Sickle Cell Disease

By Tracy Hagemann, Pharm.D., FCCP

Reviewed by Lea S. Eiland, Pharm.D., BCPS; and Lisa C. Hutchison, Pharm.D., MPH, FCCP, BCPS

Learning Objectives

decreased by about 50%. However, with advances in

care and longer life spans, medical expenditures have
increased for this patient population. Children with
SCD may incur medical costs up to 10 times those of
children without SCD. Sickle cell disease primarily
affects people of African ancestry. This chapter focuses
on the recent advances in the management of SCD in
childhood.

1. Distinguish the underlying causes of sickle cell disease (SCD) and their relationships to patient signs
and symptoms.
2. Develop a care plan for a child with SCD that may
decrease the incidence of complications.
3. Assess the increased risk of morbidity and mortality associated with stroke in a child with SCD.
4. Design a treatment plan for iron chelation for a
child maintained on chronic transfusion therapy.
5. Evaluate a plan of care for a pediatric patient with
acute complications of SCD.
6. Construct a pharmacotherapy plan for health
maintenance in a child with SCD, including immunizations, antimicrobials, nutritional supplements,
pain management, and hydroxyurea.

Epidemiology
Normal adult hemoglobin (HbA) contains two a-globin chains and two -globin chains. Sickle hemoglobin
(HbS) occurs when there is a single substitution of the
amino acid valine for glutamic acid at position 6 of the
b-polypeptide chain. Different genetic mutations encode
for other hemoglobin variants such as hemoglobin C
(HbC), which is produced when lysine is substituted for
glutamic acid at position 6 of the -polypeptide chain.
The a-globin chain is structurally identical in all variants (i.e., HbA, HbS, and HbC). Changes in the -globin
chain are primarily responsible for sickling of red blood
cells (RBCs) and the associated sequelae.
Sickle cell trait is the heterozygous form of SCD, in
which one normal HbA gene and one HbS gene are
inherited. Individuals with SCT are usually asymptomatic and are denoted as carriers of the sickle cell gene.
Only individuals with the homozygous or compound
heterozygous genotypes of SCD are symptomatic. Four
genotypes account for most SCD in the United States:
sickle cell anemia (HbSS), sickle hemoglobin C disease

Introduction
Sickle cell disease (SCD) is a complex group of
autosomal recessive genetic disorders associated with
frequent and unpredictable crisis episodes. Substantial
progress in management and maintenance of this
chronic disease has improved overall life expectancy in
recent years. Individuals with SCD have an average life
expectancy of 4050 years, whereas those with sickle
cell trait (SCT) have mortality rates similar to individuals without SCD. Between 1968 and 1992, the rate of
SCDrelated deaths in children in the United States

Baseline Review Resources

The goal of PSAP is to provide only the most recent information or topics. Chapters do not provide an overall review.
Suggested resources for background information on this topic include:
The management of sickle cell disease, 4th ed. NHLBI-NIH publication 14-2117, 2002. Available at www.nhlbi.nih.
gov/health/prof/blood/sickle/index.htm. Accessed September 3, 2010.
Chan CYJ, Moore R. Sickle cell disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.
Pharmacotherapy: A Pathophysiologic Approach. Boston: McGraw-Hill, 2008:1685700.

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oxygen more tightly than HbA. Normal HbA and HbF

have inhibitory effects on this gelation process, which
typically occurs with HbS concentrations greater than
20.8%.

Abbreviations in This Chapter

ACS
HbA
HbC
HbF
HbS
HbSC
HbSS
HLA
HSCT
PCA
SCD
SCT

Acute chest syndrome

Normal adult hemoglobin
Hemoglobin C
Fetal hemoglobin
Sickle hemoglobin
Compound heterozygous (HbS
and hemoglobin C)
Homozygous sickle hemoglobin
Human leukocyte antigen
Hematopoietic stem cell
transplantation
Patient-controlled analgesia
Sickle cell disease
Sickle cell trait

Viscosity and Sickle Cell Adhesion

When HbS becomes reoxygenated, the RBC polymers disappear, and the cells resume their normal shape.
As the RBCs are repeatedly sickled and unsickled, cell
membrane damage occurs, causing the membrane to
lose flexibility. Cell membrane damage results in a loss
of potassium and water; this leads to dehydrated, dense,
sickled cells that remain irreversibly sickled even when
oxygenated. The normal RBC life span is 100120 days;
an irreversibly sickled RBC lives about 1020 days,
leading to the characteristic anemia seen in patients
with SCD. Blood viscosity increases as the intracellular
membrane viscosity of the HbS RBCs increases, contributing to vaso-occlusion. Evidence shows that sickled
RBCs adhere to the vascular endothelium, obstructing
small blood vessels; this ultimately results in local tissue
hypoxia.

(HbSC), and two types of sickle beta-thalassemia (Sb+thalassemia and Sb0-thalassemia).

Incidence
Annually, 2000 infants in the United States are given a
diagnosis of SCD. It is estimated that 2 million people in
the United States carry the gene, and most of these people are of African ancestry. The HbS gene is present in
about 9% of African Americans and is the most common
genotypic occurrence (45%), followed by HbC (25%).

Other Pathophysiologic Effects

Sickled RBCs may obstruct bloodflow to the spleen,
leading to functional asplenia and increasing the potential for infection from encapsulated organisms such as
Streptococcus pneumoniae. Coagulation abnormalities
may also occur in the patient with SCD because most
hemostasis components are altered in the course of the
disease, including decreased levels of protein C, protein
S, and antithrombin III and increased thrombin generation and platelet aggregation.

Pathophysiology
Erythrocyte Physiology
Thirty-four percent of a RBC is hemoglobin. Fetal hemoglobin (HbF) is the predominant oxygen transport
protein in the fetus, and at birth, HbF constitutes 60% to
90% of the RBC hemoglobin. Adult RBCs contain less
than 1% HbF. Unlike HbA and HbS, HbF contains two
g-chains instead of b-chains. Shortly before birth, HbF
undergoes conversion from g-chains to b-chains. After
birth, only a small proportion of RBC clones remain to
produce HbF. Because RBCs with HbF do not sickle,
some treatment strategies for SCD are aimed at increasing the amount of HbF.

Clinical Presentation and Diagnosis

Neonatal Screening
Newborn screening for SCD is mandated in all 50 of the
United States and the District of Columbia. Most states
use high-performance liquid chromatography or thinlayer isoelectric focusing. Both tests have extremely high
sensitivity and specificity for SCT and SCD. It is recommended that a positive screening test be confirmed, with
a second sample within 2 months. Extremely premature
infants may have false positives when adult hemoglobin is
not yet detectable. Most infants with SCD appear healthy
at birth and become symptomatic only later in infancy as
HbF concentrations decline during the first 6 months of
life. Identification of children with SCD before 2 months
of age is optimal and allows caregiver education and early
initiation of comprehensive care plans.

HbS Polymerization
Red blood cell proteins must be extremely soluble
because of their high hemoglobin concentrations. When
oxygenated, HbS and HbA solubility are the same, and
HbS carries oxygen normally. However, when oxygen
is unloaded from the cell, HbS solubility decreases; this
promotes hydrophobic interactions between the hemoglobin molecules and causes polymerization to occur.
Valine may bind to sites on adjacent globin chains, and
the deoxygenated HbS begins to form a gel-like substance that distorts RBCs into the characteristic crescent
or sickle shape. Red blood cells containing HbF exert a
protective effect because they sickle less readily and bind
Sickle Cell Disease

Signs and Symptoms

Children with SCT are generally asymptomatic. Girls
with SCT have a tendency to have more frequent urinary
tract infections. Although microscopic hematuria seldom
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with SCD. Predictors for increased morbidity and mortality in children include having dactylitis before age 1
year, severe anemia (hemoglobin concentration less than
7 g/dL) in the second year of life, and leukocytosis in the
absence of infection. Chronic manifestations of SCD that
contribute to morbidity and mortality later in life include
repeated acute pain crises, anemia, ACS, kidney insufficiency, cerebrovascular complications, and lung disease.

occurs, patients with SCT may exhibit gross hematuria

after high-intensity exercise.
Signs and symptoms of SCD usually manifest early
in childhood and typically involve pain and anemia.
Anemia is chronic, hemolytic, and usually well tolerated,
with hemoglobin concentrations commonly between
7 g/dL and 10 g/dL. Because of increased RBC turnover and folate use, the anemia may be complicated by
megaloblastic changes secondary to folate deficiency.
In addition, splenic enlargement during the first year of
life is common. Splenic sequestration crisis occasionally
may occur as the spleen undergoes a sudden very painful
enlargement secondary to the pooling of a large number
of sickled RBCs. As the spleen enlarges, its function is
impaired; over time, it will become fibrotic and shrink,
leading to increased risk of infection with encapsulated
microorganisms.
Clinical presentation of SCD may differ based on the
age of the child at symptom onset. In infancy, dactylitis
(swelling of the hands and feet), pneumococcal sepsis or
meningitis, severe anemia, acute chest syndrome (ACS),
pallor, jaundice, or splenomegaly may be present. In
older children, the clinical presentation may include
anemia, aplastic crisis, ACS, splenomegaly or splenic
sequestration, cholelithiasis, and severe or recurrent musculoskeletal or abdominal pain.

Quality Patient Care

Family and Patient Education
Education of the family and caregivers of the child
identified as having SCD is crucial to positive outcomes.
The initial focus should be on the genetics and basic
pathophysiology of SCD and the importance of regular health maintenance visits and preventive treatments
for complications. Education is vital regarding the recognition of signs and symptoms that require immediate
medical attention (e.g., febrile illness, shortness of breath,
pain, mental status changes, acute splenic sequestration,
aplastic crisis, ACS). Caregivers should be warned to
seek immediate medical attention if the child is pale and
listless; they also should be instructed about abdominal
palpation to determine spleen size. Other topics (e.g.,
stroke, enuresis, priapism, cholelithiasis, delayed puberty,
retinopathy, avascular necrosis of the hip or shoulder, leg
ulcers) should be introduced as the child ages. Children
approaching the preteen and adolescent years should be
actively involved in the education and management of
their disease. Additional issues to discuss in adolescence
include contraception and genetic counseling.

Health Supervision Monitoring

Children with SCD should be monitored regularly. In
the first year of life, comprehensive medical evaluations
should be conducted every 24 months and include documentation of spleen size, baseline complete blood cell
count, and reticulocyte count. The reticulocyte count may
change markedly as the HbF concentration decreases. If the
infant requires RBC transfusions for acute illnesses, RBC
minor antigen phenotype should be determined to match
transfusions and prevent alloimmunization. Additional laboratory monitoring is summarized in Table 2-1.

Preventive Pharmacotherapy
Immunizations
Children with SCD should receive routine immunizations as recommended by the Advisory Committee on
Immunization Practices of the Centers for Disease Control
and Prevention and the American Academy of Pediatrics
(see Table 2-1). Influenza immunization should be administered yearly to children with SCD who are 6 months and
older. Because of impaired splenic function, children with
SCD are at increased risk of infection with encapsulated
organisms such as S. pneumoniae, Haemophilus influenzae, and Salmonella spp. Vaccination with the 13-valent
conjugate pneumococcal vaccine is required for infants
and children younger than 2 years; this provides protection against the 13 most common isolates seen in this age
group.
The use of pneumococcal vaccine in children with
SCD has dramatically decreased morbidity and mortality rates. However, some groups of children with SCD
still have high rates of invasive pneumococcal infections.
The 23-valent polysaccharide vaccine contains the most
common pneumococcal isolates identified in older children and adults. Because of the differences in serotypes

Growth and Development

Children with SCD often have growth delays during
puberty and exhibit a decreased growth velocity. The
decrease in growth velocity is independently associated with the decreased hemoglobin concentration and
increased total energy expenditure. Puberty progresses
more slowly in children with SCD, and delayed sexual
maturation is common. Decreased growth velocity and
underweight status are often seen in children and adolescents with SCD.
Morbidity and Mortality
Complications of SCD contribute to its high mortality.
Thirty years ago, 50% of patients with SCD did not survive to adulthood. Recent reports suggest 85% of these
patients now survive to 18 years of age. Infection is the
leading cause of death in children younger than 3 years
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Table 2-1. Health Maintenance Recommendations for Children with SCD

Age Range
Birth to
1 year

Intervention
Comprehensive medical
evaluation
Immunizations

15 years

Prophylactic penicillina
Comprehensive medical
evaluation

Immunizations

613 years

Prophylactic penicillina
Comprehensive medical
evaluation

Immunizations
Prophylactic penicillina
1421 years Comprehensive medical
evaluation

Immunizations

Timing and Type

Every 24 months
Spleen size
Baseline CBC and reticulocyte count
Routine childhood vaccines, especially Hib, 13-valent pneumococcal conjugate,
and annual influenza (starting at age 6 months)
Penicillin V potassium 125 mg PO bid (by age 2 months)
Every 612 months
Spleen size
CBC and reticulocyte count
Growth and development
Neurologic status
Baseline kidney and liver tests
Cardiac and pulmonary function testing
Consider TCDb
Routine childhood immunizations, including annual influenza vaccine
23-valent pneumococcal polysaccharide vaccine at age 2 years and 5 years
Increase penicillin V potassium to 250 mg PO bid (at age 3 years)
Every 612 months:
Spleen size
CBC and reticulocyte count
Growth and development
Neurologic status
Kidney and liver tests
Assess for cholelithiasis
Assess for proteinuria
Cardiac and pulmonary function testing
Retinal examination (starting at age 10 years)
Consider TCDb
Annual influenza vaccine
Consider extension of use for children with history of invasive pneumococcal
infection or surgical splenectomy (after age 5 years)
Every 612 months:
Spleen size
CBC and reticulocyte count
Growth and development
Neurologic status
Kidney and liver tests
Assess for cholelithiasis
Assess for proteinuria
Cardiac and pulmonary function testing
Retinal examination (starting at age 10 years)
Consider TCDb
Annual influenza vaccine

For infants with HbSS and Sb0thalassemia. Use is controversial with other forms of SCD.
NIH guidelines: transcranial Doppler ultrasonography to assess/exclude ischemic events; repeat every 312 months depending on
results. bid = two times/day; CBC = complete blood cell (count); HbSS = homozygous sickle hemoglobin; Hib = Haemophilus influenzae
conjugate vaccine; NIH = National Institutes of Health; PO = orally (by mouth); SCD = sickle cell disease; TCD = transcranial Doppler
ultrasonography.
Information from The management of sickle cell disease, 4th ed. 2002. NHLBI-NIH publication 14-2117. Available at www.nhlbi.nih.gob/
health/prof/blood/sickle/index.htm. Accessed August 9, 2010.

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addition, hydroxyurea decreases RBC adhesion to the

endothelium and increases concentrations of nitric oxide,
a regulator involved in vasodilation. Several landmark
studies of adults with SCD treated with hydroxyurea
have shown a reduction in pain crises, hospitalization
rates, RBC transfusions, incidence of ACS, and mortality. Hydroxyurea is the only agent with U.S. Food and
Drug Administration (FDA)-approved labeling for use in
adults with SCD. Emerging data from trials of hydroxyurea use in children support its efficacy. Although most
studies have been small, they have shown hydroxyurea to
be safe and effective in children as young as 6 months.
Growth and pubertal development appear to be unaffected by hydroxyurea use.
Children receiving hydroxyurea show marked
increases in HbF concentrations and appear to tolerate
the drug well; however, the dose should be individualized
based on hematologic response and HbF concentrations.
In children with SCD, hydroxyurea is initiated at a dosage of 15 mg/kg given orally once daily, and the dosage
is increased in increments of 5 mg/kg every 12 weeks to
a maximal dosage of 35 mg/kg/day. Complete blood cell
counts should be evaluated every 2 weeks while the dose
is being titrated and then every 46 weeks once the dosage is stabilized.
Mean corpuscular volume should increase as the HbF
concentration increases. If the mean corpuscular volume does not increase, the bone marrow may be unable
to respond, the hydroxyurea dosage may be inadequate,
or the patient may be nonadherent to the therapy. If the
hemoglobin concentration is less than 5 g/dL, the absolute neutrophil count is less than 2000/mm3, the platelet
count is less than 80,000/mm3, or the reticulocyte count
is less than 80,000/mm3 when the hemoglobin concentration is less than 9 g/dL, then hydroxyurea should be
discontinued until one (or more) of these cell counts
recover. After recovery, hydroxyurea may be reinitiated
at a reduced daily dosage that is 2.5 mg/kg less than the
daily dosage at which the toxicity occurred. The daily
hydroxyurea dosage may then be titrated every 12 weeks
by 2.5 mg/kg until the patient is hematologically stable
for 24 weeks. If a dosage results in toxicity twice, titration
to that dosage should not be attempted.
Hydroxyurea is commercially available only in a solid
oral dosage form, but an extemporaneous suspension can
be compounded for use in younger children. When the
solid dosage form is used, the dosage should be rounded
to the nearest available tablet or combination of tablets.
Hydroxyurea should be considered for any child with
SCD who is severely anemic or who has a history of frequent complications such as pain crises, priapism, or ACS
episodes. Common adverse events with hydroxyurea use
include mild to moderate neutropenia, mild thrombocytopenia, severe anemia, rash, nail changes, and headache;
all are reversible on drug discontinuation. Severe adverse
events are rare. Ongoing studies are evaluating the use of

contained in the two vaccines, it is recommended that

all children with SCD older than 2 years also receive
the 23-valent polysaccharide vaccine. The first dose of
the 23-valent vaccine should be separated from the last
dose of the 13-valent vaccine by at least 2 months. To
ensure adequate antibody response, a second dose of the
23-valent vaccine is recommended 5 years after the first
dose for all individuals older than 2 years who have SCD
or functional or anatomic asplenia. Meningococcal conjugate vaccine should be administered to any patient older
than 2 years with SCD who is scheduled for surgical splenectomy or who has functional asplenia. If the first dose
is given between age 2 years and 6 years, a second dose
of meningococcal conjugate vaccine is recommended 3
years after the first dose.
Penicillin Prophylaxis
The use of prophylactic penicillin dramatically
decreases mortality from invasive pneumococcus in
young children with SCD, even in the era of increasingly resistant strains. All children with SCD should
be initiated on prophylactic penicillin at age 2 months,
and prophylaxis should be continued until at least age 5
years (Table 2-1). Typically, penicillin V potassium 125
mg orally twice daily is given until age 3 years; then, the
dosage is increased to 250 mg orally twice daily until age
5 years. If adherence to this regimen is a concern, one
option is benzathine penicillin 600,000 units given intramuscularly every 4 weeks beginning at age 6 months and
continued until age 6 years. Patients who are allergic to
penicillin may receive erythromycin at a dosage of 10
mg/kg given orally twice daily.
Despite the use of penicillin prophylaxis, some children will develop invasive pneumococcal infections.
The risk of recurrent pneumococcal sepsis is higher in
patients with previous infections, and sepsis may occur
at an older age. Continuation of penicillin prophylaxis
should be considered in children older than 5 years who
have a history of invasive pneumococcal infection.
Folic Acid Supplementation
Available evidence is conflicting regarding the need
for folic acid supplementation in patients with SCD.
Daily supplementation with folic acid 1 mg is generally
recommended in adults with SCD and any patient with
SCD and chronic hemolysis. For children with SCD and
chronic hemolysis, supplementation is generally recommended. Infants should receive 0.1 mg orally daily,
children aged 14 years should receive 0.3 mg orally
daily, and children and adults older than 4 years should
receive 0.41 mg orally daily.
Hydroxyurea
Hydroxyurea, a ribonucleotide reductase inhibitor
that prevents DNA synthesis, increases HbF production and decreases neutrophils in patients with SCD. In

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Iron Chelation
Each milliliter of packed RBCs contains about 1 mg
of elemental iron. Iron overload typically becomes a
concern after 1 year of chronic transfusion therapy. No
consensus exists on the best method of determining iron
overload in children requiring chronic RBC transfusion therapy; however, the mainstay of diagnosis is liver
biopsy. Although liver biopsy is safe in children with
SCD, it is not always practical because the procedure is
typically performed in the operating room and requires
general anesthesia. Thus, several noninvasive techniques
have been used to assess iron overload, including serum
ferritin concentrations, cumulative transfusion volumes,
magnetic resonance imaging of the liver, and the superconducting quantum interference device (also known as
SQUID). Each method has limitations.
Serum ferritin concentrations may not reliably indicate
total body iron stores because ferritin is an acute-phase
reactant. Transfusion volumes have been correlated only
with liver iron content and may underestimate total body
iron stores. Although magnetic resonance imaging can
estimate liver iron content, it cannot determine the actual
iron content, and SQUID is not yet widely available in
the United States. Most comprehensive sickle cell centers in the United States rely on a combination of serum
ferritin concentrations, cumulative RBC transfusion
volumes, and liver biopsy to determine a patients iron
status. Chelation therapy should be considered when a
child receives a cumulative total of 120 mL/kg of packed
RBCs (about 20 units) and/or the serum ferritin concentration is greater than 15002000 ng/mL. If liver biopsy
is available, then chelation should be initiated when the
liver tissue iron content is greater than 7 mg/g of dry tissue weight. Two drugs are used in the United States for
iron chelation, deferoxamine and deferasirox. Table 2-2
gives information regarding the dosing and toxicities of
these agents.

hydroxyurea in reducing the need for chronic RBC transfusions in children with SCD who have suffered a stroke
and in preventing chronic organ damage in young children with SCD.
Chronic Transfusion Therapy
Packed RBC transfusions are used chronically to reduce
SCD complications such as stroke and stroke recurrence,
vasoocclusive pain crises, and ACS. Chronic transfusions
in children with SCD have decreased stroke recurrence
from about 50% to 10% during a 3-year period. In the
absence of chronic transfusions, up to 93% of children
with SCD who suffer a stroke will have stroke recurrence.
The goal of chronic RBC transfusions is to suppress
erythropoiesis and provide normal RBCs to maintain
the HbS concentration at less than 30%. Transfusions
are administered every 34 weeks depending on the HbS
concentration. For secondary stroke prevention, lifelong
chronic RBC transfusions are required. Patients with
SCD who should be considered candidates for chronic
RBC transfusions include those with severe or recurrent
ACS, recurrent priapism, debilitating pain, chronic organ
failure, transient ischemic attacks, abnormal transcranial
Doppler studies, intractable leg ulcers, and severe chronic
anemia in the presence of heart failure.
Risks associated with chronic RBC transfusions
include alloimmunization, hyperviscosity, viral transmission, volume overload, transfusion reactions, and
iron overload. Alloimmunization can be minimized by
the use of leukocyte-reduced RBCs or human leukocyte
antigen (HLA)-matched units. Although the risk of viral
transmission from RBC transfusion is low, patients with
SCD should be vaccinated for hepatitis B and should be
monitored serially for hepatitis C and other bloodborne
infections. Parvovirus may be present in 1 of every 40,000
units of packed RBCs and is associated with aplastic crisis in patients with SCD. Aplastic crisis usually manifests
as a very rapid drop in hemoglobin concentration that is
self-limited, with recovery within 710 days followed by
a reticulocytosis.
Sickle cell hemolytic transfusion reaction syndrome,
which occurs secondary to alloimmunization, may result
in an acute or delayed transfusion reaction. Alloantibodies
and autoantibodies that arise after previous transfusions
may trigger this reaction, which mimics symptoms of a
pain crisis. Suppression of erythropoiesis accompanied by
a rapid decrease in hemoglobin and hematocrit may result
in severe anemia after a transfusion. Additional transfusions will worsen the situation because of the presence of
autoimmune antibodies. Recovery occurs after suspension of all transfusions. In patients with SCD requiring
chronic transfusions, iron overload presents another set
of complications. Iron may accumulate in the heart, liver,
and endocrine system and lead to end-organ damage. Iron
overload is especially of concern in children because it may
cause growth failure and abnormal sexual maturation.

Sickle Cell Disease

Deferoxamine
Deferoxamine is a parenterally administered iron chelator that complexes with trivalent ferric ions to form
ferrioxamine, which is then removed by the kidneys.
The binding ratio of deferoxamine to iron is about 1:1. It
has poor oral bioavailability and a short half-life, necessitating an 8-hour to 12-hour subcutaneous infusion.
Supplementation with oral ascorbic acid, 50150 mg/
day, should be considered after 1 month of deferoxamine
therapy because ascorbic acid increases the availability
of iron for chelation. Cardiac function should be monitored closely, and ascorbic acid supplementation should
be avoided if the child develops heart failure. Patients
with severe kidney impairment should not receive deferoxamine. Other complications of deferoxamine therapy
include ototoxicity, allergic reactions, growth failure,
visual disturbances, pulmonary hypersensitivity, and
arthralgias. Difficulty with adherence to treatment with
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Acute Complication Management

RBC Transfusions
Indications for packed RBC transfusions include an
acute exacerbation of anemia (i.e., decrease in hemoglobin concentration) that results in an increased
oxygenation requirement, an acute severe vaso-occlusive
crisis including ACS, stroke, acute multiorgan failure,
and preparation for surgery or radiologic procedures that
involve general anesthesia or the use of ionic contrast.
Blood transfusions are not without risk. If anemia is corrected too rapidly, volume overload is likely to occur that
may lead to congestive heart failure. Hyperviscosity may
occur if the hemoglobin concentration is increased to
greater than 1011 g/dL.

deferoxamine is common because of the dosing route

and regimen. Eye and auditory examinations are recommended annually for those on chronic therapy.
Deferasirox
Deferasirox is an orally administered iron chelator that
selectively binds iron with a high affinity in a 2:1 ratio,
forming complexes that are excreted primarily through
the feces. It has FDA-approved labeling for use in children
2 years and older. Deferasirox is available in an orally dispersible tablet that should be dispersed in water, orange
juice, or apple juice and taken 30 minutes before food.
Deferasirox should be discontinued when the serum ferritin concentration decreases to less than 500 ng/mL and
reinitiated if the serum ferritin concentration increases to
500 ng/mL or higher.
Adverse effects of deferasirox include headache, rash,
abdominal pain, diarrhea, nausea, elevated serum hepatic
transaminases and creatinine, arthralgia, visual disturbances, and ototoxicity. Baseline and annual eye and
auditory examinations are recommended. If the serum
creatinine is above the age-appropriate upper limit of
normal on two consecutive measurements, the daily
deferasirox dose should be decreased by 10 mg/kg. If
the serum creatinine increases to more than 2 times the
age-appropriate upper limit of normal, or the creatinine clearance is less than 40 mL/minute, deferasirox is
contraindicated and should be discontinued until these
measurements return to the patients baseline. Once at
baseline, doses may be reinitiated and gradually titrated
if the clinical benefits of deferasirox use outweigh the
potential risks to the patient.

Infection and Fever

Because of splenic dysfunction, children with SCD
have a high risk of infectious complications from encapsulated bacteria such as S. pneumoniae. Furthermore, the
clinical condition of children with SCD, fever, and infection may deteriorate rapidly. It is recommended that all
children with SCD who have a temperature of 101.3F
(38.5C) or higher seek immediate medical attention.
The patient should have a physical examination, complete blood cell count, reticulocyte count, blood culture
(and other cultures if indicated), and chest radiograph (if
presenting with cough or if abnormalities are heard on
chest auscultation), and the child should receive empiric
broad-spectrum intravenous antibiotics (e.g., ceftriaxone, cefuroxime, cefotaxime) as soon as possible.
For patients with a documented cephalosporin allergy,
clindamycin can be used. Macrolide antimicrobials, such

Table 2-2. Iron Chelators Used in Children with SCD and Iron Overload
Drug
Deferoxamine

Route
SC

Dosage Regimen
2040 mg/kg/day for 47 days/
week
Maximal dose: 2 g/day
Infuse over 812 hours

Deferasirox

Oral

20 mg/kg once daily

Maximal dose: 40 mg/kg/day
(Round to available whole-tablet
dose: 125, 250, 500 mg)

Toxicities
Ototoxicity
Visual impairment
Arthralgia
Headache
ARDS
Hypersensitivity
Headache
Rash
Abdominal pain
Nausea
Arthralgia
Visual impairment
Increased hepatic transaminases
Increased SCr

Notes
Supplement with oral
ascorbic acid 50150
mg/daya
Do not use in severe kidney dysfunction
Disperse tablet in water or
orange or apple juice
before administration
Adjust dose in kidney
dysfunction

a
Do not use supplemental ascorbic acid in patients with preexisting cardiac conditions.
ARDS = acute respiratory distress syndrome; SC = subcutaneous; SCD = sickle cell disease; SCr = serum creatinine.

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Stroke
By age 20 years, about 11% of patients with SCD will
have had a stroke, with the highest incidence in children aged 25 years. Presenting signs and symptoms of
stroke in children with SCD include aphasia or dysphasia, hemiparesis, severe headache, cranial nerve palsy,
seizures, stupor, and coma; therefore, any acute neurologic symptom should be immediately assessed. Ischemic
central nervous system injury may present with nonfocal
signs such as developmental delay or poor performance
in school. Transcranial Doppler ultrasonography can
be used as a screening tool for early detection of ischemic stroke. In the Stroke Prevention Trial in Sickle Cell
Anemia, the incidence of stroke was significantly reduced
by this screening method. Annual screening is recommended for all children older than 2 years with SCD.
Patients with positive findings may be candidates for
primary stroke prevention with chronic RBC transfusions. Clopidogrel and other antiplatelet agents have not
been studied in children with SCD and their use is not
recommended.
Initial assessment of children with stroke should
include a physical examination, complete blood cell
count, reticulocyte count, and noncontrast computed
tomography or magnetic resonance imaging to exclude
acute hemorrhage. Acute stroke treatment may include
exchange transfusion or RBC transfusion to maintain the
hemoglobin concentration at about 10 g/dL and the HbS
concentration at less than 30%. Interventions to decrease
intracranial pressure should be initiated if needed, and
patients who seized during the stroke event may require
anticonvulsants. All children with SCD who have a history of stroke should receive chronic RBC transfusions.

as erythromycin or azithromycin, should be initiated

if Mycoplasma pneumoniae is suspected. The urgency of
rapid initiation of broad-spectrum parenteral antibiotics exists regardless of a documented or suspected site
of infection (e.g., otitis media, viral respiratory infection). Because of the increasing incidence of resistant
S. pneumoniae, vancomycin should be added for suspected or proven meningitis or in patients presenting
with severe illness. Pain and swelling of an extremity
may indicate bone infarcts or sickling in the periosteum.
In these cases, osteomyelitis should be considered. The
most common organism causing osteomyelitis in children with SCD is Salmonella, followed by Staphylococcus
aureus. Appropriate empiric antibiotics (e.g., ceftriaxone for Salmonella, vancomycin for S. aureus) should be
selected while awaiting culture results. While the patient
is receiving broad-spectrum antibiotics, the regular use of
prophylactic penicillin can be withheld. Fever should be
controlled as needed with acetaminophen or ibuprofen,
and extra fluids should be given to prevent dehydration.
Acute Chest Syndrome
A patient with SCD is given a diagnosis of ACS if there
is a new infiltrate on chest radiography together with
symptoms of a lower respiratory tract infection and/or
hypoxemia. Acute chest syndrome may present during an
acute illness or 23 days after a severe vasoocclusive pain
crisis, and it is also a common complication of general
anesthesia. Patients with ACS will require hospitalization for symptom management because of the possibility
of rapid deterioration leading to respiratory failure and
death. Early recognition of symptoms (e.g., cough, difficulty breathing, chest pain) and aggressive treatment
are crucial and may be lifesaving. Causes of ACS include
infection (viral and bacterial, including Mycoplasma and
Chlamydia spp.), pulmonary infarction, and pulmonary
fatty emboli.
Treatment of ACS includes oxygen therapy if the
patient has hypoxia or is in respiratory distress. Oxygen
saturations as measured by pulse oximeter should be
maintained at 92% or higher. Packed RBC transfusions
may be indicated to improve oxygenation. The use of
incentive spirometry should be encouraged every 2
hours to assist with lung expansion and to prevent atelectasis. Appropriate fluid balance should be maintained
and monitored carefully because fluid overload may
lead to pulmonary edema and worsen respiratory distress. Broad-spectrum parenteral antibiotics that cover
gram-negative, gram-positive, and atypical microorganisms should be initiated as soon as possible. Patients
who present with wheezing will require inhaled bronchodilators such as albuterol. The use of corticosteroids
is controversial; although corticosteroids may decrease
endothelial cell adhesion and inflammation, their use has
been associated with a higher readmission rate for other
complications.

Sickle Cell Disease

Priapism
By age 18 years, about 90% of male children with SCD
will have had at least one priapism episode, a prolonged,
painful penile erection. There are two types of priapism:
stuttering episodes that may recur but last anywhere
from a few minutes to less than 2 hours and resolve spontaneously; and severe episodes that last longer than 24
hours and require medical intervention to avoid permanent complications such as impotence. Patients should
be instructed to increase oral fluid intake, urinate, take
a warm bath, and use analgesics before seeking care for
most cases of priapism. If the episode lasts longer than 2
hours, medical attention is warranted.
Initial treatment of severe priapism episodes should
include aggressive hydration with intravenous fluids and
analgesic agents. Patients who are anemic may require an
RBC transfusion. Ice packs to the affected area should
be avoided to reduce the chance of tissue damage. Drugs
used to treat severe episodes include both vasodilators
and vasoconstrictors. Aspiration of the penile blood followed by intracavernous irrigation with epinephrine
(1:1,000,000) has been used successfully.
36

PSAP-VII Pediatrics

 The first-line oral treatment for prevention of recurrent

priapism is pseudoephedrine given in a dose of 3060 mg
at bedtime. If pseudoephedrine is not effective, terbutaline 5 mg given orally at bedtime may prevent priapism,
although studies show variable results. In severe cases,
hydroxyurea therapy may be beneficial.

exhibit mild to moderate thrombocytopenia. Treatment

should include RBC and platelet transfusions, as needed.
Recurrent episodes may occur, which can be managed
with chronic RBC transfusions and/or splenectomy.
Splenectomy is typically delayed until after age 2 years to
decrease the risk of postsplenectomy sepsis.

Management of Crises
Aplastic Crisis
Aplastic crisis manifests as an exacerbation of the
patients baseline anemia with an acute, dramatic decrease
in the reticulocyte count (usually to less than 1%). In
addition, patients may present with severe pain, ACS,
and splenic sequestration. Infection with human parvovirus B19 is the most common cause of aplastic crisis.
Most patients in aplastic crisis will recover spontaneously; thus, treatment is supportive. Because parvovirus
is highly contagious, patients should be isolated from
individuals considered at high risk, such as those who are
pregnant or immunosuppressed.

Vasoocclusive Pain Crisis

Sickle cell disease is characterized by unpredictable
episodes of mild to severe pain caused by vasoocclusion.
The pain may involve the extremities, back, chest, and
abdomen. Most instances of mild to moderate pain can
be managed at home with an increase in oral fluids, rest,
warm compresses to the affected areas, and oral analgesics such as acetaminophen or ibuprofen with or without
an adjunctive opioid such as codeine or hydrocodone.
Many children with SCD will have an active outpatient
prescription for oral opioid analgesics so that they can
begin adequate analgesia as soon as possible. The use of
tramadol or propoxyphene is generally avoided in children because of limited information on dosing and the
potential for toxicity. Table 2-3 describes drug regimens
for vasoocclusive pain crises in children with SCD.
Because infection is a known trigger for pain crises,
the presence of signs and symptoms of infection including fever or severe illness should be determined, and
empiric broad-spectrum antibiotics should be initiated,

Sequestration Crisis
In young children with SCD, splenic sequestration of
RBCs may lead to an acutely enlarged spleen and a rapid
drop in the hemoglobin concentration to more than
2 g/dL below the patients baseline. This rapid shift may
lead to hypovolemia, shock, and death. Patients may also

Table 2-3. Drug Regimens for Vasoocclusive Pain Crises in Children with SCD
Mild to Moderate Pain

Severe Pain

Adjunctive Treatment

Acetaminophen with codeine: 1 mg/kg PO every 6 hours (based on codeine)

Hydrocodone with acetaminophen: 0.2 mg/kg PO every 6 hours (based on hydrocodone)
Ibuprofen: 10 mg/kg PO every 68 hoursa
Naproxen: 5 mg/kg PO every 12 hoursa
Morphine:
Intermittent doses: 0.050.15 mg/kg IV every 34 hours
CI: 0.05 mg/kg/h; titrated to effect
PCA: 0.020.03 mg/kg/h basal + 0.020.06 mg/kg IV every 10 minutes
Hydromorphone:
Intermittent doses: 0.0050.015 mg/kg IV every 34 hours
CI: 0.004 mg/kg/h IV; titrate to effect
PCA: 0.0030.005 mg/kg/h basal + 0.0030.005 mg/kg IV every 10 minutes
Ketorolac: 0.5 mg/kg up to 30 mg/dose IV every 6 hours a,b
Docusate: 5 mg/kg/day PO divided in 14 doses
Diphenhydramine: 1 mg/kg/dose IV/PO every 6 hours
Naloxone (for itching): 0.251 mcg/kg/h IV infusion; mix in 0.9% NS
Promethazine: 0.25 mg/kg IV/PO every 6 hours (maximal dose: 25 mg)c
Ondansetron: 0.15 mg/kg/dose IV/PO every 8 hours

Use with caution in patients with kidney failure, dehydration, or bleeding.

Use in children aged 1 year and older. Use with caution in children aged 612 months.
c
Contraindicated in children younger than 2 years because of potential for severe and potentially fatal respiratory depression.
CI = continuous infusion; IV = intravenously; NS = normal saline; PCA = patient-controlled analgesia; PO = orally (by mouth); SCD =
sickle cell disease.
a

PSAP-VII Pediatrics

37

Sickle Cell Disease

is contraindicated in children younger than 2 years

because of the increased risk of respiratory depression.
Constipation is also a concern with the use of opioids;
thus, all patients receiving opioids should be assessed
for stool frequency and initiated prophylactically on
a stool softener and stimulant laxative. Sedation and
drowsiness are difficult to control, and the concurrent use of an opioid with diphenhydramine or other
sedative drugs can exacerbate drowsiness and lead to
hypoxemia. When pruritus is extreme, use of an antihistamine on a scheduled basis may be necessary and
may better control the itching. Some evidence suggests
that a continuous, low-dose naloxone infusion at a dose
of 0.251 mcg/kg/hour is helpful when itching is unrelieved by other agents.

if indicated. In addition, when the pain crisis is severe,

anemia should be treated with RBC transfusions to
increase the hemoglobin concentration to the patients
baseline. Adequate hydration with intravenous or oral
fluids is required during a pain crisis; however, close
monitoring is imperative to avoid fluid overload, which
may lead to ACS or heart failure.
Patients in severe vasoocclusive crisis may develop
life-threatening complications and should be assessed
often for any clinical changes such as increasing oxygen
needs, decreasing hemoglobin concentration or platelet count, and alterations in mental status. In severe
vasoocclusive pain crisis, pain management with parenteral opioids such as morphine or hydromorphone
is required. Meperidine should be avoided because its
toxic metabolite may accumulate with repeated dosing,
especially in patients with reduced kidney function, and
lead to seizures.
Analgesia should be individualized and titrated to
effect. Intermittent intravenous doses should be scheduled rather than ordered on an as-needed basis, or
opioids can be given by continuous infusion, usually
through a patient-controlled analgesia (PCA) infusion pump. Advantages of PCA include an overall lower
opioid consumption, compared with intermittent intravenous bolus dosing, and the patients greater sense
of control over his/her pain management. Children
as young as 5 years can use a PCA pump. Pain control
should be assessed on a regular basis with a self-reported
pain scale and documented. In children, the WongBaker FACES Pain Rating Scale is preferred.
All patients on a continuous infusion of opioid should
be on continuous pulse oximetry, with oxygen saturation maintained at 92% or higher using supplemental
oxygen, if needed. Patients with bone or joint pain who
require parenteral analgesia may benefit from the use
of ketorolac. Because of its adverse effects (e.g., gastrointestinal bleeding, kidney dysfunction), ketorolac use
should be limited to a maximum of 5 consecutive days.
When using products that contain acetaminophen, it
is important to assess the total daily acetaminophen
intake. Childrens doses are typically calculated in milligrams per kilogram; therefore, children at different
weights will receive different doses, and it is difficult to
pinpoint a definitive maximal dose in this population.
In children, acetaminophen is dosed at 1015 mg/kg/
dose, and the maximal dose for a child younger than 12
years is 6090 mg/kg or five doses during a 24-hour
period. In older adolescents, the maximal daily dose is
4 g/day.
There are other considerations for patients receiving intravenous opioids. Incentive spirometry should
be encouraged to prevent atelectasis. Nausea and
vomiting are common and can be treated with antiemetics, such as promethazine, or a 5HT3 antagonist,
such as ondansetron; however, the use of promethazine
Sickle Cell Disease

Hematopoietic Stem Cell Transplantation

The only known curative therapy for SCD is a hematopoietic stem cell transplantation (HSCT) using
marrow from a donor who does not have SCD, typically an HLA-matched sibling. The first transplant for
SCD was performed in 1984, but only about 300 individuals with SCD have received a transplant. Although
there are no well-designed studies assessing the benefit or risk of different types of HSCT in children with
SCD, selection criteria have been proposed. Ideal transplant candidates are younger than 16 years, have an
HLA-identical related donor, and have at least one of
the following signs or symptoms: stroke, ACS, recurrent severe pain episodes, impaired neuropsychological
function with an abnormal magnetic resonance imaging scan, mild to moderate chronic sickle lung disease,
sickle nephropathy, bilateral proliferative retinopathy,
osteonecrosis of multiple joints, or RBC alloimmunization because of long-term transfusion therapy.
In a summary of five small reports with a combined
total of 276 children aged 223 years with SCD undergoing a transplant, overall and event-free survival rates
were about 90% and 80%, respectively. The risk of graft
failure is 10% to 20%, risk of acute graft-versus-host
disease is 15% to 20%, and risk of chronic graft-versushost disease is 10% to 20%. The risk of graft failure after
reduced-intensity myeloablative conditioning for transplant in patients with SCD is high, which limits its use
in some patients. There are issues with gonadal function after transplant in children with SCD. Growth
and development do not appear to be affected, especially in younger patients. One main barrier to the more
widespread use of HSCT for children with SCD is the
difficulty in finding a suitable HLA-identical donor. Less
than 1% of children with SCD have an HLA-identical
sibling who does not have SCD. Research into the identification and use of alternative donors is ongoing.
38

PSAP-VII Pediatrics

Patient Outcomes

This randomized trial was conducted in children 216

years old with SCD who had two abnormal transcranial Doppler ultrasound examinations but had not had
a stroke. Enrolled children were randomized to receive
standard care or chronic RBC transfusions to reduce
their HbS concentration to less than 30%. The main end
point evaluated was incidence of stroke between the two
groups. The investigators reported that the incidence of
stroke in the RBC transfusion group was decreased by
92% over the control group (p<0.0001). This trial was
terminated 16 months early so that RBC transfusions
could be offered to patients receiving standard care. A
subgroup analysis showed that higher bloodflow velocities on transcranial Doppler ultrasound examinations
indicated a higher stroke risk in screened patients. As
expected, serum ferritin concentrations in patients in
the intervention group increased such that chelation
therapy would most likely be indicated. This was the
first study designed to evaluate the utility of chronic
RBC transfusions in preventing a first stroke in at-risk
children with SCD. The authors were unable to identify
an optimal age at which to begin screening or how often
screening should be done.

The goals of SCD treatment focus on preventing

complications and preventing or minimizing symptoms
related to the disease. Treatment interventions should
maintain or increase the hemoglobin concentration
to the patients baseline, increase the HbF concentration, decrease the HbS concentration to less than 30%,
prevent infectious complications, prevent and/or manage pain, and prevent central nervous system damage,
including stroke. The outcome of treatment should be
decreased morbidity and mortality, as measured by the
number of hospitalizations and the extent of end-organ
damage.
All children with SCD should have regularly scheduled health assessments starting shortly after birth.
Regular assessments should include growth and development, hearing and vision screening, urinalysis,
complete blood cell counts, reticulocyte counts, liver
function tests, serum ferritin concentration or other
assessment of iron status, blood urea nitrogen, and
serum creatinine. Education of the patient and caregivers of children with SCD should be routinely performed.
All children with SCD should have a plan in place for
what to do in the event of fever, pain, or symptoms of
infection. Adherence to prophylactic penicillin therapy and childhood immunizations should be routinely
assessed in all children with SCD.

2.

This consensus statement offers a good review of

the available data on hydroxyurea use in patients with
SCD, including children and adults. Efficacy was evaluated in three groups: infants, preadolescents, and
adolescents and adults. The authors stated that although
there are fewer studies in children and infants than in
adults, the evidence for efficacy is strong, and research
is continuing. Short- and long-term effects of treatment
with hydroxyurea are summarized. The authors note
that further studies are needed to assess the effects of
hydroxyurea on both sperm counts and pregnancy/
fertility, especially in younger patients, who may be
initiated on treatment earlier and receive treatment
for a long period. The authors also evaluated barriers
to treatment and potential solutions from the patient,
caregiver, and provider viewpoints, including use of
multidisciplinary care teams, improved access to insurance coverage, and better partnerships and advocacy.
Suggested areas for future research include prospective
surveillance, additional efficacy and effectiveness studies in individuals in all age groups, and determination
of when to begin treatment and how long to continue to
prevent complications.

The Role of the Pharmacist

Caring for the child with SCD requires an interprofessional team-based approach. Patients should be
encouraged to develop a medical home and to be seen
regularly at a comprehensive sickle cell center, if possible, because of their unique needs. The pharmacist
must ensure that the child with SCD receives appropriate childhood and supplemental immunizations;
prophylactic penicillin until at least age 5 years and
older, if warranted; treatment of painful vasoocclusive
crises; HbF inducers, when appropriate; iron chelation,
if needed because of chronic RBC transfusion therapy;
antibiotic drug therapy during episodes of fever and
infection; and other therapies to treat complications as
they develop. Drug therapy should be monitored and
adjusted periodically to ensure appropriate dosing and
selection as the child ages. The pharmacist should assess
the patient for efficacy end points, adherence to drug
therapy, and adverse effects from any drug administered.

3.

Annotated Bibliography
1.

Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E,

Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal
results on transcranial Doppler ultrasonography. N
Engl J Med 1998;339:511.

PSAP-VII Pediatrics

Brawley OW, Cornelius LJ, Edwards LR, Gamble VN,

Green BL, Inturrisi C, et al. National Institutes of
Health consensus development conference statement:
hydroxyurea treatment for sickle cell disease. Ann
Intern Med 2008;148:9328.

Strouse JJ, Lanzkron S, Beach MC, Haywood C, Park

H, Witkop C, et al. Hydroxyurea for sickle cell disease:
a systematic review for efficacy and toxicity in children.
Pediatrics 2008;122:133242.
In this review, the authors synthesized the published
literature (26 articles) on hydroxyurea use in children
with SCD. Most of the children had severe disease and
showed significantly increased HbF concentrations,

39

Sickle Cell Disease

decreased hospitalization rates, and decreased frequency of pain crises. Adverse effects included nail
changes, rash, thrombocytopenia, neutropenia, and
headache, which were reversible on discontinuation
or dose adjustment. Because of the small number of
patients in the studies and the types of articles, no conclusions were made about the potential long-term effects
of hydroxyurea. Only one randomized, controlled trial
was included, together with 22 observational studies
and three case reports. The source of information limits
the ability of the authors to extract the data needed to
make a meaningful overall assessment. Large, ongoing
studies are under way.
4.

6.

This study was designed to evaluate the maximal tolerated hydroxyurea dosage in children aged 515 years
with severe disease and to treat a cohort of 50 children
for 1 year at the maximal tolerated dosage. Patients were
initiated on 15 mg/kg/day, which was increased to a
maximum of 30 mg/kg/day or until laboratory-determined toxicity. These toxicities were placed into three
groups: hematologic, hepatic, or renal. Hematologic
toxicity was defined as one or more of the following:
absolute neutrophil count below 2.0 109/L; absolute
reticulocyte count below 80 109/L, unless the hemoglobin concentration was 9.0 g/dL or higher; platelet
count below 80,000/mm3; a 20% decrease in hemoglobin concentration from baseline; or a hemoglobin
concentration less than 4.5 g/dL. Hepatic toxicity was
defined as an alanine aminotransferase greater than
twice the upper limit of normal. Renal toxicity was
defined as a 50% increase in serum creatinine from
baseline. After 6 months and 12 months of treatment,
there were significant increases in HbF and hemoglobin concentrations and in mean corpuscular volume.
Cytopenias were the most common adverse event, but
these were reversed on drug discontinuation or dose
adjustment. There was no renal toxicity. The authors
concluded that hydroxyurea was safe during a 1-year
to 2-year period in children closely monitored. Because
this was a relatively short-term study, there is no assessment of long-term use and potential adverse effects
(both acute and chronic) that may occur, together
with toxicities that may develop with extended use of
the drug. Ongoing phase III studies are evaluating the
long-term use and complications that may be seen in
children.

Bolaos-Meade J, Brodsky RA. Blood and marrow

transplantation for sickle cell disease: overcoming barriers to success. Curr Opin Oncol 2009;21:15861.
This article reviews the most recent clinical trial
information regarding bone marrow transplantation
(BMT) for potential cure of SCD. A review of the history of BMT (19842009) is presented. Alternative
donors to HLA-matched siblings are discussed, as are
barriers to the more widespread use of BMT in this population. Most reports have described patients younger
than 16 years with severe disease and have shown that
patients with HLA-identical siblings have the best outcomes, with survival at about 80% overall. However,
because of limited matches, BMT remains an option
in selected patients only. Alternative donors discussed
include umbilical cord blood and unrelated or haploidentical bone marrow, although limited reports exist
of the use of these alternatives in children with SCD. A
potential concern is that if BMT becomes a more available option, then one set of problems (i.e., SCD-related
complications) will be exchanged for another set (e.g.,
graft-versus-host disease, opportunistic infections,
toxic conditioning regimens, graft failure).

5.

Buison AM, Kawchak DA, Schall JI, Ohene-Frempong

K, Stallings VA, Leonard MB, et al. Bone area and bone
mineral content deficits in children with sickle cell disease. Pediatrics 2005;116:9439.

7.

Because children with SCD often exhibit poor

growth, this study compared deficits in bone mineral
content and bone area in children with HbSS with
healthy children. Using dual-energy x-ray absorptiometry in children aged 419 years, whole-body bone
mineral content was found to be decreased in children
with SCD. Bone mineral accrual was most affected in
adolescent boys, and there was a positive, although
modest, correlation between bone z scores, hemoglobin
concentration, and hematocrit. Children in the study
had low dietary calcium and vitamin D intakes, which
could have affected the results. Another limitation was
that the controls were assessed for pubertal onset by
examination, whereas children with SCD used a selfreport with a pictorial questionnaire. Nutrition status
and activity also play a role in bone development, and
the authors point out that more research is needed in
this area.

Sickle Cell Disease

Kinney TR, Helms RW, OBranski EE, OheneFrempong K, Wang W, Daeschner C, et al. Safety of
hydroxyurea in children with sickle cell anemia: results
of the HUG-KIDS study, a phase I/II trial. Pediatric
Hydroxyurea Group. Blood 1999;94:15504.

Ware RE, Zimmerman SA, Sylvestre PB, Mortier NA,

Davis JS, Treem WR, et al. Prevention of secondary
stroke and resolution of transfusional iron overload in
children with sickle cell anemia using hydroxyurea and
phlebotomy. J Pediatr 2004;145:34652.
In this prospective trial, which included 35 children
with SCD and previous stroke, patients were switched
from chronic RBC transfusion therapy to a combination of hydroxyurea and phlebotomy for secondary
stroke prevention. Transfusions were continued during
hydroxyurea dose escalation to the maximal tolerated
dose, with an average overlap of about 6 months. Once
RBC transfusions were discontinued, serial monthly
phlebotomy was initiated to relieve iron overload, and
serum ferritin concentrations were monitored. The
rate of recurrent stroke was 3.5 per 100 patient-years,
similar to that seen with chronic RBC transfusions
(2.24.2 per 100 patient-years). Seven patients had
recurrent stroke, but most of these were attributed to
nonadherence to hydroxyurea therapy. Although the
effectiveness of this switch therapy should be further
evaluated in larger multicenter trials, and extended

40

PSAP-VII Pediatrics

to assess long-term efficacy, this approach presents a

viable alternative to lifelong transfusions and the complications from iron overload that may occur. However,
ensuring patient adherence to the hydroxyurea treatment will be an issue with this therapy.
8.

10. Wang WC, Morales KH, Scher CD, Styles L, Olivieri

N, Adams R, et al. Effect of long-term transfusion on
growth in children with sickle cell anemia: results of the
STOP trial. J Pediatr 2005;147:2447.
As another subset analysis of the STOP trial, this
study determined whether chronic RBC transfusion
therapy improved growth in children aged 216 years
who were enrolled in the STOP study. Patient growth
velocities were also assessed and compared with other
published trials in similar populations in which children
with SCD did not receive chronic RBC transfusions.
After 2 years of follow-up, the chronic RBC transfusion group had z scores that were significantly different
from the standard therapy group, approaching the agespecific normal mean for growth. Patients receiving
RBC transfusions approached neutral z scores in both
height-for-age and weight-for-age, whereas those receiving standard therapy had no change over time. Growth
velocity for weight and height were also significantly
increased compared with historic controls. Although
risks are associated with chronic RBC transfusion therapy (e.g., iron overload, alloimmunization), this study
supports an added benefit on growth that should be
evaluated when a decision is made to place a child on
chronic RBC transfusions.

Hankins JS, Ware RE, Rogers ZR, Wynn LW, Lane

PA, Scott JP, et al. Long-term hydroxyurea therapy for
infants with sickle cell anemia: the HUSOFT extension
study. Blood 2005;106:226975.
Infants completing 2 years of hydroxyurea therapy
as part of the Hydroxyurea Safety and Organ Toxicity
(HUSOFT) study were offered extension with dosage
escalation to 30 mg/kg/day to assess long-term effects.
In total, 21 patients were enrolled, with 17 completing
4-year extensions and 11 completing 6-year extensions.
Efficacy, as evidenced by increased hemoglobin, HbF,
and mean corpuscular volume with decreased reticulocyte counts and platelet counts (p<0.01), continued
throughout the study. Splenic function was better than
in historic controls; there were fewer incidences of
ACS (p=0.001) and improved growth in the extension group. Although the study was small, it appears
that hydroxyurea has a role in the avoidance of chronic
organ dysfunction in this patient population. Chronic
organ dysfunction is a special consideration in very
young children with SCD who are initiated earlier on
the drug and will potentially receive it throughout their
life. Larger, longer multicenter studies are needed to
assess the function of other organ systems (e.g., central
nervous system, kidney), and adherence to daily therapy should be stressed.

9.

11. Saad STO, Lajolo C, Gilli S, Marques JFC Jr, Lima CS,
Costa FF, et al. Follow-up of sickle cell disease patients
with priapism treated by hydroxyurea. Am J Hematol
2004;77:459.

This small study (n=5) examined the effectiveness

of hydroxyurea for 10 years in preventing stuttering or
major episodes of priapism in men with SCD who were
still capable of achieving an erection on demand. Three
patients were adolescents (aged 13, 16, and 17 years).
Hydroxyurea was initiated at a daily dose of 10 mg/kg
and increased by 5 mg/kg (maximal dose, 2035 mg/
kg) every 8 weeks until no priapism episodes occurred.
As the hydroxyurea dose was increased, the incidence
and length of the priapism episodes decreased. Within
2 months of reaching the maximal dose, priapism episodes had ceased in all patients. Hydroxyurea was
discontinued in two patients because of oligospermia and leg ulceration. On discontinuation, priapism
returned within 3 months to 1 year. One older patient
(35 years) developed a major priapism episode (lasting longer than 24 hours) while receiving 20 mg/kg/
day of hydroxyurea; he delayed receiving medical attention and subsequently required exchange transfusion,
penile aspiration, and finally placement of a cavernosal shunt. Detumescence occurred 1 month after shunt
placement, and he became impotent. Although this
was a small study, it shows that the use of hydroxyurea
to prevent priapism may be beneficial and may enable
men with SCD to maintain their ability to have normal
erections.

Miller ST, Wright E, Abboud M, Berman B, Files B,

Scher CD, et al. Impact of chronic transfusion on incidence of pain and acute chest syndrome during the
Stroke Prevention Trial (STOP) in sickle-cell anemia.
J Pediatr 2001;139:7859.
The Stroke Prevention Trial (STOP) showed that
chronic transfusion therapy to keep HbS concentration
less than 30% reduces the risk of first stroke in children
who have an abnormal transcranial Doppler ultrasound
examination. This subanalysis evaluated the impact of
chronic RBC transfusions in this patient population
(216 years) on the number and frequency of pain crises and ACS. There was a significant reduction in ACS
events. Although pain crises were reduced, this finding was not statistically significant. One critique of this
study is that some of the events classified as pain crises
may not have been SCD related, because four episodes
occurred in one patient hospitalized five times with
RBC transfusion reactions. Because hemolytic transfusion reactions may mimic sickle-like pain, this patient
could have skewed the number of pain crises overall.
In patients adherent to RBC transfusion therapy, there
were 9.7 pain events per 100 patient-years compared
with 27.1 per 100 patient-years in the standard care
group. Although more study is needed, chronic RBC
transfusion appears to provide an additional benefit in
reducing pain crises and preventing ACS in children.

PSAP-VII Pediatrics

12. Adamkiewicz TV, Abboud MR, Paley C, Olivieri N,

Kirby-Allen M, Vichinsky E, et al. Serum ferritin level
changes in children with sickle cell disease on chronic

41

Sickle Cell Disease

blood transfusion are nonlinear and are associated with

iron load and liver injury. Blood 2009;114:46328.

recommendations for a quality assurance measure. In

both children and adults, PCA has become the standard
for management of severe pain crises and, if possible,
should be begun while the patient is in the emergency
department. Although the authors note that the practice
of pain management in SCD is limited to expert opinion
and inferences from observational studies, with each
center developing its own standard of care guidelines,
the approach should be based on a sound understanding
of the therapeutic risks, benefits, and pharmacokinetics
of the opioid, with ongoing monitoring of the therapy in
the patient. Additional trials in both children and adults
are needed to develop evidence-based guidelines.

Serum ferritin is widely used to monitor iron load

in patients on chronic transfusion therapy because it
is noninvasive and easy to obtain. However, because
serum ferritin concentrations increase in inflammatory states, the relationship between serum ferritin and
other iron load measurements varies among studies.
This study examined data gathered from the STOP and
STOP2 trials, specifically serum ferritin concentrations
and their relationship to transfusional iron loads and
liver iron concentrations, from 271 children without
viral hepatitis. Transfusional iron load was estimated
from the cumulative blood volume received from simple transfusions before the start of chelation therapy,
where 1 mL of packed RBCs was estimated to contain
1 mg of iron. Liver iron concentration measurements
were obtained by liver biopsy and were at the discretion
of the investigators (n=103). An acceptable iron load
range was defined as a transfusional iron load of 25100
mg/kg or liver iron concentration of 2.510 mg/g of
dry weight. Serum ferritin changes appeared nonlinear
compared with the other measurements. Most patients
with serum ferritin 7501500 ng/mL had acceptable
iron load ranges, whereas most patients with serum ferritin concentrations above 3000 ng/mL had greater than
the acceptable iron load ranges. The authors propose
a combination of methods to monitor for iron overload. Determination of total iron load is the simplest
and most accurate measure of iron load to determine
when to start chelation, and serum ferritin concentrations less than 1500 ng/mL indicate an acceptable iron
load for most patients. Serial alanine aminotransferase
measures may also be helpful because concentrations
change in response to iron overload. However, because
serum ferritin concentrations between 1500 ng/mL
and 3000 ng/mL did not fully correlate with acceptable
iron loads, optimal iron load assessment should include
yearly tissue iron determination.

14. Caboot JB, Allen JL. Pulmonary complications of

sickle cell disease in children. Curr Opin Pediatr
2008;20:27987.
Pulmonary complications are a substantial cause of
morbidity and mortality in children with SCD. This
review examines the evidence of a strong association
between asthma and airway hyperreactivity and SCD,
including the link with the incidence and severity of
ACS and vasoocclusive crisis. The clinical diagnosis of
asthma is more common in children with SCD compared with age- and race-matched controls. In addition,
several studies have found that children with SCD
have a higher incidence of airway hyperreactivity in
response to cold air, exercise, or methylcholine challenges. The link between asthma and ACS appears to
be strong, for which there is no definitive explanation.
However, several explanations have been proposed and
explored, including ventilation-perfusion mismatching, leading to local tissue hypoxia and increased RBC
sickling. Children with SCD who have ACS episodes
have worse lung function than children with SCD who
have not had ACS episodes. Data are conflicting on the
prevalence of pulmonary hypertension in children with
SCD, with possible selection bias. Some small studies have not shown a link between ACS episodes and
development of pulmonary hypertension, whereas one
study described a different phenotype in children versus adults and indicated that children with ACS were
more likely to develop pulmonary hypertension. There
appears to be a link between children with SCD and
sleep-disordered breathing, although the exact prevalence, cause, and natural history remain poorly defined.
The authors point out that further research is needed to
understand the interplay of SCD and pulmonary conditions to develop improved treatments.

13. Field JJ, Knight-Perry JE, Debaun MR. Acute pain in

children and adults with sickle cell disease: management in the absence of evidence-based guidelines. Curr
Opin Hematol 2009;16:1738.
This review focuses on the epidemiology, clinical presentation, and management of acute pain in children
and adults with SCD. The authors discuss the landmark
Cooperative Study of Sickle Cell Disease, published in
1991, and the applicability of the results to patients with
SCD today. Since this landmark study, hydroxyurea is
much more widely used, standard pain protocols are
in place at sickle cell centers, and many adults manage
pain episodes at home. Pain diary studies have shown
that most adults with SCD have pain on an almost
daily basis but that few adults seek medical attention, indicating that hospital admissions for pain may
vastly underestimate the pain rate, and that pain rate
may not accurately reflect disease severity. In children
with SCD, readmission within 30 days has been established as a benchmark for quality medical care despite
failing to meet many of the Institute of Medicines

Sickle Cell Disease

15. Boyd JH, DeBaun MR, Morgan WJ, Mao J, Strunk RC.
Lower airway obstruction is associated with increased
morbidity in children with sickle cell disease. Pediatr
Pulmonol 2009;44:2906.
This retrospective study of 102 children with SCD,
aged 618 years, who completed both a lung volume
and spirometry evaluation determined the relationship between abnormalities in pulmonary function
and morbidity as represented by hospitalization rates
for pain or ACS. Pulmonary function tests were categorized into three groups: lower airway obstruction

42

PSAP-VII Pediatrics

because of non-adherence as well as for identifying

children with good adherence but poor response secondary to biologic factors such as pharmacodynamics.
Interventions to improve adherence should be targeted
at both the child and the parent.

(FEV1 [forced expiratory volume in 1 second] less than

95%), restricted (total lung capacity less than 80% predicted), and normal lung function. Pulmonary function
testing was normal in 75% of the cohort. Diagnosis of
asthma was common, affecting 53% of those with normal lung function, 38% with restriction, and 77% with
obstruction. Children in the obstruction group had a
higher incidence of hospitalization rates for pain and
ACS and spent twice as many days per year admitted to
the hospital compared with those having normal lung
function. Restrictive lung function was not associated
with a difference in hospitalization rates for pain or
ACS, and these patients had hospital length of stay rates
similar to the normal lung function group. The authors
concluded that increased surveillance of children with
lower airway obstruction is needed to reduce morbidity.
16. Thornburg CD, Calatroni A, Telen M, Kemper AR.
Adherence to hydroxyurea therapy in children with
sickle cell anemia. J Pediatr 2010;156:4159.
Treatment adherence was evaluated in a single-institution, cross-sectional study of 75 children with SCD
taking hydroxyurea. Good adherence was defined as
a scheduled visit within 1 week for subjects with visits scheduled monthly, 2 weeks for subjects with visits
scheduled every 2 months, and 3 weeks for subjects
with visits scheduled every 3 months. Caregiver reports
used a visual analog scale and the Modified Morisky
Scale. The visual analog scale asked caregivers to mark
an X on a line from 0 to 100 indicating the percentage
of doses taken within the past 34 weeks, where good
adherence was indicated by greater than 75% of doses
taken. The Modified Morisky Scale was composed of
four yes/no questions, and good adherence was indicated by scores of 1 or more on a 04 scale. In addition,
the patients physician provided an estimate of adherence (estimates of often or always indicated good
adherence), and pharmacy prescription refill data were
obtained (5-month or greater supply refills in the 6
months before enrollment, indicating good adherence).
Barriers to adherence were collected through caregiver questionnaires, and hematologic outcomes were
evaluated through assessing HbF and mean corpuscular. Good adherence was estimated at 77% to 85% with
self-report, medical provider report, and clinic visits.
Adherence was substantially lower based on pharmacy
refills at 49% achieving good adherence. Significant
increases occurred in HbF and mean corpuscular volume, although the increase in HbF was variable and
moderately associated with good adherence as measured by Morisky score and prescription refills when
adjusted for confounding factors. Fetal hemoglobin
F concentration was not predicted by age or length of
treatment. Primary barriers included coming to the
clinic and obtaining refills. The authors concluded that
a variation in hematologic response existed among
their patients that was partly explained by adherence.
Moreover, the authors noted that although no single
measure of adherence was ideal, pharmacy refills and
the Modified Morisky Scale may be useful for identifying children at risk of poor response to hydroxyurea

PSAP-VII Pediatrics

43

Sickle Cell Disease

Sickle Cell Disease

44

PSAP-VII Pediatrics

Self-Assessment Questions
400 mg orally every 8 hours as needed for pain
and acetaminophen/hydrocodone 325 mg/7.5 mg
orally every 6 hours as needed for pain. His oral
temperature is 99.5F (37.5C). His oxygen saturation is 86% on room air by nasal cannula. His
laboratory results show a hemoglobin concentration of 5.4 g/dL, WBC count of 5 103 cells/mm3,
and hemoglobin S (HbS) concentration of 20%.
He has been initiated on intravenous fluids. Which
one of the following is most likely to have the
greatest impact on this patients symptoms?

21. A 6-month-old girl (weight, 7.5 kg) who screened

positive for sickle cell disease (SCD) at birth is seen
in the clinic. She was determined to be homozygous
for sickle hemoglobin (HbSS). She is up to date
on her routine pediatric vaccinations, receives no
chronic drugs, and has had no hospital admissions.
Her complete blood cell count (CBC) is within
normal limits. Her laboratory results show a hemoglobin concentration of 10.1 g/dL, white blood cell
(WBC) count of 6 103 cells/mm3, hematocrit concentration of 33%, and platelet count of 235,000/
mm3. Which one of the following is the most
appropriate treatment to initiate in this patient?

A. Ceftriaxone 2.5 g given intravenously every 12

hours.
B. Oxygen by nasal cannula to keep saturations
greater than 95%.
C. Hydroxyurea 500 mg orally once daily.
D. Packed RBC transfusion.

A. Folic acid 1 mg orally daily.

B. Penicillin V potassium 125 mg orally twice
daily.
C. Hydroxyurea 10 mg/kg orally daily.
D. Red blood cell (RBC) transfusions 10 mL/kg
every 4 weeks.

Questions 2527 pertain to the following case.

The patient is a 3-year-old girl with SCD who lives with
her parents in a rural area about 2 hours from the nearest
hospital. She presents to the clinic today for a scheduled
checkup. She was hospitalized at age 8 months for dactylitis and at age 26 months for aplastic crisis. She has
received all of her routine childhood immunizations,
and at age 2 years, she received a 23-valent pneumococcal polysaccharide vaccine. Her current drugs include
penicillin V potassium 125 mg orally twice daily, folic
acid 0.4 mg orally daily, and acetaminophen/codeine
120 mg/12 mg per 5 mL orally every 6 hours as needed
for pain.

22. An 11-year-old boy (weight, 46 kg) with SCD is

admitted for acute chest syndrome (ACS). He has
an oral temperature of 102.2F (39C), is undergoing appropriate fluid resuscitation, and is receiving
oxygen by nasal cannula because his oxygen saturations on room air were 89%. His drug profile
includes intravenous morphine for pain and oral
diphenhydramine for itching. Which one of the
following is most appropriate to add to this
patients regimen at this time?
A. Methylprednisolone 20 mg intravenously
every 12 hours.
B. Albuterol metered-dose inhaler 2 puffs by
mouth every 4 hours.
C. Ceftriaxone 1 g intravenously every 12 hours.
D. Cephalexin 500 mg orally every 6 hours.

25. Which one of the following is best to protect this

patient against invasive pneumococcal disease?
A. Continue penicillin V potassium 125 mg
orally twice daily.
B. Increase penicillin V potassium to 250 mg
orally twice daily.
C. Revaccinate with 23-valent pneumococcal
polysaccharide vaccine.
D. Revaccinate with 13-valent pneumococcal
conjugate vaccine.

23. A 6-year-old boy (weight, 18 kg) with HbSS has a

diagnosis of stroke. Which one of the following is
the most appropriate therapy to prevent further
strokes in this patient?
A.
B.
C.
D.

Exchange transfusion every 4 weeks.

Hydroxyurea 270 mg orally once daily.
Clopidogrel 37.5 mg orally once daily.
Chronic RBC transfusion therapy.

26. The patients mother, who recently lost a 6-year-old

nephew to complications from SCD, wants to discuss her daughters medical care. Which one of the
following most increases this patients risk of
morbidity and mortality?

24. A 13-year-old boy (weight, 50 kg) with SCD presents to the emergency department with complaints
of increasing lethargy and tiredness for the past 2
weeks. He states he can hardly get out of bed in the
morning because he is so tired. He takes ibuprofen

PSAP-VII Pediatrics

A. Living in a rural area distant from

comprehensive health care facilities.
B. Having a history of dactylitis before 1 year of age.
45

Sickle Cell Disease

A. Decrease hydroxyurea to 275 mg orally once

daily.
B. Increase hydroxyurea to 440 mg orally once
daily.
C. Increase hydroxyurea to 660 mg orally once
daily.
D. Continue hydroxyurea at 330 mg orally once
daily.

C. Requiring analgesic drugs to treat symptoms

before 18 months of age.
D. Having a history of aplastic crisis at 26 months
of age.
27. Six months later, this patient (weight, 14 kg) is
admitted to the hospital with chest pain and fever.
She has a nonproductive cough, and pulmonary
infiltrates are noted on chest radiography. Her
WBC count is 16 103 cells/mm3, hemoglobin is 8
g/dL, and temperature is 104F (40C). The patient
is initiated on ceftriaxone 400 mg intravenously
every 12 hours, oxygen by nasal cannula to keep
oxygen saturations above 92%, and morphine 1 mg
intravenously every 3 hours as needed for pain. On
day 3 of hospitalization, she is still febrile, and her
WBC count is 18 103/mm3. Which one of the following antibiotics is best to add to the patients
regimen?

30. The patient is now 10 years old (weight, 25 kg).

His hydroxyurea has been titrated to the maximal tolerated daily dosage of 900 mg. However, he
was recently admitted to the hospital for thrombocytopenia, neutropenia, and severe anemia.
Hydroxyurea was discontinued, and supportive care was given. His cell counts recovered, and
the decision was made to reinitiate hydroxyurea
therapy. Which one of the following is the most
appropriate initial daily hydroxyurea dose for
this patient?

A. Clindamycin 140 mg intravenously every 8

hours.
B. Penicillin G 875,000 units intravenously every
6 hours.
C. Erythromycin 175 mg intravenously every 8
hours.
D. Ciprofloxacin 140 mg intravenously every 12
hours.

A.
B.
C.
D.

31. Which one of the following patients is the best

candidate for a hematopoietic stem cell transplantation for a potential cure of his/her SCD?

Questions 2830 pertain to the following case.

The patient is an 8-year-old boy (weight, 22 kg) with
SCD who has had four hospital admissions for ACS
during the past 2 years. The decision is made to start
hydroxyurea therapy.

A. A 19-year-old woman with severe sickle

nephropathy.
B. A 4-year-old boy with recurrent stroke and
RBC alloimmunization.
C. A 9-month-old boy with splenic sequestration.
D. A 15-year-old girl with three admissions for
severe vasoocclusive pain crises.

28. Which one of the following combinations of

baseline laboratory measurements is best to
obtain as an indicator of this patients response
to therapy?

32. A 7-year-old girl (weight, 19 kg) visits your clinic

for a scheduled transfusion. She had a stroke at age
5 years and has been on chronic RBC transfusion
therapy every 4 weeks to maintain her HbS concentration at less than 30%. Today, her serum ferritin
concentration is 1820 ng/mL, hemoglobin concentration is 11.6 g/dL, and hematocrit is 34%. Which
one of the following is the most appropriate recommendation for this patient?

A. WBC count with differential and reticulocyte

count.
B. Reticulocyte count and HbS concentration.
C. HbS and fetal hemoglobin (HbF)
concentrations.
D. Mean corpuscular volume (MCV) and HbF
concentration.

A. Continue with scheduled RBC transfusion;

return to the clinic for CBC and reticulocyte
count in 4 weeks.
B. Continue with scheduled RBC transfusion;
initiate iron chelation therapy.
C. Hold scheduled RBC transfusion; return to
the clinic for CBC and reticulocyte count in 4
weeks.

29. The patient is initiated on hydroxyurea 330 mg

orally once daily. After 12 weeks at this dosage,
his hemoglobin is 9.5 g/dL, WBC count, 7 103
cells/mm3; platelet count, 250,000/mm3; HbF,
21%; MCV, 87.4 f/L; and reticulocyte count,
146,000/mm3. Which one of the following is the
most appropriate response after reviewing this
patients laboratory findings?
Sickle Cell Disease

500 mg.
700 mg.
800 mg.
900 mg.

46

PSAP-VII Pediatrics

D. Hold scheduled RBC transfusion; initiate iron

chelation therapy.

complain of pain in her lower leg, which is now edematous and warm but with good perfusion and pulses.

Questions 33 and 34 pertain to the following case.

A 14-year-old boy with SCD has been maintained on
chronic RBC transfusion therapy for several years secondary to a stroke. He is admitted to the hospital because
of an acute decrease in urine output and weight gain of 4
kg during the past week. Laboratory values include the
following: aspartate aminotransferase (AST), 98 international units/L; total bilirubin, 4 mg/dL; blood urea
nitrogen, 55 mg/dL; serum creatinine, 2.5 mg/dL; and
serum ferritin, 415 ng/mL.

35. Which one of the following infectious organisms is the most likely etiology of this patients
illness?
A.
B.
C.
D.

36. The girl rates her pain as a 9 on a 110 scale, with

1 being no pain and 10 denoting severe pain. She
has been taking acetaminophen/hydrocodone
(325 mg/5 mg) tablets at home with no pain relief.
Which one of the following is the best alternative analgesic regimen for this patient during
her hospitalization?

33. The patient is scheduled for his usual deferoxamine

dose today. Which one of the following is the best
option for him?
A. Administer his scheduled deferoxamine dose
today.
B. Hold the scheduled deferoxamine dose until
his urine output returns to baseline.
C. Hold the scheduled deferoxamine dose;
resume deferoxamine when his ferritin
concentration is greater than 1500 ng/mL.
D. Discontinue deferoxamine; initiate iron
chelation with deferasirox orally given daily.

A. Ketorolac 15 mg intravenously every 6 hours

as needed for pain.
B. Morphine 3-mg intravenous boluses every 3
hours as needed for pain.
C. Acetaminophen/hydrocodone 325 mg/10 mg
orally every 4 hours.
D. Morphine administered by patient-controlled
analgesia with a 0.6-mg continuous infusion
basal rate and 0.6-mg on-demand dosing.

34. Two years later, this patients kidney function has

fully recovered, and he continues on chronic RBC
transfusion therapy and iron chelation with deferoxamine. He recently acquired both a girlfriend
and a drivers license, and he has admitted to nonadherence to his iron chelation therapy. He
expresses frustration with the chelation regimen
and asks whether it would be possible to stop the
deferoxamine therapy. Which one of the following is the best action to take regarding this
patients deferoxamine therapy?

37. On hospital day 2, this patient complains of severe

itching, which is very distressful to her. Which one
of the following is the best option for treating
her pruritus?
A. Diphenhydramine 25 mg given orally every 6
hours as needed for itching.
B. Diphenhydramine cream 1% applied topically
to the affected area every 6 hours.
C. Hydroxyzine 15 mg given intramuscularly
every 6 hours as needed for itching.
D. Diphenhydramine 25 mg given intravenously
every 6 hours.

38. By hospital day 3, this patient is afebrile, and her
pain is somewhat improved. She complains that her
stomach hurts, and she is quite nauseated. She is
also quite drowsy, although easily roused. Which
one of the following is the best option for treating this patients nausea?

A. Discontinue RBC transfusion therapy;

continue deferoxamine.
B. Continue RBC transfusion therapy; continue
deferoxamine.
C. Discontinue RBC transfusion therapy;
discontinue deferoxamine; initiate deferasirox.
D. Continue RBC transfusion therapy;
discontinue deferoxamine; initiate deferasirox.
Questions 3538 pertain to the following case.
A 9-year-old girl (weight, 30 kg) with SCD is admitted
to the hospital with a temperature of 103.6F (39.8C)
and leg pain. She has been taking around-the-clock oral
analgesics at home without pain relief. She is initiated on
intravenous fluids, empiric antibiotics, and intravenous
opioid analgesics, and she will receive an RBC transfusion and oxygen, as needed. The patient continues to
PSAP-VII Pediatrics

Streptococcus pneumoniae.
Mycoplasma pneumoniae.
Salmonella.
Staphylococcus aureus.

A. Promethazine 7.5 mg intravenously every 6

hours as needed.
B. Ondansetron 4 mg orally every 8 hours as
needed.
C. Promethazine 7.5 mg intramuscularly every 6
hours as needed.
47

Sickle Cell Disease

D. Ondansetron 12 mg orally every 8 hours as

needed.

B Chronic RBC transfusion therapy to maintain

HbS concentration less than 30%.
C. Assess for potential bone marrow transplant.
D. Repeat transcranial Doppler in 1 month.

39. A 5-year-old boy (weight, 17 kg) who has taken

deferasirox 375 mg orally daily for 8 months because
of iron overload from chronic RBC transfusion
therapy is in the clinic today for a routine follow-up
visit. His only complaint is of occasional headaches,
which are relieved by acetaminophen. His mother
denies any adherence issues with deferasirox. On a
clinic visit 4 weeks ago, his laboratory values were
as follows: serum creatinine, 0.5 mg/dL; AST, 30
international units/L; alanine aminotransferase
(ALT), 24 international units/L; and serum ferritin, 671 ng/mL. Todays laboratory values are
serum creatinine, 0.9 mg/dL; AST, 35 international
units/L; ALT, 30 international units/L; and serum
ferritin, 470 ng/mL. Which one of the following
options regarding deferasirox therapy is most
appropriate for this patient?
A. Hold deferasirox therapy; repeat laboratory
assessment in 2 weeks.
B. Increase deferasirox dosage to 500 mg.
C. Discontinue deferasirox; do not restart.
D. Decrease deferasirox dosage to 250 mg.
40. A 17-year-old boy (weight, 63 kg) with SCD has had
six hospital admissions for pain crises in the past
10 years. He has no history of stroke or ACS. He
recently began complaining of increased episodes
of stuttering priapism, occurring once or twice
weekly and lasting about 15 minutes. His hemoglobin concentration is 9.4 g/dL, hematocrit is 30%,
and serum creatinine is 0.8 mg/dL. Which one of
the following is the best therapeutic option for
this patient?
A. Aspirate the penile blood and irrigate with
epinephrine.
B. Administer hydroxyurea 1000 mg orally once
daily.
C. Administer chronic RBC transfusion therapy
to maintain HbS less than 20%.
D. Give pseudoephedrine 30 mg orally at
bedtime.
41. A 5-year-old boy with SCD has had two pain crises within the past 2 years, but he has no history of
stroke or ACS. His grades at school have dropped
during the past 6 months. The results of transcranial Doppler ultrasonography were abnormal,
showing elevated cerebral bloodflow velocities but
no evidence of stroke. Which one of the following
is the best option for this patient at this time?
A. Hydroxyurea daily to induce HbF production.

Sickle Cell Disease

48

PSAP-VII Pediatrics