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.

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.

TUMOR LYSIS SYNDROME

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).

Hyperuricemia

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.

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.

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.

HYPERLEUKOCYTOSIS

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.