Continuing Education Activity

Diabetic ketoacidosis (DKA) is a serious complication of relative insulin deficiency affecting primarily type-1 diabetes mellitus (DM). DKA can occur in type-2 DM when insulin levels fall far behind the body’s needs. DKA is so named due to high levels of water-soluble ketone bodies (KBs), leading to an acidotic physiologic state. Ketone bodies, while always present in the blood, increase to pathologic levels when the body cannot utilize glucose: low blood glucose levels during fasting, starvation, vigorous exercise, or secondary to a defect in insulin production. This activity reviews the etiology, presentation, evaluation, and management of diabetic ketoacidosis in the pediatric population and examines the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Describe the pathophysiology of pediatric diabetic ketoacidosis.
• Review the evaluation of a patient with pediatric diabetic ketoacidosis, including all necessary laboratory tests.
• Summarize the management options for diabetic ketoacidosis.
• Explain modalities to improve care coordination among interprofessional team members to improve outcomes for pediatric patients affected by diabetic ketoacidosis.

Introduction

Diabetic ketoacidosis (DKA) is a serious complication of relative insulin deficiency affecting primarily type-1 diabetes mellitus (DM). DKA can occur in type-2 DM when insulin levels fall far behind the body's needs. DKA is so named due to high levels of water-soluble ketone bodies (KBs), leading to an acidotic physiologic state.[1][2]

According to the International Society for Pediatric and Adolescent Diabetes, DKA is defined by the presence of all of the following in a patient with diabetes:

• Hyperglycemia – Blood glucose >200 mg/dL (11 mmol/L)
• Metabolic acidosis – Venous pH <7.3 or serum bicarbonate <15 mEq/L (15 mmol/L)
• Ketosis – Presence of ketones in the blood (>3 mmol/L beta-hydroxybutyrate) or urine ("moderate or large" urine ketones)[3]

Produced by the liver during fatty acid metabolism, KBs can be utilized by the brain, cardiac, and skeletal muscle tissues as a fuel when the body is deficient in or cannot effectively import glucose.[4][5]

Etiology

Ketone bodies, while always present in the blood, increase to pathologic levels when the body cannot utilize glucose (e.g., fasting, starvation, vigorous exercise, or secondary to a defect in insulin production). In type-2 DM, insulin production may be normal but below the level needed to shunt glucose into cells.[6][7]

Most body fat is stored as triglyceride (TG). When the body's glucose storage sites become depleted, the liver dismantles the TG into three fatty acids (FAs) and a glycerol molecule. The FAs can undergo oxidation while glycerol converts to glucose. In the presence of enough insulin, this glucose will be consumed as energy. In the absence of insulin, the body cannot utilize the glucose released from the glycerol metabolism; unused glucose rises to dangerous levels, with spillover into the urine.

When the blood glucose is low or cannot be used due to a lack of insulin, ketones are the major energy source for the brain. The brain does not store fuel and can only utilize glucose and ketones for fuel.

In contrast, skeletal muscle stores and can utilize glycogen. Approximately 70% of the total body glycogen is stored in muscles and can be converted, when needed, to glucose via glycogenolysis.

Epidemiology

DKA is frequently present at diagnosis of type 1 diabetes (in approximately 3% percent of children in the United States and Canada) and, along with its complications, is the most common cause of hospitalization, mortality, and morbidity in children with type 1 diabetes mellitus.[8] The fatality rate is approximately 0.15-0.31% of cases. DKA in children with type 2 diabetes is also observed but at lower rates.[9]

DKA at initial presentation of type 1 diabetes mellitus: DKA occurs at the time of diagnosis of type 1 diabetes in approximately 30 percent of children in the United States and Canada.[10] Factors that increase the likelihood of DKA at the initial presentation of type 1 diabetes in children are as follows:

• Young age (<5 years of age and especially <2 years)
• Ethnic minority
• Low socioeconomic status
• Children living in countries with a low prevalence of type 1 diabetes
• Ethnic minority
• Delayed diagnosis of diabetes[11][12]

The importance of socioeconomic status was observed in a review of 139 patients with newly diagnosed type 1 diabetes mellitus attended at a single center in the United States.[13] In addition, the frequency of DKA at the presentation of type 1 diabetes is shown to be inversely related to the prevalence of type 1 diabetes in the population, reflecting a greater frequency of missed diagnoses of type 1 diabetes.[14]

DKA in established type 1 diabetes mellitus: In children with an established diagnosis of type 1 diabetes, DKA occurs at an annual rate of 6 to 8%.[15][16]

The following factors contribute to the development of DKA:

• Poor metabolic control
• Peripubertal and pubertal adolescent girls
• Gastroenteritis with vomiting and dehydration
• History of psychiatric disorders (including eating disorders) or family discord
• Limited access to medical care (underinsured)
• Omission of insulin, including failure of an insulin pump

In a large prospective study in the United States, almost 60 percent of DKA episodes in children with established diabetes occurred in only 5 percent of all children.[15] Similar findings were reported in the United Kingdom.[8]

DKA in type 2 diabetes mellitus: Ketosis and DKA can occur less frequently in children with type 2 diabetes and are usually observed mainly in African American adolescents with obesity.[17] About 13 percent had type 2 diabetes in a retrospective review of 69 patients (9 to 18 years of age) who presented with DKA.[9]

Pathophysiology

The physiologic disturbance in DKA involves several interrelated processes:

1. Hyperglycemia is present, which leads to serum hyperosmolarity and osmotic diuresis.
2. Glucosuria is the precursor to osmotic diuresis, hyperosmolarity, and dehydration. Free water losses can be substantial, with decompensation and impaired renal function.
3. Ketones accumulate and cause metabolic acidosis. Compensatory hyperventilation eliminates carbon dioxide.
4. Approximate potassium deficits in children with DKA are 3 to 6 mEq/kg. However, serum potassium levels are usually normal or slightly elevated at presentation due to the shift of potassium ions from the intracellular to extracellular space. Osmotic diuresis, elevated aldosterone concentrations in response to intravascular volume depletion, and ketoacid excretion may also result in urinary potassium loss.
5. The measured serum sodium is reduced by 1.6 mEq/L for every 100 mg/dL (5.5 mEq/L) increase in the blood glucose concentration above 100 mg/dL leading to pseudohyponatermia.[18]
6. Glucosuria-induced osmotic diuresis also causes phosphate deficit in children. However, the serum phosphate concentration is usually normal or even slightly elevated initially as both metabolic acidosis and insulin deficiency cause extracellular phosphate shift. As this transcellular shift reverses during DKA treatment, phosphate levels typically decline.[19]
7. Elevated blood urea nitrogen (BUN) concentration may be found in patients with DKA, which correlates with the degree of hypovolemia. Acute increases in serum creatinine reflecting acute kidney injury (AKI) may also be observed.

Ketoacidosis

Glucose is the primary carbon-based substrate in blood necessary for the production of adenosine triphosphate (ATP), which is the energy currency of cells after glucose is metabolized during glycolysis, Kreb's cycle, and the electron transport chain. Ketone bodies are fat-derived fuels used by tissues at the time of limited glucose availability. Hepatic generation of ketone bodies is usually stimulated by the combination of low insulin levels and high counter-regulatory hormone levels, including glucagon.[20]

Deficiency and resistance (e.g., due to high catecholamine levels during physiological stress) lead to an unfavorable ratio of insulin to glucagon that activates hormone-sensitive lipase, which breaks down triglycerides in peripheral stores, releasing long-chain fatty acids and glycerol. The fatty acids, mainly bound to albumin, are transported to the splanchnic bed and taken up by hepatocytes. The fatty acids undergo beta-oxidation in the hepatic mitochondria and, by linking the fatty acid to coenzyme A (CoA), generate acetyl-CoA. The combination of low insulin and increased glucagon activity in the liver cells leads to the accelerated entry of the acyl-CoA into the mitochondria, mediated by a pair of carnitine palmityl transferase reactions.[21][22]

Acetyl coenzyme A can have one of three fates:

1. Enter the Krebs cycle to be oxidized to carbon dioxide (CO2) and water (H2O), forming adenosine triphosphate (ATP)
2. Used to synthesize fatty acids in the cytoplasm
3. Enter the ketogenic metabolic path to form acetoacetic acid

With the generation of large quantities of acetyl-CoA in the more severe forms of each of these conditions, the oxidative capacity of the Krebs cycle gets saturated, and there is a spillover entry of acetyl-CoA into the ketogenic pathway and subsequent generation of acetoacetic acid, which is the first "ketone body.". The acetoacetic acid may then be reduced to beta-hydroxybutyric acid, which is also an organic acid, or nonenzymatically decarboxylated to acetone, which is not an acid.[23] Acetone does not convert back to acetyl-CoA; instead excreted through urine or exhaled. Through this process, ketones provide an alternate water-soluble energy source when glucose availability is reduced.

Histopathology

Diabetes mellitus is a chronic illness; episodes of DKA recur in poorly controlled patients. It is difficult to characterize the consequences of repeated episodes, but chronically elevated HbA1c measurements predict micro-vascular and macro-vascular complications of diabetes.

Up to 1% of DKA patients will have cerebral edema due to rapid osmolar shifts. Look for signs of sudden increased intracranial pressure: bradycardia, headache, papilledema, irritability, rising blood pressure, and decreasing Glasgow coma scale (GCS). Cerebral edema mortality approaches 25%. Survivors suffer significant neurological morbidity. 

Toxicokinetics

Three ketone molecules predominate in human physiology: beta-hydroxybutyrate (BHB), acetoacetate, and acetone.

Beta-hydroxybutyrate represents the most precise approach to measuring the severity of DKA, making up roughly 75% of ketones in DKA. Whole blood ketone test strips and serum laboratory tests quantify BHB. Most urine strips test for acetoacetate and acetone.

BHB can be confirmed in the blood up to 24 hours before acetone and acetoacetate appear in the urine, as BHB is converted into these molecules. Therefore, urine ketone testing can increase even after proper DKA treatment ceases the formation of BHB. Acetone, which is stored in adipose tissue, is slowly released in the blood and excreted in the urine.

Serum Ketone Levels

1. Less than 0.6 mmol/L=normal
2. Between 0.6 mmol/L to 1.5 mmol/L=low to moderate
3. Between 1.6 mmol/L to 3.0 mmol/L=high with a risk of developing DKA
4. Over 3.0 mmol/L: Likely DKA, requires immediate emergency treatment[24]

Urine Ketone Strip Levels

• Having no ketones in the urine is normal.
• One plus (+) ketones in urine ketones strips are equal to low/moderate blood ketones levels.
• Two plus (++) ketones in urine are equal to a high blood level of ketones.
• Three plus (+++) ketones in urine are equal to severe blood ketones.
• False-positive ketones in urine can occur with the intake of some medications like captopril and valproate. False-negative ketones in urine can occur with expired urine strips or delayed urine testing. As mentioned above, blood ketone levels should be the first choice to monitor the treatment. If blood testing is unavailable, urine ketone levels can help make the diagnosis but are of low yield in monitoring response to treatment.[25]

History and Physical

Ill patients with Type-1 DM should be evaluated for DKA, which can coexist with or be triggered by other acute illnesses (infection, trauma, etc.). There may be a history of polydipsia, polyuria, polyphagia (early), anorexia (late), weight loss, fatigue, or recurrent infection. Patients and parents may also report poor school performance, lack of concentration, altered mental status, and confusion as well.

Commonly new-onset type 1 diabetic children appear thin and dehydrated on examination. Dehydration, thirst, and polyuria are common at the time of presentation due to glucosuria and osmotic diuresis.

Abdominal tenderness, abdominal pain, nausea, and vomiting are also common; some children in the first DKA episode may be misdiagnosed with viral gastroenteritis.

Patients with metabolic acidosis classically display rapid, deep breathing (Kussmaul respirations). The breath may have a fruity odor due to respiratory acetone elimination.

Neurologic findings range from alert, to lethargic and drowsy, to comatose correlated with the extent of acidosis.[26]

Evaluation

DKA is definitively diagnosed by serology showing metabolic acidosis and hyperglycemia. Ketone testing can be helpful but is not necessary.

Several point-of-care and laboratory tests aid in the diagnosis of DKA.[27] These include:

• Anion gap: The anion gap is calculated as follows: (Na+K)-(Cl+HCO3). Ketoacids (primarily BHB) are unmeasured ions, leading to the “gap” in anions. The AG is normally between 6 mEq/L to 12 mEq/L, with levels above 15 typically present in DKA.[28][29][30]
• Blood glucose: It is usually above 200 mg/dL (11 mmol/l) and may be above 1000 mg/dL. Pediatric patients have DKA with relatively mild elevations in blood glucose. 
• Serum BHB concentration: BHB is usually above 31 mg/dL in these patients.[31]
• Blood urea nitrogen (BUN) and creatinine
• Serum electrolytes
• Venous pH and partial pressure of carbon dioxide (pCO2): A pH below 7.2 portends a worse prognosis and often indicates the need for intensive care unit admission.
• Urinary ketone: Nitroprusside test strip reacts with acetoacetate and acetone but not BHB. Though less accurate and precise, many health centers use urine test strips for diagnosis. 
• Blood lactate concentration: The presence of lactate can help rule out lactic acidosis. It is also an important prognostic marker in the presence of sepsis, which may be a precipitating cause in many DKA patients.
• Hemoglobin A1c (HbA1c): This is helpful in patients with known diabetes to evaluate the degree of glucose control.
• Diabetes-associated antibodies: Glutamic acid decarboxylase antibodies, insulin autoantibodies, islet cell antibodies, and zinc transporter 8 antibodies are not useful for managing DKA. However, their presence confirms the diagnosis of type 1 diabetes mellitus in 80 to 85% of new patients.[32]
• C-peptide levels: It is a useful marker of beta-cell function, allowing discrimination between insulin-sufficient and insulin-deficient individuals with diabetes. A value of less than 0.2 nmol/l is associated with a diagnosis of type 1 diabetes mellitus (T1DM).

DKA can be categorized as mild, moderate, and severe based on the following criteria:

Table 1. The severity of diabetic ketoacidosis in children

Higher thresholds for bicarbonate may be used for vulnerable patients such as those in resource-limited settings or in young children, e.g., bicarbonate <7 mEq/L for severe DKA and <18 mEq/L for mild DKA.

Treatment / Management

Treatment for DKA begins with ABCs and fluid resuscitation. Insulin therapy, usually by continuous infusion, can begin once the patient is stabilized.[1][33][34][35]

1. General resuscitation: Provide 100% oxygen and consider intubation if needed. Insert a nasogastric tube and urinary catheter for comatose patients. Reliable intravenous (IV) access (preferably two large-bore accesses) should be obtained, one for insulin treatment and the other for blood samples and other medications.
2. Clinical assessment: Identify any signs of infection or other precipitating causes and treat as indicated.
3. Precise patient weight is necessary for calculating insulin and other medication dosing.
4. Insulin Therapy: Regular Insulin should be administered with a continuous drip at a rate of 0.1 unit/kg/hour.[27] Subcutaneous insulin may be used in case of milder diabetic ketoacidosis or when IV infusion pumps are unavailable. Dextrose should be added to the IV fluid infusion when serum glucose concentration decreases to 250 mg/dL.[27] Higher concentrations of dextrose may be used, for example, 10 to 12.5%, when the blood glucose level falls below 150 mg/dL. This allows for complete resolution of ketoacidosis with continued insulin infusion. Ideally, the insulin infusion rate is reduced only after ketoacidosis is corrected or nearly corrected. However, in malnourished patients with increased sensitivity to insulin, insulin infusion rates may be decreased to avoid hypoglycemia. There is no role for insulin bolus in pediatric DKA patients – this is thought to increase the risk of cerebral edema. Consider waiting to initiate insulin infusion until after serum potassium is known, thus preventing critical worsening of hypokalemia.
5. The insulin infusion is stopped when the following targets are achieved:
   1. The patient can take orally administered medications
   2. Blood glucose less than 200 mg/dL
   3. Serum anion gap closed or BHB less than or equal to 10.4 mg/dL
   4. Venous pH >7.3 or serum bicarbonate >15 mEq/L
6. IV Fluids:  Treats dehydration and also hyperglycemia.
   1. Initial IV fluid bolus of 10 mL/kg of normal saline or lactated ringers.
   2. If the patient presents with shock, a second 10 mL/kg IV fluid bolus may be given.
7. As mentioned above, hyperglycemia contributes to pseudohyponatremia. Therefore sodium should be continuously monitored, and higher concentrations of sodium should be used in IV fluids if sodium levels do not improve or continue to fall with treatment.[36]
8. Potassium replacement should depend on close observation and interpretation of lab values. If the initial potassium level reveals hyperkalemia, potassium replacement should be held until potassium normalizes, urinary voiding is confirmed to be intact, and there is normal renal function.  Normal initial potassium in an acidotic patient could indicate severely low total body potassium. Patients with normal or low serum potassium require replacement after ruling out renal dysfunction. DKA patients with hypokalemia should have delayed initial insulin infusion; potassium replacement should precede insulin dosing as above.[27] The serum potassium concentration and electrocardiogram can be used for monitoring as needed.
9. Ketoacidosis is resolved when the anion gap is normal, serum BHB is ≤10.4 mg/dL, and venous pH is ≥7.3. It is achieved through decreased hepatic production of ketones, enhanced metabolism by insulin, and increased removal by improved rehydration.[27][37]
10. Lactic acidosis is also corrected with improved rehydration.
11. Bicarbonate therapy is generally avoided in children with DKA except in peri-arrest or cardiac arrest patients, life-threatening hyperkalemia, or severe acidosis (pH <6.9 with symptoms).
12. High-level nursing and frequent clinical assessments are necessary; biochemical blood markers every two hours.
13. Once acidosis is resolved, the anion gap has closed, and the patient is improving clinically, then diet can be reintroduced, and insulin can be switched to subcutaneous injection. Long-acting/baseline insulin should be administered prior to discontinuation of the infusion.
14. Prevention: Determine the cause of the acute DKA episode and work closely with the child and caregivers on a regime.

Differential Diagnosis

• Gastroenteritis
• Hyperosmolar hyperglycemic nonketotic syndrome
• Starvation ketosis
• Myocardial infarction
• Pancreatitis
• Alcoholic ketoacidosis
• Lactic acidosis
• Sepsis
• Toxicologic exposure (ethylene glycol, methanol, paraldehyde, salicylate)
• Diabetic medication overdose
• Uremia
• Respiratory acidosis
• Respiratory distress syndrome

Prognosis

Prognosis improves with advances in medical and intensive care. Mortality rates range from 0.15 to 0.31% in the United States and other resource-developed countries like Canada and United Kingdom.[38] The majority of deaths result from cerebral injury.[39] Mortality rates or higher and resource-limited settings.

Complications

The most feared complication of pediatric DKA is cerebral injury/cerebral edema:

1. Develops in 0.3%-0.9% of pediatric DKA cases. [38]
2. Mortality ranges from 21-24%[38][40][41][40][38]
3. Risk factors:  Severe acidosis, severe dehydration, elevated blood pressure, markedly elevated BUN[39]
4. Etiology:  Unclear, however initially thought to be to due rapid IV fluid replacement but this is now controversial as a recent PECARN study in 2018 showed no difference in neurological outcomes.[42]
5. Presents at any time before, during, or after treatment, but typically onset is within 12 hours of treatment.[39]
6. Signs/Symptoms:  Altered mental status, new headache, recurrent vomiting, urinary incontinence, Cushing Triad (bradycardia, irregular respirations, hypertension)
7. Cerebral Edema may not initially be seen on CT imaging of the brain, therefore may still require starting treatment even if the CT head is normal.[43]
8. Treat if high suspicion:
   1. Mannitol (0.5-1 g/kg IV over 15 minutes): Osmotic diuretic causing withdrawing water from the brain parencyma. May give a second dose if there is no initial response.
   2. Hypertonic (3%) saline 2.5 mL/kg over 30 minutes
9. Neurosurgical consultation

Other Complications include:

• Cognitive impairment
• Venous thrombosis[44]
• Pancreatic enzyme elevations
• Acute kidney injury[45]
• Hypokalemia
• Hypoglycemia
• Rhabdomyolysis
• Pulmonary edema
• Multiple organ dysfunction syndrome
• Cardiac arrhythmias

Deterrence and Patient Education

Education on the disease process of diabetes, including short and long-term complications, should be given to all patients. Parents and children should be taught how and when to check glucose. They should receive education about how to use oral hypoglycemic meds and/or insulin, medication, side effects, and the importance of compliance. Dietitians, nurses, and multi-disciplinary home health can be essential team members in assisting with this education.

Pearls and Other Issues

Recurrent DKA is a particular problem in adolescents and may be fatal. Early help is advised as soon as the DKA diagnosis is made.

It may be precipitated by:

1. Poor compliance or understanding of insulin therapy
2. Infections
3. Alcohol and substance use disorders
4. Psychological stress and lifestyle changes
5. Psychiatric disorders

Enhancing Healthcare Team Outcomes

Pediatric diabetic ketoacidosis is a life-threatening disorder best managed by an interprofessional team that includes an emergency department clinician, endocrinologist, pediatrician, intensivist, critical care nursing staff, and pharmacists. These individuals are best managed in the ICU and monitored by nurses. Providers should investigate the cause of DKA while providing initial hydration and correction of acidosis. Primary caregivers, pharmacists, and diabetes educators must work together to ensure that the patient is compliant with insulin therapy and monitoring. Nurses can provide dosing for inpatients and can counsel all patients. Pharmacists will verify dosing and monitor potential drug interactions, providing counsel to patient parents. All interprofessional team members are responsible for documenting their observations, interactions, and interventions and informing other team members regarding the case, so additional interventions can be instituted if necessary. Interprofessional care is the best methodology for patient management in pediatric diabetic ketoacidosis. [Level 5]

Any interprofessional team member who detects a change in status should immediately document their findings in the patient's medical record and notify other team members so corrective action can be taken to ensure optimal outcomes in this potentially very ill patient population.[46][28][47]