Semin Neurol
DOI: 10.1055/s-0044-1785647
Review Article

Temperature Control in Acute Brain Injury: An Update

Victor Lin
1   Department of Neurology, University of Washington, Seattle, Washington
Cindy Tian
2   Department of Emergency Medicine, University of Washington, Seattle, Washington
Sarah Wahlster
1   Department of Neurology, University of Washington, Seattle, Washington
3   Department of Neurosurgery, University of Washington, Seattle, Washington
4   Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
Carlos Castillo-Pinto
5   Department of Pediatric Neurology, Seattle Children's Hospital, Seattle, Washington
Shraddha Mainali
6   Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
Nicholas J. Johnson
2   Department of Emergency Medicine, University of Washington, Seattle, Washington
7   Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington
› Author Affiliations


Temperature control in severe acute brain injury (SABI) is a key component of acute management. This manuscript delves into the complex role of temperature management in SABI, encompassing conditions like traumatic brain injury (TBI), acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage (aSAH), and hypoxemic/ischemic brain injury following cardiac arrest. Fever is a common complication in SABI and is linked to worse neurological outcomes due to increased inflammatory responses and intracranial pressure (ICP). Temperature management, particularly hypothermic temperature control (HTC), appears to mitigate these adverse effects primarily by reducing cerebral metabolic demand and dampening inflammatory pathways. However, the effectiveness of HTC varies across different SABI conditions. In the context of post-cardiac arrest, the impact of HTC on neurological outcomes has shown inconsistent results. In cases of TBI, HTC seems promising for reducing ICP, but its influence on long-term outcomes remains uncertain. For AIS, clinical trials have yet to conclusively demonstrate the benefits of HTC, despite encouraging preclinical evidence. This variability in efficacy is also observed in ICH, aSAH, bacterial meningitis, and status epilepticus. In pediatric and neonatal populations, while HTC shows significant benefits in hypoxic-ischemic encephalopathy, its effectiveness in other brain injuries is mixed. Although the theoretical basis for employing temperature control, especially HTC, is strong, the clinical outcomes differ among various SABI subtypes. The current consensus indicates that fever prevention is beneficial across the board, but the application and effectiveness of HTC are more nuanced, underscoring the need for further research to establish optimal temperature management strategies. Here we provide an overview of the clinical evidence surrounding the use of temperature control in various types of SABI.

Publication History

Article published online:
09 April 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18 (05) 459-480
  • 2 Feigin VL, Stark BA, Johnson CO. et al; GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2021; 20 (10) 795-820
  • 3 GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18 (01) 56-87
  • 4 Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol 1954; 179 (01) 85-88
  • 5 Fay T. Early experiences with local and generalized refrigeration of the human brain. J Neurosurg 1959; 16 (03) 239-259 , discussion 259–260
  • 6 Cooper KE. The role of the hypothalamus in the genesis of fever. Proc R Soc Med 1965; 58 (09) 740
  • 7 Mackowiak PA. Physiological rationale for suppression of fever. Clin Infect Dis 2000; 31 (Suppl. 05) S185-S189
  • 8 Jiang JY, Gao GY, Li WP, Yu MK, Zhu C. Early indicators of prognosis in 846 cases of severe traumatic brain injury. J Neurotrauma 2002; 19 (07) 869-874
  • 9 Kammersgaard LP, Jørgensen HS, Rungby JA. et al. Admission body temperature predicts long-term mortality after acute stroke: the Copenhagen Stroke Study. Stroke 2002; 33 (07) 1759-1762
  • 10 Malavera A, You S, Zheng D, Delcourt C, Anderson CS. INTERACT2 Investigators. Prognostic significance of early pyrexia in acute intracerebral haemorrhage: the INTERACT2 study. J Neurol Sci 2021; 423: 117364
  • 11 Schwarz S, Häfner K, Aschoff A, Schwab S. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology 2000; 54 (02) 354-361
  • 12 Badjatia N. Hyperthermia and fever control in brain injury. Crit Care Med 2009; 37 (7, suppl): S250-S257
  • 13 Thompson HJ, Kirkness CJ, Mitchell PH. Intensive care unit management of fever following traumatic brain injury. Intensive Crit Care Nurs 2007; 23 (02) 91-96
  • 14 Rabinstein AA, Sandhu K. Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors. J Neurol Neurosurg Psychiatry 2007; 78 (11) 1278-1280
  • 15 Rossi S, Zanier ER, Mauri I, Columbo A, Stocchetti N. Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage. J Neurol Neurosurg Psychiatry 2001; 71 (04) 448-454
  • 16 Institute of Medicine (US) Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001: 360
  • 17 Bro-Jeppesen J, Hassager C, Wanscher M. et al. Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest. Resuscitation 2013; 84 (12) 1734-1740
  • 18 Thompson HJ, Tkacs NC, Saatman KE, Raghupathi R, McIntosh TK. Hyperthermia following traumatic brain injury: a critical evaluation. Neurobiol Dis 2003; 12 (03) 163-173
  • 19 Suehiro E, Fujisawa H, Ito H, Ishikawa T, Maekawa T. Brain temperature modifies glutamate neurotoxicity in vivo. J Neurotrauma 1999; 16 (04) 285-297
  • 20 Ginsberg MD, Sternau LL, Globus MY, Dietrich WD, Busto R. Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 1992; 4 (03) 189-225
  • 21 Sharma HS, Hoopes PJ. Hyperthermia induced pathophysiology of the central nervous system. Int J Hyperthermia 2003; 19 (03) 325-354
  • 22 Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia; its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperatures. Ann Surg 1950; 132 (05) 849-866
  • 23 Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 2009; 37 (7, suppl): S186-S202
  • 24 Weng Y, Sun S. Therapeutic hypothermia after cardiac arrest in adults: mechanism of neuroprotection, phases of hypothermia, and methods of cooling. Crit Care Clin 2012; 28 (02) 231-243
  • 25 González-Ibarra FP, Varon J, López-Meza EG. Therapeutic hypothermia: critical review of the molecular mechanisms of action. Front Neurol 2011; 2: 4
  • 26 Choi HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury–mechanisms and practical aspects. Nat Rev Neurol 2012; 8 (04) 214-222
  • 27 Steen PA, Newberg L, Milde JH, Michenfelder JD. Hypothermia and barbiturates: individual and combined effects on canine cerebral oxygen consumption. Anesthesiology 1983; 58 (06) 527-532
  • 28 Carre E, Ogier M, Boret H, Montcriol A, Bourdon L, Jean-Jacques R. Metabolic crisis in severely head-injured patients: is ischemia just the tip of the iceberg?. Front Neurol 2013; 4: 146
  • 29 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 (12, suppl): S490-S494
  • 30 Larsson IM, Wallin E, Rubertsson S. Cold saline infusion and ice packs alone are effective in inducing and maintaining therapeutic hypothermia after cardiac arrest. Resuscitation 2010; 81 (01) 15-19
  • 31 Kim F, Nichol G, Maynard C. et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA 2014; 311 (01) 45-52
  • 32 de Waard MC, Banwarie RP, Jewbali LS, Struijs A, Girbes AR, Groeneveld AB. Intravascular versus surface cooling speed and stability after cardiopulmonary resuscitation. Emerg Med J 2015; 32 (10) 775-780
  • 33 Glover GW, Thomas RM, Vamvakas G. et al. Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest - an analysis of the TTM trial data. Crit Care 2016; 20 (01) 381
  • 34 Nordberg P, Taccone FS, Truhlar A. et al. Effect of trans-nasal evaporative intra-arrest cooling on functional neurologic outcome in out-of-hospital cardiac arrest: the PRINCESS randomized clinical trial. JAMA 2019; 321 (17) 1677-1685
  • 35 Dietrichs ES, McGlynn K, Allan A. et al. Moderate but not severe hypothermia causes pro-arrhythmic changes in cardiac electrophysiology. Cardiovasc Res 2020; 116 (13) 2081-2090
  • 36 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 (08) 557-563
  • 37 Nielsen N, Wetterslev J, Cronberg T. et al; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013; 369 (23) 2197-2206
  • 38 Lascarrou JB, Merdji H, Le Gouge A. et al; CRICS-TRIGGERSEP Group. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med 2019; 381 (24) 2327-2337
  • 39 Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003; 54 (06) 1127-1130
  • 40 Jacob M, Hassager C, Bro-Jeppesen J. et al. The effect of targeted temperature management on coagulation parameters and bleeding events after out-of-hospital cardiac arrest of presumed cardiac cause. Resuscitation 2015; 96: 260-267
  • 41 Soleimanpour H, Rahmani F, Golzari SE, Safari S. Main complications of mild induced hypothermia after cardiac arrest: a review article. J Cardiovasc Thorac Res 2014; 6 (01) 1-8
  • 42 Jain A, Gray M, Slisz S, Haymore J, Badjatia N, Kulstad E. Shivering treatments for targeted temperature management: a review. J Neurosci Nurs 2018; 50 (02) 63-67
  • 43 Deakin CD, Morrison LJ, Morley PT. et al; Advanced Life Support Chapter Collaborators. Part 8: Advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2010; 81 (Suppl. 01) e93-e174
  • 44 Tveita T, Sieck GC. Physiological impact of hypothermia: the good, the bad, and the ugly. Physiology (Bethesda) 2022; 37 (02) 69-87
  • 45 Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model. Crit Care 2017; 21 (01) 90
  • 46 Sandroni C, Cronberg T, Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med 2021; 47 (12) 1393-1414
  • 47 Arrich J, Herkner H, Müllner D, Behringer W. Targeted temperature management after cardiac arrest. A systematic review and meta-analysis of animal studies. Resuscitation 2021; 162: 47-55
  • 48 Olai H, Thornéus G, Watson H. et al. Meta-analysis of targeted temperature management in animal models of cardiac arrest. Intensive Care Med Exp 2020; 8 (01) 3
  • 49 Holzer M, Poole JE, Lascarrou JB, Fujise K, Nichol G. A commentary on the effect of targeted temperature management in patients resuscitated from cardiac arrest. Ther Hypothermia Temp Manag 2023; 13 (03) 102-111
  • 50 Polderman KH, Varon J. Interpreting the results of the targeted temperature management trial in cardiac arrest. Ther Hypothermia Temp Manag 2015; 5 (02) 73-76
  • 51 Morrison LJ, Thoma B. Translating targeted temperature management trials into postarrest care. N Engl J Med 2021; 384 (24) 2344-2345
  • 52 Wyckoff MH, Greif R, Morley PT. et al; Collaborators. 2022 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations: Summary from the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces. Circulation 2022; 146 (25) e483-e557
  • 53 Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346 (08) 549-556
  • 54 Nolan JP, Morley PT, Vanden Hoek TL. et al; International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation 2003; 108 (01) 118-121
  • 55 Gaieski DF, Band RA, Abella BS. et al. Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest. Resuscitation 2009; 80 (04) 418-424
  • 56 Don CW, Longstreth Jr WT, Maynard C. et al. Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital. Crit Care Med 2009; 37 (12) 3062-3069
  • 57 Kim Y-M, Yim H-W, Jeong S-H, Klem ML, Callaway CW. Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: a systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation 2012; 83 (02) 188-196
  • 58 Dumas F, Grimaldi D, Zuber B. et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation 2011; 123 (08) 877-886
  • 59 Perman SM, Grossestreuer AV, Wiebe DJ, Carr BG, Abella BS, Gaieski DF. The utility of therapeutic hypothermia for post-cardiac arrest syndrome patients with an initial nonshockable rhythm. Circulation 2015; 132 (22) 2146-2151
  • 60 Doshi P, Patel K, Banuelos R. et al. Effect of therapeutic hypothermia on survival to hospital discharge in out-of-hospital cardiac arrest secondary to nonshockable rhythms. Acad Emerg Med 2016; 23 (01) 14-20
  • 61 Dankiewicz J, Schmidbauer S, Nielsen N. et al. Safety, feasibility, and outcomes of induced hypothermia therapy following in-hospital cardiac arrest-evaluation of a large prospective registry*. Crit Care Med 2014; 42 (12) 2537-2545
  • 62 Mikkelsen ME, Christie JD, Abella BS. et al; American Heart Association's Get With the Guidelines-Resuscitation Investigators. Use of therapeutic hypothermia after in-hospital cardiac arrest. Crit Care Med 2013; 41 (06) 1385-1395
  • 63 Moler FW, Silverstein FS, Holubkov R. et al; THAPCA Trial Investigators. Therapeutic hypothermia after in-hospital cardiac arrest in children. N Engl J Med 2017; 376 (04) 318-329
  • 64 Moler FW, Silverstein FS, Holubkov R. et al; THAPCA Trial Investigators. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med 2015; 372 (20) 1898-1908
  • 65 Bray JE, Stub D, Bloom JE. et al. Changing target temperature from 33°C to 36°C in the ICU management of out-of-hospital cardiac arrest: a before and after study. Resuscitation 2017; 113: 39-43
  • 66 Salter R, Bailey M, Bellomo R. et al; Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation (ANZICS-CORE). Changes in temperature management of cardiac arrest patients following publication of the target temperature management trial. Crit Care Med 2018; 46 (11) 1722-1730
  • 67 Young PJ, Bailey M, Bellomo R. An update on temperature management following cardiac arrest in Australian and New Zealand ICUs. Crit Care Med 2021; 49 (10) e1040-e1042
  • 68 Johnson NJ, Danielson KR, Counts CR. et al. Targeted temperature management at 33 versus 36 degrees: a retrospective cohort study. Crit Care Med 2020; 48 (03) 362-369
  • 69 Dankiewicz J, Cronberg T, Lilja G. et al; TTM2 Trial Investigators. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med 2021; 384 (24) 2283-2294
  • 70 Simpson RFG, Dankiewicz J, Karamasis GV. et al. Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial. Crit Care 2022; 26 (01) 356
  • 71 Düring J, Annborn M, Cariou A. et al. Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial. Crit Care 2022; 26 (01) 231
  • 72 Blanc A, Colin G, Cariou A. et al. Targeted temperature management after in-hospital cardiac arrest: an ancillary analysis of targeted temperature management for cardiac arrest with nonshockable rhythm trial data. Chest 2022; 162 (02) 356-366
  • 73 Chan PS, Berg RA, Tang Y, Curtis LH, Spertus JA. Investigators AHAsGWtG-R. association between therapeutic hypothermia and survival after in-hospital cardiac arrest. JAMA 2016; 316 (13) 1375-1382
  • 74 Wolfrum S, Roedl K, Hanebutte A. et al; Hypothermia After In-Hospital Cardiac Arrest Study Group. Temperature control after in-hospital cardiac arrest: a randomized clinical trial. Circulation 2022; 146 (18) 1357-1366
  • 75 Nichol G, Huszti E, Kim F. et al; American Heart Association Get With the Guideline-Resuscitation Investigators. Does induction of hypothermia improve outcomes after in-hospital cardiac arrest?. Resuscitation 2013; 84 (05) 620-625
  • 76 Callaway CW, Coppler PJ, Faro J. et al. Association of initial illness severity and outcomes after cardiac arrest with targeted temperature management at 36 °C or 33 °C. JAMA Netw Open 2020; 3 (07) e208215
  • 77 Okazaki T, Hifumi T, Kawakita K, Kuroda Y. Japanese Association for Acute Medicine out-of-hospital cardiac arrest (JAAM-OHCA) registry. Targeted temperature management guided by the severity of hyperlactatemia for out-of-hospital cardiac arrest patients: a post hoc analysis of a nationwide, multicenter prospective registry. Ann Intensive Care 2019; 9 (01) 127
  • 78 Nutma S, Tjepkema-Cloostermans MC, Ruijter BJ. et al. Effects of targeted temperature management at 33 °C vs. 36 °C on comatose patients after cardiac arrest stratified by the severity of encephalopathy. Resuscitation 2022; 173: 147-153
  • 79 Nishikimi M, Ogura T, Nishida K. et al. Outcome related to level of targeted temperature management in postcardiac arrest syndrome of low, moderate, and high severities: a nationwide multicenter prospective registry. Crit Care Med 2021; 49 (08) e741-e750
  • 80 Granfeldt A, Holmberg MJ, Nolan JP, Soar J, Andersen LW. International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force. Targeted temperature management in adult cardiac arrest: systematic review and meta-analysis. Resuscitation 2021; 167: 160-172
  • 81 Sandroni C, Nolan JP, Andersen LW. et al. ERC-ESICM guidelines on temperature control after cardiac arrest in adults. Intensive Care Med 2022; 48 (03) 261-269
  • 82 Arrich J, Schütz N, Oppenauer J. et al. Hypothermia for neuroprotection in adults after cardiac arrest. Cochrane Database Syst Rev 2023; 5 (05) CD004128
  • 83 Hickey RW, Kochanek PM, Ferimer H, Alexander HL, Garman RH, Graham SH. Induced hyperthermia exacerbates neurologic neuronal histologic damage after asphyxial cardiac arrest in rats. Crit Care Med 2003; 31 (02) 531-535
  • 84 Bengualid V, Talari G, Rubin D, Albaeni A, Ciubotaru RL, Berger J. Fever in trauma patients: evaluation of risk factors, including traumatic brain injury. Am J Crit Care 2015; 24 (02) e1-e5
  • 85 Li J, Jiang JY. Chinese Head Trauma Data Bank: effect of hyperthermia on the outcome of acute head trauma patients. J Neurotrauma 2012; 29 (01) 96-100
  • 86 Greer DM, Funk SE, Reaven NL, Ouzounelli M, Uman GC. Impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive meta-analysis. Stroke 2008; 39 (11) 3029-3035
  • 87 Hinson HE, Rowell S, Morris C, Lin AL, Schreiber MA. Early fever after trauma: does it matter?. J Trauma Acute Care Surg 2018; 84 (01) 19-24
  • 88 Bramlett HM, Dietrich WD. The effects of posttraumatic hypothermia on diffuse axonal injury following parasaggital fluid percussion brain injury in rats. Ther Hypothermia Temp Manag 2012; 2 (01) 14-23
  • 89 Hirst TC, Klasen MG, Rhodes JK, Macleod MR, Andrews PJD. A systematic review and meta-analysis of hypothermia in experimental traumatic brain injury: why have promising animal studies not been replicated in pragmatic clinical trials?. J Neurotrauma 2020; 37 (19) 2057-2068
  • 90 Gressens P, Dingley J, Plaisant F. et al. Analysis of neuronal, glial, endothelial, axonal and apoptotic markers following moderate therapeutic hypothermia and anesthesia in the developing piglet brain. Brain Pathol 2008; 18 (01) 10-20
  • 91 Sinclair HL, Andrews PJ. Bench-to-bedside review: Hypothermia in traumatic brain injury. Crit Care 2010; 14 (01) 204
  • 92 Hirst TC, Watzlawick R, Rhodes JK, Macleod MR, Andrews PJ. Study protocol - a systematic review and meta-analysis of hypothermia in experimental traumatic brain injury: why have promising animal studies not been replicated in pragmatic clinical trials?. Evid Based Preclin Med 2016; 3 (02) e00020
  • 93 Clifton GL, Allen S, Barrodale P. et al. A phase II study of moderate hypothermia in severe brain injury. J Neurotrauma 1993; 10 (03) 263-271 , discussion 273
  • 94 Polderman KH, Tjong Tjin Joe R, Peerdeman SM, Vandertop WP, Girbes AR. Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury. Intensive Care Med 2002; 28 (11) 1563-1573
  • 95 Zhao QJ, Zhang XG, Wang LX. Mild hypothermia therapy reduces blood glucose and lactate and improves neurologic outcomes in patients with severe traumatic brain injury. J Crit Care 2011; 26 (03) 311-315
  • 96 Zhi D, Zhang S, Lin X. Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. Surg Neurol 2003; 59 (05) 381-385
  • 97 Jiang J, Yu M, Zhu C. Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1-year follow-up review of 87 cases. J Neurosurg 2000; 93 (04) 546-549
  • 98 Crossley S, Reid J, McLatchie R. et al. A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury. Crit Care 2014; 18 (02) R75
  • 99 Crompton EM, Lubomirova I, Cotlarciuc I, Han TS, Sharma SD, Sharma P. Meta-analysis of therapeutic hypothermia for traumatic brain injury in adult and pediatric patients. Crit Care Med 2017; 45 (04) 575-583
  • 100 Maekawa T, Yamashita S, Nagao S, Hayashi N, Ohashi Y. Brain-Hypothermia Study Group. Prolonged mild therapeutic hypothermia versus fever control with tight hemodynamic monitoring and slow rewarming in patients with severe traumatic brain injury: a randomized controlled trial. J Neurotrauma 2015; 32 (07) 422-429
  • 101 Clifton GL, Valadka A, Zygun D. et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol 2011; 10 (02) 131-139
  • 102 Hui J, Feng J, Tu Y. et al; LTH-1 Trial collaborators. Safety and efficacy of long-term mild hypothermia for severe traumatic brain injury with refractory intracranial hypertension (LTH-1): a multicenter randomized controlled trial. EClinicalMedicine 2021; 32: 100732
  • 103 Watson HI, Shepherd AA, Rhodes JKJ, Andrews PJD. Revisited: a systematic review of therapeutic hypothermia for adult patients following traumatic brain injury. Crit Care Med 2018; 46 (06) 972-979
  • 104 Chen H, Wu F, Yang P, Shao J, Chen Q, Zheng R. A meta-analysis of the effects of therapeutic hypothermia in adult patients with traumatic brain injury. Crit Care 2019; 23 (01) 396
  • 105 Carney N, Totten AM, O'Reilly C. et al. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery 2017; 80 (01) 6-15
  • 106 Cooper DJ, Nichol AD, Bailey M. et al; POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the POLAR randomized clinical trial. JAMA 2018; 320 (21) 2211-2220
  • 107 Schreckinger M, Marion DW. Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia?. Neurocrit Care 2009; 11 (03) 427-436
  • 108 Andrews PJ, Sinclair HL, Rodríguez A. et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT. Health Technol Assess 2018; 22 (45) 1-134
  • 109 Andrews PJ, Sinclair HL, Rodriguez A. et al; Eurotherm3235 Trial Collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med 2015; 373 (25) 2403-2412
  • 110 Hawryluk GWJ, Aguilera S, Buki A. et al. A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med 2019; 45 (12) 1783-1794
  • 111 Binder NF, Glück C, Middleham W. et al. Vascular response to spreading depolarization predicts stroke outcome. Stroke 2022; 53 (04) 1386-1395
  • 112 Hartings JA, Shuttleworth CW, Kirov SA. et al. The continuum of spreading depolarizations in acute cortical lesion development: examining Leão's legacy. J Cereb Blood Flow Metab 2017; 37 (05) 1571-1594
  • 113 Powers WJ, Rabinstein AA, Ackerson T. et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50 (12) e344-e418
  • 114 Reith J, Jørgensen HS, Pedersen PM. et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996; 347 (8999): 422-425
  • 115 Karaszewski B, Carpenter TK, Thomas RG. et al. Relationships between brain and body temperature, clinical and imaging outcomes after ischemic stroke. J Cereb Blood Flow Metab 2013; 33 (07) 1083-1089
  • 116 Broessner G, Beer R, Lackner P. et al. Prophylactic, endovascularly based, long-term normothermia in ICU patients with severe cerebrovascular disease: bicenter prospective, randomized trial. Stroke 2009; 40 (12) e657-e665
  • 117 Den Hertog HM, van der Worp HB, Tseng MC, Dippel DW. Cooling therapy for acute stroke. Cochrane Database Syst Rev 2009; 2009 (01) CD001247
  • 118 de Ridder IR, den Hertog HM, van Gemert HM. et al; Trial Organization. PAIS 2 (paracetamol [acetaminophen] in stroke 2): results of a randomized, double-blind placebo-controlled clinical trial. Stroke 2017; 48 (04) 977-982
  • 119 den Hertog HM, van der Worp HB, van Gemert HM. et al; PAIS Investigators. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol 2009; 8 (05) 434-440
  • 120 Graus F, Titulaer MJ, Balu R. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15 (04) 391-404
  • 121 Chamorro A, Horcajada JP, Obach V. et al. The Early Systemic Prophylaxis of Infection After Stroke study: a randomized clinical trial. Stroke 2005; 36 (07) 1495-1500
  • 122 Harms H, Prass K, Meisel C. et al. Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One 2008; 3 (05) e2158
  • 123 Dumitrascu OM, Lamb J, Lyden PD. Still cooling after all these years: meta-analysis of pre-clinical trials of therapeutic hypothermia for acute ischemic stroke. J Cereb Blood Flow Metab 2016; 36 (07) 1157-1164
  • 124 van der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain 2007; 130 (Pt 12): 3063-3074
  • 125 van der Worp HB, Macleod MR, Bath PM. et al; EuroHYP-1 investigators. Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial. Eur Stroke J 2019; 4 (03) 254-262
  • 126 van der Worp HB, Macleod MR, Bath PM. et al; EuroHYP-1 investigators. EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke. Int J Stroke 2014; 9 (05) 642-645
  • 127 De Georgia MA, Krieger DW, Abou-Chebl A. et al. Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 2004; 63 (02) 312-317
  • 128 Hemmen TM, Raman R, Guluma KZ. et al; ICTuS-L Investigators. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 2010; 41 (10) 2265-2270
  • 129 Lyden P, Hemmen T, Grotta J. et al; Collaborators. Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke 2016; 47 (12) 2888-2895
  • 130 Ansari J, Triay R, Kandregula S, Adeeb N, Cuellar H, Sharma P. Endovascular intervention in acute ischemic stroke: history and evolution. Biomedicines 2022; 10 (02) 418
  • 131 Shibata K, Hashimoto T, Miyazaki T, Miyazaki A, Nobe K. Thrombolytic therapy for acute ischemic stroke: past and future. Curr Pharm Des 2019; 25 (03) 242-250
  • 132 Lavinio A, Andrzejowski J, Antonopoulou I. et al. Targeted temperature management in patients with intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke: updated consensus guideline recommendations by the Neuroprotective Therapy Consensus Review (NTCR) group. Br J Anaesth 2023; 131 (02) 294-301
  • 133 Kollmar R, Staykov D, Dörfler A, Schellinger PD, Schwab S, Bardutzky J. Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage. Stroke 2010; 41 (08) 1684-1689
  • 134 Staykov D, Wagner I, Volbers B, Doerfler A, Schwab S, Kollmar R. Mild prolonged hypothermia for large intracerebral hemorrhage. Neurocrit Care 2013; 18 (02) 178-183
  • 135 Volbers B, Herrmann S, Willfarth W. et al. Impact of hypothermia initiation and duration on perihemorrhagic edema evolution after intracerebral hemorrhage. Stroke 2016; 47 (09) 2249-2255
  • 136 Staykov D, Schwab S, Dörfler A, Kollmar R. Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage: but does it influence functional outcome and mortality?. Ther Hypothermia Temp Manag 2011; 1 (02) 105-106
  • 137 Lord AS, Karinja S, Lantigua H. et al. Therapeutic temperature modulation for fever after intracerebral hemorrhage. Neurocrit Care 2014; 21 (02) 200-206
  • 138 Rincon F, Friedman DP, Bell R, Mayer SA, Bray PF. Targeted temperature management after intracerebral hemorrhage (TTM-ICH): methodology of a prospective randomized clinical trial. Int J Stroke 2014; 9 (05) 646-651
  • 139 Kollmar R, Juettler E, Huttner HB. et al; CINCH investigators. Cooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German-Austrian clinical trial. Int J Stroke 2012; 7 (02) 168-172
  • 140 Baker TS, Kellner CP, Colbourne F. et al. Consensus recommendations on therapeutic hypothermia after minimally invasive intracerebral hemorrhage evacuation from the hypothermia for intracerebral hemorrhage (HICH) working group. Front Neurol 2022; 13: 859894
  • 141 Greenberg SM, Ziai WC, Cordonnier C. et al; American Heart Association/American Stroke Association. 2022 Guideline for the Management of Patients with Spontaneous Intracerebral Hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke 2022; 53 (07) e282-e361
  • 142 Lv O, Zhou F, Zheng Y, Li Q, Wang J, Zhu Y. Mild hypothermia protects against early brain injury in rats following subarachnoid hemorrhage via the TrkB/ERK/CREB signaling pathway. Mol Med Rep 2016; 14 (04) 3901-3907
  • 143 Choi W, Kwon SC, Lee WJ. et al. Feasibility and safety of mild therapeutic hypothermia in poor-grade subarachnoid hemorrhage: prospective pilot study. J Korean Med Sci 2017; 32 (08) 1337-1344
  • 144 Kobata H, Tucker A, Sarapuddin G. et al. Targeted temperature management for severe subarachnoid hemorrhage using endovascular and surface cooling systems: a nonrandomized interventional study using historical control. Neurosurgery 2022; 91 (06) 863-871
  • 145 Rhim JK, Park JJ, Kim H, Jeon JP. Early and prolonged mild hypothermia in patients with poor-grade subarachnoid hemorrhage: a pilot study. Ther Hypothermia Temp Manag 2022; 12 (04) 229-234
  • 146 Badjatia N, Fernandez L, Schmidt JM. et al. Impact of induced normothermia on outcome after subarachnoid hemorrhage: a case-control study. Neurosurgery 2010; 66 (04) 696-700 , discussion 700–701
  • 147 Hoh BL, Ko NU, Amin-Hanjani S. et al. 2023 Guideline for the management of patients with aneurysmal subarachnoid hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke 2023; 54 (07) e314-e370
  • 148 Mourvillier B, Tubach F, van de Beek D. et al. Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA 2013; 310 (20) 2174-2183
  • 149 Pirracchio R, Journois D. Hypothermia for bacterial meningitis. JAMA 2014; 311 (13) 1357
  • 150 Maconochie IK, Bhaumik S. Fluid therapy for acute bacterial meningitis. Cochrane Database Syst Rev 2016; 11 (11) CD004786
  • 151 Kutleša M, Lepur D, Baršić B. Therapeutic hypothermia for adult community-acquired bacterial meningitis-historical control study. Clin Neurol Neurosurg 2014; 123: 181-186
  • 152 Engrand N, Welschbillig S, Taylor G. Comment on: therapeutic hypothermia for severe adult community-acquired bacterial meningitis. Clin Neurol Neurosurg 2016; 145: 102-103
  • 153 Oddo M, Frangos S, Maloney-Wilensky E, Andrew Kofke W, Le Roux PD, Levine JM. Effect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury. Neurocrit Care 2010; 12 (01) 10-16
  • 154 Hoen B, Varon E, de Debroucker T. et al; expert and reviewing group. Management of acute community-acquired bacterial meningitis (excluding newborns). Long version with arguments. Med Mal Infect 2019; 49 (06) 405-441
  • 155 van de Beek D, Cabellos C, Dzupova O. et al; ESCMID Study Group for Infections of the Brain (ESGIB). ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect 2016; 22 (Suppl. 03) S37-S62
  • 156 Tunkel AR, Hartman BJ, Kaplan SL. et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39 (09) 1267-1284
  • 157 Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011; 134 (Pt 10): 2802-2818
  • 158 Trinka E, Höfler J, Zerbs A. Causes of status epilepticus. Epilepsia 2012; 53 (4, suppl 4) 127-138
  • 159 Orlowski JP, Erenberg G, Lueders H, Cruse RP. Hypothermia and barbiturate coma for refractory status epilepticus. Crit Care Med 1984; 12 (04) 367-372
  • 160 Corry JJ, Dhar R, Murphy T, Diringer MN. Hypothermia for refractory status epilepticus. Neurocrit Care 2008; 9 (02) 189-197
  • 161 Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure 2019; 68: 72-78
  • 162 Cross JH. Fever and fever-related epilepsies. Epilepsia 2012; 53 (Suppl. 04) 3-8
  • 163 Dubé CM, Brewster AL, Richichi C, Zha Q, Baram TZ. Fever, febrile seizures and epilepsy. Trends Neurosci 2007; 30 (10) 490-496
  • 164 Liu Z, Gatt A, Mikati M, Holmes GL. Effect of temperature on kainic acid-induced seizures. Brain Res 1993; 631 (01) 51-58
  • 165 Lundgren J, Smith ML, Blennow G, Siesjö BK. Hyperthermia aggravates and hypothermia ameliorates epileptic brain damage. Exp Brain Res 1994; 99 (01) 43-55
  • 166 Suchomelova L, Lopez-Meraz ML, Niquet J, Kubova H, Wasterlain CG. Hyperthermia aggravates status epilepticus-induced epileptogenesis and neuronal loss in immature rats. Neuroscience 2015; 305: 209-224
  • 167 Yu L, Zhou Y, Chen W, Wang Y. Mild hypothermia pretreatment protects against pilocarpine-induced status epilepticus and neuronalapoptosis in immature rats. Neuropathology 2011; 31 (02) 144-151
  • 168 Legriel S. Hypothermia as a treatment in status epilepticus: a narrative review. Epilepsy Behav 2019; 101 (Pt B): 106298
  • 169 Mohammed HS. Hypothermia mitigates neurochemical alterations in rat's cerebral cortex during status epilepticus induced by pilocarpine. Gen Physiol Biophys 2015; 34 (04) 425-432
  • 170 Legriel S, Lemiale V, Schenck M. et al; HYBERNATUS Study Group. Hypothermia for neuroprotection in convulsive status epilepticus. N Engl J Med 2016; 375 (25) 2457-2467
  • 171 Brophy GM, Bell R, Claassen J. et al; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17 (01) 3-23
  • 172 Topjian AA, de Caen A, Wainwright MS. et al. Pediatric post-cardiac arrest care: a scientific statement from the American Heart Association. Circulation 2019; 140 (06) e194-e233
  • 173 Kochanek PM, Tasker RC, Bell MJ. et al. Management of pediatric severe traumatic brain injury: 2019 consensus and guidelines-based algorithm for first and second tier therapies. Pediatr Crit Care Med 2019; 20 (03) 269-279
  • 174 Bona E, Hagberg H, Løberg EM, Bågenholm R, Thoresen M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res 1998; 43 (06) 738-745
  • 175 Taylor DL, Mehmet H, Cady EB, Edwards AD. Improved neuroprotection with hypothermia delayed by 6 hours following cerebral hypoxia-ischemia in the 14-day-old rat. Pediatr Res 2002; 51 (01) 13-19
  • 176 Agnew DM, Koehler RC, Guerguerian AM. et al. Hypothermia for 24 hours after asphyxic cardiac arrest in piglets provides striatal neuroprotection that is sustained 10 days after rewarming. Pediatr Res 2003; 54 (02) 253-262
  • 177 Shankaran S, Laptook AR, Ehrenkranz RA. et al; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353 (15) 1574-1584
  • 178 Gluckman PD, Wyatt JS, Azzopardi D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365 (9460): 663-670
  • 179 Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998; 102 (4, Pt 1): 885-892
  • 180 Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med 2012; 166 (06) 558-566
  • 181 Oliveira V, Kumutha Jr JR. e N, et al. Hypothermia for encephalopathy in low-income and middle-income countries: feasibility of whole-body cooling using a low-cost servo-controlled device. BMJ Paediatr Open 2018; 2 (01) e000245
  • 182 Moler FW. Pediatric Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (P-ICECAP). Accessed December 10, 2023 at:
  • 183 Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL. Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cereb Blood Flow Metab 1991; 11 (01) 114-121
  • 184 Dietrich WD, Alonso O, Busto R, Globus MY, Ginsberg MD. Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 1994; 87 (03) 250-258
  • 185 Lyeth BG, Jiang JY, Liu S. Behavioral protection by moderate hypothermia initiated after experimental traumatic brain injury. J Neurotrauma 1993; 10 (01) 57-64
  • 186 Adelson PD, Wisniewski SR, Beca J. et al; Paediatric Traumatic Brain Injury Consortium. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol 2013; 12 (06) 546-553
  • 187 Hutchison JS, Ward RE, Lacroix J. et al; Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008; 358 (23) 2447-2456
  • 188 Du Q, Liu Y, Chen X, Li K. Effect of hypothermia therapy on children with traumatic brain injury: a meta-analysis of randomized controlled trials. Brain Sci 2022; 12 (08) 1009
  • 189 Li P, Yang C. Moderate hypothermia treatment in adult patients with severe traumatic brain injury: a meta-analysis. Brain Inj 2014; 28 (08) 1036-1041
  • 190 Zhang BF, Wang J, Liu ZW. et al. Meta-analysis of the efficacy and safety of therapeutic hypothermia in children with acute traumatic brain injury. World Neurosurg 2015; 83 (04) 567-573
  • 191 Ferriero DM, Fullerton HJ, Bernard TJ. et al; American Heart Association Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of stroke in neonates and children: a scientific statement from the American Heart Association/American Stroke Association. Stroke 2019; 50 (03) e51-e96
  • 192 Ziai W. Intrepid Trial Results. Currents. 2023. Accessed March 21, 2024 at: