Association for Academic Surgery
Increasing Blood Glucose Variability Heralds Hypoglycemia in the Critically Ill1

https://doi.org/10.1016/j.jss.2011.03.008Get rights and content

Background

Control of hyperglycemia improves outcomes, but increases the risk of hypoglycemia. Recent evidence suggests that blood glucose variability (BGV) is more closely associated with mortality than either isolated or mean BG. We hypothesized that differences in BGV over time are associated with hypoglycemia and can be utilized to estimate risk of hypoglycemia (<50 mg/dL).

Materials and Methods

Patients treated with intravenous insulin in the Surgical Intensive Care Unit of a tertiary care center formed the retrospective cohort. Exclusion criteria included death within 24 h of admission. We describe BGV in patients over time and its temporal relationship to hypoglycemic events. The risk of hypoglycemia for each BG measurement was estimated in a multivariable regression model. Predictors were measures of BGV, infusions of dextrose and vasopressors, patient demographics, illness severity, and BG measurements.

Results

A total of 66,592 BG measurements were collected on 1392 patients. Hypoglycemia occurred in 154 patients (11.1%). Patient BGV fluctuated over time, and increased in the 24 h preceding a hypoglycemic event. In crude and adjusted analyses, higher BGV was positively associated with a hypoglycemia (OR 1.41, P < 0.001). Previous hypoglycemic events and time since previous BG measurement were also positively associated with hypoglycemic events. Severity of illness, vasopressor use, and diabetes were not independently associated with hypoglycemia.

Conclusions

BGV increases in the 24 h preceding hypoglycemia, and patients are at increased risk during periods of elevated BG variability. Prospective measurement of variability may identify periods of increased risk for hypoglycemia, and provide an opportunity to mitigate this risk.

Introduction

Hyperglycemia in both the perioperative and intensive care unit (ICU) settings is associated with increased morbidity and mortality among diverse patient populations 1, 2, 3, 4, 5, 6, 7. As a result, the use of intensive insulin therapy (IIT) to control blood glucose has been widely adopted in the ICU setting. Since the first study on IIT and outcomes by Van den Berghe [8], an extensive body of literature has emerged. While the 2001 study showed a decrease in mortality associated with IIT, a number of large randomized studies since that time have not been able to reproduce the benefits in terms of morbidity and mortality 9, 10, 11. A recent meta-analysis showed no significant benefit with the use of IIT when combining all studies [12]. However, a subgroup analysis showed that the data still favor the use of IIT in the surgical ICU population. In this group, IIT still appears to be beneficial in decreasing infectious complications and improving survival 8, 13, 14, 15, 16, 17, 18, 19. However, controversy persists over the appropriate patient population and optimum target range for blood glucose (BG) control. This is due, in part, to concerns over hypoglycemia with tight glucose control (80–110 mg/dL) 9, 11, 12, 20, 21.

A number of factors have been shown to be associated with risk of hypoglycemia, including time on intensive insulin therapy [22], requirement for dialysis, decreases in nutrition provided without concurrent decreases in insulin, diabetes mellitus, sepsis, need for vasopressors, and BMI 23, 24, 25. Hypoglycemia’s contribution to the risk of mortality remains uncertain, due to variability in the severity of hypoglycemia, accuracy of monitoring, time intervals between monitoring (altering the period of hypoglycemia), institutional differences in insulin therapy protocols, and the variability in patient severity of illness and clinical disease state among various studies. Thus, studies have yielded conflicting results 26, 27, 28. While target range for glucose control and insulin protocol type and compliance contribute to hypoglycemic events, patient-specific factors also contribute to the overall risk of hypoglycemia. Recent evidence suggests that BG variability is more strongly associated with mortality than either isolated or mean BG levels in the critically ill patient population 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45. In the outpatient diabetic population, wide fluctuations in BG level and increased BG variability have been associated with hypoglycemia [46]. Whether or not a patient’s blood glucose variability is associated with subsequent hypoglycemia in critically ill patients has not been previously studied. We hypothesized that individual differences in BG variability over time in critically ill surgical patients are associated with hypoglycemia and can be utilized to estimate a patient’s risk of hypoglycemia.

Section snippets

Materials and Methods

A retrospective analysis was performed on a cohort of critically ill surgical patients admitted to the surgical intensive care unit (SICU) of a tertiary care, academic medical center from June 1, 2006 to September 1, 2009. All patients within the SICU receive critical care consultation and management until discharge from the ICU. Patient care management is at the discretion of the ICU attending physician according to established evidence-based practice management guidelines.

This study was

Results

During the study period, a total of 78,136 BG measurements were collected on 1392 patients. After excluding BG measurements taken in the first 12 h after SICU admission and following 6 h gaps in IIT treatment, 66,592 BG measurements (85.2%) remained for analysis and modeling. Hypoglycemia (<50 mg/dL) occurred in 154/1392 patients (11.1%). Demographics and clinical characteristics of those who experienced one or more hypoglycemic events compared with those who did not are displayed in Table 1.

Discussion

The use of IIT to control BG in ICU settings has been fairly widely adopted, particularly in surgical ICUs. Controversy regarding appropriate targets for glycemic control persists and interpretation of the data from various trials are confounded by varying rates of hypoglycemia and hypoglycemia’s possible influence on outcome. In addition, there is considerable controversy surrounding the issue of whether IIT is beneficial or harmful, and to which populations. In surgical patients, the weight

Conclusions

Patients who experience hypoglycemia are characterized by higher BG variability prior to the hypoglycemic event. BG variability increases in the 24 h preceding a hypoglycemic event, and patients with high BG variability are at increased risk of hypoglycemia during the period of time their BG remains highly variable. Prospectively measuring BG variability may provide a means for early identification of high-risk patients on IIT, and provide new diagnostic and therapeutic opportunities to

Acknowledgments

Financial support was provided in part by NIH T32 training grant in Diabetes and Endocrinology 5T32DK007061-35 (RK).

References (56)

  • H. White

    Maximum likelihood estimation of misspecified models

    Econometrica

    (1982)
  • M. Egi et al.

    Blood glucose concentration and outcome of critical illness: The impact of diabetes

    Crit Care Med

    (2008)
  • G.E. Umpierrez et al.

    Hyperglycemia: An independent marker of in-hospital mortality in patients with undiagnosed diabetes

    J Clin Endocrinol Metab

    (2002)
  • R. Latham et al.

    The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients

    Infect Control Hosp Epidemiol

    (2001)
  • M. Masla et al.

    HbA1c and diabetes predict perioperative hyperglycemia and glycemic variability in on-pump coronary artery bypass graft patients

    J Cardiothorac Vasc Anesth

    (2010 Nov 24)
  • G. Van den Berghe et al.

    Intensive insulin therapy in the critically ill patients

    N Engl J Med

    (2001)
  • P. Devos et al.

    Current controversies around tight glucose control in critically Ill patients

    Curr Opin Clin Nutr Metab Care

    (2007)
  • F.M. Brunkhorst et al.

    Intensive insulin therapy and pentastarch resuscitation in severe sepsis

    N Engl J Med

    (2008)
  • Intensive versus conventional glucose control in critically ill patients

    N Engl J Med

    (2009)
  • D.E. Griesdale et al.

    Intensive insulin therapy and mortality among critically ill patients: A meta-analysis including NICE-SUGAR study data

    CMAJ

    (2009)
  • J.J. Blondet et al.

    Glycemic control and prevention of perioperative infection

    Curr Opin Crit Care

    (2007)
  • G. Van den Berghe et al.

    Intensive insulin therapy in the medical ICU

    N Engl J Med

    (2006)
  • J.C. Preiser et al.

    Clinical experience with tight glucose control by intensive insulin therapy

    Crit Care Med

    (2007)
  • M.J. Schultz et al.

    Clinical review: Strict or loose glycemic control in critically ill patients–Implementing best available evidence from randomized controlled trials

    Crit Care

    (2010)
  • Mowery NT, Dossett LA, Gunter OL, et al. Duration on protocol predicts severe hypoglycemia while on intensive insulin...
  • T.M. Vriesendorp et al.

    Predisposing factors for hypoglycemia in the intensive care unit

    Crit Care Med

    (2006)
  • Y.M. Arabi et al.

    Hypoglycemia with intensive insulin therapy in critically ill patients: Predisposing factors and association with mortality

    Crit Care Med

    (2009)
  • R.N. Dickerson et al.

    Increased hypoglycemia associated with renal failure during continuous intravenous insulin infusion and specialized nutritional support

    Nutrition

    (2010 Oct 23)
  • Cited by (24)

    • Glycemic control in the intensive care unit: A control systems perspective

      2019, Annual Reviews in Control
      Citation Excerpt :

      However, poor control leading to low BG or hypoglycemia is also linked with increased mortality (Bagshaw et al., 2009; Egi et al., 2010; Finfer et al., 2012; Krinsley et al., 2011), indicating the difficulty of the control problem in regulating BG to a band. These issues clearly state any control, automated or manual, must be achieved safely, despite the high inter- and intra- patient variability in response to care (Chase, Le Compte, Suhaimi, et al., 2011; Kauffmann et al., 2011; Krinsley, Bruns, & Boyd, 2015; Langouche et al., 2007; Pielmeier, Rousing, Andreassen, Nielsen, & Haure, 2012; Pretty et al., 2012; Waeschle et al., 2008), which can define these patients. Equally, and in contrast, safe, effective control has shown equivalent association of high times in intermediate BG bands with reduced mortality (Al-Tarifi, Abou-Shala, Tamim, Rishu, & Arabi, 2011; Krinsley & Preiser, 2015; Omar et al., 2015; Penning et al., 2014; Penning et al., 2015; Signal, Le Compte, Shaw, & Chase, 2012).

    • A randomized controlled trial of one bag vs. two bag system of fluid delivery in children with diabetic ketoacidosis: Experience from a developing country

      2018, Journal of Critical Care
      Citation Excerpt :

      Since there were no previous studies with blood glucose variability as the primary outcome variable, we planned this study as a pilot trial with a minimum of 15 children with DKA in each group i.e. control (one bag) group and experimental (two bag) group. The median absolute BG change (current BG − previous BG), standard deviation (SD) of absolute BG measurements and coefficient of variance (CV) (SD/Mean BG ∗ 100) for each patient were calculated [13,15,16]. Normally distributed continuous variables are summarized by reporting the mean and standard deviation and compared using two sample t-tests for independent samples.

    • Comparison of basal insulin regimens on glycemic variability in noncritically ill patients with type 2 diabetes

      2015, Endocrine Practice
      Citation Excerpt :

      In a retrospective study of a medical and surgical ICU population, Mackenzie et al (22) found that GV measured by SD, MAGE, and coefficient of variation (CV) was an independent predictor of hospital and ICU mortality. In addition, GV has been associated with increased risk of hypoglycemic events among critically ill patients (23). In the outpatient setting, higher GV has been associated with both asymptomatic and symptomatic hypoglycemia in patients with T2D (24,25).

    • Glycemic Variability and Glycemic Control in the Acutely Ill Cardiac Patient

      2012, Heart Failure Clinics
      Citation Excerpt :

      In hospitalized patients, glycemic variability has been associated with age, diabetes, and total insulin requirements.101 However, measures that minimize fluctuations are more likely to achieve overall glycemic control without increasing the risk of hypoglycemia.102,103 Studies in the outpatient setting suggest that physiologic insulin regimens reduce both mean glucose level and glycemic fluctuations.104–106

    View all citing articles on Scopus
    1

    Presented at the Academic Surgical Congress, Huntington Beach, California, February, 2011.

    View full text