Diabetic Ketoacidosis and Hyperosmolar Nonketotic Coma

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Diabetic Ketoacidosis and Hyperosmolar Nonketotic
Coma
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Diabetic Ketoacidosis

• A condition precipitated by stress or other
  illness or omission of insulin

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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

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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

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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

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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

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Admission Findings in DKA

• Polys 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

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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

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Differential Diagnosis of DKA

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

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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

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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

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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

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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

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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

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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

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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

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Initial Laboratory Findings
DKA Hyperosmolar
Glucose 475 1166
Sodium 132 144
Potassium 4.8 5.0
Bicarb lt10 17
BUN 25 87
Acetoacetate 4.8 ND
B-hydroxybut 13.7 ND
Free fatty acids 2.1 0.73
Lactate 4.6 ND
Osmolarity 310 384
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Treatment of DKA

• Fluids and electrolytes
• Insulin
• Glucose

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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

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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

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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

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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 lt7.0 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

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Indications for Bicarbonate Therapy

• Unresponsive hypotension
• Hyperkalemia
• Arrhythmia
• Hypoventilation

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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

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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

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Treatment of DKA
Glucose Insulin U/hr D5W cc/hr
lt70 0.5 150
71-100 1.0 125
101-150 2.0 100
151-200 3.0 100
201-250 4.0 75
251-300 6.0 50
301-350 8.0 0
351-400 10.0 0
401-450 12.0 0
451-500 15.0 0
gt500 20.0 0
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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

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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

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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

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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

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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

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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

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

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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

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