Therapeutic hypothermia

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 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 strokes. 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. Its use for cardiac arrest was called into question in November 2013 with findings that a temperature of 36 C results in the same outcomes as 33 C.

Medical uses
The types of medical events that hypothermic therapies may effectively treat fall into five primary categories: hypothermia therapy for neonatal encephalopathy, cardiac arrest, ischemic stroke, traumatic brain or spinal cord injury without fever, and neurogenic fever following brain trauma.

Cardiac arrest
It is questionable if cooling a person after cardiac arrest with return of spontaneous circulation (ROSC) but without return of consciousness improves neurological outcomes. Death rates in the hypothermia group were initially believed to be 35% lower. While associated with some complications these are generally mild. A November 2013 trial, however, called this idea into question with findings that a temperature of 36 C results in the same outcomes as 33 C. And a second trial looking at earlier versus later cooling found no difference.

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 was represented an effective neuroprotectant. The use of hypothermia to control intracranial pressure (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.

Traumatic brain or spinal cord injury
Animal studies have shown the benefit of therapeutic hypothermia in traumatic central nervous system (CNS) injuries. Clinical trials have shown mixed results with regards to the optimal temperature and delay of cooling. Achieving therapeutic temperatures of 33 C is thought to prevent secondary neurological injuries after severe CNS trauma. A systematic review of randomised controlled trials in traumatic brain injury (TBI) suggests there is no evidence that hypothermia is beneficial and further trials are needed. Two large randomised, controlled trials are in progress investigating the effect of early hypothermia (POLAR-RCT) and hypothermia for raised intracranial pressure (Eurotherm3235) on functional outcome at 6 months.

Neurogenic fever
According to one study, elevated body temperature strongly correlates with an extended stay in the Intensive Care Unit 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.

Neonatal encephalopathy
Hypothermia therapy for neonatal encephalopathy 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, 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.

Adverse effects
Therapeutic hypothermia increases the risk of pneumonia and sepsis but not the overall risk of infection.

Mechanism
The earliest rationale for the effects of hypothermia as a neuroprotectant focused on the slowing of cellular metabolism 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.

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 infection, 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. 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—patients may 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, and (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. 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 a femoral vein. Cooled saline solution is circulated through either a metal coated tube or a balloon in the catheter. 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 (DVT). Infection caused by cooling catheters is particularly harmful, as resuscitated patients are highly vulnerable to the complications associated with infections. Bleeding represents a significant danger to patients, due to a decreased clotting threshold caused by hypothermia. The risk of deep vein thrombosis may 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 lungs 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 minimize some of the benefit of invasive methods' more rapid cooling.

Trans Nasal Evaporative Cooling
Trans Nasal Evaporative cooling is a method of inducing the hypothermia process and provides a means of continuous cooling of a patient throughout the early stages of therapeutic hypothermia and during movement throughout the hospital environment. This technique uses two cannulae, inserted into a patients nasal cavity, to deliver a spray of coolant mist that evaporates directly underneath the brain and base of the skull. As blood passes through the cooling area, it reduces the temperature throughout the rest of the body.

The method is compact enough to be used at the point of cardiac arrest, during ambulance transport, or within the hospital proper. It is intended to rapidly reduce the patients temperature to below 34 C while targeting the brain as the first area of cooling. This technique was mentioned in publication of the PRINCE study in 2010 which showed the effectiveness of the device when cooling was started even before the return of circulation, and very shortly after the point of cardiac arrest. Research into the device has shown cooling rates of 2.6°C per hour in the brain (measured through infrared tympanic measurement) and 1.6°C per hour for core body temperature reduction.

Water blankets, torso vest, leg wraps
With 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 along with two litres of cold intravenous saline, patients can be cooled to 33 °C 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, resulting in increased adverse events. They have also rewarmed patients at too fast 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 and 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 over 24 hours.

Cool Caps
There are a number of non-invasive head cooling caps and helmets designed to target cooling at the brain. Hypothermia caps are typically made of a synthetic such as neoprene, silicone, or polyurethane, and filled with a coolant agent such as ice or gel which is either frozen to a very cold temperature -25 to -30 C before application or continuously cooled by an auxiliary control unit. Their most notable uses are in preventing or reducing alopecia in chemotherapy, and for preventing cerebral palsy in babies born with hypoxic ischemic encephalopathy. In the continuously cooled iteration, coolant is cooled with the aid of a compressor and then pumped out into cooling caps. Circulation is controlled by temperature sensors in the cap and regulated by valves. If the temperature deviates or if other errors are detected, an alarm system is activated. The frozen iteration involves continuous application of caps filled with crylon gel cooled to -30 C to the scalp before, during and after intravenous chemotherapy. As the caps warm on the head, multiple cooled caps must be kept on hand and applied every 20 to 30 minutes.

History
Hypothermia has been applied therapeutically since antiquity. The Greek physician Hippocrates, the namesake of the Hippocratic Oath, advocated the packing of wounded soldiers in snow and ice. Napoleonic surgeon Baron Dominique Jean 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. 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. 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.