Diabetic Ketoacidosis (DKA) & Hyperglycemic Hyperosmolar State (HHS)

1. Diabetic Ketoacidosis (DKA) &Hyperglycemic Hyperosmolar State (HHS) Ulrich K. Schubart, MD JMC/AECOM

2. DKA/HHSPresenting Symptoms • Nausea and Vomiting • Polyuria and Polydipsia • Weakness and/or Anorexia • Abdominal Pain • Visual Disturbances • Somnolence

3. DKA/HHSPresenting Signs • Tachycardia • Hypotension • Dehydration • Hypothermia • Warm dry Skin • Kussmaul Respiration • Lethargy or Coma • Fruity Odor

4. Compensatory Hyperventilation in DKA From UpToDate Kety et al. JCI 1948

5. DKA/HHSPrecipitating Factors Any major Stress/Acute Illness • Infection • Pneumonia • Gastroenteritis • UTI • Sepsis • Meningitis • Influenza • Mucormycosis • Emotional Problems • Trauma • Acute Pancreatitis • Myocardial Infarction • Stroke • Endocrine • Acromegaly • Thyrotoxicosis • Cushing’s S. • Omission of Antidiabetic Mx’s • Drugs

6. DKA/HHSDrugs that can Precipitate • Psychotropic Drugs • Chlorpromazine • Clozapine • Risperidone • Loxapine • Steroids • Immunosuppressants • Beta Blockers • Calcium Channel Blockers • Diuretics • Anticonvulsants • Diazoxide

7. DKA/HHSPathogenesis Precipitating Factors Absolute Insulin Deficiency Relative Insulin Deficiency Glucagon Catecholamines Cortisol Growth Hormone Lipolysis Proteolysis Minimal Lipolysis Gluconeogenic Substrates FFAs Ketogenesis Gluconeogenesis Glycogenolysis Ketoacidosis Hyperglycemia Hyperosmolality Glucosuria (Osmotic Diuresis) Triglycerides Decreased GFR Hyperlipidemia Loss of Water & Electrolytes Dehydration

8. - + + PKA PFK-1 F1,6BP DKA/HHSEnhanced Glucose Production Glucagon cAMP Glycogen Glucose G-6-P PFK-2 F-6-P F-2,6P2 F-1,6-P2 Glycerol Alanine PYR CO2 Fat

9. Insulin DKA/HHSKetone Body Formation in Liver Glucagon Fatty Acids Glucose Fatty Acyl-CoA Triglycerides Fatty Acyl-CoA Acetyl-CoA Acetoacetyl-CoA b-Hydroxy-b-methylglutaryl CoA Acetoacetate b -Hydroxybutyrate NADH NAD Acetone

10. Fatty Acid Oxidation DKA/HHSGlucagon-inducedCatabolic Cascade in Liver Glucose Glucose Glycogenolysis Gluconeogenesis Glycogen Formation Glycolysis Fatty Acids Fatty acyl CoA CPT1 Malonyl-CoA ACC Acetyl-CoA Ketones

11. NAD NADH + H+ DKA/HHSKetone Body Utilization in Muscle EXTACELLULAR MITOCHONDRION b -Hydroxybutyrate b -Hydroxybutyrate Acetoacetate Acetoacetate Succinyl-CoA Succinate Acetoacetyl-CoA CoA Acetyl-CoA Fatty Acids Citric Acid Cycle

12. DKA/HHSGlucotoxicty & Lipotoxicity • Relatively Short Term: Reversible Inhibition of: a) Glucose Uptake and Utilization in Insulin-Responsive Target Tissues b) Insulin Secretion • Long-term: a) & b) +Apoptosis of Beta-Cells

13. DKA/HHSEssential to R/o Infection • Look for meningeal signs - Head CT/MR followed by LP may be indicated • Look for necrotic lesions in nasal turbinates to r/o mucormycosis • For abdominal pain consider appendicitis cholecystitis pancreatitis diverticulitis PID • Obtain CXR • Check urine sediment

14. DKA/HHSHyperosmolality Measure and Calculate Serum Osmolality = 2 x measured Na+ (mEq/l) + glucose (mg/dl) /18 + BUN (mg/dl)/2.8 Osmolar Gap = Measured – Calculated Serum Osmolality Effective Serum Osmolality OsmEff (>320 =HHS) =2 x measured Na+ (mEq/l) + glucose (mg/dl) /18

15. DKA/HHSSodium Correction Corrected Sodium = Measured Sodium + 1.6 x plasma glucose (mg/dl) – 100 100

16. DKA/HHSMetabolic Acidosis Plasma Anion Gap = Na+ - [Cl-+ HCO3-] (mEq/l)

17. DKA/HHSDiagnosis (Average Values)

18. DKA/HHSTypical Water and Electrolyte Deficits

19. DKA/HHSPoor Prognostic Indicators • Advanced Age • Low pH • Hypotension • Marked Hyperosmolality • High BUN • Associated Diseases

20. DKA/HHSTreatment Considerations • Precipitating Cause evident in 80% • ECG indicated in all adult patients • Isotonic NaCl preferred for initial rehydration • IV Insulin preferred mode of administration • Potassium depletion in all patients • Prevention is long-term goal of management • Bicarbonate administration rarely indicated

21. DKA/HHSOther Considerations in Tx • Type & Cross-match as indicated • Blood (and other) Cultures as indicated • Aspirate Gastric Contents if Comatose • Catherize if needed for Output Measurement • Give Oxygen if indicated • Keep patient NPO

22. DKA/HHSEssential Components in Tx • IV Fluids • Insulin • Potassium

23. DKA/HHSEssential Components in Tx IV Fluids • 2-3 L 0.9% saline during first 3 h • Subsequently, 0.45% saline at 150-300 ml/h • Add 5% dextrose when plasma glucose reaches 250 mg/dl

24. DKA/HHSEssential Components in Tx Insulin • 10 U/h iv infusion of short-acting insulin • Increase rate 2-10 fold if no response by 4 h • Decrease to 1-2 U/h when acidosis is corrected • Administer sc insulin before stopping iv infusion

25. DKA/HHSEssential Components in Tx Potassium • 10-20 mEq/h when plasma K<6.0, ECG normal, urine flow documented • 40-80 mEq/h when plasma K <3.5 or if bicarb is given

26. DKA/HHSClinicalMonitoring

27. DKA/HHSMonitoring Lab Values

28. DKA/HHSMonitoring Therapy

29. + + F1,6BP PFK-1 DKA/HHSStimulation of Glucose Utilization and Glycogen Formation by Insulin Glycogen G-6-P Glucose PFK-2 F-6-P F-2,6P2 F-1,6-P2 PYR CO2 Fat

30. Fatty Acid Oxidation - DKA/HHS-inducedAnabolic Cascade in Liver Insulin Glucose Glucose Glycogenolysis Gluconeogenesis Glycolysis Glycogen Formation Fatty Acids Fatty acyl CoA Malonyl-CoA CPT1 ACC TG Acetyl-CoA Ketones

31. DKA/HHSAdverse Effects of Severe Acidosis • Impaired Cardiac Contractility • Decreased Response to Vasoconstrictors • Inhibition of Respiration

32. DKA/HHSPotential Adverse Effect of Bicarbonate Administration • Significantly Increased Risk of Hypokalemia • Decreased Tissue Oxygen Delivery

33. DKA/HHSIndications for ConsideringBicarbonate Administration • pH < 7.0 or HCO3- < 5.0 • K+> 6.5 • Hypotension refractory to fluid replacement • Severely impaired LV function • Respiratory depression • Marked late hyperchloremic acidosis • Significant lactic acidosis

34. Compensatory Hyperventilation in DKA From UpToDate Kety et al. JCI 1948

35. DKA/HHSComplications of Therapy • Hypoglycemia • Hypokalemia or Hyperkalemia • Fluid Overload • Hyperchloremic Acidosis • Cerebral Edema • ARDS • Thromboembolic Episodes

36. DKA/HHSPrevention • Education of Patient and Health Care Providers