Alpesh Amin, MD, MBA

Medical centers are faced with multiple competing priorities when deciding how to focus their improvement efforts and meet the ever expanding menu of publicly reported and regulatory issues. In this article we expand on the rationale for supporting inpatient glycemic control programs as a priority that should be moved near the top of the list. We review the evidence for establishing glycemic range targets, and also review the limitations of this evidence, acknowledging, as does the American Diabetes Association (ADA), that in both the critical care and non‐critical care venue, glycemic goals must take into account the individual patient's situation as well as hospital system support for achieving these goals.1, 2 We emphasize that inpatient glycemic control programs are needed to address a wide variety of quality and safety issues surrounding the care of the inpatient with diabetes and hyperglycemia, and we wish to elevate the dialogue beyond arguments surrounding adoption of one glycemic target versus another. The Society of Hospital Medicine Glycemic Control Task Force members are not in unanimous agreement with the American Association of Clinical Endocrinologists (AACE)/ADA inpatient glycemic targets. However, we do agree on several other important points, which we will expand on in this article:

• 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.

DIABETES AND HYPERGLYCEMIA ARE VERY COMMON INPATIENT CONDITIONS

Diabetes mellitus (DM) has reached epidemic proportions in the United States. A reported 9.3% of adults over 20 years of age have diabetes, representing over 20 million persons. Despite increasing awareness, diabetes remains undiagnosed in approximately 30% of these persons.3 Concurrent with the increasing prevalence of diabetes in the U.S. population from 1980 through 2003, the number of hospital discharges with diabetes as any listed diagnosis more than doubled, going from 2.2 to 5.1 million discharges.4 Hospital care for patients with diabetes and hyperglycemia poses a significant health economic burden in the United States, representing over 40 billion dollars in annual direct medical expenditures.5

Hyperglycemia in the hospital may be due to known diabetes, to previously unrecognized diabetes, to prediabetes, and/or to the stress of surgery or illness. Deterioration in glycemic control in the hospital setting is most commonly associated with one or more factors, including stress‐induced release of insulin counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone), exogenous administration of high dose glucocorticoids, and suboptimal glycemic management strategies.68 In a Belgian medical intensive care unit (MICU) randomized controlled trial (RCT) of strict versus conventional glycemic control, mean blood glucose (BG) on admission to the unit in the intention to treat group was 162 70 mg/dL (n = 1200),9 and in this group's RCT of 1548 surgical intensive care unit (SICU) patients, BG > 110 mg/dL was observed in over 70% of subjects.10 Mean BG of >145 mg/dL has been reported in 39%11 and BG >200 mg/dL in anywhere from 11% to 31% of intensive care unit (ICU) patients.10, 12 For general medicine and surgery, 1 study of 2030 patients admitted to a teaching hospital revealed that 26% of admissions had a known history of DM and 12% had new hyperglycemia, as evidenced by an admission or in‐hospital fasting BG of 126 mg/dL or more or a random BG of 200 mg/dL or more on 2 or more determinations.13 National and regional estimates on hospital use maintained by the Agency for Healthcare Research and Quality include data concerning diabetes diagnoses alone, without hyperglycemia, and may be displayed by querying its Web site.14 In cardiovascular populations almost 70% of patients having a first myocardial infarction have been reported to have either known DM, previously unrecognized diabetes, or impaired glucose tolerance.15

THE EVIDENCE SUPPORTS INPATIENT GLYCEMIC CONTROL

INPATIENT GLYCEMIC CONTROL IS INCREASINGLY INCORPORATED INTO PUBLIC REPORTING, GUIDELINES, REGULATORY AGENCY, AND NATIONAL QUALITY INITIATIVE PRIORITIES

National quality initiatives, public reporting, pay‐for‐performance, and guideline‐based care continue to play an increasingly important role in the U.S. healthcare system. Over the years these initiatives have focused on various disease states (venous thromboembolism, congestive heart failure, community‐acquired pneumonia, etc.) in an attempt to standardize care and improve patient safety and quality. Inpatient hyperglycemic control is also increasingly being incorporated into public reporting, regulatory compliance, and national quality initiatives.

Professional organizations such as the ADA2 and AACE50 have published guidelines supporting improved glycemic control, the safe use of insulin, and other measures to improve care for hyperglycemic inpatients. The AACE has a Web site dedicated to hospital hyperglycemia.52 The Society of Hospital Medicine48 has created a resource room on its Web site and a workbook for improvement49 on optimizing the care of inpatients with hyperglycemia and diabetes. The guidelines and Web sites help raise awareness and educate physicians and healthcare workers in inpatient glucose management. The American Heart Association has incorporated specific recommendation regarding inpatient diabetic management in its Get With the Guidelines.53

The Joint Commission54 has developed an advanced disease‐specific certification on inpatient diabetes. Disease management programs are important components of complex healthcare systems that serve to coordinate chronic care, promote early detection and prevention, and reduce overall healthcare costs. Certification is increasingly important to providers, payers, and healthcare institutions because it demonstrates a commitment to quality and patient safety. The Joint Commission disease‐specific care certification is a patient‐centered model focusing on the delivery of clinical care and relationship between the practitioner and the patient. The evaluation and resulting certification by the Joint Commission is based on 3 core components: (1) an assessment of compliance with consensus‐based national standards; (2) the effective use of established clinical practice guidelines to manage and optimize care; and (3) an organized approach to performance measurement and improved activities.55 For inpatient diabetes, the Joint Commission program has 7 major elements following the ADA recommendations, including general recommendations regarding diabetic documentation, BG targets, preventing hypoglycemia, diabetes care providers, diabetes self‐management education, medical nutrition therapy, and BG monitoring.54 This mirrors the Call to Action Consensus Conference essential elements for successful glycemic control programs.1

Other organizations such as the Surgical Care Improvement Partnership (SCIP) and National Surgical Quality Improvement Program (NSQIP) have included perioperative glycemic control measures, as it impacts surgical wound infections. The University HealthSystem Consortium (UHC) has benchmarking data and endorses perioperative glycemic control measures, whereas the Institute for Healthcare Improvement (IHI) has focused on safe use of insulin practices in its 5 Million Lives campaign.

HOSPITALIZATION IS A MOMENT OF OPPORTUNITY TO ASSESS AND INTERVENE

The benefits of outpatient glycemic control and quality preventive care are well established, and the reduction of adverse consequences of uncontrolled diabetes are a high priority in ambulatory medicine.5658 Hospitalization provides an opportunity to identify previously undiagnosed diabetes or prediabetes and, for patients with known diabetes, to assess and impact upon the long term course of diabetes.

As a first step, unless a recent hemoglobin A1C (HbA1c) is known, among hospitalized hyperglycemic patients an HbA1C should be obtained upon admission. Greci et al.59 showed that an HbA1c level >6.0% was 100% specific (14/14) and 57% sensitive (12/21) for the diagnosis of diabetes. Among patients having known diabetes, an HbA1C elevation on admission may justify intensification of preadmission management at the time of discharge. If discharge and postdischarge adjustments of preadmission regimens are planned in response to admission A1C elevations, then the modified long‐term treatment strategy can improve the A1C in the ambulatory setting.60 Moreover, the event of hospitalization is the ideal teachable moment for patients and their caregivers to improve self‐care activities. Yet floor nurses may be overwhelmed by the tasks of patient education. For ideal patient education, both a nutritionist and a diabetes nurse educator are needed to assess compliance with medication, diet, and other aspects of care.6163 There also is need for outpatient follow‐up education. Finally, at the time of discharge, there is a duty and an opportunity for the diabetes provider to communicate with outpatient care providers about the patient's regimen and glycemic control, and also, based on information gathered during the admission, to convey any evidence that might support the need for a change of long‐term strategy.64 Unfortunately, the opportunity that hospitalization presents to assess, educate, and intervene frequently is underused.1, 8, 51, 65

LARGE GAPS EXIST BETWEEN CURRENT AND OPTIMAL CARE

Despite the evidence that inpatient glycemic control is important for patient outcomes, and despite guidelines recommending tighter inpatient glycemic control, clinical practice has been slow to change. In many institutions, inpatient glycemic management has not improved over the past decade, and large gaps remain between current practice and optimal practice.

Studies of individual institutions provide several insights into gaps in care. For example, Schnipper et al.66 examined practices on the general medicine service of an academic medical center in Boston in 2004. Among 107 prospectively identified patients with a known diagnosis of diabetes or at least 1 glucose reading >200 mg/dL (excluding patients with diabetic ketoacidosis, hyperglycemic hyperosmolar state, or pregnancy), they found scheduled long‐acting insulin prescribed in 43% of patients, scheduled short‐acting/rapid‐acting insulin in only 4% of patients, and 80 of 89 patients (90%) on the same sliding scale insulin regimen despite widely varying insulin requirements. Thirty‐one percent of glucose readings were >180 mg/dL compared with 1.2% of readings <60 mg/dL (but 11% of patients had at least 1 episode of hypoglycemia). Of the 75 patients with at least 1 episode of hyperglycemia or hypoglycemia, only 35% had any change to their insulin regimen during the first 5 days of the hospitalization.

Other studies have confirmed this concept of clinical inertia (ie, recognition of the problem but failure to act).67 A study by Cook et al.68 of all hospitalized non‐ICU patients with diabetes or hyperglycemia and length of stay of 3 days between 2001 and 2004 showed that 20% of patients had persistent hyperglycemia during the hospitalization (defined as a mean glucose >200 mg/dL). Forty‐six percent of patients whose average glucose was in the top tertile did not have their insulin regimen intensified to a combination of short‐acting/rapid‐acting and long‐acting insulin, and 35% of these patients either had no change in their total daily insulin dose or actually had a decrease in their dose when comparing the last 24 hours with the first 24 hours of hospitalization, a concept they term negative therapeutic momentum.

Perhaps the most well‐balanced view of the current state of medical practice comes from the UHC benchmarking project.69 UHC is an alliance of 90 academic health centers. For the diabetes project, each institution reviewed the records of 50 randomly selected patients over 18 years of age with at least a 72‐hour length of stay, 1 of 7 prespecified Diagnosis Related Group (DRG) codes, and at least 2 consecutive glucose readings >180 mg/dL or the receipt of insulin any time during the hospitalization. Patients with a history of pancreatic transplant, pregnant at the time of admission, receiving hospice or comfort care, or receiving insulin for a reason other than glucose management were excluded. The study showed widespread gaps in processes and outcomes (Table 1). Moreover, performance varied widely across hospitals. For example, the morning glucose in the ICU on the second measurement day was 110 mg/dL in 18% of patients for the median‐performing hospital, with a range of 0% to 67% across all 37 measured hospitals. In the non‐ICU setting on the second measurement day, 26% of patients had all BG measurements = 180 mg/dL in the median‐performing hospital, with a range of 7% to 48%. Of note, hypoglycemia was relatively uncommon: in the median hospital, 2.4% of patient‐days had 1 or more BG readings <50 mg/dL (range: 0%8.6%). Finally, in the median‐performing hospital, effective insulin therapy (defined as short‐acting/rapid‐acting and long‐acting subcutaneous insulin, continuous insulin infusion, or subcutaneous insulin pump therapy) was prescribed in 45% of patients, with a range of 12% to 77% across measured hospitals.

FREQUENT PROBLEMS WITH COMMUNICATION AND COORDINATION

Those who work closely with frontline practitioners striving to improve inpatient glycemic management have noticed other deficiencies in care.1, 70 These include: a lack of coordination between feeding, BG measurement, and insulin administration, leading to mistimed and incorrectly dosed insulin; frequent use of sliding‐scale only regimens despite evidence that they are useless at best and harmful at worst;6, 47, 60, 71 discharge summaries that often do not mention follow‐up plans for hyperglycemic management; incomplete patient educational programs; breakdowns in care at transition points; nursing and medical staffs that are unevenly educated about the proper use of insulin; and patients who are often angry or confused about their diabetes care in the hospital. Collectively, these gaps in care serve as prime targets for any glycemic control program.

HYPOGLYCEMIA IS A PROMINENT INPATIENT SAFETY CONCERN

Hypoglycemia is common in the inpatient setting and is a legitimate safety concern. In a recently reported series of 2174 hospitalized patients receiving antihyperglycemic agents, it was found that 9.5% of patients experienced a total 484 hypoglycemic episodes (defined as 60 mg/dL).72 Hypoglycemia often occurred in the setting of insulin therapy and frequently resulted from a failure to recognize trends in BG readings or other clues that a patient was at risk for developing hypoglycemia.73 A common thread is the risk created by interruption of carbohydrate intake, noted by Fischer et al.73 and once again in the recent ICU study by Vriesendorp et al.74 Sources of error include: lack of coordination between feeding and medication administration, leading to mistiming of insulin action; lack of sufficient frequency in BG monitoring; lack of clarity or uniformity in the writing of orders; failure to recognize changes in insulin requirements due to advanced age, renal failure, liver disease, or change in clinical status; steroid use with subsequent tapering or interruption; changes in feeding; failure to reconcile medications; inappropriate use of oral antihyperglycemic agents, and communication or handoff failures.

It has been difficult to sort out whether hypoglycemia is a marker of severity of illness or whether it is an independent factor leading to poor outcomes. Observational studies lend credibility to the concept that patients having congestive heart failure or myocardial infarction may be at risk for excessive mortality if their average BG resides in the low end of the normal range.7578 Sympathetic activation occurs as the threshold for hypoglycemia is approached, such as occurs at BG = 70 or 72 mg/dL.79 Patients living with BG levels observed to be in the low end of the normal range might experience more severe but unobserved and undocumented episodes of neuroglycopenia. Arrhythmia and fatality have been directly attributed to strict glycemic control.80, 81 We are confronted with the need to interpret well conducted observational studies, evaluating subgroups at risk, and using multivariate analysis to assess the impact of hypoglycemia upon outcomes.82 In such studies, we will need to examine high‐risk subgroups, including cardiac patients, in particular, for the possibility that there is a J‐shaped curve for mortality as a function of average BG.

Unfortunately, clinical inertia exists in response to hypoglycemia just as it does with hyperglycemia. One recent study examined 52 patients who received intravenous 50% dextrose solution for an episode of hypoglycemia.83 Changes to insulin regimens were subsequently made in only 21 patients (40%), and diabetes specialists agreed with the changes for 11 of these patients. The other 31 patients (60%) received no changes in treatment, and diabetes specialists agreed with that decision for only 10 of these patients.

Although some increase in hypoglycemia might be expected with initiation of tight glycemic control efforts, the solution is not to undertreat hyperglycemia. Hyperglycemia creates an unsafe setting for the treatment of illness and disease. Sliding‐scaleonly regimens are ineffective in securing glycemic control and can result in increases in hypoglycemia as well as hyperglycemic excursions.6, 66 Inappropriate withholding of insulin doses can lead to severe glycemic excursions and even iatrogenic diabetic ketoacidosis (DKA). Systems approaches to avoid the errors outlined above can minimize or even reverse the increased risk of hypoglycemia expected with tighter glycemic targets.51

A SYSTEMS APPROACH IS NEEDED FOR THESE MULTIPLE COMPLEX PROBLEMS

Care is of the hyperglycemic inpatient is inherently complex. Previously established treatments are often inappropriate under conditions of altered insulin resistance, changing patterns of nutrition and carbohydrate exposure, comorbidities, concomitant medications, and rapidly changing medical and surgical status. Patients frequently undergo changes in the route and amount of nutritional exposure, including discrete meals, continuous intravenous dextrose, nil per orem (nothing by mouth status; NPO) status, grazing on nutritional supplements or liquid diets with or without meals, bolus enteral feedings, overnight enteral feedings with daytime grazing, total parenteral nutrition, continuous peritoneal dialysis, and overnight cycling of peritoneal dialysis. Relying on individual expertise and vigilance to negotiate this complex terrain without safeguards, protocols, standardization of orders, and other systems change is impractical and unwise.

Transitions across care providers and locations lead to multiple opportunities for breakdown in the quality, consistency, and safety of care.64, 65 At the time of ward transfer or change of patient status, previous medication and monitoring orders sometimes are purged. At the time of discharge, there may be risk of continuation of anti‐hyperglycemic therapy, initiated to cover medical stress, in doses that will subsequently be unsafe.

In the face of this complexity, educational programs alone will not suffice to improve care. Institutional commitment and systems changes are essential.

MARKED IMPROVEMENT IS POSSIBLE AND TOOLS EXIST: A ROADMAP IS IN PLACE

Fortunately, a roadmap is in place to help us achieve better glycemic control, improve insulin management, and address the long list of current deficiencies in care. This is imperative to develop consistent processes in order to achieve maximum patient quality outcomes that effective glycemic management offers. This roadmap entails 4 components: (1) national awareness, (2) national guidelines, (3) consensus statements, and (4) effective tools. As mentioned above, the first two components of this roadmap are now in place.

As these national guidelines become more widely accepted, the next step will be the incorporation of this into programs like Pay‐for Performance and the Physician Quality Reporting Initiative (PQRI), which will impact reimbursement to both hospitals and providers.

Regarding the third component, a recent multidisciplinary consensus conference1 outlined the essential elements needed for successful implementation of an inpatient glycemic control program which include:

• An appropriate level of administrative support.

• Formation of a multidisciplinary steering committee to drive the development of initiatives and empowered to enact change.

• Assessment of current processes, quality of care, and barriers to practice change.

• Development and implementation of interventions including standardized order sets, protocols, policies and algorithms with associated educational programs.

• Metrics for evaluation of glycemic control, hypoglycemia, insulin use patterns, and other aspects of care.

Finally, extensive resources and effective tools are now available to help institutions achieve better inpatient glucose control. The Society of Hospital Medicine (SHM), in conjunction with the ADA, AACE, the American College of Physicians (ACP), the Case Management Society of America (CMSA), the American Society of Consultant Pharmacists, nursing, and diabetic educators have all partnered to produce a comprehensive guide to effective implementation of glycemic control and preventing hypoglycemia.49 This comprehensive workbook is a proven performance improvement framework and is available on the SHM Web site.48 Details and examples of all essential elements are covered in this workbook along with opportunities for marked improvement bolstered by integration of high reliability design features and attention to effective implementation techniques. The remainder of this supplement crystallizes a substantial portion of this material. The AACE has also recently offered a valuable web‐based resource to encourage institutional glycemic control efforts.49

GLYCEMIC CONTROL INITIATIVES CAN BE COST‐EFFECTIVE

Achieving optimal glycemic control safely requires monitoring, education, and other measures, which can be expensive, labor intensive, and require coordination of the services of many hospital divisions. This incremental expense has been shown to be cost‐effective in a variety of settings.1, 84, 85 The costs of glycemic control initiatives have demonstrated a good return on investment via:

• Improved LOS, readmission rates, morbidity, and mortality.

• Improved documentation of patient acuity and related payment for acuity.

• Income generated via incremental physician and allied health professional billing.

CONCLUSION AND SUMMARY

Evidence exists that appropriate management of hyperglycemia improves outcomes, whereas the current state of affairs is that most medical centers currently manage this suboptimally. This is concerning given the magnitude of diabetes and hyperglycemia in our inpatient setting in the United States. To bring awareness to this issue, multiple initiatives (guidelines, certification programs, workbooks, etc.) are available by various organizations including the ADA, AACE, SCIP, NSQIP, IHI, UHC, the Joint Commission, and SHM. However, this is not enough. Change occurs at the local level, and institutional prioritization and support is needed to empower a multidisciplinary steering committee, with appropriate administrative support, to standardize and improve systems in the face of substantial cultural issues and complex barriers. Improved data collection and reporting, incremental monitoring, creation of metrics, and improved documentation are an absolutely necessary necessity to achieve breakthrough levels of improvement.

Now the time is right to make an assertive effort to improve inpatient glycemic control and related issues, and push for appropriate support at your institution to help achieve this in the interest of patient safety and optimal outcomes.

Medical centers are faced with multiple competing priorities when deciding how to focus their improvement efforts and meet the ever expanding menu of publicly reported and regulatory issues. In this article we expand on the rationale for supporting inpatient glycemic control programs as a priority that should be moved near the top of the list. We review the evidence for establishing glycemic range targets, and also review the limitations of this evidence, acknowledging, as does the American Diabetes Association (ADA), that in both the critical care and non‐critical care venue, glycemic goals must take into account the individual patient's situation as well as hospital system support for achieving these goals.1, 2 We emphasize that inpatient glycemic control programs are needed to address a wide variety of quality and safety issues surrounding the care of the inpatient with diabetes and hyperglycemia, and we wish to elevate the dialogue beyond arguments surrounding adoption of one glycemic target versus another. The Society of Hospital Medicine Glycemic Control Task Force members are not in unanimous agreement with the American Association of Clinical Endocrinologists (AACE)/ADA inpatient glycemic targets. However, we do agree on several other important points, which we will expand on in this article:

• 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.

DIABETES AND HYPERGLYCEMIA ARE VERY COMMON INPATIENT CONDITIONS

Diabetes mellitus (DM) has reached epidemic proportions in the United States. A reported 9.3% of adults over 20 years of age have diabetes, representing over 20 million persons. Despite increasing awareness, diabetes remains undiagnosed in approximately 30% of these persons.3 Concurrent with the increasing prevalence of diabetes in the U.S. population from 1980 through 2003, the number of hospital discharges with diabetes as any listed diagnosis more than doubled, going from 2.2 to 5.1 million discharges.4 Hospital care for patients with diabetes and hyperglycemia poses a significant health economic burden in the United States, representing over 40 billion dollars in annual direct medical expenditures.5

Hyperglycemia in the hospital may be due to known diabetes, to previously unrecognized diabetes, to prediabetes, and/or to the stress of surgery or illness. Deterioration in glycemic control in the hospital setting is most commonly associated with one or more factors, including stress‐induced release of insulin counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone), exogenous administration of high dose glucocorticoids, and suboptimal glycemic management strategies.68 In a Belgian medical intensive care unit (MICU) randomized controlled trial (RCT) of strict versus conventional glycemic control, mean blood glucose (BG) on admission to the unit in the intention to treat group was 162 70 mg/dL (n = 1200),9 and in this group's RCT of 1548 surgical intensive care unit (SICU) patients, BG > 110 mg/dL was observed in over 70% of subjects.10 Mean BG of >145 mg/dL has been reported in 39%11 and BG >200 mg/dL in anywhere from 11% to 31% of intensive care unit (ICU) patients.10, 12 For general medicine and surgery, 1 study of 2030 patients admitted to a teaching hospital revealed that 26% of admissions had a known history of DM and 12% had new hyperglycemia, as evidenced by an admission or in‐hospital fasting BG of 126 mg/dL or more or a random BG of 200 mg/dL or more on 2 or more determinations.13 National and regional estimates on hospital use maintained by the Agency for Healthcare Research and Quality include data concerning diabetes diagnoses alone, without hyperglycemia, and may be displayed by querying its Web site.14 In cardiovascular populations almost 70% of patients having a first myocardial infarction have been reported to have either known DM, previously unrecognized diabetes, or impaired glucose tolerance.15

THE EVIDENCE SUPPORTS INPATIENT GLYCEMIC CONTROL

INPATIENT GLYCEMIC CONTROL IS INCREASINGLY INCORPORATED INTO PUBLIC REPORTING, GUIDELINES, REGULATORY AGENCY, AND NATIONAL QUALITY INITIATIVE PRIORITIES

National quality initiatives, public reporting, pay‐for‐performance, and guideline‐based care continue to play an increasingly important role in the U.S. healthcare system. Over the years these initiatives have focused on various disease states (venous thromboembolism, congestive heart failure, community‐acquired pneumonia, etc.) in an attempt to standardize care and improve patient safety and quality. Inpatient hyperglycemic control is also increasingly being incorporated into public reporting, regulatory compliance, and national quality initiatives.

Professional organizations such as the ADA2 and AACE50 have published guidelines supporting improved glycemic control, the safe use of insulin, and other measures to improve care for hyperglycemic inpatients. The AACE has a Web site dedicated to hospital hyperglycemia.52 The Society of Hospital Medicine48 has created a resource room on its Web site and a workbook for improvement49 on optimizing the care of inpatients with hyperglycemia and diabetes. The guidelines and Web sites help raise awareness and educate physicians and healthcare workers in inpatient glucose management. The American Heart Association has incorporated specific recommendation regarding inpatient diabetic management in its Get With the Guidelines.53

The Joint Commission54 has developed an advanced disease‐specific certification on inpatient diabetes. Disease management programs are important components of complex healthcare systems that serve to coordinate chronic care, promote early detection and prevention, and reduce overall healthcare costs. Certification is increasingly important to providers, payers, and healthcare institutions because it demonstrates a commitment to quality and patient safety. The Joint Commission disease‐specific care certification is a patient‐centered model focusing on the delivery of clinical care and relationship between the practitioner and the patient. The evaluation and resulting certification by the Joint Commission is based on 3 core components: (1) an assessment of compliance with consensus‐based national standards; (2) the effective use of established clinical practice guidelines to manage and optimize care; and (3) an organized approach to performance measurement and improved activities.55 For inpatient diabetes, the Joint Commission program has 7 major elements following the ADA recommendations, including general recommendations regarding diabetic documentation, BG targets, preventing hypoglycemia, diabetes care providers, diabetes self‐management education, medical nutrition therapy, and BG monitoring.54 This mirrors the Call to Action Consensus Conference essential elements for successful glycemic control programs.1

Other organizations such as the Surgical Care Improvement Partnership (SCIP) and National Surgical Quality Improvement Program (NSQIP) have included perioperative glycemic control measures, as it impacts surgical wound infections. The University HealthSystem Consortium (UHC) has benchmarking data and endorses perioperative glycemic control measures, whereas the Institute for Healthcare Improvement (IHI) has focused on safe use of insulin practices in its 5 Million Lives campaign.

HOSPITALIZATION IS A MOMENT OF OPPORTUNITY TO ASSESS AND INTERVENE

The benefits of outpatient glycemic control and quality preventive care are well established, and the reduction of adverse consequences of uncontrolled diabetes are a high priority in ambulatory medicine.5658 Hospitalization provides an opportunity to identify previously undiagnosed diabetes or prediabetes and, for patients with known diabetes, to assess and impact upon the long term course of diabetes.

As a first step, unless a recent hemoglobin A1C (HbA1c) is known, among hospitalized hyperglycemic patients an HbA1C should be obtained upon admission. Greci et al.59 showed that an HbA1c level >6.0% was 100% specific (14/14) and 57% sensitive (12/21) for the diagnosis of diabetes. Among patients having known diabetes, an HbA1C elevation on admission may justify intensification of preadmission management at the time of discharge. If discharge and postdischarge adjustments of preadmission regimens are planned in response to admission A1C elevations, then the modified long‐term treatment strategy can improve the A1C in the ambulatory setting.60 Moreover, the event of hospitalization is the ideal teachable moment for patients and their caregivers to improve self‐care activities. Yet floor nurses may be overwhelmed by the tasks of patient education. For ideal patient education, both a nutritionist and a diabetes nurse educator are needed to assess compliance with medication, diet, and other aspects of care.6163 There also is need for outpatient follow‐up education. Finally, at the time of discharge, there is a duty and an opportunity for the diabetes provider to communicate with outpatient care providers about the patient's regimen and glycemic control, and also, based on information gathered during the admission, to convey any evidence that might support the need for a change of long‐term strategy.64 Unfortunately, the opportunity that hospitalization presents to assess, educate, and intervene frequently is underused.1, 8, 51, 65

LARGE GAPS EXIST BETWEEN CURRENT AND OPTIMAL CARE

Despite the evidence that inpatient glycemic control is important for patient outcomes, and despite guidelines recommending tighter inpatient glycemic control, clinical practice has been slow to change. In many institutions, inpatient glycemic management has not improved over the past decade, and large gaps remain between current practice and optimal practice.

Studies of individual institutions provide several insights into gaps in care. For example, Schnipper et al.66 examined practices on the general medicine service of an academic medical center in Boston in 2004. Among 107 prospectively identified patients with a known diagnosis of diabetes or at least 1 glucose reading >200 mg/dL (excluding patients with diabetic ketoacidosis, hyperglycemic hyperosmolar state, or pregnancy), they found scheduled long‐acting insulin prescribed in 43% of patients, scheduled short‐acting/rapid‐acting insulin in only 4% of patients, and 80 of 89 patients (90%) on the same sliding scale insulin regimen despite widely varying insulin requirements. Thirty‐one percent of glucose readings were >180 mg/dL compared with 1.2% of readings <60 mg/dL (but 11% of patients had at least 1 episode of hypoglycemia). Of the 75 patients with at least 1 episode of hyperglycemia or hypoglycemia, only 35% had any change to their insulin regimen during the first 5 days of the hospitalization.

Other studies have confirmed this concept of clinical inertia (ie, recognition of the problem but failure to act).67 A study by Cook et al.68 of all hospitalized non‐ICU patients with diabetes or hyperglycemia and length of stay of 3 days between 2001 and 2004 showed that 20% of patients had persistent hyperglycemia during the hospitalization (defined as a mean glucose >200 mg/dL). Forty‐six percent of patients whose average glucose was in the top tertile did not have their insulin regimen intensified to a combination of short‐acting/rapid‐acting and long‐acting insulin, and 35% of these patients either had no change in their total daily insulin dose or actually had a decrease in their dose when comparing the last 24 hours with the first 24 hours of hospitalization, a concept they term negative therapeutic momentum.

Perhaps the most well‐balanced view of the current state of medical practice comes from the UHC benchmarking project.69 UHC is an alliance of 90 academic health centers. For the diabetes project, each institution reviewed the records of 50 randomly selected patients over 18 years of age with at least a 72‐hour length of stay, 1 of 7 prespecified Diagnosis Related Group (DRG) codes, and at least 2 consecutive glucose readings >180 mg/dL or the receipt of insulin any time during the hospitalization. Patients with a history of pancreatic transplant, pregnant at the time of admission, receiving hospice or comfort care, or receiving insulin for a reason other than glucose management were excluded. The study showed widespread gaps in processes and outcomes (Table 1). Moreover, performance varied widely across hospitals. For example, the morning glucose in the ICU on the second measurement day was 110 mg/dL in 18% of patients for the median‐performing hospital, with a range of 0% to 67% across all 37 measured hospitals. In the non‐ICU setting on the second measurement day, 26% of patients had all BG measurements = 180 mg/dL in the median‐performing hospital, with a range of 7% to 48%. Of note, hypoglycemia was relatively uncommon: in the median hospital, 2.4% of patient‐days had 1 or more BG readings <50 mg/dL (range: 0%8.6%). Finally, in the median‐performing hospital, effective insulin therapy (defined as short‐acting/rapid‐acting and long‐acting subcutaneous insulin, continuous insulin infusion, or subcutaneous insulin pump therapy) was prescribed in 45% of patients, with a range of 12% to 77% across measured hospitals.

FREQUENT PROBLEMS WITH COMMUNICATION AND COORDINATION

Those who work closely with frontline practitioners striving to improve inpatient glycemic management have noticed other deficiencies in care.1, 70 These include: a lack of coordination between feeding, BG measurement, and insulin administration, leading to mistimed and incorrectly dosed insulin; frequent use of sliding‐scale only regimens despite evidence that they are useless at best and harmful at worst;6, 47, 60, 71 discharge summaries that often do not mention follow‐up plans for hyperglycemic management; incomplete patient educational programs; breakdowns in care at transition points; nursing and medical staffs that are unevenly educated about the proper use of insulin; and patients who are often angry or confused about their diabetes care in the hospital. Collectively, these gaps in care serve as prime targets for any glycemic control program.

HYPOGLYCEMIA IS A PROMINENT INPATIENT SAFETY CONCERN

Hypoglycemia is common in the inpatient setting and is a legitimate safety concern. In a recently reported series of 2174 hospitalized patients receiving antihyperglycemic agents, it was found that 9.5% of patients experienced a total 484 hypoglycemic episodes (defined as 60 mg/dL).72 Hypoglycemia often occurred in the setting of insulin therapy and frequently resulted from a failure to recognize trends in BG readings or other clues that a patient was at risk for developing hypoglycemia.73 A common thread is the risk created by interruption of carbohydrate intake, noted by Fischer et al.73 and once again in the recent ICU study by Vriesendorp et al.74 Sources of error include: lack of coordination between feeding and medication administration, leading to mistiming of insulin action; lack of sufficient frequency in BG monitoring; lack of clarity or uniformity in the writing of orders; failure to recognize changes in insulin requirements due to advanced age, renal failure, liver disease, or change in clinical status; steroid use with subsequent tapering or interruption; changes in feeding; failure to reconcile medications; inappropriate use of oral antihyperglycemic agents, and communication or handoff failures.

It has been difficult to sort out whether hypoglycemia is a marker of severity of illness or whether it is an independent factor leading to poor outcomes. Observational studies lend credibility to the concept that patients having congestive heart failure or myocardial infarction may be at risk for excessive mortality if their average BG resides in the low end of the normal range.7578 Sympathetic activation occurs as the threshold for hypoglycemia is approached, such as occurs at BG = 70 or 72 mg/dL.79 Patients living with BG levels observed to be in the low end of the normal range might experience more severe but unobserved and undocumented episodes of neuroglycopenia. Arrhythmia and fatality have been directly attributed to strict glycemic control.80, 81 We are confronted with the need to interpret well conducted observational studies, evaluating subgroups at risk, and using multivariate analysis to assess the impact of hypoglycemia upon outcomes.82 In such studies, we will need to examine high‐risk subgroups, including cardiac patients, in particular, for the possibility that there is a J‐shaped curve for mortality as a function of average BG.

Unfortunately, clinical inertia exists in response to hypoglycemia just as it does with hyperglycemia. One recent study examined 52 patients who received intravenous 50% dextrose solution for an episode of hypoglycemia.83 Changes to insulin regimens were subsequently made in only 21 patients (40%), and diabetes specialists agreed with the changes for 11 of these patients. The other 31 patients (60%) received no changes in treatment, and diabetes specialists agreed with that decision for only 10 of these patients.

Although some increase in hypoglycemia might be expected with initiation of tight glycemic control efforts, the solution is not to undertreat hyperglycemia. Hyperglycemia creates an unsafe setting for the treatment of illness and disease. Sliding‐scaleonly regimens are ineffective in securing glycemic control and can result in increases in hypoglycemia as well as hyperglycemic excursions.6, 66 Inappropriate withholding of insulin doses can lead to severe glycemic excursions and even iatrogenic diabetic ketoacidosis (DKA). Systems approaches to avoid the errors outlined above can minimize or even reverse the increased risk of hypoglycemia expected with tighter glycemic targets.51

A SYSTEMS APPROACH IS NEEDED FOR THESE MULTIPLE COMPLEX PROBLEMS

Care is of the hyperglycemic inpatient is inherently complex. Previously established treatments are often inappropriate under conditions of altered insulin resistance, changing patterns of nutrition and carbohydrate exposure, comorbidities, concomitant medications, and rapidly changing medical and surgical status. Patients frequently undergo changes in the route and amount of nutritional exposure, including discrete meals, continuous intravenous dextrose, nil per orem (nothing by mouth status; NPO) status, grazing on nutritional supplements or liquid diets with or without meals, bolus enteral feedings, overnight enteral feedings with daytime grazing, total parenteral nutrition, continuous peritoneal dialysis, and overnight cycling of peritoneal dialysis. Relying on individual expertise and vigilance to negotiate this complex terrain without safeguards, protocols, standardization of orders, and other systems change is impractical and unwise.

Transitions across care providers and locations lead to multiple opportunities for breakdown in the quality, consistency, and safety of care.64, 65 At the time of ward transfer or change of patient status, previous medication and monitoring orders sometimes are purged. At the time of discharge, there may be risk of continuation of anti‐hyperglycemic therapy, initiated to cover medical stress, in doses that will subsequently be unsafe.

In the face of this complexity, educational programs alone will not suffice to improve care. Institutional commitment and systems changes are essential.

MARKED IMPROVEMENT IS POSSIBLE AND TOOLS EXIST: A ROADMAP IS IN PLACE

Fortunately, a roadmap is in place to help us achieve better glycemic control, improve insulin management, and address the long list of current deficiencies in care. This is imperative to develop consistent processes in order to achieve maximum patient quality outcomes that effective glycemic management offers. This roadmap entails 4 components: (1) national awareness, (2) national guidelines, (3) consensus statements, and (4) effective tools. As mentioned above, the first two components of this roadmap are now in place.

As these national guidelines become more widely accepted, the next step will be the incorporation of this into programs like Pay‐for Performance and the Physician Quality Reporting Initiative (PQRI), which will impact reimbursement to both hospitals and providers.

Regarding the third component, a recent multidisciplinary consensus conference1 outlined the essential elements needed for successful implementation of an inpatient glycemic control program which include:

• An appropriate level of administrative support.

• Formation of a multidisciplinary steering committee to drive the development of initiatives and empowered to enact change.

• Assessment of current processes, quality of care, and barriers to practice change.

• Development and implementation of interventions including standardized order sets, protocols, policies and algorithms with associated educational programs.

• Metrics for evaluation of glycemic control, hypoglycemia, insulin use patterns, and other aspects of care.

Finally, extensive resources and effective tools are now available to help institutions achieve better inpatient glucose control. The Society of Hospital Medicine (SHM), in conjunction with the ADA, AACE, the American College of Physicians (ACP), the Case Management Society of America (CMSA), the American Society of Consultant Pharmacists, nursing, and diabetic educators have all partnered to produce a comprehensive guide to effective implementation of glycemic control and preventing hypoglycemia.49 This comprehensive workbook is a proven performance improvement framework and is available on the SHM Web site.48 Details and examples of all essential elements are covered in this workbook along with opportunities for marked improvement bolstered by integration of high reliability design features and attention to effective implementation techniques. The remainder of this supplement crystallizes a substantial portion of this material. The AACE has also recently offered a valuable web‐based resource to encourage institutional glycemic control efforts.49

GLYCEMIC CONTROL INITIATIVES CAN BE COST‐EFFECTIVE

Achieving optimal glycemic control safely requires monitoring, education, and other measures, which can be expensive, labor intensive, and require coordination of the services of many hospital divisions. This incremental expense has been shown to be cost‐effective in a variety of settings.1, 84, 85 The costs of glycemic control initiatives have demonstrated a good return on investment via:

• Improved LOS, readmission rates, morbidity, and mortality.

• Improved documentation of patient acuity and related payment for acuity.

• Income generated via incremental physician and allied health professional billing.

CONCLUSION AND SUMMARY

Evidence exists that appropriate management of hyperglycemia improves outcomes, whereas the current state of affairs is that most medical centers currently manage this suboptimally. This is concerning given the magnitude of diabetes and hyperglycemia in our inpatient setting in the United States. To bring awareness to this issue, multiple initiatives (guidelines, certification programs, workbooks, etc.) are available by various organizations including the ADA, AACE, SCIP, NSQIP, IHI, UHC, the Joint Commission, and SHM. However, this is not enough. Change occurs at the local level, and institutional prioritization and support is needed to empower a multidisciplinary steering committee, with appropriate administrative support, to standardize and improve systems in the face of substantial cultural issues and complex barriers. Improved data collection and reporting, incremental monitoring, creation of metrics, and improved documentation are an absolutely necessary necessity to achieve breakthrough levels of improvement.

Now the time is right to make an assertive effort to improve inpatient glycemic control and related issues, and push for appropriate support at your institution to help achieve this in the interest of patient safety and optimal outcomes.

Medical centers are faced with multiple competing priorities when deciding how to focus their improvement efforts and meet the ever expanding menu of publicly reported and regulatory issues. In this article we expand on the rationale for supporting inpatient glycemic control programs as a priority that should be moved near the top of the list. We review the evidence for establishing glycemic range targets, and also review the limitations of this evidence, acknowledging, as does the American Diabetes Association (ADA), that in both the critical care and non‐critical care venue, glycemic goals must take into account the individual patient's situation as well as hospital system support for achieving these goals.1, 2 We emphasize that inpatient glycemic control programs are needed to address a wide variety of quality and safety issues surrounding the care of the inpatient with diabetes and hyperglycemia, and we wish to elevate the dialogue beyond arguments surrounding adoption of one glycemic target versus another. The Society of Hospital Medicine Glycemic Control Task Force members are not in unanimous agreement with the American Association of Clinical Endocrinologists (AACE)/ADA inpatient glycemic targets. However, we do agree on several other important points, which we will expand on in this article:

• 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.

DIABETES AND HYPERGLYCEMIA ARE VERY COMMON INPATIENT CONDITIONS

Diabetes mellitus (DM) has reached epidemic proportions in the United States. A reported 9.3% of adults over 20 years of age have diabetes, representing over 20 million persons. Despite increasing awareness, diabetes remains undiagnosed in approximately 30% of these persons.3 Concurrent with the increasing prevalence of diabetes in the U.S. population from 1980 through 2003, the number of hospital discharges with diabetes as any listed diagnosis more than doubled, going from 2.2 to 5.1 million discharges.4 Hospital care for patients with diabetes and hyperglycemia poses a significant health economic burden in the United States, representing over 40 billion dollars in annual direct medical expenditures.5

Hyperglycemia in the hospital may be due to known diabetes, to previously unrecognized diabetes, to prediabetes, and/or to the stress of surgery or illness. Deterioration in glycemic control in the hospital setting is most commonly associated with one or more factors, including stress‐induced release of insulin counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone), exogenous administration of high dose glucocorticoids, and suboptimal glycemic management strategies.68 In a Belgian medical intensive care unit (MICU) randomized controlled trial (RCT) of strict versus conventional glycemic control, mean blood glucose (BG) on admission to the unit in the intention to treat group was 162 70 mg/dL (n = 1200),9 and in this group's RCT of 1548 surgical intensive care unit (SICU) patients, BG > 110 mg/dL was observed in over 70% of subjects.10 Mean BG of >145 mg/dL has been reported in 39%11 and BG >200 mg/dL in anywhere from 11% to 31% of intensive care unit (ICU) patients.10, 12 For general medicine and surgery, 1 study of 2030 patients admitted to a teaching hospital revealed that 26% of admissions had a known history of DM and 12% had new hyperglycemia, as evidenced by an admission or in‐hospital fasting BG of 126 mg/dL or more or a random BG of 200 mg/dL or more on 2 or more determinations.13 National and regional estimates on hospital use maintained by the Agency for Healthcare Research and Quality include data concerning diabetes diagnoses alone, without hyperglycemia, and may be displayed by querying its Web site.14 In cardiovascular populations almost 70% of patients having a first myocardial infarction have been reported to have either known DM, previously unrecognized diabetes, or impaired glucose tolerance.15

THE EVIDENCE SUPPORTS INPATIENT GLYCEMIC CONTROL

INPATIENT GLYCEMIC CONTROL IS INCREASINGLY INCORPORATED INTO PUBLIC REPORTING, GUIDELINES, REGULATORY AGENCY, AND NATIONAL QUALITY INITIATIVE PRIORITIES

National quality initiatives, public reporting, pay‐for‐performance, and guideline‐based care continue to play an increasingly important role in the U.S. healthcare system. Over the years these initiatives have focused on various disease states (venous thromboembolism, congestive heart failure, community‐acquired pneumonia, etc.) in an attempt to standardize care and improve patient safety and quality. Inpatient hyperglycemic control is also increasingly being incorporated into public reporting, regulatory compliance, and national quality initiatives.

Professional organizations such as the ADA2 and AACE50 have published guidelines supporting improved glycemic control, the safe use of insulin, and other measures to improve care for hyperglycemic inpatients. The AACE has a Web site dedicated to hospital hyperglycemia.52 The Society of Hospital Medicine48 has created a resource room on its Web site and a workbook for improvement49 on optimizing the care of inpatients with hyperglycemia and diabetes. The guidelines and Web sites help raise awareness and educate physicians and healthcare workers in inpatient glucose management. The American Heart Association has incorporated specific recommendation regarding inpatient diabetic management in its Get With the Guidelines.53

The Joint Commission54 has developed an advanced disease‐specific certification on inpatient diabetes. Disease management programs are important components of complex healthcare systems that serve to coordinate chronic care, promote early detection and prevention, and reduce overall healthcare costs. Certification is increasingly important to providers, payers, and healthcare institutions because it demonstrates a commitment to quality and patient safety. The Joint Commission disease‐specific care certification is a patient‐centered model focusing on the delivery of clinical care and relationship between the practitioner and the patient. The evaluation and resulting certification by the Joint Commission is based on 3 core components: (1) an assessment of compliance with consensus‐based national standards; (2) the effective use of established clinical practice guidelines to manage and optimize care; and (3) an organized approach to performance measurement and improved activities.55 For inpatient diabetes, the Joint Commission program has 7 major elements following the ADA recommendations, including general recommendations regarding diabetic documentation, BG targets, preventing hypoglycemia, diabetes care providers, diabetes self‐management education, medical nutrition therapy, and BG monitoring.54 This mirrors the Call to Action Consensus Conference essential elements for successful glycemic control programs.1

Other organizations such as the Surgical Care Improvement Partnership (SCIP) and National Surgical Quality Improvement Program (NSQIP) have included perioperative glycemic control measures, as it impacts surgical wound infections. The University HealthSystem Consortium (UHC) has benchmarking data and endorses perioperative glycemic control measures, whereas the Institute for Healthcare Improvement (IHI) has focused on safe use of insulin practices in its 5 Million Lives campaign.

HOSPITALIZATION IS A MOMENT OF OPPORTUNITY TO ASSESS AND INTERVENE

The benefits of outpatient glycemic control and quality preventive care are well established, and the reduction of adverse consequences of uncontrolled diabetes are a high priority in ambulatory medicine.5658 Hospitalization provides an opportunity to identify previously undiagnosed diabetes or prediabetes and, for patients with known diabetes, to assess and impact upon the long term course of diabetes.

As a first step, unless a recent hemoglobin A1C (HbA1c) is known, among hospitalized hyperglycemic patients an HbA1C should be obtained upon admission. Greci et al.59 showed that an HbA1c level >6.0% was 100% specific (14/14) and 57% sensitive (12/21) for the diagnosis of diabetes. Among patients having known diabetes, an HbA1C elevation on admission may justify intensification of preadmission management at the time of discharge. If discharge and postdischarge adjustments of preadmission regimens are planned in response to admission A1C elevations, then the modified long‐term treatment strategy can improve the A1C in the ambulatory setting.60 Moreover, the event of hospitalization is the ideal teachable moment for patients and their caregivers to improve self‐care activities. Yet floor nurses may be overwhelmed by the tasks of patient education. For ideal patient education, both a nutritionist and a diabetes nurse educator are needed to assess compliance with medication, diet, and other aspects of care.6163 There also is need for outpatient follow‐up education. Finally, at the time of discharge, there is a duty and an opportunity for the diabetes provider to communicate with outpatient care providers about the patient's regimen and glycemic control, and also, based on information gathered during the admission, to convey any evidence that might support the need for a change of long‐term strategy.64 Unfortunately, the opportunity that hospitalization presents to assess, educate, and intervene frequently is underused.1, 8, 51, 65

LARGE GAPS EXIST BETWEEN CURRENT AND OPTIMAL CARE

Despite the evidence that inpatient glycemic control is important for patient outcomes, and despite guidelines recommending tighter inpatient glycemic control, clinical practice has been slow to change. In many institutions, inpatient glycemic management has not improved over the past decade, and large gaps remain between current practice and optimal practice.

Studies of individual institutions provide several insights into gaps in care. For example, Schnipper et al.66 examined practices on the general medicine service of an academic medical center in Boston in 2004. Among 107 prospectively identified patients with a known diagnosis of diabetes or at least 1 glucose reading >200 mg/dL (excluding patients with diabetic ketoacidosis, hyperglycemic hyperosmolar state, or pregnancy), they found scheduled long‐acting insulin prescribed in 43% of patients, scheduled short‐acting/rapid‐acting insulin in only 4% of patients, and 80 of 89 patients (90%) on the same sliding scale insulin regimen despite widely varying insulin requirements. Thirty‐one percent of glucose readings were >180 mg/dL compared with 1.2% of readings <60 mg/dL (but 11% of patients had at least 1 episode of hypoglycemia). Of the 75 patients with at least 1 episode of hyperglycemia or hypoglycemia, only 35% had any change to their insulin regimen during the first 5 days of the hospitalization.

Other studies have confirmed this concept of clinical inertia (ie, recognition of the problem but failure to act).67 A study by Cook et al.68 of all hospitalized non‐ICU patients with diabetes or hyperglycemia and length of stay of 3 days between 2001 and 2004 showed that 20% of patients had persistent hyperglycemia during the hospitalization (defined as a mean glucose >200 mg/dL). Forty‐six percent of patients whose average glucose was in the top tertile did not have their insulin regimen intensified to a combination of short‐acting/rapid‐acting and long‐acting insulin, and 35% of these patients either had no change in their total daily insulin dose or actually had a decrease in their dose when comparing the last 24 hours with the first 24 hours of hospitalization, a concept they term negative therapeutic momentum.

Perhaps the most well‐balanced view of the current state of medical practice comes from the UHC benchmarking project.69 UHC is an alliance of 90 academic health centers. For the diabetes project, each institution reviewed the records of 50 randomly selected patients over 18 years of age with at least a 72‐hour length of stay, 1 of 7 prespecified Diagnosis Related Group (DRG) codes, and at least 2 consecutive glucose readings >180 mg/dL or the receipt of insulin any time during the hospitalization. Patients with a history of pancreatic transplant, pregnant at the time of admission, receiving hospice or comfort care, or receiving insulin for a reason other than glucose management were excluded. The study showed widespread gaps in processes and outcomes (Table 1). Moreover, performance varied widely across hospitals. For example, the morning glucose in the ICU on the second measurement day was 110 mg/dL in 18% of patients for the median‐performing hospital, with a range of 0% to 67% across all 37 measured hospitals. In the non‐ICU setting on the second measurement day, 26% of patients had all BG measurements = 180 mg/dL in the median‐performing hospital, with a range of 7% to 48%. Of note, hypoglycemia was relatively uncommon: in the median hospital, 2.4% of patient‐days had 1 or more BG readings <50 mg/dL (range: 0%8.6%). Finally, in the median‐performing hospital, effective insulin therapy (defined as short‐acting/rapid‐acting and long‐acting subcutaneous insulin, continuous insulin infusion, or subcutaneous insulin pump therapy) was prescribed in 45% of patients, with a range of 12% to 77% across measured hospitals.

FREQUENT PROBLEMS WITH COMMUNICATION AND COORDINATION

Those who work closely with frontline practitioners striving to improve inpatient glycemic management have noticed other deficiencies in care.1, 70 These include: a lack of coordination between feeding, BG measurement, and insulin administration, leading to mistimed and incorrectly dosed insulin; frequent use of sliding‐scale only regimens despite evidence that they are useless at best and harmful at worst;6, 47, 60, 71 discharge summaries that often do not mention follow‐up plans for hyperglycemic management; incomplete patient educational programs; breakdowns in care at transition points; nursing and medical staffs that are unevenly educated about the proper use of insulin; and patients who are often angry or confused about their diabetes care in the hospital. Collectively, these gaps in care serve as prime targets for any glycemic control program.

HYPOGLYCEMIA IS A PROMINENT INPATIENT SAFETY CONCERN

Hypoglycemia is common in the inpatient setting and is a legitimate safety concern. In a recently reported series of 2174 hospitalized patients receiving antihyperglycemic agents, it was found that 9.5% of patients experienced a total 484 hypoglycemic episodes (defined as 60 mg/dL).72 Hypoglycemia often occurred in the setting of insulin therapy and frequently resulted from a failure to recognize trends in BG readings or other clues that a patient was at risk for developing hypoglycemia.73 A common thread is the risk created by interruption of carbohydrate intake, noted by Fischer et al.73 and once again in the recent ICU study by Vriesendorp et al.74 Sources of error include: lack of coordination between feeding and medication administration, leading to mistiming of insulin action; lack of sufficient frequency in BG monitoring; lack of clarity or uniformity in the writing of orders; failure to recognize changes in insulin requirements due to advanced age, renal failure, liver disease, or change in clinical status; steroid use with subsequent tapering or interruption; changes in feeding; failure to reconcile medications; inappropriate use of oral antihyperglycemic agents, and communication or handoff failures.

It has been difficult to sort out whether hypoglycemia is a marker of severity of illness or whether it is an independent factor leading to poor outcomes. Observational studies lend credibility to the concept that patients having congestive heart failure or myocardial infarction may be at risk for excessive mortality if their average BG resides in the low end of the normal range.7578 Sympathetic activation occurs as the threshold for hypoglycemia is approached, such as occurs at BG = 70 or 72 mg/dL.79 Patients living with BG levels observed to be in the low end of the normal range might experience more severe but unobserved and undocumented episodes of neuroglycopenia. Arrhythmia and fatality have been directly attributed to strict glycemic control.80, 81 We are confronted with the need to interpret well conducted observational studies, evaluating subgroups at risk, and using multivariate analysis to assess the impact of hypoglycemia upon outcomes.82 In such studies, we will need to examine high‐risk subgroups, including cardiac patients, in particular, for the possibility that there is a J‐shaped curve for mortality as a function of average BG.

Unfortunately, clinical inertia exists in response to hypoglycemia just as it does with hyperglycemia. One recent study examined 52 patients who received intravenous 50% dextrose solution for an episode of hypoglycemia.83 Changes to insulin regimens were subsequently made in only 21 patients (40%), and diabetes specialists agreed with the changes for 11 of these patients. The other 31 patients (60%) received no changes in treatment, and diabetes specialists agreed with that decision for only 10 of these patients.

Although some increase in hypoglycemia might be expected with initiation of tight glycemic control efforts, the solution is not to undertreat hyperglycemia. Hyperglycemia creates an unsafe setting for the treatment of illness and disease. Sliding‐scaleonly regimens are ineffective in securing glycemic control and can result in increases in hypoglycemia as well as hyperglycemic excursions.6, 66 Inappropriate withholding of insulin doses can lead to severe glycemic excursions and even iatrogenic diabetic ketoacidosis (DKA). Systems approaches to avoid the errors outlined above can minimize or even reverse the increased risk of hypoglycemia expected with tighter glycemic targets.51

A SYSTEMS APPROACH IS NEEDED FOR THESE MULTIPLE COMPLEX PROBLEMS

Care is of the hyperglycemic inpatient is inherently complex. Previously established treatments are often inappropriate under conditions of altered insulin resistance, changing patterns of nutrition and carbohydrate exposure, comorbidities, concomitant medications, and rapidly changing medical and surgical status. Patients frequently undergo changes in the route and amount of nutritional exposure, including discrete meals, continuous intravenous dextrose, nil per orem (nothing by mouth status; NPO) status, grazing on nutritional supplements or liquid diets with or without meals, bolus enteral feedings, overnight enteral feedings with daytime grazing, total parenteral nutrition, continuous peritoneal dialysis, and overnight cycling of peritoneal dialysis. Relying on individual expertise and vigilance to negotiate this complex terrain without safeguards, protocols, standardization of orders, and other systems change is impractical and unwise.

Transitions across care providers and locations lead to multiple opportunities for breakdown in the quality, consistency, and safety of care.64, 65 At the time of ward transfer or change of patient status, previous medication and monitoring orders sometimes are purged. At the time of discharge, there may be risk of continuation of anti‐hyperglycemic therapy, initiated to cover medical stress, in doses that will subsequently be unsafe.

In the face of this complexity, educational programs alone will not suffice to improve care. Institutional commitment and systems changes are essential.

MARKED IMPROVEMENT IS POSSIBLE AND TOOLS EXIST: A ROADMAP IS IN PLACE

Fortunately, a roadmap is in place to help us achieve better glycemic control, improve insulin management, and address the long list of current deficiencies in care. This is imperative to develop consistent processes in order to achieve maximum patient quality outcomes that effective glycemic management offers. This roadmap entails 4 components: (1) national awareness, (2) national guidelines, (3) consensus statements, and (4) effective tools. As mentioned above, the first two components of this roadmap are now in place.

As these national guidelines become more widely accepted, the next step will be the incorporation of this into programs like Pay‐for Performance and the Physician Quality Reporting Initiative (PQRI), which will impact reimbursement to both hospitals and providers.

Regarding the third component, a recent multidisciplinary consensus conference1 outlined the essential elements needed for successful implementation of an inpatient glycemic control program which include:

• An appropriate level of administrative support.

• Formation of a multidisciplinary steering committee to drive the development of initiatives and empowered to enact change.

• Assessment of current processes, quality of care, and barriers to practice change.

• Development and implementation of interventions including standardized order sets, protocols, policies and algorithms with associated educational programs.

• Metrics for evaluation of glycemic control, hypoglycemia, insulin use patterns, and other aspects of care.

Finally, extensive resources and effective tools are now available to help institutions achieve better inpatient glucose control. The Society of Hospital Medicine (SHM), in conjunction with the ADA, AACE, the American College of Physicians (ACP), the Case Management Society of America (CMSA), the American Society of Consultant Pharmacists, nursing, and diabetic educators have all partnered to produce a comprehensive guide to effective implementation of glycemic control and preventing hypoglycemia.49 This comprehensive workbook is a proven performance improvement framework and is available on the SHM Web site.48 Details and examples of all essential elements are covered in this workbook along with opportunities for marked improvement bolstered by integration of high reliability design features and attention to effective implementation techniques. The remainder of this supplement crystallizes a substantial portion of this material. The AACE has also recently offered a valuable web‐based resource to encourage institutional glycemic control efforts.49

GLYCEMIC CONTROL INITIATIVES CAN BE COST‐EFFECTIVE

Achieving optimal glycemic control safely requires monitoring, education, and other measures, which can be expensive, labor intensive, and require coordination of the services of many hospital divisions. This incremental expense has been shown to be cost‐effective in a variety of settings.1, 84, 85 The costs of glycemic control initiatives have demonstrated a good return on investment via:

• Improved LOS, readmission rates, morbidity, and mortality.

• Improved documentation of patient acuity and related payment for acuity.

• Income generated via incremental physician and allied health professional billing.

CONCLUSION AND SUMMARY

Evidence exists that appropriate management of hyperglycemia improves outcomes, whereas the current state of affairs is that most medical centers currently manage this suboptimally. This is concerning given the magnitude of diabetes and hyperglycemia in our inpatient setting in the United States. To bring awareness to this issue, multiple initiatives (guidelines, certification programs, workbooks, etc.) are available by various organizations including the ADA, AACE, SCIP, NSQIP, IHI, UHC, the Joint Commission, and SHM. However, this is not enough. Change occurs at the local level, and institutional prioritization and support is needed to empower a multidisciplinary steering committee, with appropriate administrative support, to standardize and improve systems in the face of substantial cultural issues and complex barriers. Improved data collection and reporting, incremental monitoring, creation of metrics, and improved documentation are an absolutely necessary necessity to achieve breakthrough levels of improvement.

Now the time is right to make an assertive effort to improve inpatient glycemic control and related issues, and push for appropriate support at your institution to help achieve this in the interest of patient safety and optimal outcomes.

Stroke is a leading cause of disability and the third leading cause of death in the United States.1 Transient ischemic attack (TIA) carries a substantial short‐term risk for stroke.1 The risk of stroke following TIA ranges from 2% to 5% within 48 hours, is 10.5% within 90 days, and ranges from 24% to 29% within 5 years.24 Among the 780,000 new or recurrent strokes that occur each year, 180,000 are recurrent attacks.1, 5 Several evidence‐based guidelines for secondary prevention of stroke are available. To reduce variability in the assessment, diagnostic evaluation, and treatment of patients with TIA in actual clinical practice and to simplify the management of TIA or ischemic stroke, this article will review the available guidelines for secondary prevention of stroke and the data from clinical trials that support these guidelines.

PATHOPHYSIOLOGY AND SUBTYPES/CLASSIFICATION

Stroke is broadly classified as hemorrhagic or ischemic stroke. Hemorrhagic stroke, including intraparenchymal and subarachnoid hemorrhage, accounts for 13% of strokes and ischemic stroke for 87%.1 Ischemic stroke is caused by inadequate cerebral blood flow as a result of either stenosis or occlusion of the vessels supplying the brain.6 The average rate of cerebral blood flow is 50 mL/100 g a minute. Flow rates below 2025 mL/100 g a minute are usually associated with cerebral impairment, and rates below 10 mL/100 g a minute are associated with irreversible brain damage.

Approximately 20% of ischemic strokes are of cardioembolic origin; 25% are a result of atherosclerotic cerebrovascular disease; 20% are a result of penetrating artery disease (lacunes); 5% are due to other causes, such as hypercoagulable states, including protein S and C deficiency, sickle cell disease, and various types of vasculitis; and 30% are cryptogenic.7, 8 Cardioembolic stroke can be a manifestation of atrial fibrillation, valvular disease, ventricular thrombi, and other cardiac conditions.9 Large arteries, such as the carotid arteries and the proximal aorta, are a source of atherogenic emboli.10 Atherosclerotic plaques in the arteries may narrow the lumen of the blood vessel or produce emboli, which results in occlusion of the distal arteries, causing a stroke.

RISK FACTORS

Several risk factors, both nonmodifiable and modifiable, predispose individuals to stroke. Nonmodifiable risk factors include age, sex, race, and family or personal history of stroke or myocardial infarction (MI).1, 5 After the age of 55, the stroke rate doubles for every 10‐year increase in age.1 African Americans have a 50% greater risk of death due to stroke than whites.1 The appropriate management of modifiable risk factors can significantly reduce the risk of recurrent stroke and improve survival. The many modifiable factors include hypertension, heart disease, smoking, diabetes, atrial fibrillation, dyslipidemia, obesity, and alcohol abuse.1, 5 The mechanisms of how these factors increase the risk for stroke and management of these factors are discussed later in this article. It is important to educate individuals, particularly those who also have nonmodifiable risk factors, about modifiable risk factors in order to enable early and appropriate intervention.

DIAGNOSIS

Most patients with TIA are asymptomatic when they present to the emergency department (ED). The risk of stroke following an episode of TIA has been found to be 3.5% within 48 hours in a meta‐analysis based on a random effects model;11 therefore, it is critical to quickly identify patients with high short‐term risk for recurrent stroke.12 The ABCD2 score was recently validated in TIA patients to estimate the near‐term risk of completed stroke.13 Patients with a score of 03 on the ABCD2 are at low risk, those with a score of 4 or 5 are at moderate risk, and those with a score 6 or 7 are at severe risk for recurrent stroke (Table 1).13 Risk scores, although highly predictive, should complement clinical judgment in the assessment of individual stroke risk.

Currently, there are no specific guidelines for the diagnostic evaluation of patients with suspected TIA. However, the following approach, including elements of acute evaluation for both stroke and TIA as well as risk factor identification that may aid in choosing specifics of secondary prevention, may be adopted in the management of patients with TIA (Table 2).14, 15

A computed tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the brain should be performed as soon as possible to distinguish between ischemic and hemorrhagic stroke, eliminate other pathologies that mimic TIA or stroke, and guide selection of the appropriate treatment approach. CT scanning is often the best initial imaging choice because it reliably excludes intracranial hemorrhage and is rapidly available in most settings. For those for whom the diagnosis is uncertain, diffusion‐weighted MRI may be more helpful. Because of the time issues surrounding the use of tissue plasminogen activator, waiting for an MRI may not always be the best choice, although some institutions are now able to provide quick access to MRI imaging. Imaging can detect silent cerebral infarcts associated with an increased risk of stroke. In patients with previous TIA and/or stroke, MRI is more sensitive than CT in detecting small, old infarcts (although most are seen on CT) and in visualizing the posterior fossa (cerebellum and brain stem).12

Holter electrocardiography or inpatient telemetry monitoring can be performed to identify atrial fibrillation, a known risk factor for stroke or TIA.16 Transesophageal echocardiography (TEE) has been reported to be more sensitive than transthoracic echocardiography (TTE) for detecting cardioembolic sources of TIA or ischemic stroke across multiple age groups.17 TEE has several advantages over TTE, such as the creation of clearer images of the aorta, the pulmonary artery, valves of the heart, both atria, the atrial septum, and the left atrial appendage.

Cerebral angiography is indicated in several instances, including in children or young patients with ischemic stroke because vascular abnormalities and cerebral vasculitis are relatively more common causes in patients in these age groups.18 Furthermore, in centers in which intra‐arterial procedures are frequently performed, angiography is indicated to confirm the suspicion of posterior circulation vessel (ie, vertebral or basilar artery) occlusion prior to intervention. Angiography has the highest diagnostic validity compared with other noninvasive techniques and may be indicated if cerebral vasculitis or nonatherosclerotic disease of extracranial arteries (eg, dissections, vascular malformations) is suspected. Angiography of intracranial vessels is the gold standard for the study of cerebral aneurysms and is recommended in patients with subarachnoid hemorrhage, but there is evidence that magnetic resonance angiography (MRA) and digital subtraction angiography have better discriminatory ability in the 70%99% range of stenosis compared with duplex ultrasonography (DUS) for determining candidacy for carotid endarterectomy (CEA) or stenting.19, 20

The MRA and CT angiography (CTA) are generally used to visualize the intracranial and extracranialboth anterior and posteriorcerebral circulation. The use of MRA or CTA to image cerebral circulation has generally supplanted the use of carotid and transcranial ultrasonography and obviated the need for catheter angiography in investigating the etiology of most ischemic strokes and TIAs. The degree of carotid stenosis should be primarily estimated using noninvasive techniques (DUS, MRA, CTA).21 Duplex ultrasonography is recommended after CEA 6 months and every 1 2 years after the procedure in order to monitor recurrent stenosis.22 Angiography should be performed when the results of noninvasive examinations are discordant; when significant atherosclerotic disease of intracranial arteries is suspected, especially in vertebrobasilar arteries; or when MRA or CT angiography provides technically poor images.23

Transcranial Doppler ultrasonography and color Doppler ultrasound (TCD) are used to evaluate the intracranial vessels and may provide additional information on patency of cerebral vessels, recanalization, and collateral pathways. Compared with the gold standard of conventional angiography, TCD has a positive predictive value of 36% and a negative predictive value of 86% for a diagnosis of intracranial stenosis.24 This technique also can be used as a complementary examination in patients undergoing CEA in order to aid in preoperative evaluation and intraoperative monitoring of blood flow in the territory of the operated artery.12

TREATMENT

The management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors, and appropriate surgical and medical intervention.12

SUMMARY OF GUIDELINES FOR SECONDARY PREVENTION OF STROKE

The AHA/ASA, American College of Chest Physicians (ACCP), and National Stroke Association (NSA) have developed and published practice guidelines for the management of TIA, with detailed information on secondary prevention of stroke.5, 79, 80 The key recommendations from these 3 organizations are summarized in Table 5 .5, 79, 80 This section summarizes the current guidelines regarding the use of antiplatelets and anticoagulants for the secondary prevention of stroke.

FUTURE DEVELOPMENTS

One of the largest stroke prevention trials currently ongoing is the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) study. The PRoFESS trial is a large (N = 20,333), randomized, double‐blind, placebo‐controlled, multinational study comparing the efficacy and safety of aspirin plus ER‐DP with that of clopidogrel and the efficacy of telmisartan versus placebo in the presence of background blood pressure treatments in preventing recurrent stroke.86 The primary outcome of the study is time to first recurrent stroke. Recently, the baseline demographics were published.86 The mean age of patients was 66.1 years at enrollment, 36% of patients were women, and mean time from event to randomization was 15 days (40% randomized within 10 days). Most participants had had a stroke of arterial origin (29% large vessel disease and 52% small vessel disease), whereas 2% had had a stroke due to cardioembolism and 18% due to other causes. These baseline data suggest that the trial involves a representative international population of patients with stroke. The PRoFESS trial will provide additional insight into the benefits of the combination of aspirin plus ER‐DP for secondary prevention of stroke in addition to providing direct comparison of efficacy with clopidogrel. The latest information on this and other ongoing stroke prevention trials can be accessed at http://www.strokecenter.org/trials/.

Stroke is a leading cause of disability and the third leading cause of death in the United States.1 Transient ischemic attack (TIA) carries a substantial short‐term risk for stroke.1 The risk of stroke following TIA ranges from 2% to 5% within 48 hours, is 10.5% within 90 days, and ranges from 24% to 29% within 5 years.24 Among the 780,000 new or recurrent strokes that occur each year, 180,000 are recurrent attacks.1, 5 Several evidence‐based guidelines for secondary prevention of stroke are available. To reduce variability in the assessment, diagnostic evaluation, and treatment of patients with TIA in actual clinical practice and to simplify the management of TIA or ischemic stroke, this article will review the available guidelines for secondary prevention of stroke and the data from clinical trials that support these guidelines.

PATHOPHYSIOLOGY AND SUBTYPES/CLASSIFICATION

Stroke is broadly classified as hemorrhagic or ischemic stroke. Hemorrhagic stroke, including intraparenchymal and subarachnoid hemorrhage, accounts for 13% of strokes and ischemic stroke for 87%.1 Ischemic stroke is caused by inadequate cerebral blood flow as a result of either stenosis or occlusion of the vessels supplying the brain.6 The average rate of cerebral blood flow is 50 mL/100 g a minute. Flow rates below 2025 mL/100 g a minute are usually associated with cerebral impairment, and rates below 10 mL/100 g a minute are associated with irreversible brain damage.

Approximately 20% of ischemic strokes are of cardioembolic origin; 25% are a result of atherosclerotic cerebrovascular disease; 20% are a result of penetrating artery disease (lacunes); 5% are due to other causes, such as hypercoagulable states, including protein S and C deficiency, sickle cell disease, and various types of vasculitis; and 30% are cryptogenic.7, 8 Cardioembolic stroke can be a manifestation of atrial fibrillation, valvular disease, ventricular thrombi, and other cardiac conditions.9 Large arteries, such as the carotid arteries and the proximal aorta, are a source of atherogenic emboli.10 Atherosclerotic plaques in the arteries may narrow the lumen of the blood vessel or produce emboli, which results in occlusion of the distal arteries, causing a stroke.

RISK FACTORS

Several risk factors, both nonmodifiable and modifiable, predispose individuals to stroke. Nonmodifiable risk factors include age, sex, race, and family or personal history of stroke or myocardial infarction (MI).1, 5 After the age of 55, the stroke rate doubles for every 10‐year increase in age.1 African Americans have a 50% greater risk of death due to stroke than whites.1 The appropriate management of modifiable risk factors can significantly reduce the risk of recurrent stroke and improve survival. The many modifiable factors include hypertension, heart disease, smoking, diabetes, atrial fibrillation, dyslipidemia, obesity, and alcohol abuse.1, 5 The mechanisms of how these factors increase the risk for stroke and management of these factors are discussed later in this article. It is important to educate individuals, particularly those who also have nonmodifiable risk factors, about modifiable risk factors in order to enable early and appropriate intervention.

DIAGNOSIS

Most patients with TIA are asymptomatic when they present to the emergency department (ED). The risk of stroke following an episode of TIA has been found to be 3.5% within 48 hours in a meta‐analysis based on a random effects model;11 therefore, it is critical to quickly identify patients with high short‐term risk for recurrent stroke.12 The ABCD2 score was recently validated in TIA patients to estimate the near‐term risk of completed stroke.13 Patients with a score of 03 on the ABCD2 are at low risk, those with a score of 4 or 5 are at moderate risk, and those with a score 6 or 7 are at severe risk for recurrent stroke (Table 1).13 Risk scores, although highly predictive, should complement clinical judgment in the assessment of individual stroke risk.

Currently, there are no specific guidelines for the diagnostic evaluation of patients with suspected TIA. However, the following approach, including elements of acute evaluation for both stroke and TIA as well as risk factor identification that may aid in choosing specifics of secondary prevention, may be adopted in the management of patients with TIA (Table 2).14, 15

A computed tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the brain should be performed as soon as possible to distinguish between ischemic and hemorrhagic stroke, eliminate other pathologies that mimic TIA or stroke, and guide selection of the appropriate treatment approach. CT scanning is often the best initial imaging choice because it reliably excludes intracranial hemorrhage and is rapidly available in most settings. For those for whom the diagnosis is uncertain, diffusion‐weighted MRI may be more helpful. Because of the time issues surrounding the use of tissue plasminogen activator, waiting for an MRI may not always be the best choice, although some institutions are now able to provide quick access to MRI imaging. Imaging can detect silent cerebral infarcts associated with an increased risk of stroke. In patients with previous TIA and/or stroke, MRI is more sensitive than CT in detecting small, old infarcts (although most are seen on CT) and in visualizing the posterior fossa (cerebellum and brain stem).12

Holter electrocardiography or inpatient telemetry monitoring can be performed to identify atrial fibrillation, a known risk factor for stroke or TIA.16 Transesophageal echocardiography (TEE) has been reported to be more sensitive than transthoracic echocardiography (TTE) for detecting cardioembolic sources of TIA or ischemic stroke across multiple age groups.17 TEE has several advantages over TTE, such as the creation of clearer images of the aorta, the pulmonary artery, valves of the heart, both atria, the atrial septum, and the left atrial appendage.

Cerebral angiography is indicated in several instances, including in children or young patients with ischemic stroke because vascular abnormalities and cerebral vasculitis are relatively more common causes in patients in these age groups.18 Furthermore, in centers in which intra‐arterial procedures are frequently performed, angiography is indicated to confirm the suspicion of posterior circulation vessel (ie, vertebral or basilar artery) occlusion prior to intervention. Angiography has the highest diagnostic validity compared with other noninvasive techniques and may be indicated if cerebral vasculitis or nonatherosclerotic disease of extracranial arteries (eg, dissections, vascular malformations) is suspected. Angiography of intracranial vessels is the gold standard for the study of cerebral aneurysms and is recommended in patients with subarachnoid hemorrhage, but there is evidence that magnetic resonance angiography (MRA) and digital subtraction angiography have better discriminatory ability in the 70%99% range of stenosis compared with duplex ultrasonography (DUS) for determining candidacy for carotid endarterectomy (CEA) or stenting.19, 20

The MRA and CT angiography (CTA) are generally used to visualize the intracranial and extracranialboth anterior and posteriorcerebral circulation. The use of MRA or CTA to image cerebral circulation has generally supplanted the use of carotid and transcranial ultrasonography and obviated the need for catheter angiography in investigating the etiology of most ischemic strokes and TIAs. The degree of carotid stenosis should be primarily estimated using noninvasive techniques (DUS, MRA, CTA).21 Duplex ultrasonography is recommended after CEA 6 months and every 1 2 years after the procedure in order to monitor recurrent stenosis.22 Angiography should be performed when the results of noninvasive examinations are discordant; when significant atherosclerotic disease of intracranial arteries is suspected, especially in vertebrobasilar arteries; or when MRA or CT angiography provides technically poor images.23

Transcranial Doppler ultrasonography and color Doppler ultrasound (TCD) are used to evaluate the intracranial vessels and may provide additional information on patency of cerebral vessels, recanalization, and collateral pathways. Compared with the gold standard of conventional angiography, TCD has a positive predictive value of 36% and a negative predictive value of 86% for a diagnosis of intracranial stenosis.24 This technique also can be used as a complementary examination in patients undergoing CEA in order to aid in preoperative evaluation and intraoperative monitoring of blood flow in the territory of the operated artery.12

TREATMENT

The management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors, and appropriate surgical and medical intervention.12

SUMMARY OF GUIDELINES FOR SECONDARY PREVENTION OF STROKE

The AHA/ASA, American College of Chest Physicians (ACCP), and National Stroke Association (NSA) have developed and published practice guidelines for the management of TIA, with detailed information on secondary prevention of stroke.5, 79, 80 The key recommendations from these 3 organizations are summarized in Table 5 .5, 79, 80 This section summarizes the current guidelines regarding the use of antiplatelets and anticoagulants for the secondary prevention of stroke.

FUTURE DEVELOPMENTS

One of the largest stroke prevention trials currently ongoing is the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) study. The PRoFESS trial is a large (N = 20,333), randomized, double‐blind, placebo‐controlled, multinational study comparing the efficacy and safety of aspirin plus ER‐DP with that of clopidogrel and the efficacy of telmisartan versus placebo in the presence of background blood pressure treatments in preventing recurrent stroke.86 The primary outcome of the study is time to first recurrent stroke. Recently, the baseline demographics were published.86 The mean age of patients was 66.1 years at enrollment, 36% of patients were women, and mean time from event to randomization was 15 days (40% randomized within 10 days). Most participants had had a stroke of arterial origin (29% large vessel disease and 52% small vessel disease), whereas 2% had had a stroke due to cardioembolism and 18% due to other causes. These baseline data suggest that the trial involves a representative international population of patients with stroke. The PRoFESS trial will provide additional insight into the benefits of the combination of aspirin plus ER‐DP for secondary prevention of stroke in addition to providing direct comparison of efficacy with clopidogrel. The latest information on this and other ongoing stroke prevention trials can be accessed at http://www.strokecenter.org/trials/.

Stroke is a leading cause of disability and the third leading cause of death in the United States.1 Transient ischemic attack (TIA) carries a substantial short‐term risk for stroke.1 The risk of stroke following TIA ranges from 2% to 5% within 48 hours, is 10.5% within 90 days, and ranges from 24% to 29% within 5 years.24 Among the 780,000 new or recurrent strokes that occur each year, 180,000 are recurrent attacks.1, 5 Several evidence‐based guidelines for secondary prevention of stroke are available. To reduce variability in the assessment, diagnostic evaluation, and treatment of patients with TIA in actual clinical practice and to simplify the management of TIA or ischemic stroke, this article will review the available guidelines for secondary prevention of stroke and the data from clinical trials that support these guidelines.

PATHOPHYSIOLOGY AND SUBTYPES/CLASSIFICATION

Stroke is broadly classified as hemorrhagic or ischemic stroke. Hemorrhagic stroke, including intraparenchymal and subarachnoid hemorrhage, accounts for 13% of strokes and ischemic stroke for 87%.1 Ischemic stroke is caused by inadequate cerebral blood flow as a result of either stenosis or occlusion of the vessels supplying the brain.6 The average rate of cerebral blood flow is 50 mL/100 g a minute. Flow rates below 2025 mL/100 g a minute are usually associated with cerebral impairment, and rates below 10 mL/100 g a minute are associated with irreversible brain damage.

Approximately 20% of ischemic strokes are of cardioembolic origin; 25% are a result of atherosclerotic cerebrovascular disease; 20% are a result of penetrating artery disease (lacunes); 5% are due to other causes, such as hypercoagulable states, including protein S and C deficiency, sickle cell disease, and various types of vasculitis; and 30% are cryptogenic.7, 8 Cardioembolic stroke can be a manifestation of atrial fibrillation, valvular disease, ventricular thrombi, and other cardiac conditions.9 Large arteries, such as the carotid arteries and the proximal aorta, are a source of atherogenic emboli.10 Atherosclerotic plaques in the arteries may narrow the lumen of the blood vessel or produce emboli, which results in occlusion of the distal arteries, causing a stroke.

RISK FACTORS

Several risk factors, both nonmodifiable and modifiable, predispose individuals to stroke. Nonmodifiable risk factors include age, sex, race, and family or personal history of stroke or myocardial infarction (MI).1, 5 After the age of 55, the stroke rate doubles for every 10‐year increase in age.1 African Americans have a 50% greater risk of death due to stroke than whites.1 The appropriate management of modifiable risk factors can significantly reduce the risk of recurrent stroke and improve survival. The many modifiable factors include hypertension, heart disease, smoking, diabetes, atrial fibrillation, dyslipidemia, obesity, and alcohol abuse.1, 5 The mechanisms of how these factors increase the risk for stroke and management of these factors are discussed later in this article. It is important to educate individuals, particularly those who also have nonmodifiable risk factors, about modifiable risk factors in order to enable early and appropriate intervention.

DIAGNOSIS

Most patients with TIA are asymptomatic when they present to the emergency department (ED). The risk of stroke following an episode of TIA has been found to be 3.5% within 48 hours in a meta‐analysis based on a random effects model;11 therefore, it is critical to quickly identify patients with high short‐term risk for recurrent stroke.12 The ABCD2 score was recently validated in TIA patients to estimate the near‐term risk of completed stroke.13 Patients with a score of 03 on the ABCD2 are at low risk, those with a score of 4 or 5 are at moderate risk, and those with a score 6 or 7 are at severe risk for recurrent stroke (Table 1).13 Risk scores, although highly predictive, should complement clinical judgment in the assessment of individual stroke risk.

Currently, there are no specific guidelines for the diagnostic evaluation of patients with suspected TIA. However, the following approach, including elements of acute evaluation for both stroke and TIA as well as risk factor identification that may aid in choosing specifics of secondary prevention, may be adopted in the management of patients with TIA (Table 2).14, 15

A computed tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the brain should be performed as soon as possible to distinguish between ischemic and hemorrhagic stroke, eliminate other pathologies that mimic TIA or stroke, and guide selection of the appropriate treatment approach. CT scanning is often the best initial imaging choice because it reliably excludes intracranial hemorrhage and is rapidly available in most settings. For those for whom the diagnosis is uncertain, diffusion‐weighted MRI may be more helpful. Because of the time issues surrounding the use of tissue plasminogen activator, waiting for an MRI may not always be the best choice, although some institutions are now able to provide quick access to MRI imaging. Imaging can detect silent cerebral infarcts associated with an increased risk of stroke. In patients with previous TIA and/or stroke, MRI is more sensitive than CT in detecting small, old infarcts (although most are seen on CT) and in visualizing the posterior fossa (cerebellum and brain stem).12

Holter electrocardiography or inpatient telemetry monitoring can be performed to identify atrial fibrillation, a known risk factor for stroke or TIA.16 Transesophageal echocardiography (TEE) has been reported to be more sensitive than transthoracic echocardiography (TTE) for detecting cardioembolic sources of TIA or ischemic stroke across multiple age groups.17 TEE has several advantages over TTE, such as the creation of clearer images of the aorta, the pulmonary artery, valves of the heart, both atria, the atrial septum, and the left atrial appendage.

Cerebral angiography is indicated in several instances, including in children or young patients with ischemic stroke because vascular abnormalities and cerebral vasculitis are relatively more common causes in patients in these age groups.18 Furthermore, in centers in which intra‐arterial procedures are frequently performed, angiography is indicated to confirm the suspicion of posterior circulation vessel (ie, vertebral or basilar artery) occlusion prior to intervention. Angiography has the highest diagnostic validity compared with other noninvasive techniques and may be indicated if cerebral vasculitis or nonatherosclerotic disease of extracranial arteries (eg, dissections, vascular malformations) is suspected. Angiography of intracranial vessels is the gold standard for the study of cerebral aneurysms and is recommended in patients with subarachnoid hemorrhage, but there is evidence that magnetic resonance angiography (MRA) and digital subtraction angiography have better discriminatory ability in the 70%99% range of stenosis compared with duplex ultrasonography (DUS) for determining candidacy for carotid endarterectomy (CEA) or stenting.19, 20

The MRA and CT angiography (CTA) are generally used to visualize the intracranial and extracranialboth anterior and posteriorcerebral circulation. The use of MRA or CTA to image cerebral circulation has generally supplanted the use of carotid and transcranial ultrasonography and obviated the need for catheter angiography in investigating the etiology of most ischemic strokes and TIAs. The degree of carotid stenosis should be primarily estimated using noninvasive techniques (DUS, MRA, CTA).21 Duplex ultrasonography is recommended after CEA 6 months and every 1 2 years after the procedure in order to monitor recurrent stenosis.22 Angiography should be performed when the results of noninvasive examinations are discordant; when significant atherosclerotic disease of intracranial arteries is suspected, especially in vertebrobasilar arteries; or when MRA or CT angiography provides technically poor images.23

Transcranial Doppler ultrasonography and color Doppler ultrasound (TCD) are used to evaluate the intracranial vessels and may provide additional information on patency of cerebral vessels, recanalization, and collateral pathways. Compared with the gold standard of conventional angiography, TCD has a positive predictive value of 36% and a negative predictive value of 86% for a diagnosis of intracranial stenosis.24 This technique also can be used as a complementary examination in patients undergoing CEA in order to aid in preoperative evaluation and intraoperative monitoring of blood flow in the territory of the operated artery.12

TREATMENT

The management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors, and appropriate surgical and medical intervention.12

SUMMARY OF GUIDELINES FOR SECONDARY PREVENTION OF STROKE

The AHA/ASA, American College of Chest Physicians (ACCP), and National Stroke Association (NSA) have developed and published practice guidelines for the management of TIA, with detailed information on secondary prevention of stroke.5, 79, 80 The key recommendations from these 3 organizations are summarized in Table 5 .5, 79, 80 This section summarizes the current guidelines regarding the use of antiplatelets and anticoagulants for the secondary prevention of stroke.

FUTURE DEVELOPMENTS

One of the largest stroke prevention trials currently ongoing is the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) study. The PRoFESS trial is a large (N = 20,333), randomized, double‐blind, placebo‐controlled, multinational study comparing the efficacy and safety of aspirin plus ER‐DP with that of clopidogrel and the efficacy of telmisartan versus placebo in the presence of background blood pressure treatments in preventing recurrent stroke.86 The primary outcome of the study is time to first recurrent stroke. Recently, the baseline demographics were published.86 The mean age of patients was 66.1 years at enrollment, 36% of patients were women, and mean time from event to randomization was 15 days (40% randomized within 10 days). Most participants had had a stroke of arterial origin (29% large vessel disease and 52% small vessel disease), whereas 2% had had a stroke due to cardioembolism and 18% due to other causes. These baseline data suggest that the trial involves a representative international population of patients with stroke. The PRoFESS trial will provide additional insight into the benefits of the combination of aspirin plus ER‐DP for secondary prevention of stroke in addition to providing direct comparison of efficacy with clopidogrel. The latest information on this and other ongoing stroke prevention trials can be accessed at http://www.strokecenter.org/trials/.