Endocrine and metabolic emergencies in children: hypocalcemia, hypoglycemia, adrenal insufficiency, and metabolic acidosis including diabetic ketoacidosis

1. Definition and etiologies

Any patient with a whole blood glucose concentration less than 50 mg/dL should be undertaken diagnostic and therapeutic procedures1). Transient neonatal hypoglycemia is caused by enzyme immaturity or low substrates amount (prematurity, normal newborn), transient hyperinsulinism and persistent hyperinsulinism (small for gestational age, discordant twin, neonatal asphyxia). Persistent hypoglycemia is caused by hyperinsulinism (abnormal K⁺-ATP channel, abnormal glucokinase, abnormal glutamate dehydrogenase, acquired focal adenomatosis of pancreas islet, Beckwith-Wiedemann syndrome, insulin injection, sulfonylurea), counter-regulatory hormone deficiency (growth hormone [GH] deficiency, adrenocorticotropin hormone [ACTH] deficiency, Addison disease, epinephrine deficiency), glycogenolysis defects (glycogen storage disease 0, 3, 6 ,9), gluconeogenesis defects (GSD 1a, 1b, galactosemia, fructose 1,6 diphosphatase deficiency, pyruvate carboxylase deficiency), lipolysis defect (propranolol) and fatty acid oxidation defects. But the most common cause of childhood hypoglycemia is ketotic hypoglycemia.

2. Pathophysiology

The utilization of glucose in most tissues is regulated by insulin and by the ability of the tissue to use ketones as an alternative energy source in the absence of glucose. Thus, disorders characterized by increased insulin secretion or by a relative inability to synthesize ketones (disorders of fatty acid oxidation) may lead to hypoglycemia caused by increased utilization and absence of ketones in blood and urine (nonketotic hypoglycemia)2).

The approximate glucose utilization rate of premature newborns is 10 mg/kg/min, term newborns 8 mg/kg/min, young children 6-8 mg/kg/min, older children and adolescents 4-6 mg/kg/min, adults 2-4 mg/kg/min. When glucose utilization begins to exceed production, the counterregulatory hormones (cortisol, GH, epinephrine, and glucagon) are secreted to prevent hypoglycemia. These hormones, acting individually or in concert, stimulate glycogenolysis and gluconeogenesis to restore and maintain normal serum glucose concentration. Deficiencies in the secretion of counterregulatory hormones or in the enzymes or substrates involved in either of these 2 processes can result in hypoglycemia, usually accompanied by excessive breakdown of triglycerides (TGs) and the production of ketones in the blood and urine2). The CNS effects of hypoglycemia children beyond the newborn period are headache, irritability, confusion, fatigue, abnormal behavior, amnesia, altered level of consciousness, coma, and seizure. The adrenergic (epinephrine) effects are diaphoresis, cold extremities, tachycardia, pallor, tremor, anxiety, weakness, nausea, vomiting, and chest pain3).

3. Laboratory evaluation of hypoglycemia

Initial sample should be checked for blood glucose, liver function tests, electrolytes, and bicarbonate from comprehensive metabolic profile and included urinalysis for presence or absence of ketones. Archival sample has to be measured serum insulin, ketones, GH, cortisol, c-peptide (for suspected exogenous hyperinsulinism), carnitine profile, amino acids, and toxins (ethanol, salicylates). Urine amino and organic acids and toxin screen are needed.

4. Treatment

Nonspecific therapy after initial and archival samples are obtained should go starting intravenous glucose 0.2 g/kg (10% dextrose 2 mL/kg) quickly1). Ongoing therapy is required 6-8 mg/kg/min glucose infusion rate for maintenance of euglycemia. Occasionally 10-20 mg/kg/min of glucose infusion rate is needed via central venous line. Other nonspecific therapy are glucagon 0.03 mg/kg (subcutaneous or intramuscular injection) or Solu-Cortef 25 to 50 mg/m² or 2 to 3 mg/kg intravenous injection1). Specific therapies of hyperinsulinism are long-acting somatostatin analogue 10 µg/kg every 6 to 12 hour subcutaneous injection and diazoxide 5-15 mg/kg/day (#2) per oral, which may have several side effects.

1. Definition and etiologies

Serum calcium concentration is maintained by dietary intake and absorption from the gut (mediated primarily by "active" vitamin D [1,25 dihydroxyvitamin D3]), and mobilization of calcium from the bone and across the renal tubules as a result of parathyroid hormone (PTH) secretion and action. PTH secretion is magnesium dependent, and its action is dependent on both magnesium and vitamin D. Deficiency in active vitamin D or magnesium, or in other causes of decreased secretion or action of PTH may result in hypocalcemia4). The definition of hypocalcemia in neonate is total serum calcium concentration less than 7.5 mg/dL (ionized <3.8 mg/dL) and in children is below 8.7 mg/dL (ionized <4.6 mg/dL)5).

2. Pathophysiology

The daily calcium requirement of the children and adolescence is 600 to 1,200 mg/day. This is provided primarily in milk, milk products, and certain green vegetables. Vitamins D2 and D3 must be further metabolized sequentially in the liver (25- hydroxylase) and the kidney (1-α hydroxylase) to become their respective fully active derivatives, 1,25-dihydroxyvitamins D2 and D3 , which are necessary to promote maximal absorption of calcium and phosphorus into the blood. The conversion of vitamin D2 or D3 to its active form is stimulated by PTH. Deficiencies of sunlight, milk or milk products, malabsorption of vitamin D, failure to activate vitamin D, or tissue unresponsiveness to vitamin D can predispose the child to hypocalcemia. Because vitamin D is the primary regulator of phosphorus homeostasis, hypocalcemia caused by insufficient vitamin D synthesis or action is usually accompanied by a decreased serum phosphorus concentration67), in contrast to that caused by defects in PTH secretion or action. PTH is secreted by the parathyroid glands in response to hypocalcemia7). PTH mobilizes calcium and phosphorus from the bone. At kidney, calcium is retained, and mobilized phosphorus is actively excreted. Defects in the secretion or action of PTH (pseudohypoparathyroidism) lead to hypocalcemia and a relative inability to excrete phosphorus7). Hypocalcemia caused by one of these defects is accompanied by an increased serum phosphorus concentration. Defects in the calcium-sensing receptors in the parathyroid glands and the kidney may also result in abnormalities in the serum concentration of calcium5).

3. History and physical examination

Children who may be prone to hypocalcemia include those whose dietary problems predispose to vitamin D deficiency, premature infants (inadequate vitamin D storage), congenital heart defects (Di George syndrome), and hypoparathyroidism (autoimmune or removal of the parathyroid glands after surgery for thyroid carcinoma), pseudohypoparathyroidism, or chronic renal disease8). Signs of hypocalcemia include lethargy, poor feeding and vomiting in infants, jitteriness, irritability, muscle spasm, laryngeal stridor, and tetany. Generalized seizures are common, so hypocalcemia should be ruled out in any child with an unexplained seizure5). Carpopedal spasm is typical sign of hypocalcemia and facial muscle hyperirritability (Chvostek sign) may be elicited by tapping on the maxilla. Trousseau sign may be elicited in hypocalcemic patients by inflating a sphygmomanometer to 20 mmHg above the systolic blood pressure.

4. Laboratory evaluation

The initial blood sample should be used to determine the total serum calcium, phosphorus, magnesium, sodium, potassium, and alkaline phosphatase levels. Hypocalcemia caused by disorders of vitamin D is usually characterized by decreased serum calcium and phosphorus levels with an elevated alkaline phosphatase level, whereas hypocalcemia caused by disorders of PTH secretion or action is accompanied by decreased serum calcium and alkaline phosphatase levels but increased serum phosphorus level6). Archival blood sample should be sent for measurement of PTH and vitamin D metabolites. An archival urine sample may be sent for measurement of calcium and creatinine, to rule out a rare form of hypocalcemia termed "familial hypercalciuric hypocalcemia". The urinary calcium excretion (urinary calcium-creatinine ratio) is increased, in contrast to all other causes of hypocalcemia. Electrocardiography may be seen prolonged QT interval. If severe vitamin D deficient rickets may be evident, characteristic radiologic images show bowed appearance of the legs along with flaring at the wrists and knees7).

5. Treatment

Acute treatment consists of the intravenous (IV) administration of a dilute calcium solution, usually 10% calcium gluconate or lactate, 2 mL/kg (20 mg/kg) every 6 to 8 hours with cardiac monitoring and careful watching for extravasation of drug. Maintenance management usually consists of 50-75 mg/kg of elemental calcium daily as calcium carbonate or calcium lactate57). Pharmacologic doses of vitamin D3 for rickets are 150,000-600,000 U once intramuscular injection for severe vitamin D deficient rickets or 2,000-10,000 U/day (50-250 µg/day) per oral during 4-6 weeks5). 1,25-dihydroxyvitamin D3 20-60 ng/kg/day is required in the treatment of hypoparathyroidism and pseudohypoparathyroidism5). Magnesium deficiency of any etiology should be corrected before long-term treatment of hypocalcemia is undertaken, since it may be the primary defect, and the success of treatment of hypocalcemia is limited in cases of coexisting hypomagnesemia8). Treatment consists of 50% magnesium sulfate 0.1 mL/kg when serum magnesium concentration is below 1.5 mg/dL every 8 to 12 hours59).

1. Etiologies

The congenital causes of primary adrenal insufficiency are congenital adrenal hyperplasia (CAH), autoimmune (Addison disease), adrenocortical hypoplasia congenita (AHC), adrenoleukodystrophy (ALD), Zellweger syndrome and Wolman syndrome. The acquired causes of primary adrenal insufficiency are adrenal hemorrhage, infections of adrenal gland and other infiltrative diseases. The secondary causes are hypothalamic disorders (empty sella syndrome, septo-optic dysplasia, craniopharyngioma, tumor and surgery/radiotherapy, infection), pituitary disorders (infections, congenital anomaly, tumor, and surgery/radiotherapy), and adrenal suppression from high-dose long-term steroid therapy1011). Children receiving pharmacological steroids for treatment of severe asthma, leukemia, organ transplantation or autoimmune diseases and children who are taking physiologic replacement steroids for central or primary hypoadrenalism are prone to adrenal crisis during acute febrile illness particularly vomiting (dehydration)101112). Glucocorticoids administered for more than 10 to 14 days can suppress ACTH release for weeks and render the child susceptible to adrenal crisis131415).

2. Pathophysiology

Hypovolemia and elevated serum potassium concentrations stimulate mineralocorticoid (aldosterone) release from the adrenal gland's zona glomerulosa under the stimulus of the renin-angiotensin II axis. Aldosterone acts on the distal renal tubule to effect sodium and water retention and enhanced hydrogen and potassium excretion into the urine. Thus, aldosterone serves a critical function by maintaining normal levels of total body sodium and water and protecting the body from hyperkalemia, dehydration, and shock1314). A striking feature of mineralocorticoid deficiency at any age, especially in the dehydrated infant, is polyuria. Corticotropin-releasing factor is released from the hypothalamus during times of stress or hypoglycemia and stimulates the release of ACTH from the pituitary gland. ACTH stimulates the adrenal gland's zona fasciculata to secrete the glucocorticoid (hydrocortisone), which is one of the body's major defenses against hypoglycemia and shock14). Adrenal insufficiency results in a relative inability to maintain electrolyte balance, plasma volume, blood pressure, and blood glucose during times of stress, and may have a fatal outcome15).

3. History and physical examination

The patients with adrenal insufficiency have weakness, anorexia, vomiting, weight loss, salt craving, and hyperpigmentation. They have tachycardia and hypotension and other signs of shock, which are pallor, poor peripheral perfusion, cold clammy skin, disturbed consciousness or even coma12). With dehydration, there may be decreased skin turgor, sunken eyes, and dry mucous membranes. Hyperpigmentation of gums, areolae, flexion creases reflects excessive secretion of ACTH. Ambiguous genitalia in girls with virilizing CAH may be present14).

4. Laboratory evaluation

The results of comprehensive metabolic profile from initial sample will show hyponatremia, metabolic acidosis (normal anion gap, increased serum chloride), hypoglycemia, and hypernatremia. If this pattern is found, blood should be drawn for level of plasma renin activity. The archival sample will be sent for serum cortisol and ACTH so that primary hypoadrenalism (decreased cortisol with elevated ACTH) may be differentiated from central causes (decreased cortisol without elevated ACTH). Neonates or infants suspected of having CAH, serum should be measured 17-hydroxyprogesterone or a complete adrenal metabolic profile, so that the specific enzymatic block may be identified14). If hypopituitarism is suspected free T4 and GH should be determined11).

5. Treatment

Acute treatment of adrenal crisis is for rapid restoration of tissue perfusion. After an IV line is secured, a 20 mL/kg bolus of normal saline (5% dextrose/0.9% NaCl) is given over a period of an hour. If significant hypoglycemia is present, a glucose of bolus 0.2 g/kg (2 mL/kg of 10% dextrose) is given to restore euglycemia. Stress doses of glucocorticoid, Solu-Cortef should be loading (25-50 mg/m² or 2-3 mg/kg). Hydrocortisone has a desirable mineralocorticoid effect as well as its glucocorticoid effect (20-35 mg Solu-Cortef has the mineralocorticoid effect of 0.1-mg fludrocortisone [Florinef]), whereas methylprednisolone (Solu-Medrol) and dexamethasone have only a glucocorticoid effect and are not suitable therapies in this case13).

Ongoing IV steroid therapy consists of Solu-Cortef given as a total daily dose of 25-50 mg/m² or 2-3 mg/kg in divided doses every 6 hours. Hyperkalemia higher than 6 mEq/L can induce fatal cardiac arrythmias and requires aggressive therapy with sodium bicarbonate, 1 to 2 mEq/kg IV over 10 to 15 minutes; calcium gluconate, 50 to 100 mg/kg (maximum dose, 1 g) by slow (5-10 minutes) IV drip; or IV glucose, 500 mg/kg (2 mL/kg 25% glucose solution) plus insulin, 0.1 units/kg. A potassium-binding resin, sodium polystyrene sulfonate (Kayexalate), 1 g/kg rectally or orally, should be given if tolerated13).

1. Etiologies

The metabolic acidosis can be resulting from (1) a loss of base (bicarbonate) from the body, either through the kidneys or the gastrointestinal tract (normal anion gap), or from (2) abnormal accumulation of acid through overproduction (diabetic ketoacidosis [DKA], lactic acidosis, or inborn errors of metabolism), (3) under excretion (type 1 [distal] renal tubular acidosis or chronic renal failure)16), or toxic ingestion (increased anion gap)17).

2. Pathophysiology

Acidosis that ultimately exceeds the body's compensatory buffering mechanisms leads to an increase in extracellular fluid H+ concentration so that the pH of the blood is reduced below 7.35. This state is referred to as "academia", and its presence warrants prompt treatment to prevent severe alterations in extracellular and intracellular pH that might be incompatible with life. To maintain electrical neutrality in the body, the total positively charged ions (cations) must always equal the total negatively charged ions (anions). Normally, Na⁺ accounts for more than 90% of the extracellular cations, whereas Cl^- and HCO₃^- constitute approximately 85% of the anions. The "anion gap" is the calculated difference between the majority of measured cations (Na⁺) and the majority of measured anions (the sum of Cl^- and HCO₃^-)17).

3. History and physical examination

In patients with new or established type 1 DM, there is often a history of recent emotional stress or infection that can be a precipitating factor in the development of DKA. In many cases, no particular precipitating event can be identified. Known metabolic disease in the family is a valuable clue. Symptoms of hypoglycemia during fasting or after specific foods (e.g., fruit [fructose containing]) can be diagnostic of an inborn error of metabolism, history of unusual urine odor. These include persistent vomiting and tachypnea resulting from the body's attempt to compensate for the acidosis by ridding itself of the excess acid through the gastrointestinal tract or lungs. Changes caused by acidosis in the peripheral and central vasculature give rise to warm, flushed skin, abdominal pain, and headache. If the abdominal pain and vomiting in a child with DKA do not resolve as the acidosis is corrected, then an evaluation of the "acute abdomen" should be undertaken. Acidemia and hyperosmolality also result in CNS dysfunction, manifested as altered levels of consciousness progressing to coma, seizures, and even death if they are not treated in a timely manner. In the patient with DKA, variable degrees of dehydration, from mild to severe, may be present and will be manifest as lack of normal skin turgor, sunken eyes, tachycardia, and hypotension. In patient with severe acidosis (pH<7.0), suppression of cardiac and pulmonary function may occur, and ventilatory assistance may be necessary. The patient in DKA may have a characteristic "fruity" odor to the breath because of exhaling the ketone body acetoacetate19).

4. Laboratory tests

A comprehensive metabolic profile in the initial blood sample will reveal the decrease in serum bicarbonate that defines the acidosis. The electrolyte/BUN/creatinine portion of the profile is a reasonable guide to renal function and in DKA case, hyperglycemia is present. Note that in the presence of metabolic acidosis, intracellular potassium is displaced into the extracellular space. Thus, midnormal concentration of 4.2 mEq/L of K⁺ would not be normal at pH less than 7.3 and indicate potassium deficiency. If the measured serum osmolality is more than 10 to 15 mOsm/kg greater than the calculated osmolality, a significant "osmole gap" exists, and suggests the presence of an unmeasured osmole (e.g., methanol or ethylene glycol). Since DKA is the most common cause of significant metabolic acidosis beyond infancy, obtaining serum ketones is important. Serum calcium, magnesium, phosphate, and HbA1c concentrations should be measured20). A complete urinalysis is also helpful in assessing renal function and in documenting ketonuria in DKA. Occasionally, a patient has severe hyperglycemia (>1,000 mg/dL) in the absence of metabolic acidosis. This is often accompanied by a significantly reduced level of consciousness as a result of extracellular hyperosmolality, and has been termed "nonketotic hyperglycemic coma (NKHC)"20).

The archival samples of blood and urine may be sent for toxin screens, especially if a significant serum osmole gap is present or if the history suggests ingestion of a toxin. Infants with metabolic acidosis may have an inborn error of metabolism, and determination of serum amino and urine amino and organic acids are useful diagnostically. In patient with sepsis or hypoxia/hypovolemia, measurements of serum lactic and pyruvic acid concentrations are useful. In this case, both acids may be elevated, but the lactate-to-pyruvate ratio will be increased (>10:1), because of the patient's relative anaerobic metabolic state. In infants with primary (inborn) lactic acidosis, both lactic and pyruvic acid concentrations are elevated in the serum, but the ratio is usually normal.

5. Treatment