Skip to main content
SpringerLink
Log in

Therapeutic Hypothermia in Acute Ischemic Stroke—a Systematic Review and Meta-Analysis

Current Neurology and Neuroscience Reports volume 20, Article number: 13 (2020) Cite this article

Abstract

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.

Recent Findings

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).

Summary

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.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 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.

    CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. 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.

    Article  Google Scholar 

  5. 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.

    Article  Google Scholar 

  6. 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.

    Article  Google Scholar 

  7. 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.

    Article  Google Scholar 

  8. 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.

    Article  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res. 1994;654:265–72.

    Article  CAS  Google Scholar 

  12. 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.

    Article  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. 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.

    Article  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  Google Scholar 

  18. 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

  19. 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.

  20. 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.

    Article  Google Scholar 

  21. 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.

    Article  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. 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.

  25. 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.

    Article  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. 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.

    PubMed  PubMed Central  Google Scholar 

  29. Luscombe M, Andrzejowski JC. Clinical applications of induced hypothermia. Contin Educ Anaesth Crital Care Pain. 2006;6:23–7.

    Article  Google Scholar 

  30. Choi HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury--mechanisms and practical aspects. Nat Rev Neurol. 2012;8:214–22.

    Article  CAS  Google Scholar 

  31. 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.

    Article  CAS  Google Scholar 

  32. 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.

    Article  Google Scholar 

  33. 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.

  34. 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;

  35. 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.

  36. 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.

    Article  Google Scholar 

  37. 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.

    Article  Google Scholar 

  38. 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.

    Article  Google Scholar 

  39. 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.

    Article  Google Scholar 

  40. 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.

    Article  CAS  Google Scholar 

Download references

Acknowledgment

A.M.K. receives funding from the Alberta Innovates—Health Solutions MD/PhD studentship.

Author information

Authors and Affiliations

  1. Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Andrea M Kuczynski, Sina Marzoughi, Abdulaziz S. Al Sultan, Bijoy K. Menon, Mayank Goyal, Andrew M. Demchuk & Mohammed A. Almekhlafi

  2. Department of Psychology, University of Alberta, Edmonton, AB, Canada

    Frederick Colbourne

  3. Department of Clinical Neurosciences, Hotchkiss Brain Institute, Calgary, AB, Canada

    Bijoy K. Menon, Andrew M. Demchuk & Mohammed A. Almekhlafi

  4. Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands

    Adriaan C. G. M. van Es

  5. Alembic, LLC, Mountain View, CA, 94043, USA

    Aaron L. Berez

  6. Department of Radiology, University of Calgary, Calgary, AB, Canada

    Mayank Goyal

Authors
  1. Andrea M Kuczynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sina Marzoughi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdulaziz S. Al Sultan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frederick Colbourne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bijoy K. Menon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adriaan C. G. M. van Es
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aaron L. Berez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mayank Goyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrew M. Demchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mohammed A. Almekhlafi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammed A. Almekhlafi.

Ethics declarations

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.

Additional information

Publisher’s Note

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

ESM 1

(DOC 64 kb)

Supplementary Figure1

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)

ESM 2

(DOCX 58 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-020-01029-3

Keywords

search

Navigation