Despite advances in diabetes management, diabetic ketoacidosis (DKA) continues to be a leading cause of morbidity and mortality, and is associated with costly hospital admissions.1-10 In 2009, according to the CDC, the hospitalization rate for DKA was 7.1 per 1,000 people with diabetes.11 Each case of DKA carries a mortality of 1% to 5%.3 DKA can affect patients with either type 1 or type 2 diabetes but is estimated to be more than twice as common in patients with type 1 diabetes than in those with type 2 diabetes.5 In patients with type 2 diabetes, DKA usually results from medication mismanagement or complicating factors such as infection or dehydration. In patients with type 1 diabetes, DKA often is the presenting feature of diagnosis. Many studies indicate that the occurrence of type 1 diabetes is increasing by 3% to 5% per year worldwide.2,5,10 Researchers find that up to one-third of children manifest DKA as the original presentation of type 1 diabetes.5,6,9,12 These children develop hyperglycemia, acidosis, and ketosis.
Cerebral edema is a possible devastating complication of DKA, carrying a 20% to 25% mortality and remaining the leading cause of death in children with DKA.1,4,5,8,9,13-16 Although no standard treatment protocol exists for DKA, the goal of management is to correct hyperglycemia and ketoacidosis while avoiding cerebral edema.1,4-6,8,17 The International Society for Pediatric and Adolescent Diabetes (ISPAD) revised its treatment guidelines for DKA in 2014; however, treatment protocols continue to differ from one institution to another; and the optimal approach to management of DKA continues to be studied. Clinicians should be familiar with the risk factors and clinical manifestations of DKA and the management of this potentially life-threatening complication.
DKA results from a lack of insulin and a cycle of glucogenesis, lipolysis, and ketogenesis associated with elevated levels of insulin counterregulatory hormones (catecholamines, cortisol, and glucagon).1,3,10,17,18 After a patient is diagnosed with type 1 diabetes, DKA can result from poor insulin compliance, during illnesses that cause vomiting, as a result of infections (especially Klebsiella pneumoniae), during periods of stress, or because of insulin delivery issues such as pump failure. DKA in patients with type 2 diabetes frequently results from acute illnesses, such as infection or cardiovascular events, or from medications that affect glucose metabolism.
Type 1 diabetes is an autoimmune disease caused by destruction of pancreatic beta cells that produce insulin.1,10,13,14,18 Glucose is needed for energy, glycogen storage, and lipogenesis. Without sufficient insulin, glucose cannot move from the bloodstream into the cells, resulting in hyperglycemia.1,17 In patients with a lack of insulin, a surge in the insulin counterregulatory hormones is triggered in an effort to keep blood glucose levels within the normal range.1,3,9,17 Hyperglycemia leads to shifts in electrolyte concentration and extracellular fluid composition, causing osmotic diuresis and dehydration.1,3,4,17 Insulin deficiency and the excess of counterregulatory hormones stimulate lipolysis.1,3,9,17 Lipolysis prompts oxidation of free fatty acids to ketones, contributing to ketonemia and consequently the metabolic acidosis seen in DKA.1,3,4,13,17
Misdiagnosis or a delay in diagnosis are the primary risk factors for developing DKA.2 Fifty-five percent of children with DKA at time of new-onset type 1 diabetes were initially diagnosed with more common, less-severe illnesses, delaying treatment for DKA.2 DKA is more prevalent in children younger than age 4 years, those from lower socioeconomic groups, those who lack healthcare insurance, and those with concomitant autoimmune thyroid or celiac disease.1,2,5,9,10,15,17,18 Parental education level has an inverse correlation with the development of DKA in children with type 1 diabetes.5,10 A lower body mass index (BMI) also has been associated with a greater risk of developing DKA.9,10
Children with DKA generally present with the classic triad of polydipsia, polyuria, and weight loss.1,3,9,14 Although children may also complain of abdominal pain, nausea, and vomiting, many may present with nonspecific symptoms such as fatigue or drowsiness.1,4,9 The symptoms of DKA are often overlooked or diagnosed as more common illnesses, such as gastroenteritis, streptococcal throat infection, or a viral illness, causing a delay in treatment and subsequently sicker patient.10 Late findings of DKA include hypotension, tachycardia, Kussmaul respirations, headache, lethargy or change in mental status, and fruity breath.1,3,4,9,17 Children may exhibit signs of dehydration such as dry mucous membranes.1,3,9 Electrolyte abnormalities associated with DKA include hyponatremia, hypokalemia, hypophosphatemia, and hypomagnesemia.9
Obtain a capillary blood sample for immediate blood glucose measurement at point of care to help confirm a suspected diagnosis of type 1 diabetes. A blood glucose measurement above 200 mg/dL is consistent with DKA. Obtain a serum sample for a C-peptide level; a low or absent level confirms the diagnosis of type 1 diabetes because C-peptide is secreted in a 1:1 ratio to insulin.19 Once the diagnoses of type 1 diabetes and DKA are confirmed, initial laboratory studies should include a serum chemistry, a complete blood cell count, a venous blood gas for pH determination, and a urinalysis for ketones.3,9,17 An ECG is recommended because of the potentially fatal dysrhythmias associated with hypokalemia and hypomagnesemia in patients with DKA.3,9,17
Perform a comprehensive physical examination including current height and weight.17 Weight loss, another symptom of type 1 diabetes, occurs in more than 80% of patients; review and compare previous weight measurements in the history when available.9 Current height and weight measurements are needed for fluid deficit calculations in patients with DKA because the hyperglycemia often produces a dilutional effect on electrolytes.1,17 See Table 1 for corrected serum chemistry calculations.
The diagnostic criteria for DKA, as defined by the American Diabetes Association, are:
- hyperglycemia, defined as a serum glucose level greater than 200 mg/dL or about 11 mmol/L
- venous pH less than 7.3 or serum bicarbonate less than 15 mmol/L
- ketonemia greater than 31 mg/dL or ketouria greater than 80 mg/dL.1,3-5,9,16,17
DKA is classified as mild if the patient's pH is less than 7.3 and serum bicarbonate is less than 15 mmol/L; moderate if the venous pH is less than 7.2 and the bicarbonate is less than 10 mmol/L; and severe if the venous pH is less than 7.1 and bicarbonate is less than 5 mmol/L.1,4,9,17
The differential diagnosis of DKA includes hyperosmolar hyperglycemic state, gastroenteritis, pancreatitis, starvation ketosis, myocardial infarction, and disorders with high anion gap metabolic acidosis.1,3,17
Cerebral edema, when present, most often occurs in patients under age 20 years.3,8,9,12,14 Cerebral edema can present in 1% to 5% of children with DKA and is associated with the highest mortality of all complications of DKA.1,3,4,6,8,9,12,17,20 Risk factors for developing cerebral edema with DKA include newly diagnosed type 1 diabetes, low bicarbonate, low PaCO2, and high blood urea nitrogen (BUN).3,12,17
Headache is the classic presenting symptom of cerebral edema and warrants further evaluation.1,3,9,12,16,17 Other late manifestations of cerebral edema include bradycardia, irritability, lethargy, increase in BP, cranial nerve palsies, papilledema, and hypoxemia.1,3,16,17
The pathophysiology of cerebral edema in patients with DKA is not well understood.1,8,12 Cerebral edema most often manifests and is diagnosed after management has been started for type 1 diabetes and DKA.12,13 Research suggests that the condition may result from overaggressive fluid therapy to correct hyperglycemia.4,8,12 But because some children have been diagnosed with cerebral edema before treatment, this is an area of dispute among researchers.13 Another theory suggests that cerebral hypoperfusion and cerebral ischemia develop early in DKA, and these are further aggravated by the restoration of blood flow during fluid resuscitation, leading to cerebral edema.9,12,16
Many studies demonstrate that patients with DKA at new-onset type 1 diabetes develop temporary hypercoagulability. This hypercoagulable state may predispose the patient to deep vein thrombosis (DVT), cerebral venous thrombosis, and cerebral ischemia.3,12 Studies also indicate that the significant dehydration that occurs in DKA is associated with rhabdomyolisis.4,13 An elevated BUN or creatinine in patients with DKA is a risk factor for the development of rhabdomyolisis.12 Pulmonary complications are rare, but patients may develop pulmonary edema or pneumomediastinum secondary to vomiting and Kussmaul respirations that increase the alveolar pressure gradient.1,3,12 Children who develop pulmonary edema may require intubation.12 Researchers suggest that the development of pulmonary edema may be secondary to the osmotic pressure changes in the circulatory system that occur with fluid therapy.12
Additionally, studies have documented that about 2% of children with DKA develop pancreatitis.12 CT imaging may be necessary to diagnose pancreatitis, as elevated lipase and amylase are common enzyme abnormalities in children with DKA.12 Researchers report that some children with DKA, especially younger children, who present with severe acidosis are more likely to suffer long-term memory dysfunction and attention deficit, months after resolution of the acute event.3,12
No standard protocol exists for managing DKA.16 Therefore, the treatment protocol for DKA varies from one institution to another. The ISPAD guidelines are most commonly followed.17
Patients who present with DKA at the diagnosis of type 1 diabetes should be admitted to the hospital for care and management, with many children requiring admission to the pediatric ICU.1,6 The goals of management are to rehydrate the child and correct the ketoacidosis, hyperglycemia, and the electrolyte disturbances while avoiding the development of cerebral edema.1,3,9,13,17 Because cerebral edema may be the result of overaggressive fluid replacement therapy, monitor the patient's volume status closely.17
Though fluid therapy is the cornerstone in the treatment of DKA, the possible link to cerebral edema leads to inconsistencies in treatment strategies.9,16 Many studies are under way to provide more consistent treatment guidelines.
ISPAD recommends starting fluid therapy with 0.9% sodium chloride solution at 10 to 20 mL/kg over 1 to 2 hours.17 After the administration of the initial fluid, ISPAD recommends that the remaining fluid deficit be corrected starting with 0.9% sodium chloride solution, Ringer lactate, or balanced crystalloid solution at 4 to 14 mL/kg for 4 to 6 hours.17 A solution of 0.45% sodium chloride solution with potassium should follow.9,16,17 Fluid replacement therapy generally occurs over 48 hours.9,13,17 If the patient's blood glucose falls below 200 mg/dL during fluid therapy, add dextrose to the fluids.9,16,17
Most patients with DKA will be treated with IV insulin.1,16,17 ISPAD recommends insulin therapy at 0.05 to 0.1 U/kg/hour, starting 1 to 2 hours after fluid resuscitation.1,9,16,17,21 Start subcutaneous insulin when the patient's serum glucose levels range between 200 and 250 mg/dL and oral fluids are tolerated.
Monitor the patient's potassium levels hourly because insulin administration causes potassium levels to decrease.1,17 If the patient's potassium levels are within normal limits, administer potassium 40 mEq/L in the infusate or 20 mEq/L at a rate greater than 10 mL/kg/hour.17 The ISPAD guidelines do not recommend bicarbonate replacement except for treatment of life-threatening hyperkalemia.1,3,8,9,17
The patient can be considered for discharge when he or she is clinically stable and the ketosis and acidosis have resolved.4 DKA has resolved when the patient's serum glucose level is less than 200 mg/dL, pH is greater than 7.3, and bicarbonate is 18 mEq/L or greater.3,17 Both the patient with newly diagnosed type 1 diabetes and their family receive diabetes management education while in the hospital and outpatient follow-up is established before discharge.
DKA is a serious complication of diabetes that is associated with high rates of morbidity and mortality and costly hospital admissions. Studies confirm that children manifest symptoms of diabetes before presenting with DKA.3,9,10 Clinicians must be able to identify patients at risk, recognize common symptoms, and start prompt management of this potentially life-threatening complication. To further reduce the incidence of DKA, clinicians need increased education about and awareness of the signs and symptoms of diabetes.
1. Corwell B, Knight B, Olivieri L, Willis GC. Current diagnosis and treatment of hyperglycemic emergencies. Emerg Med Clin North Am
2. Szypowska A, Ramotowska A, Grzechnik-Gryziak M, et alHigh frequency of diabetic ketoacidosis
in children with newly diagnosed type 1 diabetes
. J Diabetes Res. 2016;2016:9582793.
3. Westerberg DP. Diabetic ketoacidosis
: evaluation and treatment. Am Fam Physician
4. Lavoie ME. Management of a patient with diabetic ketoacidosis
in the emergency department. Pediatr Emerg Care
5. Rewers A, Klingensmith G, Davis C, et al Presence of diabetic ketoacidosis
at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics
6. Klingensmith GJ, Tamborlane WV, Wood J, et al Diabetic ketoacidosis
at diabetes onset: still an all too common threat in youth. J Pediatr
7. Patel A, Singh D, Bhatt P, et al Incidence, trends, and outcomes of cerebral edema
among children with diabetic ketoacidosis
in the United States. Clin Pediatr (Phila)
8. Gee SW. The lethargic diabetic: cerebral edema
patients in diabetic ketoacidosis
. Air Med J
9. Olivieri L, Chasm R. Diabetic ketoacidosis
in the pediatric
emergency department. Emerg Med Clin North Am
10. Jefferies CA, Nakhla M, Derraik JG, et al Preventing diabetic ketoacidosis
. Pediatr Clin North Am
11. Centers for Disease Control and Prevention. Crude and age-adjusted hospital discharge rates for diabetic ketoacidosis
) as first-listed diagnosis per 1,000 diabetic population, United States, 1998-2009. http://www.cdc.gov
/diabetes/statistics/dkafirst/fig3.htm. Accessed May 9, 2017.
12. Bialo SR, Agrawal S, Boney CM, Quintos JB. Rare complications of pediatric diabetic ketoacidosis
. World J Diabetes
13. von Saint Andre-von Arnim A, Farris R, Roberts JS, et al Common endocrine issues in the pediatric
intensive care unit. Crit Care Clin
14. Tivener K, Liggett A, Mitchell D. Onset of type 1 diabetes
mellitus presenting with diabetic ketoacidosis
requiring hospitalization in a 20-year-old male: a case report. Int J Athl Ther Train
15. Dabelea D, Rewers A, Stafford JM, et al Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study. Pediatrics
16. Wolfsdorf J, Craig ME, Daneman D, et al Diabetic ketoacidosis
in children and adolescents with diabetes. Pediatr Diabetes
. 2009;10(suppl 12):118–133.
17. Wolfsdorf JI, Allgrove J, Craig ME, et al ISPAD Clinical Practice Consensus Guidelines 2014. Diabetic ketoacidosis
and hyperglycemic hyperosmolar state. Pediatr Diabetes
. 2014;15(suppl 20):154–179.
18. Chiang JL, Kirkman MS, Laffel LM, Peters AL. Type 1 diabetes
through the life span: a position statement of the American Diabetes Association. Diabetes Care
19. Marques RG, Fontaine MJ, Rogers J. C-peptide: much more than a byproduct of insulin biosynthesis. Pancreas
20. Brink SJ. Paediatric and adolescent diabetic ketoacidosis
. Pract Diabetes
21. Nallasamy K, Jayashree M, Singhi S, Bansal A. Low-dose vs standard-dose insulin in pediatric diabetic ketoacidosis
: a randomized clinical trial. JAMA Pediatr
Keywords:Copyright © 2017 American Academy of Physician Assistants
diabetic ketoacidosis; DKA; type 1 diabetes; cerebral edema; hyperglycemia; pediatric