Applying therapeutic hypothermia (TH) for the purposes of neuroprotection, originally termed “hibernation,” started nearly 100 years ago. Because TH cooling systems have improved to the point where it is practical and safe for general application, interest in providing such treatment in conditions such as spinal cord injury, traumatic brain injury, stroke, and cardiac arrest has increased. This article reviews the mechanisms by which TH mitigates secondary neurologic injury, the clinical scenarios where TH is being applied, and reviews selected published studies using TH for central nervous system neuroprotection.
Key points
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Applying hypothermia for the purposes of neuroprotection started nearly 100 years ago, initially used to treat brain abscesses. Applied therapeutic hypothermia has evolved over the years and with modern techniques has become more practical to use.
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Therapeutic hypothermia has been used to provide neuroprotection and minimize tissue injury in several conditions. These conditions include but are not limited to spinal cord injury, traumatic brain injury, stroke, cardiac arrest, burn injury, and subarachnoid hemorrhage.
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Therapeutic hypothermia can help after spinal cord injury at both phases of injury—the primary phase that leads to direct spinal cord tissue damage and the secondary injury phase that leads to apoptosis and further spinal cord damage.
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Initial pilot studies suggest that applying therapeutic hypothermia might lead to improved functional outcome. However, larger multicenter trials are needed to prove these findings.
Introduction: history of hypothermia as a neuroprotectant
Applying hypothermia for the purposes of neuroprotection, originally termed “hibernation,” started nearly 100 years ago. Initially, the treatment was used in patients with intracranial disease from abscess and high fevers, which could lead to severe brain injury. As knowledge regarding neurotrauma has increased and revealed the complex pathophysiology of “secondary neural injury cascades,” interest in preventing such secondary damage using hypothermia (and preventing hyperthermia) re-emerged.
More recently, sophisticated cooling systems using thermocouples and feedback sensors have enabled precise and sustained core temperature regulation. These new systems have improved the safety of therapeutic hypothermia (TH) to the point that TH can be applied in a more practical manner. These advances have fueled further interest in hypothermia research, and neuroprotection treatment protocols have been developed for a wide variety of central nervous system pathologies, such as traumatic brain injury and spinal cord injury (SCI). Finally, with increased interest, new outcome studies have been started and results are being published that support TH as a safe and effective intervention.
The first publication on the use of TH in clinical neuroprotection was a case of traumatic brain injury in 1943. The process was termed “generalized refrigeration.” In 1951 and 1956, two additional case reports using TH, now termed “hibernation,” on patients with brain abscesses were published. Later studies focused on development of animal models and the idea that TH could reduce secondary damage after brain trauma by reducing cerebral ischemia. This idea was paramount in a study published in 1996 looking prospectively at effects of moderate hypothermia (core temperature 32.5°C–33.0°C for 24 hrs.) in 10 patients with severe closed head injury (Glasgow Coma Scale score <7). Seven of these patients made a good recovery. The effects seen were reductions in intracranial hypertension, cerebral oxygen consumption, and cerebral ischemia. Another study looked at 46 patients subjected to TH versus standardized treatment. They found the cooling group had reduced seizures and more patients recovering to a good recovery/moderate disability level versus remaining at a severe disability/vegetative/dead level.
However, concerns were also raised in these studies regarding potential hazards of the TH treatment. Although reversible with rewarming, increased levels of lipase and amylase were seen. Although a statistically significant increase in the partial tromboplastin time and prothrombin time, just out of the normal range, was found during and after rewarming, there were no clinically significant problems with bleeding. Increased rates of sepsis were not clinically significant.
Introduction: history of hypothermia as a neuroprotectant
Applying hypothermia for the purposes of neuroprotection, originally termed “hibernation,” started nearly 100 years ago. Initially, the treatment was used in patients with intracranial disease from abscess and high fevers, which could lead to severe brain injury. As knowledge regarding neurotrauma has increased and revealed the complex pathophysiology of “secondary neural injury cascades,” interest in preventing such secondary damage using hypothermia (and preventing hyperthermia) re-emerged.
More recently, sophisticated cooling systems using thermocouples and feedback sensors have enabled precise and sustained core temperature regulation. These new systems have improved the safety of therapeutic hypothermia (TH) to the point that TH can be applied in a more practical manner. These advances have fueled further interest in hypothermia research, and neuroprotection treatment protocols have been developed for a wide variety of central nervous system pathologies, such as traumatic brain injury and spinal cord injury (SCI). Finally, with increased interest, new outcome studies have been started and results are being published that support TH as a safe and effective intervention.
The first publication on the use of TH in clinical neuroprotection was a case of traumatic brain injury in 1943. The process was termed “generalized refrigeration.” In 1951 and 1956, two additional case reports using TH, now termed “hibernation,” on patients with brain abscesses were published. Later studies focused on development of animal models and the idea that TH could reduce secondary damage after brain trauma by reducing cerebral ischemia. This idea was paramount in a study published in 1996 looking prospectively at effects of moderate hypothermia (core temperature 32.5°C–33.0°C for 24 hrs.) in 10 patients with severe closed head injury (Glasgow Coma Scale score <7). Seven of these patients made a good recovery. The effects seen were reductions in intracranial hypertension, cerebral oxygen consumption, and cerebral ischemia. Another study looked at 46 patients subjected to TH versus standardized treatment. They found the cooling group had reduced seizures and more patients recovering to a good recovery/moderate disability level versus remaining at a severe disability/vegetative/dead level.
However, concerns were also raised in these studies regarding potential hazards of the TH treatment. Although reversible with rewarming, increased levels of lipase and amylase were seen. Although a statistically significant increase in the partial tromboplastin time and prothrombin time, just out of the normal range, was found during and after rewarming, there were no clinically significant problems with bleeding. Increased rates of sepsis were not clinically significant.
Core temperature regulation and hypothermia
TH is defined simply as the reduction of mean body core temperature to create some medical benefit. As warm-blooded mammals, humans regulate their core body temperature within a constant and narrow range and will not tolerate even short periods of hypothermia without engaging compensatory mechanisms. Hypothermia induces a variety of human responses to combat the hypothermia. These thermoregulatory mechanisms in humans have 2 components: behavioral and hypothalamic. External behavioral mechanisms to increase core temperature could include clothing, shelter, warm baths, or seeking environments with higher external temperature. In the intensive care unit (ICU) setting, patients often have no or limited control over these mechanisms.
Internal mechanisms of reducing hypothermia include arteriovenous shunting, inducted vasoconstriction, and shivering. The site of internal thermoregulation is considered to be the hypothalamus. Shivering is involuntary and creates muscle activity that increases metabolic heat production. In general, as the temperature drops less than 36.5°C, shivering begins. Shivering is initiated by regional vasoconstriction and becomes severe at core temperatures under 35.5°C. Nonshivering thermogenesis does occur in adults to combat hypothermia but plays a minor role compared with shivering. Shivering is a highly effective mechanism that increases metabolic heat production many times over, thus effectively raising core body temperature. Therefore, in any type of TH treatment, these compensatory mechanisms need to be curtailed, monitored, or modified.
Mechanism of neuroprotection in hypothermia
Metabolic Rate of Oxygen Consumed
The primary neuroprotective effect of hypothermia applied as therapy in acute neurotrauma is a reduction in the metabolic rate of oxygen consumed by the brain and spinal cord. By reducing the metabolic rate of oxygen consumption, the energy rate used might be reduced and glucose utilization might be improved. One measure of brain oxygen consumption places the magnitude of the reduction at 5% for each degree Celsius the body temperature is reduced.
Additionally, neurotrauma often causes a hypermetabolic state because the damaged neuronal tissue deals with repair and inflammatory mediators and free radicals that need to be “cleaned up.” As a result, lactate accumulates and alters pH, creating an acidotic state. Applied hypothermia, by slowing metabolism, has been thought to reduce interstitial lactate accumulation. For every degree (Celsius) that body temperature decreases, the pH increases by 0.016. Therefore, one theory is that TH protects from neurologic injury by reducing acidosis. Despite the “neatness” of this theory, other investigators have questioned the actual measurements and theory altogether.
Clinical application
Patient Evaluation Overview
The patients who are felt to be candidates for TH share certain aspects of their neurologic pathophysiology. The main unifying theme is that all patients have conditions exacerbated by secondary injury to the central nervous system. The mechanisms of such secondary injury include the following: Wallerian degeneration, vascular ischemia, ionic alterations, accumulation of neurotransmitters in a pathologic fashion, release of arachidonic acid and production of free radicals, formation of cytotoxic edema, hyperinflammatory response, and failure of adenosine triposphate–dependent processes. The protective effects of hypothermia are multimodal, involving suppression of the injury-induced immune response and inflammation reductions in vasogenic edema, inhibited polymorphonuclear chemotaxis, and reductions in gliosis. Hypothermia also reduces glutamate-mediated neurotoxicity and oxygen-free radical production. The classic conditions where these processes occur is traumatic brain injury and SCI; thus, these are 2 key problem areas where TH has been used to prevent secondary neuronal damage. Similarly, patients post-acute ischemic stroke and hemorrhagic stroke also fit the profile of those who could stand to benefit from TH.
In the setting of neurotrauma, when a new intervention is proposed, complete neurologic recovery is typically the main goal. However, with even small or incremental gains, these patients can often see tremendous functional improvements. For cervical SCI patients, incremental recovery of just one spinal level can translate into meaningful gains in the ability to perform self-care and functional tasks. For example, improving from a C6 SCI level to a C7 injury level can translate into the ability to propel a manual wheelchair or manipulate a urinary catheter. Improvement to a C8 level increases hand function to the point that an assistive device may not be needed. Therefore, interventions that allow even incremental neurologic improvement are important in this group of patients.
Another group where TH is being explored is in those with aneurysmal subarachnoid hemorrhage (SAH). TH has been used to treat the development of delayed cerebral ischemia, which can progress to cerebral infarction associated with poor outcomes. The focus of hypothermia treatment has been to reduce cerebral vasospasm, which is a delayed morphologic narrowing of cerebral arteries, occurring 4 to 10 days after SAH. TH has also been considered for patients with SAH during aneurysm surgery and immediately after rupture at initial presentation.
Cooling methodologies
The development of closed circuit intravascular cooling catheters has greatly enhanced the safety and efficacy of hypothermia delivery. External cooling through transcutaneous pads or suits can provide a noninvasive method for reducing body temperature, but precise control remains elusive and surface heat exchange devices can interfere with sensory neurologic testing ( Fig. 1 ).
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