Pediatric Oncologic Emergencies
Authors:
Melissa R. Jefferson, MD, Assistant Professor of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC.
Beng Fuh, MD, PhD, Assistant Professor of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC.
Ronald M. Perkin, MD, MA, Professor and Chairman, Department of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC.
Peer Reviewer:
Dennis A. Hernandez, MD, FAAP, FACEP, Medical Director, Pediatric Emergency Services, Florida Hospital for Children, Walt Disney Pavilion, Orlando, FL.
Although the diagnosis of cancer in childhood is relatively rare, with an annual incidence of 165 cases per million,1 it remains the leading cause of death by disease in children, accounting for approximately 10% of all childhood fatalities.2 Since 1970, childhood cancer survival rates have increased from 45% to more than 80%.3 This dramatic increase in survival has been accomplished due to the availability of new therapies and therapeutic strategies, as well as to prompt diagnosis and enhanced supportive care, including that provided in the emergency department setting.
The pediatric oncology patient may present with a variety of life-threatening situations, including those resulting from structural or functional compromise of the cardiopulmonary or neurologic systems, hematologic abnormalities, or a compromised immune system. Emergencies in these patients may occur as a result of the disease itself or as a consequence of treatment. The emergency department is often the first point of contact for newly diagnosed pediatric oncology patients, and they may be quite ill on initial presentation. Children with known malignancies often are immunocompromised secondary to their treatment and, as a result, pose unique diagnostic and therapeutic challenges.
This article will highlight six of the most commonly encountered oncologic emergencies.
Ann Dietrich, MD, FAAP, FACEP, Editor
Emergencies Related to Structural Compromise
Malignancies of the Central Nervous System (CNS). Brain Tumors. Brain tumors are the most common solid tumors in childhood and the second most common type of childhood cancer overall.4 Patients with CNS lesions are at risk for rapid deterioration as a result of increased intracranial pressure (ICP). Consequently, rapid diagnosis may be life-saving in this population. However, children and adolescents with brain tumors often present with non-specific complaints and, as a result, pediatric patients with CNS masses often make several visits to their primary care physician or emergency department prior to obtaining a diagnosis. Careful attention to the history and physical exam can assist the practitioner in determining which patients warrant imaging studies to evaluate for an intracranial mass.
Headache is perhaps the most common presenting complaint for a CNS mass. In a study of 3,291 subjects in the Childhood Brain Tumor Consortium Databank, 62% of children with brain tumors experienced chronic or frequent headaches prior to their first hospitalization.5 Headache is a common complaint in the pediatric population, and accounts for a significant number of visits to emergency departments and pediatrician offices. Most patients presenting with such a complaint do not require further radiologic investigation. However, specific features of the headache and associated signs and symptoms should increase the practitioner's suspicion that this may be the result of a more serious condition. The practitioner should evaluate for signs of increased ICP or localizing signs or symptoms. Table 1 lists symptoms that should raise suspicion that the headache may be secondary to a brain tumor.
Table 1. Symptoms Suggestive of a Brain Tumor as the Etiology of Headache
- Occipital location of headache
- Worsening symptoms
- Awakens patient at night
- Associated with focal symptoms
- Emesis
A thorough physical examination, including a complete neurological and fundoscopic exam, is essential in making the diagnosis of a brain tumor and evaluating for increased ICP. More than 97% of patients with a brain tumor, presenting with a headache, will have a documentable neurologic abnormality found on physical exam.5,6 Macrocephaly and splitting of sutures may be present in infants. Limitation in eye movement, visual field defects, seizures, and gait disturbance are suggestive of significant CNS pathology.
A computed tomography (CT) scan should be obtained for gross brain structural evaluation and signs of increased ICP if magnetic resonance imaging (MRI) cannot be performed. CT imaging must be reviewed with caution because it is not very accurate for evaluating brain tumors, especially posterior fossa tumors. MRI is the preferred test to evaluate brain structure, but may not be feasible in the emergency setting. Lumbar puncture should be approached with caution, and preferably deferred if increased ICP is suspected, as this can lead to herniation.
Emergent treatment of increased ICP consists of elevation of the head of the bed, intravenous dexamethasone at a loading dose of 0.5-2 mg/kg, followed by 0.25-0.5 mg/kg IV every 6 hours. Mannitol 20% solution and hypertonic saline solution should also be considered. Intravenous fluids of normal saline at a rate of 75% maintenance may be started. Endotracheal intubation should be considered in severe cases to control airway and partial pressure of carbon dioxide. Immediate pediatric neurosurgical consultation should be obtained. Oncology and radiation oncology consultations should be obtained.
Spinal Cord Compression (SCC). SCC occurs in approximately 3-5% of all pediatric oncology patients.7 If not detected and treated in a timely manner, SCC may lead to irreversible neurologic damage, including permanent paralysis. SCC is the most common cause of lower limb paralysis in children.8 Early recognition and treatment of cord compression is essential to decrease long-term morbidity. Appropriate, definitive management is best determined through multidisciplinary consultation with pediatric oncology, neurosurgery, and radiation oncology. SCC may result from virtually any malignancy and can present either at the time of diagnosis or as the disease progresses.
SCC may occur as a result of an infiltrative paraspinous process, tumors originating from the vertebral process, intrinsic spinal cord tumors, or infiltrative lesions. In the pediatric patient, cord compression most frequently results from a paravertebral tumor extending through the intervertebral foramina (e.g., soft-tissue sarcomas, tumors of neurogenic origin).8 Tumors growing through the intervertebral foramina initially cause mechanical nerve root compression. If growth continues, transverse myelitis (inflammation of gray and white matter of the spinal cord) ultimately may occur. Also, the venous plexus may be compressed at the intravertebral level, resulting in ischemic injury to the cord.10 Intradural spinal metastasis from an intracranial process (e.g., medulloblastoma) also may lead to cord compromise. These lesions tend to occur in the lumbosacral region. Primary spinal cord tumors, such as an intramedullary astrocytoma, also may be the cause of pain and neurologic symptoms in children. More rarely, leukemic chloromas may be a cause of SCC. Chloromas are more commonly due to acute myelogenous leukemia (AML) as opposed to acute lymphoblastic leukemia (ALL).11 Leukemic infiltration of the spinal cord has a predilection for the cauda equina or conus medullaris,12 and patients should be screened for symptoms of cord involvement.13
SCC should be suspected in any pediatric oncology patient presenting with back pain or suggestive neurologic findings. Localized or radicular back pain occurs in 80% of children with SCC.7 Back pain in any child with a malignancy is highly suspicious for SCC and deserves further investigation. Patients with SCC also may present with complaints of motor or sensory abnormalities. Depending on the rate of tumor growth, the pain and/or deficits may be long-standing (present for weeks to months) and slowly progressive, or more acute in nature. History should elicit the time course and include questioning about changes in gait and bowel or bladder habits. Tenderness to palpation tends to localize to the site of the lesion. A thorough neurologic examination should be performed, with attention to motor strength, reflexes, gait abnormalities, sensation, and sphincter tone. The diagnosis of SCC is particularly challenging in the infant or young child who cannot verbalize back pain; regression in motor milestones or refusal to ambulate may be initial symptoms.
Imaging studies should be obtained as soon as possible. Plain radiographs are insufficiently sensitive. The optimal study in a patient with potential SCC is an MRI. In the rare case where an MRI cannot be performed in a timely manner, CT myelography is an acceptable alternative.
If SCC is suspected, dexamethasone should be initiated without delay. Corticosteroid therapy may decrease cord edema and preserve neurologic function while plans for more definitive therapy are underway. Optimal dosing of dexamethasone is not known; a loading dose of 1-2 mg/kg IV, followed by 0.25-0.5 mg/kg every 6 hours, has been suggested. If lymphoma or a leukemic infiltrate is the cause of the SCC, dexamethasone has the potential to be cytolytic and may lead to tumor lysis syndrome.
Definitive therapeutic options include surgical resection, radiation therapy, and/or chemotherapy. The optimal choice of treatment is best determined by a multidisciplinary team. Treatment choice will be influenced by whether a tissue diagnosis has been made, radio- and chemosensitivity of the tumor, extent of disease, and the degree of neurologic compromise present. Studies have suggested that the degree of neurologic deficit at the time of presentation and the duration of symptoms prior to initiating therapy both correlate with the ultimate functional outcome, regardless of the treatment method employed. When planning definitive therapy, both acute relief of SCC as well as long-term sequelae of the treatment modality used should be considered. Radiation therapy and surgical resection, while offering more immediate benefit in terms of local tumor control, may lead to long-term sequelae in terms of growth problems and scoliosis. For this reason, chemotherapy is generally the treatment of choice in a child with a chemosensitive process such as lymphoma, leukemia, or disseminated neuroblastoma and who has minimal symptoms of SCC.14 If SCC occurs in the setting of progressive refractory disease, palliative therapy for SCC should not be withheld, as it may have a substantial positive impact on the quality of life.
Mediastinal Mass, Superior Mediastinal/Superior Vena Caval Syndrome. Masses within the mediastinum are fairly common in children, and the differential diagnosis is quite different than one would consider for an adult patient.15 In the young infant, congenital anomalies should be considered. Children may present with a mass in the posterior mediastinum, often representing a neurogenic tumor such as neuroblastoma. The differential diagnosis of a mediastinal mass in a pediatric patient depends on the age of the child, the rapidity with which symptoms develop, and the mediastinal compartment that contains the mass. The majority of children or adolescents presenting with a mediastinal mass who are experiencing respiratory compromise ultimately will be diagnosed with a malignancy, most often lymphoma. Table 2 shows the differential diagnosis of a mediastinal mass by location within the mediastinum.
Table 2. Differential Diagnosis of a Mediastinal Mass by Location Within the Mediastinum
Anterior
- Lymphoma
- Leukemia
- Malignant germ-cell tumor
- Benign teratoma
- Thymic lesion (thymic hyperplasia, thymoma, thymic cyst)
- Substernal thyroid
Middle
- Lymphoma
- Tuberculosis
- Histiocytosis
- Sarcoidosis
- Anomalies of the great vessels
Posterior
- Neuroblastoma
- Ganglioneuroblastoma
- Sarcoma
Children presenting with an anterior mediastinal mass often have symptoms suggestive of a respiratory infection, such as cough, fever, and wheezing. It is not uncommon for a child with a mediastinal mass to present to a medical facility and receive a diagnosis of a respiratory tract infection or asthma exacerbation on more than one occasion prior to receiving imaging studies and detection of the mass. Therefore, it is critical that the practitioner keep broad differential diagnoses in mind and perform a thorough physical exam and detailed history, especially in the child with wheezing or dyspnea with no previous history of asthma.
Masses in the anterior mediastinum have the potential to create life-threatening compromise of the airway or cardiovascular system. Superior mediastinal syndrome (SMS) refers to compression of the trachea or mainstem bronchi by a mediastinal mass. SMS is closely related to superior vena caval syndrome (SVCS), which refers to compression or obstruction of the vena cava. These two entities often coexist. In children, the trachea and mainstem bronchi are very compliant and vulnerable to collapse from external compression. The superior vena cava is a thin-walled vessel with low intraluminal pressure. Compression by a mediastinal mass or obstruction by a tumor or thrombosis leads to venous stasis and diminished blood return to the heart. (See Table 3.) It should be noted that a child with an indwelling central venous catheter may develop SVCS secondary to thrombosis of the catheter. SMS and SVCS generally result from compression from a mass in the anterior compartment of the mediastinum, with lymphoma being the most common cause. Children with leukemia also may present with a mediastinal mass; therefore, it is important that all newly diagnosed leukemia patients have a chest X-ray performed as part of their initial evaluation.
Table 3. Signs and Symptoms of SVCS
- Facial swelling
- Upper body edema
- Cyanosis of the face or upper body
- Plethora
- Conjunctival edema or suffusion
- Headache
- Tachycardia
- Elevated venous pressure
- Vocal cord paralysis, hoarseness
- Dyspnea
- Cough
- Decreased mentation
- Horner's syndrome
A thorough history and physical exam should be performed on any child or adolescent with a suspected mediastinal mass, with particular attention to signs and symptoms of SMS/SVCS.
Children with SMS and/or SVCS may be asymptomatic at the time of presentation, or they may come to medical attention just prior to cardiopulmonary collapse. In some cases, the airway may be so tenuous that total airway loss may be precipitated by simply placing the child in a supine or flexed position. Once there is suspicion of a mediastinal process, care must be taken to protect the airway. When performing the physical exam or while obtaining imaging studies, it is important that the child not be forced to lie in a position that may precipitate airway collapse. Diagnosis and initiation of therapy should occur in the most expeditious and least invasive manner possible.
Children with evidence of SMS/SVCS must be managed with care to avoid complete loss of the airway or cardiovascular collapse. In particular, the use of procedural sedation or general anesthesia should be avoided until a thorough evaluation of the child's anesthesia risk has been completed. Several clinical factors have been associated with an increased risk for life-threatening anesthesia-related complications in the context of SMS. Orthopnea, upper body edema, and dyspnea at rest have all been associated with increased anesthesia risk.16 Orthopnea most closely correlates with the level of risk assumed, and questioning for this symptom should occur directly, as parents may not give such information unless it is specifically asked. Although these elements of the physical exam and history should be taken into consideration, it should be noted that the degree of symptoms does not always correlate with the degree of airway compromise,17 since anesthesia-related deaths have been reported in asymptomatic children with anterior mediastinal masses.18-20 Therefore, in a child with a known mediastinal mass, a CT scan and pulmonary function testing should be performed prior to subjecting the child to anesthetics. A CT scan can assess the tracheal cross-sectional area (TCA), which can then be compared to well-established norms for age and gender.21 Pulmonary function testing to determine the peak expiratory flow rate (PEFR) may be done fairly easily at the child's bedside with a handheld device, and readings should be done in both the sitting and supine position. Studies have shown that children with a TCA and PEFR of > 50% for age can be safely given general anesthesia or procedural sedation if needed.22 Table 4 shows findings for relative contraindications for anesthesia in a child with a mediastinal mass.
Table 4. Critical Airway: Relative Contraindications to Anesthesia in a Child with a Mediastinal Mass
- Orthopnea
- Upper body edema
- Dyspnea
- Clinical findings of impending respiratory failure
- Tracheal cross-sectional area < 50% normal for age and sex
- Severe compression of one or both mainstem bronchi
- Peak expiratory flow rate of < 50% predicted (performed in sitting and supine position)
In severe cases of SMS, empiric therapy may need to be employed prior to making a tissue diagnosis. In most cases, empiric corticosteroid therapy will provide sufficient tumor reduction.23 However, administration of steroids may result in tumor lysis syndrome and may impair the ability to make a diagnosis. Steroids, therefore, should be given only in an immediately life-threatening situation after consultation with a pediatric oncologist. Even more rarely, the mass may not be sensitive to corticosteroids, and emergent radiation therapy may be considered.24 However, in most cases, a tissue diagnosis can be made prior to instituting therapy. If general anesthesia or sedation must be avoided, the use of local anesthesia with the child in a seated position should be considered.
Hematologic Emergencies
Hyperleukocytosis. Leukemia is the most common type of childhood malignancy. Approximately 3500 children are diagnosed with acute leukemia in the United States each year, accounting for approximately one-third of childhood cancers.25 The presentation of leukemia varies widely, from children presenting with only mild symptoms, such as fatigue, to those presenting in extremis. Likewise, the degree of hematologic derangement in a newly diagnosed pediatric patient ranges from a normal peripheral blood count to life-threatening hyperleukocytosis, defined as a white blood cell (WBC) count of greater than 100,000 per μL.
Hyperleukocytosis is present at the time of diagnosis in approximately 10% of cases of ALL.26 Among ALL patients, those with infant leukemia, hypodiploid chromosome blasts, and those with T-cell ALL are at particular risk for hyperleukocytosis.26 The clinician should be certain to obtain a chest X-ray early in the initial management of the ALL patient with hyperleukocytosis, as the presence of a mediastinal mass in these patients is not uncommon.26 Five percent to 20% of pediatric AML cases will present with hyperleukocytosis, and virtually all patients with chronic myelogenous leukemia (CML) will have hyperleukocytosis at diagnosis.27,28
Hyperleukocytosis results in hyperviscosity and leukostasis. Aggregation of leukemic blasts occurs in the microvasculature, which may result in multisystem organ dysfunction. End-organ damage results from interaction between aggregates of leukemic blasts and injured epithelium. This interaction leads to tissue hypoxia, with resultant release of inflammatory cytokines.29 Myeloblasts are more apt to cause damage due to their larger size and increased adhesiveness.30 Leukostasis may cause devastating dysfunction in any organ system. In the central nervous system, cerebrovascular accidents, both thrombotic and hemorrhagic, may occur spontaneously. This is most common in the setting of AML.27 From a cardiovascular standpoint, fatal pericardial hemorrhages secondary to hyperleukocytosis have been reported. Pulmonary complications also may occur, including hypoxia, pulmonary hemorrhage, and respiratory failure. Intra-abdominal complications, including gastrointestinal bleeds, are also possible.27 Splenic rupture is most commonly a risk in the patient with extreme hyperleukocytosis and CML. In addition to the damage caused by leukostasis, children with hyperleukocytosis from acute leukemia are at risk for the metabolic complications from tumor lysis syndrome, including renal failure, hypocalcemia, hyperphosphatemia, and hyperuricemia. Life-threatening metabolic abnormalities occur more commonly in the setting of hyperleukocytosis in ALL.27 This topic is covered more thoroughly in the tumor lysis section. Disseminated intravascular coagulation (DIC) is most common in high white-blood-cell count AML patients. All patients with hyperleukocytosis should be screened for a coagulopathy, as correction of these abnormalities may decrease the incidence of bleeding complications.27
Patients with hyperleukocytosis should be closely monitored for signs and symptoms of end-organ damage. Neurologic symptoms may include headache, seizures, and altered mental status. On examination, papilledema or retinal vascular distention may be detected. Pulse oximetry should be employed to detect hypoxia, and the patient should be screened for other signs and symptoms of respiratory compromise. Priapism, clitoral enlargement, and dactylitis, all secondary to leukostasis, may be present on physical examination.
Children with hyperleukocytosis are at increased risk of death early in their course of treatment. The threshold at which hyperleukocytosis becomes clinically significant varies by leukemia type. This is most likely due to differences in adhesiveness of the leukemic blasts in different types of leukemia. The risk of fatal complications is highest in patients with AML with hyperleukocytosis. In patients with hyperleukocytosis, early death occurs in approximately 20% of patients with AML and 5% of patients with ALL.27 Studies have suggested that life-threatening viscosity becomes increasingly prevalent at WBC greater than 200,000/μL in AML and greater than 300,000/μL in ALL and CML.23
Table 5. Initial Supportive Therapy in the Setting of Hyperleukocytosis
- Hydration: D5 1/2 NS at 3000 mL/m2/day. No supplemental potassium should be given. Consider alkalinized fluids if allopurinol is being used and patient is not hyperphosphatemic.
- Treatment of hyperuricemia
Allopurinol 300 mg/m2 divided TID
Consider administration of rasburicase if patient is hyperuricemic and not G6PD deficient.
- Transfuse platelets if platelet count is < 25,000/μL.
- Correct other significant coagulopathies.
- Avoid transfusion of packed red blood cells if hemodynamically stable.
NOTE: Management of hyperuricemia and tumor lysis covered more thoroughly in tumor lysis section.
Aggressive supportive care and prompt consultation with a pediatric oncologist for initiation of cytoreductive chemotherapy reduces the risk of early death in these patients. Supportive care is directed at correction and prevention of metabolic abnormalities and coagulopathies. Table 5 outlines the suggested initial studies and management of the patient with hyperleukocytosis. Hydration should be instituted. Supplemental potassium should not be given, even in the setting of hypokalemia, as hyperkalemia may result from tumor lysis even prior to the initiation of therapy. The patient should be monitored very closely for the development of metabolic abnormalities. Efforts should be made to correct coagulopathies, including the transfusion of platelets if the platelet count is < 25,000 per μL. For the anemic patient, red blood cell transfusion should be avoided if the patient is hemodynamically stable, as this will further increase the blood viscosity. Emergent cranial radiation, which has been used in the past in an effort to prevent intracranial bleeds, is of no proven benefit and is no longer routinely employed or recommended.27 Leukapheresis and exchange transfusion may be considered as temporizing measures or to reduce the leukemic burden prior to initiation of cytoreductive therapy; however, this remains controversial.26,31,32 It should be noted that the blast count will rise again quickly after these procedures are completed. Prompt initiation of effective cytoreductive therapy remains critical.
Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) is an oncologic emergency characterized by a triad of hyperkalemia, hyperuricemia, and hyperphosphatemia, and it is often complicated by secondary renal failure and symptomatic hypocalcemia. TLS may occur prior to the initiation of cytoreductive therapy and up to one week after initiation of therapy. When tumor cells lyse, large amounts of intracellular chemicals are released into the circulation and may cause metabolic derangements, which may lead to renal dysfunction and cardiac dysrhythmia.
TLS may occur with any malignancy with rapid cell turnover and high tumor burden. It most commonly occurs in the setting of leukemia or high-grade lymphoma. Children with hyperuricemia or renal insufficiency at presentation are at particularly high risk. Evidence of tumor lysis may be present prior to the initiation of the chemotherapy or after the child receives corticosteroids.
Conditions at highest risk for TLS include:
ALL or AML (WBC >100,000/μL)
Leukemia with massive lymphadenopathy and/or organomegaly
T-cell ALL
Infant leukemia
Burkitt's lymphoma
Large cell lymphoma.
Laboratory monitoring should include CBC and blood chemistries, with specific attention paid to serum potassium, calcium, magnesium, phosphate, uric acid, creatinine, urea nitrogen, and lactate dehydrogenase. Initially, these studies should be done every 6 hours, and then spread out as the tumor lysis improves. Fluid input and output should be monitored closely, and body weight documented twice daily. Sequential vital signs should be performed and a cardiopulmonary monitor with multi-lead ECG should be used to monitor for effects of hyperkalemia. (See Table 6.)
Table 6. Laboratory Studies and Clinical Monitoring
- CBC, calcium, phosphate, magnesium, uric acid, urea nitrogen, creatinine, lactate dehydrogenase at presentation and then every 6-12 hours depending on risk
- Sequential vital signs
- Strict assessment of intake and output
- Body weight once to twice daily
- Cardiorespiratory monitor with multi-lead ECG as needed for hyperkalemia (e.g., if K > 6 mEq/L, look for wide QRS and peaked T waves)
- Close clinical evaluation for signs of hypocalcemia or renal failure
Interventions should be initiated to prevent TLS in tumors with a risk of TLS, and aggressive treatments should be started if there is evidence of TLS. These include hydration and alkalinization. Urine alkalinization helps with excretion of uric acid but should be performed with care because a urine pH > 7.5 may lead to precipitation of CaPO4 and xanthine crystals. Hyperkalemia should be treated with hydration, sodium polystyrene sulfonate, calcium gluconate, or insulin and dextrose as needed. Dialysis may be needed. Hyperphosphatemia can be treated with aluminium hydroxide, and dialysis may be necessary.
Hyperuricemia is treated with allopurinol and, when possible, should be started prior to initiation of cytolytic therapy. For severe hyperuricemia, rasburicase may be used. Table 7 outlines suggested intervention for the management of TLS.
Table 7. Prevention and Treatment of TLS
|
Delay and/or titrate cytolytic therapy (if possible) until prophylactic measures can be implemented (see "hydration therapy," "urinary alkalinization," "hyperuricemia management" below). AVOID intravenous radiologic contrast agents that might precipitate renal failure. |
|
|
Hydration therapy |
|
|
Urinary alkalinization (see IV fluid above) |
|
|
Hyperkalemia |
–Calcium gluconate 100-200 mg/kg IV –D25 (2 mL/kg) IV + regular insulin 0.1 units/kg IV –Dialysis may be necessary |
|
Hyperphosphatemia |
|
|
Hyperuricemia (uric acid crystals form in renal tubules and distal collecting system and cause oliguria) |
OR
|
Infections in the Immunocompromised Child
Febrile Neutropenia. The advances made in the overall survival rates for children over the past few decades have been due, in part, to an increased intensity of chemotherapy given to pediatric patients. Cancer-directed therapy for this population is often quite cytotoxic to rapidly growing cells, often resulting in hematologic and immunologic suppression and breakdown of normal mucosal barriers. Selected patients may also be receiving radiation therapy, which may result in further tissue injury and impairment of the body's innate immunologic barriers. Additionally, most pediatric cancer patients have indwelling central venous access, representing a further breakdown in the body's natural defenses against infection. As a result, children receiving therapy for cancer are at high risk for life-threatening infections, which are known to occur, especially in the setting of neutropenia. Although fever in the general pediatric patient is a fairly common, often benign presenting complaint, fever in the potentially neutropenic pediatric cancer patient is a medical emergency and needs to be recognized quickly as such, with prompt initiation of treatment.
The generally accepted definition of fever in the neutropenic patient is a single temperature of greater than 38.3°C (101° F) or two consecutive temperatures greater than 38.0°C (100.4°F) taken orally in a 12-hour period and lasting at least 1 hour.33 It should be noted that axillary temperature is, on average, about 0.6°C lower than oral temperature. Rectal temperature should never be performed in children with neutropenia. Note that the absence of fever in a neutropenic patient with localizing signs or symptoms does not exclude infection. This is particularly true of the child receiving steroid therapy as a part of treatment. Such patients may present with non-specific complaints as the only sign of bacteremia. Clinically significant neutropenia is defined as an absolute neutrophil count (ANC) < 500/µL or < 1,000/µL and expected to decline due to recent chemotherapy administration.
Certain risk factors place the febrile neutropenic patient at particularly high risk. Patients with severe neutropenia, prolonged neutropenia, and those who developed neutropenia over a short period of time are at highest risk for the development of septicemia.34 Individuals with an ANC of less than 200 are particularly vulnerable, as are those patients who have been neutropenic for more than 10 days.
A thorough history and physical examination should be performed, with particular attention to potential sites of infection (oral lesions, perirectal tenderness, and central venous access sites). Rectal temperatures should be avoided due to the risk of bacteremia from colorectal organisms. Neutropenic patients do not have the ability to mount the same degree of inflammatory response as an immunocompetent host. As a result, the localizing signs and symptoms may be subtle (e.g., pneumonia may present with mild respiratory symptoms and may not have characteristic findings on examination or CXR). Any reported areas of discomfort should be pursued as potential sites of infection.
The initial laboratory work-up of a febrile neutropenic pediatric oncology patient should include, at a minimum, a CBC, electrolytes, BUN/creatinine, and blood cultures for bacteria and fungi from all lumens of the central venous access device. Peripheral blood cultures are not routinely needed. Urinalysis and urine culture should be obtained. A chest X-ray should be considered and certainly obtained if hypoxia, tachypnea, physical exam findings suggestive of a respiratory infection, or respiratory complaints are present.35 Stool studies and wound cultures should be considered if the history warrants. Meningitis is fairly rare in the febrile neutropenic patient; however, a lumbar puncture should be considered if there is alteration of mental status or neck stiffness.
Neutropenic patients are at risk for both common and opportunistic infections; therefore, the differential diagnosis of the febrile neutropenic patient is broad. Bacterial infections are the most common type of infection in this patient population and they present the most immediate risk to life. Broad-spectrum antimicrobials should be instituted within 30 minutes of presentation to a medical facility. Administration of broad-spectrum antimicrobials should not be delayed while awaiting laboratory results or imaging studies. The optimal choice of empiric antibiotic therapy is guided by institutional susceptibility and resistance patterns and history and exam findings unique to the individual patient. At a minimum, treatment should include a broad-spectrum beta-lactam antibiotic with antipseudomonal coverage. Potential agents for monotherapy include piperacillin/tazobactam, third- and fourth-generation cephalosporins (ceftazidime, cefepime), or carbapenems (imipenem, meropenem).36-40
In certain circumstances, monotherapy may be inadequate as empiric coverage. In the case of clinical sepsis, triple therapy with vancomycin and an aminoglycoside should be considered. Recent data suggest a shift in the overall trend of positive cultures toward increased infection with Gram-positive organisms in the febrile neutropenic patient.41 There are several circumstances under which Gram-positive coverage should be broadened, including severe mucositis, potential line infections, and concern for cellulitis. In addition, recent treatment with high-dose cytarabine raises the risk for Gram-positive infection, particularly Streptococcus viridans.42 If any of these risk factors are present, there should be a low threshold for adding vancomycin. Abdominal pain may be a particularly ominous symptom in the neutropenic patient, as it may indicate the onset of neutropenic enterocolitis (typhlitis). In such a setting, or in the case of a perirectal infection, coverage should include a broad-spectrum beta-lactam antibiotic with antipseudomonal coverage, vancomycin, and additional anaerobic coverage such as metronidazole. If respiratory symptoms are present, coverage for atypical organisms, and perhaps vancomycin, should be considered. Table 8 shows the suggested initial antibiotic management of the febrile neutropenic patient, and Table 9 shows additional antibiotic coverage for specific indications.
Table 8. Frequently Chosen Antibiotics for Febrile Neutropenia
|
Coverage |
Antibiotic |
|
Broad spectrum |
Ceftazidime; cefepime; piperacillin-tazobactam; meropenem |
|
Additional Gram-negative coverage |
Amikacin; gentamicin; tobramycin |
|
Additional Gram-positive coverage |
Vancomycin |
|
Additional anaerobic coverage |
Clindamycin; metronidazole |
|
Atypical bacterial coverage |
Azithromycin; clarithromycin |
Table 9. Indications for Specific Antimicrobial Therapy in Addition to Broad-spectrum Antibiotic
|
Indication |
Antimicrobial Therapy |
|
Clinical sepsis |
Broad-spectrum antibiotic + vancomycin + aminoglycoside |
|
High-dose cytarabine chemotherapy or mucositis or cellulitis or concern for CVC infection |
Broad-spectrum antibiotic + vancomycin |
|
Pulmonary infiltrates |
Broad-spectrum antibiotic + vancomycin + atypical antibacterial agent; if infiltrates are diffuse and hypoxia is present, consider treatment for PJP (PCP) |
|
Abdominal symptoms |
Broad-spectrum antibiotic + vancomycin + aminoglycoside + metronidazole or clindamycin |
|
Perirectal lesions |
Broad-spectrum antibiotic + vancomycin + metronidazole or clindamycin |
In addition to bacterial infections, oncology patients with prolonged severe neutropenia are at risk for opportunistic infections. Pediatric oncology patients routinely receive prophylaxis against Pneumocystis jirovecii (carinii), but there are instances of noncompliance, and breakthrough infections may occur even in the patient receiving prophylaxis. Significant hypoxia and diffuse infiltrates on chest X-ray should raise concern for Pneumocystis jirovecii pneumonia (formerly PCP). Fungal infections are possible causes of fever in the neutropenic patient. Antifungal coverage should be considered after consultation with the patient's oncologist. Viral infections such as HSV, varicella, RSV, and influenza may be life-threatening in the neutropenic pediatric patient and should be considered in the differential diagnosis. When symptoms and community infection patterns are suggestive, rapid RSV or influenza testing should be employed, and practitioners should have a low threshold for administering antiviral agents to such patients when the situation warrants.
Other Common Oncologic Emergencies
Pleural and Pericardial Effusions. Pleural or pericardial effusions may result from the primary malignancy, from complications of treatment such as radiation therapy, or from infectious complications. Dyspnea and cough are common presenting symptoms. Evaluation should include a chest radiograph, ECG, echocardiography, and monitoring of central venous pressure. Echocardiography is the most useful test in the confirmation of pericardial effusions. If there is significant respiratory distress or circulatory compromise, thoracentesis and pericardiocentesis for pleural effusion and pericardial effusions, respectively, should be considered in addition to routine resuscitative measures. Steroids should be considered for steroid-responsive tumors.
Bowel Obstruction or Perforation. This may result from the tumor process, such as Burkitt's lymphoma, or as a complication of treatment, such as steroids. Vincristine often leads to constipation and, if not treated, may cause obstipation. Whenever an acute abdomen is suspected in an oncologic patient, the patient should be placed on NPO status and surgical consultation should be obtained.
Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Several agents may cause SIADH with resultant hyponatremia, which may result in mental status changes and seizures. Fluid restriction is usually sufficient in mild cases. Administration of hypertonic solution should be considered in severe cases. Furosemide to promote free water excretion may be helpful. Electrolytes, especially sodium, should be monitored closely.
Pancreatitis. This frequently occurs as a complication of chemotherapy and may present with abdominal pain, nausea and vomiting, anorexia, and fever. Evaluation should include complete blood count, complete metabolic panel, and lipase and amylase enzyme levels. Treatment should include pain management, NPO status, intravenous fluids, and hospital admission. A nasogastric tube should be placed in patients with ongoing emesis, and antibiotics should be administered to febrile or septic patients.
Coagulopathy. This can result either in bleeding or deep venous thrombosis. A complete physical exam, including a careful neurologic exam, should be performed. Laboratory studies should include a complete blood count, PT, APTT, D-dimer, and fibrinogen. Imaging of suspected deep vein thrombosis (DVT) sites should be performed. Treatment with fresh frozen plasma and cryoprecipitate should be considered.44 Careful anticoagulation should be initiated in patients with DVT with no evidence of bleeding.
Summary
Cancer is the leading medical cause of death in children. Morbidity and mortality are either directly secondary to the cancer or to complications of treatment. The significant improvements in childhood cancer survival that have been witnessed in the past 25 years are due to improvements in chemotherapy, radiation therapy, surgical techniques, supportive care, and the recognition and treatment of oncologic emergencies. Prompt recognition and appropriate management of oncologic emergencies can decrease patient agony, decrease mortality, and minimize long-term sequelae. A multidisciplinary approach involving the emergency department physician, the oncologist, and radiation oncologist is essential in achieving optimal outcomes.
Brain tumors and other cancers that spread to the CNS can cause increased intracranial pressure, the symptoms of which can range from subtle to obvious. Management ranges from observation to administration of corticosteroids, mannitol, cytoreductive chemotherapy, to emergent radiation therapy. Spinal cord compression can result from intradural or extradural malignancies. If not treated promptly, it can result in paralysis and other sequelae. Management includes observation, cytoreductive chemotherapy, corticosteroids, intrathecal chemotherapy, radiation therapy, and surgical decompression.
Mediastinal tumors can result in airway compromise or vascular compromise. If airway compromise is suspected, care should be taken to avoid placing the patient in positions that may worsen airway compromise. Sedation and anesthesia should be considered with care. Emergent cytoreductive therapy with steroids and/or radiation therapy may be necessary.
Rapid proliferating and high tumor-burden cancers can lead to tumor lysis syndrome. Tumor lysis may occur even prior to the initiation of cytoreductive chemotherapy. Hydration, alkalinization, and allopurinol may be necessary. Rasburicase should be considered in severe hyperuricemia, provided the patient is not G6PD deficient. Severe tumor lysis syndrome may necessitate dialysis.
Fever in the neutropenic patient is an emergency, and prompt evaluation and administration of broad-spectrum antibiotics are needed. Blood culture from indwelling catheters should be collected, preferably prior to initiation of antibiotics. However, the administration of antibiotics should not be delayed for diagnostic studies.
The awareness and vigilance of emergency care providers and other physicians for possible oncologic emergencies are critical in maintaining and further improving good outcomes for children with malignancies.
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