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Management of diabetic ketoacidosis - · PDF fileDefinition of Diabetic Ketoacidosis ... Acidemia Plasma anion gap increased Alkalemia HCO 3-- ... Metabolic acidosis – metabolic

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  • Management of diabetic ketoacidosis:

    from a perspective of nephrologist


  • DKA and HHS are Life-Threatening Emergencies

    Abbas E et al. Diabetes Care 2009; 32: 1335

    Diabetic Ketoacidosis (DKA) Hyperglycemic Hyperosmolar

    State (HHS)

    Plasma glucose >250 mg/dL

    Arterial pH 600 mg/dL

    Arterial pH >7.3

    Bicarbonate >15 mEq/L

    Minimal ketonuria and ketonemia

    Anion gap variable

    Serum osmolality >320 mosm/L

  • Characteristics of DKA and HHS

    Abbas E et al. Diabetes Care 2009; 32: 1335


    Absolute (or near-absolute) insulin

    deficiency, resulting in

    Severe hyperglycemia

    Ketone body production

    Systemic acidosis

    Develops over hours to 1-2 days

    Most common in type 1 diabetes, but

    increasingly seen in type 2 diabetes

    Severe relative insulin deficiency,

    resulting in

    Profound hyperglycemia


    No significant ketosis or acidosis

    Develops over days to weeks

    Typically presents in type 2 or

    previously unrecognized diabetes

  • Definition of Diabetic Ketoacidosis

    Adapted from Kitabchi AE, Fisher JN. Diabetes Mellitus. In: Glew RA, Peters SP, ed. Clinical Studies in Medical Biochemistry. New York, NY: Oxford University Press; 1987:105.




  • Diabetic Ketoacidosis: Pathophysiology

    Unchecked gluconeogenesis Hyperglycemia

    Osmotic diuresis Dehydration

    Unchecked ketogenesis Ketosis

    Dissociation of ketone bodies into hydrogen ion and anions

    Anion-gap metabolic acidosis

    Often a precipitating event is identified (infection, lack of insulin administration)

  • Normal Acid-Base Homeostasis

    Chemical buffering: the regulation of PaCO2 by the respiratory system, and the regulation of [HCO3-] by the kidneys, act in concert to maintain a systemic arterial pH between 7.35 and 7.45

    Lung : Eliminate CO2 Kidney : Excrete NH4


    Regenerating HCO3-








    H+ + HCO3- H2CO3 H2O + CO2

    CA: Carbonic Anhydrase

  • Acid-Base Diagnosis


    High Normal Low

    Mixed disorders if

    PaCO2 and HCO3- both low

    PaCO2 and HCO3- both high

    Plasma anion gap increased Acidemia Alkalemia

















    pH : 7.35-7.45

    PaCO2 : 40 mmHg


    : 24 mEq/L

  • Compensatory response on simple acid-base disturbances

    Disorder Prediction of Compensation

    Metabolic acidosis PaCO2 = (1.5 HCO3-) + 8


    PaCO2 will 1.25 mmHg per mmol/L in [HCO3-]


    PaCO2 = [HCO3-] + 15

    Metabolic alkalosis PaCO2 will 0.75 mmHg per mmol/L in [HCO3-]


    PaCO2 will 6 mmHg per 10-mmol/L in [HCO3-]


    PaCO2 = [HCO3-] + 15

    Respiratory alkalosis

    Acute [HCO3-] will 0.2 mmol/L per 1mmHg in PaCO2

    Chronic [HCO3-] will 0.4 mmol/L per 1mmHg in PaCO2

    Respiratory acidosis

    Acute [HCO3-] will 0.1 mmol/L per 1mmHg in PaCO2

    Chronic [HCO3-] will 0.4 mmol/L per 1mmHg in PaCO2 9

  • Serum Anion Gap

    AG = [A-] = [Na+] {[Cl-] + [HCO3-]}

    Normal : 12 2 mmol/L High AG metabolic acidosis

    Acid production (gain)

    Normal AG metabolic acidosis Hyperchloremic metabolic acidosis Alkail loss





  • Acid Gain vs. Alkali (HCO3-) Loss

    High anion gap = acid gain Normal anion gap = hyperchloremia

    = = =


    Cl- Cl- Cl-







    Normal Acid Gain Alkail loss

    A- Cl-

  • Bicarbonate Concentration in DKA

    Kamel et al. New Eng J Med 2015

    In DKA state,

    large deficit of HCO3 in ECF

    severe contraction of the volume of ECF

    Plasma bicarbonate concentration [HCO3] only moderately reduced

    Bicarbonate deficit becomes evident during re-expansion of the volume

    ECF bicarbonate concentration [HCO3]

    = Extracellular Fluid HCO3 content Extracellular Fluid Volume

  • Delta-delta (AG/HCO3-) in Metabolic Acidosis

    AG (pts AG level - 10)/ HCO3- (25 - pts HCO3

    -) 1~2: pure high anion gap M.acidosis > 2 : combined with M.alkalosis < 1 : combined with non-gap acidosis

  • Delta-delta (AG/HCO3-) in DKA

    HCO3 deficit = (25 mmol/L x 10L) (10 mmol/L x 7L) = 180 mmol

    Ketoacid anion gain = (15 mmol/L x 7L) - (0 mmol/L x 10L) = 105 mmol

    type 1 DM, BW 50kg,

    [HCO3] = 25 mmol/L, Anion gap = 12 mmol/L, ECF 10L

    [HCO3] = 10 mmol/L, Anion gap = 27 mmol/L, ECF 7L

    The bicarbonate deficit and the amount of ketoacids retained in

    the extracellular fluid are not equal

  • Indirect loss of Sodium Bicarbonate in DKA

    The loss of HCO3 occurs after it reacts with H+ producing carbon

    dioxide (CO2) and water (H2O); The loss of Na+ occurs during its

    excretion in the urine with -hydroxybutyrate.

    Kamel et al. New Eng J Med 2015

  • Initial Monitoring

    Complete initial evaluation

    Check capillary glucose

    Check serum/urine ketones

    Obtain blood metabolic profile: electrolyte, anion gap, plasma


    Start IV fluids: 1.0 L of 0.9% NaCl per hour

  • IV Fluids Therapy

    Determine hydration status

    Severe Hypovolemia

    Mild hypovolemia Cardiogenic shock

    Administer 0.9% NaCl (1.0L/hr)

    Evaluate corrected serum Na

    Hemodynamic monitoring/pressor

    Serum Na should be corrected for hyperglycemia (for each 100 mg/dl glucose, add 1.6 mEq to sodium value for corrected serum value)

  • IV Fluids Therapy

    Evaluate corrected serum Na

    High Normal

    [Na+]=135 meq/L Low

    0.45% NaCl (250-500 ml/hr)

    0.9% NaCl (250-500 ml/hr)

    Serum Glu 200 mg/dL 5% DW + 0.45% NaCl

    (150-250 ml/hr)

  • Insulin Therapy

    Serum Glu does not fall by 50-70 mg/dL in first hr double IV or SC insulin bolus Serum Glu 200 mg/dL Reduce insulin to keep Glu 150-200 mg/dL

    IV Route Uncomplicated DKA

    SC Route

    RI insulin 0.1 U/kg as IV bolus

    Rapid-actin insulin 0.3 U/kg 0.2 U/kg 1 hr later

    Continuous IV 0.1 U/kg/hr

    Rapid-actin insulin 0.2 U/kg SC q 2 hrs

  • Edge al. Diabetologia 2006

    Administration of a large volume of fluid over the first 4 hours were associated with an increased risk of cerebral edema

  • Plasma Osmolality


    - Transported across most cell membranes

    - Achieves equal concentrations in ECF and ICF

    Total osmolality in plasma

    = 2 [Na+] + [Glucose]/18 + [BUN] /2.8

    Effective osmolality in plasma

    = 2 [Na+] + [Glucose]/18

  • Kamel et al. New Eng J Med 2015

    Severity of Acidosis

    Bolus Insulin

    Large Volume of Fluid

  • Potassium Replacement

    Give 20-30 mEq/L K+

    to keep [K+] 4-5 mEq/L

    [K+] < 3.3 mEq/L

    [K+] = 3.3-5.2 mEq/L

    [K+] > 5.2 mEq/L

    Hold insulin Give 20-30 mEq/hr

    Until [K+] > 3.3 mEq/L

    Do not give K+

    Check [K+] q 2hrs

  • Bicarbonate Infusion

    pH > 6.9 pH < 6.9

    No HCO3- 100 mmol in 400ml H2O

    + 20 mEq KCL for 2 hrs

    Repeat q 2 hrs until pH > 7.0 Monitor [K+] q 2 hrs

  • Severe Acidemia

    Decreased cardiac contractility

    Diminished responses to catecholamines

    Predisposition to cardiac arrhythmias

    Hemodynamic instability

    Impair the capacity of insulin to slow the rate of ketoacid


  • From 508 potentially relevant articles, 44 were included

    Two RCTs demonstrated transient improvement in metabolic

    acidosis with bicarbonate treatment within the initial 2 hours.

    There was no evidence of improved glycemic control or

    clinical efficacy.

    Increased risk for cerebral edema and prolonged

    hospitalization in children who received bicarbonate

    Chua et al. Annals of Intensive Care 2011

  • Oxidization of Ketoacids

    Brain 800 mmol/day

    Kidney Oxidization 250 mmol/day Excretion 150 mmol/day

    Owen et al. J Clin Invest 1967 & 1969

    Infused insulin will slow the rate of ketoacid production

    except initial several hours

  • Bicarbonate Therapy

    Considered in the initial treatment of a subgroup

    Patients who are expected to have a low rate of ketoacid removal

    Marked decrease in their level of consciousness

    Preexisting advanced renal dysfunction

    Combined with normal anion gap metabolic acidosis

    The decision in adult patients with diabetic ketoacidosis should be individualized and not based solely on an arbitrary blood pH value

    Kamel et al. New Eng J Med 2015

  • Delta-delta (AG/HCO3-) in Metabolic Acidosis

    AG (pts AG level - 10)/ HCO3- (25 - pts HCO3

    -) 1~2: pure high anion gap M.acidosis > 2 : combined with M.alkalosis < 1 : combined with non-gap acidosis

  • Metabolic acidosis metabolic alkalosis

    Key: Only d