Hypothermic neuroprotection

Abstract

Summary:The possibility that hypothermia during or after resuscitation from asphyxia at birth, or cardiac arrest in adults, might reduce evolving damage has tantalized clinicians for a very long time. It is now known that severe hypoxia-ischemia may not necessarily cause immediate cell death, but can precipitate a complex biochemical cascade leading to the delayed neuronal loss. Clinically and experimentally, the key phases of injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. Studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Two large controlled trials, one of head cooling with mild hypothermia, and one of moderate whole body cooling have demonstrated that post resuscitation cooling is generally safe in intensive care, and reduces death or disability at 18 months of age after neonatal encephalopathy. These studies, however, show that only a subset of babies seemed to benefit. The challenge for the future is to find ways of improving the effectiveness of treatment.

Limited predictive value of early changes in EEG spectral power for neural injury after asphyxia in preterm fetal sheep

“…Two hours after release of occlusion, the metabolic and respiratory acidosis had resolved in both groups; 72 h after occlusion partial pressure of CO 2 and HCO 3 − were slightly lower in the 25-min group.…”

“…In the first 48 h after premature birth abnormal electroencephalogram (EEG) activity, including seizures, is common and is associated with adverse outcome (2). For potential trials of neuroprotection, it is essential to identify infants with a high risk of adverse outcome as early as possible in the first 6 h of life (3). Amplitude-integrated EEG is an easily applied bedside technology that at term can be used to identify high-risk infants after neonatal hypoxia-ischemia (4).…”

How Long is Too Long for Cerebral Cooling after Ischemia in Fetal Sheep?

“…1 In part, partial protection is likely related to the formidable clinical difficulties involved in starting hypothermia within the optimal window of opportunity. 5 A recent study found that asphyxiated infants cooled within 3 hours of birth had better motor outcomes than when hypothermia was started between 3 and 6 hours. 6 However, in a controlled trial, hypothermia was only started in 12% of infants within 4 hours of birth.…”

Cooling Combined with Immediate or Delayed Xenon Inhalation Provides Equivalent Long-Term Neuroprotection after Neonatal Hypoxia—Ischemia

“…Currently, hypothermia (HT) is the only intervention that improves neurologic outcome after HI injury showing promise both experimentally in the neonatal rats, pigs, and sheeps (Bona et al, 1998;Ginsberg et al, 1992;Gunn and Thoresen, 2006) and clinically in asphyxiated infants (Eicher et al, 2005;Gluckman et al, 2005;Shankaran et al, 2005) as well as in adults after out-of-hospital cardiac arrest (Bernard and Rosalion, 2008;Polderman, 2008;Zeiner et al, 2000). From the neonatal asphyxia studies, one in six children benefit from this treatment (Gluckman et al, 2005), and there is an urgent need to improve outcomes for affected infants who might be gained by adding other interventions.…”