No description available.

Traumatic brain injury (TBI) is a major problem with an estimated cost of $76 billion per year in the US alone. The Center for Disease Control and Prevention (CDC) documented 2.53 million TBI-related emergency department visits, with approximately 288,000 TBI-related hospitalizations and 56,800 TBI-related deaths in 2014 in the US. The lack of FDA-approved treatment strategies for TBI drives the need for novel therapeutic and preventative measures. In a quest to reduce TBI-related injuries and deaths, automotive companies have focused their efforts to make safer cars for both occupants and pedestrians. Computational finite element (FE) models have been used to advance research efforts in automotive safety systems engineering in hopes of ameliorating the burden caused by TBI. The current use of FE models in the automotive industry focuses on predicting stresses and strains that occur during the accident itself to predict primary injury. However, contemporary models lack the appropriate mechanical properties required to make accurate predictions of brain tissue deformation after injury and lack the ability to model secondary injuries such as cerebral edema (brain swelling). With cerebral edema being a major cause of death and disability after TBI, and with the pattern and magnitude of cerebral edema being dependent on the initiating strain field in brain tissue during TBI, automotive safety systems could be further improved if 1) FE head models contained more accurate mechanical properties and 2) if FE models could simulate secondary injuries such as cerebral edema. Therefore, the driving purpose of this thesis is two-fold: 1) to determine the mechanical properties of different regions of the brain and 2) to present a new computational methodology that allows for modeling of cerebral edema to better predict patient outcome following TBI. The use of FE models requires appropriate constitutive formulations and associated parameters to accurately model and predict the initial mechanical response of the brain to injury loading conditions. Since patient outcome is dependent on the resulting strain field within brain tissue post-injury, accurate modeling of brain tissue deformation is important for testing the efficacy of engineered automotive safety systems using FE simulations. To address this need, the first aim of this thesis employed an inverse FE approach to characterize mechanical properties of the human hippocampus (CA1, CA3, dentate gyrus), cortex white matter, and cortex gray matter. Anatomical regions were significantly different in their mechanical properties. Although no sex dependency was observed, there were trends indicating that some male brain regions were generally stiffer than corresponding female regions. In addition, mechanical properties were not dependent on age within the examined age range (4-58 years old). Ultimately, this study provides a structure-specific description of fresh human brain tissue mechanical properties, which will be an important step toward explicitly modeling the heterogeneity of brain tissue deformation during TBI using FE modeling. Fatal brain injuries may also result from physiological changes in the brain that occur after the primary injury that immediately occurs during head injury. Secondary injuries such as cerebral edema are associated with poor outcome. Despite the severe consequences of cerebral edema, its mechanism is not fully understood. The second aim of this thesis, therefore, was to elucidate the driving mechanism of cerebral edema by demonstrating that cleavage of intracellular fixed-charge density (FCD) reduces brain swelling pressure and to measure the FCD content of rat and pig brain tissue. Thin brain samples were placed into a confined pressure chamber, and FCD content was calculated from measured swelling pressure and the Gibbs-Donnan equation. We observed that cleavage of FCD using enzymes reduced swelling pressure in rat brain tissue samples and determined that pig cortex gray matter contains more FCD than pig cortex white matter. These results demonstrate that cerebral edema may occur in accordance with principles of triphasic swelling biomechanics and demonstrates the plausibility of computationally modeling cerebral edema with triphasic material formulations. Cerebral edema leads to increased intracranial pressure (ICP) as the brain swells within the fixed volume of the skull, and there is overwhelming evidence of ICP as a powerful predictor of patient outcome following TBI. Current industry standards of patient outcome evaluation use tissue-level metrics solely from primary injury such as maximum principal strain (MPS) or cumulative strain damage measure (CSDM), but these methods can be improved especially in regards to predicting mortality. Therefore, the third aim of this thesis was to develop a new FE head model and computational methodology incorporating triphasic swelling biomechanics to simulate brain swelling following impact to improve patient outcome predictions. Patient outcome was predicted by simulating swelling and calculating the resulting ICP, which is a strong indicator of patient mortality. Calculating ICP in addition to predicting primary injury metrics such as MPS and CSDM may allow automotive safety engineers to make better predictions of patient outcome following TBI so they can develop better safety systems. Another common indicator of poor outcome following TBI is acute subdural hematoma (ASDH). ASDH is an intracranial bleed that often results from TBI because of stretching and tearing of the bridging veins which causes blood to collect in the innermost layer of the dura. Despite the poor prognosis associated with the presence of ASDH following TBI, the mechanism as to why its presence is associated with a higher likelihood of death remains uncertain. Current state of the art FE head models used in automotive safety engineering efforts do not consider ASDH, which may drastically reduce their effectiveness in predicting patient outcome following TBI. Therefore, the fourth and final aim of this thesis was to incorporate ASDH into our FE head model of swelling and elucidate the underlying secondary brain injury mechanism of ASDH that contributes to increased mortality in hopes of increasing the efficacy of current FE models to predict patient outcome and ultimately design better safety systems. Using our novel FE head model and methodology from aim 3, we showed that the higher likelihood of death associated with the presence of ASDH may be caused by exacerbated ischemic injury which increases ICP, demonstrating that modeling of ASDH is necessary for accurately modeling patient outcome following TBI. Despite decades of TBI research and FE head model improvements, more work is required to enhance the biofidelity of these models to better predict patient outcome. The work in this thesis is important, as it introduces a new tool that will allow automotive safety engineers to incorporate cerebral edema and ASDH, both of which may drastically influence patient outcome following TBI, into models of head injury to allow for better predictions of patient outcome. It is hoped that the work in this thesis lays the foundation for future work that aids in the design of improved automotive safety systems that will save countless human lives.

Die vorliegende Arbeit setzt sich mit der klinischen Anwendung von zwei neuen Monitoringparametern - Hirngewebe-PO2 in der weißen Substanz (PtiO2), und online intrakranielle Compliance (cICC) - im Rahmen des multimodalen zerebralen Monitorings bei Patienten mit schwerem Schädel-Hirn-Trauma auseinander. Bezüglich des PtiO2 konnte erstmalig eine Hypoxiegrenze von 8,5 mmHg durch vergleichende Messungen mit der jugular-venösen Oxymetrie ermittelt werden. Ferner konnte gezeigt werden, dass, bei intakter zerebraler Autoregulation, der PtiO2 bei einem zerebralen Perfusionsdruck (CPP) >60 mmHg über dem pathologischen Grenzwert liegt. Eine forcierte bzw. moderate Hyperventilation hingegen, induziert, trotz adäquatem CPP, eine Reduktion des PtiO2, die im individuellen Fall zur Unterschreitung des hypoxischen Grenzwerts führt. Das PtiO2-Verfahren ist somit v.a. dann indiziert, wenn eine Hyperventilationstherapie zur Kontrolle eines pathologisch erhöhten intrakraniellen Drucks (ICP) eingesetzt werden muss. PtiO2-Messwerte bedürfen aber einer kritischen Interpretation, sofern der PtiO2-Katheter in der Nähe einer Kontusion lokalisiert ist. Hier ist der PtiO2, als Ausdruck des perikontusionell reduzierten zerebralen Blutflusses, signifikant erniedrigt und somit nicht repräsentativ für die globale zerebrale Oxygenierung. Für die cICC konnte ebenfalls ein pathologischer Grenzwert angegeben werden (0,5 ml/mmHg). Die Dateninterpretation ist aber, durch die offensichtliche Abnahme der intrakraniellen Compliance mit zunehmendem Lebensalter, erschwert. Ferner bleibt die cICC bzgl. ihrer Datenqualität weit hinter etablierten Parametern zurück, so dass ihre routinemäßige Anwendung zum jetzigen Zeitpunkt nicht zu empfehlen ist. Basierend auf unseren Untersuchungen hat sich das PtiO2-Verfahren international als Langzeitmonitoring der zerebralen Oxygenierung etablieren können. Die cICC hingegen bedarf umfangreicher Systemänderungen, um eine frühe Risikoabschätzung bezüglich eines drohenden ICP-Anstiegs suffizient zu ermöglichen. / The aim of our clinical and experimental studies was to evaluate two new monitoring parameters -brain tissue PO2 (PtiO2) of cerebral white matter, and online intracranial compliance (cICC) - in patients with severe traumatic brain injury by using a computerized multimodal cerebral monitoring system. By comparing PtiO2 with jugular vein oxygen saturation, we were able to establish the hypoxic PtiO2-threshold of 8.5 mmHg. Moreover, we demonstrated that in case of an intact cerebral autoregulation, PtiO2 was well above the hypoxic threshold as long as cerebral perfusion pressure (CPP) stayed above 60 mmHg. However, forced or moderate hyperventilation carried an individual risk of a PtiO2 reduction below the hypoxic threshold despite an adequate CPP. PtiO2 monitoring is therefore particularly indicated, if hyperventilation therapy is necessary for control of pathologically increased intracranial pressure (ICP). However, PtiO2-values needed critical interpretation, if catheters were placed close to contusions. In these situations, PtiO2 has been shown to be significantly reduced, presumably due to low peri-contusional blood flow. Thus, such PtiO2 measurements cannot be taken as representatives of global cerebral oxygenation. In cICC monitoring, a pathological threshold was accomplished (0.5 ml/mmHg). Due to a stepwise cICC reduction with increasing age, cICC data interpretation was aggravated, and cICC data quality was significantly reduced in comparison to other established monitoring parameters. Hence, a routine use of this device is currently not advisable. Based on ours results, the PtiO2-methode has been established internationally as an ideal tool for long-term monitoring of cerebral oxygenation. On the contrary, the cICC system needs extensive alterations in order to anticipate sufficiently pathological ICP rises.

A monitoração intraventricular da pressão intracraniana (PIC) com drenagem contínua do líquido cefalorraquiano (LCR) já é um procedimento difundido na prática da neurocirurgia e considerado de grande importância diagnóstica, terapêutica e prognóstica por sua precisão. Entretanto, por se tratar de um método invasivo, apresenta riscos potenciais de complicações, sendo a infecção a mais freqüente. O presente estudo teve como objetivo verificar e analisar as taxas de infecções decorrentes deste método de monitoração da PIC, assim como as taxas de seus fatores de risco. As informações obtidas através de prontuários e arquivo dos exames laboratoriais foram registradas em duas fichas de coleta de dados próprias e posteriormente submetidas a testes estatísticos como o de Kruskal-Wallis, de Mann-Whitney, de qui-quadrado, teste exato de Fisher e o coeficiente de correlação de Spearman. Obtidas as freqüências relativas e absolutas, médias e desvio-padrão, sendo de 5% o nível de significância utilizado para os testes. A população deste estudo foi de 79 pacientes dos quais 70.9% eram do sexo masculino com média de 33.7 anos, sendo que os diagnósticos presentes em 82.3% eram referentes ao trauma craniencefálico (TCE) seguido de tumores intracranianos e acidentes vasculares cerebrais (AVCs). Todos fizeram uso de antibioticoprofilaxia. A taxa de ventriculite foi de 26.6%, permanecendo o cateter, em média, 6.7 dias e apresentando taxas diárias desta infecção variáveis. Não encontramos associação estatisticamente significativa entre tempo de monitoramento e infecção, porém houve um aumento no índice diário de ventriculite após os três primeiros dias e picos no 6°, 9° e 12° dia indicando uma provável ligação não acumulativa ou linear. Outras variáveis avaliadas neste estudo que apresentaram associação direta com a ocorrência de ventriculite foram o sexo masculino, hemorragia subdural e infecções em outros sítios, principalmente a sepses. Variáveis como idade, procedimentos invasivos, TCE aberto, fístulas liquóricas, hemorragia intraventricular, múltiplas ventriculostomias, presença de PIC acima de 20mmHg, intercorrências durante a cateterização ou manutenção desta não apresentaram associação com a taxa ventriculite, no entanto muitas destas variáveis estiveram presentes em poucos casos dificultando uma conclusão definitiva. / Intraventricular monitoring of the intracranial pressure (ICP) with continuous drainage of cerebrospinal fluid (CSF) is already a widespread procedure in neurosurgical practice and considered as of great diagnostic, therapeutic and prognostic importance due to its precision. However, as it is an invasive method, it presents a potential risk of complications, the infection being the most frequent. The present study aims at verifying and analyzing the rates of infection originating from this monitoring method of ICP, as well as the rates of its risk factors. The information obtained from case histories and laboratory test files were recorded on two own separate data collection cards and later submitted to statistical tests like the Kruskal-Wallis, Mann-Whitney, Chi-Square, Fisher’s exact test, and Spearman correlation coefficients. Relative and absolute, average and standard deviation frequency were verified, 5% was the significance level utilized for the tests. The population of this study was of 79 patients, 70.9% of which were male averaging 37.7 years of age, this being so that the diagnostics present in 82.3% are related to traumatic head injury followed by intracranial tumors and stroke. All of them made use of antibioticprophylaxis. The ventriculitis rate was of 26.6 %, the catheter remaining, on average, 6.7 days and showing variable daily rates of this infection. We have not found a statistically meaningful association between monitoring time and infection, however there was an increase in the daily ventriculitis rate after the first three days and peaks on the 6th, 9th and 12th days showing a probable non-cumulative or linear link. Other variables evaluated in this study which presented a direct association with the occurrence of ventriculitis were the male sex, subdural hemorrhage and infections at other sites, mainly sepsis. Variables such as age, invasive procedures, open traumatic head injury, CSF leaks, intraventricular hemorrhage, multiple ventriculostomies, presence of ICP above 20mmHg, intercurrences during catheterization or its maintenance did not show association with the ventriculitis rate, nevertheless many of these variables were present in few cases making a definite conclusion difficult.

This thesis explores physiological changes occurring after acute brain injury. The first two chapters focus on traumatic brain injury (TBI), a significant cause of disability and death worldwide. I discuss the evidence behind current management of secondary brain injury with emphasis on partial brain oxygen tension (PbtO2) and intracranial pressure (ICP). The second chapter describes a subgroup analysis of the effect of hypothermia on ICP and PbtO2 in 17 patients enrolled to the Eurotherm3235 trial. There was a mean decrease in ICP of 4.1 mmHg (n=9, p < 0.02) and a mean decrease in PbtO2 (7.8 ± 3.1 mmHg (p < 0.05)) in the hypothermia group that was not present in controls. The findings support previous studies in demonstrating a decrease in ICP with hypothermia. Decreased PbtO2 could partially explain worse outcomes seen in the hypothermia group in the Eurotherm3235 trial. Further analysis of PbtO2 and ICP guided treatment is needed. The third chapter focuses on delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH), another form of acute brain injury that causes significant morbidity and mortality. I include a background of alpha-calcitonin gene-related peptide (αCGRP), a potential treatment of DCI, along with results from a systematic review and meta-analysis of nine experimental models investigating αCGRP. The meta-analysis demonstrates a 40.8 ± 8.2% increase in cerebral vessel diameter in those animals treated with αCGRP compared with controls (p < 0.0005, 95% CI 23.7 to 57.9). Neurobehavioural scores were reported in four publications and showed a Physiological responses to brain tissue hypoxia and blood flow after acute brain injury standardised mean difference of 1.31 in favour of αCGRP (CI -0.49 to 3.12). I conclude that αCGRP reduces cerebral vessel narrowing seen after SAH in animal studies but note that there is insufficient evidence to determine its effect on functional outcomes. A review of previous trials of αCGRP administration in humans is included, in addition to an original retrospective analysis of CSF concentrations of αCGRP in humans. Enzyme-linked immunosorbent assay of CSF (n = 22) was unable to detect αCGRP in any sample, which contrasts with previous studies and was likely secondary to study methodology. Finally, I summarise by discussing a protocol I designed for a dose-toxicity study involving the intraventricular administration of αCGRP to patients with aSAH and provide some recommendations for future research. This protocol was based upon the systematic review and was submitted to the Medical Research Council's DPFS funding stream during the PhD.

Introdução: O aumento da pressão intracraniana (PIC) é um problema comum na prática neurocirúrgica, e a monitoração invasiva deste parâmetro faz parte da rotina de unidades de terapia intensiva. O Doppler transcraniano vem sendo testado na avaliação da hemodinâmica cerebral como parâmetro de avaliação não invasiva da PIC, porém há controvérsias na literatura sobre seu real benefício e utilidade nesta situação. Este estudo objetivou correlacionar os dados de avaliação do fluxo sanguíneo cerebral através da técnica de Doppler com as variações da monitoração invasiva da PIC na fase aguda de hipertensão intracraniana em um modelo animal. Métodos: Trata-se de um estudo experimental realizado em suínos. O experimento constou de dois grupos de animais (A e B) com hipertensão intracraniana gerada por insuflação com soro fisiológico de um balão no parênquima cerebral, sendo o grupo A com 4 mL e o grupo B com 7 mL. Nos dois grupos houve uma intervenção clínica com infusão de solução salina a 3% e uma simulação de intervenção cirúrgica (desinsuflação do balão). Em todos os momentos de insuflação do balão e das intervenções foram registrados os valores dos monitores de PIC e do Doppler: velocidades sistólica (VS), diastólica (VD), média (VM) do fluxo sanguíneo cerebral e índice de pulsatilidade (IP). Foram realizadas comparações do comportamento dos parâmetros avaliados pela ultrassonografia Doppler craniana (VS, VD, VM e IP) em relação às variações da PIC intraparenquimatosa. Resultados: Foram estudados 20 suínos sendo 10 no grupo A e 10 no grupo B. Um animal do grupo B foi excluído do estudo, pois foi a óbito antes do término do experimento. Após a insuflação do balão, como era de se esperar, a PIC no grupo B foi superior à do grupo A em todos os momentos, até a desinsuflação do mesmo. Realizada a correlação de Spearman observou-se correlação significativa entre IP e PIC, principalmente logo após insuflação do balão, ou seja, na elevação abrupta da PIC. Não houve correlação entre a PIC e os parâmetros VS, VD e VM. Também não houve variação significativa da PIC após infusão endovenosa de solução salina hipertônica. Conclusão: Este resultado demonstra o potencial do IP como bom parâmetro de avaliação de pacientes com suspeita de elevação hiperaguda e recente da PIC. Não se conseguiu demonstrar os mesmos resultados de correlação entre a PIC e as demais variáveis VS, VD e VM. Diante destes achados, adicionados aos dados conflitantes da literatura disponível até o momento, não se recomenda, por enquanto, a utilização desses parâmetros isoladamente como substitutos da monitoração invasiva da PIC, evidenciando a necessidade de mais estudos clínicos e experimentais / Introduction: Increased intracranial pressure (ICP) is a common problem in neurosurgical practice. Invasive monitoring of ICP in these cases is part of the intensive care unit routine. Transcranial Doppler has been tested in the evaluation of cerebral hemodynamics as a non-invasive evaluation of ICP, but there are controversies in the literature about its real benefit and usefulness in this situation. Thus, this study aimed to correlate the data of cerebral blood flow assessment using the Doppler technique and the invasive monitoring of ICP in the acute phase of intracranial hypertension in an animal model. Methods: This is an experimental study in pigs. During the experiment, an intracerebral expansive mass with an inflatable balloon was simulated. The experiment consisted of two groups (A and B) of animals with intracranial hypertension generated by a ballon inflation inside the cerebral parenchima, group A with 4 mL and group B with 7 mL. In both groups there was a clinical intervention with infusion of 3% saline solution and a simulation of surgical intervention (balloon drain out). The values of ICP and Doppler parameters (systolic (FVs), diastolic (FVd), and mean (FVm) cerebral blood flow velocities) were collected at all moments of balloon inflation and interventions, as well as the pulsatility index (PI). Comparisons of the behavior of the parameters evaluated by Doppler ultrasound (FVs, FVd, FVm and PI) were performed in relation to intraparenchymal ICP. Results: Twenty pigs were studied, 10 in group A and 10 in group B. One pig died in group B and it was excluded. After balloon inflation, as expected, ICP in group B was higher than in group A at all times, until the ballon was empty again. Significant correlation between PI and ICP was obtained when Spearman correlation was performed, mainly shortly after balloon inflation, that is, in the abrupt elevation of ICP. There was no correlation between ICP and FVs, FVd or FVm. There was also no significant change in ICP after intravenous infusion of hypertonic saline solution. Conclusion: These results demonstrate the potential of PI as a good parameter for the evaluation of patients with suspected ICP elevation. It was not possible to demonstrate the same correlation results between the ICP and FVs, FVd or FVm. Due to these results and also to the literature conflicting data to date, the use of these parameters alone as substitutes for the invasive monitoring of ICP is not recommended until now, which shows the need for further clinical and experimental studies

<p>Traumatic brain injury (TBI) is a major cause of death and disability. Intracranial secondary insults (e.g. intracranial haematoma, brain oedema) and systemic secondary insults (e.g. hypotension, hypoxaemia, hyperthermia) lead to secondary brain injury and affect outcome adversely. In order to minimise secondary insults and to improve outcome in TBI-patients, a secondary insult program and standardised neurointensive care (NIC) was implemented. The aim of this thesis was to describe patient outcome and to explore the occurrence and prognostic value of secondary insults after the implementation.</p><p>Favourable outcome was achieved in 79% and 6% died of the 154 adult TBI patients treated in the NIC unit 1996-97. In an earlier patient series from the department, 48% made a favourable outcome and 31% died. Hence, the outcome seems to have improved when NIC was standardised and dedicated to avoiding secondary insults. </p><p>Secondary insults counted manually from hourly recordings on surveillance charts did not hold any independent prognostic information. When utilising a computerised system, which enables minute-by-minute data collection, the proportion of monitoring time with systolic blood pressure > 160 mm Hg decreased the odds of favourable outcome independent of admission variables (odds ratio 0.66). Hyperthermia was related to unfavourable outcome. Hypertension was correlated to hyperthermia and may be a part of a hyperdynamic state aggravating brain oedema. </p><p>Increased proportion of monitoring time with cerebral perfusion pressure (CPP) < 60 mm Hg increased the odds of favourable outcome (odds ratio 1.59) in patients treated according to an intracranial pressure (ICP)-oriented protocol (Uppsala). In patients given a CPP-oriented treatment (Edinburgh), CPP <60 mm Hg was coupled to an unfavourable outcome. It was shown that pressure passive patients seem to benefit from an ICP-oriented protocol and pressure active patients from a CPP-oriented protocol. The overall outcome would improve if patients were given a treatment fit for their condition.</p>

Our brain, perhaps the most sophisticated and mysterious part of the human body, to some extent, determines who we are. However, it’s a vulnerable organ. When subjected to an impact, such as a traffic accident or sport, it may lead to traumatic brain injury (TBI) which can have devastating effects for those who suffer the injury. Despite lots of efforts have been put into primary injury prevention, the number of TBIs is still on an unacceptable high level in a global perspective. Brain edema is a major neurological complication of moderate and severe TBI, which consists of an abnormal accumulation of fluid within the brain parenchyma. Clinically, local and minor edema may be treated conservatively only by observation, where the treatment of choice usually follows evidence-based practice. In the first study, the gravitational force is suggested to have a significant impact on the pressure of the edema zone in the brain tissue. Thus, the objective of the study was to investigate the significance of head position on edema at the posterior part of the brain using a Finite Element (FE) model. The model revealed that water content (WC) increment at the edema zone remained nearly identical for both supine and prone positions. However, the interstitial fluid pressure (IFP) inside the edema zone decreased around 15% by having the head in a prone position compared with a supine position. The decrease of IFP inside the edema zone by changing patient position from supine to prone has the potential to alleviate the damage to axonal fibers of the central nervous system. These observations suggest that considering the patient’s head position during intensive care and at rehabilitation should be of importance to the treatment of edematous regions in TBI patients. In TBI patients with diffuse brain edema, for most severe cases with refractory intracranial hypertension, decompressive craniotomy (DC) is performed as an ultimate therapy. However, a complete consensus on its effectiveness has not been achieved due to the high levels of severe disability and persistent vegetative state found in the patients treated with DC. DC allows expansion of the swollen brain outside the skull, thereby having the potential in reducing the Intracranial Pressure (ICP). However, the treatment causes stretching of the axons and may contribute to the unfavorable outcome of the patients. The second study aimed at quantifying the stretching and WC in the brain tissue due to the neurosurgical intervention to provide more insight into the effects upon such a treatment. A nonlinear registration method was used to quantify the strain. Our analysis showed a substantial increase of the strain level in the brain tissue close to the treated side of DC compared to before the treatment. Also, the WC was related to specific gravity (SG), which in turn was related to the Hounsfield unit (HU) value in the Computerized Tomography (CT) images by a photoelectric correction according to the chemical composition of the brain tissue. The overall WC of brain tissue presented a significant increase after the treatment compared to the condition seen before the treatment. It is suggested that a quantitative model, which characterizes the stretching and WC of the brain tissue both before as well as after DC, may clarify some of the potential problems with such a treatment. Diffusion Weighted (DW) Imaging technology provides a noninvasive way to extract axonal fiber tracts in the brain. The aim of the third study, as an extension to the second study was to assess and quantify the axonal deformation (i.e. stretching and shearing)at both the pre- and post-craniotomy periods in order to provide more insight into the mechanical effects on the axonal fibers due to DC. Subarachnoid injection of artificial cerebrospinal fluid (CSF) into the CSF system is widely used in neurological practice to gain information on CSF dynamics. Mathematical models are important for a better understanding of the underlying mechanisms. Despite the critical importance of the parameters for accurate modeling, there is a substantial variation in the poroelastic constants used in the literature due to the difficulties in determining material properties of brain tissue. In the fourth study, we developed a Finite Element (FE) model including the whole brain-CSF-skull system to study the CSF dynamics during constant-rate infusion. We investigated the capacity of the current model to predict the steady state of the mean ICP. For transient analysis, rather than accurately fit the infusion curve to the experimental data, we placed more emphasis on studying the influences of each of the poroelastic parameters due to the aforementioned inconsistency in the poroelastic constants for brain tissue. It was found that the value of the specific storage term S_epsilon is the dominant factor that influences the infusion curve, and the drained Young’s modulus E was identified as the dominant parameter second to S_epsilon. Based on the simulated infusion curves from the FE model, Artificial Neural Network (ANN) was used to find an optimized parameter set that best fit the experimental curve. The infusion curves from both the FE simulations and using ANN confirmed the limitation of linear poroelasticity in modeling the transient constant-rate infusion. To summarize, the work done in this thesis is to introduce FE Modeling and imaging technologiesincluding CT, DW imaging, and image registration method as a complementarytechnique for clinical diagnosis and treatment of TBI patients. Hopefully, the result mayto some extent improve the understanding of these clinical problems and improve theirmedical treatments. / QC 20120201

Traumatic brain injury (TBI) is a major cause of death and disability. Intracranial secondary insults (e.g. intracranial haematoma, brain oedema) and systemic secondary insults (e.g. hypotension, hypoxaemia, hyperthermia) lead to secondary brain injury and affect outcome adversely. In order to minimise secondary insults and to improve outcome in TBI-patients, a secondary insult program and standardised neurointensive care (NIC) was implemented. The aim of this thesis was to describe patient outcome and to explore the occurrence and prognostic value of secondary insults after the implementation. Favourable outcome was achieved in 79% and 6% died of the 154 adult TBI patients treated in the NIC unit 1996-97. In an earlier patient series from the department, 48% made a favourable outcome and 31% died. Hence, the outcome seems to have improved when NIC was standardised and dedicated to avoiding secondary insults. Secondary insults counted manually from hourly recordings on surveillance charts did not hold any independent prognostic information. When utilising a computerised system, which enables minute-by-minute data collection, the proportion of monitoring time with systolic blood pressure &gt; 160 mm Hg decreased the odds of favourable outcome independent of admission variables (odds ratio 0.66). Hyperthermia was related to unfavourable outcome. Hypertension was correlated to hyperthermia and may be a part of a hyperdynamic state aggravating brain oedema. Increased proportion of monitoring time with cerebral perfusion pressure (CPP) &lt; 60 mm Hg increased the odds of favourable outcome (odds ratio 1.59) in patients treated according to an intracranial pressure (ICP)-oriented protocol (Uppsala). In patients given a CPP-oriented treatment (Edinburgh), CPP &lt;60 mm Hg was coupled to an unfavourable outcome. It was shown that pressure passive patients seem to benefit from an ICP-oriented protocol and pressure active patients from a CPP-oriented protocol. The overall outcome would improve if patients were given a treatment fit for their condition.

Severe Traumatic Brain Injury (TBI) and aneurysmal Subarachnoid Hemorrhage (SAH) are severe cerebral emergencies. They are common reasons for extensive morbidity and mortality in young people and adults in the western world. This thesis, based on five clinical studies in patients with severe TBI (I-IV) and SAH (V), is concentrated on examination of pathophysiological developments and of evaluation of therapeutic approaches in order to improve outcome after cerebral emergency. The treatment for severe TBI patients at Umeå University Hospital, Sweden is an intracranial pressure (ICP)-targeted therapy according to “the Lund-concept”. This therapy is based on physiological principles for cerebral volume regulation, in order to preserve a normal cerebral microcirculation and a normal ICP. The main goal is to avoid development of secondary brain injuries, thus avoiding brain oedema and worsened microcirculation. Study I is evaluating retrospectively 41 children with severe TBI, from 1993 to 2002. The boundaries of the ICP-targeted protocol were obtained in 90%. Survival rate was 93%, and favourable outcome (Glasgow Outcome Scale, score 4+5) was 80%. Study II is retrospectively analysing fluid administration and fluid balance in 93 adult patients with severe TBI, from 1998 to 2001.The ICP-targeted therapy used, have defined fluid strategies. The total fluid balance was positive day one to three, and negative day four to ten. Colloids constituted 40-60% of total fluids given/day. Severe organ failure was evident for respiratory insufficiency and observed in 29%. Mortality within 28 days was 11%. Study III is a prospective, randomised, double-blind, placebo-controlled clinical trial in 48 patients with severe TBI. In order to improve microcirculation and prevent oedema formation, prostacyclin treatment was added to the ICP-targeted therapy. Prostacyclin is endogenously produced, by the vascular endothelium, and has the ability to decrease capillary permeability and vasodilate cerebral capillaries. Prostacyclin is an inhibitor of leukocyte adhesion and platelet aggregation. There was no significant difference between prostacyclin or placebo groups in clinical outcome or in cerebral microdialysis markers such as lactatepyruvate ratio and brain glucose levels. Study IV is part of the third trial and focus on the systemic release of pro-inflammatory mediators that are rapidly activated by trauma. The systemically released pro-inflammatory mediators, interleukin-6 and CRP were significantly decreased in the prostacyclin group versus the placebo group. Study V is a prospective pilot study which analyses asymmetric dimethylarginine (ADMA) concentrations in serum from SAH patients. Acute SAH patients have cerebral vascular, systemic circulatory and inflammatory complications. ADMA is a marker in vascular diseases which is correlated to endothelial dysfunction. ADMA concentrations in serum were significantly elevated seven days after the SAH compared to admission and were still elevated at the three months follow-up. Our results show overall low mortality and high favourable outcome compared to international reports on outcome in severe TBI patients. Prostacyclin administration does not improve cerebral metabolism or outcome but significantly decreases the levels of pro-inflammatory mediators. SAH seems to induce long-lasting elevations of ADMA in serum, which indicates persistent endothelial dysfunction. Endothelial dysfunction may influence outcome after severe cerebral emergencies.