Hyperglycemia in the hospital is generally classified as known diabetes, newly diagnosed diabetes, or stress hyperglycemia.1 Persons with preexisting type 1 diabetes, type 2 diabetes, or gestational diabetes are classified as having "known diabetes," since this diagnosis was established prior to the hospital admission. Patients may be diagnosed with diabetes during their hospital stay if they meet the American Diabetes Association (ADA) diagnostic criteria.2 An elevated hemoglobin A1c is the most appropriate way of determining whether or not blood glucose levels were high prior to admission. A hemoglobin A1c level of 6.5% or greater is diagnostic of diabetes. These individuals would then be classified as newly diagnosed even though their diabetes likely preceded their hospital stay. Also, some patients may exhibit stress hyperglycemia during their hospital stay. This hyperglycemia is usually transient and due to the stress of critical illness. Patients with stress hyperglycemia do not meet ADA diagnostic criteria of a hemoglobin A1c 6.5% or greater, and their blood glucose will normalize with resolution of their illness.1
The number of hospital discharges with diabetes as any-listed diagnosis has more than doubled in the last 25 years to an estimated 5.2 million in 2006.3 This increase can be attributed to many factors including the overall rise in obesity in the United States that parallels the rise in type 2 diabetes. Regardless of its derivation, hyperglycemia in the hospital can cause many complications including prolonged hospital length of stay, increased risk of infection, and increased mortality.4
Glycemic goals for critically ill patients
Randomized controlled trials of critically ill patients with hyperglycemia show mixed results of both an increase and a decrease in mortality.5–7 The increase in hypoglycemia that can occur with tight glycemic control in this patient population has been linked to adverse outcomes including an increase in mortality.7 Because of these contradictory findings, the glycemic goals for inpatient control in critically ill individuals with hyperglycemia have become less stringent. In critically ill patients, the American Association of Clinical Endocrinologists (AACE) and ADA consensus statement for inpatient glycemic control recommends the initiation of treatment at a glucose level of no higher than 180 mg/dL.4 The preferred treatment regimen for critically ill patients is the use of an I.V. insulin infusion. The insulin infusion should optimally keep glucose levels between 140 and 180 mg/dL.2,4
Insulin infusions are usually most effective when a written or computerized I.V. insulin protocol (IIP) is used.4 There are several published IIPs available (see IIPs published in the literature). Whether using one of these protocols or developing an original one, each features key elements that are an important part of any IIP.5 Most IIPs are nurse-driven protocols that include frequent glucose monitoring, adjustment in insulin dosages based on glycemic rate of change, and hypoglycemia treatment guidelines. It is also important that the IIP clearly identify the glycemic target range and when to notify the provider when the blood glucose is out of range. For patient safety, it is recommended that the IIP also include instructions for treatment of hypoglycemia or a reference to a preexisting hypoglycemia protocol.
Glycemic goals for non-critically ill patients
In non-critically ill patients, the AACE and ADA consensus statement of inpatient glycemic control recommends a preprandial blood glucose target of less than 140 mg/dL and a random blood glucose target of greater than 180 mg/dL.4 The blood glucose guidelines should be evaluated using clinical judgment based upon the patient's medical condition and current outpatient glycemic control. For instance, patients who are accustomed to tighter glycemic targets in the outpatient setting may elect for a more aggressive treatment regimen to achieve a premeal glucose level closer to 100 mg/dL.
In non-critically ill hospitalized patients, subcutaneous insulin is most commonly used for glycemic management.4 The most effective subcutaneous insulin regimens are those that attempt to mimic normal physiologic insulin production. Subcutaneous insulin is administered through basal, nutritional, and correctional insulin.2 Basal insulin, also called background insulin, is responsible for maintaining daily glucose homeostasis through regulation of hepatic glucose output. Basal insulin can be long-acting (insulin glargine or insulin detemir), intermediate-acting (insulin isophane suspension [NPH]), or administered through a continual basal rate via a continuous subcutaneous insulin infusion (CSII) pump. In contrast to NPH insulin, the long-acting insulins are generally preferred because they more closely match normal physiologic basal insulin production in that they last about 24 hours and generally have no significant peak effect. Rapid-acting (insulin lispro, insulin aspart, or insulin glulisine) or short-acting insulin (insulin injection regular), also called bolus insulin, is used to control both blood glucose excursions after meals (nutritional) and hyperglycemia (correctional). The term "nutritional insulin" is also used to describe insulin given to cover carbohydrates from enteral nutrition (EN), parenteral nutrition (PN), or I.V. infusions containing dextrose.2Correctional insulin is generally given in addition to nutritional insulin to help "correct" for hyperglycemia. In contrast to regular insulin, the rapid-acting insulins are generally preferred because they have a quick onset, earlier peak to better cover postmeal glucose excursions, and have a shorter duration, which avoids overlapping insulin dosages. Long-acting and rapid-acting insulins have made it easier to more closely mimic normal insulin patterns by using basal/bolus insulin therapy.
There are multiple approaches to initial insulin dosing. For patients who were previously on insulin therapy, preadmission insulin dosages can be used as a guide for inpatient treatment. If the patient is insulin naive, a recommended starting dose can be calculated based upon current weight in kilograms. The first step is to estimate a starting total daily dosage (TDD) of insulin. The TDD includes all the insulin (long-acting and short-acting) that a patient requires in a day. The TDD can be calculated by using 0.2 to 0.4 units/kg/day, starting at the lower range for patients who may be more insulin sensitive (such as thin patients or those with stress hyperglycemia) and starting at the higher end for patients who may be more insulin resistant (such as obese patients, those taking corticosteroids, known uncontrolled diabetes mellitus).8Of this total daily dose calculation, approximately 50% is ordered as long-acting basal insulin and 50% is ordered as bolus insulin to cover nutritional and correctional needs.8 For example, if the stress hyperglycemia patient weighs 80 kg, the TDD of insulin could be calculated as 16 units (80 kg 0.2 units/kg/day). Next you would calculate basal/bolus dosages; 50% of the TDD given as basal glargine insulin = 8 units once a day. The other 50% of the TDD is given as nutritional insulin to cover meals equals approximately 3 units rapid-acting insulin with each meal. In addition to nutritional insulin, a correctional dose should be ordered to control any hyperglycemia. A common way to prescribe correctional insulin is to use a "correction" scale where extra insulin is given if the blood glucose level is elevated. Using a dosing range with increments of 50 mg/dL of blood glucose above the premeal blood glucose goal is a good starting point. For example, if the premeal blood glucose goal is 100 mg/dL, the "correction" scale would be written so that the patient receives 1 unit of insulin for every 50 mg/dL above goal ( for example if blood glucose is 150 to 199 mg/dL then 1 unit of rapid-acting insulin is given; if the blood glucose is 200 to 249 mg/day then 2 units of rapid-acting insulin is given). The nutritional and correctional dose are added together to give the total rapid-acting insulin dose for a meal.
The Rabbit-2 trial adds another factor to the total daily dosing algorithm for patients with type 2 diabetes who were insulin naive. In this study, the start dose calculation was based not only on the patient's weight but also on current blood glucose levels. The recommendation from that study was that TDD of insulin for patients with a blood glucose level of 140 to 200 mg/dL was 0.4 units/kg/day and patients with a blood glucose level of 201 to 400 mg/dL were started at 0.5 units/kg/day.9
Daily titration of insulin dosages to reach glycemic goals is often required. In general, basal insulin should not be adjusted to manage postmeal rises in blood glucose values and bolus insulin should not be adjusted to manage elevated fasting blood glucose levels. Adequacy of basal insulin can be assessed by looking at the difference between the bedtime glucose level if it is at goal and the fasting glucose level. If the basal insulin dose is correct, there should be little difference between the bedtime glucose level and the fasting glucose level. When these values are similar, it indicates that the basal insulin dose is appropriately covering only the hepatic glucose output. If the fasting blood glucose level is significantly higher than the bedtime value, an increase in basal insulin dosage is suggested. If the fasting blood glucose level is significantly lower, a decrease in basal insulin dosage is suggested. The bolus insulin dosage can be evaluated by looking at the blood glucose levels before lunch, before dinner, and at bedtime. If the nutritional dosage is sufficient, and it has been about 4 hours since the last dose of bolus insulin, blood glucose levels should be at a goal of less than 140 mg/dL.8 If the goal is not met, appropriate adjustment of bolus insulin dosages should be made. Although sometimes difficult to obtain in the hospital setting, 2-hour postprandial checks are also used to determine the adequacy of the nutritional dose. However, clinical judgment should always be applied as many factors can influence blood glucose levels during the inpatient day, including late delivery of meal tray, decreased appetite, bedtime snacking, and overtreatment of hypoglycemic episodes.10
Oral agents and noninsulin injectables
Although routinely used in the outpatient setting, there are many potential precautions to consider when using oral diabetes agents in the hospital setting.10 Namely, oral diabetes agents are difficult to rapidly titrate for tight glycemic control. In addition, oral diabetes agents have several potential adverse reactions that are of particular concern in hospitalized patients. Due to renal metabolism and excretion, metformin is contraindicated in patients with renal failure, hypoxemia, and for patients undergoing diagnostic testing that requires the injection of contrast dye. Use of insulin secretagogues, such as sulfonylureas (glipizide, glyburide), can increase the chance of hypoglycemia, especially if nutritional intake is interrupted. Thiazolidinediones (pioglitazone, rosiglitazone) have a delayed onset of action and are associated with increased edema and therefore should be used with caution especially in patients with heart failure. Because of the potential for cardiovascular risk associated with rosiglitazone, the FDA announced on September 23, 2010 that access to rosiglitazone would be restricted through use of a Risk Evaluation and Mitigation Strategy (REMS). Additional information can be found at the FDA website: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm226976.htm.
In some cases, oral diabetes agents might be appropriate in the hospital setting. For example, if the patient is clinically stable with no contraindications for use of the oral agent, insulin is not necessary for blood glucose control and the patient will be prescribed an oral agent as part of the discharge plan (for example, uncomplicated orthopedic surgery with good preoperative control on an oral agent).
Other oral diabetes agents that are usually not used in the hospital setting are the noninsulin injectables pramlintide (Symlin) and the GLP-1 agonists exenatide (Byetta) and liraglutide (Victoza). These noninsulin injectables can cause nausea and vomiting, especially with limited oral intake. In addition, the GLP-1 agonists are not FDA approved for concomitant use with insulin.11,12
Hypoglycemia in the hospital is defined as a blood glucose level less than 70 mg/dL.2,4 At a blood glucose level of less than 70 mg/dL, counterregulatory hormones are released to try to maintain euglycemia. Cognitive impairment can occur at a glucose level of less than 40 mg/dL, which is defined as severe hypoglycemia.13 Hypoglycemia has been associated with tachycardia, elevated blood pressure, myocardial ischemia, angina, cardiac dysrhythmias, transiently prolonged corrected QT interval, and sudden death.
Krinsley et al. studied the clinical characteristics of 102 patients extracted from a cohort of 5,365 consecutive patients admitted to the ICU who experienced at least one episode of severe hypoglycemia.14 The study demonstrated an increase in mortality after just one episode of severe hypoglycemia. When each one of the 102 patients with severe hypoglycemia was equally matched with three different controls, there was a statistically significant difference in mortality, 55.9% versus 39.5%. In addition, the authors were able to identify factors that predispose patients to the development of severe hypoglycemia. These factors included diabetes, an admitting diagnosis to the ICU of septic shock, mechanical ventilation, and severity of illness. There was also a noteworthy increase in severe hypoglycemia in patients who received subcutaneous insulin versus I.V. insulin. However, the authors concluded that the benefits of tight glycemic control outweighed the risk of hypoglycemia.
Early recognition and treatment of hypoglycemia can obviate adverse outcomes. It is important that the clinician identifies risk factors for hypoglycemia such as improvement of illness, change in nutritional status, or a reduction in cortiocosteroid dosages. Hypoglycemia protocols initiated by nursing staff can prompt early treatment of hypoglycemia.2 This protocol should include medically appropriate therapy. In patients who are able to tolerate oral intake, 15 g of rapidly digested carbohydrates (4 ounces [1/2 cup] of fruit juice or regular soda, one tube of glucose paste, or four glucose tablets) is recommended. In patients who are NPO or unable to intake oral treatment, glucagon injection or dextrose 50% (D50) via I.V. bolus is an appropriate treatment.
Diverse situations that affect glycemia
Glucocorticoids cause an increase in hepatic glucose production and inhibit glucose uptake into muscle cells, therefore leading to hyperglycemia. Approximately 64% of patients with or without diabetes can develop hyperglycemia when taking high dosages of corticosteroids.15 Patients without a previous history of diabetes who are taking glucocorticoids should be monitored for any rise in blood glucose levels. In patients with preexisting diabetes, blood glucose levels should be closely monitored and a possible preemptive increase in insulin dosing may be appropriate.
Insulin therapy is the standard treatment for glucocorticoid-induced hyperglycemia. In patients requiring a high dose of glucocorticoids such as posttransplant, an IIP is the best choice. There are limited studies on the best practice for treatment of glucocorticoid hyperglycemia; however, since the major effect of glucocorticoids is on muscle glucose uptake, there is a greater increase in postprandial blood glucose levels and increased rapid-acting dosages may be used to maintain glucose control. In addition, Clore and Thurby-Hay proposed a simple equation for the utilization of intermediate-acting NPH insulin.15 NPH administration is based on the dose of prednisone given and the patient's weight (see Clore and Thurby-Hay's algorithm for treatment of corticosteroid-induced hyperglycemia). It is important to remember to adjust insulin dosages as corticosteroid dosages are lowered to avoid hypoglycemia.
Another potential treatment for corticosteroid-induced hyperglycemia is the use of correctional (bolus) insulin. Corticosteroids have a greater effect on postprandial glucose elevations, so the use of a correction scale may be a good option for glycemic control.8
Enteral nutritional formulas are generally high in carbohydrates, contributing to 45% to 92% of the total carbohydrates.5 One randomized clinical trial (RCT) evaluated the use of sliding scale insulin injection regular alone or with the addition of insulin glargine in a continual enteral feeding population. NPH was added to the sliding scale insulin injection regular cohort to treat incessant hyperglycemia. Comparable levels of glucose control were achieved in each group, indicating that initiating both a basal and bolus insulin is an appropriate approach to treatment of hyperglycemia.16 Basal insulin should be started at a lower dosage and bolus insulin should be used for correction dosages. Basal insulin can be slowly increased to help achieve euglycemia.5 Although glargine was used in the aforementioned RCT, long-acting insulin can increase the risk of hypoglycemia if EN is disrupted. Starting an I.V. fluid containing dextrose upon termination of EN can help prophylactically prevent hypoglycemia.
For cyclic EN, treatment may consist of use of intermediate-acting insulin at the start of EN administration with correctional rapid- or short-acting insulin as needed. Bolus tube feeds can be treated as a meal and be covered with either rapid- or short-acting insulin at the time of the bolus.17 It is very important to pay attention to changing clinical status of the patient to prevent hypoglycemia.
Hyperglycemia from PN can be attributed to multiple factors including patient age, clinical stability, and rate of dextrose infusion.2 There are no controlled trials examining which strategies are best for this situation. Adding incremental doses of insulin to the PN is an option, but may require days to determine the correct insulin dose.5 Conversely, using an effective IIP to achieve glycemic control can produce better long-term outcomes. Once glycemic goals are reached, add 66% to 100% of the total daily dose of insulin to the PN solution the next day.16
Continuous subcutaneous insulin infusion
Individuals who control their diabetes with CSII, also known as an insulin pump, can continue this therapy while in inpatient care. The individuals need to be mentally and physically competent in order to self-manage their insulin pump.18 Written CSII self-management protocols are important tools to have in place for these situations. The protocol should include documentation of patients' current basal and bolus insulin pump settings. In most instances patients are required to sign a consent stating that they understand they are to self-manage the pump and notify nursing staff if their condition changes and they can no longer safely manage the insulin pump.19
As the patient prepares to transition to outpatient diabetes self-management, diabetes education is essential. Prior to any discharge education, the patient's barriers to learning such as cognitive ability, literacy level, and visual acuity should be evaluated.4 Diabetes discharge education should consist of basic "survival" skills4 (see Diabetes "survival" skills). In addition to verbal instructions, clear written instructions should also be provided to help the patient retain the material and clarify medication administration. Referral to an outpatient diabetes education program is recommended for additional self-management education. Follow-up within 1 month with either a primary care provider or endocrinologist is recommended.4
Hospitalized patients with hyperglycemia are a unique population. With the CDC predicting prediabetes and diabetes will affect 50% of the population by the year 2020, further changes to inpatient hyperglycemia recommendations will likely occur. As more research is conducted and new technology is developed, our understanding and treatment of hyperglycemia can only improve.
IIPs published in the literature
The following is a list and brief description of several published IIPs.
Yale Insulin Infusion protocol20,21
The Yale IIP was developed to treat hyperglycemic adult patients in the critical care setting. It is not intended for use in patients with diabetic emergencies such as diabetic ketoacidosis or hyperglycemic hyperosmolar states. The protocol includes parameters for initiating the insulin infusion, blood glucose monitoring and changing the insulin infusion rates. The protocol was originally published in 2004 and an updated protocol was published in 2005 with revised blood glucose goals of 90–119 mg/dL.
The Markovitz protocol was developed to treat postoperative glycemic control in cardiac patients. This is the oldest published protocol of column method for insulin titration. It is not intended for use in patients with diabetic emergencies such as diabetic ketoacidosis or hyperglycemic hyperosmolar states. The protocol includes parameters for initiating the insulin infusion, blood glucose monitoring and changing the insulin infusion rates. The protocol was published in 2002 with blood glucose goals of 120–199 mg/dL.
The Leuven protocol is one of the first published intensive insulin drip protocols. The protocol was developed for surgical intensive care patients and is not intended for use in patients with diabetic emergencies such as diabetic ketoacidosis or hyperglycemic hyperosmolar states. The protocol includes parameters for initiating the insulin infusion, blood glucose monitoring and changing the insulin infusion rates for a glycemic goal of 80–110 mg/dL. The protocol was published in 2001.
The Portland protocol was developed to treat hyperglycemia in postoperative coronary artery bypass patients. It is not intended for use in patients with diabetic emergencies such as diabetic ketoacidosis or hyperglycemic hyperosmolar states. The protocol was utilized only in patients with diabetes mellitus and includes parameters for initiating the insulin infusion, blood glucose monitoring and changing the insulin infusion rates for a blood glucose goal of 100–150 mg/dL. The protocol was published in 2004.
University of Washington24
The University of Washington protocol is based on the Markovitz protocol. It utilizes four algorithms based on insulin sensitivity and can be utilized in all patient populations (diabetes and corticosteroid/stress induced hyperglycemia). The protocol includes parameters for blood glucose monitoring and changing the insulin infusion rates for a glycemic goal of 80–180 mg/dL. The protocol was published in 2005.
Luther Midelfort Mayo Health System14
The Luther Midelfort Mayo Health System protocol is very simple protocol. It is not intended for use in patients with diabetic emergencies such as diabetic ketoacidosis or hyperglycemic hyperosmolar states. The protocol includes parameters for initiating the insulin infusion, blood glucose monitoring and changing the insulin infusion rates for a glycemic goal of less than 140 mg/dL. The protocol was published in 2004.
The Atlanta protocol is based on a complex 10 column algorithm and can be used in all patient populations. The protocol includes parameters for initiating the insulin infusion, blood glucose monitoring and changing the insulin infusion rates for a glycemic goal of 80–110 mg/dL. The protocol was published in 2006.
The Northwestern University protocol uses three tables to adjust insulin rates and was studied in a post-operative patient population. It is not intended for use in patients with diabetic emergencies such as diabetic ketoacidosis or hyperglycemic hyperosmolar states. The protocol includes parameters for initiating the insulin infusion, blood glucose monitoring and changing the insulin infusion rates for a glycemic goal of 80–110 mg/dL. The protocol was published in 2006.
Diabetes "survival" skills4
* Determine level of understanding related to the diagnosis of diabetes
* Demonstrate self-monitoring of blood glucose levels and glucose goals
* Teach definition, recognition, treatment, and prevention of hyperglycemia and hypoglycemia
* Review sick-day management
* Instruct on when and how to take blood glucose-lowering medications (include demonstration of insulin injection technique if applicable)
* Information on medical nutritional therapy
* Identification of healthcare provider who will be responsible for diabetes care after discharge
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