浙江大学 文本 新生儿黄疸、HIE_儿科学第二部分

医学院临床医学一系儿科堂（新生儿山）课程教案 课程名称 儿科学 教师及职称 俞惠民教授 授课内容 新生儿缺氧缺血性脑病：新生儿 黄疸 学时数 3学时 授课方式 理论课 上课学期 2005-2006第三学期 授课对象 02级临床医学 一、新生儿缺血缺氧性脑病（日IE):1.熟卷病因及病理：2.熟卷发表机制： 教学目的 3常握临依表现、辅助检查，除断与整别诊斯要点：4，章捉临床治疗累则及措连。 (教学大 二、新生儿黄疽：1.了解新生儿胆红素代谢的特点：2了解发生核黄植的有关因 纲要求) 素和防治方法：3熟无生理性黄箱与病理性黄直的鉴别要点：4.熟悉病理性黄珀常 见的几种病因及其特点， 教学内容*一、 新生儿缺血缺氧性脑病(IE) 65分钟 及时间分 *二、新生儿黄直 70分钟 配（双语 教学用· 注明) 1.H1E的病因及病理：2.IE的发病机制：3.H1E的临床表现及临 散学重点 重点 床分度、辅助检查、诊断与鉴别诊断：4.IE的治疗原则及具体措 与难点 施：5，几种常见的病理性黄疽的临床特点及诊断，鉴别诊断要点。 难点 E的临床表现及临床分度、辅助检查：常见柄理性黄植的鉴别诊 斯要点。 教学方法 多媒体教学十双语教学 hypoxic-ischemic encephalopathy(HIE).perinatal asphyxia,excitoxic amino acid,delaryed neuronal death,selective vulnerabiity.watershed infarcts, 专业词汇 subependymal germinal matrix,periventricular hemorrhage,convulsion,mental 要求 retardation,physiological Jaundice,pathological Jaundice.hyperbiirubinemia, breast milk jaundice.congenital biliary atresia,inspissated bile syndrome. kernicterus.hototherapy.exchange transfusion 教具准备CAI课件 1.HIE的基本鹏理变化是什么？ 复习思考 2.IE的诊断要点有哪些？ 题 3. 如何识别新生儿病理性黄疸？ 4. 新生儿病理性黄疸的处理原则是什么？ 要求自学E的预后与预防： 内容 生理性黄旗的特征及其产生机理。 教材及参 1.中文教材：《儿科学)（人民卫生出版社，七年制规划教材），薛辛东主编： 考书 2.英文教材：Nelson's Essential8 of Pediatries(节选本)， 教学网站 网址

医学院 临床医学一 系 儿科学（新生儿 II）课程教案 课程名称 儿科学 教师及职称 俞惠民 教授 授课内容 新生儿缺氧缺血性脑病；新生儿 黄疸 学时数 3 学时 授课方式 理论课 上课学期 2005-2006 第三学期 授课对象 02 级临床医学 教学目的 （教学大 纲要求） 一、新生儿缺血缺氧性脑病（HIE）：1.熟悉病因及病理；2.熟悉发表机制； 3.掌握临床表现、辅助检查、诊断与鉴别诊断要点；4.掌握临床治疗原则及措施。 二、新生儿黄疸：1.了解新生儿胆红素代谢的特点；2.了解发生核黄疸的有关因 素和防治方法；3.熟悉生理性黄疸与病理性黄疸的鉴别要点；4.熟悉病理性黄疸常 见的几种病因及其特点。 教学内容 及时间分 配（双语 教学用* 注明） *一、新生儿缺血缺氧性脑病（HIE） *二、新生儿黄疸 65 分钟 70 分钟 教学重点 与难点 重点 1.HIE 的病因及病理；2.HIE 的发病机制；3.HIE 的临床表现及临 床分度、辅助检查、诊断与鉴别诊断；4.HIE 的治疗原则及具体措 施；5. 几种常见的病理性黄疸的临床特点及诊断，鉴别诊断要点。 难点 HIE 的临床表现及临床分度、辅助检查；常见病理性黄疸的鉴别诊 断要点。 教学方法 多媒体教学＋双语教学 专业词汇 要求 hypoxic-ischemic encephalopathy(HIE), perinatal asphyxia, excitoxic amino acid, delayed neuronal death, selective vulnerability, watershed infarcts, subependymal germinal matrix, periventricular hemorrhage, convulsion, mental retardation,, physiological Jaundice, pathological Jaundice, hyperbilirubinemia, breast milk jaundice, congenital biliary atresia, inspissated bile syndrome, kernicterus, hototherapy, exchange transfusion 教具准备 CAI 课件 复习思考 题 1. HIE 的基本病理变化是什么？ 2. HIE 的诊断要点有哪些？ 3. 如何识别新生儿病理性黄疸？ 4. 新生儿病理性黄疸的处理原则是什么？ 要求自学 内容 HIE 的预后与预防； 生理性黄疸的特征及其产生机理。 教材及参 考书 1.中文教材：《儿科学》 （人民卫生出版社，七年制规划教材），薛辛东主编； 2.英文教材: Nelson’s Essentials of Pediatrics (节选本)。 教学网站 网址

授课详细致案（具体教学过程） 注解 HYPOXIC-ISCHEMIC ENCEPHALOPATHY DEFINITION Anorexia: consequences of a complete lack of oxygen owing to a number of primary causes. Hyporia: arterial concentration of oxygen is less than normal. Ischemin: blood flow to cells or organs is insufficient to maintain their normal function HIE: Hypoxic-ischemic damage of the brain resulting from perinatal asphyxia:primary cause of permanent damage to CNS (cerebral palsy.mental deficiency.death) ETIOLOGY Fetal asphyxia (80%-90%) .Inadequate oxygenation of matemal blood low materal blood pressure .Inadequate relaxation of the uterus to permit placental filling .Premature separation of the placenta .Impedance to the circulation of blood through the umbilical cord .placental inadequacy Diseases after birth (10%) ●Severe anemia .Shock .Respiratory failure (central or peripheral) PATHOPHYSIOLOGY ●CBF changes due to impairs of'cerebrovascular autoregulation Abnormal metabolism of brain tissue .Failure of energy metabolism .Neurologic toxity of the excitory amino acid ●Ca++influx .Reperfution ●Oxygen free radicals ◆NO/PAF

授课详细教案（具体教学过程） 注解 HYPOXIC-ISCHEMIC ENCEPHALOPATHY DEFINITION Anorexia: consequences of a complete lack of oxygen owing to a number of primary causes. Hypoxia: arterial concentration of oxygen is less than normal. Ischemia: blood flow to cells or organs is insufficient to maintain their normal function HIE: Hypoxic-ischemic damage of the brain resulting from perinatal asphyxia; primary cause of permanent damage to CNS (cerebral palsy, mental deficiency, death) ETIOLOGY Fetal asphyxia (80%-90%) ⚫ Inadequate oxygenation of maternal blood ⚫ low maternal blood pressure ⚫ Inadequate relaxation of the uterus to permit placental filling ⚫ Premature separation of the placenta ⚫ Impedance to the circulation of blood through the umbilical cord ⚫ placental inadequacy Diseases after birth (10%) ⚫ Severe anemia ⚫ Shock ⚫ Respiratory failure (central or peripheral) PATHOPHYSIOLOGY ⚫ CBF changes due to impairs of cerebrovascular autoregulation ⚫ Abnormal metabolism of brain tissue ⚫ Failure of energy metabolism ⚫ Neurologic toxity of the excitory amino acid ⚫ Ca++ influx ⚫ Reperfution ⚫ Oxygen free radicals ⚫ NO /PAF

Asphyxia increase in lactate pH Hypoxia decreased ATP GS depletion Icardiac output cerebrovascular autoregulation ↓CBF ↓ failure of ATP production impairs ion pumps (Na+-K+ATPase) excitoxic amino acid (glutamate,NMDA) Cainflux open ion channels Na+,Cl-and H2O influx delayed neuronal death ↓ immediate neuronal death NMDA activate phosphoinositol 2nd messenger system open voltage-dependent Ca++channel Ca++influx activation of undesirable enzyme (lipases and proteases) pertubation of mitochondrial respiratory electron chain transport generation of free radicals and leukotrienes depletion of energy stores delayed neuronal death (apoptosis)

Asphyxia increase in lactate ( pH ↓) Hypoxia ↓ decreased ATP & GS depletion ↓ ↓ cardiac output ↓ cerebrovascular autoregulation ↓ ↓CBF ↓ failure of ATP production ↓ impairs ion pumps (Na+-K+ ATPase) ↓ excitoxic amino acid (glutamate, NMDA) Ca++ influx ↓ open ion channels ↓ Na+, Cl- and H2O influx delayed neuronal death ↓ immediate neuronal death NMDA ↓ activate phosphoinositol 2nd messenger system ↓ open voltage-dependent Ca++ channel ↓ Ca++ influx ↓ activation of undesirable enzyme (lipases and proteases) pertubation of mitochondrial respiratory electron chain transport generation of free radicals and leukotrienes depletion of energy stores ↓ delayed neuronal death (apoptosis)

病理改变 ①大脑中动脉分布区局灶性或多灶性环死： ②白质囊性软化、脑水肿或疱痕酷回形成： ③选择性神经元坏死（海马CA1区、小脑的浦氏纤推）： ④丘脑、酷干及基底神经节坏死： ®分水岭梗塞（早产儿脑室周围白质软化，足月儿矢状窦皮层坏死和白质软 化)。 病理图片展示（略） 选择易损性(selective vulnerability) ？慢性、部分性室息常导致大脑弥漫性坏死，尤以皮层为甚 ？而急性、完全性室息主要累及脑干、丘脑以及基底神经节。 PATHOLOGY ●Edema 。Hemorrhage ·Subarachnoid Periventricular (subependymal germinal matrix) Intraventricular ●Necrosis .Focal or multifocal cortical necrosis Cystic encephalomalacia.ulegyria (attenuation of depth of sulci) 。Watershed infarcts Neuronal necrosis of brainstem nuclei .Necrosis of thalamic nuclei and basal ganglia PATHOLOGY Sensitive regions (White matter,boundary zones)vary with GA ◆preterm subependymal germinal matrix ●fullterm cortex (especially parietooccipital cortex) CLINICAL MANIFESTATIONS A.Hx of'fetal distress: ●Slow fetal heart rate .Scalp blood analysis:pH bellow 7.20

病理改变 ①大脑中动脉分布区局灶性或多灶性坏死； ②白质囊性软化、脑水肿或瘢痕脑回形成； ③选择性神经元坏死（海马CA1区、小脑的浦氏纤维）； ④丘脑、脑干及基底神经节坏死； ⑤分水岭梗塞（早产儿脑室周围白质软化，足月儿矢状窦皮层坏死和白质软 化）。 病理图片展示（略） 选择易损性(selective vulnerability） ? 慢性、部分性窒息常导致大脑弥漫性坏死，尤以皮层为甚 ? 而急性、完全性窒息主要累及脑干、丘脑以及基底神经节。 PATHOLOGY ⚫ Edema ⚫ Hemorrhage ⚫ Subarachnoid ⚫ Periventricular (subependymal germinal matrix) ⚫ Intraventricular ⚫ Necrosis ⚫ Focal or multifocal cortical necrosis Cystic encephalomalacia, ulegyria (attenuation of depth of sulci) ⚫ Watershed infarcts ⚫ Neuronal necrosis of brainstem nuclei ⚫ Necrosis of thalamic nuclei and basal ganglia PATHOLOGY Sensitive regions (White matter, boundary zones) vary with GA ⚫ preterm subependymal germinal matrix ⚫ fullterm cortex (especially parietooccipital cortex) CLINICAL MANIFESTATIONS A. Hx of fetal distress: ⚫ Slow fetal heart rate ⚫ Scalp blood analysis: pH bellow 7.20

.Yellow,meconium-stained amniotic fluid ●Low Apgar score CLINICAL MANIFESTATIONS B.Symptoms of HIE 1.Abnormal consciousness 2.Change of muscle tone 3.Change of primary reflex 4.Seizures 5.Brainstem dysfunction CLINICAL MANIFESTATIONS C.Symptoms of other organ systems: Kidneys:tubular (proximal)necrosis oliguria GI:NEC Lungs:ARDS,MAS Heart:CHF Neurologic Sequelae ●Cerebral palsy .pyramidal .extrapyramidal .Spastic paralysis ●Mental retardation Auditory dysfunction ·Visual dysfunction Language difficuhties ·Epilepsy Lab.Findings .Ultrasonic Examination of'the Brain: .hemorrhage (useful in preterm infants) .the extent of edema(midline shift,ventricular compression) .Cranial Computed Tomography Scan: assessing degree of edema(2-4days after the insult) encephalomalacia (at least 2 to 4 weeks later) .MRI (More clear sensitive) .EEG and Evoked Potentials Biochemistry:CK-BB.neuron-specific enolase

⚫ Yellow, meconium-stained amniotic fluid ⚫ Low Apgar score CLINICAL MANIFESTATIONS B. Symptoms of HIE 1. Abnormal consciousness 2. Change of muscle tone 3. Change of primary reflex 4. Seizures 5. Brainstem dysfunction CLINICAL MANIFESTATIONS C. Symptoms of other organ systems: Kidneys: tubular (proximal) necrosis oliguria GI: NEC Lungs: ARDS, MAS Heart: CHF Neurologic Sequelae ⚫ Cerebral palsy: ⚫ pyramidal ⚫ extrapyramidal ⚫ Spastic paralysis ⚫ Mental retardation ⚫ Auditory dysfunction ⚫ Visual dysfunction ⚫ Language difficulties ⚫ Epilepsy Lab. Findings ⚫ Ultrasonic Examination of the Brain: ⚫ hemorrhage (useful in preterm infants) ⚫ the extent of edema (midline shift, ventricular compression) ⚫ Cranial Computed Tomography Scan: ⚫ assessing degree of edema (2-4days after the insult) ⚫ encephalomalacia (at least 2 to 4 weeks later) ⚫ MRI (More clear & sensitive) ⚫ EEG and Evoked Potentials ⚫ Biochemistry: CK-BB, neuron-specific enolase

MANAGEMENT ·CPR Intensive Care (monitor vital signs) ◆Oxygen supply .PaO2 50-70mmHg (6.65-9.31kPa) .PaCO2<40 mmHg (5.32 kPa) keep adequate brain perfusion (systolic P above 50 mmHg) .Dopamine 3-5 ug/kg/min i.v.gtt. dobutamine 2.5-10 ug/kg/min i.v.gtt. MANAGEMENT ●Anti-convulsion 1.Phenobarbital (1st line) Lording dose 10-20 mg/kg iv Maintain dose (after 12 hr.)5 mg/kg/d b.i.d.for 7 days 2.Dilantin(2nd1ine） Lording dose:15-20 mg/kg iv.slowly I mg/kg/Min .Maintain dose (after 6-12 hr.)3-4 mg/kg/d b.i.d.or t.i.d. 3.Valium (Ist choice for seizures status) 0.3-0.5 mg/kg iv. 4.Chloral hydrate 0.5 mlkg MANAGEMENT 。Control of brain edema 1.20%Mannitol 1.25 ml-2 5 ml/kg q4h-q6h 2.DXM0.5-1.0 mg/kg/d iv.b.id.? 3.Furosemide (Lasix)0.5-1.0 mg/kg b.i.d. 4.Fluid intake:60-80 ml/kg/d .Correct acidosis,hypoglycemia,hypocalcemia Sodium Bicarbonate iv.keep pH 7.3-7.4 ◆Energy Mixture MANAGEMENT(Neuron rescue) ？Hypothermia? Calcium chanel blockor? Antagonist of NMDA receptor? Cell membrane stablizer? Free radical scavenger? Neuron nutrition factor(IGF-1)? NO thynsase inhihitor?

MANAGEMENT ⚫ CPR ⚫ Intensive Care (monitor vital signs) ⚫ Oxygen supply ⚫ PaO2 50-70mmHg (6.65-9.31kPa) ⚫ PaCO2＜40 mmHg (5.32 kPa) ⚫ keep adequate brain perfusion (systolic P above 50 mmHg) ⚫ Dopamine 3-5 ug/kg/min i.v. gtt. ⚫ dobutamine 2.5-10 ug/kg/min i.v. gtt. MANAGEMENT ⚫ Anti-convulsion 1. Phenobarbital (1st line) ⚫ Lording dose 10-20 mg/kg iv ⚫ Maintain dose (after 12 hr.) 5 mg/kg/d b.i.d. for 7 days 2. Dilantin (2nd line) ⚫ Lording dose: 15-20 mg/kg i.v. slowly 1 mg/kg/Min ⚫ Maintain dose (after 6-12 hr.) 3-4 mg/kg/d b.i.d. or t.i.d. 3. Valium (1st choice for seizures status) 0.3-0.5 mg/kg i.v. 4. Chloral hydrate 0.5 ml/kg MANAGEMENT ⚫ Control of brain edema 1. 20% Mannitol 1.25 ml-2.5 ml/kg q4h-q6h 2. DXM 0.5-1.0 mg/kg/d i.v. b.i.d. ? 3. Furosemide (Lasix) 0.5-1.0 mg/kg b.i.d. 4. Fluid intake: 60-80 ml/kg/d ⚫ Correct acidosis, hypoglycemia, hypocalcemia Sodium Bicarbonate i.v. keep pH 7.3-7.4 ⚫ Energy Mixture MANAGEMENT(Neuron rescue) ? Hypothermia? ? Calcium chanel blockor? ? Antagonist of NMDA receptor? ? Cell membrane stablizer? ? Free radical scavenger? ? Neuron nutrition factor (IGF-1)? ? NO thynsase inhibitor?

Neonatal Jaundice (Hyperbilirubinemia) Introduction *Definition Abnormal metabolism of Bili. Increased Bili.In blood Yellow stain in skin,mucomembrane,sclera *Specialty -Very common -Complicated causes CNS toxicity Metabolisn of Bilirubin in Adult Production Combine Uptake Conjugation Excretion Metabolisn of Bilirubin in Newborn 。Great production 。Poor combine ·Lower uptake 。Limited conjugation *Defected excretion Classification of the Neonatal Jaundice ● Physiological Jaundice Pathological Jaundice早，快，重，长，高，退而复现

Neonatal Jaundice (Hyperbilirubinemia) Introduction •Definition Abnormal metabolism of Bili. Increased Bili. In blood Yellow stain in skin, mucomembrane, sclera •Specialty – Very common – Complicated causes – CNS toxicity Metabolism of Bilirubin in Adult Production Combine Uptake Conjugation Excretion Metabolism of Bilirubin in Newborn • Great production • Poor combine • Lower uptake • Limited conjugation • Defected excretion Classification of the Neonatal Jaundice ⚫ Physiological Jaundice ⚫ Pathological Jaundice 早，快，重，长，高，退而复现

Pathological Jaundice Direct (conjugated)Hyperbilirubinemia Indirect (unconjugated)Hyperbilirubinemia Physiological Jaundice 。Appear after Ist day With peak level at 4~6th day (s205~256 u mol/L) .Unconjugated Bili.Mainly Disappear in 10~14 days (full term)or in 3~4 weeks (preterm) ·No other symptoms Pathological Jaundice Appear early (within 24 or36 hrs) Progress rapidly,increase>85.5 u molL per day Higher level of Bili.>205~256 u mol/L Last longer.>2 weeks in full term or 4 weeks in preterm ·Increased conjugated Bili.>34.2μmoL Increase progressively or reappear afterdisappearing Common causes of neonatal hyperbilirubinemia Production Conjugation Excretion Mixed

Pathological Jaundice ⚫ Direct (conjugated) Hyperbilirubinemia ⚫ Indirect (unconjugated) Hyperbilirubinemia Physiological Jaundice • Appear after 1st day • With peak level at 4～6th day（205～256μmol/L • Last longer , >2 weeks in full term or 4 weeks in preterm • Increased conjugated Bili. >34.2μmol/L • Increase progressively or reappear after disappearing Common causes of neonatal hyperbilirubinemia • Production • Conjugation • Excretion • Mixed

Increased production ·Hemolytic diseases -Isoimmunization:ABO,Rh Enzyme deficiency of RBC:G-6-P-D deficiency -Defects of RBC membrane:hereditary spherocytosis Enclosed hemorrhage:head hematoma,ICH Increased resorption:feeding delay,breast milk jaundice,digestive tract anormalous Polyeythemia:fetal-fetal transfusion,delayed ligation of umbilical cord. SGA Dysfunction of conjugation ·Inhibition of UDPGT -Hypoxia.Lucey-Driscoll Syndrome ·Deficiency of UDPGT -Crigler-najiar syndrome.Gilbert syndrome .Others -Hypoproteinemia.Hypoglycemia,Drugs (oxytocin) -Congenital hypothyroid ism.Down syndrome Dysfunction of Excretion *Intrahepatic Obstruction (hepatitis) -TORCH.TPN,Byler disease .Extrahepatic Obstruction (congenital biliary atresia)

Increased production • Hemolytic diseases – Isoimmunization：ABO, Rh – Enzyme deficiency of RBC: G-6-P-D deficiency – Defects of RBC membrane:hereditary spherocytosis • Enclosed hemorrhage：head hematoma, ICH • Increased resorption：feeding delay, breast milk jaundice, digestive tract anormalous • Polycythemia：fetal –fetal transfusion, delayed ligation of umbilical cord, SGA Dysfunction of conjugation • Inhibition of UDPGT – Hypoxia, Lucey-Driscoll Syndrome • Deficiency of UDPGT – Crigler-najiar syndrome、 Gilbert syndrome • Others – Hypoproteinemia, Hypoglycemia, Drugs (oxytocin) – Congenital hypothyroidism, Down syndrome Dysfunction of Excretion • Intrahepatic Obstruction（hepatitis） – TORCH、TPN, Byler disease • Extrahepatic Obstruction（congenital biliary atresia）

-Common,hepatic or intrahepatic bile duct Inborn Metabolic Defects -Galactocemia,tyrosinosis,Gausher disease.a 1-antitrypsin deficiency Inspissated bile syndrome Mixed Facts ·Infection -Sepsis -UTI 一Pneumonia ·HMD Infant of diabetes mother Toxicity of Bilirubin on CNS Bilirubin encephalopathy accumulate (reversible) combine (maybe reversible) deposite (inreversible.kemicterus) Free bilirubin increase: BBB window open

– Common, hepatic or intrahepatic bile duct • Inborn Metabolic Defects – Galactocemia, tyrosinosis, Gausher disease, α1-antitrypsin deficiency • Inspissated bile syndrome Mixed Facts • Infection – Sepsis – UTI – Pneumonia • HMD • Infant of diabetes mother Toxicity of Bilirubin on CNS Bilirubin encephalopathy accumulate (reversible) combine （maybe reversible） deposite （inreversible, kernicterus) Free bilirubin increase; BBB window open