EVALUATION OF CONVENTIONAL V. INTENSIVE BLOOD GLUCOSE CONTROL Glycemic Control in Critically Ill Patients DANELLE BLUME UNIVERSITY OF GEORGIA COLLEGE OF PHARMACY 2013 PHARM.D. CANDIDATE

Hyperglycemia in the ICU A common occurrence in both diabetic and non- diabetic patients Defined as a blood glucose > 200 mg/dl Etiology  Severe trauma, disease, infection, surgery, etc. result in the activation of the hypothalamic pituitary adrenal (HPA) axis  Release of glucagon, growth hormone, and cortisol in addition to norepinephrine and epinephrine  Blood insulin levels remain normal or low  Insulin resistance, preexisting or not  Fluids (D5W), Medications, TPN, etc.

Treatment of Hyperglycemia Insulin infusion Titrate every hour according to protocol

Hypoglycemia in the ICU Blood glucose < 70mg/dl Result of overcorrection of hyperglycemia Whipple’s triad  Signs and/or symptoms consistent with hypoglycemia  Low plasma glucose  Relief of symptoms after plasma glucose is increased Life threatening

Treatment of Hypoglycemia Intravenous glucose (25g) as a 50% solution Followed by constant infusion of 5% or 10% dextrose If IV access not possible:  Glucagon (1.0 mg for adults) SC or IM Goal glucose: , but this is a wide range and a debatable one

Conflicting Findings Initial trials suggested that intensive glucose control could reduce mortality among patients in surgical ICU and reduce morbidity among those in a medical ICU*  Subsequent studies have NOT confirmed this NICE-SUGAR trial shows increased risk of death in patients assigned to intensive glucose control * Van den Berghe G, Wouters P, Week- ers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: Van den Berghe G, Wilmer A, Her- mans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:

NICE-SUGAR Normoglycemia in Intensive Care Evaluation— Survival Using Glucose Algorithm Regulation A multicenter, randomized, controlled trial  6104 adults in ICUs in 42 hospitals between 2004 & 2008  Intensive blood glucose control group (target BG range mg/dl) v. conventional glucose control (target 180 mg/dl or less)  Intervention continued until patient was eating, discharged from ICU, or died  Primary outcome: death within 90 days after randomization  Severe hypoglycemia = 40 mg/dl or less  Moderate hypoglycemia = between 41 and 70 mg/dl

NICE-SUGAR Evidence: Ia Recommendation Grade: A Overall Conclusion: Although hypoglycemia was significantly more common among patients assigned to intensive versus conventional glucose control, the association of hypoglycemia with death was similar in the two groups

NICE-SUGAR Post-hoc analysis Whether hypoglycemia leads to death in critically ill patients is unclear Findings  Even after adjustment for events occurring after the first episode of hypoglycemia, moderate hypoglycemia was associated with an increased risk of death of 40% and severe hypoglycemia with a doubling of the risk  Causal relationship is plausible because hypoglycemia may increase mortality by impairment of other systems  Hypoglycemia may be a marker of severe underlying disease processes Autonomic function, alteration of blood flow and composition, white-cell activation, vasoconstriction, and the release of inflammatory cytokines

Relevance A wise man once said, “Hyperglycemia in the acute setting isn’t going to kill you but hypoglycemia will.”  Hal Richards, Pharm.D., BCNSP, Candler Hospital Thus, until we have data that says otherwise, intensive glucose control in the ICU should be avoided. A target blood glucose of mg/dl is a reasonable goal

References Annetta MG, Ciancia M, Proietti R. Diabetic and nondiabetic hyperglycemia in the ICU. Current Anaesthesia & Critical Care, :6, LexiComp. Version (159), McDonnell ME, and Umpierrez GE. Insulin therapy for the management of hyperglycemia in hospitalized patients. Endocrinology and Metabolism Clinics of North America, March :1, NICE-SUGAR investigators. Hypoglycemia and Risk of Death in Critically Ill Patients. N Engl J Med 2012;367: