C L I N I C A L F E AT U R E S

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Management of the Hospitalized Patient With Type 1 Diabetes Mellitus

Carlos E. Mendez, MD1 Guillermo Umpierrez, MD2

1Assistant Professor of Medicine, Albany Medical College, Director, Diabetes Management Program, Samuel S. Stratton VA Medical Center, Albany, NY; 2Professor of Medicine, Emory University School of Medicine, Director, Endocrinology and Diabetes, Grady Health System, Atlanta, GA

Correspondence: Carlos E. Mendez, MD, Director, Diabetes Management Program, Samuel S. Stratton VA Medical Center, 113 Holland Avenue, Albany, NY 12208. Tel: 518-626-6404 Fax: 518-626-6511 E-mail: carlos.mendez2@va.gov

DOI: 10.3810/hp.2013.08.1072

Abstract: Patients with type 1 diabetes mellitus (T1DM) have minimal to absent pancreatic β-cell function and rely on the exogenous delivery of insulin to obtain adequate and life-sustaining glucose homeostasis. Maintaining glycemic control is challenging in hospitalized patients with T1DM, as insulin requirements are influenced by the presence of acute medical or surgical conditions, as well as altered nutritional intake. The risks of hyperglycemia, ketoacido-sis, hypoglycemia, and glycemic variability are increased in hospitalized patients with T1DM. Diabetic ketoacidosis and severe hypoglycemia are the 2 most common emergency conditions that account for the majority of hospital admissions in patients with T1DM. The association between hyperglycemia and increased risk of complications and mortality in patients with type 2 diabetes (T2DM) is well established; however, the impact of glycemic control on clinical outcomes has not been determined in patients with T1DM who present without ketoacidosis. To decrease complications associated with insulin therapy, health care professionals must be well versed in the use of insulin because it is a common source of medication error. For non-critically ill, hospitalized patients, subcutaneous insulin given to cover basal and prandial needs instead of sliding scale is the preferred method of insulin dosing. Protocols are available for initiating and titrating insulin doses, as well as for transitioning from an insulin infusion to a subcutaneous regimen. In our review, we identify and discuss special considerations related to inpatient glycemic control of non-ketotic patients with T1DM. Additionally, point differences and similarities associated with the management of patients with T2DM are discussed.

Keywords: hyperglycemia; hypoglycemia; type 1 diabetes; inpatient diabetes management; inpatient glycemic control

Case Presentation62-year-old male with past medical history of hypertension, dyslipidemia, and T1DM presents to the emergency department (ED) with complaints of generalized fatigue, worsening shortness of breath, productive cough, and fever for the last 3 days. His diabetes was diagnosed at age 14 and has been well controlled with the assistance of his endocrinologist. His medications include lisinopril 20 mg daily, simvastatin 40 mg at night, glargine insulin 16 units at bedtime, and aspart insulin 0–8 units before meals. He weighs 68 kg and looks acutely ill. His temperature is 101.3°F with tachypnea and O2 saturation is 92% at room air. There are diminished respiratory sounds in the auscultation of his right lower base. Laboratory results include a WBC of 15 700 with 95% neutrophils, non-fasting serum glucose of 223 mg/dL, creatinine 1.2 mg/dL, and HbA1c of 7.1%. Chest radiographs show a right lower lobe consolidation suggestive of an acute infectious process. A medicine consultation is requested.

In addition to intravenous antibiotic therapy and supplemental oxygen, what would be the most appropriate inpatient insulin regimen to order for this patient?

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IntroductionThe most common form of type 1 diabetes mellitus (T1DM) is characterized by the autoimmune destruction of pancreatic β cells resulting in profound insulin deficiency (type 1A).1 Before the isolation of insulin in 1921, patients with T1DM had a short life expectancy and were subjected to starvation diets in the attempt to decrease blood glucose levels through carbohydrate restriction.2 After the adoption of subcutaneous (SC) insulin therapy as the preferred method for glycemic control, overall mortality rates of patients with T1DM have drastically improved over the years.3,4

The worldwide epidemic of type 2 diabetes mellitus (T2DM) is well known,5 however, the number of patients with T1DM has also increased during the last 2 decades. In a literature review that included data from large epidemiologic studies worldwide, the annual incidence of T1DM has increased by 2% to 5% worldwide, and prevalence of the disease in the US population was estimated to be 1 in 300 for persons aged # 18 years of age.6 Combined with longer life expectancy, it is anticipated that a growing number of individuals with T1DM will present with acute illnesses requiring hospitalization.7

To reach optimal glycemic control in the outpatient setting, patients with T1DM are compelled to engage in daily tasks that require significant discipline and self-motivation.8 Frequent glucose monitoring, and a careful balance between carbohydrate intake, insulin dosing, and physical activity level provide glucose stability in these patients.9 Once in the hospital, finding this balance can be a difficult task for patients and for the health care team. In the setting of acute medical or surgical conditions (including infection, tissue injury, or trauma), inflammatory mediators and stress hormones can produce a transient state of insulin resistance making the inpatient management of patients with T1DM even more challenging.10,11

Hospitalized patients with T1DM are at higher risk of developing acute diabetic complications compared with patients with T2DM. In the complete absence of insulin, severe hyperglycemia and diabetic ketoacidosis (DKA) can rapidly develop.12 Conversely, given the general lack of insulin resistance in non-obese patients with T1DM treated with intensive insulin therapy, the risk of severe hypoglycemia is significantly higher than in patients with T2DM.13

There are few reports that differentiate outcomes between hospitalized patients with T1DM and T2DM. Viens et al14 examined the role of diabetes type in perioperative outcomes after hip and knee arthroplasty in the United States.

The Nationwide Inpatient Sample (NIS), a component of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality of the United States Department of Health and Human Services included patients with T1DM (n = 8728) and T2DM (n = 57 041) who underwent total hip and knee arthroplasty from 1988 to 2003. The researchers examined and compared the rate of patient perioperative complications, mortality, and hospital course alterations. Patients with T1DM had longer lengths of stay (6.1 vs 4.9 days; P , 0.01) and higher inpatient costs (33 155 vs 30 802 USD, P , 0.05) compared with patients with T2DM. Patients with T2DM, on the other hand, were significantly less likely to die (odds ratio [OR], 0.44; 95% CI, 0.31–0.62), have a myocardial infarction (OR, 0.21; 95% CI, 0.07–0.67), urinary tract infection (OR, 0.71; 95% CI, 0.62–0.80), pneumonia (OR, 0.68; 95% CI, 0.5–0.9), postoperative hemorrhage (OR, 0.67; 95% CI, 0.55–0.81), or infection (OR, 0.47; 95% CI, 0.36–0.63) compared with patients with T1DM. The authors suggested that the longer disease duration and higher prevalence of diabetic complica-tions might translate into greater perioperative risk and use of health care resources in patients with T1DM compared with patients with T2DM.

The developments of hyperglycemia, hypoglycemia, and increased glycemic variability have each been independently associated with increased morbidity and mortality in critically ill hospitalized patients.15 Determining the proper insulin regimen and dosing to be used in hospitalized patients with T1DM will vary depending on several factors, including outpatient insulin therapy (SC injections vs pump therapy), adherence to prescribed regimen, diabetes self-management skills, glycemic control prior to admission, required inpatient level of care (critically ill vs non-critically ill), and nutritional status.16

Management of Non-Critically Ill Hospitalized Patients With T1DMDue to the high complexity attributed to the inpatient management of hyperglycemia, a multidisciplinary team approach has been demonstrated to improve clinical outcomes and reduce costs in hospitalized patients with diabetes.17 In many institutions, nonetheless, endocrinology consultation or a dedicated diabetes management team is not available, and the inpatient care of patients with T1DM is provided by house staff and general internal medicine physicians. Unfamiliarity and discomfort concerning the use of multidose insulin or insulin pump therapy has been reported as a barrier that can negatively impact inpatient glycemic control.18,19

Management of the Hospitalized Patient With T1DM

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Additionally, poor coordination between point of care (POC) glucose testing, insulin administration, and food tray delivery has also been identified as a significant obstacle to achieve adequate inpatient glycemic control in hospitalized patients with diabetes.16

Glycemic Targets in Non-ICU SettingsRandomized controlled trials to determine specific goal glycemic levels in patients with T1DM are lacking; however, a systematic review and meta-analysis in non-critically ill hos-pitalized patients reported that in surgical patients, the rate of overall infections can be significantly reduced by maintaining blood glucose concentrations between 100 and 180 mg/dL.20 In 2012, the Endocrine Society published practical guidelines for the management of hyperglycemia in non-critically ill hospitalized patients.21 The recommended glycemic targets for patients with either T1DM or T2DM are to maintain fast-ing and pre-meal blood glucose levles at , 140 mg/dL and random blood glucose level at , 180 mg/dL. These glycemic targets are also aligned with those previously published in 2009 in a consensus statement on inpatient glycemic control by the American Association of Clinical Endocrinologists and the American Diabetes Association (ADA).22

Glucose Monitoring in HospitalBedside capillary POC testing is the preferred method for guiding ongoing glycemic management of individual patients with diabetes.22 The testing is usually performed 4 times a day: before meals and at bedtime for patients who are eating.16,22 Pre-meal POC testing should be obtained as close to the time of meal-tray delivery as possible. For patients restricted to nothing by mouth (NPO) or receiving continuous enteral nutrition, POC testing is recommended every 4 to 6 hours. More frequent glucose monitoring is indicated in patients treated with continuous intravenous (IV) insulin infusion,23,24 or after a medication change that could alter glycemic control, such as corticosteroid use or abrupt discontinuation of enteral or parenteral nutrition (PN),25–27 or in patients with frequent episodes of hypoglycemia.16,28

Health care workers should keep in mind that the accuracy of most hand-held glucose meters is far from optimal.29 There is an accepted variance between meter readings and central laboratory results (allowed to be up to 20% by FDA regulations), which can potentially lead to inappropriate therapy.22,30 There are potential inaccuracies of POC testing, including intrinsic issues with the technol-ogy and variability between different lots of test strips, inadequate sampling site, varying hemoglobin concentra-

tions, and other interfering hematologic factors in acutely ill patients.29,31

Medical Nutrition Therapy in Hospitalized Patients With DiabetesMedical nutrition therapy (MNT) plays an important role in the management of hospitalized patients with hyperglycemia who have T1DM and T2DM. The goals of inpatient MNT for patients with diabetes are to help optimize glucose control, provide adequate calories to meet metabolic demands, address individual needs based on personal food preferences, and pro-vide a discharge plan for follow-up care.16,17,32 Individualized MNT should be provided by a registered dietitian. Use of MNT in the hospital can be challenging for patients in the presence of acute medical illness, poor appetite, inability to eat, increased nutrient and calorie needs due to catabolic stress, and variation in diabetes medications.

Providing 25 to 35 calories/kg/day can support the meta-bolic needs of most hospitalized patients,33 although some malnourished critically ill patients may require less caloric intake at 15 to 25 calories/kg/day. This will translate into a diet, on average, containing 1800 to 2000 calories/day or a diet containing approximately 200 grams/day of carbo-hydrates, divided between meals. There is no single, ideal meal-planning system for hospitalized patients, however, it is suggested that hospitals consider implementing a consistent-carbohydrate diabetes meal-planning system.34 This system uses meal plans without a specific calorie level but with consistency in the carbohydrate content of meals. The carbo-hydrate components of breakfast, lunch, dinner, and snacks may vary, but the day-to-day carbohydrate content of specific meals and snacks is kept constant.16 It is recommended that the term “ADA diet” no longer be used because the ADA no longer endorses a single nutrition prescription or percentages of macronutrients.34

Diabetes Self-ManagementAlthough there is no compelling evidence on the efficacy and safety of diabetes self-management in hospitalized patients with T1DM, a systematic review of 16 clinical studies concluded that patients who possess excellent self-management skills may be suitable for successful inpatient diabetes self-management.35 In the 2013 ADA clinical practice recommendations, patient self-management of diabetes in the hospital is considered appropriate in selected patients.17 In agreement, the Joint British Diabetes Societies for Inpatient Care Group published a communication addressing the issue of hospitalized patient self-management

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of diabetes.36 The Society endorsed the development of hospital policies for diabetes self-management where clear, but flexible patient-centered guidelines define the responsibilities of both health care staff and patients in the management of inpatient diabetes and hyperglycemia.

We recognize the value of patient diabetes self-management in the hospital, but we also believe that the competence and readiness of each patient with T1DM needs to be carefully determined in an individualized manner. Patients with unaltered mental status, proven proficient outpatient skills―such as carbohydrate counting, frequent glucose monitoring, sick-day management, strong knowledge related to the management of insulin pump or injection techniques―and who are tolerating a decent oral intake could be considered good candidates for diabetes self-management in the hospital.37 Certified diabetes educators, when available, can be a valuable resource to assist in evaluating the level of pro-ficiency of a patient’s self-management skills on admission.38 In addition, well-trained nursing staff, as well as clear policies and procedures need to be in place in order to avoid potential errors and complications that could inadvertently derive from uncoordinated diabetes self-management in the hospital.

Insulin TherapyThere is epidemiologic evidence linking hypoglycemia and hyperglycemia with morbidity and mortality but few randomized, controlled trial data in the non-ICU setting to inform therapy.20 Improved glycemic control has been shown to reduce short- and long-term mortality, multi-organ failure and systemic infections, length of hospital stay, and total hospitalization cost in patients with diabetes.22 In patients with T1DM, insulin therapy must provide both basal and nutritional components in order to achieve the target blood glucose level goals.16,39 Hospitalized patients frequently require higher insulin doses to achieve target blood glucose levels due to increased counterregulatory hormones and insulin resistance in the presence of stress; thus, in addition to basal and nutritional insulin requirements, hospitalized patients will often require supplemental or correction insulin for treatment of hypergly-cemia. Health care professionals should keep in mind that in the absence of a basal insulin component, the prolonged use of sliding-scale insulin as a sole insulin regimen is discour-aged and can result in metabolic decompensation or DKA in patients with T1DM.40,41

Resuming Home Insulin RegimenInsulin therapy following a basal/bolus approach, either through the use of an insulin pump (also known as continuous

SC insulin infusion [CSII]), or through multi-dose injec-tions (MDI) is generally indicated for the management of patients with T1DM.17 A focused medical history is critical to adequately select the proper insulin regimen to be used upon the patient’s hospital admission. Special attention needs to be taken at the admission medication reconciliation, as important details may be missed, possibly leading to medication errors.42 It is important to ask the patient directly about his or her adherence to their prescribed insulin regimen (eg, how often are insulin doses missed?), times and amounts of each prescribed insulin, recent dietary habits, including changes in appetite, and level of physical activity.21

Once the decision of admission to the hospital is made, physicians and patients should assess the need to modify the outpatient insulin regimen.39 Assessment of previous outpa-tient glycemic control and admission blood glucose levels are needed to guide inpatient insulin therapy. The patient’s glycosylated hemoglobin (HbA1c) level provides a general idea of the average glucose values for the last 2 to 3 months; however, it does not give information regarding hypoglycemia occurrence or glycemic variability.43 Directly asking the patient about the frequency and range of readings from home glucose monitoring can offer a better indication of the effectiveness and safety of the patient’s current insulin regimen. Review of the patient’s recent glucose values obtained directly from the glucose meter device can also be of value to assess changes in glycemic control due to acute stress or illnesses.

Patients on Multi-Dose Insulin RegimenTo meet the daily insulin requirements, SC regimens should be designed to cover each patient’s basal and nutritional needs. For most non-critically ill inpatients with T1DM, the treatment of choice to control glucose is the use of insulin analogs with basal (glargine and detemir) once or twice daily, and prandial insulin (lispro, aspart, and glulisine) before meals.21 In addition, correction-dose or supplemental insulin should be available to address episodes of hyperglycemia. The use of split-mixed insulin regimen with twice-daily administration of neutral protamine Hagedorn (NPH) insu-lin and regular insulin before meals can also be used but is associated with increased risk of hypoglycemia.44,45

Basal InsulinIt is particularly important that patients with T1DM receive daily basal insulin in order to inhibit hepatic glucose production and prevent DKA. It has been estimated that non-obese patients with T1DM require approximately 0.3 to 0.4 units of basal insulin per kg of body weight to cover for

Management of the Hospitalized Patient With T1DM

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their requirements.16,45 However, learning the type, dosage, and schedule of patient home insulin administration is cru-cial for a successful in-hospital regimen transition. Although glargine and detemir basal insulins are usually administered every 24 hours, this can vary and some patients require twice-daily administration.46,47 The timing of administration, or total daily insulin doses can often differ from those reflected in the admission medication list. If the insulin doses at home are continued in the hospital, patients with T1DM may also be at risk of hypoglycemia in the presence of altered nutrition or impaired kidney function.48 Given that typically the inpatient food intake is lower than outpatient, decreasing basal insulin by 10% to 20% in patients with good glycemic control prior to the admission may be appropriate to decrease risk of inpatient hypoglycemia.

Prandial and Supplemental InsulinConsistency in the carbohydrate content of meals offered to patients in the hospital is of special importance to avoid hypoglycemia, hyperglycemia, or glycemic variability for patients with T1DM. Patients with T1DM often use insulin-to-carbohydrate ratios to calculate meal doses and individualized insulin sensitivity factors to calculate supplemental insulin doses in the outpatient setting.1 However, once in the hospital, the options to order insulin based on carbohydrate content, or on individualized target blood glucose levels and insulin sensitivity factors are generally not available. Inquiring directly from the patient the amount of insulin frequently used for a meal containing a moderate amount of carbohydrates (45–65 g) will help to estimate the safest insulin dose to be ordered in a fixed scheduled while the patient is in the hospi-tal. Another way to assess individual patient insulin require-ments is to estimate the total nutritional insulin component as 50% of the total daily insulin dose, or as the equivalent of the basal insulin component. This insulin dose can then be equally divided and given before the 3 daily meals. To decrease risk of hypoglycemia, initially reducing nutritional doses by 20% to 30%, and later adjusting the dose based on the use of supplemental insulin may as well be appropriate. Also, in patients with decreased appetite, rapid insulin analogs can be administered immediately after meals, based on how much food was eaten.16

For the individualized supplemental or correctional insulin component, the 1500 or 1700 rule can be used to calculate the insulin sensitivity factor.49 The insulin sensitivity factor will estimate the level of blood glucose reduction (mg/dL) caused by administration of 1 unit of insulin. To calculate the insulin sensitivity factor, 1500 or 1700 (1500 for regular

insulin and 1700 for rapid insulin analogs) is divided by the patient’s total daily insulin dose (basal and bolus insulins combined).50,51 Once the insulin sensitivity factor is known, an individualized correctional scale can be constructed for each patient. Alternatively, using an insulin sensitive supplemental scale built with a factor of 50 and a goal blood glucose level of 100 mg/dL can be a safe option for non-obese patients with T1DM (Table 1).

Continuous SC Insulin Infusion (Insulin-Pump Therapy)Successful management of inpatients with diabetes by use of a continuous insulin pump has been previously demonstrated in selected patients.52,53 However, current recommendations advocate for the establishment of clear policies and procedures to guide patients and hospital staff in the management of patients with diabetes in the use of insulin pumps. These policies should encompass detailed information regarding the indications or contraindications for continuous insulin pump therapy, patient-staff responsibilities, and procedures to be followed by hospital staff. A signed patient agreement, where the patient consents to perform all the necessary tasks, to share with the health care staff information regarding pump settings, and to report any problems is also recommended. Clear physician’s orders with specifics on the type of diet, frequency of POC blood glucose testing, basal rate, bolus, and correctional insulin settings should also be in place. Addition-ally, a patient-staff pump/blood glucose log that records time and date of POC blood glucose value, basal insulin rate, bolus and correctional insulin used, carbohydrates consumed, and infusion site changes should be continuously updated and kept by the patient’s bedside.54

Given the relative infrequency of patients with T1DM using this technology in the hospital, and the education and training that is required to become proficient in its use, hos-pital staff should not be expected to be experts in the use of insulin pumps.52 We recommend the prompt involvement of

Table 1. Supplemental Insulin Scale for Insulin-Sensitive Patients

Blood Glucose Level Range, mg/dL

Insulin Dose,a Units

150−199 1

200−249 2

250−299 3

300−349 4

$ 350 5

aSupplemental insulin scale built using a factor of 50 and target blood glucose level of 100 mg/dL. Supplemental insulin dose would be given in addition to the nutritional insulin scheduled before meals. Decreasing dose by half at bedtime may decrease risk of overnight hypoglycemia

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inpatient diabetes specialists to assist with the assessment and management of patients with T1DM who use insulin pumps. If inpatient diabetes resources are not available, discontinua-tion of insulin pump and transition to a MDI insulin regimen (pump holiday) may be the safest and most appropriate step.

To successfully transition from insulin pump therapy to an SC basal bolus MDI regimen, it is necessary to inquire directly from the patient or family the current insulin pump settings being used. Most patients knowledgeable in use of an insulin pump would be able to display in their pump screen the average total daily insulin used for the past few days. Based on such information, safe estimations of SC basal, bolus, and supplemental insulin can be calculated.55 Alternatively, records from the latest outpatient encounter with the patient’s diabetes specialist should also have this information. To avoid severe hyperglycemia or DKA from periods of no basal insulin, it is important to administer the SC basal insulin component ideally 2 hours before discon-necting the insulin pump from the patient.

Management of the Critically Ill Hospitalized Patient With T1DMAlthough evidence specific to critically ill patients with T1DM is lacking, numerous studies in intensive care unit (ICU) patients initially demonstrated the beneficial effects of IV intensive insulin therapy.56 Compared with conven-tional insulin therapy, IV intensive insulin therapy has been shown to be associated with reductions in the rate of infections, the need for prolonged hospital stay, disability after hospital discharge, and mortality in numerous patient groups, including patients undergoing cardiac surgery, with acute myocardial infarction, and ICU patients.57–59 However in recent years, a large multicenter, randomized, controlled trial demonstrated that the use of IV intensive insulin therapy was associated with increased risk of hypoglycemia and mortality.60 Subsequently, it has then been proposed that the absence of a positive effect on mortality from the use of IV intensive insulin therapy results from the increased risk of hypoglycemia that accompanies insulin use.60,61 Despite the lack of direct evidence that inpatient hypoglycemia causes mortality, hypoglycemia continues to be the main limiting factor in the management of hyperglycemia. Therefore, insulin protocols for the management of patients with hyperglycemia should inherently address the prevention and treatment of hypoglycemia.

The use of IV insulin infusion protocols designed to safely maintain blood glucose levels at desired targets while avoiding hyperglycemia and hypoglycemia is recommended

for the management of patients with T1DM who are critically ill.22 Although numerous algorithms for IV insulin infusions are available,62 no head-to-head comparisons of the different algorithms have been published in patients with T1DM. An ideal IV insulin algorithm should account for current as well as previous blood glucose levels, the rate of change of blood glucose levels, the current IV infusion rate, and it should include frequent glucose testing.17

Glycemic Targets in the ICU SettingThe American Association of Clinical Endocrinologist and the ADA Task Force on inpatient glycemic control22 recom-mends targeting a blood glucose level between 140 and 180 mg/dL for the majority of patients in the ICU and a lower blood glucose level target, between 110 and 140 mg/dL in selected ICU patients (ie, centers with extensive experience and appropriate nursing support, cardiac surgical patients, patients with stable glycemic control without hypoglycemia). Glucose targets . 180 mg/dL or , 110 mg/dL are not recommended in ICU patients. A more recent guideline from the Society of Critical Care recommended maintaining blood glucose levels at , 150 mg/dL in most critically ill patients in the ICU and at , 180 mg/dL in all patients.63

Transition From IV Insulin Infusion to SC InsulinPatients who are ready to be transitioned from IV to SC insulin often are rapidly recovering from DKA, major surgery, or severe illness. An unplanned transition, or no transition, may cause hyperglycemia that can require significant time to correct, or much worse, cause DKA in the patient with T1DM. A major mistake is to discontinue insulin infusions and begin sliding-scale insulin monotherapy until the patient is able to eat or is clinically stable. This approach is associated with severe meta-bolic decompensation, hyperglycemia, and DKA. Successful transition can follow 3 general principles: 1) the 24-hour insulin requirement is extrapolated from an appropriately selected hourly insulin rate; and 2) the SC insulin program is based on the outpatient insulin requirements; or 3) total insulin requirement is calculated based on patient body weight. Patients suitable for transition from IV to SC insulin ideally have a stable infusion rate and blood glucose levels in goal range for $ 4 to 6 hours before the transition. Patients also should be well enough to eat scheduled meals or be receiving enteral/parenteral feedings at a stable rate (with no imminent plans to decrease or increase the enteral/parenteral feedings rate).64

A small prospective study recently reported that starting basal insulin during continuous insulin infusion prevents

Management of the Hospitalized Patient With T1DM

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rebound hyperglycemia during the patient transition to an SC insulin regimen.65 We consider it extremely valuable to generate a plan of action that takes into account the estimated time that the patient will be transferred off the ICU or when the start of oral diet is scheduled. By doing this, the discon-tinuation of IV insulin infusion can be successfully arranged to take place ideally 2 hours after intermediate or long-acting insulin are administered SC.16 (Figure 1)

The ultimate SC insulin regimen should address the 3 components of patient insulin requirements: basal, nutri-tional, and supplemental. To decrease the risk of hypogly-cemia, using 60% to 80% of the calculated total daily dose may be safe. Half of this dose can be then administered as basal insulin, and the other half can be divided into 3 equal parts, provided the patient is ready to eat regular meals by mouth.66 If the patient’s appetite is not completely reestab-lished, we recommend decreasing nutritional insulin doses, or even changing the schedule for rapid insulin analogs to be given immediately after meals based on how much food was consumed by the patient.67,68

Special ScenariosPerioperative ManagementPatients with T1DM should have active basal insulin before, during, and after any surgical or nonsurgical procedures to avoid hyperglycemia and DKA. Reducing basal insulin prior to the procedure may not be necessary to the extent often implemented in patients with T2DM. Mucha et al69 showed no increased risk of hypoglycemia during a study where patients with T1DM who received full doses of glargine

insulin were submitted to a fasting period of 18 hours. Nonetheless, for patients with unknown prior glycemic control, or in those whose blood glucose levels have been well controlled, a mild reduction of 10% to 20% of their basal insulin dose may be appropriate to reduce the risk of hypoglycemia.22 If NPH insulin is used, a 50% reduction in the morning dose on the day of the procedure is also suggested.37 Supplemental insulin can be used in case of periprocedural hyperglycemia, even if the patient is NPO.

Continuous IV insulin infusion is the preferred option for patients with T1DM undergoing major surgical procedures for whom attaining glycemic control has been difficult prior to the procedure. In such cases, frequent glucose monitoring (every hour) and dextrose-containing IV solutions, to be used as necessary, should be available to avoid hyper- or hypoglycemia.16 Recent guidelines developed by the American College of Physicians for the use of intensive insulin therapy in hospitalized patients endorse target blood glucose levels of 140 to 200 mg/dL for medical and surgical critically ill patients.70 However, results of several studies underscore differences in mortality between medical and surgical patients undergoing intensive insulin therapy in the ICU. In a meta-analysis of 26 trials, including the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial (n = 13 567), tight glucose control had no effect on patient overall risk of mortality (RR, 0.93; 95% CI, 0.83–1.04), however, there was a reported pooled relative risk of death between inten-sive and conventional insulin therapy for medical (RR, 0.99: 95% CI, 0.87–1.12) compared with surgical ICU patients

Figure 1. Successful transition from intravenous (IV) to subcutaneous (SC) insulin. Given the short half-life of IV insulin and the delayed onset of action of intermediate or long-acting insulin, it is recommended to ideally allow for a 2-hour overlap period between the administration of SC insulin and discontinuation of IV insulin as shown.

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(RR, 0.63; CI, 0.44–0.91). The study results71 suggested a potential beneficial effect of tight blood glucose control in patients undergoing surgery in ICU settings. This finding was in agreement with a previous meta-analysis performed by Wiener at el.72

Glucocorticoid TherapyCorticosteroid use is known to increase patient insulin requirements by inducing a transient state of insulin resistance resulting in hyperglycemia in patients with T1DM.73 In critically ill patients, studies investigating the effect of tight glucose control in those who receive corticosteroids compared with patients who do not, failed to show a significant improvement in mortality with tight blood glucose control in this population.72 In general medicine wards, patients with steroid-induced hyperglycemia should be managed with basal bolus insulin therapy. In the major-ity of these patients, daily basal insulin dose adjustment and supplemental insulin are needed to correct hyperglycemia.74,75 A blood glucose level target between 110 and 180 mg/dL is recommended for patients with hyperglycemia and diabetes during corticosteroid therapy.22

Patients who are being already treated with NPH insulin (basal component) and who develop hyperglycemia from daily prednisone or prednisolone therapy may benefit from an increase in the morning NPH insulin dose. This is recom-mended based on the similar action profile of these steroids formulations and NPH insulin.76 However, in patients receiv-ing long-acting insulin (glargine or detemir), titration of the nutritional insulin component may be more appropriate. Based on the need for frequent supplemental insulin and blood glucose values, increasing the insulin dose before breakfast, lunch, or supper may be necessary.

Enteral and Parenteral NutritionThe majority of non-critically ill hospitalized patients receive nutrition support as 3 discrete meals with or without scheduled snacks each day, however, some patients require enteral nutrition or PN support. Standard enteral formulas reflect the reference values for macro- and micronutri-ents for a healthy population and contain 1 to 2 calories per mL. Standard diabetes-specific formulas provide low amounts of lipids (30% of total calories) combined with a high-carbohydrate content (55–60% of total calories); however, newer diabetic formulas have replaced part of the carbohydrate component with monounsaturated fatty acids (# 35% of total calories), 10 to 15 g/L dietary fiber, and # 30% fructose.77,78 Although no previous studies have

been conducted specifically in patients with T1DM, several outpatient and inpatient studies in subjects with T2DM have reported better glycemic control (lower mean fasting and/or post-prandial blood glucose levels), a trend towards decreased HbA1c levels, and lower insulin requirements with a low-carbohydrate, high monounsaturated fatty acids (LCHM) formula compared with standard high carbohydrate formulas.79,80 In a meta-analysis of studies comparing newer enteral LCHM formulas with standard formulations, the postprandial rise in blood glucose was reduced by 18 mg/dL to 29 mg/dL with the newer formulations.81

The beneficial effect of PN in improving the nutritional status of critically ill patients is well established78; however, recent randomized trials and meta-analyses have suggested that PN may be associated with increased risk of infectious complications and mortality in critically ill patients.82 In addition, the use of PN is frequently linked to aggravation of hyperglycemia in patients with T2DM.74 Blood glucose levels . 150 mg/dL prior to and within 24 hours of initiation of PN were predictors of both increased inpatient complications and hospital mortality.83 To correct hyperglycemia, insulin can be added to PN mixture, but to date, there are no randomized controlled studies that guide effective and safe administration of insulin in patients with T1DM.

In critically ill patients with T1DM receiving either enteral nutrition or PN, IV insulin infusion is the preferred approach.16 However, in non-critically ill hospitalized patients managed either with MDI or insulin pump, regimen adjustment is usu-ally done based on results of blood glucose level monitoring. Frequent use of supplemental insulin combined with hyper-glycemia indicate the need for adjusting the patient’s current insulin regimen.22 In patients receiving bolus tube feedings, nutritional insulin can be given prior to each bolus tube feed as would be with regular meals. If the patient is receiving multiple feedings, the nutritional component of the insulin dose may need to be divided by the numbers of feedings. For example, if a patient requires 8 units of insulin before each meal (3/day) and is now scheduled to have bolus tube feedings every 4 hours, the total insulin nutritional component should be divided by the number of feedings (24 units/6 feeds = 4 units before each tube feeding).

For patients receiving PN or continuous tube feedings, the sole use of long-acting insulin to cover for the increased carbohydrate amount is discouraged. Sudden discontinuation or interruption of PN or tube feedings can translate into severe hypoglycemia for the patient76; a combination of basal, bolus, and correctional insulins can still provide safe and effective glycemic control in these patients. Nutritional

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requirements should be covered with either regular or any of the newer insulin analogs. Use of this strategy allows for flexibility to discontinue these insulins as soon as the PN or continuous tube feedings have been stopped, reducing patient risk of hypoglycemia. Use of regular insulin may have an advantage over the newer analogs in these circumstances, as it has a more gradual onset of action and it can be given every 6 hours instead of every 4 hours.37

Patients With Undetermined Type 1 or Type 2 Diabetes and Significant Insulin DeficiencyPatients with T2DM can also be affected by a significant β-cell secretory defect leading to profound insulin deficiency. In the later stages of T2DM, the pancreatic islet is characterized by a deficit in β cells, increased β-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide.84 This defect on insulin secretion with variable degrees of insu-lin resistance poses challenges in the inpatient management of patients with T2DM similar to those of patients with T1DM.

There are no standardized diagnostic tests generally recommended for hospitalized patients to identify patients with a significant insulin deficiency. A history of pancreatectomy or pancreatic insufficiency, high glycemic variability, prior history of DKA, insulin use for . 5 years, and long dura-tion of diabetes (. 10 years) have been suggested as clinical characteristics that can help identify patients with significant insulin deficiency.16 Also, patients previously diagnosed as having T2DM, but with a need for insulin therapy shortly after diagnosis, low body mass index, and the presence of glutamic acid decarboxylase antibodies could have late autoimmune diabetes of the adult (LADA) instead. Distinctively, patients with ketosis-prone type 2 diabetes (KPDM) may present to the hospital with DKA and no prior history of diabetes.85 The inpatient treatment of DKA and hyperglycemia in these patients is similar to that of patients with T1DM. However, as these patients frequently have a significant component of insulin resistance, higher insulin doses (0.5–0.8 units/kg) may be necessary to achieve glycemic control.86 In contrast to patients with T1DM, patients with KPDM are usually from ethnic minorities, obese, and have a strong family history of T2DM. Also, the need for insulin therapy to achieve glycemic control in these patients is not permanent; most of the patients are able to discontinue insulin therapy within a few months of initiating treatment.85

Determination of serum C-peptide level has been used to assess residual β-cell function in patients with T1DM or

T2DM and in patients presenting to the hospital with DKA.87

In outpatients, the complementary use of urinary C-peptide-to-creatinine ratio can also be useful to confirm suspected severe insulin deficiency in patients with longstanding T2DM.88 However, based on the variable factors that can affect the interpretation of results (fasting vs postprandial blood glucose levels, exogenous insulin administered), we do not recommend routinely checking for C-peptide levels in hospitalized patients with suspected insulin deficiency.

Inpatient management of the patient with significant insulin deficiency should be handled no differently than that of patients with T1DM. Attention must be given to the continuous supply of basal insulin in order to avoid the patient experiencing severe hyperglycemia and DKA. To minimize the risk of hypoglycemia or glycemic variability, consistency in carbohydrate content, and frequent insulin dose adjustment based on POC blood glucose level testing is necessary in patients with significant insulin deficiency as well.

Summary and RecommendationsThe case presented at the commencement of our article denoted a 62-year-old man with a history of T1DM who was admitted to the medical service from the ED with a diagnosis of right lower community-acquired pneumonia. His admission non-fasting serum glucose level was 223 mg/dL, and his most recent HbA1c level reflected good glycemic control (7.1%) on his current insulin regimen. Upon interviewing the patient, he reported having decreased appetite at home and to be only eating small meals for the previous few days. He estimated that most of his meals recently contained 30 to 45 grams of carbohydrates. He reported taking all of his insulin injections, including 16 units of glargine at bedtime and approximately 3 to 4 units of aspart insulin with most of his meals. Review of his glucose meter showed that during the past 3 days his blood glucose level had ranged between 180 and 220 mg/dL in the morning and between 200 and 250 mg/dL before meals and bedtime.

In the direction to provide a safe and effective inpatient management of this patient’s diabetes, POC glucose testing before meals and bedtime should be ordered upon admission. If available, the inpatient diabetes team should be promptly notified of this patient admission. Based on the above information, the patient’s sustained hyperglycemia was likely due to increased insulin requirements caused by the acute infection. To compensate for increased insulin requirements, adding to his current insulin regimen a supplemental compo-nent of the aspart insulin (Table 1) would be the next most appropriate step. Subsequently, depending on his inpatient

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blood glucose levels and how frequently supplemental doses of the aspart insulin are needed, both basal and nutritional insulin components may need to be adjusted accordingly to cover for his increased requirements. As the infectious process resolves, insulin requirements may return to baseline. In order to decrease patient risk of hypoglycemia, frequent assessment of blood glucose levels will be necessary to proactively adjust insulin doses.

ConclusionThe increased prevalence and life expectancy of patients with T1DM has resulted in a growing number of patients requiring hospitalization. The inpatient management of patients with T1DM is complex and best provided by a multidisciplinary diabetes team. In the absence of such resources, providers and health care staff must become familiar with the features of the condition to avoid patient complications, such as severe hyperglycemia, DKA, hypoglycemia, or glycemic variability. Emphasis on a focused patient history and medication recon-ciliation can provide valuable information that will facilitate transition of the outpatient insulin regimen to the hospital. Hospitals should have protocols in place to address the prevention and treatment of hyperglycemia in patients with diabetes. Outside of the ICU, patient blood glucose levels can be controlled with SC insulin regimens, while patients in the ICU and other patients at high risk for hyperglycemia require an IV insulin infusion. Studies are needed to determine the best protocols for use of IV and SC insulin in the hospital setting for patients with T1DM.

Conflict of Interest StatementCarlos E. Mendez, MD, and Guillermo Umpierrez, MD, disclose no conflicts of interest.

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