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Out of hospital cardiac arrest and therapeutic hypothermia

Created: 21/5/2007


Therapeutic Hypothermia after Cardiac Arrest

Dr John Griffiths DICM MRCP FRCA MA 
CriticalCareUK Editor

Focus on out of hospital cardiac arrest

Out of hospital cardiac arrest is a common event, particularly in the Western world. Cardiac arrest kills more than 90% of its victims before they reach the hospital, causing more than 300,000 deaths in the United States each year. The onset is sudden and dramatic, typically related to ventricular tachycardia, ventricular fibrillation or both. Brain death can occur in four to six minutes. With an ever increasing and ageing population out of hospital cardiac arrest is likely to become even more frequent, despite a drive towards public education regarding cardiac risk and cardiological and health advances and the availability of portable defibrillators.

Focus on therapeutic (induced) hypothermia

Therapeutic hypothermia is defined as the controlled lowering of core temperature for therapeutic reasons. The earliest recorded clinical use of induced hypothermia was in 1937 when Dr. Temple Fay cooled a female patient to 32°C for 24 hrs in an attempt to relieve the symptoms of metastatic cancer. Induced hypothermia as a therapy was proposed on the basis of laboratory work suggesting that cancer cells would not divide at a lower body temperature. The induced hypothermia was undertaken in a general ward, with the patient sedated by using an oral barbiturate before being packed in ice. After 24 hrs, the patient was rewarmed, apparently without ill effect. Induced hypothermia has been used routinely in the operating room since the early 1950s for patients undergoing cardiac surgery and more recently for neurologic surgery. Increasingly, mild to moderate induced hypothermia (32–34°C) is being used in the intensive care unit (ICU) for selected patients with neurologic injury. In particular, recent clinical studies have suggested that induced hypothermia after resuscitation improves outcome in patients with anoxic neurologic injury following out-of-hospital cardiac arrest. There also have been preliminary clinical studies of induced hypothermia for patients in the ICU with other types of neurologic injury, including severe traumatic brain injury, neurologic infection, major stroke, hepatic encephalopathy, ARDS and newborn hypoxic-ischemic encephalopathy.

Focus on induced hypothermia after cardiac arrest

Two recent landmark randomised trials of induced hypothermia initiated after out of hospital cardiac arrest exist in the literature. Both studies cooled the study patients to mild hypothermic levels of 32-34°C (Tables 1 and 2). Both these studies demonstrated a moderate neurologic benefit in survivors. In the Australian study, half of the 43 patients treated with hypothermia were discharged alive, compared to about a third of the 34 patients who received standard care. In the European study, more than half of the 136 hypothermic patients had a "favorable neurological outcome" at six months—meaning they were living independently—compared with less than 40% of the 137 patients who were given standard care. However, the exclusion criteria applied in both studies were numerous and vast and extrapolation to the entire out-of hospital cardiac arrest population (including all those aged over 75 years) must be done with caution. In the European study 3551 patients were screened to recruit 275 patients while in the Australian study only 84 suitable patients were admitted to four centres over a period of 33 months. In addition the apparent lack of a significant difference in complications between the hypothermia and normothermia groups in the European study may simply be a reflection of a study that was not powered to detect a difference in the incidence of complications. If, however, cooling patients that have suffered an out-of-hospital arrest does translate into improved neurological outcome and survival then this approach should be widely adopted. There is no clear understanding of the mechanism(s) by which hypothermia may improve neurologic outcome. Mild hypothermia only marginally decreases oxygen consumption (Table 3). Other postulated mechanisms include the reduction in the production, release and uptake of damaging excitatory neurotransmitters, suppression of free-radical reactions and calcium shifts, maintenance of the integrity and fluidity of lipoprotein membranes and reduction in intracellular acidosis that can all lead to mitochondrial damage and apoptosis.

Table1. The European Study*

Multi-centre randomized clinical trial

275 patients with witnessed out of hospital cardiac arrest

Inclusion criteria:

· ventricular fibrillation or pulseless ventricular tachycardia as the initial cardiac rhythm

· presumed cardiac origin of the arrest

· 5-15 minute delay between collapse and attempted resuscitation by emergency medical personnel

· restoration of spontaneous circulation in <60 mins

Exclusion criteria included:

· spontaneous hypothermia (<30°C)

· drug induced coma prior to cardiac arrest

· pregnancy

· terminal illness

· coagulopathy

· response to verbal commands, hypotension or hypoxaemia after return of spontaneous rhythm and prior to randomization

All patients were sedated, paralyzed and mechanically ventilated

Hypothermia group

· Cooled to a target bladder temperature of 32-34°C for a period of 24 hours from the start of cooling

· Cooling was carried out using a cooling mattress, with the addition of ice packs if the target temperature was not achieved within 4 hours.

· Followed by a period of passive rewarming


At 6 months significantly more patients in the hypothermia group (55%) than in the normothermia group (39%) had a favourable outcome (good recovery or moderate disability on the Pittsburgh cerebral-performance scale)

Mortality was also lower in the hypothermia group (41 vs. 55%).

Trend to more complications in the hypothermia group but the proportion of patients with any specific complication did not differ between groups.

* The Hypothermia after Cardiac Arrest Study Group. NEJM 2003.

Table 2. The Australian group**

"Randomized" 77 patients into hypothermia and normothermia groups

· randomization was by day of month and therefore the group patient would be assigned to was known prior to recruitment

Inclusion criteria:

· ventricular fibrillation as the initial cardiac rhythm

· return of spontaneous rhythm in the field

· persistent coma

Exclusion criteria included:

· age <18 years

· female aged <50 years (because of the risk of pregnancy)

· cardiogenic shock

· other possible causes of coma

Hypothermia group:

· attempts at cooling were initiated in the field and were continued for 12 hours after admission to hospital

· target temperature of 33°C within 2 hours of return of spontaneous circulation

Both groups

· targets were set for arterial partial pressure of oxygen and carbon dioxide, mean arterial pressure, blood glucose and serum potassium

· all patients received a bolus dose of lidocaine followed by an infusion for 24 hours

· patients with an ECG suggestive of acute myocardial infarction and no contraindication received thrombolysis, while those with an ECG suggestive of ischaemia without infarction receive intravenous heparin


· Significantly more patients in the hypothermia group than in the normothermia group had a good outcome (moderate disability or better) despite more patients in the normothermia group receiving bystander cardiopulmonary resuscitation

· At the time of hospital discharge 49% of patients in the hypothermia group and 26% of the normothermia group were moderately disabled or better.

Incidence of complications was not reported.

** Bernard et al.  NEJM 2003.

Focus on targeted hypothermia after cardiac arrest in practice

The results of the European and Australian studies have led the International Liaison Committee on Resuscitation (ILCOR) to recommend the use of therapeutic hypothermia in some patients who present with cardiac arrest. Despite these guidelines, therapeutic hypothermia appears underused by the critical care community at the present time. A recent US survey confirmed its use by only 20% of respondents. The majority of physicians felt there was insufficient data to support its use after cardiac arrest. Others found cooling methods to be technically too difficult or slow. There are also many potential complications associated with therapeutic hypothermia. Dysrthythmias are common. Cooling shifts potassium into the cells, causing hypokalaemia, while warming shifts potassium back into the serum. Hypothermia results in significant peripheral vasoconstriction and hypotension can occur on rewarming. There is a potential for coagulopathy, thrombocytopenia and neutropenia. Hypothermic patients are also at risk of aspiration pneumonia. Skin breakdown can occur secondary to the intense vasoconstriction and frequent repositioning is required. Shivering impairs the ability to achieve and maintain the target temperature. This can be prevented by the use of neuromuscular blocking drugs.

What is also uncertain from the current literature is the exact timing of the hypothermia. It would seem logical to initiate it as early as possible. The required level of hypothermia (33°C) was achieved in the above patient hours after the cardiac arrest. It would seem intuitive that the earlier the cooling is instigated the greater the benefit. This could mean that patients are actively cooled during transport to hospital. There are, however, logistic problems to overcome if ambulances and paramedics are to transport ice, or cooling devices to patients. This is in addition to their ever evolving other responsibilities: defibrillation, intubation and ventilation, and the administration of medications, if these are shown to be of benefit. Moreover, there is now interest in pre-hospital administration of thrombolytic agents to patients suffering out-of-hospital cardiac arrest. Clearly, much further work is needed to elucidate the means by which therapeutic hypothermia is helpful to neurological protection and recovery and at what stage should it be initiated and what is the optimal technique.

Table 3. Physiological effects of hypothermia

Maintaining a temperature of 32° - 34° C for 12 - 24 hours:

Reduces intracranial pressure

Decreases the cerebral metabolic rate

· for each 1° C decrease in temperature, there is a 6% - 7% decrease in the cerebral metabolic rate

Decreases heart rate

Decreases phosphate and potassium concentrations

Decreases gut motility

Increases blood glucose concentrations

Increases systemic vascular resistance

Increases the solubility of gases in the blood

Prolongs clotting times

May increase the risk of aspiration pneumonia

May cause diuresis

May cause neutopenia

May cause thrombocytopenia

Key References

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; 346:557-563

The Hypothermia after Cardiac Arrest Study Group.
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
N Engl J Med 2002; 346:549-556.

Bernard SA, Buist M.
Induced hypothermia in critical care medicine: A review.
Crit Care Med 2003; 31 (7): 2041-2051.

Nolan JP, Morley PT et al.
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): 118-21

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