PRACTICAL ISSUES IN MANAGEMENT OF
NEONATAL HYPOGLYCEMIA
DR.RHISHIKESH THAKRE
DM (NEO),MD,DNB,FCPS,DCH.
INTRODUCTION
Although there are literally hundreds
of papers in the literature focusing on neonatal hypoglycemia this subject
remains controversial and puzzling, yet of urgent diagnostic and therapeutic
challenge. Controversies continue to involve definition, method and site of
sampling, symptoms, significance of asymptomatic status, management and its effect
on neurodevelopmental outcome. An attempt is made to answer these issues in the
present communication.
WHAT SUGAR VALUE BE TAKEN TO DEFINE HYPOGLYCEMIA ?
Substantial variation in the
definition of hypoglycemia not only amongst the pediatricians in general but
also among pediatricians within a particular nursery is well known(1). There
are four possible approaches to the definition of hypoglycemia in neonate – 1)
Statistical II) Clinical III) Neurophysiological and IV) Neurodevelopmental.
There are enough data to support a
change in the attitude based on these different approaches to the definition of
hypoglycemia.
A blood glucose concentration at/or
above 40 mg/dl, preferably in the 54 to 72 mg/dl range represents a more
acceptable euglycemic value. (2,3,4,5).
KEY POINT :
1. Monitor
carefully any neonate or infant with a blood glucose concentration less than 50
mg/dl.
WHEN
SHOULD ONE CLINICALLY SUSPECT HYPOGLYCEMIA IN NEWBORN?
There is no pathognomic sign or
symptom of hypoglycemia.These are
non-specific in the neonate(4). These include -
i)
Lethargy.
ii)
Apathy.
iii)
Irritability.
iv)
Tachypnea.
v)
Jitteriness.
vi)
Seizures.
vii)
Apnea.
viii)
Bradycardia.
ix)
Cyanosis.
x)
Coma.
xi)
ASYMPTOMATIC HIGH RISK INFANT.
A
similar presentation may be seen in several other disorders, including
septicemia, brain injury, severe respiratory distress, and congenital heart
disease. Therefore clinical presentations for hypoglycemia are vague, hence
high index of suspicion is required. Universal screening for neonatal hypoglycemia
is not recommended(6).
KEYPOINTS
:
1. Seizures
occur in a minority of babies with hypoglycemia. When they do occur, however,
they usually imply long standing hypoglycemia(7)
2. Infants
with glycogen storage disease can tolerate very low blood glucose
concentrations without having significant symptoms(8).
3. Closely
monitor those babies at higher risk for hypoglycemia.
HIGH RISK GROUP FOR
HYPOGLYCEMIA :
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1)
PRETERMS. |
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2)
SMALL FOR
GESTATION. (SGA) |
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3)
MACROSOMIC. |
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4)
INFANT OF
DIABETIC MOTHER. (IDM) |
|
5)
ASPHYXIATED
BABIES. |
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6)
RHESUS
HEMOLYTIC DISEASE |
|
7)
HYPOTHERMIA. |
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8)
POLYCYTHEMIA. |
|
9)
BECKWITH
WIEDMANN SYNDROME |
WHAT IS THE OPTIMUM TIME TO SCREEN FOR
HYPOGLYCEMIA?
Physiologically, the nadir in blood
glucose in newborn takes place at 2 to 3 hours after birth(9). Hence this would
be an ideal time for screening an asymptomatic “high risk” newborn. However
intrapartum risk factors would warrant early screening.
INTRAPARTUM
RISK FACTORS FOR HYPOGLYCEMIA
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1)
Maternal
un-controlled diabetes. |
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2)
Maternal
glucose drip. |
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3)
Maternal
tocolytic therapy. |
|
4)
Maternal
use of propronolol / chlorpropamide/ salicylates /
benzothiazide. |
|
5)
Periniatal
asphyxia. (Cord blood arterial pH<7.20) |
KEY
POINTS:
1) There is
a normal dip in blood glucose in first 2-4 hours postnatally.
2) Earliest
marker for predicting hypoglycemia in the first few hours of life would be cord
blood glucose. A high cord glucose would give rise to rebound hypoglycemia in
newborn hence would warrant close monitoring immediately following birth.
3) Cord
blood glucose should be done in “at risk” neonates especially in SGA and IDM.
4) Monitoring
for glucose be done 4 hourly in first 24 hours or whenever baby is symptomatic.
THE MAXIMUM RISK FOR HYPOGLYCEMIA IS IN
FIRST 24 HOURS AND DEFINITELY NOT AFTER 72 HOURS, UNLESS IT IS MULTIFACTORIAL
IN “AT RISK GROUP”
WHAT BLOOD SAMPLE BE USED FOR DIAGNOSIS OF HYPOGLYCEMIA?
1.
For screening purposes reagent strips are
commonly used on capillary samples by heel prick, with the help of dextrometer.
Reagent strips measure whole blood glucose.
2. Whole
blood glucose is 15% lower than plasma levels.
3. It is
imperative to measure the level of true glucose rather than the reducing
ability of the blood either by glucose oxidase or Nelson and Somogyi methods.
PRACTICAL POINTS:
1. Dextrostix
reagent strip (Bayer Corp) in the package insert warns that its use is not
intended for neonatal blood sample(10).We have been using Haemo-Glukotest
20800R (Boehringer Mainheim
2.
Reagent strips are subject to false
positive and false negative results.
False positive
- Low hematocrit values (<35%)
-
Contamination with iso propylalcohol.
False negative
- High hematocrit values (>55%)
-
Glucose values > 200mg/dl.
- Hyperglycemic- hyperosmolar states with or without ketosis.
- Delay in lab analysis.
3. Do not
perform blood glucose determination by reagent strip at temperature below 18
degree C or above 35 degree C.
4. The
glucose level can fall by 14-18 mg/dl
per hour in a blood sample that awaits analysis.
WHEN
SHOULD ACTIVE INTERVENTION BE STARTED?
1.PREVENTION OF HYPOGLYCAEMIA IS THE THERAPEUTIC GOAL.
Hence active
intervention must be started in labor room ensuring all
babies receive breastfeeds in
first half hour of life.
2. If a reagent
strip shows a concentration less than 40 mg/dl, treatment should not be delayed
while one is awaiting confirmation of hypoglycemia by lab analysis.
3. A
confirmatory lab glucose determination is required before one can diagnose
hypoglycemia.
WHAT
INTERVENTIONS BE DONE IN HYPOGLYCEMIC NEONATE?
1. Ensure
neutral thermal environment.
2. Secure
an IV access.Collect blood for basic investigations.
3. If symptomatic
give a bolus of 2- 4 cc/kg, IV, 10% Dextrose.
If asymptomatic
do not give bolus as it may cause rebound hypoglycemia.
4. Start
glucose infusion with 10% Dextrose at 6mg/kg/mt preferably using a infusion
pump.
5. Check
blood glucose level after 30 mts.
6. If low,
increment glucose infusion rate by Sion Hospital Formula. Following changes in
infusion rate check glucose after 30 min.
7. Calculate
separately glucose infusion rate (mg/kg/min) and fluid requirement (cc/kg/day).
8. Need for
glucose > 12 mg/kg/min or > 12.5%D to maintain euglycemia suggests
refractory (intractable) hypoglycemia.
9. Start
HYDROCORTISONE 5 mg/kg/dose, IV, 12 hrly, Collect sample for insulin and
cortisol before giving hydrocortisone.
10. Consider GLUCAGON,
0.1 mg/kg/ dose, IV/IM as a temporary measure to raise blood glucose or when IV
access is difficult.
11. Consider DIAZOXIDE
l0 mg/kg/day, q8hr.
12. Evaluate for
underlying aetiology.
Treat underlying specific cause.
AT RISK
NEWBORN
ANTICIPATION
AND PREVENTION
HYPOGLYCEMIA
GLUCOSE
INFUSION RATE (GIR)
CALCULATE
GLUCOSE AND FLUID RATE
INCREMENT
OF GIR, IF HYPOGLYCEMIC.
USE OF HYDROCORTISONE/DIAZOXIDE/
OCTREOTIDE.
TAPPERING
OF GIR
REFRACTORY
HYPOGLYCEMIA
AETIOLOGIC
EVALUATION.
PROTOCOL
FOR MANAGEMENT OF HYPOGLYCEMIA :
AT RISK NEWBORN
·
First feed within half hour of birth.
·
Provide thermo-neutral environment.
·
Reagent
strip monitoring.
Reagent strip < 40 mg%
· IV
Access.
· Collect
blood for lab
· B
glucose < 40 mg %
( In
case of difficulty in IV access give glucagon, 0.1 mg/kg )
SYMPTOMATIC ASYMPTOMATIC
2-4 cc/kg 10% D
NO BOLUS.
IV
infusion of 6-8 mg/kg/mt.
IV infusion of 6-8 mg/kg/mt.
LOW BLOOD GLUCOSE
-Make increments in
glucose infusion. - Continue glucose
infusion (see SION HOSPITAL FORMULA) - Tappering of GIR.
-The glucose level
should be checked after 30 min of each change, in
infusion.
-The
maximal glucose concentration is usually limited to 12.5%D to
safeguard against the risk of
thrombophlebitis in peripheral line.
-Calculate
separately glucose intake (mg/kg/min) and fluid requirements
(cc/kg/day)
depending upon the daily fluid requirements.The concentration of dextrose solution
to be infused can be worked out to provide the desired amount of constant
delivery of glucose.
-Need
for > 12 mg/kg/mt of GIR or > 12.5%D suggests refractory
hypoglycemia.
-The
concentration of glucose and rate of infusion are increased as
necessary to maintain a normal glucose level using central line.
REFRACTORY
HYPOGLYCEMIA:
(Need
for GIR >12 mg/kg/mt or >12.5%D)
1. Start
HYDROCORTISONE 5 mg/kg/dose IV, 12 hrly Before administering hydrocortisone
collect blood sample for insulin and cortisol level.
2. Consider
GLUCACON, 0.1 mg/kg/dose, 1M/IV 2-3 hrly
as a temporary measure as it mobilizes glucose for only 2-3 hours (to
ensure euglycemia)
3. Consider
OCTREOTIDE 2-4 mg/kg/d, q 12 w.
4. Search
for underlying aetiology
5. Treat
for specific conditon.
TAPPERING (4)
1. When
glucose level crosses 60 mg/dl glucose infusion rate is gradually tappered with
decrements of 2 mg/kg/min every 12 hourly, till glucose infusion rate comes
down to 6 mg/kg/min with satisfactory blood glucose values > 50 mg/dl.
2. Oral
feeds are gradually introduced when glucose infusion is being tappered
depending upon infant condition.
3. The
infant is completely weaned off intravenous infusion when blood glucose values
are stable at an infusion of 4 mg/kg/min.
4. Continue
hydrocortisone until the infant is stable for 48hr off IV fluid. This usually
takes for 5 to 7 days.
KEY POINTS
:
1. Oral
glucose or feeding alone are not enough once hypoglycemia has occurred because
oral glucose is more likely to stimulate insulin release as compared to
intravenous glucose infusion. (12)
2. Bolus
administration is not recommended in asymptomatic babies.
3. Before
proceeding further, check patency of IV line, and ensure glucose rate is
delivered by infusion pump.
Sion hospital formula for calculation of glucose infusion rate
(GIR).
1.CALCULATION OF GLUCOSE INFUSION RATE WITH
10% D
FIRST DIGIT OF FLUID RATE (ML/KG/DAY) X 7
10
( OR
FIRST TWO DIGITS IF FLUID RATE = OR > 100 ml/kg/day )
EXAMPLE
: IF PATIENT IS GETTING 70 ML / KG/ DAY OF 10% D GIR = 7X7 = 4.9
mg/kg/min
10
IF
PATIENT IS GETTING 110 ML/KG/DAY OF 10% D GIR = 11X7 = 7.7mg/kg/min 10
2.TO INCREASE THE GIR BY 1 mg/kg/min
ADD 2 ML
/KG OF 25% D TO EACH 8 HR DRIP (OR 1.5 ML / KG TO A 6-HR DRIP)
EXAMPLE
:
ADD 2 ML / KG OF 25% D TO EACH 8 – HR DRIP IN
THE EXAMPLES ABOVE TO INCREASE THE GIR FROM 4.9 TO 5.9 mg/kg/min IR FROM 7.7
mg/kg/min to 8.7 mg/kg/min
3.WHILE USING
FORMULA 2, TO ENSURE THAT THE
CONCENTRATION OF THE DRIP DOES NOT EXCEED 12.5% D
DO NOT
EXCEED THE GIR BY THE FIRST DIGIT OF THE FLUID RATE (ML/KG/DAY) (OR FIRST TWO
DIGITS IF FLUID RATE = OR > 100 ml/kg/day)
EXAMPLE
:
FOR THE
PATIENT GETTING 70 ML/KG/DAY DO NOT EXCEED 7 mg/ kg/ min AND FOR THE PATIENT
GETTING 110 ML/KG/DAY DO NOT EXCEED 11 mg / kg/min
NOTE :
a) The
total fluid increases by 0.25 ml/kg/hour for every 1 mg/kg/min increase in GIR
b) While
using formula 3, if a further increase in GIR is required increase the total
fluid (ml/kg/min
ADVANTAGES
OF THESE FORMULAE :
1. Easy,
accurate and quick to calculate at the bedside.
2. The GIR
can be increased slowly by 1 mg/kg/min to the required amount.
3. Mixing
of solutions to prepare different concentrations of dextrose solutions is
avoided
NEURODEVELOPMENTAL OUTCOME OF HYPOGLYCEMIA
1. There is
no single value below which brain injury definitely occurs.
(Schwartz
K. Neonatal hypoglycemia – Back to basics in diagnosis and treatment. Diabetes
40:71, 1991.
2. The
absence of overt symptoms at low glucose levels does not rule out CNS injury.
3. More the
depth of hypoglycemia and longer its duration more adverse is the neurologic
sequalae.
CLINICAL EVALUATION
- Family
history.
- Intrapartum
risk factors
- Course
of illness.
APPEARANCE
i)
Macrosomic : LGA/IDM/Hyperinsulinemic states.
ii)
SGA
iii)
Preterm.
iv)
Sick baby
CLINICAL
CLUES
i) Plethora - Polycythemia
ii) Midline defects, cholestatic
jaundice,micropenis - Hypopitutrism
iii) Ambigous genitalia – Cong. adrenal hyperplasia
iv) Cataracts - IU infections/Galactosemia.
v) Foul smelling cord - Infection
vi) Hydrops - Rh
hemolytic disease
vii)
Visceromegaly,umbilical hernia,microcephaly
macroglossia,
Beckwith
widmeinn syndrome
viii) Hairy pinna, macrosomia - IDM
ix) Hepatomegaly - Glycogen storage
x) Fundus - IUGR
xi) Sweet odour of urine - MSUD.
AETIOLOGIC EVALUATION
BASIC TESTS
- B. SUGAR
- S.
ELECTROLYTES
- URINE
FOR NON GLUCOSE REDUCING SUBSTANCES/KETONE
- SEPSIS SCREEN
WORKUP
1. S.
Insulin levels
2. Endocrine
profile – GH, cortisol, glucagon ACTH
3. Inborn
errors of metabolism – Urine aminoacidogram
Urine
for organic acid
Plasma aminoacidogram
4.USG abdomen.
5.S.Lactate.
KEY POINTS
1. Hyperinsulinism
is the most common cause of intractable hypolycemia in neonates (8)
2. For
diagnosis of hyperinsulinemic hypoglycemia – (13)
a) Insulin
level > 6 uU/ml
b) C-Peptide
level > 0.2 mmol/L
c) Pro-insulin
level > 5pmol/L
(Normative
data for children not available).
3. A rise
in plasma glucose greater than 25 mg/dl strongly suggests hyperinsulinism in
response to glucagon. (8).
4. Sulfonylureas
if ingested accidentally or intentionally by infants/children cause an increase
in both insulin and C-Peptide levels (8)
5. Recessively
inherited hyperinsulinism is not responsive to diazoxide. Autosomal dominant
hyperinsulinism is responsive to diazoxide and most infants are not large for
gestation.(8)
6. Insulin
(uU/ml) to glucose (mg/dl) ratio 0.4 or
greater suggests hyperinsulinemia.
7. In all
other cases of hypoglycemia with the exception of galactosemia and fructose
intolerance, ketonemia and ketonuria are present at the time of fasting
hypoglycemia.
Causes of hyperinsulinism
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1.
SMALL FOR
GESTATION BABY |
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2.
INFANT OF
DIABETIC MOTHER |
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3.
GLUCOSE
INFUSION IN MOTHER |
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4.
IV BOLUS OF
GLUCOSE |
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5.
AUTOSOMAL
RECESSIVE HYPERINSULINISM |
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6.
AUTOSOMAL
DOMINANT HYPERINSULINISM |
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7.
NESIDIOBLASTOSIS
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8.
PERINATAL
ASPHYXIA. |
HYPOGLYCEMIA
KETOTIC NONKETOTIC
LACTATE REDUCING SUBSTANCES
Elevated
-
Glycogen - Glycogen -Hyperinsulinemia -Heridatory fructose
storage storage
-FA oxidation defect intolerance
disease I disease - Drugs
3.4 - Galactosemia
-
Pyruvate - Ketotic - Maple syrup
carboxylase hypoglycemia urine disease
defeciency - Hormonal
defeciency
-
Phosphoenol
pyruvate
carloxylase def
-
Fructose 1-6 diphosphatase
defeciencey
POINTS TO PONDER
1. Recurrent
Reye like episodes should raise the possibility of fatty acid oxidation
defects.
2. Hypoglycoracchia
despite normal plasma glucose concentration has been described in infants with
seizure disorder.
(De Vico
DC, Trifileth RR, Jacobson RI et al : Defective glucose transport across the
blood brain barrier as a cause of persistent hypoglycoarcchia, seizures and
developmental delay, N Eng J Med 325 : 703; 1991).
3. Hypoglycemia
carries a bad prognosis when it occurs in setting of severe diarrhoea.
(Bemnish
ML, Kalam Asad A, Kalman O et al : Hypoglycemia during diarrhea in childhood. N
Engl J Med 322 : 1357, 1990).
4. Hypoglycemia
can also occur in children with sever malaria.
(White
NJ, Marshk, Turner RC etal : Hypoglycemia in African children with sever
malaria Lancet 1: 708, 1987)
5. Some
infants with glucose being infused through an umbilical artery line may have
normal glucose levels in their feet but hypoglycemic levels in the hands and
brain.
(Nagel
Jw, Sims S, Aplin CE, et al . Refractory hypoglycemia associated with a
malpositioned umbilical artery catheter. Pediatrics 1979; 64 : 315.)
6. Congenital
syphilis has been reported to cause hypopituitrism and hypoglycemia.
Daaboul
J, Kartchner W, Jones K. Neonatal hypoglycemia caused by hypopituitrism in
infants with congenital syphilis. J pediatr 1993; 123 : 983.)
CONCLUSIONS
1. Prevention
of hypoglycemia is the therapeutic goal.
2. There is
a normal dip in level of glucose in the first 2 to 4 hours
postnatally.
3. Monitor
carefully any infant with blood glucose less than 50 mg/dl.
4. Reagent
strips measure whole blood glucose which is 15 % lower than plasma levels.
Reagent strips measure whole blood glucose. Which is 15% lower than plasma
levels. Reagent strips are subject to false positive and false negative
results.
5. When
plasma glucose is less than 40 mg/dl, diagnostic and therapeutic measures
should be promptly started.
6. Hyperinsulinemia
is the commonest cause of refractory hypoglycemia in neonate.
7. The
significance of hypoglycemia depends on the babies gestational age, chronologic
age and other risk factors in addition to low blood glucose level.
8. There is
no single value below which brain injury definitely occurs.
9. Prompt
recognition, prevention, and management of neonatal hypoglycemia are important
to reduce as yet unquantified but worrying risk of neurological sequalae.
REFERENCES
1) Koh T,
Eyre JA, Aynsley Green A : Neonatal hypoglycemia : The controversy regarding
defination. Arch Dis Child 63 : 1386-88, 1988.
2) Koh T.
Neural dysfunction during hypoglycemia. Arch Dis Child 63: 1353, 1988.
3) Cornblath
M, et al : Hypoglycemia in the neonate. Endocrinol 6:113, 1993.
4) Cornblath
M, et al : Disorders of carbohydrate metabolism in Infancy (3d Ed.)
5) LaFranchi
S: Hypoglycemia in infancy and childhood. Pediatr Clin North Am 34 : 961, 1987.
7) Kurban
KCK, Fibiano J. Neonatal seizures. Manual of Neonatal care Ed; J.P. Cloherty
and A.R. Start. Lippincott Rawen Publisher, 1998 : Page 496.
8) Lteif
A.N., Schwerik W.F. Hypoglycemia in infants and children Endocrinology and
metabolism clinics 28 (3) Sept 1999.
9) Srinivasan
G, Pildes RS, Ca Hamanchi G et al. Plasma glucose values in normal neonates : a
new look. J pediatr 1986; 109 : 114 – 7.
10)Dextrostix
[ package insert].
11)S.
Mathai, Rhishikesh Thakre, JA.
12)Meharban
Singh. In Care of the Newborn 5th Ed:, Sagar Publications, 1999,
Pg 370.
13)Services
FJ OBrienPC, McMohan et al : C-Peptide during prolonged fast in insulinoma. J
Clin Endocrinol Metab 76: 655, 1993.