Cold and Not-So-Dead: Real life application of therapeutic hypothermia

Cold and Not-So-Dead: Real life application of therapeutic hypothermia Jon Rittenberger, MD, MS Frank Guyette, MD, MPH University of Pittsburgh Department of Emergency Medicine Objectives Recognize patients eligible for hypothermia Understand implementation of a complete care package Recognize and treat the sequelae of these treatments Why Cardiac Arrest? Mortality is 95% Critically ill patients with bad timing - Death does not care about holidays - No longer Q04L Resource and Emotionally intensive

Can t be Fixed Viral infections Back Pain Abdominal Pain, chronic Diabetes Fibromyalgia RSD Headaches Dementia HTN Scleroderma Dental Pain Sjogren s SLE Stupidity Can be Fixed Bacterial Infections (Many) Sudden Cardiac Death Case Review: DK 71 y/o male with witnessed V-fib arrest during a stress test Fell striking his head Defibrillator at MD office was not functioning CPR started immediately

Case Review: DK EMS arrived and shocked 3 times into asystole Meds given: 6 Epinephrine, 3 Atropine, and Amiodarone Total down-time: 25 minutes Initial GCS: 3 Out of Hospital Cardiac Arrest- A Common Disease 600-1000 Americans will suffer OOHCA today 600-1000 Americans will suffer OOHCA tomorrow 25+ will suffer OOHCA during this talk High morbidity and mortality - 47% never make it to the hospital Proportion Surviving 0.4 0.3 0.2 0.1 Survival after Cardiac Arrest in Pittsburgh Proportion Surviving 0.4 0.3 0.2 0.1 0 Large reduction in initial Hazard of Death if VF arrest 0 3 6 9 12 15 18 21 24 27 30 Days after Event 0 0 360 720 1080 1440 1800 Days after Event Wang, 2005

Two Hurdles to Consider Cardiac Death- The HARD Way Brain Death- The Soft(er) Way Must work on both if the patient is to survive Multiple Ways to Die 100% 80% 60% 40% Survive without Symptoms Survive with Neurological Deficit Neurological Death 20% 0% Out-of-Hospital In-Hospital Location of Cardiac Arrest Cardiovascular Death Multi-System Organ Failure Data from Laver (2004) Therapeutic Hypothermia

Inclusion Criteria HACA In ED after ROSC Witnessed VF / VT Presumed Cardiac 18-75 years old <60 min since collapse 5-15 min collapse to resuscitation Bernard Arrival at participating ED VF / VT ROSC Coma after ROSC Exclusions HACA Responds to verbal commands MAP<60 mmhg x 30 min SaO2<85% x 15 min Coagulopathy Tympanic temp < 30 C Arrested after EMS arrival Pregnancy Coma before cardiac arrest Terminal illness, in another study, unavailable for follow-up Bernard Systolic BP < 90 despite pressors (epinephrine) <18 yrs old for men <50 years old for women (surrogate for pregnancy) Alternative cause of coma (Drug OD, head trauma, CVA) No ICU bed available Treatment HACA Normothermia (N=138) - Standard hospital bed and kept warm Hypothermia (N=137) - 32-34 C (tympanic and bladder) for 24 hours - TheraKool mattress/blanket - If not at goal within 4 hours, add ice packs Bernard Normothermia (N= 34) - Usual care with passive rewarming to 37 C Hypothermia (N=43) - In field, expose, cold packs to head/torso - In ED / ICU, further icepacks - Core temperature of 33 C for 12 hours.

Good Outcome (95% CI) 70% 60% 50% 40% 30% 20% 10% 0% HACA Bernard Normothermia Hypothermia Normothermia Hypothermia Outcome Risk Ratio Outcome Odds Ratio Favorable Outcome 1.40 (1.08-1.81) Good Outcome 2.65 (1.02 6.88) Death at 6 months 0.74 (0.58-0.95) Good Outcome 5.25 (1.47 ----------------------------------------------------------------- 18.76) ----------------------------------------------------------------- NNT (Favorable Outcome) = 6.4 NNT (Good Outcome) = 4.5 NNT (Not Dead) = 7.0 Relative Risk Reduction (Neuro) = 26% NNT (Not Dead) = 6.1 Relative Risk Reduction (Death) = 26% Relative Risk Reduction (Neuro) = 30% University of Pittsburgh School of Medicine - Department Relative of Emergency Risk Reduction Medicine (Death) = 24% Compare ICU Strategies (Gropper, Anesth Analg 2004: 99:566) Treatment NNT (mortality) Early Goal-directed therapy 7 Low-dose steroid 10 ARDSnet low TV ventilation 12 Activated protein C 17 Intensive glycemic control 28 Hypothermia 6.1-7.0 Optimizing Therapeutic Hypothermia HCASG, 2002 Bernard, 2002 55% Good Outcome 49% Good Outcome? Outcome

Let s Do It! Let s Do It! Umm How? Who?

Who do we cool? The Mostly Dead 2005 AHA Consensus Statement Class IIA Comatose adult pt with ROSC after out of hospital V-Fib cardiac arrest Should be cooled to 32-34 C for 12-24hrs Class IIB Comatose adult pt with ROSC with non V-Fib cardiac arrest both in/out hospital arrest Should be cooled to 32-34 C for 12-24 hrs Simplified entry criteria Suffered cardiac arrest - Chest compressions or rescue shock Comatose after cardiac arrest - Not following verbal commands

Effects of Hypothermia Effects of Hypothermia First, it prevents HYPERTHERMIA - For each 1 C over 37 C for T max during the first 48 hours, likelihood of poor outcome increased with Odds Ratio (Poor) = 2.26 (1.24 4.12) Your odds of survival were 1:20, now 1:40 Effects of Hypothermia First, it prevents HYPERTHERMIA - For each 1 C over 37 C for T max during the first 48 hours, likelihood of poor outcome increased with Odds Ratio (Poor) = 2.26 (1.24 4.12) Your odds of survival were 1:20, now 1:40 FYI: Powerball odds of winning (something) are 1:37

Effects of Hypothermia Second, it may decrease your vasopressor use! 10 pigs survived to 1 hour after arrest 5/6 pigs that did not require pressors were cooled Norepinephrine (mcg/kg) after ROSC 80 70 60 50 40 30 20 10 0 Normothermia Hypothermia Why? Decreasing temperature increases myocardial contractility - isometric twitch force in isolated muscle - dp/dt, stroke volume in vivo - heart rate in vivo (like B-blockade) - cardiac output - No real change in SVR, PVR in this temp range Decreasing temperature may save myocardium Hypothermia and the Injured Heart Mild hypothermia reduces ultimate infarct size. - LAD occlusions in 60-80 kg swine for 60 minutes - Endovascular cooling to 34ºC from 20-75 minutes. Dae et al., (2002) Am J Physiol Circ Physiol 282: H1584-1591

How? 1. Temperature Monitor Initial Temperature for OOHCA in Pittsburgh Cranial Core Nasopharyngeal 10 Tympanic 8 35 10 Esophageal 35.5 8 Number 6 4 Number 6 4 2 2 0 30 30.5 31 31.5 32 32.5 33 33.5 34 34.5 35 35.5 36 36.5 37 37.5 38 0 30 30.5 31 31.5 32 32.5 33 33.5 34 34.5 35 35.5 36 36.5 37 37.5 38 Cranial Temperature (ºC) Core Temperature (ºC)

2. Cooling Devices Cold (refrigerator) IV Saline 37.5 Room Temp 37.0 36.5 4 ºC * 36.0 0 10 20 30 40 50 60 Time (minutes) 30 ml/kg NS (~2 liters) administered to conscious volunteers over 30 minutes. Core temperature measured using wireless pill thermometer. Cold IV Saline + Shivering Suppression 37.6 Control Low Dose High Dose 37.4 37.2 37.0 36.8 Shivering 36.6 36.4 36.2 36.0 35.8 35.6 Valium 10-20 mg Benzodiazepine enhanced cooling 35.4 0 5 10 15 20 25 30 Infusion time (min)

Brrr, that s cold! Normal people will shiver and not cool more than 1 C We can abate that with benzos or propofol Last resort is paralysis, but watch for seizures Cold IVF gets people cold faster, but you will need more than fluids to maintain. Cooling blankets are available in essentially every ED and ICU. Other Options NG Lavage with iced saline- D Cruz method Cool Guard Catheter - 50k for machine - 1k for catheter

Take Home on Devices Induction Phase - Cold saline is best - NG Lavage may help - Cold packs if nothing else available Maintenance Phase - Blanket is cheap and effective - Catheter is sexy Just do it! Cooling blankets, ice packs, Cool-Guard Catheter for maintenance Keep them cool for 24 hours at 34 C - <24 may work as well Then, gradually warm them: <1 C/hr Watch for seizures! - Incidence of ~10% Perilous Side Effects? Cardiovascular Effects Electrolytes and Fluid Shifts Bleeding Infection Side effects of cooling method

38 C 37 C Brain Injury 36 C 35 C 34 C 33 C Brain Protection 32ºC - 34ºC Positive Inotropy, Increased SV, Decreased HR, Heart Protection 32 C 31 C 30 C University of Pittsburgh School of Medicine - Department of Emergency Dysrhythmia Medicine / Irritability Blood Gases and Temperature When a patient is cooled, pco2, po2 decrease, and ph increases, measured at the patient s temperature. pco2 = 4.5% / ºC ph = -0.015 / ºC At 37ºC in Machine: 7.35 / 45 / 100 At 33ºC in Patient: 7.41 / 40 / 90 33 pco2 37 CO2 Blood Gases in Hypothermia ph-stat method: paco2 and ph are corrected for the patient s temperature. Alpha-stat method: paco2 and ph are measured at 37 C. - Easier (Just run the ABG and ignore temp) - In stroke, preserves normal brain autoregulation at mild to moderate hypothermia. (=mild hyperventilation) (Georgiadis; 2002, Stroke 33: 3026-9)

Take Home: Just run the gas, and adjust the ventilator as you would in the normothermic patient Electrolyte and Fluid Shifts As you cool the patient, vasoconstriction will decrease effective vascular volume. - Diuresis - Lose potassium - Lose phosphate Potassium shifts intracellularly K+ K+ (Abiki 2001; CCM 29: 1726-30; Zeiner 2004; Resuscitation 60: 253-61) Mg+ PO4- K+ Mg+ PO4- Electrolyte and Fluid Shifts As you warm up, patient intravascular space expands, and potassium shifts out of cells - Danger of hyperkalemia if you replaced potassium earlier - May appear volume depleted K+ Mg+ PO4- K+

Urine Out Potassium Replace K Gently Check K Often Central Venous Pressure Fluids as Needed Temperature Hypothermia effects on blood Fever is common after cardiac arrest u Pneumonitis develops in 25% u Some infection develops in 40-50% Infections increase with hypothermia > 24 hours u u Macrophage / leucocyte function is slowed Effect is minimal if hypothermia < 24 hours Bleeding increases below ~35ºC u u Clotting factor reactions are slowed Caution if serious bleeding occurs HACA Complications (all N.S. between groups) Normothermia Hypothermia Bleeding 19% 26% Pneumonia 29% 37% Sepsis 7% 13% Pulmonary Edema 4% 7% Renal Failure / HD 10% / 4% 10% / 4% Seizure 8% 7% Serious Arrhythmia 32% 36% Pancreatitis 1% 1%

Hypothermia after Trauma? Wang 2005; CCM 33:1296-1301 Hypothermia after trauma is associated with increased mortality All bleeding eventually stops 3. Treat ACS Up to 80% have MI as etiology for CA 2 Recent Consults: - 33 M with 99% LAD and 70% Circumflex - 35 F with 100% RCA 12 lead ASAP Consider anticoagulation after CT Brain Not IF they need a cath, WHEN! 4. Pump them up! Many patients exhibit sepsis-like physiology Increased HR, decreased SVR and contractility Support it and things will improve!

Pressure (mmhg) After more than a few minutes of circulatory arrest, ROSC is followed by CRUMP 250 200 150 100 50 CPR Drug You better be mixing up pressors here ROSC Shock CRUMP dopamine 0 360 480 600 720 840 960 1080 1200 1320 1440 1560 1680 1800 1920 Seconds 4. Pump them up! Dobutamine is my first choice - Many patients have myocardial stunning post arrest - This is transient and lasts <24 hours Consider Norepinephrine if necessary Shoot for MAP >80 mmhg 5. Control the Glucose Better outcome with moderate glucose control (80-140 mg/dl) Similar to Surgical ICU patients- NEJM Linear increase in myocardial infarct with glucose levels in blood Worse stroke outcomes with hyperglycemia

6. Rehab is key Many patients have subtle cognitive changes post-arrest Look great from a galloping horse - Eat + Poop + Walk = D/C If you rehab them, they regain function If not Take Home: Post-Resuscitation Induce mild hypothermia Treat acute coronary syndrome Watch for seizures Pump them up! Control glucose Questions?

It is the WHOLE PACKAGE that Matters Most Langhelle - 459 subjects in 4 cities in Norway 0.6 0.5 0.4 Survivors 0.3 0.2 0.1 0 University of Pittsburgh Oslo School of Medicine Akerhus - Department of Emergency Ostfold Medicine Stavanger Variability in Outcome - Pittsburgh 100% 80% 60% 40% 20% 0% 1 2 3 4 5 6 7 8 9 10 Hospital

The Whole Package It is possible to dramatically increase survival in a given system (31% to 56% of admitted patients surviving to one year) Unlikely that it is one particular intervention. More likely, it is the whole package of proactive critical care delivered with a sense of urgency. Sunde (2007) Resuscitation 73: 29-39 Implementation of a standard postresuscitation protocol: Sunde (2006) Number of Patients Protocol includes therapeutic hypothermia 70 60 50 40 30 20 10 0 Control Intervention CPC 1 CPC 2 CPC 3 CPC 4 Died in ICU Died in ED Hypothermia- Is it Used? National database (NRCPR)- 2% UPMC- Presby (IHCA- 2006)- 24% UPMC- Presby ED (OHCA 2006)- 76%

What do I do with this? Referral center for hypothermia Institute it locally Send them out What do I do with this? Referral center for hypothermia Institute it locally Send them out Post Cardiac Arrest Team Cardiology Rapid Emergency Service Brain Preservation with Hypothermia Rehabilitation Feedback and System Improvement Critical Care

412-647-7000 Would you like a helicopter with that? Emergency Department Cardiac Arrest Team Call Schedule ĞApril 2007 SUNDAY MONDAY TUESDAY WEDNESDAY THURSDAY FRIDAY SATURDAY A 8a-8p B 8p-8a Callaway pager 412-433-0660 Rittenberger pager 412-958-2643 Guyette cell 412-651-1077 1) A Rittenberger 2) A Rittenberger 3) A Rittenberger 4) A 5) A Guyette 6) A Callaway (to 7) A Rittenberger Rittenberger 3p) B B Rittenberger B Rittenberger B Guyette B Guyette B Rittenberger B Callaway Rittenberger (from 3p) 13) A Callaway 8) A Callaway 9) A Rittenberger 10) A 11) A Guyette 12) A Callaway 14) A Rittenberger Rittenberger B B Guyette B Rittenberger B B Callaway B Guyette B Guyette Rittenberger Rittenberger 15) A 16) A) Callaway 17) A Callaway 18) A Callaway 19) A Callaway 20) A Callaway 21) A Callaway Rittenberger (to 5p) B Rittenberger 412-647-7000 Post-Cardiac Arrest Service B Callaway B Guyette B Callaway B Guyette (from 5p) B Callaway B Callaway Provide the second hour of critical care for our ED partners Help make a consistent plan of care on the inpatient side Address common post-cardiac arrest pathophysiology Follow on to the floor / rehab 22) A Callaway 23) A Callaway 24) A 25) A Rittenberger (to Rittenberger 6pm) B Guyette B Guyette B Guyette B Rittenberger 29) A Guyette 30) A Guyette 26) A Guyette 27) A Guyette 28) A Callaway B Guyette B Guyette B Callaway B Guyette B Callaway Process Print on Demand - CCM

Prehospital Hypothermia Is Early Better? NAEMSP Annual Meeting January 10, 2008 Francis Guyette, MD, MPH UPMC Presbyterian STAT MedEvac Case Review: DK Brought to a Community Hospital and placed on a balloon pump Air medical crew began prehospital hypothermia approximately 2 hours post arrest Neuro exam upon arrival - Myoclonic jerking - 4mm pupils minimally reactive - Corneal reflex on right side - Gag reflex present Case Review: DK Treatment Issues - Prolonged arrest - Potential head injury - Possible C-spine injury - Bleeding from facial lacerations

Case Review: DK Outcome - Extubated on day 4 - Minor memory deficit - Minor executive function compromise - Beginning Neuro rehab - Awaiting CABG Mechanism of Hypothermia Decrease in cerebral metabolism - 6% reduction for every 1 0 C drop in temperature Suppression of reperfusion injury - Decreased free radical production - Reduction in excitatory neurotransmitters - Suppression of Ca +2 mediated cell death - Anti-inflammatory effects Nolan et al. (2003) Circulation Froehler and Geocadin. (2007) J of Neuro Sci Is Early Better? Ischemic injury occurs in neuronal tissue within minutes. Reperfusion injury may begin within minutes and is followed by a period of hypoperfusion which persists for 12 hours or more. Reducing demand during periods of ischemia while mitigating reperfusion injury makes intuitive sense.

Is Early Better? Animal data suggest early induction of hypothermia improves outcome. - Stertz et al. (1991) Crit Care Med - Kuboyama et al. (1993) Crit Care Med No studies comparing early versus delayed hypothermia in humans. Is Early Better? HACA patients required 4-16 hours to reach target temperature and still demonstrated benefit. Are there risks to early hypothermia without continued hospital cooling? - Increased incidence of hypothermia associated complications? - Neuro-protective benefit is nullified Is Early Better? Abella and Suffoletto describe the use of hypothermia as infrequent. Prehospital induction of hypothermia may overcome institutional inertia. Prehospital hypothermia may allow medical directors to redirect post arrest patients to centers capable of delivering hypothermia and other potentially related services such as PTCA.

Is Early Better? Davis et al. recently suggested that diversion to Cardiac Arrest centers may be feasible as most patients are resuscitated in the field and there was no relationship between survival and transport time. Analogous to a Trauma Center. Most facilities can initiate care but the survival benefit depends on tertiary care elsewhere. Is Early Feasible? Australians began cooling in the field using only ice packs and wet cloth. Early is feasible. - Kamarainen- 5 patients treated with 4 degree saline. - Kim-63 patients with cold saline. Cold Saline in the Field? Patients given 2 L of 4 C normal saline postarrest. Without cooling blanket, the patients re-warmed rapidly.

Is Hypothermia Safe for Prehospital Providers? Both large RCT s had highly selective populations. - Nolan et al. (2003) Circulation - Bernard et al. (2002) NEJM - HACA (2002) NEJM Mild hypothermia has not been associated with increased incidence of sepsis and bleeding. Hovdenes included hemodynamically unstable patients on pressers and IABP s. Is Hypothermia Safe for Prehospital Providers? Inclusion Criteria - ROSC - Age >18 - GCS <8 or unable to follow verbal commands Is Hypothermia Safe for Prehospital Providers? Exclusion Criteria - Pregnant - Environmental Hypothermia - Traumatic Arrest - Active Bleeding - Cardiac Instability Refractory or recurrent dysrhythmia Inability to maintain MAP>70 despite use of a vasopressor

What is the Best Method of Prehospital Cooling? What is the Best Method of Prehospital Cooling? Busch et al. demonstrated successful cooling in Norway with ice packs and towels. In controlled environments, ice packs and exposure reduce temperature by 0.1 0 C per hour. Forced air systems similar to HACA study cool at 0.3 0 C per hour. What is the Best Method of Prehospital Cooling? Bernard s initial protocol relying on surface cooling decreased temperature by 0.9 0 C per hour. Catheter based systems may be more efficient but are invasive and require equipment not available to prehospital providers.

What is the Best Method of Prehospital Cooling? What is the Best Method of Prehospital Cooling? A combination of exposure and cold saline is effective and practical for prehospital providers. Bernard et al. demonstrated that the core temperature could be reduced 1.6 0 C using 30 ml/kg of 4 0 C saline in 30 min. What is the Best Method of Prehospital Cooling? Virkkunen et al. decreased core temperature by 1.9 0 C using 30 ml/kg of 4 0 C Lactated Ringers in an average of 27 min. Crystalloid fluids can be kept at 4 0 C in specialized coolers.

What Adjuncts are Useful for Cooling? Thermometer - For initial temperature Sedatives - For patient comfort and to prevent shivering Paralytics - May be required to prevent shivering Airway management - Most patients will require intubation or alternative airway use. STAT MedEVAC Protocol 211 POST CARDIAC ARREST HYPOTHERMIA Criteria: - Patient with cardiac arrest and return of spontaneous circulation - GCS <8 - No trauma or active bleed - No environmental hypothermia

Protocol: 1. Intubate per Airway protocol 2. Establish IV/IO access 3. Sedate the patient as per the sedation protocol 4. Remove space blanket and any other coverings from the patient. 5. Place ice packs in the axilla and groin. 6. Infuse a bolus of 1 liter of cold saline as fast as possible using a pressure bag. 7. If systolic blood pressure is less than 90, Initiate Levophed infusion at 1-10 micrograms/min [norepinephrine 2 milligrams/ 250 cc NSS] and titrate in increments of 5 micrograms/kilogram/min every 5 minutes until: Systolic blood pressure of 90-100 mmhg Improvement of tissue perfusion Development of ventricular dysrhythmia 8. Consider administration of dobutamine infusion at 5-20 micrograms/ kilogram/min [dobutamine 500 milligrams/250 cc NSS]. Titrate per medical command. City of Pittsburgh EMS Inclusions: 1. All patients with sustained ROSC > 5 minutes post cardiac arrest (defined as chest compressions or defibrillation performed) and: a. Unable to follow verbal commands if intubated b. Unable to open eyes and verbalize if not intubated Exclusions: 1. Age < 18 y/o 2. Traumatic cardiac arrest 3. Significant head trauma 4. Actual or suspected significant hemorrhage (GI bleeding, AAA, etc.) 5. Suspected significant hypothermia already present 6. Frank pulmonary edema

Procedure: 1. Notify command MD that post ROSC hypothermia protocol is being initiated 2. Obtain 2 nd large bore IV or IO access if feasible 3. Pressure infuse one (1) liter of chilled NSS at maximum feasible rate a. Label bag with hypothermia protocol label 4. If SBP > 100 administer 10 mg Diazepam IVP, give an additional 5 mg q5 minutes x2 (Maximum total 20mg) as needed to suppress shivering 5. On arrival at receiving facility notify staff that the hypothermia protocol has been initiated Delivering the Whole Package On-call service since January 2007 Formalized bedside care started in July 2007 Available through UPMC MedCall Data are Jan-Nov 2007 - All prehospital cardiac arrests reviewed for QA Results to Date- OHCA 31 total OHCA patients 26/27 eligible patients received hypothermia - 96% of OHCA patients!

Results to date- OHCA 31 total OHCA patients 26/27 patients received hypothermia - 96% of OHCA patients! Overall Survival: 47% Results to Date- OHCA 31 total OHCA patients 26/27 eligible patients received hypothermia - 96% of OHCA patients! Overall survival: 47% Good outcome: 38% Summary Hypothermia is part of a care package Prehospital hypothermia will not improve survival UNLESS - Hospitals continue therapy - Patients receive rehab and secondary prevention Transport to closest appropriate facility Feedback to EMS as part of CQI

Alternative Cooling Advanced Cooling System Acknowledgements Clif Callaway, MD, PhD Rene Alvarez, MD Michael DeVita, MD Samuel Tisherman, MD Margo Holm, PhD Dave Hostler, PhD James Menegazzi, PhD Ron Roth, MD John Cole, MD Mark Pinchalk, EMT-P, MS References The Hypothermia After Cardiac Arrest (HACA) Group (2002). "Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest." N Engl J Med 346(8): 549-56. Bernard, S., M. Buist, et al. (2003). "Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report." Resuscitation 56(1): 9-13. Bernard, S. A., T. W. Gray, et al. (2002). "Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia." N Engl J Med 346(8): 557-63. Busch, M., E. Soreide, et al. (2006). "Rapid implementation of therapeutic hypothermia in comatose out-of-hospital cardiac arrest survivors." Acta Anaesthesiol Scand 50(10): 1277-83. Davis, D. P., R. Fisher, et al. (2007). "The feasibility of a regional cardiac arrest receiving system." Resuscitation 74(1): 44-51. Froehler, M. T. and R. G. Geocadin (2007). "Hypothermia for neuroprotection after cardiac arrest: mechanisms, clinical trials and patient care." J Neurol Sci 261(1-2): 118-26. Hovdenes, J., J. H. Laake, et al. (2007). "Therapeutic hypothermia after out-of-hospital cardiac arrest: experiences with patients treated with percutaneous coronary intervention and cardiogenic shock." Acta Anaesthesiol Scand 51(2): 137-42. Kamarainen, A., I. Virkkunen, et al. (2007). "Prehospital induction of therapeutic hypothermia during CPR: A pilot study." Resuscitation. Kim, F., M. Olsufka, et al. (2007). "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 115(24): 3064-70.

References Laish-Farkash, A., S. Matetzky, et al. (2007). "Therapeutic hypothermia for comatose survivors after cardiac arrest." Isr Med Assoc J 9(4): 252-6. Marion, D. W., Y. Leonov, et al. (1996). "Resuscitative hypothermia." Crit Care Med 24(2 Suppl): S81-9. Merchant, R. M., B. S. Abella, et al. (2006). "Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets." Crit Care Med 34(12 Suppl): S490-4. Nolan, J. P., P. T. Morley, et al. (2003). "Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation." Resuscitation 57(3): 231-5. Rea, T. D. and V. L. Paredes (2004). "Quality of life and prognosis among survivors of out-of-hospital cardiac arrest." Curr Opin Crit Care 10(3): 218-23. Stertz, F., Safar, P., Tisherman, S., Radovsky, K., Kuboyama, K.O. (1991)Mild Hypothermic Cardiopulmonary Resuscitation Improves Outcome After Prolonged Cardiac Arrest In Dogs. Critical care medicine 19:33, 379-389. Virkkunen, I., A. Yli-Hankala, et al. (2004). "Induction of therapeutic hypothermia after cardiac arrest in prehospital patients using ice-cold Ringer's solution: a pilot study." Resuscitation 62(3): 299-302.