Therapeutic hypothermia in treatment of different cerebral injuries

A.V. Butrov1, B.D. Torosyan1, D.V. Cheboksarov1,2, G.R. Makhmutova1,2

1 Peoples Friendship University of Russia (RUDN University), Moscow

2 Moscow City clinical hospital named author V.V. Vinogradov, Moscow

For correspondence: Andrey V. Butrov, DSci, Professor, department of anaestesiology and reanimatology with clinical rehabilitation course RUDN University, Moscow; e-mail:

For citation: Butrov AV, Torosyan BD, Cheboksarov DV, Makhmutova GR. Therapeutic hypothermia in treatment of different cerebral injuries. Alexander Saltanov Intensive Care Herald. 2019;2:75-81.

DOI: 10.21320/1818-474X-2019-2-75-81

There is an increasing incidence of various cerebral eventsin Russia, as well as throughout the world. At the same time, despite of all the successes of modern medicine, the treatment outcomes of these patient groups haven’t improved. The main successes are based on faster patient delivery to hospitals and on the creation of specialized centers for this cohort of patients. At the same time, the effectiveness of pharmacological agents with neuroprotective activity is questionable. On the other hand, therapeutic hypothermia techniques have proven to be an effective method of neuroprotection in various cerebral events. These methods can be divided into local and general hypothermia. Each of these options has its own advantages and indications. Thus, the use of general hypothermia techniques maintains the target temperature of the whole body, these techniques are more controllable, but at the same time, the methods of local craniocerebral hypothermia allows to affect the target organ. The methods of hypothermia and thermostabilization have been proven to improve the treatment results of patients post-CPR and in children with neonatal hypoxia. The effectiveness of hypothermia in the remaining pathological conditions of the brain has not yet been investigated. Studies of the last 5 years have not revealed high efficacy of general hypothermia at TBI, so almost of all studies indicated that normothermia and hypothermia are equally effective. Studies are ongoing in patients with subarachnoid hemorrhage, subdural hematomas and ischemic stroke. Identifying groups of patients who are recommended for these methods for complex treatment can lead to progress in improving survival and neurological outcome.

Keywords: therapeutic hypothermia, craniocerebral hypothermia, traumatic brain injury, cerebral infarction, subarachnoid hemorrhage, cerebral hemorrhage

Received: 04.02.2019


  1. 01_Заболеваемость всего населения России в 2017 году [электронный документ]. Доступно по: Ссылка активна на 20.01.2019. [Zabolevaemost’ vsego naseleniya Rossii v 2017 godu [Internet] Available from: (accessed 20.01.2019). (In Russ)]
  2. Simon D.J., Weimer R.M., McLaughlin T., et al. Caspase Cascade Regulating Developmental Axon Degeneration. Journal of Neuroscience, 2012 5; 32(49): 17540–17553. DOI: 10.1523/jneurosci.3012–12.2012
  3. Усенко Л.В., Царев А.В. Искусственная гипотермия в современной реаниматологии. Общая реаниматология. 2009; 5(1): 21–23. DOI: 10.15360/1813-9779-2009-1-21 [Usenko L.V., Carev A.V. Iskusstvennaya gipotermiya v sovremennoy reanimatologii. Obshaya reanimatologiya. 2009; 5(1): 21–23. DOI: 10.15360/1813-9779-2009-1-21. (In Russ)]
  4. MacLellan C.L., Davies L.M., Fingas M.S., Colbourne F. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke; 2006; 37(5): 1266–1270. DOI: 10.1161/01.STR.0000217268.81963.78
  5. Lazzaro M.A., Prabhakaran S. Induced hypothermia in acute ischemic stroke. Expert Opin. Investig. Drugs, 2008; 17(8): 1161–1174. DOI: 10.1517/13543784.17.8.1161
  6. Keller E., Imhof H.G., Gasser S., et al. Endovascular cooling with heat exchange catheters: a new method to induce and maintain hypothermia. Intensive Care Med., 2003; 29(6): 939–943. DOI: 10.1007/s00134-003-1685-3
  7. Guluma K.Z., Hemmen T.M., Olsen S.E., Rapp K.S., Lyden P.D. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad. Emerg. Med., 2006; 13(8): 820–827.
  8. Van der Worp H.B., Macleod M.R., Kollmar R. Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials. J. Cereb. Blood Flow Metab., 2010; 30(6): 1079–1093. DOI: 10.1038/jcbfm.2010.44
  9. Qiu W., Shen H., Zhang Y., Wang W., et al. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J. Clin. Neurosci. 2006; 13(10): 995–1000.
  10. Lazzaro M.A., Prabhakaran S. Induced hypothermia in acute ischemic stroke. Expert Opin. Investig. Drugs, 2008; 17(8): 1161–1174. DOI: 10.1517/13543784.17.8.1161
  11. Kallmünzer B., Krause C., Pauli E., et al. Standardized antipyretic treatment in stroke: a pilot study. Cerebrovasc. Dis. 2011; 31(4): 382–389. DOI: 10.1159/000321733
  12. Guluma K.Z., Oh H., Yu S.W., et al. Effect of endovascular hypothermia on acute ischemic edema: morphometric analysis of the ICTuS trial. Neurocrit. Care, 2008; 8(1): 42–47.
  13. Mayer S.A., Kowalski R.G., Presciutti M., et al. Clinical trial of a novel surface cooling system for fever control in neurocritical care patients. Crit. Care Med. 2004; 32: 2508–2515.
  14. Qiu W., Shen H., Zhang Y., et al. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J. Clin. Neurosci. 2006; 13(10): 995–1000.
  15. Wang H., Olivero W., Lanzino G., et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet. J. Neurosurg. 2004; 100(2): 272–277.
  16. Harms H., Prass K., Meisel C.,et al. Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One. 2008; 3(5): e2158. DOI: 10.1371/journal.pone.0002158
  17. Chen J., Ji X., Ding Y., et al. A novel approach to reduce hemorrhagic transformation after interventional management of acute stroke: catheter-based selective hypothermia. Med. Hypotheses, 2009; 72(1): 62–63. DOI: 10.1016/j.mehy.2008.07.056
  18. Keller E., Mudra R., Gugl C., et al. Theoretical evaluations of therapeutic systemic and local cerebral hypothermia. J. Neurosci Methods. 2009; 178(2): 345–349. DOI: 10.1016/j.jneumeth.2008.12.030
  19. Бутров А.В., Шевелев О.А., Петрова М.В. и др. «АТГ-01 (аппарат терапевтической гипотермии — 01)» у больных в критических состояниях: учебное пособие. М.: Медиамед, 2014. [Butrov A.V., ShevelevO.A., PetrovaM.V., et al. “ATG-01 (apparat terapevticheskoy gipotermii — 01)” ubolnikh v kriticheskikh sostoyaniyakh: uchebnoyeposobiye. M.: Mediamed, 2014. (In Russ)]
  20. Polderman K.H. Mechanisms of action, physiological effects, and complications of hypothermia. Crit. Care Med. 2009; 37(7 Suppl.): S186–S202. DOI: 10.1097/CCM.0b013e3181aa5241
  21. Van der Worp H.B., Sena E.S., Donnan G.A., et al. Hypotermia in animal models of acute ishaemic stroke: a systematic review and meta-analysis. Brain. 2007; 130(Pt 12): 3063–3074.
  22. Faridar A., Bershad E.M., Emiru T., et al. Therapeutic hypothermia in stroke and traumatic brain injury. Front. Neurol. 2011; 27(2): 80. DOI: 10.3389/fneur.2011.00080
  23. Каленова И.Е., Шаринова И.А., Шевелев О.А., Бутров А.В. Опыт применения терапевтической гипотермии в лечении ишемического инсульта. Неврология, нейропсихиатрия, психосоматика. 2012; 2: 41–45. DOI: 10.14412/2074-2711-2012-380 [Kalenova I.E., Sharinova I.A., Shevelev O.A., Butrov A.V. Opit primeneniya terapevticheskoy gipotermii v lechenii ishemicheskogo insulta. Nevrologiya, neyropsikhiatriya, psikhosomatika. 2012; 2: 41–45. (In Russ)]
  24. Абудеев С.А., Попугаев К.А., Кругляков Н.М. и др. Влияние гипотермии на напряжение кислорода в паренхиме головного мозга при аневризматическом субарахноидальном кровоизлиянии. Анестезиология и реаниматология. 2016; 61(2): 155–158. DOI: 10.18821/0201-7563-2016-61-2-155-158 [Abudeev S.A., Popugev K.A., Kruglyakov N.M., et al. Vliyaniye gipotermii na napryajeniye kisloroda v parenkhime golovnogo mozga pri anevrizmaticheskom subarakhnoidalnom kroovoizliyanii. Anesteziologiya I reanimatologiya. 2016; 61(2): 155–158. (In Russ)]
  25. Prasad K., Krishnan P.R. Fever is associated with doubling of odds of short-term mortality in ischemic stroke: an updated meta-analysis. Acta Neurol. Scand., 2010; 122(6): 404–408. DOI: 10.1111/j.1600-0404.2010.01326.x
  26. Broessner G., Beer R., Lackner P., et al. Endovascularly based, long-term normothermia in ICU patients with cerebrovascular disease. Stroke. 2009; 40(12): e657–e665. DOI: 10.1161/STROKEAHA.109.557652
  27. Lazzaro M.A., Prabhakaran S. Induced hypothermia in acute ischemic stroke. Expert Opin. Investig. Drugs. 2008; 17(8): 1161–1174. DOI: 10.1517/13543784.17.8.1161
  28. Pastukhov A., Krisanova N., Maksymenko V., Borisova T. Personalized approach in brain protection by hypothermia: individual changes in non-pathological and ischemia-related glutamate transport in brain nerve terminals. EPMA J. 2016; 7: 26. DOI: 10.1186/s13167-016-0075-1
  29. Hua C., Ju W., Jin H., et al. Molecular chaperones and hypoxic-ischemic encephalopathy. Neural. Regen. Res. 2017; 12(1): 153–160. DOI: 10.4103/1673–5374.199008
  30. Giraud R., Siegenthaler N., Bendjelid K. Cardiac index during therapeutic hypothermia: which target value is optimal? Crit. Care. 2013; 17(2): 214. DOI: 10.1186/cc12523
  31. Bergman R., van Zanten A.R., et al. Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest. Eur. J. Anaesthesiol. 2010; 27(4): 383–387. DOI: 10.1097/EJA.0b013e3283333a7d
  32. Arabi Y.M., Casaer M.P., Chapman M., et al. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med. 2017; 43(9): 1239–1256. DOI: 10.1007/s00134-017-4711-6
  33. Bergman R., van Zanten A.R., et al. Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest. Eur. J. Anaesthesiol. 2010; 27(4): 383–387. DOI: 10.1097/EJA.0b013e3283333a7d
  34. Leslie K., Bjorksten A.R., Ugoni A., Mitchell P. Mild core hypothermia and anesthetic requirement for loss of responsiveness during propofol anesthesia for craniotomy. Anesth. Analg., 2002; 94(5): 1298–1303.
  35. Martinello K., Hart A.R., Yap S., Mitra S., Robertson N.J. Management and investigation of neonatal encephalopathy: 2017 update. Arch. Dis. Child Fetal. Neonatal. Ed. 2017; 102(4): F346–F358. DOI: 10.1136/archdischild-2015-309639
  36. Perkins G.D., Olasveengen T.M., Maconochie I., et al. European Resuscitation Council Guidelines for Resuscitation: 2017 update. Resuscitation. 2018; 123: 43–50. DOI: 10.1016/j.resuscitation.2017.12.007
  37. Moler F.W., Silverstein F.S., Holubkov R., et al. THAPCA Trial Investigators. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. N. Engl. J. Med., 2017; 376(4): 318–329. DOI: 10.1056/NEJMoa1610493
  38. Crompton E.M., Lubomirova I., Cotlarciuc I., et al. Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients. Crit. Care Med., 2017; 45(4): 575–583. DOI: 10.1097/CCM.0000000000002205
  39. Puccio A.M., Fischer M.R., Jankowitz B.T.,et al. Induced normothermia attenuates intracranial hypertension and reduces fever burden after severe traumatic brain injury. Neurocrit. Care, 2009; 11(1): 82–87. DOI: 10.1007/s12028-009-9213-0
  40. Sydenham E., Roberts I., Alderson P. Hypothermia for traumatic head injury. Cochrane Database Syst. Rev. 2017; 9: CD001048. DOI: 10.1002/14651858.CD001048
  41. Cooper D.J., Nichol A.D., 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. DOI: 10.1001/jama.2018.17075
  42. Shoji Y., Hiroyuki Y. Targeted temperature management in traumatic brain injury. J. Intensive Care, 2016; 4: 28. DOI: 10.1186/s40560-016-0137-4
  43. Broderick J., Connolly S., Feldmann E., et al., American Heart Association/American Stroke Association Stroke Council; American Heart Association/American Stroke Association. High Blood Pressure Research Council. Quality of Care and Outcomes in Research Interdisciplinary Working Group. Circulation. 2007; 116(16): e391–e413.
  44. Zazulia A.R., Diringer M.N., Derdeyn C.P., Powers W.J. Progression of mass effect after intracerebral hemorrhage. Stroke. 1999; 30(6): 1167–1173.
  45. Venkatasubramanian C., Mlynash M., Finley-Caulfield A., et al. Natural History of Perihematomal Edema After Intracerebral Hemorrhage Measured by Serial Magnetic Resonance Imaging. Stroke. 2011; 42(1): 73–80. DOI: 10.1161/strokeaha.110.590646
  46. MacLellan C.L., Davies L.M., Fingas M.S., Colbourne F. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke. 2006; 37(5): 1266–1270.
  47. Gasser S., Khan N., Yonekawa Y., et al. Long-term hypothermia in patients with severe brain edema after poor-grade subarachnoid hemorrhage: feasibility and intensive care complications. J. Neurosurg. Anesthesiol. 2003; 15(3): 240–248.
  48. Kollmar R., Schellinger P.D., Steigleder T., et al. Ice-cold saline for the induction of mild hypothermia in patients with acute ischemic stroke: a pilot stud. Stroke. 2009; 40(5): 1907–1909. DOI: 10.1161/strokeaha.108.530410
  49. Georgiadis D., Schwarz S., Kollmar R., Schwab S. Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach. Stroke. 2009; 40(5): 1907–1909.
  50. Торосян Б.Д., Бутров А.В., Шевелев О.А. и др. Краниоцеребральная гипотермия — эффективное средство нейропротекции у пациентов с инфарктом мозга. Анестезиология и реаниматология, 2018; 3: 58–63. DOI: 10.17116/anaesthesiology201803158 [Torosyan B.D., Butrov A.V., Shevelev O.A., et al. Kraniocerebralnaya gipotermiya — effektivnoe sredstvo neyroprotekcii u pacientov s infarktom mozga. Anesteziologiya i reanimatologiya. 2018; 3: 58–63. (In Russ)]
  51. Winkel P., Bath P.M., Gluud C., et al. EuroHYP-1 trial investigators. Statistical analysis plan for the EuroHYP-1 trial: European multicentre, randomised, phase III clinical trial of the therapeutic hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke. 2017; 18(1): 573. DOI: 10.1186/s13063-017-2302-z