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Introduction The use of therapeutic hypothermia is not a new concept; its implementation can be found in literature dating back to the ancient Egyptians. The idea that cooling a person can slow biological processes and subsequently death was first described by Hippocrates (circa 450 B.C), who advised packing wounded soldiers in the snow. In the early 1800s, during the French invasion of Russia, a battlefield surgeon noticed that wounded soldiers placed closer to campfires died sooner than those placed in colder bunks. During this period, cryoanalgesia was also used for amputations, and surgeons noticed that hypothermia not only acted as an analgesic but also slowed bleeding. Clinical interest in the application of therapeutic hypothermia began in the 1930s with case reports on drowning victims who were resuscitated successfully despite prolonged asphyxia.
[1] In 1943, Temple Fay published one of the first scientific papers relating to therapeutic hypothermia. Fay observed improved outcomes after traumatic brain injury (TBI) when temperatures were lowered from 38.3 to 32.7 degrees Celsius. In the 1950s and 1960s, clinical trials using very deep hypothermia were started but abandoned soon after due to adverse effects. In the 1990s, mild hypothermia was implemented in three cardiac arrest cases after successful resuscitation, and all three made a complete recovery without residual neurological damage.
[2] Therapeutic hypothermia began getting serious attention after two prospective randomized controlled trials published in the New England Journal of Medicine in 2002 found significant improvements in short and long-term survival, as well as neurological outcomes.
[3] Today, the term targeted temperature management (TTM) is used instead of therapeutic hypothermia. TTM can be used to prevent fever, maintain normothermia, or induce hypothermia.
Go to: Anatomy and Physiology
Thermoregulation Thermoregulation is the ability to maintain a steady-state core body temperature by balancing heat production and heat loss. Normal body temperature ranges from 36.1 to 37.2 degrees Celsius. The thermoregulatory center is located in the hypothalamus and constantly receives input from thermoreceptors located in the hypothalamus and the skin, which monitors the internal and external temperature. A decrease in temperature will activate various thermogenic and heat conserving responses.
The output from the hypothalamus is to the sweat glands, skin arterioles, and adrenal medulla via the sympathetic nervous system and skeletal muscles via motor neurons. Shivering thermogenesis is the primary means of heat production during hypothermia. Efferent motor nerve stimulation results in a rhythmic contraction of skeletal muscles, and since there is no work being performed, most of this energy is given off as heat. Sympathetic stimulation of superficial arteriole smooth muscle causes peripheral vasoconstriction, limiting convective heat loss and redirecting warm blood to the core. Sympathetic stimulation also causes epinephrine and norepinephrine release from the adrenal medulla, which increases basal heat production. During prolonged hypothermia, the hypothalamus stimulates thyroid hormone production from the anterior pituitary gland.
Mechanism of Action Targeted temperature management improves neurological outcomes and decreases mortality through multiple mechanisms that alter the cascade of deleterious metabolic, cellular, and molecular changes that occur following global ischemia. The three main temperature-dependent pathological processes that hypothermia acts on are ischemic brain injury, reperfusion injury, and secondary brain damage.
[4] Hypothermia decreases the metabolic rate by 5% to 7% per 1 C decrease in core body temperature.
[5] This is one of the main mechanisms underlying its protective effects since oxygen deprivation and the accumulation of lactate and other waste products of anaerobic metabolism are central to the progression of ischemic cerebral cell death. The accumulation of aspartate, glutamate, and other excitatory neurotransmitters also plays a significant role in neuronal death following cerebral ischemia. The severity of excitotoxicity and neuronal damage is proportional to the quantity of these neurotransmitters.
[6] In animal models, it was shown that the release of glutamate following global cerebral ischemia is temperature-dependent. A mild to moderate hypothermia is associated with the most profound reduction in glutamate levels compared to severe hypothermia and hyperthermia.
[7] Hypothermia decreases free radical production and suppresses the various inflammatory processes that occur following global ischemia and reperfusion.
Reperfusion causes a massive increase in the production of free radicals such as hydrogen peroxide, superoxide, nitric oxide, and hydroxyl radicals. The high levels overwhelm the defensive antioxidant mechanisms throughout the body and cause the peroxidation of lipids, proteins, and nucleic acids, which contribute to neuronal damage.
[8] One study using an in vitro model of cerebral ischemia found that the neuroprotective effects of hypothermia were associated with a significant reduction in nitric oxide and superoxide formation when temperatures were reduced to 31 to 33 C.
[9] The inflammatory response that follows reperfusion has both beneficial and detrimental effects, with some mediators being transiently neuroprotective. However, this exaggerated response may last up to 5 days, and persistently high levels of cytokines are destructive over this protracted time course. Hypothermia suppresses the inflammatory cascade and, in turn, prevents the exacerbation of cerebral injury by inflammation.