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  The   new england journal of    medicine n engl j med   nejm.org   1 From the Departments of Diabetes, En-docrinology, Clinical Nutrition, and Me-tabolism (L.B., E.A., C.S.) and General Internal Medicine (L.B., M.M.W.), Insel-spital, Bern University Hospital, Univer-sity of Bern, Bern, Switzerland; and the Wellcome Trust–MRC Institute of Meta-bolic Science (L.B., H.T., Y.R., M.E.W., M.L.E., A.P.C., R.H.) and the Department of Pediatrics (M.E.W., R.H.), University of Cambridge, and the Wolfson Diabetes and Endocrine Clinic, Cambridge Univer-sity Hospitals NHS Foundation Trust (S.H., M.L.E., A.P.C.), Cambridge, and the Manchester University Hospitals NHS Foundation, Manchester Academic Health Science Centre (H.T.), and the Di-vision of Diabetes, Endocrinology, and Gastroenterology, Faculty of Biology, Med-icine and Health, University of Manches-ter (H.T.), Manchester — all in the United Kingdom. Address reprint requests to Dr. Hovorka at the University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Box 289, Adden-brooke’s Hospital, Cambridge CB2 0QQ, United Kingdom, or at rh347@ cam . ac . uk. Drs. Bally and Thabit contributed equally to this article.This article was published on June 25, 2018, at NEJM.org. DOI: 10.1056/NEJMoa1805233 Copyright © 2018 Massachusetts Medical Society. BACKGROUND In patients with diabetes, hospitalization can complicate the achievement of recom-mended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabe-tes. We wanted to investigate whether a closed-loop system could also improve glyce-mic control in patients with type 2 diabetes who were receiving noncritical care. METHODS In this randomized, open-label trial conducted on general wards in two tertiary hos-pitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge. RESULTS The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P = 0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P = 0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia oc-curred in either trial group. CONCLUSIONS Among inpatients with type 2 diabetes receiving noncritical care, the use of an au-tomated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565.) ABSTRACT Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care Lia Bally, Ph.D., Hood Thabit, Ph.D., Sara Hartnell, B.Sc., Eveline Andereggen, R.N., Yue Ruan, Ph.D., Malgorzata E. Wilinska, Ph.D., Mark L. Evans, M.D., Maria M. Wertli, Ph.D., Anthony P. Coll, M.D., Christoph Stettler, M.D., and Roman Hovorka, Ph.D. Original Article The New England Journal of Medicine Downloaded from nejm.org on June 25, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  n engl j med   nejm.org   2 The   new england journal of    medicine T he burden of diabetes is increasing  worldwide, 1  as is the proportion of patients  with diabetes in hospitals. More than one quarter of hospitalized patients in the United States and other developed countries have diabe-tes. 2-4  In such patients, the achievement of recom-mended glycemic targets 5,6  is complicated by vari-able metabolic responses to acute illness, changes in the amounts and timing of dietary intake, nu-tritional support, and drug-induced temporally rapid alterations in insulin sensitivity from medi-cations such as glucocorticoids. 7-9 Strong associations have been reported between the rate of hyperglycemia among inpatients and an increased length of hospital stay and increased rates of complications and death. 10,11  Although the correction of hyperglycemia diminishes the risk of adverse clinical outcomes, 12  conventional insu-lin therapy increases the risk of hypoglycemia,  which is associated with increased morbidity and length of hospital stay. 13  The implementation of current guidelines for inpatient glycemic man-agement is hindered by the need for vigilant and constant blood glucose monitoring and the ad-ministration of insulin with meals, which increas-es the workload of hospital staff members and reduces staff adherence. 5,6  Consequently, glycemic control in hospitalized patients is often inade-quate, 2,14  which has spurred the development of more effective and safe management strategies. 15 An automated system that delivers insulin in response to glucose levels can address this need. Closed-loop glucose control (also known as the artificial pancreas) consists of a continuous glu-cose monitor and an insulin pump, coupled with a control algorithm that directs insulin delivery on the basis of real-time sensor glucose measure-ments. 16  Such autonomous glucose control obvi-ates the need for the input of hospital staff mem-bers. There is increasing evidence that closed-loop technology improves glucose control in patients  with type 1 diabetes. 17,18  In the critical care set-ting, closed-loop technology has been evaluated for intravenous insulin delivery. 19,20  However, for staffing and safety reasons, subcutaneous insulin delivery has been feasible and pragmatic in pa-tients receiving noncritical care. 21  Here, we report the results of a two-center, randomized, open-label trial of closed-loop insulin delivery without meal-associated bolus administration in a diverse co-hort of patients receiving noncritical care. We hypothesized that closed-loop insulin delivery  would be safe and improve glycemic control with-out increasing the risk of hypoglycemia. Methods Patients From August 2, 2016, to December 11, 2017, we recruited patients on general wards at the Univer-sity Hospital in Bern, Switzerland, and at Adden-brooke’s Hospital in Cambridge, United Kingdom. Inclusion criteria included an age of 18 years or older and inpatient hyperglycemia requiring sub-cutaneous insulin therapy. Exclusion criteria were type 1 diabetes, pregnancy or breast-feeding, and any physical or psychological disease or the use of medication that was likely to interfere with the conduct of the trial or the interpretation of the results. Inpatients were identified through hospital electronic records. All the patients provided writ-ten informed consent before the initiation of trial procedures. Trial Design We randomly assigned the patients to receive in-sulin by means of a fully automated, closed-loop system (closed-loop group) or conventional sub-cutaneous therapy (control group). Patients were followed for a maximum of 15 days or until hos-pital discharge. Randomization was performed by means of the minimization method with the use of Minim randomization software, 22  which is a biased-coin approach with a probability of 0.7 to 0.8 for allocation of the “best fitting” treatment. Randomization was stratified according to glycat-ed hemoglobin level, body-mass index (the weight in kilograms divided by the square of the height in meters), and pretrial total daily insulin dose to balance the two groups. Investigators who analyzed the trial data were aware of the trial-group assign-ments. Trial Procedures The body weight, height, and total daily insulin dose were recorded for each patient after enroll-ment. Throughout the trial, the patients chose standard hospital meals at usual mealtimes, ac-cording to local practice. The patients were free to consume other meals and snacks and were unrestricted in their usual activity on the general  ward. In the two groups, glucose levels were measured with the use of a continuous glucose monitor (Freestyle Navigator II, Abbott Diabetes The New England Journal of Medicine Downloaded from nejm.org on June 25, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  n engl j med   nejm.org   3 Closed-Loop Insulin Delivery in Noncritical Care Care). A glucose sensor was inserted subcutane-ously into the abdomen or upper arm by the in- vestigator and calibrated according to the manu-facturer’s instructions. Point-of-care capillary glucose measurements (StatStrip Glucose Hospi-tal Meter System, Nova Biomedical, or Accu-Chek Inform II, Roche Diagnostics) were performed by nursing staff members according to local clinical practice in the two trial groups. Closed-Loop Insulin Delivery Investigators discontinued each patient’s usual insulin therapy and sulfonylurea medication, if prescribed, on the day of closed-loop initiation. All other medications were continued. The inves-tigator inserted a subcutaneous cannula into the abdomen for delivery of a rapid-acting insulin ana-logue (Humalog, Eli Lilly, or NovoRapid, Novo Nordisk) by means of a trial pump (Dana Diabe-care R, Sooil). The investigator initialized the con-trol algorithm by using the patient’s weight and pretrial total daily insulin dose. When sensor readings became available, the investigator initi-ated automated closed-loop glucose control, which continued for up to 15 days. A low-glucose sensor alarm on the continuous glucose-monitoring re-ceiver was initialized at a threshold of 63 mg per deciliter (3.5 mmol per liter).The automated closed-loop system consisted of a model predictive control algorithm (version 0.3.70) residing on a control algorithm device (Dell Latitude 10 Tablet, Dell) linked by a USB cable to the continuous glucose-monitoring receiver (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The tab-let device communicated with the pump by means of a Bluetooth wireless communication protocol. No prandial insulin boluses were delivered, and the timing or carbohydrate content of meals was not included in the control algorithm. (Additional details regarding the closed-loop system are pro- vided in the Supplementary Appendix.)At the end of the closed-loop period, patients completed a brief questionnaire to evaluate their satisfaction and trust of automated glucose con-trol with the closed-loop system, their acceptance of wearing trial devices, and their views as to  whether they would recommend the technology to other patients. Conventional insulin therapy and sulfonylurea medication were resumed at the end of closed-loop use as appropriate. Conventional Insulin Therapy For each patient, the usual insulin and other anti-hyperglycemic therapies were continued through-out the trial period. To reflect usual care, the continuous glucose monitor was masked to the patient, investigators, and hospital staff members. Each patient’s glucose control was managed by the clinical team, according to local clinical practice on the basis of capillary glucose measurements. The clinical team was allowed to modify and ad- just each patient’s insulin and other antihypergly-cemic therapies and to initiate additional point-of-care capillary glucose measurements as appropriate. Trial Oversight The protocol (available at NEJM.org) was approved by the local research ethics committee at each center and by regulatory authorities in Switzer-land (Swissmedic) and in the United Kingdom (Medicines and Healthcare Products Regulatory Agency). The safety aspects of the trial were over-seen by an independent data and safety monitor-ing board. The trial was performed in accordance  with the principles of the Declaration of Helsinki.Abbott Diabetes Care supplied discounted con-tinuous glucose-monitoring devices, sensors, and details regarding the communication protocol to facilitate real-time connectivity; company repre-sentatives reviewed the manuscript before sub-mission but otherwise had no role in the trial conduct. All the authors participated in the design of the trial or provided patient care and obtained samples. The first, second, and last author wrote the first draft of the manuscript. The last author designed and implemented the control algorithm, and all the authors critically reviewed the manu-script. The first and last authors vouch for the completeness and accuracy of the data and analy-ses and for the adherence of the trial to the proto-col. All the authors made the decision to submit the manuscript for publication. Primary and Secondary Outcomes The primary outcome was the percentage of time that the sensor glucose measurement was in the target glucose range of 100 to 180 mg per deci-liter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge. Secondary outcomes  were the percentage of time that the sensor glu-cose measurement was either above or below the target range; the percentage of time spent above The New England Journal of Medicine Downloaded from nejm.org on June 25, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  n engl j med   nejm.org   4 The   new england journal of    medicine 360 mg per deciliter (20.0 mmol per liter), below 70 mg per deciliter (3.9 mmol per liter), below 54 mg per deciliter (3.0 mmol per liter), and be-low 50 mg per deciliter (2.8 mmol per liter); the area under the curve below 63 mg per deciliter (3.5 mmol per liter) and below 54 mg per deciliter; the mean daily sensor glucose measurement; and the total daily insulin dose. We used data collected throughout the trial period to evaluate glucose  variability according to the standard deviation and the coefficient of variation in the sensor glucose measurement. We calculated the between-day co-efficient of variation in the sensor glucose mea-surement from daily mean glucose values (mid-night to midnight). Additional secondary outcomes and exploratory analyses are described in the Sup-plementary Appendix.Safety end points included clinically signifi-cant hyperglycemia (>360 mg per deciliter) with ketonemia and severe hypoglycemia (<40 mg per deciliter), as determined by point-of-care capillary measurements, along with other adverse events and serious adverse events. Statistical Analysis The trial was designed to have a power of 80% to detect a clinically significant between-group difference in the primary outcome of 20 percent-age points with the use of a two-sided t-test and an alpha level of 0.05. To reflect heterogeneity among the patients, a standard deviation of ±39 for the primary outcome was used for the power calcu-lations. We planned that 150 patients would un-dergo randomization in order to permit the analy-sis of at least 48 hours of data from 120 patients.The intention-to-treat analysis was performed on data collected during subcutaneous insulin delivery. Data from patients who participated in a separate feasibility study  21  were not included in the present analysis. Outcomes were calculated  with the use of GStat software, version 2.2 (Uni- versity of Cambridge), and statistical analyses were performed with the use of SPSS software, version 21.0 (IBM). We used the unpaired t-test to compare normally distributed variables and the Mann–Whitney U test for highly skewed variables. The numbers of events that were related to a capillary glucose measurement of less than 63 mg per deci-liter and 40 mg per deciliter and more than 360 mg per deciliter were tabulated in each trial group and compared with the use of Fisher’s exact test. Values are reported as means (±SD) or medians (interquartile range), unless stated otherwise. All P values are two-tailed, and P values of less than 0.05 were considered to indicate statistical sig-nificance. Results Patients Of the 165 patients who were invited to enroll in the trial, 138 consented to participate (Fig. S2 in the Supplementary Appendix). One patient was  withdrawn before randomization because of im-minent hospital discharge. Of the remaining 137 patients, 70 were assigned to the closed-loop group and 67 to the control group. One patient in the control group was excluded from the analysis be-cause the transition from intravenous insulin to subcutaneous insulin did not occur as srcinally planned.The demographic and clinical characteristics of the patients were similar with respect to sex, age, body-mass index, glycated hemoglobin level, duration of diabetes, receipt of insulin, and insulin requirements (Table 1). Sepsis was the predomi-nant reason for admission (in 43% of the patients); approximately two thirds of the patients were being treated with basal bolus insulin therapy. Additional data regarding the patients, including reasons for admission and antidiabetic treat-ment before randomization, are provided in Ta-bles S1 and S2 in the Supplementary Appendix. The burden of coexisting illnesses was signifi-cantly higher in the closed-loop group than in the control group, according to the mean score on the Charlson Comorbidity Index (9.4±3.4 vs. 7.0±2.8, P<0.001). Scores on this index range from 0 to 33, with a score of ≥5 indicating a severe burden of illness. Additional details are provided in Ta-ble S3 and Fig. S3 in the Supplementary Appendix. Overall Glucose Control The mean (±SD) percentage of time that the sen-sor glucose measurement was in the target glu-cose range (primary outcome) was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the con-trol group, for a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001) (Table 2). The mean sensor glucose mea-surement was significantly lower in the closed-loop group than in the control group (154±29 mg The New England Journal of Medicine Downloaded from nejm.org on June 25, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.
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