1. D IABETIC KETOACIDOSIS (DKA) Hannah Allegretto University of Pittsburgh School of Pharmacy PharmD Candidate 2013

2. T HE C ASE JJ is a 59yo male admitted into the ER on 8/01/2012 with severe hyperglycemia and confusion Patient did not know how he arrived at the hospital, and states, “I don’t feel like myself.” Diagnosis: Diabetic Ketoacidosis PMH: DM2 x 13 years, hypercholesterolemia x 12 years, cardiac catheterization (2009), cholecystectomy (2010), laminectomy at L4-5 (unknown date)

3. T HE C ASE (C ONTINUED ) Labs upon arrival: Glucose: 461 mg/dL K: 4.7 mmol/L Bicarbonate: 9 mEq/L Scr: 1.75 mg/dL pH: 7.26 Ketones: >80mg/dL Vitals: BP: 137/79, Pulse: 94 beats/min, RR: 20, Temp: 36.7C Weight: 105.7kg Medications: Lantus 40u SQ daily, Lipitor 10mg daily, ASA 81mg daily, Glucovance 5/500mg QID Anion Gap: 31.7 mmol/L

4. OBJECTIVES Describe the epidemiology and pathophysiology of DKA Identify the diagnostic lab parameters for DKA Recognize the signs and symptoms of DKA Identify patient specific precipitating causes to developing DKA Select appropriate treatment regimens and monitoring parameters for managing DKA Describe how to prevent future DKA episodes

5. E PIDEMIOLOGY OF DKA Estimated Incidence: 4-8 cases per 1,000 persons with diabetes per year More common in type 1 diabetics Accounts for 1-2% of all diabetes related admissions 50% of diabetes-related admissions in young people Hospital costs may exceed $1 billion annually Death occurs in ~2% of patients if not treated promptly http://emedicine.medscape.com/article/118361-overview#a0156

6. P ATHOPHYSIOLOGY OF DKA Characterized by: Hyperglycemia Ketosis Acidosis Occurs due to a relative or absolute insulin deficiency which causes an increase of counter- regulatory hormones Glucagon, cortisol, growth hormone, epinephrine This imbalance promotes: Hepatic gluconeogenesis Glycogenolysis Lipolysis http://emedicine.medscape.com/article/118361-overview#a0104

7. P ATHOPHYSIOLOGY, CONTINUED Increased hepatic gluconeogenesis and glycogenolysis leads to severe hyperglycemia Lipolysis leads to an increase of free fatty acids in the serum Metabolism of free fatty acids produces ketones In early stages, the body can buffer the effects of excess ketones, resulting in a normal arterial pH, but having a base deficit and mild anion gap As ketones continue to accumulate in the body, they eventually flow into urine. If left untreated, pH and bicarbonate levels will drop http://emedicine.medscape.com/article/118361-overview#a0104

8. E LECTROLYTE DISTURBANCES When glucose in the body rises above 220mg/dL, it will begin to spill into the urine Glucose will draw H 2 0 into the renal tubules, producing excess urine  osmotic diuresis Osmotic diuresis leads to: Dehydration Volume depletion Net loss of Na +, K +, Ca 2+, Mg 2+, Cl -, and PO 4 2- Ketones also spill into the urine, but are buffered before excreted Na+ used as the buffer  water follows Na+  further volume depletion and dehydration Mistovich J. Understanding the presentation of diabetic ketoacidosis.

9. D IAGNOSTIC C RITERIA MildModerateSevere Plasma glucose (mg/dL) >250 Arterial pH7.25-7.307.00-<7.24<7.00 Serum Bicarbonate (mEq/L) 15-1810-<15<10 Urine ketonesPositive Serum ketonesPositive Anion Gap>10>12 Alteration in sensoria or mental obtundation AlertAlert/drowsyStupor/coma Diabetes Care. 2009; 32:1335-43.

10. S IGNS AND S YMPTOMS Early signs: Tired/fatigued Excessive thirst Excessive urination Dry mouth Later signs: Nausea/vomiting Abdominal pain Confusion Kussmaul’s respirations “Fruity” smelling breath Fever Treat Endocrinol. 2003; 2: 95-108

11. P RECIPITATING C AUSES Infection UTI Pneumonia Psychological stress Noncompliance with DM medications Trauma Stroke Alcohol abuse Pulmonary embolism Medications Treat Endocrinol. 2003; 2: 95-108

12. P RECIPITATING CAUSES, CONTINUED Infection On admission, JJ’s WBC count: 12.9 x 10 3 Uroscreen (08/01/12): negative Possible blood infection Tx: Levaquin 500mg PO QAM 08/06/2012: WBC 5.6 x 10 3 Noncompliance JJ was very confused upon admission Did not know what medications he should be taking and when he should be taking them

13. T REATMENT Therapeutic Goals: Improve circulatory volume and tissue perfusion Decrease serum glucose and plasma osmolality Clearing serum and urine of ketones at a steady rate Correcting electrolyte imbalances Identifying and treating precipitating events Diabetes Care. 2001; 24: 131-53.

14. T REATMENT, CONTINUED Start IV fluids 1L of 0.9% NaCl in the first hour, followed by: If corrected serum sodium normal or elevated: 0.45% NaCl at 250-500mL/hr If corrected serum sodium low: 0.9% NaCl at 250-500mL/hr Successful fluid replacement evidenced by: Increase in BP Measurement of fluid input/output Deficits should be corrected within the first 24 hours Diabetes Care. 2001; 24: 131-53.

15. T REATMENT, CONTINUED Fluids, continued 5% dextrose with 0.45% NaCl at 150-250mL/hr initiated when serum glucose reaches 200mg/dL Insulin Therapy: Regular 0.1u/kg IV bolus dose, then 0.1u/kg/hr IV continuous infusion Goal: Reduce plasma glucose concentration at a rate of 50- 75mg/dL per hour. If serum glucose does not fall by at least 10% in the first hour, give 0.14u/kg IV bolus, then resume previous therapy Diabetes Care. 2001; 24: 131-53.

16. T REATMENT, CONTINUED Insulin therapy Plasma glucose reaches 200mg/dL Decrease insulin infusion rate to 0.02-0.05u/kg per hour Add 5% dextrose with 0.45% NaCl at 150-250mL/hr to IV fluids Keep serum glucose between 150 and 200 mg/dL until resolution REMEMBER: hyperglycemia corrects faster than ketoacidosis After resolution: Initiate SC multidose regimen Continue IV infusion for 1-2 hours after SC insulin begun Insulin naïve: 0.5-0.8u/kg daily and adjust insulin as needed Known diabetes: resume previous insulin dosing, so long as it is sufficient Diabetes Care. 2001; 24: 131-53.

17. T REATMENT, CONTINUED Potassium therapy Potassium depleted by: Insulin therapy Correction of acidosis Volume expansion K + > 5.2 mEq/L Do not give K + but check level every 2 hours K + < 3.3 mEq/L Hold insulin and give 20-30 mEq/hr until K + > 3.3 mEq/L K + 3.3-5.2 mEq/L Give 20-30 mEq K + in each liter of IV fluid to keep serum K + between 4-5 mEq/L Diabetes Care. 2009; 32:1335-43.

18. T REATMENT, CONTINUED Bicarbonate therapy pH > 6.9 No HCO 3 - administered pH < 6.9 100mmol in 400mL H 2 O + 20 mEq KCl infused over 2 hours Repeat every 2 hours until pH > 7 Risks: Increased risk of hypokalemia Decreased tissue oxygen uptake Cerebral edema Development of paradoxical CNS acidosis Diabetes Care. 2001; 24: 131-53.

19. M ONITORING Monitoring is KEY! Check electrolytes, BUN, venous pH, creatinine, and glucose every 2 hours until stable Resolution of DKA Criteria: Blood glucose < 200 mg/dL Serum bicarbonate >18 mEq/L Venous pH > 7.3 Anion gap < 12 mEq/L Diabetes Care. 2001; 24: 131-53.

20. P REVENTION Intensive patient education Effective communication with health care providers during acute illness Patient compliance Increased access to heath care Diabetes Care. 2001; 24: 131-53.

21. T HE CASE Labs upon arrival: Glucose: 461 mg/dL K: 4.7 mmol/L Bicarbonate: 9 mEq/L Scr: 1.75 mg/dL pH: 7.26 Ketones: >80mg/dL Anion Gap: 31.7 mmol/L

22. T REATMENT FOR JJ IV Fluids 1L of 0.9% NaCl in the first hour, followed by 0.45% NaCl at 500mL/hr Insulin: Regular 11u IV bolus dose, then 11u/hr IV continuous infusion Goal: Reduce plasma glucose concentration at a rate of 50-75mg/dL per hour. Potassium: Give 25 mEq K + in each liter of IV fluid to keep serum K + between 4-5 mEq/L

23. T REATMENT FOR JJ, CONTINUED Bicarbonate: None, JJ’s pH > 6.9 When plasma glucose reaches 200mg/dL: Decrease insulin infusion rate to 4 units per hour Add 5% dextrose with 0.45% NaCl at 250mL/hr to IV fluids SQ Insulin: resume Lantus 40 units SQ. Continue IV infusion for 1-2 hours after Lantus restarted Assess efficacy of Lantus dosing, consider short acting insulin before meals if needed Monitoring: Check electrolytes, BUN, venous pH, creatinine, and glucose every 2 hours until stable

24. E NDPOINT G OALS Blood glucose < 200 mg/dL Serum bicarbonate >18 mEq/L Venous pH > 7.3 Anion gap < 12 mEq/L Education/Counseling: Taking medications as prescribed Contacting health care provider immediately in acute illness Warning signs/symptoms of emergency Discount programs if financially unstable Diabetic testing logs

25. REFERENCES Medscape Reference. Drugs, Diseases, and Procedures. Diabetic Ketoacidosis. http://emedicine.medscape.com/article/118361-overview (accessed 2012 Aug 6). Mistovich J. Understanding the presentation of diabetic ketoacidosis. http://www.ems1.com/ems-products/education/articles/385223- Understanding-the-Presentation-of-Diabetic-Ketoacidosis (accessed 2012 Aug 6). Kitabchi AE, Umpierrez GE, Miles JM et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009; 32:1335-43. Kitabchi AE, Umpierrez GE, Murphy MB et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care. 2001; 24: 131-53. Umpierrez GE, Kitabchi AE. Diabetic ketoacidosis: risk factors and management strategies. Treat Endocrinol. 2003; 2: 95-108.

26. Questions??