THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 3, Number 4, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2013.1517

Abstracts from the 3rd Innsbruck Targeted Temperature Management Symposium— A Multidisciplinary Conference September 21, 2013 Vienna, Austria

Abstracts 3rd Innsbruck Targeted Temperature Management Symposium – A Multidisciplinary Conference Gregor Broessner, Marlene Fischer, Erich Schmutzhard Department of Neurology, Neurologic Intensive Care Unit, Medical University Innsbruck, Austria Introduction The organizers are glad to announce the 3rd Innsbruck Targeted Temperature Symposium, for which we have been able to gather most renowned scientists, neurointensivists and intensivists as well as emergency physicians, cardiologists and a broad range of other specialists to cover the scientific and clinical spectrum of temperature management, all essential technical aspects of cooling and management of side effects. As neurologists we aim mainly, as do other emergency and intensive care physicians, to protect the brain, and other organ tissues from secondary insults. It is mainly secondary insults that emergency medical procedures, critical care medicine at large and neurocritical care, in particular, aim at. The scientific progress and the clinical development in the field of neuroprotection and in the field of targeted body temperature management, aiming to achieve and maintain optimal levels, grows exponentially and includes the reduction of potentially hazardous side effects. Therefore, the exchange of most recent findings is essential. The concept of this symposium on Targeted Temperature Management is to present most recent, most relevant research by researchers who are involved in both laboratory and clinical daily practice. Dalton Dietrich, Miami, USA, will start the symposium with a key note lecture on ‘‘Temperature management in spinal cord injury’’. He will share with the participants his experience in a prospective study carried out as a major scientific project of the Miami Project to Cure Paralysis, based in Miami, Florida, USA. Michael Holzer, Vienna, Austria, will discuss present and future aspects of targeted temperature management in an interdisciplinary approach. The second session will deal with new fields for temperature management, including temperature management in burns, in sepsis, in trauma, in particular, polytrauma patients, cardiogenic shock, as well as discuss potential biomarkers to guide neuroprotective therapy by targeted temperature management and to use these biomarkers for prognostication in the setting of either therapeutic hypothermia or prophylactic controlled normothermia. The third session is focused on temperature management as a tool to modulate raised intracranial pressure. Claudius Thome´, Innsbruck, Austria, will give the state of the art information on ‘‘How to treat elevated ICP’’, Peter Andrews, Edinburgh, UK, and Emanuela Zeller, Zu¨rich, Switzerland, will discuss the PROs and CONs of therapeutic hypothermia for ICP/CPP control and management. In session 4 special aspects of targeted temperature management after cardio-pulmonary resuscitation will be discussed. Starting off from the timing of therapeutic hypothermia to the

duration, adjunctive therapies which should potentially improve outcome and the feasibility of early prognostication in resuscitated patients treated with therapeutic hypothermia. Even the notion of temperature management, therapeutic hypothermia and cooling without critical care doctors, intensivists or doctors at large will be discussed. In the 5th session the present state of the art in therapeutic hypothermia after cardiopulmonary resuscitation, temperature management in potentially life-threatening and severe neurologic diseases as well as therapeutic hypothermia in acute myocardial infarction will be discussed. Temperature management has become state of the art in most neurocritical and advanced critical care medicine units. It is mainly the brain which needs to be taken care of, avoiding secondary insults by influencing inflammatory, infectious and degenerative processes kicked off by a severe, potentially lifethreatening direct insult onto the brain itself, or, indirectly, via dysfunction of the myocardium, lung, metabolic system, skin, and other organs. Taken together this symposium and consecutively this comprehensive abstract volume aims to comprise the optimal up-todate knowledge of targeted temperature management in critical care medicine in 2013 as well as the pooled visions of renowned scientists publishing in this exponentially growing field. Temperature Management and Spinal Cord Injury – The Miami Experience W. Dalton Dietrich, Michael Wang, Barth Green and Allan Levi The Miami Project to Cure Paralysis, The Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida Spinal cord injury (SCI) is a serious clinical problem that can result in long-term paralysis and other significant quality of life issues (1). The use of hypothermia to treat experimental and clinical SCI has a rich history (2–4). In early studies, different strategies for inducing local profound hypothermia to the injured spinal cord were attempted. Although, some studies reported beneficial effects, the quality of the research and clinical publications that resulted was somewhat limited in terms of the number of subjects that were evaluated as well as the lack of long-term functional outcomes. Also, the potential confounding effects of decompression surgery or pharmacological treatments also complicated the interpretation of these findings (5). More recently, the use of more moderate levels of prolonged systemic hypothermia has been tested in the various experimental settings (6–10). Thus, a number of research groups have reported the beneficial effects of systemic hypothermia in multiple animal models of SCI including compression and contusive injury. Within The Miami Project to Cure Paralysis, our research group has also reported that moderate hypothermia (33C) sustained for several hours after injury leads to improvements in both motor and histopathological outcomes using both thoracic and cervical injury models (7,9). Based on these encouraging findings, the translation of systematically applied therapeutic

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ABSTRACTS hypothermia to the clinical arena was reasonable (11). Thus, a single institution clinical study was conducted to evaluate the effects of prolonged (48 hrs) systemic hypothermia followed by a slow controlled rewarming phase on functional outcomes in patients with severe cervical SCI (11–13). A total of 35 subjects have been cooled using an approved University of Miami Institutional Research Board protocol that utilizes endovascular catheters to systemically cool subjects to 33C beginning 6 hours after the traumatic insult. To date, only cervical SCI subjects that were neurologically evaluated to have an AIS A score have been included in the study. Published findings first demonstrated the relative safety of this procedure in terms of not significantly increasing the incidence of pneumonia, deep vein thrombosis or cardiac arrhythmias (11). Thus, the Miami experience of using this protocol to administer therapeutic hypothermia has been that this cooling strategy is safe when careful monitoring procedures are conducted during the cooling and rewarming phases. The beneficial effects of therapeutic hypothermia on long-term neurological outcome have also been evaluated (12, 13). Recent publications have summarized one year outcome measures showing that approximately 43% of the cooled individuals show a conversion from the initial AIS A state to AIS B or C. Based on historical data, this appears to be an impressive conversion rate compared to severely injured SCI subjects not undergoing cooling strategies. A multi-center trial is now required to evaluate therapeutic hypothermia in a large number of SCI subjects (14, 15). A randomized clinical trial will be an important step in determining whether systemic hypothermia combined with state-of-the-art critical care protocols can improve outcome in these severely injured subjects (16).

A-3 10. Batchelor PE, Kerr NF, Gatt AM, Cox SF, Ghasem-Zadeh A, et al. (2011). Intracanal pressure in compressive spinal cord injury: reduction with hypothermia. Journal of Neurotrauma 28:809–820. 11. Levi AD, Casella G, Green B, et al. (2009). Spinal cord injury and modest hypothermia. J. Neurotrauma. 26:407–415. 12. Levi AD, Casella G, Green BA, et al. (2010). Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery 66:670–677. 13. Dididze M, Green BA, Dietrich WD, Vanni S, Wang MY, Levi AD. (2013). Systemic hypothermia in acute cervical spinal cord injury: a case-controlled study. Spinal Cord. 51:395–400. 14. Resnick D, Kaiser M, Fehlings M, McCormick P, Hypothermia and human spinal cord injury; position statement and evidence based recommendations. AANS/CNS Joint Section on Disorders of the Spine and the AANS/CNS Joint Section on Trauma. Available at: http://spinesectionorg/ hypothermia php. Assessed February 10, 2009. 15. Fawcett JW, Curt A, Steeves JD, et al. (2007). Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 48:190–205. 16. Dietrich WD. (2012). Therapeutic hypothermia for acute severe spinal cord injury: ready to start large clinical trials? Crit. Care Med. 40:691–692. Targeted Temperature Management - An Interdisciplinary Approach Michael Holzer

References 1. National Spinal Cord Injury Statistical Center. Spinal Cord Injury Facts and Figures at a Glance. (2010). Birmingham, Alabama: National Spinal Cord Injury Statistical Center, University of Alabama. 2. Albin MS, White RJ, Acosta-Rua G, Yashon D. (1968). Study of functional recovery produced by delayed localized cooling of spinal cord injury in primates. J. Neurosurg. 29:113–120. 3. Tator CH, Deecke L. (1973). Value of normothermic perfusion, hypothermic perfusion and durotomy in the treatment of experimental acute spinal cord trauma. J. Neurosurg. 39:52–64. 4. Martinez-Arizala A, Green BA. (1992). Hypothermia in spinal cord injury. J. Neurotrauma. 9 (Suppl 2):S497–S505. 5. Dietrich WD, Levi AD, Wang M, Green BA. (2011). Hypothermic treatment for acute spinal cord injury. Neurotherapeutics. 8:229–239. 6. Westergren H, Yu WR, Farooque M, et al. (1999). Systemic hypothermia following spinal cord compression injury in the rat: axonal changes studied by beta-APP, ubiquitin, and PGP 9.5 immunohistochemistry. Spinal Cord. 37:696–704. 7. Yu CG, Jimenez O, Marcillo AE, et al. (2000). Beneficial effects of modest systemic hypothermia on locomotor function and histopathological damage following contusion-induced spinal cord injury in rats. J. Neurosurg. 93:35–93. 8. Batchelor PE, Kerr NF, Gatt AM, Aleksoska E, Cox SF, et al. (2010). Hypothermia prior to decompression: buying time for treatment of acute spinal cord injury. J Neurotrauma 27:1357–1368. 9. Lo TP, Cho K-S, Garg MS, et al. (2009). Systemic hypothermia improves histological and functional outcome after cervical spinal cord contusion in rats. J. Comp. Neurol. 514:433–448.

Department of Emergency Medicine, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20 / 6D, 1090 Wien, Austria More than one decade ago the two landmark studies of targeted temperature management (TTM) after cardiac arrest have been published [1, 2]. The implementation of TTM was sometimes slow, but has accelerated significantly in recent years. One of the hindrances of implementation was the interdisciplinary nature of this new therapy. Additionally, technical difficulties and the perception of lack of evidence were aggravating factors of delay [3]. In the last few years the implementation rates of TTM on intensive care units increased substantially up to 95% [4, 5]. The implementation and execution of TTM is interdisciplinary in many different ways; either from a temporal aspect, where TTM is maybe initiated already in the pre-hospital arena and then has to be further performed in the emergency department (ED) and intensive care unit (ICU) [6–8]. Here the continuous appliance to a TTM protocol and exact temperature measurements would be important to assure that no rewarming or overcooling during the individual transfers between each receiving ED and ICU can occur [9–11]. But TTM is also interdisciplinary from the different tasks of the treatment team. Especially in cardiac arrest where TTM was used first, the individual members of the chain of survival have a total different focus on the patient, making continuous administration of TTM difficult. The emergency medical service physician or paramedic has to focus all his efforts to successfully resuscitate the victim [12]. But already during this phase it is possible to initiate TTM and to cool the patient during cardiac arrest [13–15]. If TTM is not started during cardiac arrest, the next possible time is to do so immediately after cardiac arrest. Although current randomized studies comparing pre- to in-hospital initiation of TTM have failed to show an improvement of outcome [6–8], animal data

A-4 still suggest that an earlier initiation of TTM would lead to improved outcomes [16]. If TTM is not started pre-hospital it should at least be started on hospital admission. Most patients successfully resuscitated after cardiac arrest are admitted via an ED to the ICU. Here in the ED the patient is initially stabilized and necessary diagnostic procedures (echocardiography, CT scan or percutaneous coronary interventions) are on the agenda. Although the evidence of the impact of the time to reach the target temperature is conflicting [17–21], animal data show that delay of cooling leads to diminished effect of TTM [16, 22]. Therefore it is essential that special attention is laid on the initiation and continuation of TTM during this phase or cooling would be unnecessarily delayed. Beside the initiation of TTM it is also important to decide the form of concomitant sedation, analgesia and paralysis. This could significantly influence time to awakening [23] and outcome [24]. A key task in the TTM process has the critical care nurse who is with the patient most of the time and can also initiate non-invasive cooling very early. The inclusion of the nursing staff is also critical during initiation of a TTM program [25]. Beside the staff of emergency medical service, ED and ICU further medical specialities are involved. In patients with myocardial infarction an interventional cardiologist would be involved and for prognostic evaluation a neurologist would be part of the treatment team. It is the task of the treating physician to coordinate the various professions so that an optimal outcome for the patient can be achieved. References 1. The Hypothermia After Cardiac Arrest (HACA) study group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002, 346:549–556. 2. 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, 346:557–563. 3. Merchant RM, Soar J, Skrifvars MB, et al: Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest. Crit Care Med 2006, 34:1935–1940. 4. Kliegel A, Gamper G, Mayr H: Therapeutic hypothermia after cardiac arrest in Lower Austria–a cross-sectional survey. Eur J Emerg Med 2011, 18:105–107. 5. Binks AC, Murphy RE, Prout RE, et al: Therapeutic hypothermia after cardiac arrest - implementation in UK intensive care units. Anaesthesia 2010, 65:260–265. 6. Bernard SA, Smith K, Cameron P, et al: Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation 2010, 122:737–742. 7. Bernard SA, Smith K, Cameron P, et al: Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest*. Crit Care Med 2012, 40:747–753. 8. 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, 115:3064–3070. 9. Merchant RM, Abella BS, Peberdy MA, et al: Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets. Crit Care Med 2006, 34:S490–S494. 10. Flint AC, Hemphill JC, Bonovich DC: Therapeutic Hypothermia after Cardiac Arrest: Performance Characteristics and Safety of Surface Cooling with or without Endovascular Cooling. Neurocrit Care 2007, 7:109–118.

ABSTRACTS 11. Knapik P, Rychlik W, Siedy J, et al: Comparison of intravascular and conventional hypothermia after cardiac arrest. Kardiol Pol 2011, 69:1157–1163. 12. Deakin CD, Nolan JP, Soar J, et al: European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation 2010, 81:1305–1352. 13. Castren M, Nordberg P, Svensson L, et al: Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation 2010, 122:729–736. 14. Bruel C, Parienti JJ, Marie W, et al: Mild hypothermia during advanced life support: a preliminary study in out-of-hospital cardiac arrest. Crit Care 2008, 12:R31. 15. Kamarainen A, Virkkunen I, Tenhunen J, et al: Induction of therapeutic hypothermia during prehospital CPR using icecold intravenous fluid. Resuscitation 2008, 79:205–211. 16. Colbourne F, Corbett D: Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995, 15:7250– 7260. 17. Wolff B, Machill K, Schumacher D, et al: Early achievement of mild therapeutic hypothermia and the neurologic outcome after cardiac arrest. Int J Cardiol 2009, 133:223–228. 18. Haugk M, Testori C, Sterz F, et al: Relationship between time to target temperature and outcome in patients treated with therapeutic hypothermia after cardiac arrest. Crit Care 2011, 15:R101. 19. Nielsen N, Hovdenes J, Nilsson F, et al: Outcome, timing and adverse events in therapeutic hypothermia after out-ofhospital cardiac arrest. Acta Anaesthesiol Scand 2009, 53:926– 934. 20. Benz-Woerner J, Delodder F, Benz R, et al: Body temperature regulation and outcome after cardiac arrest and therapeutic hypothermia. Resuscitation 2012, 83:338–342. 21. The Italian Cooling Experience Study Group: Early- versus late-initiation of therapeutic hypothermia after cardiac arrest: preliminary observations from the experience of 17 Italian intensive care units. Resuscitation 2012, 83:823–828. 22. Zhang H, Zhou M, Zhang J, et al: Initiation time of postischemic hypothermia on the therapeutic effect in cerebral ischemic injury. Neurol Res 2009, 31:336–339. 23. Bjelland TW, Dale O, Kaisen K, et al: Propofol and remifentanil versus midazolam and fentanyl for sedation during therapeutic hypothermia after cardiac arrest: a randomised trial. Intensive Care Med 2012, 38:959–967. 24. Salciccioli JD, Cocchi MN, Rittenberger JC, et al: Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients. Resuscitation 2013. 25. Vaga A, Busch M, Karlsen TE, et al: A pilot study of key nursing aspects with different cooling methods and devices in the ICU. Resuscitation 2008, 76:25–30. Burns Intensive Care – Significance of Temperature Management Sameer Bhandari Anaesthesia & Intensive Care, Pinderfields General Hospital, Wakefield, United Kingdom It is a major challenge for the clinician to manage the patients with severe burn injury, however better understanding of the pathophysiology and major developments in the field of burns intensive care has led to improved clinical outcomes (1). In the initial stages of management of a patient with major burns, the

ABSTRACTS prime focus is on fluid resuscitation, ventilatory support, wound care, infection control, enteral nutrition and temperature management. Hyper and hypothermia are known complications in patients with major burn. Rapid intervention is essential to maintain the normal temperature. Major burn injury is associated with most profound of hypermetabolic responses. Hyperthermia secondary to systemic inflammatory response is a well recognised phenomenon; however the incidence of this complication is not very clear. Uncontrolled increase in body temperature and associated increase in metabolic rate is known to have a significant impact on resuscitation and prognosis. The pathophysiology of hyperthermic response in major burn is not well understood. Irrespective of the reason, sustained hyperthermia can result in irreversible cellular injury and death. Hyperthermia in patients with burns is often due to noninfective cause and can present itself early in the course of the illness and can be refractory to treatment. Severely burned patients are considerably catabolic and hyperthermia in this patient population adds up to the energy expenditure. Hypothermia – defined as core body temperature less than 35 degrees Celsius is found in up to 35% of patients admitted with major burn injury and is shown to be associated with higher mortality rate compared to the normothermic patients (2). The patients with burns are often cared for in a warm environment and given warmed fluids to avoid this preventable complication. It is essential that we give due diligence to temperature management in patients with burn injury. The conventional treatment options for hyperthermia including the antipyretics and surface cooling could prove difficult and ineffective in this challenging patient group. We reported the successful use of the novel intravenous temperature management system Thermogard XP in our unit (3). We found this system of intravenous temperature management using the technique of forced core thermoregulation very effective in maintaining normothermia in patients with severe burns. While the role of therapeutic cooling in patients with out of hospital cardiac arrests (4) and hyperthermic patients in neuro intensive care is well established, its role in burns intensive care warrants a multi-centre trial. References 1. Barbara A. Latenser, MD, FACS, Critical Care of the Burn Patient: The First 48 Hours Crit Care Med. 2009;37(10):2819– 2826. 2. Singer AJ, Taira BR, Thode HC Jr, McCormack JE, Shapiro M, Aydin A, Lee C, The association between hypothermia, prehospital cooling, and mortality in burn victims. Acad Emerg Med. 2010;17(4):456. 3. Meyyappan Nachiappan*, Dilnath Gurusinghe and Sameer Bhandari. Hypothermia in burns intensive care: use of the intravenous temperature management system Thermogard XP. Critical Care 2012, 16(Suppl 2):A15. 4. Hypothermia after Cardiac Arrest Study Group, 2002. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med. 346, 549–556.

Temperature Management in Sepsis Jonathan Rhodes Department of Anaesthesia, Critical Care & Pain Medicine, Intensive Care Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK

A-5 The control of high body temperatures in patients with sepsis has strong historical associations and intuitively seems the correct thing to do. Indeed this view is often reinforced by those with commercial interests. Furthermore several sound reasons for controlling temperature are often cited in the literature, reinforcing the perception that the control of fever in the septic patient is appropriate, reducing suffering and improving outcome. However, the development of a fever in response to infection is common in many animals. It is the consequence of the resetting of the hypothalamic thermoregulatory set point to a higher value. Vasoconstriction, increased muscle tone and shivering then follow, conserving/generating heat. It could be argued that such a stereotyped response is the product of evolution and therefore should confirm a survival advantage to the host. Indeed evidence that increased body temperature prejudices infectious organisms or increases the efficacy of antibiotics exists in the literature. This talk will review the evidence for and against the control of body temperature in patients with sepsis. In particular clinical trials of antipyretic treatment strategies will be examined. Temperature Management in Trauma & Other Patients Peter Paal Department of Anaesthesiology and Critical Care Medicine, Innsbruck University Hospital, Anichstr. 35, 6020 Innsbruck, Austria Severe trauma destabilizes thermoregulation, patients with central-nervous-system or multiple trauma are particularly prone to hypothermia. Hypothermia may induce a vicious circle, because it augments bleeding and transfusion requirements and may also increase mortality. With a body core-temperature < 34C clotting-factor activity and platelet-function diminish and a critical coagulopathy will result [1]. Even a mild perioperative reduction in core-temperature (< 1C) increased blood loss by 16% and transfusion requirements by 22% [2]. Cooling rates of 9h - 1 have been documented [3–5], with cold water immersion they are likely higher. Analgesia and anaesthesia may be required in trauma patients, they may trigger further cooling due to 1. sympathetic inhibition and consecutive vasodilation and 2. by elevating the threshold for shivering. Ketamine may be the least detrimental analgesic [6]. While the vicious circle progresses the deadly triad of hypothermia, coagulation disorder and lactic-acidosis may kick-in and exponentially increase mortality [7]. Hence preservation of euthermia is of utmost importance. Prehospitally, core-temperature measurement via an epitympanic-access may be prone to false low readings (up to 10C) due to cold debris in the ear and insufficient ear-insulation from the cold environment. If the patient’s trachea has been intubated the midesophageal site is recommended [5]. Trauma patients will cool substantially even in a temperately warm environment, and most patients will reach the trauma-departement with a core-temperature < 35C. Prehospital rewarming is not feasible in most emergency medical systems with short transport times, but it should be considered in protracted transports [8, 9]. Removal of cool and wet clothings is not indicated if patients are wrapped tightly into insulating layers [10]. In hypothermic major trauma patients the appropriate hospital for damage-control and rewarming may be life-saving [11]. In-hospital temperature management should primarily consist of removal of cold clothing, warm infusions and forced-air

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ABSTRACTS Table 1. Techniques and Rewarming Rates [5]. HT I Indicates Patients with a Core Temperature of 32–35C, HT II 28–32C, HT III 24–28C, HT IV 3) had a constant elevation or increase of NSE concentrations during the same time frame. S100B levels decreased into normal range between 24 and 48 hours independent of outcome and prognostication. These findings influenced the post-cardiac arrest and cooling protocols for patients with hypoxic origin of CA and all patients with initial high and constant increased levels of brain damage markers leading to a targeted temperature management including aggressive normothermia after a slow rewarming process (0,1C/hr) for more than 144 hours. Obtaining daily levels of brain damage markers obviously provide additional and valuable information about the patient’s course during post-cardiac arrest treatment and therefore can improve the diagnostic and therapeutic approach leading towards extended duration of RTH. The NSE course showed superior performance to S100B as guide for prolonged cooling. For defining optimal duration of RTH after CA and determination of patients to be selected for this therapeutical approach more randomized studies should be initiated. References Tiainen M, Roine R, Pettila¨ V, Takkunen O: Serum NeuronSpecific Enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 2003: 34; 2881–2886. Colbourne F, Corbett D: Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Research 1994: 654; 265–272. Colbourne F, Corbett D: Delayed postischemic hypothermia: a sixth month survival study using behavorial and histological assessments of neuroprotection. The Journal of Neuroscience 1995: 15(11); 7250–7260. Guenther U, Varelmann D, Putensen C, Wrigge H: Extended therapeutic hypothermia for several days during extracorporal membran-oxygenation after drowning and cardiac arrest. Two cases of survival with no neurological sequelae. Resuscitation 2009: 80; 379–381. Che D, Li L, Kopil CM, Liu Z, Guo W, Neumar W: Impact of hypothermia onset and duration on survival, neurological function and neurodegeneration after cardiac arrest. Crit. Care Med. 2011: 39(6); 1423–1430.

Early Prognostication – Feasible? Rainer Kollmar, Klinikum Darmstadt, Germany After successful resuscitation, the neurological prognosis of patients is often very unclear. Reliable information about the actual status and the prognosis is required for medical decisions that should be taken in close discussion with the relatives of the patient. Recent data complicate the situation by the finding that late recovery from vegetative state and minimally conscious state appears more often than considered formerly (1).

A-12 Many parameters influence decision making, but most of them are of limited reliability. Since therapeutic hypothermia has been successfully implemented as the treatment of choice after cardiac arrest, even formerly approved parameters for decision making are at discussion and need re-evaluation. Formerly, the clinical examination including motor response to pain and brain stem reflexes on day 3, myoclonic state within the first 24 hours after resuscitation, missing N20 response in SEP of the median nerve as well as a serum concentration of 33ug/l between day 1 and 3 have been considered for reliable prognostication. However, further studies including new data on therapeutic hypothermia brought new insights for prognosis. Information on circumstances of resuscitation have to be considered with caution, since e.g. the extent of cardicocirculatory failure before resuscitation can not be calculated safely (2). The clinical examination outside the hospital is not useful as well. Even for normothermic treated patients the motor reaction to pain might fail to show poor prognosis in many cases. A recent study showed that 2 of 10 patients had a good outcome although showing a GCS-M p 2 three days after resuscitation (3). Myoclonic state within the first 24 hours is also very doubtful for prognostication, since good outcomes have been described and epileptic seizures have to be considered for differential diagnosis. However, the lack of pupil reactivity or corneal response at 72 h was associated with death (pupil: 0/ 17; 95% CI 0, 2.9%; corneal: 0/21; 95% CI 0, 2.4%) (3). Median nerve SEP during hypothermia (FPR 3; 95% CI, 1–7) and after rewarming (FPR 0; 95% CI, 0–18) were reliable predictors for prognostication. NSE levels have to be very high ( > 100ug/l) to identify poor prognosis reliably. Characteristics (ROC) curve for poor outcome for the highest observed NSE value for each patient determined a cut-off value for NSE of 97 ng/mL to predict a poor neurological outcome with a specificity of 100% [95% CI = 87–100] and a sensitivity of 49% [95% CI = 37– 60] (5). In conclusion, an approach based on a combination of SSEPs, NSE and clinical-EEG tests can be considered to give the best information about the prognosis, so far. References 1. Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pickard JD, Tshibanda L, Owen AM, Laureys S. Willful modulation of brain activity in disorders of consciousness. N Engl J Med. 2010 Feb 18;362(7):579–89. 2. Aguila A, Funderburk M, Guler A, McNitt S, Hallinan W, Daubert JP, Delehanty JM, Aktas MK. Clinical predictors of survival in patients treated with therapeutic hypothermia following cardiac arrest. Resuscitation. 2010 Dec;81(12): 1621–6. 3. Rittenberger JC, Sangl J, Wheeler M, Guyette FX, Callaway CW. Association between clinical examination and outcome after cardiac arrest. Resuscitation. 2010 Sep;81(9):1128–32. 4. Bouwes A, Binnekade JM, Kuiper MA, Bosch FH, Zandstra DF, Toornvliet AC, Biemond HS, Kors BM, Koelman JH, Verbeek MM, Weinstein HC, Hijdra A, Horn J. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol. 2012 Feb;71(2):206–12. 5. Daubin C, Quentin C, Allouche S, Etard O, Gaillard C, Seguin A, Valette X, Parienti JJ, Prevost F, Ramakers M, Terzi N, Charbonneau P, du Cheyron D. Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study. BMC Cardiovasc Disord. 2011 Aug 8;11:48.

ABSTRACTS Cooling Without Doctors? Ard Struijs Erasmus Medical Centre, Rotterdam, The Netherlands Today we live in the age of new technologies, highly specialized treatment and care and highly trained and certified personnel. We are used to ventilation practitioners, respiratory therapists, renal practitioners, research nurses and so on. In case of temperature management, which is not only limited to OHCA, we still think that the doctor must take care of the patient and all decision making along with that. But who is the doctor? What is his specialty, what is his expertise? Is it a senior specialist, the doctor on call, the resident? Is it an anesthesiologist, a neurologist, a surgeon or neurosurgeon? Temperature management is being performed throughout the whole hospital by different medical specializations and consists of cooling, warming and maintaining normotemperature. It has become a concept that requires people trained in the use and troubleshooting of the equipment and specialized patient care. Temperature management must be performed and supervised by specialists. This should not be necessarily a doctor but could also be a specialized and certified well trained nurse who is 24/7 available throughout the hospital. Therefore you need to invest in a team of specialized ICU nurses who are trained in temperature management throughout the whole hospital. One of the highlights of my first ‘‘Chilling at the Beach’’ congress in Miami was the presentation of a nurse who was in charge of a team of nurses which were 24 hours 7 day a week on call in the hospital for temperature management. They were specially trained to bring in lines for cooling or maintaining temperature and always available for advice or eyes on the patient. That project was a great success and all specialists judged the project useful and an increase in patient care and safety. Even the best intensivist has no longer than 3 hours of patient contact a day. Nurses are the eyes and ears of the doctors. Eyes on the patient is essential in the case of temperature management. Therefore it is of outmost importance that the patient on active temperature management is treated by a team of specialized nurses. They will notice immediately, when the patient gets fever, starts to shiver or is having a seizure and start appropriate treatment after consulting the doctor. On our Intensive Care Cardiology we trained all our nurses in using the Coolgard and Thermogard in treating and monitoring OHCA patients for more than 10 years. They intervene in case of shivering, modulate sedation and take care of these patients during active temperature management. Their expertise is now being used on our other ICUs, when temperature management is initiated in patients with CVA’s and traumatic brain injury. Temperature management is not only cooling after OHCA anymore. It is throughout departments and specializations like OR and neurology. Successful temperature management in a hospital will reduce cost, reduce infections, reduce blood transfusions and mortality and morbidity. This is extremely important for SMR and quality of care. This increase in quality of care and cure can be used in the benchmarking of your hospital. Therefore I suggest that doctors must invest in creating a training program and certification of a specialized nursing team called ‘‘Temperature Practitioner’’, who takes care of the whole temperature management in a complete hospital. You will not need inexperienced doctors anymore, who see the patient only after call or trouble, but create a cost-effective team of temperature practitioners, who increase the quality of cure and care for

ABSTRACTS your patients by many specialties and in the end for your ranking of your hospital. In the mean time they can participate in collecting data to support the evidence based use of temperature management in all this aspects. State of the Art in Therapeutic Hypothermia After CPR Wilhelm Behringer Department of Emergency Medicine, Medical University of Vienna, Vienna General Hospital, Vienna, Austria Background: The most recent Cochrane review 2012 about therapeutic hypothermia suggests that ‘‘patients with out-of-hospital cardiac arrest, a presumed cardiac cause of cardiac arrest, and for patients with ventricular fibrillation or ventricular tachycardia as the first recorded cardiac rhythm benefit from therapeutic hypothermia. For patients with in-hospital cardiac arrest, asystole and non-cardiac causes of arrest the group sizes are too small to make firm inferences.’’ This review will present a summary of the latest literature on various aspects of therapeutic hypothermia after cardiac arrest, such as: Who should be cooled? When should be cooled? How should be cooled? Who should be cooled? Randomized trials in patients with non-shockable rhythm were most likely under-powered to show a benefit of therapeutic hypothermia. A meta-analysis of nonrandomized clinical trials suggests a benefit of mild hypothermia also in patients with non-shockable rhythm. When should be cooled? While numerous animal studies clearly show a benefit of early and fast cooling, retrospective human data show conflicting results in that regard: depending on the study, time to target temperature is not associated with outcome, or associated with good outcome, or with poor outcome. Retrospective studies cannot assess the cause and effect relationship between time to target temperature and outcome, e.g. it is not possible to differentiate, if early and fast cooling causes poor outcome, or if a damaged brain loses temperature control and thus enables fast cooling. Randomized trials investigating early cooling in the pre-hospital setting are limited by inefficient cooling methods, thus do not allow drawing a final conclusion about the effect of early cooling. How should be cooled? A cooling protocol enables a standardized cooling procedure for all patients. Numerous invasive and non-invasive cooling methods are available for induction and maintenance of therapeutic hypothermia, with no difference in the effect on neurologic outcome. Infusion of ice-cold saline is safe, cheap, and effective for induction of mild hypothermia, under the condition of a pressure bag for fast infusion and sufficient infusion volume. For maintenance hypothermia 12–24 hours, it is essential to continue as fast as possible with another cooling method to reach target temperature without rewarming. Sedation, analgesia, and paralysis allow cooling without shivering, but altered pharmacokinetics during hypothermia has to be taken into account. Accurate temperature monitoring is essential. Esophageal temperature closely reflects core temperature, bladder temperature lacks behind core temperature during fast cooling; tympanic and rectal temperatures are not reliable. Conclusions: Randomized clinical trials showed that therapeutic hypothermia 32–34C, achieved within 8 hours and maintained for 12–24 hours improves neurologic outcome after out of hospital cardiac arrest with shockable rhythm. If therapeutic hypothermia benefits also patients with non-shockable rhythm or in-hospital cardiac arrest, or if early and fast cooling is essential, needs further studies.

A-13 Temperature Management in Neurology Stefan Schwab Neurologische Klinik, Universita¨tsklinikum Erlangen, Germany The detrimental effect of elevated body temperature on outcome after ischemic or hemorrhagic stroke has been demonstrated in experimental and clinical studies and provides a rationale for targeted temperature control in patients with different subtypes of stroke. The clinical approach to fever includes two major strategies of treatment: a pharmacological strategy using antipyretic drugs and physical methods for lowering body temperature. Clinical studies available to date have been investigating either a purely pharmacological treatment regimen, or combinations of antipyretics with different methods of surface or endovascular cooling to achieve normothermia in stroke patients, however, a beneficial effect of fever treatment on outcome could not be demonstrated as yet. Pharmacological antipyretic strategies in stroke treatment are being further investigated within ongoing large clinical trials (PAIS 2). The proven clinical benefit from therapeutic hypothermia in global ischemia (cardiac arrest, perinatal asphyxia) and the robust experimental evidence supporting the various neuroprotective effects of hypothermia in animal models of stroke strongly encourages the investigation of this approach in the clinical setting. Mild therapeutic hypothermia in awake stroke patients is currently being tested in two large-scale international phase III clinical trials (ICTUS 2/3 and EuroHYP-1). Several small studies on the use of hypothermia for treatment of large hemispheric stroke have indicated clinical benefit as compared to conservative treatment, however, rebound of edema and mass effect associated mortality during rewarming have been a major problem in this setting. An ongoing German trial is testing the add-on use of hypothermia in patients with large hemispheric stroke who were primarily treated with hemicraniectomy, as compared to hemicraniectomy alone (DEPTH SOS). Data on the use of hypothermia in intracerebral hemorrhage (ICH) are even scarcer. One small pilot study has indicated that prolonged mild hypothermia reduces perihemorrhagic edema growth after large ICH. The clinical impact of this finding is being currently investigated (CINCH). One large randomized clinical trial (IHAST) failed to show a beneficial effect of perioperative hypothermia in patients with aneurysmal subarachnoid hemorrhage (SAH). The use of prolonged hypothermia for treatment of elevated ICP or vasospasm after SAH has only been assessed in non-randomized clinical trials. In summary, the available data on therapeutic hypothermia in the treatment of ischemic and hemorrhagic stroke currently does not provide sufficient evidence for its routine clinical use. There is, however, a robust basis from experimental and clinical studies, justifying further research and the results of ongoing randomized clinical trials are eagerly expected. Hypothermia for STEMI David Erlinge Lund University, Department of Cardiology, Sweden Hypothermia is an established form of treatment employed following cardiac arrest to limit cerebral injury. The question addressed in this review is whether it is possible to use hypothermia to protect the heart during ischemia resulting from ST-elevation myocardial infarction (STEMI). Mild hypothermia

A-14 (32–35C) may be of benefit as an adjunctive treatment for STEMI by reducing the extent of the infarct and the effects of the four components of ischemia reperfusion injury: myocardial stunning, microvascular obstruction, reperfusion arrhythmia and lethal reperfusion injury. In order to reduce cerebral injury after cardiac arrest, hypothermia can be initiated after reperfusion, and should be maintained for 24–48 h. However, evidence suggests that in order to protect the heart in cases of STEMI, hypothermia should be initiated as early as possible after the onset of ischemia, at least before reperfusion. Clinical and experimental results indicate that it is of paramount importance to achieve a body temperature below 35C before reperfusion in order to reduce the size of the infarct in the treatment of STEMI patients, and that treatment needs only to

ABSTRACTS be continued for a relatively short period after reperfusion. Hypothermia has wide-ranging effects on most of the mechanisms involved in ischemia and reperfusion injury, which may explain the potent, highly reproducible cardioprotective effects seen in a large number of studies in different species. Subjecting conscious patients with STEMI to hypothermia is safe, feasible and well tolerated, but anti-shivering strategies must be employed. Large clinical studies are ongoing to evaluate hypothermia as an adjunctive treatment for myocardial infarction. This review discusses the experimental basis for using mild hypothermia to provide cardioprotection, methods of inducing hypothermia, the timing and duration of treatment, and ways in which the knowledge gained can be translated into clinical treatment.