Jeroen Hermanides

Glucose variability is associated with intensive care unit mortality.

Objective:Mounting evidence suggests a role for glucose variability in predicting intensive care unit (ICU) mortality. We investigated the association between glucose variability and intensive care unit and in-hospital deaths across several ranges of mean glucose. Design:Retrospective cohort study. Setting:An 18-bed medical/surgical ICU in a teaching hospital. Patients:All patients admitted to the ICU from January 2004 through December 2007. Interventions:None. Measurements and Main Results:Two measures of variability, mean absolute glucose change per hour and sd, were calculated as measures of glucose variability from 5728 patients and were related to ICU and in-hospital death using logistic regression analysis. Mortality rates and adjusted odds ratios for ICU death per mean absolute glucose change per hour quartile across quartiles of mean glucose were calculated. Patients were treated with a computerized insulin algorithm (target glucose 72–126 mg/dL). Mean age was 65 ± 13 yrs, 34% were female, and 6.3% of patients died in the ICU. The odds ratios for ICU death were higher for quartiles of mean absolute glucose change per hour compared with quartiles of mean glucose or sd. The highest odds ratio for ICU death was found in patients with the highest mean absolute glucose change per hour in the upper glucose quartile: odds ratio 12.4 (95% confidence interval, 3.2–47.9; p < .001). Mortality rates were lowest in the lowest mean absolute glucose change per hour quartiles. Conclusions:High glucose variability is firmly associated with ICU and in-hospital death. High glucose variability combined with high mean glucose values is associated with highest ICU mortality. In patients treated with strict glycemic control, low glucose variability seemed protective, even when mean glucose levels remained elevated.

Hypoglycemia is associated with intensive care unit mortality.

Objective:The implementation of intensive insulin therapy in the intensive care unit is accompanied by an increase in hypoglycemia. We studied the relation between hypoglycemia on intensive care unit mortality, because the evidence on this subject is conflicting. Design:Retrospective database cohort study. Setting:An 18-bed medical/surgical intensive care unit in a teaching hospital (Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, The Netherlands). Patients:A total of 5961 patients admitted to from 2004 to 2007 were analyzed. Readmissions and patients with a withholding care policy or with hypoglycemia on the first glucose measurement were excluded. Patients were treated with a computerized insulin algorithm (target glucose range, 72-126 mg/dL). Interventions:None. Measurements and Main Results:All first episodes of hypoglycemia (glucose ≤45 mg/dL) were derived from 154,015 glucose values. Using Poisson regression, the incidence rates for intensive care unit death and incidence rate ratio comparing exposure and nonexposure to hypoglycemia were calculated. Patients were considered to be exposed to hypoglycemia from the event until the end of intensive care unit admittance. We corrected for severity of disease using the daily Sequential Organ Failure Assessment score. Age, sex, cardiothoracic surgery, sepsis, and diabetes mellitus were also included as possible confounders. Two hundred eighty-eight (4.8%) patients experienced at least one episode of hypoglycemia. Median age was 68 yrs (range, 58-75 yrs), 66% were male, and 6.4% died in the intensive care unit. The incidence rate of death in patients exposed to hypoglycemia was 40 per 1000 intensive care unit days compared with 17 per 1000 intensive care unit days in patients without exposure. The adjusted incidence rate ratio for intensive care unit death was 2.1 (95% confidence interval, 1.6-2.8; p < .001). Conclusions:Hypoglycemia is related to intensive care unit mortality, also when adjusted for a daily adjudicated measure of disease severity, indicating the possibility of a causal relationship.

The effect of diabetes mellitus on the association between measures of glycaemic control and ICU mortality: a retrospective cohort study

IntroductionIn critical illness, four measures of glycaemic control are associated with ICUmortality: mean glucose concentration, glucose variability, the incidence ofhypoglycaemia (≤ 2.2 mmol/l) or low glucose (2.3 to 4.7 mmol/l). Underlyingdiabetes mellitus (DM) might affect these associations. Our objective was to studywhether the association between these measures of glycaemic control and ICUmortality differs between patients without and with DM and to explore the cutoffvalue for detrimental low glucose in both cohorts.MethodsThis retrospective database cohort study included patients admitted betweenJanuary 2004 and June 2011 to a 24-bed medical/surgical ICU in a teachinghospital. We analysed glucose and outcome data from 10,320 patients: 8,682 withoutDM and 1,638 with DM. The cohorts were subdivided into quintiles of mean glucoseand quartiles of glucose variability. Multivariable regression models were used toexamine the independent association between the four measures of glycaemic controland ICU mortality, and for defining the cutoff value for detrimental lowglucose.ResultsRegarding mean glucose, a U-shaped relation was observed in the non-DM cohort withan 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 DMcohort. Glucose variability was related to ICU mortality only in the non-DMcohort, with highest ICU mortality in the upper variability quartile (odds ratio =1.7, P < 0.001). Hypoglycaemia was associated with ICU mortality inboth 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 wereassociated with an increased risk of ICU mortality in the non-DM cohort and up to3.5 mmol/l in the DM cohort.ConclusionMean glucose and high glucose variability are related to ICU mortality in thenon-DM cohort but not in the DM cohort. Hypoglycaemia (≤ 2.2 mmol/l) wasassociated with ICU mortality in both. The cutoff value for detrimental lowglucose is higher in the non-DM cohort (4.9 mmol/l) than in the DM cohort (3.5mmol/l). While hypoglycaemia (≤ 2.2 mmol/l) should be avoided in bothgroups, DM patients seem to tolerate a wider glucose range than non-DMpatients.

Current Application of Continuous Glucose Monitoring in the Treatment of Diabetes: Pros and cons

The ultimate goal of diabetes technology is to create an artificial pancreas, or closed-loop system. In the early 1970s, the first prototypes became available (1). Although recent advances are promising, the closed-loop system is currently confined to the clinical research center (2). The continuous subcutaneous insulin infusion (CSII) pump became commercially available in the 1980s, and it is now a common and accepted way of providing insulin (3,4). The emergence of continuous glucose monitoring (CGM) followed in the 1990s, with the first reports on CGM by microdialysis in 1992 (5,6). Retrospective needle-type CGM systems were introduced just before the turn of the century (7–10). Currently, there are four subcutaneous CGM systems on the market that have real-time glucose values on display every 1–5 min and feature an alarm function for hypo- and hyperglycemia: the Freestyle Navigator (Abbot Diabetes Care, Alameda, CA), the Guardian Real-Time (Medtronic MiniMed, Northridge, CA), the Dexcom SEVEN (Dexcom, San Diego, CA), and the GlucoDay (Menarini Diagnostics). The first three are needle-type CGMs and the latter is a microdialysis-type sensor. All of these measure glucose via the glucose-oxidase reaction. In this article, we will discuss the pros and cons of the current application of CGM in the treatment of diabetes.nnFrom the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study, we learned that lowering HbA1c reduces morbidity and mortality (11,12) and that tight glycemic control is associated with an increased rate of severe hypoglycemic episodes. We therefore should judge the pros of CGM by its HbA1c-lowering potency and its influence on severe hypoglycemia rates. Table 1 summarizes all intervention trials that have been performed with real-time CGM regarding HbA1c and the incidence of severe hypoglycemia.nnView this table:nnTable 1 nCGM trials in type 1 diabetesnnnnThe …

Mean glucose during ICU admission is related to mortality by a U-shaped curve in surgical and medical patients: a retrospective cohort study

IntroductionLowering of hyperglycemia in the intensive care unit (ICU) is widely practiced. We investigated in which way glucose regulation, defined as mean glucose concentration during admission, is associated with ICU mortality in a medical and a surgical cohort.MethodsRetrospective database cohort study including patients admitted between January 2004 and December 2007 in a 20-bed medical/surgical ICU in a teaching hospital. Hyperglycemia was treated using a computerized algorithm targeting for glucose levels of 4.0-7.0 mmol/l. Five thousand eight hundred twenty-eight patients were eligible for analyses, of whom 1,339 patients had a medical and 4,489 had a surgical admission diagnosis.ResultsThe cohorts were subdivided in quintiles of increasing mean glucose. We examined the relation between these mean glucose strata and mortality. In both cohorts we observed the highest mortality in the lowest and highest strata. Logistic regression analysis adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, admission duration and occurrence of severe hypoglycemia showed that in the medical cohort mean glucose levels <6.7 mmol/l and >8.4 mmol/l and in the surgical cohort mean glucose levels < 7.0 mmol/l and >9.4 mmol/l were associated with significantly increased ICU mortality (OR 2.4-3.0 and 4.9-6.2, respectively). Limitations of the study were its retrospective design and possible incomplete correction for severity of disease.ConclusionsMean overall glucose during ICU admission is related to mortality by a U-shaped curve in medical and surgical patients. In this cohort of patients a safe range of mean glucose regulation might be defined approximately between 7.0 and 9.0 mmol/l.

Early Postoperative Hyperglycemia Is Associated With Postoperative Complications After Pancreatoduodenectomy

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.

Postprandial Glycemic Excursions with the Use of a Closed-Loop Platform in Subjects with Type 1 Diabetes: A Pilot Study

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.

Sensor-augmented insulin pump therapy to treat hyperglycemia at the coronary care unit: a randomized clinical pilot trial

BACKGROUNDnThe 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.nnnMETHODSnIn 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.nnnRESULTSnThe 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 <or= 70 mg/dL was 8.9% (IQR, 8.3-12.5%) in the SAP group versus 0% (IQR, 0-2%) in the Control group (P < 0.001). Plasma glucose decreased significantly in the SAP group compared to the Control group (P = 0.025).nnnCONCLUSIONSnSAP therapy is effective in reducing hyperglycemia in STEMI patients on the coronary care unit. This is accompanied by a small but significant increase in hypoglycemia. Although a promising tool for in-hospital hyperglycemia therapy, SAP needs improvement before continuing to large-scale randomized controlled trials.

The Clinical Benefits and Accuracy of Continuous Glucose Monitoring Systems in Critically Ill Patients—A Systematic Scoping Review

Continuous Glucose Monitoring (CGM) systems could improve glycemic control in critically ill patients. We aimed to identify the evidence on the clinical benefits and accuracy of CGM systems in these patients. For this, we performed a systematic search in Ovid MEDLINE, from inception to 26 July 2016. Outcomes were efficacy, accuracy, safety, workload and costs. Our search retrieved 356 articles, of which 37 were included. Randomized controlled trials on efficacy were scarce (n = 5) and show methodological limitations. CGM with automated insulin infusion improved time in target and mean glucose in one trial and two trials showed a decrease in hypoglycemic episodes and time in hypoglycemia. Thirty-two articles assessed accuracy, which was overall moderate to good, the latter mainly with intravascular devices. Accuracy in critically ill children seemed lower than in adults. Adverse events were rare. One study investigated the effect on workload and cost, and showed a significant reduction in both. In conclusion, studies on the efficacy and accuracy were heterogeneous and difficult to compare. There was no consistent clinical benefit in the small number of studies available. Overall accuracy was moderate to good with some intravascular devices. CGM systems seemed however safe, and might positively affect workload and costs.

Comparison of continuous nerve block versus patient-controlled analgesia for postoperative pain and outcome after talar and calcaneal fractures

Background: Talar and calcaneal fractures and their treatment can cause severe postoperative pain. We hypothesized that a continuous peripheral nerve block (CPNB) would reduce pain scores more effectively than systemic analgesics, improve recovery, and lead to reduced length of stay (LOS). Methods: Over a 3-year period patients undergoing open reduction and internal fixation (ORIF) of a talar or calcaneal fracture were retrospectively analyzed. Patients received a CPNB catheter preoperatively or intravenous patient-controlled analgesia (PCA) postoperatively. Primary endpoint was Numerical Rating Scale (NRS) scores on postoperative day 1. Secondary endpoints were NRS scores up to day 3, opioid requirement, analgesia-related side effects, intraoperative blood loss, infection, and LOS. Eighty-seven patients were analyzed; 70 with calcaneal fracture, 21 with talar fracture, 4 with both. In all, 40 patients received CPNB, 47 patients PCA. Results: Median NRS scores on day 1 were 1.0 (IQR 3) in the CPNB group and 2.0 (IQR 3) in the PCA group (ns). Median LOS for patients with CPNB was 5 days (IQR3) and PCA 4 days (IQR 2 ns). Blood loss and incidence of local infections were comparable in both groups. Opioid requirement was significantly increased in the PCA group (P < .01). Conclusion: Significant advantages or disadvantages were not seen in either group. However, the PCA group required about 30-fold more opioids compared to the CPNB group on day 1, although that did not lead to an increased number of side effects. Level of Evidence: Level III, retrospective comparative series.