metabolic diseases - jones & bartlett...

Metabolic DiseasesNicole Glaser, MDElka Jacobson-Dickman, MDNathan Kuppermann, MD, MPH, FAAPDebra L. Weiner, MD, PhD, FAAP

chapter 16

Introduction

Diabetic Ketoacidosis

Hypoglycemia in Children With Diabetes

Hypoglycemia in Nondiabetic Children

Adrenal Insufficiency/Congenital Adrenal Hyperplasia

Diabetes Insipidus

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Water Intoxication

Metabolic Disease of the Newborn and Young Child: Inborn Errors of Metabolism

Chapter Outline

1 Describe the epidemiology, clinical features, and emergency management of diabetes mellitus (DM), adrenal insufficiency, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), water intoxication, and diabetes insipidus (DI).

2 Describe the fluid and electrolyte problems associated with these conditions.

3 Discuss the clinical features and emergency management of metabolic diseases of the newborn and young child.

Objectives

Copyright © 2012 by the American Academy of Pediatrics and the American College of Emergency Physicians

16-3

CASE

SCE

NARI

O 1 A 10-year-old boy presents to the emergency department (ED) with altered mental status and a

2-week history of polyuria and weight loss. He is experiencing abdominal pain. On examination, he has a respiratory rate of 36/min, a heart rate of 150/min, a systolic blood pressure of 80 mm Hg, and a temperature of 37.9°C (100.2°F). Pulse oximetry oxygen saturation is 97% on room air. On examination, he appears lethargic, has dry mucous membranes, has normal abdominal examination results, and has a nonfocal neurologic examination results. Bedside rapid glucose measurement is above the upper limit of the glucose meter (>500 mg/dL).

1. What therapeutic actions must be taken immediately?2. What laboratory tests would you order?3. What is the most important potential complication?

IntroductionThe emergency management of endocrine and metabolic disorders presents diagnostic and therapeutic challenges. Many of these disor-ders, such as congenital adrenal hyperplasia (CAH) and inborn errors of metabolism, occur relatively infrequently. Nonetheless, rapid and appropriate intervention is necessary to prevent complications. Awareness of key clinical and laboratory findings that differentiate endocrine and metabolic disorders from other entities with similar presenting features is essential.

Diabetic KetoacidosisDiabetic ketoacidosis (DKA) is the most impor-tant complication of type 1 DM (Figure 16.1). Diabetic ketoacidosis occurs when insulin con-centrations are low relative to the concentrations of counterregulatory hormones, particularly glucagon. This imbalance results in hypergly-cemia along with the breakdown of fat to form ketone bodies, eventually resulting in acidosis. Diabetic ketoacidosis occurs in 25% to 40% of children with new onset of type 1 diabetes melli-tus (DM).1–3 Repeat episodes of DKA in children


16-4 Metabolic Diseases

causes of dehydration. Acidosis results in com-pensatory tachypnea, and a characteristic fruity (acetone) breath odor can often be detected. Because the hyperosmolar state allows for the relative preservation of intravascular volume, some signs of dehydration can be less obvious than in dehydrated patients with more normal serum osmolality. Alterations in mental status can range from disorientation to depressed con-sciousness. This alteration of mental status can

with known diabetes can occur during episodes of illness or with diabetes mismanagement or malfunction of diabetes care equipment (insulin pumps). Presumed omission or incorrect ad-ministration of insulin injections is the most common cause of DKA in children with known DM (69%); bacterial infections are infrequently present (13%).4

Clinical FeaturesDiabetic ketoacidosis is characterized by hyper-glycemia and elevated serum ketone concentra-tions, resulting in acidosis. Inadequate insulin concentrations allow the partial oxidation of fatty acids to form ketone bodies. This process then results in acidosis with an increased anion gap. Hyperglycemia results in osmotic diuresis with polyuria, polydipsia, and eventual dehy-dration. Presenting features of DKA include a history of polyuria, polydipsia, nausea, and vomiting. Abdominal pain and intestinal ileus are common features and can mimic an acute abdomen. In a patient with clinical signs of de-hydration, the presence of polyuria helps dif-ferentiate DKA from gastroenteritis and other

Pathophysiology of Diabetic Ketoacidosis

fatty acid oxidation gluconeogenesis glycogenolysis

osmotic diuresis

peripheral glucose uptake and metabolism

Ketone Bodies

Acidosis

Hyperglycemia

Dehydrationhyperkalemia

renal K+ loss

increased insensible fluid losses

increased lactate

poor tissue perfusion

vomiting

renal Na+ lossrenal Ca, phos, Mg loss

Figure 16.1 Diabetic ketoacidosis.

Behrman RE, Kliegman RM. Nelson Essentials of Pediatrics. 4th ed. Philadelphia, PA: WB Saunders; 2002:185. Reprinted with permission.

Y O U R F I R S T C L U E

Signs and Symptoms of DKA

• Historyofpolyuria,polydipsia,weightloss, nausea, and vomiting

• Signsofdehydration

• Breathwithfruityodor

• Abdominalpain

• Tachypnea

• Lethargy


Diabetic Ketoacidosis 16-5

are total body concentrations of sodium, phos-phate, calcium, and magnesium. Although total body sodium is depleted, the degree of deple-tion is less than that suggested by the measured serum sodium concentration, which is artifi-cially depressed due to hyperglycemia. Blood urea nitrogen (BUN) concentrations are usually elevated due to prerenal azotemia. The white blood cell count is often elevated and frequently left-shifted as a result of the ketoacidotic state alone.4 It is generally unnecessary to search for a source of infection beyond performing a care-ful physical examination unless fever or other specific signs of infection are present.

Differential DiagnosisThe presenting symptoms and signs of DKA can initially be confused with gastroenteritis or other gastrointestinal disorders that present with vomiting and abdominal pain. Infections such as pneumonia, meningitis, and urinary tract infec-tions also can present with metabolic acidosis, tachypnea, and altered mental status or can be a cause of the development of DKA. The history of polyuria despite clinical dehydration, absence of diarrhea, and presence of tachypnea with fruity breath odor should differentiate DKA from these other entities even before laboratory tests are or-dered. Diabetic ketoacidosis must also be differ-entiated from hyperglycemic hyperosmolar state (HHS) (formerly known as hyperglycemic hyper-osmolar nonketotic coma), which presents with severe hyperglycemia (serum glucose concentra-tion >600 mg/dL and often >1,000 mg/dL) and hyperosmolality (serum osmolality >330 mOsm), profound dehydration, and a depressed level of consciousness, but mild or no ketosis.10 Hyper-glycemic hyperosmolar state can in fact represent

be due to acidosis and dehydration but can also reflect more serious underlying intracranial dis-ease. Rarely, children with DKA present to the ED with clinically apparent cerebral edema,5 as well as cerebral infarctions or thromboses.

ComplicationsThe most frequent complications of DKA treat-ment include hypokalemia and hypoglycemia. Hypocalcemia, hypophosphatemia, and hypo-magnesemia can also occur but are much less common. Of the more serious complications of DKA, clinically apparent cerebral edema is the most frequent, occurring in approximately 1% of DKA episodes. Cerebral edema is the most important diabetes-related cause of mortality in children with type 1 DM.6,7

Although cerebral edema can occur before hospital treatment of DKA, this complication more typically occurs several hours after initia-tion of therapy. The clinical presentation of ce-rebral edema can take different forms. Typically, patients with cerebral edema experience head-ache and exhibit alterations in mental status. Obtundation, papilledema, pupillary dilation or anisocoria, blood pressure variability, brady-cardia, and apnea can also occur in severe cases.

Deep venous thromboses can occur in chil-dren with DKA, particularly when central ve-nous catheters are used.8,9 Other complications of DKA are rare but include cerebral infarctions or thrombosis, acute renal tubular necrosis lead-ing to renal failure, pulmonary edema, pulmo-nary embolus, arrhythmia, pancreatitis, and intestinal necrosis.

Diagnostic StudiesDiabetic ketoacidosis is defined as hyperglyce-mia (serum glucose concentration >200 mg/dL), acidosis (venous pH <7.25 or serum bicarbon-ate concentration <15 mEq/L), and the presence of ketones in the serum or urine.6,7 Electrolyte abnormalities also occur as a result of urinary losses and shifts due to acidosis. High serum concentrations of potassium are often found at the time of presentation of DKA, but normal or low concentrations can occur if the ketoaci-dotic state is prolonged. Intracellular potassium concentrations are characteristically depleted, as

T H E C L A S S I C S

Laboratory Findings in DKA

• Hyperglycemia

• Metabolicacidosis

• Ketonemiaorketonuria



should not be compromised by theoretical con-cerns associated with fluid administration.

The average degree of dehydration in chil-dren with DKA is approximately 7%.12 The typical child with DKA should receive an ini-tial fluid bolus of 10 mL/kg of isotonic fluid (ie, isonatremic fluids such as 0.9% saline [normal saline] or lactated Ringer’s solution) for 30 to 60 minutes. If there is evidence of poor perfusion or significant hypovolemia, 20 mL/kg can be used as the initial bolus. Greater administra-tion of fluids is indicated if signs of shock are present. Isotonic fluid boluses can be repeated if necessary to restore perfusion. Once perfusion has been restored, the remaining fluid deficit plus maintenance fluids can be replaced dur-ing the next 36 to 48 hours using half normal (0.45% sodium chloride solution) to normal saline (0.9% sodium chloride solution).6,7

HyperglycemiaAfter the initial fluid bolus(es), insulin should be administered via continuous intravenous (IV) infusion at a dosage of 0.1 U/kg per hour. Maximal suppression of ketogenesis occurs rap-idly using a continuous insulin infusion at this dosage and an initial IV bolus or “loading dose” of insulin is unnecessary. When serum glucose concentrations fall below 250 to 300 mg/dL during treatment, glucose should be added to the IV fluids to ensure that hypoglycemia does not occur. The insulin infusion rate generally should not be decreased until ketoacidosis re-solves (pH >7.30 and bicarbonate >15). This will like take roughly 10 to 24 hours to achieve, so the insulin infusion must often continue on the inpatient service.

AcidosisThe acidosis in DKA is due primarily to two factors: the production of ketone bodies due to relative insulin deficiency and the accumula-tion of lactate due to dehydration and poor tis-sue perfusion. Insulin treatment promotes the metabolism of ketone bodies and halts further ketone production, whereas the administration of IV fluids treats the dehydration. This thera-peutic combination is generally sufficient for the correction of acidosis. Bicarbonate admin-istration generally should be avoided because associations between bicarbonate therapy and

one extreme in a continuum of presentations of DKA and a mixed presentation with features of DKA and HHS can also occur. Although HHS is uncommon in children, recent reports suggest that the frequency might be rising.10 Hypergly-cemic hyperosmolar state occurs more frequently in patients with type 2 rather than type 1 diabe-tes and in children with neurologic abnormali-ties that lead to abnormal thirst mechanisms or limited access to liquids. The treatment approach for HHS differs from DKA. Discussion of HHS treatment is beyond the scope of this chapter but has been reviewed elsewhere.10

ManagementThe fundamental treatment measures for DKA include replacement of fluid deficits, correction of acidosis and hyperglycemia via insulin ad-ministration, replacement of depleted electro-lytes, and monitoring for complications.

Fluid ReplacementOptimal fluid management of DKA has been a subject of great controversy, mainly due to theoretical concerns about the role of fluid ad-ministration in contributing to cerebral edema. Available evidence, however, does not confirm a primary role for fluid administration in caus-ing this complication.5,11 The most compelling evidence suggests that children who present with low Pco

2 and high BUN concentration and

those treated with bicarbonate are at higher risk for cerebral edema.5 Appropriate restoration of perfusion and hemodynamic stability, therefore,

W H AT E L S E ?

Differential Diagnosis of DKA

• Gastroenteritis

• Abdominalsurgicalemergency

• Toxicingestion

• Infections(pneumonia,meningitis,urinary tract infections)

• Hyperglycemichyperosmolarstate


Diabetic Ketoacidosis 16-7

K E Y P O I N T S

DKA Management GuidelinesIV fluids:

- Administer initial 10- to 20-mL/kg bolus of normal saline. Fluid bolus can be repeated if necessary to restore perfusion.

- Subsequent fluid administration should replace the remaining fluid deficit (typically approximately 70 mL/kg) plus maintenance fluids during 36 to 48 hours using half normal to normal saline. Normal saline can be used initially with a transition to half normal saline after several hours.

Insulin:

- Insulin should be administered after initial fluid bolus(es).

- Insulin should be administered as a continuous infusion of 0.1 U/kg per hour.

- An initial insulin bolus dose is not necessary.

- Insulin should be administered at the above rate until ketoacidosis resolves (pH >7.30 and bicarbonate >15 mEq/L). To prevent hypoglycemia, glucose-containing IV fluids should be used after the plasma glucose concentration declines below approximately 250 to 300 mg/dL (13.9 to 16.7 mmol/L).

Electrolyte replacement:

- For DKA patients presenting initially with hypokalemia, potassium replacement should begin immediately. If potassium levels are normal, potassium replacement should begin concurrent with insulin administration, provided that renal function is adequate. For patients with hyperkalemia, potassium replacement should begin when serum potassium levels decline to the normal range.

- Potassium replacement should be given as potassium chloride (KCl) or a 50:50 mixture of potassium chloride (KCl) and potassium phosphate or potassium acetate to sum to 40 mEq of potassium per liter of IV fluids. Serum potassium concentrations should be monitored frequently and rates of administration adjusted according to measured concentrations.

- Calcium, magnesium, and phosphate concentrations should be monitored. Phosphate concentrations typically decrease during treatment, and replacement of phosphate (see above) can be considered. Replacement of calcium and magnesium is rarely required.

Bicarbonate treatment:

- Bicarbonate treatment should be avoided except in rare circumstances of symptomatic hyperkalemia and/or cardiovascular instability caused by severe acidosis and not responding to fluid and insulin therapy.

Monitoring:

- Vital signs should be measured hourly.

- Continuous cardiac monitoring is recommended.

- Accurate recording of fluid intake and output should be performed.

- Blood glucose concentrations should be measured hourly. Electrolytes, serum urea nitrogen, creatinine, venous pH, and Pco2 should be measured every 2 to 4 hours. Calcium, magnesium, and phosphate should be monitored approximately every 6 hours. More frequent measurements might be needed in patients with abnormal or rapidly changing electrolyte concentrations.

- Mental status should be assessed hourly or more frequently in patients with headache or other symptoms or signs of cerebral edema (see text).

Admission to the pediatric intensive care unit vs pediatric ward:

- Admission to the pediatric intensive care unit is recommended for children requiring more intensive monitoring or those at risk for complications. These patients include:

- Children younger than 5 years

- Children with altered mental status

- Children with very high initial BUN concentration and/or very low initial Pco2 levels or severe acidosis

- Children with mixed presentation of DKA and hyperglycemic hyperosmolar state



ness of cerebral edema treatment interventions is unclear, patients who have deterioration in mental status generally should be treated for presumed cerebral edema and subsequently evaluated us-ing computed tomography or magnetic reso-nance imaging (MRI). It is commonly believed that early treatment with hyperosmolar agents, such as mannitol or 3% saline (hypertonic saline), in patients with DKA and cerebral edema can be beneficial, although clinical data are lacking.16 The potential adverse effects of hyperosmolar agents in this setting, however, are relatively minor in rela-tion to the potential for cerebral injury caused by cerebral edema, and therefore hyperosmolar treat-ment should be strongly considered if cerebral edema is suspected. Aggressive hyperventilation has been shown to be associated with a greater likelihood of an adverse outcome in DKA-related cerebral edema; therefore, this should probably be avoided unless necessary to avoid cerebral herniation.16

Hypoglycemia in Children With DiabetesHypoglycemia, the most common complication of type 1 diabetes in childhood, can occur in any child in whom the dose of administered insulin exceeds insulin requirements. Albeit less frequent-ly, hypoglycemia can also occur in patients with type 2 diabetes on oral hypoglycemic or insulin regimens. Responses to hypoglycemia include release of counterregulatory hormones, such as glucagon, epinephrine (adrenaline), cortisol, and growth hormone. However, over time both the glucagon and epinephrine (adrenaline) responses might be impaired, increasing the risk of persistent hypoglycemia due to lack of adrenergic symptoms.

The American Diabetes Association criteria for the clinical classification of hypoglycemia in patients with DM include all episodes of an abnormally low plasma glucose concentration (<70 mg/dL or <3.9 mmol/L) with or with-out symptoms that expose the individual to harm.17,18 A glucose concentration of 70 mg/dL is higher than the value used to diagnose hypo-glycemia in people without diabetes; however, it is considered an appropriate threshold because it approximates the lower limit of the physi-ologic fasting nondiabetic range, the normal

cerebral edema have been found in a large study of DKA5 and administration of bicarbonate has not been found to hasten resolution of DKA.13

In rare cases of symptomatic hyperkalemia or acidosis severe enough to cause hemodynamic instability not responsive to other therapeutic measures, however, cautious administration of bicarbonate should be considered.

Electrolyte ImbalancesRegardless of the serum potassium concentration at presentation, total body potassium is depleted in patients with DKA. With the treatment of DKA, serum potassium concentrations can decrease rapidly as insulin and fluid therapy improve the state of acidosis and potassium shifts to the in-tracellular space. Potassium should typically be added to the IV fluids at the time of initiation of insulin treatment, provided that adequate renal function is verified. For patients presenting with hypokalemia, potassium replacement should begin sooner. For patients with initial hyper-kalemia, potassium replacement should begin after potassium levels decrease to the normal range. Potassium replacement should be given as a mixture of potassium chloride and potas-sium phosphate or potassium acetate at a con-centration of 30 to 40 mEq/L. Although severe hypophosphatemia occurs rarely in children with DKA, the consequences (eg, rhabdomyolysis and hemolytic anemia) can be devastating.14,15 There-fore, it seems prudent to administer a portion of the potassium replacement as the phosphate salt, although a thorough study of this issue is lacking.

Monitoring and Treating ComplicationsGlucose concentrations should be measured hourly using a bedside glucose meter throughout the period of IV insulin treatment. A reasonable rate of decline in the serum glucose concentration is approximately 50 to 100 mg/dL per hour.6,7 With the initial infusion of IV fluids and restora-tion of renal perfusion, however, glucose concen-trations might decrease more rapidly. Electrolyte concentrations should be measured every 3 to 4 hours or more frequently if severe abnormalities are present.

Careful monitoring is essential for early detec-tion of complications of DKA, particularly cerebral edema. Therefore, neurologic and mental status should be checked hourly. Although the effective-


Hypoglycemia in Children With Diabetes 16-9

glycemic threshold for glucose counterregu-latory hormone secretion, and the highest antecedent glucose level reported to reduce sympathoadrenal responses to subsequent hy-poglycemia.19 It has been debated that a cutoff value of less than 63 mg/dL (3.5 mmol/L) is preferable to avoid overclassification of hypo-glycemia in asymptomatic patients.20–23

In children, the risk of hypoglycemia is as-sociated with younger age,24 tighter glycemic control,25 insulin regimens with fixed dosing (as opposed to therapy that delivers a basal insulin dose/infusion rate with intermittent boluses to cover for intake),26–29 exercise (due to increased insulin absorption, more rapid glucose utiliza-tion, and increased insulin sensitivity), acute illness (particularly when associated with nau-sea, vomiting, and anorexia), psychological disturbance, lower socioeconomic status, and occurrence of one or more prior hypoglycemic episodes.30 In children and adolescents receiv-ing intensive therapy, the risk of severe hypogly-cemia is increased more than threefold. Finally, the risk is also increased at night due to a sleep-induced blunted counterregulatory hormone response to hypoglycemia.17,19,31

Clinical FeaturesHypoglycemic symptoms can be adrenergic due to epinephrine (adrenaline) release and/or neuro-glycopenic due to direct effects of hypoglycemia on the central nervous system (CNS). Adrenergic symptoms include tremor, pallor, tachycardia, palpitations, and diaphoresis. Neuroglycopenic symptoms include fatigue, lethargy, headaches, behavior changes, drowsiness, unconsciousness, seizures, or coma. The severity of the neuroglyco-penic symptoms increases with the severity of hy-poglycemia and resultant CNS energy deprivation.

The severity of hypoglycemia is classified by both symptoms and the clinical intervention required.17 Mild hypoglycemia is associated with adrenergic and mild neuroglycopenic symptoms, such as headaches and mood changes in older children and poor feeding, lethargy, jitteriness, and hypotonia in infants and toddlers. In such cases, oral intake of a rapidly absorbed carbohy-drate is generally adequate treatment. Patients with moderate hypoglycemia are neurologi-

cally impaired to a level that requires help from a second person to administer oral therapy. In the absence of a person to aid therapy, moderate episodes could escalate in severity. Severe hypo-glycemia is recognized by the presence of criti-cal neurologic symptoms (seizures or coma) or requirement for intervention with subcutaneous glucagon and/or IV dextrose. Case reports exist of acute and transient cortical blindness and stroke-like hemiparesis associated with severe hypogly-cemia.32,33 Unlike mild episodes of hypoglycemia that are relatively frequent in children with type 1 DM, severe hypoglycemic events are uncom-mon, occurring at a rate of approximately 5 to 19 events per 100 patient-years.1,2

Diagnostic Studies and ManagementPatients with mild and moderate hypoglycemia should be treated orally with a concentrated and rapidly absorbed simple carbohydrate source, such as glucose tablets, fruit juice, or cake frost-ing; 15 to 20 g of oral glucose is typically suf-ficient. A snack containing a mixed food source should follow to sustain normal blood glucose level. Blood glucose levels should be checked every 15 to 20 minutes for approximately 2 hours to confirm that glucose values have nor-malized and to determine whether further inter-vention is necessary. The patient might require additional carbohydrates until normal blood glucose levels are sustained.

A patient with diabetes presenting with altered mental status should have glucose concentration assessed rapidly with a bedside glucose meter. Hypoglycemia, if present, should be corrected as rapidly as possible with an IV infusion of 0.5 g/kg of dextrose. This can be accomplished by infusing 5 mL/kg of 10% dex-trose in an infant, 2 mL/kg of 25% dextrose in a toddler, or 1 mL/kg of 50% dextrose in older children (note the “50 rule”: the product of the milliliters per kilogram dose and the percentage of dextrose should equal 50). In the event that IV access cannot be established rapidly, gluca-gon should be given via subcutaneous or intra-muscular injection. The accepted dose is 0.02 to 0.03 mg/kg or 0.5 mg for children weighing less than 20 kg and 1 mg for children weighing greater than 20 kg. If neurologic or mental status



venous sample should be sent to the laboratory for measurement with greater accuracy. Treat-ment for hypoglycemia should not be delayed while awaiting results. At the time that the confirmatory sample is drawn, an additional serum sample (enough for special studies) should be obtained for future measurement of hormone concentrations and other biochemi-cal measures. It is essential that this sample be drawn at the time of the hypoglycemic event. Without information from this sample, it is usu-ally impossible to determine the cause of the hypoglycemic episode. If hypoglycemia is con-firmed, the measurements to be obtained on the initial sample include serum insulin, cortisol, and growth hormone concentrations, as well as serum ketones, lactate, and free fatty acid concentrations.36 A toxicologic evaluation for ethanol, salicylates, -blockers, and oral hypoglycemic agents should also be considered. Remaining serum from the initial sample should be stored for additional biochemical testing if necessary. Finally, a urine sample should also be obtained and tested for ketones and reduc-ing substances. An additional sample of urine should likewise be stored for future testing.

Differential DiagnosisThere are many possible causes of hypoglyce-mia, and a discussion of all causes is beyond the scope of this chapter. Among the more fre-quent causes (in patients without DM) are toxic

abnormalities persist for prolonged periods after correction of hypoglycemia, other possibilities should be considered, such as toxic ingestions and other intracranial disease.

Hypoglycemia in Nondiabetic Children Hypoglycemia can result from excessive insulin production (insulinoma or hyperinsulinism) or decreased concentrations of counterregulatory hormones (deficiencies of growth hormone, cortisol, or both). Hypoglycemia can also result from inborn metabolic errors that impair gluco-neogenesis, glycogenolysis, or fatty acid oxida-tion. Unsuspected hypoglycemia can be found when patients present to the ED with episodes of acute illness. A recent study revealed that a substantial percentage (28%) of these patients had previously undiagnosed fatty acid oxidation defects (19%) or endocrine disorders (9%).34

Clinical FeaturesInfants with hypoglycemia can present with jitteriness, poor feeding, lethargy, hypotonia, hypothermia, apneic episodes, or seizures. Symptoms of hypoglycemia in infants might also be subtle and less obvious than those in older children. In older children, symptoms of hypoglycemia include headaches; vision changes; mental status changes, such as con-fusion, lethargy, irritability, or anxiety; and seizures. Adrenergic symptoms, such as palpita-tions, sweating, pallor, and tremulousness, are usually also present. Hypoglycemia should be considered in all patients presenting with un-explained alterations in mental status, seizure, or loss of consciousness, and a routine bedside test for hypoglycemia should be part of pediatric resuscitation procedures.35

Diagnostic StudiesIf hypoglycemia is suspected, a rapid glucose test should be performed using a bedside blood glucose meter. A glucose concentration less than 50 mg/dL should be considered abnormal and the patient treated. If the bedside test reveals a low glucose concentration, a confirmatory

W H AT E L S E ?

Differential Diagnosis of Hypoglycemia

• Toxins(oralhypoglycemicagents,

ᵝ-blockers, ethanol)

• Hypopituitarism

• Adrenalinsufficiency

• Fattyacidoxidationdefects

• Hyperinsulinism

• Ketotichypoglycemia

• Sepsis


Adrenal Insufficiency/Congenital Adrenal Hyperplasia 16-11

should equal 50). Subsequently, an IV infusion of 10% dextrose at 1.5 times maintenance rates should be provided to maintain glucose con-centrations in the normal range and reverse the catabolic state. If adrenal insufficiency is known or strongly suspected and adequate samples have been set aside for further study, IV hydro-cortisone should be given (50 mg for children younger than 4 years and 100 mg for children older than 4 years).

Adrenal Insufficiency/Congenital Adrenal HyperplasiaAdrenal insufficiency can be related to processes directly affecting the adrenal gland (primary), or it can result from adrenocorticotropic hormone (ACTH) deficiency (secondary). Both primary and secondary adrenal insufficiency are char-acterized by inadequate production of cortico-steroids that can culminate in “adrenal crisis,” a life-threatening cardiovascular collapse. How-ever, in secondary adrenal insufficiency miner-alocorticoid function is preserved.

The causes of adrenal insufficiency in child-hood are varied. Congenital adrenal hyperplasia is the most common form of primary adrenal insufficiency in children, with an incidence of 1 in 10,000 to 18,000 live births.37 Congeni-tal adrenal hyperplasia is a group of autosomal recessive inherited adrenal steroidogenesis en-zyme deficiencies (most often 21-hydroxylase) that cause various degrees of adrenal cortical inability to synthesize cortisol. In childhood, acquired primary adrenal insufficiency is rela-tively uncommon and can result from autoim-mune adrenal destruction, infectious infiltration (by tuberculosis, most commonly worldwide), or inherited adrenoleukodystrophy syndromes. Furthermore, long-term treatment with glu-cocorticoids can result in secondary adrenal insufficiency by the suppressive effect on the hypothalamic-pituitary-adrenal axis.38 In fact, the most common cause of acute adrenal insuffi-ciency in North America today is glucocorticoid withdrawal or omission in patients being treated for a variety of disorders with pharmacologic

ingestions (eg, oral hypoglycemic agents,

ᵝ-blockers, and ethanol), sepsis, hypopituita-rism, adrenal insufficiency, fatty acid oxidation defects, hyperinsulinism, and ketotic hypogly-cemia. Analysis of the initial serum sample will differentiate among many of these entities and will indicate whether additional analyses are necessary to investigate less frequent causes of hypoglycemia.

ManagementHypoglycemia should be corrected as rapidly as possible with an IV infusion of 0.5 g/kg of glucose (dextrose). This can be accomplished by infusing 5 mL/kg of 10% dextrose in an infant, 2 mL/kg of 25% dextrose in a toddler, and 1 mL/kg of 50% dextrose in older children (note the “50 rule”: the product of the milliliters per kilogram dose and the percentage of dextrose


Signs and Symptoms of Hypoglycemia

• Infants:jitteriness,poorfeeding,lethargy,hypotonia, hypothermia, apnea, seizures

• Children:headaches,alteredmentalstatus, diaphoresis, pallor, palpitations, tremulousness, seizure

K E Y P O I N T S

Diagnosis and Management of Hypoglycemia

• Performrapidbedsideglucosetesting for altered level of consciousness, seizure, or lethargy.

• Obtainadditionalbloodandurinesamples at the time of the hypoglycemic event.

• Administerdextrose:5mL/kgof 10% dextrose in an infant, 2 mL/kg of 25% dextrose in a toddler, and 1 mL/kg of 50% dextrose in older children.



secondary adrenal insufficiency is commonly as-sociated with signs and symptoms of additional pituitary hormone deficiencies, such as growth failure, delayed puberty, secondary hypothy-roidism, and/or diabetes insipidus (DI).

Adrenal crisis continues to occur in children with known primary or secondary adrenal in-sufficiency during intercurrent illness because of failure to increase glucocorticoid dosing.

It is important to recognize that other hormones affect cortisol metabolism and can influence the onset or progression of adrenal insufficiency. It is well documented that ini-tiation of thyroid hormone replacement in an individual with hypothyroidism accompanied by unrecognized adrenal insufficiency can precipi-tate an adrenal crisis. The mechanism that pre-cipitates adrenal crisis is not fully understood, but it is hypothesized that hypothyroid patients have reduced cortisol requirements secondary to a reduced metabolic rate.41,42 When thyroxine therapy is initiated, the metabolic rate and cortisol requirements increase, and an adrenal crisis can ensue. Accordingly, hyperthyroidism can increase cortisol metabolism. It is suggested that in the individual with hyperthyroidism and adrenal insufficiency, cortisol replacement should be in-creased as much as twofold because of increased cortisol clearance.38 Growth hormone appears to decrease conversion of inactive cortisone to ac-tive cortisol. Therefore, after growth hormone therapy is initiated, a patient with unrecognized concomitant adrenal dysfunction might be vul-nerable.43 Pregnancy is associated with increased corticosteroid-binding globulin and therefore

corticosteroid doses administered by various routes. Treatment courses as brief as 2 weeks can result in transient suppression of endogenous cortisol production.39

Clinical FeaturesClinical manifestations of adrenal insufficiency depend on the age of the patient, the cause, and whether it is a chronic or an acute process. All cas-es must be considered potentially life-threatening.

Infants with adrenal insufficiency can pres-ent with poor feeding, vomiting, and lethargy. On physical examination, patients are typically hypotensive and have tachycardia. In primary adrenal insufficiency, electrolyte abnormalities can occur due to additional mineralocorticoid deficiency. Severe hyperkalemia can cause life-threatening cardiac arrhythmias. Depending on the specific enzymatic defect and karyotype of an infant with CAH, the genitalia can appear malformed. In the most common form of CAH (21-hydroxylase deficiency), genetic female infants will likely have ambiguous genitalia, whereas genetic male infants have normally formed genitalia. Infants of both sexes with CAH can have skin hyperpigmentation, particu-larly in the genitalia, due to high concentrations of ACTH. The salt-wasting form of classic CAH presents with a primary metabolic crisis in the first weeks of life, regardless of sex. Infants with secondary adrenal insufficiency due to hypopi-tuitarism might have midline facial malforma-tions (Figure 16.2) and male infants might have a microphallus.

Patients of all ages with acute adrenal insuf-ficiency can present with dehydration, hypoten-sion, hypoglycemia, or altered mental status. Hypoglycemia is more common in young chil-dren. Altered mental status can occur at any age with or without hypoglycemia.40 Patients with chronic adrenal insufficiency usually experience fatigue, anorexia, nausea, vomiting, loss of ap-petite, weight loss, and recurring abdominal pain. Salt craving is common in chronic primary adrenal insufficiency, as is postural hypotension. Hyperpigmentation and salt craving are not ob-served in patients with secondary adrenal insuf-ficiency. Furthermore, unless there is a history of recent pharmacologic glucocorticoid therapy,

Figure 16.2 Midline facial malformation.


Adrenal Insufficiency/Congenital Adrenal Hyperplasia 16-13

disorders, neurologic diseases, or child abuse. The presence of hyperkalemia, hyponatremia, acidosis, skin hyperpigmentation, and mascu-linized genitalia in a genetic female can help to differentiate primary adrenal insufficiency from these other entities. In an older child, mild symptoms of primary adrenal insufficien-cy might be confused with mononucleosis or anorexia nervosa. More severe symptoms can mimic infections (eg, sepsis), hematologic dis-ease, psychiatric illness, or even an acute abdo-men. Again, the presence of hyperpigmentation and the characteristic laboratory abnormalities serve to differentiate these entities. Secondary adrenal insufficiency can be even more diffi-cult to differentiate from other entities because of the lack of hyperpigmentation and the lack of specific laboratory features other than hy-poglycemia. In these cases, a history of CNS

lower free cortisol levels during the last trimester, thus necessitating an increase in hydrocortisone dosing by 50%. In addition, increasing intrapar-tum progesterone levels antagonize the mineralo-corticoid effect, which can dictate adjustment of fludrocortisone supplementation as well.38

Certain medications interfere with cortisol metabolism as well and must be considered in patients with adrenal disorders. Some drugs inhibit cortisol biosynthesis, including amino-glutethimide, etomidate, ketoconazole, metyra-pone, medroxyprogesterone, and megestrol.39,44 In addition, certain drugs accelerate cortisol metabolism, such as phenytoin, barbiturates, and rifampin.40

Diagnostic StudiesBlood should be drawn to test for cortisol, elec-trolytes, glucose, ACTH, plasma renin activity, and aldosterone before glucocorticoid therapy, if possible. When CAH is suspected, serum 17-hydroxyprogesterone concentration should be measured as well. Measurement of urinary sodium and potassium concentrations is helpful in assessing mineralocorticoid status and in dif-ferentiating from other hyponatremic conditions.

In primary adrenal insufficiency, testing typically reveals hyperkalemia, hyponatremia, hypoglycemia, and acidosis. However, not all patients manifest all of these laboratory abnor-malities, and the diagnosis cannot be excluded based on the absence of one or more of these findings. Both BUN and creatinine concentra-tions can be elevated due to dehydration. In sec-ondary adrenal insufficiency, hyperkalemia and hyponatremia are absent due to preservation of mineralocorticoid production, and hypoglycemia might be the primary biochemical abnormality.

Differential DiagnosisMost of the symptoms of adrenal insufficiency are nonspecific, and many overlap with other, more common, diagnoses. In infancy, for ex-ample, adrenal insufficiency might be confused with other illnesses that present with lethargy, vomiting, poor weight gain, hypotension, and tachycardia, including sepsis, gastrointestinal malformations, congenital heart disease, in-born errors of metabolism, certain hematologic


Signs and Symptoms of Adrenal Insufficiency

• Infants:poorfeeding,inadequateweightgain, vomiting, lethargy, hypotension, and tachycardia, with or without hyperpigmentation or masculinization of genetic female genitalia

• Children:fatigue,weightloss,andpostural hypotension, with or without hyperpigmentation, and abdominal pain

• Otherclues:historyofCNSsurgeryor tumors or prolonged or long-term corticosteroid use


Classic Laboratory Findings in Adrenal Insufficiency

• Primaryadrenalinsufficiency:hyperkalemia, hyponatremia, hypoglycemia, and acidosis

• Secondaryadrenalinsufficiency:hypoglycemia



is even suspected. If the patient has good gas-trointestinal function, fludrocortisone (0.1 to 0.2 mg/d), a synthetic mineralocorticoid, can be administered orally. However, typically, admin-istration of IV sodium chloride along with stress doses of hydrocortisone are sufficient to begin normalizing electrolyte abnormalities, making the addition of mineralocorticoid unnecessary in the initial phase of treatment.48

Severe hyperkalemia, resulting in a non-perfusing dysrhythmia, should be treated im-mediately with IV calcium gluconate to restore a perfusing rhythm. This should be followed by IV sodium bicarbonate, nebulized albuterol (sal-butamol), and/or glucose with insulin to shift

tumors, neurosurgical procedures, congenital CNS malformations, other coincident pituitary hormone deficiencies (suggested clinically by short stature, inappropriately absent or delayed puberty, or polyuria, as examples), or prolonged exogenous glucocorticoid use must be relied on for the diagnosis. Secondary adrenal insufficien-cy can evolve over time in patients with cranial radiation, septo-optic dysplasia, autoimmune hypophysitis, and head trauma.45–47

ManagementIn the hypotensive patient with adrenal insuf-ficiency, it is imperative to rapidly restore intra-vascular volume with isotonic sodium chloride containing glucose and to administer glucocor-ticoids expeditiously. An initial fluid bolus of normal saline (20 mL/kg) should be given and repeated as necessary to improve perfusion. Af-ter the initial bolus(es), a continuous infusion of normal saline with 5% dextrose should be given. On the basis of body surface area, the recom-mended stress dose of IV hydrocortisone is 50 to 75 mg/m2 initially followed by 50 to 75 mg/m2 per day divided into four doses.40 It is reason-able to approximate IV hydrocortisone dosing and administer immediately 50 mg for children younger than 4 years and 100 mg for children older than 4 years. The benefits of sufficient dosing greatly outweigh the risk of underdos-ing in such cases. Hydrocortisone can be given intramuscularly if no IV access exists, although the effects of intramuscular administration is slower and can be ineffectively absorbed if pe-ripheral perfusion is poor. Comparable body surface area stress doses are 10 to 15 mg/m2

for methylprednisolone and 1.5 to 2 mg/m2 for dexamethasone; the latter two corticosteroids have minimal mineralocorticoid activity. Pred-nisone is not a preferred glucocorticoid because it must be converted to prednisolone for it to have glucocorticoid activity, and in patients with liver failure, this conversion might be impaired. Dexamethasone can be used if one desires to treat the patient urgently but wishes to perform a diagnostic ACTH-stimulation test because this glucocorticoid will not interfere with diagnostic laboratory assays. Treatment should never be withheld if the diagnosis of adrenal insufficiency

W H AT E L S E ?

Differential Diagnosis of Adrenal Insufficiency

• Infants:infections,gastrointestinalmalformations, congenital heart disease, inborn errors of metabolism, hematologic disorders, neurologic disease, or child abuse

• Children:mononucleosis,anorexianervosa, infections, hematologic disease, psychiatric illness, or an acute abdomen

K E Y P O I N T S

Management of Adrenal Insufficiency

• Initiatefluidresuscitation(20mL/kgofnormal saline bolus).

• Administerhydrocortisone(50mgforchild <4 years and 100 mg for child >4 years).

• Treatsymptomatichyperkalemia(calciumgluconate, bicarbonate, insulin, albuterol [salbutamol]).

• Treatmentconsistsofstressdosagesofhydrocortisone, IV fluids, and correction of hyperkalemia.


Diabetes Insipidus 16-15

gene or autosomal recessive or dominant muta-tions in the AQP-2 gene. These cases typically present in infancy.56 Acquired nephrogenic DI can be caused by various conditions, includ-ing primary renal disease, obstructive uropathy, hypokalemia, hypercalcemia, sickle cell disease, and medications such as lithium and demeclo-cycline (a tetracycline). In addition, prolonged polyuria of any cause can also lead to some de-gree of nephrogenic DI because of a reduction of tonicity in the renal medullary interstitium and a subsequent decrease in the gradient necessary to concentrate urine.50,53,57

Clinical FeaturesCharacteristic symptoms of DI are pronounced polyuria and polydipsia. Older children typi-cally present without any obvious abnormalities on physical examination as long as they have an intact sense of thirst, access to fluids, and no ongoing losses, such as diarrhea. They might report a history of nocturia and secondary en-uresis. Infants, in addition to polyuria and poly-dipsia, frequently demonstrate irritability, poor weight gain, failure to thrive, hyperthermia, and signs of dehydration. Developmental delays and arrest of variable severity can ensue after repeated episodes of dehydration if the condi-tion remains untreated. Hydronephrosis can be detected in all age groups. Interestingly, symp-toms of DI might not be apparent in patients with coexisting untreated anterior pituitary-mediated adrenal glucocorticoid insufficiency because cortisol is required to generate normal free water excretion.58

Diagnostic StudiesInfants generally present with hypernatremia and serum hyperosmolality because they have limited access to fluids. Coincident inappro-priately dilute urine (<300 mOsm/L) helps to establish the diagnosis. Older children usually do not present with hypernatremia or hyperos-molality unless their fluid intake is restricted, their thirst mechanism is abnormal, or they are experiencing excessive losses. In unclear cases, a carefully monitored “water deprivation test” is recommended, whereby the fasting patient is monitored for 8 to 10 hours with serial

potassium intracellularly. If there is a coexisting cardiomyopathy and/or acute renal failure pro-hibiting rapid rehydration, aggressive therapy of hyperkalemia might be needed.

Diabetes InsipidusUnder normal circumstances, plasma osmolality is maintained within a narrow range (280–295 mOsm/L). This homeostasis requires adequate water intake, regulated by an intact thirst mech-anism and appropriate free water excretion by the kidneys, which is mediated by adequate posterior pituitary secretion and peripheral ac-tion of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH). Diabetes insipi-dus is caused by a deficiency in the produc-tion or secretion of ADH (central DI) or due to resistance to ADH in the kidneys (nephrogenic DI).49,50 Symptoms of DI result from the effec-tive inability to reabsorb free water at the level of the collecting duct in the nephrons of the kidney. Polyuria, polydipsia, and hypo-osmolar urine characterize this disorder. Hypernatremia might be present as well at the time of diagnosis, particularly in infants or children with develop-mental delay. An intact thirst mechanism and access to drinking water minimize the risk of dehydration and hypernatremia.

Central DI is rarely congenital and more frequently acquired. Congenital central DI can be caused by structural malformations or by autosomal dominant or recessive mutations in the gene encoding vasopressin-neurophysin II.51 Acquired forms of central DI can occur at any age in association with a variety of disorders in which there is destruction or degeneration of vaso-pressinergic neurons that can be caused by CNS tumors (craniopharyngioma or germinoma), infections (meningtis or encephalitis), head trauma, neurosurgery, vascular disorders, granuloma, and autoimmune disorders (lymphocytic in-fundibuloneurohypophysitis). Idiopathic DI is a diagnosis of exclusion and one that is made with decreasing frequency as a result of improved sensitivity of diagnostic technology.50,52–55

Much like central DI, nephrogenic DI can be genetic or acquired. The genetic causes de-scribed are inactivating mutations of the AVPR2



Differential DiagnosisThe principal presenting sign of DI is polyuria, which, in addition to deficiency or impaired responsiveness to ADH, can result from an os-motic agent, such as hyperglycemia as seen in DM, or from excessive water intake (primary polydipsia). Patients with hypercalcemia or hypokalemia can also have impaired urinary concentrating ability, resulting in polyuria.

ManagementPatients without hypernatremia and dehydration do not require immediate intervention for DI but should undergo evaluation to determine the underlying cause. Patients with hypernatremic dehydration and hyperosmolality should be treated with fluid resuscitation. This includes an initial 20-mL/kg fluid infusion of normal saline to restore perfusion followed by subsequent slow correction because overly aggressive free water replacement can lead to cerebral edema. In ad-dition to correcting the fluid deficit, the manage-ment of central DI includes treating the primary disease and normalization of urine output with

measurements of body weight, serum sodium and osmolality, and urine volume and osmolality. If urine osmolality of greater than 750 mOsm/L is achieved with any degree of water depriva-tion, DI can be excluded.59 The diagnosis of DI is established at any time point if serum osmolality rises above 300 mOsm/L and urine osmolality remains below 300 mOsm/L Urine osmolality in the 300- to 750-mOsm/L range during water deprivation can indicate par-tial DI.53 During the test, if DI is suspected, an ADH plasma sample should be obtained, and then ADH, or a synthetic analog (desmopres-sin), should be administered to further distin-guish ADH deficiency (central DI) from ADH unresponsiveness (nephrogenic DI).

If central DI is suspected, an MRI of the brain, with particular attention to the hypo-thalamic-pituitary region, is indicated. The posterior pituitary hyperintensity (bright spot) on T1-weighted MRIs is often absent in central DI.54,60–62 However, the absence of the bright spot is neither sensitive nor specific for this di-agnosis because it can be absent in healthy in-dividuals63 and, conversely, present in children with central DI as well.64 In central DI patients, a normal MRI does not exclude the possibility of an evolving occult hypothalamic-stalk lesion, and therefore follow-up with cerebrospinal flu-id (CSF) tumor markers and cytology, serum tumor markers, and serial contrast-enhanced brain MRIs for early detection is critical.55 In-tracerebral calcifications of the frontal lobes and basal ganglia can result from repeated episodes of dehydration.65 Ultrasonography can be help-ful in detecting nonobstructive hydronephrosis, hydroureter, and megabladder, resulting from longstanding polyuria and polydipsia.66


Signs and Symptoms of DI

• Infants:failuretothrive,irritability,hyperthermia, dehydration

• Children:polyuria,polydipsia,absence of DM


Laboratory Findings in Infants and Children With DI

• Infants:hypernatremia,hyperosmolality,inappropriately dilute urine

• Children:diluteurine,nocturia,secondaryenuresis

W H AT E L S E ?

Differential Diagnosis of DI

• HyperglycemiafromDM

• Primarypolydipsia

• Hypercalcemia

• Hypokalemia


Syndrome of Inappropriate Secretion of Antidiuretic Hormone 16-17

agents (eg, phenothiazines or tricyclic antidepres-sants); (4) various pulmonary disorders and in-terventions (eg, pneumonia, asthma, or positive pressure ventilation); (5) non-CNS tumors with ectopic production of ADH; (6) patients treated with desmopressin acetate who drink excessive amounts of fluids (typically habit driven); and (6) miscellaneous causes, such as AIDS, postopera-tive state, glucocorticoid deficiency, and severe hypothyroidism.70,71

Clinical FeaturesPatients with SIADH frequently will not mani-fest symptoms of hyponatremia until the serum sodium concentration falls below 120 mEq/L. Below this level, symptoms can include anorex-ia, nausea, vomiting, lethargy, irritability, and confusion. Severe hyponatremia can culminate in seizures and loss of consciousness.

Diagnostic StudiesOn the basis of criteria established by Bartter and Schwartz,72 the diagnosis of SIADH is made when the following constellation occurs: (1) plasma hypo-osmolality (<275 mOsm/L), (2) less than maximally dilute urine (urine osmolality >100 mOsm/L), (3) clinical euvolemia, (4) natriuresis (urine sodium >40 mEq/L), (5) normal renal func-tion, and (6) no evidence of thyroxine or corti-sol deficiency. Typically, BUN concentrations are normal or low. Causes of pseudohyponatremia should be excluded such as that due to hyperlip-idemia, hyperproteinemia, and the osmotic effect of hyperglycemia. Most patients with SIADH have inappropriately measurable or elevated levels of plasma ADH relative to plasma osmolality.

Differential DiagnosisOther causes of hyponatremia include water in-toxication (primary polydipsia or iatrogenic), hyponatremic dehydration, adrenal insufficien-cy, renal failure, diuretic medications, nephrotic syndrome, cirrhosis, congestive heart failure, severe hypothyroidism, cystic fibrosis, and cerebral salt-wasting (CSW) syndrome. These diagnoses can generally be excluded based on the absence of corresponding diagnostic signs, such as dehydration, edema, and hyperkalemia.

desmopressin. Desmopressin is an ADH analog with markedly reduced pressor activity in com-parison with native ADH and a longer half-life and can be administered orally, intranasally, or by subcutaneous injection. In infancy, if polyuria is not excessive, central DI can be best managed with extra fluid intake alone to avoid a potential risk of hyponatremia associated with desmopres-sin treatment. In cases of nephrogenic DI, the mainstay of treatment, particularly in infancy, is thiazide diuretics in combination with either amiloride or indomethacin.65–68

Syndrome of Inappropriate Secretion of Antidiuretic HormoneSyndrome of inappropriate secretion of antidi-uretic hormone (ADH or AVP) is characterized by excessive kidney resorption of free water, result-ing in hyponatremia and hypo-osmolar serum in association with inappropriately concentrated urine and natriuresis.69–71 Several disorders and medications are associated with SIADH: (1) CNS disorders or damage, such as meningitis or en-cephalitis, cerebral hemorrhage, head trauma, or after neurosurgical procedures; (2) psychiatric disorders; (3) a large variety of pharmacologic

T H E B O T T O M L I N E

Key Concepts in the Diagnosis and Management of DI

• DIshouldbesuspectedinchildrenwithout DM who present with polyuria and dilute urine.

• Hypernatremiagenerallywillnotoccurinchildren with normal thirst mechanisms and free access to water.

• Hypernatremiaismorefrequentlyencountered in infants.

• EDmanagementincludescautiousfluidadministration to correct dehydration while promoting gradual hypernatremia correction and, in appropriate situation, diagnostic evaluation initiation.



ManagementThe mainstay of SIADH therapy for patients with mild or no symptoms is fluid restriction, treatment of the underlying disorder, or discon-tinuation of use of an offending drug. Ultimately, replacement of sodium loss might also be nec-essary, but it can usually be achieved through dietary salt intake. Severe hyponatremia (serum sodium <120 mEq/L), particularly when asso-ciated with CNS disturbance (lethargy, coma, or seizures), might require treatment with IV hypertonic saline (3% sodium chloride solu-tion). The correct dosage of 3% sodium chlo-ride solution can be calculated based on the assumption that 12 mL/kg of 3% sodium chlo-ride solution will increase the serum sodium concentration by 10 mEq/L. It is generally rec-ommended that plasma sodium be corrected at a rate of no greater than 0.5 mEq/L per hour, with an overall correction that does not exceed 12 mEq/L in the initial 24 hours and 18 mEq/L in the initial 48 hours of treatment. Therapy should continue until neurologic symptoms improve and a safe level of approximately 120 to 125 mEq/L is achieved. Further treatment can then be accomplished with fluid restriction. Serial rapid bedside serum sodium testing is preferred when administering hypertonic saline

Euvolemia in chronic SIADH is a critical distinguishing factor in the evaluation of a pa-tient with serum hypo-osmolality; it is thought to represent an adaptation to water overload me-diated, in part, at the cellular level through de-pletion of intracellular electrolytes (potassium) and organic osmolytes.70 Natriuresis, thought to be mediated in part through secretion of atrial natriuretic peptide, also contributes to volume regulation in chronic SIADH.73

The CSW syndrome is particularly important to exclude because it occurs in overlapping clini-cal settings with SIADH.74 Cerebral salt-wasting syndrome is characterized by renal sodium and fluid loss. However, the hypo-osmolality, hypo-natremia, and natriuresis in CSW syndrome are associated with volume contraction and clinical signs of dehydration (including elevated BUN and creatinine concentrations), helping to dis-tinguish this syndrome from SIADH.70


Signs and Symptoms of SIADH

• Hyponatremiainassociationwithheadtrauma, cerebral hemorrhage, or other intracranial conditions

• Clinicalsymptomsandsignsofhyponatremia, including anorexia, nausea, vomiting, lethargy, irritability, altered level of consciousness, and seizures


Laboratory Findings in Patients With SIADH

• Serumhypo-osmolality(<275mOsm/kg)

• Urinehyperosmolality(>100mOsm/L)

• Inappropriatenatriuresis(>40mEq/L)

• Normalrenal,thyroid,andadrenalcortical function

W H AT E L S E ?

Differential Diagnosis of SIADH

• Waterintoxication

• CSWsyndrome

• Hyponatremicdehydration

• Adrenalinsufficiency

• Renalfailure

• Diureticuse

• Nephroticsyndrome

• Hypothyroidism

• Cysticfibrosis

• Congestiveheartfailure

• Cirrhosis


Water Intoxication 16-19

well. Certain psychiatric illnesses, particularly schizophrenia, can be associated with compul-sive water drinking. It is presumed that a central defect in thirst regulation plays an important role in the pathogenesis of primary polydipsia in these patients.77–80 In some cases, for example, the osmotic threshold for thirst is reduced below the threshold for the release of ADH81; therefore, these patients will continue to drink until the plasma tonicity is less than the threshold level. Drug therapy can also contribute to the increase in water intake in schizophrenic patients. Many antipsychotic drugs induce the sensation of a dry mouth, which will enhance thirst.82

Clinical FeaturesClinical manifestations of water intoxication re-sult from hyponatremia. Infants typically present with poor feeding, vomiting, and lethargy. Hypo-thermia and edema might also be present. With severe hyponatremia, seizures can occur and might be prolonged. It has been suggested that hypothermia can be a specific marker for hypo-natremia in infants with a new onset of seizures.83

Diagnostic StudiesHyponatremia (serum sodium concentration <130 mEq/L) with coinciding dilute urine is the hallmark of this condition. Serum potas-sium, urea nitrogen, and creatinine concentra-tions are typically normal, and acidosis is not present, which helps exclude other causes of hyponatremia. Fictitious hyponatremia should be excluded which can occur with hyperlipid-emia, hyperproteinemia, or due to the osmotic effect of hyperglycemia.

Differential DiagnosisThe differential diagnosis of hyponatremia is ex-tensive and includes renal failure, diuretic use, renal tubular defects (renal tubular acidosis), SIADH, adrenal insufficiency, cystic fibrosis, ne-phrotic syndrome, cirrhosis, and congestive heart failure. Iatrogenic hyponatremia can also occur in infants or children when insensible losses are replaced with free water or other fluids deficient in sodium; this scenario differs, however, from classic water intoxication in that clinical and

to avoid excessive sodium correction. If SIADH and hyponatremia are acute (<48 hours), it is thought that hyponatremia can be corrected rapidly. However, if SIADH and hyponatremia are chronic (>48 hours), overzealous treatment can result in CNS damage, including central pontine myelinolysis.70 Concurrent use of a di-uretic, such as furosemide, might be indicated if volume expansion is severe. Other therapeutic approaches include the use of agents that in-duce nephrogenic DI, such as demeclocycline and lithium, although both are contraindicated, particularly in younger pediatric patients, be-cause of adverse effects. Urea has been used as an osmotic diuretic in pediatric SIADH.75 Once patient stabilization is achieved, a careful search for an underlying cause for SIADH is necessary if the cause is unknown.

Water IntoxicationWater intoxication occurs when daily water intake is excessive in relation to sodium. In infants, this situation occurs most frequently because of inappropriate dilution of formulas or misguided supplemental feedings of solute-free water.15,16 Excess water ingestion during infant swimming lessons has also been associated with this condition. Iatrogenic water intoxication is a well-known phenomenon, particularly in la-bor and delivery rooms.76 Water intoxication can be seen as a manifestation of child abuse as

K E Y P O I N T S

Management of SIADH

• Restrictfluidsinpatientswithmildornosymptoms.

• Treatwith3%sodiumchlorideincasesofsevere hyponatremia (serum sodium <120 mEq/L), particularly when associated with neurologic disturbance.

•Rapidcorrectionofchronichyponatremiacan precipitate central pontine myelinolysis.



laboratory features of dehydration are present and the urine is concentrated. A careful history, including infant feeding practices and psychiatric illness, in addition to the detection of dilute urine can lead to the diagnosis of water intoxication.

ManagementFor infants who are asymptomatic or have mild symptoms of hyponatremia, reinstitution of normal daily sodium with more restricted fluid intake is generally all that is required. For infants with severe manifestations of hyponatre-mia (pronounced lethargy, seizures, or coma), treatment with 3% sodium chloride solution should be initiated with caution.


Signs and Symptoms of Water Intoxication

• Poorfeeding

• Vomiting

• Lethargy

• Seizures

• Hypothermia


Laboratory Findings in Patients With Water Intoxication

• Hyponatremia(sodiumconcentration <130 mEq/L)

• Diluteurine

• Absenceofmetabolicacidosisanddehydration

K E Y P O I N T S

Diagnosis and Management of Water Intoxication

• Presentswithhyponatremiawithahistory of excessive water intake (relative to sodium).

• Infantwhopresentswithhypothermiawith seizures is a specific indicator for hyponatremia.

• Freewaterrestrictionandnormalizationof sodium intake are sufficient treatment in most instances.

• Hypertonic3%sodiumchloridesolutiontreatment can be used prudently in severely affected patients.


Metabolic Disease of the Newborn and Young Child: Inborn Errors of Metabolism 16-21

peroxisomes), metals, or complex molecules.90 Most IEMs are due to a defect in an enzyme or transport protein that results in a block in a metabolic pathway. Effects are caused by toxic accumulations of substrates before the block or from alternative metabolic pathway intermediates (disorders of protein metabolism, carbohydrate intolerance, metal metabolism, and porphyrias); defects in energy production and use within the brain, heart, liver, skeletal muscle, and other or-gans due to a deficiency of products beyond the block (disorders of carbohydrate metabolism [eg, gluconeogenesis, glycogenolysis, and glycogen storage disorders], fatty acid oxidation defects, and mitochondrial disorders); or disturbances in the synthesis or catabolism of complex molecules (lysosomal storage and peroxisomal disorders or defects in the metabolism of cholesterol, purines and pyrimidines, and neurotransmitters; and de-fects in glycosylation).85 Most IEMs have multiple forms that differ in age of clinical onset, severity, and even mode of inheritance. The IEMs most likely to result in acute, potentially life-threaten-ing decompensation include disorders of protein metabolism, defects in carbohydrate metabolism, fatty acid oxidation defects, and early-onset forms of mitochondrial and peroxisomal disorders. Lysosomal storage disorders, certain glyco-gen storage disorders, and late-onset forms of mitochondrial and peroxisomal disorders tend to have a chronic insidious progression that results in organ dysfunction and ultimately fail-ure. Inheritance is autosomal recessive for most IEMs (because many are enzyme deficiencies),

Metabolic Disease of the Newborn and Young Child: Inborn Errors of MetabolismEarly recognition of a possible inborn error of metabolism (IEM) in acutely ill patients is critical to minimize the high morbidity and mortality rates associated with these conditions. Although individually rare, IEMs collectively are relatively common.84 A diagnosis of IEM should be con-sidered not only in the evaluation and treatment of critically ill patients but also in patients with recurrent episodes of vomiting, lethargy, and/or seizures and those with chronically progressive neurologic abnormalities and/or organ dysfunc-tion. Usually, IEMs manifest in the neonatal pe-riod or infancy; however, presentation, can occur at any time throughout childhood and even in adulthood. Initial treatment of the critically ill child with an IEM does not require a detailed knowledge of individual IEMs or biochemical pathways but rather an understanding and early recognition of life-threatening clinical manifes-tations and consequences of the metabolic de-rangements.85–87 Prompt initiation of appropriate treatment is crucial for optimizing immediate and long-term outcome and is often lifesaving.

More than 400 IEMs have been identified since 1908.88 The incidence of IEMs is estimated to be as high as 1 in 1,000 live births.89 Inborn errors of metabolism are caused by single gene defects that result in abnormal synthesis, catabo-lism, and/or function of proteins, carbohydrates, fats, organelles (ie, lysosomes, mitochondria, and

CASE

SCE

NARI

O 2

A 14-month-old girl presents to the ED with a 1-day history of tactile fever, loss ofappetite,andintermittentemesis.Thismorning,shedidnotseeminterestedin her usual breakfast and seemed sleepier than usual. On examination, she has respirations of 40/min, a heart rate of 170/min, blood pressure of 80/40 mm Hg, and a temperature of 36.0°C (96.8°F). She appears lethargic and has mildly dry mucous membranes and no obvious source of infection. Bedside rapid glucose measurement reveals a blood glucose level of 20 mg/dL.

1. What therapeutic measures must be taken immediately?2. What laboratory tests would you order?3. What complications can occur as part of the disease process and secondary to

therapeutic intervention?



in gastroenteritis). Unusual dietary preferences, particularly protein or carbohydrate aversion, and symptoms occurring during diet changes are often seen in patients with an IEM. By late infancy or early childhood, it is often apparent that with routine illnesses, children with an IEM become more severely symptomatic and/or re-quire longer to recover than expected. In older children and adults, vigorous exercise, sleep deprivation, hormonal changes, intercurrent illness, anesthesia or surgery, and pregnancy or delivery commonly precipitate symptoms.

A family history of siblings and/or a history of relatives with similar findings is an important clue to possible IEM. A family history of sud-den infant death or unexplained neonatal death, particularly due to sepsis or neurologic, cardiac, and/or hepatic dysfunction, should also raise concern for a possible IEM. Parental consan-guinity increases the likelihood of an autoso-mal recessive IEM. Maternal history of HELLP (hemolysis, elevated liver enzyme, low plate-let count) during pregnancy is associated with maternal heterozygosity for fatty acid oxidation defect and suggests the possibility of homozy-gosity for the disease in the child. Decreased fetal movement has been described with certain glycogen and lysosomal storage disorders and peroxisomal disorders. A negative family history does not rule out an IEM.

Clinical Manifestations Clinical manifestations of IEMs reflect the mul-tiorgan system involvement typical of these dis-orders. Common clinical presentations include a sepsis-like illness or cardiac, hepatic, and/or neurologic dysfunction.85–87,97–104 Physical ex-amination findings are normal for most IEMs. Abnormal odor or hair, hearing deficit, visual dysfunction, organomegaly, and/or chronic der-matitis should prompt consideration of an IEM. Dysmorphic features are seen commonly with mitochondrial disorders, peroxisomal disorders, lysosomal storage, and other disorders of com-plex molecules. The risk of mortality can be very high, particularly with initial presentation of an undiagnosed IEM. Features of specific IEMs can be found in the texts referenced in this chap-ter85,95,96 and on Web sites, including Online Mendelian Inheritance in Man.88,90

but there are IEMs with autosomal dominant, X-linked, and mitochondrial inheritance.

Nearly all states in the United States test newborns for at least 29, and some for more than 50, genetic diseases, most of which are IEMs.91,92 A table of newborn screening tests performed by state is available online.93 Results are usually available within days but might take weeks. In at least some states, parents can opt to not have their child screened. False-negative newborn screens can result and are most com-monly due to screening too soon after birth, weight less than 1,500 g, neonatal illness, medi-cations, transfusions, and problems related to sample collection and handling. Cutoff values are set to minimize false-negative rates, which results in relatively high false-positive rates. Ne-onates who test positive on newborn screens for an IEM that can result in acute, life-threatening decompensation require emergent evaluation.94

Clinical Features

History History can vary from abrupt onset of rapidly progressing illness that results in death within hours, to intermittent recurrent acute episodes of potentially life-threatening decompensation in an otherwise well child, to chronic, slow-ly progressive deterioration throughout de-cades.85,90,95,96 Inborn errors of metabolism that result in acutely life-threatening critical illness present most commonly within the first year of life and usually within the newborn period, those that cause intermittent decompensation most often manifest later in infancy or early in childhood, and those with insidious, progressive symptoms tend to present in older childhood, adolescence, or even throughout adulthood. In the neonate, the most important clue to an IEM is a history of deterioration after an initial period of apparent good health ranging from hours to weeks.97,98 In neonates and infants, a history of poor feeding, vomiting, chronic diar-rhea, failure to thrive, lethargy, and seizures is common.99–101 Developmental delay in infants, particularly with loss of milestones, is strongly suggestive of an IEM. Symptoms can be precipi-tated by increased intake of protein or carbo-hydrate and/or by a reduction in feeds (eg, as



retinopathy, optic atrophy, chronic dermato-ses, skin photosensitivity, nodules, dilated or hypertrophic cardiomyopathy, cardiac arrhyth-mia, jaundice, hepatomegaly, liver dysfunction, splenomegaly, pancreatitis, skeletal abnormali-ties, hypotonia, dystonia, weakness, periph-eral neuropathy, and/or developmental delay, in some cases with loss of milestones. Inborn errors of metabolism most likely to present in this age group include partial enzyme deficiency urea cycle defects, disorders of carbohydrate metabolism, fatty acid oxidation defects, and lysosomal storage disorders. Reye syndrome–like symptoms are now recognized often to be due to IEMs. The differential diagnosis of IEMs in infants and young children with IEMs is ex-tensive and, in addition to that for the neonates, includes routine illness, cyclic vomiting, diabe-tes, drug or toxin ingestion, malignant tumor, and Münchausen by proxy.

Older Children, Adolescents, and Adults In older children, adolescents, and adults, pre-viously undiagnosed IEMs usually manifest as neurologic and/or psychiatric abnormalities that can range from recent to longstanding and from subtle to severe.103,105 Although rare, the initial presentation of an IEM can be that of critical illness with rapid progression to death. Manifes-tations of life-threatening IEMs most commonly include profound lethargy, coma, encephalop-athy, seizures, stroke, other thromboembolic event, cardiac or hepatic dysfunction or fail-ure, weakness, and/or paresis. More commonly, manifestations are not acute in onset or immi-nently life-threatening and include learning disabilities, autism, developmental delay, visual deficits, ocular abnormalities, exercise intoler-ance, muscle cramps, ataxia, abnormal move-ments, abnormal or aggressive behaviors, and psychiatric disturbances, such as anxiety, panic attacks, hallucinations, delirium, paranoia, and/or psychosis. Findings particularly concerning for IEMs include ophthalmologic abnormali-ties, progressive neurologic disease, abnormal movements, cerebellar symptoms, and mixed psychiatric and neurologic symptoms. Among the most common IEMs on the growing list of recognized IEMs with late onset are partial orni-thine transcarbamylase deficiency (particularly

Neonates Inborn errors of metabolism should be consid-ered in neonates who are critically ill, particu-larly those with encephalopathy and/or hepatic dysfunction. Clinical manifestations of IEMs in neonates are nonspecific and most commonly include decreased feeding, hiccups, vomiting, diarrhea, dehydration, temperature instability, tachypnea or apnea, bradycardia, poor perfu-sion, unusual odor, jaundice, irritability, in-voluntary movements or posturing, abnormal tone, seizures, stroke, and/or altered level of consciousness. These same findings are also manifestations of many other causes, making the differential diagnosis extensive. Presence of one diagnosis does not rule out the possibility of a concomitant IEM. In fact, some IEMs, such as galactosemia, certain organic aminoacidopa-thies, and glycogen storage diseases, are asso-ciated with an increased risk of sepsis. Inborn errors of metabolism should be considered in neonates with fetal hydrops or pulmonary or intracranial hemorrhage in utero or after birth. It should also be recognized that an undiagnosed IEM is a possible cause of sudden infant death, most commonly fatty acid oxidation defects. The time to onset of symptoms for inborn er-rors of substrate and intermediary metabolism is dependent on significant accumulation of toxic metabolites, which for severe forms can occur within hours after the initiation of feed-ing. Neonates with IEMs that result in defects in energy production and use are often symp-tomatic at birth or within the first 24 hours of life. These neonates are less likely to have coma as an early manifestation and are more likely to have dysmorphic features, cardiopulmonary compromise, organomegaly, skeletal malforma-tions, and hypotonia.

Infants and Young Children Infants and children with IEMs can have re-current episodes of vomiting, dehydration, hepatoencephalopathy, ataxia, seizures, stroke, lethargy, and coma but can appear completely normal between episodes. Others have dysmor-phic features, failure to thrive, microcephaly or macrocephaly, alopecia or sparse hair, hearing and vision deficits, corneal opacities, cataracts, subluxed or dislocated lens, cherry red spots,



IEMs. For most patients with primary metabolic acidosis, it is appropriate to test plasma amino acids, acylcarnitine profile, urine organic acids, and acylglycines.

Hyperammonemia An ammonia concentration greater than 100 mcg/dL (60 mcmol/L) in neonates and greater than 80 mcg/dL (50 mcmol/L) in children is abnormal and potentially neurotoxic. Early clinical manifestations of hyperammonemia are tachypnea, anorexia, and irritability. Older indi-viduals might report headache, abdominal pain, and fatigue. Progression to vomiting, lethargy,

in females), homocystinuria, certain glycogen storage disorders, mitochondrial and peroxi-somal disorders, and Wilson disease.

Diagnostic StudiesIn the acutely ill patient with an undiagnosed condition, results of routine laboratory tests often provide clues to IEMs and should guide further evaluation.85,86,97,100,106 Most patients with acute, life-threatening presentations of metabolic disease have metabolic acidosis, hy-perammonemia, and/or hypoglycemia. Labora-tory abnormalities can be transient; therefore, specimens should be collected as soon as pos-sible, preferably before initiation of any therapy, including fluids and glucose. If samples were not collected before treatment, remaining pre-treatment specimens are likely to be more infor-mative than posttreatment samples and should be used if available. A metabolic specialist can be helpful in directing the evaluation of patients with suspected or known IEMs.

Metabolic AcidosisClinical manifestations of metabolic acidosis include tachypnea and vomiting. Initial labo-ratory studies to evaluate acid-base status in-clude electrolytes and blood gas. Laboratory manifestations of primary metabolic acidosis are low pH, Pco

2, and bicarbonate level and an

elevated anion gap. Severe metabolic acidosis and ketonuria, with or without hyperammone-mia or hypoglycemia, are hallmarks of organic acidemias. An elevated anion gap accompanies acidosis in organic acidemias, mitochondrial disorders, aminoacidopathies, and disorders of carbohydrate metabolism. Lactate and pyruvate should also be obtained in patients with sus-pected or confirmed acidosis. Lactic acidosis, although seen in many IEMs, is a nonspecific finding in critically ill patients that results from hypoxia and poor tissue perfusion. An elevated lactate:pyruvate ratio (usually >20), provides an important clue to determining whether a patient has an IEM, most commonly due to a mitochondrial or cytoplasmic enzyme disorder. Urine with low specific gravity and pH of 5.0 or higher in the setting of metabolic acidosis suggests renal tubular acidosis, which, although not specific for an IEM, is a feature of many


Signs and Symptoms of IEMs

• History

- Acute and/or episodic decompensation, symptoms out of proportion to expected with illness

- Siblings, other relatives with signs, symptoms of IEMs, sudden infant death

- Parental consanguinity

• Signs,symptoms

-Gastrointestinal:feedingdifficulties,failure to thrive, vomiting, diarrhea

- Neurologic: irritability, lethargy, seizures, stroke, ataxia, developmental delay, loss of milestones, autism, behavioral abnormalities

- Musculoskeletal: abnormal tone, muscle weakness, pains, cramps, exercise intolerance

- Other: dysmorphic features, abnormal hair, hearing, vision deficits, chronic dermatitis, unusual odor (urine, sweat, cerumen breath, saliva)

• Commonpresentations

- Acute neonatal catastrophe

- Neurologic abnormality, dysfunction

- Cardiac dysfunction, failure, arrest

-Gastrointestinalorhepaticdysfunction,failure

- Skeletal myopathy

- Psychiatric disturbance



acidopathies or mitochondrial disorders might have ketonuria with normal glucose levels. In addition to plasma for amino acids and acylcar-nitine profile and urine for organic acids and acylglycines, serum ketones, plasma free-fatty acids, and endocrine studies, including insulin and serum cortisol, should be performed.

Other Studies Liver function tests, including bilirubin, trans-aminases, and coagulation studies, most com-monly reveal elevated levels in patients with disorders of protein metabolism or fatty acid oxidation defects but can reveal elevated levels in IEMs within most categories. Triglycerides and uric acid levels can be elevated in glyco-gen storage disorders. Lactate dehydrogenase, creatine kinase, and aldolase levels are most commonly elevated in patients with disorders of carbohydrate metabolism, fatty acid oxida-tion defects, and mitochondrial disorders and should be tested in patients with symptoms of skeletal muscle myopathy and/or with myo-globinuria. Urine test results positive for non–glucose-reducing substances suggest possible aminoacidopathy or carbohydrate intolerance disorder (eg, galactosemia).

In select cases, CSF, collected at approxi-mately the same time as plasma, should be frozen for possible measurement of lactate, pyruvate, and IEM-specific neurometabolites, particularly neurotransmitters.

Histologic evaluation of affected tissues, most commonly liver and/or skeletal muscle, and enzyme assay or DNA analysis in leuko-cytes, erythrocytes, skin fibroblasts, and liver or other tissues might be appropriate but are not usually emergent. Other studies, includ-ing evaluation for bacterial or viral infection, radiography, computed tomography, MRI, ultrasonography, electrocardiography, and/or echocardiography, should be obtained emergently as clinically indicated for evaluation and manage-ment of life-threatening manifestations of IEMs.

In the child who has died, identifying an IEM might still be important because currently asymptomatic family members and/or future children might be affected. Samples of plasma, serum, urine, and possibly CSF and skin, bile, vitreous humor, bone marrow, and selected organ

seizures, coma, and death can occur within hours. Patients with consistently elevated am-monia levels can have modestly increased lev-els without obvious clinical symptoms. Hepa-tomegaly and mild elevation of transaminases and/or abnormal clotting factors are other mani-festations. Ammonia concentration is high-est with urea cycle defects, usually 340–1700 mcg/dL (200–1000 mcmol/L) or higher. With organic acidemias, ammonia levels do not usu-ally exceed 850 mcg/mL (500 mcmol/L). Lower concentrations of ammonia and higher concen-trations of acids in these patients result in primary metabolic acidosis, usually with marked ketosis. With fatty acid oxidation defects, the level of am-monia does not usually exceed 425 mcg/dL (250 mcmol/L), and acid-base status is usually normal. Ammonia concentration in the normal range does not rule out an IEM. To prevent a falsely elevated value, blood for ammonia should be collected by free flow without a tourniquet and the speci-men put on ice immediately. In patients with hyperammonemia, plasma for amino acids and acylcarnitine profile and urine for organic acids, acylglycine, and orotic acid should be tested.

Hypoglycemia A serum glucose level less than 40 mg/dL should be considered abnormally low in neonates and a level less than 40 to 50 mg/dL should be con-sidered abnormally low beyond the neonatal pe-riod. Clinical findings of hypoglycemia include repeated yawning, irritability, pallor, jitteriness, altered mental status, and seizures. Neonates can also have a high-pitched cry, hypothermia, hypotonia, apnea, cyanosis, and poor feeding. Older children and adolescents often report headache, lightheadedness, diaphoresis, pal-pitations, and nausea. Normally, hypoglycemia results in ketonuria, except in neonates due to a high capacity to use ketones. In neonates, significant ketonuria can be an acute manifes-tation of an IEM. Beyond the neonatal period, inappropriately low or absent ketone levels in a patient with hypoglycemia suggest a hyper-insulinemic state, a glycogen storage disorder, carbohydrate intolerance disorder, or fatty acid oxidation defect. The presence of ketones (ke-totic hypoglycemia), however, does not rule out these disorders. Patients with organic amino-



ManagementIn addition to rapid assessment and aggressive management of airway, breathing, and circu-lation, goals of treatment of IEMs are to stop intake of harmful substances, correct metabol-ic abnormalities, and eliminate toxic metabo-lites.85,86,107,108 Even the apparently stable patient with mild symptoms can deteriorate rapidly with progression to death within hours. For an undiagnosed suspected IEM, this means initiat-ing treatment empirically as soon as the diag-nosis is considered. For patients with a known IEM, treatment should be disease and patient specific. Families should have an emergency treatment plan specifically for their child devel-oped by their IEM specialist with them or avail-able electronically. In addition, families might have a plan detailing their desired interventions should lifesaving resuscitation be necessary.

Once airway, breathing, ventilation, and vascular access have been established, hydra-tion, glucose as necessary to correct hypogly-cemia and prevent catabolism, and therapy to correct acidosis and hyperammonemia must be initiated. Protocols for treatment of acute illness in patients with a suspected IEM and some diagnosed IEMs are available on the New England Consortium Web site.107 Consultation with a metabolic specialist should be initiated

specimens, including skin, heart, liver, kidney, spleen, skeletal muscle, and/or brain, should be collected and frozen, preferably, but not limited to, within 1 to 2 hours of death.86 Consider ob-taining photographs of patients with dysmorphic features. If the family declines autopsy, consider obtaining permission to collect vitreous humor, skin, and/or organ tissue by needle biopsy.

Differential DiagnosisBecause the signs and symptoms of inborn er-rors of metabolism are nonspecific, IEMs are frequently not considered in the differential di-agnosis. Therefore, a high index of suspicion is important because the physician must initiate appropriate therapy without delay (and without a final diagnosis in hand) to decrease morbidity and mortality. A concomitant acquired disorder can obscure the diagnosis of an inherited meta-bolic disease condition. For example, neutrope-nia can occur in organic acidemias, leading to an increased susceptibility of bacterial infection. The underlying disorder might be missed if an infection is also present and focus is directed solely toward antimicrobial therapy. Escherichia coli sepsis frequently supervenes in neonates with galactosemia, and the typical jaundice, liver failure, and vomiting that accompany that disorder might wrongly be ascribed solely to sepsis as well.


Findings of Routine Laboratory Studies in Children With IEMs

• Metabolicacidosis

• Hypoglycemia(hypoketosisorabsentketones)

• Hyperammonemia,respiratoryalkalosis

• Elevatedlactatelevel,lactate:pyruvateratio

• Elevatedliverfunctionstudies(bilirubin,aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase)

• Urine-reducingsubstances,myoglobin

W H AT E L S E ?

Differential Diagnosis of IEM in the Critically Ill Patient

• Infection:sepsis,meningitis,encephalitis

• Shock

• Respiratoryillness

• Cardiacdisease

• Gastrointestinalillnessorobstruction

• Hepaticdisease

• Renaldisease

• Neurologicabnormality,disease

• Trauma

• Toxinordrugwithdrawal

• Behavioral,psychiatricdisorder



For patients with an aminoacidopathy, organic acidemia, or fatty acid oxidation defect, hyper-ammonemia usually improves with rehydration and the reversal of acidosis and hypoglycemia. For severe hyperammonemia in patients with urea cycle defects, hemodialysis is the mainstay of treatment. Extracorporeal membrane oxygen-ation–assisted hemodialysis is the most effective form of hemodialysis but has increased risks, particularly in neonates. Exchange transfusion is not effective. Recommendations of the New England Consortium are to consider dialysis for ammonia levels greater than 300 mcg/dL (175 mcmol/L) and transfer to a facility or unit with dialysis capability for ammonia levels greater than 200 to 250 mcg/dL (120–150 mcmol/L). If dialysis is not immediately available for am-monia levels between 100 and 200 mcg/dL (60–175 mcmol/L), sodium phenylacetate and sodium benzoate (available as Ammonul) should be administered to patients with known or suspected urea cycle defect to augment ni-trogen excretion.109 The combination of sodium phenylacetate and sodium benzoate is approved as adjunctive therapy for acute hyperammone-mia and associated encephalopathy due to urea cycle defects but is also used to treat hyperam-monemia of unknown origins. Ondansetron should be administered with sodium phenyl-acetate and sodium benzoate. Potassium, which can be depleted by sodium phenylacetate and sodium benzoate, should be monitored and re-placed as potassium acetate, 0.5 to 1 mEq/kg per hour, as needed. In addition, 10% arginine hydrochloride, which enhances urea cycle activ-ity, should be given for treatment of urea cycle defects with the exception of arginase deficiency. Citrulline can be administered to augment ni-trogen clearance in urea cycle defects with the exception of argininosuccinic acid synthetase (citrullinemia) and argininosuccinase acid lyase deficiencies. Although data are limited, recent literature suggests hypertonic saline should be given for cerebral edema rather than mannitol. Corticosteroids increase catabolism and there-fore should not be given. To assess patient re-sponse to treatment, glucose, acid-base status, ammonia, and electrolytes should be monitored serially.

if available. With appropriate therapy, patients can recover completely without sequelae.

Hydration is critical not only to restore in-travascular volume but also to promote urinary excretion of toxic metabolites. For IEMs that are potentially acutely life-threatening, fluid bo-luses should be administered as 10% dextrose normal saline unless the patient is hypoglyce-mic, in which case a glucose bolus is indicated (0.5 g/kg as 10% dextrose for neonates and 10% or 25% dextrose for children; note the “50 rule” described earlier). Preferentially, colloids should be avoided because they increase nitrogen load. After bolus fluid, maintenance fluid should be administered as 10% to 12.5% dextrose half normal saline at a rate high enough to prevent catabolism by maintaining serum glucose at 120 to 170 mg/dL. Large fluctuations in serum glucose should be avoided. Although contro-versial, 0.1 to 0.2 U/kg per hour of insulin can be administered to prevent hyperglycemia. For a suspected IEM, stop all oral intake to ensure that potentially harmful protein or sugars are avoided. For a known IEM, dietary restriction should be disease specific.

Treatment of acidosis with bicarbonate is thought to be indicated for IEMs because of on-going acid production; however, data regarding the degree of acidosis for which it should be initiated and dose are lacking. Recommenda-tions for administration of bicarbonate range from pH 7.0 to 7.2 and serum bicarbonate as low as 14 to 16 mEq/L. The recommended dose range is 0.25 to 2 mEq/kg per hour, depending in part on the specific IEM. Bicarbonate should be administered cautiously in patients with hy-perammonemia because alkalinization converts NH4

+ to NH3, which is less readily excreted in

urine and more readily crosses the blood-brain barrier, increasing the risk of brain complica-tions. If administering sodium bicarbonate, po-tassium should be given as potassium acetate. For severe, intractable metabolic acidosis, he-modialysis should be considered. Acidosis must be corrected cautiously to minimize paradoxical effects on the CNS that can be caused by rapid or overcorrection.

Hyperammonemia can be acutely life-threatening and must be treated immediately.



oxidation disorders but is usually used after consultation with a metabolic specialist. The child might need immediate admission to an intensive care unit for further monitoring and other procedures (eg, hemodialysis).

In children who are already known to have an IEM, the importance of listening closely to the history provided by the parents or regular caregiver must be stressed. A child with a meta-bolic disorder can appear relatively well but might decompensate rapidly. If such a child is not maintaining adequate fluid and caloric intake, “does not seem to be his usual self,” or both, the metabolic specialist should be contacted, and IV fluids with dextrose should be administered even in the absence of documented hypoglycemia or other markers of metabolic imbalance. The goal in such cases is to provide therapy in a timely manner to prevent a metabolic crisis.

Appropriate antibiotics should be given if there is concern about possible serious bacte-rial infection. As necessary, fresh frozen plasma should be administered to treat coagulopathy.

Intravenous l-carnitine, 25 to 50 mg/kg, can be administered empirically in life-threatening situations associated with known or suspected carnitine deficiency (eg, primary carnitine defi-ciency, certain organic aminoacidopathies, and fatty acid oxidation defects); however, because it can be harmful with some IEMs, consultation with an IEM specialist is highly recommended. Carnitine should not be administered with so-dium phenylacetate and sodium benzoate. In-travenous pyridoxine (B

6), 100 mg; IV folate,

2.5 mg; and/or biotin, 10 to 40 mg, orally or via nasogastric tube can be given empirically to neo-nates with seizures unresponsive to conventional anticonvulsants to treat a possible vitamin or co-factor responsive IEM. Although there are other disease-specific adjunctive therapies, administra-tion of these agents in the ED is rarely indicated.

Rapid assessment, establishment of vascu-lar access, and administration of appropriate fluids (with glucose) are priorities in treating patients with IEMs in acute crisis. Dehydration and hypoglycemia should be treated with bo-luses of normal saline and dextrose solutions, respectively. Maintenance IV fluids should then be started to prevent recurrence of hypoglyce-mia and hypovolemia and stop the catabolic spiral. Administration of 10% dextrose (with electrolytes based on the child’s weight) at 1.5 times maintenance is usually adequate. General supportive measures (maintenance of oxygen-ation and acid/base balance and treatment of infection) should, of course, be provided. In-travenous carnitine (100 mg/kg) can be benefi-cial in certain organic acidemias and fatty acid

T H E B O T T O M L I N E

Issues in the Diagnosis and Management of IEMs

• Maintainahighindexofsuspicion,especially in the presence of hypoglycemia, metabolic acidosis, hyperammonemia, and or inappropriate ketosis.

• Althoughspecializedtestsareneededto arrive at a final diagnosis, simple laboratory studies often provide the first clues to the presence of an IEM. Obtain pretreatment specimens when possible.

• Earlydetectionandtreatmentareessential to optimize immediate and long-term outcome.



K E Y P O I N T S

Initial Treatment of Patients With IEMs

• Evaluation

- Contact metabolic specialist immediately once diagnosis is suspected.

- Obtain specimens, ideally before treatment.

* Blood: venous blood gas, glucose, electrolytes, BUN, creatinine, complete blood cell count

* If lethargic, ammonia (free flow, ice)

* Lactate dehydrogenase, aldolase, creatinine kinase if skeletal muscle myopathy is suspected

* Lactate, pyruvate if acidosis (free flow, special perchloric acid tube for pyruvate)

* Plasma amino acids, acylcarnitine profile if initial evaluation supports possible IEM

* Urine: urinalysis, urine culture if concern of infection; urine amino, organic acids, acylglycine if initial evaluation supports possible IEM

• Treatment

- Stop all oral feedings

- Fluid hydration with 10% dextrose normal saline

-Glucosetotreathypoglycemia,preventcatabolism(usethe“50rule”)

- IV bicarbonate corrects acidosis but could worsen hyperammonemia equilibrium

- For hyperammonemia, plan for detoxification by hemodialysis and/or sodium phenylacetate and sodium benzoate (Ammonul) and arginine (except for arginase deficiency); if using sodium phenylacetate and sodium benzoate, administer ondansetron and treat hypokalemia with potassium acetate

- Seizures: IV pyridoxine (B6), 100 mg; IV folate, 2.5 mg; and/or biotin, 10 to 40 mg, orally or via nasogastric tube

- Suspected carnitine deficiency: IV l-carnitine, 25 to 50 mg/kg



Check Your Knowledge1. Which of the following is most associated

with the development of cerebral edema in a child with diabetic ketoacidosis (DKA)?A. KetosisB. High fluid administration (20 mL/kg

per hour)C. Urinary tract infectionD. Treatment with sodium bicarbonate

2. Which of the following is a prominent finding in female newborns with congenital adrenal hyperplasia?A. Acanthosis nigricansB. Ambiguous genitaliaC. HyperpigmentationD. Midline facial defects and

microphallus3. Syndrome of inappropriate secretion of

antidiuretic hormone should be treated with:A. intravenous hydrocortisone.B. oral sodium supplements.C. hypertonic saline, 10-mL/kg infusion

if the sodium concentration is 130 mEq/L.

D. fluid restriction unless the patient is seizing or severely lethargic or comatose.

E. sodium restriction.4. Which of the following statements

regarding hypernatremia in patients with diabetes insipidus (DI) is correct?A. Never occurs in infants with DI

because of high fluid intakeB. Occurs in all patients with DIC. Rare in older children with DI and

normal thirst mechanismsD. Should be treated with 3% sodium

chloride solution

5. Of the following inborn errors of metabolism (IEMs), which is most likely to present with an insidious onset and progressive worsening?A. Organic acidemiasB. AminoacidopathiesC. Fatty acid oxidation defectsD. Lysosomal storage disorders

6. Laboratory abnormalities due to IEMs commonly include which of the following (best choice)?A. Metabolic acidosis, hyperammonemia,

hypoglycemiaB. Hypoglycemia, ketosis, leukopeniaC. Hematuria, azotemia,

hypercholesterolemiaD. Proteinuria, hypercholesterolemia,

hypoalbuminemiaE. Hypocalcemia, hyponatremia,

hypokalemia7. The most appropriate initial rapid fluid

infusion for a patient with a suspected IEM who is tachycardic, hypoglycemic, and acidotic is:A. normal saline (20 mL/kg).B. lactated Ringer solution (20 mL/kg).C. 10% Dextrose normal saline (20 mL/

kg).D. 25% Dextrose (2 mL/kg) and normal

saline (20 mL/kg).E. 10% Dextrose (2 mL/kg) and normal

saline (20 mL/kg).8. The most effective treatment for severe

hyperammonemia due to an IEM is:A. hemodialysis. B. exchange transfusion.C. peritoneal dialysis.D. sodium phenylacetate and sodium

benzoate (Ammonul).E. hyperventilation.

C H A P T E R R E V I E W


Chapter Review 16-31

References1. Levine B, Anderson B, Butler D, Antisdel J, Brackett J, Laffel L.

Predictors of glycemic control and short-term adverse outcomes in youth with type 1 Diabetes. J Pediatr. 2001;39:197-203.

2. Rewers A, Chase H, Mackenzie T, et al. Predictors of acute complications in children with type 1 Diabetes. JAMA. 2002;287:2511-2518.

3. Rewers A, Klingensmith G, Davis C, et al. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics. 2008;121:e1258-e1266.

4. Flood R, Chiang V. Rate and prediction of infection in children with diabetic ketoacidosis. Am J Emerg Med. 2001;19:270-273.

5. 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.

6. Sperling M, Dunger D, Acerini C, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Pediatrics. 2003;113:e133-e140.

7. Wolfsdorf J, Glaser N, Sperling M. Diabetic ketoacidosis in infants, children and adolescents: a consensus statement from the American Diabetes Association. Diab Care. 2006;29:1150-1159.

8. Gutierrez J, Bagatell R, Sampson M, Theodorou A, Berg R. Femoral central venous catheter-associated deep venous thrombosis in children with diabetic ketoacidosis. Crit Care Med. 2003;31:80-83.

9. Worly J, Fortenberry J, Hansen I, Chambliss C, Stockwell J. Deep venous thrombosis in children with diabetic ketoacidosis and femoral central venous catheters. Pediatrics. 2004;113:e57-e60.

10. Zeitler P, Haaq A, Rosenbloom A, Glaser N. Hyperglycemic hyperosmolar syndrome in children: pathophysiologic considerations and suggested guidelines for treatment. J Pediatr. 2011;158:9-14.

11. Glaser N, Marcin J, Wooton-Gorges S, et al. Correlation of clinical and biochemical findings with DKA-related cerebral edema in children using magnetic resonance diffusion weighted imaging. J Pediatr. 2008;153:541-546.

12. Koves I, Neutze J, Donath S, et al. The accuracy of clinical assessment of dehydration during diabetic ketoacidosis in childhood. Diab Care. 2004;27:2485-2487.

13. Green S, Rothrock S, Ho J, et al. Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. 1998;31:41-48.

14. Buckingham B, Roe T, Yoon J. Rhabdomyolysis in diabetic ketoacidosis. Am J Dis Child. 1981;135:352-354.

15. Shilo S, Werner D, Hershko C. Acute hemolytic anemia caused by severe hypophosphatemia in diabetic ketoacidosis. Acta Haemat. 1985;73:55-57.

16. Marcin J, Glaser N, Barnett P, et al. Clinical and therapeutic factors associated with adverse outcomes in children with DKA-related cerebral edema. J Pediatr. 2003;141:793-797.

17. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28:1245-1249.

18. Clarke W, Jones T, Rewers A, Dunger D, Klingensmith GJ. Assessment and management of hypoglycemia in children and adolescents with Diabetes. Pediatr Diabetes. 2009;10(suppl 12):134-145.

19. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94:709-728.

20. Frier BM. Defining hypoglycaemia: what level has clinical relevance? Diabetologia. 2009;52:31-34.

21. Swinnen SG, Mullins P, Miller M, Hoekstra JB, Holleman F. Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia. Diabetologia. 2009;52:38-41.

22. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in type 2 diabetes. Diabet Med. 2008;25:245-254.

23. Cryer, PE. Preventing hypoglycaemia: what is the appropriate glucose alert value? Diabetologia. 2009;52:35-37.

24. Rewers A, Chase HP, Mackenzie T, et al. Predictors of acute complications in children with type 1 diabetes. JAMA. 2002;287:2511-2518.

25. Davis EA, Keating B, Byrne GC, Russell M, Jones TW. Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus. Arch Dis Child. 1998;78:111-115.

26. Nimri R, Weintrob N, Benzaquen H, Ofan R, Fayman G, Phillip M. Insulin pump therapy in youth with type 1 diabetes: a retrospective paired study. Pediatrics. 2006;117:2126-2131.

27. Berhe T, Postellon D, Wilson B, Stone R. Feasibility and safety of insulin pump therapy in children aged 2 to 7 years with type 1 diabetes: a retrospective study. Pediatrics. 2006;117:2132-2137.

28. Colino E, Lopez-Capape M, Golmayo L, Alvarez MA, Alonso M, Barrio R. Therapy with insulin glargine (Lantus) in toddlers, children and adolescents with type 1 diabetes. Diabetes Res Clin Pract. 2005;70:1-7.

29. Alemzadeh R, Berhe, Wyatt DT. Flexible insulin therapy with glargine insulin improved glycemic control and reduced severe hypoglycemia among preschool-aged children with type 1 diabetes mellitus. Pediatrics. 2005;115:1320-1324.

30. Rewers A, Chase HP, Mackenzie T, et al. Predictors of acute complications in children with type 1 diabetes. JAMA. 2002;287:2511.

31. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;57:3169-3176.

32. Mukamel M, Weitz R, Nissenkorn I, Yassur I, Varsano I. Acute cortical blindness associated with hypoglycemia. J Pediatr. 1981;98:583-584.

33. Garty BZ, Dinari G, Nitzan M. Transient acute cortical blindness associated with hypoglycemia. Pediatr Neurol. 1987;3:169-170.

34. Weinstein DA, Butte AJ, Raymond K, Korson MS, Weiner DL, Wolfsdorf JI. High incidence of unrecognized metabolic and endocrinologic disorders in acutely ill children with hypoglycemia. Pediatr Res. 2001;49:88A.

35. Losek JD. Hypoglycemia and the ABCs (sugar) of pediatric resuscitation. Ann Emerg Med. 2000;35:43-46.

36. Lteif AN, Schwenk WF. Hypoglycemia in infants and children. Endocrinol Metabol Clin. 1999;28:620-646.

37. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21:245-291.

38. Arlt W, Allollo B. Adrenal insufficiency. Lancet. 2003;361:1881-1893.

39. Root AW, Shulman DI. Clinical adrenal disorders. In: Pescovitz OH, Eugster EA, eds. Pediatric Endocrinology, Mechanisms, Manifestations, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:568-600.

40. Wilson TA, Speiser P. Adrenal insufficiency. www.emedicine.com/PED/topic47.htm. Accessed April 30, 2006.

41. Shaikh MG, Lewis P, Kirk JM. Thyroxine unmasks Addison’s disease. Acta Paediatr. 2004;93:1663-1665.

42. Havard CW, Saldanha VF, Bird R, Gardner R. Adrenal function in hypothyroidism. BMJ. 1970;1:337-339.

43. Giavoli C, Libe R, Corbetta S, et al. Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients. J Clin Endocrinol Metab. 2004;89:5397-5401.



60. Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med. 2000;343:998-1007.

61. Alter CA, Bilaniuk LT. Utility of magnetic resonance imaging in the evaluation of the child with central diabetes insipidus. J Pediatr Endocrinol Metab. 2002;15(suppl 2):681-687.

62. Ghirardello S, Garrè ML, Rossi A, Maghnie M. The diagnosis of children with central diabetes insipidus. J Pediatr Endocrinol Metab. 2007;20:359-375.

63. Brooks BS, el Gammal T, Allison JD, et al. Frequency and variation of the posterior pituitary bright signal on MR images. AJNR Am J Neuroradiol. 1989;10:943-948.

64. Alonso G, Bergada I, Heinrich JJ. Magnetic resonance imaging in central diabetes insipidus in children and adolescents: findings at diagnosis and during follow-up. An Esp Pediatr. 2000;53: 100-105.

65. Kirchlechner V, Koller DY, Seidl R, et al. Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride. Arch Dis Child. 1999;80:548-552.

66. van Lieburg AF, Knoers NV, Monnens LA. Clinical presentation and follow-up of 30 patients with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol. 1999;10:1958-1964.

67. Alon U, Chan JC. Hydrochlorothiazide-amiloride in the treatment of congenital nephrogenic diabetes insipidus. Am J Nephrol. 1985;5:9-13.

68. Knoers N, Monnens LA. Amiloride-hydrochlorothiazide versus indomethacin hydrochlorothiazide in the treatment of nephrogenic diabetes insipidus. J Pediatr. 1990;117:499-502.

69. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42:790-806.

70. Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 suppl 1):S1-S21.

71. Baylis PH. The syndrome of inappropriate antidiuretic hormone secretion. Int J Biochem Cell Biol. 2003;35:1495-1499.

72. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42:790-806.

73. Cogan E, Debieve MF, Pepersack T, et al. Natriuresis and atrial natriuretic factor secretion during inappropriate antidiuresis. Am J Med. 1988;84(3 pt 1):409-418.

74. Albanese A, Hindmarsh P, Stanhope R. Management of hyponatremia in patients with acute cerebral insults. Arch Dis Child. 2001;85:246-251.

75. Huang EA, Feldman BJ, Schwartz ID, Geller DH, Rosenthal SM, Gitelman SE. Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children. J Pediatr. 2006;148:128-131.

76. Ophir E, Solt I, Odeh M, Bornstein J. Water intoxication-a dangerous condition in labor and delivery rooms. Obstet Gynecol Surv. 2007;62:731-738.

77. Jose CJ, Perez-Cruet J. Incidence and morbidity of self-induced water intoxication in state mental hospital patients. Am J Psychiatry. 1979;136:221.

78. Illowsky BP, Kirch DG. Polydipsia and hyponatremia in psychiatric patients. Am J Psychiatry. 1988;145:675.

44. den Brinker M, Joosten KF, Liem O, et al. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab. 2005;90:5110-5117.

45. Oberfield SE, Chin D, Uli N, David R, Sklar C. Endocrine late effects of childhood cancers. J Pediatr. 1997;131(1 pt 2):S37-S41.

46. Bottner A, Keller E, Dratzsch J, Stobbe H, Weigel JF, Keller A. PROP 1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab. 2004;89:5256-5265.

47. Benvenga S, Campenni A, Ruggeri RM, Trimarchi F. Clinical review 113: hypopituitarism secondary to head trauma. J Clin Endocrinol Metab. 2000;85:1353-1361.

48. Shulman DI, Palmert MR, Kemp SF; Lawson Wilkins Drug and Therapeutics Committee. Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007;119:e484-e494.

49. Cheetham T, Baylis PH. Diabetes insipidus in children: pathophysiology, diagnosis and management. Paediatr Drugs. 2002;4:785-796.

50. Verbalis JG. Diabetes insipidus. Rev Endocr Metab Disord. 2003;4:177-185.

51. Mahone C, Weinberger E, Bryant C, Ito M, Jameson, JL, Ito M. Effects of aging on vasopressin production in a kindred with autosomal dominant neurohypophyseal diabetes insipidus due to the delta-E47 neurophysin mutation. J Clin Endocr Metab. 2002;87:870-876.

52. Bichet DG, Birnbaumer M, Lonergan M, et al. Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. Am J Hum Genet. 1994;55:278-286.

53. Baylis PH, Cheetham T. Diabetes insipidus. Arch Dis Child. 1998;79:84-89.

54. Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med. 2000;343:998-1007.

55. Mootha SL, Barkovich AJ, Grumbach MM, et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab. 1997;82:1362-1367.

56. Rutishauser J, Kopp P, Gaskill MB, et al. Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene. Eur J Endocrinol. 2002;146:649-656.

57. Morello JP, Bichet DG. Nephrogenic diabetes insipidus. Annu Rev Physiol. 2001;63:607-630.

58. Robinson AG, Verbalis JG. Posterior pituitary gland. In: Larsen PR, Kronenberg HM, Melmed S, et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: Saunders; 2003:281-329.

59. Muglia LJ, Majzoub JA. Disorders of the posterior pituitary. In: Sperling MA, ed. Pediatric Endocrinology. Philadelphia, PA: Saunders; 2002.





79. de Leon J. Polydipsia—a study in a long-term psychiatric unit. Eur Arch Psychiatry Clin Neurosci. 2003;253:37.

80. Goldman MB, Luchins DJ, Robertson GL. Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med. 1988;318:397.

81. Thompson CJ, Edwards CR, Baylis PH. Osmotic and non-osmotic regulation of thirst and vasopressin secretion in patients with compulsive water drinking. Clin Endocrinol (Oxf). 1991;35:221-228.

82. Rao KJ, Miller M, Moses A. Water intoxication and thioridazine. Ann Intern Med. 1975;82:61.

83. Farrar HC, Chande VT, Fitzpatrick DF, Shema SJ. Hyponatremia as the cause of seizures in infants: a retrospective analysis of incidence, severity and clinical predictors. Ann Emerg Med. 1995;26:42-48.

84. Arn PH, Valle DL, Brusilow SW. Inborn errors of metabolism: not rare, not hopeless. Contemp Pediatr. 1988;5:47-63.

85. Fernandes J, Saudubray JM, van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 4th ed. Heidelberg, Germany: Springer Medizin Verlag; 2006.

86. Weiner DL. Metabolic emergencies. In: Fleisher GR, Ludwig S. Textbook of Pediatric Emergency Medicine. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:972-991.

87. Kwon KT, Tsai VW. Metabolic emergencies. Emerg Med Clin North Am. 2007;25:1041-1060.

88. McKusik VA. OMIM Online Mendelian Inheritance in Man [database online]. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, MD, and National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD; 2000. http://www.ncbi.nlm.nih.gov/omim. Accessed September 26, 2010.

89. Ellaway C, Wilcken B, Christodoulou J. Clinical approach to inborn errors of metabolism presenting in the newborn period. J Paediatr Child Health. 2002;38:511-517.

90. Valle, D, Beaudet, AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2007. http://www.ommbid.com/. Accessed April 11, 2011.

91. Chace DH, Kalas TA, Naylor EW. Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem. 2003;49:1797-1817.

92. Kaye CI; American Academy of Pediatrics, Committee on Genetics. Newborn screening fact sheets. Pediatrics. 2006;118:e934-e963. www.pediatrics.org/cgi/content/full/118/3/e934. Accessed September 25, 2010.

93. Newborn Screening Status Report. National Newborn Screening and Genetics Resource Center (NNSGRC). United States table of newborn screening tests performed by state. http://genes-r-us.uthscsa.edu/nbsdisorders.pdf. Accessed September 25, 2010. International screening programs. http://genes-r-us.uthscsa.edu/resources/newborn/international.htm. Accessed September 25, 2010.

94. ACGME Newborn Screening Work Group: Levy HL, Watson, MS, Metabolic Disorders: Berry G, Goodman S, Marsden D, et al. Newborn Screening Act Sheet and Confirmatory Algorithms. http://www.acmg.net/resources/policies/ACT/condition-analyte-links.htm. Accessed September 25, 2010.

95. Clarke JTR. A Clinical Guide to Inherited Metabolic Diseases. 3rd ed. Cambridge, England: Cambridge University Press; 2006.

96. Hoffmann GF, Zschocke J, Nyhan WL. Inherited Metabolic Diseases: A Clinical Approach. New York, NY: Springer; 2006.

97. Goodman SI. Inherited metabolic disease in the newborn: approach to diagnosis and treatment. Adv Pediatr. 1986;33: 197-223.

98. Enns GM, Packman S. Diagnosing inborn errors of metabolism in the newborn: clinical features. Neo Rev. 2001;2000:e183-e190.

99. Ward JC. Inborn errors of metabolism of acute onset in infancy. Pediatr Rev. 1990;11:205-216.

100. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998;102:e69.

101. Ficicioglu C, Haack K. Failure to thrive: when to suspect inborn errors of metabolism. Pediatrics. 2009;124:972-975.

102. Calvo M, Artuch R, Macia E, et al. Diagnostic approach to inborn errors of metabolism in an emergency unit. Pediatr Emerg Care. 2000;16:405-408.

103. Calvin J, Hogg S. Biochemical investigation for inborn errors of metabolism in adults presenting with neurological disorders. Adv Clin Neurosci Rehabil. 2010;9:12-16.

104. Mannenbach MS. Children with Inborn Errors of Metabolism: Recognizing the Unusual and Life-threatening. AllBusiness.com. LexisNexis: 2010. http://www.allbusiness.com/print/12780095-1-22eeq.html Accessed September 25, 2010.

105. Gray RGF, Preece MA, Green SH, Whitehouse W, Winer J, Green A. Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neurol Neurosurg Psychiatry. 2000;69:5-12.

106. Blau N, Duran M, Blaskovics ME, Gibson KM. Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. New York, NY: Springer; 2002.

107. Acute Illness Protocols. New England Consortium of Metabolic Programs. http://newenglandconsortium.org/for-professionals/acute-illness-protocols/. Accessed September 25, 2010.

108. Ogier de Baulny H. Management and emergency treatments of neonates with a suspicion of inborn errors of metabolism. Semin Neonatol. 2002;7:17-26.

109. Ammonul package insert. http://www.medicis.com/products/pi/pi_ammonul.pdf. Accessed April 11, 2011.




A 10-year-old boy presents to the emergency department (ED) with altered mental status and a 2-week history of polyuria and weight loss. He is experiencing abdominal pain. On examination, he has a respiratory rate of 36/min, a heart rate of 150/min, a systolic blood pressure of 80 mm Hg, and a temperature of 37.9°C (100.2°F). Pulse oximetry oxygen saturation is 97% on room air. On examination, he appears lethargic, has dry mucous membranes, has normal abdominal examination results, and has nonfocal neurologic examination results. Bedside rapid glucose measurement is above the upper limit of the glucose meter (>500 mg/dL).

1. What therapeutic actions must be taken immediately?2. What laboratory tests would you order?3. What is the most important potential complication?

Thischildishypotensive,mainlyduetodehydration.Immediatevolumeresuscitationwith boluses of normal saline (20 mL/kg) should be administered to restore perfusion. An insulin infusion should be initiated as soon as possible after intravenous fluid therapy has been initiated.

A reasonable set of initial laboratory tests would include measurement of serum electrolytes, a venous blood gas analysis, and urinalysis for ketones. Complete blood cell counts are not usually helpful.4Thischildmustbecloselymonitoredforthedevelopment or progression of cerebral edema. Clinically apparent cerebral edema occursinapproximately1%ofchildrenwithDKA.Therefore,frequentneurologicmonitoring is indicated for all children with DKA.

A 14-month-old girl presents to the ED with a 1-day history of tactile fever, loss of appetite,andintermittentemesis.Thismorning,shedidnotseeminterestedinherusual breakfast and seemed sleepier than usual. On examination, she has respirations of 40/min, a heart rate of 170/min, blood pressure of 80/40 mm Hg, and a temperature of 36.0°C (96.8°F). She appears lethargic and has mildly dry mucous membranes and no obvious source of infection. Bedside rapid glucose measurement reveals a blood glucose level of 20 mg/dL.

1. What therapeutic measures must be taken immediately?2. What laboratory tests would you order?3. What complications can occur as part of the disease process and secondary to therapeutic

intervention?

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The child is hypoglycemic and likely volume depleted. Resuscitation with boluses of 2 mL/kg of 25% dextrose (or 5 mL/kg of 10% dextrose) to normalize blood glucose levels should be started without delay, followed by administration of volume (normal saline bolus of 20 mL/kg) until perfusion is restored. Fluids consisting of 10% dextrose and 0.45% sodium chloride at 1.5 times maintenance should be started. Appropriate potassium supplementation is added as needed. Initial studies include measurement of electrolytes, measurement of glucose, blood gas analysis, complete blood cell count, blood and urine cultures, and urinalysis for ketones. If possible, samples should be obtained before initiation of therapy, including administration of glucose and fluids. The finding of nonketotic (hypoketotic) hypoglycemia is a clue to the presence of an underlying fatty acid oxidation defect. Ammonia levels might be mildly elevated. Metabolic disorders might be unmasked by an infection severe enough to cause catabolism, but an obvious infection or clear exacerbating factor is not always present. Because of the risk of multiorgan system failure, measurement of liver enzymes, blood urea nitrogen, creatinine, and creatine phosphokinase levels can also be helpful. Metabolic studies include measurement of lactate, ammonia, plasma amino acids, carnitine, acylcarnitine profile, and urine organic acids. Freezing aliquots of serum and urine and contacting a metabolic specialist for further guidance with respect to specialized testing are appropriate alternatives if your laboratory does not routinely handle such specimens.

Fatty acid oxidation disorders can progress to multiorgan system failure (Reye-like syndrome). Seizures, cardiomyopathy, cardiac arrest, liver failure, and kidney failure might supervene. There is a significant risk of death.

Secondary to therapeutic interventions, cerebral edema of unclear pathogenesis might occur in some IEMs, particularly those with hyperammonemia. This complication can also occur if a high rate of relatively dilute dextrose solution (eg, 5% dextrose) is used. Close monitoring of fluid resuscitation and neurologic status is therefore imperative.

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