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 ^r5c1c2
• 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 that are found variably include:
  • Nausea, vomiting, and abdominal pain (40%-75% of cases) ^r10c8c9c10
    • Abdominal pain attributable solely to diabetic ketoacidosis 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 ^r4c28c29
• Dry mucous membranes, poor skin turgor, and sunken eyes ^r4c30c31c32
• Prolonged capillary refill time (especially useful for predicting dehydration in young children) ^r3c33c34
• Kussmaul respiration (tachypnea with deep inspirations) ^r4c35
• Fruity breath odor ^r4c36
• Altered mental status, ranging from drowsiness to coma with increasing severity of diabetic ketoacidosis ^r4c37c38c39
• 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) ^r13
    • Infection (eg, sepsis, pneumonia, urinary tract infection, meningitis) ^{c42c43c44c45c46}
      • COVID-19 infection may precipitate diabetic ketoacidosis in patients with preexisting diabetes or not-yet-diagnosed diabetes ^r14c47
    • Myocardial ischemia ^c48
    • Cerebrovascular accident ^c49
    • Gastrointestinal bleeding ^c50
    • Pancreatitis (common in adults,^r11but rare in children^r15) ^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) in patients with type 1 diabetes ^r16c65
      • Fasting (eg, during Ramadan) ^r17r18c66
  • Inadequate exogenous insulin (accounts for 40% of cases) ^r13c67
    • Omission of insulin due to nonadherence or self-administration error ^c68
    • Unrecognized interruption of insulin delivery in 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 ^r19c71c72
  • Use of sodium-glucose cotransporter 2 inhibitors (gliflozins) ^{r8r20r21r22c73}
    • Associated with almost 3-fold increased risk of diabetic ketoacidosis ^r23
• Treatment with immune checkpoint inhibitors may precipitate ketoacidosis secondary to autoimmune diabetes in patients with previously normal glucose tolerance ^r20r24c74

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 in 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 ^r5
  • 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 ^r32
  • Hyperglycemia: blood glucose level greater than 250 mg/dL (13.9 mmol/L)
  • Arterial or venous pH less than 7.3 or bicarbonate level less than 15 to 18 mEq/L ^r1r32
  • Ketonemia (positive acetoacetate^r33 or β-hydroxybutyrate level greater than 31 mg/dL [3 mmol/L] ^r32r33)
  • Ketonuria (2+ or more on standard urine sticks) ^r32
  • Anion gap greater than 10 mmol/L
• Biochemical diagnostic criteria for diabetic ketoacidosis in children ^r3
  • 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 15 mmol/L
  • Ketonemia (positive acetoacetate or β-hydroxybutyrate level greater than 31 mg/dL [3 mmol/L] ^r33r34)
  • Moderate or large ketonuria (2+ or more on standard urine sticks)
• Diagnostic caveats
  • In euglycemic diabetic ketoacidosis, as may be seen with use of sodium-glucose cotransporter 2 inhibitors, the glucose level is below 200 mg/dL, but other criteria apply ^r6r20
  • 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 ^r35
  • Acetoacetate may be negative early in ketoacidosis

Laboratory

• Initial diagnostic testing
  • Capillary blood glucose level (while chemistry panel results are pending) ^r5c87
  • Chemistry panel, including levels of glucose, sodium, potassium, phosphate, magnesium, bicarbonate, BUN, and creatinine ^{r5c88c89c90c91c92c93c94c95c96}
    • Sodium must be corrected for hyperglycemia ^r13
      • 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, as acidosis drives potassium from intracellular to extracellular compartments ^r13
      • Subtract 0.6 mEq/L from measured laboratory test value for each decrease of 0.1 in blood gas pH ^r36
  • Calculated anion gap level ^r37c97
    • 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 diabetic ketoacidosis
  • Serum osmolality ^c98
    • Differentiates diabetic ketoacidosis 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 diabetic ketoacidosis ^r38
    • 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 1 parameter used to classify diabetic ketoacidosis 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 diabetic ketoacidosis
      • pH 7 to 7.24: consistent with moderate diabetic ketoacidosis
      • pH less than 7: consistent with severe diabetic ketoacidosis
  • Serum ketone level ^r2c100
    • Direct measurement of β-hydroxybutyrate is preferred diagnostic test of ketonemia because it is an early and most abundant ketoacid that may first signal development of diabetic ketoacidosis ^r39
      • May be measured either via a laboratory service or by a point-of-care meter ^r40
    • Serum β-hydroxybutyrate level in diabetic ketoacidosis has been shown to greater than 31 mg/dL (3 mmol/L) in children and greater than 40 mg/dL (3.8 mmol/L) in adults ^r33r34
    • In practice, a threshold of 31 mg/dL (3 mmol/L) has been adopted for all age groups ^r32r40
    • 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 diabetic ketoacidosis (approximately 35%) ^r41
  • Hemoglobin A1C test ^c102
    • Not essential for diagnosis or management of diabetic ketoacidosis 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 diabetic ketoacidosis even without infection, owing to stress, dehydration, and demargination of leukocytes ^r4
  • 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 diabetic ketoacidosis; elevated levels are found in almost one-third of patients with diabetic ketoacidosis overall ^r42
    • If levels are elevated, follow up with abdominal CT scan ^r5c112

Imaging

• Imaging is not a required component to make a diagnosis of diabetic ketoacidosis, but it may be necessary to evaluate for precipitating causes
• If imaging is obtained, direct it at specific anatomic 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 in all adults
  • Acute coronary syndrome and acute myocardial infarction are common precipitants of diabetic ketoacidosis ^r11c118
  • Hyperkalemia resulting from diabetic ketoacidosis may cause characteristic ECG changes, such as prolonged PR interval, peaked T-waves, and wide QRS complexes ^r43
  • Rarely, a pseudoinfarction pattern, with ST-elevation that resolves with correction of biochemical abnormalities may be seen ^r43

Procedures

Other diagnostic tools

• Calculation of water deficit ^c120
  • For hypernatremic patients with 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]) ^r44
• Calculation of anion gap ^r37c121
  • 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 diabetic ketoacidosis
  • 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]) ^r37c124
• 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) ^r37
  • 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) ^r45

Most common

• Hyperglycemic hyperosmolar state ^c127
  • An acute metabolic complication of diabetes that most often occurs in patients with type 2 diabetes ^r13
  • Defined by hyperglycemia (usually greater than 600 mg/dL), serum osmolality greater than 320 mOsm/kg, and absence of appreciable metabolic acidosis or ketonemia ^r13
  • 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 ^r13
    • Hyperglycemia is elevated in both conditions but more pronounced in hyperglycemic hyperosmolar state, in which glucose concentrations are frequently greater than 600 mg/dL ^r13
    • Osmolality is usually within reference range or mildly elevated in diabetic ketoacidosis but is elevated in hyperglycemic hyperosmolar state to more than 320 mOsm/kg ^r13
    • Typically, there is no metabolic acidosis in hyperglycemic hyperosmolar state (the latter shows bicarbonate level greater than 18 and pH greater than 7.3) ^r13
    • Severity of dehydration is typically more severe in hyperglycemic hyperosmolar state ^r13
    • Onset of hyperglycemic hyperosmolar state occurs over several days, whereas diabetic ketoacidosis can occur within several hours to up to 2 days ^r2

Admission criteria

Most patients with diabetic ketoacidosis require admission owing to the need for prolonged clinical and laboratory assessment and correction/treatment of the precipitating event, even if fluid resuscitation and correction of acidosis has been accomplished in the emergency department ^r49

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

• Diabetic ketoacidosis 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 diabetic ketoacidosis

Recommendations for specialist referral

• Refer to an intensivist when admission to ICU is warranted
• Refer to an endocrinologist/diabetologist or glucose management team for inpatient management ^r50
• For children with diabetic ketoacidosis, 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 ^r4

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 (diabetic ketoacidosis), 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) ^r54
      • Continuous IV insulin infusion has the advantage of rapid half-life and easy titration, but it usually requires greater hospital resources (nursing personnel)
      • Use of subcutaneous injections of rapid-acting insulin analogues lispro^r55 or aspart^r56 leads to resolution of diabetic ketoacidosis 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 ^r54
    • IV route
      • Administer regular insulin bolus of 0.1 units/kg ^r2
      • Continue regular insulin infusion of 0.1 units/kg/hour ^r2
        • Glucose typically falls at a rate of approximately 60 to 120 mg/dL/hour with insulin and hydration ^r2
      • Reduce regular insulin rate to 0.05 units/kg/hour (or half of initial rate) once blood glucose level reaches 250 mg/dL ^r2
      • Thereafter, adjust regular insulin infusion rate (range of 0.02-0.05 units/kg/hour) to maintain glucose level between 150 and 200 mg/dL until resolution of ketoacidosis ^r1
    • Subcutaneous route
      • Administer rapid-acting insulin analogue bolus of 0.2 units/kg ^r2
      • Continue rapid-acting insulin analogue with doses of 0.2 units/kg every 2 hours ^r2
      • Reduce insulin rate to 0.1 units/kg (or half of initial rate) every 2 hours once blood glucose level reaches 250 mg/dL ^r2
      • Thereafter, adjust insulin dose and frequency to maintain glucose level between 150 and 200 mg/dL until resolution of ketoacidosis ^r1
  • Pediatric insulin therapy ^r3
    • 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 ^r3
      • During the COVID-19 pandemic, subcutaneous insulin may be considered for uncomplicated mild to moderate DKA in order to avoid ICU admission (for IV insulin) when ICU resources are constrained or risk of acquiring COVID-19 infection in this setting is high ^r57
    • IV route
      • Give regular insulin via IV infusion without an initial bolus
      • IV bolus of insulin is not advisable in children with DKA because it may increase risk of cerebral edema, precipitate shock, and exacerbate hypokalemia
      • Start infusion at 0.05 to 0.1 units/kg/hour IV
      • Continue insulin infusion at this rate 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
      • Progressively reduce rate (ie, to 0.05 units/kg/hour, then 0.03 units/kg/hour) as glucose level falls
    • Subcutaneous route ^r3
      • Administer rapid-acting insulin analogue bolus of 0.3 units/kg
      • After 1 hour, administer subcutaneous lispro or aspart at 0.15 to 0.2 units/kg every 2 to 3 hours
      • Once blood glucose level falls to 250 mg/dL, reduce subcutaneous insulin lispro or aspart to 0.05 unit/kg/hour to keep blood glucose level at about 200 mg/dL until resolution of DKA
      • Do not use subcutaneous route in patients whose peripheral circulation is impaired
  • Regular insulin (preferred) ^c138
    • Regular insulin is preferred over the rapid-acting insulin analogues for the IV route
    • Insulin Regular (Recombinant) Solution for injection; Infants, Children, and Adolescents: 0.05 to 0.1 unit/kg/hour IV continuous infusion, beginning at least 1 hour after starting fluid replacement therapy; continue until DKA resolves. If patient is very sensitive to insulin, the infusion rate may be reduced if acidosis continues to resolve. Add 5% Dextrose injection to IV fluid when blood glucose reaches 250 to 300 mg/dL or sooner if blood glucose decline is precipitous. Once DKA has resolved and the patient is tolerating oral intake, transition to subcutaneous insulin. Give first dose of rapid-acting insulin 15 to 30 minutes or regular insulin 1 to 2 hours prior to stopping insulin infusion and providing a meal.
    • Insulin Regular (Recombinant) Solution for injection; Adults: Initially, 0.14 units/kg/hour IV continuous infusion. Alternatively, 0.1 units/kg IV bolus, followed by 0.1 units/kg/hour via continuous IV infusion. If serum glucose does not decrease by at least 10% in the first hour, give 0.14 units/kg as an IV bolus, then continue the previous treatment. Adequate fluid therapy must also be initiated (usually 0.9% NaCl injection for the first hour, then 0.45% NaCl injection if indicated); adjust fluid type and requirements as needed. Adjust insulin infusion to achieve a blood glucose reduction rate of about 50 to 75 mg/dL/hour. When the blood glucose reaches 250 mg/dL, reduce the insulin infusion rate to 0.02 to 0.05 units/kg/hour or give rapid-acting insulin at 0.1 units/kg subcutaneously every 2 hours. Once blood glucose is approximately 200 to 250 mg/dL, add 5% dextrose to IV fluid. Adjust insulin and IV fluids to maintain a blood glucose of roughly 150 to 200 mg/dL until the acidosis is resolved.
  • Insulin lispro ^c139
    • Subcutaneous route
      • Insulin Lispro Solution for injection; Children and Adolescents: 0.3 unit/kg subcutaneously, followed 1 hour later by 0.1 unit/kg/dose subcutaneously every 1 hour or 0.15 to 0.2 units/kg/dose subcutaneously every 2 to 3 hours. If blood glucose falls to less than 250 mg/dL before DKA resolves, reduce to 0.05 unit/kg/dose subcutaneously every 1 hour to keep blood glucose approximately 200 mg/dL until DKA resolves. Consider adding 5% Dextrose Injection to IV fluids if there is a concern of hypoglycemia or precipitous fall in blood glucose.
      • Insulin Lispro Solution for injection; Adults: ADA recommends regular insulin continuous IV, unless DKA is mild. Initially, 0.2 units/kg subcutaneously, then 0.2 unit/kg subcutaneously every 2 hours until blood glucose level is 250 mg/dL or lower, then 0.1 units/kg subcutaneously every 2 hours. Check blood glucose every 1 to 2 hours; concentrations should decrease 80 to 100 mg/dL/hour. Rapid blood glucose decrease is associated with adverse effects. Initiate IV fluids. Monitor serum potassium and replace as indicated.
    • IV route
      • Insulin Lispro Solution for injection; Children and Adolescents: 0.05 to 0.1 unit/kg/hour IV continuous infusion, beginning at least 1 hour after starting fluid replacement therapy; continue until DKA resolves. If patient is very sensitive to insulin, the infusion rate may be reduced if acidosis continues to resolve. Add 5% Dextrose Injection to IV fluid when blood glucose reaches 250 to 300 mg/dL or sooner if blood glucose decline is precipitous. Once DKA has resolved and the patient is tolerating oral intake, transition to subcutaneous insulin. Give the first dose of rapid-acting insulin 15 to 30 minutes or regular insulin 1 to 2 hours prior to stopping insulin infusion and providing a meal. Use Admelog or Humalog 100 units/mL only to prepare infusions. Do NOT administer Humalog 200 units/mL intravenously.
      • Insulin Lispro Solution for injection; Adults: 0.1 to 0.15 units/kg IV bolus followed by 0.1 units/kg/hour via continuous IV infusion. Use adequate fluid therapy as well. Check blood glucose concentrations hourly and adjust the insulin infusion rate as needed. When the blood glucose falls to 250 mg/dL or less, usually decrease insulin to 0.05 to 0.1 unit/kg/hour IV and change fluid therapy to a 5% Dextrose-containing fluid infusion; adjust to maintain a blood glucose of 150 to 250 mg/dL until the acidosis is corrected. Monitor serum potassium; replace as indicated. Use Admelog or Humalog 100 units/mL only to prepare infusions. Do NOT administer Humalog 200 units/mL intravenously.
  • Insulin aspart ^c140
    • Subcutaneous route
      • Insulin Aspart (Recombinant) Solution for injection; Children and Adolescents: 0.3 unit/kg subcutaneously, followed 1 hour later by 0.1 unit/kg/dose subcutaneously every 1 hour or 0.15 to 0.2 units/kg/dose subcutaneously every 2 hours. If blood glucose falls to less than 250 mg/dL before DKA resolves, reduce to 0.05 unit/kg/dose subcutaneously every 1 hour to keep blood glucose approximately 200 mg/dL until DKA resolves. Consider adding 5% Dextrose injection to IV fluids if there is concern of hypoglycemia or precipitous fall in blood glucose.
      • Insulin Aspart (Recombinant) Solution for injection; Adults: Studies have used Novolog insulin aspart products. Initially, 0.2 units/kg subcutaneously, then 0.2 unit/kg subcutaneously every 2 hours until blood glucose is 250 mg/dL or less; then, reduce insulin dose to 0.1 units/kg subcutaneously every 2 hours. Check blood glucose every 1 or 2 hours; blood glucose should decline by 80 to 100 mg/dL per hour; more rapid lowering is associated with adverse effects. Initiate IV fluids. When the blood glucose is 250 mg/dL or less, change fluids to a 5% dextrose-containing fluid infusion and adjust to maintain blood glucose at roughly 200 to 250 mg/dL until the acidosis is corrected. Monitor serum potassium; replace as indicated. Treatment with subcutaneous insulin aspart has been shown to be an effective alternative for mild and moderate DKA; however, patients with severe DKA, hypotension, anasarca, or associated severe critical illness should be managed with intravenous regular insulin in the ICU.
    • IV route
      • Insulin Aspart (Recombinant) Solution for injection; Children and Adolescents: 0.05 to 0.1 unit/kg/hour IV continuous infusion, beginning at least 1 hour after starting fluid replacement therapy; continue until DKA resolves. If patient is very sensitive to insulin, the infusion rate may be reduced if acidosis continues to resolve. Add 5% Dextrose injection to IV fluid when blood glucose reaches 250 to 300 mg/dL or sooner if blood glucose decline is precipitous. Once DKA has resolved and the patient is tolerating oral intake, transition to subcutaneous insulin. Give first dose of rapid-acting insulin 15 to 30 minutes or regular insulin 1 to 2 hours prior to stopping insulin infusion and providing a meal.
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 0.1 to 0.15 units/kg IV bolus followed by 0.1 units/kg/hour via continuous IV infusion. Use adequate fluid therapy as well. Check blood glucose levels hourly and adjust the insulin infusion rate as needed. When the blood glucose falls to 250 mg/dL or less, usually decrease insulin to 0.05 to 0.1 unit/kg/hour IV and change fluid therapy to a 5% Dextrose-containing fluid infusion; adjust to maintain a blood glucose of 150 to 250 mg/dL until the acidosis is corrected. Monitor serum potassium; replace as indicated.

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 ^r39
• Pediatric fluids
  • Administer 0.9% normal saline at 10 to 20 mL/kg over the first 30 to 60 minutes ^r3
    • Higher-volume fluid infusion rates (20 mL/kg bolus + 1.5 × maintenance rate) for pediatric patients with diabetic ketoacidosis shorten metabolic normalization time compared with lower-volume rates (10 mL/kg bolus + 1.25 × maintenance rate) ^r58
    • Rapidity of IV fluid replacement and sodium chloride content (0.45% or 0.9%) does not influence rates of cerebral injury ^r59
  • Subsequent choice of fluid depends on serum sodium level, state of hydration, and glucose levels
    • After 1 to 2 hours, replace fluid deficit with an isotonic solution (0.9% saline or lactated Ringer solution) for at least 4 to 6 hours ^r3
    • Thereafter, replace fluid deficit with an isotonic solution or 0.45% saline solution, with added potassium ^r3
    • Aim to replace the estimated fluid deficit evenly over 24 to 48 hours ^r3
    • Measure and assess glucose level every hour
      • Add 5% dextrose to IV fluids when glucose level falls to approximately 250 to 300 mg/dL ^r3
        • If blood glucose level falls very rapidly after fluid expansion, consider adding glucose before glucose level decreases to 300 mg/dL ^r3
      • If metabolic acidosis persists, change to 10% or 12.5% dextrose while continuing insulin infusion to prevent hypoglycemia ^r3

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 20 to 30 mEq/hour of potassium chloride 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 (20 mEq/L) when initiating volume expansion (before starting an insulin infusion) ^r3
      • 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, or 20 mEq/L potassium in a patient receiving fluid at a rate greater than 10 mL/kg/hour ^r3
        • 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 diabetic ketoacidosis in adults because it has not been found to hasten rate of recovery from ketoacidosis or hyperglycemia and may contribute to hypokalemia and cerebral edema ^r53r60
    • 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 ^r5
      • 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 in pediatric patients ^r60
    • Bicarbonate is not recommended in children, except for treatment of life-threatening hyperkalemia or unusually severe acidosis (pH less than 6.9) with evidence of compromised cardiac contractility ^r3
• Phosphate ^c146
  • Adults
    • Phosphate is rarely required in management of diabetic ketoacidosis because replacement has not been found to affect clinical outcomes and because aggressive repletion can precipitate hypocalcemia ^r61
    • Correction of hypophosphatemia is recommended only under very limited circumstances (ie, cardiogenic shock, respiratory failure, serum phosphorus level less than 1 mg/dL) ^r62
      • 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 ^r62
        • 1 mL of potassium phosphate = 4.4 mEq potassium + 3 mmol (93 mg) phosphate ^r62
        • 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 ^r62
      • Monitor serum phosphate, magnesium, and calcium levels in patients receiving phosphate infusion ^r1
  • Children
    • Phosphate is rarely required in management of diabetic ketoacidosis in children because replacement has not shown clinical benefit ^r63
    • Correction of hypophosphatemia is recommended only when serum phosphate level is lower than 1 mg/dL and the patient is symptomatic (eg, encephalopathy, respiratory failure, myopathy) ^r3
      • Potassium phosphate may be added to replacement IV fluids alone or in combination with potassium chloride or potassium acetate ^r3
      • Monitor serum calcium level in patients receiving phosphate infusion ^r3

Comorbidities

• COVID-19 ^r57c148
  • COVID‐19 infection may precipitate severe metabolic complications of diabetes including diabetic ketoacidosis, which may be the initial presentation of new-onset diabetes ^r14r64r65
  • During the COVID-19 pandemic, utilize telehealth for sick day management and routine diabetes care
  • An increased prevalence of diabetic ketoacidosis has been noted during the pandemic, which may be a result of inadequate treatment in patients who delay scheduled clinic visits for fear of contracting COVID-19 as well as a direct effect of the SARS-CoV-2 virus ^r66
  • Patients admitted with diabetic ketoacidosis who are COVID-positive have increased mortality secondary to more severe COVID-19 rather than diabetic ketoacidosis ^r66

Special populations

• Adolescents with recurrent diabetic ketoacidosis
  • Psychologic evaluation for concurrent psychiatric disease is recommended ^r67
    • Depression in this population may lead to more missed insulin doses
      • Children's Depression Inventory is a validated tool to screen for depression ^r68
    • Higher incidence of recurrent diabetic ketoacidosis is also seen in adolescents with eating disorders
• Diabetic ketoacidosis in patients with chronic kidney disease ^r39
  • Clinical presentation and laboratory values in patients with diabetic ketoacidosis on dialysis may differ from those not on dialysis
    • Patients on dialysis usually have minimal or no signs of volume depletion
    • Hyperkalemia is typically more severe in patients on dialysis compared with those not on dialysis for the same levels of hyperglycemia
    • Metabolic acidosis is usually present in diabetic ketoacidosis, 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^r39)
  • Optimal treatment strategies for diabetic ketoacidosis in patients with advance chronic kidney disease and dialysis have not been determined by prospective studies ^r69
    • 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)^r39 while monitoring respiratory and hemodynamic parameters closely
    • Suggested initial rate of IV insulin administration for patients on dialysis is similar to that of patients not on dialysis, with initial insulin bolus of 0.1 units/kg followed by continuous insulin infusion at 0.05 units/kg/hour^r39
    • Insulin is typically the only treatment necessary for hyperkalemia due to diabetic ketoacidosis in patients on dialysis; give potassium only if the level falls below 3.3 mEq/L ^r39
    • Emergent hemodialysis for patients with diabetic ketoacidosis is controversial; the main indications are pulmonary edema and severe hyperkalemia
• Diabetic ketoacidosis in patients with cardiac disease
  • Administer IV fluids cautiously to avoid volume overload and pulmonary edema ^r13
• Diabetic ketoacidosis in pregnant patients
  • Pregnant patients develop diabetic ketoacidosis at significantly lower blood glucose values, and it progresses more rapidly in this population than in patients who are not pregnant ^r70
  • After 24 weeks of gestation, continuously monitor fetal status owing to fetal hypoxemia and acidosis ^r71
  • 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) ^r70
  • Preterm labor management must take into account maternal condition, viability of the fetus (gestational age), and fetal heart rate tracings ^r70
    • Magnesium sulfate is the tocolytic of choice
    • Avoid β-adrenergic tocolytics, which can exacerbate hyperglycemia and nifedipine if patient is dehydrated and hypotensive
• Diabetic ketoacidosis associated with sodium-glucose cotransporter 2 inhibitor therapy (gliflozins) ^r34
  • Be aware that low serum bicarbonate level and/or presence of positive urinary ketones may not correctly identify diabetic ketoacidosis; 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