yusuf transient & persistent hypoglycemia in neonates

Neonatal Hypoglycemia : Transient & Persistent

MODERATORS-

PROF. S.M ALI

DR. UZMA FIRDAUS

DR. KASHIF ALI

PRESENTED BY- DR. YUSUF IMRAN

Date 19/12/2013

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.

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.

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).

Glucose Metabolism After Birth

Cessation of maternal glucose supply

Surge in glucagon, catecholamineDecrease insulin

Gluconeogenesis: Hepatic glycogen, amino acid, fatty acid metabolism

Normal blood glucose

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

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.

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.

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.

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%

ETIOLOGY

1. Endocrine disorders

2. Decreased substrate

3. Increased utilization

4. Mixed

ETIOLOGY - I

1. Endocrine disordersi. 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.

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

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

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)

ETIOLOGY III

3. Increased utilization

A. Increased brain wt to body wt and liver wt ratio (P)

B. Perinatal asphyxia

C. Hypothermia

D. Polycythemia

ETIOLOGY IV

4. Miscellaneous/multiple mechanisms

A. Sepsis

B. Congenital heart disease

C. Central nervous system abnormalities (P)

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.

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.

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.

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.

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.

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

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))

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)

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

HOW TO SCREEN?

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.

SCREENING TOOLSA 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

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.

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.

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.

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.

Feeding? IV therapy? Medication?

MANAGEMENT : TREATMENT

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.

Asymptomatic hypoglycemia –

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

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 .

GIR can also be calculated as:

GIR = Total glucose given (IV + Oral ) per 24 hr mg/kg/min

Wt x 1.44

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

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.

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

VI. Urine ketones

VII. Urine reducing substance

VIII. Urine amino acids

IX. Urine organic acids

X. Genetic testing for mutations like SUR1 & Kir6.2

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

V. Adrenal insufficiency

VI. Heart failure

VII. Renal failure

VIII. Liver failure

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

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

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.

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.

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

SURGERY

Pancreatectomy – Decreases insulin secretion.

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 .

Thank You

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