AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Diabetic ketoacidosis (DKA) is a state of absolute or relative insulin deficiency aggravated by ensuing hyperglycemia, dehydration, and acidosis-producing derangements in intermediary metabolism. The most common causes are underlying infection, disruption of insulin treatment, and new onset of diabetes. DKA is typically characterized by hyperglycemia over 300 mg/dL, low bicarbonate level (<15 mEq/L), and acidosis (pH <7.30) with ketonemia and ketonuria.

Pathophysiology

Many of the underlying pathophysiologic disturbances in DKA are directly measurable by the clinician and need to be monitored throughout the course of treatment. Close attention to clinical laboratory data allows for tracking of the underlying acidosis and hyperglycemia as well as prevention of common potentially lethal complications such as hypoglycemia, hyponatremia, and hypokalemia.

The absence of insulin, the primary anabolic hormone, means that tissues such as muscle, fat, and liver do not take up glucose. Counterregulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis, which is the main cause for the elevation in serum glucose level in DKA. Beta-oxidation of these free fatty acids leads to increased formation of ketone bodies. Overall, metabolism in DKA shifts from the normal fed state characterized by carbohydrate metabolism to a fasting state characterized by fat metabolism.

Secondary consequences of the primary metabolic derangements in DKA include an ensuing metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers. The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water as well as ketones and glucose. Patients are often profoundly dehydrated and have a significantly depleted potassium level (as high as 5 mEq per kg of body weight). A normal or even elevated serum potassium concentration may be seen due to the extracellular shift of potassium in acidotic conditions, and this very poorly reflects the patient's total potassium stores. The serum potassium concentration can drop precipitously once insulin treatment is started, so great care must be taken to repeatedly monitor serum levels. Urinary loss of ketoanions with brisk diuresis and intact renal function may also lead to a component of hyperchloremic metabolic acidosis.

Frequency

United States

DKA occurs primarily in patients with type 1 diabetes. The incidence is roughly 2 episodes per 100 patient years of diabetes, with about 3% of patients with type 1 diabetes initially presenting with DKA. It can occur in patients with type 2 diabetes as well; however, this is less common.

Mortality/Morbidity

With modern fluid management, the mortality rate of DKA is about 2% per episode. Before the discovery of insulin in 1922, the mortality rate was 100%.

Sex

No predilection exists.

Age

DKA tends to occur in individuals younger than 19 years, but it may occur in patients with diabetes at any age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Classic symptoms of hyperglycemia
• • Thirst
  • Polyuria, polydipsia
  • Nocturia
• Other symptoms
• • Generalized weakness
  • Malaise/lethargy
  • Nausea/vomiting
  • Decreased perspiration
  • Fatigue
  • Anorexia or increased appetite
  • Confusion
• Symptoms of associated infections and conditions
• • Fever
  • Dysuria
  • Chills
  • Chest pain
  • Abdominal pain
  • Shortness of breath

Physical

• General signs
• • Ill appearance
  • Dry skin
  • Labored respirations
  • Dry mucous membranes
  • Decreased skin turgor
  • Decreased reflexes
• Vital signs
• • Tachycardia
  • Hypotension
  • Tachypnea
  • Hypothermia
  • Fever, if infection
• Specific signs
• • Ketotic breath (fruity, with acetone smell)
  • Confusion
  • Coma
  • Abdominal tenderness

Causes

• The most common scenarios are underlying or concomitant infection (40%), missed insulin treatments (25%), and newly diagnosed, previously unknown diabetes (15%). Other associated causes make up roughly 20% in the various series.
• Urinary tract infections (UTIs) are the single most common infection associated with DKA, but many other associated illnesses need to be considered as well.
• Myocardial infarction
• Cerebrovascular accident
• Complicated pregnancy
• Trauma
• Stress
• Cocaine
• Surgery
• Heavy use of concentrated carbohydrate beverages such as sodas and sports drinks
• Acromegaly
• Idiopathic (20-30%)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Uremia
Acute hypoglycemia coma
Catheter-related venous thrombosis, especially with femoral central venous catheters in children

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Glucose: Levels may be as low as 250 mg/dL. The clinician can do a fingerstick glucose test while waiting for the serum chemistry panel.
• Sodium: The osmotic effect of hyperglycemia moves extravascular water to the intravascular space. For each 100 mg/dL of glucose over 100 mg/dL, the serum sodium level is lowered by approximately 1.6 mEq/L. When glucose levels fall, the serum sodium level rises by a corresponding amount.
• Potassium: This needs to be checked frequently, as values drop very rapidly with treatment. An ECG may be used to assess the cardiac effects of extremes in potassium levels.
• Bicarbonate: Use these levels in conjunction with the anion gap to assess degree of acidosis.
• Complete blood cell (CBC) count: High white blood cell (WBC) counts (>15 X 10⁹/L) or marked left shift may suggest underlying infection.
• Arterial blood gas (ABG) levels: pH is often <7.3. Venous pH may be used for repeat pH measurements.¹ Brandenburg and Dire found that pH on a venous blood gas level in patients with DKA was 0.03 lower than pH on an ABG.² Because this difference is relatively reliable and not of clinical significance, there is almost no reason to perform the more painful ABG. End tidal CO₂ has been reported as a way to assess acidosis as well.
• Ketones: The Acetest and Ketostix products measure blood and urine acetone and acetoacetic acid. They do not measure the more common ketone body, beta-hydroxybutyrate, so the patient may have paradoxical worsening as the latter is converted into the former during treatment. Specific testing for beta-hydroxybutyrate can be performed by many laboratories.
• Urinalysis (UA): Look for glycosuria and urine ketosis. Use this to detect underlying urinary infection.
• Osmolality: Measured as 2(Na⁺) (mEq/L) + glucose (mg/dL)/18 + BUN(mg/dL)/2.8. Patients with DKA who are in a coma typically have osmolalities >330 mOsm/kg H₂O. If the osmolality is less than this in a patient who is comatose, search for another cause of obtundation.
• Phosphorous: If the patient is at risk for hypophosphatemia (eg, poor nutritional status, chronic alcoholism), then the serum phosphorous level should be determined.
• Hyperamylasemia may be seen, even in the absence of pancreatitis.
• BUN level is increased.
• Anion gap is higher than normal.
• Repeat laboratory tests are critical. Potassium level needs to be checked every 1-2 hours during initial treatment. Glucose and other electrolyte levels should be checked every 2 hours or so during initial aggressive volume, glucose, and electrolyte management. If the initial phosphorous level was low, it should be monitored every 4 hours during therapy.
• Be aware that high serum glucose levels may lead to dilutional hyponatremia; high triglyceride levels may lead to factitious low glucose level; and high levels of ketone bodies may lead to factitious elevation of creatinine level.

Imaging Studies

• Chest radiography: Use this to rule out pulmonary infection.
• CT scanning: The threshold should be low for obtaining a head CT scan in children with DKA who have altered mental status, as this may be caused by cerebral edema. Many of the changes may be seen late on head imaging and should not delay administration of hypertonic saline or mannitol in those pediatric cases where cerebral edema is suspected.

Other Tests

• Electrocardiography (ECG): DKA may be precipitated by a cardiac event, and the physiological disturbances of DKA may cause cardiac complications. An ECG is also a rapid way to assess significant hypokalemia or hyperkalemia.
• Telemetry: Consider telemetry in those with comorbidities (especially cardiac), known significant electrolyte abnormalities, severe dehydration, or profound acidosis.

Procedures

• Airway management and potential intubation should be a primary concern in any patient with a significantly depressed mental status or with respiratory distress.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Infusion of an isotonic saline solution should be initiated early, especially in the presence of hypotension, tachycardia, or other overt signs of volume depletion.

Emergency Department Care

Maintain extreme vigilance for any concomitant process such as infection, cerebrovascular accident (CVA), MI, sepsis, or deep venous thrombosis (DVT).

• Fluid resuscitation is a critical part of treating diabetic ketoacidosis (DKA). Intravenous solutions replace extravascular and intravascular fluids and electrolyte losses. They also dilute both the glucose level and the levels of circulating counterregulatory hormones. Insulin is needed to help switch from a catabolic state to an anabolic state, with uptake of glucose in tissues and the reduction of gluconeogenesis as well as free fatty acid and ketone production.
• • Administer high volumes of isotonic saline (1-3 L) in the first hour. Further isotonic saline should be administered at a rate appropriate to maintain adequate blood pressure and pulse, urinary output, and mental status. If a patient is severely dehydrated and significant fluid resuscitation is needed, switching to a balanced electrolyte solution (such as Normosol-R, in which some of the chloride in isotonic saline is replaced with acetate) may help to avoid the development of a hyperchloremic acidosis.
  • After initial stabilization with isotonic saline, switch to half-normal saline at 200-1000 mL/h (half-normal saline matches losses due to osmotic diuresis).
  • Insulin should be started about an hour after intravenous fluid replacement is started to allow for checking potassium levels and because insulin may be more dangerous and less effective before some fluid replacement has been obtained. Although the incidence of life-threatening hypokalemia due to aggressive insulin administration is very low, there is little to no advantage in starting insulin prior to rehydration and evaluation of serum potassium levels. 
  • Pediatric protocols to minimize the risk of cerebral edema by reducing the rate of fluid repletion vary. Initial fluid repletion in pediatric patients should be 10-20 mL/kg over the first 1-2 hours with a maximum of 50 mL/kg over the first 4 hours. Although classically thought to result in cerebral edema, rapid administration of intravenous fluids itself is not likely the cause of the edema. It is therefore important to not be overly cautious with fluid administration, because rehydration remains as vital in children as in adults.
• Potassium replacement
• • Potassium replacement should be started with initial fluid replacement if potassium levels are normal or low.  
  • Add 20-40 mEq/L of KCl to each liter of fluid once K⁺ is under 5.5 mEq/L.
  • Potassium can be given as follows: two thirds as KCl, one third as KPO₄.
• Bicarbonate typically is not replaced since acidosis will improve with the above treatments alone. Administration of bicarbonate has been correlated with cerebral edema in children.
• Phosphate and magnesium replacements are not typically needed, since levels correct when patient resumes eating.
• Use data flow sheets to monitor timing of laboratory tests and therapy.

Consultations

Consultation with an intensivist may be required for admission to an intensive care unit and assistance with care of patients who are critically ill. An endocrinologist may also be consulted to assist with management after the patient has been adequately stabilized.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treatment of ketoacidosis should aim at correcting dehydration, reversing the acidosis and ketosis, reducing plasma glucose concentration to normal, replenishing electrolyte and volume losses, and identifying the underlying cause.

See Diabetes Mellitus, Type 1 - A Review and Diabetes Mellitus, Type 2 - A Review for dosing regimens.

Drug Category: Antihyperglycemic agent

These agents lower plasma glucose and ketone levels.

Drug Category: Mineral solutions

These solutions replenish mineral deficiencies.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit to ICU or monitored unit depending on clinical status. Patients undergoing continuous insulin require frequent monitoring, which is best completed in the ICU.
• Occasionally, patients with mild acidosis and fluid/electrolyte deficits can be stabilized adequately in the emergency department (ED) if very close follow-up can be arranged.

Further Outpatient Care

• Upon discharge from the hospital (or uncommonly directly from the ED), patients require very close follow-up with their primary care provider, endocrinologist, or both.

Complications

• Complications of associated illnesses, including sepsis and diffuse ischemic processes, are possible.
• The leading cause of diabetic ketoacidosis (DKA) mortality in children is cerebral edema, which occurs 4-12 hours into treatment. Recent research by Glaser et al indicated that cerebral edema occurs in 1% of children with DKA, with a mortality rate of 21% and neurologic sequelae in another 21% of patients.⁴
• • Cerebral edema begins with mental status changes and is believed to be due partially to "idiogenic osmoles," which have stabilized brain cells from shrinking while the DKA was developing. The risk of cerebral edema is related to the severity and duration of DKA. It is often associated with ongoing hyponatremia. Cerebral edema is correlated with the administration of bicarbonate. Concerns about the role of overaggressive or overly hypotonic fluid resuscitation as a cause of the edema that have been raised in the past correlate more closely with disease severity than with rapid administration of fluids itself.
  • Cerebral edema is a complication that affects primarily children. Glaser et al suggest up to half of children with DKA have subtle brain MRI findings, in particular narrowing of the lateral ventricles.⁴
  • Mannitol or hypertonic saline should be available if cerebral edema is suspected. According to Wolfsdorf et al, 0.5-1 g/kg intravenous mannitol may be given over 20 minutes and repeated if no response is seen in 30-120120 minutes.⁵ Also, if no response to mannitol occurs, hypertonic saline (3%) may be given at 5-10 mg/kg over 30 minutes.
• Hypokalemia is a complication that is precipitated by failing to rapidly address the total body potassium deficit brought out by rehydration and insulin treatment, which not only reduces acidosis but directly facilitates potassium reentry into the cell.
• Hypoglycemia may result from inadequate monitoring of glucose levels during insulin therapy.
• Acute pulmonary edema is potentially related to aggressive or excessive fluid therapy. Although initial aggressive fluid replacement is necessary in all patients, particular care must be taken in those with comorbidities such as renal failure or congestive heart failure.
• Other complications include the following:
• • CVT
  • MI
  • DVT
  • Acute gastric dilatation
  • Erosive gastritis
  • Late hypoglycemia
  • Respiratory distress
  • Infection
  • Hypophosphatemia
  • Mucormycosis

Prognosis

• DKA accounts for 14% of all hospital admissions of patients with diabetes and 16% of all diabetes-related fatalities.
• The overall mortality rate is 2% or less currently.
• In children younger than 10 years, DKA causes 70% of diabetes-related fatalities.

Patient Education

• Control blood glucose level carefully.
• Monitor glucose level particularly closely during infection, trauma, and other periods of stress.
• For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetic Ketoacidosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider other coexisting illnesses, such as pelvic or rectal abscess, pneumonia, and silent MI
• Failure to evaluate for other causes of coma if osmolality is relatively normal
• Failure to initiate fluid resuscitation and potassium replacement before starting insulin

Special Concerns

• Pregnant patients
• • A fetal mortality rate as high as 30% is associated with DKA. The rate is as high as 60% in DKA with coma.
  • Fetal death typically occurs in women with overt diabetes, but it may occur with gestational diabetes.
• Children: Be alert to headache and altered mental status (eg, decreased alertness) since these are signs of impending cerebral edema.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Ma OJ, Rush MD, Godfrey MM, Gaddis G. Arterial blood gas results rarely influence emergency physician management of patients with suspected diabetic ketoacidosis. Acad Emerg Med. Aug 2003;10(8):836-41. [Medline].
2. Brandenburg MA, Dire DJ. Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis. Ann Emerg Med. Apr 1998;31(4):459-65. [Medline].
3. Umpierrez GE, Cuervo R, Karabell A, Latif K, Freire AX, Kitabchi AE. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care. Aug 2004;27(8):1873-8. [Medline].
4. Glaser NS, Wootton-Gorges SL, Buonocore MH, Marcin JP, Rewers A, Strain J. Frequency of sub-clinical cerebral edema in children with diabetic ketoacidosis. Pediatr Diabetes. Apr 2006;7(2):75-80. [Medline].
5. Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, Lee WR, et al. Diabetic ketoacidosis. ISPAD Clinical Practice Consensus Guidelines 2006-2007. Pediatr Diabetes. Feb 2007;8(1):28-43. [Medline].
6. Charfen MA, Fernández-Frackelton M. Diabetic ketoacidosis. Emerg Med Clin North Am. Aug 2005;23(3):609-28, vii. [Medline].
7. Fearon DM, Steele DW. End-tidal carbon dioxide predicts the presence and severity of acidosis in children with diabetes. Acad Emerg Med. Dec 2002;9(12):1373-8. [Medline].
8. Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med. Jan 25 2001;344(4):264-9. [Medline].
9. Green SM, Rothrock SG, Ho JD, Gallant RD, Borger R, Thomas TL, et al. Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. Jan 1998;31(1):41-8. [Medline].
10. Grimberg A, Cerri RW, Satin-Smith M, Cohen P. The "two bag system" for variable intravenous dextrose and fluid administration: benefits in diabetic ketoacidosis management. J Pediatr. Mar 1999;134(3):376-8. [Medline].
11. Kitabchi AE, Nyenwe EA. Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am. Dec 2006;35(4):725-51, viii. [Medline].
12. Kreshak A, Chen EH. Arterial blood gas analysis: are its values needed for the management of diabetic ketoacidosis?. Ann Emerg Med. May 2005;45(5):550-1. [Medline].
13. McDonnell CM, Pedreira CC, Vadamalayan B, Cameron FJ, Werther GA. Diabetic ketoacidosis, hyperosmolarity and hypernatremia: are high-carbohydrate drinks worsening initial presentation?. Pediatr Diabetes. Jun 2005;6(2):90-4. [Medline].
14. Muir AB, Quisling RG, Yang MC, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis: natural history, radiographic findings, and early identification. Diabetes Care. Jul 2004;27(7):1541-6. [Medline].
15. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med. Sep 27 2004;164(17):1925-31. [Medline].
16. Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med. Mar 7 2006;144(5):350-7. [Medline].
17. Warner EA, Greene GS, Buchsbaum MS, Cooper DS, Robinson BE. Diabetic ketoacidosis associated with cocaine use. Arch Intern Med. Sep 14 1998;158(16):1799-802. [Medline].
18. Whiteman VE, Homko CJ, Reece EA. Management of hypoglycemia and diabetic ketoacidosis in pregnancy. Obstet Gynecol Clin North Am. Mar 1996;23(1):87-107. [Medline].
19. Wolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. May 2006;29(5):1150-9. [Medline].

Article Last Updated: Feb 12, 2008