Hypoxic Ischaemic Encephalopathy

Overview Background Definition Etiology Pathophysiology Clinical features Diagnosis

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.

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

Epidimiology Frequencya: Birth asphyxia is the cause of 23% of all neonatal deaths worldwide. It is one of the top 20 leading causes of burden of disease in all age groups by the World Health It is the fifth largest cause of death of children younger than 5 years (8%) More than a million children who survive birth asphyxia develop problems such as cerebral palsy, mental retardation, learning difficulties, and other disabilities.

• Mortality/Morbidity:a In severe hypoxic-ischemic encephalopathy, the mortality rate is reportedly 25%. As many as 30-50% of infants who survive severe hypoxic-ischemic encephalopathy develop serious complications, 10-20% develop moderately serious disabilities, and as many as 10% are healthy. The infants who survive moderately severe hypoxic-ischemic encephalopathy, 30-50% may have serious long-term complications, and 10-20% have minor neurological morbidities. Infants with mild hypoxic-ischemic encephalopathy tend to be free from serious CNS complications.

• Sex No predilection is observed. • Age Most often, the condition is noted in infants who are term at birth.

Risk factors • Hypoxemia • Cord prolapse • Placental abruption • Induction .

Pathophysiology

ضایعات با نواحی کاهش جریان خون مغزی همراه است ضایعات با نواحی کاهش جریان خون مغزی همراه است. بعد از یک حمله هایپوکسی – ایسکمی متابولیسم بی هوازی اتفاق می افتد. سبب افزایش لاکتات و فسفات افزایش و تجمع اسید آمینه های مضر مانند گوتامات در بافت آسیب دیده افزایش مقادیر سلولی سدیم و کلسیم ممکن است منجر به تورم و ادم مغزی شود. افزایش تولید رادیکال های آزاد و نیتریک اکساید.

نامساوی واکنش ضعیف به نور مرحله 3 مرحله 2 مرحله 1 نشانه ها استوپور، کما لتارژیک بیش از حد سطح هوشیاری شل هیپوتون طبیعی تون عضلانی دسربره فلکسیون وضعیت قرار گیری )Posture( وجود ندارد هیپراکتیو رفلکس های تاندونی وجود دارد میوکلونوس ضعیف قوی رفلکس مورو نامساوی واکنش ضعیف به نور میوز میدریاز مردمک ها وضعیت دسربره شایع است تشنج مکیدن آپنه و آتاکسیک پریودیک، تنفس برادیکاردی تاکی کارد یا طبیعی ضربان قلب

تظاهرات بالینی clinical sign محدودیت رشد داخل رحمی به همراه افزایش مقاومت عروقی آهسته شدن ضربان قلب حین زایمان مایع آمینوتیک آغشته به مکونیوم رنگ پریدگی سیانوز آپنه عدم پاسخ به تحریک تشنج

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

Cranial MRI The most sensitive and specific imaging technique for examining infants with suspected hypoxic- ischemic brain injury. 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.

electroencephalography (aEEG) electroencephalography (aEEG). 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.

Treatment :Medical care 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

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.

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.

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

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

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.

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.

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.