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Perioperative Glycemic Control an Evidence-Based Review Angela K Ⅵ REVIEW ARTICLES David S. Warner, M.D., and Mark A. Warner, M.D., Editors Anesthesiology 2009; 110:408–21 Copyright © 2009, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Perioperative Glycemic Control An Evidence-based Review Angela K. M. Lipshutz, M.D., M.P.H.,* Michael A. Gropper, M.D., Ph.D.† Hyperglycemia in perioperative patients has been identified insulin therapy (IIT) (target blood glucose [BG], 80–110 as a risk factor for morbidity and mortality. Intensive insulin mg/dL) reduced in-hospital mortality by 34% when com- therapy (IIT) has been shown to reduce morbidity and mortality among the critically ill, decrease infection rates and improve pared to standard therapy (target BG, 180–200 mg/dL) survival after cardiac surgery, and improve outcomes in acute and significantly decreased morbidity, including blood- neurologic injury and acute myocardial infarction. However, stream infections, acute renal failure, red-cell transfu- recent evidence of severe hypoglycemia and adverse events sions, and critical-illness polyneuropathy.1 Other studies associated with IIT brings its safety and efficacy into question. have shown that tight glycemic control during cardiac In this article, we summarize the mechanisms and rationale of hyperglycemia and IIT, review the evidence behind the use of surgery is associated with decreased infection rates and 2–5 IIT in the perioperative period, and discuss the implications improved survival, that postoperative glycemic con- of including glycemic control in national quality benchmarks. trol in cadaveric renal transplantation decreases allograft We conclude that while avoidance of hyperglycemia is clearly rejection,6 and that intensive insulin improves outcomes beneficial, the appropriate glucose target and specific subpopu- 7,8 lations who might benefit from IIT have yet to be identified. in the setting of acute neurologic injury and acute 9 Given the potential for harm, inclusion of glucose targets in myocardial infarction. Widespread implementation of national quality benchmarks is premature. IIT in the perioperative period ensued on the basis of these data; the Joint Commission (formerly known as HYPERGLYCEMIA has been identified as a risk factor for JCAHO) has included postoperative BG in cardiac surgi- perioperative morbidity and mortality. In 2001, Van den cal patients in its core measure set,‡ and the Centers for Berghe et al. published the first Leuven study, a random- Medicare & Medicaid Services (CMS) has included it in ized controlled trial (RCT) of more than 1500 surgical the Surgical Care Improvement Project (SCIP).§ The data intensive care unit (ICU) patients in which intensive from SCIP will yield evidence-based guidelines and na- tional benchmarks and may eventually be used in pay- for-performance (P4P) programs in which a portion of This article is featured in “This Month in Anesthesiology.” reimbursement for patient care depends on the attain- ᭛ Please see this issue of ANESTHESIOLOGY, page 9A. ment of certain quality benchmarks. This article is accompanied by an Editorial View. Please see: More recently, however, there has been considerable ᭜ Fahy BG, Sheehy AM, Coursin DB: Perioperative glucose con- controversy over the safety and efficacy of IIT. The trol: What is enough? ANESTHESIOLOGY 2009; 110:204–6. second Leuven study showed that medical ICU patients may not benefit from IIT in the same way as their surgical counterparts,10 and two studies were stopped * Resident, Department of Medicine, Stanford University Medical Center; † Professor and Vice-Chair, Department of Anesthesia and Perioperative Care, early by data safety monitoring boards due to the high and Director, Critical Care Medicine, Chair for Medical Quality, University of incidence of severe hypoglycemic events (BG Յ 40 mg/ California, San Francisco. dL) and other serious adverse events.11,12 Intraoperative Received from the Department of Anesthesia and Perioperative Care, Univer- sity of California, San Francisco, California. Submitted for publication May 21, IIT during cardiac surgery may increase the incidence of 2008. Accepted for publication October 2, 2008. death and stroke.13 Furthermore, the use of insulin, in Mark A. Warner, M.D., served as Handling Editor for this article. general, is not without its risks: along with anticoagu- Address correspondence to Dr. Gropper: Department of Anesthesia and Peri- operative Care, University of California, San Francisco, 505 Parnassus Ave., Room lants, opiates, potassium chloride, and hypertonic saline, M917, San Francisco, California 94143-0624. [email protected]. insulin is considered a “high-alert medication,” one that This article may be accessed for personal use at no charge through the Journal 14 Web site, www.anesthesiology.org. has the highest risk of causing injury when misused. ‡ Joint Commission. Specifications Manual for National Hospital Quality Mea- Given the inconclusiveness of the data and the potential sures, April 2008. Available at: http://www.jointcommission.org/Performance for harm, it is unclear if adequate evidence exists to sup- Measurement/PerformanceMeasurement/CurrentϩNHQMϩManual.htm. Accessed July 12, 2008. port the widespread adoption of IIT, not to mention its § MedQIC Surgical Care Improvement Project Program Information. Available inclusion in quality measures and P4P programs. This re- at: http://www.qualitynet.org/dcs/ContentServer?cidϭ1136495755695&pagenameϭ view intends to summarize the pathophysiology and mech- Medqic%2FOtherResource%2FOtherResourcesTemplate&cϭOtherResource. Accessed July 19, 2008. anisms of hyperglycemia and insulin therapy, review the Anesthesiology, V 110, No 2, Feb 2009 408 PERIOPERATIVE GLYCEMIC CONTROL: A REVIEW 409 Fig. 1. Pathophysiology of hyperglycemia. Anesthesia, metabolic stress, and critical illness lead to metabolic derangements, resulting in hyperglycemia. Hyperglycemia is associated with increased inflammation, susceptibility to infection, and organ dysfunction. evidence behind the use of IIT in the perioperative period that have implications for the clinical decision-making of (intraoperatively, postoperatively, and in the ICU), and dis- practicing anesthesiologists: well-designed, adequately cuss the implications of the inclusion of glycemic control in powered prospective observational studies and RCTs. Ret- Joint Commission core measures, SCIP, and P4P for prac- rospective studies were also included when their analysis ticing anesthesiologists and intensivists. was robust and/or topic novel to the literature. Pathophysiology of Hyperglycemia Materials and Methods Hyperglycemia is a common response to critical illness and metabolic stress.15,16 Figure 1 summarizes the patho- We searched MEDLINE and the Cochrane Library for physiology of hyperglycemia. Stress-induced release of RCTs, observational studies, review articles, meta-analy- counterregulatory hormones cortisol, glucagon, epi- ses, and editorials on IIT in the perioperative period. We nephrine, and growth hormone leads to upregulation in evaluated articles published between January 1, 1999 hepatic gluconeogenesis and glycogenolysis despite hy- and January 31, 2008, and we limited our search to perinsulinemia and compromised insulin-regulated pe- articles published in the English language. The following ripheral glucose uptake.17–20 Interestingly, total body search terms were used: intensive insulin, glycemic glucose uptake is increased but occurs primarily in insu- control, glucose control, hyperglycemia, intraopera- lin-independent tissues such as the brain and red blood tive, intensive care, critically ill, and postoperative. Bib- cells.18,20 Glucose uptake and glycogen synthesis in skel- liographies of all relevant articles from the search were etal muscle is decreased, primarily due to a defect in the examined manually for additional articles. We also glucose transporter-4 (GLUT4).21 Historically, hypergly- searched for and reviewed abstracts published in meeting cemia in critical illness was considered a beneficial ad- proceedings as well as information on relevant ongoing aptation intended to supply energy to vital organs. How- clinical trials from ClinicalTrials.gov. We focused primarily ever, evidence that hyperglycemia is an independent risk on studies in which mortality was the primary endpoint; factor for morbidity and mortality in the perioperative however, studies evaluating infectious complications will period refutes this notion.1,2,10,22 Although the adaptive also be discussed in brief. Given the wealth of literature on rationale for the hyperglycemic response is not well this topic, we will focus on the major influential studies understood, acute hyperglycemia has many deleterious Anesthesiology, V 110, No 2, Feb 2009 410 A. K. M. LIPSHUTZ AND M. A. GROPPER effects, including decreased vasodilation, impaired reactive the dentate gyrus of the hippocampus; the cerebellum endothelial nitric oxide generation, decreased complement and brainstem are spared injury.32 Low BG levels also function, increased expression of leukocyte and endothe- lead to increased secretion of glucagon, epinephrine, lial adhesion molecules, increased cytokine levels, and im- growth hormone, and cortisol. In diabetic patients, hy- paired neutrophil chemotaxis and phagocytosis, leading to poglycemia is associated with neurogenic and neurogly- increased inflammation, vulnerability to infection, and mul- copenic symptoms, including seizure, coma, or even tiorgan system dysfunction.23 IIT ameliorates some of the
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