Diabetic Ketoacidosis

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4 Diabetic Ketoacidosis

Jennifer A. Danzig, Mirna M. Farah

Diabetes is a chronic disease defined by hyperglycemia caused by insulin deficiency. (Chapter 71 provides a detailed discussion of diabetes mellitus.). This may be the result of a lack of insulin production, as in type 1 diabetes mellitus (T1DM) or the body’s ineffective use of the insulin it produces, as in type 2 diabetes mellitus. The most common form of diabetes in children is T1DM.

The World Health Organization and International Diabetes Foundation have established the diagnosis of diabetes as meeting any of the following criteria: (1) fasting (≥8 hours) plasma glucose above 126 mg/dL; (2) plasma glucose above 200 mg/dL 2 hours after a glucose load as given by an oral glucose tolerance test; (3) any random plasma glucose above 200 mg/dL along with the presence of symptoms of diabetes, including increased thirst and urination or unexplained weight loss, or (4) a hemoglobin A1C ≥6.5%.

Diabetes is one of the most common chronic diseases in the United States. Approximately 8.0% of the U.S. population meets criteria for diabetes. It is estimated that about 150,000 people in the United States younger than 20 years of age have diabetes; about one in every 500 children and adolescents has T1DM. There is a bimodal distribution of age at onset, with a peak age at presentation around age 5 years and another at early puberty.

This chapter focuses on the care of acutely ill children with T1DM presenting with diabetic ketoacidosis (DKA), a complication of T1DM in which hyperglycemia, dehydration, electrolyte derangement, ketonemia, and acidemia result from absolute insulin deficiency. DKA can be the presenting manifestation of T1DM in up to 25% of children; it is also seen in children with known T1DM secondary to failure of or noncompliance with insulin therapy.

Etiology and Pathogenesis

T1DM is the result of an inflammatory process within the pancreas. It is thought that children inherit a susceptibility to the disease through specific genes. There is then a triggering event, such as a viral infection, that is either directly toxic to pancreatic β-cells or triggers a widespread generalized immune response. Affected individuals tend to become symptomatic when 90% of β-cell mass is destroyed and carbohydrate intolerance occurs.

DKA is a result of insulin deficiency. Insulin is a hormone that responds to an increase in serum glucose via receptor-mediated utilization. This includes stimulation of glucose uptake from the blood by peripheral tissues; glycogen synthesis in the liver; and inhibition of processes that increase serum glucose, such as gluconeogenesis and glycogenolysis (Figure 4-1). In the absence of insulin, blood glucose levels increase. There is inability to store glucose that is absorbed through the gut, and because of the absence of insulin’s suppression of these pathways, production of new glucose via gluconeogenesis continues. This process is perpetuated by increased production of hormones that increase blood glucose, including glucagon, cortisol, and catecholamines. As blood glucose increases, osmotic diuresis occurs, resulting in urinary losses of electrolytes. Because the body cannot use the glucose that has been supplied, it responds as if in the fasting state. Fat is then broken down into free fatty acids to be used as fuel. Free fatty acids are converted to ketoacids, including β-hydroxybutyrate and acetoacetate, leading to metabolic acidosis (Figure 4-2).

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Figure 4-1 Insulin action.

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Figure 4-2 Ketoacidosis.

The presenting signs and symptoms of DKA reflect this progression. Initially, hyperglycemia and hyperosmolarity cause osmotic diuresis leading to polyuria and compensatory polydipsia. Progressive insulin deficiency leads to catabolism of protein and fat stores, resulting in weight loss and fatigue. As production of counterregulatory hormones increases, ketosis worsens, leading to acute symptoms of nausea, vomiting, and abdominal pain. Progressive dehydration can lead to lethargy and confusion. Ongoing metabolic acidosis stimulates respiratory compensation via hyperpnea, leading to deep, sighing breaths known as Kussmaul respirations.

Clinical Presentation

Patients with DKA typically present with acute symptoms of nausea and vomiting. In patients presenting with T1DM for the first time, there may be a history of polyuria, polydipsia, enuresis, or weight loss. As ketosis progresses, patients may become obtunded and unable to provide a history. Therefore, a glucose measurement should be obtained quickly in any patient who presents with altered mental status. (Hypoglycemia may also be manifested as altered mental status.) Ketosis may also result in presence of a fruity breath, which can help direct the diagnosis. On physical examination, patients generally show signs related to the degree of dehydration from chronic hyperglycemia and osmotic diuresis. This may include tachycardia, presence of dry mucous membranes, and delayed capillary refill. DKA should be suspected in patients with signs of dehydration who maintain a high urine output. Abdominal examination often reveals diffuse tenderness. It is important to document a detailed neurologic examination at presentation because patients who present with normal mental status may have an acute change in status with therapy. DKA leads to physical examination findings affecting many systems (Table 4-1).

Table 4-1 Physical Exam Findings in Diabetic Ketoacidosis

Physical Examination Component Findings Interpretation
General Can range from alert and interactive to obtunded based on the degree of dehydration and acidosis Obtain a glucose measurement immediately on any patient presenting with altered mental status
HEENT Dry mucous membranes, blurred vision, presence of fruity odor to breath Ketosis tends to result in fruity odor to breath
Cardiovascular Tachycardia Indicative of dehydration
Lungs Kussmaul respirations Deep, sighing breaths used as respiratory compensation for metabolic acidosis
Lungs are clear to auscultation, indicating the absence of an underlying lung pathology
Abdomen Diffuse abdominal tenderness Ileus may result from ketosis and can mislead the diagnosis toward an acute abdominal process
Extremities Delayed capillary refill, decreased skin turgor Indicative of dehydration
Intake and output Increased Indicative of thirst and increased fluid intake caused by osmotic diuresis

HEENT, head, ears, eyes, nose, and throat.

Differential Diagnosis

The diagnosis of DKA can be difficult because of the presenting signs and symptoms, which are similar to those of other acute illnesses. The history of polyuria and polydipsia are also signs of urinary tract infection or diabetes insipidus. The weight loss and abdominal pain may be indicative of anorexia or inflammatory bowel disease. Abdominal pain can also be a symptom of appendicitis or other acute surgical problems in the abdomen. Vomiting may be a symptom of gastroenteritis. The presence of hyperpnea may be concerning for pneumonia or an asthma exacerbation. In patients who are obtunded, DKA may be confused with head trauma or central nervous system infection. Laboratory testing can be both misleading and helpful in terms of narrowing the differential diagnosis. Elevation of stress hormones, including epinephrine and cortisol, in DKA may lead to leukocytosis, suggestive of infection. In addition, infection may be a precipitating factor in development of DKA, and patients may manifest with a chief complaint related to the underlying infectious process. The best way to narrow the differential diagnosis is by rapidly obtaining serum glucose, electrolytes, blood pH, and urinalysis. DKA is defined as blood glucose above 240 mg/dL with the presence of ketones in the urine or blood and pH below 7.3.

Evaluation and Management

The management of patients with DKA focuses on correction of the dehydration, electrolyte loss, acidosis, and hyperglycemia. This requires frequent monitoring and admission to the hospital.

Dehydration

Management begins with an initial bolus of isotonic crystalloid fluid (hypotonic fluids should be avoided), usually 10 to 20 mL/kg of normal saline given over 1 hour. Initial fluid therapy is aimed at correcting the cardiovascular compensation for the degree of dehydration. Patients who present in shock may need more rapid fluid resuscitation. However, care must be taken not to administer too much fluid initially because of the risk of potentially fatal cerebral edema (see Complications). In general, the vital signs and clinical status should be reassessed between boluses of 10 mL/kg to avoid fluid overload. The goal is to gradually replace the fluid deficit over 36 to 48 hours.

Electrolyte Loss

DKA results in electrolyte loss, specifically related to sodium, potassium, and phosphate. Sodium deficit at presentation is attributable to hyperosmolarity resulting from hyperglycemia and osmotic shift of water into the intravascular space, resulting in dilutional hyponatremia. Serum sodium is reduced by 1.6 mEq/L for each 100-mg/dL increase in glucose; thus, it is important to calculate the sodium concentration corrected for hyperglycemia with the formula:

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It is important to follow the serum sodium as treatment continues; an increase in sodium does not indicate a worsening of the hypertonic state. In contrast, a failure of the sodium value to increase may indicate overly rapid rehydration and increase the risk for complications, namely cerebral edema. All children with DKA are total body potassium depleted but the initial serum potassium concentration may be low, normal, or elevated. Treatment of hyperglycemia with insulin and acidosis correction will move potassium intracellularly, resulting in hypokalemia. Therefore, except in cases of extreme elevation of serum potassium concentration (e.g., >5mEq/dL) or when patients are anuric, potassium should be added to rehydration fluids regardless of the initial serum potassium concentration. The initial concentration of potassium added to intravenous (IV) fluids should be 40 mmol/L if the initial serum potassium is in the “normal” range. The concentration of potassium should then be adjusted based on frequent reassessments of serum potassium. Generally, half of the potassium is given as potassium chloride, and half is given as potassium phosphate. The phosphate loss in DKA results in reduction in 2,3-diphosphoglycerate, which is important in the affinity of hemoglobin for oxygen. As a result, less oxygen is available to the tissues, resulting in increased anaerobic metabolism, production of lactic acid, and worsening metabolic acidosis. It is important to recognize that phosphate administration may result in hypocalcemia, so serum calcium concentration should be monitored simultaneously. It is recommended to follow electrolyte values every 2 hours during initial treatment for DKA.

Acidosis

In DKA, production of ketoacids and bicarbonate loss results in acidosis. With correction of DKA, there is replacement of intravascular fluids and improvement in peripheral perfusion, which help to improve acidosis. In addition, with the administration of insulin (see below), ketoacids are metabolized to produce bicarbonate and replace bicarbonate losses. The administration of bicarbonate has been shown to worsen cerebral edema and may cause exacerbation of hypokalemia; thus, it is not recommended in the acute management of DKA. If it is believed that bicarbonate is necessary (e.g., in cases of extreme acidosis, i.e., blood pH <7.0), it should be given in small doses and over a slow infusion. Even with pH below 7.0, bicarbonate is not recommended in most cases.

Hyperglycemia

Because DKA results from insulin deficiency, insulin administration is critical to correction. Insulin treatment generally begins after the first hour of therapy, when the fluid bolus is complete. Insulin is generally given as a continuous infusion at a rate of 0.1 U/kg/h. Hyperglycemia will be corrected by insulin faster than the acidosis, and ketosis will resolve. Therefore, as the serum glucose decreases, it is necessary to administer some dextrose along with the insulin infusion until the acidosis resolves and the ketones begin to clear. Generally, addition of dextrose-containing solutions begins when the glucose has reached 300 mg/dL. Some institutions have adopted the use of a “two-bag system” in which fluids of identical electrolyte content and the presence or absence of dextrose are infused simultaneously (i.e., one bag of normal saline without dextrose and one bag with 10% dextrose in normal saline). With this method, the amount of dextrose provided can be gently titrated based on hourly assessment of serum glucose, with the target blood glucose range between 100 and 200 mg/dL. This helps to ensure a gradual decline in serum glucose, with a goal of decreasing by 50 to 100 mg/dL/h.

Monitoring

Patients with DKA should be followed closely to avoid and detect complications. Patients should not be allowed to eat or drink by mouth until the acidosis has resolved. Serum glucose should be tested every hour. Blood pH (via venous blood gas) and electrolytes need to be followed at least every 2 hours until major abnormalities are corrected. Urinalysis is also checked with each void to monitor for clearance of urine ketones. Continuous electrocardiographic monitoring is recommended for patients receiving high concentrations of potassium.

Complications

Cerebral edema is the complication most associated with morbidity and mortality in DKA, occurring in approximately 1% of patients. The cause is not clearly identified, but current hypotheses include cerebral hypoperfusion during DKA treatment and rapid fluid shifts caused by rapid changes in osmolarity. Risk factors at presentation include pH below 7.0, age younger than 3 years, low pCO2, high blood urea nitrogen, treatment with bicarbonate, lack of increase in serum sodium during treatment, corrected serum sodium above 155 mEq/L, and glucose above 1000 mg/dL. The symptoms include headache, new findings on neurologic examination (abnormal response to pain, posturing, cranial nerve palsy), a sudden decline in mental status, and hypertension. Cerebral edema is a clinical diagnosis, and if it is suspected, treatment should begin rapidly with infusion of IV mannitol at 0.25 to 1.0 g/kg, elevation of the head of the bed, and reduction in the rate of IV fluids by one-third. When stabilized, an emergent cranial computed tomography should be performed.

Resolution

When pH and bicarbonate have normalized, ketones have decreased, and the patient feels well enough to begin to maintain hydration by mouth, treatment can be switched to a regimen of subcutaneous insulin. Because the half-life of IV insulin is several minutes, a subcutaneous insulin injection should be given before the insulin infusion is stopped. Management after DKA resolves is discussed in Chapter 71.

When the patient is beyond the acute stage of illness, it is important to determine what caused the patient to develop DKA. Some patients present with diabetes for the first time and have families that are unfamiliar with the signs and symptoms of DKA. For these patients, it important to provide education about diabetes management and to develop a good relationship with an endocrinologist for follow-up. For some patients, acute illnesses can increase the need for insulin that is not met by the current maintenance regimen. In these instances, identification and treatment of the underlying illness is necessary.

In patients with known T1DM, it is important to determine if DKA is the result of noncompliance with the demanding insulin regimen of several injections per day or with failure of insulin pump therapy (see Figure 71-2). Insulin pump therapy is designed to deliver subcutaneous insulin continuously with bolus dosing on demand. In these patients, it is important to emphasize compliance and education with current equipment.

Future Directions

Although efforts to prevent or reverse T1DM have not met good results thus far, there have been significant developments in the management of patients with diabetes. Advances in glucose monitoring and ease of insulin delivery have made living with T1DM easier and less painful than in the past. While awaiting the next development in diabetes management, patients should be empowered to optimize control while living with a chronic disease.

Suggested Readings

American Diabetes Association. Available at http://www.diabetes.org

Cooke DW, Plotnick L. Management of diabetic ketoacidosis in children and adolescents. Pediatr Rev. 2008;29:431-436.

Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344:264-269.

Sherry NA, Levitsky LL. Management of diabetic ketoacidosis in children and adolescents. Paediatr Drugs. 2008;10(4):209-215.

Vanelli M, Chiarelli F. Treatment of diabetic ketoacidosis in children and adolescents. Acta Bio Medica. 2003;74:59-68.

Weinzimer SA, Magge S. Type 1 diabetes mellitus in children. In: Moshang TJr, Bell LM, editors. Pediatric Endocrinology: The Requisites in Pediatrics. ed 1. Philadelphia: Elsevier Mosby; 2005:3-18.

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