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Prolonged, mild hypothermia can improve outcomes from neonatal hypoxic-ischemic encephalopathy.
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Hypothermia during hypoxia-ischemia/reperfusion helps reduce anoxic depolarization, excitotoxicity, free radical exposure, and blood-brain barrier dysfunction.
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The latent phase of recovery, before delayed deterioration after hypoxia-ischemia, represents the window of opportunity for hypothermic neuroprotection.
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Key targets of delayed hypothermia in the latent phase include programmed cell death,
Mechanisms of Hypothermic Neuroprotection
Section snippets
Key points
The evolution of HI injury
The central insight that underpinned development of therapeutic hypothermia was that HI injury evolves over time. It is now known that although neurons may die during the actual ischemic or asphyxial event (the primary phase), many cells initially recover at least partially from the primary insult in a latent phase during which oxidative metabolism is at least partially restored despite continuing suppression of electroencephalogram activity.6, 7, 8 After moderate to severe injury, this is
What can be learned from the window of opportunity for hypothermia?
It is not completely clear when in this process evolving cell death becomes irreversible. Empirically, neuroprotection requires that hypothermia is started during the so-called latent or early recovery phase of transient restoration of cerebral oxidative metabolism, before secondary failure of oxidative metabolism, and continued until after resolution of the secondary phase.9, 13, 14, 15, 16 Thus, pragmatically, the window for treatment seems to close after the start of secondary energy
Mechanisms of action of hypothermia during HI
At the most fundamental level, injury requires a period of insufficient delivery of oxygen and substrates, such as glucose (and lactate in the fetus), such that neurons and glia cannot maintain homeostasis. As outlined in Fig. 1, the key mechanism of primary injury and death includes anoxic depolarization. Once the neuron’s supply of high-energy metabolites, such as ATP, can no longer be maintained during HI, the energy-dependent mechanisms of intracellular homeostasis including the Na+/K+
Cooling during reperfusion
After cerebral circulation and oxygenation are restored at the end of the insult, oxidative metabolism rapidly recovers in surviving cells and cytotoxic edema resolves over approximately 30 to 60 minutes.7, 19, 32 The key events outlined in Fig. 2 include (1) EAA levels rapidly fall in parallel with resolution of the acute cell swelling19; (2) the rapid restoration of tissue oxygenation is associated with a further rapid burst of NO and superoxide formation27; and (3) breakdown of the
Are excitotoxicity and free radicals relevant to postinsult cooling?
Both extracellular accumulation of EAAs and excess free radical production largely resolve during reperfusion after the insult and seem to have returned to normal values during the latent phase of recovery from HI.19, 21, 27, 36 In vitro, intrainsult hypothermia did not prevent intracellular accumulation of calcium during cardiac arrest in vivo,37 or during EAA exposure in vitro.38 Cooling initiated after wash-out of EAAs prevented neuronal degeneration in vitro.38
Thus, the ability of
Cell death mechanisms in the latent phase
Although the mechanisms of delayed cell loss are clearly multifactorial, there is increasing evidence that key pathways include activation of programmed cell death pathways, augmented by the inflammatory reaction and abnormal receptor activity as shown in Fig. 3. Programmed cell death is activated by (1) excessive calcium influx during and after HI,39 which promotes depolarization of the mitochondria (the intrinsic pathway of apoptosis),40 leading to permeabilization of the outer membrane of
Hypothermia in the secondary phase
There is compelling evidence that hypothermia started in the latent phase must be continued for 48 hours or more to achieve optimal neuroprotection.11 The precise reasons are unknown. The most likely explanation is that it is necessary to continue suppressing the programmed cell death and inflammatory pathways until normal homeostasis returns. However, it could in part reflect suppression of secondary events in this phase, including hyperperfusion, cytotoxic edema, and delayed seizures (Box 2,
Summary
The mechanisms underlying hypothermic neuroprotection are multifactorial, as summarized in Table 1. Suppression of excitotoxicity, oxidative stress, inflammation, intracellular signaling, and programmed cell death are all effects of hypothermia at different times. Critically, it is suppression of downstream events after anoxic depolarization and excitotoxity that seems to be critical to hypothermic neuroprotection. We speculate that the differential effects of mild hypothermia to suppress
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Disclosure/Conflict of Interest: All authors report no conflict of interest.
This work was supported by grants from the Health Research Council of New Zealand, the Auckland Medical Research Foundation, and Lottery Health Grants Board New Zealand. P.P. Drury was supported by the New Zealand Neurologic Foundation W&B Miller Doctoral Scholarship.