Patients admitted in similar clinical condition after spontaneous SAH can develop very different clinical courses. This could depend on the severity of the initial global ischemic brain injury at ictus. In the present study, we explored relations between clinical and radiological parameters at admission that indicate a more severe initial impact, and the following days hormone levels and brain metabolism. Early global cerebral oedema (GCE) on computed tomography occurred in 57 % of SAH patients and was associated with a more severe clinical condition. The brain’s glucose metabolism, measured with intracerebral microdialysis (MD), changed the first days. MD-glucose was initially high and MD-pyruvate low. MD-glucose gradually decreased and MD-pyruvate and MD-lactate increased, suggesting a transition to a hyperglycolytic state. This was more pronounced in patients with GCE. Similar patterns were seen for interstitial non-transmitter amino acids. From initial low concentrations, they gradually increased in parallel with MD-pyruvate. The amino acid concentrations were higher for patients admitted in better clinical condition. Insulin lowered MD-glucose and MD-pyruvate even when plasma glucose values remained high. P-ACTH and S-cortisol were elevated early after SAH. GCE was associated with higher S-cortisol acutely. Urine cortisol excretion, indicating levels of free cortisol, were higher in patients in a better clinical condition. Suppressed P-ACTH occurred in periods of brain ischemia. We suggest that GCE on the first CT scan is a warning sign indicating increased vulnerability if the patient is exposed to compromised energy supply or increased energy demand. Reduction of blood glucose after SAH should be done with caution. The temporal change of the glucose metabolism and the amino acid concentrations probably reflect activated repair mechanisms. This should be considered in the intensive care treatment of SAH patients. Finally, our results support earlier observations that the response of the hypothalamic-pituitary-adrenal system is important in critical care.

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.

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.

Univerzita Karlova v Praze 1. lékařská fakulta Autoreferát disertační práce Optimalizace indikací chirurgického a endovaskulárního ošetření intrakraniálních aneurysmat Anna Štekláčová 2018 2 Doktorské studijní programy v biomedicíně Univerzita Karlova v Praze a Akademie věd České republiky Obor: Neurovědy Předseda oborové rady: Prof. MUDr. Karel Šonka, DrSc. Školicí pracoviště: Neurochirurgická a neuroonkologická klinika 1. LF UK a ÚVN, Praha Školitel: Prof. MUDr. Vladimír Beneš, DrSc. Disertační práce bude nejméně pět pracovních dnů před konáním obhajoby zveřejněna k nahlížení veřejnosti v tištěné podobě na Oddělení pro vědeckou činnost a zahraniční styky Děkanátu 1. lékařské fakulty. 3 Obsah Abstrakt - Česky ..................................................................................... 4 Abstract - English ................................................................................... 5 Úvod........................................................................................................ 6 Hypotézy a cíle studie............................................................................. 6 Materiál a metody ................................................................................... 7 Výsledky...