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Experience With Intravenous Glucagon Infusions as a Treatment for Resistant Neonatal Hypoglycemia
Robin E. Miralles, MB, BCh, MRCPCH;
Abhay Lodha, MD, DM;
Max Perlman, MB, FRCPC;
Aideen M. Moore, MD, FRCPC
Arch Pediatr Adolesc Med. 2002;156:999-1004.
ABSTRACT
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Background Based on limited anecdotal evidence, glucagon is used for the management
of intractable neonatal hypoglycemia persisting in the face of high glucose
administration rates.
Objective To evaluate the short-term response of blood glucose levels to an intravenous
infusion of glucagon.
Design A retrospective observational study in which all newborns who received
glucagon infusions (usual dose, 0.5-1 mg/d) during a 5-year period were identified
(N = 55). The common causes of hypoglycemia were perinatal stress, intrauterine
growth restriction, prematurity, and maternal diabetes mellitus. Laboratory
blood glucose measurements made between 24 hours before and 72 hours after
the start of the glucagon infusion and the rates of glucose administration
during the same period were analyzed. The effects of glucagon on sodium and
platelet levels were also examined.
Setting University referral hospital.
Results A statistically and clinically significant rise in blood glucose concentration,
from a mean of 36.3 to 93.0 mg/dL (2.02-5.17 mmol/L), was observed within
4 hours of starting glucagon administration. The change was unrelated to the
cause of the hypoglycemia. The frequency of hypoglycemic episodes was significantly
reduced, and no further episodes of severe hypoglycemia (glucose level, <20
mg/dL [<1.1 mmol/L]) occurred. Five patients, 4 of whom were preterm newborns
with intrauterine growth restriction, required additional glycemic treatment.
Seventy-five percent of newborns were thrombocytopenic before starting glucagon
infusion, and in 9 newborns platelet counts decreased following glucagon infusion.
There was no hyponatremia attributable to glucagon.
Conclusion Glucagon infusions appear to be beneficial for problematic neonatal
hypoglycemia of different causes.
INTRODUCTION
GLUCOSE IS the primary fuel used by the brain and is essential for cerebral
metabolism. At birth, the healthy newborn adapts to an environment that provides
an intermittent supply of glucose. Glycogenolysis and gluconeogenesis are
therefore needed to maintain blood glucose levels.1
Insulin secretion, high in the fetus, is suppressed following delivery by
an adrenergic mechanism, and glucagon secretion is stimulated.2
Endogenous glucagon is thought to play a primary role in inducing hepatic
gluconeogenesis; under normal circumstances, levels of glucagon rise rapidly
when the umbilical cord is clamped. An impaired endogenous rise in pancreatic
glucagon has been reported in infants of diabetic mothers.3
Factors such as asphyxia, intrauterine growth restriction, prematurity, or
sepsis may disturb the metabolic transition to postnatal life so that the
release of blood glucose from the liver is insufficient to meet the newborn's
utilization rate.4 When hypoglycemia is severe
(glucose level, 0-18 mg/dL [0-1 mmol/L]) and prolonged, permanent brain injury
or death is likely to occur.5-7
However, less severe hypoglycemia (glucose level, <47 mg/dL [<2.6 mmol/L]),
even in asymptomatic newborns, may lead to neural dysfunction and subsequent
permanent neurologic impairment.8-10
Consensus is lacking on the definition of normoglycemia and hypoglycemia in
neonates, although many authorities recommend intervention if blood glucose
levels fall below 47 mg/dL (2.6 mmol/L).9, 11
A recent consensus statement suggested that intervention should be considered
for newborns with symptoms suggestive of hypoglycemia with blood glucose levels
below 45 mg/dL (2.5 mmol/L).12
In most cases, neonatal hypoglycemia responds to early feeding or intravenous
(IV) dextrose infusion given at an adequate rate. In a few newborns, this
first-line treatment is not sufficient, and hormonal treatment with either
glucagon or glucocorticoids may be started.13
The effect of bolus doses of glucagon has been studied. Glucagon has been
in use in our neonatal intensive care unit (NICU) for more than 20 years,
but there is little information available on the use of IV glucagon infusions
in the management of neonatal hypoglycemia.14
Other authorities recommend hydrocortisone before giving glucagon.5, 15-16 Because there is no
consensus as to which approach is most efficacious, there is a need for evaluation
of the different treatments for refractory hypoglycemia. Therefore, we summarized
our recent experience with IV glucagon infusions in the treatment of resistant
neonatal hypoglycemia, including an evaluation of recently reported adverse
effects.17
PARTICIPANTS AND METHODS
STUDY PARTICIPANTS
Our NICU is the outborn referral center (ie, the referral center for
those born outside that unit) for severely ill newborns from a defined geographic
area with approximately 65 000 annual births. We identified all patients
admitted to our NICU who received a glucagon infusion for hypoglycemia during
a 5-year period (1994-1998) and who had at least one laboratory-determined
blood glucose level both before and after commencing the glucagon infusion
(N = 55, 37 male and 18 female newborns). Data on growth parameters, gestational
age, causes of hypoglycemia, age of glucagon administration, and initial dosage
and duration of treatment were collected. Prematurity was defined as a gestational
age less than 37 completed weeks. The designation of perinatal stress was
based on both intrapartum monitoring (including fetal heart rate monitoring,
cord blood pH) and postnatal clinical evidence of encephalopathy (persisting
after correction of hypoglycemia), including radiologic evidence of brain
abnormality. The definition of intrauterine growth restriction (IUGR) was
based on a birth weight less than the 10th centile.18
Approval for this study was obtained from the hospital institutional review
board.
BLOOD GLUCOSE MEASUREMENTS
Only laboratory-determined plasma glucose levels were recorded in this
study because of inaccuracy of bedside measures.19
For this study, hypoglycemia was defined as a blood glucose level less than
47 mg/dL (2.6 mmol/L).10-11 Data
were collected on blood glucose levels from 24 hours before glucagon administration
to 72 hours after (24, 16-8, 8-4, and 4-0 hours before glucagon use and 0-4,
4-8, 8-16, 24, 48, and 72 hours after the start of the infusion). Recognizing
that blood glucose values are a continuum, the severity of hypoglycemia was
stratified into 3 groups: less than 47 mg/dL (2.6 mmol/L), less than 36 mg/dL
(2.0 mmol/L), and less than 20 mg/dL (1.1 mmol/L).12
Categorization was thought to be important for 2 reasons. First, there is
no agreement as to what constitutes a significant level of hypoglycemia, although
it is agreed that the lower the glucose level, the more likely it is to be
significant. Second, the effect of glucagon on the varying degrees of hypoglycemia
could be observed.
The number of episodes of hypoglycemia and the number of days on which
hypoglycemia occurred were documented. Information was obtained on the timing
of these episodes and whether they occurred before, during, or after the glucagon
infusion. Episodes of hypoglycemia occurring at the referring hospitals were
included. Generally, repeated laboratory glucose levels were obtained at the
NICU until stable normoglycemia was achieved. Because the number of episodes
of hypoglycemia detected would depend to some extent on the frequency with
which blood glucose levels were checked, the results were also expressed as
the number of days on which hypoglycemia was detected and the number of patients
who had hypoglycemic episodes.
For most patients (n = 49), 1 mg of glucagon was infused over 24 hours
(average dose, 10-20 µg/kg hourly) regardless of gestational age or
birth weight. At the time glucagon was initiated, rates of glucose infusion
were mostly between 6 and 12 mg/kg per minute. Once blood glucose levels were
stable on average glucose requirements, glucagon was weaned by decreasing
infusion rates over 24 to 72 hours.
The infusion rates of dextrose-containing solutions and the amounts
of enteral feed at each time point (24, 12, and 6 hours before glucagon administration
and 0, 6, 12, 24, 48, and 72 hours after the glucagon infusion was started)
were recorded. The composition of any expressed breast milk was assumed to
approximate that previously quoted.20 Daily
weights were recorded to calculate the administration rates of glucagon and
glucose.
Serum sodium values and platelet counts were examined from 48 hours
before glucagon administration to 72 hours after the start of the infusion.
In a limited number of patients, additional biochemical data obtained during
hypoglycemia included the presence of ketonuria and "critical blood work"
information (insulin, ß-hydroxybutyrate, and free fatty acid concentrations).
STATISTICAL ANALYSIS
Median values with ranges, means, and SDs are presented for blood glucose
levels; box plots were constructed using the SPSS statistical package version
9 (SPSS Inc, Chicago, Ill). The Wilcoxon signed rank test for 2 groups of
nonparametric paired data was used to analyze the initial change in blood
glucose after the administration of glucagon. The Mann-Whitney U test was used to compare the changes in blood glucose in different
subgroups. Change in glucose administration rates during the study period
was examined by repeated-measures analysis of variance. Relative risks of
hypoglycemia occurring during the glucagon infusion were calculated from 2
x 2 tables.21
RESULTS
STUDY POPULATION
During the 5-year study period, 55 newborns were observed to have received
glucagon infusions. Gestational ages ranged from 24 weeks to 41 weeks (mean
and median, 36 weeks) and birth weights from 0.46 to 5.2 kg (mean ±
SD, 2.35 ± 0.99 kg). Hypoglycemia was attributed to more than a single
cause in 29 patients, whereas in 2 cases the cause was undetermined (Figure 1). The largest subgroups were perinatal
stress alone and in combination (n = 26) and IUGR alone and in combination
(n = 25). In 39 patients there was evidence of fetal distress, leading to
emergency cesarean delivery in 38. The overall cesarean delivery rate was
69%. Reduced or absent fetal movements were reported in 14 patients (25%).
Seizures were observed in 10 neonates, and phenobarbital was given in addition
to glucose and glucagon. In 4 cases, the seizures were temporally associated
with hypoglycemia. Body mass indexes (calculated as weight in kilograms divided
by the square of height in meters) were available in 16 of the patients with
IUGR. These ranged from 7.4 to 11.8, with a median of 9.0 (mean, 9.4 ±
1.4).The mean ± SD age of patients when they started glucagon infusion
was 4.5 ± 7.1 days. In 32 newborns (58%), episodes of hypoglycemia
had been occurring for more than 24 hours before the administration of glucagon.
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Figure 1. Venn diagram showing the causes
of hypoglycemia and the numbers of patients in each group. Five newborns are
not graphed: 1 because of poor feeding; 1, Beckwith-Wiedemann syndrome; 1,
hyperinsulinism; and 2, cause unknown. IUGR indicates intrauterine growth
restriction; IDM, infant of diabetic mother.
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INITIAL RESPONSE TO GLUCAGON
The initial response to glucagon was assessed by calculating the difference
between the last preglucagon blood glucose level and the first blood glucose
level after starting the infusion. A statistically and clinically significant
rise in blood glucose concentration, from a mean of 38.9 to 110 mg/dL (2.16-6.11
mmol/L), was observed within 1 hour of starting glucagon infusion. The median
rise in glucose concentration was 45 mg/dL (2.5 mmol/L) (P<.001) (Figure 2). There
was no significant increase in glucose administration to account for this
rise in blood glucose level. The mean glucose delivery rate was 8.8 mg/kg
per minute 6 hours before and 9.4 mg/kg per minute 6 hours after the addition
of glucagon. Only 1 patient, a severely growth-restricted, 26-week gestation
newborn (480-g birth weight), did not show an early rise in glucose concentration.
This newborn subsequently showed a rise in blood glucose level to 48.6 mg/dL
(2.7 mmol/L) at 8 hours after glucagon infusion.
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Figure 2. Box and whisker plots of blood
glucose concentrations from 24 hours before to 72 hours after initiation of
the glucagon infusions. Blood glucose concentrations rose significantly (P= .001) within 4 hours of commencing glucagon administration.
To convert glucose to milligrams per deciliter, divide by 0.05551. Error bars
indicate SD.
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There was no correlation seen in our data between the glucagon dose
per kilogram (range, 6-95 µg/kg hourly) and the initial rise in glucose
levels. In addition, there was no significant difference in the rise in glucose
produced by glucagon infusion rates less than 20 µg/kg hourly (n = 32)
and those greater than 20 µg/kg hourly (n = 23) (Mann-Whitney U test, P = .63).
GLUCOSE ADMINISTRATION
There were no statistically significant differences in glucose administration
during the study period. Glucose infusions ranged from medians of 9.27 mg/kg
per minute at the start of glucagon infusion to 9.16 mg/kg per minute 48 hours
later.
ASSOCIATION BETWEEN GLUCAGON INFUSION AND HYPOGLYCEMIC EPISODES
No patient had severe hypoglycemia (glucose level, <20 mg/dL [<1.1
mmol/L]) after the glucagon infusions were started. The relative risk (RR)
of a patient having a blood glucose level less than 47 mg/dL (2.6 mmol/L)
during the glucagon infusion compared with the period before glucagon administration
was 0.47 (95% confidence interval [CI], 0.36-0.62). For blood glucose levels
less than 36 mg/dL (2.0 mmol/L), the corresponding RR was 0.32 (95% CI, 0.21-0.48)
on any day (Figure 3). The RRs for
the number of days on which blood glucose concentrations were less than 47
and 36 mg/dL (2.6 and 2.0 mmol/L) were 0.40 (95% CI, 0.32-0.51) and 0.21 (95%
CI, 0.13-0.31), respectively (Figure 3).
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Figure 3. Risk of recurrence of hypoglycemia.
Relative risks and 95% confidence intervals (error bars) of the occurrence
of hypoglycemia (blood glucose concentrations <36 mg/dL [<2.0 mmol/L])
during glucagon infusion for the different diagnostic categories. IDM indicates
infant of diabetic mother; IUGR, intrauterine growth restriction.
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EFFECT OF GLUCAGON IN DIFFERENT SUBGROUPS
In 29 patients there was more than one cause of hypoglycemia so that
the subgroups analyzed included combinations of causes and single causes alone.
The association between the blood glucose concentration and glucagon infusion
for the various diagnostic groups is shown in Table 1. The initial rise in glucose ranged from a mean of 44.5
mg/dL (2.47 mmol/L) for the preterm newborn group to 65.2 mg/dL (3.62 mmol/L)
in the perinatal stress group. There were no statistically significant between-group
differences. However, the maximum increase was smaller in the preterm group
(79 mg/dL [4.4 mmol/L]) compared with the other subgroups (144-173 mg/dL [8-9.6
mmol/L]). The mean increase in the 4 newborns weighing less than 1 kg was
22.1 mg/dL (1.23 mmol/L), with a range of -5.4 to 46.8 mg/dL (-0.3
to 1.23 mmol/L). All 4 patients subsequently died of causes other than hypoglycemia
(necrotizing enterocolitis with sepsis in 2 newborns, overwhelming sepsis
in 1, and pulmonary hypoplasia and asphyxia in 1). The median age of the start
of glucagon administration was 26 days compared with a median age of 2 days
for the study group as a whole. Among the subgroups, the infants of diabetic
mothers group showed the largest reduction in the occurrence of hypoglycemia
(Figure 3).
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Initial Rise in Blood Glucose Concentration Following Glucagon Administration
for the Different Diagnostic Groups*
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The change in blood glucose concentration in patients who were receiving
enteral or IV lipids (n = 12) at the time that the glucagon administration
was started compared with the change in glucose in the patients not receiving
lipids (n = 43) was not significant (P = .62).
OTHER INVESTIGATIONS AND TREATMENTS
Insulin levels were measured in 12 cases, and ß-hydroxybutyrate
and free fatty acid levels in 13 patients. In 2 patients, the insulin level
was unrecordable (appropriate during hypoglycemia). In the remaining 10 patients,
the range of insulin was 3.5 to 23.1 µU/mL (25-166 pmol/L). The 2 patients
with undetectable insulin responded to glucagon with a mean rise in blood
glucose level of 69 mg/dL (3.85 mmol/L). In no case was ketonuria detected
during hypoglycemia (n = 12).
CHANGES IN SERUM SODIUM
Serum sodium values for 48 hours before to 72 hours after glucagon administration
were available for 38 newborns. Serum sodium was unchanged following glucagon
infusion in 21 newborns, was initially normal then decreased while taking
glucagon in 7, and was initially low and became normal while taking glucagon
in 10.
CHANGES IN PLATELET COUNTS
Of 45 newborns who had platelet counts measured before the glucagon
infusion, 9 (25%) had normal values (>150 x103/µL)
and 20 had counts less than 100 x103/µL. Platelet counts
for 48 hours before to 72 hours after glucagon use were available for 36 newborns.
The platelet count was unchanged after glucagon administration in 26 newborns
(variation of <1 SD), the count increased in 1, and it decreased in 9.
Of the 9, 2 had major venous thromboses, and 1 had group B streptococcal sepsis
concomitant with the initiation of glucagon. Of the remaining 6 cases, 4 were
infants of diabetic mothers.
RECURRENCE OF HYPOGLYCEMIA AND THE ADMINISTRATION OF OTHER GLYCEMIC
TREATMENTS
In 11 patients (20%), glucagon administration was restarted after it
was discontinued, within 24 hours in 6 of the 11. Of the 29 newborns who had
no episodes of hypoglycemia during the glucagon infusion, 4 had episodes of
hypoglycemia (glucose level, 36 mg/dL [<2.0 mmol/L]) after glucagon use
was discontinued. Five patients (9%) were treated with other glycemic medications.
Three newborns received diazoxide (all 3 were preterm and had IUGR, and 1
proved to have undetectable insulin), 1 was given dexamethasone (preterm and
IUGR), and 1 received hydrocortisone (perinatal stress).
COMMENT
This study demonstrates a striking association between glucagon infusion
and rising blood glucose levels (median rise of 45 mg/dL [2.5 mmol/L] within
4 hours of initiating the infusion) and a significant reduction in the number
of hypoglycemic episodes. The variable age of starting glucagon treatment,
yet the very strong association with rising blood glucose concentration, suggests
that the rise in blood glucose levels immediately after starting the glucagon
infusion was not a chance association due to spontaneous resolution of the
hypoglycemia. The mean rise in blood glucose levels in this study (52.6 mg/dL
[2.92 mmol/L]) is higher than that previously reported after a single IV bolus
of glucagon (29 mg/dL [1.6 mmol/L] after 200 µg/kg of IV glucagon).11
A recent case report17 described severe
hyponatremia (serum sodium level, 116 mEq/L) and thrombocytopenia following
glucagon infusion. In our case series, no patient developed hyponatremia attributable
to glucagon, although in some patients serum sodium levels decreased following
glucagon administration and in others it increased. Thrombocytopenia is common
in critically ill newborns22 and is particularly
associated with IUGR and asphyxia.22-23
Thus, the high incidence of severe thrombocytopenia in our cohort before glucagon
administration is expected. Although platelet counts were unchanged following
glucagon administration in most newborns, 6 showed an otherwise unexplained
reduction in counts. Whether this is a chance association or is attributable
to glucagon or the underlying diagnoses is unclear. Regular monitoring of
platelet counts while administering glucagon to these critically ill newborns
is advisable.
The major limitation of this study is its retrospective nature. Because
of this, the timing of blood glucose estimations could not be controlled.
Most newborns did not have measurements of plasma insulin or other metabolic
studies, but had obvious causes of hypoglycemia. The standard infusion of
0.5 or 1 mg over 24 hours translates into a wide variation in dosage per kilogram.
The pharmacologic doses of glucagon that we used are significantly greater
than circulating physiologic concentrations and may exceed those actually
required for an effect. As indicated by the lack of difference between infusion
rates above and below 20 µg/kg hourly, the higher rates may not provide
added benefit. Although our results seem to support the suggested upper limit
of 10 µg/kg hourly,24 they should be
interpreted with caution since the newborns receiving the higher doses in
this study were the preterm and IUGR newborns. On the other hand, our results
suggest that preterm newborns are likely to be relatively less responsive
to glucagon.
Monitoring blood glucose levels in high-risk newborns and attempts to
maintain euglycemia are standard practices in neonatal nurseries. Blood glucose
levels show a continuum, and thus it is difficult to define hypoglycemia as
a single set of values12, 19; this
served as our rationale for stratifying the degree of hypoglycemia. In most
cases, hypoglycemia responds to early and frequent feeding; however, if blood
glucose levels fall below 47 mg/dL (2.6 mmol/L), IV dextrose given at a high
enough rate to meet the newborn's glucose use rate is recommended.11 In a few newborns, this IV glucose proves insufficient
and hormonal treatment, with either glucocorticoids or glucagon, is required.
In our NICU, an infusion of glucagon is used when increased glucose infusion
rates are insufficient to normalize blood glucose levels, in particular in
cases such as perinatal stress, where the total volume of infused solutions
is restricted.
The glycemic effect of glucagon was first demonstrated more than 40
years ago.25 The response to glucagon given
by IV bolus has been studied in infants with hypoglycemia due to a variety
of causes.2, 14, 25-26
Infusions of glucagon have not been well studied, but have been shown to increase
the blood glucose levels to a satisfactory level in most IUGR infants27 and the other etiologic groups of newborns included
in this study. However, our understanding of how glucagon exerts its effect
remains incomplete. Endogenous glucagon is important in promoting early neonatal
glycogenolysis and gluconeogenesis. In our study, similar rises in blood glucose
following glucagon use were seen in the diagnostic groups likely to have depleted
glycogen stores. Thus, it is unlikely that glucagon acts solely by glycogenolysis.
Phosphoenolpyruvate carboxykinase is the rate-limiting enzyme in gluconeogenesis,
and it has been suggested that induction of this enzyme is determined by the
plasma glucagon–insulin ratio. This ratio may be lowered by IV dextrose,
which can inhibit glucagon secretion,28 or
by the increased insulin levels that can occur in association with perinatal
stress,29 IUGR,30
and maternal diabetes mellitus. Under these circumstances, administration
of glucagon may possibly increase the glucagon-insulin ratio, thus promoting
gluconeogenesis. Glucagon may also contribute to the increase in capacity
for fatty acid oxidation in the liver, a process essential for gluconeogenesis.31
Because episodes of hypoglycemia may cause brain injury, close attention
to the prevention and management of neonatal hypoglycemia is required. The
results of our analyses strongly suggest that glucagon infusions are a useful
adjunctive treatment for resistant neonatal hypoglycemia. Further studies
are needed to define the exact role of glucagon in the management of neonatal
hypoglycemia and to compare the effect of glucagon with other glycemic treatments.
The dosing, route, and timing of glucagon therapy in the different diagnostic
groups need further clarification. A randomized control trial comparing glucagon
to steroids or the effect of glucagon infusions in different doses may be
good starting points.
| What This Study Adds
Management of hypoglycemia is an important problem in all newborn nurseries.
Most cases of neonatal hypoglycemia respond to early feeding or intravenous
dextrose administration, but in some severe cases, hormonal treatment with
either glucagon or glucocorticoids is required. There is no consensus regarding
which approach is the most effective. Despite limited evidence, glucagon is
widely used for the management of persistent neonatal hypoglycemia. This retrospective
study, to our knowledge the first from North America, shows that intravenous
glucagon infusions significantly increased blood glucose concentrations in
neonatal hypoglycemia. Glucagon was also able to prevent further episodes
of severe hypoglycemia and was effective in a wide variety of conditions,
including hypoglycemia associated with asphyxia, intrauterine growth restriction,
prematurity, and infants of diabetic mothers.
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AUTHOR INFORMATION
Accepted for publication May 9, 2002.
Corresponding author and reprints: Aideen M. Moore, MD, FRCPC, Division
of Neonatology, Hospital for Sick Children and University of Toronto, 555
University Ave, Toronto, Ontario, Canada M5G 1X8 (e-mail: aideen.moore{at}sickkids.ca).
From the Division of Neonatology, Hospital for Sick Children and University
of Toronto, Toronto, Ontario.
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