Hyperglycemia syndromes UTHSCSA Pediatric Resident Curriculum for the PICU Hyperglycemia syndromes Diabetic Ketoacidosis Ketoacidosis-Hypersomolar Coma

Spectrum of DKA and Hyperosmolar Coma Ketoacidosis- Hyperosmolar Coma Pure Hyperosmolar Coma Pure Ketoacidosis Rapid Onset Marked Insulin Lack Intermediate Slow Onset Mild Insulin Lack

Diabetic Ketoacidosis Hyperglycemia Ketonemia Metabolic Acidosis

Pathophysiology Insulin Deficiency is the primary defect in patients with DKA Adipose Muscle Hepatocyte Glycogen Glucose Glucose Glucose-P Free fatty acids Amino Acids Pyruvate, CO2 Ketoacids Normal Insulin Activity

Insulin Deficiency Breakdown of storage forms of energy to meet energy needs. (Catabolism) Glycogenolysis Lipolysis Gluconeogenesis (from amino acids, lipids) Glucagon unopposed by Insulin stimulates this catabolic reaction

Pathophysiology Skeletal and cardiac tissues are able to use free fatty acids and ketone bodies as an energy source. Glucose can not be used by these tissues in the absence of insulin. The brain is an insulin-independent tissue and continues to use available glucose.

Persistent Catabolism Hyperglycemia is worsened by further intake of glucose. Excess Ketone bodies from Lipolysis Acetone -hydroxybutyrate (BHB) Acetoacetate (AA) Ratio of BHB/AA normally 3:1 is driven to 15:1 in severe DKA Ketone test measures only acetoacetate

Hyperosmolar State Hyperglycemia acts as an osmotic diuretic with obligatory loss of water and electrolytes. Osmolality = 2(Na) + Glucose/18 + BUN/2.8 (normal  293 ) Ketosis/hyperglycemia stimulate vomiting with aggravation of dehydration

Hyperosmolar State Hypovolemia secondary to dehydration can promote decreased tissue perfusion with anaerobic metabolism and elevated lactate production Total fluid deficit in severe DKA usually averages around 10% of the total body weight

Electrolyte Loss K I D N E Y Intracellular exchange of potassium with hydrogen ions K+ H+ Ketoacids draw out intravascular cations of Sodium and Potassium Glucose Ketoacids Phosphorous is also depleted in the osmotic diuresis

Fluid Balance in Diabetic Hyperosmolarity ECF = 14 L ICF = 28 L ICF ECF H2O ECF hyperosmolar from ICF autotransfusion Osmotic Diuresis H2O ECF and ICF both hyperosmolar Osmotic Diuresis

Clinical Findings in DKA Polyuria, Polydipsia, Polyphagia Dehydration + orthostasis Vomiting (50-80%) Küssmaul respiration if pH < 7.2 Temperature usually normal or low, if elevated think infection! Abdominal pain present in at least 30%.

Clinical Findings of Hyperosmolarity Lethargy, delirium Hyperosmolar coma is the first sign of diabetes in 50-60 % of adult patients. Hyperglycemia usually > 700-800mg/dl Osmolarity above 340 mOsm/L is required for coma to be present.

Precipitating Factors for Hyperosmolarity Too little insulin Infection, even minor. Severe stress. Hypokalemia (Required by insulin). Inadequate fluid intake Infancy (can not ask for fluids) Incapacitation (can not get to fluids/ask)

Laboratory Findings in DKA-Hyperosmolarity Glucose > 700mg/dl Total body sodium low, level high, normal or low. Potassium high, normal or low. Large urine ketones Bicarbonate < 15 mEq/L, pH < 7.2 Leukocytosis 15,000-40,000 even without infection. High temp = infection.

Calculation of Osmolarity Effective Osmolarity(mOsm/L) 2(Na = K) + Glucose (mg/dl)/20 = 280 - 295 mOsm/L A calculated osmolarity less than 340 mOsm/L is unlikely to cause coma. Other processes must be considered (stroke, infection, toxin). DKA does not cause coma in the absence of hyperosmolarity.

Effective Osmolarity The effective osmolarity calculation uses only those biologically effective molecules which are able to draw water out of the cell. Urea and other molecules measured in the lab (alcohol) move freely between the intra and extravascular spaces and don’t draw water out of the cell.

Approach to Therapy Correcting the hyperosmolar state and dehydration is the initial aim of therapy. Insulin therapy should be undertaken only after the patient is stable hemodynamically. Glucose and H2O H2O lost in urine Loss of ECF, vascular collapse and death

Rehydration Consider most patients with DKA to be approximately 10% dehydrated. The difference between the patient’s weight at baseline and presentation is an accurate measure of volume loss. Normal Saline is the replacement fluid of choice to restore hemodynamics.

Rehydration Bolus fluids until correction of circulatory failure. Correct deficit over 36 to 48 hours. Provide maintenance fluids (1600cc/m2/d) at the same time. Subtract resuscitation fluids from deficit. Avoid fluid administration > 4L/m2/d

Electrolytes Sodium content varies between 75 to 154 mEq/L. Reduce as sodium levels approach normal. Total body potassium is reduced. When K levels reach “normal” add 20-40 mEq/L as both KCL and Kphos. Maximum K infusion rate 0.5 mEq/kg/hr.

Insulin Replacement Insulin is essential for lowering glucose to normal and correcting acidosis. Following initial fluid replacement, then administer 0.1U/kg IV and initiate an infusion at 0.1U/kg/hr. (Regular Insulin). Check serum glucose hourly and avoid dropping glucose > 100mg/dl/h.

Insulin Replacement When serum glucose falls below 300 mg/dl, add 5% Dextrose to maintain stable glucose levels. Falling glucose should be managed with increased glucose concentration. Do not decrease insulin infusion until the metabolic acidosis is corrected.

Bicarbonate Should only be used to treat symptomatic hyperkalemia. May be used for pH less than 7.0 to provide some relief of Küssmaul respiration (1mEg/kg over 1-2 hours). Inappropriate use may result in hypokalemia and paradoxical CNS acidosis.

Intubation Most patients requiring intubation have hypovolemia. Avoid drugs which lower blood pressure. Consider a small volume load first. For patients with cerebral edema, avoid medication which raise ICP (Ketamine, Succinylcholine). Consider Thiopental and Lidocaine. Have Mannitol available for sudden ICP.

Cerebral Edema May be sub-clinical at start of therapy. CSF pressure is usually normal initially. Usually occurs unpredictably within the first 24 hours of therapy. Classically, patient’s labs are improving. No way to determine who will get this complication.

Pathophysiology Brain conserves water by producing osmoprotective molecules (taurine). Osmolarity becomes disproportionately higher in the brain than other tissues. Sudden fall in serum osmolarity moves fluid across the blood-brain barrier. Brain becomes relatively hypervolemic.

Cerebral Edema-Clinical Signs Initial complaint of headache. Progresses to decreasing level of consciousness, hypertension, papilledema and bradycardia. Coma and death soon follow. Cerebral edema is a complication of therapy, not a progression of DKA.

Cerebral Edema - Therapy The best therapy is to prevent it with careful rehydration. Diagnosis available with CT scan. Therapy for acute episode: Intubation and hyperventilation IV Mannitol 0.5 - 1.0 Gram/Kg as bolus. IV sedation. Slow the rate of osmolar correction.

Evaluation of Therapy Controlled reduction in serum glucose. Correction of acidosis “closing the gap”. Clearing of serum ketones. Clinical improvement fall in respiratory rate improved perfusion improving mental status.

Complications Infection esp. urinary tract infection. Pancreatitis Disseminated intravascular coagulation. Arterial and venous thrombosis. Hypoglycemia with seizure. Hypokalemia with dysrhythmias.

Thromboembolism in Diabetes In several studies, thromboembolism accounted for 20 to 50% of mortality. Virchow’s triad: stasis, endothelial damage and hypercoagulopathy. Hypercoagulopathy: Hyperreactivity of platelets Hyperfibrinogenemia (Especially Type 2) Elevated plasminogen activator (Type 2).

Thromboembolism Endothelial Damage Elevated levels of von Willebrand factor associated with endothelial damage Seen in decompensated diabetes esp. those with microvascular disease Catheter placement Promotes venous stasis Potential endothelial damage

DKA in Type 2 Diabetics Recent study: Arch of Internal Medicine 39% of patients had Type 2 diabetes. Majority of patients with Type 2 diabetes were Hispanic. 51% of patients were obese Type 2 diabetics more likely to have slow onset of ketoacidosis and progression to hyperosmolar coma.

DKA in Type 2 Diabetes Hyperosmolarity, obesity, lethargy, and a relative hypercoagulopathy increase the propensity for EMBOLISM and THROMBOSIS in Type 2 diabetics.