Paula Midgley

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.)

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.

A randomised controlled trial of early insulin therapy in very low birth weight infants, "NIRTURE" (neonatal insulin replacement therapy in Europe)

BackgroundStudies in adult intensive care have highlighted the importance of insulin and improved glucose control on survival, with 32% reduction in mortality, 22% reduction in intensive care stay and halving of the incidence of bacteraemia. Very low birth weight infants requiring intensive care also have relative insulin deficiency often leading to hyperglycaemia during the first week of life. The physiological influences on insulin secretion and sensitivity, and the potential importance of glucose control at this time are not well established. However there is increasing evidence that the early postnatal period is critical for pancreatic development. At this time a complex set of signals appears to influence pancreatic development and β cell survival. This has implications both in terms of acute glucose control but also relative insulin deficiency is likely to play a role in poor postnatal growth, which has been associated with later motor and cognitive impairment, and fewer β cells are linked to risk of type 2 diabetes later in life.MethodsA multi-centre, randomised controlled trial of early insulin replacement in very low birth weight babies (VLBW, birth weight < 1500 g). 500 infants will be recruited from 10 centres in the UK and Europe. Babies will be randomised to receive a continuous insulin infusion (0.05 units/kg/h) or to receive standard neonatal care from the first day of life and for the next 7 days. If blood glucose (BG) levels fall infants will receive 20% dextrose titrated to maintain normoglycaemia (4–8 mmol/l). If BG is consistently above 10 mmol/l babies will receive standard treatment with additional insulin infusion. The primary end point will be mortality on or before expected date of delivery, secondary end points will be markers of morbidity and include episodes of sepsis, severity of retinopathy, chronic lung disease and growth.Trial RegistrationCurrent Controlled Trials ISRCTN78428828. EUDRACT Number 2004-002170-34

A re-investigation of saliva collection procedures that highlights the risk of potential positive interference in cortisol immunoassay.

BACKGROUND The use of saliva for measurement of cortisol permits non-invasive study of adrenal function, but collection can be technically difficult, particularly in small infants. Saliva collection can be assisted by citric acid to increase saliva flow, or by the use of cotton or polyester swabs in the mouth. AIM To determine whether different methods of saliva collection affect cortisol radioimmunoassay (RIA) performance. EXPERIMENTAL Cortisol was measured in saliva collected from 16 adults using intra-oral cotton swabs or polyester swabs, compared with saliva dribbled directly into a pot either alone (plain saliva) or after citric acid had been placed on the tongue. An in-house RIA, without prior extraction, was used to measure cortisol with an encapsulated sheep antibody. RESULTS Mean (median) salivary cortisol was 10.9 (10.5) nmol L(-1) in plain saliva, 10.4 (8.4) nmol L(-1) in citric acid stimulated saliva; 25.3 (25.1) nmol L(-1) in saliva collected on cotton swabs, and 27.9 (27.3) nmol L(-1) collected on polyester swabs. Cortisol in saliva collected using citric acid was not significantly different from plain saliva (p=0.997), but cortisol in saliva collected using cotton and polyester swabs was significantly higher than that of plain saliva (p<0.01). CONCLUSION The use of cotton or polyester swabs for collection of saliva can result in spuriously high levels of cortisol when measured by RIA.

Validation of the continuous glucose monitoring sensor in preterm infants

Objective Recent studies have highlighted the need for improved methods of monitoring glucose control in intensive care to reduce hyperglycaemia, without increasing the risk of hypoglycaemia. Continuous glucose monitoring is increasingly used in children with diabetes, but there are little data regarding its use in the preterm infant, particularly at extremes of glucose levels and over prolonged periods. This study aimed to assess the accuracy of the continuous glucose monitoring sensor (CGMS) across the glucose profile, and to determine whether there was any deterioration over a 7 day period. Design Prospectively collected CGMS data from the NIRTURE Trial was compared with the data obtained simultaneously using point of care glucose monitors. Setting An international multicentre randomised controlled trial. Patients One hundred and eighty-eight very low birth weight control infants. Outcome measures Optimal accuracy, performance goals (American Diabetes Association consensus), Bland Altman, Error Grid analyses and accuracy. Results The mean (SD) duration of CGMS recordings was 156.18 (29) h (6.5 days), with a total of 5207 paired glucose levels. CGMS data correlated well with point of care devices (r=0.94), with minimal bias. It met the Clarke Error Grid and Consensus Grid criteria for clinical significance. Accuracy of single readings to detect set thresholds of hypoglycaemia, or hyperglycaemia was poor. There was no deterioration over time from insertion. Conclusions CGMS can provide information on trends in glucose control, and guidance on the need for blood glucose assessment. This highlights the potential use of CGMS in optimising glucose control in preterm infants.

Cortisol and growth hormone responses to spontaneous hypoglycaemia in infants and children

Aims: To evaluate responses of cortisol and growth hormone (GH) to spontaneous hypoglycaemia in infants and children. Methods: Retrospective review of laboratory and clinical data in paediatric patients investigated for suspected hypoglycaemia over a five year period. Thirty patients (16 aged <3 months) had hypoglycaemia confirmed by laboratory analysis (glucose <2.5 mmol/l) and were compared with 26 patients (11 aged <3 months) with glucose ⩾2.5 mmol/l. Results: The commonest causes of hypoglycaemia were transient hyperinsulinism in infants <3 months and intercurrent infection in those >6 months of age. In both hypo- and non-hypoglycaemic patients, cortisol was positively (rs +0.66 and +0.68) and GH inversely (rs −0.65 and −0.75) correlated with age. Hypo- and non-hypoglycaemic infants <3 months had median cortisol concentrations of 205 and 116 nmol/l respectively compared with 1370 and 736 nmol/l in hypo- and non-hypoglycaemic children >6 months. Conversely, median GH was 46.5 and 51.2 mU/l in hypo- and non-hypoglycaemic infants compared with 14.3 and 12.1 mU/l in older hypo- and non-hypoglycaemic patients. Older non-hypoglycaemic patients with glucose levels below the glycaemic thresholds established for cortisol and GH secretion in adults had higher cortisol and GH concentrations than patients whose glucose levels exceeded these thresholds. Conclusions: Cortisol and GH responses to spontaneous hypoglycaemia in children are highly age dependent. Young infants mount a poor cortisol response compared with older infants and children. Children older than 6 months may have glycaemic thresholds for cortisol and GH similar to those established for adults.

Adrenal function in preterm infants: ACTH may not be the sole regulator of the fetal zone.

The fetal zone of the adrenal gland is known to persist after preterm birth, but there is uncertainty as to how long adrenal fetal zone steroid production continues and how it is regulated. The purpose of this study was to test two hypotheses. First, that the urinary excretion of 3β-OH-5-ene steroids persists until term, and then declines, as it does in full-term infants. Second, that the persistence of the fetal zone is due to continuing ACTH stimulation. A longitudinal observational study was undertaken in 22 preterm infants of 24-31-wk gestation. Sequential measurements were made of urinary 3β-OH-5-ene steroids (fetal zone steroid metabolites), plasma dehydroepiandrosterone sulfate (DHEAS), and ACTH. Excretion of urinary 3β-OH-5-ene steroids was 1500-2000 µg kg-1 d-1, persisting until term, and declining abruptly at ∼42 wk postconceptional age (PCA), to levels comparable to term infants at the same PCA. Median plasma ACTH levels rose from <7.6 pg mL-1 at 25-wk PCA to 34.5 pg mL-1 at 46-wk PCA. Urinary 3β-OH-5-ene steroids were highest when ACTH levels were lowest, and were declining when ACTH was rising. In four infants given dexamethasone, urinary excretion of 3β-OH-5-ene steroids and plasma DHEAS were not suppressed fully, when plasma ACTH and cortisol, and urinary cortisol metabolites were. These data suggest that ACTH is not the sole regulator of the adrenal fetal zone steroid synthesis and that involution of the fetal zone is related to gestation rather than birth.

Blood pressure in children aged 4–8 years: comparison of Omron HEM 711 and sphygmomanometer blood pressure measurements

Objective: To collect normal data on blood pressure (BP) in healthy children aged 4–8 and to compare measurements of BP made in the same subjects with a sphygmomanometer and a portable automated oscillometric BP monitor (Omron HEM 711 with child cuff). Methods: Cross-sectional observational study of 764 children. BP measurements were made at school, using both a sphygmomanometer and an Omron HEM 711. Immediately after the BP measurement children were asked to state which device they preferred (if any). Results: Children had no preference for whether the sphygmomanometer or the Omron was used. Bland-Altman plots showed a lack of consistency between the two methods of BP measurement. With systolic BP there was a trend for the Omron to underestimate when low and overestimate when high. Conclusions: Children were equally distributed in their preference for BP device. There was a wide variation between the two methods of BP measurement, which suggests that comparison of automated BP measurements with normative data obtained by sphygmomanometer is not valid.

Who is blaming the baby

FIGURE 6. TRAILshort is both necessary and sufficient to cause TRAIL resistance. (A) Jurkat T cells, which constitutively express TRAILshort, were induced to die by the addition of sk-TRAIL, in the presence or absence of increasing amounts of anti-TRAILshort Ab. Cell death was measured by active caspase-3 staining. Control cells were treated with increasing anti-TRAILshort Ab alone. (B) HeLa cells, which do not express TRAILshort, were stimulated to die by the addition of sk-TRAIL in the absence or presence of increasing amounts of a fusion protein consisting of the extracellular domain of TRAILshort fused to Fc (TRAILshort-ECD:Fc) or with BSA control and analyzed as in (A). Additional control cells were treated with increasing TRAILshort-ECD:Fc alone. Data are representative of six independent experiments. p , 0.05 considered statistically significant (linear regression).Sudden unexplained collapse within the first 12 h of life is a rare but recognised event. Over a 2-year period, five infants, previously assessed as healthy, were found collapsed in our maternity unit in the care of their primiparous mothers. Two were found prone on their mother’s chest, and two were in their mother’s bed. The outcomes were poor, with four neonatal deaths and one death at 18 months. The rate of sudden unexplained neonatal collapse was 0.4 per 1000 live births. No cause for collapse was identified despite extensive investigations, which included postmortem in all the neonatal deaths. One infant, however, showed widespread antenatal brain damage at postmortem. It is postulated that some infants with an underlying vulnerability may maladapt to extrauterine life following an hypoxic stressor possibly caused by positional airway obstruction.

Lack of Adult-Type Salivary Cortisol Circadian Rhythm in Hospitalized Preterm Infants

Background/Aims: Knowledge of the presence or absence of cortisol (F) circadian rhythm in preterm infants is important for the interpretation of F measurements made in samples taken for both clinical and research purposes. Little is known about its emergence in very preterm infants. This study examines circadian rhythm in F secretion in hospitalized infants born before 30 weeks’ gestation. Methods: Design: Prospective longitudinal observational study. Subjects: 11 infants admitted consecutively and born before 30 completed weeks of gestation. Measurements: F was measured by highly specific radioimmunoassay on morning and evening saliva samples gathered at weekly intervals until discharged home. Circadian rhythm was defined as ≧40% reduction from morning to evening level. Results: For all data, the median salivary F was 10.3 nmol/l (range <0.5–372.8). F levels were highest in the first 3 weeks of life. No infants displayed classical circadian rhythm for 4 weeks or more prior to being discharged from hospital. The other infants showed randomly distributed morning and evening F values with a trend in 4 infants towards periods of consistently higher evening than morning values. Conclusion: Adult-type F circadian rhythm is rarely evident in hospitalized preterm infants born before 30 weeks’ gestation.