Mechanisms of hypothermic neuroprotection

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Summary

There is now compelling clinical evidence that prolonged, moderate cerebral hypothermia initiated within a few hours after severe hypoxia–ischemia and continued until resolution of the acute phase of delayed cell death can reduce subsequent neuronal loss and improve behavioral recovery in term infants and adults after cardiac arrest. Perhaps surprisingly, the specific mechanisms of hypothermic neuroprotection remain unclear, at least in part because hypothermia suppresses a broad range of potential injurious factors. In the present review we critically examine proposed mechanisms in relation to the known window of opportunity for effective protection with hypothermia. Better knowledge of the mechanisms of hypothermia is critical to help guide the rational development of future combination treatments to augment neuroprotection with hypothermia, and to identify those most likely to benefit from it.

Introduction

There is now compelling clinical evidence that prolonged, moderate cerebral hypothermia initiated within a few hours after severe hypoxia–ischemia and continued until resolution of the acute phase of delayed cell death can reduce subsequent neuronal loss and improve behavioral recovery in term infants and adults after cardiac arrest.1, 2, 3 The specific mechanisms of this protection remain unclear. In part, paradoxically this reflects the range of potentially deleterious mechanisms that are suppressed, making it difficult to distinguish between changes during cooling that are critical to benefit, indifferent or perhaps even deleterious – but balanced by other, beneficial, effects. In some ways this may seem to be moot given that hypothermia has proved itself in clinical practice. However, the protective effects of hypothermia are incomplete, and many children continue to die of neural injury or survive with handicap with current hypothermia protocols.3 Better knowledge of the key therapeutic targets of cooling will help to rationally improve protection using hypothermia, and will be central to developing innovative combination therapies to augment the protective effects of hypothermia alone.4 In the present review we will critically assess the multiple effects of hypothermia in relation to the known window of opportunity to start cooling after severe hypoxia–ischemia.5

Section snippets

Hypoxic–ischemic (HI) injury evolves

The seminal insight that underpinned development of therapeutic hypothermia was that hypoxic–ischemic encephalopathy (HIE) is not a single ‘event’ but is rather an evolving process.6 We now know that although neurons may die during the actual ischemic or asphyxial event (the ‘primary’ phase, as shown schematically in Fig. 1), many neurons initially recover at least partially from the primary insult in a ‘latent’ phase, only to die many hours or even days later (secondary or delayed cell death).

What can we learn from the window of opportunity for hypothermia?

Although we do not know exactly when the series of events leading to final cell death and dissolution becomes irreversible, there is overwhelming evidence that the early recovery (latent) phase, before the start of the secondary deterioration, represents the effective window of opportunity for initiation of post-insult cooling. For example, in the near-term fetal sheep, moderate hypothermia induced 90 min after reperfusion from a severe episode of cerebral ischemia, in the early latent phase,

Metabolic inhibition in the primary phase and reperfusion

The best-known feature of hypothermia is the associated graded reduction in cerebral metabolism of about 5% for every degree of temperature reduction.21, 22 Cooling during hypoxia–ischemia, for example, is partially protective through delaying the onset of anoxic cell depolarization. However, the protective effects of hypothermia even in this phase are not simply due to reduced metabolism, since mild cooling disproportionately improves outcome even when the absolute duration of depolarization

Conclusions

Suppression of cerebral metabolism has historically been regarded as the primary mechanism of protection. It is now clear that the mechanisms underlying hypothermic neuroprotection are multifactorial. Key potential mechanisms in the latent phase that have been shown to be suppressed by hypothermia include programmed cell death (‘apoptosis’), inflammation and the extrinsic cell death pathway, and abnormal receptor activity. It is likely that it is the intracytoplasmic, ‘downstream’ effects of

Conflict of interest statement

None declared.

Funding sources

This work was supported by grants from the Health Research Council of New Zealand, the March of Dimes Birth Defects, the Auckland Medical Research Foundation and Lottery Health Grants Board New Zealand. Paul Drury is supported by the New Zealand Neurological Foundation W&B Miller Doctoral Scholarship.

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