HYPOGLYCEMIA IN INFANTS 17-07-2020

HYPOGLYCEMIA IN INFANTS

Dr. Arti Yadav

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OUTLINE OF PRESENTATION

• Introduction

• Principle of glucose metabolism

• Hormonal and metabolic systems of fasting adaptation

• Definition of Hypoglycemia

• Clinical features

• Diagnostic approach

• Categories of Hypoglycemic disorders

• Treatment and Outcome

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INTRODUCTION

• Hypoglycemic disorders are rare, but their consequence can be severe and disabling.

• Severe hypoglycemia may result in seizure & brain damage, rarely death.

• Given these severe consequence, prompt diagnosis & appropriate management is crucial.

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Hypoglycemia, functional brain failure, and brain death Philip E. Cryer

PRINCIPLE OF GLUCOSE METABOLISM

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GLUCOSE METABOLISM

• Plasma glucose concentration is a function of the rate of glucose entering the circulation (glucose appearance) balanced by the rate of glucose removal from the circulation (glucose disappearance).

• Circulating glucose (3 sources)-

• Intestinal absorption during the fed state

• Glycogenolysis

• Gluconeogenesis

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GLUCOREGULATORY HORMONES

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FASTING STATE

(1) Plasma glucose is derived from glycogenolysis under the direction of glucagon.

(2) Basal levels of insulin control glucose disposal.

(3) Insulin’s role in suppressing gluconeogenesis and glycogenolysis is minimal due to low insulin secretion in the fasting state

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FED STATE

(1) Plasma glucose is derived from ingestion of nutrients.

(2) Glucagon secretion is suppressed through the action of endogenous insulin secretion (paracrine route).

(4) In the fed state, insulin suppresses gluconeogenesis and glycogenolysis in the liver

(5) Promotes glucose disposal in the periphery.

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ROLE OF AMYLIN AND GLP-1

• Amylin is cosecreted with insulin by pancreatic β-cells in response to nutrient stimuli.

• Amylin exerts its actions through the CNS (Area postrema part of the dorsal vagal complex)

• GLP-1 is secreted by the L-cells in the ileum and colon

• Degraded by the enzyme dipeptidyl peptidase-IV (DPP- IV)

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HORMONAL ADAPTATION OF FASTING

• Hypoglycemia- Always a problem with fasting adaptation.

• Three metabolic systems-• hepatic glycogenolysis,

• hepatic gluconeogenesis, and

• hepatic ketogenesis.

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METABOLIC PATHWAYS

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PHYSIOLOGY OF DEFENSE AGAINST HYPOGLYCEMIA

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Cryer, P. E. (1997). Hypoglycemia: pathophysiology, diagnosis, and treatment.

GLUCOSE METABOLISM IN THE FETUS & NEWBORN

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GLUCOSE METABOLISM IN THE FETUS

• 80% of fetal energy comes from glucose and 20% from metabolism of lactate and amino acids

• GLUT1 is the major isoform for transfer of glucose across the placenta to the fetus

• Maternal-fetal glucose gradient is the major determinant of placental glucose transfer independent of the maternal insulin

• The insulin resistance of the mother results in an increased availability of glucose to meet the increasing energy demands of the fetus

• In utero, the raised insulin/glucagon ratio drives metabolism toward anabolism (rapid growth of the fetus)

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Williams Textbook Of Endocrinology

FETAL METABOLISM

Fetus is entirely dependent on mother for nutrients but it is hormonally independent of the mother

ADAPTIVE CHANGES AT BIRTH

Rise in plasma glucose

Mobilization of glycogen,

fatty acid

Epinephrine, norepinephrine,

Glucagon rises

Plasma insulin

decreases

• Plasma epinephrine and nor-epinephrine rise 3 to 10 fold.

• In 1st 2 hours, glucagon rise and continue to increase during the first 3 days of life.

• By 8-12 hours, gluconeogenesis becomes fully effective.

• Ketosis is impaired for the first 12 hours of life.

• Ketone utilization provide 25% of the energy needs of the neonate >12 hours of life.

Blood Glucose in the Neonate and its clinical significanceCORNBLATH M

CHANGES AT BIRTH• During transition, glucose levels fall in the

first 2 hours (as low as 25- 30 mg/dl), stabilize to 65 – 70 mg/dl by 3 to 4 hours of life

• 30% of normal newborns will have glucose concentrations <50 mg/dL in the first 24 hours of life.

• This physiologic drop in glucose levels in the first 24 hours of life is transitional hypoglycemia, which occurs in normal healthy newborns.

19Blood Glucose in the Neonate and its clinical significanceCORNBLATH M

ABNORMALITIES OF TRANSITION

• In IUGR, the diminished glycogen reserves, results in hypoglycemia in first 24 hours of life.

• SGA infants have a transient state of hyperinsulinism persisting over few days.

• IDM –Lack normal drop in insulin after birth, impaired glycogenolysis and

lipolysis.

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DEFINITION OF HYPOGLYCEMIA

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CLINICAL DEFINITION

• Clinically significant hypoglycemia is diagnosed if Whipple’s triad (Whipple & Frantz 1935) is

present:

➢Symptoms of hypoglycaemia

➢Symptoms occurring in presence of low plasma glucose

➢Clinical signs resolve within minutes to hours, after normalization of blood glucose

• Limitations:

➢Clinical signs of hypoglycemia are not specific in newborn and infant

➢May be different from the levels at which biochemical injury occurs

➢Does not take into account “asymptomatic hypoglycemia”

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• Metabolic Definition- The concentration of blood glucose at which counter-regulatory hormonal response is elicited.

• Neurophysiological Definition- Blood glucose concentration at which there is abnormalities of brain-stem auditory or somatosensory evoked potentials.

• Operational Definition- Plasma or whole blood glucose concentration at which clinicians should consider an intervention.

• Normal plasma glucose- After 1st week of life, plasma glucose conc of 70-100 mg/dl.• Diagnostic threshold- Hypoglycemia is defined as plasma glucose <50 mg/dl.• Treatment Goal- To maintain plasma glucose > 70 mg/dl

Re-Evaluating “Transitional Neonatal Hypoglycemia”: Mechanism and Implications for ManagementStanley et al

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Awareness of hypoglycemia is largely, the result of perception of neurogenic rather than neuroglycopenic symptoms.

Mechanism of Awareness of Hypoglycemia Perception of Neurogenic (Predominantly Cholinergic) Rather Than Neuroglycopenic SymptomsDWIGHT A. et al

CLASSIFICATION OF CAUSES OF HYPOGLYCEMIA

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Sperling Pediatric Endocrinology Textbook- 4th Edition

A. DISORDER OF INSULIN EXCESS OR ACTION

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INSULIN-MEDIATED DISORDERS

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HYPERINSULINEMIC HYPOGLYCEMIA

• Can be catergorized as:• Transient

• Perinatal stress induced

• Congenital (monogenic)

• Syndromic

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1. TRANSIENT HYPERINSULINISM

• Infant of Diabetic mother• Hyperinsulinemia

• Diminished glucagon secretion.

• Hypertrophy and hyperplasia of islets

• Reduced endogenous glucose production

• Other maternal factors

Oral hypoglycemics (sulfonylureas)

Medications (terbutaline or propranolol)

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INFANT OF DIABETIC MOTHER

• Onset of hypoglycaemia- within first few hours after birth

• Preterm/ SGA- more risk

• Well controlled GDM- near-normal-sized infants, less likely to develop neonatal hypoglycemia and other complications .

• Treatment of IDM commonly requires iv glucose until the hyperinsulinemia resolves (2-4 days).

• During labor and delivery, maternal hyperglycemia should be avoided because it result in fetal hyperglycemia which predisposes to rebound hypoglycaemia.

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Management of Infant of Diabetic MothersL Cordero

2. PERINATAL STRESS-INDUCED HYPERINSULINISM

• Transient alteration in β-cell regulation of insulin secretion

• Suspected in neonates with hypoglycemia persisting beyond the first 2-3 days of life

• Respond very well to diazoxide (5-10 mg/kg/d).

• Continue diazoxide for at least 4-8 weeks before attempting to withdraw

• Median age of resolution- 6 months

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Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism, Francis et al

3. SYNDROMIC HYPERINSULINISM

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Syndrome Gene Features

Beckwith-Wiedemann

H19, IGF2, KCNQ1, CDKN1C

Macroglossia, abdominal wall defect, hemihypertrophy, embryonal tumors

Kabuki KMT2D, KDM6A Eversion of lower lateral eyelid, arched eyebrows, depressed nasal tip, prominent ears, fetal finger pads, short stature, cardiac defect, Intellectual disability

Sotos NSD1 Prenatal & postnatal overgrowth, frontal bossing, intellectual disability

Turner KDM6A Short stature, premature ovarian failure, CHD, Renal abnormality

Hyperinsulinemia with Hypopituitarism

FOXA2 Hypopituitarism, dysmorphism, hypoplastic pituitary gland & stalk

SYNDROMIC HYPERINSULINISM

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Syndrome Gene Features

Hyperinsulinemia with polycystic kidneys

PMM2 Polycystic kidneys & liver cyst

Tyrosinemia type 1 FAH Liver dysfunction, renal tubular defect, rickets, growth failure

Usher syndrome type 1C ABCC8, KCNJ11 SNHL, RP, Vestibular hypofunction

Rubinstein -Taybi CREBBP, EP300 Distal limb abnormality, short stature, intellectual disability

Congenital disorder of Glycosylation

PMM2, MP1, PGM1 FTT, Developmental delay, epilepsy, ataxia, hepatopathy

4. MONOGENIC HYPERINSULINISM

• Idiopathic hypoglycemia of infancy/ Congenital hyperinsulinism

• Most common cause of persistent hypoglycemia in children

• Results from genetic defect in insulin secretory pathway of beta cell

• Mutations in nine genes have been identified

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(Insulin indep)

(Exercise ind hypoglycemia)

(NDM & MODY)

(Sulfonylurea)

(Diazoxide)

(Somatostatin analogue)

(AR PHHI)

(AD PHHI)

(Hypoglycemia with hyperammonemia

MONOGENIC HYPERINSULINESIM

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Mutation in sulfonyl receptor gene in familial persistent hyperinsulinemic hypoglycaemia of infancyThomas et al

DIFFERENTIAL DIAGNOSIS OF HI HYPOGLYCEMIA

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Panhypopituitarism

• Similar biochemical response to fasting & glucagon stimulation test

• Midline defect & microphallus

• Low cortisol & GH in critical sample

• Stimulation test for confirmation

Sulfonylurea ingestion

• Glipizide or glyburide

• Biochemical features similar to HI

Insulinoma

• Rare in children

• In association with MEN1

• Persistent & recurrent hypoglycaemia in adolescence

DIAGNOSTIC AND TREATMENT APPROACH

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B. DEFECTS IN COUNTER-REGULATORY RESPONSE

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DEFECTS IN COUNTER-REGULATORY RESPONSE

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ACTH

• Congenital ACTH deficiency due to mutation in TPIT (encodes TBX19)-Severe and persistent hypoglycaemia in neonatal period

Cortisol

• Reduced liver glycogen reserves & gluconeogenesis

• CAH, or hypoplasia of the adrenals- hyponatremia, hyperkalemia or ambiguous genitalia

• Diagnosis by stimulation test

• Treated with cortisol replacement

GH

• Decreased lipolysis

• Diagnosis by stimulation test

• Treated with GH replacement


• Panhypopituitarism- Isolated GH deficiency, or combined ACTH & GH deficiency

• Incidence of hypoglycaemia in panhypopituitarism -20%

• C/F-

• Microphallus- coexistent deficiency of gonadotropin

• Cholestatic jaundice

• Midline malformation (septo-optic dysplasia)

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Neonatal cholestasis and hypopituitarismKaufman et al


• Older infants and children- Ketotic hypoglycaemia

• Neonates- Hyperinsulinimic hypoglycaemia

• Not responsive to diazoxide

• Remits with replacement of deficient hormones (thyroxine, GH, cortisol)

• Epinephrine deficiency is rare & considered in familial dysautonomia or in children treated with beta-blockers

• Glucagon deficiency- Rare , SCHAD hyperinsulinism.

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C. DEFECTS IN GLYCOGENOLYSIS AND GLUCONEOGENESIS

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GLYCOGEN STORAGE TYPE1a

• Glucose 6-Phosphatase Deficiency (GSD Type 1a) • G6Pase catalyze terminal step of gluconeogenesis & glycogenolysis• Type 1b- defect in G6Pase transporter• C/F- Hypoglycemia (neonatal period), hepatomegaly (late infancy), FTT

1b- Intermittent neutropeniaMetabolic abnormalities- Elevation of lactate, TGs, uric acid, transaminases

Renal disease (30%)-proximal renal tubular dysfunction, distal tubular acidification defect, and hypercalciuria, nephrocalcinosis

T/t- Avoidance of fastingUncooked cornstarchCitrate supplementation (for hypercalciuria)

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D. DISORDERS OF FATTY ACID OXIDATION

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DISORDERS OF FATTY ACID OXIDATION

• End products- Ketone bodies (β-hydroxybutyrate & acetoacetate).

• Important fuels in peripheral tissues (brain, which can partially substitute ketone bodies for glucose during periods of fasting).

• Involve tissues with a high β-oxidation flux

(liver, skeletal and cardiac muscle).

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• AR

• Provoked by fasting

• Life-threatening hypoglycemia with deficiency of ketone bodies.

• Divided according to the site of the defect:

• defects of fatty acid and carnitine transport,

• b-oxidation defects

• electron transport chain defects

• defects of ketone body synthesis and utilization


• Presents beyond the neonatal period

• MCAD deficiency- Most common defect of fatty acid oxidation

• MCAD- Required for the initial dehydrogenation of acyl-CoAs (4-12 carbon)

• Defects in MCAD enzyme leads to accumulation of medium-chain fatty acids, detected by mass spectrometry

• The most prominent metabolite in MCAD deficiency is octanoylcarnitine (C8)

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Fatty acid oxidation disorders: a new class of metabolic diseasesHale et al


• Children with MCAD deficiency- normal at birth

• Presents- 3-24 months in response to prolonged fasting or intercurrent illnesses

• C/F- Intermittent hypoketotic hypoglycaemia

• No acidemia

• Liver function abnormalities, and hepatic steatosis

• The risk of severe complications and death is very high

• The diagnosis of these cases may be confused with Reye syndrome

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• Decreased plasma carnitine and increase in the ratio of esterified to free carnitine

• Evaluation of suspected FAOD- profile of plasma acylcarnitines by mass spectrometry

• The primary treatment of disorders of fatty acid oxidation is avoidance of fasting

• High-fat diets should be avoided

• An adjunct approach may involve the use of cornstarch in doses of 1.5 to 2 g/kg

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E. DEFECT OF GLUCOSE TRANSPORTER

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GLUT1 DEFICIENCY

• AD inborn error of glucose transport

• C/F- Seizures, developmental delay, spasticity, acquired microcephaly, and ataxia

• GLUT1 (encoded by SLC2A1) facilitates glucose entry into the brain

• Diagnosis- Low CSF glucose in the absence of hypoglycemia

Identification of SLC2A1 mutation (chr 1)

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Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorderLeen et al

GLUT1 DEFICIENCY

• Classic phenotype- Severe form of early onset epileptic encephalopathy in approximately 90% of cases

• Non-epileptic (10% cases)- Paroxysmal nonepileptic manifestations that include intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia.

• Treatment- Ketogenic diet (effectively controls the seizures, but less effect on the cognition)

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GLUT2 DEFICIENCY

• Originally described by Fanconi and Bickel

• AR mutations of the GLUT2 plasma membrane transporter for glucose (encoded by SLC2A2).

• Characterized by- Hypoglycemia and ketonuria in the fasting state

• Hyperglycemia in the postabsorptive state (decreased monosaccharide uptake by the liver and low insulin secretion due to impaired glucose sensing by the pancreatic β-cells)

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Fanconi-Bickel syndrome Manz et al

GLUT2 DEFICIENCY

• GLUT2 is expressed in hepatocyte, pancreatic β-cells, and the basolateral membranes of intestinal and renal tubular epithelial cells

• Hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose

• Impairment of glucose release from liver and reabsorption from renal tubular cells

• Galactose clearance and conversion to glucose is delayed.

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GLUT2 DEFICIENCY

• Age of presentation- 3-10 months

• Clinical features- Hepatomegaly (glycogen accumulation), Fanconi-type renal tubulopathy, hypophosphatemic rickets, stunted growth.

• T/t- Replacing water, electrolytes, and alkali, phosphate and vitamin D supplementation

• Diet-

• Adequate caloric intake to compensate for renal and intestinal glucose loss

• Frequent feeding

• Sowly absorbing carbohydrates (such as cornstarch) to avoid fasting hypoglycemia.

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STEPWISE APPROACH

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HISTORY

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Timing of Hypoglycemia

• Immediate post- prandial period: Reactive hypoglycaemia (suggests excess insulin secretion)

•Early postabsorptive hours: Hyperinsulinism, severe glycogen storage diseases

•After several hours of fasting: FAO, Disorder of gluconeogenesis

Sulfonylureas, insulin, or

alcohol

• Ingestion or injection

Fundoplication or other gastric

surgery

•Alimentary hyperinsulinism.

CLINICAL EXAMINATION

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Hepatomegaly

• GSD or an FAO disorder

Short stature or FTT

• GSD, Fanconi-Bickel syndrome

• Hypopituitarism (midline defects)

Neuromuscular signs

• FAOD

• Adrenoleukodystrophy

FASTING STUDIES (UNIT PROTOCOL)

• Prerequisite-• Admit patient• Secure an IV cannula.• Hydration must be maintained throughout the test• Oral and IV dextrose solutions should be available on bedside

• A general guide for maximum fasting times: • Neonates and infants (<3 months) - 4 to 8 hours (usually miss 1 feed only) • Infants (3-6 months) - 8 to 12 hours • 6 months-2 yrs - 12 to 16 hours • 2-10 years - 16 to 24 hours • >10 years - 24 to 48 hours

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FASTING STUDIES (UNIT PROTOCOL)

BG (mg/dl) Freq of monitoring

>72 every 60 minutes

54-72 every 30 minutes

<54 every 15 minutes

Symptomatic Immediately

• Draw critical sample if patient reaches blood glucose <50 mg/dl or time criterion as

decided is reached.

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Sample Amount

Glucose 0.5 mL oxalate

Insulin 1 mL purple top

Cortisol 1 mL purple top

Growth hormone 1 mL purple top

Lactate 0.5 mL grey top

Blood ketones 2 mL green top

Uric acid 1 mL red top

ACTH 2 mL purple top on ice

Pyruvate Special tube on ice

Acylcarnitines Blood dot on card, 1 mL serum

FFAs 2 mL red top

Urine ketones 2 mL urine

Urine organic acids 10 mL fresh

METHOD OF GLUCOSE ESTIMATION

• Reagent strips with electronic meters

• Laboratory analysis

• Blood gas analyser

• Continuous glucose monitoring systems (CGMS)

REAGENT STRIPS WITH ELECTRONIC METERS

• Point of care test

• Glucose oxidase method

• Current generated from the reaction is propotional to the glucose concentration

• Precision of ± 10-20%

• 75% of the time, the glucometer overestimates blood glucose

• Affected by hematocrit and high bilirubin levels

• Confirmatory lab test required esp. at low levels (less sensitive)

• Treatment not to be delayed awaiting lab value

LABORATORY ANALYSIS

• Gold standard

• Not affected by metabolites or hematocrit

• A valid laboratory plasma glucose determination required before diagnosing hypoglycemia

• Sample should be analyzed as soon as possible as glucose levels fall by 6mg/dl/hr

BLOOD GAS ANALYSER• Use electrochemical biosensors• Sensitivity- 89 %• Specificity- 90%

CGMS• S.c. placed glucose oxidase based

platinum sensor

• Catalyses interstitial glucose & an average of glucose values of 5 mins generated

• 3 times more likely to pick up low glucose readings as compared to intermittent monitoring

Measurement of glucose levels in the newbornKathryn Beardsall

VARIOUS TREATMENT OPTIONS

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DIAZOXIDE

• Agonist of KATP channel & suppresses insulin secretion

• Useful in hyperinsulinemic hypoglycemia (responsive to diazoxide)

• Dose: 8-15 mg/kd/day orally

• No response to diazoxide indicate defect in potassium channel

• Side effects: hypertrichosis & fluid retention

OCTREOTIDE:

• Long acting somatostatin analog

• Inhibits insulin release by inhibition of voltage gated Ca channel

• Useful when diazoxide is ineffective

• Dose: 5-20 µg/kg/day SC

GLUCAGON:

• Only a temporary measure to mobilize glucose for 2-3 hrs

• Useful if glycogen stores are adequate

• Dose: 0.2 mg/kg IM/SC

• Side effects: Thrombocytopenia and hyponatremia

HYDROCORTISONE

• Dose is 10mg/kg/day

• Before administering hydrocortisone it is important to take sample for serum cortisol

SURGICAL MANAGEMENT

• Lesionectomy or near total pancreatectomy if medical therapy fails to control hyperinsulinism

• 18F-fluoro-L-DOPA PET scan used to identify the extent of pancreatic involvement

NEURODEVELOPMENTAL OUTCOMES

• Hypoglycemia can cause pathological changes in the brain

• Typical pattern - Parietooccipital cortex & subcortical white matter

• Can also cause various cortical changes and hemorrhagic lesions

• Cerebellum and brain stem are generally spared

• Long-term sequelae- Cognitive impairment, recurrent seizure activity, CP, visual impairment and autonomic dysregulation

NEURODEVELOPMENTAL OUTCOMES

• Best modality for detecting hypoglycemic brain injury is MRI (including DWI)

• More common in hyperinsulinemic states where production of alternative fuels is also reduced

• Infant should also be assessed at 3, 6, 9, 12 & 18 months for growth, neurodeveloment, vision & hearing

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THANK YOU

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HYPOGLYCEMIA IN INFANTS 17-07-2020

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