Diabetic Ketoacidosis

Definition 2009 ADA consensus statement on DKA 2009 ADA consensus statement on DKA Life-threatening condition characterized by Life-threatening condition characterized by hyperglycemia (glucose >250mg/dl) hyperglycemia (glucose >250mg/dl) Ketonemia or ketonuria Ketonemia or ketonuria Arterial pH <7.3 Arterial pH <7.3 Bicarb < 15mmol/L Bicarb < 15mmol/L

Epidemiology/Statistics Annual incidence 5-8 episodes/1000 person-years Annual incidence 5-8 episodes/1000 person-years Mortality ~5% in adult DKA Mortality ~5% in adult DKA Underlying precipitating illness Underlying precipitating illness Annual hospitalizations for DKA – 100,000 Annual hospitalizations for DKA – 100,000 Annual hospitalization cost exceeds $1 billion. Annual hospitalization cost exceeds $1 billion.

Pathogenesis Insulin deficiency and/or resistance Insulin deficiency and/or resistance Excess of counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) Excess of counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) Increased gluconeogenesis, glycogenolysis, proteolysis, lypolysis Increased gluconeogenesis, glycogenolysis, proteolysis, lypolysis Decreased glucose utilization in peripheral tissues Decreased glucose utilization in peripheral tissues

Pathogenesis (cont’d)

Precipitating Factors Infections (30-50%) Infections (30-50%) Medication non-compliance or inadequate treatment (30%) Medication non-compliance or inadequate treatment (30%) New onset diabetes (20%) New onset diabetes (20%) Others- CVA, MI, trauma, pancreatitis, alcohol and drug abuse, pregnancy, thyrotoxicosis, hypercortisolism, drugs Others- CVA, MI, trauma, pancreatitis, alcohol and drug abuse, pregnancy, thyrotoxicosis, hypercortisolism, drugs

History Polyuria Polyuria Polydipsia Polydipsia Polyphagia Polyphagia Weight loss Weight loss Nausea, vomiting Abdominal pain Weakness Clouding sensorium

Physical Exam Evidence of dehydration Evidence of dehydration dry mucus membrane dry mucus membrane decreased skin turgor decreased skin turgor orthostatic hypotension orthostatic hypotension decreased UOP decreased UOP Fruity odor Tachycardia Hypotension Kussmaul’s respiration Altered mental status Shock Coma

Diagnostic Studies Blood work – Blood work – Chemistry panel, including Mg, PO4 Chemistry panel, including Mg, PO4 Serum ketones Serum ketones UA with urine ketones UA with urine ketones ABG/VBG ABG/VBG Serum Osmolality Serum Osmolality Cbc with differential Cbc with differential Others: autoantibodies (anti-GAD, anti-islet cells), C- peptide, A1c, fasting lipid Others: autoantibodies (anti-GAD, anti-islet cells), C- peptide, A1c, fasting lipid

Diagnostic Studies (cont’d) K+, Mg++, PO4-- depletion are usually found. K+, Mg++, PO4-- depletion are usually found. Initial serum K+ can be high due to extracellular shift of K+ secondary insulin deficiency and acidemia Initial serum K+ can be high due to extracellular shift of K+ secondary insulin deficiency and acidemia Hyponatremia - osmotic pull of water into intravascular space, vomiting with fluid loss and free water replacement, or severe hyperlipidemia (pseudohyponatremia) Hyponatremia - osmotic pull of water into intravascular space, vomiting with fluid loss and free water replacement, or severe hyperlipidemia (pseudohyponatremia)

Diagnostic Studies (cont’d) Cr may be falsely elevated due to acetoacetate interference with measuring method Cr may be falsely elevated due to acetoacetate interference with measuring method Leukocytosis is usually present, but usually wbc <25K and no left shift Leukocytosis is usually present, but usually wbc <25K and no left shift Amylase, lipase, and LFT can be elevated Amylase, lipase, and LFT can be elevated In rare cases, patients can have severe hyperlipidemia, requiring sample dilution, leading to factitiously pseudohypo- or normoglycemia In rare cases, patients can have severe hyperlipidemia, requiring sample dilution, leading to factitiously pseudohypo- or normoglycemia

Diagnostic Studies (cont’d) Ketones in DKA are acetoacetate, acetone and B hydroxybutyrate (BHB is not detected by nitroprusside reaction) Ketones in DKA are acetoacetate, acetone and B hydroxybutyrate (BHB is not detected by nitroprusside reaction) During treatment for DKA, B hydroxybutyrate is converted to acetoacetate, so test for ketones may become more strongly positive despite improvement DKA During treatment for DKA, B hydroxybutyrate is converted to acetoacetate, so test for ketones may become more strongly positive despite improvement DKA

EKG EKG CXR if pneumodrome present CXR if pneumodrome present Blood cx, urine cx, throat cx if indicated Blood cx, urine cx, throat cx if indicated Diagnostic Studies (cont’d)

Diagnosis Diagnostic criteria Diagnostic criteria BG >250, HCO3 250, HCO3 <15, pH <7.3 Ketonemia or ketonuria Ketonemia or ketonuria Differential diagnoses Differential diagnoses Ketoacidosis – alcohol, starvation Ketoacidosis – alcohol, starvation AG metabolic acidosis - MUDPILES AG metabolic acidosis - MUDPILES

Diagnosis (cont’d)

Treatment 1. IV fluid 1. IV fluid Initially administer 1-2 L 0.9%NS bolus Initially administer 1-2 L 0.9%NS bolus Switch to 0.45% NS infusion at rate ml/hr if corrected Na+ is normal or high Switch to 0.45% NS infusion at rate ml/hr if corrected Na+ is normal or high When BG < or = 200 mg/dL, switch to 5% dextrose with 1/2NS at ml/hr When BG < or = 200 mg/dL, switch to 5% dextrose with 1/2NS at ml/hr

Treatment (cont’d) 2. Insulin 2. Insulin Traditionally, IV regular insulin is used Traditionally, IV regular insulin is used Give loading dose at 0.1 units/kg as IV bolus then infuse at rate 0.1 units/kg/hr or Give loading dose at 0.1 units/kg as IV bolus then infuse at rate 0.1 units/kg/hr or Start continuous infusion at 0.14 units/kg/hr Start continuous infusion at 0.14 units/kg/hr If BG does not fall by mg/dl per hour, double infusion dose If BG does not fall by mg/dl per hour, double infusion dose Once BG reaches 200 mg/dl can reduce infusion rate (by 2-3units) to keep BG between mg/dl until DKA resolves Once BG reaches 200 mg/dl can reduce infusion rate (by 2-3units) to keep BG between mg/dl until DKA resolves

Treatment (cont’d) 2. Insulin (cont’d) 2. Insulin (cont’d) Transition to SC insulin Transition to SC insulin Once AG 7.3, AG 18 mEq/L, and pH > 7.3, AG < 12 meq/L] if patient feels hungry and would like to eat, if patient feels hungry and would like to eat, not in NPO status not in NPO status

Treatment (cont’d) 2. Insulin (cont’d) 2. Insulin (cont’d) Start with both long- and rapid-acting insulin or around- the-clock regular insulin Start with both long- and rapid-acting insulin or around- the-clock regular insulin Give 60 minutes before discontinuing IV insulin Give 60 minutes before discontinuing IV insulin Long-acting – NPH or glargine Long-acting – NPH or glargine Rapid-acting – aspart, or lispro Rapid-acting – aspart, or lispro Newly diagnosed patients usually requires 0.5 – 0.8 units/kg/day Newly diagnosed patients usually requires 0.5 – 0.8 units/kg/day Half given as long acting and remaining half given before meals Half given as long acting and remaining half given before meals Check FBG qac and hs and supplement with sliding scale insulin to keep BG mg/dL Check FBG qac and hs and supplement with sliding scale insulin to keep BG mg/dL

Treatment (cont’d) 2. Insulin (cont’d) 2. Insulin (cont’d) SC or IM route can also be used SC or IM route can also be used Advantages Advantages reduced nursing support, cost reduced nursing support, cost Disadvantages Disadvantages Pt’s discomfort Pt’s discomfort Uncertain absorption Uncertain absorption

Treatment (cont’d) 2. Insulin (cont’d) 2. Insulin (cont’d) Prospective, randomized open trial Prospective, randomized open trial Efficacy of subcutaneous lispro insulin (n = 20) compared to standard low dose intravenous regular insulin (n = 20) in uncomplicated DKA Efficacy of subcutaneous lispro insulin (n = 20) compared to standard low dose intravenous regular insulin (n = 20) in uncomplicated DKA No statistical differences in mean duration of treatment or amount of insulin administration, length of hospital stay, or mortality No statistical differences in mean duration of treatment or amount of insulin administration, length of hospital stay, or mortality Treatment of DKA in the ICU was associated with 39% higher hospitalization charges than was treatment with subcutaneous lispro in a non-intensive care setting ($14,429 +/- $5243 vs. $8801 +/- $5549, P <0.01). Treatment of DKA in the ICU was associated with 39% higher hospitalization charges than was treatment with subcutaneous lispro in a non-intensive care setting ($14,429 +/- $5243 vs. $8801 +/- $5549, P <0.01). Am J Med 2004; 117: 291 Am J Med 2004; 117: 291

Treatment (cont’d) 2. Insulin (cont’d) 2. Insulin (cont’d) Prospective, randomized, open trial Prospective, randomized, open trial Efficacy of aspart insulin given at 1hr (SC-1h) or 2hr (SC-2h) compared to IV regular insulin in uncomplicated DKA Efficacy of aspart insulin given at 1hr (SC-1h) or 2hr (SC-2h) compared to IV regular insulin in uncomplicated DKA 45 patients – SC-1h, n =15, SC-2hr, n =15, IV-R, n = patients – SC-1h, n =15, SC-2hr, n =15, IV-R, n = 15 No statistical differences in mean duration of treatment or amount of insulin administration until correction of hyperglycemia or resolution of ketoacidosis No statistical differences in mean duration of treatment or amount of insulin administration until correction of hyperglycemia or resolution of ketoacidosis No difference in mortality or length of hospital stay No difference in mortality or length of hospital stay Diabetes Care 2004; 27: 1873

Treatment (cont’d) 2. Insulin (cont’d) 2. Insulin (cont’d) SC rapid-acting insulin SC rapid-acting insulin Uncomplicated mild DKA Uncomplicated mild DKA 0.3 U/kg, then 0.2 U/kg one hour later and then q2 hrs 0.3 U/kg, then 0.2 U/kg one hour later and then q2 hrs JCEM 2008; 93:1541. JCEM 2008; 93:1541.

Treatment (cont’d) 3. Electrolytes 3. Electrolytes Potassium Potassium If initial serum K+ > 5.3 mEq/L, no supplement If initial serum K+ > 5.3 mEq/L, no supplement If serum K+ between 3.3 and 5.3 mEq/L, give mEq K+ in each liter of IV fluid to keep K at 4-5mEq/L If serum K+ between 3.3 and 5.3 mEq/L, give mEq K+ in each liter of IV fluid to keep K at 4-5mEq/L If serum K+ 3.3 mEq/L If serum K+ 3.3 mEq/L

Treatment (cont’d) 3. Electrolytes (cont’d) 3. Electrolytes (cont’d) Bicarbonate (100mmol in 400ml water with 20 mmol KCL over 2 hours until pH >7) Bicarbonate (100mmol in 400ml water with 20 mmol KCL over 2 hours until pH >7) Give only if pH <6.9 Give only if pH <6.9 Phosphate Phosphate Replace if serum phosphate < 1.0 mg/dL Replace if serum phosphate < 1.0 mg/dL Magnesium Magnesium Replace with IV MgSO4 if serum Mg++ <1.5 mg/dL Replace with IV MgSO4 if serum Mg++ <1.5 mg/dL

Treatment (cont’d) 4. Monitoring frequency 4. Monitoring frequency Initially q1-2 hrs for first few hours, then q2-4 hrs until stable Initially q1-2 hrs for first few hours, then q2-4 hrs until stable Flow sheet Flow sheet

Disposition Discharge from ER Discharge from ER Mild DKA Mild DKA Alert Alert Able to tolerate oral intake Able to tolerate oral intake Compliant Compliant Good social support Good social support Admission Admission All other cases, including those with comorbidities and poor social support All other cases, including those with comorbidities and poor social support

Complications Cardiac arrhythmias Cardiac arrhythmias From electrolyte abnormalities or acidosis From electrolyte abnormalities or acidosis Hypoglycemia Hypoglycemia From overzealous insulin dosage From overzealous insulin dosage Hypokalemia Hypokalemia Due to administration of insulin and bicarbonate Due to administration of insulin and bicarbonate Hyperglycemia/DKA recurrence Hyperglycemia/DKA recurrence Due to discontinuation of IV insulin prematurely or failure to cover with SC insulin Due to discontinuation of IV insulin prematurely or failure to cover with SC insulin

Complications (cont’d) Hyperchloremic metabolic acidosis Hyperchloremic metabolic acidosis Excessive Cl- from IV fluid Excessive Cl- from IV fluid Loss of HCO3- due to excretion of ketoanions as Na and K salts Loss of HCO3- due to excretion of ketoanions as Na and K salts Cerebral edema Cerebral edema Due to osmotically-driven movement of water into CNS Due to osmotically-driven movement of water into CNS Occurs primarily in children Occurs primarily in children When plasma osmolality decreases too rapidly When plasma osmolality decreases too rapidly Suspect when patient’s sensorium deteriorates or remains impaired despite resolution of DKA Suspect when patient’s sensorium deteriorates or remains impaired despite resolution of DKA

Complications (cont’d) Pulmonary edema Pulmonary edema Patients with widened A-a gradients, wet crackles on lung exam Patients with widened A-a gradients, wet crackles on lung exam Frequently monitor patients with cardiac disease or renal insufficiency Frequently monitor patients with cardiac disease or renal insufficiency Venous and arterial thrombosis Venous and arterial thrombosis DKA is a hypercoagulable state from endothelia injury, hypofibrogenolysis, and platelet hyperaggregation DKA is a hypercoagulable state from endothelia injury, hypofibrogenolysis, and platelet hyperaggregation DVT prophylaxis DVT prophylaxis

Prevention Diabetic education Diabetic education Sick day management Sick day management Frequent measurement of blood glucose Frequent measurement of blood glucose Home monitoring of ketones Home monitoring of ketones Easily digestible liquid diet Easily digestible liquid diet Hold short acting insulin if not eating Hold short acting insulin if not eating Continue long acting insulin Continue long acting insulin Early access to professional advice Early access to professional advice Case management for high-risk patients Case management for high-risk patients

Management Errors Not giving enough IV fluid Not giving enough IV fluid Overly rapid correction of hyperglycemia Overly rapid correction of hyperglycemia Transitioning to SQ insulin too soon Transitioning to SQ insulin too soon Not allowing enough time for SQ insulin to start working before stopping IV insulin Not allowing enough time for SQ insulin to start working before stopping IV insulin Not repleting electrolytes Not repleting electrolytes

References 1. Kitabchi, AE et al. “Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association.” Diabetes Care 2006; 29: Kitabchi, AE et al. “Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association.” Diabetes Care 2006; 29: Kitabchi, AE et al. “Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state.” JCEM 2008; 93: Kitabchi, AE et al. “Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state.” JCEM 2008; 93: American Diabetes Association. “Hospital Admission Guidelines for Diabetes.” Diabetes Care 2004; 27(Suppl 1): S American Diabetes Association. “Hospital Admission Guidelines for Diabetes.” Diabetes Care 2004; 27(Suppl 1): S Charfen, MA. “Diabetic Ketoacidosis.” Emerg Med Clin N Am 2005; 23: Charfen, MA. “Diabetic Ketoacidosis.” Emerg Med Clin N Am 2005; 23:609.

References (cont’d) 5. Umpierrez, GE. “Treatment of Diabetic Ketoacidosis with Subcutaneous Insulin Aspart.” Diabetes Care 2004;27: Umpierrez, GE. “Treatment of Diabetic Ketoacidosis with Subcutaneous Insulin Aspart.” Diabetes Care 2004;27: Umpierrez, GE. “Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis.” Am J Med 2004; 117 (5): Umpierrez, GE. “Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis.” Am J Med 2004; 117 (5): Kitabchi, AE. “Management of Hyperglycemic Crises in Patients with Diabetes.” Diabetes Care 2001;24: Kitabchi, AE. “Management of Hyperglycemic Crises in Patients with Diabetes.” Diabetes Care 2001;24: American Diabetes Association. “Hyperglycemic Crises in Diabetes.” Diabetes Care 2004; 27 (Suppl 1): S American Diabetes Association. “Hyperglycemic Crises in Diabetes.” Diabetes Care 2004; 27 (Suppl 1): S