- Title
- Elucidating the mechanisms involved in intracranial pressure elevation and hypothermia treatment for ischaemic stroke
- Creator
- Omileke, Daniel Kolawole
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: It has become increasingly evident that patients with minor stroke who initially present with improving symptoms, can undergo drastic deterioration 24-72 h post-stroke. Delayed infarct expansion is the cause of this deterioration in most cases. Our group has previously demonstrated, using experimental stroke studies, that there is a transient elevation of intracranial pressure (ICP) around this same 24 h time point that neurological deterioration is observed in patients. The leptomeningeal collaterals provide perfusion to the ‘at-risk’ penumbral tissue after stroke. Our group demonstrated that this ICP rise is likely a key driver of collateral failure and therefore implicates ICP elevation as a potential mechanism for delayed infarct expansion and associated neurological deterioration in stroke patients. Recent work suggests that the mechanism of ICP elevation may be due to CSF volume dynamics, however, our understanding of these processes remain incomplete. Prevention of ICP rise after stroke may improve patient outcomes. Short-duration hypothermia has had robust efficacy in animal models of stroke, and completely prevents ICP rise in rodents. Long-duration hypothermia has been examined in stroke clinical trials. However, the long cooling protocols and associated complications have made all efforts to determine efficacy inconclusive. These protocols have contributed to the major difficulties observed in patient recruitment, which has resulted in very small trial sizes. Short-duration hypothermia may be a promising treatment strategy in patients. Animal studies have cooled faster than is achievable in patients, therefore there is a mismatch in the cooling rates between experimental and clinical studies. The aims of this thesis were to: 1) Determine whether clinically relevant cooling rates are feasible in rodents; 2) Investigate whether short-duration cooling using these clinically relevant cooling rates prevent ICP elevation and reduce infarct volume post-stroke; 3) Determine the importance of cooling during reperfusion on ICP elevation; 4) Investigate whether clinically relevant cooling alters CSF outflow resistance after stroke. Methods: A short-duration hypothermia model using clinically relevant cooling rates was developed. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Short-duration hypothermia treatment was administered following occlusion. The change in ICP from baseline to 18 h or 24 h was monitored and recorded, and infarct and oedema volumes were assessed at 24 h. CSF outflow resistance was determined using a steady-state infusion method. Artificial CSF was infused into the lateral ventricle and infusion rates were adjusted incrementally in response to ICP. Results: ICP elevation was prevented in animals that were treated with short-duration hypothermia at a rate of 2°C/h to 33°C compared with normothermia controls (Chapter 3 ΔICP = 1.56 ± 2.26 mmHg vs. 8.93 ± 4.82 mmHg, respectively, p=0.02; Chapter 5 ΔICP = 0.8 ± 3.6 mmHg vs. 4.4 ± 2.0 mmHg, respectively, p=0.04). There was a significant reduction in infarct volumes in hypothermia treated animals to 33°C compared with normothermia controls (Chapter 3 = 46.4 ± 12.3 mm3 vs. 85.0 ± 17.5 mm3, respectively, p=0.01; Chapter 5 = 78.6 ± 21.3 mm3 vs. 108.1 ± 17.8 mm3, respectively, p=0.01). Animals that were treated with hypothermia and rewarmed before reperfusion had significantly lower ICP and infarct volume at 24 h compared with normothermia (ΔICP = 0.3 ± 3.9 mmHg vs. 5.2 ± 2.1 mmHg, respectively, p=0.02: Infarct volume = 78.6 ± 23.7 mm3 vs. 125.1 ± 44.3 mm3, respectively, p=0.04). There was no significant difference in ICP or infarct volume between animals rewarmed before reperfusion and animals rewarmed after reperfusion. Hypothermia treatment showed a strong trend towards reducing CSF outflow resistance at 18 h compared with normothermia controls. Conclusions: Hypothermia treatment using clinically relevant cooling rates prevents the elevation of ICP and reduces infarct volume post-stroke. The cooling rates achieved in this thesis match the cooling rates of the most recent endovascular hypothermia clinical trial in stroke patients. The clinically relevant model utilised also resembles endovascular cooling in that it caused a reduction in core temperature, without the need to cool the skin. I also showed that hypothermia treatment during reperfusion is not critical for ICP rise prevention. I demonstrated that the completion of short-duration hypothermia prior to reperfusion still results in significant cerebroprotection, which suggests that short-duration hypothermia may also be beneficial to stroke patients who have yet to receive thrombolysis or thrombectomy. These findings also suggests that an earlier cooling onset prior to reperfusion may enhance the benefits of hypothermia. Finally, I demonstrated that CSF outflow resistance may be a mechanism by which hypothermia prevents ICP elevation, which further supports the hypothesis that ICP elevation may be a cause of infarct expansion in stroke patients. Taken together, these findings address some of the translational hurdles between experimental and clinical stroke studies and provide further rationale for the pursuit of short-duration hypothermia as a potential strategy for stroke patients.
- Subject
- stroke; hypothermia; intracranial pressure; ischaemic stroke; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1470170
- Identifier
- uon:48390
- Rights
- Copyright 2022 Daniel Kolawole Omileke
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Thesis | 8 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 292 KB | Adobe Acrobat PDF | View Details Download |