Published 2019-05-02
Keywords
- ischemic stroke,
- general hypothermia,
- selective cerebral hypothermia,
- neuroprotection
How to Cite
Copyright (c) 2019 Fartakov E. I., Tarkova A. R., Kretov E. I., Lomivorotov V. V., Zykov I. S.

This work is licensed under a Creative Commons Attribution 4.0 International License.
Abstract
Today the Russian Federation has one of the worst indicators in the world in terms of morbidity and mortality from stroke. Currently, two methods are used to treat ischemic stroke: thrombolysis and thrombextraction. However, despite their effectiveness, the methods have limited use due to the presence of strict indications and contraindications. In this regard, the search for new methods of treating ischemic stroke, which can be effective both with independent use and as an addition to already existing methods, is an urgent task. The purpose of this paper is to review research studies on the use of hypothermia in ischemic stroke. Hypothermia has a proven neuroprotective effect in cerebral ischemia. In this context, interest is the method of intracarotid selective cerebral hypothermia, which, according to a number of preclinical studies, significantly reduces the volume of cerebral infarction after ischemic stroke. The advantage of this method is the rapid achievement of the target temperature, a targeted effect on the brain and a minimal effect on the system temperature. Thus, intracarotid selective cerebral hypothermia is a very promising method for the treatment of ischemic stroke and deserves further study. In this regard, the authors decided to conduct a preclinical study on this subject.
Received 9 October 2018. Revised 25 January 2019. Accepted 30 January 2019. Published online 11 March 2019.
Funding: The work was funded by the Russian Foundation for Basic Research (grant No. 18-415-540025).
Conflict of interest: Authors declare no conflict of interest.
ORCID ID
E.I. Fartakov, https://orcid.org/0000-0002-1847-7291
A.R. Tarkova, http://orcid.org/0000-0002-4291-6047
E.I. Kretov, http://orcid.org/0000-0002-7109-9074
V.V. Lomivorotov, https://orcid.org/0000-0001-8591-6461
I.S. Zykov, http://orcid.org/0000-0001-6253-9026
References
- Kim A.S., Cahill E., Cheng N.T. Global stroke belt: geographic variation in stroke burden worldwide. Stroke. 2015;46(12):3564-70. PMID: 26486867. http://dx.doi.org/10.1161/STROKEAHA
- Emberson J., Lees K.R., Lyden P., Blackwell L., Albers G., Bluhmki E., Brott T., Cohen G., Davis S., Donnan G., Grotta J., Howard G., Kaste M., Koga M., von Kummer R., Lansberg M., Lindley R.I., Murray G., Olivot J.M., Parsons M., Tilley B., Toni D., Toyoda K., Wahlgren N., Wardlaw J., Whiteley W., del Zoppo G.J., Baigent C., Sandercock P., Hacke W.; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomized trials. Lancet. 2014;384(9958):1929-35. PMID: 25106063, PMCID: PMC4441266. http://dx.doi.org/10.1016/S0140-6736(14)60584-5
- Boode B., Welzen V., Franke C., van Oostenbrugge R. Estimating the number of stroke patients eligible for thrombolytic treatment if delay could be avoided. Cerebrovasc Diseases. 2007;23(4):294-8. PMID: 17199087. http://dx.doi.org/10.1159/000098330
- Powers W.J., Rabinstein A.A., Ackerson T., Adeoye O.M., Bambakidis N.C., Becker K., Biller J., Brown M., Demaerschalk B.M., Hoh B., Jauch E.C., Kidwell C.S., Leslie-Mazwi T.M., Ovbiagele B., Scott P.A., Sheth K.N., Southerland A.M., Summers D.V., Tirschwell D.L.; American Heart Association Stroke Council. 2018 guidelines for the early management of patients with acute ischemic stroke. Stroke. 2018;49(3):e46-e110. PMID: 29367334. http://dx.doi.org/10.1161/STR.0000000000000158
- Saver J.L., Goyal M., Bonafe A., Diener H.C., Levy E.I., Pereira V.M., Albers G.W., Cognard C., Cohen D.J., Hacke W., Jansen O., Jovin T.G., Mattle H.P., Nogueira R.G., Siddiqui A.H., Yavagal D.R., Baxter B.W., Devlin T.G., Lopes D.K., Reddy V.K., du Mesnil de Rochemont R., Singer O.C., Jahan R.; SWIFT PRIME Investigators. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285-95. PMID: 25882376. http://dx.doi.org/10.1056/NEJMoa1415061
- McMeekin P., White P., James M.A., Price C.I., Flynn D., Ford G.A. Estimating the number of UK stroke patients eligible for endovascular thrombectomy. Eur Stroke J. 2017;2(4):319-326. http://dx.doi.org/10.1177/2396987317733343.
- Nogueira R.G., Jadhav A.P., Haussen D.C., Bonafe A., Ronald F. Budzik, M.D., Bhuva P., Yavagal D.R., Ribo M., Cognard C., Hanel R.A., Sila C.A., Hassan A.E., for the DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. New Engl J Med. 2018;378:11-21. http://dx.doi.org/10.1056/NEJMoa1706442
- Albers G.W., Marks M.P., Kemp S., Christensen S., Tsai J.P., Ortega-Gutierrez S., McTaggart R.A., Torbey M.T., Kim-Tenser M., Leslie-Mazwi T., Sarraj A., Kasner S.E., Ansari S.A., Yeatts S.D., Hamilton S., Mlynash M., Heit J.J., Zaharchuk G., Kim S., Carrozzella J., Palesch Y.Y., Demchuk A.M., Bammer R., Lavori P.W., Broderick J.P., Lansberg M.G.; DEFUSE 3 Investigators. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. New Engl J Med. 2018;378(8):708-18. http://dx.doi.org/10.1056/NEJMoa1713973.
- Jovin T.G., Demchuk A.M., Gupta R. Pathophysiology of acute ischemic stroke. Continuum Lifelong Learning Neurol. 2008;14(6):28-45. http://dx.doi.org/10.1212/01.CON.0000275639.07451.e7
- Boysen G. Cerebral blood flow measurement as a safeguard during carotid endarterectomy. Stroke. 1971;2(1):1-10. PMID: 5112002.
- Jennett W.B., Harper A.M., Gillespie F.C. Measurement of regional cerebral blood-flow during carotid ligation. Lancet. 1966;2(7474):1162-3. PMID: 4162546.
- Jones T.H., Morawetz R.B., Crowell R.M., Marcoux F.W., FitzGibbon S.J., DeGirolami U., Ojemann R.G. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg. 1981;54(6):773-82. PMID: 7241187. http://dx.doi.org/10.3171/jns.1981.54.6.0773
- Astrup J., Siesjo B.K., Symon L. Thresholds in cerebral ischemia - the ischemic penumbra. Stroke. 1981;12(6):723-5. PMID: 6272455.
- Mergenthaler P., Dirnagl U., Meisel A. Pathophysiology of stroke: lessons from animal models. Metab Brain Dis. 2004;19(3-4):151-67. PMID: 15554412.
- Yenari M., Kitagawa K., Lyden P., Perez-Pinzon M. Metabolic downregulation: a key to successful neuroprotection? Stroke. 2008;39(10):2910-7. http://dx.doi.org/10.1161/STROKEAHA.108.514471
- Kurisu K., Yenari M.A. Therapeutic hypothermia for ischemic stroke; pathophysiology and future promise. Neuropharmacology. 2017;134(Pt B):302-309. PMID: 28830757. http://dx.doi.org/10.1016/j.neuropharm.2017.08.025
- Kurisu K., Abumiya T., Nakamura H., Shimbo D., Shichinohe H., Nakayama N., Kazumata K., Shimizu H., Houkin K. Transarterial regional brain hypothermia inhibits acute Aquaporin-4 surge and sequential microvascular events in ischemia/reperfusion injury. Neurosurgery. 2016;79(1):125-34. PMID: 26516820. http://dx.doi.org/10.1227/NEU.0000000000001088
- Yenari M.A., Han H.S. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat. Rev. Neurosci. 2012;13(4):267-78. PMID: 22353781. http://dx.doi.org/10.1038/nrn3174
- Perrone S., Szabo M., Bellieni C.V., Longini M., Bango M., Kelen D., Treszl A., Negro S., Tataranno M.L., Buonocore G. Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury. Pediatr Neurol. 2010;43(4):236-40. PMID: 20837300. http://dx.doi.org/10.1016/j.pediatrneurol.2010.05.009
- Deng H., Han H.S., Cheng D., Sun G.H., Yenari M.A. Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation. Stroke. 2003;34(10):2495-501. PMID: 12970518. http://dx.doi.org/10.1161/01.STR.0000091269.67384.E7
- Wang Q., Tang X.N., Yenari M.A. The inflammatory response in stroke. J Neuroimmunol. 2007;184(1-2):53-68. PMID: 17188755, PMCID: PMC1868538. http://dx.doi.org/10.1016/j.jneuroim.2006.11.014
- Terao Y., Ohta H., Oda A., Nakagaito Y., Kiyota Y., Shintani Y. Macrophage inflammatory protein-3alpha plays a key role in the inflammatory cascade in rat focal cerebral ischemia. Neurosci Res. 2009;64(1):75-82. PMID: 19428685. http://dx.doi.org/10.1016/j.neures.2009.01.017
- Lee J.E., Yoon Y.J., Moseley M.E., Yenari M.A. Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke. J Neurosurg. 2005;103(2):289-97. PMID: 16175859. http://dx.doi.org/10.3171/jns.2005.103.2.0289
- Baumann E., Preston E., Slinn J., Stanimirovic D. Post-ischemic hypothermia attenuates loss of the vascular basement membrane proteins, agrin and SPARC, and the blood-brain barrier disruption after global cerebral ischemia. Brain Res. 2009;1269:185-97. PMID: 19285050. http://dx.doi.org/10.1016/j.brainres.2009.02.062
- Therapeutic hypothermia. Mayer S.A., Sessler D.I., editors. New York: Marcel Dekker; 2005. 629 p.
- Ломивотротов В.В., Чернявский А. М., Князькова Л.Г., Могутнова Т. А., Постнов В. Г., Захаров С.Л. Ретроградная перфузия головного мозга как компонент противоишемической защиты головного мозга при реконструктивных операциях на дуге аорты. Патология кровообращения и кардиохирургия. 2010;14(1):44-48. [Lomivorotov V.V., Chernyavsky A.M., Knyazkova L.G., Postnov V.G., Zakharov S.L. Retrograde cerebral perfusion as a component protection of the brain during reconstructive operations on the aortic arch. Patologiya krovoobrashcheniya i kardiokhirurgiya = Circulation Pathology and Cardiac Surgery. 2010;14(1):44-48. (In Russ.)
- Ломиворотов В.Н. Гипотермическая защита мозга в кардиохирургии. Патология кровообращения и кардиохирургия. 2010;13(3):7-10.
- Shankaran S., Laptook A.R., Ehrenkranz R.A., Tyson J.E., McDonald S.A., Donovan E.F., Fanaroff A.A., Poole W.K., Wright L.L., Higgins R.D., Finer N.N., Carlo W.A., Duara S., Oh W., Cotten C.M., Stevenson D.K., Stoll B.J., Lemons J.A., Guillet R., Jobe A.H.; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. N Engl J Med. 2012;353(15):1574-84. PMID: 16221780. http://dx.doi.org/10.1056/NEJMcps050929
- Johnston M.V., Fatemi A., Wilson M.A., Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol. 2011;10(4):372-82. PMID: 21435600, PMCID: PMC3757153. http://dx.doi.org/10.1016/S1474-4422(11)70016-3
- Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. New Engl J Med. 2002;346(8):549-56. PMID: 11856793. http://dx.doi.org/10.1056/NEJMoa012689
- Bernard S.A., Gray T.W., Buist M.D., Jones B.M., Silvester W., Gutteridge G., Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. New Engl J Med. 2002;346:557-63. http://dx.doi.org/10.1056/NEJMoa003289
- De Georgia M.A., Krieger D.W., Abou-Chebl A., Devlin T.G., Jauss M., Davis S.M., Koroshetz W.J., Rordorf G., Warach S. Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology. 2004;63(2):312-7. PMID: 15277626.
- Hemmen T.M., Raman R., Guluma K.Z., Meyer B.C., Gomes J.A., Cruz-Flores S., Wijman C.A., Rapp K.S., Grotta J.C., Lyden P.D., ICTuS-L Investigators. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010;41(10):2265-70. PMID: 20724711, PMCID: PMC2947593. http://dx.doi.org/10.1161/STROKEAHA.110.592295
- Lyden P., Hemmen T., Grotta J., Rapp K., Ernstrom K., Rzesiewicz T., Parker S., Concha M., Hussain S., Agarwal S., Meyer B., Jurf J., Altafullah I., Raman R.; Collaborators. Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke. 2016;47(12):2888-95. PMID: 27834742, PMCID: PMC5134910. http://dx.doi.org/10.1161/STROKEAHA.116.014200
- Straus D., Prasad V., Munoz L. Selective therapeutic hypothermia. A review of invasive and noninvasive techniques. Arq Neuropsiquiatr. 2011;69(6):981-7. PMID: 22297891.
- Andrews P.J.D., Harris B., Murray G.D. A randomised cross-over trial of the effects of airflow through the upper respiratory tract of intubated, brain injured patients on brain temperature and selective brain cooling. Br J Anaesth. 2005;94:330-5. PMID: 15531619. http://dx.doi.org/10.1093/bja/aei025
- Qiu W., Shen H., Zhang Y., Wang W., Liu W., Jiang Q., Luo M., Manou M. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J Clin Neurosci. 2006;13(10):995-1000. PMID: 17113984. http://dx.doi.org/10.1016/j.jocn.2006.02.027
- Mattingly T.K., Denning L.M., Siroen K.L., Lehrbass B., Lopez-Ojeda P., Stitt L., Pelz D.M., Das S., Ang L.C., Lee D.H., Lownie S.P. Catheter based selective hypothermia reduces stroke volume during focal cerebral ischemia in swine. J Neurointerv Surg. 2016;8(4):418-22. PMID: 25676148. http://dx.doi.org/10.1136/neurintsurg-2014-011562
- Chen J., Fredrickson V., Ding Y., Jiang L., Luo Y., Ji. X. The effect of a microcatheter-based selective intra-arterial hypothermia on hemodynamic changes following transient cerebral ischemia. Neurol Res. 2015;37(3):263-8. PMID: 25310355. http://dx.doi.org/10.1179/1743132814Y.0000000451
- Schwartz A.E., Finck A.D., Stone J.G., Connolly E.S., Edwards N.M., Mongero L. Delayed selective cerebral hypothermia decreases infarct volume after reperfused stroke in baboons. J Neurosurg Anesthesiol. 2011;23(2):124-30. PMID: 21150463. http://dx.doi.org/10.1097/ANA.0b013e3181fa75ca
- Song W., Wu Y.M., Ji Z., Wang S.N., Pan S.Y. Intra-carotid cold magnesium sulfate infusion induces selective cerebral hypothermia and neuroprotection in rats with transient middle cerebral artery occlusion. Neurol Sci. 2013;34(4):479-86. PMID: 22466873. http://dx.doi.org/10.1007/s10072-012-1064-3
- Chen J., Fredrickson V., Ding Y., Cheng H., Wang N., Ling F., Ji X. Enhanced neuroprotection by local intra-arterial infusion of human albumin solution and local hypothermia. Stroke. 2013;44(1):260-2. PMID: 23192754. http://dx.doi.org/10.1161/STROKEAHA.112.675462
- Kurisu K., Abumiya T., Ito M., Gekka M., Osanai T., Shichinohe H., Nakayama N., Kazumata K., Houkin K. Transarterial regional hypothermia provides robust neuroprotection in a rat model of permanent middle cerebral artery occlusion with transient collateral hypoperfusion. Brain Res. 2016;1651:95-103. PMID: 27663968. http://dx.doi.org/10.1016/j.brainres.2016.09.017
- Chen J., Liu L., Zhang H., Geng X., Jiao L., Li G., Coutinho J.M., Ding Y., Liebeskind D.S., Ji X. Endovascular hypothermia in acute ischemic stroke: a pilot study of selective intra-arterial cold saline infusion. Stroke. 2016;47(7):1933-5. PMID: 27197848, PMCID: PMC4927369. http://dx.doi.org/10.1161/STROKEAHA.116.012727.