1. Diabetic Ketoacidosis and Hyperosmolar Nonketotic Coma

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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

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

10. 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

11. 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

12. 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 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. Treatment of DKA
Fluids and electrolytes
Insulin
Glucose

19. 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

20. 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 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

21. Fluids and Electrolytes
Phosphate deficit ranges from 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 mmol of the anion

22. 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

23. Indications for Bicarbonate Therapy
Unresponsive hypotension
Hyperkalemia
Arrhythmia
Hypoventilation

24. 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

25. 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 mg/dl

26. Treatment of DKA Glucose Insulin U/hr D5W cc/hr <70 0.5 150 71-100
1.0
125
2.0
100
3.0
4.0 75
6.0 50
8.0
10.0
12.0
15.0
>500
20.0

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

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

34. 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

35. 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