Hypothermic Neuroprotection

Dept of Physiology, The University of Auckland, New Zealand.
NeuroRx 05/2006; 3(2):154-69. DOI: 10.1016/j.nurx.2006.01.007
Source: PubMed


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.

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Available from: Marianne Thoresen
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    • "Thus, maintaining mitochondria intact after severe HI is crucial in promoting neuroprotection. There is compelling evidence that hypothermia started in the latent phase must be continued for 48 h or more to maintain improved recovery of mitochondrial membrane potential and respiration (Gong et al., 2013), and prevent cell death (Gunn and Thoresen, 2006). "
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    ABSTRACT: Acute post-asphyxial encephalopathy occurring around the time of birth remains a major cause of death and disability. The recent seminal insight that allows active neuroprotective treatment is that even after profound asphyxia (the "primary" phase), many brain cells show initial recovery from the insult during a short "latent" phase, typically lasting approximately 6 h, only to die hours to days later after a "secondary" deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Although many of these secondary processes are potentially injurious, they appear to be primarily epiphenomena of the "execution" phase of cell death. Animal and human studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible but before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, has been associated with potent, long-lasting neuroprotection. Recent clinical trials show that while therapeutic hypothermia significantly reduces morbidity and mortality, many babies still die or survive with disabilities. The challenge for the future is to find ways of improving the effectiveness of treatment. In this review, we will dissect the known mechanisms of hypoxic-ischemic brain injury in relation to the known effects of hypothermic neuroprotection.
    Full-text · Article · Feb 2014 · Frontiers in Neuroscience
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    • "However, cerebral oxidative metabolism may deteriorate in the hours following an asphyxic period, and this phase may last for many days. This secondary energy failure can be marked by the onset of seizures, further oedema, accumulation of excitotoxins and cytotoxic inflammatory substances, failure of cerebral mitochondrial activity and ultimately cell death (Gunn and Thoresen, 2006). The duration and severity of this second, delayed wave of cerebral compromise is closely associated with the degree of neurodevelopmental compromise at 1 year of age (Roth et al., 1992). "
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    ABSTRACT: In the research, clinical and wider community there is great interest in the use of stem cells to reduce the progression, or indeed repair brain injury. Perinatal brain injury may result from acute or chronic insults sustained during fetal development, during the process of birth, or in the newborn period. The most readily identifiable outcome of perinatal brain injury is cerebral palsy, however this is just one consequence in a spectrum of mild to severe neurological deficits. As we review, there are now clinical trials taking place worldwide targeting cerebral palsy with stem cell therapies. It will likely be many years before strong evidence-based results emerge from these trials. With such trials underway, it is both appropriate and timely to address the physiological basis for the efficacy of stem-like cells in preventing damage to, or regenerating, the newborn brain. Appropriate experimental animal models are best placed to deliver this information. Cell availability, the potential for immunological rejection, ethical and logistical considerations, together with the propensity for native cells to form terratomas, make it unlikely that embryonic or fetal stem cells will be practical. Fortunately, these issues do not pertain to the use of human amnion epithelial cells (hAECs), or umbilical cord blood (UCB) stem cells that are readily and economically obtained from the placenta and umbilical cord discarded at birth. These cells have the potential for transplantation to the newborn where brain injury is diagnosed or even suspected. We will explore the novel characteristics of hAECs and undifferentiated UCB cells, as well as UCB-derived endothelial progenitor cells and mesenchymal stem cells, and how immunomodulation and anti-inflammatory properties are principal mechanisms of action that are common to these cells, and which in turn may ameliorate the cerebral hypoxia and inflammation that are final pathways in the pathogenesis of perinatal brain injury.
    Full-text · Article · Oct 2013 · Frontiers in Neuroscience
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    • "Although dexamethasone is a potent anti-inflammatory agent, there was no effect on microglial induction by day 7 [11]. As previously reviewed [27], even after surprisingly severe insults there can be transient normalization of oxidative metabolism in a critical ‘latent’ phase when cell survival can be modulated, followed by a secondary phase of progressive cell death hours to days after reperfusion. Loss of neural suppression in the latent phase can increase neural injury [14], [15]. "
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    ABSTRACT: Maternal glucocorticoid treatment for threatened premature delivery dramatically improves neonatal survival and short-term morbidity; however, its effects on neurodevelopmental outcome are variable. We investigated the effect of maternal glucocorticoid exposure after acute asphyxia on injury in the preterm brain. Chronically instrumented singleton fetal sheep at 0.7 of gestation received asphyxia induced by complete umbilical cord occlusion for 25 minutes. 15 minutes after release of occlusion, ewes received a 3 ml i.m. injection of either dexamethasone (12 mg, n = 10) or saline (n = 10). Sheep were killed after 7 days recovery; survival of neurons in the hippocampus and basal ganglia, and oligodendrocytes in periventricular white matter were assessed using an unbiased stereological approach. Maternal dexamethasone after asphyxia was associated with more severe loss of neurons in the hippocampus (CA3 regions, 290±76 vs 484±98 neurons/mm(2), mean±SEM, P<0.05) and basal ganglia (putamen, 538±112 vs 814±34 neurons/mm(2), P<0.05) compared to asphyxia-saline, and with greater loss of both total (913±77 vs 1201±75/mm(2), P<0.05) and immature/mature myelinating oligodendrocytes in periventricular white matter (66±8 vs 114±12/mm(2), P<0.05, vs sham controls 165±10/mm(2), P<0.001). This was associated with transient hyperglycemia (peak 3.5±0.2 vs. 1.4±0.2 mmol/L at 6 h, P<0.05) and reduced suppression of EEG power in the first 24 h after occlusion (maximum -1.5±1.2 dB vs. -5.0±1.4 dB in saline controls, P<0.01), but later onset and fewer overt seizures. In preterm fetal sheep, exposure to maternal dexamethasone during recovery from asphyxia exacerbated brain damage.
    Full-text · Article · Oct 2013 · PLoS ONE
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