Purpose of Review
Therapeutic hypothermia (TH) in stroke demonstrates robust neuroprotection in animals but clinical applications remain controversial. We assessed current literature on the efficacy of TH in ischemic stroke.
We conducted a meta-analysis comparing TH versus controls in studies published until June 2019. Controlled studies reporting on ≥ 10 adults with acute ischemic stroke were included. Primary outcome was functional independence (modified Rankin Scale [mRS] ≤ 2). Twelve studies (n = 351 TH, n = 427 controls) were included. Functional independence did not differ between groups (RR 1.17, 95% CI 0.93–1.46, random-effects p = 0.2). Five studies reported individual mRS outcomes and demonstrated a shift toward better outcome with TH (unadjusted cOR 1.57, 95% CI 1.01–2.44, p = 0.05). Overall complications were higher with TH (RR 1.18, 95% CI 1.06–1.32, p < 0.01).
We did not observe an overall beneficial effect of TH in this analysis although some studies showed a shift toward better outcome. TH was associated with increased complications.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance
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;4:189–225.
Karibe H, Chen J, Zarow GJ, Graham SH, Weinstein PR. Delayed induction of mild hypothermia to reduce infarct volume after temporary middle cerebral artery occlusion in rats. J Neurosurg. 1994;80:112–9.
van der Worp HB, Macleod MR, Kollmar R. Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab. 2010;30:1079.
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 J Neurol. 2007;130:3063–74.
Clark DL, Penner M, Wowk S, Orellana-Jordan I, Colbourne F. Treatments (12 and 48 h) with systemic and brain-selective hypothermia techniques after permanent focal cerebral ischemia in rat. Exp Neurol. 2009;220:391–9.
Kuczynski AM, Demchuk AM, Almekhlafi MA. Therapeutic hypothermia: applications in adults with acute ischemic stroke. Brain Circ. 2019;5:43–54 This study provides a thorough and up-to-date review of therapeutic hypothermia in the literature.
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–63.
Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–56.
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet Lond Engl. 2005;365:663–70.
Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165:692–700.
Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res. 1994;654:265–72.
Bi M, Ma Q, Zhang S, Li J, Zhang Y, Lin L, et al. Local mild hypothermia with thrombolysis for acute ischemic stroke within a 6-h window. Clin Neurol Neurosurg. 2011;113:768–73.
Poli S, Purrucker J, Priglinger M, Diedler J, Sykora M, Popp E, et al. Induction of cooling with a passive head and neck cooling device: effects on brain temperature after stroke. Stroke. 2013;44:708–13.
Wang C-H, Lin Y-T, Chou H-W, Wang Y-C, Hwang J-J, Gilbert JR, et al. Novel approach for independent control of brain hypothermia and systemic normothermia: cerebral selective deep hypothermia for refractory cardiac arrest. J Neurointerventional Surg. 2017;9:e32.
Chen J, Liu L, Zhang H, Geng X, Jiao L, Li G, et al. Endovascular hypothermia in acute ischemic stroke: pilot study of selective intra-arterial cold saline infusion. Stroke. 2016;47:1933–5.
Wu C, Zhao W, An H, Wu L, Chen J, Hussain M, et al. Safety, feasibility, and potential efficacy of intraarterial selective cooling infusion for stroke patients treated with mechanical thrombectomy. J Cereb Blood Flow Metab. 2018;38:2251. https://doi.org/10.1177/0271678X18790139This study is a large and recent trial of selective hypothermia in ischemic stroke.
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.
Higgins J, Green S. Cochrane Risk of Bias Tool for Randomized Controlled Trials. Cochrane Handb Syst Rev Interv [Internet]. 5.1.0. 2011 [cited 2018 Nov 8]. Available from: www.handbook.cochrane.org
Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis. [Internet]. 2011 [cited 2018 Nov 8]. Available from: www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
Hong JM, Lee JS, Song H-J, Jeong HS, Jung H-S, Choi HA, et al. Therapeutic hypothermia after recanalization in patients with acute ischemic stroke. Stroke. 2014;45:134–40.
Geurts M, Petersson J, Brizzi M, Olsson-Hau S, Luijckx G-J, Algra A, et al. COOLIST (cooling for ischemic stroke trial): a multicenter, open, randomized, phase II, Clinical Trial. Stroke. 2017;48:219–21.
Krieger DW, De Georgia MA, Abou-Chebl A, Andrefsky JC, Sila CA, Katzan IL, et al. Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke. 2001;32:1847–54.
Piironen K, Tiainen M, Mustanoja S, Kaukonen K-M, Meretoja A, Tatlisumak T, et al. Mild hypothermia after intravenous thrombolysis in patients with acute stroke: a randomized controlled trial. Stroke. 2014;45:486–91.
van der Worp HB, Macleod M, Bath PM, Bathula R, Christensen H, Colam B, et al. Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial. Eur stroke J. 2019; Most recent randomized controlled trial of therapeutic hypothermia in ischemic stroke.
De Georgia MA, Krieger DW, Abou-Chebl A, Devlin TG, Jauss M, Davis SM, et al. Cooling for acute ischemic brain damage (COOL AID): a feasibility trial of endovascular cooling. Neurology. 2004;63:312–7.
Lyden P, Hemmen T, Grotta J, Rapp K, Ernstrom K, Rzesiewicz T, et al. Results of the ICTuS 2 trial (intravascular cooling in the treatment of stroke 2). Stroke. 2016;47:2888–95.
Ovesen C, Brizzi M, Pott FC, Thorsen-Meyer HC, Karlsson T, Ersson A, et al. Feasibility of endovascular and surface cooling strategies in acute stroke. Acta Neurol Scand. 2013;127:399–405.
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;6:1–8.
Luscombe M, Andrzejowski JC. Clinical applications of induced hypothermia. Contin Educ Anaesth Crital Care Pain. 2006;6:23–7.
Choi HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury--mechanisms and practical aspects. Nat Rev Neurol. 2012;8:214–22.
Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke. 2001;32:2033–5.
Esposito E, Ebner M, Ziemann U, Poli S. In cold blood: intraarteral cold infusions for selective brain cooling in stroke. J Cereb Blood Flow Metab. 2014;34:743–52 Landmark review supporting the benefit of local hypothermia in animal models.
Zhao J, Mu H, Liu L, Jiang X, Wu D, Shi Y, et al. Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury. J Cereb Blood Flow Metab. 2018; 271678X18808174.
Assis FR, Bigelow MEG, Chava R, Sidhu S, Kolandaivelu A, Halperin H, et al. Efficacy and safety of transnasal coolStat cooling device to induce and maintain hypothermia. Ther Hypothermia Temp Manag. 2018;
King R, Mitchell J, Brooks O, Abou-Chebl A, Merrill TL, Gounis M, et al. Focal cooling through a novel insulated catheter allows fast and safe therapeutic hypothermia in a canine ischemic stroke model. 2018.
Abou-Chebl A, Sung G, Barbut D, Torbey M. Local brain temperature reduction through intranasal cooling with the RhinoChill device: preliminary safety data in brain-injured patients. Stroke. 2011;42:2164–9.
Castrén M, Nordberg P, Svensson L, Taccone F, Vincent J-L, Desruelles D, et al. Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation. 2010;122:729–36.
Poli S, Purrucker J, Priglinger M, Sykora M, Diedler J, Rupp A, et al. Safety evaluation of nasopharyngeal cooling (RhinoChill®) in stroke patients: an observational study. Neurocrit Care. 2014;20:98–105.
Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010;41:2265–70.
Kammersgaard LP, Rasmussen BH, Jørgensen HS, Reith J, Weber U, Olsen TS. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a case-control study: the Copenhagen stroke study. Stroke. 2000;31:2251–6.
A.M.K. receives funding from the Alberta Innovates—Health Solutions MD/PhD studentship.
Conflict of Interest
The authors declare that they have no conflict 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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Stroke
Electronic Supplementary Material
(DOC 64 kb)
Funnel plot of the 14 studies of TH in acute ischemic stroke. Each grey circle on the plot represents an individual study in the meta-analysis. The two diagonal lines represent the expected distribution of studies while the horizontal line indicates the log of the pooled odds ratio (PDF 117 kb)
(DOCX 58 kb)
About this article
Cite this article
Kuczynski, A.M., Marzoughi, S., Al Sultan, A.S. et al. Therapeutic Hypothermia in Acute Ischemic Stroke—a Systematic Review and Meta-Analysis. Curr Neurol Neurosci Rep 20, 13 (2020). https://doi.org/10.1007/s11910-020-01029-3