A Physical Model of the Intracranial System for the Study of the Mechanisms of the Cerebral Blood Flow Autoregulation

This paper introduces a novel physical model of the intracranial system, which was built with the specific purpose of gaining a better insight into the fundamental mechanisms involved in the cerebral circulation. Specifically, the phenomena of passive autoregulation of the blood flow and the variation of the intracranial compliance as a function of the mean intracranial pressure have been investigated. The physical model allows to go beyond state-of-the-art mathematical models that are often based on strong assumptions or simplifications on the physical mechanisms governing the cerebral circulation. Indeed, the physical model based on passive components was able to correctly replicate some fundamental mechanisms of the blood flow autoregulation. In particular, it allows to highlight the role of the venous outflow, which behaves as a Starling resistor. The physical model can be employed as a demonstrator for educational purpose and to test the behavior of shunts for the therapy of hydrocephalus

Whole-body mathematical model for simulating intracranial pressure dynamics

A whole-body mathematical model (10) for simulating intracranial pressure dynamics. In one embodiment, model (10) includes 17 interacting compartments, of which nine lie entirely outside of intracranial vault (14). Compartments (F) and (T) are defined to distinguish ventricular from extraventricular CSF. The vasculature of the intracranial system within cranial vault (14) is also subdivided into five compartments (A, C, P, V, and S, respectively) representing the intracranial arteries, capillaries, choroid plexus, veins, and venous sinus. The body's extracranial systemic vasculature is divided into six compartments (I, J, O, Z, D, and X, respectively) representing the arteries, capillaries, and veins of the central body and the lower body. Compartments (G) and (B) include tissue and the associated interstitial fluid in the intracranial and lower regions. Compartment (Y) is a composite involving the tissues, organs, and pulmonary circulation of the central body and compartment (M) represents the external environment

Modeling, simulation and hemodynamic response analysis of arteriovenous malformation occlusion

The cerebral Arteriovenous Malformation system (AVM) or fistula, is a network with large caliber vessels that yields an alternate pathway for blood flow between arteries and veins. Neurosurgical and interventional radiological techniques are the common way to treat AVM patients so that the normal capillary blood flow would be restored. Several patients who underwent this procedure had different degrees of brain swelling and subsequent hemorrhage. To understand this, Blesser et al. developed a simplified model to simulate the effect of AVM occlusion on cerebrovascular pressure and flow. Their model does not include the cerebrovascular regulatory mechanism which is an important part in cerebral pressure and flow regulation. Three different factors that may affect the hemodynamic response after AVM occlusion were investigated in this work. They are: autoregulation mechanism failure, sympathetic nervous system dysfunction and increased intracranial pressure. The revised model predicted the relationship between each of these three factors and the severity of the hemorrhage. The simulation results predicted that autoregulation mechanism dysfunction is the most important factor of all three factors, whereas increased intracranial pressure is the least important factor. Possible future study would include developing a model where autoregulation failure and sympathetic system dysfunction are considered simultaneously and the addition of other possible pathologies such as the failure of chemical regulation mechanisms, and to investigate the relationship between these factors and the potential for hemorrhage

Towards clinical assessment of cerebral blood flow regulation using ultrasonography : model applicability in clinical studies

For preservation of its vital functions, the brain is largely dependent of a sufficient delivery of oxygen and nutrients. Blood flow to the brain is essentially regulated by 2 control mechanisms i.e. neurovascular coupling and cerebral autoregulation. Cerebral autoregulation aims for constant adequate blood supply by compensating for blood pressure variations by dilatation or narrowing of the cerebral microvasculature. Neurovascular coupling adjusts blood supply to the local metabolic need. Cerebral perfusion and blood flow regulation are compromised in several pathological conditions. Clinical examination of cerebral blood flow and its regulation may therefore provide helpful diagnostic, predictive and therapeutic information. The work in this thesis was aimed at putting a step forward towards development of reliable and clinically usable parameters for cerebral blood flow regulation assessment using ultrasonography. Regarding early diagnostics, screening and monitoring of cerebral blood flow and its regulation, ultrasonography has major advantages over other imaging tools because of its noninvasiveness, cost-effectiveness, easy usability and its good time resolution. It allows examination of blood flow velocities at multiple locations throughout the extra- and intracranial circulation and evaluation of both control mechanisms by transfer function analysis. For evaluation of cerebral autoregulation, transcranial Doppler blood flow velocities in the large middle cerebral arteries have been recorded simultaneously with plethysmographic (finger) blood pressure. Gain and phase of the pressure-flow transfer function have been determined to obtain quantitative measures for cerebral autoregulation. Neurovascular coupling has been assessed by presenting a visual block stimulus to a subject and simultaneous measurement of the blood flow velocity in the artery exclusively supplying the visual cortex. The obtained visually-evoked blood flow response (VEFR) has been considered as the step response of a linear second order control system model providing patient-specific parameters such as gain and damping as quantitative measures for neurovascular coupling . In chapter 2, a clinical study has been described in which extra- and intracranial blood flow velocities (BFVs), measured at multiple sites in the circulation, have been compared between Alzheimer patients (AD), patients with mild cognitive impairment (MCI) and healthy aging controls (HC). BFVs of AD were significantly lowered at proximal sites but preserved at distal sites for the internal carotid artery and middle and posterior cerebral arteries as compared to those of MCI or HC. This specific pattern can presumably be ascribed to reduced distal diameters resulting from AD pathology. MCI BFV were similar to HC BFV in the extracranial and intracranial posterior circulation, whereas they were intermediate between AD and HC in the intracranial anterior circulation. This suggests that intracranial anterior vessels are most suitable for early detection of pathological alterations resulting from AD. The study findings further indicate that extensive ultrasonographic screening of intra- and extracranial arteries is useful for monitoring BFV decline in the MCI stage. Future follow-up of MCI patients may reveal the predictive value of location-specific BFV for conversion to AD. In the same study cohort, dynamic cerebral autoregulation has been studied as discussed in chapter 3. Cerebral autoregulatory gain and phase values were similar for AD, MCI and HC which implies that the cerebral autoregulatory mechanism is preserved in AD. However, the cerebrovascular resistance index i.e. the ratio between absolute time-averaged blood pressure and flow velocity, was significantly higher in AD as compared to MCI and HC indicating that vessel stiffness is increased in AD. Indeed, it appeared to be a potential biomarker for AD development of MCI. The cerebrovascular resistance increase in AD was furthermore confirmed by windkessel model findings of a significantly elevated peripheral resistance in AD. Arterial resistance and peripheral compliance were equal for all groups. From chapter 4, the focus was shifted to assessment of local blood flow regulation. Visuallyevoked blood flow responses (VEFRs) of formerly (pre-)eclamptic patients and healthy controls have been examined to evaluate neurovascular coupling first in a relative young study population. The aim of the study was to investigate whether possible local (pre)eclampsia-induced endothelial damage was reversible or not. The measured VEFRs have been fitted with the step response of a 2nd order control system model. Although inter-group differences in model parameters were not found, a trend was observed that critical damping (z>1) occurred more frequently in former patients than in controls. Critical damping reflects an atypical VEFR, which is either uncompensated (sluggish, z>1; Tv <20) or compensated by a rise in rate time (intermediate, z>1; Tv > 20). Since these abnormal VEFRs were mainly found in former patients (but not exclusively), these response types were hypothesized to result from pathological disturbances. A revised VEFR analysis procedure to account for reliability and blood pressure dynamics has been proposed in chapter 5. This revised procedure consists of the introduction of a reliability measure for model parameters and of a model extension to consider possible blood pressure contribution to the measured VEFR. The effects of these adjustments on study outcomes have been evaluated by applying both the standard VEFR analysis procedure (applied in chapter 4) and the revised procedure to the AD study cohort. Reliability consideration resulted in about 40% VEFR exclusion, mainly due to the models’ inability to fit critically damped responses. Reliability consideration reduced parameter variability substantially. Regarding the influence of blood pressure variation, a significantly increased damping was found in AD for the standard but not for the revised model. This reversed the study conclusion from altered to normal neurovascular coupling in AD. Considering their influence on obtained parameters, both aspects i.e. reliability and blood pressure variation should be included in VEFR-analysis. Regarding clinical study outcomes, neurovascular coupling seems to be unaffected in AD since the finding of an increased damping may be ascribed to ignorance of blood pressure contribution to VEFR. Study conclusions of earlier chapters (4 and 5) emphasize the need for a model incorporating physiological features. In chapter 6, preliminary results have been reported of the application of a newly developed lumped parameter model of the visual cortex vasculature to the 3 different VEFR types. In the new model, regulatory processes i.e. neurogenic, metabolic, myogenic and shear stress mechanisms, act on smooth muscle tone which inherently leads to adjustment of microcirculatory resistance and compliance. This allows the study of effects of pathological changes on the VEFR. It may be concluded that the model provides an improved link between VEFR and physiology. Preliminary results show that the physiology-based model can describe VEFR type representatives reasonably well obtaining physiologically plausible parameter values. Thus, from a clinical perspective it may be concluded that (Duplex) ultrasonography has great potential as a standard screening tool for MCI patients. It seems worthwhile to examine all future MCI patients on extra- and intracranial blood flow velocity and to determine their cerebrovascular resistance index by simultaneous blood pressure recording. Follow-up of MCI patients will reveal the predictive value of these parameters for future AD development. Furthermore, from a methodological perspective, it can be concluded that the current standard of control system analysis to assess local cerebral blood flow regulation has limitations regarding parameter reliability and VEFR interpretation. Both reliability and interpretation may be improved by optimization and control of data acquisition quality and by use of physiology-based models. Physiological mechanisms influencing VEFR establishment should be incorporated in such a model to possibly explain part of its variance. Efforts should be directed to development and validation of physiology-based models aimed at reliable description of VEFRs by physiologically meaningful parameters

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

The effects of dexmedetomidine on cerebral glucose metabolism, systemic cytokine release and cerebral autoregulation: Studies on healthy volunteers and aneurysmal subarachnoid haemorrhage patients

Dexmedetomidine is a very selective α2-agonist that has become a popular sedative in the intensive care unit. It has characteristics that make it appealing especially for neurologically compromised patients. Aneurysmal subarachnoid haemorrhage (aSAH) is a complicated disease where cerebral physiology and the regulation of cerebral blood flow, i.e., autoregulation, are often disturbed. It is important that the used anaesthetic and sedative drugs do not cause further damage. The aim of this study was to explore how dexmedetomidine affects cerebral glucose metabolism, systemic cytokine response, and cerebral autoregulation. The first two studies included healthy male volunteers. The first study investigated the effects of dexmedetomidine on cerebral glucose metabolism along with three other anaesthetic drugs (propofol, sevoflurane, S-ketamine) and a placebo group. The second study investigated the effects of dexmedetomidine and propofol on the release of cytokines, chemokines, and growth factors. The third study included 10 aSAH patients. We examined the effects of dexmedetomidine on cerebral autoregulation with three increasing doses after the baseline sedation with propofol and/or midazolam was suspended. In the volunteer studies, we found that the cerebral glucose metabolism was lowest with dexmedetomidine. In addition, we found that dexmedetomidine induced an anti-inflammatory cytokine response, whereas propofol induced a partly pro-inflammatory and slightly anti-inflammatory cytokine response. In aSAH patients, dexmedetomidine did not alter the static cerebral autoregulation compared to baseline. However, after the dose of 1.0 µg/kg/h, we observed a minor but statistically significant decrease in dynamic cerebral autoregulation which may suggest that in aSAH patients sedated with dexmedetomidine, sudden decreases in mean arterial pressure should be avoided

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