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Four primary etiologies underlie most emergencies that occur in the field of pediatric oncology. Each of the causes may result in an additional emergency, ie, pain, which is best reviewed independently. This article is organized according to the underlying pathophysiology of the oncologic emergency as follows:

• Metabolic emergencies
• Hematologic emergencies
• Infectious and inflammatory emergencies
• Mechanical emergencies

Multiple metabolic and endocrinologic problems can potentially occur in patients with cancer. Tumor lysis syndrome (TLS) is the most common of the problems found in the pediatric population, and it frequently requires emergent therapy despite substantive prophylactic treatment. Hypercalcemia, hyponatremia, hypoglycemia, adrenal failure, and lactic acidosis occur less commonly.

Tumor lysis syndrome

TLS is defined as a metabolic triad of hyperuricemia, hyperkalemia, and hyperphosphatemia. Renal failure and symptomatic hypocalcemia are associated secondary complications. The primary triad results from rapid release of intracellular contents into the bloodstream and is most likely to occur in the setting of large tumor burden, rapid cell turnover, and rapid tumor response to therapy. These conditions frequently are present in the context of acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), and high-grade lymphoma (eg, Burkitt lymphoma) and following initial chemotherapy treatment for some large solid tumors.

Uric acid is derived from the breakdown of nucleic acid and results from catabolism of hypoxanthine and xanthine by the enzyme xanthine oxidase. Potassium and phosphate are present naturally in the cytoplasm of tumor cells at concentrations significantly higher than in the extracellular space. Hyperuricemia, hyperkalemia, and hyperphosphatemia result from the release of these intracellular substances from the tumor cell. Also released, but not considered part of the TLS triad, is lactate dehydrogenase (LDH). Secondary hypocalcemia results from compensatory down-regulation of calcium in the context of hyperphosphatemia. An elevated level of uric acid, potassium, phosphate, or LDH prior to initiation of chemotherapy indicates present or impending TLS. Therapy is both prophylactic and emergent.

Prophylactic treatment in patients with TLS

Prophylactic treatment is appropriate for pediatric patients with leukemia, lymphoma, or a large, particularly anaplastic, solid tumor in whom TLS may be present at the time of diagnosis. Therapy is directed at maximizing excretion of released intracellular contents and minimizing production of uric acid. Prophylactic treatment may begin hours or days before initiation of chemotherapy and includes limitation of both potassium and phosphate intake.

• Hydration: The purpose of hydration is to maximize renal excretion of potassium, phosphate, and uric acid. Optimal hydration volume for a pediatric patient is twice the normal maintenance requirement and may be increased up to 4 times the maintenance volume as necessary and as tolerated. Although oral hydration is possible, intravenous (IV) therapy is more reliable and is preferred. A solution of dextrose 5% in water (D5W) with one-fourth isotonic sodium chloride solution (40 mEq NaCl/L), sodium bicarbonate, and no potassium is the appropriate initial IV fluid. Quantities of sodium chloride and sodium bicarbonate should be adjusted as necessary. Insufficient diuresis may be treated with mannitol or furosemide if hypocalcemia is not severe.
• Alkalization: Uric acid is less soluble in acidic environments; alkalization inhibits precipitation of uric acid crystals in the renal tubules. Sodium bicarbonate is added to IV fluids to maintain a urine pH level between 7.0-8.0. Initially, a sodium bicarbonate concentration of 40-60 mEq/L should be added to IV hydration fluids; this should be adjusted as necessary to maintain an appropriate urine pH level. Overly intensive alkalinization exacerbates precipitation of both calcium phosphate and xanthine. Alkalization may be discontinued when the uric acid level is no longer rising and has attained a level within the reference range.
• Reduction of uric acid level: Allopurinol inhibits xanthine oxidase and decreases uric acid production. Allopurinol dosage is 10 mg/kg/d or 200-300 mg/m²/d PO/IV administered in 2-4 divided doses with a maximum dose of 800 mg/d. Incidence of allopurinol-associated skin rash may increase after 7-10 days of therapy. Urate oxidase is a new agent that catalyzes the conversion of uric acid to the 5- to 10-times more soluble compound, allantoin. Rasburicase (Elitek) is a recombinant form of the enzyme urate oxidase. The dose for adult and pediatric patients is 0.15-0.2 mg/kg/d IV infused over 30 min for 5-7 d. Urate oxidase is rapidly active, highly effective, and safe for use in children. Increased use of this agent as it becomes more available may decrease the need for dialysis.
• Monitoring: The most rapid evaluation for symptomatic hyperkalemia is accomplished via bedside electrocardiogram (ECG) and serial evaluation of T-wave morphology. Serum potassium measurements usually are obtained most rapidly via arterial or venous blood gas electrolyte evaluation. Regardless, metabolic evaluation should include serum electrolytes, blood urea nitrogen, creatinine, LDH, phosphate, magnesium, calcium, and uric acid levels.
• Monitor the patient at least every 8 hours during the first 24 hours of therapy. More frequent monitoring often is practical in an ICU.
• Frequency of subsequent evaluations should be adjusted as necessary during the first 2-5 days after diagnosis and initiation of therapy. Early monitoring includes a coagulation profileand accurate measurements of fluid intake, urine output, and body weight.
• Serial physical examinations are important to assess changes in vital signs, evidence of edema, or signs of electrolyte abnormality (eg, Chvostek or Trousseau sign).
• Despite appropriate prophylactic treatment, emergent interventions frequently are necessary.

Emergent treatment of patients with TLS

Intervention beyond the prophylactic measures outlined above is focused on maintaining normal end-organ function. The specific response to serum abnormalities is best modulated when both absolute serum level and rate of change are considered.

A compensatory down-regulation of serum calcium often is present in patients with hyperphosphatemia. In this setting, administration of exogenous calcium should be avoided unless the ionized calcium is reduced significantly, since a product of greater than 50-60 when the serum calcium level is multiplied by the serum phosphate level may lead to precipitation, particularly in renal tubules. The potential for precipitation is increased due to the elevated urine pH level that is necessary to minimize uric acid precipitation. Effective treatment of patients with specific electrolyte abnormalities often requires alterations in the composition of IV-fluid infusions that require several hours before an effect is observed. In addition, treatment is critically dependent on adequate renal function. Acute renal failure and active TLS require early initiation of renal dialysis and appropriate modification of chemotherapeutic agents.

Hypercalcemia

Abnormalities in calcium levels may be sufficiently severe to constitute a metabolic emergency. Hypercalcemia is encountered more frequently than hypocalcemia. Although the incidence of hypercalcemia has not been estimated accurately, hypercalcemia is significantly more prevalent in the adult oncology population; elevated calcium levels have been reported in 40-50% of patients with breast cancer or multiple myeloma and 12.5% of patients with lung cancer. In the pediatric population, a 29-year retrospective evaluation indicated an overall incidence of hypercalcemia of 0.4%, but a higher incidence was reported in other pediatric patient series.

Regardless of incidence, hypercalcemia is a metabolic emergency for pediatric patients with cancer. Hypercalcemia has been observed in patients with acute lymphoblastic leukemia and non-Hodgkin lymphoma and as a dose-limiting toxicity in 13-cis-retinoic acid treatment of patients with neuroblastoma. Hypercalcemia also is a recognized complication in patients with pediatric renal tumors, astrocytoma, desmoplastic round cell tumor, and solid tumors with significant bone metastasis.

Hypercalcemia refers to a serum calcium level greater than 10.5 mg/dL and usually results from increased bone resorption. The observed serum calcium level may be adjusted for the serum concentration of albumin using the following formula:

corrected calcium (mg/dL) = measured calcium (mg/dL) - serum albumin (g/dL) + 4

In the absence of elevated serum protein levels, disturbances to other organ systems are observed at levels greater than 12.0-13.0 mg/dL; levels greater than 20 mg/dL may be fatal.

Clinical manifestations of hypercalcemia

Clinical manifestations include the following neuropsychological, neuromuscular, gastrointestinal, cardiac, and renal symptoms:

• Neuropsychological signs include confusion, psychosis, seizure, obtundation, stupor, and coma.
• Neuromuscular signs include fatigue, lethargy, muscle weakness, hypotonia, and hyporeflexia.
• Gastrointestinal tract signs include anorexia, nausea, vomiting, constipation, obstipation, and ileus.
• Cardiac signs include prolonged PR interval, shortened QT interval, wide T wave, bradycardia, and atrial or ventricular arrhythmia.
• Renal signs include polyuria.

Pediatric patients with hypercalcemia also may present with bone pain. Bone pain may result from significant bone marrow infiltration by disease, pathologic fracture of severely demineralized bone, or direct osteolysis of bone caused by metastatic disease.

Pathophysiology of hypercalcemia

The principal pathophysiology underlying malignant hypercalcemia is excessive osteoclast-mediated bone resorption resulting from direct dysregulation of normal calcium homeostasis. Normal bone resorption is stimulated by parathyroid hormone (PTH), prostaglandin E₂, osteoclast-activating factor, other polypeptide growth factors, and osteoclasts derived from mononuclear phagocytes.

Although blast cells from patients with ALL and AML have been shown to produce PTH in vitro, in vivo neoplasms are associated more commonly with elevation of a similar compound, parathyroid hormone-related polypeptide (PTHrP). PTHrP binds the PTH receptor, but it is immunologically distinct from PTH. Hibi and coworkers reported hypercalcemia and elevated PTHrP levels in vivo in 4 of 83 (4.8%) pediatric patients with early pre–B-cell ALL.

Hypercalcemia also has occurred in the context of elevated prostaglandin E₂ levels in infants with mesoblastic nephroma or malignant rhabdoid tumor of the kidney. Elevated prostaglandin E₂ production also was suggested in a patient with primary disseminated Ewing sarcoma who presented with hypercalcemia in the context of normal PTH and PTHrP levels that improved following indomethacin treatment.

Although an increased level of osteoclast-activating factor frequently is associated with the hypercalcemia of multiple myeloma, it has not been associated with pediatric malignancy. Multiple other cytokines are involved in bone resorption and may be related to malignancy-induced hypercalcemia. Transforming growth factor b is released as a result of osteoclast activity and increases PTHrP production by tumor cells. Tumor necrosis factor and interleukin 6 (IL-6) levels often are elevated in the context of malignancy and have been shown to increase osteoclast production and differentiation. The in vivo contribution of these and other cytokines to malignancy-associated hypercalcemia remains unclear.

Treatment of patients with hypercalcemia

Traditional treatment of pediatric patients with hypercalcemia and malignancies has relied on forced diuresis and calcitonin, corticosteroids, and mithramycin use.

Recently, bisphosphonates have proven to be more useful for treatment of hypercalcemia. Bisphosphonates have a chemical structure similar to inorganic pyrophosphate, but they are resistant to hydrolysis in an acidic environment. Although the exact mechanism of action and spectrum of activity are incompletely understood, these compounds are potent inhibitors of both normal and pathologic osteoclast-mediated bone resorption.

Bisphosphonates that most closely resemble inorganic pyrophosphate (clodronate, etidronate, tiludronate) are incorporated metabolically into nonhydrolyzable analogs of adenosine triphosphate (ATP), which accumulate intracellularly and induce osteoclast apoptosis. The more potent nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate, zoledronate, ibandronate) appear to act as transitional-state analogs of isoprenoid diphosphates to inhibit production of farnesyl diphosphate synthase and the mevalonate pathway. Inhibition of the mevalonate pathway prevents the necessary posttranslational modification of small guanosine triphosphatases (GTPases) necessary for intracellular osteoclast signaling.

The compounds are safe and effective for the treatment of pediatric patients with malignancy-induced hypercalcemia, and they appear to be useful for treatment of other malignancy-associated skeletal morbidities such as pain and osteoporosis. Treatment with bisphosphonates should be considered for all patients with a corrected serum calcium level greater than or equal to 12 mg/dL (3.0 mmol).

Hyponatremia

Severe hyponatremia, which is defined as a serum sodium level of less than 125 mEq/L, is a known complication for pediatric patients with malignancy and can result from systemic illness, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), or iatrogenic factors acting individually or collectively. Symptoms primarily are neurologic, but no significant symptoms of early mild hyponatremia exist. Anorexia, nausea, and malaise are the first overt findings, which then progress to headache, confusion, lethargy, seizure, coma, and death. Although a gradual change in serum sodium concentration may be tolerated by the central nervous system (CNS), rapid changes of 1-2 mEq/L/h lead to cerebral edema and neurologic dysfunction. Severe life-threatening symptoms are seen almost uniformly at a serum sodium concentration of less than 105 mEq/L, but these symptoms also may be seen if the level falls to 120 mEq/L within 24 hours.

Pathophysiology of hyponatremia

Hyponatremia most often results from water retention combined with administration of normal or excessive amounts of fluid. Water retention is a consequence of antidiuretic hormone (ADH) release induced by decreased effective circulating intravascular volume.

Hyponatremia can occur both in edematous states and in true volume depletion. Hyponatremia associated with edematous states is more common in patients with cancer and may result from liver disease, veno-occlusive disease, infection, drug toxicity, or multiple other etiologies. Hyponatremia associated with true volume depletion is less common and typically is consequent to identifiable fluid losses, such as severe diarrhea, bleeding, and drainage of effusions or ascites. In either situation, hyponatremia results from disproportionate accumulation of water from administered hypotonic fluids.

Patients usually are oliguric with urine sodium levels less than 15 mEq/L. Excessive renal salt wasting also may cause hyponatremia and can result from drug-induced nephropathy, adrenal insufficiency, or use of thiazide diuretics. Patients with renal-induced hyponatremia usually are nonoliguric and have inappropriately high urine sodium levels.

Abnormal release of ADH also may result in hyponatremia, as in SIADH. In one case series, SIADH accounted for approximately one third of all cases of hyponatremia diagnosed in hospitalized patients with cancer. In the series, hyponatremia was defined as a serum sodium level of less than 130 mg/dL. SIADH results from persistent release of ADH and subsequent water retention with expansion of intravascular volume.

Hyponatremia is secondary both to dilution of sodium from retention of free water and to progressive increase in urinary loss of sodium. SIADH is defined by an inappropriately elevated urine osmolality in the context of decreased serum osmolality, and it frequently is associated with a urine sodium concentration greater than 20 mEq/L. The rate of development of hyponatremia depends on the rate and volume of fluid administration. SIADH occurs in the context of CNS disturbances, pulmonary disease, use of specific drugs, and a variety of tumors.

Cyclophosphamide is the chemotherapeutic agent most commonly associated with impaired renal excretion of water. This complication occurs more frequently in patients receiving doses higher than those used to treat malignancy (30 mg/kg) and used in myeloablation prior to stem cell transplantation; however, impaired renal excretion of water also has been observed at doses of 10-15 mg/kg used in treating patients with autoimmune diseases.

To a lesser extent, vincristine, vinblastine, melphalan, and thiotepa have had similar effects. SIADH associated with vincristine therapy may be coincident with severe vincristine neurotoxicity. Chemotherapy-induced nausea and emesis also produce a significant increase in plasma ADH levels independent of changes in serum osmolality or blood pressure. Therefore, highly emetogenic chemotherapy regimens, particularly when administered with hypotonic fluid hyperhydration, may lead to significant hyponatremia. Enhanced ADH activity also has occurred with administration of morphine, carbamazepine, and other medications.

SIADH has been reported to follow both major and minor surgical procedures, and 18-27% of patients may be affected following surgery of the head and neck. CNS tumors in the pediatric population and small cell carcinoma in adults are the malignancies most commonly associated with SIADH. A retrospective review of 122 pediatric patients with brain tumor requiring craniotomy revealed a 12% incidence of SIADH.

Hyponatremia also is a frequent iatrogenic result or consequence of underlying systemic illness. Overhydration with hypotonic solutions frequently results in mild or moderate hyponatremia. Failure to administer stress-dose levels of glucocorticoids to patients who are adrenally suppressed also results in hyponatremia. Alternatively, patients with suprasellar tumors or Langerhans cell histiocytosis may self-hydrate with hypotonic fluids in the setting of diabetes insipidus and cause hyponatremia.

Treatment of patients with hyponatremia

Treatment is dictated by the patient’s symptoms and underlying pathophysiology. These 2 factors dictate both the optimal rate at which the serum sodium level should be corrected and the optimal volume of fluid necessary to achieve the correction. In an asymptomatic patient, serum sodium concentrations should be corrected at a rate of less than or equal to 0.5 mEq/L/h during the first 24 hours of intervention or 12 mEq/L total. A more rapid correction of 1-2 mEq/L/h in the serum sodium concentration is indicated only if a patient is symptomatic. In symptomatic patients, rapid correction is indicated only for the first 1-3 hours of therapy, with a goal to improve the serum sodium concentration 12-15 mEq/L in the first 24 hours.

Management of fluid volume depends on underlying pathophysiology. In the setting of true extracellular hypovolemic hyponatremia, saline administration corrects hyponatremia and suppresses ADH secretion, thereby improving free water excretion. In patients with evidence of fluid retention, such as edema or ascites, treatment consists of salt and water restriction, improvement of effective intravascular volume, and direct treatment of any underlying disorder. Primary therapy for asymptomatic patients with SIADH is water restriction; however, administration of hypertonic 3% saline 2-4 mL/kg/dose with or without furosemide 1 mg/kg should be considered if CNS symptoms are present. Chronic SIADH may be managed using furosemide with or without salt tablets. Demeclocycline, a tetracycline antibiotic, also induces nephrogenic diabetes insipidus and can be used if control of SIADH is inadequate using the aforementioned regimen.

Other metabolic emergencies

Metabolic emergencies such as hypoglycemia, adrenal failure, and lactic acidosis are significantly less common in the pediatric population than in the adult population.

Hypoglycemia

Hypoglycemia often is defined as a serum glucose level of less than 40 mg/dL; however, initial symptoms may occur at higher levels, particularly if the blood glucose level is decreased rapidly. Symptoms often are worse in the early morning and may include weakness, dizziness, diaphoresis, and nausea. Symptoms may progress to diffuse neurologic deficits, seizure, coma, and death.

Hypoglycemia most commonly results from insulin-producing islet cell tumors that occur alone or as part of multiple endocrine neoplasia syndrome. Symptomatic hypoglycemia also may result from tumor production of compounds with low molecular weight with nonsuppressible insulinlike activity. The best characterized of these compounds include insulinlike growth factor-1, insulinlike growth factor-2 (IGF-2), somatomedin A, and somatomedin C. Production of these substances extends beyond islet cell tumors as evidenced by the report of IGF-2–induced hypoglycemia by a pediatric renal tumor. Although excessive glucose use by large tumors is a possible cause of hypoglycemia, few data support this as an etiology in pediatric patients with malignancies.

A graded response to hypoglycemia is appropriate. Mild hypoglycemia may be managed best by increased frequency of feedings. More severe or symptomatic hypoglycemia may require corticosteroid and glucagon administration. Diazoxide is useful therapy for known hyperinsulinemia. Regardless of the type of treatment used in patients with chronic hypoglycemia, IV infusion of dextrose-containing solutions provides temporary support, and specific treatment of the underlying tumor provides definitive therapy.

Adrenal insufficiency

Adrenal insufficiency in pediatric patients with cancer is rare and usually is secondary to adrenal suppression resulting from extended use of glucocorticoids at supraphysiologic doses combined with abrupt termination of therapy. Symptoms of adrenal insufficiency are exaggerated in the setting of physiologic stress and can manifest as mild acidosis, hyponatremia, and hypokalemia. Severe circulatory collapse and shock are uncommon.

Lactic acidosis

Lactic acidosis in pediatric patients with malignancy is rare and most frequently is associated with hypoperfusion and tissue hypoxia, as seen in patients with sepsis, low cardiac output, or extreme anemia. Lactic acidosis resulting from rapidly progressive hematologic malignancy or extensive liver involvement is documented best in adult patients with cancer. Treatment is appropriately directed at the underlying etiology of acidosis. Regardless, a serum lactate level greater than 4 mEq/L is associated with a poor prognosis.

Hematologic abnormalities that require emergent treatment result from abnormal hematopoiesis or coagulopathy. With respect to hematopoiesis, underproduction of specific cell lines is more common than overproduction. Underproduction is consequent to disease infiltration of the bone marrow, syndromes of bone marrow failure, or treatment-related myelotoxicity. Underproduction results in anemia, thrombocytopenia, neutropenia, or a combination of the three. Overproduction of hematopoietic tissue primarily is observed in the form of leukocytosis associated with acute leukemia. Coagulopathy manifests as hemorrhage, thrombosis, or both. Coagulopathy is a primary consequence of disease, results from a primary toxicity due to treatment, or is secondary to other known complications.

Depression of bone marrow activity

Depression of normal bone marrow activity results in anemia, thrombocytopenia, and neutropenia. These signs are best treated with supportive care, regardless of etiology. Supportive care often includes transfusion of individual blood components, which requires the following considerations in the context of the immunosuppressed patient with cancer:

• All blood, platelets, and granulocytes administered to immunosuppressed patients must be irradiated to prevent the lethal complication of graft versus host disease.
• Until known, nonimmunity to cytomegalovirus (CMV) should be assumed in pediatric patients with malignancy, and patients should receive blood products from donors without CMV. In the absence of known CMV status, blood product testing with leukocyte filtration may be substituted. Although minimizing CMV exposure in immunosuppressed patients without CMV immunity is considered the standard of care, controversy remains regarding the use of CMV-negative products in immunosuppressed patients who were previously exposed to CMV. The controversy results from the small risk associated with exposure to a second CMV strain.
• Use of leukocyte-poor blood and platelets is recommended to minimize the risk of CMV contamination and to decrease both the risk of alloimmunization and the incidence of febrile transfusion reactions.
• Minimize patient exposure to blood products. Judicious use of blood products decreases infectious risks and is particularly important for patients newly diagnosed with aplastic anemia in whom engraftment of transplanted stem cells is inversely related to the number of previous donor exposures.

Blood products may be obtained from the general blood supply or through directed donation. Directed-donor blood products appear to have an infectious risk equal to the general blood supply. Intrafamilial-directed donations should be discouraged in patients who may need stem cell transplantation to limit familial human lymphocyte antigen (HLA) exposure.

Anemia

Usually, anemia in pediatric patients who are not critically ill is well tolerated and does not require transfusion unless the hematocrit level is less than 20-25%, with no evidence of recovery, or if transfusion is necessary for symptomatic improvement. Transfusion of packed red blood cells (PRBCs) also may be necessary to maintain optimal intravascular volume in a patient who is critically ill or who has acute hemorrhage. The use of recombinant erythropoietin is limited by the weeks of therapy necessary to increase hemoglobin (Hb) levels significantly. Once developed, severe anemia usually requires transfusion.

PRBCs are the blood product of choice for treatment of patients with anemia. The volume of a single unit varies and ranges from 250-300 mL. The hematocrit range of an individual unit also varies and ranges from 70-85%. A transfusion of 10 mL PRBCs per kilogram ideally raises the Hb level 2-3 g/dL. Generally, 10-15 mL of PRBCs per kilogram can be transfused safely over 2-4 hours. Rate of transfusion should be decreased by at least 50% in patients with heart failure or severe chronic anemia in whom the Hb level is less than or equal to 5 g/dL. 

Thrombocytopenia

Thrombocytopenia in pediatric patients with cancer results from underproduction of platelets or from excessive consumption of platelets. Although thrombopoietin has been known to have strong positive effects on platelet production and its use continues in clinical trials, the degree to which this cytokine impacts platelet transfusion therapy remains unclear. Therefore, platelet transfusions remain the primary treatment for thrombocytopenia in pediatric patients with cancer. Platelet transfusions are used to treat bleeding and as prophylaxis. General considerations for the use of platelets in pediatric patients with malignancy include the following:

• Avoid platelet transfusion in the absence of bleeding if thrombocytopenia is secondary to platelet consumption.
• Consider empiric platelet transfusion in patients with platelet counts less than 10,000/mm³ if thrombocytopenia results from underproduction.
• Consider empiric platelet transfusion in patients with platelet counts less than 15,000-20,000/mm³ who have acute nonlymphocytic (myeloid) leukemia (ANLL) and are receiving induction chemotherapy, particularly if the platelet count is decreasing by 50% or more per day.
• Consider empiric platelet transfusion in patients with platelet counts less than 20,000/mm³ who have leukocyte counts greater than 100,000/mm³ in ANLL or leukocyte counts greater than 300,000-400,000/mm³ in ALL.
• Transfuse platelets in any patient with overt bleeding (not ecchymosis or petechiae) and a platelet count less than 50,000/mm³ in the context of adequate prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen levels.
• Surgical microvascular bleeding usually requires platelet transfusion in patients with a platelet count less than 50,000/mm³.
• Lumbar punctures are safe in patients with platelet counts greater than 40,000-50,000/mm³. A recent study has suggested that lumbar puncture may be safe at platelet counts greater than 10,000/mm³, but this observation has yet to be confirmed and is not considered the standard of care in most institutions performing invasive procedures on children with thrombocytopenia.
• Transfuse platelets slowly, over 2-6 hours, if the patient has acute bleeding and known platelet alloimmunization.

Platelets are available as single-donor products or as pooled random-donor products. Single-donor products are preferred to limit infectious risks and, for patients in potential need of stem cell transplantation, to reduce exposure to nonself HLA. Irradiation of platelet products, CMV status of platelet donors, and leukocyte filtration issues were previously discussed in Depression of bone marrow.

Studies in adults with normal splenic activity indicate that a dose of 1 platelet unit/m² (5.5 X 10¹⁰ platelets/m²) increases the peripheral platelet count 10,000-12,000/mm³. One single-donor plateletpheresis unit contains approximately 4 X 10¹¹ platelets and is equivalent to approximately 6 random-donor platelet units. In patients with active bleeding from thrombocytopenia, an incremental increase of 40,000-45,000/mm³ usually is sufficient to attain hemostasis.

A rise of less than 5000-6500/mm³ for each transfused unit/m² (ie, <50% of expected) on 2 consecutive transfusions suggests active destruction resulting from alloimmunization, which can be confirmed by a low posttransfusion platelet count obtained 15-20 minutes after platelet transfusion and by the presence of antiplatelet antibodies. Antiplatelet antibodies precipitate platelet destruction more rapidly than other forms of consumption, and no substantive rise is noted at 15 minutes posttransfusion. Unfortunately, no reliable predictors determine which patients are most at risk for developing antiplatelet antibodies. Once present, alloimmunization requires either crossmatching or HLA typing of platelets prior to transfusion.

Neutropenia

Neutropenia is the most common toxic result of myelosuppressive chemotherapy, but it also may result from either failure or suppression of the bone marrow. Absolute neutrophil counts lower than 500/mL are associated with increased risk of infection. Neutropenia extending beyond 2 weeks is associated with increased risk of systemic fungal infection.

Prolonged neutropenia resulting from myelotoxic chemotherapy is treated primarily with myeloid growth factors, granulocyte colony-stimulating factor (GCSF) and granulocyte-macrophage colony-stimulating factor (GMCSF), if concern does not exist for stimulating growth of the underlying malignancy. Neutropenia associated with bone marrow failure syndromes may respond to immunosuppressive therapy alone or in combination with androgens and growth factors. Although granulocyte transfusion is a viable therapeutic modality for patients with neutropenia with active unresponsive bacterial or fungal infection, no reliable criteria exist that predict which patients are likely to benefit from this moderately toxic and expensive therapy.

Hyperleukocytosis

Hyperleukocytosis is the most common hematologic overproduction syndrome necessitating emergent treatment of pediatric patients with cancer. Hyperleukocytosis is defined as a peripheral leukocyte count greater than 100,000/mm³. Hyperleukocytosis is present at diagnosis in 6-15% of pediatric patients with ALL, 13-22% of patients with ANLL, and nearly all children with chronic myelogenous leukemia. Hyperleukocytosis is a poor prognostic indicator in the setting of either ALL or ANLL because it is associated with metabolic and hemorrhagic complications. Respiratory complications are a more prominent feature of elevated leukocyte counts in patients with ANLL. Hemorrhagic complications and death rates significantly increase when peripheral leukocyte counts are greater than 100,000/mm³ in the context of ANLL and greater than 300,000-400,000/mm³ in the context of ALL.

When present, clinical manifestations of hyperleukocytosis result from anaerobic metabolism and proliferation of blast cells within the microvasculature. Physical findings result from the increased viscosity associated with blast cell aggregates and thrombi in combination with damage to vessels and secondary hemorrhage. Resultant clinical findings primarily include respiratory and neurologic signs. Respiratory signs include dyspnea and hypoxia. Neurologic signs include focal deficit, ataxia, agitation, confusion, delirium, and stupor. Other signs include plethora, cyanosis, papilledema, and retinal artery or retinal vein distension. Specific treatment algorithms for hyperleukocytosis have not been evaluated in prospective randomized trials. Therapies are directed toward decreasing the peripheral leukocyte count and controlling concomitant metabolic, hemorrhagic, and thrombotic risks. Specific therapeutic considerations exist for each of the risks.

Hyperleukocytosis and transfusion

PRBC transfusions increase the viscosity of blood and should be avoided, if possible, in the context of hyperleukocytosis. Platelet transfusions do not significantly change the viscosity of circulating blood, and platelets may be transfused safely if indicated.

Leukocytosis

Specific antileukemic therapy is the treatment of choice for decreasing the peripheral leukocyte count. In the absence of definitive antileukemic therapy, leukophoresis or exchange transfusion may be considered; however, specific indications for either therapy remain controversial. The goal of the therapies is to decrease blood viscosity and the metabolic risks associated with a large tumor burden. Either procedure may be considered if a delay is expected in initiating specific antileukemic therapy and leukocyte counts are greater than 100,000/mm³ in patients with ANLL or 300,000-400,000/mm³ in patients with ALL.

Partial-exchange transfusion is considered primarily in the youngest patients or in patients with congestive heart failure resulting from severe anemia in combination with leukocytosis. No controlled trial data are available to address empiric use of cytoreductive procedures, such as leukopheresis, prior to antileukemic chemotherapy in patients with hyperleukocytosis.

Metabolic risk

Risk of TLS is elevated in the setting of leukocytosis. Prophylactic and emergent treatment regimens in patients with TLS are outlined above (see Tumor lysis syndrome).

Coagulopathy

Pediatric patients with cancer are subject to have significant abnormalities in procoagulation, inhibitors of coagulation, and fibrinolysis. The abnormalities result in hypocoagulable and hypercoagulable conditions that manifest as hemorrhage or thrombosis. Hemorrhage and thrombosis are significant problems in the setting of hyperleukocytosis. Hemorrhage also is a significant complication during induction chemotherapy for class M3, M4, and M5 AML, even at lower peripheral leukocyte counts.

Bleeding predominates in this setting secondary to the relative excess of fibrinolytic proteases, compared to prothrombotic thromboplastic materials, released from blast cells. Hemorrhage also may result from consumption of coagulation factors in the setting of chronic activation of the procoagulation cascade, or it may result from underproduction of necessary coagulation factors in the setting of severe systemic illness and relative hepatic insufficiency.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is characterized by excessive activation of blood coagulation with consumption of clotting factors. DIC causes hemorrhage, microangiopathic hemolytic anemia, and thrombosis of varying degrees. DIC may contribute to hemorrhagic and thrombotic events. In children with cancer, DIC is associated most commonly with ANLL induction chemotherapy in which thromboplastic materials are released from leukemic blast cells. DIC also occurs in patients with sepsis or, less frequently, widely disseminated solid tumors.

Diagnosis is demonstrated by elevated PT, elevated aPTT, and decreased platelet counts. Fibrinogen levels also may be decreased with a concomitant elevation of fibrin monomers or fibrin degradation products. Primary therapy is supportive care and treatment of the inciting etiology. Patients with significant hemorrhage or thrombosis associated with DIC may benefit from low-dose heparin therapy (7.5 U/kg/h). Thrombocytopenia is treated with platelet transfusion. Most specifically, fibrinogen is replaced using cryoprecipitate, 1 unit (bag)/10 kg. Hyperfibrinolysis, as evidenced by low antiplasmin levels, is treated with e-aminocaproic acid if evidence of hematuria is lacking.

Thrombosis

Thrombosis is a less common oncologic emergency in children than in adults. In the pediatric population, symptomatic thrombosis may be associated with central venous catheters, but thrombosis is most common in the setting of hyperleukocytosis and ALL treated with L-asparaginase in which severe thromboembolism, primarily of the cerebral venous sinus, is reported in 2.4-11.5% of patients. L-asparaginase therapy is associated with decreased plasminogen, antithrombin III and, to a lesser extent, protein C and protein S levels.

A coordinated in vivo increase in thrombin generation also has been identified after L-asparaginase therapy, and thrombotic events are significantly more likely to occur in patients with at least 1 prothrombotic defect, such as factor V G1691A (Leiden) mutation, prothrombin G20210A mutation, or deficiency of protein C, protein S, or antithrombin III. Unfortunately, none of these measures accurately predicts the risk of thrombosis in an individual patient.

Clinical presentation of thrombosis of the sagittal sinus varies and ranges from asymptomatic to life threatening. Most patients present with seizure, focal motor deficits, cognitive deficits including aphasia, or a combination of signs. Treatment of patients with thrombosis associated with L-asparaginase therapy primarily is supportive, and good long-term recovery is observed in most reported cases.

Children with cancer are at increased risk for acute life-threatening infection and acute inflammatory processes as a direct result of the underlying disease, treatment, or both. Infectious emergencies include infections resulting from bacteria, parasites, mycoplasmata, viruses, and fungi. Pneumonitis, pancreatitis, hemorrhagic cystitis, enterocolitis, and tissue necrosis from extravasation of chemotherapeutic agents are representative of the severe inflammatory states that may occur. Patients with both infectious and inflammatory conditions may require emergent treatment, and the conditions are considered independently.

Infectious emergencies

Immunosuppression is the primary underlying factor that predisposes patients with cancer to infectious complications. Patients are variably subject to quantitative and qualitative decreases in granulocyte function (neutropenia), B-cell function (hypogammaglobulinemia), T-cell function, splenic function, and normal immunologic and integument barriers. In addition, alteration of typical body flora can result in overgrowth of pathogenic organisms. Individually and in combination, these factors increase the risk of serious systemic infection by bacterial, viral, fungal, and other opportunistic organisms.

Patients are primarily susceptible to systemic dissemination of endogenous bacteria and fungi that colonize the skin and gastrointestinal tract, reactivation of endogenous viruses (eg, herpes simplex virus), or reactivation of latent cysts (eg, Pneumocystis carinii). Secondarily, patients are at increased risk of systemic infection from aerosolized viruses, Legionella species, and fungal spores. Relative risk for infection with a particular agent is influenced by the degree of compromise in specific arms of the immune system. Please refer to Table 5 for more information.

Bacterial infections

Bacterial pathogens may induce focal or systemic infections, and the incidence of bacterial infections increases as the absolute neutrophil count (ANC) decreases from 1000/mm³ to 500/mm³ to 100/mm³. The most common etiologic agents are bacteria that colonize the skin and gastrointestinal tract of the host. Neutropenia is the primary risk factor for bacterial infections, and fever is the most common presenting symptom. In this context, neutropenia commonly is defined as an ANC less than 500/mm³, and fever may be defined as a temperature greater than 38.0°C twice within 24 hours or a temperature greater than 38.3-38.5°C once. The institution of empiric antibiotic therapy for a patient with neutropenia who is febrile has decreased infection-related mortality rates, particularly in death due to gram-negative organisms.

Patients with neutropenia who are febrile require thorough evaluation. Physicians should be aware that subtle indications of inflammation should be considered a presumptive sign of infection. Close attention to central venous catheter sites, skin, oropharynx, and perirectal areas is necessary. Cultures of the blood, skin lesions, and diarrheal stool and a workup involving chest radiographs, complete blood counts, and blood urea nitrogen, creatinine, transaminase, and serum electrolyte levels are recommended aspects of the initial evaluation. Other cultures, radiologic evaluations, and laboratory studies should be obtained as indicated.

An extensive diagnostic evaluation identifies an established or occult infection in fewer than 48-60% of patients. Bacteremia is present in 10-20% of patients with neutropenia who are febrile. Gram-positive organisms account for approximately 60-70% of microbiologically identified organisms, and antibiotic resistance has been increasing among isolated organisms. The most common gram-positive organisms are Staphylococcus aureus, Staphylococcus epidermidis, S pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Enterococcus faecalis, Enterococcus faecium, and Corynebacterium species. Gram-negative isolates of E coli, P aeruginosa, and Klebsiella species are more common than Enterobacter, Proteus, Salmonella, and Acinetobacter species. Anaerobic cocci and bacilli are other common bacteriologic isolates.

Guidelines for the use of antimicrobial agents to treat patients with neutropenia who are febrile have been published by the Infectious Diseases Society of America. Initial antibiotic therapy should consist of broad-spectrum monotherapy using cefepime, ceftazidime, or imipenem. Dual therapy consisting of an aminoglycoside in combination with an antipseudomonal beta-lactam is an equivalent alternative and should be considered, particularly when the patient’s presentation suggests gram-negative bacteremia or sepsis.

Initial empiric use of vancomycin in combination with single or dual therapy is appropriate in the setting of severe mucositis, quinolone prophylaxis, known colonization with resistant strains of S aureus or S pneumoniae, catheter-related infections, and hypotension/sepsis syndrome. Vancomycin should be discontinued after 48-72 hours if warranted by clinical course or culture results. A confirmed or suggested infectious focus also may require antibiotics beyond empiric coverage. Typhlitis or suggested perirectal abscess requires increased antibiotic coverage for anaerobic organisms. C difficile enterocolitis requires either metronidazole or oral vancomycin. Additional coverage should be guided by organism sensitivity and clinical syndrome.

Empiric antibiotics typically are discontinued when the patient is afebrile and has an ANC greater than 500/mm³ if both occur within the first 7 days of therapy. Continuation of antibiotics usually is recommended regardless of fever when neutropenia is profound, which is indicated by an ANC less than 100/mm³. Controversy exists regarding treatment of patients who have no evidence of infection and become afebrile but remain neutropenic at higher ANC levels. In this situation, clinical practice depends on many factors and ranges from discontinuation of antibiotics to continuation of inpatient treatment using broad-spectrum IV antibiotics.

Antibiotic chemoprophylaxis for patients with profound neutropenia to selectively decontaminate the gut has been studied. Orally administered absorbable antibiotics, such as trimethoprim-sulfamethoxazole (TMP-SMZ) and quinolones, are preferable to nonabsorbable polymyxin, aminoglycosides, or vancomycin secondary to the increasing incidence of resistant bacteria to the latter 2 drugs.

One larger study compared TMP-SMZ and ofloxacin and demonstrated no difference in the number of gram-positive infections, but fewer gram-negative infections were observed in the ofloxacin cohort. An increase in quinolone-resistant gram-negative bacilli has been observed in patients receiving quinolone prophylaxis, and an increased rate of fungal colonization has been demonstrated among patients receiving prophylactic antibiotics. Although antibiotic prophylaxis during neutropenia results in fewer bacterial infections, the concern of increased bacterial resistance and lack of reduction in mortality rates argues against antibiotic prophylaxis as a routine practice.

The use of antibiotics in a patient with cancer who is febrile but does not have neutropenia requires special consideration when an indwelling venous catheter is in place. In addition to a complete examination and appropriate individualized diagnostic studies, blood cultures should be obtained from all catheter lumens. In the absence of an obviously infectious site, a broad-spectrum third-generation cephalosporin (ceftriaxone) may be used. Alternative regimens are governed by known, prominent, local bacterial isolates and identifiable infectious sites found on initial patient evaluation. Antibiotics should be continued for 24-72 hours, culture results should be monitored, and patients with positive results should be treated with a full course of appropriate antibiotics.

Fungal infections

Fungi are categorized broadly by morphology as either yeasts or filamentous molds. Infection in children with cancer by these and other opportunistic fungal pathogens has increased since the 1980s. The increase reflects the more intensive immunosuppression that results from current antineoplastic treatment regimens. Candidal organisms are now the fourth most commonly occurring bloodstream pathogen, and undiagnosed invasive fungal infections are identified increasingly at autopsy, suggesting that incidence is underdiagnosed. Consistent with these findings is the result of a 1990 series of 161 pediatric autopsies; the report identified mycotic infection as most common instead of bacterial infection, as initially believed by the clinician.

In a patient with neutropenia, persistent or recurrent fever after defervescence despite broad-spectrum antibiotic therapy is the most common presenting symptom in patients with invasive fungal disease. This finding is supported by a lower incidence of documented fungal infection in neutropenia cohorts treated empirically with amphotericin B after 7 days, and more recently 4 days, of persistent unexplained fever. Fungal infections may present as focal or disseminated disease. Candida and Aspergillus species are the most common cause of fungal infections in immunocompromised hosts.

Candidal organisms are the most common invasive fungal pathogens in pediatric patients with cancer and account for approximately 65% of documented fungal infections. Although Candida albicans is the most common pathogen historically, infection with other species is increasing and accounts for approximately 50% of candidal fungemias. The most common organisms are Candida tropicalis (23%), Candida glabrata (8%), Candida parapsilosis (6%), and Candida krausei (4%). The prophylactic use of thiazole antifungal agents (fluconazole) is associated with C glabrata and C krausei infection. C tropicalis infection is associated with antileukemic therapies that induce significant mucosal toxicity. Systemic infections caused by candidal species present primarily as fungemia and hepatosplenic candidiasis.

Molds account for approximately 35% of all invasive fungal infections, 65% of which are caused by Aspergillus species. Fusarium species, members of the Mucorales order, and other molds also infect severely immunocompromised hosts. Unlike yeast and bacterial pathogens, molds are not part of the typical body flora and usually are not acquired via person-to-person contact. Therefore, exposure to spores remains a significant risk factor for patients. Aspergillus species and other molds principally cause pneumonia, sinusitis, and cerebral abscess formation.

Antifungal agents are administered as prophylactic, empiric, or therapeutic treatment. Most antifungal agents are administered prophylactically or empirically to minimize the risk of systemic disease, reflecting the difficulty in treating established infections. Initiation of antifungal therapy and the choice of an antifungal agent depend on several factors relating to the risk of infection and risk of infection by a particular organism.

Prophylactic antifungal therapy is common for patients undergoing stem cell transplant and patients receiving severely myelotoxic chemotherapy. The thiazole compound fluconazole is the most common agent used and is credited with decreasing the incidence of systemic candidal infection from 11.4% to 4% in patients undergoing stem cell transplantation. Although fluconazole use has decreased the overall rate of systemic fungal infection, the offending organism, when present, is more commonly a thiazole-resistant Aspergillus organism or a candidal yeast species other than C albicans.

Itraconazole is another thiazole compound with a broader spectrum of activity than fluconazole. Use of itraconazole for prophylaxis is complicated by variable oral bioavailability and interactions with cytochrome P450–metabolized drugs, particularly cyclosporine and tacrolimus. Low-dose amphotericin B also has been used for prophylaxis during stem cell transplantation; however, information from prospective randomized trials is insufficient to address the use of this approach compared to fluconazole therapy.

Empiric antifungal therapy for patients with neutropenia who have persistent unexplained fever reduces the risk of invasive fungal infection. Empiric antifungal therapy is recommended after 4-7 days of persistent unexplained fever, despite broad-spectrum antibiotic therapy, or new fever after defervescence to antibiotics.

Although amphotericin B has been the drug of choice in this setting, fluconazole may be considered if a high level of suspicion exists for infection by a susceptible Candida species as may be expected in patients after only 7-10 days of neutropenia, colonization with C albicans, and no prior fluconazole prophylaxis. Otherwise, amphotericin B is recommended. A dose of 0.5-0.7 mg/kg/d is appropriate when targeting Candida species, but 1 mg/kg/d is appropriate to target Aspergillus species and other molds. Amphotericin B also has been used intranasally in an attempt to decrease the rate of fatal infections by Aspergillus species in patients undergoing bone marrow transplant, but the practice is not widespread.

Treatment of established fungal infections is individualized and often difficult. Amphotericin B currently is the principal agent used. Treatment with amphotericin B is limited by substantial nephrotoxicity and infusion-associated toxicity. Lipid-associated forms of amphotericin currently are available and circumvent dose-limiting toxicities. Both amphotericin B lipid complex (Abelcet) and liposomal amphotericin (AmBisome) are less nephrotoxic, and liposomal amphotericin has less infusion-related toxicity. Lipid-associated forms of amphotericin B may be administered safely at higher doses and decrease the need for dose reduction in amphotericin B therapy. Unfortunately, prospective randomized trials of these agents are insufficient to determine if or when a dose of amphotericin B greater than 1 mg/kg/d has a therapeutic advantage.

New antifungal agents include second-generation thiazole compounds (eg, voriconazole) and echinocandin, which is a new class of cell wall synthesis inhibitors. Use of these compounds for prophylactic, empiric, or therapeutic antifungal indications presently is unclear and under investigation.

Inflammatory emergencies

Pneumonitis, pancreatitis, hemorrhagic cystitis, and extravasation of vesicant chemotherapy products are significant noninfectious inflammatory conditions that require emergent treatment in pediatric patients with malignancy. Typhlitis and C difficile enterocolitis are considered infectious conditions and are addressed above.

Noninfectious pneumonitis is a complication of radiation therapy, chemotherapy, stem cell transplantation, and transfusion. The spectrum of clinical presentation varies and ranges from asymptomatic to respiratory failure. Chest radiographs may demonstrate an interstitial infiltrate or interstitial-alveolar pattern that may be unilateral or bilateral. Bronchoalveolar lavage is performed to exclude infectious etiologies and typically reveals a lymphocytic infiltrate. Pulmonary function tests demonstrate decreased compliance and decreased diffusion capacity. Corticosteroid therapy is the primary treatment.

Whole-lung or high-dose partial-lung irradiation directly damages alveolar type II cells and capillary endothelial cells; weeks later, the damage results in alveolar hyalinization and reactive pulmonary infiltrates. Decreased pulmonary function and pulmonary fibrosis are consequent to these early effects and often are demonstrated within 12 months of radiation. The findings may be present in the absence of clinical symptoms. Subacute pneumonitis or late fibrosis occurs in 5-10% of patients receiving whole-lung irradiation of 18-20 Gy (delivered at standard dose rate). Similar changes may occur at a 25% lower dose of radiation in the context of systemic chemotherapy.

Specific chemotherapeutic agents are associated with acute lung injury. Bleomycin is the drug most commonly associated with pneumonitis and fibrosis. Other drugs frequently reported to cause pulmonary injury are carmustine, mitomycin (with and without vinca alkaloids), and methotrexate (systemic and intrathecal). All-trans-retinoic acid (ATRA) is associated with a pneumonitis syndrome that consists of fever and respiratory distress, which may include hypoxia and pulmonary infiltrates. ATRA syndrome responds well to dexamethasone therapy.

Pneumonitis and pulmonary fibrosis are complications of hematopoietic stem cell transplantation and may occur in several settings. Acute noninfectious pneumonitis is associated with high-dose chemotherapy-conditioning regimens, including those using drugs not primarily associated with pneumonitis. An idiopathic pneumonia syndrome has been observed after allogeneic transplantation and may result from minor histocompatibility differences between donor and host as suggested by a murine transplant model. A late effect of allogeneic stem cell transplant is pulmonary fibrosis, which may result from chronic graft versus host disease or earlier acute inflammation.

Transfusion-related acute lung injury (TRALI) is characterized by noncardiogenic pulmonary edema variably associated with respiratory distress and hypoxia following transfusion of a blood product. TRALI results from granulocyte-agglutinating anti-HLA antibody-induced pulmonary leukoagglutination. TRALI typically occurs within 6 hours of transfusion and is a potentially life-threatening and often-overlooked diagnosis. Mechanical ventilation may be necessary for respiratory support.

Pancreatitis

Pancreatitis is a complication of immunosuppressive therapy, and approximately 18% of all pediatric cases occur in the context of antineoplastic therapy. In particular, pancreatitis is associated with L-asparaginase chemotherapy and systemic steroid administration. Although severe abdominal pain is the primary symptom, only 4 of 385 serum amylase levels obtained from pediatric patients in an emergency department were elevated. In an autopsy review of 40 pediatric patients with pancreatitis, the prominent presenting clinical features were emesis or excessive nasogastric drainage (60%), pleural effusion (40%), and abdominal pain (25%). Interestingly, the diagnosis was suggested initially in only 5 of the 40 patients. Reported mortality rate is 5-15%.

Practice guidelines for the care of patients with acute pancreatitis are published. Physical examination of patients with pancreatitis requires close attention to respiratory and cardiovascular status and the abdominal examination. Severity of illness as measured by either Ranson's criteria or the revised Acute Physiology and Chronic Health Evaluation (APACHE II) correlates with outcome. Laboratory evaluation of patients should include complete blood counts and amylase, lipase, blood urea nitrogen, serum electrolyte, creatinine, glucose, lactate dehydrogenase, transaminase, and calcium levels. Abdominal ultrasound is the initial radiographic evaluation and should be obtained within 24-48 hours of hospitalization. Abdominal computed tomography (CT) scan is recommended for patients with severe pancreatitis. In the absence of renal insufficiency, IV contrast is recommended.

Treatment primarily is supportive with an emphasis on bowel rest, fluid resuscitation, and close electrolyte monitoring, particularly for hypocalcemia. Principal complications of pancreatitis include pseudocyst formation in approximately 17% of patients without trauma and bacterial infection in 20-30% of patients. No prospective randomized trials are available to address the use of alterations in diet, total parenteral nutrition, proton pump inhibitors, H2-blocking agents, or octreotide in the medical treatment of patients with pancreatitis, although all of these agents have been used.

Hemorrhagic cystitis

Hemorrhagic cystitis is hematuria that results from an inflammation of the bladder. The condition is defined as painful urination with leukocytes and erythrocytes or clots in the urine. Cyclophosphamide and ifosfamide are the most common chemotherapeutic agents causing hemorrhagic cystitis via an acrolein dye byproduct of metabolism. The byproduct is a chemical irritant of the bladder mucosa and renal collecting system.

Clinical symptoms may occur hours, days, weeks, or years after chemotherapy administration, and once established, recurrent bleeding is a common complication. Cystitis progresses from mucosal edema and ulceration to late fibrosis, reflux, and hydronephrosis. Prior or concurrent pelvic irradiation is a risk factor for the development of hemorrhagic cystitis, and a significant positive association is found between hemorrhagic cystitis and infection by both adenovirus (primarily type 11) and the BK virus. Severe hemorrhagic cystitis occurs in approximately 5% of patients who have undergone bone marrow transplant, and it is nearly twice as frequent in patients with allogeneic transplants than in patients with autologous transplants.

Optimal treatment in patients with hemorrhagic cystitis begins with vigorous prophylaxis to minimize contact between noxious metabolites and the bladder mucosa. Primary prophylaxis consists of hyperhydration and either continuous bladder irrigation or administration of the thiol compound, sodium 2-mercaptoethane sulfonate (mesna). Mesna combines with the metabolites of ifosfamide and cyclophosphamide to form nontoxic compounds in the urine. These preventive measures appear to reduce the incidence of cystitis to less than 5%, and they likely account for a recent decrease in incidence of hemorrhagic cystitis.

Once present, hemorrhagic cystitis is treated best with hyperhydration, continuous bladder irrigation, platelet transfusion, and treatment of existing coagulopathy. Oxybutynin chloride (Ditropan) may provide symptomatic relief of associated bladder spasms. Urinary obstruction may require cystoscopic removal of clots or placement of a suprapubic catheter. Bleeding refractory to these measures has been treated using Nd:YAG laser–induced coagulation and local installation of prostaglandin E₁, alum, silver nitrate, or formalin. Hyperbaric oxygen has been used successfully to treat refractory radiation-induced cystitis. Hemorrhagic cystitis unresponsive to these measures may require bladder resection.

Extravasation

Extravasation of chemotherapy products is reported to occur in 0.1-6.5% of chemotherapy infusions and may cause severe, irreversible, local injury. Chemotherapeutic agents may be classified as irritant, vesicant, or nonvesicant based on the local toxicity to subcutaneous tissues. Irritant drugs cause pain at the injection site and may be associated with local inflammation. Vesicant drugs cause local tissue necrosis or induce blister formation. Nonvesicant drugs produce acute reactions only occasionally.

Tissue damage from extravasation occurs via several mechanisms. Anthracycline drugs are absorbed by local cells, induce cell death through DNA damage, then are released to similarly affect other cells. Significant anthracycline levels are locally present for weeks to months following extravasation. Local tissue damage from vinca alkaloids and epipodophyllotoxins results from the lipophilic solvents used in the drug preparations and is treated more easily.

In general, residual drugs should be aspirated from the infiltrated area, and antidotes, if available, should be administered soon after extravasation. Avoid direct pressure on the site to minimize risk of spread to a broader area. Apply heat or cold appropriately. Daily evaluation of the effected area is recommended, and consultation with a plastic surgeon may be necessary.

Mechanical emergencies in pediatric patients with malignancy refer to acute events that result from direct compression, obstruction, or displacement of vital tissues by a neoplastic process. These emergencies are conveniently classified according to the affected organ system. Neurologic, respiratory, cardiovascular, gastrointestinal tract, and urologic mechanical emergencies require immediate medical attention.

Neurologic emergencies

The principal neurologic mechanical emergencies requiring acute medical treatment manifest as spinal cord compression, increased intracranial pressure (ICP) in association with cerebral herniation, and status epilepticus.

Spinal cord compression

Spinal cord compression refers to impingement of the spinal cord or cauda equina, which may occur via an intramedullary mass from a primary CNS tumor or compression of the thecal sac from a tumor in the epidural space. The latter occurs most commonly by direct extension of metastases in the vertebral bone, but it also may result from tumor growth through intervertebral foramina.

Pain is the first symptom of spinal cord compression and may occur hours or months prior to neurologic dysfunction. Pain associated with epidural spinal cord compression is exacerbated when the patient is recumbent and improves with the patient in the upright position. The pattern of pain is opposite that experienced with a herniated disc or degenerative spinal disease. Radicular pain is a less common but excellent localizing symptom. Weakness usually occurs after the onset of pain, and sensory complaints follow shortly thereafter.

Magnetic resonance imaging (MRI) of the entire spine is the best diagnostic test to localize the disease and distinguish between tumor, abscess, hematoma, and disc herniation.

Spinal cord compression requires rapid intervention to minimize irreversible dysfunction. Although a paucity of data exists from prospective trials and few evidence-based therapeutic guidelines are available, acute treatment of cord compression likely requires a combination of corticosteroids, radiation, and surgery. Chemotherapy also may be appropriate in the context of initial disease presentation or chemotherapy-responsive recurrent disease. Optimal treatment requires collaboration by the medical oncologist, radiation oncologist, and surgical oncologist.

In addition to appropriate analgesia, corticosteroid therapy is the usual initial treatment, particularly in patients with paresis or in nonambulatory patients with paraparesis. The use of systemic steroids is discouraged or contraindicated in favor of local radiation or diagnostic evaluation if symptoms are suspected to arise from an undiagnosed lymphoproliferative disease. Otherwise, studies of adult patients suggest that high-dose (100-mg bolus followed by 96 mg/d) or moderate-dose (10-mg bolus followed by 16 mg/d) dexamethasone is the preferred treatment. Dexamethasone may be used in combination with radiotherapy and surgery as appropriate.

Local radiotherapy alone may be used for patients who are ambulatory and as nonparetic pretreatment. Radiotherapy dose is variable and, in part, determined by quantity of prior local radiation, tumor type, and the tissue field requiring radiation. Systemic chemotherapy is appropriate for patients with responsive tumors.

Surgical intervention as a primary treatment for cord compression is restricted to patients with an unstable spine. Previously, decompressive laminectomy was a standard treatment despite affording poor access to approximately 85% of tumors located anteriorly and despite possibly destabilizing the spine. Therefore, vertebral body resection followed by stabilization has been pursued, but further studies are necessary to better determine the safety and use of the approach. Nevertheless, surgery is suggested for the treatment of spinal cord compression in patients with no prior history of cancer, patients with spinal instability or bony compression of the spinal cord, and patients with previously irradiated areas.

Cerebral herniation

Cerebral herniation may result from a mass expanding within the cranial vault or from an obstruction of cerebrospinal fluid circulation. Either process may result from tumor mass, hemorrhage, thrombosis, abscess, or infarction. Classic clinical findings suggestive of impending herniation include impaired consciousness, abnormal extraocular movements, pupil size abnormality, nausea, emesis, and stiff neck. Papilledema is a more common finding if the presentation is subacute. Cushing reflex of hypertension and bradycardia are late signs of increased ICP.

If evidence exists of impending cerebral herniation, immediate treatment and diagnostic efforts are necessary. Although MRI is a superior neuroimaging technique, CT scans usually are most readily available and can be obtained without contrast to depict both hemorrhage and hydrocephalus. Mild hyperventilation is the most rapid method available to decrease ICP. A decrease in PCO₂ to 30-35 mm Hg is sufficient to induce vasoconstriction and a subsequent decrease in cerebral blood volume. Equilibration occurs within several hours, during which time more definitive therapy should be instituted. Mannitol is the agent most frequently used to lower ICP. Mannitol is administered IV over 20-30 minutes as a 20-25% solution at a dose of 0.5-2.0 g/kg. Dexamethasone is most useful when increased ICP results from intracranial tumor or abscess.

Status epilepticus

Status epilepticus is defined as prolonged or recurrent seizure activity lasting over 30 minutes in which the patient never regains consciousness. Seizure may result from mechanical or metabolic perturbation of the CNS consequent to a tumor or tumor therapy. Proper diagnosis and treatment are important because seizure duration is a significant predictor of CNS damage. Diagnosis methods and acute treatment of status epilepticus in children with cancer are equivalent to techniques used to diagnose and treat afebrile seizure in children without cancer.  

Respiratory emergencies

Airway obstruction is the primary mechanical emergency of the respiratory system in pediatric patients with malignancy. Obstruction can occur at the level of the larynx, trachea, or bronchi. Airway obstruction is the most common complication in pediatric patients presenting with a mediastinal mass and has been reported in 60% of patients. Leukemia, lymphoma, Hodgkin disease, rhabdomyosarcoma, and neuroblastoma are the most common diagnoses in these patients. Laryngeal obstruction is uncommon in pediatric patients with cancer, but it is most likely to occur in the context of vocal cord paralysis. Airway compromise in the absence of mediastinal mass or adenopathy also has been reported in pediatric patients presenting with hemangioma, lymphangioma, teratoma (cervical and mediastinal), respiratory papillomatosis, thymoma, and a variety of head and neck tumors.

Clinical symptoms depend on the level of obstruction. Stridor is associated with extrathoracic obstruction, and a hoarse voice suggests unilateral vocal cord paralysis. Increased obstruction of the trachea or mainstem bronchi may be manifested as wheezing, dyspnea, orthopnea, or increased effort of breathing. Rapid CT scan is the preferred imaging study for children. More than 30% of symptomatic patients with a mediastinal mass have a 35-93% decrease in tracheal cross-sectional area as measured using CT scans.

Although uncommon, symptomatic airway obstruction may be encountered at presentation or as a complication of refractory disease. Prompt diagnosis using tissue samples is paramount for patients who initially present with airway compromise, and institution of appropriate antitumor therapy is the optimal treatment strategy. Local radiotherapy may be used to treat patients, but it can induce inflammation that worsens symptoms transiently. Fortunately, primary airway support usually is sufficient until definitive therapy is initiated. Symptomatic relief is the primary objective for patients with airway obstruction as a terminal medical complication and may require a multimodality approach with radiotherapy, surgery, and pharmacotherapy.

Cardiovascular emergencies

Mechanical emergencies of the cardiovascular system in pediatric patients are uncommon, but they may result from compromise in cardiac function or vascular flow. Although anthracycline chemotherapy may depress myocardial contractility and result in long-term medical complications, it is an unusual acute emergency. The primary acute emergency is tamponade resulting from malignant or reactive pericardial effusion. Although vessel compression from a tumor mass frequently occurs, it rarely precipitates a medical emergency. The primary exception to this is superior vena cava (SVC) syndrome, which often is observed in association with a large mediastinal mass.

Cardiac tamponade

Cardiac tamponade is defined as the inability of the ventricle to maintain cardiac output because of extrinsic pressure or intrinsic mass. Although pericardial and pleural effusions frequently are observed, tamponade physiology is a rare complication of pediatric malignancy. The largest pediatric series reported to date is 9 patients in whom pericardial effusion and tamponade occurred in the context of AML (3), ALL (1), Hodgkin disease (1), B-cell lymphoma (1), medulloblastoma (1), desmoplastic small round cell tumor (1), and rhabdomyosarcoma (1). Effusion volume in this series ranged from 82-500 mL. The quantity of fluid required to induce tamponade depends on the rate of accumulation, with the largest volume accommodated only gradually.

Clinical findings of impending tamponade are similar to heart failure and include chest pain, cough, dyspnea, hiccups, nonspecific abdominal pain, and a pulsus paradoxus greater than 10 mm Hg. Chest radiographs may reveal the classic water-bag cardiac silhouette. ECG may demonstrate low-voltage QRS complexes and flattened or inverted T waves. Echocardiography is the best single study used, and it demonstrates pericardial effusion and atrial or ventricular collapse with hemodynamic compromise. Percutaneous catheter drainage is the treatment of choice and may be performed under echocardiographic or fluoroscopic guidance. Pericardial fluid may contain malignant cells and should be evaluated accordingly. Resolution of the effusion is expected with treatment of the underlying malignancy.

SVC syndrome

SVC syndrome results from obstruction of the SVC by external compression or internal thrombosis. Pediatric patients account for only 0.4-1.4% of reported cases, and SVC syndrome is found in approximately 10% of pediatric patients with a large anterior mediastinal mass. Thrombosis of the SVC in children with cancer is unusual and most likely is a result of extension from an indwelling central venous catheter.

Symptoms include cough, hoarse voice, chest pain, dyspnea, and orthopnea and progress to headache, confusion, altered vision, and syncope. Symptoms are aggravated with patients in the supine position or performing the Valsalva maneuver. Signs of SVC syndrome are swelling and plethora of the head, neck, and upper extremities. Blood flow within the SVC and presence of a thrombus are best assessed using ultrasound, but rapid CT is recommended for evaluation of a mediastinal mass. Removal of the indwelling catheter and short-term anticoagulation therapy usually is sufficient to treat a thrombus. Diagnosis using tissue samples and initiation of definitive anticancer therapy are the objectives if SVC syndrome results from external compression from a tumor mass. Emergent local radiotherapy usually can be avoided for a short time in pediatric patients in favor of supportive medical treatment.

Gastrointestinal tract emergencies

Gastrointestinal tract obstruction, pseudo-obstruction, and ileus are much more common in adults than in children with cancer. Although uncommon, gastrointestinal tract obstruction in children is reported most commonly secondary to intussusception in which a neoplasm within the bowel wall creates a lead point to initiate the process. Burkitt lymphoma in the terminal ileum frequently comes to medical attention in this manner.

In addition, intussusception has been reported in patients with adenomyoma of the Meckel diverticulum, hamartoma of the ileum, acute lymphoblastic leukemia, leiomyosarcoma, and following resection of a Wilms tumor. Gastrointestinal tract obstruction also has been reported following a volvulus resulting from a mesenteric lymphangioma. Obstruction of the large colon primarily occurs in the context of large pelvic tumors and as a complication of constipation/obstipation induced by chemotherapy (eg, vincristine), narcotic analgesia, or both. A temporary ileus also may be precipitated by typhlitis, sepsis, or other severe illness.

The complete clinical intussusception triad of cramping abdominal pain, palpable abdominal mass, and currant jelly stool may not be present in pediatric patients with malignancy; symptoms may be atypical and limited to abdominal pain and emesis. Nonreducible intussusception and intussusception outside of the expected age range for children also are suggestive of a pathologic, perhaps neoplastic, lead point.

Abdominal ultrasound or fluoroscopy with air-soluble or water-soluble contrast is the recommended diagnostic procedure. Fluoroscopic procedures also may be therapeutic. Surgery may be necessary for reduction, tissue diagnosis, or both. Reduction of the intussusception and treatment of the primary pathology are the principal approaches in these patients. In general, large tumor masses that cause gastrointestinal tract obstruction via external compression are best treated with chemotherapy, surgery, radiation, or a combination of the three. Treatment-related complications respond to interim gastrointestinal decompression and supportive medical treatment.

Urologic emergencies

Similar to many other mechanical emergencies, urinary obstruction is a more common complication in adult patients with cancer. Nevertheless, urinary obstruction may occur in the upper or lower urinary tract of children with cancer.

Upper urinary tract obstruction

With regard to the upper urinary tract, ureteral obstruction may result from direct tumor invasion, compression, or encasement. Most tumors causing ureteral obstruction are genitourinary in origin, such as rhabdomyosarcoma. Ureteral obstruction also is a long-term complication of external beam radiation. Although acute ureteral obstruction often is associated with flank pain and colic, chronic unilateral obstruction usually occurs without symptoms. Acute or chronic bilateral obstruction is associated with decreased urine output and uremia. IV urography, renal ultrasound, CT scan, radionuclide renography, or retrograde pyelogram may be used to diagnose ureteral obstruction. In addition, CT scan best defines extrarenal pathology.

Ureteral stents and palliative urinary diversions are useful surgical procedures that improve renal function and facilitate delivery of effective chemotherapy. In recent years, percutaneous and cystoscopic procedures have increasingly replaced open surgical procedures to decompress the obstructive kidney.

Lower urinary tract obstruction

Lower urinary tract obstruction may result from bladder outlet obstruction or urinary retention. Bladder outlet obstruction may result from extrinsic compression from a large pelvic tumor or obstruction from an intrinsic neoplasm at the bladder neck or as a complication of hemorrhagic cystitis. Urinary retention in pediatric patients with malignancy primarily results from neoplasms in the brain, spinal cord, or nerve routes. Clinical findings of lower tract obstruction include suprapubic pain and suprapubic fullness, which result from a distended bladder. Unless treated emergently, complete outlet obstruction results in bilateral hydronephrosis and renal insufficiency or failure. Renal ultrasound is a rapid cost-effective method to evaluate the lower urinary tract; however, the other modalities are useful for specific indications.

Primary therapy is decompression of the bladder using a small urethral catheter. If the obstruction results from blood clots, a large catheter or cystoscopic removal of clots is necessary. Bladder distension resulting from neurologic dysfunction often requires clean intermittent self-catheterization every 4-6 hours to preserve kidney function and decrease infection rates.

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