Therapeutic Hypothermia for Hypoxic-Ischemic Brain Injury Is More Effective in Newborn Infants than in Older Patients: Review and Hypotheses

Posthypoxic therapeutic hypothermia has been tested in newborn infants, with seven randomized trials showing consistent evidence of reduction in death, cerebral palsy, and cognitive impairment at school age. In contrast, randomized trials of hypothermia after cardiac arrest in adults have not shown consistent evidence of lasting neurological protection. The apparently greater effectiveness of therapeutic hypothermia in newborns may be due to important biological and clinical differences. One such difference is that adults are heavily colonized with microbes, and many have active inflammatory processes at the time of arrest, but few newborns are heavily colonized or infected at the time of birth. Inflammation can interfere with hypothermia's neuroprotection. A second difference is that apoptosis is more commonly the pathway of neuronal death in newborns than in adults. Hypothermia inhibits apoptosis but not necrosis. Newborns have a larger endogenous supply of stem cells (which reduce apoptosis) than adults and this may favor regeneration and protection from hypothermia and regeneration. A third difference is that immature oligodendroglia are more sensitive to free radical attack then mature oligodendroglia. Hypothermia reduces free radical release. In addition, immature brain has increased N-methyl-D-aspartate receptor subunits compared with adults and hypothermia reduces excitotoxic amino acids. Adults suffering cardiac arrest often have comorbidities such as diabetes, hypertension, and atherosclerosis, which complicate recovery, but newborn infants rarely have comorbidities before asphyxia. Adult hypothermia treatment may have been too short as no trial has cooled for longer than 48 hours, some only 24 or 12 hours, but neonatal therapeutic hypothermia has routinely lasted 72 hours. We hypothesize that this combination of differences favors the effectiveness of therapeutic hypothermia in newborn infants compared with adults.