Insulin Therapy in Hospitalization

Outline

•Impact of hyperglycemia

•Glucose the 6th vital sign

•Indication of insulin therapies

•Insulin using strategies

•2013 ADA recommendation

•Other specific conditions

•Summary

Impact of Hyperglycemia

and Diabetes and the Hospital

• Hyperglycemia affects the body’s ability to heal, resulting in increased lengths of stay and leading to complications

• Mortality risk increases dramatically when diabetes is not diagnosed and not effectively treated during a hospital stay

• Diabetes causes a 2-4 fold increase in rates of hospitalizations and increases lengths of stay by 1-3 days.

Factors Affecting Blood Glucose

Levels in the Hospital Setting

• Increased counter-regulatory hormones

• Changing IV glucose rates

• TPN and enteral feedings

• Lack of physical activity

• Unusual timing of insulin injections

• Use of glucocorticoids

• Unpredictable or inconsistent food intake

• Fear of hypoglycemia

• Cultural acceptance of hyperglycemia.

Important counter-regulatory hormones and mediators of

inflammation known to be associated with acute hyperglycemia

Glucoregulatory Hormone Metabolic Effect

Cortisol ↑ Skeletal muscle IR, ↑ lipolysis ↑gluconeogenesis

Epinephrine ↑ Skeletal muscle IR, ↑ gluconeogenesis and

glycogenolysis, ↑ Lipolysis, ↓ insulin secretion from βcell

Norepinephrine ↑ Gluconeogenesis (at high levels), ↑ lipolysis

Glucagon ↑ Gluconeogenesis and glycogenolysis

Growth hormone ↑ Skeletal muscle IR, ↑ gluconeogenesis, ↑ lipolysis

Inflammation Mediators Metabolic Effect

TNF-a ↑ Skeletal and hepatic IR

IL-1 ↑ Skeletal and hepatic IR

IL-6 ↑ Skeletal and hepatic IR

IL-18 ↑ Skeletal and hepatic IR

FFAs ↑ Skeletal and hepatic IR, ↑ gluconeogenesis

“Glucose: the 6th vital sign”

Measure blood glucose in Measure blood glucose in allall patients patients

admitted with acute illnessadmitted with acute illness

–– AllAll patients with type 1 diabetes will require at patients with type 1 diabetes will require at

least basal insulin replacementleast basal insulin replacement

–– MostMost insulin treated patients will require insulin treated patients will require

continued insulin therapycontinued insulin therapy

–– Consider insulin therapy in Consider insulin therapy in anyany patient with patient with

random blood glucose random blood glucose > > 180 mg/dl180 mg/dl

Inpatient Glycemic Management

• Definition of terms:

• Hospital hyperglycemia: Any BG > 140 mg/dl (7.8 mmol/L)

• Stress hyperglycemia: Elevations in blood glucose levels that occur in patients with no prior history of diabetes and A1c levels that are not significantly elevated (<6.5%)

– A1c values above 6.5 in patients with hyperglycemia suggests a prior history of diabetes

• Hypoglycemia: Any BG < 70 mg/dl (3.9 mmol/L)

• Severe hypoglycemia: Any BG < 40 mg/dl (2.2 mmol/L)

Stress Hyperglycemia Associated with

Increased Morbidity/Mortality

• Acute MI

• Acute stroke

• Medical and surgical admits to an

inner city hospital

• CABG patients

Recommended Inpatient

Glycemic Targets

• Maintain fasting and preprandial BG <140 mg/dL(7.8 mmol/L)

• Modify therapy for BG < 100 mg/dl to avoid risk for hypoglycemia

• Maintain random BG <180 mg/dL (10 mmol/L)

• More stringent targets may be appropriate in stable patients with previous tight glycemic control.

• Less stringent targets may be appropriate in terminally ill patients or in patients with severe co-morbidities.

Features of noninsulin, glucose-lowering agents

that limit in-hospital use

Class of Agent Limitations Limitations

Sulfonylureas (eg, glyburide, glipizide) Long action

Hypoglycemia

Meglitinides (eg, repaglinide, nateglinide) Primarily prandial in effect

Hypoglycemia

Biguanides (eg, metformin) Risk of lactic acidosis

Thiazolidinediones (eg, pioglitazone,

rosiglitazone)

Delayed onset of effect

Increased intravascular volume

Glucagon-like peptide-1 agonists (eg,

exenatide)

Inappropriate for patients who are not

eating

Nausea

Dipeptidyl peptidase-4 inhibitors (eg,

vildagliptin, sitagliptin)

Inappropriate for patients who are not

eating

Indications for IV insulin therapy

• Critical illness

• Prolonged NPO status

• Perioperative period

• Following organ transplantation

• Cardiogenic shock

• Use of total parenteral nutrition

• Hyperglycemia exacerbated by high-dose

• glucocorticosteroid therapy

• Stroke

• Diabetic ketoacidosis

• Nonketotic hyperosmolar state

• Pregnancy

• Any illness requiring prompt glucose control

Temporal profile of glucose management in acute ischemic stroke.

Fuentes B et al. Stroke 2010;41:2362-2365

Kaplan-Meier survival curves according to the presence of persistent (dotted line) or isolated hyperglycemia ≥155 mg/dL (gray line) or glycemia <155 mg/dL (bold line).

Fuentes B et al. Stroke 2010;41:2362-2365

Endogenous Insulin

• Protein Hormone• Secreted Beta Cells-Pancreas

• 1-2 Units per hour• 4-6 Units per meal

– 1 units x 24hrs + – 4 units x 3 meals

• Total 36 Units per day

Insulin Degradation

• Hydrolysis of the disulfide linkage between

A&B chains

• 60% liver, 40% kidney (endogenous insulin)

half life 5-7 minutes

– Inhibit by hypoxia, hypothermia,

• 60%kidney, 40% liver (exogenous) delayed

release form

• Category B (not teratogenic)

Key Concepts of Insulin Therapy

•• BasalBasal insulininsulin

–– Controls hepatic glucose productionControls hepatic glucose production

•• FoodFood ((prandialprandial) insulin) insulin

–– Based on meal carbohydrate contentBased on meal carbohydrate content

•• CorrectionCorrection ((supplementalsupplemental) insulin) insulin

–– Treats acute elevation in blood glucoseTreats acute elevation in blood glucose

Using Insulin in the

Hospital

First, Determine Source/Route of Nutrition

Second, Estimate a Starting Dose of Scheduled Insulin

Third, Know the Kinetics of the insulin you are using and make a plan

Prandial

insulin

Source of Nutrition- Effects

on Insulin Secretion

B L DB L D

Basal insulinBasal insulin Basal insulin

Prandial insulin

The Eating PatientPt. Receiving Continuous Feeds

Estimating a Starting

DoseUse patient’s home regimen� Adjust as clinically indicated

Make a weight based estimate*� Start 0.4units/kg for glucose 140-200

� Start 0.5 units/kg for glucose 201-400

� Consider lower starting dose with significant renal or hepatic impairment

Estimate basal insulin and carb count � Difficult to achieve in the hospital

� If attempting, estimate basal insulin (.2-.25 units/kg/day)

� Type I: Give 1 unit per 15g carbohydrates

� Type II: Give 1 unit per 10g carbohydrates

Diabetes Care 30:2181-2186, 2007

Kinetics of Insulins

Regular

NPH

0 126 18 24

aspart/glulisine/lispro

glargine

Mimicking Nature With Insulin

Basal/Bolus ConceptPhysiologic Insulin Secretion

Insu

lin

(µU

/mL

)

Glu

co

se

(mg

/dL

)

9

B L D

150

100

50

07 8 91011121 2 3 4 5 6 7 8

AM PMTime of Day

Basal glucose

50

25

0

24-hr profile

Basal insulin

Adapted from Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology.

4th ed. Philadelphia, Pa: WB Saunders Co.; 2001:821

Insulin aspart/glulisine/lispro Insulin glargine

Basal-Bolus Insulin Therapy:

Insulin Glargine at HS

and Mealtime Lispro or Aspart

B DL HS

Ins

ulin

Eff

ect

Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker Inc.; 2002:87

Example: Patient’s Total

Daily Insulin Estimate=60

Units

10 units aspart

glulisinelispro

10 unitsaspart

glulisinelispro

10 unitsaspart

glulisinelispro

30 unitsglargine

Ins

ulin

Eff

ect

Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker Inc.; 2002:87

Twice-Daily Split-Mixed

Regimens

Regular

NPH

B DL HS B

Endogenous insulin

Dawn

phenomenon

Hyperglycemia

13 units NPH

Example: Patient’s Total Daily

Insulin Estimate=60 Units

27 units NPH

40 units of insulin

in the a.m.

20 units of insulin

in the p.m.

+13 units regular +7 units regular

Intensive Insulin Therapy in Hospitalized Patients: A Systematic Review

Ann Intern Med. 2011;154(4):268-282. doi:10.1059/0003-4819-154-4-201102150-00008

Short-term mortality in studies of intensive

insulin therapy, by inpatient setting.

Ann Intern Med. 2011;154(4):268-282. doi:10.1059/0003-4819-154-4-201102150-00008

Short-term mortality in studies of intensive insulin therapy, by the mean glucose

level achieved in the intervention group.

Ann Intern Med. 2011;154(4):268-282. doi:10.1059/0003-4819-154-4-201102150-00008

Mortality at 90 or 180 d in studies of intensive insulin therapy, by inpatient setting.

Ann Intern Med. 2011;154(4):268-282. doi:10.1059/0003-4819-154-4-201102150-00008

Effects of intensive insulin therapy on rates of infection in various inpatient settings.

Ann Intern Med. 2011;154(4):268-282. doi:10.1059/0003-4819-154-4-201102150-00008

Risk for hypoglycemia in studies of intensive insulin therapy in various inpatient settings.

Ann Intern Med. 2011;154(4):268-282. doi:10.1059/0003-4819-154-4-201102150-00008

2013 American Diabetes Association recommendations

for diabetes care in the hospital

• For patients who have diabetes and are admitted to the hospital,diabetes should be clearly identified in the medical record.

• All patients with diabetes should have an order for blood glucose monitoring.

• Goals for blood glucose levels:– Critically ill patients: Blood glucose levels should be kept as close as

possible to 6.1 mmol/L (110 mg/dL) and generally <7.8 mmol/L (140 mg/dL) through use of a safe and effective intravenous insulin protocol.

– Noncritically ill patients: Fasting blood glucose levels should be <7.0 mmol/L (126 mg/dL), and random glucose levels should be <10.0 to11.1 mmol/L (180–200 mg/dL).

• Use of scheduled prandial and basal insulin is recommended.

• Prandial doses should be appropriately timed in relation to meals and should be adjusted according to point-of-care glucose levels.

2013 American Diabetes Association recommendations

for diabetes care in the hospital

• Supplementary insulin may be used in addition to scheduled insulin to correct premeal hyperglycemia.

• Glucose monitoring with orders for correction insulin should be initiated for patients who are not known to be diabetic but receive therapy associated with a high risk for hyperglycemia.

• A plan for treating hypoglycemia should be established for each patient.

• Episodes of hypoglycemia should be tracked.

• All patients with diabetes who are admitted to the hospital should have their glycosylated hemoglobin level determined

• if the results of testing in the previous 2 to 3 months are not available.

• A diabetes education plan should be developed for each patient.

• Patients who have hyperglycemia in the hospital but do not have a diagnosis of diabetes should undergo appropriate follow-up testing.

• Extra rapid acting insulin for premeal

hyperglycemia

• Lispro and aspart ideal:• rapid onset of action controls hyperglycemia

• rapid offset makes later hypoglycemia less likely

• NO doses less than 4 hours apart to avoid

“STACKING” and hypoglycemia

• Bedtime supplemental insulin: selected

patients

Supplemental Insulin AKA Correction

Dose AKA Sliding Scale

Barriers to Inpatient Diabetes

Management

•• Increased insulin requirement due to illnessIncreased insulin requirement due to illness

•• Exaggerated variability in subcutaneous insulin Exaggerated variability in subcutaneous insulin

absorptionabsorption

•• NPO status; inconsistent oral intake; interruption of NPO status; inconsistent oral intake; interruption of

meals by proceduresmeals by procedures

•• Unpredictable arrival of meals Unpredictable arrival of meals

•• Inability of patient to participate in management Inability of patient to participate in management

decisionsdecisions

•• Medication errorsMedication errors

Indications for IV Insulin Therapy

•• DKA/ HHSDKA/ HHS

•• Critical illnessCritical illness

•• Major surgeryMajor surgery

–– Cardiopulmonary bypass surgeryCardiopulmonary bypass surgery

–– Transplantation surgeryTransplantation surgery

–– Abdominal surgery (NPO postAbdominal surgery (NPO post--op)op)

IV Insulin Therapy- Considerations

•• Define target blood glucose.Define target blood glucose.

•• Define threshold for initiating therapy.Define threshold for initiating therapy.

•• Determine starting dose (& bolus) based on glucose Determine starting dose (& bolus) based on glucose

level.level.

•• Adjust infusion rate based on rate of change in blood Adjust infusion rate based on rate of change in blood

glucose. Infusion rates will vary depending on glucose. Infusion rates will vary depending on

individual patientindividual patient’’s insulin sensitivity.s insulin sensitivity.

•• Define when to interrupt therapy for low blood Define when to interrupt therapy for low blood

glucose.glucose.

IV to SC Insulin

•• Begin subcutaneous basal insulin while the patient continues Begin subcutaneous basal insulin while the patient continues to receive iv insulin.to receive iv insulin.

•• Add prandial insulin when the patient is able to resume oral Add prandial insulin when the patient is able to resume oral intake.intake.

•• Taper iv insulin, maintaining predetermined targets. IV Taper iv insulin, maintaining predetermined targets. IV insulin can be discontinued when:insulin can be discontinued when:–– IV insulin requirements are IV insulin requirements are <<1 u/hr 1 u/hr

–– Glucose is Glucose is <<120 mg/dl on two consecutive determinations120 mg/dl on two consecutive determinations

–– The patient is eating solid foods without difficultyThe patient is eating solid foods without difficulty

•• If the patient can immediately resume usual diet, and insulin If the patient can immediately resume usual diet, and insulin requirements are known, iv insulin can be stopped after first requirements are known, iv insulin can be stopped after first injection of basal insulin.injection of basal insulin.

Use of Subcutaneous Insulin in Hospital

•• UnpredictableUnpredictable

•• Best choice for insulin treated patient who is Best choice for insulin treated patient who is

able to eatable to eat

•• Options:Options:

–– Once daily NPH insulin (type 2 diabetes only)Once daily NPH insulin (type 2 diabetes only)

–– Twice daily Twice daily ““splitsplit--mixmix”” insulin/preinsulin/pre--mix insulinmix insulin

–– MDI or CSIIMDI or CSII

•• Listen to the experienced patientListen to the experienced patient

Starting Insulin in the Newly Diagnosed Patient

•• Calculate the total daily doseCalculate the total daily dose

•• Determine basal insulin requirementDetermine basal insulin requirement

–– 40 to 50% of total daily dose40 to 50% of total daily dose

•• Determine the mealtime insulin requirementDetermine the mealtime insulin requirement

–– 50 to 60% of total daily dose50 to 60% of total daily dose

•• Determine the correction doseDetermine the correction dose

–– Based on estimate of insulin sensitivityBased on estimate of insulin sensitivity

Daily Insulin Requirements

Patient Description Insulin (units/kg.day)

Trained athlete 0.5

Mod. active man 0.6

Sedentary man; 1st trimester of pregnancy

0.7

Mod. stressed man; 2nd

trimester of pregnancy0.8

Severely stressed man; 3rd

trimester of pregnancy0.9

Systemic bacterial infection; full term pregnancy

1.0

Severely ill man 1.5-2.0

Corticosteroid Therapy and Diabetes

•• Minimal elevation of fasting glucose Minimal elevation of fasting glucose

•• Exaggeration of postprandial hyperglycemiaExaggeration of postprandial hyperglycemia

•• Lack of sensitivity to exogenous insulinLack of sensitivity to exogenous insulin

Consider:Consider:

•• Prandial insulin in patients without prior history of Prandial insulin in patients without prior history of

diabetesdiabetes

•• 70% prandial insulin, 30% basal insulin in patients 70% prandial insulin, 30% basal insulin in patients

with established diabetes historywith established diabetes history

TPN and Diabetes

•• TPN commonly leads to hyperglycemia in the TPN commonly leads to hyperglycemia in the absence of diabetes.absence of diabetes.

•• Insulin requirements are increased in patients Insulin requirements are increased in patients

with diabetes; 75% of patients with type 2 with diabetes; 75% of patients with type 2 diabetes not previously treated with insulin diabetes not previously treated with insulin

will require insulin with TPN.will require insulin with TPN.

•• IV insulin should be infused separately until IV insulin should be infused separately until requirements are known; insulin can then be requirements are known; insulin can then be

added to the TPN solutionadded to the TPN solution.

Enteral Nutrition and Diabetes

•• Enteral nutritional support can result in hyperglycemia, Enteral nutritional support can result in hyperglycemia, even in the absence of diabetes. In patients with even in the absence of diabetes. In patients with

established diabetes, insulin requirements increase established diabetes, insulin requirements increase

substantially.substantially.

•• High fat formulas (monounsaturated fats) achieve better High fat formulas (monounsaturated fats) achieve better

metabolic control that traditional high carbohydrate metabolic control that traditional high carbohydrate

preparations.preparations.

•• Blood glucose control may be attainable with long acting Blood glucose control may be attainable with long acting

subcutaneous insulin preparationssubcutaneous insulin preparations-- insulin glargine (with insulin glargine (with constant nutrition).constant nutrition).

–– Previous diabetes: Previous diabetes: ¾¾ TDDTDD

–– Insulin naInsulin naïïve: 0.6 units/kgve: 0.6 units/kg

Intermittent Enteral Nutrition

•• Basal insulin as NPH at the start of nutritional Basal insulin as NPH at the start of nutritional

supportsupport

–– Previous diabetes: Previous diabetes: ½½ TDDTDD

–– Insulin naInsulin naïïve: 0.4 units/kgve: 0.4 units/kg

•• Regular insulin usually required at start of Regular insulin usually required at start of

feedingfeeding

–– 25 to 50% of NPH dose25 to 50% of NPH dose

Insulin Regimen

Maynard et al., 2008. J Hosp Med (3) S5

Insulin at Hospital Discharge

Titrate based on the morning fasting blood sugar: Decrease 4 units if below 60 mg/dL, Decrease 2 units if 60 to 80 mg/dL, No change if 80 to 100 mg/dL, Increase 2 units if 100 to 120 mg/dL, Increase 4 units if 121 to 140 mg/dL, Increase 6 units if 141 to 160 mg/dL, Increase 8 units if 161 to 180 mg/dL, Increase10 units if fasting blood sugar is >180 mg/dL.

O’Malley et al., 2008. J Hosp Med (3) S5

Pitfalls with Insulin Drips

• Turning off dextrose while insulin still running

hypoglycemia

• Failing to notice when blood glucose is falling

too fast

• Stopping an insulin drip without having given

subQ insulin – this causes patients to develop

(or RE-develop DKA)

Transition to SubQ Insulin

• When able to eat

• Best time to stop is when a dose of basal insulin would usually be given – AFTER the dose has been given

• Strategies for glargine (typically dosed at bedtime)

– Continue IVF and drip at “basal” rate and give prandial insulin SQ

– give 1/2 usual glargine dose as NPH in the morning before stopping the drip

What if I can’t use an insulin drip?

• BASAL insulin - 2/3 of NPH dose or glargine dose (use 100% of glargine dose ONLY if type 1 AND no fasting hypoglycemia)

• AT UWMC/HMC -use RAPID acting insulin to correct hyperglycemia if CBG > 180-200

• No rapid acting doses < 4 hours apart!!

• Adjust basal insulin dose if extra insulin required

住院病人住院病人住院病人住院病人(non-critical ill patients)高血糖之治療高血糖之治療高血糖之治療高血糖之治療住院高血糖定義: 住院時血糖超過140mg/dl

血糖機做血糖監測(註1)，所有病患需測HbA1C一次。

註1. 監測血糖點：1正常三餐飲食：測三餐餐前及睡前血糖共4次。2NPO患者：每六小時測一次血糖值。註2. NPO患者僅用基礎(Basal)胰島素註3.住院血糖管控目標:Non-critical ill patients: pre-meal BG <7.8mmol/L (140 mg/dl)、random BG <10mmol/L (180 mg/dl)

1停用所有口服降血糖藥2使用皮下胰島素Basal-bonus(基礎加三餐餐前)(註2)。

步驟四：每日依血糖值調整胰島素劑量至達到管控目標(註3)

當血糖值<100mg/dl注意胰島素是否過量或有低血糖發生

當血糖值<70mg/dl需立刻減少胰島素劑量

出院準備•確認出院藥物，搭配血糖監測無發生低血糖狀況，方可準備出院。(讓病人在住院時，使用出院會帶回的藥，先確認這個藥品及劑量是適合)

•務必開立糖尿病衛教會診單，對病患及家屬做衛教。•鼓勵自我患者血糖監測並定期回診。

步驟一：計算每日胰島素總劑量(1) 0.2-0.3 U/kg: 年齡 > 70 y/o, or eGFR < 60 ml/min or 肝硬化(2) 0.4 U/kg: 血糖值: 140-200 mg/dl

(3) 0.5-0.6 U/kg: 血糖值 > 200 mg/dl

步驟二：50%的總劑量為基礎胰島素，使用Detemir或Lantus在睡前注射

步驟三：50%的總劑量平均分配在三餐餐前，使用Novorapid

Summary

• Hyperglycemia will induce systemic noxious reactions which cause series vicious cycles.

• The role of controlling blood sugar became the 6th vital signs.

• Indication of insulin therapies and strategies are basic clinical skills for any kind of doctors as the maintain the vital survives.

• ADA revised the commendations about inpatient glycemia control annually which emphasized the important roles.

Summary

• Doctors shall make different decisions when

meet the distinct status with variant

treatments.

• Each hospital can set own flow chart for

enhancing the care abilities about glucose

controls.