Glycemic Control for Inpatient Diabetes

Evidence of Increased Morbidity and Mortality

Associated with In-Hospital Hyperglycemia …

Stress Hyperglycaemia and Increased Risk of Death After Myocardial Infarction in Patients with and without Diabetes: A Systematic Review. SE Capes et al. Lancet 2000 355: 773-778.

• Meta-analysis of 15 studies reported that hyperglycemia (blood glucose >110 mg/dl) with or without a prior diagnosis of diabetes increased both in-hospital mortality and congestive heart failure (CHF) in patients admitted for acute myocardial infarction.

Hyperglycemia: an Independent Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes.

Umpierrez GE, et al. J Clin Endocrinol Metab. 2002; 87: 978–982.

• Hyperglycemia occurred in 38% of patients admitted to the hospital– 26% with known history of diabetes

– 12% with no history of diabetes

• Newly discovered hyperglycemia was associated with:– Higher in-hospital mortality rate (16%) compared with

patients with a history of diabetes (3%) and patients with normoglycemia (1.7%; both P < 0.01)

– Longer hospital stays (9 vs 4.5 days)

– Greater risk of infection

– Higher admission rates to intensive care units

– Less chance to be discharged to home (required more transitional or nursing home care)

Hyperglycemia: A Predictor of Mortality Following CABG in Diabetes.

Furnary AP, Zerr KJ, et al. Circulation. 1999;100:I-591.

• Hyperglycemic patients undergoing cardiac surgery suffer greater mortality, increased deep wound infections and overall infection.

• Hyperglycemia, on the first and second postoperative days, was the single most important predictor of serious infectious complications.

Intensive Insulin Therapy in Critically Ill Patients.

Van den Berghe, et al. N Engl J Med, 2001,345:1359-1367

• In patients treated for critical illness, it was noted that hyperglycemic patients treated with conventional therapy suffer increased overall mortality and an increased risk of sepsis, acute renal failure and critical illness-related neuropathy.

Association Between Hyperglycmia and Increased Hospital Mortality in a Heterogenous Population of Critically Ill Patients

James S. Krinsley, et al. Mayo Clinic Proceedings, 2003;78:1471 • In 1,826 ICU patients, mortality was directly correlated wi

th increasing glucose levels above 80 mg/dl, showing a direct and proportional correlation.

• Hospital mortality increased progressively as glucose values increased, reaching 42.5% among patients with mean glucose values exceeding 300 mg/dL. Within each of 3 groupings of APACHE II scores (0-14; 15-24; ≥ 25), mean and maximum glucose values were higher among nonsurvivors than among survivors.

Stress Hyperglycemia and Prognosis of Stroke in Nondiabetic and Diabetic Patients. A System

atic Overview. Capes SE, Hunt D, Malmberg K et al. Stroke. 2001; 32: 2426-2432

• Both diabetes and hyperglycemia have been associated with a poor outcome in patients with cerebrovascular accidents. A meta-analysis of 26 studies on stroke showed increased in-hospital mortality in patients with blood glucose levels of 110-126 mg/dl.

Stroke Topography and Outcome in Relat

ion to Hyperglycaemia and Diabetes. Kiers L, et al. J Neurol Neurosurg Psychiatry, 1992, 55:263 -270

• Stroke survivors with a blood glucose of 121-144 mg/dl without known diabetes showed worse functional recovery.

• Patients with known diabetes and/or newly-discovered hyperglycemia (blood glucose 140 m>g/dl) had more severe strokes with greater mortality.

Insulin and Glucose Requirements During the First Stage of Labor in Insulin-Dependent Diabeti

c Women. Jovanovic L, Peterson CM. Am J Med. 1983;75:607-612.

• Pregnancy complicated by uncontrolled diabetes results in poor fetal outcomes.

• Intensive glycemic control during labor and delivery also significantly benefits fetal well-being.

Evidence of Improving Outcome with Reduction of

Hyperglycemia …

Intensive Insulin Therapy in Critically Ill Patients. Van den Berghe, et al. N Engl J Med, 2001,345:1359-1367

• In ICU, patients treated for hyperglycemia (>110 mg/dl) with intensive intravenous insulin infusions, hospital mortality was reduced by 34%.

• Intensive insulin therapy in ICU patients resulted in decreases in sepsis (46%), acute renal failure (41%), transfusions (50%) and critical illness polyneuropathy (44%).

Continuous Insulin Infusion Reduces Mortality in Patients with Diabetes Undergoing Coronary

Artery Bypass Grafting. Furnary AP, et al. J Thorac Cardiovasc Surg 2003;125:1007-1021.

• Hyperglycemic cardiac surgery patients treated with intravenous insulin infusions used for the first 3 postoperative days demonstrated reductions in absolute, and risk-adjusted mortality of 57% and 50%, respectively.

Glycometabolic State at Admission: Important Risk Marker of Mortality in Conventionally Treated Patients With Diabetes Mellitus and Acute Myocardial Infarction Long-Term Results From the Diabetes and Insulin-Glucose Infusio

n in Acute Myocardial Infarction (DIGAMI) Study Klas Malmberg, et al. Circulation 1999;99:2626-2632

• Long-term survival rates in diabetic patients with acute myocardial infarction were improved by 28% at 3.4 years when treated with insulin infusions designed to achieve normoglycemia at the time of infarct.

Effects of Insulin1. Insulin inhibits lipolysis. Elevated free fatty acids result in

cardiac sympathetic overactivity, which increases the risk of cardiac arrhythmias and sudden death in patients with diabetes.

2. Insulin inhibits inflammatory growth factors (activator protein 1 and early growth response gene-1), which are particularly important in acute myocardial infarction.

3. Insulin stimulates endothelial nitric oxide (NO) synthase, which subsequently enhances NO resulting in arterial vasodilation.

4. Insulin, in the environment of euglycemia or near-euglycemia, appears to inhibit proinflammatory cytokines, adhesion molecules, and chemokines, in addition to acute phase proteins.

Nitric Oxide

• Inhibits – Vascular smooth muscle cell growth

and migration

– Platelet aggregation and thrombosis

– Monocyte adhesion

– Inflammation

– Oxidation

American College of EndocrinologyConsensus Conference on InpatientDiabetes and Metabolic Control (2003)

Glycemic Targets in Hospitalized Patients ︰• Intensive care unit

– 110 mg/dL (6.1 mmol/L)

• Medical/surgical floors (non-critical care units)– 110 mg/dL (6.1 mmol/L) preprandial– 180 mg/dL (10.0 mmo/L) maximal glucose

American College of EndocrinologyConsensus Conference on InpatientDiabetes and Metabolic Control (2003)

Glycemic Targets in Pregnant Patients ︰• Pre-Labor

– preprandial ︰ 100 mg/dl– 1-hour postprandial ︰ 120 mg/dl

• Labor and Delivery– 100 mg/dl

Values above 180 mg/dL are an indication to monitor BG more frequently to determine the direction of any glucose trend and the need for more intensive intervention. Achieving these targets may require consultation with an endocrinologist or diabetes specialist.

Follow-up of Hyperglycemic Patients

• The occurrence of significant hyperglycemia in the hospital requires close follow-up after discharge.

• In those with previously diagnosed diabetes and an elevated A1C, the pre-admission diabetes care plan requires revision.

• In those without previously diagnosed diabetes, the differentiation between hospital-related hyperglycemia and undiagnosed diabetes requires follow-up testing (FBG, 2H OGTT) once metabolically stable using established criteria.

How to Achieve Good Glycemic Control ?

• Insulin, is currently the only available agent for effectively controlling glycemia in the hospital.– Continuous intravenous infusion with regular insulin– Multiple subcutaneous injection (Long-acting and

rapid-acting insulin)

• Effective insulin therapy must provide both basal and nutritional coverage in order to achieve the target goals.

How to Achieve Good Glycemic Control ?

• Use of "sliding scale" insulin alone –discouraged﹗– Evidence does not support this technique bec

ause it has resulted in unacceptably high rates of hyperglycemia, hypoglycemia, and iatrogenic diabetic ketoacidosis in hospitalized patients. (Swing of blood sugar)

Indications for Intravenous Insulin Therapy

• Diabetic ketoacidosis (DKA)• Nonketotic hyperosmolar state (HHS)• Critical care illness (surgical and medical)• Myocardial infarction (MI) or cardiogenic shock• Stroke• Postoperative period following heart surgery• Labor and delivery• NPO status in Type 1 diabetes• General pre-, intra-, and postoperative care• After organ transplantation• Total parenteral nutrition therapy• Exacerbated hyperglycemia during high-dose

glucocorticoid therapy

Protocols of Intravenous Insulin Therapy

• DIGAMI (studied in acute MI setting)• Van den Berghe (studied in critical care setting)• Portland protocol (used in surgical setting)• Markovitz (studied in postoperative heart surgery

patients)• Yale protocol (studied in medical intensive care setting)

Protocols of Intravenous Insulin Therapy

• DIGAMI (IV insulin glucose infusion followed by outpatient multidose subcutaneous insulin regimen)

• Van den Berghe (IV insulin therapy to maintain blood glucose between 80 - 110 mg/dL)

• Portland Protocol (perioperative use of IV insulin for ICU and floor. Various target levels available : 70 - 110; 80 - 120; 100 - 150; 125 - 175)

• Markovitz (IV insulin therapy to maintain blood glucose between 120 - 199 mg/dL)

• Yale Protocol (IV insulin therapy to maintain blood glucose between 100 - 139 mg/dL)

Goals of Inpatient glycemic Control

• Avoid hypoglycemia

• Avoid hyperglycemia, volume depletion, and electrolyte abnormalities

• Assess the comprehensiveness of diabetes care

• Ensure adequate nutrition

• Assess patient educational needs

Avoidance of Hypoglycemia

• Hospitalized patients - vulnerable to severe and prolonged hypoglycemia since they may be unable to sense or respond to the early warning signs and symptoms of low blood glucose.

• Ongoing renal insufficiency predisposes hypoglycemia• The usual causes of hypoglycemia in the hospital includ

e ︰ – Continued antihyperglycemic therapy when caloric intake is stop

ped or reduced – Use of a standard "sliding scale" of insulin without consideration

of the patient's specific circumstances – Attempt to provide "tight" glycemic control intraoperatively

Avoidance of Hyperglycemia

• Hyperglycemia and insulin resistance are common in critically ill patients, independent of a history of diabetes mellitus.

• Immune and neutrophil function are impaired during marked hyperglycemia due to non-enzymatic glycosylation of proteins critical to adequate function of the immune system. These include ︰ – Inactivation of IgG– Impaired opsin binding of compliment– Activation of collagenase– Inhibition of neutrophil functions including delayed chemotaxis, i

mpaired phagocytosis and hindered bacteriocidal capability

Avoidance of Hyperglycemia

• Poor glycemic control in critical illness is associated with advanced age, cardiac surgery, postoperative complications, nosocomial infections, prolonged mechanical ventilation, and multiple medications.

• Hyperglycemia is often compounded by the initiation of TPN or enteral feeding or by the use of high-dose glucocorticoids.

• The presence of in-hospital hyperglycemia also appears to be a marker of poor clinical outcome, even in patients who are not critically ill.