Table 1 Possible mechanisms underlying the beneficial effects of hypothermia

Prevention of apoptosis^a

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 homeostasis^b

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 production^b

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 injury^b

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 formation^a

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 metabolism^a

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 reactions^a

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 thermopooling^a

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 effects^a

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 seizures^a

Seizures after ischaemic injury or trauma are common and may add to injury. Hypothermia has been shown to mitigate epileptic activity.

Hours to days