Susan S. Braithwaite, MD, FACP, FACE

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.

Until recently it had been argued that hospitalization was not the time in the life of a patient to insist on tight glycemic control. Hyperglycemia was understood to be a consequence of medical stress.1 It was well known that infection, sepsis, or other medical stress might exacerbate hyperglycemia or promote a diabetic crisis.25 Admittedly, the severity of hyperglycemia among patients who have diabetes was thought to predict the risk for hospitalization with infection as well as the outcome of the infectious condition.68 However, until recently strict glycemic control in the hospital was not strongly advocated because hypoglycemia might occur and might be directly and uniquely traceable to actions taken in the hospital.9, 10 Furthermore, the complications of diabetes were thought to be divided into acute metabolic emergencies and chronic tissue complications such as polyneuropathy, retinopathy, nephropathy, and macrovascular disease that would have evolved over a period longer than the duration of hospitalization, and the possibility that short‐term hyperglycemia might affect outcomes was considered unproven.

The purpose of this article is to define the specific populations, disorders, and hospital settings for which there now is strong evidence that short‐term glycemic control will affect the outcome of a course of hospital treatment.

PHYSIOLOGIC LINK BETWEEN HYPERGLYCEMIA AND ADVERSE OUTCOMES

Five years ago a caregiver would not have been likely to think of glycemic control as a contributing factor when considering specific complex problems such as pump failure or arrhythmia after cardiac surgery, long‐term mortality after myocardial infarction, acute renal failure, the need for transfusion during treatment of a complicated surgical illness, or prolonged dependence on a ventilator in the surgical ICU. Although it now known that these and other complications are linked to hospital hyperglycemia, the mechanisms of harm are several steps removed from the hyperglycemia itself. The causes of these adverse outcomes are multifactorial. The causal dependence of the injury on hyperglycemia is not easy to see. In fact, it required randomized prospectively designed trials to convincingly demonstrate the contributory role of hyperglycemia to these and other adverse outcomes.

Now that this link has been convincingly demonstrated, there is intense interest in discovering the probable mechanisms by which control of hyperglycemia and specifically the use of insulin might improve outcomes.1114 Mortality, predominantly sepsis related, was the primary outcome for which the Leuven, Belgium, report of 2001 on the surgical ICU showed improvement.15 Simplistically, in seeking a mechanism of benefit with respect to sepsis, it might be argued that if gross hyperglycemia were prevented in patients with surgical wounds, improvement of host defenses against infective organisms might be expected.1622 However, additional mechanisms of protection probably should be invoked, including those by which glycemic control and specifically insulin therapy affect endothelial function and the coagulation pathway, thus improving the ability of a patient to withstand and recover from sepsis. Insulin promotes beneficial nitric oxide synthase activation (e‐NOS) in capillary endothelium.2326 In patients with prolonged critical illness, intensive insulin therapy lowers ICAM‐1 levels, reflecting reduced endothelial activation. Whereas e‐NOS exerts a beneficial endothelial effect, hepatic iNOS activation is harmful. One proposed mechanism of benefit from adequate insulin therapy is suppression of excessive hepatic iNOS‐induced release of circulating NO, which might contribute to endothelial dysfunction, organ failure, and death.27

Additional proposed mechanisms of hyperglycemia‐induced harm to hospitalized patients, some potentially specifically reduced by insulin therapy, resemble those discussed in relation to macrovascular disease and include activation of inflammatory cytokines, matrix metalloproteinases, and adhesion molecules, and the adverse arrhythmogenic effects of elevated circulating nonesterified fatty acids (Figure 1).2834

Figure 1

CRITICAL WINDOW OF TIME

The results of several retrospectively or prospectively conducted single‐institution observational studies suggest there is a critical window of time within which clinicians must get it right, when attempting glycemic control or else jeopardize therapeutic goals, such as duration of remission in treatment of acute lymphocytic leukemia35 or avoidance of acute rejection in renal allograft surgery.36 Additionally, delayed risk of infection appears to be linked to previous glycemic control during specific early time frames surrounding surgery, renal transplantation, admission for trauma, and induction chemotherapy for leukemia (Table 1).3541 For patients who have diabetes, the potential to reduce the consequences of infections through intensified glycemic control probably begins prior to admission and in the hospital has still not been fully realized.4244

KEY STUDIES SHOWING CLINICAL BENEFIT OF TIGHT GLYCEMIC CONTROL

A summary of several key studies that demonstrated the clinical benefit of tight glycemic control is shown in Table 2. These studies successfully separated the intensively and conventionally managed study groups according blood glucose. Although trials using glucose‐insulin‐potassium infusions (GIK) such that blood glucose was lowered have shown benefit for patients who have had myocardial infarctions4547 or cardiac surgery,48 not all GIK studies have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.49 In the setting of acute myocardial infarction, the DIGAMI 2 trial and the HI‐5 trials failed to achieve the intended separation between treatment groups.50, 51 It has been speculated that if insulin is delivered so as to not achieve normoglycemia, then hyperinsulinemia in the presence of hyperglycemia actually may be proinflammatory.52

The findings of the negative intensive insulin studies do not offset the evidence favoring glycemic control, derived from studies that actually achieved the lowering of blood glucose in the intensive groups, such as the successful prospectively designed trials in myocardial infarction or surgical or medical intensive care units15, 45, 47, 53, 54 and the long‐running, large, prospectively monitored Portland series utilizing insulin infusion for cardiac surgery,40, 5557 which have demonstrated the beneficial effects of euglycemia on mortality and morbidity, or the findings of Krinsley, reported elsewhere in this issue.58, 59 The well‐recognized correlation between outcomes of acute stroke and poststroke hyperglycemia has led to the design of a multicenter trial of glucose‐insulin‐potassium infusion for stroke, in which separation of groups by blood glucose has been achieved.6062 The success of GIK therapy in controlling hyperglycemia depends in part on the particular formulation of the infusion as it matches patient needs, and it is probable that insulin infusion following stroke is capable of safely achieving even tighter glycemic control than GIK.63 Intravenous insulin infusion therapy is more difficult to conduct than GIK therapy. However, because of concern about the proinflammatory and prothrombotic effects of hyperglycemia and recognition of the occasional failure of GIK infusions to control hyperglycemia and of the anti‐inflammatory, antithrombotic, and vasodilatory actions of insulin, there have been calls for additional trials of insulin infusions (as opposed to glucose‐insulin infusions) for both acute myocardial infarction and stroke.52, 64

HYPOGLYCEMIA

Serious or fatal sequelae of hypoglycemia are the principal safety risks in intensive insulin management.9, 65 Case ascertainment cannot be assured by glucose averaging methods but instead requires a method of searching for isolated episodes of hypoglycemia.10 One of the most dreaded consequences of nonfatal hypoglycemia is permanent impairment of intellectual function. Because many euglycemic medically ill patients experience alteration of sensorium while acutely ill, there is a risk that the consequences of an actual episode of severe hypoglycemia will be ascribed to other comorbidities, overlooking or misattributing the altered cognitive function that may persist at discharge to causes other than the obvious iatrogenic one. Because there is an increased risk of hypoglycemia during intensive insulin therapy, controversy has arisen over glycemic targets, especially among critically ill nonsurgical patients.54, 6669

On the other hand, the consequences of hypoglycemia during intensive intravenous insulin therapy in a surgical ICU were said to be negligible.15 In hospitalized elderly patients, hypoglycemia in association with increased mortality risk may not be an independent predictor.70 In the critical care unit, predictors of hypoglycemia are identifiable after the introduction of strict glycemic control that include not only insulin therapy but also CVVH treatment with bicarbonate substitution fluid, discontinuation of nutrition without insulin adjustment, prior diagnosis of diabetes mellitus, sepsis, and the need for inotropic or vasopressor drugs.71 A prudent policy for the future would be not only to treat hypoglycemia promptly when it does occur, with attention to subsequent monitoring to avoid relapse or recurrence, but also to actively introduce strategies for predicting the risk of hypoglycemia and preventing it, especially when high risk is identified.10 The fear of hypoglycemia should not paralyze efforts to achieve better glycemic control in hospitalized patients.

UNANSWERED QUESTIONS AND VISION FOR THE FUTURE

On general wards, 38% of admitted patients may have hyperglycemia.72 As shown in the Leuven, Belgium, study, to achieve the target BG of less than 110 mg/dL in the intensive group in the surgical critical care unit, it was necessary to administer intravenous insulin infusion to essentially all patients. In a study that utilized continuous glucose monitoring, normoglycemia in patients in the intensive care unit was achieved as little as 22% of the time.73

An actively debated subject is how best to assess hospital performance in glycemic control (glucometrics). Hospitals need to show satisfactory control of variability between patients and within the treatment course of individual patients. That is, it is not sufficient to be satisfied with reasonable results of average blood glucose, using blood glucose as the unit of observation (where n is the number of blood glucose determinations). Alternatives are to use patient day or individual patient as a unit of observation (where n is the number of patient days and the number of patients, respectively). Time‐weighting methods are cumbersome but increase the validity of the averaging method used. When the patient is the unit of observation, possible measures include a per‐patient blood glucose average, percentage of blood glucose measurements with certain ranges, time spent within certain blood glucose ranges, or area under the curve of blood glucose versus time. Caveats about glucometrics pertain to both intravenous insulin infusion and also subcutaneous insulin management.74

Although awaiting additional evidence, diabetes experts have widely accepted the proposition that hospitals should focus on prevention of hyperglycemia as an important patient safety factor.75 Although the target range for glycemic control remains controversial, many students of the subject have endorsed the recommendations mentioned in the lead article in this issue, with the understanding that these criteria were developed from the results of the Leuven, Belgium, study, in which a whole blood glucose analyzer was used for measurement, and that the method of measurement of blood glucose must be considered in interpreting applicability of the target range at individual hospitals, many of which use plasma‐correlated methods yielding higher results. However, in new settings and for medical conditions that have not yet been rigorously evaluated by clinical trials, it is an unanswered question whether intensification of glycemic control can be achieved safely outside the critical care unit and, if so, what type of insulin therapy should be used and for what conditions the benefits would outweigh the risks and justify the costs.

Most inpatient management probably will continue to be conducted using subcutaneous injection therapy,7682 designed to match carbohydrate exposure through the appropriate use of analogs or conventional insulin products. One argument for the use of insulin analogs in the hospital, using basal‐prandial‐correction therapy, is the probability of reducing hypoglycemia and getting closer to target range control among patients who are eating but who are at risk for abrupt suspension of meals. Aggressive subcutaneous management strategies are likely to be most effective when standardized protocols, order sets, and informative computerized order entry systems gain widespread hospital acceptance.

If the importance of gaining glycemic control is highly time dependent and if hyperglycemia is uncontrolled, then a strong argument can be made for routine use of intravenous insulin infusion. For appropriately selected patients, intravenous insulin infusion is cost effective,83, 84 and its use can be extended to appropriate patients outside the critical care unit.8587 Many hospitals have protocols for intravenous insulin but use them only sporadically. For patients who already are in the intensive care setting, it is imperative to develop policies that require introduction of intravenous insulin infusion at a given glycemic threshold. On general wards that lack sufficient staffing to conduct intravenous insulin therapy, it is appropriate either to transfer candidate patients to a ward that has adequate staffing when medical condition requires improved control or to develop policies and procedures that will extend the use of intravenous insulin infusion to general wards. In the future, new technologies can be envisioned that will unburden nursing staff, making intravenous insulin infusion realizable as the treatment of choice for hemodynamically stable patients in most hospital settings. These technologies will include continuous monitoring of blood glucose, dose‐defining algorithms, and the eventual development of a fully automated closed‐loop system of monitoring and delivery that might automatically match insulin delivery to carbohydrate exposure and patient insulin sensitivity.8893

Until recently it had been argued that hospitalization was not the time in the life of a patient to insist on tight glycemic control. Hyperglycemia was understood to be a consequence of medical stress.1 It was well known that infection, sepsis, or other medical stress might exacerbate hyperglycemia or promote a diabetic crisis.25 Admittedly, the severity of hyperglycemia among patients who have diabetes was thought to predict the risk for hospitalization with infection as well as the outcome of the infectious condition.68 However, until recently strict glycemic control in the hospital was not strongly advocated because hypoglycemia might occur and might be directly and uniquely traceable to actions taken in the hospital.9, 10 Furthermore, the complications of diabetes were thought to be divided into acute metabolic emergencies and chronic tissue complications such as polyneuropathy, retinopathy, nephropathy, and macrovascular disease that would have evolved over a period longer than the duration of hospitalization, and the possibility that short‐term hyperglycemia might affect outcomes was considered unproven.

The purpose of this article is to define the specific populations, disorders, and hospital settings for which there now is strong evidence that short‐term glycemic control will affect the outcome of a course of hospital treatment.

PHYSIOLOGIC LINK BETWEEN HYPERGLYCEMIA AND ADVERSE OUTCOMES

Five years ago a caregiver would not have been likely to think of glycemic control as a contributing factor when considering specific complex problems such as pump failure or arrhythmia after cardiac surgery, long‐term mortality after myocardial infarction, acute renal failure, the need for transfusion during treatment of a complicated surgical illness, or prolonged dependence on a ventilator in the surgical ICU. Although it now known that these and other complications are linked to hospital hyperglycemia, the mechanisms of harm are several steps removed from the hyperglycemia itself. The causes of these adverse outcomes are multifactorial. The causal dependence of the injury on hyperglycemia is not easy to see. In fact, it required randomized prospectively designed trials to convincingly demonstrate the contributory role of hyperglycemia to these and other adverse outcomes.

Now that this link has been convincingly demonstrated, there is intense interest in discovering the probable mechanisms by which control of hyperglycemia and specifically the use of insulin might improve outcomes.1114 Mortality, predominantly sepsis related, was the primary outcome for which the Leuven, Belgium, report of 2001 on the surgical ICU showed improvement.15 Simplistically, in seeking a mechanism of benefit with respect to sepsis, it might be argued that if gross hyperglycemia were prevented in patients with surgical wounds, improvement of host defenses against infective organisms might be expected.1622 However, additional mechanisms of protection probably should be invoked, including those by which glycemic control and specifically insulin therapy affect endothelial function and the coagulation pathway, thus improving the ability of a patient to withstand and recover from sepsis. Insulin promotes beneficial nitric oxide synthase activation (e‐NOS) in capillary endothelium.2326 In patients with prolonged critical illness, intensive insulin therapy lowers ICAM‐1 levels, reflecting reduced endothelial activation. Whereas e‐NOS exerts a beneficial endothelial effect, hepatic iNOS activation is harmful. One proposed mechanism of benefit from adequate insulin therapy is suppression of excessive hepatic iNOS‐induced release of circulating NO, which might contribute to endothelial dysfunction, organ failure, and death.27

Additional proposed mechanisms of hyperglycemia‐induced harm to hospitalized patients, some potentially specifically reduced by insulin therapy, resemble those discussed in relation to macrovascular disease and include activation of inflammatory cytokines, matrix metalloproteinases, and adhesion molecules, and the adverse arrhythmogenic effects of elevated circulating nonesterified fatty acids (Figure 1).2834

Figure 1

CRITICAL WINDOW OF TIME

The results of several retrospectively or prospectively conducted single‐institution observational studies suggest there is a critical window of time within which clinicians must get it right, when attempting glycemic control or else jeopardize therapeutic goals, such as duration of remission in treatment of acute lymphocytic leukemia35 or avoidance of acute rejection in renal allograft surgery.36 Additionally, delayed risk of infection appears to be linked to previous glycemic control during specific early time frames surrounding surgery, renal transplantation, admission for trauma, and induction chemotherapy for leukemia (Table 1).3541 For patients who have diabetes, the potential to reduce the consequences of infections through intensified glycemic control probably begins prior to admission and in the hospital has still not been fully realized.4244

KEY STUDIES SHOWING CLINICAL BENEFIT OF TIGHT GLYCEMIC CONTROL

A summary of several key studies that demonstrated the clinical benefit of tight glycemic control is shown in Table 2. These studies successfully separated the intensively and conventionally managed study groups according blood glucose. Although trials using glucose‐insulin‐potassium infusions (GIK) such that blood glucose was lowered have shown benefit for patients who have had myocardial infarctions4547 or cardiac surgery,48 not all GIK studies have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.49 In the setting of acute myocardial infarction, the DIGAMI 2 trial and the HI‐5 trials failed to achieve the intended separation between treatment groups.50, 51 It has been speculated that if insulin is delivered so as to not achieve normoglycemia, then hyperinsulinemia in the presence of hyperglycemia actually may be proinflammatory.52

The findings of the negative intensive insulin studies do not offset the evidence favoring glycemic control, derived from studies that actually achieved the lowering of blood glucose in the intensive groups, such as the successful prospectively designed trials in myocardial infarction or surgical or medical intensive care units15, 45, 47, 53, 54 and the long‐running, large, prospectively monitored Portland series utilizing insulin infusion for cardiac surgery,40, 5557 which have demonstrated the beneficial effects of euglycemia on mortality and morbidity, or the findings of Krinsley, reported elsewhere in this issue.58, 59 The well‐recognized correlation between outcomes of acute stroke and poststroke hyperglycemia has led to the design of a multicenter trial of glucose‐insulin‐potassium infusion for stroke, in which separation of groups by blood glucose has been achieved.6062 The success of GIK therapy in controlling hyperglycemia depends in part on the particular formulation of the infusion as it matches patient needs, and it is probable that insulin infusion following stroke is capable of safely achieving even tighter glycemic control than GIK.63 Intravenous insulin infusion therapy is more difficult to conduct than GIK therapy. However, because of concern about the proinflammatory and prothrombotic effects of hyperglycemia and recognition of the occasional failure of GIK infusions to control hyperglycemia and of the anti‐inflammatory, antithrombotic, and vasodilatory actions of insulin, there have been calls for additional trials of insulin infusions (as opposed to glucose‐insulin infusions) for both acute myocardial infarction and stroke.52, 64

HYPOGLYCEMIA

Serious or fatal sequelae of hypoglycemia are the principal safety risks in intensive insulin management.9, 65 Case ascertainment cannot be assured by glucose averaging methods but instead requires a method of searching for isolated episodes of hypoglycemia.10 One of the most dreaded consequences of nonfatal hypoglycemia is permanent impairment of intellectual function. Because many euglycemic medically ill patients experience alteration of sensorium while acutely ill, there is a risk that the consequences of an actual episode of severe hypoglycemia will be ascribed to other comorbidities, overlooking or misattributing the altered cognitive function that may persist at discharge to causes other than the obvious iatrogenic one. Because there is an increased risk of hypoglycemia during intensive insulin therapy, controversy has arisen over glycemic targets, especially among critically ill nonsurgical patients.54, 6669

On the other hand, the consequences of hypoglycemia during intensive intravenous insulin therapy in a surgical ICU were said to be negligible.15 In hospitalized elderly patients, hypoglycemia in association with increased mortality risk may not be an independent predictor.70 In the critical care unit, predictors of hypoglycemia are identifiable after the introduction of strict glycemic control that include not only insulin therapy but also CVVH treatment with bicarbonate substitution fluid, discontinuation of nutrition without insulin adjustment, prior diagnosis of diabetes mellitus, sepsis, and the need for inotropic or vasopressor drugs.71 A prudent policy for the future would be not only to treat hypoglycemia promptly when it does occur, with attention to subsequent monitoring to avoid relapse or recurrence, but also to actively introduce strategies for predicting the risk of hypoglycemia and preventing it, especially when high risk is identified.10 The fear of hypoglycemia should not paralyze efforts to achieve better glycemic control in hospitalized patients.

UNANSWERED QUESTIONS AND VISION FOR THE FUTURE

On general wards, 38% of admitted patients may have hyperglycemia.72 As shown in the Leuven, Belgium, study, to achieve the target BG of less than 110 mg/dL in the intensive group in the surgical critical care unit, it was necessary to administer intravenous insulin infusion to essentially all patients. In a study that utilized continuous glucose monitoring, normoglycemia in patients in the intensive care unit was achieved as little as 22% of the time.73

An actively debated subject is how best to assess hospital performance in glycemic control (glucometrics). Hospitals need to show satisfactory control of variability between patients and within the treatment course of individual patients. That is, it is not sufficient to be satisfied with reasonable results of average blood glucose, using blood glucose as the unit of observation (where n is the number of blood glucose determinations). Alternatives are to use patient day or individual patient as a unit of observation (where n is the number of patient days and the number of patients, respectively). Time‐weighting methods are cumbersome but increase the validity of the averaging method used. When the patient is the unit of observation, possible measures include a per‐patient blood glucose average, percentage of blood glucose measurements with certain ranges, time spent within certain blood glucose ranges, or area under the curve of blood glucose versus time. Caveats about glucometrics pertain to both intravenous insulin infusion and also subcutaneous insulin management.74

Although awaiting additional evidence, diabetes experts have widely accepted the proposition that hospitals should focus on prevention of hyperglycemia as an important patient safety factor.75 Although the target range for glycemic control remains controversial, many students of the subject have endorsed the recommendations mentioned in the lead article in this issue, with the understanding that these criteria were developed from the results of the Leuven, Belgium, study, in which a whole blood glucose analyzer was used for measurement, and that the method of measurement of blood glucose must be considered in interpreting applicability of the target range at individual hospitals, many of which use plasma‐correlated methods yielding higher results. However, in new settings and for medical conditions that have not yet been rigorously evaluated by clinical trials, it is an unanswered question whether intensification of glycemic control can be achieved safely outside the critical care unit and, if so, what type of insulin therapy should be used and for what conditions the benefits would outweigh the risks and justify the costs.

Most inpatient management probably will continue to be conducted using subcutaneous injection therapy,7682 designed to match carbohydrate exposure through the appropriate use of analogs or conventional insulin products. One argument for the use of insulin analogs in the hospital, using basal‐prandial‐correction therapy, is the probability of reducing hypoglycemia and getting closer to target range control among patients who are eating but who are at risk for abrupt suspension of meals. Aggressive subcutaneous management strategies are likely to be most effective when standardized protocols, order sets, and informative computerized order entry systems gain widespread hospital acceptance.

If the importance of gaining glycemic control is highly time dependent and if hyperglycemia is uncontrolled, then a strong argument can be made for routine use of intravenous insulin infusion. For appropriately selected patients, intravenous insulin infusion is cost effective,83, 84 and its use can be extended to appropriate patients outside the critical care unit.8587 Many hospitals have protocols for intravenous insulin but use them only sporadically. For patients who already are in the intensive care setting, it is imperative to develop policies that require introduction of intravenous insulin infusion at a given glycemic threshold. On general wards that lack sufficient staffing to conduct intravenous insulin therapy, it is appropriate either to transfer candidate patients to a ward that has adequate staffing when medical condition requires improved control or to develop policies and procedures that will extend the use of intravenous insulin infusion to general wards. In the future, new technologies can be envisioned that will unburden nursing staff, making intravenous insulin infusion realizable as the treatment of choice for hemodynamically stable patients in most hospital settings. These technologies will include continuous monitoring of blood glucose, dose‐defining algorithms, and the eventual development of a fully automated closed‐loop system of monitoring and delivery that might automatically match insulin delivery to carbohydrate exposure and patient insulin sensitivity.8893

Until recently it had been argued that hospitalization was not the time in the life of a patient to insist on tight glycemic control. Hyperglycemia was understood to be a consequence of medical stress.1 It was well known that infection, sepsis, or other medical stress might exacerbate hyperglycemia or promote a diabetic crisis.25 Admittedly, the severity of hyperglycemia among patients who have diabetes was thought to predict the risk for hospitalization with infection as well as the outcome of the infectious condition.68 However, until recently strict glycemic control in the hospital was not strongly advocated because hypoglycemia might occur and might be directly and uniquely traceable to actions taken in the hospital.9, 10 Furthermore, the complications of diabetes were thought to be divided into acute metabolic emergencies and chronic tissue complications such as polyneuropathy, retinopathy, nephropathy, and macrovascular disease that would have evolved over a period longer than the duration of hospitalization, and the possibility that short‐term hyperglycemia might affect outcomes was considered unproven.

The purpose of this article is to define the specific populations, disorders, and hospital settings for which there now is strong evidence that short‐term glycemic control will affect the outcome of a course of hospital treatment.

PHYSIOLOGIC LINK BETWEEN HYPERGLYCEMIA AND ADVERSE OUTCOMES

Five years ago a caregiver would not have been likely to think of glycemic control as a contributing factor when considering specific complex problems such as pump failure or arrhythmia after cardiac surgery, long‐term mortality after myocardial infarction, acute renal failure, the need for transfusion during treatment of a complicated surgical illness, or prolonged dependence on a ventilator in the surgical ICU. Although it now known that these and other complications are linked to hospital hyperglycemia, the mechanisms of harm are several steps removed from the hyperglycemia itself. The causes of these adverse outcomes are multifactorial. The causal dependence of the injury on hyperglycemia is not easy to see. In fact, it required randomized prospectively designed trials to convincingly demonstrate the contributory role of hyperglycemia to these and other adverse outcomes.

Now that this link has been convincingly demonstrated, there is intense interest in discovering the probable mechanisms by which control of hyperglycemia and specifically the use of insulin might improve outcomes.1114 Mortality, predominantly sepsis related, was the primary outcome for which the Leuven, Belgium, report of 2001 on the surgical ICU showed improvement.15 Simplistically, in seeking a mechanism of benefit with respect to sepsis, it might be argued that if gross hyperglycemia were prevented in patients with surgical wounds, improvement of host defenses against infective organisms might be expected.1622 However, additional mechanisms of protection probably should be invoked, including those by which glycemic control and specifically insulin therapy affect endothelial function and the coagulation pathway, thus improving the ability of a patient to withstand and recover from sepsis. Insulin promotes beneficial nitric oxide synthase activation (e‐NOS) in capillary endothelium.2326 In patients with prolonged critical illness, intensive insulin therapy lowers ICAM‐1 levels, reflecting reduced endothelial activation. Whereas e‐NOS exerts a beneficial endothelial effect, hepatic iNOS activation is harmful. One proposed mechanism of benefit from adequate insulin therapy is suppression of excessive hepatic iNOS‐induced release of circulating NO, which might contribute to endothelial dysfunction, organ failure, and death.27

Additional proposed mechanisms of hyperglycemia‐induced harm to hospitalized patients, some potentially specifically reduced by insulin therapy, resemble those discussed in relation to macrovascular disease and include activation of inflammatory cytokines, matrix metalloproteinases, and adhesion molecules, and the adverse arrhythmogenic effects of elevated circulating nonesterified fatty acids (Figure 1).2834

Figure 1

CRITICAL WINDOW OF TIME

The results of several retrospectively or prospectively conducted single‐institution observational studies suggest there is a critical window of time within which clinicians must get it right, when attempting glycemic control or else jeopardize therapeutic goals, such as duration of remission in treatment of acute lymphocytic leukemia35 or avoidance of acute rejection in renal allograft surgery.36 Additionally, delayed risk of infection appears to be linked to previous glycemic control during specific early time frames surrounding surgery, renal transplantation, admission for trauma, and induction chemotherapy for leukemia (Table 1).3541 For patients who have diabetes, the potential to reduce the consequences of infections through intensified glycemic control probably begins prior to admission and in the hospital has still not been fully realized.4244

KEY STUDIES SHOWING CLINICAL BENEFIT OF TIGHT GLYCEMIC CONTROL

A summary of several key studies that demonstrated the clinical benefit of tight glycemic control is shown in Table 2. These studies successfully separated the intensively and conventionally managed study groups according blood glucose. Although trials using glucose‐insulin‐potassium infusions (GIK) such that blood glucose was lowered have shown benefit for patients who have had myocardial infarctions4547 or cardiac surgery,48 not all GIK studies have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.49 In the setting of acute myocardial infarction, the DIGAMI 2 trial and the HI‐5 trials failed to achieve the intended separation between treatment groups.50, 51 It has been speculated that if insulin is delivered so as to not achieve normoglycemia, then hyperinsulinemia in the presence of hyperglycemia actually may be proinflammatory.52

The findings of the negative intensive insulin studies do not offset the evidence favoring glycemic control, derived from studies that actually achieved the lowering of blood glucose in the intensive groups, such as the successful prospectively designed trials in myocardial infarction or surgical or medical intensive care units15, 45, 47, 53, 54 and the long‐running, large, prospectively monitored Portland series utilizing insulin infusion for cardiac surgery,40, 5557 which have demonstrated the beneficial effects of euglycemia on mortality and morbidity, or the findings of Krinsley, reported elsewhere in this issue.58, 59 The well‐recognized correlation between outcomes of acute stroke and poststroke hyperglycemia has led to the design of a multicenter trial of glucose‐insulin‐potassium infusion for stroke, in which separation of groups by blood glucose has been achieved.6062 The success of GIK therapy in controlling hyperglycemia depends in part on the particular formulation of the infusion as it matches patient needs, and it is probable that insulin infusion following stroke is capable of safely achieving even tighter glycemic control than GIK.63 Intravenous insulin infusion therapy is more difficult to conduct than GIK therapy. However, because of concern about the proinflammatory and prothrombotic effects of hyperglycemia and recognition of the occasional failure of GIK infusions to control hyperglycemia and of the anti‐inflammatory, antithrombotic, and vasodilatory actions of insulin, there have been calls for additional trials of insulin infusions (as opposed to glucose‐insulin infusions) for both acute myocardial infarction and stroke.52, 64

HYPOGLYCEMIA

Serious or fatal sequelae of hypoglycemia are the principal safety risks in intensive insulin management.9, 65 Case ascertainment cannot be assured by glucose averaging methods but instead requires a method of searching for isolated episodes of hypoglycemia.10 One of the most dreaded consequences of nonfatal hypoglycemia is permanent impairment of intellectual function. Because many euglycemic medically ill patients experience alteration of sensorium while acutely ill, there is a risk that the consequences of an actual episode of severe hypoglycemia will be ascribed to other comorbidities, overlooking or misattributing the altered cognitive function that may persist at discharge to causes other than the obvious iatrogenic one. Because there is an increased risk of hypoglycemia during intensive insulin therapy, controversy has arisen over glycemic targets, especially among critically ill nonsurgical patients.54, 6669

On the other hand, the consequences of hypoglycemia during intensive intravenous insulin therapy in a surgical ICU were said to be negligible.15 In hospitalized elderly patients, hypoglycemia in association with increased mortality risk may not be an independent predictor.70 In the critical care unit, predictors of hypoglycemia are identifiable after the introduction of strict glycemic control that include not only insulin therapy but also CVVH treatment with bicarbonate substitution fluid, discontinuation of nutrition without insulin adjustment, prior diagnosis of diabetes mellitus, sepsis, and the need for inotropic or vasopressor drugs.71 A prudent policy for the future would be not only to treat hypoglycemia promptly when it does occur, with attention to subsequent monitoring to avoid relapse or recurrence, but also to actively introduce strategies for predicting the risk of hypoglycemia and preventing it, especially when high risk is identified.10 The fear of hypoglycemia should not paralyze efforts to achieve better glycemic control in hospitalized patients.

UNANSWERED QUESTIONS AND VISION FOR THE FUTURE

On general wards, 38% of admitted patients may have hyperglycemia.72 As shown in the Leuven, Belgium, study, to achieve the target BG of less than 110 mg/dL in the intensive group in the surgical critical care unit, it was necessary to administer intravenous insulin infusion to essentially all patients. In a study that utilized continuous glucose monitoring, normoglycemia in patients in the intensive care unit was achieved as little as 22% of the time.73

An actively debated subject is how best to assess hospital performance in glycemic control (glucometrics). Hospitals need to show satisfactory control of variability between patients and within the treatment course of individual patients. That is, it is not sufficient to be satisfied with reasonable results of average blood glucose, using blood glucose as the unit of observation (where n is the number of blood glucose determinations). Alternatives are to use patient day or individual patient as a unit of observation (where n is the number of patient days and the number of patients, respectively). Time‐weighting methods are cumbersome but increase the validity of the averaging method used. When the patient is the unit of observation, possible measures include a per‐patient blood glucose average, percentage of blood glucose measurements with certain ranges, time spent within certain blood glucose ranges, or area under the curve of blood glucose versus time. Caveats about glucometrics pertain to both intravenous insulin infusion and also subcutaneous insulin management.74

Although awaiting additional evidence, diabetes experts have widely accepted the proposition that hospitals should focus on prevention of hyperglycemia as an important patient safety factor.75 Although the target range for glycemic control remains controversial, many students of the subject have endorsed the recommendations mentioned in the lead article in this issue, with the understanding that these criteria were developed from the results of the Leuven, Belgium, study, in which a whole blood glucose analyzer was used for measurement, and that the method of measurement of blood glucose must be considered in interpreting applicability of the target range at individual hospitals, many of which use plasma‐correlated methods yielding higher results. However, in new settings and for medical conditions that have not yet been rigorously evaluated by clinical trials, it is an unanswered question whether intensification of glycemic control can be achieved safely outside the critical care unit and, if so, what type of insulin therapy should be used and for what conditions the benefits would outweigh the risks and justify the costs.

Most inpatient management probably will continue to be conducted using subcutaneous injection therapy,7682 designed to match carbohydrate exposure through the appropriate use of analogs or conventional insulin products. One argument for the use of insulin analogs in the hospital, using basal‐prandial‐correction therapy, is the probability of reducing hypoglycemia and getting closer to target range control among patients who are eating but who are at risk for abrupt suspension of meals. Aggressive subcutaneous management strategies are likely to be most effective when standardized protocols, order sets, and informative computerized order entry systems gain widespread hospital acceptance.

If the importance of gaining glycemic control is highly time dependent and if hyperglycemia is uncontrolled, then a strong argument can be made for routine use of intravenous insulin infusion. For appropriately selected patients, intravenous insulin infusion is cost effective,83, 84 and its use can be extended to appropriate patients outside the critical care unit.8587 Many hospitals have protocols for intravenous insulin but use them only sporadically. For patients who already are in the intensive care setting, it is imperative to develop policies that require introduction of intravenous insulin infusion at a given glycemic threshold. On general wards that lack sufficient staffing to conduct intravenous insulin therapy, it is appropriate either to transfer candidate patients to a ward that has adequate staffing when medical condition requires improved control or to develop policies and procedures that will extend the use of intravenous insulin infusion to general wards. In the future, new technologies can be envisioned that will unburden nursing staff, making intravenous insulin infusion realizable as the treatment of choice for hemodynamically stable patients in most hospital settings. These technologies will include continuous monitoring of blood glucose, dose‐defining algorithms, and the eventual development of a fully automated closed‐loop system of monitoring and delivery that might automatically match insulin delivery to carbohydrate exposure and patient insulin sensitivity.8893