Optimal EPO dosing in hemodialysis patients using a non-linear model predictive control approach.

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.

The rise, fall, and future direction of computer-assisted personalized sedation.

PURPOSE OF REVIEW: The first computer-assisted personalized sedation (CAPS) device was developed to address the growing demand for routine endoscopy procedures in the United States in the early 2000s. This review will describe the environment that gave rise to CAPS and summarize the design of that first device. It will then discuss the market forces that led to the fall of CAPS, with sales of the device ending 2 years after commercialization. RECENT FINDINGS: CAPS was initially conceived as a means to enable proceduralists to administer conscious sedation with propofol safely. In the nearly 20 years since its conception, the expectations of patients and proceduralists for endoscopy sedation, have evolved from conscious sedation to deep. Due to the increased risk inherent in deep sedation, future CAPS devices should be tools for anesthesiologists, not proceduralists. SUMMARY: Over $2 billion are spent annually for anesthesia services in routine endoscopic procedures for low-risk patients; a spending rate that is not sustainable. CAPS, in an 'anesthesia oversight' model similar to medical supervision, has a future as a cost-efficient means for anesthesia services to provide sedation in endoscopy and other nonoperating room venues. Anesthesiologists should work with medical device companies and payers to develop a CAPS 'anesthesia oversight' model.

Fully closed-loop insulin delivery improves glucose control of inpatients with type 2 diabetes receiving hemodialysis.

Inpatient diabetes management of those on hemodialysis poses a major challenge. In a post hoc analysis of a randomized controlled clinical trial, we compared the efficacy of fully automated closed-loop insulin delivery vs. usual care in patients undergoing hemodialysis while in hospital. Compared to control patients receiving conventional subcutaneous insulin therapy, those patients receiving closed-loop insulin delivery significantly increased the proportion of time when a continuous glucose monitor was in the target range of 5.6-10.0 mmol/l by 37.6 percent without increasing the risk of hypoglycemia. Thus, closed-loop insulin delivery offers a novel way to achieve effective and safe glucose control in this vulnerable patient population.

Dental anaesthesia for children - effects of a computer-controlled delivery system on pain and heart rate: a randomised clinical trial.

Local anaesthesia in dentistry is usually given by conventional injection through a syringe. In this randomised, single-blind, split-mouth clinical study we evaluated the perception of pain and changes in heart rate in children being given dental local anaesthesia using a computer-controlled device compared with that given using a traditional syringe. Participants were in good general health with no contraindications to local anaesthetics. One half of each maxilla was anaesthetised using each technique, the order having been randomly selected according to a computer-generated sequence. The hypothesis was that the controlled anaesthetic flow rate results in virtually imperceptible injections. The outcomes were the perception of pain and the heart rate. Seventy-six children aged from 5-12 years old participated in this study. The mean (SD) pain score of the conventional injection was 5.51 (2.46) and the mean (SD) heart rate was 2.72 (6.76), which were significantly higher than those of the computerised delivery system, which were 4.74 (2.8) and 0.34 (7.3) (p=0.04). More patients anaesthetised with the traditional syringe technique required a second injection (n=21). These results suggest that dental anaesthesia given to children with a computer-controlled delivery system reduced pain better than that given with a conventional syringe.

SmartPilot® view-guided anaesthesia improves postoperative outcomes in hip fracture surgery: a randomized blinded controlled study.

BACKGROUND: Both under-dosage and over-dosage of general anaesthetics can harm frail patients. We hypothesised that computer-assisted anaesthesia using pharmacokinetic/pharmacodynamic models guided by SmartPilot® View (SPV) software could optimise depth of anaesthesia and improve outcomes in patients undergoing hip fracture surgery. METHODS: This prospective, randomized, single-centre, blinded trial included patients undergoing hip fracture surgery under general anaesthesia. In the intervention group, anaesthesia was guided using SPV with predefined targets. In the control group, anaesthesia was delivered by usual practice using the same agents (propofol, sufentanil and desflurane). The primary endpoint was the time spent in the "appropriate anaesthesia zone" defined as bispectral index (BIS) (blinded to the anaesthetist during surgery) of 45-60 and systolic arterial pressure of 80-140 mm Hg. Postoperative complications were recorded for one month in a blinded manner. RESULTS: Of 100 subjects randomised, 97 were analysed (n=47 in SPV and 50 in control group). Anaesthetic drug consumption was reduced in the SPV group (for propofol and desflurane). Intraoperative duration of low BIS (<45) was similar, but cumulative time of low systolic arterial pressure (<80 mm Hg) was significantly shorter in the SPV group (median (Q1-Q3); 3 (0-40) vs 5 (0-116) min, P=0.013). SPV subjects experienced fewer moderate or major postoperative complications at 30-days (8 (17)% vs 18 (36)%, P=0.035) and shorter length of hospitalisation (8 (2-20) vs 8 (2-60) days, P=0.017). CONCLUSIONS: SmartPilot® View-guided anaesthesia reduces intraoperative hypotension duration, occurrence of postoperative complications and length of stay in hip fracture surgery patients. CLINICAL TRIAL REGISTRATION: NCT 02556658.

Robotic Assistance in Medication Management: Development and Evaluation of a Prototype.

An increasing number of elderly people and the prevalence of multimorbid conditions often lead to age-related problems for patients in handling their common polypharmaceutical, domestic everyday medication. Ambient Assisted Living therefore provides means to support an elderly's everyday life. In the present paper we investigated the viability of using a commercial mass-produced humanoid robot system to support the domestic medication of an elderly person. A prototypical software application based on the NAO-robot platform was implemented to remind the patient for drug intakes, check for drug-drug-interactions, document the compliance and assist through the complete process of individual medication. A technical and functional evaluation of the system in a laboratory setting revealed versatile and viable results, though further investigations are needed to examine the practical use in an applied field.

Model-based drug administration: current status of target-controlled infusion and closed-loop control.

PURPOSE OF REVIEW: Drug administration might be optimized by incorporating pharmacokinetic-dynamic (PK/PD) principles and control engineering theories. This review gives an update of the actual status of target-controlled infusion (TCI) and closed-loop computer-controlled drug administration and the ongoing research in the field. RECENT FINDINGS: TCI is becoming mature technology clinically used in many countries nowadays with proven safety. Nevertheless, changing populations might require adapting the established PK/PD models. As TCI requires accurate PK/PD models, new models have been developed which should now be incorporated into the pumps to allow more general use of this technology. Closed-loop administration of hypnotic drugs using an electro-encephalographic-derived-controlled variable has been well studied and has been shown to outperform manual administration. Computer administration for other drugs and fluids have been studied recently. Feasibility has been shown for systems controlling multiple components of anaesthesia, but more work is required to show clinical safety and efficiency. SUMMARY: Evidence in the literature is increasing that TCI and closed-loop technology could assist the anaesthetists to optimize drug administration during anaesthesia.

Blood glucose control using a computer-guided glucose management system in allogeneic hematopoietic cell transplant recipients.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for patients with hematological malignancies. However, is associated with substantial rates of morbidity and mortality. We and others have shown that malglycemia is associated with adverse transplant outcome. Therefore, improving glycemic control may improve transplant outcome. In this prospective study we evaluated the feasibility of using Glucommander (a Computer-Guided Glucose Management System; CGGM) in order to achieve improved glucose control in hospitalized HCT patients. Nineteen adult patients contributed 21 separate instances on CGGM. Patients were on CGGM for a median of 43 h. Median initial blood glucose (BG) on CGGM was 244 mg/dL, and patients on 20 study instances reached the study BG target of 100-140 mg/dL after a median of 6 h. After BG reached the target range, the median average BG level per patient was 124 mg/dL. Six patients had a total of 10 events of BG <70 mg/dL (0.9% of BG measurements), and no patients experienced BG level <40 mg/dL. The total estimated duration of BG <70 mg/dL was 3 h (0.2% of the total CGGM time). In conclusion, our study demonstrates that stringent BG control in HCT patients using CGGM is feasible.

Fiabilidad de los registros electrónicos de prescripción de medicamentos de Atención Primaria / Reliability of Primary Care computerised medication records

OBJETIVO: Cuantificar y evaluar la fiabilidad de los registros electrónicos de medicación de Atención Primaria (AP) como fuente de información de la medicación crónica del paciente, así como identificar los factores asociados a la presencia de discordancias. DISEÑO: Estudio transversal descriptivo. EMPLAZAMIENTO: Hospital General de Referencia de un Área de Salud de la Región de Murcia. PARTICIPANTES: Pacientes ingresados en la unidad de Cardio-Neumología durante los meses de febrero a abril del 2013, con tratamiento domiciliario previo, que aceptaron participar en el estudio. MEDICIONES PRINCIPALES: Evaluación de la fiabilidad de los registros de AP analizando la concordancia, mediante la identificación de discrepancias, entre la medicación activa en dichos registros y la registrada mediante entrevista de un farmacéutico con el paciente/cuidador. Identificación de los factores asociados a la presencia de discrepancias analizados mediante una regresión logística multivariante. RESULTADOS: Se incluyó a 308 pacientes con una media ± desviación estándar de 70,9 ± 13,0 años. La concordancia en principios activos fue del 83,7%, disminuyendo al 34,7% al tener en cuenta la posología. Se encontraron discrepancias en el 97,1% de los pacientes, siendo las más frecuentes la omisión de pauta (35,6%), comisión (medicamento añadido injustificadamente) (14,6%) y omisión de medicamentos (12,7%). Ser mayor de 65 años (1,98 [1,08-3,64]), pluripatológico (1,89 [1,04-3,42]) y tener prescrito un estupefaciente o psicótropo (2,22 [1,16-4,24]) fueron los factores asociados a la presencia de discordancias. CONCLUSIONES: Los registros electrónicos de medicación de AP, aunque de indudable interés, pueden no ser lo suficientemente fiables como para poder ser utilizados como fuente única de información sobre la medicación crónica del paciente al ingreso hospitalario

OBJECTIVE: To quantify and to evaluate the reliability of Primary Care (PC) computerised medication records of as an information source of patient chronic medications, and to identify associated factors with the presence of discrepancies. DESIGN: A descriptive cross-sectional study. LOCATION: General Referral Hospital in Murcia. PARTICIPANTS: Patients admitted to the cardiology-chest diseases unit, during the months of February to April 2013, on home treatment, who agreed to participate in the study. MAIN MEASUREMENTS: Evaluation of the reliability of Primary Care computerised medication records by analysing the concordance, by identifying discrepancies, between the active medication in these records and that recorded in pharmacist interview with the patient/caregiver. Identification of associated factors with the presence of discrepancies was analysed using a multivariate logistic regression. RESULTS: The study included a total of 308 patients with a mean of 70.9 years (13.0 SD). The concordance of active ingredients was 83.7%, and this decreased to 34.7% when taking the dosage into account. Discrepancies were found in 97.1% of patients. The most frequent discrepancy was omission of frequency (35.6%), commission (drug added unjustifiably) (14.6%), and drug omission (12.7%). Age older than 65 years (1.98 [1.08 to 3.64]), multiple chronic diseases (1.89 [1.04 to 3.42]), and have a narcotic or psychotropic drug prescribed (2.22 [1.16 to 4.24]), were the factors associated with the presence of discrepancies. CONCLUSIONS: Primary Care computerised medication records, although of undoubted interest, are not be reliable enough to be used as the sole source of information on patient chronic medications when admitted to hospital

Reducing Intermittent Infusion Syringe Pump Errors via Weight-Based Safety Parameters.

UNLABELLED: Historically, smart infusion pumps with dose error reduction software were implemented to improve safety associated with programming of continuous infusion modes on large-volume infusion pumps. Much of the published literature related to smart infusion pumps and safety alerts is focused on continuous medication infusions, with little available information related to their use with intermittent infusions. As a result of the focus on continuous infusions, an impression exists that intermittent infusions are less prone to programming errors and/or do not require comparably rigorous safety parameters, such as use of weight-based medication programming. METHODS: A retrospective study was conducted with data from 10 pediatric inpatient hospitals, all of which used syringe infusion pumps for intermittent medications, to describe the impact of weight-based safety parameters on the occurrence of potential programming errors. The data were analyzed based on recorded safety alerts and alert triggers for weight-based (dose/kilogram/time) and non-weight-based (volume-over-time [VOT]) intermittent infusions. RESULTS: Data from a total of 4,162 pumps, 943,448 total infusions, and 810,359 intermittent infusions between January 1 and December 31, 2013, were reviewed. Weight-based infusions had a greater percentage of safety alerts (83.3%) compared with VOT infusions (16.7%). CONCLUSION: Weight-based intermittent infusion modes can prevent programming errors and, compared with non-weight-based intermittent infusion modes, can be used to improve safety in the pediatric population. Additional research should be conducted to confirm a decrease in adverse drug events resulting from implementation of weight-based safety parameters.

PERFORM: a system for monitoring, assessment and management of patients with Parkinson's disease.

In this paper, we describe the PERFORM system for the continuous remote monitoring and management of Parkinson's disease (PD) patients. The PERFORM system is an intelligent closed-loop system that seamlessly integrates a wide range of wearable sensors constantly monitoring several motor signals of the PD patients. Data acquired are pre-processed by advanced knowledge processing methods, integrated by fusion algorithms to allow health professionals to remotely monitor the overall status of the patients, adjust medication schedules and personalize treatment. The information collected by the sensors (accelerometers and gyroscopes) is processed by several classifiers. As a result, it is possible to evaluate and quantify the PD motor symptoms related to end of dose deterioration (tremor, bradykinesia, freezing of gait (FoG)) as well as those related to over-dose concentration (Levodopa-induced dyskinesia (LID)). Based on this information, together with information derived from tests performed with a virtual reality glove and information about the medication and food intake, a patient specific profile can be built. In addition, the patient specific profile with his evaluation during the last week and last month, is compared to understand whether his status is stable, improving or worsening. Based on that, the system analyses whether a medication change is needed--always under medical supervision--and in this case, information about the medication change proposal is sent to the patient. The performance of the system has been evaluated in real life conditions, the accuracy and acceptability of the system by the PD patients and healthcare professionals has been tested, and a comparison with the standard routine clinical evaluation done by the PD patients' physician has been carried out. The PERFORM system is used by the PD patients and in a simple and safe non-invasive way for long-term record of their motor status, thus offering to the clinician a precise, long-term and objective view of patient's motor status and drug/food intake. Thus, with the PERFORM system the clinician can remotely receive precise information for the PD patient's status on previous days and define the optimal therapeutical treatment.

[Closed-Loop at night for the treatment of type 1 diabetes]. / "Closed Loop": Wann kommt die künstliche Bauchspeicheldrüse für Typ-1-Diabetes?

This mini-review describes the latest efforts, challenges, and experience of using automated insulin delivery systems at outpatient settings and home studies. Predictive low glucose management (PLGM) may help prevent hypoglycemia by stopping insulin pump delivery based on predicted sensor glucose values. In silico modeling and early feasibility data demonstrate that PLGM may further reduce the severity of hypoglycemia beyond that already established for algorithms that use a threshold-based suspension. Recent studies have shown that an closed-loop system can improve glucose control and reduce nocturnal hypoglycemia. In the multinational, multicenter DREAM project patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. Studies using closed-loop systems at patients' home are currently being carried out. The preliminary results of these experiments are encouraging and enhance our confidence in this tool as suitable for use in clinical daily practice.

Implementation of a clinical decision support system for computerized drug prescription entries in a large tertiary care hospital.

BACKGROUND: Prescription errors are common in hospitalized patients and result in significant morbidity, mortality and costs. Electronic prescriptions with computerized physician order entry systems (CPOE) and integrated computerized decision support systems (CDSS providing online alerts) reduce prescription errors by approximately 50%. However, the introduction of CDSS is often met by opposition due to the flood of alerts, and most prescribers eventually ignore even crucial alerts ("alert fatigue"). OBJECTIVES: To describe the implementation and customization of a commercial CDSS (SafeRx) for electronic prescribing in Internal Medicine departments at a tertiary care center, with the purpose of improving comprehensibility and substantially reducing the number of alerts to minimize alert fatigue. METHODS: A multidisciplinary expert committee was authorized by the hospital administration to customize the CDSS according to the needs of six internal medicine departments at Sheba Medical Center. We assessed volume of prescriptions and alert types during the period February-August 2012 using the statistical functions provided by the CDSS. RESULTS: A mean of 339 +/- 13 patients per month per department received 11.2 +/- 0.5 prescriptions per patient, 30.1% of which triggered one or more CDSS alerts, most commonly drug-drug interactions (43.2%) and dosing alerts (38.3%). The review committee silenced or modified 3981 alerts, enhancing comprehensibility, and providing dosing instructions adjusted to the patient's renal function and recommendations for follow-up. CONCLUSIONS: The large volume of drug prescriptions in internal medicine departments is associated with a significant rate of potential prescription errors. To ensure its effectiveness and minimize alert fatigue, continuous customization of the CDSS to the specific needs of particular departments is required.

Dashboard systems: implementing pharmacometrics from bench to bedside.

In recent years, there has been increasing interest in the development of medical decision-support tools, including dashboard systems. Dashboard systems are software packages that integrate information and calculations about therapeutics from multiple components into a single interface for use in the clinical environment. Given the high cost of medical care, and the increasing need to demonstrate positive clinical outcomes for reimbursement, dashboard systems may become an important tool for improving patient outcome, improving clinical efficiency and containing healthcare costs. Similarly the costs associated with drug development are also rising. The use of model-based drug development (MBDD) has been proposed as a tool to streamline this process, facilitating the selection of appropriate doses and making informed go/no-go decisions. However, complete implementation of MBDD has not always been successful owing to a variety of factors, including the resources required to provide timely modeling and simulation updates. The application of dashboard systems in drug development reduces the resource requirement and may expedite updating models as new data are collected, allowing modeling results to be available in a timely fashion. In this paper, we present some background information on dashboard systems and propose the use of these systems both in the clinic and during drug development.