Therapeutic Hypothermia Management
Submitted by Seng Eap, BSN, RN, CCRN
Seng Eap, BSN, RN, CCRN is a Graduate Student in the Adult-Gerontology Acute Care Nurse Practitioner Program
The leading cause of death in North America is heart disease, resulting in 611,105 deaths in the last year.28 Cardiac arrest accounts for more than 300,000 heart disease related deaths.47 Patients that receive early quality chest compressions and defibrillation present with increased survival rate,40 however, the degree of brain dysfunction varies.48 The advancement in cardiopulmonary resuscitation after cardiac arrest and the use of therapeutic hypothermia have minimized brain injury and improved neurologic outcome.47,48 In 2002, two studies demonstrated the use of therapeutic hypothermia after cardiac arrest proving to lower mortality rate and have neuroprotective effect.7,22 This led the American Heart Association and the International Liaison Committee on Resuscitation to recommend the implementation of therapeutic hypothermia after the return of spontaneous circulation post-cardiac arrest.11 Mild hypothermia is also utilized in traumatic brain injury to control cerebral edema and to decrease intracranial pressure (ICP),60,61 cerebral ischemia,2,61 and subarachnoid hemorrhage (SAH).52 However, clinical effectiveness for subarachnoid hemorrhage is still questionable.2,61 This paper will focus on the recommendations for therapeutic hypothermia after cardiac arrest as well as a briefly discuss its use for clinical trials in traumatic brain injury, cerebral ischemia, and SAH.
Therapeutic Hypothermia Management
Cardiopulmonary arrest can lead to ischemia of the heart and hypoperfusion to vital organs such as the lung, liver, kidney, and brain. The brain is particularly vulnerable from lack of oxygen due to high rates of metabolic demand and low metabolic reserves. Ischemic brain injury after cardiac arrest is the main cause of death after hospitalization.14 Ischemic brain injury is highest amongst the unconscious survivor14,36 and can lead to early death due to unfavorable neurological outcomes.36
Induced therapeutic hypothermia has been shown to provide a neuroprotective effect after cardiac arrest.11,14,36 The purpose of therapeutic hypothermia in medicine has been documented back over 5000 years ago.25 In 1950, Bigelow and colleagues noted the positive effect on the brain after cardiac surgery in animals.9 Throughout the 1970s, experiments with moderate hypothermia in animals continued to show promising results.38,58 In the 1990s, induced mild hypothermia, further showed a neuroprotective effect after cardiac arrest, ischemic attack, and meningitis.25 In 2002, two prominent clinical trials further demonstrated better neurological outcomes with mild hypothermia after the success of the return of spontaneous circulation (ROSC) post cardiac arrest. This led the American Heart Association to adopt the usage of therapeutic hypothermia as part of post-arrest care guideline.11,25
Fever development is very common within the first 72 hours after cardiac arrest3 and can worsen neurological injury and overall prognosis.3,16 An increase of 1 °C in brain temperature has an adverse effect on cerebral ischemia conducted in animal studies.12,64 In a study consisting of 151 patients, for every one degree of core body temperature that increased above 37 °C, the risk of death subsequently increased.47
In another study conducted by Gebhardt et al. (2013) evaluating the effect of fever post cardiac arrest, 42% of the 336 patients studied, developed fever within 48 hours after their arrest. Thirty-six percent of those that were on therapeutic hypothermia did not develop fever versus 54% of those that were in the normothermia cohort developed fever. Those that developed fever were less likely to survive in the normothermia cohort. In the therapeutic hypothermia cohort, subjects that were febrile demonstrated similar survival outcome to those that had no fever, associated with shorter fever duration. Similar to other studies, fever is associated with decrease in survival rate in non-therapeutic hypothermia.17,66 Therefore, fever control is very important for best survival outcome in the first 48 hours post-cardiac arrest.
Mild therapeutic hypothermia has been recommended as the standard of care from the European Resuscitation Council’s guidelines on post-cardiac arrest treatment in 2010. The guideline states that all patients who suffer from cardiac arrest and remain unconscious should undergo therapeutic hypothermia treatment.37 Similarly, the 2010 American Heart Association guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care and the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation (ILCOR) also recommend that unconscious, out-of hospital cardiac arrest patients from the initial rhythm of ventricular fibrillation (VF) with ROSC should be cooled to 32 – 34 °C for 12 – 24 hours (Class I).29 Many hospitals with the available resources have adopted mild therapeutic hypothermia as the standard of care after cardiac arrest.56 Mild therapeutic hypothermia has been shown to improve hospital outcomes with ROSC after the initial rhythm of VF or pulseless ventricular tachycardia (VT).7,22
A study conducted by Vaahersalo et al. (2013) collected data over a 1 year period on 572 patients that assessed neurological outcomes on the out-hospital cardiac arrest patients with shockable rhythms (VF or VT) and non-shockable rhythms (PEA or asystole) that were placed on mild therapeutic hypothermia. At the conclusion of the study, the hospital mortality rate from comatose patients resuscitated from a shockable rhythm with mild hypothermia was 34% and 53% achieved good neurological outcome in 1 year. Mortality rate for the non-shockable rhythms was higher than shockable rhythms, however, a proportion of those patients survived.
Another study by Lundbye et al. (2012) focused on non-shockable rhythms (PEA or asystole). Candidates were initially cooled to a target temperature of 32 – 34 °C by receiving a bolus of chilled normal saline at 4 °C, then endovascular cooling was initiated for 18 hours. The patient was then re-warmed to a target temperate of 37 °C slowly after 24 hours at goal temperature. A total of 100 patients were in the study. Fifty-two patients received therapeutic hypothermia and 48 patients did not. At the end of the study, 20 of the 52 patients (38%) who received therapeutic hypothermia treatment survived to hospital discharge. Only 9 of the 48 patients (19%) who were not in the hypothermia subgroup survived. According to this study, the use of mild therapeutic hypothermia after a non-shockable cardiac arrest was shown to improve survival with better neurological outcomes. Lundbye et al. (2012) further stated that for every 6 patients after cardiac arrest who were treated with therapeutic hypothermia, one would have better neurological outcome regardless of the underlying non-shockable rhythms (PEA or asystole). In addition, for every 5 patients that were treated with therapeutic hypothermia, one will survive until discharged regardless of the underlying non-shockable rhythms (PEA or asystole). This study, by far, is the only one that demonstrates favorable outcome on non-shockable rhythms after cardiac arrest using therapeutic hypothermia. Due to the lack of data on randomized controlled trials on therapeutic hypothermia in non-shockable rhythms, ILCOR and the 2010 American Heart Association guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend that all patients with non-shockable rhythms that undergo resuscitation should also be treated with therapeutic hypothermia (Class IIb).41
Complications of Hypothermia
Therapeutic hypothermia has become the modality of care post-cardiac arrest, however, it does pose risks for the cardiovascular system, immune system, and can trigger electrolyte disorders, and coagulation dysfunction.
Bradycardia and QT prolongation are very common during the hypothermic state.47 A heart rate of 40 – 45 bpm at 32 °C is seen most often43,55 but does not require any intervention.47 Hypothermia-induced bradycardia allows the left ventricle to have more filling time and therefore exert a positive inotropic effect.25 If treatment is warranted, atropine will not be effective, instead slight rewarming, use of isoprenaline, or in very severe case, transvenous pacing can be used.6,8
Arrhythmia is less common with temperatures greater than 30 °C.43 The risk of arrhythmia transition increases between temperatures of 28 – 30 °C and will usually manifest initially as atrial fibrillation (A-Fib) and later into VT or VF.55 The hypothermic heart is very sensitive to manipulation and mishandling can place the patient into arrhythmia.33,55 A lower cardiac index and increase in peripheral vascular resistance have also been noted.7,50 QTc prolongation is due to hypothermia induced delayed spontaneous repolarization of cardiac myocyte that prolongs action potential and impulse conduction.43 QTc prolongation can lead to arrhythmia, therefore, regular assessment of the cardiac rhythm by the 12-lead electrocardiography is warranted.
Immune system. Therapeutic hypothermia increases the rate of infection by reducing inflammatory reactions, impairing the secretion of cytokines, and suppressing leukocyte migration and phagocytosis.10,55 This increases the risk for infection complication, most commonly pneumonia.25,34 Hypothermia also causes insulin resistance, resulting in hyperglycemia which may further increase the chance for infection.10,42
Electrolyte disturbance. Electrolyte disturbances are very common with therapeutic hypothermia and frequent serum electrolytes monitoring is required. Electrolyte disorder in the hypothermic state is due to intracellular shifting and increased renal excretion of electrolytes.55 Hypomagnesmia can worsen neurological outcome in the brain injury patient43,55 and is associated with atrial and ventricular arrhythmia, seizure, coronary vasoconstriction, bronchospasm, and insulin resistance.55 Hypophosphatemia and hypokalemia can cause arrhythmia, neuromuscular disorder, and generalized weakness. Hypophosphatemia can also cause diaphragm weakness, prolonging intubation period, and resulting in an increased risk for infection.55 Correcting these electrolytes to near normal level is very important, however, should not be over-corrected due to extracellular shifting of electrolytes that occurs during the rewarming phase. This can result in a higher level of electrolytes and possible life-threatening arrhythmias once patient is warmed to 37 °C.
Coagulation dysfunction. Mild therapeutic hypothermia can lead to coagulation dysfunction by affecting platelet counts, coagulation cascade, and prolonged clotting time.44 At temperatures of 33-35°C, coagulation cascade is affected and platelet function is decreased.25 Low platelet counts are due to platelets remaining in the liver and spleen during hypothermia treatment.30 A study conducted by Ruzick et al. (2012) looked at thromboelastography in healthy people undergoing hypothermia at temperature of 38 °C to 12 °C. The study concluded that decreasing core body temperature leads to a decrease in thrombus formation and can prolong clotting time. Anticoagulation effect can also be influenced in the presence of acidosis, however, it can be corrected with the administration of DDAVP or fibrinogen when the acidotic state is reversed.19 Despite the risk of coagulation dysfunction, no large studies involving the use of mild therapeutic hypothermia have reported an increased risk of bleeding associated with its use.44
Shivering is a normal physiological function to help the body conserve heat. Vasoconstriction starts at 36.5 °C and shivering is triggered at 35.5 °C.4 Shivering increases oxygen consumption,24 increases metabolic demand and rate of respiration,1 reduces brain tissue oxygenation,39 and can be uncomfortable for the patient. It can also inhibit the patient reaching the target therapeutic temperature goal. Ineffective control of shivering can lead to further damage of the already ischemic tissues in post-cardiac arrest or brain injury patients.3 It can lead to a dysfunction in lipid, protein, and carbohydrate metabolism and catabolism in the critically ill.3
The benefit from induced therapeutic hypothermia treatment will be eliminated from uncontrolled shivering. A validated tool, such as the Bedside Shivering Assessment Scale (BSAS), should be utilized at the initiation and throughout the duration of hypothermia therapy. BSAS provides an assessment tool to correlate metabolic consumption to shivering.5 It is a four-point scale that assesses bedside shivering using observation of muscular involvement of limbs and the trunk. From the grading score based on shivering observation, pharmacological intervention can be implemented. Pharmacological intervention includes scheduled Buspirone. If shivering persists, continuous intravenous magnesium can be used with a goal of magnesium levels between 3 to 4 mg/dl. Magnesium promotes mild muscle relaxation, cutaneous vasodilation, and may be neuroprotectant.3 Meperidine is the only opiate that has the most effective anti-shivering property and can be used for moderate to severe shivering.13 Due to its short half-life, multiple doses may need to be given if shivering persists. Propofol may be used to control severe shivering in the hypothermic patient and it should be titrate to suppress shiver.4
Induced mild therapeutic hypothermia post-cardiac arrest is recommended for 24 hours duration. After the 24 hours period, rewarming should be done slowly and in a controlled manner.45 The rate of the rewarming should not exceed 0.5 °C per hour,47 however, most clinicians recommend a rate of 0.2 to 0.25 °C per hour.5,48 Quick rewarming can cause an abrupt disturbance in the electrolyte concentrations,35 seizure, and cerebral edema.47 In therapeutic hypothermia, electrolytes shift intracellular and if these electrolytes are corrected excessively, during the rewarming, a rebound phenomenon will cause these electrolytes to be excessive, especially potassium.50 Hyperkalemia can be avoided by slowly rewarming and frequently reassessing these basic electrolytes parameter. In a studying using rat model in therapeutic hypothermia, rapid rewarming involves with more hemodynamic disturbances than rewarming at a slower rate.43 Rapid rewarming can also cause hypoglycemia and will require tapering of insulin doses as the body readjust to normal glycemic control.50
Therapeutic Hypothermia Clinical Trials in Neurosurgery
The notion of utilizing mild therapeutic hypothermia in controlling refractory elevation of intracranial pressure (ICP) in traumatic brain injury patients, acute ischemic stroke, and aneurysmal subarachnoid hemorrhage are still being examined, especially in ischemic stroke. Currently there are no recommended guidelines utilizing hypothermia with aneurysmal subarachnoid hemorrhage (aSAH).25 However, some studies do support the use of hypothermia in the management of refractory elevation of ICP in severe aSAH.15,53
Elevated ICP and Traumatic Brain Injury
Cerebral swelling after a traumatic brain injury (TBI) is due to vasogenic and cytotoxic swelling.32,63 Vasogenic edema results from a disruption in the blood brain barrier causing an influx of volume into the extracellular membrane.32 Cytototoxic edema is due to “homeostatic uptake of excitatory amino acids, water movement through aquaporins, and ionic pump failure”.62 Cerebral edema contributes to elevation of ICP. A review study done by Schreckinger and Marion (2009) looked at 11 randomized clinical trials consisting of a total of 367 TBI patients that were randomized to either mild induced hypothermia or normothermia to control elevation of ICP. Patients that were in the mild induced hypothermia group had lower ICP in comparison with patients that were treated with normothermia. Mild induced hypothermia, therefore, can be useful in lowering ICP and provide a protective mechanism decreasing the risk of secondary brain injury.46 Tokutomi et al. (2009) states that treatment with hypothermia at 35 to 35.5 °C is sufficient to decrease elevated ICP and optimize cerebral perfusion without compromising cardiac function.
A study by Jiang et al (2006), examined the length of time a patient should be induced in therapeutic hypothermia. The study consisted of 215 patients (107 patients treated with mild therapeutic hypothermia for an average of 2 days and 108 for an average of 5 days). The study concluded that mild induced hypothermia greater than 2 days in severe TBI had better clinical management of cerebral edema and elevation of ICP. In contrast, a review study by Sydenhan, Roberts, & Alderson (2009) involving 22 randomized control trials with 1587 patients, the mortality rate in mild induced hypothermia as compared to normothermia was not much different. However, mild induced hypothermia revealed lower morbidity versus normothermia treatment. Based on clinical trials, several neuro intensive care units have come to adopt therapeutic cooling as a secondary line of management to refractory elevation of ICP.54,62 At this time, there are no national guidelines that recommend the use of therapeutic hypothermia as the definitive treatment for controlling elevate ICP.25,46,54
Ischemic stroke. Despite the treatment with tissue plasminogen activator (tPA), only 1/3 of ischemic stroke patients are without disability.65 Hypothermia has shown to potentially reduce intracranial pressure and cerebral edema post-stroke.18 As stated in the above sections, induced therapeutic hypothermia after cardiac arrest does provide neuroprotection property, however, these patients are sedated and paralyzed during the 24 hours of treatment. A Majority of patients that have sustained thrombotic, ischemic cerebral vascular accident (CVA) are awake and not mechanically ventilated.25 This makes it difficult for treatment with induced hypothermia.
Intravascular Cooling in the Treatment of Stroke (ICTuS), is designed to study these patient populations. The initial pilot trial, ICTuS, demonstrated that stroke patients can be safely cooled to achieve hypothermia. Shivering is treated with buspirone orally or via nasogastric tube if dysphagia is present, as well as intravenous meperidine, and surface body counter warming.31 ICTuS-L involved 58 patients and half were randomized into hypothermia. This study examined the safety of endovascular cooling after tPA, which concluded that no complications common with hypothermia after cardiac arrest, such as coagulation dysfunction, infection, intracranial bleed, and catheter-related dysfunction were seen.20
The current phase of study is ICTuS 2/3 trial, with enrollment plan of 1600 patients who meet the criteria for thrombolysis treatment. These patients will be randomized to either normothermia or hypothermia at 33 °C. The study will be conducted in 10 different hospital centers in the United States and 1 in Austria.25 The trial will provide information on whether a combination of tPA and hypothermia at 33 °C is better than the standard treatment of ischemia stroke. In Europe, a similar study to ICTuS 2/3, EuroHYP-1, involving the plan to enroll 1500 patients over 60 hospitals is still undergoing.27 At this time, the answer still remains on whether hypothermia with thrombolysis is effective in the treatment of ischemic stroke.
Aneurysmal Subarachnoid Hemorrhage (aSAH). The presence of cerebral edema, symptomatic cerebral vessel spasm (CVS), and elevated ICP after a poor-grade aSAH can lead to worsening neurological outcome. Currently there is only a small amount of clinical trials showing the use of mild hypothermia therapy to benefit these risk factors and to provide neuroprotective effect.15,26,35 Recent randomized trials only support the use of mild hypothermia therapy with certain complications caused by aSAH as mentioned above.52 Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) is a study involving intraoperative good-grade aSAH consisting of 1001 patients, stating that there is no difference in neurological improvement after 3 months with hypothermia versus normothermia therapy.21,59 Therefore, there is no benefit to outcome in using hypothermia therapy as a prophylactic measure.
In contrast with a study done by Seule and colleagues, consisting of 100 patients being treated with mild hypothermia therapy due to refractory elevation of ICP and/or CVS, 35.6% of patients achieved mild to moderate disability or no disability after 12 months.53 In a randomized trial consisting of 8 patients with severe CVS refractory to standard treatments therapy done by Nagao et al. (2003), five patients recovered with good outcome after 5-10 days of mild hypothermia therapy, and 2 patients with moderate disability. This shows that patient with only severe CVS without elevation of ICP unresponsive to standard treatments will benefit from mild hypothermia therapy.53 In addition, a study conducted in rats’ model done by Torok and colleagues concluded that neurological outcome is best preserved when mild hypothermia therapy is implemented before 3 hours of SAH.61 After 3 hours, the prevention of cerebral edema by hypothermia therapy fails.61 Therefore, early implementation of mild hypothermia therapy with the first indication of cerebral edema by computer tomography is warranted.52 Currently there is no guideline for mild hypothermia therapy usage in aSAH.25,52 Further studies on aSAH outcome from mild hypothermia therapy are still needed.
Patients induced in mild hypothermia therapy are at risk for cardiac and coagulation dysfunction, shivering, skin integrity compromise, electrolyte abnormalities and infection. An evidenced based surveillance protocol for nursing care can help to minimize these risks. Nurses can help prevent cardiac arrhythmia such as ventricular fibrillation from the already stunted heart by minimizing rough handling.33 Anti-shivering assessment should be done at bedside using the BSAS assessment scale and skin integrity should be checked frequently if surface cooling device is implemented during hypothermia therapy. Laboratory testing should be done per the hospital’s hypothermia policy and may include POCT for glucose monitoring, electrocardiogram, basic serum electrolytes, complete blood count, coagulation study, lactic acid, and arterial blood gas.33
Cerebral ischemia from anoxic brain injury post cardiac arrest is the leading cause of death after ROSC. Induced mild hypothermia provides neuroprotective effect that can lead to better survival outcome when it is being implemented after ROSC for both shockable and nonshockable rhythms. Therefore, mild therapeutic hypothermia at 32 – 34 °C has been accepted by the American Heart Association as part of management guidelines after cardiac arrest. The use of mild therapeutic hypothermia for the management of cerebral edema and refractory elevation of ICP after TBI has shown to provide better neurological outcome. However, there is still a lack of randomized controlled trials that support the use of therapeutic hypothermia to improve mortality. Currently there are no management guidelines for mild therapeutic hypothermia for TBI, ischemic stroke, and aSAH. While cooling the body to such a low temperature does not come without risks such as infection, coagulation dysfunction, electrolytes disturbance, shivering, and cardiac dysfunction, it has been shown to increase patient outcomes. Frequent patient assessment for shiver, 12-lead electrocardiography, laboratory tests, and rewarming at a rate of 0.2 °C per hour can help to minimize the complication associated therapeutic hypothermia.
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