II. Neonatal Acute Metabolic Disturbances

DR. MAHMOUD MOHAMED OSMAN

MBBCh, MSc (Pedia), MRCPCH (UK), FRCP (Edinburgh)

Consultant Pediatrician & Neonatologist

Al Yammamah Hospital , MOH

1

بسم الله الرحمن الرحيم

�م� ُك �َص�ِّو�ُر� �ِذ�ي ُي ) ُه�ِّو� ال�َف� �ي � ُك ح�اِم ُر�

� ِف�ي اَأل� ُه�ِّو� �َّال ه� ِإ ـ� �ل � ِإ اء َّال �َش� ُي

) �َح�ِك�يم� �َع�ُز�ُيُز� ال ال6سِّوُرة آل عمران :

He is Who shapes you in the wombs as He pleases. There is no god but He, the Exalted in Might, the Wise.

Learning Objectives: Neonatal Hypoglycemia

Normal glucose homeostasis.

Pathophysiology & Causes of neonatal hypoglycemia.

Diagnostic strategies

Teatment of neonatal hypoglycemia.

Other Acute Metabolic disturbances

Neonatal hypocalcemia

Neonatal Hypomagnesemia

1. NEONATAL HYPOGLYCEMIA

1- BACKGROUND and PATHOPHYSIOLOGY:

Glucose is the major energy source for fetus and neonate.

The newborn brain depends upon glucose almost exclusively. Up to 90% of total glucose used is consumed by the brain.

Alternate fuels(ketones, lactate) are produced in very low quantities.

The usual rate of glucose utilization is 4-8 mg/kg/min.

Glucose regulatory mechanisms are sluggish at birth. Thus, the infant is susceptible to hypoglycemia when glucose demands are increased or when exogenous or endogenous glucose supply is limited.

Severe or prolonged hypoglycemia may result in long term neurologic damage.

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

2- DEFINITION:

Hypoglycemia in the first few days after birth is defined as blood glucose <40 mg/dL.

In preterm infants, repeated blood glucose levels below 50 mg/dL may be associated with neurodevelopmental delay.

1. Decreased substrate availability: Prematurity Intra-uterine growth retardation Prolonged fasting without IV glucose Glycogen storage disease

4. Increased glucose utilization: Cold stress Increased work of breathing Sepsis Perinatal asphyxia

2. Hyperinsulinemia: Infant of diabetic mother Islet cell hyperplasia Erythroblastosis fetalis Exchange transfusion Beckwith-Wiedemann Syndrome

5. Miscellaneous conditions: Polycythemia Congenital heart disease CNS abnormalities

3. Other endocrine abnormalities: Pan-hypopituitarism Hypothyroidism Adrenal insufficiency

3- ETIOLOGY: Conditions associated with an increased risk for neonatal hypoglycemia:

Infant of diabetic mother

This premature infant with respiratory distress syndrome. Retractions and inward collapse of the lower anterior chest

wall can be seen

Severe intra-uterine growth retardation IUGR

Beckwith–Wiedemann syndrome

4- SIGNS AND SYMPTOMS : Symptomatic Hypoglycemia:

Signs and symptoms of hypoglycemia are nonspecific and include: jitteriness, irritability, lethargy, seizures, apnea, grunting and sweating (uncommon).

Asymptomatic Hypoglycemia:Hypoglycemic Infants may not always be

symptomatic. Therefore, routine glucose monitoring for at-risk infants is mandatory.

Lack of symptoms does not guarantee absence of long term sequelae.

CLINICAL SYMPTOMS AND SIGNS OF HYPOGLYCEMIA

Clinical signs should be alleviated with concomitant correction of plasma glucose levels.

5- DIAGNOSTIC WORKUP: Specimens for measurement of glucose should be

obtained from heel-stick, veni-puncture, or from an indwelling catheter that does not have glucose infusion.

6- SCREENING OF AT- RISK INFANTS: Infants at risk for hypoglycemia should be screened by

measuring blood sugar by Gluco-meter at ages 1, 2, 4, 6, 9, 12, and 24hs.

Less frequent measurements are appropriate if blood glucose is stable.

However continued surveillance and more frequent measurements may be needed until blood glucose is stable >40 mg/dL or >50 mg/dL in very preterm infants.

7- MANAGEMENT OF HYPOGLYCEMIA: Early feeding as soon as the infant is ready, preferably

within 1 hour of birth.

What feed? Breast milk (colostrum); But Not dextrose-water!!!!!.

When Gluco-meter reading is >40 mg/dL and infant is feeding normally; follow usual nursery protocol.

When Glucometer reading 20-40 mg/dL, and infant is term and able to feed:

- Draw blood for stat blood glucose.

- Feed 5 mL/kg of D5W.

- Repeat blood glucose or Glucometer 20 min after feeding.

When Glucometer reading are:

a) <20 mg/dL

b) <40 mg/dL and NPO or preterm

c) <40 mg/dL after feeding

d) <40 mg/dL and symptomatic

- Draw blood for stat glucose measurement.

- Give IV bolus of 2-3 mL/kg of D10W.

- Begin continuous infusion of D10W at 4-6 mg/kg/min.

- If infant of diabetic mother, begin D10W at 8-10 mg/kg/min.

- Repeat blood glucose in 20 min with treatment until blood sugar >40 mg/dL.

Weaning IV dextrose infusion: When blood glucose has been stable for 12-24 h, begin decreasing IV infusion gradually if blood glucose remains ≥60 mg/dL.

For persistent hypoglycemia despite above measures:

• Increase rate of glucose infusion stepwise in 2 mg/kg/min increments up to 12-15 mg/kg/min glucose.

• Use increased volume with caution in infants where volume overload is a concern.

• Maximal concentration of glucose in peripheral IV is D12.5.

Do not use D25W or D50W IV or large IV volume boluses !!!!

• As this creates rebound hypoglycemia in infants who are hyperinsulinemic.

• Administration of D25W or D50W can also cause dangerous increase in plasma osmolarity.

If hypoglycemia is not controlled with above measures: Obtain Endocrine Consult to guide further

diagnostic evaluation and management. While awaiting consult, send blood (while

blood sugar is low “Critical sample”) for glucose, plasma cortisol, growth hormone and insulin concentrations.

Further management may include: Glucocorticoids, diazoxide, somatostatin or pancreatectomy.

Adjunct Therapies for Resistant Hyoglycemia

Summary of 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 mg, give IV for 24 hrs start tapering once reading above

50mg

BS <50,increase GIR in steps of 1-2 up-to

12mg/kg/min

2. NEONATAL HYPOCALCEMIA

1. INTRODUCTION: Regulation of serum ionized calcium concentration

within a narrow range is critical for many biochemical processes such as: Blood coagulation, Neuromusrular excitability, Cell membrane integrity and function, Cellular enzymatic and secretory activity.

Significant aberrations of serum calcium concentrations are frequently observed in the neonatal period

2.DEFINITION. Neonatal hypocalcemia is defined as a total serum

calcium concentration of <7 mg/dL or an ionized calcium

concentration of <4 mg/dL(1 mmol/L).

In very low birth weight (VLBW) infants, ionized calcium

values of 0.8 to 1 mmol/L are common and not usually

associated with clinical symptoms.

In larger infants and in infants of >32 weeks' gestation,

symptoms may more readily occur with an ionized

calcium concentration of <1 mmol/L.

3. PATHOPHYSIOLOGY: The principal calcium-regulating hormones are:

Parathyroid hormone (PTH) and

1,25-dihydroxyvitamin D (Calcitriol).

PTH mobilizes calcium from bone, increases calcium resorption in the renal tubule, and stimulates renal production of 1,25-dihydroxyvitamin D.

PTH secretion causes the serum calcium level to rise and the serum phosphorus level either to be maintained or to fall.

Calcitriol increases intestinal calcium and phosphate absorption and mobilizes them from bone.

There are three fractions of calcium in serum: Ionized calcium (~ 50% of serum total calcium);

Calcium bound to serum proteins, principally albumin (~ 40% )

Calcium complexed to phosphates, citrate, and sulfates (~10%).

Ionized calcium is the only biologically available form of calcium.

At birth, serum calcium level is (10-11 mg/ dL). Then decline for the first 24 to 48 hours; the nadir is usually 7.5 to 8.5 mg/dL. Thereafter, progressively rise to the mean values observed in older children

1. EARLY HYPOCALCEMIA : (1-4 DAYS OF AGE)

Prematurity

Maternal diabetes

Perinatal stress, asphyxia

Intrauterine growth restriction

Maternal anticonvulsants

4. ETIOLOGY:

2. LATE HYPOCALCEMIA: (5-15 DAYS OF AGE)

Hyperphosphatemia (High phosphate load)

Hypomagnesemia

Vitamin D deficiency (Acquired or inherited)

Parathyroid hormone resistance (Transient neonatal pseudohypoparathyroidism)

Hypoparathyroidism: Primary: Parathyroid agenesis, 22q11 deletion,

Secondary: Maternal hyperparathyroidism

Neonatal hypocalcemia with skeletal dysplasia

Other causes (Alkalosis, citrated blood transfusions, phototherapy, viral gastroenteritis, lipid infusions)

5. DIAGNOSIS:

1. Clinical presentarlon Early-onset hypocalcemia :The signs are usually nonspecific:

apnea, seizures, jitteriness, increased extensor tone, clonus, hyperreflexia, and stridor.

In preterm newborns it is often asymptomatic but may show apnea, seizures, or abnormalities of cardiac function.

Late-onset syndromes: may present as hypocalcemic seizures.

2. History For late-onset presentation, mothers may report partial breast

feeding or whole cow’s milk may be reported.

Abnormal movements and lethargy may precede obvious seizure activity.

Symptoms are usually described beginning from 3-4 days of age.

3. Physical examination General physical findings associated with

seizure disorder in the newborn may be present in some cases.

Usually, there are no apparent physical findings.

6. INVESTIGATIONS: Total serum and ionized calcium, magnesium,

phosphorus, glucose

Acid-base balance

Urinary calcium, magnesium, phosphorus, creatinine, drug screen

Vitamin D metabolites

Parathyroid hormone & Calcitonin

Others (malabsorption, lymphocyte count, T-cell numbers and function).

deletionChest radiograph (Thymic shadow, aortic arch position)

Genetic studies for chromosome 22q11

7. MONITORING Suggested schedule for monitoring calcium levels in

infants, such as VLBW, IDM, and birth depression, who

are at risk for developing hypocalcemia are as follows:

- Total and ionized calcium at 12, 24, and 48 hours.

- Total serum phosphorus and total serum magnesium

for infants with hypocalcemia.

- Serum concentrations of PTH, 25(0H)D, and

1,25(0H)2D are not usually needed.

8. TREATMENT: Therapy with calcium is usually adequate for most

cases.

In some cases, concurrent therapy with magnesium is indicated.

Rapid intravenous infusion of calcium can cause a sudden elevation of serum calcium level, leading to bradycardia or other dysrhythmias.

Intravenous calcium should only be "pushed" for treatment of hypocalcemic crisis (seizures) and done with careful cardiovascular monitoring.

Calcium gluconate 10% solution is preferred for intravenous use.

Calcium glubionate syrup (Neo-Calglucon) is a convenient oral preparation.

If the ionized calcium level drops severly, a continuous intravenous calcium gluconate 10% infusion may be commenced.

Monitor heart rate and rhythm and the infusion site are mandatory throughout the infusion.

3. Neonatal Hypomagnesemia

Introduction: Abnormalities of magnesium and calcium metabolism

are commonly seen in the neonatal intensive care unit.

Calcium disturbances may be mirrored by magnesium, as in hypocalcemia with hypomagnesemia or hypercalcemia with hypermagnesemia.

Infants of diabetic mothers (IDMs) and infants with intrauterine growth restriction (IUGR) may present with hypocalcemia, hypomagnesemia, or both.

Abnormalities in serum values for calcium and magnesium are of concern in any infant and warrant further investigation.

Definition: Normal serum levels for magnesium are

typically 0.6–1.0 mmol/L. Hypomagnesemia is usually seen as any value

<0.66 mmol/L; however, clinical signs do not manifest until levels drop below 0.5 mmol/L .

Incidence: True overall incidence in neonates is not well

documented and remains to be determined. However, neonates appear to be more

predisposed than other groups of patients, and it tends to follow in infants with hypocalcemia.

Pathophysiology: Magnesium is a key trace element for maintaining

skeletal integrity, and it acts as a catalyst for intracellular enzymes for adenosine triphosphate (ATP) activation in skeletal and myocardial contractility.

It has an important role in different processes related to cell physiology, hormonal and metabolic pathways, nerve conduction, and blood coagulation.

It is also integral to protein synthesis, vitamin D metabolism, parathyroid function, and calcium homeostasis.

Risk factors:

1. Hypocalcemia.

2. Preterm and late-preterm infants.

3. Inadequate intake of magnesium.

4. Infant of diabetic mother (IDM), reflecting maternal

magnesium deficiency secondary to diabetes.

5. IUGR, especially if mother had preeclampsia.

6. Inherited renal wasting (Gitelman syndrome).

7. Hypoparathyroidism.

8. Associated hypocalciuria and nephrocalcinosis.

9. Magnesuria secondary to Furosemide or Gentamicin.

10. Citrated blood exchange transfusions.

Clinical presentation:

1. Similar to hypocalcemia ( jitteriness, apnea, feeding intolerance), and may also present as seizures.

2. Clinical signs may be masked as hypocalcemia. If symptoms persist after adequate calcium gluconate therapy, hypomagnesemia should be considered.

Diagnosis: Laboratory testing to establish serum levels.

Serum magnesium level.

Normal values are 0.6–1.0 mmol/L, although it may vary

minimally with gestational age.

Twin gestation, multiple births, or vaginal delivery may result in

lower levels of magnesium.

It is important to note that most methods to assess magnesium

levels measure total magnesium concentration, while only free

magnesium is biologically active and almost 30% is inactive

bound to albumin.

Total and ionized calcium levels.

Usually hypomagnesemia is associated with hypocalcemia, and

hypercalcemia may inhibit magnesium reabsorption in the distal

loop of Henle and cause hypomagnesemia.

Prevention. Adequate intake of magnesium should be

assured in parenteral and enteral nutrition to prevent hypomagnesemia.

Recommend dose is 8–15 mg/kg/d.

Management. Acute hypomagnesemia should be treated with

intravenous magnesium sulfate. Infusion must be monitored closely for cardiac

arrhythmias and hypotension. Maintenance magnesium can be by parenteral

nutrition solutions or by oral feeds with 5-fold dilution of magnesium salt solution.

Magnesium infusion should be used cautiously if patient has impaired renal function due to its accumulated toxicity

Prognosis. Hypomagnesemia generally has good

outcome if diagnosed promptly and treated adequately.

The exception is a clinical presentation that includes hypomagnesemia -induced seizures with follow-up studies suggesting 20% incidence of neurologic abnormalities.

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