September 2013 Question 1 Answer: B

Of 10 critically ill children with a positive biomarker assay test result, approximately 1 patient will
have venous thromboembolism (VTE).  Of interest, a similar question was posed to 160 gynecologists
regarding the risk of breast cancer in women with a positive mammography result; the majority
answered incorrectly.  There is increasing evidence that physicians and patients do not have the
requisite understanding of the concept of risk.  The question is framed in terms of a conditional
probability. In general terms, given 2 events A and B, the conditional probability that A will occur,
given that you know that B has occurred, may be computed from the following equation:

p(A|B) = p(A and B)/p(B)   (Eq 1)

where p(A|B) is the conditional probability, p(A and B) is the joint probability that events A and B
occur, and p(B) is the probability that event B occurs.

In the question, we are trying to calculate the conditional probability that a critically ill child has VTE if
he or she tests positive: 

p(VTE|Test Positive) = p(VTE and test positive)/p(test positive)   (Eq 2)

We therefore need to know the probability of having both VTE and a positive test result and the
probability of having a positive test result.  The astute reader will recognize that we are essentially
trying to determine the predictive value of a positive test result, otherwise known as the positive
predictive value (PPV).  Unfortunately, we do not have all of the information laid out in a nice 2 × 2
table, which would make this calculation much easier.  However, we can still calculate the PPV from
the information provided in the vignette.  We know that a critically ill child in the pediatric intensive
care unit (PICU) has a 1% chance of having VTE (based on the point prevalence) and a 99% chance of
not having VTE.  Of the 1% of critically ill children with VTE, 90% will test positive and 10% will test
negative.  Of the 99% of critically ill children without VTE, 9% will test positive and 91% will test
negative. 

P(VTE|test positive) = (0.01 ×

0.9)/[(0.01 × 0.9) + (0.99 × 0.09)] =
0.009/0.0981 = 0.09 (Eq 3)

Therefore, approximately 10% of

critically ill children with VTE will test
positive, or 1 in 10.

A discussion of risk and diagnostic

testing would not be complete without
discussing the other statistical measures
of test performance (specificity, sensitivity, negative predictive value [NPV], and likelihood ratios).  As
stated, it is helpful to use a 2 × 2 table to discuss these concepts.  In Table 1, we are comparing a
new diagnostic test to a previously accepted criterion standard, which is the best single test that is
considered the preferred method for diagnosing a particular disease or condition.  The results of the
criterion standard will indicate whether or not the disease condition is present (D+) or absent (D−). 
The results of the new diagnostic test will have either a positive result (T+) or negative result (T−). 
Using this information, we can build our 2 × 2 table to determine the sensitivity, specificity, PPV, NPV,
and likelihood ratios of the new diagnostic test.

Using the information provided in the case vignette (assuming a sample size of 1000 critically ill
children in the PICU), we can determine the number of positive and negative test results (Table 2).

The point-prevalence of VTE in this sample is then the total number of patients who have the disease
divided by the sample size:

Prevalence = No. of individuals with the disease/No. of individuals in the population (Eq 4)

Therefore, in this example, the prevalence of VTE is 10 per 1000, or 1%.

The sensitivity of a diagnostic test is the probability of a patient testing positive, given that he or she
actually has the disease:

Sensitivity = p(T+|D+) (Eq 5)

Sensitivity = No. of True-Positive Results/(No. of True-Positive Results + No. of False-Negative

Results)

If the sensitivity of a test is extremely high, a negative test result will essentially rule-out the disease;
this can be easily recalled using the mnemonic SnOUT (a sensitive test with a negative result rules out
the disease).  In the vignette, the sensitivity of the diagnostic test is 9/(9+1), or 0.9.
The specificity of a diagnostic test is the probability of a patient testing negative, given that he or she
does not have the disease:

Specificity = p(T−/D−) (Eq 6)

Specificity = No. of True-Negative Results/(No. of True-Negative Results + No. of False-Positive

Results)

If the specificity of a test is extremely high, we can be sure that a positive test result will essentially
rule-in the disease; this can be easily recalled using the mnemonic SpIN (a specific test with a positive
result rules in the disease).  In the vignette, the specificity of the diagnostic test is 901/(901+89), or
0.9.

The PPV of a diagnostic test is the probability that a person who tests positive has the disease. 

PPV = p(D+|T+) (Eq 7)

PPV=No. of True-Positive Results/No. of Positive Test Results

In the case vignette, the PPV of the diagnostic test is 9/(9+89), or 0.09. 

The NPV of a diagnostic test is the probability that a person who tests negative does not have the
disease.

NPV = p(D−|T−) (Eq 8)

NPV = No. of True-Negative Results/No. of Negative Test Results

In the case vignette above, the NPV of the diagnostic test is 901/902, or 0.99.

It is important to emphasize that sensitivity and specificity are inversely proportional.  In other words,
as sensitivity increases, the specificity decreases (and vice versa).  In addition, the PPV and NPV
depend significantly on the disease prevalence (whereas sensitivity and specificity do not).  The
disease prevalence is also known as the pretest probability.  Assuming all things are equal, the PPV
will increase with increasing disease prevalence, and the NPV will decrease with increasing disease
prevalence.  The low PPV in the vignette is due to the low prevalence of VTE in this particular
population (note also that the NPV is 99%).

The sensitivity and specificity cannot be used alone to determine the probability of a disease in a
particular patient.  However, the 2 parameters are frequently combined into a single measure, known
as the likelihood ratio, which can be used in conjunction with the disease prevalence to estimate the
probability that a patient has a particular disease.  The positive likelihood ratio (LR+) is defined as the
probability that an individual with the disease has a positive test result divided by the probability that
an individual without the disease has a positive test result.  This is essentially the sensitivity of the
test divided by the converse of specificity:

LR+ = Sensitivity/(1 − Specificity) (Eq 9)

An LR+ greater than 1 indicates that a positive test result is more likely to occur in patients with the
disease than in patients without the disease.  Conversely, an LR+ less than 1 indicates that a positive
test result is less likely in patients with the disease compared with patients without the disease.  In
general, for patients with a positive test result, an LR+ of 10 or more essentially “rules in” a disease,
whereas an LR+ less than 0.1 “rules out” the disease.

The negative likelihood ratio (LR−) is defined as the probability that an individual with the disease has
a negative test result divided by the probability that an individual without the disease has a negative
test result.  This is essentially the converse of sensitivity divided by specificity:

LR− = (1 − Sensitivity)/Specificity (Eq 10)

An LR− greater than 1 indicates that a negative test result is more likely to occur in patients with the
disease than in patients without the disease.  An LR− less than 1 indicates that a negative test result
is more likely to occur in patients without the disease compared with patients with the disease. 
Therefore, in general, for patients with a negative test result, an LR− of 10 or more “rules in” the
disease, whereas an LR− less than 0.1 “rules out” the disease.

As stated, the advantage of using likelihood ratios is that they can be adapted to individual patients. 
Using Bayes theorem, the posttest probability (ie, the probability that an individual patient has the
disease after the results of the test are known) can be calculated using the pretest probability (ie,
disease prevalence) and the likelihood ratio.

Posttest Probability = Pretest Probability × Likelihood Ratio (Eq 11)

The classic definition of a type I error is when a researcher rejects the null hypothesis when the null
hypothesis is, in fact, true.  Recall that the null hypothesis typically reflects the default position; for
example, when comparing a new diagnostic test to a criterion standard, the null hypothesis
(symbolized as H0) would be that there is no difference between the 2 tests.  The alternative
hypothesis (denoted as H1) is the rival hypothesis; in the current discussion, this hypothesis is that
there is a difference between the 2 tests.  Therefore, a type I error (rejecting a “true” null hypothesis)
means that the statistical analysis suggests that there is a difference between the new diagnostic test
and the criterion standard when in fact there is no difference.  In Table 1, if the presence or absence
of the disease is determined by the criterion standard test, the new diagnostic test has a high number
of false-positive results and has classified patients as having the disease, when in fact they do not
have the disease.  A type I error is equivalent to “convicting an innocent person” in a jury trial.  The
rate of type I error is denoted by the Greek letter α, which is the significance level (the probability of a
type I error is α).  The probability of a type I error is NOT the same as the p value (the p value is the
probability of obtaining a test statistic at least as extreme as the one that was actually observed,
assuming that the null hypothesis is true; the null hypothesis is “rejected” if the p value is less than a
predefined significance level, α).

The classic definition of a type II error is when the researcher accepts the null hypothesis (which
states that there is no difference between the 2 tests) when, in fact, he or she should have rejected
it.  In Table 1, a type II error occurs when the diagnostic test has a high number of false-negative
results and has classified patients as not having the disease when, in fact, they do have the disease. 
A type II error is therefore equivalent to setting a guilty person free in a jury trial.  The rate of type II
error is denoted by the Greek letter β (recall that the power of a study equals 1 − β).

American Board of Pediatrics Content Specification(s)

 Understand the appropriate use of statistical methods in data analysis

 Understand the use of p values in the interpretation of results
 Understand the concept of the null hypothesis
 Distinguish between type I and type II statistical errors
 Understand the "power" of a statistical analysis
 Understand the concept of "significant" as it applies to statistical analysis
September 2013 Question 2 Answer: E

The child described in the vignette most likely has gastroenteritis and is experiencing uncompensated,
hypovolemic shock. Shock occurs when delivery of oxygen and other nutrients is not sufficient to meet
the metabolic demands of the body. Shock represents a progressive process that is characterized by 3
stages:

1. Compensated shock: neurohumoral compensatory physiologic mechanisms are designed to

maintain blood pressure and vital organ perfusion. This is a reversible stage. Blood pressure,
urine output, and cardiac function will appear normal or nearly so.
2. Uncompensated shock: compensatory mechanisms fail and blood pressure and organ
perfusion decrease. At this stage, with appropriate intervention, shock is reversible.
3. Irreversible shock: organ and tissue injury occur, and conventional therapy cannot restore
their function. This stage leads to death.

Children with shock usually present with tachycardia, tachypnea, and signs of decreased organ and
peripheral perfusion, including the following: decreased volume of peripheral pulses compared with
central pulses, decreased alertness (as with the child described in the vignette), slowed capillary refill,
mottled or cool extremities, and decreased urine output. Hypovolemic shock is sufficient to explain
lethargy, and encephalitis is unlikely. Hypotension is usually a late sign and signifies uncompensated
shock.  Other findings may include orthostatic hypotension, metabolic acidosis, and increased blood
lactate.

Hypovolemia remains the most common cause of shock in children. Causes of hypovolemia include
hemorrhage, fluid and electrolyte losses (eg, gastroenteritis or excessive diuretic use), and endocrine
abnormalities (eg, adrenal insufficiency, diabetes mellitus, or diabetes insipidus). Hypovolemic shock
may overlap with other types of shock, such as distributive (eg, sepsis and spinal cord injury), so a
high index of suspicion should be maintained, especially when response to fluid replacement therapy
seems inadequate. The cause of hypovolemic shock is often apparent from the history and physical
examination.  Evaluation of serum electrolytes and glucose, renal function tests, and a complete blood
cell count are important components of evaluation of hypovolemic shock.

Hypovolemia produces a decrease in preload, resulting in decreased stroke volume and cardiac output.
Compensatory increase in production and release of catecholamines in response to decreased
baroreceptor activity causes peripheral vasoconstriction and tachycardia. These mechanisms maintain
normal blood pressure.  However, as losses exceed approximately 10% to 15% of circulating blood
volume, these mechanisms become strained and eventually inadequate unless normal circulating
blood volume is restored.

Therapy for hypovolemic shock consists primarily of volume resuscitation with appropriate fluids, as
well as supportive measures, such as oxygen administration. The choice of resuscitation fluid depends
on the cause of the hypovolemia. In the case of hemorrhage, transfusion of packed red blood cells is
the preferred choice. With other causes of hypovolemia, isotonic crystalloid is safe, relatively
inexpensive, and effective. In addition to restoring preload, administration of large amounts of
crystalloid will result in a transient hemodilution and decrease in blood viscosity. This decrease in
viscosity will lower resistance to flow in arterial and venous beds. This mechanism results in an
additional increase in venous return, albeit a modest one. Colloid has never been found to be superior
to crystalloid for acute resuscitation of hypovolemia.  Under normal conditions in a patient with
hypovolemic shock that has not progressed to the irreversible stage, heart rate, pulse pressure, blood
pressure, perfusion, mentation, and urine output should improve rapidly with fluid administration. The
quantity of fluid needed for effective resuscitation will depend on the extent of fluid loss.

Although treatment of relative adrenal insufficiency with corticosteroids is part of the management of
septic shock that is refractory to both fluid and pressor therapy, the child described in the vignette
appears to have hypovolemic rather than septic shock.  Even if she were septic, aggressive fluid
resuscitation should precede corticosteroid administration.  Similarly, she has no clinical evidence of
primary cardiac dysfunction, so treatment with inotropic drugs should not be part of her management
at this time.

The brain and myocardium are the cell types most sensitive to acute oxygen deprivation in shock
states. Even short periods of ischemia can lead to serious and irreversible effects. The
pathophysiologic effects of hypovolemic shock relate primarily to the acute deficiency of oxygen.

Within seconds of ischemia, oxidative phosphorylation activity decreases and cellular adenosine
triphosphate (ATP) levels decrease. Cellular metabolism becomes anaerobic, which is much less
efficient than aerobic metabolism (only 2 moles of ATP produced per mole of glucose consumed vs 38
moles of ATP for aerobic metabolism). Anaerobic metabolism results in increased levels of cellular
lactate and acidosis.

Consequences of this low-energy state include accumulation of breakdown products of adenine

nucleotides, such as inorganic phosphates and adenosine. Membrane ion pump (Na +/H+ exchanger)
function becomes impaired, altering cellular ion concentrations (decreased potassium and increased
sodium and calcium). The increase in sodium will be followed by cytoplasmic and organelle swelling. 
Protein synthesis decreases with the exception of specific proteins that are cellular responses to
hypoxemia, such as heat shock protein 70 and protein kinase C. These changes decrease cellular
function. In the heart, contractility decreases, whereas in the gut, altered intestinal absorption
function results in translocation of bacteria from the intestines to the lymphatics and blood vessels.

If ischemia persists, cytosolic and mitochondrial calcium concentrations increase.  The mitochondrial
permeability transition pores open, increasing mitochondrial inner membrane permeability. Stored
calcium is released into the cytosol, and the inner transmembrane potential is lost, with resultant
uncoupling of the electron transport system. Energy failure ensues. The increases in calcium in the
cytosol and mitochondria activate enzymes (proteases, phospholipases, and adenosine
triphosphatase) that further disrupt cell function. The terminal event is cell death by necrosis with
leakage of cellular contents into the interstitium and plasma.

The earlier reperfusion occurs during the treatment of shock, the more favorable the clinical outcome.
However, reoxygenation commences a series of responses that may lead to additional injury, known
as reperfusion injury. Although a discussion of the full extent of reperfusion injury rests beyond the
scope of this question, the major components include the following:

1. Oxidative stress with excessive production of reactive oxygen species and reactive nitrosative
species
2. Endothelial dysfunction and macrovascular injury
3. Activation of the complement system
4. Neutrophil activation

All organs are at risk for injury from shock and reperfusion.  Such injury may include respiratory pump
failure or acute lung injury; acute kidney injury, ranging from prerenal azotemia to acute tubular or
cortical necrosis; coagulation abnormalities; gastrointestinal and cardiac dysfunction; and endocrine
dysfunction, which may include disruption of the hypothalamic-pituitary-adrenal axis; and hepatic
dysfunction. Consequently, postresuscitation care requires meticulous monitoring and physiologic
support of end-organ function.

American Board of Pediatrics Content Specification(s)

 Know the complications and sequelae of circulatory shock

 Recognize the signs of perfusion failure, including altered mental status
 Differentiate between the various types of shock
 Recognize the signs of hypovolemic shock
 Know how to investigate causes of hypovolemic shock
 Understand the treatment of hypovolemic shock
 Understand the pathophysiology of hypovolemic shock
September 2013 Question 3 Answer: A

The newborn described in the vignette presents with failure to thrive, vomiting, lethargy, poor oral
intake, dehydration, jaundice, and hepatomegaly and is found to be in fulminant sepsis caused by
gram-negative bacilli.  The child also has reducing substances present in the urine in the absence of
glycosuria.  This patient’s clinical picture is strongly suggestive of a diagnosis of galactosemia. 

The normal metabolism of lactose, the principal carbohydrate in human milk, involves its breakdown
in the intestinal villi to glucose and galactose. Galactose is then quickly converted into glucose via the
Leloir pathway, which involves 3 enzymes sequentially: galactokinase (GALK), galactose-1-phosphate
uridyltransferase (GALT), and UDP-galactose-4’-epimerase (GALE). Deficiency of GALT results in
classic galactosemia, a serious autosomal recessive disorder that results in accumulation of galactose-
1-phosphate in the liver, kidneys, eyes, brain, myocardium, spleen, and erythrocytes. Alternative
pathways are activated with the production of intermediaries, such as galactitol and galactonate,
which also accumulate in the tissues. Another form of galactosemia, which results from deficiency of
the enzyme GALK, is milder and less common than classic galactosemia.

The incidence of classic galactosemia is approximately 1 in 60,000.  Infants may present in the latter
half of the first week of life with failure to thrive, vomiting, hypoglycemia, direct hyperbilirubinemia,
and hepatomegaly.  There is an increased incidence of fulminant Escherichia coli septicemia in these
newborns, presumably due to decreased neutrophil bactericidal activity.  Cataracts become evident in
the first few weeks of life and are due to accumulation of galactitol and water in the lens.  Intellectual
disability (mental retardation) is typically detected around 6 to 12 months of age.  Injury to the
proximal renal tubule due to massive intracellular accumulation of galactose-1-phosphate in
galactosemia leads to aminoaciduria.  Neonates with galactosemia are also at increased risk of liver
failure, hemolysis, and coagulopathy. 

The presence of reducing substances in the urine in the absence of glycosuria is highly suggestive of
galactosemia.  More reliable tests to confirm this diagnosis include the direct identification of the
deficient enzyme GALT in leukocytes or erythrocytes.  In the United States, most newborns are
screened soon after birth for deficiency of GALT using a blood test.  This test is not dependent on the
infant’s feeding status.  GALT enzyme screening is inaccurate in infants who have been transfused
with red blood cells before the test because GALT activity in transfused erythrocytes will be detected. 
Additional testing for galactose and galactose-1-phosphate is required for infants who are transfused
before newborn screening.  The GALT screening assay also does not detect the variant forms of
galactosemia caused by deficiency of GALK or GALE.  It is possible to obtain a prenatal diagnosis of
galactosemia by evaluating GALT activity in amniotic fluid cells or measuring galactitol levels in the
amniotic fluid. 

The diagnosis of galactosemia should be considered in any newborn or infant who presents with any of
the following clinical manifestations: failure to thrive, vomiting, jaundice, hepatomegaly, lethargy or
irritability, hypoglycemia, seizures, cataracts, liver failure, or aminoaciduria.  The presence of E
coli neonatal septicemia should also alert the clinician to the possibility of galactosemia because the
onset of sepsis frequently occurs before the diagnosis of galactosemia.

Treatment for classic galactosemia involves implementation of lactose-free nutrition.

Constipation is more suggestive of hypothyroidism.  Classic signs and symptoms include prolonged
jaundice, feeding difficulties, hypothermia, hoarse cry, constipation, hypotonia, umbilical hernia,
coarse facies, large fontanel, and dry skin. 

Exophthalmos is common in neonatal hyperthyroidism.  Newborns with neonatal hyperthyroidism are

typically premature with a low birth weight, present with microcephaly or craniosynostosis, and
develop hyperthermia and exophthalmos. They may also present with vomiting, diarrhea, feeding
difficulties, and weight loss.  Most will have a goiter on physical examination. 

Hemiparesis is suggestive of stroke or stroke-like episodes, such as those that would occur in
homocystinuria or MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). 

Hyperpigmentation is suggestive of adrenal insufficiency. Neonates with adrenal insufficiency typically

present with vomiting, dehydration, polyuria, and weight loss.  Hypotension and death may ensue
rapidly in the setting of infection or trauma.

The child described in the vignette also has a normal ammonia level.  Hyperammonemia in the
presence of an elevated anion gap, metabolic acidosis, and ketosis suggests an organic acidemia. 
Markedly elevated ammonia levels with normal serum glucose and a normal anion gap suggest a urea
cycle defect. Positive reducing substances in the urine other than glucose are not present in any of the
described disorders.

American Board of Pediatrics Content Specification(s)

 Understand the pathogenesis and pathophysiology of galactosemia

 Recognize the clinical manifestations and life threatening complications of galactosemia
 Recognize galactosemia as a cause of acute neurologic disease
September 2013 Question 4 Answer: B

Congenital heart disease is common, affecting 1% of infants. It is essential that a pediatric intensivist
understand the complications and risks of cardiac surgery, including bypass, cardioplegia, cross-
clamp, hypothermia, and circulatory arrest, to help communicate with parents and to anticipate and
prepare for the complications that may occur.  There are risks common to all operations and risks that
are more specific for given lesions and operations.

For the infant described in the vignette who appears to have done well in the first few days after his
initial (stage 1) palliative surgery for hypoplastic left heart syndrome, he will most likely return at 3 to
6 months of age for the second stage of single ventricle repair, a bidirectional cavopulmonary
anastomosis or hemi-Fontan. Data shared from multiple institutions through the National Pediatric
Cardiology Quality Improvement Collaborative have shown that the factor with the highest risk of
complications during this procedure is having a low weight-for-age z score.  It is inferred therefore
that close attention to nutrition and growth should be paid in the time between the stage 1 repair and
the cavopulmonary anastomosis.  It has also been shown that low weight-for-age z score is associated
with a higher risk of death between the bidirectional cavopulmonary anastomosis and Fontan
operations stages 2 and 3.

Chylothorax is a complication of open heart repair of congenital heart lesions and is most common in
cases of elevated central venous pressure, increased right-sided intracardiac pressure, and when
extensive dissection increases the risk of transecting the thoracic duct and other lymphatic channels.
Because surgery that involves the aortic arch, such as the Norwood procedure, is a risk factor, a
pleural effusion after a Norwood procedure should make one consider this complication.  Typically,
pleural drainage increases after feeding a child with chylothorax and becomes milky when long-chain
fatty acids are absorbed in the intestine, are absorbed into lacteals as chylomicrons, and enter the
cisterna chyli and then the thoracic duct.  A diet that contains no long chain fatty acids or very few
long-chain fatty acids (supplementing with intravenous fats to ensure adequate calories and essential
fatty acids), along with measures to reduce central venous pressures and good forward flow, usually
allows chylothoraces to resolve within several days.  There is no direct evidence that having a
chylothorax after a Norwood procedure affects the long-term outcome or causes a higher risk of
complications at subsequent stages of single ventricle repair.

Another fairly frequent complication of open heart surgery is phrenic nerve injury, leading to
hemidiaphragmatic paralysis or paresis.  Such injury can be caused by transsection, nerve stretch,
electrocautery, or topical hypothermia.  Because the phrenic nerves are anatomically close to the
surgical sites during a Norwood operation, phrenic nerve injury is not rare.  There is, however, no
evidence that the subsequent risk of complications during later stages of repair is higher for those
infants so affected.  Most phrenic nerve injuries recover without therapy over time, and if surgical
plication of the diaphragm is performed, the patient usually recovers well.
Cardiopulmonary bypass requires cannulation of the large veins to empty the right atrium of blood and
of the large arteries (usually the ascending aorta) to return blood (Video). Heparin is used to prevent
thrombosis within the extracorporeal circuit.  Cross-clamping of the aorta proximal to the cannula is
usual to prevent coronary blood flow that would impair visualization.  To minimize myocardial
metabolic needs during this ischemic time, the heart is cooled and cardioplegia solution is
administered through the coronary arteries and sometimes retrograde through the coronary sinus. 
Cardioplegia solution with high potassium content stops contraction in the diastolic phase (when
metabolic rate is minimal).  Bypass leads to potential mechanical complications, including microemboli
and macroemboli (including myocardial air emboli), to various organs.  There is an inflammatory
response to bypass, which is thought to be due to exposure of blood to nonendothelialized surfaces in
the circuit that affects multiple organs directly and indirectly through endocrine effects.  Cytokine
concentrations, including interleukin 6 and interleukin 8, increase during bypass.  These cytokines
interact with neutrophils to release free radicals, lysosomal enzymes, and other products that injure
endothelial cells.  The complement system is also activated during bypass. Preoperative
glucocorticoids are used to reduce the inflammation, although the ideal dosage and timing of
administration are unknown.  In some cases, bypass flows are reduced to complete circulatory arrest
to repair certain lesions.  This can be thought of as total body ischemic time and can lead to
dysfunction of all organs.  Deep hypothermia is used during total circulatory arrest to minimize
metabolic demands.

Neurologic adverse effects are fairly common, with many being subtle and transient.  Most neurologic
adverse effects could be from combinations of abnormal anatomy, hypoxemia, ischemia, and
inflammation.  There have been many efforts to improve cerebral blood flow during bypass.  It is
important to reduce cerebral metabolism during low or no-flow states, so hypothermia as low as 18°C
to 20°C is used.  Excessive hypothermia or prolonged hypothermia can damage neurons, so extremely
careful monitoring of core temperature is essential. 

End-organ effects of cardiopulmonary bypass include a 2% to 10% risk of neurologic sequelae that
most commonly include subtle behavioral issues and learning disabilities, but overt stroke, seizures,
and choreoathetosis can occur.  Hypothermia and an elevated vasopressin and renin-aldosterone
response to bypass lead to oliguria postoperatively.  Renal impairment is most common if there is
preoperative kidney injury and when cardiac output is impaired postoperatively.

The lungs are usually deflated during open heart surgery after initiating cardiopulmonary bypass. 
Although bronchial artery oxygenation and blood flow meet most of the lung’s metabolic needs, there
may be areas of ischemia.  Reinflation from an atelectatic state causes inflammation that compounds
with the general inflammatory state from bypass to lead to reduced lung compliance and increased
airway resistance.  Acute lung injury may also be the result of exposure to blood component
transfusion.  Pulmonary arterial hypertension may be present from preexisting large left-to-right
shunting lesions or pulmonary venous or mitral valve obstruction.  Bypass and hypothermia lead to
increased levels of epinephrine and norepinephrine.  Insulin secretion and the response to insulin are
altered, so hyperglycemia is common.  Growth hormone and glucagon are also increased during
bypass, contributing to further hyperglycemia.  This hyperglycemia may contribute to adverse
neurologic outcomes and an inappropriate diuresis that affects preload and electrolyte balance. 
Thyroid hormone levels are usually depressed after bypass.

Cardiopulmonary bypass–induced inflammation leads to a generalized capillary leak that can result in
tissue edema that compromises wound healing.  Patients may have low-grade fevers without
infectious cause for the first few days after cardiopulmonary bypass.  These patients are at elevated
risk for true infection because of inflammatory derangements associated with bypass in addition to
large wounds and invasive catheters and tubes. Despite all of the many adverse effects associated
with cardiopulmonary bypass, even somewhat prolonged bypass times are not associated with
increased complications at subsequent operations.

William Norwood’s innovative operation has made a previously inoperable condition into one with
reasonable long-term results.  More recently, the Sano modification has been developed.  This
procedure uses a right ventricle to pulmonary artery shunt instead of a modified Blalock-Taussig
shunt.  The Sano modification theoretically improves diastolic perfusion of the heart and other organs
because there is not the runoff seen with the Blalock-Taussig shunt.  There is also less ventricular
volume loading.  There could be more difficulty during poor contractility with pulmonary perfusion and
oxygenation because blood flow is only during systole.  Larger shunts require larger ventriculotomies
with associated risk of ventricular dysfunction or aneurysm formation.  There currently is no clear
evidence of superiority in long-term outcomes or a higher risk of complications during subsequent
operations for one procedure over the other.

American Board of Pediatrics Content Specification(s)

 Understand the complications and risks of cardiac surgery including bypass, cardioplegia,
cross-clamp, hypothermia, and circulatory arrest
 Understand and plan the management of common complications following first-stage surgery
for single ventricles
 Recognize and interpret important data in the preoperative evaluation of a patient scheduled
for cardiac surgery
 Know the common techniques and indications for the repair/palliation of congenital cardiac
diseases
September 2013 Question 5 Answer: D

Congestive heart failure (CHF) is most commonly associated with elderly people but may occur in
childhood from a variety of causes.  CHF is a condition in which the heart cannot pump blood forward
well enough.  When the left heart fails, elevated pressure in the pulmonary veins occurs, which causes
pulmonary edema and dyspnea. If the right ventricle cannot pump blood forward well enough,
pressures build in the right atrium and jugular veins, causing jugular venous distension, and in the
abdominal veins, causing hepatic congestion.  This congestion manifests as hepatomegaly, but
elevated venous pressures may adversely affect perfusion pressure to any intra-abdominal organs. 
Systemic edema can be observed.  When heart failure is severe enough and compensatory
mechanisms are overwhelmed, the circulation is unable to supply enough oxygen and other substrate
to meet the metabolic requirements of the tissues.  This condition is cardiogenic shock.  Chronic
congestive heart failure is thought to begin with an insult that reduces myocardial contractility. 
Initially, a patient has several compensatory responses to this, including increased adrenergic
response; elevated concentration of cytokines, such as tumor necrosis factor α; and increased renin-
angiotensin system. These compensatory responses prevent the patient from being symptomatic for a
while. However, over time these responses actually lead to deleterious changes, such as ventricular
remodeling and myocyte damage.

The medical history of a patient with CHF may suggest increased respiratory effort, prolonged time
feeding, poor weight gain, and excessive sweating. Other physical examination features may include
rales from alveolar edema, wheezing and prolonged exhalation from edema of bronchi and
bronchioles, compensatory
tachycardia, tachypnea, cool
extremities with delayed
capillary refill, weak pulses,
cough, cyanosis, diaphoresis,
and hypotension.  Pallor can be
present, particularly in the
peripheral extremities from
vasoconstriction compensating
for poor contractility to maintain
blood pressure.  Severe pallor,
particularly in preschool-aged
children as in the child in the
vignette, often suggests severe
anemia, most commonly from
iron deficiency, as the cause for
CHF (Table).
Myocardial dysfunction can be secondary to shock from other causes.  This dysfunction occurs from
some combination of circulating myocardial depressant chemicals related to inflammation and sepsis,
adrenergic receptor dysfunction, inadequate coronary blood flow to meet the heart’s own demands,
abnormal calcium flux, and myocardial edema.  Although most congestive heart failure results from
poor contractility of the ventricles, some patients (especially those with chronic ischemia or
hypertrophic cardiomyopathy) have diastolic dysfunction.  The heart cannot relax enough to allow
normal filling of the ventricle during diastole, and a higher filling pressure is needed for the same
stroke volume.  This fluid pressure is transmitted to the lungs and abdominal organs and leads to
pulmonary edema, hepatic congestion, and ascites.  At the same time, elevated diastolic pressures
within the ventricle can impair coronary blood flow, particularly to the subendocardial muscle, leading
to ischemia.  When the intensivist or cardiologist is evaluating a patient with signs of congestive heart
failure, both systolic and diastolic function should be assessed.

Cardiac output is a result of the preload, the afterload, myocardial contractility, and the heart rate. 
Each of these factors should be considered and optimized when treating patients with CHF or
cardiogenic shock.  It is also important to consider the Pao2 and hemoglobin (Hgb) because when
either of these is low, the heart has to increase its output to deliver oxygen to the tissues.  When the
myocardium is unable to contract more strongly, or when the heart failure is from sustained high
output due to anemia or left to right shunting, it becomes even more important to optimize Pao 2 and
Hgb.

The child in the vignette has a fairly short prodrome, leading to signs of heart failure decompensating
to cardiogenic shock (as evidenced by his abnormal neurologic examination findings). Administering
generous oxygen supplementation should increase his Pao 2 from slightly low (from pulmonary edema)
to a significantly higher value.  We do not know the child’s Hgb level, but one might guess it is very
low to have such severe CHF and pallor.  If one estimates the oxygen content of his blood, one might
guess the following:

(Hgb of 3 g/dL)(94%)(1.34 mL/dL of oxygen) + (Pao2 80)(0.003 mL/dL of oxygen) = 3.7788 + 0.24 =

4.0188 mL/dL of oxygen
(Note: some authors use 1.36 and some 1.39 for the 1.34 value.)

If one provides oxygen to increase the Pao2 to 400 mm Hg, one increases the oxygen content
significantly (30%):

(Hgb of 3 g/dL)(100%)(1.34 mL/dL of oxygen) + (Pao2 of 400 mm Hg)(0.003 mL/dL of oxygen) =

4.02 + 1.2 = 5.22 mL/dL

This increase in oxygen delivery to the tissues can support the patient while further diagnostic and
therapeutic interventions are considered.  There are essentially no adverse effects, and the procedure
can be performed rapidly.  Therefore, it is the best initial therapy for a patient with CHF.
Most children with shock have hypovolemic shock, and volume resuscitation is appropriate.  Even
patients with cardiogenic shock may benefit from judicious volume expansion, such as those with
diastolic dysfunction.  It is, however, likely that the heart is overstretched in this patient with CHF and
that giving more fluid will lead to worsening heart failure. The Frank-Starling curve (Figure) shows
how increasing preload (end-
diastolic pressure or volume)
can improve or worsen stroke
volume and cardiac output,
depending on where a patient
is on his/her own curve.

When one administers fluid to a

patient with suspected
cardiogenic shock, it is
recommended to use smaller,
5- to 10-mL/kg aliquots, rather
than the 20-mL/kg boluses
recommended for hypovolemic
and septic shock.  A dose of
250 mL is more than should be given to this 16-kg patient.  When fluid is given, the patient should be
closely monitored during the bolus and the fluids stopped should signs of deterioration occur.

A patient with CHF or cardiogenic shock may well benefit from increased inotropy, as would be
expected from beginning an epinephrine infusion.  However, one must also consider the other 3
contributors to cardiac output.  Venous constriction may occur with α-agonists, and preload may
increase (for better or worse).  Peripheral vasoconstriction may raise blood pressure but is expected to
increase afterload, which would likely worsen cardiac output.  The patient in the vignette also has
significant tachycardia, and the chronotropic effects of epinephrine or other β-agonists could shorten
the filling time of the heart, which may lower stroke volume and cardiac output.  Myocardial oxygen
consumption usually increases when epinephrine is administered.  A patient with very low oxygen
content and heart failure may develop myocardial injury from increasing oxygen demand from
epinephrine.  Increasing inotropy has the effect of raising the Frank-Starling curve at any level of end-
diastolic pressure, but a safer choice to achieve more contractility would be an inodilator, such as
milrinone, that does not increase heart rate or afterload.  Milrinone also has lusitropic effects, meaning
diastolic function is enhanced.  Stroke volume increases at the same left atrial pressure.  Both
improved lusitropy and reduced afterload have similar effects as inotropic agents to raise the Frank-
Starling curve at a given filling pressure.  The CHF of the patient in the vignette is more likely caused
by anemia and volume overload than from myocardial dysfunction.

Orotracheal intubation should be considered for any patient in shock, but the benefits must be
carefully weighed against the potential for harm.  Most agents used to sedate or anesthetize a patient
to tolerate intubation have negative inotropic actions that can worsen heart function.  The acute
changes in cardiopulmonary interactions of going from negative pressure ventilation to positive
pressure ventilation are often poorly tolerated, and some patients experience cardiac arrest during the
attempt.  Intubation may be necessary for the patient in the vignette if other measures do not
improve his physiologic state.  Positive pressure ventilation provides several benefits to patients with
CHF. Positive intrathoracic pressure reduces venous and lymphatic return to the thorax, which may
reduce preload to a better part of the Frank-Starling curve. Positive pressure ventilation may improve
oxygenation more than supplemental oxygen alone, thereby increasing oxygen delivery to the
tissues.  It may improve lung inflation.  If the patient with CHF has areas of atelectasis and edema,
pulmonary vascular resistance (right ventricular afterload) may be improved (reduced) by positive
pressure (however, further inflation above functional residual capacity will increase right ventricular
afterload).  Positive pressure ventilation reduces left ventricular afterload by reducing the pressure
differential from inside the ventricle and the outside.  These potential physiologic benefits can often be
obtained without orotracheal intubation by using noninvasive positive pressure breathing or simple
continuous positive airway pressure.

The patient in the vignette is probably very anemic as evidenced by pallor.  However, he is also icteric,
and his signs and symptoms have evolved over a fairly short time.  These findings suggest a
possibility of a hemolytic anemia.  Although it would almost certainly improve this patient’s condition
to increase the Hgb, the initial therapy should be administering oxygen while evaluating the cause of
anemia and sending the patient’s blood for type and cross-match.  The patient could have an
autoimmune hemolytic anemia and may not be able to be cross-matched.  In that case, supportive
care with oxygen along with immune suppression would be advised before attempting transfusion with
the most compatible blood. If the severe anemia is related to iron deficiency or aplastic anemia (such
as from parvovirus infection), transfusion while monitoring for signs of worsening congestion from
fluid overload would likely make the patient much better quickly.  Many would administer diuretics,
such as furosemide, while giving the transfusion to try to avoid worse myocardial overstretch.
Although some advocate very slow transfusion in this setting, larger volumes are usually well tolerated
and may reduce exposure to multiple blood donors.

American Board of Pediatrics Content Specification(s)

 Understand the pathogenesis of congestive heart failure

 Understand the pathophysiology of congestive heart failure
 Know the differential diagnosis of congestive heart failure
 Plan medical therapy for a patient with congestive heart failure
 Understand the effect of mechanical ventilatory strategies in congestive heart failure
September 2013 Question 6 Answer: C

Ammonia is produced in the colon by bacterial metabolism of fecal urea and is poorly detoxified by
patients with severe liver failure. Lactulose is a nonabsorbable disaccharide, consisting of fructose and
galactose, which is metabolized by bacteria in the colon. The primary product of metabolism is lactic
acid, along with smaller amounts of acetic and formic acid. In the resulting acidic environment ammonia
is converted to nonabsorbable ammonium ion, thus helping to avoid progressive hyperammonemia. Its
value is actually controversial, but its use remains quite common.

Lactulose has an osmotic effect, which increases stool water and promotes elimination of ammonia in
the stool. This is not, however, thought to be its primary mechanism of action. The goal of treatment is
to give sufficient lactulose to cause 2 to 4 liquid stools per day. Greater frequency and large-volume
stools risk fluid and electrolyte imbalances, usually dehydration and hypernatremia from massive free
water loss, and may complicate patient care.

Increased colonic acidity creates a hostile environment for gut bacteria, which may decrease bacterial
production of ammonia. However, this is not considered the primary mechanism of action. Decreased
bacterial production of ammonia is thought to be the primary mechanism of action for nonabsorbable
antibiotics, such as neomycin and rifaximin, when used for treating hepatic encephalopathy.

Some ammonia may be drawn into the colon from the splanchnic circulation.  However, this is not
considered a key mechanism of action.

American Board of Pediatrics Content Specification(s)

 Know the principles of treatment of hepatic failure

 Know the principles of management of encephalopathy in hepatic failure
September 2013 Question 7 Answer: C

The intubation of the child described in the vignette presents a significant challenge. His facial trauma
and associated bleeding prevent him from being able to lie down comfortably, most likely because of
blood collecting in his pharynx from his lip and nasal injuries. No approach to intubation will be easy,
but intubating him awake, perhaps in the operating room, thereby allowing him to maintain
spontaneous breathing and airway protective reflexes, is probably safest. Judicious sedation with a
benzodiazepine and narcotic will help minimize his pain and anxiety and the risk of lost protective
reflexes. Availability of good suction is essential to make it possible to identify airway landmarks. 

While awake he is able to protect his airway, but if anesthetized with an inhalational agent or IV
drugs, he is likely to aspirate blood. Moreover, in the presence of oropharyngeal blood, airway
landmarks may be obscured, making intubation difficult, and interference with spontaneous breathing
increases the risk of catastrophe. Bag-valve-mask ventilation will increase the risk of blood aspiration
and should only be used if his spontaneous respiratory effort is inadequate. In the presence of facial
fractures and facial instability, it may be difficult to achieve a good mask fit and effective ventilation.

Nasotracheal intubation is contraindicated in a child with nasal and maxillary fractures, as is likely in
this boy’s case, because the tube may take an unintended path into soft tissues or even into the
cranial vault because of the altered anatomy. Nasotracheal intubation is not recommended in a setting
of a basilar skull fracture. Although aerosolized phenylephrine may decrease or even stop the
bleeding, the anatomical concerns remain.

Although cricothyrotomy is an alternative, it is rarely necessary in a child able to protect his airway
and maintain effective breathing, and it will not provide a mechanism for ventilatory support. If awake
intubation cannot be accomplished, a primary tracheotomy (without an endotracheal tube in place)
would be preferable, although associated with significant risk of tracheal injury, because it would allow
manual or mechanical ventilation during the planned computed tomography. Another alternative might
be a laryngeal mask airway, although in an awake patient placement would likely be difficult and is
potentially associated with gagging and vomiting. It doesn’t protect effectively from gastric aspiration
but may minimize aspiration of blood and facilitate fiberoptic airway visualization and intubation.

American Board of Pediatrics Content Specification(s)

 Know the conditions in which nasotracheal intubation is safe

 Identify the conditions in which nasotracheal intubation is indicated or contraindicated
 Understand the advantages and risks associated with nasotracheal intubation
 Recognize the risks and difficulties associated with the intubation of patients with facial
lacerations
 Recognize the difficulties of using bag-mask ventilation in patients with oropharyngeal
bleeding, possible foreign body aspiration, facial burns, or anaphylaxis
September 2013 Question 8 Answer: B

Clonidine is a α2-adrenoreceptor agonist, acting both centrally and peripherally, that was initially
developed as an antihistamine a half-century ago and was subsequently found to be an effective
antihypertensive agent.  It is classified chemically as an imidazoline.  Other commonly used drugs in
this class include tetrahydrozoline and dexmedetomidine, which have similar toxicologic features. 
Most adverse events for drugs of this class have been associated with clonidine, however.

As alternative antihypertensive agents were developed, clonidine’s use for that indication has waned. 
However, clonidine has been increasingly used off-label for a wide variety of seemingly unrelated
conditions, including smoking cessation, alcohol withdrawal, opiate withdrawal, and management of
attention-deficit/hyperactivity disorder in children.  As a consequence, unintentional poisoning with
this agent appears to be increasing, particularly in children. 

Available dosage forms include tablets and a transdermal delivery patch, and serious poisonings have
been reported from both.  Severe intoxication in children may be seen with very small ingestions,
sometimes as little as 1 or 2 tablets of 0.1 mg for the typical toddler. Clonidine is rapidly absorbed,
and clinical findings typically appear within as little as 1 hour of ingestion.  Toxic manifestations
usually resolve within 24 hours.

Clinically, clonidine exposure mimics opioid poisoning,

with lethargy and coma being by far the most common
findings, reported in 87% of hospitalized children and
78% of hospitalized adults. Other findings in children are
noted in the Table.

In young children, the diagnosis of clonidine ingestion is

often known at presentation, as in the patient described
in the vignette.  Should this not be the case, the
manifestations of clonidine exposure are not sufficiently
characteristic to allow diagnosis on clinical features
alone, so the diagnostic problem generally becomes that
of determining the cause of coma.  There may be some
suggestive findings, however.  Clonidine exposure should
be considered a possibility in a patient whose
presentation is consistent with that of opiate ingestion.
Some patients (15%-40%) with clonidine poisoning
improve transiently after naloxone administration.  Many
children comatose even to the point of severe respiratory
depression exhibit a significant arousal with fairly minor
aversive stimuli, such as placement of an intravenous
catheter, but then quickly lapse back into coma when the stimulus ceases; the pattern is characteristic
enough that it should bring clonidine poisoning to mind. 

Laboratory data are neither helpful nor characteristic.  Clonidine is not detected in available toxicology
screens; concentrations in body fluids are extremely small in any case.  Measurement of clonidine in
blood or plasma is not generally available; some reference laboratories are capable of measuring
clonidine concentrations, but results would not be available for several days.  Mainly, diagnosis of
suspected clonidine poisoning depends on considering the possibility of exposure and then seeking a
history of ingestion.

Management of clonidine poisoning is almost purely supportive. As noted above, some patients may
respond to naloxone administration.  The mechanism of this effect is unclear because opiates and
clonidine act at different receptors.  Respiratory depression and apnea are managed with respiratory
support.  Patients with hypotension generally respond to intravenous fluid administration.  Dopamine
infusion has been effective in those who do not and is said to be superior to norepinephrine for this
purpose because of its chronotropic effects.  Atropine in usual doses is said to be effective for
bradycardia, and recovery can be expected within 24 hours.

American Board of Pediatrics Content Specification(s)

 Recognize the clinical and laboratory manifestations of clonidine intoxication

 Know the pathophysiology and toxic effects of clonidine intoxication
 Know the normal metabolism, excretion, and pharmacokinetics of clonidine
 Plan appropriate therapy for a child with clonidine intoxication
October 2013 Question 1 Answer: D

Thoracic trauma only affects about 7% to 8% of children presenting to trauma centers, and less than
1% have thoracic trauma without other injuries. The heart is directly affected by trauma in less than
3% of cases. Like the patient in the vignette, the majority of patients with thoracic injuries also have
head or abdominal injuries or significant musculoskeletal trauma.  Over 90% of pediatric thoracic
injuries are blunt injuries. Motor vehicle accidents are the most common causes of thoracic trauma,
with pedestrian-versus-vehicle strikes, bicycle accidents, and falls comprising the majority of the rest.
Severe cardiac injuries are a common cause of death at the scene. Most patients with cardiac trauma
also have other thoracic trauma, such as pulmonary contusions and rib fractures. Myocardial contusion
is by far the most common traumatic cardiac injury. Myocardial contusion can present similarly to
myocardial infarction, with impaired contractility or with dysrhythmias (both ventricular and
supraventricular), and, less commonly, with ruptured chordae tendineae and resultant valvular
regurgitation.  Fortunately, most myocardial contusions have limited clinical significance.  

Most patients with cardiac injury do not develop severe cardiac dysfunction. However, one must act
quickly to evaluate and treat cardiac issues when a patient has significant rhythm disturbances or
hemodynamic compromise early after the injury. If a patient does not have significant arrhythmias or
cardiac output (other than the volume replacement needs expected from concurrent injuries) within
the first several hours after injury, he is unlikely to develop such problems later. 

Computed tomography (CT) is commonly done to evaluate patients with traumatic injuries. CT of the
head, as performed in the vignette, is essential when there are abnormalities of mentation to evaluate
for intracranial injuries that might require neurosurgical interventions.  CT of the abdomen is
recommended when there is history or physical examination suggestive of possible abdominal injury
(particularly when mental status changes make the examination less reliable). CT of the chest may be
appropriate in selected cases. Chest CT reveals far more anatomic detail than is available with plain
radiographs of the chest. Most studies evaluating diagnostic imaging for intrathoracic injuries show
that CT is far superior to identify a variety of diagnoses, including pneumothorax, hemothorax,
pulmonary contusion, bony injuries, and major injuries to large blood vessels and airways. However,
CT scanning exposes patients to significant radiation and should therefore be reserved for cases in
which findings are likely to affect management. For patients without hemodynamic compromise,
identifying cardiac injury on CT is uncommon, and echocardiography is a better diagnostic choice.
Many of the abnormal findings on CT of the chest that are not seen on chest radiography are minor
and usually do not affect management. Outcomes generally are not different when minor injuries seen
on chest radiograph are elucidated by CT. Pulmonary contusions are already identified for the patient
in the vignette, and seeing them more clearly is not likely to affect management.

Troponin levels are good markers of myocardial injury. Elevated troponin levels can be seen as a
result of myocardial contusion but are frequently elevated in the absence of cardiac trauma when
there is significant head trauma. Troponin levels do not correlate with the severity of traumatic cardiac
injury and therefore do not add information that helps with management. Both left and right heart
contractility can be impaired from brain injury in the absence of cardiac trauma.

Echocardiography is the imaging modality of choice when evaluating for potential cardiac traumatic
injury. It can demonstrate pericardial effusion, myocardial dyskinesia, chamber rupture, and valvular
injury. Transesophageal echocardiography (TEE) is the best modality to evaluate injuries, including
dissections, to the ascending and descending aorta. TEE can be necessary when traumatic air leaks
prevent good transthoracic windows. Only about 5% of patients with cardiac injury have long-term
sequelae, most commonly valvular insufficiency and traumatic ventricular septal defects. In the
absence of clinical findings suggestive of cardiac injury, echocardiography is unlikely to find something
that requires specific management.

Although pericardial effusions are not common after blunt thoracic trauma, if a patient has clinical
signs of possible pericardial tamponade, such as tachycardia, narrow pulse pressure, distant heart
tones, liver enlargement, or jugular venous distension, one should perform echocardiography (or
emergent pericardiocentesis if the patient is hemodynamically unstable). 

PREP Pearls:

 Myocardial contusion is the most common cardiac traumatic injury but is usually of limited
clinical significance.
 Thoracic computed tomography infrequently leads to changes in management and should be
obtained only for specific reasons.
 Echocardiography, including transesophageal echocardiography, is the imaging modality of
choice when a patient has clinical evidence of impaired cardiac function after trauma.

American Board of Pediatrics Content Specification(s)

 Understand the pathogenesis of cardiac injury in trauma

 Understand the pathophysiology of cardiac injury in trauma
 Know how to diagnose traumatic cardiac injury
 Know the therapy (including indications for surgery) of cardiac injury in trauma
October 2013 Question 2 Answer: E

An intensivist must understand how atmospheric pressure, oxygen delivery methods, and gas exchange
at the alveolar level work together to affect arterial blood gases. The alveolar gas equation can be
expressed in many ways, but a common form of the equation is as follows:

Pao2 = Fio2 (Patm – Ph2o) – Paco2 (1 - Fio2 [1 –RQ])

                                                     RQ

This equation is used to estimate the partial pressure of oxygen in the alveolus (Pao 2). Fio2 is the fraction
of inspired oxygen. Patm is the atmospheric pressure. Ph 2o is the partial pressure of water in the
alveolus. Ph2o is generally estimated at 47 mm Hg at normal body temperature, even as ambient
pressures change. PaCO2 is the alveolar pressure of carbon dioxide.  In most settings there is good
equilibration between Paco2 and Paco2,the partial pressure of carbon dioxide in arterial blood. RQ is the
respiratory quotient. The respiratory quotient is the CO 2 exhaled divided by the O2 consumed. Although
RQ changes with diet, it is common to estimate this as 0.8, particularly given the lack of recent caloric
intake in the vignette.

A regular face mask to deliver oxygen should have gas flow of at least 5 L/min to flush carbon dioxide
from the mask that otherwise might be rebreathed. Even at more generous gas flows, it is hard to
exceed an Fio2greater than 0.4. A non-rebreather oxygen mask has valves to allow exhaled gas to leave
but prevents ambient air from being entrained into the inhaled gas. There is a reservoir of fresh gas that
allows the Fio2 to approach 1.0 with a good mask fit and seal. One can assume that the increased
Fio2 from about 0.4 to 0.8 should increase the Pao 2 by more than the decrease caused by the drop in
atmospheric pressure. Using the alveolar gas equation:

Pao2 at sending facility = (0.4) (700 – 47) – 65 (0.6) (0.2) = 251.25 mm Hg at FiO2 of 0.4
                          0.8

Pao2 at altitude = (0.8) (570 – 47) – 65 (0.6) (0.2) =  408 mm Hg at Fio2 of 0.8
                        0.8

One could consider positive pressure ventilation for this child. Either orotracheal intubation or
noninvasive ventilation could be used to reduce the work of breathing, increase the Fio 2, and possibly
improve ventilation. However, there are significant risks to this, particularly in a patient with
hyperinflation and wheezing. As the atmospheric pressure falls during this transport, gas-filled
structures will expand, including the air in poorly ventilated lung units and the stomach. Should the child
require positive pressure ventilation, one should place a nasogastric tube to prevent gastric distention.
Generous sedation is needed for intubation and, often, for noninvasive positive-pressure ventilation. It is
hard to pick ventilator settings that optimize ventilation without leading to dynamic hyperinflation.
Although the Paco2 is elevated, the pH is not so low as to necessitate mechanical ventilation because of
some metabolic compensation for what is probably chronic hypercarbia. The transport team should
certainly be closely monitoring the effectiveness of spontaneous breathing, providing oxygen and
bronchodilator medications and being prepared for urgent intubation.

If this child is transported by ground, the ambient pressure will never be lower than 599 mm Hg. The
benefits for gas exchange between this and 570 mm Hg are too small to offset the extra 3.5 hours of
mountainous road driving without the resources of a hospital. Personnel costs with long transports
increase such that helicopter transport may no longer be more expensive. The patient in the vignette
has enough potential for deterioration over the next few hours to warrant the more expeditious
transport.

One cannot perfectly estimate the change in Paco 2 as the elevation and ambient pressure drop. A
healthy person increases his ventilation as his Pao 2 falls, leading to a decreased Paco2 and respiratory
alkalosis, as demonstrated by the equation Pco 2 = Vco2/Va (production of carbon dioxide per
min/minute ventilation). The increased minute ventilation lasts only about 30 minutes, and as
Paco2 climbs back toward normal, the Pao2falls again. Over a few days, a person at high altitude
acclimatizes to that altitude, in part, by adjusting their ventilation to sustain Paco 2 levels far lower than
usual.  This allows for more “room” for oxygen in the alveolus of an acclimatized person. For the child in
the vignette with evidence of obstructive lung disease and no sustained exposure to high altitude,
should the Pao2 fall, her respiratory rate would likely increase, but given her obstructive lung disease,
that would not necessarily improve CO2 elimination. Her Paco2 may not change at all and is more related
to her metabolism and alveolar ventilation than to barometric pressure.

As shown earlier, the alveolar gas equation suggests that for the child in the vignette the

Pao2 at sending facility is (0.4) (700 – 47) – 65 (0.6) (0.2) = 251.45 mm Hg at FiO2 of 0.4
                                                                          0.8
Yet, the Pao2 is 62 mm Hg. This demonstrates a significant shunt or diffusion defect. If the shunt and
diffusion defects are static during transport, the effect of climbing in altitude from 2,400 to 8,200 feet
would make ambient pressure drop from 700 to 570 mm Hg, so without a change in Fio 2, RQ, shunt
fraction, or Paco2, the Pao2 would fall from 62 to 50.4 mm Hg. It is unlikely that all the variables would
stay constant during the flight.

PREP Pearls:

 Elevation in altitude reduces the partial pressures of oxygen and other gases but not of
obligatory water vapor pressure.
 The alveolar gas equation helps understand the effects of respiratory quotient, Fio 2, atmospheric
pressure, and Paco2 on alveolar oxygen levels.
 Regular oxygen masks cannot be relied upon to deliver over 40% oxygen.

American Board of Pediatrics Content Specification(s)

 Understand that patients rarely receive more than 40% oxygen effectively by simple masks
 Understand the principles of the use of a nonrebreathing mask
 Know the effect of altitude on partial pressure of gases in the alveolus
 Know how to use the alveolar gas equation
October 2013 Question 3 Answer: E

The patient described in the vignette has cystic fibrosis (CF) with severe pulmonary disease,
hepatosplenomegaly, hypoproteinemia, and thrombocytopenia. Cystic fibrosis is a relatively common
autosomal recessive condition, especially among the white population, and affects approximately 1 in
3,000 live births. First described in the 1930s, for decades it was almost universally fatal in childhood. 
With advances in care, the average life expectancy of a patient with cystic fibrosis is now into the
fourth decade of life. Although the most common serious, life-limiting problems experienced by
patients with CF relate to the disease’s pulmonary complications, it can cause severe hepatobiliary
disease. The most likely explanation for this patient’s hepatosplenomegaly and thrombocytopenia is
portal venous hypertension secondary to cirrhosis. Chronic portal hypertension from any cause often
results in hypersplenism, with splenic sequestration of platelets and leukocytes. While the majority of
patients with CF will develop some degree of hepatobiliary disease over the course of their lives, only
one-third or fewer will ultimately develop clinically significant liver disease. The more severe end of
the spectrum of CF liver disease is multilobular biliary cirrhosis (MBC) that may occur in a small
minority of CF patients and usually develops within the first decade of life. It is estimated that fewer
than 10% of CF patients will develop portal hypertension; there appears to be a male predominance
among these patients.

Hepatobiliary complications of CF range greatly in severity. Many patients with CF demonstrate gall
bladder sludge, experience cholelithiasis, or have steatosis. Less common complications include
cholangiocarcinoma and biliary cirrhosis, which can be either focal or multilobular. CF is caused by a
defect in the gene that encodes the cystic fibrosis transmembrane conductance regulator
(CFTR) protein. This gene is located on chromosome 7 and encodes a very large protein that localizes
to the apical surface of secretory and absorptive cells in many organs, including the airways,
pancreas, liver, intestines, sweat glands, and vas deferens. The unique regulatory domain
of CFTR serves as a cyclic adenine monophosphate (cAMP)–dependent chloride channel. The clinical
manifestations of CF are largely related to defects in the CFTR protein and subsequent inability of the
duct lumen in the affected organ system to hydrate macromolecules appropriately, resulting in
inspissation of viscous secretions and plugging of ductules, with resultant organ dysfunction.
Hepatobiliary disease in patients with CF, like manifestations in the other organ systems mentioned, is
related to defects in CFTR, causing inspissation of thick bile in the biliary ductules, periductal
inflammation, bile duct proliferation, and varying degrees of hepatic fibrosis. Currently, it is not clear
why severe liver disease and cirrhosis develop in only a minority of patients with CF. At least 1,500
mutations of CFTR have been described to date. While it appears that significant liver disease develops
almost exclusively in patients with CFTR mutations classified as “severe,” the relationship between
genotype and phenotype is not yet clear enough to use genetic testing to predict development of
serious hepatobiliary disease.

Clinically detectable hepatobiliary disease develops usually around the time of puberty and occurs with
a prevalence of approximately 15%. Progression to MBC occurs in only 5% to 7%. Based on studies of
adults with CF older than 40 years at the time of study, the prevalence of portal hypertension was
approximately 8%. Diagnosis of CF-related liver disease can be challenging.  Biochemical markers,
such as serum levels of transaminases, are notoriously unreliable and do not correlate with severity of

disease. Although liver biopsy with histology is critical to the diagnosis of MBC, this is made difficult by
the patchy, inhomogeneous nature of the disease. Radiologic imaging studies are important in the
diagnosis, with ultrasonography preferred as the primary, noninvasive screening test (Figure 2)
(Figure 3). Computed tomography may also be performed (Figure 4).  For more precise delineation
of intrahepatic or extrahepatic ductal lesions, magnetic resonance cholangiopancreatography (MRCP)
is preferred. 

Medical therapy for CF-related liver disease mostly consists of supplementation of pancreatic enzymes
and fat-soluble vitamins, excellent nutrition, and therapy with ursodeoxycholic acid.  Improvement in
hepatic and biliary function and nutritional status with ursodeoxycholic acid therapy has been
demonstrated in both children and adults with CF. Once liver disease has progressed to end stage with
serious portal hypertension, some surgical options are possible for treatment.  Transjugular
portosystemic shunt (TIPS) is sometimes helpful in management of portal hypertension.  In some
children with cirrhosis, portal hypertension, and splenomegaly, partial or full splenectomy has been
helpful in slowing the progression of portal hypertension and in slowing declining pulmonary function.
The organomegaly and ascites caused by cirrhosis and portal hypertension in CF exacerbate the
decline in pulmonary function in these
patients, as is the case for the child in the
vignette. The prognosis of CF patients who
develop MBC and portal hypertension is
poor, with some studies noting a mean
survival time of only 4 years without liver
transplantation. Several studies have
demonstrated acceptable outcomes after
liver transplantation in patients with CF,
sometimes demonstrating concomitant
improvement in pulmonary function as well
post-transplant. Thus, liver transplantation
has become the definitive treatment for patients with CF-related end-stage liver disease. A recent
study reviewed almost 200 recipients (148 children) of liver transplants for CF-related liver disease
and found a 5-year survival rate for those undergoing liver transplantation of approximately 86% in
children and 73% in adults. While these survival rates are inferior to those of patients undergoing liver
transplantation for other etiologies of liver disease, they compare quite favorably to the outcomes of
patients with CF-related liver disease who remained on the liver transplant waiting list. 

PREP Pearls:

 Biliary cirrhosis and portal hypertension are uncommon but severe complications of cystic
fibrosis (CF).
 Less severe hepatobiliary disease is common in patients with CF.
 Like disease manifestations in the lungs and other organ systems, hepatobiliary disease in CF
is the result of pathophysiology resulting from mutations in CFTR. 

American Board of Pediatrics Content Specification(s)

 Recognize cirrhosis and hepatic failure as complications of cystic fibrosis

October 2013 Question 4 Answer: C

Flexible fiber–optic bronchoscopy (FFB) is an invasive procedure used increasingly often in children for
diagnostic or therapeutic purposes. It
involves the passage of a flexible fiber–optic
bronchoscope through the nose or mouth
(ie, in a patient without an artificial airway)
or through an artificial airway for direct
inspection of the upper and lower airway
anatomy. Common indications for FFB are
listed in Table. Rigid bronchoscopy is
commonly used for removal of foreign body
or, in rare cases, removal of clotted blood.
An extension of FFB is the performance of
bronchoalveolar lavage (BAL), which
typically involves the instillation of sterile
normal saline in the airway for sampling of
distal airway secretions. Cytologic and
microbiologic analysis of the BAL fluid (BALF)
is then performed. BALF analysis may aid in
the diagnosis of certain conditions. 

BAL may be indicated in children in a number of instances:

1. Acute onset of respiratory distress with new diffuse interstitial or alveolar infiltrates on chest
radiograph; ideally, BAL should be performed before the institution of antibiotic therapy or in
children who do not improve despite antibiotic therapy 
2. Previous positive BAL diagnosis in patients who deteriorate despite institution of appropriate
therapy
3. Acute focal infiltrates that have not improved with broad-spectrum antibiotics within 48 hours
4. Investigation of etiology of respiratory failure in immunocompromised patients

While alveolar fluid samples are not usually obtained from healthy children, samples have been
obtained by numerous investigators from children undergoing bronchoscopy for reasons other than
lower respiratory infections (ie, children undergoing surgical procedures, evaluation of main bronchus
stenosis, stridor or foreign body aspiration follow-up, etc). It should be kept in mind that procedures for
the acquisition and processing of the BAL sample have not been standardized in children, and many
factors (ie, size of the bronchoscope, volume of saline instilled, dwell time, use of the first aliquot, and
the number of aliquots obtained) may affect the interpretation of the results obtained. Of note, the first
aliquot is typically of bronchial origin and may contain more neutrophils and fewer lymphocytes than
the other aliquots. 

The studies performed in children have

demonstrated with some variation that the
differential cell count in BALF in healthy children
is similar to that in healthy adults. The
predominant cellular component is the alveolar
macrophage (Figure) (over 80% of total cell
count [TCC]) followed by the lymphocyte
(approximately 9%–12% of TCC).  Neutrophils
comprise roughly 3% of the TCC in the BALF of
healthy children, while eosinophils account for
1% to 2% of the TCC. One difference between children and adults is the ratio of CD4/CD8 T lymphocytes,
with lower values found in children.  Erythrocytes are present in situations of alveolar hemorrhage. The
child in the vignette is expected to have predominantly alveolar macrophages in the BALF analysis. Type
II pneumocytes present in BALF are found in patients with acute lung injury, Pneumocystis
jirovecii pneumonia, drug-induced pneumonitis, or extrinsic allergic alveolitis. Increased concentrations
of T lymphocytes in BALF may be seen in hypersensitivity pneumonitis, Crohn disease, drug-induced
pneumonitis, interstitial lung disease associated with collagen vasculitis, and lymphoproliferative
disorders. A high concentration of eosinophils in the BALF (Figure) suggests an allergic etiology, such as
asthma, Churg–Strauss syndrome, allergic bronchopulmonary aspergillosis (ABPA), drug-induced
pneumonitis, interstitial lung disease, or acute eosinophilic pneumonitis and may also be present in
infections with bacterial, fungal (including Pneumocystis), or helminthic agents. High concentrations of
neutrophils in BALF (>3%) also occur with interstitial lung disease, as well as asthma, chronic bronchitis,
collagen vascular disease, or infections with bacterial or fungal agents. The presence of greater than
50% neutrophils in BALF is highly suggestive of acute respiratory distress syndrome, aspiration
pneumonia, or suppurative infection.

Noncellular components of BALF in healthy children are slightly different from those in adults. Technical
difficulties and lack of standardization of sample acquisition in children also affect the results obtained.
It is accepted that serum-derived proteins such as albumin and urea are present in higher
concentrations in the BALF of children as compared to adults. This may be due to higher alveolar–
capillary permeability in children or, simply, higher suction pressures from the smaller pediatric suction
catheters bringing in more protein. Mediators produced locally are similar in adults and in children, as
are the concentrations of fibronectin and hyaluronic acid. Younger children (3–8 years) have a higher
concentration of surfactant phospholipids than do older age groups. These differences may reflect a
maturational process of the lung or immune system in the pediatric population.

Provision of adequate sedation to the pediatric patient and performance of bronchoscopy by skilled
personnel in a monitored facility (with transcutaneous oximetry and resuscitation equipment) are
essential for the success of the procedure and to avoid complications. Bronchoscopy may be associated
with complications in approximately 5% to 6% of children. Minor complications (5% of patients) may
arise during the procedure (eg, excessive coughing, isolated desaturation, epistaxis, transient
laryngospasm, and reflex nausea) or after the procedure (eg, moderate or high fever, desaturation
requiring oxygen supplementation, and cough). Major complications occur in less than 2% of cases and
include significant desaturations from the procedure or are associated with sedation, pneumothorax,
laryngospasm, and bronchospasm.  Arrhythmias may also occur. In a small number of cases, retrieval of
foreign body via rigid bronchoscopy has been associated with vocal cord injury, tracheal laceration, or
subglottic edema.

On average, the performance of BAL increases the duration of bronchoscopy by 2 to 3 minutes. This
increases the risk of hypoxia and hypercapnia slightly. Most critically ill patients with stable
hemodynamic status tolerate the procedure well. There is a risk of the pulmonary infection spreading as
a consequence of the lavage, with the appearance of transient fever and, occasionally, development of
pulmonary infiltrates. Children with coagulopathies have a higher risk of mucosal bleeding. There are
reports of children with severe thrombocytopenia (platelet counts <20 × 10 3/ µL [20 × 109/L]) who have
undergone flexible bronchoscopy and BAL without complications. FFB has also been performed in
patients supported with extracorporeal membrane oxygenation (ECMO) without complications.
Bronchospasm may also occur in 1% of cases and may be avoided with premedication with
bronchodilators or the use of warmed saline.

PREP Pearls: 
  The macrophage is the predominant cell in bronchoalveolar lavage fluid (BALF) of healthy
children and adults (80%), followed by lymphocytes.
 Neutrophils comprise approximately 3% of cells in BALF of healthy individuals.
 The presence of greater than 50% neutrophils in BALF suggests acute respiratory distress
syndrome, suppurative pneumonia, or aspiration pneumonia.
 Bronchoscopy may be associated with complications in 5% to 6% of patients. Most
complications are minor (cough, isolated desaturation, epistaxis, nausea, transient
laryngospasm, fever), but major complications (significant desaturations, pneumothorax,
laryngospasm, and bronchospasm) may occur in 2% of patients undergoing bronchoscopy. 

American Board of Pediatrics Content Specification(s)

 Know the indications for bronchoscopy

 Know the acute complications associated with bronchoscopy
 Know the indications for bronchoalveolar lavage
 Know the acute complications associated with bronchoalveolar lavage
 Know the constituents of normal bronchoalveolar lavage fluid
October 2013 Question 5 Answer: D

The patient described in the vignette most likely has septic shock, as evidenced by a purpuric rash,
fever, and hypotension coupled with leukopenia and thrombocytopenia on his complete blood cell
count.  Further, the patient has clinical signs of reduced systemic vascular resistance (ie,
vasodilation), exhibiting a broad pulse pressure, diastolic blood pressure less than half of systolic
blood pressure, and warm extremities with a flushed, vasodilated appearance.  Finally, the child’s
hypotension persists despite appropriate and aggressive fluid resuscitation and low-dose dopamine
infusion.  In this setting, of the options available, institution of a norepinephrine infusion is the most
appropriate next step. 

It is true that in the most widely accepted clinical practice parameters for management of septic shock
in children, from the American College of Critical Care Medicine, dopamine is suggested as the first-
line agent as both an inotrope and a vasopressor.  However, in the case of a vasodilated patient who
has not responded to lower-dose dopamine, norepinephrine is a more appropriate choice for targeting
the patient’s pathophysiology than further increases in the dopamine infusion.  Recent data may
suggest that norepinephrine is a superior drug in any case for septic shock.  There is some indication
that dopamine administration is associated with increased mortality in shock, whereas a recent meta-
analysis concluded that norepinephrine is superior to dopamine for septic shock, with the major
outcome variable being mortality.  For younger children, dopamine may be inferior because a portion
of its vasopressor activity results from causing release of norepinephrine from endogenous stores,
which are incompletely developed in infants and young children. 

Adult guidelines for management of sepsis published in 2008 also recommend either dopamine or
norepinephrine as the initial vasopressor for management of hypotension in septic shock.  However,
the recommendation has been changed in the most recently updated version of the guidelines so that
norepinephrine is strongly recommended as the initial agent, with dopamine recommended for only
select patients.  Other published work has also questioned the appropriateness of dopamine as a first-
line agent.  The topic is still evolving, but at this point it would appear that the recommendation of
dopamine as a first-line inotropic/vasopressor agent has been based as much on familiarity and habit
as on evidence.

Although it is not one of the options given in the vignette, epinephrine might also be a possible choice
in this patient, combining inotropic and vasopressor activities, although its chronotropic properties
might argue against its use in a patient with considerable tachycardia.  Epinephrine is suggested as a
first-line vasopressor/inotropic agent in children with vasoconstricted (“cold”) shock but is regarded as
a second- or third-line agent in adults. 

Vasopressin is a non-catecholamine vasopressor that may retain effectiveness in catecholamine-

refractory septic shock (eg, patients who remain hypotensive despite fluid resuscitation and dopamine,
norepinephrine, or epinephrine infusion). Some work has suggested that vasopressin deficiency might
exist in septic shock.  A large comparison study found no difference in survival in adult patients
treated with norepinephrine vs vasopressin.  Vasopressin may be of use in catecholamine-refractory
septic shock but is considered second-line treatment in both adult and pediatric guidelines and
published reviews and meta-analyses.

Activated protein C is an anticoagulant and inflammatory modulator that showed initial promise as
adjunctive treatment for sepsis and was approved by the US Food and Drug Administration for that
purpose.  Use in children was limited because a randomized trial was halted because of excessive
bleeding.  Subsequent placebo-controlled trials revealed the drug to have no benefit in adults with
sepsis, and it is no longer available.

High-dose methylprednisolone in a placebo-controlled trial was found to provide no benefit in severe

sepsis and cannot be recommended.  Lower-dose hydrocortisone has been judged to be of possible
benefit in adults with catecholamine-refractory septic shock, although it is recommended only for
documented adrenal insufficiency in children.  Available data are limited and inconsistent, but some
studies have suggested benefit in restoring blood pressure and in mortality. 

Hemodynamic support for patients with septic shock must be individualized according to the
hemodynamic pattern of the patient receiving care.  The pattern described in the vignette, that of a
hyperdynamic, vasodilated circulation, is typical in adults and older children but not necessarily in
younger children and infants, who more commonly exhibit a picture of decreased cardiac output, cold
extremities, and increased systemic vascular resistance.  In such cases, a vasopressor such as
norepinephrine would be inappropriate.  Use of either milrinone or dobutamine, vasodilatory inotropic
agents, is typically suggested in such a scenario for both children and adults.  Use of dobutamine is
associated with significant tachycardia, increases in myocardial oxygen demand, and
proarrhythmogenic activity.

American Board of Pediatrics Content Specification(s)

 Recognize the manifestations of life-threatening complications of bacterial sepsis

 Plan appropriate therapy for a child with bacterial sepsis
October 2013 Question 6 Answer: B

There are nearly 2 million health care–associated infections (HAIs) reported every year in the United
States that result in 98,000 deaths. The vast majority of these infections and deaths are preventable.
Of note, the oft-cited Institute of Medicine report To Err is Human estimated that there are
approximately 98,000 deaths every year from medical errors. Importantly, HAIs were not included in
these statistics, which means there are nearly 200,000 deaths every year in the United States from
medical errors and preventable infections. Medical errors and HAIs, when considered together, would
be the third most common cause of death in the United States, behind only heart disease (almost
600,000 deaths per year) and cancer (approximately 570,000 deaths per year). 

Nosocomial urinary tract infections (UTIs) are one of the most common HAIs reported in the United
States and Canada. These infections have long been considered less important in terms of the
morbidity and mortality they cause when compared to ventilator-associated pneumonia (VAP) and
central line–associated bloodstream infections (CLA-BSIs). However, studies have shown that
nosocomial UTIs are associated with a threefold increase in mortality, as well as significant increases
in hospital length of stay and healthcare costs. In fact, it is estimated that CA-UTIs cause
approximately 13,000 deaths every year in the United States.

The most common risk factor for nosocomial UTIs is the presence of an indwelling urinary catheter (ie,
Foley catheter); that is, a catheter-associated urinary tract infection (CA-UTI).  Other commonly
reported risk factors include duration of catheterization, female sex, catheter insertion outside the
operating room, the presence of other devices, and the quality of catheter care.

According to the National Nosocomial Infection Surveillance System (NNIS), the incidence of CA-UTI in
the pediatric intensive care unit is 4.0 per 1,000 urinary catheter days. There are few studies
examining the impact of CA-UTI on critically ill children. Unfortunately, there are no studies comparing
different antibiotic treatment regimens for CA-UTI, so treatment is largely directed against the most
common offending microorganisms (Escherichia coli, Klebsiella, Enterobacter, Proteus,
and Pseudomonas). Here, as the saying goes, an ounce of prevention is worth a pound of cure.
Prevention of CA-UTI requires a multidisciplinary team focused on removing Foley catheters when they
are no longer necessary, using a closed drainage system, sterile insertion practices, and protocols for
catheter site care.

PREP PEARLS:

 Healthcare-associated infections are a significant problem in the United States.

 Catheter-associated urinary tract infections (CA-UTIs) are associated with increased length of
stay, increased mortality, and increased healthcare costs.
 The duration of urinary catheterization is by far the single most important risk factor for CA-
UTI.
American Board of Pediatrics Content Specification(s)

 Understand the natural history of infectious complications associated with the use of a Foley
catheter
 Know the appropriate evaluation for suspected infectious complications associated with the
use of a Foley catheter
 Know the appropriate treatment for infectious complications associated with the use of a Foley
catheter
October 2013 Question 7 Answer: D

Spinal trauma is a relatively rare, yet important, category of injury in pediatrics. Children account for
only 10% of spinal injuries, but represent 25% of the mortality rate. Unique anatomic and
developmental features place pediatric patients at risk for spinal injuries that are not typically seen in
adults. Unlike adult patients, there is little consensus on the most appropriate workup for pediatric
patients, and the practitioner must often use limited clinical data and weigh the risk and benefits of
various imaging modalities. Sixty percent to 80% of spinal injuries occur in the cervical region. Boys
are more likely than girls to experience spinal trauma. 76% of pediatric spinal cord trauma occurs in
children older than 8 years, with motor vehicle accidents (non–seat belted) as the most common
cause. It is the combination of large head size and relative flexibility of the spinal column that puts
children at risk for C-spine injury. The pediatric spine has a greater degree of flexibility and is able to
tolerate a significant amount of motion. The combination of underdeveloped paraspinal musculature
and relative laxity of the ligaments and joint capsule allows for the increased motion, which increases
the chance for subluxation. This laxity allows the pediatric spine to bend before it breaks and as a
result, children are more at risk for soft-tissue injuries and can experience injuries to the spinal cord
without any radiographic abnormality (SCIWORA), a term coined by Pang and Wilberger in 1982.

Plain radiographs are the most appropriate initial screening test for patients suspected of having spinal
trauma. The lateral C-spine view has the highest sensitivity for detecting cervical spine injury when
compared to other views using plain radiographs. Adding additional views such as the open mouth
odontoid view did not improve the sensitivity and caused a decrease in specificity. Studies have shown
that lateral and AP radiographs were able to identify 87% of C-spine injuries in patients younger than
9 years. The physician must be aware of pseudosubluxation that may occur in children where there is
an anterior displacement of the vertebrae. While this anterior displacement may be a normal variant,
any child with a history of trauma, pain in the cervical region, and an abnormal appearing radiograph
should be treated as if they have a real C-spine injury until proven otherwise.

Flexion–extension radiographs have been used to evaluate patients who were thought to have a
potential ligamentous injury. Typically, these patients have neurologic deficits with an obvious fracture
on traditional radiographs. Flexion–extension films are difficult to obtain, with up to 50% of adult
patients unable to undergo these views due to pain and muscle spasm. Patients with suspected
ligamentous injury and negative plain films should undergo a magnetic resonance imaging (MRI) or a
computed tomography (CT) scan.

Computed tomography scans are more accurate at identifying spinal injury when compared to plain
radiographs. Despite its superior characteristics, performing a CT on a pediatric patient involves
exposure to a considerable amount of radiation and is not a benign endeavor. The biggest risk is the
associated exposure to ionizing radiation and a linear association between this radiation exposure and
thyroid cancer later in life, with the highest association in children younger than 15 years of age.
While superior to plain radiographs in identifying bony injury, it should not be used to routinely clear
the entire cervical spine. Guidelines from the American College of Neurosurgeons state that “CT of the
C-spine should be used judiciously to define bony anatomy at specific levels, but it is not
recommended as a means to clear the entire cervical spine in children.” Providers should consider CT
with reformatted views if there is continued clinical concern for spinal injury after the initial
assessment. In children younger than age 5 years, ligamentous injury is more common than bony
injury. Although CT outperforms plain radiography to detect bony injuries, it is much less sensitive in
terms of detecting ligamentous injury. In summary, given the insensitivity of CT in detecting
ligamentous injury, the adequacy of plain radiographs, and the exposure to ionizing radiation, various
authors have suggested that CT plays a very limited role in the workup of pediatric patients with a
suspected C-spine injury. 
Magnetic resonance imaging is better than CT at identifying ligamentous or soft-tissue injury to the
cervical spine. Given the somewhat limited availability and need for sedation, MRI is not commonly
used as the first imaging modality to evaluate a pediatric trauma patient. In younger nonverbal
patients and in obtunded adults with suspected C-spine injury, it has been shown to be useful. One
study looked at MRIs that were obtained in obtunded patients or nonverbal pediatric patients who had
equivocal plain films, SCIWORA, or continued pain on clinical testing after 3 days of immobilization. In
the pediatric group, 66% had the initial diagnosis confirmed and 34% received a new diagnosis based
on the MRI. For the majority of pediatric trauma patients, MRI is not necessary, as plain radiographs
and the physical examination are used to identify or exclude the large majority of cases; MRI may be
helpful in patients in whom the examination is limited or the workup remains somewhat equivocal.

Typically patients arrive like the one in this vignette with spinal immobilization in place that was
started by the pre-hospital providers. Despite widespread prevalence of spinal immobilization
protocols, the science behind these protocols is somewhat limited. In 2000, a Cochrane Collaboration
systematic review looked at the role of spinal immobilization and found no connection between
immobilization and mortality, neurologic injury, or spinal stability. Despite the lack of evidence for its
use, it is standard practice to immobilize patients with suspected spinal trauma. Patients who have
their spine immobilized have an increase in pain and have been noted to have a diminished vital
capacity. Maintaining a neutral position in a child can be difficult because of the size of the child’s head
relative to the rest of the body. Up to 20% of pediatric patients placed in a spinal backboard had
greater than 10° of cervical flexion. While no low risk clinical criteria have been prospectively validated
in pediatric patients, if a patient is verbal, has normal neurologic examination findings, and lacks any
high-risk features, it is reasonable to remove the cervical collar without further testing. In patients
with pain on exam or higher suspicion of injury, plain radiographs should be the initial imaging study.
CT can be used to clarify any areas on the plain film that are concerning for bony injury; MRI is the
study of choice in patients who are obtunded or have abnormal neurologic findings or in any patient
with suspected ligamentous injury. There are adult clinical decision rules and tools such as NEXUS and
Canadian Cervical Spine Rule, but they were not designed specifically to evaluate pediatric patients.
The NEXUS adult criteria consist of 5 clinical high-risk features and include altered mental status,
intoxication, focal neurologic deficit, cervical spine tenderness, and distracting injury. If a trauma
patient has none of these risks, the sensitivity to exclude a spinal injury was 99%.
A lengthy discussion of medical management of SCI patients is beyond the scope of this question.
However, it should be noted that data from adult studies remain controversial with insufficient data to
support administration of methylprednisolone for treatment of traumatic SCIs. Randomized clinical
trials are needed in the pediatric population to assess advantages of steroid use after SCI in children.
The use of steroids in patients is controversial.

PREP Pearls:

 Cervical fractures are the most common type of pediatric spinal injuries.
 Plain radiographs are the most appropriate initial screening test for patients suspected of
having spinal trauma.
 Children with Marfan syndrome, achondroplasia, or Down syndrome have increased
atlantoaxial instability have an increased risk of cervical spine injury.

American Board of Pediatrics Content Specification(s)

 Recognize the syndrome of spinal cord injury without radiologic abnormalities (SCIWORA)
 Recognize the syndrome of spinal cord injury without radiologic abnormalities (SCIWORA)
 Plan basic supportive care for patients with spinal cord injury
 Recognize the characteristic clinical presentations of spinal cord injury
 Understand the role of high-dose methylprednisolone therapy in the treatment of spinal cord
injury
October 2013 Question 8 Answer: B

Patients allocated to the SBGX group who mistakenly received placebo were appropriately included in
the data analysis. This is called intention-to-treat (ITT) analysis, a methodology defined by the
inclusion of all randomized patients in the groups to which they were randomly assigned, regardless of
their adherence with the entry criteria, treatment they actually received, subsequent withdrawal from
treatment, or deviation from the protocol. In other words, ITT analysis includes every subject who is
randomized according to the randomized treatment assignment. It ignores noncompliance, protocol
deviations, withdrawal, or any other issues that occur after randomization. ITT analysis avoids
overoptimistic estimates of the efficacy of an intervention resulting from the removal of noncompliers
by accepting that noncompliance and protocol deviations are likely to occur in actual clinical practice.

Intention-to-treat analysis can be regarded as a complete trial strategy for design, conduct, and
analysis rather than as an approach to analysis alone. The Consolidated Standards of Reporting Trials
(CONSORT) guidelines on the reporting of randomized clinical trials states that full reporting of any
deviations from random allocation and missing response is essential in the assessment of the
necessity and appropriateness of an ITT approach and that the number of participants in each group
should be analyzed by the “intention-to-treat” principle. ITT analysis reflects the practical clinical
scenario because it admits noncompliance and protocol deviations. ITT analysis maintains prognostic
balance generated from the original random treatment allocation. It gives an estimate of treatment
effect that is free of investigator-induced bias and avoids potential problems caused by the exclusion
of noncompliant subjects or dropouts, which could create important prognostic differences among
treatment groups, especially if the noncompliance is due to an effect of treatment. ITT analysis limits
inferences based on arbitrary or ad hoc subgroups of patients in the trial and emphasizes greater
accountability for all patients enrolled in the study.

There are, however, arguments against the use of ITT analysis. When a subject who actually did not
receive any treatment is included as a subject who received treatment, noise is added to the signal
(eg, the effect of treatment) being evaluated. ITT analysis has been criticized for being too
conservative and, thus, more susceptible to type II error.

As outlined above, according to the ITT principle, patients allocated to the control group who
mistakenly received SBGX should not be excluded from the data analysis.  

The fact that a number of patients (approximately 10%) were excluded from the study prior to
randomization for legitimate reasons should not cast doubt on the validity of the results. Those
patients did not meet study criteria or were removed from eligibility by the treating physician prior to
randomization; therefore, the introduction of potential selection bias is minimized.
According to the Table, the
Sepsis-related Organ Failure
Assessment (SOFA) scores of
patients randomized to the
control group were
significantly lower than those
patients assigned to the SBGX
group. This unfortunate
imbalance places sicker
patients in the SBGX-treated
group and might influence the
final results since patients
with higher SOFA scores tend
to have worse outcomes
following severe sepsis.
However, should the SBGX
group have improved outcome, one could argue that these improved outcomes happened despite a
SOFA score disadvantage in the SBGX group. 
According to the Table, patients assigned to the SBGX group were older than those assigned to the
control group (45 ± 5 years and 42 ± 3 years, respectively). That difference, however, was not
statistically significant; therefore, one need not worry about a potential confounder caused by older
patients potentially having worse prognosis.

PREP Pearls:

 Intention-to-treat analysis (ITT) is a methodology that includes every subject who is

randomized in a study according to the randomized treatment assignment, regardless of
subsequent deviations from the protocol.
 ITT analysis maintains prognostic balance generated from the original random treatment
allocation.
 ITT analysis gives an estimate of treatment effect free of investigator-induced bias and avoids
potential problems caused by the deliberate exclusion of noncompliant subjects or dropouts.

American Board of Pediatrics Content Specification(s)

 Understand the use of intent-to-treat analysis