Focus On: Therapeutic Hypothermia
By Michael Lutes, MD and Nathan Larsen, MD
After reading this article, the physician should be able to:
- Describe therapeutic hypothermia, its purpose, and its goals.
- Describe methods ofinitiating and maintaining hypothermia.
- List several possible future uses oftherapeutic hypothermia.
Survival rates from out-of-hospital cardiac arrest are poor. The number of survivors who make a meaningful neurologic recovery is similarly dismal. There have been numerous studies to evaluate neuroprotective agents for comatose survivors of cardiac arrest, which have shown little promise. Recently, much attention has been directed toward the use of mild therapeutic hypothermia in comatose survivors of cardiac arrest.
Two prospective, randomized, controlled trials published in the New England Journal of Medicine have brought therapeutic hypothermia into the limelight of the cerebral resuscitation stage.1,2 The American Heart Association cited these two studies in their 2005 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
Mild therapeutic hypothermia is a now a Class IIa recommendation for the unconscious adult patient with return of spontaneous circulation (ROSC) after out-of-hospital ventricular fibrillation (VF) arrest. It is a Class IIb recommendation in non-VF arrest patients and in-hospital arrest patients.3
In this article, we will review the pertinent literature on the subject of therapeutic hypothermia and discuss the implementation of cooling protocols for the emergency department.
Review of Pertinent Literature
Therapeutic hypothermia has been used in surgical procedures for decades. The means by which hypothermia provides neuroprotection are uncertain, but it is thought to involve a decrease in metabolic demand and diminished production of free radicals and inflammatory cytokines.
Two recent articles have focused attention on the application of therapeutic hypothermia in the resuscitated but comatose survivor of cardiac arrest.
Bernard et al. studied a group of 77 such patients. All patients were adult survivors of out-of-hospital VF arrest. Subjects were randomly assigned to normothermia (n=34) or hypothermia (n=43) treatment groups.
Patients in the hypothermia group were cooled using surface methods, beginning with the removal of clothing and application of cold packs in the prehospital setting and continuing with more aggressive surface measures in the emergency department and ICU. Patients were maintained at a temperature of 33° C for a period of 12 hours.
Twenty-one of 43 patients (49%) in the hypothermia group had a "good outcome," which consisted of discharge home or to a rehabilitation facility.
In the normothermia group, 9 out of 34 (26%) were determined to have a good outcome. There were no significant differences in adverse events in either group. The major limitation of the study is that the treatment groups were not blinded.
The Hypothermia After Cardiac Arrest (HACA) Study Group published a similarly important article on the use of mild therapeutic hypothermia for comatose survivors of VF or pulseless VT arrest. This study involved a larger number of patients - 138 in the normothermia group, and 137 in the hypothermia group.
Patients in the hypothermia group were cooled to a temperature of 32° to 34° C using an external cooling device (TheraKool, Kinetic Concepts, based in Wareham, United Kingdom). Patients were kept at the target temperature for 24 hours.
The primary outcome measured in this study was favorable neurologic outcome at 6 months' time. Seventy-five of the 136 patients in the hypothermia group had a good neurologic outcome (55%). In comparison, 54 of 137 patients in the normothermia group had a similarly good outcome (39%). There was no significant difference in the rate of complications between the two groups, though there was an increase in sepsis rates in the hypothermia group that did not reach statistical significance.
The 2005 American Hospital Association guidelines also cite a small, 30-patient feasibility study in their recommendations.4
All patients in this study were survivors of PEA or asystolic arrest. Three patients survived in the hypothermia group, one in the normothermia group. The authors note a statistically significant improvement in metabolic end points (lactate concentration and oxygen extraction) in the hypothermia group.
Implementation of Mild Therapeutic Hypothermia
The implementation of clinical protocols for mild therapeutic hypothermia requires a multidisciplinary approach that may include prehospital personnel, emergency physicians and ED staff, intensivists and ICU staff, and specialists in neurology and cardiology.
Emergency department and EMS personnel will be essential in selecting appropriate patients for cooling. Both the HACA study group and Bernard study included only adult patients, 18 years or older. The Bernard group excluded women who were of childbearing age, while the HACA group excluded patients who were older than age 75 years. Both of these groups excluded hemodynamically unstable patients.
Although these studies included patients resuscitated from VF or VT arrest, the AHA suggests (IIb) mild therapeutic hypothermia for survivors of PEA and asystolic arrest as well.
The means of achieving the target temperature have been an area of much debate. The Bernard study utilized surface cooling methods, including the removal of clothing and the application of ice packs to the head and torso. The target temperature of 33.5° C was reached in 120 minutes, although it is important to consider that the temperature at 30 minutes from ROSC was 34.9° C. One patient in the hypothermia group was inadvertently rewarmed.
Patients in the HACA study were cooled using a cooling blanket. The mean time from ROSC to target temperature was 8 hours. The target temperature could not be reached in 19 patients. The placement of ice packs was required in 70% of patients.
A feasibility study by Feldberg et al. reports a mean time of 301 minutes from initiation to a goal temperature of 33° C.5
Their group wrapped each patient in two cooling blankets, placed ice packs in the axilla and groin, and performed gastric lavage with iced saline. They report maintaining the target temperature for 91.7% of the 24-hour cooling period. Interestingly, all nine of their patients experienced rebound hyperthermia.
Other noninvasive means of cooling have also been explored. Hachimi-Idrissi et al. reported achieving the target temperature in an average of 225 minutes using a cooling helmet.4
Several studies have examined the use of cold intravenous fluid infusion as means of cooling.
Bernard et al. reported on a study of 22 comatose survivors of out-of-hospital arrest.6 Each subject was given a 30-mL/kg infusion of 4° C-lactated Ringers over 30 minutes. They reported a mean decrease in core temperature of 1.6° C. There were no significant adverse events in the study patients.
If any of these external measures are utilized to achieve and maintain therapeutic hypothermia, some method of measuring a continuous core temperature must be used, such as temperature sensing urinary catheters or esophageal temperature probes.
While these external measures have proven to be a safe and effective means to achieve mild therapeutic hypothermia, they are not without their limitations.
External measures are labor intensive, requiring the repeated placement of cold packs, close monitoring of core temperature, and vigilance to avoid inadvertent overcooling and rewarming.
Furthermore, surface measures may take a prolonged and unpredictable period of time to reach the goal temperature.
Several studies have evaluated endovascular cooling devices that purport to avoid the limitations of external cooling measures.
Guluma et al. recently published a methodology study of 10 patients undergoing therapeutic hypothermia for treatment of acute ischemic stroke.7 The investigators used the Celsius control catheter (InnerCOOL Therapies, based in San Diego, Calif.). This device consists of a flexible metallic heat-exchange catheter connected to a programmable external console.
The catheter is positioned in the IVC, and then cooled saline is circulated through the device.
Patients in the study were cooled to a median temperature of 33.4° C in a mean time of 1.7 hours. They were then maintained at a median temperature of 33.8° C for a period of 24 hours. The lowest temperature recorded in the study was 33.1° C. No patient experienced rebound hyperthermia. No complications were reported in the study.
Proponents of endovascular devices cite the controlled fashion in which the patient can be cooled, maintained in a hypothermic state, and rewarmed as the major advantages of this technology.
These devices should also decrease the hands-on nursing time required to achieve and maintain hypothermia.
Patients being treated with mild therapeutic hypothermia should be cared for in an ICU setting with standard ICU protocols in place, including glucose control via an insulin sliding scale, electrolyte supplementation as indicated, and close monitoring of hemodynamics and oxygenation. Most patients treated with mild therapeutic hypothermia will be comatose and subsequently will require intubation with mechanical ventilation. These patients will typically need to be sedated and can be chemically paralyzed to avoid shivering.
Therapeutic hypothermia has successfully been attempted in awake patients. For example, in the Guluma et al. study, awake patients were placed on a meperidine drip,7 as meperidine has been shown to reduce the shivering response.8 A warming blanket was also applied to minimize the contribution of skin thermoreceptors to the shivering response. The combination of buspirone and meperidine has a synergistic effect on the reduction of shivering threshold and can also be used in awake patients.9
The rewarming phase deserves consideration in any therapeutic hypothermia protocol. The patients in the HACA trial were allowed to passively rewarm to a temperature of 36° C.2 Passive rewarming occurred over a median period of 8 hours. The Bernard study utilized a heated-air blanket for active rewarming over a period of 6 hours.1
Slow rewarming is considered important to avoid harmful systemic responses, including vasodilation, hypotension, and rebound cerebral edema.10
Therapeutic hypothermia is already being studied for a variety of disease states. Hypothermia has been evaluated as an adjunctive treatment for patients undergoing PCI for ST segment elevation MI.11
There are also ongoing trials examining hypothermia for ischemic stroke patients. Other areas of investigation include traumatic brain injury, spinal cord injury, and septic shock.
Mild therapeutic hypothermia is the only modality shown to improve neurologic outcome in comatose survivors of cardiac arrest.
Cooling can safely begin in the emergency department or even the prehospital environment. However, coordination with inpatient services is necessary, as therapeutic hypothermia must be maintained at 32° to 34° C for 12-24 hours.
External cooling methods are safe and effective, but they can be labor intensive. Endovascular devices provide for controlled cooling, maintenance, and rewarming.
Therapeutic hypothermia does not preclude important treatment modalities such as PCI, invasive hemodynamic monitoring, and the administration of pressors or blood products.
- Bernard S.A., Gray T.W., Buist M.D., et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 2002;346:557-63.
- The Hypothermia after Cardiac Arrest Study Group, et al. Mild therapeutic hypothermia to improve outcome after cardiac arrest. N. Engl. J. Med. 2002;346: 549-56.
- 2005 AHA Guidelines for CPR and ECC. Circulation 2005;112 [Suppl I]:IV-84 - IV-88.
- Hachimi-Idrissi S., Corne L., Ebinger G., et al. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001;51:275-81.
- 5. Feldberg R.A., Krieger D.W., Chuang R., et al. Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol. Circulation 2001;104:1799-804.
- Bernard S., Buist M., Monteiro O., Smith K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of cardiac arrest: a preliminary report. Resuscitation 2003; 56:9-13.
- Guluma K.Z., Hemmen T.M., Olsen S.E., et al. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad. Emerg. Med. 2006;13:820-7.
- Alfonsi P., Sessler D.I., DuManoir B., et al. The effects of meperidine and sufentanil on the shivering threshold in postoperative patients. Anesthesiology 1998;89:43-8.
- Mokhtarani M., Mahgoub A., Morioka N., et al. Buspirone and meperidine synergistically reduce the shivering threshold. Anesth. Analg. 2001;93:1233-9.
- Steiner T., Meisel F., Mayer S.A. Complications of rewarming. In: Mayer S.A., Sessler D.I., eds. Therapeutic Hypothermia. New York. Marcel Dekker, 2005:211-28.
- 11. Kandzari D.E., Chu A., Brodie B.R., et al. Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study). Am. J. Cardiol. 2005;93:636-9.
Dr. Michael Lutes is an assistant professor in the department of emergency medicine at the Medical College of Wisconsin. Dr. Nathan Larsen is a third-year resident in emergency medicine at the Medical College of Wisconsin. Medical Editor Dr. Robert C. Solomon is an attending emergency physician at Trinity Health System in Steubenville, Ohio, and clinical assistant professor of emergency medicine at the West Virginia School of Osteopathic Medicine.
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, contributors and editors must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.
Dr. Lutes, Dr. Larsen, and Dr. Solomon have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this educational activity.
"Focus On: Therapeutic Hypothermia" has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME).
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"Focus On: Therapeutic Hypothermia" is approved by ACEP for one ACEP Category 1 credit.
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Focus On: Therapeutic Hypothermia CME Quiz