Anemia management with erythropoiesis stimulating agents is a challenging task in hemodialysis patients since their response to treatment varies highly. In general, it is difficult to achieve and maintain the predefined hemoglobin (Hgb) target levels in clinical practice. The aim of this study is to develop a fully personalizable controller scheme to stabilize Hgb levels within a narrow target window while keeping drug doses low to mitigate side effects. First in-silico results of this framework are presented in this paper. Based on a model of erythropoiesis we formulate a non-linear model predictive control (NMPC) algorithm for the individualized optimization of epoetin alfa (EPO) doses. Previous to this work, model parameters were estimated for individual patients using clinical data. The optimal control problem is formulated for a continuous drug administration. This is currently a hypothetical form of drug administration for EPO as it would require a programmable EPO pump similar to insulin pumps used to treat patients with diabetes mellitus. In each step of the NMPC method the open-loop problem is solved with a projected quasi-Newton method. The controller is successfully tested in-silico on several patient parameter sets. An appropriate control is feasible in the tested patients under the assumption that the controlled quantity is measured regularly and that continuous EPO administration is adjusted on a daily, weekly or monthly basis. Further, the controller satisfactorily handles the following challenging problems in simulations: bleedings, missed administrations and dosing errors.
Red blood cells (RBC) are the most abundant cells in the blood. Despite powerful defense systems against chemical and mechanical stressors, their life span is limited to about 120 days in healthy humans and further shortened in patients with kidney failure. Changes in the cell membrane potential and cation permeability trigger a cascade of events that lead to exposure of phosphatidylserine on the outer leaflet of the RBC membrane. The translocation of phosphatidylserine is an important step in a process that eventually results in eryptosis, the programmed death of an RBC. The regulation of eryptosis is complex and involves several cellular pathways, such as the regulation of non-selective cation channels. Increased cytosolic calcium concentration results in scramblase and floppase activation, exposing phosphatidylserine on the cell surface, leading to early clearance of RBCs from the circulation by phagocytic cells. While eryptosis is physiologically meaningful to recycle iron and other RBC constituents in healthy subjects, it is augmented under pathological conditions, such as kidney failure. In chronic kidney disease (CKD) patients, the number of eryptotic RBC is significantly increased, resulting in a shortened RBC life span that further compounds renal anemia. In CKD patients, uremic toxins, oxidative stress, hypoxemia, and inflammation contribute to the increased eryptosis rate. Eryptosis may have an impact on renal anemia, and depending on the degree of shortened RBC life span, the administration of erythropoiesis-stimulating agents is often insufficient to attain desired hemoglobin target levels. The goal of this review is to indicate the importance of eryptosis as a process closely related to life span reduction, aggravating renal anemia.
In the present paper a semilinear boundary control problem is considered. For its numerical solution proper orthogonal decomposition (POD) is applied. POD is based on a Galerkin type discretization with basis elements created from the evolution problem itself. In the context of optimal control this approach may suffer from the fact that the basis elements are computed from a reference trajectory containing features which are quite different from those of the optimally controlled trajectory. Therefore, different POD basis update strategies which avoid this problem of unmodelled dynamics are compared numerically.
Background and Aims Preciado et al. have identified half-hourly relative blood volume (RBV) targets (at 30, 60…180 min) during hemodialysis (HD) that are associated with significantly improved patient survival. Attainment of these RBV targets would necessitate incessant adjustments to the ultrafiltration rate (UFR) by the dialysis nurse, which is logistically not feasible. We developed a novel proportional-integral controller that takes RBV data from the commercially available CLiC® device as an input and provides UFR suggestions to guide the RBV curve into the desired targets. The clinician specifies the desired UF goal and the maximum allowed upward/downward deviation from this goal, and the Controller then optimizes the RBV trajectory within the limits allowed by the clinician’s prescription. The present study is aimed to characterize the behavior of this novel feedback controller. Method We conducted a single-arm, prospective, interventional pilot study in subjects on chronic HD at three Avantus Renal Therapy Dialysis Centers in New York City. Subjects were treated with Fresenius 2008T HD machines. RBV was measured with the CLiC® device. CLiC® and HD machine data were fed into a research laptop running the UFR Feedback Controller software. The UFR recommendations (generated every 10 minutes) were evaluated by dialysis nurses who then either implemented or rejected them as they deemed clinically appropriate. The nurses were instructed to only override Controller recommendations if medically indicated, but not in an attempt to manage the subjects’ RBV trajectories themselves. Results Fifteen subjects (58.9 ± 15.3 years, 33% white, 53% black, dialysis vintage 4.1 ± 2.4 years, baseline interdialytic weight gain 2.6 ± 0.8 L, treatment time 222 ± 28 min) were studied (63 study visits, 4.2 ± 1.9 visits per subject). Of 300 analyzed RBV target timepoints, 63% had RBVs within the desired target range, 33% of the RBVs were above and 4% were below target. Stratified by timepoint, the on-target percentage increased from 37% at 30 min to 73% at 180 min into HD, while the proportion of RBVs above or below target decreased. In subjects with at least 4 complete study visits (N=8), looking at each of their first 4 complete visits, on average 71.8% of subjects were within the desired RBV target at 180 min into HD. The rate of intradialytic morbid events did not appear to be outside of the ordinary. There was no indication of adverse events related to the use of the UFR Feedback Controller. The Figure shows an example study visit where the UFR Feedback Controller modulates the UFR on an ongoing basis throughout the treatment to keep the RBV curve close to the ideal target trajectory (red line, defined by connecting the RBVs associated with the lowest all-cause mortality). Solid black line: RBV curve (left y-axis); dashed black line: UFR (right y-axis); green boxes: half-hourly RBV target ranges associated with improved survival. Conclusion The UFR Feedback Controller behaves as expected, steering the patients’ RBV curves toward the predefined target ranges where possible, while simultaneously guaranteeing that the prescribed fluid removal goal will be achieved. Preciado et al. had reported approx. one third of patients within the favorable RBV target range at 3h into HD. In contrast, while our pilot study was relatively small, with use of our novel UFR Feedback Controller, approx. 72% of subjects were within the desired RBV target range at 3h into HD. This novel UFR feedback control technology holds great promise for improving fluid management and clinical outcomes in HD patients without requiring additional staff time.
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