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P e d i a t r i c H e m a t o l o g i c an d

On c o l o g i c Em e r g e n c i e s
a, b
Kathleen Stephanos, MD *, Sarah B. Dubbs, MD

KEYWORDS
 Sickle cell disease  Immune thrombocytopenia  Tumor lysis syndrome
 Neutropenic fever  Typhlitis  Pediatric  Hematologic emergency
 Oncologic emergency

KEY POINTS
 Hemoglobinopathies have a high risk of life-threatening complications, with which emer-
gency providers must be comfortable identifying and appropriately managing.
 Bleeding disorders, although rare, can present with life-threatening bleeding, but the
treatment of these varies depending on the disorder.
 Patients with new-onset cancer often present with nonspecific symptoms, and tumor lysis
must be considered and be a part of the evaluation.
 The therapies used for patients with cancer can pose life-threatening risks to patients for
which emergency providers must be prepared.

INTRODUCTION

Pediatric hematologic and oncologic emergencies are in 3 major categories: compli-


cations of hematologic disorders, emergencies associated with the new onset of can-
cers, and treatment-associated oncologic emergencies. Although the overall number
of these patients remains low, the mortality associated with these diseases remains
high despite significant advances in management. This article presents a review of
the most commonly encountered pediatric hematologic and oncologic complications
that emergency physicians and providers need to know.

Hematologic Disorders
Hematologic disorders affecting the pediatric population include hemoglobinopathies,
platelet disorders, and bleeding disorders. The hemoglobinopathies encompass a

a
Departments of Emergency Medicine and Pediatrics, University of Rochester School of
Medicine, 601 Elmwood Avenue, Box 655, Rochester, NY 14642, USA; b Department of Emer-
gency Medicine, University of Maryland School of Medicine, 110 S. Paca Street, 6th Floor, Suite
200, Baltimore, MD 21201, USA
* Corresponding author.
E-mail address: katsand@gmail.com
Twitter: @pemkats (K.S.); @sbuidubbs (S.B.D.)

Emerg Med Clin N Am 39 (2021) 555–571


https://doi.org/10.1016/j.emc.2021.04.007 emed.theclinics.com
0733-8627/21/ª 2021 Elsevier Inc. All rights reserved.

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556 Stephanos & Dubbs

broad range of disorders, including sickle cell disease (SCD), hereditary spherocyto-
sis, and the thalassemias. Platelet and other bleeding disorders, such as von Wille-
brand disease and hemophilia, present as a spectrum from a mild disorder to
severe disease with life-threatening bleeding. The most common pediatric bleeding
disorder, immune thrombocytopenia (ITP), is discussed in this article.

New-onset Cancers
New malignancies in pediatric patients often present as a vague constellation of
symptoms. Unlike in adult patients, many newly identified malignancies are admitted
to the hospital for work-up and initiation of therapy. Tumor lysis syndrome is a com-
mon complication of lymphoproliferative disease treatment; it can also be a complica-
tion of pediatric solid organ tumors, although these masses more often present with
compressive complications.

Cancers Undergoing Therapy


Patients who are undergoing therapy often have complications that are directly asso-
ciated with therapy. Radiation has localizing effects, whereas chemotherapy can have
a variety of targeted organ effects. This article briefly reviews the common drug side
effects and explains the management of neutropenic fever and typhlitis in the pediatric
patients with cancer.

DISCUSSION
Sickle Cell Disease
Overview
The hemoglobinopathies encompass a broad range of disorders, including SCD, he-
reditary spherocytosis, and the thalassemias. SCD is the most common of these; it is a
genetic autosomal recessive hemoglobin disorder that affects millions worldwide.
There are multiple mutations that lead to variants of SCD and coinherited thalassemia
with a range of clinical manifestations. The mutations cause abnormal hemoglobin
polymerization, causing the red blood cells (RBCs) to take on an elongated and rigid
morphology similar to a crescent, or sickle sword. The sickled erythrocytes cause
microvascular and larger vessel occlusion as well as other cell and endothelial effects
leading to acute and chronic complications. Although the sickling is reversible, these
erythrocytes have a shorter half-life, which causes significant anemia. Hypoxia, dehy-
dration, and other factors drive sickling, and thus compound a cycle of further
ischemia and RBC sickling.
SCD complications leading to emergency department visits include vaso-occlusive
episode (VOE)/crisis, acute chest syndrome (ACS), thromboembolic and hemorrhagic
stroke, infection, and acute anemia. A more comprehensive listing of acute SCD com-
plications is presented in Box 1.

Prevalence/incidence/mortality
Globally, the prevalence of SCD varies greatly between regions but reaches 40% in
some areas of sub-Saharan Africa, eastern Saudi Arabia, and central India.1 In devel-
oping areas, it is a disease that causes significant early childhood mortality despite
improving access to medications such as hydroxyurea.2
SCD affects approximately 100,000 Americans.3 A review of United States mortality
data revealed that the mortality for pediatric patients with SCD decreased between
1979 and 2017, but the mortality increased for adults during the same period of
time. The median age at death increased from 28 years to 43 years. Deaths during

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Pediatric Hematologic and Oncologic Emergencies 557

Box 1
Acute complications of sickle cell disease

VOE (also known as vaso-occlusive crisis)


Acute anemia
Hemolysis
Aplastic crisis
Sequestration (splenic or hepatic)
ACS
Infection
Sepsis/bacteremia caused by encapsulated organisms
Septic arthritis
Osteomyelitis
Stroke (ischemic or hemorrhagic)
Pulmonary/venous thromboembolism
Solid organ infarction (renal, splenic, hepatic)
Avascular necrosis
Priapism

childhood trend toward acute complications as a cause, whereas adult deaths were
more associated with chronic complications of SCD.4

Clinical presentation
Acute complications of SCD leading to emergency department visits include VOE/
crisis, ACS, thromboembolic and hemorrhagic stroke, venous thromboembolism
(VTE), infection, and acute anemia. VOEs are the classic and most common type of
acute SCD complication, occurring in isolation or in tandem with other complications.
VOE manifests as muscle and/or joint pain, most commonly in the back and lower
extremities, and more specifically as dactylitis of the fingers and toes, especially in
patients less than 2 years of age. In patients with SCD, pain crises are frequently
recurrent in similar locations of the body, which typically includes long bones, and
may also be present in the abdomen. It is important to characterize a current pain
event in terms of onset, associated symptoms (such as fever), and comparison
with prior pain events.
Patients presenting with chest pain, fever, tachypnea, cough, or wheezing must be
evaluated for ACS, defined as those symptoms plus a new infiltrate on chest imaging.
ACS is a leading cause of death in adults with SCD.5 Cardiopulmonary symptoms on
presentation should also raise consideration for other SCD-related and non–SCD-
related diagnoses, including myocardial infarction and pulmonary embolism. It is
well established that adults with SCD have higher rates of VTE, and new data from
a multicenter retrospective cohort analysis suggest a significant prevalence of VTE
in pediatric patients with SCD (1.7%), with independent association of VTE with death
(odds ratio [95% confidence interval]; P 5 8.95 [3.55–22.56]; P<.0001).6
Strokes in patients with SCD, similarly to other patients without SCD, present with
sudden acute neurologic dysfunction. The lifetime prevalence of neurologic complica-
tions in patients with SCD (vasculopathy, territorial infarction, intracranial hemorrhage,
or silent cerebral ischemia) is 25%, often occurring in early childhood.7,8 Because chil-
dren with SCD are at high risk for ischemic strokes, any focal neurologic symptoms or
signs warrant further investigation.

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558 Stephanos & Dubbs

Infection may present with constitutional symptoms with or without fever, and may
also localize to a source; for example, pneumonia, joint infection, or elsewhere. Func-
tional asplenia from intraparenchymal sickling leaves the patient at risk for life-
threatening bacterial infection, especially from encapsulated organisms such as
Streptococcus pneumoniae and Haemophilus influenzae type B. Pneumococcal con-
jugate vaccines and the implementation of penicillin prophylaxis have reduced the
incidence of infection greatly.9
Acute anemia is another potentially life-threatening complication of SCD. Patients
present with symptoms suggestive of anemia, such as fatigue, shortness of breath,
or exertional chest pain. The anemia can be induced by one of several distinct pro-
cesses: (1) acute splenic or hepatic sequestration, (2) transient red cell aplasia (aplas-
tic crisis), or (3) increased hemolysis. New or worsened jaundice suggests a hemolytic
process, and new organomegaly may suggest splenic or hepatic sequestration.10

Diagnostics
The sickle cell trait is routinely assessed in prenatal screening for expectant mothers.
In the United States and other developed countries, SCD is typically diagnosed on
newborn screening, with all 50 states plus the District of Columbia screening for
SCD as part of the newborn screening program.11
For patients presenting with VOE or other potential SCD-related complications,
serum tests are indicated. Laboratory evaluation for patients presenting with concern
for SCD complications should include a complete blood count (CBC) and comprehen-
sive metabolic panel inclusive of aspartate aminotransferase (AST), alanine amino-
transferase (ALT), alkaline phosphatase, bilirubin, lipase, prothrombin time (PT),
partial thromboplastin time (PTT), reticulocyte count, and lactate dehydrogenase
(LDH). In addition, any patient with SCD with a fever requires rapid assessment with
a blood culture, and transfusion tests should be ordered if transfusion is anticipated.
Table 1 provides a summary of recommended diagnostics.
Acute anemia is defined as a decrease of greater than 2 g/dL from baseline hemo-
globin.12 A very low or nil reticulocyte count suggests an erythrocyte aplasia, whereas
a normal or somewhat increased reticulocyte count in combination with increased in-
direct bilirubin, AST/ALT, and LDH levels suggests hemolysis and/or sequestration.
Note that, despite investigations into inflammatory markers and other laboratory
tests, there are no diagnostic markers for vaso-occlusive pain. Pain assessment in

Table 1
Suggested diagnostic evaluation for patients with sickle cell disease

Diagnostic Test Application


CBC Assess hemoglobin level compared with baseline.
White blood cell and platelet counts may be increased
but nonspecific
Reticulocyte count Very low count in setting of acute anemia suggests
aplastic crisis
AST/ALT/alkaline phosphatase Can suggest hepatobiliary complications, hemolysis
Direct bilirubin, LDH Increase suggests hemolysis
Blood and/or urine culture Assess for bacteremia or bacteriuria as a cause of
fever/infection
Chest radiograph Assess for infiltrates or pulmonary effusion
Computed tomography chest Assess for pulmonary infiltrates or infarction;
angiogram for assessment of pulmonary embolism

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Pediatric Hematologic and Oncologic Emergencies 559

the pediatric population is challenging, because the developmental stage in these pa-
tients may not be advanced enough to understand or describe their pain. Further, pa-
tients with chronic pain, such as those with SCD, experience pain in a more complex
manner, often complicated further with anxiety.13
In this chronically ill pediatric population, it is imperative to balance the risks of ra-
diation exposure against the risk of delayed complication diagnosis. If the patient is
afebrile and the pain is similar to prior events, imaging is likely to be of low yield. How-
ever, if the clinical presentation includes chest pain, hypoxia, shortness of breath, fe-
ver, or cough, a chest radiograph should be obtained immediately to assess for ACS.
Computed tomography (CT) imaging may also be helpful, especially with angiography
if pulmonary embolism (PE) is suspected. Several studies have shown increased
D-dimer levels in patients with SCD and VOE,14–16 although there is currently no pro-
posed threshold or clinical decision tool for PE assessment in patients with SCD.
Neurologic deficits should be evaluated similarly to the general population, with the
understanding that the threshold for work-up is low in this high-risk population. If oste-
omyelitis or avascular necrosis is suspected based on history or examination findings,
further advanced imaging, such as MRI, is recommended.

Management
Pain control is an important factor that must be addressed in VOE. The American So-
ciety of Hematology (ASH) published updated guidelines in treatment of acute and
chronic SCD pain in 2020.17 Among the recommendations pertaining to treatment
of acute pain in children are:
 Rapid (within 1 hour of emergency department arrival) assessment and adminis-
tration of analgesia with frequent reassessments (every 30–60 minutes)
 Tailored opioid dosing based on baseline opioid therapy and prior effective ther-
apy: individualized care plans developed by acute care and SCD care providers
 Short course (5–7 days) of nonsteroidal antiinflammatory drugs in addition to opi-
oids for acute pain management
 Steroids should not be used for acute pain management
The ASH guideline panel did not offer a recommendation for or against intravenous
fluids in management of acute pain, but notes that the nonrecommendation does not
preclude administration of fluids to patients with clinically significant dehydration.17
For suspected ACS, patients should be managed with supplemental oxygen, pain
control, and incentive spirometry to prevent splinting/hypoventilation, and empiric an-
tibiotics to include coverage of encapsulated and atypical organisms. Hematology
should be consulted early for consideration of exchange transfusion in the case of
ACS, as well as in the case of ischemic stroke. If the patient is dehydrated or hypovo-
lemic, isotonic solution and oral hydration should be administered with the goal of
euvolemia. Overhydration or rapid hydration should be avoided, because complica-
tions of pulmonary edema may occur.17
Undifferentiated fever must also be addressed with empiric antibiotics to cover
encapsulated organisms. Patients with indwelling lines or ports should also receive
adequate skin flora coverage against methicillin-sensitive Staphylococcus aureus
and methicillin-resistant S aureus (MRSA).
Simple blood transfusion may be considered in cases of acute symptomatic red cell
aplasia. In the case of sequestration crisis, transfusion should only be used if the pa-
tient is hemodynamically unstable, because there is significant risk of hyperviscosity
leading to stroke, ACS, and VOE from transfusion and/or release of sequestered
RBCs back into circulation.17

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560 Stephanos & Dubbs

Patients with uncontrolled painful VOEs or concern for any of the discussed life-
threatening complications should be admitted for continued management and hema-
tology consultation.

Clinics care points


 Painful VOE can occur in isolation, but can also overlap with other complications;
a thorough history and physical must be performed to exclude other
complications
 Maintain a low threshold to obtain chest radiographs in the assessment of ACS, a
life-threatening complication of SCD
 Children with SCD are at high risk of ischemic stroke, so prompt detection is key
and management includes consideration of exchange transfusion
 Acute anemia is defined as a decrease of greater than 2 g/dL from baseline he-
moglobin level; the physical examination, reticulocyte count, and hemolysis tests
are key in assessing the cause

Immune Thrombocytopenia
Overview
ITP is the most common bleeding disorder diagnosed in children. ITP was previously
referred to as idiopathic thrombocytopenic purpura, but the change in nomenclature
reflects recognition that the disease process is caused by immune effects on platelets,
and that most patients with the disease process do not have purpura.18
Thrombocytopenia is defined as a platelet count less than 100  109/L. Primary ITP
is thought to be caused by immune destruction of platelets, and secondary ITP is
associated with other underlying disorders. There is also mounting evidence that
platelet production is impaired in ITP.19

Prevalence/incidence/mortality
The incidence of ITP has trimodal peaks in childhood, young adulthood, and the geri-
atric years. From 2011 to 2016, the incidence of ITP for children less than 18 years old
in the United States was 8.8 (95% confidence interval; 8.5–9.1) per 100,000 person-
years.20

Clinical presentation
ITP is often self-limiting, however one-quarter of cases become chronic. Bleeding
associated with thrombocytopenia can be life threatening. Most adults and children
do not present with purpura,18 which contributes to the reason for the change in
nomenclature.
Common presenting symptoms include mucosal bleeding such as hemorrhagic
mucosal blisters, gum bleeding, or epistaxis. Patients may be asymptomatic and
thrombocytopenia incidentally discovered when tests are obtained for an unrelated
reason.
Life-threatening bleeding is a feared but uncommon clinical presentation of ITP. A
systematic review found the weighted proportion for intracerebral hemorrhage (ICH)
in children with acute or chronic ITP is 0.4%.21 The same study found the weighted
proportion for all other types of severe non-ICH bleeding was 20.8% in children,
although the investigators acknowledge that the definition of severe bleeding was var-
iable in the primary studies.

Diagnostics
The initial basic evaluation for patients presenting with potential ITP or other bleeding
or clotting disorder includes a CBC with reticulocyte count and peripheral blood

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Pediatric Hematologic and Oncologic Emergencies 561

smear, as well as PT/PTT. Serum quantitative immunoglobulin panels can assist he-
matology consultants in the diagnostic work-up of ITP.
CT imaging of the head must be expedited in all patients with ITP or other bleeding
disorders who are presenting with head trauma or atraumatic headache. In cases
where the patient is altered or there is high suspicion for ICH, treatment should be initi-
ated even before the expedited imaging. In patients with a prior history of ITP,
commonly used clinical decision tools, such as the Pediatric Emergency Care Applied
Research Network head injury algorithm, should be applied with caution.
Management
A hematologist should be consulted in the management of pediatric patients with ITP.
An ASH panel published updated guidelines for adult and pediatric management of
ITP in 2019,22 summarized later. The recommendations are based on symptoms
rather than platelet count.
 In the case of severe, life-threatening bleeding, the cornerstones of treatment are
platelet transfusion, corticosteroids, and intravenous immunoglobulin (IVIG).
 For non–life-threatening mucosal bleeding and/or patients with diminished
health-related quality of life:
 First-line treatment: short course (7 days) of corticosteroids
 Second-line treatment: thrombopoietin receptor agonists
 Observation (without steroids, IVIG, or other treatments) is recommended
regardless of the platelet count for patients with no or minor bleeding.

Clinics care points


 ITP can be incidentally diagnosed in asymptomatic children, or can present with
minor to life-threatening bleeding
 Obtain CBC, reticulocyte count, and peripheral smear  coagulation studies
 In all cases of head trauma or atraumatic headache, obtain expedited head
imaging
 Treatment and disposition are based on symptoms rather than platelet count
New-onset Malignancies
Overview
The diagnosis of pediatric oncologic processes often occurs because of vague or
persistent symptoms over time. Constitutional symptoms such as weight loss or
poor weight gain for age, bone pain, fatigue, or unexplained persistent fevers should
prompt evaluation (Table 2). The most common pediatric cancers are leukemia,

Table 2
Typical signs and symptoms associated with childhood malignancies

Diagnosis Symptoms
Leukemia Fatigue, pallor, fevers, bleeding, bruising, weight loss
Neuroblastoma Hypertension, abdominal mass, abnormal eye and body movements,
raccoon eyes
Wilms tumor Abdominal mass, fevers, loss of appetite
Lymphoma Fatigue, lymphadenopathy, weight loss, fever
Bone tumors Bone pain, pathologic fractures, nighttime limb pain
B tumors Morning headaches, vomiting, focal neurologic deficits, seizures
Retinoblastoma Leukokoria

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562 Stephanos & Dubbs

lymphoma, bone cancers, intracranial tumors, Wilms tumor, neuroblastoma, rhabdo-


myosarcoma, and retinoblastoma.23 There must be a high index of suspicion for these
in order to identify the diagnosis. At times, these patients present in extremis. Present-
ing emergent conditions include superior vena cava syndrome, airway compromise
caused by mass compression, clot or compression of the venous flow caused by
abdominal masses, and stroke symptoms caused by hyperleukocytosis.24 Critically,
patients may also present with tumor lysis syndrome. Although often a complication
of initial therapy (specifically in lymphoproliferative diseases), this can also be a pre-
senting diagnosis that requires rapid recognition and management.25
Cancer is an atypical overgrowth of cells caused by spontaneous or environmentally
induced genetic mutations.26 Its emergent complications are often cell specific and
location specific caused by localized effects. There are genetic variables that increase
the risk of specific oncologic diagnoses. For example, leukemias (both acute myelo-
blastic and acute lymphoblastic) are associated with Down syndrome, gliomas are
associated with Noonan syndrome, and neuroblastomas are associated with
Beckwith-Wiedemann syndrome, among many others.27 Compared with adult onco-
logic diagnoses, there are more genetic rather than acquired or environmental factors
that contribute to the development of cancer.28
In solid organ masses or lymphomas, tumor lysis syndrome is a presenting compli-
cation of large-volume tumors that have begun to develop necrosis because of lack of
internal blood supply. This process results in cellular apoptosis and release of intracel-
lular ions into the bloodstream. Symptoms and complications are often caused by
overwhelming the renal system, the main source of excretion for these electrolytes.
This condition results in an obstructive uropathy, which, in turn, increases ion reten-
tion, causing worsening intracellular levels.25

Prevalence/incidence/mortality
Overall, the incidence of childhood cancer is approximately 15 per 100,000 children
(<16,000 new diagnoses) per year.29 Leukemia is the most common, comprising
nearly 25% of all pediatric cancers. Brain tumors are the second most common,
with 17% of cases, followed by lymphomas, carcinomas, gonadal tissue tumors, sar-
comas, and bone tumors.30 In 1 study, the diagnosis of cancer occurred in approxi-
mately 2 in every 10,000 pediatric emergency department patients, with nearly 5%
missed on initial visits.31 Although the incidence of specific emergent complications
of many of these diseases is not known, tumor lysis may be found in up to 30% of pa-
tients with non-Hodgkin lymphoma.32
Mortality has improved over the years. More than 80% of patients with childhood
cancer now survive to cure.33 Still, cancer remains the second most common cause
of death in children in the United States between the ages of 1 and 14 years, account-
ing for approximately 1200 deaths annually in this population. An additional 540
deaths occur in adolescent patients each year.30 Patients who develop tumor lysis
syndrome (either preceding or during treatment) have a high in-hospital mortality of
up to 21%.25

Clinical presentation
As noted previously, patients typically present with vague symptoms (see Table 2).
Examination should focus on abdominal examination for masses and hepatospleno-
megaly; lymph node palpation for lymphadenopathy; and skin examination for jaun-
dice, pallor, bruising or rashes.23 Tumor lysis syndrome should be of concern in all
patients who are being evaluated for malignancy, but most particularly those with
signs or symptoms of lymphomas (specifically Burkitt), leukemias, and large solid

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Pediatric Hematologic and Oncologic Emergencies 563

cancers.25 Evaluation should also focus on identifying clinical findings that would sug-
gest electrolyte derangements, including carpal or pedal spasms, wheezing, Chvostek
or Trousseau signs, or signs of uremia, including changes in mental status, pruritis,
lethargy, symptoms of pericarditis, or signs of fluid overload.25

Diagnostics
When there is concern for cancer, parents and patients (who are old enough to under-
stand) should be counseled on the necessity of obtaining bloodwork. These authors
think that transparency is crucial to effective patient care, and informing parents of
findings of concern on examination helps improve the therapeutic alliance.
Imaging for suspected tumors or mass can often be initially obtained with simple ra-
diographs (for the chest or bones) or ultrasonography (for the abdomen). If the results
are concerning for a mass, the patients often require further imaging for evaluation.
However, additional nonemergent imaging may be completed under the direction of
the oncologist, to avoid excessive radiation to the patient and ensure all necessary
body areas are imaged. In unstable patients with suspected intracranial lesions, CT
of the head should be obtained; in stable patients, MRI is often the test of choice.
This distinction is important because patients with cancer are at risk for a second ma-
lignant neoplasm and ionizing radiation from imaging may increase this risk.33 Howev-
er, consideration should be given to obtaining a chest radiograph to screen for a
mediastinal mass in patients being evaluated for cancers.
In suspected new malignancies, laboratory work focuses on signs of leukemic pro-
cesses, including anemia, platelet count, and white blood cell count. For every new
diagnosis of cancer, tumor lysis syndrome should be considered. Laboratory testing
for this requires electrolyte evaluation, specifically creatinine, potassium, calcium,
and phosphorus, along with LDH level and uric acid level. An electrocardiogram
(ECG) is also required because electrolyte derangements associated with tumor lysis
syndrome can result in cardiac dysrhythmias. Alternatively, an abnormal ECG may
also be the first indication of electrolyte derangements while awaiting laboratory
results.25
Tumor lysis may be diagnosed using the following criteria:
 Two or more laboratory abnormalities, including:
 Uric acid 8.0 mg/dL
 Potassium 6.0 mEq/L
 Phosphorus 6.5 mg/dL
 Calcium 7.0 mg/dL
Or:
 One of the above laboratory abnormalities plus any of the following:
 Creatinine level more than 1.5 times higher than age-adjusted normal
 Seizure
 Cardiac arrhythmia

Management
In patients with thrombosis, anticoagulation is initiated in consultation with a pediatric
hematologist. Although there are currently no drugs approved for use in children,
enoxaparin and heparin are often the preferred anticoagulants.34
In patients presenting with tumor lysis syndrome, the initial therapy of choice is crys-
talloid intravenous fluids without potassium. These patients may require large volumes
of fluid to prevent renal failure. Typically, this is approximately 2.5 times the mainte-
nance dosing based on weight, with a target urine output of 4 mL/kg/h in infants

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564 Stephanos & Dubbs

and 100 mL/m2/h in older patients.35 Allopurinol and rasburicase may also be
needed.36 In patients with signs and symptoms of tumor lysis syndrome, the most
common complications include acute kidney injury and dysrhythmias, which can
lead to death.25 A high-risk patient is defined as one with a markedly increased white
blood cell count (typically >100,000/mL) and increased LDH levels.25
Unlike in adults, most new diagnoses of malignancy in pediatrics are admitted to the
hospital for definitive diagnosis and initiation of management, even if they are clinically
stable. Consultation with a pediatric hematologist/oncologist is necessary for this
planning. For a hospital without a pediatric oncologist on staff, this requires contact
and transfer to the nearest care facility with available resources. Patients with
compressive symptoms warrant admission and often require early surgical involve-
ment. Patients with suspected tumor lysis syndrome should be admitted to an inten-
sive care unit because of the high risk of associated morbidity and significant
complications.
Aside from the medical aspects of cancer, the diagnosis itself is a life-changing
event for patients and their families. It is important to have frank, clear discussions
with the family about concerns without revealing details regarding a specific diag-
nosis, prognosis, or plans, which are best reviewed by an oncologist. In very young
children, this can be done with the child in the room, although even toddlers and pre-
school children can understand subtle cues, so talking with parents privately in this
emotional situation may be necessary. Children who are old enough to understand
the diagnosis, or some details of the diagnosis, should be involved and informed as
early as possible. This involvement has been shown to allow an improved therapeutic
alliance in the future with these patients.37 Although some families worry about telling
children, studies have shown that nondisclosure does not decrease stress to the child,
and may be harmful.38

Clinical care points


 The index of suspicion for cancer should remain high in patients with unexplained
symptoms, including fatigue, bone pain, prolonged fevers, headaches, rashes,
abdominal pain, or weight loss
 A complete evaluation for malignancy includes assessment for tumor lysis syn-
drome assessing potassium, calcium, uric acid, phosphorus, and creatinine
 Patients with tumor lysis should receive prompt fluid resuscitation and ECG eval-
uation for dysrhythmias
 Once a cancer diagnosis is suspected or supported by laboratory testing or im-
aging, the provider should consult a pediatric oncologist for further planning
 Families should be counseled on findings that indicate a cancer diagnosis when
adequate support is available

Complications of Pediatric Cancer Therapies


Overview
Patients who have a known diagnosis of a malignancy may present to an emergency
department for a variety of reasons. Although they may still present with the usual in-
juries and illnesses of childhood, most commonly there is concern for a therapy-
induced or associated complication.39 Many of the commonly used chemotherapeutic
agents have both immediate and long-term complications associated with their use
(Table 3). Two critical complications associated with treatment are neutropenic fever
and typhlitis (also called neutropenic enterocolitis).
Neutropenia is a common complication of many chemotherapeutic agents, because
these drugs rapidly suppress or kill multiplying cells (see Table 3). This complication

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Pediatric Hematologic and Oncologic Emergencies 565

Table 3
Some emergent complications of common pediatric chemotherapeutic agents

Side Effect Medications


Cytopenias 6-MP, 6-TG, cyclophosphamide, cytarabine
(cytosine arabinoside or ara-C), etoposide,
idarubicin, methotrexate, vincristine
Cardiac toxicity Cyclophosphamide, cytarabine (cytosine arabinoside
(dysrhythmias, heart failure) or ara-C), daunorubicin, (daunomycin), doxorubicin
(adriamycin), idarubicin, mitoxantrone, vincristine
Pancreatitis 6-MP, L-asparaginase, PEG-L-asparaginase (pegaspargase),
methotrexate
Hypercoagulability L-asparaginase,PEG-L-asparaginase (pegaspargase),
methotrexate
GI- perforation/necrosis/ Corticosteroids, cyclophosphamide, cytarabine
bleeding/typhlitis (cytosine arabinoside or ara-C), doxorubicin
(adriamycin), methotrexate, mitoxantrone, vincristine
Hepatic injury 6-MP, 6-TG, etoposide, vincristine
Electrolyte disturbances Cyclophosphamide, mitoxantrone
Neurotoxicity Cytarabine (cytosine arabinoside or ara-C),
idarubicin (seizures)
Dermatologic- Stevens Johnson Doxorubicin (adriamycin), methotrexate
like reaction
Other Mitoxantrone for secondary leukemia; cytarabine
(cytosine arabinoside or ara-C) for interstitial
pneumonitis; etoposide for hypotension;
corticosteroids for hypertension, hyperglycemia

Note that this is not a comprehensive list.49–61


Abbreviations: 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine.

often occurs within the first week of therapy. As a result, this leaves the immune sys-
tem vulnerable to even typically minor infections. Fever in these patients can be an
ominous sign of a serious bacterial infection. It is essential to note neutropenic fever,
defined by a fever more than 38.3 C for more than 1 hour in a patient with a known
absolute neutrophil count (ANC) of less than 500 cells/mL (or <1000 cells/mL with antic-
ipated decline as the cutoff) or anticipated neutropenia caused by recent medication
use.32,40 Although there is no official recommendation, these authors currently recom-
mend use of a caregiver-reported temperature as a reliable indicator of fever, espe-
cially if an antipyretic was given before arrival.
The pathophysiology of typhlitis is unclear, although it may be related to chemo-
therapy causing friable intestinal mucosa, which allows bacteria to penetrate its lining.
This condition occurs predominantly in patients with severe neutropenia
(ANC<500 cells/mL), and more often with hematologic malignancies.41

Prevalence/incidence/mortality
Undifferentiated fever is a common presenting complaint to the emergency depart-
ment, and this makes up 19% of emergency visits for patients undergoing chemo-
therapy. Of these, more than 42% have a neutropenic fever.39
Overall, typhlitis is less common and may be overlooked. Typhlitis has an estimated
occurrence of up to 6% of all hospitalized patients on high-dose chemotherapeutic
agents with severe neutropenia.42

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566 Stephanos & Dubbs

The mortality of neutropenic fevers in pediatric patient is less than 5%, whereas the
mortality of typhlitis has been found to be as high as 50%.43,44

Diagnostics
Patients with complications of chemotherapy require immediate evaluation and exclu-
sion of life-threatening disorders. Patients on a medication known to cause neutrope-
nia who develop a fever require immediate evaluation and interventions. These
patients can rapidly decompensate and should be treated as having severe sepsis.
Evaluation must focus on signs or symptoms revealing potential sources of infection,
including cough, dyspnea, dysuria, rashes or lesions (including evidence of necrotizing
fasciitis), ear pain, headache, abdominal pain, or joint pain and swelling. The severity
and occurrence of neutropenic fever is often medication associated but may also be
related to other factors, including the severity of illness, a history of fever with neutro-
penia, and mucositis.32
Patients with concern for neutropenic fever require a CBC to assess for neutropenia.
Blood cultures are imperative, specifically a peripheral culture, with additional cultures
from any central lines the patient has (patients with more than 1 port in a line require a
culture from each port).40 Lumbar punctures are rarely indicated in these patients,
although the literature is sparse and the decision to perform the procedure should
be discussed in detail with the patient’s oncologist. Because thrombocytopenia and
other bleeding disorders are common, it is more advisable to treat empirically than
to perform a lumbar puncture on these patients if the clinical presentation cannot
be discussed with a member of the oncology team. In patients with a history of urinary
tract infections, a urinalysis may be indicated; however, in those children who are not
yet toilet trained, a bagged sample should be obtained. Catheter insertion is contra-
indicated in patients who are neutropenic.40 Patients with neutropenic fever do not
require routine imaging. Images should be targeted to specific symptoms, including
a chest radiograph for any respiratory symptoms or limb radiographs if there is joint
pain or swelling.
Patients with neutropenic enterocolitis often present with abdominal pain, fever, and
diarrhea, which may or may not be bloody. Patients commonly have received chemo-
therapy or had mucositis in the preceding 14 days. The examination may reveal diffuse
or localized abdominal tenderness, often in the right lower quadrant.42 In patients with
concern for typhlitis, rapid imaging should be obtained. Initial assessment with ultra-
sonography may show thickened bowel, although CT is often the preferred modality
because of its ability to more readily diagnose this high-risk disorder. There are no
specific laboratory tests that can either confirm or exclude typhlitis as a diagnosis.44
Although a hemoccult test may support occult blood in the stool, this should only
be performed on excreted stool because rectal examinations are contraindicated in
neutropenic patients.
Additional evaluations of patients with cancer should include consideration of other
acute disorders, including pericardial effusions, pleural effusions, or pulmonary hem-
orrhage. Specific imaging should target symptoms. Patients with hemoptysis, cough,
or shortness of breath require prompt chest radiograph to assess for masses, effu-
sions, hemorrhage, or pneumonia.24 Patients with shortness of breath may also
require a bedside ultrasonography scan to assess for pericardial fluid. Higher-risk pa-
tients with a suggestive history or physical examination may require a CT scan with
angiography to evaluate for PE. Patients with intracranial lesions with new or wors-
ening symptoms, including severe headache, altered sensorium, or neurologic defi-
cits, may warrant immediate CT or MRI.24 Likewise, the essential tests for a patient
may be contingent on the medication being used for treatment. For example, patients

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Pediatric Hematologic and Oncologic Emergencies 567

on 6-mercaptopurine (6-MP), L-asparaginase, PEG-L-asparaginase (pegaspargase),


or methotrexate with abdominal pain should have amylase and lipase obtained. Pa-
tients on methotrexate also warrant a creatinine level to assess for renal function,
because of the risk of renal failure (see Table 3).
Management
Neutropenic fever requires immediate administration of empiric broad-spectrum anti-
biotics. This administration should not be delayed while awaiting an ANC. The goal of
initiation of antibiotic therapy should be less than 1 hour from hospital arrival.45 The
antibiotic regimen for pediatric patients is typically cefepime as a primary agent. In
accordance with antibiotic stewardship, vancomycin (or linezolid if allergic to vanco-
mycin) is only added if the patient has a history of MRSA bacteremia or is critically ill.46
Additional agents may be required based on prior susceptibilities. Antifungals may be
considered based on prior illnesses as well, although typically these are added by the
inpatient team when no improvement is seen with treatment.40 Patients with fever who
have confirmed neutropenia most often require inpatient hospital admission. They
should be isolated with no additional patients in their rooms.40
In patients with concern for typhlitis, surgical consultation is also standard, although
frequently conservative measures with antibiotics alone are attempted first. Patients
with neutropenic enterocolitis should receive prompt antibiotics before other interven-
tions. This treatment can be with monotherapy of piperacillin-tazobactam or imipe-
nem-cilastatin or with dual therapy with ceftazidime/cefepime plus metronidazole.44
Future directions
Therapeutic interventions such as monoclonal antibody treatment are currently in
development for pediatric patients. It is suspected that the complications may be
similar to those in adult patients, including hypotension, fever, rashes, or gastrointes-
tinal symptoms.47,48 Because this is a rapidly growing field of research, these authors
advise seeking early consultation in patients presenting with atypical or unusual symp-
toms who are undergoing new or experimental therapies to better assess and treat the
patient.

Clinical care points


 Patients who are undergoing treatment protocols for oncologic processes typi-
cally require very prompt assessment in the emergency department
 Those patients presenting with fevers and known or possible neutropenia should
receive empiric antibiotics in a room isolated from other patients
 Catheterized urine specimens and rectal examinations are contraindicated in pa-
tients with neutropenic fevers
 Typhlitis is a serious and potentially life-threatening complication presenting with
fever, abdominal pain, diarrhea, and occasionally bloody stools

SUMMARY

There are a range of hematologic and oncologic emergencies that may present during
childhood. Prompt recognition and management is key to reducing morbidity and
mortality in these patients.
 Many hematology and oncologic emergencies require rapid assessment and
interventions.
 In patients with SCD, have a high clinical suspicion for life-threatening complica-
tions, particularly ACS and stroke.
 Life-threatening hemorrhage is rare but can occur in children with ITP.

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568 Stephanos & Dubbs

 Newly diagnosed malignancies often present with a vague constellation of symp-


toms, require a high index of suspicion for diagnosis, and typically require admis-
sion to the hospital.
 Neutropenic fever is the most common severe complication in patients being
treated for a known malignancy.

DISCLOSURE

The authors have nothing to disclose.

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