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Review Article
1
Department of Pharmaceutical Services, West Virginia University Hospitals, Morgantown, West Virginia; 2Division
of Neonatology, Department of Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia
While hypoglycemia occurs commonly among neonates, treatment can be challenging if hypoglycemia
persists beyond the first few days of life. This review discusses the available treatment options for both tran-
sient and persistent neonatal hypoglycemia. These treatment options include dextrose infusions, glucagon,
glucocorticoids, diazoxide, octreotide, and nifedipine. A stepwise, practical approach to the management
of these patients is offered.
Hypoglycemia continues to represent a com- During fetal life, glucose passively diffuses
mon metabolic issue facing the neonatal popu- across the placenta, using a concentration gradi-
lation. Both healthy and ill-appearing neonates ent. This process results in a fetal plasma glucose
can be affected by hypoglycemia during the first concentration approximately 70% to 80% of that
days of life. Factors placing neonates at higher of the maternal venous plasma glucose concen-
risk for developing hypoglycemia are prema- tration.8 Insulin does not cross the placenta; there-
turity, perinatal stress1 or asphyxia2, small size fore, the fetus must secrete insulin independently.
for gestational age,1,2 and being born to diabetic With the clamping of the umbilical cord, the
mothers.3 The goals of treating low-serum glu- neonates supply of glucose ceases while insulin
cose concentrations are to prevent poor neurode- secretion continues. The residual fetal insulin
velopmental outcomes4 and to encourage normal leads to a rapid decline in plasma glucose within
feeding behaviors.5 Should the hypoglycemia the first hours of life.10 To overcome decreasing
persist, another goal for the medical team is to glucose concentrations, the release of counterregu-
determine the underlying cause. latory hormones such as glucagon and cortisol in
The definition of hypoglycemia remains contro- combination with the production of endogenous
versial.6,7 Approaches to defining hypoglycemia glucose through gluconeogenesis and glycoge-
have included a statistical approach with standard nolysis occurs. In healthy neonates, feeding is also
deviations, counterregulatory responses with a initiated within approximately 12 hours of birth,
metabolic approach, neurophysiological changes, further aiding in the increase of serum glucose
and neurodevelopmental outcomes of symptom- concentrations. If feeding cannot be initiated,
atic versus asymptomatic hypoglycemia.8 Using other metabolic substrates such as ketones will
any of these techniques alone has not provided a likely increase to offset the effects of lower glucose
clear definition of hypoglycemia. Considering the concentrations. Transient hypoglycemia can occur
lack of data to support a definitive breakpoint for during the first hours of life because of a slow or
serum glucose concentrations, general consensus immature fasting adaptation process.
appears to accept the definition of concentration
less than 47 mg/dL as hypoglycemia in need of GLUCOSE HOMEOSTASIS
intervention, although for practical purposes less
than 50 mg/dL is generally used.6,9 Insulin and glucagon are released from pan-
J Pediatr Pharmacol Ther 2013 Vol. 18 No. 3 www.jppt.org 199
JPPT CB Sweet, et al
creatic islet cells during the fed and fasting states. often secrete higher amounts of insulin to accom-
-cells within islet cells contain ATP-sensitive modate for excess fetal glucose concentrations.
potassium channels (KATP channels) and volt- Preterm neonates and small-for-gestational-age
age- gated calcium channels (VGCC) that coor- infants have fewer glycogen and fat stores than
dinate the secretion of insulin; while glucagon is full-term neonates.8 This lack of storage in com-
secreted from -cells. bination with high insulin levels15 places them
Increasing glucose concentrations activate at risk for hypoglycemia. Birth asphyxia and
glucokinase, and -cell glycolysis begins. This perinatal stress increase the risk of hyperinsulin-
glycolytic pathway along with free fatty acids ism in the neonatal period because of the use of
increases adenosine triphosphate (ATP) produc- anaerobic metabolism to maintain blood glucose
tion within the -cell. KATP channels consist of two concentrations.2 Transient hypoglycemia in these
subunits, the sulfonylurea (SUR) and the inward patients is a common occurrence during the first
rectifier potassium channel (Kir6.2) subunits. The hours to days of life.
increase of ATP activates the SUR subunit, which Congenital conditions such as Beckwith-Wie-
closes the KATP channel. With the closing, depolar- demann, Mosaic Turner syndrome, and Costello
ization of the cell occurs, leading to an influx of syndromes have also been linked to hyperinsu-
Ca2+ through the VCGG, stimulating the release linemia and subsequent hypoglycemia.16,17 These
of insulin.11 In contrast, decreasing glucose con- patients may experience a more prolonged hy-
centrations during the fasting state stimulate the perinsulinism lasting from several days to weeks.
release of glucagon. The exact mechanism is not Persistent hyperinsulinemic hypoglycemia of in-
completely understood; however, the mechanism fancy (PHHI), previously termed nesidioblastosis
may also be related to KATP channels within the and congenital hyperinsulinism of infancy, is a
-cells.12 Glucagon helps regulate gluconeogen- rare condition that presents treatment challenges.
esis and glycogenolysis within the liver as a It is associated with persistently elevated levels
counterregulatory agent to insulin. of circulating insulin caused by hypersecretion
Exaggerated insulin secretion from -cells can by pancreatic -cells and an absence of ketone
occur during the first few hours to days of life, production. PHHI may present in the first few
resulting in hyperinsulinemia, which is the lead- days of life or may present later in infancy.11
ing cause of hypoglycemia in neonates.5 Many Many different metabolic disorders can also lead
mechanisms have been associated with this to persistent hypoglycemia, including glycogen
hypersecretion of insulin. The most prevalent storage disorders, disorders of gluconeogenesis,
cause of persistent hyperinsulinemia is the loss and fat oxidation.18
of function mutation of the KATP channel, which Understanding the glucose adaptation pro-
may lead to profound hypoglycemia. Other less cess that occurs shortly after birth, conditions
common mechanisms include mutations of mi- leading to transient hypoglycemia, and the
tochondrial enzyme (GDH), activating mutation possible conditions affecting insulin secretion
in glucokinase, and mutations of short-chain is necessary prior to selecting treatment. For
3-hydroxyacyl-coenzyme A dehydrogenase.5 Hy- infants experiencing transient hypoglycemia,
perinsulinemia may be of a transient, prolonged, an extensive diagnostic workup is not necessary.
or persistent nature, leading to various degrees If persistent hyperinsulinism is suspected, the
of severity of hypoglycemia. diagnostic workup will include plasma insulin,
-hydroxybutyrate, and free fatty acid levels.
TRANSIENT VERSUS PERSISTENT Additional tests may include plasma ammonia
HYPOGLYCEMIA levels, plasma acyl-carnitine profile, and urine
organic acids.5 The underlying cause of hypogly-
Factors related to transient hypoglycemia cemia and severity will also dictate the approach
are often related to conditions or events occur- to management.
ring during birth. Infants of mothers receiving
intravenous dextrose during delivery 13 and THERAPEUTIC MANAGEMENT
those treated with hypoglycemic agents dur-
ing pregnancy14 have been linked to neonatal There are several treatment options available
hypoglycemia. Infants born to diabetic mothers for the management of neonatal hypoglycemia
200 J Pediatr Pharmacol Ther 2013 Vol. 18 No. 3 www.jppt.org
Strategies for Neonatal Hypoglycemia JPPT
Table. Pharmacologic Agents for Treatment of Neonatal Hypoglycemia
Agent Dosing Administration Side Effectsa
(Table); however, selecting the appropriate in- Dextrose concentrations of up to 20% to 25%
tervention can be challenging as the underlying may be required in order to deliver glucose in-
cause may take weeks to diagnose. Therefore, fusion rates in the 15 to 30 mg/kg/min range.5
during the diagnostic process, it is important to Glucose infusions rates of up to 30 mg/kg/min
prevent or minimize periods of hypoglycemia have been used in patients unresponsive to lower
in an effort to mitigate potential adverse neuro- rates.21 Most of these patients will require the
logical outcomes caused by insufficient glucose placement of central lines in order to deliver a
availability for optimal brain function. sufficient amount of dextrose in a volume that
does not overload the patient with fluids. Pe-
Dextrose ripheral access can be a concern not only from
Hyperinsulinism is the most common cause of a volume perspective but also because of the
both transient and persistent/permanent forms hypertonicity of dextrose infusions. Concentra-
of neonatal hypoglycemia. Administration of tions greater than 12.5% must be administered
dextrose titrated to maintain euglycemia is the using a central line.22 Because these patients
most practical and expedient initial approach.5 require frequent serum glucose monitoring, it
Dextrose infusions may be used regardless of may be prudent to place an arterial line until
the presence of enteral feeds. Conventionally, a stable euglycemia is established to minimize or
2 mL/kg to 3 mL/kg (200300 mg/kg) intrave- prevent pain and tissue damage to the infants
nous bolus of 10% dextrose is given, followed by heels, toes, and fingers.
a continuous infusion.8,19 Initial glucose infusion If patients continue to experience hypogly-
rates generally used for full-term infants are 4 to cemia episodes with a glucose infusion rate
6 mg/kg/min, while rates for premature infants of approximately 20 mg/kg/min, additional
may be 6 to 8 mg/kg/min.6 An isotope tracer therapeutic options may need to be explored, if
study noted that the glucose production rate of the infants serum glucose cannot be maintained
the liver in a single-term neonate was approxi- above 60 mg/dL.6 Unfortunately, the issue of
mately 5 mg/kg/min.20 Glucose infusion rates when to progress to additional therapies for
should be titrated to achieve euglycemia, and hypoglycemia is not well described. Many case
hypoglycemic infants may require considerably reports begin to use additional medications after
higher rates. the glucose infusion rate remains at 12 mg/kg/
min without the ability to wean therapy. The lutions in addition to the volume required to ad-
times of additional interventions in these case minister the glucagon. There are reports of crys-
reports vary greatly from within the first 36 hours tallization of glucagon when delivered in small
of life23 to 7 to 10 days of life.24 It may be prudent volumes, resulting in occlusion of intravenous
to delay additional therapies as long as possible catheters. Further diluting the glucagon solution
(up to 14 days of life) to allow the transient forms and or changing the solution more frequently
of hypoglycemia to resolve in order not to expose than once a day may minimize the problem of
infants to unnecessary drug therapy. Other than crystallization. Monitoring of serum sodium
the infant who continues to experience consistent should be conducted while receiving glucagon
episodes of hypoglycemia or requires persistent- therapy. Other rare adverse effects described
ly high dextrose concentrations (>D25%), most in case reports include thrombocytopenia and
infants should remain on dextrose infusions for a rare cutaneous paraneoplastic phenomenon,
at least 7 to 10 days before the addition of other erythema necrolyticum migrans.23,29
therapeutic options is considered. However,
infants who continue to experience profound Glucocorticoids
hypoglycemia while receiving dextrose infusions The use of glucocorticoids, as an acute treat-
may benefit from additional short-term therapy ment of hypoglycemia, has been advocated
options such as glucagon and glucocorticoids. by some.30 Data to support this use are limited
During this time, the focus should remain on the to case reports; however, dosing is found in
differential diagnosis. common tertiary references. Physiologically
glucocorticoids reduce insulin secretion and
Glucagon increase insulin resistance as well as enhancing
Endogenous glucagon is secreted from both gluconeogenesis and glycogenolysis. In
-cells in the pancreas as a counterregulatory theory these effects should induce an increase
hormone of insulin. Under normal physiologic in serum glucose concentrations. Dexametha-
conditions, hypoglycemia will induce the secre- sone23 and hydrocortisone31,32 have been used
tion of glucagon to raise serum glucose levels. to treat hypoglycemia. In case reports, patients
Glucagon injections have been used for many received glucocorticoids at varying stages during
years in neonatal intensive care units for the the treatment process (initially versus salvage).
treatment of hypoglycemia. Glucagon has dem- Belik et al.23 gave a 35-week-gestation infant
onstrated less effectiveness in infants with PHHI dexamethasone at 0.25 mg/kg every 12 hours;
or familial hyperinsulinism.25 However, glucagon however, the infant later required glucagon
is quite effective in elevating serum glucose therapy. Two other investigators, Bhownick et
concentrations in preterm and term neonates not al.31 and Lindley et al.,32 gave hydrocortisone at
exhibiting hyperinsulinemia.27,28 2.5 mg/kg/dose intravenously every 6 hours
Intermittent glucagon doses have been vari- to a small-for-gestational-age term infant and
able. Doses have ranged from 200 mcg/kg to 50 mg/m2/day intravenously divided every 6
as low as 3 mcg/kg in a single patient.26 More hours to a 31-week gestation female, respectively.
commonly, glucagon is given as a continuous Both patients required additional therapies after
infusion over 24 hours. Doses range from 20 to 40 the addition of steroids for prolonged glycemic
mcg/kg/hr in sick, preterm infants to a flat dose control.
of 1 mg/day infused over 24 hours for infants Systemic glucocorticoid therapy carries sig-
regardless of gestational age or birth weight.27,28 nificant risks. Common side effects associated
Reports of severe hyponatremia with the use of with glucocorticoid therapy include growth
glucagon have drawn attention to potential risks suppression, feed intolerance, and hypertension.
associated with this therapy.23 Hypertonic saline Preterm, very-low-birth weight infants treated
(3% sodium chloride) has been used to treat with hydrocortisone have an increased risk of
hyponatremia in infants receiving glucagon.25 spontaneous perforation of the gastrointestinal
While the use of glucagon may contribute to tract.33 In addition, glucocorticoids may unneces-
the decrease in serum sodium, another possible sarily elevate blood pressure in patients without
explanation is a dilutional effect decrease caused hypotension and may increase the risk for ad-
by the large volumes of intravenous dextrose so- verse neurodevelopmental outcomes.34
Asymptomatic Symptomatic
Euglycemia Hypoglycemia
achieved persists
Bolus D10
May consider (2 mL/kg)
continuous feeds
Ketotic Non-ketotic
or underlying cause. Further studies in PHHI are 5. De Leon DD, Stanley CA. Mechanisms of
still needed to develop a more consistent treat- disease: advances in diagnosis and treat-
ment approach; however, given its rarity, a mul- ment of hyperinsulinism in neonates. Nat
ticenter strategy would best address the problem Clin Pract Endocrinol Metab. 2007;3(1):57-68.
in a timely manner. Prospective multicenter trials 6. Cornblath M, Hawdon JM, Williams
are necessary to determine the kinds of treatment AF, et al. Controversies regarding the
approaches that may maximize infants functional definition of neonatal hypoglycemia: sug-
and neurodevelopmental outcomes. gested operational thresholds. Pediatrics.
For patients in whom a metabolic disorder has 2000;105(5):1141-1145.
been diagnosed, appropriate disease-specific 7. Hay WW, Cornblath M. Historical per-
therapy should correct the hypoglycemia. There spectives: transient symptomatic neonatal
is continuing evolvement of the molecular and hypoglycemia. NeoReviews. 2003;4:e1-4.
genetic causes of congenital hyperinsulinism 8. World Health Organization. Hypoglycemia
which is beyond the scope of this review.5 The of the newborn: review of the literature.
therapies previously described are palliative in Geneva, Switzerland: World Health Or-
that they are used until the specific diagnosis can ganization;1997. http://www.who.int/
be determined. child_adolescent_health/documents/
chd_97_1/en/index.html. Accessed April
DISCLOSURE The authors declare no conflicts or finan- 24, 2013.
cial interest in any product or service mentioned in the 9. Lucas A, Morley R, Cole TJ. Adverse
manuscript, including grants, equipment, medications, neurodevelopmental outcome of moder-
employment, gifts, and honoraria. ate neonatal hypoglycaemia. Br Med J.
1988;297(6659):1304-1308.
ABBREVIATIONS ATP, adenosine triphosphate; D25, dex-
10. Srinivasan G, Pildes RS, Cattamachi G, et al.
trose 25%; KATP, ATP-sensitive potassium channels; Kir6.2,
inward rectifier potassium channel; PHHI, persistent hy-
Plasma glucose values in normal neonates
perinsulinemia hypoglycemia of infancy; SUR, sulfonylurea a new look. J Pediatr. 1986;109(1):114-117.
subunit; VGCC, voltage-gated calcium channels 11. Schwitzgebel VM, Gitelman SE. Neo-
natal hyperinsulinism. Clin Perinatol.
CORRESPONDENCE Courtney B. Sweet, PharmD, BCPS, 1998;25(4):1015-1038.
West Virginia University Hospitals, Department of Pharma- 12. Munoz A, Hu M, Hussain K, et al. Reg-
cy, Medical Center Drive, Morgantown, WV 26505, email: ulation of glucagon secretion at low
sweetc@wvuhealthcare.com. glucose concentrations: evidence for
adenosine triphosphate-sensitive potas-
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