By Saadia R. Akhtar, MD, MSc, Idaho Pulmonary Associates, Boise, is Associate Editor for Critical Care Alert.
Dr. Akhtar reports no financial relationship to this field of study.
The American Heart Association reports that there are approximately 310,000 annual cases of out-of-hospital (OOH) cardiac arrest. In 20-38% of these persons, the initial rhythm is ventricular fibrillation or pulseless ventricular tachycardia (vfib/tach). Of those patients with return of spontaneous circulation (ROSC), approximately 80% are comatose after resuscitation. Median reported survival is 6.4%.1 Meaningful neurological recovery (typically evaluated at 6-month follow up) occurs in ≤10-30% of survivors of OOH cardiac arrest; most studies report numbers well below 10%.2 To date, therapeutic hypothermia is the only intervention proven in robust clinical trials to improve these outcomes.
This review will address briefly the pathophysiology of hypoxic-ischemic brain injury, the rationale for considering hypothermia, 2 large clinical studies of therapeutic hypothermia for OOH cardiac arrest, current recommendations for and some specific issues relating to implementation of therapeutic hypothermia protocols, and potential future clinical applications of hypothermia.
Pathophysiology: Time Is Brain
During cardiac arrest and loss of circulation, cerebral oxygen stores and consciousness are lost within 10-20 seconds; glucose and ATP stores are expended within ≤5 minutes.2 It is clear that cerebral injury occurs during this initial ischemic period and as a result of subsequent reperfusion.
Global cerebral ischemia leads to ion-pump failure, depletion of ATP stores, and subsequent loss of the normal cellular calcium ion gradient. Furthermore, cerebral ischemia is associated with intracellular acidosis, glutamate release, lipolysis and accumulation of free fatty acids, activation of apoptosis, release of inflammatory cytokines, influx of leukocytes, and disruption of the blood-brain barrier (contributing to edema). Subsequent reperfusion is associated with an initial period of hyperemia followed by vasospasm with risk of secondary ischemic injury. Reperfusion allows rapid breakdown of free fatty acids (accumulated during ischemia) to oxygen free radicals that may cause further cellular damage. These are only some of the components that appear to be important in the complex cascade of hypoxic-ischemic-reperfusion cerebral injury.3
Hypothermia and Neuroprotection
Therapeutic hypothermia was first investigated in small clinical studies in the 1950s and 1960s. The first published report of the benefits of therapeutic hypothermia after cardiac arrest occurred in 1959.4 Researchers applied severe hypothermia at that time. Although some positive results were noted, the work was ultimately abandoned due to the difficulty of managing cardiovascular and other side effects of hypothermia, including bradyarrhythmias, hypotension, cardiac arrest, shivering, "cold diuresis," electrolyte abnormalities, coagulopathy, and increased susceptibility to infection.
Investigation resurged during the 1990s when animal studies of mild-to-moderate (30-34° C) hypothermia for brain injury after cardiac arrest suggested benefit. Side effects were reduced, compared to those seen with severe hypothermia, and modern critical care resources greatly facilitated management of these usual complications. A greater understanding of the mechanisms of anoxic brain injury and potential neuroprotective effects of hypothermia provided further support for ongoing investigation. Hypothermia appears to slow cerebral oxygen metabolism, diminish the loss of the normal calcium ion gradient, reduce glutamate release, decrease free radical formation, and reduce markers of apoptosis and inflammation.5
Two large multicenter randomized controlled clinical trials of mild-to-moderate hypothermia were published in the same issue of the New England Journal of Medicine in February 2002.
The Hypothermia after Cardiac Arrest Study Group, a European network, compared standard care with 24 hours of hypothermia (bladder temperature 32-34° C) for adult patients with witnessed OOH cardiac arrest, initial rhythm of vfib/tach, initiation of resuscitation within 5-15 minutes of collapse, and post-resuscitation coma. The primary outcome measure was neurological outcome at 6 months (per the Glasgow-Pittsburgh Cerebral Performance Scale); 6-month mortality and acute complications of hypothermia were secondary outcomes. Patients were excluded for failure of ROSC within 60 minutes. The study enrolled 275 patients (median age 59 years; median time to ROSC, 20 minutes). For those in the hypothermia arm, external cooling (cooling air mattress, ice packs) was initiated in the emergency department followed by passive rewarming after 24 hours at the goal temperature. Median time from ROSC to initiation of cooling was 105 minutes and achievement of goal temperature was 8 hours. Favorable neurological outcome at 6 months was found in 55% of subjects in the hypothermia group vs 39% in the control group. Mortality was 14% less in the treatment arm. The authors found no significant differences in complications between the 2 groups, including bleeding, pressure sores, seizures, lethal or long-lasting arrhythmias, or sepsis.6
The second study was an Australian multicenter trial of standard care vs 12 hours of moderate hypothermia (core temperature by pulmonary artery catheter 33° C) for adult patients with witnessed OOH cardiac arrest, initial rhythm of vfib/tach, and post-resuscitation coma. The primary outcome was survival to hospital discharge with a good neurological outcome (defined as discharge to home or rehabilitation); acute complications of hypothermia were measured as secondary outcomes. The study enrolled 75 patients (median age 65 years; median time to ROSC, 25 minutes). External cooling was initiated by medics in the field, followed by active rewarming after 12 hours at the goal temperature. Median time from ROSC to achieving goal temperature was 2.5 hours. Good neurological outcome was found in 49% of patients in the hypothermia arm vs 26% in the control arm. There were no differences in adverse outcomes between the 2 groups. The authors did note higher systemic vascular resistance, glucose, and potassium, and lower heart rate in the hypothermia group.7
Based on this evidence, the number needed to treat to achieve one favorable neurological outcome is about 6.
Recommendations and Implementation
In 2003, the International Liaison Committee on Resuscitation's Advanced Life Support Task Force published an advisory statement recommending that "unconscious adult patients with spontaneous circulation after OOH cardiac arrest should be cooled to 32-34° C for 12-24 hours when the initial rhythm was vfib/tach." They further suggested that "Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest."8 Subsequently, the 2005 Advanced Cardiac Life Support (ACLS) guidelines and multiple other national and international cardiology and resuscitation councils have made similar endorsements.9
The potential impact of these recommendations is quite substantial. One recent modeling study suggested that full implementation of this hypothermia protocol across the United States could result in 2298 additional patients annually surviving OOH cardiac arrest with good neurological outcome.10
However, surveys from as recently as 2006 reveal that implementation of therapeutic hypothermia has been quite limited: Only 25% of U.S. and 35% of non-U.S. specialty physicians (emergency medicine, cardiology, and critical care) use therapeutic hypothermia. These numbers and the reasons cited for not adopting the protocol are similar to what has been reported for other interventions such as low tidal volume ventilation for ARDS: not enough data, do not believe the data, protocol too difficult to implement, etc.11,12 We see that translation of evidence-based knowledge into clinical practice remains a challenge.
On a practical level, there are some specific issues to be aware of when initiating a protocol for therapeutic hypothermia. Overly rapid cooling may induce cardiac arrest; thus, target temperatures should be achieved over a moderate time frame of about 2-4 hours. A paralytic is usually indicated for shivering, a normal response to cooling, until the goal temperature is reached; once at goal temperature, paralytics may often be stopped. (Another option for management of shivering is meperidine.) "Over-shooting" and reaching temperatures below 32° C may also increase risk of cardiac and other complications. There is a downward "drift" of temperature that may occur even when active external cooling has stopped. This is one problem that has prompted development of novel mechanisms of cooling.13
Cooling methods may be categorized as surface or endovascular. Traditionally, and in the cited 2 large randomized clinical trials, surface cooling with ice packs (at the head, neck, axillae, torso, and groin) and cooling blankets (relying on circulation of cool air) has been utilized. (Infusion of cold intravenous fluids may allow initiation of cooling early, such as in the field but is not appropriate for longer-term cooling.) Newer surface cooling methods use rapid water circulation through hydrogel-coated skin pads placed over the torso and thighs or similarly coated blankets combined with continuous patient core temperature monitoring to achieve and maintain goal temperatures. Although there are potential concerns about skin breakdown, skin necrosis, and the limitation of access to covered areas for examination, early experience has been positive.13,14
Another approach to cooling is endovascular: Most recently, specialized central venous catheters (femoral or subclavian) achieve and maintain goal temperatures by rapidly circulating water through a closed system. Because this is invasive, it presents greater potential risks (arterial puncture, bleeding, thrombosis, endovascular infection, etc).14
Comparison of traditional cooling methods to the newer surface cooling devices (circulating water blankets and gel pads) and endovascular cooling catheters suggests that these newer methods achieve goal temperature more quickly and maintain it more effectively (without drift).15
Future of Therapeutic Hypothermia
There is interest and ongoing study of therapeutic hypothermia for spinal cord injury, traumatic brain injury, and nonhemorrhagic stroke. Other potential future applications of therapeutic hypothermia that will not be addressed here include near-drowning, neonatal hypoxic-ischemic brain injury, acute encephalomyelitis, hepatic encephalopathy, and even ARDS.13
The case of National Football League player Kevin Everett brought a great deal of media and public attention to therapeutic hypothermia. In September 2007, Mr. Everett sustained a cervical spinal cord injury on the field with initial quadriparesis. External cooling was initiated immediately and maintained for about 48 hours. Mr. Everett has essentially had full return of spinal cord function.16 Some animal models of spinal cord injury demonstrate improved outcomes with hypothermia. Intra-operative hypothermia has also been used to limit spinal cord damage during aortic cross-clamping in thoracoabdominal aneurysm repairs.17 However, there are no published clinical trials of hypothermia for spinal cord injury.
Hypothermia has been used anecdotally for management of elevated ICP in acute brain injury. There have been several small randomized controlled clinical trials of prophylactic hypothermia for patients with traumatic brain injury and one larger adult multicenter trial (392 patients).18 Although the results are not always consistent and the largest trial showed no benefit, meta-analyses of adult studies suggest that early initiation of moderate hypothermia (32-35° C) may improve neurological outcome; hypothermia for >48 hours may reduce mortality. Rewarming patients who are hypothermic at presentation may worsen outcome.19 On the contrary, a recent large multicenter pediatric study of moderate hypothermia for severe traumatic brain injury confirmed no benefit and a trend towards worsened mortality and neurological outcomes in this population.20
Finally, animal studies of nonhemorrhagic stroke suggest application of hypothermia reduces infarct size.21 Small feasibility trials in adults show safety but no apparent clinical benefit. Phase III clinical trials are now ongoing.22
Hypoxic-ischemic brain injury secondary to OOH cardiac arrest is common and often devastating. Therapeutic hypothermia is the only intervention to date proven (in 2 well-designed randomized controlled clinical trials) to improve neurological outcomes in these patients. Implementation of such protocols is recommended by multiple international resuscitation and medical specialty organizations and this must be a focus and priority for each of us. Ultimately, evidence may even broaden indications for therapeutic hypothermia to include spinal cord injury, traumatic brain injury, and ischemic stroke.
- American Heart Association. Out-of-Hospital (Sudden) Cardiac Arrest—Statistics. Available at: www.americanheart.org. Accessed Sept. 8, 2008.
- Booth CM, et al. Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 2004:291:870-879.
- Froehler MT, Geocadin RG. Hypothermia for neuroprotection after cardiac arrest: Mechanisms, clinical trials and patient care. J Neurol Sci 2007:261:118-126.
- Benson DW, et al. The use of hypothermia after cardiac arrest. Anesth Analg 1959:38:423-428.
- Froehler MT, et al. Therapeutic hypothermia for global and focal ischemic brain injury—a cool way to improve neurological outcomes. The Neurologist 2007;13:331-342.
- 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, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002:346:557-563.
- Nolan JP, et al. Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison Committee on Resuscitation. Resuscitation 2003:57:231-235.
- 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 4: Advanced life support. Resuscitation 2005:67:213-247.
- Majersik JJ, et al. Public health impact of full implementation of therapeutic hypothermia after cardiac arrest. Resuscitation 2008:77:189-194.
- Merchant RM, et al. Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest. Crit Care Med 2006:34:1935-1940.
- Soreide E, Sunde K. Therapeutic hypothermia after out-of hospital cardiac arrest: How to secure world-wide implementation. Curr Opin Anaesthesiol 2008;21:209-215.
- Varon J, Acosta P. Therapeutic hypothermia: Past, present, and future. Chest 2008;133:1267-1274.
- Jordan JD, Carhuapoma JR. Hypothermia: Comparing technology. J Neurol Sci 2007:261:35-38.
- Hoedemaekers CW, et al. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: A prospective intervention study. Crit Care 2007:11:R91.
- Cappuccino A. Moderate hypothermia as treatment for spinal cord injury. Orthopedics 2008:31:243-246.
- Conrad MF, et al. Thoracoabdominal aneurysm repair: A 20-year perspective. Ann Thorac Surg 2007:83:S856-S861.
- Clifton GL, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001:344:556-563.
- Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS; Bratton SL, et al. Guidelines for the management of severe traumatic brain injury. III. Prophylactic hypothermia. J Neurotrauma 2007:24:S21-S25.
- Hutchison JS, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008:358:2447-2456.
- van der Worp HB, et al. Hypothermia in animal models of acute ischemic stroke: A systematic review and meta-analysis. Brain 2007:130:2063-2074.
- Hoesch RE, Geocadin RG. Therapeutic hypothermia for global and focal ischemic brain injury—a cool way to improve neurologic outcomes. Neurologist 2007:13:331-342.