Linking To And Excerpting From StatPearls’ “Pediatric Diabetic Ketoacidosis”

Today, I review, link to, and excerpt from StatPearls‘ Pediatric Diabetic Ketoacidosis. Noha EL-Mohandes; Garrett Yee; Beenish S. Bhutta; Martin R. Huecker. Last Update: August 21, 2023.

All that follows is from the above resource.

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.

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

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