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Title: Rat middle cerebral artery vasoreactivity in controls, sham operative controls, and following acute subarachnoid haemorrhage by arterial rupture without craniotomy
Author: Marshman, Laurence A. G.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2003
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The principle hypothesis of the current study is that events associated with the acute ictus of acute subaraclmoid haemorrhage (SAH) elicit changes in cerebrovascular physio-pharmacology that are independent of any subsequent effects of chronic clot lysis. As a result, such changes might interact with the effects of chronic clot lysis in a way that may, in consequence, ultimately explain why currently favoured 'clot-VSM' fail to adequately explain delayed VSM and DCI. The principle aim of the current thesis was to formally categorize cerebrovascular physio-pharmacological properties in sham and non-operative controls, and to compare these with those obtained in the acute period after SAH in a model more representative of the true clinical scenario. Clearly, the most ideal SAH model would be one in which arterial rupture is created inside a closed skull, since only here will the acute intracranial pressure changes be faithfully recreated. Ironically, the earliest SAH models came close to such an ideal: nevertheless, all utilized a prior craniotomy. More recently, endovascular filament (EF) models have instead gained credence. Because, in such models, intracranial arterial rupture is created in small animals by EF advancement through the intracranial internal carotid artery from an extracranial source in the neck, the potential disadvantages associated with a prior craniotomy are avoided. However, to date no EF-SAH model has yet been used to study cerebrovascular reactivity: this thesis is the first to do so. Hypothetically, however, two sources of 'side bias' potentially thwart the application of EF-SAH cerebrovascular study. One source relates to the manipulation and temporary ischaemia suffered during EF insertion (in particular, with prolonged carotid clamping). Another relates to relative uncertainty regarding the precise site of intracranial rupture. A secondary aim of the thesis, then, was to formally assess the hypothesis that EF-SAH introduce procedural 'side bias' by comparing cerebrovascular responses ipsilateral and contralateral to EF insertion using a range of constrictory and dilatory agonists-conceivably all relevant to SAH. The successful exclusion of 'side bias' would be important to any future study of delayed (i.e. chronic) VSM because, should any side differences be subsequently found in such delayed studies, then these could be attributable to focal factors-such as thickened clot lateralization-with somewhat greater confidence. Another potential flaw with current 'clot-VSM' models, however, resides not in their design but in their application. Thus, many do not use as substrate for cerebrovascular study vessels from the anterior cerebral circulation-where both VSM and DCI are most frequently apparent. Instead, most choose vessels from the posterior circulation: in particular, the basilar artery. Furthermore, many do not appear to restrict study to particular segments of specific arteries, and thus potentially thwart 'like-wit-like' comparisons. Most studies also do not quote vessel diameters in relation to subgroups and their responses: in this regard, most assume that randomisation for vessel side would make up for any 'size effects' on vessel responses. And finally, most ignore a principle implied by Brandt, that variation in vasoreactivity in individual arteries might be discontinuous-and not continuous-and so therefore not amenable to routine statistical analysis. It was therefore considered critical in this thesis to assess and limit such potentially confounding factors by fully reviewing what is already known about cerebral vessels before and after SAH, by critically reviewing all experimental models used to derive such data, and by assiduously analyzing normal vessel responses in a standard small vessel study model before progressing to their ultimate study post-SAH. To this end, middle cerebral arteries (MCA) medial to the olfactory tract were analyzed by 'wire myography'. Whilst the ultimate aim of all DCI research must clearly be in the effects of delayed VSM on a post-ictal brain, it is a scientific duty to delineate cerebrovascular reactivity at all stages prior to this. Unfortunately, it is not possible to apply the methodology of this current thesis to assess all of the 192 hours that pass between the acute ictus and the typically delayed start of VSM: instead, restriction of study to a shorter time interval would only be possible in one thesis. As a result, the current thesis was restricted to an analysis of the first three hours of EF-SAH for the following reasons: 1. To assess the principle hypothesis that events associated with acute SAH elicit changes in MCA physio-pharmacology that are independent of any subsequent effects of chronic clot lysis 2. To assess the secondary hypothesis that EF-SAH models introduce a procedural 'side bias' by comparing constrictory and dilatory MCA responses ipsilateral and contralateral to EF insertion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral