Background• Despite major advances in monitoring technology and knowledge of fetal and neonatal pathologies, perinatal asphyxia or, more appropriately, hypoxic-ischemic encephalopathy (HIE), remains a serious condition that causes significant mortality and long-term morbidity.• Hypoxic-ischemic encephalopathy is characterized by clinical and laboratory evidence of acute or subacute brain injury due to asphyxia (ie, hypoxia, acidosis). Most often, the exact timing and underlying cause remain unknown.
Definition• Anoxiais a term used to indicate the consequences of complete lack of oxygen as a result of a number of primary causes• Hypoxiarefers to an arterial concentration of oxygen that is less than normal• Ischemiarefers to blood flow to cells or organs that is insufficient to maintain their normal function Biagioni E, Mercuri E, Rutherford M, et al: Combined use of electroencephalogram and magnetic resonance imaging in full-term neonates with acute encephalopathy. Pediatrics 2001;107:461
• Hypoxic-ischemic encephalopathy Is an abnormal neurobehavioral state in which the predominant pathogenic mechanism is impaired cerebral blood flow that may result in neonatal death or be manifested later as cerebral palsy or mental deficiency.1996 guidelines from the AAP and ACOG for hypoxic-ischemic encephalopathy (HIE)• Profound metabolic or mixed acidemia (pH < 7) in an umbilical artery blood sample, if obtained• Persistence of an Apgar score of 0-3 for longer than 5 minutes• Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)• Multiple organ involvement (eg, kidney, lungs, liver, heart, intestines Nelson Textbook of Pediatrics 19th ed.2010 . pages 566 - 568
Epidimiology• Frequencya) Birth asphyxia is the cause of 23% of all neonatal deaths worldwide.b) It is one of the top 20 leading causes of burden of disease in all age groups by the World Health Organization.c) It is the fifth largest cause of death of children younger than 5 years (8%)d) More than a million children who survive birth asphyxia develop problems such as cerebral palsy, mental retardation, learning difficulties, and other disabilities. Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet. Mar 26-Apr 1 2005;365(9465):1147-52.
• Mortality/Morbidity:a) In severe hypoxic-ischemic encephalopathy, the mortality rate is reportedly 25-50%.b) As many as 80% of infants who survive severe hypoxic-ischemic encephalopathy develop serious complications, 10-20% develop moderately serious disabilities, and as many as 10% are healthy.c) The infants who survive moderately severe hypoxic-ischemic encephalopathy, 30-50% may have serious long-term complications, and 10-20% have minor neurological morbidities.d) Infants with mild hypoxic-ischemic encephalopathy tend to be free from serious CNS complications. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet. 2005;365:663-70.
• Race No predilection is noted.• Sex No predilection is observed.• Age Most often, the condition is noted in infants who are term at birth. van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review. Eur J Pediatr. Jul 2007;166(7):645-54
Fetal response to asphyxia illustrating the initial redistribution of bloodflow to vital organs. With prolonged asphyxial insult and failure ofcompensatory mechanisms, cerebral blood flow falls, leading to ischemicbrain injury.
Pathophysiology of hypoxic-ischemic brain injury in thedeveloping brain. During theinitial phase of energyfailure, glutamate mediatedexcitotoxicity and Na+/K+ATPase failure lead to necroticcell death. After transientrecovery of cerebral energymetabolism, a secondaryphase of apoptotic neuronaldeath occurs. ROS = Reactiveoxygen species.
Clinical features- Sarnat Staging System Stage 1 Stage 2 Stage 3 Level of Hyperalert Lethargic/obtunded Stuporous conciousness Neuromuscular control Muscle tone Normal Mild hypotonia Flaccid Posture Mild distal flexion Strong distal flexion Intermittent decerebration Stretch reflex Overactive Overactive Decreased/absent Segmental Present Present Absent myoclonus Complex Reflexes Suck Weak Weak/absent Absent Moro Strong, low Weak; incomplete, Absent threshold high threshold Oculovestibular Normal Overactive Weak/absent Tonic neck Slight Strong Absent
Autonomic Generalised Generalised Both systemsfunction sympathetic parasympathetic depressedPupils Mydriasis Miosis Variable;ofetn unequal;poor light reflexHeart rate Tachycardia Bradycardia VariableBronchial & Sparse Profuse Variablesalivary secretionsGI motility Normal/decreased Increased,diarrhea VariableSeizures None Common; focal / Uncommon multifocalEEG Normal Early : low voltage Early: periodic with continuous delta & isopotential phases. theta. Later: periodic Later: totally pattern isopotential Seizures: focal 1 Hz spike and waveDuration 1-3 days 2-14 days Hours . weeks
Diagnosis • There are nor specific tests to confirm or exclude a diagnosis of hypoxic- ischemic encephalopathy (HIE) because the diagnosis is made based on the history, physical and neurological examinations, and laboratory evidence. • Laboratory studies include :-StudySerum electrolyte Markedly low serum sodium, potassium, and chloride levels in the presence of reduced urine flow and excessive weight gain may indicate acute tubular damage or (SIADH) secretion, particularly during the initial 2-3 days of life.Renal function Serum creatinine levels, creatinine clearance, and BUN levelsCardiac & liver enzymes Assess the degree of hypoxic-ischemic injury to other organsCoagulation system Prothrombin time, partial thromboplastin time, and fibrinogen levels.ABG Assess acid-base status and to avoid hyperoxia and hypoxia as well as hypercapnia and hypocapnia.
Imaging studies:- PV-cysts (swiss cheese appearance)Cranial US:a) Convenient, noninvasive, relatively low-cost and non –radiation screening examination of the hemodynamically unstable neonate at the bedside.b) Doppler study and resistive index (RI) provide additional information on cerebral perfusion.c) RI decreases with increasing gestational age, and thus correlation with gestational age is necessary for accurate interpretation of RI results.d) Decreased RI is abnormal & is postulated to be caused by impairment in cerebral autoregulation.e) Sustained asphyxia & ICH or diffuse cerebral edema results in increased RI and is indicative of a poor outcome.
Cranial CT:a) CT technology provides a rapid mode of screening for ICH & hydrocephalus in a sick neonate without the need for sedation.b) CT is the least sensitive Unenhanced CT scan shows diffuse cortical swelling modality for evaluation of HIE and hypoattenuation in the white matter relative to because of poor parenchymal areas of preserved cortex, A small amount of contrast resolution due to: extraaxial hemorrhage adjacent to the left frontal lobe is also seen (arrow). high water content in the neonatal brain. high protein content of the cerebrospinal fluid, which result in. CT has the inherent disadvantage of radiation exposure.
Cranial MRIa) The most sensitive and specific imaging technique for examining infants with suspected hypoxic- ischemic brain injury.b) Hypoxic-ischemic injury (deep grey matter,cortex)demonstrat relatively subtle increases in signal intensity in the perirolandic es characteristic T1 regions, posterior aspect of the putamen, lateral aspects of the thalamus, and corpus callosum. hyperintensity and Bottom: show diffuse abnormally high signal intensity in the variable T2 intensity. supratentorial parenchyma in comparison with the superior aspect of the cerebellum, which has normal signal intensity.c) Ischemic injury generally results in T1 hypointensity &T2 hyperintensity (white matter)due to ischemia- induced edema.
Histological findings Bilateral acute infarctions of the frontal lobe are shown. The infarctions depicted in the figure (arrows) are consistent with watershed infarctions secondary to global hypoperfusion.presence of pyknotic and hyperchromaticnuclei, the loss of cytoplasmic Nisslsubstance, and neuronal shrinkage andangulation (arrow). These alterations begin toappear approximately 6 hours following hypoxic-ischemic insult.
Reactive astrocytosis is evident approximately 24-48 hours after the primary hypoxic-ischemic event.Periventricular leukomalacia is depicted.Note the extensive hemorrhage within the cystic space as wellas the hemosiderin-laden macrophages around the lesionalrim.
Other studiesAmplitude-integrated electroencephalography (aEEG)a) The abnormalities seen in infants with moderate-to-severe hypoxic- ischemic encephalopathy include the following:b) Discontinuous tracing characterized by a lower margin below 5 mV and an upper margin above 10 mVc) Burst suppression pattern characterized by a background with minimum amplitude (0-2 mV) without variability and occasional high voltage bursts (>25 mV)d) Continuous low voltage pattern characterized by a continuous low voltage background (< 5 mV)e) Inactive pattern with no detectable cortical activityf) Seizures, usually seen as an abrupt rise in both the lower and upper margin
Standard EEG Generalized depression of the background rhythm and voltage, with varying degrees of superimposed seizures, are early findings. EEG characteristics associated with abnormal outcomes includea) background amplitude of less than 30 mV.b) interburst interval of more than 30 seconds.c) electrographic seizures.d) absence of sleep-wake cycle at 48 hours.
TreatmentMedical carea) Initial Resuscitation and Stabilization-• Delivery room management follows standard Neonatal Resuscitation Program (NRP) guidelines. Close attention should be paid to appropriate oxygen delivery, perfusion status, and avoidance of hypoglycemia and hyperthermia.• A lot of attention is currently focused on resuscitation with room air versus 100% oxygen in the delivery room. Several clinical trials indicate that room air resuscitation for infants with perinatal asphyxia is as effective as resuscitation with 100% oxygen.• International Liaison Committee on Resuscitation (ILCOR) recommendations include initiating neonatal resuscitation with concentrations of oxygen between 21-100% Guideline] Ten VS, Matsiukevich D. Room air or 100% oxygen for resuscitation of infants with perinatal depression. Curr Opin Pediatr. Apr 2009;21(2):188-93
b) Supportive Care in Patients with Hypoxic-ischemic Encephalopathy• Most infants with severe hypoxic-ischemic encephalopathy need ventilatory support during first days of life.• The role of mechanical ventilation is to maintain the blood gases and acid-base status in the physiological ranges and prevent hypoxia, hyperoxia, hypercapnia, and hypocapnia.• Infants with hypoxic-ischemic encephalopathy are also at risk for pulmonary hypertension and should be monitored. Nitric oxide (NO) may be used according to published guidelines. [Guideline] American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. Aug 2000;106(2 Pt 1):344-5.
c) Perfusion and Blood Pressure Management• A mean blood pressure (BP) above 35-40 mm Hg is necessary to avoid decreased cerebral perfusion.• Hypotension is common in infants with severe hypoxic-ischemic encephalopathy and is due to myocardial dysfunction, capillary leak syndrome, and hypovolemia; hypotension should be promptly treated.• Dopamine or dobutamine can be used to achieve adequate cardiac output in these patients. Avoiding iatrogenic hypertensive episodes is also important.
d) Fluid and Electrolytes Management• Prophylactic theophylline, given early after birth helps in reducing renal dysfunction• A single dose of theophylline (5-8 mg/kg) given within 1 hour of birth resulted in(1) decreased severe renal dysfunction (defined as creatinine level >1.5 mg/dL for 2 consecutive days);(2) increased creatine clearance;(3) increased glomerular filtration rate (GFR); and(4) decreased b2 microglobulin excretion.• Avoid hypoglycemia and hyperglycemia because both may accentuate brain damage. Jenik AG, Ceriani Cernadas JM, Gorenstein A, et al. A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia.Pediatrics. 2000;105:E45
e) Treatment of Seizures• Hypoxic-ischemic encephalopathy is the most common cause of seizures in the neonatal period.• Current therapies available to treat neonates with seizures include phenobarbital, phenytoin, and benzodiazepines.• Phenobarbital has been shown to be effective in only 29-50% of cases,• Phenytoin only offers an additional 15% efficacy.• Benzodiazepines, particularly lorazepam, may offer some additional efficacy Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. Feb 10 2004;62(3):486-8.
g) Medication summary Anti Cardiovascular convulsants agents Phenobarbital Dopamine (20mg/kg I V) Phenytoin dobutamine (20mg/kg) Lorazepam (0.1mg/kg)
f) Hypothermia Therapy• Mild hypothermia (3-4°C below baseline temperature) applied within a few hours (no later than 6 h) of injury is neuroprotective. Possible mechanisms include(1) reduced metabolic rate and energy depletion;(2) decreased excitatory transmitter release;(3) reduced alterations in ion flux;(4) reduced apoptosis due to hypoxic-ischemic encephalopathy; and(5) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions.• Therapeutic hypothermia when applied within 6 hours of birth and maintained for 48-72 hours is a promising therapy for mild-to-moderate cases of hypoxic-ischemic encephalopathy. Best Evidence] Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. Oct 1 2009;361(14):1349-58.
h) Diet• In most cases, the infant is restricted to nothing by mouth (NPO) during the first 3 days of life or until the general level of alertness and consciousness improves.• In addition, infants undergoing hypothermia therapy should remain NPO until rewarmed. Enteral feeds should be carefully initiated and the use of trophic feeds is initially advisable (about 5 mL every 3-4 h).• Infants should be monitored carefully for signs and symptoms of necrotizing enterocolitis, for which infants with perinatal asphyxia are at high risk.
Surgical care• In cases of posterior cranial fossa hematoma, surgical drainage may be lifesaving if no additional pathologies are present.Further Inpatient Care• Close physical therapy and developmental evaluations are needed prior to discharge in patients with hypoxic-ischemic encephalopathy (HIE).
Further Outpatient Care• The goal of follow-up is to detect impairments and promote early intervention for those infants who require it.• Growth parameters including head circumference should be closely monitored in all infants with hypoxic-ischemic encephalopathy.• In infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy with either abnormal neurologic examination findings or feeding difficulties, intensive follow-up is recommended. include follow-up by developmental pediatrician and pediatric neurologic.• In infants with moderate hypoxic-ischemic encephalopathy but no feeding difficulties and normal neurologic examination findings, routine care is appropriate.
Prognosis• Lack of spontaneous respiratory effort within 20-30 minutes of birth is almost always associated with death.• The presence of seizures is an ominous sign.• Abnormal clinical neurological findings persisting beyond the first 7-10 days of life usually indicate poor prognosis.• EEG at about 7 days that reveals normal background activity is a good prognostic sign.• Persistent feeding difficulties, which generally are due to abnormal tone of the muscles of sucking and swallowing, also suggest significant CNS damage.• Poor head growth during the postnatal period and the first year of life is a sensitive finding predicting higher frequency of neurologic deficits. Patel J, Edwards AD. Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr. Apr 1997;9(2):128-32.
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