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 ( هُوَ الَّذِي يُصَوِّرُكُمْ فِي الأَرْحَامِ كَيْفَ يَشَاء لاَ إِلَـهَ إِلاَّ هُوَ الْعَزِيزُ الْحَكِيمُ ) ( هُوَ الَّذِي يُصَوِّرُكُمْ فِي الأَرْحَامِ كَيْفَ يَشَاء لاَ إِلَـهَ إِلاَّ هُوَ الْعَزِيزُ الْحَكِيمُ ) سورة آل عمران : 6 He is Who shapes you in the wombs as He pleases. There is no god but He, the Exalted in Might, the Wise He is Who shapes you in the wombs as He pleases. There is no god but He, the Exalted in Might, the Wise.

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

Premature Infant With Respiratory Distress Syndrome.

Intra-uterine growth retardation

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 in term, or >50 mg/dL in preterm infants.

7- MANAGEMENT OF HYPOGLYCEMIA:  Early feeding as soon as the infant is ready, preferably within 1 hour of birth.  What is the 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 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 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 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.  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 Bolus of 2 mL/kg of 10% dextrose Symptomatic hypoglycemia Start Glucose 6-8mg/kg/min Check Blood sugar at 30-60min BS >50 mg, give IVF 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,  Neuromuscular 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 (1.8 mmol/L) 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.EARLY HYPOCALCEMIA (1- 4 DAYS OF AGE) :  Prematurity  Maternal diabetes  Perinatal stress, asphyxia  Intrauterine growth restriction  Maternal anticonvulsants 4. ETIOLOGY:

2. 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: 5. DIAGNOSIS: Clinical presentarlon  Early-onset hypocalcemia : The signs are usually nonspecific: apnea, seizures, jitteriness, increased extensor tone, clonus, hyper-reflexia, 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 seizures.  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.  Chest radiograph (Thymic shadow, aortic arch position).  Urinary calcium, magnesium, phosphorus, creatinine, drug screen.  Vitamin D metabolites.  Parathyroid hormone & Calcitonin.  Others (Tests for malabsorption, lymphocyte count, T-cell numbers and function).  Genetic studies for chromosome 22q11 deletion.

7. MONITORING 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: 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 should be given slowly 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 0.66 –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 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.