Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State

Epidemiology

Diabetic Ketoacidosis (DKA)

  • Highest Risk Group: most commonly occurs in patients with type 1 diabetes mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]])
  • Average Age of Onset: 30’s
  • Mortality Rate: lower than HHS

Precipitating Factors for Diabetic Ketoacidosis

  • Insulin/Medication Non-Compliance
    • Includes Malfunction of Subcutaneous Insulin Pumps
  • New-Onset Diabetes Mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]]): 20-25% of cases
  • Infection/Sepsis (see Sepsis, [[Sepsis]])
  • Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
  • Myocardial Infarction (MI) (see Coronary Artery Disease, [[Coronary Artery Disease]])
  • Drugs
    • Anti-Psychotics
      • Clozapine (Clozaril) (see Clozapine, [[Clozapine]])
      • Olanzapine (Zyprexa) (see Olanzapine, [[Olanzapine]])
    • Lithium (see Lithium, [[Lithium]])
    • Sympathomimetics: these agents alter carbohydrate metabolism

Hyperosmolar Hyperglycemic State (HHS)

  • Highest Risk Group: most commonly occurs in patients with type 2 diabetes mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]])
    • Usually Associated with a Concomitant Illness with Associated Decrease in Oral Intake
  • Average Age of Onset: 57-69 y/o
  • Mortality Rate: higher than DKA
    • Mortality Rate in HHS Can Be as High as 10-20%

Precipitating Factors for Hyperosmolar Hyperglycemic State


Physiology

Diabetic Ketoacidosis (DKA)

  • Insulin Deficiency
    • Hyperglycemia: occurs due to decreased glucose utilization in peripheral tissues (adipocytes, muscles), decreased glycogen storage in muscles and hepatocytes, and glucagon-mediated stimulation of hepatocyte gluconeogenesis
      • Glycosuria/Hyperosmolarity-Associated Osmotic Diuresis Leads to Renal Loss of Sodium and Potassium
        • Normally, All Glucose Filtered by the Kidney is Reabsorbed
        • However, When Glucose Reaches 180 mg/dL, Renal Proximal Tubular Reabsorption of Glucose (from Tubular Lumen Back into the Renal Interstititium) is Overwhelmed and Glycosuria Occurs
      • Hyperglycemia Further Inhibits Insulin Release by Pancreatic β-Cells
    • Ketogenesis: with resulting accumulation of ketones/acids
      • Acetoacetate: this is the only true ketoacid
      • Acetone: this is a ketone (not an acid) derived from the decarboxylation of acetoacetate
      • ß-Hydroxybutyrate: this is a hydroxyacid formed from the reduction of acetoacetate

Fate of Ketoacids (Acetoacetate, ß-Hydroxybutyrate) During Treatment of DKA

  • Urinary Excretion of Ketoacids (30% of ketoacids are excreted in urine with normal renal function)
    • Ketoacids Excreted in Urine with Hydrogen or Ammonium: results in loss of protons and correction of acidosis and anion gap
    • Ketoacids Excreted in Urine in form of Potassium/Sodium salts: results in the effective loss of these bicarbonate precursors
  • Conversion of Ketoacids to Acetone: approximately 15-25% of ketoacids are converted to acetone, neutralizing the ketoacid

Hyperosmolar Hyperglycemic State (HHS)

  • Acute Illness-Associated Absolute/Relative Decrease in Insulin Synthesis
    • Hyperglycemia: occurs due to decreased glucose utilization in peripheral tissues (adipocytes, muscles), decreased glycogen storage in muscles and hepatocytes, and glucagon-mediated stimulation of hepatocyte gluconeogenesis
      • Glycosuria/Hyperosmolarity-Associated Osmotic Diuresis Leads to Renal Loss of Sodium and Potassium
        • Normally, All Glucose Filtered by the Kidney is Reabsorbed
        • However, When Glucose Reaches 180 mg/dL, Renal Proximal Tubular Reabsorption of Glucose (from Tubular Lumen Back into the Renal Interstititium) is Overwhelmed and Glycosuria Occurs
      • Hyperglycemia Further Inhibits Insulin Release by Pancreatic β-Cells
    • Concomitant Increase in Counter-Regulatory Hormones (Epinephrine, Glucagon, Growth Hormone, Cortisol): high levels of these hormones cause insulin resistance
  • Possible Explanations for Observation That Patients with HHS Do Not Develop Significant Ketonemia
    • Sufficient Insulin is Present to Prevent Ketogenesis, But Not Enough to Prevent Hyperglycemia
    • Presence of Higher Portal Vein Insulin Levels
    • Hyperosmolarity May Decrease Lipolysis (Which Limits the Free Fatty Acids Available for Ketogenesis)
    • The Levels of Counter-Regulatory Hormones are Lower in HHS (as Compared to Patients with DKA)

Mechanisms of Insulin Resistance

  • Obesity (see Obesity, [[Obesity]]): most common etiology
  • Pregnancy (see Pregnancy, [[Pregnancy]]): due to effect of plcental hormones on the matenal circulation
  • High Levels of Counter-Regulatory Hormones (Epinephrine, Glucagon, Growth Hormone, Cortisol)
  • All-Trans Retinoic Acid (ATRA) (see All-Trans Retinoic Acid, [[All-Trans Retinoic Acid]])
  • Anti-Psychotics
    • Aripiprazole (Abilify) (see Aripiprazole, [[Aripiprazole]])
    • Clozapine (Clozaril) (see Clozapine, [[Clozapine]])
    • Olanzapine (Zyprexa) (see Olanzapine, [[Olanzapine]])
  • Anti-Retrovirals (see see Anti-Retrovirals, [[Anti-Retrovirals]])
    • Nucleoside Reverse Transcriptase Inhibitors
    • Protease Inhibitors: Indinavir, Ritonavir
  • Cyclosporine A (see Cyclosporine A, [[Cyclosporine A]])
  • Glucocorticoids (see Corticosteroids, [[Corticosteroids]])
  • Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition, [[Total Parenteral Nutrition]])

Diagnosis

  • Hemoglobin A1C (Glycosylated Hemoglobin) (see Hemoglobin A1C, [[Hemoglobin A1C]]): elevated
    • Often Useful to Determine the Chronicity of the Underlying Diabetes Mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]])

Clinical Manifestations of Diabetic Ketoacidosis (DKA)

General Comments

  • Overlap Between DKA and HHS
    • In Approximately 33% of Cases, the Clinical Features of DKA and HHS Overlap and are Observed Simultaneously
    • This Suggests that These Two States May Differ Only with Respect to the Magnitude of Dehydration and the Severity of Acidosis
  • Rapidity of Onset: symptoms usually evolve over 24 hrs

Cardiovascular Manifestations

  • Dehydration/Hypotension/Hypovolemic Shock (see Hypotension, [[Hypotension]] and Hypovolemic Shock, [[Hypovolemic Shock]])
    • Clinical: average amount of volume depletion is 6L
  • Takotsubo Cardiomyopathy (Stress-Induced Cardiomyopathy) (see Takotsubo Cardiomyopathy, [[Takotsubo Cardiomyopathy]])
    • Epidemiology: case reports

Constitutional Manifestations

  • Fatigue (see Fatigue, [[Fatigue]])

Endocrinologic Manifestations

  • Hyperglycemia (see Hyperglycemia, [[Hyperglycemia]]): >250 mg/dL
    • Euglycemic DKA Has Been Described in Patients with Poor Oral Intake, Prior Treatment with Insulin, or in Pregnancy
  • Hyperlipidemia/Hypertriglyceridemia (see Hyperlipidemia, [[Hyperlipidemia]] and Hypertriglyceridemia, [[Hypertriglyceridemia]]): may occur in some cases
    • May Be Severe and Result in Lipemic Serum
    • Due to Lipolysis Associated with Insulin Deficiency (as Insulin is a Potent Anti-Lipolytic Hormone) and Elevated Lipolytic Hormones (Catecholamines, Glucagon, Growth Hormone, Corticotropin)

Gastroenterologic Manifestations

  • Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])
    • Epidemiology
      • Abdominal Pain Occurs in 46% of Cases
      • More Commonly Manifested in Children
      • Associated with Degree of Acidosis: abdominal pain occurs in 86% of cases with bicarbonate <5 mEq/L
      • Not Associated with the Degree of Hyperglycemia or Dehydration
    • Possible Mechanisms of Abdominal Pain: mechanism is poorly understood
      • Bowel Ischemia
      • Delayed Gastric Emptying/Ileus: due to acidosis
      • Esophagitis with Ulceration
      • Hepatic Capsule Distention
      • Subacute Pancreatitis
  • Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]])
    • Clinical: may precipitate DKA or occur as a complication of DKA
  • Fruity Odor to Breath (see Abnormal Breath Odor, [[Abnormal Breath Odor]])
    • Physiology: due to exhaled acetone
  • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])

Hematologic Manifestations

  • Leukocytosis (see Leukocytosis, [[Leukocytosis]])
    • Physiology: due to elevated cortisol and catecholamines
    • Clinical: correlated with the degree of ketonemia

Neurologic Manifestations

  • Delirium (see Delirium, [[Delirium]])
    • Clinical: may occur with severe acidosis
  • Obtundation-Coma (see Obtundation-Coma, [[Obtundation-Coma]])
    • Clinical: may occur in severe DKA associated with severe acidosis

Pulmonary Manifestations

Renal Manifestations

Abnormal Serum Phosphate (with Associated Phosphate Depletion)

  • Normophosphatemia-Hyperphosphatemia (see Hyperphosphatemia, [[Hyperphosphatemia]])
    • Mechanism
      • Hyperphosphatemia Occurs Due to Insulin Deficiency and Metabolic Acidosis Shifting Phosphate Out of the Cells into the Extracellular Fluid
    • Diagnosis: usually normal-high serum phosphate
      • However, These Patients Have Phosphate Depletion Due to Multiple Mechanisms
        • Phosphaturia Due to Osmotic Diuresis
        • Decreased Phosphate Intake
        • Acidosis-Related Shift of Phosphate into Extracellular Fluid

Abnormal Serum Potassium (with Associated Potassium Depletion)

  • Normokalemia: usually
  • Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])
    • Epidemiology: occurs in 33% of cases
    • Mechanism: due to insulin deficiency and hyperosmolality (but is not believed to be due to the ketoacidosis) -> both drive potassium out of the cells
  • Hypokalemia (see Hypokalemia, [[Hypokalemia]])
    • Epidemiology: occurs in only 5% of cases
    • Mechanism: due to urinary potassium loss (due to osmotic diuresis and excretion of potassium ketoacid salts)

Abnormal Serum Sodium

  • Hyponatremia (see Hyponatremia, [[Hyponatremia]]): usually mild hyponatremia
    • To Calculate the True Serum Sodium, Need to Correct Sodium Upward by 2 mEq/L for Each 100 mg/dL of Glucose Above 100 to Account for the Component of Hyperglycemia-Associated Pseudohyponatremia

Ketonemia (see Ketonemia, [[Ketonemia]])

  • Diagnosis
    • Nitroprusside Reaction (only detects acetoacetate and, to a far lesser extent, acetone): usually positive
      • Acetest (Using Nitroprusside Tablets)
      • Ketostix (Using Nitroprusside Reagent Sticks)
      • False-Positive Nitroprusside Test: may be due to drugs with sulfhydryl groups (captopril, penicillamine, mesna), which react with nitroprusside
    • Beta Hydroxybutyrate Level (see Serum β-Hydroxybutyrate, [[Serum β-Hydroxybutyrate]])
      • Normal Beta Hydroxybutyrate Level: <0.6 mmol/L
      • Beta Hydroxybutyrate Level in DKA: usually ranges from 3 to >8 mmol/L
      • Beta Hydroxybutyrate Level is the Preferred Test in DKA (Especially for Monitoring the Therapeutic Response), Since this is the Predominant Ketone Present in Severe DKA
  • Clinical: present

Ketonuria (see Urinalysis, [[Urinalysis]])

  • Diagnosis
    • Nitroprusside Reaction (only detects acetoacetate and, to a far lesser extent, acetone): may be negative or only weakly positive
      • Acetest (Using Nitroprusside Tablets)
      • Ketostix (Using Nitroprusside Reagent Sticks)
      • False-Positive Nitroprusside Test: may be due to drugs with sulfhydryl groups (captopril, penicillamine, mesna), which react with nitroprusside
  • Clinical: present

Metabolic Acidosis

  • Anion Gap Metabolic Acidosis (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]])
    • Epidemiology: occurs as part of initial presentation
    • Physiology: the degree of anion gap elevation depends on the rate/duration of ketoacid production, rate of metabolism of ketoacids, degree of urinary ketoacid loss, and volume of distribution of the ketoacids
    • Diagnosis
      • Anion gap is usually >20
      • Delta Gap/Delta Bicarbonate Ratio: usually 1.1
      • pH is variable (depending on severity of DKA), but pH can be <7.0 in severe cases
  • Non-Anion Gap Metabolic Acidosis (NAGMA) (see Metabolic Acidosis-Normal Anion Gap, [[Metabolic Acidosis-Normal Anion Gap]])
    • Epidemiology: occurs during the course of DKA therapy in almost all patients who have relatively intact renal function (due to the urinary excretion of ketoacids)
    • Mechanism: urinary excretion of ketoacids (acetoacetate, ß-hydroxybutyrate) in the form of potassium/sodium salts -> this represents an effective loss of bicarbonate precursors
    • Resolution: resolves as kidneys excrete ammonium chloride (NH4Cl) and regenerate bicarbonate

Elevated Osmolal Gap (see Serum Osmolality, [[Serum Osmolality]])

  • Physiology: presence of osmotically-active solutes
    • Glycerol: derived from fat breakdown
    • Acetone/Acetone Metabolites

Polydipsia (see Polydipsia, [[Polydipsia]])

  • Clinical: usually present

Polyuria (see Polyuria, [[Polyuria]])

  • Clinical: usually present

Clinical Manifestations of Hyperosmolar Hyperglycemic State

General Comments

  • Overlap Between DKA and HHS
    • In Approximately 33% of Cases, the Clinical Features of DKA and HHS Overlap and are Observed Simultaneously
    • This Suggests that These Two States May Differ Only with Respect to the Magnitude of Dehydration and the Severity of Acidosis
  • Rapidity of Onset: symptoms usually evolve over days

Cardiovascular Manifestations

  • Dehydration/Hypotension/Hypovolemic Shock (see Hypotension, [[Hypotension]] and Hypovolemic Shock, [[Hypovolemic Shock]])
    • Clinical: average amount of volume depletion is 9L

Endocrinologic Manifestations

  • Hyperglycemia (see Hyperglycemia, [[Hyperglycemia]]): usually >600 mg/dL
  • Hyperlipidemia/Hypertriglyceridemia (see Hyperlipidemia, [[Hyperlipidemia]] and Hypertriglyceridemia, [[Hypertriglyceridemia]]): may occur in some cases
    • May Be Severe and Result in Lipemic Serum
    • Due to Lipolysis Associated with Insulin Deficiency (as Insulin is a Potent Anti-Lipolytic Hormone) and Elevated Lipolytic Hormones (Catecholamines, Glucagon, Growth Hormone, Corticotropin)

Gastrointestinal Manifestations

Neurologic Manifestations

  • Delirium (see Delirium, [[Delirium]])
  • Focal Neurologic Signs
    • Hemianopsia
    • Hemiparesis
  • Obtundation-Coma (see Obtundation-Coma, [[Obtundation-Coma]]): occurs in <20% of HHS cases
    • Usually Occurs in Patients with Plasma Osmolality >320-330 mosmol/kg
    • Neurologic Symptoms are More Common in HHS than DKA Due to the Higher Plasma Osmolality Observed in HHS
  • Seizures (see Seizures, [[Seizures]])

Renal Manifestations

Abnormal Serum Phosphate (with Associated Phosphate Depletion)

  • Mechanism: hyperphosphatemia occurs due to insulin deficiency and metabolic acidosis shifting phosphate out of the cells into the extracellular fluid
  • Diagnosis: usually normal-high serum phosphate (see Hyperphosphatemia, [[Hyperphosphatemia]])
    • However, These Patients Have Phosphate Depletion Due to Multiple Mechanisms
      • Phosphaturia Due to Osmotic Diuresis
      • Decreased Phosphate Intake
      • Acidosis-Related Shift of Phosphate into Extracellular Fluid

Abnormal Serum Potassium (with Associated Potassium Depletion)

  • Normokalemia: usually
  • Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]]): occurs in 33% of cases
    • Mechanism: due to insulin deficiency and hyperosmolality (but is not believed to be due to the ketoacidosis) -> both drive potassium out of the cells
  • Hypokalemia (see Hypokalemia, [[Hypokalemia]]): occurs in only 5% of cases
    • Mechanism: due to urinary potassium loss (due to osmotic diuresis and excretion of potassium ketoacid salts)

Abnormal Serum Sodium

  • Hyponatremia (see Hyponatremia, [[Hyponatremia]]): usually mild hyponatremia
    • To Calculate the True Serum Sodium, Need to Correct Sodium Upward by 2 mEq/L for Each 100 mg/dL of Glucose Above 100 to Account for the Component of Hyperglycemia-Associated Pseudohyponatremia

Ketonemia (see Ketonemia, [[Ketonemia]])

  • Diagnosis
    • Nitroprusside Reaction: absent-small
      • Acetest (using nitroprusside tablets)
      • Ketostix (using nitroprusside reagent sticks)
      • False-Positive Nitroprusside Test: may be due to drugs with sulfhydryl groups (captopril, penicillamine, mesna), which react with nitroprusside
    • Beta Hydroxybutyrate Level (see Serum β-Hydroxybutyrate, [[Serum β-Hydroxybutyrate]]) (Normal: <0.6 mmol/L): normal
  • Clinical: absent-to-low ketonemia

Ketonuria (see Ketonuria, [[Ketonuria]])

  • Clinical: small ketonuria may be present

Metabolic Acidosis

  • Anion Gap Metabolic Acidosis (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]])
    • Diagnosis
      • Anion gap metabolic acidosis is variably observed
      • Usually with serum bicarbonate >15 mEq/L
      • Usually with serum pH >7.30

Hyperosmolality (see Serum Osmolality, [[Serum Osmolality]])

  • Diagnosis: effective serum osmolality at least 320 mOsm/kg
    • Effective Plasma Osmolality Includes Sodium and Glucose Only, Since Urea is Freely Permeable Across Most Membranes and its Accumulation Does Not Induce Water Shifts Between the Intracellular Spaces (Including the Brain) and the Extracellular Space

Polydipsia (see Polydipsia, [[Polydipsia]])

  • Clinical: usually present

Polyuria (see Polyuria, [[Polyuria]])

  • Clinical: usually present

Treatment

Diabetic Ketoacidosis (DKA)

Protocol-Driven Care

  • Clinical Efficacy
    • Protocol-Driven Care for Adult Patients with DKA Decreases ICU and Hospital Length of Stay, Time to Anion Gap Closure, and Time to Ketone Clearance (Crit Care Med, 2007) [MEDLINE]
    • Compliance with the 2006 ADA Hyperglycemic Crises in Adult Patients with Diabetes Clinical Guidelines for DKA was Low (Am J Health Syst Pharm, 2015) [MEDLINE]

Intravenous Fluid Resuscitation

  • General Comments
    • Volume Repletion Alone May Initially Reduce the Serum Glucose by 35-70 mg/dL Per Hour (Due to Expansion of Extracellular Fluid, Dilution, and Increased Urinary Elucose Excretion Resulting from Improved Renal Perfusion)
  • Bolus with 1L Per Hour of 0.9% Normal Saline (Max: <50 mL/kg in First 2-3 hrs) Before Insulin is Administered (see Normal Saline, [[Normal Saline]])
    • This is Critical Since Insulin Therapy Will Drive Glucose Out of Vascular Space (and Into the Cell), Dropping Serum Osmolality
  • Normal Saline Infusion at 200 mL/hr (see Normal Saline, [[Normal Saline]])
    • If the Glucose-Corrected Serum Sodium is Normal or High, 0.45% Saline Can Be Alternately Administered (Based on Volume Status) During the Next Few Hours of Therapy
  • Once Blood Glucose Reaches 200 mg/dL: change IV fluid to D5/0.45% saline at 200 mL/hr
    • Continue D5/0.45% saline + insulin drip together (titrating only the insulin drip up/down based on blood glucose) until the anion gap clears

Insulin Administration (see Insulin, [[Insulin]])

  • General Comments
    • Necessary in DKA
    • Insulin Therapy Should Not Be Started Until Potassium and Fluid Deficits are Repleted
    • Insulin Infusion Will Be Expected to Decrease Serum Glucose by Approximately 50-75 mg/dL Per Hour (Higher Insulin Infusion Rates Likely Will Not Lower Serum Glucose Faster Than This, Due to Probable Saturation of the Insulin Receptors)
  • Effects of Insulin Therapy
    • Inhibition of Hepatic Gluconeogenesis
    • Increase in Peripheral Glucose Utilization: to a lesser extent
    • Decrease in Ketone Production: due to inhibition of lipolysis and glucagon secretion (amti-lipolytic effect of insulin occurs at lower doses than that required to decrease the serum glucose)
    • Enhancement of ketone utilization
  • Dosing
    • Bolus (optional): regular insulin 10U IV (or 0.1 U/kg IV)
    • Insulin Infusion: run per insulin drip protocol (usually start at 0.5-0.1 U/kg/hr)
      • Titrate Insulin to Maintain Blood Glucose Between 150-200 mg/dL (Avoid Decreasing the Serum Glucose Below This to Avoid Inducing Cerebral Edema)
      • Continue D5/0.45% Saline + Insulin Drip Together (Titrating Only the Insulin Drip Up/Down Based on Blood Glucose) Until the Anion Gap Clears
      • Once Anion Gap Clears (and Patient is Able to Tolerate Oral Intake), Administer Long-Acting Insulin (Lantus, etc) and Then Stop Both the D5/0.45% Saline + Insulin Drip Together 1 hr After the Long-Acting Insulin is Given
  • Clinical Data
    • Addition of Glargine Insulin to Standard Therapy within 3 hrs of Presentation for DKA Decreased the Average Recovery Time from DKA without Incurring Episodes of Hypoglycemia or Hypokalemia (J Clin Diagn Res, 2015) [MEDLINE]: small trial (n = 40), requires validation in larger trials

Repletion of Serum Phosphate

  • Indications: hypophosphatemia in the setting of myocardial dysfunction, hemolytic anemia, or respiratory depression (note that routine phosphate replacement is not recommended)
    • Randomized Trials Have Not Demonstrated a Benefit of Phosphate Replacement in DKA: replacement does not change the duration of ketoacidosis, dose of insulin required, the rate of fall of serum glucose, or morbidity/mortality
    • Potential Harmful Effects of Phosphate Replacement in DKA
      • Hypocalcemia
      • Hypomagnesemia
  • Monitoring (at least q4 hrs): critical since insulin therapy can cause a decrease in the serum phosphate

Repletion of Serum Potassium

  • Indications: serum potassium between <5 mEq/L
  • Monitoring (at least q4 hrs): critical since insulin therapy can cause a marked decrease in the serum potassium

Sodium Bicarbonate (see Sodium Bicarbonate, [[Sodium Bicarbonate]])

  • Indications: serum pH <6.9-7.0 (although randomized trials supporting this are lacking)
    • Patients with Hemodynamic Compromise (Due to Impaired Myocardial Contractility and Vasodilation) or Life-Threatening Hyperkalemia May Particularly Benefit from Bicarbonate Administration to Correct the pH
    • Potential Adverse Effects of Bicarbonate in DKA
      • Hypokalemia (see Hypokalemia, [[Hypokalemia]]): sodium bicarbonate drives potassium intracellularly -> close monitoring of potassium is required when bicarbonate therapy is used (see Hypokalemia, [[Hypokalemia]])
      • Post-Treatment Metabolic Alkalosis (see Metabolic Alkalosis, [[Metabolic Alkalosis]]): due to fact that insulin induces metabolism of ketoacid anions with generation of bicarbonate
      • Paradoxical Decrease in Cerebral pH: due to fact that bicarbonate administration decreases ventilatory drive, increasing pCO2 -> increased pCO2 is more quickly reflected across the blood-brain barrier than increased bicarbonate
      • Slowed Rate of Ketone Clearance
  • Cautions: when the bicarbonate concentration increases, the serum potassium may decrease -> close monitoring of potassium is required when bicarbonate therapy is used

Monitoring of Diabetic Ketoacidosis Therapy

  • Serial Serum Glucose: q1hr serum glucose monitoring is standard while on an insulin drip
  • Serum Electrolytes: q4hrs is standard

    • Follow the Anion Gap: anion gap returns to normal when ketoacids have disappeared from the serum
      • If Serum or Urine Testing is Done During Insulin Therapy with a Nitroprusside Reaction Method (Only Detects Acetoacetate and, to a Far Lesser Extent, Acetone), Ketonemia/Ketonuria May Appear to Persist for >36 hrs Due to the Slow Elimination of Acetone via the Lungs (However, Since Acetone is Not an Acid, it Does Not Cause Acidosis)
      • During Insulin Therapy, ß-Hydroxybutyrate is Converted to Acetoacetate, Resulting in an Increasingly Positive Nitroprusside Test for Acetoacetate as the Degree of Ketosis is Improving
  • Serial Serum ß-Hydroxybutyrate Level (see Serum β-Hydroxybutyrate, [[Serum β-Hydroxybutyrate]]): this is the best test to follow ketoacids during insulin therapy

Complications of Diabetic Ketoacidosis Therapy

  • Development of Non-Anion Gap Metabolic Acidosis During the Course of DKA Therapy
    • Incidence: occurs in almost all patients with relatively intact renal function
    • Mechanism: urinary excretion of ketoacids (acetoacetate, ß-hydroxybutyrate) in the form of potassium/sodium salts -> this represents an effective loss of bicarbonate precursors
    • Resolution: resolves as kidneys excrete ammonium chloride (NH4Cl) and regenerate bicarbonate
  • Cerebral Edema (see Increased Intracranial Pressure, [[Increased Intracranial Pressure]])
    • Epidemiology
      • More Common in DKA than HHS
      • Almost All Cases Occur in Patients <20 y/o
    • Clinical: symptoms typically emerge within 12-24 hrs of the initiation of DKA treatment, but may be present prior to the onset of therapy in some cases
    • Preventative Measures
      • Gradual Replacement of Sodium and Water Deficits in Patients with Hyperosmolarity: bolus with 1L per hour of normal saline in first few hrs (Max: <50 mL/kg in first 2-3 hrs)
      • Addition of Dextrose to IV Fluids Once Serum Glucose Reaches 200 mg/dL in DKA or 250-300 mg/dL in HHS
    • Treatment
      • Mannitol (0.25 to 1.0 g/kg) or Hypertonic (3%) Saline (5 to 10 mL/kg over 30 min): although data is from case reports only, these measures increase plasma osmolality, resulting in osmotic movement of water out of the brain and a decrease in cerebral edema
    • Prognosis: 20-40% mortality rate
  • Hypoxemia/Noncardiogenic Pulmonary Edema: may result from excessive IV fluid administration
    • Hypoxemia May Occur Due to a Decrease in Colloid Osmotic Pressure that Results in Increased Lung Water Content and Decreased Lung Compliance
    • Patients with DKA Who Have a Widened A-a Oxygen Gradient on Initial ABG or Rales on Physical Examination Appear to Be at Higher Risk for the Development of Pulmonary Edema

Hyperosmolar Hyperglycemic State

Intravenous Fluid Resuscitation

  • General Comments
    • Volume Repletion Alone May Significantly Reduce the Serum Glucose (Often faster than that Observed in DKA, Due to a Greater Degree of Hypovolemia Present in HHS
  • Bolus with 1L Per Hour of 0.9% Normal Saline (Max: <50 mL/kg in First 2-3 hrs) Before Insulin is Administered (see Normal Saline, [[Normal Saline]])
    • This is Critical Since Insulin Therapy Will Drive Glucose Out of Vascular Space (and Into the Cell), Dropping Serum Osmolality
  • Normal Saline (0.9%) Infusion at 200 mL/hr (see Normal Saline, [[Normal Saline]])
    • If the Glucose-Corrected Serum Sodium is Normal or High, 0.45% Saline Can Be Alternately Administered (Based on Volume Status) During the Next Few Hours of Therapy
  • Once Blood Glucose Reaches 250 mg/dL: change IV fluid to D5/0.45% saline at 200 mL/hr
    • Continue D5/0.45% Saline + Insulin drip together (titrating only the insulin drip up/down based on blood glucose) until the anion gap clears

Insulin Administration (see Insulin, [[Insulin]])

  • General Comments
    • Variably Necessary, as Many Patients with HHS May Respond to IV Fluids Alone
  • Dosing
    • Bolus (optional): regular insulin 10U IV (or 0.1 U/kg IV)
    • Insulin Infusion: run per insulin drip protocol (usually start at 0.5-0.1 U/kg/hr)
      • Titrate Insulin to Maintain Blood Glucose Between 250-300 mg/dL (Avoid Decreasing the Serum Glucose Below This to Avoid Inducing Cerebral Edema)
      • Continue D5/0.45% Saline + Insulin Drip Together (Titrating Only the Insulin Drip Up/Down Based on Blood Glucose) Until the Anion Gap Clears
      • Once Anion Gap Clears (and Patient is Able to Tolerate Oral Intake), Administer Long-Acting Insulin (Lantus, etc) and Then Stop Both the D5/0.45% Saline + Insulin Drip Together 1 hr After the Long-Acting Insulin is Given

Repletion of Serum Phosphate

  • Indications: hypophosphatemia in the setting of myocardial dysfunction, hemolytic anemia, or respiratory depression (note that routine phosphate replacement is not recommended)
    • Randomized Trials Have Not Demonstrated a Benefit of Phosphate Replacement in DKA: replacement does not change the duration of ketoacidosis, dose of insulin required, the rate of fall of serum glucose, or morbidity/mortality
    • Potential Harmful Effects of Phosphate Replacement
  • Monitoring (at least q4 hrs): critical since insulin therapy can cause a decrease in the serum phosphate

Repletion of Serum Potassium

  • Indications: serum potassium between <5 mEq/L
  • Monitoring (at least q4 hrs): critical since insulin therapy can cause a marked decrease in the serum potassium

Monitoring of Hyperosmolar Hyperglycemic State Therapy

  • Serial Serum Glucose: q1hr serum glucose monitoring is standard while on an insulin drip
  • Serum Electrolytes: q4hrs is standard

Complications of Hyperosmolar Hyperglycemic State Therapy

  • Cerebral Edema (see Increased Intracranial Pressure, [[Increased Intracranial Pressure]])
    • Epidemiology
      • More Common in DKA than HHS
      • Almost All Cases Occur in Patients <20 y/o
    • Clinical: symptoms typically emerge within 12-24 hrs of the initiation of DKA treatment, but may be present prior to the onset of therapy in some cases
    • Preventative Measures
      • Gradual Replacement of Sodium and Water Deficits in Patients with Hyperosmolarity: bolus with 1L per hour of normal saline in first few hrs (Max: <50 mL/kg in first 2-3 hrs)
      • Addition of Dextrose to IV Fluids Once Serum Glucose Reaches 200 mg/dL in DKA or 250-300 mg/dL in HHS
    • Treatment
      • Mannitol (0.25 to 1.0 g/kg) or Hypertonic (3%) Saline (5 to 10 mL/kg over 30 min) (see Mannitol, [[Mannitol]] and Hypertonic Saline, [[Hypertonic Saline]]): although data is from case reports only, these measures increase plasma osmolality, resulting in osmotic movement of water out of the brain and a decrease in cerebral edema
    • Prognosis: 20-40% mortality rate

References

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  • Pulmonary edema; a complication of diabetic ketoacidosis. Chest. 1980 May;77(5):687-8 [MEDLINE]
  • Recurrent high-permeability pulmonary edema associated with diabetic ketoacidosis. Crit Care Med. 1985 Jan;13(1):55-6 [MEDLINE]
  • Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19 Suppl 1:1-93 [MEDLINE]
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  • Mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care unit and hospital lengths of stay: results of a nonrandomized trial. Crit Care Med. 2007 Jan;35(1):41-6 [MEDLINE]
  • Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul;32(7):1335-43. doi: 10.2337/dc09-9032 [MEDLINE]
  • Diabetes: Advances in Diagnosis and Treatment. JAMA. 2015 Sep 8;314(10):1052-62. doi: 10.1001/jama.2015.9536 [MEDLINE]
  • Effectiveness of Insulin Glargine on Recovery of Patients with Diabetic Ketoacidosis: A Randomized Controlled Trial. J Clin Diagn Res. 2015 May;9(5):OC01-5. doi: 10.7860/JCDR/2015/12005.5883. Epub 2015 May 1 [MEDLINE]
  • Evaluation of the treatment of diabetic ketoacidosis in the medical intensive care unit. Am J Health Syst Pharm. 2015 Dec 1;72(23 Suppl 3):S177-82. doi: 10.2146/sp150028 [MEDLINE]