Opinion statement
In the past two decades, there has been much focus on the adverse effect of fever on neurologic outcome, the benefits of hypothermia on functional outcomes, and the interplay of associated complications. Despite decades of experience regarding randomized, safety and feasibility, case-controlled, retrospective studies, there has yet to be a large, randomized, multicenter, clinical trial with the appropriate power to address the potential benefits of targeted temperature modulation compared to hypothermia alone. What remains unanswered is the appropriate timing of initiation, duration, rewarming speed, and depth of targeted temperature management. We learn from the cardiac arrest literature that there is a neuroprotective value to hypothermia and, most recently, near normothermia (36 °C) as well. We have also established that increased depths of cooling are associated with increases in shivering, which warrant more aggressive pharmacologic management. Normothermia also has the advantage of allowing for more rapid clearance of sedating medications and less confounding of neuroprognostication. More difficult to quantify is the increased nursing and patient care complexity associated with moderate hypothermia compared to normothermia. It remains crucial, for those patients who are being considered for hypothermia/normothermia, to be cared for in an experienced ICU, driven under protocol, with aggressive shivering management and an expectation and acceptance of the complications associated with targeted temperature management. If targeted temperature management is not of consideration, then aggressive fever control should be undertaken pharmacologically and non-invasively, as they have been shown to be safe.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: ••Of major importance
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):3029–35. doi:10.1161/STROKEAHA.108.521583.
•• Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33degreeC versus 36degreeC after cardiac arrest. N Engl J Med. 2013;369(23):2197–206. This paper established that mild hypothermia is equally as neuroprotective compared to deeper hypothermia.
Group TH after CAS. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56. doi:10.1056/NEJMoa012689.
Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63. doi:10.1056/NEJMoa003289.
Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947. doi:10.1161/STR.0b013e318284056a.
Sulter G, Elting JW, Maurits N, Luijckx GJ, Luyckx GJ, De Keyser J. Acetylsalicylic acid and acetaminophen to combat elevated body temperature in acute ischemic stroke. Cerebrovasc Dis. 2004;17(2–3):118–22. doi:10.1159/000075779.
Dippel DW, van Breda EJ, van Gemert HM, et al. Effect of paracetamol (acetaminophen) on body temperature in acute ischemic stroke: a double-blind, randomized phase II clinical trial. Stroke. 2001;32(7):1607–12. http://www.ncbi.nlm.nih.gov/pubmed/11441208. Accessed 22 Aug 2016.
Kasner SE, Wein T, Piriyawat P, et al. Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial. Stroke. 2002;33(1):130–4. http://www.ncbi.nlm.nih.gov/pubmed/11779901. Accessed 22 Aug 2016.
den Hertog HM, van der Worp HB, van Gemert HMA, et al. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol. 2009;8(5):434–40. doi:10.1016/S1474-4422(09)70051-1.
Georgiadis D, Schwarz S, Aschoff A, Schwab S. Hemicraniectomy and moderate hypothermia in patients with severe ischemic stroke. Stroke. 2002;33(6):1584–8. http://www.ncbi.nlm.nih.gov/pubmed/12052995. Accessed 22 Aug 2016.
Milhaud D, Thouvenot E, Heroum C, Escuret E. Prolonged moderate hypothermia in massive hemispheric infarction: clinical experience. J Neurosurg Anesthesiol. 2005;17(1):49–53. http://www.ncbi.nlm.nih.gov/pubmed/15632543. Accessed 22 Aug 2016.
Den Hertog HM, van der Worp HB, Tseng M-C, Dippel DW. Cooling therapy for acute stroke. Cochrane Database Syst Rev. 2009;1, CD001247. doi:10.1002/14651858.CD001247.pub2.
Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015;46(7):2032–60. doi:10.1161/STR.0000000000000069.
Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(6):1711–37. doi:10.1161/STR.0b013e3182587839.
Diringer MN, Bleck TP, Hemphill JC, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the neurocritical care society’s multidisciplinary consensus conference. Neurocrit Care. 2011;15(2):211–40. doi:10.1007/s12028-011-9605-9.
Schmutzhard E, Fischer M, Dietmann A, Brössner G. Therapeutic hypothermia: the rationale. Crit Care. 2012;16(Sppl 2):A2. doi:10.1186/cc11260.
Kochanek KD, Xu J, Murphy SL, Minino AM, Kung H-C. National vital statistics reports deaths: final data for 2009. Natl Cent Heal Stat. 2012;60(3):1–117.
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. 2015;131. doi:10.1161/CIR.0000000000000152.
Leira R, Dávalos A, Silva Y, et al. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology. 2004;63(3):461–7. http://www.ncbi.nlm.nih.gov/pubmed/15304576. Accessed 16 Aug 2016.
Schwarz S, Häfner K, Aschoff A, Schwab S. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology. 2000;54(2):354–61. http://www.ncbi.nlm.nih.gov/pubmed/10668696. Accessed 22 Aug 2016.
Rincon F, Lyden P, Mayer SA. Relationship between temperature, hematoma growth, and functional outcome after intracerebral hemorrhage. Neurocrit Care. 2013;18(1):45–53. doi:10.1007/s12028-012-9779-9.
Reith J, Jørgensen HS, Pedersen PM, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet (London, England). 1996;347(8999):422–5. http://www.ncbi.nlm.nih.gov/pubmed/8618482. Accessed 23 Aug 2016.
Kammersgaard LP, Jorgensen HS, Rungby JA, et al. Admission body temperature predicts long-term mortality after acute stroke: the Copenhagen Stroke Study. Stroke. 2002;33(7):1759–62. doi:10.1161/01.STR.0000019910.90280.F1.
Prasad K, Krishnan PR. Fever is associated with doubling of odds of short-term mortality in ischemic stroke: an updated meta-analysis. Acta Neurol Scand. 2010;122(6):404–8. doi:10.1111/j.1600-0404.2010.01326.x.
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(7):1083–9. doi:10.1038/jcbfm.2013.52.
de Ridder I, den Hertog H, van Gemert M, Dippel D, van der Worp B. Increased benefit of alteplase in patients with ischemic stroke and a high body temperature. Cerebrovasc Dis. 2013;35(1):60–3. doi:10.1159/000345335.
Oliveira-Filho J, Ezzeddine MA, Segal AZ, et al. Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome. Neurology. 2001;56(10):1299–304. doi:10.1212/WNL.56.10.1299.
Fernandez A, Schmidt JM, Claassen J, et al. Fever after subarachnoid hemorrhage: risk factors and impact on outcome. Neurology. 2007;68:1013–9.
Naidech AM, Bendok BR, Bernstein RA, et al. Fever burden and functional recovery after subarachnoid hemorrhage. Neurosurgery. 2008;63(2):212–7. doi:10.1227/01.NEU.0000320453.61270.0F.
Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Severe middle cerebral artery infarction. 1998.
Schwab S, Georgiadis D, Berrouschot J, et al. Massive hemispheric infarction. 2001;(C):2033–5.
Krieger DW, Georgia MA De, Abou-chebl A, et al. An open pilot study of induced hypothermia in acute ischemic stroke. 2001.
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(2):312–7. doi:10.1212/01.WNL.0000129840.66938.75.
Guluma KZ, Oh H, Yu SW, Meyer BC, Rapp K, Lyden PD. Effect of endovascular hypothermia on acute ischemic edema: morphometric analysis of the ICTuS trial. Neurocrit Care. 2008;8(1):42–7. doi:10.1007/s12028-007-9009-z.
Hemmen TM, Raman R, Guluma KZ, et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010;41(10):2265–70. doi:10.1161/STROKEAHA.110.592295.
Horn CM, Sun C-HH, Nogueira RG, et al. Endovascular reperfusion and cooling in cerebral acute ischemia (ReCCLAIM I). J Neurointerv Surg. 2014;6(2):91–5. doi:10.1136/neurintsurg-2013-010656.
Su Y, Fan L, Zhang Y, et al. Improved neurological outcome with mild hypothermia in surviving patients with massive cerebral hemispheric infarction. Stroke. 2016;47(2):457–63. doi:10.1161/strokeaha.115.009789.
Lakhan SE, Pamplona F. Application of mild therapeutic hypothermia on stroke: a systematic review and meta-analysis. Stroke Res Treat. 2012;2012. doi:10.1155/2012/295906.
Mendez AL, Uceda MP. Therapeutic hypothermia for ischemic stroke: a systematic review and meta-analysis. Emergencias. 2014;26(2):138–46. <Go to ISI>://WOS:000333001900011.
Wan YH, Nie C, Wang HL, Huang CY. Therapeutic hypothermia (different depths, durations, and rewarming speeds) for acute ischemic stroke: a meta-analysis. J Stroke Cerebrovasc Dis. 2014;23(10):2736–47. doi:10.1016/j.jstrokecerebrovasdis.2014.06.017.
Li LR, You C, Chaudhary B. Intraoperative mild hypothermia for postoperative neurological deficits in intracranial aneurysm patients. Cochrane Database Syst Rev. 2012;2(2), CD008445. doi:10.1002/14651858.CD008445.pub2.
Seule MA, Muroi C, Mink S, Yonekawa Y, Keller E. Therapeutic hypothermia in patients with aneurysmal subarachnoid hemorrhage, refractory intracranial hypertension, or cerebral vasospasm. Neurosurgery. 2009;64(1):86–92. doi:10.1227/01.NEU.0000336312.32773.A0. discussion 92–93.
Seule M, Keller E, Feigin V, et al. Hypothermia after aneurysmal subarachnoid hemorrhage. Crit Care. 2012;16 Suppl 2:A16. doi:10.1186/cc11274.
Seule M, Muroi C, Sikorski C, Hugelshofer M, Winkler K, Keller E. Therapeutic hypothermia reduces middle cerebral artery flow velocity in patients with severe aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2014;20(2):255–62. doi:10.1007/s12028-013-9927-x.
Andrews PJD, Sinclair HL, Rodriguez A, et al. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med. 2015;373(25):2403–12. doi:10.1056/NEJMoa1507581.
Wu T-C, Grotta JC. Hypothermia for acute ischaemic stroke. Lancet Neurol. 2013;12(3):275–84. doi:10.1016/S1474-4422(13)70013-9.
Badjatia N, Strongilis E, Gordon E, et al. Metabolic impact of shivering during therapeutic temperature modulation: the bedside shivering assessment scale. Stroke. 2008;39(12):3242–7. doi:10.1161/STROKEAHA.108.523654.
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(1):10–6. doi:10.1007/s12028-009-9280-2.
Choi HA, Ko SB, Presciutti M, et al. Prevention of shivering during therapeutic temperature modulation: the Columbia anti-shivering protocol. Neurocrit Care. 2011;14(3):389–94. doi:10.1007/s12028-010-9474-7.
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):e657–65. doi:10.1161/STROKEAHA.109.557652.
•• Fischer M, Lackner P, Beer R, et al. Cooling activity is associated with neurological outcome in patients with severe cerebrovascular disease undergoing endovascular temperature control. Neurocrit Care. 2015;23(2):205–9. doi:10.1007/s12028-015-0122-0. This post-hoc analysis of the 2009 Broessner study illustrates the importance of fever prevention on favorable outcomes as seen with higher cooling activity to maintain normothermia at 36.5°C.
Kammersgaard L, Rasmussen B, Jørgensen H. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a case–control study the Copenhagen stroke. Stroke. 2000. http://stroke.ahajournals.org/content/31/9/2251.short.
Els T, Oehm E, Voigt S, Klisch J, Hetzel A, Kassubek J. Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis. 2006;21(1–2):79–85. doi:10.1159/000090007.
Piironen K, Tiainen M, Mustanoja S, et al. Mild hypothermia after intravenous thrombolysis in patients with acute stroke a randomized controlled trial. Stroke. 2014;45(2):486–91. doi:10.1161/STROKEAHA.113.003180.
Kollmar R, Staykov D, Dörfler A, Schellinger PD, Schwab S, Bardutzky J. Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage. Stroke. 2010;41(8):1684–9. doi:10.1161/STROKEAHA.110.587758.
Staykov D, Schwab S, Dörfler A. Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage: but does it influence functional outcome and mortality? Ther Hypothermia Temp Manag. 2011;1(2):105–6. doi:10.1089/ther.2011.0004.
•• Rainer Kollmar SSDS. Therapeutic hypothermia decreases growth of perihemorrhagic edema and prevents critical increase of intracranial pressure in large intracerebral haemorrhage. Crit Care. 2012;16 Suppl 2:A14. doi:10.1186/CC11272. Promising results showing lack prevention of edema formation and no ICP crisis or deaths in ICH patients using mild hypothermia.
Lord AS, Karinja S, Lantigua H, et al. Therapeutic temperature modulation for fever after intracerebral hemorrhage. Neurocrit Care. 2014;21(2):200–6. doi:10.1007/s12028-013-9948-5.
Badjatia N, Fernandez L, Schmidt JM, et al. Impact of induced normothermia on outcome after subarachnoid hemorrhage: a case–control study. Neurosurgery. 2010;66(4):696–700. doi:10.1227/01.NEU.0000367618.42794.AA.
Lyden PD, Hemmen TM, Grotta J, Rapp K, Raman R. Endovascular therapeutic hypothermia for acute ischemic stroke: ICTuS 2/3 protocol. Int J Stroke. 2014;9(1):117–25. doi:10.1111/ijs.12151.
de Ridder IR, de Jong FJ, den Hertog HM, et al. Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36.5 d. Int J Stroke. 2015;10(3):457–62. doi:10.1111/ijs.12053.
van der Worp HB, Macleod MR, Bath PM, et al. 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(5):642–5. doi:10.1111/ijs.12294.
Kollmar R, Juettler E, Huttner HB, et al. Cooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German-Austrian clinical trial. Int J Stroke. 2012;7(2):168–72. doi:10.1111/j.1747-4949.2011.00707.x.
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(5):646–51. doi:10.1111/ijs.12220.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Critical Care Neurology
Rights and permissions
About this article
Cite this article
Marehbian, J., Greer, D.M. Normothermia and Stroke. Curr Treat Options Neurol 19, 4 (2017). https://doi.org/10.1007/s11940-017-0437-6
Published:
DOI: https://doi.org/10.1007/s11940-017-0437-6