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
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
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Uncertainty quantification techniques with diverse applications to stochastic dynamics of structural and nanomechanical systems and to modeling of cerebral autoregulation
This dissertation develops uncertainty quantification methodologies for modeling, response analysis and optimization of diverse dynamical systems. Two distinct application platforms are considered pertaining to engineering dynamics and precision medicine.
First, the recently developed Wiener path integral (WPI) technique for determining, accurately and in a computationally efficient manner, the stochastic response of diverse dynamical systems is employed for solving a high-dimensional, nonlinear system of stochastic differential equations governing the dynamics of a representative model of electrostatically coupled micromechanical oscillators. Compared to alternative modeling and solution treatments in the literature, the current development exhibits the following novelties: a) typically adopted linear, or higher-order polynomial, approximations of the nonlinear electrostatic forces are circumvented; and b) stochastic modeling is employed, for the first time, by considering a random excitation component representing the effect of diverse noise sources on the system dynamics.
Further, the WPI technique is enhanced and extended based on a Bayesian compressive sampling (CS) treatment. Specifically, sparse expansions for the system response joint PDF are utilized. Next, exploiting the localization capabilities of the WPI technique for direct evaluation of specific PDF points leads to an underdetermined linear system of equations for the expansion coefficients. Furthermore, relying on a Bayesian CS solution formulation yields a posterior distribution for the expansion coefficient vector. In this regard, a significant advantage of the herein-developed methodology relates to the fact that the uncertainty of the response PDF estimates obtained by the WPI technique is quantified. Also, an adaptive scheme is proposed based on the quantified uncertainty of the estimates for the optimal selection of PDF sample points. This yields considerably fewer boundary value problems to be solved as part of the WPI technique, and thus, the associated computational cost is significantly reduced.
Second, modeling and analysis of the physiological mechanism of dynamic cerebral autoregulation (DCA) is pursued based on the concept of diffusion maps. Specifically, a state-space description of DCA dynamics is considered based on arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), and their time derivatives. Next, an eigenvalue analysis of the Markov matrix of a random walk on a graph over the dataset domain yields a low-dimensional representation of the intrinsic dynamics. Further dimension reduction is made possible by accounting only for the two most significant eigenvalues. The value of their ratio indicates whether the underlying system is governed by active or hypoactive dynamics, indicating healthy or impaired DCA function, respectively. The reliability of the technique is assessed by considering healthy individuals and patients with unilateral carotid artery stenosis or occlusion.
It is shown that the proposed ratio of eigenvalues can be used as a reliable and robust biomarker for assessing how active the intrinsic dynamics of the autoregulation is and for indicating healthy versus impaired DCA function. Further, an alternative joint time-frequency analysis methodology based on generalized harmonic wavelets is utilized for assessing DCA performance in patients with preeclampsia within one week postpartum, which is associated with an increased risk for postpartum maternal cerebrovascular complications. The results are compared with normotensive postpartum individuals and healthy non-pregnant female volunteers and suggest a faster, but less effective response of the cerebral autoregulatory mechanism in the first week postpartum, regardless of preeclampsia diagnosis
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Contusion Progression in Traumatic Brain Injury
Cerebral contusions that result from brain trauma have the propensity to enlarge over the days following injury, including extension of the haemorrhage core and swelling of the surrounding peri-contusional brain. This secondary injury increases the likelihood of death and severe disabil- ity, and interventions to prevent or limit contusion progression may improve clinical outcomes. In preclinical studies a number of pathophysiological process have been identified that contribute to brain oedema including blood brain barrier (BBB) disruption, neuroinflammation, and cerebral metabolic dysfunction. This work has set out to measure and quantify contusion progression in TBI patients, characterise BBB permeability with computed tomography imaging, and identify key mediators of this process using intracerebral microdialysis.
• Study I: A robust and effective stereological method for measuring the volume of brain lesions was validated and applied to a cohort of TBI patients to examine the temporal course of contusion progression. Intracranial pressure and brain lactate/pyruvate ratio were found to be associated with the magnitude of contusion expansion.
• Study II: Dynamic contrast enhanced computed tomography (DCE-CT) was applied in pa- tients with brain contusions to quantify BBB permeability. The imaging showed profound reduction in cerebral blood flow associated with contusions but did not show evidence of contrast extravasation or BBB permeability.
• Study III: Paired microdialysis catheters, one inserted in proximity to a contusion and an- other in non-injured brain, were used to characterise the peri-contusional inflammatory response with a multiplex assay of 42 cytokines, chemokines, and growth factors. Peri- contusional tissue was found to exhibit an early pro-inflammatory signature.
• Study IV: A paired microdialysis study of pericontusional expression of matrix metalloproteinases (MMP). Specific increase in the expression of MMP-9 was identified in pericontusional brain.
• Study V: Nitric oxide (NOx) concentrations were assayed in pericontusional and uninjured brain with paired microdialysis. NOx levels were lower in pericontusional brain and exhibited significant correlations with brain glucose, pyruvate, and lactate.
• Study VI: Microdialysis data from 619 TBI patients with collated to explore the physiological correlates of deranged metabolism and elevated LPR. Cerebral glucose was found to a key determinant of LPR.
The implications of these findings in the context of existing knowledge of BBB permeability, in- flammation, and cerebral metabolism in TBI are discussed. Future investigations to clarify the mechanisms highlighted, and potential therapeutic studies directed at reducing contusion pro- gression and brain oedema are suggested
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Clinical Applications of Neuromonitoring Following Acute Brain Injury
Various invasive and non-invasive cranial monitoring techniques can be applied clinically to describe the extent to which cerebral hemodynamics and subsequently, patient outcome, have been impacted following acute brain injury (ABI).
This Ph.D. thesis examines both prospective and retrospective patient data in both neurocritical and general intensive care patients. Thirty neurotrauma patients and forty general intensive care patients with neurological complications were prospectively monitored after ABI. Retrospective patient data was harvested from a database of 1,023 traumatic brain injury (TBI) patients with invasive intracranial pressure (ICP), arterial blood pressure (ABP), and transcranial Doppler ultrasonography (TCD) recordings. Data analysis focused on ICP microsensor accuracy, compensatory reserve, the pulsatility of brain signals (ICP and TCD), and cerebral arterial blood volume (CaBV) based on TCD. The main results are summarized below:
I. Intracranial hypertension has a profound negative influence on cerebrovascular parameters and patient outcome.
II. ICP microsensor accuracy is limited, with an average error of approximately ± 6.0 mm Hg.
III. ICP weighted with the compensatory reserve better predicts outcome than mean ICP alone.
IV. ICP and TCD pulsatility are functions of mean ICP and cerebral perfusion pressure (CPP).
V. Continuous blood flow forward (CFF) and pulsatile blood flow forward (PFF) models can approximate CaBV with derived TCD signals; CFF best models TCD pulsatility.
VI. The pressure reactivity index (PRx) and the pulse amplitude index (PAx) can be estimated non-invasively using slow waves of TCD estimated by CaBV with similar outcome-predictive power.
VII. Multi-parametric TCD-based monitoring of general intensive care patients is clinically feasible; the joint estimation of autoregulation, dysautonomia, non-invasive ICP, and critical closing pressure is possible.
The culmination of these projects should have an impact on current monitoring practices in ABI patients, emphasizing the continued validation and refinement of TCD methodology in clinical neurosciences
Interplay between blood-brain barrier disruption and neuroinflammation following severe traumatic brain injury
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
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
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
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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