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

Kuczynski, Andrea M.; Marzoughi, Sina; Sultan, Abdulaziz S Al; Colbourne, Frederick; Menon, Bijoy K; Es, Adriaan C G M van; Berez, Aaron L.; Goyal, Mayank; Demchuk, Andrew M.; Almekhlafi, Mohammed

doi:10.1007/s11910-020-01029-3

Cited by 36 publications

(33 citation statements)

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“…Here, we compare the example of therapeutic hypothermia (TH), studied clinically in both acute ischaemic stroke (AIS) and hypoxic brain injury after cardiopulmonary arrest. Hypothermia failed translationally in ischaemic stroke (negative story) (Kuczynski et al, 2020) but succeeded in brain hypoxia after cardiopulmonary resuscitation (positive story).…”

Section: What Do We Learn From the Application Of Therapeutic Hypothermia In Stroke? (Comparing A Positive And A Negative Translational Smentioning

confidence: 99%

“…Therapeutic hypothermia has not reached bedside translation in the case of large territorial AIS (Kuczynski et al, 2020). Numerous positive preclinical studies (rats and mice) report (neuro)protection via post-ischaemic moderate hypothermia (Baron, 2018;Wu et al, 2020): it decreases brain metabolism and inhibits deleterious effects of ischaemia, including excessive neuroinflammation, cytokine release, blood-brain-barrier disruption, apoptosis, and free radical production, activated matrix metalloproteinases, ion channel change, and excitotoxicity (for extended reviews see Truettner et al, 2005;Liu et al, 2016;Wu et al, 2020).…”

Section: What Do We Learn From the Application Of Therapeutic Hypothermia In Stroke? (Comparing A Positive And A Negative Translational Smentioning

confidence: 99%

“…However, the available clinical evidence shows rather neutral brain effects and negative systemic complications in humans (Schneider et al, 2017;Wu et al, 2020). Global hypothermia induces multiple and severe systemic side effects, such as shivering, cardiac arrhythmias, vasoconstriction, pneumonia, kidney dysfunction, diffuse coagulopathy, and electrolyte imbalances (Huber et al, 2019;Kuczynski et al, 2020). Moreover, the neuroprotective effects of TH are largely time-sensitive (early hypothermia is protective, late is deleterious) (Kawamura et al, 2005;Huber et al, 2019) and depend on magnitude (mild or strong), duration of application, site of application (local on brain versus systemic application), and inherent characteristics of the organism (age and comorbidities, rodent vs. human differences) (Wu et al, 2020).…”

Section: What Do We Learn From the Application Of Therapeutic Hypothermia In Stroke? (Comparing A Positive And A Negative Translational Smentioning

confidence: 99%

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Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

et al. 2021

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Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box.

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Section: What Do We Learn From the Application Of Therapeutic Hypothermia In Stroke? (Comparing A Positive And A Negative Translational Smentioning

confidence: 99%

Section: What Do We Learn From the Application Of Therapeutic Hypothermia In Stroke? (Comparing A Positive And A Negative Translational Smentioning

confidence: 99%

Section: What Do We Learn From the Application Of Therapeutic Hypothermia In Stroke? (Comparing A Positive And A Negative Translational Smentioning

confidence: 99%

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Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

et al. 2021

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“…Until recently, TH methods have been limited to systemic cooling by use of cooling blankets and endovascular approaches, or via exogenous regional cooling through cooling helmets or nasopharyngeal approaches (3,18). Systemic cooling often takes hours to reach target temperatures and frequently results in complications [e.g., shivering, pneumonia; (3,19,20)]. Despite avoiding systemic complications, exogenous regional cooling may not penetrate subcortical brain regions that are commonly affected after ischemic stroke, and prolonged cooling with these methods is not yet feasible (3).…”

Section: Introductionmentioning

confidence: 99%

A Systematic Review and Meta-Analysis of Animal Studies Testing Intra-Arterial Chilled Infusates After Ischemic Stroke

et al. 2021

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Background: As not all ischemic stroke patients benefit from currently available treatments, there is considerable need for neuroprotective co-therapies. Therapeutic hypothermia is one such co-therapy, but numerous issues have hampered its clinical use (e.g., pneumonia risk with whole-body cooling). Some problems may be avoided with brain-specific methods, such as intra-arterial selective cooling infusion (IA-SCI) into the arteries supplying the ischemic tissue.Objective: Our research question was about the efficacy of IA-SCI in animal middle cerebral artery occlusion models. We hypothesized that IA-SCI would be beneficial, but translationally-relevant study elements may be missing (e.g., aged animals).Methods: We completed a systematic review of the PubMed database following the PRISMA guidelines on May 21, 2020 for animal studies that administered IA-SCI in the peri-reperfusion period and assessed infarct volume, behavior (primary meta-analytic endpoints), edema, or blood-brain barrier injury (secondary endpoints). Our search terms included: “focal ischemia” and related terms, “IA-SCI” and related terms, and “animal” and related terms. Nineteen studies met inclusion criteria. We adapted a methodological quality scale from 0 to 12 for experimental design assessment (e.g., use of blinding/randomization, a priori sample size calculations).Results: Studies were relatively homogenous (e.g., all studies used young, healthy animals). Some experimental design elements, such as blinding, were common whereas others, such as sample size calculations, were infrequent (median methodological quality score: 5; range: 2–7). Our analyses revealed that IA-SCI provides benefit on all endpoints (mean normalized infarct volume reduction = 23.67%; 95% CI: 19.21–28.12; mean normalized behavioral improvement = 35.56%; 95% CI: 25.91–45.20; mean standardized edema reduction = 0.95; 95% CI: 0.56–1.34). Unfortunately, blood-brain barrier assessments were uncommon and could not be analyzed. However, there was substantial statistical heterogeneity and relatively few studies. Therefore, exploration of heterogeneity via meta-regression using saline infusion parameters, study quality, and ischemic duration was inconclusive.Conclusion: Despite convincing evidence of benefit in ischemic stroke models, additional studies are required to determine the scope of benefit, especially when considering additional elements (e.g., dosing characteristics). As there is interest in using this treatment alongside current ischemic stroke therapies, more relevant animal studies will be critical to inform patient studies.

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“…Current guidelines and recent trials support the use of TTM (in the range of 32–36 °C [ 2 , 3 ]) in all CA patients who remain in a state of coma after return of spontaneous circulation (ROSC) [ 2 , 7 – 11 ]. The benefit of systemic and selective TTM in stroke patients is supported by recent trials and meta-analyses [ 12 , 13 ]. Despite a broad consensus on TTM benefits, the application of pre-hospital TTM, for example in out-of-hospital CA, is still controversial [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Insight into the use of tympanic temperature during target temperature management in emergency and critical care: a scoping review

et al. 2021

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Background Target temperature management (TTM) is suggested to reduce brain damage in the presence of global or local ischemia. Prompt TTM application may help to improve outcomes, but it is often hindered by technical problems, mainly related to the portability of cooling devices and temperature monitoring systems. Tympanic temperature (TTy) measurement may represent a practical, non-invasive approach for core temperature monitoring in emergency settings, but its accuracy under different TTM protocols is poorly characterized. The present scoping review aimed to collect the available evidence about TTy monitoring in TTM to describe the technique diffusion in various TTM contexts and its accuracy in comparison with other body sites under different cooling protocols and clinical conditions. Methods The scoping review was conducted following the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis extension for scoping reviews (PRISMA-ScR). PubMed, Scopus, and Web of Science electronic databases were systematically searched to identify studies conducted in the last 20 years, where TTy was measured in TTM context with specific focus on pre-hospital or in-hospital emergency settings. Results The systematic search identified 35 studies, 12 performing TTy measurements during TTM in healthy subjects, 17 in patients with acute cardiovascular events, and 6 in patients with acute neurological diseases. The studies showed that TTy was able to track temperature changes induced by either local or whole-body cooling approaches in both pre-hospital and in-hospital settings. Direct comparisons to other core temperature measurements from other body sites were available in 22 studies, which showed a faster and larger change of TTy upon TTM compared to other core temperature measurements. Direct brain temperature measurements were available only in 3 studies and showed a good correlation between TTy and brain temperature, although TTy displayed a tendency to overestimate cooling effects compared to brain temperature. Conclusions TTy was capable to track temperature changes under a variety of TTM protocols and clinical conditions in both pre-hospital and in-hospital settings. Due to the heterogeneity and paucity of comparative temperature data, future studies are needed to fully elucidate the advantages of TTy in emergency settings and its capability to track brain temperature.

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

Cited by 36 publications

References 36 publications

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

A Systematic Review and Meta-Analysis of Animal Studies Testing Intra-Arterial Chilled Infusates After Ischemic Stroke

Insight into the use of tympanic temperature during target temperature management in emergency and critical care: a scoping review

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