In-hospital management of type 2 diabetes mellitus

Med Clin N Am 88 (2004) 1085–1105

In-hospital management of type 2 diabetes mellitus Lillian F. Lien, MD*, M. Angelyn Bethel, MD, Mark N. Feinglos, MD, CM Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Box 3921, Durham, NC 27710, USA

The economic burden of type 2 diabetes mellitus and inpatient hospitalization The detrimental effects of diabetes mellitus on quality of life have been well described, but recently, an increasing economic burden has been identified. Hospitalization costs for the diabetic population represent a significant economic impact, and with the increasing prevalence of type 2 diabetes, the importance of minimizing hospital costs is paramount. Studies such as the 1998 pan-European multicenter study, Cost of Diabetes in Europe—type 2 (CODE-2) [1], for example found that the costs for 777 Swedish patients with type 2 diabetes represented approximately 6% of the national total health expenditures in 1997. Furthermore, hospitalizationrelated costs were 42% of the total direct costs, and 25% of the patients were hospitalized at any given time during a 1-year period [1]. Similar findings have been described in the United States. Bhattacharyya and Else [2] studied principal cost drivers in patients with type 2 diabetes in a managed care setting in Honolulu, Hawaii, in 1995 and found that ‘‘hospitalized patients, on average, incur an almost 424% higher medical cost compared with patients with no experience with inpatient care.’’ O’Brien et al [3] studied acute care inpatient profiles in discharge databases from five American states from 1994 to 1995. The average cost per event for a cardiovascular complication such as acute myocardial infarction was $27,630, of which 60% was the result of acute care hospitalization.

Dr. Feinglos has received research support from Aventis Pharmaceuticals, Glaxo-SmithKline, Pfizer Pharmaceuticals, Novartis, and Hoffman La-Roche. * Corresponding author. E-mail address: [email protected] (L.F. Lien). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2004.04.002

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Admitting diagnoses leading to hospitalization in patients with type 2 diabetes The association between type 2 diabetes and cardiovascular disease is well established [4,5]. Erkens et al [6] compiled data from patients with type 2 diabetes over several years throughout six cities in the Netherlands. The risks of cardiovascular drug use and cardiovascular hospitalization were markedly increased in the diabetic patients at the time of initiation of oral antidiabetic therapy versus matched nondiabetic subjects (relative risks 1.28 and 1.54, respectively). In the Scotland database, Donnan et al [7] described a group of patients with type 2, type 1, or no diabetes in 1995. Finished consultant episodes detailing inpatient hospital time spent under the care of a particular specialist were recorded for each patient. Cardiovascular disease was responsible for 27% of the finished consultant episodes in type 2 diabetic patients, whereas the corresponding percentages were 8% and 12% in the type 1 and nondiabetic cohorts, respectively. Additionally, 6% of patients with type 2 diabetes were hospitalized for neurologic complications, compared with 2% in type 1 diabetic patients and 2% in nondiabetic patients. Levetan and Magee [4] note that there are considerable data linking unspecified diabetes to the incidence, morbidity, and mortality of stroke. Moss et al [8] also studied risk factors for hospitalization in the Wisconsin Epidemiologic Study of Diabetic Retinopathy cohort. In the group of participants with ‘‘older-onset’’ diabetes, self-reported reasons for hospitalizations showed a distribution that included heart disease, 7.8%, glycemic control, 3%, stroke, 1.8%, amputation, 1.5%, and renal complications 0.9%. Baseline characteristics of this group also revealed that 39.4% of patients with elevated glycosylated hemoglobin of 10.5% to 18.3% had been hospitalized within the year before the survey, compared with only 20.1% of patients with glycosylated hemoglobin of 5.0% to 7.9%. Higher systolic blood pressure in patients with type 2 diabetes was also associated with increased risk of hospitalization.

Impact of type 2 diabetes on the patient’s hospital course In the Scotland database, the median length of stay was significantly increased in patients who had been diagnosed with type 2 diabetes; nondiabetic patients were hospitalized for 3 days, patients with type 1 diabetes for 3 days, and patients with type 2 diabetes were hospitalized for 7 days (P \ 0.0001) [7]. The mean length of stay in the Swedish CODE-2 study was even longer at 14.8 days [1]. Diabetes has also been shown to affect infection rate and mortality. Yellin et al [9] showed that in a group of 10,863 patients who had cardiovascular surgery with median sternotomy, 280 patients developed deep sternal infection, and a subset of 15 patients experienced major bleeding; the mortality rate for the subset of patients with major bleeding was 53.3%. In

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the authors’ analysis of predisposing risk factors, 13 of the 15 patients with major bleeding had underlying comorbidities, and nine had type 2 diabetes. Likewise, Berger et al [10] showed a significant increase in mortality at 30 days and 1 year for patients with diabetes in a cohort of Medicare beneficiaries hospitalized for acute myocardial infarction in US nonfederal medical centers from 1994 to1996. Donnan et al [11] also demonstrated that patients with type 2 diabetes had a 40% higher death rate after a first acute myocardial infarction, even after adjustment for factors such as age, smoking and hypertension status. Inpatient management: laying the groundwork Education and nursing care The care of a hospitalized patient with diabetes can be particularly challenging for the nursing staff. Many patients with long-standing diabetes are accomplished at managing their disease in the outpatient setting. The loss of control during hospitalization resulting from issues of diet, glucose monitoring, and the medication regimen can be stressful; however, among patients who do not have a thorough understanding of diabetes management, the hospital stay provides an opportunity to improve diabetes education. Unfortunately, the rapid turnover of staff nurses creates a dearth of personnel who are qualified to provide such education. In this setting, the use of a Certified Diabetes Educator has proven beneficial. Feddersen and Lockwood [12] showed that in an experimental group having both patient and nursing staff diabetes education, the mean length of stay for patients on insulin was shortened (10.1  9.1 vs 11.4  8.5 days, P  0.05). Several studies have attempted to demonstrate cost savings resulting from the implementation of specialized diabetes nursing care. A recent trial by Davies et al [13] randomized patients with type 1 or type 2 diabetes either to control or to an intervention group in which a diabetes specialist nurse provided care and advice. The authors found a significant shortening of length of hospital stay in the intervention group (8.0 days vs 11.0 days, respectively). Results also showed a significant improvement in knowledge and satisfaction in the intervention group, although no difference was found in quality of life measures. Levetan et al [14] demonstrated not only the importance of diabetes education but also the value of a multidisciplinary approach to diabetes management. Patients seen by the diabetes team had a significantly lower length of stay than patients seen by an individual consultant or primary physician. In many institutions, the multidisciplinary team approach has become the standard of care. Glycemic goals Although the diagnosis of diabetes is clearly a predictor of poor outcome, hyperglycemia has been shown to be an independent marker of in-hospital

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mortality, even when diabetes is undiagnosed [15]. Glycemic control has been shown to promote white blood cell function and facilitate wound healing [4,16,17]. Improvements in hyperglycemia have also reduced morbidity and mortality. A study of patients with diabetes and acute myocardial infarction randomized the patients to either an insulin–glucose infusion or conventional therapy (control). The patients given insulin– glucose infusion received insulin intravenously (IV) for at least 24 hours, with the goal of reaching normoglycemia, followed by multidose subcutaneous insulin, whereas control patients received insulin only if it was ‘‘clinically indicated.’’ Overall mortality at 1 year was reduced by 30% in the insulin infusion group versus the control [18]. Furthermore, a mortality benefit was still persistent even after a longer-term follow-up period (average 3.4 years) [19]. Furnary et al demonstrated in multiple studies that the use of continuous IV insulin infusion decreases the risk of deep sternal wound infection by 66% and perioperative absolute mortality by 57% [20–22]. Not only has continuous insulin infusion been shown to reduce cardiovascular and perioperative mortality, Van den Berghe et al [23] showed that insulin infusions reduce morbidity and mortality in a general intensive care setting. Patients in intensive care were randomized to one of two groups. One group received intensive insulin therapy by IV insulin infusion initiated for glucose levels exceeding 110 mg/dL, with maintenance values between 80 and 110 mg/dL. The other group underwent conventional treatment and received an insulin infusion only for glucose levels greater than 215 mg/dL, with maintenance values between 180 and 200 mg/dL. The study showed substantial reductions in intensive care unit mortality, inhospital mortality, and morbidity; specifically, intensive care unit mortality was reduced from 8.0% in the conventional group to 4.6% in the intensive group (P  0.04). These studies provide a basis for the recommendation of glycemic goals in the hospitalized patient. For general glycemic goals for people with diabetes, the American Diabetes Association (ADA) recommends a preprandial plasma glucose level between 90 and 130 mg/dL and peak postprandial glucose level of less than 180 mg/dL [24]. In a recent ADA technical review, the Diabetes in Hospitals Writing Committee recommends a preprandial plasma glucose level of less than 110 mg/dL and peak postprandial less than 180 mg/dL for hospital management of hyperglycemia [25]. Management goals The first goal of inpatient diabetes management is safety. In most cases, the medical regimen used in the outpatient setting will need to be modified. Oral hypoglycemic agents may need to be discontinued in favor of scheduled insulin (see later discussion), and insulin requirements may be markedly different. Multiple issues may contribute to the difficulty in attaining

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glycemic control in the hospitalized patient. Hirsch et al [17] have identified variables of erratic insulin absorption, the effects of stress-induced counter-regulatory hormone responses, change in gut motility, and poor coordination of timing of insulin administration and meals. Additionally, medications other than those for treatment of diabetes should be critically reviewed for incompatibility under conditions of any acute illness. Another common safety concern is the occurrence of hypoglycemia during the hospital stay. The possibility of hypoglycemia is increased in the hospitalized patient because of acute illness, erratic caloric intake, poor coordination of insulin dosing with mealtime, and altered consciousness. Hypoglycemia may also be more difficult to detect in the hospital setting. Inquiring if patients have ever had documented hypoglycemia or if they suffer from hypoglycemic unawareness may provide useful information. Many patients with long-standing diabetes are at particular risk for unheralded hypoglycemia. The second inpatient management goal is to achieve control of hyperglycemia. A detailed description of choices for inpatient diabetes management is discussed later. Hospital staff should be especially vigilant for the development of diabetic ketoacidosis (DKA) because the diagnosis of type 2 diabetes does not preclude this possibility. Many patients with long-standing type 2 diabetes may have b-cell exhaustion to a degree that approaches type 1 diabetes. A severe stress in such patients may precipitate the development of DKA. In chronically ill patients, the development of DKA may be particularly insidious because it may present without hyperglycemia. Management of acute hyperglycemia should also entail a search for the underlying cause. In addition to insufficient insulin dosing, other possibilities include infection, dehydration, a cardiac event, medication effects (ie, steroids, epinephrine), and rebound from a previous hypoglycemic episode. Monitoring Bedside glucose monitoring should be performed at least four times daily (ie, before meals and at bedtime for the patient who is eating). A glucose check at 3 AM can also be useful in patients with fasting hyperglycemia because an elevated 3 AM glucose level could indicate insufficient night time insulin dosing, whereas low 3 AM glucose may be indicative of an early peak in PM insulin or insufficient caloric intake at bedtime. Patients with persistent hypoglycemia may require an overall reduction in insulin dose. The patient who is assigned to no oral intake of food or liquid (NPO, ‘‘nothing by mouth’’) or to continuous tube feedings should have glucose levels checked at least every 6 hours. In special circumstances, such as an unusual bolus tube feeding schedule, the timing of the bedside glucose checks should be carefully coordinated with the timing of the feedings.

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Careful monitoring may also detect undiagnosed diabetes. Levetan et al [26] examined a group of patients with documented plasma glucoses greater than 200 mg/dL. After examining hospital notes pertaining to this group, the authors found that two thirds of the inpatients’ daily progress records failed to refer to the possibility of undiagnosed diabetes.

Inpatient insulin administration The administration of insulin to patients with type 2 diabetes is the most common treatment for hyperglycemia in the inpatient setting. The following recommendations address issues pertaining to insulin monotherapy. Subcutaneous insulin Baseline data collection One of the first steps in determining an appropriate insulin regimen for an inpatient with type 2 diabetes consists of gathering important baseline data on the diabetes history, if any. Crucial data items include outpatient insulin or oral agent regimen, dietary habits, usual weight, duration of diabetes, assessment of home glucose control (frequency of glucose monitoring, glucose values, and compliance), frequency and severity of hypoglycemia, and the presence and severity of diabetic complications. Assessment of outpatient compliance may be particularly valuable; the stated outpatient regimen may be excessive in patients who are not regularly taking their medications. For example, a patient who reportedly takes a total of 40 units of subcutaneous insulin twice daily at home but is, in truth, noncompliant could suffer from hypoglycemia if this full regimen is instituted on admission. A history of severe diabetes complications should suggest the possibility of autonomic neuropathy, which can complicate inpatient management of blood glucose and hemodynamic monitoring. Insulin dosing schedule definitions A discussion of insulin dosing requires an understanding of common terminology. ‘‘Standing dose insulin’’ refers to insulin received on a fixed schedule. ‘‘Sliding scale insulin’’ refers to an insulin dose calculated according to the current, measured glucose level and given only on an asneeded basis. (The use of supplemental insulin is preferred to the use of sliding scale insulin alone, as discussed later.) Standing dose insulin regimens Standing-dose regimens use widely varying types of insulin (Table 1) and number of daily injections. Conventional regimens generally require injections once or twice daily. These regimens offer an advantage in convenience and simplicity but lack flexibility and are limited in their ability

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Table 1 Types of insulin formulations Insulin formulations Ultra-short–acting Lispro (Humalog) Aspart (Novolog) Short Acting Regular Long Acting Neutral protamine Hagedorn (NPH) Ultralente Glargine (Lantus)

Onset to peak Duration Appearance Comments 15 min–1 h 15 min–1 h

3–4 h 3–4 h

Clear Clear

30 min–4 h

4–6 h

Clear

1–8 h

12–20 h

Cloudy

3–10 h ‘‘No peak’’

18–24 h 24 h

Cloudy Clearb

Combination insulins Long-acting component 70/30 (regular) 70% NPH NovoLog mix 70/30 70% aspart-protamine suspension 75/25 75% lispro-protamine suspension

Must be taken with food Must be taken with food

Can be mixed, but draw the short acting insulin firsta

The only long-acting insulin that is clearb NPH dose should be cut by approximately 20% when converting to glargine Cannot be mixed with short-acting insulin Short-acting component 30% regular 30% aspart 25% lispro

a The NPH insulin should not be drawn first because contamination of the regular insulin bottle by a needle containing NPH can alter the kinetics of the regular insulin. b Clear. Data from Refs. [28,32,66].

to achieve tight glycemic control [27,28]. Thus, the concept of regimen intensification, arises frequently, albeit temporarily, in the inpatient setting. Various types of insulin are used, but these regimens all require the use of three to four daily injections to achieve tight glycemic control [27]. Regardless of which style of insulin regimen is chosen, the most important governing principle is to individualize the regimen to suit the patient’s unique needs [29]. Determining insulin dose. Calculating a weight-based dosing regimen is appropriate not only for the patient who is newly diagnosed and being initiated to insulin therapy but also for the patient who has an established home regimen that has provided insufficient control in the outpatient setting. Alternatively, patients with adequate home glucose control will likely have similar insulin requirements during hospitalization. Patients with an established history of insulin resistance may require insulin doses in excess of the amount calculated from weight. For patients with type 2 diabetes, the total daily insulin dosage can be estimated at 0.3 to 0.6 units/kg/day. This range reflects varying degrees of

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insulin sensitivity in patients with type 2 diabetes. Patients who are very insulin resistant may require dosages as high as 0.6 to 1.0 units/kg/day [30], whereas a patient who is previously insulin naıı¨ ve may be more sensitive and benefit from a lower starting dosage. After estimating total daily insulin dose, the next step is to determine the frequency of standing dose insulin administration. Several options are available. One injection daily. One daily injection of long-acting insulin is rarely appropriate for diabetes management in the inpatient setting. This regimen is typically used in the outpatient setting. Single daily insulin injections seldom provide adequate glucose control but may be used in combination with oral hypoglycemic agents. Two injections daily. For patients who are eating, the estimated daily insulin dose should be divided into two injections:  Sixty-seven percent (two thirds) of the total daily dosage is administered in the morning, before breakfast.  Of this amount, 67% (two thirds) is given as neutral protamine Hagedorn (NPH) insulin and 33% (one third) as regular insulin.  Thirty-three percent (one third) of the total daily dosage is administered before the evening meal.  Of this evening amount, the dose is divided into 50% NPH and 50% regular. Alternatively, in patients on this regimen with persistent fasting hyperglycemia, the evening amount can be divided into 67% (two thirds) NPH insulin and 33% (one third) regular insulin. A premixed preparation of 70% NPH and 30% regular insulin is available for the patient who has difficulty learning how to mix the insulins. For the patient who can mix insulin, a ‘‘split-mix’’ regimen can provide additional flexibility. In this regimen, the ratio of NPH to regular insulin can be adjusted as needed [28]. For patients who are NPO, all doses of insulin are typically reduced by 50%. Three injections daily. Regimens of three injections are not recommended for patients who are NPO; however, they can be useful in patients who are eating and experience fasting hyperglycemia:  Sixty-seven percent (two thirds) of the total daily dosage is administered before breakfast.  As in two-injection regimens, this amount should consist of approximately 67% (two thirds) NPH insulin and 33% (one third) regular insulin.  Seventeen percent (one sixth) of the total daily dosage is administered as regular insulin before the evening meal.  Seventeen percent (one sixth) of the total daily dosage is administered as NPH before bedtime [28].

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Four injections daily. There are two options for using a four-injection regimen for the patient who is eating. The first option is to use regular insulin and NPH insulin:  Twenty-five percent (one fourth) of the total daily dosage is administered as regular insulin before breakfast, and again before lunch, and again before dinner.  Twenty-five percent (one fourth) of the total daily dosage is administered as NPH insulin before bedtime. For optimal efficacy of the pre-meal regular and bedtime NPH intensive regimens, it is important to consider proper timing of the regular insulin in relation to meals. The most challenging aspect of this regimen in the inpatient setting is to ensure the delivery of regular insulin 30 to 45 minutes before a meal [4,17]. In the patient who is not eating, the total daily insulin dosage is reduced by 50%. Twenty-five percent of the reduced total daily dosage is given as regular insulin every 6 hours. NPH should not be used at bedtime in patients who are NPO for an extended period of time. In the patient who is NPO only overnight (ie, in preparation for a procedure), however, NPH can be given at full dose to prevent fasting hyperglycemia. The second option is to use ultra-short–acting insulin and long-acting, peakless insulin:  Seventeen percent (one sixth) of the total daily dosage is administered as ultra-short acting insulin (eg, lispro or aspart) before breakfast, and again before lunch, and again before dinner.  Fifty percent (half) of the total daily dosage is administered before bedtime as long-acting, peakless insulin (glargine). An alternative method is to use 0.1 units/kg of ultra-short–acting insulin at each meal and 0.3 to 0.7 units/kg of long-acting, peakless insulin at bedtime [29]. Although glargine can be given consistently at any time of the day, it is commonly given at bedtime, in part to prevent the mistake of mixing it with a short-acting insulin [31]. Glargine is maintained at an acidic pH level of 4 to maintain solubility, which is incompatible with other insulin types [32]. Patients who are not eating should not receive ultra-short–acting insulin. These patients can either be converted to regular insulin every 6 hours, as above, or glargine can be used alone. Although there is little evidence to support the use of glargine alone, when used at an appropriate dose, it should not cause fasting hypoglycemia.

Continuous subcutaneous insulin infusion Subcutaneous insulin pump therapy provides a continuous basal dose of insulin, combined with as-needed bolus doses. In the inpatient setting,

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continuous subcutaneous insulin infusion can be continued provided the hospital does not have specific regulations prohibiting patient self administration of medications. For continuous subcutaneous insulin infusion to be continued safely, the patient must be alert and oriented and desire the responsibility of maintaining glucose control. Even when the patient chooses self-management of diabetes, supervision by nursing staff may be necessary to maintain documentation of administered doses. If the patient’s mental status changes during the hospitalization, the insulin regimen should be changed to one of the nurse-administered injection regimens described earlier. Close monitoring of the infusion site for signs of infection is essential [33]. Supplemental insulin Inappropriate use of sliding scale alone. A common misconception is that a sliding scale insulin regimen alone is sufficient for diabetes management. A sliding scale, when used alone, cannot achieve adequate management of hyperglycemia. These regimens react to the presence of hyperglycemia instead of acting to prevent the occurrence of hyperglycemia [17,25,29]. Therefore, by definition, patients using this regimen must reach an unacceptable level of hyperglycemia before receiving insulin. Sliding scale insulin given at meal times alone also provides no coverage at night and, therefore, may result in the development of fasting hyperglycemia. Therefore, a sliding scale regimen should be used only as a supplemental regimen in conjunction with a scheduled insulin dosage [17,25,28,29,34]. Calculating supplemental insulin dose. Supplemental insulin should be administered at meals only (Table 2). The addition of supplemental insulin at bedtime or 3 AM is discouraged because it may cause hypoglycemia. The type of insulin used for the supplement should correspond to the type of short-acting insulin given in the standing dose regimen. A patient receiving standing dose lispro should also receive lispro in the supplement rather than regular insulin.

Table 2 Calculating supplemental insulin dose (The interval of the supplement should be 5% of the total daily scheduled standing dose insulin. The number of dosage units shown in the table are provided based on a patient receiving 100 units of insulin daily.) Plasma glucose (mg/dL)

Supplemental regular insulin

70–200 201–250 251–300 301–350 351–400

Give scheduled insulin Add 5 units to scheduled insulin dose Add 10 units to scheduled insulin dose Add 15 units to scheduled insulin dose Add 20 units and notify on-call physician

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Intravenous insulin Intravenous insulin administration protocols A number of protocols have been developed to assist with titration of IV insulin infusion rates. One of the first published protocols was the Portland protocol described by Furnary et al [20–22]. The need for an IV insulin infusion protocol that addresses individual characteristics of the patient has gradually received further attention by other authors as well [25]. Trence et al [35] published an IV insulin infusion protocol consisting of four algorithms that take into account the patient’s level of insulin sensitivity. Similarly, Lien et al [36] developed an IV insulin nomogram that dictates the rate of change of the insulin infusion according to the rate of change of glucose levels through the novel method of using a multiplication factor obtained from an easily accessed format. This allows an even more individualized approach to patients with varying insulin sensitivity. Implementation of the new nomogram was found to significantly reduce errors in the delivery of IV insulin, which also reduced persistent hyperglycemia in critical care patients [36]. Using intravenous insulin in the inpatient setting Initiation of the insulin infusion. A patient with DKA always requires an insulin infusion. Additionally, even in the absence of DKA, a critically ill patient with unacceptable hyperglycemia for 24 to 48 hours is a candidate for IV insulin, particularly if the hyperglycemia persists despite increasing doses of subcutaneous insulin. Many surgical units now also consider IV insulin to be the treatment of choice in diabetic patients during the perioperative and postoperative period, based on the data for improved rates of morbidity and mortality [18,20,23]. Bedside glucose monitoring should be performed hourly for the patient on IV insulin. Regular insulin is typically used for IV administration. Although ultra-short–acting types of insulin have been given IV, the efficacy and safety in this setting is not well studied. Initial insulin infusion rates differ in insulin resistant and non-insulin resistant states. For the patient in DKA, 0.1 units/ kg/hour is a typical starting rate. For patients not in DKA, insulin at a rate of 0.025 units/kg/hour is a more appropriate initial infusion rate. Discontinuation of the insulin infusion. The method of discontinuation of an insulin infusion is as important as its initiation. One of the most frequently encountered errors is to discontinue the insulin infusion without administration of subcutaneous insulin [36]. Because the half-life of IV insulin is less than 10 minutes, the first dose of subcutaneous insulin must be given 1 hour before discontinuing the insulin infusion. Failure to do so allows the rapid development of hyperglycemia in any patient without sufficient endogenous insulin secretory capacity. Patients with type 1 diabetes or long-standing type 2 diabetes are at particular risk for this complication.

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Several methods are used to transition patients from IV to subcutaneous insulin; however, these practices have not been studied objectively. Typically, some fraction of the 24-hour IV insulin requirement is used as the total daily subcutaneous dosage. Suggestions range from a reduction of 0% to 50%. The choice of insulin dosage depends on several factors: the level of glucose control in the last 24 hours, the level of physiologic stress in the last 24 hours, nutritional status, and pre-hospital insulin regimen, if known. Once the total daily dosage is calculated, it should be divided into four subcutaneous injections and titrated as described above. Management of hypoglycemia Administration of IV dextrose (D50) is the most rapid method of alleviating hypoglycemia and is appropriate for patients who are unconscious, severely symptomatic, or NPO. Patients who are alert and able to eat should be given 15 g of carbohydrate in a rapidly available form (ie, one half cup of fruit juice, 4 oz. of nondiet soda, or 3 glucose tablets [glucose tablet dosages vary depending on the over-the-counter brand. Most contain approximately 4 g of fast-acting carbohydrate per tablet.]). A common error is to over-treat hypoglycemia with an excess of carbohydrate. This, in combination with the counter-regulatory hormone response to hypoglycemia, facilitates subsequent hyperglycemia. After treatment of any hypoglycemic episode, frequent bedside glucose monitoring should be continued until a stable glucose level is assured. Inpatient use of oral agents Value of oral agents for inpatients Oral hypoglycemic agents are another option for inpatient diabetes control. They can be used alone or in combination with insulin [37]. The value of oral agents, however, is limited in the inpatient population by several factors. Severity of illness, planned procedures, and potential complications should be considered when choosing a diabetes management regimen. Patients who are too ill to maintain adequate caloric intake should not be managed with an oral hypoglycemic agent. Likewise, patients who may be NPO because of illness or planned procedures are not appropriate candidates for oral agents. A common error in this population of patients is the discontinuation of oral agents in the absence of an alternate method for diabetes control. These patients should instead be converted to a subcutaneous or IV insulin regimen during hospitalization, as described above. Management with insulin in these circumstances is safer and has the added benefit of increased dosing flexibility when caloric intake is erratic. When oral hypoglycemic therapy is maintained during hospitalization, particular attention must be given to the potential for complications of

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therapy and adverse outcomes. Each class of hypoglycemic agents carries a unique risk and benefit profile in this population. Biguanides Metformin is currently the only biguanide available for use in the United States. This agent acts primarily by reducing hepatic glucose output and increasing peripheral glucose uptake [38]. Metformin is presently considered a first-line agent for treatment of obese patients with type 2 diabetes because it does not promote weight gain and may facilitate weight loss. It has the additional advantage of not causing hypoglycemia. The most feared complication of metformin is the development of lactic acidosis. Lactic acidosis can be classified into two types. Type A is typically caused by marked tissue hypoperfusion with resulting anaerobic production of lactic acid. In contrast, the mechanism of type B lactic acidosis is less well understood. Patients with type B lactic acidosis do not exhibit signs of hypoperfusion. Postulated mechanisms include toxin-induced impairment of cellular metabolism or regional areas of ischemia [39]. Lactic acidosis associated with metformin therapy is of the type B and has been attributed to accumulation of the drug [40]. The actual incidence of lactic acidosis attributable to metformin is unclear. The use of another biguanide, phenformin, was clearly associated with the development of lactic acidosis, and this medication was withdrawn from the market in the late 1970s. Phenformin was estimated to cause an incidence of lactic acidosis of 40 to 64 cases per 100,000 patient-years. In contrast, recent examinations of lactic acidosis attributable to metformin estimate the incidence to be 9 cases per 100,000 patient-years [41]. The incidence of lactic acidosis is presumed to be higher in patients who have conditions predisposing to hypoxia, including renal insufficiency, congestive heart failure requiring medical therapy, cardiovascular collapse, acute myocardial infarction, and septicemia. According to the product labeling, metformin is contraindicated in these patients; and caution should be used in patients older than 80, those with hepatic disease, and in those with chronic obstructive pulmonary disease associated with hypoxemia [42]. However, there are abundant data that demonstrates that metformin is frequently prescribed for patients who have one or more contraindications to its use [43–45]. The impact of this prescribing pattern is difficult to evaluate. In a recent systematic review of 176 prospective and cohort studies [46] (including 17,156 patients taking metformin and 8943 not taking metformin), no cases of lactic acidosis were identified. Within the 164 prospective studies included in the systematic review, 156 cases allowed the inclusion of patients with at least one contraindication, and no adverse effects were observed; however, there was insufficient information to estimate the number of participants having a contraindication. These and other studies have speculated that the association of metformin and lactic

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acidosis may be coincidental rather than causal, but until the drug is studied in this population, the safety of metformin in this setting remains unproven. Concern regarding lactic acidosis and the use of metformin also arises in conjunction with the use of contrast media. Metformin is excreted unchanged in the urine, and, in patients with normal renal function, over 90% of the drug is eliminated within 24 hours. When renal function is impaired, however, metformin accumulates, theoretically increasing the risk of lactic acidosis. The administration of contrast media carries the risk of contrastinduced nephropathy with a peak incidence occurring after approximately 24 to 48 hours. The risk of contrast-induced nephropathy is increased in patients who are volume-depleted and in those with diabetic nephropathy. Although the development of lactic acidosis in this setting is a rare complication, it has been estimated that the incidence of lactic acidosis in diabetic patients receiving metformin and contrast media is 2 cases per million patients per year [47]. Current recommendations are that metformin be stopped before and for 48 hours after contrast administration. Serum creatinine should be followed closely to detect the development of renal insufficiency. Pretreatment with adequate hydration and N-acetylcysteine has also been shown to reduce the risk of contrast-induced nephropathy [48–50]. Sulfonylureas Sulfonylureas act by binding to and closing an ATP-dependent potassium channel (KATP). In the pancreatic b-cell, this binding-closing mechanism results in sustained membrane depolarization, activation of voltage-dependent calcium channels, calcium influx, and migration of insulin-containing vesicles to the cell surface, culminating in insulin release. The most commonly used sulfonylureas in the United States are glyburide, glipizide, and glimepiride. In the inpatient setting, the use of sulfonylurea therapy is limited by the propensity for hypoglycemia. Sulfonylureas should be discontinued in any patient who is NPO. The kinetics of sulfonylureas may be changed with hepatic or renal dysfunction; thus, they should be avoided in patients with significant impairment. Although the morbidity and mortality benefits of intensive glycemic control in the acute setting have been demonstrated, particularly among patients after acute myocardial infarction, the role of sulfonylureas in achieving glucose control is uncertain. In fact, the debate over the safety of sulfonylurea therapy is ongoing in patients with concomitant heart disease. The findings of the University Group Diabetes Program [51] demonstrated excess cardiovascular mortality in a group treated with tolbutamide, compared with groups treated with placebo or insulin. However, subsequent criticism of the University Group Diabetes Program study design and lack of demonstrable risk in other large studies, such as the United Kingdom Prospective Diabetes Study [52] revitalized the use of these agents for diabetes control.

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Recently, the safety of sulfonylureas has again come into question. Further investigation into the phenomenon of ischemic preconditioning raises concern regarding direct effects of sulfonylurea therapy on the myocardium, especially in the setting of acute injury. KATP channels found in the myocardium are similar, although not identical, to those found in the b-cell. When myocardium is subjected in vitro to repeated ischemia before prolonged coronary artery occlusion, it is resistant to infarction. This ‘‘conditioning’’ has been shown to be dependent on the activation of KATP channels [53]. Recent studies using sequential balloon angioplasty to model ischemic preconditioning compared treatment with glyburide and glimepiride [54,55]. Glimepiride binds the pancreatic KATP channel with more affinity than the KATP channel found in myocardium. In patients pretreated with glimepiride or placebo, chest pain scores and ST segment elevations were improved after sequential balloon angioplasty, indicating the presence of ischemic preconditioning. In contrast, glyburide appeared to block ischemic preconditioning, resulting in persistent chest pain and ST segment elevation after sequential balloon inflation. There are no studies assessing the effect of glipizide on ischemic preconditioning. No studies have been designed or powered to address morbidity or mortality endpoints related to the use of sulfonylureas in this setting. It remains unclear whether the surrogate endpoints of chest pain and ST segment elevation will, in fact, correlate with morbidity or mortality. Therefore, given the paucity of data available and the suggestion that glyburide may have unwanted effects, it seems reasonable to avoid glyburide, at least in patients with active coronary artery disease [56]. Thiazolidinediones Thiazolidinediones bind to peroxisome proliferator-activator receptors and enhance peripheral insulin sensitivity through a series of mechanisms resulting in transcription of insulin-responsive genes [57]. Both pioglitazone and rosiglitazone are currently available for use in the United States. Troglitazone, the first thiazolidinedione was removed from the market because of reports of liver failure. Thiazolidinediones should not be used in patients with active liver disease or those with transaminases increased more than 2.5 times normal. If thiazolidinediones are discontinued in the inpatient setting, effects on insulin sensitivity may persist. Therefore, as the drug effect wanes, insulin requirements may increase. The use of thiazolidinediones has been implicated in the exacerbation of fluid retention, a particular concern in patients with congestive heart failure. Although both animal and human studies have demonstrated a beneficial effect of thiazolidinediones on markers of congestive heart failure (ie, increased cardiac output and stroke volume, decreased peripheral vascular resistance, decreased left ventricular cavity dilatation), the contribution of excess edema to worsening heart failure has been more difficult to assess

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[58,59]. A recent cross-sectional examination of Medicare patients with heart failure demonstrated that more than 20% of patients with moderately to severely reduced left ventricular dysfunction were treated with a thiazolidinedione [60]. In one retrospective study of health insurance claims, patients receiving thiazolidinediones had a 12.4% adjusted risk of developing heart failure compared with 8.4% in the control group after 36 months of follow-up [61]. The experience in a specialized heart failure clinic, however, indicates that although 17% of patients using thiazolidinediones experienced significant fluid retention, the fluid was predominately peripheral. Furthermore, fluid retention did not correlate with baseline heart failure severity or the development of worsening heart failure. Only two of the 19 patients with worsening edema attributed to thiazolidinedione therapy had signs of pulmonary edema at the time of drug discontinuation. All patients experienced resolution of peripheral edema after stopping the drug [62]. The mechanism of fluid retention caused by thiazolidinediones is poorly understood, and the clinical benefit of thiazolidinedione therapy in patients with heart failure remains to be seen. Certainly the initiation of thiazolidinedione therapy is not warranted in patients with poorly compensated heart failure, and recent initiation of thiazolidinediones should remain in the differential diagnosis of patients exhibiting worsening heart failure. Although large studies evaluating the safety of thiazolidinedione therapy in patients with heart failure have not been carried out, recent evidence indicates that these medications can be used safely and effectively in patients with stable chronic heart failure if careful monitoring is performed. Other oral hypoglycemic agents Other commonly used oral hypoglycemic agents are the meglitinides (repaglinide, nateglinide) and a-glucosidase inhibitors (acarbose, miglitol). The clinical value of both these classes in the inpatient setting has not been studied. Although the potential for hypoglycemia in both classes is limited, their major role is in modifying postprandial hyperglycemia. Therefore, in hospitalized patients with erratic or absent food intake, there is no clear role for these agents. Patients should have these medications discontinued in favor of a scheduled insulin regimen as described above.

Inpatient management: diet therapy Appropriate nutrition in the hospital is paramount, not only for those patients who rely solely on dietary control of their diabetes but also for any inpatient with diabetes. Although standardized meal patterns based on exchanges have been used, a variety of alternative systems are also available. Particularly useful for the inpatient setting is the consistent carbohydrate diet [25]. In this regimen, the carbohydrate content in each meal is

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reproducible from day to day. However, all three meals should not have identical carbohydrate content [63]. The consistent carbohydrate approach also emphasizes the importance of a mixed meal. Meals consisting solely of carbohydrates, although palatable, may not be tolerated by inactive inpatients. Carbohydrate should be consumed in a balanced meal with protein, fat, and fiber. The patient diagnosed with type 2 diabetes who has been managed by dietary control requires careful attention in the inpatient setting. The stress of acute illness may prompt an intensification of treatment that can be accomplished with either insulin or oral agents, as outlined above. In patients receiving continuous tube feeding, 25% of the total daily insulin dose should be administered as regular insulin every 6 hours. In patients receiving bolus tube feeding, the most important aspect of insulin administration is coordination of the timing of the insulin with the timing of the feeding. Collaboration with the inpatient nutritionist is essential. For example, if a patient is being initiated to bolus feeds, suggest a feeding schedule of every 3 hours to help correspond better with the insulin administered on an every 6-hour schedule.

Discharge planning and follow-up after hospitalization Preparation for discharge is an important component of care for the inpatient with type 2 diabetes, particularly if significant treatment changes have been made. The following items should be considered:  Outpatient regimen. When possible, the final outpatient medication regimen should be initiated at least 24 hours in advance of discharge. Because the patterns of food intake, amount of physical activity, and levels of physiologic stress may change after discharge, it is likely that the regimen will require adjustment [64]. However, evaluating the recommended regimen in a controlled environment may help avoid immediate problems after discharge. This is especially important when the outpatient insulin regimen differs from the inpatient schedule. If an oral agent has been initiated, the patient should be carefully educated about the possibility of hypoglycemia or other common side effects. On discharge, patients with diabetes should have access to a home glucose meter, test strips, lancets, and, if applicable, syringes for insulin. If financial or psychosocial issues are an impediment to adequate diabetes care, a multidisciplinary approach to outpatient planning, including a social service consultation should be initiated early in the hospitalization.  Follow-up care. It is important to identify a health care professional who will assume responsibility for supervising diabetes management. Ideally, this person should be readily available for consultation, as it is likely that the diabetes regimen will change when the patient resumes

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normal activity. Continuity of care is best maintained if this individual receives information regarding changes made to the diabetes regimen during hospitalization.  Education. Any hospitalization is an opportunity to reinforce the principles of diabetes education [65]. Patients should be reminded of proper dietary therapy, the risks and benefits of oral agents and insulin, and proper technique of medication administration. For patients whose ability to follow the treatment regimen is limited, it is especially important to identify a responsible caregiver who should be educated in diabetes management. Patients taking hypoglycemic medications should be counseled to maintain an available supply of glucose gel or tablets in the home or car for treatment of hypoglycemia. For patients at risk of significant hypoglycemia, a Glucagon Emergency Kit (consisting of an intramuscular injection of glucagon for unconscious hypoglycemia) may be useful. However, use of this device requires that the patient have adequate hepatic function and a caregiver to administer the injection. All patients taking hypoglycemic medications should obtain a Medic-Alert bracelet identifying their disease.

Summary Hospital management of the patient with type 2 diabetes poses many challenges but also a unique opportunity to improve glycemic control and patient care. A basic understanding of the goals of inpatient management and glycemic targets is essential. Proper administration of subcutaneous and IV insulin, as well as appropriate use or discontinuation of oral hypoglycemic agents, can reduce the complexity of a patient’s hospital course and potentially reduce overall morbidity and mortality. References [1] Henriksson F, Agardh C, Berne C, Bolinder J, Lonnqvist F, Stenstrom P, et al. Direct medical costs for patients with type 2 diabetes in Sweden. J Intern Med 2000;248:387–96. [2] Bhattacharyya S, Else B. Medical costs of managed care in patients with type 2 diabetes mellitus. Clin Ther 1999;21(12):2131–42. [3] O’Brien J, Shomphe L, Kavanagh P, Raggio G, Caro J. Direct medical costs of complications resulting from type 2 diabetes in the US Diabetes Care 1998;21(7):1122–8. [4] Levetan C, Magee M. Hospital management of diabetes. Endocrinol Metab Clin North Am 2000;29(4):745–70. [5] Jarrett R, Shipley M. Type 2 (non-insulin dependent) diabetes mellitus and cardiovascular disease – putative association via common antecedents; further evidence from the Whitehall Study. Diabetologia 1988;31:737–40. [6] Erkens J, Klungel O, Stolk R, Spoelstra J, Grobbree D, Leufkens H. Cardiovascular drug use and hospitalizations attributable to type 2 diabetes. Diabetes Care 2001;24(8): 1428–32.

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