Relationship between insulin-like growth factor I levels, early insulin treatment, and clinical outcomes of very low birth weight infants.

OBJECTIVES: Insulin regulates the secretion of insulin-like growth factor I (IGF-I) in the newborn, and low levels of IGF-I have been linked to neonatal morbidity. As part of the Neonatal Insulin Replacement Therapy in Europe Trial, we investigated the impact of early insulin treatment on IGF-I levels and their relationship with morbidity and growth. STUDY DESIGN: Prospective cohort analyses of data collected as part of an international randomized controlled trial. Blood samples (days 1, 3, 7, and 28), were taken for IGF-I bioassay from 283 very low birth weight infants (<1500 g). RESULTS: Early insulin treatment led to a late increase in IGF-I levels between day 7 and 28 (P = .028). In the first week of life IGF-I levels were lower in infants with early hyperglycemia; mean difference -0.10 µg/L (95% CI -0.19, -0.02, P = .02). Lower levels of IGF-I at day 28 were independently associated with an increased risk of chronic lung disease, OR 3.23 (95% CI, 1.09-9.10), and greater IGF-I levels were independently associated with better weight gain, 0.10 kg (95% CI, 0.03-0.33, P = .02). CONCLUSIONS: Early intervention with insulin is related to increased IGF-I levels at 28 days. Low IGF-I levels are associated with hyperglycemia, increased morbidity, and reduced growth. Increasing IGF-I levels may improve outcomes of very low birth weight infants.

End-of-life decisions in neonates and infants: a nationwide mortality follow-back survey.

OBJECTIVES: Neonatology has undergone important clinical and legal changes; however, the implications for end-of-life decision-making in seriously ill neonates to date are unknown. Our aim was to examine changes in prevalence and characteristics of end-of-life decisions (ELDs) in neonatology. METHODS: We performed a nationwide mortality follow-back survey in August 1999 to July 2000 and September 2016 to December 2017 in Flanders, Belgium. Data were linked to information from death certificates. For each death under the age of 1, physicians were asked to complete an anonymous questionnaire about which ELDs were made preceding death. RESULTS: The response rate was 87% in 1999-2000 (253/292) and 83% in 2016-2017 (229/276). The proportion of deaths of infants born before 26 weeks' gestation was increased (14% vs 34%, p=0.001). Prevalence of ELDs remained stable at 60%, with non-treatment decisions occurring in about 35% of all deaths. Use of medication with an explicit life-shortening intention was prevalent in 7%-10% of all deaths. In early neonatal death (<7 days old) medication with an explicit life-shortening intention decreased from 12% to 6%, in late neonatal death (7-27 days old), it increased from 0% to 26%, and in postneonatal death (>27 days old), it increased from 2% to 10%. CONCLUSIONS: Over a timespan of 17 year, the prevalence of neonatal ELDs has remained stable. A substantial number of deaths was preceded by the intentionally hastening of death by administrating medication. While surveying solely the physician perspective in this paper, there is a need for an open multidisciplinary debate, including, for example, nursing staff and family members, based on clinical as well as ethical and jurisdictional reflections to discuss the need for international guidelines.

Early insulin therapy in very-low-birth-weight infants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.)

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial.

BACKGROUND: Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants. METHODS/DESIGN: The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis. DISCUSSION: This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.

Successful treatment of liver rupture in a premature infant.

Subcapsular rupture of the liver is a rare and usually lethal complication in preterm infants. A multidisciplinary approach is warranted to achieve the best possible outcome for these children.

Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study.

OBJECTIVES: To investigate the prevalence and determinants of hyperglycemia in the preterm population, as part of the Neonatal Insulin Therapy in Europe (NIRTURE) Trial. STUDY DESIGN: We conducted prospective cohort analyses of continuous glucose monitoring data from control infants participating in an international randomized controlled trial. Data were collected from 188 very low birth weight infants (<1500 g). RESULTS: In the first week of life, 80% of infants had evidence of glucose levels >8 mmol/L, and 32% had glucose levels >10 mmol/L >10% of the time. Independent risk factors for hyperglycemia included increasing prematurity, small size at birth, use of inotropes, lipid infusions, and sepsis. There was a lack of association between rate of dextrose infused and risk of hyperglycemia. CONCLUSION: The prevalence of hyperglycemia in the very low birth weight infant is high, with marked variability in prevalence between infants, not simply related to rates of glucose infused, but to other potentially modifiable risk factors.

Enteral nutrition regimen for neonates with short bowel syndrome.

Short bowel syndrome is characterized as a state of malabsorption after massive resection of the small intestine. It has a wide spectrum of clinical presentations, from mild to severe depending predominantly on the length of intestine remnant. Management is challenging and requires vigorous attention to every detail. Enteral nutrition is the key to intestinal adaptation and reduction of dependency on parenteral nutrition. Therefore, creative ways are essential to maximize enteral nutrition despite obstacles to its use.

Conservative treatment for patent ductus arteriosus in the preterm.

BACKGROUND: A patent ductus arteriosus (PDA) is common among preterms, and prophylactic medical treatment has been advocated as the first-line approach. Conservative treatment may result in similar outcome, but without exposure to the harmful side effects of medication. A retrospective analysis revealed a ductal closure rate of 94% after conservative treatment with adjustment of ventilation (lowering the inspiratory time and increasing positive end expiratory pressure) and fluid restriction. OBJECTIVE: To study prospectively over one year the rate of PDA closure, and morbidity and mortality following conservative treatment. METHOD: Prospective study (1 January 2005 - 31 December 2005) including 30 newborns

Continuous glucose monitoring and retinopathy of prematurity.

PURPOSE: To use the continuous glucose monitoring system (CGMS) in very low birthweight (VLBW) infants to further explore the association between elevated glucose levels and retinopathy of prematurity (ROP) and to find new preventive strategies for ROP. METHODS: A secondary analysis of risk factors for ROP in VLBW infants was performed in the neonatal intensive care units of University Hospital Leuven and ZOL Genk, Belgium. The subjects were part of the NIRTURE trial (ISRCTN78428828). Only control subjects with conclusive ROP assessments who received standard clinical care were included in this analysis. A total of 100 VLBW infants (birthweight = 1500 g) were included. Twenty-three (23%) infants developed ROP; 77 (77%) did not. RESULTS: Development of ROP was linked to the known classic risk factors. In addition, ROP was associated with higher glycemia levels across the first week (p between 0.01 and <0.0001). Across the first week, glycemia predicted ROP with receiver operating characteristic (ROC) scores between 0.67 and 0.80, and with a median glycemia cutoff of 6.7 mmol/L. Comparison of ROC curves revealed first-week glycemia as an important variable in the development of ROP with a predictive power as high as the classic risk factors. CONCLUSIONS: Moderately elevated glucose levels in the first week of life are associated with the development of ROP. They contribute to this multifactorial disease in a way equal to the known classical risk factors for ROP. Therefore, careful monitoring of glucose levels by CGMS can be helpful in the prevention of ROP.

A comparison of the pharmacokinetics of two dosing regimens of cisapride and their effects on corrected QT interval in premature infants.

OBJECTIVE: To compare the pharmacokinetics of two dosing regimens of cisapride and their effects on QT(c) interval. DESIGN: Thirty-one pre-term infants were enrolled in two neonatal intensive care units. In 16 infants, cisapride was started at 0.2 mg/kg orally every 6 h (group A) and in 15 infants at 0.1 mg/kg orally every 3 h (group B). Electrocardiograms were performed before and after 72 h of treatment to calculate the QT(c) interval according to the Bazett formula. After 72 h of treatment, cisapride and norcisapride trough concentrations, and concentrations 1 h after the next cisapride administration were quantified in serum. A linear regression analysis was performed to analyse the effect of postnatal and postconception age. RESULTS: At the start of cisapride treatment, mean postnatal age was 22.9+/-13.9 days (mean+/-SD) for group A and 23.3+/-15.0 days for group B, and mean postconception age was 34.0+/-1.8 weeks for group A and 33.3+/-0.8 weeks for group B. The QT(c) interval increased equally in both groups (group A: +37+/-20 ms, and group B: + 38+/-25 ms; P=0.9). Mean concentration of cisapride 1 h after administration was, as expected from the dosing regimen, significantly higher in group A than in group B (123.7+/-43.2 ng/ml versus 86.7+/-27.8 ng/ml; P=0.03).The difference in trough concentration was not significant (107.4+/-44.3 ng/ml versus 78.2+/-35.4 ng/ml; P=0.09). There was a positive correlation between QT(c) prolongation and cisapride serum concentration (peak: R(2)=0.20, P=0.015; trough: R(2)=0.24, P=0.008) and an inverse correlation between postnatal age and concentration 1 h after administration concentration of cisapride (R(2)=0.19, P=0.02). No correlation was found for postconception age. CONCLUSION: Postnatal age has an inverse relationship with cisapride serum concentration in premature infants, whereas postconception age is not correlated. The maturation process of the biotransformation system of cisapride during the first weeks of life, triggered by birth, but independent of gestational age at birth can explain this observation. The effect of cisapride on cardiac repolarisation is positively related with the cisapride serum concentration. Administering cisapride every 3 h instead of every 6 h could be advantageous, as it is associated with lower peak cisapride serum concentrations. Further investigations are required to confirm this and its potential clinical benefit on QT(c )and arrhythmia risk.