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Viele Studien haben sich bereits mit Nutzen und Risiken einer intensivierten Insulintherapie (IIT) intensivmedizinischer Patienten auseinandergesetzt. Die unterschiedlichen Ergebnisse gaben Anlass, die Auswirkungen einer Hyperglykämie auf Patienten mit einer Subarachnoidalblutung (SAB) weiter zu analysieren. In diesem Zusammenhang war der Stellenwert einer IIT von besonderem Interesse. Um den Einfluss des erhöhten Blutzuckers möglichst genau zu erfassen, wurde mittels Integralfunktion die Blutzuckerhöhe in Abhängigkeit der Zeit bestimmt. Es konnte ein negativer Einfluss einer hyperglykämen Stoffwechsellage auf den Krankheitsverlauf der Patienten dargestellt werden. Hervorzuheben sind hier vor allem Patienten, die sich initial in einem besseren Zustand befanden. Anschließend erfolgte die Einführung einer intensivierten Insulintherapie. In der IIT war es nicht immer möglich, den gewünschten Zielbereich des Blutzuckers zu erreichen, um einen signifikanten Unterschied beider Therapiegruppen bezüglich der Blutzuckereinstellung zu erhalten. Dennoch zeigte sich ein deutlicher Trend zugunsten der intensiviert therapierten Gruppe und dessen Krankheitsverlauf. Die Behandlung der Hyperglykämie durch eine IIT bleibt ein wichtiger Aspekt in der Intensivmedizin. Anzustreben ist eine moderate Insulintherapie, damit sowohl Hypo- als auch Hyperglykämien weitestgehend verhindert und so das Genesungspotential der Patienten unterstützt werden kann.

Thesis (doctoral)--Lund University, 1999. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1999. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Cerebral ischaemia, or stroke, is a leading cause of death and disability worldwide. Ischaemic stroke, as a result of arterial occlusion, and subarachnoid haemorrhage (SAH), as a consequence of arterial rupture in the subarachnoid space, are major subtypes of stroke. Treatment options for both are limited, and many therapeutic strategies have failed. In ischaemic stroke, lack of evidence of brain penetration of treatments has been cited as a major weakness and contributing factor to failed clinical trials. In SAH, animal models do not always mimic key pathophysiological hallmarks of the disease, hindering development of new therapeutics. Inflammation is strongly associated with brain injury after cerebral ischaemia and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents apossible therapeutic target. Therefore, the key objectives of this thesis were; (1) to improve preclinical data on a promising stroke treatment, interleukin-1 receptor antagonist (IL-1Ra), by investigating its pharmacokinetic profile and brain penetration in a rat model of ischaemic stroke, (2) to investigate the endovascular perforation model of SAH in rat, as a tool for the investigation of neuroprotectants, and (3) to examine the role of the inflammatory response in the SAH model and the effects of IL-1Ra. The neuroprotective effect, pharmacokinetic profile and brain penetration of IL-1Ra were assessed after a single subcutaneous (s.c.) dose (100mg/kg) in rats, after transient (90 min) middle cerebral artery occlusion (MCAo). A single s.c. dose of IL-1Ra reduced neuronal damage, resulted in sustained, high concentrations of IL-1Ra in plasma and cerebrospinal fluid and also penetrated brain tissue exclusively in areas of blood brain-barrier (BBB) breakdown. An endovascular perforation model of SAH in rat was investigated and produced widespread multifocal infarcts. In this model, administration of IL-1Ra (s.c.) reduced BBB breakdown, which correlated with injury at 48 h. IL-1_ was expressed in the brain early after SAH in areas associated with haem oxygenase-1 (HO-1) expression, indicating the presence of free haem. Stimulation of primary mouse mixed glial cells in vitro with haem induced expression and release of IL-1 alpha but not IL-1 beta. These data, after MCAo in rat, are the first to show that a single s.c. dose of IL-1Ra rapidly reaches salvageable brain tissue and is neuroprotective. This allows confidence that IL-1Ra is able to confer its protective actions both peripherally and centrally. After experimental SAH, we suggest that haem, a breakdown product of haemoglobin, released from lysed red blood cells in the subarachnoid space, acts as a danger associated molecular pattern (DAMP) driving IL-1- dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate treatment for the disease. Overall, these findings strengthen preclinical data supporting IL-1Ra as a neuroprotective therapy for ischaemic stroke, and identify SAH as a new indication for treatment with IL-1Ra.

INTRODUCTION: Traumatic brain injury (TBI) is a major public health problem, causing approximately 52,000 deaths from 1.7 million injuries in the United States annually, with a combined direct and indirect economic cost estimated at $60-75 billion per year. Traumatic subarachnoid hemorrhage (tSAH), a subtype of closed head injury, has a high prevalence within TBI—evident in up to two-thirds of moderately and severely brain injured patients. tSAH is also associated with poor clinical outcomes; some research suggests mortality and unfavorable outcome rates are two-to-three times higher in patients with tSAH, based on brain imaging, compared to those without. To date, no pharmacological treatment has been conclusively shown to improve outcomes in humans for either moderate or severe TBI or for specific tSAH injury. The aim of this study was to assess whether the effect of PROG was substantially different in study TBI patients with evidence of tSAH on initial brain imaging compared to those that did not have evidence of tSAH. METHODS: ProTECT III clinical trial data was used for an exploratory, post hoc subgroup analysis to determine the effect of the hormone progesterone (PROG) on outcome. Study subjects with any abnormality on baseline brain imaging were included in the analysis and two subgroups, tSAH positive (+tSAH) and tSAH negative (–tSAH), were selected. The primary outcome evaluated was a favorable/unfavorable dichotomy derived from the 6-months post-injury Extended Glasgow Outcome Scale (GOSE) assessment, which evaluates both mortality and functional outcomes. Risk ratios (RRs) were calculated for the total sample and each of the two subgroups and used as statistical evidence for interaction between PROG and tSAH. RESULTS: All subjects from the original ProTECT III trial cohort (N=882) with no abnormalities found on baseline computed tomography (CT) image (n=125) or missing image (n=1) were excluded from this analysis. Subjects with one or more abnormalities noted on CT (+CT, n=756) were then divided into subgroups based on presence (n=582) or absence (n=174) of tSAH. Subjects with +tSAH were more severely injured than –tSAH (mean Rotterdam CT score 3.3 vs. 2.2; 3.1 overall) and had a lesser proportion of favorable outcomes (47.4% vs. 74.3%; 53.6% overall). Compared to placebo, patients treated with progesterone had marginally better likelihood of favorable outcomes (risk ratio among +tSAH 1.06, 95% confidence interval [CI], 0.89 to 1.26; and RR among –tSAH 1.02, 95% CI 0.85 to 1.22). A multivariable model, adjusted for baseline differences in treatment group covariates did not yield substantially different results for the effect of progesterone on favorable outcomes (+tSAH 1.07; 95% confidence interval [CI], 0.84 to 1.36, –tSAH 1.08; 95% CI 0.75 to 1.56, +CT 1.06; 95% CI 0.87 to 1.29). CONCLUSION: Our study demonstrated that progesterone did not result in different effects in patients with or without tSAH than those without based on initial brain imaging. This investigation supports previous research findings; tSAH is correlated with more severe injury and worsened outcomes. Concomitant injuries found in +tSAH group are likely worsening the outcomes over –tSAH, but this was not evaluated here. More complex statistical modeling should be used on this data to determine if it provides evidence that tSAH is an independent prognosticator of unfavorable outcome or merely associated with more severely injured patients.

<p><strong>Background</strong> Subarachnoid hemorrhage is a condition with high rates of mortality and morbidity. The diagnosis requires an urgent cerebral computed tomography scan and also a lumbar puncture if the scan fails to demonstrate intracranial blood. In Sweden the cerebrospinal fluid (CSF) is analyzed by spectrophotometric scanning for the presence of hemoglobin and bilirubin. The aim of the study was to develop a quantitative diazo reagent based analysis of cerebrospinal fluid bilirubin as a replacement for spectrophotometric scanning.</p><p><strong>Methods</strong> The CSF bilirubin assay on an Architect C8000 chemistry analyzer was compared with spectrophotometry using patient samples.</p><p><strong>Results</strong> The method correlates with spectrophotometry, has a good linearity and precision.</p><p><strong>Conclusions</strong> Quantitative bilirubin measurement offers shorter turnaround times, simplifies the interpretation of the results and reduces work load in comparison with spectrophotometry.</p>

Background Subarachnoid hemorrhage is a condition with high rates of mortality and morbidity. The diagnosis requires an urgent cerebral computed tomography scan and also a lumbar puncture if the scan fails to demonstrate intracranial blood. In Sweden the cerebrospinal fluid (CSF) is analyzed by spectrophotometric scanning for the presence of hemoglobin and bilirubin. The aim of the study was to develop a quantitative diazo reagent based analysis of cerebrospinal fluid bilirubin as a replacement for spectrophotometric scanning. Methods The CSF bilirubin assay on an Architect C8000 chemistry analyzer was compared with spectrophotometry using patient samples. Results The method correlates with spectrophotometry, has a good linearity and precision. Conclusions Quantitative bilirubin measurement offers shorter turnaround times, simplifies the interpretation of the results and reduces work load in comparison with spectrophotometry.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 73-84).