Therapeutic Hypothermia

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, occurring in approximately 1 per 1000 births and causing around 20% of all cases of cerebral palsy. 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 (Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. 2007).

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 (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.

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

In selective head cooling, a cap (CoolCap) 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 34-35C for 72 hours.

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. The relative merits and limitations of these 2 methods have not been established (Santina A Zanelli, MD; Ted Rosenkrantz, MD.2011).

Rewarming is a critical period. In clinical trials, rewarming was carried out gradually, over 6-8 hours (Santina A Zanelli, MD; Ted Rosenkrantz, MD.2011).

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 neuro-protective 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. 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. TH is the most promising neuro-protective 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.

Presently, only 1 in 6 babies with encephalopathy will benefit from hypothermia therapy; many infants still develop significant adverse outcomes. 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 neuro-protective effect.

Uncertainties exist regarding mild to moderate hypothermia as a safe and effective neuro-protective 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.

A recent clinical report “Hypothermia and Neonatal Encephalopathy” found in Pediatrics 2014, 133:1146-1150 showed data from a large randomized clinical trials that indicated that TH using either systemic or head cooling was effective therapy for neonatal encephalopathy, providing the criteria outlined in published clinical trials was met.

Terms used at hospitals using TH is post cardiac arrest syndrome or post arrest organ injury. 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 main clinical considerations in post cardiac arrest syndrome.

1. Post cardiac Arrest Brain Injury: Disruption on both a micro- and macro- circulatory levels may result in either ischemia or hyperanemia.
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.

Mayo Clinic researchers confirmed that patients who receive TH after resuscitation from cardiac arrest have favorable chances of surviving the event and recovering good functional status. In TH, 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 (Science Daily, Feb. 18, 2011)

Data concerning hypothermias neuroprotectant qualities following cardiac arrest was 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 515 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 (90-93 F). Greater 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 (Winslow, R. 2009). 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 (Bernard, S, et al, 2002).

Another 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 (AED) at airports and other public places, and improvements in cardiopulmonary resuscitation techniques." (Winslow, R. 2009). However, of 140 patients since 2006 treated at the Minneapolis Heart Institute, 52% have survived by using therapeutic hypothermia (Winslow, R. 2009).

Current recommendations support use with Ventricular Fibrillation (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%) (eMedicine, 2010).

Hypothermia Proves Successful in Younger Cardiac Patients

Young adult patients with genetic heart diseases, such as hypertrophic cardiomyopathy (HCM), substantially benefited from therapeutic hypothermia, 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. (Science Daily, Apr. 3, 2011)

"Therapeutic hypothermia is an effective survival and neuroprotective treatment strategy increasingly employed in unconscious patients with out-of-hospital cardiac arrest and restored spontaneous circulation," explained the study's senior author Barry J. Maron, MD, director of the Hypertrophic Cardiomyopathy Center at the Minneapolis Heart Institute Foundation in Minneapolis. "However, there are no reports of therapeutic hypothermia employed in the patients with HCM."

Retrospectively examining patient records at Minneapolis Heart Institute at Abbott Northwestern Hospital in Minneapolis and Tufts Medical Center in Boston, the researchers found that seven young, asymptomatic patients with HCM (mean age 43), unexpectedly incurred cardiac arrest within a 46-month period, and survived after receiving therapeutic hypothermia.

"This success rate was unexpectedly high, especially given the experience with HCM and the CPR/defibrillation era," Maron said. Researchers found that the response was prompt at both facilities, including: collapse to resuscitation within three minutes; transport from collapse to the hospital for initiation of cooling (mean of 172 minutes); and the initial Glasgow coma score was 3 in each patient. Therapeutic hypothermia was administered with rapid cooling to 31 to 33 Celsius core body temperature for 24-29 hours, with intact cardiac function and complete restoration of normal neural, cerebral and cognitive functions six to 52 months after the event. Several reversible complications occurred. Each patient survived with neuroprotection, preserved cognitive function and intact cardiac function six to 52 months after their event, the researchers reported.

Hypothermia was successful despite HCM risk factors, including marked left ventricular wall thickness of more than 20 mm in six patients, outflow obstruction, asystole initially in one patient and a long delay to cooling of more than four hours in one patient. "These findings support the idea of more widespread availability and utilization of therapeutic hypothermia, due to its successful outcomes with out-of-hospital cardiac arrest," This study proves the worth of TH in younger patients with genetic disease."

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 are needed to determine its effect on patient outcome and whether it can be prevented. A definitive efficacy trial is necessary to evaluate the efficacy of therapeutic hypothermia for acute stroke (Hemmen, T. MD. Et al. 2010).

Background and Purpose: Induced hypothermia is a promising neuroprotective therapy. The feasibility and safety of hypothermia and thrombolysis after acute ischemic stroke was studied.

Methods: Intravenous Thrombolysis plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) was a randomized, multicenter trial of hypothermia and intravenous tissue plasminogen activator in patients treated within 6 hours after ischemic stroke. Enrollment was 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 33C followed by 12 hours of controlled rewarming or normothermia treatment. Patients presenting between 3 and 6 hours were randomized twice: to receive tissue plasminogen activator or not and to receive hypothermia or not.

Results In total, 59 patients were enrolled. One patient was enrolled but not treated when pneumonia was discovered just before treatment. 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). 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, and it has become the most widely used clinical outcome measure for stroke clinical trials.

The Modified Rankin Scale (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 This study demonstrates the feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis. Pneumonia was more frequent after hypothermia. Further studies are needed to determine its effect on patient outcome and whether it can be prevented. A definitive efficacy trial is necessary to evaluate the efficacy of therapeutic hypothermia for acute stroke (Hemmen, T. MD. Et al. 2010).

Most of the data concerning hypothermias effectiveness in treating stroke is limited to animal studies. Currently, no evidence supporting therapeutic hypothermia use in humans and clinical trials has been completed (eMedicine, 2010). Completed 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 (Krieger, Derk, et al., 2001). The use of hypothermia to control intracranial pressure (ICP) after an ischemic stroke was found to be both safe and practical (Schwab, S, et.al, 1998). 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 (Florian, B, Vintilescu R, Balseanu, AT, Buga A-M et al. 2008).

TH 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.

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.

A medical team recently reported a case study of an NFL football player who sustained a spinal injury during a helmet-to-helmet hit. The player had complete paralysis and sensory loss below the clavicles at his initial evaluation. His medical team applied a moderate hypothermia treatment during his ambulance ride, which was continued throughout his standard treatment (Cappuccino A, Bisson LJ, Carpenter B, et al. 2010).

Within 3 days, the player was showing considerable motor and sensory improvement, and continued to improve even after his subsequent discharge. Although the researchers noted that it was difficult to evaluate the amount of recovery directly related to the systemic hypothermia, they believe the treatment was a valuable one (Cappuccino A, Bisson LJ, Carpenter B, et al. 2010).

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 (91 F) is thought to prevent secondary neurological injuries after severe CNS trauma (Jess, Arcure BS, MSC: Eric E. Harrison, MD. 2009).

An Australian and New Zealand government funded study began in 2010 in which 512 patients were being randomized to being cooled and gradually rewarmed after suffering a Traumatic Brain Injury (TBI), while the secondary group was randomized 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.

Recent findings indicate that despite experimental evidence, the clinical utility of therapeutic hypothermia has still to be conclusively demonstrated in terms of reduced mortality or improved functional recovery after TBI (even in pediatric TBI). Current findings support that hypothermia should be initiated as soon as possible, for at least 48 hours duration. 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 therapeutic hypothermia.

Studies indicate that a discussion has to be focused around the possibility that a better outcome could be achieved if protocols for therapeutic hypothermia are reviewed. It is possible that the negative effects of the cooling and the rewarming procedure currently overshadow the neuroprotective effects.

Neurogenic fever occurs when a patient has an abnormally high fever associated with any one of the ischemic events described in this article. 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.

According to one study, elevated body temperature strongly correlates with an extended stay in the ICU or patients suffering from either ischemic brain injury or brain trauma (Dringer, M et al. 2004). Other studies 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 (Kammersgaard, L.P. et al. 2002). Combating fever through the use of temperature dampening devices represents a critical aspect of care for stroke patients (Ginsberg, M et al. 1997).

When infants suffer from perinatal asphyxia it appears that apoptosis is a prominent cause of cell death and that hypothermia therapy for neonatal encephalopathy interrupts the apoptotic pathway. 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 is not able to make the ATP it needs to regulate ion concentrations and maintain homeostasis (Polderman, Kees, 2004).

Discovered was that 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. 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 hypothermias ability to minimize the trauma resultant from ischemic injuries (Polderman, Kees, 2004).

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 patients inflammatory immune responses during reperfusion. TH helps to reduce reperfusion injury, damage caused by oxidative stress when the blood supply is restored to a 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 (DCruz, B.J. et al. 2002). 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.

Jacobs SE, Berg, M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG  discovered in their study on “Cooling for newborns with hypoxic ischemic encephalopathy” evidence from 11 randomized controlled trials which included a systematic review (N = 1505 infants) that therapeutic hypothermia 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 Therapeutic Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischemic encephalopathy if identified before six hours of age. (Cochrane Database Syst Rev 2013, Jan)

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 procedure:

• bleeding,
• infection,
• blood clots, and
• 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 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 TH is patients receiving this need to be sedated to prevent shivering, since this is a natural body response to the drop in body temperature.

• 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. 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 down side 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 has to be measured by core temperature probes inserted into the body (rectally) and then adjustments in the blanket temperature have to 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 verses internal cooling, increased compensatory response, decreased patient access, and discontinuation of cooling for invasive procedures such as cardiac catherization (Jones, P. G., Inouye M. 1994).

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. TH decreases the metabolic rate by 6-7% for every decrease of 1 degree Celsius in temperature.

Arctic Sun is a medical device that induces hypothermia non-invasively using Gel conductive pads which cover 40% of the patient’s surface area (as opposed to 80% with the water blankets). These pads circulate temperature-controlled water and modulate the patient’s temperature by about 1.5 to 2 degrees per hour. This apparatus is devoid of all the side effects of the other methods. *The most important point of the Arctic Sun device is that it is able to achieve the same goals as the more invasive cooling catheters, with even more accuracy in achieving the correct core temperature over an accurate time frame. It can be initiated much faster because there is no need to wait for a trained physician to begin the treatment. Cooling catheters require a physician to insert them and generally on average, there is at least a 60-75 minute delay before treatment is begun. The Arctic Sun device can be applied immediately upon a physicians order and he or she does not have to be present to start the process.