Glycemic Control in the Hospitalized Patient Inpatient Management of Hyperglycemia : a review Rod Marianne Arceo-Mendoza, MD. Assistant Professor Department of Medicine Division of Endocrinology, DIABETES and metabolism Loyola University Medical Center 9 august 2019

Objectives Definition of Diabetes Prevalence Inpatient Glycemic Management Insulin Therapy Non-insulin Therapy Goals of Treatment Treatment Strategies and Common Pitfalls Discharge Planning and Transition of Care

Diabetes Mellitus The term diabetes mellitus describes several diseases of abnormal carbohydrate metabolism that are characterized by hyperglycemia. It is associated with a relative or absolute impairment in insulin secretion, along with varying degrees of peripheral resistance to the action of insulin.

Classification of Diabetes TYPE 1 DIABETES (beta cell destruction, usually leading to absolute insulin deficiency) Immune-mediated Idiopathic Latent autoimmune diabetes in adults (LADA) TYPE 2 DIABETES (insulin resistance with relative insulin deficiency) GESTATIONAL DIABETES MELLITUS OTHER TYPES: GENETIC DEFECTS Maturity onset diabetes of the young (MODY) DISEASES OF THE EXOCRINE PANCREAS Cystic fibrosis, Hereditary hemochromatosis, Chronic pancreatitis, Fibrocalculous pancreatic diabetes ENDOCRINOPATHIES/ DRUG-INDUCED DIABETES

Diabetes is a huge and growing problem… 2014 2035

Diabetes is a huge and growing problem…

Diabetes is a human and economic burden … and the costs to society are high and escalating Diabetes is a human and economic burden 4.9 million deaths per year 50% of deaths under 60 years of age Intersects with all dimensions of development US$612 billion 11% of worldwide healthcare expenditure

Healthcare Impact People with diabetes are more likely to be hospitalized and to have longer durations of hospital stay than those without diabetes 22% of all hospital inpatient days were incurred by people with diabetes Hospital inpatient care accounted for half of the $174 billion total US medical expenditures for this disease Clement et al. Management of Diabetes and Hyperglycemia in Hospital. Diabetes Care 27(2): 553- 591, 2004

CONSIDERATIONS ON ADMISSION Initial orders should state that the patient has type 1 diabetes or type 2 diabetes or no previous history of diabetes. If the patient has diabetes, an order for an A1C should be placed if none is available within the prior 3 months. In addition, diabetes self-management education should be ordered and should include appropriate skills needed after discharge, such as taking glycemic medication, glucose monitoring, and coping with hypoglycemia.

GLYCEMIC TARGETS IN HOSPITALIZED PATIENTS Standard Definition of Glucose Abnormalities: Hyperglycemia in hospitalized patients has been defined as blood glucose > 140 mg/dL An admission A1C value >/ 6.5% suggests that diabetes preceded hospitalization.

Hypoglycemia ADA now defines clinically significant hypoglycemia as glucose values <54 mg/dL, while severe hypoglycemia is defined as that associated with severe cognitive impairment regardless of blood glucose level. A blood glucose level of <70 mg/dL is considered an alert value and may be used as a threshold for further titration of insulin regimens.

HYPOGLYCEMIA Hypoglycemia is associated with increased mortality. Iatrogenic hypoglycemia triggers: reduction of corticosteroid dose reduced oral intake emesis new NPO status inappropriate timing of short-acting insulin in relation to meals unexpected interruption of oral, enteral, or parenteral feedings altered ability of the patient to report symptoms. Predictors of Hypoglycemia In one study (Ulmer et al 2015), 84% of patients with an episode of severe hypoglycemia (<40 mg/dL) had a prior episode of hypoglycemia during the same admission.

HYPOGLYCEMIA In another study of hypoglycemic episodes(Dandy et al 2014), 78% of patients were using basal insulin, with the incidence of hypoglycemia peaking between midnight and 6 A.M. Despite recognition of hypoglycemia, 75% of patients did not have their dose of basal insulin changed before the next insulin administration.

Moderate Versus Tight Glycemic Control Glycemic goals within the hospital setting have changed in the last 15 years. The initial target of 80–110 mg/dL was based on a 42% relative reduction in intensive care unit mortality in critically ill surgical patients. However, a meta-analysis of over 26 studies, including the largest, Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR), showed increased rates of severe hypoglycemia and mortality in tightly versus moderately controlled cohorts. This evidence established new standards: initiate insulin therapy for persistent hyperglycemia greater than 180 mg/dL

Inpatient Glycemic target Once insulin therapy is initiated, a glucose target of 140–180 mg/dL is recommended for most critically ill patients. More stringent goals, such as 110–140 mg/dL may be appropriate for select patients, such as cardiac surgery patients, and patients with acute ischemic cardiac or neurological events provided the targets can be achieved without significant hypoglycemia. American Heart Association (AHA) recommends the use of an insulin infusion when glucose values are >180 mg/dL (10 mmol/L) in patients with an MI and a complicated course A glucose target between 140 and 180 mg/dL is recommended for most patients in non- critical care units.

Bedside Blood Glucose Monitoring In a patient who is eating meals, glucose monitoring should be performed before meals. In a patient who is not eating, glucose monitoring is advised every 4–6 h. More frequent blood glucose testing ranging from every 60 min to every 2 h is required for patients receiving intravenous insulin.

Hospital setting: Insulin therapy is preferred. Treatment Options Hospital setting: Insulin therapy is preferred. Orally administered agents have a limited role in the inpatient setting. ICU setting: IV infusion is the preferred route of insulin administration in patients with labile sugars allows rapid dosing adjustments to address alterations in the status of patients, given its short half life Non ICU setting: subcutaneous administration of insulin

Subcutaneous Insulin Therapy in Hospitalized Patients Three components to a basal/bolus regimen: Basal insulin Meal/prandial or nutritional bolus insulin Correction scale insulin

Physiological Insulin Components Basal: Targets fasting hyperglycemia Nutritional: Targets IV dextrose, TPN, enteral feeds, nutritional supplements or meals (prandial) Correction: “supplemental” insulin for hyperglycemia

Normal Insulin Secretion Basal (background) insulin needs 10 20 30 40 50 2 4 6 8 12 14 16 18 22 24 Serum insulin (µU/mL) Time Meal Bolus (meal) insulin needs 60

Physiological principles of the basal/bolus insulin regimen.9 Copyright © 2011 American Diabetes Association, Inc.

Pharmacokinetics of Insulin Products Rapid (lispro, aspart, glulisine) Insulin Level Short (regular) Intermediate (NPH) Long (glargine) Long (detemir) 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours Adapted from Hirsch I. N Engl J Med. 2005;352:174-183.

Basal Insulin Provides a constant 24-hour peakless level of insulin to suppress the liver's release of glucose during the fasting state and between meals Glargine: Provides relatively peakless basal insulin Basal insulin, when dosed correctly, should not cause hypoglycemia when patients are restricted from oral nutritional intake (NPO)

Bolus insulin / Carbohydrate Coverage Designed to prevent predicted postprandial rise in glucose Best provided with one of the rapid-acting analogs (lispro, aspart, or glulisine) with each meal Have a rapid onset of action and usually reach peak levels within 60 minutes Should be given 0–15 minutes before a meal Insulin to carbohydrate ratio allows flexibility with carbohydrates at meals while maintaining glycemic control

Correction insulin Intended to lower hyperglycemic glucose levels, not to cover nutritional hyperglycemia The mealtime bolus insulin dose + correction insulin dose can be added and administered simultaneously before each meal

LUMC Correction Factor Algorithm Correction Factor - Algorithm A (low dose) For patients requiring a TOTAL of 40 units or less per day: 1 unit if pre-meal glucose 180-210 mg/dL 2 units if pre-meal glucose 211-260 mg/dL 3 units if pre-meal glucose 261-310 mg/dL 4 units if pre-meal glucose 311-360 mg/dL 5 units if pre-meal glucose is greater than 360 mg/dL Correction Factor - Algorithm B (moderate dose) For patients requiring a TOTAL of 41-80 units per day: 2 units if pre-meal glucose 180-210 mg/dL 3 units if pre-meal glucose 211-260 mg/dL 5 units if pre-meal glucose 261-310 mg/dL 7 units if pre-meal glucose 311-360 mg/dL 9 units if pre-meal glucose is greater than 360 mg/dL

LUMC Correction Factor Algorithm Correction Factor - Algorithm "C" (high dose) For patients requiring a TOTAL of 81-120 units per day: 3 units if pre-meal glucose 180-210 mg/dL 5 units if pre-meal glucose 211-260 mg/dL 7 units if pre-meal glucose 261-310 mg/dL 9 units if pre-meal glucose 311-360 mg/dL 11 units if pre-meal glucose is greater than 360 mg/dL Correction Factor - Algorithm "D" For patients requiring a TOTAL of 121-160 units per day: 5 units if pre-meal glucose 180-210 mg/dL 9 units if pre-meal glucose 211-260 mg/dL 13 units if pre-meal glucose 261-310 mg/dL 17 units if pre-meal glucose 311-360 mg/dL 21 units if pre-meal glucose is greater than 360 mg/dL

Subcutaneous Insulin Therapy in inSULin NAÏVE Hospitalized Patients Estimating patients' total daily insulin requirement, or total daily dose (TDD), is the first step in ordering insulin Optimal glycemic control: 50% of TDD is provided as basal insulin and 50% is provided as bolus insulin.

Carbohydrate Coverage Method for setting carbohydrate ratio   1. The 500 rule and Total daily dose (TDD) of insulin Divide 500 by the person’s TDD (all the insulin a patient uses in a day –basal and bolus) Example: The patient is on Lantus 20 units, and Novolog 4 units before each meal This patient’s TDD is then 32 units ( 20 + 12) 500/TDD 500/32 = 15.6 This patients initial ICR would then be set at 1/15 or one unit of insulin for every 15 grams of carbohydrate consumed

Correction Scale: Insulin Sensitivity Factor Sensitivity factor (also referred to as the correction factor) is the drop in blood glucose level, measured in milligrams per deciliter (mg/dl), caused by each unit of insulin taken  

Insulin Sensitivity Factor Two most common methods for figuring the sensitivity factor 1500 and 1800 rules 1500 rule: sensitivity factor for regular insulin 1800 rule: sensitivity factor for rapid acting insulin To figure the sensitivity factor: Figure the person’s total daily dose of insulin (TDD) Divide 1800 by the TDD : This is the person’s sensitivity factor.  

Insulin Sensitivity Factor Example: The patient takes 20 units of Lantus at night and 5 units of Novolog before each meal TDD of insulin is 35 1800/35= 51 (Round to 50) This person’s sensitivity factor is 50 1 unit of rapid acting insulin will drop this person’s blood glucose levels about 50 mg/dl. Using the sensitivity factor: Patient’s blood glucose level is 300 mg/dl with their goal blood glucose set at 150 mg/dl. This patient’s blood glucose is 150 mg/dl above goal. Take 150 and divide by 50 (sensitivity factor). 150/50=3 This patient would need to take 3 units of rapid acting insulin to bring their blood glucose level down to their goal of 12=50mg/dl  

Adjusting Inpatient Insulin Therapy Fasting glucose is the best indicator of adequacy of the basal insulin dose Glargine can be adjusted every 24–48 hours until fasting glucose is < 140 mg/dl. Glucose levels during the rest of the day: appropriateness of mealtime bolus insulin doses (rapid-acting insulin) Prelunch glucose: breakfast dose Predinner glucose: lunchtime dose Bedtime glucose: dinnertime dose

When should we administer insulin and check POC glucose levels? If the patient is eating, insulin injections should align with meals. In such instances, POC glucose testing should be performed immediately before meals. If oral intake is poor, a safer procedure is to administer the rapid-acting insulin immediately after the patient eats or to count the carbohydrates and cover the amount ingested.

RABBIT 2 TRIAL RABBIT 2 Trial: (Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes) Prospective, multicenter, randomized trial Insulin-naive type 2 diabetic patients on general medicine floor Compared basal-bolus vs. SSI Primary end point: mean daily blood glucoses Secondary outcomes: hypoglycemic events, severe hyperglycemia, LOS & mortality rate Umpierrez et al. Diabetes Care 30(9): 2181-2186, 2007.

RABBIT 2 TRIAL Glycemic control rapidly improved after switching to basal-bolus regimen after persistent severe hyperglycemia Basal/bolus insulin regimen is preferred over SSI in the management of noncritically-ill, hospitalized patients with type 2 diabetes

Sliding Scale

SELF MANAGEMENT IN THE HOSPITAL: Continuous subcutaneous insulin infusion (CSII) pump therapy Candidates: patients who successfully conduct self-management of diabetes at home have the cognitive and physical skills needed to successfully self-administer insulin have adequate oral intake be proficient in carbohydrate estimation have stable insulin requirements

CRITERIA FOR SELF MANAGEMENT OF Insulin PUMP Mentally alert and oriented x 3 Has no physical/dexterity limitations Alternatively, if patient unable to self-manage, a non-health system caregiver (i.e. family member/guardian) is available to provide support/assistance to manage insulin pump 24 hours/day Medically stable No identified reasons for pump discontinuation Criteria for pump discontinuation: Cognitive or psychological limitations: Altered, deteriorating or fluctuating changes to state of consciousness and/or cognitive status, including use of medications that may interfere with cognition or may be sedating (e.g. narcotics) Psychiatric illness that interferes with the patient’s ability to self-manage (at risk of selfharm/suicide) Medical conditions: DKA, or persistent unexplained hyperglycemia Persistent/recurrent severe hypoglycemia Critically ill (sepsis, trauma) and needs intensive care Other inter-current illnesses where use of the insulin pump is risky or non-effective, as determined by the medical staff

CRITERIA FOR SELF MANAGEMENT OF Insulin PUMP Pump functionality or performance limitations: Pump not functioning Hyperglycemia fails to respond to appropriate action (bolus insulin) Insufficient pump supplies (hospital will not provide) Physical limitations to using the insulin pump Refusal or unwillingness to participate in self-care or to agree to self-management terms Non-health system guardian or caregiver support/assistance (for patients under 18), required to manage insulin pump, is not available 24 hours/day

ORAL ANTIHYPERGLYCEMIC AGENTS IN HOSPITALIZED PATIENTS In most instances in the hospital setting, insulin is the preferred treatment for glycemic control. However, in certain circumstances, it may be appropriate to continue home regimens including oral antihyperglycemic medications.

DM Type 2: Diet Treated Minor surgery/imaging procedure/non-critical acute illness: no specific anti-hyperglycemic therapy Continue Blood glucose monitoring Insulin therapy should be instituted if the preprandial blood glucose concentration exceeds 180 mg/dL Insulin may not be necessary after the episode is over On NPO: correction insulin can be administered every six hours if the patient is eating with BG >180 mg/dL: basal-bolus insulin regimen should be initiated

Specific Clinical Situations Patients Receiving Glucocorticoid Therapy Hyperglycemia is a common complication of corticosteroid therapy (post prandial glucose) Institute glucose monitoring for at least 24 hours in all patients receiving high-dose glucocorticoid therapy During corticosteroid tapers, insulin dosing should be proactively adjusted to avoid hypoglycemia Glucocorticoid type and duration of action must be considered in determining insulin treatment regimens. Once-a- day, short-acting glucocorticoids such as prednisone peak in about 4 to 8 h so coverage with intermediate- acting For long-acting glucocorticoids such as dexamethasone or multidose or continuous glucocorticoid use, long-acting insulin may be used.

Situation Basal/Nutritional Correctional Continuous enteral feedings Continue prior basal If no known basal: calculate from TDD or consider 10 units glargine daily Nutritional: rapid-acting insulin every 4-6 hour Rapid-acting insulin every 4-6h for hyperglycemia Bolus enteral feedings Continue prior basal or, if none, calculate from TDD or consider 10 units glargine daily Nutritional: rapid-acting insulin SQ before each feeding Rapid-acting insulin every 4-6 h for hyperglycemia Parenteral feedings Add regular insulin to TPN IV solution Rapid-acting insulin every 4 h for hyperglycemia

Common Treatment Pitfalls Using order set as “SS” Bolus + correction factor Not using basal Rabbit 2 trial Uptitrating basal w/o bolus Basal and Bolus= 50:50 Holding basal when NPO not required if dosed properly Adjusting insulin w/o discussing w/ nurse Team Work

Discharge planning Preparation for transition to the outpatient setting should begin at the time of hospital admission Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management. Appointment-keeping behavior is enhanced when the inpatient team schedules outpatient medical follow- up prior to discharge.

Discharge pLANNING Following areas of knowledge be reviewed and addressed prior to hospital discharge: Identify the health care provider who will provide diabetes care after discharge. Level of understanding related to the diabetes diagnosis, self- monitoring of blood glucose, explanation of home blood glucose goals, and when to call the provider. Definition, recognition, treatment, and prevention of hyperglycemia and hypoglycemia. Information on consistent nutrition habits. It is important that patients be provided with appropriate durable medical equipment, medications, supplies (e.g., insulin pens), and prescriptions along with appropriate education at the time of discharge in order to avoid a potentially dangerous gap in care.

TRANSITION FROM THE ACUTE CARE SETTING An outpatient follow-up visit with the primary care provider, endocrinologist, or diabetes educator within 1 month of discharge is advised for all patients having hyperglycemia in the hospital. If glycemic medications are changed or glucose control is not optimal at discharge, an earlier appointment (in 1–2 weeks) is preferred, and frequent contact may be needed to avoid hyperglycemia and hypoglycemia.

PREVENTING ADMISSIONS AND READMISSIONS Preventing Hypoglycemic Admissions in Older Adults Insulin-treated patients 80 years of age or older are more than twice as likely to visit the emergency department and nearly five times as likely to be admitted for insulin-related hypoglycemia than those 45–64 years of age. To further lower the risk of hypoglycemia- related admissions in older adults, providers may, on an individual basis, relax A1C targets to <8% or <8.5% in patients with shortened life expectancies and significant comorbidities

Summary Managing diabetes and hyperglycemia during hospitalization : vital for optimal clinical outcomes Insulin: best treatment for inpatient management but can be very challenging given the stress of illness, changing caloric intake throughout the hospital stay and limitations to care provided by hospital personnel Understanding of physiological insulin administration and the use of the three components of subcutaneous insulin therapy (basal, mealtime bolus, and correctional insulin)

SUMMARY Perform an A1C for all patients with diabetes or hyperglycemia admitted to the hospital if not performed in the prior 3 months.  Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold ≥180 mg/dL. Once insulin therapy is started, a target glucose range of 140–180 mg/dL is recommended for the majority of critically ill patients and noncritically ill patients.    Sole use of sliding scale insulin in the inpatient hospital setting is strongly discouraged.  Early and thoughtful discharge planning: helps to ensure continued glucose control in the outpatient setting

ENDOCRINE QUESTIONS

Glycemic Control in the Hospitalized Patient Inpatient Management of Hyperglycemia : a review THANK YOU!