The future of inpatient diabetes management: glucose as the sixth vital sign

Abstract

Diabetes is an ever increasing health problem in our society. Due to associated small and large vessel conditions, patients with diabetes are two- to four-fold more likely to require hospitalization than nondiabetic individuals. Furthermore, hyperglycemia in hospitalized patients results in increased susceptibility to wound infections, worse outcomes postcardiac and cerebrovascular events, longer hospital length of stay and increased inpatient mortality. Several studies suggest that tight control of glucose levels yields improvement in these factors. Conversely, other studies have suggested increased mortality after tight glucose management, perhaps as a result of an increased incidence of hypoglycemic events. The most reasonable approach to control of hyperglycemia is to normalize glucose levels as much as possible without triggering hypoglycemia. In the hospital, insulin therapy of hyperglycemia is preferred due to the ability to flexibly manage glucose levels without side effects associated with many alternative antidiabetic agents. Due to the increasing burden of inpatient diabetes, and the detrimental effects of both hyper and hypoglycemia, the authors predict that blood–glucose levels will become the sixth vital sign to be frequently monitored in hospitalized patients and controlled in a narrow range. The future is in the use of insulin pumps controlled by continuous glucose monitors. This technology is complex and has not yet become standard. The development of future inpatient diabetes care will depend on adaptation of hospital systems to advance the new technology.

Keywords::

• continuous glucose monitors
• diabetes
• hospital systems
• hyperglycemia
• insulin pumps

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Release date: 1 March 2013; Expiration date: 1 March 2014

Learning objectives

Upon completion of this activity, participants will be able to:

• • Assess the effect of hyperglycemia on clinical outcomes of hospitalized patients

• • Distinguish glycemic targets for hospitalized patients

• • Evaluate the treatment of hyperglycemia among hospitalized patients

• • Analyze the argument for continuous glucose monitoring among hospitalized patients

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Marc Rendell

Professor, Division of Endocrinology, Creighton University School of Medicine; Medical Director, Creighton Diabetes Center, the Rose Salter Medical Research Foundation, Omaha, Nebraska, USA.

Disclosure: Marc Rendell, MD, has disclosed no relevant financial relationships.

Saraswathi Saiprasad

Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA.

Disclosure: Saraswathi Saiprasad, MBBS, MRCP (UK), has disclosed no relevant financial relationships.

Alejandro G Trepp-Carrasco

Endocrinology and Metabolism, Creighton University School of Medicine, Omaha, Nebraska, USA.

Disclosure: Alejandro G Trepp-Carrasco, MD, has disclosed no relevant financial relationships.

Andjela Drincic

Associate Professor, Internal Medicine, Division of Diabetes, Endocrine ;& Metabolism, University of Nebraska School of Medicine, Nebraska Medical Center, Omaha, Nebraska, USA.

Disclosure: Andjela Drincic, MD, has disclosed no relevant financial relationships.

Diabetes affects 8.3% of the US population. Among US residents aged 65 years and older, 10.9 million or 26.9% had diabetes in 2010 [101]. These patients have a two- to four-fold increase in rates of hospitalization [1] due to an increased risk for coronary artery, cerebrovascular and peripheral vascular disease, nephropathy, infection and lower extremity amputations [2]. From 1988 to 2009, the number of annual hospital discharges with diabetes as any-listed diagnosis increased from 2.8 million to nearly 5.5 million [3].

Hyperglycemia worsens clinical outcomes

The mean length of stay (LOS) and mortality for nondiabetic patients with high mean glucose on admission is significantly longer and the short-term mortality is greater compared with those with normoglycemia [4]. Hyperglycemia in hospitalized patients, without previously diagnosed diabetes, occurs with high frequency and is associated with markedly worse clinical outcomes. In a Swedish study of patients admitted with acute myocardial infarction, almost a third of these patients had glucose tolerance tests in the range of diabetes, although they had not been previously diagnosed [5]. In a study of over 250,000 admissions to hospital critical care units, there was a strong correlation between mean glucose levels and mortality, approaching a threefold increase for individuals with glucose values >300 mg/dl [6].

There is a clear association between hyperglycemia and infection [7]. Postoperative wound infections are much more common in hyperglycemic patients for a variety of different surgical procedures including a fourfold increased risk for knee replacement [8] and a twofold increase for surgical site infection after liver transplantation [9]. Among 1090 patients undergoing coronary bypass grafting, of whom 400 had Type 2 diabetes mellitus, high preoperative mean glucose levels were the main risk factor for the development of postoperative infection [10]. Early mortality was higher for the diabetic than for the nondiabetic patients (3 vs 1.7%; p = 0.048). Glucose values greater than 150 mg/dl, whether in diagnosed diabetes patients or in those with no previous diagnosis, were associated with a threefold increased risk for surgical site infection after mastectomy [11] and after cardiothoracic surgery [12].

Multiple studies have shown that mortality is higher for hyperglycemic patients after acute coronary events. In-hospital mortality in 607 patients in the Krakow Registry of Acute Coronary Syndromes correlated strongly with glucose levels, irrespective of a prior diabetes diagnosis [13]. In a different study of 252 acute ST-segment elevation myocardial infarction patients without earlier known diabetes, peak hyperglycemia was an independent predictor of mortality [14]. A comprehensive review of 24 outcome studies of new onset hyperglycemia following acute myocardial infarction showed a significant risk of in-hospital (odds ratio [OR]: 3.62; 95% CI: 3.09–4.24; p < 0.0001), 30-day (OR: 4.81; 95% CI: 2.18–10.61; p < 0.0001) and long-term mortality (OR: 2.02; 95% CI: 1.62–2.51; p < 0.0001) compared with normoglycemic patients [15]. In a systematic review of 14 studies of congestive heart failure following acute myocardial infarction, patients with no prior diabetes diagnosis who had glucose concentrations in or over the range of 6.1–8.0 mmol/l had a 3.9-fold (95% CI: 2.9–5.4) higher risk of death than nondiabetic patients who had lower glucose concentrations [16].

Outpatient hyperglycemia has been shown to increase the incidence of ischemic stroke. In a large collaborative study of nine European cohorts totaling 18,360 individuals, a significantly increased hazard ratio was observed for previously diagnosed diabetes (2.26; 95% CI: 1.51–3.38) and for screen-detected diabetes defined by fasting plasma glucose (1.48; 95% CI: 1.08–2.02) and 2-h postprandial plasma glucose (1.60; 95% CI: 1.18–2.16) [17]. Hyperglycemia also predicts worse clinical outcomes for strokes. Among 447 consecutive patients with acute ischemic stroke, patients with hyperglycemia exhibited significantly greater stroke severity (p = 0.002) and greater functional impairment (p = 0.004) than those with normoglycemia [18], and these patients were 2.3-times more likely to be dead at 90 days compared with those with normal glucose (p < 0.001). In a study of 138 consecutive stroke patients with a documented middle cerebral artery occlusion, admission glucose level >140 mg/dl independently predicted poor outcome at 3-month follow-up [19].

The overwhelming evidence that hyperglycemia has a major deleterious influence on critically ill hospitalized patients has been duly documented by the American Diabetes Association (ADA), the American Association of Clinical Endocrinologists (AACE) and the Endocrine Society [1,20,21]. These groups have all issued guidelines addressing present day inpatient management of hyperglycemic patients. The guidelines represent a compromise between aggressive normalization of glycemic levels (‘tight control’) and a less vigorous approach.

The case for tight glucose control in the hospital

Several studies have shown that aggressive glycemic control leads to improved clinical outcomes. The DIGAMI study compared intensive insulin therapy of hyperglycemic myocardial infarction patients to conventional treatment. They found that reduction of mean glucose levels to 170 mg/dl resulted in a 28% reduction in mortality compared with patients with a mean glucose level of 211 mg/dl [22]. In a Belgian study by Van den Berghe et al., 1548 patients in surgical intensive care were randomized to intravenous (iv.) insulin therapy and a target glucose of 80–110 mg/dl or conventional therapy with a target glucose between 180 and 200 mg/dl [23]. Patients randomized to intensive insulin therapy had a 40% reduction in intensive care unit (ICU) mortality, overall hospital mortality (34%), sepsis (46%), need for dialysis (41%) and transfusion rates (50%). The lower mortality rate was attributed mainly to patients whose ICU stay was longer than 5 days. In the Portland Study of almost 5000 patients with diabetes who underwent an open-heart surgical procedure, increasing blood glucose (BG) levels were found to be directly associated with increasing rates of death, deep sternal wound infections, mortality, LOS and hospital cost; continuous iv. insulin therapy, targeted to BG levels less than 150 mg/dl, reduced the risk of death by 57% and that of wound infections by 66% [24].

The case against tight glucose control in the hospital

The success of the DIGAMI study, the Portland Study and the first Van den Berghe study led to a confirmatory study, which was also led by Van den Berghe, and carried on in medical ICUs [25]. This time, the results were less clear cut; overall mortality was not improved by intensive insulin therapy. Those patients in the ICU for 3 days or more did have lower in-hospital mortality rates as well as lower rates of kidney injury, mechanical ventilation and duration of ICU stay, but more deaths occurred in the intensive insulin treatment group among patients whose ICU stay was less than 3 days.

These findings were amplified by the results of the NICE Sugar study, comparing ICU patients on intensive-glucose control with a target BG range of 81–108 mg/dl (4.5–6.0 mmol/l) to those on conventional-glucose control with a target of 180 mg or less per deciliter (10.0 mmol or less per liter) [26]. After 90-day follow-up, 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group had died (OR for intensive control: 1.14; 95% CI: 1.02–1.28; p = 0.02). This unfavorable outcome did not differ between surgical and nonsurgical cases. Nor was there any advantage in LOS in the ICU or the hospital, days on mechanical ventilation, or on need for dialysis.

It is not clear why these landmark studies of the effect of intensive treatment of in-hospital hyperglycemia have given such discrepant results. The one unifying theme appears to be the much higher incidence of hypoglycemia in the intensively treated subjects. In the second Van den Berghe study, hypoglycemia was considerably more common among intensively controlled patients than among conventionally controlled patients in the surgical ICU (5.2 vs 0.7%) and medical ICU (18.7 vs 3.1%) [25]. In the NICE trial, severe hypoglycemic reactions were recorded in 6.8% of the intensively treated patients versus only 0.5% of the conventionally treated group [26]. Hypoglycemia appears to be significantly detrimental to the older population. It is unclear if hypoglycemia is a marker of severe illness due to serious comorbidities such as sepsis or hepatic and renal failure or if it is a direct cause of adverse outcomes. Several recent studies that have controlled for these comorbidities or segregated the analysis based on spontaneous versus iatrogenic hypoglycemia appeared reassuring because they demonstrated no association between iatrogenic hypoglycemia and mortality [27–29].

However, in the ACCORD study, a benchmark long-term outpatient trial, intensive treatment was associated with a 2.5-fold increase in hypoglycemic events [30,31]. The ACCORD trial was terminated due to increased cardiovascular mortality in the intensively treated groups, possibly related to the unfavorable effect of hypoglycemia in susceptible patients such as those with underlying coronary disease. In a recent meta-analysis by Griesdale et al. of 26 trials that reported mortality, the pooled relative risk of death with intensive insulin therapy compared with conventional therapy was 0.93 (95% CI: 0.83–1.04), but among the 14 trials that reported hypoglycemia, the pooled relative risk with intensive insulin therapy was 6.0 (95% CI: 4.5–8.0) [32].

Goals for management of inpatient hyperglycemia

In light of the conflicting results of the major trials of intensive in-hospital management of diabetes, it was logical to propose that the goal should be to normalize glycemic levels while avoiding hypoglycemia [33]. The evidence favoring tight glycemic control in patients on general medical and surgical wards is not as strong as that for critically ill patients [34–36].

Current guidelines from the Endocrine Society, ADA and the AACE recommend a pre-meal glucose target of 140 mg/dl (<7.8 mmol/l) for the majority of hospitalized patients with noncritical illness, in conjunction with random BG values <180 mg/dl (<10.0 mmol/l), as long as these targets can be safely achieved [1,20,21]. In order to avoid hypoglycemia, readjustments in the insulin regimen are considered if BG levels decline below 100 mg/dl (5.6 mmol/l). When BG levels are <70 mg/dl, modification of the regimen is necessary, unless an easy explanation can be found (such as a missed meal). In terminally ill patients or patients with limited life expectancy, slightly higher glucose ranges are acceptable (<200 mg/dl or 11.1 mmol/l). The ADA/AACE Practice Guideline also recommends maintaining a glucose level of 140–180 mg/dl (7.8–10.0 mmol/l) for critically ill patients in the ICU setting. Although strong evidence is lacking, they suggest somewhat lower glucose targets may be appropriate in selected patients. Targets less than 110 mg/dl (6.1 mmol/l), however, are not recommended [20]. Pregnant patients are targeted to a premeal glucose of less than 100 mg/dl and 1-h postprandial glucose of less than 120 mg/dl (AACE); a level of 100 mg/dl is preferred for those in labor and delivery [20].

Glucose as the sixth vital sign

Traditionally, the parameters considered ‘vital’ for frequent hospital observation include pulse, blood pressure, temperature and respiration. Recently, pulse oximetry has become a commonly used procedure to monitor vascular oxygen levels. In light of the importance of hyperglycemia as an agent of deleterious hospital outcomes and the recognized risks of hypoglycemia in vulnerable patients, the authors propose that glucose be added to the spectrum of closely monitored functions as the ‘sixth vital sign’.

Present day attempts to achieve inpatient glucose targets

Control of glucose levels in the hospital to meet the guidelines is difficult for a number of reasons. Diabetes is a chronic disease which responds to a controlled standard regimen. This means a daily repetitive routine, particularly related to meal planning. Hospitalization is the antithesis of a controlled situation. In our era, patients are hospitalized primarily for acute events. They undergo diagnostic and surgical procedures which require a prolonged fasting state. The patient’s diabetes therapeutic regimen is disrupted by the illness and the performance of diagnostic procedures which typically interfere with the customary meal plan [37].

Insulin resistance

Insulin resistance is a major problem in hospitalized patients [38]. Certainly, obesity is an insulin-resistant state, and over 30% of the US population and a much higher percentage of diabetic patients are obese [39–41]. Glucocorticoid therapy is often used in acute situations in the hospital and markedly increases the insulin requirement [42,43]. Hyperalimentation, either intravenous or by the enteric route, is typically accompanied by substantial glucose elevation [44,45], which is associated with poor outcomes and increased mortality [46,47]. Pregnancy is an insulin-resistant state [48,49]. Insulin requirements usually triple by the third trimester and remain elevated until delivery [50–52].

The stress of severe illness leads to the secretion of counter-regulatory hormones including cortisol, epinephrine and glucagon, and inflammatory peptides which worsen insulin resistance and promote hyperglycemia [53–56].

The changes in glucose levels which occur in hospitalized patients are best managed with insulin therapy. Oral hypoglycemics have disadvantages in the rapidly changing hospital situation. Currently used sulfonylureas have a long duration of action which creates a significant risk of hypoglycemia in patients who may not be eating [57]. Meglitinides have a shorter duration of action but must be given at time of meals, often impractical in hospitalized patients with erratic oral intake [58]. Metformin carries a risk of lactic acidosis, and is contraindicated in patients with renal failure, severe liver disease and congestive heart failure as well as in those who are receiving radioiodinated contrast agents, and it is relatively contraindicated in very elderly patients, all clinical situations which are quite common in the hospital. The overall use of thiazolidinediones has decreased due to a succession of unfavorable findings including weight gain, lower extremity edema, bone loss and fractures, and, most recently, a risk of bladder cancer with pioglitazone [59,60]. Both medications now carry a US FDA black box warning after multiple studies have confirmed that they increase the risk of heart failure and related adverse events [61].

Experience with exenatide and liraglutide, the currently available glucagon-like peptide-1 (GLP-1) mimetics, and the dipeptidyl peptidase-4 inhibitors, is very limited in the inpatient setting [62]. Because the GLP-1 agents can cause nausea and vomiting, confounding the picture in critical illness, they typically should be discontinued upon hospital admission as should the α-glucosidase inhibitors acarbose and miglitol. Although the dipeptidyl peptidase-4 inhibitors do not have major gastrointestinal side effects and have a much lower incidence of associated hypoglycemia than the sulfonylureas, they have fairly limited effect on glucose levels.

Inpatient insulin therapy

Exogenous insulin treatment is the most effective means of controlling glucose levels in rapidly changing situations due to the ability to imitate physiologic insulin release. In nondiabetic individuals who are in the fasting state, insulin is released continuously into the portal venous system from the normal pancreas at a fairly constant ‘basal’ level [63]. With ingestion of a meal, there is a surge of insulin secretion, triggered by neural and hormonal stimuli, which include GLP-1. This surge raises insulin levels many fold over the basal level to prevent post prandial hyperglycemia [64]. As BG levels fall after the meal is completed, insulin levels rapidly fall back to the basal level, usually within 2 h [64]. The challenge in managing diabetes is to mimic this exquisitely controlled physiologic servomechanism with exogenous insulin.

At this point in time, hospital insulin management is provided either by continuous intravenous infusions of insulin or by periodic injections of basal insulin and short acting insulin at meals. iv. insulin infusion is the quickest way to introduce insulin into the circulation and the most controllable form of insulin delivery due to the short half-life of venous insulin. As long as caloric intake is constant, iv. insulin infusions can be easily regulated to control glucose levels. Typically, patients who are not eating, such as perioperative and critically ill patients, and pregnant women in labor are best managed with iv. insulin. There are a number of well-documented and effective iv. insulin algorithms which are useful in treating such patients [65–69].

Standardization of iv. insulin therapy improves the efficiency and safety of glycemic control in critically ill adults [70]. In the present era, adjustment of intravenous infusion rates is performed based on hourly fingerstick measurements. The disadvantage of iv. insulin infusion is that there is currently no automatic feedback regulation of intravenous infusion rate as a function of BG. A typical meal contains 100–200 g of carbohydrate convertible to glucose. The whole body water content of glucose is only approximately 50 g while intravascular glucose content is only approximately 5 g. It is remarkable that glucoregulation by the normal pancreas can suppress the surge caused by such a large exogenous glucose load at mealtime. Conversely, intravenous infusion at a constant rate does not supply prandial insulin peaks. Thus, iv. insulin infusion can be used to provide a basal insulin level but not a meal peak. Nor can iv. insulin boluses be used to treat postprandial hyperglycemia because of the short half-life of iv. insulin [71]. Therefore, iv. insulin infusion is reserved for inpatient management of patients with relatively constant caloric ingestion, such as those either fasting or on hyperalimentation. Enteral and parenteral hyperalimentation pose a significant challenge. Usually, the composition of the feedings is very high in glucose. The quick absorption of high glucose concentrations results in substantial hyperglycemia which is hard to combat, even with very large doses of insulin [72]. There are many strategies used to deal with hyperalimentation. Short-acting insulin can be added to intravenous and central hyperalimentation solutions, but, usually, separately run iv. insulin must be used to obtain the flexibility of response required to deal with rapidly changing conditions. In patients who are likely to receive long-term continuous hyperalimentation, subcutaneous long-acting insulin is effective. Once a stable caloric regimen is established, it is relatively easy to control glucose levels with 12-hourly shots of glargine insulin or detemir, provided that there are no interruptions in the feeding routine [73,74].

The authors typically must rely on very high doses of insulin to treat the often extreme hyperglycemia which occurs in insulin resistant states. When it is necessary to rapidly lower glucose levels, iv. insulin is the most useful tool. In patients with chronic insulin resistance, high basal insulin doses, often surpassing 200 units per 24 h, are used. There is a significant risk of hypoglycemia when an insulin resistant state suddenly disappears. An unfortunate example is ‘turnoff hypoglycemia’ which occurs when hyperalimentation is suddenly interrupted in Type 2 patients who may have significant endogenous insulin production [75,76]. This problem can be mitigated by close communication to alert various team members that a decision to stop hyperalimentation is imminent. The insulin resistant state of pregnancy ceases abruptly upon delivery of the placenta as a result of cessation of human placental lactogen release. Here again, an iv. insulin drip is the ideal method to manage insulin requirements during the delivery, since it can be quickly interrupted. Another example is the rapid decrease in insulin resistance which follows gastric bypass surgery in the morbidly obese [77].

For inpatients who are receiving periodic meals, typically on general medical and surgical wards, current day practice is to use a long-acting insulin such as glargine to provide basal insulin levels and premeal subcutaneous boluses of rapid-acting insulin such as glulisine, lispro or aspart to provide meal peak insulin. There are countless variations of these regimens, depending on experience and personal preference. Because inpatient conditions are rapidly changing, the authors prefer not to use insulin glargine as a single 24-hourly dose, rather utilizing 12-h doses in order to respond to patient status changes over a 24-h period. There is no evidence that glargine is superior to detemir insulin, or, in fact, neutral protein hagedorn (NPH) insulin to provide basal insulin coverage. Detemir and glargine are relatively peakless insulins. When we use NPH, we tend to order it more frequently, three- or four-times daily, in order to achieve overlap of NPH insulin peaks [78]. When estimating the 24-h basal insulin dose, we prefer to initially dose below the estimated requirement and increase at each subsequent injection until we achieve an optimal dosage without triggering hypoglycemic episodes. iv. insulin infusion is a temporary measure; for critically ill or postsurgical patients receiving iv. insulin, it is important to begin a subcutaneous basal insulin as soon as possible during the intravenous infusion period, even at a low level such as 0.1–0.2 units/kg. Discontinuation of iv. insulin leads to almost immediate reduction of plasma insulin levels due to the short half-life of circulating insulin. Titration of the appropriate dose of basal insulin, typically starting from low doses with periodic increases, can be performed while using iv. insulin to control hyperglycemia. iv. insulin can be discontinued safely if we are achieving acceptable glucose control with basal subcutaneous insulin.

In the past and, unfortunately, sometimes in the present, physicians may discontinue basal insulin and rely solely on short-acting insulin titrated on the basis of BG. This time-honored approach of ‘sliding scale insulin’ has been justifiably criticized as chasing BG levels and setting up perturbations ranging from very high glucose levels down to hypoglycemia [79]. The concept of ‘sliding scale insulin’ is flawed only in the failure to provide adequate doses of basal insulin. The use of short-acting insulin boluses to modulate glucose levels is quite appropriate and continues today in the practice known as ‘correctional insulin’. This technique is based upon measurement of BG at 2 h or preferably 1 h after meal consumption with addition of a small bolus dose of rapid-acting insulin if levels exceed certain parameters. Furthermore, adjustment of premeal short-acting insulin doses by accounting for carbohydrate intake as well as fingerstick glucose values significantly improves the estimation of short-acting insulin requirements [80].

Measuring glucose as the sixth vital sign

At the present time, fingerstick glucose levels remain the standard of care. However, outside the hospital, our most effective present day techniques in ambulatory patients use continuous glucose monitors to measure interstitial cutaneous glucose levels [81]. The devices allow for a disposable minipump to be placed on the skin surface, measuring interstitial glucose enzymatically and transmitting signals for display to a central unit [82,83]. There is a lag phase between interstitial fluid glucose levels and plasma glucose which must be projected in order to more accurately predict the effect of meals on BG [84].

The authors anticipate rapid evolution of interstitial glucose monitors to soon provide continuous recording for instantaneous evaluation in hospital. Undoubtedly, this technique will first take hold in critical care units, but it is expected that with continued development, continuous glucose monitoring (CGM) will become as generally used as continuous electrocardiographic monitoring is today. At the same time, the most effective technique of insulin administration to improve glucose levels and avoid hypoglycemia is by use of subcutaneous insulin infusion pumps [85,86]. It is certainly plausible that with continued evolution of CGM, we may be able to reduce the incidence of hypoglycemia which has currently blocked the aggressive normalization of plasma glucose levels. Coupled with continuous glucose measurements, the use of insulin pumps, either via intravenous or subcutaneous delivery, will make it possible to come much closer to the goal of normalization of blood sugar levels without increasing the risk of hypoglycemia.

There have been several studies to introduce inpatient subcutaneous insulin pumps and continuous glucose monitors into the hospital setting [87,88]. These are complex techniques which require experience and competence in using the devices. Considerable training is necessary to avoid errors. Individuals whose diabetes is being treated in the outpatient setting via an insulin pump often wish to maintain this therapy during hospitalization. They do not necessarily have to discontinue treatment while hospitalized [89]. However, significant training of the hospital staff is required since management of glucose levels is being transferred to the patient, and errors can occur [90]. The availability of hospital personnel with expertise in continuous subcutaneous insulin infusion therapy is essential [91]. The Endocrine Society appointed a Task Force to determine settings where patients are most likely to benefit from the use of CGM. They recommended against the use of real-time CGM alone, without corroborative testing, for glucose management in the ICU or operating room until further studies provide sufficient evidence for its accuracy and safety in those settings [92].

Challenges to diabetes management in the hospital

The importance of management of diabetes patients is well understood. The advancing technology of glucose monitoring and feedback controlled insulin infusion holds out great hope for improvement. However, it must also be recognized that the care of diabetes patients represents an organizational challenge to hospital functions. The hospital is a complex administrative entitity where care is delivered simultaneously by numerous providers with different areas of emphasis and concerns. There is a hierarchical system of care delivery with physicians delegating care to many different staff with varying levels of expertise, and there are ever changing patient and institutional priorities. Care patterns are multidimensional with frequent transfers of care among multidisciplinary teams. In this dynamic setting, with so many different providers, standardization of care is essential. For example, standardized insulin protocols which cover iv. insulin delivery as well as standard basal and premeal insulin routines have been shown to provide benefit [93–95]. However, the adoption of standardized insulin protocols is not a guarantee of success unless other barriers to glycemic control are addressed. Obstacles can be knowledge based (those related to lack of understanding of principles of insulin therapy among providers and support staff), attitudes (buying into the concept of a need to maintain strict glucose control, while dealing with the fear of hypoglycemia), and system issues inherent to any complex organization where multiple teams are involved in the care of one patient with different providers impacting glycemic control. For example, there may be contradictions when one physician is writing insulin orders, another is prescribing glucocorticoids, and a third is implementing parenteral nutrition. Frequent transfers of care among provider teams and interruption of nutrition for diagnostic testing disrupts attempts to stabilize glycemic levels.

One of the key vulnerabilities of hospitalized patients is failure of continuity of care upon hospital discharge [96]. Many patients are first diagnosed with diabetes upon admission to the hospital. In addition to dealing with an acute illness, they must begin a process of learning how to self-manage their own illness. In a short time, teaching must proceed, focusing on diet, glucose monitoring, recognizing hypoglycemia, proper foot care, ketone testing, sick days, use of diabetes medications and insulin. This requires a considerable commitment from diabetes educators. The most important element of discharge planning for the diabetic patient is to arrange adequate follow-up care. Here, coordination of care becomes critical. Items as simple as providing adequate diabetes management supplies until the first outpatient visit can prove a stumbling block to adequate care. The use of advanced technology in the inpatient setting can make transition to outpatient care even more difficult.

As the technology of in-hospital diabetes management progresses toward insulin pumps controlled by continuous glucose monitors, the need for an administrative infrastructure to pursue care of diabetic patients becomes ever more clear. Maynard et al. proposed a Hospital Diabetes Steering Committee consisting of a multidisciplinary team with representation from all the departments playing a role [94]. This team would be charged to identify best diabetes care practices, help choose the protocols that best fit the particular institutional culture and promote staff education and implementation of the protocols. Monitoring of outcomes is integral to this process. This includes obtaining measures of consistency of protocol use, hypoglycemic and hyperglycemic events, degree of overall glycemic control as well as provider and patient satisfaction with the care approaches. Effective adoption of protocols for glucose control is not possible without hospital commitment and resource allocation. There is a need for an officially sanctioned program, with a director, preferably an endocrinologist, and multiple diabetes educators to provide education and guidance to floor nurses. As the approach moves toward CGM and insulin pump infusion, the skills required will also evolve. Bioengineers and information systems specialists will be needed to more frequently assess function of this complex equipment and correct problems. At the same time, it will be a challenge to merge these professionals with the traditional clinical providers in a hospital setting. The very different training of these individuals will require a management approach to enhance collaboration and sharing of knowledge.

There is a large financial investment required from the hospital to provide salaries for the very labor intensive processes of diabetes management. At a time of shrinking health care budgets, it is difficult to make the necessary allocations. Economic arguments must be made, pointing out that effective diabetes management prevents expensive adverse outcomes, including hypoglycemia, and ultimately reduces LOS for diabetes patients [97]. As we argue that glucose is the sixth vital sign, we must be efficient in dealing with the direct and indirect costs of CGM and insulin infusion. Insulin pumps cost over US$6000. Glucose monitors add US$1000, and the cost of glucose sensors is about US$5.00 daily, but the highest cost is related to the need for highly trained nurses and technicians to use and monitor the devices. Furthermore, patients who are newly managed with insulin pumps and sensors will need significant training, if they are to be discharged with these new modalities.

Expert commentary

With the increasing prevalence of diabetes in our society and the high frequency of serious illness in diabetic patients, there is a preponderant increase in hospital care for these patients. Hyperglycemia is associated with deleterious effects and increased mortality in hospitalized patients. There is strong evidence that normalization of glucose levels is beneficial in reducing surgical wound infections, sepsis, need for dialysis, LOS and in-hospital mortality, but only if hypoglycemic events can be avoided. The administration of insulin is the primary technique to control glucose levels in hospitalized diabetes patients. Adjustment of insulin dosages is based on knowledge of BG levels. The methodology to monitor continuous glucose levels exists but has not yet become standard in-hospital settings. The intricacy of CGM and insulin pumps constitutes a present day obstacle to the routine use of these devices. However, the currently unfulfilled promise of this technology is that we may be able to obtain the demonstrated benefits of normoglycemia without the unfavorable effects of hypoglycemia. Hospitals are complex organizations, with many different providers and care protocols. Cost constraints on medical care create significant obstacles to implementation of systematic protocols to deal with inpatient hyperglycemia.

Five-year view

No one can deny the importance of inpatient control of hyperglycemia. The benefits of normalization of plasma glucose are clear, but counterbalanced by the risks of hypoglycemia. The expense of management of the ‘sixth vital sign’ is considerable and has slowed the evolution to the needed techniques to establish glycemic control. The technology to do so exists today and is used frequently in ambulatory patients, who are alerted to hypoglycemia and receive instant feedback of estimated plasma glucose, by which they adjust the administration of insulin via their insulin pumps. There is no technological limitation which prevents the deployment of similar technology in the inpatient setting. In fact, we expect rapid progress in improving both interstitial glucose monitoring devices and insulin pump administration. These advances in outpatient management of diabetes using insulin pumps and glucose sensors are inevitable and will drive the progression of glucose management in the hospital setting. We predict that there will be rapid advancement toward integrated hospital systems to monitor and control glucose. At present, patients in intensive care are monitored with units which periodically measure blood pressure and pulse, temperature and oxygenation. Electrocardiographic monitoring is continuous with alerts for arrythmias. Similarly, there will be a progression in hospitals to CGM using interstitial glucose analyzers. The next great advance will be communication between the glucose monitor and the insulin pump to allow glucose values to modulate pump insulin delivery. At present, when there is no oral intake, management of glucose values is not difficult. It is the rise in glucose levels which follows eating which makes it so difficult to regulate diabetes. With CGM, we expect that algorithmic control of insulin delivery will eventually allow smooth control of glycemic levels in hospitalized patients with much less involvement of floor nurses than exists today. When the technology of feedback regulated control of insulin administration by BG has been fully developed, we should finally be able to realize the full benefits of normalization of glucose levels for hospital inpatients.

Key issues

• • Patients with diabetes are two- to four-fold more likely to require hospitalization than nondiabetic individuals.

• • Hyperglycemia in hospitalized patients results in increased susceptibility to postoperative wound infections, worse outcomes post cardiac and cerebrovascular events, longer hospital length of stay and increased inpatient mortality.

• • Several studies show that normalization of glucose levels results in decreased wound infections, sepsis, renal failure, length of stay and mortality.

• • Conversely, a number of studies of intensive in-hospital glucose control have resulted in no improvement or even increased mortality.

• • Hypoglycemia in adult patients with cardiovascular risk factors may contribute to mortality in this population.

• • Our current approach is limited by the feasibility of normalizing glucose levels while avoiding hypoglycemia. This goal is difficult to achieve in the rapidly moving acute care hospital situation.

• • We propose that glucose measurement become the ‘sixth vital sign’ in the hospital, coupled with pulse, blood pressure, respirations, temperature and oxygen concentration.

• • The technology to normalize glucose levels exists today and is quickly evolving: insulin pumps and continuous glucose monitors.

• • We foresee that hospitalized patients with diabetes will be managed, at least acutely, with continuous glucose monitoring and insulin administration by infusion pumps.

• • The approach to in-hospital glucose normalization will require significant administrative cooperation and resource utilization.

References

• Garber AJ, Moghissi ES, Bransome ED Jr et al.; American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr. Pract. 10(Suppl. 2), 4–9 (2004).
   PubMedGoogle Scholar
• Clement S, Braithwaite SS, Magee MF et al.; American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 27(2), 553–591 (2004).
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. Economic costs of diabetes in the US in 2007. Diabetes Care 31(3), 596–615 (2008).
   PubMed Web of Science ®Google Scholar
• Evans NR, Dhatariya KK. Assessing the relationship between admission glucose levels, subsequent length of hospital stay, readmission and mortality. Clin. Med. 12(2), 137–139 (2012).
   Web of Science ®Google Scholar
• Norhammar A, Tenerz A, Nilsson G et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 359(9324), 2140–2144 (2002).
   PubMed Web of Science ®Google Scholar
• Falciglia M, Freyberg RW, Almenoff PL, D’Alessio DA, Render ML. Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis. Crit. Care Med. 37(12), 3001–3009 (2009).
   PubMed Web of Science ®Google Scholar
• Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N. Engl. J. Med. 341(25), 1906–1912 (1999).
   PubMedGoogle Scholar
• Jämsen E, Nevalainen P, Kalliovalkama J, Moilanen T. Preoperative hyperglycemia predicts infected total knee replacement. Eur. J. Intern. Med. 21(3), 196–201 (2010).
   PubMed Web of Science ®Google Scholar
• Park C, Hsu C, Neelakanta G et al. Severe intraoperative hyperglycemia is independently associated with surgical site infection after liver transplantation. Transplantation 87(7), 1031–1036 (2009).
   PubMedGoogle Scholar
• Guvener M, Pasaoglu I, Demircin M, Oc M. Perioperative hyperglycemia is a strong correlate of postoperative infection in Type II diabetic patients after coronary artery bypass grafting. Endocr. J. 49(5), 531–537 (2002).
   PubMed Web of Science ®Google Scholar
• Vilar-Compte D, Alvarez de Iturbe I, Martín-Onraet A, Pérez-Amador M, Sánchez-Hernández C, Volkow P. Hyperglycemia as a risk factor for surgical site infections in patients undergoing mastectomy. Am. J. Infect. Control 36(3), 192–198 (2008).
   Web of Science ®Google Scholar
• Latham R, Lancaster AD, Covington JF, Pirolo JS, Thomas CS Jr. The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Infect. Control Hosp. Epidemiol. 22(10), 607–612 (2001).
   PubMed Web of Science ®Google Scholar
• Bolk J, van der Ploeg T, Cornel JH, Arnold AE, Sepers J, Umans VA. Impaired glucose metabolism predicts mortality after a myocardial infarction. Int. J. Cardiol. 79(2–3), 207–214 (2001).
   PubMedGoogle Scholar
• Lazzeri C, Valente S, Chiostri M, Picariello C, Gensini GF. In-hospital peak glycemia and prognosis in STEMI patients without earlier known diabetes. Eur. J. Cardiovasc. Prev. Rehabil. 17(4), 419–423 (2010).
   Google Scholar
• Angeli F, Verdecchia P, Karthikeyan G et al. New-onset hyperglycemia and acute coronary syndrome: a systematic overview and meta-analysis. Curr. Diabetes Rev. 6(2), 102–110 (2010).
   Google Scholar
• Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 355(9206), 773–778 (2000).
   PubMed Web of Science ®Google Scholar
• Hyvärinen M, Tuomilehto J, Mähönen M et al.; DECODE Study Group. Hyperglycemia and incidence of ischemic and hemorrhagic stroke-comparison between fasting and 2-hour glucose criteria. Stroke 40(5), 1633–1637 (2009).
   PubMed Web of Science ®Google Scholar
• Stead LG, Gilmore RM, Bellolio MF et al. Hyperglycemia as an independent predictor of worse outcome in non-diabetic patients presenting with acute ischemic stroke. Neurocrit. Care 10(2), 181–186 (2009).
   PubMed Web of Science ®Google Scholar
• Alvarez-Sabín J, Molina CA, Ribó M et al. Impact of admission hyperglycemia on stroke outcome after thrombolysis: risk stratification in relation to time to reperfusion. Stroke. 35(11), 2493–2498 (2004).
   PubMed Web of Science ®Google Scholar
• Moghissi ES, Korytkowski MT, DiNardo M et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 32(6), 1119–1131 (2009).
   PubMed Web of Science ®Google Scholar
• Umpierrez GE, Hellman R, Korytkowski MT et al.; Endocrine Society. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 97(1), 16–38 (2012).
   PubMed Web of Science ®Google Scholar
• Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 314(7093), 1512–1515 (1997).
   PubMed Web of Science ®Google Scholar
• Van den Berghe G, Wouters PJ, Bouillon R et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit. Care Med. 31(2), 359–366 (2003).
   PubMed Web of Science ®Google Scholar
• Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr. Pract. 10(Suppl. 2), 21–33 (2004).
   PubMedGoogle Scholar
• Van den Berghe G, Wilmer A, Hermans G et al. Intensive insulin therapy in the medical ICU. N. Engl. J. Med. 354(5), 449–461 (2006).
   PubMed Web of Science ®Google Scholar
• Finfer S, Chittock DR, Su SY et al.; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N. Engl. J. Med. 360(13), 1283–1297 (2009).
   PubMed Web of Science ®Google Scholar
• Vriesendorp TM, DeVries JH, van Santen S et al. Evaluation of short-term consequences of hypoglycemia in an intensive care unit. Crit. Care Med. 34(11), 2714–2718 (2006).
   PubMed Web of Science ®Google Scholar
• Kosiborod M, Inzucchi SE, Goyal A et al. Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA 301(15), 1556–1564 (2009).
   PubMed Web of Science ®Google Scholar
• Kagansky N, Levy S, Rimon E et al. Hypoglycemia as a predictor of mortality in hospitalized elderly patients. Arch. Intern. Med. 163(15), 1825–1829 (2003).
   PubMed Web of Science ®Google Scholar
• Ismail-Beigi F, Craven T, Banerji MA et al.; ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in Type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 376(9739), 419–430 (2010).
   PubMed Web of Science ®Google Scholar
• Gerstein HC, Miller ME, Genuth S et al.; ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N. Engl. J. Med. 364(9), 818–828 (2011).
   PubMed Web of Science ®Google Scholar
• Griesdale DE, de Souza RJ, van Dam RM et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ 180(8), 821–827 (2009).
   PubMed Web of Science ®Google Scholar
• Van den Berghe G, Schetz M, Vlasselaers D et al. Clinical review: intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose target? J. Clin. Endocrinol. Metab. 94(9), 3163–3170 (2009).
   PubMed Web of Science ®Google Scholar
• Pichardo-Lowden AR, Fan CY, Gabbay RA. Management of hyperglycemia in the non-intensive care patient: featuring subcutaneous insulin protocols. Endocr. Pract. 17(2), 249–260 (2011).
   Google Scholar
• Wexler DJ, Cagliero E. Inpatient diabetes management in non-ICU settings: evidence and strategies. Curr. Diabetes Rev. 3(4), 239–243 (2007).
   Google Scholar
• Wexler DJ. Inpatient diabetes management in general medical and surgical settings: evidence and update. Expert Rev. Pharmacoecon. Outcomes Res. 7(5), 491–502 (2007).
   Google Scholar
• Boucher JL, Swift CS, Franz MJ et al. Inpatient management of diabetes and hyperglycemia: implications for nutrition practice and the food and nutrition professional. J. Am. Diet. Assoc. 107(1), 105–111 (2007).
   Google Scholar
• Petersen KF, Shulman GI. Etiology of insulin resistance. Am. J. Med. 119(5 Suppl. 1), S10–S16 (2006).
   PubMed Web of Science ®Google Scholar
• Bray GA. Medical consequences of obesity. J. Clin. Endocrinol. Metab. 89(6), 2583–2589 (2004).
   PubMed Web of Science ®Google Scholar
• James WP. The epidemiology of obesity: the size of the problem. J. Intern. Med. 263(4), 336–352 (2008).
   PubMed Web of Science ®Google Scholar
• Gallagher EJ, Leroith D, Karnieli E. Insulin resistance in obesity as the underlying cause for the metabolic syndrome. Mt. Sinai J. Med. 77(5), 511–523 (2010).
   PubMed Web of Science ®Google Scholar
• Boden G. Obesity, insulin resistance and free fatty acids. Curr. Opin. Endocrinol. Diabetes. Obes. 18(2), 139–143 (2011).
   PubMed Web of Science ®Google Scholar
• Rizza RA, Mandarino LJ, Gerich JE. Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. J. Clin. Endocrinol. Metab. 54(1), 131–138 (1982).
   PubMed Web of Science ®Google Scholar
• Lansang MC, Hustak LK. Glucocorticoid-induced diabetes and adrenal suppression: how to detect and manage them. Cleve. Clin. J. Med. 78(11), 748–756 (2011).
   PubMed Web of Science ®Google Scholar
• Lee H, Koh SO, Park MS. Higher dextrose delivery via TPN related to the development of hyperglycemia in non-diabetic critically ill patients. Nutr. Res. Pract. 5(5), 450–454 (2011).
   Google Scholar
• Via MA, Mechanick JI. Inpatient enteral and parenteral [corrected] nutrition for patients with diabetes. Curr. Diab. Rep. 11(2), 99–105 (2011).
   Google Scholar
• Lin LY, Lin HC, Lee PC, Ma WY, Lin HD. Hyperglycemia correlates with outcomes in patients receiving total parenteral nutrition. Am. J. Med. Sci. 333(5), 261–265 (2007).
   PubMed Web of Science ®Google Scholar
• Pasquel FJ, Spiegelman R, McCauley M et al. Hyperglycemia during total parenteral nutrition: an important marker of poor outcome and mortality in hospitalized patients. Diabetes Care 33(4), 739–741 (2010).
   PubMed Web of Science ®Google Scholar
• Harlev A, Wiznitzer A. New insights on glucose pathophysiology in gestational diabetes and insulin resistance. Curr. Diab. Rep. 10(3), 242–247 (2010).
   PubMed Web of Science ®Google Scholar
• Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin. Obstet. Gynecol. 50(4), 938–948 (2007).
   PubMed Web of Science ®Google Scholar
• Fagulha A, Carvalheiro M, Fagulha I et al. Insulin sensitivity and insulin secretion in lean and obese normal pregnant women. Ann. Ist. Super. Sanita 33(3), 367–370 (1997).
   Google Scholar
• García-Patterson A, Gich I, Amini SB, Catalano PM, de Leiva A, Corcoy R. Insulin requirements throughout pregnancy in women with Type 1 diabetes mellitus: three changes of direction. Diabetologia 53(3), 446–451 (2010).
   PubMed Web of Science ®Google Scholar
• McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit. Care Clin. 17(1), 107–124 (2001).
   PubMed Web of Science ®Google Scholar
• Lager I. The insulin-antagonistic effect of the counterregulatory hormones. J. Intern. Med. Suppl. 735, 41–47 (1991).
   PubMedGoogle Scholar
• Bolli GB, Perriello G. Impact of activated glucose counterregulation on insulin requirements in insulin-dependent diabetes mellitus. Horm. Metab. Res. Suppl. 24, 87–96 (1990).
   Google Scholar
• Smith U, Lager I. Insulin-antagonistic effects of counterregulatory hormones: clinical and mechanistic aspects. Diabetes. Metab. Rev. 5(6), 511–525 (1989).
   Google Scholar
• Rendell M. The role of sulphonylureas in the management of Type 2 diabetes mellitus. Drugs 64(12), 1339–1358 (2004).
   PubMed Web of Science ®Google Scholar
• Rendell MS, Jovanovic L. Targeting postprandial hyperglycemia. Metab. Clin. Exp. 55(9), 1263–1281 (2006).
   PubMed Web of Science ®Google Scholar
• Lipska KJ, Ross JS. Switching from rosiglitazone: thinking outside the class. JAMA 305(8), 820–821 (2011).
   Google Scholar
• Erdmann E, Charbonnel B, Wilcox RG et al.; PROactive investigators. Pioglitazone use and heart failure in patients with Type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care 30(11), 2773–2778 (2007).
   PubMed Web of Science ®Google Scholar
• Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and Type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370(9593), 1129–1136 (2007).
   PubMed Web of Science ®Google Scholar
• Madsbad S, Krarup T, Deacon CF, Holst JJ. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials. Curr. Opin. Clin. Nutr. Metab. Care 11(4), 491–499 (2008).
   PubMed Web of Science ®Google Scholar
• Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes mellitus. Am. J. Med. 70(3), 579–588 (1981).
   PubMed Web of Science ®Google Scholar
• Wolever TM, Bolognesi C. Prediction of glucose and insulin responses of normal subjects after consuming mixed meals varying in energy, protein, fat, carbohydrate and glycemic index. J. Nutr. 126(11), 2807–2812 (1996).
   PubMed Web of Science ®Google Scholar
• Moghissi ES. Insulin strategies for managing inpatient and outpatient hyperglycemia and diabetes. Mt. Sinai J. Med. 75(6), 558–566 (2008).
   PubMedGoogle Scholar
• Goldberg PA, Siegel MD, Sherwin RS et al. Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit. Diabetes Care 27(2), 461–467 (2004).
   PubMed Web of Science ®Google Scholar
• Rea RS, Donihi AC, Bobeck M et al. Implementing an intravenous insulin infusion protocol in the intensive care unit. Am. J. Health. Syst. Pharm. 64(4), 385–395 (2007).
   PubMed Web of Science ®Google Scholar
• Nazer LH, Chow SL, Moghissi ES. Insulin infusion protocols for critically ill patients: a highlight of differences and similarities. Endocr. Pract. 13(2), 137–146 (2007).
   Google Scholar
• DeSantis AJ, Schmeltz LR, Schmidt K et al. Inpatient management of hyperglycemia: the Northwestern experience. Endocr. Pract. 12(5), 491–505 (2006).
   PubMedGoogle Scholar
• Kanji S, Singh A, Tierney M, Meggison H, McIntyre L, Hebert PC. Standardization of intravenous insulin therapy improves the efficiency and safety of blood glucose control in critically ill adults. Intensive Care Med. 30(5), 804–810 (2004).
   Google Scholar
• Hipszer B, Joseph J, Kam M. Pharmacokinetics of intravenous insulin delivery in humans with Type 1 diabetes. Diabetes Technol. Ther. 7(1), 83–93 (2005).
   PubMedGoogle Scholar
• Alish CJ, Garvey WT, Maki KC et al. A diabetes-specific enteral formula improves glycemic variability in patients with Type 2 diabetes. Diabetes Technol. Ther. 12(6), 419–425 (2010).
   PubMed Web of Science ®Google Scholar
• Korytkowski MT, Salata RJ, Koerbel GL et al. Insulin therapy and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a randomized controlled clinical trial. Diabetes Care 32(4), 594–596 (2009).
   PubMed Web of Science ®Google Scholar
• Umpierrez GE. Basal versus sliding-scale regular insulin in hospitalized patients with hyperglycemia during enteral nutrition therapy. Diabetes Care 32(4), 751–753 (2009).
   PubMedGoogle Scholar
• Vogel CM, Kingsbury RJ, Baue AE. Intravenous hyperalimentation: a review of two and one-half years’ experience. Arch. Surg. 105(3), 414–419 (1972).
   Google Scholar
• Piraino AJ, Firpo JJ, Powers DV. Prolonged hyperalimentation in catabolic chronic dialysis therapy patients. JPEN. J. Parenter. Enteral. Nutr. 5(6), 463–477 (1981).
   Google Scholar
• Reed MA, Pories WJ, Chapman W et al. Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of Type 2 diabetes. J. Clin. Endocrinol. Metab. 96(8), 2525–2531 (2011).
   Google Scholar
• Rossetti P, Pampanelli S, Fanelli C et al. Intensive replacement of basal insulin in patients with Type 1 diabetes given rapid-acting insulin analog at mealtime: a 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime. Diabetes Care 26(5), 1490–1496 (2003).
   PubMed Web of Science ®Google Scholar
• Nau KC, Lorenzetti RC, Cucuzzella M, Devine T, Kline J. Glycemic control in hospitalized patients not in intensive care: beyond sliding-scale insulin. Am. Fam. Physician 81(9), 1130–1135 (2010).
   PubMed Web of Science ®Google Scholar
• Franc S, Dardari D, Boucherie B et al. Real-life application and validation of flexible intensive insulin-therapy algorithms in Type 1 diabetes patients. Diabetes Metab. 35(6), 463–468 (2009).
   PubMedGoogle Scholar
• Cengiz E, Sherr JL, Weinzimer SA, Tamborlane WV. New-generation diabetes management: glucose sensor-augmented insulin pump therapy. Expert Rev. Med. Devices 8(4), 449–458 (2011).
   PubMed Web of Science ®Google Scholar
• Oliver NS, Toumazou C, Cass AE, Johnston DG. Glucose sensors: a review of current and emerging technology. Diabet. Med. 26(3), 197–210 (2009).
   PubMed Web of Science ®Google Scholar
• Girardin CM, Huot C, Gonthier M, Delvin E. Continuous glucose monitoring: a review of biochemical perspectives and clinical use in Type 1 diabetes. Clin. Biochem. 42(3), 136–142 (2009).
   PubMed Web of Science ®Google Scholar
• Rebrin K, Sheppard NF Jr, Steil GM. Use of subcutaneous interstitial fluid glucose to estimate blood glucose: revisiting delay and sensor offset. J. Diabetes Sci. Technol. 4(5), 1087–1098 (2010).
   PubMedGoogle Scholar
• Tamborlane WV, Beck RW, Bode BW et al. Continuous glucose monitoring and intensive treatment of Type 1 diabetes. N. Engl. J. Med. 359(14), 1464–1476 (2008).
   PubMed Web of Science ®Google Scholar
• Cohen O, Körner A, Chlup R et al.; Central and Eastern Europe, Greece, and Israel Continuous Glucose Sensing Collaborative Study Group. Improved glycemic control through continuous glucose sensor-augmented insulin pump therapy: prospective results from a community and academic practice patient registry. J. Diabetes Sci. Technol. 3(4), 804–811 (2009).
   Google Scholar
• Hermanides J, Engström AE, Wentholt IM et al. Sensor-augmented insulin pump therapy to treat hyperglycemia at the coronary care unit: a randomized clinical pilot trial. Diabetes Technol. Ther. 12(7), 537–542 (2010).
   Google Scholar
• Leonhardi BJ, Boyle ME, Beer KA et al. Use of continuous subcutaneous insulin infusion (insulin pump) therapy in the hospital: a review of one institution’s experience. J. Diabetes Sci. Technol. 2(6), 948–962 (2008).
   Google Scholar
• Nassar AA, Partlow BJ, Boyle ME, Castro JC, Bourgeois PB, Cook CB. Outpatient-to-inpatient transition of insulin pump therapy: successes and continuing challenges. J. Diabetes Sci. Technol. 4(4), 863–872 (2010).
   Google Scholar
• Bailon RM, Partlow BJ, Miller-Cage V et al. Continuous subcutaneous insulin infusion (insulin pump) therapy can be safely used in the hospital in select patients. Endocr. Pract. 15(1), 24–29 (2009).
   Google Scholar
• Einis SB, Mednis GN, Rogers JE, Walton DA. Cultivating quality: a program to train inpatient pediatric nurses in insulin pump use. Am. J. Nurs. 111(7), 51–55 (2011).
   Google Scholar
• Continuous Glucose Monitoring: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 96(10), 2968–2979 (2011).
   Google Scholar
• Magee MF, Clement S. Subcutaneous insulin therapy in the hospital setting: issues, concerns, and implementation. Endocr. Pract. 10(Suppl. 2), 81–88 (2004).
   PubMedGoogle Scholar
• Maynard G, Wesorick DH, O’Malley C, Inzucchi SE; Society of Hospital Medicine Glycemic Control Task Force. Subcutaneous insulin order sets and protocols: effective design and implementation strategies. J. Hosp. Med. 3(Suppl. 5), 29–41 (2008).
   PubMed Web of Science ®Google Scholar
• Larsen J, Goldner W. Approach to the hospitalized patient with severe insulin resistance. J. Clin. Endocrinol. Metab. 96(9), 2652–2662 (2011).
   Google Scholar
• Cook CB, Seifert KM, Hull BP et al. Inpatient to outpatient transfer of diabetes care: planning for an effective hospital discharge. Endocr. Pract. 15(3), 263–269 (2009).
   Google Scholar
• Newton CA, Young S. Financial implications of glycemic control: results of an inpatient diabetes management program. Endocr. Pract. 12(Suppl. 3), 43–48 (2006).
   PubMedGoogle Scholar

Website

• National Diabetes Information Clearing House. Fast facts on diabetes. http://diabetes.niddk.nih.gov/DM/PUBS/statistics/#fasttes (Accessed 30 January 2012)
   Google Scholar

The future of inpatient diabetes management: glucose as the sixth vital sign

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 66-year-old man on postoperative day 1 after right total knee replacement. He has multiple comorbid disease along with his history of osteoarthritis, including coronary artery disease and diabetes. His current serum glucose level is 270 mg/dl. What should you consider regarding hyperglycemia among inpatients and clinical outcomes?

• □ A Only glucose levels of 300 mg/dl or higher have been demonstrated to complicate surgical outcomes

• □ B Hyperglycemia is insignificant among patients with myocardial infarction but no prior history of diabetes

• □ C Hyperglycemia is associated with a higher risk of stroke as well as worse outcomes of stroke

• □ D Frequent hypoglycemia should be accepted in attempting to normalize this patient's glucose level

2. What is an appropriate target glucose level for this patient?

• □ A Less than 110 mg/dl before meals; less than 130 mg/dl at random exams

• □ B Less than 140 mg/dl before meals; less than 180 mg/dl at random exams

• □ C Less than 110 mg/dl before meals; less than 200 mg/dl at random exams

• □ D Less than 220 mg/dl at any given time

3. What should you consider regarding the treatment of hyperglycemia among hospitalized patients?

• □ A Metformin is the first-line therapy for hyperglycemia

• □ B Intravenous insulin should not be given to patients who are not eating

• □ C Intravenous insulin is useful to treat postprandial hyperglycemia

• □ D The use of short-acting insulin boluses to control postprandial elevations in glucose is appropriate

4. You decide to advocate for a new system to control hyperglycemia in your hospital. What should you consider as you prepare an argument to the hospital administration to invest in such a system?

• □ A Over 25% of US adults at age 65 or older have diabetes

• □ B Current recommendations call for the use of continuous glucose monitoring in the intensive care unit

• □ C The biggest cost of continuous glucose monitoring and insulin pump systems are the monitors themselves

• □ D Standardized insulin protocols have yet to be demonstrated to improve clinical outcomes of diabetes among hospitalized patients