Compensatory increase of CBF in preterm infants during hypoglycaemia

Cerebral blood flow (CBF00) was investigated in 24 preterm infants (mean 30.8 weeks of gestational age) by use of intravenous 133-Xe clearance technique while screening simultaneously for low blood glucose after birth (mean 3 hours). CBF was significantly increased in 10 infants with blood glucose lower than 1.7 mmol/l compared to normoglycaemic infants and tended to decrease rapidly after treatment. Nine of the 10 hypoglycaemic infants were monitored for cerebral function. Well defined visual evoked cortical potentials were elicitable in all and the aEEG was not less active during the hypoglycaemic episode. Therefore, it is suggested that compensatory increase of CBF may have supported the cerebral metabolism during uncomplicated hypoglycaemia.     

Compensatory Increase of CBF in Preterm Infants during Hypoglycaemia

ABSTRACT. Cerebral blood flow (CBF₀₀) was investigated in 24 preterm infants (mean 30.8 weeks of gestational age) by use of intravenous 133-Xe clearance technique while screening simultaneously for low blood glucose after birth (mean 3 hours). CBF was significantly increased in 10 infants with blood glucose lower than 1.7 mmol/l compared to normoglycaemic infants and tended to decrease rapidly after treatment. Nine of the 10 hypoglycaemic infants were monitored for cerebral function. Well defined visual evoked cortical potentials were elicit-able in all and the aEEG was not less active during the hypoglycaemic episode. Therefore, it is suggested that compensatory increase of CBF may have supported the cerebral metabolism during uncomplicated hypoglycaemia.     

Clinical and metabolic consequences of two regimens of total parenteral nutrition in the newborn

The clinical and metabolic effects of two regimens of total parenteral nutrition delivering the same amino-acid (2·8 g/kig per 24 h), fat (4·8 g/kg per 24 h), and glucose (12 g/kg per 24 h) load over 24 hours were studied. The regimens differed in the distribution of the infusate during the 24-hour period. With the continuous regimen (7 infants) all nutrients were infused together at a constant rate, whereas with the sequential regimen (9 infants) the daily doses of Vamin/glucose and Intralipid were infused together, followed by the glucose dose. The infants studied had a mean birthweight of 2·8 kg and mean gestational age of 37·9 weeks. Blood levels of glucose, lactate, pyruvate, 3-hydroxybutyrate, acetoacetate, alanine, glycerol, and insulin were measured longitudinally from day 1 to day 21 of total parenteral nutrition. The 7 infants who received the continuous regimen had blood metabolite levels comparable with those of infants fed enterally, with minor fluctuations. Insulin levels were higher than in enterally-fed infants. The 9 infants who received the sequential regimen had wide fluctuations in alanine, glycerol, insulin, 3-hydroxybutyrate, and acetoacetate levels with high peak levels of ketones at the end of the Vamin/glucose and Intralipid infusion, falling to low levels at the end of the 24-hour cycle. There was a gradual reduction in the peak ketone levels from day 6-8 to day 18-21. Clinically unsuspected hypoglycaemia occurred on 6 occasions in each group of infants. There was no significant difference in the incidence of jaundice or infection between the two groups, and the weight velocity during total parenteral nutrition was similar. Wide fluctuations in the infusion rates of individual substrates should be avoided during total parenteral nutrition in the newborn.     

Neurodevelopmental outcome of hypoglycaemia in healthy, large for gestational age, term newborns

AIMS: To evaluate the effects of transient hypoglycaemia on the first day of life in 75 healthy term large for gestational age (LGA) infants, born to non-diabetic mothers, on their neurodevelopmental outcome at the age of 4 years. METHODS: Screening for hypoglycaemia was performed 1, 3, and 5 hours after birth, and continued if blood glucose levels were low. Treatment with intravenous glucose for hypoglycaemia was started if hypoglycaemia was severe or symptomatic. Patients' development and behaviour was examined at the age of 4 years by the Denver Developmental Scale, a non-verbal intelligence test, and the Child Behaviour Check List. RESULTS: There were no significant differences between children with neonatal normoglycaemia (n = 15) and hypoglycaemia (plasma glucose <2.2 mmol/l 1 hour after birth, or <2.5 mmol/l subsequently; n = 60) in Denver developmental scale scores and child behaviour checklist scores. Although total IQ did not differ between hypoglycaemic and normoglycaemic children, one subscale (reasoning) did (mean difference 9.3, 95% CI 1.3 to 17.2). The correlation between reasoning IQ and neonatal blood glucose levels was weak and not statistically significant. When other definitions for hypoglycaemia were applied, the difference in reasoning IQ was not found. There were no differences in any of the test scores between hypoglycaemic children who had and who had not been treated with intravenous glucose. CONCLUSION: Transient mild hypoglycaemia in healthy, term LGA newborns does not appear to be harmful to psychomotor development at the age of 4 years.     

Hypoglycaemia and the neonatal brain

There has been much controversy and confusion regarding potential damage caused to the neonatal brain by low blood glucose levels. Previous studies of outcome after neonatal hypoglycaemia are flawed by many factors including retrospective data collection and inability to control for co-existing clinical complications. There is no doubt that hypoglycaemic brain damage does occur but the severity and duration of low blood glucose levels required to cause lasting harm varies between subjects and is related to the ability of each baby to mount a protective response such as the production of ketone bodies which are alternative cerebral fuels. Evidence from studies of humans and other animals suggests that cortical damage and long-term sequelae occur after prolonged hypoglycaemia sufficiently severe to cause neurological signs. Conclusion Prolonged hypoglycaemia should be avoided by close clinical observation of vulnerable infants whilst avoiding excessively invasive management in populations of neonates which may jeopardise the successful establishment of breast feeding.     

Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate

AIMS: To define, in a prospective study, the risk of hypoglycaemia-defined as blood glucose concentration < 1.8 mmol/l-in term infants exposed in utero to valproate and to describe the withdrawal symptoms. METHODS: Twenty epileptic women were treated with valproate only during pregnancy and two were treated with valproate and carbamazepine. In the first trimester, the daily median dose of valproate was 1.0 g (range 0.3-4.2) and in the third trimester 1.2 g (range 0.3-4.8). RESULTS: Thirteen of the 22 infants became hypoglycaemic. One infant had eight episodes of hypoglycaemia, one had three episodes, two had two episodes, and nine had one episode each. The lowest blood glucose concentration was 1.0 mmol/l. All episodes were asymptomatic. The maternal mean plasma concentration of total valproate during the third trimester correlated negatively with blood glucose concentration one hour after delivery (p < 0.0003) and with the development of hypoglycaemia (p < 0.0001). There was no evidence for hyperinsulinaemia as the cause of hypoglycaemia. Ten infants developed withdrawal symptoms, which correlated positively with the mean dose of valproate in the third trimester and the concentration of the free fraction of valproate in maternal plasma at delivery (p < 0.02). CONCLUSIONS: Infants exposed to valproate in utero had a significantly elevated risk of hypoglycaemia, and withdrawal symptoms were often observed.     

Pitfalls in the diagnosis of congenital hyperinsulinism: a case report and review of the literature

BACKGROUND: Congenital hyperinsulinism is the most common cause for recurrent hypoglycaemia in neonates and infants. Uncontrolled hypoglycaemia leads to seizures and long-term cerebral damage. Often, the diagnosis is delayed because of nonspecific symptoms and confusing laboratory results. PATIENT: We report a patient with hyperinsulinism who was initially wrongly diagnosed as having idiopathic cerebral convulsions and treated accordingly. CONCLUSIONS: Diagnosis of congenital hyperinsulinism is based on a strong suspicion and a thorough family history. Normal random blood glucose or random insulin levels are not helpful in excluding this disease.     

Neonatal hypoglycaemia in infants of diabetic mothers

OBJECTIVE: To determine whether umbilical cord blood glucose correlates with subsequent hypoglycaemia after birth in infants of well-controlled diabetic mothers. METHODOLOGY: Thirty-eight term infants of well-controlled diabetic mothers were enrolled. Five mothers had pre-existing diabetes. Of the 33 gestational diabetic mothers, 16 were managed on insulin and 17 on diet. Maternal blood glucose was maintained between 4 and 8 mmol/L during labour and delivery. Infants' plasma glucose levels were measured from venous cord blood and serially, at less than 30 min, 1 h and 2 h of life by glucose hexokinase method. Blood glucose levels were further monitored by bedside Dextrostix for 24 h. RESULTS: Eighteen (47%) infants developed hypoglycaemia (blood glucose level less than 2 mmol/L) during the first 2 h of life. There was no difference in the cord blood glucose levels between infants with or without hypoglycaemia (3.7 +/- 1.1 vs 4.5 +/- 1.1 mmol/L, respectively). Infants of mothers with diabetes diagnosed prior to 28 weeks gestation were at a higher risk of developing hypoglycaemia (8 of 10 vs 10 of 28, OR 7.2, 95%CI 1.3-40.7). Hypoglycaemic infants were of significantly higher birthweight, and were more likely to be born to Caucasian mothers and by Caesarean section. Raised maternal fructosamine blood level, the need for insulin treatment or the infant's haematocrit were not different between infants with or without hypoglycaemia. CONCLUSIONS: In well-controlled diabetic mothers, the incidence of early hypoglycaemia in infants is still high, particularly in those mothers who had a longer duration of diabetes. Cord blood glucose level did not identify the infants with hypoglycaemia.     

CLINICAL ASPECTS OF NEONATAL HYPOGLYCAEMIA

ABSTRACT. Fluge, G. (Department of Paediatrics, University of Bergen, Bergen, Norway). Clinical aspects of neonatal hypoglycaemia. Acta Paediatr Scand, 63: 826, 194.—Fifty cases of neonatal hypoglycaemia were detected by routine blood glucose determination in 323 low birth weight infants during a three-year period (15.4%) and, in addition, hypoglycaemia was diagnosed in 17 full-term infants. The patients were divided in three groups according to clinical findings, with special reference to age at diagnosis, pretreatment blood glucose values and duration of hypoglycaemia. In asymptomatic hypoglycaemia the diagnosis was made during the first few hours after birth, and the mean pretreatment blood glucose value was 14 mg/100 ml. Except for one patient, the hypoglycaemia was of short duration. Symptomatic, transient hypoglycaemia was characterized by a delay in onset of symptoms until the second and third day after birth, low pretreatment blood glucose level and hypoglycaemia of long duration. Hypoglycaemia associated with other neonatal disorders classified as secondary hypoglycaemia usually was noted during the first few hours of life, and tended to he of short duration. Frequency of hypoglycaemia in small for gestational age infants was markedly higher when toxaemia of pregnancy was noted, compared with infants born to non-toxaemic mothers.     

Neonatal hypoglycaemia: clinical and legal aspects

Transiently low blood glucose levels are common in the neonatal period and may be considered a normal feature of adaptation to extrauterine life. There is no evidence that this causes brain injury in the absence of concurrent clinical manifestations. Conversely, persistent and severe hypoglycaemia may be associated with other underlying pathologies which themselves predispose to brain injury. Attribution of brain injury therefore requires demonstration of both 'significant' hypoglycaemia and a characteristic resulting pattern of brain injury. The prevention of hypoglycaemic brain injury requires early detection in infants considered 'at risk' and appropriate intervention. No single concentration of plasma glucose can be associated universally with either the appearance of clinical signs or causation of cerebral injury. For this reason we suggest that treatment be based upon 'operational thresholds' and guided by clinical assessment, not by the plasma glucose concentration alone. For example, the infant displaying neurological signs requires more urgent elevation of blood glucose concentration than the 'asymptomatic' one, regardless of the absolute plasma glucose value.     

Intravenous Glucose Tolerance and Plasma Insulin Studies in Small-for-dates Infants

A study of infants who were small-for-dates is described. A proportion of them developed hypoglycaemia, and in these, intravenously administered glucose disappeared abnormally rapidly from the blood, shown by a raised kG value. Some of these infants also showed raised levels of plasma insulin. Those with the high levels of plasma insulin showed significant change in fasting `true'' blood glucose, and mean maximum plasma insulin levels at the end of the first week of life. Hypoglycaemia of the newborn is probably more closely related to other factors as yet still undefined, than to changes in plasma insulin alone.     

Definition of neonatal hypoglycaemia: Is there a change?

Objective : To compare the definitions of neonatal hypoglycaemia in textbooks and among paediatricians in 1992 with those used in 1986. Methodology : A questionnaire was sent to 420 neonatal paediatricians in the UK and to 88 Australian neonatal paediatricians in 1992 asking for their definition of hypoglycaemia in term babies and preterm/small-for-gestational-age (SGA) babies. Fourteen textbooks on neonatal paediatrics (published since 1990) were also surveyed for the definition of hypoglycaemia used in the text. The UK paediatricians were also asked, ‘Do you believe that a baby who is hypoglycaemic but has no abnormal clinical signs is at less risk of neurological damage than a baby who is hypoglycaemic with abnormal signs?’ The 1992 results were compared with the published results of a similar survey in 1986. Results : There was a 68% response from neonatal paediatricians both in the UK and Australia. Similar to the 1986 results there continued in 1992 to be a wide range in the definition for hypoglycaemia (<1-4mmol/L) among neonatal paediatricians and in textbooks. The median of the definition of hypoglycaemia for both term and preterm/SGA babies among paediatricians and in textbooks in 1992 was significantly different from the results in 1986. Compared with 1986 there was a significant increase in 1992 in the number of paediatricians and textbooks defining a safe blood glucose concentration as being at least 2mmol/L. Sixty per cent of UK neonatal paediatricians believe that a baby who is hypoglycaemic but has no abnormal clinical signs is at less risk of neurological damage than a baby who is hypoglycaemic with abnormal signs. Conclusions : From 1986 to 1992 there was a significant change in the definition of hypoglycaemia both among paediatricians and in neonatal textbooks compared with the definition in use during 1965-86. The findings suggest that neonatal paediatricians do change in their practice. The changes in the definition of hypoglycaemia may be due to the data available and discussion on hypoglycaemia since 1988. Neonatal paediatricians still attach significance to clinical signs associated with hypoglycaemia.     

Moderate hypoglycemia in the preterm infant: is it relevant?]

Glucose monitoring and management of hypoglycaemia in preterm infants remain controversial. However, recent animal studies have shown that hypoglycaemia is associated to increased generation of reactive oxygen and nitrogen species, to inhibition of cellular maturation and to apoptosis in brain. Despite potential consequences of hypoglycaemia on brain development in preterm infants, only few studies are available on this topic. Available clinical studies on neurological development of hypoglycaemic preterm infants are not conclusive but suggest detrimental effect of repeated mild hypoglycaemia on brain development. Both experimental and clinical arguments are sufficient to mind to this problem with great awareness. Therefore, routine repeated measurements of blood glucose concentration are necessary and active intervention is proposed if glucose plasma level decreases below 2.5 mmol/l.     

Insulin induced hypoglycaemia: comparison of glucose and glycerol concentrations in plasma and microdialysate from subcutaneous adipose tissue

AIMS—To investigate the dynamics between plasma and dialysate glucose during hypoglycaemia in children.
STUDY DESIGN—Six children in prepuberty or early puberty were investigated by multiple blood sampling and microdialysis of subcutaneous adipose tissue during a standard arginine-insulin tolerance test. Glucose and glycerol, as an index of lipolysis, were measured in samples from both compartments. Plasma concentrations of insulin and the main counterregulatory hormones were also measured.
RESULTS—Plasma and dialysate glucose concentrations were very similar at baseline and increased in concert after infusion of arginine, probably in response to glucagon release. After insulin injection, glucose in both plasma and dialysate fell in parallel. The subsequent hypoglycaemic stress response induced a rapid rebound in the plasma concentration with a mean (SD) delay in the dialysate of 16 (3) minutes. Plasma glycerol was approximately fivefold lower than in the dialysate and did not fluctuate significantly. Dialysate glycerol decreased with arginine infusion and reached a nadir immediately following insulin administration. Subsequently, the antilipolytic effect of insulin was overcome by the hypoglycaemic stress response, and lipolysis prevailed in spite of hyperinsulinaemia.
CONCLUSION—After rapidly induced hypoglycaemia, rebound of interstitial glucose concentrations is significantly delayed compared with plasma concentrations, and the antilipolytic effect of hyperinsulinaemia is opposed possibly by the hypoglycaemic stress response.

     

Hyperinsulinaemic hypoglycaemia in small for dates babies.

Blood glucose concentrations were measured prospectively in 27 small for dates infants in the first 48 hours after birth: 10 infants became hypoglycaemic. Of these, five had inappropriately raised plasma insulin concentrations. Plasma free fatty acids were lower and carbohydrate intake higher in these five infants, further supporting the diagnosis of hyperinsulinism. The hypoglycaemia recurred in four of the five hyperinsulinaemic infants, but in none of those who were not hyperinsulinaemic. Hyperinsulinism is common in small for dates babies. It is important to recognise this because hypoglycaemia is likely to recur and appropriate treatment is needed to prevent long term sequelae.     

Five-hour Oral Glucose Tolerance Test in Obese Children

Concentrations of blood glucose, plasma free fatty acids, and plasma glycerol during a 5-hour oral glucose tolerance test on 46 obese children are reported.Seven children had unequivocally impaired glucose tolerance. However in the group as a whole, there was a delay in return of blood glucose to baseline levels after oral glucose, 27 children (60%) having a blood glucose concentration greater than 110 mg/100 ml at 2 hours. It was concluded that some degree of glucose intolerance is common in childhood obesity. No relation was seen among the following: impairment of glucose tolerance and age, degree or duration of obesity, or family history of diabetes.Fasting plasma free fatty acids and glycerol concentrations were high (mean ± 1SD, 1030 ± 221 μEq/litre FFA and 121 ± 44 μmol/l. glycerol). For all children, concentrations of FFA and glycerol decreased during the first hour after glucose, though minimal levels were not reached until 90-120 minutes (mean ± 1SD, 395 ± 170 μEq/litre FFA, 77 ± 24 μmol/l. glycerol). For those children (27) who had raised blood glucose at 2 hours, there was a positive correlation between fasting plasma glycerol concentration and glucose tolerance sum, suggesting that impaired glucose tolerance was associated with increased basal lipolysis.     

Isolated ACTH deficiency. Metabolic and endocrine studies in a 7-year-old boy.

Metabolic and endocrine studies on a 7-year-old boy who presented with hypoglycaemic convulsions are reported in detail, proving the diagnosis of isolated ACTH deficiency--a rare cause of hypoglycaemia in childhood. Adrenaline secretion during insulin-induced hypoglycaemia was reduced. Low blood alanine levels occurred during starvation-induced hypoglycaemia, together with raised total blood ketone bodies; blood glucose did not increase adequately after oral alanine at this time. Hypoglycaemia in isolated ACTH deficiency appears to be due to a combination of impaired alanine mobilisation and a decreased rate of gluconeogenesis.     

Nocturnal hypoglycaemia and sleep disturbances in young teenagers with insulin dependent diabetes mellitus

OBJECTIVE: To determine the effect of nocturnal hypoglycaemia on sleep architecture in adolescents with insulin dependent diabetes mellitus (IDDM). DESIGN: 20 adolescents with IDDM (mean age 12.8 years, mean glycated haemoglobin (HbA1c) 8.9%) were studied on one night. Plasma glucose was measured every 30 minutes and cortisol and growth hormone levels every 60 minutes. Sleep was recorded using standard polysomnographic montages, and sleep architecture was analysed for total sleep time, stages 1-4, rapid eye movement, fragmentation, and arousals. RESULTS: Six subjects (30%) became hypoglycaemic (five subjects < 2.5 mmol/l), with one being symptomatic. There were no differences in age, HbA1c, duration of diabetes, or insulin regimen between hypoglycaemic and non-hypoglycaemic subjects. Hypoglycaemia was not predicted by glucose measurements before bed. There was no detectable rise in plasma cortisol or growth hormone concentrations during hypoglycaemia. Sleep architecture was not disturbed by nocturnal hypoglycaemia with no differences found in sleep stages, fragmentation, or arousals. CONCLUSIONS: Nocturnal hypoglycaemia is a common and usually asymptomatic complication of treatment in adolescents with IDDM. Moderate hypoglycaemia has not been shown to affect sleep architecture adversely. These findings are consistent with, and may explain, the observation that severe hypoglycaemia, with consequent seizure activity, is more common at night than during the day. Counterregulatory hormone responses to nocturnal hypoglycaemia may be less marked than with similar degrees of diurnal hypoglycaemia.     

The predictive value of glucose utilization rate in neonatal hypoglycaemia of small-for-gestational-age infants.

The glucose utilization constant K was determined in 50 small-for-gestational-age neonates. In 11 cases the K value was higher than 2.0, and 5 out of these babies developed asymptomatic hypoglycaemia. In 39 infants the K value was under 2.0, and except in one false negative instance, no hypoglycaemia was observed. The results suggest that early determination of the glucose disappearance rate is useful in predicting the probability of hypoglycaemia.     

Abnormal blood glucose concentrations on admission to a rural Kenyan district hospital: prevalence and outcome.

AIMS: To determine the prevalence, clinical characteristics, and outcome of hypoglycaemia on admission in children at a rural Kenyan district hospital. METHODS: Observational study of 3742 children (including 280 neonates) in Kilifi District Hospital, Kenya. Main outcome measures: hypoglycaemia (blood glucose <2.2 mmol/l) and hyperglycaemia (blood glucose >10.0 mmol/l). RESULTS: Non-neonates: the prevalence of hypoglycaemia on admission was 7.3%. Severe illness, malnutrition, last meal >12 hours ago, and a positive malaria slide were independently associated with hypoglycaemia. Overall, mortality in hypoglycaemic children was 20.2% compared to 3.8% in normoglycaemic children (p < 0.001). The brunt of mortality in hypoglycaemic children was borne by those who were severely ill or malnourished (31.8%) as opposed to those who were neither severely ill nor malnourished (9.0%). Neonates: 23.0% of neonates were hypoglycaemic on admission. Inability to breast feed and weight <2500 g were independently associated with hypoglycaemia. Mortality was 45.2% compared to 19.6% in normoglycaemic neonates (p < 0.001). Hyperglycaemia was present in 2.7% of children and was associated with a higher mortality than normoglycaemia, 14.0% versus 3.8% respectively (p < 0.001). CONCLUSIONS: Hypoglycaemia is common in children admitted to a rural Kenyan district hospital and is associated with an increased mortality. Apart from features of severe illness and poor feeding, clinical signs have a low sensitivity and specificity for hypoglycaemia. Where diagnostic facilities are lacking, presumptive treatment of severely ill children is recommended. For other children, the continuation of feeding (by nasogastric tube if necessary) should be part of standard management.