16 Metabolic Diseases

chapter 16
Metabolic Diseases
Nicole Glaser, MD
Elka Jacobson-Dickman, MD
Nathan Kuppermann, MD, MPH, FAAP
Debra L. Weiner, MD, PhD, FAAP
Objectives
Chapter Outline
Describe the
epidemiology,
clinical features,
and emergency
management of
diabetes mellitus (DM),
adrenal insufficiency,
syndrome of
inappropriate secretion
of antidiuretic
hormone (SIADH),
water intoxication, and
diabetes insipidus (DI).
Introduction
Diabetic Ketoacidosis
Hypoglycemia in Children With Diabetes
Hypoglycemia in Nondiabetic Children
Adrenal Insufficiency/Congenital Adrenal Hyperplasia
Diabetes Insipidus
Syndrome of Inappropriate Secretion of Antidiuretic Hormone
Water Intoxication
Metabolic Disease of the Newborn and Young Child: Inborn
Errors of Metabolism
Describe the fluid and

electrolyte problems
associated with these
conditions.
Discuss the clinical

features and emergency
management of
metabolic diseases of
the newborn and young
child.
Copyright 2012 by the American Academy of Pediatrics and the American

College of Emergency Physicians
1
CASE SCENARIO
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 37.9C (100.2F). 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
Diabetic Ketoacidosis
The emergency management of endocrine and

metabolic disorders presents diagnostic and
therapeutic challenges. Many of these disorders, such as congenital adrenal hyperplasia
(CAH) and inborn errors of metabolism, occur
relatively infrequently. Nonetheless, rapid and
appropriate intervention is necessary to prevent
complications. Awareness of key clinical and
laboratory findings that differentiate endocrine
and metabolic disorders from other entities with
similar presenting features is essential.
Diabetic ketoacidosis (DKA) is the most important complication of type 1 DM (Figure 16.1).
Diabetic ketoacidosis occurs when insulin concentrations are low relative to the concentrations
of counterregulatory hormones, particularly
glucagon. This imbalance results in hyperglycemia along with the breakdown of fat to form
ketone bodies, eventually resulting in acidosis.
Diabetic ketoacidosis occurs in 25% to 40% of
children with new onset of type 1 diabetes mellitus (DM).13 Repeat episodes of DKA in children

16-3
with known diabetes can occur during episodes

of illness or with diabetes mismanagement or
malfunction of diabetes care equipment (insulin
pumps). Presumed omission or incorrect administration of insulin injections is the most
common cause of DKA in children with known
DM (69%); bacterial infections are infrequently
present (13%).4
Clinical Features
Diabetic ketoacidosis is characterized by hyperglycemia and elevated serum ketone concentrations, resulting in acidosis. Inadequate insulin
concentrations allow the partial oxidation of
fatty acids to form ketone bodies. This process
then results in acidosis with an increased anion
gap. Hyperglycemia results in osmotic diuresis
with polyuria, polydipsia, and eventual dehydration. Presenting features of DKA include
a history of polyuria, polydipsia, nausea, and
vomiting. Abdominal pain and intestinal ileus
are common features and can mimic an acute
abdomen. In a patient with clinical signs of dehydration, the presence of polyuria helps differentiate DKA from gastroenteritis and other
causes of dehydration. Acidosis results in compensatory tachypnea, and a characteristic fruity

(acetone) breath odor can often be detected.
Because the hyperosmolar state allows for the
relative preservation of intravascular volume,
some signs of dehydration can be less obvious
than in dehydrated patients with more normal
serum osmolality. Alterations in mental status
can range from disorientation to depressed consciousness. This alteration of mental status can
YO U R F I R S T C LU 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
Pathophysiology of Diabetic Ketoacidosis
fatty acid oxidation
gluconeogenesis
Ketone Bodies
glycogenolysis
peripheral glucose
uptake and
metabolism
Hyperglycemia
osmotic diuresis
Acidosis
vomiting
hyperkalemia
renal
Ca, phos,
Mg loss
renal K+ loss
increased
insensible
fluid losses
renal Na+ loss

Dehydration
poor tissue perfusion
increased lactate
Figure 16.1 Diabetic ketoacidosis.

Behrman RE, Kliegman RM. Nelson Essentials of Pediatrics. 4th ed. Philadelphia, PA: WB Saunders; 2002:185. Reprinted with permission.
16-4
Metabolic Diseases
be due to acidosis and dehydration but can also

reflect more serious underlying intracranial disease. Rarely, children with DKA present to the
ED with clinically apparent cerebral edema,5 as
well as cerebral infarctions or thromboses.
Complications
The most frequent complications of DKA treatment include hypokalemia and hypoglycemia.
Hypocalcemia, hypophosphatemia, and hypomagnesemia can also occur but are much less
common. Of the more serious complications of
DKA, clinically apparent cerebral edema is the
most frequent, occurring in approximately 1%
of DKA episodes. Cerebral edema is the most
important diabetes-related cause of mortality in
children with type 1 DM.6,7
Although cerebral edema can occur before
hospital treatment of DKA, this complication
more typically occurs several hours after initiation of therapy. The clinical presentation of cerebral edema can take different forms. Typically,
patients with cerebral edema experience headache and exhibit alterations in mental status.
Obtundation, papilledema, pupillary dilation
or anisocoria, blood pressure variability, bradycardia, and apnea can also occur in severe cases.
Deep venous thromboses can occur in children with DKA, particularly when central venous catheters are used.8,9 Other complications
of DKA are rare but include cerebral infarctions
or thrombosis, acute renal tubular necrosis leading to renal failure, pulmonary edema, pulmonary embolus, arrhythmia, pancreatitis, and
intestinal necrosis.
Diagnostic Studies
Diabetic ketoacidosis is defined as hyperglycemia (serum glucose concentration >200 mg/dL),
acidosis (venous pH <7.25 or serum bicarbonate concentration <15 mEq/L), and the presence
of ketones in the serum or urine.6,7 Electrolyte
abnormalities also occur as a result of urinary
losses and shifts due to acidosis. High serum
concentrations of potassium are often found at
the time of presentation of DKA, but normal
or low concentrations can occur if the ketoacidotic state is prolonged. Intracellular potassium
concentrations are characteristically depleted, as

are total body concentrations of sodium, phosphate, calcium, and magnesium. Although total
body sodium is depleted, the degree of depletion is less than that suggested by the measured
serum sodium concentration, which is artificially depressed due to hyperglycemia. Blood
urea nitrogen (BUN) concentrations are usually
elevated due to prerenal azotemia. The white
blood cell count is often elevated and frequently
left-shifted as a result of the ketoacidotic state
alone.4 It is generally unnecessary to search for
a source of infection beyond performing a careful physical examination unless fever or other
specific signs of infection are present.
Differential Diagnosis
The presenting symptoms and signs of DKA
can initially be confused with gastroenteritis or
other gastrointestinal disorders that present with
vomiting and abdominal pain. Infections such as
pneumonia, meningitis, and urinary tract infections also can present with metabolic acidosis,
tachypnea, and altered mental status or can be a
cause of the development of DKA. The history of
polyuria despite clinical dehydration, absence of
diarrhea, and presence of tachypnea with fruity
breath odor should differentiate DKA from these
other entities even before laboratory tests are ordered. Diabetic ketoacidosis must also be differentiated from hyperglycemic hyperosmolar state
(HHS) (formerly known as hyperglycemic hyperosmolar nonketotic coma), which presents with
severe hyperglycemia (serum glucose concentration >600 mg/dL and often >1,000 mg/dL) and
hyperosmolality (serum osmolality >330 mOsm),
profound dehydration, and a depressed level of
consciousness, but mild or no ketosis.10 Hyperglycemic hyperosmolar state can in fact represent
THE CLASSICS
Laboratory Findings in DKA
Hyperglycemia
Metabolic acidosis
Ketonemia or ketonuria
Diabetic Ketoacidosis 16-5

W H AT E L S E ?
Differential Diagnosis of DKA
Gastroenteritis
Abdominal surgical emergency
Toxic ingestion
Infections (pneumonia, meningitis,
urinary tract infections)
Hyperglycemic hyperosmolar state
one extreme in a continuum of presentations of

DKA and a mixed presentation with features of
DKA and HHS can also occur. Although HHS is
uncommon in children, recent reports suggest
that the frequency might be rising.10 Hyperglycemic hyperosmolar state occurs more frequently
in patients with type 2 rather than type 1 diabetes and in children with neurologic abnormalities that lead to abnormal thirst mechanisms or
limited access to liquids. The treatment approach
for HHS differs from DKA. Discussion of HHS
treatment is beyond the scope of this chapter but
has been reviewed elsewhere.10
Management
The fundamental treatment measures for DKA
include replacement of fluid deficits, correction
of acidosis and hyperglycemia via insulin administration, replacement of depleted electrolytes, and monitoring for complications.
Fluid Replacement
Optimal fluid management of DKA has been
a subject of great controversy, mainly due to
theoretical concerns about the role of fluid administration in contributing to cerebral edema.
Available evidence, however, does not confirm
a primary role for fluid administration in causing this complication.5,11 The most compelling
evidence suggests that children who present
with low Pco2 and high BUN concentration and
those treated with bicarbonate are at higher risk
for cerebral edema.5 Appropriate restoration of
perfusion and hemodynamic stability, therefore,
16-6
should not be compromised by theoretical concerns associated with fluid administration.

The average degree of dehydration in children with DKA is approximately 7%.12 The
typical child with DKA should receive an initial fluid bolus of 10 mL/kg of isotonic fluid (ie,
isonatremic fluids such as 0.9% saline [normal
saline] or lactated Ringers solution) for 30 to 60
minutes. If there is evidence of poor perfusion
or significant hypovolemia, 20 mL/kg can be
used as the initial bolus. Greater administration of fluids is indicated if signs of shock are
present. Isotonic fluid boluses can be repeated
if necessary to restore perfusion. Once perfusion
has been restored, the remaining fluid deficit
plus maintenance fluids can be replaced during the next 36 to 48 hours using half normal
(0.45% sodium chloride solution) to normal
saline (0.9% sodium chloride solution).6,7
Hyperglycemia
After the initial fluid bolus(es), insulin should
be administered via continuous intravenous
(IV) infusion at a dosage of 0.1 U/kg per hour.
Maximal suppression of ketogenesis occurs rapidly using a continuous insulin infusion at this
dosage and an initial IV bolus or loading dose
of insulin is unnecessary. When serum glucose
concentrations fall below 250 to 300 mg/dL
during treatment, glucose should be added to
the IV fluids to ensure that hypoglycemia does
not occur. The insulin infusion rate generally
should not be decreased until ketoacidosis resolves (pH >7.30 and bicarbonate >15). This
will like take roughly 10 to 24 hours to achieve,
so the insulin infusion must often continue on
the inpatient service.
Acidosis
The acidosis in DKA is due primarily to two
factors: the production of ketone bodies due to
relative insulin deficiency and the accumulation of lactate due to dehydration and poor tissue perfusion. Insulin treatment promotes the
metabolism of ketone bodies and halts further
ketone production, whereas the administration
of IV fluids treats the dehydration. This therapeutic combination is generally sufficient for
the correction of acidosis. Bicarbonate administration generally should be avoided because
associations between bicarbonate therapy and
Metabolic Diseases
KEY POINTS
DKA Management Guidelines
IV fluids:
- Administer initial 10- to 20-mL/kg bolus of normal saline. Fluid bolus can be repeated if necessary
to restore perfusion.
- Subsequent fluid administration should replace the remaining fluid deficit (typically approximately
70 mL/kg) plus maintenance fluids during 36 to 48 hours using half normal to normal saline. Normal
saline can be used initially with a transition to half normal saline after several hours.
Insulin:
- Insulin should be administered after initial fluid bolus(es).
- Insulin should be administered as a continuous infusion of 0.1 U/kg per hour.
- An initial insulin bolus dose is not necessary.
- Insulin should be administered at the above rate until ketoacidosis resolves (pH >7.30 and bicarbonate
>15 mEq/L). To prevent hypoglycemia, glucose-containing IV fluids should be used after the plasma
glucose concentration declines below approximately 250 to 300 mg/dL (13.9 to 16.7 mmol/L).
Electrolyte replacement:
- For DKA patients presenting initially with hypokalemia, potassium replacement should begin
immediately. If potassium levels are normal, potassium replacement should begin concurrent with
insulin administration, provided that renal function is adequate. For patients with hyperkalemia,
potassium replacement should begin when serum potassium levels decline to the normal range.
- Potassium replacement should be given as potassium chloride (KCl) or a 50:50 mixture of
potassium chloride (KCl) and potassium phosphate or potassium acetate to sum to 40 mEq of
potassium per liter of IV fluids. Serum potassium concentrations should be monitored frequently
and rates of administration adjusted according to measured concentrations.
- Calcium, magnesium, and phosphate concentrations should be monitored. Phosphate
concentrations typically decrease during treatment, and replacement of phosphate (see above)
can be considered. Replacement of calcium and magnesium is rarely required.
Bicarbonate treatment:
- Bicarbonate treatment should be avoided except in rare circumstances of symptomatic
hyperkalemia and/or cardiovascular instability caused by severe acidosis and not responding to
fluid and insulin therapy.
Monitoring:
- Vital signs should be measured hourly.
- Continuous cardiac monitoring is recommended.
- Accurate recording of fluid intake and output should be performed.
- Blood glucose concentrations should be measured hourly. Electrolytes, serum urea nitrogen,
creatinine, venous pH, and Pco2 should be measured every 2 to 4 hours. Calcium, magnesium,
and phosphate should be monitored approximately every 6 hours. More frequent measurements
might be needed in patients with abnormal or rapidly changing electrolyte concentrations.
- Mental status should be assessed hourly or more frequently in patients with headache or other
symptoms or signs of cerebral edema (see text).
Admission to the pediatric intensive care unit vs pediatric ward:
- Admission to the pediatric intensive care unit is recommended for children requiring more
intensive monitoring or those at risk for complications. These patients include:
- Children younger than 5 years
- Children with altered mental status
- Children with very high initial BUN concentration and/or very low initial Pco2 levels or severe
acidosis
- Children with mixed presentation of DKA and hyperglycemic hyperosmolar state
Diabetic Ketoacidosis 16-7

cerebral edema have been found in a large study

of DKA5 and administration of bicarbonate has
not been found to hasten resolution of DKA.13
In rare cases of symptomatic hyperkalemia or
acidosis severe enough to cause hemodynamic
instability not responsive to other therapeutic
measures, however, cautious administration of
bicarbonate should be considered.
Electrolyte Imbalances
Regardless of the serum potassium concentration
at presentation, total body potassium is depleted
in patients with DKA. With the treatment of DKA,
serum potassium concentrations can decrease
rapidly as insulin and fluid therapy improve the
state of acidosis and potassium shifts to the intracellular space. Potassium should typically be
added to the IV fluids at the time of initiation of
insulin treatment, provided that adequate renal
function is verified. For patients presenting with
hypokalemia, potassium replacement should
begin sooner. For patients with initial hyperkalemia, potassium replacement should begin
after potassium levels decrease to the normal
range. Potassium replacement should be given
as a mixture of potassium chloride and potassium phosphate or potassium acetate at a concentration of 30 to 40 mEq/L. Although severe
hypophosphatemia occurs rarely in children with
DKA, the consequences (eg, rhabdomyolysis and
hemolytic anemia) can be devastating.14,15 Therefore, it seems prudent to administer a portion of
the potassium replacement as the phosphate salt,
although a thorough study of this issue is lacking.
Monitoring and Treating Complications
Glucose concentrations should be measured
hourly using a bedside glucose meter throughout
the period of IV insulin treatment. A reasonable
rate of decline in the serum glucose concentration
is approximately 50 to 100 mg/dL per hour.6,7
With the initial infusion of IV fluids and restoration of renal perfusion, however, glucose concentrations might decrease more rapidly. Electrolyte
concentrations should be measured every 3 to 4
hours or more frequently if severe abnormalities
are present.
Careful monitoring is essential for early detection of complications of DKA, particularly cerebral
edema. Therefore, neurologic and mental status
should be checked hourly. Although the effective16-8
ness of cerebral edema treatment interventions is

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

Diabetes
Hypoglycemia, the most common complication
of type 1 diabetes in childhood, can occur in any
child in whom the dose of administered insulin
exceeds insulin requirements. Albeit less frequently, hypoglycemia can also occur in patients with
type 2 diabetes on oral hypoglycemic or insulin
regimens. Responses to hypoglycemia include
release of counterregulatory hormones, such as
glucagon, epinephrine (adrenaline), cortisol, and
growth hormone. However, over time both the
glucagon and epinephrine (adrenaline) responses
might be impaired, increasing the risk of persistent
hypoglycemia due to lack of adrenergic symptoms.
The American Diabetes Association criteria
for the clinical classification of hypoglycemia
in patients with DM include all episodes of an
abnormally low plasma glucose concentration
(<70 mg/dL or <3.9 mmol/L) with or without symptoms that expose the individual to
harm.17,18 A glucose concentration of 70 mg/dL
is higher than the value used to diagnose hypoglycemia in people without diabetes; however, it
is considered an appropriate threshold because
it approximates the lower limit of the physiologic fasting nondiabetic range, the normal
Metabolic Diseases
glycemic threshold for glucose counterregulatory hormone secretion, and the highest
antecedent glucose level reported to reduce
sympathoadrenal responses to subsequent hypoglycemia.19 It has been debated that a cutoff
value of less than 63 mg/dL (3.5 mmol/L) is
preferable to avoid overclassification of hypoglycemia in asymptomatic patients.2023
In children, the risk of hypoglycemia is associated with younger age,24 tighter glycemic
control,25 insulin regimens with fixed dosing (as
opposed to therapy that delivers a basal insulin
dose/infusion rate with intermittent boluses to
cover for intake),2629 exercise (due to increased
insulin absorption, more rapid glucose utilization, and increased insulin sensitivity), acute
illness (particularly when associated with nausea, vomiting, and anorexia), psychological
disturbance, lower socioeconomic status, and
occurrence of one or more prior hypoglycemic
episodes.30 In children and adolescents receiving intensive therapy, the risk of severe hypoglycemia is increased more than threefold. Finally,
the risk is also increased at night due to a sleepinduced blunted counterregulatory hormone
response to hypoglycemia.17,19,31
Clinical Features
Hypoglycemic symptoms can be adrenergic due
to epinephrine (adrenaline) release and/or neuroglycopenic due to direct effects of hypoglycemia
on the central nervous system (CNS). Adrenergic
symptoms include tremor, pallor, tachycardia,
palpitations, and diaphoresis. Neuroglycopenic
symptoms include fatigue, lethargy, headaches,
behavior changes, drowsiness, unconsciousness,
seizures, or coma. The severity of the neuroglycopenic symptoms increases with the severity of hypoglycemia and resultant CNS energy deprivation.
The severity of hypoglycemia is classified
by both symptoms and the clinical intervention
required.17 Mild hypoglycemia is associated with
adrenergic and mild neuroglycopenic symptoms,
such as headaches and mood changes in older
children and poor feeding, lethargy, jitteriness,
and hypotonia in infants and toddlers. In such
cases, oral intake of a rapidly absorbed carbohydrate is generally adequate treatment. Patients
with moderate hypoglycemia are neurologi
cally impaired to a level that requires help from

a second person to administer oral therapy. In
the absence of a person to aid therapy, moderate
episodes could escalate in severity. Severe hypoglycemia is recognized by the presence of critical neurologic symptoms (seizures or coma) or
requirement for intervention with subcutaneous
glucagonand/or IV dextrose. Case reports exist of
acute and transient cortical blindness and strokelike hemiparesis associated with severe hypoglycemia.32,33 Unlike mild episodes of hypoglycemia
that are relatively frequent in children with type
1 DM, severe hypoglycemic events are uncommon, occurring at a rate of approximately 5 to
19 events per 100 patient-years.1,2
Diagnostic Studies and Management

Patients with mild and moderate hypoglycemia
should be treated orally with a concentrated and
rapidly absorbed simple carbohydrate source,
such as glucose tablets, fruit juice, or cake frosting; 15 to 20 g of oral glucose is typically sufficient. A snack containing a mixed food source
should follow to sustain normal blood glucose
level. Blood glucose levels should be checked
every 15 to 20 minutes for approximately 2
hours to confirm that glucose values have normalized and to determine whether further intervention is necessary. The patient might require
additional carbohydrates until normal blood
glucose levels are sustained.
A patient with diabetes presenting with
altered mental status should have glucose
concentration assessed rapidly with a bedside
glucose meter. Hypoglycemia, if present, should
be corrected as rapidly as possible with an IV
infusion of 0.5 g/kg of dextrose. This can be
accomplished by infusing 5 mL/kg of 10% dextrose in an infant, 2 mL/kg of 25% dextrose in
a toddler, or 1 mL/kg of 50% dextrose in older
children (note the 50 rule: the product of the
milliliters per kilogram dose and the percentage
of dextrose should equal 50). In the event that
IV access cannot be established rapidly, glucagon should be given via subcutaneous or intramuscular injection. The accepted dose is 0.02
to 0.03 mg/kg or 0.5 mg for children weighing
less than 20 kg and 1 mg for children weighing
greater than 20 kg. If neurologic or mental status
Hypoglycemia in Children With Diabetes 16-9

abnormalities persist for prolonged periods after

correction of hypoglycemia, other possibilities
should be considered, such as toxic ingestions
and other intracranial disease.
Hypoglycemia in Nondiabetic
Children
Hypoglycemia can result from excessive insulin
production (insulinoma or hyperinsulinism) or
decreased concentrations of counterregulatory
hormones (deficiencies of growth hormone,
cortisol, or both). Hypoglycemia can also result
from inborn metabolic errors that impair gluconeogenesis, glycogenolysis, or fatty acid oxidation. Unsuspected hypoglycemia can be found
when patients present to the ED with episodes
of acute illness. A recent study revealed that a
substantial percentage (28%) of these patients
had previously undiagnosed fatty acid oxidation
defects (19%) or endocrine disorders (9%).34
Clinical Features
Infants with hypoglycemia can present with
jitteriness, poor feeding, lethargy, hypotonia,
hypothermia, apneic episodes, or seizures.
Symptoms of hypoglycemia in infants might
also be subtle and less obvious than those in
older children. In older children, symptoms
of hypoglycemia include headaches; vision
changes; mental status changes, such as confusion, lethargy, irritability, or anxiety; and
seizures. Adrenergic symptoms, such as palpitations, sweating, pallor, and tremulousness, are
usually also present. Hypoglycemia should be
considered in all patients presenting with unexplained alterations in mental status, seizure,
or loss of consciousness, and a routine bedside
test for hypoglycemia should be part of pediatric
resuscitation procedures.35
16-10
venous sample should be sent to the laboratory

for measurement with greater accuracy. Treatment for hypoglycemia should not be delayed
while awaiting results. At the time that the
confirmatory sample is drawn, an additional
serum sample (enough for special studies)
should be obtained for future measurement of
hormone concentrations and other biochemical measures. It is essential that this sample be
drawn at the time of the hypoglycemic event.
Without information from this sample, it is usually impossible to determine the cause of the
hypoglycemic episode. If hypoglycemia is confirmed, the measurements to be obtained on the
initial sample include serum insulin, cortisol,
and growth hormone concentrations, as well as
serum ketones, lactate, and free fatty acid
concentrations. 36 A toxicologic evaluation
for ethanol, salicylates, -blockers, and oral
hypoglycemic agents should also be considered.
Remaining serum from the initial sample should
be stored for additional biochemical testing if
necessary. Finally, a urine sample should also
be obtained and tested for ketones and reducing substances. An additional sample of urine
should likewise be stored for future testing.
There are many possible causes of hypoglycemia, and a discussion of all causes is beyond
the scope of this chapter. Among the more frequent causes (in patients without DM) are toxic
W H AT E L S E ?
Differential Diagnosis of Hypoglycemia
Toxins (oral hypoglycemic agents,
-blockers, ethanol)
Hypopituitarism
Diagnostic Studies
Adrenal insufficiency
If hypoglycemia is suspected, a rapid glucose

test should be performed using a bedside blood
glucose meter. A glucose concentration less than
50 mg/dL should be considered abnormal and
the patient treated. If the bedside test reveals
a low glucose concentration, a confirmatory
Fatty acid oxidation defects

Hyperinsulinism
Ketotic hypoglycemia
Sepsis
Metabolic Diseases
Signs and Symptoms of Hypoglycemia
Infants: jitteriness, poor feeding, lethargy,
hypotonia, hypothermia, apnea, seizures
Children: headaches, altered mental
status, diaphoresis, pallor, palpitations,
tremulousness, seizure
ingestions (eg, oral hypoglycemic agents,

-blockers, and ethanol), sepsis, hypopituitarism, adrenal insufficiency, fatty acid oxidation
defects, hyperinsulinism, and ketotic hypoglycemia. Analysis of the initial serum sample will
differentiate among many of these entities and
will indicate whether additional analyses are
necessary to investigate less frequent causes of
hypoglycemia.
Management
Hypoglycemia should be corrected as rapidly
as possible with an IV infusion of 0.5 g/kg of
glucose (dextrose). This can be accomplished by
infusing 5 mL/kg of 10% dextrose in an infant,
2 mL/kg of 25% dextrose in a toddler, and 1
mL/kg of 50% dextrose in older children (note
the 50 rule: the product of the milliliters per
kilogram dose and the percentage of dextrose
KEY POINTS
Diagnosis and Management of
Hypoglycemia
Perform rapid bedside glucose testing
for altered level of consciousness,
seizure, or lethargy.
Obtain additional blood and urine
samples 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.
should equal 50). Subsequently, an IV infusion

of 10% dextrose at 1.5 times maintenance rates
should be provided to maintain glucose concentrations in the normal range and reverse the
catabolic state. If adrenal insufficiency is known
or strongly suspected and adequate samples
have been set aside for further study, IV hydrocortisone should be given (50 mg for children
younger than 4 years and 100 mg for children
older than 4 years).
Adrenal Insufficiency/
Congenital Adrenal
Hyperplasia
Adrenal insufficiency can be related to processes
directly affecting the adrenal gland (primary), or
it can result from adrenocorticotropic hormone
(ACTH) deficiency (secondary). Both primary
and secondary adrenal insufficiency are characterized by inadequate production of corticosteroids that can culminate in adrenal crisis,
a life-threatening cardiovascular collapse. However, in secondary adrenal insufficiency mineralocorticoid function is preserved.
The causes of adrenal insufficiency in childhood are varied. Congenital adrenal hyperplasia
is the most common form of primary adrenal
insufficiency in children, with an incidence of
1 in 10,000 to 18,000 live births.37 Congenital adrenal hyperplasia is a group of autosomal
recessive inherited adrenal steroidogenesis enzyme deficiencies (most often 21-hydroxylase)
that cause various degrees of adrenal cortical
inability to synthesize cortisol. In childhood,
acquired primary adrenal insufficiency is relatively uncommon and can result from autoimmune adrenal destruction, infectious infiltration
(by tuberculosis, most commonly worldwide),
or inherited adrenoleukodystrophy syndromes.
Furthermore, long-term treatment with glucocorticoids can result in secondary adrenal
insufficiency by the suppressive effect on the
hypothalamic-pituitary-adrenal axis.38 In fact,
the most common cause of acute adrenal insufficiency in North America today is glucocorticoid
withdrawal or omission in patients being treated
for a variety of disorders with pharmacologic
Adrenal Insufficiency/Congenital Adrenal Hyperplasia 16-11

corticosteroid doses administered by various

routes. Treatment courses as brief as 2 weeks can
result in transient suppression of endogenous
cortisol production.39
Clinical Features
Clinical manifestations of adrenal insufficiency
depend on the age of the patient, the cause, and
whether it is a chronic or an acute process. All cases must be considered potentially life-threatening.
Infants with adrenal insufficiency can present with poor feeding, vomiting, and lethargy.
On physical examination, patients are typically
hypotensive and have tachycardia. In primary
adrenal insufficiency, electrolyte abnormalities
can occur due to additional mineralocorticoid
deficiency. Severe hyperkalemia can cause lifethreatening cardiac arrhythmias. Depending on
the specific enzymatic defect and karyotype of
an infant with CAH, the genitalia can appear
malformed. In the most common form of CAH
(21-hydroxylase deficiency), genetic female
infants will likely have ambiguous genitalia,
whereas genetic male infants have normally
formed genitalia. Infants of both sexes with
CAH can have skin hyperpigmentation, particularly in the genitalia, due to high concentrations
of ACTH. The salt-wasting form of classic CAH
presents with a primary metabolic crisis in the
first weeks of life, regardless of sex. Infants with
secondary adrenal insufficiency due to hypopituitarism might have midline facial malformations (Figure 16.2) and male infants might have
a microphallus.
Patients of all ages with acute adrenal insufficiency can present with dehydration, hypotension, hypoglycemia, or altered mental status.
Hypoglycemia is more common in young children. Altered mental status can occur at any age
with or without hypoglycemia.40 Patients with
chronic adrenal insufficiency usually experience
fatigue, anorexia, nausea, vomiting, loss of appetite, weight loss, and recurring abdominal
pain. Salt craving is common in chronic primary
adrenal insufficiency, as is postural hypotension.
Hyperpigmentation and salt craving are not observed in patients with secondary adrenal insufficiency. Furthermore, unless there is a history
of recent pharmacologic glucocorticoid therapy,
16-12
Figure 16.2 Midline facial malformation.
secondary adrenal insufficiency is commonly associated with signs and symptoms of additional
pituitary hormone deficiencies, such as growth
failure, delayed puberty, secondary hypothyroidism, and/or diabetes insipidus (DI).
Adrenal crisis continues to occur in children
with known primary or secondary adrenal insufficiency during intercurrent illness because
of failure to increase glucocorticoid dosing.
It is important to recognize that other
hormones affect cortisol metabolism and can
influence the onset or progression of adrenal
insufficiency. It is well documented that initiation of thyroid hormone replacement in an
individual with hypothyroidism accompanied by
unrecognized adrenal insufficiency can precipitate an adrenal crisis. The mechanism that precipitates adrenal crisis is not fully understood,
but it is hypothesized that hypothyroid patients
have reduced cortisol requirements secondary
to a reduced metabolic rate.41,42 When thyroxine
therapy is initiated, the metabolic rate and cortisol
requirements increase, and an adrenal crisis can
ensue. Accordingly, hyperthyroidism can increase
cortisol metabolism. It is suggested that in the
individual with hyperthyroidism and adrenal
insufficiency, cortisol replacement should be increased as much as twofold because of increased
cortisol clearance.38 Growth hormone appears to
decrease conversion of inactive cortisone to active cortisol. Therefore, after growth hormone
therapy is initiated, a patient with unrecognized
concomitant adrenal dysfunction might be vulnerable.43 Pregnancy is associated with increased
corticosteroid-binding globulin and therefore
Metabolic Diseases
lower free cortisol levels during the last trimester,

thus necessitating an increase in hydrocortisone
dosing by 50%. In addition, increasing intrapartum progesterone levels antagonize the mineralocorticoid effect, which can dictate adjustment of
fludrocortisone supplementation as well.38
Certain medications interfere with cortisol
metabolism as well and must be considered in
patients with adrenal disorders. Some drugs
inhibit cortisol biosynthesis, including aminoglutethimide, etomidate, ketoconazole, metyrapone, medroxyprogesterone, and megestrol.39,44
In addition, certain drugs accelerate cortisol
metabolism, such as phenytoin, barbiturates,
and rifampin.40
Signs and Symptoms of Adrenal
Insufficiency
Infants: poor feeding, inadequate weight
gain, 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
Diagnostic Studies
Blood should be drawn to test for cortisol, electrolytes, glucose, ACTH, plasma renin activity,
and aldosterone before glucocorticoid therapy,
if possible. When CAH is suspected, serum
17-hydroxyprogesterone concentration should
be measured as well. Measurement of urinary
sodium and potassium concentrations is helpful
in assessing mineralocorticoid status and in differentiating from other hyponatremic conditions.
In primary adrenal insufficiency, testing
typically reveals hyperkalemia, hyponatremia,
hypoglycemia, and acidosis. However, not all
patients manifest all of these laboratory abnormalities, and the diagnosis cannot be excluded
based on the absence of one or more of these
findings. Both BUN and creatinine concentrations can be elevated due to dehydration. In secondary adrenal insufficiency, hyperkalemia and
hyponatremia are absent due to preservation of
mineralocorticoid production, and hypoglycemia
might be the primary biochemical abnormality.
Most of the symptoms of adrenal insufficiency
are nonspecific, and many overlap with other,
more common, diagnoses. In infancy, for example, adrenal insufficiency might be confused
with other illnesses that present with lethargy,
vomiting, poor weight gain, hypotension, and
tachycardia, including sepsis, gastrointestinal
malformations, congenital heart disease, inborn errors of metabolism, certain hematologic

disorders, neurologic diseases, or child abuse.

The presence of hyperkalemia, hyponatremia,
acidosis, skin hyperpigmentation, and masculinized genitalia in a genetic female can help
to differentiate primary adrenal insufficiency
from these other entities. In an older child,
mild symptoms of primary adrenal insufficiency might be confused with mononucleosis or
anorexia nervosa. More severe symptoms can
mimic infections (eg, sepsis), hematologic disease, psychiatric illness, or even an acute abdomen. Again, the presence of hyperpigmentation
and the characteristic laboratory abnormalities
serve to differentiate these entities. Secondary
adrenal insufficiency can be even more difficult to differentiate from other entities because
of the lack of hyperpigmentation and the lack
of specific laboratory features other than hypoglycemia. In these cases, a history of CNS
THE CLASSICS
Classic Laboratory Findings in Adrenal
Insufficiency
Primary adrenal insufficiency:
hyperkalemia, hyponatremia,
hypoglycemia, and acidosis
Secondary adrenal insufficiency:
hypoglycemia
Adrenal Insufficiency/Congenital Adrenal Hyperplasia 16-13

tumors, neurosurgical procedures, congenital

CNS malformations, other coincident pituitary
hormone deficiencies (suggested clinically by
short stature, inappropriately absent or delayed
puberty, or polyuria, as examples), or prolonged
exogenous glucocorticoid use must be relied on
for the diagnosis. Secondary adrenal insufficiency can evolve over time in patients with cranial
radiation, septo-optic dysplasia, autoimmune
hypophysitis, and head trauma.4547
Management
In the hypotensive patient with adrenal insufficiency, it is imperative to rapidly restore intravascular volume with isotonic sodium chloride
containing glucose and to administer glucocorticoids expeditiously. An initial fluid bolus of
normal saline (20 mL/kg) should be given and
repeated as necessary to improve perfusion. After the initial bolus(es), a continuous infusion of
normal saline with 5% dextrose should be given.
On the basis of body surface area, the recommended stress dose of IV hydrocortisone is 50 to
75 mg/m2 initially followed by 50 to 75 mg/m2
per day divided into four doses.40 It is reasonable to approximate IV hydrocortisone dosing
and administer immediately 50 mg for children
younger than 4 years and 100 mg for children
older than 4 years. The benefits of sufficient
dosing greatly outweigh the risk of underdosing in such cases. Hydrocortisone can be given
intramuscularly if no IV access exists, although
the effects of intramuscular administration is
slower and can be ineffectively absorbed if peripheral perfusion is poor. Comparable body
surface area stress doses are 10 to 15 mg/m2
for methylprednisolone and 1.5 to 2 mg/m2 for
dexamethasone; the latter two corticosteroids
have minimal mineralocorticoid activity. Prednisone is not a preferred glucocorticoid because
it must be converted to prednisolone for it to
have glucocorticoid activity, and in patients with
liver failure, this conversion might be impaired.
Dexamethasone can be used if one desires to
treat the patient urgently but wishes to perform
a diagnostic ACTH-stimulation test because this
glucocorticoid will not interfere with diagnostic
laboratory assays. Treatment should never be
withheld if the diagnosis of adrenal insufficiency
16-14
W H AT E L S E ?
Differential Diagnosis of Adrenal
Insufficiency
Infants: infections, gastrointestinal
malformations, 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
is even suspected. If the patient has good gastrointestinal function, fludrocortisone (0.1 to
0.2 mg/d), a synthetic mineralocorticoid, can be
administered orally. However, typically, administration of IV sodium chloride along with stress
doses of hydrocortisone are sufficient to begin
normalizing electrolyte abnormalities, making
the addition of mineralocorticoid unnecessary
in the initial phase of treatment.48
Severe hyperkalemia, resulting in a nonperfusing dysrhythmia, should be treated immediately with IV calcium gluconate to restore
a perfusing rhythm. This should be followed by
IV sodium bicarbonate, nebulized albuterol (salbutamol), and/or glucose with insulin to shift
KEY POINTS
Management of Adrenal Insufficiency
Initiate fluid resuscitation (20 mL/kg of
normal saline bolus).
Administer hydrocortisone (50 mg for
child <4 years and 100 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.
Metabolic Diseases
potassium intracellularly. If there is a coexisting

cardiomyopathy and/or acute renal failure prohibiting rapid rehydration, aggressive therapy
of hyperkalemia might be needed.
Diabetes Insipidus
Under normal circumstances, plasma osmolality
is maintained within a narrow range (280295
mOsm/L). This homeostasis requires adequate
water intake, regulated by an intact thirst mechanism and appropriate free water excretion by
the kidneys, which is mediated by adequate
posterior pituitary secretion and peripheral action of arginine vasopressin (AVP), also known
as antidiuretic hormone (ADH). Diabetes insipidus is caused by a deficiency in the production or secretion of ADH (central DI) or due to
resistance to ADH in the kidneys (nephrogenic
DI).49,50 Symptoms of DI result from the effective inability to reabsorb free water at the level
of the collecting duct in the nephrons of the
kidney. Polyuria, polydipsia, and hypo-osmolar
urine characterize this disorder. Hypernatremia
might be present as well at the time of diagnosis,
particularly in infants or children with developmental delay. An intact thirst mechanism and
access to drinking water minimize the risk of
dehydration and hypernatremia.
Central DI is rarely congenital and more
frequently acquired. Congenital central DI can
be caused by structural malformations or by
autosomal dominant or recessive mutations in
the gene encoding vasopressin-neurophysin II.51
Acquired forms of central DI can occur at any age
in association with a variety of disorders in which
there is destruction or degeneration of vasopressinergic neurons that can be caused by CNS
tumors (craniopharyngioma or germinoma),
infections (meningtis or encephalitis), head trauma,
neurosurgery, vascular disorders, granuloma,
and autoimmune disorders (lymphocytic infundibuloneurohypophysitis). Idiopathic DI is
a diagnosis of exclusion and one that is made
with decreasing frequency as a result of improved
sensitivity of diagnostic technology.50,5255
Much like central DI, nephrogenic DI can
be genetic or acquired. The genetic causes described are inactivating mutations of the AVPR2

gene or autosomal recessive or dominant mutations in the AQP-2 gene. These cases typically
present in infancy.56 Acquired nephrogenic DI
can be caused by various conditions, including primary renal disease, obstructive uropathy,
hypokalemia, hypercalcemia, sickle cell disease,
and medications such as lithium and demeclocycline (a tetracycline). In addition, prolonged
polyuria of any cause can also lead to some degree of nephrogenic DI because of a reduction of
tonicity in the renal medullary interstitium and
a subsequent decrease in the gradient necessary
to concentrate urine.50,53,57
Clinical Features
Characteristic symptoms of DI are pronounced
polyuria and polydipsia. Older children typically present without any obvious abnormalities
on physical examination as long as they have an
intact sense of thirst, access to fluids, and no
ongoing losses, such as diarrhea. They might
report a history of nocturia and secondary enuresis. Infants, in addition to polyuria and polydipsia, frequently demonstrate irritability, poor
weight gain, failure to thrive, hyperthermia, and
signs of dehydration. Developmental delays
and arrest of variable severity can ensue after
repeated episodes of dehydration if the condition remains untreated. Hydronephrosis can be
detected in all age groups. Interestingly, symptoms of DI might not be apparent in patients
with coexisting untreated anterior pituitarymediated adrenal glucocorticoid insufficiency
because cortisol is required to generate normal
free water excretion.58
Diagnostic Studies
Infants generally present with hypernatremia
and serum hyperosmolality because they have
limited access to fluids. Coincident inappropriately dilute urine (<300 mOsm/L) helps to
establish the diagnosis. Older children usually
do not present with hypernatremia or hyperosmolality unless their fluid intake is restricted,
their thirst mechanism is abnormal, or they are
experiencing excessive losses. In unclear cases,
a carefully monitored water deprivation test
is recommended, whereby the fasting patient
is monitored for 8 to 10 hours with serial
Diabetes Insipidus 16-15

Signs and Symptoms of DI
Infants: failure to thrive, irritability,
hyperthermia, dehydration
Children: polyuria, polydipsia, absence
of DM
measurements of body weight, serum sodium

and osmolality, and urine volume and osmolality.
If urine osmolality of greater than 750 mOsm/L
is achieved with any degree of water deprivation, DI can be excluded.59 The diagnosis of DI
is established at any time point if serum
osmolality rises above 300 mOsm/L and
urine osmolality remains below 300 mOsm/L
Urine osmolality in the 300- to 750-mOsm/L
range during water deprivation can indicate partial DI.53 During the test, if DI is suspected, an
ADH plasma sample should be obtained, and
then ADH, or a synthetic analog (desmopressin), should be administered to further distinguish ADH deficiency (central DI) from ADH
unresponsiveness (nephrogenic DI).
If central DI is suspected, an MRI of the
brain, with particular attention to the hypothalamic-pituitary region, is indicated. The
posterior pituitary hyperintensity (bright spot)
on T1-weighted MRIs is often absent in central
DI.54,6062 However, the absence of the bright
spot is neither sensitive nor specific for this diagnosis because it can be absent in healthy individuals63 and, conversely, present in children
with central DI as well.64 In central DI patients,
a normal MRI does not exclude the possibility
of an evolving occult hypothalamic-stalk lesion,
and therefore follow-up with cerebrospinal fluid (CSF) tumor markers and cytology, serum
tumor markers, and serial contrast-enhanced
brain MRIs for early detection is critical.55 Intracerebral calcifications of the frontal lobes and
basal ganglia can result from repeated episodes
of dehydration.65 Ultrasonography can be helpful in detecting nonobstructive hydronephrosis,
hydroureter, and megabladder, resulting from
longstanding polyuria and polydipsia.66
16-16
THE CLASSICS
Laboratory Findings in Infants and
Children With DI
Infants: hypernatremia, hyperosmolality,
inappropriately dilute urine
Children: dilute urine, nocturia, secondary
enuresis
The principal presenting sign of DI is polyuria,
which, in addition to deficiency or impaired
responsiveness to ADH, can result from an osmotic agent, such as hyperglycemia as seen in
DM, or from excessive water intake (primary
polydipsia). Patients with hypercalcemia or
hypokalemia can also have impaired urinary
concentrating ability, resulting in polyuria.
Management
Patients without hypernatremia and dehydration
do not require immediate intervention for DI
but should undergo evaluation to determine the
underlying cause. Patients with hypernatremic
dehydration and hyperosmolality should be
treated with fluid resuscitation. This includes an
initial 20-mL/kg fluid infusion of normal saline
to restore perfusion followed by subsequent slow
correction because overly aggressive free water
replacement can lead to cerebral edema. In addition to correcting the fluid deficit, the management of central DI includes treating the primary
disease and normalization of urine output with
W H AT E L S E ?
Differential Diagnosis of DI
Hyperglycemia from DM
Primary polydipsia
Hypercalcemia
Hypokalemia
Metabolic Diseases
T H E B OT TO M L I N E
Key Concepts in the Diagnosis and
Management of DI
DI should be suspected in children
without DM who present with polyuria
and dilute urine.
Hypernatremia generally will not occur in
children with normal thirst mechanisms
and free access to water.
Clinical Features
Hypernatremia is more frequently

encountered in infants.
Patients with SIADH frequently will not manifest symptoms of hyponatremia until the serum
sodium concentration falls below 120 mEq/L.
Below this level, symptoms can include anorexia, nausea, vomiting, lethargy, irritability, and
confusion. Severe hyponatremia can culminate
in seizures and loss of consciousness.
ED management includes cautious fluid

administration to correct dehydration
while promoting gradual hypernatremia
correction and, in appropriate situation,
diagnostic evaluation initiation.
desmopressin. Desmopressin is an ADH analog

with markedly reduced pressor activity in comparison with native ADH and a longer half-life
and can be administered orally, intranasally, or
by subcutaneous injection. In infancy, if polyuria
is not excessive, central DI can be best managed
with extra fluid intake alone to avoid a potential
risk of hyponatremia associated with desmopressin treatment. In cases of nephrogenic DI, the
mainstay of treatment, particularly in infancy,
is thiazide diuretics in combination with either
amiloride or indomethacin.6568
Syndrome of Inappropriate
Secretion of Antidiuretic
Hormone
Syndrome of inappropriate secretion of antidiuretic hormone (ADH or AVP) is characterized by
excessive kidney resorption of free water, resulting in hyponatremia and hypo-osmolar serum
in association with inappropriately concentrated
urine and natriuresis.6971 Several disorders and
medications are associated with SIADH: (1) CNS
disorders or damage, such as meningitis or encephalitis, cerebral hemorrhage, head trauma, or
after neurosurgical procedures; (2) psychiatric
disorders; (3) a large variety of pharmacologic

agents (eg, phenothiazines or tricyclic antidepressants); (4) various pulmonary disorders and interventions (eg, pneumonia, asthma, or positive
pressure ventilation); (5) non-CNS tumors with
ectopic production of ADH; (6) patients treated
with desmopressin acetate who drink excessive
amounts of fluids (typically habit driven); and (6)
miscellaneous causes, such as AIDS, postoperative state, glucocorticoid deficiency, and severe
hypothyroidism.70,71
Diagnostic Studies
On the basis of criteria established by Bartter and
Schwartz,72 the diagnosis of SIADH is made when
the following constellation occurs: (1) plasma
hypo-osmolality (<275 mOsm/L), (2) less than
maximally dilute urine (urine osmolality >100
mOsm/L), (3) clinical euvolemia, (4) natriuresis
(urine sodium >40 mEq/L), (5) normal renal function, and (6) no evidence of thyroxine or cortisol deficiency. Typically, BUN concentrations are
normal or low. Causes of pseudohyponatremia
should be excluded such as that due to hyperlipidemia, hyperproteinemia, and the osmotic effect
of hyperglycemia. Most patients with SIADH have
inappropriately measurable or elevated levels of
plasma ADH relative to plasma osmolality.
Other causes of hyponatremia include water intoxication (primary polydipsia or iatrogenic),
hyponatremic dehydration, adrenal insufficiency, renal failure, diuretic medications, nephrotic
syndrome, cirrhosis, congestive heart failure,
severe hypothyroidism, cystic fibrosis, and
cerebral salt-wasting (CSW) syndrome. These
diagnoses can generally be excluded based on
the absence of corresponding diagnostic signs,
such as dehydration, edema, and hyperkalemia.
Syndrome of Inappropriate Secretion of Antidiuretic Hormone 16-17

Signs and Symptoms of SIADH
Hyponatremia in association with head
trauma, cerebral hemorrhage, or other
intracranial conditions
Clinical symptoms and signs of
hyponatremia, including anorexia, nausea,
vomiting, lethargy, irritability, altered level
of consciousness, and seizures
Euvolemia in chronic SIADH is a critical

distinguishing factor in the evaluation of a patient with serum hypo-osmolality; it is thought
to represent an adaptation to water overload mediated, in part, at the cellular level through depletion of intracellular electrolytes (potassium)
and organic osmolytes.70 Natriuresis, thought to
be mediated in part through secretion of atrial
natriuretic peptide, also contributes to volume
regulation in chronic SIADH.73
The CSW syndrome is particularly important
to exclude because it occurs in overlapping clinical settings with SIADH.74 Cerebral salt-wasting
syndrome is characterized by renal sodium and
fluid loss. However, the hypo-osmolality, hyponatremia, and natriuresis in CSW syndrome are
associated with volume contraction and clinical
signs of dehydration (including elevated BUN
and creatinine concentrations), helping to distinguish this syndrome from SIADH.70
Management
The mainstay of SIADH therapy for patients
with mild or no symptoms is fluid restriction,
treatment of the underlying disorder, or discontinuation of use of an offending drug. Ultimately,
replacement of sodium loss might also be necessary, but it can usually be achieved through
dietary salt intake. Severe hyponatremia (serum
sodium <120 mEq/L), particularly when associated with CNS disturbance (lethargy, coma,
or seizures), might require treatment with IV
hypertonic saline (3% sodium chloride solution). The correct dosage of 3% sodium chloride solution can be calculated based on the
assumption that 12 mL/kg of 3% sodium chloride solution will increase the serum sodium
concentration by 10 mEq/L. It is generally recommended that plasma sodium be corrected at
a rate of no greater than 0.5 mEq/L per hour,
with an overall correction that does not exceed
12 mEq/L in the initial 24 hours and 18 mEq/L
in the initial 48 hours of treatment. Therapy
should continue until neurologic symptoms
improve and a safe level of approximately 120
to 125 mEq/L is achieved. Further treatment
can then be accomplished with fluid restriction.
Serial rapid bedside serum sodium testing is
preferred when administering hypertonic saline
W H AT E L S E ?
Differential Diagnosis of SIADH
Water intoxication
THE CLASSICS
CSW syndrome
Hyponatremic dehydration
Adrenal insufficiency
Laboratory Findings in Patients With

SIADH
16-18
Renal failure
Diuretic use
Serum hypo-osmolality (<275 mOsm/kg)
Nephrotic syndrome
Urine hyperosmolality (>100 mOsm/L)
Hypothyroidism
Inappropriate natriuresis (>40 mEq/L)
Cystic fibrosis
Normal renal, thyroid, and adrenal

cortical function
Congestive heart failure

Cirrhosis
Metabolic Diseases
KEY POINTS
Management of SIADH
Restrict fluids in patients with mild or no
symptoms.
Treat with 3% sodium chloride in cases of
severe hyponatremia (serum sodium <120
mEq/L), particularly when associated with
neurologic disturbance.
Rapid correction of chronic hyponatremia
can precipitate central pontine
myelinolysis.
well. Certain psychiatric illnesses, particularly

schizophrenia, can be associated with compulsive water drinking. It is presumed that a central
defect in thirst regulation plays an important
role in the pathogenesis of primary polydipsia
in these patients.7780 In some cases, for example,
the osmotic threshold for thirst is reduced below
the threshold for the release of ADH81; therefore,
these patients will continue to drink until the
plasma tonicity is less than the threshold level.
Drug therapy can also contribute to the increase
in water intake in schizophrenic patients. Many
antipsychotic drugs induce the sensation of a
dry mouth, which will enhance thirst.82
Clinical Features
to avoid excessive sodium correction. If SIADH
and hyponatremia are acute (<48 hours), it is
thought that hyponatremia can be corrected
rapidly. However, if SIADH and hyponatremia
are chronic (>48 hours), overzealous treatment
can result in CNS damage, including central
pontine myelinolysis.70 Concurrent use of a diuretic, such as furosemide, might be indicated
if volume expansion is severe. Other therapeutic
approaches include the use of agents that induce nephrogenic DI, such as demeclocycline
and lithium, although both are contraindicated,
particularly in younger pediatric patients, because of adverse effects. Urea has been used as
an osmotic diuretic in pediatric SIADH.75 Once
patient stabilization is achieved, a careful search
for an underlying cause for SIADH is necessary
if the cause is unknown.
Water Intoxication
Water intoxication occurs when daily water
intake is excessive in relation to sodium. In
infants, this situation occurs most frequently
because of inappropriate dilution of formulas or
misguided supplemental feedings of solute-free
water.15,16 Excess water ingestion during infant
swimming lessons has also been associated with
this condition. Iatrogenic water intoxication is
a well-known phenomenon, particularly in labor and delivery rooms.76 Water intoxication
can be seen as a manifestation of child abuse as

Clinical manifestations of water intoxication result from hyponatremia. Infants typically present
with poor feeding, vomiting, and lethargy. Hypothermia and edema might also be present. With
severe hyponatremia, seizures can occur and
might be prolonged. It has been suggested that
hypothermia can be a specific marker for hyponatremia in infants with a new onset of seizures.83
Diagnostic Studies
Hyponatremia (serum sodium concentration
<130 mEq/L) with coinciding dilute urine is
the hallmark of this condition. Serum potassium, urea nitrogen, and creatinine concentrations are typically normal, and acidosis is not
present, which helps exclude other causes of
hyponatremia. Fictitious hyponatremia should
be excluded which can occur with hyperlipidemia, hyperproteinemia, or due to the osmotic
effect of hyperglycemia.
The differential diagnosis of hyponatremia is extensive and includes renal failure, diuretic use,
renal tubular defects (renal tubular acidosis),
SIADH, adrenal insufficiency, cystic fibrosis, nephrotic syndrome, cirrhosis, and congestive heart
failure. Iatrogenic hyponatremia can also occur
in infants or children when insensible losses are
replaced with free water or other fluids deficient
in sodium; this scenario differs, however, from
classic water intoxication in that clinical and
Water Intoxication 16-19

KEY POINTS
Signs and Symptoms of Water

Intoxication
Diagnosis and Management of Water

Intoxication
Poor feeding
Presents with hyponatremia with a

history of excessive water intake (relative
to sodium).
Vomiting
Lethargy
Seizures
Hypothermia
Infant who presents with hypothermia

with seizures is a specific indicator for
hyponatremia.
Free water restriction and normalization
of sodium intake are sufficient treatment
in most instances.
laboratory features of dehydration are present

and the urine is concentrated. A careful history,
including infant feeding practices and psychiatric
illness, in addition to the detection of dilute urine
can lead to the diagnosis of water intoxication.
Hypertonic 3% sodium chloride solution

treatment can be used prudently in
severely affected patients.
THE CLASSICS
Management
For infants who are asymptomatic or have
mild symptoms of hyponatremia, reinstitution
of normal daily sodium with more restricted
fluid intake is generally all that is required. For
infants with severe manifestations of hyponatremia (pronounced lethargy, seizures, or coma),
treatment with 3% sodium chloride solution
should be initiated with caution.
16-20
Laboratory Findings in Patients With

Water Intoxication
Hyponatremia (sodium concentration
<130 mEq/L)
Dilute urine
Absence of metabolic acidosis and
dehydration
Metabolic Diseases
2
CASE SCENARIO
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 36.0C (96.8F). She appears lethargic and has mildly dry
mucous membranes and no obvious source of infection. Bedside rapid glucose
measurement reveals a blood glucose level of 20 mg/dL.
1. What therapeutic measures must be taken immediately?
3. What complications can occur as part of the disease process and secondary to
therapeutic intervention?
Metabolic Disease of the

Newborn and Young Child:
Inborn Errors of Metabolism
Early recognition of a possible inborn error of
metabolism (IEM) in acutely ill patients is critical
to minimize the high morbidity and mortality
rates associated with these conditions. Although
individually rare, IEMs collectively are relatively
common.84 A diagnosis of IEM should be considered not only in the evaluation and treatment
of critically ill patients but also in patients with
recurrent episodes of vomiting, lethargy, and/or
seizures and those with chronically progressive
neurologic abnormalities and/or organ dysfunction. Usually, IEMs manifest in the neonatal period or infancy; however, presentation, can occur
at any time throughout childhood and even in
adulthood. Initial treatment of the critically ill
child with an IEM does not require a detailed
knowledge of individual IEMs or biochemical
pathways but rather an understanding and early
recognition of life-threatening clinical manifestations and consequences of the metabolic derangements.8587 Prompt initiation of appropriate
treatment is crucial for optimizing immediate and
long-term outcome and is often lifesaving.
More than 400 IEMs have been identified
since 1908.88 The incidence of IEMs is estimated
to be as high as 1 in 1,000 live births.89 Inborn
errors of metabolism are caused by single gene
defects that result in abnormal synthesis, catabolism, and/or function of proteins, carbohydrates,
fats, organelles (ie, lysosomes, mitochondria, and

peroxisomes), metals, or complex molecules.90

Most IEMs are due to a defect in an enzyme
or transport protein that results in a block in a
metabolic pathway. Effects are caused by toxic
accumulations of substrates before the block or
from alternative metabolic pathway intermediates
(disorders of protein metabolism, carbohydrate
intolerance, metal metabolism, and porphyrias);
defects in energy production and use within the
brain, heart, liver, skeletal muscle, and other organs due to a deficiency of products beyond the
block (disorders of carbohydrate metabolism [eg,
gluconeogenesis, glycogenolysis, and glycogen
storage disorders], fatty acid oxidation defects,
and mitochondrial disorders); or disturbances in
the synthesis or catabolism of complex molecules
(lysosomal storage and peroxisomal disorders or
defects in the metabolism of cholesterol, purines
and pyrimidines, and neurotransmitters; and defects in glycosylation).85 Most IEMs have multiple
forms that differ in age of clinical onset, severity,
and even mode of inheritance. The IEMs most
likely to result in acute, potentially life-threatening decompensation include disorders of protein
metabolism, defects in carbohydrate metabolism,
fatty acid oxidation defects, and early-onset forms
of mitochondrial and peroxisomal disorders.
Lysosomal storage disorders, certain glycogen storage disorders, and late-onset forms of
mitochondrial and peroxisomal disorders tend
to have a chronic insidious progression that
results in organ dysfunction and ultimately failure. Inheritance is autosomal recessive for most
IEMs (because many are enzyme deficiencies),
Metabolic Disease of the Newborn and Young Child: Inborn Errors of Metabolism 16-21
but there are IEMs with autosomal dominant,

X-linked, and mitochondrial inheritance.
Nearly all states in the United States test
newborns for at least 29, and some for more
than 50, genetic diseases, most of which are
IEMs.91,92 A table of newborn screening tests
performed by state is available online.93 Results
are usually available within days but might take
weeks. In at least some states, parents can opt
to not have their child screened. False-negative
newborn screens can result and are most commonly due to screening too soon after birth,
weight less than 1,500 g, neonatal illness, medications, transfusions, and problems related to
sample collection and handling. Cutoff values
are set to minimize false-negative rates, which
results in relatively high false-positive rates. Neonates who test positive on newborn screens for
an IEM that can result in acute, life-threatening
decompensation require emergent evaluation.94
Clinical Features
History
History can vary from abrupt onset of rapidly
progressing illness that results in death within
hours, to intermittent recurrent acute episodes
of potentially life-threatening decompensation
in an otherwise well child, to chronic, slowly progressive deterioration throughout decades.85,90,95,96 Inborn errors of metabolism that
result in acutely life-threatening critical illness
present most commonly within the first year
of life and usually within the newborn period,
those that cause intermittent decompensation
most often manifest later in infancy or early in
childhood, and those with insidious, progressive
symptoms tend to present in older childhood,
adolescence, or even throughout adulthood.
In the neonate, the most important clue to an
IEM is a history of deterioration after an initial
period of apparent good health ranging from
hours to weeks.97,98 In neonates and infants, a
history of poor feeding, vomiting, chronic diarrhea, failure to thrive, lethargy, and seizures is
common.99101 Developmental delay in infants,
particularly with loss of milestones, is strongly
suggestive of an IEM. Symptoms can be precipitated by increased intake of protein or carbohydrate and/or by a reduction in feeds (eg, as
16-22
in gastroenteritis). Unusual dietary preferences,

particularly protein or carbohydrate aversion,
and symptoms occurring during diet changes
are often seen in patients with an IEM. By late
infancy or early childhood, it is often apparent
that with routine illnesses, children with an IEM
become more severely symptomatic and/or require longer to recover than expected. In older
children and adults, vigorous exercise, sleep
deprivation, hormonal changes, intercurrent
illness, anesthesia or surgery, and pregnancy or
delivery commonly precipitate symptoms.
A family history of siblings and/or a history
of relatives with similar findings is an important
clue to possible IEM. A family history of sudden infant death or unexplained neonatal death,
particularly due to sepsis or neurologic, cardiac,
and/or hepatic dysfunction, should also raise
concern for a possible IEM. Parental consanguinity increases the likelihood of an autosomal recessive IEM. Maternal history of HELLP
(hemolysis, elevated liver enzyme, low platelet count) during pregnancy is associated with
maternal heterozygosity for fatty acid oxidation
defect and suggests the possibility of homozygosity for the disease in the child. Decreased
fetal movement has been described with certain
glycogen and lysosomal storage disorders and
peroxisomal disorders. A negative family history
does not rule out an IEM.
Clinical Manifestations
Clinical manifestations of IEMs reflect the multiorgan system involvement typical of these disorders. Common clinical presentations include
a sepsis-like illness or cardiac, hepatic, and/or
neurologic dysfunction.8587,97104 Physical examination findings are normal for most IEMs.
Abnormal odor or hair, hearing deficit, visual
dysfunction, organomegaly, and/or chronic dermatitis should prompt consideration of an IEM.
Dysmorphic features are seen commonly with
mitochondrial disorders, peroxisomal disorders,
lysosomal storage, and other disorders of complex molecules. The risk of mortality can be very
high, particularly with initial presentation of an
undiagnosed IEM. Features of specific IEMs can
be found in the texts referenced in this chapter85,95,96 and on Web sites, including Online
Mendelian Inheritance in Man.88,90
Metabolic Diseases
Neonates
Inborn errors of metabolism should be considered in neonates who are critically ill, particularly those with encephalopathy and/or hepatic
dysfunction. Clinical manifestations of IEMs in
neonates are nonspecific and most commonly
include decreased feeding, hiccups, vomiting,
diarrhea, dehydration, temperature instability,
tachypnea or apnea, bradycardia, poor perfusion, unusual odor, jaundice, irritability, involuntary movements or posturing, abnormal
tone, seizures, stroke, and/or altered level of
consciousness. These same findings are also
manifestations of many other causes, making
the differential diagnosis extensive. Presence of
one diagnosis does not rule out the possibility
of a concomitant IEM. In fact, some IEMs, such
as galactosemia, certain organic aminoacidopathies, and glycogen storage diseases, are associated with an increased risk of sepsis. Inborn
errors of metabolism should be considered in
neonates with fetal hydrops or pulmonary or
intracranial hemorrhage in utero or after birth. It
should also be recognized that an undiagnosed
IEM is a possible cause of sudden infant death,
most commonly fatty acid oxidation defects.
The time to onset of symptoms for inborn errors of substrate and intermediary metabolism
is dependent on significant accumulation of
toxic metabolites, which for severe forms can
occur within hours after the initiation of feeding. Neonates with IEMs that result in defects
in energy production and use are often symptomatic at birth or within the first 24 hours of
life. These neonates are less likely to have coma
as an early manifestation and are more likely
to have dysmorphic features, cardiopulmonary
compromise, organomegaly, skeletal malformations, and hypotonia.
Infants and Young Children
Infants and children with IEMs can have recurrent episodes of vomiting, dehydration,
hepatoencephalopathy, ataxia, seizures, stroke,
lethargy, and coma but can appear completely
normal between episodes. Others have dysmorphic features, failure to thrive, microcephaly or
macrocephaly, alopecia or sparse hair, hearing
and vision deficits, corneal opacities, cataracts,
subluxed or dislocated lens, cherry red spots,

retinopathy, optic atrophy, chronic dermatoses, skin photosensitivity, nodules, dilated or

hypertrophic cardiomyopathy, cardiac arrhythmia, jaundice, hepatomegaly, liver dysfunction,
splenomegaly, pancreatitis, skeletal abnormalities, hypotonia, dystonia, weakness, peripheral neuropathy, and/or developmental delay,
in some cases with loss of milestones. Inborn
errors of metabolism most likely to present in
this age group include partial enzyme deficiency
urea cycle defects, disorders of carbohydrate
metabolism, fatty acid oxidation defects, and
lysosomal storage disorders. Reye syndrome
like symptoms are now recognized often to be
due to IEMs. The differential diagnosis of IEMs
in infants and young children with IEMs is extensive and, in addition to that for the neonates,
includes routine illness, cyclic vomiting, diabetes, drug or toxin ingestion, malignant tumor,
and Mnchausen by proxy.
Older Children, Adolescents, and Adults
In older children, adolescents, and adults, previously undiagnosed IEMs usually manifest as
neurologic and/or psychiatric abnormalities that
can range from recent to longstanding and from
subtle to severe.103,105 Although rare, the initial
presentation of an IEM can be that of critical
illness with rapid progression to death. Manifestations of life-threatening IEMs most commonly
include profound lethargy, coma, encephalopathy, seizures, stroke, other thromboembolic
event, cardiac or hepatic dysfunction or failure, weakness, and/or paresis. More commonly,
manifestations are not acute in onset or imminently life-threatening and include learning
disabilities, autism, developmental delay, visual
deficits, ocular abnormalities, exercise intolerance, muscle cramps, ataxia, abnormal movements, abnormal or aggressive behaviors, and
psychiatric disturbances, such as anxiety, panic
attacks, hallucinations, delirium, paranoia, and/
or psychosis. Findings particularly concerning
for IEMs include ophthalmologic abnormalities, progressive neurologic disease, abnormal
movements, cerebellar symptoms, and mixed
psychiatric and neurologic symptoms. Among
the most common IEMs on the growing list of
recognized IEMs with late onset are partial ornithine transcarbamylase deficiency (particularly
in females), homocystinuria, certain glycogen

storage disorders, mitochondrial and peroxisomal disorders, and Wilson disease.
Diagnostic Studies
In the acutely ill patient with an undiagnosed
condition, results of routine laboratory tests
often provide clues to IEMs and should guide
further evaluation.85,86,97,100,106 Most patients
with acute, life-threatening presentations of
metabolic disease have metabolic acidosis, hyperammonemia, and/or hypoglycemia. Laboratory abnormalities can be transient; therefore,
specimens should be collected as soon as possible, preferably before initiation of any therapy,
including fluids and glucose. If samples were
not collected before treatment, remaining pretreatment specimens are likely to be more informative than posttreatment samples and should
be used if available. A metabolic specialist can
be helpful in directing the evaluation of patients
with suspected or known IEMs.
Metabolic Acidosis
Clinical manifestations of metabolic acidosis
include tachypnea and vomiting. Initial laboratory studies to evaluate acid-base status include electrolytes and blood gas. Laboratory
manifestations of primary metabolic acidosis
are low pH, Pco2, and bicarbonate level and an
elevated anion gap. Severe metabolic acidosis
and ketonuria, with or without hyperammonemia or hypoglycemia, are hallmarks of organic
acidemias. An elevated anion gap accompanies
acidosis in organic acidemias, mitochondrial
disorders, aminoacidopathies, and disorders of
carbohydrate metabolism. Lactate and pyruvate
should also be obtained in patients with suspected or confirmed acidosis. Lactic acidosis,
although seen in many IEMs, is a nonspecific
finding in critically ill patients that results from
hypoxia and poor tissue perfusion. An elevated
lactate:pyruvate ratio (usually >20), provides
an important clue to determining whether a
patient has an IEM, most commonly due to a
mitochondrial or cytoplasmic enzyme disorder.
Urine with low specific gravity and pH of 5.0
or higher in the setting of metabolic acidosis
suggests renal tubular acidosis, which, although
not specific for an IEM, is a feature of many
16-24
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 difficulties,
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
IEMs. For most patients with primary metabolic

acidosis, it is appropriate to test plasma amino
acids, acylcarnitine profile, urine organic acids,
and acylglycines.
Hyperammonemia
An ammonia concentration greater than 100
mcg/dL (60 mcmol/L) in neonates and greater
than 80 mcg/dL (50 mcmol/L) in children is
abnormal and potentially neurotoxic. Early
clinical manifestations of hyperammonemia are
tachypnea, anorexia, and irritability. Older individuals might report headache, abdominal pain,
and fatigue. Progression to vomiting, lethargy,
Metabolic Diseases
seizures, coma, and death can occur within

hours. Patients with consistently elevated ammonia levels can have modestly increased levels without obvious clinical symptoms. Hepatomegaly and mild elevation of transaminases
and/or abnormal clotting factors are other manifestations. Ammonia concentration is highest with urea cycle defects, usually 3401700
mcg/dL (2001000 mcmol/L) or higher. With
organic acidemias, ammonia levels do not usually exceed 850 mcg/mL (500 mcmol/L). Lower
concentrations of ammonia and higher concentrations of acids in these patients result in primary
metabolic acidosis, usually with marked ketosis.
With fatty acid oxidation defects, the level of ammonia does not usually exceed 425 mcg/dL (250
mcmol/L), and acid-base status is usually normal.
Ammonia concentration in the normal range does
not rule out an IEM. To prevent a falsely elevated
value, blood for ammonia should be collected
by free flow without a tourniquet and the specimen put on ice immediately. In patients with
hyperammonemia, plasma for amino acids and
acylcarnitine profile and urine for organic acids,
acylglycine, and orotic acid should be tested.
Hypoglycemia
A serum glucose level less than 40 mg/dL should
be considered abnormally low in neonates and
a level less than 40 to 50 mg/dL should be considered abnormally low beyond the neonatal period. Clinical findings of hypoglycemia include
repeated yawning, irritability, pallor, jitteriness,
altered mental status, and seizures. Neonates
can also have a high-pitched cry, hypothermia,
hypotonia, apnea, cyanosis, and poor feeding.
Older children and adolescents often report
headache, lightheadedness, diaphoresis, palpitations, and nausea. Normally, hypoglycemia
results in ketonuria, except in neonates due
to a high capacity to use ketones. In neonates,
significant ketonuria can be an acute manifestation of an IEM. Beyond the neonatal period,
inappropriately low or absent ketone levels in
a patient with hypoglycemia suggest a hyperinsulinemic state, a glycogen storage disorder,
carbohydrate intolerance disorder, or fatty acid
oxidation defect. The presence of ketones (ketotic hypoglycemia), however, does not rule out
these disorders. Patients with organic amino
acidopathies or mitochondrial disorders might

have ketonuria with normal glucose levels. In
addition to plasma for amino acids and acylcarnitine profile and urine for organic acids and
acylglycines, serum ketones, plasma free-fatty
acids, and endocrine studies, including insulin
and serum cortisol, should be performed.
Other Studies
Liver function tests, including bilirubin, transaminases, and coagulation studies, most commonly reveal elevated levels in patients with
disorders of protein metabolism or fatty acid
oxidation defects but can reveal elevated levels
in IEMs within most categories. Triglycerides
and uric acid levels can be elevated in glycogen storage disorders. Lactate dehydrogenase,
creatine kinase, and aldolase levels are most
commonly elevated in patients with disorders
of carbohydrate metabolism, fatty acid oxidation defects, and mitochondrial disorders and
should be tested in patients with symptoms of
skeletal muscle myopathy and/or with myoglobinuria. Urine test results positive for non
glucose-reducing substances suggest possible
aminoacidopathy or carbohydrate intolerance
disorder (eg, galactosemia).
In select cases, CSF, collected at approximately the same time as plasma, should be
frozen for possible measurement of lactate,
pyruvate, and IEM-specific neurometabolites,
particularly neurotransmitters.
Histologic evaluation of affected tissues,
most commonly liver and/or skeletal muscle,
and enzyme assay or DNA analysis in leukocytes, erythrocytes, skin fibroblasts, and liver
or other tissues might be appropriate but are
not usually emergent. Other studies, including evaluation for bacterial or viral infection,
radiography, computed tomography, MRI,
ultrasonography, electrocardiography, and/or
echocardiography, should be obtained emergently
as clinically indicated for evaluation and management of life-threatening manifestations of IEMs.
In the child who has died, identifying an
IEM might still be important because currently
asymptomatic family members and/or future
children might be affected. Samples of plasma,
serum, urine, and possibly CSF and skin, bile,
vitreous humor, bone marrow, and selected organ
THE CLASSICS
W H AT E L S E ?
Findings of Routine Laboratory Studies

in Children With IEMs
Differential Diagnosis of IEM in the

Critically Ill Patient
Metabolic acidosis
Infection: sepsis, meningitis, encephalitis
Hypoglycemia (hypoketosis or absent

ketones)
Shock
Hyperammonemia, respiratory alkalosis
Cardiac disease
Elevated lactate level, lactate:pyruvate

ratio
Gastrointestinal illness or obstruction
Elevated liver function studies (bilirubin,

aspartate aminotransferase, alanine
aminotransferase, lactate dehydrogenase)
Urine-reducing substances, myoglobin
Respiratory illness
Hepatic disease
Renal disease
Neurologic abnormality, disease
Trauma
Toxin or drug withdrawal
Behavioral, psychiatric disorder
specimens, including skin, heart, liver, kidney,

spleen, skeletal muscle, and/or brain, should be
collected and frozen, preferably, but not limited
to, within 1 to 2 hours of death.86 Consider obtaining photographs of patients with dysmorphic
features. If the family declines autopsy, consider
obtaining permission to collect vitreous humor,
skin, and/or organ tissue by needle biopsy.
Because the signs and symptoms of inborn errors of metabolism are nonspecific, IEMs are
frequently not considered in the differential diagnosis. Therefore, a high index of suspicion is
important because the physician must initiate
appropriate therapy without delay (and without
a final diagnosis in hand) to decrease morbidity
and mortality. A concomitant acquired disorder
can obscure the diagnosis of an inherited metabolic disease condition. For example, neutropenia can occur in organic acidemias, leading to
an increased susceptibility of bacterial infection.
The underlying disorder might be missed if an
infection is also present and focus is directed
solely toward antimicrobial therapy. Escherichia
coli sepsis frequently supervenes in neonates
with galactosemia, and the typical jaundice,
liver failure, and vomiting that accompany that
disorder might wrongly be ascribed solely to
sepsis as well.
16-26
Management
In addition to rapid assessment and aggressive
management of airway, breathing, and circulation, goals of treatment of IEMs are to stop
intake of harmful substances, correct metabolic abnormalities, and eliminate toxic metabolites.85,86,107,108 Even the apparently stable patient
with mild symptoms can deteriorate rapidly
with progression to death within hours. For an
undiagnosed suspected IEM, this means initiating treatment empirically as soon as the diagnosis is considered. For patients with a known
IEM, treatment should be disease and patient
specific. Families should have an emergency
treatment plan specifically for their child developed by their IEM specialist with them or available electronically. In addition, families might
have a plan detailing their desired interventions
should lifesaving resuscitation be necessary.
Once airway, breathing, ventilation, and
vascular access have been established, hydration, glucose as necessary to correct hypoglycemia and prevent catabolism, and therapy to
correct acidosis and hyperammonemia must
be initiated. Protocols for treatment of acute
illness in patients with a suspected IEM and
some diagnosed IEMs are available on the New
England Consortium Web site.107 Consultation
with a metabolic specialist should be initiated
Metabolic Diseases
if available. With appropriate therapy, patients

can recover completely without sequelae.
Hydration is critical not only to restore intravascular volume but also to promote urinary
excretion of toxic metabolites. For IEMs that
are potentially acutely life-threatening, fluid boluses should be administered as 10% dextrose
normal saline unless the patient is hypoglycemic, in which case a glucose bolus is indicated
(0.5 g/kg as 10% dextrose for neonates and 10%
or 25% dextrose for children; note the 50 rule
described earlier). Preferentially, colloids should
be avoided because they increase nitrogen load.
After bolus fluid, maintenance fluid should be
administered as 10% to 12.5% dextrose half
normal saline at a rate high enough to prevent
catabolism by maintaining serum glucose at
120 to 170 mg/dL. Large fluctuations in serum
glucose should be avoided. Although controversial, 0.1 to 0.2 U/kg per hour of insulin can
be administered to prevent hyperglycemia. For
a suspected IEM, stop all oral intake to ensure
that potentially harmful protein or sugars are
avoided. For a known IEM, dietary restriction
should be disease specific.
Treatment of acidosis with bicarbonate is
thought to be indicated for IEMs because of ongoing acid production; however, data regarding
the degree of acidosis for which it should be
initiated and dose are lacking. Recommendations for administration of bicarbonate range
from pH 7.0 to 7.2 and serum bicarbonate as
low as 14 to 16 mEq/L. The recommended dose
range is 0.25 to 2 mEq/kg per hour, depending
in part on the specific IEM. Bicarbonate should
be administered cautiously in patients with hyperammonemia because alkalinization converts
NH4+ to NH3, which is less readily excreted in
urine and more readily crosses the blood-brain
barrier, increasing the risk of brain complications. If administering sodium bicarbonate, potassium should be given as potassium acetate.
For severe, intractable metabolic acidosis, hemodialysis should be considered. Acidosis must
be corrected cautiously to minimize paradoxical
effects on the CNS that can be caused by rapid
or overcorrection.
Hyperammonemia can be acutely lifethreatening and must be treated immediately.

For patients with an aminoacidopathy, organic

acidemia, or fatty acid oxidation defect, hyperammonemia usually improves with rehydration
and the reversal of acidosis and hypoglycemia.
For severe hyperammonemia in patients with
urea cycle defects, hemodialysis is the mainstay
of treatment. Extracorporeal membrane oxygenationassisted hemodialysis is the most effective
form of hemodialysis but has increased risks,
particularly in neonates. Exchange transfusion
is not effective. Recommendations of the New
England Consortium are to consider dialysis for
ammonia levels greater than 300 mcg/dL (175
mcmol/L) and transfer to a facility or unit with
dialysis capability for ammonia levels greater
than 200 to 250 mcg/dL (120150 mcmol/L).
If dialysis is not immediately available for ammonia levels between 100 and 200 mcg/dL
(60175 mcmol/L), sodium phenylacetate
and sodium benzoate (available as Ammonul)
should be administered to patients with known
or suspected urea cycle defect to augment nitrogen excretion.109 The combination of sodium
phenylacetate and sodium benzoate is approved
as adjunctive therapy for acute hyperammonemia and associated encephalopathy due to urea
cycle defects but is also used to treat hyperammonemia of unknown origins. Ondansetron
should be administered with sodium phenylacetate and sodium benzoate. Potassium, which
can be depleted by sodium phenylacetate and
sodium benzoate, should be monitored and replaced as potassium acetate, 0.5 to 1 mEq/kg
per hour, as needed. In addition, 10% arginine
hydrochloride, which enhances urea cycle activity, should be given for treatment of urea cycle
defects with the exception of arginase deficiency.
Citrulline can be administered to augment nitrogen clearance in urea cycle defects with the
exception of argininosuccinic acid synthetase
(citrullinemia) and argininosuccinase acid lyase
deficiencies. Although data are limited, recent
literature suggests hypertonic saline should be
given for cerebral edema rather than mannitol.
Corticosteroids increase catabolism and therefore should not be given. To assess patient response to treatment, glucose, acid-base status,
ammonia, and electrolytes should be monitored
serially.
Appropriate antibiotics should be given if

there is concern about possible serious bacterial infection. As necessary, fresh frozen plasma
should be administered to treat coagulopathy.
Intravenous l-carnitine, 25 to 50 mg/kg, can
be administered empirically in life-threatening
situations associated with known or suspected
carnitine deficiency (eg, primary carnitine deficiency, certain organic aminoacidopathies, and
fatty acid oxidation defects); however, because
it can be harmful with some IEMs, consultation
with an IEM specialist is highly recommended.
Carnitine should not be administered with sodium phenylacetate and sodium benzoate. Intravenous pyridoxine (B6), 100 mg; IV folate,
2.5 mg; and/or biotin, 10 to 40 mg, orally or via
nasogastric tube can be given empirically to neonates with seizures unresponsive to conventional
anticonvulsants to treat a possible vitamin or cofactor responsive IEM. Although there are other
disease-specific adjunctive therapies, administration of these agents in the ED is rarely indicated.
Rapid assessment, establishment of vascular access, and administration of appropriate
fluids (with glucose) are priorities in treating
patients with IEMs in acute crisis. Dehydration
and hypoglycemia should be treated with boluses of normal saline and dextrose solutions,
respectively. Maintenance IV fluids should then
be started to prevent recurrence of hypoglycemia and hypovolemia and stop the catabolic
spiral. Administration of 10% dextrose (with
electrolytes based on the childs weight) at 1.5
times maintenance is usually adequate. General
supportive measures (maintenance of oxygenation and acid/base balance and treatment of
infection) should, of course, be provided. Intravenous carnitine (100 mg/kg) can be beneficial in certain organic acidemias and fatty acid
16-28
oxidation disorders but is usually used after

consultation with a metabolic specialist. The
child might need immediate admission to an
intensive care unit for further monitoring and
other procedures (eg, hemodialysis).
In children who are already known to have
an IEM, the importance of listening closely to
the history provided by the parents or regular
caregiver must be stressed. A child with a metabolic disorder can appear relatively well but
might decompensate rapidly. If such a child is not
maintaining adequate fluid and caloric intake,
does not seem to be his usual self, or both, the
metabolic specialist should be contacted, and IV
fluids with dextrose should be administered even
in the absence of documented hypoglycemia or
other markers of metabolic imbalance. The goal
in such cases is to provide therapy in a timely
manner to prevent a metabolic crisis.
T H E B OT TO M L I N E
Issues in the Diagnosis and
Management of IEMs
Maintain a high index of suspicion,
especially in the presence of
hypoglycemia, metabolic acidosis,
hyperammonemia, and or inappropriate
ketosis.
Although specialized tests are needed
to arrive at a final diagnosis, simple
laboratory studies often provide the first
clues to the presence of an IEM. Obtain
pretreatment specimens when possible.
Early detection and treatment are
essential to optimize immediate and
long-term outcome.
Metabolic Diseases
KEY POINTS
Initial Treatment of Patients With IEMs
Evaluation
- Contact metabolic specialist immediately once diagnosis is suspected.
- Obtain specimens, ideally before treatment.
* Blood: venous blood gas, glucose, electrolytes, BUN, creatinine, complete blood cell count
* If lethargic, ammonia (free flow, ice)
* Lactate dehydrogenase, aldolase, creatinine kinase if skeletal muscle myopathy is suspected
* Lactate, pyruvate if acidosis (free flow, special perchloric acid tube for pyruvate)
* Plasma amino acids, acylcarnitine profile if initial evaluation supports possible IEM
* Urine: urinalysis, urine culture if concern of infection; urine amino, organic acids, acylglycine if
initial evaluation supports possible IEM
Treatment
- Stop all oral feedings
- Fluid hydration with 10% dextrose normal saline
- Glucose to treat hypoglycemia, prevent catabolism (use the 50 rule)
- IV bicarbonate corrects acidosis but could worsen hyperammonemia equilibrium
- For hyperammonemia, plan for detoxification by hemodialysis and/or sodium phenylacetate
and sodium benzoate (Ammonul) and arginine (except for arginase deficiency); if using sodium
phenylacetate and sodium benzoate, administer ondansetron and treat hypokalemia with
potassium acetate
- Seizures: IV pyridoxine (B6), 100 mg; IV folate, 2.5 mg; and/or biotin, 10 to 40 mg, orally or via
nasogastric tube
- Suspected carnitine deficiency: IV l-carnitine, 25 to 50 mg/kg
CHAPTER REVIEW
Check Your Knowledge
Which of the following is most associated
with the development of cerebral edema
in a child with diabetic ketoacidosis
(DKA)?
A. Ketosis
B. High fluid administration (20 mL/kg
per hour)
C. Urinary tract infection
D. Treatment with sodium bicarbonate
2. Which of the following is a prominent
finding in female newborns with
congenital adrenal hyperplasia?
A. Acanthosis nigricans
B. Ambiguous genitalia
C. Hyperpigmentation
D. Midline facial defects and
microphallus
3. Syndrome of inappropriate secretion of
antidiuretic hormone should be treated
with:
A. intravenous hydrocortisone.
B. oral sodium supplements.
C. hypertonic saline, 10-mL/kg infusion
if the sodium concentration is 130
mEq/L.
D. fluid restriction unless the patient
is seizing or severely lethargic or
comatose.
E. sodium restriction.
4. Which of the following statements
regarding hypernatremia in patients with
diabetes insipidus (DI) is correct?
A. Never occurs in infants with DI
because of high fluid intake
B. Occurs in all patients with DI
C. Rare in older children with DI and
normal thirst mechanisms
D. Should be treated with 3% sodium
chloride solution
1.
16-30
Of the following inborn errors of

metabolism (IEMs), which is most likely
to present with an insidious onset and
progressive worsening?
A. Organic acidemias
B. Aminoacidopathies
C. Fatty acid oxidation defects
D. Lysosomal storage disorders
6. Laboratory abnormalities due to
IEMs commonly include which of the
following (best choice)?
A. Metabolic acidosis, hyperammonemia,
hypoglycemia
B. Hypoglycemia, ketosis, leukopenia
C. Hematuria, azotemia,
hypercholesterolemia
D. Proteinuria, hypercholesterolemia,
hypoalbuminemia
E. Hypocalcemia, hyponatremia,
hypokalemia
7. The most appropriate initial rapid fluid
infusion for a patient with a suspected
IEM who is tachycardic, hypoglycemic,
and acidotic is:
A. normal saline (20 mL/kg).
B. lactated Ringer solution (20 mL/kg).
C. 10% Dextrose normal saline (20 mL/
kg).
D. 25% Dextrose (2 mL/kg) and normal
saline (20 mL/kg).
E. 10% Dextrose (2 mL/kg) and normal
saline (20 mL/kg).
8. The most effective treatment for severe
hyperammonemia due to an IEM is:
A. hemodialysis.
B. exchange transfusion.
C. peritoneal dialysis.
D. sodium phenylacetate and sodium
benzoate (Ammonul).
E. hyperventilation.
5.
Metabolic Diseases
CHAPTER REVIEW
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Levine B, Anderson B, Butler D, Antisdel J, Brackett J, Laffel L.

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53. Baylis PH, Cheetham T. Diabetes insipidus. Arch Dis Child.
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regulation of thirst and vasopressin secretion in patients with
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rare, not hopeless. Contemp Pediatr. 1988;5:47-63.
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eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 4th ed.
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Chapter Review
16-33
CASE SUMMARY
CHAPTER REVIEW
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 37.9C (100.2F). Pulse
oximetry oxygen saturation is 97% on room air. On examination, he appears lethargic,
has dry mucous membranes, has normal abdominal examination results, and has
nonfocal neurologic examination results. Bedside rapid glucose measurement is above
the upper limit of the glucose meter (>500 mg/dL).
1. What therapeutic actions must be taken immediately?
3. What is the most important potential complication?
This child is hypotensive, mainly due to dehydration. Immediate volume resuscitation
with boluses of normal saline (20 mL/kg) should be administered to restore perfusion.
An insulin infusion should be initiated as soon as possible after intravenous fluid
therapy has been initiated.
CASE SUMMARY
A reasonable set of initial laboratory tests would include measurement of serum

electrolytes, a venous blood gas analysis, and urinalysis for ketones. Complete blood
cell counts are not usually helpful.4 This child must be closely monitored for the
development or progression of cerebral edema. Clinically apparent cerebral edema
occurs in approximately 1% of children with DKA. Therefore, frequent neurologic
monitoring is indicated for all children with DKA.
A 14-month-old girl presents to the ED with a 1-day history of tactile fever, loss of
appetite, 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 36.0C (96.8F). She appears lethargic and has mildly dry mucous membranes and
no obvious source of infection. Bedside rapid glucose measurement reveals a blood
glucose level of 20 mg/dL.
1. What therapeutic measures must be taken immediately?
3. What complications can occur as part of the disease process and secondary to therapeutic
intervention?
16-34
Metabolic Diseases
CASE SUMMARY
C O N T.
CHAPTER REVIEW
The child is hypoglycemic and likely volume depleted. Resuscitation with boluses
of 2 mL/kg of 25% dextrose (or 5 mL/kg of 10% dextrose) to normalize blood glucose
levels should be started without delay, followed by administration of volume (normal
saline bolus of 20 mL/kg) until perfusion is restored. Fluids consisting of 10% dextrose
and 0.45% sodium chloride at 1.5 times maintenance should be started. Appropriate
potassium supplementation is added as needed. Initial studies include measurement
of electrolytes, measurement of glucose, blood gas analysis, complete blood cell count,
blood and urine cultures, and urinalysis for ketones. If possible, samples should be
obtained before initiation of therapy, including administration of glucose and fluids.
The finding of nonketotic (hypoketotic) hypoglycemia is a clue to the presence of
an underlying fatty acid oxidation defect. Ammonia levels might be mildly elevated.
Metabolic disorders might be unmasked by an infection severe enough to cause
catabolism, but an obvious infection or clear exacerbating factor is not always present.
Because of the risk of multiorgan system failure, measurement of liver enzymes,
blood urea nitrogen, creatinine, and creatine phosphokinase levels can also be helpful.
Metabolic studies include measurement of lactate, ammonia, plasma amino acids,
carnitine, acylcarnitine profile, and urine organic acids. Freezing aliquots of serum
and urine and contacting a metabolic specialist for further guidance with respect to
specialized testing are appropriate alternatives if your laboratory does not routinely
handle such specimens.
Fatty acid oxidation disorders can progress to multiorgan system failure (Reye-like
syndrome). Seizures, cardiomyopathy, cardiac arrest, liver failure, and kidney failure
might supervene. There is a significant risk of death.
Secondary to therapeutic interventions, cerebral edema of unclear pathogenesis might
occur in some IEMs, particularly those with hyperammonemia. This complication can
also occur if a high rate of relatively dilute dextrose solution (eg, 5% dextrose) is used.
Close monitoring of fluid resuscitation and neurologic status is therefore imperative.
Photo Credits
Opener Ted Kinsman/Photo Researchers, Inc.; 16-2 Visuals Unlimited
Unless otherwise indicated, all photographs and illustrations are under copyright of Jones & Bartlett
Learning, courtesy of Maryland Institute for Emergency Medical Services Systems, or the American
Academy of Pediatrics.
Some images in this book feature models. These models do not necessarily endorse, represent, or
participate in the activities represented in the images.
Chapter Review
16-35

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16 Metabolic Diseases

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chapter 16

Describe the fluid and

Discuss the clinical

Copyright 2012 by the American Academy of Pediatrics and the American

The emergency management of endocrine and

Copyright 2012 by the American Academy of Pediatrics and the American

with known diabetes can occur during episodes

causes of dehydration. Acidosis results in compensatory tachypnea, and a characteristic fruity

Pathophysiology of Diabetic Ketoacidosis

fatty acid oxidation

renal Na+ loss

Figure 16.1 Diabetic ketoacidosis.

be due to acidosis and dehydration but can also

Diabetic Ketoacidosis 16-5

one extreme in a continuum of presentations of

should not be compromised by theoretical concerns associated with fluid administration.

Diabetic Ketoacidosis 16-7

cerebral edema have been found in a large study

ness of cerebral edema treatment interventions is

Hypoglycemia in Children With

cally impaired to a level that requires help from

Diagnostic Studies and Management

Copyright 2012 by the American Academy of Pediatrics and the American

abnormalities persist for prolonged periods after

venous sample should be sent to the laboratory

If hypoglycemia is suspected, a rapid glucose

Fatty acid oxidation defects

ingestions (eg, oral hypoglycemic agents,

should equal 50). Subsequently, an IV infusion

Copyright 2012 by the American Academy of Pediatrics and the American

corticosteroid doses administered by various

Figure 16.2 Midline facial malformation.

lower free cortisol levels during the last trimester,

disorders, neurologic diseases, or child abuse.

Adrenal Insufficiency/Congenital Adrenal Hyperplasia 16-13

tumors, neurosurgical procedures, congenital

potassium intracellularly. If there is a coexisting

Copyright 2012 by the American Academy of Pediatrics and the American

measurements of body weight, serum sodium

Hypernatremia is more frequently

ED management includes cautious fluid

desmopressin. Desmopressin is an ADH analog

Syndrome of Inappropriate Secretion of Antidiuretic Hormone 16-17

Euvolemia in chronic SIADH is a critical

Laboratory Findings in Patients With

Serum hypo-osmolality (<275 mOsm/kg)

Urine hyperosmolality (>100 mOsm/L)

Inappropriate natriuresis (>40 mEq/L)

Normal renal, thyroid, and adrenal

Congestive heart failure

well. Certain psychiatric illnesses, particularly

Copyright 2012 by the American Academy of Pediatrics and the American

Signs and Symptoms of Water

Diagnosis and Management of Water

Presents with hyponatremia with a

Infant who presents with hypothermia

laboratory features of dehydration are present

Hypertonic 3% sodium chloride solution

Laboratory Findings in Patients With

Metabolic Disease of the

peroxisomes), metals, or complex molecules.90

but there are IEMs with autosomal dominant,

in gastroenteritis). Unusual dietary preferences,

retinopathy, optic atrophy, chronic dermatoses, skin photosensitivity, nodules, dilated or