Early recognition, prevention, and treatment of oncological emergencies improves clinical outcomes. Both at initial presentation and during treatment, pediatric cancer patients can develop acute, severe, and life-threatening conditions (Table 133-1). This chapter reviews the presentation and management of the most commonly encountered emergent conditions seen in pediatric cancer patients. The pediatric hospitalist should be able to identify at-risk patients, adopt preventive strategies, recognize clinical deterioration, and initiate prompt treatment of these emergencies.
TABLE 133-1Pediatric Oncologic Emergencies ||Download (.pdf) TABLE 133-1 Pediatric Oncologic Emergencies
|Metabolic emergencies |
| Tumor lysis syndrome |
| Hyperuricemia |
| Hyperkalemia |
| Hyperphosphatemia/hypocalcemia |
| Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
|Hematologic emergencies |
| Hyperleukocytosis, leukostasis |
| Hemorrhage and DIC |
| Thrombosis |
|Infectious and inflammatory emergencies |
| Febrile neutropenia |
| Septicemia, shock |
| Neutropenic enterocolitis |
| Pancreatitis |
|Mechanical emergencies |
| Superior vena cava syndrome, superior mediastinal syndrome |
| Pleural and pericardial effusions |
| Cardiac tamponade |
|Neurologic emergencies |
| Spinal cord compression |
| Increased intracranial pressure |
| Pain |
| Altered mental status |
| Malignant hypertension |
| Seizure |
When a new diagnosis of cancer or an oncologic emergency is suspected, a pediatric oncologist should be consulted to aid in the initial diagnostic evaluation and therapeutic management. Pediatric cancer patients benefit from rapid referral to a tertiary care center with a subspecialty pediatric oncology program. Ideal treatment of some oncologic emergencies will involve the initiation of chemotherapy or radiation therapy, which must be done at a facility experienced in the administration of these modalities in children and adolescents.
The rapid release of the intracellular contents of tumor cells into the plasma can cause significant metabolic derangements that can progress to multiorgan failure and death. The laboratory abnormalities most often associated with this tumor lysis syndrome (TLS) include hyperuricema, hyperphosphatemia, hyperkalemia, and hypocalcemia. There are no strict criteria defining TLS, but recently it has been proposed that TLS can be categorized into “laboratory” and “clinical” entities, the former being defined by simultaneous presence of two or more electrolyte abnormalities and the latter by the presence of renal dysfunction, seizures, cardiac dysrhythmia, or multiorgan system failure.1
TLS is most commonly encountered shortly after initiation of therapy for malignancies with high tumor burden. TLS can also be identified prior to the initiation of therapy, especially in tumors with high cellular proliferation such as acute lymphoblastic leukemia (ALL) or Burkitt lymphoma. Recently, TLS management guidelines based on risk stratification have been proposed.2,3 High-risk clinical features include diagnoses of acute myelogenous leukemia (AML), ALL and advanced stage non-Hodgkin lymphoma (NHL), WBC count greater than 100,000 cells/mm3, elevated lactate dehydrogenase (LDH), presence of renal dysfunction, or multiple electrolyte abnormalities (Table 133-2). Incorporation of these guidelines into prospective pediatric studies may lead to further improvement in TLS prevention and treatment. Rapid identification of at-risk patients should expedite the initiation of prophylactic strategies to avoid complications of TLS (Table 133-3).
TABLE 133-2TLS: Risk-Stratified Prophylaxis Strategies ||Download (.pdf) TABLE 133-2 TLS: Risk-Stratified Prophylaxis Strategies
| ||Low Risk ||Intermediate Risk* ||High Risk |
|AML || |
WBC <25 K and
LDH <2 X ULN
|WBC 25 N 100 K ||WBC >100 K |
|ALL || ||WBC <100 K and LDH <2 X ULN || |
WBC >100 K or
LDH >2 X ULN
|Hodgkin lymphoma ||All stages || || |
|Burkitt lymphoma || || |
Stage I/II and
LDH <2 X ULN
Stage III/IV or
LDH >2 X ULN
|Lymphoblastic lymphoma || || |
Stage I/II and
LDH <2 X ULN
Stage III/IV or
LDH >2 X ULN
|Anaplastic large cell lymphoma ||Stage I/II ||Stage III/IV || |
|Other NHL ||Stage I/II || |
Stage III/IV and
LDH <2 X ULN
Stage III/IV and
LDH >2 X ULN
|Solid tumors ||Most ||Few** || |
|TLS prophylaxis recommendation |
| || |
TABLE 133-3Tumor Lysis: General Guidelines for Prevention and Treatment ||Download (.pdf) TABLE 133-3 Tumor Lysis: General Guidelines for Prevention and Treatment
|Hydration 3000 ml/m2/day of D5 ½ NS or D5 NS to maintain urine output >100 mL/m2/hr and specific gravity <1.010 |
|May use furosemide (1–2 mg/kg) or mannitol (0.5 g/kg) to increase urine output if necessary; avoid in hypovolemic or hypotensive patients |
|Consider initiating uric acid–reducing therapy—allopurinol or rasburicase (see Tables 133-2 and 133-4)* |
|Monitor strict intake and output; measure weight bid |
|Take vital signs at least q4h; place on cardiovascular-respiratory monitor if any significant metabolic abnormalities |
|Monitor lysis laboratory studies q8h, or more frequently if indicated: electrolytes, blood urea nitrogen, creatinine, uric acid, ionized calcium, magnesium, phosphorus, lactate dehydrogenase |
|Avoid nephrotoxic medications or IV contrast material |
|Avoid supplemental potassium or phosphorus intake even when potassium and phosphorus levels are not elevated |
|Monitor for associated hyperkalemia, hyperphosphatemia, and hypocalcemia and treat as clinically indicated (see Table 133-4) |
|For severe metabolic abnormalities, persistent oliguria, or renal failure, hemofiltration or dialysis may be warranted |
Hyperuricemia results from the breakdown of the purine components of DNA that are released in the circulation when tumor cells lyse. As shown in Figure 133-1, the purine metabolites hypoxanthine and xanthine are converted by xanthine oxidase to uric acid. In the acidic environment of the urine, uric acid (a weak acid) becomes protonated, precipitates and deposits in renal tubules causing uric acid nephropathy, which can lead to renal failure. The key strategies in both the prevention and management of hyperuricemia are to increase uric acid elimination and decrease uric acid production.
Hyperhydration and forced diuresis are the most common strategies used to eliminate uric acid. Most pediatric patients can tolerate 3000 mL/m2/day of IV fluid administration. The rare patient who does not respond to this therapy with copious urine output can be treated with diuretics. In settings where hyperhydration must be used with caution (pulmonary/pericardial effusions, preexisting heart dysfunction, large anterior mediastinal masses), maintaining a minimum urine output of at least 2 mL/kg/hr with a lower rate of IV fluid administration may suffice.
The classic teaching is that excretion of purine metabolites can be improved by alkalization of the urine, which is most commonly achieved by addition of sodium bicarbonate to IV fluids. However, alkalization can promote calcium-phosphate crystal formation and deposition in the renal tubules. Furthermore, the use of alkalized fluids is falling out of favor owing to decreased availability of sodium bicarbonate, lack of evidence of clinical benefit, and increased use of alternative therapies (i.e. rasburicase).
Allopurinol has been the mainstay of the prevention and treatment of hyperuricemia for decades. Allopurinol inhibits xanthine oxidase and prevents the formation of uric acid. However, allopurinol does not aid in the elimination of previously formed uric acid and may also increase the concentrations of upstream purine metabolites, such as hypoxanthine and xanthine, which can also lead to renal dysfunction.
The use and availability of recombinant urate oxidase (rasburicase) has significantly changed the landscape of TLS management in children. As an enzyme, rasburicase directly breaks down uric acid into highly soluble metabolites (allantoins) that are easily excreted by the kidney. Rasburicase not only eliminates uric acid but also promotes the elimination of upstream purine precursors. Rasburicase is approved for use in children for management of hyperuricemia associated with malignancy. It has been proven to be a safe alternative to allopurinol, while demonstrating increased efficacy.4-6 Unfortunately, rasburicase is much more expensive than allopurinol and thus should be reserved for a select population of patients. Strong consideration of rasburicase should be given to patients with elevated uric acid levels in combination with other predictive markers of severe TLS. Guidelines for administration of allopurinol and rasburicase are presented in Tables 133-3 and 133-4. Of note, when obtaining uric acid levels after the administration of rasburicase, blood samples should be delivered to the clinical laboratory on ice in order to inhibit the continued enzymatic breakdown of uric acid in the test tube. G6PD deficiency is an absolute contraindication to rasburicase administration.
TABLE 133-4 Tumor Lysis Syndrome: Guidelines for Administration of Allopurinol and Rasburicase ||Download (.pdf) TABLE 133-4 Tumor Lysis Syndrome: Guidelines for Administration of Allopurinol and Rasburicase
|Begin 24-48 hr before start of cytoreductive chemotherapy |
|Administer IV or PO; children often have difficulty with oral administration |
| Allopurinol PO 10 mg/kg/day divided tid (maximum dose 800 mg/day) |
| Allopurinol IV 200 mg/m2/day in 1–3 divided doses |
|Recommended dose: 0.2 mg/kg daily for up to 5 days |
|Urine should not be alkalinized |
|Do not administer to G6PD-deficient patients; if G6PD deficiency is suspected, status should be confirmed before administration |
Additional Electrolyte Abnormalities Associated with Tumor Lysis Syndrome
Hyperkalemia is the most life-threatening complication of TLS, as it can cause sudden cardiac death. Avoiding exogenous potassium sources and implementing hyperhydration are usually adequate to avoid clinically significant hyperkalemia. While avoidance of potassium-containing fluids is often encouraged, some patients receiving hyperhydration can develop hypokalemia secondary to profuse urinary output (“solvent drag”). In these patients, supplemental potassium can be cautiously administered (preferably by mouth) with frequent laboratory assessment. In cases of severe hyperkalemia, additional modalities should be considered. Hyperphosphatemia can develop as a consequence of tumor lysis and lead to the development of calcium-phosphate crystals that can precipitate in the renal tubule and contribute to renal dysfunction. These calcium-phosphate complexes can also result in hypocalcemia. Treatment of hypocalcemia is usually reserved for only patients presenting with clinical signs such as positive Trousseau or Chvostek signs or tetany. Calcium supplementation in asymptomatic patients should be avoided, as this may enhance calcium-phosphate deposition. The clinical symptoms of the metabolic derangements seen in TLS and specific management guidelines are presented in Table 133-5.
TABLE 133-5Tumor Lysis Syndrome: Treatment of Metabolic Abnormalities ||Download (.pdf) TABLE 133-5 Tumor Lysis Syndrome: Treatment of Metabolic Abnormalities
|Disorder ||Clinical Features ||Treatment |
|Hyperkalemia || |
ECG abnormalities: peaked T waves, lengthening of P-R interval, widened QRS comple
Arrhythmias and cardiac arrest
Avoid potassium administration
Oral potassium-binding resin (sodium polystyrene sulfonate) 1 g/kg q6h
IV furosemide 0.5–1 mg/kg/dose
IV dextrose and insulin: 1 g/kg dextrose with 0.25 unit/kg regular insulin
IV sodium bicarbonate 1–2 mEq/kg
IV calcium gluconate 60–100 mg/kg slow bolus; use only for severe life-threatening arrhythmias; may cause calcium phosphate precipitation
|Hyperphosphatemia ||Can lead to hypocalcemia || |
Oral phosphate binder: aluminum hydroxide 150 mg/kg/day divided every 4–6 hours
Forced diuresis (hydration, furosemide, mannitol)
IV glucose and insulin (see hyperkalemia above)
|Hypocalcemia || |
Positive Trousseau or Chvostek sign, tetany, seizure, laryngospasm, carpopedal spasm
Prolonged Q-T interval on ECG
Implement seizure precautions
If severely symptomatic, treat with IV 10% calcium gluconate 30–50 mg/kg slow bolus; must monitor for bradycardia; may cause calcium phosphate precipitation
|Hyperuricemia ||Clinical symptoms usually associated with levels >10 mg/dL and include lethargy, nausea, vomiting, uric acid calculi, hematuria, oliguria, anuria || |
Allopurinol or rasburicase (see Table 133-4)
SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can develop as a side effect of certain chemotherapeutics or can be associated with intracranial malignancies and infections such as pneumonia. The resulting hyponatremia can be clinically significant and require intervention. While fluid restriction is the mainstay of therapy, this can compromise the hydration strategies utilized around certain chemotherapy regimes or clinical scenarios. For instance, in patients receiving hyperhydration for prevention of TLS or to aid clearance of methotrexate, fluid restriction may be contraindicated. Consultation with a pediatric oncologist is recommended in these cases.
The initial presentation of childhood ALL or acute myelogenous leukemia (AML) can be complicated by the presence of a very elevated circulating blast count. Hyperleukocytosis is defined as a WBC greater than 100,000 cells/mm3 and can be seen in both ALL and AML. Hyperleukocytosis is more commonly seen in ALL, but clinical evidence of vascular obstruction by blasts (leukostasis) is more commonly encountered in patients with AML.
Hyperleukocytosis increases blood viscosity, which can ultimately result in leukostasis, small vessel obstruction, and decreased perfusion. The circulatory anatomy of the brain and lungs puts these organs at particular risk of developing life-threatening complications. Classic presenting symptoms of pulmonary leukocytosis include hypoxia, tachypnea, and respiratory distress. Chest x-rays are generally not useful in the diagnosis of leukostasis, but when they are performed, they may demonstrate bilateral “whiteout” of the lung fields, sometimes prompting an incorrect diagnosis of pneumonia. Chest imaging is not informative and should not be used to diagnose leukostasis. Central nervous system (CNS) manifestations of cerebral leukostasis may be subtle, so a thorough neurologic exam is essential. Common signs or symptoms include headache or somnolence, but altered metal status, seizure, or comas are also possible. Less common presentations of leukostasis include renal dysfunction, cardiac ischemia, priapism, and dactylitis. Close monitoring of patients presenting with hyperleukocytosis is important, as leukostasis is diagnosed clinically rather than by laboratory or imaging assessment.
Critical goals in the initial management of a patient with hyperleukocytosis include reduction of blood viscosity and initiation of TLS prevention. Administration of intravenous fluids aids both of these goals and should be promptly initiated. While patients with leukemia can present with exceptional anemia, red cell transfusions should be avoided if possible, because increasing the hematocrit will directly increase blood viscosity. Early consultation with a pediatric oncologist is critical, as initiation of hydroxyurea or induction chemotherapy should be started as soon as possible.
Cytoreduction by leukapheresis or exchange transfusion can be considered as alternative methods to decrease blood viscosity, but is controversial. Generally, these procedures are considered when peripheral blood WBC count is greater than 100,000 cells/mm3 in AML or greater than 300 to 500,000 cells/mm3 in ALL. However, these are typically offered only to patients whose chemotherapy is delayed and who are symptomatic of leukostasis. There are no studies comparing the use of leukapheresis to initiation of chemotherapy in pediatric patients with hyperleukocytosis or leukostasis. In addition, in cases where hyperleukocytosis is accompanied by coagulopathy (see below) or septic shock, leukapheresis may be unsafe. As a result, there are no uniformly accepted criteria supporting the use of leukapheresis or exchange transfusion in children with hyperleukocytosis. Leukapheresis should be initiated on a case-by-case basis after consultation with a pediatric oncologist. Considering the complexities of preparing for leukapheresis (e.g. catheter placement, blood product administration, and critical care support), the local blood bank and/or apheresis team should be quickly notified of any patient being considered for this procedure.
HEMORRHAGE AND DISSEMINATED INTRAVASCULAR COAGULATION
Severe thrombocytopenia is commonly seen in pediatric oncology patients, either as a result of direct invasion of the bone marrow by cancer cells or as a consequence of cancer therapy. Abnormal bleeding associated with thrombocytopenia typically presents with either petechiae or spontaneous mucosal bleeding, such as epistaxis. Less commonly, more severe bleeding such as intracranial hemorrhage or gastrointestinal bleeding can occur. Transfusing asymptomatic patients when their platelet count is below a specific threshold can prevent thrombocytopenia-related bleeding. Typically, this platelet count threshold is between 10,000 and 30,000 platelets/mm3, but is variable among different centers and in certain clinical situations.
Hemorrhage in cancer patients can also occur because of acquired coagulation factor deficiency that occurs as a result of disseminated intravascular coagulation (DIC) or secondary to specific chemotherapeutics such as asparaginase, which blocks production of numerous coagulation factors. DIC in oncology patients is most commonly encountered when these patients are experiencing overwhelming infections, such as sepsis. However, certain subtypes of childhood AML, especially acute promyelocytic leukemia (APML), can present with life-threatening DIC prior to or immediately after initiation of therapy. The management of DIC in the setting of sepsis in the oncology patient is similar to non-oncology patients, with emphasis on fibrinogen and coagulation factor replacement through the administration of cryoprecipitate and fresh frozen plasma (FFP), respectively. In the case of APML-associated DIC, initiation of appropriate chemotherapy should be expedited, in addition to supportive administration of FFP and cryoprecipitate.
L-Asparaginase, a chemotherapeutic commonly used in the treatment of childhood ALL and AML, depletes asparagine, which starves tumor cells of this essential amino acid. Unfortunately, asparagine depletion also reduces the production of numerous coagulation factors, predisposing these patients to both hemorrhage and thrombosis.
A detailed explanation of the management of blood product support in cases of severe hemorrhage and DIC is outside the scope of this chapter and may be found elsewhere in this text. However, the pediatric hospitalist should be knowledgeable about transfusion management strategies that are particular to the pediatric oncology patient. In general, transfusions of blood products should be minimized as much as possible to avoid the development of alloimmunization, transfusion reactions, infections, and iron overload. The transfusion thresholds for platelets and red blood cells vary by center but should always be tailored to the particular clinical scenario (Table 133-6).
TABLE 133-6Transfusions in the Oncology Patient ||Download (.pdf) TABLE 133-6 Transfusions in the Oncology Patient
|Blood Product and Indication ||Transfusion Threshold |
|Major surgery or trauma ||>100 K/mm3 |
|Active bleeding ||>100 K/mm3 |
|Minor Surgery and lumbar punctures ||>50 K/mm3 |
|Mild Mucosal bleeding ||>20–30 K/mm3 |
|Prevention of spontaneous bleeding ||>10 K/mm3 |
|Red cells |
|Prophylaxis against symptomatic anemia ||>7 g/dl |
|Mildly symptomatic anemia ||>7 g/dl |
|Severe illness or sepsis ||>9 g/dl |
|Radiation therapy ||>10 g/dl |
|Product Guidelines ||Platelet ||Red Cells ||Comment |
|Type and Cross ||Yes ||Yes ||Type not required for platelet transfusion if prior type available in Blood bank |
|ABO matched ||Preferred ||Yes || |
|Rh matched ||Preferred ||Yes ||If Rh+ platelets give to Ph- donor, must administer anti-D product within 72 hours |
|Irradiated ||Yes ||Yes ||For prevention of graft-versus-host-disease |
|Leukoreduced ||Yes ||Yes ||Reduces risk of transfusion reactions and CMV transmission |
|CMV negative ||No ||No ||Leukoreduction is sufficient |
|HLA matched ||Rarely ||No ||Only in platelet refractory patients |
|Single donor ||Preferred ||No || |
|Premedications ||Possible ||Possible || |
Acetaminophen if h/o fevers
Diphenhydramine if h/o allergic reaction
Hydrocortisone if h/o allergic reaction despite administration of diphenhydramine or h/o severe allergic reaction
|Amount ||1 unit/10 kg || |
~ 10–15 ml/kg
(2 units for pts >50 kg)
|Many institutional standards exist |
It is common for family members of a newly diagnosed pediatric oncology patient to request direct donation of blood products for their loved one. This practice should be discouraged for two reasons. First, directly donated blood products have not been shown to be safer than anonymously donated blood products. Second, oncology patients may at some point need an allogeneic hematopoietic stem cell transplant, and exposure to familial human lymphocyte antigens may increase the risk of graft rejection and poor outcome.
Risk of thrombosis is increased in pediatric cancer patients for numerous reasons. The most common risk factor in children is the presence of an indwelling central venous catheter. As mentioned earlier, certain medications, such as L-asparaginase, increase the risk of thrombosis through depletion of the coagulation factors like antithrombin III (ATIII), plasminogen, protein C, and protein S. Mechanical compression of large veins by tumor can also result in thrombosis. Other risk factors for thrombosis in the cancer setting include sepsis, prolonged immobility, and the underlying inflammatory state intrinsic to malignancy.
Presenting symptoms of thrombosis are related to location and may include extremity or facial swelling. When occurring in the cerebral venous sinuses, patients can present with headache, seizures, or other neurological manifestations. Central venous line (CVL)-associated thrombosis can present with line malfunction. Pulmonary embolism should be considered in patients with respiratory distress, chest pain, hypoxia, syncope, or with sustained tachycardia of unclear etiology. Once identified by appropriate imaging, the management of venous thrombosis must be tailored with consideration of thrombus location (superficial vs. deep vein thrombosis), provocative triggers (CVL vs. mass), type/duration of chemotherapy, and age of the child (ambulating vs. toddling), as these factors will influence the type and duration of anticoagulation as well as supportive care. For instance, during periods of chemotherapy-induced severe thrombocytopenia, anticoagulation may be reduced or discontinued. Furthermore, patients receiving anticoagulation with enoxaparin may need frequent repletion of ATIII in order to achieve therapeutic levels of enoxaparin; this is especially relevant if they are receiving L-asparaginase, which is known to inhibit ATIII synthesis.
While thrombosis in pediatric oncology patients is not uncommon, it is rarely associated with an underlying hypercoagulability syndrome (e.g. Factor V Leiden). The involvement of a pediatric hematologist is encouraged to help guide therapy and to determine the need for a hypercoagulability evaluation.
Neutropenia is a common side effect of chemotherapy administered to children, particularly alkylating agents, anthracyclines, and cytarabine. In contrast to thrombocytopenia and anemia, which can be treated with the transfusion of blood products, neutropenia resolves only after recovery of bone marrow function. While the transfusion of donor granulocytes is possible, this practice is controversial without clear clinical benefit. Severe neutropenia is commonly encountered in pediatric oncology patients and can lead to the development of life-threatening bacterial and fungal infections. The febrile and neutropenic patient is a true emergency, as overwhelming sepsis and death can occur in a matter of hours if appropriate interventions are not emergently implemented.
Recently, new fever and neutropenia guidelines have been published by the Infectious Diseases Society of America and the International Pediatric Fever and Neutropenia Guideline Panel.7,8 Common definitions used in these guidelines are presented in Table 133-7. The guidelines stress the importance of utilizing risk stratification in determining treatment strategies. However, there are still no universally accepted pediatric criteria to categorize neutropenic patients at low or high risk of developing severe infections. As a result, many institutions adopt specific algorithms that differentiate risk based on neutrophil count, clinical status, malignancy, and chemotherapy most recently given. What follows are general approaches to the neutropenic patient at high risk for serious infections.
TABLE 133-7 Fever and Neutropenia: Definitions and Initial Laboratory Assessment ||Download (.pdf) TABLE 133-7 Fever and Neutropenia: Definitions and Initial Laboratory Assessment
|Clinical Feature ||Definition |
|Fever || |
Single temperature greater than 38.3° C, or
Temperature greater than 38° C lasting more that 1 hour, or obtained twice within 12–24 hours
|Neutropenia ||ANC <500 cells/mm3 or with expected nadir <500 cells/mm3 within the next 48 hours |
|Absolute neutrophil count (ANC) ||(% Granulocytes + % Bands) × WBC |
|Initial laboratory assessment || |
Blood culture from each lumen of indwelling catheter (no peripheral culture needed)
Urine analysis/culture if patients able to obtain clean catch specimen (no catheterizations)
CBC with differential
Chemistries including creatinine
Liver function tests (AST, ALT, direct and indirect bilirubin
If abdominal pain: Amylase and lipase
The pediatric hospitalist should understand the microbiology of neutropenia-associated infections in order to optimize initial therapy. The most common pathogens encountered in neutropenic patients comprise Gram-negative organisms, including Escherichia coli, Klebsiella and Pseudomonas species, and Gram-positive bacteria such as Staphylococcus aureus, enterococci, viridans group streptococci, and Streptococcus pneumoniae. Historically, Gram-negative infections were the most commonly encountered organisms. However, over the last few decades, Gram-positive organisms have accounted for the majority of documented infections in neutropenic patients. The use of prophylactic antibiotics, increased colonization of drug-resistant organisms, and use of indwelling catheters have been identified as contributing factors to this change.
Fungal infections are less commonly encountered, but can result in deep-seated infections that may require prolonged antifungal treatment and/or surgery. The likelihood of fungal infection increases with prolonged neutropenia and in neutropenic patients with prolonged fever despite administration of empiric antibiotics. The most common fungal pathogens are Candida and Aspergillus species.
APPROACH TO PATIENT WITH FEVER AND NEUTROPENIA
A detailed history and physical examination must be obtained from each patient presenting with febrile neutropenia. Details of the expected duration of neutropenia, type and timing of chemotherapy administered, past infectious history, and presence or absence of indwelling catheter will help guide empiric therapy. Often, localizing symptoms of infection are absent, but localized pain or redness can guide initial antibiotic selection and appropriate ancillary testing (Table 133-8). The physical examination of the febrile neutropenic patient must be efficient but thorough, and include an examination of the perianal area, even in well-appearing patients. The laboratory evaluation should include aerobic and anaerobic blood cultures from each lumen of any indwelling catheter. A culture obtained off the line (peripheral) is not usually needed. The laboratory assessment of every febrile oncology patient with suspected neutropenia should include a CBC with differential, liver function tests, and full chemistry panel, including creatinine. In addition, urine analysis and culture can be considered in patients who can provide a clean catch sample. Neutropenic patients should not be routinely catheterized and should never have a digital rectal exam performed. A lumbar puncture to assess for meningitis is not indicated unless the patient presents with clinical signs or symptoms of meningitis or encephalitis. Patients presenting with abdominal pain should also have amylase or lipase obtained, particularly if they have recently received L-asparaginase, which is a known risk factor for pancreatitis (Tables 133-7 and 133-8).
TABLE 133-8 Fever and Neutropenia: Guidelines for Modifying Treatment ||Download (.pdf) TABLE 133-8 Fever and Neutropenia: Guidelines for Modifying Treatment
|Clinical Finding ||Action |
|Well-appearing child, non-focal exam ||Standard empiric antibiotic plan. |
|Abdominal pain || |
Add anaerobic coverage. Consider abdominal imaging.
Obtain amylase and lipase (pancreatitis).
|Perianal pain or redness ||Add anaerobic coverage. |
|Cough, dyspnea, or hypoxia ||Obtain CXR, consider testing for respiratory viruses (Influenza, RSV). |
|CVL-site infection ||Add vancomycin. |
|Diarrhea ||Test for C. differens. Consider testing of SSYCE organisms, rotavirus. |
|History of drug-resistant organism ||Choose broad-spectrum antibiotic that covers particular organism or add additional agent. |
|Dysuria ||Obtain UA and urine culture. Consider renal imaging. |
|Meningismus || |
All patients: Switch to meningitic dosing of a broad-spectrum BBB-penetrant antibiotic. Obtain lumbar puncture (platelets should be greater than 50,000/mm3).
Patients with VP shunt or Ommaya reservoir: Consider CNS imaging and neurosurgical consult prior to obtaining CSF
|Periodontal infection ||Add anaerobic coverage |
|Pulmonary infiltrates by CXR || |
Diffuse/interstitial: consider coverage for atypical microorganisms (macrolide antibiotic).
Localized: Consider adding antifungal coverage and advanced imaging (CT) if persistently febrile.
|Vital sign instability ||Add vancomycin, consider removal of CVL. |
|Vesicular or ulcerative lesions ||Test and culture for herpes simplex and varicella. |
|Positive Blood Cultures |
|Bacillus species ||Add vancomycin or meropenem and remove CVL. Consider solid-organ and CNS imaging after ANC recovery. |
|Candida species ||Remove CVL, add antifungal agent. Consider solid-organ imaging at baseline and after ANC recovery. |
|Methicillin-resistant S. aureus ||Add vancomycin, remove CVL. |
|Vancomycin-resistant enterococcus ||Remove CVL, discuss antibiotic plan with infectious disease consultant. |
|Failure to clear positive blood culture by 48 hours ||Remove CVL. |
|Persistent Fevers |
|Febrile and neutropenic for ≥4 to 7 days ||Add empiric antifungal therapy: ambisome or echinocandin. Obtain fungal cultures and assay fungal markers. |
CONSIDERATIONS IN INITIAL ANTIBIOTIC SELECTION
Prompt administration of antibiotics is paramount and should be considered a top priority. For ill-appearing patients, antibiotics should be administered emergently, even prior to obtaining a blood culture. The ideal antibiotic regimen will have broad-spectrum coverage of Gram-positive and Gram-negative organisms, including Pseudomonas species. Several monotherapy regimens are widely utilized including third- or fourth-generation cephalosporin, carbapenems, and piperacillin/tazobactam (Table 133-9). The addition of vancomycin may also be considered, especially in patients with a history of methicillin-resistant Staphylococcus aureus infections or those with vital sign instability. For patients with a cephalosporin allergy, a combination of aztreonam (for Gram-negative coverage) and a Gram-positive agent such as clindamycin or vancomycin should be considered. Certain other clinical situations may warrant an alternative antibiotic choice (Table 133-8). For instance, the patient presenting with abdominal or perianal pain should have additional anaerobic coverage. These are general guidelines for empiric coverage, and individual institutions may have different algorithms based on the local prevalence of drug-resistant organisms. Antibiotic selection should be tailored further if a microbe is isolated from any culture. Isolation of certain organisms also warrants urgent removal of the indwelling CVL.
TABLE 133-9Fever and Neutropenia: Guidelines for Initial Antibiotic Selection ||Download (.pdf) TABLE 133-9 Fever and Neutropenia: Guidelines for Initial Antibiotic Selection
PROLONGED FEVER—MODIFICATIONS TO EMPIRIC COVERAGE
Empiric antifungal therapy should be considered for the persistently febrile and neutropenic patient who has not defervesced after several days of empiric therapy with broad-spectrum antibiotics. While regimens and timing may vary among institutions, if a patient continues to have fevers for more than 4 days, most guidelines recommend the initiation of antifungal therapy. Liposomal amphotericin is commonly used in this scenario, but newer agents, such as the echinocandins (e.g. micafungin) are also increasingly utilized because of their favorable side effect profile. Evaluation of fungal markers such as galactomannan and beta-D-glucan can also be obtained, ideally prior to the initiation of antifungal agents, though the results must be interpreted carefully. Consultation with a pediatric oncologist or infectious disease expert should be considered in these cases.
Most institutions discontinue antibiotics once the patient has been afebrile for 24 hours, ANC is greater than 500 cells/mm3 (or is greater than 200 cells/mm3 and rising), and blood cultures have been negative for at least 48 hours. For patients receiving antifungal therapy, imaging of the lungs and abdominal viscera should be considered once neutropenia has resolved. A computed tomography (CT) scan of the chest and CT or MRI of the abdomen is typically performed.
ANTERIOR MEDIASTINAL MASS
Large intrathoracic masses can lead to life-threatening cardiac and pulmonary complications. The management of anterior mediastinal masses (AMM) can be very challenging, because in addition to potentially devastating effects on ventilation and cardiac output, they can significantly delay or compromise the diagnosis of a new malignancy. The most common diagnoses presenting with an AMM are Hodgkin and non-Hodgkin lymphomas. In addition, AMM can present as an extramedullary complication of leukemia; this is most commonly seen in patients diagnosed with T-cell ALL. Solid tumors that can present with large anterior mediastinal masses include thymomas, thyroid cancers, germ cell tumors, neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma. The compression of vital mediastinal structures causes two main clinical phenomena: tracheal compression and superior vena cava (SVC) syndrome. In superior mediastinum syndrome, these complications occur simultaneously.
Compression of the trachea or main stem bronchi can present with cough, wheeze, dyspnea (at rest or on exertion), orthopnea, chest pain, and syncope. These clinical manifestations can occur gradually over time or suddenly, depending on the location and proliferative capacity of the mass. Occasionally patients may be asymptomatic from the mass, or may only have symptoms that present with particular positions, such as laying supine. Patients will sometimes assume positions of comfort, such as “tripoding,” which shift the mass away from the airways, alleviating the obstruction. The patient with a suspected mediastinal mass should be maintained in an upright or prone position during initial evaluation.
The workup of a patient with a suspected mediastinal mass should start with a chest x-ray (PA and lateral views) which can assess the size of the mass and identify tracheal deviation or compression. Once AMM is identified, the patient should be maintained in an upright position pending further evaluations. Subsequent diagnostic evaluations, including advanced imaging (CT, MRI) and biopsies, need to be carefully planned to avoid precipitating sudden cardiopulmonary arrest with improper positioning or sedation. An echocardiogram should be considered to assess cardiac compromise.
Ideally, the biopsy should be attempted through the least invasive method. For patients with suspected leukemia, peripheral blood blast analysis may lead to a diagnosis without the need for invasive procedures or sedation. Alternatively, an unsedated bone marrow or peripheral lymph node biopsy using local anesthesia can be considered. Additional sources of diagnostic material include pleural and pericardial effusions, though tapping these fluid collections would be contraindicated in the uncooperative, non-sedated child. Presence of specific tumor biomarkers, such as elevated urinary catecholamines (in neuroblastoma) or AFP/BHCG (in some germ cell tumors), may be of diagnostic assistance.
If sedation is required for biopsy, airway risk should be assessed with consultation from pediatric oncology and anesthesia.9,10 It is critical to recognize that endotracheal intubation may not maintain or secure the airway in these patients, especially patients whose obstruction is at or below the level of tip of the endotracheal tube (carina). In addition, sedation of these patients during attempted intubation, imaging, or biopsy can lead to sudden cardiopulmonary arrest and death.
The presence of orthopnea has been associated with a high risk of respiratory collapse. The best radiologic evaluation of the trachea is with lateral films and CT scan, which may need to be obtained in the prone position. Risk of anesthesia can be assessed by measurement of the cross-sectional diameter of the trachea on CT as well as pulmonary function tests—in particular, peak expiratory flow rates (PEFRs). Patients with a >50% tracheal cross-section and PEFRs of >50% have been shown to tolerate anesthesia well.11-13
In extreme circumstances, such as impending respiratory failure, implementation of empiric antineoplastic therapy must be considered prior to obtaining tissue for diagnosis. Strategies employed in this scenario include initiation of steroids, chemotherapy, or radiation therapy. In these situations, a pediatric oncologist should always be involved. Some malignancies, such as lymphoma, may have an exceptional response to empiric therapy with rapid resolution of both AMM size and symptoms. Such a response may make biopsy more challenging or infeasible, thus jeopardizing the ability to make an accurate pathological diagnosis.
SUPERIOR VENA CAVA SYNDROME/SUPERIOR MEDIASTINAL SYNDROME
SVC syndrome classically presents with upper extremity swelling and/or facial plethora resulting from decreased venous return from the head and upper extremities. Rarely, SVC syndrome is associated with cardiogenic shock or signs of increased intracranial pressure. SVC syndrome can also be caused by an occlusive thrombus resulting from the placement of an indwelling catheter into venous structures already narrowed by the mediastinal mass. One must also be careful with fluid administration in patients presenting with significant vascular compromise from anterior mediastinal masses. The increased intrathoracic pressure or direct compression of the right atrium from the tumor may make these patients particularly pre-load sensitive; hypovolemia in these patients may precipitate cardiopulmonary arrest secondary to poor cardiac output. On the other hand, hyperhydration may worsen symptoms of SVC syndrome, increasing upper extremity and facial swelling. As in the case of severe tracheal compression, antineoplastic therapy should be urgently initiated.
Rapid identification of spinal cord compression in the pediatric oncology patient is necessary in order to avoid permanent neurological disability. Spinal cord compression is most commonly encountered in solid tumors such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, metastatic CNS tumors, lymphoma, and AML-related chloromas. Spinal cord compression can be associated with both advanced stage metastatic disease or at initial presentation. The presenting signs are dependent upon the location and severity of cord compression, but can include back pain, weakness, loss of bladder/bowel function, and changes in sensation. Clinicians must remain vigilant and be on the lookout for spinal cord compression lest the diagnosis be missed. In patients who are very young, for whom the neurologic exam is difficult to interpret, or for patients who are otherwise very ill, new findings consistent with spinal cord compression may be overlooked.
The workup of suspected spinal cord compression should be expedited as a medical emergency requiring a multidisciplinary approach, beginning with an efficient, thorough neurological examination followed by MRI of the spine. If cord compression is strongly suspected based on known areas of disease or clinical presentation, IV dexamethasone (1–2 mg/kg over 30 minutes) may be administered prior to imaging. If imaging confirms cord compression, an emergent consultation with neurosurgery, radiation oncology, and pediatric oncology should be obtained in order to decide whether surgery, chemotherapy, or radiation therapy should be emergently initiated.14,15
INCREASED INTRACRANIAL PRESSURE
The presence of an expanding intracranial mass or hydrocephalus can result in increased intracranial pressure (ICP) that can progress to uncal herniation. Intracranial malignancies can cause increased ICP by means of either mass effect or an obstructive hydrocephalus, depending on location. Increased ICP can also be caused by thrombosis, infarction, infection, or hemorrhage. Finally, malfunction of an indwelling ventriculoperitoneal (VP) shunt can cause elevated ICP.
Presenting symptoms of increased ICP include headache, nausea, emesis, and visual complaints. On physical examination, cranial nerve abnormalities (including papilledema), deficits in strength and sensation, and altered mental status may be encountered. Cushing’s triad of bradycardia, hypertension, and respiratory irregularities must be recognized immediately, as they herald impending herniation.
A rapid evaluation of the patient with suspected increased ICP must occur concurrently with consideration of starting therapy. Imaging of the brain is most rapidly obtained with a CT scan. CT is able to identify the presence of increased ICP, impending cerebral herniation, and hemorrhage. MRI has the advantage of obtaining superior anatomical detail compared to CT, especially in the posterior fossa, and can be used initially if available, or after initial evaluation with CT. Patients with an indwelling ventricular shunt or Ommaya reservoir should have a radiographic shunt series performed and be referred for emergency neurosurgical consultation.
For emergent therapy, IV mannitol can be administered as a 25% solution at a dose of 0.25 to 1 g/kg over 30 minutes. IV dexamethasone may also be indicated, and can be administered at a dose of 1 to 2 mg/kg IV over 30 minutes. Once intubated, hyperventilation with a goal PCO2 to 30–35 mmHg can be effective in the management of increased ICP. Early discussion with neurosurgery and critical care consultants will help optimize patient care.
Despite favorable long-term outcomes in many forms of pediatric cancer, pain, whether acute or chronic, remains a significant clinical challenge. Patients can experience pain as a presenting symptom at time of diagnosis (e.g. bone pain with osteosarcoma), as a side effect of therapy (e.g. mucositis pain) or as a sign of tumor progression (e.g. gastrointestinal obstruction). Controlling pain in patients with advanced-stage disease or at end of life is particularly challenging. Unfortunately, there is evidence that pain and other discomfort at the end of life is often undertreated;16 however, recent studies indicate that patterns of end-of-life care are improving.17 A full discussion of palliative care can be found elsewhere in this text, but the pediatric hospitalist should be familiar with strategies to control pain in patients with advanced-stage disease or those approaching end of life. Severe pain in these patients is a medical emergency and should be approached with urgency.
In general, severe pain should be treated with a multidisciplinary approach, including pharmacologic interventions as well as nonpharmacologic integrative therapies.18 Initial interventions need to be closely monitored so as to capture pain control as quickly as possible. Advanced-stage oncology patients are likely to require rapid escalation of opioids or doses of opioids that are significantly larger than typically administered to opioid-naïve patients. Adequate pain control is determined by the amount of relief or comfort acceptable to the patient, not by the cumulative dosages of analgesics. The pediatric hospitalist should become familiar with institution-specific algorithms and policies around rapid escalation of opioids. In addition to opioids, non-opioid analgesics (e.g. acetaminophen) and integrative approaches (e.g. massage, music therapy, biofeedback) should be maximized. Not uncommonly, patients may require adjuvant therapies (e.g. anticonvulsants, benzodiazepines, dissociative agents) or more invasive approaches such placement of epidural catheters or nerve blocks. Palliative care expertise is invaluable in these settings and can assist the pediatric hospitalist in optimizing comfort at end of life.
Altered mental status in an oncology patient has a broad differential ranging from relatively benign causes to etiologies that are truly life threatening. The hospitalist should be familiar with this differential, as it will help guide a rapid assessment (Table 133-10).
TABLE 133-10Etiologies of Altered Mental Status in the Oncology Patient ||Download (.pdf) TABLE 133-10 Etiologies of Altered Mental Status in the Oncology Patient
Primary CNS tumor
Metastatic CNS tumor
Leukemic or carcinomatous meningitis
Ischemic or hemorrhagic stroke
Sagittal venous sinus thrombosis
Increased intracranial pressure
Supportive care medications
Overall, outcomes for childhood malignancies are superior to those seen in adults despite the relative rarity of pediatric cancer. However, expected and unexpected complications of the underlying malignancy and its treatment influence both morbidity and mortality.
A pediatric hospitalist must recognize patients who are at risk for developing oncologic emergencies and implement appropriate preventive strategies when available.
A pediatric hospitalist must recognize the most common oncologic emergencies and be knowledgeable about appropriate emergency management. Although early consultation with a pediatric oncologist is critical to the management of pediatric oncologic emergencies, treatment often needs to be initiated by the hospitalist.
Institution-specific treatment algorithms for these emergencies exist at many pediatric hospitals and should be readily available for review.
A thorough but efficient history and physical examination are critical to ensure that appropriate radiographic and laboratory studies are obtained.
Novel targeted antineoplastic therapies with fewer side effects are actively being studied in pediatric clinical trials. It is hoped that these therapies will decrease the toxicity associated with the classic cytotoxic agents, yet reproduce or improve upon patient outcomes.
These targeted therapies will have their own idiosyncratic side effects, and the pediatric hospitalist will be expected to be familiar with these as newer agents are incorporated into standard therapy.
Improved genomic profiling of both the pediatric patient and their tumor will identify patients with both favorable and unfavorable prognoses.
Risk stratification on the basis of genomic profiling will allow for personalized tailoring of therapeutic regimens aimed to decrease short- and long-term treatment-associated toxicity while improving survival.
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