Hypoglycemia of Newborn Dr. Ilya Rozin

הצגת מקרה תאומים, בן ובת, נולדו לאם בת 30 בהריונה הראשון (IVF ). מעקב הריון תקין. אם אושפזה בשבוע 32 עקב יתר לחץ-דם. מספר שעות טרם הלידה היתה ירידת מים. ילדה בניתוח קיסרי. הבת, מצג ראש, משקל לידה1825 גרם, אפגר 8 ו-9, נזקקה למעט חמצן. סבלה מ-RDS , אינטובציה כשעה לאחר הלידה, קיבלה סורפקטנט, הונשמה למשך יממה.

הצגת מקרה הבן, מצג ראש, משקל 1600 גרם, אפגר 9 ו-10. החל לקבל כלכלה (חלב אם) ביום השני לחיים. ביממה הרביעית היו ערכי גלוקוז גבוהים בסטיק. בדיקה גופנית – תקינה, בדיקות דם – תקינות, תרביות דם עקרות. עקב היפרגליקמיה עקשנית הוחל במתן אינסולין, למרות זאת ערכי גלוקוז המשיכו להיות גבוהים. ביממה הששית התינוק נראה חולה מאוד והחל לפרכס. נעשה ברור זיהומי מלא – שלילי. ב- CSF גלוקוז 12 מג%, בסטיק בדם – 234 מג%, גלוקוז במעבדה 39 מג%.

הצגת מקרה הבת החלה לקבל חלב אם ביום השלישי לחיים. ביממה החמישית הופיעו ערכי סוכר גבוהים בסטיק. בהדרגה נראתה פחות טוב: חוורת, אפטית, ירדה 13% ממשקל לידה. קיבלה עירוי של גלוקוז בריכוז נמוך עם אינסולין. עקב החמרה כללית במצב ואפנאות הונשמה. נעשה ברור זיהומי – שלילי. ב-CSF סוכר 1 מג%, גלוקוז בדם בסטיק 196 מג%, גלוקוז במעבדה – 14 מג%.

הצגת מקרה פער בין בדיקת הסוכר במעבדה ובסטיק. הסטיק בודק חומרים מחזרים ולא גלוקוז בלבד. נשלח דם ל- Galactose 1-Phosphate Uridyltransferase ונמצאה פעילות נמוכה מאוד של האנזים. אבחנה: Classical Galactosemia

הצגת מקרה הוחל במתן גלוקוז בריכוזים עולים, הופסק אינסולין, בהמשך קבלו כלכלה נטולת galactose. US מוח ביום השני לחיים לשניהם תקין. US מוח בשחרור: אזורים אקוגנים סביב החדרים עם ציסטות דו צדדיות. במעקב: בעיות טונוס קשות, תנועות עיניים אבנורמליות, פיגור קוגניטיבי, CP.

HYPOGLYCEMIA IN THE NEWBORN INFANT Glucose metabolism in the fetus Glucose metabolism in the neonate Definition of hypoglycemia in the newborn Etiology and types of hypoglycemia Clinical presentation of hypoglycemia Infant of diabetic mother Management and outcome

Glucose metabolism in the fetus Maternal glucose is the major substrate delivered to the human fetus for energy metabolism. Fetal uptake of glucose is regulated by maternal glucose concentration. Glucose transport: concentration gradient – facilitated diffusion. Fetal plasma glucose is ~ 70%-80% of mother’s. When gestational age increases, uterine blood flow increases, therefore, blood flow to the fetus increases. Glucose transport to the fetus is only 40-50% of the total uptake by the placenta.

Glucose metabolism in the fetus Insulin in the 8 weeks of gestation and in 13-18 weeks fetal Insulin response to maternal hyperglycemia. Insulin: stimulates glucose incorporation into liver glycogen, acts as growth hormone Growth Hormone in the 9 weeks and rapidly increased between 11-16 weeks of gestation. Fetal GH level is high to maternal plasma.

Glucose metabolism in the fetus Hepatic glycogen content is low in early gestation and increases slowly ( between 15-20 weeks of gestation). Glycogenolysis and glycogenesis enzymes are present and increase slowly through pregnancy. Absence of gluconeogenesis (gluconeogenesis enzymes are not active in utero). 80% of fetal glucose to energy 20% of fetal glucose to lactate, amino acid and other means.

Glucose metabolism in the newborn: At birth… Discontinuation of maternal substrates and nutrient supply: need to mobilize glucose or other substrates to meet energy requirements. Glucose falls (nadir ~ 1-2 hours of age) and rises by 2-4 hours in all infants. Glucoregulatory hormones (epinephrine, norepinephrine, glucagon) rise rapidly, insulin decreases (mobilization of glycogen and fatty acids).

Levels of hormones and metabolic fuels change after birth

Glucose metabolism in the newborn Breast milk provides lactose but not more than 50% of glucose utilization rate. Therefore, neonates are markedly dependent on active gluconeogenesis to maintain hepatic glucose production. Role of elevated Growth Hormone is not defined. In first 48-72 hours level is low with elevation in the 8 weeks after birth.

Glucose kinetics in the newborn Rates of glucose production and utilization in the newborn are between 4-6 mg/kg/min Rates are higher in the newborn compared with adults due to: - Higher metabolic rate - Higher brain-to-body weight ratio of the newborn brain After 2 days, with the introduction of feeding, the normal infant maintains plasma glucose at 40-70 mg/dl (2.5-6 mmol /L).

Definition of neonatal hypoglycemia Statistical approach. Clinical approach (Most infants recover after birth, lack of correlation with CNS side effects, lack of outcome studies, studies based on different populations, changes in mothers’ and infants’ care). Most investigators would consider serum glucose concentration < 2.5 mmol/L or 45 mg/dl to be low in the first 72 hours of life. The definition is the same for term and preterm infants. Differ to transient and persistent ,symptomatic and asymptomatic hypoglycemia.

Etiology of neonatal hypoglycemia I. TRANSIENT HYPOGLYCEMIA A. Changes in maternal metabolism: 1. Intrapartum administration of glucose 2. Drugs: terbutalin, ritodrin, propranolol 3. Diabetes in pregnancy (IDM) B. Neonatal problems: 1. IUGR/SGA infant 5. Preterm infant 2. Birth asphyxia 6. Rh-incompatibility 3. Infection 7. Hyperviscosity 4. Hypothermia 8. Cardiac malformations 9. Iatrogenic causes

II. Persistent or recurrent hypoglycemia A. Hyperinsulinism: 1. Beta-cell hyperplasia: nesidioblastosis -adenoma spectrum, sulfonylurea receptor defect. 2. Beckwith- Wiedemann Syndrome. B. Endocrine disorders: 1. Pituitary insufficiency. 2. Cortisol deficiency. 3. Congenital glucagon deficiency. 4. Epinephrine deficiency. C. Inborn errors of metabolism: 1. Carbohydrate metabolism – galactosemia, fructose intolerance, glycogen storage disease, gluconeogenesis disorders. 2. Amino-acid metabolism – Maple-syrup urine disease, aminoacidopathies 3. Fatty-acid metabolism – carnitine defects, acyl-CoA dehydrogenase defects. D. Nerohypoglycemia (hypoglycorrhahia): defective glucose transport.

Beckwith’s syndrome with glossoptosis

Incidence of hypoglycemia according to birth weight and gestational age

Symptoms and signs of neonatal hypoglycemia Abnormal cry Apnea, cyanosis Feeding difficulties Respiratory distress Hypothermia Hypotonia Irritability Jitteriness, tremor Lethargy, stupor Seizures Sweating Tachycardia

Infants of Diabetic Mothers Macrosomy, visceromegaly, unexplained fetal demise congenital anomalies: Cardiac – VSD, TGA, TOF, double-outlet.. Skeletal and CNS – caudal regression Gastrointestinal – small left colon organs and systems abnormalities: Hypoglycemia Heart failure, septal hypertrophy Polycythemia Hyperbilirubinemia Hypocalcemia Renal vein thrombosis

Infants of Diabetic Mothers

Maternal hyperglycemia Fetal hyperglycemia Fetal Hyperinsulinism Increased fetal substrate uptake Activity hepatic enzymes Metabolic rate Suppressed production of surfactant Lipid synthesis Oxygen consumption RDS Macrosomia Hypoxemia Cardiomegaly Synthesis of erythropoietin Adipose tissue Stillbirth? RBC mass - polycythemia

Blood-work in neonatal hypoglycemia Free fatty acid Amino acids Acetoacetate/beta hydroxybutirate Urine: Ketones, organic acids, reducing substances TSH Glucose to lab (ASAP, on ice) Electrolytes +chloride Cortisol, growth hormone Insulin level Blood gases Lactate + pyruvate Ammonia

Management of neonatal hypoglycemia Anticipation in the high-risk group: LGA/SGA infants, IDM, acutely ill neonates, preterm infant, weight <2500 or > 4000 gr. Treatment: transient vs. persistent symptomatic vs. asymptomatic Investigation and treatment of the underlying cause

Management of neonatal hypoglycemia I. TRANSIENT HYPOGLYCEMIA: Most are early, Asymptomatic and will recover with early feeding Symptomatic Hypoglycemia: Bolus of 2 ml/kg glucose 10%. If seizure 4 ml/kg of glucose 10%. All infants, irrespective of cause and age should be treated with parenteral glucose infusion: 6-8 mg/kg/min of dextrose 10%. THE AIM: To maintain serum glucose above 45 mg/dl. Therefore: Glucose should be monitored frequently No response: Bolus of 2 ml/kg glucose 10% Increase rate or concentration. When blood glucose is stable for 4-6 hours feeding can be initiated and infusion can be weaned.

Management of neonatal hypoglycemia Persistent hypoglycemia glucose infusion rate > 12 mg/kg/min Consider a diagnosis of hyperinsulinism, hormonal or metabolic disorders. Add other drugs: - Hydrocortisone - Glucagon - Diazoxide - Somatostatin - Octreotide Pancreatectomy

-היפרגליקמיה, היפוקלאמיה -כאבי ראש, אי שקט תרופה מינון תופעות לוואי Hydrocortisone 1-2 mg/kg/dose 3-4 / day I.V. -עליה בלחץ דם -היפרגליקמיה, היפוקלאמיה -כאבי ראש, אי שקט Diazoxide Initial: 5-10 mg/kg/day in 2-3 dose In Hyperinsulinemia: 10-15 mg/kg/day – 8-12 hr. P.O. or I.V. -רטנציה של נתרן ומים – בצקות -היפרגליקמיה -צהבת של ילוד -אריטמיה, טכיקרדיה -ירדה בלחץ דם Somatostatin ( Octreotide ) Initial: 1 mcg/kg/dose – 4/day with titration. Max. dose: 10 mcg/kg/day S/C or I.V. -הקאות, שלשול -תפיחות בטן Glucagon 0.1-0.3 mg/kg/dose Max. dose: 1 mg/dose I.V. I.M. S/C. -הקאות, בחילות -טכיקרדיה, ירידה בלחץ דם -רגישות יתר

Prognosis and outcome in neonatal hypoglycemia Even asymptomatic hypoglycemia in healthy full term infants can be associated with abnormal neurologic exam (VEP). Preterm infants have lower IQ results when exposed to recurrent hypoglycemia. They may be asymptomatic for long periods and need to be monitored. IDM with hypoglycemia in the past, suffer lower school achievements compared with healthy newborns Attention should be put when dealing with early discharge. Brain MRI’S: damage of posterior hemispheres (occipital and parietal).

Polycythemia Hematocrit greatly exceeds normal values for gestational and postnatal age. Affects approximately 1% to 5% of newborns. Many affected infants are asymptomatic. Mean Ht and Hb from capillary samples at birth are 61% +/- 7.4 and 19.3 g/dl +/- 2.2. The diagnosis is based upon peripheral venous samples.

Polycythemia Polycythemia must be distinguished from hyperviscosity: if greater than 12 centipoise, measured at shear rate of 11.5 per sec ( 6 centipoise at rate of 106 per sec). Viscosity and Ht have linear relationship when Ht is less than 60%. Hyperviscosity occurred in only 47% of infant with polycythemia.

Polycythemia Incidence 1%-5% of healthy newborns screened. Factors of influence the Ht during the first day after birth: - time delay between birth and clamping of the umbilical cord, - site of blood sampling, - age of the time sampling, - method of Ht measurement.

Reduced blood flow to organ Polycythemia Pathophysiology Hyperviscosity Reduced blood flow to organ Poor tissue perfusion

Polycythemia Causes Two major mechanism: - active ( increased intrauterine erythropoesis) - passive ( erythrocyte transfusion )

Polycythemia Causes Passive: Daley clamping of the umbilical cord – most common. Intrapartum hypoxia (increased placental transfusion). Twin-to-twin transfusion (10%-15% of monochorionic twin). Maternal-fetal transfusion.

Polycythemia Causes Active: Chronic intrauterine hypoxia and placental insufficiency: - SGA. - maternal preeclampsia or other vascular disorder. - maternal hypoxemia due to cardiac or pulmonary disorders. - drugs – propranolol. - smoking, high altitude, postterm date. - diabetic mother, LGA, Beckwith-Wiedemann syndrome. Endocrine abnormalities: congenital adrenal hyperplasia, hypothyroidism, hyperthyroidism. Chromosomal abnormalities: trisomy 21,18,13.

Polycythemia Clinical features Often begin by two hours after birth. May delayed to the 2-3 day because of excessive extracellular fluid loss. Infants with no symptoms by 48 to 72 hours of age are likely to remain asymptomatic. Signs and symptoms usually due to reduced tissue perfusion or associated metabolic abnormalities.

Polycythemia - Clinical features CVS & Respiratory:- acrocyanosis and sluggish peripheral perfusion, - plethora, - cyanosis (17%), - tachypnea & distress, - heart murmur, heart failure and increased vascular resistance.

Polycythemia - Clinical features Neurologic effects:- irritability, - abnormal cry, - jitteriness, - lethargy, - hypotonia, - apnea. (associated with reduce cerebral blood flow)

Polycythemia - Clinical features Gastrointestinal disorder: - abdominal distention, - poor feeding. - NEC ( sometimes). ( in 20% of affected infants).

Polycythemia - Clinical features Genitourinary:-hematuria, proteinuria, RVT. Hypoglycemia:- common, in 14%-40%, - Increased Gluc. utilization. Hyperbilirubinemia:-in 1/3 of infants, -breakdown and increased number of circulated RBC. Thrombocytopenia:- one report ( 6 of 32 ) - if Ht > 70% - Plt. <100.K

Polycythemia Diagnosis Should be in infant who appear plethoric or who have signs or symptoms my be due to polycythemia. Ht on a capillary blood sample from a wormed heel. If Ht capillary > 65% - repeat on a venous blood. Diagnosis of polycythemia if the venous Ht is > 65%.

Management of polycythemia Controversial – uncertain whether intervention affect long-term outcome, may be associated with some GIT morbidity. Asymptomatic newborn with polycythemia do not appear to benefit from treatment. All polycythemic infant should be monitoring to hypoglycemia and hyperbilirubinemia.

Management of polycythemia Asymptomatic: Ht between 60%-70% - observation, adequate hydration and glucose intake (oral intake, body weight, urine output), - repeat Ht in 12 – 24 hours. Ht > 70% - many clinicians perform Partial Exchange Transfusion; - however, continued observation with hydration may be appropriate.

Management of polycythemia Symptomatic: If Ht > 65% - partial exchange transfusion (PET), - or observation with I.V. fluids for first 24-48 hours of age at rate 100 cc/kg/day, with glucose rate of 6-8 mg/kg/min. If worsening of symptoms – PET.

Partial exchange transfusion Reduced Ht without causing hypovolemia. Reverses the reduction in cerebral blood flow, cardiac index and oxygen transport attributed to hyperviscosity. Dose not appear to affect long-term outcome. My be increased risk of NEC after treatment.

Partial exchange transfusion Exchange volume = [(observed Ht-desire Ht) x blood volume] / observed Ht. Blood volume – 80 ml ( to 100 )/kg of BW. Desire Ht – 45%. With NaCl 0.9% only. Through peripheral or central vein and artery.

Outcome of polycythemia Outcome depend more upon associated condition, such as hypoglycemia, or underline disorder, such as placental insufficiency. Important benefit from PET has not been show. Infant with hyperviscosity have poorer neurologic outcome (lower IQ, lower score in spilling and arithmetical achievement).

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