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CHAPTER 146: Metabolic Emergencies in Infants and Children 965 Initial evaluation of a seizure in a child with cancer should include brain imaging with CT or MRI to identify the cause. If there are no contraindications, perform lumbar puncture to exclude infection. See Chapter 138, “Seizures in Infants and Children, ” for further discussion. CATHETER-RELATED COMPLICATIONS The vast majority of pediatric cancer patients undergo central venous line placement for their treatment. These devices include external catheters (e.g., Broviac ® ), totally implantable catheters (e.g., Port® ), and peripherally inserted central catheters. Rates of catheter-related com plications are 40% to 50%, 63,64 and the complications fall primarily into three categories: infectious, mechanical, and thrombotic. Infection of the central line occurs from contamination of the hub and luminal migration of pathogens within the catheter, from hematogenous seeding of the intravascular portion of the catheter, or from fractures within the catheter itself. The morbidity and mortality attributable to central line–associated bloodstream infections is significant. The incidence of central line infections is three times greater in ambulatory pediatric oncology patients compared to inpatients. 65 Risk factors include frequent access, poor hygiene and sterility, previous infection, and <1-month duration from line insertion. Tunnel infections of the soft tissue surrounding the catheter may also occur shortly after placement, with typical signs of infection. Totally implantable catheters are associ ated with the least catheter-associated infectious morbidity. 66,67 Treatment requires IV antibiotics and possible device removal. For further discussion, see “Infection” section. A central venous line is the single most important risk factor for developing thromboembolism in any child, 64 and 50% of children with cancer are reported to have central line–associated thrombosis.63 Common morbidities from thrombosis include infection, embolism to other vessels (including pulmonary embolism), catheter malfunction, loss of venous access, and delay of treatment. Venous Doppler ultraso nography can identify upper extremity or jugular vein thrombosis, but ultrasonography is limited in its inability to visualize more proximal (i.e., central) thrombosis. CT or magnetic resonance venogram may also be used for diagnosis. Treatment of central line–associated throm boembolism may require tissue plasminogen activator (a small alteplase infusion administered to the catheter site if there are concerns for an intraluminal partial occlusion of the catheter), removal of the catheter, and/or anticoagulation for more significant thromboembolisms. ED staff should not infuse tissue plasminogen activator into a central line without consulting oncology and/or surgery. When anticoagulant ther apy is indicated, low-molecular-weight heparin, using pediatric-specific dosing protocols, is usually the preferred choice in children. Mechanical complications are also quite common in pediatric oncol ogy patients, with a prevalence of 20% to 39%, and are an independent risk factor for poor outcomes. 63 External catheters have increased rates of mechanical complications and failure. 67 Potential nonthrombotic occlusions include intraluminal precipitation of calcium, bicarbonate, or drugs (e.g., phenytoin).

ric oncol ogy patients, with a prevalence of 20% to 39%, and are an independent risk factor for poor outcomes. 63 External catheters have increased rates of mechanical complications and failure. 67 Potential nonthrombotic occlusions include intraluminal precipitation of calcium, bicarbonate, or drugs (e.g., phenytoin). OTHER COMPLICATIONS OF MALIGNANCY  CARDIOPULMONARY COMPLICATIONS There are a variety of cardiac and pulmonary oncologic complications that are not unique to pediatrics. These include malignant pericardial effusion through direct or metastatic involvement of the pericardium, treatment-induced transudative pericardial effusion, cardiac tampon ade, and pleural effusions. These complications and their management are addressed in the adult chapters of this textbook. Chemotherapeutic agents and adjunct therapies can also be associated with cardiomyopa thy, hypertension, arrhythmias, and pulmonary fibrosis.  GASTROINTESTINAL COMPLICATIONS Mechanical bowel obstruction due to mass effect may occur with any intra-abdominal tumor, most commonly lymphoma. Malignancy should be on the differential for a child presenting with intussusception, because masses can act as lead points for telescoping of the bowel. Postoperatively, patients with oncologic abdominal surgery are at increased risk for developing a bowel obstruction due to adhesions. Patients are also at risk for constipation and ileus due to narcotic administration. Any component of the GI tract, from mouth to anus, can be affected by mucositis induced by chemotherapeutic agents. Mucosal breakdown can lead to pain, infection, dehydration due to poor oral intake, and bleeding at any location. Herpetic or fungal esophagitis can develop. Typhlitis, or neutropenic enterocolitis, was previously discussed in this chapter (see “Infection” section and Figure 145-6). Appendicitis must remain a consideration in the oncology patient with right lower quadrant abdominal pain. Of note, the typical appendicitis presentation may be blunted in children with neutropenia and/or on cortico steroids. 69 Imaging with CT or US can help to differentiate between appendicitis, typhlitis, and other intra-abdominal processes. GI bleeding can result from mucositis, high-dose steroids or radia tion in the treatment regimen, primary tumor or metastatic invasion, or tumor- or treatment-related cytopenias or coagulopathies. Mallory- Weiss tears can develop from severe chemotherapy-related emesis. Primary colorectal cancers are extremely rare in children, but those numbers increase when including secondary GI malignancies following a previously treated pediatric cancer.  GENITOURINARY COMPLICATIONS Mass effect from abdominal or pelvic tumors can lead to ureteral obstruction and hydronephrosis, necessitating urgent stent placement. Other causes of acute urinary retention include drugs (e.g., narcotics, anticholinergics) or spinal cord compression. Viruses, radiotherapy, and chemotherapeutic agents can all induce hemorrhagic cystitis. Hemorrhagic cystitis treatment requires IV hydration, correction of underlying cytopenias and coagulopathy, and antiviral medications if appropriate. Severe cases warrant urologic consultation for placement of a double-lumen Foley catheter for continuous bladder irrigation or for cystoscopy. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Metabolic Emergencies in Infants and Children Nadeem Qureshi Irene A. Oriaifo INTRODUCTION Metabolic emergencies are challenging childhood disorders, often pre senting with nonspecific signs and symptoms that may mimic more common conditions such as sepsis.

te reference list is available online at www.TintinalliEM.com. Metabolic Emergencies in Infants and Children Nadeem Qureshi Irene A. Oriaifo INTRODUCTION Metabolic emergencies are challenging childhood disorders, often pre senting with nonspecific signs and symptoms that may mimic more common conditions such as sepsis. Delay in accurate diagnosis can lead to significant morbidity and mortality, whereas early aggressive management can be lifesaving and reduce long-term neurologic sequelae. Indi vidually, these disorders are uncommon, but taken together as an entity, they are likely to be encountered by most emergency providers, who must be familiar with the general steps to facilitate expedited emergency management. 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 meta bolic emergencies. Appropriate management can be started in the ED without a definitive diagnosis. This chapter reviews the most common metabolic disorders presenting as acute decompensation in the young CHAPTER Tintinalli_Sec12_p0669-0996.indd 965 8/2/19 7:59 PM

or feeding are the most common clinical features of meta bolic emergencies. Appropriate management can be started in the ED without a definitive diagnosis. This chapter reviews the most common metabolic disorders presenting as acute decompensation in the young CHAPTER Tintinalli_Sec12_p0669-0996.indd 965 8/2/19 7:59 PM 966 SECTION 12: Pediatrics stimulation such as tachycardia, diaphoresis, tremor, anxiety, and tachypnea. Neonates and infants may not manifest adrenergic 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 the weight and compare with birth weight (if known) in the neonate. Macrosomia, growth retardation, or dysmorphic features may provide a quick clue to a potential cause. 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 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 the 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. Evaluation of serum for beta-hydroxybutyrate (or urine ketones) is the second important step. Ketonemia or ketonuria is characteristic of ketotic hypoglycemia, adrenal or growth hormone deficiency, and other inborn errors of metabolism . A lack of serum or urine ketone elevation suggests hyperinsulinemia or fatty acid oxidation defects. 8-11 Serum insulin, C-peptide, and hormone analysis, as described earlier, 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 146-1). 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.

emia 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 It is important to treat hypoglycemia promptly while awaiting further diagnostic results. 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 administra tion. Newborns should receive 5 mL/kg of 10% dextrose, whereas infants and children can receive 1 to 2 mL/kg of 25% dextrose . With adequate vascular 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 vascular injury associated with more concen trated fluids given through small-gauge IVs. infant and their emergency management. 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 diseases, are often diagnosed and managed outside of the ED and so are not included here.  HYPOGLYCEMIA Hypoglycemia is defined as at least one blood glucose concentration <47 milligrams/dL (2.65 mmol/L); it is considered severe if the glu cose concentration is <36 milligrams/dL (2 mmol/L) and recurrent if three or more episodes have occurred. 1 Hypoglycemia also includes any glucose concentration low enough to cause symptoms or signs of impaired brain function. 2 Transient neonatal hypoglycemia (within 48 hours of birth) has been linked with a decreased proficiency on literary and mathematics fourth-grade achievement tests, as well as low execu tive and visual motor function. 1,3 This makes detection and treatment of neonatal hypoglycemia especially important to avoid long-term negative neurodevelopmental outcomes. 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 levels, and the majority of transient hypoglycemic episodes resolve within 48 hours of birth. Any hypoglycemic episode after 48 hours of birth requires a detailed evaluation to identify the cause. 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 (a hypoglycemic hormone) and its counterregulatory hormones cortisol, growth hor mone, 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 the absence of urinary ketones.

rmones cortisol, growth hor mone, 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 the absence of urinary ketones. Hypoglycemia in the neonate or infant may result from inadequate oral intake, excess insulin, deficient hyperglycemic hor mones (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 severe systemic illness (e.g., 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. 4-6 CLINICAL FEATURES  HISTORY Neonates and infants with hypoglycemia typically present with altera tions in mental status. Nonspecific symptoms include poor feeding, an abnormal or high-pitched cry, cyanosis, hypothermia, and varying degrees of irritability and jitteriness or lethargy. 7 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 Tintinalli_Sec12_p0669-0996.indd 966 8/2/19 7:59 PM

igns 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 Tintinalli_Sec12_p0669-0996.indd 966 8/2/19 7:59 PM CHAPTER 146: Metabolic Emergencies in Infants and Children 967 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 (see Table 146-1 and Chapter 132, “Fluid and Electrolyte Therapy in 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 summa rized in Table 146-1. Because sepsis is always in the differential diagnosis of the critically ill neonate, infant, or child with altered mental status, provide prompt broad-spectrum antibiotics as indicated by the clinical picture. This includes ampicillin and gentamycin for neonates, cefotaxime for infants age 28 to 90 days of life, and ceftriaxone for older infants and children (see Table 120-1 in Chapter 120, “Meningitis in Infants and Children” and Chapter 119, “Fever and Serious Bacterial Illness in 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.  INBORN ERRORS OF METABOLISM Although the diversity and complexity of inborn errors of metabolism in infants and children may seem overwhelming, it should be noted that making a definitive diagnosis is not as important as maintaining a high index of suspicion and that acute stabilization and management are relatively simple. As a group, these disorders generally involve enzyme deficiencies that lead to errors of metabolism resulting in the accumulation of toxic metabolic products or deficiencies of downstream 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 800 to 1 in 2500 live births. 9,10 Clinical manifestations of inborn errors of metabolism are usually the result of 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. 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 has been discussed earlier (see “Hypoglycemia”). Jaundice and hepatic dysfunction can be seen in a number of inherited disorders such as galactosemia or tyrosinemia.

c and present after varying delays once enteral feeding begins. Hypoglycemia may be the primary presentation of some inherited disorders of metabolism and has been discussed earlier (see “Hypoglycemia”). Jaundice and hepatic dysfunction can be seen in a number of inherited disorders such as galactosemia or tyrosinemia. 11 Shock and cardiovascular collapse can occur with congenital adrenal insufficiency, but nonmetabolic Fasting/starvation Galactosemia Hereditary fructose intolerance Panhypopituitarism Adrenal insufficiency Organic acidemia Mitochondrial defects Serum or urine ketones absent Hyperinsulinemic States Nesidoioblastosis Persistent hyperinsulinemic hypoglycemia of infancy Infant of a diabetic mother Exogenous insulin Fatty acid oxidation disorder Mitochondrial disorder Elevated serum β-hydroxybutyrate or urinary ketones + Glucagon test Blood glucose No response Hypoglycemia FIGURE 146-1. Evaluation of hypoglycemia in the emergency department. TABLE 146-1 Management of Hypoglycemia in the ED Patient Age Dextrose Bolus Dose Dextrose Maintenance Dosage Other Treatments to Consider Neonate D10 5 mL/kg PO/NG/IV/IO 6 mL/kg/h D10 Glucagon, 0.03 milligram/kg IM Hydrocortisone, 25 grams PO/IM/IV/IO Infant D10 5 mL/kg PO/NG/IV/IO D25 2 mL/kg 6 mL/kg/h D10 Glucagon, 0.03 milligram/kg IM Hydrocortisone, 25 grams PO/IM/IV/IO Child D25 2 mL/kg PO/NG/IV/IO 6 mL/kg/h D10 for the first 10 kg + 3 mL/kg/h for 11–20 kg + 1.5 mL/kg/h for each additional kg >20 kg Glucagon, 0.03 milligram/kg/IM Hydrocortisone, 50 grams PO/IM/IV/IO Adolescent D25 2 mL/kg PO/NG/IV/IO D50 1 mL/kg PO/NG/IV/IO 6 mL/kg/h D10 for the first 10 kg + 3 mL/kg/h for 11–20 kg + 1.5 mL/kg/h for each additional kg >20 kg Glucagon, 0.03 milligram/kg IM Hydrocortisone, 100 grams PO/IM/IV/IO Abbreviations: D10 = 10% dextrose; D25 = 25% dextrose; D50 = 50% dextrose; NG = (via) nasogastric tube. Tintinalli_Sec12_p0669-0996.indd 967 8/2/19 7:59 PM

/h D10 for the first 10 kg + 3 mL/kg/h for 11–20 kg + 1.5 mL/kg/h for each additional kg >20 kg Glucagon, 0.03 milligram/kg IM Hydrocortisone, 100 grams PO/IM/IV/IO Abbreviations: D10 = 10% dextrose; D25 = 25% dextrose; D50 = 50% dextrose; NG = (via) nasogastric tube. Tintinalli_Sec12_p0669-0996.indd 967 8/2/19 7:59 PM 968 SECTION 12: Pediatrics conditions such as congenital heart disease and sepsis must be considered in the differential diagnosis of infants presenting in extremis (see Chapter 116, “Neonatal Emergencies and Common Neonatal Problems”). 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, most commonly autosomal recessive. The defects result in abnormal metabolism of protein, fat, carbohy drates, 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 neurologic abnormalities (secondary to metabolic acidosis as in glycogen storage disease type I or fatty acid oxidation defects), hypoglycemia (as in organic acidemias and glycogen storage disease type I), hyperam monemia (as in urea cycle disorders and organic acidemias), seizures or apnea (as in mitochondrial respiratory chain defects and Zellweger’s syndrome), liver dysfunction (galactosemia, tyrosinemia), and cardiac abnormalities (fatty acid oxidation disorders, glycogen storage disease type II). 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 only 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 dehydroge nase deficiency. Disorders of carbohydrate, lipid, or fatty acid metabolism include glycogen storage diseases and medium-chain acyl-coenzyme A dehydro genase 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, ” earlier), which is a distinguishing characteristic. Secondary carnitine defi ciency 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, tyrosin emia, or α 1-antitrypsin deficiency.

ier), which is a distinguishing characteristic. Secondary carnitine defi ciency 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, tyrosin emia, or α 1-antitrypsin deficiency. Galactosemia results from the defi ciency 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 overwhelm ing 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 academia and glutaric academia (sweaty feet) and maple syrup urine disease, which, as the name indicates, 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 an 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 possibly signal the presence of an inherited disorder of metabolism.  PHYSICAL EXAMINATION The physical examination begins with attention to the vital signs. Tachycardia is often present during an acute metabolic crisis; congenital adrenal hyperplasia may cause hypotension. Hypothermia may accompany many metabolic diseases, particularly 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 diseases, liposomal storage diseases, and mucopolysaccharidoses, may manifest with specific phenotypical features that suggest the diagnosis. 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 later section, “Congenital Adrenal Hyperplasia [Adrenal Insufficiency]”).

ings, 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 later section, “Congenital Adrenal Hyperplasia [Adrenal Insufficiency]”). 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 ED management have yet to be well defined. A simplified, although not exhaustive, generalized approach to inborn errors of metabolism is presented in the following sections and in Figure 146-2. The key laboratory studies that are most useful to the emergency physician in directing immediate management and sug gesting 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 146-2). 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. 10,11 A summary of laboratory evaluations for suspected metabolic disease and their utility and significance is provided in Table 146-2. Bedside Glucose and Serum or Urine Ketone Levels Hypoglycemia may be a feature of several inborn errors of metabolism, including Tintinalli_Sec12_p0669-0996.indd 968 8/2/19 7:59 PM

s. 10,11 A summary of laboratory evaluations for suspected metabolic disease and their utility and significance is provided in Table 146-2. Bedside Glucose and Serum or Urine Ketone Levels Hypoglycemia may be a feature of several inborn errors of metabolism, including Tintinalli_Sec12_p0669-0996.indd 968 8/2/19 7:59 PM CHAPTER 146: Metabolic Emergencies in Infants and Children 969 glycogen storage diseases, fatty acid oxidation disorders, and disorders of gluconeogenesis. Some organic acidemias may also be associated with hypoglycemia. Hypoglycemia in the absence of serum or urine ketones suggests a fatty acid oxidation defect, and hypoglycemia with serum or urine ketone elevation suggests 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 con centrations 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, Basic Metabolic Panel, and Plasma Lactate Level Evaluation of the acid-base status is best achieved through analysis of blood gas samples and serum electrolyte levels. Serum lactate levels (discussed later 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 (also associated with ketosis). Other inborn errors of metabolism associated with metabolic acidosis include respiratory chain disorders, disorders of pyruvate metabolism, and some glycogen stor age diseases. In comparison with organic acidemias, these conditions typically include significant lactic acidosis, which helps distinguish them from organic acidemia. 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 acido sis, and encephalopathy, which must be immediately addressed . Therefore, the goals of treatment are to remove the inciting metabolic substrate (formula or breast milk), provide energy substrate to halt catabolism and toxin production and help eliminate toxic metabolites, and improve circulatory status by restoring circulatory volume as well as electrolyte balance. 9,11  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 supple mental oxygen. Metabolic acidosis can be worsened by respiratory acidosis if sufficient ventilation is not provided .

circulation, disability [neurologic status]) is the first step. Apnea, hypoventilation, and hypoxia are treated with positive-pressure ventilation or endotracheal intubation and administration of supple mental oxygen. Metabolic acidosis can be worsened by respiratory acidosis if sufficient ventilation is not 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) and 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 Poor feeding Vomiting Blood glucose/Calcium/ Ammonia/pH/CO2 Serum or urine ketones Lethargy Convulsion Coma Blood glucose, calcium Ammonia pH, CO2 Serum or urine ketones Hypoglycemia–glycogen storage disease Hyperammonemia– urea cycle defect Hyperammonemia + acidosis Organic acid disorders + Acidosis / − Urinary ketones Fatty acid oxidation defect Normal ammonia + acidosis Aminoacidopathies (e.g., maple syrup urine) Crisis mimics sepsis (attain appropriate cultures) FIGURE 146-2. Approach to suspected metabolic disorders. CO2 = carbon dioxide. TABLE 146-2 Additional Laboratory Tests in the Diagnosis of Metabolic Disease Test Result Diagnostic Implications Liver function tests Unconjugated hyperbilirubinemia Hepatic failure Galactosemia Fatty acid oxidation disorders, mitochondrial disorders, urea cycle disorders CBC Pancytopenia Aminoacidopathies (propionic acidemia, isovaleric acidemia, methylmalonic acidemia) Creatine kinase Elevated Mitochondrial disorders Aldolase Elevated Fatty acid oxidation defects Serum amino acids Abnormal quantitative results Aminoacidopathies, organic aciduria, urea cycle defect, mitochondrial disorder Serum acylcarnitine levels Abnormal profile Organic acidurias, fatty acid oxidation defects, mitochondrial disorders, carnitine deficiency Urine-reducing substances A positive test result is always abnormal Aminoacidopathies (tyrosinemia), carbohydrate intolerance disorders (galactosemia) Urine organic acids Abnormal profile Aminoacidopathies, organic aciduria, fatty acid oxidation defects, mitochondrial disorders, peroxisomal disorders Urine orotic acid Elevated Urea cycle defects (ornithine transcarbamylase deficiency) Urine acylglycines Abnormal Aminoacidopathies, organic acidurias Tintinalli_Sec12_p0669-0996.indd 969 8/2/19 7:59 PM

ile Aminoacidopathies, organic aciduria, fatty acid oxidation defects, mitochondrial disorders, peroxisomal disorders Urine orotic acid Elevated Urea cycle defects (ornithine transcarbamylase deficiency) Urine acylglycines Abnormal Aminoacidopathies, organic acidurias Tintinalli_Sec12_p0669-0996.indd 969 8/2/19 7:59 PM 970 SECTION 12: Pediatrics determined and may be reversible but is difficult to assess in the para lyzed or sedated patient (see below). Metabolic acidosis during metabolic crisis can arise from dehydra tion, 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, treat ment may be associated with side effects, including sodium overload, cerebral edema, and cardiac dysfunction. All patients in metabolic crisis should be kept nothing by mouth 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 one and a half to twice the usual maintenance rates. 12,13  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 ® ); a dose of 250 milli grams/kg (≤20 kg) or 5.5 grams/m 2 (>20 kg) in 25 mL/kg 10% dextrose is administered through a central venous or intraosseous line over 1.5 to 2 hours followed by a repeat of the same dose over 24 hours as a continuous infusion. Arginine can also be provided, the dosing of which depends on the specific disorder. 12 Empiric therapy with arginine with or without sodium benzoate can reduce ammonia levels drastically. Early aggres sive 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, although no prospective trials have been performed.  ADDITIONAL THERAPIES For ammonia levels >500 micromoles/L, hemodialysis is indicated.11 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 (goal: 3 to 5 milligrams/kg/d), or biotin, 10 milligrams by nasogastric tube (5 to 20 mg/d), can be con sidered. 15,16 A summary of second-tier therapies for specific suspected inborn errors of metabolism is provided in Table 146-3. 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, with an incidence of 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. 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 hypoand hyperventilation.

ebral 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 hypoand 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 (ADRENAL INSUFFICIENCY) Congenital adrenal hyperplasia results from an autosomal recessive 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 most cases. 17 Seventy-five percent of affected newborns manifest the classic salt-losing, virulizing variant in which urinary salt wasting with hyperkalemia and hyponatremia dominates the clinical picture. Twenty-five percent of cases are the non–salt-losing simple virulizing 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 146-3). 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.

riants 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 TABLE 146-3 Specific Therapies for Inborn Errors of Metabolism Inborn Error of Metabolism Drug Dosage Urea cycle defects Arginine HCl 10% Sodium benzoate and/or phenylacetate 210 milligrams/kg IV/IO over 90 min 250 milligrams/kg IV/IO continuous infusion over 24 h Organic acidemias Carnitine 400 milligrams IV/IO or PO Fatty acid oxidation defects Biotin 10 milligrams IV/IO or PO Pyridoxine-dependent seizures Pyridoxine 100 milligrams IV/IO Maple syrup urine disease, primary lactic acidosis Thiamine 25–100 milligrams IV/IO Tintinalli_Sec12_p0669-0996.indd 970 8/2/19 7:59 PM