Limin Peng, PhD

METHODS

RESULTS

DISCUSSION

CONCLUSION

METHODS

RESULTS

DISCUSSION

CONCLUSION

METHODS

RESULTS

DISCUSSION

CONCLUSION

Observational studies in hospitalized patients with and without diabetes indicate that hyperglycemia is a predictor of poor clinical outcome and mortality.14 Early randomized controlled trials of intensified insulin therapy in patients with surgical and medical acute critical illness reported a reduction on the risk of multiorgan failure and systemic infections,35 as well as short‐ and long‐term mortality.1, 4 Recent randomized controlled trials, however, have failed to confirm the previously suggested benefits of intensive glucose control,6 and the large multicenter normoglycaemia in intensive care evaluation and survival using glucose algorithm regulation (NICE‐SUGAR) study reported an absolute increase in mortality rate with intensive glucose control.7 In addition, intensified insulin therapy in critically‐ill patients has been shown to be associated with a higher rate of severe hypoglycemic events than less aggressive glycemic control protocols.710 These results have led to a heightened interest in improving the quality and safety of the management of diabetes and hyperglycemia in the hospital.

The use of intravenous continuous insulin infusion (CII) is the preferred route of insulin administration for the management of hyperglycemia in the critical care setting.1, 11 Numerous examples of successful CII algorithms in achieving glycemic control are reported in the literature.4, 5, 12 Traditionally, order forms to titrate drip to achieve a target blood glucose (BG) range using an established algorithm or by the application of mathematical rules have been used in clinical practice. Recently, computer‐based algorithms aiming to direct the nursing staff adjusting insulin infusion rate have become commercially available.13, 14 It is not known, however, if computer‐based algorithms are superior to standard paper form‐based protocols in achieving glucose control and in reducing hypoglycemic events in critically‐ill patients. Accordingly, this multicenter randomized study aimed to determine differences in glycemic control and hypoglycemic events between treatment with a computer‐guided CII device and a standard column‐based paper algorithm in critically‐ill patients in the medical intensive care unit (ICU).

Research Design and Methods

In this multicenter, prospective, open‐label randomized study, 160 adult patients admitted to a medical ICU with new hyperglycemia or with a known history of diabetes treated with diet, insulin therapy or with any combination of oral antidiabetic agents were enrolled after written informed consent had been obtained from the patient or closest family member (Figure 1). Patients with known history of diabetes had 2 BG readings >120 mg/dL while subjects without a history of diabetes had 2 BG readings >140 mg/dL prior to enrollment. We excluded patients with acute hyperglycemic crises such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state,15 patients with severely impaired renal function (serum creatinine 3.5 mg/dL), dementia, and pregnancy. This study was conducted at 4 hospital centers including Grady Memorial Hospital, Emory University Hospital, and Piedmont Hospital in Atlanta, Georgia and the Regional Medical Center in Memphis, Tennessee.

Figure 1

Figure 2

Patients were randomized using a computer randomization table to receive CII following a computer‐guided algorithm (Glucommander) or CII following a standard paper form insulin infusion algorithm. Both protocols used glulisine (Apidra) insulin and targeted a BG between 80 mg/dL and 120 mg/dL. Insulin management was directed by the specific assigned protocol and was carried out daily by the nursing staff and by members of the internal medicine residency program. The ICU physician and primary care team decided on the treatment for all other medical problem(s) for which patients were admitted. Data were collected during CII up to the first 10 days of ICU stay.

Results

The admission characteristics and clinical outcomes of interest of the study patients are shown in Table 1. A total of 160 adult patients admitted to a medical ICU with new hyperglycemia (47%) or with a known history of diabetes (53%) were randomized into the study. Of them, 7 patients were excluded due to withdrawal of consent, treatment with subcutaneous basal or supplemental short‐acting insulin during CII, or receiving less than 4 hours of CII. There were no differences in the mean age, gender, race, history of diabetes, or primary admitting diagnosis between treatment groups. The most common admitting diagnosis categories included pulmonary (22.1%), cardiovascular (21.4%), infectious (20.0%), and central nervous system (16.6%) disorders.

The mean admission glucose concentration for study patients was 190.6 58.2 mg/dL and the mean A1C was 7.0 1.7%. Glycemic control parameters achieved with the CII protocols are listed in Table 2. At the start of CII, the mean BG value was similar for the Glucommander and paper protocols (189.7 64.8 mg/dL and 188.4 54.8 mg/dL, P = 0.419). The mean time to reach the BG target was shorter in the Glucommander group (4.8 2.8 vs. 7.8 9.1 hours, P < 0.001). The Glucommander group had a lower mean glucose value during insulin infusion (115.5 20.7 vs. 131.0 24.6 mg/dL, P < 0.001) and once at target goal, in a lower mean BG values (103.3 8.8 vs. 117.3 16.5 mg/dL, P < 0.001) than the standard algorithm (Figure 2). The mean inpatient BG difference between treatment groups was 15.5 mg/dL (P < 0.001), with a mean daily BG difference ranging from 17.4 mg/dL to 24.4 mg/dL less for the Glucommander group during days 2 to 6 of therapy (P < 0.01).

The Glucommander algorithm was associated with tighter glycemic control and less glucose variability than the standard paper form protocol. Once patients achieved BG target, on average 71.1% of BG readings in the Glucommander and 51.3% in the standard group remained within the 80 mg/dL to 120 mg/dL target range (P < 0.001). In addition, the Glucommander was associated with a significantly lower rate of severe hyperglycemia during insulin infusion. The number of patients with 1 or more episodes of BG >200 mg/dL (11.7% vs. 25%, P = 0.057 before adjusting for potential site difference and P = 0.034 after adjusting for site difference) were less in the Glucommander group than in the standard paper regimen. In addition, 4 of these patients in spite of being on the highest insulin delivery column failed to achieve glucoses <180 and had an average in‐hospital glucose level of 204.5 32.2 mg/dL. These patients were transitioned to the Glucommander arm and withdrawn from the study. All episodes of hypoglycemia occurred after the patients achieved 1 glucose measurement within the target range. The number of patients who experienced one or more BG <40 mg/dL and <60 mg/dL was 3.9% and 42.9% in the Glucommander and 5.6% and 31.9% in the standard regimen, respectively (both, P = not significant [NS]). Similar results were obtained when site effect was accommodated (both, P = NS). Based on repeated measures analyses, the probabilities of BG reading <40 mg/dL or <60 mg/dL were not significantly different between groups (P = 0.969, P = 0.084) after accounting for within‐patient correlations with or without adjusting for time effect. None of these episodes resulted in seizures or were otherwise judged to be associated with deterioration of clinical status.

The mean insulin infusion rate was slightly higher in the Glucommander regimen but the difference was not statistically significant between groups. Patients treated with the Glucommander protocol received a mean infusion rate of 0.035 0.024 unit/kg/hour for a total of 2.85 1.93 units per hour, and those treated with the paper protocol received a 0.028 0.021 units/kg/hour for a total of 2.50 2.28 units per hour, P = 0.12 and P = 0.09, respectively.

The numbers of BG measurements were similar between the Glucommander and standard paper algorithms (44.2 39.8 and 41.2 34.5 respectively, P = NS) with the number of glucose testing per patient ranging from 6 to 175 in the Glucommander and 3 to 168 in the standard group. Similarly, when normalized to the duration of insulin infusion, the frequency of BG monitoring was not different with the protocols (0.68 0.18 and 0.62 0.22 tests/hour respectively, P = NS).

Compared to the standard paper insulin infusion algorithm, patients treated with the Glucommander device had a similar mean ICU LOS (13.4 13.8 vs. 8.5 7.6 days, P = 0.145), mean hospital LOS (17.5 15.0 days vs. 23.9 26.3 days, P = 0.704) and hospital mortality (26.0% vs. 21.9%, P = 0.561).

Discussion

This study is the first to compare the safety and efficacy of a CII via a computer‐guided algorithm and a standard paper form protocol in nonsurgical patients in the ICU. Both treatment algorithms resulted in significant improvement in glycemic control with the Glucommander achieving glycemic glucose target in a shorter time of treatment, a lower mean glucose concentration, and in greater percentage of glucose measurements maintained within target range, without an increased risk of severe hypoglycemia compared to the standard paper protocol.

Hyperglycemia in hospitalized patients is a common, serious, and costly health care problem. Evidence from observational and interventional studies indicate that hyperglycemia in critical illness is associated with an increased risk of complications and mortality.25 There is ongoing debate, however, about the optimal glucose level in hospitalized patients with critical illness. Although, several cohort studies as well as early randomized trials in ICU patients reported that intensified insulin treatment to achieve a target glucose between 80 mg/dL to 110 mg/dL reported a reduction in short‐term and long‐term mortality and rates of multiorgan failure and systemic infections compared with conventionally treated patients.3, 4, 17 More recent randomized controlled trials and meta‐analyses, however, have shown that this low BG target has been difficult to achieve without increasing the risk for severe hypoglycemia.710 In addition, recent multicenter trials have failed to show significant improvement in clinical outcome or have even shown increased mortality risk with intensive glycemic control.610 Based on these reports, the American Association of Clinical Endocrinologist (AACE) and American Diabetes Association (ADA) task force on inpatient glycemic control recommended different glycemic targets in the ICU setting. Current guidelines suggest targeting a BG level between 140 mg/dL and 180 mg/dL (7.8 and 10.0 mmol/L) for the majority of ICU patients and a lower glucose targets between 110 mg/dL and 140 mg/dL (6.1 and 7.8 mmol/L) in selected ICU patients (ie, centers with extensive experience and appropriate nursing support, cardiac surgical patients, patients with stable glycemic control without hypoglycemia). Glucose targets >180 mg/dL or <110 mg/dL are no longer recommended in ICU patients.

The rate of severe hypoglycemic events (<40 mg/dL) observed in both arms of our trial was significantly lower than those reported in recent international trials of intensive glycemic control.3, 4, 8 The overall rate of severe hypoglycemic events in international trials ranged between 5% to 28.6%.3, 4, 7, 8, 18, 19 In this trial, the number of patients with severe hypoglycemia was 3.9% in the computer‐based and 5.6% in the standard paper algorithm. Repeated measures analyses show the probabilities of BG readings <40 mg/dL were similar and not significantly different between groups (P = 0.969). We observed, however, a high rate of mild hypoglycemic events in patients treated with both insulin algorithms. The number of patients with BG <60 mg/dL was 42.9% in the Glucommander and 31.9% in the standard (P = NS). Minimizing the rate of hypoglycemia events is of major importance in hospitalized patients because it has been shown that hypoglycemia may be an independent risk factor of poor clinical outcome and mortality.20 Hypoglycemia may increase the risk of ventricular arrhythmias, in part due to the prolongation QT interval21 and can impair cerebral glucose metabolism resulting in brain metabolic dysfunction, as suggested by recent clinical studies.22 Moreover, insulin‐induced hypoglycemia is also associated with increased proinflammatory cytokines (tumor necrosis factor [TNF]‐alpha, interleukin [IL]‐1beta, IL‐6, and IL‐8) and oxidative stress23 that correlate with elevations of counterregulatory hormones (catecholamines, cortisol).

The Glucommander was associated with lower glycemic variability and with a higher percentage of BG readings within target range than patients treated with the standard paper form regimen. The clinical importance of the degree of variability and rapidity of fluctuations in glucose levels in critically ill patients is a topic of recent interest. Glycemic variability has been identified as a strong independent contributor to the risk of mortality in critically ill and surgical patients.24 Low levels of glycemic variability (standard deviation [SD] <10 mg/dL or 10‐20 mg/dL) have been shown to have a statistically significant lower risk of mortality, even after adjustment for severity of illness. Further studies are needed to determine benefits on clinical outcomes from the more consistent BG control from computer‐based titration protocols.

We acknowledge the following limitations in this multicenter open label study. First, this study was conducted in the medical ICU and excluded postsurgical patients and subjects expected to undergo a major surgical procedure during the hospital stay. Although a recent meta‐analysis9 of 26 studies involving 13,567 patients reported no benefits in the general ICU population, it found a favorable effect of intensive glycemic control on mortality in surgical ICU patients (relative risk [RR], 0.63; confidence interval [CI], 0.44‐0.91). We also excluded patients with severe renal insufficiency and patients with a history of hyperglycemic crises. In addition, our study was not powered to demonstrate differences in mortality or clinical outcome between treatment groups, and the BG targets used in this study were lower than glycemic targets recently recommended by the AACE and ADA inpatient glycemic control task force.25 Raising the BG targets is likely to reduce or prevent the rate of mild and severe hypoglycemic events in the ICU.

In conclusion, the computer‐guided algorithm resulted in a more rapid and tighter glycemic control with a similar rate of hypoglycemic events than the standard paper form protocol in medical ICU patients. Our study suggests that, both treatment algorithms are appropriate alternatives for the management of hyperglycemia in critically ill patients, and the choice depends on a physician's preferences, cost considerations, and the availability of the computer guided algorithm. Large randomized clinical trials are needed to test the impact of the new AACE/ADA recommended BG targets in reducing hypoglycemic events, hospital complications, and hospital mortality in critically ill patients in the ICU.

Observational studies in hospitalized patients with and without diabetes indicate that hyperglycemia is a predictor of poor clinical outcome and mortality.14 Early randomized controlled trials of intensified insulin therapy in patients with surgical and medical acute critical illness reported a reduction on the risk of multiorgan failure and systemic infections,35 as well as short‐ and long‐term mortality.1, 4 Recent randomized controlled trials, however, have failed to confirm the previously suggested benefits of intensive glucose control,6 and the large multicenter normoglycaemia in intensive care evaluation and survival using glucose algorithm regulation (NICE‐SUGAR) study reported an absolute increase in mortality rate with intensive glucose control.7 In addition, intensified insulin therapy in critically‐ill patients has been shown to be associated with a higher rate of severe hypoglycemic events than less aggressive glycemic control protocols.710 These results have led to a heightened interest in improving the quality and safety of the management of diabetes and hyperglycemia in the hospital.

The use of intravenous continuous insulin infusion (CII) is the preferred route of insulin administration for the management of hyperglycemia in the critical care setting.1, 11 Numerous examples of successful CII algorithms in achieving glycemic control are reported in the literature.4, 5, 12 Traditionally, order forms to titrate drip to achieve a target blood glucose (BG) range using an established algorithm or by the application of mathematical rules have been used in clinical practice. Recently, computer‐based algorithms aiming to direct the nursing staff adjusting insulin infusion rate have become commercially available.13, 14 It is not known, however, if computer‐based algorithms are superior to standard paper form‐based protocols in achieving glucose control and in reducing hypoglycemic events in critically‐ill patients. Accordingly, this multicenter randomized study aimed to determine differences in glycemic control and hypoglycemic events between treatment with a computer‐guided CII device and a standard column‐based paper algorithm in critically‐ill patients in the medical intensive care unit (ICU).

Research Design and Methods

In this multicenter, prospective, open‐label randomized study, 160 adult patients admitted to a medical ICU with new hyperglycemia or with a known history of diabetes treated with diet, insulin therapy or with any combination of oral antidiabetic agents were enrolled after written informed consent had been obtained from the patient or closest family member (Figure 1). Patients with known history of diabetes had 2 BG readings >120 mg/dL while subjects without a history of diabetes had 2 BG readings >140 mg/dL prior to enrollment. We excluded patients with acute hyperglycemic crises such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state,15 patients with severely impaired renal function (serum creatinine 3.5 mg/dL), dementia, and pregnancy. This study was conducted at 4 hospital centers including Grady Memorial Hospital, Emory University Hospital, and Piedmont Hospital in Atlanta, Georgia and the Regional Medical Center in Memphis, Tennessee.

Figure 1

Figure 2

Patients were randomized using a computer randomization table to receive CII following a computer‐guided algorithm (Glucommander) or CII following a standard paper form insulin infusion algorithm. Both protocols used glulisine (Apidra) insulin and targeted a BG between 80 mg/dL and 120 mg/dL. Insulin management was directed by the specific assigned protocol and was carried out daily by the nursing staff and by members of the internal medicine residency program. The ICU physician and primary care team decided on the treatment for all other medical problem(s) for which patients were admitted. Data were collected during CII up to the first 10 days of ICU stay.

Results

The admission characteristics and clinical outcomes of interest of the study patients are shown in Table 1. A total of 160 adult patients admitted to a medical ICU with new hyperglycemia (47%) or with a known history of diabetes (53%) were randomized into the study. Of them, 7 patients were excluded due to withdrawal of consent, treatment with subcutaneous basal or supplemental short‐acting insulin during CII, or receiving less than 4 hours of CII. There were no differences in the mean age, gender, race, history of diabetes, or primary admitting diagnosis between treatment groups. The most common admitting diagnosis categories included pulmonary (22.1%), cardiovascular (21.4%), infectious (20.0%), and central nervous system (16.6%) disorders.

The mean admission glucose concentration for study patients was 190.6 58.2 mg/dL and the mean A1C was 7.0 1.7%. Glycemic control parameters achieved with the CII protocols are listed in Table 2. At the start of CII, the mean BG value was similar for the Glucommander and paper protocols (189.7 64.8 mg/dL and 188.4 54.8 mg/dL, P = 0.419). The mean time to reach the BG target was shorter in the Glucommander group (4.8 2.8 vs. 7.8 9.1 hours, P < 0.001). The Glucommander group had a lower mean glucose value during insulin infusion (115.5 20.7 vs. 131.0 24.6 mg/dL, P < 0.001) and once at target goal, in a lower mean BG values (103.3 8.8 vs. 117.3 16.5 mg/dL, P < 0.001) than the standard algorithm (Figure 2). The mean inpatient BG difference between treatment groups was 15.5 mg/dL (P < 0.001), with a mean daily BG difference ranging from 17.4 mg/dL to 24.4 mg/dL less for the Glucommander group during days 2 to 6 of therapy (P < 0.01).

The Glucommander algorithm was associated with tighter glycemic control and less glucose variability than the standard paper form protocol. Once patients achieved BG target, on average 71.1% of BG readings in the Glucommander and 51.3% in the standard group remained within the 80 mg/dL to 120 mg/dL target range (P < 0.001). In addition, the Glucommander was associated with a significantly lower rate of severe hyperglycemia during insulin infusion. The number of patients with 1 or more episodes of BG >200 mg/dL (11.7% vs. 25%, P = 0.057 before adjusting for potential site difference and P = 0.034 after adjusting for site difference) were less in the Glucommander group than in the standard paper regimen. In addition, 4 of these patients in spite of being on the highest insulin delivery column failed to achieve glucoses <180 and had an average in‐hospital glucose level of 204.5 32.2 mg/dL. These patients were transitioned to the Glucommander arm and withdrawn from the study. All episodes of hypoglycemia occurred after the patients achieved 1 glucose measurement within the target range. The number of patients who experienced one or more BG <40 mg/dL and <60 mg/dL was 3.9% and 42.9% in the Glucommander and 5.6% and 31.9% in the standard regimen, respectively (both, P = not significant [NS]). Similar results were obtained when site effect was accommodated (both, P = NS). Based on repeated measures analyses, the probabilities of BG reading <40 mg/dL or <60 mg/dL were not significantly different between groups (P = 0.969, P = 0.084) after accounting for within‐patient correlations with or without adjusting for time effect. None of these episodes resulted in seizures or were otherwise judged to be associated with deterioration of clinical status.

The mean insulin infusion rate was slightly higher in the Glucommander regimen but the difference was not statistically significant between groups. Patients treated with the Glucommander protocol received a mean infusion rate of 0.035 0.024 unit/kg/hour for a total of 2.85 1.93 units per hour, and those treated with the paper protocol received a 0.028 0.021 units/kg/hour for a total of 2.50 2.28 units per hour, P = 0.12 and P = 0.09, respectively.

The numbers of BG measurements were similar between the Glucommander and standard paper algorithms (44.2 39.8 and 41.2 34.5 respectively, P = NS) with the number of glucose testing per patient ranging from 6 to 175 in the Glucommander and 3 to 168 in the standard group. Similarly, when normalized to the duration of insulin infusion, the frequency of BG monitoring was not different with the protocols (0.68 0.18 and 0.62 0.22 tests/hour respectively, P = NS).

Compared to the standard paper insulin infusion algorithm, patients treated with the Glucommander device had a similar mean ICU LOS (13.4 13.8 vs. 8.5 7.6 days, P = 0.145), mean hospital LOS (17.5 15.0 days vs. 23.9 26.3 days, P = 0.704) and hospital mortality (26.0% vs. 21.9%, P = 0.561).

Discussion

This study is the first to compare the safety and efficacy of a CII via a computer‐guided algorithm and a standard paper form protocol in nonsurgical patients in the ICU. Both treatment algorithms resulted in significant improvement in glycemic control with the Glucommander achieving glycemic glucose target in a shorter time of treatment, a lower mean glucose concentration, and in greater percentage of glucose measurements maintained within target range, without an increased risk of severe hypoglycemia compared to the standard paper protocol.

Hyperglycemia in hospitalized patients is a common, serious, and costly health care problem. Evidence from observational and interventional studies indicate that hyperglycemia in critical illness is associated with an increased risk of complications and mortality.25 There is ongoing debate, however, about the optimal glucose level in hospitalized patients with critical illness. Although, several cohort studies as well as early randomized trials in ICU patients reported that intensified insulin treatment to achieve a target glucose between 80 mg/dL to 110 mg/dL reported a reduction in short‐term and long‐term mortality and rates of multiorgan failure and systemic infections compared with conventionally treated patients.3, 4, 17 More recent randomized controlled trials and meta‐analyses, however, have shown that this low BG target has been difficult to achieve without increasing the risk for severe hypoglycemia.710 In addition, recent multicenter trials have failed to show significant improvement in clinical outcome or have even shown increased mortality risk with intensive glycemic control.610 Based on these reports, the American Association of Clinical Endocrinologist (AACE) and American Diabetes Association (ADA) task force on inpatient glycemic control recommended different glycemic targets in the ICU setting. Current guidelines suggest targeting a BG level between 140 mg/dL and 180 mg/dL (7.8 and 10.0 mmol/L) for the majority of ICU patients and a lower glucose targets between 110 mg/dL and 140 mg/dL (6.1 and 7.8 mmol/L) in selected ICU patients (ie, centers with extensive experience and appropriate nursing support, cardiac surgical patients, patients with stable glycemic control without hypoglycemia). Glucose targets >180 mg/dL or <110 mg/dL are no longer recommended in ICU patients.

The rate of severe hypoglycemic events (<40 mg/dL) observed in both arms of our trial was significantly lower than those reported in recent international trials of intensive glycemic control.3, 4, 8 The overall rate of severe hypoglycemic events in international trials ranged between 5% to 28.6%.3, 4, 7, 8, 18, 19 In this trial, the number of patients with severe hypoglycemia was 3.9% in the computer‐based and 5.6% in the standard paper algorithm. Repeated measures analyses show the probabilities of BG readings <40 mg/dL were similar and not significantly different between groups (P = 0.969). We observed, however, a high rate of mild hypoglycemic events in patients treated with both insulin algorithms. The number of patients with BG <60 mg/dL was 42.9% in the Glucommander and 31.9% in the standard (P = NS). Minimizing the rate of hypoglycemia events is of major importance in hospitalized patients because it has been shown that hypoglycemia may be an independent risk factor of poor clinical outcome and mortality.20 Hypoglycemia may increase the risk of ventricular arrhythmias, in part due to the prolongation QT interval21 and can impair cerebral glucose metabolism resulting in brain metabolic dysfunction, as suggested by recent clinical studies.22 Moreover, insulin‐induced hypoglycemia is also associated with increased proinflammatory cytokines (tumor necrosis factor [TNF]‐alpha, interleukin [IL]‐1beta, IL‐6, and IL‐8) and oxidative stress23 that correlate with elevations of counterregulatory hormones (catecholamines, cortisol).

The Glucommander was associated with lower glycemic variability and with a higher percentage of BG readings within target range than patients treated with the standard paper form regimen. The clinical importance of the degree of variability and rapidity of fluctuations in glucose levels in critically ill patients is a topic of recent interest. Glycemic variability has been identified as a strong independent contributor to the risk of mortality in critically ill and surgical patients.24 Low levels of glycemic variability (standard deviation [SD] <10 mg/dL or 10‐20 mg/dL) have been shown to have a statistically significant lower risk of mortality, even after adjustment for severity of illness. Further studies are needed to determine benefits on clinical outcomes from the more consistent BG control from computer‐based titration protocols.

We acknowledge the following limitations in this multicenter open label study. First, this study was conducted in the medical ICU and excluded postsurgical patients and subjects expected to undergo a major surgical procedure during the hospital stay. Although a recent meta‐analysis9 of 26 studies involving 13,567 patients reported no benefits in the general ICU population, it found a favorable effect of intensive glycemic control on mortality in surgical ICU patients (relative risk [RR], 0.63; confidence interval [CI], 0.44‐0.91). We also excluded patients with severe renal insufficiency and patients with a history of hyperglycemic crises. In addition, our study was not powered to demonstrate differences in mortality or clinical outcome between treatment groups, and the BG targets used in this study were lower than glycemic targets recently recommended by the AACE and ADA inpatient glycemic control task force.25 Raising the BG targets is likely to reduce or prevent the rate of mild and severe hypoglycemic events in the ICU.

In conclusion, the computer‐guided algorithm resulted in a more rapid and tighter glycemic control with a similar rate of hypoglycemic events than the standard paper form protocol in medical ICU patients. Our study suggests that, both treatment algorithms are appropriate alternatives for the management of hyperglycemia in critically ill patients, and the choice depends on a physician's preferences, cost considerations, and the availability of the computer guided algorithm. Large randomized clinical trials are needed to test the impact of the new AACE/ADA recommended BG targets in reducing hypoglycemic events, hospital complications, and hospital mortality in critically ill patients in the ICU.

Observational studies in hospitalized patients with and without diabetes indicate that hyperglycemia is a predictor of poor clinical outcome and mortality.14 Early randomized controlled trials of intensified insulin therapy in patients with surgical and medical acute critical illness reported a reduction on the risk of multiorgan failure and systemic infections,35 as well as short‐ and long‐term mortality.1, 4 Recent randomized controlled trials, however, have failed to confirm the previously suggested benefits of intensive glucose control,6 and the large multicenter normoglycaemia in intensive care evaluation and survival using glucose algorithm regulation (NICE‐SUGAR) study reported an absolute increase in mortality rate with intensive glucose control.7 In addition, intensified insulin therapy in critically‐ill patients has been shown to be associated with a higher rate of severe hypoglycemic events than less aggressive glycemic control protocols.710 These results have led to a heightened interest in improving the quality and safety of the management of diabetes and hyperglycemia in the hospital.

The use of intravenous continuous insulin infusion (CII) is the preferred route of insulin administration for the management of hyperglycemia in the critical care setting.1, 11 Numerous examples of successful CII algorithms in achieving glycemic control are reported in the literature.4, 5, 12 Traditionally, order forms to titrate drip to achieve a target blood glucose (BG) range using an established algorithm or by the application of mathematical rules have been used in clinical practice. Recently, computer‐based algorithms aiming to direct the nursing staff adjusting insulin infusion rate have become commercially available.13, 14 It is not known, however, if computer‐based algorithms are superior to standard paper form‐based protocols in achieving glucose control and in reducing hypoglycemic events in critically‐ill patients. Accordingly, this multicenter randomized study aimed to determine differences in glycemic control and hypoglycemic events between treatment with a computer‐guided CII device and a standard column‐based paper algorithm in critically‐ill patients in the medical intensive care unit (ICU).

Research Design and Methods

In this multicenter, prospective, open‐label randomized study, 160 adult patients admitted to a medical ICU with new hyperglycemia or with a known history of diabetes treated with diet, insulin therapy or with any combination of oral antidiabetic agents were enrolled after written informed consent had been obtained from the patient or closest family member (Figure 1). Patients with known history of diabetes had 2 BG readings >120 mg/dL while subjects without a history of diabetes had 2 BG readings >140 mg/dL prior to enrollment. We excluded patients with acute hyperglycemic crises such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state,15 patients with severely impaired renal function (serum creatinine 3.5 mg/dL), dementia, and pregnancy. This study was conducted at 4 hospital centers including Grady Memorial Hospital, Emory University Hospital, and Piedmont Hospital in Atlanta, Georgia and the Regional Medical Center in Memphis, Tennessee.

Figure 1

Figure 2

Patients were randomized using a computer randomization table to receive CII following a computer‐guided algorithm (Glucommander) or CII following a standard paper form insulin infusion algorithm. Both protocols used glulisine (Apidra) insulin and targeted a BG between 80 mg/dL and 120 mg/dL. Insulin management was directed by the specific assigned protocol and was carried out daily by the nursing staff and by members of the internal medicine residency program. The ICU physician and primary care team decided on the treatment for all other medical problem(s) for which patients were admitted. Data were collected during CII up to the first 10 days of ICU stay.

Results

The admission characteristics and clinical outcomes of interest of the study patients are shown in Table 1. A total of 160 adult patients admitted to a medical ICU with new hyperglycemia (47%) or with a known history of diabetes (53%) were randomized into the study. Of them, 7 patients were excluded due to withdrawal of consent, treatment with subcutaneous basal or supplemental short‐acting insulin during CII, or receiving less than 4 hours of CII. There were no differences in the mean age, gender, race, history of diabetes, or primary admitting diagnosis between treatment groups. The most common admitting diagnosis categories included pulmonary (22.1%), cardiovascular (21.4%), infectious (20.0%), and central nervous system (16.6%) disorders.

The mean admission glucose concentration for study patients was 190.6 58.2 mg/dL and the mean A1C was 7.0 1.7%. Glycemic control parameters achieved with the CII protocols are listed in Table 2. At the start of CII, the mean BG value was similar for the Glucommander and paper protocols (189.7 64.8 mg/dL and 188.4 54.8 mg/dL, P = 0.419). The mean time to reach the BG target was shorter in the Glucommander group (4.8 2.8 vs. 7.8 9.1 hours, P < 0.001). The Glucommander group had a lower mean glucose value during insulin infusion (115.5 20.7 vs. 131.0 24.6 mg/dL, P < 0.001) and once at target goal, in a lower mean BG values (103.3 8.8 vs. 117.3 16.5 mg/dL, P < 0.001) than the standard algorithm (Figure 2). The mean inpatient BG difference between treatment groups was 15.5 mg/dL (P < 0.001), with a mean daily BG difference ranging from 17.4 mg/dL to 24.4 mg/dL less for the Glucommander group during days 2 to 6 of therapy (P < 0.01).

The Glucommander algorithm was associated with tighter glycemic control and less glucose variability than the standard paper form protocol. Once patients achieved BG target, on average 71.1% of BG readings in the Glucommander and 51.3% in the standard group remained within the 80 mg/dL to 120 mg/dL target range (P < 0.001). In addition, the Glucommander was associated with a significantly lower rate of severe hyperglycemia during insulin infusion. The number of patients with 1 or more episodes of BG >200 mg/dL (11.7% vs. 25%, P = 0.057 before adjusting for potential site difference and P = 0.034 after adjusting for site difference) were less in the Glucommander group than in the standard paper regimen. In addition, 4 of these patients in spite of being on the highest insulin delivery column failed to achieve glucoses <180 and had an average in‐hospital glucose level of 204.5 32.2 mg/dL. These patients were transitioned to the Glucommander arm and withdrawn from the study. All episodes of hypoglycemia occurred after the patients achieved 1 glucose measurement within the target range. The number of patients who experienced one or more BG <40 mg/dL and <60 mg/dL was 3.9% and 42.9% in the Glucommander and 5.6% and 31.9% in the standard regimen, respectively (both, P = not significant [NS]). Similar results were obtained when site effect was accommodated (both, P = NS). Based on repeated measures analyses, the probabilities of BG reading <40 mg/dL or <60 mg/dL were not significantly different between groups (P = 0.969, P = 0.084) after accounting for within‐patient correlations with or without adjusting for time effect. None of these episodes resulted in seizures or were otherwise judged to be associated with deterioration of clinical status.

The mean insulin infusion rate was slightly higher in the Glucommander regimen but the difference was not statistically significant between groups. Patients treated with the Glucommander protocol received a mean infusion rate of 0.035 0.024 unit/kg/hour for a total of 2.85 1.93 units per hour, and those treated with the paper protocol received a 0.028 0.021 units/kg/hour for a total of 2.50 2.28 units per hour, P = 0.12 and P = 0.09, respectively.

The numbers of BG measurements were similar between the Glucommander and standard paper algorithms (44.2 39.8 and 41.2 34.5 respectively, P = NS) with the number of glucose testing per patient ranging from 6 to 175 in the Glucommander and 3 to 168 in the standard group. Similarly, when normalized to the duration of insulin infusion, the frequency of BG monitoring was not different with the protocols (0.68 0.18 and 0.62 0.22 tests/hour respectively, P = NS).

Compared to the standard paper insulin infusion algorithm, patients treated with the Glucommander device had a similar mean ICU LOS (13.4 13.8 vs. 8.5 7.6 days, P = 0.145), mean hospital LOS (17.5 15.0 days vs. 23.9 26.3 days, P = 0.704) and hospital mortality (26.0% vs. 21.9%, P = 0.561).

Discussion

This study is the first to compare the safety and efficacy of a CII via a computer‐guided algorithm and a standard paper form protocol in nonsurgical patients in the ICU. Both treatment algorithms resulted in significant improvement in glycemic control with the Glucommander achieving glycemic glucose target in a shorter time of treatment, a lower mean glucose concentration, and in greater percentage of glucose measurements maintained within target range, without an increased risk of severe hypoglycemia compared to the standard paper protocol.

Hyperglycemia in hospitalized patients is a common, serious, and costly health care problem. Evidence from observational and interventional studies indicate that hyperglycemia in critical illness is associated with an increased risk of complications and mortality.25 There is ongoing debate, however, about the optimal glucose level in hospitalized patients with critical illness. Although, several cohort studies as well as early randomized trials in ICU patients reported that intensified insulin treatment to achieve a target glucose between 80 mg/dL to 110 mg/dL reported a reduction in short‐term and long‐term mortality and rates of multiorgan failure and systemic infections compared with conventionally treated patients.3, 4, 17 More recent randomized controlled trials and meta‐analyses, however, have shown that this low BG target has been difficult to achieve without increasing the risk for severe hypoglycemia.710 In addition, recent multicenter trials have failed to show significant improvement in clinical outcome or have even shown increased mortality risk with intensive glycemic control.610 Based on these reports, the American Association of Clinical Endocrinologist (AACE) and American Diabetes Association (ADA) task force on inpatient glycemic control recommended different glycemic targets in the ICU setting. Current guidelines suggest targeting a BG level between 140 mg/dL and 180 mg/dL (7.8 and 10.0 mmol/L) for the majority of ICU patients and a lower glucose targets between 110 mg/dL and 140 mg/dL (6.1 and 7.8 mmol/L) in selected ICU patients (ie, centers with extensive experience and appropriate nursing support, cardiac surgical patients, patients with stable glycemic control without hypoglycemia). Glucose targets >180 mg/dL or <110 mg/dL are no longer recommended in ICU patients.

The rate of severe hypoglycemic events (<40 mg/dL) observed in both arms of our trial was significantly lower than those reported in recent international trials of intensive glycemic control.3, 4, 8 The overall rate of severe hypoglycemic events in international trials ranged between 5% to 28.6%.3, 4, 7, 8, 18, 19 In this trial, the number of patients with severe hypoglycemia was 3.9% in the computer‐based and 5.6% in the standard paper algorithm. Repeated measures analyses show the probabilities of BG readings <40 mg/dL were similar and not significantly different between groups (P = 0.969). We observed, however, a high rate of mild hypoglycemic events in patients treated with both insulin algorithms. The number of patients with BG <60 mg/dL was 42.9% in the Glucommander and 31.9% in the standard (P = NS). Minimizing the rate of hypoglycemia events is of major importance in hospitalized patients because it has been shown that hypoglycemia may be an independent risk factor of poor clinical outcome and mortality.20 Hypoglycemia may increase the risk of ventricular arrhythmias, in part due to the prolongation QT interval21 and can impair cerebral glucose metabolism resulting in brain metabolic dysfunction, as suggested by recent clinical studies.22 Moreover, insulin‐induced hypoglycemia is also associated with increased proinflammatory cytokines (tumor necrosis factor [TNF]‐alpha, interleukin [IL]‐1beta, IL‐6, and IL‐8) and oxidative stress23 that correlate with elevations of counterregulatory hormones (catecholamines, cortisol).

The Glucommander was associated with lower glycemic variability and with a higher percentage of BG readings within target range than patients treated with the standard paper form regimen. The clinical importance of the degree of variability and rapidity of fluctuations in glucose levels in critically ill patients is a topic of recent interest. Glycemic variability has been identified as a strong independent contributor to the risk of mortality in critically ill and surgical patients.24 Low levels of glycemic variability (standard deviation [SD] <10 mg/dL or 10‐20 mg/dL) have been shown to have a statistically significant lower risk of mortality, even after adjustment for severity of illness. Further studies are needed to determine benefits on clinical outcomes from the more consistent BG control from computer‐based titration protocols.

We acknowledge the following limitations in this multicenter open label study. First, this study was conducted in the medical ICU and excluded postsurgical patients and subjects expected to undergo a major surgical procedure during the hospital stay. Although a recent meta‐analysis9 of 26 studies involving 13,567 patients reported no benefits in the general ICU population, it found a favorable effect of intensive glycemic control on mortality in surgical ICU patients (relative risk [RR], 0.63; confidence interval [CI], 0.44‐0.91). We also excluded patients with severe renal insufficiency and patients with a history of hyperglycemic crises. In addition, our study was not powered to demonstrate differences in mortality or clinical outcome between treatment groups, and the BG targets used in this study were lower than glycemic targets recently recommended by the AACE and ADA inpatient glycemic control task force.25 Raising the BG targets is likely to reduce or prevent the rate of mild and severe hypoglycemic events in the ICU.

In conclusion, the computer‐guided algorithm resulted in a more rapid and tighter glycemic control with a similar rate of hypoglycemic events than the standard paper form protocol in medical ICU patients. Our study suggests that, both treatment algorithms are appropriate alternatives for the management of hyperglycemia in critically ill patients, and the choice depends on a physician's preferences, cost considerations, and the availability of the computer guided algorithm. Large randomized clinical trials are needed to test the impact of the new AACE/ADA recommended BG targets in reducing hypoglycemic events, hospital complications, and hospital mortality in critically ill patients in the ICU.

Increasing evidence suggests that in hospitalized adult patients with and without diabetes, hyperglycemia is associated with increased risk of complications, prolonged length of hospitalization, and death.15 Past studies have shown that intensive glucose control in the intensive care unit (ICU) with continuous insulin infusion (CII) improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality. Effective management of hyperglycemia, an independent marker of poor outcome,1, 3, 6 is also associated with a decreased length of ICU and hospital stay79 and decreased total hospitalization cost.10 Based on several observational and interventional studies, improved control of blood glucose (BG) has been recommended for most adult patients with critical illness.2, 6, 11

Detrimental effects of hyperglycemia on outcome are not limited to patients in the ICU setting and CII has increasingly been used in non‐ICU settings. In such patients, the presence of hyperglycemia has been associated with prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 6 In general medicine and surgery services, however, hyperglycemia is frequently overlooked and inadequately addressed. Numerous reports have shown that sliding scale regular insulin (SSRI) continues to be the most common insulin prescribed regimen in the non‐ICU setting.12 This regimen is challenged by limited and variable efficacy and continued concern for hypoglycemia13; thus, a more structured, target‐driven protocol such as scheduled SC insulin or a CII protocol could facilitate glycemic control in the non‐ICU setting. Recently, we reported that a scheduled regimen using basal‐bolus insulin subcutaneously was safe, effective, and superior to SSRI in controlling BG levels in hospitalized subjects with type 2 diabetes. As in many institutions in the United States, we have used CII protocols as an alternative to subcutaneous (SC) insulin for the management of persistent hyperglycemia in non‐ICU areas during the past 10 years, particularly during the postoperative period, transplant recipients, or patients transferred from the ICU. There is, however, no clinical evidence regarding the safety, efficacy, or outcomes with the use of CII in the non‐ICU setting. Accordingly, we analyzed our experience on the efficacy and safety of CII in the management of hyperglycemia in general medicine and surgical services.

Research Design and Methods

This retrospective chart analysis was conducted in adult patients >18 years of age who were consecutively admitted to the general medical and surgical wards between July 1, 2004 and June 30, 2005 at Emory University Hospital, a 579‐bed tertiary care facility staffed exclusively by Emory University School of Medicine faculty members and residents. The CII protocol, employing regular insulin (Novolin‐R Novo Nordisk Pharmaceuticals, Princeton, NJ) with a very short half‐life, in this study is a dynamic protocol14 that has been available at all nursing stations at Emory Hospital for the past decade (Table 1). The insulin rate is calculated using the formula (BG 60) (multiplier) = units of insulin per hour. The multiplier is a value used to denote the degree of insulin sensitivity based on glucose pattern and response to insulin. The multiplier typically starts at a value of 0.02 and is adjusted by the nurse as needed to achieve target BG levels based on bedside capillary glucose measurements. Blood glucose levels were checked every 1 to 2 hours by the nursing staff (nurse:patient ratio = 1:5) according to the protocol.

Of 1404 patients treated with CII during the hospital stay, 1191 patients received CII in the ICU and 213 patients received CII in non‐ICU areas. The final analysis included a total of 200 non‐ICU patient records after excluding 13 patients with diabetic ketoacidosis, incomplete documentation of glycemic records, or with duration of CII for less than 3 hours. Data collected included demographics, medical history, admission diagnoses, inpatient medications, inpatient laboratory values, bedside BG measurements, insulin doses used, nutrition status during CII, length of stay, disposition at discharge, and mortality rate. Nutrition status was defined in 3 ways: (1) nil per os or nothing by mouth (NPO); (2) oral nutrition (PO‐regular or PO‐liquid); and (3) tube feeds or total parenteral nutrition (TF/TPN). Data collection was limited to the first 10 days of CII use. This study was approved by the Institutional Review Board at Emory University.

The primary aim of the study was to determine the efficacy (mean daily BG levels) and safety (number of hyperglycemic [200 mg/dL] and hypoglycemic [60 mg/dL] events) during CII. We also determined the presence of potential risk factors associated with hypoglycemic and hyperglycemic events (age, body mass index [BMI], nutrition status, renal function, corticosteroid therapy, and use of enteral and parenteral nutrition) during CII.

Results

The cohort of 200 patients consisted of 54% males and 46% females, 53% Caucasian, 37% Black, with a mean age of 52 16 years (Table 2). Forty‐five percent of patients were admitted to the general medicine service and the remaining 55% were admitted to the surgical service for admission diagnoses that included cardiovascular disorders, trauma/surgery gastrointestinal disorders, renal disorders, and infection.

The primary indication for CII was poor glycemic control in 93.4% of patients. Forty‐one percent of subjects were receiving corticosteroids and 16% were continued on the insulin drip after transferring from an ICU. Nearly 90% of subjects had a history of diabetes and 11% were diagnosed with new‐onset diabetes. The mean admission BG concentration was 325 235 mg/dL (mean SD) and the mean A1c in 121 subjects in whom it was measured was 9.1 3%. The mean BG prior to the initiation of CII (323 184) was similar to the admission BG.

Of the 173 subjects that had well‐documented glycemic goals, the BG targeted during CII was 150 mg/dL in 85% of patients while the remaining subjects had a target BG goal that ranged from 70 to 250 mg/dL. The most commonly prescribed BG target goals were 80 to 110 mg/dL (41.6%), 80 to 120 mg/dL (13.9%), and 100 to 150 mg/dL (5.8%).

BG improved rapidly after the initiation of CII. BG on the first day of CII was 182 71 mg/dL; day 2: 142 42 mg/dL; day 3: 131 38 mg/dL; and day 4: 132 43 in response to receiving an average of 84 66 units/day, 71 61 units/day, 70 61 units/day, and 64 29 units/day, respectively (Table 3). Irrespective of the target BG goal, 67% of patients reached BG levels of 150 mg/dL by 48 hours of CII initiation. The duration of CII ranged between 4 and 240 hours, with an average of 41.6 hours and a median of 28 hours. The average insulin infusion rate during CII was 4.29 2.99 units/hour and the mean amount of insulin required to attain glycemic goals was 1.96 1.88 units/kg/day.

During CII, 48% and 35% of patients had at least 1 episode of hyperglycemia (BG >200 mg/dL) on the second and third day of CII, respectively. Hypoglycemia (BG <60 mg/dL) was noted at least once in 22% of the cohort (day 1: 11%; day 2: 16%; and day 3: 14%); however, severe hypoglycemia (BG <40 mg/dL) only occurred in 5% of subjects. During the CII, 37% of patients experienced a BG <70 mg/dL. When BG targets were stratified (<120 mg/dL vs. 120‐180 mg/dL vs. >180 mg/dL), we found no significant association between the target BG goal and the frequency of hypoglycemic or hyperglycemic events during CII. None of the episodes of hypoglycemia were associated with significant or permanent complications.

The analysis of collected variables for influence on glycemic control (ie, BMI, age, corticosteroid use, renal function, and nutrition status) revealed that subjects with a creatinine level >1.5 mg/dL may have an increased risk of hyperglycemia (BG >200 mg/dL) (P = 0.047) but not hypoglycemia. The analysis also found that younger patients (51 16 years) were more likely to have episodes of hyperglycemia than older patients (57 13 years) (P = 0.027). Hospital length of stay and mortality rate (3%) were not associated with the rate of hyperglycemic or hypoglycemic events.

Eighty‐two percent of patients received nutrition support at some point while on the CII: 48% PO‐regular diet; 14% PO‐liquid diet; and 20% TF/TPN. Due to the titration of nutrition from NPO at CII initiation to PO, NPO status was analyzed in a time‐dependent fashion. Thus, among patients on CII on day 1, day 2, day 3, day 4, and days 510; 34.0%, 26.3%, 11.3%, 12.5%, and 10.5%, respectively, were NPO.

As compared to subjects maintained NPO, subjects that received oral nutrition while on CII had an increased rate of hyperglycemic events (BG >200 mg/dL: 86% vs. 76%, P = 0.19; >300 mg/dL: 57% vs. 53%, P = 0.69; >400 mg/dL: 32% vs. 21%, P = 0.22) and a decreased rate of hypoglycemic events (BG <70 mg/dL: 33% vs. 41%, P = 0.39; BG <60 mg/dL: 20% vs. 26%, P = 0.49; and BG <40 mg/dL: 4% vs. 6%, P = 0.65). The multivariate regression analyses, however, which considered age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests, showed that nutrition status during CII was associated with increased frequency of hyperglycemic (P = 0.042) and hypoglycemic events (P = 0.086). As compared to NPO, oral intake (PO‐regular or PO‐liquid) was associated with a significantly increased frequency of hyperglycemic (P = 0.012) and hypoglycemic events (P = 0.035). Patients treated with TPN had lower BG values than those not on TPN. Although we observed no increased number of hypoglycemic events, TPN‐treated subjects had higher mortality than non‐TPN treated subjects (P < 0.001).

Discussion

Our study aimed to determine the safety and efficacy of CII in non‐critically‐ill patients with persistent hyperglycemia in general medicine and surgical services. We observed that the use of CII was effective in controlling hyperglycemia, with two‐thirds of patients achieving their target BG 150 mg/dL by 48 hours of insulin infusion. The rate of hypoglycemic events with the use of CII in non‐ICU patients was similar to that reported in recent ICU trials with intensive glycemic control7, 8, 15, 16 and is comparable to that reported in studies using SC insulin therapy in non‐ICU settings.17, 18 The number of hypoglycemic and hyperglycemic events was significantly higher in patients allowed to eat compared to those patients kept NPO during CII. There is substantial observational evidence linking hyperglycemia in hospitalized patients (with and without diabetes) to poor outcomes. There is ongoing debate, however, about the optimal level of BG in hospitalized patients. Early cohort studies as well as randomized controlled trials (RCTs) suggest that intensive treatment of hyperglycemia reduces length of hospital and ICU stay, multiorgan failure and systemic infections, and mortality.7, 9 These positive reports led the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) to recommend tight glycemic control (target of 80‐110 mg/dL) in critical care units. Recent multicenter controlled trials, however, have not been able to reproduce these results and in fact, have reported an increased risk of severe hypoglycemia and mortality in ICU patients in association with tight glycemic control.15, 16, 19 New glycemic targets call for more reasonable, achievable, and safer glycemic targets20, 21 in patients receiving CII in the ICU setting. The recent ADA/AACE Inpatient Task Force now recommends against aggressive BG targets of <110 mg/dL for patients in the ICU, and suggests maintaining glucose levels between 140 and 180 mg/dL during insulin therapy. However, lower targets between 110 and 140 mg/dL, while not evidence‐based, may be acceptable in a subset of patients as long as these levels can be achieved safely by a well‐trained staff.

There are no RCTs examining the effect of intensive glycemic control on outcomes or the optimal glycemic target in hospitalized patients outside the ICU setting. However, several observational studies point to a strong association between hyperglycemia and poor clinical outcomes, including prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 5 Despite the paucity of randomized controlled trials on general medical‐surgical floors, a premeal BG target of <140 mg/dL with random BG <180 mg/dL are recommended as long as this target can be safely achieved.21

Our study indicates that the use of CII in the non‐ICU setting is effective in improving glycemic control. After the first day of CII, the mean glucose level was within the recommended BG target of <180 mg/dL for patients treated with CII in the ICU. Moreover, the mean daily BG level during CII was lower than those recently reported with the use of SC basal‐bolus and insulin neutral protamine hagedorn (NPH) and regular insulin combinations in non‐ICU settings.17, 18 In the Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2) trial, a study that compared the efficacy and safety of an SC basal‐bolus to a sliding scale insulin regimen, showed that 66% and 38% of patients, respectively, reached a target BG of <140 mg/dL.17 The Comparison of Inpatient Insulin Regimens: DEtemir plus Aspart vs. NPH plus regular in Medical Patients with Type 2 Diabetes (DEAN Trial) trial reported daily mean BG levels after the first day of 160 38 mg/dL and 158 51 mg/dL in the detemir/aspart and NPH/regular group, respectively with an achieved BG target of <140 mg/dL in 45% of patients in the detemir/aspart and in 48% in the NPH/regular18; whereas in this study we observed that most patients reached the target BG goal by 48 hours of the CII regimen.

Increasing evidence indicates that inpatient hypoglycemia is associated with short‐term and long‐term adverse outcomes.22, 23 The incidence of severe hypoglycemia (<40 mg/dL) with intensified glycemic control has ranged between 9.8% and 19%7, 15 vs. <5% in conventional treatment. In the present study, 35% of patients experienced a BG <70 mg/dL, 22% had a BG <60 mg/dL, and 5% of patients had a BG <40 mg/dL. The lower rate of hypoglycemic events with the use of CII in the non‐ICU setting observed in this study is likely the result of a more relaxed glycemic target of 80 to 150 mg/dL for the majority of subjects, as well as fewer severe comorbidities compared to patients in the ICU, where the presence of sepsis or hepatic, adrenal, or renal failure increase the risk of hypoglycemia.2224

Multivariate analyses adjusted for age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests showed that nutrition status during CII was an important factor associated with increased frequency of hyperglycemic and hypoglycemic events. Compared to subjects maintained NPO, subjects who received oral intake while on CII had a significantly increased rate of hyperglycemic and hypoglycemic events. The increased risk of hypoglycemia for those allowed to eat is expected as the protocol would mandate an increase in the CII rate in response to the prandial BG increase but does not make provisions for BG assessments or CII adjustments in relationship to the meal. These results indicate that in stable patients who are ready to start eating, CII should be stopped and transitioned to SC insulin regimen. In patients who may benefit from the continued use of CII (eg, patients requiring multistep procedures/surgeries), treatment with CII could be continued with supplemental mealtime insulin (intravenous [IV] or SC).

CII may be useful in cases of patients with persistent hyperglycemia despite scheduled SC insulin regimen; in patients where rapid glycemic control may be warranted in order to decrease the risk of increased inflammation and vascular dysfunction in acute coronary syndromes; and to enhance wound healing status post surgical procedures. Other clinical scenarios in which CII may be preferred and no ICU bed is required include cases of new‐onset diabetes with significant hyperglycemia (BG >300 mg/dL), type 1 diabetes poorly controlled with SC insulin, uncontrolled gestational diabetes, parenteral nutrition use, perioperative states, or the use of high‐dose steroids or chemotherapy.

Our findings are limited by the retrospective nature of our study and the evaluation of patients in a single university medical center. Selection bias should be considered in the interpretation of the results since each index case was selected by the attending physician to be treated with CII as opposed to another regimen for inpatient glycemic control. The selection bias, however, may be limited by the fact that the subjects in this study placed on CII seemed to be similar to those in the general hospital population. A previous pilot study from a different academic institution, however, reported that implementing CII protocols in non‐ICU patients is safe and improved glycemic control without increasing hypoglycemia.25 In addition, because most subjects in this study had a history of diabetes prior to admission, these results may not be generalizable to populations with stress‐induced hyperglycemia.

In summary, our study indicates that a CII regimen is an effective option for the management of patients with persistent hyperglycemia in the non‐critical care setting. Most patients achieved and remained within targeted BG levels during CII. The overall rate of hypoglycemic events was similar to that reported in recent randomized clinical trials in the ICU and with SC insulin therapy. The frequency of hypoglycemic and hyperglycemic events was significantly increased in patients allowed to eat during CII suggesting that CII should be stopped and patients should be transitioned to an SC insulin regimen once oral intake is initiated. Future prospective, randomized studies are needed to compare the efficacy and safety of CII protocols to SC insulin protocols in the management of patients with persistent hyperglycemia in the non‐ICU setting.

Increasing evidence suggests that in hospitalized adult patients with and without diabetes, hyperglycemia is associated with increased risk of complications, prolonged length of hospitalization, and death.15 Past studies have shown that intensive glucose control in the intensive care unit (ICU) with continuous insulin infusion (CII) improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality. Effective management of hyperglycemia, an independent marker of poor outcome,1, 3, 6 is also associated with a decreased length of ICU and hospital stay79 and decreased total hospitalization cost.10 Based on several observational and interventional studies, improved control of blood glucose (BG) has been recommended for most adult patients with critical illness.2, 6, 11

Detrimental effects of hyperglycemia on outcome are not limited to patients in the ICU setting and CII has increasingly been used in non‐ICU settings. In such patients, the presence of hyperglycemia has been associated with prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 6 In general medicine and surgery services, however, hyperglycemia is frequently overlooked and inadequately addressed. Numerous reports have shown that sliding scale regular insulin (SSRI) continues to be the most common insulin prescribed regimen in the non‐ICU setting.12 This regimen is challenged by limited and variable efficacy and continued concern for hypoglycemia13; thus, a more structured, target‐driven protocol such as scheduled SC insulin or a CII protocol could facilitate glycemic control in the non‐ICU setting. Recently, we reported that a scheduled regimen using basal‐bolus insulin subcutaneously was safe, effective, and superior to SSRI in controlling BG levels in hospitalized subjects with type 2 diabetes. As in many institutions in the United States, we have used CII protocols as an alternative to subcutaneous (SC) insulin for the management of persistent hyperglycemia in non‐ICU areas during the past 10 years, particularly during the postoperative period, transplant recipients, or patients transferred from the ICU. There is, however, no clinical evidence regarding the safety, efficacy, or outcomes with the use of CII in the non‐ICU setting. Accordingly, we analyzed our experience on the efficacy and safety of CII in the management of hyperglycemia in general medicine and surgical services.

Research Design and Methods

This retrospective chart analysis was conducted in adult patients >18 years of age who were consecutively admitted to the general medical and surgical wards between July 1, 2004 and June 30, 2005 at Emory University Hospital, a 579‐bed tertiary care facility staffed exclusively by Emory University School of Medicine faculty members and residents. The CII protocol, employing regular insulin (Novolin‐R Novo Nordisk Pharmaceuticals, Princeton, NJ) with a very short half‐life, in this study is a dynamic protocol14 that has been available at all nursing stations at Emory Hospital for the past decade (Table 1). The insulin rate is calculated using the formula (BG 60) (multiplier) = units of insulin per hour. The multiplier is a value used to denote the degree of insulin sensitivity based on glucose pattern and response to insulin. The multiplier typically starts at a value of 0.02 and is adjusted by the nurse as needed to achieve target BG levels based on bedside capillary glucose measurements. Blood glucose levels were checked every 1 to 2 hours by the nursing staff (nurse:patient ratio = 1:5) according to the protocol.

Of 1404 patients treated with CII during the hospital stay, 1191 patients received CII in the ICU and 213 patients received CII in non‐ICU areas. The final analysis included a total of 200 non‐ICU patient records after excluding 13 patients with diabetic ketoacidosis, incomplete documentation of glycemic records, or with duration of CII for less than 3 hours. Data collected included demographics, medical history, admission diagnoses, inpatient medications, inpatient laboratory values, bedside BG measurements, insulin doses used, nutrition status during CII, length of stay, disposition at discharge, and mortality rate. Nutrition status was defined in 3 ways: (1) nil per os or nothing by mouth (NPO); (2) oral nutrition (PO‐regular or PO‐liquid); and (3) tube feeds or total parenteral nutrition (TF/TPN). Data collection was limited to the first 10 days of CII use. This study was approved by the Institutional Review Board at Emory University.

The primary aim of the study was to determine the efficacy (mean daily BG levels) and safety (number of hyperglycemic [200 mg/dL] and hypoglycemic [60 mg/dL] events) during CII. We also determined the presence of potential risk factors associated with hypoglycemic and hyperglycemic events (age, body mass index [BMI], nutrition status, renal function, corticosteroid therapy, and use of enteral and parenteral nutrition) during CII.

Results

The cohort of 200 patients consisted of 54% males and 46% females, 53% Caucasian, 37% Black, with a mean age of 52 16 years (Table 2). Forty‐five percent of patients were admitted to the general medicine service and the remaining 55% were admitted to the surgical service for admission diagnoses that included cardiovascular disorders, trauma/surgery gastrointestinal disorders, renal disorders, and infection.

The primary indication for CII was poor glycemic control in 93.4% of patients. Forty‐one percent of subjects were receiving corticosteroids and 16% were continued on the insulin drip after transferring from an ICU. Nearly 90% of subjects had a history of diabetes and 11% were diagnosed with new‐onset diabetes. The mean admission BG concentration was 325 235 mg/dL (mean SD) and the mean A1c in 121 subjects in whom it was measured was 9.1 3%. The mean BG prior to the initiation of CII (323 184) was similar to the admission BG.

Of the 173 subjects that had well‐documented glycemic goals, the BG targeted during CII was 150 mg/dL in 85% of patients while the remaining subjects had a target BG goal that ranged from 70 to 250 mg/dL. The most commonly prescribed BG target goals were 80 to 110 mg/dL (41.6%), 80 to 120 mg/dL (13.9%), and 100 to 150 mg/dL (5.8%).

BG improved rapidly after the initiation of CII. BG on the first day of CII was 182 71 mg/dL; day 2: 142 42 mg/dL; day 3: 131 38 mg/dL; and day 4: 132 43 in response to receiving an average of 84 66 units/day, 71 61 units/day, 70 61 units/day, and 64 29 units/day, respectively (Table 3). Irrespective of the target BG goal, 67% of patients reached BG levels of 150 mg/dL by 48 hours of CII initiation. The duration of CII ranged between 4 and 240 hours, with an average of 41.6 hours and a median of 28 hours. The average insulin infusion rate during CII was 4.29 2.99 units/hour and the mean amount of insulin required to attain glycemic goals was 1.96 1.88 units/kg/day.

During CII, 48% and 35% of patients had at least 1 episode of hyperglycemia (BG >200 mg/dL) on the second and third day of CII, respectively. Hypoglycemia (BG <60 mg/dL) was noted at least once in 22% of the cohort (day 1: 11%; day 2: 16%; and day 3: 14%); however, severe hypoglycemia (BG <40 mg/dL) only occurred in 5% of subjects. During the CII, 37% of patients experienced a BG <70 mg/dL. When BG targets were stratified (<120 mg/dL vs. 120‐180 mg/dL vs. >180 mg/dL), we found no significant association between the target BG goal and the frequency of hypoglycemic or hyperglycemic events during CII. None of the episodes of hypoglycemia were associated with significant or permanent complications.

The analysis of collected variables for influence on glycemic control (ie, BMI, age, corticosteroid use, renal function, and nutrition status) revealed that subjects with a creatinine level >1.5 mg/dL may have an increased risk of hyperglycemia (BG >200 mg/dL) (P = 0.047) but not hypoglycemia. The analysis also found that younger patients (51 16 years) were more likely to have episodes of hyperglycemia than older patients (57 13 years) (P = 0.027). Hospital length of stay and mortality rate (3%) were not associated with the rate of hyperglycemic or hypoglycemic events.

Eighty‐two percent of patients received nutrition support at some point while on the CII: 48% PO‐regular diet; 14% PO‐liquid diet; and 20% TF/TPN. Due to the titration of nutrition from NPO at CII initiation to PO, NPO status was analyzed in a time‐dependent fashion. Thus, among patients on CII on day 1, day 2, day 3, day 4, and days 510; 34.0%, 26.3%, 11.3%, 12.5%, and 10.5%, respectively, were NPO.

As compared to subjects maintained NPO, subjects that received oral nutrition while on CII had an increased rate of hyperglycemic events (BG >200 mg/dL: 86% vs. 76%, P = 0.19; >300 mg/dL: 57% vs. 53%, P = 0.69; >400 mg/dL: 32% vs. 21%, P = 0.22) and a decreased rate of hypoglycemic events (BG <70 mg/dL: 33% vs. 41%, P = 0.39; BG <60 mg/dL: 20% vs. 26%, P = 0.49; and BG <40 mg/dL: 4% vs. 6%, P = 0.65). The multivariate regression analyses, however, which considered age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests, showed that nutrition status during CII was associated with increased frequency of hyperglycemic (P = 0.042) and hypoglycemic events (P = 0.086). As compared to NPO, oral intake (PO‐regular or PO‐liquid) was associated with a significantly increased frequency of hyperglycemic (P = 0.012) and hypoglycemic events (P = 0.035). Patients treated with TPN had lower BG values than those not on TPN. Although we observed no increased number of hypoglycemic events, TPN‐treated subjects had higher mortality than non‐TPN treated subjects (P < 0.001).

Discussion

Our study aimed to determine the safety and efficacy of CII in non‐critically‐ill patients with persistent hyperglycemia in general medicine and surgical services. We observed that the use of CII was effective in controlling hyperglycemia, with two‐thirds of patients achieving their target BG 150 mg/dL by 48 hours of insulin infusion. The rate of hypoglycemic events with the use of CII in non‐ICU patients was similar to that reported in recent ICU trials with intensive glycemic control7, 8, 15, 16 and is comparable to that reported in studies using SC insulin therapy in non‐ICU settings.17, 18 The number of hypoglycemic and hyperglycemic events was significantly higher in patients allowed to eat compared to those patients kept NPO during CII. There is substantial observational evidence linking hyperglycemia in hospitalized patients (with and without diabetes) to poor outcomes. There is ongoing debate, however, about the optimal level of BG in hospitalized patients. Early cohort studies as well as randomized controlled trials (RCTs) suggest that intensive treatment of hyperglycemia reduces length of hospital and ICU stay, multiorgan failure and systemic infections, and mortality.7, 9 These positive reports led the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) to recommend tight glycemic control (target of 80‐110 mg/dL) in critical care units. Recent multicenter controlled trials, however, have not been able to reproduce these results and in fact, have reported an increased risk of severe hypoglycemia and mortality in ICU patients in association with tight glycemic control.15, 16, 19 New glycemic targets call for more reasonable, achievable, and safer glycemic targets20, 21 in patients receiving CII in the ICU setting. The recent ADA/AACE Inpatient Task Force now recommends against aggressive BG targets of <110 mg/dL for patients in the ICU, and suggests maintaining glucose levels between 140 and 180 mg/dL during insulin therapy. However, lower targets between 110 and 140 mg/dL, while not evidence‐based, may be acceptable in a subset of patients as long as these levels can be achieved safely by a well‐trained staff.

There are no RCTs examining the effect of intensive glycemic control on outcomes or the optimal glycemic target in hospitalized patients outside the ICU setting. However, several observational studies point to a strong association between hyperglycemia and poor clinical outcomes, including prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 5 Despite the paucity of randomized controlled trials on general medical‐surgical floors, a premeal BG target of <140 mg/dL with random BG <180 mg/dL are recommended as long as this target can be safely achieved.21

Our study indicates that the use of CII in the non‐ICU setting is effective in improving glycemic control. After the first day of CII, the mean glucose level was within the recommended BG target of <180 mg/dL for patients treated with CII in the ICU. Moreover, the mean daily BG level during CII was lower than those recently reported with the use of SC basal‐bolus and insulin neutral protamine hagedorn (NPH) and regular insulin combinations in non‐ICU settings.17, 18 In the Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2) trial, a study that compared the efficacy and safety of an SC basal‐bolus to a sliding scale insulin regimen, showed that 66% and 38% of patients, respectively, reached a target BG of <140 mg/dL.17 The Comparison of Inpatient Insulin Regimens: DEtemir plus Aspart vs. NPH plus regular in Medical Patients with Type 2 Diabetes (DEAN Trial) trial reported daily mean BG levels after the first day of 160 38 mg/dL and 158 51 mg/dL in the detemir/aspart and NPH/regular group, respectively with an achieved BG target of <140 mg/dL in 45% of patients in the detemir/aspart and in 48% in the NPH/regular18; whereas in this study we observed that most patients reached the target BG goal by 48 hours of the CII regimen.

Increasing evidence indicates that inpatient hypoglycemia is associated with short‐term and long‐term adverse outcomes.22, 23 The incidence of severe hypoglycemia (<40 mg/dL) with intensified glycemic control has ranged between 9.8% and 19%7, 15 vs. <5% in conventional treatment. In the present study, 35% of patients experienced a BG <70 mg/dL, 22% had a BG <60 mg/dL, and 5% of patients had a BG <40 mg/dL. The lower rate of hypoglycemic events with the use of CII in the non‐ICU setting observed in this study is likely the result of a more relaxed glycemic target of 80 to 150 mg/dL for the majority of subjects, as well as fewer severe comorbidities compared to patients in the ICU, where the presence of sepsis or hepatic, adrenal, or renal failure increase the risk of hypoglycemia.2224

Multivariate analyses adjusted for age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests showed that nutrition status during CII was an important factor associated with increased frequency of hyperglycemic and hypoglycemic events. Compared to subjects maintained NPO, subjects who received oral intake while on CII had a significantly increased rate of hyperglycemic and hypoglycemic events. The increased risk of hypoglycemia for those allowed to eat is expected as the protocol would mandate an increase in the CII rate in response to the prandial BG increase but does not make provisions for BG assessments or CII adjustments in relationship to the meal. These results indicate that in stable patients who are ready to start eating, CII should be stopped and transitioned to SC insulin regimen. In patients who may benefit from the continued use of CII (eg, patients requiring multistep procedures/surgeries), treatment with CII could be continued with supplemental mealtime insulin (intravenous [IV] or SC).

CII may be useful in cases of patients with persistent hyperglycemia despite scheduled SC insulin regimen; in patients where rapid glycemic control may be warranted in order to decrease the risk of increased inflammation and vascular dysfunction in acute coronary syndromes; and to enhance wound healing status post surgical procedures. Other clinical scenarios in which CII may be preferred and no ICU bed is required include cases of new‐onset diabetes with significant hyperglycemia (BG >300 mg/dL), type 1 diabetes poorly controlled with SC insulin, uncontrolled gestational diabetes, parenteral nutrition use, perioperative states, or the use of high‐dose steroids or chemotherapy.

Our findings are limited by the retrospective nature of our study and the evaluation of patients in a single university medical center. Selection bias should be considered in the interpretation of the results since each index case was selected by the attending physician to be treated with CII as opposed to another regimen for inpatient glycemic control. The selection bias, however, may be limited by the fact that the subjects in this study placed on CII seemed to be similar to those in the general hospital population. A previous pilot study from a different academic institution, however, reported that implementing CII protocols in non‐ICU patients is safe and improved glycemic control without increasing hypoglycemia.25 In addition, because most subjects in this study had a history of diabetes prior to admission, these results may not be generalizable to populations with stress‐induced hyperglycemia.

In summary, our study indicates that a CII regimen is an effective option for the management of patients with persistent hyperglycemia in the non‐critical care setting. Most patients achieved and remained within targeted BG levels during CII. The overall rate of hypoglycemic events was similar to that reported in recent randomized clinical trials in the ICU and with SC insulin therapy. The frequency of hypoglycemic and hyperglycemic events was significantly increased in patients allowed to eat during CII suggesting that CII should be stopped and patients should be transitioned to an SC insulin regimen once oral intake is initiated. Future prospective, randomized studies are needed to compare the efficacy and safety of CII protocols to SC insulin protocols in the management of patients with persistent hyperglycemia in the non‐ICU setting.

Increasing evidence suggests that in hospitalized adult patients with and without diabetes, hyperglycemia is associated with increased risk of complications, prolonged length of hospitalization, and death.15 Past studies have shown that intensive glucose control in the intensive care unit (ICU) with continuous insulin infusion (CII) improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality. Effective management of hyperglycemia, an independent marker of poor outcome,1, 3, 6 is also associated with a decreased length of ICU and hospital stay79 and decreased total hospitalization cost.10 Based on several observational and interventional studies, improved control of blood glucose (BG) has been recommended for most adult patients with critical illness.2, 6, 11

Detrimental effects of hyperglycemia on outcome are not limited to patients in the ICU setting and CII has increasingly been used in non‐ICU settings. In such patients, the presence of hyperglycemia has been associated with prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 6 In general medicine and surgery services, however, hyperglycemia is frequently overlooked and inadequately addressed. Numerous reports have shown that sliding scale regular insulin (SSRI) continues to be the most common insulin prescribed regimen in the non‐ICU setting.12 This regimen is challenged by limited and variable efficacy and continued concern for hypoglycemia13; thus, a more structured, target‐driven protocol such as scheduled SC insulin or a CII protocol could facilitate glycemic control in the non‐ICU setting. Recently, we reported that a scheduled regimen using basal‐bolus insulin subcutaneously was safe, effective, and superior to SSRI in controlling BG levels in hospitalized subjects with type 2 diabetes. As in many institutions in the United States, we have used CII protocols as an alternative to subcutaneous (SC) insulin for the management of persistent hyperglycemia in non‐ICU areas during the past 10 years, particularly during the postoperative period, transplant recipients, or patients transferred from the ICU. There is, however, no clinical evidence regarding the safety, efficacy, or outcomes with the use of CII in the non‐ICU setting. Accordingly, we analyzed our experience on the efficacy and safety of CII in the management of hyperglycemia in general medicine and surgical services.

Research Design and Methods

This retrospective chart analysis was conducted in adult patients >18 years of age who were consecutively admitted to the general medical and surgical wards between July 1, 2004 and June 30, 2005 at Emory University Hospital, a 579‐bed tertiary care facility staffed exclusively by Emory University School of Medicine faculty members and residents. The CII protocol, employing regular insulin (Novolin‐R Novo Nordisk Pharmaceuticals, Princeton, NJ) with a very short half‐life, in this study is a dynamic protocol14 that has been available at all nursing stations at Emory Hospital for the past decade (Table 1). The insulin rate is calculated using the formula (BG 60) (multiplier) = units of insulin per hour. The multiplier is a value used to denote the degree of insulin sensitivity based on glucose pattern and response to insulin. The multiplier typically starts at a value of 0.02 and is adjusted by the nurse as needed to achieve target BG levels based on bedside capillary glucose measurements. Blood glucose levels were checked every 1 to 2 hours by the nursing staff (nurse:patient ratio = 1:5) according to the protocol.

Of 1404 patients treated with CII during the hospital stay, 1191 patients received CII in the ICU and 213 patients received CII in non‐ICU areas. The final analysis included a total of 200 non‐ICU patient records after excluding 13 patients with diabetic ketoacidosis, incomplete documentation of glycemic records, or with duration of CII for less than 3 hours. Data collected included demographics, medical history, admission diagnoses, inpatient medications, inpatient laboratory values, bedside BG measurements, insulin doses used, nutrition status during CII, length of stay, disposition at discharge, and mortality rate. Nutrition status was defined in 3 ways: (1) nil per os or nothing by mouth (NPO); (2) oral nutrition (PO‐regular or PO‐liquid); and (3) tube feeds or total parenteral nutrition (TF/TPN). Data collection was limited to the first 10 days of CII use. This study was approved by the Institutional Review Board at Emory University.

The primary aim of the study was to determine the efficacy (mean daily BG levels) and safety (number of hyperglycemic [200 mg/dL] and hypoglycemic [60 mg/dL] events) during CII. We also determined the presence of potential risk factors associated with hypoglycemic and hyperglycemic events (age, body mass index [BMI], nutrition status, renal function, corticosteroid therapy, and use of enteral and parenteral nutrition) during CII.

Results

The cohort of 200 patients consisted of 54% males and 46% females, 53% Caucasian, 37% Black, with a mean age of 52 16 years (Table 2). Forty‐five percent of patients were admitted to the general medicine service and the remaining 55% were admitted to the surgical service for admission diagnoses that included cardiovascular disorders, trauma/surgery gastrointestinal disorders, renal disorders, and infection.

The primary indication for CII was poor glycemic control in 93.4% of patients. Forty‐one percent of subjects were receiving corticosteroids and 16% were continued on the insulin drip after transferring from an ICU. Nearly 90% of subjects had a history of diabetes and 11% were diagnosed with new‐onset diabetes. The mean admission BG concentration was 325 235 mg/dL (mean SD) and the mean A1c in 121 subjects in whom it was measured was 9.1 3%. The mean BG prior to the initiation of CII (323 184) was similar to the admission BG.

Of the 173 subjects that had well‐documented glycemic goals, the BG targeted during CII was 150 mg/dL in 85% of patients while the remaining subjects had a target BG goal that ranged from 70 to 250 mg/dL. The most commonly prescribed BG target goals were 80 to 110 mg/dL (41.6%), 80 to 120 mg/dL (13.9%), and 100 to 150 mg/dL (5.8%).

BG improved rapidly after the initiation of CII. BG on the first day of CII was 182 71 mg/dL; day 2: 142 42 mg/dL; day 3: 131 38 mg/dL; and day 4: 132 43 in response to receiving an average of 84 66 units/day, 71 61 units/day, 70 61 units/day, and 64 29 units/day, respectively (Table 3). Irrespective of the target BG goal, 67% of patients reached BG levels of 150 mg/dL by 48 hours of CII initiation. The duration of CII ranged between 4 and 240 hours, with an average of 41.6 hours and a median of 28 hours. The average insulin infusion rate during CII was 4.29 2.99 units/hour and the mean amount of insulin required to attain glycemic goals was 1.96 1.88 units/kg/day.

During CII, 48% and 35% of patients had at least 1 episode of hyperglycemia (BG >200 mg/dL) on the second and third day of CII, respectively. Hypoglycemia (BG <60 mg/dL) was noted at least once in 22% of the cohort (day 1: 11%; day 2: 16%; and day 3: 14%); however, severe hypoglycemia (BG <40 mg/dL) only occurred in 5% of subjects. During the CII, 37% of patients experienced a BG <70 mg/dL. When BG targets were stratified (<120 mg/dL vs. 120‐180 mg/dL vs. >180 mg/dL), we found no significant association between the target BG goal and the frequency of hypoglycemic or hyperglycemic events during CII. None of the episodes of hypoglycemia were associated with significant or permanent complications.

The analysis of collected variables for influence on glycemic control (ie, BMI, age, corticosteroid use, renal function, and nutrition status) revealed that subjects with a creatinine level >1.5 mg/dL may have an increased risk of hyperglycemia (BG >200 mg/dL) (P = 0.047) but not hypoglycemia. The analysis also found that younger patients (51 16 years) were more likely to have episodes of hyperglycemia than older patients (57 13 years) (P = 0.027). Hospital length of stay and mortality rate (3%) were not associated with the rate of hyperglycemic or hypoglycemic events.

Eighty‐two percent of patients received nutrition support at some point while on the CII: 48% PO‐regular diet; 14% PO‐liquid diet; and 20% TF/TPN. Due to the titration of nutrition from NPO at CII initiation to PO, NPO status was analyzed in a time‐dependent fashion. Thus, among patients on CII on day 1, day 2, day 3, day 4, and days 510; 34.0%, 26.3%, 11.3%, 12.5%, and 10.5%, respectively, were NPO.

As compared to subjects maintained NPO, subjects that received oral nutrition while on CII had an increased rate of hyperglycemic events (BG >200 mg/dL: 86% vs. 76%, P = 0.19; >300 mg/dL: 57% vs. 53%, P = 0.69; >400 mg/dL: 32% vs. 21%, P = 0.22) and a decreased rate of hypoglycemic events (BG <70 mg/dL: 33% vs. 41%, P = 0.39; BG <60 mg/dL: 20% vs. 26%, P = 0.49; and BG <40 mg/dL: 4% vs. 6%, P = 0.65). The multivariate regression analyses, however, which considered age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests, showed that nutrition status during CII was associated with increased frequency of hyperglycemic (P = 0.042) and hypoglycemic events (P = 0.086). As compared to NPO, oral intake (PO‐regular or PO‐liquid) was associated with a significantly increased frequency of hyperglycemic (P = 0.012) and hypoglycemic events (P = 0.035). Patients treated with TPN had lower BG values than those not on TPN. Although we observed no increased number of hypoglycemic events, TPN‐treated subjects had higher mortality than non‐TPN treated subjects (P < 0.001).

Discussion

Our study aimed to determine the safety and efficacy of CII in non‐critically‐ill patients with persistent hyperglycemia in general medicine and surgical services. We observed that the use of CII was effective in controlling hyperglycemia, with two‐thirds of patients achieving their target BG 150 mg/dL by 48 hours of insulin infusion. The rate of hypoglycemic events with the use of CII in non‐ICU patients was similar to that reported in recent ICU trials with intensive glycemic control7, 8, 15, 16 and is comparable to that reported in studies using SC insulin therapy in non‐ICU settings.17, 18 The number of hypoglycemic and hyperglycemic events was significantly higher in patients allowed to eat compared to those patients kept NPO during CII. There is substantial observational evidence linking hyperglycemia in hospitalized patients (with and without diabetes) to poor outcomes. There is ongoing debate, however, about the optimal level of BG in hospitalized patients. Early cohort studies as well as randomized controlled trials (RCTs) suggest that intensive treatment of hyperglycemia reduces length of hospital and ICU stay, multiorgan failure and systemic infections, and mortality.7, 9 These positive reports led the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) to recommend tight glycemic control (target of 80‐110 mg/dL) in critical care units. Recent multicenter controlled trials, however, have not been able to reproduce these results and in fact, have reported an increased risk of severe hypoglycemia and mortality in ICU patients in association with tight glycemic control.15, 16, 19 New glycemic targets call for more reasonable, achievable, and safer glycemic targets20, 21 in patients receiving CII in the ICU setting. The recent ADA/AACE Inpatient Task Force now recommends against aggressive BG targets of <110 mg/dL for patients in the ICU, and suggests maintaining glucose levels between 140 and 180 mg/dL during insulin therapy. However, lower targets between 110 and 140 mg/dL, while not evidence‐based, may be acceptable in a subset of patients as long as these levels can be achieved safely by a well‐trained staff.

There are no RCTs examining the effect of intensive glycemic control on outcomes or the optimal glycemic target in hospitalized patients outside the ICU setting. However, several observational studies point to a strong association between hyperglycemia and poor clinical outcomes, including prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 5 Despite the paucity of randomized controlled trials on general medical‐surgical floors, a premeal BG target of <140 mg/dL with random BG <180 mg/dL are recommended as long as this target can be safely achieved.21

Our study indicates that the use of CII in the non‐ICU setting is effective in improving glycemic control. After the first day of CII, the mean glucose level was within the recommended BG target of <180 mg/dL for patients treated with CII in the ICU. Moreover, the mean daily BG level during CII was lower than those recently reported with the use of SC basal‐bolus and insulin neutral protamine hagedorn (NPH) and regular insulin combinations in non‐ICU settings.17, 18 In the Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2) trial, a study that compared the efficacy and safety of an SC basal‐bolus to a sliding scale insulin regimen, showed that 66% and 38% of patients, respectively, reached a target BG of <140 mg/dL.17 The Comparison of Inpatient Insulin Regimens: DEtemir plus Aspart vs. NPH plus regular in Medical Patients with Type 2 Diabetes (DEAN Trial) trial reported daily mean BG levels after the first day of 160 38 mg/dL and 158 51 mg/dL in the detemir/aspart and NPH/regular group, respectively with an achieved BG target of <140 mg/dL in 45% of patients in the detemir/aspart and in 48% in the NPH/regular18; whereas in this study we observed that most patients reached the target BG goal by 48 hours of the CII regimen.

Increasing evidence indicates that inpatient hypoglycemia is associated with short‐term and long‐term adverse outcomes.22, 23 The incidence of severe hypoglycemia (<40 mg/dL) with intensified glycemic control has ranged between 9.8% and 19%7, 15 vs. <5% in conventional treatment. In the present study, 35% of patients experienced a BG <70 mg/dL, 22% had a BG <60 mg/dL, and 5% of patients had a BG <40 mg/dL. The lower rate of hypoglycemic events with the use of CII in the non‐ICU setting observed in this study is likely the result of a more relaxed glycemic target of 80 to 150 mg/dL for the majority of subjects, as well as fewer severe comorbidities compared to patients in the ICU, where the presence of sepsis or hepatic, adrenal, or renal failure increase the risk of hypoglycemia.2224

Multivariate analyses adjusted for age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests showed that nutrition status during CII was an important factor associated with increased frequency of hyperglycemic and hypoglycemic events. Compared to subjects maintained NPO, subjects who received oral intake while on CII had a significantly increased rate of hyperglycemic and hypoglycemic events. The increased risk of hypoglycemia for those allowed to eat is expected as the protocol would mandate an increase in the CII rate in response to the prandial BG increase but does not make provisions for BG assessments or CII adjustments in relationship to the meal. These results indicate that in stable patients who are ready to start eating, CII should be stopped and transitioned to SC insulin regimen. In patients who may benefit from the continued use of CII (eg, patients requiring multistep procedures/surgeries), treatment with CII could be continued with supplemental mealtime insulin (intravenous [IV] or SC).

CII may be useful in cases of patients with persistent hyperglycemia despite scheduled SC insulin regimen; in patients where rapid glycemic control may be warranted in order to decrease the risk of increased inflammation and vascular dysfunction in acute coronary syndromes; and to enhance wound healing status post surgical procedures. Other clinical scenarios in which CII may be preferred and no ICU bed is required include cases of new‐onset diabetes with significant hyperglycemia (BG >300 mg/dL), type 1 diabetes poorly controlled with SC insulin, uncontrolled gestational diabetes, parenteral nutrition use, perioperative states, or the use of high‐dose steroids or chemotherapy.

Our findings are limited by the retrospective nature of our study and the evaluation of patients in a single university medical center. Selection bias should be considered in the interpretation of the results since each index case was selected by the attending physician to be treated with CII as opposed to another regimen for inpatient glycemic control. The selection bias, however, may be limited by the fact that the subjects in this study placed on CII seemed to be similar to those in the general hospital population. A previous pilot study from a different academic institution, however, reported that implementing CII protocols in non‐ICU patients is safe and improved glycemic control without increasing hypoglycemia.25 In addition, because most subjects in this study had a history of diabetes prior to admission, these results may not be generalizable to populations with stress‐induced hyperglycemia.

In summary, our study indicates that a CII regimen is an effective option for the management of patients with persistent hyperglycemia in the non‐critical care setting. Most patients achieved and remained within targeted BG levels during CII. The overall rate of hypoglycemic events was similar to that reported in recent randomized clinical trials in the ICU and with SC insulin therapy. The frequency of hypoglycemic and hyperglycemic events was significantly increased in patients allowed to eat during CII suggesting that CII should be stopped and patients should be transitioned to an SC insulin regimen once oral intake is initiated. Future prospective, randomized studies are needed to compare the efficacy and safety of CII protocols to SC insulin protocols in the management of patients with persistent hyperglycemia in the non‐ICU setting.