Therapeutic Hypothermia

In 2012, emergency medical services (EMS) personnel in the United States treated more than 382,000 out-of-hospital cardiac arrests.1 Only 11.4% survived to hospital discharge.1

The largest modern report of cardiac arrest was published by the National Registry of Cardiopulmonary Resuscitation, and it found that of the 36,902 adults and 880 children who experienced in-hospital cardiac arrest, 19,819 adults and 524 children regained spontaneous circulation. Mortality rates were 67% in the adult patients and 55% in the children.2 Because a high number of cardiac arrests occur outside the hospital setting, EMS protocols were introduced to begin therapeutic hypothermia (TH) in the field. The thinking was that earlier initiation would decrease mortality and improve neurologic outcomes. Earlier initiation of TH correlated with increased survival in patients who did not have multiple comorbidities. In patients who have experienced anoxic brain injury, induction of TH with a goal temperature range between 32º and 34º C for 12 to 24 hours after arrest was determined beneficial in preventing further neurologic injury.3

The concept of TH is not new4; canine models were used to document the protective mechanism of TH and the successful outcomes prior to trials on humans, which began in 1961.4 TH has also been used in cardiac surgery to reduce the body temperature (28º to 32º C) to prevent ischemia and provide neurologic protection.3

Return of spontaneous circulation after cardiopulmonary resuscitation results in reperfusion injury and can be classified as a systemic inflammatory response syndrome (SIRS).5 These post-cardiac arrest immune markers reflect increases in serologic markers, endothelial dysfunction and microcirculatory perfusion with increased levels of IL-1ra, IL-6, IL-8 and IL-10.5 The reperfusion injury with these increased levels is evident as early as 3 hours post-arrest5 and can last 2 to 12 hours after the initial arrest.6

Levels of these inflammatory mediators can be limited or controlled with the use of TH. Because the brain receives 20% of cardiac output,6 TH can allow for the decrease in cerebral metabolic demands of oxygen consumption.7 For every 1º C decrease in body temperature, metabolic demands decrease by 6% to 7%.8 This is especially beneficial because permanent neuronal injury and death begin within 6 to 8 minutes of ischemia.6 Along with the reperfusion injury, hypotension, hypoxemia, impaired cerebrovascular autoregulation and brain edema can affect cerebral blood flow and oxygen delivery.9

Landmark Studies
Two major studies have examined TH use in humans after ventricular fibrillation-associated cardiac arrest.10,11 The first was conducted in Melbourne, Australia, by Bernard et al from September 1996 to June 1999.10 The researchers evaluated patients discharged to home or rehabilitation facility versus death after therapeutic hypothermia. Once the return of spontaneous circulation occurred after cardiac arrest, the patient was assigned to a treatment group (Table 1). On odd-numbered days, patients were assigned to the hypothermia group.10

At the time of emergency department arrival, medical and laboratory assessments were completed on all patients. These included assessments of mechanical ventilation with adjustment according to arterial blood gases (ABGs); the goal was to maintain a partial pressure of pO2 100 mg Hg and PCO2 40 mm Hg. Patients also received a neurologic assessment followed by the administration of Archive ImageAmidazolam and vecuronium.Other medications administered included thrombolytic therapy or heparin (if indicated by electrocardiogram, on the basis of an acute ischemic-based coronary syndrome); lidocaine bolus and infusion for arrhythmias; potassium to maintain a serum level of 4.0; and aspirin.

Temperature measurements were obtained using a tympanic or bladder temperature catheter until insertion of a pulmonary artery catheter.10 Hemodynamic measurements were then completed at intervals during the hospital stay, along with lab analyses.

For patients assigned to the hypothermia group, emergency medical technicians began the cooling process during transport to the emergency department by removing the patient’s clothing and applying ice packs. On arrival, the cooling process continued with the application of cold packs to the body. The goal core temperature for the hypothermia group was 33º C; midazolam and vecuronium were used to prevent shivering, averting a further increase in body temperature.

After 18 hours of induced hypothermia, the patients were slowly rewarmed over 6 hours with air-heated blankets. During the rewarming phase and throughout the rest of the stay, institution-specific intensive care unit protocols were followed. These included temperature, mean arterial blood pressure, pulse, cardiac index and systemic vascular resistance. Patients assigned to the normothermic group had a goal core temperature of 37º C. If anyone in this group had hypothermia, passive rewarming was initiated on arrival.

Twenty-one of the 43 patients (49%) in the hypothermia group had a good outcome. This was defined as discharge to home or a rehabilitation center and ability to perform self-care. Poor outcome was defined as death or as discharge to a long-term nursing facility awake but completely dependent.

In the group that did not undergo hypothermia, only 9 of 34 patients (26%) had good outcomes (P = 0.046). The study demonstrated a better prognosis when hypothermia was initiated early and maintained after cardiac arrest as opposed to normothermia.

The second landmark study was conducted in nine medical centers in five European countries from March 1996 to January 2001.11 The Hypothermia After Cardiac Arrest Study Group evaluated hypothermia for post v-fib cardiac arrest patients. Effectiveness was defined as the ability to live independently or work part time in the 6 months after cardiac arrest, based on the Pittsburgh Cerebral Performance Category (CPC) of 1 (good recovery) or 2 (moderate disability) on a five-category scale.11 Once patients met the study criteria (Table 2), they were assigned to a group while in the emergency department; group selection was randomized by biostatistical center.

Archive Image6The medications used during TH include midazolam and fentanyl for ventilator management (titrated over 32 hours as needed) and pancuronium to prevent shivering. Temperature was monitored via a thermometer embedded in a urinary catheter. The goal core temperature for the hypothermia patients was 32º to 34º C for the 4 hours after TH initiation. This intervention was delivered via use of a mattress with a cover that continuously delivered cold air to the body. Patients were maintained at this temperature for 24 hours, at which point passive rewarming was permitted over the next 8 hours.

The researchers found that 75 of the 136 patients (55%) in the hypothermia group had favorable neurologic outcomes indicated by a CPC of 1 or 2, as compared with 54 of the 137 (39%) in the normothermia group (risk ratio 1.40; 95% confidence interval, 1.08 to 1.81). Notably, some patients demonstrated increased frequency of bleeding (26% in the TH group, 19% in the normothermic group), sepsis (13%/7%), pneumonia (37%/29%) and pancreatitis (1%/1%).11

Cooling Techniques
Cooling should be initiated as soon as possible after the return of spontaneous circulation. This means a goal temperature between 32º and 34º at 12 to 24 hours after v-fib arrest.3 Achieving this body temperature can be accomplished with the administration of intravenous fluids12 and external cooling devices10 or through the use of intravascular devices.12 Each of these methods has been studied and used in order to achieve a given temperature (Table 3).

The use of IV fluids of 0.9 NS at 4º C for cooling has been studied in healthy volunteer patients13 and sick patients.14 This research has documented more success achieving TH with cold IV infusions on younger patients and those with lower amounts of body mass. Body surface area did not seem to affect the outcomes.14

As an example, Kim et al administered 2 liters of saline over 20 to 30 minutes to patients who had experienced cardiac arrest.15 Core body temperature dropped an average of -1.7º C in 30 minutes, when used concomitantly with the administration of vecuronium and midazolam. This suggests that neuromuscular blockade augments the effect of cooled saline. The study authors noted no adverse effects on blood pressure, heart rate or cardiac hemodynamics.15 However, they did not control for patient body weight, did not take into account the patient’s weight, and excluded patients weighing less than 50 kg.

In study by Kliegel et al,12 researchers measured rate of cooling with lactate ringers cooled to 4º C. Patients received 2000 mL intravenous bolus, and core temperatures decreased to a TH temperature goal (33 +/- 1 degrees C) with a median decrease in core temperature 1.5 ± 2º C per hour.12 The majority of studies completed have documented highly reliable maintenance of core temperature and rapid cooling rates once IV infusion has begun.16

External devices have also been studied to determine both the effects and rates of decreasing core body temperature. As seen in the Bernard study, ice packs can be extensively applied to the head, neck, torso and limbs to achieve a goal core temperature of 33º C.10

Another external cooling device is a cooling mattress.11 It is essential that all parts of the body are covered. The cooling rates for these external devices are considerably lower than with other methods.16 In a study by Ihachismi-Idrissi, a helmet with a temperature of – 4º C just prior to use was applied to reduce body temperature to 34º C.17 It was the first time in which an easy-to-use, safe and effective device lowered the central (tympanic) temperature in a median time of 60 minutes and the core (bladder) temperature in a median time of 180 minutes without the use of any other cooling devices.17 Application of this subzero temperature to the scalp did not cause any freezing or necrosis lesions, possibly because the scalp was partially insulated from the cold solution by the cooling cap material and the surgical paper cap.17

Although all methods for achieving TH have been proven beneficial, each can have harmful side effects. The prevailing opinion is that the best way to achieve a rapid decrease in temperature is with the use of cold fluids delivered through an intravascular device.16 In a study that used endovascular cooling alone or in combination with ice cold IV or ice packs, researchers documented a significantly faster achievement of goal temperature in patients who received cold IV fluids.18 In the Kliegel study,12 endovascular access was used when access was obtained in a femoral vein with attachment to a cooling machine. This allowed for a quicker cooling method when used in addition to other methods.

Surveillance & Monitoring
Essential body systems require monitoring during TH. These include temperature, central venous pressure (CVP), hemoglobin (Hgb), mean arterial pressure (MAP) and oxygen saturation. Each of these system indicators has been studied in the context of TH. TH outcomes are improved when hemodynamics are within a given range. Examples include Hgb greater than 8 g/dL, CVP 8 mm Hg to 12 mm Hg, MAP 65 mm Hg to 100 mm Hg, and arterial oxygen saturation between 94% and 96%.9 The keys to success seem to be TH initiation as soon as possible and the achievement of optimal hemodynamics.9

The temperature range for TH that has proven most effective is between 32º and 34º C.3 When core body temperature begins to decrease to 28º to 30º C, complications can include arrhythmias leading to v-fib, increased systemic vascular resistance, reduced cardiac output, and diuresis.16 Although the majority of studies have shown that a temperature range of 32º to 34º C is effective, no optimal temperature has been determined.9

Another variable that must be evaluated while monitoring a patient during TH is CVP. Because the reperfusion injury has a SIRS-like effect,5 the goal for CVP is 8 mm Hg to 12 mm Hg.19 A goal for CVP has not been defined; the stated goal is that used and cited in published studies.

The important evaluations that must be considered for CVP elevation unrelated to volume status include tamponade, myocardial infarction, pulmonary embolism and pneumothorax. Volume status must be considered with use of CVP, and volume replacement is usually required soon afterward due to intravascular volume depletion.9 This was demonstrated in a study20 in which researchers infused cold IV fluids and documented an increase in CVP from 8 mm Hg to 12 mm Hg with no evidence of pulmonary edema. This supports the safety of large-fluid resuscitation.

An optimal hemoglobin level in the context of TH has not been defined.9 In the early goal-directed therapy for sepsis, hematocrit was evaluated and treated to obtain a level greater than 30%, but few patients were transfused to remain above this level.19 A study of ICU patients who were placed in a control group and transfused to maintain Hgb 7.0 g/dL to 9.0 g/dL showed superior effects as compared to the liberal group maintained at 10 g/dL to 12 g/dL.21 A protocol developed by Sunde et al used 9 g/dL to 10 g/ dL as a transfusion goal to maintain this level. Another study found no significant difference in outcomes when Hgb was maintained between 10 g/dL and 12 g/dL as opposed to 7 g/dL to 9 g/dL.22

No goal for MAP has been defined, but the value remains important in order to perfuse the brain without causing harmful effects on an ischemic heart. For a patient who is experiencing cardiac dysfunction or an evolving MI, a lower MAP may be more beneficial to the heart and allow for optimal perfusion.9 MAP, as any other variable, should be optimized to maintain adequate blood pressure and organ perfusion.

A study involving ICU patients with sepsis aimed for a goal MAP of greater than 65 mm Hg with the use of a vasopressor if lower or the use of vasodilators if MAP exceeded 90 mm Hg.19 Rivers et al documented less mortality in the group treated with early goal-directed therapy than in the group not treated in this manner.19 Further study indicated that patients treated with TH had higher MAPs and increased use of vasopressor and IV fluids, but these produced no effect on patient outcomes.23

No studies have determined the optimal arterial blood pressure during the reperfusion stage. In a study by Sunde, arterial blood pressure was controlled so as not to place too much strain on the myocardium because of increased blood pressure.18

Archive Image6As stated, vasopressors can be used to increase MAP and optimize hemodynamic goals. The first-line treatment for hypotension in TH is intravenous fluids.9 No single medication or combination of drugs has been proven superior in the context of TH, but multiple medications have been studied.9 In several studies,17-19,23 vasopressors were used to reach the goal MAP pressure. In one of these studies,18 dopamine was used to help with goal MAP. If a patient became too tachycardic, the medication was changed to norepinephrine. Dobutamine and epinephrine have also been used for patients who experience pump failure or cardiogenic shock.18 The use of inotropes or a vasopressor should ultimately be guided by blood pressure, heart rate, echocardiographic estimate of myocardial dysfunction, surrogate measures of tissue oxygen delivery, cardiac index, and systemic vascular resistance.9

Published guidelines emphasize the use of a fraction of inspired (FiO2) oxygen of 1.0 during CPR, and clinicians often maintain 100% oxygen for variable periods. Adjustment of FiO2 to produce an arterial oxygen saturation of 94% to 96% can prevent acute hyperoxia,9 which should be avoided in the initial post-arrest period.Close and frequent monitoring of ABGs should occur for management of ventilator setting with the adjusted temperatures caused by TH.15 No data are available to support the use of a specific tidal volume during post-cardiac arrest care.9

Because reperfusion after hypothermia mimics SIRS, the guidelines for SIRS should be followed to achieve optimal hemodynamics. Using early goal-directed therapy at the earliest onset of shock can have significant short-term and long-term benefits (Table 4).19

Adjuncts for Effective TH
During both the initiation phase and maintenance phase of TH, sedation and paralytics must be administered. The drugs must be given continuously via infusion in order to prevent shivering, which increases body temperature. The sedative medications used in multiple studies include fentanyl infusion8,11,12,14,23-25 with doses between 0.002 mcg/kg/hr and 3.0 mcg/kg/hr continuous infusion in addition to or in combination with propofol (Diprivan)8,13,25 titration drip, morphine 2 mg/hr to 4 mg/hr25 or midazolam 0.04 mg/kg/hr to 0.2 mg/kg/hr.8,10,12-15,23,24 Medications used as paralytics during both processes include vecuronium bolus and infusion8,10,15,23 in combination with or in addition to rocuronium5,24 or pancuronium bolus doses.17,24

Published data support the use of sedation and paralytics after cardiac arrest.9 The use of paralytics and sedatives, however, is essential with the use of TH in order to prevent shivering, which would increase body temperature during all phases.9 Sedation and paralytic medications cause the body to demand less oxygen consumption when it is adequate and allow the patient to reach goal temperature in a shorter amount of time. In addition to these adjunct medications, if continued infusions of neuromuscular blocking agents are needed, the addition of continuous electroencephalography monitoring is advised.9

A slow rewarming process is essential for best TH outcomes.10,11 For example, patients in the Bernard study10 underwent rewarming after 18 hours of TH, with the rewarming process taking place over 6 hours. The Hypothermia After Cardiac Arrest Study11 allowed for TH over 24 hours, with rewarming occurring over a median time of 6 hours. Further studies18,25 have shown that rewarming must occur slowly, at a rate of 0.25º to 0.5º C per hour.

Once the patient reaches the appropriate temperature specified by the protocol in use, he or she can be weaned from the sedation and neuromuscular agents. Rewarming should not be initiated too early for fear of diminishing the neuroprotective effects created and maintained by cooling.25 It is essential to continue monitoring the patient’s vital signs and electrolytes. During the rewarming phase, a shift occurs in the intravascular compartment, causing vasodilation leading to hypovolemia and electrolyte imbalances.25 Rebound hyperthermia can be minimized by using cooling pads for up to 48 hours afterward, to prevent temperatures greater than 37º C.25

Better Prognosis Possible
TH adds to the arsenal of treatment options for patients recovering from ventricular fibrillation-associated cardiac arrest and contributes to a better prognosis. TH has become a more widely implemented medical treatment. Early initiation, close and careful monitoring of specific surveillance variables, delivery of proper medications for sedation and paralysis, and implementation of a slow rewarming process appear to increase the likelihood of positive neurologic outcomes after a ventricular fibrillation-related cardiac arrest.

Evidence-based conclusions about the optimal duration of TH are lacking, and the best method for initiating TH also is not clear. Continued use of TH requires determination of the best method of initiation, optimal duration and optimal rewarming time. Studies focused on other arrhythmias resulting in cardiac arrest would be beneficial in determining other possible applications of TH.


Lauren M. Schroeder is an acute care nurse practitioner who practices in the emergency department at the University of Maryland Medical Center in Baltimore. She has completed a disclosure statement and reports no relationships related to this article.


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