M P Ward Platt

Patterns of metabolic adaptation for preterm and term infants in the first neonatal week.

There have been few comprehensive accounts of the relationships between glucose and other metabolic fuels during the first postnatal week, especially in the context of modern feeding practises. A cross sectional study was performed of 156 term infants and 62 preterm infants to establish the normal ranges and interrelationships of blood glucose and intermediary metabolites in the first postnatal week, and to compare these with those of 52 older children. Blood glucose concentrations varied more for preterm than for term infants (1.5-12.2 mmol/l v 1.5-6.2 mmol/l), and preterm infants had low ketone body concentrations, even at low blood glucose concentrations. Breast feeding of term infants and enteral feeding of preterm infants appeared to enhance ketogenic ability. Term infants had lower prefeed blood glucose concentrations than children but, like children, appeared to be capable of producing ketone bodies. This study demonstrates that neonatal blood glucose concentrations should be considered in the context of availability of other metabolic fuels, and that the preterm infant has a limited ability to mobilise alternative fuels.

Association between blood lactate and acid-base status and mortality in ventilated babies

AIM To investigate the relation between common acid-base parameters and blood lactate concentrations and their prognostic importance in sick, ventilated neonates. METHODS Two hundred and seventy eight serial simultaneous measurements of arterial acid-base status and blood lactate concentrations were carried out in 75 mechanically ventilated neonates with indwelling arterial catheters (gestational age and birthweight, median (range) - 29 (23-40) weeks, and 1340 (550-4080) g, respectively). RESULTS There were no correlations between arterial blood lactate and pH and base excess within subjects (r=0.07 and r= -0.06, respectively) and only weakly positive but clinically irrelevant positive correlations between subjects (r=0.28 and r=0.27) in this group. Even in those infants who had not received any bicarbonate before their initial measurements (n=48), there were no correlations between initial blood lactate concentrations and pH (r=0.27), base excess (r=0.17), or serum bicarbonate concentrations (r=-0.18). There was no relation between peak lactate concentration (PLC) and base excess (r=0.16), and only a weak correlation between peak lactate concentration (PLC) and pH (r=0.28). Negative base excess was an insensitive indicator of raised lactate concentrations. Only two out of 33 (6%) instances of hyperlactataemia (lactate >2.5 mmol/l) would have been identified with a base excess <-10 mmol/l as a cutoff. Lower cutoff values of base excess or pH performed no better. Raised lactate concentrations were associated with increased mortality at all levels. While six of 53 (11%) infants with a PLC <2.5 mmol/l died, this proportion increased to four of 15 (27%) with a PLC between 2.5-5.0 mmol/l, and four of seven (57%) with a PLC >5.0 mmol/l. Infants showing little rise or a substantial fall in blood lactate fared better than those with persistently raised values. A clinically important increase in blood lactate preceded the development of clinical markers of deterioration and complications in six infants. CONCLUSIONS Contrary to popular belief, pH or base excess cannot be used as proxy measures for blood lactate concentration, and independent measurements of the latter are needed. Blood lactate concentrations may provide an early warning signal and important prognostic information in ill, ventilated neonates. In this regard, serial measurements of blood lactate are more useful than a single value.

Sudden infant death syndrome and sleeping position in pre-term and low birth weight infants: an opportunity for targeted intervention

Aims: To determine the combined effects of sudden infant death syndrome (SIDS) risk factors in the sleeping environment for infants who were “small at birth” (pre-term (<37 weeks), low birth weight (<2500 g), or both). Methods: A three year population based, case-control study in five former health regions in England (population 17.7 million) with 325 cases and 1300 controls. Parental interviews were carried out after each death and reference sleep of age matched controls. Results: Of the SIDS infants, 26% were “small at birth” compared to 8% of the controls. The most common sleeping position was supine, for both controls (69%) and those SIDS infants (48%) born at term or ⩾2500 g, but for “small at birth” SIDS infants the commonest sleeping position was side (48%). The combined effect of the risk associated with being “small at birth” and factors in the infant sleeping environment remained multiplicative despite controlling for possible confounding in the multivariate model. This effect was more than multiplicative for those infants placed to sleep on their side or who shared the bed with parents who habitually smoked, while for those “small at birth” SIDS who slept in a room separate from the parents, the large combined effect showed evidence of a significant interaction. No excess risk was identified from bed sharing with non-smoking parents for infants born at term or birth weight ⩾2500 g. Conclusion: The combined effects of SIDS risk factors in the sleeping environment and being pre-term or low birth weight generate high risks for these infants. Their longer postnatal stay allows an opportunity to target parents and staff with risk reduction messages.

Metabolic adaptation in small for gestational age infants.

Hypoglycaemia has long been recognised as a feature of the failure of metabolic adaptation in infants who are small for gestational age (SGA). This study examined the process of metabolic adaptation by measuring, longitudinally, the concentrations of metabolic fuels and substrates in 33 SGA infants in the first postnatal week, and relating these to cross sectional data in 218 infants of appropriate weight for gestational age (AGA). SGA term infants had higher mean blood lactate concentrations than AGA term infants at delivery (2.98 v 2.10 mmol/l) and in the first few postnatal hours (3.05 v 1.91 mmol/l). Subsequently, although there were no differences in blood glucose concentrations, SGA term infants had lower mean ketone body concentrations (for example day 2: 0.07 v 0.41 mmol/l), and failed to mount a ketogenic response to low blood glucose concentrations. At birth, SGA preterm infants had lower mean blood glucose concentrations than AGA preterm infants (3.17 v 4.16 mmol/l), but there were few postnatal metabolic differences between the two groups. Mean blood glucose concentrations did not differ between AGA and SGA preterm infants. For variables that differed between the groups, multiple regression analysis suggested that both the degree and asymmetry of growth retardation were related to the severity of the metabolic abnormalities. These data suggest that, although there are early metabolic differences between SGA and AGA infants, it is possible that current clinical management is effective in preventing subsequent hypoglycaemia. This is important because of the failure of SGA infants to mount a ketogenic response.

The role of pancreatic insulin secretion in neonatal glucoregulation. I. Healthy term and preterm infants.

The glucoregulatory role of insulin in adult subjects is undisputed. However, less is known about the secretion of insulin and its actions in the neonatal period, either for healthy subjects, or for those at risk of disordered blood glucose homoeostasis. The relationships between blood glucose and plasma immunoreactive insulin concentrations were therefore examined in 52 healthy children (aged 1 month-10 years), 67 appropriate birth weight for gestational age (AGA) term infants, and 39 AGA preterm neonates. In children and AGA neonates, plasma immunoreactive insulin concentration was positively related to blood glucose concentration. However, although both groups of neonates had significantly lower blood glucose concentrations than children, plasma immunoreactive insulin concentrations were significantly higher in both term and preterm neonates, when compared with children. The variation in plasma immunoreactive insulin concentrations was greater for neonates than for children. These data suggest, that compared with older subjects, plasma immunoreactive insulin concentrations are high in newborn babies and that neonatal pancreatic insulin secretion is less closely linked to circulating blood glucose concentrations. There are important implications for the interpretation of studies in hypoglycaemic and hyperglycaemic neonates.

Prevention and management of neonatal hypoglycaemia.

lines the evidence for a ketogenic response by term infants to blood glucose concentrations as low as <2-0 mmol/l. Therefore, it is not possible to claim that counter-regulation has failed if only blood glucose concentrations are measured. We feel that the presence of symptoms or the features of an underlying disorder are more important determinants of treatment than the blood glucose concentration alone, and would suggest that treating all asymptomatic term infants with blood glucose concentrations transiently below 2-0 mmol/l with intravenous glucose is over aggressive management. If clinicians are not comfortable with blood glucose concentrations as low as this, we suggest that the first line of treatment should be to increase enteral feed volumes and frequency with formula supplementation of breast feeds, and check postprandial increases in blood glucose concentration, rather than to separate mother and baby and commence invasive management. In fact, we do not agree that enteral feeds should be withheld from hypoglycaemic infants who have previously tolerated milk feeds, as there is no scientific support for Dr Mehtas speculation in section c (1) (iii) and he has not examined the effect of withholding enteral feeds on ketone body production. Rather, milk contains more energy/ml than 10% dextrose and its high fat content will provide substrate for ketogenesis. In addition, there is published evidence that enteral feeding may stimulate glucagon release and ketone body production.4 5 We agree that adequate intakes of intravenous glucose or enteral milk prevent hypoglycaemia in most preterm infants, but point out that there is a high prevalence of hypoglycaemia in preterm infants who are fluid restricted.5 In summary, we feel that it is inappropriate and potentially confusing to base the management of neonatal hypoglycaemia on hypotheses which are not fully scientifically tested. However, it should be noted that there is agreement between the two papers on the identification of groups at risk of failure of metabolic adaptation. J M HAWDON M P WARD PLATT A AYNSLEY-GREEN

Hormonal and metabolic response to hypoglycaemia in small for gestational age infants.

Little is known of the ability of hypoglycaemic infants who are small for gestational age (SGA) to mount the coordinated hormonal and metabolic counterregulatory response that is seen in healthy older subjects during glycopenia. This response was studied in 22 SGA infants (birth weight < 10th centile) by measuring the blood concentrations of glucose, intermediary metabolites, and glucoregulatory hormones. Plasma non-esterified fatty acid and blood ketone body concentrations were low, even when blood glucose concentrations were low. Plasma insulin and glucagon varied widely (< 1.0-53.1 mU/l and 16.6-87.1 pmol/l, respectively). Concentrations of noradrenaline and glucagon were raised, but cortisol and adrenaline were lower than those found in hypoglycaemic adults. There was no relationship between the concentration of any hormone and blood glucose concentration. We postulate that hypoglycaemia and the failure to mobilise alternative fuels in some SGA infants is secondary both to a poorly coordinated counterregulatory hormone response and to a peripheral insensitivity to the actions of the hormones. Those infants, who fail to mount a counterregulatory response, should be identified by accurate and reliable blood glucose monitoring, and an adequate exogenous supply of energy, either enteral or parenteral, should be ensured.

Repeat testing for congenital hypothyroidism in preterm infants is unnecessary with an appropriate thyroid stimulating hormone threshold

Background: Revised UK neonatal screening guidelines recommend that a second blood sample for assay of thyroid stimulating hormone (TSH) be taken when preterm infants reach a postmenstrual age of 36 weeks. Objective: To examine the results of a regional screening programme to see whether a rise in TSH concentration was observed in some preterm infants between the first sample taken around 5 days after delivery and the second sample taken at around 36 weeks. Methods: Whole-blood TSH concentrations in preterm infants born over a 2-year period (April 2005 to March 2007) were assessed, and the number of infants in whom there was a fall or rise to values below or above the local screening threshold (6 mU/l) was determined. Results: Baseline TSH samples were obtained from 2238 preterm infants (median gestational age 32 weeks, range 21–35) with second samples obtained from 2039 (median gestational 32 weeks, range 23–35). In 19 infants, TSH concentrations fell from above to below the screening threshold, and in five infants values rose from below the screening threshold to 6–10 mU/l. However, TSH concentrations fell to <6 mU/l on a further blood spot in four of these infants, and the remaining infant had a serum TSH of 6.8 mU/l. Three infants had raised TSH concentrations on both occasions with unequivocal hypothyroidism (serum TSH >80 mU/l). The initial TSH concentration in one of these infants was 6–10 mU/l. Conclusions: No infant with a normal TSH concentration on first sampling had a TSH concentration that rose above 10 mU/l on second sampling, and no infants with a normal TSH concentration on first screening are receiving long-term thyroxine treatment. This study suggests that a second sample may not be necessary with a screening threshold of 6 mU/l.

The role of pancreatic insulin secretion in neonatal glucoregulation. II. Infants with disordered blood glucose homoeostasis.

Some neonates, such as those who are preterm or small for dates, become hypoglycaemic or hyperglycaemic. These disorders represent a failure of neonatal metabolic adaptation, but the underlying mechanisms are unclear. Data from studies of hypoglycaemic and hyperglycaemic infants were reviewed in the light of new data from studies of healthy neonates. Data from 28 neonates, who had disordered blood glucose homoeostasis, were analysed to determine the interrelationships between circulating concentrations of glucose, intermediary metabolites, glucagon and insulin, and glucose production rates. Blood glucose concentrations ranged from 2.5 to 26.1 mmol/l, and glucose production rates from 0 to 19.2 mg/kg/min. Blood glucose concentrations were positively related to intravenous glucose infusion rates and to glucose production rates. A negative relationship existed between plasma glucagon and blood glucose concentrations, but there was a wide variation in plasma insulin levels at all blood glucose concentrations. No relationship between either plasma insulin or glucagon concentration and glucose production rate was shown. It is concluded that in neonates with disordered blood glucose homoeostasis, blood glucose concentration is influenced by the rate of administration of glucose, with less precise internal control mechanisms than older subjects. This emphasises the importance of blood glucose monitoring and careful prescribing of exogenous glucose by clinicians caring for such infants.

Neonatal blood glucose concentrations: metabolic effects of intravenous glucagon and intragastric medium chain triglyceride.

Neonatal hypoglycaemia is a common clinical problem and the traditional treatment for the condition is intravenous glucose administration. The glycaemic effects of two additional treatments were investigated, in a randomised trial, in 23 neonates who were receiving intravenous glucose as treatment for hypoglycaemia. Eleven infants received an intravenous bolus dose of glucagon (200 micrograms/kg) and 12 infants received intragastric medium chain triglyceride (MCT) (5 ml/kg). Blood concentrations of glucose and intermediary metabolites were measured before and one hour after treatment, and, using stable isotope infusion, glucose production rates were calculated. After glucagon, there was a mean rise in blood glucose concentration of 1.6 mmol/l and in the glucose production rate of 2.6 mg/kg/min. After MCT, there was a small mean rise in blood glucose concentration of 0.4 mmol/l, but the effect of MCT on glucose production rate was variable. Intravenous bolus glucagon administration exerted a glycaemic effect which was associated with an increase in glucose production rate. The use of glucagon, as an alternative treatment to intravenous glucose, should be investigated further.