Diabetes Management in Primary Care

Authors: Unger, Jeff

Title: Diabetes Management in the Primary Care Setting, 1st Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > 10 - In-Patient Management of Patients with Diabetes

10

In-Patient Management of Patients with Diabetes

Take Home Points

• Improved short- and long-term outcomes in patients with hyperglycemia can be achieved by attaining the following upper glycemic targets:

  • Intensive care unit (ICU): 80 to 110 mg per dL.

  • Non critical care units: Preprandial, 110 mg per dL: 180 mg per dL maximal glucose (values >180 mg per dL are an indication to monitor glucose levels more frequently to determine the direction of any glucose trend and the need for more-intensive intervention).

  • Prelabor: Preprandial, 100 mg per dL; 1 hour postprandial, 120 mg per dL.

  • Labor and delivery: 100 mg per dL.

• Insulin, given either intravenously as a continuous infusion or subcutaneously via injections or pump therapy, is the only available agent for effective glycemic control within the hospital setting

• Patients admitted to the hospital with hyperglycemia and no prior diagnosis of diabetes require follow-up outpatient testing (fasting blood glucose, 2-hour postprandial glucose) once metabolically stable by using established criteria

• Diabetic ketoacidosis (DKA) is the major cause of death in patients older than 24 with type 1 diabetes (T1DM)

• Patients with hyperglycemic hyperosmolar syndrome having blood glucose levels greater than 600 mg per dL experience severe volume depletion and focal neurologic deficits, which resolve once their metabolic state is normalized.

Introduction: The Impact of Hyperglycemia on In-patient Morbidity and Mortality

More than $120 billion is spent annually in the United States managing patients admitted to hospitals with significant hyperglycemia.¹ In 2000, the diagnosis of diabetes was listed in 12% of all hospital discharges, with the average

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Because the prevalence of diabetes in the general population, as well as in the private practices of primary care physicians (PCPs), exceeds that of all other chronic disease states, expanding our knowledge of in-patient care assessment and management is critical. Several professional organizations have published guidelines³ and position statements⁴ for in-hospital care of patients with diabetes. Although these guidelines are comprehensive and detail virtually all aspects of in-patient diabetes management, including medical nutrition therapy, their impact has not been appreciated outside of specialty circles. Few PCPs are even aware that these guidelines have been published.

Nevertheless, in-hospital mortality rates are directly related to the severity of hyperglycemia experienced by patients, both at the time of admission and during the acute hospital stay, especially in intensive care and surgical units.

• Meta-analysis of 15 studies reported that hyperglycemia (defined as blood glucose >110 mg per dL with or without a prior diagnosis of diabetes) increased both in-hospital mortality and congestive heart failure (CHF) in patients admitted for acute myocardial infarction (MI).⁵

• Hyperglycemia (fasting blood glucose >126 mg per dL) or a random blood glucose greater than 200 mg per dL on general medical and surgical units is associated with an 18-fold increase in in-hospital mortality, a longer stay (9 vs. 4.5 days), more subsequent nursing-home care, and a greater risk of infection.⁶

• Hyperglycemia resulted in higher risk of mortality, deep sternal wound infections, and sepsis in patients undergoing cardiac surgery. Hyperglycemia occurring on postoperative day 1 or 2 is the single most important predictor of serious infectious complications associated with cardiac surgery.^5,7,8

• When intensive care patients with hyperglycemia are treated to a glycemic target of 80 to 110 mg per dL, their intensive care unit (ICU) and in-hospital mortality rates are reduced 8% and 34%, respectively, when compared with those of patients whose target glycemic control is 180 to 200 mg per dL. Each 20 mg per dL increase in blood glucose levels results in a 30% increase risk of ICU mortality.⁹

• Doubling the admission blood glucose from 90 to 180 mg per dL results in a 60% increase in the size of the stroke.¹⁰

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• An admission blood glucose level greater than 110 to 120 mg per dL increases the risk of acute stroke mortality.^11,12

• Patients with newly diagnosed hyperglycemia and an acute MI had a 52% reduction in mortality 1 year post-MI if treated with intravenous insulin infusion targeting serum glucose levels in the range of 126 to 180 mg per dL when compared with similar patients treated with conventional care. ¹³

• Intensive glycemic control during labor and delivery significantly benefits fetal well-being.³

In approximately 25% of patients admitted to the hospital with abnormal glucose tolerance (blood glucose levels 140 199 mg per dL), diabetes will develop within 3 months of discharge. An A1C of 6% or more on admission in patients with a random blood glucose of 126 mg per dL or higher and no history of diabetes predicts a higher likelihood that diabetes will develop within 3 months of the hospital discharge.¹⁴ Once the patient's medical and metabolic conditions have been stabilized, a fasting blood glucose or a 2-hour post-glucose challenge test should be performed to determine if the patient has either a prediabetic state or clinical diabetes.

The course of hyperglycemia in the hospital setting may be variable. Patients who have been previously diagnosed with diabetes by a physician should be intensively managed to reduce the incidence of acute complications and limit their number of inpatient hospital days. Other patients on admission are noted for the first time to have previously unrecognized hyperglycemia (fasting blood glucose >126 mg per dL or a random blood glucose >200). These patients often have been living in a hyperglycemic state for years and, as such, are at high risk for developing microvascular and macrovascular complications.

The acute metabolic response, which occurs in response to illness or trauma, activates the hypothalamic-pituitary-adrenocortical axis, invoking a temporary state of insulin resistance.¹⁵ Increased levels of serum cortisol acutely shift carbohydrate, fat, and protein metabolism so that energy is instantly and selectively available to vital organs such as the brain. However, insulin-like growth factor I (IGF-I), testosterone, and endogenous thyroid levels are inappropriately reduced during an acute illness. Nutritional intake is necessary for survival. Patients who are not provided with proper nutrition shift their normally anabolic metabolic state to one favoring protein hypercatabolism. Muscles become atrophic. Failure of the muscular ventilatory system increases one's need for mechanical support. Atrophy of the intestinal mucosa and loss of gastrointestinal motility results in malabsorption and malnutrition. Virtually all components of the immune response are inhibited by cortisol.¹⁵

Thus, during an acute illness, the bodily mechanisms of defense become dysfunctional. In clinical practice, patients with hyperglycemia who survive an acute life-threatening illness may require weeks or months to reverse their catabolic state. Those patients who do manage to become euglycemic after

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The Mechanistic Link between Hyperglycemia and Poor Outcomes in the Hospital Setting

Hyperglycemia impairs normal immune function. Blood glucose levels greater than 200 mg per dL appear to reduce the ability of neutrophils and monocytes to bind to and kill bacteria.^17,18 Metabolic changes that have been linked to microvascular complications, such as the aldose reductase (AR) pathway, advance glycation end (AGE) pathway, reactive oxygen species pathway, and protein kinase C (PKC) pathway (see Chapter 11), may all contribute to immune dysfunction during periods of hyperglycemia. In animal models, the formation of AGEs appears to reduce phagocytosis.¹⁹ The induction of the AR pathway has also been shown to reduce superoxide formation in human neutrophils.²⁰ AR-inhibitor drugs have improved production of superoxide, suggesting that activation of the AR pathway appears to affect the incidence of diabetes-related bacterial infections.²⁰

Patients with hyperglycemia who have an acute MI have poorer short- and long-term prognoses than do patients without diabetes. The size of the MI increases in the setting of hyperglycemia as coronary collateral blood flow is reduced.^21,22 Multiple studies have linked hyperglycemia to abnormal hemostasis and thrombosis. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) activity associated with chronic hyperglycemia favor a prothrombotic state.²³ Just 4 hours of acute hyperglycemia enhances platelet activation in patients with type 2 diabetes (T2DM).²⁴

Acute hyperglycemia, equivalent to that often seen in the hospital setting (142 300 mg per dL), has been shown experimentally to result in endothelial dysfunction.^25,26 Endothelial cells provide a barrier between blood and tissues while serving to maintain an antithrombotic, relaxant, antioxidant, and antiadhesive state within the vasculature. During an acute illness, the endothelial cells become dysregulated and dysfunctional, and they are unable to maintain a healthy endovascular environment. Endothelial dysfunction is linked to increased cellular adhesion, increased cell permeability, inflammation, and thrombosis.

The extent of brain injury associated with stroke is dependent on the damage caused by the ischemic penumbra surrounding core of the ischemic neuronal tissue. During the stroke's evolution, the ischemic penumbra may either evolve into infarcted tissue or recover fully. Hyperglycemia results in increased tissue acidosis as well as a reduction in cerebral perfusion. Thus,

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Insulin improves short- and long-term outcomes in hospitalized patients. However, uncertainty exists as to whether these beneficial effects are due primarily to insulin action or to the secondary effects insulin has on target tissues during acute injury.

Insulin infusion can reduce circulating plasma levels of free fatty acids (FFAs). FFAs are associated with cardiac sympathetic overactivity, cardiac arrhythmias, and extensive myocardial ischemia.²⁸ Insulin infusion also improves left ventricular contractility, decreases tissue acidosis, and decreases myocardial infarct size in animal models.²⁹

Insulin infusion directly improves endothelial cell function whether provided over a brief period or provided during a 2-month sustained treatment interval.^30,31 Insulin has vasodilatory properties in the femoral and internal carotid arteries, mediated by improving nitric oxide levels within endothelial cells.^32,33 Intravascular thrombosis and intravascular adhesion are also lessened with insulin.³⁴

The relationships between metabolic stress, hyperglycemia, hypoinsulinemia, and poor hospital outcomes are summarized in Figure 10-2.

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Glycemic Targets for Hospitalized Patients

Improved outcomes for hospitalized patients are dependent on managing both the acute medical or surgical pathology and the coexisting hyperglycemia. Therefore, all patients admitted to the hospital should be clearly identified in the medical record as having diabetes and followed up with frequent blood glucose monitoring. The targeted glycemic goals for patients with hyperglycemia and diabetes are based on the severity of their illness.^35,36

• Patients in the ICU/critical care unit (CCU) setting should be placed on IV insulin infusion therapy to keep blood glucose levels at 80 to 110 mg per dL.

• Noncritically ill patients should use IV or subcutaneous insulin as necessary to maintain premeal glucose levels as close to 90 to 130 mg per dL as possible and postprandial glucose levels less than 180 mg per dL.

Preoperative Evaluation of Patients with Diabetes

Patients with diabetes may need to undergo elective or emergency operative procedures, just as individuals with normal glycemia. However, the metabolic response to the physiologic stress induced by surgery is inherently more complicated with diabetes, requiring additional preparation, monitoring, and postoperative care. The innate imbalance between circulating insulin levels and counterregulatory hormones is responsible for the difficulties one may experience in maintaining normal perioperative homeostasis.

Insulin is an anabolic hormone that promotes glucose uptake by skeletal muscle cells and adipose tissue while limiting hepatic glucose production by suppressing glyconeogenesis and glycogenolysis. As a result of insulin action, glucose levels decrease. The counterregulatory hormones (epinephrine, glucagons, cortisol, growth hormone, and somatostatin) raise blood glucose by stimulating glycogenolysis and gluconeogenesis while increasing lipolysis and ketogenesis. Glucose utilization by muscle and fat is also limited by the counterregulatory hormones. The physiologic stress caused by surgery and anesthesia will induce a counterregulatory response, the magnitude of which depends on the severity of the surgery, the level of preoperative hyperglycemia, and the overall metabolic status of the patient. Stress hormone levels are increased in response to hypovolemia, sepsis, and acidosis.³⁷

Patients without diabetes simply increase their insulin production and secretion in response to these added stressors. In patients with diabetes who are unable to compensate for the catabolic effects of the counterregulatory hormones, DKA or hyperglycemic hyperosmolar nonketotic syndrome (HHNK) may develop in the perioperative period.

When assessing a patient's risk status before undergoing any elective surgical procedure, emphasis should be placed on the cardiovascular system. In the general population, a patient has a 6% rate of reinfarction or death if surgery is performed within 3 months of an MI and a 2% chance of reinfarction

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A patient whose resting electrocardiogram (ECG) shows evidence of ischemia or who has a history suggestive of ischemic symptoms should be referred to a cardiologist for further preoperative diagnostic testing. Patients with a history of diabetic autonomic neuropathy (DAN), especially cardiomyopathy, may be at risk for silent ischemia and sudden death (for a comprehensive review of this topic, see Chapter 11). A useful tool with which to assess preoperative cardiac risk is the Goldman Cardiac Risk Index³⁹ (Fig. 10-3). The scale assesses nine different risk factors, which, when considered additively, can predict perioperative mortality. Patients in a high-risk category should have elective surgeries delayed when possible until their overall medical status improves. The specific type of surgical procedure can also be categorized based on the potential for complications to which the patient may be exposed (Table 10-1).

In a joint effort, the American College of Cardiology (ACC) and the American Heart Association (AHA) produced a guideline for preoperative cardiovascular evaluation for noncardiac surgery.⁴⁰ The guideline incorporates clinical predictors and functional status into the preoperative risk-assessment

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Renal function should be established before performing any surgical or IV contrast-dye procedure. A patient with microalbuminuria should undergo a 24-hour urine collection to determine the creatinine clearance and glomerular filtration rate (GFR). Patients with advanced stage 3 or stage 4 chronic kidney disease (CKD) should avoid exposure to contrast material and nephrotoxic agents. Patients taking metformin should be advised to discontinue the drug on the day of the procedure. The drug may be resumed after 24 hours, assuming the renal status [blood urea nitrogen (BUN) and creatinine] remains normal. As an IV contrast agent, gadolinium, or gadodiamide, may offer a safe alternative to patients with impaired renal function. However, the physician ordering any dye study should verbally communicate his or her concerns regarding an individual's renal status directly to the radiologist so that the proper and safest contrast material may be used.^40a

Hypertension is not a contraindication for surgical intervention because blood pressure can be controlled by the anesthesiologist during surgery. Patients with orthostatic hypotension (a >30 mm Hg difference in blood pressure from the supine to standing position) should have their perioperative volume status carefully monitored for at least 24 hours.³⁷

Patients with DAN can present the surgical team with difficult challenges in the perioperative course. The signs and symptoms of DAN include resting

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Gastroparesis may complicate a patient's ability to resume postoperative feeding and may increase the risk of aspiration pneumonia. Hyperglycemia inherently delays gastric emptying and may result in symptomatic abdominal bloating and abdominal distention postoperatively. Perioperative management of patients with DAN would certainly include careful monitoring of fluid balance as well as the patient's core vital signs. Frequent bedside glucose monitoring is essential. Communication with the surgical team and nursing staff regarding the patient's DAN is also necessary so that potential complications can be appropriately addressed in a timely manner. Because patients with cardiac autonomic dysfunction are at high risk for sudden death due to silent myocardial ischemia, cardiology consultation should be obtained on such patients before undergoing elective surgical procedures.

On the day of the scheduled surgical procedure, patients with diabetes should have a laboratory assessment of serum electrolytes, blood glucose, creatinine, and urine ketones. Patients with blood glucose levels greater than 350 mg per dL or those with ketonemia or ketonuria or electrolyte imbalances should have their elective surgical procedures postponed until their metabolic status improves.

Preparing the Patient for Surgery

All patients with T1DM undergoing minor or major surgery and patients with T2DM undergoing major surgery are considered appropriate candidates for intensive diabetes management. The management approach in these categories of patients always includes insulin therapy in combination with dextrose and potassium infusion. Major surgery is defined as one requiring general anesthesia of 1 hour or more.¹⁰ T2DM patients undergoing minor surgery are managed based on their usual diabetes regimen, their state of glycemic control, the nature and extent of the surgical procedure, and available expertise. Tables 10-2 and 10-3 suggest treatment regimens for patients with T1DM and T2DM admitted for surgical procedures.

Patients in whom diabetes is well controlled by a regimen of dietary modification and physical activity may require no special preoperative intervention for diabetes. Fasting blood glucose should be measured on the morning of surgery, and intraoperative blood glucose monitoring is desirable if the surgical procedure is lengthy (>1 hour). If surgery is minor, no specific therapy is required. If surgery is major or if diabetes is poorly controlled (blood

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Sulfonylureas should be discontinued 1 day before surgery. Patients taking nateglinide or repaglinide may hold those drugs on the morning of the scheduled procedure. Metformin should be stopped 24 hours in advance of the surgery, especially in ill patients who are at increased risk for renal hypoperfusion and tissue hypoxia.

Blood glucose levels must be monitored before and immediately after surgery. Intraoperative monitoring is recommended for procedures lasting more than 1 hour. Perioperative hyperglycemia (>200 mg per dL) during minor surgery can be managed with small subcutaneous doses (4 10 units) of a rapid-acting insulin analogue (Tables 10-2 and 10-3). Glucose monitoring should continue for 4 to 6 hours after a correction dose of rapid-acting insulin, which is the time required for 100% of the insulin to be absorbed from the subcutaneous depot (see Fig. 5-3). Sulfonylureas may be resumed once the patient has resumed his or her normal diet. Metformin may be restarted 24 hours after a procedure involving iodinated radiocontrast dye, assuming that renal function is normal and there is no evidence of contrast-induced nephropathy.

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Approximately 5% of people with diabetes will require emergency surgery over their lifetime.¹⁰ Common emergency procedures managed in the primary care setting include the acute abdomen (once DKA has been ruled out), sepsis from a gangrenous extremity, and laparotomy for tubo-ovarian abscess or ectopic pregnancy or trauma. Many patients who require emergency surgery will have suboptimal glycemic control. However, this is not necessarily a contraindication to the timely performance of potentially life-saving surgery. An IV access should be secured, and immediate blood specimens should be sent for glucose, electrolyte, and acid-base assessment. Gross derangements of volume and electrolytes (e.g., hypokalemia, hypernatremia) should be corrected. Surgery should be delayed, whenever feasible, in patients with DKA, so that the underlying acid-base disorder can be corrected or, at least, ameliorated. Often the symptoms associated with the patient's acute abdomen will resolve once the metabolic defects associated with DKA are corrected.

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IV infusion of insulin, glucose, and potassium is now standard therapy and has replaced subcutaneous insulin therapy for the perioperative management of diabetes, especially in T1DM patients, and patients with T2DM undergoing major procedures. Adequate fluids must be administered to maintain intravascular volume. Fluid deficits from osmotic diuresis in poorly controlled diabetes can be considerable. The preferred fluids are normal saline and dextrose in water. Fluids containing lactate (i.e., Ringer's lactate) cause exacerbation of hyperglycemia and lactic acidosis.⁴²

Table 10-4 lists the indications for using IV insulin infusion in nonpregnant adults with hyperglycemia. Because the half-life of IV insulin is only 7 minutes, treatment-emergent hypoglycemia is very short lived. Hypoglycemia induced by subcutaneous insulin stacking (repeat insulin injections given before the previously injected dose has been fully absorbed, a period requiring at least 6 hours to complete) can be prolonged and problematic in the hospital setting when glucose levels are not frequently monitored. By using IV insulin infusions, the glycemic threshold for the initiation and titration of dosing, as well as the correction of hyperglycemia out of the target range, can be determined in advance. Management of hypoglycemia by using infusions of dextrose solutions and lower doses of IV insulin may also be written into the standard protocol.

Insulin infusions may be initiated by mixing regular insulin in a solution of 1 unit per 1 mL of normal saline (100 units regular insulin in 100 mL of normal saline). The insulin infusion is then piggybacked into a dedicated running IV line. Most patients require at least 1 unit per hour, although higher infusion rates may be necessary, depending on the degree of physiologic insulin

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Patients receiving insulin infusions should have hourly blood glucose determinations until their glucose stability has been maintained for 6 hours. At that time, testing can be performed every 2 to 3 hours. Patients who are being converted to subcutaneous insulin should have the insulin drip discontinued 1 to 2 hours after the initial subcutaneous dose is provided.

A sample ICU/CCU IV insulin protocol is shown in Figure 10-5. A form for recording metabolic changes while patients are receiving either IV or subcutaneous (SQ) insulin therapy is demonstrated in Figure 10-6. Table 10-5 suggests

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For surgical procedures lasting more than 1 hour, IV insulin infusions should be used for glycemic management by using the protocol shown in Table 10-3. The initial insulin infusion rate can be estimated as between one half and three fourths of the patient's total daily insulin dose expressed as units per hour. Regular insulin, 0.5 to 1 unit per hour, is an appropriate starting dose for most patients with T1DM. Patients treated with oral antidiabetic agents who require perioperative insulin infusion, as well as insulin-treated patients with T2DM, can be given an initial infusion rate of 1 to 2 units per hour.

Adjustments to the insulin infusion rate are made to maintain blood glucose between 120 and 180 mg per dL (see Tables 10-2 and 10-3). The duration of insulin (and dextrose) infusions depends on the clinical status of the patient. The infusions should be continued postoperatively until oral intake is established, after which the usual diabetes treatment can be resumed. The initial dose of subcutaneous rapid-acting analogue insulin may be given 1 to 2 hours before discontinuing the IV infusion.

Adequate glucose should be provided to prevent catabolism, starvation ketosis, and insulin-induced hypoglycemia. The physiologic amount of glucose required to prevent catabolism in an average nondiabetic adult is approximately 120 g per day (or 5 g per hour).¹ With preoperative fasting,

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The infusion of insulin and glucose induces an intracellular translocation of potassium, resulting in a risk for hypokalemia. In patients with initially normal serum potassium, potassium chloride, 10 mEq, should be added routinely to each 500 mL of dextrose to maintain normokalemia if renal function is normal. Hyperkalemia (confirmed with repeated measurement and electrocardiogram) and renal insufficiency are contraindications to infusion.

Pharmacologic Management of Hospitalized Patients with Diabetes

Oral Agents

Although oral agents are the cornerstone of outpatient management for T2DM, continued use of these medications within the hospital setting may be ill advised. The long duration of action of sulfonylureas favors a tendency toward hypoglycemia, especially in elderly patients who are deprived of adequate nutritional supplements in the postoperative course. Sulfonylureas do not allow rapid dose adjustments to match metabolic changes associated with surgical or illness-induced hyperglycemia.

Metformin has many in-patient limitations. The most common contraindications for metformin use relate to the potentially fatal complication of lactic acidosis. Risk factors for lactic acidosis in metformin-treated patients include heart failure, renal insufficiency, sepsis, and chronic pulmonary disease.^43,44 Of all hospitalized patients, 50% have at least one of these diagnoses on their discharge summaries, yet metformin continues to be prescribed to many of these patients at the time of their discharge.⁴⁵ The side effects of metformin include diarrhea, nausea, and a decreased appetite, which can impair recovery during an acute illness and confound symptom assessment in acutely ill patients.

Several recent studies have suggested that metformin may be safely used in the hospital setting. The actual risk of lactic acidosis attributable to metformin is either zero or so close to zero that it cannot be factored into ordinary clinical decision making. ⁴⁴ In one study, 208 patients with T2DM and CHF who used metformin during the course of their hospitalization actually had less morbidity and mortality than did similar patients who used a sulfonylurea. No cases of lactic acidosis were reported in this patient population.⁴⁶ Therefore, when prescribed to patients with normal renal function in the hospital setting, metformin may be an appropriate adjunctive medication for diabetes management.

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Thiazolidinediones (TZDs) have few adverse effects, yet can increase intravascular volume, which can be problematic in patients with CHF and left ventricular dysfunction. TZDs also require several weeks to improve hypoglycemia once the drugs are started, so initiation in the hospital setting will not improve glycemic control immediately. Patients with T2DM who survive an acute MI and are discharged on either metformin or a TZD have been found to have a lower readmission rate for CHF, favoring the use of metformin.⁴⁷

Thus, oral agents are limited in their ability to restore normoglycemia immediately in the hospital setting, and their potential side effects may interfere with patient assessment or increase the risk of potentially harmful short- and long-term adverse events. The drug that is best suited to managing hyperglycemia in hospitalized patients is insulin.

Safe and Effective Use of Insulin Therapy in the Hospital Setting

Insulin therapy has three components: basal, prandial, and corrective dosing. Basal insulin refers to the amount of drug required to maintain euglycemia while the patient remains in the fasting state. Essentially, basal insulin limits the hyperglycemia caused by hepatic glucose production. In patients with T1DM who are insulinopenic and have low levels of circulating endogenous insulin, ketogenesis and DKA will develop unless exogenous insulin is administered. Approximately 50% of an individual's total daily dose of insulin is provided as basal insulin. Basal insulin requirements are likely to increase in response to the physiologic stresses caused by an acute illness. Catecholamine levels will increase during surgery as well as during a critical illness, triggering a hyperglycemic response.

Prandial insulin, also known as nutritional insulin, is given to patients based on their intake of carbohydrates during scheduled meals. Prandial insulin must be provided to match the carbohydrate content of IV dextrose infusions, total parenteral nutrition (TPN), enteral feedings, and nutritional supplements. Patients who are NPO (nothing by mouth) and who are being nutritionally managed with TPN or enteral feedings will receive nutritional rather than prandial insulin. The timing of the prandial insulin administration is critical. Patients who are able to eat should receive adequate doses of rapid-acting prandial insulin at the time of their meal, rather than at random intervals (i.e., by using an ineffective sliding-scale regimen, as discussed further on). Those patients who may not consume their entire meal can receive their prandial insulin when they have finished eating, with the actual dose dependent on the amount of carbohydrates actually consumed as well as the preprandial glucose level. Fifty percent of the patient's total daily insulin requirements are provided in the form of prandial or nutritional insulin.

The absolute doses of basal and prandial insulin required by an individual in the hospital setting varies significantly depending on (a) the length of time the patient has had diabetes, (b) the status of the patient's diabetes control

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Patients who are unable to eat, yet are receiving TPN or enteral nutrition, must replace their prandial insulin with nutritional insulin based on the carbohydrate content and infusion rates of those supplements (Table 10-6). In general, higher doses of nutritional insulin are necessary to maintain euglycemia than would normally be needed in patients using prandial insulin. Supplemental insulin may be provided to correct unexpected hyperglycemia in patients receiving TPN or enteral therapy. As the patient's physical condition improves, daily insulin requirements may lessen, making accurate predictions of daily doses of insulin in the hospital setting difficult.

A patient's total daily dose of insulin is approximately 0.7 U per kg per day (Table 10-7). Thus, a 70-kg person would require about 50 units of insulin in 24 hours, with 25 units provided as basal insulin (glargine or detemir) and 25 units as bolus insulin (aspart, lispro, or glulisine). The insulin sensitivity factor (ISF) can be used to estimate the amount of supplemental insulin required to reduce one's blood glucose level to a prescribed target. To determine the ISF, 1,700 is divided by the patient's calculated total daily dose of insulin. For example, a patient requiring a total daily dose of 50 units of insulin would have an ISF = 1,700/50 = 34. For an initial glucose level of 220 mg per dL, and a target glucose of 150 mg per dL, approximately 2 units of supplemental rapid-acting analogue insulin would be required to reduce the glucose level to target.

Supplemental insulin is not to be confused with sliding-scale insulin dosing. Sliding-scale insulin dosing regimens are written at the time of admission regardless of the patient's weight, nutritional status, or diabetes history. Usually the sliding scales are so broad that effective glycemic management is impossible in the hospital setting. For example, a patient on a sliding-scale regimen is prescribed 2 units of regular insulin for a blood glucose of 200 to 300 mg per dL. Such dosing is ineffective, nonphysiologic, and provides a reactive approach to hyperglycemia rather than providing a deterrent against possible hyperglycemia.^48,49 Use of sliding scales in the hospital setting provides little more than a simple way to increase a patient's risk of developing either hypoglycemia or DKA.

The goal of exogenous insulin therapy, especially during an acute illness, is to mimic the body's normal response to physiologic stressors. Normally pancreatic beta cells produce supplemental insulin in an attempt to maintain euglycemia. Thus, providing patients with additional insulin to reduce intermittent hyperglycemia is warranted. The controversy surrounding the dreaded sliding insulin scale is based on its inappropriate use in the acute care setting. For example, if a patient taking oral agents is admitted to the hospital,

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Unfortunately, many patients are placed on a sliding scale, which simply reacts to peaks in glucose levels rather than maintaining euglycemia. Supplemental or correction-dose insulin is used in conjunction with basal-bolus therapy. The following case demonstrates the difference between the use of supplemental insulin and a sliding scale in the hospital setting.

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Case 1

Dylan, 49 years old, is admitted to the hospital electively for a laparoscopic cholecystectomy. He has had well-controlled T2DM for 5 years with microvascular or macrovascular complications. Dylan weighs 100 kg and is taking glipizide XL, 20 mg at bedtime, as an outpatient. He was advised to discontinue his oral agents at bedtime on the day preceding his admission to the surgical unit. Before surgery, IV insulin infusion is begun and maintained until he is able to resume his oral intake. He is then placed on basal-bolus insulin for the remainder of his hospitalization. Although the surgery is uncomplicated, a postoperative wound infection develops, requiring him to extend his hospital stay by 5 days. The insulin regimen is calculated as follows:

• Total daily dose (TDD) of insulin: 100 kg 0.7 U per kg = 70 U per day

• Daily basal insulin requirements = 50% of TDD or 35 U per day (glargine or detemir)

• Daily prandial insulin requirements = 50% of TDD or 35 units per day (lispro, aspart, or glulisine): 14 units will be given 10 minutes before breakfast; 6 units, 10 minutes before lunch; and 15 units, 10 minutes before dinner.

• ISF: 1,700/TDD = 1,700/70 = 24.2. This means that each unit of rapid-acting insulin analogue can be expected to reduce the blood glucose level 25 mg per dL (rounded off for easier calculation). The target for correction is 150.

• Target blood glucose levels (noncritical care patient):

  • Fasting: 110 mg per dL

  • Postprandial: 180 mg per dL

  • Preprandial correction target for supplemental insulin dosing: 150 mg per dL

• Before administering the prandial insulin, Dylan's blood glucose level is checked and the ISF is used to supplement the prescribed dose. For example, if the prebreakfast blood glucose is 250 mg per dL, the dose of insulin will be increased from 14 to 18 U.

Next, we will use a simulated sliding-scale regimen and evaluate the difference in therapy outcome:

Finally, we can use a sliding scale to rehydrate a patient:

The supplemental insulin-dosing regimen should be evaluated daily. If one observes the necessity for frequent use of supplemental dosing, the scheduled basal/bolus insulin doses should be increased. An attempt to educate residents on efficient use of basal-bolus therapy with supplemental insulin (with insulin analogues rather than NPH and regular insulin) in hospitalized patients resulted in a doubling of blood glucose levels between 80 and 140 mg per dL and a reduction of values greater than 250 mg per dL by 75%.⁵⁰ Thus, basal-bolus insulin regimens appear to be a safe and efficient strategy for in-patient glycemic management.⁵¹

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Use of Insulin Pump Therapy within the Acute Care Setting

More than 280,000 Americans are using continuous subcutaneous insulin infusion (CSII, or pump therapy) to manage their diabetes (see Chapter 6). Pumps can be useful in treating patients with either type 1 or type 2 diabetes. Insulin pumps are extremely helpful in improving glycemic control during pregnancy and have proven to be safe and effective in managing pediatric and adolescent diabetes. The vast majority of pump patients are very adept at diabetes self-management. Yet, like anyone else, these patients may require scheduled or emergency hospitalizations.

No published guidelines exist for managing insulin pumps in patients within the hospital setting. For patients admitted to either ICU or CCU, insulin infusion therapy is the preferential way to manage the rapidly fluctuating glycemic excursions associated with an acute illness. However, in less acute settings, pump therapy may continue, assuming the patient is eating regularly and is able to participate in his own diabetes self-management. Patients should have their glucose levels monitored before each meal and 2 hours after eating, at bedtime, and between 2 and 3 AM. Monitoring should be performed if the patient feels symptomatic hypoglycemia. Patients who are self-managing pumps in the hospital should always be allowed to perform their own glucose testing whenever possible or be apprised of their glucose levels. From 7 AM to midnight, pump patients should target glucose levels of 70 to 100 mg per dL, providing supplemental bolus insulin as needed. From midnight to 7 AM, targeting glucose levels of 100 to 150 mg per dL will safely keep the patient from becoming hypoglycemic.

Patients with pumps may need to place themselves on a temporary basal rate, allowing them to reduce the rate of insulin delivery to avoid nocturnal hypoglycemia while in the hospital. Other patients may need to increase basal delivery, as they become less active in the hospital setting. Their mealtime boluses are simplified while hospitalized, because the carbohydrate content of each meal is clearly specified by the nutritional staff, allowing the patient to practice and perform carbohydrate counting accurately. Dieticians should also be available to educate able-bodied pumpers on proper carbohydrate (carb)-counting techniques and the use of the bolus wizard, which is available on newer pump models, while they remain hospitalized. Members of the diabetes support team may also use the hospitalization to discuss the insulin-to-carbohydrate ratio, the use of supplemental insulin, and even newer concepts such as determining one's personal absorption lag time with pump patients (for further information, see Chapter 6).

Patients using insulin pumps should be reminded to change their infusion sets every 72 hours to avoid infections at the delivery site.

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Preparing Patients with Diabetes for Their Hospital Discharge

As patients prepare for hospital discharge, diabetes self-management skills should be discussed with all medically stable, competent adult patients. These individuals should have the appropriate skills to check their blood glucose levels, self-administer either oral agents or insulin, and agree to participate in follow-up visits with a physician or a member of the diabetes support team. Patients should be informed how to use the home blood glucose monitoring devices properly and when in relation to meals they are expected to perform their blood sampling. Patients taking multiple daily doses of insulin will need to check blood glucose levels before each meal and at bedtime so that the insulin dose may be accurately determined and administered before each meal. Patients using oral agents should not have to check blood glucose levels as often, possibly only at fasting and bedtime, because their management will not require instantaneous knowledge of their glucose readings. Patients using insulin pumps should understand how to troubleshoot their pumps should mechanical problems arise so that they can avoid hospitalizations resulting from acute DKA if the insulin infusion is interrupted.

Sick-day regimen protocols should be discussed with all patients (Fig. 10-7) to reduce hospitalizations required to treat dehydration and minor illnesses. Patients on insulin therapy should be advised that they should never stop using insulin, even if they are unable to tolerate oral intake. Patients who are ketosis prone should consider purchasing a glucose meter such as a Precision XTRA (Abbott) (http://www.abbottdiabetescare.com/content/en_US/20.10.30:30/product/Product_Profile_0004.htm),

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Treatment of Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome

The two most common life-threatening complications of diabetes mellitus include DKA and hyperglycemic hyperosmolar syndrome (HHS). Although important differences exist in their pathogenesis, the basic underlying mechanism for both disorders is a reduction in the net effective concentration of circulating insulin coupled with a concomitant elevation of counterregulatory hormones.

DKA is reported to be responsible for more than 100,000 hospital admissions per year in the United States and accounts for 4% to 9% of all hospital discharge summaries among patients with diabetes.⁴⁵ The incidence of HHS is lower than that of DKA and accounts for less than 1% of all primary diabetic admissions.⁴⁵ Most patients with DKA have T1DM; however, patients with T2DM are also at risk during the catabolic stress of acute illness. Contrary to popular belief, DKA is more common in adults than in children. In community-based studies, more than 40% of African-American patients with DKA were older than 40 years, and more than 20% were older than 55 years.⁵² Many of these adult patients with DKA were classified as having T2DM because 29% of patients were obese, had measurable insulin secretion, and had a low prevalence of autoimmune markers of beta-cell destruction.⁵³

DKA and HHS are serious medical emergencies. Although these conditions are rarely observed in daily practice, the mortality rate for patients in DKA is 2% to 5%, and for HHS, approximately 15%.⁴⁵ DKA remains the most common cause of death in children and adolescents with T1DM while accounting for 50% of all deaths in patients with diabetes younger than 24.⁴⁵ Between 25% and 50% of patients in whom DKA develops during pregnancy will experience fetal death.^54,55 Death from DKA is the result of the precipitating event rather than the fluid, electrolyte, and acid-base imbalances associated with the disorder.

DKA is characterized by hyperglycemia in association with metabolic acidosis and increased circulating ketone bodies. The combination of reduced endogenous or circulating insulin levels with increased production of counter-regulatory hormones in response to physiologic stress results in lipolysis and the production of ketone bodies. This increase in FFAs will promote a state of severe and acute insulin resistance. Glucose utilization by peripheral tissues (liver, adipose, and skeletal muscle cells) is reduced, further adding to the level of hyperglycemia. As serum lactate levels increase, gluconeogenesis within the liver (and kidney) is accelerated, and the glucose levels rise even further. Both hyperglycemia and ketonemia result in osmotic diuresis, leading to hypovolemia, reduced GFR, dehydration, and hypotension.

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HHS is characterized by a relative deficiency of insulin concentration to maintain normoglycemia, but adequate levels to prevent lipolysis and ketogenesis. To date, very few studies have been performed comparing differences in counterregulatory response in DKA versus HHS. Patients with HHS have been reported to have higher insulin concentration (demonstrated by basal and stimulated C-peptide levels)⁵⁶ and reduced concentrations of FFA, cortisol, growth hormone, and glucagon compared with patients with DKA.

The clinical presentation of DKA usually develops rapidly, over a period of less than 24 hours. Polyuria, polydipsia, and weight loss may be present for several days before the development of ketoacidosis, and vomiting and abdominal pain are frequently the presenting symptoms. Abdominal pain, sometimes mimicking an acute abdomen, is reported in 40% to 75% of cases of DKA.⁵⁷ Although the potential of an acute abdominal problem requiring surgical intervention should not be overlooked, in the majority of patients, the abdominal pain spontaneously resolves after correction of the metabolic disturbance. Physical examination reveals signs of dehydration, including loss of skin turgor, dry mucous membranes, tachycardia, and hypotension. Mental status can vary from full alertness to profound lethargy; however, fewer than 20% of patients are hospitalized with loss of consciousness.⁵⁸ Most patients are normothermic or even hypothermic at presentation. Acetone on the breath and labored Kussmaul respiration may also be present on admission, particularly in patients with severe metabolic acidosis.

Typical patients with HHS have undiagnosed diabetes, are between 55 and 70 years of age, and frequently are nursing home residents. Most patients in whom HHS develops experience days to weeks during which they have polyuria, polydipsia, and progressive decline in the level of consciousness. The most common clinical presentation for patients with HHS is altered sensorium. Patients originally seen with HHS may exhibit abnormal neurologic signs and symptoms, such as hemiparesis, seizures, tremors, disorientation, and hyporeflexia. However, the focal neurologic signs often disappear as the metabolic status of the patient improves.

Table 10-8 lists the updated diagnostic criteria for both DKA and HHS.⁵⁹ The diagnostic criteria for HHS include a plasma glucose concentration greater than 600 mg per dL, a serum osmolality greater than 320 mOsm per kg of water, and the absence of significant ketoacidosis. The assessment of ketonemia, the key diagnostic feature of ketoacidosis, is usually performed by the nitroprusside reaction. Clinicians should be aware that the nitroprusside reaction provides a semiquantitative estimation of acetoacetate and acetone levels but does not recognize the presence of -hydroxybutyrate, which is the main ketoacid in DKA. Therefore, this test may underestimate the level of ketosis. Direct measurement of -hydroxybutyrate is now available by fingerstick method (Precision XTRA, Abbott), which is a more accurate indicator of ketoacidosis (Fig. 10-7).

Patients with DKA frequently are initially seen with leukocytosis in the absence of infection. However, a leukocyte count greater than 25,000 mm³ or

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The admission serum potassium concentration is usually elevated in patients with DKA. In a recent series, the mean serum potassium in patients with DKA and those with HHS was 5.6 and 5.7 mEq per L, respectively. These high levels occur because of a shift of potassium from the intracellular to the extracellular space due to acidemia, insulin deficiency, and hypertonicity. Similarly, the admission serum phosphate level may be normal or elevated because of metabolic acidosis. Dehydration also can lead to increases in total serum protein, albumin, amylase, and creatine phosphokinase concentration in patients with acute diabetic decompensation.

Important differential diagnoses for DKA include chronic alcohol abuse and starvation ketosis. Whereas DKA is characterized by severe hyperglycemia, the presence of ketoacidosis without hyperglycemia in an alcoholic patient

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Treatment protocols based on the American Diabetes Association (ADA) position statement for management of hyperglycemic emergencies⁶⁰ are shown in Figures 10-8 and 10-9. The initial management of both DKA and HHS requires volume-replacement therapy. The estimated fluid deficit is 100 mL per kg body weight.⁶¹ Normal saline is infused initially at a rate of 500 to 1,000 mL per hour during the first 2 hours. Additional fluid volume replacement may be necessary to restore blood pressure and tissue perfusion. A safe goal is to replace 50% of the estimated water deficit over a period of 12 to 24 hours. Once the volume depletion has been corrected, the rate of normal saline infusion should be reduced to 250 mL per hour or changed to 0.45% saline (250 to 500 mL per hour). Once the plasma glucose reaches 250 mg per dL in DKA and 300 mg per dL in HHS, replacement fluids should contain 5% to 10% dextrose to allow continued insulin administration until ketonemia is controlled, while avoiding hypoglycemia. An additional important aspect of fluid management in hyperglycemic states is to replace the volume of urinary losses. Failure to adjust fluid replacement for urinary losses may delay correction of electrolytes and water deficit.

Patients with DKA and HHS should be treated with IV insulin infusion therapy (Fig. 10-5). When plasma glucose levels reach 250 mg per dL in DKA or 300 mg per dL in HHS, the insulin infusion rate is reduced to 0.05 unit per kg per hour (3 5 U per hour), and dextrose (5% 10%) should be added to IV fluids. Thereafter, the rate of insulin administration may need to be adjusted to maintain these glucose values until ketoacidosis or mental obtundation and hyperosmolality are resolved. Blood should be drawn every 2 to 4 hours for determination of serum electrolytes, glucose, BUN, creatinine, magnesium, phosphorus, and venous pH.

Despite a total body potassium deficit of approximately 3 to 5 mEq per kg of body weight, most patients with DKA have a serum potassium level at or above the upper limits of normal. These high levels occur because of a shift of potassium from the intracellular to the extracellular space due to acidemia, insulin deficiency, and hypertonicity. Both insulin therapy and correction of acidosis decrease serum potassium levels by stimulating cellular potassium uptake in peripheral tissues. Therefore, to prevent hypokalemia, most patients require IV potassium during the course of DKA therapy. Replacement with IV potassium [two thirds as potassium chloride [KCl] and one third as potassium phosphate (KPO₄)] should be initiated as soon as the serum potassium concentration is less than 5.0 mEq per L. The treatment goal is to maintain serum potassium levels within the normal range of 4 to 5 mEq per L.

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Patients with moderate to severe DKA should be treated with continuous IV insulin until ketoacidosis is resolved. Criteria for resolution of ketoacidosis include a blood glucose level less than 200 mg per dL, a serum bicarbonate level of 18 mEq per L or greater, a venous pH higher than 7.3, and a calculated anion gap of 12 mEq per L or less. The criteria for resolution of HHS include improvement of mental status, blood glucose level less than 300 mg per dL, and a serum osmolality of less than 320 mOsm per kg. Table 10-8 provides a protocol for initiating subcutaneous rapid-acting insulin while the patient remains on insulin infusion therapy. Once the patient is tolerating the regular oral (PO) intake and the acidosis has stabilized, conversion to subcutaneous insulin can begin. A patient previously diagnosed with diabetes may simply be placed back on the routine insulin dose. A newly diagnosed patient should be placed on a basal-bolus regimen, as studies have shown long-term reduction in microvascular and macrovascular complication rates when diabetes is aggressively managed at an early stage.^62,63,64,65 If patients are not able to eat, IV insulin should be continued, while an infusion of 5% dextrose in half-normal saline is given at a rate of 100 to 200 mL per hour.

Summary

The management of hospitalized patients with diabetes actually begins before their admission. From a primary care standpoint, physicians should always attempt to identify patients who are at risk for long-term complications related to diabetes. Early intervention in patients at risk for microvascular and macrovascular disease will certainly reduce the morbidity, mortality, and bed days that are equated with the diagnosis of long-standing diabetes.

We must also do our best in educating our patients in every aspect of diabetes management, including home blood glucose monitoring and adherence with both oral agents and insulin therapy. Omission of drugs will lead to higher emergency admission rates for acute complications such as DKA, which is responsible for the majority of deaths in patients with T1DM younger than 24 years. Running out of blood pressure or lipid-lowering medications can increase one's likelihood of having a coronary event or a stroke.

Outcomes of both MI and stroke are dependent on the level of glycemic control the patient is experiencing at the time of admission. Therefore, a patient who is well managed is likely to be discharged from an acute hospital setting quickly and with minimal complications, in comparison to an individual admitted with a stroke and a blood glucose level greater than 280 mg per dL. Patients often tell their physicians that they feel great, no problems

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Patients who are admitted to the hospital for elective procedures should have their diabetes well controlled before undergoing their surgical procedures. Those who are admitted on an emergency basis to an ICU or CCU will have the best long-term outcomes if they are managed to the targeted goals established by the ADA and the American Association of Clinical Endocrinologists (AACE). PCPs should be aware of these strict glycemic guidelines, and, when necessary, a consultation with an endocrinologist for assistance in achieving these blood glucose targets is certainly warranted.

Finally, once the patient is stabilized, focus should be placed on diabetes self-education so that further hospital admissions can be avoided, whenever possible.

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