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Aging and disease    2018, Vol. 9 Issue (3) : 507-522     DOI: 10.14336/AD.2017.0628
Review Article |
Effects of Therapeutic Hypothermia Combined with Other Neuroprotective Strategies on Ischemic Stroke: Review of Evidence
Zhang Zheng1,2, Zhang Linlei3, Ding Yuchuan4, Han Zhao3,*, Ji Xunming1,5,*
1Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
2Department of Neurology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
3Department of Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
4Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA
5China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
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Ischemic stroke is a major cause of death and disability globally, and its incidence is increasing. The only treatment approved by the US Food and Drug Administration for acute ischemic stroke is thrombolytic treatment with recombinant tissue plasminogen activator. As an alternative, therapeutic hypothermia has shown excellent potential in preclinical and small clinical studies, but it has largely failed in large clinical studies. This has led clinicians to explore the combination of therapeutic hypothermia with other neuroprotective strategies. This review examines preclinical and clinical progress towards developing highly effective combination therapy involving hypothermia for stroke patients.

Keywords ischemic stroke      neuroprotection      therapeutic hypothermia      combination therapy     
Corresponding Authors: Han Zhao,Ji Xunming   
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These authors have contributed equally to this work.

Issue Date: 05 June 2018
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Zhang Zheng
Zhang Linlei
Ding Yuchuan
Han Zhao
Ji Xunming
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Zhang Zheng,Zhang Linlei,Ding Yuchuan, et al. Effects of Therapeutic Hypothermia Combined with Other Neuroprotective Strategies on Ischemic Stroke: Review of Evidence[J]. Aging and disease, 2018, 9(3): 507-522.
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Main Function of combined strategiesCombined strategiesSpecified treatment
Reduce energy consumptionAnestheticsMethohexital
Thiopentone sodium Xenon Dexmedetomidine
Psychotropic agentsChlorpromazine and promethazine
Suppress calcium overloadNMDA receptor antagonists
Ryanodine receptor inhibitor
MK-801 Delfotel Magnesium with or without tirilazad Dantrolene
Increase blood supplyReperfusion
Vessel dilator Induce arteriogenesis
Intra-arterial recanalization Statin Granulocyte colony stimulating factor (G-CSF)
Anti-oxidative stressOxidative stress scavengersEdaravone
Repair damaged cellsBiosynthesis of cell componentCiticoline
Increase oxygen supplyOxygenNormobaric oxygen
Hyperbaric oxygen
Reduce intracranial pressure-Decompressive craniectomy
Anti-apoptosisAnti-apoptosis proteinFNK protein
Gene of anti-apoptosis proteinBcl-2 gene
Multiple protection-Caffeinol (caffeine and ethanol)
Insulin-like growth factor-1 (IGF-1) Brain-derived neurotrophic factor (BDNF) Albumin
Table 1  summary of the second neuroprotective strategies combined with hypothermia in ischemic stroke.
Transient (T) Ischemia
Temperature degree(°C)Combined TreatmentAim of studyYes/No
[10]P33Mk-801Enhanced effectNo
[12]T30Mk-801Enhanced effectYes
[18]T34SelfotelEnhanced effectNo
[19]Repetitive34SelfotelEnhanced effectYes
[21]T35.4MagnesiumEnhanced effectYes
[22]P35MagnesiumEnhanced effectYes
[23]T33-34MagnesiumEnhanced effectYes
[24]P35MagnesiumEnhanced effectNo
[27]T33t-PAReduce the side effect of t-PAYes
[28]T34t-PAReduce the side effect of t-PAYes
[29]T32Delayed t-PAEnhanced effectNo
[30]T33t-PAEnhanced effectNo
[42]T35TacrolimusEnhancec/expand time window of tacrolimusYes
[52]T32-33AtorvastatinEnhanced effect/
expand time window of hypothermia
[57]T35EdaravoneEnhanced effectYes
[65]T34CiticolineEnhanced effectYes
[25]T33MinocyclineEnhanced effectYes
[48]P34MinocyclineEnhanced effectNo
[49]P34-35MinocyclineEnhanced effectNo
[69]T35CaffeinolEnhanced effectYes
[72]T35Chlorpromazine and PromethazineEnhanced effectYes
[77]T33MethohexitalEnhanced effectNo
[84]T36XenonEnhanced effectYes
[88]Incomplete35DexmedetomidineEnhanced effectNo
[98]T33t-PA and Normobaric Oxygen (NBO)Enhanced effectYes
t-PA And normobaric oxygen (NBO)
Hyperbaric oxygenation (HBO2)
Enhanced effect
Enhanced effect
[100]T33t-PA and normobaric oxygen (NBO)reduce the side effect of t-PAYes
[115]T33.5-35Granulocyte-Macrophage Colony-Stimulating Factor (G-CSF)Enhanced effectYes
[120]T32Insulin-Like Growth Factors -1(IGF-1)Enhanced effectYes
[121]T30-33Insulin-Like Growth Factors -1(IGF-1)Enhanced effectNo
[128]P33Brain-Derived Neurotrophic Factor (BDNF)Enhanced effectYes
[133]T33Magnesium and TirilazadEnhanced effectYes
[134]T33Magnesium and TirilazadEffectiveYes
[135]T33Magnesium and TirilazadEnhanced effectYes
[59]P32-34MannitolEnhanced effectNo
[60]T33MannitolEnhanced effectNo
[137]T30-31AlbuminEnhanced effectYes
[141]P32Decompressive CraniectomyEnhanced effectYes
[142]P29-31Decompressive CraniectomyEnhanced effectYes
[147]T35PTD-FNKEnhanced effectYes
[150]T33Gene of Bcl-2Expand time window/Enhanced effectYes
Neuronal culture
[78]-22/32Thiopentone Sodium (TPS)Enhanced effectYes
[93]-33DantroleneEnhanced effectYes
[31]T33t-PAEnhanced effectNo
[32]T32-34t-PAEnhanced effectNo
[33]T<35.5t-PAFeasible/improve outcomeYes
[34]T34.5t-PAReduce the side effect of tPAYes
[37]Tdecrease 2
in brain
Intra-Arterial RecanalizationFeasible and safeYes
[69]T33-35Caffeinol and T-PAFeasibleYes
[143]P35Decompressive CraniectomyEnhanced effectYes
Table 2  Summary of outcomes of neuroprotective treatments combined with therapeutic hypothermia in ischemic stroke.
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