Please use this identifier to cite or link to this item:
Full metadata record
DC FieldValueLanguage
dc.contributor.advisorVink, Roberten
dc.contributor.advisorVan Den Heuvel, Corinnaen
dc.contributor.advisorMathias, Jane Leanneen
dc.contributor.authorGabrielian, Levon A.en
dc.description.abstractTraumatic brain injury (TBI) is the leading cause of death in the population below 40 years of age. Patients who survive TBI suffer from ongoing physical disabilities as well as mental and emotional deficits that significantly impact their quality of life. While a number of factors have been implicated in the brain injury cascade that is initiated by TBI, increased intracranial pressure (ICP) has been identified as one factor that is strongly associated with outcome. This is largely because increased ICP results in a fall in cerebral perfusion pressure (CPP) and in brain oxygenation (PbtO₂ [bt subscript]), thus starving the brain of essential substrates and oxygen necessary for repair and recovery. Nonetheless, treatments targeting increased ICP are largely ineffective and have not changed for over 40 years. In part, this is because the mechanisms responsible for oedema formation after trauma are unknown and also because existing small animal models of TBI might not duplicate all the pathophysiological features of human TBI. The aim of this thesis was therefore to study changes in ICP and PbtO₂ [bt subscript] in two different experimental animal models of TBI, both large and small, and subsequently investigate the effects of different pharmacotherapies on these variables following TBI. The thesis shows that TBI does not consistently produce increases in ICP in rodent models unless a haemorrhagic mass lesion is present. Accordingly, rodents may not be the ideal species for the development of ICP targeted pharmacotherapies. By then studying the effects of TBI on ICP, cerebral perfusion pressure (CPP) and PbtO₂ [bt subscript] in an ovine, large animal model, we noted that the sheep model of injury produces similar changes in these variables to clinical (human) TBI, and was therefore well suited to the development of ICP targeted pharmacotherapies. The targeted therapy we chose to investigate was the substance P, NK1 antagonists which have been previously shown in our laboratory to reduce blood brain barrier breakdown and oedema formation following rodent TBI. We characterized the effects of two different NK1 receptor antagonists on ICP, PbtO₂ [bt subscript] and CPP in an ovine model of TBI at both moderate and severe injury levels, and compared the effects to those to that of the clinically used osmotic agents, mannitol and hypertonic saline. We noted that in contrast to the osmotic agents, the NK1 antagonists consistently reduced ICP and improved PbtO₂ [bt subscript] irrespective of the severity of injury. As a further comparison, we examined the effects of the putative neuroprotective compounds magnesium and progesterone on ICP and PbtO₂ [bt subscript] following ovine, moderate TBI, and noted that both agents were ineffective. This finding highlighted the importance of using large animal models of TBI to investigate novel interventional pharmacologies. Having acquired a considerable amount of physiological data in a large animal model of TBI that largely replicated the temporal changes in ICP and CPP in human TBI, we then applied Gaussian processes for data analyses to investigate the dynamic interrelationship between PbtO₂ [bt subscript], ICP, and mean arterial blood pressure (MABP) and CPP after trauma. This facilitated the development of a contour plot describing these dynamic interrelationships and enabling the prediction of mean PbtO₂ [bt subscript] values for any given ICP and MABP, the identification of critical thresholds in ICP, and the physiological basis and refinement of the CPP formula. We noted that PbtO₂ [bt subscript] had critical thresholds that might be related to the compression of post-capillary venules, capillaries and precapillary met-arterioles, respectively. Real CPP thus depends upon the pressure within the vascular tree, and whether their flow has been restricted by increased ICP. In conclusion, NK1 antagonists offer a novel intervention for increased ICP and reduced PbtO₂ [bt subscript] after TBI that is superior to existing, alternative therapies irrespective of injury severity.en
dc.subjectbrain injury; intracranial pressure; PO₂en
dc.titleDevelopment of novel pharmacological treatments for intracranial pressure using appropriate experimental models of traumatic brain injury.en
dc.contributor.schoolSchool of Medical Sciencesen
dc.provenanceThis electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
dc.description.dissertationThesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2013en
Appears in Collections:Research Theses

Files in This Item:
File Description SizeFormat 
01front.pdf144.97 kBAdobe PDFView/Open
02whole.pdf3.64 MBAdobe PDFView/Open
  Restricted Access
Library staff access only380.2 kBAdobe PDFView/Open
  Restricted Access
Library staff access only3.18 MBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.