Return of the Ice Age: Therapeutic Hypothermia

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Journal Article - July 2008



By Ralph McCleskey, MD, FACP

Send reprint requests to Ralph McCleskey, MD, Medical Director, Cardiac Rehabilitation, Hendrick Health Systems, 1850 N 18th #400, Abilene, TX 79601.


The prognosis of patients who suffer an out-of-hospital cardiac arrest continues to be poor despite 60 years of progress in cardiopulmonary resuscitation. Three trials have demonstrated the effectiveness of mild hypothermia in improving both neurological recovery and survival in patients with ventricular fibrillation (VF) and return of spontaneous circulation. Despite recommendation from the International Liaison Committee on Resuscitation that hypothermia should be used, it has not received widespread acceptance. Additional trials to explore the utility of mild hypothermia are recommended. Until new data are available, the use of mild hypothermia in patients with out-of-hospital VF is recommended.




The modern era of cardiopulmonary resuscitation began nearly 60 years ago with the work of Elam, Safar, and Kouwenhoven, who described the use of mouth-to-mouth resuscitation and chest compression. 1,2 Despite nearly 40 years of prehospital advanced life support, the survival rate of out-of-the-hospital cardiac arrest continues to be poor. 3 More than half of the victims who develop return of spontaneous circulation (ROSC) die in the hospital, usually of anoxic brain injury. This review will evaluate the use of mild therapeutic hypothermia to improve neurologic outcomes in patients with cardiac arrest and ROSC.



Historical Background

The use of hypothermia dates back to Hippocrates, but the use of cold temperatures in modern clinical medicine is probably only 200 years old. In 1803, the Russian method of resuscitation consisted of covering a patient with snow and hoping for ROSC. 4 During Napoleon's Russian campaign in 1812, surgeon Baron de Larrey attempted to preserve injured limbs and provoke anesthesia by packing injured soldiers in the snow. The first recorded clinical use of hypothermia occurred in 1937, when Fay cooled a patient to 32° C for 24 hours in an attempt to prevent multiplication of cancer cells. In 1941, Smith and Fay reported on a large series of patients with severe head injury in which they found that induced therapeutic hypothermia improved the recovery of the conscious state. 5 Since the 1950s, moderate hypothermia (28° C to 32° C) induced prior to cardiac arrest has been used successfully to protect the brain against the ischemia that occurs during some open-heart procedures. The use of this technique after cardiac arrest in humans was also described in the late 1950s. Complications of arrhythmias, coagulopathy, and infection, as well as uncertain benefits, however, caused this technique to be largely abandoned. 6 In subsequent years, this technique was rarely used, and only a few publications described the applications of therapeutic hypothermia. 5 Safar and his colleagues rekindled interest in therapeutic hypothermia using a relevant model in dogs in the early 1980s. In 1987, Safar discovered that mild hypothermia, accidentally present during prolonged cardiac arrest in dogs, was beneficial. 7 Subsequent dog studies confirmed that mild hypothermia after resuscitation for ventricular fibrillation resulted in normal brain function and normal histological findings.

In the early days of therapeutic hypothermia, the benefit was believed to be due to a reduction in oxygen requirements. However, the discovery of the benefit of mild hypothermia, which does not lower oxygen uptake, made it more likely that hypothermia provides protection against multiple harmful biochemical reactions. 8 The cerebral reperfusion injury that occurs when cerebral blood flow is restored is related to increased intracellular levels of glutamate. This increased level activates ion-channel complexes that cause calcium to shift from extracellular to intracellular fluid. This leads to the accumulation of oxygen-free radicals and the activation of degradative enzymes. 9

Along with other harmful mechanisms (eg, excitotoxicity, lipid peroxidation, DNA damage, and inflammation), this leads to neuronal death in vulnerable regions of the brain, including the hippocampus and cerebellum. 8  The demonstration of the benefit of mild hypothermia in animal models led to promising preliminary human studies. 6 The evidence was insufficient, however, to recommend use of therapeutic hypothermia in the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. 10



Clinical Studies

In 2002, the results of two prospective randomized trials that evaluated neurologic recovery in comatose survivors of out-of-hospital cardiac arrest were published.

One study was performed in nine centers in five European coutries. 11  The other study was conducted in four hospitals in Melbourne, Australia. 12

Inclusion criteria for these trials were similar: ROSC, and patients remaining intubated and ventilated, with persistent coma after out-of-hospital cardiac arrest due to ventricular fibrillation. Additional criteria for the European study included witnessed cardiac arrest, an interval of 5 to 15 minutes from patient collapse to first resuscitation attempts, and an interval of less than 60 minutes from collapse to ROSC. Exclusion criteria included arrests that were not of cardiac origin, severe cardiogenic shock, pregnancy, or age younger than 18 years or older than 75 years.

In the European study, patients assigned to the hypothermia group were cooled to a target temperature of 32° C to 34° C by use of a cold air mattress and ice packs. The goal was to achieve target temperature within 4 hours of ROSC and maintain it for 24 hours, followed by rewarming. In the Australian study, patients were cooled by application of cold packs to the head and torso begun in the field. Target temperature was 33° C. Hypothermia was maintained for 12 hours after hospital admission, and rewarming was started at 18 hours. An overview of the trials is shown in  Table 1 .

The hypothermia groups experienced some adverse events more frequently than did the control groups. The Australian group had a lower cardiac index, higher systemic vascular resistance, and more hyperglycemia. 12 The European group had more cases of pneumonia, bleeding, and sepsis, but this was not statistically significant. 11

The results of the Australian and European groups were similar and demonstrated a striking neurologic protection by mild hypothermia. In the Australian study, 49% of hypothermia patients had good neurologic function at discharge compared with 26% of normothermia patients. Mortality at discharge was 51% in the hypothermia patients and 68% in the normothermia patients.

In the European study, 55% of hypothermia patients had a favorable outcome at 6 months compared with 39% of the normothermia patients. The 6-month mortality was 41% in hypothermia patients and 55% in the normothermia patients. In addition to the neurologic protection afforded by mild hypothermia, the number needed to treat is quite low and is comparable to that for other important emergent treatments, such as thrombolytic therapy for acute myocardial infarction. 13 The outcomes are shown in  Table 2 .

Hachimi-Idrissi reported similar results in patients with asystole or pulseless electrical activity and ROSC. This study reported favorable neurologic recovery at hospital discharge in 25% of hypothermia patients, compared with 6% of normothermia patients. 14  A meta-analysis of these three trials concluded that mild hypothermia improves both short-term neurologic recovery and survival in patients resuscitated from cardiac arrest. 15

In October 2002, the American Heart Association (AHA) and the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation recommended that unconscious adult patients with ROSC after out-of-hospital cardiac arrest should be cooled to 32° C to 34° C for 12 to 24 hours when the initial rhythm was ventricular fibrillation. The evidence for this recommendation was considered to be Level I (one or more randomized clinical trials in which the lower limit of confidence interval for treatment effect exceeds the minimal clinically important benefit). 6

The 2005 AHA guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care revised the recommendation to Class IIa. (Data are obtained from randomized controlled trials, but trial size is small with less significant effect of treatment. Benefit of therapy exceeds risk. Intervention is considered standard of care and is acceptable, safe, and useful.) 16

In 2004, The European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study Group was founded. This registry entered data on 650 patients from 19 sites between March 2003 and June 2005. The group concluded that therapeutic hypothermia is feasible and can be used safely and effectively outside a randomized clinical trial. The group found the rate of adverse events to be lower and the cooling rate faster than the rates in previously published clinical trials. 17




Therapeutic hypothermia has been applied both in the field and in delayed hospital cooling. It has been used successfully in academic tertiary centers and in the community hospital setting. 18 Various methods have been used to produce hypothermia, including ice packs applied to the body, covering the body with a cooling blanket, and infusing cold saline. 6,19

The best means and optimal duration of cooling are not yet determined, but in the available trials, all methods and durations have shown benefit when compared with no cooling.

Currently, mild therapeutic hypothermia is the only available clinical tool for the remission of brain damage by ischemia and subsequent reperfusion. Despite this, therapeutic hypothermia for cardiac arrest has not been widely adopted. 20

An international Internet-based survey found that most cardiology and emergency medicine specialists (74% of US respondents) who care for cardiac arrest victims had never used hypothermia for this indication. The most common reasons cited for nonuse were "not enough data," "not part of Advanced Cardiac Life Support guidelines," and "too technically difficult to use." 21 All of these reasons contradict the available evidence. This situation is comparable to the lag that occurred in the adoption of the use of beta-blockers after myocardial infarction despite strong data demonstrating their effectiveness. 22 The European Hypothermia Group predicts with 95% confidence that treatment with hypothermia would prevent an unfavorable neurologic outcome in 1200 to 7500 patients a year. 11 Widespread adoption of the use of hypothermia in the United States could be expected to provide similar results.




Further clinical trials are needed to determine the optimum method of cooling and the maximum duration of cooling. Additional trials are recommended for patients with other arrhythmias, stroke, traumatic brain injury, spinal cord injury, and hemorrhagic shock. In the meantime, it is recommended that survivors of cardiac arrest associated with ventricular fibrillation receive treatment with mild hypothermia as soon as possible for a minimum of 12 hours. 23




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  3. Cobb LA. Variability in resuscitation rates for out-of-hospital cardiac arrest. Arch Intern Med . 1993;153(10):1165-1166.
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  6. Nolan JP, Morley PT, Vanden Hoek TL, et al; International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation . 2003;108(1):118-121.
  7. Safar P. Resuscitation from clinical death: pathophysiologic limits and therapeutic potentials. Crit Care Med . 1988;16(10):923-941.
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  9. White BC, Grossman LI, O'Neil BJ, et al. Global brain ischemia and reperfusion. Ann Emerg Med . 1996;27(5):588-594.
  10. American Heart Association in collaboration with the International Liason Committee on Resuscitation. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: An International Consensus on Science. Resuscitation . 2000;46(1-3):1-447.
  11. Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med . 2002;346(8):549-556.
  12. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med . 2002;346(8):557-563.
  13. Deem S, Hurford WE. Respiratory conferences in the critical care setting. Should all patients be treated with hypothermia following cardiac arrest? Respir Care . 2007;52(4):443-450.
  14. H achimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation . 2001;51(3):275-281.
  15. Holzer M, Bernard SA, Hachimi-Idrissi S, Roine RO, Sterz F, Müllner M; Collaborative Group on Induced Hypothermia for Neuroprotection After Cardiac Arrest. Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data meta-analysis. Crit Care Med . 2005;33(2):414-418.
  16. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2005;112(24 suppl):IV1-203.
  17. Arrich J; European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study Group. Clinical application of mild therapeutic hypothermia after cardiac arrest. Crit Care Med . 2007;35(4);1041-1047.
  18. Scott BD, Hogue T, Fixley MS, Adamson PB. Induced hypothermia following out-of-hospital cardiac arrest: initial experience in a community hospital. Clin Cardiol . 2006;29(12):525-529.
  19. Kim F, Olsufka M, Longstreth WT Jr, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation . 2007;115(24):3064-3070.
  20. Rincon F. Therapeutic hypothermia after cardiac arrest, slow to catch on. Ann Intern Med . 2007;143(3):171.
  21. Merchant RM, Soar J, Skrifvars MB, et al. Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest. Crit Care Med . 2006;34(7):1935-1940.
  22. Rogers WJ, Bowlby LJ, Chandra NC, et al. Treatment of myocardial infarction in the United States (1990 to 1993): observations from the National Registry of Myocardial Infarction. Circulation . 1994;90(4):2103-2114.
  23. Texas Medical Association Council on Scientific Affairs. Meeting Minutes; January 23, 2008.


Table 1. Overview of Clinical Trials to Evaluate Neurologic Recovery in Comatose Survivors of Out-of-Hospital Cardiac Arrest.




Age (years)

No.  (%)

No.  (%)

Minutes  to ROSC

Temperature (C)

Duration of Cooling (hours)



Hypothermia   (N=137)

    59 (51-69)

 33 (24)

 133 (97)

   21 (15-28)



Cool air

Normothermia   (N=138)

    59 (49-67)

 32 (23)

 132 (96)

   22 (17-33)



Hypothermia    (N=43)

  66.8 (49-89)    

 18 (42)

    43 (100)

  26.5 (14-39)



Ice packs

Normothermia    (N=34)

    65 (41-85)

  7 (21)

    34 (100)

   25 (16-34)



VF=Ventricular fibrillation
ROSC= Return of spontaneous circulation

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Table 2. Outcomes of Clinical Trials to Evaluate Neurologic Recovery in Comatose Survivors of Out-of-Hospital Cardiac Arrest.



 No.    (%)

   No.    (%)

    P Value



Alive at hospital discharge with favorable neurological recovery

   21/43  (49)

   9/34   (26)










Alive at 6 months with favorable neurological recovery

  75/136  (55)

   54/137  (39)









NNT=Number needed to treat

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