Optimal design of feasible clinical tests for the identification of physiological models of type 1 diabetes mellitus

Questa tesi concerne la progettazione di test clinici per l'identificazione di modelli fisiologici del diabete mellito di tipo 1. La progettazione ottimale di esperimenti basata su modello si applica a tal proposito e la fattibilità dei test ideati viene valutata tramite una serie di indici introdotti ad hoc. Il lavoro si conclude con l'impiego di tecniche di progettazione robusta che siano in grado di garantire al test i requisiti di applicabilità clinica necessar

A methodology for direct exploitation of available information in the online model-based redesign of experiments

Online model-based design of experiments techniques were proposed to exploit the progressive increase of the information resulting from the running experiment, but they currently exhibit some limitations: the redesign time points are chosen “a-priori” and the first design may be heavily affected by the initial parametric mismatch. In order to face such issues an information driven redesign optimisation (IDRO) strategy is here proposed: a robust approach is adopted and a new design criterion based on the maximisation of a target profile of dynamic information is introduced. The methodology allows determining when to redesign the experiment in an automatic way, thus guaranteeing that an acceptable increase in the information content has been achieved before proceeding with the intermediate estimation of the parameters and the subsequent redesign of the experiment. The effectiveness of the new experiment design technique is demonstrated through two simulated case studies

REGULATION OF BLOOD GLUCOSE IN TYPE I DIABETIC PATIENTS

Ph.DDOCTOR OF PHILOSOPH

Hyperglycaemia, insulin and acute ischaemic stroke

Background: Hyperglycaemia is common in acute stroke and is associated with a poor outcome. Underlying aetiology and mechanism of action is poorly understood. Management remains uncertain. Methods: We undertook a randomised placebo controlled trial to assess the effect of GKI (Glucose-Potassium-Insulin) versus placebo on lesion volume progression and cerebral lactate levels using magnetic resonance imaging (MRI) and spectroscopy (MRS). An observational study of the capillary blood glucose within 48 hours of stroke onset was performed to define the temporal profile of glucose, with a subset followed prospectively to determine the prevalence of abnormal glucose metabolism in patients with stress hyperglycaemia. The association between insular cortex involvement and hyperglycaemia was determined by analysing MRI data sets from two randomised trials. Stroke unit practice for the management of glucose was assessed in a review of the stroke unit trialists’ collaboration data set. Results: • GKI infusion failed to attenuate infarct growth in patients with moderate hyperglycaemia within 24 hours of acute ischaemic stroke. A trend towards attenuation of increased lactate concentration was evident in the GKI treatment arm. Exploratory analyses raised the possibility that GKI may be harmful in patients with persistent arterial occlusion. • Over the 48hour monitoring period 75% of patients developed Hyperglycaemia. Stroke severity was not predictive of admission hyperglycaemia whereas glycosylated haemoglobin was (OR 2.97; 95%CI 1.84-4.78; p<0.001). 50% of patients screened were found to have abnormal glucose metabolism at follow-up. • Insular cortex involvment on MRI was not predictive of admission hyperglycaemia. • Testing for blood glucose concentration in stroke units was infrequent. Of the minority of units that had a protocol in place, the threshold for intervention with insulin was >10mmol/l. Conclusion: We found no evidence that GKI infusion attenuated infarct growth in patients with mild hyperglycaemia following acute ischaemic stroke. In post-hoc analysis the possibility that GKI infusion may be harmful in patients with total occlusion suggests an effect dependent on recanalisation status. A non-significant trend towards attenuation of increased lactate concentration was evident. Stroke severity was not found to be a predictor of post stroke hyperglycaemia. Underlying dysglycaemia was common in non-diabetic patients manifesting hyperglycaemia within 48hours of stroke ictus. Screening of high risk patients with oral glucose tolerance testing is justified and provides a potential opportunity for secondary prevention. Insular cortex involvement did not independently predict hyperglycaemia in acute stroke. Current management of hyperglycaemia is guided by consensus guidelines with little evidence base. Stroke unit practice varies with little change across stroke units over the years

Applications of CT Perfusion-Based Triaging and Prognostication in Acute Ischemic Stroke

CT Perfusion (CTP) is a minimally invasive imaging technique that aids acute ischemic stroke (AIS) triage and prognostication by determining tissue viability based on hemodynamic parameters. The goals of this research are to determine: 1) CTP thresholds for estimation of infarct and penumbra volume, 2) how CTP scan duration impacts infarct and penumbra volume estimates, and 3) reliability of CTP for predicting functional outcomes following intra-arterial therapy (IAT). Chapter 2 introduced an experimental study for determining ischemia-time dependent thresholds for brain infarction using multimodal imaging in a porcine stroke model that is easier to implement than previous large animal stroke models. CTP determined an absolute cerebral blood flow (CBF) threshold of 12.6±2.8mL∙min-1∙100g-1 for brain infarction after 3h of ischemia, which was close to that derived using hydrogen clearance in a previous study by Jones et al (Journal of Neurosurgery, 1981;54(6):773-782). Chapter 3 retrospectively investigated the impact of CTP scan duration on cerebral blood volume (CBV), CBF, and time-to-maximum (Tmax) and found optimal scan durations that minimized radiation dose while not under- or over-estimating infarct volumes measured using two previously derived CBF thresholds for infarction. We found that CBV and Tmax decreased at shorter scan durations, whereas CBF was independent of scan duration, consequently, infarct volume estimated by both CBF thresholds was independent of scan duration. Chapter 4 compared reperfusion seen on follow-up CTP to reperfusion predicted by post-IAT digital subtraction angiography (DSA) and the ability of the two modalities to predict good 90-day functional outcome in a retrospective study. We found that patients with ‘complete reperfusion’ grades on DSA often had ischemic tissue on follow-up CTP and that follow-up CTP had superior specificity and accuracy for predicting functional outcome compared to DSA. In summary, this research has shown that CBF thresholds can reliably detect infarct in AIS and are independent of scan duration, allowing radiation dose to be minimized by limiting scans to 40s without compromising accuracy of infarct volume estimates. Finally, CTP is a more specific and accurate predictor of functional outcome than the commonly used post-procedural DSA, this could help select patients for neuroprotective therapy

Improving Acute Stroke Management with CT Perfusion Imaging: Approaches to Treatment Guidance and Brain Tissue Salvage

CT Perfusion (CTP) provides measurement of perfusion at the capillary level which can be used to characterize tissue viability, and blood-brain-barrier (BBB) compromise. Using CTP, the goals of this research are to: 1) select patients that will benefit from acute stroke treatment, and 2) determine if pre-stroke neuroprotection reduces stroke severity. Chapter two investigates the cerebral blood volume (CBV) parameter in a small acute ischemic stroke (AIS) patient set. Overestimation of the acute CBV defect is caused by incomplete wash-out of the CT contrast due to a shortened CTP acquisition time (“truncation artifact”). In chapter three we examine the prognostic reliability of the acute CBV defect to predict infarct core and penumbra in AIS. We determine that hypervolemia, the “truncation artifact” and recanalization are all important variables which affect the relationship between the acute CBV defect volume and the final infarct volume. Chapter four implements a novel porcine model of ischemic stroke using the transient vasoconstrictor, endothelin-1. Using this model, we show that the CTP-cerebral blood flow (CBF) parameter is as good as MR-DWI for acute infarct core delineation, and the CBF/CBV mismatch may not indicate penumbral tissue in the acute stroke setting. In Chapter five, it we show that vascular integrity measured with the CTP-BBB permeability surface area product (PS) is a strong predictor of sub-acute bleeding in the brain (hemorrhagic transformation). Chapter six shows that different rates of CT contrast extravasation exist for primary intracerebral hemorrhage (ICH) patients with/without the CTA-Spot Sign and/or post-contrast leakage. Furthermore, early rates of extravasation are correlated with sub-acute hematoma expansion. Chapter seven describes the development of an improved, reproducible and survivable rabbit large clot embolic model (RLCEM) of cerebral ischemia for testing treatment options for AIS. We demonstrate that pre-stroke treatment with dipyridamole provides a neurovascular advantage post stroke onset. In summary, the current uses of CTP imaging in acute stroke include: 1) quantifying ischemia to define infarct core and penumbra in AIS, 2) predicting hemorrhagic transformation of AIS, 3) predicting hematoma expansion in primary ICH, and 4) assessing treatment response in animal models of stroke to facilitate new drug development

The Physiological Basis of Myocardial Hibernation

Introduction Myocardial hibernation is the active downregulation of myocardial function in response to recurrent episodes of non-lethal ischaemia. It develops as part of an adaptive programme which favours cell survival over contractility, with clear evidence of progressive cellular changes including metabolic switches, regression of the contractile apparatus and glycogen deposition. Early hibernation is reversible if the ischaemic stimulus is removed or reduced; whilst this was traditionally considered specific to revascularisation, emerging evidence suggests that any intervention which favourably alters the balance of myocardial oxygen supply against demand has comparable effects. Due to the potential for functional recovery, hibernation has become a key therapeutic target in ischaemic left ventricular dysfunction. Viability testing refers to the prospective identification of the substrate of myocardial hibernation using a variety of non-invasive imaging methods including cardiac magnetic resonance imaging (CMR), nuclear imaging and stress echocardiography, and has become an important part of the assessment of patients with ischaemic left ventricular dysfunction being considered for revascularisation. All modalities have similar diagnostic performance, though techniques which assess both the viability of the myocardial tissue and the presence of inducible ischaemia have higher specificity for reversibility and functional recovery. However, the need for multiple tests, including invasive coronary angiography and non-invasive viability testing, is a potential barrier to patients undergoing revascularisation and places a significant burden on healthcare resources. Invasive coronary physiology is an established alternative to non-invasive imaging. Assessment of arterial physiology with fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) is the most widely accepted vessel specific surrogate for inducible myocardial ischaemia, and there is emerging evidence that pathophysiological states of the myocardium can be differentiated through assessing myocardial physiology by coronary wave intensity analysis (cWIA), by measuring the magnitude of the myocardial-originating backward compression wave (BCW) and backward expansion wave (BEW). The studies in this thesis have been designed to further our understanding of both the invasive and non- invasive assessment of myocardial viability and ischaemia in patients with ischaemic left ventricular dysfunction (ILVD). Methods Patients with a recent diagnosis of ILVD, defined as the presence of extensive coronary artery disease (British Cardiovascular Intervention Society jeopardy score ≥ 6) and left ventricular dysfunction (ejection fraction ≤ 40%) were enrolled. Those with a recent acute myocardial infarction or severe valvular heart disease were excluded. Participants underwent invasive physiological assessment during cardiac catheterisation, with simultaneous measurement of aortic and distal coronary pressure, and coronary blood flow velocity, measured at rest, during adenosine induced hyperaemia and low dose dobutamine stress. Pressure-based indices of coronary stenosis severity, coronary stenosis resistance, microvascular resistance, and coronary wave intensity analysis were calculated from ensemble-averaged signals. Myocardial viability was determined by CMR using a dark-blood late gadolinium-enhanced phase-sensitive inversion-recovery (PSIR) turbo field echo pulse sequence at either 1.5 or 3-Tesla, with viability defined as scar burden ≤ 25% on quantitative assessment. Stress perfusion data were acquired using a saturation-recovery k-t sensitivity encoding accelerated gradient-echo method at 3-Tesla. Regional left ventricular function was assessed at baseline and 6-month or 12-month follow up after optimisation of medical therapy +/- revascularisation, using transthoracic echocardiography. The primary outcome was functional recovery, defined either regionally (as an improvement in wall motion score index ≥ 0.5 across the subtended territory) or segmentally (as an improvement in wall motion score ≥1). In the first study, hyperaemic stenosis resistance was used as a reference standard to investigate the diagnostic accuracy of FFR and iFR in 40 patients with ILVD who underwent cardiac catheterisation and invasive coronary physiology studies, compared to a control population of 13 patients with normal left ventricular function. The second study assessed the ability of backward-originating coronary wave energy (the BCW and BEW) to predict the presence of hibernation (defined as the observation of functional recovery in the subtended territory): the same forty patients also underwent CMR (the current clinical reference standard viability test) and baseline echocardiography; 25 had follow-up echocardiography. The ability of BCW, BEW and CMR to predict functional recovery were compared by the area under the curve (AUC) on receiver operator characteristic (ROC) analysis. The final study determined whether the combination of ischaemia and viability assessment, with a combined stress perfusion/late gadolinium enhancement (SP/LGE) CMR protocol, would improve the prediction of hibernation (defined as segmental functional recovery) compared to LGE alone, in twenty-nine patients with ILVD who underwent CMR and baseline and follow-up echocardiography. Results In the ILVD group, hyperaemic stenosis resistance was positive in 20 vessels, FFR positive in 26 vessels and iFR positive in 32 vessels: FFR had a sensitivity of 95% and specificity of 83% whilst iFR had a sensitivity of 95% and specificity of 68%. In controls, hyperaemic stenosis resistance was positive in 12 vessels, FFR positive in 13 vessels and iFR positive in 23 vessels; FFR had a sensitivity of 100% and specificity of 93%, and iFR had a sensitivity of 100% and specificity of 21%. However, when FFR and iFR were assessed as a continuum, there was increasing inaccuracy with increasing stenosis resistance, with a tendency to underestimate severity in high grade lesions in ILVD compared to normal controls. Microvascular resistance, wall thickening, and late enhancement were all found to influence FFR results in patients with ILVD. The resting BCW was significantly larger in recovering than non-recovering territories (-5564 ± 4054 vs. -1853 ± 1735 W.m-2.s-1, p &lt;0.001). The BEW did not differ significantly (-6377 ± 4833 vs. -5053 ± 5929 W.m-2.s-1, p = 0.476) (figure 4.3). The BCW was the most effective predictor of functional recovery (AUC 0.814, 95% CI 0.671-0.957), with comparable diagnostic accuracy to LGE-CMR (AUC 0.771, 95% CI 0.617-0.925), difference between AUC 0.0425, 95% CI -0.140-0.225, p = 0.649). A BCW threshold of -2351 W.m2.s-1 had 92% sensitivity and 73% specificity for predicting functional recovery. Dobutamine stress did not improve the diagnostic accuracy of cWIA. The BEW, previously identified as the most effective predictor of functional recovery following an acute coronary syndrome, did not predict functional recovery but was closely related to the regional scar burden at baseline. Microvascular resistance did not differentiate viable from non-viable territories. Four-hundred and fifty-eight segments were included in the analysis. Scar was identified in 162 segments (1-25% in 48, 26-50% in 49, 51-75% in 25 and 76-100% in 40); 296 segments had no evidence of scar. Stress perfusion defects were identified in 166 segments in 26 patients. The primary outcome occurred in 167 of 458 segments (36.5%). On univariate analysis, the demonstration of the full substrate of hibernation (both inducible ischaemia and viability), assessed by a combined SP/LGE-CMR protocol, significantly increased specificity for predicting functional recovery (76.8% vs. 26.8%, p &lt; 0.001) compared to LGE-CMR alone. The increase in specificity came at a significant cost to sensitivity (34.3% with SP/LGE-CMR vs. 78.4% with LGE- CMR alone, p &lt;0.001). Diagnostic accuracy was greatest in segments which exhibited both inducible ischaemia and preserved viability (60.3%), followed by SP-CMR alone (57.9%): both were significantly more accurate than LGE- CMR (45.6%, p &lt; 0.001). On multiple regression analysis, however, scar burden and baseline wall motion predicted segmental recovery, whilst the presence of an inducible perfusion defect and revascularisation status did not. Conclusion The combined assessment of inducible ischaemia and viability during invasive cardiac catheterisation is feasible. Backward expansion wave magnitude measured with cWIA in resting conditions provides an accurate prediction of functional recovery, comparable to LGE-CMR and as an adjunct to coronary angiography may permit timely, streamlined revascularisation for patients with ischaemic left ventricular dysfunction. The addition of pharmacological stress does not improve diagnostic performance. The results of both FFR and iFR are influenced by microvascular function and myocardial pathology in patients with ILVD, producing a less accurate estimation of stenosis resistance. Further validation of pressure-derived indices in ILVD is needed. The addition of ischaemia assessment to LGE-CMR improved overall diagnostic performance, although the diagnostic accuracy was limited with all techniques, with a low observed rate of functional recovery in this population. Adjusted analyses demonstrated that scar burden and baseline wall motion remained the best predictors of functional recovery, and the routine addition of stress perfusion sequences to LGE-CMR in ILVD is unlikely to be beneficial. This thesis advances our understanding of the invasive and non-invasive assessment of ischaemia and viability as integral parts of the physiology of hibernation. In time such detailed phenotyping may provide the key to truly personalised decision making for patients in this high-risk population