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Purpose of Review: Dysglycaemia complicates most critical care admissions and is associated with harm, yet glucose targets, particularly in those with preexisting diabetes, remain controversial. This review will summarise advances in the literature regarding personalised glucose targets in the critically ill., Recent Findings: Observational data suggest that the degree of chronic hyperglycaemia in critically ill patients with diabetes attenuates the relationship between mortality and several metrics of dysglycaemia, including blood glucose on admission, and mean blood glucose, glycaemic variability and hypoglycaemia in the intensive care unit. The interaction between acute and chronic hyperglycaemia has recently been quantified with novel metrics of relative glycaemia including the glycaemic gap and stress hyperglycaemia ratio. Small pilot studies provided preliminary data that higher blood glucose thresholds in critically ill patients with chronic hyperglycaemia may reduce complications of intravenous insulin therapy as assessed with biomakers. Although personalising glycaemic targets based on preexisting metabolic state is an appealing concept, the recently published CONTROLLING trial did not identify a mortality benefit with individualised glucose targets, and the effect of personalised glucose targets on patient-centred outcomes remains unknown., Summary: There is inadequate data to support adoption of personalised glucose targets into care of critically ill patients. However, there is a strong rationale empowering future trials utilising such an approach for patients with chronic hyperglycaemia., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aims/hypothesis: During hyperglycaemia, some glucose bypasses glycolysis and is metabolised via the potentially neurotoxic polyol pathway, in which glucose is metabolised to sorbitol and fructose. Increased polyol concentrations have been demonstrated in the cerebrospinal fluid (CSF) of neurological patients with and without diabetes mellitus. However, polyol levels in patients without evident neurological abnormalities have not been investigated so far. The aim of this study was to determine CSF polyol concentrations in patients without major neurological disease with normal or elevated CSF glucose concentrations., Methods: This observational cohort study used CSF and plasma analyses, as well as clinical data, from 30 participants of the Anaesthetic Biobank of Cerebrospinal Fluid study. Biomaterial was collected from adult patients scheduled for elective surgery under spinal anaesthesia. CSF polyol concentrations were measured by GC/flame ionisation detector in ten patients with normal CSF glucose levels (group 1), ten patients with elevated CSF glucose levels (group 2) and ten patients with elevated CSF glucose levels and type 2 diabetes (group 3). We compared the concentrations of plasma glucose, CSF glucose, sorbitol and fructose, and CSF polyol/glucose ratios between the three groups, and determined the correlation between plasma glucose levels and CSF glucose, sorbitol and fructose levels., Results: Groups 2 and 3 had significantly higher CSF fructose levels compared with group 1 (p=0.036 and p<0.001, respectively). Group 3 showed significant differences compared with groups 1 and 2 for CSF sorbitol (p<0.001 and 0.036, respectively). Moreover, patients with diabetes had a significantly higher CSF sorbitol/glucose ratio compared with patients without diabetes. There was a strong positive correlation between plasma glucose and CSF glucose, sorbitol and fructose. Finally, age, sex, CSF/plasma albumin ratio and preoperative cognitive function scores were significantly correlated with plasma glucose and CSF glucose, sorbitol and fructose levels., Conclusions/interpretation: Hyperglycaemia causes a proportional increase in polyol concentrations in CSF of patients without major neurological disease. Furthermore, this study provides the first indication of upregulation of the cerebral polyol pathway in patients with diabetes without evident neurological abnormalities., (© 2022. The Author(s).)

Aims: Most cardiac surgery patients, with or without diabetes, develop perioperative hyperglycaemia, for which intravenous insulin is the only therapeutic option. This is labour-intensive and carries a risk of hypoglycaemia. We hypothesized that preoperative administration of the glucagon-like peptide-1 receptor agonist liraglutide reduces the number of patients requiring insulin for glycaemic control during cardiac surgery., Materials and Methods: In this randomized, blinded, placebo-controlled, parallel-group, balanced (1:1), multicentre randomized, superiority trial, adult patients undergoing cardiac surgery in four Dutch tertiary hospitals were randomized to receive 0.6 mg subcutaneous liraglutide on the evening before surgery and 1.2 mg after induction of anaesthesia or matching placebo. Blood glucose was measured hourly and controlled using an insulin-bolus algorithm. The primary outcome was insulin administration for blood glucose >8.0 mmol/L in the operating theatre. Research pharmacists used centralized, stratified, variable-block, randomization software. Patients, care providers and study personnel were blinded to treatment allocation., Results: Between June 2017 and August 2018, 278 patients were randomized to liraglutide (139) or placebo (139). All patients receiving at least one study drug injection were included in the intention-to-treat analyses (129 in the liraglutide group, 132 in the placebo group). In the liraglutide group, 55 (43%) patients required additional insulin compared with 80 (61%) in the placebo group and absolute difference 18% (95% confidence interval 5.9-30.0, P = 0.003). Dose and number of insulin injections and mean blood glucose were all significantly lower in the liraglutide group. We observed no difference in the incidence of hypoglycaemia, nausea and vomiting, mortality or postoperative complications., Conclusions: Preoperative liraglutide, compared with placebo, reduces insulin requirements while improving perioperative glycaemic control during cardiac surgery., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: Preliminary evidence suggest a possible relationship between perioperative hyperglycemia, postoperative delirium (POD) or cognitive dysfunction (POCD). We aim to present the available clinical evidence related to chronic (i.e. diabetes mellitus) or acute perioperative hyperglycemia as risk factors for POD/POCD., Evidence Acquisition: A literature search of EMBASE (via Ovid, 1974-present) online medical database and MEDLINE (via PubMed or Ovid, 1946-present) was performed. All types of clinical studies including randomized controlled trials, prospective, as well as retrospective cohort studies were screened. Clinical studies that reported original information on the relationship between diabetes mellitus (DM) and/or acute perioperative abnormal glucose levels and POD or POCD were selected. Reviews and editorials (i.e. articles not presenting original preclinical or clinical research) were excluded and case-reports were not considered for analysis., Evidence Synthesis: Our search resulted in 2356 papers for screening, from which we selected 29 studies that met our inclusion criteria. DM was investigated in 24 observational papers, acute perioperative hyperglycemia in six observational studies and two randomized controlled trials examined the effect of perioperative glucose lowering on POD/POCD. Diabetes was associated with POD or POCD in 18/24 observational studies and 6/6 of the included observational studies found that perioperative hyperglycemia was associated with POD/POCD, independent of diabetes. The two randomized controlled trials had a different trial design and reported conflicting results., Conclusions: According to the available evidence, DM and acute perioperative hyperglycemia may be associated with an increased risk for POD/POCD. These conclusions are based mostly on observational studies and deserve more and dedicated research. This systematic review may direct the design of future studies.

Introduction: Perioperative hyperglycaemia is common during cardiac surgery and associated with postoperative complications. Although intensive insulin therapy for glycaemic control can reduce complications, it carries the risk of hypoglycaemia. GLP-1 therapy has the potential to lower glucose without causing hypoglycaemia. We hypothesise that preoperative liraglutide (a synthetic GLP-1 analogue) will reduce the number of patients requiring insulin to achieve glucose values<8 mmol l -1 in the intraoperative period., Methods and Analysis: We designed a multi-centre randomised parallel placebo-controlled trial and aim to include 274 patients undergoing cardiac surgery, aged 18-80 years, with or without diabetes mellitus. Patients will receive 0.6 mg liraglutide or placebo on the evening before, and 1.2 mg liraglutide or placebo just prior to surgery. Blood glucose is measured hourly and controlled with an insulin bolus algorithm, with a glycaemic target between 4-8 mmol l -1 . The primary outcome is the percentage of patients requiring insulin intraoperatively., Ethics and Dissemination: This study protocol has been approved by the medical ethics committee of the Academic Medical Centre (AMC) in Amsterdam and by the Dutch competent authority. The study is investigator-initiated and the AMC, as sponsor, will remain owner of all data and have all publication rights. Results will be submitted for publication in a peer-reviewed international medical journal., Trial Registration Number: NTR6323; Pre-results., Competing Interests: Competing interests: Novo Nordisk, the manufacturer of liraglutide, was contacted after design of the trial. After approving the protocol, Novo Nordisk provided financial support. The Department of Anaesthesiology of the Academic Medical Centre received financial support for this project from Novo Nordisk. JHdV sits on a GLP-1 advisory board and speaker bureau for Novo Nordisk., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The glycemic response and its relation to postoperative complications following gynecologic laparotomies is unknown, although these surgeries carry a substantial risk for postoperative morbidity. Therefore, our objective was to assess the prevalence of perioperative hyperglycemia and glucose variability in women undergoing a gynecologic laparotomy., Methods: In this prospective cohort study, capillary glucose was measured every hour during the perioperative period. The primary outcome measures were the proportion of patients with postoperative hyperglycemia (glucose >180 mg d l(-1)) and the glucose variability in the intra- and postoperative period. Postoperative complications were assessed as secondary outcome measure., Results: We included 150 women undergoing a gynecologic laparotomy. Perioperative hyperglycemia occurred in 33 patients without diabetes (23.4%) and in 8 patients with diabetes (89%). Glucose variability was significantly higher (mean absolute glucose change [MAG] 11 mg dl(-1) hr(-1) [IQR 8-18]) in the intraoperative compared to the postoperative period (MAG 10 mg dl(-1) hr(-1) [IQR 3-16], P = .03). Neither hyperglycemia nor glucose variability was associated with postoperative complications., Conclusions: Hyperglycemia and glucose variability seem to be a minor problem during gynecologic laparotomy. Based on the current data, we would not advocate standardized glucose measurements in every patient without diabetes undergoing gynecologic laparotomy., (© 2015 Diabetes Technology Society.)

Stress-induced hyperglycaemia is common during orthopaedic surgery. In addition, hyperglycaemia activates coagulation. The aim of the study was to assess whether stress-induced hyperglycaemia is associated with symptomatic or asymptomatic venous thromboembolism (VTE) following orthopaedic surgery. We performed post-hoc analyses in the four RECORD studies (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of Deep venous thrombosis and pulmonary embolism). Separate analyses were performed for patients undergoing elective total hip or knee replacement. Outcome measures were symptomatic VTE and "total VTE" (defined as the composite of symptomatic VTE, asymptomatic DVT assessed by per protocol venography and all cause mortality). Glucose levels were measured pre-op and 6 hours post-op, categorised into quartiles, based on the distribution in the respective cohorts. The influence of glucose, adjusted for body mass index, age, gender and diabetes mellitus on VTE was assessed by logistic regression analyses. A total of 12,383 patients were eligible for assessment of symptomatic VTE, and 8,512 patients were eligible for assessment of total VTE. Increased glucose levels after total hip replacement were associated with total VTE; adjusted odds ratio (OR) highest versus lowest quartile 1.9 (95% confidence interval [CI] 1.3 to 3.0). Furthermore, increase in glucose levels during total hip replacement was associated with total VTE (OR highest versus lowest quartile 1.8 (95%CI 1.2 to 2.8). This was not observed in patients undergoing total knee replacement, probably due to differences in the applied surgical procedures.

Objective: To investigate the relation between perioperative hyperglycemia and complications after pancreatoduodenectomy., Background: Perioperative hyperglycemia is associated with complications after various types of surgery. This relation was never investigated for pancreatoduodenectomy., Methods: In a consecutive series of 330 patients undergoing pancreatoduodenectomy, glucose values were collected from the hospital information system during 3 periods: pre-, intra-, and early postoperative. The average glucose value per period was calculated for each patient and divided in duals according to the median group value. Odds ratios for complications were calculated for the upper versus lower dual, adjusted for age, sex, American Society of Anesthesiologists Classification, body mass index, diabetes mellitus, intraoperative blood transfusion, duration of surgery, intraoperative insulin administration, and octreotide use. The same procedures were carried out to assess the consequences of increased glucose variability, expressed by the standard deviation., Results: Average glucose values were 135 (preoperative), 133 (intraoperative) and 142 mg/dL (early postoperative). Pre- and intraoperative glucose values were not associated with postoperative complications. Early postoperative hyperglycemia (≥140 mg/dL) was significantly associated with complications [odds ratio (OR) 2.9, 95% confidence interval (CI), 1.7-4.9]. Overall, high glucose variability was not significantly associated with postoperative complications, but early postoperative patients who had both high glucose values and high variability had an OR for complications of 3.6 (95% CI, 1.9-6.8) compared to the lower glucose dual., Conclusions: Early postoperative hyperglycemia is associated with postoperative complications after pancreatoduodenectomy. High glucose variability may enhance this risk. Future research must demonstrate whether strict glucose control in the early postoperative period prevents complications after pancreatoduodenectomy.

Background: The relationship between admission hyperglycemia and adverse outcome in myocardial infarction has been shown consistently. However, achieving and maintaining normoglycemia in ST elevated myocardial infarction (STEMI) patients has proven difficult. This study aimed to investigate the efficacy of sensor-augmented insulin pump (SAP) therapy to treat hyperglycemia., Methods: In a randomized controlled pilot trial, we assigned 20 patients, 30-80 years old, admitted with STEMI and hyperglycemia (>or=140 mg/dL) to receive either 48 h of strict glycemic control with an subcutaneous insulin pump augmented with a continuous glucose monitor (SAP group) or to treatment according to standard practice (Control group) with glucose measured by blinded continuous glucose monitoring. The main outcome measure was proportion of time spent in hyperglycemia., Results: The median treatment time was 47.0 h (interquartile range [IQR], 46.2-48.0 h) in the SAP group and 44.6 h (IQR, 22.0-48.6 h) in the Control group. The median proportion of time >or= 140 mg/dL was 14.6% (IQR, 10.5-18.5%) in the SAP group and 36.3% (IQR, 26.0-80.4%) in the control group (P = 0.006). The proportion of time

Background: The aim of this study was to evaluate the efficacy of a proportional derivative algorithm closed-loop system to control postprandial glucose concentrations in subjects with type 1 diabetes., Methods: Six subjects treated with continuous subcutaneous insulin infusion received a standardized meal on three days. The first day served as control, the second day as learning experiment for the algorithm, and the third day to compare the closed loop to the control day. Venous blood glucose was measured as reference until 300 min postprandially. The artificial pancreas platform consisted of a subcutaneous continuous glucose monitor (CGM), the GlucoDay S (Menarini Diagnostics), two D-Tron+ pumps (Disetronic Medical Systems) for subcutaneous insulin, and glucagon administration connected to a personal computer., Results: One subject was excluded due to technical failure of the CGM. Two of five subjects were male, mean age was 50.8 years (range 38-60), and mean hemoglobin A1c was 8.7% (range 7.0-12.2). The mean postprandial venous blood glucose concentration of day 1 was 205 mg/dl (range 94-265 mg/dl) compared with 128 mg/dl (range 128-158 mg/dl) on day 3 (p = .14). Percentage of time spent in euglycemia postprandially on day 1 was 31% versus 60% on day 3 (p = .08). Time spent below 3.9 mmol/liter (70 mg/dl) was 19% on day 1 compared with 11% on day 3 (p = 1.0). Time above 10 mmol/liter (180 mg/dl) on day 1 was 60% versus 29% on day 3 (p = .22)., Conclusion: The artificial pancreas provided comparable postprandial glycemic control to usual care., (2010 Diabetes Technology Society.)

Background: Most perioperative diabetes mellitus (DM) guidelines do not distinguish between patients with type 1 (DM1) and type 2 (DM2). We hypothesised that similar treatment of DM1 and DM2 patients leads to differences in their perioperative glucose control.Methods: We performed a retrospective cross-sectional study, of all DM patients undergoing surgery between May 2013 and November 2015 in a Dutch university hospital. We compared DM1 with DM2 patients, treated according to the same perioperative glucose protocol. Our primary outcome was the incidence of hyperglycaemia (glucose ≥10 mmol/L). Secondary outcomes were short-term glycaemic control (glucose before surgery and peak glucose perioperatively), long-term glycaemic control (HbA1c in 90 days before and after surgery) and the incidence of hypoglycaemia (glucose <4 mmol/L).Results: We included 2259 patients with DM, 216 (10%) of which had DM1. The calculated incidences in our population were 7 out of 1000 patients with DM1 and 69 out of 1000 patients with DM2. Compared to those with DM2, patients with DM1 were younger, had a lower BMI, a higher glucose concentration before surgery, and a higher perioperative peak glucose concentration (11.0 [8.2-14.7] vs 9.4 [7.7-11.7], P < 0.001). The incidence of the primary endpoint, perioperative hyperglycaemia, was significantly higher in DM1 compared to DM2 patients (63% vs 43%, P < 0.001). Hypoglycaemia occurred more often in the DM1 population (7.1% vs 1.3%, P < 0.001).Conclusion: Providing similar perioperative treatment to patients with DM1 and DM2 is associated with poorer short-term and long-term glycaemic control in DM1 throughout the perioperative period as well as an increased risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Introduction: In critical illness, four measures of glycaemic control are associated with ICU mortality: mean glucose concentration, glucose variability, the incidence of hypoglycaemia (= 2.2 mmol/l) or low glucose (2.3 to 4.7 mmol/l). Underlying diabetes mellitus (DM) might affect these associations. Our objective was to study whether the association between these measures of glycaemic control and ICU mortality differs between patients without and with DM and to explore the cutoff value for detrimental low glucose in both cohorts. Methods: This retrospective database cohort study included patients admitted between January 2004 and June 2011 to a 24-bed medical/surgical ICU in a teaching hospital. We analysed glucose and outcome data from 10,320 patients: 8,682 without DM and 1,638 with DM. The cohorts were subdivided into quintiles of mean glucose and quartiles of glucose variability. Multivariable regression models were used to examine the independent association between the four measures of glycaemic control and ICU mortality, and for defining the cutoff value for detrimental low glucose. Results: Regarding mean glucose, a U-shaped relation was observed in the non-DM cohort with an increased ICU mortality in the lowest and highest glucose quintiles (odds ratio = 1.4 and 1.8, P < 0.001). No clear pattern was found in the DM cohort. Glucose variability was related to ICU mortality only in the non-DM cohort, with highest ICU mortality in the upper variability quartile (odds ratio = 1.7, P < 0.001). Hypoglycaemia was associated with ICU mortality in both cohorts (odds ratio non-DM = 2.5, P < 0.001; odds ratio DM = 4.2, P = 0.001), while low-glucose concentrations up to 4.9 mmol/l were associated with an increased risk of ICU mortality in the non-DM cohort and up to 3.5 mmol/l in the DM cohort. Conclusion: Mean glucose and high glucose variability are related to ICU mortality in the non-DM cohort but not in the DM cohort. Hypoglycaemia (= 2.2 mmol/l) was associated with ICU mortality in both. The cutoff value for detrimental low glucose is higher in the non-DM cohort (4.9 mmol/l) than in the DM cohort (3.5 mmol/l). While hypoglycaemia (≤2.2 mmol/l) should be avoided in both groups, DM patients seem to tolerate a wider glucose range than non-DM patients. [ABSTRACT FROM AUTHOR]

In patients with diabetes, metabolic disorders disturb the physiological balance of coagulation and fibrinolysis, leading to a prothrombotic state characterized by platelet hypersensitivity, coagulation disorders and hypofibrinolysis. Hyperglycemia and insulin resistance cause changes in platelet number and activation, as well as qualitative and/or quantitative modifications of coagulatory and fibrinolytic factors, resulting in the formation of fibrinolysis-resistant clots in patients with diabetes. Other coexisting factors like hypoglycemia, obesity and dyslipidemia also contribute to coagulation disorders in patients with diabetes. Management of the prothrombotic state includes antiplatelet and anticoagulation therapies for diabetes patients with either a history of cardiovascular disease or prone to a higher risk of thrombus generation, but current guidelines lack recommendations on the optimal antithrombotic treatment for these patients. Metabolic optimizations like glucose control, lipid-lowering, and weight loss also improve coagulation disorders of diabetes patients. Intriguing, glucose-lowering drugs, especially cardiovascular beneficial agents, such as glucagon-like peptide-1 receptor agonists and sodium glucose co-transporter inhibitors, have been shown to exert direct anticoagulation effects in patients with diabetes. This review focuses on the most recent progress in the development and management of diabetes related prothrombotic state. [ABSTRACT FROM AUTHOR]