A controlled trial of insulin infusion and parenteral nutrition in extremely low birth weight infants with glucose intolerance. Early insulin therapy in very-low-birth-weight infants. Hyperglycemia in extremely- low-birth-weight infants. Introduction of intravenous lipid administration on the first day of life in the very low birth weight neonate. Special management of insulin lispro in continuous subcutaneous insulin infusion in young diabetic children: a randomized cross-over study. Early elective insulin therapy can reduce hyperglycemia and increase insulin-like growth factor-I levels in very low birth weight infants. Continuous perioperative insulin infusion decreases major cardiovascular events in patients undergoing vascular surgery: a prospective, randomized trial. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes: the RealTrend study.
To determine whether a continuous insulin infusion improves glucose tolerance in extremely low birth weight infants, we conducted a prospective, randomized trial in 24 neonates 4 to 14 days old (mean birth weight 772.9 +/- 128 gm; mean gestational age 26.3 +/- 1.6 weeks). Infants who had glucose intolerance were randomly assigned to receive either intravenous glucose and total parenteral nutrition with insulin through a microliter-sensitive pump or standard intravenous therapy alone. One infant assigned to receive insulin never required it. The groups were similar in birth weight, gestational age, race, gender, medical condition, and energy intake before the study. The mean duration of therapy was 14.6 days (range 7 to 21 days). During the study, the 11 insulin-treated infants tolerated higher glucose infusion rates (20.1 +/- 2.5 vs 13.2 +/- 3.2 mg/kg/min (1.1 +/- 0.1 vs 0.7 +/- 0.2 mmol/L); p less than 0.01), had greater nonprotein energy intake (124.7 +/- 18 vs 86.0 +/- 6 kcal/kg/day; p less than 0.01), and had better weight gain (20.1 +/- 12.1 vs 7.8 +/- 5.1 gm/kg/day; p less than 0.01) than the 12 control infants. The incidence of hypoglycemia, electrolyte imbalance, chronic lung disease, and death did not differ between groups. We conclude that a controlled insulin infusion improves and sustains glucose tolerance, facilitates provision of calories, and enhances weight gain in glucose-intolerant premature infants. Studies involving adults and children being treated in intensive care units indicate that insulin therapy and glucose control may influence survival. Hyperglycemia in very-low-birth-weight infants is also associated with morbidity and mortality. This international randomized, controlled trial aimed to determine whether early insulin replacement reduced hyperglycemia and affected outcomes in such neonates.
                In this multicenter trial, we assigned 195 infants to continuous infusion of insulin at a dose of 0.05 U per kilogram of body weight per hour with 20% dextrose support and 194 to standard neonatal care on days 1 to 7. The efficacy of glucose control was assessed by continuous glucose monitoring. The primary outcome was mortality at the expected date of delivery. The study was discontinued early because of concerns about futility with regard to the primary outcome and potential harm.
                As compared with infants in the control group, infants in the early-insulin group had lower mean (+/-SD) glucose levels (6.2+/-1.4 vs. 6.7+/-2.2 mmol per liter [112+/-25 vs. 121+/-40 mg per deciliter], P=0.007). Fewer infants in the early-insulin group had hyperglycemia for more than 10% of the first week of life (21% vs. 33%, P=0.008). The early-insulin group had significantly more carbohydrate infused (51+/-13 vs. 43+/-10 kcal per kilogram per day, P<0.001) and less weight loss in the first week (standard-deviation score for change in weight, -0.55+/-0.52 vs. -0.70+/-0.47; P=0.006). More infants in the early-insulin group had episodes of hypoglycemia (defined as a blood glucose level of <2.6 mmol per liter [47 mg per deciliter] for >1 hour) (29% in the early-insulin group vs. 17% in the control group, P=0.005), and the increase in hypoglycemia was significant in infants with birth weights of more than 1 kg. There were no differences in the intention-to-treat analyses for the primary outcome (mortality at the expected date of delivery) and the secondary outcome (morbidity). In the intention-to-treat analysis, mortality at 28 days was higher in the early-insulin group than in the control group (P=0.04).
                Early insulin therapy offers little clinical benefit in very-low-birth-weight infants. It reduces hyperglycemia but may increase hypoglycemia (Current Controlled Trials number, ISRCTN78428828.)
                2008 Massachusetts Medical Society The cause of hyperglycemia in extremely-low-birth-weight (ELBW) infants is not well understood. We studied infants weighing <1,000 g to investigate the relationship of hyperglycemia to blood levels of insulin-like growth factor (IGF)-I and IGF-II. We also compared two methods of treatment for hyperglycemia: continuous insulin infusion and reduction of glucose intake. Fifty-six ELBW infants were enrolled on day 2 of life. Intravenous glucose intake was increased incrementally to a maximum of 12 mg/kg/min on day 6. Infants who developed hyperglycemia were randomly assigned to receive reduced glucose intake (n = 11) or insulin infusion (n = 12). Infants whose blood sugar remained normal served as controls (n = 33). Blood was drawn on days 3, 8 and 15 in all infants, and again when they developed hyperglycemia. Nutritional intake and laboratory results for the treatment groups were compared with controls. Hyperglycemic infants had lower birth weights than controls. Hyperglycemic infants treated with glucose reduction remained <60 kcal/kg/day longer than control or insulin infusion groups (8.6 +/- 1.3 days vs. 4.1 +/- 0.2 and 5.5 +/- 0.6 days). No infants became hypoglycemic during insulin infusion. There was no difference in baseline blood levels of IGF-I or IGF-II among the groups, and these growth factors did not change in response to hyperglycemia. Hyperglycemic infants had baseline levels of insulin which were similar to normal controls, and endogenous insulin increased in response to hyperglycemia in 15 of the 23 infants who developed hyperglycemia. IGF-I and IGF-II are not related to hyperglycemia. In our population, hyperglycemic infants did not have baseline insulin deficiency and most had a normal insulin response to hyperglycemia. Insulin infusion appears safe in these infants and helped to maintain normal caloric intake, whereas glucose reduction was associated with a prolonged caloric deprivation. To investigate lipid tolerance in sick, ventilator-dependent, very low birth weight infants from the first day of life and the effects of early introduction of intravenously administered lipid (IVL) on glucose homeostasis.
                Twenty-nine infants in the neonatal intensive care unit with birth weight less than 1500 gm received isocaloric, isonitrogenous parenteral feedings from day 1 with either IVL, 1 gm/kg from day 1 to 3 gm/kg from day 4 (group I; n = 16), or IVL added only from day 8 (group II; n = 13). Possible adverse clinical effects were monitored. Blood metabolites, nonesterified fatty acids, serum triglycerides, and insulin levels were determined daily. Arterial blood gases were measured and changes in partial pressures of oxygen and of carbon dioxide in arterial blood were compared between the two groups.
                Early lipid infusion did not appear to have deleterious effects on blood gas tensions or to increase respiratory morbidity. The incidence of other adverse clinical effects that may be associated with IVL was not increased by earlier introduction of lipid. Serum lipid values were comparable to those of preterm infants receiving IVL at a later postnatal age. Blood glucose concentrations were higher in group II (mean, 7.50 (SEM 0.43) mmol/L) than in group I (mean, 6.01 (SEM 0.28) mmol/L; p less than 0.05). There was no evidence of increased gluconeogenesis in infants in group I and no correlation between blood glucose concentrations and serum nonesterified fatty acid concentrations.
                When given infusion rates not exceeding 0.15 gm/kg/hr, sick, very low birth weight infants can tolerate IVL with stepwise dose increases from the first day of life without an increased incidence of possible adverse effects. To compare the safety, efficacy and management of insulin lispro (LP) with regular human insulin (RH) in young diabetic children treated with continuous subcutaneous insulin infusion (CSII).
                27 very young diabetic children (age 4.6 +/- 2.2 years) treated with CSII participated in an open-label, randomized cross-over multicenter study comparing 2 periods of 16 weeks of CSII with LP or RH.
                Mean daily basal rate was significantly higher during the LP period (p = 0.04). No differences were seen in changes in HbA1c levels, number of hypoglycemic events, cutaneous infections and catheter occlusions. There was no significant difference between the two treatments for preprandial and postprandial glucose values, although prandial glucose excursions tended to be lower with LP (significant at dinner, p = 0.01). Mean blood glucose levels were significantly higher at 0.00 and 3.00 a.m. during LP therapy (p < 0.05). No episode of ketoacidosis occurred during LP treatment. More parents indicated that LP made their own and the child's daily life easier (p = 0.02) and preferred LP (p = 0.01).
                LP in CSII therapy in children is safe, as effective as RH, improved postprandial excursions, met the needs of young children in their daily life well, and gained their parents' satisfaction and preference. However, a shorter duration of LP resulted in hyperglycemia during the first part of the night, which must be compensated for by increasing nocturnal basal rates during this time. To investigate the use of insulin throughout the first week of life in very low birth weight (VLBW) infants (birth weight <1.5 kg) to improve glucose control and increase insulin-like growth factor-I (IGF-I) levels. IGF-I is the dominant hormone involved in fetal growth, and low levels have been implicated in neonatal morbidities, such as retinopathy of prematurity.
                In this pilot randomized controlled study (n = 16), the intervention group received insulin (0.025 U/kg/hr) on days 1 to 7, with 20% dextrose to maintain normoglycemia. Control infants received standard neonatal care. All infants received continuous glucose monitoring.
                The intervention and standard care groups had similar mean gestational age (+/- standard deviation), 26.2 (+/- 2.5) vs 26.9 (+/- 2.7) weeks, and birth weight, 0.79 (+/- 0.26) vs 0.73 (+/- 0.16) kg. The standard care infants were hyperglycemic (sensor glucose >10 mmol/L [180 mg/dL]) for 35.9% of the study period, compared with 7.6% for the insulin-treated infants (P = .035). The duration of time with hypoglycemia (<2.6 mmol/L [47 mg/dL]) did not differ between the 2 groups (P = .746). The insulin-treated group had a 2.4-fold increase in mean IGF-I bioactivity (P = .005).
                Early insulin therapy improves blood glucose control and increases IGF-I bioactivity levels. This could result in less morbidity associated with hyperglycemia and reduced IGF-I levels. A growing body of evidence suggests that hyperglycemia is an independent predictor of increased cardiovascular risk. Aggressive glycemic control in the intensive care decreases mortality. The benefit of glycemic control in noncardiac surgery is unknown.
                In a single-center, prospective, unblinded, active-control study, 236 patients were randomly assigned to continuous insulin infusion (target glucose 100-150 mg/dl) or to a standard intermittent insulin bolus (treat glucose > 150 mg/dl) in patients undergoing peripheral vascular bypass, abdominal aortic aneurysm repair, or below- or above-knee amputation. The treatments began at the start of surgery and continued for 48 h. The primary endpoint was a composite of all-cause death, myocardial infarction, and acute congestive heart failure. The secondary endpoints were blood glucose concentrations, rates of hypoglycemia (< 60 mg/dl) and hyperglycemia (> 150 mg/dl), graft failure or reintervention, wound infection, acute renal insufficiency, and duration of stay.
                The groups were well balanced for baseline characteristics, except for older age in the intervention group. There was a significant reduction in primary endpoint (3.5%) in the intervention group compared with the control group (12.3%) (relative risk, 0.29; 95% confidence interval, 0.10-0.83; P = 0.013). The secondary endpoints were similar. Hypoglycemia occurred in 8.8% of the intervention group compared with 4.1% of the control group (P = 0.14). Multivariate analysis demonstrated that continuous insulin infusion was a negative independent predictor (odds ratio, 0.28; 95% confidence interval, 0.09-0.87; P = 0.027), whereas previous coronary artery disease was a positive predictor of adverse events.
                Continuous insulin infusion reduces perioperative myocardial infarction after vascular surgery. To assess in a randomized crossover trial the efficacy of continuous subcutaneous insulin infusion in improving glycemic control and health-related quality of life in type 1 diabetic patients with long-standing poor glycemic control.
                A total of 79 patients in 11 Dutch centers were randomized to 16 weeks of continuous subcutaneous insulin infusion followed by 16 weeks intensive injection therapy or the reverse order. Glycemic control was assessed by HbA(1c), self-reported hypoglycemic events, and blood glucose memory meter read outs. Changes in quality of life were assessed by self-report questionnaires administered at baseline and 16 weeks.
                As the drop-out rate after crossover was high (17 of 79 patients [22%]), we analyzed the trial as a parallel clinical trial, using data of the first half of the crossover phase only. At 16 weeks, mean HbA(1c) was 0.84% (95% CI -1.31 to -0.36) lower in the continuous subcutaneous insulin infusion group compared with the insulin injection group (P = 0.002). Stability of blood glucose self-measurement values, expressed as SD of the nine-point blood glucose profiles, improved in the insulin pump group by 29.3 +/- 41.1 vs. 8.2 +/- 36.5% in the injection group (P = 0.039). The number of mild hypoglycemic episodes per patient-week was 0.99 (95% CI 0.11-1.87) higher in the insulin pump group (P = 0.028). Weight gain was similar in both groups. Scores on the Short-Form 36-Item subscales 'general health' and 'mental health' improved in the continuous subcutaneous insulin infusion group, compared with stable values in the injection group (P = 0.048 and 0.050, respectively).
                Continuous subcutaneous insulin infusion improves glycemic control and some aspects of health-related quality of life in patients with a history of long-term poor glycemic control. To compare the improvements in glycemic control associated with transitioning to insulin pump therapy in patients using continuous glucose monitoring versus standard blood glucose self-monitoring.
                The RealTrend study was a 6-month, randomized, parallel-group, two-arm, open-label study of 132 adults and children with uncontrolled type 1 diabetes (A1C >or=8%) being treated with multiple daily injections. One group was fitted with the Medtronic MiniMed Paradigm REAL-Time system (PRT group), an insulin pump with integrated continuous subcutaneous glucose monitoring (CGM) capability, with instructions to wear CGM sensors at least 70% of the time. Conventional insulin pump therapy was initiated in the other group (continuous subcutaneous insulin infusion [CSII] group). Outcome measures included A1C and glycemic variability.
                A total of 115 patients completed the study. Between baseline and trial end, A1C improved significantly in both groups (PRT group -0.81 +/- 1.09%, P < 0.001; CSII group -0.57 +/- 0.94%, P < 0.001), with no significant difference between groups. When the 91 patients who were fully protocol-compliant (including CGM sensor wear >or=70% of the time) were considered, A1C improvement was significantly greater in the PRT group (P = 0.004) (PRT group -0.96 +/- 0.93%, P < 0.001; CSII group -0.55 +/- 0.93%, P < 0.001). Hyperglycemia parameters decreased in line with improvements in A1C with no impact on hypoglycemia.
                CGM-enabled insulin pump therapy improves glycemia more than conventional pump therapy during the first 6 months of pump use in patients who wear CGM sensors at least 70% of the time.
Glucose infusion rate: There is insufficient evidence from trials comparing lower with higher glucose infusion rates to inform clinical practice. Large randomized trials are needed, powered on clinical outcomes including death, major morbidities and adverse neurodevelopment.
Insulin infusion: The evidence reviewed does not support the routine use of insulin infusions to prevent hyperglycemia in VLBW neonates. Further randomized trials of insulin infusion may be justified. They should enrol extremely low birth weight neonates at very high risk for hyperglycemia and neonatal death. They might use real time glucose monitors if these are validated for clinical use. Refinement of algorithms to guide insulin infusion is needed to enable tight control of glucose concentrations within the target range.