Endocrinology

1

What are the symptoms of adrenal insufficiency?

• Newborns: Nonspecific findings of vomiting, irritability, and poor weight gain; may progress to cardiovascular shock

• Children: Lethargy, easy fatigability, poor weight gain, and vague abdominal complaints; hyperpigmentation (primary insufficiency); symptoms of hypoglycemia (primary or secondary insufficiency); may also exhibit vascular collapse with intercurrent illness

2

What distinguishes primary and secondary adrenal insufficiency?

• Primary: Abnormality of the adrenal gland, low cortisol concentration accompanied by an elevated adrenocorticotropic hormone (ACTH) level; may also have mineralocorticoid deficiency

• Secondary: Hypothalamic or pituitary dysfunction, low cortisol concentration accompanied by an inappropriately normal or low ACTH level; normal mineralocorticoid production; often associated with multiple pituitary deficiencies

3

What is the differential diagnosis of primary adrenal insufficiency?

• Inherited enzymatic defects: congenital adrenal hyperplasia (multiple enzymatic defects are known), congenital adrenal hypoplasia

• Autoimmune disease: isolated, autoimmune polyendocrinopathy syndrome (APS) types 1 and 2; type 2 is also known as Schmidt syndrome

• Infectious disease: tuberculosis, meningococcemia, disseminated fungal infections

• Trauma: bilateral adrenal hemorrhage (hemorrhage is common, but adrenal insufficiency is rare)

• Adrenal hypoplasia: due to inherited defects in the adrenal ACTH receptors

• Iatrogenic: use of exogenous steroids

4

What is the most common form of congenital adrenal hyperplasia (CAH)?

CAH refers to a group of autosomal recessive disorders that results from various enzymatic defects in the biosynthesis of cortisol. Depending on the enzyme involved, the blockade can result in deficiencies and/or excesses in the other steroid pathways (i.e., mineralocorticoids and androgens). 21-hydroxylase deficiency accounts for more than 90% of cases; the complete (salt-losing, about two-thirds of cases) and partial (simple virilizing) forms occur in about 1 in 12,000 births and have an equal sex distribution. There are substantial differences in prevalence in various racial and ethnic groups. A late-onset or nonclassic attenuated form (mild deficiency) manifests in adolescent girls with hirsutism and menstrual irregularities.

5

In newborns with CAH, why are girls likely to be diagnosed earlier than boys?

The most common forms of CAH result in excess androgen production in the fetus; the effects of prenatal androgen excess on the development of the clitoris and labia majora can be easily identified in the newborn period. In boys, androgen excess does not cause any clearly abnormal appearance of the external genitalia. CAH should always be considered in the differential diagnosis of disorders of external sexual development, particularly in infants with a 46,XX karyotype.

6

How do physiologic, stress, and pharmacologic doses of hydrocortisone differ?

• Physiologic : Careful studies have shown that adrenal glucocorticoid production in the normal individual is about 7 to 8 mg/m ² per 24 hours. Because 50% to 60% of oral hydrocortisone is absorbed, the recommended oral physiologic replacement is about 12 to 15 mg/m ² per 24 hours.

• Stress : On the basis of studies performed before the development of high-quality radioimmunoassays, the consensus opinion was that production of glucocorticoid increased about three fold when individuals were physiologically stressed. Hence, when the term stress dose is used, it generally means that the dose is at least three times above physiologic replacement, that is, 50 to 100 mg/m ² per 24 hours of hydrocortisone.

• Pharmacologic : Glucocorticoids are extensively used in pharmacologic doses for the treatment of various inflammatory processes and in surgery or trauma to reduce or prevent swelling and inflammation. Doses of glucocorticoid higher than 50 mg/m ² per 24 hours of hydrocortisone that are being used to treat these conditions are referred to as pharmacologic doses ; that is, the medication is not being used for adrenal replacement or stress dosing.

7

When does adrenal–pituitary axis suppression occur in prolonged glucocorticoid treatment?

As a general rule, the longer the duration of treatment and the higher the dose of glucocorticoid, the greater the risk for adrenal suppression. If pharmacologic doses of glucocorticoids are used for less than 10 days, there is a relatively low risk for permanent adrenal insufficiency, whereas daily use for more than 30 days carries a high risk for prolonged or, rarely, permanent adrenal suppression. The reason for glucocorticoid treatment must also be considered; that is, a child with severe head trauma may have initially been on treatment with glucocorticoids to reduce brain swelling but is also at significant risk for secondary pituitary deficiencies.

8

A 4-year-old boy presents to your office for recent onset of body odor. On examination, he is noted to have Tanner II pubic hair. What are the causes of early hair and odor?

Premature pubarche is defined by the early onset of pubic hair, axillary hair, or body odor in girls < 8 years and boys < 9 years. The differential includes premature adrenarche (early signs accompanied by rise in adrenal hormone levels such as dehydroepiandrosterone [DHEAS]), precocious puberty (accompanied by testicular enlargement), CAH , adrenal tumor , or exogenous steroid/androgen exposure .

9

What are common symptoms of pheochromocytoma in children?

Pheochromocotyoma is a neuroendocrine tumor arising from the chromaffin cells of the adrenal medulla and/or sympathetic chain that secrete catecholamines. This tumor is rare in children and often associated with familial syndromes such as von Hippel-Lindau, multiple endocrine neoplasia (MEN IIA or IIB), or neurofibromatosis and may be inherited as an autosomal dominant trait. Children often present with sustained hypertension (60% to 90%) versus paroxysmal hypertension in adults. Other signs and symptoms include headache , sweating , pallor , anxiety , and nausea .

10

How is pheochromocytoma diagnosed?

The gold standard is to measure fractionated metanephrine levels in the urine or plasma. Expected levels more consistent with this tumor are at least three to more than four times the upper limit of the normal reference range. Medications that may interfere with testing include labetalol, levodopa, acetaminophen, tricyclic antidepressants, phenoxybenzamine, calcium channel blockers, and some stimulants (such as caffeine). Imaging studies to confirm the presence of pheochromocytoma can include ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), or metaiodobenzylguanidine (MIBG) scan.

11

How does cortisol excess manifest in growth measurements?

In children with exogenous obesity, linear growth is typically enhanced. In children with either endogenous or exogenous hypercortisolism (Cushing syndrome), significant obesity can occur in the absence of adequate height growth.

12

How do the major steroid preparations vary in potency?

See Table 6.1 .

13

What are the causes of hypercalcemia?

Remember the “ H igh 5-I-S ” mnemonic: H ( h yperparathyroidism) plus the five I’s ( i diopathic, i nfantile, i nfection, i nfiltration, and i ngestion) and S ( s keletal disorders).

• Hyperparathyroidism: familial, isolated; syndromic

• Idiopathic: Williams syndrome

• Infantile: subcutaneous fat necrosis; maternal hypoparathyroidism and inadequate transfer of calcium across the placenta

• Infection: tuberculosis

• Infiltrative: cancer (primary bone or metatstatic)

• Ingestion: milk-alkali syndrome (e.g., excessive supplemental calcium and antacids); thiazide diuretics; vitamin A intoxication; vitamin D intoxication

• Skeletal disorders: hypophosphatasia; immobilization; skeletal dysplasias

14

What are the causes of hypoparathyroidism?

Parathyroid hormone (PTH) is a calcium regulatory hormone released by the parathyroid glands that increases serum calcium by increasing the resorption of Ca ^{2 +} from bone and by increasing gastrointestinal and urinary absorption of calcium through the increasing synthesis of calcitriol. Hypoparathyroidism can result from a developmental defect, from destruction by surgery or an autoimmune process, or from a biosynthetic defect in hormone production. The result can be acute or chronic hypocalcemia. An intact PTH level should be obtained in all children presenting with hypocalcemia. The result should be interpreted in light of the calcium level; that is, is the PTH appropriately elevated for the degree of hypocalcemia?

15

In what clinical circumstances should hypoparathyroidism be suspected?

• Manifestations of hypocalcemia (e.g., carpopedal spasm, bronchospasm, tetany, seizures)

• Lenticular cataracts (these can also occur with other causes of long-standing hypocalcemia)

• Changing behaviors, ranging from depression to psychosis

• Mucocutaneous candidiasis (seen in familial form)

• Dry and scaly skin, psoriasis, and patchy alopecia

• Brittle hair and fingernails

• Enamel hypoplasia (if hypocalcemia is present during dental development)

16

What are the main causes of hypocalcemia in children?

• Nutritional: Inadequate intake of vitamin D and, in rare instances, severely inadequate intake of calcium and/or excessive intake of phosphate may cause this condition.

• Renal insufficiency: This may be the result of the following: (1) increased serum phosphorus from a decreased glomerular filtration rate with depressed serum calcium and secondary hyperparathyroidism or (2) decreased activity of renal α-hydroxylase, which converts 25-hydroxyvitamin D into the biologically active form, 1,25-(OH) ₂ D.

• Nephrotic syndrome: With lowered serum albumin, total calcium levels are reduced. Additionally, intestinal absorption of calcium is decreased, urinary losses of cholecalciferol-binding globulin are increased, and urinary losses of calcium are increased with prednisone therapy (standard treatment for minimal-change nephrotic syndrome). In patients with hypoalbuminemia, there will be a decrease in total calcium but no decrease in ionized calcium. The corrected calcium is estimated by adding 0.8 mg/dL to the total calcium for every 1-mg decrease in the serum albumin below 4 mg/dL.

• Hypoparathyroidism: In infants, this may result from a developmental defect during embryogenesis (parathyroid gland aplasia or hypoplasia) and may occur in the context of a syndrome such as DiGeorge syndrome caused by a deletion in chromosome 22q11. In older children, it may occur in the context of autoimmune polyglandular syndrome (type 1) or mitochondrial myopathy syndromes.

• Pseudohypoparathyroidism: This is a group of peripheral resistance syndromes in which resistance to PTH results in elevated PTH levels in the setting of normal renal function and subsequent hypocalcemia due to blunted or absent PTH effect in the setting of high serum concentrations of PTH.

• Disorders of calcium sensor genes: Activating mutations of the calcium-sensing receptor gene (CaSR) result in calcium being sensed as normal at subphysiologic levels and PTH secretion switched off inappropriately causing hypoparathyroidism.

17

What is the most likely diagnosis in a child with hypocalcemia who has abnormally shaped fingers?

Albright hereditary osteodystrophy (AHO) , a type of pseudohypoparathyroidism, is characterized by short stature, obesity, developmental delay, and brachydactyly, specifically a shortening of the fourth and fifth metacarpals ( Fig. 6.1 ).

18

What is the difference between rickets and osteomalacia?

Both are due to impaired bone mineralization from one or more factors: vitamin D deficiency, calcium deficiency, or disorders of phosphate or vitamin D metabolism. Rickets results in problems with mineralization or bone architecture in growing children when growth plates are open . Osteomalacia involves the same bony structures, but after growth plates have fused .

19

A toddler presents with difficult and delayed walking, bowed legs, and widened wrists. What are other clinical and laboratory features of rickets?

Children may also have frontal bossing and palpable swelling of the costochondral junction (rachitic rosary). Radiologic findings include widening of the growth plate and eventual splaying, cupping, and fraying of the metaphyses, which manifests clinically as an expanded wrist margin ( Fig. 6.2 ). Laboratory evaluation will most commonly reveal low phosphorous, low to normal calcium, low to normal 25-hydroxyvitamin D levels, normal to high PTH, and elevated alkaline phosphatase.

20

What are two common factors that make vitamin D deficiency such a common problem?

Changes in sun exposure/use of sunscreen and increases in obesity . Very few foods naturally contain vitamin D or are fortified with vitamin D. Exceptions are cod liver, tuna, fortified milk, and orange juice. The major source of vitamin D has been exposure to natural sunlight. If an individual wears a sunscreen with a protection factor of 30 or more, vitamin synthesis in the skin is reduced by > 95%. If an individual has darker skin, which provides more natural sun protection, he or she requires three to five times longer exposure to make the same amount of vitamin D as a person with a white skin tone. Obesity is also a risk factor, because fat sequesters vitamin D. As sun exposure is reduced because of concerns about potential future malignancies and as obesity rates remain high, vitamin D deficiency is likely to remain a problem.

21

How much vitamin D should children receive on a daily basis?

Consensus guidelines are that children without risk factors should receive the following amounts of vitamin D at a minimum:

• Infants (< 1 year): 400 IU/day

• Children (1 to 18 years): 600 IU/day

All exclusively breastfed infants should receive 400 IU/day of vitamin D supplement because breast milk is low in vitamin D. Some formula-fed infants also require supplementation if their intake is less than approximately 33 ounces of formula daily, which is the quantity needed to receive the recommended amount of vitamin D.

22

What are the cutoffs for vitamin D deficiency and sufficiency?

The American Association of Pediatrics (AAP) classifies vitamin D status in the pediatric population using the following 25(OH)D concentrations: severe deficiency for values < 5 ng/mL; deficiency for values between 5 and 15 ng/mL; insufficiency for values between 16 and 20 ng/mL; sufficiency for values between 21 and 100 ng/mL; excess for values between 101 and 150 ng/mL; intoxication for values > 150 ng/mL.

23

A 9-year-old undergoing chemotherapy (including the use of vincristine) is noted to have decreasing urine output and develops a seizure. What electrolyte abnormality is a highly likely cause of his seizure?

Hyponatremia due to SIADH (syndrome of inappropriate secretion of antidiuretic hormone). Antidiuretic hormone (ADH), also known as vasopressin , is released from the posterior pituitary gland and serves as a regulator of extracellular fluid volume. The secretion of ADH is regulated by changes in osmolality sensed by the hypothalamus and alterations in blood volume detected by carotid and left atrial stretch receptors. By definition, the secretion of ADH in SIADH is inappropriate ; therefore the person cannot be given this diagnosis if dehydrated. Medications (including chemotherapeutic agents such as vincristine and cyclophosphamide) can directly promote ADH release and enhance its renal effects. SIADH is usually asymptomatic until symptoms of water intoxication and hyponatremia develop. In this case, a seizure developed. Other symptoms of hyponatremia include nausea, vomiting, irritability, personality changes, and progressive obtundation. An individual with hyponatremia that has developed over a prolonged period is less likely to have symptoms than one in whom the hyponatremia has developed acutely.

24

What are other causes of SIADH?

• Intracranial pathology (increases ADH secretion directly by local central nervous system [CNS] effects): brain tumors, meningitis, encephalitis, stroke, Guillain-Barré syndrome

• Intrathoracic pathology (direct stimulation of volume receptors): respiratory failure, pneumonia, tuberculosis, tumors

• Medications (either by direct induction of ADH release, by increased sensitivity of vasopressin receptors, by direct agonistic stimulation of renal vasopressin receptor): chlorpropamide, phenothiazine, ifosfamide, carbamazepine, valproic acid, selective serotonin reuptake inhibitors (SSRIs), MDMA (ecstasy)

25

What are the five criteria for the diagnosis of SIADH?

• 1.

  Hyponatremia with reduced serum osmolality

• 2.

  Urine osmolality elevated compared with serum osmolality (a urine osmolality < 100 mOsm/dL usually excludes the diagnosis)

• 3.

  Urinary sodium concentration excessive for the extent of hyponatremia (usually > 20 mEq/L)

• 4.

  Normal renal, adrenal, and thyroid function

• 5.

  Absence of volume depletion

26

What is cerebral salt wasting (CSW), and how is it separated from SIADH?

CSW is defined as excessive urinary sodium losses in individuals with intracranial disease that result in hyponatremia and dehydration. The mechanism is still not clear. CSW typically develops in the first week after brain injury and generally resolves over time. Both CSW and SIADH are associated with hyponatremia. However, individuals with CSW have signs of intravascular volume depletion (e.g., rapid pulse, low blood pressure), whereas children with SIADH have evidence of intravascular volume overload. In SIADH, fluid restriction often leads to an increase in the serum sodium. In contrast, fluid restriction in CSW will not increase serum sodium but will further impair intravascular volume; therefore it can be dangerous and may result in cardiovascular compromise.

27

What clinical features suggest diabetes insipidus (DI)?

Because DI is caused by an insufficiency of ADH or the inability to respond to ADH, the signs and symptoms tend to be directly related to excessive fluid loss. The clinical spectrum may vary depending on the child’s age. The infant may present with symptoms of failure to thrive as a result of chronic dehydration, or there may be a history of repeated episodes of hospitalizations for dehydration. There may also be a history of intermittent low-grade fever.

Often, caretakers report a large volume of intake or an inability to keep a dry diaper on the infant. The higher absorbency of disposable diapers may delay the diagnosis in infants. In the young child, DI may appear as difficulty with toilet training. In the older child, the reappearance of enuresis, increasing frequency of urination, nocturia, or dramatic increases in fluid intake may be noted. Frequent urination with large urinary volumes should lead to the suspicion of DI.

28

How is the diagnosis of DI made?

Deprivation of water intake for a limited time and judicious monitoring of physical and biochemical parameters may be required. The diagnosis of DI rests on the demonstration of the following: (1) an inappropriately dilute urine in the face of a rising or elevated serum osmolality; (2) urine output that remains high despite the lack of oral input; and (3) changes in physical parameters that are consistent with dehydration (weight loss, tachycardia, loss of skin turgor, dry mucous membranes). A child who, with water deprivation, appropriately concentrates urine (> 800 mOsm/L) and whose serum osmolality remains constant (< 290 mOsm/L) is unlikely to have DI. When DI is considered, a pediatric endocrinology consultation is strongly recommended.

If a child meets the criteria for the diagnosis of DI, the water-deprivation test is usually ended with the administration of some form of ADH, such as desmopressin, and the provision of fluids. If the urine subsequently becomes appropriately concentrated, this confirms the diagnosis of ADH deficiency (central DI). Failure to concentrate suggests renal resistance to ADH (nephrogenic DI). DI may often be the first clinical sign of tumor of the hypothalamus or base of the skull (e.g., Wegener granulomatosis, histiocytosis). Brain MRI is recommended if a diagnosis of DI is confirmed.

29

What is the pathogenesis of type 1 diabetes mellitus (T1DM)?

T1DM is an autoimmune disease characterized by the destruction of the beta cells in the pancreas. T1DM is a combination of a genetic risk, most strongly associated with genes located in the major histocompatibility complex region on chromosome 6, and a triggering environmental factor that has yet to be elucidated. Mostly newly diagnosed patients do not have a first-degree relative with T1DM; however, a sibling or parent with TIDM increases the risk compared with the general population.

30

What are the clinical presentations of T1DM?

T1DM can present with classic symptoms of polyuria , polydipsia (increased thirst), polyphagia (increased hunger), and weight loss . There may be additional findings of fatigue, irritability, sore throat, blurry vision, and nocturia. These symptoms may be present for weeks or months before medical attention is sought. New-onset T1DM can also be found incidentally at a well-child checkup. About one-quarter of cases will present with diabetic ketoacidosis (DKA), in which nausea, vomiting, and acidosis have developed. In the most severe cases, there will be altered mental status and Kussmaul respirations (deep and labored breathing). It is important to be vigilant for the symptoms, especially in younger children, in whom polyuria/nocturia is easy to miss if a child is still in diapers.

31

What is the basis of treatment for T1DM?

Care needs to be tailored to the age of the child. The goal is to keep the blood sugar predominantly in the normal range of 80 to 180 mg/dL without excessively low or high blood sugars, both of which are detrimental to the developing child and increase the risk for diabetes complications. The basis of treatment is the basal bolus insulin regimen, with a once-daily basal insulin and bolus doses given before meals based on the amount of carbohydrate consumed and the blood sugar. This allows for safety and flexibility in dosing. Patients with type 1 diabetes are best served in a diabetes center with a team approach, including physicians, diabetes educators, nutritionists, social workers, and, if possible, mental health services.

32

What is DKA?

DKA is a state of severe metabolic derangement that results from both severe insulin deficiency and increased amounts of counterregulatory hormones (catecholamines, glucagon, cortisol, and growth hormone). The main features are hyperglycemia (glucose > 200 mg/dL), ketone production, and acidosis (venous pH < 7.30 or serum HCO ₃ < 15 mEq/L). Patients are generally dehydrated, 5% to 15%, at presentation.

33

What are the mainstays of therapy for DKA?

• Adequate initial supportive care (airway maintenance if necessary, supplemental oxygen as needed)

• Volume resuscitation (which should begin before starting insulin therapy)

• Insulin administration (initial dose of 0.05 to 0.1 unit/kg/hr)

• Frequent monitoring of vital signs, electrolytes, glucose, acid–base status, and mental status

34

What should be the initial fluid management in DKA?

The association of the rate of sodium and fluid administration in DKA and the development of cerebral edema remains controversial. The concern is that falling osmolarity might contribute to cerebral edema. The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends the following:

Initial:

• In the rare patient who presents in shock , circulatory volume should be rapidly restored with isotonic saline (or lactated Ringer solution) in 20-mL/kg boluses with reassessment after each bolus.

• In patients who are severely volume depleted but not in shock, the initial volume is typically 10 mL/kg given over 1 to 2 hours.

Subsequent:

• Once a patient is hemodynamically stable, fluid replacement is given more slowly. Replacement of the remainder of the fluid deficit (after subtracting the volume of the boluses that were received) is given over the next 48 hours at a rate not to exceed 1.5 to 2 times the maintenance rate. Generally, DKA is associated with an initial weight loss of 7% to 10%.

• Choice of fluid tonicity should be made based on each patient’s clinical status (degree of hyperosmolarity, CNS status, serum sodium trend, etc.). ISPAD guidelines state that “no treatment strategy can be definitively recommended as being superior to another based on evidence.”

In a 2018 randomized, controlled study involving 13 centers, no difference was found in neurologic outcome of children with DKA with the rate of intravenous (IV) fluid administration or the sodium chloride content (0.9% or 0.45%) of the fluid.

35

Why is a falling serum sodium concentration during the treatment of DKA a concern?

Most patients with DKA have a significant sodium deficit of 8 to 10 mEq/kg, which needs to be replaced. After initial fluid boluses, fluids containing 0.5% normal saline or greater are generally required. As a general rule, the serum sodium concentration is low at the outset and rises throughout the course of treatment. An initial sodium concentration of more than 145 mEq/L suggests severe dehydration or hyperosmolarity.

The “corrected” serum sodium should be followed throughout treatment. This value can be calculated using the following equation: Corrected sodium = Measured sodium (mEq/L) + 0.016 × [serum glucose (mg/dL) - 100]. A corrected serum sodium that begins to fall with treatment merits prompt attention because it indicates either inappropriate fluid management or the onset of SIADH and can signal impending cerebral edema.

36

What is the typical potassium status in children with DKA?

In almost all children with DKA, there is a depletion of intracellular potassium and a substantial total body potassium deficit of 3 to 6 mmol/kg, although the initial measured serum potassium value may be normal or high, in large part because of acidosis. Replacement therapy will be needed. If the patient is hypokalemic, potassium should be given with the initial volume expansion and before insulin administration. Insulin administration results in potassium transport into cells with a further decrease in serum levels. If the initial potassium level is within a normal range, potassium replacement should be initiated (with the concentration in the infusate at 40 mEq/L) after the initial volume expansion and concurrent with starting insulin therapy, provided that urine output can be documented. If the initial potassium measurement is significantly elevated, potassium replacement should be deferred until urine output has been documented and the hyperkalemia abates. Of note, if rapid serum potassium levels are not available, an electrocardiogram (ECG) to look for changes of hypokalemia or hyperkalemia (e.g., T-wave changes) can be valuable in guiding management.

37

Are there any indications for the use of bicarbonate?

Bicarbonate administration for acidosis in DKA has not been shown to be beneficial in controlled trials. The establishment of an adequate intravascular volume and the provision of sufficient quantities of insulin are far more important in the treatment of DKA than bicarbonate. The decision to initiate bicarbonate therapy should be based on an arterial blood gas level and not a venous blood gas level. Two possible indications include the following:

• Profound metabolic acidosis (arterial pH < 6.9), which may be compromising cardiac contractility and/or adversely affecting the action of epinephrine during resuscitation

• Life-threatening hyperkalemia with bradycardia and severe muscle weakness

38

When should glucose be added to the IV fluids in patients with DKA?

This will depend on the rate at which the serum glucose level is decreasing. Generally, when the glucose level approaches 300 mg/dL, glucose should be added to the IV fluid. It is usually wise to order the appropriate glucose-containing fluid in advance to avoid hypoglycemia. Many centers now use the “two-bag” method: they order two bags of IV fluid, with identical electrolyte content except for the glucose concentration. One contains 10% or 12.5% glucose, and the other contains no glucose. As the blood sugar approaches 300 mg/dL, glucose is added to the infusate through a Y tube. With the two-bag system, it is possible to alter the concentration of glucose anywhere between 0% and 12.5%, with a goal of maintaining the blood sugar in the 100- to 200-mg/dL range, thereby avoiding hypoglycemia. It is important to note that if the blood glucose concentration decreases too quickly or is too low before the resolution of acidosis, it is preferable to increase glucose levels by adding glucose to the infusate rather than decreasing the rate of insulin infusion.

39

Describe the use of insulin in the management of DKA

Hydration should run for 1 to 2 hours before beginning the insulin drip. Continuous IV insulin infusion should be run at 0.1 u/kg/hr. In small children it can be initiated at 0.05 u/kg/hr. The goal is to drop the glucose at about 50 to 100 mg/dL/hr. There is NO indication for insulin boluses at the start of therapy. It is essential to not stop the insulin infusion, as this will only delay the resolution of the acidosis. If needed, more dextrose can be added to the fluid, or the rate of the insulin infusion can be lowered.

40

What is the main cause of mortality in DKA?

Cerebral edema . Clinically apparent cerebral edema is rare (occurs in 0.5% to 1% of pediatric cases), but it has been associated with a mortality rate of up to 25% and neurologic impairment in 15% to 30% of cases. Cerebral edema is a clinical diagnosis, not a radiologic one. There can be clinical signs in the absence of radiologic findings, and treatment should never be delayed to obtain a CT.

41

What risk factors are associated with the development of cerebral edema?

The pathogenesis of cerebral edema is incompletely understood. There are likely vasogenic and cytotoxic mechanisms at play. CT studies have demonstrated that subclinical cerebral edema may occur in a majority of pediatric patients with DKA. The escalation to life-threatening cerebral edema is unpredictable, often occurring as biochemical abnormalities are improving. It may be sudden in onset or occur gradually, but it typically occurs during the first 5 to 15 hours after therapy begins. It can, however, also occur before treatment. Risk factors identified include the following:

• Younger age

• Newly diagnosed patients

• More profound acidosis

• Attenuated rise in serum sodium during therapy

• Greater hypocapnia (after correcting for acidosis)

• Increased blood urea nitrogen (BUN)

• Bicarbonate therapy for acidosis

• Administration of insulin in first hour of fluid treatment

• Higher volumes of fluid given during the first 4 hours

42

What signs and symptoms suggest worsening cerebral edema during the treatment of DKA?

• Headache

• Recurrent vomiting

• Change in mental status: increased drowsiness, irritability, restlessness

• Change in neurologic status: cranial nerve palsy, abnormal pupillary responses, abnormal posturing

• Incontinence (age inappropriate)

• Rising blood pressure

• Inappropriate heart rate slowing

• Decreased oxygen saturation

43

How is cerebral edema treated?

If clinical symptoms are present, treatment must be initiated rapidly. Mannitol (0.25 to 1.0 g/kg) or hypertonic (3%) saline (5 to 10 mL/kg) over 30 minutes can be used under the guidance of an experienced emergency department (ED) or intensive care unit (ICU) attending physician.