Basics
Description
- Severe metabolic derangement in patients with diabetes mellitus (DM) secondary to insulin deficiency and/or stress hormone excess
- Clinical features include hyperglycemia, ketosis, metabolic acidosis, dehydration, and electrolyte deficits.
Epidemiology
Incidence
- Diabetes ketoacidosis (DKA) occurs more commonly in type 1 DM but can also occur in type 2 DM.
- 20-40% of children with new-onset type 1 DM present in DKA.
- Risk of DKA in established type 1 DM is 1-10% per patient per year (most episodes caused by insulin omission/diabetes mismanagement).
- DKA accounts for majority of diabetes-related deaths in childhood (most secondary to cerebral edema/brain injury).
Risk Factors
- For type 1 DM presenting as DKA:
- Very young children (<5 years)
- Ethnic minority
- Inadequate health insurance
- A missed diagnosis of DM in preceding clinic visits is frequent in DKA patients (~35%).
- For DKA in established diabetes:
- Adolescence
- Lack of health insurance
- Poor glycemic control
- Ethnic minority
- Low socioeconomic status (SES).
General Prevention
- Prompt diagnosis of new-onset diabetes (e.g., urinalysis in patients with poor weight gain, polyuria, flulike symptoms/vomiting)
- Patient/parental education regarding ketone testing (with any symptoms of illness or unexplained high blood glucose level)
- Strict supervision of long-acting (glargine, detemir) insulin injections by parents
- Detection and avoidance of insulin pump interruptions by frequent blood glucose testing and strict protocols for changing infusion sets
Pathophysiology
- Excess of counterregulatory "stress"¯ hormone concentrations (glucagon, cortisol, and epinephrine) in relation to insulin concentrations occurs, either as a result of insulin absence (new-onset diabetes or insulin omission) or illness (raising stress hormone levels)
- Imbalance between counterregulatory hormones and insulin results in increased glycogenolysis and gluconeogenesis and decreased peripheral glucose uptake (causing hyperglycemia) as well as lipolysis and ketogenesis (causing ketosis).
- Hyperglycemia causes osmotic diuresis resulting in dehydration and electrolyte losses.
- Ketogenesis results in metabolic acidosis, causing vomiting and tachypnea.
- Dehydration causes poor tissue perfusion, raising lactate levels and is contributing to metabolic acidosis.
Etiology
- Insulin deficiency
- New diagnosis of diabetes
- Insulin omission (diabetes mismanagement or insulin pump malfunction)
- Acute illness (leading to rise in counterregulatory hormone levels)
Commonly Associated Conditions
- Acute illness as a precipitating factor
- Autoimmune disorders (especially hypothyroidism) for persons with type 1 DM
Diagnosis
History
- Symptoms of new-onset diabetes (polyuria, polydipsia, weight loss)
- Nausea, vomiting, abdominal pain, weakness, lethargy
Physical Exam
- Vital signs: tachycardia, tachypnea (deep, "Kussmaul"¯ respirations), occasional hypothermia
- Dehydration: dry mucous membranes, sunken eyes, poor distal perfusion
- Fruity breath odor
- Abdominal tenderness and decreased bowel sounds (intestinal ileus)
- Altered mental status, lethargy, obtundation
Diagnostic Tests & Interpretation
Lab
- Glucose: >200 mg/dL (usual range 200-1,200 mg/dL)
- Urinalysis: glucosuria and ketonuria
- Electrolytes: total body depletion of sodium, chloride, potassium, phosphate, calcium, magnesium (depletion generally not reflected in serum electrolyte concentrations which may be low, normal, or high at presentation)
- Sodium: initial Na usually normal or low
- Hyperglycemia depresses serum Na by about 1.6 mEq/L for every 100 mg/dL-elevation in glucose greater than 100 mg/dL.
- Elevated Na at presentation implies extreme dehydration.
- Potassium: Initial serum levels typically normal or elevated, may fall rapidly with therapy.
- Serum bicarbonate (total CO2) is low, consistent with metabolic acidosis.
- Bicarbonate <18 mEq/L suggests pH <7.3.
- Bicarbonate <10 mEq/L suggests pH <7.1.
- Phosphate: typically normal or slightly elevated at presentation
- Blood pH low (<7.3) due to metabolic acidosis. Low Pco2 secondary to respiratory compensation for metabolic acidosis
- CBC: White blood cell counts frequently elevated and may be left shifted (even in the absence of infection). Hematocrit may be elevated due to hemoconcentration.
- Serum ketones (β-hydroxybutyrate) are elevated (typically >5 mmol/L).
- Liver enzymes (ALT, AST) may be mildly elevated.
- Amylase and lipase are often mildly elevated.
Differential Diagnosis
- Gastroenteritis
- Acute abdomen (pancreatitis, appendicitis, bowel ischemia)
- UTI
- Pneumonia, bronchiolitis
- Stress hyperglycemia (particularly during gastroenteritis in young children-ketosis may also be present due to lack of oral intake and may be difficult to differentiate from DKA)
- Salicylate ingestion
- Rare inborn errors of ketolysis (succinyl-CoA: 3-ketoacid CoA transferase deficiency)
Treatment
General Measures
Initial emergency treatment consists of fluid resuscitation to insure hemodynamic stability. Most DKA patients require admission to a pediatric critical care unit or other unit with similar capabilities.
Issues for Referral
The pediatric endocrinology service should be advised of all DKA admissions. New-onset diabetes patients will require diabetes education. Patients with recurrent DKA may require reeducation or other counseling.
Inpatient Considerations
IV Fluids
- Initial isotonic IV fluid bolus (0.9% saline) of 10-20 cc/kg-may be repeated as necessary to restore perfusion and hemodynamic stability.
- IV fluid rate after initial bolus(es)
- Average fluid deficit is ~7% of body weight.
- Replace deficit evenly over 24-48 hours.
- Add maintenance fluids to deficit replacement (minus initial boluses) to calculate total rate.
- Replacement of ongoing urinary fluid losses is generally unnecessary, but urine output should be monitored.
- Urine output and specific gravity do not reflect state of hydration.
- Adjust fluid infusion rate based on fluid intake and output balance, clinical measures of perfusion, and laboratory indicators of hydration.
- Composition of IV fluids:
- After initial isotonic fluid bolus(es), IV fluids should consist of 0.45-0.9% saline.
- Potassium replacement is essential and should be added to IV fluids as soon as renal failure or extreme hyperkalemia is ruled out.
- Typical initial K replacement is 40 mEq/L, using 1/2 KCl and 1/2 K phosphate.
- Dextrose should be added to IV fluids when serum glucose level is below ~250 mg/dL. The "2 bag method"¯ (see reference) is ideal.
- Dextrose concentrations in IV fluids should be adjusted to maintain serum glucose in the range of 100-200 mg/dL. Rates of insulin infusion generally should not be decreased until acidosis resolves.
Insulin
- Insulin treatment should begin after initial isotonic fluid bolus(es).
- Insulin should be administered via continuous IV infusion at a rate of 0.1 units/kg/h.
- An initial insulin "bolus"¯ or "loading dose"¯ is not necessary.
Other
Treatment with bicarbonate is generally unnecessary and has been associated with increased risk of cerebral edema.
Ongoing Care
Patient Monitoring
- Recommended monitoring:
- Frequent (at least hourly) assessment of mental status and perfusion
- Hourly vital signs
- Cardiac monitor and pulse oximeter
- Hourly intake and output
- Hourly fingerstick or serum glucose
- Electrolytes and venous blood gas every 2-4 hours
- Ca, Mg, phosphate every 4-6 hours
Prognosis
Mortality of DKA in children is ~0.2-0.3%, (most frequently caused by cerebral edema/ cerebral injury).
Complications
- Cerebral injury is the most frequent DKA-related cause of death (57-87% of DKA deaths).
- Patients at highest risk for cerebral injury are those with the most severe dehydration and acidosis (often younger children).
- The cause of brain injury in DKA is unclear but may be related to reduced cerebral perfusion during untreated DKA, followed by injury related to reperfusion.
- Commonly occurs 2-12 hours after starting treatment with insulin and saline
- Symptoms may include mental status changes in association with severe headache, recurrence of vomiting, inappropriate slowing of heart rate or hypertension.
- Loss of consciousness, seizures, apnea, or signs of increased intracranial pressure may also occur.
- Treatment of suspected cerebral edema includes mannitol (0.5-1 g/kg by IV infusion over 15 minutes) or hypertonic saline.
- Cerebral imaging studies should be done to evaluate edema or other signs of cerebral injury, but treatment should not be delayed to obtain imaging studies.
- Cardiovascular collapse from shock is rare and usually due to delayed or inadequate IV fluids.
- Other complications:
- Hypokalemia is frequent and can be avoided with frequent serum K reassessments and adjustment of potassium content of IV fluids.
- Hypoglycemia may occur but can be avoided with frequent glucose checks and adjustment of dextrose concentration of IV fluids.
- Mild hypophosphatemia is common, but severe hypophosphatemia is rare. Severe hypophosphatemia has been associated with rhabdomyolysis and hemolytic anemia.
- Hyperchloremic acidosis may occur, particularly with higher NaCl concentrations in IV fluids.
- Other rare complications include the following:
- Pulmonary edema or acute respiratory distress syndrome (ARDS)
- Pneumomediastinum from hyperventilation
- Arrhythmias due to electrolyte disturbances
- Thrombosis, especially at central line site
- Disseminated intravascular coagulation (DIC)
- Rhinocerebral mucormycosis
- Pancreatitis
Additional Reading
- Glaser N. Cerebral injury and cerebral edema in children with diabetic ketoacidosis: could cerebral ischemia and reperfusion injury be involved? Pediatric Diabetes. 2009;10(8):534-541. [View Abstract]
- Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344(4):264-269. [View Abstract]
- Orlowski JP, Cramer CL, Fiallos MR. Diabetic ketoacidosis in the pediatric ICU. Pediatr Clin North Am. 2008;55(3):577-587. [View Abstract]
- Wolfsdorf JI, Allgrove J, Craig ME, et al. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2014;(15)(Suppl 20):154-179. doi:10.1111/pedi.12165. [View Abstract]
Codes
ICD09
- 250.11 Diabetes with ketoacidosis, type I [juvenile type], not stated as uncontrolled
- 250.10 Diabetes with ketoacidosis, type II or unspecified type, not stated as uncontrolled
- 250.1 Diabetes with ketoacidosis
ICD10
- E10.10 Type 1 diabetes mellitus with ketoacidosis without coma
- E13.10 Oth diabetes mellitus with ketoacidosis without coma
SNOMED
- 420422005 ketoacidosis in diabetes mellitus (disorder)
- 420270002 Ketoacidosis in type I diabetes mellitus (disorder)
- 421750000 Ketoacidosis in type II diabetes mellitus (disorder)
FAQ
- Q: Is DKA in children with known diabetes usually caused by infection or other illness?
- A: Diabetes mismanagement resulting in inappropriate insulin omission is a far more frequent cause of DKA in children than infection. It is generally unnecessary to evaluate children with DKA for infection unless fever or other symptoms of infection are present.
- Q: Does rapid infusion of intravenous fluids or excessive administration of insulin cause cerebral edema in DKA?
- A: At present, neither the IV fluid administration rate nor the rate of insulin administration has been convincingly shown to increase the risk of DKA-related cerebral edema. Recent data suggest that cerebral edema is more likely related to alterations in cerebral perfusion during DKA, and that rates of fluid and insulin administration (within a reasonable range) do not play a primary role.
- Q: How can DKA episodes in children with diabetes be prevented?
- A: Greater supervision of diabetes care by parents or guardians can decrease the likelihood of insulin omission. Parents should also be instructed to test for ketones at the first sign of any illness or with unexplained high glucose levels and to contact the diabetes care team immediately if ketones are positive.