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      Time in blood glucose range 70 to 180 mg/dL and survival rate in critically ill patients: A retrospective cohort study

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          Abstract

          Background

          While time in targeted blood glucose range (TIR) 70–140 mg/dL is a known factor associated with mortality in critically ill patients, it remains unclear whether TIR is associated with 28-day mortality under the glycemic control with a less tight target glucose range of 70–180 mg/dL. We aimed to examine whether TIR 70–180 mg/dL was associated with 28-day mortality.

          Methods

          This is a retrospective cohort study using data from a tertiary care center in Japan collected from January 2016 through October 2019. We included adult patients (aged ≥20 years) admitted to the ICU. We excluded patients 1) with diabetic ketoacidosis patients, 2) discharged within 48 hours, 3) with repeated ICU admissions. We calculated TIR 70–180 mg/dL using the measured blood glucose values (≥3 times per day). The primary outcome was 28-day mortality. We examined the association between TIR and 28-day mortality using a logistic regression and Cox proportional hazard models with a stratification by glycosylated hemoglobin (HbA1c) level of 6.5%. Additionally, we repeated the analyses using the TIR category to assess the optimal TIR. For the sensitivity analysis, we repeated the primary analysis using TIR during the first three days from ICU admission.

          Results

          Of 1,230 patients, the median age was 72 years, 65% were male, and 250 patients (20%) had HbA1c ≥6.5% on admission. In patients with HbA1c <6.5%, TIR <80% was associated with an increased risk of 28-day mortality, with an adjusted odds ratio (OR) of 1.88 (95%CI: 1.36–2.61). Likewise, when using 10% incremental TIR as a categorical variable, lower TIR was associated with a worse 28-day mortality compared with TIR ≥90% (e.g., adjusted OR of TIR <60%, 3.62 [95%CI 2.36–5.53]). Similar associations were found in the analyses using Cox proportional hazards model and using TIR during the first three days. By contrast, in patients with HbA1c ≥6.5%, there was no consistent association of TIR with 28-day mortality.

          Conclusions

          We found that lower TIR 70–180 mg/dL was associated with a higher 28-day mortality in critically ill patients with HbA1c <6.5%, whereas there was no consistent association in patients with HbA1c ≥6.5%.

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          Most cited references27

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          Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

          To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012".
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            Intensive versus conventional glucose control in critically ill patients.

            The optimal target range for blood glucose in critically ill patients remains unclear. Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization. Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39). In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987.) 2009 Massachusetts Medical Society
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              Intensive insulin therapy in critically ill patients.

              Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]). At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care. Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: ConceptualizationRole: Investigation
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 May 2021
                2021
                : 16
                : 5
                : e0252158
                Affiliations
                [1 ] Department of Emergency and Critical Care Medicine, Hitachi General Hospital, Hitachi, Ibaraki, Japan
                [2 ] TXP Medical Co., Ltd., Bunkyo, Tokyo, Japan
                [3 ] Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Bunkyo, Tokyo, Japan
                [4 ] Department of Social Medicine, Public Health, Osaka University Graduate School Medicine, Suita, Osaka, Japan
                International University of Health and Welfare, School of Medicine, JAPAN
                Author notes

                Competing Interests: Although one or more of the authors are employed by a commercial company: TXP Medical Co., Ltd., all authors have declared that no competing interests exist related to the current manuscript. Dr. Sonoo is the CEO of TXP Medical Co., Ltd. and receives an executive salary. Dr. Naraba, Dr. Shirakawa, and Dr. Goto are members of the research team of TXP Medical Co., Ltd. and receive salary income, but they have no direct interest in the contents of this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                ‡ TS, NK, HN, YT, HH and KN also contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-5663-2213
                Article
                PONE-D-20-39742
                10.1371/journal.pone.0252158
                8158903
                34043681
                6c774ea2-d576-49b7-82f8-ac0f97c273d4
                © 2021 Naraba et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 December 2020
                : 11 May 2021
                Page count
                Figures: 3, Tables: 3, Pages: 14
                Funding
                The funder, TXP Medical, was not involved in the study design, data analysis, publication decisions, or manuscript preparation and provided support only in the form of authors' salaries and research materials. This study was not conducted in partnership with a commercial organization.
                Categories
                Research Article
                Medicine and health sciences
                Diagnostic medicine
                Diabetes diagnosis and management
                HbA1c
                Biology and life sciences
                Biochemistry
                Proteins
                Hemoglobin
                HbA1c
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                Health Care
                Health Care Facilities
                Hospitals
                Intensive Care Units
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                Body Fluids
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                Anatomy
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                Physical Sciences
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                Carbohydrates
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                Glucose
                Medicine and Health Sciences
                Diagnostic Medicine
                Diabetes Diagnosis and Management
                Biology and Life Sciences
                Biochemistry
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                Custom metadata
                The datasets are not publicly available due to no Institutional Review Board’s approval of data sharing. Data are available from the Institutional Review Board of Hitachi General Hospital (contact via swebkanrisha.nichibyo.gd@ 123456hitachi.com ) for researchers who meet the criteria for access to confidential data.

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