Tissue microvascular flow and oxygenation in critically ill patients

PhDThe use of fluid resuscitation and vasoactive agents to optimise global haemodynamics has been demonstrated to improve outcomes in patients undergoing major surgery and in early sepsis. Whether changes in global haemodynamics result in similar improvements in the microcirculation in critically ill patients remains unclear. The aim of this thesis was to investigate the changes in tissue microvascular flow and oxygenation that occur in patients undergoing major surgery and in those with sepsis, and specifically how haemodynamic therapies may affect these changes. The first part of this thesis investigates the treatment pathway of the high risk surgical patient. Analysis of two large health databases was performed and confirmed the existence of a high risk sub-population within the local surgical population. Only about a third of these high-risk patients were admitted to a critical care unit at any stage during their hospital admission. An observational trial was performed examining the relationship between global oxygen delivery, microvascular flow and tissue oxygenation in 25 surgical patients receiving usual care. Data including global haemodynamics, sublingual and cutaneous microvascular flow, and tissue oxygenation were collected before, and for eight hours after surgery. Abnormalities in sublingual microvascular flow were found to be associated with worse outcomes. 4 A randomised controlled study investigating the effects of two goal directed haemodynamic therapy (GDHT) algorithms on tissue microvascular flow and oxygenation compared to central venous pressure guided fluid therapy in 135 perioperative patients was performed. For eight hours after surgery, intravenous fluid therapy was guided by measurements of central venous pressure (CVP group) or stroke volume (SV group). In a third group stroke volume guided fluid therapy was combined with dopexamine (SV & DPX group). In the SV & DPX group, increased global oxygen delivery was associated with improved sublingual and cutaneous microvascular flow. Microvascular flow remained constant in the SV group but deteriorated in the CVP group. Cutaneous PtO2 improved only in the SV & DPX group. There were no differences in complication rates between groups. The importance of derangements in microvascular flow in patients with established sepsis is well recognized. However, little data is available to describe microvascular changes in early sepsis. Observational data were collected in 16 healthy volunteers and within six hours of presentation in 48 patients with sepsis and severe sepsis. Sublingual microvascular flow was impaired in patients with sepsis and severe sepsis compared to healthy volunteers. Greater alterations in flow were seen with increasing severity of illness. The dose-related effects of vasopressor therapy on microvascular flow and tissue oxygenation in sepsis have not been previously fully investigated. The effects of increasing doses of noradrenaline, targeted to achieve successively greater mean arterial pressures, on microvascular flow and tissue oxygenation in 16 patients with septic shock were investigated. Increasing doses of noradrenaline were associated with improvements in 5 global oxygen delivery, cutaneous PtO2 and cutaneous microvascular red blood cell flux. No changes in sublingual microvascular flow were identified. This thesis confirms the existence of a large sub-population of high risk surgical patients. It demonstrates that abnormal microvascular flow in the perioperative period may be associated with poor outcomes. The use of flow guided fluid therapy alongside low dose dopexamine infusion is shown to improve global haemodynamics, microvascular flow and tissue oxygenation in perioperative patients. Microvascular abnormalities are shown to occur in the earliest stages of sepsis with increasing severity of disease being associated with greater changes. Increasing doses of noradrenaline were found to improve global haemodynamics, cutaneous microvascular flow and cutaneous tissue oxygenation in septic shock. Further work is required to investigate the effects of haemodynamic therapies on microvascular flow and organ dysfunction in critically ill patients and the use of the microcirculation as a resuscitation endpoint

Pressure, volume and flow: studies of ventricular, valvular and vascular haemodynamics in the human cardiovascular system

BACKGROUND: Pressure, volume and flow form the three pillars of quantification in cardiovascular physiology. Newer approaches to their assessment provide opportunities to further assess their interactions. METHODS: 4 projects were conducted. Project 1 evaluated mechanisms of myocardial oxygen supply:demand imbalance in 3682 healthy volunteers using aortic pressure-time integrals measured with radial arterial tonometry (AT) and generalised transfer function. Project 2 evaluated the acute left ventricular (LV) contractile response to transcatheter mitral valve replacement (TMVR) in 9 high-risk patients. Intraoperative left and right heart catheterisation, 3D transoesophageal echocardiography and pressure-volume analyses were performed at baseline, immediately following TMVR and late post-TMVR. Project 3 mathematically evaluated the current definition of paradoxical low-flow, low-gradient aortic stenosis (PLFLGAS) by deriving an equation for LV end-diastolic volume in terms of mean pressure gradient, aortic valve area and LV ejection fraction. Project 4 evaluated feasibility and reproducibility of non-invasive LV pressure-volume and aortic pressure-flow quantification in 21 patients who underwent simultaneous AT and cardiovascular magnetic resonance imaging (CMRI). RESULTS: In project 1, more unfavourable age-related myocardial oxygen supply:demand profiles were seen in women than men, driven by sex differences in arterial aging, pressure wave reflection and cardiac ejection duration. In project 2, TMVR caused acute LV dilatation and reduction in contractility, but changes returned to baseline by a median time of 17 minutes. LV end-diastolic pressure and forward stroke volume were preserved at the three study timepoints. In project 3, the derived LV end-diastolic volume equation incorporating defining criteria for PLFLGAS could not mathematically resolve the combined input parameters based on current definitions, raising concerns regarding the internal consistency of the consensus definition. In project 4, non-invasive LV pressure-volume and aortic pressure-flow analyses, using simultaneous AT and CMRI, were feasible, reproducible and showed good and appropriately directed correlation to more conventional markers of cardiovascular function. CONCLUSIONS: Newer approaches to pressure, volume and flow assessment can lead to better understanding of the interactions between the ventricles, valves and vasculature in states of health and disease

The selection of electrical analog components from computational model impedance spectra

Lumped parameter models can be used as accurate boundary conditions in hemodynamic modeling, requiring only the estimation of a few physiologically relevant parameters. The best way to estimate these parameters (typically resistances and capacitances) has seen much investigation, but all current techniques require experimental (or periodic time-domain) blood pressure or blood flow data. A method that can estimate lumped parameter model components using only impedance spectra would widen the scope of usefulness for lumped parameter models as boundary conditions. Their usefulness would then include cases where such data cannot be obtained. The methods presented in this work estimate the resistance and capacitance values of two- and three-element Windkessel models using only features found in typical impedance spectra. Comparing these methods to "gold standard" pressure and flow data, each other, and previously published methods can determine the accuracy of a 'Fourier-domain only' strategy

Evidence of left ventricular wall movement actively decelerting aortic

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Efficient function of the left ventricle (LV) is achieved by coherent behaviour of its circumferential and longitudinal myocardial components. Little was known about the direct association between the long and minor axis velocities and the overall haemodynamics generated by ventricular systolic function such as aortic waves. The forward running expansion wave (FEW) during late systole contains important information about the condition of the LV and its interaction with the arterial system. The aim of this thesis was to underpin the mechanics and timing of the LV wall velocities, which are associated with the deceleration of flow. Both invasive and noninvasive data have been analysed in canines and humans and the following conclusions can be drawn. LV long axis peak shortening velocity lags consistently behind the minor axis, representing a degree of normal asynchrony. The FEW is seen to have a slow onset before a rapid increase in energy. The slow onset corresponds with the time that the long axis reaches its peak velocity of shortening. After both axes reach their respective maximum shortening velocity they continue to contract, although at a slow steady velocity until late ejection when there is a sudden simultaneous change of shortening velocity of both axes. This time corresponds with peak aortic pressure and the rapid increase in energy of the FEW. The time that the minor axis reaches its maximum velocity of shortening interestingly coincides with the arrival of the reflected wave at the LV during mid-systole. During canine aortic manipulation through the introduction of total occlusions along the aorta, the sequence of events observed in control conditions remains unchanged. In humans both LV wall movement and carotid wave intensity can be measured successfully using non-invasive methods. The FEW is generated when the last long axis segment begins to slow. The minor axis begins to slow before this time and corresponds to the time of peak aortic flow

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 307)

This bibliography lists 203 reports, articles, and other documents introduced into the NASA scientific and technical information system in January, 1988

Lattice-Boltzmann simulations of cerebral blood flow

Computational haemodynamics play a central role in the understanding of blood behaviour in the cerebral vasculature, increasing our knowledge in the onset of vascular diseases and their progression, improving diagnosis and ultimately providing better patient prognosis. Computer simulations hold the potential of accurately characterising motion of blood and its interaction with the vessel wall, providing the capability to assess surgical treatments with no danger to the patient. These aspects considerably contribute to better understand of blood circulation processes as well as to augment pre-treatment planning. Existing software environments for treatment planning consist of several stages, each requiring significant user interaction and processing time, significantly limiting their use in clinical scenarios. The aim of this PhD is to provide clinicians and researchers with a tool to aid in the understanding of human cerebral haemodynamics. This tool employs a high performance fluid solver based on the lattice-Boltzmann method (coined HemeLB), high performance distributed computing and grid computing, and various advanced software applications useful to efficiently set up and run patient-specific simulations. A graphical tool is used to segment the vasculature from patient-specific CT or MR data and configure boundary conditions with ease, creating models of the vasculature in real time. Blood flow visualisation is done in real time using in situ rendering techniques implemented within the parallel fluid solver and aided by steering capabilities; these programming strategies allows the clinician to interactively display the simulation results on a local workstation. A separate software application is used to numerically compare simulation results carried out at different spatial resolutions, providing a strategy to approach numerical validation. This developed software and supporting computational infrastructure was used to study various patient-specific intracranial aneurysms with the collaborating interventionalists at the National Hospital for Neurology and Neuroscience (London), using three-dimensional rotational angiography data to define the patient-specific vasculature. Blood flow motion was depicted in detail by the visualisation capabilities, clearly showing vortex fluid ow features and stress distribution at the inner surface of the aneurysms and their surrounding vasculature. These investigations permitted the clinicians to rapidly assess the risk associated with the growth and rupture of each aneurysm. The ultimate goal of this work is to aid clinical practice with an efficient easy-to-use toolkit for real-time decision support

Investigations of photoplethysmography in the assessment of haemodynamics, vascular mechanics and haemorheology

Real‐time cardiovascular assessment is vital for monitoring patients at an early stage of cardiovascular diseases (CVDs), at risk of reoccurrence of heart attacks and strokes and during pharmacological and non‐pharmacological treatments. Blood Pressure (BP), Arterial Stiffness (AS) and Blood Viscosity (BV) are three essential parameters that can provide a reliable assessment of hypertension, atherosclerosis, and hyperviscosity associated with the development and progression of cardiovascular pathologies to complex stages. The currently available methods designed for evaluation of such parameters incur limitations and challenges that stand as an obstacle to the development of non‐invasive, portable and reliable all‐in‐one device intended for personal use. This project engaged in novel fundamental and rigorous in vivo and in vitro investigations in an effort to shed more light on the photoplethysmographic signals (AC and DC) during induced changes of BP, AS, and BV. The underlying hypothesis is to show for the first time that Photoplethysmography (PPG) has the potential to non‐invasively assess, in a qualifying and quantifying manner, the above parameters. Positives outcomes from such approach will establish the potential of the PPG as a preferential monitoring (screening and possible diagnosis) technique for the assessment of CVDs. Novel miniature PPG sensors were developed along with a state of the art PPG processing unit, a data acquisition system and a customised manuscript for offline signal analyses. ECG and temperature processing systems were also designed and developed for use in the in vivo investigations. State of the art in vitro experimental rig was developed to mimic the human circulation under a wide range of flow conditions. A pilot volunteer investigation highlighted the effect of a cold pressor test in one hand on the PPG signals from both hands. The results indicated that there are changes in flow regulation mechanisms and hemodynamics besides the expected vasoconstriction effects of local cooling. These findings led to the controlled in vitro experiments. The in vitro investigations were completed in four stages where the potential of the PPG to provide a measure of blood pressure values, volume elastic modulus (Ev) and to detect fluid viscosity and haemorheological changes. Results from the in vitro investigations highlighted that Adjusted Pulse Volume (APV) was found to be the optimum method for measuring BP values using Red (R) and Infrared (IR) wavelengths as validated under a range of BP values simulating hypotensive to hypertensive scenarios. The correlation was significant with Rsquare ranging between 0.96 and 0.99 for different arterial models and circulating fluids. Moreover, a proposed mathematical derivation allowed the PPG to provide a direct measure of AS using Ev. The method showed strong agreement with the gold standard measurement of material testings, the Instron device, with a percent error of 0.26% and 1.9% for different arterial models. Furthermore, the PPG signals also responded to changes in rheological characteristics in relation to fluid viscosities, the presence of the red blood cells, changes in shear rates and blood clotting. These results strongly suggest that PPG has the potential to be used as a non‐invasive and continuous method for the assessment of cardiovascular disease markers such as blood pressure, arterial stiffness and blood viscosity

MR image based measurement, modelling and diagnostic interpretation of pressure and flow in the pulmonary arteries: applications in pulmonary hypertension

Pulmonary hypertension (PH) is a clinical condition characterised by an increased mean pulmonary arterial pressure (mPAP) of over 25 mmHg measured, at rest, by right heart catheterisation (RHC). RHC is currently considered the gold standard for diagnosis, follow-up and measurement of response to treatment. Although the severe complications and mortality risk associated with the invasive procedure are reduced when it is performed in a specialist centre, finding non-invasive PH diagnosis methods is highly desirable. Non-invasive, non-ionising imaging techniques, based on magnetic resonance imaging (MRI) and on echocardiography, have been integrated into the clinical routine as means for PH assessment. Although the imaging techniques can provide valuable information supporting the PH diagnosis, accurately identifying patients with PH based upon images alone remains challenging. Computationally based models can bring additional insights into the haemodynamic changes occurring under the manifestation of PH. The primary hypothesis of this thesis is that that the physiological status of the pulmonary circulation can be inferred using solely non-invasive flow and anatomy measurements of the pulmonary arteries, measured by MRI and interpreted by 0D and 1D mathematical models. The aim was to implement a series of simple mathematical models, taking the inputs from MRI measurements, and to evaluate their potential to support the non-invasive diagnosis and monitoring of PH. The principal objective was to develop a tool that can readily be translated into the clinic, requiring minimum operator input and time and returning meaningful and accurate results. Two mathematical models, a 3 element Windkessel model and a 1D model of an axisymmetric straight elastic tube for wave reflections were implemented and clinically tested on a cohort of healthy volunteers and of patients who were clinically investigated for PH. The latter group contained some who were normotensive, and those with PH were stratified according to severity. A 2D semi-automatic image segmentation workflow was developed to provide patient specific, simultaneous flow and anatomy measurements of the main pulmonary artery (MPA) as input to the mathematical models. Several diagnostic indices are proposed, and of these distal resistance (Rd), total vascular compliance (C) and the ratio of reflected to total wave power (Wb/Wtot) showed statistically significant differences between the analysed groups, with good accuracy in PH classification. A machine learning classifier using the derived computational metrics and several other PH metrics computed from MRI images of the MPA and of the right ventricle alone, proposed in the literature as PH surrogate markers, was trained and validated with leave-one-out cross-validation to improve the accuracy of non-invasive PH diagnosis. The results accurately classified 92% of the patients, and furthermore the misclassified 8% were patients with mPAP close to the 25 mmHg (at RHC) threshold (within the range of clinical uncertainty). The individual analysis of all PH surrogate markers emphasised that wave reflection quantification, although with lower diagnosis accuracy (75%) than the machine learning model embedding multiple markers, has the potential to distinguish between multiple PH categories. A finite element method (FEM) based model to solve a 1D pulmonary arterial tree linear system, has been implemented to contribute further to the accurate, non-invasive assessment of pulmonary hypertension. The diagnostic protocols, including the analysis work flow, developed and reported in this PhD thesis can be integrated into the clinical process, with the potential to reduce the need for RHC by maximising the use of available MRI data