Diabetic Ketoacidosis

See Also

Epidemiology

Age distribution of DKA Cases
1. Age over 70 years: 14%
2. Age 51 to 70 years: 23%
3. Age 30-50 years: 27%
4. Age under 30 years: 36%
5. Henricksen (2007) Diabetes Res Clin Pract 76(1): 51-6 [PubMed]
Incidence of DKA in children
1. Up to 30% of children present with DKA at the time of diagnosis
2. Incidence of DKA after initial diagnosis 6 to 8% per year
References
1. Fritsch (2011) Pediatr Diabetes 12(4 pt 1): 307-12 [PubMed]

Pathophysiology

Insulin deficiency
1. Diabetes Mellitus
  1. Type I Diabetes Mellitus
  2. Type II Diabetes Mellitus with Ketosis-prone diabetes (accounts for 20-50% of DKA cases)
    1. Black or latino
    2. Male
    3. Overweight
    4. Middle-aged
    5. Diabetes Mellitus Family History
2. Uncontrolled Blood Sugars (see precipitating factors below)
  1. See Medication Causes of Hyperglycemia
  2. New onset Diabetes Mellitus
  3. Insulin non-compliance
  4. Acute Infection (e.g. Pneumonia, Urinary Tract Infection)
  5. Insulin Pump failure
  6. Diabulimia (Eating Disorder variant of skipping Insulin to lose weight)
  7. Physiologic stressors (Myocardial Infarction, Cerebrovascular Accident)
Compensatory response to lack of usable fuel sources (in the absence of Insulin)
1. Paradoxical exacerbation of Hyperglycemia
  1. Release of Glucagon, Catecholamines, Cortisol, and Growth Hormone
  2. Catabolism to Glucose of Proteins and glycogen by liver
2. Lipase secretion results in increased Ketones
  1. Free Fatty Acid Metabolism (lipolysis)
  2. Results in increased Ketone production (acetone, acetoacetone, Beta hydroxybutyrate)
  3. Results in Metabolic Acidosis
3. Increased Renal Clearance of Ketones and Glucose
  1. Results in osmotic diuresis, Dehydration and hyperosmolar state

Causes
Precipitating Factors

Uncontrolled Diabetes Mellitus
1. New onset Diabetes Mellitus
2. Insulin Pump failure
3. Insulin non-compliance (e.g. financial, social)
Infection
Medical condition
1. Cerebrovascular Accident
2. Myocardial Infarction
3. Pregnancy
4. Acute Pancreatitis
5. Hypovolemia
6. Trauma
7. Starvation (Starvation Ketosis)
Other Endocrine Disorder
Medications
1. SGLT2 Inhibitors (risk for Euglycemic Ketoacidosis)
2. Antipsychotics (e.g. Clozapine, Olanzapine, Risperidone, Quetiapine)
3. Substance Abuse (e.g. Methamphetamine Abuse, Alcohol Use Disorder, Cocaine)
4. Corticosteroids
5. Interferon
6. Pentamidine
7. Sympathomimetics
8. Thiazide Diuretics

Symptoms

Timing
1. Rapid onset of symptoms
2. Follows febrile illness (40%)
Hyperglycemia symptoms
1. Polyuria and polydipsia (98%)
2. Polyphagia (23%)
Gastrointestinal symptoms
1. Nausea and Vomiting (50-80% of cases)
2. Abdominal Pain (30% of patients)
  1. May present as a vague Abdominal Pain with minimal tenderness on exam
  2. Consider Pancreatitis or Pyelonephritis (both are common in DKA)
Miscellaneous symptoms
1. Weight loss (81%)
2. Fatigue (62%)
3. Dyspnea (57%)
4. Headache
5. Weakness
6. Lethargy

Signs

Mental clouding (lethargy to coma)
Metabolic Acidosis findings
1. Tachypnea with Kussmaul Breathing
2. Acetone on breath (sweet or fruity breath smell)
Dehydration (often >10% dehydrated)
1. Dry Skin with loss of Skin Turgor
2. Eyes sunken
3. Tachycardia and possibly Hypotension
4. Temperature below normal

Differential Diagnosis

See Anion Gap Metabolic Acidosis
Other types of Ketoacidosis or hyperglycemic states
1. Euglycemic Ketoacidosis (associated with SGLT2 Inhibitors)
2. Alcoholic Ketoacidosis
3. Starvation Ketosis
4. Hyperosmolar Hyperglycemic State (HHS)
Other conditions with similar presentations

Labs

Bedside Glucose
1. See diagnosis below (variable Serum Glucose criteria, and Glucose is normal in Euglycemic Ketoacidosis)
2. Glucose >250 mg/dl (some organizations use >250 mg/dl)
Urinalysis
1. Glucosuria
2. Urinary Tract Infection
3. Ketonuria
  1. See Urine Ketones
  2. High Test Sensitivity (98%) for Diabetic Ketoacidosis
    1. High Negative Predictive Value
    2. Negative Urine Ketone excludes DKA diagnosis
    3. Schwab (1999) Ann Emerg Med 34:342-6 [PubMed]
  3. Poor Test Specificity (35%)
    1. Confirm with Serum Beta Hydroxybutyrate
      1. Beta hydroxybutyrate is converted to Acetoacetate which is then detected on the Urine Dipstick as Ketones
    2. Normal serum bicarbonate and Anion Gap suggests resolving DKA or False Positive ketonuria
Chemistry Panel (Chem8)
1. Serum Glucose increased (Hyperglycemia)
2. Serum Sodium decreased (Hyponatremia)
  1. See Corrected Serum Sodium for Hyperglycemia
  2. Requires correction for Glucose (Pseudohyponatremia secondary to Hyperglycemia)
  3. Serum Sodium correction calculation: sNa + 0.016 * (Glu - 100)
3. Serum Potassium
  1. Metabolic Acidosis results in initial underestimation of Serum Potassium
    1. Hypokalemia is present in only 5-10% of Diabetic Ketoacidosis presentations
  2. As acidosis corrects, Potassium enters cells in exchange for Hydrogen Ion and Serum Potassium falls
    1. Hypokalemia develops in in up to 80% of Diabetic Ketoacidosis cases with management
  3. Low Serum Potassium on presentation suggests severe Hypokalemia
    1. Must be corrected before Insulin initiation
4. Serum Chloride depressed (Hypochloremia)
5. Serum Bicarbonate depressed (<15 to 18 mEq/L)
6. Anion Gap elevated
  1. Typically >10-12 and often >16 in DKA
  2. Anion Gap calculation: Na - (Cl + HCO3)
7. Serum Osmolality (calculate and measure if available)
  1. Should be >320 mOsm/kg if DKA present
  2. Serum Osmolality calculation: 2*(Na + K) + (glu/18) + (BUN/2.8)
8. Serum Creatinine (and eGFR)
  1. Acute Kidney Injury is common (prerenal related to severe Dehydration and Metabolic Acidosis)
Other Electrolytes (Phosphorus and Magnesium)
1. Serum Phosphorus decreased (Hypophosphatemia)
2. Serum Magnesium decreased (Hypomagnesemia)
Arterial Blood Gas (ABG) or Venous Blood Gas (VBG)
1. Metabolic Acidosis (serum pH <7.30)
2. Venous Blood Gas is equivalent to monitoring Arterial Blood Gas for pH and bicarbonate
Beta hydroxybutyrate (or Serum Ketones if not available)
1. Beta hydroxybutyrate is the most important Ketone in Diabetic Ketoacidosis
2. Test Sensitivity: High
3. Test Specificity: 85%
4. Levels do not correlate with disease severity
  1. Arora (2011) Diabetes Research and Clinical Practice 94(3): e86-8
Precipitating factor evaluation
1. Complete Blood Count with differential
  1. Leukocytosis is often present in DKA regardless of underling infection
  2. Bandemia (Neutrophil band forms or Left Shifts) is highly predictive of infection
2. Blood Culture
3. Urine Culture
4. Chest XRay
5. Electrocardiogram (EKG)
  1. Detects Hypokalemia related changes
  2. Also indicated for ischemia evaluation over age 40 or over 10 years of Diabetes Mellitus
Evaluation of Diabetes and Endocrine Status
1. Hemoglobin A1C
2. Anti-GAD65 Antibody (identifies Type I diabetics)
3. Thyroid Stimulating Hormone (TSH)
Complications (obtain as needed)
1. Serum Lipase
  1. Frequently increased regardless of Pancreatitis
  2. Pancreatitis is present in 10-15% of DKA patients
2. Hepatic Transaminases (AST and ALT)
  1. Typically increased in non-Alcoholic Fatty Liver disease (NASH)
3. Troponin
  1. Troponin Is increased in absence of myocardial injury in more than 25% of DKA patients

Diagnosis
Criteria - Hyperglycemia, Ketosis, Acidosis

Blood Glucose >250 mg/dl (>200 mg/dl in children)
1. Glucose is normal in Euglycemic Ketoacidosis
Metabolic Acidosis
1. Serum pH < 7.30 or
2. Serum Bicarbonate <18 meq/L (prior guidelines used <15 meq/L)
Serum Ketones or Beta hydroxybutyrate
1. Increased Serum Ketones (>3-4 mmol/L or >1:2 dilution)
Anion Gap (using uncorrected Serum Sodium)
1. Anion Gap without Potassium in calculation: >12 mEq/L
2. Anion Gap with Potassium in calculation (or lab calculated): >15 to 17 mEq/L

Evaluation
Severity

Arterial pH (or venous pH) in Adults (ADA)
1. Mild DKA: 7.25 to 7.30
2. Moderate DKA: 7.00 to 7.24
3. Severe DKA: < 7.00
Arterial pH (or venous pH) in Infants and Children (ISPAD, NICE)
1. Mild DKA: 7.2 to 7.3 (some other guidelines list pH 7.25 to 7.30)
2. Moderate DKA: 7.1 to 7.2 (some other guidelines list pH 7.2 to 7.25)
3. Severe DKA: <7.1 (some other guidelines list pH < 7.2)
Serum bicarbonate
1. Mild: 15-18
2. Moderate: 10 to 14
3. Severe: < 10
Mental status
1. Mild: Alert
2. Moderate: Drowsy
3. Severe: Stupor

Management

See Diabetic Ketoacidosis Management in Adults
See Diabetic Ketoacidosis Management in Children
See Euglycemic Ketoacidosis
See Hyperosmolar Hyperglycemic State
Evaluate and manage underlying causes
1. Underlying infection (e.g. urosepsis, Pneumonia, Cellulitis)
Consider noncompliance due to financial concerns
1. Facilitate lower cost options for medications
2. See Diabetes Cost Reduction

Complications

See Diabetic Ketoacidosis Related Cerebral Edema
Metabolic Complications
1. Severe Metabolic Acidosis
2. Hypokalemia
3. Hypoglycemia
4. Hypocalcemia
Non-metabolic Complications
1. Septic Shock
2. Hypovolemic Shock
3. Vascular Thrombosis
4. Pulmonary Edema (aggressive rehydration)
5. Acute Renal Failure
6. Rhabdomyolysis
7. Prolonged QT Interval
8. Cerebral Edema (See Diabetic Ketoacidosis Related Cerebral Edema)

Prevention

See Diabetes Sick Day Management
Early diagnosis of new onset Diabetes Mellitus
1. New onset Diabetes Mellitus develops symptoms an average of 24 days before DKA presentation
2. Kin (2010) J Paediatr Child Health 46(4): 171-5 [PubMed]
Diabetic action plan based on Blood Glucose Monitoring
1. Home monitoring of beta hydroxybutyrate or Ketones when Serum Glucose >240 mg/dl
2. Plan for adjusting short acting Insulin
  1. Sick day Insulin coverage (reduced dose but not eliminated)
  2. Liquid diets when sick
3. Back-up plan for Insulin Pump failure
4. Early contact with medical provider when Glucose control acutely changes
Insulin Pumps and Monitors
1. Consider Continuous Glucose Monitoring
2. Consider Insulin Pump in established diabetes
3. Make Basal insulin available for times of pump failure
Case management
1. Diabetic educator
2. Frequent phone contact

Prognosis

Case fatality rate: 1-5%
1. Mortality typically due to cerebral edema
2. Leading cause of death in diabetes under age 24 years
3. Wang (2006) Diabetes Care 29(9): 2018-22 [PubMed]

References

Fahlsing and Ponce (2024) Crit Dec Emerg Med 38(3): 18-9
Kirschke (2020) Crit Dec Emerg Med 34(8): 3-7
Orland in Stine (1994) Emergency Med, p. 204-5
Orman and Willis in Herbert (2017) EM:Rap 17(9): 19-20
Chiasson (2003) CMAJ 168:859-66 [PubMed]
Kitabchi (2001) Diabetes Care 24:131-53 [PubMed]
Trachtenbarg (2005) Am Fam Physician 71(9): 1705-22 [PubMed]
Trence (2001) Endocrinol Metab Clin North Am 30:817-31 [PubMed]
Westerberg (2013) Am Fam Physician 87(5): 337-46 [PubMed]
Veauthier (2024) Am Fam Physician 110(5): 476-86 [PubMed]