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Targeted Temperature Management (Therapeutic Hypothermia)

1.5 Contact Hours
This course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Nursing Student, Registered Nurse (RN), Respiratory Therapist (RT)
This course will be updated or discontinued on or before Friday, September 10, 2021
Course Description
This course is to educate the healthcare professional on when to initiate Targeted Temperature Management (TTM), what criteria to use in initiating this progress and when/how to rewarm patients of all ages. Healthcare professionals will become knowledgeable on all the benefits and possible effects of this process.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Donna Thomas (RN, MSN, BSHEd)

Outcomes

90% of participants will apply the positive effects of Targeted Temperature Management (TTM) or therapeutic hypothermia (TH).

Objectives

After completing this course, the learner will be able to:

  1. Discuss five ischemic events when TTM produces positive outcomes.
  2. Explain the mechanism of action and the neuroprotection that is achieved with TTM.
  3. Describe how TTM is administered and how to prevent side effects.
  4. List the medical methods through which TTM is induced.
  5. Describe neurogenic fever and the effects of TTM.

Introduction

Targeted Temperature Management (TTM) or Therapeutic Hypothermia (TH) is currently one of the most important methods of neuroprotection. It involves lowering a patient’s body temperature in order to help reduce the risk of ischemic injury to tissues following a period of insufficient blood flow. Periods of insufficient blood flow may be due to cardiac arrest and the occlusion of an artery by an embolism as occurs in the case of strokes.1,2,10

The mechanisms of action of TTM are varied and can affect many metabolic pathways, reactions of inflammation, apoptosis processes, and promote neuronal integrity. Invasive methods to induce TTM are initiated by using a catheter which is inserted into the inferior vena cava via the femoral vein, or by non-invasive means. Non-invasive means may utilize a chilled water blanket or torso vest and leg wraps which are 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 TTM in a timely manner. The major goal of using TTM as a treatment is to achieve the target temperature as quickly as possible. This may take between 3-4 hours after initiating the cooling process. The recommended duration of TTM after reaching the target temperature is at least 24 hours.1,4,10,12

History

Since antiquity, TTM has been applied therapeutically. Hippocrates, the Greek physician, historically noted for the Hippocratic Oath and was considered the first modern doctor and advocated the packing of wounded soldiers in snow and ice. Hippocrates felt that placing his bleeding patients in the snow decreased blood flow. Surgeons during the Napoleonic war used the same technique on soon-to-be-amputated limbs. Napoleon's surgeon, Baron Dominque-Jean Larrey recorded that officers, who were kept closer to the fire, survived less often than the minimally pampered infantrymen. During the 1940s, hypothermia was used to treat pain and retard cancer growth. The 1950's led the way to the use of hypothermia as a means of reducing blood flow to vital organs during surgery.

The first medical article in 1945 described a study on the effects of hypothermia on patients suffering from severe head injury. In 1950 TTM received its first medical application when it was used in intracerebral aneurysm surgery to create a bloodless operating field. Initially, early research mainly focused on the applications of deep hypothermia when the body’s temperature was between 20-25 degrees centigrade (68-77 degrees F). This temperature range had many side effects, which at the time made deep hypothermia impractical in most clinical situations. Today, the temperature range is between 320°c (89.60° f) to 360° c (96.8° f) which has demonstrated fewer side effects and more positive results.1,2,4,10

During the 1950's more research was done utilizing mild forms of hypothermia. The body temperature was kept between 32° and 34° C (90°-93° F). In the 1980's animal studies indicated the ability of mild hypothermia to act as a general neuro-protectant following a blockage of blood flow to the brain.

In 2000 according to the BBC News, following a skiing accident, Anna Bgenholm's heart stopped for more than three hours, and her body temperature dropped to 13.7°c, prior to being resuscitated. According to author and researcher, R. Winslow in 2009 there were two human studies which were published simultaneously in 2002 by M. Holzer in 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.

The American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR) endorsed the use of TTM following cardiac arrest. They recommend cooling comatose (lack of meaningful verbal response to verbal commands) adult victims with Return of Spontaneous Circulation (ROSC) after out of hospital Ventricular Fibrillation cardiac arrest to 32 degrees to 34 degrees centigrade for 12 to 24 hours. This is also being considered when a person suffers an out of hospital initial rhythm of PEA or asystole.1

AHA guidelines state that following a cardiac arrest when the patient has return of spontaneous circulation (ROSC) and is Comatose the targeted temperature management should be 32 degrees to 36 degrees centigrade (89.6°-96.8o° F) for at least 24 hours. Note table with Guidelines and recommendations in this text.1,2,4

Indications and Contraindications

TTM is being considered by healthcare providers on those adult patients who are comatose with Return of Spontaneous Circulation (ROSC) after in hospital cardiac arrest of any initial rhythm. Presently, 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. AHA states that hemodynamically stable patients with spontaneous mild hypothermia (>33 degrees C) after resuscitation from cardiac arrest should not be actively rewarmed.2,4,10,12

Numerous studies and controlled clinical trials have proven that TTM is one of the most important methods of neuroprotection. Hypothermia after cardiac arrest improves the outcome in a variety of clinical scenarios such as post-cardiac arrest, and traumatic brain injury and spinal cord injury. TTM has been used in other diseases where it has proven to be useful, such as with victims of a stroke and acute liver failure. 1,2, 4,6,10,12,14

Current indications and contraindications for TTM vary between institutions. Inclusion criteria used by many institutions are 1,2,7,10,12:

  1. Any case of Post Arrest
  2. ROSC <30 minutes from CODE team arrival
  3. Time <6 hours from ROSC
  4. Patient is comatose and not responding to verbal commands
  5. Patient able to maintain a systolic blood pressure >90 mm HG, with or without pressers after CPR

Exclusions may include2,10,12:

  1. Traumatic arrest
  2. Valid do not resuscitate order (DNR)
  3. Active bleeding, including intracerebral bleeding. TTM may impair the clotting system; however, patients may receive chemical thrombolysis, antiplatelet agents, or anticoagulants if deemed necessary in the treatment of the primary cardiac condition
  4. Pregnancy
  5. Sepsis
  6. Major surgery within 14 days due to possible risk for infection and bleeding

Side Effects

TTM may independently alter the patient’s physiology. Potassium and magnesium levels drop and should be replaced. Other normal findings are low WBC, and high PT/APPT and LFTs, which do not require treatment. Blood gas analysis may show low pH and HCO3- and high pCO2 and pO2. These values may or may not be temperature adjusted, depending on the institutions blood-gas analyzer.2,4.7,10,13

Drug metabolism is generally slowed, leading to increased half-life, and hence drug accumulation.

ECG and cardiac changes occur with TTM. Patients may become hypotensive, bradycardic and have reduced cardiac output. Atrial fibrillation is also common although research demonstrated severe dysrhythmias are seen with temperatures below 30C (86F). There can be a prolongation of the PR, QRS, and QT intervals, as well as J-waves.10,12,13

TTM may induce cold diuresis, leading to volume loss. Although coagulopathy and platelet dysfunction are known side effect of hypothermia, there has been no observed difference in adverse bleeding events following TTM, even in those who underwent Pre-cutaneous Coronary Intervention (PCI) or thrombolysis in the immediate post-arrest period. In patients with intracerebral bleeding, TTM does not increase morbidity or mortality.2,7,10,12,13

Shivering occurs at a core temperature of approximately 35.5°C (96°F) and may be counterproductive to induction of cooling. This should be treated because it slows the rate of cooling and increases metabolic activity. Treatment includes adequate sedation, followed by muscle paralysis if needed. This could be an uncomfortable treatment modality, and therefore adequate sedation and analgesia must be maintained throughout the hypothermia protocol until the patient has been rewarmed and has returned to normothermia. According to the Swedish Council of CPR short-acting medications are preferred due to the frequent reduced clearance of these medications in this patient population.

Rewarming should be initiated at 12-24 hours after TTM initiation. It should occur slowly at a rate of 0.25°-0.5o°C per hour until the patient reaches normothermia. Rapid rewarming increases the risk of significant complications including hypotension from substantial vasodilation as well as hypoglycemia and hyperkalemia.2,8,9,10

Types of Ischemic Events

TTM is effective in five primary categories of medical events:

  • Neonatal encephalopathy
  • Cardiac arrest
  • Ischemic stroke
  • Traumatic brain or spinal cord injury without a fever
  • Neurogenic fever following brain trauma

TTM for Neonatal Encephalopathy

Birth Asphyxia caused by a reduction in the supply of blood or oxygen to a baby's brain during birth is a major cause of death and brain damage. It occurs in approximately 1 per 1000 births and causing around 20% of all cases of cerebral palsy.

Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P., in 2007 found that brain hypothermia, induced by cooling a baby to around 33 degrees C for 3 days after birth has recently proven to be the only medical intervention which reduces brain damage and improves an infant's chance of normal survival after birth asphyxia.

TTM 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 (91°-93° F), begun within 6 hours of birth and continued for 72 hours, significantly reduces mortality and reduces cerebral palsy and neurological deficits in survivors.8,9,11

The optimal duration of brain cooling in the human newborn has not been established.

In selective head cooling, a cap (Cool Cap) with channels for circulating cold water is placed over the infant's head, and a pumping device facilitates continuous circulation of cold water. Nasopharyngeal or rectal temperature is then maintained at 34°-35°C for 72 hours.3,9

In whole-body hypothermia, the infant is placed on a commercially available cooling blanket, through which circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72 hours. Rewarming is a critical period and in clinical trials, rewarming should be carried out gradually over 6-8 hours.3,9

A major contributor to global child mortality and morbidity is neonatal encephalopathy after perinatal hypoxic-ischemic insult. Brain injury in term infants as a result of hypoxic-ischemic insult is a complex process evolving over hours to days. This time frame provides a unique window of opportunity for neuroprotective treatment interventions. Advances in neuroimaging, brain monitoring techniques, and tissue biomarkers have improved the ability to diagnose, monitor, and care for newborn infants with neonatal encephalopathy. This helps to predict their outcome.6,7,9

Challenges remain in early identification of infants at risk for neonatal encephalopathy, determination of timing, and extent of hypoxic-ischemic brain injury, as well as optimal management and treatment duration. TTM is the most promising neuroprotective intervention to date for infants with moderate to severe neonatal encephalopathy after perinatal asphyxia and has currently been incorporated in many neonatal intensive care units in developed countries.3,8,9,11

Presently, only 1 in 6 babies with encephalopathy benefit from TTM. Many infants still develop significant adverse outcomes. In order to enhance the outcome, specific diagnostic predictors are needed to identify patients likely to benefit from hypothermia treatment. Studies are being done to determine the efficacy of combined therapeutic strategies with hypothermia therapy to achieve maximal neuroprotective effect.

Uncertainties exist regarding mild to moderate hypothermia as a safe and effective neuroprotective intervention for newborns who have sustained a perinatal hypoxic-ischemic insult resulting in encephalopathy. Completion of ongoing trials, worldwide and long-term follow-up of survivors is vital to evaluate whether widespread implementation should be initiated or if this action is premature.

Cardiac Arrest

Cardiac arrest (CA) is associated with very high mortality and causes neurological dysfunction in the survivors. A decrease in metabolism in the brain from TTM may be one of the most important mechanisms of neuroprotection.1, 2, 4,6,14

Table - Guidelines and Recommendations for the use of Therapeutic Hypothemia Following Cardiac Arrest

2015 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care

Comatose (i.e., lack of meaningful response to verbal commands) adult patient with ROSC after out-of-hospital ventricular fibrillation or pulse-less ventricular tachycardia (pVT) cardiac arrest should undergo targeted temperature management (TTM) with goal temperature 32-36°C (89.6-96.8°F) for at least 24h (class I, level of evidence B).

Comatose adult patients with ROSC after in-hospital cardiac arrest of any initial rhythm or after out-of-hospital cardiac arrest with an initial rhythm of pulseless electric activity or asystole should undergo targeted temperature management (TTM) with goal temperature 32-36°C (89-6-96-8°F) for at least 24 h (class I, level of evidence C).

2015 Recommendations from the International Liaison Committee on Resuscitation

Targeted temperature management with goal temperature 32-36°C (89.6-96-8°F) for at least 24 h should be part of a standardized treatment strategy for comatose survivors of cardiac arrest.

2010 European Resuscitation Council Guidelines for Resuscitation

Use of therapeutic hypothermia should include comatose survivors of cardiac arrest associated initially with non-shockable rhythms and shockable rhythms. (The lower level of evidence for use after cardiac arrest from non-shockable rhythms is acknowledged.)

TTM is the terms used at hospitals in which post-cardiac arrest syndrome or post-arrest organ injury have occurred. The pathophysiology is complex. Hypoperfusion and ischemia cause a cascade of events: disruption of homeostasis, free radical formation and protease activation among other things. The disruption may continue for hours or days. Hypothermia may slow down this cascade. There are four primary clinical considerations in post-cardiac arrest syndrome.

  1. Post cardiac Arrest Brain Injury: Disruption on both a micro and/or macro-circulatory level may result in either ischemia or hyper-anemia.
  2. Post cardiac arrest myocardial dysfunction: Usually within 72 hours, the hyperkinetic heart, (likely due to circulating catecholamines and global hypokinesis) often resolves.
  3. Systemic Ischemia/Reperfusion Response: The response of the body is similar to that of septic shock with activation of the immune and complement systems, and release of inflammatory cytokines and a wide range of cellular responses.
  4. Persistent precipitating pathology: The cause(s) of the arrest may continue to impact physiological parameters.

Patients who receive TTM after resuscitation from cardiac arrest have favorable chances of surviving the event and recovering good functional status. In TTM, a patient's body temperature is cooled to 33 degrees Celsius following resuscitation from cardiac arrest, in order to slow the brain's metabolism and protect the brain against the damage initiated by the lack of blood flow and oxygenation.

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 (AED) at airports and other public places, and improvements in cardiopulmonary resuscitation techniques. Treatment with TTM improves survival rates.

Hypothermia proves successful in younger cardiac patients. Young adult patients with genetic heart diseases, such as hypertrophic cardiomyopathy (HCM), substantially benefited from TTM, which could further extend the role for this treatment strategy in new patient populations, according to a scientific presentation at the American College of Cardiology (ACC) Scientific Sessions in New Orleans.

Because of these findings more support for TTM with the idea of more widespread availability of TTM, and utilization of this process due to its successful outcomes with out-of-hospital cardiac arrest has been initiated in ACLS protocols following return of circulation when a patient is unconscious. Studies also proved the worth of TTM in younger patients with genetic disease.1,9

TTM is defined as a body temperature of below 34°C. Differences of opinion exist as to what the goal temperature should be when TTM should be initiated, which cardiac arrest (CA) victims should have the treatment, and so on. Because the pathophysiology for neurologic injury following CA is similar regardless of rhythm or location of arrest, the decision to initiate TTM should be made on an individual patient basis considering the etiology of the arrest, time before initiation of CPR, duration of CPR prior to ROSC, and overall prognosis based on underlying comorbidities.9

Below is the summary of a study which demonstrates the feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis. Pneumonia was more frequent after hypothermia, but further studies still are needed to determine its effect on patient outcome and whether it can be prevented. To evaluate the efficacy of TTM for acute stroke a definitive efficacy trial is necessary.2

The background and purpose of the study are vital to its reliability: Induced hypothermia is a promising neuroprotective therapy and has demonstrated positive outcomes. The feasibility and safety of hypothermia and thrombolysis after acute ischemic stroke also needs to be evaluated.

Ischemic Stroke

Specific methods used in this study included Intravenous Thrombolysis plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L). This process had to be randomized, and a multicenter trial of hypothermia and intravenous tissue plasminogen activator in patients treated within 6 hours after ischemic stroke was initiated. Enrollment also had to be stratified to the treatment time windows 0 to 3 and 3 to 6 hours. Patients presenting within 3 hours of symptom onset received standard dose intravenous alteplase and were randomized to undergo 24 hours of endovascular cooling to 33°C. This was followed by 12 hours of controlled rewarming or normothermia treatment. Those patients presenting between 3 and 6 hours were randomized twice: to receive tissue plasminogen activator or not and to receive hypothermia or not.

Results of the 59 patients who were enrolled in the study demonstrated the following:

  • All 44 patients enrolled within 3 hours and 4 of 14 patients enrolled between 3 to 6 hours received tissue plasminogen activator.
  • Overall, 28 patients randomized to receive hypothermia (HY) and 30 to normothermia (NT).
  • Baseline demographics and risk factors were similar between groups.
  • Mean age was 65.
  • Baseline National Institutes of Health Stroke Scale score was 14.05.0; 32 (55%) were male.
  • Cooling was achieved in all patients except 2 in whom there were technical difficulties.
  • The median time to target temperature after catheter placement was 67 minutes (Quartile 1 57.3 to Quartile 3 99.4).
  • At 3 months, 18% of patients treated with hypothermia had a modified Rankin Scale score of 0 or 1 versus 24% in the normothermia groups (nonsignificant).
  • Symptomatic intracranial hemorrhage occurred in 4 patients; all were treated with tissue plasminogen activator <3 hours (1 received hypothermia).
  • Six patients in the hypothermia and 5 in the normothermia groups died within 90 days (nonsignificant).
  • Pneumonia occurred in 14 patients in the hypothermia and in 3 of the normothermia groups (P=0.001).
  • Surprisingly the pneumonia rate did not significantly adversely affect 3 month modified Rankin Scale score (P=0.32).

The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. It has become the most widely used clinical outcome measure for stroke in clinical trials.

The - (mRS) runs from 0-6, running from perfect health without symptoms to death.

  • 0 - No symptoms.
  • 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.
  • 2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
  • 3 - Moderate disability. Requires some help, but able to walk unassisted.
  • 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
  • 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
  • 6 - Dead

Conclusion of Study demonstrated:

  • The feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis.
  • Pneumonia was more frequent after hypothermia.
  • Further studies were needed to determine its effect on patient outcome and whether it can be prevented.
  • A definitive efficacy trial was necessary to evaluate the efficacy of TTM for acute stroke.

Most of the data concerning hypothermia’s effectiveness in treating stroke is limited to animal studies. Currently, no evidence supporting TTM use in humans and clinical trials has been completed. Completed studies have focused primarily on ischemic stroke as opposed to hemorrhagic stroke. Hypothermia is associated with a lower clotting threshold. In animal studies, hypothermia represented an effective neuroprotectant.

TTM does not seem to be effective in hemorrhagic stroke (bleeding on the brain). However, there seems to be evidence that hypothermia lowers the body temperature to reduce intracranial pressure and can thus prevent further brain damage by allowing the tissues to heal.1,2,4,14

Traumatic Brain or Spinal Cord Injury

Complete spinal cord injuries do not often occur in professional sports, but they can produce devastating results when they do. The primary injury is serious, but a substantial amount of damage occurs during the secondary response to the injury. Research has focused on reducing this secondary response by slowing inflammation, cell death, or bleeding.1,2,4,6,13

Animal studies show the benefit of TTM 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 (91° F) is thought to prevent secondary neurological injuries after severe CNS trauma.

Recent findings indicated that despite experimental evidence, the clinical utility of TTM has still to be conclusively demonstrated in terms of reduced mortality or improved functional recovery after a Traumatic Brain Injury (TBI), (even in pediatric TBI). Current findings support that hypothermia should be initiated as soon as possible, for at least 48 hours duration. The outcome is worse when barbiturates are part of ICU management.

Currently, available cooling techniques, including pre-hospital cooling protocols, expand and improve clinical management of TTM. The negative effects of the cooling and the rewarming procedure currently overshadow the neuroprotective effects.1,2,4,6,14

Neurogenic Fever

Neurogenic fever occurs when a patient has an abnormally high fever associated with any ischemic events. The higher the temperature in the patient, the more damage occurs to the brain and body. In a patient with either brain trauma of any kind or ischemic brain injury combined with a fever, the mortality rate goes up 14% higher than patients with normal temperatures.1,2,4,6,14 Elevated body temperature strongly correlates with an extended stay in the ICU or patients suffering from either ischemic brain injury or brain trauma.

Therapeutic Hypothermia in Stroke

The use of TTM had been well established to improve survival with favorable neurological outcome in the case of global cerebral ischemia after cardiac arrest or perinatal hypoxia-ischemic insult; however, the efficacy of TTM for treating focal cerebral ischemia had not yet been well studied.

When infants suffer from perinatal asphyxia, it appears that apoptosis is a prominent cause of cell death in which cells activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins. Fragments of the apoptotic cell then break off giving the appearance that is responsible for the name apoptosis which can occur under normal or abnormal conditions.8,9,11

TTM for neonatal encephalopathy interrupts the apoptotic pathway. Noted was that 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, which is 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. Cells need oxygen to manufacture the necessary ATP to regulate ion levels and thus to 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 is not able to make the ATP it needs to regulate ion concentrations and maintain homeostasis.

Even a small drop in temperature encourages cell membrane stability during periods of oxygen deprivation. Therefore, because of 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. 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.

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. TTM helps to reduce reperfusion injury, damage caused by oxidative stress when the blood supply is restored to the tissue after a period of ischemia. The oxidation that occurs during reperfusion also increases free radical production.

Recent data suggests that even a modest reduction in temperature can function as a neuroprotectant. This indicates that possibly hypothermia affects pathways that extend beyond a decrease in cellular metabolism. Now the hypothesis centers on the series of reactions that occur following oxygen deprivation, particularly those concerning ion homeostasis.

TTM is beneficial in term and late preterm newborns with hypoxic-ischemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweighed the short-term adverse effects. It was determined that TTM should be instituted in term and late preterm infants with moderate-to-severe hypoxic-ischemic encephalopathy if identified before six hours of age.8,9,11

Treatment Administration

In patients facing ischemic injury, it is important that to ensure a successful outcome the administration of TTM should be initiated as soon as possible.TTM remains partially effective when initiated as long as 6 hours after collapse. Based on the current data from observational studies as well as randomized control trials, the optimal timing to initiate TTM and achieve target temperature still remains unclear.

There are three phases of TTM: induction, maintenance and re-warming.

  1. The induction phase is used to reduce the core body temperature to between 32°-36°C (90°-96.8°F) within 6 hours.
  2. The maintenance phase keeps the core body temperature for 12 to 24 hours.
  3. The re-warming phase is either controlled or passive re-warming to normothermia 37°C (98.6°F). This is done by keeping the temperature between 0.2° - 0.5°C (0.5°-1°F) per hour over 8-12 hours.2,3,5,8,11,13,14

Invasive Methods

Cooling catheters are placed into the inferior vena cava by inserting into the femoral vein. Cooled saline solution is circulated through a tube or balloon. The saline cools the patient’s entire body by cooling the blood as it passes through the heart. Conversely, the catheter method can raise the patient’s body temperature if it begins to dip too low.

Adverse effects of this method are associated with an invasive procedure2,4,7,10,13:

  • bleeding
  • infection
  • blood clots
  • arterial puncture

Excessive bleeding can become a problem because the patient has a decreased threshold due to lowered temperature. Infection can be deadly in patients already compromised by the original insult. This method can also lead to the development of blood clots and thus cause pulmonary embolism. Naturally, when using an invasive method, a specialist is needed to insert the catheter via the femoral vein, and this may cause a delay in cooling the patient while waiting for a provider certified in this procedure.

Another aspect of TTM is patients receiving this need to be sedated to prevent shivering since this is a natural body response to the drop-in body temperature.

External Method

External Method

  • Water Blanket
  • Torso vest
  • Leg wraps
  • Ice packs

Water blankets are used with cool water which circulates through the blanket. If a person needs their body temperature lowered, the blankets have to cover 80% of the patient’s surface area. In order to achieve a faster temperature lowering condition, ice packs can be used. This method is primarily geared at lowering the patient’s skin temperature and requires no invasive procedures.

The downside of this method is that the water blankets can leak. This creates a safety hazard since there may be other electrical equipment nearby. Water blankets lower the body temp at a slower rate than other cooling methods. The temperature must be measured by core temperature probes inserted into the body (rectally), and then adjustments in the blanket temperature must be made. If not monitored closely they can quickly go beyond the target temperature. This can lead to spikes in intracranial pressure. There is also a slower induction time versus internal cooling, increased compensatory response, decreased patient access, and discontinuation of cooling for invasive procedures such as cardiac catheterization.

If therapy with water blankets is given with two liters of cold intravenous saline, patients can be cooled to 33 degrees C (91 degrees F) in 65 minutes. Newer water blankets have sophisticated software that prevents warming at too rapid a pace allowing a patient to be rewarmed at a very slow rate of just 0.17 degrees C (0.31 degrees F) an hour when placed in the automatic mode. This allows rewarming to occur from 33-37 degrees C (91-99 degrees F) over 24 hours. This helps to prevent spikes in intracranial pressure. TTM decreases the metabolic rate by 6-7% for every decrease of 1 degree Celsius in temperature.

Case Studies

90% of persons suffering a cardiac arrest never reach the hospital alive. An example of the benefits of TTM is illustrated when a facility in Reno, Nevada published a study illustrating the benefits of TTM. Abella, B.S. et al. in 2005 stated that recovery correlates with body temperature. They discovered that the lower the body temperature is after the event, the greater the possibility for neurologic recovery.

In their case study, they describe the events of a 56-year-old male smoker with diabetes who suffered a cardiac arrest. CPR was not initiated until paramedics arrived. His first pulse was detected 17 minutes after CPR was started. He was started on TTM protocol within 20 minutes after arrival to the Emergency Room. He was treated with body surface cooling pads for 22 hours. The target hypothermic temperature was achieved 6 hours into treatment. Rewarming was started 22 hours rather than 24 hours because he was showing signs of awakening. Six hours after rewarming began, he was responding and 2 hours after that, he was responding to pain.

The following morning, which would have been about 12 hours of normal body temperature, he was opening his eyes to commands and moving. By day 5 after his cardiac arrest, he was able to follow simple commands. On the sixth day, he was being treated with physical and speech therapy because of some slowness in his responses. However, by day 11, he had no neurological deficits. He was discharged home on day 12. Several months later he returned to work.

Another case occurred in Montgomery, Minn., on July 21, 2008. This involved a 43- year woman who was found unconscious in her home by her twin daughters. They called 911, and after 20 minutes, the ambulance crew was able to restore her heartbeat.

She was taken to 28-bed Queen of Peace Hospital in nearby New Prague, where an emergency team packed her body in blue ice bags before loading her on a helicopter to Abbott Northwestern Hospital in Minneapolis about 40 miles away. There she was wrapped in a cooling blanket that they kept her body temperature at about 92 degrees Fahrenheit before it was restored to normal the following day. Five days later, she regained consciousness and went home five days after that. She returned to work within the month.

The rationale behind the new treatment is that the brain is more resilient than previously believed during the early period after the heart goes down. Of course, the brain cannot live long without the oxygen provided by normal blood flow. But an initial rush of blood to the brain, when resuscitation gets the heart beating again, also kills tissue and is a more important insult.

Side Effects May Occur with TTM

TTM may independently alter the patient’s physiology. Potassium and magnesium levels are seen to drop and should be replaced. Other normal findings are low WBC, and high PT/APPT and LFTs, which do not require treatment. Blood gas analysis may show low pH and HCO3- and high pCO2 and pO2. These values may or may not be temperature adjusted, depending on the institution's blood-gas analyzer. Drug metabolism is generally slowed, leading to increased half-life, and hence drug accumulation.

ECG and cardiac changes occur with TTM. Patients may become hypotensive, bradycardic and have reduced cardiac output. Atrial fibrillation is also common although research demonstrated severe dysrhythmias are seen with temperatures below 30°C (86°F). There can be a prolongation of the PR, QRS, and QT intervals, as well as J-waves.

TTM may induce cold diuresis, leading to volume loss.

Although coagulopathy and platelet dysfunction are a known side effect of hypothermia, there has been no observed difference in adverse bleeding events following TTM, even in those who underwent PCI or thrombolysis in the immediate post-arrest period. In patients with intracerebral bleeding, TTM has not been shown to increase morbidity or mortality.

Shivering occurs at a core temperature of approximately 35.5°C (96°F) and may be counterproductive to induction of cooling. Treatment includes adequate sedation, followed by muscle paralysis if needed.2, 3,4,7,10,12,13

Conclusion

TTM is one of the most important therapies for providing neuroprotection and can be used in different clinical scenarios. This includes but is not limited to those suffering from neonatal encephalopathy, post-cardiac arrest, stroke, traumatic brain injury, and neurogenic fever.

At normal temperatures, the restoration of blood flow triggers a cascade of inflammatory and other responses over the following minutes and hours, which can injure tissue in the brain and exact a lethal toll. The mechanisms of action of TTM are multiple and varied. TTM can affect many metabolic pathways, reactions of inflammation, apoptosis processes, and other pathways.

Today, many think that the success of TTM is due to the multiple mechanisms of action blocking the cascade of ischemia on many levels, and this is responsible for its success. Scientists say icing the body slows metabolism and protects the brain from at least some of the damage caused by the restored blood flow. More and more clinical trials using animals and humans are taking place worldwide. The emergence of more controlled clinical trials evaluating the synergistic effects of TTM in association with other therapies will open the doors so that survival of those who would have perished now can survive.

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References

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  2. American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care (2015). Guidelines and Recommendations for the use of therapeutic hypothermia following cardiac arrest. Retrieved July 4, 2019. Visit Source.
  3. Arctic Sun 5000 for therapeutic hypothermia after cardiac.. Jul 01, 2017. Retrieved July 4, 2019. Visit Source.
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  8. Hypothermia and Neonatal Encephalopathy found in Pediatrics 2014, 133:1146-1150. Retrieved July 5, 2019. Visit Source.
  9. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG., Cooling for newborns with hypoxic ischaemic encephalopathy, January 31, 2013. Retrieved July 5, 2019. Visit Source.
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