Emergency Medicine Journal Club Thursday, January 30, Therapeutic Hyothermia for Survivors of Cardiac Arrest

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1 Page 1 Emergency Medicine Journal Club Thursday, January 30, 2014 The January journal club is sponsored by RCRMC, and will be held in the upstairs room at Mu Restaurant in Redlands (map on next page) on Thursday January 30 from 5 to 9 pm. The real topic for this journal club is "Critical Analysis and Interpretation of Randomized Controlled Trials", but since that might not sufficiently excite everyone let's instead call it: Therapeutic Hyothermia for Survivors of Cardiac Arrest RCRMC and LLUMC both have therapeutic hypothermia protocols for survivors of cardiac arrest. But does this intervention improve neurologic outcomes? The following individuals have been assigned to present articles (maximum of 5-10 minutes each). Everyone is expected, however, to have read the articles and to be prepared to critically discuss them! Page Presenter and Item 3 Steve Green. RCRMC and LLUMC hypothermia protocols Nellie Ekmekjian. Bolte: The use of extracorporeal rewarming in a child 5 submerged for 66 minutes. JAMA 1988; 260: Steve Green. Sterz: Mild hypothermic cardiopulmonary resuscitation improves 8 outcome after prolonged cardiac arrest in dogs. Crit Care Med 1991; 19: Steve Green. Bernard: Clinical trial of induced hypothermia in comatose 9 survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997; 30(2): Graham Mooey. Bernard: Treatment of comatose survivors of out-of-hospital 10 cardiac arrest with induced hypothermia. N Engl J Med 2002; 346(8): Steve Green. The CONSORT checklist for randomized controlled trials Randy Frederick. Holzer: Mild therapeutic hypothermia to improve the 18 neurologic outcome after cardiac arrest. N Engl J Med 2002; 346(8): Steve Green. ILCOR: Circulation. 2003;108: Steve Green. Arrich: Hypothermia for neuroprotection in adults after 27 cardiopulmonary resuscitation. Cochrane Database 2012; 9:CD Sassan Ghassemzadeh. Kim: Effect of prehospital induction of mild 28 hypothermia on survival and neurological status among adults with cardiac arrest. JAMA 2013 Nov 17. Chelsea Cosand. Nielsen: Targeted Temperature Management at 33 C versus C after Cardiac Arrest. N Engl J Med. 2013; 369: BRING THIS PACKET WITH YOU TO JOURNAL CLUB!!

2 Mu Restaurant, 309 W. State Street, Redlands Page 2

3 RCRMC Hypothermia Protocol Page 3

4 Therapeutic Hypothermia and Post Cardiac Arrest Care Flow Chart ROSC after cardiac arrest Page 4 STEMI No Comatose No Yes Yes PCI per AHA guidelines Exclusion Criterion?* Yes Optimize Supportive Care No 1. Initiate therapeutic hypothermia with 4 o C NS 2 liters 2. Insert rectal temperature probe, record temperature every hour 3. Target o C within 2 hours and continue for 24 hours a. Initiate blanket cooling (head, neck, torso, extremities) b. Insert orogastric tube and lavage with ice cold water c. Insert foley catheter and irrigate bladder with 4 o C normal saline d. Initiate intravascular cooling (femoral vein catheterization) if available *Exclusion Criteria: 1. Age < 18 years 2. Temp < 30 o C 3. Severe cardiogenic shock despite epinephrine 4. Persistent life-threatening arrhythmia 5. Pregnancy 6. Coagulopathy 7. Drug overdose 8. Acute stroke 9. Trauma 10. Post-surgery 11. Existing terminal illness Optimize mechanical ventilation Initiate CVP/ScvO 2 monitoring and optimize hemodynamic support Sedate and paralyze to avoid shivering Initiate continuous EEG monitoring Obtain formal neurology consult examination Initiate DVT and stress ulcer prophylaxis 1. Discontinue active cooling after 24 hours 2. Controlled re-warming to temperature > 36 o C after 24 hours of cooling 3. Avoid temperature > 38 o C during re-warming 4. Continuous EEG monitoring for total 48 hours Therapeutic Hypothermia and Post Cardiac Arrest Care Clinical Pathway Loma Linda University Medical Center

5 Page 5 The Use of Extracorporeal Rewarming in a Child Submerged for 66 Minutes Robert G. Bolte, MD; Philip G. Black, MD; Robert S. Bowers, CCP; J. Kent Thorne, MD; Howard M. Corneli, MD A 21/2year-old girl had a good neurologic recovery after submersion in cold water for at least 66 minutes; as far as we know, this is the longest time ever reported. Cardiopulmonary resuscitation was maintained for more than two hours before the initiation of extracorporeal rewarming in this child who had a core temperature of 19\s=deg\C.To our knowledge, this is the first successful use of extracorporeal rewarming in a child suffering from accidental hypothermia. Extension of this technique to children offers rapid rewarming and cardiovascular support for pediatric victims of severe hypothermia. We emphasize the importance of a coordinated response by the entire emergency medical system integrated with hospital-based personnel. Where it is geographically feasible, regionalization of triage and care for the pediatric victim of severe accidental hypothermia should be considered. (JAMA 1988;260: ) SUBMERSION injury represents a significant cause of morbidity and mortality in the pédiatrie and young adult population. Previous reports have noted neurologically intact survival af ter cold-water submersions of up to 45 For editorial comment see p 390. minutes.1 Several authors have de scribed the successful use of ex tracorporeal rewarming (ECR) in hypothermic adult victims of exposure.2'8 We report a good neurologic outcome in a 2V2-year-old child submerged in cold water for at least 66 minutes. Extracor poreal rewarming was effectively uti lized in the resuscitation of this child. From the Department of Pediatrics (Drs Bolte, Black, and Corneli) and the Division of Cardiothoracic Surgery (Mr Bowers and Dr Thorne), Primary Children's Medical Center, Salt Lake City. Reprint requests to Emergency Services, Primary Children's Medical Center, 32012th Ave, Salt Lake City, UT (Dr Bolte). Report of a Case On June 10, 1986, a 2V2-year-old girl fell into a creek near Salt Lake City. A sibling saw the child fall into the water and immediately informed his mother. The mother, after searching for between four and ten minutes, called the emergency number. Late spring runoff from a heavy mountain snowpack created unusually high, cold water flows in the creek. The water temperature was measured the next day at 5 C. Emergency personnel arrived within eight minutes of the call. Finding no trace of the child, they reduced the out flow from a reservoir above the site. As the water level dropped, rescuers saw the child's arm 20 m from the entry They site. removed the child from the water 62 minutes after they received the ini tial call. Rescuers stated that she was wedged against the upstream side of a rock, and they saw no evidence of an air pocket. The child was cyanotic, apneic, and flaccid, with fixed and dilated pupils and no palpable pulse (Glasgow Coma Scale score of 3). A cardiac monitor re vealed asystole. The child felt cold to the touch, but her temperature was not measured. Cardiopulmonary resuscitation was begun, and the child was transported to Primary Children's Medical Center, Salt Lake City. When the child arrived in the emergency department, her rec tal temperature was 22.4CC. Core rewarming with mist/oxygen at 40 C via an endotracheal tube, warmed (40 C) isotonic intravenous fluids, and continuous 40 C gastric lavage was begun, although active external rewarming techniques were withheld. The initial arterial blood gas tests (uncorrected for temperature; fraction of inspired oxygen, 1.0) revealed the following results: ph, 7.25; carbon diox ide pressure, 50 mm Hg; oxygen pres sure, 83 mm Hg; oxygen saturation, 94%; and base excess, -6.5 mmol/l. The initial chemistry test results were normal except for elevated liver func tion test results (aspartate aminotrans ferase, 831 IU; alanine aminotransfer ase, 431 IU) and a glucose level of 18.7 mmol/l. A complete blood cell count showed a hemoglobin level of 119 g/l, a platelet count of2.3 x 10'7L, and a white blood cell count of 6.8 x 109/L, with an absolute neutrophil count of 0. The urine contained 3 + protein and occult blood. A chest roentgenogram faint left perihilar showed a infiltrate. With the consent of her parents, the child was transferred to the operating Downloaded From: by a SCELC - Loma Linda University User on 12/07/2013

6 Page 6 room for ECR. Rectal and nasopharyngeal temperatures in the operating room were 19 C (Figure). Large-bore cannulae were placed in the right femo ral artery and right femoral vein, and the latter was advanced into the right atrium. Approximately three hours after the child had been submerged, ECR was instituted, and external chest compres sions were discontinued. The ECR cir cuit included a membrane oxygenator system with a pédiatrie heat exchanger. A warming gradient of 10 C was main tained between the perfusate and core body temperature until the perfusate temperature reached 38 C. The mean perfusion pressure during ECR was 60 mm Hg, with an average blood flow of 2.2 L/m2/min. Medications administered while the bypass system was in place included heparin sodium, mannitol, cal cium chloride, and sodium bicarbonate. Arterial blood gas values (uncorrected for temperature) were maintained in the following ranges: oxygen pressure, 120 to 180 mm Hg; carbon dioxide pres sure, 30 to 40 mm Hg; and ph, 7.35 to When the core (nasopharyngeal) tem perature reached 25 C, a single sponta neous gasp and fine ventricular fibrilla tion were noted. A few minutes later, the patient spontaneously opened her eyes, and her pupils became reactive. Pancuronium bromide and lidocaine hydrochloride were administered. The rhythm changed to coarse ventricular fibrillation, which converted spontane ously to normal sinus rhythm. When the core temperature reached 37 C, ECR was discontinued (total bypass time, 53 minutes). Because an occipital scalp hematoma developed during ECR, a computed tomographic scan was done, revealing a minor amount of extra-axial (subarachnoid) blood along the superior falx and no evidence of increased intracranial pressure. Postoperatively, barbiturate coma was not employed, but phénobarbital sodium was given for seizure prophy laxis (serum levels <30 mg/l). Neither controlled hypothermia nor intracranial pressure monitoring was instituted. Se vere noncardiogenic pulmonary edema developed, necessitating mechanical ventilation for six days. A nondisplaced fracture of the proxi mal left tibia was noted. Other complica tions included a mild case of varicella and an intra-abdominal abscess second ary to a perforation of the ileum. The child's neurologic course showed gradual but steady improvement. One day after admission the patient exhib ited minimal withdrawal on neurologic examination. By seven days after p D => a 1 a CL E SB Submersion ' I M 1 Asystole CPR i r-1 r T~~l i I I i i i r Time, h Course and treatment of 21/2-year-old girl submerged in cold water for at least 66 minutes. FIB indicates ventricular fibrillation; NSR, normal sinus rhythm; CPR, cardiopulmonary resuscitation; and ECR, extracor poreal rewarming. Open circles indicate rectal temperature; and solid circles, nasopharyngeal temperature. admission she cried spontaneously. After two weeks she smiled responsively. After three weeks she whispered a few words, and by four weeks she was using four-word phrases and sitting for 10 s. Apparent cortical blindness re solved over seven weeks. At her discharge after more than eight weeks of hospitalization, her receptive and expressive language skills were at the level of a 3-year-old. Her fine motor skills were appropriate for her age, but a tremor interfered with these skills. Gross motor testing showed decreased pelvic girdle and lower-extremity strength, but she could take a few inde pendent steps. At this writing, 12 months after her submersion, the child, now 3V2 years old, was functioning at her age level. Her tremor has shown progressive improvement. Comment Drowning claims more than 8000 lives each year in the United States. Only motor-vehicle accidents exceed drownings as a cause of accidental death for those under 45 years of age.9 Forty per cent of drowning victims are less than 4 years old.10 Remarkable recoveries have been reported after prolonged cold-water submersion (generally in water <10 C). Recent reviews10"14 cited 28 cases of intact neurologic recovery after sub mersions of 15 minutes or more. All cases were associated with hypother mia. All but two of the initially recorded body temperatures were less than 32 C, and in at least one of these cases, the initial temperature was recorded two hours after extraction. The lowest recorded body temperature in these series was 21 C.16,16 Twenty (71%) of 28 victims were 7 years of age or less, with a range of 16 months17 to 40 years.12 longest The reported submersion was 45 minutes.1 In the present case, given that at least four minutes elapsed from the time of submersion until the mother called 911 (central dispatch), the child's total submersion time was at least 66 min utes. As far as we know, this represents the longest submersion with intact neu rologic recovery ever reported. To our knowledge, this is the first successful use of ECR in a child suffering from accidental hypothermia, and it is one of few reports of the use of ECR in a sub mersion victim. This case emphasizes the importance of aggressive resuscita tion and rewarming even after pro longed submersion in patients with marked hypothermia. Recent reports support the use of core rewarming techniques for patients with core temperatures less than 32 C to reduce the problems of afterdrop, rewarming shock, dysrhythmias, and thermal injury associated with external rewarming.18"20 Many authors have advocated ECR as the method of choice for severe hypothermia (temperature <28 C) associated with a persistent nonperfusing cardiac rhythm (asystole or ventricular fibrillation).4'5'7'21,22 The advantages of ECR over other core techniques include the reinstitu tion of perfusion regardless of the car diac rhythm, reduction of the high blood viscosity associated with severe hypo thermia, and rapid restoration of nor- Downloaded From: by a SCELC - Loma Linda University User on 12/07/2013

7 mothermia. Several authors have described the successful use of ECR in hypothermie adult exposure victims.2"8 The use of ECR for submersion victims has also been rarely reported.23 The pre sent report demonstrates that ECR can be effectively and rapidly employed in small children. The disadvantages of ECR include the lack of general availability and the risks of heparinization. Massive epi staxis and gastrointestinal bleeding have been reported.24 Severe bleeding resulting in death, however, has also been reported during rewarming by peritoneal lavage.26 The presence of intracranial, intra-abdominal, or intrathoracic bleeding is a contraindication to the use of ECR in patients who have sustained concomitant trauma. Other disadvantages include the vascular damage associated with catheterization, shear stresses to formed blood ele ments, activation of the complement cascade, and the possibility of embolie phenomena.26 Pulmonary edema, as described in this case report, has been reported after rewarming in severely hypothermie patients both with and without ECR.6 Hypothermia can develop rapidly with submersion in cold water. The rate of heat loss in water is 32 times that in air.18 The cooling effect may be accentu ated by involuntary swallowing or aspi ration." Children cool proportionately faster due to reduced fatty insulation and large surface-to-mass ratios.27 The importance of the "diving reflex" in humans is controversial.28"31 Hypothermia plays an important role in the neurologic outcome after pro longed submersion.32 The child in the present case was deeply hypothermie, with rectal and nasopharyngeal tem peratures measuring 19 C. To our knowledge, this represents the lowest reported temperature recorded in a submersion victim who achieved intact neurologic survival. Hypothermia affords a protective effect to the brain through reduction of the basal metabolic rate. This reduction is substantial only below 32 C.33 At 20 C, oxygen consumption is approxi mately 24% of normal.19 To maximize this protective effect, however, sub stantial hypothermia must occur before significant hypoxic insult. Orlowski10 speculated that a heart that gradually slows to asystole in the presence of sub mersion hypothermia may protect the brain from anoxia, whereas the devel opment of a nonperfusing rhythm dur ing cooling may negate any beneficial effects. The upper limits of cerebral nonperfusion in hypothermia are unknown. Complete recovery has been reported after nearly four hours of cardiac arrest in an adult avalanche victim with a core temperature of 22 C.6 Juvenile rhesus monkeys have demonstrated neurologic recovery after arrest for up to 75 min utes at 16 C to 20 C.34 Experience in cardiac surgery has documented a toler ance for 60 minutes of circulatory arrest in hypothermia,36,36 but more recent re ports suggest limiting the arrest time to 45 minutes. This concern arises from histologie changes in neural tissue seen after 60 minutes.26 The present report documents intact neurologic recovery after 66 minutes of cold-water submer sion and a total arrest time of more than two hours. Where it is geographically feasible, regionalization of care for markedly hypothermie patients, similar to triage systems for major trauma,37,38 reasonable.39 Hypothermie pédiatrie seems patients may be stabilized at primaryor secondary-care centers. Patients in critical condition, however, should be rapidly referred to pédiatrie tertiarycare centers, where ECR and pédiatrie intensive care are available. References 1. Derbyshire DR, Clark RG: Cerebral recovery after prolonged global brain ischemia. Lancet 1980;2: Kugelberg J, Schuller H, Berg B, et al: Treatment of accidental hypothermia. Scand J Thorac Cardiovasc Surg 1967;1: Fell RH, Gunning AJ, Bardhan KD, et al: Severe hypothermia as a result ofbarbiturate overdose complicated by cardiac arrest. Lancet 1968;1: Truscott DG, Firor WB, Clein LJ: Accidental profound hypothermia: Successful resuscitation by core rewarming and assisted circulation. Arch Surg 1973;106: Althaus U, Aeberhard P, Schupbach P, et al: Management of profound accidental hypothermia with cardiorespiratory arrest. Ann Surg 1982; 195: Thorpe AD, White DE: Accidental hypothermia treated by cardiopulmonary bypass. ICPS Digest 1986;1: Wickstrom P, Ruiz E, Lilja GP, et al: Accidental hypothermia: Core rewarming with partial bypass. Am J Surg 1976;131: Towne WD, Geiss WP, Yanes HO: Intractable ventricular fibrillation associated with profound accidental hypothermia: Successful treatment with partial cardiopulmonary bypass. N Engl J Med 1972;287: Baker SP, O'Neill B, Karpf RS: Drowning, in Baker SP, O'Neill B, Karpf RS (eds): The Injury Fact Book. Lexington, Mass, DC Heath & Co, 1984, pp Orlowski JP: Drowning, near-drowning, and ice-water submersions. Pediatr Clin North Am 1987;34: Conn AW, Barker GA, Edmonds JF, et al: Submersion hypothermia and near-drowning, in Pozos RS, Wittmers LE Jr (eds): The Nature and Treatment of Hypothermia. Minneapolis, University ofminnesota Press, 1983, pp Young RSK, Zalneraitis EL, Dooling EC: Neurological outcome in cold water drowning. JAMA 1980;244: Page Southwick FS, Dalglish PH Jr: Recovery after prolonged asystolic cardiac arrest in profound hypothermia. JAMA 1980;243: Danzl DF, Pozos RS: Multicenter hypothermia survey. Ann Emerg Med1987;16: Jessen K, Hagelsten JO: Peritoneal dialysis in the treatment of profound accidental hypothermia. Aviat Space Environ Med 1978;49: Klarskov P, Amter F: Hypothermia following submersion corrected by peritoneal dialysis. Ugeskr Laeg 1976;138: De Villota ED, Barat G, Peral P, et al: Recovery from profound hypothermia with cardiac arrest after immersion. Br Med J 1973;17: Reuler JB: Hypothermia: Pathophysiology, clinical settings, and management. Ann Intern Med 1978;89: Wong KC: Physiology and pharmacology hypothermia. of West J Med1983;138: Feldman KW, Morray JP, Schaller RT: Thermal injury caused by hot pack application in hypothermic children. Am JEmerg Med 1985;3: Abramowicz M (ed): Treatment of hypothermia. Med Lett DrugsTher 1983;25: Martin TG: Neardrowning and cold water immersion. Ann Emerg Med1984;13: Harries MG, Golden FC, Fowler M: Ventricular fibrillation as a complication of salt-water immersion. Br MedJ 1981;283: O'Keeffe KM: Accidental hypothermia: A review of 62 cases. J Am Coll Emerg Phys 1977;6: Mahajan S, Myers TJ, Baldini MG: Disseminated intravascular coagulation during rewarming following hypothermia. JAMA 1981;245: Kirklin JW, Barratt-Boyes BG: Hypothermia, circulatory arrest, and cardiopulmonary bypass, in Kirklin JW, Barratt-Boyes BG (eds): Cardiac Surgery: Morphology, Diagnostic Criteria, Natural History, Techniques, Results, and Indications. New York, John Wiley & Sons Inc, 1986, pp Sloan REG, Keatinge WR: Cooling rates of young people swimming in cold water. J Appl Physiol 1973;35: Gooden BA: Drowning and the diving reflex in man. Med J Aust1972;2: Hayward JS, Hay C, Matthews BR, et al: Temperature effect on the human dive response in relation to cold water near-drowning. J Appl Physiol 1984;56: Wittmers LE Jr, Pozos RS, Fall G, et al: Cardiovascular responses to face immersion (the diving reflex) in human beings after alcohol consumption. Ann Emerg Med1987;16: Conn AW, Barker GA: Fresh water drowning and near-drowning: An update. Can Anaesth Soc J 1984;31:S38-S Ornato JP: The resuscitation of near-drowning victims. JAMA 1986;256: Stern WE, Good RG: Studies on the effect of hypothermia upon cerebrospinal fluid, oxygen tension, and carotid blood flow. Surgery 1960;48: Kopf G, Mirvis D, Meyers R: Central nervous system tolerance to cardiac arrest during profound hypothermia. J Surg Res1975;18: Stevenson JG, Stone EF, Dillard DH, et al: Intellectual development of children subjected to prolonged circulatory arrest during hypothermic open heart surgery in infancy. Circulation 1974;49 and 50(suppl 2): Wagner HR, Subramanian S: Deep hypothermia in infant cardiac surgery. Pediatrics 1978;61: Cales RH: Trauma mortality in Orange County: The effect of implementation of a regional trauma system. Ann Emerg Med 1984;13: Clemmer TP, Orme JF, Thomas F, et al: Prospective evaluation of the CRAMS scale for triaging major trauma. J Trauma 1985;25: Seuffert G: An Alaskan experience with cardiopulmonary bypass in resuscitating patients with profound hypothermia and cardiac arrest. Alaska Med 1984;26: Downloaded From: by a SCELC - Loma Linda University User on 12/07/2013

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9 GENERAL CLINCAL INVESTIGATION/BRIEF REPORT Page 9 Clinical Trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest From the Department of Intensive Care, Dandenong Hospital,* and the Department of Neurosciences, Monash Medical Centre, Southern Health Care Network, ~ Victoria, Australia. Received for publication December 12, Revisions received August 27, 1996, November27, 1996, and April 2, Accepted for publication Apri115, Copyright by the American College of Emegency Physicians. Stephen A Bernard, MB BS* Bruce MacC Jones, MB BS* Malcolm K Horne, BMedSci, MB BS, PhD* Study objective: To examine the effects of moderate hypothermia (33 C), induced by surface cooling in the ED and maintained for 12 hours in the ICU, on patients with anoxic brain injury after out-of-hospital cardiac arrest. Methods: We conducted the study in a teaching hospital in Melbourne, Victoria, Australia. Participants were 22 adults who remained unconscious after return of spontaneous circulation following out-of-hospital cardiac arrest. This treatment group was studied prospectively, and a control group of 22 similar patients was studied by retrospective chart review. Moderate hypothermia (33 C) was induced in the ED by means of surface cooling and maintained for 12 hours in the ICU with rewarming to normothermia over 6 hours; control patients were maintained at normothermia. Results: There were no significant adverse effects of induced hypothermia. Cardiovascular changes included decreased pulse rate, but there were no significant differences in mean arterial blood pressure between the two groups. Small increases in serum potassium and decreases in ph at 18 hours in the hypothermic patients compared with normothermic controls were of no clinical significance. There were no septic complications. There was a significant increase in the number of patients with good outcome (Glasgow Outcome Coma Scale category 1 or 2) with induced hypothermia (11 of 22, versus 3 of 22 for normothermic controls; P<.05), and the mortality rate was significantly lower (10 of 22 versus 17 of 22; P<.05). Conclusion: Compared with historical normothermic controls, outcome was significantly improved and there was no increase in complications when moderate hypothermia was induced in comatose survivors of out-of-hospital cardiac arrest and maintained for 12 hours. Larger, prospective, randomized, controlled studies of induced moderate hypothermia in comatose survivors of out-ofhospital cardiac arrest are warranted ANNALS OF EMERGENCY MEDICINE 30:2 AUGUST 1997

10 Page 10 INDUCED HYPOTHERMIA AFTER OUT-OF-HOSPITAL CARDIAC ARREST TREATMENT OF COMATOSE SURVIVORS OF OUT-OF-HOSPITAL CARDIAC ARREST WITH INDUCED HYPOTHERMIA STEPHEN A. BERNARD, M.B., B.S., TIMOTHY W. GRAY, M.B., B.S., MICHAEL D. BUIST, M.B., B.S., BRUCE M. JONES, M.B., B.S., WILLIAM SILVESTER, M.B., B.S., GEOFF GUTTERIDGE, M.B., B.S., AND KAREN SMITH, B.SC. ABSTRACT Background Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from outof-hospital cardiac arrest. Methods The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33 C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility. Results The demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome that is, they were discharged home or to a rehabilitation facility as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events. Conclusions Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest. (N Engl J Med 2002;346: ) Copyright 2002 Massachusetts Medical Society. CARDIAC arrest outside the hospital is a major cause of unexpected death in developed countries, with survival rates ranging from less than 5 percent to 35 percent. 1-3 In patients who are initially resuscitated, anoxic neurologic injury is an important cause of morbidity and mortality. 4 Currently, the treatment of patients with coma after resuscitation from out-of-hospital cardiac arrest is largely supportive. Because cerebral ischemia may persist for some hours after resuscitation, 5 the use of induced hypothermia to decrease cerebral oxygen demand has been proposed as a treatment option. 6 Although this suggestion has been supported by studies in animal models, 7-12 the studies in humans that have been reported to date have been uncontrolled or retrospective After a pilot study that suggested the feasibility, safety, and possible efficacy of this treatment, 16 we conducted a prospective, controlled trial comparing moderate induced hypothermia with normothermia in comatose survivors of out-of-hospital cardiac arrest. METHODS Study Design The study was performed in Melbourne, Australia, between September 1996 and June The ambulance service has treatment protocols that follow the recommendations of the Australian Resuscitation Council. 19 Patients were enrolled in the study when the following criteria were fulfilled: an initial cardiac rhythm of ventricular fibrillation at the time of arrival of the ambulance, successful return of spontaneous circulation, persistent coma after the return of spontaneous circulation, and transfer to one of four participating emergency departments. The exclusion criteria were an age of less than 18 years for men, an age of less than 50 years for women (because of the possibility of pregnancy), cardiogenic shock (a systolic blood pressure of less than 90 mm Hg despite epinephrine infusion), or possible causes of coma other than cardiac arrest (drug overdose, head trauma, or cerebrovascular accident). Patients were also excluded if an intensive care bed was not available at a participating institution. After the return of spontaneous circulation had been accomplished outside the hospital, eligible patients were randomly assigned to hypothermia or normothermia according to the day of the month, with patients assigned to hypothermia on odd-numbered days. For these patients, the paramedics began measures in the field to initiate hypothermia by removing the patient s clothing and applying cold packs (CoolCare, Cheltenham, Victoria, Australia) to the patient s head and torso. The treatment of patients assigned to normothermia followed usual prehospital treatment protocols. On arrival at a participating emergency department, the patients underwent routine initial assessment and treatment, includ- From the Intensive Care Unit, Dandenong Hospital, Dandenong (S.A.B., M.D.B.); the Intensive Care Unit, Knox Hospital, Wantirna South, Melbourne (S.A.B., M.D.B., B.M.J.); the Metropolitan Ambulance Service, Victoria (S.A.B.); the Department of Emergency Medicine, Monash Medical Centre, Clayton (T.W.G.); the Department of Intensive Care, Austin and Repatriation Medical Centre, Heidelberg (W.S., G.G.); and the Monash University Department of Epidemiology and Preventive Medicine, St. Kilda (K.S.) all in Australia. Address reprint requests to Dr. Bernard at Dandenong Hospital, David St., Dandenong, VIC 3175, Australia, or at N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

11 Page 11 ing mechanical ventilation and correction of cardiovascular instability. After an evaluation of neurologic status, all patients were given intravenous midazolam (2 to 5 mg) and vecuronium (8 to 12 mg). Arterial blood gas values, corrected for temperature, were used to adjust the ventilator to maintain a partial pressure of arterial oxygen of 100 mm Hg and a partial pressure of arterial carbon dioxide of 40 mm Hg. The mean arterial blood pressure was maintained between 90 and 100 mm Hg by infusion of epinephrine or nitroglycerin, as indicated. Thrombolytic therapy was administered to patients with electrocardiographic changes suggestive of acute myocardial infarction, unless it was contraindicated. Intravenous heparin was administered if the history, electrocardiogram, or both suggested an ischemic coronary syndrome without infarction. All patients were given a lidocaine bolus (1 mg per kilogram of body weight) followed by an infusion (2 mg per minute for 24 hours) in an attempt to prevent recurrent ventricular tachyarrhythmias. Potassium was given intravenously to maintain a serum level of 4.0 mmol per liter, and insulin was administered subcutaneously to maintain a blood glucose level of 180 mg per deciliter (10 mmol per liter) or less. Aspirin was administered to all patients. Core body temperature was monitored by reading the tympanic temperature or bladder temperature until a pulmonary-artery catheter was placed. Initial investigations in the emergency department included 12-lead electrocardiography and measurement of arterial blood gases, electrolytes, glucose, creatine kinase (total and MB fractions), and lactate. These measurements were repeated at 1 to 3 hours (on admission to the intensive care unit) and at 6, 12, 18, and 24 hours after arrival at the hospital. Complete blood counts were performed on arrival and repeated at 12 and 24 hours. After the admission of the patient to the intensive care unit, a pulmonary-artery catheter was inserted, and hemodynamic data were obtained 1 to 3, 6, 12, 18, and 24 hours after arrival at the hospital. Some patients (7 of 39 undergoing hypothermia and 11 of 33 undergoing normothermia) were treated without the use of a pulmonary-artery catheter, as requested by the attending physician in the intensive care unit. The study was approved by the Medical Standards Committee of the Metropolitan Ambulance Service and the institutional ethics committee at each participating hospital. Because of the emergency conditions under which this study was performed, written informed consent for participation in the study was sought from the next of kin as soon as possible after the arrival of the patient at the hospital. Treatment Protocol Patients assigned to hypothermia underwent initial basic cooling measures in the ambulance. After arrival at the hospital, they underwent vigorous cooling in the emergency department (or the intensive care unit if a bed was immediately available), as soon as possible after the initial assessment, by means of extensive application of ice packs around the head, neck, torso, and limbs. When the core temperature reached 33 C, the ice packs were removed, and this temperature was maintained until 12 hours after arrival at the hospital while the patient continued to be sedated and paralyzed with small doses of midazolam and vecuronium, as required, to prevent shivering that might lead to warming. Beginning at 18 hours, the patients were actively rewarmed for the next 6 hours by external warming with a heated-air blanket, with continued sedation and neuromuscular blockade to suppress shivering. Patients assigned to normothermia were also sedated and paralyzed initially, but the target core temperature was 37 C. Passive rewarming was used in these patients if there was mild spontaneous hypothermia on arrival. After 24 hours, patient care followed the usual intensive care unit protocols. Patients who had regained consciousness underwent extubation and were transferred to a coronary care unit. Active life support was withdrawn from most patients who remained deeply comatose at 72 hours. Patients with an uncertain prognosis underwent tracheostomy and were discharged from the intensive care unit. Assessment of Outcome When the patients were ready for discharge from the hospital, they were assessed by a specialist in rehabilitation medicine who was unaware of the treatment group. On the basis of this evaluation, patients were discharged to home, to a rehabilitation facility, or to a long-term nursing facility. Discharge home or to a rehabilitation facility was regarded as a good outcome, whereas death in the hospital or discharge to a long-term nursing facility, whether the patient was conscious or unconscious, was regarded as a poor outcome. Statistical Analysis The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be sent home or to a rehabilitation facility. Secondary outcome measures included the hemodynamic, biochemical, and hematologic effects of hypothermia. Statistical analysis was performed with the Stata statistical package. 20 Continuous variables, such as vital signs and biochemical results, were analyzed by repeated-measures analysis of variance, which was modeled by generalized estimating equations with unstructured correlation and robust standard errors. Data for some variables were insufficient at certain time points, and for these a first-order autoregression correlation structure with robust standard errors was used. Base-line data (measurements on arrival at the hospital) were compared by t-tests for continuous variables and by the chi-square test or Fisher s exact test for categorical variables. An adjusted odds ratio for a good outcome as compared with a bad outcome was calculated by multivariate logistic regression. On the basis of our previous study, 16 it was determined that a sample of 62 patients (31 in each group) would be required to show a change in the rate of a good outcome (discharge to home or to a rehabilitation facility) from 14 percent to 50 percent, with a power of 80 percent and a significance level of An analysis of results from 62 eligible patients found that the outcome in the control group was better than our previously published rate, 16 but that there was a strong trend toward improved outcome in the hypothermia group. The study was continued for a further 12 months, at which time 84 patients had been eligible for enrollment, 77 had been enrolled, and 72 had been treated according to the correct treatment assignment. RESULTS Characteristics of the Patients Eighty-four patients were eligible for enrollment in the study over a period of 33 months. Data on seven of these patients were excluded from the analysis (five because they were transferred from the initial hospital to a nonparticipating intensive care unit and two because the next of kin refused consent for data collection). Of the remaining 77 patients, 43 were assigned to hypothermia and 34 to normothermia. The clinical characteristics of the 77 patients are shown in Table 1. Four patients assigned to hypothermia did not receive this treatment because the emergency physician erred by not initiating cooling (three patients) or because the patient was inadvertently rewarmed shortly after admission to the intensive care unit (one patient). One patient who was assigned to normothermia became moderately hypothermic 558 N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

12 Page 12 INDUCED HYPOTHERMIA AFTER OUT-OF-HOSPITAL CARDIAC ARREST TABLE 1. CLINICAL CHARACTERISTICS OF THE 77 PATIENTS WITH ANOXIC BRAIN INJURY WHO WERE ELIGIBLE FOR RANDOMIZATION.* CHARACTERISTIC Age (yr) Median Range HYPOTHERMIA (N=43) NORMOTHERMIA (N=34) *Plus minus values are means ±SD. DC denotes direct current. P VALUE 0.55 Male sex (%) Arrest witnessed (%) Bystander performed cardiopulmonary resuscitation (%) Time from collapse to emergencymedical-services 2.1± ± call (min) Time from call to emergencymedical-services 7.9± ± arrival (min) Time from arrival to first DC 2.5± ± shock (min) Time from first shock to return of 13.6± ± spontaneous circulation (min) Time from collapse to return of 26.5± ± spontaneous circulation (min) Number of DC shocks 4.2± ± Dose of epinephrine (mg) 2.2± ± (33 C) for a prolonged period (four hours) during emergency angioplasty. We analyzed data for these patients on arrival at the emergency department but not on admission to the intensive care unit or at 6, 12, 18, and 24 hours. Outcomes for all patients were analyzed. Systemic and Cerebral Characteristics The hemodynamic data for the first 24 hours are shown in Table 2. In the hypothermia group, the core temperature decreased from 34.9 C 30 minutes after return of spontaneous circulation to 33.5 C 120 minutes after the return of spontaneous circulation, a decrease of 0.9 C per hour. In the hypothermia group, 59 percent required an infusion of epinephrine during the first 24 hours, as compared with 49 percent of the normothermia group. Two patients, both in the normothermia group, had cardiac complications in the first 24 hours. One patient had cardiogenic shock and died at two hours, and another had complete heart block at eight hours, which was treated with transvenous cardiac pacing. The biochemical data during the first 24 hours are shown in Table 3. Three patients with chronic renal failure who were undergoing long-term dialysis were enrolled in the study (two treated with hypothermia and one with normothermia); however, the creatinine levels of these patients (7.9 to 11.3 mg per deciliter [700 to 1000 µmol per liter]) are not included. These patients underwent dialysis after admission. No other patient required renal support. The hematologic data are shown in Table 4. Because many patients were treated with anticoagulants and clotting times were adjusted to the therapeutic range, it was not possible to compare coagulation times between the two groups. Three patients (one undergoing hypothermia and two undergoing normothermia) received thrombolytic therapy, and three (two undergoing hypothermia and one undergoing normothermia) underwent urgent angioplasty. There were no significant hemorrhagic complications in either group. Outcomes The outcomes of the patients at discharge from the hospital are shown in Table 5. Twenty-one of 43 patients in the hypothermia group (49 percent) were considered to have a good outcome (discharged to home or to a rehabilitation facility), as compared with 9 of 34 in the normothermia group (26 percent, P=0.046). Univariate analysis revealed that the patient s age and the time from collapse to return of spontaneous circulation significantly affected the outcome. For each two-year increase in age, there was a 9 percent decrease in the likelihood of a good outcome (odds ratio, 0.91; 95 percent confidence interval, 0.84 to 0.98; P=0.014), and each additional 1.5 minutes in the time from collapse to return of spontaneous circulation was associated with a 14 percent decrease in the likelihood of a good outcome (odds ratio, 0.86; 95 percent confidence interval, 0.78 to 0.94; P=0.001). Cardiopulmonary resuscitation administered by a bystander was associated with a nonsignificant improvement in outcome (odds ratio, 1.40; 95 percent confidence interval, 0.55 to 3.57; P= 0.49). According to multivariate logistic-regression analysis with adjustment for base-line differences in age and in time from collapse to return of spontaneous circulation, the odds ratio for good outcome in the hypothermia group as compared with the normothermia group was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). The primary cause of death was considered to be cardiac failure in 5 of the 22 patients in the hypothermia group who died (these deaths occurred between 18 and 48 hours after collapse) and 4 of 23 in the normothermia group (these deaths occurred between 2 and 50 hours after collapse). One patient each in the hypothermia and normothermia groups was diagnosed as brain-dead, on day 2 and day 4, respectively. The remaining deaths in both groups re- N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

13 Page 13 TABLE 2. PHYSIOLOGICAL AND HEMODYNAMIC VALUES.* VARIABLE TREATMENT GROUP ADMISSION TO ED ADMISSION TO ICU 6 HR 12 HR 18 HR 24 HR Number of patients Hypothermia Normothermia Temperature ( C) Hypothermia 35.0± ± ± ± ± ±0.85 Normothermia 35.5± ± ± ± ± ±0.59 P value 0.02 <0.001 <0.001 <0.001 < Mean arterial blood pressure (mm Hg) Hypothermia Normothermia 90.4± ± ± ± ± ± ± ± ± ± ± ±11.76 P value Pulse (per minute) Hypothermia 97± ± ± ± ± ±17.9 Normothermia 105± ± ± ± ± ±15.5 P value <0.001 <0.001 < Cardiac index (liters/min/m 2 of body-surface area) Systemic vascular resistance (dyn-sec cm 5 ) Hypothermia Normothermia 2.0 ( ) 2.6 ( ) 2.1 ( ) 2.7 ( ) 2.4 ( ) 3.2 ( ) 2.9 ( ) 3.3 ( ) 3.4 ( ) 3.0 ( ) P value Hypothermia Normothermia 2213 ( ) 1356 ( ) 1808 ( ) ( ) 1564 ( ) 1056 ( ) 1198 ( ) 964 ( ) 987 ( ) 1072 ( ) P value 0.02 < *Plus minus values are means ±SD. Medians and ranges (in parentheses) are given for the cardiac index and systemic vascular resistance, which were log-transformed before analysis of variance was performed, because of nonparametric distribution. One patient in the hypothermia group and two in the normothermia group died during the first 24 hours. ED denotes emergency department, and ICU intensive care unit. P<0.05 for the comparison with the value on admission to the emergency department. P values are for the differences between the hypothermia and the normothermia groups. P<0.01 for the comparison with the value on admission to the emergency department. Cardiac index and systemic vascular resistance values are given for the 32 patients treated with hypothermia and the 22 patients treated with normothermia who had a pulmonary-artery catheter. sulted primarily from severe neurologic injury and withdrawal of all active therapy. These deaths occurred between days 2 and 30. The difference in mortality rates between the hypothermia group (51 percent) and the normothermia group (68 percent) did not reach statistical significance (P=0.145). DISCUSSION Cerebral reperfusion injury occurs when cerebral blood flow is restored after cardiac arrest and resuscitation. 21 Increased intracellular levels of glutamate, an excitatory neurotransmitter released from presynaptic terminals, activate ion-channel complexes that cause calcium to shift from the extracellular to the intracellular fluid, leading to the accumulation of oxygen free radicals and the activation of degradative enzymes. In addition, cerebral hemodynamics may remain abnormal after resuscitation from cardiac arrest. 5 Randomized, controlled studies of pharmacologic interventions to improve patients neurologic outcome after cardiac arrest have tested thiopental, 22 corticosteroids, 23 lidoflazine, 24 and nimodipine 25 but have found no benefit. The use of hypothermia after resuscitation from cardiac arrest has been studied in laboratory animals These studies demonstrated significantly improved outcome when moderate hypothermia was induced after resuscitation. However, the mechanism by which hypothermia may be beneficial is uncertain. Hypothermia decreases cerebral oxygen demand and may thus provide protection from ongoing cerebral ischemia. Hypothermia also reduces the glutamate level and the subsequent production of oxygen free radicals. 26 Moreover, hypothermia decreases intracranial pressure, 27 which may be raised in some patients after resuscitation from cardiac arrest. 28 There is concern that hypothermia may have adverse effects on cardiac function, coagulation, the immune system, and acid base status. Accidental hypothermia is associated with increased mortality in patients with major trauma 29 or sepsis syndrome. 30 On the other hand, induced hypothermia has been studied with promising results in patients with severe stroke 31,32 and with variable results in patients with severe head injury. 27,33, N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

14 Page 14 INDUCED HYPOTHERMIA AFTER OUT-OF-HOSPITAL CARDIAC ARREST TABLE 3. BIOCHEMICAL VALUES.* VARIABLE TREATMENT GROUP ADMISSION TO ED ADMISSION TO ICU 6 Hr 12 Hr 18 Hr 24 Hr Number of patients Hypothermia Normothermia Potassium (mmol/liter) Hypothermia 3.8 ( ) 3.6 ( ) 3.6 ( ) 4.1 ( ) 4.3 ( ) 4.5 ( ) Normothermia 3.9 ( ) 3.9 ( ) 4.0 ( ) 4.2 ( ) 4.1 ( ) 3.9 ( ) P value <0.001 Lactate (mmol/liter) Hypothermia 8.3 ( ) 2.7 ( ) 3.7 ( ) 4.4 (1 11.1) 3.4 ( ) 2.5 ( ) Normothermia 7.5 (2 14) 2.6 ( ) 3.3 ( ) 3.5 (1 12.4) 2.6 (0.7 11) 1.6 (0.6 11) P value Glucose (mmol/liter) Hypothermia 13.3 ( ) 16.2 ( ) 16.0 ( ) 16.1 (4.2 28) 10.5 (4.2 25) 8.0 ( ) Normothermia 12.6 ( ) 10.5 ( ) 12.1 (5.8 25) 11.6 (6.2 28) 10.7 (5.3 21) 7.5 ( ) P value Creatine kinase (mmol/liter) Hypothermia 149 ( ) 261 ( ) 635 ( ) 1544 ( ) 2221 ( ) 1079 ( ). Normothermia 111 (67 635) 525 ( ) 651 ( ) 1205 ( ) 1295 ( ) 1274 (95 11,061) P value Creatine kinase MB (mmol/liter) Hypothermia 21 (4 120) 27 (8 133) 50 (5 247) 39 (5 559) 66 (5 432) 57 (4 321) Normothermia 21 (10 117) 40 (5 224) 27 (5 259) 31 (5 875) 25 (5 190) 33 (6 423) P value Creatinine (µmol/liter) Hypothermia 140 (38 211) 122 (62 215) 110 (50 220) 108 (35 345) 104 (35 270) 109 (47 310) Normothermia 125 (75 297) 120 (72 311) 110 (66 260) 127 (55 354) 95 (45 375) 111 (50 394) P value Arterial ph Hypothermia 7.29± ± ± ± ± ±0.10 Normothermia 7.27± ± ± ± ± ±0.06 P value *Plus minus values are means ±SD. Medians and ranges (in parentheses) are given for other variables, which were log-transformed before analysis of variance was performed, because of nonparametric distribution. One patient in the hypothermia group and two in the normothermia group died during the first 24 hours. ED denotes emergency department, and ICU intensive care unit. P<0.05 for the comparison with the value on admission to the emergency department. P<0.01 for the comparison with the value on admission to the emergency department. P values are for the differences between the hypothermia and the normothermia groups. To convert the values for glucose to milligrams per deciliter, divide by To convert the values for creatinine to milligrams per deciliter, divide by N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

15 Page 15 TABLE 4. HEMATOLOGIC VALUES.* VARIABLE TREATMENT GROUP ADMISSION TO ED 12 HR 24 HR Number of patients Hypothermia Normothermia Platelet count ( 10 3 /mm 3 ) Hypothermia 209± ± ±63.3 Normothermia 221± ± ±54.2 P value White-cell count ( 10 3 /mm 3 ) Hypothermia 10.9 ( ) 14.5 ( ) 14.6 ( ) Normothermia 11.1 ( ) 14.6 (8.5 29) 15.8 ( ) P value *Values for platelet counts are means ±SD. Medians and ranges (in parentheses) are given for white-cell counts, which were log-transformed before analysis of variance was performed, because of nonparametric distribution. One patient in the hypothermia group and two in the normothermia group died during the first 24 hours. ED denotes emergency department. P<0.05 for the comparison with the value on admission to the emergency department. P values are for the differences between the hypothermia and the normothermia groups. P<0.01 for the comparison with the value on admission to the emergency department. The results of our study suggest that moderate induced hypothermia lasting for 12 hours is not associated with clinically significant adverse effects. Although hypothermia decreased the pulse rate and increased systemic vascular resistance, there were no clinically significant cardiac arrhythmias in the hypothermia group. The levels of creatine kinase (both the total and the MB fractions) were similar in both groups, suggesting that hypothermia does not increase the extent of myocardial damage in patients resuscitated after cardiac arrest. The increase in potassium at 24 hours in the hypothermia group has been previously observed during rewarming 15 and was not considered to be clinically important. The increase in blood glucose has also been previously described in patients with hypothermia. 35 Although previous studies have shown adverse effects on platelet and white-cell counts when hypothermia is used for more prolonged periods, 14,34 we found no statistically significant differences between the two groups when hypothermia was used for 12 hours. Although we did not specifically test immune function, no clinically significant infections were noted in either group. There are several limitations to this study. Because it was not feasible to blind clinicians to the patients treatment-group assignments, there is a possibility that bias affected patient care and outcome. However, we attempted to treat all patients according to a protocol that minimized individual variation among physicians. It is unlikely that therapy was withdrawn from any patient inappropriately, since this was always a consensus decision of the treating medical OUTCOME* TABLE 5. OUTCOME OF PATIENTS AT DISCHARGE FROM THE HOSPITAL. HYPOTHERMIA (N=43) NORMOTHERMIA (N=34) number of patients Normal or minimal disability (able to care for 15 7 self, discharged directly to home) Moderate disability (discharged to a rehabilitation 6 2 facility) Severe disability, awake but completely 0 1 dependent (discharged to a long-term nursing facility) Severe disability, unconscious (discharged to a long-term nursing facility) 0 1 Death22 23 *The difference between the rates of a good outcome (normal or with minimal or moderate disability) in the hypothermia and the normothermia groups (49 percent and 26 percent, respectively) was 23 percentage points (95 percent confidence interval, 13 to 43 percentage points; P=0.046). The unadjusted odds ratio for a good outcome in the hypothermia group as compared with the normothermia group was 2.65 (95 percent confidence interval, 1.02 to 6.88; P=0.046). The odds ratio for a good outcome in the hypothermia group as compared with the normothermia group, after adjustment by logistic regression for age and time from collapse to return of spontaneous circulation, was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). and nursing staff, made in consultation with the family of the patient. Out-of-hospital randomization of patients in emergency medical systems is problematic. We used the method of odd and even days because it was the only one feasible for immediate use by large numbers of 562 N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

16 Page 16 INDUCED HYPOTHERMIA AFTER OUT-OF-HOSPITAL CARDIAC ARREST ambulance officers and by the physicians in four emergency departments. Despite the potential for bias in randomization, it appears that the two patient groups were comparable. In particular, the degree of anoxic neurologic insult, as indicated by the duration of cardiac arrest, was similar in both groups. In fact, the higher rate of bystander cardiopulmonary resuscitation among the patients treated with normothermia would be expected to improve the outcome in this group. Improved outcome in the group treated with hypothermia might be explained by the exclusion of patients with a poor prognosis; however, we are not aware of eligible patients who were not included in the outcome analysis. The assessment of outcome after cardiac arrest has been debated. 36 In this study, we considered the place to which the patient was discharged by a rehabilitation physician who was unaware of initial treatment protocols (home, rehabilitation facility, or longterm nursing facility) to be an important outcome measure. Although a patient may be discharged to a long-term nursing facility because of a lack of social support, this was not the case in the one conscious patient (in the normothermia group) who was discharged to a long-term nursing facility. We conclude that induced hypothermia improves outcomes in patients who are comatose after resuscitation from out-of-hospital cardiac arrest. However, treatment assignment was not blinded, and there is the possibility that some aspects of care differed between the groups. Therefore, further studies are required to confirm these findings and determine the optimal duration of hypothermia. REFERENCES 1. Myerburg RJ, Castellanos A. Cardiac arrest and sudden cardiac death. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 5th ed. Vol. 1. Philadelphia: W.B. Saunders, 1997: Eisenberg MS, Horwood BT, Cummins RO, Reynolds-Haertle R, Hearne TR. Cardiac arrest and resuscitation: a tale of 29 cities. Ann Emerg Med 1990;19: Bernard SA. Outcome from prehospital cardiac arrest in Melbourne, Australia. Emerg Med 1998;10: Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P. Assessment of neurological prognosis in comatose survivors of cardiac arrest. Lancet 1994;343: Oku K, Kuboyama K, Safar P, et al. Cerebral and systemic arteriovenous oxygen monitoring after cardiac arrest: inadequate cerebral oxygen delivery. Resuscitation 1994;27: Bernard S. Induced hypothermia in intensive care medicine. Anaesth Intensive Care 1996;24: Sterz F, Safar P, Tisherman SA, Radovsky A, Kuboyama K, Oku K. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med 1991;19: Weinrauch V, Safar P, Tisherman SA, Kuboyama K, Radovsky A. Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. Stroke 1992;23: Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. 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: Illievich UM, Zornow MH, Choi KT, Scheller MS, Strnat MA. Effects of hypothermic metabolic suppression on hippocampal glutamate concentrations after transient global cerebral ischemia. Anaesth Analg 1994;78: Colburne F, Li H, Buchan AM. Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats. J Cereb Blood Flow Metab 1999;19: Hicks SD, DeFranco DB, Callaway CW. Hypothermia during reperfusion after asphyxial cardiac arrest improves functional recovery and selectively alters stress-induced protein expression. J Cereb Blood Flow Metab 2000;20: Benson DW, Williams GR Jr, Spencer FC, Yates AJ. The use of hypothermia after cardiac arrest. Anesth Analg 1959;38: Williams GR Jr, Spencer FC. The clinical use of hypothermia following cardiac arrest. Ann Surg 1958;148: Bohn DJ, Biggar WD, Smith CR, Conn AW, Barker GA. Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning. Crit Care Med 1986;14: Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997;30: Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. Resuscitation 1998;39: Zeiner A, Holzer M, Sterz F, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest: a clinical feasibility trial. Stroke 2000;31: Adult advanced life support: the Australian Resuscitation Council guidelines. Med J Aust 1993;159: Stata statistical software, version 6. College Station, Tex.: Stata, White BC, Grossman LI, O Neil BJ, et al. Global brain ischemia and reperfusion. Ann Emerg Med 1996;27: Brain Resuscitation Clinical Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med 1986;314: Jastremski M, Sutton-Tyrrell K, Vaagenes P, Abramson N, Heiselman D, Safar P. Glucocorticoid treatment does not improve neurologic recovery following cardiac arrest. JAMA 1989;262: Brain Resuscitation Clinical Trial II Study Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med 1991;324: Roine RO, Kaste M, Kinnunen A, Nikki P, Sarna S, Kajaste S. Nimodipine after resuscitation from out-of-hospital ventricular fibrillation: a placebo-controlled, double-blind, randomized trial. JAMA 1990;264: Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989;20: Morimoto Y, Kemmotsu O, Kitami K, Matsubara I, Tedo I. Acute brain swelling after out-of-hospital cardiac arrest: pathogenesis and outcome. Crit Care Med 1993;21: Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997;336: Gentilello LM, Jurkovich GJ, Stark MS, Hassantash SA, O Keefe GE. Is hypothermia in the victim of major trauma protective or harmful? A randomized, prospective study. Ann Surg 1997;226: Clemmer TP, Fisher CJ Jr, Bone RC, Slotman GJ, Metz CA, Thomas FO. Hypothermia in the sepsis syndrome and clinical outcome. Crit Care Med 1992;20: Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998;29: Kammersgaard LP, Rasmussen BH, Jørgensen HS, Reith J, Weber U, Olsen TS. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a case-control study: the Copenhagen Stroke Study. Stroke 2000;31: Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344: Bernard SA, Jones BM, Buist MD. Experience with prolonged induced hypothermia in patients with severe head injury. Crit Care (Lond) 1999;3: Curry DL, Curry KP. Hypothermia and insulin secretion. Endocrinology 1970;87: Hsu JWY, Madsen CD, Callaham ML. Quality-of-life and formal functional testing of survivors of out-of-hospital cardiac arrest correlates poorly with traditional neurologic outcome scales. Ann Emerg Med 1996; 28: Copyright 2002 Massachusetts Medical Society. N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

17 CONSORT 2010 Statement Page 17 Academia and Clinic Table. CONSORT 2010 Checklist of Information to Include When Reporting a Randomized Trial* Section/Topic Item Number Checklist Item Title and abstract 1a Identification as a randomized trial in the title 1b Structured summary of trial design, methods, results, and conclusions (for specific guidance, see CONSORT for abstracts [21, 31]) Reported on Page Number Introduction Background and objectives 2a Scientific background and explanation of rationale 2b Specific objectives or hypotheses Methods Trial design 3a Description of trial design (such as parallel, factorial), including allocation ratio 3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons Participants 4a Eligibility criteria for participants 4b Settings and locations where the data were collected Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were actually administered Outcomes 6a Completely defined prespecified primary and secondary outcome measures, including how and when they were assessed 6b Any changes to trial outcomes after the trial commenced, with reasons Sample size 7a How sample size was determined 7b When applicable, explanation of any interim analyses and stopping guidelines Randomization Sequence generation 8a Method used to generate the random allocation sequence 8b Type of randomization; details of any restriction (such as blocking and block size) Allocation concealment mechanism 9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 11b If relevant, description of the similarity of interventions Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses Results Participant flow (a diagram is strongly recommended) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analyzed for the primary outcome 13b For each group, losses and exclusions after randomization, together with reasons Recruitment 14a Dates defining the periods of recruitment and follow-up 14b Why the trial ended or was stopped Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Numbers analyzed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups Outcomes and estimation 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) 17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing prespecified from exploratory Harms 19 All important harms or unintended effects in each group (for specific guidance, see CONSORT for harms [28]) Discussion Limitations 20 Trial limitations; addressing sources of potential bias; imprecision; and, if relevant, multiplicity of analyses Generalizability 21 Generalizability (external validity, applicability) of the trial findings Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Other information Registration 23 Registration number and name of trial registry Protocol 24 Where the full trial protocol can be accessed, if available Funding 25 Sources of funding and other support (such as supply of drugs), role of funders CONSORT Consolidated Standards of Reporting Trials. * We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration (13) for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomized trials (11), noninferiority and equivalence trials (12), nonpharmacologic treatments (32), herbal interventions (33), and pragmatic trials (34). Additional extensions are forthcoming: For those and for up-to-date references relevant to this checklist, see June 2010 Annals of Internal Medicine Volume 152 Number Downloaded From: on 12/07/2013

18 Page 18 The New England Journal of Medicine Copyright 2002 by the Massachusetts Medical Society VOLUME 346 F EBRUARY 21, 2002 NUMBER 8 MILD THERAPEUTIC HYPOTHERMIA TO IMPROVE THE NEUROLOGIC OUTCOME AFTER CARDIAC ARREST ABSTRACT Background Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation. Methods In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32 C to 34 C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days. Results Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebralperformance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups. Conclusions In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality. (N Engl J Med 2002;346: ) Copyright 2002 Massachusetts Medical Society. THE HYPOTHERMIA AFTER CARDIAC ARREST STUDY GROUP* AN estimated 375,000 people in Europe undergo sudden cardiac arrest yearly. 1 Recovery without residual neurologic damage after cardiac arrest with global cerebral ischemia is rare. After cardiac arrest with no blood flow for more than five minutes, the generation of free radicals, together with other mediators, during reperfusion creates chemical cascades that result in cerebral injury. 2 Until recently, there was no therapy with documented efficacy in preventing brain damage after cardiac arrest. Several studies have shown that moderate systemic hypothermia (30 C) 3 or mild hypothermia (34 C) 4-8 markedly mitigates brain damage after cardiac arrest in dogs. The exact mechanism for this cerebral resuscitative effect is not clear. A reduction in cerebral oxygen consumption 9,10 and other multifactorial chemical and physical mechanisms during and after ischemia have been postulated These include retardation of destructive enzymatic reactions, suppression of free-radical reactions, protection of the fluidity of lipoprotein membranes, reduction of the oxygen demand in lowflow regions, reduction of intracellular acidosis, and inhibition of the biosynthesis, release, and uptake of excitatory neurotransmitters. Preliminary clinical studies have shown that patients treated with mild hypothermia after cardiac arrest have an improved neurologic outcome, without important side effects, as compared with the outcome in historical controls We compared mild hypothermia with standard normothermia in patients who had had cardiac arrest due to ventricular fibrillation. The primary end point Michael Holzer, M.D., Universitätsklinik für Notfallmedizin, Vienna, Austria, assumes overall responsibility for the integrity of the report. Address reprint requests to Dr. Fritz Sterz, Universitätsklinik für Notfallmedizin, Allgemeines Krankenhaus der Stadt Wien, Währinger Gürtel 18 20/6D, 1090 Vienna, Austria or at *The investigators who participated in the Hypothermia after Cardiac Arrest Study Group are listed in the Appendix. N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

19 Page 19 was a favorable neurologic outcome within six months after cardiac arrest Secondary end points were mortality at six months and the incidence of complications during the first seven days. Nine centers in five European countries participated in the study. METHODS Patients Patients seen consecutively in the emergency department in whom spontaneous circulation had been restored after cardiac arrest were eligible for the study. The criteria for inclusion were a witnessed cardiac arrest, ventricular fibrillation or nonperfusing ventricular tachycardia as the initial cardiac rhythm, a presumed cardiac origin of the arrest, an age of 18 to 75 years, an estimated interval of 5 to 15 minutes from the patient s collapse to the first attempt at resuscitation by emergency medical personnel, and an interval of no more than 60 minutes from collapse to restoration of spontaneous circulation. Patients were excluded if they met any of the following criteria: a tympanic-membrane temperature below 30 C on admission, a comatose state before the cardiac arrest due to the administration of drugs that depress the central nervous system, pregnancy, response to verbal commands after the return of spontaneous circulation and before randomization, evidence of hypotension (mean arterial pressure, less than 60 mm Hg) for more than 30 minutes after the return of spontaneous circulation and before randomization, evidence of hypoxemia (arterial oxygen saturation, less than 85 percent) for more than 15 minutes after the return of spontaneous circulation and before randomization, a terminal illness that preceded the arrest, factors that made participation in follow-up unlikely, enrollment in another study, the occurrence of cardiac arrest after the arrival of emergency medical personnel, or a known preexisting coagulopathy. Study Design The study was designed as a randomized, controlled trial with blinded assessment of the outcome. The protocol and consent procedure were approved by the institutional review board of each participating center. For all patients, the requirement of informed consent was waived in accordance with the ethical standards of the local institutional review board and the guidelines for good clinical practice of the European Agency for the Evaluation of Medicinal Products. 24 The patient s family was informed about the trial, and the protocol specified that if there were any objections, the patient would be withdrawn from the study. However, there were no objections. Treatment assignments were randomly generated by computer in blocks of 10, with stratification according to center. Sealed envelopes containing the treatment assignments were provided by the biostatistics center. Immediately after a patient had been enrolled, an envelope was opened, and the patient was assigned to the specified group. Personnel involved in the care of patients during the first 48 hours after cardiac arrest could not be blinded with respect to treatment assignments. However, the physicians responsible for assessing the neurologic outcome within the first six months after the arrest were unaware of the treatment assignments. Treatment All patients received standard intensive care according to a detailed protocol. Sedation was induced by the intravenous administration of midazolam (0.125 mg per kilogram of body weight per hour initially) and fentanyl (0.002 mg per kilogram per hour initially), and the doses were adjusted as needed for 32 hours for the management of mechanical ventilation. To prevent shivering, paralysis was induced by the intravenous administration of pancuronium (0.1 mg per kilogram) every 2 hours for a total of 32 hours. Intracranial pressure was not monitored. The temperature on admission was measured with an infrared tympanic thermometer (Ototemp LighTouch, Exergen, Watertown, Mass.). Further temperature measurements were made with a bladder-temperature probe (Foley catheter). Patients randomly assigned to the normothermia group were placed on a conventional hospital bed, and normothermia was maintained. Those randomly assigned to the hypothermia group were cooled to a target temperature of 32 C to 34 C with the use of an external cooling device (TheraKool, Kinetic Concepts, Wareham, United Kingdom). This device consists of a mattress with a cover that delivers cold air over the entire body. The goal was to reach the target bladder temperature within four hours after the return of spontaneous circulation. If this goal was not achieved, ice packs were applied. The temperature was maintained at 32 C to 34 C for 24 hours from the start of cooling, followed by passive rewarming, which we expected would occur over a period of 8 hours. Data Collection Data on cardiac arrest for individual patients were recorded in the Utstein style. 25 Laboratory tests were performed at base line, 12 and 48 hours after cardiac arrest, and as clinically indicated. Risk factors for an unfavorable outcome (hypotension or a nonfatal cardiac arrest after resuscitation) were documented. Outcome The primary outcome was a favorable neurologic outcome within six months, defined as a Pittsburgh cerebral-performance category of 1 (good recovery) or 2 (moderate disability) on a fivecategory scale; the other categories were 3 (severe disability), 4 (a vegetative state), and 5 (death) The neurologic outcome was determined without knowledge of the patient s treatment assignment. Patients with good recovery or moderate disability had sufficient cerebral function to live independently and work at least part-time. Secondary end points were overall mortality at six months and the rate of complications during the first seven days after cardiac arrest. Bleeding of any severity, pneumonia, sepsis, pancreatitis, renal failure, pulmonary edema, seizures, arrhythmias, and pressure sores were recorded. Since an individual patient might have more than one complication at a time, the occurrence of at least one complication of any kind per patient was also documented. Statistical Analysis Continuous variables, which were not normally distributed, are reported as medians and interquartile ranges. Categorical variables are reported as counts and percentages. Primary and secondary outcomes were binary, and the chi-square test or Fisher s exact test, as appropriate, was used to compare outcomes in the hypothermia and normothermia groups. Trends across subgroups were measured with an extension of the Wilcoxon rank-sum test. 26 The difference in risk between the two groups, with the corresponding 95 percent confidence interval, was calculated as a measure of the absolute risk, which was then used to calculate the number needed to treat. Risk ratios are reported as a measure of relative risk. We used a multivariate logistic-regression model to determine whether the association between the intervention and the primary and secondary outcomes (neurologic recovery and mortality) was confounded by base-line differences between the study groups. All the covariables listed in Table 1 were entered into the model, except for the dose of epinephrine, which was excluded because of collinearity with the interval from the patient s collapse to the restoration of spontaneous circulation. We converted odds ratios to risk ratios using the following formula: 550 N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

20 Page 20 MILD THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST TABLE 1. BASE-LINE CHARACTERISTICS OF THE PATIENTS. CHARACTERISTIC NORMOTHERMIA (N=138) HYPOTHERMIA (N=137) Age yr Median Interquartile range * Female sex no./total no. (%) 32/138 (23) 33/137 (24) Medical history no./total no. (%) Diabetes Coronary heart disease Cerebrovascular disease NYHA class III or IV 26/138 (19) 59/138 (43) 11/138 (8) 16/132 (12) 11/135 (8) 43/135 (32) 10/135 (7) 14/130 (11) Location of cardiac arrest no./total no. (%) Home Public place Other 70/138 (51) 53/138 (38) 15/138 (11) 69/135 (51) 48/135 (36) 18/135 (13) Arrest witnessed no./total no. (%) 136/138 (99) 134/137 (98) Presumed cardiac origin of arrest no./total no. (%) 135/138 (98) 135/137 (99) Ventricular fibrillation or pulseless ventricular tachycardia 132/138 (96) 133/137 (97) no./total no. (%) Basic life support provided by bystander no./total no. (%) 68/138 (49) 59/137 (43) Interval between collapse and restoration of spontaneous circulation min Median Interquartile range Total epinephrine dose mg Median Interquartile range * Hypotension after resuscitation no./total no. (%) 68/138 (49) 75/137 (55) Subsequent nonfatal arrest no./total no. (%) 11/138 (8) 15/137 (11) Thrombolysis after resuscitation no./total no. (%) 24/133 (18) 27/135 (20) *Data were not available for two patients. NYHA denotes New York Heart Association. Other locations included a physician s office, the workplace, and the hospital. Although this was a criterion for inclusion in the study, in a few cases, the initial information was incorrect. Data were not available for three patients in the normothermia group and four in the hypothermia group. risk ratio=odds ratio ([1 incidence in normothermia group]+ incidence in normothermia group odds ratio). 27 Confounding can be assumed if the crude risk ratio differs from the adjusted risk ratio. Goodness of fit was assessed with the Hosmer Lemeshow chi-square test. A reasonable fit can be assumed if the result is not significant at the 5 percent level. Analysis was carried out according to the intention-to-treat principle. Stata software (version 7, Stata, College Station, Tex.) was used to analyze the data. RESULTS The study was carried out between March 1996 and January Since the enrollment rate was lower than expected and funding had ended by July 2000, enrollment was stopped at this date. A total of 3551 patients were assessed for eligibility; 3246 of these patients did not meet the inclusion criteria, and 30 were not included because of logistic problems. Thus, 275 patients were enrolled, with 137 patients randomly assigned to the hypothermia group and 138 to the normothermia group (i.e., the group that received standard care after resuscitation). Hypothermia was discontinued early in 14 patients for the following reasons: death (6 patients), arrhythmia and hemodynamic instability (3), technical problems with the cooling device (2), liver rupture (1), previous random assignment to the hypothermia group (1), and an error in the duration of cooling (1). All randomized patients were included in the analysis of mortality. One patient in each group was lost to follow-up for neurologic status. At base line, the patients in the two groups were generally similar, although the patients in the normothermia group were more likely to have a history of diabetes mellitus or coronary heart disease and to have received basic life support from a bystander than were those in the hypothermia group. These differences appear to have been due to random variation (Table 1). N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

21 Page 21 Cooling In patients randomly assigned to the hypothermia group, the median interval between the restoration of spontaneous circulation and the initiation of cooling was 105 minutes (interquartile range, 61 to 192). The median interval between the restoration of spontaneous circulation and the attainment of a temperature between 32 C and 34 C was 8 hours (interquartile range, 4 to 16). In 19 patients, the target temperature could not be reached. Ice packs were required for 93 of the 132 patients for whom data were available (70 percent). The median duration of cooling was 24 hours (interquartile range, 24 to 25), and among patients in whom the target temperature was reached, it was maintained for a median of 24 hours (interquartile range, 12 to 29). Passive rewarming to a temperature above 36 C lasted for a median of 8 hours (interquartile range, 8 to 12). The temperature curves for the normothermia and hypothermia groups are shown in Figure 1. Outcome at Six Months A total of 75 of the 136 patients (55 percent) in the hypothermia group had a favorable neurologic outcome, as compared with 54 of the 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81) (Table 2). To prevent one unfavorable neurologic outcome, 6 patients would need to be treated with hypothermia (95 percent confidence interval, 4 to 25 patients). After adjustment for a history of diabetes mellitus, a history of coronary heart disease, and receipt of basic life support from a bystander, the risk ratio changed only marginally (data not shown). After adjustment for all the base-line variables shown in Table 1, the risk ratio increased slightly, to 1.47 (95 percent confidence interval, 1.09 to 1.82). The rate of death six months after cardiac arrest was 14 percentage points lower in the hypothermia group than in the normothermia group (risk ratio for the hypothermia group, 0.74 [95 percent confidence interval, 0.58 to 0.95]) (Table 2 and Fig. 2). On the basis of the difference in the risk of death between the two groups, 7 patients would need to be treated with hypothermia (95 percent confidence interval, 4 to 33 patients) to prevent 1 death. After adjustment for base-line differences in the proportions of patients with a history of diabetes mellitus, a history of coronary heart disease, and receipt of basic life support from a bystander, the risk ratio changed only minimally (data not shown). After adjustment for all the base-line variables shown in Table 1, the effect Normothermia (n=124) Bladder Temperature ( C) Hypothermia (n=123) Hours after Restoration of Spontaneous Circulation Figure 1. Bladder Temperature in the Normothermia and Hypothermia Groups. The T bars indicate the 75th percentile in the normothermia group and the 25th percentile in the hypothermia group. The target temperature in the hypothermia group was 32 C to 34 C, and the duration of cooling was 24 hours. Only patients with recorded temperatures were included in the analysis. 552 N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

22 Page 22 MILD THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST TABLE 2. NEUROLOGIC OUTCOME AND MORTALITY AT SIX MONTHS. OUTCOME NORMOTHERMIA HYPOTHERMIA RISK RATIO (95% CI)* P VALUE no./total no. (%) Favorable neurologic outcome 54/137 (39) 75/136 (55) 1.40 ( ) Death 76/138 (55) 56/137 (41) 0.74 ( ) 0.02 *The risk ratio was calculated as the rate of a favorable neurologic outcome or the rate of death in the hypothermia group divided by the rate in the normothermia group. CI denotes confidence interval. Two-sided P values are based on Pearson s chi-square tests. A favorable neurologic outcome was defined as a cerebral-performance category of 1 (good recovery) or 2 (moderate disability). One patient in the normothermia group and one in the hypothermia group were lost to neurologic follow-up. 100 Survival (%) Hypothermia Normothermia Days NO. AT RISK Hypothermia Normothermia Figure 2. Cumulative Survival in the Normothermia and Hypothermia Groups. Censored data are indicated by tick marks. of hypothermia on mortality was slightly stronger (risk ratio, 0.62; 95 percent confidence interval, 0.36 to 0.95). Most of the patients with unfavorable neurologic outcomes died within six months after discharge from the hospital. In this subgroup of patients, mortality after discharge did not differ significantly according to the assigned treatment (Table 3). Complications The proportion of patients with any complication did not differ significantly between the two groups (93 of 132 patients in the normothermia group [70 percent] and 98 of 135 in the hypothermia group [73 percent], P=0.70). Sepsis was more likely to develop in the patients with hypothermia than in those with normothermia, although this difference was not statistically significant (Table 4). The total number of complications was not significantly higher in the hypothermia group than in the normothermia group (P=0.09). DISCUSSION Our results show that among patients in whom spontaneous circulation had been restored after cardiac arrest due to ventricular fibrillation, systemic cool- N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

23 Page 23 TABLE 3. DEATHS BEFORE DISCHARGE AND DEATHS AFTER DISCHARGE ACCORDING TO THE CEREBRAL-PERFORMANCE CATEGORY. TABLE 4. COMPLICATIONS DURING THE FIRST SEVEN DAYS AFTER CARDIAC ARREST.* OUTCOME NORMOTHERMIA HYPOTHERMIA Death in hospital no Not discharged no. 2 2 Death after discharge no./ total no. discharged* CPC 1 CPC 2 CPC 3 CPC 4 0/30 0/12 1/16 6/8 1/45 0/19 1/14 4/6 *One patient in the normothermia group and one in the hypothermia group were lost to follow-up. There were no significant differences between the two groups (chi-square=0.30, with 3 df; P=0.96). A cerebralperformance category (CPC) of 1 indicates good cerebral performance (the patient is alert and has normal cerebral function). CPC 2 indicates moderate disability (the patient is alert and has sufficient cerebral function to live independently and work part-time). Such patients might have hemiplegia, seizures, ataxia, dysarthria, dysphasia, or permanent memory loss or other mental changes. CPC 3 indicates severe cerebral disability (the patient is conscious but dependent on others for daily support because of impaired brain function). CPC 4 indicates a vegetative state. COMPLICATION NORMOTHERMIA HYPOTHERMIA no./total no. (%) Bleeding of any severity 26/138 (19) 35/135 (26) Need for platelet transfusion 0/138 (0) 2/135 (1) Pneumonia 40/137 (29) 50/135 (37) Sepsis 9/138 (7) 17/135 (13) Pancreatitis 2/138 (1) 1/135 (1) Renal failure 14/138 (10) 13/135 (10) Hemodialysis 6/138 (4) 6/135 (4) Pulmonary edema 5/133 (4) 9/136 (7) Seizures 11/133 (8) 10/136 (7) Lethal or long-lasting arrhythmia 44/138 (32) 49/135 (36) Pressure sores 0/133 (0) 0/136 *None of the comparisons between the two groups, performed with the use of Pearson s chi-square test, indicated significant differences. The sites of bleeding were mucous membranes, the nose, the urinary tract, the gastrointestinal tract, subcutaneous tissue, and skin, as well as intracerebral and intraabdominal sites. ing to a bladder temperature between 32 C and 34 C for 24 hours increased the chance of survival and of a favorable neurologic outcome (a cerebralperformance category of 1 or 2), as compared with standard normothermic life support. The use of moderate hypothermia after cardiac arrest was initially reported in the late 1950s and early 1960s Although the target temperature was lower in these studies than in ours and the method and duration of cooling also differed from those in our study, the results were similar. However, the findings were inconclusive, and the rate of complications was higher than that observed with the mild hypothermia used in our study. There were no further investigations of hypothermia as a resuscitative measure until the 1990s, when laboratory studies demonstrated the benefit of mild hypothermia. 4-8,16 These studies led to preliminary clinical studies of mild hypothermia. In the study by Bernard et al., 17 cooling was induced more rapidly (with ice packs) and for a shorter period than in our study. Nevertheless, the results were similar to ours. The neurologic outcome has also been consistently favorable in studies of mild hypothermia in animals In the pilot studies by Yanagawa et al. 18 and Nagao et al., 19 the frequency of a favorable neurologic outcome was similar to that in our study, although the method and duration of cooling in these studies differed from those in our study. In contrast to these encouraging findings, a study of hypothermia in patients with traumatic brain injury 35 showed no improvement in the neurologic outcome. The reasons for this discrepancy are thought to include the different pathogenesis of direct central nervous system injury, as well as the late initiation of cooling in some of the patients and variations in intensive care and life support among participating hospitals. 35,36 Although the proportions of patients with any complication did not differ significantly between the two treatment groups in our study, a detailed analysis of the complications and an analysis of the total number of complications revealed a trend toward a higher rate of infectious problems in the hypothermia group. Nevertheless, the benefit of hypothermia exceeded its possible adverse effects. One limitation of our study was the fact that the attending physicians could not be blinded to the treatment assignments. The relative risk may be slightly exaggerated in studies that are not double blind. 37 Although the outcome was assessed without knowledge of the treatment assignments, we did not verify that the blinding was successful. Even if it was not successful in a few cases, we do not believe that any bias that might have been introduced would have been strong enough to invalidate our findings. The study population was restricted to a group of patients with a high risk of brain damage because of the specified interval between the patient s collapse and the first attempt at resuscitation by emergency 554 N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

24 Page 24 MILD THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST medical personnel, as well as other factors, so only 8 percent of the patients assessed for eligibility were included in the trial. Further studies are warranted to determine whether our findings apply to patients at lower risk for brain damage and to those with cardiac arrest due to causes other than ventricular fibrillation. Treatment with hypothermia may be of value in terms of public health. Each year, cardiac arrest occurs in approximately 375,000 people in Europe, 1 about 30,000 of whom would meet our inclusion criteria. We can be 95 percent confident that treatment with hypothermia would prevent an unfavorable neurologic outcome in 1200 to 7500 of these patients. Supported by grants from the Biomedicine and Health Programme (BIOMED 2) implemented under the Fourth RTD Framework Programme of the European Union (BMH4-CD ), the Austrian Ministry of Science and Transport (GZ 5.550/12-Pr/4/95 and GZ /2-IV/6/96), and the Austrian Science Foundation (P11405-MED). K. Heaton and R. Meier (Kinetic Concepts, Wareham, United Kingdom) provided technical support and the TheraKool cooling device. We are indebted to the nurses and staff of the participating centers for their enthusiastic cooperation, to Elaine Ward for editorial assistance, and to the patients in the study for their trust and support. APPENDIX The following investigators participated in the Hypothermia after Cardiac Arrest Study Group (the number of patients enrolled at each center is shown): Chair, Central Coordinating Office M. Holzer (Universitätsklinik für Notfallmedizin, Vienna, Austria); Steering Committee E. Cerchiari (Ospedale Niguarda Ca Granda, Milan, Italy), P. Martens (A.Z. Sint Jan, Bruges, Belgium), R. Roine (Helsinki University Hospital, Helsinki, Finland), F. Sterz (Universitätsklinik für Notfallmedizin, Vienna, Austria); Central Coordinating Office P. Eisenburger, C. Havel, J. Kofler, E. Oschatz, K. Rohrbach, W. Scheinecker, W. Schörkhuber; hospital investigators W. Behringer, A. Zeiner (Universitätsklinik für Notfallmedizin, Vienna, Austria; 88 patients); A. Valentin (Krankenhaus Rudolfstiftung, Vienna, Austria; 2 patients); M. De Meyer (A.Z. Sint Jan, Bruges, Belgium; 35 patients); O. Takunen, M. Tiainen (Helsingin Yliopistollisen Keskussairaalan, Helsinki, Finland; 71 patients); S. Hachimi-Idrissi, L. Huyghens (Academisch Ziekenhuis van de Vrije Universiteit Brussel, Brussels, Belgium; 25 patients); M. Fischer, P. Walger (Medizinische Fakultat der Rheinischen Friedrich-Wilhems-Universitat Bonn, Bonn, Germany; 15 patients); A. Bartsch, M. Foedisch (Evangelisches Waldkrankenhaus Bonn, Bonn, Germany; 15 patients); E. Cerchiari (Ospedale Niguarda Ca Granda, Milan, Italy; 12 patients); M. Bonizzoli, E. Pagni (Azienda Ospedalieria Careggi, Florence, Italy; 12 patients); Monitoring Committee A.N. Laggner (Universitätsklinik für Notfallmedizin, Vienna, Austria), A. Kaff (Rettungs- und Krankenbeförderungsdienst der Stadt Wien, Vienna, Austria), B. Schneider (randomization procedure) (Institut für Medizinische Statistik, Universität Wien, Vienna, Austria); Data Analysis M. Müllner (Universitätsklinik für Notfallmedizin, Vienna, Austria). REFERENCES 1. de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al. Outof-hospital cardiac arrest in the 1990 s: a population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol 1997;30: Negovsky VA. Postresuscitation disease. Crit Care Med 1988;16: Leonov Y, Sterz F, Safar P, Radovsky A. Moderate hypothermia after cardiac arrest of 17 minutes in dogs: effect on cerebral and cardiac outcome. Stroke 1990;21: Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab 1990;10: Sterz F, Safar P, Tisherman S, Radovsky A, Kuboyama K, Oku K. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med 1991;19: Weinrauch V, Safar P, Tisherman S, Kuboyama K, Radovsky A. Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. Stroke 1992;23: Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. 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: Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 1996;27: Hegnauer AH, D Amato HE. Oxygen consumption and cardiac output in the hypothermic dog. Am J Physiol 1954;178: Mezrow CK, Sadeghi AM, Gandsas A, et al. Cerebral blood flow and metabolism in hypothermic circulatory arrest. Ann Thorac Surg 1992;54: Chopp M, Knight R, Tidwell CD, Helpern JA, Brown E, Welch KM. The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat: comparison to normothermia and hyperthermia. J Cereb Blood Flow Metab 1989;9: Dempsey RJ, Combs DJ, Maley ME, Cowen DE, Roy MW, Donaldson DL. Moderate hypothermia reduces postischemic edema development and leukotriene production. Neurosurgery 1987;21: Kramer RS, Sanders AP, Lesage AM, Woodhall B, Sealy WC. The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest. J Thorac Cardiovasc Surg 1968;56: Natale JA, D Alecy LG. Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs. Stroke 1989;20: Sterz F, Leonov Y, Safar P, et al. Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs: reperfusion with open-chest CPR or cardiopulmonary bypass. Resuscitation 1992;24: Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989;20: Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997;30: Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. Resuscitation 1998;39: Nagao K, Hayashi N, Kanmatsuse K, et al. Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patients with cardiac arrest outside the hospital. J Am Coll Cardiol 2000;36: Zeiner A, Holzer M, Sterz F, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest: a clinical feasibility trial. Stroke 2000;31: Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975;1: Brain Resuscitation Clinical Trial II Study Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med 1991;324: Safar P, Bircher NG. Cardiopulmonary cerebral resuscitation: basic and advanced cardiac and trauma life support: an introduction to resuscitation medicine. 3rd ed. London: W.B. Saunders, 1988: Human Medicines Evaluation Unit. Note for guidance on good clinical practice (clinical practice medicinal products [CPMP]/International Conference of Harmonization [ICH]/135/95). Guidelines for good clinical practice. ICH topic E6. London: European Agency for the Evaluation of Medicinal Products, 1995:1-58. (Also available at org/emca.html.) 25. Cummins RO, Chamberlain DA, Abramson NS, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style: a statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation 1991;84: Cuzick J. A Wilcoxon-type test for trend. Stat Med 1985;4: Zhang J, Yu KF. What s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280: Benson DW, Williams GR Jr, Spencer FC, Yates AJ. The use of hypothermia after cardiac arrest. Anesth Analg 1958;38: Williams GR Jr, Spencer FC. The clinical use of hypothermia following cardiac arrest. Ann Surg 1959;148: N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

25 Page Ravitch MM, Lane R, Safar P, Steichen FM, Knowles P. Lightning stroke: report of a case with recovery after cardiac massage and prolonged artificial respiration. N Engl J Med 1961;264: Markarian GZ, Lee JH, Stein DJ, Hong SC. Mild hypothermia: therapeutic window after experimental cerebral ischemia. Neurosurgery 1996; 38: Coimbra C, Wieloch T. Hypothermia ameliorates neuronal survival when induced 2 hours after ischaemia in the rat. Acta Physiol Scand 1992; 146: Colbourne F, Li H, Buchan AM. Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats. J Cereb Blood Flow Metab 1999;19: Hickey RW, Ferimer H, Alexander HL, et al. Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats. Crit Care Med 2000;28: Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344: Safar P, Kochanek PM. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;345: Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273: Copyright 2002 Massachusetts Medical Society. 556 N Engl J Med, Vol. 346, No. 8 February 21, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 2, For personal use only. No other uses without permission. Copyright 2002 Massachusetts Medical Society. All rights reserved.

26 ILCOR Advisory Statement Page 26 Therapeutic Hypothermia After Cardiac Arrest An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation Writing Group J.P. Nolan, FRCA; P.T. Morley, MD; T.L. Vanden Hoek, MD; R.W. Hickey, MD Members of the Advanced Life Support Task Force W.G.J. Kloeck, MBBCh, DipPEC(SA), Chair*; J. Billi, MD ; B.W. Böttiger, MD ; P.T. Morley, MD ; J.P. Nolan, FRCA ; K. Okada, MD ; C. Reyes, MD#; M. Shuster, MD, FRCPC**; P.A. Steen, MD ; M.H. Weil, MD, PhD ; V. Wenzel, MD Member of the Pediatric Life Support Task Force R.W. Hickey, MD Additional Contributors P. Carli, MD ; T.L. Vanden Hoek, MD ; D. Atkins, MD ILCOR Recommendations On the basis of the published evidence to date, the Advanced Life Support (ALS) Task Force of the International Liaison Committee on Resuscitation (ILCOR) made the following recommendations in October 2002: Unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32 C to 34 C for 12 to 24 hours when the initial rhythm was ventricular fibrillation (VF). Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest. Introduction Induction of moderate hypothermia (28 C to 32 C) before cardiac arrest has been used successfully since the 1950s to protect the brain against the global ischemia that occurs during some open-heart surgeries. Successful use of therapeutic hypothermia after cardiac arrest in humans was also described in the late 1950s 1 3 but was subsequently abandoned because of uncertain benefit and difficulties with its use. 4 Since then, induction of hypothermia after return of spontaneous circulation (ROSC) has been associated with improved functional recovery and reduced cerebral histological deficits in various animal models of cardiac arrest. 5 8 Additional promising preliminary human studies have been completed At the time of publication of the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, the evidence was insufficient to recommend use of therapeutic hypothermia after resuscitation from cardiac arrest. 17 Clinical Studies In 2002 the results of 2 prospective randomized trials were published that compared mild hypothermia with normothermia in comatose survivors of out-of-hospital cardiac arrest. 18,19 One study was undertaken in 9 centers in 5 European countries 19 ; the other was conducted in 4 hospitals in Melbourne, Australia. 18 Every effort has been made to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation in April 2003 and by the American Heart Association Science Advisory and Coordinating Committee on November 14, A single reprint is available by calling (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX Ask for reprint No To purchase additional reprints: up to 999 copies, call (US only) or fax ; 1000 or more copies, call , fax , or To make photocopies for personal or educational use, call the Copyright Clearance Center, From the *Resuscitation Council of Southern Africa (RCSA), American Heart Association (AHA), European Resuscitation Council (ERC), Australia and New Zealand Council on Resuscitation (ANZCOR), Japanese Resuscitation Council (JRC), #Latin American Resuscitation Council (CLAR), and **Heart and Stroke Foundation of Canada (HSFC). This statement has been copublished in the July 8, 2003, issue of Circulation and the June 2003 issue of Resuscitation. (Circulation. 2003;108: ) 2003 by the American Heart Association, Inc, and Elsevier Science Ireland Ltd. Circulation is available at DOI: /01.CIR Downloaded from by guest on December 2, 2013

27 Page 27 Main results We included four trials and one abstract reporting on 481 patients in the systematic review. The updated search resulted in no new studies to include. Quality of the included studies was good in three out of five studies. For the three comparable studies on conventional cooling methods all authors provided individual patient data. With conventional cooling methods, patients in the hypothermia group were more likely to reach a best cerebral performance categories (CPC) score of one or two (five point scale: 1 = good cerebral performance, to 5 = brain death) during the hospital stay (individual patient data; RR 1.55; 95% CI 1.22 to 1.96) and were more likely to survive to hospital discharge (individual patient data; RR 1.35; 95% CI 1.10 to 1.65) compared to standard post-resuscitation care. Across all studies, there was no significant difference in reported adverse events between hypothermia and control. Authors conclusions Conventional cooling methods to induce mild therapeutic hypothermia seem to improve survival and neurologic outcome after cardiac arrest. Our review supports the current best medical practice as recommended by the International Resuscitation Guidelines. P L A I N L A N G U A G E S U M M A R Y Cooling the body after cardiac arrest Sudden cardiac death means that the heart and subsequently the circulation stops. Patients with a structural heart disease like coronary heart disease have a higher risk for sudden cardiac death. Around 30% to 50% of all patients with coronary heart disease suffer sudden cardiac death at some stage of their illness. In cardiac arrest the brain lacks blood and oxygen and the patient loses consciousness. After a few minutes of lack of oxygen brain cells begin to be irreversibly damaged. Although potentially lethal, if a patient in cardiac arrest is found and resuscitated early, they may be saved and brain damage prevented. To date about one tenth to a third of successfully resuscitated patients leave hospital to live an independent life again. One form of therapy that may help to improve these neurologic deficits is called therapeutic hypothermia or resuscitative hypothermia. It is a form of therapy where patients that have been resuscitated after cardiac arrest and are still unconscious after resuscitation are cooled to 33 C for several hours. Clinical trials have shown that with therapeutic hypothermia the neurologic damage caused by the cardiac arrest may be attenuated. Pathophysiologic studies discovered that therapeutic hypothermia works in many different ways. One way is that it lowers cell metabolism and prevents the production of harmful substances that form during resuscitation and continuously damage the brain cells. Hypothermia may be initiated by different methods like cold drips, cooling pads or cooling catheters. We have summarized three randomized trials with conventional cooling methods on a total of 383 patients that evaluated the effects of therapeutic hypothermia in patients resuscitated after cardiac arrest in comparison to resuscitated patients treated without therapeutic hypothermia. With conventional cooling methods like cooling blankets or cooling helmets, patients were 55% more likely to leave the hospital without major brain damage. When the results of two additional studies (one study only published as an abstract and another comparing cooling through haemofiltration) were added, this effect remained unchanged. No cooling specific adverse events were reported. One of the limitations of our review is that the majority of patients had a specific form of cardiac arrest, with ventricular fibrillation and ventricular tachycardia as the underlying cardiac rhythm. In summary, there is current evidence supporting the use of conventional cooling to induce mild hypothermia in cardiac arrest survivors within the first hours of resuscitation. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

28 Research Page 28 Original Investigation Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest A Randomized Clinical Trial Francis Kim, MD; Graham Nichol, MD, MPH; Charles Maynard, PhD; Al Hallstrom, PhD; Peter J. Kudenchuk, MD; Thomas Rea, MD, MPH; Michael K. Copass, MD; David Carlbom, MD; Steven Deem, MD; W. T. Longstreth Jr, MD; Michele Olsufka, RN; Leonard A. Cobb, MD IMPORTANCE Hospital cooling improves outcome after cardiac arrest, but prehospital cooling immediately after return of spontaneous circulation may result in better outcomes. Editorial Supplemental content at jama.com OBJECTIVE To determine whether prehospital cooling improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and without VF. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trial that assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling, accomplished by infusing up to 2 L of 4 C normal saline as soon as possible following return of spontaneous circulation. Adults in King County, Washington, with prehospital cardiac arrest and resuscitated by paramedics were eligible and 1359 patients (583 with VF and 776 without VF) were randomized between December 15, 2007, and December 7, Patient follow-up was completed by May 1, Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomization. MAIN OUTCOMES AND MEASURES The primary outcomes were survival to hospital discharge and neurological status at discharge. RESULTS The intervention decreased mean core temperature by 1.20 C (95% CI, 1.33 C to 1.07 C) in patients with VF and by 1.30 C (95% CI, 1.40 C to 1.20 C) in patients without VF by hospital arrival and reduced the time to achieve a temperature of less than 34 C by about 1 hour compared with the control group. However, survival to hospital discharge was similar among the intervention and control groups among patients with VF (62.7% [95% CI, 57.0%-68.0%] vs 64.3% [95% CI, 58.6%-69.5%], respectively; P =.69) and among patients without VF (19.2% [95% CI, 15.6%-23.4%] vs 16.3% [95% CI, 12.9%-20.4%], respectively; P =.30). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either patients with VF (57.5% [95% CI, 51.8%-63.1%] of cases had full recovery or mild impairment vs 61.9% [95% CI, 56.2%-67.2%] of controls; P =.69) or those without VF (14.4% [95% CI, 11.3%-18.2%] of cases vs 13.4% [95% CI,10.4%-17.2%] of controls; P =.30). Overall, the intervention group experienced rearrest in the field more than the control group (26% [95% CI, 22%-29%] vs 21% [95% CI, 18%-24%], respectively; P =.008), as well as increased diuretic use and pulmonary edema on first chest x-ray, which resolved within 24 hours after admission. CONCLUSION AND RELEVANCE Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34 C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT JAMA. doi: /jama Published online November 17, Author Affiliations: Department of Medicine, School of Medicine, University of Washington, Seattle (Kim, Nichol, Kudenchuk, Rea, Carlbom, Olsufka, Cobb); Department of Health Services, School of Public Health, University of Washington, Seattle (Maynard); Department of Biostatistics, School of Public Health, University of Washington, Seattle (Hallstrom); Department of Neurology, School of Medicine, University of Washington, Seattle (Copass, Longstreth); Department of Anesthesiology, School of Medicine, University of Washington, Seattle (Deem); Department of Epidemiology, School of Public Health, University of Washington, Seattle (Longstreth). Corresponding Author: Francis Kim, MD, Harborview Medical Center, 325 Ninth Ave, Seattle, WA E1 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: by a SCELC - Loma Linda University User on 11/24/2013

29 Research Original Investigation Page 29 Induction of Mild Hypothermia for Cardiac Arrest Brain injury causes morbidity and mortality after resuscitation from cardiac arrest, and many patients never awaken. 1-4 Hypothermia is a promising treatment that can help brain recovery. In randomized trials of humans resuscitated from prehospital ventricular fibrillation (VF), mild hypothermia (32-34 C) for 12 to 24 hours improved neurological recovery and survival despite delays of 4 to 8 hours in achieving goal temperatures. 5,6 Hospital-based induction of hypothermia is now recommended for patients who remain comatose after resuscitation from VF. 7,8 The optimal timing for induction of hypothermia is uncertain. In animal models of cardiac arrest, the benefit of hypothermia declines when it is started more than 15 minutes after reperfusion. 9 Bernard et al 10,11 hypothesized that early initiation of cooling in the field after return of spontaneous circulation (ROSC) would improve both survival and neurological outcome. Rapid cooling after resuscitation from cardiac arrest with an intravenous infusion of cold saline appears feasible and safe. 12 However, no benefit was observed among 234 patients resuscitated from prehospital VF and then randomized to early field cooling. 13 The only randomized trial of prehospital hypothermia in patients resuscitated from cardiac arrest without VF (ie, first rhythm of asystole or pulseless electrical activity) lacked power to detect a difference in outcomes. 14 Therefore, we evaluated whether early prehospital cooling improved survival to hospital discharge and neurological outcome in patients with a presenting arrest rhythm of VF or without VF. We also examined whether prehospital cooling was associated with adverse effects in the prehospital and hospital phases of care. Methods Participants The trial was conducted under waiver from informed consent during emergency research conditions in accordance with all applicable federal regulations, including investigational new drug provisions by the US Food and Drug Administration, approval by the institutional review board at the University of Washington and all the acute care hospitals in Seattle and King County, Washington, and oversight by an independent data and safety monitoring board. Study personnel contacted the patient s family as soon as feasible after enrollment to explain the study and seek written informed consent to review the medical records of each patient. Families of deceased patients were notified of their participation by mail. Study Setting and Population This randomized trial assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling with an infusion of up to 2 L of 4 C normal saline as soon as possible following ROSC. Seattle and King County, Washington, emergency medical services (EMS) serve a population of nearly 2 million residents and respond to more than 1100 nontraumatic cardiac arrests annually using a 2-tiered response. First-tier responders are trained in high-performance cardiopulmonary resuscitation and are equipped with automated external defibrillators. Second-tier responders are paramedics who provide advanced cardiac life support including defibrillation, intubation, and administration of resuscitation drugs. Cardiac arrest was defined as being unconscious due to a sudden pulseless collapse and ROSC was defined as a return of a palpable pulse after cardiac arrest. The inclusion criteria included ROSC, tracheal intubation, intravenous access, successful placement of esophageal temperature probe, and unconsciousness. Exclusion criteria included traumatic cardiac arrest, age younger than 18 years, being awake, following commands, and having a temperature of less than 34 C. All causes of cardiac arrest were considered, including those presenting with VF and those without VF. Eligible patients were randomized to receive standard care alone (control) or standard care plus induction of mild hypothermia (intervention). Paramedics called an emergency department (ED) physician at Harborview Medical Center to verify eligibility and to learn treatment assignment. Randomization was stratified by first recorded rhythm (VF or without VF) and destination hospital and by using randomly permuted blocks of concealed size to ensure temporal equality of assignment in each stratum. Sample Size We based the sample size calculations on the results of our pilot study 12 and planned separate analyses for patients with VF and those without VF. For patients with initial VF, we assumed a survival rate of 65% with the intervention and 50% with the control (standard care alone). With a 2-sided significance level of.05, a power of 90%, and 6 interim analyses with a conservative O Brien-Fleming boundary, 483 patients with VF were needed to detect a 30% relative improvement in survival with cooling in the field. The sample size for patients without VF was determined by the expected recruitment of patients with VF and was estimated to be approximately 756. This provided a power of 90% to detect a worsening of survival from 20%to10%withaP value of.05 (1-sided test). Study Intervention For patients randomized to the intervention group, paramedicsgaveupto2lof4 Cnormal saline, 7 to 10 mg of pancuronium, and 1 to 2 mg of diazepam. 12 The saline was infused through a peripheral intravenous line, 18-gauge or larger, using a pressure bag inflated to 300 mm Hg, with a goal temperature of less than 34 C. If the patient had recurrent arrest during transport, standard resuscitation protocols were started, and the saline infusion was stopped until circulation again returned. The intervention and control groups were otherwise treated the same according to standard prehospital resuscitation protocols. Paramedics transported patients to all acute care hospitals in King County, Washington, and provided information sheets describing the study to ED physicians and nurses. All participating hospitals in King County receiving patients resuscitated from VF and 1 hospital receiving patients without VF used cooling protocols involving surface and intravascular cooling devices for up to 24 hours. Serial temperatures (measured by esophageal or tympanic thermometers) and whether the patient received hospital cooling were abstracted from the hospital charts. E2 JAMA Published online November 17, 2013 jama.com Copyright 2013 American Medical Association. All rights reserved. Downloaded From: by a SCELC - Loma Linda University User on 11/24/2013

30 Induction of Mild Hypothermia for Cardiac Arrest Page 30 Original Investigation Research Outcome Measures The primary outcomes were survival and neurological status at hospital discharge. Paramedics, ED staff, inpatient physicians, and nursing staff at receiving hospitals were not blinded to treatment assignment; however, study personnel who abstracted the medical records for the primary outcome were unaware of study allocation. Safety data were collected as follows. We collected initial blood pressure, heart rate, use of pressors, rearrest or recurrent VF from standard run reports that provide paramedic documentation of the resuscitation. From hospital records, we collected data on demographics; whether cooling was initiated or continued in the hospital; blood pressure, heart rate, and pulse oximetry data during the first 12 hours; first arterial blood gas; first chest film interpretations (we abstracted data when the interpreting radiologist mentioned pulmonary edema, pulmonary congestion, hilar abnormalities, cardiomegaly, pleural effusion); use of intravenous diuretics; and use of pressors (eg, dobutamine, dopamine, norepinephrine, epinephrine, phenylephrine). We also collected data on the number of days ventilated and performance of reintubation as indirect measures of adverse pulmonary effects from fluid administration. Any use of antibiotics during hospital stay was used as a surrogate for infection. We determined the number of days to death without awakening and to awakening, which was defined as the patient following commands, having comprehensible speech, or both. Neurological status at time of discharge was assessed by reviewing daily progress records and nursing notes and was assigned as full recovery, mildly to moderately impaired, severely impaired, comatose, or dead. 15,16 Statistical Methods Safety analyses were performed on the combined groups with VF and without VF. Efficacy analyses were performed separately for the groups with VF and without VF and were based on the intention-to-treat principle. We used SPSS version 19.0 (SPSS Inc) toperformthestatisticalanalyses.differencesbetweenthegroups were analyzed with the t test for normal variables, the Wilcoxon rank sum test for nonnormal variables, and the χ 2 statistic for categoricalvariables.two-tailedtestswereperformedwithanαlevel of.05. Continuous values were presented as mean ± 1 SD. Results Enrollment and Randomization The study began on December 15, 2007, and the 1364th patient was enrolled on December 7, Patient follow-up was completed on May 1, During the enrollment period, participating paramedics attended to 5696 patients with cardiac arrest (Figure 1). Most patients (n = 3319; 58%) were ineligible because cardiopulmonary resuscitation was not successful. A total of 1013 eligible patients were not enrolled because 497 were simply missed (49%), 211 were deemed by the paramedics as being too unstable (21%), and 305 were due to other reasons (30%) (eg, equipment failure, hospital arrival prior to randomization, and inability to obtain randomization information). Of 2377 eligible patients, 1364 were enrolled (57%). Five patients were withdrawn from the study and their data recordswerenotusedbecausetheywereincarceratedatthetime of enrollment. Their unintentional enrollments were recorded and reported as protocol violations to the institutional review board. Thus, 1359 patients were included in the primary analysis. Eleven patients or their representatives did not consent for review of hospital medical records, and only their prehospital, ED, and discharge data were used in the primary analysis. Two patients were enrolled who did not meet all eligibility requirements; however, both were included in the primary analysis. Baseline characteristics of the enrolled patients appear in Table 1 and were not significantly different by VF status between the 2 treatment groups. Interventions None of the patients randomized to standard care alone (291 with VF and 380 without VF) received prehospital cooling. Most but not all of the patients randomized to cooling (292 with VF and 396 without VF) received 4 C normal saline intravenously before hospital arrival. The intervention decreased mean core temperature by 1.20 C (95% CI, 1.33 C to 1.07 C) in patients with VF and by 1.30 C (95% CI, 1.40 C to 1.20 C) in patients without VF by hospital arrival and reduced the time to achieve a temperature of less than 34 C by about 1 hour compared with the control group. Twelve patients with VF (4%) and 27 patients without VF (7%) did not receive any fluid. Almost 50% of all patients (with VF or without VF) received2loffluid(etable 1 in Supplement). The reasons why the full 2Lwerenotadministered included recurrent arrest, death in the field, and lack of time before hospital arrival to complete the infusion. Temperatures at randomization did not differ between treatment groups for patients either with VF or without VF, but those at admission to the ED did differ significantly, as did the temperature differences between the time of randomization and hospital arrival (etable 1 in Supplement). Among patients with VF, 26% (95% CI, 21%-31%) of the intervention group had a temperature of less than 34 C at the time of hospital arrival. Among patients without VF, 29% (95% CI, 25%-34%) of the intervention group had a temperature of less than 34 C. Of enrolled patients with VF who survived to hospital admission, 448 (77%) received hospital cooling with an equal number having field cooling (n = 224) or not (n = 224). The average time to reach a goal temperature was calculated for patients who reached a temperature of less than 34 C. Patients randomized to prehospital cooling and who also received hospital cooling achieved a goal temperature by a mean (SD) of 4.2 (3.0) hours (95% CI, hours) compared with 5.5 (3.7) hours (95% CI, hours) in patients who only received hospital cooling (P <.001; etable 2 in Supplement), suggesting that out-ofhospital cooling reduced time to goal temperature by more than 1 hour. A similar effect was observed in patients without VF. Outcomes Among patients with VF, 62.7% (95% CI, 57.0%-68.0%) of the intervention group and 64.3% (95% CI, 58.6%-69.5%) of the control group survived to discharge (P =.69). Among patients without VF, 19.2% (95% CI, 15.6%-23.4%) of the intervention group and 16.3% (95% CI, 12.9%-20.4%) of the control jama.com JAMA Published online November 17, 2013 E3 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: by a SCELC - Loma Linda University User on 11/24/2013

31 Research Original Investigation Page 31 Induction of Mild Hypothermia for Cardiac Arrest group survived to discharge (P =.30). Among both patients with VF and those without VF, significant differences in neurological status at time of discharge between the intervention and control groups were not evident (Table 2). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either the group with VF (57.5% [95% CI, 51.8%-63.1%] of cases had full recovery or mild impairment vs 61.9% [95% CI, 56.2%-67.2%] of con- Figure 1. Study Flow Diagram 5696 Patients with out-of-hospital cardiac arrest assessed for eligibility 3319 Excluded (not eligible) a 2823 No return of pulse 233 Temperature <34 C 163 Following commands 219 Other reasons b 2377 Eligible to participate 1013 Excluded (not enrolled) 497 Eligible but not enrolled 211 Unstable or rearrest 305 Other reasons 1364 Randomized c 583 With ventricular fibrillation 776 Without ventricular fibrillation 292 With ventricular fibrillation randomized to receive standard care plus induction of mild hypothermia 274 Received intervention as randomized 18 Did not receive intervention as randomized (no cold fluid administered) 291 With ventricular fibrillation randomized to receive standard care alone 291 Received standard care as randomized 396 Without ventricular fibrillation randomized to receive standard care plus induction of mild hypothermia 364 Received intervention as randomized 32 Did not receive intervention as randomized (no cold fluid administered) 380 Without ventricular fibrillation randomized to receive standard care alone 380 Received standard care as randomized 292 Included in primary analysis 291 Included in primary analysis 396 Included in primary analysis 380 Included in primary analysis No patients were lost to follow-up. a Some patients were excluded for more than 1 reason. b Included traumatic cardiac arrest, age younger than 18 years, no esophageal temperature, or no intravenous catheter. c Ofthe1364patientsenrolled,prehospitalemergencymedicalservicesrecordsand discharge data from only 1359 patients were used for the analyses of primary outcomes because 5 patients were later found to be incarcerated at the time of enrollment, thus data from these patients were not included in any of the analyses. Table 1. Baseline Characteristics of Randomized Eligible Patients (n=1359) a With Ventricular Fibrillation Intervention (n = 292) Control (n = 291) Without Ventricular Fibrillation Intervention (n = 396) Control (n = 380) Age, y 62.1 (14.2) 62.1 (15.6) 68.3 (16.3) 67.5 (16.5) Men, No. (%) 227 (78) 217 (75) 216 (55) 205 (54) Witnessed cardiac arrest, No. (%) 208 (71) 215 (74) 212 (54) 196 (52) CPR before EMS arrival, No. (%) 199 (68) 186 (64) 196 (50) 200 (53) Time from call to randomization, min (n = 288) 32.9 (10.6) Time from call to first responder arrival, min (n = 290) 5.3 (2.0) (n = 286) 32.5 (9.5) (n = 291) 5.2 (2.1) (n = 389) 34.4 (10.6) (n = 395) 5.4 (2.1) (n = 373) 35.2 (12.6) (n = 379) 5.2 (2.1) Sustained ROSC, No. (%) 273 (94) 274 (94) 354 (89) 343 (90) Time from call to sustained ROSC, min (n = 142) 25 (14) Time to first shock, min b (n = 175) 9.4 (3.3) Heart rate at randomization, beats/min Systolic blood pressure at randomization, mm Hg (n = 284) 109 (28) (n = 271) 140 (37) (n = 146) 24 (13) (n = 179) 9.2 (2.5) (n = 285) 113 (28) (n = 275) 144 (39) (n = 178) 28 (14) NA (n = 389) 110 (30) (n = 374) 130 (43) (n = 159) 27 (14) NA (n = 370) 106 (31) (n = 354) 131 (41) Abbreviations: CPR, cardiopulmonary resuscitation; EMS, emergency medical services; NA, not applicable; ROSC, return of spontaneous circulation. a Values are expressed as mean (SD) unless otherwise indicated. b For cardiac arrest occurring before EMS arrival. E4 JAMA Published online November 17, 2013 jama.com Copyright 2013 American Medical Association. All rights reserved. Downloaded From: by a SCELC - Loma Linda University User on 11/24/2013

32 Induction of Mild Hypothermia for Cardiac Arrest Page 32 Original Investigation Research Table 2. Status at Time of Discharge Intervention (n = 292) Vital status Dead 109 (37.3) [ ] Alive 183 (62.7) [ ] Neurological status at discharge Full recovery 125 (42.8) [ ] Mildly impaired 43 (14.7) [ ] Severely impaired 6 (2.1) [ ] Disabled (severity unknown) 2 (0.7) [ ] Comatose 4 (1.4) [ ] Alive (status unknown) 3 (1.0) [ ] With Ventricular Fibrillation (n = 583) No. (%) [95% CI] Control (n = 291) 104 (35.7) [ ] 187 (64.3) [ ] 145 (49.8) [ ] 35 (12.0) [ ] 8 (2.7) [ ] P Value.69 Intervention (n = 396) 320 (80.8) [ ] 76 (19.2) [ ] 36 (9.1) [ ] 21 (5.3) [ ] Without Ventricular Fibrillation (n = 776) No. (%) [95% CI] Control (n = 380) 318 (83.7) [ ] 62 (16.3) [ ] 34 (8.9) [ ] 17 (4.5) [ ] 5 (1.3) [ ] (2.4) [ ] 2 (0.7) [ ] 12 (3.0) [ ] 2 (0.5) [ ] 2 (0.5) [ ] 7 (1.8) [ ] 2 (0.5) [ ] P Value Figure 2. The Proportion of Comatose Patients Achieving Either Death Without Awakening or Awakening as a Function of Days After Cardiac Arrest for Enrolled Patients A With ventricular fibrillation B Without ventricular fibrillation Proportion Achieving Outcomes Coma Death without awakening Awakening Proportion Achieving Outcomes Coma Death without awakening Intervention Control Days Since Cardiac Arrest Awakening Days Since Cardiac Arrest The area between the 2 curves represents the proportion of patients who remain comatose. All patients at time = 0 are comatose and over time either awaken or die without awakening. A, There were 568 patients with ventricular fibrillation (VF) and known event times (284 in intervention group and 284 in control group). For patients with initial rhythm of VF at 7 days, 157 patients died without awakening (28%), 355 had awakened (62%), and 56 were still comatose (10%). At 30 days, 34 more patients died without awakening, 14 more had awakened, and 8 patients remained comatose. B, There were 771 patients without VF but with known event times (395 in the intervention group and 376 in the control group). At 7 days, 566 patients died without awakening (73%), 138 had awakened (18%), and 67 were still comatose (9%). At 30 days, 46 more patients died without awakening, 8 more had awakened, and 13 patients remained comatose. trols; P =.69) or without VF (14.4% [95% CI, 11.3%-18.2%] of cases vs 13.4% [95% CI,10.4%-17.2%] of controls). Next we examined the effect of intervention groups on the proportion of patients who either awakened from a coma or died without awakening (Figure 2). For randomized patients with VF, the proportion of patients who awakened was higher than the proportion who died without awakening; however, significant differences between the intervention and control groups were absent (Figure 2A). Most randomized patients without VF died without awakening, but again significant differences between the intervention and control groups were lacking (Figure 2B). Median length of stay was similar for the intervention and control groups among those with VF (9.1 days [25th-75th percentiles, days] and 9.4 days [25th-75th percentiles, days], respectively, P =.75 by Wilcoxon rank sum test) and among those without VF (11.8 days [25th-75th percentiles, days] and 10.5 days [25th-75th percentiles, days], respectively, P =.45 by Wilcoxon rank sum test). Post hoc analyses examined use of coronary angiography within 6 hours of hospital admission and any withdrawal or jama.com JAMA Published online November 17, 2013 E5 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: by a SCELC - Loma Linda University User on 11/24/2013

33 Research Original Investigation Page 33 Induction of Mild Hypothermia for Cardiac Arrest Table 3. Prehospital, Emergency Department, and In-Hospital Safety Data Rearrest postrandomization a (n = 686) 176 (26) [22 to 29] Use of pressors postrandomization a (n = 686) 62 (9) [7 to 11] Prehospital deaths a (n = 688) 9 (1.3) [0.7 to 2.5] Time from first dispatch to hospital arrival, min b (n = 654) 51 (50 to 52) [13] First heart rate on ED arrival, beats/min b (n = 665) 89 (86 to 92) [39] First systolic blood pressure on ED arrival, mm Hg b (n = 666) 116 (112 to 120) [54] Difference from randomization to ED arrival Heart rate, beats/min b (n = 651) 21 ( 24 to 18) [40] Systolic blood pressure, mm Hg b (n = 624) 18 ( 22 to 14) [56] Deaths in emergency department a (n = 688) 88 (12.8) [10.5 to 15.5] Use within first 12 h of arrival Pressors a (n = 674) 374 (56) [52 to 59] Diuretics a (n = 674) 119 (18) [15 to 21] Use of diuretics within h of arrival a (n = 667) 151 (23) [20 to 26] First arterial blood gas ph b (n = 612) 7.16 (7.14 to 7.18) [0.23] PaO 2,mmHg b (n = 609) 189 (178 to 200) [135] PaCO 2,mmHg b (n = 670) 59 (57 to 61) [28] First SaO 2 on ED arrival, % b (n = 601) 94 (93 to 95) [10] Pulmonary edema First chest film a (n = 631) 256 (41) [37 to 44] Second chest film a (n = 498) 133 (27) [23 to 31] Third chest film a (n = 420) 104 (25) [21 to 29] Antibiotic use a (n = 673) 434 (64) [61 to 68] Glucose >300 mg/dl a (n = 674) 168 (25) [22 to 28] Intervention Control P Value (n = 671) 138 (21) [18 to 24].008 (n = 671) 59 (9) [7 to 11].82 (n = 671) 11 (1.6) [0.9 to 2.5].61 (n = 629) 49 (48 to 50) [14].006 (n = 632) 93 (90 to 96) [40].07 (n = 637) 116 (112 to 120) [51].84 (n = 616) 17 ( 20 to 14) [40].09 (n = 647) 20 ( 24 to 16) [56].47 (n = 671) 85 (12.7) [10.4 to 15.4].95 (n = 647) 365 (56) [53 to 60].93 (n = 648) 81 (13) [10 to 15].009 (n = 640) 109 (17) [14 to 20].01 (n = 590) 7.20 (7.18 to 7.22) [0.29].005 (n = 585) 218 (206 to 230) [144] <.001 (n = 641) 58 (55 to 61) [34].36 (n = 573) 96 (95 to 97) [8].02 (n = 609) 184 (30) [27 to 34] <.001 (n = 464) 123 (27) [23 to 31].95 (n = 392) 81 (21) [17 to 25].23 (n = 649) 418 (64) [61 to 68].98 (n = 648) 208 (32) [29 to 36].004 Abbreviations: ED, emergency department; SaO 2, oxygen saturation. a Indicates values are expressed as No. (%) [95% CI]. b Indicates values are expressed as mean (95% CI) [SD]. change in the level of life support during hospitalization to assess whetherrandomizationtoprehospitalcoolingwasassociatedwith treatment decisions for admitted patients. Among patients admitted to the hospital, no significant differences between treatment groups were evident for early coronary angiography within 6 hours from hospital arrival (25% for the intervention groups vs 27% for the control groups) or reduction in level or withdrawal of life support (44% for both intervention and control groups). Safety Prehospital deaths and deaths in the ED between the intervention and control groups did not differ significantly for patients with VF or those without VF (Table 3). The use of pressors by paramedics was similar (9% for both treatment groups); however, the proportion of patients who had a rearrest during transport (defined as loss of pulse) was 26% in the intervention group compared with 21% in the control group (P =.008). The intervention group had significantly lower oxygenation, increased pulmonary edema on first chest x-ray, and greater use of diuretics during the first 12 hours of hospitalization compared with the control group (Table 3). The incidence of pulmonary edema noted on subsequent chest x- rays during hospitalization, the number of days receiving ventilation, the incidence of reintubation, and the use of antibiotics (a surrogate marker for infection) were not significantly different between the treatment groups. Discussion This large randomized trial found that prehospital, rapid infusion of up to 2 L of 4 C normal saline did induce mild hypo- E6 JAMA Published online November 17, 2013 jama.com Copyright 2013 American Medical Association. All rights reserved. Downloaded From: by a SCELC - Loma Linda University User on 11/24/2013

34 Induction of Mild Hypothermia for Cardiac Arrest Page 34 Original Investigation Research thermia faster than standard care but did not improve survival or neurological status at discharge after resuscitation from prehospital shockable (VF) or nonshockable (without VF) cardiac arrest. The resuscitation and intervention were performed by paramedics from EMS agencies with a high overall rate of resuscitation. The intervention reduced core body temperature by hospital arrival, and patients reached the goal temperature about 1 hour sooner than in the control group. The intervention was associated with significantly increased incidence of rearrest during transport, time in the prehospital setting, pulmonary edema, and early diuretic use in the ED. Mortality in the out-of-hospital setting or ED and hospital length of stay did not differ significantly between the treatment groups. Current guidelines for postresuscitation care recommend application of induced hypothermia in the hospital to patients resuscitated from prehospital VF. 8 The optimal timing, duration, and method of cooling remain unclear but animal studies have provided a strong rationale for early induction of therapeutic hypothermia soon after ROSC. 9 Infusion of cold intravenous fluid is an attractive strategy to achieve early cooling because of its portability, ease in administration, and potential widespread availability in the prehospital setting. During the enrollment period of the current trial, Bernard et al 13 published their results from a prehospital cooling study in patients resuscitated from VF. There were 234 patients with VF randomized to rapid cooling with 2 L of ice-cold lactated Ringer solution or to cooling after hospital admission and 47.5% of the paramedic-cooled group had a favorable outcome at hospital discharge vs 52.6% of the hospital-cooled group. Even though the paramedic-cooled group was colder at hospital arrival, differences in temperature between the intervention and control groups disappeared within 1 hour. The results of the current randomized study, in conjunction with the prior randomized human investigation, 13 do not support the routine use of cold saline following ROSC among patients resuscitated from prehospital cardiac arrest. Why did prehospital hypothermia not improve outcomes in this study given prior promising results? Potential bias from incomplete blinding seems an unlikely explanation. Perhaps early cooling needs to be applied during resuscitation and not after ROSC to achieve the desired benefit. Early cooling during resuscitation might attenuate the cascade of reperfusion injury that begins with ROSC. 17 This use of intra-arrest cooling is supported by animal studies, although a recent trial that used evaporative intranasal cooling during attempted resuscitation suggests that intra-arrest hypothermia was not associated with a large clinical effect. 18 Whether earlier cooling will improve survival and outcomes in humans awaits further study. The dose or method of hypothermia may have been suboptimal. The study used a goal threshold temperature of 34 C rather than 33 C. A lower temperature goal may have afforded better clinical outcomes. Importantly, the method of prehospital hypothermia may have been associated with early harm that could have masked subsequent improvement. There are some potential limitations of the current trial. First, patients randomized to the intervention were more likely to experience rearrest and pulmonary edema, although early deaths did not differ by treatment status. Rearrest possibly worsened brain ischemia that did not affect early mortality but manifested as increased risk of death later during the hospitalization. Second, in an animal model of cardiac arrest, induction of hypothermia using intravenous volume loading was associated with significantly decreased coronary artery perfusion pressure compared with postresuscitation surface cooling methods. 19 In animal and human studies, decreased coronary artery perfusion pressure is associated with a decrease in survival. In addition, cold prehospital fluid administration was associated with significant reduction in first arterial blood gas ph and PaO 2 levels (Table 3), which are both predictors of poor outcomes. Thus, a potential benefit from prehospital cooling may have been mitigated by these associated adverse effects. Third, we measured end points at the time of hospital discharge to help ensure comprehensive outcome ascertainment. Functional status can improve for at least 6 months after resuscitation from cardiac arrest, 20 but the current study could not detect such a late intervention effect. However, functional status at hospital discharge is a strong predictor of longterm survival. 21 These potential limitations should be considered in the context of the trial s strengths. The investigation evaluated a generalizable, low-cost intervention for a condition that accounts for substantial public health mortality. The study was conducted in an EMS system with an established record of research and prehospital resuscitation, which are characteristics essential for successfully completion of such a trial. The investigation achieved robust randomization and had adequate power to detect clinically significant differences in survival or neurological status at discharge in patients resuscitated from VF. The effect of prehospital hypothermia in this trial was not likely to be modified or confounded by the quality of prehospital emergency care because the baseline outcomes achieved by EMS agencies that participated in this study were high. In addition, the effect of out-of-hospital hypothermia was unlikely to be modified by the quality of hospital-based care because post hoc secondary analyses did not demonstrate a relationship between outcomes and early angiography or withdrawal of life support. Lastly, a high percentage of admitted patients received hospital cooling and achieved temperatures of less than 34 C, thereby minimizing the effects of hospital cooling on outcomes. Thus, we believe that our results have both internal and external validity. Conclusions Early out-of-hospital cooling by rapid infusion with 4 C of normal saline reduced core temperature by more than 1 C and reduced the time to achieve the therapeutic temperature goal of 34 C by more than 1 hour. Nonetheless, early, rapid cooling did not improve survival or neurological status at discharge in patients with VF or without VF. Rapid fluid administration was associated with higher rates of rearrest during transport jama.com JAMA Published online November 17, 2013 E7 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: by a SCELC - Loma Linda University User on 11/24/2013

35 Research Original Investigation Page 35 Induction of Mild Hypothermia for Cardiac Arrest and increased transient pulmonary edema, which resolved within the first 24 hours. Although hypothermia is a promising strategy to improve resuscitation and brain recovery following cardiac arrest, the results of the current study do not support routine use of cold intravenous fluid in the prehospital setting to improve clinical outcomes. ARTICLE INFORMATION Published Online: November 17, doi: /jama Author Contributions: Drs Kim and Maynard had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kim, Nichol, Hallstrom, Kudenchuk, Carlbom, Deem, Longstreth, Olsufka, Cobb. Acquisition of data: Kim, Maynard, Hallstrom, Rea, Copass, Carlbom, Olsufka, Cobb. Analysis and interpretation of data: Kim, Nichol, Maynard, Hallstrom, Kudenchuk, Rea, Olsufka, Cobb. Drafting of the manuscript: Kim, Nichol. Critical revision of the manuscript for important intellectual content: Kim, Nichol, Maynard, Hallstrom, Kudenchuk, Rea, Copass, Carlbom, Deem, Longstreth, Cobb. Statistical analysis: Maynard, Hallstrom. Obtained funding: Kim, Cobb. Administrative, technical, or material support: Kim, Kudenchuk, Rea, Copass, Carlbom, Deem. Study supervision: Kim, Copass, Cobb. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nichol reported receiving institutional grant funding from the Asmund S. Laerdal Foundation for Acute Medicine, the National Heart, Lung, and Blood Institute, the National Institutes of Health, Medtronic Foundation, Velomedix Inc, Philips Healthcare Inc, Physio-Control Inc, HealthSine Technologies Inc, and Zoll Inc; serving on the board of Medic One Foundation; being part of a patent assigned to the University of Washington; and receiving travel reimbursement from the American Heart Association. Dr Hallstrom reported receiving grants, support for travel to meetings, fees for participating in review activities, payment for writing or reviewing a manuscript, and provision for writing assistance, medicines, equipment, or administrative support from the National Heart, Lung, and Blood Institute; and serving as a consultant to Amarin and St Jude Medical for data and safety monitoring board activity on several trials. Dr Rea reported receiving grant support for community-based resuscitation from Medtronic Foundation. Dr Deem reported receiving institutional grant funding from the National Institutes of Health and Medic One Foundation. No other author reported disclosures. Funding/Support: This study was funded by grants RO1 HL and 5U01HL07786 from the National Heart, Lung, and Blood Institute and with additional support from the Medic One Foundation (Seattle, Washington). Role of Sponsor: The National Heart, Lung, and Blood Institute and the Medic One Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Data and Safety Monitoring Committee: Kyra Becker, MD (chair); Margaret Neff, MD; Tina Chang, MD; Karl B. Kern, MD; Nancy Temkin, PhD; Ralph D Agostino, PhD; Chief Earl Sodeman, Seattle Fire Department; Thomas Hearne; and Michele Plorde, King County Public Health, Emergency Medical Services Division. Medical Directors: Seattle Medic One: Michael Copass, MD, Jonathan Larsen (medical services captain). King County Medic One: Mickey Eisenberg, MD. Evergreen Medic One: Adrian Whorton, MD. Shoreline Medic One: Gary Sommers, MD. Bellevue Medic One: James Boehl, MD. Vashon Island Medic One: Sam Warren, MD. Participant Applications: Tony J. Gerbino, MD (Virginia Mason Medical Center); Mark Reisman, MD (Swedish Medical Center); Steve Marshall, MD (Overlake Medical Center); and Daniel Markowitz, MD (Steven s Hospital). Study Nurses: Dianne K. Staloch, Karen Dong, Sue Scruggs, Alana C. Clark, Jane Edelson, Debi Solberg, Sally Ragsdale, Kathleen Fair, and Barbara Ricker. Review of Prehospital Records: Roy Waugh, Dianne K. Staloch, and Karen Dong. Database Entry and Management: Regina LaVassaur and Lihua Yin. Additional Contributions: We thank the paramedics from Seattle Medic One, King County Medic One, Bellevue Medic One, Evergreen Medic One, Shoreline Medic One, and Vashon Island Medic One. We also thank the emergency department physicians and medical resident physicians rotating through the emergency department at Harborview Medical Center for providing randomization assignment to the paramedics. REFERENCES 1. Raichle ME. The pathophysiology of brain ischemia.ann Neurol. 1983;13(1): Rea TD, Eisenberg MS, Becker LJ, et al. Emergency medical services and mortality from heart disease: a community study. Ann Emerg Med. 2003;41(4): Longstreth WT Jr. Brain resuscitation after cardiopulmonary arrest. Acta Anaesthesiol Belg. 1988;39(3)(suppl 2): Longstreth WT Jr, Fahrenbruch CE, Olsufka M, et al. Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest. Neurology. 2002;59(4): Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8): 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): Nolan JP, Morley PT, Vanden Hoek TL, et al; International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac arrest. Circulation. 2003;108(1): Peberdy MA, Callaway CW, Neumar RW, et al; American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18)(suppl 3):S768-S 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. Crit Care Med. 1993;21(9): Bernard S. Hypothermia after cardiac arrest. Crit Care Med. 2004;32(3): Bernard S, Buist M, Monteiro O, Smith K. 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): 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): Bernard SA, Smith K, Cameron P, et al; Rapid Infusion of Cold Hartmanns (RICH) Investigators. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation.2010;122(7): Bernard SA, Smith K, Cameron P, et al; Rapid Infusion of Cold Hartmanns Investigators. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest. Crit Care Med. 2012;40(3): Brain Resuscitation Clinical Trial II Study Group. A randomized clinical trial of calcium entry blocker administration to comatose survivors of cardiac arrest: design, methods, and patient characteristics. Control Clin Trials. 1991;12(4): Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1(7905): Neumar RW, Nolan JP, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. Circulation. 2008;118(23): Castrén M, Nordberg P, Svensson L, et al. Intra-arrest transnasal evaporative cooling. Circulation. 2010;122(7): Yannopoulos D, Zviman M, Castro V, et al. Intra-cardiopulmonary resuscitation hypothermia with and without volume loading in an ischemic model of cardiac arrest. Circulation. 2009;120(14): Roine RO, Kajaste S, Kaste M. Neuropsychological sequelae of cardiac arrest. JAMA. 1993;269(2): Phelps R, Dumas F, Maynard C, Silver J, Rea T. Cerebral performance category and long-term prognosis following out-of-hospital cardiac arrest. Crit Care Med. 2013;41(5): E8 JAMA Published online November 17, 2013 jama.com Copyright 2013 American Medical Association. All rights reserved. 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36 The new england journal of medicine Page 36 original article Targeted Temperature Management at 33 C versus 36 C after Cardiac Arrest Niklas Nielsen, M.D., Ph.D., Jørn Wetterslev, M.D., Ph.D., Tobias Cronberg, M.D., Ph.D., David Erlinge, M.D., Ph.D., Yvan Gasche, M.D., Christian Hassager, M.D., D.M.Sci., Janneke Horn, M.D., Ph.D., Jan Hovdenes, M.D., Ph.D., Jesper Kjaergaard, M.D., D.M.Sci., Michael Kuiper, M.D., Ph.D., Tommaso Pellis, M.D., Pascal Stammet, M.D., Michael Wanscher, M.D., Ph.D., Matt P. Wise, M.D., D.Phil., Anders Åneman, M.D., Ph.D., Nawaf Al-Subaie, M.D., Søren Boesgaard, M.D., D.M.Sci., John Bro-Jeppesen, M.D., Iole Brunetti, M.D., Jan Frederik Bugge, M.D., Ph.D., Christopher D. Hingston, M.D., Nicole P. Juffermans, M.D., Ph.D., Matty Koopmans, R.N., M.Sc., Lars Køber, M.D., D.M.Sci., Jørund Langørgen, M.D., Gisela Lilja, O.T., Jacob Eifer Møller, M.D., D.M.Sci., Malin Rundgren, M.D., Ph.D., Christian Rylander, M.D., Ph.D., Ondrej Smid, M.D., Christophe Werer, M.D., Per Winkel, M.D., D.M.Sci., and Hans Friberg, M.D., Ph.D., for the TTM Trial Investigators* ABSTRACT Background Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. Methods In an international trial, we randomly assigned 950 unconscious adults after out-ofhospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33 C or 36 C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. Results In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33 C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36 C group (225 of 466 patients) (hazard ratio with a temperature of 33 C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P = 0.51). At the 180-day follow-up, 54% of the patients in the 33 C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36 C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P = 0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P = 0.87). The results of analyses adjusted for known prognostic factors were similar. Conclusions In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33 C did not confer a benefit as compared with a targeted temperature of 36 C. (Funded by the Swedish Heart Lung Foundation and others; TTM ClinicalTrials.gov number, NCT ) The authors affiliations are listed in the Appendix. Address reprint requests to Dr. Nielsen at the Department of Anesthesia and Intensive Care, Intensive Care Unit, Helsingborg Hospital, S Vallgatan 5, , Helsingborg, Sweden, or at *A complete list of investigators participating in the Target Temperature Management 33 C versus 36 C after Out-of- Hospital Cardiac Arrest (TTM) trial is provided listed in the Supplementary Appendix, available at NEJM.org. This article was published on November 17, 2013, at NEJM.org. N Engl J Med 2013;369: DOI: /NEJMoa Copyright 2013 Massachusetts Medical Society n engl j med 369;23 nejm.org december 5, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 7, For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

37 The new england journal of medicine Page 37 Unconscious patients admitted to critical care units after out-of-hospital cardiac arrest are at high risk for death, and neurologic deficits are common among those who survive. 1 Two previous trials, involving patients who remained unconscious after resuscitation from cardiac arrest (of presumed cardiac cause, with an initial shockable rhythm), compared therapeutic hypothermia (32 C to 34 C for 12 to 24 hours) with standard treatment. These trials showed a significant improvement in neurologic function 2,3 and survival 3 with therapeutic hypothermia. Therapeutic hypothermia (also called targeted temperature management) is now recommended in international resuscitation guidelines, and its use has been extended to cardiac arrest of other causes and with other presenting rhythms as well as to the in-hospital setting. 4 Although a Cochrane review supports these guidelines, 5 some investigators have suggested a need for additional trials to confirm or refute the current treatment strategy. 6-8 Furthermore, one trial showed that fever developed in many patients in the standardtreatment group. 3 It is therefore unclear whether the reported treatment effect was due to hypothermia or to the prevention of fever, which is associated with a poor outcome We conducted a trial to investigate the benefits and harms of two targeted temperature regimens, both intended to prevent fever, in a broader population of patients with cardiac arrest than previously studied. Methods Trial Design The Target Temperature Management 33 C versus 36 C after Out-of-Hospital Cardiac Arrest (TTM) trial was a randomized clinical trial recruiting patients in 36 intensive care units (ICUs) in Europe and Australia. The rationale for and design of the trial, as well as the statistical analysis plan, have been published previously. 12,13 The protocol (available with the full text of this article at NEJM.org) was approved by the ethics committees in each participating country and institution. An independent data and safety monitoring committee reviewed the data and performed one prespecified, blinded interim analysis. The steering group (see the Supplementary Appendix, available at NEJM.org) vouches for the accuracy and completeness of the data and analysis and for the adherence of this report to the trial protocol. Patients We consecutively screened patients 18 years of age or older who were unconscious (a score of <8 on the Glasgow Coma Scale [on which scores range from 3 to 15, with lower scores indicating reduced levels of consciousness]) on admission to the hospital after out-of-hospital cardiac arrest of presumed cardiac cause, irrespective of the initial rhythm. Eligible patients had more than 20 consecutive minutes of spontaneous circulation after resuscitation. 14 The main exclusion criteria were an interval from the return of spontaneous circulation to screening of more than 240 minutes, unwitnessed arrest with asystole as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke, and a body temperature of less than 30 C. A full list of exclusion criteria is provided in the Supplementary Appendix. In accordance with national requirements and the principles of the Declaration of Helsinki, written informed consent was waived, delayed, or obtained from a legal surrogate, depending on the circumstances, and was obtained from each patient who regained mental capacity. 15 Randomization and Trial Intervention After being screened for eligibility, patients were randomly assigned in a 1:1 ratio to targeted temperature management with a target body temperature of either 33 C or 36 C. Randomization was performed centrally with the use of a computergenerated assignment sequence. Intervention assignments were made in permuted blocks of varying size and were stratified according to site. Health care professionals caring for the trial patients were aware of the intervention assignments because of inherent problems with blinding of body temperature. Physicians performing neurologic prognostication, assessors of neurologic follow-up and final outcome, study administrators, statisticians, and the authors were unaware of the intervention assignments. During the analysis phase, the intervention groups were identified only as 0 and 1, and the manuscript was written and approved by all the authors before the randomization code was broken. 16 The intervention period of 36 hours commenced at the time of randomization. Sedation was mandated in both groups until the end of the intervention period. The goal was to achieve the assigned temperature as rapidly as possible with the use of ice-cold fluids, ice packs, and intravascular or surface temperature-management 2198 n engl j med 369;23 nejm.org december 5, 2013 Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 7, For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

38 Targeted Temperature Management after Cardiac Arrest Page 38 devices at the discretion of the sites. Details of the trial interventions, including the management of an initial body temperature below the assigned target, are provided in the Supplementary Appendix. After 28 hours, gradual rewarming to 37 C in hourly increments of 0.5 C was commenced in both groups. At 36 hours, mandatory sedation was discontinued or tapered. After the intervention period, the intention was to maintain the body temperature for unconscious patients below 37.5 C until 72 hours after the cardiac arrest, with the use of fever-control measures at the discretion of the sites. Neurologic Prognostication and Withdrawal of Life-Sustaining Therapies A physician who was unaware of the intervention assignments performed a neurologic evaluation 72 hours after the end of the intervention for patients who remained unconscious and issued a recommendation for the continuation or withdrawal of therapy. The trial protocol established prespecified criteria for withdrawal of life-sustaining therapy 12 (see the Supplementary Appendix). All clinical decisions remained at the discretion of the treating team. Follow-up and Outcomes All surviving patients were followed until 180 days after the enrollment of the last patient. The primary outcome was all-cause mortality through the end of the trial. The main secondary outcome was a composite of poor neurologic function or death, defined as a Cerebral Performance Category 17,18 (CPC) of 3 to 5 and a score of 4 to 6 on the modified Rankin scale, 19,20 at or around 180 days. The CPC scale ranges from 1 to 5, with 1 representing good cerebral performance or minor disability, 2 moderate disability, 3 severe disability, 4 coma or vegetative state, and 5 brain death. Scores on the modified Rankin scale range from 0 to 6, with 0 representing no symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death. Mortality at 180 days and individual neurologic scores were also analyzed separately. Other secondary outcomes were the CPC at discharge from the ICU and from the hospital and the best (numerically lowest) reported CPC during the trial period. Predefined serious adverse events 21 were recorded up to day 7 in the ICU. Data collection and verification for all trial data and for the outcome measures are described in the Supplementary Appendix. Statistical Analysis We estimated that a sample of 900 patients would provide 90% power to detect a 20% reduction in the hazard ratio for death in the 33 C group as compared with the 36 C group, at a two-sided alpha level of Alternatively, to detect a relative risk reduction of 20%, with the assumption of a mortality of 44% in the 33 C group versus 55% in the 36 C group, a sample of 850 patients would be needed. On the basis of these assumptions, a sample of 950 patients was chosen, to allow for a loss to follow-up of 50 patients. The principal trial analyses were performed in the modified intention-to-treat population, defined as all randomly assigned patients except those withdrawing consent for use of all trial data and those not fulfilling inclusion criteria and never receiving the intervention. 22 Additional analyses were performed in the intention-to-treat population, which included all randomly assigned patients except those withdrawing consent, and in the per-protocol population, which excluded patients with one or more major protocol violations (listed in the Supplementary Appendix). The Wilcoxon signed-rank test was used to compare distributions of continuous outcome measures. Kaplan Meier survival curves were compared between the intervention groups with the use of the log-rank test. Relative risks were compared with the use of Cochran Mantel Haenszel statistics. Trends were assessed with the use of the Cochran Armitage test. Logisticregression and Cox analyses were performed as appropriate, with adjustment for site and for five baseline variables: age, sex, presence or absence of shockable rhythm, presence or absence of circulatory shock on admission, and the time from cardiac arrest (or from the emergency call for unwitnessed cardiac arrests) to the return of spontaneous circulation. Odds ratios were converted to relative risks. 23 All primary analyses were adjusted for site. 24 Temperature data were analyzed with the use of a mixed model with repeated measures. The effect of time was modeled with the use of a polynomial; the use of compound symmetry and first-order autoregressive covariance structures was compared, and the better-fitting model was used. SAS software, version 9.3, and SPSS software, version 17.1, were used for all analyses. All tests were two-sided n engl j med 369;23 nejm.org december 5, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 7, For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

39 The new england journal of medicine Page 39 Table 1. Characteristics of the Modified Intention-to-Treat Population before Randomization.* Characteristic 33 C Group (N = 473) 36 C Group (N = 466) Demographic characteristics Age yr 64±12 64±13 Male sex no. (%) 393 (83) 368 (79) Medical history no. (%) Chronic heart failure 32 (7) 29 (6) Previous AMI 107 (23) 86 (18) Ischemic heart disease 145 (31) 115 (25) Previous cardiac arrhythmia 87 (18) 79 (17) Arterial hypertension 193 (41) 181 (39) Previous TIA or stroke 35 (7) 38 (8) Diabetes mellitus 61 (13) 80 (17) Asthma or COPD 48 (10) 49 (11) Previous percutaneous coronary intervention 58 (12) 50 (11) Previous coronary-artery bypass grafting 47 (10) 42 (9) Characteristics of the cardiac arrest Location of cardiac arrest no. (%) Place of residence 245 (52) 255 (55) Public place 197 (42) 188 (40) Other 31 (7) 22 (5) Bystander witnessed cardiac arrest no. (%) 420 (89) 418 (90) Bystander performed CPR no. (%) 344 (73) 339 (73) First monitored rhythm no. (%) Shockable rhythm 375 (79) 377 (81) Ventricular fibrillation 349 (74) 356 (77) Nonperfusing ventricular tachycardia 12 (3) 12 (3) Unknown rhythm but responsive to shock 5 (1) 5 (1) Perfusing rhythm after bystander- initiated defibrillation 9 (2) 4 (1) Asystole 59 (12) 54 (12) Pulseless electrical activity 37 (8) 28 (6) Unknown first rhythm, not responsive to shock or not shocked 2 (<0.5) 6 (1) Time from cardiac arrest to event min Start of basic life support Median 1 1 Interquartile range Start of advanced life support Median 10 9 Interquartile range Return of spontaneous circulation Median Interquartile range n engl j med 369;23 nejm.org december 5, 2013 Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 7, For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

40 Targeted Temperature Management after Cardiac Arrest Page 40 Table 1. (Continued.) Characteristic 33 C Group (N = 473) 36 C Group (N = 466) Clinical characteristics on admission First measured body temperature C 35.2± ±1.1 Glasgow Coma Scale score Median 3 3 Interquartile range Corneal reflex present no./total no. (%) 264/407 (65) 258/392 (66) Pupillary reflex present no./total no. (%) 344/460 (75) 363/458 (79) Serum ph 7.2± ±0.2 Serum lactate mmol/liter 6.7± ±4.5 Circulatory shock no. (%) 70 (15) 67 (14) ST-segment elevation myocardial infarction no. (%) 190 (40) 194 (42) * Plus minus values are means ±SD. P>0.05 for all comparisons. AMI denotes acute myocardial infarction, COPD chronic obstructive pulmonary disease, CPR cardiopulmonary resuscitation, and TIA transient ischemic attack. In the 36 C group, data for location of cardiac arrest and first monitored rhythm were missing for one patient. For unwitnessed arrests, intervals were calculated from the time of the emergency call. Scores on the Glasgow Coma Scale range from 3 to 15, with lower scores indicating reduced levels of consciousness. The distribution of Glasgow Coma Scale motor scores is provided in Table S1 in the Supplementary Appendix. Circulatory shock was defined as a systolic blood pressure of less than 90 mm Hg for more than 30 minutes or endorgan hypoperfusion (cool extremities, a urine output of <30 ml per hour, and a heart rate of <60 beats per minute). and adjusted for multiple comparisons. A P value of 0.05 or less was considered to indicate statistical significance. Results Patients A total of 950 patients were enrolled between November 2010 and January 2013; of these patients, 476 were randomly assigned to the 33 C group and 474 to the 36 C group. The modified intention-to-treat population (the primary-analysis population) consisted of 473 patients assigned to 33 C and 466 assigned to 36 C (Fig. S1 in the Supplementary Appendix). The two groups had similar prerandomization characteristics (Table 1). Glasgow Coma Scale scores on admission, cardiovascular Sequential Organ Failure Assessment scores, and details of diagnostic procedures, interventions, and the use of health services are provided in Tables S1, S2, and S3, respectively, in the Supplementary Appendix. Temperature Intervention The mean values of the initial recorded body temperature (tympanic) were 35.2 C and 35.3 C in the 33 C and 36 C groups, respectively. Temperature was managed with an intravascular cooling catheter in 24% of patients and with a surface cooling system in 76% of patients in both groups. The temperature curves are depicted in Figure 1 (P<0.001 for separation of the curves). Three patients in the 33 C group and four in the 36 C group did not receive the assigned intervention (Table S4 in the Supplementary Appendix). Sixteen patients assigned to the 33 C group were rewarmed before reaching the intended time point of 28 hours after randomization, at the discretion of the treating physician and as allowed by the protocol (Table S5 in the Supplementary Appendix). Additional information regarding shivering and fever is available in the Supplementary Appendix. Withdrawal of Life-Sustaining Therapy During the first 7 days of hospitalization, lifesustaining therapy was withdrawn in 247 patients (132 in the 33 C group and 115 in the 36 C group). Reasons for withdrawal of life-sustaining therapy included brain death, multiorgan failure, and ethical concerns (Table S7 in the Supplementary Appendix). A protocol-defined approach to neu- n engl j med 369;23 nejm.org december 5, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 7, For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

41 Page 41

42 The new england journal of medicine Page C group 33 C group Body Temperature ( C) Hours since Randomization Figure 1. Body Temperature during the Intervention Period. Shown are body-temperature curves in the 33 C and 36 C groups for the 860 patients in whom a bladder temperature was recorded. In the remaining 79 patients, the temperature was recorded with an intravascular or esophageal probe, with a similar temperature profile (data not shown). Rewarming was commenced at 28 hours after randomization. The temperature curves display the means, and the I bars indicate ±2 SD (95% of the observations are within the error bars). Table 2. Outcomes. Outcome 33 C Group 36 C Group Hazard Ratio or Risk Ratio (95% CI)* P Value no./total no. (%) Primary outcome: deaths at end of trial 235/473 (50) 225/466 (48) 1.06 ( ) 0.51 Secondary outcomes Neurologic function at follow-up CPC of /469 (54) 242/464 (52) 1.02 ( ) 0.78 Modified Rankin scale score of /469 (52) 239/464 (52) 1.01 ( ) 0.87 Deaths at 180 days 226/473 (48) 220/466 (47) 1.01 ( ) 0.92 * The hazard ratio is shown for the primary outcome, and risk ratios are shown for the secondary outcomes. CI denotes confidence interval. The neurologic follow-up was specified in the protocol to be performed at 180 days ±2 weeks, but the time to follow-up was in some cases several weeks longer for logistic reasons. The Cerebral Performance Category (CPC) scale ranges from 1 to 5, with 1 representing good cerebral performance or minor disability, 2 moderate cerebral disability (function is sufficient for independent activities of daily life), 3 severe cerebral disability, 4 coma or vegetative state, and 5 brain death. Scores on the modified Rankin scale range from 0 to 6, with 0 representing no symptoms, 1 no clinically significant disability despite some symptoms, 2 slight disability (patient is able to look after own affairs without assistance), 3 moderate disability (patient requires some help but is able to walk unassisted), 4 moderately severe disability (patient is unable to attend to own bodily needs), 5 severe disability (patient is bedridden), and 6 death n engl j med 369;23 nejm.org december 5, 2013 Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 7, For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

43 Targeted Temperature Management after Cardiac Arrest Page 43 rologic prognostication was used to make recommendations regarding the continuation or withdrawal of life-sustaining therapy (Table S8 in the Supplementary Appendix). Follow-up and Outcomes Follow-up was obtained by means of a face-to-face interview with the patient (for 86% of patients), a structured telephone interview with the patient (6%), a telephone call to the patient or a relative (5%), or a telephone call to a proxy provider of information (i.e., a staff member of a nursing home or a general practitioner) (3%). The last follow-up assessment was performed on July 9, The mean period of follow-up for all patients was 256 days. At the end of the trial, 235 of 473 patients in the 33 C group (50%) and 225 of 466 patients in the 36 C group (48%) had died (hazard ratio in the 33 C group, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P = 0.51) (Table 2 and Fig. 2). The groups did not differ significantly with respect to the composite outcome of death or poor neurologic function at 180 days with the use of either the CPC or the modified Rankin scale score (risk ratio for a CPC of 3 to 5 in the 33 C group, 1.02; 95% CI, 0.88 to 1.16; P = 0.78; and risk ratio for a score of 4 to 6 on the modified Rankin scale in the 33 C group, 1.01; 95% CI, 0.89 to 1.14; P = 0.87) (Table 2). The neurologic scores on both scales are shown in Table 3 and in Table S9 in the Supplementary Appendix. There were no significant differences in the distribution of CPCs or modified Rankin scale scores between the two groups (P = 0.85 and P = 0.67 for trend, respectively). With the use of the best reported CPC during the trial (Table 3), the relative risk of death or poor neurologic function in the 33 C group was 1.04 (95% CI, 0.89 to 1.17; P = 0.67). Similar results were obtained in adjusted analyses and in the intention-to-treat and perprotocol populations (see the Supplementary Appendix, including Tables S10 and S11). The effect of the intervention was consistent across predefined subgroups (Fig. S2 in the Supplementary Appendix). One or more serious adverse events occurred in 439 of 472 patients in the 33 C group (93%) as compared with 417 of 464 patients in the 36 C group (90%) (risk ratio, 1.03; 95% CI, 1.00 to 1.08; P = 0.09). Hypokalemia was more frequent in the 33 C group (19%, vs. 13% in the 36 C group, Probability of Survival No. at Risk 33 C group 36 C group P= Days since Randomization P = 0.02). For the full list of serious adverse events, see Table S12 in the Supplementary Appendix. The presumed causes of death as assessed by the trial investigators were similar in the two groups (Table S13 in the Supplementary Appendix). Discussion In this international, multicenter, randomized trial, we compared a target body temperature of 33 C with one of 36 C in patients who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac cause. There were no significant differences between the two groups in overall mortality at the end of the trial or in the composite of poor neurologic function or death at 180 days. The results were consistent in six predefined subgroups. We did not find any harm with a targeted temperature of 33 C as compared 36 C group 33 C group Figure 2. Probability of Survival through the End of the Trial. Shown are Kaplan Meier estimates of the probability of survival for patients assigned to a target temperature of either 33 C or 36 C and the number of patients at risk at each time point. The P value was calculated by means of Cox regression, with the effect of the intervention adjusted for the stratification variable of study site n engl j med 369;23 nejm.org december 5, Downloaded from nejm.org at LOMA LINDA UNIV LIBRARY on December 7, For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

44 Page 44 Figure S2. Hazard ratio of death, according to subgroup The forest plot shows the hazard ratios for six predefined subgroups. The horizontal bars represent 95% confidence intervals. The events are the total events at end of trial. P values are for the tests of subgroup heterogeneity (tests of interactions). ROSC denotes return of spontaneous circulation. For unwitnessed cardiac arrests the time to ROSC was calculated form time of emergency call. Shock at admission was defined as a systolic blood pressure<90mmhg for >30min or end-organ hypoperfusion (cool extremities, urine output<30ml/hour, heart rate <60 beats/min). 14

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