Diabetic Ketoacidosis

History

• Adult patients most often have a history of type 1 diabetes, although DKA can rarely develop in patients with ketosis-prone type 2 diabetes ^r8c1c2
• Children and young adults (younger than 20 years) present with DKA as the initial manifestation of diabetes in 30% of cases ^r9
• Most common symptoms, which usually develop over a period of hours to days ^r5
  • 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) ^r5r10c8c9c10
    • 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 DKA
    • 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) ^r13c33c34
• Kussmaul respiration (tachypnea with deep inspirations) ^r4c35
• Fruity breath odor ^r4c36
• Altered mental status, ranging from drowsiness to coma with increasing severity of DKA ^r4c37c38c39
• Fever, in the setting of infection ^c40

Causes

• Type 1 diabetes plus precipitating factors ^c41
  • 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 SGLT2 inhibitors by patients with type 1 diabetes ^r17c65
      • Treatment with immune checkpoint inhibitors ^r18c66
      • Fasting (eg, during Ramadan) ^r19r20c67
  • Inadequate exogenous insulin (accounts for 40% of cases) ^r14c68
    • Omission of insulin due to nonadherence or self-administration error ^c69
    • Unrecognized interruption of insulin delivery by users of insulin pumps (eg, insulin pump malfunction) ^c70
• Type 2 diabetes plus precipitating factors ^c71
  • Acute decrease in insulin production owing to pancreatic β-cell dysfunction and elevated insulin resistance ^r21c72c73
  • Use of SGLT2 inhibitors ^{r22r23r24r25c74}
    • Associated with almost 3-fold increased risk of DKA ^r26
    • Patients using SGLT2 inhibitors who are consuming very low carbohydrate diets, engaging in prolonged fasting, or dehydrated or using excessive alcohol are at greatest risk for DKA ^r27

Risk factors and/or associations

Primary diagnostic tools

• History and physical examination findings suggest the condition, but biochemical criteria define it ^c86
• To make the biochemical diagnosis, obtain initial laboratory evaluation for all patients, including determination of plasma glucose, BUN and creatinine, serum or urine ketone levels, serum electrolytes (with calculated anion gap), serum osmolality, urinalysis, venous or arterial blood gases, and CBC with differential ^r3
  • A tentative diagnosis can be made with bedside tests of capillary blood glucose level and urinary dipstick ketone level
• Diagnostic criteria for DKA in adults include the following (all 3 must be met): ^r3
  • Hyperglycemia: blood glucose level greater than 200 mg/dL (11.1 mmol/L) OR history of diabetes, regardless of the glucose value at time of presention
  • Metabolic acidosis: arterial or venous pH less than 7.3 with or without bicarbonate level less than 18 mEq/L
  • Ketonemia (β-hydroxybutyrate level greater than 31 mg/dL [3 mmol/L]) OR ketonuria (2+ or more on standard urine sticks)
• Diagnostic criteria for DKA in children (similar but not identical to adults) ^r6
  • Hyperglycemia: blood glucose level greater than 200 mg/dL (11 mmol/L)
  • Metabolic acidosis: 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]^r36r37) OR ketonuria (2+ or more on standard urine sticks)
• Diagnostic caveats
  • DKA can occur with normal or only mildly elevated blood glucose levels, and in these instances, it is referred to as euglycemic DKA ^r6
    • May occur in patients taking SGLT2 inhibitors; may also be caused by a variety of other factors such as reduced carbohydrate intake, pregnancy, or liver failure ^r7r38
    • Blood glucose level is below 200 mg/dL, but other criteria still apply ^r25r38
  • 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 ^r39
  • Acetoacetate may be negative early in ketoacidosis
  • Anion gap is not a recommended first line diagnostic (or resolution) criterion but may be used in settings where ketone measurement is unavailable ^r3
• Categorizing severity
  • Once a diagnosis of DKA is made, categorizing the severity helps guide decisions on the optimal level of care (eg, home, observational nursing unit, step-down unit, or intensive care unit) ^r3

  • Severity of DKA in Adults- Classification

    Not all variables need to be fulfilled to be defined as either mild, moderate, or severe

    Information from: Umpierrez GE et al. Hyperglycemic crises in adults with diabetes: a consensus report. Diabetes Care. 2024;47(8):1257-75. PMID 39052901 https://doi.org/10.2337/dci24-0032

    Criterion	Mild	Moderate	Severe
    Ketonemia	β-Hydroxybutyrate 3.0–6.0 mmol/L	β-Hydroxybutyrate 3.0–6.0 mmol/L	β-Hydroxybutyrate > 6.0 mmol/L
    Acidosis	pH >7.25 to <7.30 or bicarbonate 15–18 mmol/L	pH 7.0–7.25 Bicarbonate 10 to <15 mmol/L	pH <7.0 Bicarbonate <10 mmol/L
    Mental status	Alert	Alert or drowsy	Stupor/coma

Laboratory

• Initial diagnostic testing
  • Capillary blood glucose level (while chemistry panel results are pending) ^r8c87
  • Serum chemistry panel, including levels of glucose, sodium, potassium, phosphate, magnesium, bicarbonate, BUN, and creatinine ^{r5c88c89c90c91c92c93c94c95c96}
    • Sodium must be corrected for hyperglycemia. Calculations are as follows: ^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 ^r40
  • Blood gas analysis ^c97
    • Venous blood gas is comparable to arterial blood gas for measuring pH in DKA ^r41
    • 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 the severity of DKA as mild, moderate, or severe ^r1
  • Serum ketone level ^r2c98
    • Direct measurement of venous or capillary β-hydroxybutyrate is preferred diagnostic test for ketonemia because it is an early and most abundant ketoacid that may first signal development of DKA ^r42
      • May be measured either via a laboratory service or by a point-of-care meter ^r43
    • Serum β-hydroxybutyrate level is greater than 31 mg/dL (3 mmol/L) in children and greater than 40 mg/dL (3.8 mmol/L) in adults in DKA. However, in practice, a threshold of 31 mg/dL (3 mmol/L) has been adopted for all age groups ^r36r43r44
    • Serum acetoacetate (via nitroprusside reaction) is an acceptable alternative test if testing for β-hydroxybutyrate is not available
  • Urine ketones ^c99
    • 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%) ^r45
    • Urine ketone measurement is an acceptable alternative to serum ketone measurement when the serum test is not available ^r3
  • Calculated anion gap level ^r46c100
    • Anion gap is not a first line diagnostic criterion, but may have value if ketone measurement is unavailable ^r3
    • Calculation of anion gap is made with the following formula: sodium (mEq/L) − (chloride [mEq/L] + bicarbonate [mEq/L])
    • Reference range is 6 to 10 mEq/L; a value greater than 12 mEq/L is consistent with DKA
  • Serum osmolality ^c101
    • 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
  • 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 ^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 patients with DKA; elevated levels are found in almost one-third of patients with DKA overall ^r47
    • If levels are elevated, follow up with abdominal CT scan ^r8c112

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 toward 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

• Obtain 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 ^r48
  • Rarely, a pseudoinfarction pattern, with ST-elevation that resolves with correction of biochemical abnormalities, may be seen ^r48

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
  • Calculation of water deficit is made with the following formula: water deficit: 0.6 × (body weight in kg) × (1 − [corrected sodium / 140]) ^r49
• Calculation of anion gap ^r46c121
  • 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]) ^r46c124
• 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) ^r46
  • 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) ^r50

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 greater than 320 mOsm/kg ^r14
    • Typically, there is no metabolic acidosis in hyperglycemic hyperosmolar state (in hyperglycemic hyperosmolar state, the 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, at least to an observational nursing unit, 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 ^r54

Discharge 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 glucose testing device (glucometer or continuous glucose monitor) 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 endocrinologist or diabetologist or glucose management team for inpatient management ^r55
• 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 are insulin naïve to a clinical diabetes educator ^r4

Drug therapy

• Insulin
  • Short-acting insulin
    • Regular insulin ^c137
      • IV
        • Insulin Regular (Recombinant) Solution for injection; Infants, Children, and Adolescents: 0.05 to 0.1 units/kg/hour continuous IV infusion, initially, starting at least 1 hour after starting fluid replacement therapy and continuing until the acidosis is corrected. Adjust dose every hour based on blood glucose. Transition to a basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
        • Insulin Regular (Recombinant) Solution for injection; Adults: 0.1 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. When the blood glucose concentration is less than 250 mg/dL, reduce dose to 0.05 units/kg/hour continuous IV infusion or transition to rapid-acting subcutaneous insulin. Adjust dose every 2 to 4 hours to maintain blood glucose of 150 to 200 mg/dL until the acidosis is corrected.
      • Subcutaneous
        • 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 basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
  • Rapid-acting insulin
    • Insulin aspart ^c138
      • 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 basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 0.1 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. When the blood glucose concentration is less than 250 mg/dL, reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours. Adjust dose every 2 to 4 hours to maintain blood glucose of 150 to 200 mg/dL until the acidosis is corrected. Transition to a basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
  • Insulin lispro ^c139
    • 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 basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
    • Insulin Lispro Solution for injection; Adults: 0.1 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. When the blood glucose concentration is less than 250 mg/dL, reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours. Adjust dose every 2 to 4 hours to maintain blood glucose of 150 to 200 mg/dL until the acidosis is corrected. Transition to a basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated.
• Electrolyte repletion
  • Potassium
    • Potassium Chloride Solution for injection; Infants, Children, and Adolescents: 20 to 40 mEq IV in 1,000 mL IV replacement fluid to maintain serum potassium within normal limits. For low or low-normal serum potassium on admission, 0.5 mEq/kg/hour or less IV until serum potassium is more than 3.5 mmol/L. Adjust dose every 1 to 3 hours based on serum potassium concentration. Administer one-half of the total potassium dose as potassium chloride and one-half as potassium acetate or phosphate.
    • Potassium Chloride Solution for injection; Adults: 10 to 40 mEq IV in 1,000 mL IV replacement fluid to maintain serum potassium 4 to 5 mmol/L. For low or low-normal serum potassium on admission, 10 to 20 mEq IV every hour until serum potassium is more than 3.5 mmol/L. Adjust dose every 2 to 4 hours based on serum potassium concentration. Higher doses up to 80 mEq/L may be necessary. Administer one-half of the total potassium dose as potassium chloride and one-half as potassium acetate or phosphate.
  • Bicarbonate
    • Sodium Bicarbonate Solution for injection; Infants, Children, and Adolescents: 1 to 2 mEq/kg/dose IV as a single dose over 60 minutes.
    • Sodium Bicarbonate Solution for injection; Adults: 100 mEq in 400 mL of Sterile Water for Injection IV every 2 hours until pH is more than 7.

Nondrug and supportive care

IV fluids for adults ^r2c140c141

• Immediately begin therapy to replace fluids, preceding insulin therapy ^c142
• Administer 0.9% normal saline or a balanced crystalloid at 0.5 to 1 L/hour for the first 2 to 4 hours ^r3r62
• Subsequent choice of IV fluids depends on hemodynamics, serum sodium level, and state of hydration ^r3r63
  • Recent data suggest that DKA resolves more rapidly and has a lower risk of hyperchloremia for adults who are given balanced crystalloid fluids, as compared to those given normal saline ^r62r64
• Aim to replace 50% of estimated fluid deficit in the first 8 to 12 hours
  • After the initial fluid bolus (resuscitation), 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; a change to 0.45% normal saline is appropriate 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 falls below 250 mg/dL
    • Continue 5% dextrose in IV fluids (typically with 0.45% normal saline by this point) until resolution of ketoacidosis ^r11

Pediatric IV fluids ^r6

• Initially administer 0.9% normal saline at 10 to 20 mL/kg over 20 to 30 minutes to restore circulatory volume ^r6
  • 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) ^r65
  • Rapidity of IV fluid replacement and sodium chloride content (0.45% or 0.9%) does not influence rates of cerebral injury ^r66
  • 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) ^r6
  • 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)
    • Recent data suggest that time to resolution of DKA is shorter in children who receive Ringer's lactate versus normal saline, both for resuscitation and replacement ^r67r68
  • 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 ^c143
  • 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
  • May use potassium chloride, potassium phosphate, or potassium acetate individually or in combination ^r6
    • Administration of potassium entirely as potassium chloride increases the risk of hyperchloremic metabolic acidosis, whereas administration entirely as potassium phosphate can result in hypocalcemia
  • 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
      • 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) ^r6
      • 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
• Bicarbonate ^c144
  • 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 ^r61r69
    • Correction of acidosis with bicarbonate is recommended only if venous pH is less than 7 ^r3
  • Children
    • Bicarbonate replacement is associated with elevated risks of cerebral edema and prolonged hospitalization for pediatric patients ^r69
    • 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 ^r6
• Phosphate ^c145
  • 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 ^r70
    • Correction of hypophosphatemia is recommended only under very limited circumstances (ie, cardiogenic shock, respiratory failure, serum phosphorus level less than 1.0 mg/dL) ^r3
    • Potassium phosphate may be added to replacement IV fluids alone or in combination with potassium chloride or potassium acetate ^r3r6
      • 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 less than 1 mg/dL, irrespective of symptoms ^r6
      • 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 ^r6
    • Potassium phosphate may be added to replacement IV fluids alone or in combination with potassium chloride or potassium acetate ^r6
      • Monitor serum phosphate, magnesium, and calcium level in patients receiving phosphate infusion

Comorbidities

• COVID-19 ^r71c147
  • COVID‐19 infection may precipitate severe metabolic complications of diabetes, including DKA, which may be the initial presentation of new-onset diabetes ^r15r72r73

Special populations

• Adolescents with recurrent DKA
  • Psychological evaluation for concurrent psychiatric disease is recommended ^r74
    • Depression in this population may lead to more missed insulin doses
      • Children's Depression Inventory is a validated tool to screen for depression ^r75
    • Higher incidence of recurrent DKA is also seen in adolescents with eating disorders
• DKA in patients with chronic kidney disease ^r76
  • 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, greater than 20 mEq/L^r42)
  • Optimal treatment strategies for DKA in patients with advanced chronic kidney disease receiving dialysis have not been determined by prospective studies ^r77
    • 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 (250 ml each) of normal saline ^r42 or crystalloid solutions while closely monitoring respiratory and hemodynamic parameters ^r3
    • Suggested initial rate of IV insulin administration for patients receiving dialysis is similar to that of patients not receiving dialysis; lower continuous infusion rates may be needed
    • 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 ^r42
    • 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 ^r3
• DKA in pregnant patients
  • Pregnant patients develop DKA at significantly lower blood glucose values, and it progresses more rapidly than in non-pregnant patients ^r78
  • After 24 weeks of gestation, continuously monitor fetal status owing to risk for fetal hypoxemia and acidosis ^r79
  • 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) ^r78
  • Preterm labor management must take into account maternal condition, viability of the fetus (gestational age), and fetal heart rate tracings ^r78
    • Magnesium sulfate is the tocolytic of choice
    • Avoid β-adrenergic tocolytics, which can exacerbate hyperglycemia, and nifedipine if patient is dehydrated and hypotensive
• Euglycemic DKA
  • Euglycemic DKA is an uncommon variant of DKA that occurs when ketosis and metabolic acidosis are present, but blood glucose is less than 250 mg/dL. SGLT2 inhibitor use can trigger euglycemic DKA ^r80
  • 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 of euglycemic DKA, first stop SGLT2 inhibitor use, if applicable. Resumption of SGLT2 inhibitors after resolution is not advisable for patients with either type 1 or type 2 diabetes, unless another etiology of DKA is identified ^r63
  • Management and monitoring is similar to standard DKA protocols, except that hydration must be started with a 10% dextrose-containing fluid simultaneously, and should be continued to maintain the glucose between 120 and 180 mg/dL ^r63
  • Some patients may require insulin infusion at 2 to 3 units/hr to correct acidosis ^r81
  • Risk of relapse into DKA is high in the setting of SGLT-2 inhibitor use, so do not rush to discontinue insulin infusion ^r81