Desarrollo y Simulación de un Algoritmo de Control Automatizado para Insulinoterapia de Urgencias Hiperglucémicas en Diabetes / Development and Simulation of an Automated Control Algorithm for Insulin Therapy of Hyperglycemic Emergencies in Diabetes

Resumen El presente trabajo describe el desarrollo y simulación de un algoritmo para el control automático de la infusión de insulina en el manejo glucémico de pacientes con cetoacidosis diabética (CAD) y estado hiperosmolar hiperglucémico (EHH). Se programó un algoritmo que calcula la insulina necesaria para lograr un descenso glucémico de 50 mg/dL/h hasta llegar a glucemias de 250 mg/dL, para posteriormente mantenerlas en 220 mg/dL hasta la remisión de la patología. La simulación del software se realizó haciendo uso de registros glucémicos de 10 pacientes con CAD manejados en el Hospital Juárez de México. Los resultados de la simulación mostraron una incidencia 6 veces menor de hipoglucemias, así como un 33.7% menos de insulina necesaria dentro del tratamiento, sin diferencias entre los descensos medios de glucosa por hora de las mediciones reales y simuladas. Este software propone un uso innovador de los llamados páncreas artificiales al aplicarlos en urgencias hiperglucémicas, implementando además el uso de la sensibilidad a la insulina como variable para el funcionamiento de los mismos. Los resultados demuestran que el algoritmo podría ser capaz de lograr un manejo glucémico apegado a las guías de tratamiento, generando un menor gasto de insulina y evitando hipoglucemias durante la terapéutica, con una posible aplicación en dispositivos biomédicos autónomos.

Abstract This paper describes the development and simulation of an algorithm for the automatic control of insulin infusion, in the glycemic management of patients with diabetic ketoacidosis (CAD) and hyperglycemic hyperosmolar state (EHH). An algorithm was programmed to calculate the requirement insulin for a glycemic decrease of 50 mg/dL/h until reach 250 mg/dL in blood glucose levels, and thus maintaining it at 220 mg/dL until the pathology remission. The software simulation was performed using glycemic records of 10 patients with CAD managed in the Hospital Juárez de México. The results of the simulation showed a lower incidence of hypoglycemia, as well as a lower insulin requirement within the treatment, without differences in the average glucose decreases per hour between real and simulated measurements. This software proposes an innovative use of the artificial pancreas in hyperglycemic emergencies, and also implementing the use of insulin sensitivity as a variable for their function. The results show that the algorithm could be able to achieve glycemic management attached to the treatment guidelines, generating lower insulin expenditure and avoiding hypoglycemia during therapy, with a possible application in autonomous biomedical devices.

Efficacy and safety of simulated artificial pancreas in modulating stress hyperglycemia in critically ill patients:a prospective randomized controlled study / 中华危重病急救医学

Objective To explore efficacy and safety of simulated artificial pancreas in modulating stress hyperglycemia in critically ill patients. Methods A prospective randomized controlled study was performed. Seventy-two critically ill patients with stress hyperglycemia, aged 18-85 years, acute physiology and chronic health evaluationⅡ(APACHEⅡ) score over 15, two consecutive random blood glucose 11.1 mmol/L or higher, glycated hemoglobin (HbA1C) below 0.065, unable to eat food for 3 days after inclusion, or only accepting parenteral nutrition, admitted to intensive care unit (ICU) in Shanghai Punan Hospital of Pudong New District from January 1st, 2015 to June 30th, 2017 were enrolled. The patients were divided into three groups according to the random number table method, high-intensity group and low-intensity group were injected Novolin R (high-intensity group 2/3 dosage, low-intensity group 1/3 dosage) to modulate stress hyperglycemia by simulated artificial pancreas. Simulated artificial pancreas consisted of Guardian real time glucose monitoring system (GRT system), close-circle control algorithm and micro-pump;subcutaneous injection of Humulin 70/30 was applied to modulate stress hyperglycemia in humulin group. Real-time glucose levels of interstitial fluid in abdominal wall, equivalent to blood glucose levels, 10 minutes each time, were monitored by using of GRT system for all patients in three groups. Fasting serum levels of stress hormones including epinephrine and cortisol and insulin resistance index (IRI) were recorded within 24 hours after inclusion. Mean blood glucose, blood glucose variation coefficient, blood glucose target-reaching rate, blood glucose target-reaching time, hypoglycemia rate and 6-month mortality were measured. Twenty healthy adults from health administration department of the hospital were recruited as healthy control group. Results A total of 60 eligible critically ill patients were included in this study, each group with 20 patients. There was no significant difference in gender, age, APACHE Ⅱ scores among three groups. The levels of serum epinephrine, cortisol and IRI within 24 hours after inclusion in the three groups were significantly higher than those in healthy control group. The mean blood glucose levels of humulin group, low-intensity group, high-intensity group were decreased (mmol/L: 10.2±3.2, 8.4±2.6, 8.1±2.2), the blood glucose target-reaching rate were increased [40.2% (3 295/8 196), 71.1% (5 393/7 585), 80.4% (6 286/7 818)], the blood glucose target-reaching time were shortened (hours: 49.1±5.8, 24.6±4.6, 17.5±4.2), the hypoglycemia rates were increased respectively [1.3% (108/8 196), 2.8% (211/7 585), 4.0% (313/7 818)], with statistically significant differences (all 1 = 0.000). There was no significant difference in blood glucose variation coefficient and 6-month mortality among three groups [blood glucose variation coefficient: (29.4±3.7)%, (28.5±5.3)%, (26.1±4.6)%, 6-month mortality: 55.0%, 45.0%, 40.0%, all 1 > 0.05]. Conclusions Simulated artificial pancreas could effectively and safely modulate stress hyperglycemia in critically ill patients, high-intensity modulation could bring about better efficacy in the regulation of hyperglycemia. High-frequency blood glucose monitoring by using GRT system could promptly identify hypoglycemia and help it to be corrected.

Bombas de insulina en diabetes tipo 2, del fundamento a la práctica / Pumps in Type 2 diabetes, from basics to practice

Resumen Las bombas de insulina han sido usadas por más de 35 años, principalmente en pacientes con diabetes tipo 1 y en menor medida en diabetes tipo 2. En esta última población hay una liberación más funcional de insulina, se puede prevenir el fenómeno de alba y mantener por más tiempo los niveles adecuados de glucemia. Las indicaciones de bomba en diabetes tipo 2 son poco claras, pero los que tal vez más se benefician son aquellos con historia de mal control metabólico, hipoglucemias severas o asintomáticas. El uso de esta tecnología durante la hospitalización ha sido difícil, principalmente por el desconocimiento del personal de salud en su uso; no obstante, se ha demostrado que es factible mantener a los pacientes en esta terapia mientras están hospitalizados, siempre y cuando se tenga un adecuado protocolo, disposición del personal y educación del paciente. El costo ha sido una de las cuestiones más controversiales con el uso de estos sistemas. Los análisis de costo-efectividad han encontrado una disminución del número de hipoglucemiantes orales, las visitas a urgencias y las dosis de insulina, llegando algunos a aseverar que en tres años podrían compensarse los costos.

Abstract Insulin pumps have been used for over 35 years, mostly in patients with type 1 diabetes and to a lesser extent in type 2 diabetes. The use of pumps in this population is supported by a more physiological release of insulin, prevention of the dawn phenomenon and enabling patients to achieve better glucose targets. Pump indications in type 2 diabetes are less clear than in patients with type 1, but perhaps those who benefit most, are patients with a history of significant glycemic excursions, severe or asymptomatic hypoglycemia. Pump management as inpatient has been limited by lack of personal knowledge, however it has been reported that it is feasible to keep patients who are using this technology to continue it while they are in the hospital provided that a suitable protocol has been standardized and the patient has enough knowledge. Costs have been one of the most controversial issues with the use of these technology, cost-effectiveness analysis have found that there is a decrease in the number of oral agents, emergency room visits and insulin doses, reaching some studies to conclude that three years could offset the pump cost.

De la bomba de insulina y el monitoreo continuo de glucosa al páncreas artificial / From insulin pump and continuous glucose monitoring to the artificial pancreas

Technology for diabetes care has undergone major development during recent decades. These technological advances include continuous subcutaneous insulin infusion (CSII), also known as insulin pumps, and real-time continuous glucose monitoring system (RT-CGMS). The integration of CSII and RT-CGMS into a single device has led to sensor-augmented pump therapy and more recently, a technology that has automated delivery of basal insulin therapy, known as hybrid system. These new technologies have led to benefits in attaining better metabolic control and decreasing the incidence of severe hypoglycemia, especially in patients with type 1 diabetes. This review describes the types of technologies currently available or under investigation for these purposes, their benefits and disadvantages, recommendations and the appropriate patient selection for their use. The clinical use of the hybrid system and artificial pancreas seem to be possible in the near future.

Update in artificial pancreas clinical studies / 中华内分泌代谢杂志

[Summary] Good glycemic control can delay the occurrence and development of diabetic complications. Artificial pancreas, which autonomously mimics the physiologic glucose control of pancreas islet, regulates the blood glucose subtly. Artificial pancreas seems to be one of the promising glucose control approaches.

Clinical application value and research progress of artificial pancreas closed-Loop control in diabctes mellitus / 中国综合临床

Ideal blood glucose control requires accurate insulin injections under the guidance of frequent glucose monitoring.Artificial pancreas (AP),the closed-loop control system can adjust the input amount of insulin automatically with the body's blood glucose levels.The AP allows diabetics to control blood glucose ideal,then get the benefit of prevention of complications and bring convenience and safety in clinical application.Accuracy is the key issue of the AP.To improve the accuracy of such a system need to improve the detection accuracy and reliability,increase speed and accuracy of the output control,and improve the accuracy of the system regulation model.

Bombas de insulina (BI) / Insulin pumps (IP)

En la década pasada, el conocimiento sobre la historia natural y fisiopatogenia de la diabetes tipo 1 tuvo un importante crecimiento, particularmente en relación con predicción, heterogeneidad, patología pancreática y su epidemiología. Las mejoras tecnológicas específicamente en el desarrollo de bombas de insulina y sensores continuos de glucosa ayudan a los pacientes con diabetes tipo 1 en el desafío de la administración de insulina a largo plazo. A pesar de grandes inversiones sobre distintos aspectos de la enfermedad (financiación de proyectos, organizativos, educacionales, etc.) no existe hasta el momento la prevención ni la cura para la diabetes tipo 1, y sumado a esto la calidad sobre el manejo de la enfermedad es muy heterogéneo. Como el control glucémico mejora con un tratamiento intensificado (múltiples inyecciones de insulina), el número y frecuencia de eventos hipoglucémicos tienden a incrementarse. La hipoglucemia es generadora de cuadros de estrés, ansiedad y deterioro de la calidad de vida en los pacientes con diabetes. Una de las razones por las cuales existe gran dificultad de alcanzar los objetivos glucémicos en pacientes con diabetes tipo 1 es la variabilidad en la absorción de la insulina inyectada en forma subcutánea, la que conlleva mayor e impredecible variabilidad en la concentración glucémica y todo esto en general se relaciona con valores elevados de hemoglobina glicosilada e hipoglucemia. La terapia con bomba de insulina se inició hace más de 30 años con el objetivo de mejorar el control en pacientes con diabetes tipo 1. El objetivo de esta revisión es actualizar las herramientas tecnológicas en el tratamiento de la diabetes. (AU)

Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements in insulin pumps and continuous glucose monitors help patients with type 1 diabetes manage the challenge of lifelong insulin administration. Agents that show promise for averting debilitating disease-associated complications have also been identified. However, despite broad organisational, intellectual, and fiscal investments, no means for preventing or curing type 1 diabetes exists, and , globally, the quality of diabetes management remains uneven. As glycemic control improves with intensified insulin regimens, the frequency of hypoglycemia tends to increase. Hypoglycemia is the cause of considerable stress and anxiety, impaired well-being, and poor quality of life in patients with type diabetes. One reason for continued poor glycemic control in patients with type 1 diabetes is the erratic absorption and action of subcutaneously injected insulin, which lead to unpredictable swings in blood glucose concentrations, and those swings, in themselves, are associated with elevated glycated hemoglobin levels and hypoglycemia. Insulinpump therapy, or continuous subcutaneous insulin infusion, was introduced more than 30 years ago as a procedure for improving glycemic control in patients with type 1 diabetes. The primary goal is to perform an up date about the new technological tools in diabetes treatment. (AU)

New Technology for Type 1 Diabetes / 임상당뇨병

Type 1 diabetes is an autoimmune disease with insulin deficiency which causes microvascular complications such as retinopathy, nephropathy and neuropathy. There have been some trials to simulate the pancreatic endocrine function of insulin and glucagon for homeostatic equilibration of blood glucose, developing artificial pancreas. There are three major functional components of the modern artificial pancreas, a continuous glucose-monitoring system, an insulin-infusion pump and a control algorithm. There are commercially available continuous glucose monitoring systems with subcutaneous glucose measuring, however, there have been many attempts to develop more efficient glucose monitoring systems, including noninvasive systems. Thanks to technological advances and the miniaturization of electronics, recent advances in the accuracy and performance of these systems have placed research on the threshold of prototype commercial devices and large-scale outpatient feasibility studies. In addition, smartphone technology has created the opportunity for caregivers to receive push notification alerts and makes it possible to provide patients with advisory or decision-support systems. Even though there are still some remaining challenges to develop a successful artificial pancreas, glucose control in type 1 diabetes will be more efficient with its advent.

Pancreas transplantation for diabetes mellitus / 中华内分泌代谢杂志

Diabetes mellitus impacts patient survival and quality of life mainly due to its acute and chronic complications.Pancreas transplantation may restore normoglycemia and reduce the complication of insulin-dependent diabetes,thus improving the quality of life and prolonging patient's survival.Although pancreas transplantation requires major surgery and life-long immunosuppression therapy,it currently remains the gold stand for patients with type 1 diabetes mellitus,who do not respond to conventional therapy.Meanwhile,potential of the islet transplantation,insulin-producing cells replacement therapy,and artificial pancreas as the alternative to pancreas transplantation are under investigation.

Clinical experience with an implanted closed-loop insulin delivery system

AIM: To report the first clinical experience with a prototype of implanted artificial beta-cell. METHODS: The Long-Term Sensor System® project assessed the feasibility of glucose control by the combined implantation of a pump for peritoneal insulin delivery and a central intravenous glucose sensor, connected physically by a subcutaneous lead and functionally by PID algorithms. It was performed in 10 type 1 diabetic patients from 2000 to 2007. RESULTS: No harmful complication related to implants occurred. Insulin delivery was affected by iterative but reversible pump slowdowns due to insulin precipitation. Glucose measurement by the intravenous sensors correlated well with meter values (r = 0.83-0.93, with a mean absolute deviation of 16.5 percent) for an average duration of 9 months. Uploading of pump electronics by PID algorithms designed for closed-loop insulin delivery allowed in-patient 48 hourtrials. CONCLUSION: Although the concept of a fully implantable artificial beta-cell has been shown as feasible, improvements in the sensor structure to increase its longevity and decrease sensor delay that affected closed-loop control at meal-times are expected.

OBJETIVO: Relatar a primeira experiência clínica com um protótipo de célulabeta artificial implantável. MÉTODOS: O Projeto de Um Sistema Sensor de Longo Prazo avaliou a possibilidade do controle glicêmico através do implante combinado de uma bomba de infusão de insulina peritoneal e um gluco - sensor endovenoso central - conectados fisicamente por um dispositivo subcutâneo e funcionalmente por algoritmos PID (integral and derivative). Este projeto envolveu 10 pacientes com diabetes melito tipo 1 de 2000 a 2007. RESULTADOS: Complicações significativas relacionadas aos implantes não ocorreram. A liberação de insulina pela bomba sofreu o efeito de períodos de lentificação interativo, mas reversível, devido a precipitação do peptídeo. As medidas da glicose pelo sensor endovenoso mostraram boa correlação com os valores do glicosímetro (r = 0,83-0,93, com desvio médio absoluto de 16,5 por cento) durante período médio de 9 meses. Os dados para construção dos algoritmos PID do sistema de alça fechada de liberação de insulina foram obtidos a partir de 12 pacientes que permaneceram internados com esse sistema durante 48 horas com refeições que continham 40 a 70 g de carboidratos. CONCLUSÃO : Embora o conceito de uma célula-beta artificial totalmente implantável tenha demonstrado ser possível, aperfeiçoamentos são necessários na estrutura do sensor para aumentar a sua longevidade e no sistema de alça fechada de liberação de insulina para diminuir as lentificações que comprometem o controle glicêmico nos períodos relacionados às refeições.