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(Pediatrics in Review. 1999;20:e4-e5.)
© 1999 American Academy of Pediatrics
Introduction
Ordinarily, invited authors will write the review articles and commentaries for NeoReviews. However, as the coeditor primarily responsible for this inaugural edition, I wanted to take the prerogative to write an introduction that will set the stage for what each edition will include and explain how David Stevenson and I have developed topics, authors, content, and format. We chose the topics of hypoglycemia and hyperglycemia for this first edition for several reasons that should illustrate our vision of NeoReviews.
Hypoglycemia
Neonatal hypoglycemia is both a historical and a current "hot topic." It has been studied thoroughly and has been the subject of extensive debate, yet it remains a common problem that is difficult to define, understand, and manage. The evidence is very clear from human and animal studies that severe, prolonged hypoglycemia leads to acute neurologic injury that often can have permanent sequelae. Frequently overlooked because of this ultimate serious outcome is the more common problem of hypoglycemia leading to cellular energy failure and generalized organ dysfunction.
DEFINITION
Despite such serious and common
consequences and years of
investigation into its characteristics, the
definition of hypoglycemia remains
elusive. Fifty years ago, Norval,
Kennedy, and Berkson defined the
normal concentration range of blood
sugar (glucose) in term newborns
as 0.83 to 6.66 mmol/L (15 to
120 mg/dL), with a mean of
3.39±0.77 mmol/L (SD)
(61.0±13.8 mg/dL). Ninety-five
percent of infants had a concentration
of 2.89 to 3.89 mmol/L (52 to
70 mg/dL). Such values are
perfectly acceptable and within the
normal range today. Why, therefore, is
there still controversy over what is
considered the normal lower limit of
glucose concentration in blood or
plasma of newborns and what values
constitute hypoglycemia?
As discussed by Jane E. McGowan, MD, in this issue, many infants experience transiently low and highly variable glucose concentrations, but no data link such conditions directly to lasting neurologic impairment. Also, early surveys of preterm infants documented statistically lower "normal" glucose concentrations (ie, 1.11 to 2.22 mmol/L [20 to 40 mg/dL]) that often have been interpreted as clinically acceptable for prolonged periods despite clinical signs of hypoglycemia. Furthermore, rather inaccurate reagent strip methods of measuring glucose concentrations have led many to accept a very broad range of normal values for glucose concentrations in term or preterm newborns. In addition, animal studies show considerable variability among plasma glucose concentrations, rates of brain glucose uptake and metabolism, and neuronal function. There also is considerable variability among associated factors that should affect the relationship between plasma glucose concentration and neuronal function. These include, but certainly are not limited to, the rate of cerebral plasma flow, expression and activity of cerebral endothelial cell and neuronal glucose transporters, circulating concentrations of alternate substrates for neuronal metabolism, developmental stage of the infant, and functional aspects of the mechanisms of synaptic transport, excitotoxic neurotransmitter levels, and neuronal ion channel activity.
Thus, there appears to be no consistent threshold or lower limit single value for plasma glucose concentration below which neurologic impairment or injury invariably begins or actually develops. Not surprisingly, clinicians remain uncertain about when to say an infant is "hypoglycemic" and how aggressive to make treatment in the presence of relatively lower glucose concentrations or clinical signs of hypoglycemia.
In contrast, recent studies and management trends have indicated that the normal lower limit of glucose concentration in preterm or term newborns should be above 2.78 mmol/L (50 mg/dL). More accurate and reliable bedside methods now are available to measure blood glucose concentrations rapidly and are part of standard management. A retrospective study by Lucas et al showed greater incidences of mental and motor delays associated with increased episodes of blood glucose concentrations below about 2.66 mmol/L (48 mg/dL) in preterm infants. In support of this possible threshold value for neonatal glucose concentration, a survey study by Srinivasan et al provided mean and 95% confidence interval values of plasma glucose concentrations in normal, healthy preterm infants. Their data defined a lower 95% CI value of about 3.33 mmol/L (60 mg/dL) by the second to third day of postnatal life. Finally, a study by Marconi et al showed that healthy, normal human fetuses had umbilical venous glucose concentrations above 2.78 mmol/L (50 mg/dL) from 20 weeks' gestation to term. These data clearly demonstrate that normal human fetuses grow and develop in an environment that has a glucose concentration much closer to that in the plasma of normal term infants in postnatal life.
CLINICAL OUTCOME
The clinical outcome of neonatal
hypoglycemia also remains
uncertain, especially in relation to its
variable clinical pattern, severity, and
association with other conditions or
diseases. We still do not have
quantitative evidence, in general or in
specific cases, of how simultaneous
hypoxemia, hyperviscosity, cerebral
blood flow rate, sepsis, and many
other factors interact with plasma
glucose concentration to produce
abnormal cellular glucose uptake,
metabolism, or function that can
lead to impaired neurodevelopmental
outcome.
ETIOLOGY
Even the causes of neonatal
hypoglycemia, although generally well
understood, remain an enigma in
many clinical situations. We know
that extremely low-birthweight
(ELBW) and small for gestational
age infants have limited glycogen
reserves and, thus, a reduced
capacity for glucose production from
glycogenolysis. They also can have
limited gluconeogenesis due to low
fat stores, resulting in limited release
of free fatty acids, limited
production of glycerol, and limited
conversion of amino acids to glucose.
However, we do not know how
these processes are regulated
abnormally when severe and persistent
hypoglycemia occurs. Additionally,
abnormally persistent high insulin
concentrations can lead to
horrendously difficult cases of persistent,
severe hypoglycemia, but we do not
know how this occurs most of the
time.
The exciting developments in understanding the mechanisms of pancreatic beta-cell glucose sensing, potassium and calcium ion channel activity, and insulin secretion processes shine brightly on what has been a rather dark and poorly understood pathologic process. The fascinating findings that diabetologists are learning about insulin secretion in adults may provide important clues about how neonatal hypoglycemia can develop and get so out of hand.
Hyperglycemia
Neonatal hyperglycemia also is understood poorly, yet it is encountered commonly and frequently is frustrating. In fact, it is much more common than hypoglycemia in very preterm infants. Just when it is appropriate to increase glucose supply to provide energy and brain nutrient substrate to very small infants, the supply must be restricted in those who have hyperglycemia to prevent or treat excessively high plasma glucose concentrations. Most importantly, but often overlooked, is the strong association of hyperglycemia in the early neonatal period with increased mortality rates and poor neurodevelopmental outcomes among survivors. No one knows how this happens. Is it even the hyperglycemia that is partly at fault or is the hyperglycemia simply a marker for other, more damaging pathologic processes? If the latter is the case, what are those other processes and how are they related to hyperglycemia?
ETIOLOGY
Despite evidence defining many
causes of neonatal hyperglycemia,
which are well reviewed by Drs
Hemachandra and Cowett in this
issue, it is difficult or impossible to
determine the specific cause(s) in
individual cases. How much is due
to excessive glucose infusion? How
much is due to inadequate insulin
secretion, and how does inadequate
insulin secretion develop? How
much is due to glucose intolerance,
insulin resistance, or both, and what
are the mechanisms responsible for
these pathologic processes? How
much is due to excessive glucose
production? What are the roles of
hormones and other substrates such
as amino acids and fatty acids in the
regulation of insulin secretion,
glucose production, and glucose
utilization?
TREATMENT
Questions about treatment abound as
well. Should glucose supply be
restricted, and if so, how and to
what rate? Should insulin treatment
be used? If so, when and how?
What do amino acids, especially
leucine, glutamine, and arginine,
provide to promote insulin secretion
and insulin action? Does early, more
aggressive infusion of intravenous
amino acid actually decrease the
incidence and severity of
hyperglycemia in ELBW infants? If so, does
it do this by promoting insulin
secretion and action or by some
other mechanism?
Conclusion
If we knew the answers to the many questions about neonatal hypoglycemia and hyperglycemia, we might be much further along in more specific and beneficial prevention and treatment. We then might be able to determine how aggressive to be in preventing and treating low glucose concentrations, and what the lower limit of plasma glucose concentration should be. We also could establish whether reducing hyperglycemia is beneficial, and if so, how best to accomplish this. Clearly, neonatal hypoglycemia and hyperglycemia are both well understood and yet poorly defined, and in most clinical situations, they are managed without a clue to the specific cause(s) or what will happen following specific treatments. There is much need for further basic and clinical research.
Hopefully this inaugural edition of NeoReviews will initiate the processes that could lead to resolution of such important clinical problems. I have provided case studies of both hypoglycemia and hyperglycemia that include relevant questions for readers to consider. Each case study is followed by the review article written by experts in the field. Future editions will take issue with similarly important problems and often "hot topics." Basic science underpinnings, clinical management, and future research will be part of each edition. We look forward to a stimulating exchange of facts and ideas from both our authors and our readers.
Suggested Reading
Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycemia. Br Med J. 1988;297:1304-1308
Marconi AM, Paolini C, Buscaglia M, Zerbe G, Battaglia FC, Pardi G. The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference. Obstet Gynecol. 1996;87:937-942[Abstract]
Pildes RS, Pyati SP. Hypoglycemia and hyperglycemia in tiny infants. Clinics in Perinatology. 1986;13:351-375[Medline]
Srinivasan G, Pildes RS, Cattamanchi G, Voora S, Lilien LD. Plasma glucose values in normal neonates: a new look. J Pediatr. 1986;109:114-117[CrossRef][Medline]
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