What are the stages of Hypoxic-Ischemic Encephalopathy (HIE) in a newborn?

Hypoxic-Ischemic Encephalopathy (HIE) Stages

HIE is classified into three distinct clinical stages—mild, moderate, and severe—based on the Sarnat staging system, which evaluates level of consciousness, muscle tone, reflexes, seizure activity, and autonomic function to guide treatment decisions and predict neurodevelopmental outcomes. 1, 2

Stage Classification System

Mild HIE (Stage 1)

• Hyperalertness or mild lethargy with normal or slightly increased muscle tone 1
• Intact primitive reflexes (Moro, grasp, and suck reflexes are present but may be exaggerated) 1
• No seizures occur in this stage 1
• Complete recovery within 3 days with minimal or no long-term neurodevelopmental impairment 1
• Traditionally excluded from therapeutic hypothermia trials, though emerging evidence suggests these infants may have higher risk than previously recognized 3

Moderate HIE (Stage 2)

• Lethargy or obtundation as the predominant level of consciousness 1, 2
• Hypotonia (decreased muscle tone and stretch) with diminished primitive reflexes 1
• Seizures frequently occur within the first 24-48 hours of life, as 90% of HIE-related seizures manifest within the first 2 days 4
• Therapeutic hypothermia reduces death or major disability by 33% (RR 0.67; 95% CI 0.56-0.81) in this population 5
• Without treatment, 48% develop permanent neurological deficits including cerebral palsy, epilepsy, and cognitive impairment 1, 6

Severe HIE (Stage 3)

• Stupor or coma with absent response to stimulation 1, 2
• Severe hypotonia or flaccidity with absent primitive reflexes (no Moro, grasp, or suck) 1
• Frequent and prolonged seizures that may be refractory to treatment 1, 2
• Brainstem dysfunction manifesting as abnormal pupillary responses, absent gag reflex, and irregular respirations requiring mechanical ventilation 2
• Therapeutic hypothermia provides a 17% reduction in death or major disability (RR 0.83; 95% CI 0.74-0.92), though outcomes remain poor 5
• Mortality reaches 27% even with hypothermia treatment (compared to 35% without), and 27% of survivors have permanent neurological disability 7, 1

Temporal Evolution and Pathophysiology

Primary Phase (First 6 Hours)

• Initial energy failure occurs immediately after the hypoxic-ischemic insult with depletion of ATP and phosphocreatine 2, 8
• Cytotoxic edema develops from failure of cellular ion pumps 2
• This represents the critical therapeutic window for hypothermia initiation, as efficacy decreases significantly after 6 hours 5, 7

Latent Phase (6-24 Hours)

• Partial recovery of oxidative metabolism creates a deceptive period of apparent stabilization 2, 8
• Cellular repair mechanisms activate but may be insufficient to prevent secondary injury 2

Secondary Phase (24-72 Hours)

• Secondary energy failure occurs with renewed mitochondrial dysfunction, excitotoxicity, and apoptosis 2, 8
• Seizures peak during this period, with 90% occurring within the first 48 hours 4
• Therapeutic hypothermia targets this phase by reducing metabolic demand and inflammatory cascades 2

Tertiary Phase (Days to Months)

• Chronic inflammation and gliosis persist if brain injury continues 2
• Reduced neural plasticity and ongoing neuronal loss characterize this phase 2
• Long-term neurodevelopmental sequelae emerge, including cerebral palsy (48% reduction with hypothermia), blindness (52% reduction), and deafness (58% reduction) 5

Critical Clinical Pitfalls

• Do not rely solely on clinical staging without continuous video-EEG monitoring, as many seizures are subclinical and lack clinical correlation 4
• Do not delay hypothermia while awaiting MRI confirmation, as treatment must begin within 6 hours based on clinical criteria alone 5, 7
• Do not assume mild HIE is benign—recent evidence shows these infants may have significant risk of abnormal neurodevelopmental outcomes despite traditional exclusion from treatment protocols 3
• Ensure proper rewarming protocol at 0.5°C per hour over minimum 4 hours to prevent metabolic complications 5, 7