Hypoxic–ischemic encephalopathy14 - Neonatology at a Glance

Neonatology at a Glance, Third Edition. Edited by Tom Lissauer, Avroy A. Fanaroff, Lawrence Miall and Jonathan Fanaroff.

Neonatal encephalopathy is a clinical description of generalized disordered neurologic function in the newborn. The most common cause is birth asphyxia. Asphyxia, from the Greek word meaning pulseless, is now used to mean a state in which gas exchange – placental or pulmonary – is compromised or ceases altogether, resulting in cardiorespiratory depression. Hypoxia, hypercarbia and metabolic acidosis follow. Compromised cardiac output dimin

ishes tissue perfusion, causing hypoxic–ischemic injury to the brain and other organs. The origin may be antenatal, during labor and delivery or postnatal (Fig. 14.1).

Other causes of neonatal encephalopathy include transfer of maternal anesthetic agents, cerebral malformations, metabolic dis

orders (hypoglycemia, hypocalcemia, hyponatremia, inborn errors of metabolism), infection (septicemia and meningitis), hyperbiliru

binemia, neonatal withdrawal (abstinence) syndrome and intra

cranial hemorrhage or infarction. The term “birth asphyxia” is best avoided because it is imprecise and implies that the baby’s enceph

alopathy is a consequence of an asphyxial insult relating to birth, which may have medicolegal implications.

In hypoxic–ischemic encephalopathy (HIE), as opposed to other causes of encephalopathy, there is:

• a significant hypoxic or ischemic event immediately before or during labor or delivery or consistent fetal heart rate monitor pattern

• fetal umbilical artery acidemia (fetal umbilical artery pH < 7.0 or base deficit >/= 12 mmol/L, cord arterial pH < 7.20)

• Apgar score of < 5 at 5 and 10 minutes

• multisystem organ failure

• neuroimaging evidence of acute brain injury consistent with hypoxiaischemia.

In developed countries, 0.5–1/1000 liveborn term infants develop HIE and 0.3/1000 have significant neurologic disability. HIE is more common in developing countries.

Pathogenic mechanisms These include:

• failure of gas exchange across the placenta – excessive or pro

longed uterine contractions, placental abruption, ruptured uterus

• interruption of umbilical blood flow – cord compression, cord prolapse, delayed delivery, e.g. shoulder dystocia

• inadequate maternal placental perfusion, maternal hypotension or hypertension – often with intrauterine growth restriction (IUGR)

• compromised fetus – anemia, IUGR

• failure of cardiorespiratory adaptation at birth – failure to breathe.

Compensatory mechanisms These include:

• ‘diving reflex’ – redistribution of blood flow to vital organs (brain, heart and adrenals)

• sympathetic drive – increase in catecholamines, cortisol, antidi

uretic hormone (ADH, vasopressin)

• utilization of lactate, pyruvate and ketones as an alternative energy source to glucose.

Primary and delayed injury

Following a severe ischemic insult, some brain cells die rapidly (primary cell death due to necrosis) and an excitotoxic cascade is triggered, including release of excitatory amino acids and free rad

icals. When circulation is re‐established, there is a variable time delay before secondary energy failure and delayed cell death due to apoptosis. This offers a potential therapeutic window to ameliorate secondary damage (Fig. 14.2).

Hypoxic–ischemic encephalopathy

Hypoxic–ischemic encephalopathy 35

Clinical manifestations

The clinical manifestations, investigations and management are summarized in Fig. 14.3.

Several large multicenter trials have demonstrated the benefit of therapeutic hypothermia in reducing death and disability and increasing survival with normal outcome at 18–24 months.

The number needed to treat to prevent one death or disabled infant is seven. Selection criteria for cooling are gestation ≥36 weeks, need for prolonged resuscitation, clinical evidence of moderate or severe encephalopathy and severe metabolic acidosis within the

first hour of life. aEEG or EEG are not required to initiate cooling, but may confirm the severity of the encephalopathy and determine if subclinical seizures are present (see Chapter 80). Cooling should be initiated within 6 h of birth. Core temperature is reduced to 33–34 °C and maintained for 72 h before slowly rewarming.

Cooling is usually performed in a tertiary NICU but passive cooling (turning off radiant heaters and allowing the baby to lose heat naturally) may be commenced in the delivery room. Adjunct therapies to hypothermia that may further improve outcome are being evaluated, including xenon, melatonin and erythropoietin (see video: Hypoxic–ischemic encephalopathy).

Respiratory depression Circulatory depression

Multi-organ dysfunction Hypoxemia

Hypercarbia Respiratory acidosis

Low cardiac output Decreased tissue perfusion Ischemia

Metabolic acidosis Capillary leak, edema

Encephalopathy Abnormal neurologic exam Seizures

Respiratory failure Persistent pulmonary hypertension of the newborn (PPHN) Hypoxemia Respiratory acidosis

Myocardial dysfunction Hypotension Arrhythmias Ischemia Metabolic acidosis

Metabolic Hypo/hyperglycemia Hypocalcemia, Hypomagnesemia Lactic acidosis Hyponatremia – syndrome of inappropriate ADH secretion (SIADH)

Acute kidney injury (Renal failure) (acute tubular or cortical necrosis) Oliguria Polyuria Hematuria

Gastrointestinal Feeding intolerance Bleeding Gut ischemia – NEC Hepatic failure

Hematology Elevated nucleated red blood cells Thrombocytopenia Bleeding – DIC Thrombosis

Clinical featuresDelivery

EEG, aEEG Cerebral ultrasound, MRI, CT

Evoked potentials

Avoid overheating Therapeutic hypothermia Anticonvulsants

Arterial blood gases

Chest X-ray Blood gases

Myocardial enzymes Echocardiography ECG – raised ST segment

Blood glucose Calcium, magnesium Lactate

Electrolytes Serum and urine osmolarity

Maintain normal blood glucose, calcium and magnesium Correct metabolic acidosis

Blood urea nitrogen (BUN) Creatinine

Liver function tests Guaiac (blood) positive stools/

gastric aspirate

Complete blood count

Coagulation screen

Respiratory support Maintain normal PaO₂ and PaCO₂ Inhaled nitric oxide to treat PPHN

Maintain normal blood pressure Inotropes

Restrict fluids until passed urine Monitor urine output (catheter)

Withhold feeds

initially Blood products

Vitamin K

InvestigationsManagement

Fig. 14.3 Clinical manifestations, investigations and management of hypoxic–ischemic encephalopathy. Investigations and management are selected according to clinical features. (NEC – necrotizing enterocolitis; DIC – disseminated intravascular coagulation; EEG – electroencephalogram; aEEG – amplitude‐

integrated EEG, cerebral function monitor; CTG – cardiotochography.)

Key point

Avoid overheating – each degree above normal increases mortality and risk of brain injury.

Key point

Mild hypothermia (33–34 °C, within 6 h of birth for 72 h) has been shown to reduce morbidity and mortality of moderate and severe HIE (see Fig. 67.1).

Clinical staging of hypoxic–ischemic encephalopathy

Severity of brain injury can be systematically evaluated using a staging system which is performed sequentially and is of prog

nostic value. The most common is Sarnat (Table 14.1), although the simpler Thompson score is increasingly used.

Outcome In general:

• A normal neurologic examination and feeding orally by 2 weeks of age suggest good prognosis.

• Mild HIE – usually good outcome.

• HIE without cooling:

– moderate HIE – increased risk for motor and cognitive abnor

malities, including cerebral palsy (15–20%);

– severe HIE – 50–75% will either die or have severe disability in childhood (spastic quadriplegia, learning difficulties, visual and hearing impairment, and seizures).

• HIE with cooling:

– risk of death or disability is reduced by about 60%.

The postnatal markers of poor prognosis are shown in Table 14.3.

Table 14.1 Sarnat staging of hypoxic–ischemic encephalopathy.

Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe)

Level of consciousness Irritable/hyperalert Lethargy Coma

Muscle tone Normal or hypertonia Hypotonia Flaccid

Tendon reflexes Increased Increased Depressed or absent

Myoclonus Present Present Absent

Seizures Absent Frequent Frequent

Complex reflexes

Suck Active Weak Absent

Moro Exaggerated Incomplete Absent

Grasp Normal to exaggerated Exaggerated Absent

Oculocephalic (doll’s eye) Normal Overactive Reduced or absent

Autonomic function

Pupils Dilated, reactive Constricted, reactive Variable or fixed

Respirations Regular Periodic Ataxic, apneic

Heart rate Normal or tachycardia Bradycardia Bradycardia

EEG Normal Low‐voltage periodic or

paroxysmal

Periodic or isoelectric

Prognosis Good Variable High mortality and

neurologic disability

Neuroimaging and functional studies (Table 14.2)

Table 14.2 Neuroimaging and functional studies and their indications and interpretation.

Procedure/test Indication and interpretation EEG or aEEG (amplitude

integrated EEG) (Fig. 14.4)

Best initiated as soon after birth as possible. Identifies encephalopathy, continuous seizure detection, monitoring background activity, and prognostic information. Good prognosis if normalizes in first 24 h.

Cranial ultrasound Easy to perform at bedside. Useful for defining normal anatomy and for evidence of prenatal injury, congenital infection, intracranial hematoma or metabolic disorder. In HIE, may detect cerebral edema, hyperechogenic basal ganglia and/or abnormal blood flow velocity in middle and anterior cerebral arteries.

Useful for following sequence and timing of any changes.

MRI scan Imaging of choice for prognosis. Allows early recognition of injury to basal ganglia, internal capsule, white matter, brainstem and cortex, focal cerebral infarction, hemorrhage and malformations (Figs 14.5 and 14.6). Optimal between 7 and 21 days to determine the extent of cerebral injury. Diffusion‐weighted imaging may detect abnormalities within the first week.

Hypoxic–ischemic encephalopathy 37 Fig. 14.5 Acute changes typically seen in the first week after perinatal asphyxia on MRI (axial T1W) at the level of the basal ganglia. There is an abnormal high signal in the posterolateral lentiform nuclei and thalami, loss of the normal high signal from myelin in the posterior limb of the internal capsule (arrow), abnormal signal in the head of the caudate nuclei and low signal throughout the white matter. (Courtesy of Dr Frances Cowan.)

(a) Normal

100μV

μV 50

5 0

100 50 25

5 0 100

Transport 50 25

25 25

5 0

(b) Severe hypoxic–

ischemic encephalopathy

Phenobarbital Phenytoin

Fig. 14.4 Amplitude‐integrated EEG (aEEG) trace from cerebral function monitor showing (a) normal term newborn – normal baseline (>5 μV);

(b) severe hypoxic–ischemic encephalopathy – low baseline amplitude;

(c) seizures in severe hypoxic–ischemic encephalopathy unresponsive to phenobarbital but responsive to phenytoin, although the trace remains abnormal. (Courtesy of Professor Andrew Wilkinson.)

Fig. 14.6 Cerebral atrophy on MRI (axial T1W) developing several weeks after perinatal asphyxia. At the level of the basal ganglia there is severe atrophy of the basal ganglia (arrow), thalami and white matter with enlarged ventricles and extracerebral space. There is also plagiocephaly.

(Courtesy of Dr Frances Cowan.) Table 14.3 Postnatal markers of poor prognosis.

Abnormal EEG from birth or aEEG from 6 h with isoelectric pattern or burst suppression in noncooled infants and later in cooled infants Abnormal MRI (conventional or diffusion‐weighted) – particularly basal

ganglia/posterior limb of the internal capsule (PLIC) or marked brain atrophy or delayed myelination on later scan

Persistence of clinical seizures

Persistently abnormal neurologic exam after 1 week (reasonable sensitivity, poor specificity)

Not feeding orally by 2 weeks of age Poor postnatal head growth

Neonatology at a Glance, Third Edition. Edited by Tom Lissauer, Avroy A. Fanaroff, Lawrence Miall and Jonathan Fanaroff.

The incidence of severe birth injuries has fallen dramatically over the last 50 years. Prolonged, obstructed labor and difficult instrumental deliveries are usually avoided by cesarean section. However, birth injuries still occur, especially following instrumental deliveries, shoulder dystocia, malpresentation or preterm delivery. They are usually classified according to their anatomic location.

Common or important birth injuries

These are listed in Table 15.1. Scalp swellings can be differentiated by their position and relationship to the skull bones (Fig. 15.1).

Birth injuries

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