Therapeutic Hypothermia

Author: Mark E Brauner, DO, Emergency Physician, Eugene Emergency Physicians, PC Coauthor(s): Michael R Sayre, MD, Associate Professor, Department of Emergency Medicine, Ohio State University College of Medicine Contributor Information and Disclosures Updated: Dec 22, 2008

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Background

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The incidence of out-of-hospital sudden cardiac arrest in industrial countries is reported to be between 35.7 and 128.3 cases per 100,000, with a mean of 62 cases per year.1 This translates into approximately 300,000 people in the United States and about the same number in Europe each year. Despite nearly 40 years of prehospital advanced life support, the survival rate of out-of-hospital cardiac arrest is very poor.2 Less than half of victims who develop return of spontaneous circulation (ROSC) survive to leave the hospital alive, and the cause of death is anoxic brain injury in most patients with ROSC who die within one month of the cardiac arrest. Inducing mild therapeutic hypothermia in selected patients surviving out-of-hospital sudden cardiac arrest has a major impact on long-term neurologically intact survival and may prove to be one of the most important clinical advancements in the science of resuscitation. Some early great physicians, including Hippocrates, recognized the utility of hypothermia in attenuating injury.3 The concept has experienced periodic reemergence in the medical literature, and recent studies of the modality date back mostly to the 1950s. In 1954, Hegnauer and D'Amato demonstrated decreased oxygen consumption in hypothermic dogs4 , and the study by Benson et al of hypothermia after cardiac arrest in humans5 (1959) demonstrated decreased mortality. With n=19, survival was 6 of 12 in the cooled group and 1 of 7 without cooling with a target temperature of 31-32C. Until recently, evidence for mild therapeutic hypothermia has lacked sufficient weight and the advisory panel support that thereby follows to propel it into common practice. Despite its 2005 inclusion in American Heart Association Guidelines for CPR and Emergency Cardiovascular Care, and 2003 advisory statements by the International Liaison Committee on Resuscitation (ILCOR) and the European Resuscitation Council (ERC), hypothermia therapy is largely misunderstood and inconsistently applied.6,7,8 Two studies published in the February 2002 New England Journal of Medicine demonstrated improved survival and neurological outcomes with induction of mild therapeutic hypothermia for comatose survivors of out-of-hospital cardiac arrest. The Hypothermia after Cardiac Arrest Study Group showed that, when applied to unconscious out-of-hospital cardiac arrest patients with ROSC (n=274), mild hypothermia (cooling to 32-34C) provided significant improvement in functional recovery at hospital discharge (55% vs 39%) (number needed to treat [NNT]=6) and lower 6-month mortality rate when compared with patients who were not cooled (41% vs 55%) (NNT=7).9 The NNT is very low and comparable to other important emergent treatments such as cardiac catheterization for acute coronary syndrome.10 Bernard examined endpoint of survival to hospital discharge to home

or a rehabilitation facility (good outcome) in 77 patients and demonstrated 49% in the hypothermia group compared with 26% in the normothermic group.11 Therapeutic hypothermia may also confer benefits to patients experiencing cardiac arrest in other clinical environments,12 patients with hemorrhagic shock,13 and patients with other forms of severe brain injury14,15,16,17 Currently, at least 19 clinical trials are underway and focus principally on ROSC, traumatic brain injury, stroke, neonatal hypoxic-ischemic encephalopathy, and medical device safety.18 The process of selecting patients and initiating therapy is not complex. The ERC states that hypothermia is "safe and effective even if there is lack of experience".19 The practice has been successfully applied in the academic tertiary care environment and in the community hospital setting, and it has been successfully implemented in the prehospital environment.20,21,22,23 Implementation of hypothermia does require planning, education, and integration of multiple services within an institution. The basic framework for clinical protocols are well established, and institutions interested in establishing protocols may find a substantial amount of prior art in the literature (see hypothermia protocols). Summary of 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care regarding the use of hypothermia

Unconscious adult patients with return of spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32-34C for 12-24 hours when initial rhythm was ventricular fibrillation (VF) (class IIa). Similar therapy may be beneficial for patients with non-VF arrest out-of-hospital or with inhospital arrest (class IIb). Hemodynamically stable patients with spontaneous mild hypothermia (>33C) after resuscitation from cardiac arrest should not be actively rewarmed.

Take home points

Have a plan and buy-in from necessary departments. Experience with hypothermia is not needed to be successful. Cool early (in the emergency department). Use any cooling method. Patients can continue to be cooled during percutaneous coronary intervention (PCI). Use any pharmacologic agent necessary for primary cardiac condition (eg, aspirin, antiplatelet compounds, thrombolytics). Treat patients as you would any critical care patient (tight glycemic control, vigilance for signs of infection, maintain perfusion, and use pressors if necessary). Practice standard neuroprotective strategies such as placing the head of the bed at 30 and use seizure precautions. Predict and be proactive regarding management of complications from ROSC and hypothermia, including shivering, fever, hypotension or hypertension, hyperglycemia, hypokalemia or hyperkalemia, bradycardia, and ongoing ischemia.

Pathophysiology
Cardiac arrest and ROSC is a case of whole-body ischemia and subsequent reperfusion injury. This injury mechanism along with pre-arrest comorbidities cause enormous biochemical, structural, and functional insults, which in a complex interrelated process leads to progressive cell destruction,

multiorgan dysfunction, neuronal apoptosis, and death.24 Many of these processes are temperature sensitive. Hypothermia has been shown to attenuate or ameliorate many deleterious temperaturesensitive mechanisms, thereby contributing to protection of the brain and heart. The pathophysiologic mechanisms involved in hypothermia are incompletely understood but have been studied in cellular, animal, and human models. The following actions are associated with hypothermia:

Reducing cerebral metabolism (approximately 6-8% per 1C) Reducing excitatory amino acids (glutamate release) Attenuation and/or reversibility of ischemic depolarization of the CNS, leading to membrane stabilization, electrolyte redistribution, and normalization of intracellular water concentration and intracellular pH (stabilization of the blood-brain barrier) Attenuation of oxygen free radical production and lipid peroxidation Restoration of normal intracellular signaling mechanisms (including calcium modulation) and inhibition of deleterious signaling mechanisms, such as apoptotic signaling Restoration of protein synthesis and gene expression Inhibition of deleterious inflammatory products (ie, cytokines, interleukins, arachidonic acid cascade end products) Attenuation of CSF platelet-activating factor (PAF) Inhibition of cytoskeletal breakdown

In the heart, hypothermia may decrease the area of injury, promote epicardial reflow, decrease myocardial metabolic demand, and preserve intracellular high-energy phosphate stores.25,26,27

Patient Selection
Inclusion criteria Patients who have been shown to benefit from induced hypothermia include the following:

Intubated patients with treatment initiated within a 6-hour post cardiac arrest (nonperfusing ventricular tachycardia [VT] or VF) time window Those able to maintain a systolic blood pressure >90 mm Hg, with or without pressors, after cardiopulmonary resuscitation (CPR) Those in a coma at the time of cooling. Coma is defined as not following commands. Brainstem reflexes and pathological/posturing movements are permissible. Patients with a Glasgow Coma Score (GCS) of 3 are eligible for hypothermia.

Exclusion criteria Exclusion criteria are in part based on theoretical increases in risk. Many studies have reported increased but nonsignificant increases in risk. Patients for whom hypothermia may carry increased risk include those with the following conditions:

Recent major surgery within 14 days - Hypothermia may increase the risk of infection and bleeding. Systemic infection/sepsis - Hypothermia may inhibit immune function and is associated with a small increase in risk of infection. Patients in a coma from other causes (drug intoxication, preexisting coma prior to arrest) Patients with a known bleeding diathesis or with active ongoing bleeding - Hypothermia may impair the clotting system. Check prothrombin time/partial thromboplastin time (PT/PTT),

fibrinogen value, and D-dimer value at admission. (Note: Patients may receive chemical thrombolysis, antiplatelet agents, or anticoagulants if deemed necessary in the treatment of the primary cardiac condition.) Patients with a valid do not resuscitate order (DNR)

Induced hypothermia after pulseless electrical activity (PEA), asystolic, or in-hospital arrest has not been fully studied, but it may be applied at the discretion of the treating physicians. The physician should consider the most likely etiology of the cardiac arrest. For example, patients with PEA arrest due to septic shock may be poor candidates for hypothermia. Although their brain might benefit, the impairment to the immune system from hypothermia may be more significant. Data from a June 2007 study of prehospital hypothermia examined secondary results of clinical outcomes.23 Among 125 patients total, 74 had non-VF arrest, that is PEA (n=34), asystole (n=39), or unknown rhythm (n=1). In the non-VF group, the survival to hospital discharge was worse in the cooled group (6%) than in the noncooled group (20%). This study was not intended or powered to detect differences in clinical outcome at discharge, but it raises concern with treating patients with PEA or asystole and ROSC with hypothermia in the prehospital setting. Other preliminary data suggest that the indications for hypothermia will broaden considerably in the future. Induced hypothermia is not recommended for patients with an isolated respiratory arrest.

Treatment Protocols
Treatment goal

In most centers, the patient is actively cooled by using an induced hypothermia protocol for 24 hours to a goal temperature of 32-34C. The goal is to achieve the target temperature as quickly as possible. In most cases, this can be achieved within 3-4 hours of initiating cooling. Rewarming is begun 24 hours after the time of initiation of cooling (ie, NOT from the time the target temperature is achieved). More evidence is needed to define the optimal duration of hypothermia treatment in humans. In animal models, effective hypothermia treatment can be less than 24 hours if initiated rapidly after ROSC. In other animal models with long duration of cardiac arrest and delayed initiation of hypothermia, treatment for 48 hours is needed to achieve good neurological outcomes. Preparation Shivering, the bodys attempt at maintaining temperature homeostasis, is a concern when trying to achieve a hypothermic state. Shivering is uncomfortable, and it generates heat, interfering with the cooling process. When using conventional surface cooling, sedation and chemical paralysis is usually necessary. Use of endovascular cooling can negate the need for paralysis (see Cooling Methods). Cooling must be performed rapidly to achieve maximum effectiveness and should be instituted as early as possible. Most studies have found it necessary to use both cooling blankets and ice packs to achieve the temperature goal. Other methods such as ice lavage, cold saline infusion, and endovascular methods may be used to help achieve target temperature.

Do not actively rewarm patients who are spontaneously hypothermic. When possible, hypothermia therapy for patients with out-of-hospital cardiac arrest should be initiated in the emergency department. Treatment can be continued while in the PCI laboratory and in the ICU. Place an arterial line early for blood pressure monitoring as peripheral vasoconstriction will increase the difficulty of placing the line after the patient is cooled.

A continuous core temperature monitor should be used; this provides data to modulate cooling efforts and to avoid overcooling. An esophageal, rectal, or bladder temperature is used to monitor the temperature. Several cooling systems including liquid or gel heat transfer and endovascular systems incorporate a temperature probe (rectal, bladder, or attached to the endovascular coil system) that provides feedback to modulate the amount of cooling provided. A pulmonary artery temperature probe may be used, if available. A secondary temperature device should be used to monitor temperature as well. A bladder probe is only accurate when urine output is adequate; therefore, an alternative to the bladder temperature probe is required in the setting of oliguria. This alternative temperature probe can be any core temperature monitor (eg, esophageal).

Methods: Medication

Patient comfort and sedation: Follow agitation and pain guidelines for the institution. Parenteral narcotic analgesia can be provided with morphine or fentanyl; sedation can be maintained with agents such as midazolam or propofol. Paralysis to prevent shivering: Buspirone (serotonin 1A partial agonist) and meperidine appear to lower the shivering threshold.28 Continuous pharmacologic neuromuscular blockade is usually required. Use of an endovascular technique along with buspirone and surface warming may avert shivering without the need for paralysis.29 The train-of-four method of monitoring neuromuscular blockade may not function properly when the patient is cold. Many patients can have paralytic agents discontinued once the target core body temperature is achieved. If shivering is observed, then the neuromuscular blocking agent needs to be resumed. Cold saline infusion can be given via a peripheral line or femoral venous catheter to assist in achieving goal temperature. The infusion is 30 mL/kg of 4C normal saline over 30 minutes. This is not to be used via a jugular or subclavian line because the safety via this method is not yet known.

External cooling with cooling blankets or surface heat-exchange device and ice

Eligibility should be confirmed, and materials should be gathered. Obtain 2 cooling blankets and cables (one machine) to sandwich the patient. Each blanket should have a sheet covering it to protect the patients skin. Alternatively, place heat-exchange pads on the patient per the manufacturers recommendation. Pack the patient in ice (groin, chest, axillae, and sides of neck); use additional measures as needed to bring the patient to a temperature between 32C and 34C. Avoid packing ice on top of the chest, which may impair chest wall motion. Monitor vital signs and oxygen saturation and place the patient on a continuous cardiac monitor, with particular attention to arrhythmia detection and hypotension. Once a temperature below 34C is reached, remove ice bags, and the cooling blanket or heat-exchange device is used to maintain temperature between 32C and 34C.

Supportive therapy

A mean arterial pressure (MAP) goal of more than 80 mm Hg is preferred from a cerebral perfusion standpoint. Hypertension is potentially additive to the neuroprotection of hypothermia. Norepinephrine can be used, beginning at 0.01 mcg/kg/min and titrated to a MAP greater than 80 mm Hg. The treating team should determine the MAP goal, balancing

the cardiac safety with the theoretical advantage of higher cerebral perfusion pressures. Often, blood pressure remains elevated during hypothermia as a result of peripheral vasoconstriction. Hypotension is a concern during the warming phase. Practice standard neuroprotective strategies such as placing the head of the bed at 30.30 Monitor the patient for arrhythmia (most commonly bradycardia) associated with hypothermia. If life-threatening dysrhythmia arises and persists, or hemodynamic instability or bleeding develops, then active cooling should be discontinued and the patient rewarmed. An ECG Osbourne or camel wave may be present when cooling. Heart rate less than 40 is frequent and is not a cause for concern in the absence of other evidence of hemodynamic instability. Hematologic testing recommendations include CBC count, Chem 7, troponin level, arterial blood gas (ABG) level, and PTT at 0 hours. Hypothermia commonly causes hypokalemia, which may be exacerbated by insulin administration. Conversely, when patients are rewarmed, potassium exits cells, and hyperkalemia may occur. Repeat measurements of glucose, K+, and ABG are needed every 6 hours. Unexplained increases in serum amylase and lipase levels have been observed during hypothermic therapy and appear to have limited clinical significance. Potassium values less than 3.5 mEq/L should be treated while the patient is being cooled. Potassium administration should be stopped once rewarming begins. Elevated serum glucose level is deleterious to the injured brain. Tight glycemic control should be maintained. PCO2 should be maintained in the reference range (35-45 mm Hg). Skin care should be checked every 2-6 hours for thermal injury caused by cold blankets. Regularly check the patients temperature with a secondary temperature monitoring device when cooling. Do not provide nutrition to the patient during the initiation, maintenance, or rewarming phases of the therapy.

Controlled rewarming Rewarming of the patient is begun 24 hours after the initiation of cooling. The rewarming phase may be the most critical, as constricted peripheral vascular beds start to dilate. Peripheral hyperemia may cause hypotension. The literature recommends rewarming slowly at a temperature of 0.3-0.5C every hour. Rewarming will take approximately 8 hours. Rewarming with any device or approach:

Remove cooling blankets (and ice if still in use). The goal is to have the patient warm at about 0.3-0.5C per hour up to a target of 36C. One method is to set the water temperature in the cooling device to 35C and then increase the water temperature by 0.5C every 1-2 hours until a stable core body temperature of 36C has been reached for 1 hour. Maintain the paralytic agent and sedation until the patients temperature reaches 35C. If infusing, discontinue the paralytic agent first. The sedation may be discontinued at the physicians discretion. Monitor the patient for hypotension secondary to vasodilatation related to rewarming. Discontinue potassium infusions. The goal after rewarming is normothermia (ie, avoidance of hyperthermia).31

Cooling Methods

Mild hypothermia is induced by using surface, internal, or a combination of cooling methods. Thermal heat-exchange cooling pads (eg, Arctic Sun) using water or gel may have superior rate of cooling (1.33C/h for water and 1.04C/h for gel) compared with cooling with 30 mL/kg iced saline plus ice packs (0.31C/h).32 Endovascular cooling may obviate the need for paralysis and provide very tight temperature control. Surface cooling with ice packs This method is inexpensive and represents an appropriate way to initiate cooling. However, it can be messy and is less than optimal in the rate of cooling and target temperature maintenance. Practically, ice packs are placed in anatomic areas that have large heat-exchange capability (the head, neck, axillae, and groin) and are replaced when the ice packs have substantially melted. In addition to ice packs, evaporative cooling with fans has been used. The average temperature drop using ice packs is moderately slow and highly variable and is reported to be 0.030.98C per hour. Surface cooling with blankets or surface heat-exchange device and ice Conventional surface cooling blankets are also suboptimal because of poor surface contact with the patient's skin. However, a combination of water-circulating cooling device and ice packs are effective at rapidly cooling patients and are fair at maintaining target temperature. Many clinical studies have used this combination. The patient is sandwiched between 2 blankets or the cooling device's heatexchange pads are placed and then ice packs are applied. When the target temperature is achieved, the ice packs are removed and the blanket or device is used to maintain the target temperature. Newer medical devices are on the market that have adhesive gel that facilitates heat exchange and are considerably more effective in the rate and maintenance of cooling (see Media files 1-3). Surface cooling helmet Hachimi-Idrissi et al used a helmet cooling device in their human clinical study.33 The soft bonnetlike helmet contained a solution of aqueous glycerol that facilitated heat exchange. This method works, but it may be slower than other methods. Internal cooling methods using catheter-based technologies Two devices are currently available for use: Celsius Control System (Innercool, Inc, San Diego, CA) and Cool Line System (Alsius, Inc, Irvine, CA). These technologies are also referred to as endovascular heat-exchange catheters. Heat exchange occurs between cooled saline that passes through the heat exchange portion of the catheter (in a coil with large surface area for heat exchange) and the blood that flows over the outer surface of the catheter. Endovascular cooling and rewarming is reported to be faster (1.46C32 , 1.59C/h29 ) and better at maintaining target temperature. These devices are generally placed in the femoral vein and are associated with a low rate of complications. Guluma et al reported endovascular cooling along with buspirone and surface warming to allow mild therapeutic hypothermia without shivering and avoiding the need for chemical paralysis.29 Extremely tight temperature control was also documented.29 Thus, intravascular cooling allows:

Most rapid cooling Tightest control of target temperature Minimization of shivering and possible increase in the patient's comfort as cutaneous warming is permitted Opportunity to avoid need for chemical paralysis of the patient

Internal cooling methods using infusion of cold fluids Many have studied the effect of cold fluid infusion for the induction of mild-to-moderate hypothermia in humans. The rates of induction are variable but otherwise considered to be rapid. Cold fluid infusion with concomitant use of cooling blankets has also been shown to be efficacious. Typical infusion volume is either 30 mL/kg or 2 L of fluid using either normal saline or lactated Ringer solution. In the several studies that have investigated cold fluid infusion, there has not been an association with increased venous pressure, left atrial filling pressures, pulmonary pressures, pulmonary edema, cardiac arrhythmia, or other major complications.22,34,35,36,37,32,38

Alternative Indications
Many indications for mild, moderate, and profound therapeutic hypothermia are currently being experimentally and clinically evaluated. Preliminary data, prospective studies, and meta-analysis suggest that the indications for therapeutic hypothermia will broaden considerably in the future. Therapeutic hypothermia may be considered for any patient with a severe brain injury without evidence of hemorrhage or elevated risk of cerebral hemorrhage at the discretion of the treating physician. However, currently, no expert consensus or advisory panel support the broad application of hypothermia outside its current indication for comatose patients after ROSC due to VF or VT. Traumatic brain injury Mild therapeutic hypothermia has been shown to be effective in traumatic brain injury (TBI) with high intracranial pressure (ICP) in adults.39,40 No benefit exists for patients with TBI with normal ICP.15 Moderate therapeutic hypothermia adds no benefit and may increase incidence of hypothermiarelated complications.41,42 Compared with short-term hypothermia (2-3 d), long-term hypothermia (5 d) significantly improves the outcome of patients with severe TBI with cerebral contusion and elevated ICP without causing significant complications. Some research suggests that all patients with TBI may benefit from hypothermia (not just patients with elevated ICP) and that the level of prehospital hypothermia predicts efficacy. Regarding the importance of prehospital hypothermia and its effect on all TBI in adults aged 18-45 years, a large multicenter clinical trial (National Acute Brain Injury Study: Hypothermia II [NABIS:H II]) is currently underway and is expected to be complete by late 2008. The Cochrane Database of Systematic Reviews (2007) reports that hypothermia after TBI has not been shown to reduce death or disability. The review was in part based on one study that was stopped early due to lack of effect. The study inclusion criteria may have been too broad. The report did not take other excellent and compelling studies performed in Japan and China into proper consideration.40,15,41,42,43,44,45,46 Hypothermia in children can be considered an optional therapy for refractory intracranial hypertension, but, to date, should not be regarded as standard of care. Studies have shown that hypothermia is safe and may be effective in selected pediatric patients with TBI; however, pediatric expert consensus requires more prospective clinical trials to be conducted. Mild therapeutic hypothermia may lower the seizure threshold and cause pulmonary hypertension in approximately 30% of pediatric patients treated with hypothermia. Complications can be predicted and safely treated in the ICU environment.47,48,49 Acute stroke Considerable experimental evidence and clinical experience demonstrate that hypothermia reduces

the volume of infarct and may preserve and restore the at-risk neurons in the penumbra in focal ischemic brain injury. Strong evidence suggests that hyperthermia (fever) is correlated with poor clinical outcomes.50 Case-control studies and ongoing clinical trials in humans are examining the role of hypothermia in acute stroke. However, to date, large prospective randomized human clinical trials to support the widespread adoption of hypothermia in acute stroke have not been completed.51 Both the Cochrane Database of Systematic Reviews and the 2007 American Stroke Associations Guidelines consider therapeutic hypothermia for ischemic stroke to be level IIIb evidence. Pediatric cardiac arrest and neonatal hypoxic-ischemic encephalopathy The International Liaison Committee on Resuscitation (ILCOR) advocates the use of therapeutic hypothermia following perinatal asphyxia-related cardiac arrest in term newborns.6 Traumatic spinal cord injury Several review articles mention the use of hypothermia in patients experiencing traumatic spinal cord injury, but, currently, no large case series assess the value of this intervention in these individuals.

Controversial Areas and Adverse Effects

Cooling variables Clearly, the variables of timing of the initiation of cooling, cooling technique, rate, depth, and length of cooling and rewarming all probably have some effect on mortality and morbidity. However, at this time, these variables are not well studied and are the focus of several current experimental and clinical trials. Furthermore, these variables will most likely have different levels of importance based on clinical indications. Adverse effects Hypothermia is associated with a number of adverse effects and complications. The main adverse effects reported are shivering, cardiac arrhythmia, sepsis, coagulopathy, and electrolytes and metabolic disturbances.52,53 However, many large clinical trials and meta-analyses have reported these adverse effects to be infrequent. A trend toward increased incidence of sepsis has been noted.