopathy in patients who, after puberty, have diabetes mellitus for at least 5 years.17 However, the American Academy of Pediatrics recommends referral at 3 to 5 years after onset of diabetes in patients older than 9 years of age.18 Overall, these data indicate that the years of diabetes prior to puberty have a significant impact on the cumulative risk of microvascular complications. Furthermore, improved glycémie control offers a protective effect.
Any busy outpatient practice that provides care for children will likely include at least one child with diabetes mellitus.19 How should these cases be managed? The preceding information strongly supports the notion that patients, parents, and health care providers should all attempt to optimize metabolic control while minimizing hypoglycemia. This has led us to adopt a treatment protocol that we call graduated intensification. We base its rationale on the fact that younger children are at increased risk of hypoglycemia (and this may be asymptomatic but still results in later neurocognitive sequelae) and the beneficial effects of improved metabolic control, even in prepubertal children, on the future risk of microvascular complications. Many programs can achieve success. We outline ours to illustrate one example of how to employ the results of the DCCT. This program is not meant to be definitive or the standard of care.
We observe approximately 100 children with type I diabetes mellitus in a large, pediatric multispecialty department. Children with type I diabetes mellitus who are younger than 13 years account for 48% of the total. The patients are seen at our parent institution or at other clinics in the tristate region that includes Alaska, Idaho, and Washington. We use the concepts of graduated intensification to develop age-appropriate treatment plans that employ the key elements of the DCCT intensive treatment program.
The first key element is to determine an optimal glycémie target range for each patient. Table 1 outlines the age-dependent glucose values we would like our patients to attain. One of the difficulties in our setting is detennining the optimal hemoglobin Alc level for each patient. Unfortunately, despite national efforts to standardize the procedure to measure hemoglobin A , four different methodologies are used by laboratories in our region and each has a different normal range for patients who do not have diabetes. This led us to adopt recommendations for target hemoglobin A levels, based on a percentage above the maximum of the normal nondiabetic range for that specific test (Table 2). In older children and adolescents, these target values will need to be further negotiated among the patient, the parents, and the health care team.
Age-Specific Hemoglobin An Levels
Once the optimal glycémie target range has been set, the second key element is to empower the patients to adjust their insulin doses to improve day-to-day glycémie control. We encourage families to contact us whenever more than 20% of blood glucose values are above or below their recommended target ranges. They are also instructed to contact us whenever there has been moderate or severe hypoglycemia. Patients and parents are instructed to adjust insulin doses based on blood sugar values, anticipated activity, and caloric intake. Carbohydrate counting offers a relatively simple method by which patients can learn to adjust insulin doses to match dietary changes.
The third key element is to support the efforts of the patient and the family to achieve these goals. Whenever the hemoglobin A level or 20% or more of the home blood glucose values are outside of the target range, the treatment regimen is reviewed and altered. Therapy is individualized and a variety of tools are used, including simple algorithmic adjustment in total insulin doses, dietary modification, use of different insulin doses on days with intensive exercise (eg, competitive athletics), three or more injections of insulin per day, or continuous subcutaneous insulin infusion using an external insulin pump. The addition of an ultra-short-acting insulin analog with rapid absorption and clearance is useful in dealing with problems such as late postprandial hypoglycemia (the shorter duration of action helps prevent hypoglycemia hours later) and variations in food intake and activity in very young children. These analogs can be administered with the meal or even afterward to ensure that the child has eaten sufficient food to balance the scheduled insulin dosage. These preparations are also useful for the older child or adolescent who may be receiving 4 to 5 insulin injections daily and may be better off using ultra-short-acting insulin before each meal.
We recommend that our patients attend clinic quarterly or monthly or even more often when their metabolic control is not within target parameters. At each visit, blood glucose values are reviewed, the frequency and symptoms of hypoglycemia and hyperglycemia are assessed, insulin dosing is reviewed, algorithms for independent insulin dosing are adjusted, and barriers to compliance with the meal plan and exercise are discussed. Height, growth rate, weight gain, and blood pressure are also evaluated. Laboratory evaluation includes quarterly hemoglobin Alc and basic chemistry measurements, as well as annual thyroid function tests. A urine sample is assessed for microalbuminuria at least annually in patients who have had diabetes for more than 5 years, have poor metabolic control, or have hypertension. Once microalbuminuria is detected, patients are encouraged to improve metabolic control and the addition of an angiotensin-converting enzyme inhibitor is considered. A referral to ophthalmology is made for evaluation of diabetic retinopathy on an annual basis in children who have had diabetes for more than 3 to 5 years and are at least 9 years of age, have poor metabolic control, or have hypertension. Consultation and referral is provided for any patient with depression or dysfunctional family dynamics that prevent optimal glycémie control.
In summary, the management of type I diabetes mellitus in children and adolescents requires time and resources. The recommended intensity of metabolic control for the child younger than 10 years of age remains controversial. The pediatrician should strive for the best possible control while avoiding severe hypoglycemia. Using the age-specific parameters outlined in Tables 1 and 2, we feel we have achieved good results. Early diabetic retinopathy has not been observed in these patients and microalbuminuria has been identified in only 3%. Severe hypoglycemia has occurred but at a rate of fewer than 5 events per 100 patient-years, and none of the hypoglycemic events have required hospitalization. We believe that such treatment programs are practical, are achievable at the community level, and allow the pediatrician to implement the key elements of the DCCT for children and adolescents with diabetes.
1. The Diabetes Control and Complications Trial Research Group. 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.
2. The Diabetes Control and Complications Trial 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.
3. Rovet JF, Ehrlich RM, Hoppe M. Intellectual deficits associated with early onset of IDDM in children. Diabetes Care. 1987;10:510-515.
4. Ryan C, Vega A, Drash A. Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics. 1985;75:921-927.
5. Kaufman FR, Epport K, Halvorson M. Neurocognitive functioning in children diagnosed with diabetes before age 10 years. Diabetes. 1997;46:67A. Abstract.
6. Davis EA, Keating B, Byrne GC, et al. Hypoglycemia: incidence and clinical predictors in a large population based sample of children and adolescents with IDDM. Diabetes Care. 1997;20:22-25.
7. Porter PA, Keating B, Byrne G, Jones TW. Incidence and predictive criteria of nocturnal hypoglycemia in young children with insulin dependent diabetes mellitus. J Pediatr. 1997;130:366-372.
8. Lteif AN, Schwenk WF. Type I diabetes mellitus in early childhood: glycémie control and associated risk of hypoglycemic reactions. Mayo Clin Proc. 1999;74:211-216.
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10. Ludvigsson J, Nordfeldt S. Hypoglycemia during intensified insulin therapy of children and adolescents. J Pediatr Endoainol Metab. 1998;ll(suppl 1):159-166.
11. American Diabetes Association. Implications of the Diabetes Control and Complications Trial. Diabetes Care. 1993;16:1517-1520.
12. Kostraba JN, Dormán JS, Orchard TJ, et al. Contribution of diabetes duration before puberty to development of microvascular complications in IDDM subjects. Diabetes Care. 1989;12:686-693.
13. HoIl RW, Lang GE, Grabert M, et al. Diabetic retinopathy in pediatric patients with type I diabetes: effect of diabetes duration, prepubertal and pubertal onset of diabetes and metabolic control. J Pediatr. 1998;132:790-794.
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15. Danne T, Kordonouri O, Enders I, Hovener G. Monitoring for retinopathy in children and adolescents with type I diabetes. Acta Paediatr. 1998;425(suppl):35-41.
16. Bognetti E, Calori G, Meschi F, et al. Prevalence and correlations of early microvascular complications in young type I diabetic patients: role of puberty. J Pediatr Endocrinol Metab. 1997;10:587-592.
17. American Diabetes Association. Screening for diabetic retinopathy. Diabetes Care. 1997;20(suppl):S28-S30.
18. American Academy of Pediatrics: Section on Endocrinology and Ophthalmology. Screening for retinopathy in the pediatric patient with type I diabetes mellitus. Pediatrics. 1998;101:313-314.
19. American Diabetes Association. Diabetes 1996 Vital Statistics. Alexandria, VA: American Diabetes Association; 1996:13-20.
Age-Specific Glucose Levels
Age-Specific Hemoglobin An Levels