published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

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 (M.S.)--University of Wisconsin--Madison, 1947. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaf 45).

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

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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.

These studies investigated 1) mechanisms underlying the well-established reduction in orthostatic tolerance (OT) that occurs in humans during heat stress (HS) relative to normothermia (NT) with particular focus on determining factors contributing to the high degree of inter-individual variability in this phenomenon; and 2) influence of obesity on OT, and mechanisms underlying reduced OT, should it exist. In Study #1, OT was assessed during lower body negative pressure (LBNP), and quantified with a cumulative stress index (CSI). Differences in CSI (CSIdiff) between thermal conditions were used to categorize individuals most (LargeDiff) and least (SmallDiff) affected by HS (P<0.001). Cerebral perfusion [indexed as middle cerebral artery blood velocity (MCA Vm̳̳e̳a̳n̳)] was reduced during HS compared to NT (P<0.001); however, the magnitude of reduction did not differ between groups (P=0.51). In the initial stage of LBNP during HS (LBNP20), MCA Vm̳̳e̳a̳n̳ and end-tidal CO₂ (PETC̳O̳₂) were reduced, and heart rate (HR) was higher in the LargeDiff group compared to SmallDiff group (all P<0.05); yet, mean arterial pressure was similar (P=0.23) suggesting impaired mechanisms regulating MCA Vm̳̳e̳a̳n̳ may affect OT. In Study #2, mechanisms of cerebrovascular control were compared in LargeDiff and SmallDiff individuals. Although estimates of cerebral autoregulation (CA) and cerebrovascular reactivity to CO₂ were improved and reduced respectively, during HS compared to NT (all P<0.05), no relationship existed between CA or cerebral reactivity to hypocapnia and CSIdiff (all P>0.05). In Study #3, OT was lower in obese compared to non-obese individuals (P<0.01), and BMI was negatively correlated with CSI (R = -0.47; P < 0.01). HR was elevated at rest and in every level of LBNP (all P<0.05) in obese; yet, peak HR during LBNP was similar between groups (P=0.90). MCA Vm̳̳e̳a̳n̳ and cerebral vascular conductance were similar at rest and during LBNP (both P>0.05), and CA was similar between groups (P>0.05). In summary, a high HR prior to-, and a high HR and reduced MCA Vm̳̳e̳a̳n̳ at the onset of an orthostatic challenge result in reduced OT during HS in healthy individuals; however, reduced OT in obese is related to a higher %peak HR at rest. / text

Traumatic pelvic injuries associated with high-energy pelvic fractures are life-threatening injuries. Extensive bleeding is relatively common with pelvic fractures. However, bleeding is especially prevalent with high-energy fractures. Hemorrhage remains the major cause of death that occur within the first 24 hours after a traumatic pelvic injury. Emergent-life saving treatment is required for high-energy pelvic fractures associated with hemorrhage. A thorough understanding of potential sources of bleeding within a short period is essential for diagnosis and treatment planning. Computed Tomography (CT) images have been widely in use in identifying the potential sources of bleeding. A pelvic CT scan contains a large number of images. Analyzing each slice in a scan via simple visual inspection is very time consuming. Time is a crucial factor in emergency medicine. Therefore, a computer-assisted pelvic trauma decision-making system is advantageous for assisting physicians in fast and accurate decision making and treatment planning. The proposed project presents an automated system to detect and segment hemorrhage and combines it with the other extracted features from pelvic images and demographic data to provide recommendations to trauma caregivers for diagnosis and treatment. The first part of the project is to develop automated methods to detect arteries by incorporating bone information. This part of the project merges bone edges and segments bone using a seed growing technique. Later the segmented bone information is utilized along with the best template matching to locate arteries and extract gray level information of the located arteries in the pelvic region. The second part of the project focuses on locating the source of hemorrhage and its segmentation. The hemorrhage is segmented using a novel rule based hemorrhage segmentation approach. This approach segments hemorrhage through hemorrhage matching, rule optimization, and region growing. Later the position of hemorrhage in the image and the volume of the hemorrhage are determined to analyze hemorrhage severity. The third part of the project is to automatically classify the outcome using features extracted from the medical images and patient medical records and demographics. A multi-stage feature selection algorithm is used to select the predominant features among all the features. Finally, boosted logistic model tree is used to classify the outcome. The methods are tested on CT images of traumatic pelvic injury patients. The hemorrhage segmentation and classification results seem promising and demonstrate that the proposed method is not only capable of automatically segmenting hemorrhage and classifying outcome, but also has the potential to be used for clinical applications. Finally, the project is extended to abdominal trauma and a novel knowledge based heuristic technique is used to detect and segment spleen from the abdominal CT images. This technique is tested on a limited number of subjects and the results are promising.

Controlled hydrogel dissolution allows for: 1) atraumatic material removal after it served its function, 2) site-specific delivery of encapsulated therapeutics (e.g., proteins, small molecules), and 3) a tailored administration of an agent with high efficiency. Dissolution of covalently crosslinked hydrogels has been accomplished by incorporating cleavable moieties that undergo ester hydrolysis or enzymatic degradation. Recently, thiol-disulfide exchange, retro Michal-type reactions, retro Diels-Alder reactions, and thiol-thioester exchange chemistries have gained attention, as they provide a responsive synthetic handle for engineering hydrogel dissolution rates. We synthesized, characterized and tested in vivo two on-demand dissolvable dendritic thioester hydrogel dressings for second-degree burn care and hemorrhage control. The hydrogels are composed of lysine-based dendrons and PEG-based crosslinkers, which were prepared in high yields. In context of hemorrhage, there is an unmet clinical need for an on-demand dissolvable sealant for non-compressible hemorrhage or areas of body not amenable to treatment with a torniquet. In a model of in vivo hemorrhage control of intra-abdominal wounds, our hydrogel reduced blood loss by 33% in severe hepatic hemorrhage and by 22% in aortic injury, as compared to untreated controls. There is an unmet clinical need for a second-degree burn dressing that can be removed atraumatically and serve as a barrier to bacterial infection. When our hydrogel was used as a dressing, local and systemic bacterial proliferation after wound contamination was significantly lower than in the untreated group. The total bacterial burden of the burn wound in the positive controls was significantly higher than in the hydrogel group and the negative controls (1.39x10E8 ± 8.30x10E7 CFU/g v. 4.04x10E3 ± 3.99x10E3 CFU/g v. 6.88x10E2 ± 6.38x10E2 respectively; P = 0.009). Also, the total systemic bacterial burden in the positive controls was significantly higher than the hydrogel group and the negative controls (9x10E2 ± 7.76x10E7 CFU/g v. 5x10E1 ± 0 CFU/g v. 5x10E1 ± 0 CFU/g, respectively; P = 0.031). A unique feature of both hydrogel systems is their capability to be dissolved on-demand via thiol-thioester exchange reaction with a biocompatible solution following its initial application – thus the wound area can be re-exposed to allow for definitive surgical care.