Asphyxia and hypoxic ischemic encephalopathy

1. 
   

   Definitions

   
   
   
   
   1. 
      

      Perinatal asphyxia: Historically, the term perinatal asphyxia has been used to describe a clinical condition in the newborn associated with hypoxia and acidemia of sufficient magnitude to cause harm. In clinical practice, this term is nonspecific and should be avoided.

      
      
   2. 
      

      Hypoxic ischemic encephalopathy: Hypoxic ischemic encephalopathy (HIE) is a form of neonatal encephalopathy that occurs in term neonates who have

      
      
      
      
      1. 
         

         Evidence of severe acidosis or need for resuscitation at birth

         
         
      2. 
         

         Direct evidence of an abnormal neurobehavioral state characterized by seizures and/or abnormalities in consciousness, tone, posture, and reflexes

         
         
      3. 
         

         Evidence of an acute perinatal or sentinel event

         
         
      4. 
         

         Characteristic neuroimaging findings

         
         
      5. 
         

         Exclusion of other etiologies of neonatal encephalopathy Fulfillment of all five criteria is not always possible, particularly in the immediate postnatal period. Neonates with the majority of these findings often are treated as having presumptive HIE as early recognition is paramount to the initiation of neuroprotective therapies within the therapeutic window.

      
      
   3. 
      

      The terminology associated with this condition is controversial.

   
   
2. 
   

   Incidence or prevalence

   
   
   
   
   1. 
      

      The prevalence of HIE is 0.5 to 1 per 1000 live births in the United States and developed nations and significantly higher in low and midresource settings where precise figures are unavailable.

      
      
   2. 
      

      Limited data on the true incidence exist.

   
   
3. 
   

   Pathophysiology

   
   
   
   
   1. 
      

      The pathophysiology of HIE is extrapolated from human neuropathological studies and preclinical models with clearly defined hypoxic-ischemic insults (systemic hypoxemia, cerebral hypoperfusion or both) and is characterized at the cellular level by a biphasic process of primary and secondary energy failure.

      
      
   2. 
      

      The initial phase consists of the triggering hypoxic-ischemic interval that leads to primary energy failure (a reduction in high-energy phosphorylated metabolites and intracellular pH). This phase may be so severe that it results in permanent brain injury or if subacute may be responsive to resuscitation.

      
      
   3. 
      

      Approximately 6 to 24 hours later, secondary energy failure ensues characterized by activation of proteases and endonucleases, neuronal apoptosis, microglial activation, reduction of growth factors and protein synthesis, and further accumulation of excitatory neurotransmitters.

      
      
   4. 
      

      Neuronal cell death may be immediate or delayed and result from neuronal apoptosis or necrosis.

      
      
   5. 
      

      In human neonates, the pathway to brain injury is not always clear. Many factors such as etiology, brain maturation, extent and timing of hypoxia-ischemia, cerebral blood flow patterns, and the general health of the fetus prior to injury can affect the outcome.

   
   
4. 
   

   Risk factors: Risk factors include any condition in which resuscitation at birth may be required and may be divided into

   
   
   
   
   1. 
      

      Maternal factors: Hypertension, cardiopulmonary abnormalities, cardiac arrest, hypovolemic shock, severe anaphylactoid reactions, status epilepticus, etc.

      
      
   2. 
      

      Uteroplacental factors: Uterine rupture, placental abruption, infarction, fibrosis, underperfusion, placenta previa, etc.

      
      
   3. 
      

      Umbilical cord factors: Umbilical cord prolapse, cord entanglement or compression, abnormalities of umbilical vessels, tight nuchal cord, true knot, etc.

      
      
   4. 
      

      Intrapartum factors: Abnormal presentation, nonreassuring fetal status, thick meconium, prolonged labor, precipitous delivery, difficult delivery requiring instrumentation (forceps, vacuum), prolonged pregnancy, etc.

      
      
   5. 
      

      Fetal factors: Fetomaternal hemorrhage, severe isoimmune hemolytic disease, arrhythmias, twin-to-twin transfusion syndrome, etc.

   
   

   Perinatal events may fail to predict risk in some cases.

   
   
5. 
   

   Clinical presentation

   
   
   
   
   1. 
      

      Signs and symptoms: Signs and symptoms may be divided into physiological findings, neurological or other examination findings, and abnormalities on EEG/aEEG. All neonates >36 weeks’ gestational age with a history of poor respiratory effort at birth and a need for resuscitation or evidence of neonatal encephalopathy should be carefully evaluated.

      
      
      
      
      1. 
         

         Physiological data: The specific blood gas criteria that define HIE and are associated with subsequent neurological abnormalities remain uncertain. Threshold blood gas criteria reported in the literature and used in clinical trials of hypothermia include

         
         
         
         
         • 
           

           pH <7.0 or a base deficit of 16 mmol/L or more in umbilical cord blood or any blood sample within the first hour of life

           
           
         • 
           

           pH between 7.01 and 7.15, base deficit 10 to 15.9 mmol/L within the first hour withany of the following:

           
           
           
           
           • 
             

             An acute perinatal event

             
             
           • 
             

             A 10-minute Apgar score

             
             
           • 
             

             Assisted ventilation initiated at birth and continued for at least 10 minutes

         
         
      2. 
         

         Neurological examination findings: Seizures and evidence of neonatal encephalopathy (Table 36-1) or other signs of central nervous system dysfunction (eg, jitteriness, clonus, apnea, abnormal posturing, and movements).

         
         
      3. 
         

         Other clinical findings: Clinical signs or symptoms of multiorgan involvement.

         
         
      4. 
         

         EEG findings:Electrographic seizures or abnormalities in background pattern, reactivity, organization of states, and maturation.

         
         
      5. 
         

         aEEG findings: Electrographic seizures or abnormalities in background pattern (discontinuous background, burst suppression, continuous low voltage, or flat/isoelectric background). The sensitivity of aEEG for identifying isolated seizures is poor; short seizures, focal discharges, and low-amplitude seizures may not be detected.

      
      
   2. 
      

      Condition variability: Condition variability varies from mild to severe (see Table 36-1).

   
   
6. 
   

   Diagnosis

   
   
   
   
   1. 
      

      A diagnosis of presumptive HIE may be made based on the following criteria:

      
      
      
      
      1. 
         

         Evidence of severe acidosis or need for resuscitation at birth, followed by

         
         
      2. 
         

         Direct evidence of an abnormal neurobehavioral state characterized by seizures and/or abnormalities in consciousness, tone, posture, and reflexes, and

         
         
      3. 
         

         Exclusion of other etiologies of neonatal encephalopathy.

      
      
   2. 
      

      EEG or amplitude-integrated EEG may assist in the diagnosis.

      
      
   3. 
      

      Neuroimaging studies may also be helpful revealing a characteristic topography of acute CNS injury. The most common patterns of brain injury include watershed and basal-ganglia-thalamus distribution.

      
      
      
      
      1. 
         

         Watershed pattern of injury: Predominant pattern involves white matter injury in watershed distribution (extends to gray matter, overlying cortex when severe); often associated with partial prolonged asphyxia in experimental models.

         
         
      2. 
         

         Basal ganglia-thalamus pattern: Predominant pattern involves deep gray structures and perirolandic cortex (extends to entire cortex when severe).

   
   
7. 
   

   Management

   
   
   
   
   1. 
      

      Medical: Medical management in the NICU includes supportive intensive care (respiratory, blood pressure, infection, seizures, etc) and hypothermia (whole body or selective head cooling with systemic hypothermia). Optimization of hypothermia and adjuvant therapies (cord blood, etc) are under investigation.

   
   
8. 
   

   Early developmental/therapeutic interventions. Physical, occupational, and developmental care should be initiated as soon as possible following stabilization and treatment of life-threatening conditions. Neonates with moderate or severe encephalopathy should be enrolled in follow-up and developmental care/early intervention programs prior to discharge.

   
   
9. 
   

   Prognosis

   
   
   
   
   1. 
      

      Early predictors

      
      
      
      
      1. 
         

         Clinical predictors: The earliest predictors of mortality and neurologic morbidity among neonates with HIE include persistently low Apgar scores after birth, time to establish spontaneous respiration, and persistence or severity of encephalopathy. The sensitivity and specificity of these clinical markers are low.

         
         
      2. 
         

         Diagnostic tools and imaging modalities are also available. These include

         
         
         
         
         • 
           

           Amplitude integrated EEG (sensitivity 0.93 [95% confidence interval 0.78-0.98]; specificity 0.90 [0.60-0.83])

           
           
         • 
           

           EEG (sensitivity 0.92 [0.66-0.99]; specificity 0.83 [0.64-0.93])

           
           
         • 
           

           Visual evoked potentials (sensitivity 0.90 [0.74-0.97]; specificity 0.92 [0.68-0.98]

           
           
         • 
           

           Diffusion weighted MRI in the first week (sensitivity 0.58 [0.24-0.84]; specificity 0.89 [0.62-0.98])

           
           
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           ADC first week (sensitivity 0.79 [0.50-0.93]; specificity 0.85 [0.75-0.91])

           
           
         • 
           

           T1/T2-weighted MRI first 2 weeks (sensitivity 0.98 [0.80-1.00]; specificity 0.76 [0.36-0.94])

           
           
         • 
           

           MR spectroscopy first 2 weeks (sensitivity 0.73 [0.24-0.96]; specificity 0.84 [0.27-0.99])

         
         

         Considerable heterogeneity exists in the performance of these prognostic tests and in the definition of outcomes. Prospective studies presently are underway and may provide further information on the clinical utility of these tests.

      
      
   2. 
      

      Outcomes

      
      
      
      
      1. 
         

         Therapeutic hypothermia has been shown to be effective in minimizing death and disability in term infants with neonatal encephalopathy and acidosis at birth. However, six moderately encephalopathic and seven severely encephalopathic neonates need to be treated with hypothermia to save one neonate from death or major disability.

         
         
      2. 
         

         Despite hypothermia to 33°C to 35°C for 72 hours, more than 40% of infants with HIE develop poor outcomes.

         
         
      3. 
         

         In a recent meta-analysis of hypothermia trial data (of 1216 newborns), 26% of neonates offered hypothermia died, 26% developed major disability, and 19% developed cerebral palsy at 18 to 24 months of age. This has widespread implications for the children affected, their families, and the developmental care and assessment of these children at follow-up.

1. 
   

   Management

   
   
   
   
   1. 
      

      Adrenal insufficiency (see also Chapter 10)

      
      
      
      
      1. 
         

         Neonates with HIE or presumed HIE may have significant hypotension and a poor initial stress response requiring hydrocortisone therapy during the acute phase.

         
         
      2. 
         

         Due to prolonged use of steroids during the initial neonatal period, the infant with HIE may have relative adrenal insufficiency during convalescence requiring stress dosing in the event of acute illness or elective surgery (eg, gastrostomy tube placement).

         
         
      3. 
         

         If the infant is weaned off hydrocortisone in close proximity to discharge, consider a stimulation test in order assess HPA axis functioning.

         
         
      4. 
         

         If discharged home on a prolonged hydrocortisone taper, the infant should be prescribed solucortef, for emergency situations, and parents should be instructed on how and when to administer.

      
      
   2. 
      

      Seizures (see also Chapter 39)

      
      
      
      
      1. 
         

         Seizures on the first day of life are common in the setting of HIE, but usually resolve by 72 to 96 hours of life.

         
         
      2. 
         

         In most cases, antiepileptic medications can be discontinued by 1 to 4 weeks after the last seizure and often prior to NICU discharge.

         
         
      3. 
         

         Severe or persistent seizures, or concerning imaging or EEG findings, warrant a longer course of antiepileptics.

      
      
   3. 
      

      Feeding difficulties

      
      
      
      
      1. 
         

         Problems with feeding are very common in infants with moderate to severe HIE, especially if they have poor state regulation or tone abnormalities.

         
         
      2. 
         

         Early involvement with occupational and speech therapy may assist in acquiring oral feeding skills.

         
         
      3. 
         

         GER is quite common in infants with HIE, especially when tone abnormalities are present, and should be addressed accordingly.

         
         
      4. 
         

         It is not uncommon for neonates with severe HIE to require supplemental tube feedings through discharge.

      
      
   4. 
      

      Hypertonia

      
      
      
      
      1. 
         

         Infants with moderate-severe HIE often initially present with hypotonia but, depending on their NICU length of stay, may develop hypertonia prior to discharge.

         
         
      2. 
         

         If the child’s degree of hypertonia interferes with basic cares (ie, diapering), feeding, or emerging gross motor skills, consider starting a tone reducing medication (baclofen) prior to discharge.

         
         
      3. 
         

         Physical therapy consult prior to discharge may assist in assessing tone, positioning, infant massage, and prescribing stretching/strengthening exercises while in convalescence and postdischarge.

      
      
   5. 
      

      Irritability

      
      
      
      
      1. 
         

         It is not uncommon for neonates with severe HIE to have poor state regulation and extreme bouts of irritability.

         
         
      2. 
         

         If the severity or duration of irritable spells interferes with sleep cycles, ability to feed or provide routine care, consider pharmacotherapy aimed at the neuropathic process (clonazepam or gabapentin).

   
   
2. 
   

   Discharge

   
   
   
   
   1. 
      

      Teaching

      
      
      
      
      1. 
         

         Parents should be educated about their child’s current condition and comorbidities acquired during their NICU stay, as well as expected and possible outcomes.

         
         
      2. 
         

         Parents should be instructed how to give medications prescribed at discharge and told what condition they are treating. They should understand that if the symptoms worsen (muscle tone, reflux, seizures, etc) postdischarge that the medicine may need to be weight adjusted.

         
         
      3. 
         

         Parents should meet with a physical therapist and learn stretching/strengthening exercises applicable to their child. Also, consider teaching the parents infant massage if the child is hypertonic or very irritable.

         
         
      4. 
         

         Parents should meet with a speech/occupational therapist prior to discharge if the child has a history of feeding difficulties.

         
         
      5. 
         

         If the facilities are available, consider having the parents room-in with their baby prior to discharge.

      
      
   2. 
      

      Monitoring

      
      
      
      
      1. 
         

         Consider home apnea monitor for infants with persistent apnea and bradycardia spells related to severe GERD or poorly controlled seizure disorder.

         
         
      2. 
         

         Infants with severe brain injury should have their hypothalamic-pituitary-adrenal axis assessed prior to discharge, including thyroid function tests (TSH, FT4), fasting cortisol and ACTH, and electrolytes to assess for diabetes insipidus.

         
         
      3. 
         

         Infants with severe brain injury should demonstrate stable temperature regulation, without an external heat source, for several days prior to discharge.

      
      
   3. 
      

      Safety

      
      
      
      
      1. 
         

         Caregivers should be instructed in infant CPR.

         
         
      2. 
         

         Infants should have a car seat safety test for at least 90 minutes prior to discharge. Infants with poor head control at discharge may need to use the manufacturer’s insert to provide lateral head support.

         
         
      3. 
         

         An emergency plan should be established, instructing what to do (give rectal diazepam, call PCP, call neurologist, call 911, etc) if the child has a prolonged seizure and what medical facility to bring them to.