Multiorgan Disfunction

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    MULTIPLE ORGAN INVOLVEMENT INPERINATAL ASPHYXIA

    ThesisS : . . ; = " : : : : ~ t ~ d L: Pcrtin; r r ~ a ; I I : : 1 c n t ofM.D. Degree

    t- , Pc.e d.ui.iri.cBy

    Nader Mohammed Mohammed Mohammed(M.Sc. Paediatrics)

    SupervisorsProf. Dr.

    om Saad EI Din AshmawyProfessor ofPaediatricsFaculty ofMedicineZagazig University

    Prof. Dr.Ali Al.a} EI-Hamid AbduProfessor ofPaediatricsFaculty ofMedicineZagazig University

    Prof. Dr.Sherifa Abd Elaziz HassanProfessor ofPaediatricsFaculty a/MedicineZagazig University

    Prof. Dr.Nader Mohammed MostafaProfessor ofClinical PathologyFaculty ofMedicineZagazig University

    Faculty ofAfedicineZaga't.ig University2il04, '

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    ACKNOWLEDGEMENTFirst and foremost, thanks are due to ALLAH. to whom I relate any

    success in achieving any work in my life.My words stand short ofmy supreme gratitude and thanks to Prof Dr.Olfia Saad El Din Ashmawy, Professor of Paediatrics, Faculty of Medicine,

    Zagazig University, for her continuous supervision, valuable guidance,generous encouragement, help & overall her moral support and kindness thatgave me and this work a lift to the scope of light.

    Special thanks are due to Prof Dr. Sherifa AbdEtoziz Hassan, ProfessorofPaediatrics, Faculty ofMedicine, Zagazig University, for dedicating so muchof her precious time and effort, and for her honest and constant guidance tocomplete this work.

    I am also deeply indebted to the great help offered by Prof Dr. Ali AbdEl-Hamid Abdu, Assistant Professor of Paediatrics. Faculty of Medicine.Zagazig University. to whom lowe many valuable remarks and a lot ofprecioustime and effort. her guidance and kind assistance supported in completing thiswork.

    1 am also deeply indebted to the great help offered by Prof Dr. NaderMohammed Mostafa, Professor of Clinical Pathology, Faculty of Medicine,Zagazig University, to whom lowe many valuable remarks and a lot ofprecioustime and effort, her guidance and kind assistance supported in completing thiswork.

    My deepest gratitude, sincere thanks and great appreciation are due toMy Mother, Father, Brother Dr. Ahmed and My Sister Dr. Amira not onlyfortheir endless supply oflove, generous kind and encouragement but also for theirincomparable effort in the presentation and throughout all my life, words ofthanks are so little for their great help in preparation ofthis work

    My deepest heart feelings with my hot endless love to my share life Dr.Mona Gomaa not only for her limitless generous support, unique help andactive skillful cooperation which give me a great motive throughout this work,but alsofor her unendingpowerful love supply she give and still giving.

    It was a real pleasure and honour to work under supervision ofmy ProfDr. Isaad Khalaaf & Prof. Dr. Soheir Ibrahim and Prof. Dr. IbrahimAbdulhaq, and cooperate with my colleagues to produce this work.

    Finally, I wish to thank all members ofMy Family, my colleagues and myFriends for their continuous help, encouragement and support.

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    CONTENTSPage

    Introduction and Aim of the Work 1Review ofLiterature , 3

    Perinatal Asphyxia 3- Definition 3- Incidence 10- Risk factor 11- Mechanism of asphyxia 18- Aetiology ofperinatal asphyxia 19- Pathophysiology of perinatal asphyxia 25- Pathogenesis and clinical correlation of perinatal asphyxia .. 40- Manifestation of perinatal asphyxia 48- Diagnosis of perinatal asphyxia 66- Management ofperinatal asphyxia 94- Potential new therapies for the treatment of IDE 106- Prognosis and follow up of neonates with perinatal asphyxia 111

    Subjects and Methods 121Results 125Discussion 143Summary and Conclusion 150References 153Arabic Summary .

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    LISTOFABBREVIATIONS

    AAP : American Academy ofPaediatrics.ACOG :American Colleague ofObstetricians and Gynaecologists.ADH : Antidiuretic hormone.ATP : Adenosine triphosphate.BBB : Blood brain barrier.BP : Blood pressure.CBF : Cerebral blood flow.CK-BB : Creatine kinase.eNS : Central nervous system.CO : Carbon monoxide.CP : Cerebral palsy.CT : Computed tomographyO le : Disseminated intravascular coagulation.ECG : Electrocardiogram.EFM : Electronic foetal monitoringFENa : Fractional excretion ofNa".FHR : Foetal heart rate.GABA : Gamma amino butyric acid.GFAp : Glial fibrillary acidic protein.GGT : Gamma-glutamyltransferase.GIT : Gastrointestinal tract.HBCO : Carboxyhaemoglobin.IDE : Hypoxic ischemic encephalopathy.HR : Heart rate.

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    IL-6IVBMASMRIMRSNFpNIRSNSEPETPMNsPPHNS

    : Interleukin-f: Intraventricular Haemorrhage.: Meconium aspiration syndrome.: Magnetic resonance imaging: Magnetic Resonance spectroscopy: Neuroflament protein.: Near-infrared spectroscopy: Neuron specific enolase: Positron emission tomography.: Polymorphonuclear leukocytes: Persistent pulmonary hypertension of the newborn

    syndrome.PVE : Periventricular echodensities.PVL : Periventricular leukomalaciaSIDAH : Secretion of antidiuretic hormone.SPECT : Single- photon emission computed tomography.SPECT : Single photon emission computed tomography.TNF-alpha : Tumour necrosis factor-alphaTSH : Thyroid stimulating hormone.TXB2 : thromboxane B2VIS : UltrasonographyVEPs : Visual evoked potentials.

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    LIST OF TABLESPage

    457811252633

    49505 15 152

    64727295951 12

    No12345678

    9101 11213

    141516171819

    Essential criteria o f perinatal asphyxia.Types of acidernia.Clinical features of neonatal HIE.The multiple effects of perinatal asphyxia.Risk Fac tors of perinatal asphyxia.Types of prenatal asphyxia,Types of postnatal asphyxia.Mechanisms of brain damage during and after asphyxia1injury.Clinical features of severe HIE (Birth to 12 hrs).Clinical features of severe HIE (12-24 hrs).Clinical features of severe HIE 24-72 hrs).Clinical features of severe HIE (> 72 hrs).Sarnat and Samat stages o f hypoxic-ischemic encephalopathy(HIE).Clinical features of perinatal asphyxia.Normal blood gas values in term newborn.Apgar score.Prevention of intrauterine asphyxia.Intraparturn assessm ent o f the foetus.Useful prognostic factors in hypoxic-ischemicencephalopathy.

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    .- Tables of result

    No Page1 Mode of delivery. 1252 Apgar 1min and 5 min. 1263 Stages ofHIE. 1274 Cranial ultrasound. 1285 Oliguria. 1296 Protein in urine. 1307 BUN. 1318 Serum creatinine. 1329 Acid - base disorder. 13310 Single organ involvement. 13411 Multiple organ involvement. 13512 Association between disturbance in renal function and CNS 136

    affection.13 Association between Apgar at 5 minutes and organ affected 138

    with outcome.

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    LIST OF FIGURESNo Page1 Major relationship between perinatal asphyxia and 32cerebral blood flow.2 Mechanism of production of oxygen free radicals during 37recovery from severe asphyxia. . .3 Foetal/neonatal response to Intrapartum asphyxia. 434 Evolution of electroencephalographic sever hypoxic- 79ischemic encephalopathy.

    Figures of results.No Page1 Mode of delivery. 125

    2.a Apgar at Imin. 1262.b Apgar at 5min. 1263 Relation of stage ofHIE to outcome. 1274 Cranial ultrasound finding. 1285 Oliguria. 1296 Proteinuria. 1307 BUN. 1318 Serum creatinine. 1329 Single organ involvement. 13410.a Multiple organ involvement; No. of cases. 135

    1O.b Multiple organ involvement; Percentage of cases. 136l1.a Relation of CNS & renal affection to outcome in stage I 137HIE.l1.b Relation of CNS & renal affection to outcome in stage II 137

    & III IDE.12.a Association between Apgar at 5 minutes and organ 139affected; less than or equal 5.12.b Association between Apgar at 5 minutes and organ 139affected; more than 5.

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    1

    INTRODUCTION

    Perinatal asphyxia and its neurodevelopmental consequences remaina major clinical challenge despite recent advances in obstetric and neonatalcare.

    Dysfunction of organs other than the eNS is often recognized afterperinatal asphyxia, and organ specific studies have evaluated thepathophysiologic and clinical manifestations of hypoxic-ischemic insults tokidney, heart, lung and bowel.

    The kidneys are one of the target organs affected by perinatalasphyxia, and they arc involved in 50 percent of asphyxiated newborns(Schneider, 2001).

    During normal myocardial oxygenation, circulating free fatty acidsprovide the major fuel source for the myocardium; but during hypoxia, freefatty acids cannot be oxidized and hence the heart becomes totallydependent on anaerobic glycolysis of glycogen for energy production.Cardiac glycogen stores are rapidly depleted as the asphyxia progresses.Neonatal survival during asphyxia is dependent on the amount of cardiacglycogen available prior 10 the asphyxial episode (Gueuyener, 2001).

    The pulmonary effects of asphyxia include increased pulmonaryvascular resistance, pulmonary hemorrhage, pulmonary edema secondary10 heart failure, persistent pulmonary hypertension, and possibly failure ofsurfactant production with development of secondary hyaline membranedisease termed adult respiration distress syndrome (Snyder and Cloherty,1997).

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    Term infants who suffer asphyxia have a greater incidence of feedingdifficulty, but these are frequently only transient. The asphyxiated infant isat risk for bowel ischemia and necrotizing enterocolitis (Snyder andCloherty, 19.97). It was hypothesized that the neurological insult caused byperinatal asphyxia may affect gastrointestinal motor function and motility(Kliegman,2000).

    AIM OF THE WORKThe aim of this study is to evaluate the frequency and spectrum of

    severity ofmultisystem dysfunction in the neonatal period after a perinatalasphyxial insult and 10 evaluate the relationship between the traditionalclinical and biochemical markers of perinatal asphyxia and multiorgandysfunction to determine whether any of those early markers might help toidentity promptly the asphyxiated neonates for early recognition of infantsat greatest risk of multisystem dysfunction who would be in need of earlyintertvention to avoid late sequelae.

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    I "eVleW OJ,Iteratore

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    Definition:

    3

    PERINATAL ASPHYXIAReview ofLiterature

    Perinatal asphyxia is an insult to the foetus or newborn due to lack ofoxygen (hypoxia) and lor lack of perfusion (ischemia) to various organs. Itis associated with tissue acidosis. If accompanied with hypoventilation, it isalso associated with Hypercapnia (Schneider, 2001). The term asphyxiadenotes progressive hypoxia, accumulation of carbon dioxide, andischemia. If this process proceeds for enough, it can result in pennanentbrain injury or death (Nelson, 2003).

    Commonly hypoxia and ischemia occur simultaneously or insequence. Ischemia is likely to be the more important of these two insults(Shauhan et al., 2003).

    Perinatal asphyxia is one of the leading causes of perinatal mortalityand a recognized cause of subsequent neuromotor morbidity and disabilitylater in life among the survivors (Hankins, 2003).

    Concerning definition of perinatal asphyxia, there is no single tool ortest can yield a precise definition, however the following indices ofperinatal asphyxia are the conventionally used worldwide to document anddiagnose perinatal asphyxia in the immediate postnatal period as stated bythe American Academy of Paediatrics (AAP) and the AmericanColleague of Obstetricians and Gynaecologists (ACOG) committees onMaternal Foetal Medicine and Foetus and Newborn in 1992. Theyinclude:1- Profound metabolic or mixed acidemia.2- Persistance of an Apgar score 0 to 3 for more than 5 minutes.

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    3- Clinical neurological sequelae in the immediate neonatal periodincluding seizures, hypotonia, coma or hypoxic - ischemicencephalopathy (illE).

    4- Evidence of multiorgan system dysfunction in the immediate neonatalperiod such as renal or hepatic failure.

    (Chemnick and Greenstreet, 2002)In cases when such evidence is lacking, we cannot conclude that

    perinatal asphyxia exists (Chauhan et al., 2003).

    Table (1): Essential criteria of perinatal asphyxia.1- Profound metabolic or mixed acidemia (pH < 7.00) on an umbilical

    cord arterial blood sample.2- Persistence of an Apgar score of 0 t o 3 > 5 minutes.3- Clinical neurological sequelae in the immediate neonatal period (e.g.,

    seizures, hypotonia, coma or HIE).4- Evidence ofmultiorgan system dysfunction in the immediate neonatal

    period.(American Academy of Paediatrics and American college ofObstetricians and Gynaecologists, quoted from Guidelines for Perinatalcare, 1992). (Chemnick and Greenstreet,2002).] . Acidemia:

    In utero, varying degrees of hypoxia and transient interference withmaternal-foetal respiratory exchange are common in all labours. However,if significant hypoxemia occurs, the foetus will utilize anaerobic glycolysis

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    5to meet its energy needs. The subsequent formation of non-volatile acids,such as lactic acid, will result in a decrease in the blood pH of the foetusand lactic acidosis (Fletcher et al., 1998).

    Acidemia can be classified as respiratory, metabolic or mixedacidemia. (Carteret aL, 1993).

    Table (2): Types of acidemia.a- Respiratory acidemia PCOz is high

    HCO) is normalb- Metabolic acidemia peoz is normal

    HC03 is lowc- Mixed acidemia peoz is high

    HC03 is low

    The biochemical hallmark of asphyxia is a profound acidemia. Rossand Gala (2002) stated that the most a c c u r ~ t e and satisfactory way ofassessing whether or not a baby is asphyxiated at the moment of birth is tomeasure the blood gases and pH in a sample drawn from the umbilicalartery immediately after delivery. This data can be extremely useful inguiding the baby's subsequent management

    Indeed, the accumulation of lactic acid ~ p p e a r s to play a substantialrole in hypoxic/ischemic injury. There is, however, little correlation ofsevere acidosis with the Apgar score orwith the infant's neurological statusin the neonatal period. Most studies found approximately a 15-20%correlation between low Apgar score and low cord blood pH in terminfants. Likewise, infants often have low pH values but normal Apgar

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    scores. Furthermore, the more premature the infant, the poorer thecorrelation between cord blood pH and low Apgar scores. It was noted thatpremature infants frequently have low Apgar scores but perfectly normalcord pH values (Hermansen, 2003).

    Severe acidosis has not been shown to predict long-term neurologicaloutcome. Although an umbilical artery pH of< 7.1 with a base deficit of>13 mmollL has been considered evidence of severe acidosis and ofIntrapartum asphyxia, there is currently no established correlation of suchacidosis with long-term outcome (Shah et al., 2003).

    The normal range of umbilical artery pH may be lowered to 7.15 oreven 7.10. Between 7.00 and 7.20. PH values have no correlation with anyimmediate or long-term neonatal morbidity. A normal pH, >7.2, andperhaps even lower, can be taken as evidence that substantial asphyxia hasnot occurred in the recent past(Hermansen, 2003).However, a p ~ < 7.0and a base deficit of> 13mrnol/L represents clinically significant acidosis.Most foetuses with an arterial pH < 7.0 will not suffer evidence of perinatalasphyxia and such acidemia of itself is not evidence to establish thathypoxic injury has occurred (Shah et aL, 2003).2 ~ The Apgar score:

    The Apgar examination is a rapid scoring system based onphysiologic responses to the birth process. It is a very good method forassessing the need to resuscitate the newborn infant (Ganga et al.). TheApgar examination with be mentioned in details later.3) Neurological sequelae:

    Numerous neurological signs may be observed in the neonatewith lowApgar scores, acidemia and asphyxia. In the infant, the primarysigns of centralnervous system (CNS) injuryfollowingasphyxia include:

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    Seizures. Abnormal respiratorypatterns includingapneaand respiratoryarrest.... An apparent state of Hyperalertness, jitteriness, posturing, movement

    disorders, impaired suckling, swallowing, gag and feeding, pervasivehypotonia and bulging anterior fontanel.

    Abnormal oculomotor and pupillaryresponses.(Roberto et aL, 1002).Early neonatal seizures are not specific for asphyxia: 60% may be

    related to hypoxic-ischemic encephalopathy (HIE) which is usuallysecondary to perinatal asphyxia; but intracranial haemorrhage, hypoglycaernia,hypocalcaemia, neurodevelopmental defects, drugwithdrawal and other etiologiesmustbeconsidered(Miller et al; 2001).

    In addition to seizures, a constellation of neurological signs evolvesover the first 72 hours of life in asphyxiated newborns that comprises thesyndrome of IDE (Table 3).Table (3): Clinical features of neonatal IDE.First 12 to 24 hrs An apparent Hyperalertness or Hyperexcitability,

    seizures, apnea, jitteriness, weakness.24 to 72 hrs Obtundation or coma, ataxic respiration with

    subsequent respiratory arrest. abnormal oculomotorreflexes, impaired pupillary response, and intracranialhaemorrhage (prematures) with subsequentdeterioration.

    Beyond 72 hrs Persistent stupor, abnormal .or absent suckling,swallowing, and gag reflexes which impair feeding,generalized hypotonia, weakness

    (Volpe, 1987)

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    84) Multiple organ dysfunctions:

    In addition to the neurological sequelae of seizures and mEfollowing a significant period of ischemia, profound acidosis andhypoxemia, there are multiple organ system evidences of such an insult, asimpairment of systemic blood flow sufficient to damage the brain regularlyalso damages other organs in addition. Infants with neonatalencephalopathy but without multisystem involvement are unlikely to havetheir encephalopathy on basis of Intrapartum asphyxia (Hankins et al;2002). Neonatal multisystem dysfunction characterizes' the truly (significantly)asphyxiated infant(Cornette et at, 2001).Ta hie (4): The multiple effects of perinatal asphyxia.CNS: Hypoxic-ischemic encephalopathy, cerebral oedema,

    neonatal seizures, long term neurological sequelae.Pulmonary: Pulmonary hypertension, surfactant disruption,

    Meconium aspiration.Renal: Oliguria. Acute renal failure.Cardiovascular: Tricuspid insufficiency, myocardial necrosis,

    shock/hypotension.Adrenal: Adrenal haemorrhage.Metabolic: Metabolic acidosis, hypoglycaemia, hypocalcaemia

    and hyponatremia.Gastrointestinal: Necrotizing enterocolitis. hepatic dysfunction.Haematological: Thrombocytopenia disseminated intravascular

    coagulopathy.Death:

    (Hankins et aL, 2002)

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    9The clinical course and extent ofmultisystem involvement in these

    infants can vary depending on the onset and duration of asphyxial insult(Chauhan et aL, 2003).

    It has been observed that eNS involvement is the only organ systemthat has residual sequelae at long-term follow-up. All other organ systemsaffected in the neonatal period resolve including pulmonary, renal, cardiac,metabolic, and rheumatologic systems (Gary et al., 2002).

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    Incidence:Statistics suggest on incidence of systemic asphyxia in 1-2/1000 full

    term infants and incidence that approaches 60% in very low birth weightnewborns (Ottaviano et al; 2001).

    It is usually related to gestational age and birth weight. It occurs in9% of infants less than 36 weeks gestation and in 0.5% of infants more than36 weeks gestation, accounting for 20% of perinatal deaths (or as high as50% of deaths if stillborns are included). In term infants, the incidence ishigher in infants born to diabetic and toxaemic mothers; these factorscorrelate less well in pretenn infants. In both pretenn and term infants,intrauterine growth retardation and breech presentation are associated withan increased incidence of asphyxia, Postmature are also at risk (ShanKaranet al., 1998).

    Seven million perinatal deaths occur each year, mostly in developingcountries. Nearly 4 million newborns suffer moderate to severe perinatalasphyxia. with at least 800,000 dying and at least an equal numberdeveloping neurodevelopmental sequelae, such as epilepsy, mentalretardation, cerebral palsy and learning disabilities (Kjeltmer et al : 2002).

    In Egypt, there is no published study for the incidence of perinatalasphyxia.

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    11 Review ofLiterature

    RISK FACTORS OF PERINATAL ASPHYXIAAccording to Snyder and Cloherty (1997) any process which: (1)

    impairs maternal oxygenation; (2) decreases blood flow from mother toplacenta or from placenta to foetus: (3) impairs gas exchange across theplacenta; (4) increases Foetus O2 requirements, will exacerbate perinatalasphyxia.

    Obviously, risk factors are multiple and they overlap, particularly inthe case of asphyxia (Scher, 1001).We can summarise the risk factors in the following table.Table (5): Risk Factors of perinatal asphyxia:

    ... Placenta Previa

    Maternal/Prenatal... Preclamptic toxaemia premature rupture ofmembranes... Smoking Infection... Diabetes Placental insufficiency... Chronic hypertension Chronic illness such as

    cardiopulmonary disease... Maternal age < 15 or > 35 years.... Substance abuse during pregnancy .... Injury during pregnancyIntrapartumfoetal ... Abruption placentae.. Abnormalpresentation

    ... Prolapsed cord

    ... Umbilical cord occlusionPerinatal.... Prematurity/postmaturity Respiratory distress syndrome

    ... Growth retardation Patent ductus arteriosus

    ... Foetal distress (HR < 100) Intraventricular haemorrhage

    ... Multiple births Seizures

    ... Polyhydramnios Hyperglycemia / hypoglycemia

    ... Congenital anomalies Hyperthennial hypothermia

    ... Meconiumstaining/ aspiration Hypercalcemia / hypocalcaemia

    ... Hyperbilirubinemia Repetitive injuries.(Scher, 1001).

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    A number of risk factors may have cumulative effects that are muchmore influential than anyone factor considered in isolation. (Milsom et al.,2002)A- Metabolic Status:

    Although glucose is an important metabolic substrate. Theinteractions between hyperglycaemia and asphyxia n the perinatal periodare not clear. In adults, glucose supplementation prier to hypoxia-ischemiacan increase lactic acid accumulation, worsen neurological outcome andcause infarction (Williams et al., 1993); while mild hypoglycaemia wasreported to improve the outcome in adults follow.ng asphyxia (Huang,1994).

    Hyperglycaemia can be toxic to the foetus particularly to growthretarded foetuses and cause metabolic acidosis. Hycerglycaemia has beenassociated with intracranial haemorrhage (Pi/des, j 7 , ~ 6 ) . In contrast, somestudies have shown that postnatal newborn animals treated with glucosecan withstand longer duration of asphyxia. These studies suggest thatincreased glucose concentration does not augmer and may reduce theeffects of cerebral hypoxia/ ischemia in the immature rat brain. In newbornlambs. Hyperglycaemia had no effect on changes in intracellular pH orcerebral lactate concentration during ischemia. Hyperglycaemic newbornpiglets also displayed less disturbance of cerebral adenosine triphosphate(ATP) metabolism during ischemia than nor: noglycaemic animals.Hyperglycaemic newborn pups subjected to hypoxia/ischemia had longersurvival time than controls as well as reduced area of hypoxic/ischemiccortical infarct (Voorhies et al., 1986).

    These apparently contradictory results between newborns and adultsare due to several factors: Glucose uptake in the neonatal brain is less

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    efficient than in the adult. Resulting in a smaller increase in cerebralglucose concentration. The cerebral glucose consumption does not appearto increase in the hyperglycaemic hypoxic/ischemic newborn even thoughglucose transport is increased, thus reducing the rate of lactateaccumulation. Also, lactate formation in ischemic newborn is slower thanin adult animals. The newborn can metabolize lactate produced duringhypoxia. Energy depletion may be a significant factor in the evolution ofhypoxic/ischemic cerebral injury. Since the newborn has a lower energyreserve than the adult, the protective effect of hyperglycaernia may beattributed to preservation ofATP levels (Vannucci, 1000).

    Some authors have suggested that severe lactic acidosis worsensoutcome in the developing brain. Acidotic conditions, however, cansuppress activity of the excitatory N-methyl-D-aspartate receptors andprotect developing neurons against hypoxia in culture (Martin et ai, 1002).Similarly, moderate acidosis is protective for the developing heart(Lannettoni et al; 1991).

    Very high levels of lactic acid accumulation (> 18 roM) are thoughtto cause infarction, at least to the adult brain (Jurek et aL, 1001). Inneonatal models of asphyxia, lactate concentrations only reach about 10mM, yet infarction can still develop, which tends to refuse the claim thatlactic acid accumulation plays a critical role in brain injury. Thus, the roleof moderate lactic acidosis during perinatal asphyxia is unclear, and theconsequences of very high levels of lactic accumulation in the developingbrain need to be carefully evaluated (Williams et al., 1993).

    In contrast, hypoglycaemia may enhance hypoxic cerebral injury inneonates by decreasing the levels of high energy phosphates and causingrelease of free fatty .acids from membrane phospholipids, providing

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    substrate for free radical production. This suggests that hypoglycaemiacontributes to hypoxia induced free radical cerebral injury. However,hyperglycaernia during hypoxia could reduce both direct free radical effectson membrane lipid and enhancement of excitotoxicity by free radicals, innewborns (Vannucci, 2000).

    A recent study by Park et al., (2001) stated that hyperglycaemia butnot hypoglycaemia immediately after hypoxia ischemia, interferes with therecovery of brain cell membrane function and energy metabolism, whichsuggest that post hypoxic-ischemic hyperglycaernia is not beneficial andmight even be harmful in neonatal hypoxic ischemic encephalopathy.B- Body Temperatllre:

    Recent studies indicated that even a small decrease in braintemperature confers striking protection against ischemic neuronal injury.By contrast, small elevation of brain temperature during ischemiaaccelerates and extends pathologic changes in the brain and promotes earlydisruption of the blood brain barrier (BBB). Hypothermia retards the rate ofATP depletion during ischemia, and promotes post ischemic metabolicrecovery. Thus, mild to moderate decrease in brain temperature (3-6C) isneuroprotective in cerebral hypoxia/ischemia; while mild elevation of braintemperature is markedly deleterious in the setting of injury (Chen et al.,2001).C- GestationalAge:

    In term babies, the insult is usually inflicted antepartum, whereas inthe preterm babies, the insult is commonly (but not always) postnatal(Kumar et al; 2001). Preterm newborn mammals exhibit greater resistance

    :t-

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    ISto cerebral damage from hypoxic/ischemic insults than term newborns(Martin et al., 2002).

    In the pretenn infant, asphyxia may result in subependyrnal germinalmatrix haemorrhage, Intraventricular haemorrhage or periventricularleukornalacia, but they also may be found in term infants. In contrast,damage due to asphyxia in fullterm babies primarily is manifested innecrotic lesion in the peripheral and dorsal areas of the cerebral cortex.Necrosis occurs in the gyri at the depths of sulci and in the neuronal nucleiof the basal ganglia (Kumar et 0/., 2002).

    This shift in the distribution of damage may be a consequence ofgreater metabolic activity in this region during subcortical white matterdevelopment. Also, a disproportionate reduction in blood flow to thisregion occurs during severe asphyxia. This underperfusion of subcorticalwhite matter is probably a consequence of watershed region betweensuperficial and deep arteries (Gururaj et al., 2002).

    The Postmature foetus. has a high risk of asphyxial injury; andasphyxia after 38 weeks gestation has a 27 times higher risk of morbidity.Chronic hypoxia with diminished foetal urine production leading toreduced amniotic fluid volume are thought to increase the risk ofumbilicalcord compression .andmorbidity (Heinonen and Saarikaski, 2001).D- Growth Retardation:

    Growth-retarded infants appear to be 10 times more susceptible toasphyxial injury, particularly those with disproportionate growthretardation. They have a reduced ability to adapt during asphyxia. Thisvulnerability may simply result from lower metabolic reserves and altered

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    16maturation reducing the ability to adapt, 'withstand and recover from anasphyxial episode (Heinonen and Saarikoski, 2001).E ... Umbilical Cord Occlusion:

    Occlusion of the umbilical cord for more than 10 minutes leads tobrain injury in late-gestation foetal sheep (Ross and Gala, 2002). Duringcompression of the umbilical cord, the foetal heart rate immediately fallsfrom around 180 to about 70 beats per minute and hypotension developsafter about 5 minutes in the late-gestation foetal sheep. Similar, but lessabrupt, changes are seen during foetal asphyxia resulting from maternalplacental hypoperfusion. In both situations, the loss of blood pressure isstrongly associated with neurological injury (King and Parer, 2000).

    However, the subsequent distribution of cerebral damage differs.Following umbilical conclusion, the hippocampus is injured, in contrast tothe predominantly parasagittal cortical damage after placentalhypoperfusion (Palmer and Vannucci, 1996).Fw Repetitive Injuries:

    Intermittent umbilical cord compression secondary tooligohydramnios can cause some forms of cerebral palsy (Shields andSchifrin, 1988). Brief repeated hypoxic-ischemic injuries interactsynergistically and worsen outcome compared with isolated episodes inanimals. Recent studies have shown that brief hypoxic-ischemic insultsrepeated at l-hour intervals cause a strong shift towards striatal damage andgreatly sensitize the foetal brain to damage. Striatal damage may be afeature of multiple but not Single insults. Asphyxia-induced damage to thestriatum and thalamus is thought to cause some forms of cerebral palsy

    .:0:

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    /

    17

    such as choreoathetoid cerebral palsy (Mallard et ai; 1993 and Salati etal.,2002).

    A similar cumulative sensitization occurs during repetitive asphyxialepisodes on the developing heart. This is thought to result from depletion ofcardiac glycogen reserves (Williams et al., 1993).

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    MECHANISMOFASPHYXIANo less than five principle mechanisms of asphyxia have been

    described in the human infant during pregnancy, delivery and immediatepostpartum period.These include:1- Interruption of the umbilical circulation (cord compression or

    accidents).2- Altered placental gas exchange (placental abruption, previa, andinsufficiency).3- Inadequate perfusion of the maternal side of the placenta (maternal

    hypotension fromany cause or abnormal uterine contractions).4- Impaired maternal oxygenation (cardio-pulmonary disease, anaemia).5- Failure of the neonate to accomplish lung inflation and successful

    transition from foetal to postnatal cardiopulmonary circulation(Ottaviano et aL, 1001).

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    A E T I O L O G Y O F P E R l N A T A L A S P H ~The causes of perinatal asphyxia may be intrauterine, Intrapartum

    and postpartum:Aslntrauterine causes ofasphyxia:

    Hypoxia and ischemia: utroplacental insufficiency, abruption placentae,prolapsed cord, maternal hypotension or hypertension.

    - Anaemia and shock: vasa previa, placenta previa, foetomaternalhaemorrhage, erythroblastosis.

    B- Intrapartum causes ofasphyxia:- Birth trauma: cephalopelvic disproportion, shoulder dystocia, breech

    presentation.Hypoxia and ischemia: umbilical cord compression.

    c-Postpartum causes ofasphyxia:C.N.S: maternal medication, trauma, previous episodes of hypoxiaacidosis.

    - Congenital neuromuscular disease: congenital myasthenia gravis andmyopathy.

    - Infection: consolidated pneumonia or shock- Airway disorders: choanal atresia, severe obstructing goiter or laryngeal

    web.- Pulmonary disorders: severe immaturity, pneumothorax pleural effusion,

    diaphragmatic hernia. pulmonary hypoplasia, or Meconium aspiration.(Kliegman, et al.; 1998).

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    20Ninety percent of asphyxial insults occur in the antepartum!

    Intrapartum periods as a result of placental insufficiency, resulting in aninability to provide O2 to and remove C02 and H+ from the foetus. Theremainder are postpartum, usually secondary to pulmonary.Cardiovascularor neurological insufficiency (Snydr and Cloherty, 1997).

    Another classification by Milsom et al., (2002) which classifiedetiological factors into:I. Maternal factors.II. Foetal and placental factors.III. Neonatal factors.1. Maternal (actors:a-Maternal hypoxia:1)Acute hypoventilation, e.g., by excessive analgesia or anesthesia:

    Some degree of sympathetic blockage occurs with spinal or epiduralanesthesia which may lead to severe hypotension. If hypovolaemia isassociated, this is followed by depressed intervillous space perfusion andfoetal hypoxemia (Zhang et al., 200).

    If excessive posi tive' pressure ventilation is used in generalanesthesia, this may result in foetal hypoxemia and acidosis. Also, theApgar score decreases markedly as the duration of anesthesia increases.This is due to prolonged exposure of the baby to thiopental and nitrousoxide (Flavin, 2001)..2) Chronic pulmonary or cardiac insufficiency.3) Severe anaemia:

    Affecting one half to two thirds ofpregnant women(Flavin, 2001).

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    21

    4) Methaemoglobinemia.These previous mentioned factors interfere with 02 carrying capacity

    ofmaternal blood and hence 0 :> delivery to the growing foetus.5) Carbon monoxide (CO) poisoning:

    Smoking during pregnancy causes chronic carbon monoxide (CO)poisoning which increases the level of carboxyhaemoglobin (HBCO) inboth maternal and neonatal blood: There is a significant correlation withmaternal smoking indices (number of cigarettes smoked per day) andmaternal levels ofHBCO (Stock, 1998). It was found that the foetus is notcapable of making an effective compensation for the CO poisoningproduced by maternal smoking. This failure of effective adaptation to COexposure, may explain in part the adverse effects of smoking duringpregnancy: lower infant birth weight and intrauterine asphyxia causingneonatal death (Stadler, 2000).

    Reduction in uterine blood Dow:1)Maternal hypotension (shock).2) Vasoconstriction of uterine blood vessels, e.g., by the use ofoxytoxic

    drugs:Excessive administration of oxytocin causes inadequate relaxation of

    the uterus to pennit placental filling as a result of uterine tetany. Elevatedresting tone of the uterus .compromises foetal oxygenation. Uterinecontractions further reduce umbilical oxygenation, depressing the foetalcardiovascular and central nervous systems and resulting in low Apgarscores and hypoxia (Kliegman, 2000).3) Compression of the inferior vena cava and descending aorta by the

    contracted, gravid uterus.

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    224) Aortic compression during uterine contractions.5) Pre-eclampsia causes vasoconstriction ofuterine blood vessels.6) Maternal hypertension.7) Diabetes mellitus.

    These above listed factors interfere with the blood supply of theplacenta and hence substrate delivery to the growing foetus (Milsom et al.,2002).11 Foetal and Placental Factors:a- Placental factors:1) Reduction in placental area available for gaseous exchange.2) Small infarcted or fibrosed placenta.3) Placenta previa.4) Oedema or inflammation.5) Antepartum haemorrhage, e.g., obvious accidental haemorrhage.tJ.. Foetal factors:1) Reduction in umbilical blood flow, e.g., prolapsed cord, twisted or l

    knotted cord or foetal hypotension.2) Reduction of oxygen carrying capacity of. Foetal blood, e.g... Rhesus

    haemolytic disease.3) Multiple pregnancies.4) Cerebral insult:

    In case of marked prolonged compression of the head as incontracted pelvis, prolonged labour and mal-applied forceps, the venous

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    2J

    drainage of the brain is affected causing cerebral congestion and oedema.This leads to arterial compression and diminished oxygenation of the brain.This will lead to apnea, gasping and slow irregular breathing due totraumatic cerebral asphyxia (Zhahg et al., 2002).

    Birth conditions such as caesarean section, forceps delivery andabnormal presentation or position, are associated with a significant increasein the incidence of birth asphyxia. With the exception of prolepses andcompression of the umbilical cord, foetal causes very rarely cause asphyxia(Milsom et al., 2002).

    Foetal oxygenation is optimum at a haematocrit value 33%. From16-48%, compensatory foetal mechanism can maintain foetal oxygenationwithin a reliable normality; but increase of haematocrit value above 48% ordecrease below 16% is associated with diminished adequacy of foetaloxygenation (Bracci et al., 2001).I lL Neonatal Factors:1) Continuation of Intrapartum asphyxia.2) Aspiration of amniotic fluid, blood, Meconiumor vomitus.3) Lung immaturity and respiratory distress syndrome.4) Congenital abnormalities of the lung, e.g., hypoplastic lungs with

    diaphragmatic hernia and congenital atelectasis.5) Congenital anomalies of the heart, e.g., severe forms of cyanotic

    congenital heart disease, may cause failure of oxygenation of anadequate amount of blood (KJiegman, 1000).

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    6) Shock severe enough to interfere with the transport of oxygen to vitalcells due to adrenal haemorrhage. Intraventricular haemorrhage,overwhelming infection or massive blood loss (Kliegman, 2000).

    7) Airway obstruction due to a variety of causes as congenital bilateralchoanal atresia, hypoplastic mandible, floppy epiglottis andlaryngospasm, tracheomalacia, tracheal stenosis, bronchostenosis,bronchomalacia, tracheoesophageal fistula and various masses andcysts pressuring on the respiratory airway (Flavin,2001).

    All of these above mentioned factors interfere with the O2 delivery tothe newborn.

    In many studies on children with cerebral palsy, only about 10-15%of the children had definite evidence of severe Intrapartum hypoxicischemic cerebral insult. Of these, approximately .one third had at least onecongenital anomaly that was unrelated to the central nervous system. Thisobservation raises the possibility that a prior insult, which occurred earlierin gestation, may have predisposed such infants to subsequent hypoxicischemic injury at delivery (Slciarz et al., 2001).

    .'--

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    25 Review ofLiterature

    -

    PATHOPHYSIOLOl;YOF PERINATAL ASPHYXIATypes o(asUhyx;a:

    Asphyxia can be partial, in which gas exchange is impaired, but notabsent; or complete, where there is essentially no gaseous exchange at all.Partial asphyxia can be followed by complete asphyxia. A review of table(6) shows that the more commonly encountered asphyxial disordersproduce partial foetal asphyxia. Table (7) displays some of the causes ofasphyxia in the newborn. Again, most insults are partial rather thancomplete (Schneider, 2001).

    Table (6): Types of prenatal asphyxia.Type of asphyxia Clinical examples

    Complete Complete placental abruptionProlapsed umbilical cordUterine ruptureOther

    Partial Placental insufficiencyPartial placental abruptionRecurrent late decelerationsMaternal hypotensionMaternal vascular diseaseOther

    Partial -+ complete Maternal cardiac arrestOther combinations of above

    (Schneider, 2001)

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    Table (7): Types of postnatal asphyxiaType of asphyxia Clinical examples

    Complete ApnoeaAirway occlusionCardiac arrestOther

    Partial Respiratory distress syndromePneumoniaPneumothoraxPulmonary malformationsCongenital heart diseaseMethaemoglobinemiaMethaemoglobinemiaMeconium aspirationOther

    Partial -+ complete Combinations of above(Schneider, 2001)

    Insults due to prolonged partial asphyxial episodes seem to causecerebral (especially cortical) necrosis; while acute total asphyxia, seems tospare the cortex and affect primarily the brain stem, thalamus and basalganglia, most cases however, represent a combination of the two patterns:partial prolonged asphyxia followed by a terminal acute total asphyxialepisode (Snyder and Cloherty, 1997).Biochemical aspects:

    During normal labour there is reduced blood flow to the placenta,hence decreased 02 delivery to the foetus. Because there is concomitant

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    27increase in 02 consumption by both mother and foetus, foetal 02saturation falls. Maternal dehydration and maternal alkalosis fromhyperventilation may further reduce placental blood flow. Maternalhypoventilation may further decrease maternal and foetal 02 saturation.Some degree of cord compression occurs in many deliveries. Uterinecontractions decrease placental blood flow. These normal events causemost babies to be born with little 02 reserve. Newborns, however,including their central nervous system (eNS), are fairly resistant toasphyxic damage (Schneider, 2001).

    The primary disturbance which occurs is a deficit of oxygen supply.The perinatal brain can be deprived of oxygen by two major pathogenicmechanisms; hypoxemia, which is a diminished amount of blood supply;and ischemia, which is a diminished amount of blood perfusing the brain.In most instances, during the perinatal period, hypoxemia or ischemia orboth occur as a result of asphyxia, which refers to impairment in theexchange of respiratory gases, oxygen and carbon dioxide. Thus, inasphyxia, the major additional feature is Hypercapnia which results in anumber of other metabolic (e.g., acidosis) and physiological (e.g., initialincrease in cerebral blood flow) effects (Yolpe, 2001).Foetal Adaptive Responses to asphyxia:

    The foetus and neonate are muchmoreresistant to asphyxia than theadult, because they are equipped with an impressive range of adaptivestrategies which reduce the overall oxygen consumption and protect vitalorgans, such as the heart and brain, during asphyxia to enable them tosurvive the hypoxia (Huang, 1994).

    In the presence of a hypoxic-ischemic challenge to the foetus,reflexes are initiated, causing shunting of blood to the brain, heart and

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    28

    adrenals, and away from the carcess (skin and musculoskeletal beds) andnon-viscera (lungs, gut, liver, kidneys, spleen and bone). This process iscalled the "diving reflex" (Snyder and Cloherty, 1997).This redistributionofblood flow in the mature foetus in response to asphyxia ensures adequateoxygen and substrate delivery to these vital organs. Vascular resistancedecreases in the heart and brain and increases in the periphery, therebyredirecting cardiac output to the former organs allowing increased bloodflow to these organs if oxygen delivery is to remain at levels adequate toprevent damage (Flavin, 2001). A number of mechanisms interact toregulate this redistribution. Hypoxia and carbon dioxide accumulationstimulate cerebral vasodilatation. Increased sympathetic activity(adrenaline and noradrenalin) and chemoreceptor activity, together withrelease of arginine vasopressin, increase peripheral vascular resistance(Ergenekon, 2001).

    Blood flow is reduced first to the skin and muscles, which havegreater tolerance to asphyxia; and next to semivital organs such as the gut,kidneys, liver and lung. Many of these tissues also have lower metabolicdemands than the heart and brain, and are therefore able to withstandasphyxia better. Unfortunately, compromise of such "expendable" organsas the gut and kidney, cause many of the acute problems noted in thenursery in postasphyxial newborns (Gary et aL, 2002).

    Even within the brain, the blood flow distribution also changes inresponse to asphyxia. There is a preferential flow toward the brainstemwith less in the cerebrum, white matter, and choroid plexus (Suppiej,2001).

    The basic pathophysiology of asphyxia is the same in both pretennand fullterm neonates. However, the brain of the preterm neonate or foetus

    .,

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    29

    can develop periventricular while matter injury, in contrast to the term orpost-term brain in which the. gray matter regions, such as the overlyingparasagittal parietal cortex, are more vulnerable to damage (Ottaviano etal.,2001).

    Unlike adults, who develop tachycardia in response to hypoxia, thefoetus responds with bradycardia To achieve this, the late-gestation foetushas well-developed chemoreceptors that sense the hypoxia immediatelyand, cause a fall in heart rate via vagal nerve regulation. Furthermore,peripheral vasoconstriction increases blood pressure and stimulates arterialbarroreceptors that maintain the bradycardia (King and Pare, 2000). Theinhibitory neuromodulators, namely adenosine, gamma amino butyric acid(GABA), and opiates are released under hypoxic conditions, and theseprobably mediate the suppression of electrical activity and a concomitantreduction in oxygen consumption. Thus, the healthy late-gestation foetus isequipped with a range of physiologic and pharmacologic mechanisms toenable it to withstand an asphyxial episode (Williams et al., 1993),Cellular Effects ofAsphyxia:

    The extent of injury to an organ will depend on the type and severityof injury to the various cell lines of that organ. Cellular damage can betransient or fatal. The final effect of cell death on an organ depends on theability of the organ to regenerate the dead cells and their function(s) andlorto compensate for the permanently lost cells. For example, renal tubulecells can regenerate; in contrast, neurons cannot usually regenerate. Thus,brain recovery following an asphyxial insult will depend on how manyneurons recover and how will the developing brain can adapt to the loss ofthose that die (Aprino et al., 2001).

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    30 ReviewofLiteraJureThe effects of an asphyxial event on cellular metabolism are

    primarily due to reduced oxygen delivery and reduced removal of toxicsubstances from the tissues (Ouurk et al., 1997).

    Likewise, as foetal carbon dioxide accumulates, it causes respiratoryacidosis and a further fall in pH. During asphyxia, glucose can be releasedinto the circulation to increase the availability of the metabolic substrate tovital regions. The developing brain has lower rates of cerebral metabolismand glucose consumption than the adult. The lower metabolic rates andincreased glycogen reserves help the foetus to withstand longer periods ofasphyxia (Park et al., 2001).

    Most of the body's enzymes function best at a pH of about 7.3-7.4.As the pH falls, the ability of enzymes to catalyze reactions diminishes and,ultimately ceases. IfpH is restored in time, the enzymes may recover, but ifpH remains low too long or decreases too low, the enzymes will bepermanently denatured. Thus, prolonged or extreme acidosis will lead todestruction of the cell's enzymatic machinery (Atalay et al., 1997).Physiologicalaspects:

    Generally speaking, brain injury only occurs when the asphyxia issevere enough to impair cerebral blood flow (CBF) (Flavin, 2001).

    In severe asphyxia, in which the oxygen content of the blood fallsbelow 1 mm/L the capacity of these adaptive or protective mechanisms canbe overwhelmed. I f the asphyxia is too severe, the shunting of bloodtoward vital organs and cerebral oxygen delivery will fail, and the bloodpressure falls as cardiac output fails (King and Parer, 2000). Brain injuryis strongly associated with loss of blood pressure in the foetus, and not thedegree ofhypoxia or acidosis (Eken et aL, 1998).

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    31Initially, three cerebral circulatory effects occur following perinatal

    asphyxia: (Fig. 1).1- An alteration in the foetal circulation so that a larger proportion ofcardiac output is distributed to the brain..2- An increase in total and regional cerebral blood flow.3- Loss of cerebrovascular auto-regulation (Volpe, 2001).

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    32 Review ofLiteraturePerinatal asphyxia1Ini ially

    ~t B.P.

    ttCBF~

    Continuing

    Acidemia+

    HypercapniaHypoxemia

    Loss ofAuto-regulation

    Haemorrhage

    Of blood flowRedistribution t B.P.

    ~ l - . . L - - liCBFI1

    Ischemic brainIniurvFig. (1): Major relationship between perinatal asphyxia and cerebral bloodflow. The major consequences of the changes in cerebral blood

    flow i.e., haemorrhage and ischemic brain injury, are shown(Volpe, 2001).

    Under normal conditions, CBF is independent of variations inarterial blood pressure within a wide range and cerebral circulation is notsignificantly decreased even at quite low blood pressures because of adecrease in cerebrovascular resistance caused by arteriolar dilatation.Cerebrovascular auto-regulation ensures constant CBF and thereby the

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    33 Review 0/Literatureenergy stare of the brain is preserved, a prerequisite for normal functionalactivity and morphological integrity. Conversely. Elevations of bloodpressure normally induce arteriolar constriction, and thereby CBF remains"fairly constant (Scher, 2001).

    Because this normal auto-regulation appears to be impaired in thedistressed newborn, even moderate hypotension may lead to a proportionaldecrease in CBF and hence cerebral ischemia. The effect of ischemia maybe aggravated further in hypoxemia (Williams et al., 1993).Table (8): Mechanisms ofbrain damage during and after asphyxial injury.During Asphyxia:- Failure of cerebral autoregulation- Intracellular energy depletion and cytotoxic oedema- Accumulation of intracellular calcium- Release of excitatory amino acids or monoamine neurotransmitters- Activation of arachidonic acid cascade- Epileptogenic seizureAfterAsphyxia:- Release of oxygen free radicals- Brain oedema- Postasphyxial hypoperfusion- Postasphyxial seizure

    Huang, 1994Intracellular Energy Depletion and Cytotoxic Oedema:

    Normally cells maintain their integrity by actively controllingintracellular ion concentrations through a Na+-K+ ATP-dependent ionpump which transports Na+ out of and K+ into cells. However, during

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    34

    severe asphyxia, loss of enzyme function along with energy failure occurs,leading to depletion of intracellular high energy phosphate compounds suchas phosphocreatine and adenosine triphosphate (ATP).

    Such energy failure impairs the ion pump (Na+-K+ ATPase) withaccumulation of Na", cr, H20 and Ca2+ intracellularly and K+ andexcitatory amino acid neurotransmitters (e.g., glutamate, aspartate)intracellularly (De-Vries. Et aL, 2001).

    Failure of the ATP-dependent membrane bound Na+-K+ ATPasepump leads to depolarization of cells, allowing influxes of Na+and Ca2+ions followed by chloride-favoured osmotic entry of water into the cell,which leads to intracellular swelling. This acute swelling is described ascytotoxic oedema. This initial intracellular energy failure was shown to bereversible for up to several minutes of severe asphyxia in foetal sheep.Only longer periods of cerebral ischemia lead to permanent brain damage(Nelson, 2003).

    The calcium influx activates phospholipase-A2 generation ofarachidonic acid, which, upon action by cyclooxygenase, results ingeneration of toxic free radicals. Increased cytotoxic calcium also results inactivation of proteases that cause cyto-skeletal disruption andmitochondrial dysfunction (Bracci et al., 2001).

    Activation of nitric oxide synthetase by calcium, with generation ofdamaging nitric oxide, may especially be important in the mediation ofglutamate-induced cell death (Benneth, 1999).

    The toxicity of glutamate was shown to be exerted throughglutathione depletion. Such depletion is apparently caused by the action ofglutamate-cystine exchange mechanism, leading to depletion of cystine,

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    35which, in turn, diminishes the availability of the antioxidant-glutathione.Cell death occurs via oxygen free-radical attack. Should a similarmechanism exist in the developing human brain, it could explain the deathof developing oligodendrocytes as a result of glutamate released fromaxons, focally damaged by hypoxia ischemia occurring in the setting ofasphyxia (Vento et al., 2002).Reper[usion:

    Following brief episodes of asphyxia, reoxygenation leads torestoration of cellular metabolism in most tissues including the centralnervous system. Circulation is rapidly restored, and a period ofhypercapniaoccurs. The heart rate quickly returns to normal except for a transienttachycardia (rebound acceleration) immediately following reoxygenation.Typically, the acute cerebral cytotoxic oedema largely resolves withinabout 30 minutes, and systemic lactic acid levels are close to normal withinthe next few hours (King and Parer, 2000).Release ofOxYgen-Derived Free Radicals:

    During reperfusion, highly reactive oxygen-derived free radicals aregenerated in the developing brain from a variety of sources as a result ofincomplete reduction of oxygen (Szcttlpa et al., 2002). Oxygen freeradicals phospholipids degradation have been implicated in thepathogenesis of ischemia and reperfusion injury (Ozturk et al., 1997).

    These compounds and other potent oxidants such as hydrogenperoxide (H202) can cause membrane damage in most organs that aresusceptible to perinatal asphyxial injury including the brain, heart andlungs. Also, these agents have been shown to produce damage to bloodvessels of the brain as well as to the brain parenchyma (Huang, 1994). Free

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    36 ReviewofLiteratureradicals can be produced by several mechanisms during reoxygenationincluding oxidation of arachidonic acid and hypoxanthine, and possiblyaccumulation of nitric oxide (Llevre et al: 2001).

    During ischemia, xanthine dehydrogenase is converted to xanthineoxidase (Fig.2). When oxygenation is restored, hypoxanthine (an endproduct ofATP metabolism during hypoxia) is catabolized to xanthine andan oxygen free radical. It is interesting that this burst of oxygen radicalformation and subsequent tissue damage actually occurs when oxygensupply to the tissues is restored. Hypoxanthine/ xanthine oxidase reactionand arachidonic acid cascade require oxygen and liberate oxygen freeradicals (Szczapa et al., 2002).

    Recently, nitric oxide produced from endothelium and neurons hasbeen implicated in the pathogenesis of ischemic reperfusion injury. Duringischemia, the endothelium will not be able to synthesize nitric oxidewithout oxygen, but then, reperfusion will allow rapid nitric oxidesynthesis by providing the oxygen needed for synthesis. Nitric oxide thenreacts with superoxide both intercellularly and in the vascular lumen toform the highly reactive, toxic peroxynitrite. The resulting injury toendothelium may lead to oedema formation (due to loss of barrierfunction); adhesion of platelets and neutrophils; and abnormalvasoregulation, all ofwhich potentiate further hypoxic/ischemic pathology.The immature brain is particularly susceptible to oxidative damage,because it contains high levels of polyunsaturated fatty acids, and a lowlevel of catalase (Verman et al; 1002).

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    ISCHEMIATP

    37

    XANTIllNEDEHYOROGENASE

    1HYPOXANTHINE

    XANTHINEOXIOASE:::::;::="'"O2

    REPERFUSIONFig. (2): Mechanism of production of oxygen free radicals during recovery

    from severe asphyxia. (Szczapa et al., 2002).Postasphvxial Depression Phase:

    Following a severe asphyxial episode, neonates are oftenneurologically depressed, hypnotic and have suppressed EEG for severalhours (Vannucci; 2000). It is likely that this results from accumulation ofinhibitory neuromodulators such adenosine, opiates, and GABA.Additional insults during this depressive period have an additive effect andworsen outcome. In addition, prolonged neurological depression ispredictive of poor outcome {Zeinstra et al., 2001).Recovery Phase:

    Following an asphyxial episode, a range of neurological recoveryprofiles is seen: Some infants progressively recover from the neurologicaldepression, whereas others show signs of secondary deterioration withdevelopment of seizures, brain oedema, and infarction or worse. Loss ofneurons, but not glial cells (selective neuronal loss), can develop insusceptible regions such as cortex and hippocampus without the obvious

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    38secondary signs of hypoxic ischemic encephalopathy such as seizures oroedema. These evidences suggest that asphyxial insults producingsignificant neuronal loss in utero and leading to neurological sequelae maywell be asymptomatic at birth {Nork, 2002).Cerebra/Infarction and Secondary Deterioration:

    In contrast to the progressive neurological recovery that occursfollowing a moderate injury, some asphyxiated infants can show furtherneurological deterioration with secondary oedema and disrupted cerebralmetabolism. This is associated with neuronal Hyperexcitability, which maymanifest as convulsions (Zhang et al., 2002).Postasphvxia/ Seizures:

    Postasphyxial seizures lasting more than 30 minutes are associatedwith a poor neurological outcome and cerebral infarction (Miller et al;2002). Seizures are particularly bad prognostically very low birth weightinfants (Kumar et al., 2001). Seizures greatly increase metabolic demandsboth cerebrally and peripherally. Indeed. These seizures have been shownto worsen outcome after global hypoxic-ischemic injury in both thedeveloping and mature brain (Sykes, 2002).

    Multi-focal tonic seizures are the most common seizures seen inasphyxiated neonates. Continuous monitoring of cortical EEG activity isneeded to detect cortical seizures reliably (Ze;nstra et al., 2001).Intraventricular Haemorrhage (IVffl:

    IVH results from rupture of vessels particularly in ventricles. It isprimarily seen in preterm infants and is associated with hypoxic-ischemiclesions to the cerebrum (Kumar et al., 2001).

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    39 Review ofLiteratureThe germinal matrix is thought to be particularly vulnerable to

    hypoxic-ischemic injury and changes in blood pressure. The structuralweakness of these vessels appears to result from immaturity of basementmembranes with insufficient deposition of matrix substances such aslaminin. Treatment with Indomethacin accelerates the deposition oflamininand reduces the incidence of IVH (Ment et al., 1992), although this maycompromise cerebral oxygen delivery. Hypercapnia is an important riskfactor as CO2 is a potent vasodilator that stimulates CBF and probablystresses susceptible vessels. Thus, the precise causes of 1VH are unclear,but appear to be multifactorial with immaturity, fluctuations in bloodpressure, and hypoxic-ischemic injury as important risk factors (Eken etal.,1998).

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    40PATHOGENESIS AND CLINICALCORRELATION OF

    PERINATAL ASPHYXIATarget organs ofprenatal as'lhvxia:

    Perinatal asphyxia causes acute systemic organ injury inapproximately 60% of "asphyxiated" newborn infants (Hankins et al.,2002). The insult may be confined to only one organ, or more commonlymay involve 2 or even more organs, of varying severity determined in partby both the duration or extent of the insult. The most frequent organsinvolved in order are the kidney (approximately 50%). followed by theeNS (approximately 30%), cardiovascular (25 %) and pulmonary (23 %)systems; and finally, gastrointestinal complications, which are rare (Snyderand Cloherty, 1997). However Hankins et al., (2002) reported that eNS isinvolved in 100% of the asphyxiated newborn .Abnormalities of renal,hepatic and even myocardial functions may provide evidence of priorasphyxia and its severity (Gary et al., 2002).

    Hypoxic-ischemic encephalopathy (HIE) is the most -importanteffect of asphyxia on the newborn, as the brain is the only organ systemthat has residual sequelae at long term follow up (Trojan et at; 2001).

    HIE is. the single most important perinatal cause of neurologicalmorbidity in both the premature and full term infant (Ottaviano et al.,2001). IDE is observable clinically in the full term newborn, but may bedifficult to assess in the small premature infant (Risser et al., 1996).Pathogenesis olHIE:

    Many newborns having low Apgar scores following Intrapartumasphyxial episodes have no evidence of IDE (Fig 4, step 1). This has beenseen in asphyxiated infants who succumb because of other dysfunctions,

    ..

    r

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    41

    such as persistent foetal circulation. The lack of eNS findings could beexplained by the increased percent of cardiac output to the brain, thusattempting to maintain adequate tissue oxygenation and preventing tissueischemia.

    If the Intrapartum i n s ~ l t is not extremely severe or is quicklyterminated, small areas of multifocal tissue necrosis occur; they may notlead to significant areas of vasogenic oedema with the development ofseverely increased intracranial pressure. Brain repair processes convertthese areas ofmultifocal tissue necrosis into areas of ulegyria (necrosis ofgyri at depths of sulci). The extent and pattern of ulegyria depend on thedegree and location of cerebral necrosis (Fig. 3. step 3).

    If the Intrapartum episode is severe and prolonged, multi focal areasof tissue ischemia located at the depth of sulci and within neuronal nucleispread to the entire cerebral hemisphere. The existing tissue ischemia ifunrelieved, leads to tissue necrosis. Vasogenic oedema occurs followingdisruption of the tight junctions of the capillary endothelium, with leakageof osmotic materials into the interstitial tissues of the brain, pulling waterfrom the intravascular space. As the multifocal areas of necrotic braincoalesce, and significant increases in intracranial pressure occur inassociation with vasogenic oedema, the brain swells progressively. Thisproduces measurable increases in intracranial pressure. From animal data itis known that when intracranial pressure reaches one half to two thirds ofthe mean arterial pressure, reduced CBP causes tissue ischemia, especiallyin areas of cortex at depths of sulci. The triad ofmultifocal tissue necrosis,vasogenic oedema, and brain swelling with increasing intracranial pressure,leads to an ever-increasing oxygen dept in the brain, almost total tissuenecrosis, and death (Fig. 3-step 4).

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    In some asphyxiated neonates, increased intracranial pressure orbrain oedema at autopsy are not observed. This finding may be due tocompensation by redistribution of blood flow to protect the brain, whereasinadequate oxygen is supplied to the lung, kidney, or gastrointestinal (OIT)tract. This may lead to death secondary to dysfunction of these organs. Theabsence of oedema may be related to the type and length of the asphyxialepisode.

    The neuropathology of hypoxic-ischemic injury is dependent uponthe affected organ and the severity of the insult. Acute hypoxic damage tothe brain, sufficient to result in permanent damage to the brain, willproduce cerebral HIE in the newborn during the early days of life (Scher,2001).Neuro(!athology of Neonatal Brain Injun. due to As(!hyxia; andits Clinical Consequences:

    HIE injury due to asphyxia may involve virtually ever part of theeNS. Most often the pattern of injury found are influenced by: Nature of insult. The gestational age of infant at the time of injury.

    (Rivkin and Volpe, 1996)

    The different anatomical localization at different gestations is due tothe fact that the watershed area between the centrifugal and centripetalarterial supply to the cortex moves from the periventricular white matter inpreterm babies to the cortical white matter at term (Kumar et aL, 2001).

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    43 Review o fLiterature

    Intrapartum asphyxia I...

    Redistribution of organ flowLung Heart Variable organ effectKidney Brain 1---+ brain normalOIT Adrenal

    ...

    uxygen dept to Dram I/ -.Altered brain Altered cerebral Brain - variableH20 distribution blood flow r---+I I

    Cytotoxic Multifocal Brain - ulegyriaOedema tissue necrosis r+

    VasogenicOedema Multifocaltissue necrosis

    l g e n ~ r a l i z e d brain necrosisFig. (3): Foetal/neonatal response to Intrapartum asphyxia.

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    44

    A ~ T v p e s :

    Four main typesof lesions may result after moderate to severe asphyxia:1)Focal or multifocal cortical necrosis.2) Watershed infarcts.3) Selective neuronal necrosis.4) Status marmoratus.1) Focallmultifocal cortical necrosis:

    Is usually associated with cerebral oedema. It results in cysticencephalomalacia and/or ulegyria due to loss of perfusion (usually middlecerebral artery).Clinical correlation:

    The most prominent neonatal neurological correlate' is seizures,usually focal. It may also present as hemiparesis or quadriparesis. Longterm neurological sequelae include spastic hemiparesis quadriparesis,cognitive deficits and seizures (Volpe, 2001).2- Parasagittal cerebral injury:

    This lesion involves the cerebral cortex and the subcortical whitematter in the parasagittal areas of the brain, the injury is usually bilateraland symmetrical, involving the "watershed" areas between the end fields ofthe anterior, middle and posterior cerebral arteries. The lesion consists ofcortical necrosis which is usually non-hemorrhagic (Volpe, 2001).

    The pathogenesis of the lesion relates to decrease in cerebralperfusion secondary to systemic hypotension which is especiallypronounced in the border zones ofarterial -supply (Volpe, 2001).

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    Clinical correlation:

    45 RninJ 0/LiteratUTe

    Weakness of the shoulder girdle, hips and proximal extremities(especially the upper extremities) results in the neonatal period. Long-termsequelae result in spastic quadriparesis in the proximal limbs, upper morethan lower, as in the neonatal period. Moreover, these infants may exhibit"specific" intellectual deficits as language or visual disabilities (Volpe,2001).Periventricular leukomalacia (PVL):

    PVL represents the primary ischemic lesion of the premature infant.Necrosis of periventricular white matter dorsal and lateral to the externalangles of the lateral ventricles most commonly occurs. First, at the level ofthe occipital radiation adjacent to the trigone of the lateral ventricles and,second at the level of the foramen of Monro (Gururaj et 01., 2002). In theacute phase, venous congestion or even haemorrhage may accompanynecrosis. Later, in the chronic stage, the affected areas become gliotic,delayed in myelin development. and variably calcified (Rivkin and Volpe,1996).

    PVL also results from ischemia to the foetal brain. The affectedregions of the white matter reflect the border zones of arterial circulation asthey are found in the premature neonate. In addition, in both the term andpremature newborn. white matter distant from the ventricle may beinvolved (Gururaj et 01., 2002).C1I'nicai correlation:

    Decreased muscle tone. and weakness of the lower extremities mayoccur in the immediate neonatal period (Volpe, 2001). The neurologicalsequelae of PVL probably include the most important motor deficit in

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    46prematurely born infants, the spastic diplegia, spastic paresis of theextremities with greater affection of the lower than upper limbs (Volpe,2001). Optic radiation involvement results in visual deficits. Moreextensive lesions may involve the association and commissural fibresresulting in mental retardation or other Specific deficits (Gururaj et al.,2002).3) Selective neuronal necrosis:

    This is the commonest, lesion observed in neonatal HIE. It ischaracterized by neuronal injury at specific sites to specific cell types (e.g.,hippocampus, brainstem nuclei). It is a severe form of injury and iscommonest and more prominent in the term infant. It suggests that thetiming of the insult is perinatal (Coskum et al., 2001)Clinical correlation:

    Injury to cerebral hemispheres or brainstem may result incompromise of respiratory functions. Seizures and paresis reflect injury tocerebral cortex. Abnormalities of muscle tone and reflexes, and stupor orcoma may result from dysfunction of the cortex, cerebellum or brainstem.Abnormalities of extraocular movements, suckling, swallowing and tonguemovements may reflect brainstem dysfunction (Coskum et al., 2001).Long-term sequelae most commonly include motor dysfunction,intellectual deficits and seizures (Volpe 2001).4) Status marmoratus:

    It is a subtype of selective neuronal necrosis affecting the basalganglia and thalamus; and is more common in term infants.Hypermyelination is the characteristic feature of this lesion. The timing ofthis pattern of injury is mainly perinatal (Volpe, 2001). This pathologic

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    47 Review 01Literaturealteration is seen in the majority of children suffering form extrapyramidalCP (Nath et al., 2002).Clinical correlation:

    Choreoathetosis, dystonia, tremors and intellectual deficits are themost common long-term sequelae, which appear after one year of age,intellectual function is below average in about 50% of cases, but only lessthan 10% exhibit intelligence quotient below 70 (Volpe, 2001).

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    48

    MANIFESTATIONS OF PERINATAL ASPHYXIAA- CLINICAL PICTURE OFHIE:

    Insult, especially if the insult is mild -or has occurred early ingestation, may not exhibit major neurological abnormalities during thenewborn period. In addition, the stage ofmaturation of the central nervoussystem at the lime when the insult occurred must be- taken intoconsideration when evaluating clinical signs of encephalopathy,particularly in the premature newborn (Flavin, 2001).

    Nevertheless, there exists a definable group of term newborns whosustain significant Intrapartum asphyxia and who subsequently develop anacute hypoxic-ischemic encephalopathy during the first few days of life. Infact, the absence of clinical encephalopathy in the term newborn essentiallyprecludes the occurrence of significant hypoxic-ischemic insults sustainedduring the Intrapartum period (Hill, 1990). Similarly, the severity of theclinical encephalopathy in the asphyxiated term newborn correlates closelywith the degree of the injury as manifested by long-term outcome (Hill andVolpe, 1992).

    The signs ofHIE extends across a spectrum that correlates with theseverity of the insult; Grading ofillE is a better predictor for outcome thanApgar score (patel et aL, 1001): Stage I represents the transient butreversible phase of neuronal damage; while stage II mayor may not bereversible damage; and those with stage III HIE definitely have someirreversible destruction of neurons. There is presently treatment of. Knownefficacy for reversing or preventing neuronal injury once asphyxiation hasoccurred (Ho, 2001).

    '.

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    49

    A simplified classification was developed by Amlel-Tison andEllison (1986) as follows:Stage I (Mildly abnormal):

    Hyperexcitability and mild abnormalities of tone arc present.Responsiveness is normal; primary reflexes are present. No seizures occur.These signs persist for varying periods.Stage II (Moderately abnormal):

    In addition to increased disturbances of lone, disturbances ofresponsiveness and primary reflexes are noted. ProgressiveeNS depressionis seen, which increases to lethargy or light coma within the first days.Return to normal by the end of the first week is exceptional.Stage III (Severely abnormal):

    Deep coma and repetitive seizures define this level. The clinicalfeatures of severe IDE evolve with characteristic profile during the firstweek of life as shown below.Birth to 12 hours:

    In the first hours after the insult, signs of bilateral cerebraldysfunction predominates (Voipe, 2001). (Table 9).Table (9): Clinical features of severe HIE (Birth to 12 hrs),

    Deep stupor or comaPeriodic breathingIntact pupillary responsesDiffuse hypotonia, minimal movementSeizures

    (Volpe, 2001)

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    50

    Seizures most commonly begin prior to 24 hours of age andapproximately 50% occur within 12 hours (Volpe, 2001). Initially, seizuresare most frequently subtle (e.g., eyelid blinking, sucking or smackingmovements, apnoeic spells). Later, seizures may be multifocal, clonic,tonic or myoclonic in nature.

    Neonatal seizures are among the predictors of subsequentneurological deficit. The earlier the onset of the seizures, and the moredifficult they are to control, the more likely they are to be associated withdeath or subsequent CP and concomitant retardation. An infant withneonatal seizures is 50 to 70 times more likely to manifest later CP thanone without seizures. However, 70% of infants with seizures who survivedhad no CP (Miller et al., 2001).

    Neonatal seizures during the first 48 hours of life are now suggestedas possible indicators of the quality of Intrapartum obstetric care andevidence of Intrapartum asphyxia. Some investigators have observedneonatal seizures to be more frequent in babies born to women who werefollowed in labour with intermittent FHR monitoring than in thosefollowed with continuous monitoring. The excess of neonatal seizures wasfound to be restricted to deliveries in which oxytocin was used (Thornberget al., 2002).Table (10): Clinical features of severe HIE (12-24 hrs).

    Apparent increase in level of alertnessMore seizures .Apnoeic spells (50 %)Jitteriness (35-50%)WeaknessProximal limbs, upper> lower (full term)Hemiparesis (fullterm)Lower limbs (premature)(Volpe, 2001)

    -.

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    S1

    Table (11): Clinical features of severe IDE ( 2 4 ~ 7 2 hrs).Review ofLiterature

    Stupor or comaRespiratory arrestBrainstem oculomotor and pupillary disturbancesCatastrophic deterioration with IntraventricularHaemorrhage (premature)

    (Volpe, 2001)After 72hours:

    Those infants that survive beyond 3 days of age usually improveover the next several days to weeks however, certain neurological featurespersist. There is usually gradual, but limited improvement in the level ofconsciousness (Volpe, 2001).

    Table (12): Clinical features of severe HIE (> 72 hrs).Persistent stuporDisturbed suckling, swallowing, gag and tongue movementsHypotonia> hypertoniaWeakness more evidentProximal limbs, upper> lower (full term)Hemiparesis (full term)Lower limbs (premature)

    The severity of clinical signs and the length of time the signs persistcorrelate with the severity of the insult (Dllenge et al., 2001).

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    54

    B-RENAL EFFECTS OFASPHYXIA:The kidneys are one of the target organs affected by perinatal

    asphyxia, and they are involved in 50 percent of asphyxiated newborns(Hankins et al., 2002).

    Renal insult following severe asphyxia is mainly related to thepreferential distribution of blood and oxygenation to the brain, heart andadrenal keeping them away from the kidneys and other organs (Arpino etal.,2001).

    The proximal renal tubule is vulnerable to a reduction in renal bloodflow during foetal hypoxia. Injury to the proximal tubule may be subtle ifthe alteration in perfusion is not severe, which can be detected by elevatedconcentration of pz-microglobulin in the first voided urine. Howevermarked decrease in renal perfusion may lead to necrosis of the tubularepithelial cells, resulting in the clinical syndrome of acute tubular necrosis(Bellet et al., 2001).

    Renal injury may also occur in the form of cortical. Medullary orpapillary necrosis. The two factors regularly implicated in the pathogenesisare vasoconstriction and intravascular coagulation. In renal corticalnecrosis, Azotaemia, metabolic acidosis, albuminuria and microscopichaematuria may be found. Renal scanning may reveal poorly functioning ornon-functioning kidneys. The asphyxiated infant is risk for acute renalinsufficiency. Pre-renal failure may follow hypoxic-induced renal hypoperfusion (Per/man, 1989).

    Severe asphyxia predispose to fluid retention by causinginappropriate secretion of ADH and renal failure. The resulting fluidoverload increases the risk of heart failure, pulmonary haemorrhage and in

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    55particular oedema. For this reason fluid intake of severely asphyxiatedinfants should be held to 30-40 mllkg/24 hours after delivery, withmeticulous monitoring of urinary output. Care should be taken to avoidcausing pre-renal uraemia by fluid restriction and fluid intake should beincreased gradually as the baby gets better and start to produce urine(Jayashree et al. 1991).

    In some instances. acute tubular and cortical necrosis may coexist.The renal functions are better preserved with acute tubular necrosis thanwith cortical necrosis. Acute tubular necrosis may occur .Oliguria may betransient (urine output < I ml/kg/hr for the first 24 hours of life) orpersistent (urine output < I ml/kglhr for the first 36 hours or more of life)(Snyder and Cloherty, 1997).

    The aetiology of this Oliguria may be the syndrome of inappropriatesecretion of antidiuretic hormone (SIDAH). another cause of Oliguria isrenal parenchymal damage (Ingelfinger, 1997) 132M level in urine candifferentiate between Oliguria secondary to glomerular damage or tubularnecrosis as it increases only with the latter (Khattab, 1992). The merepresence of Oliguria in the perinatal period is a sensitive predictor of poorneurological outcome (Tack et aL, 1988). Oliguria is managed byintravenous dopamine infusion at 2.5 uglk.gthour which improves renalperfusion (Hunt and Osbarn 1002). Together with careful monitoring offluid, electrolyte and urine output (Snyder and Cloherty,1997).

    Renal medullary necrosis most often is caused by .episodes of severevascular collapse. In long term cases the heart may show left ventricularhypertrophy (Haycock. 1990).

    The kidney of the newborn is particularly at risk for vascularthrombosis. The vessels are small in caliber, the renal blood flow is

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    56relatively low, and the vascular resistance is comparatively high. Hypoxia,particularly if accompanied by hypercarbia, further decreases renal plasmaflow. The characteristic presentation of renal venous thrombosis is suddenenlargement of one kidney in association with sudden deterioration ofinfant's clinical status accompanied by haematuria, pallor and failure tothrive (Roberts et al., 1990).

    In a study carried out by (Hankins et al., 2002)t it was found that72% of asphyxiated infants with transient Oliguria were neurologicallyaffected on the long run.

    This suggests that when the asphyxial insult is severe enough tomanifest as persistent Oliguria. It is likely that the brain also has sufferedischemic injury. Thus, persistent Oliguria was found to be significantlyassociated with severe HIE and poor long-term neurological outcome(Hankins et at., 2002).

    In a study done by El-Kholi et al: (1993), it was found that urinary82 macroglobulin level showed a strong correlation with the degree ofperinatal asphyxia in full term neonates as judged by the Sarnat and Sarnatstaging ofperinatal hypoxia.Diagnosis ofrenal effects ofasphvxia:

    Urine output, urine analysis, urine specific gravity, urine and serumosmolarity and electrolytes should be monitored.The presence of epithelialcells, not white cells. Is indicative ofperinatal hypoxic insult. The perinatalasphyxia is an important differential diagnosis in cases presenting withpyuria in the neonatal period (EI.Maraghi et aL, 1992).

    Measurement of serum and urine creatinine together with serum andurine Na+allows calculation of the fractional excretion ofNa+ and the renal

    r

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    57

    index to help confirm a renal insult. Measurement of urinary levels of P2macroglobulin. A low-molecular weight protein freely filtered through theglomerulus and reabsorbed almost completely in the proximal tubule ofeven immature kidneys, may provide a sensitive indicator of subtleproximal tubular dysfunction. Renal size should be monitored byultrasound (Hankins et aL, 2002).

    Roberts et al. (1990) concluded that measurement of retinol bindingprotein excretion in urine or urinary excretion of myoglobin after birth ishelpful in the early diagnosis of acute renal failure in newborns withperinatal asphyxia.c- CARDIOVASCULAR EFFECTS OF ASPHYXIA:

    During normal myocardial oxygenation, circulating free fatty acidsprovide the major fuel source for the myocardium; but during hypoxia, freefatty acids cannot be oxidized and hence the heart becomes totallydependent on anaerobic glycolysis of glycogen for energy production.Cardiac glycogen stores are rapidly depleted as the asphyxia progresses.Neonatal survival during asphyxia is dependent on the amount of cardiacglycogen available prior to the asphyxial episode (Thompson, 1994).

    Although the myocardium in the newborn is preferentially perfusedduring asphyxia, such compensatory mechanisms become compromisedwhen the reserve is consumed(Bhuni et aL, 1992).

    Initially, the myocardium can tolerate hypoxemia because of highmyocardial blood flow in the foetus (Thompson, 1994). However, thepapillary muscles are more sensitive to the effect of hypoxia and may showsigns of infarction (A/kalay et al; 1988).

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    58 Review ofLiteratureDuring asphyxia, there is an initial increase in pulmonary and

    systemic vascular resistance. This increased after load; increase the work ofthe ventricles and thus myocardial oxygen demands increase. This will leadto coronary hypo-perfusion which will compromise coronary blood flow,and hence lower cardiac output. As a consequence, the subendocardiumrelatively ischemic under ordinary conditions becomes significantlyischemic, leading to myocardial anoxic injury.This injury leads to decreasein myocardial contractility and myocardial necrosis, leading to heartfailure, and thus decreased blood flow to other vital organs (Thompson,1994).

    Infants with perinatal asphyxia may have transient myocardialischemia, a term used to describe a syndrome of congestive heart failure inneonates with no structural heart disease. It encompasses a wide spectrumranging from short-lived tachypnea to cardiogenic shock (Gary et al.,2002).

    These infants usually have had hypoxic stress and 10 minute Apgarscore of less than four. They develop respiratory distress and cyanosisshortly after birth. They will have signs of congestive heart failure, such astachypnea, tachycardia, an enlarged liver, and a gallop rhythm, manyinfants will have a systolic murmur at the lower left stemal border(tricuspid regurgitation), and some will have a murmur at the apex (mitralregurgitation).If hypoxia perpetuates, pulmonary vasoconstrict ion causes right

    ventricular volume overload and right-sided congestive heart failuresupervenes in approximately' 30% of affected cases, in addition to thetricuspid insufficiency (Matszczak: et al., 2003).

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    59 Review ofLiteratlll'eIn case of low output congestive heart failure. Pulmonary oedema is

    often present. It presents as rapid and shallow respirations, cyanosis andbilateral fine basal crepitation (Gary et al., 2002).

    Hypoxic cardiomyopathy can also present as persistent pulmonaryhypertension, which manifests with marked central cyanosis and littlerespiratory distress, and accentuated second heart sound (Matszczak et al.,2003). The presence of a fixed heart rate without variation may raisesuspicion of clinical brain death (King and Parer, 2000)..,. Diagnosis ofcardiac effects o(asphyx;a:

    Chest X-ray is valuable, as it may show cardiomegaly, pulmonaryvenous congestion. prominent perihilar lung markings or diffuse ill-definedair space opacities of acute pulmonary oedema.

    Chest ECG may show depressed ST segment in the mid-pericardiumand T wave inversion in the left precordium.

    Creatine phosphokinase MB isoenzyme fraction greater than 5 to 10.Percent may be present in myocardial damage (Levene, 1994).ECHOlDoppler may demonstrate right to left extrapulmonary shunts atatrial and ductal levels (Agha, 1993)."'Management ofCardiac Effects ofAsphvxia:

    The treatment necessitates adequate ventilation, with correction ofhypoxemia, acidosis and hypoglycemia. These infants will requirecontinuous monitoring of mean arterial pressure through an arterial line.Hypotension and poor tissue perfusion should be identified and promptlymanaged by administration of normal saline, fresh frozen plasma oralbumin; and by the use of small doses of inotropic drugs as dopamineandlor dobutamine when myocardial dysfunction is strongly suspected

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