hypoglycemia in newborns by nishadali

Hypoglycemia in newborn

Dr.Nishadali k Resident in pediatrics

PIMS

• Hypoglycemia is one of the most common metabolic problems seen neonatal intensive care unit.

• Glucose provides the fetus with approximately 60% to 70% of its energy needs.

• Almost all fetal glucose derives from the maternal circulation by the process of transplacental-facilitated diffusion that maintains fetal glucose levels at approximately two-thirds of maternal levels

• Newborn glucose levels fall to a low point in the first 1 to 2 hours of life, and then increase and stabilize at mean levels of 65 to 70 mg/dL by the age of 3 to 4 hours.

• Blood-glucose levels are frequently lower in newborn babies, but for confirming a diagnosis interpret the blood-glucose level within the clinical context.

• Most cases of neonatal hypoglycemia are transient, respond readily to treatment, and are associated with an excellent prognosis.

• Persistent hypoglycemia is associated with abnormal endocrine conditions and possible neurologic sequelae.

Incidence

• 16% of large-for-gestational-age (LGA) infants and 15% of small-for-gestational-age (SGA) babies.

DefinitionHistorical definitions:a. Epidemiologic definition Early definitions of normal neonatal glucose levels were derived by measuring glucose levels in populations of infants, some of whom were not being fed or given other sources of glucose. The statistical definition of normal, values that are within two standard deviations of the mean, resulted in the acceptance of glucose levels in the range of 20 to 30 mg/dL.This definition was affected by clinical practice at the time, and did not define “optimal” glucose level in newborns. This definition is no longer generally accepted.

• b. Clinical definition (Whipple triad) requires the following i. Reliable measurement of a low glucose level. ii. Signs and symptoms consistent with hypoglycemia. Development of clinical signs or symptoms may be a late sign of hypoglycemia. iii. Resolution of signs and symptoms after blood- glucose level is restored to normal range.

2. Operational threshold. Cornblath recommended use of an operational threshold for blood-sugar management in newborn infants.

The operational threshold is an indication for action and is not diagnostic of disease.

a) Less than 24 hours of age—30 to 35 mg/dL may be acceptable once, but raised to 45 mg/dL if the level persists after feeding or recurs in first 24 hours.

b) After 24 hours, threshold should be increased to 45 to 50 mg/dL.

ii. Infant with abnormal signs or symptoms—45 mg/dL.iii. Asymptomatic infants with risk factors for low blood sugar

—36 mg/dL. iv. For any baby, if glucose levels are <20 to 25 mg/dL, IV

glucose is needed to raise the plasma glucose to >45 mg/dL.

• The absence of overt symptoms at low glucose levels does not rule out central nervous system (CNS) injury.

• A glucose level <40 mg/dL at any time in any newborn requires follow-up glucose measurements to document normal values.

• Within the first hours of life, normal asymptomatic babies may have transient glucose levels in the 30s (mg/dL) that will increase either spontaneously or in response to feeding. These babies have an excellent prognosis.

• On the basis of recent developmental, neuroanatomic, metabolic, and clinical studies, goal is to maintain the glucose value >45 mg/dL in the first day, and >50 mg/dL thereafter.

Etiology

1.Increased utilization of glucose: Hyperinsulinism a. Diabetic mothers . b. LGA infants. 16% incidence of hypoglycemia in LGA infants of nondiabetic mothers ‘ c. Erythroblastosis (hyperplastic islets of Langerhans). d. Islet-cell hyperplasia, hyperfunction, focal hyperinsulinism, or diffuse hyperinsulinism (mutations of SUR1 [high-affinity sulfonylurea receptor] or KIR 6.2 [potassium-channel gene]).

e. Beckwith-Weidemann syndrome (macrosomia, mild microcephaly, omphalocele, macroglossia, hypoglycemia, and visceromegaly).f. Insulin-producing tumors (nesidioblastosis, islet-cell adenoma, or islet-cell dysmaturity).g. Maternal tocolytic therapy with β-sympathomimetic agents (terbutaline).h. Maternal chlorpropamide therapy ; maternal thiazide diuretics (chlorothiazide).

j. Abrupt cessation of high-glucose infusion. i.e,After exchange transfusion with blood containing high-glucose concentration.

2. Decreased production/stores:a. Prematurity.b. Intrauterine growth restriction (IUGR).c. Inadequate caloric intake.d. Delayed onset of feeding.

3. Increased utilization and/or decreased production. Any baby with one of the following conditions should be evaluated for hypoglycemia; parenteral glucose may be necessary for the management of these infants.a. Perinatal stressi. Sepsis.ii. Shock.iii. Asphyxia.iv. Hypothermia (increased utilization).v. Respiratory distress.vi. Post resuscitation.

b. Exchange transfusion with heparinized blood that has a low glucose level in the absence of a glucose infusion; reactive hypoglycemia after exchange with relatively hyperglycemic citrate-phosphate-dextrose (CPD) blood.c. Defects in carbohydrate metabolism i. Glycogen storage disease.ii. Fructose intolerance.iii. Galactosemia.

d. Endocrine deficiencyi. Adrenal insufficiency.ii. Hypothalamic deficiency.iii. Congenital hypopituitarism.iv. Glucagon deficiency.v. Epinephrine deficiency.

e. Defects in amino acid metabolismi. Maple syrup urine disease.ii. Propionic acidemia.iii. Methylmalonic acidemia.iv. Tyrosinemia.

v. Glutaric acidemia type II.vi. Ethylmalonic adipic aciduria.f. Polycythemia. Hypoglycemia may be due to higher glucose utilization by the increased mass of red blood cells.

g. Maternal therapy with β-blockers (e.g., labetalol or propranolol). Possible mechanisms include the following:i. Prevention of sympathetic stimulation of glycogenolysis.ii. Inhibition of epinephrine-induced increases in free fatty acids and lactate after exercise.

Diagnosis

1. Symptoms that have been attributed to hypoglycemia are nonspecific. a. Tremors, jitteriness, or irritability. b. Seizures, coma. c. Lethargy, apathy, and limpness. d. Poor feeding, vomiting.

e. Apnea.f. Weak or high-pitched cry.g. Cyanosis.h. Some infants may have no symptoms.

2. Screening: Serial blood-glucose levels should be routinely measured in infants who have risk factors for hypoglycemia and in infants who have symptoms that could be due to hypoglycemia.

a. Babies with risk factors should have their glucose levels measured within the first 1 to 2 hours after birth.

The period for which screening should be continued depends on the glucose levels measured and the etiology of hypoglycemia.

i. Infants of diabetic mothers usually develop hypoglycemia in the first hours of life and should

have frequent early measurements of blood-glucose level.

ii. Preterm and SGA infants should have blood-glucose measurements soon after birth and also during the first 3 to 4 postnatal days. iii. Infants with erythroblastosis fetalis should have blood-glucose level measured after exchange transfusions with CPD blood. iv. Infants with symptoms should be evaluated for hypoglycemia when the symptoms are present.

3. Reagent strips with reflectance meter: Although in widespread use as a screening tool, reagent strips are of unproven reliability in documenting hypoglycemia in neonates.a.Reagent strips measure whole-blood glucose, which is 15% lower than plasma levels.b.Reagent strips are subject to false-positive and false-negative results, even when used with a reflectance meter.

c. A valid confirmatory laboratory glucose determination is required before one can diagnose hypoglycemia.d. If a reagent strip reveals a concentration <45 mg/dL, treatment should not be delayed. If an infant has either symptoms that could be due to hypoglycemia and/or a low glucose level as measured by reagent strip, treatment should be initiated immediately after the confirmatory blood sample is obtained.

5. Laboratory diagnosis a. The laboratory sample must be obtained and analyzed promptly to avoid the measurement being falsely lowered by glycolysis. The glucose level can fall 18mg/dL/hour in a blood sample that awaits analysis.

6. Clinical confirmation of the diagnosis of symptomatic hypoglycemia requires both of the following:a. A laboratory-determined serum glucose level of <40 mg/dL at the time symptoms are present.b. Prompt resolution of the symptoms with the administration of IV glucose and correction of the hypoglycemia.

7. Additional testing: When the hypoglycemia is refractory and severe or if the need for large glucose infusions lasts over 1 week, evaluation of some of the rare causes of hypoglycemia should be considered. At that time an endocrine consultation may be helpful and measurements of the following should be considered:a. Insulin.b. Growth hormone.c. Cortisol.d. Adrenocorticotropic hormone (ACTH).e. Thyroxine (T4).

f. Thyroid-stimulating hormone (TSH).g. Glucagon.h. Plasma amino acids.i. Urine ketones.j. Urine-reducing substance.k. Urine amino acids.l. Urine organic acids.

8. Differential diagnosis. The symptoms mentioned can be due to many other causes with or without associated hypoglycemia. If symptoms persist after the glucose concentration is in the normal range, other etiologies should be considered. Some of these are as follows:a. Sepsis.b. CNS disease.c. Toxic exposure.

d. Metabolic abnormalitiesi. Hypocalcemia.ii. Hyponatremia or hypernatremia.iii. Hypomagnesemia.iv. Pyridoxine deficiency.

e. Adrenal insufficiency.f. Heart failure.g. Renal failure.h. Liver failure.

At-risk neonates for whom routine monitoring of blood glucose is recommended

• Preterm infants• Small for gestation (SGA)• Large for gestation (LGA)• Infant of diabetic mother (IDM)• Sick infants (eg: sepsis, asphyxia, respiratory distress)• Post exchange blood transfusion • Infants on intravenous fluids and parenteral nutrition • Infants whose mothers received beta blockers , oral

hypoglycemic agents or intrapartum dextrose infusion

Management

• Anticipation and prevention, when possible, are key to the management of infants at risk of hypoglycemia

1. Well infants who are at risk for hypoglycemia should have serial blood-glucose levels measured.

2. Infants of diabetic mothers should have glucose measured, and be treated

2. Other asymptomatic infants who are at risk for hypoglycemia - glucose measured in the first 1 to 2 hours of life.• Immediately after birth and as soon as their

condition allows they should be nursed or given formula per the mother's preference.

• This feeding should be repeated every 2 to 3 hours.

3. The interval between measurement of glucose levels requires clinical judgment.• If the glucose concentration is as low as 20 to

25 mg/dL, the baby should be treated with IV glucose with a goal of maintaining the glucose at a level of >45 mg/dL in the first 24 hours, and >50 mg/dL thereafter.

4. Feeding: Some asymptomatic infants with early glucose levels in the 30s (mg/dL) will respond to feeding (breast or bottle).• A follow-up blood-glucose measurement should be done

within 1 hour of the feeding. • If the glucose level does not rise, a more aggressive therapy

may be needed. • While early feeding of glucose water will transiently raise the

serum glucose level, there is often an associated rebound hypoglycemia, within 1 to 2 hours of feeding glucose water.

• The early introduction of milk feeding is preferable - result in raising glucose levels to normal, maintaining normal stable levels, and avoiding problems with rebound hypoglycemia.

• It is useful to add Polycose (4 kcal/oz) to feedings in infants who feed well but have marginal glucose levels.

5. Breast-feeding-Babies who are breast-fed have lower glucose levels but higher ketone body levels compared with those who are formula-fed. • The use of alternates be an adaptive mechanism during the first

days of life as breast-feeding is developing. • Some infants will have difficulty in adapting to breast-feeding,

and development of symptomatic hypoglycemia has been reported in breast-fed babies after hospital discharge.

• It is important to document that breast-fed babies are latching on and appear to be sucking milk, but there is no need to routinely monitor glucose levels in healthy full-term breast-fed babies who do not have additional risk factors.

6. IV therapy a. Indicationsi. Inability to tolerate oral feeding.ii. Symptoms.iii. Oral feedings do not maintain normal glucose

levels.iv. Glucose levels <25 mg/dL.

b. Urgent treatmenti. Administration of 200 mg/kg of glucose over 1

minute, to be followed by continuing therapy. (This is equivalent to 2 mL/kg of dextrose 10% in water (10% D/W) infused intravenously over 1 minute).

c. Continuing therapyi. Infusion of glucose at a rate of 6 to 8 mg of

glucose/kg/minute.ii. Administration of 10% D/W at a rate of 86.4

mL/kg/day or 3.6 mL/kg/hour gives 6 mg/kg/minute of glucose. Glucose infusion rate (GIR) may be calculated using the following formula:

GIR in mg/kg/min=dextrose%conc x ml/kg/day 144For example, in an infant receiving 10% D/W at 80 mL/kg/day, the GIRWould be 10x80/144=5.6mg/kg/min

iii. Recheck glucose level after 20 to 30 minutes and hourly until stable, to determine if additional therapy is needed.iv. Additional bolus infusions of 2 mL/kg of 10% D/W may be needed.v. If glucose is stable and in acceptable range, feedings may be continued and the glucose infusion tapered as permitted by glucose measurements before feeding.

d. For most infants, intravenous 10% D/W at daily maintenance rates will provide adequate glucose. The required concentration of dextrose in the IV fluids will depend on the daily water requirement.

•Calculation of both glucose intake (i.e., milligrams of glucose per kilogram per minute) and water requirements be done each day, or more frequently if glucose levels are unstable. •For example, on the first day, the fluid requirement is generally approximately 80 mL/kg/day, or 0.055 mL/kg/minute; therefore, 10% D/W provides 5.6 mg of glucose/kg/minute, and 15% D/W, at 80 mL/kg/day provides 8.33 mg of glucose/kg/minute.

e. Some infants with hyperinsulinism and infants with IUGR will require 12 to 15 mg of dextrose/kg/minute (often as 15% or 20% D/W).f. The concentration of glucose and the rate of infusion are increased as necessary to maintain a normal blood-glucose level.

• A central venous catheter may be necessary to give adequate glucose (15%-20% D/W) in an acceptable fluid volume. Taper GIR and concentration, monitoring glucose levels; and wean IV slowly while feedings are advanced.

7. Add hydrocortisone, 10 mg/kg/day intravenously in two divided doses, if the infant remains hypoglycemic despite receiving >12 mg of glucose/kg/minute. •Hydrocortisone reduces peripheral glucose utilization, increases gluconeogenesis, and increases the effects of glucagon. •The hydrocortisone will usually result in stable and adequate glucose levels, and it can then be rapidly tapered over the course of a few days. •Before administering hydrocortisone, obtain a blood sample for measurements of glucose, insulin, and cortisol levels at a time when the serum sugar is low.•

8. Unless there is a suspicion of a metabolic defect, feedings of mothers milk or formula can be started and advanced as the clinical situation allows. •As the feedings are advanced and the IV glucose infusion is tapered, continue to monitor glucose levels before feeding.

9.Glucagon 0.025-0.3 mg/kg intramuscularly (maximum 1 mg) may be given to hypoglycemic infants with good glycogen stores but it is only a temporizing measure to mobilize glucose for 2 to 3 hours in an emergency until IV glucose can be given.• The glucose level will often fall after the effects of glucagon have worn off. •For infants of diabetic mothers, the dose is 0.3 mg/kg (maximum dose is 1 mg)

10. Diazoxide (2-5 mg/kg per dose orally given q8h) may be given for infants who are persistently hyperinsulinemic. It inhibits insulin release by acting as a specific adenosine triphosphate (ATP)-sensitive potassium-channel agonist in normal pancreatic β cells, decreasing insulin release. A positive response is usually seen in 48 to 72 hours if it is going to occur.11. Other: Epinephrine and growth hormone are used rarely and only in the treatment of persistent hypoglycemia. •Surgical subtotal pancreatectomy may be necessary for insulin-secreting tumors.

12. Additional evaluation. Most hypoglycemia will resolve in 2 to 3 days. A requirement of >8 mg of glucose/kg/minute suggests increased utilization due to hyperinsulinism. This is usually transient as in infants of diabetic mothers. If it lasts >7 days, endocrine evaluation may be necessary to rule out excess insulin secretion from an insulin-secreting tumor or other cause.a. A sample drawn to determine insulin level at the time of low blood glucose will document an inappropriate secretion of insulin.b. If the insulin level is normal for the blood-glucose level, other causes of persistent hypoglycemia such as defects in carbohydrate metabolism, endocrine deficiency, and defects in amino acid metabolism should be considered.

c. In severe endocrine or metabolic deficiency, the glucose level will often remain low despite glucose infusions at > 10 mg/kg/minute. Diagnosing hyperinsulinemia requires measuring an insulin level that is inappropriately high for a simultaneous serum glucose. Evaluation requires drawing blood for insulin, cortisol, and amino acids at a time when the glucose level is <40 mg/dL. d. Genetic testing for various mutations such as SUR1 and KiR 6.2.

HYPERGLYCEMIA IN NEWBORN

• Defined as a whole-blood glucose level >125 mg/dL or plasma glucose values >145 mg/dL.

• There are usually no specific symptoms associated with neonatal hyperglycemia, but the major clinical problems associated with hyperglycemia are hyperosmolarity and osmotic diuresis.

• Subsequent dehydration may occur rapidly in small premature infants with large insensible fluid losses.

• The hyperosmolar state, an increase of 25 to 40 mOsm or a glucose level of >450 to 720 mg/dL, can cause water to move from the intracellular compartment to the extracellular compartment.

• The resultant contraction of the intracellular volume of the brain may be a cause of intracranial hemorrhage.

• Rarely in the first months of life, diabetes mellitus, can present with severe clinical symptoms including polyuria, dehydration, and ketoacidosis that require prompt treatment.

Etiology

• Exogenous parenteral glucose. Administration of >4 to 5 mg/kg/minute of glucose in preterm infants weighing <1,000 g may be associated with hyperglycemia.

• Drugs: The most common association is with steroids. Other drugs associated with hyperglycemia are caffeine, theophylline, phenytoin, and diazoxide.

• VLBW infants (<1,000 g)due to variable insulin response, persistent endogenous hepatic glucose production despite significant elevations in plasma insulin, or insulin resistance that may in part be due to immature glycogenolysis enzyme systems.

• VLBW infants will often be treated with fluids in excess of 200 mL/kg/day.

• A minimum glucose concentration of dextrose 5% must be used to avoid infusing a hypotonic solution and when this fluid is administered the infant may present with an excessive glucose load.

4. Lipid infusion: Free fatty acids are associated with increased glucose levels.5. Sepsis, possibly due to depressed insulin release, cytokines, or endotoxin, resulting in decreased glucose utilization. Stress hormones such as cortisol and catecholamines are elevated in sepsis. In an infant who has normal glucose levels and then becomes hyperglycemic without an excess glucose load, sepsis should be the prime consideration.

6.Stressed premature infants requiring mechanical ventilation or other painful procedures, from persistent endogenous glucose production due to catecholamines and other “stress hormones.” Insulin levels are usually appropriate for the glucose level.7. Hypoxia: possibly due to increased glucose production in the absence of a change in peripheral utilization.8. Surgical procedures. Hyperglycemia in this setting is possibly due to the secretion of epinephrine, glucocorticoids, and glucagon as well as excess administration of glucose-containing IV fluids.

9. Neonatal diabetes mellitus. In this rare disorder, infants present with significant hyperglycemia that requires insulin treatment in the first months of life.• They are characteristically SGA term infants, they have no gender

predilection, and a third have a family history of diabetes mellitus. They present with marked glycosuria, hyperglycemia (240-2,300 mg/dL), polyuria, severe dehydration, acidosis, mild or absent ketonuria, reduced subcutaneous fat, and failure to thrive.

• Insulin values are either absolutely or relatively low for the corresponding blood-glucose elevation.

• Approximately half of the infants have a transient need for treatment but are at risk of recurrence of diabetes in the second or third decade.

• Many of the patients with permanent diabetes have mutations involving regulation of the ATP-sensitive potassium channels of the pancreatic beta cells.

• Activating mutations of either the KCNJ11 gene that encodes the Kir6.2 subunit or the ABCC8 gene that encodes the SUR1 have been implicated in the cause of neonatal diabetes.

• Treatment consists of rehydration, and most of the patients require insulin (regular 0.5-3 units/kg/day subcutaneously divided q6h or 0.01-0.1 units/kg/hour by constant infusion).

• Start with the IV dose, and then switch to the subcutaneous dose. Monitor serum electrolytes, glucose, and acid-base balance.

• Repeated plasma insulin values are necessary to distinguish transient from permanent diabetes mellitus.

• Molecular genetic diagnosis can help distinguish the infants with transient diabetes from those with permanent diabetes, and it may also be important for determining which babies are likely to respond to treatment with sulfonylureas.

• 10. Diabetes due to pancreatic lesions such as pancreatic aplasia, or hypoplastic or absent pancreatic β cells is usually seen in SGA infants who may have other congenital defects. They usually present soon after birth and rarely survive.

• 11. Transient hyperglycemia associated with ingestion of hyperosmolar formula. Clinical presentation may mimic transient neonatal diabetes with glycosuria, hyperglycemia, and dehydration. A history of inappropriate formula dilution is the key. Treatment consists of rehydration, discontinuation of the hyperosmolar formula, and appropriate instructions for mixing concentrated or powder formula. Insulin has been used briefly but cautiously.

• 12. Hepatic glucose production can persist despite normal or elevated glucose levels.

• 13. Immature development of glucose transport proteins, such as GLUT-4.

Treatment

• The primary goal is prevention and early detection of hyperglycemia by carefully adjusting GIRs, and frequently monitoring blood-glucose levels and urine for glycosuria. If present, evaluation and possible intervention are indicated.

• 1. Measure glucose levels in premature infants or infants with abnormal symptoms.

• 2. Extremely low birth weight premature infants (<1,000 g) should start with an IV glucose concentration no >5%. If hyperglycemia is documented, parenteral glucose intake is reduced to 4 to 6 mg of glucose/kg/minute by adjusting the concentration or the rate (or both) of glucose infusion and monitoring the

• P.548falling blood-glucose level. Hypotonic fluids (solutions <dextrose 5%) should be avoided.

Interconversion of glucose infusion units. (From Klaus MH, Faranoff AA, eds. Care of the high-risk neonate, 2nd ed.

Philadelphia: WB Saunders, 1979:430.)

• 3. If appropriate, decrease the glucose infusion by 2 mg/kg/minute every 4 to 6 hours (see Fig. 29A.1).

• 4. Begin parenteral nutrition as soon as possible in low birth weight infants. Some amino acids promote insulin secretion.

• 5. Feed if condition allows; feeding can promote the secretion of hormones that promote insulin secretion.

• 6. Many small infants will initially be unable to tolerate a certain glucose load (e.g., 6 mg/kg/minute) but will eventually develop tolerance if they are presented with just enough glucose to keep their glucose level high yet not enough to cause glycosuria.

• 7. Exogenous insulin therapy has been used when glucose values exceed 250 mg/dL despite efforts to lower the amount of glucose delivered or when prolonged restriction of parenterally administered glucose would substantially decrease the required total caloric intake. Neonates may be extremely sensitive to the effects of insulin. It is desirable to decrease the glucose level gradually to avoid rapid fluid shifts. Very small doses of insulin are used and the actual amount delivered may be difficult to determine because some of the insulin is adsorbed on the plastic surfaces of the IV tubing.

• a. Insulin infusion• i. The standard dilution is 15 units regular

human insulin added to 150 mL D10W, D5W, or normal saline for a concentration of 0.1 units/mL.

• P.549ii. Flush the IV tubing with a minimum of 25 mL of this insulin solution to saturate binding sites.

• iii. Bolus insulin infusion.• a) Dose 0.05 to 0.1 units/kg q4-6h PRN.• b) Infuse over 15 minutes through syringe

pump.• iv. Continuous insulin infusion.

a) Rate of infusion is 0.01 to 0.2 units/kg/hour. (Usual starting dose is 0.05 units/kg/hour.)

For example:Ordered dose: 0.05units/kg/hour and infant weighs 600 g (0.6 kg)0.05units/kg/hour × 0.6 kg = 0.03units/hourConcentration is 0.1 units/mL

• b) Check glucose levels every 30 minutes until stable to adjust the infusion rate.

• c) If glucose level remains at >180 mg/dL, titrate in increments of 0.01 unit/kg/hour.

• d) If hypoglycemia occurs, discontinue insulin infusion and administer IV bolus of 10% D/W at 2 mL/kg x 1dose.

• 8. Monitor for rebound hyperglycemia.• a. Subcutaneous insulin• i. This is rarely used except in neonatal

diabetes. Dose is 0.1 to 0.2 unit/kg every 6 hours Monitor glucose level at 1, 2, and 4 hours.

• ii. Monitor potassium level every 6 hours initially.