Neonatal Hypoglycemia, Respiratory distress and Jaundice Anchalee Yu.MD Department of Pediatrics Maharaj Hospital Nakhon Si Thammarat

Case 1 Male infant GA 36 wk ,C/S due to CPD , Apgar 8,10 at 1 and 5 min Mild retractions and grunting PE : T 36.4C ,RR 80/min, lung mild secretion sound, subcostal and intercostal retraction Otherwise normal DTX at LR : 20 mg % Management ?

Neonatal Hypoglycemia :Definition Plasma glucose < 40 mg/dl

ภาวะ HYPOGLYCEMIA 1.Transient hypoglycemia 2. Persistent hypoglycemia

ปกติหลังคลอดทารกจะมีน้ำตาลต่ำสุดเมื่ออายุ 1-2 ชั่วโมง ร่างกายมีกลไกทาง metabolic ดังนี้ Hepatic glycogenolysis Hepatic gluconeogenesis Adipose tissue lipolysis Muscle proteolysis Hepatic ketogenesis

Hepatic glycogenolysis Hepatic gluconeogenesis Muscle proteolysis Adipose tissue lipolysis glycerol ketone Hepatic ketogenesis

Transient hypoglycemia Inadequate substrate or enzyme function Prematurity, SGA, smaller twin Infant with severe RD, infant of toxemic mother Increased peripheral utilization Abnormal temp. birth asphyxia, polycythemia Associated with hyperinsulinism IDM, erythroblastosis fetalis

Persistent hypoglycemia Hyperinsulinemic state Nesidioblastosis, beta cell hyperplasia, beta cell adenoma, beckwith wiedemann syndrome Hormonal deficiency Panhypopituitarism, ACTH deficiency Substrate limited Ketotic hypoglycemia, GSD, galactosemia

Panhypopituitarism

Galactosemia

Persistent hypoglycemia If GPR > 10 mg/kg/hr and or lasting more than 2 weeks Usually symptomatic May be associated with midline defect,micropenis Work up: insulin, cortisol, growth hormone, ketone, fatty acid Treatment: hydrocortisone, glucagon, diazoxide,

อาการและอาการแสดง ภาวะ hypoglycemia เกิดได้ตั้งแต่ 1-2 ชั่วโมงหลังคลอด ส่วนใหญ่ไม่มีอาการ อาการ-ไม่มีลักษณะจำเพาะ

อาการของ hypoglycemia Common - jitteriness, tremors, convulsion - episode of cyanosis - apnea, irregular breathing - apathy, weak, high pitched cry - limbness or lethargy - poor feeding - eye rolling

การคำนวณ Glucose production rate (GPR) GPR = % dextrose x rate fluid ml/hr 6 x body weight (kg)

มีอาการผิดปกติ และ หรือ DTX< 40 mg/dl Confirm ด้วย serum blood sugar มีอาการผิดปกติ และ หรือ DTX < 30 mg/dl* ไม่มีอาการผิดปกติ หรือข้อห้ามการให้นม Early feeding ให้นม 65 cc/kg/day X 8 feed 10 % D/W 2 cc/kg/dose IV bolus DTX ทุก ½ hr X 2 ครั้ง Start IV glucose GPR 6-8 mg/kg/min* DTX >40 mg/dl DTX ทุก 1hr x 2 ครั้ง** ทุก 2 hr x 2 ครั้ง ทุก 4 hr DTX ทุก 1hr x 2 ครั้ง ทุก 2 hr x 2 ครั้ง ทุก 4 hr

Management   * GPR เพิ่มได้ครั้งละ 2-3 mg/kg/minโดย เพิ่ม rate IV (ใน preterm ไม่ควรเกิน requirement fluid per day ) หรือ strength IV   * การให้ glucose : Peripheral vein : ไม่เกิน 12.5 % Umbilical artery : ไม่เกิน 15 % Umbilical vein : ไม่จำกัด   * ในกรณีที่ glucose production rate > 12-15 mg/kg/min ให้พิจารณา เจาะ serum cortisol, ketone ,insulin level ,growth hormone ก่อน ต่อมาให้ hydrocortisone 10 mg/kg/day แบ่ง ทุก 12 hr

Neonatal Jaundice

Case 2 Male infant 4 days old presenting with marked jaundice for 2 days. Birth weight = 3200 gm. Apgar score 9,10 . No complications ,on exclusive breastfeeding , serology and screening thalassemia mom normal PE : marked icteric sclera, no pallor, no hepatosplenomegaly ,BW 2900 gm,V/S normal MB 18, Hct 45 % Further questions or examination? Differential diagnosis? Management?

Bilirubin Metabolism: * Unconjugated bilirubin is bound to albumin in plasma (hydrophobic)

Hyperbilirubinemia: Imbalance of bilirubin production and elimination In order to clear from body must be: Conjugated in liver Excreted in bile Eliminated via urine and stool

Hyperbilirubinemia & Clinical Outcomes: Deposits in skin and mucous membranes Unconjugated bilirubin deposits in the brain Permanent neuronal damage JAUNDICE ACUTE BILIRUBIN ENCEPHALOPATHY KERNICTERUS

Clinical Symptoms: Jaundice/Icterus: Newborn icterus notable once total bilirubin > 5-6 mg/dL (versus older children/adults once > 2 mg/dL) Progresses cranially to caudally CAUTION: Visual assessment is subjective, inaccurate, and dependent on observer experience! Keren et al Visual assessment of jaundice in term and late-preterm infants (2009) Nurses at HUP used 5 point-scale to rate cephalocaudal extent of jaundice Showed weak correlation between predicted and actual levels

Jaundice/Icterus:

Clinical Symptoms: Acute Bilirubin Encephalopathy/Kernicterus: Irritability, jitteriness, increased high-pitched crying Lethargy and poor feeding Back arching Apnea Seizures Long-term: Choreoathetoid CP, upward gaze palsy, SN hearing loss, dental dysplasia

Kernicterus: * Bilirubin deposits typically in basal ganglia, hippocampus, substantia nigra, etc.

Kernicterus ภาวะที่ indirect หรือ unconjugated bilirubin) เข้าสมองไปย้อมติดเซลล์สมอง อาจเรียกว่า bilirubin encephalopathy มักเกิดขึ้นที่บริเวณก้านสมอง cerebellum, basal ganglion และ hippocampus

Diagnosis of Hyperbilirubinemia: Careful clinical assessment and monitoring Thorough history: Pregnancy and delivery history General health status and infectious risk Feeding method and feeding progress Vital signs and ins/outs (hydration status) Risk factors for isoimmunization Family history and ethnicity (ie. G6PD, spherocytosis, etc.) Physical exam: Activity level, feeding ability, bruising/hematoma, plethora

Indirect Hyperbilirubinemia: Elevated levels of bilirubin due to imbalance in production, transport, uptake, conjugation, excretion, and reabsorption Most concerning due to risk for encephalopathy/kernicterus if not treated rapidly

Differential Dx of Indirect Hyperbilirubinemia: Physiologic Jaundice Disorders of Production Disorders of Hepatic Uptake Disorders of Conjugation Other Causes

Differential Dx of Indirect Hyperbilirubinemia: Physiologic Jaundice: Progressive rise in total bilirubin between 48 and 120 hours of life (peaks at 72-96 hours) Due to higher postnatal load of bilirubin and lower amount of liver conjugating enzyme (UGT) activity Occurs in virtually every newborn to some degree

Differential Dx of Indirect Hyperbilirubinemia: Disorders of Production: Increased RBC destruction Isoimmunization: Rh, ABO, other component incompatibilities RBC Biochemical defects: G6PD, pyruvate kinase deficiency RBC Structural Abnormalities: Spherocytosis, elliptocytosis, infantile pyknocytosis Infection: Bacterial, viral, protozoal Sequestration: Bruising, cephalohematomas, hemangiomas Polycythemia: IDM, delayed cord clamping Hemoglobinopathy

Differential Dx of Indirect Hyperbilirubinemia: Disorders of Hepatic Uptake: Gilbert Syndrome

Differential Dx of Indirect Hyperbilirubinemia: Disorders of Conjugation: Crigler-Najjar Syndrome Type I Crigler-Najjar Syndrome Type II Lucey-Driscoll Syndrome (transient familial neonatal hyperbilirubinemia) Hypothyroidism

Differential Dx of Indirect Hyperbilirubinemia: Other Causes: Breastfeeding Jaundice Lack of volume and increased enterohepatirecirculation Breast Milk Jaundice Unknown mechanism Possibly increased level of epidermal growth factor in breast milk that causes increased enterohepatic recirculation? Infant of Diabetic Mother

Causes of Jaundice appearing after on week Breastmilk jaundice Galactosemia Congenital hypothyroidism Congenital hemolytic anemia Cholestatic jaundice

Diagnosis of Hyperbilirubinemia: Transcutaneous measurement: Use can reduce need for blood level monitoring (Mishra et al, 2009) Blood level measurement - microbilirubin - total bilirubin

Diagnosis of Hyperbilirubinemia: Frequent additional studies to obtain: Blood type and Rh screening of mother and infant DAT/Coombs testing in infant CBC (consider reticulocyte count, blood smear) Occasional additional studies to obtain: Albumin levels LFTs TFTs Imaging: Liver/GB ultrasound, HIDA scan (r/o biliary atresia)

Neonatal Hyperbilirubinemia: Physiologic vs. Pathologic Jaundice < 24 hr is always pathologic! Indirect vs. Direct (Unconjugated vs. Conjugated)

Pre-term vs. Full-term Hyperbilirubinemia: Pre-term infants at higher risk due to further reduced activity of liver conjugating enzymes Pre-term infants can develop encephalopathy or kernicterus at lower total bilirubin levels

Management of Indirect Hyperbilirubinemia: Careful assessment and monitoring Visual assessment Blood level monitoring in high risk patients Interpretation of risk levels and need for treatment Phototherapy IVIg (reduces need for exchange when isoimmunization) Exchange Transfusions Phenobarbital (increases hepatic glucuronosyltransferase activity; used in severe and prolonged cases only)

Predischarge TSB or TcB level in the high-risk zone Risk Factors for Development of Severe Hyperbilirubinemia in Infants of 35 or More Weeks’ Gestation (in Approximate Order of Importance) Major risk factors  Predischarge TSB or TcB level in the high-risk zone  Jaundice observed in the first 24 h  Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease (eg, G6PD deficiency), elevated ETCOc  Gestational age 35–36 wk  Previous sibling received phototherapy  Cephalohematoma or significant bruising  Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive  East Asian race

Predischarge TSB or TcB level in the high intermediate-risk zone Risk Factors for Development of Severe Hyperbilirubinemia in Infants of 35 or More Weeks’ Gestation (in Approximate Order of Importance) Minor risk factors  Predischarge TSB or TcB level in the high intermediate-risk zone  Gestational age 37–38 wk  Jaundice observed before discharge  Previous sibling with jaundice  Macrosomic infant of a diabetic mother  Maternal age ≥25 y  Male gender Decreased risk (these factors are associated with decreased risk of significant jaundice, listed in order of decreasing importance)  TSB or TcB level in the low-risk zone  Gestational age ≥41 wk  Exclusive bottle feeding  Black race  Discharge from hospital after 72 h

Management of Indirect Hyperbilirubinemia: Indications for Phototherapy (Term/Near-Term Infants): * Bhutani curves (as seen in AAP recommendations and YNHH NBSCU Guidelines)

Management in preterm baby If TSB > Body weight in gram / 200 on phototherapy More vulnerable for encephalopathy than term babies

Treatment of Indirect Hyperbilirubinemia: Phototherapy: * Important factors: Spectrum, irradiance, distance, surface area

Management of Indirect Hyperbilirubinemia: Indications for Exchange Transfusion (Term/Near-Term Infants): * Adapted from AAP recommendations and YNHH NBSCU Guidelines

Treatment of Indirect Hyperbilirubinemia: Exchange Transfusion: Double-volume exchange 2 x blood volume = 2 x 80 cc/kg = 160 cc/kg Takes about 1-1.5 hours Exchange at rate of ~5cc/kg/3 min Volume withdrawn/infused based on weight

Discontinuation of phototherapy Decrease of at least 0.5 to 1 mg/dL per hour can be expected in the first 4 to 8 hours For infants readmitted after birth may be discontinued when the serum bilirubin level falls below 13 to 14 mg/dL

Improving effectiveness of phototherapy Blue light 460-490 nm gives deeper penetration Naked baby for larger skin irradiation Distance to baby 10-50 cm Cover with reflecting material Long exposure as possible Eye covering necessary

Complications of phototherapy Loose watery ,brown stool Retinal damage Photosensitivity – burn Dehydration In preterm: PDA, hypocalcemia In cholestatic Jaundice: bronze baby syndrome

Respiratory distress in the Neonate

Case 3 Female newborn , born C/S at GA 36 wk, apgar 8,9 at 1and 5 min respectively. 2 hr after birth she developed mild cyanosis and intercostal and subcostal retractions with audible grunting O2 sat room air 92 % PE : T 36.8 C, RR 80/min, PR 150/min, lung no secretion sound,heart normal S1S2 ,no murmur Most likely diagnosis? DDx? Management ?

การวินิจฉัย ประวัติ GA การเจ็บป่วยของมารดา fetal distress วิธีการคลอด meconium stained amniotic fluid perinatal asphyxia resuscitation

การตรวจร่างกาย อาการ respiratory distress: cyanosis, tachypnea ,retraction, grunting, flaring, moaning temperature blood pressure skin perfusion

Clues to Diagnosis of types of Respiratory distress INFORMATION FROM MATERNAL HISTORY MOST LIKELY CONDITION INFANT Prematurity RDS Diabetes RDS Hemorrhage in the days before RDS premature delivery Pneumonia Infection Premature rupture of membrane Pneumonia Prolonged labor Pneumonia

Meconium - Stained amniotic fluid Meconium aspiration Polyhydramnios INFORMATION FROM MATERNAL HISTORY MOST LIKELY CONDITION Meconium - Stained amniotic fluid Meconium aspiration Polyhydramnios Tracheoesophageal fistula Excessive medications Central nervous system depression Traumatic or breech delivery Central nervous system Fetal tachycardia or Bradycardia Asphyxia Prolapsed cord Asphyxia Postmaturity Asphyxia

Clues to Diagnosis of types of Respiratory distress (cont.) SIGNS IN THE BABY MOST LIKELY ASSOCIATED CONDITION Single umbilical artery Congenital anomalies Scaphoid abdomen Diaphragmatic hernia Erb / s palsy Phrenic nerve palsy Cannot breathe with mouth closed Choanal atresia Stuffy nose Overdistention of lungs Aspiration , lobar emphysema or Pneumothorax Choking after feedings Tracheoesophageal fistula or pharyngeal incoordination

Investigations Hct, CBC dextrostix,blood sugar blood gas chest X-ray hemoculture LP ultrasound,CT scan

Pulmonary disorder Common RDS TTNB MAS pneumonia pneumothorax Less common pulmonary hypoplasia upper airway obstruction rib-cage anomaly pulmonary hemorrhage diaphragmatic hernia

Extrapulmonary disorders Cardiac disorder PPHN CHD Metabolic acidosis hypoglycemia hypothermia Infectious sepsis

Extrapulmonary disorders Neuromuscular CNS damage medication hematologic hypovolemia anemia polycythemia

management 1. Supportive care 2. respiratory care 3. maintain adequate circulation 4. correct metabolic acidosis 5.specific treatment

Supportive care Neutral thermal environment keep body temperature 36.5-37.5 0C Nutrition –NPO? minimal enteral feeding parenteral nutrition position

respiratory care Oxygen therapy aim : arterial blood gas/ capillary blood gas pH 7.35-7.45 pH > 7.25 PaO2 50-80 mmHg ----- PaCO2 35-45 mmHg pCO2 45-60 Respiratory support

Respiratory support Oxygen canula low flow < 2 LPM Oxygen box High flow nasal canula > 2 LPM Nasal CPAP – NIPPV (nasal intermittent pos pres ventilation) ET tube with ventilator High frequency oscillator

Respiratory support Try non invasive respiratory support first maintain airway positive pressure by NCPAP or NIPVV in expiratory phase indication 1. PaO2 < 50-60 mmHg ขณะได้ FiO2≥0.6 2. recurrent apnea 3. respiratory acidosis

Indication on ET with Ventilator clinical criteria Retraction RR>70 /min Cyanosis Recurrent apnea Blood gas criteria 1. pH < 7.25 2. PaO2 <50 mmHg เมื่อให้ FiO2 100% 3. PaCO2 >60 mmHg

Choanal atresia

Macroglossia

Micrognathia

Esophageal Atresia

Diaphragmatic hernia

Diaphragmatic hernia

RDS

Pneumothorax

Cardiomegaly -CHF

Chronic lung disease

TTNB

Meconium Aspiration Syndrome