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Table 1 Possible mechanisms underlying the beneficial effects of hypothermia

From: Bench-to-bedside review: Hypothermia in traumatic brain injury

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
  1. This table summarises potential beneficial effects of hypothermia, based on experimental and clinical studies. aSome supporting evidence. bAnimal studies only. CPR, cardiopulmonary resuscitation.