Biochemistry and Pharmacology - Research Publications
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ItemRenal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass(WILEY, 2018-03)Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts.
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ItemNo Preview AvailableVisual evoked potentials determine chronic signal quality in a stent-electrode endovascular neural interface(IOP PUBLISHING LTD, 2018-09)
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ItemFactors that confound the prediction of renal medullary oxygenation and risk of acute kidney injury from measurement of bladder urine oxygen tension(WILEY, 2019-09)AIM: Urinary oxygen tension (uPO2 ) may provide an estimate of renal medullary PO2 (mPO2 ) and thus risk of acute kidney injury (AKI). We assessed the potential for variations in urine flow and arterial PO2 (aPO2 ) to confound these estimates. METHODS: In 28 sheep urine flow, uPO2 , aPO2 and mPO2 were measured during development of septic AKI. In 65 human patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) uPO2 and aPO2 were measured continuously during CPB, and in a subset of 20 patients, urine flow was estimated every 5 minutes. RESULTS: In conscious sheep breathing room air, uPO2 was more closely correlated with mPO2 than with aPO2 or urine flow. The difference between mPO2 and uPO2 varied little with urine flow or aPO2 . In patients, urine flow increased abruptly from 3.42 ± 0.29 mL min-1 to 6.94 ± 0.26 mL min-1 upon commencement of CPB, usually coincident with reduced uPO2 . During hyperoxic CPB high values of uPO2 were often observed at low urine flow. Low urinary PO2 during CPB (<10 mm Hg at any time during CPB) was associated with greater (4.5-fold) risk of AKI. However, low urine flow during CPB was not significantly associated with risk of AKI. CONCLUSIONS: uPO2 provides a robust estimate of mPO2 , but this relationship is confounded by the simultaneous presence of systemic hyperoxia and low urine flow. Urine flow increases and uPO2 decreases during CPB. Thus, CPB is probably the best time to use uPO2 to detect renal medullary hypoxia and risk of post-operative AKI.
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ItemSepsis-induced acute kidney injury: A disease of the microcirculation(WILEY, 2019-02)AKI is a common complication of sepsis and is significantly associated with mortality. Sepsis accounts for more than 50% of the cases of AKI, with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex, but there is emerging evidence that, at least in the first 48 hours, the defects may be functional rather than structural in nature. For example, septic AKI is associated with an absence of histopathological changes, but with microvascular abnormalities and tubular stress. In this context, renal medullary hypoxia due to redistribution of intra-renal perfusion is emerging as a critical mediator of septic AKI. Clinically, vasopressor drugs remain the cornerstone of therapy for maintenance of blood pressure and organ perfusion. However, in septic AKI, there is insensitivity to vasopressors such as norepinephrine, leading to persistent hypotension and organ failure. Vasopressin, angiotensin II, and, paradoxically, α2 -adrenergic receptor agonists (clonidine and dexmedetomidine) may be feasible adjunct therapies for catecholamine-resistant vasodilatory shock. In this review, we outline the recent progress made in understanding how these drugs may influence the renal microcirculation, which represents a crucial step toward developing better approaches for the circulatory management of patients with septic AKI.
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ItemChemoattraction and Recruitment of Activated Immune Cells, Central Autonomic Control, and Blood Pressure Regulation(FRONTIERS MEDIA SA, 2019-08-02)Inflammatory mediators play a critical role in the regulation of sympathetic outflow to cardiovascular organs in hypertension. Emerging evidence highlights the involvement of immune cells in the regulation of blood pressure. However, it is still unclear how these immune cells are activated and recruited to key autonomic brain regions to regulate sympathetic outflow to cardiovascular organs. Chemokines such as C-C motif chemokine ligand 2 (CCL2), and pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), are upregulated both peripherally and centrally in hypertension. More specifically, they are upregulated in key autonomic brain regions that control sympathetic activity and blood pressure such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. Furthermore, this upregulation of inflammatory mediators is associated with the infiltration of immune cells to these brain areas. Thus, expression of pro-inflammatory chemokines and cytokines is a potential mechanism promoting invasion of immune cells into key autonomic brain regions. In pathophysiological conditions, this can result in abnormal activation of brain circuits that control sympathetic nerve activity to cardiovascular organs and ultimately in increases in blood pressure. In this review, we discuss emerging evidence that helps explain how immune cells are chemoattracted to autonomic nuclei and contribute to changes in sympathetic outflow and blood pressure.
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ItemSignal quality of simultaneously recorded endovascular, subdural and epidural signals are comparable(NATURE PORTFOLIO, 2018-05-30)Recent work has demonstrated the feasibility of minimally-invasive implantation of electrodes into a cortical blood vessel. However, the effect of the dura and blood vessel on recording signal quality is not understood and may be a critical factor impacting implementation of a closed-loop endovascular neuromodulation system. The present work compares the performance and recording signal quality of a minimally-invasive endovascular neural interface with conventional subdural and epidural interfaces. We compared bandwidth, signal-to-noise ratio, and spatial resolution of recorded cortical signals using subdural, epidural and endovascular arrays four weeks after implantation in sheep. We show that the quality of the signals (bandwidth and signal-to-noise ratio) of the endovascular neural interface is not significantly different from conventional neural sensors. However, the spatial resolution depends on the array location and the frequency of recording. We also show that there is a direct correlation between the signal-noise-ratio and classification accuracy, and that decoding accuracy is comparable between electrode arrays. These results support the consideration for use of an endovascular neural interface in a clinical trial of a novel closed-loop neuromodulation technology.
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ItemNo Preview AvailableFeasibility of a Chronic, Minimally Invasive Endovascular Neural Interface(IEEE, 2016)Development of a neural interface that can be implanted without risky, open brain surgery will increase the safety and viability of chronic neural recording arrays. We have developed a minimally invasive surgical procedure and an endovascular electrode-array that can be delivered to overlie the cortex through blood vessels. Here, we describe feasibility of the endovascular interface through electrode viability, recording potential and safety. Electrochemical impedance spectroscopy demonstrated that electrode impedance was stable over 91 days and low frequency phase could be used to infer electrode incorporation into the vessel wall. Baseline neural recording were used to identify the maximum bandwidth of the neural interface, which remained stable around 193 Hz for six months. Cross-sectional areas of the implanted vessels were non-destructively measured using the Australian Synchrotron. There was no case of occlusion observed in any of the implanted animals. This work demonstrates the feasibility of an endovascular neural interface to safely and efficaciously record neural information over a chronic time course.