Diabetic Ketoacidosis

History

• Adult patients most often have a history of type 1 diabetes, although diabetic ketoacidosis can rarely develop in patients with ketosis-prone type 2 diabetes ^r4c1c2
• Children and young adults (younger than 20 years) present with diabetic ketoacidosis as the initial manifestation of diabetes in 30% of cases ^r9
• Most common symptoms, which usually develop over a period of hours to days
  • Polydipsia ^c3
  • Polyuria ^c4
  • Fatigue ^c5
  • Blurry vision ^c6
  • Weight loss ^c7
• Other symptoms found variably
  • Nausea, vomiting, and abdominal pain (40%-75% of cases) ^r10c8c9c10
    • Abdominal pain attributable solely to DKA is typically diffuse and follows periods of protracted vomiting and worsening acidemia ^r11c11c12c13
  • Dyspnea due to tachypnea ^c14
  • Headache due to cerebral edema (children) ^r12c15
  • New-onset enuresis (children) ^r12c16
  • Confusion or drowsiness ^c17c18
• Other symptoms that can suggest a precipitating event
  • Chest pain (acute coronary syndrome) ^c19
  • Fever (many infections), although hypothermia can also occur from peripheral vasodilation ^c20c21
  • Cough and dyspnea (pneumonia or heart failure) ^c22c23
• Medication and substance history may identify a precipitant or alternative diagnosis
  • Ingestion of agents that may cause or exacerbate hyperglycemia ^r11
    • Sympathomimetic amines ^c24
    • Corticosteroids ^c25
    • Atypical antipsychotics ^c26
  • Ingestion of agents that may cause a metabolic acidosis unrelated to diabetic ketoacidosis
    • Alcohol
    • Methanol
    • Ethylene glycol
    • Isoniazid

Physical examination

• Physical examination findings vary, depending on degree of dehydration and any other accompanying conditions ^c27
• Tachycardia and hypotension due to volume depletion ^r3c28c29
• Dry mucous membranes, poor skin turgor, and sunken eyes ^r3c30c31c32
• Prolonged capillary refill time (especially useful for predicting dehydration in young children) ^r13c33c34
• Kussmaul respiration (tachypnea with deep inspirations) ^r3c35
• Fruity breath odor ^r3c36
• Altered mental status, ranging from drowsiness to coma with increasing severity of diabetic ketoacidosis ^r3c37c38c39
• Fever, in the setting of infection ^c40

Causes

• Type 1 diabetes plus precipitating factors ^c41d1
  • Medical or surgical illness (altogether accounts for 60% of cases) ^r14
    • Infection (eg, sepsis, pneumonia, urinary tract infection, meningitis) ^{c42c43c44c45c46}
      • COVID-19 infection may precipitate DKA in patients with preexisting diabetes or not-yet-diagnosed diabetes ^r15c47
    • Myocardial ischemia ^c48
    • Cerebrovascular accident ^c49
    • Gastrointestinal bleeding ^c50
    • Pancreatitis (common in adults^r11but rare in children^r16) ^c51c52
    • Less common ^r11
      • Gastrointestinal diseases causing nausea and vomiting ^c53
      • Trauma ^c54
      • Surgery ^c55
      • Alcohol use ^c56
      • Substance misuse (eg, cocaine) ^c57c58
      • Pregnancy ^c59
      • Eating disorders ^c60
      • Ingestion of drugs that decrease carbohydrate metabolism
        • Sympathomimetics ^c61
        • Corticosteroids ^c62
        • Atypical antipsychotics ^c63
        • Thiazide diuretics ^c64
      • Off-label use of sodium-glucose cotransporter 2 inhibitors (gliflozins) by patients with type 1 diabetes ^r17c65
      • Fasting (eg, during Ramadan) ^r18r19c66
  • Inadequate exogenous insulin (accounts for 40% of cases) ^r14c67
    • Omission of insulin due to nonadherence or self-administration error ^c68
    • Unrecognized interruption of insulin delivery by users of insulin pumps (eg, insulin pump malfunction) ^c69
• Type 2 diabetes plus precipitating factors ^c70d2
  • Acute decrease in insulin production owing to pancreatic β-cell dysfunction and temporary insulin resistance ^r20c71c72
  • Use of sodium-glucose cotransporter 2 inhibitors (gliflozins) ^{r7r21r22r23c73}
    • Associated with almost 3-fold increased risk of DKA ^r24
• Treatment with immune checkpoint inhibitors may precipitate ketoacidosis secondary to autoimmune diabetes in patients with previously normal glucose tolerance ^r21r25c74

Risk factors and/or associations

Primary diagnostic tools

• History and physical examination findings suggest the disorder, but biochemical criteria define it ^c86
• Obtain initial laboratory evaluation for all patients, including determination of plasma glucose level, BUN and creatinine levels, serum or urine ketone levels, electrolyte levels (with calculated anion gap), osmolality, urinalysis, venous or arterial pH, and CBC with differential ^r4
  • A tentative diagnosis can be made with bedside tests of capillary blood glucose level and urinary dipstick ketone level
• Biochemical diagnostic criteria for diabetic ketoacidosis in adults
  • Hyperglycemia: blood glucose level greater than 250 mg/dL (13.9 mmol/L) or greater than 200 mg/dL (11 mmol/L) in British guidelines ^r1r34
  • Arterial or venous pH less than 7.3 and/or bicarbonate level less than 15 mEq/L (British guidelines) or less than 15-18 mEq/L (ADA guidelines) ^r1r34
  • Ketonemia (positive acetoacetate^r35 or β-hydroxybutyrate level greater than 31 mg/dL [3 mmol/L]^r34r35)
  • Ketonuria (2+ or more on standard urine sticks) ^r34
  • Anion gap greater than 10 mmol/L ^r1
• Biochemical diagnostic criteria for DKA in children ^r5
  • Hyperglycemia: blood glucose level greater than 200 mg/dL (11 mmol/L)
  • Arterial or venous pH less than 7.3 or bicarbonate level less than 18 mmol/L
  • Ketonemia (positive acetoacetate or β-hydroxybutyrate level greater than 31 mg/dL [3 mmol/L]^r36r35)
  • Moderate or large ketonuria (2+ or more on standard urine sticks)
• Diagnostic caveats
  • DKA can occur with normal or only mildly elevated blood glucose levels (referred to as euglycemic DKA) ^r5
    • May occur in patients who are partially treated or who have consumed little or no carbohydrate; may also be seen with use of sodium-glucose cotransporter 2 inhibitors ^r5r6
    • Blood glucose level is below 200 mg/dL, but other criteria still apply ^r6r21
  • Most patients have a low serum bicarbonate level, low pH, and elevated anion gap, but approximately 10% have at least one of these reported as within reference range ^r37
  • Acetoacetate may be negative early in ketoacidosis

Laboratory

• Initial diagnostic testing
  • Capillary blood glucose level (while chemistry panel results are pending) ^r4c87
  • Chemistry panel, including levels of glucose, sodium, potassium, phosphate, magnesium, bicarbonate, BUN, and creatinine ^{r4c88c89c90c91c92c93c94c95c96}
    • Sodium must be corrected for hyperglycemia ^r14
      • Measured sodium (mEq/L) + 0.016 × (glucose [mg/dL] − 100) for glucose level lower than 400 mg/dL
      • Measured sodium (mEq/L) + 0.024 × (glucose [mg/dL] − 100) for glucose level higher than 400 mg/dL
    • Corrected potassium (for acidemia) may be estimated because acidosis drives potassium from intracellular to extracellular compartments ^r14
      • Subtract 0.6 mEq/L from measured laboratory test value for each decrease of 0.1 in blood gas pH ^r38
  • Calculated anion gap level ^r39c97
    • Sodium (mEq/L) − (chloride [mEq/L] + bicarbonate [mEq/L])
    • Reference range is 6 to 10 mEq/L; a value greater than 10 mEq/L is consistent with DKA
  • Serum osmolality ^c98
    • Differentiates DKA from hyperglycemic hyperosmolar state in patients with type 2 diabetes ^r2
      • Reference range is 285 to 295 mOsm/kg; a value greater than 320 mOsm/kg is found in hyperglycemic hyperosmolar state ^r2
  • Blood gas analysis ^c99
    • Venous blood gas is comparable to arterial blood gas for measuring pH in DKA ^r40
    • Arterial blood gas adds information if there is suspected mixed acid-base disorder (ie, vomiting that is confusing the acid-base picture) and helps to clarify the degree of respiratory compensation
    • In the absence of a mixed acid-base disorder, pH is used to differentiate from hyperglycemic hyperosmolar state, and degree of acidosis is one parameter used to classify DKA as mild, moderate, or severe ^r1
      • pH greater than 7.3: consistent with hyperglycemic hyperosmolar state
      • pH 7.25 to 7.3: consistent with mild DKA
      • pH 7 to 7.24: consistent with moderate DKA
      • pH less than 7: consistent with severe DKA
  • Serum ketone level ^r2c100
    • Direct measurement of β-hydroxybutyrate is preferred diagnostic test for ketonemia because it is an early and most abundant ketoacid that may first signal development of DKA ^r41
      • May be measured either via a laboratory service or by a point-of-care meter ^r42
    • Serum β-hydroxybutyrate level in DKA has been shown to be greater than 31 mg/dL (3 mmol/L) in children and greater than 40 mg/dL (3.8 mmol/L) in adults ^r35r36
    • In practice, a threshold of 31 mg/dL (3 mmol/L) has been adopted for all age groups ^r34r42
    • Serum acetoacetate (via nitroprusside reaction) is an acceptable alternative test if testing for β-hydroxybutyrate is not available
  • Urine ketone bodies measurement ^c101
    • Urine ketone tests measure acetoacetate, which may be present in low concentrations initially, even when there is a high level of serum β-hydroxybutyrate
    • Urine ketone body dipstick testing is rapid, convenient, and sensitive (98%) but has poor specificity for DKA (approximately 35%) ^r43
  • Hemoglobin A1C test ^c102
    • Not essential for diagnosis or management of DKA but may be useful because it provides information about duration of hyperglycemia
• Other laboratory testing to aid differential diagnosis or to identify precipitating event, as driven by the clinical presentation ^r11
  • CBC (to evaluate for hemorrhage or infection as precipitating causes) ^c103
    • Leukocytosis with WBC counts in the range of 10,000 to 15,000 cells/µL can be observed in DKA even without infection, owing to stress, dehydration, and demargination of leukocytes ^r3
  • Blood and urine cultures if there is fever ^c104c105
  • Serum lactate level if sepsis is suspected ^c106
  • Cardiac biomarkers, such as troponin, if there is chest pain or abnormal ECG result ^c107c108
  • Specific toxin level (eg, salicylate, acetaminophen, alcohols) if toxin is suspected ^c109
  • Amylase and lipase if abdominal pain is present or pancreatitis is suspected ^c110c111
    • Not specific for pancreatitis in patients with DKA; elevated levels are found in almost one-third of patients with DKA overall ^r44
    • If levels are elevated, follow up with abdominal CT scan ^r4c112

Imaging

• Imaging is not a required component to make a diagnosis of DKA, but it may be necessary to evaluate for precipitating causes
• If imaging is obtained, direct it at specific anatomical areas as deemed appropriate according to presenting signs, symptoms, and examination findings; options include chest radiograph or CT scan of brain, abdomen and pelvis, or chest ^{r11c113c114c115c116c117}

Functional testing

• Perform ECG for all adults
  • Acute coronary syndrome and acute myocardial infarction are common precipitants of DKA ^r11c118
  • Hyperkalemia resulting from DKA may cause characteristic ECG changes, such as prolonged PR interval, peaked T waves, and wide QRS complexes ^r45
  • Rarely, a pseudoinfarction pattern, with ST-elevation that resolves with correction of biochemical abnormalities may be seen ^r45

Procedures

Other diagnostic tools

• Calculation of water deficit ^c120
  • For patients with hypernatremia and severe dehydration, an estimate of the water deficit is useful to gauge the amount of fluid necessary to restore a euvolemic state
  • Water deficit: 0.6 × (body weight in kg) × (1 − [corrected sodium / 140]) ^r46
• Calculation of anion gap ^r39c121
  • Standard anion gap: sodium (mEq/L) − (chloride [mEq/L] + bicarbonate [mEq/L]) ^c122
    • Reference range is 6 to 10 mEq/L; more than 10 mEq/L is consistent with DKA
  • Although the standard anion gap is sufficient in most cases, adjustment for albumin concentration is recommended in cases of hypoalbuminemia ^c123
    • Albumin-corrected anion gap: anion gap − 2.5 × (4 − serum albumin [g/dL]) ^r39c124
• Although the measured serum osmolality is sufficient in most cases, a calculated osmolality is needed to determine the osmolar gap, which is useful to assess for other causes of high anion gap metabolic acidosis ^c125
  • Calculated formula: (2 × measured sodium [mEq/L]) + (glucose [mg/dL] / 18) + (BUN [mg/dL] / 2.8) ^r39
  • Osmolal gap ^c126
    • Difference between measured osmolality and calculated osmolality
    • Can be used as a rapid screen for ethanol, methanol, or ethylene glycol intoxication when there is a high anion gap acidosis
    • High osmolal gap indicates presence of an abnormal solute present in significant amount
    • Osmolal gap greater than 10 can be caused by most toxic alcohols (ethanol, methanol, ethylene glycol) ^r47

Most common

• Hyperglycemic hyperosmolar state ^c127
  • An acute metabolic complication of diabetes that most often occurs in patients with type 2 diabetes ^r14
  • Defined by hyperglycemia (usually greater than 600 mg/dL), serum osmolality greater than 320 mOsm/kg, and absence of appreciable metabolic acidosis or ketonemia ^r14
  • Major overlapping clinical features include hyperglycemia, altered mental status, and dehydration
  • Differentiating factors include the following:
    • Ketonemia and ketonuria, if present, are much less severe in hyperglycemic hyperosmolar state ^r14
    • Hyperglycemia is elevated in both conditions but more pronounced in hyperglycemic hyperosmolar state, in which glucose concentrations are frequently greater than 600 mg/dL ^r14
    • Osmolality is usually within reference range or mildly elevated in DKA but is elevated in hyperglycemic hyperosmolar state to more than 320 mOsm/kg ^r14
    • Typically, there is no metabolic acidosis in hyperglycemic hyperosmolar state (the latter shows bicarbonate level greater than 18 and pH greater than 7.3) ^r14
    • Severity of dehydration is typically more severe in hyperglycemic hyperosmolar state ^r14
    • Onset of hyperglycemic hyperosmolar state occurs over several days, whereas DKA can occur within several hours to up to 2 days ^r2

Admission criteria

Most patients with DKA require admission owing to the need for prolonged clinical and laboratory assessment and correction or treatment of the precipitating event, even if fluid resuscitation and correction of acidosis have been accomplished in the emergency department ^r51

Discharge home from the emergency department or observation unit may be considered for adults if all of the following are present:

• DKA is mild
• Precipitating event is easily remedied (eg, missed doses of insulin) and all metabolic abnormalities, including hyperglycemia, acidosis, and electrolyte deficiencies, are corrected and remain stable
• Patient easily tolerates oral fluids
• Patient has insulin and glucometer at home, and clinician has confidence that patient is likely to use them correctly

Admit most children with DKA

Recommendations for specialist referral

• Refer to an intensivist when admission to ICU is warranted
• Refer to an endocrinologist or diabetologist or glucose management team for inpatient management ^r52
• For children with DKA, refer to pediatric endocrinologist and/or pediatric intensivist (when possible) for care management
• Refer all patients with newly diagnosed diabetes or patients who were previously insulin naive to a clinical diabetes educator ^r3

Drug therapy

• Insulin ^c137
  • Adult insulin therapy ^r2
    • Delay insulin administration until IV fluid is infusing and potassium level is higher than 3.3 mEq/L ^r2
    • Continuous IV infusion of regular insulin is indicated for patients with moderate to severe DKA or for patients with coexisting critical illness (ie, hypotension, anasarca)
    • Either continuous IV regular insulin infusion or subcutaneous injections of rapid-acting insulin analogues are acceptable in uncomplicated, mild DKA (non-ICU settings) ^r57
      • Continuous IV insulin infusion has the advantage of rapid half-life and easy titration, but it usually requires greater hospital resources (nursing personnel)
        • Glucose typically falls at a rate of approximately 60 to 120 mg/dL/hour with IV insulin infusion and hydration ^r2
      • Use of subcutaneous injections of rapid-acting insulin analogues lispro^r58 or aspart^r59 leads to resolution of DKA equally rapidly as IV infusion of regular insulin, but it has been studied only in mild DKA cases
      • Clinical outcomes are similar for treating mild DKA when using IV regular insulin versus subcutaneous rapid-acting analogues, provided that aggressive fluid replacement and blood glucose monitoring are frequent ^r57
  • Pediatric insulin therapy ^r5
    • Start insulin administration after starting fluid and potassium (if low initially) replacement
    • IV route is usually preferred for patients with uncomplicated DKA; however, subcutaneous insulin is acceptable in circumstances in which continuous IV administration is not possible and for children with uncomplicated mild to moderate DKA
      • During the COVID-19 pandemic, subcutaneous insulin may be considered for uncomplicated mild to moderate DKA to avoid ICU admission (for IV insulin) when ICU resources are constrained or risk of acquiring COVID-19 infection in this setting is high ^r60
    • IV route ^r5
      • Give regular insulin via IV infusion without an initial bolus
        • IV bolus of insulin is not advisable for children with DKA because it may increase risk of cerebral edema, precipitate shock, and exacerbate hypokalemia
      • Continue insulin infusion until DKA resolves (as measured by pH higher than 7.3, bicarbonate level higher than 15 mEq/L, or closure of anion gap); glucose level normalizes earlier than DKA resolves
      • Add 5% dextrose to the IV fluid when glucose falls to approximately 14 to 17 mmol/L (250-300 mg/dL), or sooner if falling precipitously
    • Subcutaneous route ^r5
      • Subcutaneous rapid-acting insulin analogue (insulin lispro or insulin aspart) is safe and may be as effective as IV regular insulin infusion for patients with uncomplicated mild to moderate DKA
      • Subcutaneous administration of short-acting (regular) insulin is another alternative for mild DKA when continuous IV infusion or subcutaneous rapid-acting insulin analogues are unavailable
      • Do not use subcutaneous route for patients whose peripheral circulation is impaired
  • Regular insulin ^c138
    • IV route
      • Insulin Regular (Recombinant) Solution for injection; Infants, Children, and Adolescents: 0.05 to 0.1 unit/kg/hour continuous IV infusion beginning at least 1 hour after starting fluid replacement therapy and continuing until the acidosis is corrected. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
      • Insulin Regular (Recombinant) Solution for injection; Adults: 0.14 units/kg/hour continuous IV infusion, or alternatively, 0.1 units/kg/dose IV bolus, followed by 0.1 units/kg/hour continuous IV infusion, initially. If serum glucose does not decrease by at least 10% in the first hour, give 0.14 units/kg/dose IV bolus. Adjust dose every 1 to 2 hours based on blood glucose concentration. When the blood glucose concentration decreases to 200 to 250 mg/dL, reduce dose to 0.02 to 0.05 units/kg/hour continuous IV infusion or transition to rapid-acting subcutaneous insulin. Adjust dose to maintain blood glucose of 150 to 200 mg/dL until the acidosis is corrected.
    • Subcutaneous route
      • Insulin Regular (Recombinant) Solution for injection; Infants, Children, and Adolescents: 0.13 to 0.17 units/kg/dose subcutaneously every 4 hours, initially. Adjust dose by 10% to 20% based on blood glucose concentration before the next insulin injection; may increase frequency to every 2 or 3 hours if acidosis is not improving. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
  • Insulin aspart ^c139
    • Insulin Aspart (Recombinant) Solution for injection; Children and Adolescents: 0.15 units/kg/dose subcutaneously every 2 hours beginning at least 1 hour after the start of fluid replacement therapy. May reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours if blood glucose continues to decrease by more than 90 mg/dL despite the addition of dextrose to intravenous fluids. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
    • Insulin Aspart (Recombinant) Solution for injection; Adults: 0.2 or 0.3 units/kg/dose subcutaneously as a single bolus dose, then 0.1 units/kg/dose subcutaneously every hour or 0.2 units/kg/dose subcutaneously every 2 hours, initially. Monitor blood glucose concentration every 1 to 2 hours, and when the blood glucose concentration decreases to 200 to 250 mg/dL, reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours to maintain blood glucose of 150 to 200 mg/dL until the acidosis is corrected. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
  • Insulin lispro ^c140
    • Insulin Lispro Solution for injection; Children and Adolescents: 0.15 units/kg/dose subcutaneously every 2 hours beginning at least 1 hour after the start of fluid replacement therapy. May reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours if blood glucose continues to decrease by more than 90 mg/dL despite the addition of dextrose to intravenous fluids. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
    • Insulin Lispro Solution for injection; Adults: 0.2 or 0.3 units/kg/dose subcutaneously as a single bolus dose, then 0.1 units/kg/dose subcutaneously every hour or 0.2 units/kg/dose subcutaneously every 2 hours, initially. Monitor blood glucose concentration every 1 to 2 hours, and when the blood glucose concentration decreases to 200 to 250 mg/dL, reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours to maintain blood glucose of 150 to 200 mg/dL until the acidosis is corrected. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.

Nondrug and supportive care

IV fluids ^r2c141c142

• Immediately begin therapy to replace fluids, preceding insulin therapy ^c143
• Adult fluids
  • Administer 0.9% normal saline at 0.5 to 1 L/hour for the first 1 to 2 hours ^r2
  • Subsequent choice of fluid depends on serum sodium level, state of hydration, and glucose levels
    • After 1 to 2 hours, evaluate corrected serum sodium level
      • If sodium level is low, reduce IV fluid rate to between 250 and 500 mL/hour, depending on state of hydration; change to 0.45% normal saline once sodium level is within reference range ^r2
      • If sodium level is within reference range or higher, switch to 0.45% normal saline at 250 to 500 mL/hour, with rate reduction depending on state of hydration ^r2
    • Measure and assess glucose level every hour ^r2
      • Add 5% dextrose to IV fluids when glucose level is approximately 200 to 250 mg/dL
      • Continue 5% dextrose in IV fluids (typically with 0.45% normal saline by this point) until resolution of ketoacidosis ^r11
  • Aim to replace the total volume loss within 24 to 36 hours, with 50% of resuscitation fluid being administered during the first 12 hours ^r41
• Pediatric fluids ^r5
  • Initially administer 0.9% normal saline at 10 to 20 mL/kg over 20 to 30 minutes to restore circulatory volume ^r5
    • Higher-volume fluid infusion rates (20 mL/kg bolus + 1.5 × maintenance rate) for pediatric patients with DKA shorten metabolic normalization time compared with lower-volume rates (10 mL/kg bolus + 1.25 × maintenance rate) ^r61
    • Rapidity of IV fluid replacement and sodium chloride content (0.45% or 0.9%) does not influence rates of cerebral injury ^r62
    • Use crystalloid not colloid
    • If patient has hypokalemia, start potassium replacement at this time and before starting insulin therapy
  • Subsequently aim to replace the estimated fluid deficit evenly over 24 to 48 hours (in addition to providing the usual daily maintenance fluid requirement) ^r5
    • Fluid deficit can be replaced with 0.45% to 0.9% saline or a balanced salt solution (Ringer's lactate, Hartmann's solution, or Plasma-Lyte)
    • Add potassium to replacement fluids concurrent with initiation of insulin therapy (required regardless of the serum potassium concentration)
    • Add 5% dextrose to IV fluids when glucose level falls to approximately 250 to 300 mg/dL or sooner if falling precipitously
      • If metabolic acidosis persists, change to 10% or 12.5% dextrose while continuing insulin infusion to prevent hypoglycemia

Electrolytes

• Potassium ^c144
  • Potassium deficit in both children and adults is approximately 3 to 5 mEq/kg (although initial serum potassium level may be measured as within reference range or frankly elevated, owing to hypertonicity, insulin deficiency, and acidosis) ^r2
  • Ensure that there is adequate urine output and kidney function before replacing potassium
    • Adults
      • Potassium repletion in IV fluids is required unless initial potassium is higher than the upper limit of reference range for the particular laboratory (usually 5-5.2 mEq/L) or there is no urine output ^r1
      • Add potassium chloride, at 20 to 30 mEq/hour, to 0.45% normal saline and infuse until serum potassium level is greater than 3.3 mEq/L; continue to add potassium chloride to each liter of IV fluid to maintain potassium level within reference range ^r1
      • If initial potassium level is low, assume that a large potassium deficit exists and that repletion may require more potassium chloride
    • Children
      • If hypokalemic at presentation, start potassium replacement when initiating volume expansion (before starting an insulin infusion) ^r5
      • If normokalemic, start potassium replacement after volume expansion (when beginning insulin)
      • If hyperkalemic, defer potassium replacement until urine output is well maintained and potassium level is falling
      • Begin with 40 mEq/L potassium in the infusate; maximum rate of IV potassium replacement is usually 0.5 mmol/kg/hour ^r5
        • May use potassium chloride, potassium phosphate, or potassium acetate individually or in combination
        • Administration of potassium entirely as potassium chloride increases the risk of hyperchloremic metabolic acidosis, whereas administration entirely as potassium phosphate can result in hypocalcemia
• Bicarbonate ^c145
  • Adults
    • Bicarbonate is rarely required in the management of DKA for adults because it has not been found to hasten rate of recovery from ketoacidosis or hyperglycemia and may contribute to hypokalemia and cerebral edema ^r56r63
    • Correction of acidosis with bicarbonate is recommended only if venous pH is less than 6.9 ^r1
      • For adults with pH less than 6.9, give 100 mEq sodium bicarbonate in 400 mL of sterile water with 20 mEq potassium chloride administered at a rate of 200 mL/hour for 2 hours until the venous pH is greater than 7 ^r4
      • If pH is less than 7 after first infusion, repeat every 2 hours until pH is greater than 7 ^r1
  • Children
    • Bicarbonate replacement is associated with elevated risks of cerebral edema and prolonged hospitalization for pediatric patients ^r63
    • Bicarbonate is not recommended for children, except for treatment of life-threatening hyperkalemia or unusually severe acidosis (pH less than 6.9) with evidence of compromised cardiac contractility ^r5
• Phosphate ^c146
  • Adults
    • Phosphate is rarely required in management of DKA because replacement has not been found to affect clinical outcomes and because aggressive repletion can precipitate hypocalcemia ^r64
    • Correction of hypophosphatemia is recommended only under very limited circumstances (ie, cardiogenic shock, respiratory failure, serum phosphorus level less than 1 mg/dL) ^r65
      • If phosphate level is lower than 1 mg/dL or if phosphate level is low and patient is in cardiac or respiratory failure, add 1 mL potassium phosphate to each liter of fluid, with fluid running at 500 mL/hour ^r65
        • 1 mL of potassium phosphate = 4.4 mEq potassium + 3 mmol (93 mg) phosphate ^r65
        • Maximal rate of phosphate replacement considered safe is 4.5 mmol/hour (1.5 mL/hour of K₂HPO₄), or a total of 90 mmol/day ^r65
      • Monitor serum phosphate, magnesium, and calcium levels in patients receiving phosphate infusion ^r1
  • Children
    • Prompt correction of hypophosphatemia is recommended when serum phosphate level is lower than 1 mg/dL, irrespective of symptoms ^r5
      • Insulin infusion may be reduced or withheld until phosphorus levels increase
    • Routine phosphate replacement to prevent hypophosphatemia is advisable when readily available, particularly for patients with severe DKA ^r5
    • Potassium phosphate may be added to replacement IV fluids alone or in combination with potassium chloride or potassium acetate ^r5
      • Monitor serum calcium level in patients receiving phosphate infusion

Comorbidities

• COVID-19 ^r60c148
  • COVID‐19 infection may precipitate severe metabolic complications of diabetes, including DKA, which may be the initial presentation of new-onset diabetes ^r15r66r67
  • During the COVID-19 pandemic, utilize telehealth for sick day management and routine diabetes care
  • An increased prevalence of DKA has been noted during the pandemic, which may be a result of inadequate treatment of patients who delay scheduled clinic visits for fear of contracting COVID-19 as well as a direct effect of the SARS-CoV-2 virus ^r68
  • Patients admitted with DKA who are COVID-positive have increased mortality secondary to more severe COVID-19 rather than DKA ^r68

Special populations

• Adolescents with recurrent DKA
  • Psychological evaluation for concurrent psychiatric disease is recommended ^r69
    • Depression in this population may lead to more missed insulin doses
      • Children's Depression Inventory is a validated tool to screen for depression ^r70
    • Higher incidence of recurrent DKA is also seen in adolescents with eating disorders
• DKA in patients with chronic kidney disease ^r41
  • Clinical presentation and laboratory values in patients with DKA on dialysis may differ from those not on dialysis
    • Patients receiving dialysis usually have minimal or no signs of volume depletion
    • Hyperkalemia is typically more severe in patients receiving dialysis compared with those not receiving dialysis for the same levels of hyperglycemia
    • Metabolic acidosis is usually present in DKA, but a mixed acid-base disorder can occur owing to concomitant metabolic alkalosis from exposure to high-bicarbonate dialysate
    • High anion gap is always present and serves as a valuable clue, particularly when the anion gap is very high (ie, more than 20 mEq/L^r41)
  • Optimal treatment strategies for DKA in patients with advanced chronic kidney disease receiving dialysis have not been determined by prospective studies ^r71
    • IV fluids may not be required; however, consider them if there is evidence or history of extracellular fluid loss such as vomiting, diarrhea, or excessive insensible losses
    • If fluids are needed, give small boluses of normal saline (250 mL)^r41 while closely monitoring respiratory and hemodynamic parameters
    • Suggested initial rate of IV insulin administration for patients receiving dialysis is similar to that of patients not receiving dialysis, with initial insulin bolus of 0.1 units/kg followed by continuous insulin infusion at 0.05 units/kg/hour
    • Insulin is typically the only treatment necessary for hyperkalemia due to DKA in patients receiving dialysis; give potassium only if the level falls below 3.3 mEq/L ^r41
    • Emergent hemodialysis for patients with DKA is controversial; the main indications are pulmonary edema and severe hyperkalemia
• DKA in patients with cardiac disease
  • Administer IV fluids cautiously to avoid volume overload and pulmonary edema ^r14
• DKA in pregnant patients
  • Pregnant patients develop DKA at significantly lower blood glucose values, and it progresses more rapidly in this population than in patients who are not pregnant ^r72
  • After 24 weeks of gestation, continuously monitor fetal status owing to risk for fetal hypoxemia and acidosis ^r73
  • If cesarean delivery of a term infant is deemed necessary owing to nonreassuring fetal heart rate tracings or fetal distress, delay until maternal metabolic status is stabilized (correction of acidosis, electrolyte replacement, and intravascular volume repletion) ^r72
  • Preterm labor management must take into account maternal condition, viability of the fetus (gestational age), and fetal heart rate tracings ^r72
    • Magnesium sulfate is the tocolytic of choice
    • Avoid β-adrenergic tocolytics, which can exacerbate hyperglycemia, and nifedipine if patient is dehydrated and hypotensive
• DKA associated with sodium-glucose cotransporter 2 inhibitor therapy (gliflozins) ^r36
  • Be aware that low serum bicarbonate level and/or presence of positive urinary ketones may not correctly identify DKA; direct measurement of serum ketones (β-hydroxybutyrate) is more accurate
  • For management, stop the drug immediately and proceed with the traditional diabetic ketoacidosis treatment protocol