Hypoglycemia

Aman Pulungan
Department of Child Health
Faculty of Medicine
University of Indonesia
 Why This Topic is Important?

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).
Osier FH, Berkley JA, Ross A, Sanderson F, Mohammed S, Newton CR.
Abnormal blood glucose concentrations on admission to a rural Kenyan district
hospital: prevalence and outcome.
Arch Dis Child. 2003 Jul;88(7):621-5.

41% newborn infants had mild (less than 2.6 mmol/l) and
11% had moderate hypoglycaemia: Hospital based study.
Pal DK, Manandhar DS, Rajbhandari S, Land JM, Patel N, de L Costello AM.
Arch Dis Child Fetal Neonatal Ed. 2000 Jan;82(1):F46-51.
Initial Presentation
6 day old female infant with jaundice

Birth Hx:
36 wk AGA born to 40 y/o G4P0 mother
Diet controlled GDM,
Maternal blood type B+, all serology negative
BW = 2735 grams

Newborn Nursery:
Required 72 hrs IVF for hypoglycemia
Required 96 hrs phototherapy
Peak total bili = 14.7 mg/dL
Discharged DOL 5, breastfeeding well
Discharge wt = 2550 grams ( 6.7%)
Discharge bili = 13.4 mg/dL
Initial Presentation (6 days of age)
Vitals normal

Weight 2.545 kg ( 5 grams)

Breastfeeding or bottle feeding

PE: Jaundiced, icteric sclera, otherwise normal

PCP total bili 21.8 mg/dL

Admit labs:
Tbili = 19.1 mg/dL
Dbili = 0.6 mg/dL
Glucose = 28 mg/dL fed then rechecked = 65
Interested yet?
 Hospital Course
72 hours of phototherapy

Lactation support, no additional hypoglycemia

Gained 65 grams

Discharge bili (DOL 9) = 14.5 mg/dL

Discharge diagnosis:
Breastfeeding jaundice
Exaggerated physiologic jaundice
Hypoglycemia?????
Case#2
a female newborn present with a seizure on day 4 of life
born full term to a 38 year old G1 mother after an
uncomplicated pregnancy.
Apgar score:9 at 1 and 5 minutes.
On examination, her length is at the 3rd percentile. She has a
high arch palate and jaundiced skin. A liver edge is easily
palpable.
Laboratory :blood glucose <20 mg/dL at the time of the
seizure and a normal calcium level. IVF given, and the blood
glucose concentration rise from 18 to 40 mg/dL.
Koivisto M, Blaco-Sequeiros M, Krause U. Neonatal
symptomatic hypoglycaemia: a follow-up study of 151
children. Dev Med. Child Neurol ; 14:603-14

vTIME is most important factor affecting

onset of sx and SYMPTOMATIC
hypoglycemia with convulsions has poor
prognosis for permanent CNS damage, while
asymptomatic hypoglycemia without
convulsions appears to have no influence on
CNS pathology
Hypoglycemia

Before we start
Conversion factors for glucose
2.5 mmol/L = 45.05 mg/dL
3 mmol/L = 54.05 mg/dL
4.5 mmol/L = 81.08 mg/dL
5.5 mmol/L = 99.1 mg/dL
 Why hypoglycemia?

Brain
ATP source : glucose and ketone bodies
Little or no storage of glycogen
2% of total body weight, 20% of total glucose
Skeletal muscle, heart muscle
Effectively utilize ketone bodies and fatty acids
MRI of hypoglycemic CNS damage

Burns CM. Pediatrics 2008;122,65

CNS damage by chronic, recurrent
hypoglycemia
Important factors predisposing to
neurological sequelae
Symptomatic
Younger age <5 y
Number of symptomatic episodes
A resident's Way of handling
hypoglycemia
A child who looks critically ill.
Place a V-line and run a set of emergency blood exam.
Blood sugar of 1 mmol/L (18 mg/dL )!
Draw some more blood as a critical sample.
20% dextrose 2 mL/kg, IV push immediately.
Start drip infusion with a high dextrose solution (e.g.10%).
Wait for the results of a critical sample.
Look into a list of differential diagnosis, try to figure out the
cause of hypoglycemia.
Is this patient hypoglycemic?
Reasonable criteria of hypoglycemia

For emergency correction

<2.5 mmol/L (45 mg/dL) for children
<3 mmol/L (54 mg/dL) for adults
For hyperinsulinemic patients
<3.9 mmol/L (70 mg/dL) all age group
Recommended by ADA workgroup 2005
 Definition

The precise definition is still controversial

presence of acute symptoms
threshold of maintaining the blood level
presence of counter-regulatory hormone
responses
statistically
presence of brain damage
etc
 Definition

For diagnostic purpose

Deficiency of glucose in the blood
40 mg% (< 2.2 mmol) regardless of age.

Hypoglycemia is a biochemical sign, not a

diagnostic
 Glucose Homeostasis
Glucose principal energy
source in the body

All body cells require glucose to

produce energy

Glucose is broken down to

produce energy by glycolysis
 Normal glucose homeostasis

Most infants and children maintain blood glucose

levels between 60 120 mg/dl
Glucose supplied from
diet
breakdown of amino acids
Glycogen in the liver
Glucose deliver to the cells via blood stream, so
the levels should be strictly controlled to ensure
that the cells have a constant supply
 Changes of glucose, insulin and glucagon in blood
after carbohydrate ingestion

Schade et al (1983)
Control of blood glucose in fed state
Fasted state of glucose homeostasis
Digestion
Glycogenolysis
Gluconeogenesis

Digestion GlycogenolysisGluconeogenesis

0 4 16
Hours after meal
 GLYCOGENOLYSIS
GLUCOSE G6P GLYCOGEN

FBPase PFK

Glycerol
glycerol 3P
PEP
TG GLUCONEOGENESIS GLYCOLYSIS

Pyrivate Lactate Alanine

Acetyl CoA
mitochondria
oxaloacetate OA
Citrate
cycle
succinate succinate

OX-PHOS
 Defects in glycogenolysis and
gluconeogenesis

DEFECTS in GLYCOGENOLYSIS
Glycogen storage diseases (GSD)
DEFECTS in GLUCONEOGENESIS
Gluconeogenic enzyme defect
Disorders in fatty acid oxidation / carnitine
metabolism
Mitochondrial disease
Drug induced (e.g., antibiotics, antiepileptics)
Physiological ketotic hypoglycemia
 Defects in glycogenolysis and
gluconeogenesis

Defects in Glycogenolysis (After 4 hours of fasting)

Defects in Gluconeogenesis (After overnight fasting)
Euglycemia maintained by dextrose infusion at
normal hepatic glucose production rate.
DO NOT respond to subQ glucagon.
Normal hepatic glucose production

Neonate 4-6 mg/kg/min

Adult 1-2 mg/kg/min
Children in between
Normal hepatic glucose production

Neonate 4-6 mg/kg/min

Adult 1-2 mg/kg/min
Children in between
 Hyperinsulinism
Occurs at anytime after meal except for immediate
postprandial period, could be 2 hours after meal
Euglycemia NOT maintained by dextrose infusion
at normal glucose production rate for age
Supportive findings
Relatively hypoketotic (< 1500 mol/L)
Responds WELL to subQ glucagon
How much dextrose should be given after
initial correction of hypoglycemia?

If the etiology is unknown, start at

normal hepatic glucose production rate
(4-6 mg/kg/min (for infants), 2-4 mg/
kg/min (for children).
Check blood glucose frequently.

 Endocrine control of glucose homeostasis

Excess glucose in blood is stored in the form of

Glycogen in the liver and muscle cells
Fat in adipose cell
Hormones have an effect on blood glucose
Insulin
Glucagon
Adrenaline
Cortisol
Growth hormone
Hormone that regulate glucose homeostasis

Insulin : Removes glucose from the blood by

stimulating its uptake into cells and its
storage in the liver, muscle and adipose
tissue
Glucagon : Stimulates the release of glucose from the
liver
Adrenalin : Secreted in response to stress and raise
blood glucose levels and inhibit insulin
secretion
Cortisol and GH :
Stimulate the conversion of amino acids
into glucose in the liver and induce insulin
resistance
Summary of opposing effects of hormones
on glucose metabolism

Glucose uptake
Lipolysis
Ketogenesis GH, cortisol,
Insulin glucagon, and
Gluconeogenesis
adrenalin
Glycogenolysis

Blood glucose
 Clinical symptoms of Hypoglycemia
Hunger and weakness
Sweating, shakiness and trembling
Adrenergic Pallor, nausea and vomiting
symptoms Palpitation
Tachycardia and tremor
Nervousness

Headache
Lethargy, lassitude
Neuroglycopenic Visual and Speech disturbances
symptoms Mental confusion
Convulsions
Apnea, Coma
Threshold of hypoglycemic symptoms
Blood glucose, mmol/l
Result
(mgdL)
5.5 (99.1) Insulin secretion increases.
4.6 (82.88) Insulin secretion decreases.
Increased secretion of
3.8 (68.47) glucagon, adrenaline and
growth hormone.
3.2 (57.66) Cortisol secretion.

2.8 (50.45) Confusion.

1.7 (30.63) Weak, sweat, nauseous.

 Glucose level and clinical symptoms

Blood glucose (mmol/l)

4

Start of brain dysfunction

Adrenalin release
3
Sweating, tremor Confusion/loss of
concentration
2

Coma/seizure
1

Permanent brain damage

 Hypoglycemia in infancy

Most common metabolic problem in newborn

The most common cause is transitional
hypoglycemia normal adaptation to the extra
uterine life
If more than 24 hours usually pathologic
 Clinical signs
Tremor, jitteriness, hypotonia, irritability
Seizures
Abnormal cry (high pitch)
Letargy, poor feeding/sucking
Apnea, tachypnea
Diaphoresis, pallor
Temperature instability
Unexplained cyanosis
Cardiac arrest
 Etiology of neonatal hypoglycemia
Etiology Duration of
hypoglycemia
Prematurity, IUGR Transient *
Asphyxia, hypothermia Transient
Sepsis Transient

Infant of diabetic mother Transient

Erythroblastosis fetalis Transient

Exposure to B agonist tocolysis Transient

Familial hyperinsulinemia Prolonged
Inborn error of metabolism Prolonged

* Generally < 7 days

 Transitional hypoglycemia

Hypoglycemia that occur in the first 12 hours of life

Transition period from intrauterine to extrauterine
glucose homeostasis
Lubchenko : 30 % infants have glucose levels < 50
mg/dl
Early breast feeding will resolve
If after 12 hours of life, glucose levels > 60 mg/dl
no further investigations are necessary
Transient hypoglycemia of newborn

Transient neonatal hyperinsulinism

Transient hypoglycemia in infancy
Infant of diabetic mother
Obstetrical Intervention-induced hyperinsulinism
Hypoglycemia in infant SGA
 Infant of diabetic mother
Specific group at risk of early hypoglycemia
Its due to increased secretion of insulin persisting
after delivery and often asymptomatic
Other findings
Macrosomia
Birth trauma
Congenital anomalies
Respiratory distress
Polycytemia
Hyperbilirubinemia
Myocardial dysfunction
 Hormone deficiency

Growth hormone deficiency

Cortisol insufficiency
Hypothyroidism
 Persistent Hyperinsulinemic Hypoglycemia of Infancy

Most common cause of recurrent hypoglycemia in

infancy
Insulin release increase due to defective K-ATP
channel function
Incidence : 1 : 50.000 live birth in North Europe
Therapy :
prevent neurologic symptoms and sequelae
Diazoxide 5 20 mg/day first choice drug
Surgical treatment is indicated if pharmacologic treatment fail
 Enzyme deficiency

Glycogen storage desease

Disorder of hepatic gluconeogenesis
Pyruvate carboxylase deficiency
Galactosemia
Hereditary fructose intolerance
Defect in fatty acid metabolism
 Drug induced hypoglycemia

Insulin
Sulfonylurea
Ethyl alcohol
Salicylate and related compounds
 Other causes of hypoglycemia

Cyanotic congenital heart desease

Ketotic hypoglycemia
Hypoglycemia associated with surgery
 Diagnostic evaluation

Critical blood sample

History, Physical Examination and Elective fast
Tolerance testing
 History

Diabetic mother
Obesity hyperinsulinism
Mikropenis & cholestasis hypopituitarism
Drugs
Diet component inborn error of metabolism
 Physical examination

Many patient have a normal PE

SGA infants suggest Hyperinsulinism
Midline defect Hypopituitarism
Hepatomegaly glycogen storage disease
Hyperpigmentation Primary adrenal insufficiency
Abn neurological signs Adrenal leucodystrophy
Short stature with weight GH deficiency
Myopathy FAO disorder
 Lab studies

Critical blood draw key to diagnosis

Blood gas analysis :
Ketoacidosis
Lactic acidosis
Hypo + lactic acidosis disorder of gluconeogenesis,GSD-I
Hypo + ketosis hypopituitarism, GSD-III,-IV,-IX
Free fatty acid and ketone
Low FFA & low ketone insulinoma
High FFA & low ketone FAO disorder
How much dextrose should be given for
initial correction of hypoglycemia?
How much dextrose should be given to
maintain normoglycemia?
 Treatment
Aim restore blood glucose levels to normal
levels > 70 mg/dl
Oral glucose
IV 25% glucose bolus 1 2 ml/kg/hr,
then 10% glucose 3 - 5 ml/kg/hr
If glucose need is > 10 mg/kg/m insulinoma
give Glucagon 5 10 ug/kg/hr

Surgery if not responded to treatment
 Correction of hypoglycemia
To correct hypoglycemia
1 mL/kg of 20% dextrose is sufficient to
raise blood glucose to > 11 mmol/L (200
mg/dL)
1.5 mL/kg of 20% dextrose is sufficient to
restore total body glucose reserve
+ steroid for adrenal insufficiency

1-1.5 mL/kg of 20% dextrose

+ 50-100 mg/m2 hydrocortisone as needed
 Adjunct therapy for hypoglycemia
Therapy Effect Dosage

Corticosteroid Decrease peripheral glucose HC 5 15 mg/kg /day

utilization Prednisone 2 mg/kg/day

Glucagon Stimulate glycogenolysis 30 mcg/kg/day for N insulin

300 mcg/kg/day for insulin

Diazoxide Inhibit insulin secretion 15 mg/kg/day

Somatostatin Inhibit insulin and GH release 5 10 mcg/kg/day every 6 8 h

Pancreatectomy Decrease insulin secretion

What you need to do at ER.
Confirm hypoglycemia.
Ask about previous medical history and the last meal (when, how
much).
Take critical samples for differential diagnosis.
IV push 20 % dextrose at 1-1.5 mL/kg.
(+ IV hydrocortisone for patients with adrenal failure)
Start IV drip of dextrose at normal hepatic glucose production
rate (at 4-6 mg/kg/min (for infants), 2-4 mg/kg/min (for children).
Check blood glucose frequently.
If euglycemia is not maintained and urine ketones are low;
indicative of the presence of hyperinsulinism.
Wait for the results of critical samples, start detailed
investigation.
 Hyperinsulinism
Occurs at anytime after meal except for immediate
postprandial period, could be 2 hours after meal
Euglycemia NOT maintained by dextrose infusion
at normal glucose production rate for age
Supportive findings
Relatively hypoketotic (< 1500 mol/L)
Responds WELL to subQ glucagon
pitfalls
Mild hyperinsulinemia
Difficult to diagnose
Defects in counterregulation hormones
might mimic hyperinsulinism
Brain MRI useful esp. for neonates
 Defects in counterregulation
Born at 39 wks, with BW of 2954g
Convulsion at 16 hours after birth
Prolonged hypoglycemia
Insulin always undetectable
TSH 5.8 (IU/ml)
fT4 0.8 (ng/dl)
GH 4.8 (ng/ml)
Cortisol 2.3 (g/dl

 Conclusion

Hypoglycemia is a biochemical sign, not a

diagnostic
Hypoglycemia is a blood glucose levels less than
40 mg/dl
Early detection and treatment is important
Diagnostic based on clinical symptoms and lab
result
HMMMM, INTERESTING
Thank You
 Diagrammatic representation concept of
hypoglycemic-associated failure in diabetes