neonatal hypoglycemia

1. NEONATAL HYPOGLYCEMIA &
HYPERGLYCEMIA
PRESENTER : Dr VIJITHAA S

2.  DEFENITION
 INCIDENCE
 ETIOLOGY
 CLINICAL FEATURES
 DIAGNOSIS
 MANAGEMENT
 DIFFERENTIAL DIAGNOSIS
 OUTCOME
 SUMMARY

3. PHYSIOLOGY OF GLUCOSE HOMEOSTASIS IN
THE NEWBORN
 During pregnancy, the fetus is dependent on the mother for a constant supply of glucose. All
Fetal Glucose is derives from maternal circulation by facilitated diffusion.
 Maternal insulin does not cross the placenta and the fetus makes its own insulin to maintain
blood glucose levels.
 Both in utero and in postnatal life, insulin secretion from the beta cells is tightly linked to
plasma glucose concentrations.
 Enzymes for gluconeogenesis, presented by 3rd month of gestation.
 Insulin starts production by 12 Weeks and increases third trimester
 Glucagon starts production by15 weeks of gestation.
 The fetus stores glucose in the form of glycogen (liver, heart, lung, and skeletal muscle). Most
of the glycogen is made and stored in the last month of the 3rd trimester

4.  When the Plasma glucose concentration drops below 80 to 85 mg/dL, still within
the physiological range, the first response is to shut off insulin secretion to prevent
further decrease in glucose levels.
 The decrease in insulin removes the inhibitory effect on lipolysis and ketogenesis,
thereby providing alternative fuel sources.
 Hepatic glycogen serves as the first and immediate source of glucose. With a
decrease in plasma glucose levels, the increase in glucagon and epinephrine
levels promotes hepatic glycogenolysis and provides a source of glucose for a few
hour

5.  Epinephrine also inhibits insulin secretion and stimulates glucagon release from the
pancreatic islets.
 Beta-oxidation of fatty acids (mediated through actions of epinephrine and glucagon) results
in the formation of ketone bodies, an alternative energy source for the brain
 Cortisol, along with epinephrine, increases gluconeogenesis from non-carbohydrate sources
such as alanine, lactate, and glycerol
 The purpose of these complex systems is to maintain PG within age-appropriate physiologic
ranges and to avoid hypoglycemia-related negative outcomes

7. MECHANISM OF INSULIN RELEASE

8. Metabolic actions of insulin include - increase in cellular glucose
uptake, deposition of glucose as glycogen, lipogenesis in adipose
tissue, and inhibition of breakdown of triglycerides (lipolysis)
and fatty acids (ketone body formation or ketogenesis).
 Insulin is a major fetal growth factor.

9. DEFENITION
 Hypoglycemia is most common metabolic problem seen in newborns
 No universally accepted definition ; Hypoglycemia cut off variable
Clinical Definition of Hypoglycemia
defined as a Plasma glucose concentration low enough to cause
symptoms and/or signs of impaired brain function

10.  Classical Defenition –blood sugar <40mg/dl or <2.6mmol/l (whole blood)
AAP DEFENITION
 Symtomatic - < 40mg/dl
 Asymtomatic - First 4 hours of life <25mg/dl
4-24 hours of life <35mg/dl
>24 hours of life <45mg/dl
 Target after 48 hours of life >60 mg/dl ;
- symptomatic/asphyxia - >70mg/dl

11. INCIDENCE
 Overall Incidence = 1- 5/1000 live births
 Normal newborns – 10% if feeding is delayed for 3-6 hours after birth
At-Risk Infants –
 LGA – 16%
 Preterm – 15%
 SGA – 15%
 IDM – 20%

12. HIGH RISK GROUP
 Preterm
 SGA
 LGA
 IDM - presence of high circulating
insulin levels and a delay in
glucagon increase
 Sick babies
 Rh isoimmunization
 Infants on TPN
 2 hours of post DVET
 Maternal beta blockers
 Midline defect

13. CLASSIFICATION OF NEONATAL
HYPOGLYCEMIA
I. TRANSIENT HYPOGLYCEMIA
II. REFRACTORY HYPOGLYCEMIA/PROLONGED
HYPOGLYCEMIA

14. TRANSIENT HYPOGLYCEMIA
 Developmental immaturity in adaptation to fasting: Prematurity, SGA
 Stress in peripartum/postnatal period: Trauma, asphyxia, hypothermia
 Transient hyperinsulinemia: IDM, Intrapartum dextrose infusion to
mother.
 Increased metabolic expenditure: Sepsis, Erythroblastosis fetalis,
Polycythemia
 Other maternal conditions: Toxaemia, administration of tocolytics ( β
sympatho mimetics)

15. II.REFRACTORY HYPOGLYCEMIA/PROLONGED
HYPOGLYCEMIA
 Refractory hypoglycemia
If the infant remains hypoglycemic despite receiving glucose
infusion of
>12mg/kg/min
 Prolonged hypoglycaemia/ Persistent hypoglycemia
if need for glucose infusion persists for >7days
Hyperinsulinism is the most common cause of persistent

16. ETIOLOGY OF HYPOGLYCEMIA
1. HYPERINSULINISM
2. DEREASED SUBSTRATE PRODUCTION
3. INCREASED DEMAND

17. 1.HYPERINSULINEMIC HYPOGLYCEMIA
 Causes persistent recurrent hypoglycemia in newborns
 Associated with increased risk of brain injury by decreases serum blood glucose levels, preventing
brain from utilizing secondary fuel sources by suppressing fatty acid synthesis and ketone body
synthesis.
 IDM is the most common example of transient hyperinsulinism.
 Hyperinsulinism is seen in mutation of genes encoding the pancreatic beta cell ATP sensitive
potassium channel -ABCC8, KCNJ11, HNF4A gene

18. Hyperinsulinism secondary to other
conditions
 Syndromes –Beck with-Wiedmann syndrome (macrosomia, mild microcephaly, omphalocele,
macroglossia, hypoglycemia and visceromegaly).
 congenital disorders of glycosylation and metabolic condition
 Erythroblastosis
 After exchange transfusion with blood containing high glucose concentration
 Insulin producing tumours( nesidioblastosis, islet cell adenoma, islet cell dysmaturity)

20. 2. DEREASED SUBSTRATE/PRODUCTION
 Prematurity
 IUGR - decreased glycogen stores at birth, low fat stores that further increase their risk
for fuel insufficiency.
 SGA
 Delayed onset of feeding
 Inadequate caloric intake

21. 3. INCREASED DEMAND
 Perinatal stress – sepsis ,shock, asphyxia, hypothermia , respiratory distress,
post resuscitation
 Polycythemia- higher glucose utilization by increased mass of RBC.
 Maternal or infant therapy with beta blockers –
mechanism - prevention of sympathetic stimulation of glycogenolysis.
- prevention of recovery from insulin induced decrease in fatty acids and glycerol
- inhibition of epinephrine induced increases in in free fatty acids and lactate after exercise
.

22.  INBORN ERROR OF METABOLISMS
Defect in carbohydrate metabolism - Glycogen storage disorder
- Fructose intolerance
- Galactosemia
Defect in amino acid metabolism - Maple syrup urine disease
- Propionic academia
- Methylmalonic academia
- Tyrosenemia
ENDOCRINE DEFICIENCY-
- Adrenal insufficiency
- Hypothalamic deficiency
- Congenital hypopituitarism
- Glucagon deficiency
- Epinephrin deficiency

23. CLINICALFEATURES
Non specific symptoms
 Irritability
 Tremors
 Jitteriness
 Exaggerated moro reflex
 High pitched cry
 Seizure
 lethargy
 Hypotonia
 Cyanosis
 Apnea
 Poor feeding
 Asymptomatic

24. SCREENING
 Serial blood sugar levels should be routinely measured in infants who have
risk factors for hypoglycaemia or infants who have symptoms suggestive
of hypoglycaemia

26. Schedule of blood monitoring
Category of infants Time schedule
1 At risk neonates(LBW, PT, SGA, IUGR,IDM, Rh
,maternal drugs)
0,2,6,12,24,48,and 72 h of
life
2 Sick neonates(sepsis, asphyxia, polycythemia,
shock during acute phase illness)
Every 6-8 hours
3 Neonates on parentral nutrition Initial 72 hours – 6-8 hours
After 72 hours – once a day

27. METHODS OF BLOOD GLUCOSE
ESTIMATION
I POINT OF CARE GLUCO- METER:
 Widely used glucose estimation method, they are useful for screening
purpose, low values should be confirmed by laboratory testing(<45mg/dl)
 Treatment of hypoglycemia should be initiated based on the results of reagent
strips without waiting for laboratory reports.
 Arterial sample blood sugar value > venous blood > capillary blood
 whole blood glucose values are 15% lower than plasma glucose
concentrations.

28.  1st generation strips – change in color by enzymatic reaction on application
of blood drop
 Color can be read by reflectance meters or naked eye.
 The results get affected by hematocrit values, acidosis, bilirubin
 Newer generation glucose reagent strips : generate current on reaction of
glucose with enzymes such as Glucose oxidase/ glucose dehydrogenase
 Amount of current is proportion to amount of sugar in plasma

29. II LABORATORY DIAGNOSIS
 Gold standard for measuring blood glucose
 Blood glucose measured by glucose oxidase method or glucose electrode
method
 Prompt analysis should be performed – reduction of glucose up to
6mg/dl/hr in a blood sample that awaits analysis.

30. III SUBCUTANEOUS CONTINUOUS
GLUCOSE MONITORING SENSORS(CGMS)
 Have been used in glucose monitoring in newborns
 Helps in detection of hypoglycemia, that missed on routine screening
 CGMS require insertion of platinum sensor in subcutaneous tissue – increase the risk of
infection.
 Interstitial glucose is catalyzed and electrical current is produced every 10 second
 Primarily used in research settings, studies required to determine the efficacy and safety
in neonatal population.

31. SECOND LINE INVESTIGATIONS
Step 1
• Insulin, cortisol
• Betahydroxybutyrate,FFA,PCV, sepsis W/U
Step 2
• Ammonia, Lactate, Urine – ketone/reducing substance
• GH, TSH, ACTH, TMS
Step 3
• Genetic testing-SUR1,KiR6.2
• DOPA-PET scan pancreas

33. HYPOGLYCEMIA MANAGEMENT
 Anticipation and prevention are key to the management of infants at risk for
hypoglycemia.
 The goal in the management of neonatal hypoglycemia is to restore plasma
glucose levels to a safe, age-appropriate range.
 Enteral feeding should be instituted in all newborns as quickly as possible unless
there are contraindications because of other morbidities
 When hypoglycemia persists on a typical feeding regimen, more frequent feeding
regimens or use of calorically dense formulas or fortification of breast milk may
be tried.

34.  Newborns with risk factors for hypoglycemia should receive oral feeding
within 1 hour after birth
 Breastfeeding - enhances gluconeogenesis and increases the production of
glucogenic precursors.
-keep ketones levels high  alternate fuel during first few days while
baby adapts to DBF.
 DEXTROSE GEL (40%) – To treat mild hypoglycemia in infants at risk
for hypoglycemia
- Under trial now.

35. Intravenous Dextrose
 Intravenous dextrose is the treatment of choice for acute management, when enteral feeding is
contraindicated or the newborn suffers from symptomatic or severe hypoglycemia,
 The standard approach is to give a 2 mL/kg (200 mg/kg) bolus of 10% dextrose followed by a
continuous dextrose infusion to achieve euglycemia
 Start GIR at 6mg/kg/min ; target blood sugar is >60mg/dl
 Blood glucose should be checked after 30 minute and then every 6 hours until blood glucose
>60mg/dl
 If Blood glucose below 60mg/dl despite bolus and glucose infusion - GIR should Increased in
2mg/kg/min every 15 -30 minute until maximum of 12mg/kg/min.

36. Tapering
 After 24 hours of IV glucose therapy, two or more consecutive blood glucose
are >60mg/dl, the infusion can be tapered off at the rate of 2mg/kg/min every
6 hours with blood glucose monitoring
 Tapering has to be accompanied by concomitant increase in oral feeds
 Once GIR of 4mg/kg/min is achieved , oral intake is adequate and the BGL
are consistently >60 mg/dl , the infusion can be stopped.
 Do not stop glucose infusion abruptly as severe rebound hypoglycemia may
occur

37. GLUCOSE INFUSION RATE ( GIR)
 GIR= dextrose % concentration × ml/kg/day
144
 Dextrose % = 144*GIR
ml/kg/day
 infusion of glucose is usually maintained at 6 to 8 mg/kg/min

39. BASIC APPROACH REFRACTORY HYPOGLYCEMIA
Non ketotic Ketotic
High Insulin Low insulin
Normal
ammonia
pancreatic
Βeta cell mutations
High
ammonia
GLUD1
mutaions
Free fatty acid
oxidation
defects
High lactate
Normal
lactate
• Hypopitutarism
• Isolated GH
deficiency
• CAH
• Organic aciduria
• Disord- gluconeogenesis
• Glycogen storage
disorders

40. . Newborn with persistent hypoglycemia. BOHB b-hydroxybutyrate; FFA free fatty acid; GH growth hormone; GLUD glutamate dehydrogenase; HI hyperinsulinism; K-ATP adenosine triphosphate
sensitive potassium channel; MCAD medium-chain acyl-CoA dehydrogenase; PG plasma glucose; SCHAD short-chain L-3-hydroxyacyl-CoA dehydrogenase; VLCAD very-long-chain acyl-CoA
dehydrogenase

41. MANAGEMENT OF PERSISTENT
HYPOGLYCEMIA cont…
 Treat the cause eg; Endocrine and glucogenic and glycogenic disorder
 Maximize the GIR
 Medications : Hydrocortisone / Diazoxide / Octreotide /Glucagon / sirolimus
 Surgery – partial and subtotal pancreatectomy

42. DRUGS USED IN MANAGEMENT OF RESISTANT
HYPOGLYCEMIA
DRUGS DOSE ROUTE MODE OF ACTION SIDE EFFECTS
Hydrocortisone 5mg/kg/day
2 divided dose
PO/IV • Reduces peripheral
glucose utilization
• Increases gluconeogenesis
• Increase glucagon effect
Hyperglycemia
Hypertension
Diazoxide 5-15mg/kg/day
TDS
PO K channel agonist Fluid retention
Hypertrichosis
Cardiac failure
Octreotide 5-35mcg/kg/day
TDS/QID
PO Somatostatin analogue
inhibits insulin secretion
Cholelithiasis
Transient growth
impairment
Tachyphylaxis
Glucagon 0.2 mg/kg SC or IM Glycogenolysis
Increased gluconeogenesis
nausea
Vomiting
Skin rash
Rebound
hypoglycemia

43. SIROLIMUS
Useful in Diazoxide resistant hyperinsulinemic hypoglycemia
0.5mg/m2 of body surface area/day(in one or two doses)
Alone or along with Octreotide
Acts by – inhibiting m-TOR complex pathway
May leads to reduced viability of Beta cells.

44. Surgery
 Failure of medical intervention to stabilize plasma glucose levels
warrants exploration of surgery as an alternative treatment for
hypoglycemia. Specialized imaging using [18F]fluoro-L-DOPA
positron emission tomography with computed tomography
distinguishes focal from diffuse lesions in the pancreas and guides
surgical intervention.

45. APPROACH TO HYPERINSULINEMIC
HYPOGLYCEMIA

46. Long term follow-up and evaluation
 Infants with hypoglycemia exhibit a typical pattern – restricted diffusion in
occipital cortex, optic radiation and corpus callosum
 Affects visuomotor and executive functons in long term.
 Brainstem and cerebellum are relatively resistant.
 Difficult clinically to separate isolated hypoglycaemia from hypoxic
ischemic encephalopathy plus hypoglycaemia.
 Close follow-up of neurodevelopmental status is warranted

47. NEONATAL HYPERGLYCEMIA
 It is relatively rare condition in neonates and is diagnosed when
 whole blood glucose level >125mg/dl or plasma glucose
value>145mg/dl

48. ETIOLOGY
1. Iatrogenic – Exogenous parentral infusion of glucose, >5mg/kg/mt in preterm
infants <1000g.
2. Drugs – Glucocorticoids, caffeine, Theyophyllin, Phenytoin, Diazoxide
3. ELBW (<1000g) – variable insulin response to persistent endogenous glucose
production
4. Lipid infusion – free fatty acids are associated with increased glucose level
5. Sepsis – due to depressed insulin release
decreased glucose utilization.
elevated stress hormones, catecholamines

49. 6. Painful procedures like mechanical ventilation – catecholamine's and stress
hormones
7. Hypoxia – increased glucose production in the absence of peripheral
utilization
8. Surgical procedures – secretion of epinephrine, glucocorticoids, and
glucagon ,excess administration of iv fluid containing glucose
9. . Pancreatic lesion- aplasia, hypoplasia, absent pancreatic beta cells
10. Hyperosmolar formula infusion – associated with transient hyperglycemia
11.Immature development of glucose transporter Eg: GLUT- 4

50. NEONATAL DIABETIS MELLITES
 Rare disorder
 Incidence 1:300,000 to 500,000 live births
 Presents with significant hyperglycemia before 1st month of life that last for at least 2 weeks,
requires insulin therapy.
 most common occurs in SGA term infants.
 Family history of DM seen in 1/3rd cases
 Caused by defects in
insulin secretion
beta cell development

51. Presents with
Glycosuria
Hyperglycemia
Polyuria
Severe dehydration
Acidosis
Mild or absent ketonuria
Reduced subcutaneous fat
Failure to thrive

52.  NDM is subclassified into
• Transient neonatal diabetes mellitus (TNDM)
• Permanent neonatal diabetes mellitus (PNDM)
 PNDM - accounts for 50% of all cases of NDM
- mutations in K+ channel on pancreatic beta cells
- leads to decreased insulin secretion

53. Transient neonatal diabetes mellitus (TNDM)
 Accounts for remaining half of NDM cases.
 Between 60% and 80% of patients with TNDM
• Display genetic mutations
• Mostly chromosome-6 abnormalities
 Course of TNDM is highly variable
• Permanent resolution within the first several weeks or months of
life to recurrence later in childhood.

54. CHALLENGES IN MANAGEMENT
 Compromise of calories, if glucose is withheld
 Lack of a pharmacokinetic profile for S/C administration of insulin in
neonates
 Use of small doses that are highly error-prone
 Limited data for dilution of Insulin's
 lack of subcutaneous fat deposits in a preterm/IUGR

55. Long-term sequelae
• Developmental delay
• Cardiac anomalies
• Seizures
• Poor weight gain
• Recurrence of diabetes at an older age.

56. REFERENCES
1. CLOHERTY AND STARKS MANUAL OF NEONATL CARE
2. Nelson Textbook of Pediatrics 21 Edition
3. IAP Textbook of Pediatrics
4. AIIMS Protocols in Neonatology
5. neoreviews.aappublications.org January 1, 2020
6. Pediatric Endocrine Society for Evaluation and Management of
Persistent Hypoglycemia in Neonates, Infants,
and Children THE JOURNAL OF PEDIATRICS. www.jpeds.com

57.  Rapid Acting Insulins
• Lispro
• Aspart
 Short acting
• Insulin Glulisine
• Regular Insulin
 Intermediate acting
• NPH- Neutral Protamine
• Hagedorn
• Pre mixed Insulins

59. MANAGEMENT
 The primary goal is to early detection of hyperglycaemia
 Measure glucose level in premature infants or infants with abnormal
symptoms
 Decrease the GIR and closely follow the blood glucose level
 Begin parentral nutrition as early as possible in LBW
 Feed if condition allows

60.  Exogenous insulin therapy is been advised only if glucose value exceeds
250mg/dl
 Bolus insulin infusion 0.05 to 0.1 units of regular human insulin over 15 min
every 4-6 hrs
 Monitor glucose every 30min-1 hr
 If glucose remain >200mg/dl after 3 bolus consider continuous infusion

61.  Continuous insulin infusion
 Rate of infusion is 0.05-0.2 unit/kg/hr (0.05)
 Check glucose levels every 30 min until stable to adjust the infusion rate
 If glucose levels remains >180mg/dl titrate in increments of 0.01 unit/kg/hr
If hypoglycemia occurs – discontinue insulin infusion ; give 10% D 2ml/kg iv
bolus.
 Monitor potassium level
 Monitor for rebound hyperglycaemia

62. Subcutaneous insulin lispro
 Rarely used ,except in NDM
 Typical dose – 0.03units/kg for glucose >200mg/dl
 Rapid onset of action (15-30 mts) and peak effect is 30 mts to 21/2 hours
 Do not administer frequently than every 3 hours to avoid hypoglycemia
 Rotate administration site
 Monitor glucose level frequently, potassium level q6h.
 SULFONYLUREA .
used in long term management of infants with Kir6.2 and SUR1 defect.

63. THANK YOU