The common problem of hypoglycemia in neonates. Its causes, diagnosis and treatment/management.

1. Neonatal Hypoglycemia :
Transient & Persistent
MODERATORS-
PROF. S.M ALI
DR. UZMA FIRDAUS
DR. KASHIF ALI
PRESENTED BY- DR. YUSUF IMRAN
Date 19/12/2013

2. GLUCOSE PHYSIOLOGY IN FETUS
 Fetus obtains 60-70 % of its energy from Glucose.
 All Fetal Glucose is derives from maternal circulation by facilitated diffusion.
 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.

3. ADAPTATION AT DELIVERY
 When the umbilical cord is cut, source of Glucose is abruptly interrupted.
 Glucose requirements exceed those of adults mainly b/c of increased ratio
of brain to body mass.
 To maintain Glucose levels newborn must respond by-
 Glycogenolysis of hepatic stores.
 Inducing Gluconeogenesis.
 Utilizing exogenous nutrients from intermittent feeding.

4. ADAPTATION CONT…
 Maintenance of physiological plasma glucose concentration depends on
a normal endocrine system.
 Enzymes of glycogenolysis, gluconeogenesis and other metabolic fuels
must be functional.
 There must be an adequate supply of endogenous fat, glycogen and
gluconeogenic substrates (amino acids,glycerol, lactate).

5. Glucose Metabolism After Birth
Cessation of maternal
glucose supply
Surge in glucagon, catecholamine
Decrease insulin
Gluconeogenesis:
Hepatic glycogen, amino acid, fatty acid metabolism
Normal blood glucose

6. DEFINITION
 The definition of clinically significant hypoglycemia remains controversial. Usually
defined as blood glucose levels of <40 mg/dl (plasma glucose <45 mg/dl ).
 Clinical Definition
 Must fulfill Whipple’s Triad
a) Low glucose
b) S&S consistent with hypoglycemia
(eg. Jitteriness, tremors, lethargy, seizures, apnea, cyanotic spells, hypotonia,
difficulty feeding, hypothermia, coma)
c) Resolution of S&S after restoring glucose

7.  Cornblath’s “operational threshold”
2000AD
 Healthy full term infant
a) < 24 hr of age – 30 to 35 may acceptable at one time, but
should not be < 45 after feeding or after 24 hrs.
b) > 24 hr threshold is 45 to 50 mg/dl
 Infants with abnormal signs or symptoms- 45 mg/dl.
 Asymptomatic Infants with risk factors- 36mg/dl.
 For any baby if glucose is < 20 to 25 I.V glucose is needed.

8.  Knowledge gaps
 The complex nature and maturational features of global and
regional brain energy use remains to be studied in human neonates.
 There is no evidence based study to identify any specific plasma
glucose concentration to define pathologic hypoglycemia.
 There is great inconsistency in the sources and sampling methods of
blood and the methods used for subsequent analysis.
 There are no noninvasive methods for measuring glucose
intermittently or continuously.
 The role of EEG and Neuroimaging in the management or prediction
of hypoglycemia related neuronal injuries remains to be determined.

9. DEFINITION
 PERSISTENT HYPOGLYCEMIA-
 Require infusions of large amounts of glucose (>12 mg/kg/min) to
maintain normoglycemia.
 Persisting or recurring beyond the first 5 - 7 days of life.
** Prompt recognition is essential!!
These conditions are associated with severe disease at substantial risk
of developing severe mental retardation and epilepsy.

10. 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%

11. ETIOLOGY
1. Endocrine disorders
2. Decreased substrate
3. Increased utilization
4. Mixed

12. ETIOLOGY - I
1. Endocrine disorders
i. Hyperinsulinemia-
 Major cause of persistent hypoglycemia
 May cause increased brain injury
 Decreased glucose levels
 Prevent brain from utilizing non glucose substrates by blocking FA
release and ketone body synthesis.

13. A. Infant of diabetic mother – most common
B. Congenital hyperinsulinism (P)
C. Beckwith-weidmann syndrome (P)
D. Erythroblastosis fetalis
E. Exchange transfusion
F. Insulin producing tumor (P)
G. Maternal beta agonist, tocolytics *P= Persistent
H. Improperly placed umbilical artery catheter
I. Inadvertent insulin administration

14. ii. Other endocrine disorders – def of antagonist hormones
A. Immaturity of hepatic enzymes for glucose production
B. Hypopituitarism (P)
C. Hypothalamic deficiency
D. Hypothyroidism (P)
E. Adrenal insufficiency (P)
F. Glucagon or epinephrine deficiency

15. ETIOLOGY - II
2. Decreased substrate availability
A. Intrauterine growth restriction
B. Prematurity
C. Reduced Glycogen stores
D. Reduced fat stores
E. Glycogen storage disease (P)
F. Inborn errors (eg. Fructose intolerance, defects in amino acid metabolism,
mitochondrial fatty acid oxidation & ketogenesis defects ) (P)

16. ETIOLOGY III
3. Increased utilization
A. Increased brain wt to body wt and liver wt ratio (P)
B. Perinatal asphyxia
C. Hypothermia
D. Polycythemia

17. ETIOLOGY IV
4. Miscellaneous/multiple mechanisms
A. Sepsis
B. Congenital heart disease
C. Central nervous system abnormalities (P)

18. ETIOLOGY - DISCUSSION
Prematurity and IUGR
 Hepatic glycogen stores are limited in both preterm infants and SGA infants.
 Increased brain-to-bodyweight ratio in IUGR babies.
 Studies in preterm and IUGR infants have found altered patterns of insulin
secretion, substrate metabolism, and hormonal responses to changes in
blood glucose concentration compared with AGA term infants.
 Asphyxia and hypothermia - increased metabolism of glucose with rapid
depletion of glycogen stores – hypoglycemia.

19. ETIOLOGY - DISCUSSION
Infants of diabetic mothers (IDMS)
 Placental glucose transport is increased, leading to fetal hyperglycemia,
which stimulates secretion of insulin by the fetal pancreas.
 Also have exaggerated pancreatic insulin secretion in response to a
given glucose load compared with non IDMs.
 Insulin inhibits gluconeogenesis and increases glucose utilization in insulin
sensitive tissues.
 After delivery, increased blood glucose concentrations no longer are
present, but the hyperinsulinemia persists for 24 to 72 hrs.

20. ETIOLOGY - DISCUSSION
Erythroblastosis fetalis and beta-agonist tocolytic agents
 Infants with erythroblastosis fetalis have increased levels of insulin and an
increase in the number of pancreatic beta cells. Mechanism unclear.
 Exchange transfusion - infant receives a significant glucose load, with
subsequent exaggerated insulin response from pancreas.
 Use of beta-agonist tocolytic agents such as terbutaline - is associated with
hyperinsulinemia in the newborn, esp if used for more than 2 weeks and
discontinued less than 1 week prior to delivery.

21. ETIOLOGY - DISCUSSION
 Hyperinsulinism
 Some perinatal asphyxia or IUGR infants demonstrate hyperinsulinemia that
may rarely persist for as long as 4 weeks.
 Congenital hyperinsulinism - most common cause of hypoglycemia
persisting beyond the first week of life.
 Autosomal recessive form - linked to a defect in the sulfonylurea receptor or K+ -ATP
channel.
 Autosomal dominant form of hyperinsulinemia also occurs but mutation not identified.
 Beckwith-Weidemann syndrome - associated with hyperplasia of multiple organs, including
the pancreas, with consequent increased insulin secretion.
 localized islet cell adenomas can also cause hyperinsulinism.

22. ETIOLOGY - DISCUSSION
Inborn errors of metabolism
 May affect either the availability of gluconeogenic precursors or the function of
the enzymes required for production of hepatic glucose.
 Glycogen storage disease, galactosemia, fatty acid oxidation defects, carnitine
deficiency, several of the amino acidemias, hereditary fructose intolerance
(fructose-1,6-diphos-phatase deficiency), and defects of other gluconeogenic
enzymes.
 Endocrine disorders such as hypopituitarism and adrenal failure also can result
in hypoglycaemia.

23. SYMPTOMS
I. Tremors, Jitteriness or Irritability
II. Seizures, Coma
III. Lethargy, Apathy and Limpness
IV. Poor feeding, Vomiting
V. Apnea
VI. Weak or High pitched cry
VII.Cyanosis
VIII.Many infants have no symptoms

24. SCREEENING
 Done in infants at risk and those with symptoms.
 Maternal risk factors
 Maternal diabetes mellitus– risk correlates with quality of control more
than category of diabetes
 Intrapartum administration of Glucose
 Maternal drug therapy including: β-blockers,Oral hypoglycaemic
agents, Valproate
 Family history of metabolic disorders (e.g. Medium-chain acyl-CoA
dehydrogenase deficiency (MCADD))

25. SCREENING
 New born Risk factors
 Prematurity less than 37 weeks
 Small for gestational age (SGA) (less than 10thpercentile) or
intrauterine growth restriction
 Low birth weight (less than 2500 gram)
 Large for gestational age (LGA) (greater than 90th percentile)

26. Other New Born Risk factors
 Macrosomia
 Perinatal hypoxic-ischaemic insult
 Respiratory distress
 Sepsis or suspected infection
 Hypothermia
 Polycythaemia
 Congenital cardiac abnormalities
 Endocrine disorders
 Family history of metabolic disorders
 Inborn errors of metabolism
 Rhesus haemolytic disease
 Erythroblastosis fetalis
 Obvious syndromes:
§ Beckwith-Wiedemann syndrome
§ Midline defects (e.g. cleft palate)
 Inadequate feeding
 Weaning of IV fluids

27. HOW TO SCREEN?

28. SRCREENING TOOLS
 Prior to blood sampling:
 Ensure the baby receives appropriate pain reducing strategies
 The use of oral sucrose is not contraindicated.
 To avoid any effect on the newborn’s blood sugar, oral sucrose should
preferably be given only a short duration (e.g. less than 30 seconds) before
the blood sampling.

29. SCREENING TOOLS
A Blood glucose level (BGL) may be measured using a:
 Formal measurement:
o Blood gas machine/analyser – use a capillary tube or blood gas syringe
o Biochemical laboratory – use, in order of preference, either a fluoride
oxalate (grey top), clotted (red top), or heparin (green top) tube.
 Bedside glucometer:
o Considered a screening tool
o Use a glucometer that uses a glucose oxidase test strip with
electrochemical sensor
o Although newer generation glucometers have improved accuracy
glucometers are less accurate than formal measurements in lower BGL ranges

30. SCREENING TOOLS
Factors affecting BGL results
 The sample collection technique:
o Squeezing a poorly perfused heel may cause haemolysis resulting in a
falsely low BGL reading
o Inadequate clearing of the umbilical catheters before sampling
o Never take BGL from a venous or arterial line where Glucose is infusing
o A delay between collection and laboratory analysis may produce a
falsely low BGL reading
 Results from arterial, venous and capillary samples may vary by 10-15%
 High haematocrit may contribute to low BGL readings in bedside
glucometers or when there is a delay in processing samples.

31. MANAGEMENT
 Why should hypoglycemia in the newborn be managed aggressively ?
I. Glucose is the predominant fuel for the newborn brain.
II. Hypoglycemia predisposes to long term neurological damage.
III. Common sequelae of hypoglycemia are disturbances of neurologic
development and intellectual function.
IV. Minor deficits - spasticity and ataxia and seizure disorders can also
occur.
V. The occurrence of these may be related to etiology of
hypoglycaemia.

32. MANAGEMENT : PREVENTION
 Discuss preventative care with the parents/carers.
 Keep the baby warm
• At birth dry and remove wet linen
• Initiate early skin to skin contact (SSC) (baby’s gestation and
condition permitting)
o Encourage ongoing SSC to assist thermoregulation and promote
frequent breastfeeds
o If required, use warmed blankets, overhead heaters, incubators and
heated mattresses ETC.

33. MANAGEMENT : PREVENTION
Provide energy by:
 Initiating early feeds within 30-60 minutes of birth with:
o Breastfeeding
o Assist feeds (Paladai or NG feeds) if baby is less than 35 weeks
gestation
o If baby is not feeding well, give colostrum (expressed)
 For at risk babies – continue oral feeding at least three hourly or more
frequently.
 Separation of mother and baby should be avoided.
 Breastfeeding may enhance ketogenesis which is alternate fuel for brain.
 If enteral feeding is not possible or contraindicated – commence IV therapy.

34. Feeding?
IV therapy?
Medication?
MANAGEMENT : TREATMENT

35. TREATMENT– Oral Feeds
 Can be used in asymptomatic infants
 Only breast milk or formula (never administer glucose water!!)
 Follow up blood glucose within 1 hour of feeding.
 If the glucose level doesn’t rise, a more aggressive therapy may be
needed.

36.  Asymptomatic hypoglycemia –

37. TREATMENT
 Management of Symptomatic hypoglycemia-
Bolus of 2 mL/kg of 10% dextrose
Symptomatic
hypoglycemia
Start Glucose infusion @ 6-8mg/kg/min
Check Blood sugar at
30-60min
BS >50, give for 24 hrs
start tapering once 2
reading above 50
BS <50,increase GIR in
steps of 1-2 upto 12

38. TREATMENT
 Calculation of Glucose Infusion Rate (GIR)
 GIR = Rate of IV fluids (in ml/kg/day) x % of dextrose infused mg/kg/min
144
 GIR in infants on IV fluids + Oral feeds
Glucose infusion rate while on feeding (mg/kg/min) =
[IV rate (ml/hr) x Dextrose conc (g/dl) x .0167 / wt (kg)] + [Feed rate(ml/hr) x Dextrose
conc* (g/dl) x
.0167 / wt (kg)]
Amount of dextrose in milk : Breast milk = 7.1 gm/dL ,Term formula = 7.1gm/dL, Preterm
formula = 8.5 gm/dL .

39.  GIR can also be calculated as:
 GIR = Total glucose given (IV + Oral ) per 24 hr mg/kg/min
Wt x 1.44

40. SEVERE,PERSISTENT OR RECURRENT HYPOGLYCEMIA
 Symptomatic including seizures or altered level of consciousness
 Severe:
o BGL less than 20 mg/dl or unexpectedly low for the clinical situation
o Baby requiring GIR >10 at any time
 Persistent or recurrent
 Early onset hypoglycaemia that is persisting/recurring after 72 hours
 Associated with other abnormalities such as
o Midline defects o Micropenis
o Exomphalos o Erratic temperature control
 Unusual in presentation and/or no maternal or neonatal risk factors present
 Family history of Sudden Infant Death Syndrome, MCADD deficiency, Reye’s
syndrome or developmental delay

41. EVALUATION FOR PERSISTENT HYPOGLYCEMIA
 First line investigations - ( For Hyperinsulinemic hypoglycemia )
Draw a blood sample when blood glucose is <40 and test for-
 Glucose
 Insulin
 Cortisol
 Beta hydroxybutyrate and FFA levels- if decreased can indicate excessive
insulin action.

42. EVALUATION CONT…
 If insulin level is normal for the blood glucose level, consider
additional testing-
I. Growth hormone
II. ACTH
III. Thyroxine (T4) and TSH
IV. Glucagon
V. Plasma amino acids

43. VI. Urine ketones
VII. Urine reducing substance
VIII. Urine amino acids
IX. Urine organic acids
X. Genetic testing for mutations like SUR1 & Kir6.2

44. OTHER CAUSES TO BE RULED OUT--
 If symptoms persist after the glucose concentration is within normal
range other etiologies should be considered-
I. Sepsis
II. CNS disease
III. Toxic exposure
IV. Metabolic abnormalities
a. Hypocalcemia
b. Hyponatremia or Hypernatremia
c. Hypomagnesemia
d. Pyridoxine deficiency

45. V. Adrenal insufficiency
VI. Heart failure
VII. Renal failure
VIII. Liver failure

46. PHARMACOLOGICAL INTERVENTION
 If the Glucose infusion rate is greater than 10-12 mg/kg/minute:
o Consider pharmacological intervention for severe, persistent or recurrent
hypoglycaemia
o Refer for specialist management (e.g. paediatric
endocrinologist/metabolic physician) where required as this is almost
certainly hyperinsulinaemia
 Ensure diagnostic samples have been collected prior to using specific
medication

47. GLUCAGON
 Dose – 0.025 – 0.2 mg/kg, maximum 1 mg i.m , sub cutaneous or i.v .
 Indication – It may be given to infants with good glycogen stores,
but effects is temporary.
 May not work if
 Reduced glycogen stores
 Glycogen storage disease

48. Hydrocortisone
 Dose: 10 mg/kg/day IV q 12 hrs
 Add after 24-48 hours of IV therapy but only for temporary
treatment for 1-2 days then slowly reduce dose.

49. Diazoxide
 Dose: 5 - 8 mg/kg/day PO q 8 hrs.
 Indication: Infants who have persistent hyperinsulinemia (e.g..
Nesidioblastosis)
 Monitor: BP – sodium and fluid retention is a common side-effect.

50. OCTREOTIDE
 Dose – 5-20 mcg/kg/day subcutaneously or intravenously q 6 – 8
hrly.
 Indication – In hyperinsulinemic patients when Diazoxide does not
successfully control glucose level.
 Avoid abrupt withdrawal
 Has been associated with necrotising enterocolitis

51. SURGERY
 Pancreatectomy – Decreases insulin secretion.

52. CONCLUSION
 Awareness of risk factors that predispose infants to hypoglycemia allows for
screening of those at risk.
 If detected hypoglycemia can be treated promptly, thereby preventing the
development of severe or symptomatic hypoglycemia, which is associated
with adverse outcome.
 Asymptomatic hypoglycaemia: It is likely that hypoglycemia contributes to
abnormal neurodevelopmental outcome in infants with other risk factors for
brain injury, such as prematurity or HIE .

53. Thank You
GGlucose molecule