Diabetic Ketoacidosis and Hyperosmolar Nonketotic Coma

Diabetic Ketoacidosis A condition precipitated by stress or other illness or omission of insulin

Insulin deficiency Blocks glucose utilization by insulin-requiring tissues Activates lipolysis in adipose tissue Enhances proteolysis in muscle Causes hyperglucagonemia Intensifies glucagon effects on the liver

Actions of glucagon Cyclic AMP rises after binding of glucagon to its receptor Enhances hepatic gluconeogenesis and inhibits glycolysis Induces ketosis and blocks hepatic lipogenesis. Block in substrate flow from glucose to acetyl Co-A and inhibition of acetyl CoA carboxylase leads to fall in intrahepatic levels of the first product in the pathway of fatty acid synthesis, malonyl CoA Malonyl CoA normally inhibits carnitine palmitoyl-transferease I which transesterifies fatty acyl-CoA to fatty acyl carnitnine, enabling it to traverse the mitochondrial membrane and undergo beta-oxidation to ketones

Actions of glucagon By reducing malonyl-CoA levels, glucagon disinhibits this enzyme, poising the hepatocyte for accelerated acetoacetate and B-hydroxybutyrate synthesis as soon as fatty acid and fatty acyl-CoA levels in the liver increase consequent to increased lipolysis resulting from insulin deficiency Glucagon also increases hepatic carnitine levels

Sum of Effects of Hormonal Abnormalities in DKA Insulin deficiency augments delivery to liver of substrates for glucose and ketone production Glucagon is the switch that activates the hepatic production machinery for glucose and ketone production Stress hormones (epinephrine, norepinephrine, cortisol, GH, angiotensin) decrease peripheral tissue sensitivity to insulin, inhibit insulin-mediated reduction in hepatic glucose production, block insulin-mediated suppression of glucagon

Admission Findings in DKA Poly’s: polyuria, polydipsia, polyphagia Abdominal pain, nausea, vomiting Mental status: slight drowsiness to profound lethargy; coma relatively rare Hyperventilation (Kussmaul respirations) Fruity or ketone odor to breath Skin turgor decreased, mucous membranes dry Tachycardia, hypotension Leukocytosis may be present without infection

Differential Diagnosis of DKA Altered consciousness from DKA is usually easily differentiated from hypoglycemia - always check fingerstick glucose before giving D50. Measurement of urinary ketones and capillary glucose should provide adequate information to begin treatment pending formal lab work

Differential Diagnosis of DKA Anion gap acidosis DKA Lactic acidosis Alcoholic ketoacidosis Renal failure Certain poisonings (ethylene glycol, methyl alcohol, paraldehyde, methanol, salicylates)

Differential Diagnosis of DKA DKA can be differentiated from other forms of ketoacidosis accompanied by fasting ketosis by measuring ketones semiquantitatively in plasma Some alcoholics with alcoholic ketoacidosis can be hyperglycemic but they usually respond to glucose infusion plus 5-10 units of insulin Diagnosis of lactic acidosis requires measurement of blood lactate but initial clue is severe acidosis with absent urinary ketones or only modestly increased plasma ketone result

Ketones Acetoacetate Betahydroxybutyrate: does not react with nitroprusside and can account for 90% of the ketoacids, especially in presence of alcohol excess and lactic acidosis. Adding a few drops of h202 to the urine converts BHB to AcAc SH containing drugs (captopril, penicillamine) yield false positive nitroprusside Acetone

Hyperosmolar Coma A syndrome of extreme hyperglycemia and dehydration An imbalance between glucose production and excretion in urine Maximal hepatic production of glucose results in a plateau of plasma glucose in the 300-500 mg/dl range provided urine output is maintained Sum of glucose excretion plus metabolism is less than the rate at which glucose enters extracellular space

Hyperosmolar Coma Most frequently occurs in older patients in whom intercurrent illness increases glucose production secondary to stress hormones and impairs the capacity to ingest fluids As ECF and plasma volumes shrink the capacity to excrete glucose decreases as urine volume falls while hepatic glucose production pours glucose into a shrinking plasma space As plasma glucose rises CNS dysfunction appears and water intake is additionally impaired and urine flow decreases further

Hyperosmolar Coma Nonketotic hyperosmolar coma is generally a complication of NIDDM but can be seen in any type of DM Mechanism by which ketosis is suppressed is unclear Hyperosmolarity inhibits lipolysis presumably providing less substrate for ketogenesis in the liver Extreme hyperglycemia breaks through the glucagon-mediated lipogenic block, permitting sufficient synthesis of malonyl CoA to restrain production of acetoacetate and B-hydroxybutyrate

Differential Diagnosis in HONK Detect underlying illness Insufficient insulin or sulfonylurea if patient replaces fluid loss with sugar-containing drinks Iatrogenic: Administration of glucocorticoids, phenytoin, diuretics, high cal tube feeds or TPN, hypertonic glucose, peritoneal dialysis

Admission Findings in HONK Stroke, myocardial infarction, pneumonia or other infections, burns, heat stroke, acute pancreatitis are common precipitating events Extreme dehydration Kussmaul breathing usually absent Confusion to coma

Initial Laboratory Findings DKA Hyperosmolar Glucose 475 1166 Sodium 132 144 Potassium 4.8 5.0 Bicarb <10 17 BUN 25 87 Acetoacetate ND B-hydroxybut 13.7 Free fatty acids 2.1 0.73 Lactate 4.6 Osmolarity 310 384

Treatment of DKA Fluids and electrolytes Insulin Glucose

Fluids and Electrolytes Average fluid deficit in adults is 3-5 liters 1-2 liters of isotonic saline administered during first 2 hours but if hypotension, extreme hyperglycemia and oliguria present more should be given If hypernatremia develops 0.45% NaCl can be given Correction of ECF volume deficit takes precedent over correction of free water deficit Ringers lactate can be given to minimize chloride load Large amounts of NaCl contribute to hyperchloremic acidosis that occurs during therapy

Fluids and Electrolytes Hyperkalemia present on admission recedes when insulin action begins and K moves back into cells K replacement is required at this point to prevent hypokalemia During first four hours of therapy K should not be given unless K was low or normal to begin with - even then only give after insulin has been administered Delay insulin administration if hypokalemia is present on admission An appropriate initial rate is 20-40 meq/hr but monitor K q2-4 hours Total amount of K required ordinarily does not exceed 160 meq in first hour Give with care, if at all, in anuric patient

Fluids and Electrolytes Phosphate deficit ranges from 0.5-1.5 mmol/kg body weight and becomes apparent only when insulin action shifts P back into cells Rhabdomyolysis, impaired cardiac function, hemolysis, and respiratory failure are potential consequences Phosphate depletion is usually clinically silent and replacement has little effect on the course of DKA If phos low K can be provided in the form of K-phos to provide 40-60 mmol of the anion

Fluids and Electrolytes Whether to give bicarbonate is unsettled Severe acidosis impairs myocardial contractility and when coupled with volume depletion may cause shock Bicarb may increase cardiovascular responsiveness to catecholamines If pH <7.0 it has been considered prudent to administer sodium bicarb (100 mmol NaHCO3/liter of 0.45% saline) as initial therapy (although one retrospective study failed to show clinical benefit) Opposition to bicarb therapy is based on the fact that a sudden rise in pH may reduce oxygen release to tissues and predispose to lactic acidosis and also that it may induce paradoxical intracellular acidification, especially in the heart

Indications for Bicarbonate Therapy Unresponsive hypotension Hyperkalemia Arrhythmia Hypoventilation

Insulin Therapy All patients in DKA require regular insulin intravenously or intramuscularly Start with an initial IV bolus: 10 units, 0.1 U/kg, 50 units? 4-20 units per hour depending on severity of hyperglycemia (0.1 unit/kg/hr, ?sliding scale) Larger doses may be needed if acidosis does not respond over a 3-4 hour period Insulin must be given until urine is free of ketones Subcutanous insulin must be given before insulin drip is stopped to avoid recurrent ketoacidosis

Glucose Administration Once insulin has restored glucose uptake by insulin-requiring tissues and suppressed the hyperglucagonemia, hypoglycemia will supervene unless exogenous glucose is provided Because glucose levels always fall before ketone levels decrease, exogenous glucose must be provided to cover the insulin needed to reverse the ketosis Infusions are begun when glucose levels reach 250-300 mg/dl

Treatment of DKA Glucose Insulin U/hr D5W cc/hr <70 0.5 150 71-100 1.0 125 101-150 2.0 100 151-200 3.0 201-250 4.0 75 251-300 6.0 50 301-350 8.0 351-400 10.0 401-450 12.0 451-500 15.0 >500 20.0

Monitoring the DKA Patient ICU or setting where insulin can be given IV Vitals q1 hour until stable Examine patient q1 hour until stable ABG intially only Urine ketones initially and q4 hours Electrolytes q1 hour initially Glucose q1 hour while on insulin infusion Hourly urine output

Clinical Errors Erroneous admission of hypertonic glucose at the outset Administration of insulin without sufficient fluids Premature administration of potassium before insulin has begun to act Failure to maintain insulin and glucose until ketones have cleared and depleted glycogen stores restocked Hypoglycemia caused by insufficient glucose administration

Complications of DKA Death is rare in properly treated DKA: precipitating illness is usually cause of death Infection: mucormycosis is uniquely associated with DKA Vascular thrombosis: volume contraction, low CO, increased viscosity of blood, underlying atherosclerosis, changes in clotting factors and platelets Cerebral edema: usually in non-adults; administer hypertonic mannitol and dexamethasone ARDS

Treatment of Nonketotic Hyperosmolar Coma Fluid repletion: the deficit may approach 10 liters. Give the first 2-3 liters rapidly even in elderly patients Given normal saline at a rate that will replete half the estimated fluid deficit within 6 hours after which 0.45% saline can be given to complete volume replacement Insulin should be given; 10 unit bolus followed by 4-20 units per hour

Avoiding DKA Sick day rules If ketones small to moderate give 10% more fast acting insulin If ketones large give 20% more fast acting insulin If unable to drink or afraid to give insulin, go to ER for IV dextrose/saline plus insulin

Calculating Volume of Fluid Needed to Correct Water Loss Na2 X BW2 = Na1 X BW1 Na2 = present Na BW2= present body water volume Na1 = normal Na of 142 BW1= original volume of body water (50% of body weight of a woman and 60% of a man

Na 162 in man weighing 70 kg 162 X BW2= 142 X 42 BW2 = 37 liters Water loss is therefore 42-37 = 5 liters

Effect of Hyperglycemia on Serum Sodium In severe hyperglycemia glucose will exert an osmotic pressure This will cause the osmotic pressure of extracellular fluid to rise above that of the cells and serum osmolality will rise As a result water will flow from cells to extracellular water, which will be diluted This will lower the concentration of sodium but represents a dilutional effect and not a true decrease or loss of sodium

The serum sodium will decrease 1 The serum sodium will decrease 1.6 mEq/L for each 100 mg/dl increase in glucose concentration above normal level of 100