1,697 research outputs found

    Cerebral Autoregulation-Based Blood Pressure Management In The Neuroscience Intensive Care Unit: Towards Individualizing Care In Ischemic Stroke And Subarachnoid Hemorrhage

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    The purpose of this thesis is to review the concept of cerebral autoregulation, to establish the feasibility of continuous bedside monitoring of autoregulation, and to examine the impact of impaired autoregulation on functional and clinical outcomes following subarachnoid hemorrhage and ischemic stroke. Autoregulation plays a key role in the regulation of brain blood flow and has been shown to fail in acute brain injury. Disturbed autoregulation may lead to secondary brain injury as well as worse outcomes. Furthermore, there exist several methodologies, both invasive and non-invasive, for the continuous assessment of autoregulation in individual patients. Resultant autoregulatory parameters of brain blood flow can be harnessed to derive optimal cerebral perfusion pressures, which may be targeted to achieve better outcomes. Multiple studies in adults and several in children have highlighted the feasibility of individualizing mean arterial pressure in this fashion. The thesis herein argues for the high degree of translatability of this personalized approach within the neuroscience intensive care unit, while underscoring the clinical import of autoregulation monitoring in critical care patients. In particular, this document recapitulates findings from two separate, prospectively enrolled patient groups with subarachnoid hemorrhage and ischemic stroke, elucidating how deviation from dynamic and personalized blood pressure targets associates with worse outcome in each cohort. While definitive clinical benefits remain elusive (pending randomized controlled trials), autoregulation-guided blood pressure parameters wield great potential for constructing an ideal physiologic environment for the injured brain. The first portion of this thesis discusses basic autoregulatory physiology as well as various tools to interrogate the brain’s pressure reactivity at the bedside. It then reviews the development of the optimal cerebral perfusion pressure as a biological hemodynamic construct. The second chapter pertains to the clinical applications of bedside neuromonitoring in patients with aneurysmal subarachnoid hemorrhage. In this section, the personalized approach to blood pressure monitoring is discussed in greater detail. Finally, in the third chapter, a similar autoregulation-oriented blood pressure algorithm is applied to a larger cohort of patients with ischemic stroke. This section contends that our novel, individualized strategy to hemodynamic management in stroke patients represents a better alternative to the currently endorsed practice of maintaining systolic blood pressures below fixed and static thresholds

    Interplay between blood-brain barrier disruption and neuroinflammation following severe traumatic brain injury

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    A severe traumatic brain injury (TBI) holds deleterious consequences for the afflicted, its next-of-kin and society. Still today, prognosis is semi-desolate. One explanation for this might be pathophysiological processes ensuing the primary trauma that are but indirectly targeted for treatment. Among such processes, blood-brain barrier (BBB) disruption and neuroinflammation constitute two astrocyte-dependent mechanisms that interplay in the aftermath of a severe TBI. The overall aim of this thesis was to characterize both BBB disruption and neuroinflammation translationally. In paper I, n = 17 patients with severe TBI were included in a prospective observational longitudinal study. Here, the protein biomarkers S100B and neuron-specific enolase (NSE) were sampled with high temporal resolution from both cerebrospinal fluid (CSF) and blood. We found that BBB disruption occurred among numerous patients and remained throughout the first week following injury. Interestingly, BBB disruption also affected clearance from brain to blood of S100B, but not NSE. This indicates that biomarkers are cleared differently from the injured CNS. We elaborated on this by utilizing a larger cohort size (n = 190 patients), which enabled outcome prediction modelling, in paper II. In this prospective, observational, cross-sectional study, we found that BBB disruption comprised a novel, independent outcome predictor that strongly related to levels of neuroinflammatory proteins in CSF and inflammatory processes within the injured brain. Among pathways assessed, particularly the complement system entailed proteins of future interest. We next assessed the relationship between in situ neuroinflammatory protein expression, BBB disruption, and brain edema in paper III. By utilizing a rodent model of severe TBI, we found that the cytotoxic edema region was associated with an innate neuroinflammatory response, and astrocytic aquaporin-4 retraction from the BBB interface. In fact, the astrocyte itself is an important neuroinflammatory cell, which we showed in paper IV, where we constructed a disease-modelling system of stem cell-derived astrocytes that we exposed to neuroinflammatory substances. Following neuroinflammatory stimulus, astrocytes exhibited an important increase in canonical stress-response pathways. Importantly, following stimulation with clinically relevant neuroinflammatory substances seen in human TBI from paper II, they also acquired a neurotoxic potential, of plausible importance for local cell survival following a severe TBI. Taken together, BBB disruption and neuroinflammation ensue a severe TBI. Neuroinflammation, particularly mediated by the complement system, stands out as a future therapeutic target in order to mitigate exacerbated BBB disruption. Locally in the lesion vicinity, additional neuroinflammatory mechanisms are in part mediated by astrocytes, where these cells seem to have an important role in local cell survival. Onwards, our findings suggest that future efforts should be directed at evaluating if neuroinflammatory modulation of complement inhibition yields improved outcome, while elaborating on the promising experimental data of astrocyte-mediated effects in the lesion vicinity

    Association between baseline pulse pressure and hospital mortality in non-traumatic subarachnoid hemorrhage patients: a retrospective cohort study

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    Background and purposePrevious studies have described an association between pulse pressure (PP) level and mortality in stroke patients. Evidence of associations between PP level and the risk of mortality remains unknown in non-traumatic subarachnoid hemorrhage (SAH) patients. We aimed to explore the relationship between the baseline PP level and hospital mortality.MethodsThis cohort study of 693 non-traumatic SAH adults used Medical Information Mart for Intensive Care (MIMIC-IV) data from 2008–2019 admissions to Intensive Care Unit (ICU). PP level was calculated as the first value after admission to the ICU. The endpoint of the study was in-hospital mortality. Cox proportional hazards models were utilized to analyze the association between baseline PP level and hospital mortality. Restricted Cubic Splines (RCS) analysis was utilized to determine the relationship curve between hospital mortality and PP level and examine the threshold saturation effect. We further applied Kaplan–Meier survival curve analysis to examine the consistency of these correlations. The interaction test was used to identify subgroups with differences.ResultsThe mean age of the study population was 58.8 ± 14.6 years, and 304 (43.9%) of participants were female. When baseline PP level was assessed in quartiles, compared to the reference group (Q1 ≤ 56 mmHg), the adjusted hazard ratio (HR) in Q2 (57–68 mmHg), Q3(69–82 mmHg), Q4 (≥83 mmHg) were 0.55 (95% CI: 0.33–0.93, p = 0.026), 0.99 (95% CI, 0.62–1.59, p = 0.966), and 0.99 (95% CI: 0.62–1.59, p = 0.954), respectively. In the threshold analysis, for every 5 mmHg increase in PP level, there was an 18.2% decrease in hospital mortality (adjusted HR, 0.818; 95% CI, 0.738–0.907; p = 0.0001) in those with PP level less than 60 mmHg, and a 7.7% increase in hospital mortality (adjusted HR, 1.077; 95% CI, 1.018–1.139; p = 0.0096) in those with PP level was 60 mmHg or higher.ConclusionFor patients with non-traumatic SAH, the association between baseline PP and risk of hospital mortality was non-linear, with an inflection point at 60 mmHg and a minimal risk at 57 to 68 mmHg (Q2) of baseline PP level

    Advanced analyses of physiological signals and their role in Neonatal Intensive Care

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    Preterm infants admitted to the neonatal intensive care unit (NICU) face an array of life-threatening diseases requiring procedures such as resuscitation and invasive monitoring, and other risks related to exposure to the hospital environment, all of which may have lifelong implications. This thesis examined a range of applications for advanced signal analyses in the NICU, from identifying of physiological patterns associated with neonatal outcomes, to evaluating the impact of certain treatments on physiological variability. Firstly, the thesis examined the potential to identify infants at risk of developing intraventricular haemorrhage, often interrelated with factors leading to preterm birth, mechanical ventilation, hypoxia and prolonged apnoeas. This thesis then characterised the cardiovascular impact of caffeine therapy which is often administered to prevent and treat apnoea of prematurity, finding greater pulse pressure variability and enhanced responsiveness of the autonomic nervous system. Cerebral autoregulation maintains cerebral blood flow despite fluctuations in arterial blood pressure and is an important consideration for preterm infants who are especially vulnerable to brain injury. Using various time and frequency domain correlation techniques, the thesis found acute changes in cerebral autoregulation of preterm infants following caffeine therapy. Nutrition in early life may also affect neurodevelopment and morbidity in later life. This thesis developed models for identifying malnutrition risk using anthropometry and near-infrared interactance features. This thesis has presented a range of ways in which advanced analyses including time series analysis, feature selection and model development can be applied to neonatal intensive care. There is a clear role for such analyses in early detection of clinical outcomes, characterising the effects of relevant treatments or pathologies and identifying infants at risk of later morbidity

    Imaging markers of cerebral small vessel disease

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    Vascular cognitive impairment (VCI) is the second most common cause of cognitive impairment in the elderly population and it very often co-occurs with impairment resulting from other neurodegenerative pathologies. Cognitive impairment due to vascular pathology is potentially treatable; i.e. the progression could be slowed or even stopped by managing the underlying vascular disease. However, there is no specific treatment available for VCI up to date. One of the main reasons for this is an insufficient understanding of the disease pathophysiology. Cerebral small vessel disease is the primary pathology leading to VCI and therefore its study provides the chance to elucidate the mechanisms leading from vascular pathology to cognitive impairment. Understanding the underlying disease mechanisms is crucial for diagnosis, prevention and managing the disease. For this purpose, markers play an important role, as they indicate which disease processes are at play within the brain. This PhD-work aimed at finding optimal imaging markers for diagnosing cerebral small vessel diseases and estimating the vascular disease burden in the brain. Advances in brain imaging tools, in particular diffusion tensor imaging (DTI), have enabled the exploration of microstructural changes in the human brain, which precede the occurrence of lesions that are visible on conventional MRI. The first project focused on developing and establishing a DTI-based imaging marker for small vessel disease that is quantitative, reliable, and fully automated. This marker (peak width of skeletonized mean diffusivity, PSMD) was then systematically investigated - along with conventional imaging markers - in patients with hereditary and sporadic SVD, memory clinic patients as well as in patients with Alzheimer pathology. The results showed that PSMD outperformed the conventional markers in explaining the cognitive impairment scores. Furthermore, in longitudinal analysis, PSMD was more sensitive to disease related changes than any other imaging markers, which resulted in low sample size estimations for a hypothetical clinical trial. Additionally. PSMD showed very high interscanner reproducibility suggesting that it might be especially useful in multicenter studies. Interestingly, increases in PSMD were mostly linked to vascular but not to neurodegenerative disease. Therefore, PSMD could be a valuable tool to disentangle effects caused by these different pathologies, a common challenge in understanding cognitive impairment. This suggests that the newly established marker PSMD could be easily applied to large samples and may be of great utility for both research studies and clinical use. The second project focused on the evaluation of cortical superficial siderosis (cSS) as a potential new marker for cerebral small vessel diseases. cSS emerged recently as a marker for cerebral amyloid angiopathy (CAA). However, the presence of cSS is associated with many other signs of cSVD, such as cerebral microbleeds (CMB) and white matter hyperintensities (WMH), and therefore its specificity for CAA was questionable. The results of the second project revealed that the distribution patterns and frequency of CMB and WMH overlap between different subtypes of cSVD. This clearly demonstrated that these imaging features have limited discriminative value. More importantly, the presence of cSS was found to be strongly indicative of CAA. To summarize, the key findings reported in this PhD-work have important implications for diagnosing patients with cerebral small vessel disease, disentangling underlying pathologies, as well as for managing and treating the disease. The newly established imaging marker PSMD can be utilized to select the target population for clinical studies and may function as a surrogate marker for treatment effects. PSMD can be further used to identify patients who have a low disease burden as targets for prevention and early treatment
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