16 metabolic diseases

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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 ChildrenAdrenal Insufficiency/Congenital Adrenal Hyperplasia

Diabetes Insipidus

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Water Intoxication

Metabolic Disease of the Newborn and Young Child: InbornErrors of Metabolism

Chapter Outline

1 Describe theepidemiology,clinical features,and emergencymanagement ofdiabetes mellitus (DM),adrenal insufficiency,syndrome ofinappropriate secretionof antidiuretichormone (SIADH),water intoxication, anddiabetes insipidus (DI).

2 Describe the fluid andelectrolyte problemsassociated with these

conditions.

3 Discuss the clinicalfeatures and emergencymanagement ofmetabolic diseases ofthe newborn and youngchild.

Objectives

Copyright © 2012 by the American Academy of Pediatrics and the American

Colle e of Emer enc Ph sicians


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16

C A S E

S C E N A R

I 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?

Introduction

The emergency management of endocrine andmetabolic disorders presents diagnostic andtherapeutic challenges. Many of these disor-ders, such as congenital adrenal hyperplasia(CAH) and inborn errors of metabolism, occurrelatively infrequently. Nonetheless, rapid andappropriate intervention is necessary to preventcomplications. Awareness of key clinical andlaboratory findings that differentiate endocrineand metabolic disorders from other entities withsimilar presenting features is essential.

Diabetic Ketoacidosis

Diabetic 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 concentrationsof counterregulatory hormones, particularlyglucagon. This imbalance results in hypergly-cemia along with the breakdown of fat to formketone bodies, eventually resulting in acidosis.Diabetic ketoacidosis occurs in 25% to 40% ofchildren with new onset of type 1 diabetes melli-tus (DM).1–3 Repeat episodes of DKA in children




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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 therelative preservation of intravascular volume,some signs of dehydration can be less obvious

than in dehydrated patients with more normalserum osmolality. Alterations in mental statuscan range from disorientation to depressed con-sciousness. This alteration of mental status can

with known diabetes can occur during episodesof illness or with diabetes mismanagement ormalfunction of diabetes care equipment (insulinpumps). Presumed omission or incorrect ad-ministration of insulin injections is the mostcommon cause of DKA in children with known

DM (69%); bacterial infections are infrequentlypresent (13%).4

Clinical Features

Diabetic ketoacidosis is characterized by hyper-glycemia and elevated serum ketone concentra-tions, resulting in acidosis. Inadequate insulinconcentrations allow the partial oxidation offatty acids to form ketone bodies. This processthen results in acidosis with an increased aniongap. Hyperglycemia results in osmotic diuresis

with polyuria, polydipsia, and eventual dehy-dration. Presenting features of DKA includea history of polyuria, polydipsia, nausea, andvomiting. Abdominal pain and intestinal ileusare common features and can mimic an acuteabdomen. 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

increasedinsensiblefluid 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

• History of polyuria, polydipsia, weight

loss, nausea, and vomiting

• Signs of dehydration

• Breath with fruity odor

• Abdominal pain

• Tachypnea

• Lethargy




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Diabetic Ketoacidosis 16

are total body concentrations of sodium, phos-phate, calcium, and magnesium. Although totalbody sodium is depleted, the degree of deple-tion is less than that suggested by the measuredserum sodium concentration, which is artifi-cially depressed due to hyperglycemia. Blood

urea nitrogen (BUN) concentrations are usuallyelevated due to prerenal azotemia. The whiteblood cell count is often elevated and frequentlyleft-shifted as a result of the ketoacidotic statealone.4 It is generally unnecessary to search fora source of infection beyond performing a care-ful physical examination unless fever or otherspecific signs of infection are present.

Differential Diagnosis

The presenting symptoms and signs of DKA

can initially be confused with gastroenteritis orother gastrointestinal disorders that present withvomiting and abdominal pain. Infections such aspneumonia, meningitis, and urinary tract infec-tions also can present with metabolic acidosis,tachypnea, and altered mental status or can be acause of the development of DKA. The history ofpolyuria despite clinical dehydration, absence ofdiarrhea, and presence of tachypnea with fruitybreath odor should differentiate DKA from theseother 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 withsevere hyperglycemia (serum glucose concentra-tion >600 mg/dL and often >1,000 mg/dL) andhyperosmolality (serum osmolality >330 mOsm),profound dehydration, and a depressed level ofconsciousness, but mild or no ketosis.10 Hyper-glycemic hyperosmolar state can in fact represent

be due to acidosis and dehydration but can alsoreflect more serious underlying intracranial dis-ease. Rarely, children with DKA present to theED with clinically apparent cerebral edema,5 aswell 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 lesscommon. Of the more serious complications ofDKA, clinically apparent cerebral edema is themost frequent, occurring in approximately 1%of DKA episodes. Cerebral edema is the mostimportant diabetes-related cause of mortality inchildren with type 1 DM.6,7

Although cerebral edema can occur beforehospital treatment of DKA, this complicationmore 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 dilationor 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 complicationsof DKA are rare but include cerebral infarctionsor thrombosis, acute renal tubular necrosis lead-ing to renal failure, pulmonary edema, pulmo-nary embolus, arrhythmia, pancreatitis, andintestinal necrosis.

Diagnostic Studies

Diabetic ketoacidosis is defined as hyperglyce-mia (serum glucose concentration >200 mg/dL),acidosis (venous pH


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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 Thetypical 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 [normalsaline] or lactated Ringer’s solution) for 30 to 60minutes. If there is evidence of poor perfusionor significant hypovolemia, 20 mL/kg can beused as the initial bolus. Greater administra-tion of fluids is indicated if signs of shock arepresent. Isotonic fluid boluses can be repeatedif necessary to restore perfusion. Once perfusionhas been restored, the remaining fluid deficitplus maintenance fluids can be replaced dur-ing the next 36 to 48 hours using half normal(0.45% sodium chloride solution) to normalsaline (0.9% sodium chloride solution).6,7

Hyperglycemia After the initial fluid bolus(es), insulin shouldbe 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 thisdosage and an initial IV bolus or “loading dose”of insulin is unnecessary. When serum glucoseconcentrations fall below 250 to 300 mg/dLduring treatment, glucose should be added to

the IV fluids to ensure that hypoglycemia doesnot occur. The insulin infusion rate generallyshould not be decreased until ketoacidosis re-solves (pH >7.30 and bicarbonate >15). Thiswill like take roughly 10 to 24 hours to achieve,so the insulin infusion must often continue onthe inpatient service.

AcidosisThe acidosis in DKA is due primarily to twofactors: the production of ketone bodies due torelative insulin deficiency and the accumula-tion of lactate due to dehydration and poor tis-sue perfusion. Insulin treatment promotes themetabolism of ketone bodies and halts furtherketone production, whereas the administrationof IV fluids treats the dehydration. This thera-peutic combination is generally sufficient forthe correction of acidosis. Bicarbonate admin-istration generally should be avoided becauseassociations between bicarbonate therapy and

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

Management

The fundamental treatment measures for DKAinclude replacement of fluid deficits, correctionof acidosis and hyperglycemia via insulin ad-ministration, replacement of depleted electro-lytes, and monitoring for complications.

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

2 and high BUN concentration and

those treated with bicarbonate are at higher riskfor cerebral edema.5 Appropriate restoration ofperfusion and hemodynamic stability, therefore,

W H A T E L S E ?

Differential Diagnosis of DKA

• Gastroenteritis

• Abdominal surgical emergency• Toxic ingestion

• Infections (pneumonia, meningitis,

urinary tract infections)

• Hyperglycemic hyperosmolar state




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Diabetic Ketoacidosis 16

K E Y P O I N T S

DKA Management Guidelines

IV fluids:

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




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ness of cerebral edema treatment interventions isunclear, patients who have deterioration in mentalstatus generally should be treated for presumedcerebral 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 bebeneficial, although clinical data are lacking.16Thepotential adverse effects of hyperosmolar agents inthis setting, however, are relatively minor in rela-tion to the potential for cerebral injury caused bycerebral edema, and therefore hyperosmolar treat-ment should be strongly considered if cerebraledema is suspected. Aggressive hyperventilationhas been shown to be associated with a greaterlikelihood of an adverse outcome in DKA-relatedcerebral edema; therefore, this should probablybe avoided unless necessary to avoid cerebralherniation.16

Hypoglycemia in Children WithDiabetes

Hypoglycemia, the most common complicationof type 1 diabetes in childhood, can occur in anychild in whom the dose of administered insulinexceeds insulin requirements. Albeit less frequent-ly, hypoglycemia can also occur in patients with

type 2 diabetes on oral hypoglycemic or insulinregimens. Responses to hypoglycemia includerelease of counterregulatory hormones, such asglucagon, epinephrine (adrenaline), cortisol, andgrowth hormone. However, over time both theglucagon and epinephrine (adrenaline) responsesmight be impaired, increasing the risk of persistenthypoglycemia due to lack of adrenergic symptoms.

The American Diabetes Association criteriafor the clinical classification of hypoglycemiain patients with DM include all episodes of anabnormally low plasma glucose concentration(


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Hypoglycemia in Children With Diabetes 16

glycemic threshold for glucose counterregu-latory hormone secretion, and the highestantecedent glucose level reported to reducesympathoadrenal responses to subsequent hy-poglycemia.19 It has been debated that a cutoffvalue 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 glycemiccontrol,25 insulin regimens with fixed dosing (asopposed to therapy that delivers a basal insulindose/infusion rate with intermittent boluses tocover for intake),26–29 exercise (due to increasedinsulin absorption, more rapid glucose utiliza-tion, and increased insulin sensitivity), acuteillness (particularly when associated with nau-

sea, vomiting, and anorexia), psychologicaldisturbance, lower socioeconomic status, andoccurrence of one or more prior hypoglycemicepisodes.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 hormoneresponse to hypoglycemia.17,19,31

Clinical Features

Hypoglycemic symptoms can be adrenergic due

to epinephrine (adrenaline) release and/or neuro-glycopenic due to direct effects of hypoglycemiaon the central nervous system (CNS). Adrenergicsymptoms include tremor, pallor, tachycardia,palpitations, and diaphoresis. Neuroglycopenicsymptoms 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 classifiedby both symptoms and the clinical interventionrequired.17 Mild hypoglycemia is associated withadrenergic and mild neuroglycopenic symptoms,such as headaches and mood changes in olderchildren and poor feeding, lethargy, jitteriness,and hypotonia in infants and toddlers. In suchcases, oral intake of a rapidly absorbed carbohy-drate is generally adequate treatment. Patientswith moderate hypoglycemia are neurologi-

cally impaired to a level that requires help froma second person to administer oral therapy. Inthe absence of a person to aid therapy, moderateepisodes 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 subcutaneousglucagon and/or IV dextrose. Case reports exist ofacute and transient cortical blindness and stroke-like hemiparesis associated with severe hypogly-cemia.32,33 Unlike mild episodes of hypoglycemiathat are relatively frequent in children with type1 DM, severe hypoglycemic events are uncom-mon, occurring at a rate of approximately 5 to19 events per 100 patient-years.1,2

Diagnostic Studies and Management

Patients with mild and moderate hypoglycemiashould be treated orally with a concentrated andrapidly 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 sourceshould follow to sustain normal blood glucoselevel. Blood glucose levels should be checkedevery 15 to 20 minutes for approximately 2hours 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 bloodglucose levels are sustained.

A patient with diabetes presenting withaltered mental status should have glucoseconcentration assessed rapidly with a bedsideglucose meter. Hypoglycemia, if present, shouldbe corrected as rapidly as possible with an IVinfusion of 0.5 g/kg of dextrose. This can beaccomplished by infusing 5 mL/kg of 10% dex-trose in an infant, 2 mL/kg of 25% dextrose ina toddler, or 1 mL/kg of 50% dextrose in olderchildren (note the “50 rule”: the product of themilliliters per kilogram dose and the percentageof dextrose should equal 50). In the event thatIV access cannot be established rapidly, gluca-gon should be given via subcutaneous or intra-muscular injection. The accepted dose is 0.02to 0.03 mg/kg or 0.5 mg for children weighingless than 20 kg and 1 mg for children weighinggreater than 20 kg. If neurologic or mental status




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venous sample should be sent to the laboratoryfor measurement with greater accuracy. Treat-ment for hypoglycemia should not be delayedwhile awaiting results. At the time that theconfirmatory sample is drawn, an additionalserum sample (enough for special studies)

should be obtained for future measurement ofhormone concentrations and other biochemi-cal measures. It is essential that this sample bedrawn at the time of the hypoglycemic event. Without information from this sample, it is usu-ally impossible to determine the cause of thehypoglycemic episode. If hypoglycemia is con-firmed, the measurements to be obtained on theinitial sample include serum insulin, cortisol,and growth hormone concentrations, as well asserum ketones, lactate, and free fatty acidconcentrations.36 A toxicologic evaluationfor ethanol, salicylates, -blockers, and oralhypoglycemic agents should also be considered.Remaining serum from the initial sample shouldbe stored for additional biochemical testing ifnecessary. Finally, a urine sample should alsobe obtained and tested for ketones and reduc-ing substances. An additional sample of urineshould likewise be stored for future testing.


There are many possible causes of hypoglyce-

mia, and a discussion of all causes is beyondthe scope of this chapter. Among the more fre-quent causes (in patients without DM) are toxic

abnormalities persist for prolonged periods aftercorrection of hypoglycemia, other possibilitiesshould be considered, such as toxic ingestionsand other intracranial disease.

Hypoglycemia in NondiabeticChildren

Hypoglycemia can result from excessive insulinproduction (insulinoma or hyperinsulinism) ordecreased concentrations of counterregulatoryhormones (deficiencies of growth hormone,cortisol, or both). Hypoglycemia can also resultfrom inborn metabolic errors that impair gluco-neogenesis, glycogenolysis, or fatty acid oxida-tion. Unsuspected hypoglycemia can be foundwhen patients present to the ED with episodes

of acute illness. A recent study revealed that asubstantial percentage (28%) of these patientshad previously undiagnosed fatty acid oxidationdefects (19%) or endocrine disorders (9%).34

Clinical Features

Infants with hypoglycemia can present with jitteriness, poor feeding, lethargy, hypotonia,hypothermia, apneic episodes, or seizures.Symptoms of hypoglycemia in infants mightalso be subtle and less obvious than those in

older children. In older children, symptomsof hypoglycemia include headaches; visionchanges; mental status changes, such as con-fusion, lethargy, irritability, or anxiety; andseizures. Adrenergic symptoms, such as palpita-tions, sweating, pallor, and tremulousness, areusually also present. Hypoglycemia should beconsidered in all patients presenting with un-explained alterations in mental status, seizure,or loss of consciousness, and a routine bedsidetest for hypoglycemia should be part of pediatricresuscitation procedures.35

Diagnostic Studies

If hypoglycemia is suspected, a rapid glucosetest should be performed using a bedside bloodglucose meter. A glucose concentration less than50 mg/dL should be considered abnormal andthe patient treated. If the bedside test revealsa low glucose concentration, a confirmatory

W H A T E L S E ?

Differential Diagnosis of Hypoglycemia

• Toxins (oral hypoglycemic agents,

ᵝ-blockers, ethanol)

• Hypopituitarism• Adrenal insufciency

• Fatty acid oxidation defects

• Hyperinsulinism

• Ketotic hypoglycemia

• Sepsis




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Adrenal Insufficiency/Congenital Adrenal Hyperplasia 16-

should equal 50). Subsequently, an IV infusionof 10% dextrose at 1.5 times maintenance ratesshould be provided to maintain glucose con-centrations in the normal range and reverse thecatabolic state. If adrenal insufficiency is knownor strongly suspected and adequate samples

have been set aside for further study, IV hydro-cortisone should be given (50 mg for childrenyounger than 4 years and 100 mg for childrenolder than 4 years).

Adrenal Insufficiency/Congenital AdrenalHyperplasia

Adrenal insufficiency can be related to processesdirectly affecting the adrenal gland (primary), orit can result from adrenocorticotropic hormone(ACTH) deficiency (secondary). Both primaryand 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 hyperplasiais the most common form of primary adrenal

insufficiency in children, with an incidence of1 in 10,000 to 18,000 live births.37 Congeni-tal adrenal hyperplasia is a group of autosomalrecessive inherited adrenal steroidogenesis en-zyme deficiencies (most often 21-hydroxylase)that cause various degrees of adrenal corticalinability 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 adrenalinsufficiency by the suppressive effect on thehypothalamic-pituitary-adrenal axis.38 In fact,the most common cause of acute adrenal insuffi-ciency in North America today is glucocorticoidwithdrawal or omission in patients being treatedfor a variety of disorders with pharmacologic

ingestions (eg, oral hypoglycemic agents,

ᵝ-blockers, and ethanol), sepsis, hypopituita-rism, adrenal insufficiency, fatty acid oxidationdefects, hyperinsulinism, and ketotic hypogly-cemia. Analysis of the initial serum sample will

differentiate among many of these entities andwill indicate whether additional analyses arenecessary to investigate less frequent causes ofhypoglycemia.

Management

Hypoglycemia should be corrected as rapidlyas possible with an IV infusion of 0.5 g/kg ofglucose (dextrose). This can be accomplished byinfusing 5 mL/kg of 10% dextrose in an infant,2 mL/kg of 25% dextrose in a toddler, and 1mL/kg of 50% dextrose in older children (note

the “50 rule”: the product of the milliliters perkilogram dose and the percentage of dextrose


Signs and Symptoms of Hypoglycemia

• Infants: jitteriness, poor feeding, lethargy,

hypotonia, hypothermia, apnea, seizures• Children: headaches, altered mental

status, diaphoresis, pallor, palpitations,

tremulousness, seizure

K E Y P O I N T S

Diagnosis and Management ofHypoglycemia

• Perform rapid bedside glucose testing

for altered level of consciousness,

seizure, or lethargy.

• Obtain additional blood and urinesamples at the time of the hypoglycemic

event.

• Administer dextrose: 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.




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

Adrenal crisis continues to occur in childrenwith known primary or secondary adrenal in-sufficiency during intercurrent illness becauseof failure to increase glucocorticoid dosing.

It is important to recognize that otherhormones affect cortisol metabolism and caninfluence the onset or progression of adrenalinsufficiency. It is well documented that ini-tiation of thyroid hormone replacement in anindividual 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 patientshave reduced cortisol requirements secondaryto a reduced metabolic rate.41,42 When thyroxinetherapy is initiated, the metabolic rate and cortisolrequirements increase, and an adrenal crisis canensue. Accordingly, hyperthyroidism can increasecortisol metabolism. It is suggested that in theindividual with hyperthyroidism and adrenalinsufficiency, cortisol replacement should be in-creased as much as twofold because of increasedcortisol clearance.38 Growth hormone appears todecrease conversion of inactive cortisone to ac-tive cortisol. Therefore, after growth hormonetherapy is initiated, a patient with unrecognizedconcomitant adrenal dysfunction might be vul-nerable.43 Pregnancy is associated with increasedcorticosteroid-binding globulin and therefore

corticosteroid doses administered by variousroutes. Treatment courses as brief as 2 weeks canresult in transient suppression of endogenouscortisol production.39

Clinical Features

Clinical manifestations of adrenal insufficiencydepend on the age of the patient, the cause, andwhether 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 typicallyhypotensive and have tachycardia. In primaryadrenal insufficiency, electrolyte abnormalitiescan occur due to additional mineralocorticoiddeficiency. Severe hyperkalemia can cause life-

threatening cardiac arrhythmias. Depending onthe specific enzymatic defect and karyotype ofan infant with CAH, the genitalia can appearmalformed. In the most common form of CAH(21-hydroxylase deficiency), genetic femaleinfants will likely have ambiguous genitalia,whereas genetic male infants have normallyformed genitalia. Infants of both sexes withCAH can have skin hyperpigmentation, particu-larly in the genitalia, due to high concentrationsof ACTH. The salt-wasting form of classic CAHpresents with a primary metabolic crisis in the

first weeks of life, regardless of sex. Infants withsecondary adrenal insufficiency due to hypopi-tuitarism might have midline facial malforma-tions (Figure 16.2) and male infants might havea 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 agewith or without hypoglycemia.40 Patients withchronic adrenal insufficiency usually experiencefatigue, anorexia, nausea, vomiting, loss of ap-petite, weight loss, and recurring abdominalpain. Salt craving is common in chronic primaryadrenal 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 historyof recent pharmacologic glucocorticoid therapy,

Figure 16.2 Midline facial malformation.




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Adrenal Insufficiency/Congenital Adrenal Hyperplasia 16-

disorders, neurologic diseases, or child abuse.The presence of hyperkalemia, hyponatremia,acidosis, skin hyperpigmentation, and mascu-linized genitalia in a genetic female can helpto differentiate primary adrenal insufficiencyfrom these other entities. In an older child,mild symptoms of primary adrenal insufficien-cy might be confused with mononucleosis oranorexia nervosa. More severe symptoms canmimic infections (eg, sepsis), hematologic dis-ease, psychiatric illness, or even an acute abdo-men. Again, the presence of hyperpigmentation

and the characteristic laboratory abnormalitiesserve to differentiate these entities. Secondaryadrenal insufficiency can be even more diffi-cult to differentiate from other entities becauseof the lack of hyperpigmentation and the lackof 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 hydrocortisonedosing by 50%. In addition, increasing intrapar-tum progesterone levels antagonize the mineralo-corticoid effect, which can dictate adjustment offludrocortisone supplementation as well.38

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

Diagnostic Studies

Blood 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, serum17-hydroxyprogesterone concentration shouldbe measured as well. Measurement of urinarysodium and potassium concentrations is helpfulin assessing mineralocorticoid status and in dif-ferentiating from other hyponatremic conditions.

In primary adrenal insufficiency, testingtypically reveals hyperkalemia, hyponatremia,hypoglycemia, and acidosis. However, not all

patients manifest all of these laboratory abnor-malities, and the diagnosis cannot be excludedbased on the absence of one or more of thesefindings. Both BUN and creatinine concentra-tions can be elevated due to dehydration. In sec-ondary adrenal insufficiency, hyperkalemia andhyponatremia are absent due to preservation ofmineralocorticoid production, and hypoglycemiamight be the primary biochemical abnormality.


Most of the symptoms of adrenal insufficiencyare nonspecific, and many overlap with other,more common, diagnoses. In infancy, for ex-ample, adrenal insufficiency might be confusedwith other illnesses that present with lethargy,vomiting, poor weight gain, hypotension, andtachycardia, including sepsis, gastrointestinalmalformations, congenital heart disease, in-born errors of metabolism, certain hematologic


Signs and Symptoms of AdrenalInsufficiency

• Infants: poor feeding, inadequate weightgain, vomiting, lethargy, hypotension,

and tachycardia, with or without

hyperpigmentation or masculinization of

genetic female genitalia

• Children: fatigue, weight loss, and

postural hypotension, with or without

hyperpigmentation, and abdominal pain

• Other clues: history of CNS surgery

or tumors or prolonged or long-term

corticosteroid use

T H E C L A S S I C S

Classic Laboratory Findings in AdrenalInsufficiency

• Primary adrenal insufciency:

hyperkalemia, hyponatremia,

hypoglycemia, and acidosis

• Secondary adrenal insufciency:

hypoglycemia




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is even suspected. If the patient has good gas-

trointestinal function, fludrocortisone (0.1 to0.2 mg/d), a synthetic mineralocorticoid, can beadministered orally. However, typically, admin-istration of IV sodium chloride along with stressdoses of hydrocortisone are sufficient to beginnormalizing electrolyte abnormalities, makingthe addition of mineralocorticoid unnecessaryin the initial phase of treatment.48

Severe hyperkalemia, resulting in a non-perfusing dysrhythmia, should be treated im-mediately with IV calcium gluconate to restorea perfusing rhythm. This should be followed by

IV sodium bicarbonate, nebulized albuterol (sal-butamol), and/or glucose with insulin to shift

tumors, neurosurgical procedures, congenitalCNS malformations, other coincident pituitaryhormone deficiencies (suggested clinically byshort stature, inappropriately absent or delayedpuberty, or polyuria, as examples), or prolongedexogenous glucocorticoid use must be relied on

for the diagnosis. Secondary adrenal insufficien-cy can evolve over time in patients with cranialradiation, septo-optic dysplasia, autoimmunehypophysitis, and head trauma.45–47

Management

In the hypotensive patient with adrenal insuf-ficiency, it is imperative to rapidly restore intra-vascular volume with isotonic sodium chloridecontaining glucose and to administer glucocor-ticoids expeditiously. An initial fluid bolus of

normal saline (20 mL/kg) should be given andrepeated as necessary to improve perfusion. Af-ter the initial bolus(es), a continuous infusion ofnormal saline with 5% dextrose should be given.On the basis of body surface area, the recom-mended stress dose of IV hydrocortisone is 50 to75 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 dosingand administer immediately 50 mg for childrenyounger than 4 years and 100 mg for childrenolder than 4 years. The benefits of sufficient

dosing greatly outweigh the risk of underdos-ing in such cases. Hydrocortisone can be givenintramuscularly if no IV access exists, althoughthe effects of intramuscular administration isslower and can be ineffectively absorbed if pe-ripheral perfusion is poor. Comparable bodysurface area stress doses are 10 to 15 mg/m2

for methylprednisolone and 1.5 to 2 mg/m2 fordexamethasone; the latter two corticosteroidshave minimal mineralocorticoid activity. Pred-nisone is not a preferred glucocorticoid becauseit must be converted to prednisolone for it tohave glucocorticoid activity, and in patients withliver failure, this conversion might be impaired.Dexamethasone can be used if one desires totreat the patient urgently but wishes to performa diagnostic ACTH-stimulation test because thisglucocorticoid will not interfere with diagnosticlaboratory assays. Treatment should never bewithheld if the diagnosis of adrenal insufficiency

W H AT E L S E ?

Differential Diagnosis of AdrenalInsufficiency

• Infants: infections, gastrointestinalmalformations, congenital heart disease,

inborn errors of metabolism, hematologic

disorders, neurologic disease, or child

abuse

• Children: mononucleosis, anorexia

nervosa, infections, hematologic disease,

psychiatric illness, or an acute abdomen

K E Y P O I N T S

Management of Adrenal Insufficiency

• Initiate uid resuscitation (20 mL/kg of

normal saline bolus).

• Administer hydrocortisone (50 mg for

child 4

years).• Treat symptomatic hyperkalemia (calcium

gluconate, bicarbonate, insulin, albuterol

[salbutamol]).

• Treatment consists of stress dosages of

hydrocortisone, IV fluids, and correction

of hyperkalemia.




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Diabetes Insipidus 16-

gene or autosomal recessive or dominant muta-tions in the AQP-2 gene. These cases typicallypresent in infancy.56 Acquired nephrogenic DIcan 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, prolongedpolyuria of any cause can also lead to some de-gree of nephrogenic DI because of a reduction oftonicity in the renal medullary interstitium anda subsequent decrease in the gradient necessaryto concentrate urine.50,53,57

Clinical Features

Characteristic symptoms of DI are pronouncedpolyuria and polydipsia. Older children typi-

cally present without any obvious abnormalitieson physical examination as long as they have anintact sense of thirst, access to fluids, and noongoing losses, such as diarrhea. They mightreport a history of nocturia and secondary en-uresis. Infants, in addition to polyuria and poly-dipsia, frequently demonstrate irritability, poorweight gain, failure to thrive, hyperthermia, andsigns of dehydration. Developmental delaysand arrest of variable severity can ensue afterrepeated 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 patientswith coexisting untreated anterior pituitary-mediated adrenal glucocorticoid insufficiencybecause cortisol is required to generate normalfree water excretion.58

Diagnostic Studies

Infants generally present with hypernatremiaand serum hyperosmolality because they havelimited access to fluids. Coincident inappro-priately dilute urine (


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The principal presenting sign of DI is polyuria,which, in addition to deficiency or impairedresponsiveness to ADH, can result from an os-motic agent, such as hyperglycemia as seen in

DM, or from excessive water intake (primarypolydipsia). Patients with hypercalcemia orhypokalemia can also have impaired urinaryconcentrating ability, resulting in polyuria.

Management

Patients without hypernatremia and dehydrationdo not require immediate intervention for DIbut should undergo evaluation to determine theunderlying cause. Patients with hypernatremicdehydration and hyperosmolality should be

treated with fluid resuscitation. This includes aninitial 20-mL/kg fluid infusion of normal salineto restore perfusion followed by subsequent slowcorrection because overly aggressive free waterreplacement can lead to cerebral edema. In ad-dition to correcting the fluid deficit, the manage-ment of central DI includes treating the primarydisease and normalization of urine output with

measurements of body weight, serum sodiumand osmolality, and urine volume and osmolality.If urine osmolality of greater than 750 mOsm/Lis achieved with any degree of water depriva-tion, DI can be excluded.59 The diagnosis of DIis established at any time point if serum

osmolality rises above 300 mOsm/L andurine osmolality remains below 300 mOsm/LUrine osmolality in the 300- to 750-mOsm/Lrange during water deprivation can indicate par-tial DI.53 During the test, if DI is suspected, an ADH plasma sample should be obtained, andthen ADH, or a synthetic analog (desmopres-sin), should be administered to further distin-guish ADH deficiency (central DI) from ADHunresponsiveness (nephrogenic DI).

If central DI is suspected, an MRI of thebrain, with particular attention to the hypo-

thalamic-pituitary region, is indicated. Theposterior pituitary hyperintensity (bright spot)on T1-weighted MRIs is often absent in centralDI.54,60–62 However, the absence of the brightspot is neither sensitive nor specific for this di-agnosis because it can be absent in healthy in-dividuals63 and, conversely, present in childrenwith central DI as well.64 In central DI patients,a normal MRI does not exclude the possibilityof 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-enhancedbrain MRIs for early detection is critical.55 In-tracerebral calcifications of the frontal lobes andbasal ganglia can result from repeated episodesof dehydration.65 Ultrasonography can be help-ful in detecting nonobstructive hydronephrosis,hydroureter, and megabladder, resulting fromlongstanding polyuria and polydipsia.66


Signs and Symptoms of DI

• Infants: failure to thrive, irritability,

hyperthermia, dehydration• Children: polyuria, polydipsia, absence

of DM


Laboratory Findings in Infants andChildren With DI

• Infants: hypernatremia, hyperosmolality,inappropriately dilute urine

• Children: dilute urine, nocturia, secondary

enuresis

W H AT E L S E ?

Differential Diagnosis of DI

• Hyperglycemia from DM

• Primary polydipsia

• Hypercalcemia

• Hypokalemia




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Syndrome of Inappropriate Secretion of Antidiuretic Hormone 16-

agents (eg, phenothiazines or tricyclic antidepres-sants); (4) various pulmonary disorders and in-terventions (eg, pneumonia, asthma, or positivepressure ventilation); (5) non-CNS tumors withectopic production of ADH; (6) patients treatedwith desmopressin acetate who drink excessive

amounts of fluids (typically habit driven); and (6)miscellaneous causes, such as AIDS, postopera-tive state, glucocorticoid deficiency, and severehypothyroidism.70,71

Clinical Features

Patients with SIADH frequently will not mani-fest symptoms of hyponatremia until the serumsodium concentration falls below 120 mEq/L.Below this level, symptoms can include anorex-ia, nausea, vomiting, lethargy, irritability, and

confusion. Severe hyponatremia can culminatein seizures and loss of consciousness.

Diagnostic Studies

On the basis of criteria established by Bartter andSchwartz,72 the diagnosis of SIADH is made whenthe following constellation occurs: (1) plasmahypo-osmolality (100mOsm/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 arenormal or low. Causes of pseudohyponatremiashould be excluded such as that due to hyperlip-idemia, hyperproteinemia, and the osmotic effectof hyperglycemia. Most patients with SIADH haveinappropriately measurable or elevated levels ofplasma ADH relative to plasma osmolality.


Other causes of hyponatremia include water in-toxication (primary polydipsia or iatrogenic),hyponatremic dehydration, adrenal insufficien-cy, renal failure, diuretic medications, nephroticsyndrome, cirrhosis, congestive heart failure,severe hypothyroidism, cystic fibrosis, andcerebral salt-wasting (CSW) syndrome. Thesediagnoses can generally be excluded based onthe absence of corresponding diagnostic signs,such as dehydration, edema, and hyperkalemia.

desmopressin. Desmopressin is an ADH analogwith markedly reduced pressor activity in com-parison with native ADH and a longer half-lifeand can be administered orally, intranasally, orby subcutaneous injection. In infancy, if polyuriais not excessive, central DI can be best managedwith extra fluid intake alone to avoid a potentialrisk of hyponatremia associated with desmopres-sin treatment. In cases of nephrogenic DI, themainstay of treatment, particularly in infancy,is thiazide diuretics in combination with eitheramiloride or indomethacin.65–68

Syndrome of InappropriateSecretion of AntidiureticHormone

Syndrome 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 serumin association with inappropriately concentratedurine and natriuresis.69–71 Several disorders andmedications are associated with SIADH: (1) CNSdisorders or damage, such as meningitis or en-cephalitis, cerebral hemorrhage, head trauma, orafter neurosurgical procedures; (2) psychiatricdisorders; (3) a large variety of pharmacologic

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

Key Concepts in the Diagnosis andManagement of DI

• DI should be suspected in childrenwithout DM who present with polyuria

and dilute urine.

• Hypernatremia generally will not occur in

children with normal thirst mechanisms

and free access to water.

• Hypernatremia is more frequently

encountered in infants.

• ED management includes cautious uid

administration to correct dehydration

while promoting gradual hypernatremia

correction and, in appropriate situation,

diagnostic evaluation initiation.




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Management

The mainstay of SIADH therapy for patientswith 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 throughdietary salt intake. Severe hyponatremia (serumsodium 40 mEq/L)

• Normal renal, thyroid, and adrenal

cortical function

W H AT E L S E ?

Differential Diagnosis of SIADH

• Water intoxication

• CSW syndrome

• Hyponatremic dehydration

• Adrenal insufciency

• Renal failure

• Diuretic use• Nephrotic syndrome

• Hypothyroidism

• Cystic brosis

• Congestive heart failure

• Cirrhosis




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Water Intoxication 16-

well. Certain psychiatric illnesses, particularlyschizophrenia, can be associated with compul-sive water drinking. It is presumed that a centraldefect in thirst regulation plays an importantrole in the pathogenesis of primary polydipsiain these patients.77–80 In some cases, for example,

the osmotic threshold for thirst is reduced belowthe threshold for the release of ADH81; therefore,these patients will continue to drink until theplasma tonicity is less than the threshold level.Drug therapy can also contribute to the increasein water intake in schizophrenic patients. Manyantipsychotic drugs induce the sensation of adry mouth, which will enhance thirst.82

Clinical Features

Clinical manifestations of water intoxication re-

sult from hyponatremia. Infants typically presentwith poor feeding, vomiting, and lethargy. Hypo-thermia and edema might also be present. Withsevere hyponatremia, seizures can occur andmight be prolonged. It has been suggested thathypothermia can be a specific marker for hypo-natremia in infants with a new onset of seizures.83

Diagnostic Studies

Hyponatremia (serum sodium concentration


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laboratory features of dehydration are presentand the urine is concentrated. A careful history,including infant feeding practices and psychiatric

illness, in addition to the detection of dilute urinecan lead to the diagnosis of water intoxication.

Management

For infants who are asymptomatic or havemild symptoms of hyponatremia, reinstitutionof normal daily sodium with more restrictedfluid intake is generally all that is required. Forinfants 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 WaterIntoxication

• Poor feeding • Vomiting

• Lethargy

• Seizures

• Hypothermia


Laboratory Findings in Patients WithWater Intoxication

• Hyponatremia (sodium concentration


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

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 ametabolic pathway. Effects are caused by toxicaccumulations of substrates before the block orfrom alternative metabolic pathway intermediates(disorders of protein metabolism, carbohydrateintolerance, metal metabolism, and porphyrias);defects in energy production and use within thebrain, heart, liver, skeletal muscle, and other or-gans due to a deficiency of products beyond theblock (disorders of carbohydrate metabolism [eg,gluconeogenesis, glycogenolysis, and glycogenstorage disorders], fatty acid oxidation defects,

and mitochondrial disorders); or disturbances inthe synthesis or catabolism of complex molecules(lysosomal storage and peroxisomal disorders ordefects in the metabolism of cholesterol, purinesand pyrimidines, and neurotransmitters; and de-fects in glycosylation).85 Most IEMs have multipleforms that differ in age of clinical onset, severity,and even mode of inheritance. The IEMs mostlikely to result in acute, potentially life-threaten-ing decompensation include disorders of proteinmetabolism, defects in carbohydrate metabolism,fatty acid oxidation defects, and early-onset formsof mitochondrial and peroxisomal disorders.Lysosomal storage disorders, certain glyco-gen storage disorders, and late-onset forms ofmitochondrial and peroxisomal disorders tendto have a chronic insidious progression thatresults in organ dysfunction and ultimately fail-ure. Inheritance is autosomal recessive for mostIEMs (because many are enzyme deficiencies),

Metabolic Disease of theNewborn and Young Child:

Inborn Errors of MetabolismEarly recognition of a possible inborn error ofmetabolism (IEM) in acutely ill patients is criticalto minimize the high morbidity and mortalityrates associated with these conditions. Althoughindividually rare, IEMs collectively are relativelycommon.84 A diagnosis of IEM should be con-sidered not only in the evaluation and treatmentof critically ill patients but also in patients withrecurrent episodes of vomiting, lethargy, and/orseizures 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 occurat any time throughout childhood and even inadulthood. Initial treatment of the critically illchild with an IEM does not require a detailedknowledge of individual IEMs or biochemicalpathways but rather an understanding and earlyrecognition of life-threatening clinical manifes-tations and consequences of the metabolic de-rangements.85–87 Prompt initiation of appropriatetreatment is crucial for optimizing immediate andlong-term outcome and is often lifesaving.

More than 400 IEMs have been identifiedsince 1908.88 The incidence of IEMs is estimatedto be as high as 1 in 1,000 live births.89 Inbornerrors of metabolism are caused by single genedefects that result in abnormal synthesis, catabo-lism, and/or function of proteins, carbohydrates,fats, organelles (ie, lysosomes, mitochondria, and

C A S E

S C E N A R I O

2

A 14-month-old girl presents to the ED with a 1-day history of tactile fever, loss

of appetite, and intermittent emesis. This morning, she did not seem interested

in 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 glucosemeasurement 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?




21/34


in gastroenteritis). Unusual dietary preferences,particularly protein or carbohydrate aversion,and symptoms occurring during diet changesare often seen in patients with an IEM. By lateinfancy or early childhood, it is often apparentthat with routine illnesses, children with an IEM

become more severely symptomatic and/or re-quire longer to recover than expected. In olderchildren and adults, vigorous exercise, sleepdeprivation, hormonal changes, intercurrentillness, anesthesia or surgery, and pregnancy ordelivery commonly precipitate symptoms.

A family history of siblings and/or a historyof relatives with similar findings is an importantclue 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 raiseconcern 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 withmaternal heterozygosity for fatty acid oxidationdefect and suggests the possibility of homozy-gosity for the disease in the child. Decreasedfetal movement has been described with certainglycogen and lysosomal storage disorders andperoxisomal disorders. A negative family history

does not rule out an IEM.Clinical ManifestationsClinical manifestations of IEMs reflect the mul-tiorgan system involvement typical of these dis-orders. Common clinical presentations includea sepsis-like illness or cardiac, hepatic, and/orneurologic dysfunction.85–87,97–104 Physical ex-amination findings are normal for most IEMs. Abnormal odor or hair, hearing deficit, visualdysfunction, organomegaly, and/or chronic der-matitis should prompt consideration of an IEM.Dysmorphic features are seen commonly withmitochondrial disorders, peroxisomal disorders,lysosomal storage, and other disorders of com-plex molecules. The risk of mortality can be veryhigh, particularly with initial presentation of anundiagnosed IEM. Features of specific IEMs canbe found in the texts referenced in this chap-ter85,95,96 and on Web sites, including OnlineMendelian Inheritance in Man.88,90

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

Nearly all states in the United States testnewborns for at least 29, and some for morethan 50, genetic diseases, most of which areIEMs.91,92 A table of newborn screening tests

performed by state is available online.93 Resultsare usually available within days but might takeweeks. In at least some states, parents can optto not have their child screened. False-negativenewborn 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 tosample collection and handling. Cutoff valuesare set to minimize false-negative rates, whichresults in relatively high false-positive rates. Ne-onates who test positive on newborn screens foran IEM that can result in acute, life-threateningdecompensation require emergent evaluation.94

Clinical Features

HistoryHistory can vary from abrupt onset of rapidlyprogressing illness that results in death withinhours, to intermittent recurrent acute episodesof potentially life-threatening decompensationin an otherwise well child, to chronic, slow-ly progressive deterioration throughout de-

cades.85,90,95,96 Inborn errors of metabolism thatresult in acutely life-threatening critical illnesspresent most commonly within the first yearof life and usually within the newborn period,those that cause intermittent decompensationmost often manifest later in infancy or early inchildhood, and those with insidious, progressivesymptoms tend to present in older childhood,adolescence, or even throughout adulthood.In the neonate, the most important clue to anIEM is a history of deterioration after an initialperiod of apparent good health ranging fromhours to weeks.97,98 In neonates and infants, ahistory of poor feeding, vomiting, chronic diar-rhea, failure to thrive, lethargy, and seizures iscommon.99–101 Developmental delay in infants,particularly with loss of milestones, is stronglysuggestive 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




22/34


retinopathy, optic atrophy, chronic dermato-ses, skin photosensitivity, nodules, dilated orhypertrophic 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. Inbornerrors of metabolism most likely to present inthis age group include partial enzyme deficiencyurea cycle defects, disorders of carbohydratemetabolism, fatty acid oxidation defects, andlysosomal storage disorders. Reye syndrome–like symptoms are now recognized often to bedue to IEMs. The differential diagnosis of IEMsin 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 AdultsIn older children, adolescents, and adults, pre-viously undiagnosed IEMs usually manifest asneurologic and/or psychiatric abnormalities thatcan range from recent to longstanding and fromsubtle to severe.103,105 Although rare, the initialpresentation of an IEM can be that of criticalillness with rapid progression to death. Manifes-tations of life-threatening IEMs most commonly

include profound lethargy, coma, encephalop-athy, seizures, stroke, other thromboembolicevent, 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 learningdisabilities, autism, developmental delay, visualdeficits, ocular abnormalities, exercise intoler-ance, muscle cramps, ataxia, abnormal move-ments, abnormal or aggressive behaviors, andpsychiatric disturbances, such as anxiety, panicattacks, hallucinations, delirium, paranoia, and/ or psychosis. Findings particularly concerningfor IEMs include ophthalmologic abnormali-ties, progressive neurologic disease, abnormalmovements, cerebellar symptoms, and mixedpsychiatric and neurologic symptoms. Amongthe most common IEMs on the growing list ofrecognized IEMs with late onset are partial orni-thine transcarbamylase deficiency (particularly

NeonatesInborn errors of metabolism should be consid-ered in neonates who are critically ill, particu-larly those with encephalopathy and/or hepaticdysfunction. Clinical manifestations of IEMs inneonates 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, abnormaltone, seizures, stroke, and/or altered level ofconsciousness. These same findings are alsomanifestations of many other causes, makingthe differential diagnosis extensive. Presence ofone diagnosis does not rule out the possibilityof 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. Inbornerrors of metabolism should be considered inneonates with fetal hydrops or pulmonary orintracranial hemorrhage in utero or after birth. Itshould also be recognized that an undiagnosedIEM 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 metabolismis dependent on significant accumulation of

toxic metabolites, which for severe forms canoccur within hours after the initiation of feed-ing. Neonates with IEMs that result in defectsin energy production and use are often symp-tomatic at birth or within the first 24 hours oflife. These neonates are less likely to have comaas an early manifestation and are more likelyto have dysmorphic features, cardiopulmonarycompromise, organomegaly, skeletal malforma-tions, and hypotonia.

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




23/34


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

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

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

Diagnostic Studies

In the acutely ill patient with an undiagnosedcondition, results of routine laboratory testsoften provide clues to IEMs and should guidefurther evaluation.85,86,97,100,106 Most patientswith acute, life-threatening presentations ofmetabolic 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 werenot collected before treatment, remaining pre-

treatment specimens are likely to be more infor-mative than posttreatment samples and shouldbe used if available. A metabolic specialist canbe helpful in directing the evaluation of patientswith suspected or known IEMs.

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

2, and bicarbonate level and an

elevated anion gap. Severe metabolic acidosisand ketonuria, with or without hyperammone-mia or hypoglycemia, are hallmarks of organicacidemias. An elevated anion gap accompaniesacidosis in organic acidemias, mitochondrialdisorders, aminoacidopathies, and disorders ofcarbohydrate metabolism. Lactate and pyruvateshould also be obtained in patients with sus-pected or confirmed acidosis. Lactic acidosis,although seen in many IEMs, is a nonspecificfinding in critically ill patients that results fromhypoxia and poor tissue perfusion. An elevatedlactate:pyruvate ratio (usually >20), providesan important clue to determining whether apatient has an IEM, most commonly due to amitochondrial or cytoplasmic enzyme disorder.Urine with low specific gravity and pH of 5.0or higher in the setting of metabolic acidosissuggests renal tubular acidosis, which, althoughnot 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: feeding difculties,

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)

• Common presentations

- Acute neonatal catastrophe

- Neurologic abnormality, dysfunction

- Cardiac dysfunction, failure, arrest

- Gastrointestinal or hepatic dysfunction,

failure

- Skeletal myopathy

- Psychiatric disturbance




24/34


acidopathies or mitochondrial disorders mighthave ketonuria with normal glucose levels. Inaddition to plasma for amino acids and acylcar-nitine profile and urine for organic acids andacylglycines, serum ketones, plasma free-fattyacids, and endocrine studies, including insulin

and serum cortisol, should be performed.

Other StudiesLiver function tests, including bilirubin, trans-aminases, and coagulation studies, most com-monly reveal elevated levels in patients withdisorders of protein metabolism or fatty acidoxidation defects but can reveal elevated levelsin IEMs within most categories. Triglyceridesand 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 disordersof carbohydrate metabolism, fatty acid oxida-tion defects, and mitochondrial disorders andshould be tested in patients with symptoms ofskeletal muscle myopathy and/or with myo-globinuria. Urine test results positive for non–glucose-reducing substances suggest possibleaminoacidopathy or carbohydrate intolerancedisorder (eg, galactosemia).

In select cases, CSF, collected at approxi-mately the same time as plasma, should befrozen 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 liveror other tissues might be appropriate but arenot usually emergent. Other studies, includ-ing evaluation for bacterial or viral infection,radiography, computed tomography, MRI,ultrasonography, electrocardiography, and/orechocardiography, should be obtained emergentlyas clinically indicated for evaluation and manage-ment of life-threatening manifestations of IEMs.

In the child who has died, identifying anIEM might still be important because currentlyasymptomatic family members and/or futurechildren 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 withinhours. Patients with consistently elevated am-monia levels can have modestly increased lev-els without obvious clinical symptoms. Hepa-tomegaly and mild elevation of transaminasesand/or abnormal clotting factors are other mani-

festations. Ammonia concentration is high-est with urea cycle defects, usually 340–1700mcg/dL (200–1000 mcmol/L) or higher. Withorganic acidemias, ammonia levels do not usu-ally exceed 850 mcg/mL (500 mcmol/L). Lowerconcentrations of ammonia and higher concen-trations of acids in these patients result in primarymetabolic acidosis, usually with marked ketosis. With fatty acid oxidation defects, the level of am-monia does not usually exceed 425 mcg/dL (250mcmol/L), and acid-base status is usually normal.

Ammonia concentration in the normal range doesnot rule out an IEM. To prevent a falsely elevatedvalue, blood for ammonia should be collectedby free flow without a tourniquet and the speci-men put on ice immediately. In patients withhyperammonemia, plasma for amino acids andacylcarnitine profile and urine for organic acids,acylglycine, and orotic acid should be tested.

Hypoglycemia A serum glucose level less than 40 mg/dL shouldbe considered abnormally low in neonates anda level less than 40 to 50 mg/dL should be con-

sidered abnormally low beyond the neonatal pe-riod. Clinical findings of hypoglycemia includerepeated yawning, irritability, pallor, jitteriness,altered mental status, and seizures. Neonatescan also have a high-pitched cry, hypothermia,hypotonia, apnea, cyanosis, and poor feeding.Older children and adolescents often reportheadache, lightheadedness, diaphoresis, pal-pitations, and nausea. Normally, hypoglycemiaresults in ketonuria, except in neonates dueto 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 ina patient with hypoglycemia suggest a hyper-insulinemic state, a glycogen storage disorder,carbohydrate intolerance disorder, or fatty acidoxidation defect. The presence of ketones (ke-totic hypoglycemia), however, does not rule outthese disorders. Patients with organic amino-




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Management

In addition to rapid assessment and aggressivemanagement of airway, breathing, and circu-lation, goals of treatment of IEMs are to stopintake of harmful substances, correct metabol-ic abnormalities, and eliminate toxic metabo-lites.85,86,107,108 Even the apparently stable patientwith mild symptoms can deteriorate rapidlywith 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 knownIEM, treatment should be disease and patientspecific. Families should have an emergencytreatment plan specifically for their child devel-oped by their IEM specialist with them or avail-able electronically. In addition, families mighthave a plan detailing their desired interventionsshould lifesaving resuscitation be necessary.

Once airway, breathing, ventilation, andvascular access have been established, hydra-tion, glucose as necessary to correct hypogly-cemia and prevent catabolism, and therapy tocorrect acidosis and hyperammonemia mustbe initiated. Protocols for treatment of acuteillness in patients with a suspected IEM andsome diagnosed IEMs are available on the NewEngland Consortium Web site.107 Consultationwith a metabolic specialist should be initiated

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


Because the signs and symptoms of inborn er-rors of metabolism are nonspecific, IEMs arefrequently not considered in the differential di-agnosis. Therefore, a high index of suspicion isimportant because the physician must initiateappropriate therapy without delay (and withouta final diagnosis in hand) to decrease morbidityand mortality. A concomitant acquired disordercan obscure the diagnosis of an inherited meta-bolic disease condition. For example, neutrope-nia can occur in organic acidemias, leading toan increased susceptibility of bacterial infection.The underlying disorder might be missed if aninfection is also present and focus is directedsolely toward antimicrobial therapy. Escherichiacoli sepsis frequently supervenes in neonateswith galactosemia, and the typical jaundice,liver failure, and vomiting that accompany thatdisorder might wrongly be ascribed solely tosepsis as well.


Findings of Routine Laboratory Studiesin Children With IEMs

• Metabolic acidosis• Hypoglycemia (hypoketosis or absent

ketones)

• Hyperammonemia, respiratory alkalosis

• Elevated lactate level, lactate:pyruvate

ratio

• Elevated liver function studies (bilirubin,

aspartate aminotransferase, alanine

aminotransferase, lactate dehydrogenase)

• Urine-reducing substances, myoglobin

W H AT E L S E ?

Differential Diagnosis of IEM in theCritically Ill Patient

• Infection: sepsis, meningitis, encephalitis• Shock

• Respiratory illness

• Cardiac disease

• Gastrointestinal illness or obstruction

• Hepatic disease

• Renal disease

• Neurologic abnormality, disease

• Trauma

• Toxin or drug withdrawal

• Behavioral, psychiatric disorder




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For patients with an aminoacidopathy, organicacidemia, or fatty acid oxidation defect, hyper-ammonemia usually improves with rehydrationand the reversal of acidosis and hypoglycemia.For severe hyperammonemia in patients withurea cycle defects, hemodialysis is the mainstay

of treatment. Extracorporeal membrane oxygen-ation–assisted hemodialysis is the most effectiveform of hemodialysis but has increased risks,particularly in neonates. Exchange transfusionis not effective. Recommendations of the NewEngland Consortium are to consider dialysis forammonia levels greater than 300 mcg/dL (175mcmol/L) and transfer to a facility or unit withdialysis capability for ammonia levels greaterthan 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 phenylacetateand sodium benzoate (available as Ammonul)should be administered to patients with knownor suspected urea cycle defect to augment ni-trogen excretion.109 The combination of sodiumphenylacetate and sodium benzoate is approvedas adjunctive therapy for acute hyperammone-mia and associated encephalopathy due to ureacycle defects but is also used to treat hyperam-monemia of unknown origins. Ondansetronshould be administered with sodium phenyl-

acetate and sodium benzoate. Potassium, whichcan be depleted by sodium phenylacetate andsodium benzoate, should be monitored and re-placed as potassium acetate, 0.5 to 1 mEq/kgper hour, as needed. In addition, 10% argininehydrochloride, which enhances urea cycle activ-ity, should be given for treatment of urea cycledefects with the exception of arginase deficiency.Citrulline can be administered to augment ni-trogen clearance in urea cycle defects with theexception of argininosuccinic acid synthetase(citrullinemia) and argininosuccinase acid lyasedeficiencies. Although data are limited, recentliterature suggests hypertonic saline should begiven 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 monitoredserially.

if available. With appropriate therapy, patientscan recover completely without sequelae.

Hydration is critical not only to restore in-travascular volume but also to promote urinaryexcretion of toxic metabolites. For IEMs thatare potentially acutely life-threatening, fluid bo-

luses should be administered as 10% dextrosenormal 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 shouldbe avoided because they increase nitrogen load. After bolus fluid, maintenance fluid should beadministered as 10% to 12.5% dextrose halfnormal saline at a rate high enough to preventcatabolism by maintaining serum glucose at

120 to 170 mg/dL. Large fluctuations in serumglucose should be avoided. Although contro-versial, 0.1 to 0.2 U/kg per hour of insulin canbe administered to prevent hyperglycemia. Fora suspected IEM, stop all oral intake to ensurethat potentially harmful protein or sugars areavoided. For a known IEM, dietary restrictionshould be disease specific.

Treatment of acidosis with bicarbonate isthought to be indicated for IEMs because of on-going acid production; however, data regardingthe degree of acidosis for which it should be

initiated and dose are lacking. Recommenda-tions for administration of bicarbonate rangefrom pH 7.0 to 7.2 and serum bicarbonate aslow as 14 to 16 mEq/L. The recommended doserange is 0.25 to 2 mEq/kg per hour, dependingin part on the specific IEM. Bicarbonate shouldbe administered cautiously in patients with hy-perammonemia because alkalinization convertsNH

4+ to NH

3, which is less readily excreted in

urine and more readily crosses the blood-brainbarrier, 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 mustbe corrected cautiously to minimize paradoxicaleffects on the CNS that can be caused by rapidor overcorrection.

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




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oxidation disorders but is usually used afterconsultation with a metabolic specialist. Thechild might need immediate admission to anintensive care unit for further monitoring andother procedures (eg, hemodialysis).

In children who are already known to have

an IEM, the importance of listening closely tothe history provided by the parents or regularcaregiver must be stressed. A child with a meta-bolic disorder can appear relatively well butmight decompensate rapidly. If such a child is notmaintaining adequate fluid and caloric intake,“does not seem to be his usual self,” or both, themetabolic specialist should be contacted, and IVfluids with dextrose should be administered evenin the absence of documented hypoglycemia orother markers of metabolic imbalance. The goalin such cases is to provide therapy in a timelymanner to prevent a metabolic crisis.

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

Intravenous l-carnitine, 25 to 50 mg/kg, canbe administered empirically in life-threatening

situations associated with known or suspectedcarnitine deficiency (eg, primary carnitine defi-ciency, certain organic aminoacidopathies, andfatty acid oxidation defects); however, becauseit can be harmful with some IEMs, consultationwith 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 vianasogastric tube can be given empirically to neo-nates with seizures unresponsive to conventionalanticonvulsants to treat a possible vitamin or co-factor responsive IEM. Although there are otherdisease-specific adjunctive therapies, administra-tion of these agents in the ED is rarely indicated.

Rapid assessment, establishment of vascu-l

16 metabolic diseases

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