Therapeutic hypothermia
Encyclopedia
Therapeutic hypothermia, also known as protective hypothermia, is a medical treatment that lowers
a patient's body temperature in order to help reduce the risk of the ischemic injury to tissue
following a period of insufficient blood flow. Periods of insufficient blood flow may be due to cardiac arrest
or the occlusion of an artery by an embolism
, as occurs in the case of stroke
s. Therapeutic hypothermia may be induced by invasive means, in which a catheter is placed in the inferior vena cava
via the femoral vein
, or by non-invasive means, usually involving a chilled water blanket or torso vest and leg wraps in direct contact with the patient's skin. Studies have demonstrated that patients at risk for ischemic brain injuries have better outcomes if treated with the hypothermia protocol.
, the namesake of the Hippocratic Oath
and arguably the world’s first modern doctor, advocated the packing of wounded soldiers in snow and ice. Napoleonic surgeon Baron Dominque Larrey recorded that officers, who were kept closer to the fire, survived less often than the minimally pampered infantrymen. In modern times the first medical article concerning hypothermia was published in 1945.This study focused on the effects of hypothermia on patients suffering from severe head injury. In the 1950s hypothermia received its first medical application, being used in intracerebal aneurysm surgery to create a bloodless field. Most of the early research focused on the applications of deep hypothermia, defined as a body temperature between 20–25 °C (68–77 F). Such an extreme drop in body temperature brings with it a whole host of side effects, which made the use of deep hypothermia impractical in most clinical situations.
This period also saw sporadic investigation of more mild forms of hypothermia, with mild hypothermia being defined as a body temperature between 32–34 °C (89.6–93.2 F). In the 1950s Doctor Rosomoff demonstrated in dogs the positive effects of mild hypothermia after brain ischemia and traumatic brain injury. In the 1980s further animal studies indicated the ability of mild hypothermia to act as a general neuroprotectant following a blockage of blood flow to the brain. In 1999, following a skiing accident Anna Bågenholm
's heart stopped for more than three hours and her body temperature dropped to 13.7C, prior to being resuscitated. Further to the animal studies and Anna Bågenholm's accident two landmark human studies were published simultaneously in 2002 by the New England Journal of Medicine
. Both studies, one occurring in Europe and the other in Australia, demonstrated the positive effects of mild hypothermia applied following cardiac arrest. Responding to this research, in 2003 the American Heart Association
(AHA) and the International Liaison Committee on Resuscitation (ILCOR) endorsed the use of therapeutic hypothermia following cardiac arrest. Currently, a growing percentage of hospitals around the world incorporate the AHA/ILCOR guidelines and include hypothermic therapies in their standard package of care for patients suffering from cardiac arrest. Some researchers go so far as to contend that hypothermia represents a better neuroprotectant following a blockage of blood to the brain than any known drug. Over this same period a particularly successful research effort showed that hypothermia is a highly effective treatment when applied to newborn infants following birth asphyxia. Meta-analysis of a number of large randomised controlled trials showed that hypothermia for 72 hours started within 6 hours of birth significantly increased the chance of survival without brain damage.
, cardiac arrest
, ischemic stroke, traumatic brain or spinal cord injury without fever, and neurogenic fever
following brain trauma
.
has been proven to improve outcomes for newborn infants affected by perinatal hypoxia-ischemia, hypoxic ischemic encephalopathy or birth asphyxia. Whole body or selective head cooling to 33–34 °C (91.4–93.2 F), begun within 6 hours of birth and continued for 72 hours significantly reduces mortality and reduces cerebral palsy and neurological deficits in survivors. The evidence and history of this treatment is given in more detail in the linked page Hypothermia therapy for neonatal encephalopathy
.
One report suggests that fewer than 10% of the 300,000 Americans who suffer cardiac arrest
each year survive "long enough to leave the hospital" despite increased use of such measures as "faster emergency squads, deployment of automated defibrillators at airports and other public places, and improvements in cardiopulmonary resuscitation
techniques." However, of 140 patients since 2006 treated at the Minneapolis Heart Institute, 52% have survived by using therapeutic hypothermia.
Current recommendations support use with VF presenting as the initial rhythm. Non-VF rhythms have not been fully studied although some studies show worsening outcomes when compared to non-cooled patients (6 vs 30%).
(ICP) after an ischemic stroke was found to be both safe and practical. In 2008, long-term hypothermia induced by low-dose hydrogen sulfide
, a weak, reversible inhibitor of oxidative phosphorylation
, was shown to reduce the extent of brain damage caused by ischemic stroke
in rats.
for patients suffering from either ischemic brain injury or brain trauma. Further, others have shown that patients presenting at the ICU with either brain trauma or ischemic brain injury in combination with a fever, have a 14% higher mortality rate than normothermic patients. Combating fever through the use of temperature dampening devices represents a critical aspect of care for stroke patients.
resulting from a drop in body temperature. For every one degree Celsius drop in body temperature, cellular metabolism slows by 5-7%. Accordingly, most early hypotheses suggested that hypothermia reduces the harmful effects of ischemia by decreasing the body’s need for oxygen. The initial emphasis on cellular metabolism explains why the early studies almost exclusively focused on the application of deep hypothermia, as these researchers believed that the therapeutic effects of hypothermia correlated directly with the extent of temperature decline.
More recent data suggests that even a modest reduction in temperature can function as a neuroprotectant, suggesting the possibility that hypothermia affects pathways that extend beyond a decrease in cellular metabolism. One plausible hypothesis centers around the series of reactions that occur following oxygen deprivation, particularly those concerning ion
homeostasis. In the special case of infants suffering perinatal asphyxia it appears that apoptosis
is a prominent cause of cell death and that hypothermia therapy for neonatal encephalopathy
interrupts the apoptotic pathway. In general, cell death is not directly caused by oxygen deprivation, but occurs indirectly as a result of the cascade of subsequent events. Cells need oxygen to create ATP
, a molecule used by cells to store energy, and cells need ATP to regulate intracellular ion levels. ATP is used to fuel both the importation of ions necessary for cellular function and the removal of ions that are harmful to cellular function. Without oxygen, cells cannot manufacture the necessary ATP to regulate ion levels and thus cannot prevent the intracellular environment from approaching the ion concentration of the outside environment. It is not oxygen deprivation itself that precipitates cell death, but rather without oxygen the cell can not make the ATP it needs to regulate ion concentrations and maintain homeostasis.
Notably, even a small drop in temperature encourages cell membrane
stability during periods of oxygen deprivation. For this reason, a drop in body temperature helps prevent an influx of unwanted ions during an ischemic insult. By making the cell membrane more impermeable, hypothermia helps prevent the cascade of reactions set off by oxygen deprivation. Even moderate dips in temperature strengthen the cellular membrane, helping to minimize any disruption to the cellular environment. It is by moderating the disruption of homeostasis caused by a blockage of blood flow that many now postulate results in hypothermia’s ability to minimize the trauma resultant from ischemic injuries.
Therapeutic hypothermia may also help to reduce reperfusion injury
, damage caused by oxidative stress
when the blood supply is restored to a tissue after a period of ischemia. Various inflammatory immune responses occur during reperfusion. These inflammatory responses cause increased intracranial pressure, which leads to cell injury and in some situations, cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effects of a patient’s inflammatory immune responses during reperfusion. The oxidation that occurs during reperfusion also increases free radical production. Since hypothermia reduces both intracranial pressure and free radical production, this might be yet another mechanism of action for hypothermia's therapeutic effect.
, and increased risk of electrolyte imbalance. The medical data suggest that these adverse events can be mitigated only if the proper protocols are followed. Medical professionals must avoid overshooting the target temperature, as hypothermia’s adverse events increase in severity the lower a patient’s body temperature. The accepted medical standards assert that a patient’s temperature should not fall below a threshold of 32 °C (89.6 °F).
Prior to the induction of therapeutic hypothermia, pharmacological agents to control shivering must be administered. When body temperature drops below a certain threshold—typically around 36 °C (96.8 °F)--patients will begin to shiver. It appears that regardless of the technique used to induce hypothermia, patients begin to shiver when temperature drops below this threshold. The drugs most commonly employed to prevent shivering in therapeutic hypothermia are desflurane
and pethidine
(meperidine or Demerol).
Clinicians should rewarm patients slowly and steadily in order to avoid harmful spikes in intracranial pressure. A patient's rewarming should occur at a rate of a minimum of 0.17 °C/hr (0.31 °F/hr) in order to avoid injury, or a rewarming phase of at least 24 hours from 33–37 °C (91.4–98.6 F). In fact, most deaths caused by therapeutic hypothermia occurred during the rewarming phase of the procedure, deaths that could have been easily avoided by slow and precise rewarming.
Adverse events associated with this invasive technique include bleeding, infection, vascular puncture, and deep vein thrombosis
(DVT). Infection caused by cooling catheters is particularly harmful, as resuscitated patients are highly vulnerable to the complications associated with infections. Bleeding too represents a significant danger to patients, due to a decreased clotting threshold caused by hypothermia. The risk of deep vein thrombosis might be the most pressing medical complication. One study (Simosa et al.) found that incidents of deep vein thrombosis increased by 33% if a patient’s catheter was kept active for 4 days or less and 75% if their catheter was left attached for 4 days or more.
However, it is important to note that in the Simosa et al. study, the authors admit that it was a retrospective study of 11 patients (1 patient was excluded because she had a DVT prior to the study), and that all patients were predisposed to DVTs because of prolonged immobilization and failure to prophylactically anticoagulate the patients. The authors also admitted that they left the catheters in for 5–15 days, well past the four day maximum recommended by the manufacturer.
Deep vein thrombosis can be characterized as a medical event whereby a blood clot forms in a deep vein, usually the femoral vein. This condition turns deadly when the clot travels to the lung
s and causes a pulmonary embolism
. Another potential problem with cooling catheters is the potential to block doctors' access to the femoral vein, which is a site normally used for a variety of other necessary medical procedures, including angiography of the venous system and the right side of the heart. However, most cooling catheters are triple lumen catheters, and the majority of post-arrest patients will require central venous access. Unlike non-invasive methods, which can be administered by nurses, the insertion of cooling catheters must be performed by a physician fully trained and familiar with the procedure. The time delay between identifying a patient who might benefit from the procedure and the arrival of an interventional radiologist or other physician to perform the insertion may minimze some of the benefit of invasive methods' more rapid cooling.
Water blankets possess several undesirable qualities. They are susceptible to leaking, which may represent an electrical hazard since they are operated in close proximity to electrically powered medical equipment. The Food and Drug Administration also has reported several cases of external cooling blankets causing significant burns to the skin of patients. Other problems with external cooling include overshoot of temperature (20% of patients will have overshoot), slower induction time versus internal cooling, increased compensatory response, decreased patient access, and discontinuation of cooling for invasive procedures such as the cardiac catheterization
If therapy with water blankets is given alongside two litres of cold intravenous saline, patients can be cooled to 33 °C (91.4 °F) in 65 minutes. Most machines now come with core temperature probes. When inserted into the rectum
of the patient, the core body temperature is monitored and constant feedback to the machine allows changes in the water blanket to achieve the desired set temperature. In the past some of the models of cooling machines have produced an overshoot in the target temperature and cooled patients to levels below 32 °C (89.6 °F), resulting in increased adverse events. They have also rewarmed patients at too quick a rate, leading to spikes in intracranial pressure. Some of the new models have more sophisticated software that attempt to prevent this overshoot by utilizing warmer water when the target temperature is close when cooling, preventing any overshoot. Some of the new machines now also have 3 rates of cooling and warming, a rewarming rate with one of these machines allows a patient to be rewarmed at a very slow rate of just 0.17°C (0.31°F) an hour in the automatic mode, allowing rewarming from 33–37 °C (91.4–98.6 F) over 24 hours.
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
a patient's body temperature in order to help reduce the risk of the ischemic injury to tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
following a period of insufficient blood flow. Periods of insufficient blood flow may be due to cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
or the occlusion of an artery by an embolism
Embolism
In medicine, an embolism is the event of lodging of an embolus into a narrow capillary vessel of an arterial bed which causes a blockage in a distant part of the body.Embolization is...
, as occurs in the case of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s. Therapeutic hypothermia may be induced by invasive means, in which a catheter is placed in the inferior vena cava
Inferior vena cava
The inferior vena cava , also known as the posterior vena cava, is the large vein that carries de-oxygenated blood from the lower half of the body into the right atrium of the heart....
via the femoral vein
Femoral vein
In the human body, the femoral vein is a blood vessel that accompanies the femoral artery in the femoral sheath. It begins at the adductor canal and is a continuation of the popliteal vein...
, or by non-invasive means, usually involving a chilled water blanket or torso vest and leg wraps in direct contact with the patient's skin. Studies have demonstrated that patients at risk for ischemic brain injuries have better outcomes if treated with the hypothermia protocol.
History
Hypothermia has been applied therapeutically since antiquity. The Greek physician HippocratesHippocrates
Hippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...
, the namesake of the Hippocratic Oath
Hippocratic Oath
The Hippocratic Oath is an oath historically taken by physicians and other healthcare professionals swearing to practice medicine ethically. It is widely believed to have been written by Hippocrates, often regarded as the father of western medicine, or by one of his students. The oath is written in...
and arguably the world’s first modern doctor, advocated the packing of wounded soldiers in snow and ice. Napoleonic surgeon Baron Dominque Larrey recorded that officers, who were kept closer to the fire, survived less often than the minimally pampered infantrymen. In modern times the first medical article concerning hypothermia was published in 1945.This study focused on the effects of hypothermia on patients suffering from severe head injury. In the 1950s hypothermia received its first medical application, being used in intracerebal aneurysm surgery to create a bloodless field. Most of the early research focused on the applications of deep hypothermia, defined as a body temperature between 20–25 °C (68–77 F). Such an extreme drop in body temperature brings with it a whole host of side effects, which made the use of deep hypothermia impractical in most clinical situations.
This period also saw sporadic investigation of more mild forms of hypothermia, with mild hypothermia being defined as a body temperature between 32–34 °C (89.6–93.2 F). In the 1950s Doctor Rosomoff demonstrated in dogs the positive effects of mild hypothermia after brain ischemia and traumatic brain injury. In the 1980s further animal studies indicated the ability of mild hypothermia to act as a general neuroprotectant following a blockage of blood flow to the brain. In 1999, following a skiing accident Anna Bågenholm
Anna Bågenholm
Anna Elisabeth Johansson Bågenholm is a Swedish radiologist from Vänersborg, who survived after a skiing accident in 1999 left her trapped under a layer of ice for 80 minutes in freezing water...
's heart stopped for more than three hours and her body temperature dropped to 13.7C, prior to being resuscitated. Further to the animal studies and Anna Bågenholm's accident two landmark human studies were published simultaneously in 2002 by the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
. Both studies, one occurring in Europe and the other in Australia, demonstrated the positive effects of mild hypothermia applied following cardiac arrest. Responding to this research, in 2003 the American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
(AHA) and the International Liaison Committee on Resuscitation (ILCOR) endorsed the use of therapeutic hypothermia following cardiac arrest. Currently, a growing percentage of hospitals around the world incorporate the AHA/ILCOR guidelines and include hypothermic therapies in their standard package of care for patients suffering from cardiac arrest. Some researchers go so far as to contend that hypothermia represents a better neuroprotectant following a blockage of blood to the brain than any known drug. Over this same period a particularly successful research effort showed that hypothermia is a highly effective treatment when applied to newborn infants following birth asphyxia. Meta-analysis of a number of large randomised controlled trials showed that hypothermia for 72 hours started within 6 hours of birth significantly increased the chance of survival without brain damage.
Medical uses
The types of medical events hypothermic therapies may effectively treat fall into five primary categories: hypothermia therapy for neonatal encephalopathyHypothermia therapy for neonatal encephalopathy
Brain hypothermia, induced by cooling a baby to around 33°C for three days after birth, is a treatment for birth asphyxia. It has recently been proven to be the only medical intervention which reduces brain damage, and improves an infant's chance of normal survival...
, cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
, ischemic stroke, traumatic brain or spinal cord injury without fever, and neurogenic fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
following brain trauma
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
.
Hypothermia therapy for neonatal encephalopathy
Hypothermia therapy for neonatal encephalopathyHypothermia therapy for neonatal encephalopathy
Brain hypothermia, induced by cooling a baby to around 33°C for three days after birth, is a treatment for birth asphyxia. It has recently been proven to be the only medical intervention which reduces brain damage, and improves an infant's chance of normal survival...
has been proven to improve outcomes for newborn infants affected by perinatal hypoxia-ischemia, hypoxic ischemic encephalopathy or birth asphyxia. Whole body or selective head cooling to 33–34 °C (91.4–93.2 F), begun within 6 hours of birth and continued for 72 hours significantly reduces mortality and reduces cerebral palsy and neurological deficits in survivors. The evidence and history of this treatment is given in more detail in the linked page Hypothermia therapy for neonatal encephalopathy
Hypothermia therapy for neonatal encephalopathy
Brain hypothermia, induced by cooling a baby to around 33°C for three days after birth, is a treatment for birth asphyxia. It has recently been proven to be the only medical intervention which reduces brain damage, and improves an infant's chance of normal survival...
.
Cardiac arrest
The data concerning hypothermia’s neuroprotectant qualities following cardiac arrest can be best summarized by two studies published in the New England Journal of Medicine. The first of these studies conducted in Europe focused on people who were resuscitated 5–15 minutes after collapse. Patients participating in this study experienced spontaneous return of circulation (ROSC) after a median time of 22 minutes (normothermia group) and 21 minutes (hypothermia group). Hypothermia was initiated within 105 minutes after ROSC. Subjects were then cooled over a 24 hour period, with a target temperature of 32–34 °C (89.6–93.2 F). More than half (55%) of the 137 patients in the hypothermia group experienced favorable outcomes, compared with only 39% in the group that received standard care following resuscitation. Notably, complications between the two groups did not differ substantially. This data was supported by another similarly run study that took place simultaneously in Australia. In this study 49% of the patients treated with hypothermia following cardiac arrest experienced good outcomes, compared to only 26% of those who received standard care.One report suggests that fewer than 10% of the 300,000 Americans who suffer cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
each year survive "long enough to leave the hospital" despite increased use of such measures as "faster emergency squads, deployment of automated defibrillators at airports and other public places, and improvements in cardiopulmonary resuscitation
Cardiopulmonary resuscitation
Cardiopulmonary resuscitation is an emergency procedure which is performed in an effort to manually preserve intact brain function until further measures are taken to restore spontaneous blood circulation and breathing in a person in cardiac arrest. It is indicated in those who are unresponsive...
techniques." However, of 140 patients since 2006 treated at the Minneapolis Heart Institute, 52% have survived by using therapeutic hypothermia.
Current recommendations support use with VF presenting as the initial rhythm. Non-VF rhythms have not been fully studied although some studies show worsening outcomes when compared to non-cooled patients (6 vs 30%).
Stroke
Most of the data concerning hypothermia’s effectiveness in treating stroke is limited to animal studies. There is currently no evidence supporting therapeutic hypothermia use in humans and clinical trials have not been completed. These studies have focused primarily on ischemic stroke as opposed to hemorrhagic stroke, as hypothermia is associated with a lower clotting threshold. In these animal studies, hypothermia represented an effective neuroprotectant. The use of hypothermia to control intracranial pressureIntracranial pressure
Intracranial pressure is the pressure inside the skull and thus in the brain tissue and cerebrospinal fluid . The body has various mechanisms by which it keeps the ICP stable, with CSF pressures varying by about 1 mmHg in normal adults through shifts in production and absorption of CSF...
(ICP) after an ischemic stroke was found to be both safe and practical. In 2008, long-term hypothermia induced by low-dose hydrogen sulfide
Hydrogen sulfide
Hydrogen sulfide is the chemical compound with the formula . It is a colorless, very poisonous, flammable gas with the characteristic foul odor of expired eggs perceptible at concentrations as low as 0.00047 parts per million...
, a weak, reversible inhibitor of oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, was shown to reduce the extent of brain damage caused by ischemic stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
in rats.
Traumatic brain or spinal cord injury
Animal studies have shown the benefit of therapeutic hypothermia in traumatic CNS injuries. Clinical trials have shown mixed results with regards to the optimal temperature and delay of cooling. Achieving therapeutic temperatures of 33 °C (91.4 °F) is thought to prevent secondary neurological injuries after severe CNS trauma. An Australian and New Zealand government funded study has begun in 2010 in which 512 patients are being randomised to being cooled and gradually rewarmed after suffering a TBI, while the secondary group is randomised to standard therapy without cooling and gradual rewarming. The 'Polar Study' is being run by the Australian and New Zealand Intensive Care Society, Clinical Trials Group. A systematic review of randomised controlled trials suggests there is no evidence that hypothermia is beneficial in the treatment of head injury.Neurogenic fever
According to one study, elevated body temperature strongly correlates with an extended stay in the Intensive Care UnitIntensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...
for patients suffering from either ischemic brain injury or brain trauma. Further, others have shown that patients presenting at the ICU with either brain trauma or ischemic brain injury in combination with a fever, have a 14% higher mortality rate than normothermic patients. Combating fever through the use of temperature dampening devices represents a critical aspect of care for stroke patients.
Mechanism of neuroprotection
The earliest rationale for the effects of hypothermia as a neuroprotectant focused on the slowing of cellular metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
resulting from a drop in body temperature. For every one degree Celsius drop in body temperature, cellular metabolism slows by 5-7%. Accordingly, most early hypotheses suggested that hypothermia reduces the harmful effects of ischemia by decreasing the body’s need for oxygen. The initial emphasis on cellular metabolism explains why the early studies almost exclusively focused on the application of deep hypothermia, as these researchers believed that the therapeutic effects of hypothermia correlated directly with the extent of temperature decline.
More recent data suggests that even a modest reduction in temperature can function as a neuroprotectant, suggesting the possibility that hypothermia affects pathways that extend beyond a decrease in cellular metabolism. One plausible hypothesis centers around the series of reactions that occur following oxygen deprivation, particularly those concerning ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
homeostasis. In the special case of infants suffering perinatal asphyxia it appears that apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
is a prominent cause of cell death and that hypothermia therapy for neonatal encephalopathy
Hypothermia therapy for neonatal encephalopathy
Brain hypothermia, induced by cooling a baby to around 33°C for three days after birth, is a treatment for birth asphyxia. It has recently been proven to be the only medical intervention which reduces brain damage, and improves an infant's chance of normal survival...
interrupts the apoptotic pathway. In general, cell death is not directly caused by oxygen deprivation, but occurs indirectly as a result of the cascade of subsequent events. Cells need oxygen to create ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, a molecule used by cells to store energy, and cells need ATP to regulate intracellular ion levels. ATP is used to fuel both the importation of ions necessary for cellular function and the removal of ions that are harmful to cellular function. Without oxygen, cells cannot manufacture the necessary ATP to regulate ion levels and thus cannot prevent the intracellular environment from approaching the ion concentration of the outside environment. It is not oxygen deprivation itself that precipitates cell death, but rather without oxygen the cell can not make the ATP it needs to regulate ion concentrations and maintain homeostasis.
Notably, even a small drop in temperature encourages cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
stability during periods of oxygen deprivation. For this reason, a drop in body temperature helps prevent an influx of unwanted ions during an ischemic insult. By making the cell membrane more impermeable, hypothermia helps prevent the cascade of reactions set off by oxygen deprivation. Even moderate dips in temperature strengthen the cellular membrane, helping to minimize any disruption to the cellular environment. It is by moderating the disruption of homeostasis caused by a blockage of blood flow that many now postulate results in hypothermia’s ability to minimize the trauma resultant from ischemic injuries.
Therapeutic hypothermia may also help to reduce reperfusion injury
Reperfusion injury
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and...
, damage caused by oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
when the blood supply is restored to a tissue after a period of ischemia. Various inflammatory immune responses occur during reperfusion. These inflammatory responses cause increased intracranial pressure, which leads to cell injury and in some situations, cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effects of a patient’s inflammatory immune responses during reperfusion. The oxidation that occurs during reperfusion also increases free radical production. Since hypothermia reduces both intracranial pressure and free radical production, this might be yet another mechanism of action for hypothermia's therapeutic effect.
Administration of treatment
Therapeutic hypothermia should be initiated as soon as possible in patients facing possible ischemic injury as time moderates hypothermia’s effectiveness as a neuroprotectant. Much of the animal data suggests that the earlier hypothermia is induced the better the subject’s outcome. However, therapeutic hypothermia remains partially effective even when initiated as long as 6 hours after collapse. Patients entering a state of induced hypothermia should be closely monitored. Clinicians must remain watchful of the adverse events associated with hypothermia. These adverse events include: arrhythmia, decreased clotting threshold, increased risk of infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, and increased risk of electrolyte imbalance. The medical data suggest that these adverse events can be mitigated only if the proper protocols are followed. Medical professionals must avoid overshooting the target temperature, as hypothermia’s adverse events increase in severity the lower a patient’s body temperature. The accepted medical standards assert that a patient’s temperature should not fall below a threshold of 32 °C (89.6 °F).
Prior to the induction of therapeutic hypothermia, pharmacological agents to control shivering must be administered. When body temperature drops below a certain threshold—typically around 36 °C (96.8 °F)--patients will begin to shiver. It appears that regardless of the technique used to induce hypothermia, patients begin to shiver when temperature drops below this threshold. The drugs most commonly employed to prevent shivering in therapeutic hypothermia are desflurane
Desflurane
Desflurane is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane and isoflurane, it is a racemic mixture of and optical isomers...
and pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
(meperidine or Demerol).
Clinicians should rewarm patients slowly and steadily in order to avoid harmful spikes in intracranial pressure. A patient's rewarming should occur at a rate of a minimum of 0.17 °C/hr (0.31 °F/hr) in order to avoid injury, or a rewarming phase of at least 24 hours from 33–37 °C (91.4–98.6 F). In fact, most deaths caused by therapeutic hypothermia occurred during the rewarming phase of the procedure, deaths that could have been easily avoided by slow and precise rewarming.
Methods
The medical methods through which hypothermia is induced break down into two categories: invasive and non-invasive.Cooling catheters
Cooling catheters are inserted into the femoral vein. Cooled saline solution is circulated through either a metal coated tube or a balloon. The saline cools the patient’s whole body by lowering the temperature of a patient’s blood. Catheters reduce temperature at rates ranging from 1.5 C-change - 2 C-change per hour. Through the use of the sophisticated control unit, catheters can bring body temperature to within 0.1 C-change of the target level. This level of accuracy allows doctors to avoid many of the pitfalls associated with excessively deep levels of hypothermia. Furthermore, catheters can raise temperature at steady rate, which helps to avoid harmful rises in intracranial pressure. Catheter-based temperature management has been shown to provide faster, more precise and more efficient cooling compared to all external methods, especially conventional. A number of studies in critically ill patients have demonstrated that therapeutic hypothermia via catheter is safe and effective in the treatment of a wide variety of patient populations.Adverse events associated with this invasive technique include bleeding, infection, vascular puncture, and deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
(DVT). Infection caused by cooling catheters is particularly harmful, as resuscitated patients are highly vulnerable to the complications associated with infections. Bleeding too represents a significant danger to patients, due to a decreased clotting threshold caused by hypothermia. The risk of deep vein thrombosis might be the most pressing medical complication. One study (Simosa et al.) found that incidents of deep vein thrombosis increased by 33% if a patient’s catheter was kept active for 4 days or less and 75% if their catheter was left attached for 4 days or more.
However, it is important to note that in the Simosa et al. study, the authors admit that it was a retrospective study of 11 patients (1 patient was excluded because she had a DVT prior to the study), and that all patients were predisposed to DVTs because of prolonged immobilization and failure to prophylactically anticoagulate the patients. The authors also admitted that they left the catheters in for 5–15 days, well past the four day maximum recommended by the manufacturer.
Deep vein thrombosis can be characterized as a medical event whereby a blood clot forms in a deep vein, usually the femoral vein. This condition turns deadly when the clot travels to the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s and causes a pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
. Another potential problem with cooling catheters is the potential to block doctors' access to the femoral vein, which is a site normally used for a variety of other necessary medical procedures, including angiography of the venous system and the right side of the heart. However, most cooling catheters are triple lumen catheters, and the majority of post-arrest patients will require central venous access. Unlike non-invasive methods, which can be administered by nurses, the insertion of cooling catheters must be performed by a physician fully trained and familiar with the procedure. The time delay between identifying a patient who might benefit from the procedure and the arrival of an interventional radiologist or other physician to perform the insertion may minimze some of the benefit of invasive methods' more rapid cooling.
Water blankets, torso vest, leg wraps
In these technologies, cold water circulates through a blanket, or torso wraparound vest and leg wraps. To lower temperature with optimal speed, medical professionals must cover 70% of a patient’s surface area with water blankets. Although this technique of temperature management dates back to the 1950s, it still remains in use today. The treatment also represents the most well studied means of controlling body temperature. Water blankets lower a patient’s temperature exclusively by cooling a patient’s skin and accordingly require no clinician performed invasive procedures.Water blankets possess several undesirable qualities. They are susceptible to leaking, which may represent an electrical hazard since they are operated in close proximity to electrically powered medical equipment. The Food and Drug Administration also has reported several cases of external cooling blankets causing significant burns to the skin of patients. Other problems with external cooling include overshoot of temperature (20% of patients will have overshoot), slower induction time versus internal cooling, increased compensatory response, decreased patient access, and discontinuation of cooling for invasive procedures such as the cardiac catheterization
If therapy with water blankets is given alongside two litres of cold intravenous saline, patients can be cooled to 33 °C (91.4 °F) in 65 minutes. Most machines now come with core temperature probes. When inserted into the rectum
Rectum
The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long...
of the patient, the core body temperature is monitored and constant feedback to the machine allows changes in the water blanket to achieve the desired set temperature. In the past some of the models of cooling machines have produced an overshoot in the target temperature and cooled patients to levels below 32 °C (89.6 °F), resulting in increased adverse events. They have also rewarmed patients at too quick a rate, leading to spikes in intracranial pressure. Some of the new models have more sophisticated software that attempt to prevent this overshoot by utilizing warmer water when the target temperature is close when cooling, preventing any overshoot. Some of the new machines now also have 3 rates of cooling and warming, a rewarming rate with one of these machines allows a patient to be rewarmed at a very slow rate of just 0.17°C (0.31°F) an hour in the automatic mode, allowing rewarming from 33–37 °C (91.4–98.6 F) over 24 hours.