PREP ICU 2013 Answers and Critiques - 3 - May & June

May 2013 Question 1 Answer: E
A thorough understanding of the relationship between oxygen delivery (Do 2) and oxygen consumption
(Vo2) is essential to caring for critically ill infants and children in the pediatric intensive care unit
(Figure). Indeed, the state of shock, one of the most common and potentially life-threatening
reasons children require intensive care, is characterized by a relative imbalance between the delivery
of oxygen and the metabolic demands of the cells and tissues of the body. Under normal, resting
conditions, Do2 is more than adequate to meet the total oxygen requirements necessary for the cells of
the body to maintain aerobic
metabolism. If Do2decreases, for
any reason, the cells of the body
respond by extracting a greater
percentage of oxygen to preserve
Vo2. Similarly, during stress or
vigorous exercise, Vo2 notably
increases, as does Do2. In other
words, the metabolic demands of
the cells and tissues of the body
largely dictate the level of Do2.
Unfortunately, very little oxygen is

stored in the cells and tissues of
the body. During pathologic states, as Do2 decreases, the oxygen extraction ratio (O2ER) can initially
increase to keep Vo2 relatively constant; this is known as delivery-independent Vo 2. There is a critical
point of Do2 when the O2ER reaches its maximum capacity, known as the anaerobic threshold. Once
Do2 decreases below this level, Vo2 must also decrease and is now said to be delivery dependent. The
cells switch to anaerobic metabolism and lactate production increases significantly beyond this critical
point and may often be readily detected in the peripheral blood.
Experimental models of sepsis and clinical data from the 1980s suggested that a so-called pathologic
supply dependency existed in critical illness. In these studies, the critical O2ER was found to be lower
than normal during critical illness; that is, Vo 2 became delivery dependent at a higher critical Do2 in
critically ill patients. In the Figure, the Do2-Vo2 relationship (depicted by the solid red line) is shifted
upward and to the right, such that the critical Do 2 (labeled point B on the graph) is reached at a higher
Do2 than under normal conditions (ie, Do 2 at point B greater than Do2 at point A). Investigators at the
time believed that this observation implied an intrinsic defect at the cellular level in the O 2ER.
Unfortunately, most of the clinical data on which this concept was based are suspect because the
formulas for Do2 and Vo2 share common variables:
Do2 = CO × (Hb × 1.34 × Sao2) + (0.003 × Pao2) (Eq 1)

Vo2 = CO × (Hb × 1.34) × (Sao2 – Svo2) + 0.003 × (Pao2 – Pvo2) (Eq 2)
In the equations, CO indicates cardiac output; Hb, hemoglobin; Sao 2, arterial oxygen saturation; Svo2,
mixed venous oxygen saturation; and Pvo2, partial pressure of oxygen. The astute observer will
readily observe that the calculation of Do2 and Vo2 both share the measurements of CO and arterial
oxygen content (Cao2). The potential for computation error arises because the calculation of Do 2 and
Vo2 result in a mathematical coupling of measurement errors in the shared variables, resulting in a
false correlation between Do2 and Vo2. To get around this problem, subsequent clinical studies were
conducted that directly measured Vo2, which were unable to find any evidence of a pathologic supply
dependency. So, the clinical studies and experimental models were unable to be reconciled, and the
concept of a pathologic supply dependency has largely fallen out of favor. Regardless, during the
shock state, the body’s compensatory mechanisms and our therapeutic efforts are largely directed at
optimizing the balance between Do2 and Vo2.
The equation for Do2 (Eq 1) provides a lot of information about how to manipulate Do 2 in the clinical
setting. For example, Eq 1 clearly shows that the best way to optimize Do 2 is by augmenting CO (eg,
inotropic support) or increasing the Cao2 by transfusing packed red blood cells to increase the
concentration of hemoglobin in the peripheral blood. Unfortunately, cardiovascular physiology is not
this simple. Each vascular bed likely has its own regional Do 2 and Vo2. The effects of increasing global
Do2 based purely on the formula are therefore not likely to be replicated at the regional level.
However, knowing and understanding these concepts provide a useful framework and starting point.
Some other important concepts deserve mention here. The O2ER may be calculated as follows:
O2ER = (Cao2 – Cvo2)/Cao2 (Eq 3)
In this equation, Cvo2 is the venous oxygen content. Under normal conditions, the O 2ER ranges from
25% to 30%. Given the preceding discussion, this makes perfect sense! Under normal conditions,
more oxygen is delivered to the cells than is required to maintain normal Vo 2 (there is an excess or
oxygen reserve). As Do2decreases, oxygen extraction increases to maintain constant Vo 2 (delivery-
independent Vo2), until a critical point is reached (maximal oxygen extraction). A Cvo2 (or, in most
clinical settings, a low superior vena cava oxygen saturation or near-infrared spectroscopy) reflects a
high O2ER; this may be due to either low Do2 or an excessive Vo2.
Finally, as suggested, Vo2 can be used to approximate the CO using the Fick equation.
CO = Vo2/(Cao2 – Cvo2) (Eq 4)

American Board of Pediatrics Content Specification(s)
 Understand the determinants of oxygen content and delivery

 Understand tissue and systemic responses to acute and chronic oxygen deprivation
 Know how to estimate the adequacy of oxygen delivery
 Understand the concept of delivery-dependent oxygen consumption
May 2013 Question 2 Answer: D
The central venous waveform depicted in the vignette is most suggestive of regurgitant blood flow
across the tricuspid valve during ventricular systole. Analysis of the central venous waveform may be
helpful in identifying hemodynamic perturbations. Therefore, a clear understanding of the relationship
among the cardiac cycle, cardiac physiology, and the central venous waveform is essential for the
pediatric critical care physician.
There are 3 prominent waves identified on

the central venous waveform (Figure 2).
The first, and typically the most prominent
wave, is the a wave. This deflection
represents the increase in right atrial
pressure that occurs during atrial
contraction. It occurs near the end of
ventricular diastole and follows just after
the electrocardiogram P wave. Once the
atrium completes its contraction, the
pressure begins to descend and the a wave decreases until there is a slight bump upward. This
deflection upward is termed the c wave and corresponds to the isovolumic contraction of the right
ventricle. The wave is created when the increased right ventricular pressure is reflected upward
against the closed tricuspid valve, causing a small increase in right atrial pressure. The c wave occurs
at the end of the electrocardiogram QRS complex. Atrial relaxation continues, ventricular contraction
occurs, and pressure in the atrium continues to decrease. This decrease in pressure is reflected as a
downward slope in the central venous pressure (CVP) waveform and is termed the x descent. It occurs
before the electrocardiogram T wave. During the end of ventricular systole, blood from the vena cavae
begins to fill the right atrium and pressure rises as the tricuspid valve is closed. This increase in
pressure reflected in the CVP waveform is termed the v wave. The v wave is typically of lower
amplitude than the a wave. Once the atrium is filled, the tricuspid valve opens and there is a decrease
in right atrial pressure. This decrease in pressure is reflected as another downward slope in the CVP
waveform and is termed the y descent. It occurs before the P wave on the electrocardiogram.
Alterations in cardiac function may result

in abnormal venous pressures reflected
in the CVP waveform. Understanding
these alterations in the CVP waveform
may assist in diagnosis. For example, in
a child with significant tricuspid
regurgitation, the usual c wave and
decrease in atrial pressure associated
with isovolumic ventricular contraction
are significantly altered by regurgitant blood flow ejected across the incompetent valve. This
regurgitant blood flow lessens the x descent and produces a distinct positive wave during ventricular
systole. Because this wave occurs between the usual c wave and v wave, it is often termed a cv wave.
The resultant waveform mirrors that of the right ventricle (Figure 3).
The CVP waveforms may be useful in

diagnosing a number of other conditions;
however, none of the other conditions is
associated with the waveform presented in
the vignette. For example, in atrial fibrillation,
the a wave is not present. In addition, a
patient with complete atrioventricular
disassociation (third-degree heart block) will
have very large a waves termed cannon
waves (Figure 4). In this setting, atrial and
ventricular contractions are not synchronized.
Therefore, the atrium contracts against a closed tricuspid valve, resulting in a large, rapidly ascending
a wave. Large a waves may also occur in any situation where the right atrium is contracting against
high resistance, including tricuspid stenosis, tricuspid atresia, pulmonary valve stenosis, or pulmonary
hypertension. In constrictive pericarditis, the venous waveform may differ from normal in a number of
ways but should not result in the pattern presented in the vignette. Commonly, the a and v waves are
of the same magnitude.
 Know the normal components of the venous waveform

 Understand the effects of altered cardiac physiology on the central venous pressure waveform
 Understand the relationship between venous waveform components and ECG
 Recognize the alterations of venous waveforms secondary to dysrhythmias
May 2013 Question 3 Answer: A
Computed tomography (CT) with intravenous contrast is typically the initial imaging modality used in
the emergency department for significant blunt trauma or if a focused abdominal sonography for
trauma (FAST) examination has indicated free
fluid in a hemodynamically stable child.
Lacerations involving the liver and spleen and
evidence of a perforated viscus can be easily
visualized. For concerns about bowel or
pancreatic injury, however, a CT scan with
intravenous and oral contrast is preferred. The
use of both intravenous and oral contrast aids in
discerning organ perfusion, presence of free
fluid, and bowel integrity and
obstruction. Figure 4 demonstrates a CT scan
with oral and intravenous contrast of the child
described in the vignette, showing a large
duodenal hematoma obstructing gastric outflow.
Although able to demonstrate free

intraperitoneal air, plain radiographs lack both sensitivity and specificity for intra-abdominal injury. A
FAST examination is a bedside ultrasound evaluation of the right upper quadrant, left upper quadrant,
subxiphoid, and pelvis to look for free fluid and hemopericardium. It is useful in the initial phase of
emergent evaluation (secondary survey) and in the hemodynamically unstable child preparing for
emergent operative procedures for extra-abdominal injuries. The FAST examination lacks sensitivity
for bowel injuries; thus, a repeat FAST examination would not be helpful for this child. In a
hemodynamically unstable child with evidence of free intra-abdominal fluid or perforated viscus,
exploratory laparoscopy may be indicated. Although upper gastrointestinal fluoroscopy may
demonstrate small bowel obstruction, it would lack the specificity needed to develop a treatment plan.
The child in the vignette is clinically stable, making an exploratory laparoscopy an inappropriate next
step in his management.
Mortality associated with blunt abdominal trauma

depends on the number of structures injured and the
type of structure. There is less than 20% mortality for
isolated liver, spleen, and pancreatic injury;
approximately 20% if the bowel is injured and
approximately 50% if a major vessel is damaged.
Children have an increased risk of intra-abdominal
injury from blunt abdominal trauma because the impact
on the abdomen involves a relatively small surface
area, a child’s abdominal wall is less muscular and has less adipose tissue to protect its internal
structures, and the thoracic cage is more compliant than an adult’s, providing less protection for the
solid organs beneath.
Evaluation of blunt abdominal injury should incorporate the mechanism of injury, medical history, and
physical findings. The assessment is part of the trauma secondary survey. Understandably, in children
with coexisting head injury, the examination may
be less reliable. Physical findings concerning for
blunt bowel injury (BBI) include right upper
quadrant pain, progressive tachycardia, vomiting,
and presence of abdominal wall bruising, termed a
seat belt sign (Figure 1). In one study, children
with abdominal bruises were found to be 232 times
more likely to have an intra-abdominal injury, and
74% of the children who had significant intra-
abdominal injury also had abdominal bruising.
Injuries associated with BBI include seat belt sign,
heart rate greater than 120/min, free intra-
abdominal air, and presence of a Chance fracture.
BBI with duodenal hematoma occurs in 2% to 10% of children with blunt abdominal trauma. In
general, those with duodenal hematoma rarely need operative intervention. The mechanism of injury
involves compression (crushing) of the retroperitoneal duodenum against the vertebral bodies,
disruption and shearing of the submucosal and muscularis vessels, and increased intraluminal
pressure. Symptoms of obstruction appear 24 to 48 hours after injury (Figure 5).
A Chance fracture (Figure 6) is the

anterior compression of the
thoracolumbar or midlumbar
vertebrae with transverse fracture
through the posterior portion of the
vertebral body, caused by severe
forward flexion of the spine and
distraction injury of the posterior
elements. Although less common
with the advent of shoulder belts in
addition to lap safety belts, these
are seen in children who put the
shoulder portion of the belt behind
them, thus leaving only the lap belt
restraint. Approximately 40% to 50% of Chance fractures are associated with significant intra-
abdominal injuries, such as duodenal injury, pancreatic fractures, and mesenteric injury.
 Recognize external evidence of internal abdominal injury

 Know the indications for ultrasonography or CT scan in patients with abdominal trauma
 Interpret the results of radiographic evaluation in abdominal trauma
 Know that lacerations occur with blunt abdominal trauma
For the patient described in the vignette, the most compelling reason for open thoracostomy is the
presence of saliva or food particles in chest tube drainage, suggestive of esophageal injury. Such
injury is an indication for surgical management in the operating room to repair the injury and to
debride and irrigate to minimize the risk of mediastinitis. Mortality increases if there is a delay in
recognition and repair of esophageal injury. Water soluble esophagram or computed tomography
after esophageal contrast can help make the diagnosis of esophageal perforation.
Trauma is the leading cause of mortality in children older than 1 year in industrialized countries. In
one large trauma center, thoracic trauma occurred in 2.1% of cases from penetrating injuries and in
97.9% of cases from blunt trauma. Thoracic trauma was caused by pedestrian injuries in 38.3%,
motor vehicle collisions in 28.1%, motorcycle crashes in 19.9%, falling from height in 6.7%, animal-
related trauma in 2.9%, and sports injury in 1.2%.
Subtypes of penetrating Occurrence,

Injury %
pulmonary contusions 27.1
rib fractures 23.9
pneumothorax 23.7
hemothorax 18
hemopneumothorax 11.8
pulmonary lacerations 6.9
surgical emphysema 6.1
tracheobronchial injury 5.3
flail chest 2.5
diaphragm injury 2.1
Associated concurrent extrathoracic traumatic injuries are common, with head injuries in 38.9%, bone
fractures in 33.5%, and abdominal injuries in 16.7%. Chest tube placement is necessary in 50% to
60% of patients with thoracic trauma, but only a small percentage of these patients require operative
management. Patients may have severe injuries to large blood vessels or airways despite an initially
mild presentation, so careful monitoring and radiographic evaluation are necessary.
When a patient inhales, air may be entrained through an open chest wound. This is often called a
“sucking” chest wound. Such wounds rarely require surgical intervention beyond local irrigation and
wound closure and can be managed simply by the application of an occlusive dressing.
Most bleeding related to blunt or penetrating thoracic trauma is self-limited and does not require open
thoracotomy. Indications for surgery related to hemorrhage include a massive hemothorax of more
than 20 mL/kg or ongoing hemorrhage of more than 2 to 4 mL/kg/h.
Although a knife or other penetrating object may introduce infectious bacteria, it is more likely that
open debridement will cause harm than benefit. One should ensure that tetanus immunization is up
to date or provide a diphtheria-tetanus booster vaccination. The use of prophylactic antibiotics,
usually cefazolin, before placement of a thoracostomy tube is controversial, and the 2012 Eastern
Association for the Surgery of Trauma guidelines state there is not enough evidence to recommend for
or against the use of prophylactic antibiotics. Good antisepsis at the time of chest tube insertion and
evacuation of as much pleural blood as possible, sometimes requiring video-assisted thoracoscopy
(VATS) or a second chest tube, reduce the risk of pleural empyema. Pneumonia and empyema both
occur after thoracic trauma with or without the use of antibiotics.
Similar to hemorrhage, ongoing air leaks generally resolve without surgical management beyond chest
tube placement. If air leak is massive, such as a requirement for multiple chest tubes or an inability to
successfully provide ventilation to a patient receiving mechanical ventilation, a disruption of a major
airway must be considered, and open thoracotomy may be necessary. In this setting fiberoptic
bronchoscopy may be helpful to evaluate for and find the location of tracheobronchial injuries. If air
leak continues for 3 days, VATS is recommended to find and treat the cause of the leak. Management
of bronchial disruption may require contralateral mainstem intubation or a double lumen endotracheal
tube so the contralateral lung can be ventilated while awaiting surgical repair.
Other indications for surgery include concurrent penetrating injuries of the head, neck, and abdomen.
Hemothorax, pneumothorax, or both (hemopneumothorax) should always be suspected after blunt or

penetrating trauma, particularly when breath sounds are diminished. Other signs of hemothorax
include pallor and hypotension from blood loss. Large air collections can cause a mass effect,
compressing the vena cavae and inhibiting venous return to the heart. This leads to tachycardia,
hypotension, and death if untreated and is known as tension pneumothorax.
Resuscitative emergency department thoracotomy has a dismal outcome in children and is no longer
routinely performed. Survival approaches zero after blunt traumatic cardiac arrest at any point during
resuscitation and after penetrating traumatic cardiac arrest absent of signs of life in the field or in the
emergency department.
 Know the physical findings of traumatic hemothorax

 Know the physical findings of a traumatic tear of the major airway
 Plan the stabilization of a patient with a penetrating chest injury
 Recognize the risk of a "sucking" chest wound in the spontaneously breathing patient
 Plan the treatment of a patient with a penetrating chest injury
 Identify the situations in which immediate surgical intervention is required
In a trial, comparisons reveal differences in mean values of study parameters and assess the
likelihood that any differences found might have occurred by chance alone. For example, finding that
the probability of a difference occurring by chance is P < .05 tells the investigator that had he/she
performed the trial 20 times, it is likely that the observed difference would be found by chance in not
more than one trial. If the investigator uses a study design that offers more than one opportunity to
find a specific difference, interpretation of the likelihood of that difference having occurred by chance
must be adjusted for this advantageous study design. Examples of such adjustments include modified
interpretation of t values to interpret their implied P values (Bonferroni or Tukey test) and adjustment
to t values in the post hoc interpretation of analysis of variance (Newman-Keuls test) by t testing. This
allows a first determination as to whether significant differences exist, followed by adjustment
of p values to determine where those differences lie.
For example, in this trial, analysis of differences between glucose determinations in the 2 groups at
each point in time requires an adjustment for multiple comparisons. Each comparison (e.g., treatment
vs placebo at 15 minutes or treatment vs placebo at 30 minutes) represents a separate opportunity to
find a difference in that parameter attributable to treatment. If there were no effect of time, the
investigator would have multiple independent opportunities to conclude that there was a treatment
effect.
To do this, data for glucose determinations in the 2 groups are analyzed by repeated-measures
analysis of variance (ANOVA). This determination automatically takes into account numbers of time
points, numbers of patients in each group, and so on.
The investigator may then ask, if and only if the test result is positive, whether the difference at each
point in time is significant. At what times did the effect of the treatments differ? This analysis is
termed a post hoc test because it is valid only if the ANOVA result is positive. To perform this test, the
investigator must compare values at baseline between groups by the t test. For this trial, there would
be 5 separate t tests, one at each time. Were there no effect of time, this would represent 5 separate
opportunities to find a difference unlikely to be a random finding. Each test must then be adjusted for
multiple comparisons to account for this special opportunity to find a difference (Newman-Keuls test).
The other comparisons cited do not require adjustments for multiple comparisons. The analysis of
mean age of patients in each group is a simple comparison of one characteristic of each group.
Changes in cortisol, potassium, calcium, and insulin from baseline at 60 minutes into infusion each
represent a single data point for each patient. Although there are 4 different tests on each patient,
none of thes is given a special opportunity to prove significant. This is again a t test without
adjustment for multiple comparisons. To compare racial profiles between the groups requires a
χ2 analysis that incorporates a measure of degrees of freedom to compensate for the several races
represented.
 Understand the limitations imposed when making multiple comparisons in data analysis
May 2013 Question 6 Answer: E
The child described in the vignette has a number of risk factors for invasive pulmonary aspergillosis,
namely, diagnosis of acute myelogenous leukemia (AML), neutropenia, and use of immunosuppressive
agents, including corticosteroids. The computed tomographic (CT) findings in this case are typical of
invasive aspergillosis (IA), so it is crucial to institute therapy as early as possible. The primary line of
therapy in this case is voriconazole. A randomized controlled trial demonstrated a higher survival rate
and improved responses of initial therapy with voriconazole when compared with deoxycholate
amphotericin B. Therefore, primary therapy with amphotericin B is not recommended.
Although one should maintain a high index of suspicion for infection with Pneumocystis jiroveci in the
immunocompromised host, the CT revelation of cavities or nodules makes the possibility of pneumonia
due to P jiroveci unlikely; therefore, sulfamethoxazole-trimethoprim is not the primary therapy. Typical
tomographic findings of pneumonia due to P jiroveci include ground-glass patchwork pattern (most
common) or an interstitial pattern.
The galactomannan index of greater than 0.5 is also highly suggestive of IA. Current recommendations
for IA also include reduced dosage or removal of corticosteroid therapy.
There are approximately 250 species of Aspergillus, but only about 20 cause disease in
humans. Aspergillus fumigatus accounts for 80% to 90% of the cases that cause disease in humans,
followed by Aspergillus flavus. Aspergillus spores measure 2 to 3 µm in diameter, allowing them to
reach as far as the terminal airways and alveoli when inhaled. Humans inhale hundreds of conidia or
spores a day, but only some individuals will develop disease, dependent primarily on their immune
status.
IA results when Aspergillus conidia are able to circumvent immunologic surveillance mechanisms and
germinate into hyphae that invade contiguous tissues or spread hematogenously.
Normally, Aspergillus spores that are inhaled are quickly phagocytized and destroyed by macrophages
with additional immunity provided by neutrophils. IA is mainly a disease of immunocompromised hosts
and occurs in patients with neutrophil or macrophage dysfunction (chronic granulomatous disease or
severe combined immunodeficiency), long-term high-dose steroid use, patients with cancer or
neutropenia as a result of chemotherapy, those infected with human immunodeficiency virus, or after
stem cell transplantation, mostly in the preengraftment stage or in graft-vs-host disease. In the
pediatric population, AML and allogeneic bone marrow transplantation have been identified as risk
factors. Profound and prolonged neutropenia seems to be the major risk factor for developing IA.
The most common sites of primary infection are the lungs, the sinuses, and the skin. Invasive pulmonary
aspergillosis (IPA) is the main form of IA. In as many as one-third of cases, hyphae invade the pulmonary
vasculature after inhalation of Aspergillus conidia. Spread may occur via contiguous extension or
hematogenous dissemination to organs such as the liver, spleen, kidneys, bone, heart, or thyroid.
Despite the use of broad-spectrum antibiotics patients may present with fever, cough, chest pain, and
hemoptysis. Patients receiving high-dose steroids who develop IA frequently do not present with fever,
requiring a high index of suspicion by the clinician to make an accurate diagnosis.
Diagnosis of IPA involves imaging studies, serologic testing, and immunologic testing. A normal chest
radiograph does not exclude the diagnosis of IPA and may be present even in patients with advanced
disease. Chest radiograph may reveal multiple nodules or consolidations. Most patients with IPA have
focal infiltrates and at least 1 macronodule that may or may not have a halo sign on chest CT. The halo
sign occurs early in IPA and represents hemorrhage and coagulation necrosis surrounding nodules that
contain the hyphae. If appropriate treatment is not instituted, these lesions coalesce, forming
consolidations or cavitations. Once treatment is instituted or neutropenia resolves, the air crescent sign
(lung necrosis around the fungal mass) may be detected on CT. With the continuation of treatment and
with time, these areas decrease in size and eventually are transformed into small scars.
The European Organization for Research and Treatment of Cancer/Invasive Fungal Infections
Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group
Consensus Group published revised definitions of invasive fungal disease in 2008. On the basis of their
revised definitions, the presence of 1 of 3 CT findings is suggestive of probable IPA: (1) dense, well-
circumscribed lesion with or without the halo sign; (2) air-crescent sign; and (3) cavitation.
Proven IA involves histologic demonstration of tissue invasion by fungal hyphae consistent

with Aspergillus or a positive culture from a specimen obtained from a normally sterile site. Probable IA
requires fulfillment of criteria in 3 categories: host factors, clinical manifestations (signs, symptoms, and
radiologic criteria), and microbiological evidence.
In critically ill patients who are hemodynamically unstable, who are severely hypoxemic, or who have
coagulopathy, it may not be feasible to obtain specimens via invasive procedures (needle aspiration or
tissue biopsy). Other markers of infection are then used. In addition to the radiologic signs (halo and air
crescent sign), the detection of galactomannan via enzyme-linked immunosorbent assay (G-EIA) has
been reported to be a surrogate of detection of IA. It has a high sensitivity in patients with neutropenia
but is less sensitive in nonneutropenic patients, possibly because of the presence of anti-
Aspergillus antibodies or a reduced fungal burden in these patients. False-positive results for G-EIA may
occur in patients receiving certain antibiotics (amoxicillin-clavulanate and piperacillin-tazobactam) and
in patients with other invasive mycoses (histoplasmosis, blastomycosis, and Penicillium). False-negative
test results occur. The combination of serum galactomannan antigen and CT findings suggestive
of Aspergillus infection allow early detection and initiation of therapy, which is critical in high-risk
patients. There has been a parallel increase in cases of invasive Aspergillus infection and in the number
of immunocompromised hosts. The case fatality rate for IA in children is higher than 50%.
The Infectious Diseases Society of America guidelines for treatment of IA include the following:
1. Early initiation of antifungal therapy in patients with strongly suspected invasive aspergillosis is
warranted while a diagnostic evaluation is conducted.
2. The primary line of therapy for IA is voriconazole, either in the oral or intravenous formulation.
The intravenous route should be used in critically ill patients.
3. An alternative therapy for IA involves the lipid formulation of amphotericin B in some patients.
4. Routine combination antifungals for primary therapy are not recommended.
5. Salvage therapy agents include the lipid formulation of amphotericin B, posaconazole,
itraconazole, caspofungin, or micafungin.
6. Consider the addition of granulocyte colony-stimulating factor or granulocyte-macrophage
colony-stimulating factor to those patients who are neutropenic.
7. Withdrawal or reduction in the dosage of corticosteroids is often crucial for successful outcome
in IA.

 Recognize the common clinical manifestations of invasive Aspergillus infection
 Plan treatment for a patient with Aspergillus infection
In the patient described in the vignette, left ventricular afterload will most likely decrease. During
spontaneous inspiration the diaphragm descends, the rib cage expands, and lung volumes increase,
augmenting the diaphragm’s recoil tension. These movements make both pleural and juxtacardiac
pressures more negative (subambient). This process increases venous return to the right atrium (RA)
from extrathoracic veins according to the following equation:
Venous return = (Pms – Pra)/Rvr
where Pms is the mean systemic pressure of the circulation (considered the inflow pressure driving
blood toward the RA), Pra is the right atrial pressure (the back pressure that opposes inflow to the
RA), and Rvr is the resistance to venous return.
Transmural pressure is the pressure difference from the inside to the outside across a hollow
structure. During spontaneous inspiration, pleural pressure and juxtacardiac pressure both become
more negative (subambient). Pra decreases but not as much as juxtacardiac pressure. Therefore, RA
transmural pressure increases. Also during spontaneous inspiration, systemic venous return to the RA
increases because of the decrease in Pra. End-diastolic volume rises. The pressure in the RA
approximates that in the right ventricle (RV) during cardiac filling, so the RV also experiences an
increase in transmural pressure. Spontaneous inspiration results in an increase in RV stroke volume
because of increased venous return, whereas spontaneous expiration produces the opposite effect.
The increased venous return to the right side of the heart during spontaneous ventilation shifts the
intraventricular septum toward the left, diminishing the compliance of the left ventricle (LV).
Decreased LV compliance tends to cause a decrease in LV stroke volume.
In a similar fashion to the RV, the decrease in juxtacardiac pressure during spontaneous inspiration
results in an increase in LV transmural pressure. LV afterload is dependent on the transmural
pressure. LV afterload may be increased by increases in arterial blood pressure or by a decrease in
pleural pressure. During spontaneous inspiration, aortic pressure may decrease slightly, but pleural
pressure decreases more; therefore, aortic and LV transmural pressure and afterload increase. This
increase in LV afterload acts to decrease LV stroke volume.
Arterial pressure normally decreases during spontaneous inspiration. This appears to be due to the
increase in LV transmural pressure and afterload at a point during the respiratory cycle that
ventricular interdependence restricts LV filling.
Compared with spontaneous ventilation, inspiration during positive pressure ventilation (PPV)
produces opposite effects on pleural, juxtacardiac, and RA pressures. During PPV, inspiration increases
all 3 pressures. PPV inspiration or application of positive end-expiratory pressure may increase
juxtacardiac pressure to a level that the wall tension required to open the aortic valve is lowered, thus
reducing the afterload of the LV. This may result in an increase in LV stroke volume, increasing cardiac
output and arterial pressure. Wall stress is determined by the equation:
σ = P × r/2h
where sigma is wall stress, P is transmural pressure, r is ventricular radius, and h is ventricular wall
thickness. SVR contributes to LV afterload as does LV wall stress. Although LV afterload is decreased
with PPV, systemic vascular resistance (SVR) generally remains unchanged.
PPV, especially during inspiration, increases the juxtacardiac pressure around the RV. This might
reduce RV transmural pressure except for simultaneous compression of the pulmonary blood vessels,
which produces an increase in RV transmural pressure that counteracts the effect of the increased
juxtacardiac pressure. Excessive compression of the pulmonary blood vessels by PPV may impede RV
ejection, resulting in RV dilation and shifting of the septum toward the left. Decreased LV compliance
tends to cause a decrease in LV stroke volume.
Passive expiration during PPV restores pleural, juxtacardiac, and right atrial pressures toward their
values at functional residual capacity, which should be the same as during spontaneous respiration
when no end-expiratory pressure is applied. However, during PPV mean pleural pressure is higher
than during spontaneous respiration. PPV decreases systemic venous return as it increases mean Pra.
When lung disease is present and pulmonary compliance is reduced, the percentages of pressure
transmission from the mechanical ventilator to the pleural and the juxtacardiac spaces are decreased
in proportion to the decrement in pulmonary compliance.
The predominant cardiopulmonary interaction of PPV may depend on the pathologic state present. So,
if a patient is hypovolemic, the influence of PPV on RA pressure and venous return may dominate and
result in a decrease in stroke volume and cardiac output. Alternatively, if significant LV dysfunction
exists, the afterload reducing effects of PPV may prove most important and result in an increase in LV
stroke volume.
Furthermore, patients with systolic dysfunction are subject to the interactions between spontaneous
breathing and the heart because atrioventricular afterload is elevated at baseline secondary to
upregulation of intrinsic catecholamines and the renin-angiotensin-aldosterone system. In addition,
pulmonary compliance is decreased and the work of breathing is elevated, and the oscillations in
pleural pressure are exaggerated. The reduced right-sided heart volumes that result from PPV may
improve cardiac performance in the failing heart with improved ventriculoventricular interactions. PPV
helps to unload respiratory muscles, thus deceasing work of breathing and the load on the heart. In
addition, PPV would help to decrease the negative intrathoracic swings in spontaneously breathing
patients with heart failure.
During PPV higher intrathoracic pressures and lung volumes also increase the pulmonary vascular
resistance (PVR). At volumes above FRC, alveolar capillary vessels become stretched, resulting in
increased PVR. RV afterload increases because of the augmented PVR, resulting in decreased RV
output independent of RV filling. Alveolar pressure causes greater reduction in flow at low pulmonary
artery pressures than at high pulmonary artery pressures. So pulmonary hypertension damps this
cardiopulmonary interaction, whereas hypovolemia accentuates it.
 Understand the effects of breathing (spontaneous or mechanical) on arterial blood pressure

and heart rate
 Understand the differential effects of spontaneous and positive airway pressure breathing on
the transmural pressure of the intrathoracic vessels and heart chambers
 Understand the differential effects of spontaneous and positive airway pressure breathing on
pulmonary and systemic arterial blood flow
The most likely cause of the illness in the patient described in the vignette is celiac crisis, which is a
rare presentation of celiac disease, more common in children than in adults. Patients with trisomy 21
are at increased risk of developing celiac disease. Celiac crisis is far less common than in the past,
most likely because of the increased awareness of celiac disease as a possible cause of diarrhea
and/or failure to thrive and improved diagnostic screening tools, specifically anti–tissue
transglutaminase IgA antibody. It is caused by an inflammatory response to the ingestion of gluten,
which leads to intestinal mucosal injury. Small intestine biopsy reveals villous atrophy of varying
degree.
Although celiac crisis most commonly occurs in patients with known celiac disease after either
intentional or inadvertent ingestion of gluten, it may be the initial presentation of the disorder. It is
characterized by diarrhea, often explosive and voluminous but usually not bloody, and may be
associated with electrolyte abnormalities and fluid losses sufficient to cause hypovolemic shock.
Hypokalemia is common, despite associated profound acidosis, and is the likely cause of this child’s
electrocardiographic findings, weakness, and diminished deep tendon reflexes. Hypoproteinemia is
also common and may represent previously unrecognized protein malabsorption in addition to acute
losses. Related physical findings are edema and abdominal distension with ascites. Abdominal
radiographs typically reveal dilated loops of bowel and evidence of free peritoneal fluid. Iron deficiency
anemia is common. This child’s low weight for height may reflect previous poor growth in addition to
third-space and acute diarrheal fluid losses. Severe celiac crisis may not respond to usual supportive
care, even if enteral intake is completely withheld. In these patients corticosteroids may be required in
addition to a gluten-free diet.
Clostridium difficile colitis is a common cause of diarrhea, usually after treatment with antibiotics
and/or admission to the hospital. There may also be an association with the use of proton pump
inhibitors. The organism is commonly acquired during hospitalization, and approximately 30% of
patients who acquire the bacterium develop diarrhea. Different strains of the organism produce 2
different toxins: toxin A is an enterotoxin, and toxin B is a cytotoxin. Both are associated with
development of mucosal inflammation and damage. It has become one of the most common hospital-
acquired infections. Most patients have mild-moderate diarrhea, but others, particularly elderly
patients, infants, and children with significant comorbid conditions, may develop severe disease,
including toxic megacolon, associated with the development of shock and the risk of death.
Colonoscopy may reveal pseudomembrane formation. The diagnosis is made by identifying the
bacterial toxin in the stool and not by culture. The negative stool cultures obtained from the child
described in the vignette do not exclude the possibility of this disorder in this child, but her history
lacks the major risk factors. Symptoms commonly include watery diarrhea (rarely bloody), crampy
abdominal pain, anorexia, malaise, and fever, especially in severe cases. Lower abdominal tenderness
with rebound should raise concern for toxic megacolon and/or intestinal perforation. Although fluid
and electrolyte imbalance is common, it is rarely associated with profound hypokalemia and
hypoproteinemia or microcytic anemia. Use of antibiotics should be discontinued if possible. Treatment
with metronidazole or enteral vancomycin for 10 days is recommended; evidence suggests that
vancomycin is superior in severe disease with more rapid effect and fewer treatment failures. Relapse
is fairly common. Oral fidaxomicin administered every 12 hours for 10 days may provide results
comparable to vancomycin.
This child is hyperglycemic and acidotic, but lacks ketones in her urine, and her electrolyte panel
demonstrates a nongap metabolic acidosis. Although a gastrointestinal infection might be the
precipitating event for onset of juvenile diabetes mellitus, the degree of hyperglycemia and the
absence of ketones make that diagnosis very unlikely in this patient. Of note, patients with diabetes
mellitus are at increased risk of developing celiac disease. Her hyperglycemia is most likely related to
stress, and perhaps intake of glucose-containing fluids. Administration of insulin might be appropriate,
particularly if hyperglycemia does not respond to volume resuscitation, but it will not treat the primary
disorder. The role of glycemic control in children generally remains uncertain.
Hemolytic-uremic syndrome is characterized by hemolytic anemia, thrombocytopenia, hematuria, and

renal insufficiency. It is typically preceded by 5 to 10 days with an episode of infectious, frequently
bloody, diarrhea caused by a specific strain of Escherichia coli (O157:H7), which elaborates a
verotoxin. The toxin causes generalized endothelial damage and platelet activation, which results in
microthrombi and thrombocytopenia. The toxin binds to the glomerular endothelium and inactivates
ADAMTS13, allowing formation of von Willebrand factor multimers. Platelet activation and
microthrombi formation partially obstruct small vessels and cause hemolysis. In most patients
hemoglobin concentration is less than 8 g/dL (80 g/L), and platelet count is less than 80 × 10 3/µL (80
× 109/L). Treatment is supportive with renal replacement therapy as needed. In the absence of central
nervous system involvement, plasmapheresis or plasma exchange is probably not indicated. Most
patients recover, but end-stage renal disease develops in 8% to 10%, and the mortality rate is 5% to
15%.
Ulcerative colitis usually presents after the first decade of life (and rarely in children younger than 2
years, although cases have occurred in infancy) with insidious diarrhea, abdominal pain (often
crampy), and rectal bleeding. Systemic signs include anorexia, weight loss, fever, and anemia. A small
percentage of patients (approximately 10%) have a severe initial presentation with frequent bloody
stools, abdominal distension and diffuse tenderness, fever, tachycardia, leukocytosis,
hypoalbuminemia, and anemia. The most severe complication is toxic megacolon, which is associated
with fever, tachycardia, hypokalemia, hypomagnesemia, hypoalbuminemia, and dehydration or shock.
Colonic dilatation may lead to perforation, gram-negative sepsis, and hemorrhage. The patient
described in the vignette would be very young to have ulcerative colitis and has not had
hematochezia, fever, or leukocytosis. Her abdominal radiographs reveal small bowel distension, not
colonic dilatation, and no free air is described. Colectomy is indicated in ulcerative colitis when
symptoms of severe colitis persist after more than 2 weeks of aggressive therapy, complications of
long-term corticosteroid or other therapy become unmanageable, or there is massive hemorrhage or
complications of toxic megacolon or perforation, none of which would apply to the patient described in
the vignette.
 Recognize the risk of celiac crisis in patients with gluten sensitive enteropathy
 Know the basic management of celiac crisis
 Know the life-threatening complications of ulcerative colitis
 Recognize the colonic perforation in ulcerative colitis as a cause of peritonitis
 Recognize the history and physical findings associated with ulcerative colitis
 Know the pathogenesis and pathophysiology of hemolytic-uremic syndrome
 Know the association of hemolytic-uremic syndrome with E. coli :0157
June 2013 Question 1 Answer: C
Of the many adverse outcomes experienced by the patients in the vignette, the young man who died
of a pulmonary embolism after pelvic fracture is the one whose family is most likely to be successful,
should they choose to sue for medical malpractice. In this case the omission of recommended deep
venous thrombosis prophylaxis can be cited as negligent and contributed to a fatal pulmonary
embolism in a patient at high risk (albeit there is much controversy about the use of
thromboprophylaxis in children).
Unfortunately, despite excellent training, best intentions, and hard work, most physicians will be sued
for malpractice during their careers. Approximately 40% of suits occur in the absence of identifiable
injury or medical error. These suits usually do not lead to monetary settlements. Intensive care
physicians are at higher risk for malpractice than primary care physicians because of the complexity of
care and likelihood of significant morbidity and mortality in their patients. The most effective tool for
minimizing both the risk of malpractice suits and for successful defense in the event of such a suit is
provision of both excellent physician-patient (physician-family) communication and excellent
documentation. Such documentation should include informed consent before procedures. It should
also include the rationale for clinical decisions and orders. It is also well described that an immediate,
sincere apology when a mistake or adverse event happens reduces the chance of a lawsuit.
Medical malpractice is defined slightly differently from state to state but can be generally defined as
the provision of care that is not within the standard of practice in the community in question. Such
care can include negligent, unskilled, improper, unethical, or inappropriate treatment. Malpractice can
only be claimed if harm occurs to the patient as the result of substandard care. Common reasons for
a medical malpractice lawsuit include the following:
1. Failure to diagnose a condition or a delay in diagnosis (in pediatrics, missed meningitis or

missed fractures are common issues)
2. Adverse events not discussed adequately during the informed consent process
3. Failure to consult others in a timely manner
4. Negligent use of medications (wrong drug, wrong dose, wrong indication, omission of
recommended prophylaxis)
5. Failure to provide and document informed consent
6. Negligently performed procedures
The National Practitioner Data Bank (NPDB) was established by the US Congress as a confidential
information clearinghouse aimed at improving health care quality by requiring licensing and
professional organizations, hospitals and other health care organizations, medical malpractice payers,
and others to report payments in medical malpractice cases against physicians and dentists, as well as
any adverse actions in licensure, privileging, or professional society membership. It was established
by the Health Care Quality Improvement Act of 1986. One purpose of the NPDB is to restrict the
ability of a physician to move from state to state without full disclosure of adverse malpractice claims
or licensing and privileging actions. If a medical malpractice claim against a physician results in
payment to the plaintiff, that information is provided to the NPDB. Such adverse actions against a
physician as revocation or suspension of a state license, revocation of clinical privileges, and several
other categories of negative findings must be reported to the NPDB. The NPDB is maintained
confidentially by the US Department of Health and Human Services and can be queried by state
licensing authorities, hospitals and other health care organizations, professional societies, and, with
some restrictions, a plaintiff’s attorney.
The child with status epilepticus develops a known but rare adverse effect of a medication
(fosphenytoin) that is approved for and commonly used to treat seizures. During emergency
treatment, as for status epilepticus, one is not obligated to go through an informed consent process.
Although the family of this child certainly may decide to sue for malpractice, the child’s critical illness
coupled with the fact that the child experienced a known adverse effect of appropriate use of a
potentially life-saving medication make successful litigation unlikely. The patient with septic shock on
aggressive support is at high risk of dying. There is no information given to suspect that the death
was related to a medical error of commission or omission. Again, these facts do not necessarily mean
that a family will not pursue legal action but certainly mitigate against such action’s chances of
success.
It would be common to discuss the risks of pneumothorax, catheter-associated infection,

thromboembolism, and hemorrhage in an informed consent process before central venous catheter
placement in the subclavian or internal jugular vein. Unintentionally letting go of the wire during
insertion is clearly a procedural mistake but is rare enough that most would not include it on their list
of possible adverse consequences. In addition, if the wire was successfully removed in the
catheterization laboratory, there would not be significant harm to the patient, as would be required for
a malpractice claim. It would, however, be advisable not to charge for the care related to this
complication.
The anasarcous infant requiring emergency surgery for bleeding related to a lacerated intercostal
artery during chest tube placement had an emergency condition requiring prompt life-saving needle or
chest tube thoracotomy. Laceration of an intercostal artery is a known complication of this
procedure. Despite efforts to avoid the artery by sliding over a palpable rib, in a patient with severe
edema, palpation of landmarks may be challenging. In the setting of emergencies, it is inappropriate
to jeopardize the patient’s life by waiting to obtain informed consent. Indeed, delaying such
treatment could be cause for a malpractice claim.
 Know the definition of malpractice

 Recognize the components of malpractice in clinical practice
 Appreciate the importance of appropriate ongoing patient-physician communication, especially
as it relates to malpractice issues
 Understand how chart documentation affects the defensibility of malpractice claims
 Understand the types of information reported to, stored, and released by the national
physician data bank
 Understand the limitations of written informed consent
 Understand the limitations of the legal system in patient physician interactions
June 2013 Question 2 Answer: E
Indications for endotracheal intubation vary, depending on the nature of the physiologic abnormality
and the aspect of ventilation that is compromised. Each of the patients described in the vignette may
require intubation, but the one meeting commonly accepted criteria at this time is the 14-year-old boy
with absent airway protective reflexes. He is at immediate risk of aspiration of oral or gastric contents.
In addition, he has a low Glasgow Coma Scale (GCS) score (2 for eye opening, 1 for vocalization, and
most likely 4 for motor), although the value of this scale in the setting of alcohol intoxication without
apparent head trauma is not clear.
The child with bilateral pneumonia clearly has abnormal respiratory function with an increased alveolar-
arterial oxygen difference and a mild respiratory acidosis, but although her respiratory rate is slightly
elevated and her intercostal retractions reflect some increased work of breathing, most clinicians would
allow her to continue to breathe spontaneously until her Pao 2 is less than 60 mm Hg (oxygen saturation
as measured by pulse oximetry <90%) on 60% oxygen or her work of breathing is more clearly
unmanageable. Although many texts recommend intubation when Paco 2 is greater than 50 mm Hg,
common practice in most intensive care units today base decisions to intubate on a combination of
elevated Paco2 and clinical indication of respiratory fatigue.
Patients with hemodynamic instability may require intubation and respiratory support to minimize
respiratory work when cardiac output is inadequate and to decrease the risk of cardiac arrest. The 4-
year-old boy might well have been intubated at presentation, depending on the severity of his shock,
but he has responded to fluid resuscitation and initiation of vasopressor therapy. He has a moderate
metabolic acidosis with a partially compensating respiratory alkalosis, but oxygenation, ventilation, and
pH are all in an acceptable range. He is still somewhat vasodilated with a slightly increased pulse
pressure. The potential for deterioration remains.
The boy with head trauma has a GCS score of 11 (3 for eye opening, 4 for vocalization, and 4 for motor).
Current recommendations regarding endotracheal intubation in this setting vary, but most regard a GCS
below either 8 or 10 as a threshold for endotracheal intubation. He has intact airway protective reflexes,
is well oxygenated (>100 mm Hg as often recommended in the setting of brain injury), and is maintaining
effective ventilation (mid 30s) so that increased cerebral blood flow from hypoventilation is unlikely.
Further swelling may well occur and be associated with progressive deterioration, so close attention to
his neurologic status and possible future need for intubation to ensure adequate oxygenation and
ventilation and prevention of secondary brain injury is essential.
Patients with neuromuscular disease and progressive weakness of respiratory muscles lose the ability to
take a sigh breath to open small areas of atelectasis or cough effectively to clear mucous and other
airway debris. Gradually, their largest breath (vital capacity) decreases to be similar to their tidal
volume. Eventually tidal volume also decreases, initially requiring an increased respiratory rate to attain
adequate minute ventilation and finally decreasing to be insufficient to allow alveolar ventilation at all.
Until atelectasis occurs, oxygenation is not significantly compromised, and ventilation is maintained until
weakness is profound. Measures of respiratory reserve, including negative inspiratory pressure and vital
capacity, provide more information about the child’s respiratory capacity than blood gases. An
inspiratory pressure more negative than −20 cm H 2O and vital capacity greater than 12 to 15 ml/kg are
usually considered adequate. The child described in the vignette has only mildly decreased oxygenation,
most likely from a minor degree of atelectasis, and is still ventilating adequately. Moreover, her negative
inspiratory pressure is more negative than the commonly accepted threshold for intubation (−20 cm
H2O), and her vital capacity is greater than 15 ml/kg, which suggests that she still has sufficient
respiratory reserve to maintain aeration and clear her airway spontaneously.
 Recognize the neurologic indications for intubation of a child who has ingested a central nervous
system depressant
 Understand that intubation may be indicated despite good respiratory function, as in the case of
head trauma or increased intracranial pressure
 Know that intubation may be indicated prior to the onset of respiratory failure in patients with
muscle weakness
 Know that hemodynamic instability may necessitate intubation prior to the onset of respiratory
failure
 Know that failure of airway protective reflexes may necessitate intubation even when
respiratory function is adequate
 Know the components of the Glasgow Coma Scale
June 2013 Question 3 Answer: D
Information in the vignette enables one to calculate the volume of distribution (Vd) for the drug in
question. Vd does not describe an actual physiologic volume. Rather, Vd represents a proportionality
calculation that relates the total amount of drug in the patient’s body to the plasma concentration and
is expressed in terms of volume (liters) or, more appropriately for pediatrics, liters per kilogram of
body weight:
Vd (L/kg) = Dose (mg)

Plasma Drug Concentration (mg/L or μg/mL) X Body Weight
By way of illustration, if after intravenous administration the drug had somehow been retained
completely inside the vasculature, the Vd would have been that of circulating blood volume, usually
estimated as 0.08 L/kg. However, drugs are distributed into other sites after administration. For the
patient in the vignette:
Vd = 500 mg = 50 L/kg

1 mg/L X 10kg
So, the Vd for this patient indicates that this drug appears to be distributed in a volume equal to 50
times the patient’s body mass. Obviously, this is not possible, and the calculation instead reflects that
the drug is distributed less into the blood volume than to other body sites.
So the question posed becomes, “What is the most likely explanation for a very large Vd such as 50
L/kg (roughly comparable to that of some commonly used drugs, such as amiodarone and digoxin)?”
Drugs with large Vd must be bound to sites outside the circulation, most commonly tissue proteins. In
addition, drugs that are highly lipid soluble will distribute into fat stores and brain, thus leading to a
large Vd. Drugs that are polarized or highly water soluble tend to remain in the blood and the
extracellular fluid and thus have a small Vd.
Drugs may also bind to plasma proteins; drugs that are weak acids bind to albumin, whereas basic
drugs will bind to α1-acid glycoprotein. However, drugs that bind to plasma proteins tend to be
retained in the circulation and thus have a small Vd.
Hepatic conjugation and other aspects of the metabolism and excretion of drugs have little direct
relationship to Vd, although a drug that is water soluble might be more likely to undergo unaltered
renal excretion and have a small Vd.
Vd has several implications for drug therapy. Because Vd describes the relationship between drug
dose and plasma concentration, it would provide a way to calculate dose based on desired
concentration. For drugs that have a large Vd, extensive drug distribution into tissues creates a
reservoir of drug that will slowly be released after drug administration is stopped, possibly prolonging
the effects of the drug. Vd is variable among patients and even for the same patient over time and
can be affected by factors that include obesity, age, nutritional status, and disease states.
These calculations are in simplified form, although a form that is commonly used. More properly, the
plasma concentration that should be used is that at time zero, which assumes that the drug is
instantaneously administered and instantaneously distributes throughout the body, with no elimination
of the drug before measurement of plasma concentration:
Vd = Dose
Cp0
where Cp0 is the plasma concentration at time zero. In clinical situations, this is not feasible, so that
Cp0 is estimated by measuring drug concentration at some time after administration (typically, 30-60
minutes) and then extrapolating backward to time zero.
 Understand the volume distribution and role of fat solubility in drug distribution
 Understand the effect of protein binding on the volume of drug distribution
The patient described in the vignette has a history of hypertrophic cardiomyopathy (HCM) and presents
with signs of congestive heart failure and pulmonary edema. HCM is one of a spectrum of lesions that
can produce left-sided heart obstruction. Lesions that result in left ventricular (LV) obstruction can be
divided into those that obstruct LV filling and those that impede LV emptying. Lesions may be congenital
or acquired. Congenital lesions that impede LV filling include pulmonary venous hypoplasia, the
membrane and embryonic remnants of cor triatriatum, and mitral valve stenosis. Acquired left-sided
obstructive lesions that impede left-sided filling include tamponade from pericardial lesions (including
effusions, pneumopericardium, and pericarditis), cardiac tumors, or mediastinal lesions (including
noncardiac tumors). LV outflow may be impeded by lesions of the ventricular septum (asymmetric
septal hypertrophy), subaortic stenosis, valvular aortic stenosis (AS), supravalvular AS, HCM, and lesions
of the aortic arch, including coarctation of the aorta. HCM causes dynamic obstruction to LV outflow
unlike the other lesions, which tend to cause fixed obstruction. Acquired LV outflow tract (LVOT)
obstruction is uncommon in children, but aortic dissection may result in such obstruction. Because of
the wide variety of lesions that cause LVOT obstruction, patients may present at any age with symptoms
ranging in severity from mild to life-threatening. Critical AS usually presents in infancy with LV failure
and acute shock. Such neonates are dependent on the ductus arteriosus for systemic blood flow. HCM
tends to be diagnosed in late childhood or adolescence.
LVOT obstructive lesions often share important physiologic features. LV obstruction results in increased
LV afterload because the LV must work harder to generate a pressure adequate to overcome the
increased resistance created by the obstruction (eg, aortic valve and subaortic obstruction). With normal
stroke volume the pressure necessary for ejection depends on the severity of obstruction. An important
cardiac compensation to outflow obstruction is LV hypertrophy, which helps to maintain normal LV
stress despite elevation in peak systolic pressure based on the Laplace relationship:
Wall Stress = Pressure × Radius/2 × Wall Thickness
However, a hypertrophied LV working against an increased afterload results in large myocardial oxygen
demand, and LV subendocardial ischemia and infarction may occur in children with LVOT obstruction
due to coronary blood flow that is inadequate to meet this demand. The cardiac ischemia may be made
worse when diastolic pressure is low because the driving force for coronary perfusion is reduced.
Because intramyocardial compressive forces are greatest in the subendocardium and the
subendocardium is the final distribution of the coronary arteries, the subendocardium and papillary
muscles are the myocardial regions most vulnerable to ischemia. In patients with HCM, dynamic LVOT
obstruction may be made worse when systemic arterial pressures decrease, causing a decrease in
ejected stroke volume and further compromising coronary perfusion. Therefore, use of systemic
vasodilators in this setting is unwise.
Heart rate (HR) is an important determinant of myocardial oxygen supply and demand. Tachycardia
leads to shortening of systolic and diastolic periods. With tachycardia, the LV must eject during a shorter
period, LV systolic pressure increases, and therefore myocardial oxygen demand is increased. The
diminished diastolic period results in decreased ventricular filling time and, hence, decreased end-
diastolic ventricular volume. Another effect of the shortened diastolic period with tachycardia is a
decrease in coronary perfusion because coronary perfusion of the LV occurs during diastole. The
negative effects of tachycardia are especially important in HCM because faster HRs tend to worsen
dynamic LVOT obstruction. In addition, because of the dynamic nature of the obstruction and the
decreased LV compliance caused by hypertrophy, it is essential to maintain LV volume. Therefore,
judicious volume loading may be acutely beneficial.
LV obstruction may result in increased left ventricular end-diastolic pressure and left atrial pressure,
pulmonary venous congestion, and pulmonary artery hypertension. Functional obstruction of the mitral
valve impairs pulmonary venous blood flow from the left atrium into the LV. Left atrial, pulmonary
venous, and capillary pressures rise. The net exchange of capillary water into the interstitial and alveolar
spaces occurs when the hydrostatic pressure gradient exceeds that of plasma oncotic pressure. At the
same time, pulmonary lymphangiectasia, resulting from increased venous and lymphatic hydrostatic
pressure, leads to decreased reabsorption of interstitial fluid, resulting in pulmonary edema and pleural
effusion. Fluid collection eventually impairs gas exchange, and pulmonary vasoconstriction may arise. In
addition, congested bronchial veins compress bronchiolar airways, increasing airway resistance.
LVOT obstruction may also result from cardiac tamponade. Cardiac tamponade may result from a
number of insults, including postcardiotomy inflammation, trauma, mediastinal tumors, other malignant
tumors, rheumatologic diseases, and infection. Normally, the pressure in the pericardial sac
approximates that of the intrapleural pressure and so is negative compared with atmospheric pressure.
When fluid collects in the pericardium, the pressure rises, but the increase depends on the rate of fluid
collection. When fluid collects slowly, the pericardium can expand to accommodate comparatively large
volumes. As pericardial pressure rises the cardiac chambers become compressed, diminishing venous
return and also equalizing mean diastolic pericardial and cardiac chamber pressures. So although the
intracardiac pressures are elevated, the transmural pressures approach zero or negative pressures,
further decreasing preload. Rising pressures obstruct venous return and cardiac filling, leading to the
Beck triad (pulsus paradoxus, a quiet precordium, and distended neck veins). Shock may ensue with
severe obstruction. Maneuvers that worsen the obstruction (eg, positive pressure ventilation) may be
poorly tolerated.
Patients may present with a range of findings, including evidence of shock, congestive heart failure,
pulmonary congestion, pulmonary hypertension, or even complete cardiovascular collapse. Patients may
have pulsus paradoxus due to decreased LV filling during inspiration. Findings specific to the disease
process (eg, lupus pericarditis) may also be present.
Electrocardiogram (ECG) abnormalities in LVOT obstruction will depend on the lesions. Many patients
will have voltage criteria for LV hypertrophy, but this may be a rather insensitive measure of the severity
of obstruction. The presence of LV hypertrophy with ST-segment depression is rather concerning for the
presence of myocardial ischemia. The ECG of patients with tamponade may show electrical alternans or
decreased voltages, and evidence of myocardial ischemia may be present.
Medical therapy for LVOT obstruction includes trying to ensure adequate preload and, when critical
obstruction is present, immediately addressing the primary lesions with cardiac surgery or interventional
cardiology procedures.
 Understand the pathophysiology of tamponade

 Recognize the risk that hypotension poses to the myocardial status of a patient with critical
valvular obstruction
 Understand the pathophysiology of left heart obstruction
 Know the signs and findings of left heart obstruction
 Know the initial medical therapy for critical left heart obstruction
 Know the effects of systemic hypertension on obstructive lesions on the left side of the heart
 Know and recognize specific disorders causing left heart obstruction
June 2013 Question 5 Answer: D
Indications for the use of neuromuscular blockers (NMBs) in the pediatric intensive care unit (PICU)
include the following: facilitation of procedures or diagnostic studies, immobilization during
interhospital transport, facilitation of mechanical ventilation, control of increased intracranial pressure,
elimination of shivering, decrease of peripheral oxygen utilization, decrease in the risk of pulmonary
vasospasm in patients with pulmonary hypertension, and treatment of patients with tetanus. Paralysis
after the administration of an adequate dose of a nondepolarizing NMB is progressive. Initially, the
small muscle groups (eyelids, facial muscles, and finger muscles) are affected, followed by the
medium to large muscle groups (tongue, mastication muscles, extensor and flexor muscles of the
limbs, shoulder, and neck) and then the abdominal muscles. Ultimately, the special muscle groups are
paralyzed: intercostals, larynx, and diaphragm (which has a large number of acetylcholine [ACh]
receptors). On recovery from NMB blockade, the diaphragm is the first muscle to regain function.
Normal neuromuscular transmission results from the release of ACh from the nerve terminal, its
movement across the synaptic cleft, and its subsequent binding to the postsynaptic nicotinic receptor
on the sarcolemma of the skeletal muscle. NMBs are described as being depolarizing or
nondepolarizing, depending on their effect on the motor endplate. Succinylcholine is the only
commonly used depolarizing relaxant. The binding of succinylcholine to the ACh nicotinic receptor on
the motor endplate causes membrane ionic channels to open in the same manner as ACh, which
explains the initial rigidity seen in patients receiving succinylcholine and perhaps the myalgia they
experience on awakening. The drug then remains bound to the receptor for several minutes, and thus
the membrane remains depolarized and unable to contract again. The short duration of action of
succinylcholine is due to its hydrolysis by butyrylcholinesterase (plasma or pseudocholinesterase),
which is synthesized in the liver.
Nondepolarizing NMBs are large, bulky, highly ionized, water-soluble drugs that contain 1 or 2
quaternary ammonium groups, making them unable to cross lipid membranes easily. The
nondepolarizing agents competitively bind to the a-units of the ACh receptor and prevent the flow of
ions. They may also physically block the ion channel at the motor endplate and thus inhibit ion flow to
trigger the muscle to contract. This competitive inhibition depends on the concentrations and the
binding characteristics of the individual agent. There are 4 routes of elimination of nondepolarizing
agents: renal, hepatic, biotransformation, and tissue binding. Currently available nondepolarizing
NMBs include pancuronium, vecuronium, rocuronium, pipecuronium, mivacurium, atracurium, cis-
atracurium, and doxacurium.
Monitoring of patients who have received NMBs may include some combination of visual, tactile, or
electronic means of measuring residual neuromuscular function after electrical stimulation. A useful
monitor of blockade effect is the train-of-four (TOF) device (4 stimuli are administered during 2
seconds), which delivers an electric current (2 stimuli per second for 2 seconds) to a peripheral nerve
and allows the operator to assess the degree of neuromuscular blockade visually. The nerves most
commonly used are the facial, ulnar, or common peroneal, which results in corresponding movement
in the muscles of the face, hand, or leg. In some circumstances, direct stimulation of the muscle may
occur, giving the false impression that an appropriate amount of neuromuscular blockade has not
been achieved. To avoid such problems, it is important to place the TOF monitor and assess the twitch
response before the administration of the initial dose of the NMB. No study has evaluated the best
nerve to monitor.
Depending on the number of ACh

receptors that are occupied by the
NMB, 0 to 4 responses (twitches) can
be seen. Stimulation of the ulnar
nerve in a patient not receiving an
NMB with TOF testing evokes 4 brisk,
maximal twitches of the adductor
pollicis brevis muscle (the thumb
adducts medially across the palm)
(Figure, A). Blockade is quantified by
counting the number of thumb
adductions. Four twitches correlate
with 75% or less receptor blockade
(normal expiratory flow rate and vital
capacity), 3 twitches indicate 80% blockade, 2 twitches suggest 85% blockade, 1 twitch indicates
90% blockade, and no twitches demonstrate 100% receptor blockade. Figure, B demonstrates 2
twitches in this patient; thus, there is an approximate 85% receptor blockade. The choice of the
number of twitches to maintain has not been prospectively studied. Most clinical evidence suggests
that maintaining 1 twitch (90% occupancy) ensures an adequate degree of neuromuscular blockade.
The use of TOF will allow the use of the lowest possible dose of agents and theoretically avoid
complications of prolonged blockade. Clinicians must recognize that the twitch response at the ulnar-
adductor pollicis brevis or other peripheral sites does not reflect completely the degree of
neuromuscular blockade at the diaphragm or the muscles responsible for maintaining patency of the
extrathoracic airway. Peripheral nerve stimulation is testing the neuromuscular blockade only of the
specific nerve and muscles being tested. The phrenic nerve connection to the diaphragm recovers
earlier than other muscle groups, and the strength of the larynx and glossal musculature returns later.
In addition, in the PICU environment, edema of the extremities, concomitant use of sedative and
analgesic medications, and electrode size and limitations on placement may influence interpretation
and usefulness of bedside monitoring.
In clinical practice, the TOF monitoring is combined with clinical assessment of muscle strength
because residual weakness may be present despite apparent reversal using TOF monitoring. Several
reliable clinical assessment measures of the degree of blockade are head lift and hand grip sustained
for 5 seconds or more and measurement of negative inspiratory pressure or maximum inspiratory
pressure. Head lift and hand grip require the ability to follow commands, whereas negative inspiratory
pressure involves the measurement of the inspiratory force a patient can generate against an occluded
airway. The test can be completed with a simple manometer attached to the 15-mm adaptor of the
endotracheal tube. Initial studies suggested that a negative inspiratory pressure of at least −20 cm
H2O indicated sufficient muscle strength to maintain adequate minute ventilation. Subsequently, a
value of −25 to −30 cm H2O became the accepted value; however, although strength may be
adequate to maintain minute ventilation, it may not be adequate to maintain upper airway patency,
and therefore the use of voluntary responses (head lift/hand squeeze for 5 seconds) was suggested as
an adjunct. The literature suggests that head lift for 5 seconds is the most sensitive clinical tool.
Figure, B demonstrates that the patient has 2 twitch responses to the TOF, which correlates with
approximately 80% of the nicotinic receptors being blocked via competitive inhibition of the NMB. In
increasing dosing of NMB, the fourth twitch is lost first, then the third, followed by the second, and
finally the first twitch. Nondepolarizing NMBs exhibit fade on TOF (Figure, B), which may progress to
no twitches if enough NMB is administered. It must be remembered that although NMBs prevent
movement, they do not provide any degree of sedation or analgesia.
Hypothermia may increase the intensity and duration of effect of NMBs. The greater intensity of
blockade at lower temperatures may be related to retardation of metabolism and renal drug excretion.
Other agents that may potentiate NMB effects include antibiotics (eg, amikacin, clindamycin,
gentamicin, neomycin, streptomycin, tetracyclines, tobramycin, and vancomycin), local anesthetics
(eg, bupivacaine, lidocaine, mepivacaine, prilocaine, and procaine), sedatives and psychotropics (eg,
benzodiazepines, droperidol, etomidate, ketamine, and lithium), β-blockers, calcium channel blockers,
cyclosporine, dantrolene, diuretics, and magnesium. In addition, acidosis, hypocalcemia, hypokalemia,
and hypomagnesemia may potentiate prolonged paralysis.
 Know the mechanism of action of commonly used muscle relaxants

 Recognize that aminoglycosides prolong neuromuscular blockade
 Know the effect of hypocalcemia/hypomagnesemia on neuromuscular blockade
 Differentiate between depolarizing and nondepolarizing drugs
 Know which drugs prolong or potentiate the effects of muscle relaxants
 Know how to assess residual neuromuscular blockade by history and physical examination
 Recognize that muscle relaxants have no sedative, analgesic, or anxiolytic properties
 Know the relative sensitivity of different muscle groups to muscle relaxants
June 2013 Question 6
[MISSING]
June 2013 Question 7 Answer: B
The male child described in the vignette currently has a history of frequent otitis media and 2 serious
infections caused by encapsulated bacteria. Such a history is concerning for an underlying primary
immunodeficiency syndrome. A diagnosis of X-linked agammaglobulinemia (Bruton
agammaglobulinemia) would be consistent with this child’s history. The defect responsible for X-
linked agammaglobulinemia (XLA) is a mutation in the gene responsible for the production of Bruton
tyrosine kinase (BTK). The BTK protein is critically important for B-cell development and normal
immune function. Lack of, or dysfunctional, BTK protein leads to improper B-cell development and
lack of appropriate antibody production.
XLA is the most commonly diagnosed primary immunodeficiency. It was first described in 1952 by
Colonel Ogden Bruton, who described an 8-year-old boy with a history of multiple pneumococcal
infections and a complete lack of immunoglobulins on serum electrophoresis. This was the first
description of a primary immunodeficiency. The disease’s X-linked inheritance was rapidly described,
as was the positive clinical response to IgG replacement therapy. The description of XLA and its
selective antibody deficiency contributed greatly to an enormous number of advances in the field of
immunology, not least of which was the conceptualization of the humoral and cellular compartments
of the immune response. With time and technological improvements, the defect in XLA was localized
to a specific region on the X-chromosome and ultimately mapped to a region responsible for
production of a tyrosine kinase, later named BTK. BTK is critical in B-cell development, and its
absence accounts for the marked reduction in circulating B-cells in patients with XLA.
Proper B-cell maturation and antibody production are critical for normal host defense. Antibodies have
an important role in neutralizing both bacteria and viruses, activating complement, and opsonizing
bacteria for effective phagocytosis by monocytes, macrophages, and neutrophils. A number of other
primary immunodeficiencies associated with antibody deficiency exist. These immunodeficiencies
include common variable immunodeficiency, IgA deficiency, transient hypogammaglobulinemia of
infancy, and defects in production of specific antibodies or immunoglobulin subtypes. As described in
the vignette, a history of recurrent otitis, sinusitis, pneumonia, and gastrointestinal infections is
common in children with an antibody deficiency syndrome. Most children have XLA diagnosed within
the first 2 years of life, after the decline in maternal, transplacentally acquired antibodies occurs.
However, appropriate antibiotic therapy can still be effective for most infections experienced by these
patients; thus, diagnosis of the antibody deficiency syndrome later in life is not uncommon. In
addition to infections with encapsulated bacteria, patients with XLA can be affected by sepsis
with Staphylococcus aureus and Pseudomonas aeruginosa, viral encephalomyelitis, and
gastrointestinal infection with Giardia lamblia. Currently, the standard treatment for the antibody
deficiency caused by XLA is γ-globulin replacement therapy for life. Traditionally, these patients have
required frequent intravenous infusions of γ-globulin. Recently, however, encouraging results have
been noted with frequent subcutaneous infusions of certain γ-globulin preparations.
A mutation causing substitution of valine for glutamic acid on the gene for the β-globin chain portion
of the hemoglobin molecule is the underlying defect in sickle cell anemia. Although children with sickle
cell anemia certainly are susceptible to serious infections with encapsulated bacteria, such
as Pneumococcus and Salmonella, this child’s white ethnicity and normal hemoglobin concentration
make sickle cell anemia an unlikely diagnosis. Dysfunction of the NAPDH oxidase system in
phagocytes, such as neutrophils, results in their inability to produce superoxide anion. Such
dysfunction results in markedly impaired killing of microbes, particularly catalase-positive bacteria, by
neutrophils and is the hallmark of chronic granulomatous disease (CGD). Patients with CGD are
particularly susceptible to infections (notably abscesses) caused by S aureus, Serratia
marcescens, Burkholderia cepacia, and Aspergillus species. Mutation of the gene encoding the
common γ-chain is the defect responsible for X-linked severe combined immunodeficiency (SCID), the
most common form of SCID. Patients usually have this form of SCID diagnosed earlier in life (<1 year
of age) and have a history that includes failure to thrive, severe diarrhea, overwhelming infection with
common viruses such as respiratory syncytial virus, opportunistic infections such as Pneumocystis
jiroveci pneumonia, and persistent oral candidiasis. The age and size of the child in the vignette make
SCID an unlikely diagnosis. Early referral of a child with a new diagnosis of SCID to an experienced
bone marrow transplant center is essential because early hematopoietic stem cell transplantation in
this condition can be curative.
A mutation in the gene encoding the WASp protein is the genetic lesion responsible for Wiskott-Aldrich
syndrome. The WASp protein is normally expressed in all lineages of hematopoietic stem cells. Lack
of normal WASp expression leads to problems with inflammatory cell recruitment, defects in signaling
pathways, and dysfunctional phagocytosis, among other immunologic issues. Wiskott-Aldrich
syndrome is X-linked, and affected males classically display a triad of immunodeficiency,
thrombocytopenia, and severe eczema, making Wiskott-Aldrich syndrome an unlikely diagnosis for the
 Recognize the manifestations of B-cell dysfunction in an acutely ill patient

 Identify the pathogens to which a patient with B cell deficiency is susceptible
 Identify the disorders associated with B-cell deficiency
 Recognize immunoglobulin deficiency
The patient described in the vignette has hemolytic uremic syndrome (HUS). HUS belongs to the
disease category of thrombotic microangiopathies and is characterized by microangiopathic hemolytic
anemia (hemoglobin, <10 g/dL [100 g/L]) with fragmented erythrocytes, thrombocytopenia (platelets,
<150 x 106/μL [<150 x 109/L]), and acute kidney injury (creatinine level above the upper limit for
age). Circulating fibrinogen levels usually remain normal or high, and prothrombin time is only slightly
elevated. HUS is a common cause of acute kidney injury (AKI) necessitating renal replacement
therapy (RRT) in the pediatric population. In countries with adequate intensive care resources,
however, neurologic complications of HUS have the greatest effect on mortality. The microvascular
thrombosis caused by HUS is systemic in nature and may occur in the cerebral vasculature.
Irritability, lethargy, and confusion may result from fatigue, cerebral microvascular thrombosis with
resultant ischemia, or (in the case of some diarrhea-associated HUS) direct neurotoxicity from Shiga
toxin (Stx). Seizures, thrombotic or hemorrhagic stroke, or coma occurs in approximately 10% of
patients.
HUS among children most commonly follows gastrointestinal infection with Stx-producing (or
enterohemorrhagic) Escherichia coli (STEC). STEC expressing somatic (O) antigen 157 and flagellar
(H) antigen 7 is the serotype that most commonly causes HUS in humans; however, cases of HUS
caused by non-O157:H7 STEC infections have been reported in Australia, Germany, and Austria during
certain periods. ECO157:H7 infection most commonly occurs in sporadic or small clusters of cases.
Non-O157:H7 STEC infections are almost surely underdetected.
STEC have a high level of resistance to gastric acid and the ability to adhere to intestinal epithelial
cells, which permits colonization. The bacteria destroy intestinal microvilli, and the resultant
malabsorption leads to diarrhea and dehydration. Diarrhea may begin from 2 to 12 days after
ingestion of STEC but usually begins in 3 to 7 days. Diarrhea initially is nonbloody, but bloody diarrhea
eventually occurs in approximately 90% of cases. The colon may be severely affected. In addition to
diarrhea, patients may present with pallor, petechiae, and, rarely, bruising or purpura. Patients
usually remain afebrile during medical care, but approximately half report preadmission fever.
After adherence to the intestinal mucosa, STEC secrete Stx, which enters the bloodstream and is
carried by leukocytes to target organs. The Stxs are A 1B5 toxins. The B subunit binds to a
glycosphingolipid on the surface of eukaryotic cells, and the A subunit is an N-glycosidase, an inhibitor
of protein synthesis that disrupts the large eukaryotic ribosomal subunit in a fashion similar to ricin.
The Stxs also induce apoptosis in human kidney cells. Stx binds the receptor Gb3
(globotriaosylceramide). The renal cortex, the main site of kidney lesions, possesses high
concentrations of Gb3, expressed on glomerular endothelial cells, mesangial cells, and tubular
epithelial cells. The bloody diarrhea and possibly the initial diarrhea may be caused by mesenteric
ischemia precipitated by circulating Stx rather than by direct STEC injury. The endothelial injury
produces a prothrombotic endothelial phenotype, resulting in the activation of platelets, leukocytes,
and coagulation proteins. Stx may also activate the alternate pathway of complement.
Mesenteric ischemia in HUS may be of such severity to cause transmural intestinal injury with
resultant intestinal perforation. Another gastrointestinal complication of HUS may be severe
pancreatitis. Cardiac dysfunction and ischemia have been documented in patients with HUS, and
elevated troponin levels should be attributed to ischemia and not azotemia. Respiratory complications
most often occur from fluid overload (pulmonary edema and effusions), but acute respiratory distress
syndrome has been documented.
Streptococcus pneumoniae may produce a rare form of HUS. Usually, the preceding pneumococcal
infection is invasive and severe (eg, sepsis, meningitis, or pneumonia with empyema). Children
with Pneumococcus- associated HUS tend to be younger and experience more severe renal and
hematologic disease and to more commonly require RRT than patients with STEC HUS. Cellular injury
appears to occur because pneumococcal neuraminidase cleaves the N-acetylneuraminic acid, thus
exposing the normally hidden Thomsen-Friedenreich or T antigen. Circulating anti–T-antigen
antibodies attack the exposed antigen on erythrocytes, platelets, and endothelial cells, producing
hemolytic anemia, thrombocytopenia, and endothelial injury.
Non–diarrhea-associated HUS, or atypical HUS, is less common than diarrhea-associated HUS and has
a poorer prognosis. Patients may have genetic or acquired factors that cause defective regulation of
the alternate complement pathway. Patients with nondiarrheal, non-Stx, relapsing HUS more
frequently develop severe hypertension and reach chronic end-stage renal disease more frequently.
They also have a very high rate (60%-100%) of graft loss after renal transplantation from disease
recurrence or thrombosis.
Thrombotic thrombocytopenia purpura (TTP) has traditionally been described as a unique entity,
clinically distinct from HUS. TTP is marked by thrombotic microangiopathy primarily with salient
dysfunction of the central nervous system, severe thrombocytopenia, fever, but relative renal sparing.
However, substantial clinical overlap may occur with HUS. In TTP, ADAMTS13 (a disintegrin and
metalloprotease with thrombospondin type 1 domains, member 13 of the family) cleaves von
Willebrand factor multimers and is deficient due to either autoantibodies or, rarely, congenital
absence. Recent evidence suggests that disordered complement activation is partially responsible for
the endothelial damage and microvascular thrombosis in STEC-HUS, atypical HUS, and TTP.
HUS treatment remains primarily supportive. Intravenous rehydration and maintenance fluids provide
the best renal protection. Isotonic fluids have been recommended. Because of diffuse edema, fluid
requirements may be difficult to assess. This management strategy may result in increased sodium
administration compared with care of patients with gastroenteritis, but adequate intravascular volume
expansion appears to be vital to limit renal injury. At the same time patients must be constantly
monitored for fluid overload. Both hypovolemia and fluid overload may exacerbate renal injury. The
indications for RRT are common to other forms of acute kidney injury: hyperkalemia, acidosis,
symptomatic fluid overload, azotemia, oliguria, or anuria that limits nutritional support. A Cochrane
review reported that plasmapheresis did not benefit patients with HUS above that of supportive care,
although it was found to be helpful for patients with TTP.
Vasodilators are the preferred therapy for hypertension, whereas angiotensin-converting enzyme
inhibitors are probably better avoided because they may diminish renal perfusion and risk
exacerbating the injury. Nephrotoxic drugs should be avoided.
Treatment with antibiotics during the prodromal diarrheal illness is contraindicated because their
administration increases the risk of developing HUS. The precise mechanism has not been elucidated
but may relate to bacterial lysis caused by antibiotics, resulting in acute release of preformed Stx.
Alternatively, antibiotics may result in induction of bacteriophage on which STX genes reside,
increasing toxin production. Antimotility agents and narcotics should also be avoided assiduously
during infectious enteritis because they have also been associated with increased risk of developing
HUS. Some authors report that abdominal pain often improves with intravenous isotonic crystalloid
fluids. Nonsteroidal anti-inflammatory agents can diminish renal blood flow and should be avoided.
Oral antitoxin does not appear to diminish the severity of HUS.
 Know the pathogenesis and pathophysiology of hemolytic-uremic syndrome

 Know the features and clinical course of hemolytic-uremic syndrome
 Recognize the manifestations and life-threatening complications of hemolytic-uremic syndrome
 Plan treatment for a patient with hemolytic-uremic syndrome
 Know the association of hemolytic-uremic syndrome with E. coli :0157

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May 2013 Question 1 Answer: E

Unfortunately, very little oxygen is

Do2 = CO × (Hb × 1.34 × Sao2) + (0.003 × Pao2) (Eq 1)

O2ER = (Cao2 – Cvo2)/Cao2 (Eq 3)

CO = Vo2/(Cao2 – Cvo2) (Eq 4)

 Understand the determinants of oxygen content and delivery

There are 3 prominent waves identified on

Alterations in cardiac function may result

The CVP waveforms may be useful in

American Board of Pediatrics Content Specification(s)

 Know the normal components of the venous waveform

Although able to demonstrate free

Mortality associated with blunt abdominal trauma

A Chance fracture (Figure 6) is the

American Board of Pediatrics Content Specification(s)

 Recognize external evidence of internal abdominal injury

Subtypes of penetrating Occurrence,

Hemothorax, pneumothorax, or both (hemopneumothorax) should always be suspected after blunt or

American Board of Pediatrics Content Specification(s)

 Know the physical findings of traumatic hemothorax

May 2013 Question 5 Answer: D

American Board of Pediatrics Content Specification(s)

Proven IA involves histologic demonstration of tissue invasion by fungal hyphae consistent

American Board of Pediatrics Content Specification(s)

Venous return = (Pms – Pra)/Rvr

American Board of Pediatrics Content Specification(s)

 Understand the effects of breathing (spontaneous or mechanical) on arterial blood pressure

Hemolytic-uremic syndrome is characterized by hemolytic anemia, thrombocytopenia, hematuria, and

American Board of Pediatrics Content Specification(s)

1. Failure to diagnose a condition or a delay in diagnosis (in pediatrics, missed meningitis or

It would be common to discuss the risks of pneumothorax, catheter-associated infection,

 Know the definition of malpractice

American Board of Pediatrics Content Specification(s)

Vd (L/kg) = Dose (mg)

Vd = 500 mg = 50 L/kg

American Board of Pediatrics Content Specification(s)

Wall Stress = Pressure × Radius/2 × Wall Thickness

American Board of Pediatrics Content Specification(s)

 Understand the pathophysiology of tamponade

Depending on the number of ACh

American Board of Pediatrics Content Specification(s)

 Know the mechanism of action of commonly used muscle relaxants

American Board of Pediatrics Content Specification(s)

 Recognize the manifestations of B-cell dysfunction in an acutely ill patient

American Board of Pediatrics Content Specification(s)

 Know the pathogenesis and pathophysiology of hemolytic-uremic syndrome

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PREP ICU 2013 Answers and Critiques - 3 - May & June

PREP ICU 2013 Answers and Critiques - 3 - May & June

PREP ICU 2013 Answers and Critiques - 3 - May & June