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Raised intracranial pressure and tissue compliance after large intracerebral hemorrhages in animal models and patients
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- Author / Creator
- Wilkinson, Cassandra M.
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Brain injuries that cause mass effect, including stroke and traumatic brain injury, can increase intracranial pressure (ICP) due to the limited space within the skull. Intracerebral hemorrhage (ICH) is a subtype of stroke in which there is bleeding in the brain. In cases of large bleeds, the bleed and the associated swelling can cause ICP to increase to dangerous levels, possibly leading to brain herniation and/or death. Cranial contents can undergo compliance (a decrease in volume after being subject to the force of increased ICP), but this compliance is limited. Treatments to reduce ICP have mixed effectiveness, and are often not enough to compensate for large bleeds. Animal models are often used to study ICH, and although this is an important way to study ICH pathophysiology and potential treatments, high quality animal research requires an awareness and mitigation of translational problems where possible. In our rodent models, we have found that when ICP is increased after large bleeds, animals can compensate for this bleed by reducing the volume of uninjured brain tissue. Neurons and astrocytes in uninjured regions shrink by up to 50% and pack more densely together. In this thesis, we studied ICP and tissue compliance after ICH with a focus on research translation.
Chapter two summarized current studies on ICP after ICH, including pathophysiology and treatment of increased ICP. We focused on translationally relevant considerations, including model choice, ICP measurement methodology, and ICP analysis. This review highlighted the need for more ICP research in the ICH field. The next chapter examined the use of isoflurane anesthetic in preclinical ICH research. Most ICH patients undergo ICH while conscious, yet almost all animal studies induce ICH under anesthetic for ethical reasons. Anesthetics can impact physiology, including temperature and blood pressure, and can exert neuroprotective effects. In this study, we induced a collagenase ICH in conscious animals using a cannula system. We found that the effects of isoflurane (reduced temperature, reduced blood pressure, increased blood glucose) were largely transient and normalized quickly after surgery. In cases of large ICH, isoflurane did not affect hematoma volume, lesion volume, or functional deficits.
The following experiment tested the effect of glibenclamide, a sulfonylurea receptor antagonist, on edema after ICH. We hypothesized that this ion channel blocker would prevent cellular edema by preventing ion influx, which would then reduce mass effect. We planned this experiment in advance in the hopes of reducing bias, we used large sample sizes, pre-planned statistical analysis, and published all data with the manuscript. Contrary to our hypothesis, we found that glibenclamide did not reduce edema, lesion volume, or functional deficits.
Chapters five and six examined tissue compliance in translationally relevant rodent models of ICH. We wanted to see if tissue compliance could be observed in a rodent population that better modelled the clinical population of ICH patients. We assessed hematoma volume, edema, ICP, and functional deficits in young and aged spontaneously hypertensive rats (SHRs). We then quantified contralateral hemisphere volume, cortical thickness, and cell volume and density in regions known to undergo tissue compliance. We found that tissue compliance was present across strains, and did not seem to be impaired by hypertension. This finding replicated in aged animals, where we again saw evidence of tissue compliance. These aged SHRs had lower ICP, smaller hematoma volumes, less edema, and a reduced mortality rate compared to young SHRs given the same amount of collagenase. Future research should explore the reasons behind this and exercise caution when using the collagenase model to study ICH in aged animals.
In the final experiment, we retrospectively analyzed CT images of ICH patients stratified by bleed volume at 24 hours post-ICH. We quantified brain tissue and CSF volumes and found that those with larger bleeds had reduced brain and CSF volume after taking gender into account. This preliminary study helps establish the methodology and justify a future clinical trial to characterize tissue compliance in people.
This work justifies future studies of tissue compliance, as there is still a lot to learn. For example, studies should examine the functional consequences and negative effects of these drastic and transient cellular changes. Additionally, adequately powered clinical trials should investigate tissue compliance in patients using both imaging and neuropathological techniques.
Brain injuries that cause mass effect, including stroke and traumatic brain injury, can increase intracranial pressure (ICP) due to the limited space within the skull. Intracerebral hemorrhage (ICH) is a subtype of stroke in which there is bleeding in the brain. In cases of large bleeds, the bleed and the associated swelling can cause ICP to increase to dangerous levels, possibly leading to brain herniation and/or death. Cranial contents can undergo compliance (a decrease in volume after being subject to the force of increased ICP), but this compliance is limited. Treatments to reduce ICP have mixed effectiveness, and are often not enough to compensate for large bleeds. Animal models are often used to study ICH, and although this is an important way to study ICH pathophysiology and potential treatments, high quality animal research requires an awareness and mitigation of translational problems where possible. In our rodent models, we have found that when ICP is increased after large bleeds, animals can compensate for this bleed by reducing the volume of uninjured brain tissue. Neurons and astrocytes in uninjured regions shrink by up to 50% and pack more densely together. In this thesis, we studied ICP and tissue compliance after ICH with a focus on research translation.
Chapter two summarized current studies on ICP after ICH, including pathophysiology and treatment of increased ICP. We focused on translationally relevant considerations, including model choice, ICP measurement methodology, and ICP analysis. This review highlighted the need for more ICP research in the ICH field. The next chapter examined the use of isoflurane anesthetic in preclinical ICH research. Most ICH patients undergo ICH while conscious, yet almost all animal studies induce ICH under anesthetic for ethical reasons. Anesthetics can impact physiology, including temperature and blood pressure, and can exert neuroprotective effects. In this study, we induced a collagenase ICH in conscious animals using a cannula system. We found that the effects of isoflurane (reduced temperature, reduced blood pressure, increased blood glucose) were largely transient and normalized quickly after surgery. In cases of large ICH, isoflurane did not affect hematoma volume, lesion volume, or functional deficits.
The following experiment tested the effect of glibenclamide, a sulfonylurea receptor antagonist, on edema after ICH. We hypothesized that this ion channel blocker would prevent cellular edema by preventing ion influx, which would then reduce mass effect. We planned this experiment in advance in the hopes of reducing bias, we used large sample sizes, pre-planned statistical analysis, and published all data with the manuscript. Contrary to our hypothesis, we found that glibenclamide did not reduce edema, lesion volume, or functional deficits.
Chapters five and six examined tissue compliance in translationally relevant rodent models of ICH. We wanted to see if tissue compliance could be observed in a rodent population that better modelled the clinical population of ICH patients. We assessed hematoma volume, edema, ICP, and functional deficits in young and aged spontaneously hypertensive rats (SHRs). We then quantified contralateral hemisphere volume, cortical thickness, and cell volume and density in regions known to undergo tissue compliance. We found that tissue compliance was present across strains, and did not seem to be impaired by hypertension. This finding replicated in aged animals, where we again saw evidence of tissue compliance. These aged SHRs had lower ICP, smaller hematoma volumes, less edema, and a reduced mortality rate compared to young SHRs given the same amount of collagenase. Future research should explore the reasons behind this and exercise caution when using the collagenase model to study ICH in aged animals.
In the final experiment, we retrospectively analyzed CT images of ICH patients stratified by bleed volume at 24 hours post-ICH. We quantified brain tissue and CSF volumes and found that those with larger bleeds had reduced brain and CSF volume after taking gender into account. This preliminary study helps establish the methodology and justify a future clinical trial to characterize tissue compliance in people.
This work justifies future studies of tissue compliance, as there is still a lot to learn. For example, studies should examine the functional consequences and negative effects of these drastic and transient cellular changes. Additionally, adequately powered clinical trials should investigate tissue compliance in patients using both imaging and neuropathological techniques. -
- Subjects / Keywords
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- Graduation date
- Fall 2022
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.