In the United States, the number of people diagnosed with diabetes is staggering. The American Diabetes Association (ADA) estimates that 23.6 million Americans (7.8% of the population) live with the disease.1 This number includes 5.7 million people who are unaware that they have diabetes and have never received treatment.1 Diabetes places individuals at higher risk for developing numerous complications, such as cardiovascular disease, stroke, renal disease, and blindness. The sequelae of diabetes result in increased morbidity and mortality.2 Patients with diabetes are hospitalized three times more frequently than patients without the disease.3 The exact prevalence of diabetes in hospitalized patients is unknown, but 12.4% of adult patients discharged from U.S. hospitals in 2000 carried a discharge diagnosis of diabetes; only 8% of these patients were admitted with diabetes as their primary diagnosis.3 The magnitude of the problem in this country creates challenges for hospitals caring for patients who have diabetes.
Managing hyperglycemia in the acute care setting may be more difficult because of concurrent illnesses, stress, medication-regimen alterations, and changes in dietary intake. Additionally, maintenance of tight glycemic control in both diabetic and nondiabetic hospitalized patients is a relatively new focus resulting from recent studies that have defined therapeutic goals and demonstrated improved patient outcomes.4
Pathophysiology of Hyperglycemia in Acute Illness
Emerging research is adding to existing knowledge of the pathophysiology of hyperglycemia in acute illness and is helping guide treatment principles. Studies show that hyperglycemia adversely affects immune function, the cardiovascular system, the brain, and a host of other pathways implicated in the morbidity and mortality attributed to acute hyperglycemia.4 Much of the information regarding how acute hyperglycemia contributes to complications in hospitalized patients--such as increased rates of infection and thrombosis, impaired wound healing, and impaired cardiac function--is limited, but it provides important direction for future research and treatment.
The exact mechanism by which hyperglycemia damages the immune system is unknown, but some studies show that elevation of serum glucose results in impairment of white blood cell (WBC) function, specifically that of phagocytes.5,6 Older research demonstrated that reducing serum glucose levels translates to better WBC function and phagocytosis.5,6 Although the data are limited, studies evaluating the effect of hyperglycemia on immune function consistently show that improving glycemic control improves immune function.3
The macrovascular effects of long-standing diabetes on the cardiovascular system are well documented. However, acute hyperglycemia negatively affects mechanisms--such as ischemic preconditioning--that protect the heart against ischemic damage.7 Moderately elevated serum glucose levels may decrease coronary blood flow and cause myocyte death through either apoptosis or cellular injury resulting from exaggerated ischemic reperfusion.8-10 In acute hyperglycemia, blood pressure and heart rate may increase and the risk of arrhythmias such as QTc prolongation is greater.11,12 In addition, inflammation and endothelial-cell dysfunction caused by hyperglycemia in the setting of acute illness contribute to cardiovascular complications.13,14
Hyperglycemia may increase a patient's risk of thrombosis. Elevations in blood glucose levels, even for a short time, have been shown to increase platelet activation and aggregation.15 Increased von Willebrand factor activity and thromboxane A2 production occur during episodes of hyperglycemia and may contribute to the increased risk of clot formation seen in hospitalized patients with hyperglycemia.15 Diabetic patients carry a much greater risk of cardiovascular disease caused by ischemia, but this risk appears to be unrelated to hypertension, hyperlipidemia, or smoking.15 These findings may explain the mechanism by which patients with hyperglycemia experience increased rates of thrombosis.
Brain tissue also may be affected by hyperglycemia. When a stroke occurs, the damaged tissue in the area around the impaired ischemic core (known as the ischemic penumbra) is considered to be viable. The ischemic penumbra appears to be the region that is sensitive to the effects of hyperglycemia.16 Animal studies have found that outcomes are worse in acute brain ischemia when hyperglycemia is present.17,18 Published studies evaluating outcomes with respect to hyperglycemia and stroke in humans for the most part have been retrospective or observational, but they also have shown worse outcomes.19-21 A recent, more controlled trial did not demonstrate that tight glycemic control improved outcomes in acute stroke, but the investigators suggested that further study is warranted.22
Evidence for Intensive Therapy
Studies evaluating outcomes with tight glycemic control have been conducted in patients with stroke, trauma, renal transplantation, acute lymphocytic leukemia, endocarditis, nosocomial infections, and pneumococcal sepsis. General medical and surgical patients also have been evaluated with regard to optimal glycemic-management goals. Trends toward reduced morbidity and mortality (evidenced by lower postoperative infection rates, shorter length of stay, and less need for ICU, transitional, or nursing home care) with better glycemic management are apparent in this patient population.23,24 The strongest evidence for managing hyperglycemia aggressively, however, comes from studies treating critically ill surgical patients and patients who present with myocardial infarction. Critically ill patients, even those without diabetes, are at increased risk for hyperglycemia because of counterregulatory hormones produced in response to stress that increase metabolism of glucose and fat; concurrent disease states; and medications, such as steroids, that are used to treat critical illness. A meta-analysis of 15 studies examining the relationship between blood glucose levels at admission and in-hospital mortality included both diabetic and nondiabetic patients. In patients who did not carry a diagnosis of diabetes when admitted, higher blood glucose levels upon admission were found to increase the risk of death from heart attack while in the hospital, compared with lower blood glucose levels. The trend was the same for patients known upon admission to have diabetes; the risk of death was only moderately increased, however.25
The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction study used a continuous insulin infusion with subsequent subcutaneous insulin for at least 3 months in diabetic patients admitted with acute myocardial infarction. In this study, which followed patients for several years after hospital discharge, the group that received intensive insulin management had greater long-term survival after myocardial infarction.26,27 It is important to note that more recent trials have not validated this finding, although the Hyperglycemia: Intensive Insulin Infusion in Infarction study did conclude that aggressive glycemic management reduced the incidence of congestive heart failure and repeat myocardial infarction.28-30
Surgical critical-care patients may benefit from intensive insulin therapy targeting a blood glucose range of 80 mg/dL to 110 mg/dL. Investigators conducting a trial comparing intensive insulin therapy with conventional care found that intensive blood glucose-lowering therapy decreased mortality not only during the ICU stay, but also during the hospital stay.31 These investigators completed a similar trial in medical critical-care patients, but even though morbidity was lower, there was no difference in mortality.32 Although studies of cardiac-surgery patients are not as strong, they support using intensive insulin therapy as a means of reducing mortality and the risk of a deep sternal wound infection.33,34
Last year, a meta-analysis of 29 studies of critically ill patients concluded that tight glycemic control was not beneficial for lowering mortality, but that it did reduce the risk of septicemia. Although the studies in the meta-analysis used a blood glucose target of 80 mg/dL to 110 mg/dL, studies with a higher range were included, and the results have experts reevaluating glucose targets in critically ill patients.35
Goals of Therapy and Treatment
Practice guidelines published by both the American Association of Clinical Endocrinologists (AACE) and the ADA address the management of hyperglycemia in hospitalized patients.2,36 Since hyperglycemia is detrimental to both patients with preexisting diabetes and those who develop hyperglycemia with acute illness, appropriate management is crucial. Besides specifying target blood glucose ranges, the guidelines outline measures for improving quality of care in patients with hyperglycemia.2,36
There are subtle differences between the two sets of guidelines in the recommended target glucose ranges. The AACE recommendations are listed in TABLE 1.36 Target levels recommended in the January 2009 ADA guidelines (TABLE 2) reflect newer evidence, since the AACE guidelines were published in 2007.2 For example, given recent study results showing that the lower blood glucose range may not be beneficial for nonsurgical critical-care patients, the ADA guidelines suggest maintaining blood glucose levels at less than 140 mg/dL.2
Insulin is the cornerstone of hyperglycemia management in hospitalized patients. Noninsulin agents are of limited use in the inpatient setting, and no studies have evaluated their use in relation to outcomes in hospitalized patients.2 In critically ill patients, a continuous insulin infusion using regular insulin should be initiated. Although there are many insulin protocols, no comparison of protocols exists; therefore, the ideal protocol not only attains goal blood glucose levels, but also minimizes hypoglycemia and ensures patient safety.2 Patients outside the critical-care setting may be managed with subcutaneous insulin. Using short-acting insulin on a sliding scale as the sole treatment for hyperglycemia is ineffective, reactive, and potentially harmful.2,36 Rather, patients should be treated with a basal dose of long-acting insulin that mimics physiologic production, with doses of shorter-acting insulin timed to be given with meals or carbohydrate intake. Correction doses of short or rapid-acting insulin, typically given as needed just before meals, are recommended to correct premeal hyperglycemia not managed by the standing basal and prandial doses.2,36
An interdisciplinary approach with attention to detail helps ensure individualized therapy that reaches the patient's treatment goals. Both the AACE and ADA guidelines emphasize the need to clearly mark the medical records of all patients with known diabetes.2,36 They also stress the importance of access to current blood glucose values, as well as recent glycosylated hemoglobin results, for all health care professionals caring for patients.2,36 Additionally, the guidelines call for proactively establishing a plan to treat hypoglycemia to help prevent complications associated with managing hyperglycemia.2,36 Patient education, particularly at the time of hospital discharge, is a key recommendation to facilitate a patient's transition to the outpatient setting with the basic knowledge necessary to safely care for himself or herself until more in-depth diabetes education can be administered.2
Conclusion
Historically, the management of hyperglycemia in hospitalized patients has not been a priority. As recent studies show, however, good glycemic control reduces complications in both diabetic and nondiabetic patients who experience hyperglycemia. Pharmacists play an integral role in improving patient outcomes with regard to glycemic control. Whether through patient education or developing policies and protocols that facilitate optimal treatment, the evidence is clear that pharmacists must work proactively to ensure patient safety and maximize good outcomes in the care of patients with hyperglycemia.
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