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The Case for Supporting Inpatient Glycemic Control Programs Now: the Evidence and Beyond

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The Case for Supporting Inpatient Glycemic Control Programs Now: the Evidence and Beyond REVIEW The Case for Supporting Inpatient Glycemic Control Programs Now: The Evidence and Beyond 1 Susan S. Braithwaite, MD, FACP, FACE edical centers are faced with multiple competing priorities 2,3 Michelle Magee, MD M when deciding how to focus their improvement efforts and 3 John M. Sharretts, MD meet the ever expanding menu of publicly reported and regula- 4,5,6 Jeffrey L. Schnipper, MD, MPH tory issues. In this article we expand on the rationale for sup- 7 Alpesh Amin, MD, MBA porting inpatient glycemic control programs as a priority that 8 Gregory Maynard, MD, MSc should be moved near the top of the list. We review the evidence for establishing glycemic range targets, and also review the lim- 1 Department of Medicine, University of North itations of this evidence, acknowledging, as does the American Carolina-Chapel Hill, Chapel Hill, North Carolina. Diabetes Association (ADA), that in ‘‘both the critical care and 2 Georgetown University School of Medicine and non-critical care venue, glycemic goals must take into account Healthcare Sciences, Washington, DC. the individual patient’s situation as well as hospital system sup- 1,2 3 MedStar Diabetes & Research Institutes, port for achieving these goals.’’ We emphasize that inpatient Washington, DC. glycemic control programs are needed to address a wide variety of quality and safety issues surrounding the care of the inpatient 4 BWH Academic Hospitalist Service, Brigham and Women’s Hospital, Boston, Massachusetts. with diabetes and hyperglycemia, and we wish to elevate the dialogue beyond arguments surrounding adoption of one glyce- 5 Division of General Medicine, Brigham and mic target versus another. The Society of Hospital Medicine Women’s Hospital, Boston, Massachusetts. Glycemic Control Task Force members are not in unanimous 6 Department of Medicine, Harvard Medical agreement with the American Association of Clinical Endocrinol- School, Boston, Massachusetts. ogists (AACE)/ADA inpatient glycemic targets. However, we do 7 Department of Medicine, Hospitalist Program, agree on several other important points, which we will expand University of California Irvine, Irvine, California. on in this article: 8 Department of Medicine, Division of Hospital Medicine, University of California San Diego, San Diego, California. 1. Uncontrolled hyperglycemia and iatrogenic hypoglycemia are common and potentially dangerous situations that are largely preventable with safe and proven methods. 2. The current state of care for our inpatients with hyperglycemia is unacceptably poor on a broad scale, with substandard education, communication, coordination, and treatment issues. 3. Concerted efforts with changes in the design of the process of care are needed to improve this state of affairs. No honoraria were paid to any authors for time DIABETES AND HYPERGLYCEMIA ARE VERY COMMON and expertise spent on the writing of this article. INPATIENT CONDITIONS Greg Maynard has received honoraria for speak- Diabetes mellitus (DM) has reached epidemic proportions in the ing engagements from Sanofi-Aventis. United States. A reported 9.3% of adults over 20 years of age have diabetes, representing over 20 million persons. Despite Alpesh Amin discloses a speaker/research affilia- increasing awareness, diabetes remains undiagnosed in approxi- tion with Sanofi-Aventis. mately 30% of these persons.3 Concurrent with the increasing Submitted on behalf of the Society of Hospital prevalence of diabetes in the U.S. population from 1980 through Medicine Glycemic Control Task Force. 2003, the number of hospital discharges with diabetes as any S6 ª 2008 Society of Hospital Medicine DOI 10.1002/jhm.350 Published online in Wiley InterScience (www.interscience.wiley.com). listed diagnosis more than doubled, going from Although it is beyond the scope of this article to 2.2 to 5.1 million discharges.4 Hospital care for discuss these mechanisms in detail, research has patients with diabetes and hyperglycemia poses a broadly focused in the following areas: (1) significant health economic burden in the United immune system dysfunction, associated with a States, representing over 40 billion dollars in an- proinflammatory state and impaired white blood nual direct medical expenditures.5 cell function; (2) metabolic derangements leading Hyperglycemia in the hospital may be due to to oxidative stress, release of free fatty acids, known diabetes, to previously unrecognized diabe- reduction in endogenous insulin secretion, and tes, to prediabetes, and/or to the stress of surgery fluid and electrolyte imbalance; and (3) a wide va- or illness. Deterioration in glycemic control in the riety of vascular system responses (eg, endothelial hospital setting is most commonly associated with dysfunction with impairment of tissue perfusion, one or more factors, including stress-induced a prothrombotic state, increased platelet aggrega- release of insulin counterregulatory hormones tion, and left ventricular dysfunction).8,16–18 (catecholamines, cortisol, glucagon, and growth Conversely administration of insulin sup- hormone), exogenous administration of high dose presses or reverses many of these abnormalities glucocorticoids, and suboptimal glycemic man- including generation of reactive oxygen species agement strategies.6–8 In a Belgian medical inten- (ROS) and activation of inflammatory mechan- sive care unit (MICU) randomized controlled trial isms,19 and leads to a fall in C-reactive protein, (RCT) of strict versus conventional glycemic con- which accompanied the clinical benefit of inten- trol, mean blood glucose (BG) on admission to the sive insulin therapy (IIT) in the Leuven, Belgium, unit in the intention to treat group was 162 Æ 70 ICU population,20 and prevents mitochondrial mg/dL (n 5 1200),9 and in this group’s RCT of abnormalities in hepatocytes.21 In the same surgi- 1548 surgical intensive care unit (SICU) patients, cal ICU cohort, Langouche et al.22 report suppres- BG > 110 mg/dL was observed in over 70% of sion of intracellular adhesion molecule-1 (ICAM- subjects.10 Mean BG of >145 mg/dL has been 1) and E-selectin, markers of inflammation, and reported in 39%11 and BG >200 mg/dL in any- reduction in plasma nitric oxide (NO) and innate where from 11% to 31% of intensive care unit nitric oxide (iNOS) expression with insulin admin- (ICU) patients.10,12 For general medicine and sur- istration in patients treated with intravenous (IV) gery, 1 study of 2030 patients admitted to a teach- IIT.22 These data further support the role of insu- ing hospital revealed that 26% of admissions had lin infusion in suppressing inflammation and a known history of DM and 12% had new hyper- endothelial dysfunction. The authors suggest that glycemia, as evidenced by an admission or in-hos- maintaining normoglycemia with IIT during criti- pital fasting BG of 126 mg/dL or more or a cal illness protects the endothelium, thereby con- random BG of 200 mg/dL or more on 2 or more tributing to prevention of organ failure and determinations.13 National and regional estimates death.22 Based on accumulating data in the litera- on hospital use maintained by the Agency for ture such as that cited above, it has been sug- Healthcare Research and Quality include data gested that a new paradigm in which glucose and concerning diabetes diagnoses alone, without insulin are related not only through their meta- hyperglycemia, and may be displayed by querying bolic action but also through inflammatory its Web site.14 In cardiovascular populations mechanisms offers important potential therapeu- almost 70% of patients having a first myocardial tic opportunities.19 infarction have been reported to have either known DM, previously unrecognized diabetes, or impaired glucose tolerance.15 Evidence: Epidemiology/Observational Studies/Non-RCT Interventional Studies A strong association between hospital hyperglyce- THE EVIDENCE SUPPORTS INPATIENT mia and negative outcomes has been reported in GLYCEMIC CONTROL numerous observational studies in diverse adult Evidence: Physiology medical and surgical settings. In over 1800 hospi- The pathophysiologic mechanisms through which tal admissions, those with new hyperglycemia had hyperglycemia is linked to suboptimal outcomes an in-hospital mortality rate of 16% compared in the hospital are complex and multifactorial. with 3% mortality in patients with known diabetes Supporting Inpatient Glycemic Control Programs Now / Braithwaite et al. S7 and 1.7% in normoglycemic patients (P < 0.01). Another large ICU study (mixed medical-surgi- These data suggest that hyperglycemia due to pre- cal, n 5 800 patients) also supports a benefit viously unrecognized diabetes may be an inde- through targeted BG control (130.7 versus 152.3 pendent marker of in-hospital mortality.13 mg/dL, P < 0.001) when compared with historical Hyperglycemia has been linked to adverse controls. This study demonstrated reduction in in- outcomes in myocardial infarction, stroke,23–28 hospital mortality (relative risk reduction 29.3%, P postoperative nosocomial infection risk, pneumo- 5 0.002), duration of ICU stay (10.8%, P 5 0.04), nia, renal transplant, cancer chemotherapy, per- acute renal failure (75%, P 5 0.03), and blood cutaneous coronary interventions, and cardiac transfusions (18.7%, P 5 0.002),40 representing a surgery.29–38 These observational studies have the similar magnitude of effect as was demonstrated usual limitations inherent in their design. Demon- by the Belgian group. strating a strong association of hyperglycemia with adverse outcomes is not a guarantee
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