Hyperglycemia is a common occurrence in hospitalized patients, with and without a prior diagnosis of diabetes mellitus.13 Estimates of prevalence of diabetes mellitus in hospitalized adult patients range from 12% to 25%.4 Hyperglycemia is a strong predictor of adverse clinical outcome in a range of diseases such as acute stroke, congestive heart failure, community‐acquired pneumonia, and acute myocardial infarction.58 Hyperglycemia is also a risk factor for surgical infection in patients undergoing cardiac surgery.9, 10 A landmark prospective randomized controlled clinical trial by van den Berghe et al.11 demonstrated that tight glucose control (target blood glucose level 80110 mg/dL) with intravenous insulin in critically ill surgical patients led to dramatic reductions in acute renal failure, critical illness polyneuropathy, hospital mortality, and bloodstream infection. Other clinical studies have demonstrated that glycemic control with intravenous insulin improves clinical outcomes and reduces length of stay in patients with diabetes undergoing cardiac surgery.12, 13

Based upon these findings, the American College of Endocrinology (ACE) published recommendations in 2004 for hospital diabetes and metabolic control.14 Similar recommendations for hospital glycemic control have been included in the American Diabetes Association (ADA) guidelines since 2005.15 There is now emerging consensus that use of continuous insulin infusion given through a standardized protocol is the standard of care to control hyperglycemia in critically ill patients.1618 Likewise, use of specific hospital insulin regimens that include basal and short‐acting insulin with appropriate bedside glucose monitoring and avoiding use of sliding scale short‐acting insulin alone has become recognized as the most effective approach for glucose management in hospitalized patients not requiring intravenous insulin.4, 1921

The University HealthSystem Consortium (UHC) is an alliance of 97 academic health centers and 153 of their associated hospitals that conducts benchmarking studies on clinical and operational topics with member academic medical centers and develops new programs to improve quality of care, patient safety, and operational, clinical, and financial performance. In late 2004, UHC launched the Glycemic Control Benchmarking Project to determine the current status of glycemic control in adult patients admitted to academic medical centers, types of treatment employed to control glucose, and operational measures and practices of care for glycemic control in the hospital setting. The goal of the project was to describe contemporary glucose management for the purpose of identifying best practices. The information was later shared with each participating medical center to allow them to better align care delivery with ADA and ACE guidelines. Thirty‐seven academic medical centers agreed to participate and submit patient level data as well as an operational survey of current policies and practices for hospital glycemic control. This report summarizes the key findings from retrospective analyses of hospital and patient‐level data and describes contemporary management of hyperglycemia in academic medical centers.

PATIENTS AND METHODS

To be eligible for the study, hospital patients at each participating medical center had to be 18 years of age, have a 72‐hour or longer length of stay, and be admitted with 1 or more of the following Diagnostic‐related group (DRG) codes: 89 (simple pneumonia/ pleurisy), 109 (coronary artery bypass grafting without catheterization), 127 (heart failure and shock), 143 (chest pain), 209 (joint/limb procedure), 316 (renal failure), 478 (other vascular procedures), or 527 (percutaneous intervention with drug eluting stent without acute myocardial infarction). The DRG codes were selected from analysis of the UHC Clinical Data Base because they were the most common adult medical and surgical admission codes that included diabetes as a secondary diagnosis for academic medical centers and were believed to best represent the majority of hospital admissions. Each participating medical center received a secure electronic listing of their eligible patients discharged between July 1, 2004 and September 30, 2004 from the UHC Clinical Data Base. Each center identified data extractors who were trained via teleconference and received technical and content support by UHC staff. The data were collected by chart review and submitted electronically to UHC from February to April 2005.

For each medical center, patients were screened in reverse chronological order proceeding back in time until the minimum number of 50 eligible cases was obtained or until all potential cases were screened. Although 50 cases was the recommended minimum sample size per site, each medical center was encouraged to submit as many eligible cases as possible. The median number of cases submitted by site was 50 (interquartile range [IQR], 4251). Cases were entered into the study if they met the eligibility criteria and at least one of the following inclusion criteria: (1) two consecutive blood glucose readings >180 mg/dL within a 24hour period, or (2) insulin treatment at any time during the hospitalization. Exclusion criteria included history of pancreatic transplant, pregnancy at time of admission, hospice or palliative care during hospital admission, and patients who received insulin for a reason other than blood glucose control (ie, hyperkalemia). Early in the data collection, DRG 209 was dropped from potential screening due to the low yield of meeting screening criteria for blood glucose readings. Of the 315 cases screened for DRG 209 only 44 met all inclusion criteria and remain in the study population.

A maximum of 3 consecutive days of blood glucose (BG) readings were collected for each patient, referred to as measurement day 1, measurement day 2, and measurement day 3. Measurement day 1 is defined as the day the first of 2 consecutive blood glucose levels >180 mg/dL occurred during the hospitalization or as the first day insulin was administered during the hospitalization, whichever came first; 40.6% of patients had the day of admission as their first measurement day. Glucose measurements were recorded by hour for each measurement day as available, and if more than 1 glucose value was available within a particular hour, only the first result was recorded. Both bedside and laboratory serum glucose values were utilized, and glycosylated hemoglobin (A1C) values were included if they were recorded during the hospitalization or within 30 days prior to admission;22 95.7% of patients had BG results reported for all 3 measurement days. We defined estimated 6 _AM glucose for each subject as: the 6 _AM glucose if it was available; otherwise the average of the 5 _AM and 7 _AM glucose values if at least 1 of them was available; otherwise the average of the 4 _AM and 8 _AM glucose values if at least 1 of them was available. Relevant demographics, medical history, hospitalization details, type and route of insulin administration, and discharge data were also collected. For subcutaneous insulin administration, use of regular, lispro, or aspart insulin was classified as short‐acting insulin; use of neutral protamine Hagedorn (NPH), ultralente, or glargine insulin was classified as long‐acting insulin. For analysis of glycemic control measures, patient‐days in which location or glucose data were not recorded were excluded from analysis. For the analysis comparing subcutaneous versus intravenous insulin treatment on glucose control, patients who received a combination of therapy with subcutaneous and intravenous insulin on the same measurement day were excluded from the analysis (44 patients on day 1, 96 on day 2, and 47 on day 3). For this retrospective analysis, UHC provided a deidentified data set to the authors. The study protocol was reviewed by the Vanderbilt University Institutional Review Board and deemed to be nonhuman subject research since the data set contained no personal or institutional identifiers. Therefore, no informed consent of subjects was required.

Measures of glucose control (median glucose and estimated 6 _AM glucose) were analyzed by patient‐day,23 and were compared by a Wilcoxon rank sum test or an analysis of variance, as indicated. P values <0.05 were considered significant. To compare effects of intravenous (IV) insulin, subcutaneous long‐acting short‐acting insulin, and subcutaneous short‐acting insulin use alone on glycemic control, mixed effects linear regression modeling for median glucose and mixed effects logistic regression modeling for hyperglycemia and hypoglycemia were used to adjust for fixed effects of age, gender, diabetes status, all patient refined diagnosis related groups (APR‐DRG) severity of illness score, outpatient diabetes treatment, patient location, admission diagnosis, and random effect of hospital site. Separate regression models were performed for measurement days 2 and 3. Statistical analyses were performed with Stata version 8 (Stata Corporation, College Station, TX), R version 2.1.0 (R Foundation for Statistical Computing, Vienna, Austria; www.r‐project.org), and SAS version 9 (SAS Institute, Cary, NC).

RESULTS

Thirty‐seven US academic medical centers from 24 states contributed to the analysis. A total of 4,367 cases meeting age, length of stay, and DRG criteria were screened for inclusion in the study; 2,649 (60.7%) screened cases were excluded due to failure to meet inclusion criteria (51%) or presence of exclusionary conditions (9.7%); 1,718 (39.3%) screened cases met all criteria and were included in this analysis. Patient characteristics are summarized in Table 1. A majority of patients (79%) had a documented history of diabetes, and most of these were classified as type 2 diabetes in the hospital record. Of the patients who were classified as having diabetes on admission, 50.8% were on some form of outpatient insulin therapy with or without oral diabetes agents. Patients with a diagnosis of diabetes had a median admission glucose of 158 mg/dL (IQR, 118221), which was significantly higher than the median admission glucose of 119 mg/dL (IQR, 100160) for patients without diabetes (P < 0.001, rank‐sum test).

To determine overall glycemic control for the cohort, median glucose was calculated for each patient, stratified by diabetes status and location for each measurement day (Table 2). Patient‐days with a location of emergency department (96 patients on day 1, 6 on day 2, and 2 on day 3) and two patients whose location was not defined were excluded from the analysis. Overall, median glucose declined from measurement day 1 to day 3. For patients with diabetes, median glucose was significantly lower in the intensive care unit (ICU) compared to the general ward or intermediate care for measurement days 1 and 2, but not day 3. This difference was more pronounced in patients without diabetes, with median glucose significantly lower in the ICU for all 3 measurement days compared to other locations. As expected, median glucose was lower for patients without diabetes compared to patients with diabetes for all measurement days and locations. Hyperglycemia was common; 867 of 1,718 (50%) patients had at least 1 glucose measurement 180 mg/dL on both days 2 and 3; 18% of all patients had a median glucose 180 mg/dL on all 3 measurement days. Daily 6 _AM glucose was the summary glycemic control measure in the clinical trial by van den Berghe et al.,11 with goal glucose of 80 to 110 mg/dL in the intensive treatment group. Since the glycemic target of the American College of Endocrinology Position Statement is <110 mg/dL (based largely on van den Berghe et al.11) we also calculated estimated 6 _AM glucose for ICU patient‐days to determine the proportion of patients attaining this target.14 Estimated 6 _AM glucose was lower in ICU patients without diabetes compared to those with diabetes. For patients with diabetes, only 20% of patients in the ICU had an estimated 6 _AM glucose 110 mg/dL on measurement day 2, and only 24% on day 3. For patients without diabetes, 27% and 25% had an estimated 6 _AM glucose 110 mg/dL on days 2 and 3, respectively.

For the overall cohort, insulin was the most common treatment for hyperglycemia, with 84.6% of all patients receiving some form of insulin therapy on the second measurement day. On the second day, 30.8% received short‐acting subcutaneous insulin only, 8.2% received intravenous insulin infusion, 22.5% received both short‐acting and long‐acting subcutaneous insulin, 3.9% received oral agents, 23% received some combination of insulin therapies and/or oral agents, and 11.9% received no treatment. To determine the effect of intravenous versus subcutaneous insulin treatment on glycemic control, we compared patients by insulin treatment and location for each measurement day (Table 3). Intravenous insulin was used predominantly in the ICU, and was associated with significantly lower median glucose compared to subcutaneous insulin in both locations for all 3 measurement days. As expected, the average number of glucose measures per patient was significantly higher for those receiving intravenous insulin. Intravenous insulin use in the ICU was associated with a significantly lower number of patients with hyperglycemia, defined as the number who had 1 or more glucose values 180 mg/dL during a given measurement day. Of note, intravenous insulin use in the ICU was associated with a significantly higher proportion of patients who had hypoglycemia (defined as the number of patients who had one or more glucose values <70 mg/dL) compared to subcutaneous insulin only on measurement day 1 (8.1% versus 2.9%; P = 0.021), but not on days 2 (12.7% versus 8.0%; P > 0.05) or 3 (12.7% versus 7.8%; P > 0.05). Severe hypoglycemia, defined as a blood glucose recording <50 mg/dL,24 was rare, and occurred in only 2.8% of all patient days. On measurement day 1, 34 patients had a total of 49 severe hypoglycemic events; on day 2, 54 patients had 68 severe hypoglycemic events; on day 3, 54 patients had 68 severe hypoglycemic events. Only 3 patients had severe hypoglycemic events on all 3 measurement days. Analysis of severe hypoglycemia events stratified by intravenous versus subcutaneous insulin did not show any significant differences for any of the 3 measurement days (data not shown).

We hypothesized that use of subcutaneous long‐acting (basal) insulin (with or without short‐acting insulin) would be associated with superior glucose control compared to use of subcutaneous short‐acting insulin (sliding scale and/or scheduled prandial insulin) alone. We performed an exploratory multivariate regression analysis to compare the effect of IV insulin, long acting subcutaneous insulin short acting insulin, or short acting subcutaneous insulin alone on median glucose, hyperglycemic events (glucose 180 mg/dL), and hypoglycemic events (glucose <70 mg/dL) for days 2 and 3 (Table 4). Compared to short‐acting subcutaneous insulin alone, use of IV insulin but not long‐acting subcutaneous insulin was predictive of lower median glucose for days 2 and 3. Use of long‐acting subcutaneous insulin was not associated with significantly lower odds of hyperglycemic events for days 2 and 3, but was associated with higher odds of hypoglycemic events on day 2 (odds ratio [OR], 1.8; P = 0.01) when compared to short‐acting subcutaneous insulin alone.

We measured the performance of recommended hospital diabetes care practices (A1C assessment, documentation of diabetes history in the hospital record, admission laboratory glucose assessment, bedside glucose monitoring, recommended insulin therapy)14, 15 for all study patients, and also stratified performance by hospital (Table 5); 98.6% of all patients with a diagnosis of diabetes had physician documentation of their diabetes status recorded in the hospital record, and there was consistently high performance of this by hospital (Table 5); 77% of all patients with a history of diabetes had a laboratory blood glucose result recorded within 8 hours of hospital admission, and 81.3% of patients with a history of diabetes had blood glucose monitored at least 4 times on measurement day 2. Performance by hospital (Table 5) varied widely for glucose monitoring (range, 56.5%95.5% of patients by hospital) and admission laboratory glucose assessment (range, 39.0%97.1% of patients by hospital).

Of all patients, 31% had A1C measurement recorded during their hospitalization or within 30 days prior to admission. There was wide variation in hospital performance of A1C assessment in patients with diabetes (Table 5). Patients with a diagnosis of diabetes had a median A1C of 7.4% (IQR, 6.4%8.9%; n = 473), and those without a diagnosis of diabetes had a median A1C of 5.9% (IQR, 5.6%6.4%; n = 70). Of the patients with a history of diabetes who had A1C recorded, 59% had a value >7%. Of the patients without a history of diabetes who had A1C recorded, 43% had a value >6.0%, suggesting previously undiagnosed diabetes.25

We found wide variation among hospitals (range, 12.1%76.5%) in use of recommended regimens of insulin therapy, defined as short‐acting and long‐acting subcutaneous insulin or IV insulin infusion or insulin pump therapy on second measurement day. Endocrine/diabetes consultation was infrequent, only 9% of all patients were evaluated by an endocrinologist or diabetologist at any time during the hospitalization.

DISCUSSION

In this retrospective analysis of hospitalized patients who had 2 consecutive blood glucose values 180 mg/dL and/or received insulin therapy, hyperglycemia was common and hypoglycemia was infrequent. Use of intravenous insulin was associated with better glucose control, and did not increase the frequency of severe hypoglycemic events (glucose <50 mg/dL). The majority of patients with a history of diabetes had physician documentation in the hospital chart, laboratory serum glucose obtained within 8 hours of hospital admission, and at least 4 blood glucose determinations on the second measurement day.

Only 35% of patients with diabetes had an A1C measurement and of these almost 60% had an A1C level >7%. Though the A1C may not greatly affect acute glucose management in the hospital setting, it does identify patients that may require intensification of diabetes therapy at hospital discharge and coordination of outpatient follow‐up. A report of a UHC clinical benchmarking project of ambulatory diabetes care in academic medical centers demonstrated high rates of diagnostic testing, but only 34% of patients were at the A1C goal, and only 40% of patients above the A1C goal had adjustment of their diabetes regimen at their last clinic visit.26 In a retrospective study of patients with diabetes mellitus admitted to an academic teaching hospital, only 20% of discharges indicated a plan for diabetes follow‐up.27 Thus, intensification of antihyperglycemic therapy and formulation of a diabetes follow‐up plan on hospital discharge in those patients with A1C >7% represents an opportunity to improve glycemic control in the ambulatory setting. Also, measurement of A1C can be used for diabetes case‐finding in hospitalized patients with hyperglycemia.25 Previously unrecognized diabetes is a common finding in patients admitted with cardiovascular disease. In a study of patients admitted with myocardial infarction, 25% were found to have previously undiagnosed diabetes.28 Hospital patients with hyperglycemia but without a prior diagnosis of diabetes who have an elevation of A1C >6.0% can be identified as at‐risk for diabetes and postdischarge glucose evaluation can be arranged.

The target of maintaining all glucose values 180 mg/dL recommended in the 20052007 American Diabetes Association guidelines for hospital diabetes management was not commonly achieved, with over 70% of patients who received subcutaneous insulin therapy having 1 or more glucose values >180 on all 3 measurement days, regardless of patient location.15 The target of maintaining critically ill patients as close to 110 mg/dL as possible was also difficult to achieve, with only 25% of ICU patients having an estimated 6 _AM glucose <110 mg/dL on measurement day 3. A prospective cohort study of 107 inpatients with diabetes at Brigham and Women's Hospital showed a 76% prevalence of patients with at least one BG >180 mg/dL.29 In that study, 90% of patients had a sliding‐scale order, 36% received an oral diabetes agent, and 43% received basal insulin at some time during hospitalization. A recently published analysis by Wexler et al.30 compiled data of hospitalized patients with diabetes from an earlier 2003 UHC Diabetes Benchmarking Project (n = 274) and patients from 15 not‐for‐profit member hospitals of VHA, Incorporated (n = 725) to examine the prevalence of hyperglycemia and hypoglycemia. Hyperglycemia (defined as a single BG value >200 mg/dL) was common, occurring in 77% of patients in the UHC cohort and 76% in the VHA, Inc. cohort. This was comparable to our findings that 76.7% of ICU patients and 78.6% of ward patients treated with subcutaneous insulin had 1 or more BG values 180 mg/dL on measurement day 2. Wexler et al.30 also determined that use of basal insulin was associated with a higher prevalence of hyperglycemia and hypoglycemia in their study. Our regression analysis finding that long‐acting (basal) insulin use was not associated with improvement in glycemic control is consistent with the findings of the aforementioned study. There are a number of potential explanations for this: (1) underdosing of basal insulin or lack of adequate prandial insulin coverage for nutritional intake; (2) lack of effective titration in response to hyperglycemia; and (3) variation in the ordering and administration of basal insulin at different hospital sites.

Use of both manual and computerized IV insulin protocols has been shown to provide effective glucose control in critically ill patients.1618 Though intravenous insulin use was associated with better overall glucose control in our study; only about 50% of ICU patients received it on measurement day 1. A recent prospective randomized clinical trial demonstrated superior glycemic control in noncritically ill hospitalized patients with type 2 diabetes with basal/bolus insulin therapy compared to sliding scale insulin alone.31 Use of basal/bolus insulin regimens as part of a comprehensive hospital diabetes management program has been shown to improve glycemic control in an academic medical center.20 Therefore, we do not believe that our regression analysis findings invalidate the concept of basal/bolus insulin for inpatients with hyperglycemia, but rather indicate the need for more research into subcutaneous insulin regimens and hospital care practices that lead to improved glucose control. We found wide variation in hospital use of basal/bolus insulin regimens. Overall only 22.5% of all patients on the second measurement day received both short‐acting and long‐acting subcutaneous insulin, compared to 30.8% who received short‐acting subcutaneous insulin only. A recent consensus statement on inpatient glycemic control by the American College of Endocrinology and American Diabetes Association highlighted the systematic barriers to improved glycemic control in hospitals, such as inadequate knowledge of diabetes management techniques, fear of hypoglycemia, and skepticism about benefits of tighter glucose control.32

There are some important limitations to this study. The data are retrospective and only a limited number of hospital days and clinical variables could be assessed for each patient. As indicated in Table 3, there were significant differences in the frequency of glucose measurement depending on treatment, which can potentially bias estimated prevalence of hyperglycemia and hypoglycemia. We did not have a practical method to assess nutritional status or the adequacy of insulin dosing over time for each patient. We also could not assess the association of glycemic control on clinical outcomes such as hospital mortality or infection rates. Since this study was exclusively in academic medical centers, the generalization of findings to community‐based medical centers may be limited. The risk‐benefit of tight glycemic control in medical ICU patients based on clinical trial evidence has been unclear, and there is not broad agreement among clinicians on the recommended target for glycemic control in this group.3335 When we analyzed glycemic control in ICU patients we did not have a practical method to control for type of ICU and variations in individual ICU glycemic control targets. We recognize that the 2004 American College of Endocrinology recommendation of maintaining glucose 110 mg/dL may not be appropriate for all critically ill patients.14 Finally, clinical trial data are lacking on the effect of tight glucose control on major clinical outcomes for noncritically ill hospital patients. This has led to significant controversy regarding glycemic targets for different subgroups of hospitalized patients.34, 36

In summary, we found a high prevalence of persistent hyperglycemia in this large cohort of hospitalized patients, and hypoglycemia was infrequent. Use of IV insulin was associated with improvement in glycemic control, but was used in less than half of ICU patients. There was wide variation in hospital performance of recommended diabetes care measures. Opportunities to improve care in academic medical centers include expanded use of intravenous and subcutaneous basal/bolus insulin protocols and increased frequency of A1C testing.

Hyperglycemia is a common occurrence in hospitalized patients, with and without a prior diagnosis of diabetes mellitus.13 Estimates of prevalence of diabetes mellitus in hospitalized adult patients range from 12% to 25%.4 Hyperglycemia is a strong predictor of adverse clinical outcome in a range of diseases such as acute stroke, congestive heart failure, community‐acquired pneumonia, and acute myocardial infarction.58 Hyperglycemia is also a risk factor for surgical infection in patients undergoing cardiac surgery.9, 10 A landmark prospective randomized controlled clinical trial by van den Berghe et al.11 demonstrated that tight glucose control (target blood glucose level 80110 mg/dL) with intravenous insulin in critically ill surgical patients led to dramatic reductions in acute renal failure, critical illness polyneuropathy, hospital mortality, and bloodstream infection. Other clinical studies have demonstrated that glycemic control with intravenous insulin improves clinical outcomes and reduces length of stay in patients with diabetes undergoing cardiac surgery.12, 13

Based upon these findings, the American College of Endocrinology (ACE) published recommendations in 2004 for hospital diabetes and metabolic control.14 Similar recommendations for hospital glycemic control have been included in the American Diabetes Association (ADA) guidelines since 2005.15 There is now emerging consensus that use of continuous insulin infusion given through a standardized protocol is the standard of care to control hyperglycemia in critically ill patients.1618 Likewise, use of specific hospital insulin regimens that include basal and short‐acting insulin with appropriate bedside glucose monitoring and avoiding use of sliding scale short‐acting insulin alone has become recognized as the most effective approach for glucose management in hospitalized patients not requiring intravenous insulin.4, 1921

The University HealthSystem Consortium (UHC) is an alliance of 97 academic health centers and 153 of their associated hospitals that conducts benchmarking studies on clinical and operational topics with member academic medical centers and develops new programs to improve quality of care, patient safety, and operational, clinical, and financial performance. In late 2004, UHC launched the Glycemic Control Benchmarking Project to determine the current status of glycemic control in adult patients admitted to academic medical centers, types of treatment employed to control glucose, and operational measures and practices of care for glycemic control in the hospital setting. The goal of the project was to describe contemporary glucose management for the purpose of identifying best practices. The information was later shared with each participating medical center to allow them to better align care delivery with ADA and ACE guidelines. Thirty‐seven academic medical centers agreed to participate and submit patient level data as well as an operational survey of current policies and practices for hospital glycemic control. This report summarizes the key findings from retrospective analyses of hospital and patient‐level data and describes contemporary management of hyperglycemia in academic medical centers.

PATIENTS AND METHODS

To be eligible for the study, hospital patients at each participating medical center had to be 18 years of age, have a 72‐hour or longer length of stay, and be admitted with 1 or more of the following Diagnostic‐related group (DRG) codes: 89 (simple pneumonia/ pleurisy), 109 (coronary artery bypass grafting without catheterization), 127 (heart failure and shock), 143 (chest pain), 209 (joint/limb procedure), 316 (renal failure), 478 (other vascular procedures), or 527 (percutaneous intervention with drug eluting stent without acute myocardial infarction). The DRG codes were selected from analysis of the UHC Clinical Data Base because they were the most common adult medical and surgical admission codes that included diabetes as a secondary diagnosis for academic medical centers and were believed to best represent the majority of hospital admissions. Each participating medical center received a secure electronic listing of their eligible patients discharged between July 1, 2004 and September 30, 2004 from the UHC Clinical Data Base. Each center identified data extractors who were trained via teleconference and received technical and content support by UHC staff. The data were collected by chart review and submitted electronically to UHC from February to April 2005.

For each medical center, patients were screened in reverse chronological order proceeding back in time until the minimum number of 50 eligible cases was obtained or until all potential cases were screened. Although 50 cases was the recommended minimum sample size per site, each medical center was encouraged to submit as many eligible cases as possible. The median number of cases submitted by site was 50 (interquartile range [IQR], 4251). Cases were entered into the study if they met the eligibility criteria and at least one of the following inclusion criteria: (1) two consecutive blood glucose readings >180 mg/dL within a 24hour period, or (2) insulin treatment at any time during the hospitalization. Exclusion criteria included history of pancreatic transplant, pregnancy at time of admission, hospice or palliative care during hospital admission, and patients who received insulin for a reason other than blood glucose control (ie, hyperkalemia). Early in the data collection, DRG 209 was dropped from potential screening due to the low yield of meeting screening criteria for blood glucose readings. Of the 315 cases screened for DRG 209 only 44 met all inclusion criteria and remain in the study population.

A maximum of 3 consecutive days of blood glucose (BG) readings were collected for each patient, referred to as measurement day 1, measurement day 2, and measurement day 3. Measurement day 1 is defined as the day the first of 2 consecutive blood glucose levels >180 mg/dL occurred during the hospitalization or as the first day insulin was administered during the hospitalization, whichever came first; 40.6% of patients had the day of admission as their first measurement day. Glucose measurements were recorded by hour for each measurement day as available, and if more than 1 glucose value was available within a particular hour, only the first result was recorded. Both bedside and laboratory serum glucose values were utilized, and glycosylated hemoglobin (A1C) values were included if they were recorded during the hospitalization or within 30 days prior to admission;22 95.7% of patients had BG results reported for all 3 measurement days. We defined estimated 6 _AM glucose for each subject as: the 6 _AM glucose if it was available; otherwise the average of the 5 _AM and 7 _AM glucose values if at least 1 of them was available; otherwise the average of the 4 _AM and 8 _AM glucose values if at least 1 of them was available. Relevant demographics, medical history, hospitalization details, type and route of insulin administration, and discharge data were also collected. For subcutaneous insulin administration, use of regular, lispro, or aspart insulin was classified as short‐acting insulin; use of neutral protamine Hagedorn (NPH), ultralente, or glargine insulin was classified as long‐acting insulin. For analysis of glycemic control measures, patient‐days in which location or glucose data were not recorded were excluded from analysis. For the analysis comparing subcutaneous versus intravenous insulin treatment on glucose control, patients who received a combination of therapy with subcutaneous and intravenous insulin on the same measurement day were excluded from the analysis (44 patients on day 1, 96 on day 2, and 47 on day 3). For this retrospective analysis, UHC provided a deidentified data set to the authors. The study protocol was reviewed by the Vanderbilt University Institutional Review Board and deemed to be nonhuman subject research since the data set contained no personal or institutional identifiers. Therefore, no informed consent of subjects was required.

Measures of glucose control (median glucose and estimated 6 _AM glucose) were analyzed by patient‐day,23 and were compared by a Wilcoxon rank sum test or an analysis of variance, as indicated. P values <0.05 were considered significant. To compare effects of intravenous (IV) insulin, subcutaneous long‐acting short‐acting insulin, and subcutaneous short‐acting insulin use alone on glycemic control, mixed effects linear regression modeling for median glucose and mixed effects logistic regression modeling for hyperglycemia and hypoglycemia were used to adjust for fixed effects of age, gender, diabetes status, all patient refined diagnosis related groups (APR‐DRG) severity of illness score, outpatient diabetes treatment, patient location, admission diagnosis, and random effect of hospital site. Separate regression models were performed for measurement days 2 and 3. Statistical analyses were performed with Stata version 8 (Stata Corporation, College Station, TX), R version 2.1.0 (R Foundation for Statistical Computing, Vienna, Austria; www.r‐project.org), and SAS version 9 (SAS Institute, Cary, NC).

RESULTS

Thirty‐seven US academic medical centers from 24 states contributed to the analysis. A total of 4,367 cases meeting age, length of stay, and DRG criteria were screened for inclusion in the study; 2,649 (60.7%) screened cases were excluded due to failure to meet inclusion criteria (51%) or presence of exclusionary conditions (9.7%); 1,718 (39.3%) screened cases met all criteria and were included in this analysis. Patient characteristics are summarized in Table 1. A majority of patients (79%) had a documented history of diabetes, and most of these were classified as type 2 diabetes in the hospital record. Of the patients who were classified as having diabetes on admission, 50.8% were on some form of outpatient insulin therapy with or without oral diabetes agents. Patients with a diagnosis of diabetes had a median admission glucose of 158 mg/dL (IQR, 118221), which was significantly higher than the median admission glucose of 119 mg/dL (IQR, 100160) for patients without diabetes (P < 0.001, rank‐sum test).

To determine overall glycemic control for the cohort, median glucose was calculated for each patient, stratified by diabetes status and location for each measurement day (Table 2). Patient‐days with a location of emergency department (96 patients on day 1, 6 on day 2, and 2 on day 3) and two patients whose location was not defined were excluded from the analysis. Overall, median glucose declined from measurement day 1 to day 3. For patients with diabetes, median glucose was significantly lower in the intensive care unit (ICU) compared to the general ward or intermediate care for measurement days 1 and 2, but not day 3. This difference was more pronounced in patients without diabetes, with median glucose significantly lower in the ICU for all 3 measurement days compared to other locations. As expected, median glucose was lower for patients without diabetes compared to patients with diabetes for all measurement days and locations. Hyperglycemia was common; 867 of 1,718 (50%) patients had at least 1 glucose measurement 180 mg/dL on both days 2 and 3; 18% of all patients had a median glucose 180 mg/dL on all 3 measurement days. Daily 6 _AM glucose was the summary glycemic control measure in the clinical trial by van den Berghe et al.,11 with goal glucose of 80 to 110 mg/dL in the intensive treatment group. Since the glycemic target of the American College of Endocrinology Position Statement is <110 mg/dL (based largely on van den Berghe et al.11) we also calculated estimated 6 _AM glucose for ICU patient‐days to determine the proportion of patients attaining this target.14 Estimated 6 _AM glucose was lower in ICU patients without diabetes compared to those with diabetes. For patients with diabetes, only 20% of patients in the ICU had an estimated 6 _AM glucose 110 mg/dL on measurement day 2, and only 24% on day 3. For patients without diabetes, 27% and 25% had an estimated 6 _AM glucose 110 mg/dL on days 2 and 3, respectively.

For the overall cohort, insulin was the most common treatment for hyperglycemia, with 84.6% of all patients receiving some form of insulin therapy on the second measurement day. On the second day, 30.8% received short‐acting subcutaneous insulin only, 8.2% received intravenous insulin infusion, 22.5% received both short‐acting and long‐acting subcutaneous insulin, 3.9% received oral agents, 23% received some combination of insulin therapies and/or oral agents, and 11.9% received no treatment. To determine the effect of intravenous versus subcutaneous insulin treatment on glycemic control, we compared patients by insulin treatment and location for each measurement day (Table 3). Intravenous insulin was used predominantly in the ICU, and was associated with significantly lower median glucose compared to subcutaneous insulin in both locations for all 3 measurement days. As expected, the average number of glucose measures per patient was significantly higher for those receiving intravenous insulin. Intravenous insulin use in the ICU was associated with a significantly lower number of patients with hyperglycemia, defined as the number who had 1 or more glucose values 180 mg/dL during a given measurement day. Of note, intravenous insulin use in the ICU was associated with a significantly higher proportion of patients who had hypoglycemia (defined as the number of patients who had one or more glucose values <70 mg/dL) compared to subcutaneous insulin only on measurement day 1 (8.1% versus 2.9%; P = 0.021), but not on days 2 (12.7% versus 8.0%; P > 0.05) or 3 (12.7% versus 7.8%; P > 0.05). Severe hypoglycemia, defined as a blood glucose recording <50 mg/dL,24 was rare, and occurred in only 2.8% of all patient days. On measurement day 1, 34 patients had a total of 49 severe hypoglycemic events; on day 2, 54 patients had 68 severe hypoglycemic events; on day 3, 54 patients had 68 severe hypoglycemic events. Only 3 patients had severe hypoglycemic events on all 3 measurement days. Analysis of severe hypoglycemia events stratified by intravenous versus subcutaneous insulin did not show any significant differences for any of the 3 measurement days (data not shown).

We hypothesized that use of subcutaneous long‐acting (basal) insulin (with or without short‐acting insulin) would be associated with superior glucose control compared to use of subcutaneous short‐acting insulin (sliding scale and/or scheduled prandial insulin) alone. We performed an exploratory multivariate regression analysis to compare the effect of IV insulin, long acting subcutaneous insulin short acting insulin, or short acting subcutaneous insulin alone on median glucose, hyperglycemic events (glucose 180 mg/dL), and hypoglycemic events (glucose <70 mg/dL) for days 2 and 3 (Table 4). Compared to short‐acting subcutaneous insulin alone, use of IV insulin but not long‐acting subcutaneous insulin was predictive of lower median glucose for days 2 and 3. Use of long‐acting subcutaneous insulin was not associated with significantly lower odds of hyperglycemic events for days 2 and 3, but was associated with higher odds of hypoglycemic events on day 2 (odds ratio [OR], 1.8; P = 0.01) when compared to short‐acting subcutaneous insulin alone.

We measured the performance of recommended hospital diabetes care practices (A1C assessment, documentation of diabetes history in the hospital record, admission laboratory glucose assessment, bedside glucose monitoring, recommended insulin therapy)14, 15 for all study patients, and also stratified performance by hospital (Table 5); 98.6% of all patients with a diagnosis of diabetes had physician documentation of their diabetes status recorded in the hospital record, and there was consistently high performance of this by hospital (Table 5); 77% of all patients with a history of diabetes had a laboratory blood glucose result recorded within 8 hours of hospital admission, and 81.3% of patients with a history of diabetes had blood glucose monitored at least 4 times on measurement day 2. Performance by hospital (Table 5) varied widely for glucose monitoring (range, 56.5%95.5% of patients by hospital) and admission laboratory glucose assessment (range, 39.0%97.1% of patients by hospital).

Of all patients, 31% had A1C measurement recorded during their hospitalization or within 30 days prior to admission. There was wide variation in hospital performance of A1C assessment in patients with diabetes (Table 5). Patients with a diagnosis of diabetes had a median A1C of 7.4% (IQR, 6.4%8.9%; n = 473), and those without a diagnosis of diabetes had a median A1C of 5.9% (IQR, 5.6%6.4%; n = 70). Of the patients with a history of diabetes who had A1C recorded, 59% had a value >7%. Of the patients without a history of diabetes who had A1C recorded, 43% had a value >6.0%, suggesting previously undiagnosed diabetes.25

We found wide variation among hospitals (range, 12.1%76.5%) in use of recommended regimens of insulin therapy, defined as short‐acting and long‐acting subcutaneous insulin or IV insulin infusion or insulin pump therapy on second measurement day. Endocrine/diabetes consultation was infrequent, only 9% of all patients were evaluated by an endocrinologist or diabetologist at any time during the hospitalization.

DISCUSSION

In this retrospective analysis of hospitalized patients who had 2 consecutive blood glucose values 180 mg/dL and/or received insulin therapy, hyperglycemia was common and hypoglycemia was infrequent. Use of intravenous insulin was associated with better glucose control, and did not increase the frequency of severe hypoglycemic events (glucose <50 mg/dL). The majority of patients with a history of diabetes had physician documentation in the hospital chart, laboratory serum glucose obtained within 8 hours of hospital admission, and at least 4 blood glucose determinations on the second measurement day.

Only 35% of patients with diabetes had an A1C measurement and of these almost 60% had an A1C level >7%. Though the A1C may not greatly affect acute glucose management in the hospital setting, it does identify patients that may require intensification of diabetes therapy at hospital discharge and coordination of outpatient follow‐up. A report of a UHC clinical benchmarking project of ambulatory diabetes care in academic medical centers demonstrated high rates of diagnostic testing, but only 34% of patients were at the A1C goal, and only 40% of patients above the A1C goal had adjustment of their diabetes regimen at their last clinic visit.26 In a retrospective study of patients with diabetes mellitus admitted to an academic teaching hospital, only 20% of discharges indicated a plan for diabetes follow‐up.27 Thus, intensification of antihyperglycemic therapy and formulation of a diabetes follow‐up plan on hospital discharge in those patients with A1C >7% represents an opportunity to improve glycemic control in the ambulatory setting. Also, measurement of A1C can be used for diabetes case‐finding in hospitalized patients with hyperglycemia.25 Previously unrecognized diabetes is a common finding in patients admitted with cardiovascular disease. In a study of patients admitted with myocardial infarction, 25% were found to have previously undiagnosed diabetes.28 Hospital patients with hyperglycemia but without a prior diagnosis of diabetes who have an elevation of A1C >6.0% can be identified as at‐risk for diabetes and postdischarge glucose evaluation can be arranged.

The target of maintaining all glucose values 180 mg/dL recommended in the 20052007 American Diabetes Association guidelines for hospital diabetes management was not commonly achieved, with over 70% of patients who received subcutaneous insulin therapy having 1 or more glucose values >180 on all 3 measurement days, regardless of patient location.15 The target of maintaining critically ill patients as close to 110 mg/dL as possible was also difficult to achieve, with only 25% of ICU patients having an estimated 6 _AM glucose <110 mg/dL on measurement day 3. A prospective cohort study of 107 inpatients with diabetes at Brigham and Women's Hospital showed a 76% prevalence of patients with at least one BG >180 mg/dL.29 In that study, 90% of patients had a sliding‐scale order, 36% received an oral diabetes agent, and 43% received basal insulin at some time during hospitalization. A recently published analysis by Wexler et al.30 compiled data of hospitalized patients with diabetes from an earlier 2003 UHC Diabetes Benchmarking Project (n = 274) and patients from 15 not‐for‐profit member hospitals of VHA, Incorporated (n = 725) to examine the prevalence of hyperglycemia and hypoglycemia. Hyperglycemia (defined as a single BG value >200 mg/dL) was common, occurring in 77% of patients in the UHC cohort and 76% in the VHA, Inc. cohort. This was comparable to our findings that 76.7% of ICU patients and 78.6% of ward patients treated with subcutaneous insulin had 1 or more BG values 180 mg/dL on measurement day 2. Wexler et al.30 also determined that use of basal insulin was associated with a higher prevalence of hyperglycemia and hypoglycemia in their study. Our regression analysis finding that long‐acting (basal) insulin use was not associated with improvement in glycemic control is consistent with the findings of the aforementioned study. There are a number of potential explanations for this: (1) underdosing of basal insulin or lack of adequate prandial insulin coverage for nutritional intake; (2) lack of effective titration in response to hyperglycemia; and (3) variation in the ordering and administration of basal insulin at different hospital sites.

Use of both manual and computerized IV insulin protocols has been shown to provide effective glucose control in critically ill patients.1618 Though intravenous insulin use was associated with better overall glucose control in our study; only about 50% of ICU patients received it on measurement day 1. A recent prospective randomized clinical trial demonstrated superior glycemic control in noncritically ill hospitalized patients with type 2 diabetes with basal/bolus insulin therapy compared to sliding scale insulin alone.31 Use of basal/bolus insulin regimens as part of a comprehensive hospital diabetes management program has been shown to improve glycemic control in an academic medical center.20 Therefore, we do not believe that our regression analysis findings invalidate the concept of basal/bolus insulin for inpatients with hyperglycemia, but rather indicate the need for more research into subcutaneous insulin regimens and hospital care practices that lead to improved glucose control. We found wide variation in hospital use of basal/bolus insulin regimens. Overall only 22.5% of all patients on the second measurement day received both short‐acting and long‐acting subcutaneous insulin, compared to 30.8% who received short‐acting subcutaneous insulin only. A recent consensus statement on inpatient glycemic control by the American College of Endocrinology and American Diabetes Association highlighted the systematic barriers to improved glycemic control in hospitals, such as inadequate knowledge of diabetes management techniques, fear of hypoglycemia, and skepticism about benefits of tighter glucose control.32

There are some important limitations to this study. The data are retrospective and only a limited number of hospital days and clinical variables could be assessed for each patient. As indicated in Table 3, there were significant differences in the frequency of glucose measurement depending on treatment, which can potentially bias estimated prevalence of hyperglycemia and hypoglycemia. We did not have a practical method to assess nutritional status or the adequacy of insulin dosing over time for each patient. We also could not assess the association of glycemic control on clinical outcomes such as hospital mortality or infection rates. Since this study was exclusively in academic medical centers, the generalization of findings to community‐based medical centers may be limited. The risk‐benefit of tight glycemic control in medical ICU patients based on clinical trial evidence has been unclear, and there is not broad agreement among clinicians on the recommended target for glycemic control in this group.3335 When we analyzed glycemic control in ICU patients we did not have a practical method to control for type of ICU and variations in individual ICU glycemic control targets. We recognize that the 2004 American College of Endocrinology recommendation of maintaining glucose 110 mg/dL may not be appropriate for all critically ill patients.14 Finally, clinical trial data are lacking on the effect of tight glucose control on major clinical outcomes for noncritically ill hospital patients. This has led to significant controversy regarding glycemic targets for different subgroups of hospitalized patients.34, 36

In summary, we found a high prevalence of persistent hyperglycemia in this large cohort of hospitalized patients, and hypoglycemia was infrequent. Use of IV insulin was associated with improvement in glycemic control, but was used in less than half of ICU patients. There was wide variation in hospital performance of recommended diabetes care measures. Opportunities to improve care in academic medical centers include expanded use of intravenous and subcutaneous basal/bolus insulin protocols and increased frequency of A1C testing.

Hyperglycemia is a common occurrence in hospitalized patients, with and without a prior diagnosis of diabetes mellitus.13 Estimates of prevalence of diabetes mellitus in hospitalized adult patients range from 12% to 25%.4 Hyperglycemia is a strong predictor of adverse clinical outcome in a range of diseases such as acute stroke, congestive heart failure, community‐acquired pneumonia, and acute myocardial infarction.58 Hyperglycemia is also a risk factor for surgical infection in patients undergoing cardiac surgery.9, 10 A landmark prospective randomized controlled clinical trial by van den Berghe et al.11 demonstrated that tight glucose control (target blood glucose level 80110 mg/dL) with intravenous insulin in critically ill surgical patients led to dramatic reductions in acute renal failure, critical illness polyneuropathy, hospital mortality, and bloodstream infection. Other clinical studies have demonstrated that glycemic control with intravenous insulin improves clinical outcomes and reduces length of stay in patients with diabetes undergoing cardiac surgery.12, 13

Based upon these findings, the American College of Endocrinology (ACE) published recommendations in 2004 for hospital diabetes and metabolic control.14 Similar recommendations for hospital glycemic control have been included in the American Diabetes Association (ADA) guidelines since 2005.15 There is now emerging consensus that use of continuous insulin infusion given through a standardized protocol is the standard of care to control hyperglycemia in critically ill patients.1618 Likewise, use of specific hospital insulin regimens that include basal and short‐acting insulin with appropriate bedside glucose monitoring and avoiding use of sliding scale short‐acting insulin alone has become recognized as the most effective approach for glucose management in hospitalized patients not requiring intravenous insulin.4, 1921

The University HealthSystem Consortium (UHC) is an alliance of 97 academic health centers and 153 of their associated hospitals that conducts benchmarking studies on clinical and operational topics with member academic medical centers and develops new programs to improve quality of care, patient safety, and operational, clinical, and financial performance. In late 2004, UHC launched the Glycemic Control Benchmarking Project to determine the current status of glycemic control in adult patients admitted to academic medical centers, types of treatment employed to control glucose, and operational measures and practices of care for glycemic control in the hospital setting. The goal of the project was to describe contemporary glucose management for the purpose of identifying best practices. The information was later shared with each participating medical center to allow them to better align care delivery with ADA and ACE guidelines. Thirty‐seven academic medical centers agreed to participate and submit patient level data as well as an operational survey of current policies and practices for hospital glycemic control. This report summarizes the key findings from retrospective analyses of hospital and patient‐level data and describes contemporary management of hyperglycemia in academic medical centers.

PATIENTS AND METHODS

To be eligible for the study, hospital patients at each participating medical center had to be 18 years of age, have a 72‐hour or longer length of stay, and be admitted with 1 or more of the following Diagnostic‐related group (DRG) codes: 89 (simple pneumonia/ pleurisy), 109 (coronary artery bypass grafting without catheterization), 127 (heart failure and shock), 143 (chest pain), 209 (joint/limb procedure), 316 (renal failure), 478 (other vascular procedures), or 527 (percutaneous intervention with drug eluting stent without acute myocardial infarction). The DRG codes were selected from analysis of the UHC Clinical Data Base because they were the most common adult medical and surgical admission codes that included diabetes as a secondary diagnosis for academic medical centers and were believed to best represent the majority of hospital admissions. Each participating medical center received a secure electronic listing of their eligible patients discharged between July 1, 2004 and September 30, 2004 from the UHC Clinical Data Base. Each center identified data extractors who were trained via teleconference and received technical and content support by UHC staff. The data were collected by chart review and submitted electronically to UHC from February to April 2005.

For each medical center, patients were screened in reverse chronological order proceeding back in time until the minimum number of 50 eligible cases was obtained or until all potential cases were screened. Although 50 cases was the recommended minimum sample size per site, each medical center was encouraged to submit as many eligible cases as possible. The median number of cases submitted by site was 50 (interquartile range [IQR], 4251). Cases were entered into the study if they met the eligibility criteria and at least one of the following inclusion criteria: (1) two consecutive blood glucose readings >180 mg/dL within a 24hour period, or (2) insulin treatment at any time during the hospitalization. Exclusion criteria included history of pancreatic transplant, pregnancy at time of admission, hospice or palliative care during hospital admission, and patients who received insulin for a reason other than blood glucose control (ie, hyperkalemia). Early in the data collection, DRG 209 was dropped from potential screening due to the low yield of meeting screening criteria for blood glucose readings. Of the 315 cases screened for DRG 209 only 44 met all inclusion criteria and remain in the study population.

A maximum of 3 consecutive days of blood glucose (BG) readings were collected for each patient, referred to as measurement day 1, measurement day 2, and measurement day 3. Measurement day 1 is defined as the day the first of 2 consecutive blood glucose levels >180 mg/dL occurred during the hospitalization or as the first day insulin was administered during the hospitalization, whichever came first; 40.6% of patients had the day of admission as their first measurement day. Glucose measurements were recorded by hour for each measurement day as available, and if more than 1 glucose value was available within a particular hour, only the first result was recorded. Both bedside and laboratory serum glucose values were utilized, and glycosylated hemoglobin (A1C) values were included if they were recorded during the hospitalization or within 30 days prior to admission;22 95.7% of patients had BG results reported for all 3 measurement days. We defined estimated 6 _AM glucose for each subject as: the 6 _AM glucose if it was available; otherwise the average of the 5 _AM and 7 _AM glucose values if at least 1 of them was available; otherwise the average of the 4 _AM and 8 _AM glucose values if at least 1 of them was available. Relevant demographics, medical history, hospitalization details, type and route of insulin administration, and discharge data were also collected. For subcutaneous insulin administration, use of regular, lispro, or aspart insulin was classified as short‐acting insulin; use of neutral protamine Hagedorn (NPH), ultralente, or glargine insulin was classified as long‐acting insulin. For analysis of glycemic control measures, patient‐days in which location or glucose data were not recorded were excluded from analysis. For the analysis comparing subcutaneous versus intravenous insulin treatment on glucose control, patients who received a combination of therapy with subcutaneous and intravenous insulin on the same measurement day were excluded from the analysis (44 patients on day 1, 96 on day 2, and 47 on day 3). For this retrospective analysis, UHC provided a deidentified data set to the authors. The study protocol was reviewed by the Vanderbilt University Institutional Review Board and deemed to be nonhuman subject research since the data set contained no personal or institutional identifiers. Therefore, no informed consent of subjects was required.

Measures of glucose control (median glucose and estimated 6 _AM glucose) were analyzed by patient‐day,23 and were compared by a Wilcoxon rank sum test or an analysis of variance, as indicated. P values <0.05 were considered significant. To compare effects of intravenous (IV) insulin, subcutaneous long‐acting short‐acting insulin, and subcutaneous short‐acting insulin use alone on glycemic control, mixed effects linear regression modeling for median glucose and mixed effects logistic regression modeling for hyperglycemia and hypoglycemia were used to adjust for fixed effects of age, gender, diabetes status, all patient refined diagnosis related groups (APR‐DRG) severity of illness score, outpatient diabetes treatment, patient location, admission diagnosis, and random effect of hospital site. Separate regression models were performed for measurement days 2 and 3. Statistical analyses were performed with Stata version 8 (Stata Corporation, College Station, TX), R version 2.1.0 (R Foundation for Statistical Computing, Vienna, Austria; www.r‐project.org), and SAS version 9 (SAS Institute, Cary, NC).

RESULTS

Thirty‐seven US academic medical centers from 24 states contributed to the analysis. A total of 4,367 cases meeting age, length of stay, and DRG criteria were screened for inclusion in the study; 2,649 (60.7%) screened cases were excluded due to failure to meet inclusion criteria (51%) or presence of exclusionary conditions (9.7%); 1,718 (39.3%) screened cases met all criteria and were included in this analysis. Patient characteristics are summarized in Table 1. A majority of patients (79%) had a documented history of diabetes, and most of these were classified as type 2 diabetes in the hospital record. Of the patients who were classified as having diabetes on admission, 50.8% were on some form of outpatient insulin therapy with or without oral diabetes agents. Patients with a diagnosis of diabetes had a median admission glucose of 158 mg/dL (IQR, 118221), which was significantly higher than the median admission glucose of 119 mg/dL (IQR, 100160) for patients without diabetes (P < 0.001, rank‐sum test).

To determine overall glycemic control for the cohort, median glucose was calculated for each patient, stratified by diabetes status and location for each measurement day (Table 2). Patient‐days with a location of emergency department (96 patients on day 1, 6 on day 2, and 2 on day 3) and two patients whose location was not defined were excluded from the analysis. Overall, median glucose declined from measurement day 1 to day 3. For patients with diabetes, median glucose was significantly lower in the intensive care unit (ICU) compared to the general ward or intermediate care for measurement days 1 and 2, but not day 3. This difference was more pronounced in patients without diabetes, with median glucose significantly lower in the ICU for all 3 measurement days compared to other locations. As expected, median glucose was lower for patients without diabetes compared to patients with diabetes for all measurement days and locations. Hyperglycemia was common; 867 of 1,718 (50%) patients had at least 1 glucose measurement 180 mg/dL on both days 2 and 3; 18% of all patients had a median glucose 180 mg/dL on all 3 measurement days. Daily 6 _AM glucose was the summary glycemic control measure in the clinical trial by van den Berghe et al.,11 with goal glucose of 80 to 110 mg/dL in the intensive treatment group. Since the glycemic target of the American College of Endocrinology Position Statement is <110 mg/dL (based largely on van den Berghe et al.11) we also calculated estimated 6 _AM glucose for ICU patient‐days to determine the proportion of patients attaining this target.14 Estimated 6 _AM glucose was lower in ICU patients without diabetes compared to those with diabetes. For patients with diabetes, only 20% of patients in the ICU had an estimated 6 _AM glucose 110 mg/dL on measurement day 2, and only 24% on day 3. For patients without diabetes, 27% and 25% had an estimated 6 _AM glucose 110 mg/dL on days 2 and 3, respectively.

For the overall cohort, insulin was the most common treatment for hyperglycemia, with 84.6% of all patients receiving some form of insulin therapy on the second measurement day. On the second day, 30.8% received short‐acting subcutaneous insulin only, 8.2% received intravenous insulin infusion, 22.5% received both short‐acting and long‐acting subcutaneous insulin, 3.9% received oral agents, 23% received some combination of insulin therapies and/or oral agents, and 11.9% received no treatment. To determine the effect of intravenous versus subcutaneous insulin treatment on glycemic control, we compared patients by insulin treatment and location for each measurement day (Table 3). Intravenous insulin was used predominantly in the ICU, and was associated with significantly lower median glucose compared to subcutaneous insulin in both locations for all 3 measurement days. As expected, the average number of glucose measures per patient was significantly higher for those receiving intravenous insulin. Intravenous insulin use in the ICU was associated with a significantly lower number of patients with hyperglycemia, defined as the number who had 1 or more glucose values 180 mg/dL during a given measurement day. Of note, intravenous insulin use in the ICU was associated with a significantly higher proportion of patients who had hypoglycemia (defined as the number of patients who had one or more glucose values <70 mg/dL) compared to subcutaneous insulin only on measurement day 1 (8.1% versus 2.9%; P = 0.021), but not on days 2 (12.7% versus 8.0%; P > 0.05) or 3 (12.7% versus 7.8%; P > 0.05). Severe hypoglycemia, defined as a blood glucose recording <50 mg/dL,24 was rare, and occurred in only 2.8% of all patient days. On measurement day 1, 34 patients had a total of 49 severe hypoglycemic events; on day 2, 54 patients had 68 severe hypoglycemic events; on day 3, 54 patients had 68 severe hypoglycemic events. Only 3 patients had severe hypoglycemic events on all 3 measurement days. Analysis of severe hypoglycemia events stratified by intravenous versus subcutaneous insulin did not show any significant differences for any of the 3 measurement days (data not shown).

We hypothesized that use of subcutaneous long‐acting (basal) insulin (with or without short‐acting insulin) would be associated with superior glucose control compared to use of subcutaneous short‐acting insulin (sliding scale and/or scheduled prandial insulin) alone. We performed an exploratory multivariate regression analysis to compare the effect of IV insulin, long acting subcutaneous insulin short acting insulin, or short acting subcutaneous insulin alone on median glucose, hyperglycemic events (glucose 180 mg/dL), and hypoglycemic events (glucose <70 mg/dL) for days 2 and 3 (Table 4). Compared to short‐acting subcutaneous insulin alone, use of IV insulin but not long‐acting subcutaneous insulin was predictive of lower median glucose for days 2 and 3. Use of long‐acting subcutaneous insulin was not associated with significantly lower odds of hyperglycemic events for days 2 and 3, but was associated with higher odds of hypoglycemic events on day 2 (odds ratio [OR], 1.8; P = 0.01) when compared to short‐acting subcutaneous insulin alone.

We measured the performance of recommended hospital diabetes care practices (A1C assessment, documentation of diabetes history in the hospital record, admission laboratory glucose assessment, bedside glucose monitoring, recommended insulin therapy)14, 15 for all study patients, and also stratified performance by hospital (Table 5); 98.6% of all patients with a diagnosis of diabetes had physician documentation of their diabetes status recorded in the hospital record, and there was consistently high performance of this by hospital (Table 5); 77% of all patients with a history of diabetes had a laboratory blood glucose result recorded within 8 hours of hospital admission, and 81.3% of patients with a history of diabetes had blood glucose monitored at least 4 times on measurement day 2. Performance by hospital (Table 5) varied widely for glucose monitoring (range, 56.5%95.5% of patients by hospital) and admission laboratory glucose assessment (range, 39.0%97.1% of patients by hospital).

Of all patients, 31% had A1C measurement recorded during their hospitalization or within 30 days prior to admission. There was wide variation in hospital performance of A1C assessment in patients with diabetes (Table 5). Patients with a diagnosis of diabetes had a median A1C of 7.4% (IQR, 6.4%8.9%; n = 473), and those without a diagnosis of diabetes had a median A1C of 5.9% (IQR, 5.6%6.4%; n = 70). Of the patients with a history of diabetes who had A1C recorded, 59% had a value >7%. Of the patients without a history of diabetes who had A1C recorded, 43% had a value >6.0%, suggesting previously undiagnosed diabetes.25

We found wide variation among hospitals (range, 12.1%76.5%) in use of recommended regimens of insulin therapy, defined as short‐acting and long‐acting subcutaneous insulin or IV insulin infusion or insulin pump therapy on second measurement day. Endocrine/diabetes consultation was infrequent, only 9% of all patients were evaluated by an endocrinologist or diabetologist at any time during the hospitalization.

DISCUSSION

In this retrospective analysis of hospitalized patients who had 2 consecutive blood glucose values 180 mg/dL and/or received insulin therapy, hyperglycemia was common and hypoglycemia was infrequent. Use of intravenous insulin was associated with better glucose control, and did not increase the frequency of severe hypoglycemic events (glucose <50 mg/dL). The majority of patients with a history of diabetes had physician documentation in the hospital chart, laboratory serum glucose obtained within 8 hours of hospital admission, and at least 4 blood glucose determinations on the second measurement day.

Only 35% of patients with diabetes had an A1C measurement and of these almost 60% had an A1C level >7%. Though the A1C may not greatly affect acute glucose management in the hospital setting, it does identify patients that may require intensification of diabetes therapy at hospital discharge and coordination of outpatient follow‐up. A report of a UHC clinical benchmarking project of ambulatory diabetes care in academic medical centers demonstrated high rates of diagnostic testing, but only 34% of patients were at the A1C goal, and only 40% of patients above the A1C goal had adjustment of their diabetes regimen at their last clinic visit.26 In a retrospective study of patients with diabetes mellitus admitted to an academic teaching hospital, only 20% of discharges indicated a plan for diabetes follow‐up.27 Thus, intensification of antihyperglycemic therapy and formulation of a diabetes follow‐up plan on hospital discharge in those patients with A1C >7% represents an opportunity to improve glycemic control in the ambulatory setting. Also, measurement of A1C can be used for diabetes case‐finding in hospitalized patients with hyperglycemia.25 Previously unrecognized diabetes is a common finding in patients admitted with cardiovascular disease. In a study of patients admitted with myocardial infarction, 25% were found to have previously undiagnosed diabetes.28 Hospital patients with hyperglycemia but without a prior diagnosis of diabetes who have an elevation of A1C >6.0% can be identified as at‐risk for diabetes and postdischarge glucose evaluation can be arranged.

The target of maintaining all glucose values 180 mg/dL recommended in the 20052007 American Diabetes Association guidelines for hospital diabetes management was not commonly achieved, with over 70% of patients who received subcutaneous insulin therapy having 1 or more glucose values >180 on all 3 measurement days, regardless of patient location.15 The target of maintaining critically ill patients as close to 110 mg/dL as possible was also difficult to achieve, with only 25% of ICU patients having an estimated 6 _AM glucose <110 mg/dL on measurement day 3. A prospective cohort study of 107 inpatients with diabetes at Brigham and Women's Hospital showed a 76% prevalence of patients with at least one BG >180 mg/dL.29 In that study, 90% of patients had a sliding‐scale order, 36% received an oral diabetes agent, and 43% received basal insulin at some time during hospitalization. A recently published analysis by Wexler et al.30 compiled data of hospitalized patients with diabetes from an earlier 2003 UHC Diabetes Benchmarking Project (n = 274) and patients from 15 not‐for‐profit member hospitals of VHA, Incorporated (n = 725) to examine the prevalence of hyperglycemia and hypoglycemia. Hyperglycemia (defined as a single BG value >200 mg/dL) was common, occurring in 77% of patients in the UHC cohort and 76% in the VHA, Inc. cohort. This was comparable to our findings that 76.7% of ICU patients and 78.6% of ward patients treated with subcutaneous insulin had 1 or more BG values 180 mg/dL on measurement day 2. Wexler et al.30 also determined that use of basal insulin was associated with a higher prevalence of hyperglycemia and hypoglycemia in their study. Our regression analysis finding that long‐acting (basal) insulin use was not associated with improvement in glycemic control is consistent with the findings of the aforementioned study. There are a number of potential explanations for this: (1) underdosing of basal insulin or lack of adequate prandial insulin coverage for nutritional intake; (2) lack of effective titration in response to hyperglycemia; and (3) variation in the ordering and administration of basal insulin at different hospital sites.

Use of both manual and computerized IV insulin protocols has been shown to provide effective glucose control in critically ill patients.1618 Though intravenous insulin use was associated with better overall glucose control in our study; only about 50% of ICU patients received it on measurement day 1. A recent prospective randomized clinical trial demonstrated superior glycemic control in noncritically ill hospitalized patients with type 2 diabetes with basal/bolus insulin therapy compared to sliding scale insulin alone.31 Use of basal/bolus insulin regimens as part of a comprehensive hospital diabetes management program has been shown to improve glycemic control in an academic medical center.20 Therefore, we do not believe that our regression analysis findings invalidate the concept of basal/bolus insulin for inpatients with hyperglycemia, but rather indicate the need for more research into subcutaneous insulin regimens and hospital care practices that lead to improved glucose control. We found wide variation in hospital use of basal/bolus insulin regimens. Overall only 22.5% of all patients on the second measurement day received both short‐acting and long‐acting subcutaneous insulin, compared to 30.8% who received short‐acting subcutaneous insulin only. A recent consensus statement on inpatient glycemic control by the American College of Endocrinology and American Diabetes Association highlighted the systematic barriers to improved glycemic control in hospitals, such as inadequate knowledge of diabetes management techniques, fear of hypoglycemia, and skepticism about benefits of tighter glucose control.32

There are some important limitations to this study. The data are retrospective and only a limited number of hospital days and clinical variables could be assessed for each patient. As indicated in Table 3, there were significant differences in the frequency of glucose measurement depending on treatment, which can potentially bias estimated prevalence of hyperglycemia and hypoglycemia. We did not have a practical method to assess nutritional status or the adequacy of insulin dosing over time for each patient. We also could not assess the association of glycemic control on clinical outcomes such as hospital mortality or infection rates. Since this study was exclusively in academic medical centers, the generalization of findings to community‐based medical centers may be limited. The risk‐benefit of tight glycemic control in medical ICU patients based on clinical trial evidence has been unclear, and there is not broad agreement among clinicians on the recommended target for glycemic control in this group.3335 When we analyzed glycemic control in ICU patients we did not have a practical method to control for type of ICU and variations in individual ICU glycemic control targets. We recognize that the 2004 American College of Endocrinology recommendation of maintaining glucose 110 mg/dL may not be appropriate for all critically ill patients.14 Finally, clinical trial data are lacking on the effect of tight glucose control on major clinical outcomes for noncritically ill hospital patients. This has led to significant controversy regarding glycemic targets for different subgroups of hospitalized patients.34, 36

In summary, we found a high prevalence of persistent hyperglycemia in this large cohort of hospitalized patients, and hypoglycemia was infrequent. Use of IV insulin was associated with improvement in glycemic control, but was used in less than half of ICU patients. There was wide variation in hospital performance of recommended diabetes care measures. Opportunities to improve care in academic medical centers include expanded use of intravenous and subcutaneous basal/bolus insulin protocols and increased frequency of A1C testing.

There is no doubt that hyperglycemia among hospitalized patients correlates with worse prognosis. Further, there are well‐documented mechanisms by which poor glycemic control may directly impact outcomes. For example, hyperglycemia and insulin deficiency can impair neutrophil function, exacerbate inflammation, and impair endothelium‐mediated dilatation,1, 2 whereas hypoglycemia increases sympathetic tone. And both severe hyperglycemia and hypoglycemia, of course, can precipitate altered mental status. But certainly not all of the morbid outcomes associated with poor glycemic control in the hospitalincluding infection, cardiac events and deathare caused by poor glycemic control in the hospital. Elevated glucose levels in the hospital are often seen in sicker patients with raging stress hormones and in brittle diabetics with a present‐on‐admission condition that has been ravaging their vasculature for years. This means that virtually all observational studies demonstrating worse outcomes in the setting of poor glucose control in the hospital will be severely confounded by comorbid illness, and much confounding will remain even after multivariate adjustment.3

Nonetheless, high‐quality randomized controlled trials that have focused on critically ill patients,4, 5 rather than general medical patients, have generated intense interest and fostered the belief that controlling the glucose level of all hospitalized patients is probably a good idea. (Although, more recently, even the data supporting glycemic control in the critically ill have been challenged.)6 Enthusiasm for implementing aggressive glycemic control protocols outside of the intensive care unit (ICU) appears widespread, as is evident in this issue of JHM.711 In this issue, two articles detail the challenges of implementing glycemia control protocols.7, 8 The research teams employed different protocols and used different metrics, but there are common themes: (1) The process was iterative. Interventions were piloted, then rolled out, and substantial effort was needed to foster continued attention to the interventions. (2) The process was multidisciplinary. Buy‐in and input were needed not only from physicians, but also from nurses, pharmacists, dieticians, clinical data system experts, and probably patients. (3) Impacting process measures was easier than impacting surrogate outcome measures. Specifically, despite dramatic changes in the use of carefully vetted order sets and protocols, the impact on glycemia was modest and sometimes inconsistent.

These studies illustrate that implementing protocols to control glycemia is neither easy, nor consistently associated with improved glycemic controllet alone improved major clinical outcomes. Three complementary observational studies911 further illustrate how hard it is to optimize glycemic control in the hospital setting. Together, the observational and interventional studies demonstrate how difficult it is to measure success. Should we focus on the mean glucose value achieved or the frequency of extreme glucose values (which are, by definition, more dangerous)? Should we look at glycemic control in every patient who is placed on a protocol, even those who barely need any insulin at all, or should we focus our interventions and analyses on those patients with more severe dysglycemia at baseline? This latter issue is fundamentally important, since the rollout of any systemwide glycemia protocol that results in higher catchment rates will appear more effective than it really is by enriching the postintervention data with healthier patients.

Before embarking on time‐intensive efforts to improve care, maybe we should be sure that the evidence supports our efforts.12 Recent recommendations from the American Diabetes Association state that for non‐critically ill patients: there is no clear evidence for specific blood glucose goals.13 (This recommendation, based on expert consensus or clinical experience, further states that because cohort data suggest that outcomes are better in hospitalized patients with fasting glucose <126 mg/dL and all random glucose values <180 to 200 mg/dL, these goals are reasonable if they can be safely achieved.) But given the challenges associated with implementing glycemia protocols, one might argue that hospitalists should invest their quality improvement efforts elsewhere.

So where does this leave us? What target glucose is not too high, not too low, but just right? Given the ever‐increasing number of quality improvement measures and interventions that are expected in the hospital, what amount of time, effort, and money devoted to improving inpatient glycemic control is just right? And what do our patients think? Should we be feeding our patients low glycemic load diets, or letting them indulge in one of the few creature comforts remaining in a semiprivate room?

What is clear from the results of the research published in this issue of JHM (regardless of whether we think that an inpatient pre‐meal glucose of 160 mg/dL is good, bad, or neither), is that we need to continue to develop systems, strategies, and teams to rapidly disseminate quality improvement interventions locally. We need multidisciplinary inputfrom physicians, nurses, dieticians, pharmacists, and patientsto do it right. So, even if the pendulum swings away from tight glycemic control in the hospital, the lessons we learned from these authors' valiant efforts to tame inpatient glycemia may provide us with the tools and knowledge required to successfully tackle other clinical issues such as delirium prevention, pain control, medication reconciliation, and handoffs. The striking obstacles (both in implementation and analysis) faced and overcome by the authors of the articles in this issue of JHM will hopefully embolden them to take on other quality improvement interventions that are perhaps more likely to help hospitalized patients.

There is no doubt that hyperglycemia among hospitalized patients correlates with worse prognosis. Further, there are well‐documented mechanisms by which poor glycemic control may directly impact outcomes. For example, hyperglycemia and insulin deficiency can impair neutrophil function, exacerbate inflammation, and impair endothelium‐mediated dilatation,1, 2 whereas hypoglycemia increases sympathetic tone. And both severe hyperglycemia and hypoglycemia, of course, can precipitate altered mental status. But certainly not all of the morbid outcomes associated with poor glycemic control in the hospitalincluding infection, cardiac events and deathare caused by poor glycemic control in the hospital. Elevated glucose levels in the hospital are often seen in sicker patients with raging stress hormones and in brittle diabetics with a present‐on‐admission condition that has been ravaging their vasculature for years. This means that virtually all observational studies demonstrating worse outcomes in the setting of poor glucose control in the hospital will be severely confounded by comorbid illness, and much confounding will remain even after multivariate adjustment.3

Nonetheless, high‐quality randomized controlled trials that have focused on critically ill patients,4, 5 rather than general medical patients, have generated intense interest and fostered the belief that controlling the glucose level of all hospitalized patients is probably a good idea. (Although, more recently, even the data supporting glycemic control in the critically ill have been challenged.)6 Enthusiasm for implementing aggressive glycemic control protocols outside of the intensive care unit (ICU) appears widespread, as is evident in this issue of JHM.711 In this issue, two articles detail the challenges of implementing glycemia control protocols.7, 8 The research teams employed different protocols and used different metrics, but there are common themes: (1) The process was iterative. Interventions were piloted, then rolled out, and substantial effort was needed to foster continued attention to the interventions. (2) The process was multidisciplinary. Buy‐in and input were needed not only from physicians, but also from nurses, pharmacists, dieticians, clinical data system experts, and probably patients. (3) Impacting process measures was easier than impacting surrogate outcome measures. Specifically, despite dramatic changes in the use of carefully vetted order sets and protocols, the impact on glycemia was modest and sometimes inconsistent.

These studies illustrate that implementing protocols to control glycemia is neither easy, nor consistently associated with improved glycemic controllet alone improved major clinical outcomes. Three complementary observational studies911 further illustrate how hard it is to optimize glycemic control in the hospital setting. Together, the observational and interventional studies demonstrate how difficult it is to measure success. Should we focus on the mean glucose value achieved or the frequency of extreme glucose values (which are, by definition, more dangerous)? Should we look at glycemic control in every patient who is placed on a protocol, even those who barely need any insulin at all, or should we focus our interventions and analyses on those patients with more severe dysglycemia at baseline? This latter issue is fundamentally important, since the rollout of any systemwide glycemia protocol that results in higher catchment rates will appear more effective than it really is by enriching the postintervention data with healthier patients.

Before embarking on time‐intensive efforts to improve care, maybe we should be sure that the evidence supports our efforts.12 Recent recommendations from the American Diabetes Association state that for non‐critically ill patients: there is no clear evidence for specific blood glucose goals.13 (This recommendation, based on expert consensus or clinical experience, further states that because cohort data suggest that outcomes are better in hospitalized patients with fasting glucose <126 mg/dL and all random glucose values <180 to 200 mg/dL, these goals are reasonable if they can be safely achieved.) But given the challenges associated with implementing glycemia protocols, one might argue that hospitalists should invest their quality improvement efforts elsewhere.

So where does this leave us? What target glucose is not too high, not too low, but just right? Given the ever‐increasing number of quality improvement measures and interventions that are expected in the hospital, what amount of time, effort, and money devoted to improving inpatient glycemic control is just right? And what do our patients think? Should we be feeding our patients low glycemic load diets, or letting them indulge in one of the few creature comforts remaining in a semiprivate room?

What is clear from the results of the research published in this issue of JHM (regardless of whether we think that an inpatient pre‐meal glucose of 160 mg/dL is good, bad, or neither), is that we need to continue to develop systems, strategies, and teams to rapidly disseminate quality improvement interventions locally. We need multidisciplinary inputfrom physicians, nurses, dieticians, pharmacists, and patientsto do it right. So, even if the pendulum swings away from tight glycemic control in the hospital, the lessons we learned from these authors' valiant efforts to tame inpatient glycemia may provide us with the tools and knowledge required to successfully tackle other clinical issues such as delirium prevention, pain control, medication reconciliation, and handoffs. The striking obstacles (both in implementation and analysis) faced and overcome by the authors of the articles in this issue of JHM will hopefully embolden them to take on other quality improvement interventions that are perhaps more likely to help hospitalized patients.

There is no doubt that hyperglycemia among hospitalized patients correlates with worse prognosis. Further, there are well‐documented mechanisms by which poor glycemic control may directly impact outcomes. For example, hyperglycemia and insulin deficiency can impair neutrophil function, exacerbate inflammation, and impair endothelium‐mediated dilatation,1, 2 whereas hypoglycemia increases sympathetic tone. And both severe hyperglycemia and hypoglycemia, of course, can precipitate altered mental status. But certainly not all of the morbid outcomes associated with poor glycemic control in the hospitalincluding infection, cardiac events and deathare caused by poor glycemic control in the hospital. Elevated glucose levels in the hospital are often seen in sicker patients with raging stress hormones and in brittle diabetics with a present‐on‐admission condition that has been ravaging their vasculature for years. This means that virtually all observational studies demonstrating worse outcomes in the setting of poor glucose control in the hospital will be severely confounded by comorbid illness, and much confounding will remain even after multivariate adjustment.3

Nonetheless, high‐quality randomized controlled trials that have focused on critically ill patients,4, 5 rather than general medical patients, have generated intense interest and fostered the belief that controlling the glucose level of all hospitalized patients is probably a good idea. (Although, more recently, even the data supporting glycemic control in the critically ill have been challenged.)6 Enthusiasm for implementing aggressive glycemic control protocols outside of the intensive care unit (ICU) appears widespread, as is evident in this issue of JHM.711 In this issue, two articles detail the challenges of implementing glycemia control protocols.7, 8 The research teams employed different protocols and used different metrics, but there are common themes: (1) The process was iterative. Interventions were piloted, then rolled out, and substantial effort was needed to foster continued attention to the interventions. (2) The process was multidisciplinary. Buy‐in and input were needed not only from physicians, but also from nurses, pharmacists, dieticians, clinical data system experts, and probably patients. (3) Impacting process measures was easier than impacting surrogate outcome measures. Specifically, despite dramatic changes in the use of carefully vetted order sets and protocols, the impact on glycemia was modest and sometimes inconsistent.

These studies illustrate that implementing protocols to control glycemia is neither easy, nor consistently associated with improved glycemic controllet alone improved major clinical outcomes. Three complementary observational studies911 further illustrate how hard it is to optimize glycemic control in the hospital setting. Together, the observational and interventional studies demonstrate how difficult it is to measure success. Should we focus on the mean glucose value achieved or the frequency of extreme glucose values (which are, by definition, more dangerous)? Should we look at glycemic control in every patient who is placed on a protocol, even those who barely need any insulin at all, or should we focus our interventions and analyses on those patients with more severe dysglycemia at baseline? This latter issue is fundamentally important, since the rollout of any systemwide glycemia protocol that results in higher catchment rates will appear more effective than it really is by enriching the postintervention data with healthier patients.

Before embarking on time‐intensive efforts to improve care, maybe we should be sure that the evidence supports our efforts.12 Recent recommendations from the American Diabetes Association state that for non‐critically ill patients: there is no clear evidence for specific blood glucose goals.13 (This recommendation, based on expert consensus or clinical experience, further states that because cohort data suggest that outcomes are better in hospitalized patients with fasting glucose <126 mg/dL and all random glucose values <180 to 200 mg/dL, these goals are reasonable if they can be safely achieved.) But given the challenges associated with implementing glycemia protocols, one might argue that hospitalists should invest their quality improvement efforts elsewhere.

So where does this leave us? What target glucose is not too high, not too low, but just right? Given the ever‐increasing number of quality improvement measures and interventions that are expected in the hospital, what amount of time, effort, and money devoted to improving inpatient glycemic control is just right? And what do our patients think? Should we be feeding our patients low glycemic load diets, or letting them indulge in one of the few creature comforts remaining in a semiprivate room?

What is clear from the results of the research published in this issue of JHM (regardless of whether we think that an inpatient pre‐meal glucose of 160 mg/dL is good, bad, or neither), is that we need to continue to develop systems, strategies, and teams to rapidly disseminate quality improvement interventions locally. We need multidisciplinary inputfrom physicians, nurses, dieticians, pharmacists, and patientsto do it right. So, even if the pendulum swings away from tight glycemic control in the hospital, the lessons we learned from these authors' valiant efforts to tame inpatient glycemia may provide us with the tools and knowledge required to successfully tackle other clinical issues such as delirium prevention, pain control, medication reconciliation, and handoffs. The striking obstacles (both in implementation and analysis) faced and overcome by the authors of the articles in this issue of JHM will hopefully embolden them to take on other quality improvement interventions that are perhaps more likely to help hospitalized patients.

A 71‐year‐old African‐American woman presented to the emergency department with chest pain, shortness of breath, and cough. She had initially presented to her primary care physician 2 weeks previously complaining of worsening cough and shortness of breath and was told to continue her inhaled albuterol and glucocorticoids and was prescribed a prednisone taper and an unknown course of antibiotics. She noted no improvement in her symptoms despite compliance with this treatment. Three days prior to admission she described the gradual onset of left‐sided pleuritic chest pain with continued cough, associated with yellow sputum and worsening dyspnea. Review of systems was remarkable for generalized weakness and malaise. She denied fever, chills, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, diarrhea, nausea, vomiting, or abdominal pain.

Her past medical history included a diagnosis of chronic obstructive pulmonary disease (COPD) but pulmonary function tests 7 years prior to admission showed an forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio of 81%. She had a 30 pack‐year history of smoking, but quit 35 years ago. The patient also carried a diagnosis of heart failure, but an echocardiogram done 1 year ago demonstrated a left ventricular ejection fraction of 65% to 70% without diastolic dysfunction but mild right ventricular dilation and hypertrophy. Additionally, she had known nonobstructive coronary atherosclerotic heart disease, dyslipidemia, hypertension, morbid obesity, depression, and a documented chronic right hemidiaphragm elevation.

At this point the history suggests that the patient does not have a clear diagnosis of COPD. The lack of definitive spirometry evidence of chronic airway obstruction concerns me; I think that she may have been mistakenly treated with chronic inhaled steroids and doses of antibiotics for an acute exacerbation of chronic lung disease. Additional review of her history gives some indication of advanced lung disease, with her recent echocardiogram showing strain on the right ventricle with right ventricular hypertrophy and dilation, but there is no mention of the presence or severity of pulmonary hypertension. Nonetheless, I would be concerned that she probably has underlying significant cor pulmonale.

The patient now re‐presents with a worsening of her pulmonary symptoms. Her left‐sided pleuritic pain would make me concerned that she had a pulmonary embolus (PE). This morbidly obese patient with new pulmonary symptoms, right ventricular strain on her previous echocardiogram, and a persistent elevated right hemidiaphragm suggests a presentation of another PE.

At this time I cannot rule out other common possibilities such as infectious pneumonia. If she does have pneumonia, I would be concerned she could be harboring a multidrug‐resistant bacterial infection given her recent course of antibiotics in addition to her use of both chronic inhaled and intermittent oral glucocorticoids.

After gathering the rest of her full medical history, I would focus my physical exam on looking for evidence of parenchymal lung disease, signs of pulmonary hypertension, and pneumonia.

Her surgical history includes a previous hysterectomy, cholecystectomy, hernia repair, and left hepatic lobectomy for a benign mass. Her outpatient medications were ibuprofen, bupropion, fluvastatin, atenolol, potassium, aspirin, clopidogrel, albuterol inhaler, fluticasone/salmeterol inhaler, and omeprazole. She reports an allergy to penicillin and to sulfa drugs. Her mother died of an unknown cancer at age 77 years. She denied any international travel and she has always lived in Georgia.

The patient has been retired since 1992, having previously worked for the U.S. Postal Service. She admits to occasional alcohol intake (2 to 3 drinks a month). No recent travel, surgery, or prolonged immobilization was noted.

On initial examination she was alert and mentally appropriate, but appeared to be in mild respiratory distress with a respiratory rate of 28 breaths/minute. Her blood pressure (BP) was 99/70, heart rate 102, temperature of 38.2C, and oxygen saturation of 93% on room air and 97% on 2 L of oxygen via nasal cannula. Auscultation of her lungs revealed crackles over her left anterior lung field, bronchial breath sounds in the left posterior midlung, and bibasilar crackles. No wheezing was noted. Her cardiovascular exam and the remainder of her physical exam were unremarkable except for morbid obesity.

While my initial thoughts were leaning toward an exacerbation of chronic lung disease or possibly a new PE, at this moment, infection seems more likely. Indeed, her pulmonary findings suggest a left‐sided inflammatory process, and her vital signs meet criteria for systemic inflammatory response syndrome (SIRS). My primary concern is sepsis due to a drug‐resistant bacterial infection, including Staphylococcus aureus or gram‐negative bacteria or possibly more unusual organisms such as Nocardia or fungi, due to her recent use of antibiotics and chronic inhaled steroid use and recent course of oral glucocorticoids.

Conversely, the SIRS could be a manifestation of a noninfectious lung process such as acute interstitial pneumonia or an eosinophilic pneumonia. Given the diagnostic complexity, I would strongly consider consulting a pulmonologist if the patient did not improve quickly. At this point, I would like to review a posterior‐anterior (PA) and lateral chest radiograph, and room air arterial blood gas (ABG) in addition to basic laboratory test values.

Laboratory data obtained on admission was remarkable for a white blood cell (WBC) count of 26,500/L with 75% neutrophils and 6% eosinophils. Hemoglobin was 14.4 gm/dL. Platelet count was 454,000/L. Serum chemistries showed a sodium of 137 mEq/dL, potassium 4.3 mEq/dL, Cl 108 mEq/dL, bicarbonate 19 mEq/dL, blood urea nitrogen (BUN) 8 mg/dL, creatinine 1.0 mg/dL, and glucose 137 mg/dL. Cardiac enzymes were normal. Calcium was 9.8 mg/dL, albumin 2.7 gm/dL, total protein 6.9 gm/dL, AST 36 U/L, ALT 54 U/L and the bilirubin was normal. Chest radiograph (Figure 1) demonstrated a left perihilar infiltrate with air bronchograms and marked right hemidiaphragm elevation as seen on previous films. Unchanged increased interstitial markings were also present. Her electrocardiogram (ECG) showed normal sinus rhythm, normal axis, and QRS duration with nonspecific diffuse T‐wave abnormalities.

Figure 1

Given her presentation, I am worried about how well she is oxygenating and ventilating. An ABG should be done to assess her status more accurately. An albumin of 2.7 gm/dL indicates that she is fairly sick. I would not hesitate to consider testing the patient for human immunodeficiency virus (HIV) given how this information would dramatically change the differential diagnoses of her pulmonary process.

I am still most concerned about sepsis secondary to pneumonia in this patient with multiple chronic comorbidities, underlying chronic lung disease, receiving chronic inhaled glucocorticoids and a recent course of oral glucocorticoids and antibiotics. While I would initiate hydration I do not see a clear indication for early goal‐directed therapy for severe sepsis. In addition to obtaining an ABG and starting intravenous fluids, I would also draw blood cultures, send sputum for gram stain, culture, and sensitivity, and perform a urinalysis. I would also administer empiric antibiotics as quickly as possible based on a number of pneumonia clinical studies suggesting improved outcomes with early antibiotic administration. Because of her use of antibiotics and both inhaled and oral glucocorticoids, she is at higher risk for potentially multidrug‐resistant bacterial pathogens, including Staphyloccocus aureus and gram‐negative bacteria such as Pseudomonas and Klebsiella (Table 1). Therefore, I would initially cover her broadly for these organisms.

In addition to initial treatment choice, the inpatient triage decision is another important issue, especially at a community hospital where intensive care unit (ICU) resources are rare and often the admission decision is between sending a moderately sick patient to a regular floor bed or the medical ICU. Both the American Thoracic Society and Infectious Diseases Society of America support an ICU triage protocol in their guidelines for the management of community‐acquired pneumonia in adults that utilizes the following 9 minor criteria, of which the presence of at least 3 should support ICU admission: respiratory rate 30 breaths/minute; oxygenation index (pressure of oxygen [PaO₂]/fraction of inspired oxygen [FiO₂] ratio) 250; multilobar infiltrates; confusion/disorientation; uremia (BUN level 20 mg/dL); leukopenia (WBC count <4,000 cells/mm³); thrombocytopenia (platelet count <100,000 cells/mm³); hypothermia (core temperature <36C); and hypotension requiring aggressive fluid. Despite the absence of these criteria in this patient, it is important to note that no triage protocol has been adequately prospectively validated. Retrospective study of the minor criteria has found that the presence of at least 2 of the following 3 clinical criteria to have the highest specificity for predicting cardiopulmonary decompensation and subsequent need for ICU care: (1) initial hypotension (BP <90/60) on presentation with response to initial intravenous fluids to a BP >90/60; (2) oxygenation failure as indicated by PaO₂/FiO₂ ratio less than 250; or (3) the presence of multilobar or bilateral infiltrates on chest radiography.

I also want to comment on the relative elevation of her calcium, especially given the low albumin. This may simply be due to volume depletion, as many older patients have asymptomatic mild primary hyperparathyroidism. However, this elevated calcium may be a clue to the underlying lung process. Granulomatous lung disease due to tuberculosis or fungal infection could yield elevated calcium levels via increases in macrophage production of the active vitamin D metabolite calcitriol. This will need to be followed and a parathormone (PTH) level would be the best first test to request if the calcium level remains elevated. If the PTH level is suppressed, granulomatous disease or malignancy would be the more likely cause.

The patient was admitted with a presumptive diagnosis of community‐acquired pneumonia, was started on ceftriaxone and azithromycin, and given intravenous fluids, oxygen, and continued on inhaled salmeterol/fluticasone. Sputum was ordered for gram stain, culture, and sensitivity, and blood cultures were obtained. Urinalysis showed 1‐5 WBCs/high‐power field. Venous thromboembolism prophylaxis was initiated with subcutaneous heparin 5,000 units 8 hours. Her blood pressure normalized rapidly and during the next few days she stated she was feeling better. Despite continued significant wheezing her oxygen saturation remained at 98% on 2 L of oxygen via nasal cannula and she was less tachypneic. Attempts at obtaining an ABG were unsuccessful, and the patient subsequently refused additional attempts. Over the first few days her WBC count remained elevated above 20,000/L, with worsening bandemia (11%), and fever ranging from 38C to 39C. Sputum analysis was initially unsuccessful and blood cultures remained negative.

I am concerned about the persistent fever and elevated WBC count, and want to emphasize that I might have treated her with broader spectrum antibiotics to cover additional multidrug‐resistant bacterial organisms. I would have initially ordered vancomycin to cover methicillin resistant Staphylococcus aureus (MRSA) plus 2 additional antibiotics that cover multidrug‐resistant gram negative pathogens including Pseudomonas aeruginosa.

On the fifth hospital day, her WBC count dropped to 13,400/L and she defervesced. However, her respiratory status worsened during that same day with increased tachypnea. Of note, no results were reported from the initial sputum cultures and they were reordered and a noncontrast chest computed tomography (CT) was also ordered.

I think at this point, even though she has remained stable hemodynamically and oxygenating easily with supplemental oxygen, the question of whether or not her primary process is infectious or noninfectious lingers. I agree with obtaining a chest CT scan.

I am not surprised that sputum was not evaluated despite the orders. Among hospitalized patients with pneumonia, we frequently find that about a third of the time sputum cannot be obtained, about a third of the time it is obtained but the quality is unsatisfactory, and only a third of the time does the sputum sample meet criteria (less than 5 squamous epithelial cells per high‐power field) for adequate interpretation of the gram‐stain and culture result. Unfortunately, no one has developed a better way to improve this process. Nonetheless, I believe we do not try hard enough to obtain sputum in the first hours of evaluating our patients. I joke with our internal medicine residents that they should carry a sputum cup with them when they evaluate a patient with possible pneumonia. One recent prospective study of the value of sputum gram‐staining in community‐acquired pneumonia has found it to be highly specific for identifying Streptococcus pneumoniae or Haemophilus influenzae pneumonia.

The CT scan (Figure 2) performed on hospital day 6 demonstrated consolidation in the left upper lobe with areas of cavitation. There was also interstitial infiltrate extending into the lingula. Elevation of the right hemidiaphragm with atelectasis in both lung bases was also noted. A small effusion was present on the left and possibly a minimal effusion on the right as well. There was no pericardial effusion and only a few small pretracheal and periaortic lymph nodes were noted.

Figure 2

Given her failure to improve significantly after 6 days of antibiotic treatment, and her recent use of glucocorticoids, I would expand my diagnostic considerations to include other necrotizing bacterial infections, tuberculosis, fungus, and Nocardia.

Given the results of the CT scan she was placed in respiratory isolation to rule out active pulmonary tuberculosis. Though tachypneic, her blood pressure and pulse remained stable. However, her oxygen saturation deteriorated, declining to 92% on 2 L of oxygen via nasal cannula during hospital days 6 and 7. Subsequent successful attempts at collecting sputum yielded rapid growth of yeast (not Cryptococcus spp.). Pulmonary and infectious disease consultations were obtained and vancomycin was added to her regimen. The patient subsequently agreed to undergo diagnostic bronchoscopy.

I agree with obtaining input from expert consultants. I think we too often underutilize consultation in patients that are better but not completely better when we are not entirely sure what is going on. Evidence of noncryptococcus yeast in sputum may sometimes indicate colonization with Candida spp. without any significant clinical consequence. This finding may alternatively suggest the possibility of a true fungal pneumonia caused by 1 of the dimorphic fungi, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitides, or Coccidioides immitis. However, in this case there is not a strong epidemiologic patient history of exposure to any of these types of fungi.

Three sputum smears were negative for acid fast bacilli (AFB). Bronchoscopy revealed grossly abnormal mucosa in the left upper lobe and bronchomalacia, but no obstructive lesions. A transthoracic echocardiogram was ordered to evaluate her degree of pulmonary hypertension.

The 3 sputum specimens that were negative for AFB despite cavitary lung disease have high sensitivity for ruling out pulmonary tuberculosis. In addition, given the absence of any bacterial pathogen isolated from these specimens, I would pursue the possibility of other potential fungal pathogens given the patient's subacute course, history of using inhaled and oral corticosteroids, sputum results, and the presence of a cavitary lesion on her CT scan images.

Cytologic examination of the bronchoalveolar lavage (BAL) sample showed a cell differential of 1% bands, 58% neutrophils, 9% lymphs, and 27% eosinophils. The routine postbronchoscopy chest radiograph showed complete opacification of the left lung. The patient's WBC count rose to 26,000/L but she remained afebrile. Echocardiogram was reported to be of very poor quality due to her obesity. The cardiologist reviewing the echocardiogram called the attending physicians and stated there was possibly something in the left pulmonary artery and aortic dissection could not be ruled out.

The presence of eosinophilia on BAL may be a very important clue as to what lung pathology she has. In fact, eosinophilia in this setting may indicate the possibility of parasitic or fungal infection of the lung, or inflammation of the airway associated to drug toxicity, asthma, or environmental toxin exposure. With this additional information, I am concerned that she may be harboring an atypical infection such as an invasive fungus. The echocardiogram results are unclear to me but will need to be clarified with additional testing.

The interpretation of the transbronchial biopsy specimen was limited but suggested invasive pseudomembranous tracheal bronchitis due to aspergillosis. The routine hematoxylin and eosin stain showed portions of alveolar lung tissue and some collapsed submucosal bronchial glands with relatively normal‐looking lung tissue but along the edge of the spaces were obvious fungal organisms. The Gomori's methenamine silver (GMS) stain suggested the presence of Aspergillus organisms (Figure 3). Fungal cultures were also negative for any of the other dimorphic fungi or for molds.

Figure 3

Despite the negative culture results, the overall clinical picture suggests a necrotizing pneumonia caused by an invasive Aspergillus affecting both the bronchial tree and the lower respiratory tract. Generally, necrotizing pneumonias usually have a slow response to antimicrobial therapy. Given the inherent difficulty in differentiating clearly between invasive and noninvasive disease based on a transbronchial biopsy specimen, initiating antifungal therapy for invasive aspergillosis is appropriate in this patient. This patient's recent use of oral glucocorticoids and chronic use of inhaled glucocorticoids are both potential risk factors that predisposed this patient to develop invasive aspergillosis.

Many times we simply follow treatment guidelines for different categories of pneumonia, and have limited or inadequate clinical information to make more definitive diagnoses. While we need these treatment protocols, physicians must avoid falling into the trap that antibiotics treat all infectious etiologies in the lung and we should make reasonable efforts to pin down the etiology. All of us have been fooled by atypical presentations of tuberculosis, fungus, and noninfectious diseases of the lung. I think it behooves us to be vigilant about alternative diagnoses and consider pursuing additional studies whenever the clinical response to initial treatment does not meet our expectations.

Subsequently, the patient's additional cultures remained negative. The official echocardiogram report was read as questionable PE in the pulmonary artery. A spiral CT angiogram revealed a pulmonary artery embolus in the left upper lobe and she was treated with anticoagulation. Her shortness of breath improved steadily and she was successfully discharged after receiving 9 days of oral voriconazole. Outpatient pulmonary function testing documented the presence of chronic obstructive lung disease. She completed a 5‐month course of voriconazole therapy with significant clinical and radiologic improvement of her pulmonary infiltrate. She also completed a 12‐month treatment with warfarin for the concomitant pulmonary embolism. On follow‐up at 12 months she was doing well.

COMMENTARY

Aspergillosis caused particularly by Aspergillus fumigatus is considered an emerging infectious disease that frequently produces significant morbidity and mortality among immunocompromised patients.1, 2 The most frequently‐affected organs by this fungal pathogen include the lung and the central nervous system. There are 3 pathogenic mechanisms of Aspergillus infection of the lung: colonization, hypersensitivity reaction, and invasive aspergillosis.1

Invasive pulmonary aspergillosis is predominantly seen among individuals with severe degrees of immunosuppression as a result of solid‐organ transplantation, immunosuppressive therapies for autoimmune diseases, systemic glucocorticoids, and chemotherapy for hematologic malignancies. Mortality due to invasive aspergillosis continues to be very high (>58%) despite our improved ability to diagnose this condition and newer therapies to treat immunocompromised individuals.1 Invasive aspergillosis can manifest clinically in multiple ways. These include: (1) an invasive vascular process in which fungal organisms invade blood vessels, causing a rapidly progressive and often fatal illness; (2) necrotizing pseudomembranous tracheal bronchitis; (3) chronic necrotizing aspergillosis; (4) bronchopleural fistula; or (5) empyema.35 In our case, while the pathologic findings were most suggestive of an invasive pseudomembranous tracheal bronchitis, the overall clinical picture was most compatible with a necrotizing pneumonia due to invasive aspergillosis.

In addition to the traditional identified risk factors for invasive pulmonary aspergillosis, a number of reports during the last decade have demonstrated the occurrence of invasive aspergillosis in patients with COPD.14 A systematic review of the literature demonstrated that among 1,941 patients with invasive aspergillosis, 26 (1.3%) had evidence of COPD as the main risk factor for developing invasive aspergillosis.1 A single report has associated the potential use of inhaled steroids with the occurrence of invasive aspergillosis in this patient population.2 However, other factors that may promote increased susceptibility to invasive fungal infection among patients with COPD include the use of long‐term or repeated short‐term glucocorticoid treatments, and the presence of multiple additional comorbidities, which may be found in this same population such as diabetes, malnutrition, or end‐stage renal disease.3, 4 Most reported series have demonstrated a high mortality rate of invasive pulmonary aspergillosis in patients with COPD.14

The diagnosis of invasive pulmonary aspergillosis represents a significant clinical challenge. Diagnostic algorithms incorporating CT, antigen detection testing (for serum galactomannan and ‐glucan) as well as polymerase chain reaction diagnostic testing appear to be beneficial in the early diagnosis of invasive aspergillosis in particular settings such as in allogeneic hematopoietic stem cell transplantation.5 The role of antigen testing to identify early invasive aspergillosis in patients with COPD remains uncertain since it has been evaluated in a limited number of patients and therefore clinical suspicion is critical to push clinicians to pursue invasive tissue biopsy and cultures to confirm the diagnosis.3, 4

Based on the available clinical case series and in our case, invasive pulmonary aspergillosis should be suspected in COPD patients with rapidly progressive pneumonia not responding to antibacterial therapy and who have received oral or inhaled glucocorticoids in the recent past. In addition, this case also illustrates that occasionally, patients present with more than 1 life‐threatening diagnosis. This patient was also diagnosed with PE despite adequate prophylaxis. In addition to the well‐known clinical risk factors of obesity and lung disease, the underlying infection may have contributed to a systemic or local hypercoagulable condition that further increased her risk for venous thromboembolism.

KEY TEACHING POINTS

• Clinicians should remember to consider a broad differential in patients presenting with pneumonia, including the possibility of fungal pathogens in patients with known risk factors and in patients with multiple, potentially immunosuppressive comorbidities, or in patients who do not improve on standard antibiotic therapy.

• There is some evidence of an association between COPD and invasive aspergillosis, likely due to the frequent use of oral corticosteroids and/or chronic inhaled steroids in this population.

A 71‐year‐old African‐American woman presented to the emergency department with chest pain, shortness of breath, and cough. She had initially presented to her primary care physician 2 weeks previously complaining of worsening cough and shortness of breath and was told to continue her inhaled albuterol and glucocorticoids and was prescribed a prednisone taper and an unknown course of antibiotics. She noted no improvement in her symptoms despite compliance with this treatment. Three days prior to admission she described the gradual onset of left‐sided pleuritic chest pain with continued cough, associated with yellow sputum and worsening dyspnea. Review of systems was remarkable for generalized weakness and malaise. She denied fever, chills, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, diarrhea, nausea, vomiting, or abdominal pain.

Her past medical history included a diagnosis of chronic obstructive pulmonary disease (COPD) but pulmonary function tests 7 years prior to admission showed an forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio of 81%. She had a 30 pack‐year history of smoking, but quit 35 years ago. The patient also carried a diagnosis of heart failure, but an echocardiogram done 1 year ago demonstrated a left ventricular ejection fraction of 65% to 70% without diastolic dysfunction but mild right ventricular dilation and hypertrophy. Additionally, she had known nonobstructive coronary atherosclerotic heart disease, dyslipidemia, hypertension, morbid obesity, depression, and a documented chronic right hemidiaphragm elevation.

At this point the history suggests that the patient does not have a clear diagnosis of COPD. The lack of definitive spirometry evidence of chronic airway obstruction concerns me; I think that she may have been mistakenly treated with chronic inhaled steroids and doses of antibiotics for an acute exacerbation of chronic lung disease. Additional review of her history gives some indication of advanced lung disease, with her recent echocardiogram showing strain on the right ventricle with right ventricular hypertrophy and dilation, but there is no mention of the presence or severity of pulmonary hypertension. Nonetheless, I would be concerned that she probably has underlying significant cor pulmonale.

The patient now re‐presents with a worsening of her pulmonary symptoms. Her left‐sided pleuritic pain would make me concerned that she had a pulmonary embolus (PE). This morbidly obese patient with new pulmonary symptoms, right ventricular strain on her previous echocardiogram, and a persistent elevated right hemidiaphragm suggests a presentation of another PE.

At this time I cannot rule out other common possibilities such as infectious pneumonia. If she does have pneumonia, I would be concerned she could be harboring a multidrug‐resistant bacterial infection given her recent course of antibiotics in addition to her use of both chronic inhaled and intermittent oral glucocorticoids.

After gathering the rest of her full medical history, I would focus my physical exam on looking for evidence of parenchymal lung disease, signs of pulmonary hypertension, and pneumonia.

Her surgical history includes a previous hysterectomy, cholecystectomy, hernia repair, and left hepatic lobectomy for a benign mass. Her outpatient medications were ibuprofen, bupropion, fluvastatin, atenolol, potassium, aspirin, clopidogrel, albuterol inhaler, fluticasone/salmeterol inhaler, and omeprazole. She reports an allergy to penicillin and to sulfa drugs. Her mother died of an unknown cancer at age 77 years. She denied any international travel and she has always lived in Georgia.

The patient has been retired since 1992, having previously worked for the U.S. Postal Service. She admits to occasional alcohol intake (2 to 3 drinks a month). No recent travel, surgery, or prolonged immobilization was noted.

On initial examination she was alert and mentally appropriate, but appeared to be in mild respiratory distress with a respiratory rate of 28 breaths/minute. Her blood pressure (BP) was 99/70, heart rate 102, temperature of 38.2C, and oxygen saturation of 93% on room air and 97% on 2 L of oxygen via nasal cannula. Auscultation of her lungs revealed crackles over her left anterior lung field, bronchial breath sounds in the left posterior midlung, and bibasilar crackles. No wheezing was noted. Her cardiovascular exam and the remainder of her physical exam were unremarkable except for morbid obesity.

While my initial thoughts were leaning toward an exacerbation of chronic lung disease or possibly a new PE, at this moment, infection seems more likely. Indeed, her pulmonary findings suggest a left‐sided inflammatory process, and her vital signs meet criteria for systemic inflammatory response syndrome (SIRS). My primary concern is sepsis due to a drug‐resistant bacterial infection, including Staphylococcus aureus or gram‐negative bacteria or possibly more unusual organisms such as Nocardia or fungi, due to her recent use of antibiotics and chronic inhaled steroid use and recent course of oral glucocorticoids.

Conversely, the SIRS could be a manifestation of a noninfectious lung process such as acute interstitial pneumonia or an eosinophilic pneumonia. Given the diagnostic complexity, I would strongly consider consulting a pulmonologist if the patient did not improve quickly. At this point, I would like to review a posterior‐anterior (PA) and lateral chest radiograph, and room air arterial blood gas (ABG) in addition to basic laboratory test values.

Laboratory data obtained on admission was remarkable for a white blood cell (WBC) count of 26,500/L with 75% neutrophils and 6% eosinophils. Hemoglobin was 14.4 gm/dL. Platelet count was 454,000/L. Serum chemistries showed a sodium of 137 mEq/dL, potassium 4.3 mEq/dL, Cl 108 mEq/dL, bicarbonate 19 mEq/dL, blood urea nitrogen (BUN) 8 mg/dL, creatinine 1.0 mg/dL, and glucose 137 mg/dL. Cardiac enzymes were normal. Calcium was 9.8 mg/dL, albumin 2.7 gm/dL, total protein 6.9 gm/dL, AST 36 U/L, ALT 54 U/L and the bilirubin was normal. Chest radiograph (Figure 1) demonstrated a left perihilar infiltrate with air bronchograms and marked right hemidiaphragm elevation as seen on previous films. Unchanged increased interstitial markings were also present. Her electrocardiogram (ECG) showed normal sinus rhythm, normal axis, and QRS duration with nonspecific diffuse T‐wave abnormalities.

Figure 1

Given her presentation, I am worried about how well she is oxygenating and ventilating. An ABG should be done to assess her status more accurately. An albumin of 2.7 gm/dL indicates that she is fairly sick. I would not hesitate to consider testing the patient for human immunodeficiency virus (HIV) given how this information would dramatically change the differential diagnoses of her pulmonary process.

I am still most concerned about sepsis secondary to pneumonia in this patient with multiple chronic comorbidities, underlying chronic lung disease, receiving chronic inhaled glucocorticoids and a recent course of oral glucocorticoids and antibiotics. While I would initiate hydration I do not see a clear indication for early goal‐directed therapy for severe sepsis. In addition to obtaining an ABG and starting intravenous fluids, I would also draw blood cultures, send sputum for gram stain, culture, and sensitivity, and perform a urinalysis. I would also administer empiric antibiotics as quickly as possible based on a number of pneumonia clinical studies suggesting improved outcomes with early antibiotic administration. Because of her use of antibiotics and both inhaled and oral glucocorticoids, she is at higher risk for potentially multidrug‐resistant bacterial pathogens, including Staphyloccocus aureus and gram‐negative bacteria such as Pseudomonas and Klebsiella (Table 1). Therefore, I would initially cover her broadly for these organisms.

In addition to initial treatment choice, the inpatient triage decision is another important issue, especially at a community hospital where intensive care unit (ICU) resources are rare and often the admission decision is between sending a moderately sick patient to a regular floor bed or the medical ICU. Both the American Thoracic Society and Infectious Diseases Society of America support an ICU triage protocol in their guidelines for the management of community‐acquired pneumonia in adults that utilizes the following 9 minor criteria, of which the presence of at least 3 should support ICU admission: respiratory rate 30 breaths/minute; oxygenation index (pressure of oxygen [PaO₂]/fraction of inspired oxygen [FiO₂] ratio) 250; multilobar infiltrates; confusion/disorientation; uremia (BUN level 20 mg/dL); leukopenia (WBC count <4,000 cells/mm³); thrombocytopenia (platelet count <100,000 cells/mm³); hypothermia (core temperature <36C); and hypotension requiring aggressive fluid. Despite the absence of these criteria in this patient, it is important to note that no triage protocol has been adequately prospectively validated. Retrospective study of the minor criteria has found that the presence of at least 2 of the following 3 clinical criteria to have the highest specificity for predicting cardiopulmonary decompensation and subsequent need for ICU care: (1) initial hypotension (BP <90/60) on presentation with response to initial intravenous fluids to a BP >90/60; (2) oxygenation failure as indicated by PaO₂/FiO₂ ratio less than 250; or (3) the presence of multilobar or bilateral infiltrates on chest radiography.

I also want to comment on the relative elevation of her calcium, especially given the low albumin. This may simply be due to volume depletion, as many older patients have asymptomatic mild primary hyperparathyroidism. However, this elevated calcium may be a clue to the underlying lung process. Granulomatous lung disease due to tuberculosis or fungal infection could yield elevated calcium levels via increases in macrophage production of the active vitamin D metabolite calcitriol. This will need to be followed and a parathormone (PTH) level would be the best first test to request if the calcium level remains elevated. If the PTH level is suppressed, granulomatous disease or malignancy would be the more likely cause.

The patient was admitted with a presumptive diagnosis of community‐acquired pneumonia, was started on ceftriaxone and azithromycin, and given intravenous fluids, oxygen, and continued on inhaled salmeterol/fluticasone. Sputum was ordered for gram stain, culture, and sensitivity, and blood cultures were obtained. Urinalysis showed 1‐5 WBCs/high‐power field. Venous thromboembolism prophylaxis was initiated with subcutaneous heparin 5,000 units 8 hours. Her blood pressure normalized rapidly and during the next few days she stated she was feeling better. Despite continued significant wheezing her oxygen saturation remained at 98% on 2 L of oxygen via nasal cannula and she was less tachypneic. Attempts at obtaining an ABG were unsuccessful, and the patient subsequently refused additional attempts. Over the first few days her WBC count remained elevated above 20,000/L, with worsening bandemia (11%), and fever ranging from 38C to 39C. Sputum analysis was initially unsuccessful and blood cultures remained negative.

I am concerned about the persistent fever and elevated WBC count, and want to emphasize that I might have treated her with broader spectrum antibiotics to cover additional multidrug‐resistant bacterial organisms. I would have initially ordered vancomycin to cover methicillin resistant Staphylococcus aureus (MRSA) plus 2 additional antibiotics that cover multidrug‐resistant gram negative pathogens including Pseudomonas aeruginosa.

On the fifth hospital day, her WBC count dropped to 13,400/L and she defervesced. However, her respiratory status worsened during that same day with increased tachypnea. Of note, no results were reported from the initial sputum cultures and they were reordered and a noncontrast chest computed tomography (CT) was also ordered.

I think at this point, even though she has remained stable hemodynamically and oxygenating easily with supplemental oxygen, the question of whether or not her primary process is infectious or noninfectious lingers. I agree with obtaining a chest CT scan.

I am not surprised that sputum was not evaluated despite the orders. Among hospitalized patients with pneumonia, we frequently find that about a third of the time sputum cannot be obtained, about a third of the time it is obtained but the quality is unsatisfactory, and only a third of the time does the sputum sample meet criteria (less than 5 squamous epithelial cells per high‐power field) for adequate interpretation of the gram‐stain and culture result. Unfortunately, no one has developed a better way to improve this process. Nonetheless, I believe we do not try hard enough to obtain sputum in the first hours of evaluating our patients. I joke with our internal medicine residents that they should carry a sputum cup with them when they evaluate a patient with possible pneumonia. One recent prospective study of the value of sputum gram‐staining in community‐acquired pneumonia has found it to be highly specific for identifying Streptococcus pneumoniae or Haemophilus influenzae pneumonia.

The CT scan (Figure 2) performed on hospital day 6 demonstrated consolidation in the left upper lobe with areas of cavitation. There was also interstitial infiltrate extending into the lingula. Elevation of the right hemidiaphragm with atelectasis in both lung bases was also noted. A small effusion was present on the left and possibly a minimal effusion on the right as well. There was no pericardial effusion and only a few small pretracheal and periaortic lymph nodes were noted.

Figure 2

Given her failure to improve significantly after 6 days of antibiotic treatment, and her recent use of glucocorticoids, I would expand my diagnostic considerations to include other necrotizing bacterial infections, tuberculosis, fungus, and Nocardia.

Given the results of the CT scan she was placed in respiratory isolation to rule out active pulmonary tuberculosis. Though tachypneic, her blood pressure and pulse remained stable. However, her oxygen saturation deteriorated, declining to 92% on 2 L of oxygen via nasal cannula during hospital days 6 and 7. Subsequent successful attempts at collecting sputum yielded rapid growth of yeast (not Cryptococcus spp.). Pulmonary and infectious disease consultations were obtained and vancomycin was added to her regimen. The patient subsequently agreed to undergo diagnostic bronchoscopy.

I agree with obtaining input from expert consultants. I think we too often underutilize consultation in patients that are better but not completely better when we are not entirely sure what is going on. Evidence of noncryptococcus yeast in sputum may sometimes indicate colonization with Candida spp. without any significant clinical consequence. This finding may alternatively suggest the possibility of a true fungal pneumonia caused by 1 of the dimorphic fungi, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitides, or Coccidioides immitis. However, in this case there is not a strong epidemiologic patient history of exposure to any of these types of fungi.

Three sputum smears were negative for acid fast bacilli (AFB). Bronchoscopy revealed grossly abnormal mucosa in the left upper lobe and bronchomalacia, but no obstructive lesions. A transthoracic echocardiogram was ordered to evaluate her degree of pulmonary hypertension.

The 3 sputum specimens that were negative for AFB despite cavitary lung disease have high sensitivity for ruling out pulmonary tuberculosis. In addition, given the absence of any bacterial pathogen isolated from these specimens, I would pursue the possibility of other potential fungal pathogens given the patient's subacute course, history of using inhaled and oral corticosteroids, sputum results, and the presence of a cavitary lesion on her CT scan images.

Cytologic examination of the bronchoalveolar lavage (BAL) sample showed a cell differential of 1% bands, 58% neutrophils, 9% lymphs, and 27% eosinophils. The routine postbronchoscopy chest radiograph showed complete opacification of the left lung. The patient's WBC count rose to 26,000/L but she remained afebrile. Echocardiogram was reported to be of very poor quality due to her obesity. The cardiologist reviewing the echocardiogram called the attending physicians and stated there was possibly something in the left pulmonary artery and aortic dissection could not be ruled out.

The presence of eosinophilia on BAL may be a very important clue as to what lung pathology she has. In fact, eosinophilia in this setting may indicate the possibility of parasitic or fungal infection of the lung, or inflammation of the airway associated to drug toxicity, asthma, or environmental toxin exposure. With this additional information, I am concerned that she may be harboring an atypical infection such as an invasive fungus. The echocardiogram results are unclear to me but will need to be clarified with additional testing.

The interpretation of the transbronchial biopsy specimen was limited but suggested invasive pseudomembranous tracheal bronchitis due to aspergillosis. The routine hematoxylin and eosin stain showed portions of alveolar lung tissue and some collapsed submucosal bronchial glands with relatively normal‐looking lung tissue but along the edge of the spaces were obvious fungal organisms. The Gomori's methenamine silver (GMS) stain suggested the presence of Aspergillus organisms (Figure 3). Fungal cultures were also negative for any of the other dimorphic fungi or for molds.

Figure 3

Despite the negative culture results, the overall clinical picture suggests a necrotizing pneumonia caused by an invasive Aspergillus affecting both the bronchial tree and the lower respiratory tract. Generally, necrotizing pneumonias usually have a slow response to antimicrobial therapy. Given the inherent difficulty in differentiating clearly between invasive and noninvasive disease based on a transbronchial biopsy specimen, initiating antifungal therapy for invasive aspergillosis is appropriate in this patient. This patient's recent use of oral glucocorticoids and chronic use of inhaled glucocorticoids are both potential risk factors that predisposed this patient to develop invasive aspergillosis.

Many times we simply follow treatment guidelines for different categories of pneumonia, and have limited or inadequate clinical information to make more definitive diagnoses. While we need these treatment protocols, physicians must avoid falling into the trap that antibiotics treat all infectious etiologies in the lung and we should make reasonable efforts to pin down the etiology. All of us have been fooled by atypical presentations of tuberculosis, fungus, and noninfectious diseases of the lung. I think it behooves us to be vigilant about alternative diagnoses and consider pursuing additional studies whenever the clinical response to initial treatment does not meet our expectations.

Subsequently, the patient's additional cultures remained negative. The official echocardiogram report was read as questionable PE in the pulmonary artery. A spiral CT angiogram revealed a pulmonary artery embolus in the left upper lobe and she was treated with anticoagulation. Her shortness of breath improved steadily and she was successfully discharged after receiving 9 days of oral voriconazole. Outpatient pulmonary function testing documented the presence of chronic obstructive lung disease. She completed a 5‐month course of voriconazole therapy with significant clinical and radiologic improvement of her pulmonary infiltrate. She also completed a 12‐month treatment with warfarin for the concomitant pulmonary embolism. On follow‐up at 12 months she was doing well.

COMMENTARY

Aspergillosis caused particularly by Aspergillus fumigatus is considered an emerging infectious disease that frequently produces significant morbidity and mortality among immunocompromised patients.1, 2 The most frequently‐affected organs by this fungal pathogen include the lung and the central nervous system. There are 3 pathogenic mechanisms of Aspergillus infection of the lung: colonization, hypersensitivity reaction, and invasive aspergillosis.1

Invasive pulmonary aspergillosis is predominantly seen among individuals with severe degrees of immunosuppression as a result of solid‐organ transplantation, immunosuppressive therapies for autoimmune diseases, systemic glucocorticoids, and chemotherapy for hematologic malignancies. Mortality due to invasive aspergillosis continues to be very high (>58%) despite our improved ability to diagnose this condition and newer therapies to treat immunocompromised individuals.1 Invasive aspergillosis can manifest clinically in multiple ways. These include: (1) an invasive vascular process in which fungal organisms invade blood vessels, causing a rapidly progressive and often fatal illness; (2) necrotizing pseudomembranous tracheal bronchitis; (3) chronic necrotizing aspergillosis; (4) bronchopleural fistula; or (5) empyema.35 In our case, while the pathologic findings were most suggestive of an invasive pseudomembranous tracheal bronchitis, the overall clinical picture was most compatible with a necrotizing pneumonia due to invasive aspergillosis.

In addition to the traditional identified risk factors for invasive pulmonary aspergillosis, a number of reports during the last decade have demonstrated the occurrence of invasive aspergillosis in patients with COPD.14 A systematic review of the literature demonstrated that among 1,941 patients with invasive aspergillosis, 26 (1.3%) had evidence of COPD as the main risk factor for developing invasive aspergillosis.1 A single report has associated the potential use of inhaled steroids with the occurrence of invasive aspergillosis in this patient population.2 However, other factors that may promote increased susceptibility to invasive fungal infection among patients with COPD include the use of long‐term or repeated short‐term glucocorticoid treatments, and the presence of multiple additional comorbidities, which may be found in this same population such as diabetes, malnutrition, or end‐stage renal disease.3, 4 Most reported series have demonstrated a high mortality rate of invasive pulmonary aspergillosis in patients with COPD.14

The diagnosis of invasive pulmonary aspergillosis represents a significant clinical challenge. Diagnostic algorithms incorporating CT, antigen detection testing (for serum galactomannan and ‐glucan) as well as polymerase chain reaction diagnostic testing appear to be beneficial in the early diagnosis of invasive aspergillosis in particular settings such as in allogeneic hematopoietic stem cell transplantation.5 The role of antigen testing to identify early invasive aspergillosis in patients with COPD remains uncertain since it has been evaluated in a limited number of patients and therefore clinical suspicion is critical to push clinicians to pursue invasive tissue biopsy and cultures to confirm the diagnosis.3, 4

Based on the available clinical case series and in our case, invasive pulmonary aspergillosis should be suspected in COPD patients with rapidly progressive pneumonia not responding to antibacterial therapy and who have received oral or inhaled glucocorticoids in the recent past. In addition, this case also illustrates that occasionally, patients present with more than 1 life‐threatening diagnosis. This patient was also diagnosed with PE despite adequate prophylaxis. In addition to the well‐known clinical risk factors of obesity and lung disease, the underlying infection may have contributed to a systemic or local hypercoagulable condition that further increased her risk for venous thromboembolism.

KEY TEACHING POINTS

• Clinicians should remember to consider a broad differential in patients presenting with pneumonia, including the possibility of fungal pathogens in patients with known risk factors and in patients with multiple, potentially immunosuppressive comorbidities, or in patients who do not improve on standard antibiotic therapy.

• There is some evidence of an association between COPD and invasive aspergillosis, likely due to the frequent use of oral corticosteroids and/or chronic inhaled steroids in this population.

A 71‐year‐old African‐American woman presented to the emergency department with chest pain, shortness of breath, and cough. She had initially presented to her primary care physician 2 weeks previously complaining of worsening cough and shortness of breath and was told to continue her inhaled albuterol and glucocorticoids and was prescribed a prednisone taper and an unknown course of antibiotics. She noted no improvement in her symptoms despite compliance with this treatment. Three days prior to admission she described the gradual onset of left‐sided pleuritic chest pain with continued cough, associated with yellow sputum and worsening dyspnea. Review of systems was remarkable for generalized weakness and malaise. She denied fever, chills, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, diarrhea, nausea, vomiting, or abdominal pain.

Her past medical history included a diagnosis of chronic obstructive pulmonary disease (COPD) but pulmonary function tests 7 years prior to admission showed an forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio of 81%. She had a 30 pack‐year history of smoking, but quit 35 years ago. The patient also carried a diagnosis of heart failure, but an echocardiogram done 1 year ago demonstrated a left ventricular ejection fraction of 65% to 70% without diastolic dysfunction but mild right ventricular dilation and hypertrophy. Additionally, she had known nonobstructive coronary atherosclerotic heart disease, dyslipidemia, hypertension, morbid obesity, depression, and a documented chronic right hemidiaphragm elevation.

At this point the history suggests that the patient does not have a clear diagnosis of COPD. The lack of definitive spirometry evidence of chronic airway obstruction concerns me; I think that she may have been mistakenly treated with chronic inhaled steroids and doses of antibiotics for an acute exacerbation of chronic lung disease. Additional review of her history gives some indication of advanced lung disease, with her recent echocardiogram showing strain on the right ventricle with right ventricular hypertrophy and dilation, but there is no mention of the presence or severity of pulmonary hypertension. Nonetheless, I would be concerned that she probably has underlying significant cor pulmonale.

The patient now re‐presents with a worsening of her pulmonary symptoms. Her left‐sided pleuritic pain would make me concerned that she had a pulmonary embolus (PE). This morbidly obese patient with new pulmonary symptoms, right ventricular strain on her previous echocardiogram, and a persistent elevated right hemidiaphragm suggests a presentation of another PE.

At this time I cannot rule out other common possibilities such as infectious pneumonia. If she does have pneumonia, I would be concerned she could be harboring a multidrug‐resistant bacterial infection given her recent course of antibiotics in addition to her use of both chronic inhaled and intermittent oral glucocorticoids.

After gathering the rest of her full medical history, I would focus my physical exam on looking for evidence of parenchymal lung disease, signs of pulmonary hypertension, and pneumonia.

Her surgical history includes a previous hysterectomy, cholecystectomy, hernia repair, and left hepatic lobectomy for a benign mass. Her outpatient medications were ibuprofen, bupropion, fluvastatin, atenolol, potassium, aspirin, clopidogrel, albuterol inhaler, fluticasone/salmeterol inhaler, and omeprazole. She reports an allergy to penicillin and to sulfa drugs. Her mother died of an unknown cancer at age 77 years. She denied any international travel and she has always lived in Georgia.

The patient has been retired since 1992, having previously worked for the U.S. Postal Service. She admits to occasional alcohol intake (2 to 3 drinks a month). No recent travel, surgery, or prolonged immobilization was noted.

On initial examination she was alert and mentally appropriate, but appeared to be in mild respiratory distress with a respiratory rate of 28 breaths/minute. Her blood pressure (BP) was 99/70, heart rate 102, temperature of 38.2C, and oxygen saturation of 93% on room air and 97% on 2 L of oxygen via nasal cannula. Auscultation of her lungs revealed crackles over her left anterior lung field, bronchial breath sounds in the left posterior midlung, and bibasilar crackles. No wheezing was noted. Her cardiovascular exam and the remainder of her physical exam were unremarkable except for morbid obesity.

While my initial thoughts were leaning toward an exacerbation of chronic lung disease or possibly a new PE, at this moment, infection seems more likely. Indeed, her pulmonary findings suggest a left‐sided inflammatory process, and her vital signs meet criteria for systemic inflammatory response syndrome (SIRS). My primary concern is sepsis due to a drug‐resistant bacterial infection, including Staphylococcus aureus or gram‐negative bacteria or possibly more unusual organisms such as Nocardia or fungi, due to her recent use of antibiotics and chronic inhaled steroid use and recent course of oral glucocorticoids.

Conversely, the SIRS could be a manifestation of a noninfectious lung process such as acute interstitial pneumonia or an eosinophilic pneumonia. Given the diagnostic complexity, I would strongly consider consulting a pulmonologist if the patient did not improve quickly. At this point, I would like to review a posterior‐anterior (PA) and lateral chest radiograph, and room air arterial blood gas (ABG) in addition to basic laboratory test values.

Laboratory data obtained on admission was remarkable for a white blood cell (WBC) count of 26,500/L with 75% neutrophils and 6% eosinophils. Hemoglobin was 14.4 gm/dL. Platelet count was 454,000/L. Serum chemistries showed a sodium of 137 mEq/dL, potassium 4.3 mEq/dL, Cl 108 mEq/dL, bicarbonate 19 mEq/dL, blood urea nitrogen (BUN) 8 mg/dL, creatinine 1.0 mg/dL, and glucose 137 mg/dL. Cardiac enzymes were normal. Calcium was 9.8 mg/dL, albumin 2.7 gm/dL, total protein 6.9 gm/dL, AST 36 U/L, ALT 54 U/L and the bilirubin was normal. Chest radiograph (Figure 1) demonstrated a left perihilar infiltrate with air bronchograms and marked right hemidiaphragm elevation as seen on previous films. Unchanged increased interstitial markings were also present. Her electrocardiogram (ECG) showed normal sinus rhythm, normal axis, and QRS duration with nonspecific diffuse T‐wave abnormalities.

Figure 1

Given her presentation, I am worried about how well she is oxygenating and ventilating. An ABG should be done to assess her status more accurately. An albumin of 2.7 gm/dL indicates that she is fairly sick. I would not hesitate to consider testing the patient for human immunodeficiency virus (HIV) given how this information would dramatically change the differential diagnoses of her pulmonary process.

I am still most concerned about sepsis secondary to pneumonia in this patient with multiple chronic comorbidities, underlying chronic lung disease, receiving chronic inhaled glucocorticoids and a recent course of oral glucocorticoids and antibiotics. While I would initiate hydration I do not see a clear indication for early goal‐directed therapy for severe sepsis. In addition to obtaining an ABG and starting intravenous fluids, I would also draw blood cultures, send sputum for gram stain, culture, and sensitivity, and perform a urinalysis. I would also administer empiric antibiotics as quickly as possible based on a number of pneumonia clinical studies suggesting improved outcomes with early antibiotic administration. Because of her use of antibiotics and both inhaled and oral glucocorticoids, she is at higher risk for potentially multidrug‐resistant bacterial pathogens, including Staphyloccocus aureus and gram‐negative bacteria such as Pseudomonas and Klebsiella (Table 1). Therefore, I would initially cover her broadly for these organisms.

In addition to initial treatment choice, the inpatient triage decision is another important issue, especially at a community hospital where intensive care unit (ICU) resources are rare and often the admission decision is between sending a moderately sick patient to a regular floor bed or the medical ICU. Both the American Thoracic Society and Infectious Diseases Society of America support an ICU triage protocol in their guidelines for the management of community‐acquired pneumonia in adults that utilizes the following 9 minor criteria, of which the presence of at least 3 should support ICU admission: respiratory rate 30 breaths/minute; oxygenation index (pressure of oxygen [PaO₂]/fraction of inspired oxygen [FiO₂] ratio) 250; multilobar infiltrates; confusion/disorientation; uremia (BUN level 20 mg/dL); leukopenia (WBC count <4,000 cells/mm³); thrombocytopenia (platelet count <100,000 cells/mm³); hypothermia (core temperature <36C); and hypotension requiring aggressive fluid. Despite the absence of these criteria in this patient, it is important to note that no triage protocol has been adequately prospectively validated. Retrospective study of the minor criteria has found that the presence of at least 2 of the following 3 clinical criteria to have the highest specificity for predicting cardiopulmonary decompensation and subsequent need for ICU care: (1) initial hypotension (BP <90/60) on presentation with response to initial intravenous fluids to a BP >90/60; (2) oxygenation failure as indicated by PaO₂/FiO₂ ratio less than 250; or (3) the presence of multilobar or bilateral infiltrates on chest radiography.

I also want to comment on the relative elevation of her calcium, especially given the low albumin. This may simply be due to volume depletion, as many older patients have asymptomatic mild primary hyperparathyroidism. However, this elevated calcium may be a clue to the underlying lung process. Granulomatous lung disease due to tuberculosis or fungal infection could yield elevated calcium levels via increases in macrophage production of the active vitamin D metabolite calcitriol. This will need to be followed and a parathormone (PTH) level would be the best first test to request if the calcium level remains elevated. If the PTH level is suppressed, granulomatous disease or malignancy would be the more likely cause.

The patient was admitted with a presumptive diagnosis of community‐acquired pneumonia, was started on ceftriaxone and azithromycin, and given intravenous fluids, oxygen, and continued on inhaled salmeterol/fluticasone. Sputum was ordered for gram stain, culture, and sensitivity, and blood cultures were obtained. Urinalysis showed 1‐5 WBCs/high‐power field. Venous thromboembolism prophylaxis was initiated with subcutaneous heparin 5,000 units 8 hours. Her blood pressure normalized rapidly and during the next few days she stated she was feeling better. Despite continued significant wheezing her oxygen saturation remained at 98% on 2 L of oxygen via nasal cannula and she was less tachypneic. Attempts at obtaining an ABG were unsuccessful, and the patient subsequently refused additional attempts. Over the first few days her WBC count remained elevated above 20,000/L, with worsening bandemia (11%), and fever ranging from 38C to 39C. Sputum analysis was initially unsuccessful and blood cultures remained negative.

I am concerned about the persistent fever and elevated WBC count, and want to emphasize that I might have treated her with broader spectrum antibiotics to cover additional multidrug‐resistant bacterial organisms. I would have initially ordered vancomycin to cover methicillin resistant Staphylococcus aureus (MRSA) plus 2 additional antibiotics that cover multidrug‐resistant gram negative pathogens including Pseudomonas aeruginosa.

On the fifth hospital day, her WBC count dropped to 13,400/L and she defervesced. However, her respiratory status worsened during that same day with increased tachypnea. Of note, no results were reported from the initial sputum cultures and they were reordered and a noncontrast chest computed tomography (CT) was also ordered.

I think at this point, even though she has remained stable hemodynamically and oxygenating easily with supplemental oxygen, the question of whether or not her primary process is infectious or noninfectious lingers. I agree with obtaining a chest CT scan.

I am not surprised that sputum was not evaluated despite the orders. Among hospitalized patients with pneumonia, we frequently find that about a third of the time sputum cannot be obtained, about a third of the time it is obtained but the quality is unsatisfactory, and only a third of the time does the sputum sample meet criteria (less than 5 squamous epithelial cells per high‐power field) for adequate interpretation of the gram‐stain and culture result. Unfortunately, no one has developed a better way to improve this process. Nonetheless, I believe we do not try hard enough to obtain sputum in the first hours of evaluating our patients. I joke with our internal medicine residents that they should carry a sputum cup with them when they evaluate a patient with possible pneumonia. One recent prospective study of the value of sputum gram‐staining in community‐acquired pneumonia has found it to be highly specific for identifying Streptococcus pneumoniae or Haemophilus influenzae pneumonia.

The CT scan (Figure 2) performed on hospital day 6 demonstrated consolidation in the left upper lobe with areas of cavitation. There was also interstitial infiltrate extending into the lingula. Elevation of the right hemidiaphragm with atelectasis in both lung bases was also noted. A small effusion was present on the left and possibly a minimal effusion on the right as well. There was no pericardial effusion and only a few small pretracheal and periaortic lymph nodes were noted.

Figure 2

Given her failure to improve significantly after 6 days of antibiotic treatment, and her recent use of glucocorticoids, I would expand my diagnostic considerations to include other necrotizing bacterial infections, tuberculosis, fungus, and Nocardia.

Given the results of the CT scan she was placed in respiratory isolation to rule out active pulmonary tuberculosis. Though tachypneic, her blood pressure and pulse remained stable. However, her oxygen saturation deteriorated, declining to 92% on 2 L of oxygen via nasal cannula during hospital days 6 and 7. Subsequent successful attempts at collecting sputum yielded rapid growth of yeast (not Cryptococcus spp.). Pulmonary and infectious disease consultations were obtained and vancomycin was added to her regimen. The patient subsequently agreed to undergo diagnostic bronchoscopy.

I agree with obtaining input from expert consultants. I think we too often underutilize consultation in patients that are better but not completely better when we are not entirely sure what is going on. Evidence of noncryptococcus yeast in sputum may sometimes indicate colonization with Candida spp. without any significant clinical consequence. This finding may alternatively suggest the possibility of a true fungal pneumonia caused by 1 of the dimorphic fungi, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitides, or Coccidioides immitis. However, in this case there is not a strong epidemiologic patient history of exposure to any of these types of fungi.

Three sputum smears were negative for acid fast bacilli (AFB). Bronchoscopy revealed grossly abnormal mucosa in the left upper lobe and bronchomalacia, but no obstructive lesions. A transthoracic echocardiogram was ordered to evaluate her degree of pulmonary hypertension.

The 3 sputum specimens that were negative for AFB despite cavitary lung disease have high sensitivity for ruling out pulmonary tuberculosis. In addition, given the absence of any bacterial pathogen isolated from these specimens, I would pursue the possibility of other potential fungal pathogens given the patient's subacute course, history of using inhaled and oral corticosteroids, sputum results, and the presence of a cavitary lesion on her CT scan images.

Cytologic examination of the bronchoalveolar lavage (BAL) sample showed a cell differential of 1% bands, 58% neutrophils, 9% lymphs, and 27% eosinophils. The routine postbronchoscopy chest radiograph showed complete opacification of the left lung. The patient's WBC count rose to 26,000/L but she remained afebrile. Echocardiogram was reported to be of very poor quality due to her obesity. The cardiologist reviewing the echocardiogram called the attending physicians and stated there was possibly something in the left pulmonary artery and aortic dissection could not be ruled out.

The presence of eosinophilia on BAL may be a very important clue as to what lung pathology she has. In fact, eosinophilia in this setting may indicate the possibility of parasitic or fungal infection of the lung, or inflammation of the airway associated to drug toxicity, asthma, or environmental toxin exposure. With this additional information, I am concerned that she may be harboring an atypical infection such as an invasive fungus. The echocardiogram results are unclear to me but will need to be clarified with additional testing.

The interpretation of the transbronchial biopsy specimen was limited but suggested invasive pseudomembranous tracheal bronchitis due to aspergillosis. The routine hematoxylin and eosin stain showed portions of alveolar lung tissue and some collapsed submucosal bronchial glands with relatively normal‐looking lung tissue but along the edge of the spaces were obvious fungal organisms. The Gomori's methenamine silver (GMS) stain suggested the presence of Aspergillus organisms (Figure 3). Fungal cultures were also negative for any of the other dimorphic fungi or for molds.

Figure 3

Despite the negative culture results, the overall clinical picture suggests a necrotizing pneumonia caused by an invasive Aspergillus affecting both the bronchial tree and the lower respiratory tract. Generally, necrotizing pneumonias usually have a slow response to antimicrobial therapy. Given the inherent difficulty in differentiating clearly between invasive and noninvasive disease based on a transbronchial biopsy specimen, initiating antifungal therapy for invasive aspergillosis is appropriate in this patient. This patient's recent use of oral glucocorticoids and chronic use of inhaled glucocorticoids are both potential risk factors that predisposed this patient to develop invasive aspergillosis.

Many times we simply follow treatment guidelines for different categories of pneumonia, and have limited or inadequate clinical information to make more definitive diagnoses. While we need these treatment protocols, physicians must avoid falling into the trap that antibiotics treat all infectious etiologies in the lung and we should make reasonable efforts to pin down the etiology. All of us have been fooled by atypical presentations of tuberculosis, fungus, and noninfectious diseases of the lung. I think it behooves us to be vigilant about alternative diagnoses and consider pursuing additional studies whenever the clinical response to initial treatment does not meet our expectations.

Subsequently, the patient's additional cultures remained negative. The official echocardiogram report was read as questionable PE in the pulmonary artery. A spiral CT angiogram revealed a pulmonary artery embolus in the left upper lobe and she was treated with anticoagulation. Her shortness of breath improved steadily and she was successfully discharged after receiving 9 days of oral voriconazole. Outpatient pulmonary function testing documented the presence of chronic obstructive lung disease. She completed a 5‐month course of voriconazole therapy with significant clinical and radiologic improvement of her pulmonary infiltrate. She also completed a 12‐month treatment with warfarin for the concomitant pulmonary embolism. On follow‐up at 12 months she was doing well.

COMMENTARY

Aspergillosis caused particularly by Aspergillus fumigatus is considered an emerging infectious disease that frequently produces significant morbidity and mortality among immunocompromised patients.1, 2 The most frequently‐affected organs by this fungal pathogen include the lung and the central nervous system. There are 3 pathogenic mechanisms of Aspergillus infection of the lung: colonization, hypersensitivity reaction, and invasive aspergillosis.1

Invasive pulmonary aspergillosis is predominantly seen among individuals with severe degrees of immunosuppression as a result of solid‐organ transplantation, immunosuppressive therapies for autoimmune diseases, systemic glucocorticoids, and chemotherapy for hematologic malignancies. Mortality due to invasive aspergillosis continues to be very high (>58%) despite our improved ability to diagnose this condition and newer therapies to treat immunocompromised individuals.1 Invasive aspergillosis can manifest clinically in multiple ways. These include: (1) an invasive vascular process in which fungal organisms invade blood vessels, causing a rapidly progressive and often fatal illness; (2) necrotizing pseudomembranous tracheal bronchitis; (3) chronic necrotizing aspergillosis; (4) bronchopleural fistula; or (5) empyema.35 In our case, while the pathologic findings were most suggestive of an invasive pseudomembranous tracheal bronchitis, the overall clinical picture was most compatible with a necrotizing pneumonia due to invasive aspergillosis.

In addition to the traditional identified risk factors for invasive pulmonary aspergillosis, a number of reports during the last decade have demonstrated the occurrence of invasive aspergillosis in patients with COPD.14 A systematic review of the literature demonstrated that among 1,941 patients with invasive aspergillosis, 26 (1.3%) had evidence of COPD as the main risk factor for developing invasive aspergillosis.1 A single report has associated the potential use of inhaled steroids with the occurrence of invasive aspergillosis in this patient population.2 However, other factors that may promote increased susceptibility to invasive fungal infection among patients with COPD include the use of long‐term or repeated short‐term glucocorticoid treatments, and the presence of multiple additional comorbidities, which may be found in this same population such as diabetes, malnutrition, or end‐stage renal disease.3, 4 Most reported series have demonstrated a high mortality rate of invasive pulmonary aspergillosis in patients with COPD.14

The diagnosis of invasive pulmonary aspergillosis represents a significant clinical challenge. Diagnostic algorithms incorporating CT, antigen detection testing (for serum galactomannan and ‐glucan) as well as polymerase chain reaction diagnostic testing appear to be beneficial in the early diagnosis of invasive aspergillosis in particular settings such as in allogeneic hematopoietic stem cell transplantation.5 The role of antigen testing to identify early invasive aspergillosis in patients with COPD remains uncertain since it has been evaluated in a limited number of patients and therefore clinical suspicion is critical to push clinicians to pursue invasive tissue biopsy and cultures to confirm the diagnosis.3, 4

Based on the available clinical case series and in our case, invasive pulmonary aspergillosis should be suspected in COPD patients with rapidly progressive pneumonia not responding to antibacterial therapy and who have received oral or inhaled glucocorticoids in the recent past. In addition, this case also illustrates that occasionally, patients present with more than 1 life‐threatening diagnosis. This patient was also diagnosed with PE despite adequate prophylaxis. In addition to the well‐known clinical risk factors of obesity and lung disease, the underlying infection may have contributed to a systemic or local hypercoagulable condition that further increased her risk for venous thromboembolism.

KEY TEACHING POINTS

• Clinicians should remember to consider a broad differential in patients presenting with pneumonia, including the possibility of fungal pathogens in patients with known risk factors and in patients with multiple, potentially immunosuppressive comorbidities, or in patients who do not improve on standard antibiotic therapy.

• There is some evidence of an association between COPD and invasive aspergillosis, likely due to the frequent use of oral corticosteroids and/or chronic inhaled steroids in this population.

Ongoing surveillance indicates that the number of hospitalizations involving patients with a diagnosis of diabetes mellitus is increasing in the United States.1, 2 Hospitalized patients with hyperglycemia have worse outcomes (eg, greater mortality, longer length of stay, and more infections) than those without high glucose levels.3, 4 The rate of adverse outcomes associated with hyperglycemia can be decreased with improved management.3, 4 Consequently, the American Diabetes Association and the American College of Endocrinology advocate lower glucose targets for all hospitalized patients regardless of whether they have a known diagnosis of diabetes.3, 4

Practitioners continue to debate the exact glucose targets that should be attained for inpatients;5, 6 however, there is more to inpatient hyperglycemia management than just trying to achieve a specific glucose range. Caring for patients with diabetes in the hospital is complex and must also encompass patient safety, but many practitioners perceive a state of glycemic chaos in the hospital.7 Because many physicians frequently overlook diabetes and glucose control in the hospital, appropriate therapeutic responses to hyperglycemia do not occur.810 National,11, 12 state,13 and specialty societies3, 4, 14 are working toimprove care for hospitalized patients with hyperglycemia. A recent consensus conference emphasized the need to develop broad‐based educational programs to increase awareness about the importance of inpatient glycemic control and to develop a standardized set of tools for hospitals to use to improve care.4 However, there is ongoing concern about the slow pace at which hospitals are implementing recommendations about glycemic control.4

Intensive and prolonged educational efforts about the importance of glycemic control will be essential ingredients of any quality improvement effort designed to create glycemic order out of glycemic chaos in the hospital.15 Before educational interventions and policies directed at improving the management of hyperglycemia in hospitalized patients can be developed, institutions need to gain a better understanding of how clinicians view the importance of inpatient glucose control and which barriers they perceive as constraints to their ability to care for inpatients with hyperglycemia.

At Atlanta Medical Center (AMC), the large urban teaching hospital where this study was conducted, the glucose control team detected resistance to changes that were implemented to improve the hospital's quality of glycemic control;16 this observation led to a desire to gain more information about practitioner attitudes regarding inpatient glucose control management. Data on practitioner attitudes and beliefs about inpatient hyperglycemia are only now emerging and are limited to studies from a single institution.17, 18 Thus, additional studies are needed to determine whether findings from these first studies are applicable to other types of hospital settings that have different inpatient populations. To gain additional insight into clinician beliefs about inpatient glucose control, we adapted a previously published questionnaire17, 18 and used it to survey resident physicians training at AMC.

METHODS

RESULTS

Beliefs About Glucose Targets and Hypoglycemia

When asked to indicate the target glucose levels that they would like to achieve, most resident physicians indicated that good glycemic control meant a target range of 80 to 110 mg/dL for critically‐ill patients and for perioperative patients. For non‐critically‐ill patients, targets were split between a target range of 80 to 110 mg/dL and 111 to 180 mg/dL. Trainees rarely suggested targets greater than 180 mg/dL (Table 1).

Most respondents believed that they were achieving their glycemic goals in 41% to 60% of their patients (Fig. 1A). More than half (56%) perceived that they were achieving their glucose targets in more than 40% of their diabetes patients. When asked at what glucose level they first considered the patient to be hypoglycemic, half of the respondents chose <60 mg/dL (Fig. 1B), although some had even lower cutoffs before they considered someone to have a diagnosis of hypoglycemia.

Figure 1

DISCUSSION

In recent years national and regional organizations have focused greater attention on the management of hyperglycemia among inpatient populations by introducing and promoting guidelines for better care.3, 4, 1114 A consensus conference in 2006 urged hospitals to move rapidly to make euglycemia a goal for all inpatients and to make patient safety in glycemic control a reality. 20 AMC has already taken some steps toward understanding and improving its hospital‐based care of hyperglycemia, including understanding the mortality associated with hyperglycemia within the institution and implementing a novel insulin infusion algorithm.16, 19

Before hospitals can develop high‐quality improvement and educational programs focused on inpatient hyperglycemia, they will need more insight into their clinicians' views on inpatient glycemic control and the perceived barriers to successful treatment of hyperglycemia. However, the only data that have been published about practitioner attitudes on inpatient diabetes and glycemic control are from a single institution.17, 18 Thus, analyses should be broadened to include different types of hospital settings to determine common beliefs on the topic.

AMC is very different from the hospital facility where earlier studies on physician attitudes about inpatient glucose management were conducted. Whereas the site of the earlier studies is located in the Southwest and has a diabetes inpatient population that is primarily white, AMC is an urban hospital in the Southeast whose diabetes inpatient population is primarily minority.21 Despite the institutional, geographic, and patient population differences, however, results of the current survey suggest that there may be similar beliefs among practitioners about inpatient glucose management as well as common knowledge deficits that can be targeted for educational interventions.

Similar to the resident physicians surveyed in previous studies,17, 18 AMC resident physicians considered diabetes to be a substantial part of their inpatient practices: 56% of respondents believed that more than 40% of their inpatients had a diagnosis of diabetes. Historically, the prevalence at AMC of hyperglycemia has been about 38% and the prevalence of diabetes about 26%.19 The increasing number of hospital dismissals attributable to diabetes likely has increased the inpatient prevalence of the disease at AMC as well, but very high rates perceived by some residents (eg, 81%‐100%) are likely not accurate. Nonetheless, this perception of such a large burden of diabetes clearly substantiates the need to provide pertinent information and essential tools to clinicians for successful management of hyperglycemia in hospital patients. We also established that most AMC resident physicians who were surveyed believed that good glucose control was very important in situations relating to critical illness or noncritical illness. For most respondents, good glucose control was also very important in the perioperative period. This finding suggests that the trainees understand the importance of good glucose control in such situations.

In keeping with findings from previous studies,17, 18 respondents to this survey indicated glucose targets that would be well within currently existing guidelines.3, 4 Glucose management training might be improved by conveying whether actual glucose outcomes match residents' perceived achievement of glycemic control.

Insulin is the recommended treatment for inpatient hyperglycemia,3, 4 yet residents' responses reflected concern about insulin use. The most commonly noted issues, cited with equal frequency, were related to insulin use: knowing what insulin type or regimen works best and fluctuating insulin demands related to stress/concomitantly used medications. Our survey did not evaluate whether residents had different degrees of comfort with different subcutaneous insulin programs (eg, sliding scale versus basal‐bolus). Future surveys could be modified to better hone in on evaluating self‐perceived competencies in these areas.

Given the increasing complexity of insulin therapy, resident physicians' perception of insulin administration as the top barrier to inpatient glucose management may not be surprising.17, 18 The number of insulin analogs has increased in recent years. Moreover, numerous intravenous insulin algorithms are available.22, 23 Errors in insulin administration are among the most frequently occurring medication errors in hospitals.24 To address patient safety and medical system errors in the fields of diabetes and endocrinology, the American College of Endocrinology published a position statement on the topic in 2005.25 Guidelines about when to initiate insulin therapy, how to choose from numerous insulin treatment options, and how to adjust therapy in response to rapidly changing clinical situations will have to be integrated into any effort to improve inpatient glucose management. One study indicated that an educational process focused on teaching residents about insulin therapy can be successful.26

Clinician fear of hypoglycemia is often perceived as the primary obstacle to successful control of inpatient glucose levels;3, 27 however, this was not the chief concern expressed by either AMC resident physicians or by practitioners surveyed in prior studies.17, 18 Emerging data suggest that hypoglycemia in the hospital is actually uncommon.21, 28 As hospitals intensify hyperglycemia management efforts, hypoglycemia and concerns about its frequency of occurrence will most likely increase. No consensus exists regarding the number of hypoglycemic events that are acceptable in a hospitalized patient. The American Diabetes Association Workgroup on Hypoglycemia has defined hypoglycemia as an (arterialized venous) plasma glucose concentration of less than or equal to 70 mg/dL.29 As a group, residents surveyed for the current study were not consistent in their definition of hypoglycemia.

The residents at AMC also reported potential obstacles to care besides insulin management that suggest system‐based problems. Unpredictable timing of patient procedures and unpredictable changes in patient diet and mealtimes were among the 5 most frequently cited concerns. Other concerns included patient not in hospital long enough to adequately control glucose and shift changes and cross‐coverage lead to inconsistent management. These findings are identical to those of prior studies17, 18 and suggest system‐based problems as common barriers to inpatient glucose management. Some of these obstacles, such as length of hospital stay and timing of procedures, would be difficult to reengineer. However, other aspects, such as adjusting therapy to mealtimes and ensuring standardization of treatment across shifts, could be addressed through institution‐wide education and changes in policies.

As in previous studies, another major finding that emerged from this survey was the lack of resident physician familiarity with existing policies and procedures related to inpatient glucose management. AMC has a longstanding policy on hypoglycemia management and has preprinted order sets for subcutaneous insulin. AMC has implemented a revised insulin infusion algorithm16 in addition to a policy and an order set for the use of insulin pumps.30 There are no specific data on how many patients receiving insulin pump therapy are hospitalized, but these patients are likely to be encountered only rarely in the hospital setting. Hence, it may not be surprising that residents are unfamiliar with policies pertaining to inpatient insulin pump use, but they should at least be aware that guidance is available. One of the first steps to enhancing and standardizing hospital glucose management may simply be to make certain that clinicians are familiar with policies that are already in place within the institution.

A limitation of this study is the small sample size. The results of the present study should not be extrapolated to nonresident medical staff such as attending physicians, but the questionnaire could be adapted, with minor modifications, to investigate how other health care professionals view inpatient glucose management. In addition, the questionnaire could be used to assess changes in beliefs over time. Future studies should be designed to correlate resident perceptions about their inpatient diabetes care and actual practice patterns.

More surveys such as the one reported on here need to be conducted in additional institutions in order to expand our understanding of practitioner attitudes regarding inpatient diabetes care. Data from the current study and previous ones suggest that practitioners share beliefs, knowledge deficits, and perceived barriers about inpatient glucose management. Most AMC resident physicians recognized the importance of good glucose control and set target glucose ranges consistent with existing guidelines. Knowledge deficits may be addressed by developing training programs that specifically spotlight insulin use in the hospital. As a first step to quality improvement, training programs should focus on familiarizing staff with existing institutional policies and procedures pertaining to hospital hyperglycemia. In addition, hospitals need to design strategies to overcome perceived and actual barriers to care so that they can realize the desired improvement in the management of hyperglycemia in their patients. We have already begun the development and implementation of educational modules directed at addressing many of these important issues.

Ongoing surveillance indicates that the number of hospitalizations involving patients with a diagnosis of diabetes mellitus is increasing in the United States.1, 2 Hospitalized patients with hyperglycemia have worse outcomes (eg, greater mortality, longer length of stay, and more infections) than those without high glucose levels.3, 4 The rate of adverse outcomes associated with hyperglycemia can be decreased with improved management.3, 4 Consequently, the American Diabetes Association and the American College of Endocrinology advocate lower glucose targets for all hospitalized patients regardless of whether they have a known diagnosis of diabetes.3, 4

Practitioners continue to debate the exact glucose targets that should be attained for inpatients;5, 6 however, there is more to inpatient hyperglycemia management than just trying to achieve a specific glucose range. Caring for patients with diabetes in the hospital is complex and must also encompass patient safety, but many practitioners perceive a state of glycemic chaos in the hospital.7 Because many physicians frequently overlook diabetes and glucose control in the hospital, appropriate therapeutic responses to hyperglycemia do not occur.810 National,11, 12 state,13 and specialty societies3, 4, 14 are working toimprove care for hospitalized patients with hyperglycemia. A recent consensus conference emphasized the need to develop broad‐based educational programs to increase awareness about the importance of inpatient glycemic control and to develop a standardized set of tools for hospitals to use to improve care.4 However, there is ongoing concern about the slow pace at which hospitals are implementing recommendations about glycemic control.4

Intensive and prolonged educational efforts about the importance of glycemic control will be essential ingredients of any quality improvement effort designed to create glycemic order out of glycemic chaos in the hospital.15 Before educational interventions and policies directed at improving the management of hyperglycemia in hospitalized patients can be developed, institutions need to gain a better understanding of how clinicians view the importance of inpatient glucose control and which barriers they perceive as constraints to their ability to care for inpatients with hyperglycemia.

At Atlanta Medical Center (AMC), the large urban teaching hospital where this study was conducted, the glucose control team detected resistance to changes that were implemented to improve the hospital's quality of glycemic control;16 this observation led to a desire to gain more information about practitioner attitudes regarding inpatient glucose control management. Data on practitioner attitudes and beliefs about inpatient hyperglycemia are only now emerging and are limited to studies from a single institution.17, 18 Thus, additional studies are needed to determine whether findings from these first studies are applicable to other types of hospital settings that have different inpatient populations. To gain additional insight into clinician beliefs about inpatient glucose control, we adapted a previously published questionnaire17, 18 and used it to survey resident physicians training at AMC.

METHODS

RESULTS

Beliefs About Glucose Targets and Hypoglycemia

When asked to indicate the target glucose levels that they would like to achieve, most resident physicians indicated that good glycemic control meant a target range of 80 to 110 mg/dL for critically‐ill patients and for perioperative patients. For non‐critically‐ill patients, targets were split between a target range of 80 to 110 mg/dL and 111 to 180 mg/dL. Trainees rarely suggested targets greater than 180 mg/dL (Table 1).

Most respondents believed that they were achieving their glycemic goals in 41% to 60% of their patients (Fig. 1A). More than half (56%) perceived that they were achieving their glucose targets in more than 40% of their diabetes patients. When asked at what glucose level they first considered the patient to be hypoglycemic, half of the respondents chose <60 mg/dL (Fig. 1B), although some had even lower cutoffs before they considered someone to have a diagnosis of hypoglycemia.

Figure 1

DISCUSSION

In recent years national and regional organizations have focused greater attention on the management of hyperglycemia among inpatient populations by introducing and promoting guidelines for better care.3, 4, 1114 A consensus conference in 2006 urged hospitals to move rapidly to make euglycemia a goal for all inpatients and to make patient safety in glycemic control a reality. 20 AMC has already taken some steps toward understanding and improving its hospital‐based care of hyperglycemia, including understanding the mortality associated with hyperglycemia within the institution and implementing a novel insulin infusion algorithm.16, 19

Before hospitals can develop high‐quality improvement and educational programs focused on inpatient hyperglycemia, they will need more insight into their clinicians' views on inpatient glycemic control and the perceived barriers to successful treatment of hyperglycemia. However, the only data that have been published about practitioner attitudes on inpatient diabetes and glycemic control are from a single institution.17, 18 Thus, analyses should be broadened to include different types of hospital settings to determine common beliefs on the topic.

AMC is very different from the hospital facility where earlier studies on physician attitudes about inpatient glucose management were conducted. Whereas the site of the earlier studies is located in the Southwest and has a diabetes inpatient population that is primarily white, AMC is an urban hospital in the Southeast whose diabetes inpatient population is primarily minority.21 Despite the institutional, geographic, and patient population differences, however, results of the current survey suggest that there may be similar beliefs among practitioners about inpatient glucose management as well as common knowledge deficits that can be targeted for educational interventions.

Similar to the resident physicians surveyed in previous studies,17, 18 AMC resident physicians considered diabetes to be a substantial part of their inpatient practices: 56% of respondents believed that more than 40% of their inpatients had a diagnosis of diabetes. Historically, the prevalence at AMC of hyperglycemia has been about 38% and the prevalence of diabetes about 26%.19 The increasing number of hospital dismissals attributable to diabetes likely has increased the inpatient prevalence of the disease at AMC as well, but very high rates perceived by some residents (eg, 81%‐100%) are likely not accurate. Nonetheless, this perception of such a large burden of diabetes clearly substantiates the need to provide pertinent information and essential tools to clinicians for successful management of hyperglycemia in hospital patients. We also established that most AMC resident physicians who were surveyed believed that good glucose control was very important in situations relating to critical illness or noncritical illness. For most respondents, good glucose control was also very important in the perioperative period. This finding suggests that the trainees understand the importance of good glucose control in such situations.

In keeping with findings from previous studies,17, 18 respondents to this survey indicated glucose targets that would be well within currently existing guidelines.3, 4 Glucose management training might be improved by conveying whether actual glucose outcomes match residents' perceived achievement of glycemic control.

Insulin is the recommended treatment for inpatient hyperglycemia,3, 4 yet residents' responses reflected concern about insulin use. The most commonly noted issues, cited with equal frequency, were related to insulin use: knowing what insulin type or regimen works best and fluctuating insulin demands related to stress/concomitantly used medications. Our survey did not evaluate whether residents had different degrees of comfort with different subcutaneous insulin programs (eg, sliding scale versus basal‐bolus). Future surveys could be modified to better hone in on evaluating self‐perceived competencies in these areas.

Given the increasing complexity of insulin therapy, resident physicians' perception of insulin administration as the top barrier to inpatient glucose management may not be surprising.17, 18 The number of insulin analogs has increased in recent years. Moreover, numerous intravenous insulin algorithms are available.22, 23 Errors in insulin administration are among the most frequently occurring medication errors in hospitals.24 To address patient safety and medical system errors in the fields of diabetes and endocrinology, the American College of Endocrinology published a position statement on the topic in 2005.25 Guidelines about when to initiate insulin therapy, how to choose from numerous insulin treatment options, and how to adjust therapy in response to rapidly changing clinical situations will have to be integrated into any effort to improve inpatient glucose management. One study indicated that an educational process focused on teaching residents about insulin therapy can be successful.26

Clinician fear of hypoglycemia is often perceived as the primary obstacle to successful control of inpatient glucose levels;3, 27 however, this was not the chief concern expressed by either AMC resident physicians or by practitioners surveyed in prior studies.17, 18 Emerging data suggest that hypoglycemia in the hospital is actually uncommon.21, 28 As hospitals intensify hyperglycemia management efforts, hypoglycemia and concerns about its frequency of occurrence will most likely increase. No consensus exists regarding the number of hypoglycemic events that are acceptable in a hospitalized patient. The American Diabetes Association Workgroup on Hypoglycemia has defined hypoglycemia as an (arterialized venous) plasma glucose concentration of less than or equal to 70 mg/dL.29 As a group, residents surveyed for the current study were not consistent in their definition of hypoglycemia.

The residents at AMC also reported potential obstacles to care besides insulin management that suggest system‐based problems. Unpredictable timing of patient procedures and unpredictable changes in patient diet and mealtimes were among the 5 most frequently cited concerns. Other concerns included patient not in hospital long enough to adequately control glucose and shift changes and cross‐coverage lead to inconsistent management. These findings are identical to those of prior studies17, 18 and suggest system‐based problems as common barriers to inpatient glucose management. Some of these obstacles, such as length of hospital stay and timing of procedures, would be difficult to reengineer. However, other aspects, such as adjusting therapy to mealtimes and ensuring standardization of treatment across shifts, could be addressed through institution‐wide education and changes in policies.

As in previous studies, another major finding that emerged from this survey was the lack of resident physician familiarity with existing policies and procedures related to inpatient glucose management. AMC has a longstanding policy on hypoglycemia management and has preprinted order sets for subcutaneous insulin. AMC has implemented a revised insulin infusion algorithm16 in addition to a policy and an order set for the use of insulin pumps.30 There are no specific data on how many patients receiving insulin pump therapy are hospitalized, but these patients are likely to be encountered only rarely in the hospital setting. Hence, it may not be surprising that residents are unfamiliar with policies pertaining to inpatient insulin pump use, but they should at least be aware that guidance is available. One of the first steps to enhancing and standardizing hospital glucose management may simply be to make certain that clinicians are familiar with policies that are already in place within the institution.

A limitation of this study is the small sample size. The results of the present study should not be extrapolated to nonresident medical staff such as attending physicians, but the questionnaire could be adapted, with minor modifications, to investigate how other health care professionals view inpatient glucose management. In addition, the questionnaire could be used to assess changes in beliefs over time. Future studies should be designed to correlate resident perceptions about their inpatient diabetes care and actual practice patterns.

More surveys such as the one reported on here need to be conducted in additional institutions in order to expand our understanding of practitioner attitudes regarding inpatient diabetes care. Data from the current study and previous ones suggest that practitioners share beliefs, knowledge deficits, and perceived barriers about inpatient glucose management. Most AMC resident physicians recognized the importance of good glucose control and set target glucose ranges consistent with existing guidelines. Knowledge deficits may be addressed by developing training programs that specifically spotlight insulin use in the hospital. As a first step to quality improvement, training programs should focus on familiarizing staff with existing institutional policies and procedures pertaining to hospital hyperglycemia. In addition, hospitals need to design strategies to overcome perceived and actual barriers to care so that they can realize the desired improvement in the management of hyperglycemia in their patients. We have already begun the development and implementation of educational modules directed at addressing many of these important issues.

Ongoing surveillance indicates that the number of hospitalizations involving patients with a diagnosis of diabetes mellitus is increasing in the United States.1, 2 Hospitalized patients with hyperglycemia have worse outcomes (eg, greater mortality, longer length of stay, and more infections) than those without high glucose levels.3, 4 The rate of adverse outcomes associated with hyperglycemia can be decreased with improved management.3, 4 Consequently, the American Diabetes Association and the American College of Endocrinology advocate lower glucose targets for all hospitalized patients regardless of whether they have a known diagnosis of diabetes.3, 4

Practitioners continue to debate the exact glucose targets that should be attained for inpatients;5, 6 however, there is more to inpatient hyperglycemia management than just trying to achieve a specific glucose range. Caring for patients with diabetes in the hospital is complex and must also encompass patient safety, but many practitioners perceive a state of glycemic chaos in the hospital.7 Because many physicians frequently overlook diabetes and glucose control in the hospital, appropriate therapeutic responses to hyperglycemia do not occur.810 National,11, 12 state,13 and specialty societies3, 4, 14 are working toimprove care for hospitalized patients with hyperglycemia. A recent consensus conference emphasized the need to develop broad‐based educational programs to increase awareness about the importance of inpatient glycemic control and to develop a standardized set of tools for hospitals to use to improve care.4 However, there is ongoing concern about the slow pace at which hospitals are implementing recommendations about glycemic control.4

Intensive and prolonged educational efforts about the importance of glycemic control will be essential ingredients of any quality improvement effort designed to create glycemic order out of glycemic chaos in the hospital.15 Before educational interventions and policies directed at improving the management of hyperglycemia in hospitalized patients can be developed, institutions need to gain a better understanding of how clinicians view the importance of inpatient glucose control and which barriers they perceive as constraints to their ability to care for inpatients with hyperglycemia.

At Atlanta Medical Center (AMC), the large urban teaching hospital where this study was conducted, the glucose control team detected resistance to changes that were implemented to improve the hospital's quality of glycemic control;16 this observation led to a desire to gain more information about practitioner attitudes regarding inpatient glucose control management. Data on practitioner attitudes and beliefs about inpatient hyperglycemia are only now emerging and are limited to studies from a single institution.17, 18 Thus, additional studies are needed to determine whether findings from these first studies are applicable to other types of hospital settings that have different inpatient populations. To gain additional insight into clinician beliefs about inpatient glucose control, we adapted a previously published questionnaire17, 18 and used it to survey resident physicians training at AMC.

METHODS

RESULTS

Beliefs About Glucose Targets and Hypoglycemia

When asked to indicate the target glucose levels that they would like to achieve, most resident physicians indicated that good glycemic control meant a target range of 80 to 110 mg/dL for critically‐ill patients and for perioperative patients. For non‐critically‐ill patients, targets were split between a target range of 80 to 110 mg/dL and 111 to 180 mg/dL. Trainees rarely suggested targets greater than 180 mg/dL (Table 1).

Most respondents believed that they were achieving their glycemic goals in 41% to 60% of their patients (Fig. 1A). More than half (56%) perceived that they were achieving their glucose targets in more than 40% of their diabetes patients. When asked at what glucose level they first considered the patient to be hypoglycemic, half of the respondents chose <60 mg/dL (Fig. 1B), although some had even lower cutoffs before they considered someone to have a diagnosis of hypoglycemia.

Figure 1

DISCUSSION

In recent years national and regional organizations have focused greater attention on the management of hyperglycemia among inpatient populations by introducing and promoting guidelines for better care.3, 4, 1114 A consensus conference in 2006 urged hospitals to move rapidly to make euglycemia a goal for all inpatients and to make patient safety in glycemic control a reality. 20 AMC has already taken some steps toward understanding and improving its hospital‐based care of hyperglycemia, including understanding the mortality associated with hyperglycemia within the institution and implementing a novel insulin infusion algorithm.16, 19

Before hospitals can develop high‐quality improvement and educational programs focused on inpatient hyperglycemia, they will need more insight into their clinicians' views on inpatient glycemic control and the perceived barriers to successful treatment of hyperglycemia. However, the only data that have been published about practitioner attitudes on inpatient diabetes and glycemic control are from a single institution.17, 18 Thus, analyses should be broadened to include different types of hospital settings to determine common beliefs on the topic.

AMC is very different from the hospital facility where earlier studies on physician attitudes about inpatient glucose management were conducted. Whereas the site of the earlier studies is located in the Southwest and has a diabetes inpatient population that is primarily white, AMC is an urban hospital in the Southeast whose diabetes inpatient population is primarily minority.21 Despite the institutional, geographic, and patient population differences, however, results of the current survey suggest that there may be similar beliefs among practitioners about inpatient glucose management as well as common knowledge deficits that can be targeted for educational interventions.

Similar to the resident physicians surveyed in previous studies,17, 18 AMC resident physicians considered diabetes to be a substantial part of their inpatient practices: 56% of respondents believed that more than 40% of their inpatients had a diagnosis of diabetes. Historically, the prevalence at AMC of hyperglycemia has been about 38% and the prevalence of diabetes about 26%.19 The increasing number of hospital dismissals attributable to diabetes likely has increased the inpatient prevalence of the disease at AMC as well, but very high rates perceived by some residents (eg, 81%‐100%) are likely not accurate. Nonetheless, this perception of such a large burden of diabetes clearly substantiates the need to provide pertinent information and essential tools to clinicians for successful management of hyperglycemia in hospital patients. We also established that most AMC resident physicians who were surveyed believed that good glucose control was very important in situations relating to critical illness or noncritical illness. For most respondents, good glucose control was also very important in the perioperative period. This finding suggests that the trainees understand the importance of good glucose control in such situations.

In keeping with findings from previous studies,17, 18 respondents to this survey indicated glucose targets that would be well within currently existing guidelines.3, 4 Glucose management training might be improved by conveying whether actual glucose outcomes match residents' perceived achievement of glycemic control.

Insulin is the recommended treatment for inpatient hyperglycemia,3, 4 yet residents' responses reflected concern about insulin use. The most commonly noted issues, cited with equal frequency, were related to insulin use: knowing what insulin type or regimen works best and fluctuating insulin demands related to stress/concomitantly used medications. Our survey did not evaluate whether residents had different degrees of comfort with different subcutaneous insulin programs (eg, sliding scale versus basal‐bolus). Future surveys could be modified to better hone in on evaluating self‐perceived competencies in these areas.

Given the increasing complexity of insulin therapy, resident physicians' perception of insulin administration as the top barrier to inpatient glucose management may not be surprising.17, 18 The number of insulin analogs has increased in recent years. Moreover, numerous intravenous insulin algorithms are available.22, 23 Errors in insulin administration are among the most frequently occurring medication errors in hospitals.24 To address patient safety and medical system errors in the fields of diabetes and endocrinology, the American College of Endocrinology published a position statement on the topic in 2005.25 Guidelines about when to initiate insulin therapy, how to choose from numerous insulin treatment options, and how to adjust therapy in response to rapidly changing clinical situations will have to be integrated into any effort to improve inpatient glucose management. One study indicated that an educational process focused on teaching residents about insulin therapy can be successful.26

Clinician fear of hypoglycemia is often perceived as the primary obstacle to successful control of inpatient glucose levels;3, 27 however, this was not the chief concern expressed by either AMC resident physicians or by practitioners surveyed in prior studies.17, 18 Emerging data suggest that hypoglycemia in the hospital is actually uncommon.21, 28 As hospitals intensify hyperglycemia management efforts, hypoglycemia and concerns about its frequency of occurrence will most likely increase. No consensus exists regarding the number of hypoglycemic events that are acceptable in a hospitalized patient. The American Diabetes Association Workgroup on Hypoglycemia has defined hypoglycemia as an (arterialized venous) plasma glucose concentration of less than or equal to 70 mg/dL.29 As a group, residents surveyed for the current study were not consistent in their definition of hypoglycemia.

The residents at AMC also reported potential obstacles to care besides insulin management that suggest system‐based problems. Unpredictable timing of patient procedures and unpredictable changes in patient diet and mealtimes were among the 5 most frequently cited concerns. Other concerns included patient not in hospital long enough to adequately control glucose and shift changes and cross‐coverage lead to inconsistent management. These findings are identical to those of prior studies17, 18 and suggest system‐based problems as common barriers to inpatient glucose management. Some of these obstacles, such as length of hospital stay and timing of procedures, would be difficult to reengineer. However, other aspects, such as adjusting therapy to mealtimes and ensuring standardization of treatment across shifts, could be addressed through institution‐wide education and changes in policies.

As in previous studies, another major finding that emerged from this survey was the lack of resident physician familiarity with existing policies and procedures related to inpatient glucose management. AMC has a longstanding policy on hypoglycemia management and has preprinted order sets for subcutaneous insulin. AMC has implemented a revised insulin infusion algorithm16 in addition to a policy and an order set for the use of insulin pumps.30 There are no specific data on how many patients receiving insulin pump therapy are hospitalized, but these patients are likely to be encountered only rarely in the hospital setting. Hence, it may not be surprising that residents are unfamiliar with policies pertaining to inpatient insulin pump use, but they should at least be aware that guidance is available. One of the first steps to enhancing and standardizing hospital glucose management may simply be to make certain that clinicians are familiar with policies that are already in place within the institution.

A limitation of this study is the small sample size. The results of the present study should not be extrapolated to nonresident medical staff such as attending physicians, but the questionnaire could be adapted, with minor modifications, to investigate how other health care professionals view inpatient glucose management. In addition, the questionnaire could be used to assess changes in beliefs over time. Future studies should be designed to correlate resident perceptions about their inpatient diabetes care and actual practice patterns.

More surveys such as the one reported on here need to be conducted in additional institutions in order to expand our understanding of practitioner attitudes regarding inpatient diabetes care. Data from the current study and previous ones suggest that practitioners share beliefs, knowledge deficits, and perceived barriers about inpatient glucose management. Most AMC resident physicians recognized the importance of good glucose control and set target glucose ranges consistent with existing guidelines. Knowledge deficits may be addressed by developing training programs that specifically spotlight insulin use in the hospital. As a first step to quality improvement, training programs should focus on familiarizing staff with existing institutional policies and procedures pertaining to hospital hyperglycemia. In addition, hospitals need to design strategies to overcome perceived and actual barriers to care so that they can realize the desired improvement in the management of hyperglycemia in their patients. We have already begun the development and implementation of educational modules directed at addressing many of these important issues.