Therapeutic Hypothermia for Out-of-Hospital Cardiac Arrest Patients Produces Promising Results

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Learning Objectives
>> Provide a rationale for the use of  early hypothermia
>> Describe effective prehospital cooling  methods and procedures
>> Describe the benefits and harm associated with prehospital induction of therapeutic hypothermia

Key Terms
Endovascular: Inside the vascular space
Morphologic: The form and structure of an organism or one of its parts
Reperfusion: Re-established coronary artery blood flow, particularly during cardiac arrest resuscitation
Tympanic route: The ear; a common site for temperature monitoring. The tympanic membrane, also referred to as the eardrum, carries sound vibrations to the inner ear by means of the bones of the middle ear.

Case Report
A 56-year-old male was walking into his place of work when he suddenly collapsed in the parking lot. He was found by a co-worker who happened to be a registered nurse. She initiated bystander compressions while the public access automatic external defibrillator (AED) was obtained from the place of business.

Prior to the arrival of the AED at the patient’s side, firefighter BLS first response and a paramedic level ambulance were on the scene (with a 9-1-1 phone ring to arrival interval of five minutes and 11 seconds). An advanced practice paramedic arrived two minutes later, carrying normal saline IV fluids chilled at 2° C.

The airway was managed with a bag-valve mask (BVM). Bilateral tibial intraosseous (IO) needles were placed via an EZ-IO device and infused with chilled saline, and the defibrillator applied during continuous chest compressions (see Figure 1, below). The patient had return of spontaneous circulation (ROSC) after the first defibrillation with a total estimated down time of less than 10 minutes. Airway management was continued with the BVM, and the post-resuscitation 12-lead ECG demonstrated an obvious ST-elevation myocardial infarction (STEMI) (See Figure 2).

The patient was emergently transported to a post-resuscitation center 30 minutes from the scene. While en route, he became combative but non-purposeful in his movements. He received 10 mg of midazolam and 1,700 mL of chilled saline, and was discovered to have thermal burns on his back and posterior arms from the hot asphalt of the parking lot where he collapsed.

Cardiac arrest occurs commonly and causes substantial morbidity and mortality. The incidence of out-of-hospital cardiac arrest ranges from 0.04—0.13% of the total population per year.(1—3) Despite advances in prevention and treatments, including external chest compression with ventilation, defibrillation and advanced life support, most patients whom paramedics resuscitate in the field remain unconscious.

Survival with good neurologic recovery has been reported achieved in 11—48% of resuscitated patients; the remaining number either die during their hospital stay or remain alive with severe neurologic deficits.(1,2) Brain-specific strategies that go beyond cardiac arrest prevention and limitation of brain insult with effective CPR are needed. Many cooling methods have been proposed for use in the field by paramedics: The use of cold 4o C IV fluid, cold metal cooling plates, and a cooling helmet. The development of new cooling methods and technology to augment or improve cooling are currently under way and are an area of commercial interest. This article will focus primarily on the use of cold fluid and briefly discuss the use of other surface cooling methods.

Rationale for Early Hypothermia
Prior to implementing any new therapy, medical providers first seek to do no harm. Both animal and human studies have consistently demonstrated that early implementation of hypothermia–either during resuscitation or after ROSC–does not cause harm and may even improve effectiveness of such traditional therapies as defibrillation.(4—7)

In considering the optimal timing of mild hypothermia as it relates to neurological outcome, several animal studies suggest that cooling earlier rather than cooling later results in more protection. In a recent study of cardiac arrest in mice, application of hypothermia (using cooling blankets) during CPR was shown to enhance outcomes compared with application after ROSC.(8)

In a dog model of ventricular fibrillation (v fib) arrest, early application of mild hypothermia with cold normal saline infusion during CPR enables intact survival; however, delay in the induction of mild hypothermia reduces its efficacy, which suggests that mild hypothermia should be applied as early as possible.(9)

In another study, researchers demonstrated that mild hypothermia induced immediately after cardiac arrest improves cerebral function and morphologic outcome, whereas delays of 15 minutes in the
initiation of cooling after reperfusion doesn’t improve outcomes.(10) Thus, these animal studies suggest that intra-arrest cooling or cooling within 15 minutes after ROSC offers the best chance for neurologic recovery.

However, these animal studies must be evaluated in the context of clinical studies, which have demonstrated that even delayed cooling started four to eight hours after resuscitation is associated with improved survival and neurologic outcomes.(11,12) Additionally, another recent study from Bernard and co-authors evaluated the effect of prehospital vs. in-hospital induction of mild hypothermia and found no difference in patient outcomes in the two groups.(4) This study deserves particular attention for two reasons.

First, it must be noted that patients in the in-hospital cooling group and patients in the prehospital cooling group all achieved identical temperatures within 30 minutes of hospital arrival. In other words, the study didn’t evaluate prehospital vs. in-hospital cooling as much as it evaluated the relative importance of reaching the target temperature 30 minutes faster in one group vs. the other group.
Second, this study didn’t evaluate the potential benefits of intra-arrest cooling because no patients received this therapy. It’s important to note that no harm was attributed to the prehospital induction of hypothermia. Thus, in this study, which contained relatively short transport times and very rapid cooling in the emergency department (ED), no benefit and no harm could be attributed to the prehospital induction of hypothermia.

Yet, the optimal timing of the initiation of mild hypothermia still needs to be determined. One of the challenges of testing such a hypothesis in humans rests on finding a simple and safe method for rapidly inducing hypothermia that paramedics can apply in the field. Several invasive and non-invasive cooling strategies have been investigated for use in hospitalized out-of-hospital cardiac arrest; however, these methods may not be applicable in the field.

Field cooling needs to be safe, portable, and easy to administer. Invasive strategies using cooling catheters are rapid in achieving goal temperature; however, they’re impractical for field application because they are placed into the inferior vena cava. External cooling techniques have the advantage of being less invasive; however, most of them, including cooling blankets or fluid pads, depend on an external energy supply or external cooling unit and aren’t practical for out-of-hospital use. Ice packs have also been used. However, wide application is limited because of slow induction time to temperatures less than 34o C or 120 minutes.(11)

Infusion of Cold Fluid
The use of IV infusion of ice-cold fluids is appealing because they are portable and easy to administer in the field. It was initially proposed by Stephen Bernard’s group in 2003.(9) Another researcher studied the use of 40 mL/kg of normal 4o C saline solution for times greater than 30 minutes in nine anesthetized volunteers who received vecuronium and demonstrated a mean temperature decrease of 2.5o C.(10)

Similar results have been demonstrated in elective surgical volunteer patients; however healthy surgical or young volunteers may not be applicable to patients with out-of-hospital cardiac arrest. In all of these studies, neuromuscular blockade was used to augment the effects of infusing cold fluid.

Before administering cold fluid in the field, the use of cold fluid was initially tested in patients who had bee resuscitated after suffering cardiac arrest. Results from three studies, including one from Seattle, have been remarkably consistent.(9,11,12) Patients have low temperatures on admission after resuscitation from out-of-hospital cardiac arrest (35.5º C, 35.4º C, and 35.6º C in these three studies) and drop them drop substantially after the infusion of ice-cold IV fluids (1.7º C, 1.7º C, 1.8º C).

In two studies, the fluids were administered with a pressure bag during a 20—30 minute time frame.(9,11) In two studies, 4º C lactated ringers solution was infused while in the other, 4º C normal saline was infused.9,11,12 In two studies, the amount infused was 2 L, while in the other it was 30 ml/kg.(9,11,12)

All protocols included paralytic agents and sedatives. The infusions were well tolerated without deterioration noted on clinical examination, blood tests and echocardiograms. In these patients, hypothermia in the target range of 32—34º C was maintained for 12—24 hours using cooling blankets or more complicated devices that allow for easy control of temperature.(11,12) One study employed an endovascular device, and one used an external cooling device.

Although these studies demonstrate the feasibility and safety of lowering temperatures rapidly with the IV infusion of ice-cold fluids initiated in the hospital, the feasibility and safety of paramedics initiating such treatments in the field, their effect on neurologic outcome, and differences between those whose initial rhythm is v fib and those whose initial rhythm is not v fib remain unclear.

Recent Studies
In a recent pilot study, the Seattle system examined the safety, efficacy and feasibility of using a rapid infusion of 4o C normal saline by paramedics in the field following ROSC in 125 patients who suffered cardiac arrest from v fib, asystole or pulseless electrical activity.(13)

Sixty-three patients received a rapid infusion of up to 2 L of cold normal saline, resulting in a mean temperature decrease of 1.24 plus or minus 1o C with a hospital arrival temperature of 34.7o C, while the 62 patients not randomized to cooling experienced a mean temperature increase of 0.10 plus or minus 0.94o C (p less than 0.0001) with a hospital arrival temperature of 35.7o C.

In-field cooling wasn’t associated with adverse consequences in terms of blood pressure, heart rate, arterial oxygenation, evidence for pulmonary edema on initial chest X-ray, or re-arrest.

Secondary endpoints of awakening and being discharged alive from hospital trended toward improvement in v fib patients randomized to in-field cooling, suggesting a potential benefit for early cooling in v fib patients. Early field cooling in non-v fib patients, however, wasn’t associated with improved outcomes.

A 2010 study from Wake County, N.C., demonstrated improved outcomes after the field cooling in conjunction with other treatment modalities to care for cardiac arrest patients. The study wasn’t designed to evaluate the impact of field cooling as an isolated therapeutic intervention, however. Thus, the relative impact of field cooling can’t be stated.(14)

An analysis of patients who achieved ROSC demonstrated a statistically significant increase in survivability for all victims of out-of-hospital cardiac arrest, with trends toward improvement not just for patients with v fib, but also for patients with pulseless electrical activity and asystole.(15)

Additional Considerations
The use of cold IV fluid for prehospital cooling requires additional training and equipment, such as portable refrigeration for cooling the IV fluid and ability to measure central body temperature in the field. In Wake County (N.C.), a district chief or advanced practice paramedic is dispatched to all cardiac arrests. Their vehicles are equipped with portable refrigeration units that maintain the normal saline at 2—4° C. Temperatures are obtained via the tympanic route and infusion of chilled saline is initiated during resuscitation for all patients with an initial temperature greater than 34°. Paralysis with vecuronium and sedation with etomidate is available for use at the discretion of the paramedics, should shivering ensue.

In Seattle, each of the paramedic units is equipped with portable refrigerators capable of storing several 1 L bags of normal saline at 4o C. Paramedics are placing esophageal temperature probes after tracheal intubation in all resuscitated out-of-hospital cardiac arrest patients. Paramedics record temperatures using a portable temperature recorder and other temperature recorders, which are directly integrated into the ALS monitors.

During a Seattle/King County pilot field study, paramedics administered up to 2 L of 4o C normal saline, pancuronium (0.1 mg/kg), and diazepam (1—2 mg) via IV. Similar to the previously mentioned pilot study of patients treated in hospital, the use of pancuronium appears to augment the cooling effect of the infusion of cold fluid.

Seattle Medic One paramedics were already using IV pancuronium and diazepam in the field but not for this indication. Not all EMS systems use these drugs routinely, and this could limit the applicability of this cooling protocol to other systems.

The use of cold fluid alone is enough to lower patients’ temperatures in the field. However, in these patients, skeletal muscle relaxation needs to be administered on arrival at the ED.

In the Seattle pilot study, the saline was infused through a peripheral IV line, 18-gauge or larger, using a pressure bag inflated to 300 mmHg. The Seattle research protocol didn’t adjust the amount of 4o C normal saline to body weight.

External Cooling Devices
External cooling devices, such as cooling helmets and cooling plates, have also been proposed for use in the prehospital setting. Cooling helmets are an attractive alternative and have been used in an in-hospital cardiac arrest pilot study.(14) The investigators used a helmet device containing a solution of aqueous glycerol and placed it around the head and neck in order to induce cooling.

Before its application, the helmet device was kept in the refrigerator to maintain a temperature at -4o C. Using this device, cooling to 34o C took a median time of 180 minutes as measured by bladder thermometer and 60 minutes as measured by tympanic thermometer.

Another external cooling device developed in Vienna, Austria, known as Emcools, consists of multiple cooling plates. The plates are pre-cooled to -11 degrees C until shortly before use. The efficacy of these cooling plates has been demonstrated in a swine model of cardiac arrest. The main advantage is the very rapid cooling rates compared with infusion of cold fluid. The cooling plates are also less invasive because an infusion of fluid isn’t needed. In this animal model, no evidence of skin trauma was detected after the application of the cooling plates.

Case Report Continued
On arrival at the post-resuscitation center, the patient was paralyzed, sedated and intubated. He was taken emergently to the cardiac catheterization lab, where he was found to have 100% occlusion of his right coronary artery. He then received successful percutaneous intervention with a door-to-balloon time of 46 minutes. The patient was continued on the hypothermia protocol for 24 hours, rewarmed, and transferred to the regional burn center for continued care of his third-degree burns.

On hospital day number 13, the patient was successfully weaned from the ventilator. On day 20, he was moved from the intensive care unit and was subsequently discharged with good neurological function.

Experimental animal work demonstrates that early cooling or even intra-arrest cooling offers the best chance or neurologic recovery following cardiac arrest. Because the majority of cardiac arrests occur outside the hospital, the application of therapeutic hypothermia presents numerous challenges.

The use of cold 4o C IV fluid has been shown to be effective and safe for use in the field by paramedics, while the use of other techniques, such as cold metal plates and helmets, awaits further testing. Whether field cooling improves neurologic outcomes and survival in resuscitated cardiac arrest patients needs to be tested in a large clinical trial before final conclusions can be made.

We wish to thank the outstanding efforts of the Seattle Fire Department paramedics and the emergency physicians at Harborview Medical Center, the providers in the Wake County EMS System, and the medical care teams of Rex Healthcare and WakeMed Health and Hospitals.

Francis Kim, MD, is an associate professor of medicine/neurology at the University of Washington (UW) Harborview Medical Center. Contact him at

Michael K. Copass, MD, is medical director of the Seattle Fire Department Medic One Program, medical director of the UW Paramedic Training Program and professor of medicine/neurology at UW School of Medicine.

Brent Myers, MD, is director and medical director of the Wake County EMS System in Raleigh, N.C. He also serves as adjunct assistant professor of emergency medicine at the University of North Carolina School of Medicine in Chapel Hill, N.C. Contact him at


1. Becker LB, Smith DW, Rhodes KV. Incidence of cardiac arrest: a neglected factor in evaluating survival rates. Ann Emerg Med. 1993;22(1):86—91.
2. de Vreede-Swagemakers J, Gorgels AP, Dubois-Arbouw WI, et al. Out-of-hospital cardiac arrest in the 1990s: A population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol. 1997;30(6):1,500—1,505.
3.  Cobb LA, Fahrenbruch CE, Copass MK, et al. Changing incidence of out-of-hospital ventricular fibrillation, 1980—2000. JAMA. 2002;288(23):3,008—3,013.
4. Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out of hospital ventricular fibrillation cardiac arrest: A randomised controlled trial. Circulation. 2010;122(7):737—742.
5. Rhee BJ, Zhang Y, Boddicker SA, et al. Effect of hypothermia on transthoracic defibrillation in a swine model. Resuscitaiton. 2005;65:79—85.
6. Boddicker SA, Zhang Y, Zimmerman MB, et al.  Hypothermia improves defibrillation success and  resuscitation outcomes from ventricular fibrillation. Circulation. 2005;111(3):195—201.
7. Wira C, Martin G, Stoner J, et al. Application of normothermic cardiac arrest algorithms to hypothermic cardiac arrest in a canine model. Resuscitaiton. 2006;69:509—516.
8. Abella BS, Zhao D, Alvarado J, et al. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation. 2004;109(22):2786—2791.
9. Nozari A, Safar P, Stezoski SW, et al. Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation. 2006;113(23):2,690—2,696.
10. Kuboyama K, Safar P, Radovsky A, et al. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: A prospective, randomized study. Crit Care Med. 1993;21(9):1,348—1,358.
11. 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.
12. 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.
13. Bernard S, Buist M, Monteiro O, et al. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: A preliminary report. Resuscitation. 2003;56(1):9—13.
14. Hinchey PR, Myers JB, Lewis RS, et al. Improved out-of-hospital cardiac arrest survival after the sequential implementation of the 2005 AHA guidelines for compressions, ventilations, and induced hypothermia: The Wake County experience. Ann Emerg Med. 2010;56(4):348—357.
15. Cabanas JG, Lewis RS, DeMaio VJ, et al. Out-of-hospital initiation of therapeutic hypothermia with cold saline improves survival in patients with return of the spontaneous circulation in the field. Ann Emerg Med. 2010;56(3)S5 [abstract].
16. Rajek A, Greif R, Sessler DI, et al. Core cooling by central venous infusion of ice-cold (4 degrees C and 20 degrees C) fluid: Isolation of core and peripheral thermal compartments. Anesthesiology. 2000;93(3):629—637.
17. Kim F, Olsufka M, Carlbom D, et al. Pilot study of rapid infusion of 2 L of 4 degrees C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest. Circulation. 2005; 112(5):715—719.
18. Kliegel A, Losert H, Sterz F, et al. Cold simple intravenous infusions preceding special endovascular cooling for faster induction of mild hypothermia after cardiac arrest: A feasibility study. Resuscitation. 2005;64(3):347—351.
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):3,064—3,070.
20. Hachimi-Idrissi S, Corne L, Ebinger G, et al. Mild hypothermia induced by a helmet device: A clinical feasibility study. Resuscitation. 2001;51(3):275—281.

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Objective 1: Provide a rationale for the use of early hypothermia

1. When did the researchers induce therapeutic hypothermia with cooling blankets in the 2004 study by Abella and co authors of cardiac arrest in mice?
a. Before initiating cardiac arrest
b. While providing CPR
c. Within 15 minutes of achieving ROSC
d. Two hours after achieving ROSC

2. How did a delay in the induction of mild hypothermia in the 2006 dog model of v fib arrest affect the efficacy of cooling?
a. Increases the efficacy
b. Decreases the efficacy
c. Did not affect the efficacy

3. Kuboyama and co-authors (1993) couldn’t demonstrate improved outcome in a dog model of cardiac arrest when cooling was delayed.  How long after reperfusion was cooling delayed?
a. Five minutes
b. 10 minutes
c. 15 minutes
d. 20 minutes

4.  When is the optimal timing for initiation of mild hypothermia following out-of-hospital cardiac arrest?
a. Remains undetermined
b. While performing CPR
c. In the ED
d. After ROSC but before transport

Objective 2: Describe effective prehospital cooling methods and procedures

5. What cooling strategy is the MOST practical and effective for the prehospital environment?
a. Invasive cooling catheters
b. External cooling blankets
c. Application of ice packs
d. Infusion of cold IV fluid

6. What was the mean temperature decrease in human volunteers found in 2000 by Rajek and co-authors after infusion of 40 ml/kg of 4o C normal saline solution?
a. 1.0°C
b. 2.5°C
c. 5.0°C
d. 8.0°C

7. What is the target temperature range when inducing therapeutic hypothermia?
a. 26°C—28°C
b. 29°C—31°C
c. 32°C—34°C
d. 35°C—37°C

Objective 3: Describe the benefits and harm associated with prehospital induction of therapeutic hypothermia

8. What was the reported harm associated with prehospital induction of hypothermia in the 2003 study by Bernard and co-authors?
a. Coagulopathy
b. Higher mortality rate
c. No reported harm
d. Increased pulmonary edema

9. What was the reported harm associated with the rapid infusion of cold saline in the 2007 study by Kim and co-authors from Seattle?
a. Re-arrest
b. Hypotension
c. No reported harm
d. Oxygen desaturation

10. Which patient presentation trended toward improvement following prehospital induction of therapeutic hypothermia in the Kim and co-authors study from 2007 from Seattle?
a. V fib
b. Pulseless electrical activity
c. Asystole
d. Bradycardia

11. Two drugs commonly used in the prehospital setting for paralysis of patients to minimize heat lost from shivering during therapeutic hypothermia therapy are:
a. Vecuronium and sedation with etomidate
b. Fentanyl and sedation with lidocaine
c. Calcium chloride and etonidate
d. Vecuronium and sedation with

12. Studies have shown no adverse consequences associated with in-field cooling in terms of blood pressure, heart rate, arterial oxygenation, evidence for pulmonary edema on initial chest X-ray, or re-arrest.

13. The incidence of out-of-hospital cardiac arrest ranges from what percentage of the total population per year?
a. 0.01—0.04%
b. 0.01—0.10%
c. 0.04—0.10%
d. 0.04—0.13%

14. Survival with good neurologic recovery has been reported achieved in what percentage of resuscitated patients?
a. 11—48%
b. 3—10%
c. 15—40%
d. 8—22%

15. IV fluids used in the field for therapeutic hypothermia during cardiac arrest resuscitations are generally cooled to:
a. 4°C
b. 5°C
c. 6°C
d. 7°C

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