Investigating the Significance of Post-Stroke Temperature Changes in Ischemic and Hemorrhagic Stroke
Creators: Liddle, Lane J
Publisher: name: University of Alberta Library
Year: 2024

<p>Stroke is a leading cause of death and disability worldwide. There are two broad stroke subtypes: ischemic and hemorrhagic. Ischemic stroke occurs when brain tissue is deprived of oxygen and nutrients; hemorrhagic stroke occurs when brain vasculature ruptures and blood extravasates. Despite revolutions in stroke research, diagnosis, and treatment, many people continue to suffer from stroke-related brain injury. Novel treatments are expected to arise from coordinated efforts between preclinical and clinical scientists. <br>
Therapeutic hypothermia (TH), the intentional reduction of body temperature, has been used for millennia. However, within the past 150 years TH has been imported into modern medicine, where therapeutic mechanisms and opportunities have been studied. Studies conducted in the 20th century were often exploratory and involved using TH in a variety of diseases including cancer, stroke, cardiac arrest (CA), and neonatal hypoxic ischemic encephalopathy (HIE). To date, TH has demonstrated efficacy in CA and HIE, but many questions remain. TH may improve outcomes in focal stroke, including intracerebral hemorrhage (ICH); these conditions share pathophysiological overlap with CA and HIE. Although preclinical studies frequently demonstrate the efficacy of TH, particularly in ischemic stroke, clinical studies have been burdened with complications (e.g., inducing and maintaining TH, side effects), which impact the effectiveness of TH. Novel local hypothermia methods have been developed to circumvent complications with body-wide hypothermia. One particular local hypothermia method that is demonstrating promise as an adjunct therapy for ischemic stroke treatments is known as intra-arterial selective cooling infusion (IA-SCI), which flushes the affected vasculature, potentially contributing to blood flow restoration. However, safety and contraindications of this therapy remain understudied. This dissertation focused on experimental quality, and attempted to address knowledge gaps in the IA-SCI literature. <br>
Chapters 2, 3, and 4 focus on translational research quality and provide a snapshot of the state of the art in intracerebral hemorrhage neuroprotection, focal hypothermia, and IA-SCI research, respectively. We conclude that contemporary research is exploratory, and many additional translational issues must be considered (e.g., identifying optimum protocols, use of treatments in heterogenous contexts).<br>
Chapters 5 and 6 tackled knowledge gaps that we identified in Chapters 2-4. For example, in Chapter 4, we noted that few safety investigations exist in the IA-SCI literature. Thus, in Chapter 5 we sought to test whether IA-SCI exacerbated active bleeding in an ICH model, which may apply to focal ischemic stroke (i.e., hemorrhagic transformation). While IA-SCI did not worsen bleeding, it also did not demonstrate efficacy, as measured by blood-brain barrier integrity, behavioural, and histological assessments. Chapter 6 acted as a confirmatory test of the efficacy of IA-SCI in an ischemic stroke model that mimics patients that do no benefit from existing therapies, and we conducted our experiments with every effort to reduce bias and achieve high statistical power. We found that IA-SCI did not improve behavioral or histological outcomes in the short- or long-term, in Sprague-Dawley or Spontaneously Hypertensive Rats. Thus, there are limits to the benefits of this therapy, which should be explored further. <br>
While it is well-known that fever worsens ischemic injury, Chapter 7 reports on our review of the literature in ICH. We found that post-ICH fever was associated with intraventricular extension of the hematoma, and that fever was associated with mortality. However, we noted that there is stark heterogeneity between studies: temperature measurement sites, antipyretic use, and even definitions of fever vary wildly. Notably, fever etiology is rarely evaluated despite likely playing a role in post-stroke outcomes. We speculate that while mortality may be worsened when ICH patients are febrile, it is not raised temperature per se that is contributing to mortality (at least for modest rises in temperature), and instead, infections and extensive brain injury (e.g., affecting hypothalamic thermoregulatory nuclei) may account for the increased mortality observed in febrile patients. Future research is desperately needed on this topic.<br><br>
Altogether, we conducted multiple studies investigating post-stroke outcomes in the context of hypo- and hyperthermia. We found that most neuroprotection studies are in their infancy, and experimental quality is often moderate, with room for improvement. We suggest that investigators reduce experimental bias and report experiments according to published guidelines to improve reproducibility efforts. Ultimately, we conclude that high-quality confirmatory experimental research is needed to aid translation efforts, as this type of research can probe the boundaries of therapeutic safety and efficacy. </p>