Table 1.
Possible mechanisms underlying the beneficial effects of hypothermia
| Secondary injury | Explanation | Time frame after injury |
|---|---|---|
| Prevention of apoptosisa | Ischaemia can induce apoptosis and calpain-mediated proteolysis. This process can be prevented or reduced by hypothermia. | Hours to days to even weeks |
| Reduced mitochondrial dysfunction and improved energy homeostasisb | Mitochondrial dysfunction is a frequent occurrence in the hours to days after a period of ischaemia and may be linked to apoptosis. Hypothermia reduces metabolic demands and may improve mitochondrial function. | Hours to days |
| Reduction in free radical productionb | Production of free radicals (for example, superoxide, peroxynitrate, hydrogen peroxide, and hydroxyl radicals) is typical in ischaemia. Mild-moderate (30°C to 35°C) hypothermia is able to reduce this event. | Hours to days |
| Mitigation of reperfusion injuryb | Cascade of reactions following reperfusion, partly mediated by free radicals but with distinctive and various features. These are suppressed by hypothermia. | Hours to days |
| Reduced permeability of the blood-brain barrier and the vascular wall and reduced oedema formationa | Blood-brain barrier disruptions induced by trauma or ischaemia are moderated by hypothermia. The same effect occurs with vascular permeability and capillary leakage. | Hours to days |
| Reduced permeability of cellular membranes (including membranes of the cell nucleus)b | Decreased leakage of cellular membranes with associated improvements in cell function and cellular homeostasis, including decrease of intracellular acidosis and mitigation of DNA injury | Hours to days |
| Improved ion homeostasis | Ischaemia induces accumulation of excitatory neurotransmitters such as glutamate and prolonged excessive influx of Ca2+ into the cell. This activates numerous enzyme systems (kinases) and induces a state of hyperexcitability (exitotoxic cascade) that can be moderated by hypothermia. | First minutes to 72 hours |
| Reduced metabolisma | Cellular oxygen and glucose requirements are reduced by 5% to 8% per degree Celsius decrease in temperature. | Hours to days |
| Depression of the immune response and various potentially harmful pro-inflammatory reactionsa | Sustained destructive inflammatory reactions and secretion of pro-inflammatory cytokines after ischaemia can be blocked or mitigated by hypothermia. | First hour to 5 days |
| Reduction in cerebral thermopoolinga | Some areas in the brain have significantly higher temperatures than others. These differences can increase dramatically after injury with temperatures that are up to 2°C to 3°C higher in injured areas. Hyperthermia can increase the damage to the injured brain cells; this is mitigated by hypothermia. | Minutes to days |
| Anticoagulant effectsa | Microthrombus formation may add to brain injury after CPR. Anticoagulant effects of hypothermia may prevent thrombus formation. | Minutes to days |
| Suppression of epileptic activity and seizuresa | Seizures after ischaemic injury or trauma are common and may add to injury. Hypothermia has been shown to mitigate epileptic activity. | Hours to days |
This table summarises potential beneficial effects of hypothermia, based on experimental and clinical studies. aSome supporting evidence. bAnimal studies only. CPR, cardiopulmonary resuscitation.