Guillermo E. Umpierrez, MD, CDE

Hyperglycemia in hospitalized patients, with or without diabetes, is associated with adverse outcomes including increased rates of infection and mortality and longer hospital length of stay.^1–3 The rates of complications and mortality are even higher in hyperglycemic patients without a history of diabetes than in those with diabetes.^1,2 Randomized clinical trials in critically ill and noncritically ill hyperglycemic patients demonstrate that improved glycemic control can reduce hospital complications, systemic infections, and hospitalization cost.^4–6 However, intensive glycemic therapy is associated with increased risk of hypoglycemia, which is independently associated with increased morbidity and mortality in hospitalized patients. The concern about hypoglycemia has led to revised blood glucose target recommendations from professional organizations and a search for alternative treatment options.

This manuscript provides a review of updated recommendations for the management of inpatients with hyperglycemia in the critical care and general medical and surgical settings.

HYPERGLYCEMIA IN CRITICAL CARE SETTINGS

A substantial body of evidence links hyperglycemia in critically ill patients to higher rates of hospital complications, longer hospital stay, higher healthcare resource utilization, and greater hospital mortality.^7,8 Although evidence from several cohort studies and randomized clinical trials suggests that tight glucose control can reduce hospital complications and mortality,^9,10 this target has been difficult to achieve without increasing the risk of severe hypoglycemia. In addition, data from trials using intense glycemic control in patients in the intensive care unit (ICU) have failed to show a significant improvement in mortality and, in some instances, showed increased mortality risk associated with the therapy.^11,12

The recommended target glucose levels are 140 to 180 mg/dL for most ICU patients.¹³ In agreement with this, the recent GLUCO-CABG trial reported no significant differences in the composite end points of complications and death between an intensive glucose target of 100 to 140 mg/dL and a conservative target of 141 to 180 mg/dL after cardiac surgery.¹⁴

HYPERGLYCEMIA IN NONCRITICAL CARE SETTINGS

In general medical and surgical patients, a strong association has been reported between hyperglycemia and prolonged hospital stay, infection, and disability after hospital discharge.^1,15,16 For example, the risk of postoperative infections in patients undergoing general surgery was estimated to increase by 30% for every 40 mg/dL rise in glucose over normo­glycemia (< 110 mg/dL).¹⁶ In general, appropriate glycemic control to maintain recommended glycemic levels in noncritically ill patients can reduce the risks and improve outcomes. 

HYPOGLYCEMIA INCIDENCE

Hypoglycemia, defined as glucose less than 70 mg/dL, is a common complication of hyperglycemia treatment.¹⁷ Severe hypoglycemia is defined as glucose less than 40 mg/dL.¹⁸ The incidence of hypoglycemia in ICU trials ranged between 5% and 28%, depending on the intensity of glycemic control,¹⁹ and between 1% and 33% in non-ICU trials using subcutaneous (SC) insulin therapy.²⁰ The most important hypoglycemia risk factors include older age, kidney failure, change in nutritional intake, interruption of glucose monitoring, previous insulin therapy, and failure to adjust therapy when glucose is trending down or steroid therapy is being tapered.^21,22

In hospitalized patients with diabetes, hypoglycemia has been associated with poor outcomes, including a 66% increased risk of death within 1 year and 2.8 days longer hospital stay compared with patients without hypoglycemia.²³ Hypoglycemia also has been associated with prolonged QT interval, ischemic electro­cardiogram changes, angina, arrhythmias, and sudden death in patients with type 1 diabetes.²⁴ Despite these observations, other studies have reported that the increased in-hospital mortality rate is limited to patients with spontaneous hypoglycemia rather than drug-associated hypoglycemia,²⁵ raising the possibility that hypoglycemia may represent a marker of disease burden rather than be a direct cause of death.

INPATIENT ASSESSMENT OF HYPERGLYCEMIA

Clinical guidelines recommend glucose measurement in all patients admitted to the hospital.^13,26 Patients with hyperglycemia (glucose > 140 mg/dL) and patients with a history of diabetes should undergo bedside point-of-care glucose testing before meals and at bedtime. Premeal testing should be done close to the time of the meal tray delivery and no longer than 1 hour before meals. For patients taking nothing by mouth or receiving continuous enteral nutrition, point-of-care testing is recommended every 4 to 6 hours.

Hemoglobin A1c (HbA1c) should be measured in patients with hyperglycemia and in those with diabetes if it has not been performed in the preceding 2 to 3 months. In hyperglycemic patients without a history of diabetes, an HbA1c of 6.5% or greater suggests that diabetes preceded hospitalization. In patients with diabetes, the HbA1c can help assess glycemic control prior to admission and tailor the treatment regimen at discharge.^13,26

TARGET GLUCOSE LEVELS

Glycemic targets recommended by several organizations are shown in Table 1. For critically ill patients, most societies recommend glucose targets below 180 mg/dL, with the lower limit being anywhere from 110 to less than 150 mg/dL.

For patients in non-ICU settings, the Endocrine Society²⁶ and the American Diabetes Association/American Association of Endocrinologists¹³ practice guidelines recommend premeal glucose levels below 140 mg/dL, and below 180 mg/dL if checked randomly. Higher glucose ranges (< 200 mg/dL) may be acceptable in terminally ill patients or in patients with severe comorbidities.²⁶ Guidelines from the Joint British Diabetes Societies recommend targeting glucose levels between 108 and 180 mg/dL with an acceptable range of between 72 and 216 mg/dL.²⁷

 

INPATIENT MANAGEMENT OF HYPERGLYCEMIA AND DIABETES

Insulin regimens in critical care settings

Insulin administration is the preferred way to control hyperglycemia in hospitalized patients. In critically ill patients, such as those with hypotension requiring pressor support, hyperglycemic crises, sepsis, or shock, insulin is best given via continuous intravenous (IV) infusion. The short half-life of IV insulin (< 15 minutes) allows flexibility in adjusting the infusion rate in the event of unpredicted changes in nutrition or the patient’s health. If the glucose level rises above 180 mg/dL, IV insulin infusion should be started to maintain levels below 180 mg/dL.^13,26,28,29

A variety of infusion protocols have been shown to be effective in achieving glycemic control with a low rate of hypoglycemia. The ideal protocol should allow flexible rate adjustment taking into account current and previous glucose values as well as changes in infusion rate. Hourly glucose measurements until stable glycemic control is established, followed by point-of-care testing every 1 to 2 hours, is needed to assess response to therapy and prevent hypoglycemia.

Insulin regimens in noncritical care settings

For most patients in a general, non-ICU setting, SC insulin therapy with basal insulin administered once or twice daily, alone or in combination with prandial insulin, is effective and safe.¹³ Inhaled insulin is approved by the US Food and Drug Administration, but its use in the hospital has not been studied. The use of sliding-scale insulin is not acceptable as the single regimen in patients with diabetes, as it results in undesirable hypoglycemia and hyperglycemia.³⁰Figure 1 presents an algorithm for selecting initial insulin treatment for patients with type 2 diabetes in the non-ICU setting.

Several SC insulin products are available, each with a different pharmacokinetic profile, as outlined in Table 2.³¹

Basal insulin prevents hyperglycemia during fasting states. Basal insulin is usually given as a once- or twice-daily long-acting insulin, such as glargine and detemir insulin. On occasion, twice-daily intermediate-acting insulin (neutral protamine Hagedorn; NPH) is used as a basal insulin.

Prandial insulin, also referred to as nutritional or bolus insulin, is given before meals as rapid-acting insulin (aspart, lispro, or glulisine) or short-acting insulin (regular) to prevent postmeal hyperglycemia. Rapid-acting insulin is preferred to regular insulin because of the faster onset and shorter duration of action, which may reduce the risk of hypoglycemia.

Correction or supplemental insulin is given to correct hyperglycemia when the glucose is above the goal. The same formulation is given together with prandial insulin.

Total daily dose of insulin is a measure that comprises basal and prandial insulin Figure 1 lists the recommended total daily dose for different clinical situations and patient populations.

Basal-bolus insulin usually refers to a regimen of long-acting basal insulin plus prandial insulin. In patients with adequate oral intake, the basal-bolus approach is preferred. The RABBIT 2 trial reported that basal-bolus regimens resulted in greater improvement in glucose control than sliding-scale regimens (correction insulin alone without basal or prandial components) in general medicine patients with type 2 diabetes.³² In general surgery patients, basal-bolus regimens significantly improved glucose control and reduced the numbers of post­operative complications, primarily wound infections compared with sliding-scale regimens.⁴

Multiple doses of NPH and regular insulin were compared with basal-bolus treatment with long-acting and rapid-acting insulin in two controlled trials in medical patients with type 2 diabetes.^20,33 Both studies reported that treatment with NPH and regular insulin resulted in similar improvements in glycemic control and no difference in the rate of hypoglycemic events or in hospital length of stay, compared with basal-bolus insulin. Because NPH has a peak of action approximately 8 to 12 hours after injection, there is a risk of hypoglycemia in patients with poor oral intake.

In hospitalized patients who have reduced total caloric intake due to lack of appetite, acute illness, medical procedures, or surgical interventions, the Basal Plus trial³⁴ reported that a single daily dose of glargine plus correction doses of rapid-acting insulin resulted in similar improvement in glycemic control and no difference in the frequency of hypoglycemia compared with a standard basal-bolus regimen. These results indicate that the basal-plus-correction regimen may be preferred for patients with poor or no oral intake, whereas an insulin regimen with basal, nutritional (basal-bolus), and correction components is preferred for patients with good nutritional intake.³⁵

SC insulin dosing refers to insulin doses administered subcutaneously calculated based either on weight or on home insulin doses. For insulin-naive patients, the starting total daily dose of insulin can usually be computed as 0.4 to 0.5 U/kg/day. Higher starting doses are associated with greater odds of hypoglycemia than doses lower than 0.2 U/kg/day.³⁶ In elderly patients and those with impaired renal function, lower initial daily doses (≤ 0.3 U/kg) may reduce the risk of hypoglycemia.²⁶

In patients treated with insulin prior to admission, the total daily insulin dose at home can be given as half long-acting basal insulin and half prandial insulin. The dose can be reduced by 20% to 25% to prevent hypoglycemia, particularly in those with poor or uncertain caloric intake.³¹

Noninsulin therapies

The use of oral antidiabetic agents is generally not recommended in hospitalized patients due to the limited data available on their safety and efficacy, frequent contraindications, risk of hypoglycemia, and slow onset of action that may preclude achieving rapid glycemic control and daily dose adjustments. Table 3 lists the pros and cons of these agents in hospitalized patients.

The safety and efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the management of inpatient hyperglycemia was evaluated in a randomized pilot study in patients with type 2 diabetes treated at home with diet, oral antidiabetic agents, or a low daily insulin dose (≤ 0.4 U/kg/day).³⁷ Patients were randomized to one of two treatments:

• Sitagliptin alone or with low-dose glargine insulin
• Basal-bolus insulin regimen plus supplemental doses of insulin lispro.

Both treatment regimens resulted in similar improvement in mean daily glucose concentrations. However, patients admitted to the hospital with glucose levels above 180 mg/dL in the sitagliptin group had higher mean daily glucose levels than patients treated with basal-bolus or sitagliptin plus glargine.

Transitioning from IV to SC insulin

When patients in critical care units are ready to be transferred to a general medical floor, appropriate transition from IV insulin to scheduled SC insulin is needed to prevent rebound hyperglycemia. This is imperative in patients with type 1 diabetes in whom just a few hours without insulin can result in diabetic ketoacidosis.

There are three general ways to calculate the SC insulin dose during the transition period. The first two methods are weight-based and based on the home dose, as previously discussed. The third method is to extrapolate from the IV insulin. A common way is to sum up the total IV insulin dose in the past 6 or 8 hours and multiply by 3 or 4, and then reduce by 20% to achieve the basal insulin dose, presuming the patient had no oral intake on the IV insulin infusion. This last method is preferred in hemodynamically stable patients with stable insulin requirements.

If long-acting insulin is chosen as basal insulin, it should be given 2 to 4 hours before discontinuation of the IV insulin infusion. Intermediate-acting insulin should be given 1 to 2 hours before IV insulin discontinuation.

 

SPECIFIC SITUATIONS AND POPULATIONS

Type 1 diabetes

Patients with type 1 diabetes have minimal to absent pancreatic beta cell function and rely on the exogenous administration of insulin to maintain glucose homeostasis. They have worse glycemic control and higher rates of acute kidney injury than patients with type 2 diabetes; however, the impact of inpatient glycemic control on clinical outcomes has not been determined in patients with type 1 diabetes. Insulin therapy must provide both basal and nutritional components to achieve the target goals. It is important to ask the patient directly to determine the times and doses of prescribed insulin, medication adherence, recent dietary habits (including changes in appetite), and level of physical activity. This information will be used to guide insulin therapy.

A systematic review of 16 clinical studies reported that patients who possess excellent self-management skills can be suitable for successful inpatient diabetes self-management.³⁸ The American Diabetes Association supports patient self-management of diabetes in the hospital.³⁹ However, the competence and readiness of each patient with type 1 diabetes need to be carefully determined in an individualized manner. Potential candidates for inpatient self-management are those with unaltered mental status, proven proficient outpatient skills (eg, carbohydrate counting, frequent glucose monitoring, strong knowledge related to the management of insulin pump or injection techniques), and who are tolerating oral intake.

Enteral nutrition and tube feeding

Accidental dislodgement of feeding tubes, temporary discontinuation of nutrition due to nausea or for diagnostic testing, and cycling of enteral nutrition with oral intake in patients with an inconsistent appetite pose unique challenges in the hospital. Although it may be tempting to give basal and nutritional requirements to these patients as a single dose of long-acting insulin, this is not recommended. Low-dose basal insulin plus scheduled doses of short-acting (regular) insulin (every 6 hours) or rapid-acting insulin (every 4 hours) with correction insulin is often used. Some providers prefer giving intermediate-acting (NPH) plus short-acting (regular) insulin every 8 hours or every 12 hours.

It is generally accepted that diabetic enteral formulas that are low in carbohydrate and high in monounsaturated fatty acids are preferable to standard high-carbohydrate formulas in hospitalized patients with diabetes. In a meta-analysis, the postprandial rise in glucose was reduced by 20 to 30 mg/dL with the low-carbohydrate high-fat formulations compared with standard formulations.⁴⁰

Parenteral nutrition

The use of parenteral nutrition has been linked to aggravation of hyperglycemia independent of a history of diabetes as well as a higher risk of complications, infections, sepsis, and death.⁴¹ Regular insulin can be added to the parenteral solution at a starting dose of 0.1 U/g of dextrose in nondiabetic patients and at 0.15 U/g of dextrose in patients with diabetes.⁴²

Alternatively, insulin can be given as a continuous IV infusion. Hemodynamically stable patients with mild to moderate hyperglycemia can be managed with basal insulin plus scheduled or as-needed doses of short-acting (regular) insulin every 6 hours. To prevent waste, it is better to underestimate the insulin added to parenteral nutrition so as to avoid having to discontinue it prematurely or add additional glucose.

Glucocorticoids

Glucocorticoids typically raise glucose starting 4 to 6 hours after administration. Low doses of glucocorticoids given in the morning tend to raise the late morning to evening glucose levels without affecting the fasting glucose. In this situation, the patient may be managed on prandial insulin without long-acting basal insulin or with intermediate-acting insulin given in the morning. Higher glucocorticoid doses may raise fasting glucose levels, in which case basal-bolus insulin would be appropriate, with the basal component comprising about 30% and the bolus about 70% of the daily dose.²⁶

Insulin pump

Approximately 400,000 US patients with diabetes use an insulin pump.⁴³ Successful management of inpatient diabetes with the continuation of insulin pump therapy has been previously demonstrated in select patients. Clear hospital policies, procedures, and physicians’ orders with specifics on the type of diet, frequency of point-of-care glucose testing, and insulin doses (ie, basal rates, carbohydrate ratios, and correction formulas) should be in place. An inpatient diabetes specialist should assist with the assessment and management of a patient with an insulin pump.

If pump use is contraindicated (Table 4)⁴⁴ or if inpatient diabetes resources are not available, discontinuation of insulin pump and transition to a basal-bolus insulin regimen (“pump holiday”) may be the safest and most appropriate step. Most patients knowledgeable in insulin pump therapy are able to display in their pump screen the average total daily insulin used for the past few days. Based on this, safe estimations of basal, bolus, and supplemental insulin can be calculated. To avoid severe hyperglycemia or ketoacidosis from lack of basal insulin, it is important to administer the basal insulin component at least 2 hours before disconnecting the insulin pump.

Concentrated insulins

U-500 regular insulin is concentrated insulin that delivers the same amount of units in one-fifth the volume of conventional insulins, which are U-100. Whereas there are 100 units of insulin in 1 mL for conventional insulins, there are 500 units of U-500 regular insulin in 1 mL. Its onset of action is similar to that of regular insulin, and the peak and duration are similar to that of NPH insulin. Concentrated insulin is often administered in the outpatient setting to patients who are insulin resistant and require close to 200 units a day. The U-500 pen device was approved in January 2016 and was projected to be available in April 2016. For now, it can only be procured in the vial form. This causes confusion in its dosing since it is given either with the usual insulin syringes, which are designed for U-100 insulin administration, or a tuberculin syringe, which is not marked in units but in milliliters.

Because of its unique nature and providers’ lack of familiarity with U-500, certain institutions have a policy for its use. In many institutions, the doses are confirmed by pharmacy staff and delivered by pharmacy to the patient’s medication bin predrawn in a tuberculin syringe.⁴⁵ In addition, a study reported that many patients on U-500 at home required significantly lower doses of insulin (average dose of 100 U/day) while hospitalized patients could be managed with conventional insulin formulations.⁴⁵

There are newer concentrated insulins in the market, such as insulin glargine 300 U/mL (Toujeo) and insulin lispro 200 U/mL (Humalog). These insulins, so far, come only in the pen device form and not in vials, obviating the need for dose calculations using a U-100 insulin syringe or tuberculin syringe. The efficacy and safety of these insulin formulations have not been determined in the hospital setting.

Transitioning from home to hospital

Transition to an outpatient setting requires planning and coordination. Although insulin is used in the hospital for most patients with diabetes, many patients do not require insulin after discharge. On the other hand, diabetes regimens sometimes need intensification in other patients. One study showed that patients with acceptable diabetes control (HbA1c < 7.5%) near or on admission could be discharged on their prehospitalization treatment regimen, while those with HbA1c between 7.5% and 9% could be discharged on oral agents plus basal insulin at 50% of the hospital basal dose.⁴⁶ Additionally, patients with an HbA1c of 9% to 10% should be discharged on a basal-bolus regimen or on a combination of oral agents plus basal insulin at 80% of hospital dose, with a reduction in HbA1c seen 12 weeks after discharge.

SUMMARY

Inpatient hyperglycemia is common and is associated with increased risk of hospital complications, higher healthcare resource utilization, and higher rates of in-hospital mortality. In the critically ill, IV insulin is most appropriate, with a starting threshold no higher than 180 mg/dL. Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL.

In noncritically ill patients, a basal-bolus regimen with basal, prandial, and correction components is preferred for patients with good nutritional intake. In contrast, a single dose of long-acting insulin plus correction insulin is preferred for patients with poor or no oral intake. Preliminary data indicate that incretin therapy has the potential to improve glycemic control in patients with mild to moderate hyperglycemia and a low risk of hypoglycemia.

Transition to an outpatient setting requires planning and coordination. Measuring HbA1c at admission is important to assess preadmission glycemic control and to tailor the treatment regimen at discharge. Patients with acceptable diabetes control could be discharged on their prehospitalization treatment regimen. Patients with suboptimal control should have more intensified therapy.

Dr. Umpierrez is supported in part by research grants from the American Diabetes Association (1-14-LLY-36), PHS grant UL1 RR025008 from the Clinical Translational Science Award Program (M01 RR-00039), and grants from the National Institutes of Health and the National Center for Research Resources. He has received unrestricted research support for inpatient studies (at Emory University) from Sanofi, Merck, Novo Nordisk, and Boehringer Ingelheim, and has received consulting fees and/or honoraria for membership on advisory boards from Novo Nordisk, Sanofi, Merck, Boehringer Ingelheim, and Regeneron.
 

Hyperglycemia in hospitalized patients, with or without diabetes, is associated with adverse outcomes including increased rates of infection and mortality and longer hospital length of stay.^1–3 The rates of complications and mortality are even higher in hyperglycemic patients without a history of diabetes than in those with diabetes.^1,2 Randomized clinical trials in critically ill and noncritically ill hyperglycemic patients demonstrate that improved glycemic control can reduce hospital complications, systemic infections, and hospitalization cost.^4–6 However, intensive glycemic therapy is associated with increased risk of hypoglycemia, which is independently associated with increased morbidity and mortality in hospitalized patients. The concern about hypoglycemia has led to revised blood glucose target recommendations from professional organizations and a search for alternative treatment options.

This manuscript provides a review of updated recommendations for the management of inpatients with hyperglycemia in the critical care and general medical and surgical settings.

HYPERGLYCEMIA IN CRITICAL CARE SETTINGS

A substantial body of evidence links hyperglycemia in critically ill patients to higher rates of hospital complications, longer hospital stay, higher healthcare resource utilization, and greater hospital mortality.^7,8 Although evidence from several cohort studies and randomized clinical trials suggests that tight glucose control can reduce hospital complications and mortality,^9,10 this target has been difficult to achieve without increasing the risk of severe hypoglycemia. In addition, data from trials using intense glycemic control in patients in the intensive care unit (ICU) have failed to show a significant improvement in mortality and, in some instances, showed increased mortality risk associated with the therapy.^11,12

The recommended target glucose levels are 140 to 180 mg/dL for most ICU patients.¹³ In agreement with this, the recent GLUCO-CABG trial reported no significant differences in the composite end points of complications and death between an intensive glucose target of 100 to 140 mg/dL and a conservative target of 141 to 180 mg/dL after cardiac surgery.¹⁴

HYPERGLYCEMIA IN NONCRITICAL CARE SETTINGS

In general medical and surgical patients, a strong association has been reported between hyperglycemia and prolonged hospital stay, infection, and disability after hospital discharge.^1,15,16 For example, the risk of postoperative infections in patients undergoing general surgery was estimated to increase by 30% for every 40 mg/dL rise in glucose over normo­glycemia (< 110 mg/dL).¹⁶ In general, appropriate glycemic control to maintain recommended glycemic levels in noncritically ill patients can reduce the risks and improve outcomes. 

HYPOGLYCEMIA INCIDENCE

Hypoglycemia, defined as glucose less than 70 mg/dL, is a common complication of hyperglycemia treatment.¹⁷ Severe hypoglycemia is defined as glucose less than 40 mg/dL.¹⁸ The incidence of hypoglycemia in ICU trials ranged between 5% and 28%, depending on the intensity of glycemic control,¹⁹ and between 1% and 33% in non-ICU trials using subcutaneous (SC) insulin therapy.²⁰ The most important hypoglycemia risk factors include older age, kidney failure, change in nutritional intake, interruption of glucose monitoring, previous insulin therapy, and failure to adjust therapy when glucose is trending down or steroid therapy is being tapered.^21,22

In hospitalized patients with diabetes, hypoglycemia has been associated with poor outcomes, including a 66% increased risk of death within 1 year and 2.8 days longer hospital stay compared with patients without hypoglycemia.²³ Hypoglycemia also has been associated with prolonged QT interval, ischemic electro­cardiogram changes, angina, arrhythmias, and sudden death in patients with type 1 diabetes.²⁴ Despite these observations, other studies have reported that the increased in-hospital mortality rate is limited to patients with spontaneous hypoglycemia rather than drug-associated hypoglycemia,²⁵ raising the possibility that hypoglycemia may represent a marker of disease burden rather than be a direct cause of death.

INPATIENT ASSESSMENT OF HYPERGLYCEMIA

Clinical guidelines recommend glucose measurement in all patients admitted to the hospital.^13,26 Patients with hyperglycemia (glucose > 140 mg/dL) and patients with a history of diabetes should undergo bedside point-of-care glucose testing before meals and at bedtime. Premeal testing should be done close to the time of the meal tray delivery and no longer than 1 hour before meals. For patients taking nothing by mouth or receiving continuous enteral nutrition, point-of-care testing is recommended every 4 to 6 hours.

Hemoglobin A1c (HbA1c) should be measured in patients with hyperglycemia and in those with diabetes if it has not been performed in the preceding 2 to 3 months. In hyperglycemic patients without a history of diabetes, an HbA1c of 6.5% or greater suggests that diabetes preceded hospitalization. In patients with diabetes, the HbA1c can help assess glycemic control prior to admission and tailor the treatment regimen at discharge.^13,26

TARGET GLUCOSE LEVELS

Glycemic targets recommended by several organizations are shown in Table 1. For critically ill patients, most societies recommend glucose targets below 180 mg/dL, with the lower limit being anywhere from 110 to less than 150 mg/dL.

For patients in non-ICU settings, the Endocrine Society²⁶ and the American Diabetes Association/American Association of Endocrinologists¹³ practice guidelines recommend premeal glucose levels below 140 mg/dL, and below 180 mg/dL if checked randomly. Higher glucose ranges (< 200 mg/dL) may be acceptable in terminally ill patients or in patients with severe comorbidities.²⁶ Guidelines from the Joint British Diabetes Societies recommend targeting glucose levels between 108 and 180 mg/dL with an acceptable range of between 72 and 216 mg/dL.²⁷

 

INPATIENT MANAGEMENT OF HYPERGLYCEMIA AND DIABETES

Insulin regimens in critical care settings

Insulin administration is the preferred way to control hyperglycemia in hospitalized patients. In critically ill patients, such as those with hypotension requiring pressor support, hyperglycemic crises, sepsis, or shock, insulin is best given via continuous intravenous (IV) infusion. The short half-life of IV insulin (< 15 minutes) allows flexibility in adjusting the infusion rate in the event of unpredicted changes in nutrition or the patient’s health. If the glucose level rises above 180 mg/dL, IV insulin infusion should be started to maintain levels below 180 mg/dL.^13,26,28,29

A variety of infusion protocols have been shown to be effective in achieving glycemic control with a low rate of hypoglycemia. The ideal protocol should allow flexible rate adjustment taking into account current and previous glucose values as well as changes in infusion rate. Hourly glucose measurements until stable glycemic control is established, followed by point-of-care testing every 1 to 2 hours, is needed to assess response to therapy and prevent hypoglycemia.

Insulin regimens in noncritical care settings

For most patients in a general, non-ICU setting, SC insulin therapy with basal insulin administered once or twice daily, alone or in combination with prandial insulin, is effective and safe.¹³ Inhaled insulin is approved by the US Food and Drug Administration, but its use in the hospital has not been studied. The use of sliding-scale insulin is not acceptable as the single regimen in patients with diabetes, as it results in undesirable hypoglycemia and hyperglycemia.³⁰Figure 1 presents an algorithm for selecting initial insulin treatment for patients with type 2 diabetes in the non-ICU setting.

Several SC insulin products are available, each with a different pharmacokinetic profile, as outlined in Table 2.³¹

Basal insulin prevents hyperglycemia during fasting states. Basal insulin is usually given as a once- or twice-daily long-acting insulin, such as glargine and detemir insulin. On occasion, twice-daily intermediate-acting insulin (neutral protamine Hagedorn; NPH) is used as a basal insulin.

Prandial insulin, also referred to as nutritional or bolus insulin, is given before meals as rapid-acting insulin (aspart, lispro, or glulisine) or short-acting insulin (regular) to prevent postmeal hyperglycemia. Rapid-acting insulin is preferred to regular insulin because of the faster onset and shorter duration of action, which may reduce the risk of hypoglycemia.

Correction or supplemental insulin is given to correct hyperglycemia when the glucose is above the goal. The same formulation is given together with prandial insulin.

Total daily dose of insulin is a measure that comprises basal and prandial insulin Figure 1 lists the recommended total daily dose for different clinical situations and patient populations.

Basal-bolus insulin usually refers to a regimen of long-acting basal insulin plus prandial insulin. In patients with adequate oral intake, the basal-bolus approach is preferred. The RABBIT 2 trial reported that basal-bolus regimens resulted in greater improvement in glucose control than sliding-scale regimens (correction insulin alone without basal or prandial components) in general medicine patients with type 2 diabetes.³² In general surgery patients, basal-bolus regimens significantly improved glucose control and reduced the numbers of post­operative complications, primarily wound infections compared with sliding-scale regimens.⁴

Multiple doses of NPH and regular insulin were compared with basal-bolus treatment with long-acting and rapid-acting insulin in two controlled trials in medical patients with type 2 diabetes.^20,33 Both studies reported that treatment with NPH and regular insulin resulted in similar improvements in glycemic control and no difference in the rate of hypoglycemic events or in hospital length of stay, compared with basal-bolus insulin. Because NPH has a peak of action approximately 8 to 12 hours after injection, there is a risk of hypoglycemia in patients with poor oral intake.

In hospitalized patients who have reduced total caloric intake due to lack of appetite, acute illness, medical procedures, or surgical interventions, the Basal Plus trial³⁴ reported that a single daily dose of glargine plus correction doses of rapid-acting insulin resulted in similar improvement in glycemic control and no difference in the frequency of hypoglycemia compared with a standard basal-bolus regimen. These results indicate that the basal-plus-correction regimen may be preferred for patients with poor or no oral intake, whereas an insulin regimen with basal, nutritional (basal-bolus), and correction components is preferred for patients with good nutritional intake.³⁵

SC insulin dosing refers to insulin doses administered subcutaneously calculated based either on weight or on home insulin doses. For insulin-naive patients, the starting total daily dose of insulin can usually be computed as 0.4 to 0.5 U/kg/day. Higher starting doses are associated with greater odds of hypoglycemia than doses lower than 0.2 U/kg/day.³⁶ In elderly patients and those with impaired renal function, lower initial daily doses (≤ 0.3 U/kg) may reduce the risk of hypoglycemia.²⁶

In patients treated with insulin prior to admission, the total daily insulin dose at home can be given as half long-acting basal insulin and half prandial insulin. The dose can be reduced by 20% to 25% to prevent hypoglycemia, particularly in those with poor or uncertain caloric intake.³¹

Noninsulin therapies

The use of oral antidiabetic agents is generally not recommended in hospitalized patients due to the limited data available on their safety and efficacy, frequent contraindications, risk of hypoglycemia, and slow onset of action that may preclude achieving rapid glycemic control and daily dose adjustments. Table 3 lists the pros and cons of these agents in hospitalized patients.

The safety and efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the management of inpatient hyperglycemia was evaluated in a randomized pilot study in patients with type 2 diabetes treated at home with diet, oral antidiabetic agents, or a low daily insulin dose (≤ 0.4 U/kg/day).³⁷ Patients were randomized to one of two treatments:

• Sitagliptin alone or with low-dose glargine insulin
• Basal-bolus insulin regimen plus supplemental doses of insulin lispro.

Both treatment regimens resulted in similar improvement in mean daily glucose concentrations. However, patients admitted to the hospital with glucose levels above 180 mg/dL in the sitagliptin group had higher mean daily glucose levels than patients treated with basal-bolus or sitagliptin plus glargine.

Transitioning from IV to SC insulin

When patients in critical care units are ready to be transferred to a general medical floor, appropriate transition from IV insulin to scheduled SC insulin is needed to prevent rebound hyperglycemia. This is imperative in patients with type 1 diabetes in whom just a few hours without insulin can result in diabetic ketoacidosis.

There are three general ways to calculate the SC insulin dose during the transition period. The first two methods are weight-based and based on the home dose, as previously discussed. The third method is to extrapolate from the IV insulin. A common way is to sum up the total IV insulin dose in the past 6 or 8 hours and multiply by 3 or 4, and then reduce by 20% to achieve the basal insulin dose, presuming the patient had no oral intake on the IV insulin infusion. This last method is preferred in hemodynamically stable patients with stable insulin requirements.

If long-acting insulin is chosen as basal insulin, it should be given 2 to 4 hours before discontinuation of the IV insulin infusion. Intermediate-acting insulin should be given 1 to 2 hours before IV insulin discontinuation.

 

SPECIFIC SITUATIONS AND POPULATIONS

Type 1 diabetes

Patients with type 1 diabetes have minimal to absent pancreatic beta cell function and rely on the exogenous administration of insulin to maintain glucose homeostasis. They have worse glycemic control and higher rates of acute kidney injury than patients with type 2 diabetes; however, the impact of inpatient glycemic control on clinical outcomes has not been determined in patients with type 1 diabetes. Insulin therapy must provide both basal and nutritional components to achieve the target goals. It is important to ask the patient directly to determine the times and doses of prescribed insulin, medication adherence, recent dietary habits (including changes in appetite), and level of physical activity. This information will be used to guide insulin therapy.

A systematic review of 16 clinical studies reported that patients who possess excellent self-management skills can be suitable for successful inpatient diabetes self-management.³⁸ The American Diabetes Association supports patient self-management of diabetes in the hospital.³⁹ However, the competence and readiness of each patient with type 1 diabetes need to be carefully determined in an individualized manner. Potential candidates for inpatient self-management are those with unaltered mental status, proven proficient outpatient skills (eg, carbohydrate counting, frequent glucose monitoring, strong knowledge related to the management of insulin pump or injection techniques), and who are tolerating oral intake.

Enteral nutrition and tube feeding

Accidental dislodgement of feeding tubes, temporary discontinuation of nutrition due to nausea or for diagnostic testing, and cycling of enteral nutrition with oral intake in patients with an inconsistent appetite pose unique challenges in the hospital. Although it may be tempting to give basal and nutritional requirements to these patients as a single dose of long-acting insulin, this is not recommended. Low-dose basal insulin plus scheduled doses of short-acting (regular) insulin (every 6 hours) or rapid-acting insulin (every 4 hours) with correction insulin is often used. Some providers prefer giving intermediate-acting (NPH) plus short-acting (regular) insulin every 8 hours or every 12 hours.

It is generally accepted that diabetic enteral formulas that are low in carbohydrate and high in monounsaturated fatty acids are preferable to standard high-carbohydrate formulas in hospitalized patients with diabetes. In a meta-analysis, the postprandial rise in glucose was reduced by 20 to 30 mg/dL with the low-carbohydrate high-fat formulations compared with standard formulations.⁴⁰

Parenteral nutrition

The use of parenteral nutrition has been linked to aggravation of hyperglycemia independent of a history of diabetes as well as a higher risk of complications, infections, sepsis, and death.⁴¹ Regular insulin can be added to the parenteral solution at a starting dose of 0.1 U/g of dextrose in nondiabetic patients and at 0.15 U/g of dextrose in patients with diabetes.⁴²

Alternatively, insulin can be given as a continuous IV infusion. Hemodynamically stable patients with mild to moderate hyperglycemia can be managed with basal insulin plus scheduled or as-needed doses of short-acting (regular) insulin every 6 hours. To prevent waste, it is better to underestimate the insulin added to parenteral nutrition so as to avoid having to discontinue it prematurely or add additional glucose.

Glucocorticoids

Glucocorticoids typically raise glucose starting 4 to 6 hours after administration. Low doses of glucocorticoids given in the morning tend to raise the late morning to evening glucose levels without affecting the fasting glucose. In this situation, the patient may be managed on prandial insulin without long-acting basal insulin or with intermediate-acting insulin given in the morning. Higher glucocorticoid doses may raise fasting glucose levels, in which case basal-bolus insulin would be appropriate, with the basal component comprising about 30% and the bolus about 70% of the daily dose.²⁶

Insulin pump

Approximately 400,000 US patients with diabetes use an insulin pump.⁴³ Successful management of inpatient diabetes with the continuation of insulin pump therapy has been previously demonstrated in select patients. Clear hospital policies, procedures, and physicians’ orders with specifics on the type of diet, frequency of point-of-care glucose testing, and insulin doses (ie, basal rates, carbohydrate ratios, and correction formulas) should be in place. An inpatient diabetes specialist should assist with the assessment and management of a patient with an insulin pump.

If pump use is contraindicated (Table 4)⁴⁴ or if inpatient diabetes resources are not available, discontinuation of insulin pump and transition to a basal-bolus insulin regimen (“pump holiday”) may be the safest and most appropriate step. Most patients knowledgeable in insulin pump therapy are able to display in their pump screen the average total daily insulin used for the past few days. Based on this, safe estimations of basal, bolus, and supplemental insulin can be calculated. To avoid severe hyperglycemia or ketoacidosis from lack of basal insulin, it is important to administer the basal insulin component at least 2 hours before disconnecting the insulin pump.

Concentrated insulins

U-500 regular insulin is concentrated insulin that delivers the same amount of units in one-fifth the volume of conventional insulins, which are U-100. Whereas there are 100 units of insulin in 1 mL for conventional insulins, there are 500 units of U-500 regular insulin in 1 mL. Its onset of action is similar to that of regular insulin, and the peak and duration are similar to that of NPH insulin. Concentrated insulin is often administered in the outpatient setting to patients who are insulin resistant and require close to 200 units a day. The U-500 pen device was approved in January 2016 and was projected to be available in April 2016. For now, it can only be procured in the vial form. This causes confusion in its dosing since it is given either with the usual insulin syringes, which are designed for U-100 insulin administration, or a tuberculin syringe, which is not marked in units but in milliliters.

Because of its unique nature and providers’ lack of familiarity with U-500, certain institutions have a policy for its use. In many institutions, the doses are confirmed by pharmacy staff and delivered by pharmacy to the patient’s medication bin predrawn in a tuberculin syringe.⁴⁵ In addition, a study reported that many patients on U-500 at home required significantly lower doses of insulin (average dose of 100 U/day) while hospitalized patients could be managed with conventional insulin formulations.⁴⁵

There are newer concentrated insulins in the market, such as insulin glargine 300 U/mL (Toujeo) and insulin lispro 200 U/mL (Humalog). These insulins, so far, come only in the pen device form and not in vials, obviating the need for dose calculations using a U-100 insulin syringe or tuberculin syringe. The efficacy and safety of these insulin formulations have not been determined in the hospital setting.

Transitioning from home to hospital

Transition to an outpatient setting requires planning and coordination. Although insulin is used in the hospital for most patients with diabetes, many patients do not require insulin after discharge. On the other hand, diabetes regimens sometimes need intensification in other patients. One study showed that patients with acceptable diabetes control (HbA1c < 7.5%) near or on admission could be discharged on their prehospitalization treatment regimen, while those with HbA1c between 7.5% and 9% could be discharged on oral agents plus basal insulin at 50% of the hospital basal dose.⁴⁶ Additionally, patients with an HbA1c of 9% to 10% should be discharged on a basal-bolus regimen or on a combination of oral agents plus basal insulin at 80% of hospital dose, with a reduction in HbA1c seen 12 weeks after discharge.

SUMMARY

Inpatient hyperglycemia is common and is associated with increased risk of hospital complications, higher healthcare resource utilization, and higher rates of in-hospital mortality. In the critically ill, IV insulin is most appropriate, with a starting threshold no higher than 180 mg/dL. Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL.

In noncritically ill patients, a basal-bolus regimen with basal, prandial, and correction components is preferred for patients with good nutritional intake. In contrast, a single dose of long-acting insulin plus correction insulin is preferred for patients with poor or no oral intake. Preliminary data indicate that incretin therapy has the potential to improve glycemic control in patients with mild to moderate hyperglycemia and a low risk of hypoglycemia.

Transition to an outpatient setting requires planning and coordination. Measuring HbA1c at admission is important to assess preadmission glycemic control and to tailor the treatment regimen at discharge. Patients with acceptable diabetes control could be discharged on their prehospitalization treatment regimen. Patients with suboptimal control should have more intensified therapy.

Dr. Umpierrez is supported in part by research grants from the American Diabetes Association (1-14-LLY-36), PHS grant UL1 RR025008 from the Clinical Translational Science Award Program (M01 RR-00039), and grants from the National Institutes of Health and the National Center for Research Resources. He has received unrestricted research support for inpatient studies (at Emory University) from Sanofi, Merck, Novo Nordisk, and Boehringer Ingelheim, and has received consulting fees and/or honoraria for membership on advisory boards from Novo Nordisk, Sanofi, Merck, Boehringer Ingelheim, and Regeneron.
 

Hyperglycemia in hospitalized patients, with or without diabetes, is associated with adverse outcomes including increased rates of infection and mortality and longer hospital length of stay.^1–3 The rates of complications and mortality are even higher in hyperglycemic patients without a history of diabetes than in those with diabetes.^1,2 Randomized clinical trials in critically ill and noncritically ill hyperglycemic patients demonstrate that improved glycemic control can reduce hospital complications, systemic infections, and hospitalization cost.^4–6 However, intensive glycemic therapy is associated with increased risk of hypoglycemia, which is independently associated with increased morbidity and mortality in hospitalized patients. The concern about hypoglycemia has led to revised blood glucose target recommendations from professional organizations and a search for alternative treatment options.

This manuscript provides a review of updated recommendations for the management of inpatients with hyperglycemia in the critical care and general medical and surgical settings.

HYPERGLYCEMIA IN CRITICAL CARE SETTINGS

A substantial body of evidence links hyperglycemia in critically ill patients to higher rates of hospital complications, longer hospital stay, higher healthcare resource utilization, and greater hospital mortality.^7,8 Although evidence from several cohort studies and randomized clinical trials suggests that tight glucose control can reduce hospital complications and mortality,^9,10 this target has been difficult to achieve without increasing the risk of severe hypoglycemia. In addition, data from trials using intense glycemic control in patients in the intensive care unit (ICU) have failed to show a significant improvement in mortality and, in some instances, showed increased mortality risk associated with the therapy.^11,12

The recommended target glucose levels are 140 to 180 mg/dL for most ICU patients.¹³ In agreement with this, the recent GLUCO-CABG trial reported no significant differences in the composite end points of complications and death between an intensive glucose target of 100 to 140 mg/dL and a conservative target of 141 to 180 mg/dL after cardiac surgery.¹⁴

HYPERGLYCEMIA IN NONCRITICAL CARE SETTINGS

In general medical and surgical patients, a strong association has been reported between hyperglycemia and prolonged hospital stay, infection, and disability after hospital discharge.^1,15,16 For example, the risk of postoperative infections in patients undergoing general surgery was estimated to increase by 30% for every 40 mg/dL rise in glucose over normo­glycemia (< 110 mg/dL).¹⁶ In general, appropriate glycemic control to maintain recommended glycemic levels in noncritically ill patients can reduce the risks and improve outcomes. 

HYPOGLYCEMIA INCIDENCE

Hypoglycemia, defined as glucose less than 70 mg/dL, is a common complication of hyperglycemia treatment.¹⁷ Severe hypoglycemia is defined as glucose less than 40 mg/dL.¹⁸ The incidence of hypoglycemia in ICU trials ranged between 5% and 28%, depending on the intensity of glycemic control,¹⁹ and between 1% and 33% in non-ICU trials using subcutaneous (SC) insulin therapy.²⁰ The most important hypoglycemia risk factors include older age, kidney failure, change in nutritional intake, interruption of glucose monitoring, previous insulin therapy, and failure to adjust therapy when glucose is trending down or steroid therapy is being tapered.^21,22

In hospitalized patients with diabetes, hypoglycemia has been associated with poor outcomes, including a 66% increased risk of death within 1 year and 2.8 days longer hospital stay compared with patients without hypoglycemia.²³ Hypoglycemia also has been associated with prolonged QT interval, ischemic electro­cardiogram changes, angina, arrhythmias, and sudden death in patients with type 1 diabetes.²⁴ Despite these observations, other studies have reported that the increased in-hospital mortality rate is limited to patients with spontaneous hypoglycemia rather than drug-associated hypoglycemia,²⁵ raising the possibility that hypoglycemia may represent a marker of disease burden rather than be a direct cause of death.

INPATIENT ASSESSMENT OF HYPERGLYCEMIA

Clinical guidelines recommend glucose measurement in all patients admitted to the hospital.^13,26 Patients with hyperglycemia (glucose > 140 mg/dL) and patients with a history of diabetes should undergo bedside point-of-care glucose testing before meals and at bedtime. Premeal testing should be done close to the time of the meal tray delivery and no longer than 1 hour before meals. For patients taking nothing by mouth or receiving continuous enteral nutrition, point-of-care testing is recommended every 4 to 6 hours.

Hemoglobin A1c (HbA1c) should be measured in patients with hyperglycemia and in those with diabetes if it has not been performed in the preceding 2 to 3 months. In hyperglycemic patients without a history of diabetes, an HbA1c of 6.5% or greater suggests that diabetes preceded hospitalization. In patients with diabetes, the HbA1c can help assess glycemic control prior to admission and tailor the treatment regimen at discharge.^13,26

TARGET GLUCOSE LEVELS

Glycemic targets recommended by several organizations are shown in Table 1. For critically ill patients, most societies recommend glucose targets below 180 mg/dL, with the lower limit being anywhere from 110 to less than 150 mg/dL.

For patients in non-ICU settings, the Endocrine Society²⁶ and the American Diabetes Association/American Association of Endocrinologists¹³ practice guidelines recommend premeal glucose levels below 140 mg/dL, and below 180 mg/dL if checked randomly. Higher glucose ranges (< 200 mg/dL) may be acceptable in terminally ill patients or in patients with severe comorbidities.²⁶ Guidelines from the Joint British Diabetes Societies recommend targeting glucose levels between 108 and 180 mg/dL with an acceptable range of between 72 and 216 mg/dL.²⁷

 

INPATIENT MANAGEMENT OF HYPERGLYCEMIA AND DIABETES

Insulin regimens in critical care settings

Insulin administration is the preferred way to control hyperglycemia in hospitalized patients. In critically ill patients, such as those with hypotension requiring pressor support, hyperglycemic crises, sepsis, or shock, insulin is best given via continuous intravenous (IV) infusion. The short half-life of IV insulin (< 15 minutes) allows flexibility in adjusting the infusion rate in the event of unpredicted changes in nutrition or the patient’s health. If the glucose level rises above 180 mg/dL, IV insulin infusion should be started to maintain levels below 180 mg/dL.^13,26,28,29

A variety of infusion protocols have been shown to be effective in achieving glycemic control with a low rate of hypoglycemia. The ideal protocol should allow flexible rate adjustment taking into account current and previous glucose values as well as changes in infusion rate. Hourly glucose measurements until stable glycemic control is established, followed by point-of-care testing every 1 to 2 hours, is needed to assess response to therapy and prevent hypoglycemia.

Insulin regimens in noncritical care settings

For most patients in a general, non-ICU setting, SC insulin therapy with basal insulin administered once or twice daily, alone or in combination with prandial insulin, is effective and safe.¹³ Inhaled insulin is approved by the US Food and Drug Administration, but its use in the hospital has not been studied. The use of sliding-scale insulin is not acceptable as the single regimen in patients with diabetes, as it results in undesirable hypoglycemia and hyperglycemia.³⁰Figure 1 presents an algorithm for selecting initial insulin treatment for patients with type 2 diabetes in the non-ICU setting.

Several SC insulin products are available, each with a different pharmacokinetic profile, as outlined in Table 2.³¹

Basal insulin prevents hyperglycemia during fasting states. Basal insulin is usually given as a once- or twice-daily long-acting insulin, such as glargine and detemir insulin. On occasion, twice-daily intermediate-acting insulin (neutral protamine Hagedorn; NPH) is used as a basal insulin.

Prandial insulin, also referred to as nutritional or bolus insulin, is given before meals as rapid-acting insulin (aspart, lispro, or glulisine) or short-acting insulin (regular) to prevent postmeal hyperglycemia. Rapid-acting insulin is preferred to regular insulin because of the faster onset and shorter duration of action, which may reduce the risk of hypoglycemia.

Correction or supplemental insulin is given to correct hyperglycemia when the glucose is above the goal. The same formulation is given together with prandial insulin.

Total daily dose of insulin is a measure that comprises basal and prandial insulin Figure 1 lists the recommended total daily dose for different clinical situations and patient populations.

Basal-bolus insulin usually refers to a regimen of long-acting basal insulin plus prandial insulin. In patients with adequate oral intake, the basal-bolus approach is preferred. The RABBIT 2 trial reported that basal-bolus regimens resulted in greater improvement in glucose control than sliding-scale regimens (correction insulin alone without basal or prandial components) in general medicine patients with type 2 diabetes.³² In general surgery patients, basal-bolus regimens significantly improved glucose control and reduced the numbers of post­operative complications, primarily wound infections compared with sliding-scale regimens.⁴

Multiple doses of NPH and regular insulin were compared with basal-bolus treatment with long-acting and rapid-acting insulin in two controlled trials in medical patients with type 2 diabetes.^20,33 Both studies reported that treatment with NPH and regular insulin resulted in similar improvements in glycemic control and no difference in the rate of hypoglycemic events or in hospital length of stay, compared with basal-bolus insulin. Because NPH has a peak of action approximately 8 to 12 hours after injection, there is a risk of hypoglycemia in patients with poor oral intake.

In hospitalized patients who have reduced total caloric intake due to lack of appetite, acute illness, medical procedures, or surgical interventions, the Basal Plus trial³⁴ reported that a single daily dose of glargine plus correction doses of rapid-acting insulin resulted in similar improvement in glycemic control and no difference in the frequency of hypoglycemia compared with a standard basal-bolus regimen. These results indicate that the basal-plus-correction regimen may be preferred for patients with poor or no oral intake, whereas an insulin regimen with basal, nutritional (basal-bolus), and correction components is preferred for patients with good nutritional intake.³⁵

SC insulin dosing refers to insulin doses administered subcutaneously calculated based either on weight or on home insulin doses. For insulin-naive patients, the starting total daily dose of insulin can usually be computed as 0.4 to 0.5 U/kg/day. Higher starting doses are associated with greater odds of hypoglycemia than doses lower than 0.2 U/kg/day.³⁶ In elderly patients and those with impaired renal function, lower initial daily doses (≤ 0.3 U/kg) may reduce the risk of hypoglycemia.²⁶

In patients treated with insulin prior to admission, the total daily insulin dose at home can be given as half long-acting basal insulin and half prandial insulin. The dose can be reduced by 20% to 25% to prevent hypoglycemia, particularly in those with poor or uncertain caloric intake.³¹

Noninsulin therapies

The use of oral antidiabetic agents is generally not recommended in hospitalized patients due to the limited data available on their safety and efficacy, frequent contraindications, risk of hypoglycemia, and slow onset of action that may preclude achieving rapid glycemic control and daily dose adjustments. Table 3 lists the pros and cons of these agents in hospitalized patients.

The safety and efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the management of inpatient hyperglycemia was evaluated in a randomized pilot study in patients with type 2 diabetes treated at home with diet, oral antidiabetic agents, or a low daily insulin dose (≤ 0.4 U/kg/day).³⁷ Patients were randomized to one of two treatments:

• Sitagliptin alone or with low-dose glargine insulin
• Basal-bolus insulin regimen plus supplemental doses of insulin lispro.

Both treatment regimens resulted in similar improvement in mean daily glucose concentrations. However, patients admitted to the hospital with glucose levels above 180 mg/dL in the sitagliptin group had higher mean daily glucose levels than patients treated with basal-bolus or sitagliptin plus glargine.

Transitioning from IV to SC insulin

When patients in critical care units are ready to be transferred to a general medical floor, appropriate transition from IV insulin to scheduled SC insulin is needed to prevent rebound hyperglycemia. This is imperative in patients with type 1 diabetes in whom just a few hours without insulin can result in diabetic ketoacidosis.

There are three general ways to calculate the SC insulin dose during the transition period. The first two methods are weight-based and based on the home dose, as previously discussed. The third method is to extrapolate from the IV insulin. A common way is to sum up the total IV insulin dose in the past 6 or 8 hours and multiply by 3 or 4, and then reduce by 20% to achieve the basal insulin dose, presuming the patient had no oral intake on the IV insulin infusion. This last method is preferred in hemodynamically stable patients with stable insulin requirements.

If long-acting insulin is chosen as basal insulin, it should be given 2 to 4 hours before discontinuation of the IV insulin infusion. Intermediate-acting insulin should be given 1 to 2 hours before IV insulin discontinuation.

 

SPECIFIC SITUATIONS AND POPULATIONS

Type 1 diabetes

Patients with type 1 diabetes have minimal to absent pancreatic beta cell function and rely on the exogenous administration of insulin to maintain glucose homeostasis. They have worse glycemic control and higher rates of acute kidney injury than patients with type 2 diabetes; however, the impact of inpatient glycemic control on clinical outcomes has not been determined in patients with type 1 diabetes. Insulin therapy must provide both basal and nutritional components to achieve the target goals. It is important to ask the patient directly to determine the times and doses of prescribed insulin, medication adherence, recent dietary habits (including changes in appetite), and level of physical activity. This information will be used to guide insulin therapy.

A systematic review of 16 clinical studies reported that patients who possess excellent self-management skills can be suitable for successful inpatient diabetes self-management.³⁸ The American Diabetes Association supports patient self-management of diabetes in the hospital.³⁹ However, the competence and readiness of each patient with type 1 diabetes need to be carefully determined in an individualized manner. Potential candidates for inpatient self-management are those with unaltered mental status, proven proficient outpatient skills (eg, carbohydrate counting, frequent glucose monitoring, strong knowledge related to the management of insulin pump or injection techniques), and who are tolerating oral intake.

Enteral nutrition and tube feeding

Accidental dislodgement of feeding tubes, temporary discontinuation of nutrition due to nausea or for diagnostic testing, and cycling of enteral nutrition with oral intake in patients with an inconsistent appetite pose unique challenges in the hospital. Although it may be tempting to give basal and nutritional requirements to these patients as a single dose of long-acting insulin, this is not recommended. Low-dose basal insulin plus scheduled doses of short-acting (regular) insulin (every 6 hours) or rapid-acting insulin (every 4 hours) with correction insulin is often used. Some providers prefer giving intermediate-acting (NPH) plus short-acting (regular) insulin every 8 hours or every 12 hours.

It is generally accepted that diabetic enteral formulas that are low in carbohydrate and high in monounsaturated fatty acids are preferable to standard high-carbohydrate formulas in hospitalized patients with diabetes. In a meta-analysis, the postprandial rise in glucose was reduced by 20 to 30 mg/dL with the low-carbohydrate high-fat formulations compared with standard formulations.⁴⁰

Parenteral nutrition

The use of parenteral nutrition has been linked to aggravation of hyperglycemia independent of a history of diabetes as well as a higher risk of complications, infections, sepsis, and death.⁴¹ Regular insulin can be added to the parenteral solution at a starting dose of 0.1 U/g of dextrose in nondiabetic patients and at 0.15 U/g of dextrose in patients with diabetes.⁴²

Alternatively, insulin can be given as a continuous IV infusion. Hemodynamically stable patients with mild to moderate hyperglycemia can be managed with basal insulin plus scheduled or as-needed doses of short-acting (regular) insulin every 6 hours. To prevent waste, it is better to underestimate the insulin added to parenteral nutrition so as to avoid having to discontinue it prematurely or add additional glucose.

Glucocorticoids

Glucocorticoids typically raise glucose starting 4 to 6 hours after administration. Low doses of glucocorticoids given in the morning tend to raise the late morning to evening glucose levels without affecting the fasting glucose. In this situation, the patient may be managed on prandial insulin without long-acting basal insulin or with intermediate-acting insulin given in the morning. Higher glucocorticoid doses may raise fasting glucose levels, in which case basal-bolus insulin would be appropriate, with the basal component comprising about 30% and the bolus about 70% of the daily dose.²⁶

Insulin pump

Approximately 400,000 US patients with diabetes use an insulin pump.⁴³ Successful management of inpatient diabetes with the continuation of insulin pump therapy has been previously demonstrated in select patients. Clear hospital policies, procedures, and physicians’ orders with specifics on the type of diet, frequency of point-of-care glucose testing, and insulin doses (ie, basal rates, carbohydrate ratios, and correction formulas) should be in place. An inpatient diabetes specialist should assist with the assessment and management of a patient with an insulin pump.

If pump use is contraindicated (Table 4)⁴⁴ or if inpatient diabetes resources are not available, discontinuation of insulin pump and transition to a basal-bolus insulin regimen (“pump holiday”) may be the safest and most appropriate step. Most patients knowledgeable in insulin pump therapy are able to display in their pump screen the average total daily insulin used for the past few days. Based on this, safe estimations of basal, bolus, and supplemental insulin can be calculated. To avoid severe hyperglycemia or ketoacidosis from lack of basal insulin, it is important to administer the basal insulin component at least 2 hours before disconnecting the insulin pump.

Concentrated insulins

U-500 regular insulin is concentrated insulin that delivers the same amount of units in one-fifth the volume of conventional insulins, which are U-100. Whereas there are 100 units of insulin in 1 mL for conventional insulins, there are 500 units of U-500 regular insulin in 1 mL. Its onset of action is similar to that of regular insulin, and the peak and duration are similar to that of NPH insulin. Concentrated insulin is often administered in the outpatient setting to patients who are insulin resistant and require close to 200 units a day. The U-500 pen device was approved in January 2016 and was projected to be available in April 2016. For now, it can only be procured in the vial form. This causes confusion in its dosing since it is given either with the usual insulin syringes, which are designed for U-100 insulin administration, or a tuberculin syringe, which is not marked in units but in milliliters.

Because of its unique nature and providers’ lack of familiarity with U-500, certain institutions have a policy for its use. In many institutions, the doses are confirmed by pharmacy staff and delivered by pharmacy to the patient’s medication bin predrawn in a tuberculin syringe.⁴⁵ In addition, a study reported that many patients on U-500 at home required significantly lower doses of insulin (average dose of 100 U/day) while hospitalized patients could be managed with conventional insulin formulations.⁴⁵

There are newer concentrated insulins in the market, such as insulin glargine 300 U/mL (Toujeo) and insulin lispro 200 U/mL (Humalog). These insulins, so far, come only in the pen device form and not in vials, obviating the need for dose calculations using a U-100 insulin syringe or tuberculin syringe. The efficacy and safety of these insulin formulations have not been determined in the hospital setting.

Transitioning from home to hospital

Transition to an outpatient setting requires planning and coordination. Although insulin is used in the hospital for most patients with diabetes, many patients do not require insulin after discharge. On the other hand, diabetes regimens sometimes need intensification in other patients. One study showed that patients with acceptable diabetes control (HbA1c < 7.5%) near or on admission could be discharged on their prehospitalization treatment regimen, while those with HbA1c between 7.5% and 9% could be discharged on oral agents plus basal insulin at 50% of the hospital basal dose.⁴⁶ Additionally, patients with an HbA1c of 9% to 10% should be discharged on a basal-bolus regimen or on a combination of oral agents plus basal insulin at 80% of hospital dose, with a reduction in HbA1c seen 12 weeks after discharge.

SUMMARY

Inpatient hyperglycemia is common and is associated with increased risk of hospital complications, higher healthcare resource utilization, and higher rates of in-hospital mortality. In the critically ill, IV insulin is most appropriate, with a starting threshold no higher than 180 mg/dL. Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL.

In noncritically ill patients, a basal-bolus regimen with basal, prandial, and correction components is preferred for patients with good nutritional intake. In contrast, a single dose of long-acting insulin plus correction insulin is preferred for patients with poor or no oral intake. Preliminary data indicate that incretin therapy has the potential to improve glycemic control in patients with mild to moderate hyperglycemia and a low risk of hypoglycemia.

Transition to an outpatient setting requires planning and coordination. Measuring HbA1c at admission is important to assess preadmission glycemic control and to tailor the treatment regimen at discharge. Patients with acceptable diabetes control could be discharged on their prehospitalization treatment regimen. Patients with suboptimal control should have more intensified therapy.

Dr. Umpierrez is supported in part by research grants from the American Diabetes Association (1-14-LLY-36), PHS grant UL1 RR025008 from the Clinical Translational Science Award Program (M01 RR-00039), and grants from the National Institutes of Health and the National Center for Research Resources. He has received unrestricted research support for inpatient studies (at Emory University) from Sanofi, Merck, Novo Nordisk, and Boehringer Ingelheim, and has received consulting fees and/or honoraria for membership on advisory boards from Novo Nordisk, Sanofi, Merck, Boehringer Ingelheim, and Regeneron.
 

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

In its January 2010 recommendations,⁹ the ADA lists criteria for the categories of normal, prediabetes, and diabetes, based on fasting and 2-hour postprandial plasma glucose levels and hemoglobin A_1c (Table 1).

 

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

 

 

Basal-bolus vs sliding-scale insulin for surgical patients: The RABBIT 2 Surgery trial

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

In its January 2010 recommendations,⁹ the ADA lists criteria for the categories of normal, prediabetes, and diabetes, based on fasting and 2-hour postprandial plasma glucose levels and hemoglobin A_1c (Table 1).

 

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

 

 

Basal-bolus vs sliding-scale insulin for surgical patients: The RABBIT 2 Surgery trial

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

In its January 2010 recommendations,⁹ the ADA lists criteria for the categories of normal, prediabetes, and diabetes, based on fasting and 2-hour postprandial plasma glucose levels and hemoglobin A_1c (Table 1).

 

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

 

 

Basal-bolus vs sliding-scale insulin for surgical patients: The RABBIT 2 Surgery trial

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.