continuous Basal Insulin Infusion: An Effective Means ... - Diabetes Care

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In 11 insulin-dependent diabetic subjects, aged 12-32 yr, we evaluated the efficacy of dual, basal-rate pumpdelivery of insulin without preprandial boluses.
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ontinuous Basal Insulin Infusion: An Effective Means to Achieve Good Glycemic Control Without Premeal Boluses JOHN A. DUNCAN, M.D., AND JOHN 1. MALONE, M.D.

In 11 insulin-dependent diabetic subjects, aged 12-32 yr, we evaluated the efficacy of dual, basal-rate pumpdelivery of insulin without preprandial boluses. Mean HbA lc fell from 11.6 ± 3.1% to 7.7 — 1.8% at 30 days (P < 0.005), and remained at 7.1 ± 1.3% at the time of this evaluation (mean duration of therapy, 6.6 mo). These data suggest that dual-rate continuous basal insulin infusion is an effective means of achieving good diabetes control. Furthermore, it is simpler than the preprandial bolus approach currently used, which may make it suitable for more patients, DIABETES CARE 7:114-117, MARCH-APRIL 1984.

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n the last decade, considerable attention has been focused on the benefits of good glycemic control in insulin-dependent diabetes mellitus (IDDM). Data suggesting that improved control can prevent, delay, or reverse the complications of diabetes have been reported.1"4 Multiple methods to achieve improved glycemic control are currently used. One approach is the pump infusion of insulin. Since the 1974 report of Slama and colleagues5 about continuous insulin infusion, an abundance of reports demonstrating its benefits have appeared in the literature.67 To date, most investigators have used premeal boluses of insulin with a low-dose, basal rate between meals in an effort to simulate the circulating insulin levels of nondiabetic subjects.5"11 It appears that the efficacy of this form of insulin delivery results from more adequate hepatic insulinization with nearnormalization of hepatic glucose production rates.12"15 Normalization of insulin concentrations results in more physiologic concentrations of counterregulatory hormones.1617 With this technique, the patient must be expert and compulsive in manipulating the pump and managing diabetes. Active patient participation in pump operation has resulted in several problems. Failure to reset the bolus mode of the pump to the basal rate has caused excessive insulin delivery and hypoglycemia.18 This is infrequent with the newer insulin delivery systems. Failure to initiate premeal boluses of insulin has resulted in insufficient insulin concentrations for adequate blood glucose control.19 Varying meal size or timing necessitates patient-selected changes in premeal boluses of insulin, which could lead to errors in blood glucose management. Children with emotional disorders have been noted to have problems with frequent pump manipulations.20 Con114

sequently, patients must be carefully selected to achieve successful treatment. In view of these problems, we have tested a technique of continuous insulin infusion that requires fewer pump manipulations and makes fewer demands on the patient for a successful result.21 This method uses continuous insulin infusion without boluses (CBII) to provide near-normal plasma glucose concentrations with improved long-term control, as indicated by HbA lc determinations. SUBJECTS AND METHODS

Eleven insulin-dependent, ketosis-prone diabetic patients with poor control, as judged by history and mean HbA lc of 11.6% (nondiabetic range, 3.7-6.9%), were managed by this technique for a mean of 6.6 mo (Table 1). Poor dietary or insulin compliance, despite frequent re-education opportunities, was the source of the poor control. Previous management had consisted of twice-daily injections of insulin, home glycemic monitoring 2-4 times daily by blood or urinary glucose quantitation, and a diet adjusted for growth and activity-related needs. Three patients had used intensive conventional insulin therapy by taking three or more injections per day before starting infusion pump therapy. Informed consent was provided by each participant. Insulin infusion rates were determined by an artificial pancreas (Biostator GCIIS, Life Science Instruments, Indianapolis, Indiana) to maintain euglycemia, 60-160 mg/dl, during a typical dietary day. The night insulin pump rate was the mean of hourly insulin delivery from midnight to 7:00 a.m. The day rate was the mean of hourly insulin delivery from 7:00 a.m. to midnight. Insulin was infused subcuta-

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TABLE 1 Patient characteristics

RESULTS

Insulin dosage (U/24 h) Age (yr) 17.0 20.6 15.6 32.4 20.3 27.25 12.25

18.0 18.25 16.6 21.3

Sex F F F M F M M M M M F

Duration diabetes (yr)

Duration CBII (mo)

Conventional therapy

7.5

13.0 13.0

56 55 85 120 68 47 40 80 60 70 52

13.0

3.6 7.0 20.0

8.0 1.25

4.5 4.0 3.0 3.5 4.0 5.0 4.0

3.6 9.9 8.0

15.0

10.0

3.5

CBII 46 42 52 60 57 45 52 61

62 55 61

180 170 •160 150

I

140

I

E in v> O U

130

I

120

I

O

1OO

/

110

I /

1\

\ I I I I

neously with an Auto-Syringe AS-6C Infusion Pump (AutoSyringe, Hooksett, New Hampshire), at insulin rates of 2 . 5 3.9 U / h from 7:00 a.m. until 1 h before bedtime. The insulin infusion rate was then slowed to 1.0-1.1 U / h until 7:00 a.m., when the rate was returned to the daytime level. One patient required 1.3 U / h as a nocturnal basal rate. Regular insulin (U-100) made from beef and pork zincinsulin crystals (Eli Lilly and Co., Indianapolis, Indiana) was diluted with 0.9% saline to make a solution containing 36 U regular insulin/ml. In this system, one pump machine unit is equal to 1 U of regular insulin. The insulin was delivered through a 27-gauge needle connected by 42-in infusion tubing to a disposable plastic syringe (supplied by Auto-Syringe). Needles were implanted subcutaneously in the anterior abdominal wall, buttock, or anterior thigh. Clear, waterproof tape was used to allow easy inspection of the needle site. Needle and syringe were changed every second day. During the second day of CBII, patient specimens were obtained every 90 min for serum free insulin measurement. 22 Continuous monitoring of glucose with the Biostator was performed during this time to assess the degree of glycemic control and the frequency of hypoglycemia (Figure 1). Food was provided as three meals and three snacks, selfselected, and comprised 55% carbohydrate, 20% protein, and 25% fat, as assessed by the NutriQuest Computer Data Program from daily dietary records. All patients returned at monthly intervals for clinical assessment, disbursement of disposable pump materials, and determination of HbA l c as an indicator of blood glucose control. HbA l c was performed by HPLC after incubation of cells in a glucose-free medium to remove the labile fraction. 23 Each patient performed home glucose monitoring by the Chemstrip technique four times daily during the first month. Additional home monitoring was performed for suspected hypoglycemia. Results are recorded as mean ± 1 SD with significance tested by Student's t test.

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igure 1 depicts the blood glucose levels obtained during continuous blood glucose monitoring on the second day of CBII. Coincident insulin levels measured on every second specimen are seen in Figure 2. Maximal levels of free insulin occurred between 6 p.m. and 11 p.m. During hospitalization, hypoglycemia, defined as a blood glucose concentration below 60 mg/dl, was observed most frequently between 8 p.m. and 1 a.m. Repeat episodes were avoided by initiating the nocturnal basal rate 0.5-1 h earlier or by increasing the bedtime snack. One patient experienced an early morning rise in blood glucose concentration consistent with the "dawn phenomenon." 24 Her overnight insulin levels, however, were consistently below 10 (xU/ml. After 1 mo of home therapy with CBII, patients reported infrequent hypoglycemia ( < 2 episodes/wk) in the late afternoon or evening hours. Most commonly, these occurred after "skipping snacks" or increased exercise. Adherence to the three meal, three snack, dietary regimen prevented hypoglycemia except after vigorous exercise. No episode required intravenous therapy or hospitalization. HbA, c , an indicator of long-term glycemic control, improved significantly and approached nondiabetic levels after 30 days of treatment (Table 2). Figure 3 depicts the individual patient results at 30 days of CBII. Patients were able to maintain or improve this degree of blood glucose control for a mean duration of 6.6 mo (3-15 mo). At the time of this evaluation, HbA l c was 7.1 ± 1.3%, which approaches the nondiabetic HbA l c level. The problems that occurred during long-term use of CBII were: (1) needle-site cellulitis (5 patients) with one abscess; (2) accidental discontinuation of insulin infusion (15 patients), with resultant hyperglycemia and ketosis on 12 occasions (maximum, 2 episodes in 2 patients); and (3) pump failure (1 patient). Of these problems, accidental discontin-

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12A1A

2A



4A

5A

6A

8A

9A 1 0 A 1 1 A 1 2 I 1e

2.

TIME (hrs.)

FIG. I. Hourly blood glucose values (mean ± SD) measured by a Biostator during CBII.

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CONTINUOUS BASAL INSULIN 1NFUSION/J. A. DUNCAN AND J. I. MALONE

SO

• — • IOD 10 pU

40

TABLE 2 HbA lc measurements' Conventional therapy

P

30 Days of CBII

Present report

11.6 ± 3.1%

18>19'28 using 10 premeal boluses. The maintenance of improved HbA lc levels up to 15 mo of treatment indicates the long-term effectiveness of this technique and its acceptance by the patient. 7A 9A 1 1 A 1P 3P 5P 7P 9 P 1 1 P 1A 3A 5A This method resembles the premeal bolus approach in the need for regularity of meal delivery and meal quantity. With FIG. 2. Serum free insulin levels (mean ± SD) measured on the same continuous basal infusion, there is some risk of hypoglycemia patients during the interval depicted in Figure I. that may be aggravated by inadequate dietary compliance or excessive exercise. Since this is an accepted feature of uation of infusion occurred most commonly in the first month routine diabetes education, no change in emphasis is reof therapy and with equal frequency in all patients. In one quired. Also, nocturnal hypoglycemia may occur if the papatient, diabetic ketoacidosis did result from the hypergly- tient fails to reduce the night basal rate. The programmable cemic ketosis. Discontinuation of infusion was caused by pumps that automatically shift to the slower night basal rate inadequate taping of needle, poor tape adherence due to have eliminated this problem. humidity or perspiration, and excessive movement during As indicated in Table 1, insulin requirements decreased sleep. Repeated education regarding this pitfall of pump therin 8 of the 11 patients. Blood glucose concentrations imapy corrected and prevented subsequent occurrences. The proved on the lower-dose, CBII system with free insulin levels prompt development of hyperglycemic ketosis after problems rarely exceeding the physiologic range.22 We speculate that 25 (2) or (3) is similar to that reported by Pickup et al. continuous insulin delivery coupled with better dietary comThe two youngest patients reported herein are a 15-yr-old pliance yielded improved glycemic control on the lower total female and a 12-yr-old male. The female presented for pump daily dose of insulin. Although this approach reduces probtherapy with a complaint of painful peripheral neuropathy. lems associated with patient pump manipulation, our youngOn twice-daily bolus injections of insulin, she maintained est patients found the wearing of a pump a problem for their good glycemic control (HbAlc, 8.5%). With pump therapy, current lifestyle. she improved her HbA lc to 5.6% without frequent hypoglycemia. While on CBII, she experienced an initial intensification of neuropathy symptoms that was followed by complete resolution in 2.5 mo. She discontinued pump therapy at 4.5 mo due to resolution of her painful symptoms and the inconvenience of the pump, which interfered with her frequent participation in water sports. The male switched from twice-daily insulin injections to CBII with an HbAlc of 12.4% because he disliked the injections. He preferred insulin administration by CBII, and his HbA lc dropped to 9.1% in 4 mo. The social stigmata of wearing a pump, however, led to its discontinuation after 4 mo. £ io

DISCUSSION

The present data support the theory that continuous insulin delivery promotes effective diabetes control. In the 11 patients presented here, insulin was delivered by dual-rate, basal infusions without preprandial boluses as we have reported previously.21 Davis et al. and Nathan have also used this approach with success.26'27 The effectiveness of the premeal bolus approach has been well demonstrated.6"11 The reduction of HbA lc reported here 116

p C005

FIG. 3. HbA,c values for individual patients on conventional insulin therapy {C1T) versus CBII at 30 days.

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CONCLUSIONS

Continuous basal insulin infusion, without boluses, is an effective form of insulin delivery for normalization of blood glucose levels in insulin-dependent diabetes. It differs from previous methods of continuous insulin infusion by the absence of premeal boluses. Like the premeal bolus approach, CBII requires that the patient adhere to a daily dietary program. We speculate that the simplicity of CBII makes it suitable for a greater variety of patients. This method may help insulin-dependent diabetic patients achieve better glycemic control. ACKNOWLEDGMENTS: This work was supported in part by a grant from Health and Rehabilitative Services, State of Florida.

This study was presented in part at the Southern Society for Pediatric Research, New Orleans, January 1982. From the Diabetes Center and Department of Pediatrics, Tampa, Florida. Address reprint requests to John A. Duncan, M.D., Diabetes Center, University of South Florida, 12901 North 30th Street, Box 45, Tampa, Florida 33612. REFERENCES 1 Engerman, R., Bloodsworth, J. M. B., and Nelson, S.: Relationship of microvascular disease to metabolic control. Diabetes 1977; 26:760-69. 2 Tchobroutsky, G.: Relation of diabetic control to development of microvascular complications. Diabetologia 1978; 15:143-52. 3 Viberti, G. C., Pickup, J. C., Jarrett, R. J., and Keen, H.: Effect of control of blood glucose on urinary excretion of albumin and S2 microglobulin in insulin-dependent diabetes. N. Engl. J. Med. 1979; 300:638-41. 4 Irsigler, K., Kritz, H., Najemnik, C , and Freyler, H.: Reversal of florid diabetic retinopathy. Lancet 1979; 2:1068. 5 Slama, G., Hautcouverture, M., Assan, R., and Tchobroutsky, G.: One to five days of continuous intravenous insulin infusion on seven diabetic patients. Diabetes 1974; 23:732-38. 6 Tamborlane, W. V., Sherwin, R. S., Genel, M., and Felig, P.: Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump. N. Engl. J. Med. 1979; 30:573-78. 7 Pickup, J. C., White, M. C., Keen, H., Kohner, E. M., et al.: Long-term continuous subcutaneous insulin infusion in diabetics at home. Lancet 1979; 2:870-73. 8 Eaton, R. P., et al.: Diabetic glucose control: matching plasma insulin concentration to dietary and stress hyperglycemia. Diabetes Care 1978; 1:40-449 Rizza, R. A., Gerich, J. E., Haymond, M. W., et al.: Control of blood sugar in insulin dependent diabetes: comparison of an artificial endocrine pancreas, continuous subcutaneous insulin infusion and intensified conventional insulin therapy. N. Engl. J. Med. 1980; 303:1313-18. 10 Nelson, J. D., Albisser, A. M., Marliss, E. B., and Zinman, B.: Role of continuous component in subcutaneous "open-loop" insulin delivery. Lancet 1980; 1:1383-86. 11 Schade, D. S., Eaton, R. P., and Spencer, W.: Normalization of plasma insulin profiles in diabetic subjects with programmed insulin delivery. Diabetes Care 1980; 3:9-14.

12 Wahren, J., Felig, P., Cerasi, E., and Luft, R.: Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus. J. Clin. Invest. 1972; 51:1870-78. 13 Sacca, L., Hendler, R., and Sherwin, R. S.: Hyperglycemia inhibits glucose production in man independent of changes in glucoregulatory hormones. J. Clin. Endocrinol. Metab. 1978; 47:116063. 14 Felig, P., and Wahren, J.: Influence of endogenous insulin secretion or splanchnic glucose and amino acid metabolism in man. J. Clin. Invest. 1971; 50:1702-11. 15 Pickup, J. C , Keen, H., Parsons, J. A., and Alberti, K. G. M. M.: Continuous subcutaneous insulin infusion: improved blood glucose and intermediary metabolite control in diabetics. Lancet 1979; 1:1255-58. 16 Raskin, P., Pietri, A., and Unger, R.: Changes in glucagon levels after four to five weeks of glucoregulacion by portable insulin infusion pumps. Diabetes 1979; 28:1033-35. 17 Tamborlane, W. V., Sherwin, R. S., Koivisto, V., Hendler, R., et al.: Normalization of the growth hormone and catecholamine response to exercise in juvenile-onset diabetic subjects treated with a portable insulin infusion pump. Diabetes 1979; 28:785-88. 18 Pickup, J. C , Keen, N., Viberti, G. C , White, M. C , et al.: Continuous subcutaneous insulin infusion in the treatment of diabetes mellitus. Diabetes Care 1980; 3:290-300. 19 Tamborlane, W. V., Sherwin, R. S., Genel, M., and Felig, P.: Outpatient treatment of juvenile-onset diabetes with a pre-programmed portable subcutaneous insulin infusion system. Am. J. Med. 1980; 68:190-96. 20 Riley, W. J., Silverstein, J. H., and Rosenbloom, A. L.: Ambulatory diabetes management by a pulse of subcutaneous insulin delivered by a portable pump: preliminary report. Diabetes Care 1979; 2:272-74. 21 Duncan, J. A., Colon, J., and Malone, J. I.: Juvenile diabetes management with constant basal infusion: a simpler method. Abstract. Clin. Res. 1981; 29:889A. 22 Malone, J. I., and Root, A. W.: Plasma free insulin concentrations: keystone to effective management of diabetes mellitus in children. J. Pediatr. 1981; 99:862-67. "Goldstein, D. E., Peth, S. B., England, J. D., Hess, R. L , and DaCosta, J.: Effects of acute changes in blood glucose on HbA,c. Diabetes 1980; 29:623-28. 24 Schmidt, M. I., Hadji-Georgopoulos, A., Rendell, M., Margolis, S., and Kowarski, A.: The dawn phenomenon, an early morning glucose rise: implications for diabetic intraday blood glucose variation. Diabetes Care 1981; 4:579-85. 25 Pickup, J. C , Viberti, G. C , Bilous, R. W., Keen, H., Alberti, K. G. M. M., Home, P. D., and Binder, C : Safety of continuous subcutaneous insulin infusion: metabolic deterioration and glycemic auto-regulation after deliberate cessation of infusion. Diabetologia 1982; 22:175-79. 26 Davis, T M. E., Holman, R. R., Eaton, P. M., and Turner, R. C.: A regular meal and insulin infusion regime—its use in treatment of acute-onset ketotic diabetes and in stabilization of poorly controlled established diabetic subjects. Diabetes Care 1982; 5:492— 96. 27 Nathan, D. M.: Successful treatment of extremely brittle, insulin-dependent diabetes with a novel subcutaneous insulin pump regimen. Diabetes Care 1982; 5:105-10. 28 Schiffrin, A., Colle, E., and Belmonte, M.: Improved control in diabetes with continuous subcutaneous insulin infusion. Diabetes Care 1980; 3:643-49.

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