Chapter 144: Metabolic Emergencies in Infants and Children

Metabolic emergencies are challenging childhood disorders, often presenting with nonspecific signs and symptoms that may mimic more common conditions such as sepsis. Delay in accurate diagnoses can lead to significant morbidity and mortality, whereas early aggressive management based on probable diagnosis can be lifesaving and reduce long-term neurologic sequelae.

In any healthy neonate, sudden acute deterioration should prompt consideration of metabolic disease. Vomiting, altered mental status, and poor feeding are the most common clinical features of metabolic emergencies. Appropriate initial management can be started in the ED without definitive diagnosis. This chapter reviews the most common metabolic disorders presenting as acute decompensation in the young infant and the ED treatment. Hypoglycemia is discussed separately. Congenital adrenal insufficiency is included here because of the overlap in presentation with other inherited metabolic disorders and the importance of prompt recognition and treatment in the critically ill neonate. Inherited metabolic disorders that present in later childhood, such as lysosomal storage disease, are often diagnosed and managed outside of the ED, and these disorders are not included here.

Hypoglycemia is a plasma glucose level of <45 milligrams/dL (2.6 mmol/L) in any symptomatic child or <35 milligrams/dL (<1.9 mmol/L) in an asymptomatic neonate.^1,2 Intellectual performance is poor at 18 months in premature infants with persistent serum glucose <47 milligrams/dL,³ and MRI of infants with episodes of hypoglycemia demonstrates patterns of brain injury.^4,5,6 This has led to the recommended treatment threshold of 45 milligrams/dL (2.6 mmol/L) for neonates, who may be at higher risk of poor neurologic outcomes than older infants and children.⁷ Hypoglycemia in children requiring resuscitation is associated with increased mortality, and hypoglycemia in the setting of seizures is associated with poor neurologic outcomes.^2,8

PATHOPHYSIOLOGY

Neonates are born with 60% to 80% of maternal glucose levels. Within 2 to 4 hours, neonates begin to regulate their own serum glucose. Maintenance of serum glucose depends on intake and endogenous gluconeogenesis and glycogenolysis mediated by various hormones. Serum glucose level is affected when there is an imbalance between insulin (hypoglycemic hormone) and its counterregulatory hormones cortisol, growth hormone, glucagon, and epinephrine (hyperglycemic hormones). Insulin stimulates cellular glucose uptake and suppresses lipolysis, whereas hyperglycemic hormones stimulate lipolysis and glycogenolysis. Excess insulin (hyperinsulinemia) results in hypoglycemia with absence of urinary ketones. Hypoglycemia in the neonate or infant may result from inadequate oral intake, excess insulin, deficient hyperglycemic hormones (e.g., growth hormone or adrenal hormone deficiency), disorders of fatty acid oxidation or carbohydrate metabolism, aminoacidopathies and organic acidurias (due to inhibition of gluconeogenesis), or systemic infection (sepsis). Infants of diabetic mothers, postterm infants, and large for gestational age infants are at risk for hypoglycemia due to excess fetal insulin levels in response to elevated maternal serum glucose levels, whereas premature infants or those small for gestational age are at risk due to inadequate glycogen stores.^9,10,11

CLINICAL FEATURES

HISTORY

Neonates and infants with hypoglycemia typically present with alterations in mental status. Nonspecific symptoms include poor feeding, an abnormal or high-pitched cry, cyanosis, and hypothermia, and varying degrees of irritability and jitteriness or lethargy.¹² Severe hypoglycemia may result in coma or seizures.

Inquire about maternal complications during pregnancy (including gestational diabetes, growth retardation, and infections) as well as any history of prior spontaneous abortions or early infant deaths, which may signal inherited metabolic disease. Obtain a detailed feeding history, and document duration and progression of symptoms as well as the presence of associated signs and symptoms of vomiting, diarrhea, abnormal urine output, jaundice, and temperature instability.

PHYSICAL EXAMINATION

The classic signs of hypoglycemia seen in older children and adults are a result of the hyperglycemic hormones and include signs of adrenergic stimulation such as tachycardia, diaphoresis, tremor, anxiety, and tachypnea. Neonates and infants may not manifest these signs, and lethargy, apnea, or seizures may be the prominent finding. A careful neurologic examination should focus on mental status, tone, and reflexes, and may reveal focal neurologic deficits similar to Todd's paralysis in cases of prolonged, severe hypoglycemia. Seizures may be noted.

A complete physical examination is important to search for primary and secondary causes of hypoglycemia. Document weight and compare with birth weight (if known) in the neonate. Macrosomia or growth retardation may provide a quick clue to potential cause. Dysmorphic features should be documented. Fever or hypothermia suggests infection. The cardiac examination may suggest congenital heart disease (e.g., critical coarctation of the aorta), and the pulmonary examination may reveal tachypnea, apnea, or respiratory distress suggestive of pneumonia or sepsis. The abdominal examination is important in an infant with a history of vomiting to exclude abdominal catastrophe or obstruction (e.g., atresia, volvulus, intussusception, or pyloric stenosis). The GU examination may reveal ambiguous genitalia suggestive of congenital adrenal hyperplasia (discussed later separately in the "Congenital Adrenal Hyperplasia [Adrenal Insufficiency]" section).

DIAGNOSIS

The most important diagnostic test in the ED for the neonate, infant, or child who is critically ill or shows altered mental status is a rapid bedside screen for serum glucose level. Confirm abnormal results with a venous sample sent to the laboratory. Although the treatment of hypoglycemia must be prompt and should not be delayed, the first blood sample taken from the hypoglycemic neonate or infant is critical for making a definitive diagnosis, and when possible, a gray-topped sample tube should be filled and placed on ice for additional studies, which may include serum insulin, C-peptide, growth hormone, cortisol, and glucagon levels.¹³

Evaluation of urine for ketones is the second important step. Ketonuria is characteristic of ketotic hypoglycemia, adrenal or growth hormone deficiency, and other inborn errors of metabolism. A lack of urinary ketones suggests hyperinsulinism or fatty acid oxidation defects.^14,15 Serum insulin, C-peptide, and hormone analysis, as described above, can help differentiate among these diagnostic possibilities.

The administration of glucagon (0.03 milligram/kg IM or IV) in hypoglycemic states can be diagnostic and therapeutic. If glucagon is effective in normalizing serum glucose level, then the presence of hepatic stores is confirmed and the hypoglycemia is likely due to hormonal deficiency (panhypopituitarism or adrenal insufficiency) (Figure 144–1). Lack of response to glucagon suggests poor glycogen stores. Among nonresponders to glucagon, fasting is the most common cause, followed by galactosemia and hereditary fructose intolerance, although children with ketotic hypoglycemia often fail to respond to glucagon as well.

Additional laboratory evaluation is directed by the clinical picture and differential diagnosis and may include cultures of the blood, urine, and cerebrospinal fluid when sepsis is suspected. Definitive diagnosis of specific inborn errors of metabolism may require evaluation of levels of urine organic acids and serum amino acids and serum lactate (discussed later in "Inborn Errors of Metabolism"), as well as serum ammonia and lactate.

Routine imaging studies are not required for most cases of hypoglycemia, but may be useful if there are underlying organ anomalies.

TREATMENT

Treat hypoglycemia promptly while awaiting diagnostic results. IV dextrose is the primary treatment and may be given enterally (PO, nasogastric tube) or parenterally (IV or IO). The dose of dextrose is 0.5 to 1.0 gram/kg regardless of the route of administration. Newborns should receive 5 mL/kg of 10% dextrose, whereas infants and children should receive 1 to 2 mL/kg of 25% dextrose. With adequate IV access, 1 mL/kg of 50% dextrose may be administered to older children as to adults. Some recommend a 0.2 gram/kg dextrose bolus to minimize hyperglycemia and resultant insulin secretion, which prolongs hypoglycemia. Use of dilute solutions in younger patients is suggested to minimize the vascular injury associated with more concentrated fluids.

Provide maintenance dextrose at a rate of 6 to 8 milligrams/kg/min with 10% dextrose, which is 1.5 times the normal maintenance rate for infants and children. If IV or IO access or nasogastric tube placement cannot readily be initiated, glucagon, 0.03 milligram/kg IM, may be given. Refractory hypoglycemia may be seen in hyperinsulinemic states such as insulin-secreting tumors and is suggested by hypoglycemia requiring administration of more than 6 to 8 milligrams/kg/min. Frequent reevaluation and titration of infused dextrose are necessary in this situation. If adrenal insufficiency is suspected, give hydrocortisone, 25 grams IV or IM for neonates and infants, 50 grams for toddlers and school-age children, and 100 grams for adolescents. The management of hypoglycemia is summarized in Table 144–1.

Because sepsis is always in the differential diagnosis of the neonate, infant, or child who is critically ill or shows altered mental status, provide prompt broad-spectrum antibiotics as indicated by the clinical picture. This includes ampicillin, 50 milligrams/kg, and gentamicin, 5 to 7.5 milligrams/kg, or cefotaxime, 50 milligrams/kg, for neonates and infants in the first 2 months of life, and ceftriaxone, 50 milligrams/kg (100 milligrams/kg if meningitis is suspected), for older infants and children.

DISPOSITION AND FOLLOW-UP

All neonates and infants with symptomatic hypoglycemia requiring ED resuscitation should be admitted to the hospital for further evaluation and treatment. Patients for whom sepsis is a concern and those requiring dextrose beyond the expected 6 to 8 milligrams/kg/h may require admission to the intensive care unit.

Although the diversity and complexity of inborn errors of metabolism in infants and children may seem overwhelming, keep in mind that making a definitive diagnosis is not as important as maintaining a high suspicion and that acute stabilization and management are relatively simple. As a group, these disorders involve enzyme deficiencies that lead to errors of metabolism resulting in the accumulation of various toxic biochemical products, which can cause dysfunction of multiple organ systems, especially the CNS. Although each individual type of inborn error of metabolism is extremely rare, as a group they are relatively common, with an incidence ranging from 1 in 1400 to 1 in 200,000 live births.^13,14

Clinical manifestations of inborn errors of metabolism are a result of the accumulation of toxic metabolites and their effects on end-organs. Common symptoms and signs of inherited metabolic disorders include acute encephalopathy with or without metabolic acidosis and hypoglycemia (discussed earlier in "Hypoglycemia"). Because most metabolic toxins cross the placenta and are cleared by maternal enzymes, most newborns are asymptomatic and present after varying delays once enteral feeding begins. Hypoglycemia may be the primary presentation of some inherited disorders of metabolism and is discussed earlier (see "Hypoglycemia"). Jaundice and hepatic dysfunction can be seen in a number of inherited disorders such as galactosemia.¹⁶ Shock and cardiovascular collapse can occur with congenital adrenal insufficiency, but nonmetabolic conditions such as congenital heart disease and sepsis must be considered in the differential diagnosis of infants presenting in extremis. The discussion here is limited to conditions that typically present in early infancy with the potential for life-threatening consequences.

PATHOPHYSIOLOGY

Most inborn errors of metabolism result from single-gene defects with a variety of inheritance patterns. The defects result in abnormal metabolism of protein, fat, carbohydrates, or other complex molecules. Affected proteins include enzymes, enzyme cofactors, and transport proteins. The result of these varied deficiencies is the accumulation of toxic substrates upstream of the impaired protein or of intermediates derived from alternate metabolic processes downstream. On the basis of metabolic and clinical manifestations, these disorders can often be grouped into those defects resulting in hyperammonemia, metabolic acidosis, hypoglycemia, or hyperbilirubinemia and liver dysfunction.¹⁶

Urea cycle defects, organic acidemias, and some fatty acid oxidation defects may result in the accumulation of ammonia, leading to encephalopathy.¹⁷ Examples of organic acidemias that present in the first 24 hours of life are glutaric acidemia and pyruvate carboxylase deficiency (which causes lactic acidemia). Urea cycle defects typically present after the first 24 hours of life and often lack associated metabolic acidosis. Examples are ornithine transcarbamylase deficiency, carbamyl phosphate synthetase deficiency, and citrullinemia. Ornithine transcarbamylase deficiency is X-linked in its inheritance, and therefore affects male infants.

Although organic acidemias can also lead to hyperammonemia, they are typically accompanied by metabolic acidosis. Examples are methylmalonic acidemia, propionic acidemia, and isovaleric acidemia. Defects in pyruvate metabolism, defects in enzymes of the respiratory chain, and mitochondrial disorders also result in metabolic acidosis, which is often independent of protein intake. These disorders result in lactic acidosis with normal urine organic acid levels and include pyruvate dehydrogenase deficiency.

Disorders of carbohydrate, lipid, or fatty acid metabolism include glycogen storage diseases and medium-chain acyl coenzyme A dehydrogenase deficiency. These disorders impair the ability to use or produce glucose, which leads to hypoglycemia, often in the setting of fasting or poor oral intake. Glycogen and lipid storage diseases usually present later in infancy or childhood with developmental delay, dysmorphic or progressively coarse features, and hepatomegaly. Fatty acid metabolism defects result in nonketotic hypoglycemia (see "Hypoglycemia" above), which is a distinguishing characteristic. Secondary carnitine deficiency is often seen in medium-chain acyl coenzyme A dehydrogenase deficiency.

Hyperbilirubinemia and liver dysfunction may be the presenting feature of inborn errors of metabolism such as galactosemia, tyrosinemia, or α1-antitrypsin deficiency. Galactosemia results from the deficiency of galactose-1-phosphate uridylyltransferase, which leads to an accumulation of galactose-1-phosphate and other metabolites that are toxic to the liver. In addition to hepatic dysfunction, these infants may develop hypoglycemia, hyperbilirubinemia, hemolysis, or overwhelming infection.

CLINICAL FEATURES

HISTORY

Many inborn errors of metabolism present with nonspecific symptoms, including irritability, lethargy, vomiting, and poor feeding; severe hypoglycemia or metabolic encephalopathy may present with seizures. A careful characterization of these symptoms, however, may point toward a metabolic disorder: poor feeding and lethargy may be more notable in the morning prior to the first feeding as a result of a relative period of fasting. Parents may note aversion to protein or carbohydrates. Diarrhea may accompany carbohydrate metabolism disorders or mitochondrial disease. Parents may report an abnormal body or urinary odor, although this is more commonly noted by clinicians. Abnormal odor is typical of isovaleric acidemia, glutaric acidemia, and maple syrup urine disease, which, as the name suggests, is accompanied by a characteristic sweet smell of the urine.

Obtain a dietary and developmental history. Frequent changes in formula due to vomiting or failure to thrive may indicate undiagnosed metabolic disease. Unexplained developmental delay may also be a clue to diagnosis. Take a thorough medical history. A history of recurrent hospitalizations with a response to IV fluids and glucose may suggest an underlying metabolic disorder. The maternal history taking should include questions about previous spontaneous abortions or miscarriages and the death of previous infants early in life. Maternal complications during pregnancy, such as acute fatty liver or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), may be related to heterozygosity for fatty acid oxidation defects. The family history should include information about relatives with early cardiac disease, sudden infant death syndrome, neurologic disease, and liver disease with onset in childhood, all of which may signal inherited disorders of metabolism.

PHYSICAL EXAMINATION

The physical examination begins with attention to the vital signs. Tachycardia is often present during acute metabolic crisis; congenital adrenal hyperplasia may cause hypotension. Hypothermia may accompany many metabolic diseases, particularly the urea cycle defects and organic acidemias. Tachypnea without increased work of breathing may be noted in patients with metabolic acidosis and may result in a respiratory alkalosis. Although the majority of inborn errors of metabolism that present in early infancy are not associated with other specific findings on physical examination, those that present later in childhood, such as glycogen storage disease, liposomal storage disease, and mucopolysaccharidoses, may manifest with hepatosplenomegaly, growth retardation, poor muscle tone, developmental delay, and coarse features.¹⁸ Some metabolic disorders have ocular findings, including cataracts (e.g., galactosemia) or dislocated lenses (e.g., homocystinuria). The GU examination is important when adrenal insufficiency is a consideration, because females with one specific defect may show signs of virilization (see "Congenital Adrenal Hyperplasia [Adrenal Insufficiency]" below). A complete head-to-toe physical examination should be performed, of course, despite the lack of characteristic findings in most inborn errors of metabolism presenting during infancy, in order to exclude alternative diagnoses, including sepsis and congenital heart disease.

DIAGNOSIS

Due to the rarity and diversity of these disorders, the aspects of their acute clinical presentations and management in the ED have yet to be well defined. A simplified, although not exhaustive, approach to inborn errors of metabolism is presented in the following sections and in Figure 144–2. The key laboratory studies that are most useful to the emergency physician in directing immediate management and suggesting potential diagnoses include bedside glucose level, urine ketone level, plasma ammonia concentration, basic metabolic screen, blood gas analysis, and plasma lactate level. These are discussed in more detail in the following sections. Additional clues may be provided by a CBC, liver function tests, and muscle function tests (lactate dehydrogenase, creatine kinase, and myoglobin levels) (Table 144–2). Definitive diagnosis often depends on plasma or serum levels of amino acids, acylcarnitine profile, and lactate and pyruvate levels, as well as urine test results for organic acids, acylglycines, and orotic acid, and potentially on results of cerebrospinal fluid studies, including tests for lactate, pyruvate, and organic and amino acids.^16,18,19 A summary of laboratory evaluations for suspected metabolic disease and their utility and significance is provided in Table 144–2.

BEDSIDE GLUCOSE AND URINE KETONE LEVELS

Hypoglycemia may be a feature of several inborn errors of metabolism, including glycogen storage disease, fatty acid oxidation disorders, and disorders of gluconeogenesis. Some organic acidemias may also be associated with hypoglycemia. Hypoglycemia in the absence of urinary ketones suggests a fatty acid oxidation defect, and hypoglycemia with urinary ketones can be seen in organic acidemias.

PLASMA AMMONIA CONCENTRATION

Ammonia is formed during the deamination of amino acids and excreted as urea in the urine. Urea is produced in the hepatocyte mitochondria and cytosol through the metabolic process known as the urea cycle. Normal neonatal ammonia concentrations are <65 micromoles/L, but may be two to three times this in stressed or nonfasting newborns and infants. Levels >200 micromoles/L suggest metabolic disease and are the hallmark of urea cycle disorders. Hyperammonemia detected in the first 24 hours of life may be seen with pyruvate carboxylase deficiency, whereas hyperammonemia associated with urea cycle defects usually presents after protein feeding has begun and may reach ammonia concentrations well above 400 micromoles/L. The severe hyperammonemia of urea cycle disorders may stimulate central hyperventilation, resulting in respiratory alkalosis. Secondary causes of more modest hyperammonemia include mitochondrial, respiratory chain, or fatty acid oxidation defects, which are often associated with metabolic and/or lactic acidosis.

BLOOD GAS ANALYSIS AND BASIC METABOLIC PANEL

Evaluation of acid-base status is best achieved through analysis of blood gas samples and serum electrolyte levels. Serum lactate levels (discussed below in "Plasma Lactate Level") provide additional information. The anion gap (sodium – [chloride + bicarbonate]) is usually <15 mEq/L but increases with excess acid production. Organic acidemias are associated with significant anion gap acidosis, often higher than 30 to 50 mEq/L. Other inborn errors of metabolism associated with metabolic acidosis include respiratory chain disorders, disorders of pyruvate metabolism, and some glycogen storage diseases. In comparison with organic acidemias, these conditions typically include significant accumulation of lactic acid, which helps distinguish them from organic acidemia.^15,16,18

PLASMA LACTATE LEVEL

Lactate is produced from pyruvate, and lactic acidosis is a common feature of severe illnesses ranging from sepsis to hypoxia from pulmonary or cardiac disease or hypovolemic shock. Dehydration often accompanies metabolic disease and may produce some degree of lactic acidosis in any critically ill neonate with a metabolic disorder; however, subtracting the plasma lactate from the anion gap can aid in distinguishing between primary lactic acidosis resulting from mitochondrial disorders, fatty acid oxidation defects, and some glycogen storage disease (normal anion gap after subtraction of lactate), and secondary metabolic causes such as organic acidemias (elevated anion gap after subtraction of lactate).¹⁶

TREATMENT

Despite the diverse etiology and complexity of inborn errors of metabolism, ED resuscitation and stabilization are relatively simple. Neonates, infants, and children presenting in metabolic crisis, regardless of cause, show some combination of dehydration, metabolic acidosis, and encephalopathy, which must be immediately addressed. Therefore, the goals of treatment are to improve circulatory status by restoring circulatory volume, provide energy substrate to halt catabolism, remove the inciting metabolic substrate (formula or breast milk), and help eliminate toxic metabolites.^20,21,22

FLUID RESUSCITATION

As with any critically ill patient, attending to the ABCDs (airway, breathing, circulation, disability [neurologic status]) is the first step. Apnea, hypoventilation, and hypoxia are treated with positive-pressure ventilation or endotracheal intubation and administration of oxygen. Take care when paralyzing the infant in metabolic crisis, because metabolic acidosis can be worsened by respiratory acidosis if insufficient ventilation is provided. Restore circulation with crystalloid boluses, typically 10 to 20 mL/kg in the neonate and 20 mL/kg in the infant, with frequent reassessment and further fluid administration as clinically indicated. (Because congenital heart disease can present similarly to metabolic crisis, careful reevaluation after each fluid bolus is essential.) Even a patient who is not in shock may benefit from a bolus of normal saline followed by double the usual level of maintenance fluids with dextrose, because aggressive hydration promotes urine output with increased clearing of toxic metabolites (e.g., organic acids, ammonia), whereas dextrose provides a substrate for metabolism. Avoid hypotonic fluids because they may increase the risk of cerebral edema, particularly in hyperammonemic states. Assess neurologic status before definitive airway management. The cause of altered mental status (hypoglycemia or hyperammonemia) must be determined and may be reversible but is difficult to assess in the paralyzed or sedated patient (see below).

Metabolic acidosis during metabolic crisis can arise from dehydration, which may respond to fluid administration, or from the underlying metabolic defect. The ongoing production of acidic metabolites may necessitate the administration of sodium bicarbonate; however, treatment may be associated with side effects, including sodium overload, cerebral edema, and cardiac dysfunction. A conservative approach is to treat a blood pH of <7.0 with 0.5 mEq/kg/h.^13,20

All patients in metabolic crisis should be kept NPO to remove potential inciting metabolic substrates (protein, carbohydrates, fats), and adequate dextrose should be provided for anabolic substrate. Dextrose 10% is usually preferred and should be administered at twice the usual maintenance rates.

ELIMINATE TOXIC METABOLITES

Elimination of toxic metabolites is the next step. Hyperammonemia, as seen in urea cycle defects and some organic acidemias, is the most common cause of metabolic encephalopathy in infants. Ammonia levels of <500 micromoles/L should be treated with a combination of sodium phenylacetate and sodium benzoate (Ammonul^®): 250 milligrams/kg in 10% dextrose is administered through a central venous line (or intraosseous line) over 90 minutes followed by 250 milligrams/kg/d as a continuous infusion. Arginine, 210 milligrams/kg IV/IO in 10% dextrose over 90 minutes followed by 210 milligrams/kg/d continuous infusion, should also be provided (Figure 144–3). Empiric therapy with arginine with or without sodium benzoate can reduce ammonia levels drastically. Early aggressive treatment may eliminate the need for hemodialysis for excessive ammonia removal. Additional therapy may include empiric carnitine, 400 milligrams IV/IO, which combines with organic acids to form acylcarnitines that are readily excreted from urine (Figure 144–4), although no prospective trials have been performed.²³ Reduction in acyl coenzyme A levels eliminates their inhibitory effect on the urea cycle, resulting in reduced serum ammonia levels.^17,21

ADDITIONAL THERAPIES

For hyperammonemia of >400 to 600 micromoles/L, consider dialysis. For infants with seizures, empiric administration of pyridoxine, 100 milligrams IV/IO, for pyridoxine-dependent metabolic disease can be tried. If this is ineffective, folinic acid, 2.5 milligrams IV/IO, or biotin, 10 milligrams by nasogastric tube, can be considered.¹³ A summary of second-tier therapies for specific suspected inborn errors of metabolism is provided in Table 144–3.

COMPLICATIONS

During metabolic crisis, the accumulation of various organic acids can suppress granulopoietic stem cells and thereby cause bone marrow suppression of all cell lines. This leads to an immunocompromised state with an increased incidence of sepsis due to unusual organisms. The incidence is 15% to 30% per 100 episodes. Therefore it is essential to rule out sepsis in all patients with metabolic crisis. Chronic anemia and thrombocytopenia may accompany a number of inborn errors of metabolism and may be exaggerated during metabolic crisis. Give empiric broad-spectrum antibiotics such as ceftazidime, 50 milligrams/kg IV.

Hyperammonemia is a specific risk factor for cerebral edema, especially when hypotonic solutions are administered during therapy. Cerebral edema is a clinical diagnosis and should be suspected when laboratory parameters improve but altered mental status continues. Treatment for cerebral edema is mannitol (0.5 gram/kg IV/IO) and avoidance of hypo-/hyperventilation. Do not give steroids because steroids exacerbate hyperammonemia.

DISPOSITION AND FOLLOW-UP

All patients in metabolic crisis should be admitted to the hospital or transferred to a tertiary care children's hospital where metabolic specialists are available to help with definitive diagnosis and dietary management. Patients with severe metabolic abnormalities requiring hemodialysis require intensive care.

Congenital adrenal hyperplasia results from deficiency in one of the five enzymes involved in the production of cortisol. Absence of these enzymes leads to decreased conversion of 17-hydroxyprogesterone to 11-desoxycortisol with resultant cortisol deficiency. Most of the enzyme deficiencies also impair conversion to progesterone and 11-desoxycorticosterone in the mineralocorticoid pathway, which leads to decreased aldosterone production. Deficiency of 21-hydroxylase accounts for up to 95% of congenital adrenal hyperplasia cases and occurs in 1 in 10,000 to 15,000 live births.²⁴ Seventy-five percent of affected newborns manifest the classic salt-losing, virilizing variant in which urinary salt wasting with hyperkalemia and hyponatremia dominate the clinical picture. Twenty-five percent of cases are the non–salt-losing simple virilizing type. Infants with salt-losing forms of congenital adrenal hyperplasia typically present during the second to fifth weeks of life in crisis, sometimes before the results of newborn screening tests for the disease are available.

PATHOPHYSIOLOGY

Congenital adrenal hyperplasia is a group of disorders of adrenal steroid biosynthesis that result from a defect in one of five enzymes (Figure 144–5). Depending on the specific enzyme deficiency, cortisol deficiency may be accompanied by mineralocorticoid deficiency, leading to hypoaldosteronism with resultant salt wasting. Because the hypothalamic-pituitary axis is suppressed by cortisol, the deficiency results in increased secretion of adrenocorticotropic hormone without feedback suppression. Uninhibited excess adrenocorticotropic hormone stimulates the adrenal gland, which leads to hypertrophy. Elevated adrenocorticotropic hormone levels can also cause hyperpigmentation of the skin, which is best observed on the labial or scrotal folds and the nipples. Steroid hormone precursors upstream of the enzyme defect build up and are shunted into alternate pathways. Deficiencies in 21-hydroxylase lead to the accumulation of precursors that are metabolized to androgens. This, in turn, causes virilization of affected females, which manifests as clitoromegaly. Affected males may go undetected at birth because their genitalia appear normal.

CLINICAL FEATURES

HISTORY

Salt-wasting variants of congenital adrenal hyperplasia typically manifest as acute crisis in the second week of life. Symptoms are vague and include lethargy, irritability, poor feeding, vomiting, and poor weight gain. Depending on the duration and severity of symptoms, infants may present with significant dehydration or even shock. Obtain a complete history of the presenting symptoms, because the differential diagnosis of adrenal salt-wasting crisis includes sepsis, congenital heart disease, and other inborn errors of metabolism. Review gestational age and birth weight as well as maternal history regarding complications of pregnancy, prior pregnancies, miscarriages, spontaneous abortions, and previous infant deaths. Try to obtain results of newborn screening.

PHYSICAL EXAMINATION

Record vital signs and weight, and assess hydration and mental status. In addition to performing a complete head-to-toe examination, carefully examine the genitalia: females may have fusion of the labia and an enlarged clitoris. Males may have normal genitalia or a small phallus or hypospadias. Note any hyperpigmentation, especially in the scrotal or labial folds and around the nipples.

DIAGNOSIS

The most important laboratory studies are a bedside glucose level and serum electrolyte levels. Although hypoglycemia is rare, poor feeding and vomiting may cause secondary hypoglycemia requiring urgent treatment. The classic electrolyte abnormalities in salt-wasting congenital adrenal hyperplasia are hyponatremia and hyperkalemia. Serum potassium level may be elevated to between 6 and 12 mEq/L, although changes in cardiac function and ECG are unusual. Metabolic acidosis typically accompanies the classic electrolyte abnormalities as a result of aldosterone deficiency and dehydration.

Definitive diagnosis depends on analysis of blood hormone levels. If possible, obtain results of a steroid profile prior to treatment, but do not delay treatment in the critically ill neonate. Because the presentation of adrenal salt-wasting crisis is nonspecific, consider alternative diagnoses such as sepsis.

Although infants generally tolerate hyperkalemia well, obtain a 12-lead ECG, because hyperkalemic changes may alter emergent therapy and disposition. Imaging studies are not routinely indicated or helpful.

TREATMENT

Circulatory collapse from cortisol deficiency and dehydration is common, so establish IV or IO access rapidly. Administer IV fluids in the form of 10 to 20 mL/kg of normal saline. Fluid loss in congenital adrenal hyperplasia is isotonic, and fluid replacement should be with normal saline. Treat hypoglycemia with 5 mL/kg of 10% dextrose as discussed above in "Hypoglycemia."

Initiate steroid hormone replacement urgently: give hydrocortisone, 25 milligrams IV/IO to neonates, 50 milligrams to toddlers and school-age children, and 100 milligrams to adolescents. Although mineralocorticoid deficiency in congenital adrenal hyperplasia is primarily treated by sodium repletion with normal saline, there is some mineralocorticoid effect at these doses of hydrocortisone.

If hyperkalemia results in ECG changes or arrhythmia, treat with IV calcium gluconate (10%), 100 milligrams/kg (1 mL/kg), and sodium bicarbonate, 1 mEq/kg. Do not give insulin and glucose for hyperkalemia in infants, because this may result in profound hypoglycemia. The administration of normal saline and hydrocortisone is usually sufficient to lower serum potassium levels in the absence of cardiac manifestations.

DISPOSITION AND FOLLOW-UP

All infants with salt-wasting crisis require admission to the hospital. Infants with signs of shock or severe hyperkalemia with ECG changes should be admitted to the intensive care unit, with endocrinology consultation.

Acknowledgment: The authors thank Ralph Cordle, author of this chapter in the previous edition.