What are the most common direct causes of death in patients with hypoxic‑ischemic encephalopathy?

Causes of Death in Hypoxic-Ischemic Encephalopathy

The most common direct cause of death in patients with hypoxic-ischemic encephalopathy (HIE) is brain injury itself, specifically uncal herniation from cerebral edema and intracranial hypertension, which occurs in 65-75% of patients reaching grade IV coma and is uniformly fatal. 1

Primary Mechanisms of Death

Brain-Related Mortality

Brain injury accounts for approximately two-thirds of deaths in patients surviving to ICU admission after out-of-hospital cardiac arrest. 1 The specific mechanisms include:

• Cerebral edema with uncal herniation is the most serious complication and uniformly fatal when it occurs 1
• The risk of cerebral edema increases dramatically with encephalopathy grade: 25-35% in grade III and 65-75% or more in grade IV coma 1
• Post-hypoxic encephalopathy with or without cerebral edema is the most common cause of death in hospitalized drowning victims (a specific form of HIE) 1
• Withdrawal of life-sustaining therapy due to poor neurological prognosis accounts for approximately 50% of deaths 1

Cardiovascular Mortality

• Cardiovascular failure accounts for most deaths in the first 3 days after cardiac arrest, while brain injury accounts for most later deaths 1
• Significant myocardial dysfunction is common after cardiac arrest, with multiorgan damage being a hallmark of HIE 2
• In ECMO patients with HIE, hypoxic-ischemic brain injury was the most common acute brain injury (44%), followed by intracranial hemorrhage (24%) 3

Temporal Pattern of Death

The timing of death follows a biphasic pattern:

• Early deaths (0-3 days): Predominantly cardiovascular failure and immediate complications of the hypoxic-ischemic insult 1
• Late deaths (>3 days): Predominantly brain injury, cerebral edema, and withdrawal of life-sustaining therapy based on poor neurological prognosis 1

Overall Prognosis

Only 25% of patients with HIE survive to hospital discharge, and survivors often have severe neurological or cognitive deficits. 4 Among those who do survive the acute phase:

• 40-50% of comatose patients admitted to ICUs after cardiac arrest ultimately survive 1
• The prognosis is extremely poor overall, with the majority of deaths attributable to the severity of brain injury 4

Critical Factors Determining Mortality

Risk factors associated with acute brain injury and death include:

• Hypertension history (p = 0.01) 3
• Higher day 1 lactate levels (10.0 vs 5.1; p = 0.02) 3
• Lower pH levels (7.09 vs 7.24; p = 0.027) in patients with hypoxic-ischemic brain injury 3
• Duration and severity of the initial hypoxic-ischemic insult 4

Common Pitfalls to Avoid

• Do not underestimate the risk of cerebral edema in grade III-IV encephalopathy—this is when mortality risk escalates dramatically from 25-35% to 65-75% 1
• Do not delay prognostication discussions—withdrawal of life-sustaining therapy is the most frequent cause of death (50%), emphasizing the importance of early, accurate prognostication 1
• Do not overlook cardiovascular dysfunction in the first 72 hours—this is when cardiovascular failure predominates as a cause of death 1