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Review article http://dx.doi.org/10.6065/apem.2015.20.4.179 Ann Pediatr Endocrinol Metab 2015;20:179-186

Endocrine and metabolic emergencies in children: , , adrenal insufficiency, and metabolic including

Se Young Kim, MD, PhD It is important to fast diagnosis and management of the pediatric patients of the endocrine metabolic emergencies because the signs and symptoms of these Department of Pediatrics, Bundang disorders are nonspecific. Delayed diagnosis and treatment may to serious Jeseang General Hospital, Daejin consequences of the pediatric patients, for example, cerebral dysfunction leading Medical Center, Seongnam, Korea to coma or death of the patients with hypoglycemia, hypocalcemia, adrenal insufficiency, or diabetic ketoacidosis. The index of suspicion of the endocrine metabolic emergencies should be preceded prior to the starting nonspecific treatment. Importantly, proper diagnosis depends on the collection of and urine specimen before nonspecific therapy (intravenous hydration, , or injection). At the same time, the taking of precise history and searching for pathognomonic physical findings should be performed. This review was described for fast diagnosis and proper management of hypoglycemic emergencies, hypocalcemia, adrenal insufficiency, and including diabetic ketoacidosis.

Keywords: Hypoglycemia, Hypocalcemia, Adrenal insufficiency, Metabolic acidosis, Diabetic ketoacidosis

Introduction

Because the symptoms and signs are nonspecific, this may lead to a missed diagnosis and serious consequences. Fast diagnosis can be possible by index of suspicion and collection of initial laboratory specimens, which could lead to rapid gain of results about patient status and prompt treatment.

Symptoms and signs Received: 9 December, 2015 Accepted: 21 December, 2015 The initial presentations of children with endocrine disturbances are not different to other Address for correspondence: emergencies, especially newborn babies and infants, such as , meningoencephalitis, and Se Young Kim, MD, PhD intoxication. The degrees of altered consciousness range from mild drowsiness to complete Department of Pediatrics, Bundang obtundation. Signs related to central nervous system (CNS) impairment are lethargy, Jeseang General Hospital, Daejin irritability, tremor, coma, seizure, and Cheyne-Stokes (irregular, shallow) respirations. Those Medical Center, 20 Seohyeon- related to metabolic acidosis are nausea, , poor feeding, weight loss, failure to thrive ro 180beon-gil, Bundang-gu, and Kussmaul (rapid, deep) respirations. The changes in muscle tone such as hypotonia are Seongnam 13590, Korea Tel: +82-31-779-0273 common. The signs of cardiovascular effects are tachycardia, hypotension, and shock. Fax: +82-31-779-0894 E-mail: [email protected]

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©2015 Annals of Pediatric & Kim SY • Endocrine emergencies in children

Sampling blood and urine before treatment 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 Appropriate simultaneous sampling of initial and archival mg/kg/min, adults 2–4 mg/kg/min. When glucose utilization specimen is very important to assess endocrine metabolic begins to exceed production, the counterregulatory hormones emergencies before nonspecific treatment (intravenous glucose, (cortisol, GH, epinephrine, and glucagon) are secreted to prevent hydration and electrolytes). Archival samples are obtained at the hypoglycemia. These hormones, acting individually or in same time as the initial samples and are held in the laboratory concert, stimulate glycogenolysis and gluconeogenesis to restore for future measurement. The initial and archival samples of and maintain normal glucose concentration. Deficiencies blood and urine are collected, as soon as possible, after the in the secretion of counterregulatory hormones or in the patient arrives in the emergency department or intensive care enzymes or substrates involved in either of these 2 processes unit. Serum electrolytes, glucose, blood gas analysis, , can result in hypoglycemia, usually accompanied by excessive calcium, magnesium, phosphorus, osmolality, , breakdown of (TGs) and the production of ketones 2) , and urine electrolytes/osmolality are in the blood and urine . The CNS effects of hypoglycemia usually assessed with initial sample. The calculation of children beyond the newborn period are headache, irritability, + - - confusion, fatigue, abnormal behavior, amnesia, altered level of the (Na -[Cl +HCO3 ]) and serum osmolality (2×Na++Glucose/18+blood nitrogen [BUN]/3) may be consciousness, coma, and seizure. The adrenergic (epinephrine) useful in the differential diagnosis. Archival sample would be effects are diaphoresis, cold extremities, tachycardia, pallor, 3) used to measure serum insulin, amino , ketone, hormones, tremor, anxiety, weakness, nausea, vomiting, and chest pain . and urine organic acids. 3. Laboratory evaluation of hypoglycemia Hypoglycemia Initial sample should be checked for blood glucose, liver func­ 1. Definition and etiologies tion tests, electrolytes, and bicarbonate from comprehensive metabolic profile and included urinalysis for presence or Any patient with a whole blood glucose concentration absence of ketones. Archival sample has to be measured serum less than 50 mg/dL should be undertaken diagnostic and insulin, ketones, GH, cortisol, c-peptide (for suspected exo­ therapeutic procedures1). Transient neonatal hypoglycemia genous hyperinsulinism), carnitine profile, amino acids, and is caused by enzyme immaturity or low substrates amount toxins (ethanol, salicylates). Urine amino and organic acids and (prematurity, normal newborn), transient hyperinsulinism and toxin screen are needed. persistent hyperinsulinism (small for gestational age, discordant 4. Treatment twin, neonatal asphyxia). Persistent hypoglycemia is caused by hyperinsulinism (abnormal K+-ATP channel, abnormal glucokinase, abnormal glutamate dehydrogenase, acquired Nonspecific therapy after initial and archival samples are focal adenomatosis of islet, Beckwith-Wiedemann obtained should go starting intravenous glucose 0.2 g/kg (10% 1) syndrome, insulin injection, sulfonylurea), counter-regulatory dextrose 2 mL/kg) quickly . Ongoing therapy is required hormone deficiency (growth hormone [GH] deficiency, 6−8 mg/kg/min glucose infusion rate for maintenance of adrenocorticotropin hormone [ACTH] deficiency, Addison euglycemia. Occasionally 10–20 mg/kg/min of glucose infusion disease, epinephrine deficiency), glycogenolysis defects rate is needed via central venous line. Other nonspecific therapy (glycogen storage disease 0, 3, 6 ,9), gluconeogenesis defects are glucagon 0.03 mg/kg (subcutaneous or intramuscular 2 (GSD 1a, 1b, galactosemia, fructose 1,6 diphosphatase deficiency, injection) or Solu-Cortef 25 to 50 mg/m or 2 to 3 mg/kg intra­ 1) pyruvate carboxylase deficiency), lipolysis defect (propranolol) venous injection . Specific therapies of hyperinsulinism are and fatty oxidation defects. But the most common cause of long-acting somatostatin analogue 10 μg/kg every 6 to 12 hour childhood hypoglycemia is ketotic hypoglycemia. subcutaneous injection and diazoxide 5–15 mg/kg/day (#2) per oral, which may have several side effects. 2. Pathophysiology Hypocalcemia The utilization of glucose in most tissues is regulated by insu­ lin and by the ability of the tissue to use ketones as an alternative 1. Definition and etiologies energy source in the absence of glucose. Thus, disorders charac­ terized by increased insulin secretion or by a relative inability to Serum calcium concentration is maintained by dietary intake synthesize ketones (disorders of fatty acid oxidation) may lead and absorption from the gut (mediated primarily by “active” to hypoglycemia caused by increased utilization and absence of vitamin D [1,25 dihydroxyvitamin D3]), and mobilization of ketones in blood and urine (nonketotic hypoglycemia)2). calcium from the and across the renal tubules as a result The approximate glucose utilization rate of premature of parathyroid hormone (PTH) secretion and action. PTH

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secretion is magnesium dependent, and its action is dependent sphygmomanometer to 20 mmHg above the systolic blood on both magnesium and vitamin D. Deficiency in active vitamin pressure. D or magnesium, or in other causes of decreased secretion or action of PTH may result in hypocalcemia4). The definition of 4. Laboratory evaluation hypocalcemia in neonate is total serum calcium concentration less than 7.5 mg/dL (ionized <3.8 mg/dL) and in children is The initial blood sample should be used to determine the total 5) below 8.7 mg/dL (ionized <4.6 mg/dL) . serum calcium, phosphorus, magnesium, , , and levels. Hypocalcemia caused by 2. Pathophysiology disorders of vitamin D is usually characterized by decreased serum calcium and phosphorus levels with an elevated alkaline The daily calcium requirement of the children and adole­ phosphatase level, whereas hypocalcemia caused by disorders scence is 600 to 1,200 mg/day. This is provided primarily in of PTH secretion or action is accompanied by decreased serum milk, milk products, and certain green vegetables. Vitamins D2 calcium and alkaline phosphatase levels but increased serum and D3 must be further metabolized sequentially in the liver phosphorus level6). Archival blood sample should be sent for (25- hydroxylase) and the (1-α hydroxylase) to become measurement of PTH and vitamin D metabolites. An archival their respective fully active derivatives, 1,25-dihydroxyvitamins urine sample may be sent for measurement of calcium and D2 and D3 , which are necessary to promote maximal , to rule out a rare form of hypocalcemia termed absorption of calcium and phosphorus into the blood. The "familial hypercalciuric hypocalcemia". The urinary calcium conversion of vitamin D2 or D3 to its active form is stimulated excretion (urinary calcium-creatinine ratio) is increased, in by PTH. Deficiencies of sunlight, milk or milk products, contrast to all other causes of hypocalcemia. Electrocardiogra­ malabsorption of vitamin D, failure to activate vitamin D, or phy may be seen prolonged QT interval. If severe vitamin D tissue unresponsiveness to vitamin D can predispose the child deficient rickets may be evident, characteristic radiologic images to hypocalcemia. Because vitamin D is the primary regulator of show bowed appearance of the legs along with flaring at the phosphorus , hypocalcemia caused by insufficient wrists and knees7). vitamin D synthesis or action is usually accompanied by a decreased serum phosphorus concentration6,7), in contrast 5. Treatment to that caused by defects in PTH secretion or action. PTH is secreted by the parathyroid glands in response to hypo­ Acute treatment consists of the intravenous (IV) administra­ 7) calcemia . PTH mobilizes calcium and phosphorus from the tion of a dilute calcium solution, usually 10% calcium gluconate bone. At kidney, calcium is retained, and mobilized phosphorus or lactate, 2 mL/kg (20 mg/kg) every 6 to 8 hours with cardiac is actively excreted. Defects in the secretion or action of PTH monitoring and careful watching for extravasation of drug. (pseudohypoparathyroidism) lead to hypo­calcemia and a Maintenance management usually consists of 50–75 mg/kg 7) relative inability to excrete phosphorus . Hypocalcemia caused of elemental calcium daily as calcium or calcium by one of these defects is accompanied by an increased serum lactate5,7). Pharmacologic doses of vitamin D3 for rickets are phosphorus concentration. Defects in the calcium-sensing 150,000–600,000 U once intramuscular injection for severe receptors in the parathyroid glands and the kidney may also vitamin D deficient rickets or 2,000–10,000 U/day (50–250 µg/ 5) result in abnormalities in the serum concentration of calcium . day) per oral during 4–6 weeks5). 1,25-dihydroxyvitamin D3 20– 60 ng/kg/day is required in the treatment of hypoparathyroidism 3. History and physical examination and pseudohypoparathyroidism5). of any etiology should be corrected before long-term treatment Children who may be prone to hypocalcemia include those of hypocalcemia is undertaken, since it may be the primary whose dietary problems predispose to vitamin D deficiency, defect, and the success of treatment of hypocalcemia is limited premature infants (inadequate vitamin D storage), congenital in cases of coexisting hypomagnesemia8). Treatment consists heart defects (Di George syndrome), and hypoparathyroidism of 50% magnesium 0.1 mL/kg when serum magnesium (autoimmune or removal of the parathyroid glands after surgery concentration is below 1.5 mg/dL every 8 to 12 hours5,9). for thyroid carcinoma), pseudohypoparathyroidism, or chronic renal disease8). Signs of hypocalcemia include lethargy, poor Adrenal insufficiency feeding and vomiting in infants, jitteriness, irritability, muscle spasm, laryngeal stridor, and tetany. Generalized seizures are 1. Etiologies common, so hypocalcemia should be ruled out in any child 5) with an unexplained seizure . Carpopedal spasm is typical sign The congenital causes of primary adrenal insufficiency of hypocalcemia and facial muscle hyperirritability (Chvostek are congenital adrenal hyperplasia (CAH), autoimmune sign) may be elicited by tapping on the maxilla. Trousseau (Addison disease), adrenocortical hypoplasia congenita (AHC), sign may be elicited in hypocalcemic patients by inflating a adreno­leukodystrophy (ALD), Zellweger syndrome and

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Wolman syndrome. The acquired causes of primary adrenal 4. Laboratory evaluation insufficiency are adrenal hemorrhage, infections of adrenal gland and other infiltrative diseases. The secondary causes are The results of comprehensive metabolic profile from initial hypothalamic disorders (empty sella syndrome, septo-optic sample will show , metabolic acidosis (normal dysplasia, craniopharyngioma, tumor and surgery/radiotherapy, anion gap, increased serum ), hypoglycemia, and infection), pituitary disorders (infections, congenital anomaly, . If this pattern is found, blood should be drawn tumor, and surgery/radiotherapy), and adrenal suppression for level of plasma renin activity. The archival sample will be sent 10,11) from high-dose long-term steroid therapy . Children for serum cortisol and ACTH so that primary hypoadrenalism receiving pharmacological steroids for treatment of severe (decreased cortisol with elevated ACTH) may be differentiated asthma, leukemia, organ transplantation or autoimmune from central causes (decreased cortisol without elevated diseases and children who are taking physiologic replacement ACTH). Neonates or infants suspected of having CAH, serum steroids for central or primary hypoadrenalism are prone to should be measured 17-hydroxyprogesterone or a complete adrenal crisis during acute febrile illness particularly vomiting adrenal metabolic profile, so that the specific enzymatic block 10-12) () . Glucocorticoids administered for more than may be identified14). If hypopituitarism is suspected free T4 and 10 to 14 days can suppress ACTH release for weeks and render GH should be determined11). the child susceptible to adrenal crisis13-15). 5. Treatment 2. Pathophysiology Acute treatment of adrenal crisis is for rapid restoration of Hypovolemia and elevated serum potassium concentrations tissue perfusion. After an IV line is secured, a 20 mL/kg bolus of stimulate mineralocorticoid (aldosterone) release from the normal (5% dextrose/0.9% NaCl) is given over a period adrenal gland’s zona glomerulosa under the stimulus of the of an hour. If significant hypoglycemia is present, a glucose of renin-angiotensin II axis. Aldosterone acts on the distal renal bolus 0.2 g/kg (2 mL/kg of 10% dextrose) is given to restore tubule to effect sodium and water retention and enhanced hyd­ euglycemia. Stress doses of glucocorticoid, Solu-Cortef should rogen and potassium excretion into the urine. Thus, aldosterone be loading (25–50 mg/m2 or 2–3 mg/kg). Hydrocortisone has serves a critical function by maintaining normal levels of a desirable mineralocorticoid effect as well as its glucocorticoid total body sodium and water and protecting the body from effect (20–35 mg Solu-Cortef has the mineralocorticoid effect of 13,14) , dehydration, and shock . A striking feature 0.1-mg fludrocortisone [Florinef]), whereas methylprednisolone of mineralocorticoid deficiency at any age, especially in the (Solu-Medrol) and dexamethasone have only a glucocorticoid dehydrated infant, is polyuria. Corticotropin-releasing factor effect and are not suitable therapies in this case13). is released from the hypothalamus during times of stress or Ongoing IV steroid therapy consists of Solu-Cortef given as a hypoglycemia and stimulates the release of ACTH from the total daily dose of 25–50 mg/m2 or 2–3 mg/kg in divided doses pituitary gland. ACTH stimulates the adrenal gland's zona every 6 hours. Hyperkalemia higher than 6 mEq/L can induce fasciculata to secrete the glucocorticoid (hydrocortisone), which fatal cardiac arrythmias and requires aggressive therapy with is one of the body's major defenses against hypoglycemia and , 1 to 2 mEq/kg IV over 10 to 15 minutes; 14) shock . Adrenal insufficiency results in a relative inability to calcium gluconate, 50 to 100 mg/kg (maximum dose, 1 g) by maintain balance, plasma volume, , slow (5–10 minutes) IV drip; or IV glucose, 500 mg/kg (2 mL/ and blood glucose during times of stress, and may have a fatal kg 25% glucose solution) plus insulin, 0.1 units/kg. A potassium- 15) outcome . binding resin, sodium polystyrene sulfonate (Kayexalate), 1 g/kg rectally or orally, should be given if tolerated13). 3. History and physical examination Metabolic acidosis The patients with adrenal insufficiency have weakness, anore­ xia, vomiting, weight loss, salt craving, and hyperpigmentation. 1. Etiologies They have tachycardia and hypotension and other signs of shock, which are pallor, poor peripheral perfusion, cold 12) The metabolic acidosis can be resulting from (1) a loss of clammy skin, disturbed consciousness or even coma . With (bicarbonate) from the body, either through the kidneys dehydration, there may be decreased skin turgor, sunken eyes, or the (normal anion gap), or from (2) and dry mucous membranes. Hyperpigmentation of gums, abnormal accumulation of acid through overproduction areolae, flexion creases reflects excessive secretion of ACTH. (diabetic ketoacidosis [DKA], lactic acidosis, or inborn errors of Ambiguous genitalia in girls with virilizing CAH may be 14) metabolism), (3) under excretion (type 1 [distal] renal tubular present . acidosis or chronic renal failure)16), or toxic ingestion (increased anion gap)17).

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2. Pathophysiology excess secretion of the counterregulatory hormones (cortisol, epinephrine, GH, and glucagon) during stress (infection, Acidosis that ultimately exceeds the body's compensatory trauma, and surgery). and relative hyperkalemia buffering mechanisms to an increase in are manifest early in the course of DKA. The increased urine H+ concentration so that the pH of the blood is reduced below output and hyperkalemia result in extracellular dehydration + - 7.35. This state is referred to as "academia", and its presence as well as electrolyte (Na and HCO3 ) loss, resulting in an warrants prompt treatment to prevent severe alterations in initial normal anion gap (hyperchloremic) metabolic acidosis. extracellular and intracellular pH that might be incompatible As insulin deficiency continues in the presence of excessive with life. To maintain electrical neutrality in the body, the counterregulatory hormone secretion, accelerated breakdown total positively charged (cations) must always equal the of glycogen and protein occurs and gluconeogenesis increases, total negatively charged ions (anions). Normally, Na+ accounts with a resulting augmented glucose production by the liver and 19) for more than 90% of the extracellular cations, whereas Cl- rapidly worsening hyperglycemia . The cellular inability to - use blood glucose, excessive cortisol and epinephrine secretion and HCO3 constitute approximately 85% of the anions. The "anion gap" is the calculated difference between the majority of and insufficient insulin, stimulates the breakdown of TGs measured cations (Na+) and the majority of measured anions to free fatty acids. These overwhelm the ability of the liver to - - 17) metabolize them for energy, and result in a rapidly increasing (the sum of Cl and HCO3 ) . accumulation of acetoacetate and beta-hydroxybutyrate, the 1) Normal anion gap ("hyperchloremic") metabolic acidosis "ketone bodies". The ketone bodies are moderately strong acids, (1) or small bowel drainage can lead to excessive which are ionized at physiologic pH and release ions + - that produce an increased anion gap metabolic acidosis. loss of Na and HCO3 from the gastrointestinal tract with the subsequent development of metabolic acidosis. Since sodi­ um and bicarbonate are lost together, and 3. History and physical examination develops, the calculated anion gap is normal. Loss of sodium bicarbonate through the kidneys may also occur, either caused In patients with new or established type 1 DM, there is often (2) by an altered renal bicarbonate reabsorption threshold in a history of recent emotional stress or infection that can be a type 2 (proximal) , early in generalized precipitating factor in the development of DKA. In many cases, renal tubular dysfunction, or caused (3) by mineralocorticoid no particular precipitating event can be identified. Known deficiency (e.g., Addison disease or some type of the CAH)17,18). metabolic disease in the family is a valuable clue. Symptoms of hypoglycemia during fasting or after specific foods (e.g., fruit 2) Increased anion gap metabolic acidosis [fructose containing]) can be diagnostic of an inborn error The endogenous production or ingestion of acid load or of metabolism, history of unusual urine odor. These include a failure of the kidneys to excrete sufficient H+ daily results persistent vomiting and tachypnea resulting from the body's in metabolic acidosis. Those may progress to acidemia if the attempt to compensate for the acidosis by ridding itself of the ability of the body's other compensatory mechanisms to neu­ excess acid through the gastrointestinal tract or lungs. Changes tralize this condition is exceeded. This is accompanied by caused by acidosis in the peripheral and central vasculature decreased serum bicarbonate levels because of the increased give rise to warm, flushed skin, abdominal pain, and headache. demands on the body's buffering capacity by excessive H+ If the abdominal pain and vomiting in a child with DKA do accumulation, and the calculated anion gap is increased. In the not resolve as the acidosis is corrected, then an evaluation of neonatal period, (1) inborn errors of metabolism that lead to the "acute abdomen" should be undertaken. Acidemia and accumulation defective substrates of amino/organic acids result hyperosmolality also result in CNS dysfunction, manifested as in increased anion gap metabolic acidosis. (2) The ingestion altered levels of consciousness progressing to coma, seizures, of toxins that are acid precursors and that may also disrupt and even death if they are not treated in a timely manner. In normal metabolism so that organic acids accumulate. Examples the patient with DKA, variable degrees of dehydration, from of these are acetylsalicylic acid, methanol, ethylene glycol mild to severe, may be present and will be manifest as lack of (antifreeze), and they may also result in a measured serum normal skin turgor, sunken eyes, tachycardia, and hypotension. osmolality much greater than calculated (“osmole gap”). The In patient with severe acidosis (pH<7.0), suppression of cardiac inborn errors of carbohydrate metabolism that lead to fasting and pulmonary function may occur, and ventilatory assistance hypoglycemia may also result in increased anion gap metabolic may be necessary. The patient in DKA may have a characteristic acidosis because of the excessive production of ketone bodies “fruity” odor to the breath because of exhaling the ketone body (acetoacetate and beta-hydroxybutyrate) that are derived from acetoacetate19). the breakdown of fatty acids being used as an alternate energy source. (3) DKA is usually occurred by absolute/relative insulin 4. Laboratory tests deficiency, either caused by noncompliance with insulin in children with known type 1 diabetes mellitus (DM) or by an A comprehensive metabolic profile in the initial blood

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sample will reveal the decrease in serum bicarbonate that patient's serum pH is less than 6.9, the deleterious effects of defines the acidosis. The electrolyte/BUN/creatinine portion of severe acidosis on cardiopulmonary function may warrant the profile is a reasonable guide to renal function and in DKA limited bicarbonate therapy. Sodium bicarbonate, 1 to 2 mEq/ case, hyperglycemia is present. Note that in the presence of kg, may be added to the IV fluids over approximately 60 minutes metabolic acidosis, intracellular potassium is displaced into the in these circumstances20,21). extracellular space. Thus, midnormal concentration of 4.2 mEq/ L of K+ would not be normal at pH less than 7.3 and indicate 2) DKA potassium deficiency. If the measured serum osmolality is more Initial fluid therapy should be begun with an IV infusion of than 10 to 15 mOsm/kg greater than the calculated osmolality, 0.9% NaCl 10 to 20 mL/kg body weight given during the first a significant "osmole gap" exists, and suggests the presence of an hour followed by continuous insulin infusion 0.1 U/kg/hr. Next unmeasured osmole (e.g., methanol or ethylene glycol). Since hour fluid therapy consist of 0.45% NaCl plus potassium 40

DKA is the most common cause of significant metabolic acidosis mEq/L (50% KCl + 50% KPO4) or depending on the estimate beyond infancy, obtaining serum ketones is important. Serum of the patient’s potassium deficit. Dextrose may be omitted calcium, magnesium, , and HbA1c concentrations from the initial IV fluids in a patient with DKA only if the should be measured20). A complete urinalysis is also helpful initial serum glucose concentration is greater than 300 mg/ in assessing renal function and in documenting ketonuria in dL. But 5% dextrose should be added to the IV fluids when DKA. Occasionally, a patient has severe hyperglycemia (>1,000 the serum glucose concentration reaches 250–300 mg/dL to mg/dL) in the absence of metabolic acidosis. This is often prevent hypoglycemia and to help minimize the rate of fall in accompanied by a significantly reduced level of consciousness extracellular osmolality. Although the average decrease in serum as a result of extracellular hyperosmolality, and has been termed glucose concentration on the standard IV "insulin plus fluid" "nonketotic hyperglycemic coma (NKHC)"20). regimen is 75 mg/dL per hour, there is considerable variation The archival samples of blood and urine may be sent for toxin between patients, and hourly monitoring of serum glucose is screens, especially if a significant serum osmole gap is present warranted. On occasion, it is necessary to use 10% dextrose or if the history suggests ingestion of a toxin. Infants with in the IV fluids to maintain serum glucose concentrations of metabolic acidosis may have an inborn error of metabolism, and 150 to 250 mg/dL. Maintenance fluids should be administered determination of serum amino and urine amino and organic evenly over each 24-hour period, but estimated fluid deficits acids are useful diagnostically. In patient with sepsis or hypoxia/ should be replaced cautiously, over at least 36 hours, with longer hypovolemia, measurements of serum lactic and pyruvic times if the initial serum osmolality is greater than 320 mOsm/ acid concentrations are useful. In this case, both acids may be kg. Potassium and phosphorus deficits are difficult to estimate elevated, but the lactate-to-pyruvate ratio will be increased based on their serum concentrations, but the addition of 20 mEq

(>10:1), because of the patient’s relative anaerobic metabolic KCl plus 20 mEq KHPO4 per liter of IV fluids usually suffices to state. In infants with primary (inborn) lactic acidosis, both lactic replace these deficits. Hourly monitoring of serum potassium and pyruvic acid concentrations are elevated in the serum, but is warranted for the first few hours of treatment, and every 2 the ratio is usually normal. hours thereafter. The prevention of cerebral is important during the course of treatment. Since the patient's brain is in 5. Treatment equilibrium with the hyperosmolar extracellular space in DKA, it is prudent to avoid rapid changes in extracellular osmolality so 1) General that fluid movement into the hyperosmolar CNS does not occur. The initial approach to the child with metabolic acidosis Since the serum sodium concentration is decreased because of involves maintenance of normal extracellular volume and the osmotic effect of hyperglycemia in DKA, it should increase correction of dehydration. This should be begun with an IV gradually as the serum glucose concentration decreases during infusion of 5% dextrose in 0.9% NaCl with potassium, 20 mEq/ insulin therapy. Monitoring the serum sodium concentration L or greater, depending on the potassium deficit. Maintaining hourly during the first few hours of therapy is therefore initial IV fluid volumes may be calculated from an estimation of the to ensure that this occurs and that rapid changes in serum degree of existing dehydration and ongoing fluid losses in osmolality do not occur. The insulin infusion should be begun an individual patient. Alkalai therapy in the form of sodium as soon as the diagnosis is made, irrespective of the patient's bicarbonate should be used sparingly. Except for some of the serum glucose, since the degree of acidemia may not correlate inborn errors of metabolism, metabolic acidosis will improve with serum glucose concentration. A solution of 1 unit/5 mL with fluid therapy alone as tissue perfusion improves and can be made by adding 50 units rapid acting insulin to 250 mL cellular metabolism normalizes. Ketones and may be 0.9% NaCl and used for this purpose. In patients whose serum endogenously metabolized to bicarbonate. Thus, bicarbonate glucose concentration is less than 300 mg/dL, dextrose should therapy may be unnecessary and may actually be harmful. be added to the initial IV fluids. The insulin infusion is usually The use of bicarbonate during the treatment of DKA poses continued until the serum bicarbonate concentration is greater a significantly increased risk of cerebral edema. If the DKA than 15 mEq/L, the venous pH is greater than 7.30, or both, and at that time, a regimen of subcutaneous insulin is begun21).

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In most cases, venous blood suffices to determine the patient's 46. acid-base balance, and arterial blood would only be required 3. Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, to assess the state of oxygenation in the obtunded patient. In Ward-Platt MP, Schwartz R, et al. Controversies regarding NKHC, the patient's serum osmolality is usually greater than definition of neonatal hypoglycemia: suggested operational 320 mOsm/kg, and fluid deficits should be replaced over 48 thresholds. Pediatrics 2000;105:1141-5. hours. In addition, an initial insulin infusion rate of 0.05 units/ 4. Shaul PW, Mimouni F, Tsang RC, Specker BL. The role kg per hour in 0.9% NaCl may be used to further minimize the of magnesium in neonatal calcium homeostasis: effects chances of rapid decreases in serum osmolality22). of magnesium infusion on calciotropic hormones and calcium. Pediatr Res 1987;22:319-23. 3) Cerebral edema 5. The Korean Society of Pediatric Endocrinology, editor. Cerebral edema may already be present when the patient arri­ Pediatric endocrinology. 3rd ed. Seoul: Koonja Co., 2014. ves in the emergency department. This usually results from a Hypocalcemia; p. 257-94. lack of appropriate treatment caused by delays in the diagnosis 6. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M; of DKA, and accounts for half of the 2% mortality rate seen in Drug and Therapeutics Committee of the Lawson Wilkins childhood DKA. A secondary form of cerebral edema presents Pediatric Endocrine Society. Vitamin D deficiency in within hours of the onset of treatment in DKA patient and is children and its management: review of current knowledge heralded by a change in level of consciousness or a complaint of and recommendations. Pediatrics 2008;122:398-417. headache. This is probably associated with rapid fluid shifts into 7. Shaw N. A practical approach to hypocalcaemia in children. the CNS when extracellular osmolality is reduced too quickly Endocr Dev 2009;16:73-92. or when bicarbonate is used inappropriately. The prevention of 8. Song JY, Shin YL, Yoo HW. Clinical characteristics of this form of cerebral edema may be accomplished by avoiding symptomatic hypocalcemic infants. J Korean Soc Pediatr the overuse of fluids (keeping the initial fluid bolus <20 mL/kg, Endocrinol 2002;7:95-104. keeping total fluids <50 mL/kg over the first 4 hours or <4 L/ 9. Root AW, Diamond FB Jr. Disorders of homeostasis m2 over the first 24 hours of treatment and by replacing deficits in the newborn, infant, child, and adolescent. In: Sperling over 36 to 48 hours22,23). If these precautions have been followed MA, editor. Pediatric endocrinology. 3rd ed. Philadelphia: and the patient’s mental status is worsening, IV mannitol (1 g/kg Elsevier Saunders Co., 2008:686-769. over 20 minutes) may be given19). 10. Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med 2009;360:2328-39. Conclusions 11. The Korean Society of Pediatric Endocrinology, editor. Pediatric endocrinology. 3rd ed. Seoul: Koonja Co., 2014. Because the symptoms and signs of the endocrine metabolic Adrenocortical insufficiency; p. 325-57. emergencies of the pediatric patients are nonspecific, a suspicion 12. Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361: and collection of the initial sample should be preceded prior 1881-93. to starting therapy. Also archival sample should be obtained 13. Miller WL, Achermann JC, Fluck CE. The adrenal cortex simultaneously and be held in the laboratory for future mea­ and its disorders. In: Sperling MA, editor. Pediatric surement. In addition to hypoglycemia, hypocalcemia, adrenal endocrinology. 3rd ed. Philadelphia: Elsevier Saunders Co., insufficiency, and metabolic acidosis including diabetic ketoa­ 2008:444-511. cidosis, these samples will be so useful for diagnosis and treat­ 14. Speiser PW, White PC. Congenital adrenal hyperplasia. N ment of other endocrine metabolic disorders in Emergency Engl J Med 2003;349:776-88. Department. 15. Langer M, Modi BP, Agus M. Adrenal insufficiency in the critically ill neonate and child. Curr Opin Pediatr 2006;18:448-53. Conflict of interest 16. Rothstein M, Obialo C, Hruska KA. Renal tubular acidosis. Endocrinol Metab Clin North Am 1990;19:869-87. No potential conflict of interest relevant to this article was 17. Lim S. Metabolic acidosis. Acta Med Indones 2007;39:145- reported. 50. 18. Lorenz JM, Kleinman LI, Markarian K, Oliver M, Fernan­ References dez J. Serum anion gap in the differential diagnosis of metabolic acidosis in critically ill newborns. J Pediatr 1. The Korean Society of Pediatric Endocrinology, editor. 1999;135:751-5. 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diabetic ketoacidosis. The Pediatric Emergency Medicine Association. Diabetic ketoacidosis in infants, children, and Collaborative Research Committee of the American adolescents: A consensus statement from the American Academy of Pediatrics. N Engl J Med 2001;344:264-9. Diabetes Association. Diabetes Care 2006;29:1150-9. 21. Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, 23. Resenbloom AL. Therapeutic controversy: prevention Lee WR, et al. Diabetic ketoacidosis. Pediatr Diabetes and treatment of diabetes in children. Cerebral edema in 2007;8:28-43. diabetic ketoacidosis. J Clin Endocrinol Metab 2000;85: 22. Wolfsdorf J, Glaser N, Sperling MA; American Diabetes 507-8.

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