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CHAPTER 145: Oncologic Emergencies in Infants and Children 955 approach. Common medications associated with thrombocytopenia are listed in Table 233-2. IMMUNE THROMBOCYTOPENIA Immune thrombocytopenia, previously called idiopathic thrombocytopenic purpura, is an autoimmune disorder of antiplatelet antibodies leading to platelet destruction and, in some cases, decreased megakaryocyte platelet production. In the childhood form, over 80% of cases are self-limited and resolve within 6 months, and the incidence of life-threatening bleeds is <0.5%. 14 Immune thrombocytopenia lasting >3 months after diagnosis is termed persistent, and the term chronic is now used for children with thrombocytopenia >12 months from the time of diagnosis.14 The typical presentation is a preschool- or school-age, previously healthy child with acute onset of petechiae and bruising, often following a viral illness. However, 25% of children present with a more insidi ous course. 14 Additional symptoms and signs are typically absent and, if found, should raise your concern for different diagnoses including hematologic, rheumatologic, oncologic, and infectious diseases. Laboratory studies typically demonstrate isolated thrombocytopenia. Pharmacologic treatment is controversial and may include corticosteroids, IV immunoglobulin, or anti-Rh(D) immunoglobulin (WinRho ® ). There are limited data regarding the use of thrombopoietic agents in children. These treatment options are discussed in further detail in Chapter 233. Consult hematology prior to management, activity restrict patients, and avoid all medications with antiplatelet activity. Admission is necessary for any child with a platelet count <20,000/mm 3, with an IV medication regimen, or with spontaneous bleeding, regardless of platelet count. If steroids are given, there are a variety of dosing regimens, ranging from 2 milligrams/kg/d of prednisone for 21 days, to 30 milligrams/kg of methylprednisolone daily for 4 days, to 20 milligrams/m 2/d of dexa methasone for 4 days. Steroids should be started only if the possibility of leukemia or aplastic anemia can be completely excluded on clinical grounds; otherwise, a bone marrow aspirate is necessary to secure the diagnosis before initiating steroid therapy. IV immunoglobulin is superior to steroids in improving platelet numbers for immune thrombocy topenia patients. 16 The typical IV immunoglobulin dose is 1 gram/kg/d. Anti-Rh(D) immunoglobulin is only effective in Rh-positive patients, and patients require admission due to the risk of severe intravascular hemolysis following infusion. The anti-Rh(D) dose is 50 to 75 micro grams/kg and can lead to a 1 to 2 gram/dL decrease in the hemoglobin concentration. Pretreatment with acetaminophen and diphenhydramine is recommended for both IV immunoglobulin treatments. On the rare occasion that a child with immune thrombocytopenia develops life-threatening hemorrhage, administer an immediate singledonor platelet transfusion (two to three times normal dose), along with IV methylprednisolone and IV immunoglobulin or anti-Rh(D). The obvious disadvantage of platelet transfusion in immune thrombocytopenia is that platelets will be rapidly consumed by circulating antiplatelet antibodies and repeat transfusions may be necessary. NEUTROPENIA Isolated neutropenia in childhood is caused by a heterogeneous group of disorders, ranging from transient and benign to chronic and profound immunodeficiency.

n immune thrombocytopenia is that platelets will be rapidly consumed by circulating antiplatelet antibodies and repeat transfusions may be necessary. NEUTROPENIA Isolated neutropenia in childhood is caused by a heterogeneous group of disorders, ranging from transient and benign to chronic and profound immunodeficiency. Neutropenia in the oncology patient is discussed in Chapter 145, “Oncologic Emergencies in Infants and Children. ” Neutropenia is an absolute neutrophil count <1500/mm 3. Lower counts can be noted in infants during the first year of life and in indi viduals of African and Middle Eastern descent, but counts should not decrease to <1000/mm 3.17,18 Neutropenia can be stratified into categories that are associated with increasing risk of pyogenic infection: mild neu tropenia with absolute neutrophil count of 1000 to 1500/mm3, moderate neutropenia with absolute neutrophil count of 500 to 1000/mm 3, and severe neutropenia with absolute neutrophil count of <500/mm3. Severe neutropenia places the patient at risk for life-threatening infections. Perform a through history and physical examination to identify a nidus of infection. Physical exam should include the oral mucosa, skin, ears, lungs, abdomen, and perineal region. Avoid digital rectal examinations and rectal temperatures, as well as catheter urine sampling, because these maneuvers can result in a portal of infection. Obtain a family his tory to evaluate for inheritable conditions. The underlying cause of isolated neutropenia is critical in defining infectious risk. A benign, transient neutropenia is quite common in healthy children and usually arises in the context of a viral infection, resolving within weeks to months. A number of medications, including antiepileptic drugs, antibiotics, antipsychotics, and antithyroid drugs, can cause severe neutropenia and comorbidities, and reports of druginduced neutropenia quote a 2.5% to 10% mortality rate. 18 Neutropenia due to bone marrow depletion is a known entity in the septic child; therefore, suspect serious bacterial infection in a critically ill child with neutropenia . Typical symptoms and signs of infection (e.g., purulence) may be absent in a neutropenic patient due to reduced inflammatory response. Chronic (>3 months) neutropenia can be idiopathic, autoimmune, nutritional, or associated with congenital or acquired bone marrow failure. Neonates may develop a self-resolving but significant isoim mune neutropenia from maternal/fetal antigen incompatibility or have placental transfer of antibodies from a mother with autoimmune neu tropenia. 17 A benign autoimmune neutropenia can also be noted during infancy or early childhood, when repeat CBCs reveal persistent neutro penia. Children with autoimmune neutropenia tend to have more fre quent (rather than more severe) infections, and the neutropenia resolves spontaneously within a few years. Lack of resolution should prompt further evaluation. If severe chronic neutropenia is noted in infancy, severe congenital neutropenia and other inherited marrow failure disorders must be excluded. Distinguishing benign neutropenia from worrisome neutropenia often requires a bone marrow examination to distinguish normal versus abnormal myelopoiesis. Cyclic neutropenia, inherited as an autosomal dominant disorder, is characterized by episodic severe neutropenia on an approximately 21-day cycle. Episodes typically last 4 to 6 days. 18 Affected children are more likely to experience fevers and non–life-threatening infections such as stomatitis, pharyngitis, cellulitis, otitis media, and lymphadeni tis. They are also at high risk for more profound infections.

severe neutropenia on an approximately 21-day cycle. Episodes typically last 4 to 6 days. 18 Affected children are more likely to experience fevers and non–life-threatening infections such as stomatitis, pharyngitis, cellulitis, otitis media, and lymphadeni tis. They are also at high risk for more profound infections. For the otherwise healthy child with acute, asymptomatic neutropenia identified on routine CBC, close outpatient observation and serial blood counts are usually performed. Consult hematology for children with persistent neutropenia, concern for a heritable cause of neutropenia, neutropenia associated with syndromic features on clinical exam, or serious pyogenic infections associated with neutropenia. Fever in children with neutropenia, regardless of etiology, must be treated as a medical emergency with broad-spectrum antibiotics. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Oncologic Emergencies in Infants and Children Jessica A. Bailey Megan Mickley Children and adolescents develop different types of cancers than adults. The 5-year survival rate for all childhood (0 to 19 years of age) cancers in the United States has been steadily increasing and is currently 83% to 84% 1; however, malignant neoplasms remain the second leading cause of death for U.S. children age 5 to 14 years.2 The most common childhood malignancies are discussed below. CHAPTER Tintinalli_Sec12_p0669-0996.indd 955 8/2/19 7:59 PM

ge) cancers in the United States has been steadily increasing and is currently 83% to 84% 1; however, malignant neoplasms remain the second leading cause of death for U.S. children age 5 to 14 years.2 The most common childhood malignancies are discussed below. CHAPTER Tintinalli_Sec12_p0669-0996.indd 955 8/2/19 7:59 PM 956 SECTION 12: Pediatrics LEUKEMIA  EPIDEMIOLOGY Acute leukemias, including acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML), are the most common cancers in children, accounting for over a quarter of all malignancies. 3-6 Chronic leukemias are rare in children and adolescents. ALL accounts for approximately 75% to 80% of pediatric leukemias and, if diagnosed early, carries a 5-year survival rate of 85% to 90% in developed countries. 4-7 The peak incidence of ALL is 3 to 5 years of age, with younger children having the best outcomes. 8 In the United States, ALL is more common in boys and more common in white and Hispanic children than in African American children. 2-5 A number of inherited risk factors, including trisomy 21, are well documented. AML accounts for approximately 15% to 20% of childhood and adolescent leukemias in the United States. 4,6,9 Cure rates have improved to 57% to 70% but remain lower than those for ALL. Relapsed AML accounts for greater than half of all childhood leukemia-related deaths. 4,9 Incidence of AML peaks in the first 2 years of life. 4,6 Environmental exposures, including chemotherapy agents and radiation received dur ing treatment of other childhood cancers, are known causes of second ary AML. Patients being treated for AML have a higher incidence of complications than those with ALL, especially infections. This is primarily due to the greater intensity of chemotherapeutic regimens necessary to achieve remission.  CLINICAL FEATURES Most signs and symptoms of acute leukemia are due to bone marrow infiltration by blasts, as well as infiltration of extramedullary sites. A detailed history may reveal nonspecific constitutional symptoms: fever, fatigue, anorexia, and weight loss. Cytopenias from marrow infiltra tion can present as pallor, easy bleeding/bruising with petechiae and ecchymoses, infections, or bone pain. The reticuloendothelial system is the most common site of extramedullary infiltration, manifesting as hepatomegaly, splenomegaly, and/or lymphadenopathy. Other sites include the CNS and testes. Consider leukemia in cases of recurrent or severe unexplained epi staxis or other mucosal bleeding or in children with unusually exten sive or abnormally located bruising. Concerning symptoms include abnormal blood counts, a history of nighttime pain, and recurrent or persistent bony complaints. 10 Bone and joint pain may present as limp ing or refusal to walk. In rare cases of AML, solid nodules of leukemic blasts (chloromas) may be noted, most commonly in the skin (leukemia cutis) or gingiva. For a subset of patients, diagnosis is made incidentally during an evaluation for infection, lymphadenopathy, priapism, or other presentations.  DIAGNOSIS Evaluate suspected leukemia with a CBC with differential count, a peripheral smear, a coagulation profile, a type and screen, and serum chemistries including calcium, phosphate, magnesium, uric acid, liver function studies, and lactate dehydrogenase. Obtain a chest radiograph, because some children with T-cell ALL can have an anterior mediastinal mass of leukemic cells. If fever or clinical suspicion of infection is pres ent, obtain a blood and urine culture. Although almost all children with leukemia have some form of hematologic abnormality including anemia, thrombocytopenia, leukocytosis, or neutropenia, very few have an extremely elevated WBC. Total WBC counts are often normal or only moderately elevated.

icion of infection is pres ent, obtain a blood and urine culture. Although almost all children with leukemia have some form of hematologic abnormality including anemia, thrombocytopenia, leukocytosis, or neutropenia, very few have an extremely elevated WBC. Total WBC counts are often normal or only moderately elevated. Hyperleukocytosis is more likely in patients with AML and in infants with either ALL or AML. 11 Definitive diagnosis requires a bone marrow aspirate. The differential diagnosis of children with marrow suppression includes aplastic anemia, profound iron deficiency anemia (com monly noted in toddlers with excessive milk intake), viral infections (e.g., Epstein-Barr virus, cytomegalovirus, parvovirus B19), primary immune thrombocytopenia, and rheumatologic diseases. A good rule of thumb is that leukemias commonly involve abnormalities in more than one cell line, whereas other conditions are often restricted to a single cell line.  TREATMENT The goal is to induce remission while minimizing treatment toxicity. Taking into consideration age and leukocyte count at the time of diag nosis, as well as other risk factors (e.g., genetic abnormalities of leukemic cells with important prognostic significance), children with ALL are usually stratified into different treatment groups. 12 Children with AML receive intensive multiagent chemotherapy. Some receive hematopoietic stem cell transplantation. Molecularly targeted therapeutic approaches are in development. 13,14  DISEASE COMPLICATIONS Most children suspected of having leukemia are stable and receive an initial diagnostic workup (see “Diagnosis” section) but no acute treat ment. Occasionally, acute treatment is needed for cytopenias, hyperleukocytosis, coagulopathy, electrolyte abnormalities, and infection. Initiate treatment after consultation with a pediatric oncologist. Anemia Anemia is extremely common and multifactorial, including impaired hematopoiesis due to leukemic marrow infiltration, decreased erythropoietin levels, iron deficiency, hemolysis, occult blood loss, and chronic inflammation. There is no universally recommended threshold for transfusion, and in the ED, the decision to transfuse should depend more on the appearance and clinical condition of the child than on any particular laboratory value. 15 Life-threatening hemorrhage, symptomatic anemia, or rapidly consumptive coagulopathy requires transfusion, with the addition of factor replacement as needed. The general goals of transfusion therapy are to raise the hemoglo bin level to >8 to 10 grams/dL, depending on the child’s condition. However, in the setting of profound anemia and hyperleukocytosis, transfuse to a much lower level to minimize the effect on blood viscosity. The exact numbers will often depend on institutional protocols (see discussion on transfusion under “Blood Products”). Thrombocytopenia Mild to moderate bruising, petechiae, and/or mucosal bleeding may occur with platelet counts <20,000/mm 3, but the risk of spontaneous intracranial hemorrhage is extremely low until the platelet count dips to <5000/mm 3. Most protocols reserve prophylactic platelet transfusions in asymptomatic patients to platelet counts <10,000/mm 3 in the absence of other bleeding risk factors. Invasive procedures require a platelet count >40,000 to 50,000/mm3.16 Blood Products A unit of packed red blood cells has a volume of about 250 mL and a hematocrit of 70% to 80%. The typical volume of packed red blood cells given to a child is 10 to 15 mL/kg. Generally, 10 mL/kg of packed red blood cells are expected to raise the hemoglobin level 3 grams/dL in a patient without active hemorrhage.

ducts A unit of packed red blood cells has a volume of about 250 mL and a hematocrit of 70% to 80%. The typical volume of packed red blood cells given to a child is 10 to 15 mL/kg. Generally, 10 mL/kg of packed red blood cells are expected to raise the hemoglobin level 3 grams/dL in a patient without active hemorrhage. A dose of platelets is 0.1 unit/kg random donor equivalent units and is expected to raise the platelet count by 30,000 to 50,000/mm 3.8,17 Some institutions release platelets as single apheresis units versus random donor units. Platelets express ABO antigens, and even though platelets do not express Rh antigens, Rh-negative donors are used for Rh-negative patients because red blood cell contamination may result in Rh alloim munization. Rh immunoglobulin can be given if Rh-negative platelets are unavailable. Institutions vary on the use of type-specific platelets and the need for Rh immunoglobulin (Table 145-1). There are several product choices for packed red blood cells and platelets: irradiated, leukocyte reduced, and cytomegalovirus seronega tive ( Table 145-2). Irradiation of blood products is recommended for profoundly immunosuppressed individuals (e.g., severe immunodefi ciency, high-dose chemotherapy, post–bone marrow transplant). Many pediatric cancer centers will transfuse only irradiated blood to all oncology patients. Consult with the pediatric oncologist for specific directions before administering blood products. Hyperleukocytosis is a WBC >100,000/mm 3. Leukocytosis can cause leukostasis, tumor lysis syndrome, and disseminated intravascular coagulation. 18 Leukostasis is a clinical diagnosis. Intravascular aggre gations of leukocytes lead to injury of many organs, most commonly the Tintinalli_Sec12_p0669-0996.indd 956 8/2/19 7:59 PM

eukocytosis is a WBC >100,000/mm 3. Leukocytosis can cause leukostasis, tumor lysis syndrome, and disseminated intravascular coagulation. 18 Leukostasis is a clinical diagnosis. Intravascular aggre gations of leukocytes lead to injury of many organs, most commonly the Tintinalli_Sec12_p0669-0996.indd 956 8/2/19 7:59 PM CHAPTER 145: Oncologic Emergencies in Infants and Children 957 lungs and CNS. In the cerebral circulation, symptoms and signs include headache, mental status changes, visual changes, seizures, and stroke (ischemic and hemorrhagic), whereas in the pulmonary circulation, leukostasis can cause dyspnea, hypoxemia, and respiratory failure. Chest radiographs may be normal or may show a diffuse, nonspecific interstitial infiltrate. AML patients are especially at risk because their leukemic blasts are larger, “stickier, ” and more rigid. ED treatment consists of aggressive IV hydration and treatment of tumor lysis syndrome (see discussion in “Tumor Lysis Syndrome” section and Table 145-4). Avoid treatments that increase blood viscosity such as diuretics and packed red blood cell transfusions. Platelets do not increase blood viscosity and should be administered for levels <20,000/mm to decrease the risk of cerebral hemorrhage. Leukapheresis is a temporizing measure until definitive antileukemic therapy can be given. Disseminated Intravascular Coagulation Disseminated intravas cular coagulation is commonly associated with AML. Some subtypes release a procoagulant tissue factor that can lead to a life-threatening consumptive coagulopathy. ED treatment includes replacement of platelets, depleted coagulation factors, fibrinogen with fresh frozen plasma, and cryoprecipitate. HODGKIN’S LYMPHOMA  EPIDEMIOLOGY Hodgkin’s lymphoma is a lymphoid neoplasm characterized by progressive enlargement of lymph nodes. Age distribution is bimodal, with peaks in young adulthood and older-aged adults. It is the most com mon malignancy in adolescents age 15 to 19 years. 4 Risk factors include Epstein-Barr virus (particularly in developing countries) and human immunodeficiency virus.  CLINICAL FEATURES AND DIAGNOSIS Hodgkin’s lymphoma typically presents with painless, firm, “rubbery” lymph nodes, usually cervical or supraclavicular ( Figure 145-1). If empiric antibiotics are prescribed for presumptive cervical adenitis, the mass continues to increase in size. The lack of overlying erythema and the absence of pain suggest lymphoma. Systemic “B” symptoms (fever >38°C [100.4°F], night sweats, and weight loss ≥10% over 6 months) are present in 39% to 50% of children and adolescents. 19,20 Two thirds of pediatric patients will present with mediastinal involve ment, which may manifest as cough, stridor, dysphagia, or dyspnea. 21 Hepatomegaly or splenomegaly can be found due to hematogenous spread. Initial ED diagnostic studies should include lab evaluation similar to that of ALL, with the addition of a chest radiograph. Diagnosis is confirmed by lymph node biopsy. A CT of the soft tissues of the neck, chest, abdomen, and pelvis will help delineate the extent of disease. Subdiaphragmatic primary disease is uncommon; more than 97% of Hodgkin’s lymphoma patients present with a lesion above the diaphragm. The differential diagnosis of cervical lymphadenopathy is extensive. See Chapter 125, “Neck Masses in Infants and Children. ”  TREATMENT ED treatment before confirmatory diagnosis is usually directed at acute complications such as superior vena cava syndrome or upper airway compression (see “Complications of Pediatric Cancer and Oncologic Emergencies” section). Use caution with sedation, given the risk of airway compromise with mediastinal involvement. Do not give steroids to patients with significant lymphadenopathy if lymphoma is in the differential diagnosis.

a syndrome or upper airway compression (see “Complications of Pediatric Cancer and Oncologic Emergencies” section). Use caution with sedation, given the risk of airway compromise with mediastinal involvement. Do not give steroids to patients with significant lymphadenopathy if lymphoma is in the differential diagnosis. Following risk categorization, therapeutic management of Hodgkin’s lymphoma incorporates chemotherapy and radiotherapy. TABLE 145-1 Transfusion of Blood Products in Children Blood Product Component Volume Dose Typical Transfusion Goals* Packed red blood cells Citrate phosphate dextrose adenine, 1 unit = 250 mL † 10 mL/kg increases Hb by 3 grams/dL Hb, 8–10 grams/dL Adsol, 1 unit = 350 mL† 12.5–15.0 mL/kg increases Hb by 3 grams/dL Platelets One apheresis unit = 200–400 mL ‡ 0.1 unit/kg increases platelets by 30,000–50,000/mm 3 50,000–100,000/mm 3 Fresh frozen plasma 1 unit = 200–250 mL (centrifuged) 20 mL/kg will replace ~50% of most coagulation factors 1 unit = 500 mL (apheresis) Cryoprecipitate 1 unit = 15 mL 0.1 unit/kg increases fibrinogen by ~50 milligrams/dL# Fibrinogen, 100 milligrams/dL 1 unit = 80–100 units factor VIII 1 unit = 150–200 milligrams fibrinogen Abbreviation: Hb = hemoglobin. *Varies by clinical circumstance. †The volume in a single unit of packed red blood cells depends on the additive/preservative used. ‡The random donor platelet unit is used when there is a shortage of apheresis units. A single random donor unit contains a volume of 50 to 70 mL. One apheresis unit = 6–8 random donor units. #In the absence of ongoing bleeding. TABLE 145-2 Blood Component Therapy Treatment Description Goal Target Recipient Leukodepleted blood 99.9% reduction in donor WBCs Reduces incidence of febrile nonhemolytic transfusion reactions Decreases sensitization to HLA-1 antigens Significantly reduces transmission of CMV* Patients likely to receive multiple platelet or packed red blood cell transfusions in future CMV-seronegative blood Gold standard for CMV-negative blood Eliminates transmission of CMV* Patients at high risk for CMV-related com plications now or in the future Irradiated blood Destroys donor lymphocytes’ ability to multiply Prevent transfusion-associated graft-versus-host disease from donor WBCs (does not prevent CMV transmission) Profoundly immunocompromised patients Stem cell transplant patients Abbreviations: CMV = cytomegalovirus; HLA-1 = human leukocyte antigen 1. *Patients at high risk for CMV-related complications include patients receiving stem cell or solid organ transplants and the severely immunocompromised. Tintinalli_Sec12_p0669-0996.indd 957 8/2/19 7:59 PM

sed patients Stem cell transplant patients Abbreviations: CMV = cytomegalovirus; HLA-1 = human leukocyte antigen 1. *Patients at high risk for CMV-related complications include patients receiving stem cell or solid organ transplants and the severely immunocompromised. Tintinalli_Sec12_p0669-0996.indd 957 8/2/19 7:59 PM 958 SECTION 12: Pediatrics NON-HODGKIN’S LYMPHOMA  EPIDEMIOLOGY Non-Hodgkin’s lymphoma accounts for 7% of cancer in children and adolescents in the United States, with a male predominance but little variation by age. 1 Non-Hodgkin’s lymphoma includes a heterogeneous group of malignant neoplasms that can originate not only in the lym phatic system but also in almost any organ in the body, including the skin, cortical bone, GI tract, and CNS. The majority of cases have no known cause, although immunodeficiencies and previous exposure to immunosuppressive agents are known risk factors. In equatorial Africa, non-Hodgkin’s lymphoma accounts for almost 50% of childhood can cers and is almost universally associated with Epstein-Barr virus.  CLINICAL FEATURES AND DIAGNOSIS The clinical presentation depends on the site and extent of disease. Constitutional symptoms are not common. Lymphadenopathy, a mass in virtually any location, hepatosplenomegaly, and cytopenias can all be seen. GI manifestations occur with abdominal tumors (usually Burkitt’s lymphoma). Mediastinal involvement may lead to pleural or pericar dial effusions, upper airway obstruction from mass effect, respiratory symptoms, or superior vena cava syndrome. Testicular, skin, and CNS or spinal manifestations are seen, but less commonly. The differential diagnosis is broad and includes infectious (tuberculosis, toxoplasmo sis, Epstein-Barr virus, Bartonella henselae, human immunodeficiency virus) and oncologic (Hodgkin’s lymphoma, leukemia, rhabdomyosarcoma) processes. Diagnosis is by lymph node biopsy.  TREATMENT Initial workup should include basic laboratory studies and a chest radiograph to evaluate for mediastinal disease. If there is concern for intraabdominal obstruction (bowel or ureteral), US or abdominal/pelvic CT may be indicated. A chest CT can further evaluate for chest mass or superior vena cava syndrome. The mainstay of treatment is multiagent chemotherapy. CENTRAL NERVOUS SYSTEM TUMORS  EPIDEMIOLOGY CNS tumors are the second most common pediatric cancer, accounting for approximately 21% of all childhood cancer diagnoses. 4 They are also the leading cause of cancer-related death in children, with survival FIGURE 145-1. Hodgkin’s lymphoma. A 13-year-old adolescent male presented with a painless, rubbery, firm cervical lymphadenopathy of 4 months’ duration. [Reproduced with permission from Shah BR, Lucchesi M: Atlas of Pediatric Emergency Medicine, © 2006, McGraw-Hill, Inc., New York.] rates lowest for young children. 23,24 For the emergency physician, the specifics of the tumor type are less important than tumor location and clinical effects. The three most common categories of pediatric CNS tumors are astrocytomas, medulloblastomas, and ependymomas. Specific genetic syndromes, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome, are predisposing factors. CNS tumors can also be secondary to high-dose cranial radiation for a previously treated childhood cancer.  CLINICAL FEATURES AND DIAGNOSIS There is heterogeneity in the presentation of CNS neoplasms depend ing on the extent of the tumor, its location, and the age of the child. In children, tumors are more often infratentorial than supratentorial. Symptoms are often nonspecific (headache, irritability, emesis, behav ioral changes), which can delay diagnosis.

ere is heterogeneity in the presentation of CNS neoplasms depend ing on the extent of the tumor, its location, and the age of the child. In children, tumors are more often infratentorial than supratentorial. Symptoms are often nonspecific (headache, irritability, emesis, behav ioral changes), which can delay diagnosis. The classic presentation of a posterior fossa tumor or other tumors causing obstructive hydrocephalus is early morning headache and subsequent vomiting. These symptoms are believed to be due to a rise in intracranial pressure during sleep caused by increased cerebral blood volume in the recumbent position as well as hypoventilation with resultant hypercarbia and increased cerebral blood flow. Addi tional clinical signs such as a bulging fontanelle, rapidly increasing head circumference in an infant, sunsetting (preferential downward gaze due to obstructive dilatation of the third ventricle with resultant tectal pressure and paresis of upward gaze), cranial nerve palsies (usu ally sixth nerve), papilledema, or somnolence also suggest increased intracranial pressure. 25 Infiltration of the brainstem can produce cranial nerve deficits, long tract corticospinal motor weakness, and cerebellar ataxia. Symptoms of supratentorial neoplasms are dictated by location and may include headache, declines in school performance, personality changes, motor weakness, and seizures. Craniopharyngiomas arise in the sellar region and produce visual changes due to their proximity to the optic chiasm, as well as significant endocrinologic abnormalities from hypothalamic dysfunction (including diabetes insipidus, stunted growth and sexual development, and hypothyroidism). Most CNS malignancies are identifiable on CT, but MRI provides superior visualization of tumors, particularly in the posterior fossa.  TREATMENT Treatment of the most serious and life-threatening brain tumor threat— increased intracranial pressure leading to herniation—is addressed in the section “Complications of Pediatric Cancer and Oncologic Emer gencies. ” In the ED setting, manage acute seizures and consider giving IV dexamethasone to treat vasogenic edema surrounding the tumor. Consult with neurosurgery and pediatric oncology to arrange definitive treatment. NEUROBLASTOMA  EPIDEMIOLOGY Neuroblastoma is a malignant tumor that arises from primitive gan glion cells of the sympathetic nervous system. It accounts for 7% of all childhood cancers and is the most common neoplasm in the first year of life.  CLINICAL FEATURES The clinical features are highly variable and depend on tumor size and location. Neuroblastoma may arise anywhere along the sympathetic nervous system. The adrenal gland is the most common primary site, but it may also arise from other intra-abdominal sites, the chest, or the neck. Metastasis is quite common to adjacent lymph nodes, liver, skin, bone, and bone marrow. The variability in tumor location and extent explains the array of signs and symptoms that may lead to the diagnosis of neuroblastoma. Tintinalli_Sec12_p0669-0996.indd 958 8/2/19 7:59 PM

ntra-abdominal sites, the chest, or the neck. Metastasis is quite common to adjacent lymph nodes, liver, skin, bone, and bone marrow. The variability in tumor location and extent explains the array of signs and symptoms that may lead to the diagnosis of neuroblastoma. Tintinalli_Sec12_p0669-0996.indd 958 8/2/19 7:59 PM CHAPTER 145: Oncologic Emergencies in Infants and Children 959 Painless abdominal masses can lead to compression of the bowel, blad der, venous, or lymphatic structures. Compression from thoracic masses can cause respiratory distress or superior vena cava syndrome, while paravertebral tumors can invade the spinal canal, causing spinal cord compression. Horner’s syndrome (ptosis, miosis, and anhidrosis) may result from disease involving the superior cervical ganglion. Unique presentations of neuroblastoma that require a high index of suspicion include proptosis and periorbital ecchymoses (“raccoon eyes”) or swelling, characteristic of orbital metastases. Opsoclonusmyoclonus is a paraneoplastic syndrome also highly associated with occult neuroblastoma.  DIAGNOSIS AND TREATMENT Obtain basic laboratory studies. Cytopenias suggest bone marrow involvement. Radiographs, US, or CT may detect an intra-abdominal or thoracic mass. Because neuroblastomas often lead to increased levels of catecholamines, the metabolites of which are detectable in the urine, urine homovanillic acid and vanillylmandelic acid can aid in diagnosis. Bone marrow and tumor biopsies confirm the diagnosis. Treatment includes surgical resection and/or radiation therapy and chemotherapy. Select patients undergo stem cell transplant. WILMS’ TUMOR (NEPHROBLASTOMA)  EPIDEMIOLOGY Wilms’ tumor, or nephroblastoma, is a malignant embryonal renal tumor that affects children predominantly under the age of 5 years. Overall survival rates are excellent, at approximately 90%.27  CLINICAL FEATURES The classic presentation of Wilms’ tumor is an asymptomatic abdominal mass, sometimes noted while dressing or bathing the child. As opposed to neuroblastoma (given that the age group and abdominal mass at the time of presentation can be similar), children often appear remarkably well with no systemic symptoms. Hypertension due to increased renin production is present in 25% of cases. 28 There can be mass effect from the tumor, leading to respiratory distress or intra-abdominal obstruc tion. Less common symptoms include anorexia, weight loss, emesis, or hematuria. Metastases at the time of diagnosis are uncommon but can occur to the lungs, liver, or lymph nodes.  DIAGNOSIS AND TREATMENT Obtain basic laboratory studies, urine catecholamines to rule out neuroblastoma, and urinalysis. Obtain a chest radiograph to identify pulmonary metastases (Figure 145-2). Ultrasonography is appropriate for initial abdominal imaging in the ED, although vigorous or excessive palpation of the mass can cause tumor rupture . CT or MRI identifies the extent of the disease. Definitive treatment is surgical resection and chemotherapy, with or without radiation therapy. RETINOBLASTOMA  EPIDEMIOLOGY Retinoblastoma is the most common pediatric intraocular malignancy, with 90% of cases diagnosed in children <3 years old. 29 There are both heritable and nonheritable forms. The retinoblastoma (RB) gene was the first tumor suppressor gene discovered in the human genome. 30 Heritable forms are usually due to a germline mutation in the RB1 gene and present within the first year of life with bilateral disease. The majority of cases of nonheritable disease are unilateral.  CLINICAL FEATURES Leukocoria (“white pupil”), in which the white light reflects off of the tumor instead of red light reflecting off of the retina, is the most FIGURE 145-2. Wilms’ tumor. A.

and present within the first year of life with bilateral disease. The majority of cases of nonheritable disease are unilateral.  CLINICAL FEATURES Leukocoria (“white pupil”), in which the white light reflects off of the tumor instead of red light reflecting off of the retina, is the most FIGURE 145-2. Wilms’ tumor. A. A 7-year-old child presented with a huge abdominal mass and respiratory distress. Pelvic CT scan followed by laparotomy confirmed the mass as Wilms’ tumor. Because of the retroperitoneal location of the kidney, these tumors can be quite large at diagnosis without significant impingement of other vital structures. B. Right-sided pleural effusion due to metastatic disease. Almost complete opacification of the right hemithorax with mediastinal shift to the left. [Reproduced with permission from Shah BR, Lucchesi M: Atlas of Pediatric Emergency Medicine, © 2006, McGraw-Hill, Inc., New York.] common presenting sign (see Figure 122-12). This may be noted by a primary physician or occasionally by family members when they note the leukocoria in photographs. Other signs may include strabis mus, decreased visual acuity, redness, pain, glaucoma, and proptosis (late stage). Y oung children do not often report visual complaints. The retinoblastoma can spread into the surrounding orbit, as well as metas tasize into the CNS and viscera.  DIAGNOSIS AND TREATMENT If leukocoria or other signs suggestive of an intraocular tumor are noted, consult ophthalmology in the ED. Definitive diagnosis is usually Tintinalli_Sec12_p0669-0996.indd 959 8/2/19 7:59 PM

etinoblastoma can spread into the surrounding orbit, as well as metas tasize into the CNS and viscera.  DIAGNOSIS AND TREATMENT If leukocoria or other signs suggestive of an intraocular tumor are noted, consult ophthalmology in the ED. Definitive diagnosis is usually Tintinalli_Sec12_p0669-0996.indd 959 8/2/19 7:59 PM 960 SECTION 12: Pediatrics obtained by exam and imaging under anesthesia. Obtain a CT or MRI if there is evidence of orbital inflammation. Treatment options depend on the extent of the disease and include enucleation, chemotherapy, cryotherapy, brachytherapy, thermotherapy, radiotherapy, and laser photocoagulation. GERM CELL TUMORS  EPIDEMIOLOGY Germ cell tumors are a heterogenous group of neoplasms that can develop at any age, although they are more common in adolescents and young adults. 4 Extragonadal tumor locations, including sacro coccygeal, mediastinal, and intracranial, are more common in young children, whereas during and after puberty, the primary location is the gonads. Testicular germ cell tumors are the most common solid tumor in young adult men ( Figure 145-3).34 An undescended testicle increases the risk for testicular cancer 10- to 50-fold.35 Prognosis for these tumors is extremely good, even if metastases are present, with an overall cure rate of 85% to 90%. 34 Despite that fact, they remain a significant cause of death in young males. This highlights the importance of encouraging young male patients to perform testicular self-examinations. The median age of diagnosis for ovarian germ cell tumors is 16 to 20 years. 36 Due to the intra-abdominal location, ovarian tumors may go undetected for a longer amount of time than testicular tumors; this increases the potential for rupture.  CLINICAL FEATURES Testicular tumors typically present with an asymptomatic, nontender testicular mass. Ovarian tumors are most likely to present with abdominal pain (85%). 36 Other ovarian symptoms include abdominal disten tion, vaginal bleeding, and weight gain. Ten percent of patients with ovarian tumors presenting with abdominal pain from tumor rupture, hemorrhage, or torsion are misdiagnosed. 36 Tumors can metastasize, most commonly to the lymph nodes, liver, lungs, and CNS. Thus, it is important to complete a genitourinary exam on any patient presenting with lymphadenopathy or chronic pulmonary symptoms.  DIAGNOSIS AND TREATMENT A testicular mass or abdominal mass may be palpated upon exam. Ultrasonography often identifies an ovarian or scrotal mass, whereas CT delineates the extent of disease. Serum tumor markers can be added to the basic laboratory tests. Treatment includes resection, chemotherapy, and/or radiotherapy. Given that many patients are of reproductive age, treatment attempts to preserve fertility if possible. BONE AND SOFT TISSUE SARCOMAS The term sarcoma refers to a diverse group of malignant neoplasms derived from mesenchymal cell origin that can arise from virtually any location at any age. Sarcomas are divided into two main types: soft tissue sarcomas and bone sarcomas. There are over 70 recognized subtypes. The most common subtypes diagnosed in pediatrics are rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma.  RHABDOMYOSARCOMA Rhabdomyosarcoma accounts for 3% of childhood cancers and 2% of adolescent cancers. 4 Risk factors include a number of inherited can cer predisposition syndromes (e.g., Li-Fraumeni, neurofibromatosis type 1). The embryonal subtype (>75% of cases) is most common in children <5 years old, tends to occur in the head and neck, and has a better prognosis. The alveolar subtype can occur at any age, is more aggressive, and is commonly found in the trunk or extremities. Orbital rhabdomyosarcoma accounts for 10% of all rhabdomyosar coma cases.

al subtype (>75% of cases) is most common in children <5 years old, tends to occur in the head and neck, and has a better prognosis. The alveolar subtype can occur at any age, is more aggressive, and is commonly found in the trunk or extremities. Orbital rhabdomyosarcoma accounts for 10% of all rhabdomyosar coma cases. Signs and symptoms depend on location, but a painless mass is characteristic. Evaluation in the ED may begin with ultrasonography. More extensive evaluation steps are determined by the oncologist. Treatment includes a combination of surgical excision, chemotherapy, and radiotherapy.  OSTEOSARCOMA Osteosarcoma, also called osteogenic sarcoma, is the most common primary pediatric bone tumor and is among the most frequent causes of cancer-related death. 38 Incidence peaks in adolescence, particularly during a growth spurt. It can occur in any bone, but the majority of cases arise from the metaphyses of long bones. Over half of cases originate near the knee joint, either at the distal femur or at the proximal tibia. Twenty percent of patients have metastases at the time of diagnosis, most commonly in the lungs, followed by bone. 4 Previous radiation during treatment for a different pediatric neoplasm increases the risk of osteosarcoma. Nonspecific symptoms can lead to a delay in diagnosis. The most common presentation is an adolescent with persistent bone pain that worsens at night or with activity . Soft tissue swelling may be noted on exam. Diagnosis is suggested by plain radiography, demonstrating a lytic lesion with cortical destruction near the metaphysis (Figure 145-4). The classic radiographic finding is the “sunburst” appearance of periosteal reaction. Pathologic fracture is an uncommon presentation. 40 The differential diagnosis of radiographically similar lesions includes Ewing’s sarcoma as well as more benign lesions. Diagnosis is by biopsy, and Left testicular mass FIGURE 145-3. Testicular tumor. This patient presented with a painless left testicular mass highly suspicious for cancer. [Photo contributed by Patrick McKenna, MD. Reproduced with permission from Knoop K, Stack L, Storrow A, Thurman RJ: Atlas of Emergency Medicine, 3rd ed. © 2010, McGraw-Hill, Inc., New York.] Tintinalli_Sec12_p0669-0996.indd 960 8/2/19 7:59 PM

presented with a painless left testicular mass highly suspicious for cancer. [Photo contributed by Patrick McKenna, MD. Reproduced with permission from Knoop K, Stack L, Storrow A, Thurman RJ: Atlas of Emergency Medicine, 3rd ed. © 2010, McGraw-Hill, Inc., New York.] Tintinalli_Sec12_p0669-0996.indd 960 8/2/19 7:59 PM CHAPTER 145: Oncologic Emergencies in Infants and Children 961 treatment includes chemotherapy and limb-sparing surgery. Osteosarcoma is radiation resistant.  EWING’S SARCOMA Ewing’s sarcoma is an aggressive tumor of uncertain origin that can occur in the bone or soft tissues. It is more common in older children and adolescents, but the incidence is half that of osteogenic sarcoma. Hematogenously spread metastases are present in approximately 25% of patients at the time of diagnosis and are most commonly located in the lungs, bone, and bone marrow. 4 Metastatic disease is the most significant prognostic factor.42 Ewing’s sarcoma typically presents with persistent pain at the tumor site. Tenderness or swelling may be noted on physical exam. The long bones (femur, tibia, humerus) and the axial skeleton (pelvis, ribs, spine) are the most common sites of disease. Plain radiographs of the primary tumor site may reveal the charac teristic “moth-eaten appearance” of the destructive lesion or the “onion peel” appearance of the periosteal reaction (Figure 145-5). Diagnosis is by biopsy, and treatment is multidisciplinary, including chemotherapy and radiotherapy or surgery.  COMPLICATIONS OF PEDIATRIC CANCER AND ONCOLOGIC EMERGENCIES For the child with cancer, the road to recovery is inevitably interrupted by complications. These complications can be generally classified as infectious (e.g., fever and neutropenia), metabolic (including tumor lysis syndrome, hypercalcemia, and the syndrome of inappropriate FIGURE 145-4. Osteosarcoma. Note the lytic femoral lesion with cortical destruction. FIGURE 145-5. Ewing’s sarcoma. Note the destruction of the proximal fibula. antidiuretic hormone secretion), and structural (superior vena cava syndrome, spinal cord compression, and increased intracranial pressure). INFECTION Most pediatric cancer patients experience an infectious complication over the course of the illness. Neutropenia is usually seen as an effect of cytotoxic therapy, 43 and many treatment protocols produce profound myelosuppression. In the context of a febrile cancer patient, “neutropenia” is defined as an absolute neutrophil count <500/mm3 or an absolute neutrophil count <1000/mm3 with a predicted decline. Relative risk of infection is highest at this time. The absolute neutrophil count nadir typically occurs 5 to 10 days after chemotherapy. Fever will occur in up to one third of neutropenic episodes, with a rate of documented infection between 10% and 40%. Fever in this setting is conservatively defined as a single oral temperature >38.3°C (101°F) or multiple temperatures ≥38.0°C (100.4°F) separated by more than 1 hour. 43 Avoid rectal temperatures due to the risk of bacteremia induced by rectal trauma. Many patients will not demonstrate a source of fever. Neutropenia, or a decrease in the ability to mount an inflammatory response, limits the development of infectious signs such as abscess, pulmonary infiltrates, or severe abdominal pain. Therefore, perform a meticulous physical examination with close attention to areas of pain, mucosal barriers, and the central line site. Chemotherapeutic regimens that produce profound neutropenia can cause severe mucositis with oral and/or perianal mucosal breakdown. Typhlitis, or neutropenic enterocolitis, warrants particular attention (Figure 145-6). Inflammation usually involves the ileocecal region.

ain, mucosal barriers, and the central line site. Chemotherapeutic regimens that produce profound neutropenia can cause severe mucositis with oral and/or perianal mucosal breakdown. Typhlitis, or neutropenic enterocolitis, warrants particular attention (Figure 145-6). Inflammation usually involves the ileocecal region. The presentation can be as subtle as mild abdominal pain, and the physical exam may be relatively unrevealing; however, maintain a high index of suspicion for infection . Other signs and symptoms include fever, nausea, emesis, right lower quadrant pain, abdominal distention, and watery or bloody diarrhea. Due to bowel wall necrosis, bowel perfora tion with resulting pneumatosis intestinalis is possible. Bacteremia is common and is often polymicrobial. Tintinalli_Sec12_p0669-0996.indd 961 8/2/19 7:59 PM

symptoms include fever, nausea, emesis, right lower quadrant pain, abdominal distention, and watery or bloody diarrhea. Due to bowel wall necrosis, bowel perfora tion with resulting pneumatosis intestinalis is possible. Bacteremia is common and is often polymicrobial. Tintinalli_Sec12_p0669-0996.indd 961 8/2/19 7:59 PM 962 SECTION 12: Pediatrics  ED TREATMENT Children with fever history (even if afebrile upon presentation) and potential for neutropenia require immediate clinical evaluation, acquisition of appropriate laboratory studies and cultures, and prompt administration of broad-spectrum antibiotics. Table 145-3 summarizes management of neutropenic fever, including the 2017 updated recom mendations from the International Pediatric Fever and Neutropenia Guideline Panel. 45 Individual recommendations may differ across insti tutions. Administration of antibiotics in patients at high risk of neu tropenia should not wait for laboratory confirmation of neutropenia. Obtain blood cultures, if at all possible, before administering empiric antibiotics. Anaerobic cultures are very low yield, and many institutions do not require them unless there are specific concerns for an anaerobic infection. If a clean-catch, midstream urine specimen is available, obtain urinalysis and urine culture because febrile neutropenic patients with urinary tract infection are often otherwise asymptomatic. 46 Other diagnostic studies are patient specific (e.g., chest radiograph, stool cultures, abdominal imaging, lumbar puncture). As shown in Table 145-3, empiric therapy for febrile neutropenia begins with broad-spectrum antibiotics directed at the most common pathogens. Antibiotic coverage can be tailored to the specific clinical situation and institutional resistance patterns and then be narrowed as more data become available. Given the high prevalence of central venous lines in this population, greater than 50% of bacteremias in neutropenic patients are caused by gram-positive bacteria. 18 The most common gram-positive organisms are coagulase-negative staphylococci, Streptococcus viridans, Staphylococcus aureus, and enterococci. Gramnegative organisms, however, are known to be particularly virulent and have an association with sepsis. Intestinal flora provide the source of gram-negative organisms, including Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, and Enterobacter species. 47 Special infectious considerations include treatment for possible Pneumocystis carinii in the immunocompromised patient with respiratory symptoms and broader anaerobic coverage for those suspected of having typhlitis or mucositis. Although some cancer patients (particularly those with AML, with relapsed leukemia, or undergoing stem cell transplant) are at high risk for fungal infections, there is little indication for beginning antifungal agents in the ED. 45 Septic patients require immediate, broad-spectrum antipseudomonal antibiotic therapy in addition to vancomycin for coverage of gram-positive organisms. Consider adding a second agent with activity against gram-negative organisms (e.g., gentamicin) in critically ill patients. Careful monitoring and reevaluation are essential once treatment has begun. There is recent literature regarding risk stratification of pediatric FIGURE 145-6. Neutropenic enterocolitis. Asterisks indicate inflamed and thickened bowel wall.

against gram-negative organisms (e.g., gentamicin) in critically ill patients. Careful monitoring and reevaluation are essential once treatment has begun. There is recent literature regarding risk stratification of pediatric FIGURE 145-6. Neutropenic enterocolitis. Asterisks indicate inflamed and thickened bowel wall. TABLE 145-3 Management of Neutropenic Fever Definition of neutropenia •   Absolute neutrophil count (segs + bands) <500/mm3 •   Absolute neutrophil count <1000/mm3 and expected to decrease* Definition of fever† •   Oral temperature ≥38.3°C (100.9°F) once •   Oral temperature ≥38°C (100.4°F) >2 times, measured 1 h apart Caveats •   Some add 0.5°C (1.0°F) to axillary temperatures for oral equivalent •   Confirm with oral temperature when possible •   Avoid rectal temperatures •   Parental history of objective fever is sufficient Cultures‡ •   One culture from each central line lumen (label appropriately) •   Peripheral culture in absence of central line or if recommended by oncologist •   Consider urine culture and urinalysis (clean catch or bagged) Antibiotics# Well-appearingƒ •   Broad-spectrum antipseudomonal monotherapy with β-lactam or carbapenem •   Cefepime, 50 milligrams/kg (maximum dose, 2 grams), or ceftazidime, 50 milligrams/kg (maximum dose, 2 grams), or piperacillin-tazobactam, 80 milligrams/kg (maximum dose, 3.375 grams) § Clinically unstable, suspected resistant infection, or center with high rate of resistant pathogens •   Addition of second gram-negative agent and/or glycopeptide: •   As above + gentamicin, 2.5 milligrams/kg, and/or vancomycin, 15 milligrams/kg (maximum, 1 gram) Abdominal/perirectal pain •   As above + metronidazole, 7.5 milligrams/kg (maximum, 1 gram) *Based on serial measurements or history of chemotherapy in the previous 5–10 days. †Definitions will vary by institution. ‡Most patients will require only aerobic cultures. Consider anaerobic cultures if significant GI symptoms or visible mucositis. #Do not wait for absolute neutrophil count results if patient is expected to be neutropenic. ƒIndications for the addition of vancomycin include relapsed acute lymphoblastic leukemia or acute myelogenous leukemia patients, significant mucositis, evidence of skin or soft tissue or line infections, and presence of orthopedic appliances. §Ceftazidime monotherapy should not be used if there are concerns for gram-positive or resistant gramnegative infections. Use vancomycin + aztreonam for cephalosporin-allergic patients. patients to determine who can safely be treated as an outpatient. The majority of patients with fever and true neutropenia, however, are admitted to the hospital. The decision to discharge should only be made in consultation with the oncologist. METABOLIC COMPLICATIONS  TUMOR LYSIS SYNDROME Tumor lysis syndrome is a constellation of metabolic derangements resulting from the rapid turnover of tumor cells with cell lysis and subsequent release of intracellular potassium, phosphate, and uric acid. Tumor lysis syndrome is associated with rapidly proliferating malignancies, cancers with a high tumor burden, and cancers that are highly sensitive to chemotherapy such as ALL (with hyperleukocytosis), Burkitt’s lymphoma, and non-Hodgkin’s lymphoma. It is most commonly pre cipitated by the induction of chemotherapy, but it can also be present at the time of diagnosis. Symptoms are variable but can be lifethreatening, including cardiac dysrhythmias, seizures, and acute renal failure. The large quantity of intracellular contents released into the cir culation can easily overwhelm the excretory capacity of the kidneys. The metabolic derangements, including hyperkalemia, hyperuricemia, Tintinalli_Sec12_p0669-0996.indd 962 8/2/19 7:59 PM

ncluding cardiac dysrhythmias, seizures, and acute renal failure. The large quantity of intracellular contents released into the cir culation can easily overwhelm the excretory capacity of the kidneys. The metabolic derangements, including hyperkalemia, hyperuricemia, Tintinalli_Sec12_p0669-0996.indd 962 8/2/19 7:59 PM CHAPTER 145: Oncologic Emergencies in Infants and Children 963 hyperphosphatemia, and hypocalcemia, are exacerbated by developing renal failure. Uric acid is insoluble at the low pH commonly found in the renal collecting duct, and crystals may precipitate in the collecting tubules, leading to acute kidney injury. 48 Hyperkalemia is the most immediate threat to life and should be treated aggressively, even in the absence of overt ECG changes. Lymphoblasts contain four times more phosphate than normal lymphocytes, 49 and the resulting excess phos phate from cell lysis can bind ionized calcium, leading to hypocalcemia. In addition, calcium phosphate crystalluria and obstructive uropathy can worsen acute kidney injury. The signs, symptoms, and treatment of these electrolyte disorders are discussed in Chapter 132, “Fluid and Electrolyte Therapy in Infants and Children. ” Laboratory studies include CBC, renal function studies, electrolytes, calcium, phosphate, uric acid, lactate dehydrogenase, and urinalysis (Table 145-4). Send laboratory studies every 4 hours in high-risk patients who remain in the ED for a prolonged period of time. ED treatment is directed at the prevention of renal failure, correction of electrolyte derangements, and reduction of uric acid levels. Coor dinate management with an oncologist and include aggressive IV hydration, administration of allopurinol or recombinant urate oxidase (rasburicase) for hyperuricemia, and treatment of hyperkalemia and symptomatic hypocalcemia. Rasburicase is contraindicated in glucose- 6-phosphate dehydrogenase deficiency due to its potential to precipitate hemolytic anemia or methemoglobinemia. 18,48 Urinary alkalinization is no longer recommended. 22,48 Avoid rectal Kayexalate ø , because rectal medication administration increases the risk of bacteremia in neutro penic patients. Refractory electrolyte abnormalities or significant acute kidney injury requires dialysis.  SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE AND HYPONATREMIA Causes of hyponatremia in oncology patients include chemotherapeutic agents, adjunct treatments (e.g., diuretics), clinical conditions (e.g., GI losses), and syndrome of inappropriate antidiuretic hormone secre tion (SIADH). SIADH is the leading cause of hyponatremia in children undergoing chemotherapy or stem cell transplant. 50 SIADH can result from CNS disease, infection, drug toxicity, surgical intervention for CNS tumors, and the primary malignancy. Cerebral salt wasting is also a possible cause of hyponatremia with CNS disease or following intracranial surgery. 51 Whereas syndrome of inappropriate antidiuretic hormone secretion is characterized by euvolemia, cerebral salt wasting is characterized by volume depletion; this distinction is critical in the ED setting, where excessive fluid administration could be catastrophic. The presentation of hyponatremia depends on the rate and severity of the decline in sodium level. Patients may be asymptomatic, with low sodium levels incidentally noted on routine laboratory studies.

depletion; this distinction is critical in the ED setting, where excessive fluid administration could be catastrophic. The presentation of hyponatremia depends on the rate and severity of the decline in sodium level. Patients may be asymptomatic, with low sodium levels incidentally noted on routine laboratory studies. Signs TABLE 145-4 Initial Management of Tumor Lysis Syndrome Labs (repeat every 4–8 h) •   CBC •   Electrolytes •   Renal function studies •   Calcium, phosphate, magnesium •   Uric acid, lactate dehydrogenase •   Urinalysis •   ECG •   IV fluids, often at >2× maintenance Specific therapies, if indicated •   Hyperuricemia: allopurinol, 100 milligrams/m2, or rasburicase,* 0.2 milligram/kg •   Symptomatic hypocalcemia: calcium gluconate •   Hyperkalemia: calcium/dextrose/insulin/bicarbonate •   Poor urine output: loop diuretic† *Contraindicated in glucose-6-phosphate dehydrogenase deficiency. †Patient must be volume replete. FIGURE 145-7. Superior vena cava syndrome. Note the prominent collateral veins of the chest and neck. [Photo contributed by William K. Mallon, MD. Reproduced with permission from Knoop K, Stack L, Storrow A, Thurman RJ: Atlas of Emergency Medicine , 3rd ed. © 2010, McGraw-Hill, Inc., New York.] and symptoms of profound hyponatremia include fatigue, lethargy, confusion, coma, and seizures. Treatment must be tailored to the patient’s underlying cause of hyponatremia. Guidelines for ED management of hyponatremia are outlined in Chapter 132. For SIADH, treatment con sists of fluid restriction and slow sodium correction to avoid inducing central pontine myelinolysis. For hypovolemic hyponatremic patients, isotonic fluids are administered. Treat acutely symptomatic patients with 3% normal saline. SUPERIOR VENA CAVA AND SUPERIOR MEDIASTINAL SYNDROMES Superior vena cava syndrome is the result of compression or obstruc tion of the superior vena cava causing impaired venous return (Figure 145-7). Over 90% of cases are attributable directly to malig nancy,48 but infection and thrombus are additional causes. Superior mediastinal syndrome is superior vena cava syndrome with associated tracheal compression. These two terms are used interchangeably in children because mediastinal pathology often leads to both. 52 Although these entities are rare, the most common pediatric malignancies pre senting with superior mediastinal syndrome are non-Hodgkin’s lym phoma, ALL, neuroblastoma, and germ cell tumors.53 The signs and symptoms of superior mediastinal syndrome are dictated by the acuity and extent of the underlying process. Some patients are asymptomatic, but young children are at particular risk due to the small size and compliance of the airway. 54 Signs and symptoms include dyspnea, cough, stridor, wheezing, chest discomfort, facial and upper body edema and/or plethora, neck/chest vein dilatation, presence of Tintinalli_Sec12_p0669-0996.indd 963 8/2/19 7:59 PM

matic, but young children are at particular risk due to the small size and compliance of the airway. 54 Signs and symptoms include dyspnea, cough, stridor, wheezing, chest discomfort, facial and upper body edema and/or plethora, neck/chest vein dilatation, presence of Tintinalli_Sec12_p0669-0996.indd 963 8/2/19 7:59 PM 964 SECTION 12: Pediatrics collateral veins, and syncope (from decreased cardiac output). The threat of acute cardiorespiratory failure makes this a true medical emergency. Equally concerning are neurologic symptoms suggestive of cerebral ischemia: headache, confusion, and altered mental status. ED treatment depends on the clinical acuity. Confirm the diagnosis by chest radiograph or CT scan. Supine positioning for imaging may critically compromise the airway, so a prone position is a preferred alternative for older, cooperative children. Avoid any intervention, such as sedation, that could potentially compromise the airway . Superior mediastinal syndrome is one of the few conditions in which rapidsequence induction and intubation for respiratory distress may be lethal if the endotracheal tube cannot bypass the site of compression. Temporizing measures include elevating the head of the bed to maintain an upright posture, high-flow oxygen, bilevel positive airway pressure, and possible consideration of heliox where available. Definitive management is treatment of the underlying malignancy to reduce the amount of compression. In cases where the syndrome is due to thrombotic occlu sion, fibrinolytic therapy can be considered. Emergency stents have been placed at centers with appropriate expertise. NEUROLOGIC EMERGENCIES  SPINAL CORD COMPRESSION Tumors involving the spine or spinal cord account for only 2% of childhood malignancies, but due to delays in diagnosis and deficits that are not always reversible, they are associated with a disproportionate degree of morbidity. 56 The most common neoplasms involving the spinal cord are CNS tumors, neuroblastoma, sarcomas, lymphoma, and germ cell tumors. Spinal cord compression can present in a child with known malignancy or as an initial presentation of disease. Most commonly, spinal cord compression arises from a hematogenously spread metastasis to vertebral bodies, with subsequent expansion and erosion of the lesion into the epidural space (Figure 145-8). 55 However, it can also result from direct extension of a paravertebral tumor through an intervertebral foramen into the spinal canal. Back pain is the most common presenting symptom of spinal cord compression in children and often precedes other symptoms, providing FIGURE 145-8. Spinal cord compression. MRI demonstrating spinal cord compression at T9 due to epidural extension of tumor. T10 vertebral body also has metastasis (decreased signal intensity). [Reproduced with permission from Schwartz D (ed). Emergency Radiology: Case Studies. Copyright © 2008 by The McGraw-Hill Companies, Inc., New York.] an opportunity for early detection and intervention.48,55,56 Consider spinal involvement in any child with a history of cancer presenting with back pain. If the diagnosis is delayed, progressive symptoms include motor weakness, worsening scoliosis, and gait disturbance. Sensory impairments and sphincter dysfunction are extremely rare in young children. Physical exam findings depend on the location of the lesion(s), the degree of spinal cord impingement, and the rate at which compression takes place. In patients in whom spinal compression is suspected, MRI is the gold standard imaging and should be obtained emergently. Plain films are ineffective for diagnosis. Given that a significant number of patients present with multiple spinal lesions, image the entire spinal cord. 48,55 Obtain brain imaging if a spinal neoplasm is identified.

m spinal compression is suspected, MRI is the gold standard imaging and should be obtained emergently. Plain films are ineffective for diagnosis. Given that a significant number of patients present with multiple spinal lesions, image the entire spinal cord. 48,55 Obtain brain imaging if a spinal neoplasm is identified. Obtain oncology, neurosurgery, and radiotherapy consultation. ED treatment is IV dexamethasone (0.1 milligram/kg to a maximum of 10 milligrams) to decrease vasogenic edema caused by obstruction of the epidural venous plexus and to improve symptoms. However, if leukemia or lymphoma is in the differential diagnosis for an initial presentation of a spinal tumor, do not administer steroids without consulting an oncologist; steroid administration can mask the tumor and prevent diagnosis and appropriate treatment. Neurologic damage is often irreversible once ischemia develops and the spinal cord infarcts. Even with aggressive interventions, studies report that 40% to 70% of children have residual impairment.  INCREASED INTRACRANIAL PRESSURE Increased intracranial pressure in children with cancer is usually due to primary CNS tumors. Childhood CNS tumors are often infratentorial, a location where there is potential for cerebrospinal fluid flow obstruc tion. 58 Clinical presentation and risk of herniation depend on the loca tion and growth rate of the tumor, as well as the age of the child. Signs and symptoms are often nonspecific. Cushing’s triad is rare but requires emergent intervention. Brain imaging with MRI or CT can identify a neoplasm, associated vasogenic edema and/or hydrocephalus, and alternative diagnoses; however, CT remains the test of choice in the emergency setting. Manage ment is guided by the severity of the presentation. Initial focus in the ED should be a primary survey; in particular, ensure airway protection in a patient with high intracranial pressure and altered mental status. Use of hyperventilation is now debated, because hypercarbia causes cerebral dilation but hypocarbia is an independent predictor of mortality. Mild hyperventilation (pulmonary end tidal carbon dioxide, 30 to 34 mm Hg) is considered appropriate in cases of herniation. Elevate the head of the bed to 30 degrees to improve venous drainage and consult neurosurgery. Administer IV dexamethasone (0.1 milligram/kg to a maximum of 10 milligrams) to reduce tumor-associated vasogenic edema. There are no pediatric data clearly supporting antiepileptic administration for seizure prophylaxis, 59,60 but fosphenytoin or another longer acting antiepileptic can be considered if the patient requires transport. Maintain appropriate electrolyte levels and correct thrombocytopenia or coagulopathy.  STROKE Stroke, occurring within the first few years of a childhood cancer diagnosis, is rare. 61 Overall prevalence is estimated at 1%.62 Hemorrhagic strokes and ischemic strokes occur with equal frequency.61 Risk factors include coagulopathy, thrombocytopenia, hyperleukocytosis, radiation, medications, and primary or metastatic CNS tumors. Stroke can be the sole clinical manifestation from hemorrhage into a previously occult CNS neoplasm. Treatment depends on the underlying cause. Standard stroke management applies, including brain imaging. Modifiable risk factors should be addressed, including correction of thrombocytopenia to keep platelet levels >100,000/mm 3. Discuss anticoagulant therapy in consultation with neurology and oncology.  SEIZURES Seizures are common in pediatric oncology patients and may have a number of causes: primary or metastatic CNS lesion, stroke, metabolic derangement (i.e., hyponatremia), infection (e.g., abscess, meningitis), chemotherapeutic agents, and radiation therapy.

therapy in consultation with neurology and oncology.  SEIZURES Seizures are common in pediatric oncology patients and may have a number of causes: primary or metastatic CNS lesion, stroke, metabolic derangement (i.e., hyponatremia), infection (e.g., abscess, meningitis), chemotherapeutic agents, and radiation therapy. Fifteen percent of pediatric brain tumor patients experience seizures, and 12% of pediatric brain tumor patients present with seizures. Tintinalli_Sec12_p0669-0996.indd 964 8/2/19 7:59 PM